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Studies in asymmetric synthesis: Development of newsynthetic methods for syntheses of natural products.
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Authors Nimkar, Sandeep Krishnaji.
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Studies in asymmetric synthesis: Development of new synthetic methods for syntheses of natural products
Nimkar, San deep Krishnaji, Ph.D.
The University of Arizona, 1993
V·M·I 300 N. Zceb Rd. Ann Arbor, MI 48106
."
STUDIES IN ASYMMETRIC SYNTHESIS: DEVELOPMENT OF
NEW SYNTHETIC METHODS FOR SYNTHESES
OF NATURAL PRODUCTS
by
San deep Krishnaji Nimkar
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF CHEMISTRY
in Partial Fulfillment of the Requirements
For the Degree of
DOCTOR OF PHILOSOPHY
in the Graduate College
THE UNIVERSITY OF ARIZONA
1993
THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE
2
As members of the Final Examination Committee, we certify that we have
read the dissertation prepared by ____ ~S=an=d~e~e~p~~K~r~i~s=h=n~a~j~i~~N=i~m~k~a~r ______ __
entitled ___ S_T_U_D_I_E_S __ I_N __ ~A~S~Y~_lli_E_'T_R~I~C __ S_Y_N_T_H~E~S~I~S~:~D~E~V~E=L~OP~r=rn=N~T~ ______ ___
OF NEH SYNTHETIC METHODS FOR SYNTHESES OF
NATURAL PRODUCTS
and recommend that it be accepted as fulfilling the dissertation
requirement for the Degree of __ ~,~~~~o~c~t~o~r __ ~o_f __ ~P~h=i~l~o=s~op~h~y~ ____________ _
-'-C- a>J J...~J/- . 11/15/93 Mash Date
11115/93 Henry K. Hall Date
11/15/93 James Date
11115/93 Date
11115/93 Remers Date
Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College.
I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation
11/15/93 Mash Date
3
This dissertation is dedicated in the memory of my parents Mrs. Usha
Nimkar and Mr. Krishnaji Nimkar for their inspiration, their warmth and for
their ethics.
4
STATEMENT BY AUTHOR
This dissertation has been submitted ,in partial fulfillment of requirements
for an advanced degree at The University of Arizona and is deposited in the
University Library to be made available to borrowers under rules of the Library.
Brief quotations from this dissertation are allowable without special
permission, provided that accurate acknowledgment of source is made. Requests
for permission for extended quotation from or reproduction of this manuscript in
whole or in part may be granted by the head of the major department or the Dean
of the Graduate College when in his or her judgment the proposed use of the
material is in the interest of scholarship. In all other instances, however,
permission must be obtained from the author.
SIGNED: -$L'~
5
ACKNOWLEDGMENTS
No usual thanks are sufficient to acknowledge my debt to the generous
friends Ziqi Lu, Benjamin Bonner and Victor Pytlewski. Ziqi Lu has been very
helpful inside and outside the laboratory throughout my stay at The University of
Arizona. I thank Benjamin Bonner for not only proof reading this dissertation but
for also being a source of useful discussion!? on my research. I am thankful to my
friend Victor pytlewski who made the graduate school experience, a pleasant and
a memorable one.
I am also very grateful to my parents Usha Nimkar and Krishnaji Nimkar
for their inspiration. I could not have achieved my goals without their support and
sacrifice. My gratitude to Professor Eugene Mash is also far ranging. He is
responsible for most of my achievements at The University of Arizona. He will
remain my friend, a mentor, a generous supporter and a model of a research
director who pays close attention toward student's progress.
Most of all, I am grateful to my wife Kalpana for her valuable suggestions
and constructive criticism which has helped me grow personally and
professionally. I am fortunate to share my life with her. She has been a constant
source of support during good and bad times.
6
TABLE OF CONTENTS
SECTION PAGE
LIST OF FIGURES 9
LIST OF TABLES 12
CHAPTER 1. SYNTHESES AND REACTIONS OF
CHIRAL ACET ALS
1.1 Introduction....... ................................................ 15
1 .2 The Noe Acetal................................................. 16 1.3 Development of Chiral Acetals......................... 20 1.4 Synthesis of Bicyclic and Tricyclic Acetals....... 23 1.5 Resolution of Racemic a-Hydroxy
Esters Using Chiral Acetal 43......................... 26 1.6 Resolution fo Racemic a-Phenethyl alcohol 50 29
1.7 Reaction of Chiral Acetal 43 with Methyl
Glycolate and trans-Crotyl Alcohol.. ............... 29
1.8 Cyclopropanation of Acetal 55...... .......... ......... 31 1 .9 Alkylation of Acetal 44...................................... 32 1 .10 Comparison of Chiral Acetal 43 with
Noe Acetal 19....................................... ............ 32 1 .11 X-ray Crystal Structure of the More Polar
Diastereomer of (R)-Pantolactone Acetal 42... 33 1.12 Conclusion...................................................... 35
7
CHAPTER 2. METHODOLOGIES FOR THE SYNTHESIS
OF THE 4-ETHYLAMINO SUGAR OF THE
CALICHEAMICINS AND ESPERAMICINS 2.1 Calicheamicins and Esperamicins .................... 37 2.2 Synthesis of the 4-Ethylamino Sugar from
Noncarbohydrate Precursors .......................... 39 2.3 Nicolaou's Approach to the Calicheamicin 4
4-Ethylamino Sugars 59a and 5gb ................. 40 2.4 Golik's Approach to the Esperamicin
4-lsopropylamino Sugar Derivative 86 ............ 42 2.5 Retrosynthesis of an Approach to the
Calicheamicin 4-Ethylamino Sugar Using Chromatographically Resolved Pyranosides .. 44
2.6 Approach to the 4-Ethylamino Sugar Using Chromatographically Resolved Pyranosides .. 46
2.7 Cyclic Sulfates .................................................. 49 2.8 Sharpless' Synthesis of 1,2 Cyclic Sulfates
from 1 ,2 Diols .................................................. 51 2.9 Application of Cyclic Sulfate Chemistry for
Manipulations of Sugars ................................. 53 2.10 Approach to the Calicheamicin 4-Ethylamino
Sugar Using a Cyclic Sulfate .......................... 55 2.11 Stannylene Acetal Intermediates ...................... 57 2.12 Regioselective Benzylation of a
Sugar Derivative ............................................. 58 2.13 Synthesis of the Calicheamicin 4-Ethylamino
Sugar Derivative 59a ...................................... 59 2.14 Synthesis of Methylamino Sugar Derivative136 63 2.15 Conclusion ........................................................ 64
8
SECTION
CHAPTER 3.
PAGE
DIASTEREOSELECTIVE RING
MANIPULATIONS OF COMMON RING
CARBOCYCLES 3.1 Introduction to Diastereoselectivity in the
Simmons-Smith Cyclopropanation.... ............. 66 3.2 Nucleophilic Additions to
Bicyclo[n.1.0]alkan-2-ones.... ............ ............. 67 3.3 Preparation of Bicyclo[5.1.0]oct-3-en-2-one..... 70 3.4 Conjugate Additions to
Bicyclo[5.1.0]oct-3-en-2-one................ .......... 71 3.5 Preparation of Bicyclo[5.1.0]octan-2-one.......... 72 3.6 Alkylations of Bicyclo[5.1.0]octan-2-one........... 73 3.7 Conclusion........................................................ 75
EXPERIMENTAL.................................................................... 76
APPENDiX..... ......................... ............ .............................. ..... 106
REFERENCES....................................................................... 185
9
LIST OF FIGURES
FIGURE PAGE
Figure 1. Reactions of DHP and DHF with Achiral Alcohols... 15
Figure 2. Reactions of DHP and DHF with Chiral Alcohols..... 16
Figure 3. Synthesis of the Noe Acetal 19................................ 17
Figure 4. Steric Effects on Transacetalization Reactions of
Substituted THP and THF Ethers...... ...... ............. 20
Figure 5. Stereoelectronic Effects on Transacetalization
Reactions of Substituted THF Ethers............ ....... 21
Figure 6. Resolution of Furanoside 29 using
Methyl (S) -(-)Lactate........................................... 22
Figure 7. Synthesis of Bicyclic Lactone 34............................. 23
Figure 8. Synthesis of Tricyclic Acetal 38...... .......... ......... ..... 24
Figure 9. Preparation of Furanoside 43.................................. 26
Figure 10. Resolution of Racemic a-Phenethyl Alcohol 50...... 29
Figure 11. Transacetalization Reactions of trans-Cratyl
Alcohol and Methyl Glycolate......... ........ ............... 30
Figure 12. Cyclopropanation of Acetal 55..... ............................. 31
Figure 13. Alkylation of Acetal 44...... ........ .................. ......... ...... 32
Figure 14. X-ray Crystal Structure of Acetal 41.......................... 34
Figure 15. Structure of Calicheamicin y 11.................................... 37
Figure 16. Amino Sugars of Calicheamicins and
Esperamicins .............. ,. ............ .................... ... ..... .... 38
10
LIST OF FIGURES (Cont)
FIGURE PAGE
Figure 17. Kahne's Approach to the Synthesis of
the Calicheamicin 4-Ethylamino Sugar
Derivative 60....................................................... 39
Figure 18. Nicolaou's Approach to the Synthesis of
the Calicheamicin 4-Ethylamino Sugar
Derivatives 59a and 59b..................................... 41
FIGURE 19. Golik's Approach to the Synthesis of the
Esperamicin 4-lsopropylamino Sugar
Derivative 86....................................................... 43
Figure 20. Retrosynthetic Analysis of an Approach to
the Synthesis of the Calicheamicin
4-Ethylamino Sugar Using
Chromatographically Separable Pyranosides.... 45
Figure 21. Approach to the Synthesis of the Calicheamicin
4-Ethylamino Sugar Using
Chromatographically Separable Pyranosides .... 47
Figure 22. Cyclic Sulfate of Ethylene Glycol ........................... 50
Figure 23. Nucleophilic Additions to Cyclic Sulfates ............... 52
Figure 24. Preparation of Fluoro-substituted Sugars 112 ....... 53
Figure 25. Nucleophilic Addition of Fluoride to
Cyclic Sulfate Derivative 115 .............................. 54
11
LIST OF FIGURES (Cant)
FIGURE PAGE
Figure 26. Approach to the Calicheamicin 4-Ethylamino
Sugar Using Cyclic Sulfate 117 ....................... 55
Figure 27. Possible Conformations of Cyclic Sulfate 117 .... 56
Figure 28. Alkylation of Stannylene Ketal 119 ..................... 57
Figure 29. Alkylation of Stannylene Ketal 122 ..................... 58
Figure 30. Stereoconvergent Synthesis of the 4-Ethylamino
Sugar of Calicheamicins and Esperamicins .... 61
Figure 31. Synthesis of the 4-Methylamino Sugar of
the Calicheamicins and Esperamicins ............... 63
Figure 32. Diastereoselective Simmons-Smith
Cyclopropanation ................................................ 66
Figure 33. Conjugate Additions and Alkylations of
Bicyclo[n.1.0jalkan-2-one Derivatives ................ 69
Figure 34. Preparation of Bicyclo[5.1 .Ojoct-3-en-2-one 152 ... 70
Figure 35. Conjugate Addition of Phenyl Cup rate to
Bicyclo[5.1.0joct-3-en-2-one 152 ......................... 71
Figure 36. Conjugate Addition of Methyl Cuprate to
Bicyclo[5.1.0joct-3-en-2-one 152 ......................... 72
Figure 37. Preparation of Bicyclo[5.1.0joctan-2-one 155 ........ 72
Figure 38. Alkylations of Bicyclo[5.1.0joctan-2-one 155 .......... 74
TABLE
Table 1.
Table 2.
Table 3.
Table 4.
Table 5.
12
LIST OF TABLES
PAGE
Resolutions of Racemic Mixtures Using Noe's
Acetal 19 .............. ".............................................. 18
Resolution of Racemic AcetaI3S............................ 25
Resolution of a-Hydroxy Esters Using Acetal
43a or 43b............................................................... 28
Preparation of Cyclic Sulfates from 1,2 Diols.......... 51
Nucleophilic Additions to
Bicyclo[n.1.0]alkan-2-ones .. " .. ".... ........................ 68
13
ABSTRACT
The research, to be discussed in three chapters, involves the development
of new synthetic methods which are applicable to the total synthesis of many
natural products.
Chapter 1 : As a part of a program to syntllesize new auxiliary agents for
asymmetric synthesis, we have prepared a structurally rigid acetal from
norbornene in three chemical steps. This enantiomerically pure acetal has been
used for resolution of racemic a-hydroxy esters and might be applied as a chiral
auxiliary for diastereoselective reactions.
Chapter 2 : The Calicheamicin and Esperamicin antibiotics have shown
remarkable biological activity as site-specific cleaving agents of double stranded
DNA. The oligosaccharide portion of these molecules plays an important role in
the site specificity. We have developed synthetic methodologies that allow
synthesis of the deoxyaminosugar components of these antibiotics and can be
extended to synthesize unnatural amino sugars for structure-activity studies.
Chapter 3 : Enantiomerically pure cyclopropyl ketones, which are available
via chiral ketals, are very useful for syntheses and diastereoselective
manipulations of common and large rings. This method has been extended to
introduce up to four contiguous chiral centers in a common ring. This extension
could be useful for the syntheses of complex natural products.
14
CHAPTER 1. SYNTHESES AND REACTIONS OF CHIRAL ACETALS
15
1.1 Introduction
Chiral auxiliaries are often used for stereoselective reactions and for
resolving racemic compounds which can give access to optically active materials.
A good auxiliary must be stable, easily prepared, and must control the
stereochemical outcome of the reaction of interest. The development of
auxiliaries derived from tetrahydrofuranyl a~d tetrahydropyranyl ethers would be
of interest.
The reaction of an achiral alcohol with 2,3-dihydropyran 1 (DHP) or 2,3-
dihydrofuran 4 (DHF) in the presence of an acid catalyst forms a pair of
enantiomers (Figure 1). Since enantiomers have identical physical properties,
they are not separable by simple chromatography or partial crystallization.
Figure 1. Reactions of DHP and DHF with Achiral Alcohols
0 + R-OH .. 0" + OOR 0 OR
1 2 3
0 + R-OH .. Q.,~ + OOR 0 OR
4 5 6
16
However, if an enantiomerically pure alcohol is similarly reacted with 2,3-
DHP or 2,3-DHF, then a pair of diastereomers is formed (Figure 2). It is
sometimes possible to separate diastereomers by simple chromatography or
fractional crystallization.
Figure 2. Reactions of DHP and DHF with Chiral Alcohols
o o 1
+ R*-OH ,... 0· .. + OOR' OR 7 8
,.. Q,~ . + VOR' OR
o o + * R-OH
4 9 10
1.2 The Noe-Acetal
Christian Noe has published a series of articles on the synthesis and
applications of chiral acetals.1-1o The synthesis of one such acetal, 19, is shown
in Figure 3. This synthesis, from d-camphor 12, is lengthy and inefficient, the
overall yield being less than 25%.
17
Figure 3 . Synthesis of the Noe Acetal 19
Me Me
MeOH/KOH COOMe ~ COOH
Me 12
o Me 0 Me 0 13 14
Me Me Me Me
--_oX-· H Hel
1) NaHBH4 ~H NaCN ------~~ ~ ~H2CN--""
Me OH 2) TsCI/Py CH20Ts Me OH
16 (56%)
Me Me
HCI DIBAL -------.,. o
17 (99%) 18 (80%) 19 (91%)
Noe has reported alternative syntheses of this acetal, however all those
syntheses led to the chiral acetal 19 in lower overall yield. Chiral acetal 19 has
been used to resolve a variety of racemic mixtures of alcohols and thiols . A few
examples are listed in Table 1.
Table 1 . Resolution of Racemic Mixtures Using Noe's Acetal 19
o
19 ~ __________ ~ ________ ~
21 22
1
X H
HX ~
Entry R1 R2 X
20a-228 CH3 CsHS 0
20b-22b ~s CsHS 0
20c-22c -(CH2)3- -CSH4- 0
20d-22d CH3 CsHS S
18
19
The diastereomeric derivatives 21 a-d and 22a-d were separated by
column chromatography or partial crystallization. Subsequent methanolysis yields
the enantiomers and recovered chiral auxiliary.
There are several disadvantages to use of the Noe acetal 19. Although
commercially available (Aldrich Chemical Company), the Noe acetal 19 is very
expensive. The best synthesis of the Noe acetal 19 involves 8 steps starting from
camphor with an overall yield of less than 25%. If both enantiomers of the acetal
are desired, the synthesis must be repeated using both enantiomers of camphor.
All these facts make acetal 19 less attractive for practical use.
Although the Noe acetal 19 had some problems associated with it, it did
show use as a powerful auxiliary for resolution of racemic mixtures. If a chiral
acetal could be disigned which overcomes these problems, it might be not only a
powerful auxiliary for resolution, but may also prove to be useful in asymmetric
synthesis. We chose to attempt the development of a new chiral acetal which can
be easily prepared from commercially available and inexpensive starting
materials.
20
1.3 Development of Chiral Acetals
An important aspect in the development of a chiral acetal involves
controlling the stereochemistry at the anomeric center during acetal exchange
reactions. In the quest to develop new chiral acetal auxiliaries, the Mash group
has studied a variety of substituted THP and THF acetals.11 In order to establish
control over the stereochemistry at the anomeric center, one can introduce
sterically bulky substituents at key positions on tile THF or THP ring, thereby
controlling the approach of nucleophiles to the anomeric oxonium ion center. For
example, t~e acetals 23 and 25 have a bulky substituent at the C5 and C4
respectively.
Figure 4 . Steric Effects on the Transacetalization Reactions of Substituted THP and THF Ethers
o q" H
X C H:3 Me COi'/le
25 26
21
Unfortunately reactions of such substituted THP and THF ethers with
methyl (S)-(-)-Iactate resulted in a mixture of all possible cis and trans isomers
(Figure 4). These results indicated that use of sterically bulky substituents located
on neighboring carbons of monocyclic acetals was not sufficient for control of the
anomeric stereochemistry. At this point it was decided to test if stereoelctronic
control in THP and THF acetals could achieve better results than steric control.
Figure 5 . Stereoelectronic Effects on the Transacetalization Reactions of Substituted THF Ethers
OMe
28
Figure 5 shows acetal exchange between acetal auxiliary 27 and methyl
(S)-(-)-Iactate. This reaction gave all possible cis and trans isomers. However,
although acetal 27 showed poor results with 2-methoxy benzene substituent at
C4, other positions might show better results. Figure 6 shows the reaction of an
acetal containing a benzyloxy group at C2 with methyl (S)-
(-)-Iactate. The results for this benzyloxy acetal 29 were much more promising
22
Figure 6 . Resolution of Furanoside 29 Using Methyl (S)-(-)-Lactate
The reaction shown in Figure 6 led to only two diastereomers, 30 and 31.
These diastereomers were separable by column chromatography.12 The
benzyloxy group at C2 probably participates with the carbocation intermediate
formed during the transacetalization reaction, and as a result the nucleophile
attacks from the face opposite to that bearing the benzyloxy group. This would
explain the formation of only trans diastereomers 30 and 31. One of the
separated diastereomers 30 was converted to the methyl acetal 32. This acetal
was used to resolve racemic mixtures of ex-hydroxy esters. Although this acetal
was very useful for resolving these racemic mixture~, it was rather unstable to
acidic conditions and partially decomposed to give furan and benzyl alcohol,
which reduced the yield of the separated
isomers.
23
1.4 Synthesis of Bicyclic and Tricyclic Acetals
The studies of the exchange reactions of several monocyclic acetals
showed promising but unacceptable results. It was decided to study furanosides
that are more biased toward anomeric stereocontrol and are more acid stable.
Figure 7 . Synthesis of Bicyclic Lactone 34
o Mn(OAc)3iCHsCOOH -----.,.. KOAc/reflux
33 34
The first furanoside examined was bicyclic lactone 34. This lactone was
made in one step from cyclopentene 33 (Figure 7). The reaction gave very poor
yields (10-15%) which made the acetal 34 a poor candidate for further
development. The volatility of cyclopentene could have been a problem in the
above reaction, since refluxing acetic acid is employed.
Since oxidation of cyclopentene had given problems, it was decided to use
a higher boiling cycloalkene. Commercially available norbornene 35 was a logical
candidate. The reaction to give the tricyclic acetal 36 was attempted under
identical conditions as before (Figure 8).
24
Figure 8 • Synthesis of Tricyclic Acetal 37
KOAc/reflux
35
37 (90%)
The reaction of norbornene 35 with Mn (III) acetate in acetic acid gave
exclusively exo lactone 36.12 Reduction of the lactone 36 gave hemiacetal 37.
Racemic acetal 37 was then resolved by conversion to mixed acetals of methyl
(S)-(-)-Iactate 39 and 40 or (R)-(+)-pantolactone 41 and 42 followed by
chromatography or fractional crystallization to separate the resulting
diastereomers. Table 2 lists the a values of the diastereomers. The a value is the
ratio of Rf values of the two diastereomers on analytical silica gel TLC plates. The
greater the a value, the easier the separation. It is important to note that these
reactions proved that acetals of this type show complete control of
stereochemistry at the anomeric center, evidenced by the fact that the reaction
led to only one pair of diastereomers.
25
Diastereomers 41 and 42 were not only easy to separate by column
chromatography (shown by their higher a value). but also could be separated by
fractional crystallization using hexanes as a solvent.
37
R*OH
0
HO~O Me
Me
Table 2 . Aesolution of Aacemic Acetal 37
OH * .r R-OHfTsOH ... 4 A molecular
* OR + * OR
sieves/CH 2CI2/AT • 41 (A = Pantolactone) 42 (A* = Pantolactone)
Chromatographically separable
Diastereomers ex OJoYield for OJoYield for
L~~~ PQlar More Polar
DiastereQmer Diastereomer
41 and 42 1.14 37 40
26
Although most of the exchange reactions for the tricyclic acetal were
performed using the methyl acetal 43a or 43b, the exchange reaction using
acetal 41 or 42 works quite as well. The methyl acetals 43a and 43b were formed
in an exchange reaction with pantolactone acetals 41 or 42. Each enantiomer of
acetal 43a and 43b was synthesized in 21 % and 14% overall yield respectively
over three steps from commercially available, inexpensive norbornene.
Figure 9 . Preparation of Methyl Furanoside 43a and 43b
42
o 0' Me TsOHf4 AO mol.sieves ~ + CH30H CH CI fRT ..... O~~Me 2 2
o
41
o , Me TsOHf4 AO mol.sieves ~ + CH30H CH CI fRT ..... O~~Me 2 2
o
1.5 Resolution of Racemic a-Hydroxy Esters Using
Chiral Acetal 43a or 43b
OCI-I:3
43a (100%)
OCI-I:3
43b (100%)
Chiral acetal 43a or 43b was used to resolve racemic mixtures of a-
hydroxy esters (Table 3). The transacetalization reactions of chiral acetal 43a or
43b with racemic methyl lactate, ethyl a-hydroxycaproate, and
27
methyl ex-hydroxydodecanoate proceeded in good yields and the product
diastereomers were separable by column chromatography. It is interesting to
note that as the number of carbon atoms of the ex-hydroxy ester chain increases,
the separation of the diastereomeric pair also increases. The separated acetals
44 to 49 are diastereomerically pure as shown by NMR.
28
Table 3 . Aesolution of a-Hydroxy Esters Using
Acetal 43a or 43b
OCHs
43a or43b
°XC02Me
~ + ~
H R
44 [A = CHs1
46 [A = (C~)2CH31
48 [A = (C~)9CH3]
R Dia~t~r~Qmer~ a
CH3 44 and 45 1.02
CH3(CH2)3 46 and 47 1.12
CH3(CH2)g 48 and 49 1.21
45
47
49
TsOH/4 A mol.siev~ CH2CI2/AT
°Xco2Me R H
[A = CHs1
[A = (C~)2CH31
[A = (C!i2)gCH31
OfoVi~lg Qf OfoVielg of
More Polar Less Polar
Diaslereomer Di~stereomer
31 39
28 38
28 50
29
1.6 Resolution of Racemic ex-Phenethyl Alcohol 50
Chiral acetal 43b was also used to resolve a racemic mixture of ex
phenethyl alcohols. The diastereomers 51 and 52 were easily separated (ex=1.4)
by column chromatography (Figure 10). The yield of the less polar diastereomer
was 54% , while the more polar diastereomer was isolated in 21 % yield.
Figure 10 . Resolution of Racemic ex-Phenethyl Alcohol 50
TsOH/4 A mol,sieves +
43b
,fJ~ o ~
. + ~
H CHs 51
1.7 Reaction of Chiral Acetal 43 with Methyl Glycolate
and trans-Crotyl Alcohol.
...
Chiral acetal 43 was reacted with methyl glycolate and trcms-crotyl alcohol
in the presence of an acid catalyst (Figure 11). The methyl glycolate acetal 56
was prepared to study the diastereoselectivity in the alkylation reaction at the ex
hydroxy ester appendage in hopes that the stereochemical course of this
alkylation would be controlled by the chirality at the anomeric
30
center. Previous reactions with simple enantiomerically pure THP acetals had
shown that such control could be accomplished.22
Trans -Crotyl acetal 55 (Figure '11) was prepared in order to determine if
diastereoselective control in reactions could be afforded by the stereochemistry
at the anomeric center. For this acetal, 55, the reaction of interest would be a
cyclopropanation of the double bond. The tr~ns acetalization reaction of acetal 43
with trans-crotyl alcohol and methyl glycolate led to the acetals 55 and 56 in 99%
and 72% yields respectively.
Figure 11 . Transacetalization Reactions of trans-Crotyl Alcohol and Methyl Glycolate
1 ~9 + Cl.:CJ -~ HOX R TsOH/4 A mol.sieves ...
H H CH2CI2/RT
42 Me~O MILd
53 R = CH=C(H)CH3 54 R=C~Me
°xR
H H 55 R = CH=C(H)CH3 56 R=C~Me
I ..
31
1.8 Cyclopropanation of Acetal 55
The cyclopropanation of acetal 55 with diethyl zinc in the presence of
diiodomethane13 gave an inseparable mixture of cyclopropanes 57a and 57b.
The diastereoselectivity in this reaction was 3:1. The observed
diastereoselectivity could be explained by chelation of Zn to the acetal oxygens
followed by preferential delivery of diiodomethane to one face of the double bond.
Figure 12 . Cyclopropanation of Acetal 55
o~ o~ Me
55 57a + 57b
32
1.9 Alkylation of Acetal 44
Figure 13 . Alkylation of Acetal 56
o 1. LDA O~ ,.. 2. CH3(CH~91 H COOMe
o o * (CHVgCH3
H COOMe
56 H
48 and 49
The alkylation of acetal 56 with 1-lododecane gavs a 1:1 mixture of
diastereomers 48 and 49 (Figure 13). It is important to note that under similar
conditions chiral acetal 30 exhibited some diastereoselectivity.
Although there was no diastereoselectivity in this alkylation, it may be
possible to modify the structure of chiral acetal 43 so that diastereoselective
reactions can occur. Such modifications are possible since the synthetic
approach to acetal 43 is general and can be applied to prepare a wide array of
chiral acetals.
1.10 Comparison of Chiral Acetal 43 with Noe Acetal 19
The enantiomers of the chiral acetal 43 were simultaneously prepared in
21 % and 14% overall yield respectively over four steps from commercially
available and inexpensive starting material norbornene. This short synthetic
scheme could provide access to a wide variety of chiral acetals. On the other
hand the Noe acetal 19 prepared in less than 25%
33
overall yield over 10 steps starting from commercially available (+)-camphor.
However in order to prepare the enantiomer of 19, identical chemistry must be
performed on (-)-camphor, making production of both enantiomers a total of 20
steps.
Both acetals 19 and 43 are useful for resolutions of <x-phenethyl alcohols
and <x-hydroxy esters. However neither acetal has been successfully employed in
asymmetric synthesis.
1.11 X-ray Crystal Structure of the More Polar Diastereomer of
(R) -pantolactone Acetal 42
In order to establish the absolute stereochemistry of the acetal, crystals of
42 were grown from a hexanes solution and an X-ray structure (Figure 14) was
obtained,78 The more polar diastereomer of (R)-pantolactone acetal 42 was
crystalline and it's structure confirmed that the five membered ring is fused exo to
the norbornane skeleton and that the anomeric center has the "s" absolute
stereochemistry .
34
Figure 14 : X-ray Crystal Structure of 42
35
1.12 Conclusion:
Chiral acetal 43a or 43b were easily prepared from commercially
available, inexpensive norbornene. The synthesis is much more efficient and
versatile than that of Noe acetal 19. The acetal 43a or 43b are useful for
resolution of a-hydroxy esters and a-phenethylalcohols. Although there was little
diastereoselectivity in the alkylation and cyclopropanation reactions attempted,
the general synthesis of the acetal auxiliary 43a or 43b could allow the production
of a wide array of such acetals which might better influence the stereochemical
course of such reactions.
36
CHAPTER 2. METHODOLOGIES FOR THE SYNTHESIS OF THE
4-ETHYLAMINO SUGAR OF THE
CALICHEAMICINS AND ESPERAMICINS
37
2.1 Calicheamicins and Esperamicins
Calicheamicins and Esperamicins are potent antitumor antibiotics that
cleave DNA site specifically.14.15 The structures of Calicheamicins and
Esperamicins are closely related. Depicted in Figure 15 is the structure of one of
the Calicheamicins.
The mechanism of the DNA cleavage involves thiol-mediated Bergman
type cyclization, producing a phenylene diradical which abstracts hydrogen
Figure 15 . Structure of Calicheamicin Y1'
MeSSS H .
Me 0 H Me .:. 'AX: Me 0 O-N~O\./O ~I S~ HO~ o ~ OMe OH 0
Mer-0,) OMe 7 - oj HO~ Et/N~
OMe OH OMe
atoms from the backbone of DNA.16·22 The oligosaccharide portion of this
molecule is responsible for the site specificity14,23.24 of this cleavage and the
amino sugar of these antibiotics is believed to be responsible for anchoring the
molecule on the DNA strand. The structures of some of the targeted amino
sugars of calicheamicins and esperamicins are shown in Figure 16. The
importance of the amino sugar to bioactivity, along with the possible use
38
of unnatural analogs for structure-activity studies, make them good targets for
synthesis.
Figure 16 . Amino Sugars of Calicheamicins and Esperamicins
Rl~ I 0 ,/N R3
Et OMe
R1 fu 59a H OMe
59b H H 60 Ac H
fu H OMe
OMe
H I r-o-J\ IN~OCH3
Me OMe
61
OCH3
~ -0) /N~
Me OMe
62
86
We were interested in developing an efficient total synthesis of 4-
ethylamino sugars 59a and 59b from a carbohydrate precursor like 2-deoxy-D
ribose.
39
2.2 Synthesis of the 4-Ethylamino Sugar from Noncarbohydrate
Precursors
Professor Daniel Kahne has published a synthesis of the Calicheamicin 4-
ethylamino sugar derivative 60 from L-serine derivative 63 (Figure 17).25 This
route is patterned on the work of Danishefsky and Garner for the construction of
1,2 amino alcohols.26·28
Figure 17 • Kahne's Approach to the Synthesis of the Calicheamicin 4-Ethylamino Sugar Derivative 60
r-R o N·Boc X 65 (75%)
r-(CHO
o N-Boc + x,' ~ "
OMe
) ZnCI2~ OSiCH3
63 64 (84%)
OH CO~HJ OCH:3
1. NaI04-Ru04(Cat)/CCI4 "/ 1. CH 30Tf " ~CHO 2. K2C03/MeOH 0 .. _""" 2,6 di-tert-butyl- n . _...., 3. 1 N HCI ~ 0yN-BOC 4-methyl pyridine ~ 0yN-BOC
4. CH2N2 .S' , 2. DIBAL .s' " 66 (77%) 67 (80%)
OCH3
1.TsOH/MeOH/ZnCI2 0) 2. A~O (Ae)HN~ EtIIKOH ---=------~ OCH3 ..
OCH3
C~CH:3 I 0 Ae-N
OCH3
68 (67%) 60 (84%)
40
Most of the steps in this synthesis of the 4-ethylamino sugar give high
yields, however the synthesis is quite long. The overall yield is 22% over 11
steps. The methodology could be used to prepare unnatural analogs of the 4-
ethylamino sugar, since the N-ethyl group is introduced in the last step.
2.3 Nicolaou's Approach to the Calich~amicin 4-Ethylamino
Sugars 59a and 59b
Nicolaou has also synthesized the Calicheamicin 4-ethylamino sugar
derivatives·59a and 59b from L-serine methyl ester hydrochloride (Figure 18).29
The overall yield for this synthesis is 14 % over 10 steps.
Since the N-alkylation is done in the very first step, the synthesis is not as
useful for construction of unnatural N-acetylated analogs of the 4-ethylamino
sugar.
41
Figure 18 . Nicolaou's Approach to the Synthesis of the Calicheamicin 4-Ethylamino Sugar Derivatives 59a and 59b
HO Et3N/MeOH HO 0
+~ MeCHO/NaBH4~ ~CarbOnYldiimidazole ~o=<~ H3N CO~e Et"~ C02Me I C02Me
H Et 69 70 (66%) 71 (64%)
(-) ~·methoxydi-
o isopinocampheylborane -.JO~ DIBAL O=< \ Allyl magnesium bromide O~
... 7-1HO .. 7 ~ I B B OH
72 (75%) o
Ag20IMei o=< .... N
I Et OMs
74 (92%)
o MeOH O=< \ H Amberlyst N~ -----I ... ~ I .,::" MeO OMs
Et OMe
76 (85%)
73 (75%)
OMe 0
75 (88%) HO
H
NaOH + 'I MeOH/H20 HN~H
.... I .,:: MeO OM Et OMe e
77 (96%)
OMe E~ReCrystallzation Et OMe Et
HCIIMeOH H~ 0 from EtOAc I [ ___ j H~ r-o'1\ ___ --I .... ~ ~ HN~ + ~ OMe
MaO MeO MeO
59a + 59b (88%) 59a 59b
42
2.4 Golik's Approach to the Esperamicin 4-lsopropylamino Sugar
Derivative 86
Golik was the first one to report the synthesis of isopropylamino sugar 86
from a carbohydrate precursor.30 The synthesis was carried out to determine the
absolute configuration of the 4-isopropyl amino sugar subunit of the trisaccharide
of Esperamicin A1. This sugar component was synthesized from methyl 2-deoxy-
a-D-ribopyranoside 78 (Figure 19).
Most of the steps in Golik's synthesis of the 4-isopropylamino sugar
derivative 86 were low yielding. The overall yield is only 0.39% over 8 steps.
However, it is important to note that this synthesis established the absolute
configuration of 4-isopropylamino sugar as 3S, 4S.
l
43
Figure 19 . Golik's Approach to the Synthesis of the Esperamicin 4-lsopropylamino Sugar Derivative 86
OH
78
Me Me Me Me
MeO OMe 0 0
--"'---~ 0 0 .... 0 0
OH HO Me-S-C
OMe g OMe
79 (80%) 80 (70%)
Me'J(Me
BU3SnH I 0 HCI ---------~~~ o~ .. HO~
81 (69%) OMe
OH
OMe 82 (50%)
MellAg20 e 0 Diethyl azodicarboxylate MeO M O~ Phthalimide/Ph 3P Phth N ~
----------~ ~
84 (36%) OMe 83 (36%) OMe
Me
Me2C=O Me-( l 0 N2H4 H~~\ NaBH3CN N~\ --..... ~ MeQ-- l .... MeO-- l
85 (36%) OMe 86 (43%) OMe
Me
p-BrPhNCO ~-(N~ ~ jMeo---l
p-8rPhHN OMe 87 (51%)
44
We were interested in developing a general and efficient synthesis of the
amino sugars of the Calicheamicins and the Esperamicins from carbohydrate
precursors that would allow syntheses of multigram quantities. The syntheses
reported above suffer from one or more of the following shortcomings: Excessive
length, poor regioselectivity, minimal flexibility, low overall yield.
In the hope of developing a more compact, yet versatile and efficient
synthesis, several approaches to amino sugars were studied. These approaches
were designed to lead to natural and unnatural analogs of the calicheamicin and
esperamicin amino sugars. These approaches are outlined below.
2.5 Retrosynthesis of an Approach to the Calicheamicin 4-Ethylamino
Sugar Using Chromatographically Resolved pyranosides
Mash group has previously used chromatographically resolved
pyranosides for natural product syntheses31 and had hoped to exploit this
methodology for the synthesis of the Calicheamicin 4-ethylamino sugar. Using a
direct disconnection approach, 4-ethylamino sugar derivatives might be prepared
via regioselective nucleophilic attack at C4 of cis-epoxide (Figure 20). This
epoxide may come from chelation controlled epoxidation of an enantiomerically
pure 3,6-dihydro-2H-pyranoside derived from an
enantiomerically pure a-hydroxy ester and the known racemic dihyropyranoside.
Although this approach appears very straightforward, all
45
attempts at acetal exchange between the racemic dihydropyranoside and methyl
(S)-(-)-Iactate were unsuccessful due to the instability of such
dihydropyranosides.
Figure 20 . Retrosynthetic Analysis of an Approach to the Synthesis of the Calicheamicin 4-Ethylamino Sugar Using Chromatographically Separable Pyranosides
Et OMe
AcJ""'Q o OMe
~ > l_A
o 0YOH
H R
--~> 0 --....loo,> 00
OMe
o O)('OH
H R
46
2.6 Approach to the 4-Ethylamino Sugar Using Chromatographically
Resolved Pyranosides
A synthesis of the 4-ethylamino sugar of the Calicheamicins and
Esperamicins was approached from dihydropyran31 8 (Figure 21). An
alkoxyselenation-elimination sequence involving 3,4-dihydro-2H-pyran and
methyl (S)-(+)-mandelate provided diastereomeric alkenes 89 and 90 which were
separable by column chromatography. The separated alkene 89 was then
subjected to LiAIH4 reduction to reduce the ester to alcohol 91. The chelation
controlled epoxidation of this alcohol using m-CPBA produced a 9:1 mixture of
chromatographically separable pyranosides 92 and 93. Treatment of the cis
diastereomer 92 with aqueous ethylamine followed by acetylation yielded
crystalline acetates 94 and 95 in 1:6 ratio in quantitative yield. These
diastereomers were easy to separate by column chromatography. However, the
identities of the regioisomers were not known. The major diastereomer 95 was
converted to amino sugar 99 by the sequence of reactions shown in Figure 21.
47
Figure 21 . Approach to the Synthesis of the Calicheamicin 4-Ethylamino Sugar Using Chromatographically Separable Pyranosides
o o
1.PhSeBr rJ 0 2. methyl (S)-(+)-mandelate ~~~~~----~~~ ~
3. H20 2 0 0 CO 2Me 0 O'-y'CO 2Me
1 89 (31%) ~Ph 90 (34%) H #-;'Ph
1. Separate 2. LiAIH4 (96%)
rJOX
OH mCPBA(96%) dO o ~ OH
91 ~ 0 0, j
o ,,\-
0- 1. Separate OH use 92 (major)
o 2. EtNH2 . ax ~ H Ph n
93 ~ 3. AC20 92 H Ph H Ph
9 : 1 Et
AcO Et '.N Ac 1 . Separate and Et _
6: N' A C(:' OAc use 95 (major) f:J Ac ,'\ C 2. NaOMe :' OMe
OH OH 3. NaHlMei D o 0.. j (1 00%) 0 ~ 4. BF3-Et2cr- HO S S
94 H ~h 95 H 'Ph 1,3 propanedhhiol V 1 : 6
1. (COClh 2. C2Hs02I'PPTs ...
Et_~ Ac 97 (90%)
:' OMe p-TsOH j)' ..
96 (85%)
Et 1. NBS/AgNO 3 - f:J Ac
:' OMe 2,4,6-trimethyl {'( Pyridine .... 2.NaB~ 0 0 OH
LJ
98 (47%)
48
Unfortunately, the 1H and 13C NMR spectra of 99 did not match with
those provided by Professor Kahne of Princeton University. This result led to the
conclusion that the epoxide 92 was opened predominantly at C3 (as shown in
Figure 21) and ultimately converted to 99, a regioisomer of the 4-ethylamino
sugar of Calicheamicins and Esperamicins.
Although this approach did not lead to the 4-ethylamino sugar, it gives us
quick entry into enantiomerically pure 3-amino-3,4-dideoxy pyranosides of the
type shown in structure 95 and would presumably provide access to other 3-
substituted sugars via regioselective ring opening of epoxide 92.
49
2.7 Cyclic Sulfates
We next attempted a total synthesis of the Calicheamicin 4-ethylamino
sugars using cyclic sulfate chemistry, which has previously been employed in
construction of substituted sugars.
Westheimer and Kaiser have done an extensive study on cyclic
sulfates.32-37 The X-ray crystal structure of ethylene sulfate38 (Figure 22) shows
that the 0-8-0 bond angle of the five membered ring is 98.4° which is
considerably smaller than the ideal tetrahedral angle of 109.5°. The dihedral
angle between C-O bond and 0~8-0 plane was found to be 20.6°. The five
membered ring apparently adopts a puckered conformation in the crystalline
state. The origin of ring strain in cyclic sulfates may be due to one or more of the
following 1) angle strain, 2) the overlap of the ring oxygen's 2p orbitals with 3d
orbital on sulfur, giving double bond character to the bond between ring oxygen
and sulfur, and 3) non-bonded interactions between ring oxygen and exocyclic
oxygen.33
The ring strain and leaving group ability of (R0803-) make these cyclic
sulfates very reactive towards a wide array of nucleophiles. The five membered
ring cyclic sulfates are found to be more reactive than six membered cyclic
sulfates which are more reactive than the open chain analogs.
Figure 22 . Cyclic Sulfate of Ethylene Glycol
o~ ~o 's~
,..c.>.. O~8.40
100
50
Although cyclic sulfates are frequently prepared from 1,2 diols by reaction
with sulfuryl chloride,39-44 N,N-sulfuryl diimidazole,45-47 or oxidation of cyclic
sulfites with permanganates,48-49 they can also be prepared from 0Iefins,5o.51
epoxides,52·54 ketones,55 dibromides or diacetates.56 Cyclic sulfates can also be
efficiently synthesized by oxidation of cyclic sulfites with ruthenium tetroxide.
Since Ru04 is very expensive, Sharpless has described a the synthesis of cyclic
sulfates from cyclic sulfites using catalytic amounts of Ru0458.
51
2.8 Sharpless' Synthesis of 1,2-Cyclic Sulfates from 1,2 Diols.
Table 4. Preparation of Cyclic Sulfates of 1,2-0iols
OH
J((R2 , 1. SOCI2, CCI4, 60°C
~R2 .... R1 2. NaI04' RuC's. 3H2O R1
CH3CN/H20, 25°C OH 0
Entry R1 B2 Yield
101 C02i-pr C02i-pr 90-93
102 C02Et CD2Et 69
103 CD2Me CD2Me 63
104 n-C8H17 H 92
105 c-C6H11 H 97
106 n-C4Hg n-C4H9 89
107 n-C15H31 C02Me 90-95
108 c-C6H11 CD2Et 95-97
109 H CD2-C6H11 88
110 H CONHCH2Ph 64
Cyclic sulfates have not been widely employed in organic synthesis, in part
due to a lack of good methods for their preparation. However Sharpless' new,
catalytic, two step one pot process for conversion of diols to
52
cyclic sulfates allows for their easy preparation. The first step involves formation
of cyclic sulfite using thionyl chloride followed by oxidation to the cyclic sulfate
using ruthenium trichloride trihydrate catalyst and sodium periodate. The
reactions are complete in less than 1 h and use as little as 1 part in 1500 of
expensive ruthenium catalyst. A wide array of cyclic sulfates can be prepared
using this process and some are shown in Table 4.
Cyclic sulfates have shown excellent reactivity towards a variety of
nucleophiles (Figure 23). For example, ethylene sulfate 100 was found to react
with amines, phenolates, carboxylates, amine oxides, carbanions and
thiophenolates to give beta substituted ethyl sulfates in high yield.36
Figure 23 . Nucleophilic Additions to Cyclic Sulfates
Once the cyclic sulfate is opened by a nucleophile, it becomes rather inert
towards further nucleophilic addition.
53
2.9 Application of Cyclic Sulfate Chemistry for Manipulations of
Sugars
Cyclic sulfates have been used in carbohydrate chemistry to prepare
different sugar derivatives. Methyl (3-D-glycoside cyclic sulfate 111 was reacted
with tetramethylammonium fluoride in acetonitrile at reflux to give the
corresponding 2-deoxy-2-flouro-glycoside in high yield. This gave 2-deoxY-2-
fluoro-D-glucose on hydrolysis (Figure 24).59 The reaction of 111 with M84NOH
and Me4N8r were slower than with the fluoride under comparable conditions.
Figure 24 . Preparation of Fluoro-substituted Sugar 112
Ph~~O o OMe o I o=s_O
1. Me4NF, CH3CN
2.8(TFAhfTFA ....
~ 111
Synthesis of 2-Deoxy-2-fluoro-D-glucose
F OH
Ho-r-I~POMe HO~
112
Tewson has synthesized fluoro derivative 116 using a cyclic sulfate
intermediate.60 The nucleophilic displacement reactions at the C2 position of
pyranosides normally give products other than those of direct displacement.
A cyclic sulfate such as 115 could be exclusively opend at C2 giving high yields
of fluoro substituted sugar 116 (Figure 25).
54
Figure 25 . Nucleophillic Addition of Fluoride to Cyclic Sulfate Derivative 115
HO 0
~hr;;.~O HO 0
113
OMe
0,/0 's/'
CI/ 'CI
114
o 0,11 'S-O 0
fhr;;.I~? OMe O~
HO t 115 +-1.Me4N F
2) HsO+
F
116
55
2.10 Approach to the Calicheamicin 4-Ethylamino
Sugar Using a Cyclic Sulfate
At this point it was believed that a short and efficient synthesis of the 4-
ethylamino sugar of calicheamicins and esperamicins could be accomplished by
exploiting the reactivity of cyclic sulfates. Although it is well known that some
cyclic sulfates can be opened regioselectiyely, to my knowledge regioselective
opening of the cyclic sulfates of the type 117 have not been studied.
Figure 26 . Approach to the Calicheamicin 4-Ethylamino Sugar Using Cyclic Sulfate 117
OMe 1. SOCI2
Pi! Et3N
o O°C .... OH
HO 2. Nal04 82 RuCls
Aq. CHsCN 25°C
OMe 1. 70% Aq. EtNH2 Ac
PI 2. 3% HCI, MeOH, reflux f};!tN OMe
o 3. AcCI, pyr 0 o .... 0, / 118a + 118b
S AcO //~ o 0
117 1. NaOMe
MeOH 2. NaHlMel
1JMe MeO
99
56
Methyl 2·deoxy·f3-D·ribo·pyranoside 82 (Figure 26) is commercially
available61 and is a logical carbohydrate precursor for the synthesis of the
Calicheamicin 4·ethylamino sugar. Methyl 2·deoxy·f3-D·ribo·pyranoside 82 can
also be prepared from 2·deoxy·D·ribose in one step using known chemistry.62
The reaction of 82 with thionyl chloride in triethylamine, followed by treatment of
the intermediate cyclic sulfite with sodium periodate and a catalytic amont
of ruthenium tetroxide gave highly reactive cyclic sulfate 117. The most important
step in this synthesis is the opening 117 by an appropriate nitrogen nucleophile.
Figure 27 . Possible Conformations of Cyclic Sulfate 117
Nu:
'pJ,Me 0-5=0
" o
NU:~?OMe 0=5 ...... T
II 0 o
There are two possible conformations of cyclic sulfate 117, both of which
are shown in Figure 27. Since cyclic sulfates behave similarly to epoxides, we
expect a diaxial opening of this intermediate. The relative reactivities and I or
populations of these conformers should govern the relative amounts of
regioisomeric products formed during the nucleophilic opening of the cyclic
sulfate.
57
Upon reaction of 117 with aqueous ethyl amine and subsequent
acetylation, a single regioisomer 118 was obtained. The identity of this
regioisomer was determined by O-methylation to give 99, which had previously
been prepared31 and shown to be a regioisomer of the desired Calicheamicin
sugar. While this strategy did not lead to the desired 4-ethylamino sugar, it does
provide a quick entry into 3-amino-2,3-dideoxy pyranosides of the type 99. In
principle cyclic sulfate 117 might be opened by a variety nucleophiles such as F-,
RS-, etc. to synthesize 3-halo, thio, or alkyl substituted sugars.
2.11 Stannylene Acetal Intermediates
It is we" known that diols, and especially 1,2 diols, can be ketalized using
dibutyltin oxide. Such ketals can then be alkylated using a CsF catalyst and a
good alkylating agent.63 Figure 28 shows an example of the alkylation of a
stannylene ketal.
Figure 28 • Alkylation of Stannylene Ketal 119
120 (99 %)
. 58
2.12 Regioselective Benzylation of a Sugar Derivative
Figure 29 . Alkylation of 8tannylene Ketal 122
HO 0 H~ 8zI0 08z1 \ 0 8u~n_~
(Bu28n) 20 ~ '§ZIO 08z1
AcN AcN I I
121 H 122 H
y C6H(jCI+.!'~ . HO 0
8zl0 08z1
AcN
123 H
The alkylation of stannylene ketals is a very slow process even with
reactive allyl or benzyl bromides and sometime requires heating for up to 8 days
with the neat halide as a solvent.64-66 A milder technique was introduced by
Veyrieres, who found that these alkylations are catalyzed by quaternary
ammonium halides.67. It was observed that higher molar proportions of Lewis
acid reduced the reaction times.68 The role of cesium fluoride in the reaction is
believed to activate the alkyl halide through the interaction of the cesium cation
with the halogen atom.68 Furthermore, the activation of 8n-0 bonds may be
caused by the formation of a
59
pentacoordinate tin complex.68 The combination of these effects is responsible
for the selective and efficient O-monoalkylation of stannylene acetals. Figure 29
shows an example of an alkylation of a stannylene ketal 122.
2.13 Synthesis of the Calicheamicin 4-Ethylamino Sugar Derivative 59a
The synthesis of the 4-ethylamino sugar derivative 59a is shown in Figure
30. The synthesis begins with methyl 2-deoxy-j3-D-ribo-pyranoside 82 which was
reacted with dibutyltin oxide in refluxing toluene to produce the corresponding
stannylene acetal (not isolated). It is important to note that this reaction is hard to
monitor since the product is unstable on TLC plates and decomposes to give the
starting materials. Alkylation with benzyl bromide provided the
chromatographically separable (cx=1.16, EtOAc) regioisomeric monobenzyl
ethers 124 and 125 in 43% and 47% yields, respectively. Although this reaction
was not regioselective, both the regioisomers can be independently processed to
give the final 4-ethylamino sugar derivative 59 via the common intermediate 128.
The less polar regioisomeric alcohol 124 was deprotonated using sodium
hydride and alkylated with methyl iodide to give methyl ether 126 in 94% yield.
Debenzylation with H2/Pd-C gave very high yields of the product alcohol 127.48
The free alcohol was reacted with tosyl chloride in pyridine to give tosylate 128 in
91% yield.
60
The regioisomeric monobenzyl ether 125 could also be converted to
tosylate 128 by changing the sequence of the steps. Reaction of 125 with tosyl
chloride produced in tosylate 129 in 95% yield. Debenzylation, using hydrogen
and palladium-on-carbon, gave alcohol 130 in 84% yield, and methylation at
room temperature using methyl iodide and silver oxide in DMF provided tosylate
128 in 96% yield. The combined yield of tosylate 128 from methyl 2-deoxy-(3-D-
ribo-pyranoside was 73%.
61
Figure 30. Stereoconvergent Synthesis of the 4-Ethylamlno Sugar of the Calicheamicins and Esperamicins
OMe 1.8u2SnO OMe
pJ PhCH3 Pi Hea ...
2. BnBr
HO PhCHa BnO
82 Heat 124 (43%)
OMe 1.NaH, THF OMe
H2
Pd. Pd 2. Mel Pd/C ... ... 94% 100%
BnO BnO
124 126
OMe TsCl OMe H2
Potn pyr
Potn Pd/C ... .... 95% 84%
HO TsO
125 129
OMe OMe H2
Pii. Na~ Nap)
Pto. ... DMSO OMe AC:!O
TsO heat MeOH
128 93% 131 87%
OMe
Ri. HO
125 (47%)
Hr1M.~ OM. 127 '-0-1
~e OMe CH:31 TsO
-0-1 A920/ 128
~ 96% TsO
130
HOMe HOMe
I -0.1 LAH '~ Ac,.N~ ... N 0
OMe Et20 I OMe heat Et
132 81°Al 59a
Ac OMe~ '~ AcCI N 0
I OM Et3N Et e 9~Al
133
62
The key step in this synthesis is the Sn2 displacement of the tosylate
intermediate 128 with an appropriate nitrogen nucleophile. Attempts at direct
displacement of the tosylate group using 70% aqueous ethylamine were
unsatisfactory. However, the tosylate was cleanly displaced by the use of sodium
azide69 in DMSO at 120-130 °C, providing azide 131 in 93% yield. Azide
reduction and concomitant N-acetylation in the presence of acetic anhydride70
produced pyranoside 132 in 87% yield. This amide was subsequently reduced
using LiAIH4 to give 4-ethylamino sugar derivative 598 in 91% yield. The proton
NMR spectrum of 598 was consistent with previously published data 29 for this
molecule. The overall yield of the 4-ethylamino sugar derivative 598 from methyl
2-deoxy-(:3-D-ribopyranoside was 54%. The rotation of the 4-ethylamino sugar
derivative 598 was found to be [a]026 -56.8° (c 1.4, CHCI3), Iit29. [a]023 -56.7° (c
1.0, CHCI3)
The 4-ethylamino sugar derivative 59 was then converted to the acetylated
amino sugar derivative 133 in 90% yield. This was compared to published
spectral and physical data. [a]025 -98° (c 0.4, CHCI3), /it26 [a]o25 -99.0° (c 0.96,
CHCI3), lit25 [a]020 -96.0° (c 0.9, CHCI3). Proton and carbon NMR spectra
obtained for N-acetyl derivative 133 were in accord with those kindly supplied by
Professor Daniel Kahne of Princeton University.
63
2.14 Synthesis of Methylamino Sugar Derivative 136
In order to prove the generality of this methodology, we have synthesized
4-methylamino sugar derivative 136 of the Calicheamicins and Esperamicins.
This synthesis is outlined in Figure 31. The synthesis is the same to the azide
intermediate 131. This intermediate was reduced to amine 134 using H2/Pd-C.
This amine was not purified but immediately treated with benzyl chloroformate to
give CBz protected amine 135 which was alkylated with MeIlAQ20 to give CBz-
protected 4-methyl-amino sugar 136. The structure of 136 was determined by 1 H
and 13C NMR data.
Figure 31 . Synthesis of the 4-Methylamino Sugar of the Calicheamicins and Esperamicins
OMe
N3~ OMe
131
135 (53% from azide131 )
OMe
H2N~ OMe
134
,0'10 OMe
Ph N'" 0)
H3C"" ~e 136 (82%)
64
2.15 Conclusion
The synthesis depicted in Figure 30 is the most efficient and versatile
reported to date. Unlike prior syntheses, it gives the 4-ethylamino sugar in very
high overall yield (54%). It is also flexible, and can give easy access to unnatural
analogs of the Calicheamicin and Esperamicin 4-amino sugars. For example, the
alkylation (ethylation or methylation) occurs late in the synthesis, so one can
alkylate the sugar with variety of electrophiles. In one of the prior syntheses, the
alkylation is carried out in the early stages, hence synthesizing unnatural analogs
would be laborious. Such analogs of the Calicheamicin and Esperamicin amino
sugars could be very useful in structure activity studies. There is a possibility that
incorporation of the unnatural analogs of the Calicheamicin 4-ethylamino sugar
can make Calicheamicins and Esperamicins even more site specific.
Although the first step of this synthesis yields a mixture of regioisomers,
they are separable by column chromatography and each regioisomer converges
to a common intermediate which is converted to the targeted 4-ethylamino or 4-
methylamino sugars.
65
CHAPTER 3. DIASTEREOSELECTIVE RING MANIPULATIONS
OF COMMON RING CARBOCYCLES
3.1 Introduction to Diastereoselectivity in the Simmons-Smith
Cyclopropanation
66
The diastereoselective eyelopropanation of eyeloalkenone ketals has been
studied in the Mash research group,?1-75 For example, 2-eyeloalken-1-ones of
type 137 can be ketalized using (2S,3S)-(+)-2,3-butanediol as shown in Figure
32. The Simmons-Smith eyelopropanation of the resulting 2-eyeloalken-1-one
dioxolane ketal 138 using a Zn-Cu couple yields predominantly one diastereomer
Figure 32 • Diastereoseleetive Simmons-Smith Cyelopropanation
Mer- Me " '\
OJ Me,---",Me n HO o~
TsOH
137 138
Me)---\ Me Me)---\ Me ,\ .,'
o~( (> Aq.HCIIMeOH ~
139 140
Major Minor
0
6:::( 141
67
as shown in Figure 32. The major product ketal 139 can then be hydrolyzed using
acidic methanol to give enantiomerically pure cyclopropyl ketone 141. The other
enantiomer of this cyclopropyl ketone can be obtained by using the opposite
enantiomer of 2,3 butanediol. This approach has been used to prepare a variety
of enantiomerically pure cycloalkanones of the type 141.
3.2 Nucleophilic Additions to Bicyclic Ketones
It has been observed that nucleophilic additions to chiral bicyclic ketones
of the type 142 are also diastereoselective (Table 5).16 The nucleophile
approaches predominantly trans to the cyclopropyl ring, which extends this
methodology to introduce up to three chiral centers in the ring. The Table 5 lists
nucleophilic additions to various bicyclic ketones of different ring sizes. The
diastereoselectivity and yields in all these reactions are generally excellent.
Table 5 . Nucleophilic Additions to Bicyclo[n.1.0] alkan-2-ones
~_~HCS TMS-I .......• (CH2ln (CH2ln
142 143
Entry n Nu: Diast. Yield%
Ratio
3 LAH > 20: 1 99
2 3 MeLi > 20: 1 99
3 3 nBuLi > 20: 1 92
4 3 PhMgBr > 20: 1 99
5 3 CH2=CHMgBr > 20: 1 99
6 3 nBu(C)2Li > 20: 1 98
7 4 MeLi > 20: 1 68
8 11 MeLi > 20: 1 94
9 2 MeLi > 20: 1 97
10 4 MeLi > 20: 1 90
11 6 MeLi > 20: 1 70
H~I (CH2ln
144
68
Professor Mash has already used this methodolgoy to synthesize the
natural product (S}-(-)-Chokol A which contains three contiguous chiral centers
on a five-membered ring. We were interested in extending this
69
methodology to the syntheses of natural products having up to five chiral centers
in the ring.
Figure 33 Conjugate Additions and Alkylations of
o
0>' (CH:un
145
Bicyclo[n.1.0]alkan-2-one Derivatives
o 0
Nu - cJ>'\' A' FJ..~,cJ>'\\ A' 1. LOA ----------~~~ --------~~~
NU"" (CH:un 2. A-X Nu"" (C~n
146 147
" HO .... Nu
FV/'o~\'A' .. l »
NU" (CH:un
148
If the conjugate addition to enones such as 145 (Figure 33) and alkylation
of corresponding ketone 146 are both diastereoselective, then one might
introduce up to five chiral centers in preparation of molecules of the type 148.
This extension would give access to a wide array of more complex, optically
active natural products. The diastereoselectivity in such reactions could be
predicted by the rigidity of the conformations of the
70
bicyclic structures such as 145 and 146. The rigidity may expose one face of the
molecule to nucleophiles or electrophiles.
We decided to explore the alkylation and conjugate additions of
bicyclo[S.1.0]oct-3-en-2-one rae-152.
Figure 34 . Preparation of Bicyclo[S.1 .0]oct-3-en-2-one 152
1\ 1\
0 +0 Ph-N (Me)a Br" Br NaOMe/OMSO .. ....
149 150
1\ 0
0 3% H2SO4 & ,..
151 rae -152
3.3 Preparation of Bieyelo[5.1.0Joct-3-en-2-one
The preparation of bicyclo[S.1.0]oct-3-en-2-one is outlined in Figure 34.
The synthesis begins with the reaction of bicyclic ketal 149 with
phenyltrimethylammonium tribromide to give the a-brominated ketal 150. The
reaction is completed within 20 minutes and longer reaction times led to side
products which do not have a cyclopropyl functionality. The crude bromide 150 is
then treated with sodium methoxide in OM SO at room
71
temperature to effect elimination to give ene ketal 151. The ketal 151 smoothly
undergoes hydrolysis to give the bicyclo[5.1.0]oct-3-en-2-one 152.
This bicyclic enone 152 is a very interesting molecule which has three
functional groups: double bond, ketone and cyclopropyl ring. Enone 152 can be
prepared in enantiomerically pure form using the cyclopropanation of chiral
ketals. We decided to study the stereochemistry of conjugate additions to the
racemic enone 152 (Figure 35) as a prelude to syntheses of natural products in
enantiomerically pure form.
Figure 35 . Conjugate Addition of Phenyl Cuprate to Bicyclo[5.1.0]oct-3-en-2-one 152
o
& o
Cu(I)Brl PhLi ~ ~-;hAJ
rac-152 153
3.4 Conjugate Additions to Bicyclo[5.1.0Joct-3-en-2-one
It was our pleasure to find that the reaction of bicyclo[5.1.0]oct-3-en-2-one
152 with phenyl cuprate was diastereoselective and led to predominantly one
diastereomer 153. Spectral data (1Hand 13C NMR) and TLC showed the
presence of only one diastereomer, which was formed in 79% yield.
Figure 36 . Conjugate Addition of Methyl Cuprate to Bicyclo[5.1.0Joct-3-en-2-one152
o
tv o
Cu{I)Brl MeLi ~ ~:e)J'
rac-152 154
72
Similarly, conjugate addition of methyl cuprate to bicyclic enone 152 gave
only one diastereomer (as determined from TLC, 1H and 13C NMR) of bicyclic
ketone 154 in 79% yield (Figure 36).
3.5 Preparation of Bicyclo[5.1.0]octan-2-one
Bicyclic ketal 149 was hydrolyzed to yield ketone 155 (Figure 37).
Figure 37 • Preparation of Bicyclo[5.1.0Joctan-2-one 155
149 rac-155
73
3.6 Alkylations of Bicyclo[5.1.0Joctan-2-one 155.
The alkylation of the enolate derived from bicyclo[5.1.0]octan-2-one 155
using three different alkylating agents, methyl iodide, allyl bromide and benzyl
bromide, was then studied (Figure 38). These alkylations were performed under
kinetic conditions. All the three alkylations were diastereoselective and gave only
one of the diastereomers of the alkylated product. The diastereoselectivity was
determined by TLC,1H and 13C NMR.
74
Figure 38 . Alkylations of Bicyclo[5.1.0Joctan-2-one 155
0 0
& 1. LDArrHF/.42"C Ph~ ... 2. Ph-CH2-Br
155 156 (75%)
0 0
& 1. LDAffHF/-30°C MaO ... 2. CH 3-1
155 157 (80%)
0
& 1. LDAffHF/-30°C ~ .... 2. H2C=C(H)-CH 2Br
155 158 (78%)
75
3.7 Conclusion
The conjugate additions of bicyclic enone 152 and alkylations of the
enolate derived from bicyclo[5.1.0]octan-2-one 151 were successful. The
diastereoselectivity in these reactions as determined by proton and carbon NMR
was greater than 20: 1. This methodology is currently being extended to five and
six membered bicyclic ketals. The bicyclo[3.1 .O]hex-3-en-2-one can be prepared
by a literature procedure, however one of the steps in the synthesis gives product
in 12% yield. Attempts to improve this literature procedure have been
unsuccessful so far.
This methodology can nevertheless give entry into enantiomerically pure
natural products containing seven membered rings. All the reactions have been
done on the racemic materials, however enantiomerically pure bicyclic ketones of
types 151 and 152 and can be prepared by the methodology developed in our
group.
76
EXPERIMENTAL
77
Experimental
Dichloromethane was distilled from calcium hydride. Diethyl ether and
tetrahydrofuran were distilled from sodium/benzophenone ketyl. Melting points
are uncorrected. 1H and 13C NMR spectra were recorded at 250 and 62.9 MHz,
respectively. Thin layer chromatographic analyses were performed on Merck
silica gel 60 plates (0.25 mm, 70-230 mesh ASTM). Column chromatography was
performed on either Merck silica gel 60 (gravity driven 70w230 mesh ASTM) or
flash silica gel 60 (230-400 mesh ASTM).
Preparation of Racemic Tricyclic Acetal 38
To a solution of lactone 3612 (3.8 g, 25 mmol) in dry methylene chloride
(30 mL) at w42 °c was added diisobutylaluminumhydride (1 M solution in
methylene chloride, 28.3 mL, 28.3 mmol). The reaction was stirred for 3 h at this
temperature and then quenched by addition of 20% sodium hydroxide (30mL)
while stirring vigorously. The reaction mixture was allowed to warm to room
temperature, then extracted with methylene chloride (3 X 60 mL), the extracts
were dried (MgS04), filtered, and volatiles removed in vacuo. The residue was
chromatographed on silica gel 60 (100 g) eluted with 30% EtOAc/hexanes,
affording 3.46 g (22.46 mmol, 90%) of 37 (At 0.17,30% EtOAc/hexanes).
Spectral data for 37 : an oil
1H NMR (CDCI3) 50.97-1.97 (10,m), 3.28 (1 ,s), 4.12 (2,d), 5.51 (1 ,d).
78
13C NMA (CDCI3) 5 23.33 (CH2), 27.72 (CH2), 32.75 (CH2), 38.79 (CH2) ,
40.28 (CH), 44.86 (CH), 85.40 (CH) and 98.82 (CH).
Transacetalization of Acetal 38 with (R)·Pantolactone
A mixture of 38 (2.6 g, 16.88 mmol) and (R)-Pantolactone in methylene.
chloride (190 mL) was stirred at room temperature with catalytic amount of tosic
acid and 4 A molecular sieves. After 23 h, the mixture was diluted with sat.
NaHCOs (40 mL), extracted with methylene chloride (3 X 50 mL), the extracts
dried (MgS04), filtered and volatiles removed in vacuo. The residue was
chromatographed on silica gel 60 (90 g) to afford a mixture of diastereomers 41
and 42. The diastereomers were separated by fractional crystallization (from
hexanes, pure crystals were used for seeding) affording 1.376 g (5.17 mmol,
31%) of of the more polar diastereomer 42 (Af 0.27, 17% EtOAc/hexanes). The
crude less polar diastereomer 41 along with some more polar diastereomer 42
were chromatographed on silica gel 60 (200 g) eluted with 5% EtOAc/hexanes to
afford 1.303 9 (4.89 mmol, 29%) of pure less polar diastereomer 41 (At 0.33,
17% EtOAc/hexanes) and a mixture (550 mg) of less polar diastereomer 41 and
more polar diastereomer 42. This mixture 41 and 42 was chromatographed of
silica gel 60 (150 g) eluted with 5% EtOAc/hexanes to afford pure 41 (346 mg,
8%) and pure 42 (388 mg, 9%)
Spectral data for 41 (less polar diastereomer) : [a]025 -1330
(c 0.45, MeOH),
white solid, mp. 43°C
79
IR (neat) cm-1, 2960, 1786, 1122, 1077, 1003,776, 772, 764, 760, 755, 738,
735,725,721 and 651.
1H NMR (CDCI3) 60.9-2.27 (17,m), 3.9-4.15(4,m), 5.55(1 ,d)
13C NMR (CDCI3) 619 (CH3) , 23 (CH3), 23.5 (CH3) , 28(CH2), 31.5 (CH2) , 38
(CH2), 40.5 (C), 41 (CH), 41 (CH), 45 (CH), 77 (CH) 86 (CH), 104 (CH) and106
(C).
Spectral data for 42 (more polar diastereomer) : [a]025 _92° (c 0.5, MeOH), white
solid, mp 100°C
IR (neat) cm-1, 2930, 1800, 1133, 1055, 1000, 790, 763, 755, 735, 725 and 658.
1H NMR (CDCI3) 61.03-2.26 (17,m), 3.92-3.99 (3,m), 4.07 (1 ,s), 5.54 (1 ,d)
13C NMR (CDCI3) 619.27 (CH3) , 22.92 (CH3), 23.27 (CH2) , 27.57 (CH2), 31.19
(CH2), 37.86 (CH2), 39.77 (C), 40.2 (CH), 40.2 (CH), 44.53 (CH), 76.14 (CH2),
76.91 (CH), 85.74 (CH), 103.58 (CH) and 175.57 (C).
Anal. Calcd for 42 C15H2204: C, 67.59; H, 8.08. Found: C, 67.64; H, 8.32
Preparation of Methyl Pyranoside 438
A mixture of the more polar diastereomer 42 (0.105 g, 0.386 mmol) and a
catalytic amount of tosic acid in dry methanol (3.5 mL) was stirred at room
temperature for 2.5 h, then diluted with sat. NaHC03 (5 mL), extracted with
diethyl ether (3 X 20 mL), dried (MgS04), filtered, and volatiles removed in
vacuo. The residue was chromatographed on silica gel 60 (25 g) eluted with ether
to afford 64 mg (0.381 mmol, 99%) of 438 as an oil contaminated with methanol
Spectral data for 43a : oil [a] 026 -122.28° (c 2.45, THF).
1_
80
1 H NMR 50.91-1.42 (5,m), 1.82-2.20 (3,m), 3.33 (3,s), 3.32 (3,s), 3.94-3.96 (1 ,m)
and 4.87 (1 ,d J=4.9 Hz).
Preparation of Methyl Acetal 43b
A mixture of the less polar diastereomer 41 (0.100 g, 0.375 mmol) and
catalytic amount of tosic acid in dry methanol (3.5 mL) was stirred at room
temperature for 2.5 h, then diluted with sat. NaHC03 (5 mL), extracted with
diethyl ether (3 X 20 mL), dried (MgS04), filtered, and volatiles removed in
vacuo. The residue was chromatographed on silica gel 60 (25 g) eluted with ether
to afford 60 mg (0.357 mmol, 97%) of 43b as an oil contaminated with methanol
Spectral data for 43b : oil [a]026 +117.060
(c 6.45, THF).
Reaction of Chiral Acetal 43 with Racemic Methyl Lactate
A mixture of 43b (179 mg, 1.065 mmol) and racemic methyl lactate (443
mg, 4.262 mmol) in dry diethyl ether (14 mL) was stirred at room temperature in
the presence of a catalytic amount of tosic acid and 4 A molecular sieves for 22
h. The reaction mixture was then diluted with diethyl ether (20 mL) and sat.
NaHCOa (10 mL), extracted with diethyl ether (3 X 15 mL), the organic extracts
dried (MgSD4), filtered, and volatiles removed in vacuo. The residue was
chromatographed on silica gel 60 (100 g) eluted with 17% EtOAc/hexanes
affording 80 mg (0.333 mmol, 31%) of the less polar diastereomer 45 (Rf 0.34,
20% EtOAc/hexanes) and 99 mg (0.412 mmol, 39%) of more polar diastereomer
44 (At 0.33, 20% EtOAc/hexanes).
Spectral data for 45: an oil, [a]026 +930
(c 6.45, CH2CI2).
81
IR (CH2C12) cm-1 2980, 1703, 1400, 1233, 1154, 1079, 10331000,900.
1H NMR 5 (CDCI3) 0.88-1.51 (10,m), 2.05 (1,br s), 2.19-2.26 (3,m), 3.72 (1,s),
3.93 (1 ,d J=5.4 Hz), 4.34 (1, q, J=7 Hz), and 5.16 (1 ,d, J=4.9 Hz).
13C NMR 5 (CDCI3) 18.83 (CH), 23.25 (CH2), 27.66 (CH2), 31.30 (CH2), 38.18
(CH2), 40.23 (CH3), 44.65 (CH), 44.65 (CH), 51.74 (CH3), 69.18 (CH), 85.56
(CH), 103.03 (CH), and 173.5 (C).
Spectral data for 44 : an oil [a]026 +66.4° (C 7.65, CH2CI2)
IR (CH2C12) cm-1 2955,1747,1420,1203,1134,1049,1024,1010,896.
1H NMR 5 (CDCI3) 0.89-1.98 (3,m), 1.26-1.42 (7,m), 1.88 (1,br s), 2.08-2.21
(3,m), 3.66 (3,s), 3.88 (1,d, J= 6.4 Hz), 3.98 (1,q, J=6.8 Hz), and 5.04 (1 ,d, J=5
Hz).
13C NMR 5 (CDCI3) 18.18 (CH), 23.19 (CH2), 27.58 (CH2) , 31.35 (CH2), 38.32
(CH2), 40.20 (CH), 40.40 (CH3) , 44.78 (CH), 51.67 (CH3) , 72.00 (CH), 85.70
(CH), 104.86 (CH), and 174.09 (C).
Reaction of Chiral Acetal 43a with Racemic Ethyl Caproate
A mixture of 43a (110 mg, 0.655 mmol) and racemic ethyl caproate (840
mg, 5.24 mmol) in dry THF (8 mL) was stirred at room temperature in the
presence of a catalytic amount of tosic acid and 4 A molecular sieves. After 21 h.
the reaction mixture was diluted with THF (20 mL) and sat. NaHC03 (10 mL),
extracted with diethyl ether (3 X 20 ml), dried (MgS04), filtered, and volatiles
removed i/1 vacuo. The residue was chromatographed on silica gel 60 (110 g)
eluted with 5% EtOAc/hexanes affording 55 mg (0.186 mmol, 28%) of the less
polar diastereomer 47 (Rf 0.45, 20% EtOAc/hexanes) and 74 mg
82
(0.251 mmol, 38%) of the more polar diastereomer 46 (At 0.4, 20%
EtOAc/hexanes).(Rf 0.4, 20% EtOAc/hexanes).
Spectral data for 47 : an oil, [aJ026 _680
(c 1.23, CH2CI2)
IR (CH2C12) cm-1 2983, 1767, 1480, 1255
1H NMR 6 (CDCI3) 0.86-1.68 (17,m), 1.96 (1,s), 2.17-2.26 (3,m), 3.84 (1,t), 4.00
(1 ,d), 4.19 (2,q), and 5.08 (1 ,d J=5 Hz).
Spectral data for 46: an oil, [aJ026 -117.680
(c 0.95, CH2CI2)
IR (CH2C12) cm-1 3100,2150,1320,1270
1H NMR 6 (CDCI3) 0.87-1.50 (17,m), 1.67-1.71 (2,m), 1.98 (1,br s), 2.19-2.26
(3,m), 3.88-3.90 (1 ,m), 4.16-4.23 (2,m), and 5.13 (1 ,d J= 4.9 Hz).
13C NMR 6 (CDCI3)13.85 (CH)14.19, (CH3). 22.22 (CH2),23.36 (CH2).27.53
(CH2), 27,66 (CH2) , 31.29 (CH2) , 32.48 (CH2), 38.13 (CH2), 40.27 (CH), 40.27
(CH), 44.72 (CH3) , 60.59 (CH2,) , 72.94 (CH), 85.59 (CH), 102.70 (CH), and
173.13 (C).
Reaction of Chiral Acetal 43b with Racemic Methyl Dodecanoate
A mixture of 43b (238 mg, 0.894 mmol) and racemic methyl dodecanoate
(849 mg, 3.57 mmol) in dry diethyl ether (25 mL) was stirred at room temperature
in the presence of a catalytic amount of tosic acid and 4 A molecular sieves. After
44 h the reaction mixture was diluted with diethyl ether (20 mL) and sat. NaHC03
(10 mL), extracted with diethyl ether (3 X 15 mL), the organic extracts dried
(MgS04), filtered, and volatiles removed in vacuo. The residue was
83
chromatographed on silica gel 60 (60 g) eluted with 5% EtOAc/hexanes affording
92 mg (0.251 mmol, 28%) of less polar diastereomer 49 (Af 0.45, 20%
EtOAc/hexanes) and 163 mg (0.445 mmol, 50%) of more polar diastereomer 48
(Af 0.37, 20% EtOAc/hexanes).
Spectral data for 49: an oil, [aJ025 +43.25° (c 4.4, Et20)
IA (CH2C12) cm-1 2980, 1750, 1265,750
1H NMA (CDCI3) b 0.77-1.60 (28,m), 1.88 (1,br s), 2.08-2.19 (3,m), 3.66 (3,m),
3.79 (1 ,t J=6.6 Hz), 3.89 (1 ,d J= 6 Hz), and 5.01 (1 ,d J= 5 Hz).
13C NMA b (CDCI3) 14.02 (CH3), 22.59 (CH2) , 23.22 (CH2) , 25.10 (CH2), 27.61
(CH2), 29.16 (CH2), 29.21 (CH2) , 29.45 (CH2), 31.40 (CH2), 31.80 (CH2), 32.68
(CH2), 38.32 (CH2) , 40.24 (CH), 40.46 (CH), 44.83 (CH), 51.62 (CH3), 76.71
(CH), 85.74 (CH), 105.90 (CH) and 173.98 (C).
Spectral data for 48 : an oil, [aJ026 +92.73° (c 3.3, Et20)
1H NMA b 0.7-1.19 (7,m), 1.26-1.41 (19,m), 1.56-1.68 (2,m), 1.91-1.92 (1, br s),
2.11-2.19 (2,m), 3.64-3.66 (3,s), 3.82 (1,d, J=4.6 Hz), 4.13-4.18 (2,m), and 5.05
(1 ,d, J=4.9 Hz)
13C NMA b 14.02 (CH2) , 22.6 (CH2), 23.32 (CH2) , 25.33 (CH2) , 27.65 (CH2) ,
29.06 (CH2), 29.25 (CH2), 29.36 (CH2), 29.50 (CH2), 29.50 (CH2), 31.26 (CH2),
31.80 (CH2), 32.75 (CH2) , 38.13 (CH2), 40.24 (CH), 40.24 (CH), 44.71 (CH),
51.62 (CH3), 72.83 (CH), 85.61 (CH), 102.69 (CH) and 173.54 (C).
84
Reaction of Chiral Acetal 43b with Racemic a-Phenethyl Alcohol
A mixture of 43b (45 mg, 0.268 mmol) and racemic a-phenethyl alcohol
(141 mg, 1.154 mmol) dry THF (8 mL) was stirred at room temperature with a
catalytic amount of tosic acid and 4 A molecular sieves. After 18 h, the mixture
was diluted with sat. NaHC03 (10 mL) and extracted with diethyl ether (3 X 15
mL). The extracts were dried (MgS04), filtered, and volatiles were removed in
vacuo. The residue was chromatographed on silica gel 60 (50 g) eluted with 5 %
EtOAc/hexanes to afford 38 mg (0.147 mmol, 54 %) of less polar diastereomer
51 (Af 0.24, 4 % EtOAc/hexanes) and 15 mg (0.058 mmol, 21 %) of more polar
diastereomer 52 (Af 0.17,4% EtOAc/hexanes)
Spectral data for 51 : an oil, [aJ026 +153.3° (c 2.15, Et20)
1H NMA 5 (CDCI3) 0.95-1.50 (10,m), 1.95 (1, br s), 2.06-2.27 (3,m), 4.02 (1,d,
J=6.5 Hz), 4.76- (1 ,q, J=6.6 Hz), 4.89 (1 ,d, J=4.9 Hz), and 7.22-7.32 (5,m).
13C NMA 5 (CDCI3) 23.41 (CH3), 24.37 (CH2), 27.85 (CH2), 29.66 (CH2), 30.27
(CH2), 31.38 (CH), 38.17 (CH), 40.28 (CH), 44.99 (CH), 72.70 (CH), 85.13 (CH),
101.49 (CH), 126.87 (CH), 128.32 (CH) and 143.64 (C).
Spectral data for 52 : an oil [aJ026 +61.09° (c 1.1, Et20)
1H NMR 5 (CDCI3) 0.91-1.05 (3,m), 1.38-1.46 (7,m), 1.96 (1,br s), 2.13-2.17
(3,m), 3.73 (1,d, J=5.9 Hz), 4.72 (1,q, J=6.4 Hz), 5.30 (1,d, J=4.9 Hz), and 7.23-
7.34 (5,m).
85
13C NMR 5 (CDCI3) 21.84 (CH3), 23.40 (CH2), 27.78 (CH2), 31.45(CH2), 38.52
(CH2), 40.35 (CH), 40.39 (CH), 45.04 (CH), 72.86 (CH), 85.27 (CH), 102.36
(CH), 125.90 (CH), 126.88 (CH), 128.15 (CH) and 144.80 (C).
Reaction of Chiral Acetal 42 with trans-Crotyl Alcohol.
A mixture of acetal 42 (116 mg,0.436 mmol) and trans-crotyl alcohol (63
mg, 0.871 mmol) in dry diethyl ether (8 mL) was stirred at room temperature with
a catalytic. amount of tosic acid and 4 A molecular sieves. After 13.5 h, the
mixture was diluted with sat. NaHC03 (5 mL), extracted with diethyl ether (25
mL), the extracts were dried (MgS04), filtered and volatiles removed in vacuo.
The residue was chromatographed on silica gel 60 (12 g) eluted with 20 %
EtOAc/hexanes to afford 80 mg (0.432 mmol, 99 %) of 55 (Rf 0.54, 20 % ethyl
acetate/hexanes) .
Spectral data for 55: an oil, [a][j5.5 -131.18° (c 6.1, CHCI3)
IR (neat)cm-1 2950, 1592, 1450, 13337,1189,1091,1023
1H NMR 5 (CDCI3) 0.91-2.30 (14,m), 3.80-4.12 (3,m), 5.12 (1,d) and 5.62-2.81
(2,m).
13C NMR 5 17.78 (CH), 23.36 (CH2), 27.78 (CH2). 31.38 (CH2), 38.23 (CH2),
40.33 (CH), 40.33 (CH), 44.91 (CH), 67.20 (CH2), 85.15 (CH), 103.41 (CH),
127.40 (CH) and 129.56 (CH).
Reaction of Chiral Acetal 42 with Methyl Glycolate
A mixture of 42 (617 mg, 2.57 mmol) and methyl glycolate (2.32 g, 25.75
mmol) in dry diethyl ether (15 mL) was stirred at room temperature with
86
a catalytic amount of tosic acid and 4 A molecular sieves. After 22 h, the mixture
was diluted with sat. NaHCD3 (15 ml), and extracted with diethyl ether (4 X 20
mL). The extracts were dried (MgS04), filtered and volatiles removed in vacuo.
The residue was chromatographed on silica gel 60 (50 g) eluted with 10 %
EtOAc/hexanes to afford 417 mg (1.84 mmol, 72 %) of 56 (Rf 0.22, 10 %
EtOAc/hexanes).
Spectral data for 56 : an oil, [a]rj6 +168.45° (c 3.1 , Et2<»
IR (neat) cm-1 3054,2955,2305, 1755
1H NMR b (CDCI3), 0.98-1.54 (7,m), 1.99 (1,br s), 2.18-2.29 (3,m), 3.74 (3,s),
3.98 (1 ,d, J=5.4 Hz), 4:13 (2,s), and 5.14-5.16 (1 ,d, J=5 Hz).
13C NMR b (CDCI3) 23.19 (CH2), 27.59 (CH2), 31.28 (CH2), 38.12 (CH2), 40.22
(CH), 40.22 (CH), 44.56 (CH), 51.65 (CH3) , 63.33 (CH2), 85.70 (CH), 104.30
(CH) and 170.89 (C).
Cyclopropanation of Acetal 55
To a solution of acetal 55 (97.4 mg, 0.468 mmol) was added diethyl zinc
(4.25 ml, 1.1 M solution in toluene, 4.68 mmol). The resulting solution was stirred
at room temperature for 0.5 h. The reaction was cooled to -42°C and solution of
diiodomethane (2.34 nil in 3 ml toluene) was added. The reaction was stirred for
1.5 h and was left in the refrigerator (-30°C) for 12.5 h. The mixture was then
brought to 0 °c temperature in an ice bath and stirred for 1 h. Water (2 ml)
followed by ether (50 ml) were then added. The organic layer was washed
successively with 5% HCI (10 ml), sat. NaHCD3 (2 X 10 mL). The organic
extracts were dried (MgS04), filtered, and the solvents removed in vacuo. The
87
residue was chromatographed on flash silica gel (25 g) eluted with 2%
EtOAc/hexanes to afford acetal 57 (84 mg, 81 %) as a mixture of diasteromers (Af
0.33,5% EtOAc/hexanes) which were not separable by column chromatography.
1H NMA 5 (CDCI3), 0.16-0.34 (2,m), 0.49-0.70 (2,m), 0.90-1.06 (5,m), 1.30-1.40
(4,m), 1.90-2.18 (5,m), 3.08-3.42 (2,m), 3.84-3.89 (1 ,m) and 5.01-5.05 (1 ,m).
13C NMA 510.95 (CH), 11.66 (CH2), 18.46 (CH), 19.12 (CH), 23.36 (CH2),27.80
(CH2), 31.36 (CH2), 38.21 (CH2), 44.29 (CH), 70.51 (CH), 70.63 (CH), 84.99
(CH), 103.49 (CH) and 103.70 (CH).
Alkylation of Acetal 56 with 1-lododecane
A three neck flask was charged with diisopropylamine (0.085 mL, 0.609
mmol) in THF (3 mL). The mixture was cooled to O°C in an ice bath and nBuLi
(0.442 mL, 0.561 mmol) was added via syringe. The solution was stirred for 20
minutes at this temperature and then cooled to -78°C. The solution of acetal 56
in THF (2 mL) was added and stirring was continued for 50 minutes.HMPA (0.181
mL) was added and the reaction mixture was stirred for additional 20 minutes. 1-
lododecane (0.111 mL, 0.524 mmol) was then added via syringe. The stirring
was continued for 1 h and the reaction was quenched by addition of sat. NaHC03
(5 mL) followed by dilution with ether (30 mL). The organic layer was separated
and the aqueous layer was extracted with ether (20 mL). The combined extracts
were dried (MgS04), filtered and solvent removed in vacuo. The residue was
chromatographed on silica gel 60 (50 g) and eluted with 20% EtOAc/hexanes to
afford 48 and 49 (57 mg, 0.16 mmol, 35%) as a 1:1 mixture of diastereomers 48
and 49.
88
Preparation of Cyclic Sulfate 117
A three necked round bottomed flask equipped with a reflux condenser
was charged with methyl 2-deoxy-~-D-ribopyranoside (100 mg, 0.675 mmol),
ethyl acetate (3 ml) and triethylamine (99 mg, 1.688 mmol).The resulting solution
was stirred at 0 °c and thionyl chloride (0.06 ml, 0.818 mmol) was added via
syringe. Stirring was continued for 5 min, then the solution was diluted with
CH3CN (15 ml) and H2O(10 ml). RuCI3·3H20 (8 mg, 30 Ill) and Nal04 (225
mg, 1.05 mmol) were added and the mixture was stirred at room temperature for
18 h. The mixture was then diluted with ether (25 ml), the organic phase was
separated, washed with H2O (10 ml), saturated aqueous NaHC03 (2 X 10 ml),
brine (10 ml) dried(MgS04), filtered, and volatiles removed in vacuo. The
residue was chromatographed on silica gel 60 (50 g) eluted with 70%
EtOAc/hexanes to afford 117 (111 mg, 0.528 mmol, 78%)
Spectral data for 117: white solid, mp. 76-77 °c (melts with decomposition)
[al027 -141.09° (c 1.92, EtOAc)
IR (CH2CI2) cm-1 1388, 1268;
1H NMR (CDCI3) 52.22-2.38 (2,m), 3.38 (3,s), 4.02-4.12 (2,m), and 4.86-5.24
(3,m)
13C NMR (CDCI3) 530.51 (CH2) , 55.38 (CH3), 57.50 (CH2), 77.46 (CH), 78.00
(CH), and 96.78 (CH).
Preparation of 2-Deoxy-3-amino-4-acetoxy-ribo-pyranosides 118a and 118b
The cyclic sulfate 117 (100 mg, 0.476 mmol) was taken up in an excess of
70 wt % aqueous ethylamine (3 ml, 37.2 mmol) and stirred at ambient
89
temperature for 25 h. The volatiles were removed in vacuo and the residual
material was dried by coevaporation with methanol (2 X 15 mL). The last traces
of solvents were removed on a vacuum pump to give a yellow foam which was
redissolved as a solution in 3% HCI in methanol (10 mL). This solvent was
heated to reflux for 10 min, then cooled to room temperature and volatiles
removed in vacuo. The residue was taken up in pyridine (3 mL) and cooled to 0
°c in an ice bath. Acetyl chloride (0.25 mL, 276 mg, 3.51 mmol) was added
dropwise and stirring was continued at O°C for 45 min. The reaction mixture was
then warmed to room temperature, stirred for an additional 30 min and diluted
with CH2C12 (10 mL). The aqueous layer was extracted with CH2C12 (2 X 10
mL), dried (MgS04), filtered, and volatiles removed in vacuo. The residue was
chromatographed on flash silica gel (75 g) eluted with ethyl acetate affording
118a (65 mg, 0.251 mmol, 53%) and 118b (27 mg, 0.104 mmol, 22%)
Spectral data for 118a: Yellow oil, [cx]026 -13.06° (c 5.3, CH2CI2)
1H NMR (CDCI3) 5 1.06-1.28 (3,m), 1.76-1.87 (1 ,m), 1.92-2.16 (7,m), 3.05-3.08
(1 ,m), 3.21-3.49 (4,m), 3.85-4.16 (2,m), 4.44-4.51
(1 ,m), and 4.76-5.05 (2,m)
13C NMR (CDCI3) 5 14.09, (CH3) , 20.53 (CH3) , 21.54 (CH3) , 34.35 (CH2) ,
39.06 (CH2), 51.72 (CH3), 56.22 (CH2), 63.88 (CH2), 67.43 (CH), 101.43 (CH),
169.95 (C), and 170.98 (C).
Preparation of 2-0eoxy-3-amino-4-methoxy-ribo-pyranoside 99
To a solution of 118a (480 mg, 1.85 mmol) in anhydrous methanol (30 mL)
was added sodium methoxide (216 mg, 3.93 mmol) and the mixture was stirred
90
at ambient temperature for 1.5 h. The volatiles were removed in vacuo and the
residue was coevaporated with THF (5 X 15 mL) to remove methanol. The
residue was taken up in THF (20 mL) and added dropwise to a suspension of
50% NaH (216 mg, 4.47 mmol) cooled in an ice bath. The mixture was stirred for
0.5 h and methyl iodide (290 /-IL, 4.66 mmol) was added. The reaction was stirred
for 2h at ambient temperature, then quenched by careful addition of H2O (25 ml),
extracted with CH2C12 (5 X 50 mL), The organic extracts were dried (MgS04),
filtered and volatiles were removed in vacuo. The residue was chromatographed
on silica gel 60 (25 g) and eluted with ethyl acetate, affording 99 (368 mg, 1.59
mmol, 86%) as a mixture of anomers. The 1 Hand 13C NMR's of 99 were
identical to the ones previously made in our group.31
Spectral data for 99: yellow oil, [cx]025 -87.33°(c 0.65,CHCI3)
IR (CHC's) cm-1, 3400,1620
1H NMR (CDC's) 51.13-1.23 (1,m), 1.73-1.90 (3,m), 2.12-2.15 (3,m) 2.34-2.41
(1 ,m), 3.03-4.09 (12,m) and 4.70-4.81 (1,m);
13C NMR (CDC's) 5 14.12 (CH3) 21.83 (CH3) 35.09 (CH2) 35.90 (CH2) 55.95
(CH3) 56.79 (CHs) 57.80 (CH) 64.23 (CH2) 75.29 (CH) and 101.25 (CH) and
170.43 (CH).
Preparation of Methyl 2-Deoxy-3-hydroxy-4-benzyloxy and Methyl 2-Deoxy-
3-benzyloxy-4-hydroxy-ribo-pyranosides 124 and 125
A mixture of 82 (1 g, 6.75 mmol) and di-n-butyltin oxide (1.741 g, 7.01
mmol) in toluene (200 mL) was refluxed under a Dean-Stark water trap for 12 h.
After removal of 50 mL of the solvent, benzyl bromide (1.386 g, 8.099 mmol) and
91
tetrabutylammonium bromide (1.31 g, 4.08 mmol) were added and the resulting
mixture was refluxed for 48 h. The solvent was removed in vacuo. The residue
was chromatographed twice on a flash silica gel column (200 g ) eluted with 30%
EtOAc/hexanes. This furnished less polar regioisomer 124 (683 mg, 2.878 mmol,
43%, Af 0.18, 30% EtOAc/hexanes) and more polar regioisomer 125 (762 mg,
3.211 mmol, 47%, Af 0.16, 30% EtOAc/hexanes).
Spectral data for 124: a White solid, [a]026 -150.95° (c 1.05, CH30H)
IA (CH2CI2) cm-1 3565, 713;
1H NMA (CDCI3) b 1.79-2.02 (2,m), 2.39 (1,br s), 3.36 (3,s), 3.57-3.85 (3,m),
4.54 (1,d, J=12 Hz), 4.02-4.09 (1,m), 4.72 (1,d, J=12 Hz), 4.75-4.77 (1,m) and
7.29-7.36 (5,m)
13C NMA (CDCI3) b 27.27 (CH2) , 34.7 (CH2), 55.00 (CH3) , 64.38(CH), 70.88
(CH2), 74.74 (CH), 98.73 (CH), 127.49 (CH), 127.57 (CH), 128.20 (CH), and
137.69 (C).
Spectral data for 125: an oil, [a]()25.5 -119.29° (c 0.85, CH2C/2)
IA (CH2CI2) cm-1 3690, 733
1H NMA (CDCI3) b 1.85-2.07 (2,m), 2.59 (1,br s), 3.33 (3,s), 3.74-3.90 (4,m),
4.57 (2,5), 4.79 (2,br s), and 7.33 (5,br s)
13C NMA (CDCI3) b 31.83 (CH2), 55.88(CH3), 64.38 (CH2), 65.02 (CH), 69.76
(CH2), 73.88 (CH), 100.05 (CH), 127.49 (CH), 127.60 (CH), 128.34 (CH), and
137.65(C).
Preparation of Methyl 2-Deoxy-3-methoxy-4-benzyloxy-ribo
pyranoside 126
92
To a suspension of NaH (497 mg, 20.69 mmol) in dry THF (10 mL) at O°C
was added a solution of 124 (1.825 g, 7.659 mmol) in THF (15 mL). The reaction
was stirred for 1 h at 0 °c and then for 17.5 h at room temperature. The reaction
was quenched by careful addition of H2O (20 mL) and extracted with ether (6 x
50 mL). The combined organic phases were dried (MgS04), filtered, and
concentrated in vacuo to give 126 (1.82 g, 7.21 mmol,94%).
Spectral data for 126: an oil, [a]D _89° (c 0.76, CH2C12)
IA (CHCIa) cm-11265, 833,722,713.
1H NMA (CDCI3 ) 5 1.82-2.16 (2,m), 3.33 (3,s), 3.34 (3,s), 3.77-3.81 (2,m),
4.71 (2.s), 4.80-4.82 (3,m), and 7.26-7.41 (5,m).
Preparation of Methyl 2-Deoxy-3-methoxy-4-hydroxy-ribo
pyranoside 127
A mixture of 126 (277 mg, 1.098 mmol) and 10% Pd/C catalyst (50 mg) in
absolute ethanol (50 mL) was stirred at room temperature under a hydrogen gas
balloon for 12 h. The catalyst was then removed by centrifugation and volatiles
removed in vacuo. Chromatography of the residue on silica gel 60 (25 g) eluted
with 50% EtOAc/hexanes afforded 127 (179 mg, 1.1 mmol, 100%)
Spectral data for 127: an oil, [a]027 -204.91° (c 2.65,CH30H);
IA (CDCIa) cm-13568;
1 H NMA (CDCI3) 5 1.87-2.02 (2,m), 2.77 (1,s), 3.34 (3,s), 3.35(3,s), 3.61-3.67
(1 ,m) 3.75 (2,d,J=2.5), 3.93 (1,br s), and 4.79 (1 ,s)
93
13C NMR (CDCI3)530.13 (CH2), 54.75 (CH). 55.42 (CH), 62.19 (CH2), 65.07
(CH3), 73.55 (CH3), and 98.61 (CH).
Preparation of Methyl 2-Deoxy-3-methoxy-4-tosyl-ribo-pyranoside 128
To a solution of 127 (977 mg, 6.024 mmol) in dry pyridine (14 mL) at 0 °c
was added p-toluene sulfonyl chloride (3.572 g, 18.734 mmol). The reaction
mixture was stirred for 0.5 h and was then kept in the refrigerator at -15°C for
another 48 h. The mixture was diluted with ether (200 mL) and washed with H2O
(50 mL), cold 10% HCI (2 x 50 mL), H2O (50 mL) and saturated NaHC03 (2 x 50
mL). The organic phase was dried (MgS04) ,filtered and volatiles were removed
in vacuo. The residue was chromatographed on silica gel 60 (250 g) eluted with
30% EtOAc/hexanes to afford tosylate 128 (1.741 g, 5.507 mmol, 91%).
Spectral data for 128: an oil, [aJ026 -137.6 ° (c 4.45, CH30H)
IR (CDCI3) cm-1 1791, 1596,979,917,738,651
1H NMR (CDCI3) 5 1.81·2.04 (2,m), 2.43 (3,s), 3.14 (3,s), 3.32 (3,s), 3.58-3.86
(3,m), 4.79 (2,br s), 7.31 (2,d,J=8), and 7.85 (2,d,J=8)
13C NMR (CDCI3) 515.13 (CH3), 31.24 (CH2), 54.98 (CH3) ,55.77 (CH), 60.68
(CH2), 71.91 (CH3), 74.50 (CH3), 98.53 (CH), 127.75 (CH), 129.52 (CH), 134.05
(C), and 144.49 (C).
Preparation of Methyl 2-Deoxy-3-benzyloxy-4-tosyl-ribo
pyranoside 129
To a solution of alcohol 125 (557 mg, 2.34 mmol) in dry pyridine (6 mL) at
o °c was added p-toluenesulfonyl chloride (1.38g, 7.24 mmol). The reaction
94
mixture was stirred for 0.5 h and was then kept in the refrigerator at -15°C for
another 72 h. The mixture was diluted with ether (200 mL), washed with H2O (50
mL). The organic layer was washed with cold 10% HCI (2 x 50 mL), H2O (50 mL)
and sat. NaHC03 (2 x 50 mL). The organic phase was dried (MgS04), filtered,
and volatiles were removed in vacuo. The residue was chromatographed on silica
gel 60 (50 g) and eluted with 30% EtOAc/hexanes to afford tosylate 129 (871 mg,
2.22 mmol, 95%)
Spectral data for 129: white solid, mp 115-116 °c, [cx]024.5 -72.75° (c 0.8,
CH2CI2)
IR (CH2CI2) cm-1 1597, 1549, 1065
1H NMR (CDCI3) 6 1.92-2.1 (2,m), 2.38 (3,s), 3.30 (3,s), 3.74-3.91 (3,m),4.41
(2,q, J=11.6 Hz), 4.80 (2,br s), 7.17-7.33 (7,m), and 7.80 (2,d, J=8.3 Hz)
13C NMR (CDCI3) 6 21.60 (CH3) , 31.68 (CH2), 55.14 (CH3) , 60.98 (CH2,)
70.08 (CH2) , 70.1 (CH), 75.23 (CH), 98.72 (CH), 127.48 (CH), 127.58 (CH).
127.87 (CH), 129.28 (CH), 129.61 (CH), 133.78 (C), 136.68 (C), and 143.93 (C).
Preparation Methyl 2-Deoxy-3-hydroxy-4-tosyl-ribo-pyranoside 130
A solution of tosylate 129 (211 mg, 0.538 mmol) and 10% Pd/C catalyst
(50 mg) in ethyl acetate (20 mL) was stirred at room temperature under a
hydrogen gas balloon for 33 h. The catalyst was then removed by centrifugation
and volatiles were removed in vacuo. Chromatography of the residue on silica gel
60 (25 g) eluted with 30% EtOAc/hexanes afforded 130
(136 mg, 0.450 mmol, 84%).
95
Spectral data for 130: a White solid, mp 115-116 °c, [a]026 -113.88° (c 1.6,
CHCI3)
IR (CHCIa) cm-13618, 1597, 1475, 1064,929
1H NMR (CDCI3) 51.88-1.92 (2,m), 2.10 (1,d, .J=7.9 Hz), 2.45 (3,s), 3.31 (3,s),
3.73 (2,d,J=2.6 Hz), 4.08-4.12 (1,m), 4.66-4.78 (2,m) 7.35 (2,d, J=8.1 Hz) and
7.84 (2,d, J=8.3 Hz).
13C NMR (CDCI3) 5 21.46 (CH3) 33.89 (CH2) , 55.07 (CH), 60.24 (CH2), 63.30
(CH3), 78.38 (CH), 98.49 (CH), 127.67 (CH), 129.78 (CH), 133.40 (C), and
144.93 (C).
Preparation of Methyl 2-Deoxy-3-methoxy-4-tosyl-ribo-pyranoside 128 from
130
To a solution of tosylate 130 (102 mg, 0.338 mmol) and methyl iodide (424
mg, 3 mmol) in DMF (1 mL) at ambient temperature was added silver oxide (151
mg, 0.650 mmol) in one portion. The solution was stirred for 27 h, then diluted
with chloroform (10 mL), filtered, and volatiles removed in vacuo. The residue
was taken up in ether (40 mL), washed with water (2 X 10 mL), the organic phase
was dried (MgS04), filtered, and volatiles removed in vacuo. The residue was
chromatographed on silica gel 60 (25 g) eluted with 20% EtOAc/hexanes to
afford 128 (103 mg, 0.326 mmol, 96%) Spectral data were as previously listed.
Preparation of Methyl 2-Deoxy-4-azido-3-methoxy-ribo-pyranoside 131
A suspension of tosylate 128 (969 mg, 3.409 mmol) and sodium azide
(1.177 g, 3.409 mmol) in dimethyl sulfoxide (30 mL) was stirred at 130-140 °c for
96
1 h. The solution was then cooled to room temperature and poured into a mixture
of ice cold H2O (150 mL) and saturated NaHCD3 (30 mL). The mixture was
extracted with hexanes (3 x 150 mL), the combined extracts were dried (MgS04),
filtered and volatiles were removed in vacuo. The residue was chromatographed
on silica gel 60 (30 g) eluted with 50% EtOAc/hexanes to afford azide 131 (0.594
g, 3.17 mmol, 93%).
Spectral data for 131: an oil, [a]rj!5 -12.5° (c 0.4, CHCI3)
IR (CDCI3) cm-1 2109
1H NMR (CDCI3) 5 1.49-1.59 (1 ,m), 2.20-2.23 (1,m), 3.32 (3,s), 3.42-3.67 (7,m),
and 4.77 (1 ,br s)
13C NMR (CDCI3) 5 34.39 (CH2), 54. n (CH), 56.63 (CH), 60.15 (CH2), 61.15
(CH3), 76.82 (CH3), and 78.62(CH).
Preparation of Methyl 2-Deoxy-3-methoxy-4-N-acetylamino-ribo-pyranoside
132
A solution of azide 131 (594 mg, 3.173 mmol) in methanol (132 mL)
containing acetic anhydride (4.3 mL) and platinum(IV) oxide (200 mg) was stirred
under a hydrogen gas balloon for 39 h. The catalyst was removed by
centrifugation and triethyl amine (10 mL) was added. The solvent was removed in
vacuo and the residue was chromatographed on silica gel 60 (50 g) eluted with
ethyl acetate to give a yellowish solid which was recrystallized from ether (30 mL)
to give white solid 132 (603 mg, 2.967 mmol, 93%)
Spectral data for 133: white solid, mp 105-106 °C, [a]rj!6.5 -79.2° (c 0.5, CH2C12)
IR (CH2C12) cm-1 3430, 1674.
97
1H NMR (CDCI3) 51.68-1.88 (2,m), 1.95 (3,s), 3.37 (3,s), 3.34 (3,s), 3.37-3.97
(3,m), 3.96 (1 ,br s), and 5.78 (1 ,br s).
13C NMR (CDCI3) 5 23.22 (CH3), 32.98 (CH2), 47.86 (CH3), 55.65 (CH), 56.19
(CH), 62.62(CH2), 75.24 (CH3), 99.26 (CH), and 169 (C).
Preparation of 2-Deoxy-4-ethylamino-ribo-pyranoside 59a
In a dry, 250 ml flask equipped with a reflux condenser was suspended
LiAIH4 (124 mg, 3.26 mmol) in THF (10 ml). The mixture was heated to reflux for
20 min. Heating was discontinued and 132 (254 mg, 1.25 mmol) in THF (35 ml)
was added dropwise over 0.5 h. Heating was then resumed and continued for 11
h. The reaction mixture was cooled to 0 °c and the reaction was quenched by
additions of water(129 Ill), 4N NaOH (129 Ill), and water (382 Ill). The salts
were removed by filtration and volatiles removed in vacuo. The salts were
extracted with ether using a sohxlet apparatus and the combined residues were
chromatographed on silica gel 60 (25 g) eluted with ethyl acetate to give ethyl
amino sugar 59a (215 mg, 1.14 mmol, 91%).
Spectral data for 598 : an oil, [a]025 -56.8° (c 1.4, CHCI3), lit. [a]023 -56.7° (c
1.0, CHCI3)
IR (CH2CI2) cm-1 3688;
1H NMR (CDCI3) 51.09-1.15 (3,m), 1.51-1.57 (1,m), 1.95 (1,s), 2.17-2.25 (1,m)
2.56-2.69 (2,m), 3.34-3.49 (9,m), 3.73-3.78 (1 ,m), and 4.79 (1 ,s)
13C NMR (CDCI3) 515.47 (CH3,) 33.61 (CH2) ,41.91 (CH2), 54.47 (CH), 55.94
(CH), 58.94 (CH3) , 61.79 (CH2), 76.7 (CH3) , and 98.84 (CH).
Preparation of 2-Deoxy-4-N-acetylam i no-ribo-pyranoside
Derivative 133
98
The amino sugar 59a (129 mg, 0.682 mmol) was taken up in triethylamine
(10 ml) and the mixture was cooled to 0 °c. Acetyl chloride (242 Ill, 3.41 mmol)
was added dropwise. The mixture was stirred at room temperature for 4 hand
poured into H2O and extracted with CH2C12 (25 mL). The organic extracts were
dried (MgS04), filtered, and volatiles removed in vacuo. The residue was
chromatographed on silica gel 60 (25 g) eluted with ethyl acetate to give N
acetylated amino sugar 133 (142 mg, 0.614 mmol, 90%).
Spectral data for of 59a; an oil, [a][)25 _98° (c 0.4, CHCI3), Iit25 [a]o -98° (c 0.4,
CHCI3), Iit26 [a]o25 -99.0° (c 0.96, CHCI3), Iit25 [a]020 -96.0° (c 0.9, CHCI3); 1H
NMR and 13C NMR were identical to those kindly provided by Professor Kahne.
IR (neat) cm-1, 3623,1600
1H NMR (COCI3) 51.09-1.25 (4,m), 1.48-1.60 (1,m), 2.08-2.15 (3,m), 2.29-2.40
(1 ,m), 3.09-4.06 (11 ,m), and 4.81 (1 ,br s).
13C NMR (COCI3) 5 15.39 (CH3), 22.36 (CH3), 35.27 (CH2), 36.82 (CH2,) 54.94
(CH), 56.4 (CH), 59.18 (CH2), 59.71 (CH3), 72.67 (CH3), and 98.86 (CH)
Preparation of 2-Deoxy-4-Nl-Carbobenzyloxyamino-ribo-Pyranoside 134
A solution of azide 131 (460 mg, 2.457 mmol) and 10% Pd/C catalyst (50
mg) in ethyl alcohol (4 ml) was stirred at ambient temperature under a hydrogen
gas balloon for 15h. The catalyst was then removed by centrifugation and the
solvent was removed in vacuo. The residue was taken up in THF (10 ml) and
mixed with sodium carbonate (520 mg). The reaction mixture was cooled to O°C
99
and benzyl chloroformate (0.526 mL, 3.686 mmol) was added. The reaction
mixture was stirred for 3 h followed by addition of NaHC03 (100 mg), ether (100
mL) and water.(15 mL). The organic phase was separated, dried (MgS0 4),
filtered, and volatiles were removed in vacuo. The residue was chromatographed
on silica gel 60 (25g) and eluted with ethyl acetate to give 135 (386 mg, 53%).
Spectral data for 135 : an oil, [a)026.5 -48.92° (c 2.5, CH2CI2)
IR (CDCI3) cm-1 3433, 1718,733;
1H NMR (CDCI3) [) 1.73 (1,br s), 1.98-2.03 (2,m), 3.36 (3,s), 3.44 (3,s), 3.48-
3.93(4,m), 4.66-4.69 (1 ,m), 5.21 (2,s), 5.23 (1 ,br s), and 7.33 (5,s)
13C NMR (CDCI3) [) 33.20 (CI-I2) 50.07 (CH), 55.26 (CH3), 56.20 (CH3), 62.23
(CH2), 66.67 (CH2), 75.55 (CH), 98.99 (CH), 127.97 (CH), 128.00 (CH), 128.40
(CH), 136.23 (C), and 155.89 (C).
Preparation of Methyl 2-Deoxy-4-methylamino-ribo-pyranoside 136
To a solution of 135 (123 mg, 0.416 mmol) and methyl iodide (261 mg,
1.84 mmol) in DMF (1.5 mL) at room temperature was added silver oxide (344
mg, 1.485 mmol) in one portion. The solution was stirred for 20 h and diluted with
chloroform (20 mL), filtered, and volatiles were removed in vacuo. The residue
was diluted with water (200 mL) and extracted with ether (3 X 100 mL), The
organic extracts were dried (MgS0 4), filtered, and volatiles were removed in
vacuo. The residue was dissolved in ethyl acetate (5 mL), filtered through a silica
gel plug and solvent was removed in vacuo to give 136 (105 mg, 0.339 mmol,
82%)
Spectral data for 136 ; an oil, [ex]025.5 -40.40° (c 0.75, CH2CI2)
IR (CH2CI2) cm-1 1720, 733
100
1 H NMR (CDCI3) 5 1.45-1.50 (1,m), 2.19-2.26 (1,m), 2.80-2.84 (3,m), 3.22-3.28
(6,m), 3.50-3.74 (4,m), 4.69 (1 ,br s), 5.03-5.09 (2,m) and 7.26-7.30 (5,m).
13C NMR (CDCI3) 5 30.29 (CH3) , 34.75 (CH2), 54.65 (CH), 55.73 (CH3), 57.01
(CH3), 58.97 (CH2), 67.04 (CH2), 72.02 (CH), 98.74 (CH), 127.63 (CH), 127.74
(CH), 128.28 (CH), 136.63 (C), and 156.37 (C).
Preparation of Bicyclo[5.1.0Joct-3-en-2-one 152
The bicyclic ketal 14977 (407 mg, 2.42 mmol) in THF (6 mL) was treated
with phenyltrimethylammonium tribromide (910 mg, 2.42 mmol) at 0 °c. After 15
min the mixture was poured into a solution of 5% K2COs (10 mL) and ether (50
mL). The ether layer was separated, dried (MgS04), filtered, and volatiles
removed by distillation at atmospheric pressure.
The residue was chromatographed on silica gel 60 (75 g) eluted with 5%
EtOAc/hexanes, affording 150 (484 mg, 1.96 mmol, 81%) of brominated ketal
Spectral data for 150: an oil,
1H NMR (CDCI3) 50.44-0.48 (1 ,m), 1.42-2.22 (6,m) and 3.61-4.3 (5,m).
13C NMR (CDCI3) l> 11.22 (CH2), 13.57 (CH), 20.22 (CH), 21.66 (CH2) , 23.27
(CH2), 29.26 (CH2), 29.86 (CH2), 32.92 (CH2), 34.03 (CH2), 61.18 (CH), 63.99
(CH2), 66.00 (CH2), and 109.58 (C).
The brominated ketal 150 (235 mg, 0.951 mmol) was added to a
suspension of sodium methoxide.(154 mg, 2.85 mmol) in DMSO (2 mL). The
101
mixture was stirred at room temperature for 3.5 h before addition of water (20
mL). The mixture was extracted with hexanes (3 X 20 mL), and the combined
organic extracts were dried (MgS04), filtered, and volatiles were removed by
distillation at atmospheric pressure. in vacuo. The residue (151) was stirred for
1.5 h with 3% H2S04 (20 mL) and the reaction mixture was neutralized using
NaHC03 (50 mL). The aqueous layer was extracted with ether (5 X 100 mL). The
combined organic extracts wers dried (MgS04), filtered and solvent removed in
vacuo. The residue was chromatographed using silica gel 69 (10 g) eluted with
8% ether Ipentane to afford 152 (104 mg, 0.851 mmol, 89 %)
Spectral data for 151
1H NMR (CDCI3) 5 0.59-0.68 (2,m), 0.86-0.98 (1,m), 1.30-2.36 (5,m), 3.86-4.08
(4,m), and 5.57-5.75 (2,m),
13C NMR (CDCI3) 58.16 (CH2), 12.90 (CH), 23.80 (CH), 25.66 (CH2),30.33
(CH2), 64.27 (CH2), 64.n (CH2), 107.79 (C), 131.11 (CH), and 133.58 (CH)
Spectral data for 152
1H NMR (CDCI3) 5 1.1-1.2 (1,m), 1.32-1.39 (1,m), 1.67-1.75 (1,m), 1.95-2.5
(5,m). 5.8-5.89 (1,m), and 6.26-6.36 (1,m).
13C NMR (CDCIa) 511.78 (CH2), 21.01 (CH), 23.45 (CH2), 28.95 (CH2), 30.00
(CH), 129.71 (CH), 143.06 (CH), and 205.12 (C).
Conjugate Addition of Phenyl Cuprate to Bicyclo[5.1.0]oct-3-en-2-one 152
To a cooled (0 °C) solution of cuprous bromide (41 mg, 0.286 mmo/) in dry
ether (3 mL) was added dropwise phenyllithium (0.33 mL of 1.8 M solution in
cyclohexane/ether, 0.594 mmol). The solution was allowed to stir for 15 minutes.
lO2
To the resulting dark green solution was added dropwise enone 152 (20 mg,
0.164 mmol) as a solution in dry ether (3 mL). The resulting dark green solution
was stirred for 0.5 h at 0 °c then quenched by addition of sat. NaHC03 (10 mL)
and ether (20 mL). The ether layer was separated and the
aqueous layer extracted with ether (3 X 20 mL). The combined organic extracts
were dried (MgS04), filtered, and volatiles were removed in vacuo. The residue
was chromatographed on silica gel 60 (10 g) eluted with 5% EtOAc/hexanes,
affording 153 (26 mg, 0.130 mmol, 79%).
Spectral data for 153 as a single diastereomer
IR (neat) cm-1 2999, 2922, 1698, 1492, 1447, 1360, 1080, 1039, 764, 729 and
700.
1H NMR (CDCI3) 5 0.7-0.85 (1,m), 0.95-1.01 (2,m), 1.63-1.78 (1,m), 1.88-1.98
(1,m), 2.07-2.16 (1,m), 2.33-2.43 (1,m), 2.57-2.67 (2,m), 2.99 (1,t, J=11.4), and
7.16-7.33 (5,m).
13C NMR (CDCI3) 5 12.51 (CH2,) , 15 (CH), 29.18 (CH2,) , 29.24 (CH2,) , 35.16
(CH2,) , 44.09 (CH), 51.03 (CH2,) , 126.37 (CH), 128.52 (CH), 145.43 (C), and
208.56 (C).
Conjugate Addition of Methyl Cuprate to Bicyclo[5.1.0]oct-3-en-2-one 152
To a cooled (0 °C) solution of cuprous bromide (204 mg 1.43 mmol) in dry
ether (15 mL) was added dropwise Methyllithium (7.4 mL of 0.4 M solution in
ether, 2.96 mmol). The solution was allowed to stir for 15 minutes. To the
resulting dark grey solution was added dropwise enone 152 (100 mg, 0.818
mmol) as a solution in dry ether (15 mL). The resulting dark green solution was
103
stirred for 0.5 h at O°C then quenched by addition of sat. NaHC03 (20 mL), ether
(60 mL), and water (50 mL). The ether layer was separated and the aqueous
layer extracted with ether (3 X 60 mL). The combined organic extracts were dried
(MgS04), filtered, and volatiles were removed in vacuo. The residue was
chromatographed on silica gel 60 (10 g) eluted with 5% EtOAc/hexanes, affording
154 (89 mg, 0.646 mmol, 79%).
Spectral data for 154: oil, IR (neat) cm-1 3497, 3001,1700,1679,1453,1363,
1269, 1180, 1165, 1129, 11 05, 1083 and 1035.
1H NMR (CDCI3) 60.93 (3,dJj=6.8 Hz), 0.97-1.1 (2,m), 1.2-1.44 (3,m), 1.87-1.96
(1,m), 2.16-2.36 (2,m), and 2.49-2.55 (1,m).
13C NMR (CDCI3) 6 12.37 (CH2), 17.33 (CH), 19.89 (CH), 25.25 (CH2) , 29.57
(CH3), 33.35 (CH2), 48.98 (CH2) and 210.03 (C).
Benzylation of Bicyclo[5.1.0]octan-2-one 155
A 100 mL flask was charged with lithium diisopropylamide (1.5 M solution
in cyclohexane, 0.676 mL, 1.014 mmol) and THF (5 mL). The solution was cooled
to -42°C and bicyclo[5.1.0Joctan-2-one 155 (120 mg, 0.966 mmol) was added as
a solution in dry THF (5 mL). The reaction was stirred at this temperature for 1 h
and benzyl bromide (198 mg, 1.14 mmol) was added. The reaction flask was left
in the refrigerator (-30°C) for 14 h. The reaction mixture was quenched by
addition of NH4CI (5 mL) and H2O (5 mL). The aqueous layer was extracted
with ether (3 X 20 mL) and the combined organic extracts were dried (MgS0 4),
filtered, and the volatiles were removed in vacuo. The residue was
chromatographed on flash silica gel (30 g) eluted with 8% EtOAc/hexanes,
104
affording 156 (155 mg, 0.723 mmol, 75%).
Spectral data for 156: oil, IR (neat) cm-1 3080, 3059,3023,2922,2850, 1672,
1600,1494,1450,1380,1225,1201,1181,1074,1061, 1030,988,942,910,
852,758,735 and 700.
1H NMR (CDCI3) l) 0.89-1.05 (2,m), 1.22-1.69 (5,m), 1.86-1.99 (3,m), 2.48-2.67
(2,m), 3.05-3.12 (d1,m), and 7.12-7.28 (5,m).
13C NMR (CDCI3) l) 12.28 (CH2), 19.08 (CH), 23.75 (CH2), 26.57 (CH2), 29.21
(CH2), 30.07 (CH), 36.78 (CH2) , 48.95 (CH), 125.75 (CH), 128.08 (CH), 128.95
(CH),140.40 (C) and 212 (C).
Methylation of Bicyclo[5.1.0]octan-2-one 155
A 100 ml flask was charged with lithium diisopropylamide (1.5 M solution
in cyclohexane, 0.676 ml, 1.014 mmol) and THF (5 ml). The solution was cooled
to -42°C and bicyclo[5.1.0]octan-2-one 155 (118 mg, 0.950 mmol) was added as
a solution in dry THF (5 mL). The reaction was stirred at this temperature for 1 h
and methyl Iodide (162 mg, 1.14 mmol) was added. The reaction flask was left in
the refrigerator (-30°C) for 17 h. The reaction mixture was quenched by addition
of NH4CI (5 mL) and H2O (5 mL). The aqueous layer was extracted with ether (3
X 20 mL) and the combined organic extracts were dried (MgS04), filtered, and
the volatiles were removed in vacuo. The residue was chromatographed on flash
silica gel (30 g) eluted with 8% EtOAc/hexanes, affording 157 (105 mg, 0.760
mmol,80%).
Spectral data for 157: oil, IR (neat) cm-1 2972, 2928, 2852, 1666, 1458, 1377,
1264,1229,953,910,733 and 647.
105
1 H NMR (CDCI3) 60.8-0.9 (1,m), 0.935 (3,d,J=6.57), 1.18-1.21 (1,m), 1.38-1.72
(4,m), 1.77-1.9 (3,m), and 2.3-2.S (1,m).
13C NMR (CDCI3) 6 12.06 (CH2), 16.59 (CH), 19.12 (CH), 23.8 (CH2), 26.77
(CH2), 29.96 (CH3), 32.13 (CH2), 41.7S (CH), and 212.94 (C).
Allylation of Bicyclo[5.1.0] octan-2-one 155
A 100 mL flask was charged with lithium diisopropylamide (1.S M solution
in cyclohexane, 0.676 mL, 1.014 mmol) and THF (S mL). The solution was cooled
to -42°C and bicyclo[S.1.0]octan-2-one 155. (118 mg, 0.9S0 mmol) was added as
a solution in dry THF (S mL). The reaction was stirred at this temperature for 1 h
and allyl iodide (138 mg, 1.14 mmol) was added. The reaction flask was left in the
refrigerator (-30°C) for 24 h. The reaction mixture was quenched by addition of
NH4CI (S mL) andf H2O (S mL). The aqueous layer was extracted with ether (3
X 20 mL) and the combined organic extracts were dried (MgS04) , filtered, and
the volatiles were removed in vacuo. The residue was chromatographed on flash
silica gel (30 g) and eluted with 8% EtOAc/hexanes, affording 158 (121 mg,O.737
mmol,78%).
Spectral data for 158: oil, IR (neat) cm-1 2926, 1668, 1264,909,736 and 649.
1H NMR (CDCI3) 50.86-1.08 (2,m), 1.2S-1.32 (1,m), 1.44-1.52 (2,m), 1.S9-1.72
(2,m), 1.9-2.0S (3,m), 2.36-2.52 (3,m), 4.96-S.03 (2,m), and S.6S-S.74 (1,m).
13C NMR (CDCI3) 5 12.21 (CH2) , 18.98 (CH), 23.7S (CH2), 26.74 (CH2) , 29.51
(CH2) , 29.98 (CH), 3S.12 (CH2) , 46.97 (CH), 116.02 (CH2) , 136.69 (CH,) and
211.83 (C).
106
APPENDIX
, , , ';', , ,
, I ,
/ I.
36
! ' ! • I I '/, : i / I
, r' ._- ,'" ,-:,1· ':- .. ::. -I'; i
. i ,I' , . I "II' : ~ / ! I "" ! ! Ii:' I '~:-j:s~~~_~~~i II',!'"
, ' , I I ..
I,
• I i
: / ! :"1 i !
' .. ,1' " ! ' I,: f II'. i '
, ,
I' I
, I
I
i , , I - I
; I: :! ,',: I': ! ,~, ,I : 'I I
i ' i ! l'i
, ",' I ' ,,; : :,"1'
I,: ':, ,:,' ". :; i !
107
108
l 37
I
109
37
L
f 00-Me Me
41 0
110
9 o~Me
41 bJ ~Me ! 1--
___ Lr---
111
I
o o ~ o=(J-Me
Me
o 42
112
42
? 00-Me Me
o
113
114
43a
o o
o ID
V1
ID
115
116
117
44
118
44
"
'i I I
-=.J
119
120
--'
~_I
121
122
123
124
_---=."'--"5'
-------========~==~=--- -~ ~ --_ .......
~ 'l
j I I
i I
i
L
125
B~R 5N.003 DATE 8-10-91
5F \500.135 5Y 16 0 01 700.000 5I 3 768 TO 3 768 511 02 •. 096 HZ/PT .366
PII RD AQ RG NS TE
2.0 0.0 2.720 6
119 297
FII (600 02 .00.000 DP "L PO
---------
1.0 .5 0.0
en ~
~ 0
><0 .-IV 0\
e§8R PAAK.OOI DATE 6-10-91
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PW 6.0 AD 0.0 AO .557 AG 200 NS 1065 TE 297
FW 36800 02 7400. DP 24L
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U1 N
't,~ -X"'" 0
IV -...J
128
51
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0 H 3
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129
o
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o .. o V1
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130
o~ H H
, ----~.-.>
,../
I ! J
;
131
o~
55
132
56
133
56
134
o
36
L
135
o~ Me
57a + 57b
I.
136
~oJM.
ra ,/ s ~" o 0
117
137
L
138
i I.
, .' , : .
. '
I; I : ; 'l : "I. ~ :
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, '
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, ' ,': .
139
Ac OMe
fJd MeO
99
140
o
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o to
("J
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o CD
Z a. a.
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99
l
142
RloMe
Bno ~H 124
RlMe HO ~Bn
125
143
144
OMe
vi HO
125
-
1
145
OMe
Bnpi. 126
146
OMe
~. 8nO
126
L
147
OMe
PiL. HO
127
OMe
H~e 127
148
" ___ ---.lID
o CD
149
OMe
~e TsO
128
l50
OMe
To pi. 128
151
OMe
Pi TsO
129
-
152
OMe
~ TsO
129
153
154 OMe
TSfoi 130
OMe
N3-O)
~e 131
l55
156
OMe
Nap) OMe
131
157
HOMe
I -O,,} Ac .. N~e
132
L
L.
158
~~OMe N 0
Ac~ OMe
132
!:.
-
L
159
OMe
H~ , 0
IN OMe Et
59a
HOMe I _,,;j N~ El OMe
59a
160
I
161
Ac OMe , . _,..A N~
Etl OMe
133
OMe
~CO~ IN~e
Et 133
162
163
134
\
164
134
·165
0'f~O OMe pr HN a OMe
135
l66
o 0 OMe
f:r~ Olde
135
167
136
168
o 0 OMe
prr~ ,...N
H3C OMe
136
169
150
I
~ . :'j 1 .1 ", .:,,+, ,I'
.,
·1' ,"I ~ i ~ , . ! I ,I I :'1;11:;:. ·1 ..
. :. . 1
;
I" , I 1 I ''/' 1;';':'1
1
i
I .. :, I ...
:':' I ! I i .. ! .. :. I.: 1
1 l
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170
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171
151
172
151
173
o
o rae ·152
l~.
. I )
>
> >-
< ,
l74
o
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175
153
176
153
:
177
154
178
154
•
l
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179
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180
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L
181
157
182
157
I
--....,
----------------
183
o
158
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-I
'\ -\ ..::J
I -
.. -
r -J J
-
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-
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184
158
-
185
REFERENCES
186
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78 I would like to thank Dr. James Fryling for providing an X-ray structure
for acetal 42.