qoang-rung bih, 3.s. - tdl
TRANSCRIPT
^n' r. . 1;» * ^ . V w W > 0 _ / _ K
/ -rr
DV
QOANG-RUNG BIH, 3 . S .
A T:-:ESIS
IN
CHLMISTRY
Submitted to the Graduate Faculty of Texas Tech University in
Partial Fulfillrr.ent of the Requirements for
the Degree of
MASTER OF SCIENCE
Approved
CL^lr/C
Chairman of the Coomittee
Q>^ A . ^ ^ : ^ ^ - > , . ^ T
ubhi/sf j^:- loi
Accepted
tAj^^ Dean of the Grafcbate School
August, 193^
/ ^
H^* '-^ I ACKNOWLEDGMENTS
I am deeply indebted to my research advisor and committee chair
man, Dr. John N. Marx, for his instruction, valuable guidance, and
assistance through this research. Also, I would-like to thank the
other members of my Committee, Dr. Joe A. Adamcik and Dr. Robert D.
Walkup, for their helpful suggestions.
In addition, I would like to extend my thanks to Miss Mary
Ettel and Mr. Hollis Boss for helping me correct the manuscript.
Special recognition should be given to my parents for their
encouragement and assistance in completing this M.S. program.
11
TABLE OF CONTENTS
Page
ACKNOWLEDGMENTS ii
I. INTRODUCTION 1
II. SYNTHESIS OF ANHYDRO-/]-ROTUNDOL 10
Proposed Synthesis 10
Preparation of 2,6-dimethyl-4-
hydroxybenzaldehyde (22) 15
Preparation of 2,6-dimethyl-4-hydroxybenzylalcohol (23) 16
Preparation of 3,5-dimethyl-4-hydroxymethyl phenyl methylsulfonate (_25.) 18
Intermolecular Coupling Reaction-Preparation of 5-(2',6'-dimethyl-4'-hydroxyphenyl)-3-methylidene-2-methyl-2-pentanol (_28.) 24
Preparation of 5-(2',6'-dimethyl-4'-hydroxyphenyl)-3-hydroxymethyl-2-methyl-2-pentanol (2£) 30
Preparation of 4-[2',6'-dimethyl-4*-(methylsulfonyl)hydroxy ]phenyl-2-isopropenyl-butyl methylsulfonate (44) 35
Formation of anhydro-H-rotundol 39
III. CONCLUSION 42
IV. EXPERIMENTAL PROCEDURES 44
General 44
2,6-dimethyl-4-hydroxybenzaldehyde (_2) 45
2,6-dimethyl-4-hydroxybenzylalcohol (_23_) 45
3,5-dimethyl-4-hydroxymethy1 phenyl methylsulfonate (25)
5-(2',6'-dimethy1-4'-hydroxyphenyl)-3-methylidene-2-methyl-2-pentanol (28)
V\J
47
5-(2',6'-dimethy1-4'-hydroxyphenyl)-3-hydroxymethyl-2-methyl-2-pentanol (2^) 48
111
4-[2*,6'-dimethy1-4'-(methylsulfonyl)hydroxy] phenyl-2-isopropenyl-butyl methylsulfonate (j44) ^8
Anhydro-A -rotundol 49
REFERENCES AND NOTES 51
APPENDICES
I. NUCLEAR MAGNETIC RESONANCE SPECTRA 53
II. INFRARED SPECTRA 61
III. MASS SPECTRUM 69
IV
CHAPTER I
INTRODUCTION
Natural products supply many valuable challenges to the organic
chemist. In studies of natural products, an organic chemist encounters
two problems. The first involves isolation and purification of some
compound from a plant or animal source and then elucidation of its
structure from chemical and spectral studies. The second is confirma
tion of its structure by its total synthesis by reasonable routes. In
working toward total synthesis of natural products, new knowledge often
results, such as new synthetic methods and determination of the
mechanisms of reactions.
One of the largest classes of natural products is the terpenes.
The terpenes, which are found in animals and plants, exist in a large
variety and complexity of structures. The terpenes are recognized as
formal derivatives of isoprene, 2-methyl-l,3-butadiene (1).
CH3
C H 2 = C — C H = C H 2
The main classification of the terpenes is on the basis of the
number of isoprene units in the molecule, a single "terpene unit" being
equal to two isoprene units. Compounds formally consisting of two,
three, four, five, six, eight and more isoprene units are known as mono-.
sesqui-, di-, sester-, tri-, tetra- and polyterpenes, respectively.
Some well known examples include geraniol (2), limonene (3), abietic
acid (4) and cedrol (5).
- ^
The largest class of the terpenes is the sesquiterpenes. Sesqui
terpenes have fifteen carbon atoms and three isoprene units. One of the
important sesquiterpene types is vetivane. The carbon skeleton of the
vetivane sesquiterpenes was previously assigned as the bicyclo [5.3.0.]-
decane carbon skeleton (_6_). However, the original structural assignments
were in error for OL - and H-vetivone. Both ketones were later found not
to have such a carbon framework, i.e., d-vetivone has the skeleton {]_)
and n -vetivone has the skeleton (8 ).
Recently, the new name "spirovetivanes" has been accepted for the
vetivone-related natural products with a spiro[4.5]-decane carbon
7 8
skeleton (8^).
One of the most interesting sesquiterpenes of the spirovetivane
class is anhydro-A-rotundol, spirovetiva-l(lO),3,ll-trien-2-one. This
thesis will desribe the first total synthesis of anhydro-/3-rotundol,
which has structure (9).
15
7 11>=12
Anhydro-/3-rotundol was obtained as a major stress metabolite from
the fungus Phytophthora infestans infected potato tissue and was purifi
ed by liquid chromatography and crystallization from pentane. This o
compound was found to have the formula C.|^^H2QO, [0.]^ 57 (EtOH) and mp
o ^i
44-44,5 C. Its structure was confirmed by spectral data: IR cm (KBr):
1666, 1620 and 1606 (dienone), 3060 and 892 (vinylidene); UV (EtOH):
X = 247, € = 20,800; H NTIR (S(CDCl^): 3H br s at 1.80, 3H s at 2.05. max
3H s at 2.09, 2H br at 4.79 and 2H s at 6.04.
The biosynthesis of anhydro-Zj-rotundol has not been studied in
detail. However, the proposed biosynthesis of solavetivone (13),
2
spirovetiva-l(lO),ll-dien-2-one, has been reported. By obvious exten
sion, anhydro-/;-rotundol is most likely formed from dehydrogenation of
solavetivone. An accepted biogenetic pathway leading to the spirocyclic
skeleton starting from farnesyl pyrophosphate is shown below. Farnesyl
pyrophosphate is regarded as the biological precursor of almost all
sesquiterpenes. The cyclization of farnesyl pyrophosphate (10) via
elimination of pyrophosphate forms the bicyclic compound (_11_). Then,
(11) is oxidized to form the ketone intermediate (12). Finally, sola
vetivone is formed by the migration of a ring carbon from C-10 to C-5.
OPP
10 11
H
12 13
Three partial syntheses of anhydro-,'3 -rotundol have been carried
out previously. These are described here briefly.
Anhydro-/3-rotundol was first synthesized by accident by
rearrangement of another sesquiterpene, /O-rotundol (J^). "-Rotundol
was isolated from the tuber of nutgrass, Cvperus rotundus linne, a
perenial herb of the tropical and temperate zone. It is a sesqui
terpene keto-alcohol whose structure was confirmed by spectroscopic
data.-^'^
This synthesis was reported before anhydro- j-rotundol was
isolated from nature, and it explains the name given to the spirocyclic
natural product. The mechanism of the formation of anhydro-_<-rotundol
is shown in Scheme I. The electron deficient center at C-5 initially
is formed by elimination of the -OH group, then the C-10 carbon
migrates to form the spirocyclic structure. Finally, deprotonation
occurs to form the second double bond of the cyclohexadienone.
POCl.
Pyridine
14
Scheme I
0
-H-
Scheme I (Conti.)
The second partial synthesis proceeded from hinesol (j^). Hinesol
is one of the main constituents of Atractylodes lancea De Candolle
(Compositae), whose structure has been elucidated clearly. The synthe
sis of anhydro-/3-rotundol was carried out by the reaction which are
shown in Scheme II. First, hinesol was oxidized to the 3-keto-
derivative, hinesolone (16) by t-butyl chromate. Then, 2,3-dicloro-5,6-
dicyano benzoquinone, DDQ, was used to dehydrogenate hinesolone to
afford the dienone derivative (17). Finally, dienone (jj ) was dehydrat
ed with phosphorous oxychloride, POCl,,, in pyridine to the resulting
product, anhydro-A-i^otundol. The dehydration step also gives substan
tial amounts of the other possible double bond isomer.
The third partial synthesis proceeded from another sesquiterpene,
nootkatone (18). Nootkatone, which is a flavoring ingredient, has been
found in heartwood of Chamalcvparis nootkatenis. grapefruit peel oil,
8 ^ and peel oil-free grapefruit juice. The interconversion of nootkatone
to anhydro-/3-rotundol was carried out as shown in Scheme III.
Nootkatone was dehydrogenated by DDQ to form 3,4-dehydronootkatone
t-butyl chromate DDQ
15 16
17
Scheme II
0
DDQ
18 19
Scheme III
0
hV hV
20
Scheme III (Conti.)
(19). This intermediate was irradiated to give the lumiproduct (_20 ).
Then the lumiproduct was irradiated in a protic solvent, acetic acid, to
give further rearrangement to anhydro-n-rotundol.
The postulated mechanisms for the formation of the lumiproduct
(20) and anhydro-H-rotundol are shown in Scheme IV and V.
hl^ -»
19
Internal
conversion '.0
zwitterion
Scheme IV
rearrangement ^^^T^'^^^r^'N'''''^
20
Scheme IV (Conti.)
20
1,2-methylene shift
-H
hV "0>^^:^\ppv^ v^
Scheme V
This thesis will describe the first total synthesis of anhydro-/;
rotundol. The work allowed the investigation of a reactive type of
intermediate, a quinone methide, for the synthesis of hindered carbon-
carbon bonds. It also used some intriguing rearrangements of mesylate
groups for key steps.
CHAPTER II
SYNTHESIS OF ANHYDRO-/I-ROTUNDOL - / 3 - .
Proposed Synthesis
The structure of anhydro-H-rotundol is relatively simple for a
sesquiterpene, especially since it has only one chiral center. However,
synthesis of the spirocyclic ring onto the cyclohexadienone ring in this
compound is challenging due to steric hindrance at the spirocyclic
center. For this reason, the key step for the synthesis of anhydro-/3-
rotundol was proposed to be the formation of a carbon-carbon bond in the
coupling reaction between the dianion (27a) and the highly reactive
quinone methide intermediate (26), as shown in scheme VI. ^
< :
»
27a
0
28 26
Scheme VI
The entire synthesis of anhydro-A-rotundol, as originally planned
as summarized in Scheme VII.
10
11
OH
CH2OH
23
HCN - ^
AlCl,
HCl
HBr
NaBH,
CH3OH
base
23a
L i - ^
27a
1. B^H^
2. H^O^
NaOH
26 28
CH2SO2CI
C5H5N OSO2CH2
29 30
Scheme VII
12
0
NaH
DMF
POCl.
31
Scheme VII (Conti.)
The Gattermann reaction on 3,5-dimethyl phenol (_2j) to give the
9 product ( 2_) has been investigated. This compound has a carb jn atom
in the crucial hindered 4-position. It should be possible to reduce it
to the alcohol with NaBH,. This alcohol (23) would then be reacted
with anhydrous hydrogen bromide to give the desired bromophenol (23a).
Several methods to synthesize the key product 5-(2',6'-dimethyl-
4'-hydroxyphenyl)-3-methylidene-2-methyl-2-pentanol (_28_) were consider
ed . The most attractive postulation is an 1,6 elimination of the
bromophenol (23a) to give the reactive quinone methide intermediate
(26), followed by trapping with the highly reactive diani. n (27a) to
give the product (_28).
The dianion (27a), the dilithium salt of 2,3-dimethyl-l-buten-3-
ol, could presumably be formed analogously to the known dilithium salt
of 2-methyl-2-propen-l-ol (^).^^ It should be more nucleophilic
through carbon than through oxygen. There are a very few examples of
reactions of this type of dianion in the literature. The synthetic
applications of such dianions^ have been limited to addition reactions
13
10 to aldehydes and ketones, as shown in Equation (1). Carlson obtained
several diol derivatives with different alkyl groups.
CH CH_ ^ II 2
t-BuOK CH^ C —CH.,OH ^ CH^—C CH^O
^ ^ n-BuLi ^ ^
32
Oc=o R ^ .CH
^1
/
2 Eq. (1)
HO ^2
CH2OH
R,= hydrogen, alkyl; R^= alkyl.
This analogy is not very similar to our desired reaction. How
ever, it is clear that the dianion (27a) should attack through carbon
rather than oxygen. With this in mind, the formation of the product
(28) seemed reasonable.
Hydroboration-oxidation of {2S) to give 5-(2',6'-dimethyl-4'-
hydroxyphenyl)-3-hydroxymethyl-2-pentanol (_29_) seemed straightforward,
though it seemed possible that the phenol would have to be protected to
avoid complex phenolic oxidation products.
Then formation of 4-[2',6'-dimethyl-4'-(methylsulfonyl)hydroxyl]
phenyl-2-hydroxyisopropyl-butyl methylsulfonate (_32) by treatment with
methanesulfonyl chloride would be necessary. It was expected that the
14
reaction would occur on the primary alcohol selectively over the
tertiary one and the less nucleophilic phenol.
For geometrical reasons, the intramolecular alkylation reaction by
mesylate in (30) should occur at the para position of the phenoxide ion
to form ring closure. Winstein called this type of reaction Ar,-5
participation. If successful, this reaction should lead to the forma
tion of spirovetiva-l(lO),3-dien-ll-ol-2-one (31). According to the few
11 12 analogies to be found in the literature, ' the reaction can only
occur by the proper selection of the structure and reaction conditions.
Although the compound (30) is very sterically hindered at the position
para to the phenol, it was expected that conditions for a successful
closure could be found. This type of reaction was first carried out as
shown in Equation (2). The spiro-(4.5)-deca-l,4-dienone-3-one (3^) was
isolated from the reaction of 4-£-hydroxyphenyl-l-butyl p-bromobenzene-
sulfonate (33) with potassium t-butoxide.
OH
OBs
t-BuOK 2q. (2)
33 34
12 Another example of Ar,-5 participation is shown in Equation (3).
The conversion of 6-hydroxy-(/3-tosyloxyethyl)-l,2,3,4-tetrahydro-
naphthalene (15) to the product (36) occured in moderately high yield.
15
The last step in our proposed synthesis, the dehydration of (H) to
anhydro-^-rotundol (£), has been done by previous workers."^ The
alcoholic group on (31) has been dehydrated by phophorous oxychloride in
pyridine to give the product (£), mixed with its isopropylidene double
bond isomer.
Eq. (3)
0 ^ ^ ^ ^
35 36
Thus, it will be seen that many problems might be encountered in
carrying out proposed steps in this total synthesis, but that much
could be learned by making the attempt.
Preparation of 2,6-dimethyl-4-hydroxybenzaldehyde (22)
The project was initiated with the attempt to synthesize 2,6-
dimethyl-4-hydroxybenzaldehyde (_22_) according to the procedures to the
9 Gatt:irmann reaction. In this experiment, powdered sodium cyanide, NaCN,
and concentrated sulfuric acid, H2S0^, were used to generate anhydrous
13 hydrogen cyanide, HCN, which was passed directly into the reaction
mixture containing 3,5-dimethyl phenol (_21.) in dry benzene. Then powder
ed aluminum chloride, A1C1«, was added and dry hydrogen chloride was
16
passed through the reaction mixture. Due to problems encountered in the
preparation and control of the stoichiometry during the generation of
anhydrous HCN, the yield of tne desired product (22) was low. An alter
native approach based upon the work by Adams and Levine was undertaken,
These authors used powdered zinc cyanide, Zn(CN)2» to replace
anhydrous HCN in the Gattermar.n reaction. Later, Adams and Montgomery
attempted to use powdered sociam or potassium cyanide in place of zinc
cyanide. The results were entirely unsatisfactory, the yields of
products being very low.
A modification of the Gattermann reaction on 3,5-dimethyl phenol
by using Zn(CN)2 to replace anhydrous HCN to synthesize (^) has been
carried out as shown in Scheme VIII.
In the Gattermann reaction on 3,5-dimethyl phenol by using
anhydrous HCN, ortho- and para-phenolic aldehydes mixtures were obtain-
9
ed. The ortho-phenolic aldehyde was separated by steam distillation.
In this modified reaction, anhydrous HCl was passed through the
reaction mixture containing (2_i_) in dry benzene, powdered Zn(CN)2 and o
AlCl. at 40-45 C for 4 hrs. After work-up, the ortho-phenolic aldehyde
was not detected. The product (2.) was purified by chromatography and
crystallization, mp 190-193 C, (lit. mp 190 C),*^ yield 40%.
Preparation of 2.6-dimi-thvl-^-hydroxvbenzvlalcohol (23)
The reduction of carbonyl group in (22) with lithium aluminum
hydride, LiAlH,, to the alcoholic derivative has been investigated by
Chen. After work-up, in addition to the expected product (23). the
side product 3,4,5-trimethyl phenol (^) was also obtained. Compound
17
(38) arose by the over reduction of (_22_) with the strong reducing agent
LiAlH,. A possible mechanism is shown in Equation (4).
OH
HCl + Zn(CN)2 + AICI3
HC=NH.HC1
21
H2O
Scheme VIII
CH2-0^1H3
+ H-AIH "2^ Eq. (4)
CH^OH
38
Later, he succeeded in preparing (23) in high yield by using
sodium borohydride, NaBH^, in the reduction of (22.). This reagent gave
IS
no over reduction. The reduction of ( 1) to 2,6-dimethyl-4-hydroxy-
benzylalcohol (£3) is shown in Scheme IX.
Excess NaBH^ in ethanol was added dropwise to a solution of (22)
in ethanol in an ice bath. Due to the steric hindrance of the carbonyl
group in (22), the time for complete reduction was 6 hrs. After work
up, 90% of (23) was isolated. The product (23) was purified by chroma-
o
tography and crystallization, mp 155-159 C.
NaBH L
C2H^0H
H30-
H2O
CH2OH
23
Scheme IX
Preparation of 3,5-dimethvl-4-hvdroxvmethvl phenyl methylsulfonate (25)
Several attempts were made to replace the hydroxy group in (23)
with bromide and chloride by a nucleophilic substitution reaction by the
addition of gaseous hydrogen bromide and hydrogen chloride respectively,
as shown in Equation (5). In the experiment, bromide and tetralin were
used to generate the gaseous HBr. The reaction of (_23_) with gaseous HBr
at room temperature was investigated in different solvents such as
methylene chloride, CH^Cl^, and tetrahydrofuran, THF. After work-up,
19
the expected product was not obtained, according to the H XMR spectrum.
OH
CH2OH
23
HX
Y A
OH
CH2X
23a X= Br
23b X= CI
Eq. (5)
An attempt was made to monitor the course of the reaction by H
NMR spectroscopy. Addition of gaseous HCl to compound (_23.) i" CH^Cl^
and in d^-DMSO in an NMR tube at room temperature gave complex mixtures.
No clear singlet expected for the -CH^Cl group was visible.
Another approach was investigated to displace the hydroxy group
with chloride under substantially different conditions. Thionyl
chloride, SOCl^, was used to react with (_23_) in pyridine at room
temperature as shown in Equation (6). The expected product was not
observed, according to the H NMR spectrum.
Possible routes were investigated to synthesize 3,5-dimethyl-4-
methoxymethyl phenol (J7) as shown in Equation (7) and (8). First, the
reaction of (^) with methylal, CH2(0CH3)2, was carried out. The reac
tion was catalyzed by sulfuric acid and by boron trifluoride etherate,
BF^'EtO^. The results were not encouraging. Second, an attempt was
made to generate the quinone methide intermediate ( 6) via an oxidation
reaction and trap it with methanol. However, the reaction of 3,^,5-
trimethyl phenol (3£) with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.
20
DDQ, in methanol under a N^ stream did not give the desired product.
With these attempts to generate a leaving group at this position
having failed, attention was focused on the use of a sulfonate leaving
group. The reaction of compound ( 3 ) with methanesulfonyl chloride,
CH^SO^Cl, in dry THF with triethyl amine or pyridine did give a methane-
sulfonate ester ("mesylate") as the only characterizable product, in
poor yield. The structure of the product was initially assumed to be
(24).
CH2OH
SOCl,
OH
A CH2C1
Eq. (6)
23
CH2(OCH3)2
^
DDQ
CH3OH
CH2OCH3
CH2OCH3
Eq. (7)
Eq. (8)
38
21
CH2OSO2CH3
24
In practice, use of triethyl amine in place of pyridine gave a
higher yield of the same product. Treatment of compound (23 ) in dry THF
with CH SOrjCl and (C2Hc.)3N at room temperature required 2-3 days for
complete reaction. The product was isolated after chromatography on
silica gel in only 25% yield, A polar material remained on the column.
It was presumably polymeric, but was not investigated further. A
number of attempts to vary the reaction conditions did not lead to
improved yields.
Examination of the NMR spectrum of the crystalline mesylate
product suggested that it did not have the desired structure (_2 ). In
particular, the chemical shift of the aromatic hydrogens in (23_) appear
at <5'6,38 and in the product at O 6.93, The product (24) should have
this signal at approximately the same place as in (23). Furthermore,
the signal for the -CH^OH group in (_23.) appears at (5 4,38 and in the
product at (3^4,60, This small shift difference is not consistent with
structure (24) either.
In the presence of triethyl amine, the compound (23) would be in
the form of the phenoxide anion, which is more electron-rich and nucleo
philic than the aliphatic alcohol. Also, triethyl amine is used as the
22
OSO2CH3
CH2OH
25
hydrogen chloride acceptor to generate the sulfene derived from methane
sulfonyl chloride.
The chemistry of sulfene was studied by many workers. The
mechanism of the formation of the sulfene is postulated to be a reason
able E-2 elimination. The sulfene is too unstable to be isolated, but
its formation is deduced from the structure of the adduct it forms.
Possible ways to describe the structure are the cumulative, the carbonyl
18 like, the 1,3-dipolar and the "ylide" formulation as illustrated in
Scheme X. However, the "ylide" structure seems to best describe the
most common mode of reaction. Thus, the sulfonyl chloride exhibits
electrophilic and the methylene nucleophilic character.
S S :S S:
II I :CH, CH^ CHl CH
1 '2 2 ""2
ylide like cumulative carbonyl like 1,3-dipolar
Scheme X
23
The mechanism for this reaction is shown in Scheme XI. The
sulfene was generated ±n_ situ by adding methanesulfonyl chloride to
triethyl amine. Then the highly nucleophilic phenoxide anion on
compound (25) attacked the S atom bearing the positive charge in the
"ylide" structure of the sulfene. Finally the product (25) was formed
by the nucleophilic methylene of the intermediate abstracting a proton
from Et^NH or other acidic site.
CH2OH
23
Et3N
CH2OH
+ Et3NH'
Et3N + H-CH2-SO2-CI Et3N-HCl + CH2=S02
sulfene
0 = S
"ylide" form
Et^NH"
CH2OH
OSO2CH3
CH2OH
OSO2CH2
CH2OH
11
Scheme XI
24
Intermolecular Coupling Reaction-Preparation of 5-(2',6'-dimethyl-4'-hydroxyphenyl)-3-methylidene-2-methyl-2-pentanol (28)
The formation of the carbon-carbon bond in the coupling reaction
of (26) and (27a) was the key step in this project. It was first
necessary to make the dianion (27a). This was to be done by deprotona
tion of 2,3-dimethyl-l-buten-3-ol (Z7).
The starting alcohol (27) is commercially available (INC Pharma
ceutical Co.) but is rather expensive. Thus, an attempt to synthesize
it was investigated. Ethyl methacrylate was treated with slightly more o
than two equivalents of the Grignard reagent, CH^MgBr, at 0 C in dry
THF for 2 hrs, followed by hydrolysis and acidification with 10% HCl.
The product, from the H NMR spectrum, was a complex mixture containing
the desired compound, the 1,4 addition product, and unidentified
compounds. Rather than pursuing this synthesis, the compound was
purchased from INC Pharmaceutical Co..
The dianion (27a) was generated ijn situ by the procedure used
previously to deprotonate methallyl alcohol. Potassium tert-butoxide
was first added to n-hexane, followed by addition of compound (27_) and o
n-butyl lithium. The reaction mixture was stirred at 0 C under a stream
of N^ for 15 minutes. A golden colored suspension resulted, suggesting
that the dianion (27a) had formed.
In the proposed reaction as shown in Scheme XII, the mesylate (24)
in an alkaline medium would form the phenoxide anion (40), Since the
mesyloxy is the good leaving group, it is expected to eliminate and form
the quinone methide intermediate (_26.). Subsequent attack by the allylic
end of the dianion (27a) at the exocylic carbon-carbon double bond
25
position of (26) should give the coupling product (28).
Since the mesylate obtained from compound (23) did not have the
correct structure (24), an attempt was made to synthesize (4.) • ^
shown in Scheme XIII, Treatment of compound (23) with one equivalent
of benzyl bromide and potassium hydroxide gave the benzyl ether (45),
This compound could only form a mesylate (46) at the desired position
removal of the benzyl group should generate the desired (_24 ).
t-BuOK
CH2OSO2CH3
24 40
27a
T-0 \
26 18
Scheme XII
26
CH2OH
23
PhCh2Br
KOH
0CH2Ph
CH2OH
45
CH3SO2CI
0CH2Ph
CH2OSO2CH3
H2/Pd
CH2OSO2CH3
46 24
Scheme XIII
However, in practice, this scheme was not carried out. Initially,
the structure of the mesylate (25) was assumed to be (24.). On this
assumption, the key coupling reaction was attempted. The mesylate (25)
was added to a solution of two equivalents of the dianion (27a) in o
n-hexane under a N2 stream. After two days at 25 C, the desired
coupling product (28) was formed in 38% yield. This highly encouraging
result delayed assignment of the correct structure to (25), since the
success of the coupling raection seemed to lend support to the idea that
27
the mesylate was indeed (24).
Only later was the NMR spectrum of (25) examined more critically
and it was realized that the mesylate group was on the phenol.
A mechanism that would explain this unusual and fortunate result
is given in Scheme XIV.
OSO2CH3
CH2OH
25
•O"
27a
OSO2CH3
25a
Eq. (9)
OSO2CH3 OSO2CH3 0-
Eq. (10)
CH2OSO2CH3 CH20"
A • B
0-SO2CH3
• * • 2 Eq. (11)
CH^OS02CH3
40
Scheme XIV
'F'
28
CH2-OSO2CH3 L
< » -
27a
H2O
H
28
Scheme XIV (Conti.)
Deprotonation of (25.) by the dianion (27a) results in a benzyl-
oxide anion (25a) [Equation (9)]. Attack by the benzyloxide ion on a
second molecule of the benzyloxide ion at the sulfur atom of the
mesylate results in the dimesylate _A and the dianion [Equation (10)].
Further attack on the aromatic mesylate end of A by the dianion B
results in two moles of (40) [Equation (11)]. Since the mesyloxy is the
good leaving group, the phenoxide group (40) then eliminates to the
quinone methide intermediate gives the coupling product ( 8.) after acid
hydrolysis.
The structure of the coupling product ( 8 ) was confirmed by NMR
29
and IR spectra. The signal for the aromatic hydrogens of (23) appears
at 0 6,52, similar to the value for compound (23), observed at (56.37.
The chemical shifts of the phenolic hydrogens in (3.) and (2S_) in d.-
DMSO appeared at (5^9.10 and at (5^8.88, respectively. In addition, there
is no singlet at (J 3.10, characteristic of a mesylate. The vinyl
signals appear at S 5,22 and (5^4.98. Broad signals, between 3.20 and
U 2.60, and a singlet peak at(5'l.32, correspond to the methylene
hydrogens and two methyl groups adjacent to the aliphatic alcohol
respectively in compound (28). The IR spectrum shows the -OH at 3421
cm , tertiary alcohol at 1143 cm"- and a vinylidene at 893 cm"" .
The coupling reaction was studied in some detail, to try to
improve the yields. One problem with the reaction is that it is run in
n-hexane. Compound (25) is very insoluble in hexane, so the reaction
was allowed to run for a long time to overcome this problem.
Several runs were made, varying the stoichiometry of the :nesylate
(25), the reagent (27), t-BuOK and n-BuLi, The experimental results,
which are summarized in Table 1, show the best yield of the coupling
product (28) as 38%.
Table 1. The reaction of (25) with the dianion (27a)
Exp. Equiv. of Equiv. of Equiv. of Equiv. of Yield of
no. 25 IZ t-BuOK n-BuLi 28*
1 1 3 6 6 38%
2 1 2 4 4 25%
3 1 1 2 2 -trace
o
*The yields of (28) were determined after chromatography, mp 113-120 C.
'•IV'':-*''!''
30
Thus, it can be seen that the first run was the best, and that an
excess of the dianion (27a) is required for success. The reaction was
run several times under these conditions and the yield was always
between 35-40%.
Preparation of 5-(2',6'-dimethyl-4'-hydroxy-phenyl )-3-hydroxymethyl-2-me thy 1-2-pentanol (29)
Compound (28) has all the atoms, including functionality in the
required position, required for the synthesis of spirovetiva-l(10),3-
dien-ll-ol-2-one (_31) • Therefore several attempts were made to cyclize
this compound directly.
Potassium ferricyanide, K3Fe(CN),, an oxidizing agent, was chosen
in order to generate a phenoxy radical in (_28.), which would hopefully
add to the double bond [Equation (12)].
This reaction would, however, be an example of a 5-endo-trig
21 cyclizdticn, a reaction type forbidden by Baldwin's rules. Since ( S.)
was in hand, the reaction was investigated briefly.
Reaction conditions for phenoxy radical generation were chosen
20 according to a somewhat analogous successful reaction. Only one trial
run was conducted. Deareated aqueous K3Fe(CN)^ solution was added in a
deareated solution of compound (_28_) in NaHC03. The reaction mixture
was allowed to stir at room temperature under a N2 stream for 30
minutes. After work-up, the desired product was not p-^^sent, according
to the NMR spectrum.
Another approach that was investigated briefly was to cyclize (28)
through the allylic carbonium ion, as shown in Equation (13). In acidic
medium, the tertiary alcohol in (28.) should be protonated and dehydrated
31
to form a carbonium ion easily. Then the cyclohexadienone spirocyclic
21 product could presumably be formed by the 5-exo-trig closure.
The course of the reaction was monitored by H NMR spectroscopy.
Compound (28) in trifluoacetic acid, CF^COOH, in an NMR tube at room
temperature gave a black solution. According to the NMR spectrum, a
complex mixture was formed, which contained no cyclohexadienone.
0-H
-H^
-Fe 2+
28
5-endo-trig
0
Eq. (12)
Since direct cyclization reactions on (28) did not appear to be
promising, hydroboration of the alkene was investigated, to allow the
introduction of a leaving group at methylene position.
A problem which may be encountered in the hydroboration-oxidation
OH
28
OH
CF3COOH
32
5-exo-trig -H + Eq. (13)
reaction of (29), is the oxidation of the phenol group by the H^O^ to
form complex oxidation products rather than the desired oxidation of the
organoborane intermediate. To avoid this problem, the phenol group of
compound (_28.) could be protected before the hydroboration-oxidation
reaction is attempted.
As IS shown in Equation (14), an attempt was made to protect the
phenol group by addition of a benzyl moiety. Several trials were run
with small 2imounts of (28) in DMF. In each case an excess of KOH.and
PhCH^Br was added to the solutions and the reaction mixture was allowed
to reflux for 24 hrs. The subsequent work-up, including chromatography.
33
did not yield the desired product. It was decided to monitor the
progress of the reaction using H NMR. Compound (28) (20 mg) was
dissolved in d^-DMSO and placed in an NMR tube, followed by the addition
of a slight excess of KOH and PhCH^Br at ambient temperature. After a
short period of time, the desired product was observed in the NMR
spectrum. A spectrum was taken 12 hrs later which showed little change
in the NMR tube's contents. Subsequently the reaction mixture was work
worked up. Although an NMR spectrum indicated that the desired product
(41) was indeed isolated, the yield of (4T_) was only 54%.
At this point, the amount of (28) remaining was rather small. A
decision was made to attempt the hydroboration-oxidation of (28) without
phenol protection as shown in Scheme XVI, rather than continue the
longer sequence in Scheme XV.
KOH
PhCH20H
0CH2Ph
Eq. (14)
28 41
The mechanism of the hydroboration-oxidation raection has been
studied extensively and elucidated clearly. It is known to be stereo-
specific, giving products which correspond to anti-Markovnikov addition
of water to the carbon-carbon double bond. Furthermore this type of
addition always occurs with syn-addition.
34
41 ' • \h
2. NaOH
H2O2
0CH2Ph
H2/Pd
OH
Scheme XV
29
'• V e 2. NaOH
H2O2
28 29
Scheme XVI
To a solution of compound (28) in THF under a N„ stream, was added
the boiane-methyl sulfide complex, BH^'SMe^. The reaction mixture was
allowed to stir for 3 hrs at ambient temperature, followed by reflux for
1 hr. Then H2O2, NaOH and H2O were added. The work-up yielded a yellow
liquid as the product. The NMR spectrum shows no vinyl hydrogens, but
shows two new methyl group signals, each a singlet, intensity 3, at (^
J.
1.25 and (j 1.29. The appearance of two methyl resonances suggest that
they are adjacent to an asymmetric center, C-2, and are therefore non-
equivalent. The indicated characteristics are consistent with the
desired product, compound (29).
With the success of this reaction, further work with the protected
compound (4T ) was abandoned.
Preparation of 4-[" 2'.6'-dimethyl-4'-(methylsulfonyl) hydroxy Ipheny 1-2-isopropenyl-butyl methylsulfonate (44)
In order to carry out the originally-proposed Ar,-5 cyclization, a
sulfonate group was again chosen as a suitable leaving group. In the
propojed step, compound (30.) would be produced from (_29.) by treatment
with CH3SO2CI in pyridine. The reaction of (29) with CH3SO2CI in
pyridine is shown in Scheme XVII.
On a small scale, compound (29) was treated with 1.2 equivalents
of CH^S02C1 in pyridine at room temperature for 2 days. After work-up,
a yellow liquid was obtained. The NMR spectrum of the yellow liquid
showed that a monomesylate had formed (singlet at (j 3.10). The chemical
shift of aromatic H's (($"6.90) suggested that the mesylate was on the
phenol, not the aliphatic -OH, as desired. Surprisingly, a vinyl signal
was observed (singlet at c3'4.80, 2H). The total spectral data allow the
structure of the product to be assigned as (42).
The probable mechanism for formation of this unexpected product is
shown in Scheme XVII.
The rxperiment was carried out in pyridine. Pyridine is a strong
enough base to deprotonate the phenol in (22) to an equilibrium extent,
OH
CH3SO2 %
Pyridine
CH^S02C1
Pyridine
Scheme XVII
OSO2CH3
30
OSO2CH3
42
36
to form a phenoxide anion. The phenoxide anion in (29a) is the nucleo-
phile which attacks on the sulfur atom of CH^S02C1 via the sulfene
mechanism to form the phenyl mesylate (29b). Pyridine hydrochloride,
PyH Cl~, is formed in situ during the formation of (29b). Although the
reaction medium is slightly basic, pyridine hydrochloride is a strong
enough acid to protonate the tertiary alcohol to form the intermediate
(29c). One would expect this protonated alcohol in (29c) to be
dehydrated to form the more substituted alkene via E-1 elimination. In
OH
29
C^H^N
xc~~ I "OH
CH3S02C1
29a
29c
OSO2CH3
29b
+^,-+ PyHXl
OSO2CH3
OSO2CH3
29c
0SO2CH3
Scheme XVIII
38
fact, absolutely none of (43) could be detected in the total product.
The amount present can not be more than 1-2% and is probably much less.
Another mechanism must be used to explain the formation of the
product (42). The evidence suggests that a neigboring group participa
tion of the primary alcohol group is involved in the formation of (42).
The electron pair on oxygen at the primary alcohol abstracts the
hydrogen on the methyl group as the H2O departs to give an intra
molecular E-2 reaction.
Compound (42) has the double bond in the required position for the
anhydro-M-rotundol synthesis. Thus, compound (42) would be an ideal
precursor if a way could be found to put a mesylate group on the primary
alcohol group instead of the phenol.
Two methods to accomplish this were considered. The first was to
use the benzylated phenol (41_). This could be hydroborated, then the
primary alcohol converted into a mesylate, then the benzyl group could
be removed by hydrogenolysis, to give the desired compound (_30) (or its
dehydrated analog). The second method considered involved using the
mesylate group in (42) as the phenol protecting group. Since this is an
aromatic sulfonate group, it should be removable with a nucleophilic
base, such as t-BuOK. If one had the dimesylate (44_), removal of the
aromatic mesylate and cyclization might occur in tha same reaction.
This intriguing idea was investigated first.
With this in mind, the product (42) was added to excess CH3SO2CI
in pyridine at room temperature for 3 days. After work-up, the NMR
spectrum of the product mixture showed two singlets at O 3.33 and (^' 3.16
where they would be expected for the sulfonate groups on the phenol and
39
primary alcohol groups respectively. These singlets were in small
amounts compared to other unexplained peaks. Nonetheless, these obser
vation gave us the desire to scale up the reaction and try to isolate
this elusive compound.
29
Excess of CH3SO2CI
Pyridine
OSO2CH3
^OS02CH3
44
Scheme XIX
The reaction was then run on compound (2.) ^^ illustrated in
Scheme XIX, under the same reaction condition for 5 days. After work-up
including chromatography, the XL-100 spectrum of the product showed all
the expected peaks for the dimesylate product (44).
Formation of anhydro-/]-rotundol (9)
The dimesylate (44 ) was treated with t-BuOK in hopes of generating
a phenoxide anion by attack on the aromatic S-0 bond. The neigboring
phenoxide anion group would then attack the remaining mesylate through
Ar,-5 participation to form the cyclohexadienone spirocyclic structure,
as shown in Scheme XX.
OS02CH3 I L
44
t-BuOK
°'°2C»3 t-BuOH
44a
Ar^-5
Scheme XX
A solution of the dimesylate (4^), t-BuOH and t-BuOK was refluxed
for 6 hrs under a N2 stream. After work-up, the N>IR spectrum of the
total product suggested that except for impurities not derived from (44),
the only product was anhydro-/3-rotundol. After chromatography, the XL-
100 NMR spectrum of the product matched the spectral data of natural (£),
22 kindly supplied by Dr. Durry S. Caine, David T. Coxon and H. Hikino
(no authentic sample of (9.) could be obtained). The synthetic sample
showed only a single peak on GC. All UV, IR and NMR data matched the
41
published data for (£). A mass spectrum was also obtained, and is
consistent with the structure of (£). These results represent the first
successful total synthesis of anhydro-H-rotundol.
CHAPTER III
CONCLUSION
The goal of this project was to synthesize anhydro-/]-rotundol,
(9.), by a route that involved some interesting chemistry. The success
ful synthesis of (£) is summarized in Scheme XXI.
Two key steps were used to make the C-C bonds required for the
synthesis of anhydro-/3-rotundol. The first was the coupling reaction
beween the dianion (27a) and the quinone methide (26), generated from
the mesylate (25). The other was the Ar,-5 participation ring closure
which completed the synthesis.
In addition, two intriguing rearrangement reactions were discover
ed during the formation and reactions of the mesylate (25) and (44).
Both of these reactions were unexpected, but were put to good use during
the synthesis.
Some of the reactions were not fully optimized but with more
develepmental work, especially on the mesylate reactions, better yields
could possibly be achieved.
OH OH
5 11
Zn(CN)^
^ AICI3
HCl
Scheme XXI
0 CHO
Tl_
NaBH, 4
C H OH ^ 3
42
43
CH2OH
23
CH3SO2CI
Et3N
QSO2CH3
CH2OH
25
t-BuOK n-BuLi
27a
0
1. B 2'6
2. NaOf!
H2O2
26 28
Excess of CH3SO2CI
OH P y r i d i n e
OS02Cil3
OSO2CH3
-+-4
t-BuOK
t-BuOH
Scheme XXI (ConL1.)
CHAPTER IV
EXPERIMENTAL PROCEDURES
General
General work-up of reactions was carried out by the addition of
water, neutralization as appropriate with 5% HCl or NaHCO^, extraction
with ether, drying over MgSO,, filtration, and removal of solvent with
a Buchi Rotavapor. Final drying and/or removal of solvents on some
small scale reactions was done with a vacuum pump at 0.1-0.3 mm Hg.
Solvents were distilled from the appropriate drying agent and
stored over molecular sieves. Benzene was distilled from CaCl2. THF
from CaH2 and then from Na/benzophenone, and t-butanol from CaH2.
Column chromatography was carried out by packing a glass column
with a 60-200 mesh silica gel (Sargent-Welch Scientific Co.) in the
appropriate solvent-usually a mixture of petroleum ether (distilled, bp
o
30-60 C) and ether, and eluting with increasing ratios of ether.
All NMR spectra were run on a Varian EM-360 spectrometer (60 MHZ)
in CDCl^ or d.-DMSO solution with TMS for internal reference. All NMR 3 o
chemical shifts were recorded in (Junits.
Infrared spectra were obtained with a Nicolet FT-IR spectrometer
in KBr pellets or as thin films on NaCl plates.
The melting points were determined with a Laboratory Devices "Mel-
Temp" apparatus.
Elemental analyses were carried out bv Atlanta Microlabs, Atlanta,
Georgia.
44
45
2,6-dimethvl-4-hydroxybenzaldehvde (22)
To a solution containing 15.0 g of 3,5-dimethyl phenol (_21) (98%
purity from Aldrich Chemical Co.) in 60 ml dry benzene was passed dry
hydrogen chloride for a few minutes in a 500 ml 3 necked round-bottom
flask. Then 28,76 g of powdered zinc cyanide was added slowly with
vigorous stirring. Dry hydrogen chloride was passed through the
solution for 1 hr further at room temeprature, A yellowish precipitate
formed, the mixture was cooled in an ice bath and 24.5 g of powdered,
anhydrous aluminum chloride was added slowly. After the aluminum
chloride was added, the ice bath was removed, and dry hydrogen chloride
o
was kept passing through the mixture for 4 hrs at 40-45 C. The mixture, o
containing a purple precipitate, was cooled to 0 C, 300 ml of distilled
water was added cautiously, followed by 90 ml of 10% HCl solution.
After stirring for 1 hr, the yellow precipitate in the solution was
separated by suction, the benzene layer of the filtrate was removed and
the aqueous layer was extracted several times with ether. The ether
extract and the solid were combined to give 7.10 g of crude product (40%
yield). Purification by column chromatography with 10% ether-90% petro-o
leum ether elution, provided pure colorless needles, mp 190-193 C, (lit.
mp 190°C):^ NMR (5'(d^-DMS0); 10.34 (s, IH), 6.52 (s, 2H), 2.50 (s, 6H);
IR cm"^ (KBr); 3165 (s, 0-H), 2980 (s, C-H), 1653 (s, C=0), 1599 (s, •
C=C). The NMR and IR spectra of '' l) are reproduced in Appendix I and
II, respectively,
2,6-dimethyl-4-hydroxybenzylalcohol (23)
In a 500 ml round-bottom flask, 5.0 g of (21) was dissolved and
46
stirred in 85 ml of 95% ethyl alcohol. 3.15 g of NaBH^ in 95 ml of 95%
ethyl alcohol was added dropwise to the solution in an ice bath during 1
hr. Some hydrogen gas was evolved. The reaction mixture was stirred in
the ice bath for 4 hrs and then at room temperature overnight. After
removal of solvent under reduced pressure, 60 ml of distilled water was
added in the residue, followed by 10% H2SO, solution to pH 2 (pHydrion
paper). After stirring for 1 hr, the mixture was extracted several
times with ether. The ethereal layer was removed under reduced pressure
to give 4.65 g of a yellow product (92% yield). Recrystallization from
ethyl acetate gave white crystals, mp 155-159 C: NMR O(d^-DMSO); 9.03
(s, IH), 6.38 ( , 2H), 4.68 (s, IH), 4.38 (s, 2H), 2.21 (s, 6H); IR cm"-
(KBr); 3410, 3103 (s, 0-H), 2980 (s, C-H), 1599 (s, C=C), 1206 (m, C-O).
The NMR and IR spectra of (23) are reproduced in Appendix I and II,
respectively. Anal. Calcd for CQH,202' ^' 72.03; H, 7.95. Found: C,
72.89; H, 7.98.
3,5-dimethy1-4-hydroxymethyl phenyl methylsulfonate (25)
In a 250 ml round-bottom flask, 5.0 g of (23) was dissolved in 60
ml of dry THF and 3.64 ml of methanesulfonyl chloride was added to the
solution with stirring. Then an excess of triethyl amine (13 ml) was
added dropwise. After the mixture was stirred for 2 days at room
temperature, white solid triethylamine hydrochloride was removed by
filtration. The solvent was removed under reduced pressure. The
residue was chromatographed on silica gel with 20% ether-80% petroleum o
ether to give 1.77 g (23% yield) of white needles (25_), mp 88-90 C: NMR
C^ (CDCI3); 6.93 (s, 2H), 4.60 (s, 2H), 3.22 (s. 3H and IH in 0-H), 2.43
^1
(s, 6H); IR cm"- (KBr); 3410 (w, 0-H), 2933 (m, C-H), 1597 (m, C=C),
1357, 1172 (s, -OSO2-). The NMR and IR spectra of 25_) are reproduced
in Appendix I and II, respectively. Anal. Calcd for C,^H,,0,S; C, 52.1
52.16; H, 6.13; S, 13.92. Found: C, 52.32, H, 6.04, S, 14.08.
5-(2'.6'-dimethyl-4'-hydroxyphenyl)-3-me-thvlidene-2-methvl-2-pentanol (28)
In a 100 ml 3 necked round-bottom flask, 2.78 g of potassium tert-
butoxide (Aldrich Chemical Co.) was added and stirred in 25 ml hexane in
an ice bath under a constant stream of dry nitrogen. Then 1.17 g of
2,3-dimethyl-3-buten-2-ol (INC Pharmaceutical Co.) was added to the
reaction by syringe, followed by 11.37 ml of n-butyl lithium (Ventron
Co.) over a 15 minute period. To the golden suspension was added rapid
ly 0.90 g of (25) with vigorous stirring. The mixture was stirred for 2
hrs at ice bath temperature and for 48 hrs at room temperature under a
N2 stream. Then 40 ml of distilled water was added and stirring
continued for 30 minutes. The solution was acidified with 10% HCl
solution and then extracted with ether. The organic layer was removed
under reduced pressure to give an oily residue. The residue was chroma
tographed on silica gel. Elution with 30% ether-70% petroleum ether
gave 0.38 g (38% yield) of white needles (_28.), mp 118-120 C: N m S
(CDCI3); 6.53 (s, 2H), 5.23 (s, IH), 4.96 (s, IH), 3.20-2.60 (m, 6H),
2.23 (s, 6H), 1.34 (s, 6H); IR cm"^ (KBr); 3421, 3200 (s, 0-H), 2970 (m,
C-H), 1601 (s, C=C), 1143 (s, C-O), 893 (s, C=CH2). The NMR and IR
spectra of (28) are reproduced in Appendix I and II, respectively. Anal
Calcd for C^3H2202: C, 76.38; H, 9.46. Found: C, 76.84; H, 9.33.
48
5-(2',6'-dimethyl-4'-hydroxyphenyl)-3-hydroxymethyl-2-methyl-2-pentanol (29)
In a 50 ml 3 necked round-bottom flask, 0.20 g of (28) was
dissolved in 20 ml of dry THF under a N2 stream. The mixture was cooled
in an ice bath and then 0.86 ml of borane-methyl sulfide (Aldrich
Chemical Co.) was added slowly via syringe. After the mixture was
stirred for 1 hr in the ice bath and 5 hrs at room temperature, it was
refluxed for 2 hrs. The mixture was cooled, 0.16 ml of distilled water
was added slowly, followed by 0.36 ml of 3N NaOH. The mixture was kept
in an ice bath, while 0.24 ml of 30% H2O2 was added. The mixture was
allowed to warm and then refluxed for 2 hrs. After removal of solvent
under reduced pressure, the residual solution wes treated with 107 HCl
solution and extracted with ether several times. The ethereal layer was
washed with water. Evaporation of the ethereal layer gave 0.212 g (99%
yield) of yellowish oil (29.): NMR (5'(CDCl3); 6.50 (s, 2H), 4.45-3.45 (m,
4H), 2.80-2.35 (m, 3H), 2.17 (s, 7H), 1.90-1.60 (m, 2H), 1.27 (s, 3H),
1.10 (s, 3H); IR cm"^ (film); 3381 (s, 0-H), 2980 (s, C-H), 1599 (ra,
C=C), 1141 (m, C-O), 1028 (m, C-O). The NMR and IR spectra of (29.) are
reproduced in Appendix I and II, respectively.
4-[2',6'-dimethyl-4'-(methvlsulfonvl)hydroxy] phenyl-2-isopropenyl-butyl methylsulfonate (44)
To a solution containing 40 mg of (29) in 5 ml of dry pyridine was
added 4 ml of methanesulfonyl chloride. After the mixture was stirred
for 5 days at room temperature, a black precipitate was removed by
filtration. The filtrate was poured into ice-water and extracted with
ether. The ethereal layer was washed with a 10% HCl solution. The
49
solvent was removed under reduced pressure. The residue was chromato
graphed on silica gel with 80% ether-20% petroleum ether to give 15 mg
(27% yield) of yellowish oil (44): NMR S(C^Cl^* 100 MHZ); 6.90 (s, 2H),
5.01 (s, IH), 4,91 (s, IH), 4.22 (s, IH), 4.16 (s, IH), 3.12 (s, 4H),
3.00 (s, 4H), 2.80-2,40 (m, 3H), 2,30 (s, 6H), 1.80 (s, 3H); IR cm"^
(film); 2943 (m, C-H), 1595 (m, C=C), 1359, 1174 (s, -OSO2-). The NMR
and IR spectra of (44) are reproduced in Appendix I and II, respectively.
Anhydro-/3-rotundol (9)
In a 25 ml 3 necked round-bottom flask, 10 mg of (44) was dissolv
ed in 10 ml of dry t-butanol under a N2 stream. The mixture was warmed
and then excess of potassium tert-butoxide (30-40 mg) was added rapidly
to the solution. The mixture was refluxed for 6 hrs. Then the mixture
was cooled, 3 ml of distilled water was added and kept stirring for a
few minutes. The solution was acidified with 10% HCl solution and then
extracted with ether. The ethereal layer was washed with distilled
water. The solvent was removed under reduced pressure. The residue was
chromatographed on silica gel with 70% ether-30% petroleum ether to give
a yellowish oil (£). The NMR and IR spectra of the product matched the
22 O spectral data of natural (9 ) supplied by other workers. NMR 0(CDC1^,
100 MHZ); 6,01 (s, 2H), 4,78 (s, 2H), 2,10 (s, 3H), 2,07 (s, 3H), 1,80
(s, 3H), Coxon^^ 6,03 (s, 2H), 4,79 (s, 2H), 2.09 (s, 3H), 2.06 (s, 3H),
1.79 (s, 3H); IR cm" (film); 1662, 1606 (s, dienone), 887 (s, vinylid
ene), Coxon^^ 1666, 1620 and 1606 (s, dienone), 892 (s, vinylidene). UV
spectral data of (9) is in accord with the published data; X (EtOH)=
243.5 nm, lit. \ (EtOH)= 247 nm. In addition, the GC data of (9) max
50
showed only one peak and indicated 99% purity with a retention time of
23.15 minutes; mass spectrum of (9); m/e [M" -= 216]. The NMR, IR and MS
spectra of (£) are reproduced in Appendix I, II and III, respectively.
REFERENCES AND NOTES
1. Coxon, D. T., Price, K. R., Howard, B., Tetrahedron Let-., 1974, 2921.
2. Stoessl, A., Stothers, J. B., Ward, E. W. B., Phvtochemistrv, 1976, 11, 855.
3. Hikino, H., Aota, K., Kuwano, D., Takemoto, T., Tetrahedron Lett., 1969, 2741.
4. Hikino, H., Aota, K., Kuwano, D., Takemoto, T., Tetrahedron, 1971, 27_, 4831.
5. Yosioka, I., Takahashi, S., Hikino, H., Sasaki, Y., Chem. Pharm. Bull., 1959, 7_. 319.
6. Caine, D., Chu, C.-Y., Tetrahedron Lett., 1974, 703.
7. Erdtman, H., Hirose, Y., Acta. Chem. Scand. , 1962, _16 , 1311.
8. Macleod, W. D., Bulges, N., J. Food Science, 1964, 29_, 565.
9. Dakshinamurty, H. , Santappa, M., J. Org. Chem. , 1962, _2_7_, 1S39.
10. Carlson, R. M., Tetrahedron Lett., 1978, 111.
11. Winstein, S., Baird, R., J. Am. Chem. Soc. , 1957, _79.. 756.
12. Masamune, S., J. Am. Chem. Soc. , 1961, Q3_, 1009.
13. Ziegler, K., Org. Syn., 1941, , 314.
14. Adams, R., Levine, I., J. Am. Chem. Soc., 1923, Ao, 2373.
15. Adams, R., Montogomery, E., J. Am. Chem. Soc, 1924, , 1518.
16o Work by Hsein-Ping David Chen at Texas Tech University.
17. Becker, H. D., J. Org. Chem., 1965, 30, 982.
18. Optiz, G., Angew. Chem. , Internat. Ed., 1967, 6_, 107.
19. Lane, C. F., J. Org. Chem., 1974, 3^. 1437.
20. Stirling, C. J. M., "Radicals in Organic Chemistry," Oldboure Press, London, 1965, p. 161.
21. Baldwin, J. E., J. Chem. Soc. Chem. Comm., 1Q76, 734.
51
52
22. Comparison spectra were kindly furnished by David T. Coxon, Durrv Caine, and H. Hikino.
APPENDIX I
NUCLEAR MAGNETIC RESONANCE SPECTRA
53
V......
J
J J
J
m
~^
DD
r j
X
56
( in
u CM o
m o
' ^
o
-A
CM
. - * -
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INFRARED SPECTRA
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APPENDIX III
MASS SPECTRUM
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SAMPLE o n i i r c t * • • Spectrun
4/18/1384 ID 1 • * aau Number
7 Date: 17. Disc
Scanned f r o n 30 to 400 F i l e type " processed Base Peak - 39.1 Base Peak Abundance - 495 Total Obundance
2:27 PM '.-lednesday Saraoie ' 7 Retent ion
of Peaks Detected - 86 Tirae 7 . 7 2 n i n
7 3 1 7
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iJULiijWii,L.i...U.i 50 100 150 200 250 300
Lower Abundance Cutof f Level • 2.5'/
MASS ABUNDANCE </.) MASS ABUNDANCE (/.)
39.1 40.2 41 .2 42.2 43.1 50.1 51 .2 52.2 53.2 5a.2 55.2 57.2 62.1 63.2 64.2 65.2 66.2 6 / . 2 69.1 70.3 71.2 73.1 75.1 77.2 78.2 79.2 80.3 81 .2
100.0 24.8 88. 1
8.9 15.4 8.1
25.7 ^2.7 ?8.2 3.1
•13.3 3.0 3.0 9.5 6.9
34.1 11.7 53.3
6.1 2.8 3.4 2.6 2.'^
40.0 12.9 40.2
6.9 13.9
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3-3. 1 91 .2 92.2 93.2 94.2 95.2
103.2 105.2 I 06.? 1U7.2 108,2 109.2 115.2 1 16.3 \\1.2 118.2 119.2 120.3 12*.3 122.3 123.2 124.3 127.3 128.2 129.2 130.3 131.2
7.7 5.1
31.7 10.9 ' 3 . 5 5.5 5.9
M . I 38.9 26.6 :6 .0 3.5 5.3
•8.2 7.1
'^J.O 5.3
21.8 25.1
9.7 11.?. 3.8 4.4 3.5
11.5 10.7 5.5
' 1 . 9
350 400
MASS ABUNDANCE (.:)
132.3 133.3 134.3 135.3 !36.3 141 .2 142.3 143.3 ^44.3 ;4S.3 146.3 147.3 :48.3 149.2 •57.? 158.3 159.3 160.3 161.3 172.3 173.3 174.3 175.3 187.3 188.3 201.3 216.4
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20.2 42.3 10.3 7.3
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Mass spectrum of compound (9^)
M- K.