canadian journal of chemistry · 114 oxadiazolines 39a-i are obtained by oxidation with lead...
TRANSCRIPT
Draft
Synthesis of carotol using a formal (4 + 1)-cycloaddition of
chiral dialkoxycarbenes
Journal: Canadian Journal of Chemistry
Manuscript ID cjc-2017-0594.R1
Manuscript Type: Article
Date Submitted by the Author: 08-Nov-2017
Complete List of Authors: Gund, Machhindra; Université de Sherbrooke, Chimie Déry, Martin; Paraza Pharma, Chemistry Spino, Claude; Universite de Sherbrooke,
Is the invited manuscript for consideration in a Special
Issue?: N/A
Keyword: [4+1]-cycloaddition, carotol, sesquiterpene, dialkoxycarbene
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Synthesis of carotol using a formal (4 + 1)-cycloaddition of chiral dialkoxycarbenes. 1
Machhindra Gund, Martin Déry, and Claude Spino* 2
Université de Sherbrooke, Département de chimie, 2500 Boul. Université, Sherbrooke, QC, J1K 3
2R1, Canada 4
5
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Abstract: We report formal intramolecular (4+1)-cycloadditions of dialkoxycarbenes used in the 6
synthesis of the daucane-type sesquiterpene carotol. We found a chiral dialkoxycarbene capable 7
of diastereoselective formation of a key oxabicyclo[3.3.0]octene adduct. Carotol was synthesized 8
in 14 linear steps from simple starting materials. 9
Key words: [4+1]-cycloaddition, carotol, sesquiterpene, dialkoxycarbene. 10
11
Introduction 12
Carotol (1) is a daucene-type sesquiterpene first isolated by Asahina et al. (1925) from seeds and 13
roots of many plants of the Apiaceae (carrots) and Zingiberaceae (ginger) families.1 It has a 14
strong larvicidal and antimicrobial activity. It also acts as a potent olfactive attractant to the black 15
bean aphid (Aphis fabae). Its core bicyclo[5.3.0]decane skeleton presents a synthetic challenge in 16
the form of two adjacent adjacent quaternary carbons, including an all-carbon quaternary center, 17
and it is part of many other natural sesquiterpenes (Figure 1). The absolute configuration of 18
natural (+)-carotol was established in 1964.2 19
20
Figure 1. Biologically important natural products exhibiting a bicyclo[5.3.0]decane core. 21
22
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Prior to our synthesis,3 only one total synthesis of carotol was achieved in 15 steps starting from 23
(+)-dihydrocarvone 4 in low overall yield (Scheme 1).4 In this synthesis, the 5,7-fused rings 24
system was installed using a ring-expansion/ring-contraction strategy. Installation of the 25
endocyclic double bond led to a mixture of many products, among which were carotol (1), 26
daucene (8) and five other alcohols. 27
Stoltz’ group made ∆11
-carotol (14) in 11 steps from cycloheptenone derivative 9, which was 28
obtained from the Pd-catalyzed asymmetric allylation of isobutyloxycycloheptenone (Scheme 29
2).5 They also made (-)-epoxydaucenal B (11) from a common intermediate 10. Interestingly, 30
reduction of ketone 10 gave a small amount of the retro-aldol product 12, in contrast to one of 31
our first approaches where one intermediate underwent a spontaneous and irreversible aldol 32
reaction (vide infra). Fortunately, compound 12 could be made to undergo the forward reaction 33
and was recycled. 34
35
Scheme 1. Synthesis of carotol by Levisalles and coworkers. 36
37
38
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39
Scheme 2. Synthesis of ∆11
-carotol and epoxydaucenal B (11) by Stoltz and coworkers. 40
41
42
Other syntheses of daucane-type terpenes have been reported, the vast majority of them starting 43
with a monoterpene obtained from the chiral pool.6 The first synthesis of daucene by Yamasaki 44
started with (+)-limonene but the acid-catalyzed final step yielded a mixture of five products 45
from which (-)-daucene 8 was isolated in 42% yield (Scheme 3).7 Vandewalle and his coworkers 46
started from (-)-piperitone and in ten steps derived into (+)-daucene. Two of their key steps 47
include a [2+2]-cycloaddition and a thermal cycloreversion, but the subsequent conversion to 48
daucene proved a bit tedious.8 A third example is the synthesis of racemic lasidiol 23 using an 49
intramolecular [4+3]-cycloaddition between a furan and a dibromoketone 21. That key reaction 50
gave a mixture of six diastereomers and by-products from which cycloadduct 22 was isolated in 51
28% yield. Finally, the group of Anita Maguire has recently developed an approach to the 52
daucane skeleton based on an intramolecular Buchner cyclisation of α-diazoketones (not 53
shown).9 54
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The bicyclo[5.3.0]decane is well suited to showcase our method based on the intramolecular 55
(4+1)-cycloaddition between dialkoxycarbenes and electron-poor dienes. Dialkoxycarbenes10
are 56
nucleophilic species and take part in many reactions with carbonyls, alkenes, alkynes,10
57
isocyanates,11
vinyl isocyanates,12
and electron-poor dienes.13
They can be generated easily using 58
Warkentin’s oxadiazoline method, but despite this fact, only a handful of applications of 59
dialkoxycarbenes to the synthesis of natural products have been reported.14
We herein wish to 60
report a short and efficient synthesis of carotol using a diastereoselective formal (4+1)-61
cycloaddition as the key step and by doing so, demonstrate the convenience and effectiveness of 62
Warkentin’s oxadiazolines as dialkoxycarbene precursors in synthesis. 63
64
65
Scheme 3 : Approaches to the bicyclo[5,3,0]decane core of daucane-type terpenes. 66
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67
68
Our initial approach to the natural product is depicted in Scheme 4. We are able to control the 69
stereochemical outcome of the key reaction (27 � 25) by controlling the number of atoms 70
tethering the diene and the carbene in 27 (three atoms in this case).13a
However, we did not know 71
if controlling the absolute configuration of the adduct by introducing a chiral auxiliary would be 72
possible (28 � 26). 73
The precursor to dialkoxycarbene 27 is oxadiazoline 29, the synthesis of which is only three 74
steps as shown in Scheme 5. 3-Butyn-1-ol (31) was subjected to Negishi’s carboalumination 75
protocol to give vinyliodide 32. The latter was efficiently coupled to methylvinylketone via a 76
Heck reaction to give diene 33 as a single E,E-geometrical isomer. Note that the geometries of 77
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the alkenes do not determine the C2-C5 relative configuration in the subsequent [4+1]-78
cycloaddition (vide infra).13a
Submitting alcohol 33 to a catalytic amount of camphorsulfonic 79
acid and Warkentin’s oxadiazoline 3415
gave an excellent yield of the dialkoxycarbene precursor 80
29. The acetate in oxadiazoline 34 can be replaced by alcohols, thiols, and amines making the 81
generation of the corresponding carbene a simple matter.10
82
83
Scheme 4. Retrosynthetic analysis of carotol 1. 84
85
86
We felt that diastereoselectivity in the intramolecular formal (4+1)-cycloaddition might be 87
possible but we were concerned by the apparent lack of rigidity (free rotation) around the C–O 88
bonds of the carbene. Moreover, in our experience, NHCs or aminoalkoxycarbenes, which may 89
have allowed the construction of a more rigid chiral carbene system, do not undergo the (4+1)-90
annulation efficiently.13
Dialkoxycarbenes can adopt two different conformations (W-28 and S-91
28) with a difference in energy expected to be less than 2 kcal/mol and a barrier to 92
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interconversion of approximately 16 kcal/mol, based on calculation for dimethoxycarbene 93
(Figure 2).16
The third one (U-28) is too high in energy and its concentration would be small. We 94
have established the mechanism of the intramolecular (4+1)-cycloaddition to consist of an initial 95
concerted cyclopropanation reaction followed by ring-opening to a zwitterionic intermediate, 96
free bond-rotation, and collapse to the (4+1)-cycloadduct.13a
Therefore, the stereochemically 97
defining event is expected to be the concerted cyclopropanation, as it fixes the stereochemistry at 98
C5 while the stereochemistry at C2 is controlled by the length of the tether as alluded to earlier. 99
The preferred orientation of the chiral appendage at transition states (e.g. W-TS-26 and S-TS-100
26) would determine the sense and level of asymmetric induction. 101
102
Scheme 5: Synthesis of oxadiazoline 29. 103
104
105
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106
Figure 2: Conformations of the dialkoxycarbenes and transition states (TS) leading to the 107
intermediate cyclopropanes. 108
109
We therefore made several chiral oxadiazolines from chiral alcohols, some commercially 110
available, others made in a few steps (Scheme 6). Starting from chiral alcohols 35a-i, mixed 111
carbonates 36a-i are fabricated and reacted with hydrazine to give the carbamates 37a-i. 112
Following Warkentin’s procedure, acetone is condensed to the hydrazones 38a-i and the 113
oxadiazolines 39a-i are obtained by oxidation with lead tetraacetate or PIDA.17
The acetate 114
group of each of those oxadiazoline can be replaced by the primary alcohol 33 to give the 115
corresponding oxadiazoline 30a-i ready to undergo the (4+1)-cycloaddition. 116
We first investigated the key reaction on the racemic oxadiazoline 29 and obtained a 89% yield 117
of a mixture of oxabicyclo [3.3.0]-octaenes 25 and 40 in 93:7 ratio, easily separable by normal 118
silica gel column chromatography (Scheme 7, top). This diastereomeric ratio was perfectly in 119
line with what was expected considering the three-atom tether leading to the 5,5-fused 120
cycloadduct ring system.13a
It is of note that this ratio remained the same for all (4+1)-121
cycloaddition regardless of the nature of the substituent R on oxadiazolines 30a-i. 122
123
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Scheme 6: Synthesis of chiral oxadiazolines 30a-i. 124
125
126
Scheme 7: (4+1)-cycloaddition of oxadiazoline 29 and 30a-i. 127
128
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We then examined the asymmetric induction of the chiral appendages on oxadiazolines 30a-i, 129
which translates into the diastereomeric ratio of cycloadducts 26:41 (Scheme 7, bottom). One of 130
the simplest chiral alcohols that we could find was 3,3-dimethyl-2-butanol (35a). The 131
corresponding oxadiazoline 30a was thermolyzed under the same conditions as per oxadiazoline 132
29 and the ratio of cycloadducts was measured by 1H NMR. A disappointing ratio of 55:45 of 133
26a:41a (or 41a:26a) was obtained. The sense of asymmetric induction was not determined at 134
this point. Thinking that perhaps polar effects, and not only steric volumes, should help 135
differentiate the two groups flanking the carbinol, we tried the trifluoromethyl homologue 35b, 136
only to realize that such polar effects are virtually absent (57:43 ratio of 26b:41b). We looked to 137
introduce a second stereogenic carbon in the form of oxadiazolines 30c and 30d, with a 138
noticeable improvement on the ratio when 30d was thermolysed (67:33). In all likeliness, this 139
result has to do with the size and orientation of the second substituent (OBn), not its polarity, as 140
demonstrated by the identical ratio of cycloadducts 26e and 41e obtained upon thermolysis of 141
oxadiazoline 30e. 142
Convinced that the size and orientation of the substituents were major factors in controlling the 143
asymmetric induction of the chiral appendage, we examined the ratios of cycloadducts formed 144
during the thermolysis of oxadiazolines 30f-h. We were happy to obtain an acceptable ratio of 145
85:15 when the oxadiazoline derivative of the commercially available cyclohexanol auxiliary 146
35h was utilized. This level of induction is slightly lower than those obtained by Rigby and 147
coworkers in their intermolecular cycloadditions with vinylisocyanates.18
Still, given the fact that 148
we cannot use a cyclic, rigid framework derived from a chiral diol or aminoalcohol because of 149
the intramolecular nature of our reaction, we were satisfied at the level of diastereoselectivity 150
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attained in this reaction. All isomeric cycloadducts were separable by normal silica gel column 151
chromatography. 152
As mentioned earlier, the mechanism of the reaction proceeds via the formation of a 153
cyclopropane,13a
which is the stereo-determining step, followed by rearrangement to the final 154
adduct. Two W-TS and two S-TS conformations (c.f. Figure 2) in competition are depicted in 155
Scheme 8. The two B conformations and the two D conformations on the right of the Scheme 156
should be the ones with the larger difference in energy because the R group is closest to the rest 157
of the molecule. The ‘W’ conformers should be favored and the average of W-TS-26-A and W-158
TS-26-B should be lower in energy than the average of W-TS-41-C and W-TS-41-D. The role 159
of the second substituent (R’) is not understood and may simply add bulk to the auxiliary or 160
produce subtle conformational change. 161
162
Scheme 8: Transition states (TS) for the cycloadditions of dialkoxycarbenes derived from 26f-h. 163
W-TS-26-A W-TS-26-B
O
O Me
E
R
O
O Me
E
R
O
OMe
E
R
O
OMe
E
R
R'R'
R' R'
S-TS-26-B
O
O Me
E
R
R'
O
OMe
E
R
R'
W-TS-41-C W-TS-41-D S-TS-41-D
S-TS-26-A
O
O Me
E
R
O
OMe
E
R
R'
R'
S-TS-41-C 164
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It seemed to us that a pseudo C2-symmetrical auxiliary should fare better, making conformations 165
A nearly identical to conformations B (and C near identical to D) decreasing the need for 166
rigidity. We thus submitted oxadiazoline 30i, derived from alcohol 35i, to the same reaction 167
conditions but a rather surprising ratio of nearly 1:1 was obtained. Clearly, the methyl groups 168
were not voluminous enough. Though more elaborate chiral alcohols with pseudo C2-symmetry 169
like 35i bearing sufficiently large groups could be envisaged, they would take several steps to 170
prepare, rendering such a chiral auxiliary less appealing. We decided not to pursue this avenue. 171
Ketone 42 is a key intermediate in the synthesis of carotol (Scheme 9). It was prepared in a 172
straightforward manner by converting cycloadduct 25 into a diene with the Petasis reagent 173
(79%). Both double bonds were hydrogenated over PtO2 (98%) and the resulting acetal was 174
hydrolyzed to ketone (±)-42 with amberlyst-15 resin (92%). Other acidic hydrolysis conditions 175
favoured epimerization at C2. Starting with pure 26f, we repeated the sequence and obtained the 176
non-racemic (-)-42.19
This compound had been made by Srikrishna and coworkers in 8 steps 177
from (+)-limonene.20
We have made it in 7 steps from 3-butyn-1-ol. The optical rotation of (-)-42 178
was compared with the one obtained by Srikrishna. In addition, the minor diastereomer 41f was 179
also transformed into the corresponding diastereomer of (+)-42 (not shown). An X-ray 180
diffraction analysis of the intermediate after the hydrogenation also confirmed the relative 181
configuration as depicted.3 182
183
184
185
186
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Scheme 9: Synthesis of hydroxy-ketone (±)-42 and (-)-42. 187
O
Me
O
O
Me
R
2526f
Me
Me
Me
HO O
(±)-42(-)-42
1. Petasis2. PtO2, H2
3. Amb.-15
Me
Me
Me
HO OH
43
M
188
189
Unfortunately, the addition of alkylmetalson ketone 42 proved impossible in our hands. 190
Protecting or not the primary alcohol in 42 made no difference. This was unfortunate as the 191
synthesis would have been more convergent this way and carotol might have been, in principle, 3 192
steps away from intermediate 43. We were not the only ones having trouble with similarly 193
congested cyclopentanones.21
Only alkynylmetals successfully added to ketone 42. The 194
alkynylcerium derivative of 3-benzyloxy-1-butyne 44 was added diastereoselectively to the 195
hindered ketone (±)-42 giving the propargyl alcohol 45 in 82% yield (Scheme 10). We then 196
attempted to hydrogenate the triple bond and hydrogenolyse the benzyl group in one step using 197
Pd/C/H2 to get the saturated triol 48. In the event, the propargylic C-O bond proved susceptible 198
to hydrogenolysis leading to the undesired diol 46 in quantitative yield. We attempted to halt the 199
hydrogenolysis of the propargyl alcohol by lowering the catalyst loading and reducing the 200
reaction time to 3h. The alkyne was only partially reduced but still we observed the formation of 201
the hydrogenolysis product 46. The diastereomeric mixture of allylic alcohols 47a and 47b 202
obtained were separable by normal silica gel column chromatography. A single crystal X-ray 203
analysis for 47b confirmed the structure and the relative configuration of the tertiary alcohol. 204
The two allylic alcohols were converted into the required triol 48 using PtO2/H2 in 35% yield 205
along with the hydrogenolysis product 46 in large quantity. It did not bode well for the alkyne-206
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to-alkane strategy and yet we could not add nucleophiles other than sp-hybridized carbons to 207
ketone 42. 208
In our minds, the best way to avoid the propargylic C-O bond fission during hydrogenation was 209
to oxidize this carbon at the level of a carbonyl. To that end, we deprotected the propargylic 210
alcohol (Scheme 11, 50 � 51) and chemoselectively oxidized it with MnO2. We were a little 211
surprised to isolate none of the desired compound 52 but instead, a mixture of products which 212
seemed to contain the cyclized product 53 (not fully characterized). While it is always possible to 213
catalyze such cyclisations, this one was spontaneous. No doubt, a strong Thorpe-Ingold effect 214
was at play here. 215
216
Scheme 10: Problem of hydrogenolysis of the propargylic functions. 217
218
219
220
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Scheme 11: Problem with an unexpectedly fast cyclisation in the synthesis. 221
Me
Me
MeHO
OHTBSO
Me
Me
OTBS
a) n-BuLi, THF
-78 oC to 0 oC
b) CeCl3, THF, 0oC
c) (±)-42, 81%5049 51
TBAF, THF Me
Me
MeHO
OHHO
Me
MnO2
52
Me
Me
MeHO
OHO
Me
O
Me
OHMe
O
MeMe
53222 223
Undaunted, we simply protected the primary alcohol as an acetate before oxidizing the propargyl 224
alcohol (Scheme 12, 50 � 54), well aware that the synthesis was taking a turn for the worse with 225
extra, unproductive steps. In any case, while this plan successfully solved the hydrogenolysis 226
problem, for some reason, the tertiary alcohol eliminated during hydrogenation of ketone 55 to 227
give keto-alkene 56, regardless of what precaution we took to avoid it. This side reaction had not 228
been observed before (though it will come up again later). Note that many terpenoids of the 229
daucane family do have an alkene at that position (e.g. daucene, daucenal). 230
We were looking for a solution that would not only lead to the desired product, but reduce the 231
number of steps in the process. We very nearly achieved that when we decided to oxidize diol 51 232
to the ketoaldehyde 57. Hydrogenation of the alkyne was not accompanied by elimination of 233
water as per the hydrogenation of the alkyne 55. Instead, it gave way to a spontaneous 234
intramolecular and stereoselective aldol reaction to give 59 in 48% yield. No doubt, the strong 235
Thorpe-Ingold effect was interfering again. Hoping this aldol product might give back 236
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ketoaldehyde 58 under the basic conditions of the Wittig reaction, we did try to transform 59 to 237
the bis-alkene 24 (c.f. Scheme 4) but to no avail. 238
239
Scheme 12: Problem with an unruly alcohol. 240
241
242
Scheme 13: Problem with a spontaneous aldol reaction. 243
244 245
As is often the case, a solution to these problems lied with a compound that had been prepared 246
for a different purpose. It turns out that the TBS-protected propargyl alcohol 50 undergoes triple 247
bond hydrogenation with only little concomitant hydrogenolysis. Indeed, treating this compound 248
with palladium on alumina gave 80% yield of the desired diol 60 along with small amounts of 249
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the partially reduced diols 61 and hydrogenolysis product 46 (Scheme 14). The steric bulk of the 250
TBS protecting group must help in preventing the hydrogenolysis of the propargyl ether. 251
The primary hydroxyl in compound 60 was oxidized quantitatively with IBX and the resulting 252
aldehyde was subjected to olefination using methylphosphonium ylide to give 62 in 84% yield. 253
When a freshly prepared Petasis reagent was used instead, the terminal alkene migrated to give 254
the corresponding internal olefin (62b not shown) in 63% yield, with no trace of the desired 255
terminal olefin 62. Then, the secondary alcohol obtained after removal of the TBS protecting 256
group in 62 was subjected to the Ley-Griffith22
oxidation to give ketone 63 in 75% yield. 257
Deprotection of 62 and subsequent oxidation using Swern or IBX gave a complex mixture of 258
products. The crude mixture from its oxidation with TPAP/NMO contained as the major 259
compound what we eventually identified as cyclic enolether 64. However, upon standing or after 260
chromatography on silica gel, ketone 63 would become the sole product. We believe that the 261
molecular sieve in the oxidation medium gave rise to the dehydration of ketone 63 to enol 64 and 262
the latter slowly reverted back to ketone 63 upon handling. This is yet another demonstration of 263
the large Thorpe-Ingold effect present in these systems. 264
With ketone (±)-63 in hand, it was easy to complete the synthesis of carotol. We performed a 265
Wittig reaction with ketone 63 and isolated bis-alkene 24 in 56% yield. Grubbs’ first generation 266
catalyst23
was able to convert the latter to racemic carotol.24
A substantial amount of dehydration 267
occurred on ketone 63 to give keto-alkene 65, analogous to keto-alkene 56 (c.f. Scheme 12), 268
making this last step somewhat unsatisfactory. 269
270
271
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Scheme 14: A solution, but not the solution. 272
273
274
Scheme 15: Synthesis of carotol. 275
276
We thought we could yet improve on the current synthesis. Starting back from ketone 42, we 277
added the alkylnylcerium 66 to give 67 (Scheme 16).25
Its increased bulk should help in 278
preventing the hydrogenolysis of the propargyl ether. Indeed, we saw no trace of such product 279
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upon hydrogenation with palladium on alumina. Oxidation of the primary alcohol and olefination 280
gave compound 69 from which the tertiary alcohol could be deprotected and eliminated in 64% 281
yield to bis-alkene 24 along with a small amount of spiro-tetrahydrofuran compound 70 (<5%). 282
We thus retracted 2 linear steps from the previous synthesis, produced fewer side products, and 283
improved on the overall yield of the synthesis. Since we have made enantiomerically pure ketone 284
(-)-42, this also constitutes a formal synthesis of non-racemic (-)-carotol. Our synthesis has a 285
total of 14 linear steps from the structurally very simple 3-butyn-1-ol, a global yield of 5.6% 286
(counting the non-racemic route) for an average of 82% yield per step. 287
288
Scheme 16: Improved synthesis of carotol. 289
290 291
EXPERIMENTAL SECTION: 292
General Considerations 293
Unless otherwise noted all reactions were performed under an argon atmosphere. Anhydrous 294
acetone was purchased. Other solvents were distilled from potassium/benzophenone ketyl (THF, 295
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Et2O), from calcium hydride (DCM, toluene, DMF, Et3N). Proton nuclear magnetic resonance 296
(1H NMR) spectra were recorded on a 300 MHz or 400 MHz spectrometer. Carbon nuclear 297
magnetic resonance (13C NMR) spectra were recorded on the same spectrometer. NMR samples 298
were dissolved in chloroform-d (unless specified otherwise) and chemical shifts are reported in 299
ppm (δ units) relative to the residual undeuterated solvent. Multiplicities are reported as follows: 300
s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, 301
ddd = doublet of doublet of doublets, m = multiplet. LRMS analyses were performed on a GC 302
system spectrometer (30 m length, 25µ OD, DB-5 ms column) coupled with a mass 303
spectrometer. High-resolution mass spectrometry was performed by electrospray time-of-flight. 304
All reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel coated 305
glass plate visualized under UV (254 nm) and TLC stains such as vanillin, KMnO4, PMA, 306
Dragen Dorff, or by 1H NMR and GCMS analysis. Silica gel (230-400 mesh) was used for flash 307
chromatography. 308
(E)-4-Iodo-3-methylbut-3-en-1-ol (32) 309
To a stirred solution of 3-butyn-1-ol (31) (4.52 g, 64.5 mmol) in dichloromethane (50 mL) at 0 310
ºC under argon was added AlMe3 (1.44 g, 20.0 mmol, 10 mL of 2M/toluene). To another flask, 311
containing a stirred suspension of zirconocene dichloride (4.15 g, 14.2 mmol) in 312
dichloromethane (240 mL) at -20 ºC under argon was added dropwise AlMe3 solution (14.41 g, 313
200.0 mmol, 99.94 mL of 2M/toluene) and continued stirring for 15 min. when water (1.80 mL, 314
20.0 mmol) was added dropwise (caution: exothermic!!) and the resulting yellow colored slurry 315
was stirred vigorously for 20 min. The solution of 3-butyn-1-ol pretreated with AlMe3 was then 316
cannulated to above the slurry at -20 ºC, the mixture was allowed to warm to rt and the mixture 317
was stirred for 2.5 h. A solution of iodine (19.64 g, 77.39 mmol) in diethyl ether (130 mL) was 318
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added slowly to the above reaction mixture at -20 ºC and continued stirring at rt for 2 h. Contents 319
of the flask were slowly poured into 2L conical flask containing stirred saturated solution of 320
potassium sodium tartrate (500 mL) at 0 ºC under argon flush (caution : exothermic!!) The 321
resulting biphasic mixture was stirred for 2 h, filtered through celite, washed with ether (100 mL) 322
and the layers were separated. The aqueous layer was extracted with ether and the combined 323
organic extracts were washed successively with satd. Na2S2O3 solution, water, brine, dried over 324
anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was 325
purified by silica gel flash chromatography using 20% ethyl acetate in hexanes to afford the 326
alkenyl iodide 32 as colorless oil. (12.0 g, 88%). 1H NMR (300 MHz, CDCl3) δ 6.02 (d, J = 0.9 327
Hz, 1H), 3.72 (t, J = 6.3 Hz, 2H), 2.48 (t, J = 6.3 Hz, 2H), 1.88 (d, J = 0.6 Hz, 3H), 1.41 (bs, 1H, 328
-OH). 13C NMR (75.5 MHz, CDCl3): δ 144.6, 76.9, 60.1, 42.3, 23.9. 329
(3E,5E)-8-Hydroxy-6-methylocta-3,5-dien-2-one (33) 330
To a stirred solution of alkenyl iodide 32 (12.0 g, 56.6 mmol) in anhydrous DMF (100 mL) at rt 331
under argon was added palladium(II)acetate (0.64 g, 2.83 mmol) followed by NaHCO3 (16.64 g, 332
198.1 mmol), Bu4NCl (15.73 g, 56.59 mmol) and methylvinylketone (7.93 g, 113 mmol). The 333
reaction mixture was stirred at rt for 5 days and quenched by addition of ice-cold water (1 L) and 334
ethyl acetate (300 mL). The contents of the flask were stirred for 15 min. and filtered through 335
celite. Layers were separated, the aqueous layer was extracted with ethyl acetate (2 x 150 mL). 336
The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, 337
filtered and concentrated under reduced pressure. The crude product was purified by silica gel 338
flash chromatography using 30% ethyl acetate/hexanes to afford the desired product 33 as 339
colorless oil. (6.85g, 78%). 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J = 11.7, 11.4 Hz, 1H), 340
6.05–6.13 (m, 2H), 3.78 (t, J = 6.3 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.27 (s, 3H), 1.95 (d, J = 1.5 341
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Hz, 3H), 1.53 (bs, 1H, -OH). 13C NMR (100.7 MHz, CDCl3): δ 199.4, 148.0, 139.5, 128.7, 342
125.3, 60.1, 43.2, 27.3, 17.5. IR (neat): ν (cm-1) 3620–3129 (br), 3045, 2941, 2878, 1631, 1264, 343
1048. LRMS (m/z, relative intensity): 177 ((M+Na)+, 100). HRMS m/z: [M+Na]
+ Calcd for 344
C9H14NaO2: 177.0886, found: 177.0887. 345
(3E,5E)-8-(2-Methoxy-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-346
dien-2-one (29) 347
To a stirred solution of crude oxadiazoline 34 (11.71 g, 62.25 mmol) in dichloromethane (35 348
mL) was added a solution of alcohol 33 (6.40 g, 41.5 mmol) in dichloromethane (30 mL) 349
followed by camphorsulfonic acid (0.39 g, 1.66 mmol). The reaction mixture was stirred at rt for 350
7 h, diluted with dichloromethane (40 mL) and washed with satd. NaHCO3 solution, water, and 351
brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated 352
under reduced pressure. The crude product was purified by silica gel flash chromatography using 353
10% ethyl acetate in hexanes to afford the desired product 29 as colorless oil (10.31 g, 88%). 1H 354
NMR (300 MHz, CDCl3): δ 7.36, 7.41 (dd, J = 11.4 Hz, 1H), 6.01-6.10 (m, 2H), 3.75-3.96 (m, 355
2H), 3.41 (s, 3H), 2.46 (t, J = 6.6 Hz, 2H), 2.26 (s, 3H), 1.92 (d, J = 0.9 Hz, 3H), 1.54 (s, 3H), 356
1.50 (s, 3H). 13C NMR (100.7 MHz, CDCl3): δ (ppm) 198.5, 146.6, 138.8, 136.8, 128.9, 125.3, 357
119.0, 62.4, 51.7, 39.9, 27.4, 24.0, 23.8, 17.4. IR (neat): ν (cm-1) 3050, 2988, 2949, 1633, 1259, 358
1160. LRMS (m/z, relative intensity): 305 ((M+Na)+, 100), 235 (30). HRMS m/z : [M+Na]
+ 359
calcd for: C14H22N2NaO4: 305.1472, found: 305.1476. 360
General procedures for the synthesis of mixed phenyl carbonates 36a-i 361
To a stirred solution of chiral alcohol 35 (1.0 equiv.) in dry dichloromethane at 0 ºC was added 362
pyridine (4.0 equiv.)equiv.) followed by dropwise addition of phenyl chloroformate (1.1 363
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equiv.)equiv.). The reaction mixture was then stirred at rt for 12 h, diluted with dichloromethane, 364
washed with 1N HCl, water, brine, dried over anhydrous MgSO4, filtered and concentrated under 365
reduced pressure to afford the desired carbonate as colorless oil. (70-97%). In most of the cases 366
the crude carbonate 36 was pure enough and used in the next step without any purification. 367
3,3-dimethylbutan-2-yl phenyl carbonate (36a) 368
Colorless oil, 4.50 g, 88% yield. 1H NMR (300 MHz, CDCl3): δ 7.45-7.36 (m, 2H), 7.30-7.27 369
(m, 2H), 7.16–7.19 (m, 1H), 4.63 (q, J = 6.3 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 0.98 (s, 9H). 370
HRMS m/z : [M+Na]+ calcd for: C13H18NaO3: 245.1153, found: 245.1164. 371
Phenyl-1,1,1-trifluoro-3-methylbutan-2-yl carbonate (36b) 372
Colorless oil, 1.90 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.43–7.40 (m, 2H), 7.30–7.26 373
(m, 2H), 7.22 (m, 1H), 5.05–4.97 (m, 1H), 2.26 (dt, J = 13.5, 6.8 Hz, 1H), 1.11 (dd, J = 6.9, 0.9 374
Hz, 6H). HRMS m/z : [M+Na]+ calcd for: C12H13F3NaO3: 285.0714, found: 285.0719. 375
(1S,2S)-2-(benzyloxy)cyclopentyl phenyl carbonate (36c) 376
Colorless oil, 1.13 g, 70% yield. 1H NMR (300 MHz, CDCl3): δ 7.43–7.36 (m, 2H), 7.35-7.34 377
(m, 4H), 7.31–7.22 (m, 2H), 7.21–7.17 (m, 2H), 5.16–5.12 (m, 1H), 4.62 (q, J = 11.3 Hz, 2H), 378
4.08–4.05 (m, 1H), 2.19–2.03 (m, 2H), 1.88–1.76 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 153.2, 379
151.2, 138.4, 129.6, 128.5, 127.7, 126.1, 121.1, 83.9, 83.7, 71.4, 30.5, 30.3, 21.7. HRMS m/z : 380
[M+Na]+ calcd for: C19H20NaO4: 335.1259, found: 335.1266. 381
(1S,2S)-2-(benzyloxy)cyclohexyl phenyl carbonate (36d) 382
Colorless oil, 1.90 g, 92% yield. 1H NMR (300 MHz, CDCl3) δ 7.33–7.25 (m, 1H), 7.24–7.11 383
(m, 1H), 7.09–7.04 (m, 1H), 4.72 (ddd, J = 10.1, 8.4, 4.5 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.54 384
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(d, J = 11.9 Hz, 1H), 3.42 (ddd, J = 9.9, 8.4, 4.4 Hz, 1H), 2.13–2.00 (m, 1H), 1.66 (dd, J = 11.8, 385
3.5 Hz, 1H), 1.48–1.15 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 153.4, 151.3, 138.8, 129.7, 386
129.5, 128.5, 127.6, 127.5, 125.9, 121.2, 121.0, 80.3, 79.2, 71.6, 29.9, 23.4. HRMS m/z : 387
[M+Na]+ calcd for: C20H22NaO4: 349.1416, found: 349.1418. 388
Phenyl (1S,2R)-2-phenylcyclohexyl carbonate (36e) 389
Colorless oil, 4.20 g, quantitative. 1H NMR (300 MHz, CDCl3): δ 7.33–7.24 (m, 7H), 7.18–7.13 390
(m, 1H), 6.86–6.83 (m, 2H), 4.92 (td, J = 10.6, 4.4 Hz, 1H), 2.79–2.70 (m, 1H), 2.30–2.25 391
(m,1H), 2.01–1.79 (m, 3H), 1.70–1.36 (m, 4H). HRMS m/z : [M+Na]+ calcd for: C19H20NaO3: 392
319.1310, found: 319.1311. 393
Phenyl (1S,2R)-2-(2-phenylpropan-2-yl)cyclohexylcarbonate (36f) 394
Colorless oil, 1.55 g, 97% yield. 1H NMR (300 MHz, CDCl3): δ 7.27-7.42 (m, 6H), 7.14-7.21 395
(m, 2H), 7.10 (d, J = 7.8 Hz, 2H), 4.70 (dt, J = 4.8, 4.2 Hz, 1H), 2.04-2.13 (m, 2H), 1.64-1.75 396
(m, 3H), 1.44-1.53 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H), 1.03-1.29 (m, 3H). 13C NMR (75 MHz, 397
CDCl3): δ 152.8, 151.2, 150.8, 129.4, 128.2, 125.8, 125.6, 125.5, 121.1, 80.0, 51.4, 40.2, 33.3, 398
27.3, 26.8, 26.7, 25.8, 24.7. HRMS m/z: [M+Na]+ Calcd for C22H26O3Na : 361.1774, found: 399
361.1788. 400
(1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyl phenyl carbonate (36g) 401
The carbonate was synthesized following a literature procedure and the spectral details matched 402
the reported data.26
Colorless gum, 1.39 g, quantitative. HRMS m/z : [M+Na]+ calcd for: 403
C23H28NaO3: 375.1936, found: 375.1940. 404
405
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406
(1S,2R,4S)-4-isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl phenyl carbonate (36h) 407
Colorless oil, 1.47 g, quantitative. 1H NMR (300 MHz, CDCl3): δ 7.38–7.28 (m, 6H), 7.23–7.08 408
(m, 4H), 4.66 (td, J = 10.7, 4.6 Hz, 1H), 2.17–2.05 (m, 2H), 1.73–1.63 (m, 2H), 1.54–1.37 (m, 409
2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.14–0.90 (m, 3H), 0.81 (d, J = 6.8 Hz, 6H). 13C NMR (75 MHz, 410
CDCl3): δ 152.9, 151.2, 150.7, 129.4, 128.2, 125.5, 121.1, 80.2, 51.0, 43.3, 40.2, 32.9, 32.5, 30.8, 411
27.3, 27.2, 26.2, 20.2, 19.6. HRMS m/z : [M+Na]+ calcd for: C25H32NaO3: 403.2249, found: 412
403.2255. 413
(2S,6S)-2,6-dimethylcyclohexyl phenyl carbonate (36i) 414
Colorless oil, 0.99 g, quantitative. 1H NMR (300 MHz, CDCl3): δ 7.41–7.35 (m, 2H), 7.29–7.23 415
(m, 1H), 7.20–7.17 (m, 2H), 4.54 (dd, J = 7.9, 4.0 Hz, 1H), 2.20–2.15 (m, 1H), 2.04–1.95 (m, 416
1H), 1.81–1.72 (m, 1H), 1.54–1.46 (m, 4H), 1.20–1.14 (m, 1H), 1.01 (s, 3H), 0.99 (s, 3H). 13C 417
NMR (75 MHz, CDCl3): δ 153.5, 151.4, 129.4, 125.8, 121.1, 85.1, 31.4, 30.9, 30.4, 19.6, 17.6, 418
14.4. HRMS m/z : [M+Na]+ calcd for: C15H20NaO3: 271.1310, found: 271.1307. 419
General procedure for the syntheses of carbamates 37a-i 420
To a stirred solution of carbonate 36 (1.0 equiv.)equiv.) in absolute ethanol at rt was added 421
hydrazine hydrate (4.3 equiv.)equiv.) and the reaction mixture was refluxed for 1 h. The reaction 422
mixture was concentrated under reduced pressure and the residue obtained was partitioned 423
between cold 10% NaOH and Et2O. The basic aqueous layer was once again extracted with 424
Et2O. The combined organic extracts were washed with water, brine, dried over anhydrous 425
Na2SO4 and concentrated under reduced pressure to afford the desired carbamate as colorless 426
gum (73–98%). The crude carbamate 37 was used in the next step without any purification. 427
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428
3,3-Dimethylbutan-2-yl hydrazinecarboxylate (37a) 429
Colorless oil, 2.7 g, 79% yield. 1H NMR (300 MHz, CDCl3): δ 5.95 (bs, 1H), 4.60 (q, J = 6.3 430
Hz, 1H), 3.56 (bs, 2H), 1.14 (d, J = 6.3 Hz, 3H), 0.88 (s, 9H). IR (neat): ν (cm-1
) 3330, 2920. 431
HRMS m/z : [M+Na]+ calcd for: C7H16NaO2: 183.1104, found: 183.1108. 432
1,1,1-Trifluoro-3-methylbutan-2-yl hydrazinecarboxylate (37b) 433
Colorless oil, 1.0 g, 73% yield. 1H NMR (300 MHz, CDCl3) δ 5.09–4.96 (m, 1H), 3.85 (bs, 2H), 434
2.14 (dq, J = 13.3, 6.8 Hz, 1H), 1.01 (dd, J = 10.4, 6.9 Hz, 6H). 13C NMR (300 MHz, CDCl3) δ 435
157.5, 124.1(q), 74.9 (q), 27.9, 18.9, 17.2. IR (neat): ν (cm-1
) 3340, 2930, 2860. HRMS m/z : 436
[M+Na]+ calcd for: C6H11F3N2NaO2: 223.0670, found: 223.0685. 437
(1S,2S)-2-(Benzyloxy)cyclopentyl hydrazinecarboxylate (37c) 438
Colorless oil, 0.72 g, 90% yield. 1H NMR (300 MHz, CDCl3): δ 7.36–7.32 (m, 5H), 5.92 (bs, 439
1H), 5.11–5.09 (m, 1H), 4.59 (q, J = 11.8 Hz, 2H), 3.91–3.90 (m, 1H), 3.48 (bs, 2H), 2.11–2.06 440
(m, 1H), 1.94–1.89 (m, 1H), 1.81–1.65 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 138.4, 136.1, 441
128.5, 128.2, 127.6, 127.5, 83.8, 80.4, 71.2, 67.2, 30.4, 30.3, 21.5. IR (neat): ν (cm-1
) 3300, 442
2910, 2850, 1700. HRMS m/z : [M+Na]+ calcd for: C13H18N2NaO3: 273.1215, found: 273.1218. 443
(1S,2S)-2-(Benzyloxy)cyclohexyl hydrazinecarboxylate (37d) 444
Colorless oil, 1.49 g, 96% yield. 1H NMR (300 MHz, CDCl3): δ 7.37–7.24 (m, 5H), 5.93 (bs, 445
1H), 4.78–4.71 (m, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 3.83 (s, 2H), 3.38–446
3.30 (m, 1H), 2.06–2.00 (m, 2H), 1.73–1.62 (m, 2H), 1.47–1.18 (m, 4H). 13C NMR (75 MHz, 447
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CDCl3): δ 158.5, 138.9, 128.2, 127.4, 78.9, 76.3, 71.1, 30.2, 29.8, 23.2. IR (neat): ν (cm-1
) 3300, 448
2926, 2820, 1690. HRMS m/z : [M+Na]+ calcd for: C14H20N2NaO3: 287.1372, found: 287.1375. 449
(1S,2R)-2-Phenylcyclohexyl hydrazinecarboxylate (37e) 450
Colorless oil, 3.10 g, 98% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.25 (m, 2H), 7.20–7.18 451
(m, 3H), 5.67 (bs, 1H), 4.88 (td, J = 10.6, 4.4 Hz, 1H), 3.63 (bs, 2H), 2.67–2.59 (m, 1H), 2.19 (d, 452
J = 10.0 Hz, 1H), 1.95–1.75 (m, 3H), 1.61–1.30 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 143.1, 453
128.3, 127.4, 126.3, 49.8, 34.2, 32.7, 25.8, 24.7. IR (neat): ν (cm-1
) 3300, 2910, 2860, 1695. 454
HRMS m/z : [M+Na]+ calcd for: C13H18N2NaO2: 257.1266, found: 257.1265. 455
(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37f) 456
Colorless gum, 1.20 g, 98% yield. 1H NMR (300 MHz, CDCl3): δ 7.27-7.32 (m, 4H), 7.12-7.18 457
(m, 1H), 4.93 (br s, 1H, -NH), 4.64 (m, 1H), 3.34 (br s, 2H, -NH2), 1.68-1.81 (m, 3H), 1.92-2.10 458
(m, 2H), 1.32 (s, 3H), 1.19-1.29 (m, 4H), 1.20 (s, 3H). 13C NMR (100 MHz, CDCl3): δ127.8, 459
125.4, 124.9, 75.9, 65.9, 51.5, 39.7, 33.8, 28.6, 26.9, 26.0, 24.8, 23.9, 15.3. IR (neat): ν (cm-1
) 460
3340, 2936, 2860, 1705. 461
(1S,2R,4R)-4-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37g) 462
The hydrazide was synthesized using usual procedure and the characterization is done at the 463
hydrazone stage. Colorless oil, 1.01 g, 93% yield. HRMS m/z : [M+Na]+ calcd for: 464
C17H26N2NaO2: 313.1892, found: 313.1899. 465
(1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37h) 466
Colorless oil, 1.04 g, 89% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.27 (m,4H), 7.18–7.13 467
(m, 1H), 4.92 (bs, 1H), 4.70–4.55 (m, 1H), 3.70–3.20 (m, 2H), 2.20–1.40 (m, 6H), 1.32 (s, 3H), 468
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1.29–1.24 (m, 1H), 1.21 (s, 3H), 1.09–0.97 (m, 2H), 0.85 (d, J = 4.7 Hz, 6H). 13C NMR (75 469
MHz, CDCl3): δ 127.8, 125.4, 124.9, 76.1, 65.9, 51.1, 43.6, 39.7, 33.4, 32.6, 30.4, 27.3, 20.2, 470
19.6, 15.4. IR (neat): ν (cm-1
) 3320, 2920, 2849, 1700. HRMS m/z : [M+Na]+ calcd for: 471
C19H30N2NaO2: 341.2205, found: 341.2210. 472
(2S,6S)-2,6-Dimethylcyclohexyl hydrazinecarboxylate (37i) 473
Colorless oil, 0.66 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 5.93 (bs, 1H), 4.49 (dd, J = 8.1, 474
4.2 Hz, 1H), 3.74 (d, J = 4.2 Hz, 2H), 2.11–2.06 (m, 1H), 1.85–1.79 (m, 1H), 1.73–1.64 (m, 1H), 475
1.51–1.40 (m, 4H), 1.17–1.07 (m, 1H), 0.91 (d, J = 5.4 Hz, 3H), 0.89 (d, J = 5.7 Hz, 3H). 13C 476
NMR (75 MHz, CDCl3): δ 158.9, 81.1, 31.4, 31.1, 30.5, 19.6, 17.7, 14.1. IR (neat): ν (cm-1
) 477
3350, 2930, 2844, 1690. HRMS m/z : [M+Na]+ calcd for: C9H18N2NaO2: 209.1266, found: 478
209.1261. 479
General procedure for the syntheses of hydrazones 38a-i 480
To a stirred solution of carbamate 37 (1.0 equiv.)equiv.) in anhydrous acetone at rt was added 481
MgSO4 (0.5 equiv.)equiv.) and the mixture was heated to reflux for 2 h, filtered and washed with 482
dichloromethane. The filtrate was concentrated under reduced pressure and dried to get the 483
desired hydrazone compound 38 as a colorless gum or a white solid in quantitative yield (93-484
100%). The crude compound was used for next step without any purification. 485
3,3-Dimethylbutan-2-yl 2-(propan-2-ylidene) hydrazinecarboxylate (38a) 486
Colorless gum, 3.01 g, 93% yield. 1H NMR (300 MHz, CDCl3) δ 7.44 (bs, 1H), 4.74 (q, J = 6.3 487
Hz, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.91 (s, 9H). 13C NMR (75 MHz, 488
CDCl3) δ 153.8, 150.5, 78.8, 34.3, 25.6, 25.3, 16.1, 15.1. IR (neat): ν (cm-1) 3230, 2930. HRMS 489
m/z: [M+Na]+ calc. for C10H20N2O2Na: 223.1417, found: 223.1424. 490
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491
492
1,1,1-Trifluoro-3-methylbutan-2-yl 2-(propan-2-ylidene) hydrazinecarboxylate (38b) 493
Colorless gum, 1.28 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.71 (bs, 1H), 5.19–5.10 (m, 494
1H), 2.19–2.13 (m, 1H), 2.07 (s, 3H), 1.88 (s, 3H), 1.06–1.00 (m, 6H). 13C NMR (75 MHz, 495
CDCl3) δ 153.1 (152.8), 124.0 (q-129.7, 125.9, 122.2, 118.9), 74.4 (q-75.0, 74.6, 74.2, 73.8), 496
27.9, 25.3, 18.8, 17.2, 16.4. IR (neat): ν (cm-1) 3200, 2920, 1710. HRMS m/z : [M+Na]+ calcd 497
for: C9H15F3N2NaO2: 263.0983, found: 263.1010. 498
(1S,2S)-2-(Benzyloxy)cyclopentyl 2-(propan-2-ylidene) hydrazinecarboxylate (38c) 499
Colorless oil, 0.81 g, 99.6% yield. 1H NMR (300 MHz, CDCl3): δ 7.39–7.36 (m, 2H), 7.34–7.32 500
(m, 3H), 5.24 (bs, 1H), 5.22–5.20 (m, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 501
3.97 (m, 1H), 2.14–1.89 (m, 2H), 1.82 (d, J = 4.8 Hz, 6H), 1.77–1.69 (m, 4H). 13C NMR (75 502
MHz, CDCl3): δ 138.4, 135.9, 128.4, 128.3, 127.5,127.3, 83.7, 71.1, 67.1, 30.4, 30.3, 25.2, 21.6, 503
16.1. IR (neat): ν (cm-1) 3210, 2930, 1700, 1693, 1033. HRMS m/z : [M+Na]+ calcd for: 504
C16H22N2NaO3: 313.1528, found: 313.1536. 505
(1S,2S)-2-(Benzyloxy)cyclohexyl 2-(propan-2-ylidene) hydrazinecarboxylate (38d) 506
Colorless gum, 1.70 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.43 (bs, 1H), 7.35–7.21 (m, 507
5H), 4.89–4.82 (m, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 3.46–3.40 (m, 1H), 508
2.13–2.00 (m, 2H), 2.05 (s, 3H), 1.80 (s, 3H), 1.73–1.63 (m, 2H), 1.46–1.21 (m, 4H). 13C NMR 509
(75 MHz, CDCl3): δ 139.0, 128.1, 127.4, 127.2, 78.6, 71.2, 29.9, 25.3, 23.2, 16.1. HRMS m/z : 510
[M+Na]+ calcd for: C17H24N2NaO3: 327.1685, found: 327.1688. 511
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512
513
(1S,2R)-2-phenylcyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38e) 514
Colorless gum, 3.64 g, 99% yield. 1H NMR (300 MHz, CDCl3): δ 7.32–7.16 (m, 5H), 5.09 (td, J 515
= 10.6, 4.4 Hz, 1H), 2.74–2.67 (m, 1H), 2.30–2.27 (m, 1H), 2.00 (s, 1H), 1.98–1.76 (m, 4H), 516
1.72 (s, 3H), 1.60–1.33 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 153.2, 150.6, 143.1, 128.3, 517
127.3, 126.2, 49.5, 34.7, 32.5, 25.8, 25.2, 24.6, 15.9. IR (neat): ν (cm-1) 3234, 2926, 1710. 518
HRMS m/z : [M+Na]+ calcd for: C16H22N2NaO2: 297.1579, found: 297.1575. 519
(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38f) 520
Colorless gum, 1.37 g, 100% yield. 1H NMR (300 MHz, CDCl3): δ 7.22-7.33 (m, 4H), 7.07 (tt, J 521
= 7.0, 1.5 Hz, 1H), 4.73 (dt, J = 10.5, 4.5 Hz, 1H), 2.16 (s, 1H), 2.03-2.13 (m, 2H), 2.01 (s, 3H), 522
1.67-1.90 (m, 3H), 1.62 (s, 3H), 1.32 (s, 3H), 1.22-1.37 (m, 2H), 1.19 (s, 3H), 1.10-1.14 (m, 2H). 523
13C NMR (75 MHz, CDCl3): δ 152.8, 149.9, 127.8, 125.5, 124.5, 75.7, 51.5, 39.6, 33.6, 26.8, 524
26.1, 25.4, 24.7, 15.9. IR (neat): ν (cm-1) 3220, 2936, 1715, 1693, 1529, 1274, 1033. HRMS 525
m/z: [M+Na]+ Calcd for C19H28N2O2Na: 339.2043, found: 339.2047. 526
(1S,2R,4R)-4-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene) hydrazine 527
carboxylate (38g) 528
Colorless gum, 1.27 g, 98% yield. 1H NMR (400 MHz, CDCl3): δ 7.30-7.17 (m, 4H), 7.03 (t, 529
1H, J = 6.8 Hz), 6.24 (s (br), 1H), 4.72 (td, 1H, J = 10.6, 3.9 Hz), 2.06-1.90 (m, 2H), 1.95 (s, 530
3H), 1.88-1.76 (m, 1H), 1.70-1.61 (m, 1H), 1.57 (s, 3H), 1.53-1.40 (m, 1H), 1.28 (s, 3H), 1.19-531
1.06 (m, 1H), 1.16 (s, 3H), 0.96-0.82 (m, 2H), 0.83 (d, 3H, J = 6.4 Hz). 13C NMR (100.7 MHz, 532
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CDCl3): δ 153.0 (s), 152.9 (s), 150.1 (s), 127.9 (d), 125.6 (d), 124.7 (d), 75.3 (d), 51.2 (d), 42.1 533
(t), 39.6 (s), 34.8 (t), 31.4 (q), 26.4 (t), 25.5 (q), 22.0 (q), 16.1 (q). IR (neat): ν (cm-1
) 3253, 2954, 534
2922, 2870, 1729, 1498, 1229, 1041. HRMS m/z : [M+Na]+ calcd for: C20H30N2NaO2: 535
353.2205, found: 353.2202. 536
(1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene) hydrazine 537
carboxylate (38h) 538
Colorless gum, 1.32 g, 96% yield. 1H NMR (300 MHz, CDCl3): δ 7.35–7.28 (m, 4H), 7.09 (t, J 539
= 7.0 Hz, 1H), 6.31 (bs, 1H), 4.72 (td, J = 10.6, 4.5 Hz, 1H), 2.19–2.06 (m, 2H), 2.04 (s, 3H), 540
1.91–1.69 (m, 2H), 1.65 (s, 3H), 1.52–1.45 (m, 1H), 1.35 (s, 3H), 1.31–1.26 (m, 1H), 1.23 (s, 541
3H), 1.15–0.92 (m, 3H), 0.89 (dd, J = 6.7, 3.7 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 152.8, 542
149.9, 127.7, 125.5, 124.5, 75.8, 51.1, 43.6, 39.6, 33.2, 32.6, 30.2, 27.2, 25.3, 20.2, 19.6, 15.9. 543
HRMS m/z : [M+Na]+ calcd for: C22H34N2NaO2: 381.2518, found: 381.2523. 544
(2S,6S)-2,6-Dimethylcyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38i) 545
White solid, 0.80 g, quantitative, M.P.: 83-85 ºC. 1H NMR (300 MHz, CDCl3): δ 7.45 (bs, 1H), 546
4.61 (dd, J = 8.5, 4.2 Hz, 1H), 2.17–2.12 (m, 1H), 2.05 (s, 2H), 1.86–1.82 (m, 1H), 1.84 (s, 3H), 547
1.74–1.65 (m, 1H), 1.53–1.41 (m, 4H), 1.20–1.07 (m, 1H), 0.93 (d, J = 2.3 Hz, 3H), 0.91 (d, J = 548
2.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 153.7, 150.3, 80.6, 31.4, 31.2, 30.9, 30.3, 25.1, 19.5, 549
17.6, 16.1, 13.9. HRMS m/z : [M+Na]+ calcd for: C12H22N2NaO2: 249.1579, found: 249.1572. 550
General procedure for the syntheses of oxadiazolines 39a-i 551
To a stirred suspension of Pb(OAc)4 (1.0 equiv.)equiv.) in dry dichloromethane at 0 ºC was 552
added AcOH (0.08 equiv.)equiv.) followed by dropwise addition (over 1 h) of a solution of 553
hydrazone 38 (0.8 equiv.)equiv.) in dichloromethane. The reaction mixture was stirred at rt for 554
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1h, the solid was filtered off, washed with dichloromethane. The filtrate was taken up in a rb 555
flask and satd. NaHCO3 (pH slightly basic) was added dropwise at 0 ºC while stirring. A brown-556
colored solid separated and was filtered off, the organic and aqueous layers were separated and 557
the aqueous layer was once extracted with dichloromethane. The combined organic extracts were 558
washed with water, brine, dried over anhydrous MgSO4 and concentrated under reduced pressure 559
to afford the oxadiazoline 39 (71–98%). The crude product was used in the next step without 560
purification. 561
2-(3,3-Dimethylbutan-2-yloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl acetate (39a) 562
Colorless oil, 0.90 g, 71% yield. 1H NMR (300 MHz, CDCl3) δ 4.83 (q, J = 6.5 Hz, 1H), 2.11 (s, 563
3H), 1.63 (d, J = 3.3 Hz, 6H), 1.31 (d, J = 6.5 Hz, 3H), 0.95 (s, 9H). 13C NMR (75 MHz, CDCl3) 564
δ 169.2, 161.6, 101.7, 83.2, 34.6, 25.6, 24.2, 21.8, 14.9. IR (neat): ν (cm-1) 2944, 1760, 1375. 565
HRMS m/z : [M+Na]+ calcd for: C12H22N2O3Na: 281.1472, found: 281.1483. 566
5,5-Dimethyl-2-(1,1,1-trifluoro-3-methylbutan-2-yloxy)-2,5-dihydro-1,3,4-oxadiazol-2-yl 567
acetate (39b) 568
Colorless oil, 1.46 g, 98% yield. 1H NMR (300 MHz, CDCl3) δ 5.22–5.13 (m, 1H), 2.31-2.24 569
(m, 1H), 2.11 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.6 Hz, 570
3H). 13C NMR (75 MHz, CDCl3) δ 169.1, 160.7, 123.5 (q), 101.9, 77.7 (q), 28.1, 24.3, 24.1, 571
21.7, 18.8, 18.7, 17.2. IR (neat): ν (cm-1) 2900, 1760, 1375. HRMS m/z : [M+Na]+ calcd for: 572
C11H17F3N2NaO4: 321.1038, found: 321.1081. 573
2-((1R,2R)-2-(Benzyloxy)cyclopentyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 574
acetate (39c) 575
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Colorless oil, 0.43 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 7.44–7.37 (m, 2H), 7.35-7.33 576
(m, 3H), 5.31-5.28 (m, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.09-4.06 (m, 577
1H), 2.23–2.18 (m, 1H), 2.11 (d, J = 2.2 Hz, 3 H), 2.01-1.99 (m, 1H), 1.85–1.73 (m, 4H), 1.64 (s, 578
3H), 1.63 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.1, 161.3, 160.9, 138.2, 134.2, 129.1, 128.6, 579
128.4, 127.6, 101.8, 83.9, 83.5, 71.4, 69.9, 30.5, 30.2, 24.2, 21.7. IR (neat): ν (cm-1) 2900, 1760, 580
1366. HRMS m/z : [M+Na]+ calcd for: C18H24N2NaO5: 371.1583, found: 371.1593. 581
2-((1S,2S)-2-(Benzyloxy)cyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 582
acetate (39d) 583
Colorless oil, 0.90 g, 76% yield. 1H NMR (300 MHz, CDCl3): δ 7.34–7.23 (m, 5H), 4.99–4.92 584
(m, 1H), 4.60 (s, 2H), 3.53–3.45 (m, 1H), 2.22–2.11 (m, 2H), 2.07 (s, 3H), 1.76–1.70 (m, 2H), 585
1.66 (s, 3H), 1.64 (s, 3H), 1.56–1.22 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 169.1, 161.2, 586
138.7, 128.3, 127.6, 127.5, 101.6, 80.6, 78.4, 71.8, 30.1, 29.7, 24.3, 24.1, 23.4, 23.3, 21.7. IR 587
(neat): ν (cm-1) 2945, 1760, 1360. HRMS m/z : [M+Na]+ calcd for: C19H26N2NaO5: 385.1739, 588
found: 385.1742. 589
5,5-Dimethyl-2-((1S,2R)-2-phenylcyclohexyloxy)-2,5-dihydro-1,3,4-oxadiazol-2-yl acetate 590
(39e) 591
Colorless oil, 0.89 g, 74% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.16 (m, 5H), 5.06 (td, J = 592
10.6, 4.4 Hz, 1H), 2.80 (ddd, J = 12.3, 10.9, 3.8 Hz, 1H), 2.32–2.26 (m, 1H), 2.05 (s, 3H), 2.02–593
1.89 (m, 2H), 1.85–1.84 (m, 1H), 1.72–1.56 (m, 3H), 1.54 (s, 3H), 1.53 (s, 3H), 1.51–1.36 (m, 594
1H). 13C NMR (75 MHz, CDCl3): δ 188.9, 160.8, 141.9, 128.3, 127.6, 126.7, 101.5, 81.1, 49.3, 595
33.3, 31.9, 25.6, 24.7, 24.1, 21.7. IR (neat): ν (cm-1) 2930, 1755, 1368. HRMS m/z : [M+Na]+ 596
calcd for: C18H24N2NaO4: 355.1634, found: 355.1627. 597
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5,5-Dimethyl-2-((1R,2S)-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2-acetoxy-2,5-dihydro-598
1,3,4-oxadiazoline (39f) 599
Colorless oil, 1.10 g, 93% yield. 1H NMR (300 MHz, CDCl3): δ 7.23-7.39 (m, 4H), 7.10-7.15 600
(m, 1H), 4.87 (dt, J = 10.5, 4.5 Hz, 1H), 2.04-2.16 (m, 1H), 2.10 (s, 3H), 1.65-1.76 (m, 2H), 1.59 601
(s, 3H), 1.55 (s, 3H), 1.43-1.52 (m, 2H), 1.35 (s, 3H), 1.31 (s, 3H), 0.98-1.26 (m, 4H). 13C NMR 602
(100 MHz, CDCl3): δ 169.1, 160.6, 150.2, 128.1, 125.7, 125.5, 101.8, 80.3, 51.2, 40.4, 33.0, 603
28.0, 27.5, 25.9, 25.7, 24.7, 24.3, 24.1, 21.8. IR (neat): ν (cm-1) 2940, 1765, 1374, 1216, 1158, 604
1085, 1046, 731. HRMS m/z: [M+Na]+ Calcd for C21H30N2O4Na : 397.2098, found : 397.2108. 605
5,5-Dimethyl-2-((1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2,5-dihydro-606
1,3,4-oxadiazol-2-yl acetate (39g) 607
The oxadiazoline 39g was not fully characterized at this stage and used for next step. 0.58 g, 608
73% yield. HRMS m/z : [M+Na]+ calcd for: C22H32N2NaO4: 411.2259, found: 411.2265. 609
2-((1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-5,5-dimethyl-2,5-610
dihydro-1,3,4-oxadiazol-2-yl acetate (39h) 611
Colorless oil, 0.60 g, 86% yield. 1H NMR (300 MHz, CDCl3): δ 7.31–7.22 (m, 4H), 7.14–7.08 612
(m, 1H), 4.83 (td, J = 10.7, 4.6 Hz, 1H), 2.19–2.08 (m, 2H), 2.10 (s, 3H), 1.72–1.67 (m, 1H), 613
1.59 (s, 3H), 1.54 (s, 3H), 1.52–1.36 (m, 2H), 1.35 (s, 3H), 1.30 (s, 3H), 1.10–0.82 (m, 4H), 0.79 614
(d, J = 2.5 Hz, 3H), 0.77 (d, J = 2.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.1, 160.5, 150.1, 615
128.1, 125.6, 125.4, 101.8, 80.5, 50.7, 43.3, 40.3, 32.6, 32.4, 30.9, 27.4, 27.2, 26.3, 24.3, 24.1, 616
21.8, 20.1, 19.5. IR (neat): ν (cm-1) 2944, 1770, 1370, 1158, 1046, 730. HRMS m/z : [M+Na]+ 617
calcd for: C24H36N2NaO4: 439.2573, found: 439.2583. 618
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2-((2S,6S)-2,6-Dimethylcyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 619
acetate (39i) 620
Colorless oil, 0.68 g, 86% yield. 1H NMR (300 MHz, CDCl3): δ 4.74 (dd, J = 8.2, 4.1 Hz, 1H), 621
2.25–2.20 (m, 1H), 2.11 (s, 3H), 2.05–1.96 (m, 1H), 1.80–1.72 (m, 1H), 1.64 (s, 6H), 1.53–1.42 622
(m, 4H), 1.21–1.11 (m, 1H), 0.98 (d, J = 5.1 Hz, 3H), 0.96 (d, J = 5.4 Hz, 3H). 13C NMR (75 623
MHz, CDCl3): δ 168.9, 161.6, 101.5, 84.9, 31.2, 31.2, 30.9, 30.4, 24.1, 24.1, 21.7, 19.5, 17.6, 624
14.1. IR (neat): ν (cm-1) 2960, 1760, 1158. HRMS m/z : [M+Na]+ calcd for: C14H24N2NaO4: 625
307.1633, found: 307.1624. 626
General procedure for the synthesis of the dialkoxycarbene precursors, oxadiazolines 30a-i 627
To a stirred solution of crude oxadiazoline 39 (1.0 equiv.) in dry dichloromethane (0.5 M) at rt 628
under argon was added a solution of alcohol 33 (0.7 equiv.) in dichloromethane (0.5 M) followed 629
by the addition of camphorsulfonic acid (0.03 equiv.). The reaction mixture was stirred at rt for 630
12 h (overnight), diluted with dichloromethane and washed with a satd. NaHCO3 solution, water 631
and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under 632
reduced pressure. The crude compound was purified by flash silica gel column chromatography 633
using 5-10% EtOAc / hexanes to afford the desired dialkoxycarbene precursor 30. 634
(3E,5E)-8-(2-(3,3-Dimethylbutan-2-yloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-635
yloxy)-6-methylocta-3,5-dien-2-one (30a) 636
Colorless oil, 1.23 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 7.38 (ddd, J = 15.3, 11.4, 1.7 637
Hz, 1H), 6.03 (dd, J = 12.7, 10.9 Hz, 2H), 3.97–3.87 (m, 0.5H), 3.80 (ddd, J = 9.2, 7.9, 4.6 Hz, 638
1H), 3.73–3.56 (m, 1H), 3.29 (q, J = 6.3 Hz, 0.5H), 2.43 (td, J = 6.3, 2.5 Hz, 2H), 2.25 (s, 3H), 639
1.93–1.88 (m, 3H), 1.52 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H), 1.13 (dd, J = 6.4, 4.5 Hz, 3H), 0.86 (d, 640
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J = 13.4 Hz, 9H).13C NMR (75 MHz, CDCl3) δ 198.7, 147.0, 139.1, 137.4, 129.0, 125.6, 118.0, 641
79.4, 77.6, 77.2, 76.8, 62.5, 40.2, 34.8, 27.6, 26.1, 24.1, 17.5, 16.4. IR (neat): ν (cm-1
) 2936, 642
1670. HRMS m/z : [M+Na]+ calcd for: C19H32N2NaO4: 375.2254, found: 375.2270. 643
(3E,5E)-8-(5,5-Dimethyl-2-(1,1,1-trifluoro-3-methylbutan-2-yloxy)-2,5-dihydro-1,3,4-644
oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30b) 645
Colorless oil, 0.67 g, 73% yield. 1H NMR (300 MHz, CDCl3) δ 7.39, 7.36 (dd, J = 15.6 Hz, 1H), 646
6.08-6.00 (m, 2H), 4.24-4.11 (m, 1H), 3.78–3.54 (m, 2H), 2.44 (t, J = 6.3 Hz, 2H), 2.24 (s, 3H), 647
2.17–2.04 (m, 1H), 1.90 (s, 2H), 1.51 (t, J = 6.0 Hz, 6H), 1.01–0.94 (m, 6H). 13C NMR (75 648
MHz, CDCl3) δ 198.8, 146.2, 138.9, 136.0, 129.3, 125.9, 119.9, 62.7, 39.8, 29.0, 27.7, 24.1, 649
23.8, 19.1, 17.7, 16.9. IR (neat): ν (cm-1
) 2928, 1666, 1630. HRMS m/z : [M+Na]+ calcd for: 650
C18H27F3N2NaO4: 415.1821, found: 415.1838. 651
(3E,5E)-8-(2-((1R,2R)-2-(Benzyloxy)cyclopentyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-652
oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30c) 653
Colorless oil, 0.39 g, 77% yield. 1H NMR (300 MHz, CDCl3) δ 7.44–7.37 (m, 1H), 7.33–7.31 654
(m, 5H), 6.06 (dd, J = 5.1 Hz, 1H), 6.05–5.99 (m, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 655
11.4 Hz, 1H), 4.56–4.51 (m, 1H), 4.35–3.70 (m, 3H), 2.45 (q, J = 6.9 Hz, 2H), 2.26 (s, 3H), 656
2.05–1.85 (m, 2H), 1.91 (dd, J = 3.9, 1.1 Hz, 3H), 1.75–1.64 (m, 4H), 1.55–1.49 (m, 6H). 13C 657
NMR (75 MHz, CDCl3): δ 198.7, 146.7, 138.9, 136.8, 129.1, 128.3, 128.0, 127.3, 125.5, 119.3, 658
118.9, 84.6, 80.4, 71.1, 66.7, 62.7, 62.3, 39.9, 31.6, 29.9, 27.6, 24.0, 21.4, 17.5. IR (neat): ν (cm-
659
1) 2930, 1660, 1630. HRMS m/z : [M+Na]
+ calcd for: C25H34N2NaO5: 465.2365, found: 660
465.2374. 661
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(3E,5E)-8-(2-((1S,2S)-2-(Benzyloxy)cyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-662
oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30d) 663
Colorless oil, 0.27 g, 92% yield. 1H NMR (300 MHz, CDCl3): δ 7.42–7.36 (m, 1H), 7.33–7.22 664
(m, 5H), 6.07–5.98 (m, 2H), 4.60 (s, 2H), 3.94–3.69 (m, 3H), 3.43–3.37 (m, 1H), 2.41 (t, J = 6.5 665
Hz, 1H), 2.24 (s, 3H), 2.09–1.91 (m, 2H), 1.88 (s, 3H), 1.63–1.54 (m, 2H), 1.50 (s, 6H), 1.49–666
1.38 (m, 2H), 1.28–1.22 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 198.6, 146.9, 138.9, 137.1, 667
128.9, 128.2, 127.5, 127.3, 125.4, 118.7, 78.4, 75.9, 71.6, 62.3, 40.0, 30.9, 29.1, 27.5, 24.1, 24.0, 668
22.7, 22.5, 17.5. IR (neat): ν (cm-1
) 2930, 1655, 1635. HRMS m/z : [M+Na]+ calcd for: 669
C26H36N2NaO5: 479.2522, found: 479.2520. 670
(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R)-2-phenylcyclohexyloxy)-2,5-dihydro-1,3,4-oxadiazol-2-671
yloxy)-6-methylocta-3,5-dien-2-one (30e) 672
Colorless oil, 0.11 g, 69% yield. 1H NMR (300 MHz, CDCl3): δ 7.43–7.33 (m, 1H), 7.28–7.14 673
(m, 5H), 6.10–5.88 (m, 2H), 3.79 (td, J = 10.3, 4.3 Hz, 1H), 3.43–3.30 (m, 2H), 2.66–2.30 (m, 674
2H), 2.27 (s, 3H), 2.23 (t, J = 6.7 Hz, 2H), 1.91–1.81 (m, 1H), 1.82 (d, J = 0.9 Hz, 3H), 1.80–675
1.70 (m, 2H), 1.55–1.40 (m, 3H), 1.35 (s, 3H), 1.32–1.26 (m, 1H), 1.16 (s, 3H). 13C NMR (75 676
MHz, CDCl3): δ 198.8, 147.1, 144.0, 139.2, 136.9, 128.9, 128.3, 128.2, 128.1, 128.0, 126.3, 677
125.3, 118.5, 78.3, 62.3, 50.7, 40.1, 34.6, 34.0, 27.6, 25.8, 25.0, 24.0, 23.7, 17.5. IR (neat): ν 678
(cm-1
) 2930, 1660, 1630. HRMS m/z : [M+Na]+ calcd for: C25H34N2NaO4: 449.2416, found: 679
449.2434. 680
(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R)-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2,5-dihydro-681
1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30f) 682
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Colorless oil, 0.56 g, 77% yield. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J = 11.4 Hz, 1H), 683
7.23-7.31 (m, 4H), 7.12 (t, J = 6.7 Hz, 1H), 6.02-6.11 (m, 2H), 3.51-4.13 (m, 3H), 2.42 (t, J = 6.1 684
Hz, 2H), 2.27 (s, 3H), 2.04-2.19 (m, 1H), 1.92 (s, 3H), 1.56-1.87 (m, 2H), 1.49 (s, 3H), 1.45 (s, 685
6H), 1.23-1.34 (m, 3H), 1.28 (s, 3H), 0.83-1.13 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 198.6, 686
151.6, 146.9, 139.0, 137.1, 129.1, 127.9, 125.8, 125.6, 125.0, 117.5, 77.1, 61.9, 51.9, 40.8, 40.0, 687
35.0, 29.5, 27.6, 27.5, 25.8, 24.6, 24.2, 24.1, 23.9, 17.5. IR (neat): ν (cm-1
) 2933, 1660, 1630, 688
1586, 1450, 1362, 1250, 1147, 1090, 987, 736, 691. HRMS m/z: [M+Na]+ Calcd for 689
C28H40N2O4Na : 491.2880, found : 491.2896. 690
(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-691
2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30g) 692
Colorless oil, 0.56 g, 91% yield. 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, 1H, J = 15.3, 11.4 693
Hz), 7.34-7.23 (m, 4H), 7.12 (t, 1H, J = 6.8 Hz), 6.09 (d, 1H, J = 15.3 Hz), 6.05 (d, 1H, J = 11.4 694
Hz), 3.87 (td, 1H, J = 10.5, 3.9 Hz), 3.67-3.60 (m, 1H), 3.58-3.51 (m, 1H), 2.43 (t, 2H, J = 6.0 695
Hz), 2.35-2.26 (m, 1H), 2.27 (s, 3H), 1.93 (s, 3H), 1.84-1.77 (m, 1H), 1.55-1.34 (m, 1H), 1.50 (s, 696
3H), 1.46 (s, 6H), 1.34-1.23 (m, 2H), 1.28 (s, 3H), 1.00 (q, 1H, J = 11.6 Hz), 0.91-0.80 (m, 1H), 697
0.85 (d, 3H, J = 6.5 Hz), 0.70 (q, 1H, J = 12.3 Hz). 13C NMR (100.7 MHz, CDCl3): δ 198.9, 698
152.0, 147.1, 139.3, 137.2, 129.2, 128.0, 126.0, 125.8, 125.1, 117.7, 77.1, 62.0, 51.8, 44.1, 40.8, 699
40.1, 34.9, 31.8, 29.8, 27.8, 27.6, 24.3, 24.2, 23.7, 22.3, 17.7. IR (neat): ν (cm-1
) 3054, 2955, 700
2922, 2868, 1633, 1258, 1147. HRMS m/z : [M+Na]+ calcd for: C29H42N2NaO4: 505.3042, 701
found: 505.3051. 702
(3E,5E)-8-(2-((1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-5,5-dimethyl-703
2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30h) 704
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Colorless oil, 0.54 g, 57% yield. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J = 15.3, 11.4 Hz, 705
1H), 7.31–7.23 (m, 4H), 7.11 (t, J = 6.8 Hz, 1H), 6.06 (t, J = 13.4 Hz, 2H), 4.13–3.47 (m, 3H), 706
2.41 (t, J = 6.3 Hz, 2H), 2.34–2.28 (m, 1H), 2.26 (s, 3H), 2.09–1.98 (m, 1H), 1.92 (s, 3H), 1.90–707
1.85 (m, 1H), 1.62–1.57 (m, 1H), 1.50–1.40 (m, 2H), 1.49 (s, 3H), 1.45 (s, 3H), 1.36–1.19 (m, 708
6H), 1.00–0.76 (m, 3H), 0.71–0.66 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 198.7, 151.6, 146.9, 709
139.1, 137.1, 129.1, 127.9, 125.8, 125.6, 125.0, 117.5, 61.9, 51.7, 43.4, 40.8, 40.1, 34.8, 32.5, 710
31.4, 29.1, 27.7, 27.4, 24.2, 24.1, 20.2, 19.5, 17.5. IR (neat): ν (cm-1
) 2930, 1666, 1645. HRMS 711
m/z : [M+Na]+ calcd for: C31H46N2NaO4: 533.3355, found: 533.3365. 712
(3E,5E)-8-(2-((2S,6S)-2,6-Dimethylcyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-713
oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30i) 714
Colorless oil, 0.33 g, 67% Yield. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 15.3, 11.4 Hz, 715
1H), 6.06 (dd, J = 15.0, 11.1 Hz, 2H), 3.93–3.73 (m, 2H), 3.39–3.33 (m, 1H), 2.45 (t, J = 6.4 Hz, 716
2H), 2.27 (s, 3H), 2.05–1.98 (m, 1H), 1.93 (s, 3H), 1.88–1.82 (m, 1H), 1.77–1.67 (m, 1H), 1.54 717
(s, 3H), 1.48 (s, 3H), 1.44–1.33 (m, 4H), 1.21–1.02 (m, 1H), 0.99 -0.86 (m, 6H). 13C NMR (75 718
MHz, CDCl3): δ 198.5, 146.9, 138.9, 137.5, 128.9, 125.5, 117.9, 81.4, 62.3, 40.1, 32.1, 31.9, 719
30.5, 27.5, 23.9, 19.6, 18.3, 17.4, 14.4. IR (neat): ν (cm-1
) 2903, 1666, 1640. HRMS m/z : 720
[M+Na]+ calcd for: C21H34N2NaO4: 401.2416, found: 401.2402. 721
rac-Cycloadduct 25 and rac-cycloadduct 40 722
A solution of oxadiazoline 29 (3.00 g, 10.6 mmol) in anhydrous toluene (1.06 L, 0.01M) under 723
argon was heated to reflux for 18 h. The solvent was evaporated under reduced pressure keeping 724
the water bath temperature below 30 ºC (since the product is slightly volatile). Gas 725
chromatography analysis of the crude reaction mixture indicated formation of diastereomers in a 726
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ratio of 93:7. Th crude mixture was purified by flash chromatography using 5% ethyl acetate in 727
hexanes. A colorless liquid (1.86 g, 89%) was obtained as a mixture of two diastereomers (25:40 728
= 93:7). The two diastereomers were separated by silica gel column chromatography using 2.5 to 729
5% ethyl acetate in hexanes. The relative configuration of the isomers was determined by 2D-730
NMR spectroscopy. 25 : 1H NMR (300 MHz, CDCl3): δ 5.72, 5.74 (dd, J = 1.5 Hz, 1H), 5.50, 731
5.52 (dd, J = 2.7, 2.4 Hz, 1H), 4.00 (td, J = 8.1 Hz, 1H), 3.80-3.82 (m, 1H), 3.67–3.75 (m, 1H), 732
3.28 (s, 3H), 2.21 (s, 3H), 1.69–1.98 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 733
207.2, 141.6, 126.2, 116.3, 67.0, 66.8, 57.5, 50.8, 37.5, 30.6, 20.9. IR (neat): ν (cm-1) 3044, 734
2964, 2883, 1713, 1063. LRMS (m/z, relative intensity): 219 ((M+Na)+, 100). HRMS m/z : 735
[M+Na]+ Calcd for: C11H16NaO3: 219.0992, found: 219.0994. 40 :
1H NMR (300 MHz, CDCl3): 736
δ 5.65 (dd, J = 6.3, 1.8 Hz, 1H), 5.54 (dd, J = 6.3, 2.3 Hz, 1H), 4.03 (td, J = 8.1, 2.6 Hz, 1H), 737
3.71 (t, J = 2.0 Hz, 1H), 3.66 (ddd, J = 10.1, 8.4, 6.5 Hz, 1H), 3.35 (s, 3H), 2.19 (s, 3H), 1.92 738
(ddd, J = 12.4, 6.5, 2.6 Hz, 1H), 1.80 (ddd, J = 12.4, 10.1, 8.1 Hz, 1H), 1.19 (s, 3H). 13C NMR 739
(75.5 MHz, CDCl3): δ 207.2, 139.2, 126.8, 116.4, 68.1, 65.4, 58.3, 50.8, 37.2, 29.4, 20.6. 740
General procedure for the synthesis of (4+1) cycloadducts: (26a-i and 41a-i) 741
A solution of oxadiazoline 30a-i (0.15 g, 0.32 mmol) in anhydrous toluene (0.01 M) was heated 742
to reflux for 18-22 h to get the desired (4+1)-cycloadducts 26a-i,41a-i. Ratios were determined 743
by 1HNMR and/or GC analysis of the crude mixture). The stereochemistries of the major 744
diastereomers for 26/41a-c were not assigned. The stereochemistries of the major diastereomers 745
26d-i were assigned based on the data for 26f, since these 5 compounds are similar. The 746
assignment for 26f was based on its conversion to 42 and comparison with the sign of optical 747
rotation from literature data. In addition, a single-crystal X-ray diffraction analysis of a 748
derivative obtained from 41f confirmed the assignement.3 The crude mixtures were purified by 749
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silica gel flash column chromatography using gradients of 1 to 5% EtOAc in hexanes to afford 750
the pure individual diasteromers. 751
Cycloadducts (26a) and (41a) 752
Colorless oils, 60 mg, 79% yield. Ratio 55:45, relative configuration of diastereomers not 753
determined. Major diastereomer : 1H NMR (300 MHz, CDCl3) δ 5.76 (dd, J = 1.5 Hz, 1H), 5.52 754
(dd, J = 3.0 Hz, 1H), 4.00-3.85 (m, 1H), 3.75–3.50 (m, 3H), 2.19 (d, J = 0.6 Hz, 3H), 1.96–1.77 755
(m, 2H), 1.34 (s, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.87 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 756
207.5, 141.7, 126.9, 114.5, 83.2, 76.1, 69.9, 67.2, 59.6, 37.6, 35.3, 30.2, 26.5, 25.6, 21.5, 16.1; 757
IR (neat): ν (cm-1) 2930, 2865, 1710. HRMS m/z : [M+Na]+ calcd for: C16H26NaO3: 289.1774, 758
found: 289.1783; Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ 5.74 (dd, J = 1.5 Hz, 1H), 759
5.52 (dd, J = 3.0 Hz, 1H), 4.00-3.85 (m, 1H), 3.75–3.50 (m, 3H), 2.24 (d, J = 0.6 Hz, 3H), 1.96–760
1.77 (m, 2H), 1.31 (s, 3H), 1.13 (d, J = 6.3 Hz, 3H), 0.84 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 761
207.2, 142.1, 126.7, 116.7, 83.2, 77.1, 68.5, 66.8, 58.2, 36.9, 35.7, 31.1, 26.4, 25.5, 21.6, 17.1. 762
Cycloadducts (26b) and (41b) 763
Colorless oil, 54 mg, 69% yield. Ratio 57:43, relative configuration of diastereomers not 764
determined. Major diastereomer: 1H NMR (300 MHz, CDCl3): δ 5.77 (dd, J = 1.5 Hz, 1H), 5.60–765
5.56 (m, 1H), 4.30-4.23 (m, 1H), 4.10–3.99 (m, 1H), 3.90–3.67 (m, 2H), 2.21 (s, 3H), 2.10–1.80 766
(m, 3H), 1.36 (s, 3H), 1.03-0.94 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 205.8, 140.6, 126.9, 767
115.4, 73.3, 70.4, 68.5, 67.6, 59.2, 36.5, 29.9, 29.8, 20.8, 19.5, 17.4. HRMS m/z : [M+Na]+ 768
calcd for: C15H21F3NaO3: 329.1340, found: 329.1356; Minor diastereomer: 1H NMR (300 MHz, 769
CDCl3): δ 5.72 (dd, J = 1.5 Hz, 1H), 5.60–5.56 (m, 1H), 4.30-4.23 (m, 1H), 4.10–3.99 (m, 1H), 770
3.89–3.67 (m, 2H), 2.19 (s, 3H), 2.10–1.80 (m, 3H), 1.33 (s, 3H), 1.03-0.94 (m, 6H). 13C NMR 771
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(75 MHz, CDCl3): δ 206.7, 141.9, 127.4, 116.3 (q), 73.7(q), 70.4, 68.8, 67.7, 58.9, 36.3, 30.8, 772
29.3, 20.6, 18.0, 17.0. 773
Cycloadducts (26c) and (41c) 774
Colorless oil, 55 mg, 77% yield. Ratio 58:42, relative configuration of diastereomers not 775
determined. Major diastereomer: 1H NMR (300 MHz, CDCl3): δ 7.37–7.27 (m, 5H), 5.79 (dd, J 776
= 6.2, 1.5 Hz, 1H), 5.60–5.49 (m, 1H), 4.62 (s, 2H), 4.14–3.59 (m, 5H), 2.19 (s, 3H), 2.03–1.80 777
(m, 3H), 1.72–1.62 (m, 3H), 1.32–1.21 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): 778
207.3, 141.7, 128.4, 127.7, 127.2, 126.5, 86.2, 79.7, 71.1, 68.3, 67.5, 66.7, 65.2, 58.0, 37.8, 32.5, 779
31.6, 31.1, 30.0, 22.0, 21.5, 21.2; HRMS m/z : [M+Na]+ calcd for: C22H28NaO4: 379.1885, 780
found: 379.1893; Minor diastereomer: 1H NMR (300 MHz, CDCl3): δ 7.37–7.27 (m, 5H), 5.72 781
(dd, J = 6.2, 1.5 Hz, 1H), 5.60–5.49 (m, 1H), 4.52 (s, 2H), 4.14–3.59 (m, 5H), 2.17 (s, 3H), 2.03–782
1.80 (m, 3H), 1.72–1.62 (m, 3H), 1.32–1.21 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): 783
207.1, 138.7, 128.3, 127.3, 126.4, 116.6, 85.2, 79.3, 71.1, 68.2, 67.1, 66.8, 65.2, 57.5, 37.6, 32.0, 784
31.3, 30.9, 29.8, 22.0, 21.6, 21.2. 785
Cycloadducts (26d) and (41d) 786
Colorless oil, 83 mg, 73% yield. Ratio of 26d:41d 67:33. Major diastereomer 26d : 1H NMR 787
(300 MHz, CDCl3): δ 7.37–7.26 (m, 5H), 5.69 (dd, J = 6.4, 1.3 Hz, 1H), 5.51 (dd, J = 6.4, 1.3 788
Hz, 1H), 4.58 (d, J = 12.3 Hz, 1H), 4.47 (d, J = 12.3 Hz, 1H), 3.98–3.42 (m, 5H), 2.22 (s, 3H), 789
1.93–1.33 (m, 10H), 1.26 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 141.5, 139.6, 128.3, 127.6, 790
127.4, 127.3, 126.5, 117.9, 76.4, 72.9, 71.1, 70.6, 68.4, 66.4, 57.7, 37.5, 31.2, 27.9, 25.7, 21.6, 791
20.9, 20.3; HRMS m/z : [M+Na]+ calcd for: C23H30NaO4: 393.2042, found: 393.2043. Minor 792
diastereomer 41d : 1H NMR (300 MHz, CDCl3): δ 7.37–7.26 (m, 5H), 5.71 (dd, J = 6.4, 1.3 Hz, 793
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1H), 5.52 (dd, J = 6.4, 1.3 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 3.98–794
3.42 (m, 5H), 2.25 (s, 3H), 1.93–1.33 (m, 10H), 1.24 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 795
141.7, 139.3, 128.3, 127.5, 127.4, 127.3, 126.4, 117.3, 77.4, 72.9, 71.1, 70.6, 68.6, 66.7, 58.1, 796
37.5, 30.0, 27.7, 25.7, 21.8, 21.6, 21.3. 797
Cycloadducts (26e) and (41e) 798
Colorless oil, 62 mg, 88% yield. Ratio of 26e:41e 67:33. Major diastereomer 26e : 1H NMR 799
(300 MHz, CDCl3) δ 7.31–7.13 (m, 5H), 5.67 (dd, J = 6.3, 1.3 Hz, 1H), 5.40 (dd, J = 6.3, 2.7 Hz, 800
1H), 4.08–3.92 (m, 2H), 3.68–3.47 (m, 3H), 2.73–2.65 (m, 1H), 2.17–2.07 (m, 1H), 1.92–1.61 801
(m, 4H), 1.59 (s, 3H), 1.57–1.20 (m, 4H), 1.16 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.0, 802
141.8, 128.4, 128.1, 128.0, 126.7, 125.9, 116.6, 74.9, 68.3, 66.9, 58.0, 50.4, 36.9, 33.9, 33.5, 803
30.3, 25.7, 24.7, 21.2. IR (neat): ν (cm-1) 2930, 2866, 1700; HRMS m/z : [M+Na]+ calcd for: 804
C22H28NaO3: 363.1936, found: 363.1935. Minor diastereomer 41e : 1H NMR (300 MHz, CDCl3) 805
δ 7.31–7.13 (m, 5H), 5.60 (dd, J = 6.3, 1.7 Hz, 1H), 5.46 (dd, J = 6.3, 2.7 Hz, 1H), 4.08–3.92 (m, 806
2H), 3.68–3.47 (m, 3H), 2.58–2.48 (m, 1H), 2.18 (s, 3H), 2.17–2.07 (m, 1H), 1.92–1.61 (s, 4H), 807
1.57–1.20 (m, 4H), 0.68 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.7, 141.6, 128.4, 128.1, 808
128.0, 126.8, 126.0, 113.8, 75.1, 70.2, 67.5, 59.1, 51.1, 36.5, 34.2, 34.1, 29.9, 25.9, 25.1, 20.3. 809
Cycloadducts (26f) and (41f) 810
Colorless oil, 92 mg, 79% yield. Ratio of 26f:41f 70:30. Isolated yield of individual 811
diastereomers after silica gel column chromatography 26f (55%) and 41f (19%). Major 812
diastereomer 26f : 1H NMR (300 MHz, CDCl3): δ 7.27-7.32 (m, 2H), 7.36-7.38 (m, 2H), 7.16 (t, 813
J = 7.2 Hz, 1H), 5.60 (dd, J = 7.2, 0.9 Hz, 1H), 5.50 (dd, J = 6.1, 2.5 Hz, 1H), 3.73-3.82 (m, 3H), 814
3.46 (dddd, J = 8.7 Hz, 1H), 2.23-2.28 (m, 1H), 2.25 (m, 3H), 1.73 (dd, J = 5.4 Hz, 2H), 1.45-815
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1.62 (m, 5H), 1.41 (s, 3H), 1.39 (t, 3H), 1.29-1.38 (m, 3H), 1.18 (s, 3H). 13C NMR (100 MHz, 816
CDCl3): δ 150.5, 141.4, 127.9, 126.7, 126.6, 125.5, 118.6, 70.8, 69.4, 65.9, 57.4, 49.2, 40.7, 817
37.7, 31.4, 29.3, 29.1, 28.2, 22.8, 22.2, 22.1, 20.3. IR (neat): ν (cm-1) 2934, 2865, 1700. IR 818
(neat): ν (cm-1
) 2939, 2871, 1698. HRMS m/z: [M+Na]+ Calcd for C25H34O3Na : 405.2400, 819
found : 405.2417. [α]23
D: +140.8 (c 4.5, CHCl3). Minor diastereomer 41f : 1H NMR (300 MHz, 820
CDCl3): δ 7.35 (t, J = 1.8 Hz, 1H), 7.27-7.33 (m, 3H), 7.15 (tt, J = 6.9, 1.5 Hz, 1H), 5.68, 5.70 821
(dd, J = 1.5 Hz, 1H), 5.49, 5.51 (dd, J = 2.7 Hz, 1H), 3.91 (dt, J = 8.4, 3.0 Hz, 1H), 3.82 (dt, J = 822
6.3, 2.7 Hz, 1H), 3.75 (m, 1H), 3.67 (q, J = 8.2 Hz, 1H), 2.17 (s, 3H), 1.99 (q, J = 5.4 Hz, 1H), 823
1.87 (dddd, J = 3.1 Hz, 1H), 1.64-1.78 (m, 3H), 1.47 (s, 3H), 1.37-1.44 (m, 3H), 1.35 (s, 3H), 824
1.20-1.29 (m, 3H), 1.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 151.1, 141.8, 128.0, 126.6, 825
126.3, 125.4, 116.4, 73.0, 69.7, 67.1, 58.9, 49.9, 40.9, 37.2, 31.2, 30.4, 29.5, 26.5, 25.3, 23.8, 826
22.0, 21.5. HRMS m/z: [M+Na]+ Calcd for C25H34O3Na : 405.2400, found : 405.2413. 827
Cycloadducts (26g) and (41g) 828
Colorless oil, 50 mg, 55% yield. Ratio of 26g:41g 60:40. Major diasteromer 26g : 1H NMR (400 829
MHz, CDCl3): δ 7.34-7.20 (m, 4H), 7.12 (t, 1H, J = 7.1 Hz), 5.67 (d, 1H, J = 6.3 Hz), 5.53 (dd, 830
1H, J = 6.1, 2.3 Hz), 4.05-3.95 (m, 2H), 3.72-3.59 (m, 2H), 2.29 (s, 3H), 2.24-2.16 (m, 1H), 831
1.97-1.77 (m, 3H), 1.47 (s, 3H), 1.43-1.35 (m, 1H), 1.30 (s, 3H), 1.29-1.25 (m, 1H), 1.28 (s, 3H), 832
1.17-1.09 (m, 1H), 0.96-0.66 (m, 3H), 0.88 (d, 3H, J = 6.0 Hz). 13C NMR (100 MHz, CDCl3): δ 833
206.5, 196.7, 153.0, 151.5, 146.9, 146.6, 142.4, 128.2, 128.1, 128.1, 128.1, 126.1, 125.7, 124.9, 834
118.5, 117.7, 77.8, 76.4, 73.2, 68.2, 67.1, 66.7, 58.5, 54.4, 53.7, 53.7, 52.5, 52.0, 45.6, 45.3, 42.9, 835
42.4, 41.9, 41.2, 37.2, 35.2, 35.1, 33.6, 31.7, 31.7, 31.4, 31.3, 29.7, 28.2, 27.7, 27.2, 26.7, 24.6, 836
22.8, 22.7, 22.6, 22.1, 20.8. IR (neat): ν (cm-1
) 3054, 2955, 2924, 2871, 1702, 1060. LRMS 837
(m/z, relative intensity) 419 ((M+Na)+, 100). HRMS m/z : [M+Na]
+ calcd for: C26H36NaO3: 838
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419.2562, found: 419.2568. Minor diastereomer 41g : 1H NMR (400 MHz, CDCl3): δ 7.32-7.23 839
(m, 4H), 7.12 (t, 1H, J = 6.4 Hz), 5.69 (d, 1H, J = 6.2 Hz), 5.55 (dd, 1H, J = 5.9, 2.6 Hz), 3.99 (q, 840
1H, J = 6.6 Hz), 3.92 (td, 1H, J = 10.1, 3.4 Hz), 3.86-3.81 (m, 1H), 3.75 (q, 1H, J = 8.3 Hz), 2.20 841
(s, 3H), 2.15-2.08 (m, 1H), 1.94 (t, 2H, J = 7.0 Hz), 1.82 (td, 1H, J = 9.5, 3.1 Hz), 1.51 (s, 3H), 842
1.45-1.31 (m, 2H), 1.29 (s, 3H), 1.26 (s, 3H), 1.16-1.10 (m, 1H), 0.89-0.63 (m, 3H), 0.85 (d, 3H, 843
J = 6.3 Hz). 13C NMR (100 MHz, CDCl3): δ 207.0, 152.2, 141.6, 128.1, 126.8, 126.0, 125.2, 844
114.7, 74.9, 71.0, 68.1, 60.0, 51.0, 42.8, 40.9, 37.2, 34.8, 31.8, 31.5, 30.2, 28.5, 23.5, 22.5, 21.3. 845
Cycloadducts (26h) and (41h) 846
Colorless oil, 74 mg, 68% yield. Ratio of 26h:41h 85:15. Major diastereomer 26h : 1H NMR 847
(300 MHz, CDCl3): δ 7.34–7.27 (m, 4H), 7.16–7.12 (m, 1H), 5.67 (dd, J = 6.3, 1.3 Hz, 1H), 5.54 848
(dd, J = 6.3, 2.6 Hz, 1H), 3.97–3.86 (m, 3H), 3.62–3.54 (m, 1H), 2.24 (s, 3H), 2.07–1.99 (m, 849
1H), 1.91–1.79 (m, 2H), 1.66–1.46 (m, 4H), 1.40 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.08–0.80 850
(m, 4H), 0.69 (d, J = 6.5 Hz, 3H), 0.67 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 150.2, 851
141.8, 128.7, 127.9, 126.6, 126.2, 125.9, 125.4, 117.9, 73.2, 69.2, 66.3, 57.9, 52.1, 40.8, 38.9, 852
37.5, 33.1, 31.2, 29.8, 29.4, 29.2, 28.4, 23.6, 23.5, 21.9, 20.3, 19.2; HRMS m/z : [M+Na]+ calcd 853
for: C28H40NaO3: 447.2875, found: 447.2883. Minor diastereomer 41h : 1H NMR (300 MHz, 854
CDCl3): δ 7.34–7.23 (m, 4H), 7.16–7.12 (m, 1H), 5.70 (dd, J = 6.3, 1.3 Hz, 1H), 5.53 (dd, J = 855
6.3, 2.6 Hz, 1H), 3.97–3.86 (m, 3H), 3.62–3.54 (m, 1H), 2.19 (s, 3H), 2.10–1.80 (m, 5H), 1.66–856
1.50 (m, 2H), 1.48 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.06–0.82 (m, 4H), 0.69 (d, J = 6.5 Hz, 857
3H), 0.66 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 151.5, 141.7, 128.0, 127.9, 126.8, 858
126.6, 125.2, 115.1, 74.8, 71.0, 67.6, 59.8, 51.2, 42.3, 40.7, 37.3, 32.7, 32.2, 31.4, 30.0, 29.2, 859
26.4, 23.5, 21.4, 20.2, 19.4. 860
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Cycloadducts (26i) and (41i) 861
Colorless oil, 87 mg, 71% yield. Ratio of 26i:41i 51:49. Diastereomer#1: 1H NMR (300 MHz, 862
CDCl3): δ 5.73 (dd, J = 6.3, 1.3 Hz, 1H), 5.54 (dd, J = 6.3, 2.7 Hz, 1H), 4.05–3.95 (m, 1H), 3.89 863
(m, 1H), 3.67–3.56 (m, 1H), 3.50–3.45 (m, 1H), 2.26 (s, 3H), 2.20–2.16 (m, 1H), 1.97–1.76 (m, 864
3H), 1.69–1.63 (m, 1H), 1.52–1.35 (m, 4H), 1.31 (s, 3H), 1.14–0.98 (m, 1H), 0.97 (d, J = 7.0 Hz, 865
3H), 0.89 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 141.6, 126.9, 116.9, 80.4, 68.5, 866
67.5, 57.6, 37.5, 32.9, 32.6, 31.8, 31.3, 21.3, 19.9, 19.3. Diastereomer#2 : 1H NMR (300 MHz, 867
CDCl3): δ 5.69 (dd, J = 6.3, 1.3 Hz, 1H), 5.52 (dd, J = 6.3, 2.6 Hz, 1H), 4.04–3.96 (m, 1H), 3.89 868
(m, 1H), 3.67–3.56 (m, 1H), 3.50–3.45 (m, 1H), 2.26 (s, 3H), 2.09–2.05 (m, 1H), 1.97–1.76 (m, 869
3H), 1.69–1.63 (m, 1H), 1.52–1.35 (m, 4H), 1.28 (s, 3H), 1.14–0.98 (m, 1H), 0.93 (d, J = 6.8 Hz, 870
3H), 0.87 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 141.5, 126.7, 116.6, 79.0, 68.1, 871
66.8, 57.7, 36.8, 32.9, 32.7, 31.6, 31.2, 21.6, 20.0, 18.9. HRMS m/z : [M+Na]+ calcd for: 872
C18H28NaO3: 315.1936, found: 315.1922. 873
Benzyloxyalkynol 45. 874
To a stirred solution of alkyne 4427
(209 mg, 1.30 mmol) in THF (1 mL) at -78 ºC was added n-875
BuLi (0.60 mL, 1.30 mmol, 2.17M in hexanes) and the reaction mixture was stirred at 0 ºC for 876
1.5 h. This alkynyllithium solution was cannulated to a pre-stirred suspension of cerium chloride 877
(320 mg, 1.30 mmol) in THF (3.3 mL) over a period of 18 h at 0 ºC (cerium chloride was 878
handled in a glove box). The reaction mixture was stirred at 0 ºC for 2 h when a solution of 879
ketone 42 (40.0 mg, 0.22 mmol) in THF (1 mL) at 0 ºC was added. The reaction mixture was 880
stirred at 0 ºC for 4 h and then at rt for 18 h. The reaction mixture was quenched by addition of 881
10% aqueous AcOH and extracted with ethyl acetate (3 x 20 mL). The combined organic 882
extracts were washed with a saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, 883
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filtered and concentrated under reduced pressure. The crude product was purified by silica gel 884
flash column chromatography using 10% ethyl acetate in hexanes to get desired propargylic 885
alcohol 45 as colorless oil (50 mg, 67%) along with 7 mg of recovered ketone 42 (corrected yield 886
= 82% based on recovered starting material). 1H NMR (300 MHz, CDCl3): δ 7.38-7.26 (m, 5H), 887
4.77 (dd, 1H, J = 11.6, 1.1 Hz), 4.50 (d, 1H, J = 11.6 Hz), 4.27 (q, 1H, J = 6.6 Hz), 3.83-3.66 (m, 888
2H), 1.99-1.39 (m, 8H), 1.46 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J = 6.6 Hz), 1.03 (s, 3H), 0.91 (d, 889
3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ 138.1, 128.6, 128.1, 127.9, 87.7, 86.6, 80.4, 890
70.7, 64.8, 60.4, 54.7, 50.8, 39.8, 32.4, 30.3, 27.3, 22.7, 22.5, 22.3, 18.2. HRMS m/z: [M+Na]+ 891
calcd for C22H32NaO3: 367.2249, found: 367.2253. 892
Fully saturated diol 46. 893
To a stirred solution of propargylic alcohol 45 (35.0 mg, 0.10 mmol) in THF (1 mL) under an 894
atmosphere of hydrogen was added Pd/C 10% w/w (3.5 mg) and the mixture was stirred for 24 h. 895
The reaction mixture was filtered through celite, washed with THF (2 mL) and the filtrate was 896
concentrated under reduced pressure. The crude compound was purified by silica gel flash 897
column chromatography using 5% EtOAc / hexanes to afford the title compound 46 as colorless 898
oil (18 mg, 73%). 1H NMR (300 MHz, CDCl3): δ 3.78 (dt, 1H, J = 10.6, 7.8 Hz), 3.70 (ddd, 1H, 899
J = 10.6, 8.6, 4.8 Hz), 1.86-1.21 (m, 16H), 0.98 (s, 3H), 0.97 (d, 3H, J = 6.5 Hz), 0.93 (d, 3H, J = 900
6.5 Hz), 0.91 (t, 3H, J = 6.9 Hz). 13C NMR (75.5 MHz, CDCl3): δ 84.4, 60.4, 51.9, 48.4, 38.8, 901
37.9, 35.4, 28.9, 26.2, 24.4, 24.0, 23.9, 20.4, 19.7, 14.3. IR (neat) ν (cm-1) 3589-3134 (br), 2955, 902
2873, 1469, 1049. HRMS m/z: [M+Na]+ calcd for C15H30NaO2: 265.2144, found: 265.2137. 903
Alkenols 47a and 47b 904
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To a stirred solution of propargylic alcohol 45 (100 mg, 0.29 mmol) in THF (10 mL) was 905
added 5% Pd/C (10 mg) and the mixture was vigorously stirred under H2 atmosphere for 3 h. The 906
reaction mixture was filtered through celite, washed with THF (5 mL) and the filtrate was 907
concentrated under reduced pressure. The crude product was purified by silica gel flash column 908
using 20% ethyl acetate / hexanes to afford allylic alcohols 47a (23 mg, 31%) and 47b (18 mg, 909
24%, structure confirmed by X-ray). 1H NMR (300 MHz, CDCl3) 47a: δ 5.41-5.42 (m, 2H), 910
4.91-4.98 (m, 1H), 3.67-3.72 (m, 2H), 1.79-1.93 (m, 2H), 1.40-1.71 (m, 7H), 1.28 (d, J = 6.3 Hz, 911
3H), 1.16-1.25 (m, 2H), 0.98 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 1H NMR 912
(300 MHz, CDCl3) 47b: δ 5.43-5.49 (m, 2H), 4.85-4.93 (m, 1H), 3.64-3.75 (m, 2H), 2.75 (bs, 913
1H), 1.79-1.95 (m, 2H), 1.42-1.68 (m, 7H), 1.27 (d, J = 6.3 Hz, 3H), 1.24-1.25 (m, 1H), 0.98 (s, 914
3H), 0.96 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H). IR (neat): ν (cm-1) 3300, 2955, 1460. 915
HRMS m/z: [M+Na]+ calcd for C15H28NaO3: 279.1936 , found: 279.1944. 916
Triol 48. 917
To a stirred solution of a mixture of allylic alcohols 47a and 47b (22.5 mg, 0.88 mmol) in THF 918
(2 mL) was added PtO2 (3.0 mg, 0.01 mmol) and the mixture was stirred vigorously under 919
hydrogen atmosphere for 20 h. The reaction mixture was filtered through celite, washed with 920
THF (3 mL) and the filtrate was evaporated under reduced pressure. The crude product was 921
purified by silica gel flash chromatography using 10% ethyl acetate / hexanes to get title 922
compound 48 as colorless oil (7.9 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 3.85-3.65 (m, 3H), 923
2.56 (s (br), 2H), 1.89-1.68 (m, 5H), 1.67-1.53 (m, 4H), 1.53-1.31 (m, 3H), 1.30-1.22 (m, 1H), 924
1.21 (d, 3H, J = 6.2 Hz), 0.99 (s, 3H), 0.98 (d, 3H, J = 6.5 Hz), 0.93 (d, 3H, J = 6.5 Hz). 13C 925
NMR (75.5 MHz, CDCl3): δ 83.7, 69.2, 60.2, 51.9, 48.4, 38.5, 36.0, 34.9, 33.3, 29.1, 24.3, 24.1, 926
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24.1, 20.3, 19.7. IR (neat) ν (cm-1) 3644-3047 (br), 2953, 2872, 1376, 1050. HRMS m/z: 927
[M+Na]+ calcd for C15H30NaO3: 281.2087, found: 281.2092. 928
(±)-(But-3-yn-2-yloxy)(t-butyl)dimethylsilane (49) 929
To a stirred solution of 3-butyn-2-ol (5.00 g, 71.3 mmol) in anhydrous DMF (25 mL) at 0 ºC 930
under argon was added a solution of imidazole (12.14 g, 178.3 mmol) in DMF (10 mL) followed 931
by dropwise addition of a solution of t-butyldimethylsilyl chloride (13.97 g, 92.74 mmol) in 932
DMF (25 mL). The reaction mixture was stirred at rt for 12 h, diluted with water (1000 mL) and 933
extracted with diethyl ether (2 x 400 mL). The combined organic extracts were washed with 1N 934
HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced 935
pressure. The crude product was purified by silica gel column chromatography using hexanes to 936
1% Et2O in hexanes to afford the desired product 49 as a colorless liquid (9.0 g, 68%). 1H NMR 937
(300 MHz, CDCl3): δ 4.51 (q, J = 6.6 Hz, 1H), 2.36 (d, J = 2.1 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H), 938
0.90 (s, 9H), 0.12 (d, J = 4.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 86.5, 71.3, 58.9, 25.9, 939
25.8, 25.5, 18.3, -4.5, -4.9. 940
t-Butyldimethylsilyloxy alkynol (50) 941
To a stirred solution of TBS protected propargylic alcohol 49 (5.93 g, 32.0 mmol) in THF (25 942
mL) at -78 ºC was added dropwise a solution of n-BuLi (2.05 g, ~12.8 mL of 2.5 M / hexanes) 943
and the mixture was stirred at 0 ºC for 1h. This alkynyllithium solution was then cannulated to a 944
pre-stirred (18 h at rt under argon atmosphere) suspension of CeCl3 (7.89 g, 32.0 mmol, handled 945
in glove box) in THF (82 mL) at 0 ºC and the mixture was stirred at that same temperature for 1 946
h. A solution of ketone 42 (1.0 g, 5.4 mmol) in THF (10 mL) was then added dropwise and 947
stirring was continued at 0 ºC for 4 h and then at rt for 18 h. The reaction mixture was quenched 948
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by dropwise addition of cold 10% AcOH (30 mL) and aqueous layer was extracted with diethyl 949
ether (3 x 40 mL). Ether extracts were washed successively with water (50 mL), brine (50 mL), 950
dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude 951
product was purified by silica gel flash column chromatography using 10% EtOAc / hexanes to 952
afford the title compound 50 as colorless oil (1.62 g, 81%). 1H NMR (300 MHz, CDCl3) δ 953
(ppm) 4.55 (q, J = 6.6 Hz, 1H), 3.69-3.77 (m, 1H), 1.73-1.90 (m, 5H), 1.44-1.61 (m, 5H), 1.39 954
(d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H), 0.88-0.91 (m, 12H), 0.11 (s, 3H), 0.10 955
(s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 89.2, 85.5, 80.3, 60.4, 59.2, 54.6, 54.5, 50.7, 39.9, 956
32.6, 30.2, 27.2, 25.9, 25.5, 22.7, 22.4, 18.4, 18.1, -4.5, -4.9. IR (neat) ν (cm-1) 3391, 2953, 957
2934, 2866, 1460, 1362, 1250, 992. HRMS m/z: [M+Na]+ calcd for C21H40NaO3Si: 391.2639, 958
found: 391.2623. 959
Alkyne triol 51. 960
To a stirred solution of compound 50 (519 mg, 1.41 mmol) in THF (4.7 mL) at 0 ºC was added 961
TBAF (1.83 mL, 1.83 mmol, 1M in THF) and the reaction mixture was stirred at rt for 2 h. A 962
satd aqueous solution of ammonium chloride (10 mL) was added and the mixture was extracted 963
with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium 964
sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash 965
chromatography using 25% ethyl acetate in hexanes to afford the desired product 51 as colorless 966
oil (344 mg, 96%). 1H NMR (300 MHz, CDCl3): δ 4.53 (q, 1H, J = 6.6 Hz ), 3.81-3.60 (m, 2H), 967
3.22-2.92 (m, 3H), 1.93-1.68 (m, 4H), 1.61-1.46 (m, 3H), 1.42 (d, 3H, J = 6.6 Hz), 1.12 (d, 3H, J 968
= 6.3 Hz), 1.00 (s, 3H), 0.88 (d, 3H, J = 6.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 88.6, 86.4, 969
80.2, 60.1, 58.2, 54.9, 50.5, 39.9, 32.9, 30.1, 27.2, 24.3, 22.6, 22.4, 18.3. IR (neat) ν (cm-1) 970
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3685-3039 (br), 2955, 2871, 1369, 1076. HRMS m/z: [M+Na]+ calcd for C15H26NaO3: 971
277.1774, found: 277.1785. 972
Acetate-diol 54. 973
To a stirred solution of alcohol 50 (200 mg, 0.54 mmol) in DCM (6 mL) at 0 ºC was added 974
triethylamine (0.46 mL, 3.31 mmol) followed by the dropwise addition of acetyl chloride (0.12 975
mL, 1.66 mmol). The reaction mixture was then stirred at rt for 3 h and the crude mixture was 976
taken up in 1N HCl. The layers were separated, the aqueous phase extracted twice with DCM, 977
the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and 978
evaporated under reduced pressure. The crude product was purified by silica gel flash column 979
chromatography using 10% EtOAc / hexanes to afford the desired acetyl compound as colorless 980
oil. (185 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 4.55 (q, J = 6.6 Hz, 1H), 4.13 (t, J = 7.5 Hz, 981
2H), 2.03 (s, 3H), 1.54–1.91 (m, 9H), 1.39 (d, J = 6.6 Hz, 3H), 1.14 (dd, J = 1.8 Hz, 3H), 1.02 (s, 982
3H), 0.89 (s, 12H), 0.11 (s, 6H). 13C NMR (75.5 MHz, CDCl3): δ 171.2, 89.3, 84.9, 80.3, 62.4, 983
59.2, 54.4, 50.7, 35.3, 32.1, 30.2, 27.2, 25.9, 25.5, 22.6, 22.5, 21.2, 18.3, 17.9, -4.6. HRMS m/z: 984
[M+Na]+ calcd for C23H42O4SiNa: 433.2744, found: 433.2746. 985
To a stirred solution of the above acetate (95.0 mg, 0.22 mmol) in THF (3 mL) at rt was added a 986
solution of TBAF (172 mg, 0.66 mmol, 0.66 mL of 1M / THF solution) and the mixture was 987
stirred at rt for 1 h. The reaction mixture was diluted with diethyl ether (4 mL) and washed with 988
water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under 989
reduced pressure. The crude compound was purified by silica gel column chromatography using 990
30% EtOAc / hexanes to afford the title compound 54 as colorless oil (61 mg, 89%). 1H NMR 991
(300 MHz, CDCl3): δ 4.54 (q, J = 6.6 Hz, 1H), 4.09-4.24 (m, 2H), 2.25-2.35 (m, 1H), 2.03 (s, 992
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3H), 1.72-1.89 (m, 4H), 1.53-1.62 (m, 4H), 1.42 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 993
1.02 (s, 3H), 0.88 (d, J = 6.3 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ 171.5, 88.8, 86.03, 80.1, 994
62.5, 58.4, 54.5, 53.5, 50.6, 35.6, 32.7, 30.2, 27.2, 24.4, 22.5, 21.2, 18.1. HRMS m/z: [M+Na]+ 995
calcd for C17H28O4Na: 319.1879, found: 319.1878. 996
Ynone 55 997
To a stirred solution of propargylic diol 54 (50.0 mg, 0.17 mmol) in EtOAc (4 mL) was added 998
IBX (142 mg, 0.51 mmol) and the solution was heated to reflux for 3 h, filtered through celite 999
and the filtrate was concentrated under reduced pressure. The crude compound was purified by 1000
silica gel column chromatography using 10% EtOAc / hexanes to afford the title compound 55 as 1001
colorless oil (46 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 4.14 (t, J = 7.35 Hz, 2H), 2.35 (s, 1002
3H), 2.04 (s, 3H), 1.43-1.99 (m, 9H), 1.14 (d, J = 6.6 Hz, 3H), 1.06 (s, 3H), 0.92 (d, J = 6.3 Hz, 1003
3H). 13C NMR (75.5 MHz, CDCl3): δ 184.3, 171.2, 94.0, 86.4, 79.9, 62.0, 54.9, 51.6, 34.9, 32.7, 1004
32.2, 30.0, 27.4, 22.4, 22.2, 21.1, 17.9. HRMS m/z: [M+Na]+ calcd for C17H26O4Na: 317.1723, 1005
found: 317.1726. 1006
Ketone 56 1007
To a stirred solution of propargylic ketone 55 (84.0 mg, 0.29 mmol) in THF (4 mL) was added 1008
5% Pd/C (8.4 mg) and the mixture was stirred under an atmosphere of H2 for 10 h. The reaction 1009
mixture was filtered through celite and concentrated under reduced pressure. The crude 1010
compound was purified by silica gel column chromatography using 30% EtOAc / hexanes to 1011
afford the title compound 56 as colorless oil. (58 mg, 73%) (Note: Hydrogenation using PtO2 as 1012
a catalyst also gave the same dehydration product). 1H NMR (300 MHz, CDCl3): δ 4.36 (bs, 1013
1H), 4.12 (t, J = 7.65 Hz, 2H), 2.13-2.59 (m, 3H), 2.03 (s, 3H), 1.45-1.83 (m, 10H), 0.97 (d, J = 1014
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6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 0.86 (s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 208.5, 1015
171.2, 143.5, 137.3, 62.4, 49.5, 44.8, 38.4, 35.7, 29.9, 27.8, 27.4, 26.6, 21.5, 21.4, 21.2, 18.9. IR 1016
(neat) ν (cm-1): 1717.9, 1737.4, 1363.9, 1233, 1028. HRMS m/z: [M+Na]+ calcd for 1017
C17H28O3Na: 303.1931, found: 303.1932. 1018
Ynone 57 1019
To a stirred solution of alcohol 51 (135 mg, 0.53 mmol) in DMSO (4 mL) was added IBX (892 1020
mg, 3.18 mmol) and the reaction mixture was stirred at rt for 2.5 h. Then, EtOAc (60 mL) was 1021
added and the mixture was filtered. Water (60 mL) was added to the filtrate and the phases were 1022
separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers 1023
were washed with brine (3 x 60 mL), dried over sodium sulfate, filtered and evaporated under 1024
reduced pressure. The crude product was purified by silica gel flash chromatography using 10% 1025
ethyl acetate in hexanes to get title compound 57 as colorless oil (106 mg, 80%). 1H NMR (300 1026
MHz, CDCl3): δ 9.83 (t, 1H, J = 2.5 Hz), 2.60 (dd, 1H, J = 15.7, 2.5 Hz), 2.45-2.35 (m, 1H), 1027
2.35-2.30 (m, 3H), 2.06-1.87 (m, 3H), 1.86-1.69 (m, 3H), 1.63-1.48 (m, 1H), 1.30-1.21 (m, 3H), 1028
1.14 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 6.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 202.2, 184.1, 1029
93.2, 86.5, 79.3, 55.6, 51.4, 51.2, 33.9, 32.7, 30.0, 27.4, 22.5, 22.1, 19.0. IR (neat) ν (cm-1) 1030
3659-3150 (br), 2958, 2872, 2206, 1717, 1677, 1223. HRMS m/z: [M+Na]+ calcd for 1031
C15H22NaO3: 273.1461, found: 273.1471. 1032
Aldol adduct 59 1033
To a stirred solution of ketoaldehyde 57 (41.0 mg, 0.16 mmol) in EtOAc (5 mL) was added 10% 1034
Pd/C (5 mg) and the mixture was stirred vigorously under a hydrogen atmosphere for 18 h. The 1035
reaction mixture was filtered through celite and the filtrate was evaporated under reduced 1036
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pressure. The crude product was purified by silica gel flash chromatography using 30% ethyl 1037
acetate in hexanes to afford the β-hydroxy ketone compound 59 as a single diastereoisomer. 1038
(colorless oil, 20 mg, 48%). 1H NMR (300 MHz, CDCl3): δ 4.03 (ddd, 1H, J = 15.2, 9.9, 5.0 1039
Hz), 2.58 (ddd, 1H, J = 13.6, 9.9, 3.7 Hz), 2.26 (dd, 1H, J = 13.6, 3.7 Hz), 2.18 (s, 3H), 2.09-1.85 1040
(m, 3H), 1.83-1.68 (m, 2H), 1.67-1.34 (m, 6H), 1.09 (d, 3H, J = 6.6 Hz), 1.01 (s, 3H), 0.95 (d, 1041
3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ 211.8, 82.3, 67.3, 55.7, 49.0, 47.6, 43.3, 36.9, 1042
33.4, 29.8, 29.1, 25.7, 23.2, 22.7, 20.0. IR (neat): ν (cm-1) 3609-3104 (br), 2953, 2926, 2869, 1043
1705, 1052. LRMS (m/z, relative intensity) 254 (M+, 10), 170 (20), 109 (65), 43 (100). HRMS 1044
m/z: [M+Na]+ calcd for C15H26O3Na: 277.1780, found: 277.1783. 1045
Diols 60 and 61 1046
To a stirred solution of alkyne 50 (217 mg, 0.59 mmol) in THF (6 mL) was added 5% 1047
Pd/alumina (10 mg) and the mixture was stirred under a H2 atmosphere for 12 h. The crude 1048
product was purified by flash silica gel column chromatography using 10% EtOAc / hexanes to 1049
afford three products as colorless oils, the desired hydrogenated product 60 (175 mg, 80%), the 1050
partial hydrogenation i.e. alkene 61 (19.64 mg, 9%), and the hydrogenolysis product 46 (8.6 mg, 1051
6%). Compound 60 : 1H NMR (300 MHz, CDCl3): δ 3.69-3.80 (m, 3 H), 1.40-1.83 (m, 14H), 1052
1.15 (dd, J = 3.0 Hz, 3H), 0.98 (s, 3H), 0.93 (d, J = 6.2 Hz, 6H), 0.88 (s, 9H), 0.05 (s, 6H). 13C 1053
NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to the diastereomer but we do not 1054
know which signal belongs to which isomer] δ 84.1 (83.9), 69.5 (69.4), 60.4 (60.3), 52.2 (51.8), 1055
48.4 (48.3), 38.9 (38.8), 35.4 (35.8), 33.8 (34.1), 33.6, 28.9, 26.1, 24.4 (24.3), 24.1 (24.0), 23.9, 1056
20.5 (20.3), 19.9 (19.7), 18.3, -4.5. IR (neat) ν (cm-1) 3454, 2954-2930, 2465, 1066, 997. 1057
HRMS m/z: [M+Na]+ Calc. for C21H44O3SiNa: 395.2952, found: 395.2944. Partial 1058
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hydrogenation product 61 : 1H NMR (300 MHz, CDCl3): δ 5.46 (dd, J = 7.8 Hz, 1H), 5.28 (dd, 1059
J = 13.5, 9.6 Hz, 1H), 4.95-5.10 (m, 1H), 3.69 (q, J = 6.2 Hz, 2H), 1.44-1.84 (m, 10H), 1.27 (d, J 1060
= 6.3 Hz, 3H), 0.98 (d, J = 10.5 Hz, 3H), 0.94 (d, J = 5.4 Hz, 3H), 0.88-0.91 (bs, 12H), 0.08 (d, J 1061
= 33.3 Hz, 3H), 0.07 (d, J = 3.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses 1062
correspond to the diastereomer but we do not know which signal belongs to which isomer] δ 1063
134.3 (134.9), 134.0 (132.3), 86.8 (86.9), 65.8 (66.9), 60.6 (60.6), 55.3 (55.1), 51.5 (51.3), 39.9 1064
(39.7), 33.1, 29.6 (29.9), 26.9, 26.2 (26.1), 25.4 (25.1), 23.1 (22-8), 22.5 (22.6), 18.9 (19.0), 18.3 1065
(18.2). IR (neat): ν (cm-1) 3330, 2950, 1466, 990. HRMS m/z: [M+Na]+ calcd for 1066
C21H42NaO3Si: 393.2795, found: 393.2791. 1067
Terminal alkene 62 1068
To a stirred solution of alcohol 60 (130 mg, 0.35 mmol) in ethyl acetate (6.0 mL) was added IBX 1069
(0.29 g, 1.05 mmol) and the reaction mixture was heated to reflux for 3 h. The reaction mixture 1070
was filtered through celite, washed with ethyl acetate (10 mL), the filtrate was dried over 1071
anhydrous Na2SO4 and concentrated under reduced pressure to afford the desired aldehyde as 1072
colorless oil (128 mg, 99%) which was used in the next reaction without purification. 1H NMR 1073
(300 MHz, CDCl3): δ 9.81 (s, 1H), 3.72-3.79 (m, 1H), 2.43 (t, J = 2.7 Hz, 2H), 1.42-1.92 (m, 1074
11H), 1.11-1.14 (m, 6H), 0.97 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 1075
6H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to the diastereomer but 1076
we do not know which signal belongs to which isomer] δ 203.9, 83.1 (83.4), 69.2, 52.2, 51.9 1077
(51.8), 51.5 (51.4), 48.4 (48.3), 38.7, 36.1 (36.2), 34.4, 33.3, 28.8 (28.7), 26.0, 24.2 (24.1), 24.1 1078
(24.0), 23.8 (23.7), 20.9 (20.8), 20.3 (20.2), 18.1, 14.2, -4.8 (-4.3). IR (neat): ν (cm-1) 3412, 1079
2959, 2886, 1470. HRMS m/z: [M+Na]+ calcd for C21H42O3SiNa: 393.2795, found: 393.2795. 1080
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To a stirred suspension of methyl triphenylphosphonium bromide (231 mg, 0.65 mmol) in THF 1081
(6 mL) at -78 ºC was added a solution of n-BuLi (41.5 mg, 0.26 mL-2.5M / toluene) and the 1082
mixture was stirred at the same temperature for 30 minutes when a solution of aldehyde (120 mg, 1083
0.32 mmol) in THF (3 mL) was added and after 30 minutes of stirring the cooling bath was 1084
removed. After 45 minutes of stirring at rt, reaction mixture was quenched by addition of ice 1085
cold 1N HCl (20 mL) and extracted with diethyl ether (2 x 40 mL). Ether extract was washed 1086
with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated 1087
under reduced pressure. The crude compound was purified by silica gel flash column 1088
chromatography using 2% EtOAc / hexanes to afford the desired product 62 as colorless oil (101 1089
mg, 84%). 1H NMR (300 MHz, CDCl3): δ 5.76-5.89 (m, 1H), 4.98-5.05 (m, 2H), 3.71-3.78 (m, 1090
1H), 1.99 (d, J = 7.5 Hz, 2H), 1.25-1.74 (m, 11H), 1.14 (d, J = 6.0 Hz, 3H), 0.93-0.98 (m, 9H), 1091
0.89 (s, 9H), 0.05 (s, 6H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to 1092
the diastereomer but we do not know which signal belongs to which isomer] δ 136.2, 116.9, 84.5 1093
(84.8), 69.5 (69.4), 52.8 (52.5), 49.5 (49.4), 41.3 (41.2), 37.1, 34.3, 33.8, 33.0, 28.5 (28.4), 26.4, 1094
26.1, 24.5(24.4), 23.9(24.1), 23.4 (23.3), 20.5 (20.3), 20.2 (19.9), 18.3, 14.3, -4.5. HRMS m/z: 1095
[M+Na]+ calcd for C22H44O2SiNa: 391.3008, found: 391.3017. 1096
Ketone 63 and dihydrofuran 64 1097
To a stirred solution of TBS protected alcohol 62 (198 mg, 0.54 mmol) in THF (6 mL) at 0 ºC 1098
was added a TBAF solution (351 mg, 1.34 mL 1M / THF) and the mixture was stirred at rt for 1 1099
h. The reaction mixture was diluted with diethyl ether (20 mL) and washed with water (20 mL), 1100
brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. 1101
The crude compound was purified by silica gel flash column chromatography using 30% EtOAc 1102
/ hexanes to afford the desired alcohol as a white solid (124 mg, 91%, MP: 73-74 ºC). 1H NMR 1103
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(300 MHz, CDCl3): δ 5.76-5.90 (m, 1H), 5.00-5.06 (m, 2H), 3.74-3.80 (m, 1H), 2.00-2.02 (m, 1104
2H), 1.36-1.91 (m, 12H), 1.21 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 3.3 Hz, 3H), 0.99 (s, 3H), 0.94 (d, 1105
J = 6.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ 136.0, 117.0, 84.5, 68.8, 52.6, 49.4, 41.3, 1106
34.2, 33.3, 32.9, 28.3, 24.5, 23.7, 23.1, 20.2, 20.0. IR (neat) ν (cm-1) 3328, 2953, 2880, 1464, 1107
1411,1134, 992. HRMS m/z: [M+Na]+ calcd for C16H30O2Na: 277.2138, found: 277.2139. 1108
To a stirred solution of alcohol (120 mg, 0.47 mmol) in DCM (4 mL) at rt was added a solution 1109
of N-methylmorpholine N-oxide (NMO, 110 mg, 0.94 mmol) in DCM (2 mL) followed by 1110
addition of 4Aº molecular sieves powder (50 mg) and tetra-n-propylammonium perruthenate 1111
(TPAP, 16.0 mg, 0.05 mmol). The reaction mixture was stirred for 30 minutes, diluted with 1112
DCM (10 mL) and water (5 mL). Biphasic mixture was filtered through celite, layers were 1113
separated, organic layer was dried over anhydrous MgSO4, filtered and concentrated under 1114
reduced pressure. The crude compound was identified as compound 64. It was purified by silica 1115
gel flash column chromatography using 2.5% EtOAc / hexanes to afford the desired product 63 1116
as colorless oil. (89 mg, 75%). Compound 63 : 1H NMR (300 MHz, CDCl3): δ 5.78–5.64 (m, 1117
1H), 5.02–4.94 (m, 2H), 2.64–2.54 (m, 1H), 2.49–2.43 (m, 2H), 2.30–2.18 (m, 1H), 2.14 (s, 3H), 1118
2.12–2.10 (m, 2H), 2.04–2.02 (m, 2H), 1.79–1.71 (m, 1H), 1.49–1.25 (m, 4H), 0.98 (s, 3H), 0.97 1119
(d, J = 3.6 Hz, 3H), 0.95 (d, J = 3.6 Hz, 3H); HRMS m/z: [M+Na]+ calcd for C16H28O2Na: 1120
275.1987, found: 275.1994. Compound 64 : 1H NMR (300 MHz, CDCl3): δ 5.74-5.88 (m, 1H), 1121
4.98-5.06 (m, 2H), 4.38 (br, 1H), 2.61 (d, J = 15.6 Hz, 1H), 2.40 (d, J = 15.3 Hz, 1H), 1.77-1.97 1122
(m, 5H), 1.74 (s, 3H), 1.45-1.68 (m, 5H), 0.98 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.84 1123
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.2, 135.9, 117.1, 99.4, 94.4, 54.2, 49.9, 40.2, 34.0, 1124
32.3, 29.9, 25.5, 22.9, 22.2, 17.5, 13.7. 1125
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Bis-alkene 24 and ketone 65 1126
To a stirred suspension of methyltriphenylphosphonium bromide (212 mg, 0.59 mmol) in THF 1127
(4 mL) at -78 ºC was added a solution of n-BuLi (38 mg, 0.23 mL 2.5M / toluene) and the 1128
mixture was stirred at the same temperature for 30 minutes when a solution of ketone 63 (50.0 1129
mg, 0.32 mmol) in THF (1 mL) was added and after 45 minutes of stirring, the cooling bath was 1130
removed and stirring was continued at rt for 30 min. The reaction mixture was quenched by 1131
addition of ice cold 1N HCl (10 mL) and extracted with diethyl ether (2 x 25 mL). Ether extracts 1132
were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and 1133
concentrated under reduced pressure. The crude compound was purified by silica gel flash 1134
column chromatography using 2% EtOAc / hexanes to afford the desired diene 24 as colorless 1135
oil (28 mg, 56%) and the elimination product 65 as colorless oil (17 mg, 37%). Compound 24: 1136
1H NMR (300 MHz, CDCl3) δ 5.77-5.91 (m, 1H), 5.01-5.06 (m, 2H), 4.71 (s,2H), 2.15-2.21 (m, 1137
2H), 2.02 (d, J = 7.2 Hz, 2H), 1.82-1.91 (m, 1H), 1.75 (s, 3H), 1.38-1.71(m, 6H), 1.22-1.30 (m, 1138
2H), 0.99 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, 1139
CDCl3): δ 146.9, 136.1, 117.2, 109.7, 84.8, 52.6, 49.5, 41.4, 35.4, 34.5, 32.3, 28.5, 24.5, 23.3, 1140
22.9, 20.3, 20.1. IR(neat): ν (cm-1) 2953, 2880, 1464, 1411, 1134, 992. HRMS m/z: [M+Na]+ 1141
calcd for: C17H30ONa : 273.2189, found: 273.2199. Compound 65: 1H NMR (300 MHz, 1142
CDCl3): δ 5.64-5.78 (m, 1H), 4.94-5.02 (m, 2H), 2.55-2.64 (m, 1H), 2.43-2.49 (m, 2H), 2.19-1143
2.25 (m, 1H), 2.14 (s, 3H), 2.10 (d, J = 6.6 Hz, 2H), 2.03 (d, J = 6.9 Hz, 2H), 1.71-1.79 (m, 1H), 1144
1.25-1.48 (m, 3H), 0.98 (s, 3H), 0.96 (d, J = 3.6 Hz, 3H), 0.94 (d, J = 3.6 Hz, 3H). 13C NMR 1145
(100 MHz, CDCl3): δ 143.4, 137.8, 136.2, 116.5, 50.8, 44.9, 44.7, 35.5, 30.0, 27.7, 27.4, 26.1, 1146
21.6, 21.4, 19.0. HRMS m/z: [M+Na]+ calcd for C16H26ONa: 257.1881, found: 257.1893. 1147
rac-Carotol (1) 1148
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To a stirred solution of bis-alkene 24 (40.0 mg, 0.16 mmol) in dry dichloromethane (7 mL) at rt 1149
under argon was added Grubb’s-I catalyst (13 mg, 0.02 mmol) and the mixture was heated to 1150
reflux for 9 h. The reaction mixture was concentrated and the crude residue was purified by silica 1151
gel column chromatography using 1% Et2O in hexanes to afford the desired product 1 as 1152
colorless oil. (24.51 mg, 69%) The spectral data obtained were identical with the literature 1153
reported data (ref. 24). 1H NMR (300 MHz, CDCl3) δ 5.31 (br t, J = 5.7 Hz, 1H, H-9), 2.26 (br 1154
d, J = 13.8 Hz, 1H, H-10a), 2.07 (br t, J = 5.7 Hz, 2H, H-7a,b), 1.90-1.98 (m, 1H, H-6a), 1.76-1155
1.83 (m, 2H, H-4,11), 1.70-1.75 (m, 1H, H-10b), 1.67 (br s, 3H, H-14), 1.44-1.64 (m, 4H), 1.29 1156
(ddd, J = 9.6, 5.7 Hz, 1H, H-2a), 1.14 (br s, 1H, -OH), 0.99 (d, J = 6.6 Hz, 3H, H-13), 0.94 (s, 1157
3H, H-15), 0.93 (d, J = 6.6 Hz, 3H, H-12). 13C NMR (100 MHz, CDCl3) δ 138.7 (C-8), 122.3 1158
(C-9), 84.7 (C-5), 52.7 (C-4), 49.2 (C-1), 39.6 (C-2), 38.8 (C-10), 34.6 (C-6), 29.6 (C-7), 27.7 1159
(C-11), 25.4 (C-14), 24.5 (C-3), 24.2 (C-12), 21.6 (C-13), 21.5 (C-15). IR(neat): ν (cm-1) 3522, 1160
2954, 2926, 1448, 1460, 1374. 1161
t-Butyldimethyl(2-methylbut-3-yn-2-yloxy)silane (66) 1162
To a stirred solution of 2-methyl-3-butyn-2-ol (15.0 g, 178 mmol) in anhydrous DMF (30 mL) at 1163
0 ºC under argon was added a solution of imidazole (30.35 g, 445.8 mmol) in DMF (20 mL) 1164
followed by dropwise addition of solution of t-butyldimethylsilyl chloride (34.94 g, 231.8 mmol) 1165
in DMF (70 mL). The reaction mixture was stirred at rt for 12 h. The mixture was then diluted 1166
with water (1 L) and extracted twice with diethyl ether (400 mL). The combined organic extracts 1167
were washed with 1N HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated) 1168
the crude product was purified by silica gel column chromatography using 1% Et2O in hexanes 1169
to afford the desired product 66 as a colorless liquid. 33.25 g (94%). 1H NMR (300 MHz, 1170
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CDCl3): δ 2.38 (s, 1H), 1.47 (s, 6H), 0.86 (s, 9H), 0.17 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 1171
89.5, 70.8, 66.3, 33.1, 25.9, 25.8, 18.2, -2.7, -2.8. 1172
Alkyne-Diol 67 1173
To a 100 mL rb flask containing anhydrous CeCl3 (3.16 g, 12.8 mmol, weighed in a glove box) 1174
at 0 ºC under argon was added THF (30 mL) and the mixture was stirred at rt for 18 h. In another 1175
flask containing a stirred solution of alkyne 66 (2.38 g, 12.8 mmol) in THF (20 mL) at -78 ºC 1176
under argon, was added dropwise n-BuLi (5.12 mL, 12.8 mmol, 2.5M in hexanes). This reaction 1177
mixture was stirred at 0 ºC for 1.5 h and then transferred slowly using a cannula to the cerium 1178
chloride-THF suspension at 0 ºC. The resulting orange suspension was stirred at 0 ºC for 2 h 1179
when a solution of ketone 42 (0.40 g, 2.17 mmol) in THF (10 mL) was added dropwise at 0 ºC. 1180
The reaction mixture was stirred at 0 ºC for 4 h and then at rt for another 18 h. The reaction 1181
mixture was cooled to 0 ºC, 10% aqueous AcOH (60 mL) was added and aqueous layer was 1182
extracted with diethyl ether (2 x 75 mL). The combined organic extracts were washed with a satd 1183
solution of NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered and evaporated under 1184
reduced pressure. The crude product (2.5 g, dark red oil) was purified by flash chromatography 1185
using ethyl acetate in hexanes (10:90) to afford the desired product 67 as light orange oil. (0.655 1186
g, 79%, corrected yield 87% -based on recovered starting material-hydroxy ketone). 1H NMR 1187
(300 MHz, CDCl3): δ 3.66-3.81 (m, 2H), 1.73-1.93 (m, 4H), 1.49-1.67 (m, 6H), 1.46 (s, 6H), 1188
1.15 (d, J = 6.3Hz, 3H), 1.02 (s, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.86 (s, 9H), 0.17 (s, 6H). 13C 1189
NMR (100 MHz, CDCl3): δ 92.0, 84.4, 80.4, 66.6, 60.4, 54.5, 50.7, 39.8, 33.1, 33.0, 32.5, 30.2, 1190
27.2, 25.8, 22.7, 22.4, 18.2, 18.0, -2.60, -2.62. IR (neat): ν (cm-1) 3610-3160 (br), 2960, 2940, 1191
2854, 1466, 1250, 1090. HRMS m/z: [M+Na]+ calcd for: C22H42O3SiNa : 405.2795, found: 1192
405.2807. 1193
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Saturated diol 68 1194
To a stirred solution of alkyne 67 (0.65 g, 1.69 mmol) in ethyl acetate (25 mL) at rt was added 1195
5% Pd/Al2O3 and the mixture was stirred vigorously under an H2 atmosphere for 5 h. The 1196
reaction mixture was filtered through celite, washed with ethyl acetate (20 mL) and concentrated 1197
under reduced pressure. The crude compound (0.6 g) was purified by silica gel flash column 1198
chromatography using 10% ethyl acetate in hexanes to afford the title compound 68 as colorless 1199
oil. (0.532 g, 81%). 1H NMR (300 MHz, CDCl3): δ 3.66-3.83 (m, 2H), 1.38-1.85 (m, 14H), 1.21 1200
(d, J = 6.9 Hz, 6H), 0.98 (s, 3H), 0.93, 0.97 (dd, J = 6.3 Hz, 6H), 0.86 (s, 9H), 0.08 (s, 6H). 13C 1201
NMR (75 MHz, CDCl3): δ 84.2, 73.6, 60.3, 52.0, 48.4, 38.9, 38.7, 35.5, 32.1, 30.4, 29.6, 28.9, 1202
26.0, 24.4, 23.9, 20.3, 19.9, 18.2, -1.9. IR (neat): ν (cm-1) 3640-3100 (br), 296, 2890, 1390, 1203
1050. HRMS m/z: [M+Na]+ calcd for: C22H46O3SiNa : 409.3108, found: 409.3118. 1204
Alkene 69 1205
To a stirred solution of alcohol compound 68 (0.41 g, 1.06 mmol) in ethyl acetate (15 mL) at rt 1206
was added IBX (0.89 g 3.18 mmol) and the mixture was heated to reflux for 3 h. The reaction 1207
mixture was filtered through celite, washed with ethyl acetate (20 mL), filtrate was concentrated 1208
under reduced pressure to afford the crude aldehyde compound as colorless oil. (0.39 g, 97%). 1209
This crude aldehyde compound was pure enough and was used for next step without purification. 1210
1H NMR (300 MHz, CDCl3): δ 9.82 (t, J = 2.1 Hz, 1H, -CHO), 2.45 (d, J = 2.1 Hz, 2H), 1.98 1211
(bs, 1H, -OH), 1.83, 1.87 (dd, J = 6.6 Hz, 1H), 1.52-1.72 (m, 8H), 1.38-1.49 (m, 1H), 1.19 (d, J = 1212
7.8 Hz, 6H), 1.11 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.84 (s, 9H), 0.07 (s, 1213
6H). 13C NMR (75 MHz, CDCl3): δ 204.0, 83.3, 73.5, 52.2, 51.7, 48.6, 38.6, 36.3, 33.0, 30.4, 1214
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29.7, 28.8, 26.1, 25.9, 24.3, 23.9, 21.0, 20.1, 18.2, -1.89. IR (neat): ν (cm-1) 3409, 2960, 2885, 1215
1477, 1369, 896. HRMS m/z: [M+Na]+ calcd for: C22H44O3SiNa : 407.2952, found: 407.2961. 1216
To a stirred suspension of methyl triphenylphosphonium bromide (0.25 g, 0.70 mmol) in dry 1217
THF (4 mL) at -78 ºC under argon was added dropwise a solution of n-BuLi (0.28 mL, 0.70 1218
mmol, 2.5 M in hexanes) and the light yellow colored suspension was stirred at the same 1219
temperature for 30 min. Then a solution of aldehyde (0.09 g, 0.23 mmol) in THF (3 mL) was 1220
added dropwise. The reaction mixture was stirred at -78 ºC for 30 min and then at rt for 45 min. 1221
0.5N HCl (10 mL) was added slowly to the reaction mixture at 0 ºC and extracted with diethyl 1222
ether (2 x 20 mL). The combined organic extracts were washed with water, brine, dried over 1223
anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified 1224
by silica gel flash column chromatography using 5% ethyl acetate/hexanes to afford the title 1225
compound 69 as colorless oil. (65 mg, 72%). 1H NMR (300 MHz, CDCl3): δ 5.77–5.91 (m, 1H), 1226
4.99–5.05 (m, 2H), 2.01 (d, J = 6.3 Hz, 2H), 1.81-1.91 (m, 1H), 1.36-1.78 (m, 9H), 1.20 (d, 1227
J=4.8 Hz, 6H), 0.93-0.98 (m, 9H), 0.86 (s, 9H), 0.08 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 1228
136.2, 116.9, 84.6, 73.6, 52.7, 49.5, 41.4, 38.9, 34.4, 31.3, 30.3, 29.7, 28.5, 26.0, 24.6, 23.3, 20.3, 1229
20.2, 18.3, -1.8. HRMS m/z: [M+Na]+ calcd for: C23H46O2SiNa : 432.3267, found: 432.3271. 1230
Diene 24 and tetrahydrofuran 70 1231
To a stirred solution of compound 69 (0.34 g, 0.89 mmol) in dry THF (7 mL) at 0 ºC under argon 1232
was added a solution of tetra-n-butylammonium fluoride (0.70 g, 2.67 mmol, 2.67 mL of 1M in 1233
THF) and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with diethyl 1234
ether (20 mL) and washed with water, brine, dried over anhydrous Na2SO4 and concentrated 1235
under reduced pressure. The crude compound was purified by silica gel flash column 1236
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chromatography using 10% ethyl acetate/hexanes to afford the desired alcohol as colorless gum. 1237
(0.231g, 97%). 1H NMR (300 MHz, CDCl3): δ 5.77-5.90 (m, 1H), 5.01-5.06 (m, 2H), 2.02 (d, J 1238
= 7.2 Hz, 2H), 1.82-1.93 (m, 1H), 1.56-1.79 (m, 6H), 1.52 (s, 3H), 1.37-1.48 (m, 2H), 1.23 (d, J 1239
= 1.2 Hz, 6H), 0.98 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 1240
MHz, CDCl3): δ 136.1, 117.1, 84.5, 71.1, 52.9, 49.5, 41.4, 37.4, 34.4, 31.1, 29.8, 29.3, 28.5, 1241
24.5, 23.3, 20.4, 20.3. IR (neat): ν (cm-1) 3690-3110 (br), 2960, 2866, 1370, 1079. HRMS m/z: 1242
[M+Na]+ calcd for: C17H32O2Na : 291.2295, found: 291.2294. 1243
To a stirred solution of the above alcohol compound (40.0 mg, 0.15 mmol) in dichloromethane 1244
(2 mL) at 0 ºC under argon was added a solution of Martin’s sulfurane (200 mg, 0.30 mmol) in 1245
dichloromethane (4 mL) and the mixture was stirred at rt for 45 min. The reaction mixture was 1246
concentrated and the residue was dissolved in diethyl ether (20 mL), washed with brine (10 mL), 1247
dried and concentrated under reduced pressure. The crude compound was purified by silica gel 1248
column chromatography using 1% ethyl acetate/hexanes to afford the diene 24 as colorless oil 1249
(24 mg, 64%) as well as compound 70 (5%). Diene 24 : 1H NMR (300 MHz, CDCl3) δ 5.77-1250
5.91 (m, 1H), 5.01-5.06 (m, 2H), 4.71 (s,2H), 2.15-2.21 (m, 2H), 2.02 (d, J = 7.2 Hz, 2H), 1.82-1251
1.91 (m, 1H), 1.75 (s, 3H), 1.38-1.71(m, 6H), 1.22-1.30 (m, 2H), 0.99 (d, J = 6.9 Hz, 3H), 0.97 1252
(s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 146.9, 136.1, 117.2, 109.7, 1253
84.8, 52.6, 49.5, 41.4, 35.4, 34.5, 32.3, 28.5, 24.5, 23.3, 22.9, 20.3, 20.1. IR(neat): ν (cm-1) 1254
2953, 2880, 1464, 1411, 1134, 992. HRMS m/z: [M+Na]+ calcd for: C17H30ONa : 273.2189, 1255
found: 273.2199. Compound 70 : 1H NMR (300 MHz, CDCl3) δ 5.89–5.75 (m, 1H), 5.03–4.96 1256
(m, 2H), 2.07–2.01 (m, 1H), 1.96–1.88 (m, 3H), 1.84–1.64 (m, 4H), 1.57–1.47 (m, 3H), 1.44–1257
1.33 (m, 1H), 1.30 (s, 3H), 1.22 (s, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H), 0.91 1258
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 136.4, 116.7, 97.9, 81.2, 53.6, 48.6, 42.7, 38.9, 34.0, 1259
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31.3, 29.4, 29.3, 27.2, 25.2, 22.0, 20.9, 20.2. HRMS m/z: [M+Na]+ calcd for: C17H30ONa : 1260
273.2189, found: 273.2194. 1261
Acknowledgements: 1262
We thank the Université de Sherbrooke and the Natural Sciences and Engineering Research 1263
Council (NSERC) of Canada for financial support. 1264
1265
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Figure captions:
Figure 1. Biologically important natural products exhibiting a bicyclo[5.3.0]decane core.
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Figure 2: Conformations of the dialkoxycarbenes and transition states (TS) leading to the
intermediate cyclopropanes.
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