An enantiospecific approach to tricyclic sesquiterpenes mayurone and thujopsenes

Article abstract of DOI:10.1021/jo0105484

An enantiospecific approach to mayurone and thujopsenes, sesquiterpenes containing three contiguous quaternary carbon atoms, starting from (R)-carvone (8), is described. (S)-3,4,4-Trimethylcarvone (7), obtained from (R)-carvone, was transformed into the bicyclo[2.2.2]octanone 13 via regioselective intramolecular alkylation of the allyl bromide 11. Regioselective ozonolysis and Criegee fragmentation of the bicyclic ketone 13 furnished the keto ester 14. Reductive deoxygenation followed by one-carbon homologation transformed the keto ester 19 into the ester 6. Intramolecular cyclopropanation of the diazo ketone 25, derived from the acid 5, furnished (-)dihydromayurone (4), thus constituting a formal enantiospecific synthesis of mayurone and thujopsenes.

Full text of DOI:10.1021/jo0105484

7102
J . Org. Chem. 2001, 66, 7102-7106
An En a n tiosp ecific Ap p r oa ch to Tr icyclic Sesqu iter p en es
Ma yu r on e a n d Th u jop sen es1
A. Srikrishna* and K. Anebouselvy
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received May 30, 2001
An enantiospecific approach to mayurone and thujopsenes, sesquiterpenes containing three
contiguous quaternary carbon atoms, starting from (R)-carvone (8), is described. (S)-3,4,4-
Trimethylcarvone (7), obtained from (R)-carvone, was transformed into the bicyclo[2.2.2]octanone
13 via regioselective intramolecular alkylation of the allyl bromide 11. Regioselective ozonolysis
and Criegee fragmentation of the bicyclic ketone 13 furnished the keto ester 14. Reductive
deoxygenation followed by one-carbon homologation transformed the keto ester 19 into the ester
6. Intramolecular cyclopropanation of the diazo ketone 25, derived from the acid 5, furnished (-)-
dihydromayurone (4), thus constituting a formal enantiospecific synthesis of mayurone and
thujopsenes.
Ch a r t 1
The tricyclic sesquiterpene thujopsene [(-)-1] was
originally isolated from the wood oil of the J apanese Hiba
tree2 and has since been found to occur widely in genera
of natural order Cupressaceae. The stereostructure of
thujopsene 1 was established by Norin and co-workers,3
which was soon confirmed by the total synthesis by
Dauben and Ashcraft.4a In 1965, the research groups of
Sukh Dev and Ito reported the isolation of the norketone
mayurone (2) from Mayur pankhi and Thujopsis dola-
brata, respectively.5 Subsequently, isolation of various
oxidized forms of thujopsenes (Chart 1) has been reported
in the literature.6 In 1985, Matsuo and co-workers
reported the isolation of ent-thujopsene [(+)-1] from the
liverwort Marchantia polymorpha along with thujopse-
none 3.7 The presence of a tricyclo[5.4.0.01,3]undecane
framework incorporating a cyclopropane ring and, in
particular, the presence of three contiguous quaternary
carbon atoms made mayurone and thujopsenes interest-
ing and challenging synthetic targets. In addition to five
approaches to racemic thujopsene reported earlier,4 two
enantioselective approaches8 to thujopsene via dihydro-
mayurone 4 have been reported by the research groups
of J ohnson and Lee. J ohnson and Barbachyn8a have
employed a â-hydroxysulfoximine-directed Simmons-
Smith reaction for the generation of both the enantiomers
of thujopsenes, whereas Lee et al.8b employed the Sharp-
less epoxidation in their enantioselective synthesis of
thujopsene. In continuation of our interest in the syn-
thesis of sesquiterpenoids containing multiple contiguous
quaternary carbon atoms, both in racemic manner and
in enantiospecific manner,9,10 we have developed an
enantiospecific methodology for these terpenoids. Since
thujopsene was converted3,7,11 into mayurone and various
oxidized forms of thujopsenes (such as thujopsenal,
hinokiic acid, thujops-3-en-5-one, etc.), and mayurone was
* To whom correspondence should be addressed. Fax: 91-80-
3600683. E-mail: ask@orgchem.iisc.ernet.in.
(1) Chiral synthons from carvone, Part 51. For part 50, see:
Srikrishna, A.; Reddy, T. J . J . Chem. Soc., Perkin Trans. 1, 2001, 2040.
(2) (a) Yano, M. J . Soc. Chem. Ind. J pn. 1913, 16, 443. (b) Uchida,
S. J . Soc. Chem. Ind. J pn. 1928, 31, 501.
(3) (a) Norin, T. Acta Chem. Scand. 1961, 15, 1676. (b) Norin, T.
Acta Chem. Scand. 1963, 17, 738. See also: (c) Nozoe, T.; Takeshita,
H.; Ito, S.; Ozeki, T.; Seto, S. Chem. Pharm. Bull. 1960, 8, 936. (d)
Sisido, K.; Nozaki, H.; Imagawa, T. J . Org. Chem. 1961, 26, 1964.
(4) For the synthesis of racemic thujopsene, see: (a) Dauben, W.
G.; Ashcraft, A. C. J . Am. Chem. Soc. 1963, 85, 3673. (b) Buchi, G.;
White, J . D. J . Am. Chem. Soc. 1964, 86, 2884. (c) Mori, K.; Ohki, M.;
Kobayashi, A.; Matsui, M. Tetrahedron 1970, 26, 2815. (d) McMurry,
J . E.; Blaszczak, L. C. J . Org. Chem. 1974, 39, 2217. (e) Branca, S. J .;
Lock, R. L.; Smith, A. B., III. J . Org. Chem. 1977, 42, 3165.
(5) (a) Chetty, G. L.; Dev, S. Tetrahedron Lett. 1965, 3773. (b) Ito,
S.; Endo, K.; Honma, H.; Ota, K. Tetrahedron Lett. 1965, 3777.
(6) (a) Erdtman, H.; Thomas, B. R. Acta Chem. Scand. 1958, 12,
267. (b) Erdtman, H.; Norin, T. Acta Chem. Scand. 1959, 13, 1124. (c)
Yoshida, T.; Endo, K.; Ito, S.; Nozoe, T. Yakugaku Zasshi 1967, 87,
434; Chem. Abstr. 1980, 93, 39472a. (d) Green, C. L.; Wood, A. B.;
Robinson, J . M. Flavour Fragrance J . 1988, 3, 105. (e) Nagahama, S.;
Tazaki, M.; Kobayashi, H.; Sumimoto, M. Phytochemistry 1993, 33,
879. (f) Cool, L. G.; J iang, K. Phytochemistry 1995, 40, 177. (g) Fang,
J .-M.; Chen, Y.-C.; Wang, B.-W.; Cheng, Y.-S. Phytochemistry 1996,
41, 1361. (h) Kuo, Y.-H.; Shiu, L.-L. Chem. Pharm. Bull. 1996, 44, 1758.
(7) Matsuo, A.; Nakayama, N.; Nakayama, M. Phytochemistry 1985,
24, 777.
(8) For enantioselective synthesis of thujopsene, see: (a) J ohnson,
C. R.; Barbachyn, M. R. J . Am. Chem. Soc. 1982, 104, 4290. (b) Lee,
E.; Shin, I.-J .; Kim, T.-S. J . Am. Chem. Soc. 1990, 112, 260.
(9) (a) Srikrishna, A.; Rao, M. S. Tetrahedron Lett. 2001, 42, 5781.
(b) Srikrishna, A.; Ramachary, D. B. Tetrahedron Lett. 2000, 41, 2231.
(c) Srikrishna, A.; Nagamani, S. A. J . Chem. Soc., Perkin Trans. 1
1999, 3393. (d) Srikrishna, A.; Ramachary, D. B. Tetrahedron Lett.
1999, 40, 6669. (e) Srikrishna, A.; Yelamaggad, C. V.; Kumar, P. P. J .
Chem. Soc., Perkin Trans. 1 1999, 2877. (f) Srikrishna, A.; Vijaykumar,
D. J . Chem. Soc., Perkin Trans. 1 1999, 1265 and references therein.
10.1021/jo0105484 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/20/2001

Enantiospecific Approach to Tricyclic Sesquiterpenes
J . Org. Chem., Vol. 66, No. 21, 2001 7103
Sch em e 1
Sch em e 2a
converted into thujopsadiene, attention was focused on
the enantiospecific synthesis of thujopsene 1 via dihy-
dromayurone 4.
The retrosynthetic analysis of thujopsene is depicted
in Scheme 1. Since Lee and co-workers have already
reported the synthesis of dihydromayurone 4 via the
intramolecular cyclopropanation of the diazoketone de-
rived from the acid 5 in their enantioselective synthesis
of thujopsene,8b the optically active ester 6 was considered
as the target molecule. It was anticipated that alkylation
with an equivalent of a propionic acid side chain at the
R-position, followed by reductive deoxygenation of the
ketone moiety and degradation of the isopropenyl group,
would convert the cyclohexenone 7 into the ester 6. The
readily available monoterpene (R)-carvone (8) was con-
sidered as a suitable starting material for the generation
of the cyclohexenone 7.
a
Reagents: (a) MeLi; (b) PCC, silica gel; (c) NBS; (d) K+ tBuO-;
(e) O3; Ac2O, NEt3, DMAP; (f) H2, 5% Pd/C.
Sch em e 3
The synthetic sequence starting from (S)-6,6-dimeth-
ylcarvone (9), obtained from 8 by sequential kinetic
alkylation using LDA and methyl iodide,12 is depicted in
Scheme 2. For the conversion of dimethylcarvone 9 into
(S)-3,4,4-trimethylcarvone (7), an alkylative 1,3-enone
transposition methodology was employed.13 Thus, regi-
oselective 1,2-addition of methyllithium to dimethylcar-
vone 9 followed by oxidation of the resulting allylic
tertiary alcohol 10 with a mixture of pyridinium chloro-
chromate (PCC) and silica gel in methylene chloride
generated the trimethylcarvone 7, in 70% yield. Instead
of the degradation of the isopropenyl group and introduc-
tion of a side chain at C-2 position, stereospecific trans-
location of the isopropenyl group from C-5 to the C-2
position as the acetate side chain was envisaged. An
intramolecular alkylation strategy14 was adopted for
joining the isopropenyl carbon and the C-2 carbon of
trimethylcarvone 7. Thus, reaction of the trimethylcar-
vone 7 with N-bromosuccinimide (NBS) in methanol-
methylene chloride medium furnished the allyl bromide
11, in 90% yield, in a highly regioselective manner.15
Generation of the thermodynamic dienolate 12 of the allyl
bromide 11 with potassium tert-butoxide in tert-butyl
alcohol and THF induced the regioselective intramolecu-
lar alkylation to furnish the bicyclo[2.2.2]octanone 13,
thus forming the second quaternary carbon atom. The
steric hindrance of the C-6 exo-methylene group was
exploited for the regioselective cleavage of the C-8 exo-
methylene group in the bicyclo[2.2.2]octanone 13. For the
selective oxidative cleavage of the C-4-C-8 bond in the
bicyclic ketone 13, a Criegee rearrangement16 was ex-
plored. Thus, controlled ozonolysis of the bicyclic ketone
13 in a mixture of methanol-methylene chloride followed
by treatment of the intermediate methoxy hydroperoxide
with a mixture of acetic anhydride, triethylamine, and a
catalytic amount of 4-N,N-(dimethylamino)pyridine
(DMAP) in refluxing benzene furnished the ketoester 14,
via the Criegee fragmentation, instead of the expected
lactone 15. The structure of the enone 14 was established
from its spectral data. Facile formation of the ester 14
can be rationalized as depicted in Scheme 3. Stereose-
lective addition of methanol to the carbonyl oxide 16,
formed in the ozonolysis reaction, from the less hindered
face of the molecule furnishes the methoxy hydroperoxide
17, which on acetylation generates the acetate 18. The
(10) (a) Srikrishna, A.; Viswajanani, R. Tetrahedron Lett. 1996, 37,
2863. (b) Srikrishna, A.; Viswajanani, R. Indian J . Chem., Sect. B 1996,
35B, 521. (c) Srikrishna, A.; Vijaykumar, D. Tetrahedron Lett. 1998,
39, 4901. (d) Srikrishna, A.; Anebouselvy, K.; Reddy, T. J . Tetrahedron
Lett. 2000, 41, 6643. (e) Srikrishna, A.; Viswajanani, R.; Dinesh, C. J .
Chem. Soc., Perkin Trans. 1 2000, 4321. (f) Srikrishna, A.; Vijaykumar,
D. J . Chem. Soc., Perkin Trans. 1 2000, 2583. (g) Srikrishna, A.; Babu,
N. C. Tetrahedron Lett. 2001, 42, 4913.
(11) Ito, M.; Nishimura, T.; Abe, K. Bull. Chem. Soc. J pn. 1972, 45,
1914.
(12) (a) Srikrishna, A.; Reddy, T. J .; Kumar, P. P. Chem. Commun.
1996, 1369. (b) Srikrishna, A.; Reddy, T. J .; Kumar, P. P.; Gharpure,
S. J . Indian J . Chem., Sect. B, (in press).
(13) (a) Buchi, G.; Egger, B. J . Org. Chem. 1971, 36, 2021. (b)
Srikrishna, A.; Hemamalini, P. Indian J . Chem., Sect. B 1990, 29B,
201.
(14) Srikrishna, A.; Sharma, G. V. R.; Danieldoss, S.; Hemamalini,
P. J . Chem. Soc., Perkin Trans. 1 1996, 1305.
(15) (a) Rodriguez, J .; Dulcere, J .-P. Synthesis 1993, 1177. (b)
Srikrishna, A.; Reddy, T. J .; Kumar, P. P. Synlett 1997, 663.
(16) (a) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24,
2363. (b) Criegee, R. Ber. Dtsch. Chem. Ges. 1944, 77, 722.

7104 J . Org. Chem., Vol. 66, No. 21, 2001
Srikrishna and Anebouselvy
Sch em e 4a
copper sulfate in refluxing cyclohexane or with rhodium
acetate in benzene at room temperature furnished (-)-
dihydromayurone (4). Mp: 105-106 °C (lit.5 mp: 106-
1
108 °C), which exhibited IR and H and 13C NMR spectral
data identical to those reported by Lee et al.8b Since
dihydromayurone 4 has been converted into thujopsene
and mayurone, which were converted into other thu-
jopsenes, the present sequence constitutes an enan-
tiospecific formal synthesis of mayurone and thujopsenes.
In conclusion, we have developed an enantiospecific
approach to mayurone and thujopsenes, the tricyclic
sesquiterpenes containing three contiguous quaternary
carbon atoms, starting from the readily available monot-
erpene (R)-carvone via (R)-6,6-dimethylcarvone and (S)-
3,4,4-trimethylcarvones. An intramolecular alkylation
reaction followed by a facile Criegee fragmentation
reaction sequence was exploited for the generation of the
key chiral center in the molecule. An intramolecular
cyclopropanation of a diazo ketone generated the requi-
site cyclopropane moiety as well as the third quaternary
carbon atom.
Exp er im en ta l Section
All the IR spectra were recorded as thin films, and the 1H
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in a
1:1 mixture of CDCl3 and CCl4. In the 13C NMR spectra, the
nature of the carbons (C, CH, CH2, or CH3) was determined
on the basis of the DEPT-135 experiment, and is given in
parentheses. [R]D values are given in units of 10-1 deg cm2
g-1. Silica gel (100-200 mesh) was used for column chroma-
tography. All the solvent extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated on a rotavap
under reduced pressure.
(+)-(5S)-5-Isop r op en yl-2,3,4,4-tetr a m eth ylcycloh ex-2-
en on e (7). To a cold (0 °C), magnetically stirred solution of
6,6-dimethylcarvone12 9 (1 g, 5.62 mmol) in ether (2 mL) was
slowly added a solution of methyllithium (1.1 M in ether, 6.1
mL, 6.7 mmol) over a period of 20 min. The reaction mixture
was slowly warmed to rt and stirred for 1 h. It was then poured
into a cold saturated aqueous NH4Cl solution and extracted
with ether. Evaporation of the solvent furnished the tertiary
alcohol 10, which was taken in 5 mL of CH2Cl2, and PCC (1.8
g, 8.4 mmol) and silica gel (1.8 g) were added. The reaction
mixture was stirred for 12 h, filtered through a small silica
gel column, and eluted from the column with more CH2Cl2.
Evaporation of the solvent and purification of the product on
a
Reagents: (a) NH2NH2, (CH2OH)2, digol; (b) CH2N2; (c)
(CH2SH)2, BF3·Et2O; (d) Raney Ni; (e) NaOH; (f) (COCl)2, CH2N2;
(g) hν, MeOH; (h) Cu, CuSO4; or Rh2(OAc)4; (i) refs 8 and 7.
orientation of the acetate group in the methoxy acetate
18 was ideally suited for the facile elimination reaction
under the basic conditions of the reaction to furnish the
ester 14 via the cleavage of the C-4-C-8 bond, instead
of generating 15 via the Criegee rearrangement.
Controlled hydrogenation of the enone 14 using 5%
Pd/C as the catalyst furnished the ketoester 19. It was
readily identified that deoxygenation of the ketoester 19
followed by homologation of the ester generates the
requisite precursor 6 for thujopsenes and mayurones.
Accordingly, Wolff-Kishner reduction of the ketoester 19
was explored first. However, Wolff-Kishner reduction of
the ketoester 19 using Huang-Minlon modified condi-
tions followed by esterification with diazomethane fur-
nished the deoxygenated ester 20, in 25% yield, along
with a substantial amount (>40%) of the hexahydrocin-
nolinone 21, obviously formed via initial conversion of
the ester to acid hydrazide followed by intramolecular
condensation with the ketone moiety (Scheme 4). Hence,
a two-step methodology via the corresponding thioketal
was employed. Thus, reaction of the ketoester 19 with
ethanedithiol and boron trifluoride etherate in benzene
furnished the thioketal 22, which on desulfurization with
Raney nickel in refluxing ethanol furnished the ester 20.
For the homologation of the ester 20, a photochemical
Wolff rearrangement was employed, as in the racemic
synthesis by Smith et al.4e Thus, hydrolysis of the ester
group in 20 furnished the acid 23. Reaction of the acid
23 with oxalyl chloride followed by treatment of the
resultant acid chloride with an excess of ethereal diaz-
omethane furnished the diazo ketone 24. Irradiation of
the diazo ketone 24 in methanol with a medium-pressure
mercury vapor lamp in a Pyrex vessel furnished the
homologated ester 6. Hydrolysis of the ester group in 6
furnished the acid 5, which was converted into the diazo
ketone 25 via the corresponding acid chloride. Reaction
of the diazo ketone 25 either with copper and anhydrous
a silica gel column using ethyl acetate-hexane (1:50) as eluent
24
furnished trimethylcarvone 7 (750 mg, 70%) as an oil. [R]D
:
+88 (c 4.3, CHCl3). IR: νmax (cm-1) 1665, 1615, 895. H NMR:
1
δ 4.93 (1 H, br s), 4.75 (1 H, br s), 2.65-2.40 (3 H, m), 1.89 (3
H, s), 1.77 (3 H, s), 1.71 (3 H, s), 1.18 (3 H, s), 1.07 (3 H, s). 13
C
NMR: δ 197.3 (C), 160.4 (C), 145.4 (C), 130.4 (C), 115.2 (CH2),
51.7 (CH), 39.5 (2 C, C and CH2), 26.9 (CH3), 23.1 (CH3), 21.8
(CH3), 16.4 (CH3), 11.6 (CH3). MS: m/z 192 (M+, 19), 177 (62),
150 (23), 135 (58), 124 (55), 109 (100). HRMS: m/z for C13H20O,
calcd 192.1514, found 192.1523.
(+)-(5R)-5-(3-Br om op r op en -2-yl)-2,3,4,4-tetr a m eth ylcy-
cloh ex-2-en on e (11). To an ice cold, magnetically stirred
solution of the enone 7 (1 g, 5.2 mmol) in a 3:2 mixture of CH2-
Cl2 and methanol (5 mL) was slowly added NBS (1.1 g, 6.2
mmol) over a period of 20 min. The reaction mixture was
stirred for 6 h, diluted with water, and extracted with CH2-
Cl2. The combined CH2Cl2 extract was washed with 5%
aqueous NaOH. Evaporation of the solvent and purification
of the residue on a silica gel column using ethyl acetate-
hexane (1:50 to 1:20) as eluent furnished the allyl bromide 11
(1.27 g, 90%) as an oil. [R]D25: +14.8 (c 6.4, CHCl3). IR: νmax
(cm-1) 1662, 1612, 920. 1H NMR: δ 5.43 (1 H, s), 5.02 (1 H, s),
3.95 and 3.90 (2 H, AB q, J ) 10.0 Hz), 2.74 (1 H, dd, J ) 9.4
and 6.9 Hz), 2.60-2.45 (2 H, m), 1.88 (3 H, s), 1.74 (3 H, s),
1.14 (3 H, s), 1.08 (3 H, s). 13C NMR: δ 196.7 (C), 160.1 (C),

Enantiospecific Approach to Tricyclic Sesquiterpenes
J . Org. Chem., Vol. 66, No. 21, 2001 7105
145.9 (C), 130.6 (C), 118.9 (CH2), 47.5 (CH), 40.6 (CH2), 39.8
(C), 38.6 (CH2), 26.7 (CH3), 21.5 (CH3), 16.5 (CH3), 11.7 (CH3).
HRMS: m/z for C13H19O (M - Br), calcd 191.1436, found
191.1433.
stirred at 0-5 °C for 2 h. The reaction was quenched with
aqueous NaHCO3 solution and extracted with ether. The ether
extract was washed with 5% aqueous NaOH solution. Evapo-
ration of the solvent and purification of the residue over a silica
gel column using ethyl acetate-hexane (1:50) as eluent
furnished the thioketal 22 (27 mg, 60% based on the starting
material consumed) as an oil. [R]D26: +14.4 (c 1.8, CHCl3). IR:
(-)-(1R,4S)-1,5,5-Tr im eth yl-6,8-bis(m eth ylen e)bicyclo-
[2.2.2]oct a n -2-on e (13). To a cold (-5 °C), magnetically
stirred 1 M solution of potassium tert-butoxide (2.2 mmol)
[prepared from potassium (87 mg, 2.2 mmol) and tert-butyl
alcohol (2.2 mL)] in 2.5 mL of THF was added a solution of
the bromo enone 11 (280 mg, 1.04 mmol) in 2.5 mL of THF.
The reaction mixture was slowly warmed to rt and stirred for
12 h. It was then quenched with water and extracted with
ether. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate-hexane (1:
50) as eluent furnished the bicyclic compound 13 (150 mg, 76%)
as an oil. [R]D24: -5.4 (c 7.9, CHCl3). IR: νmax (cm-1) 1727, 1652,
1636, 894. 1H NMR: δ 4.95 (2 H, s), 4.88 (1 H, br s), 4.74 (1 H,
br s), 2.61 (1 H, dd, J ) 18.9 and 2.6 Hz), 2.45-2.30 (2 H, m),
2.30-2.20 (1 H, m), 2.20 (1 H, dd, J ) 18.9 and 2.6 Hz), 1.14
(3 H, s), 1.12 (3 H, s), 1.09 (3 H, s). 13C NMR: δ 210.8 (C),
156.5 (C), 145.7 (C), 108.9 (CH2), 108.7 (CH2), 52.7 (C), 50.6
(CH), 40.8 (CH2), 38.6 (CH2), 37.8 (C), 31.4 (CH3), 28.6 (CH3),
16.5 (CH3). MS: m/z 190 (M+, 37), 175 (23), 161 (20), 149 (25),
147 (62), 133 (100), 119 (48), 105 (70). HRMS: m/z for C13H18O,
calcd 190.1358, found 190.1358.
(+)-Meth yl (1R)-1,5,5-Tr im eth yl-6-m eth ylen ecycloh ex-
3-en -2-on e-1-a ceta te (14). Precooled dry ozone in oxygen gas
was passed through a cold (-70 °C) suspension of the bicyclic
ketone 13 (200 mg, 1.05 mmol) and NaHCO3 (10 mg) in 1:4
MeOH-CH2Cl2 (5 mL) for 5 min. Exess ozone was flushed off
with oxygen. The solvent was evaporated in vacuo, and the
residue was dissolved in 2 mL of dry benzene. To this mixture
were added acetic anhydride (1 mL, 10.5 mmol), triethylamine
(0.7 mL, 5.2 mmol), and a catalytic amount of DMAP, and the
resulting mixture was stirred at rt for 15 min and then
refluxed for 6 h. The reaction mixture was diluted with water
and extracted with ether. The ether extract was washed with
3 N aqueous HCl and water. Evaporation of the solvent and
purification of the residue over a silica gel column using ethyl
acetate-hexane (1:50) as eluent furnished first the unreacted
starting material 13 (80 mg). Further elution of the column
with ethyl acetate-hexane (1:20 to 1:10) as eluent furnished
the Criegee fragmentation product 14 (93 mg, 67% based on
the starting material consumed) as an oil. [R]D25: +38 (c 1.08,
CHCl3). IR: νmax (cm-1) 1740, 1680, 1622, 902. 1H NMR: δ
6.52 (1 H, d, J ) 10.2 Hz), 5.98 (1 H, d, J ) 10.2 Hz), 5.15 (1
H, s), 5.10 (1 H, s), 3.55 (3 H, s), 3.33 and 2.75 (2 H, 2 × d, J
) 16.7 Hz), 1.38 (3 H, s), 1.34 (3 H, s), 1.29 (3 H, s). 13C NMR:
δ 200.0 (C), 171.1 (C), 157.4 (C), 155.6 (CH), 124.0 (CH), 110.4
(CH2), 51.3 (CH3), 49.3 (C), 42.8 (CH2), 37.5 (C), 33.1 (CH3),
31.3 (CH3), 30.9 (CH3). MS: m/z 222 (M+, 16), 191 (51), 175
(64), 163 (33), 147 (74), 135 (31), 121 (100), 105 (55), 96 (40),
91 (44).
1
νmax (cm-1) 1741, 1623, 908. H NMR: δ 5.13 (1 H, s), 5.06 (1
H, s), 3.60 (3 H, s), 3.35-3.15 (4 H, m), 3.07 and 2.72 (2 H, 2
× d, J ) 14.6 Hz), 2.48 (1 H, ddd, J ) 14.5, 11.0 and 3.7 Hz),
2.17 (1 H, td, J ) 13.9 and 4.8 Hz), 1.75 (1 H, ddd, J ) 14.2,
11.0, and 4.0 Hz), 1.60 (3 H, s), 1.56 (1 H, td, J ) 14.2 and 4.4
Hz), 1.16 (6 H, s). 13C NMR: δ 171.5 (C), 155.7 (C), 112.9 (CH2),
80.9 (C), 51.0 (CH3), 49.1 (C), 43.0 (CH2), 39.9 (CH2), 39.6
(CH2), 39.5 (CH2), 37.8 (CH2), 35.9 (C), 32.5 (CH3), 31.1 (CH3),
23.8 (CH3). Further elution of the column with ethyl acetate-
hexane (1:20 to 1:10) as eluent furnished the unreacted
ketoester 19 (78 mg). To a magnetically stirred solution of the
thioketal 22 (85 mg, 0.283 mmol) in dry ethanol was added
an excess of Raney Ni, and the resulting mixture was refluxed
for 30 min. The reaction mixture was filtered through a short
silica gel column to remove the catalyst. Evaporation of the
solvent and purification of the residue over a silica gel column
using ethyl acetate-hexane (1:50) as eluent furnished the ester
20 (53.5 mg, 90%) as an oil. [R]D25: -3.7 (c 3, CHCl3). IR: νmax
(cm-1) 1739, 1624, 902. 1H NMR: δ 4.99 (1 H, s), 4.89 (1 H, s),
3.61 (3 H, s), 2.53 and 2.48 (2 H, AB q, J ) 13.5 Hz), 1.75-
1.30 (6 H, m), 1.25 (3 H, s, CH3), 1.14 (3 H, s, CH3), 1.13 (3 H,
s, CH3). 13C NMR: δ 172.1 (C), 160.7 (C), 108.7 (CH2), 51.0
(CH3), 46.0 (CH2), 40.8 (CH2), 38.91 (CH2), 38.86 (C), 36.4 (C),
32.5 (CH3), 31.2 (CH3), 29.7 (CH3), 18.6 (CH2).
(+)-Meth yl 3-[(1R)-1,3,3-Tr im eth yl-2-m eth ylen ecyclo-
h exyl]p r op ion a te (6). To a solution of the ester 20 (25 mg,
0.12 mmol) in 1 mL of methanol was added 10% aqueous
NaOH solution (1 mL), and the resulting mixture was refluxed
for 12 h. The reaction mixture was cooled, acidified with 3 N
aqueous HCl, and then extracted with ether. Evaporation of
the solvent furnished the acid4e 23 (22 mg, 94%) as an oil. IR:
1
νmax (cm-1) 1706, 903. H NMR: δ 5.02 (1 H, s), 4.94 (1 H, s),
2.53 (2 H, s), 1.90-1.30 (6 H, m), 1.29 (3 H, s, CH3), 1.15 (6 H,
s). 13C NMR: δ 178.5 (C), 160.4 (C), 109.0 (CH2), 46.1 (CH2),
40.8 (CH2), 38.9 (CH2), 38.8 (C), 36.4 (C), 32.6 (CH3), 31.2
(CH3), 29.7 (CH3), 18.6 (CH2). A solution of the acid 23 (22
mg, 0.11 mmol) and oxalyl chloride (0.1 mL, 1.1 mmol) in dry
benzene (1 mL) was stirred for 2 h at rt. Evaporation of
benzene and the excess oxalyl chloride under reduced pressure
furnished the acid chloride, which was taken in dry ether and
added, dropwise, to a cold (0 °C), magnetically stirred ethereal
solution of diazomethane (3 mL, excess prepared from N-
nitroso-N-methylurea and 60% aqueous KOH solution), and
the resulting mixture was stirred at rt for 2 h. Careful
evaporation of the excess diazomethane and ether on a water
bath followed by purification on a short silica gel column using
ethyl acetate-hexane (1:10) as eluent furnished the diazo
ketone 24 (22 mg, 89%) as a yellow oil. IR: νmax (cm-1) 2100,
1633, 901. A solution of the diazo ketone in methanol (20 mL)
was placed in a Pyrex photochemical reactor and irradiated
with a Hanovia medium-pressure mercury vapor lamp for 1
h. Evaporation of the solvent and purification of the photo-
lyzate on a silica gel column using ethyl acetate-hexane (1:
50) as eluent furnished the homologated ester 64e (17.5 mg,
(+)-Meth yl (1R)-1,5,5-Tr im eth yl-6-m eth ylen ecycloh ex-
a n -2-on e-1-a ceta te (19). To a magnetically stirred solution
of the enone 14 (200 mg, 0.90 mmol) in EtOAc (2 mL) was
added 5% Pd-C (30 mg), and the reaction mixture was stirred
under hydrogen, created by evacuative displacement of air
(balloon) for 30 min. The reaction mixture was passed through
a short silica gel column to remove the catalyst. Evaporation
of the solvent and purification of the residue over a silica gel
column using ethyl acetate-hexane (1:20 to 1:10) as eluent
furnished the ketone 19 (182 mg, 90%) as an oil. [R]D25: +20.8
(c 1.2, CHCl3). IR: νmax (cm-1) 1740, 1713, 1627, 899. 1H
NMR: δ 5.05 (1 H, s), 4.94 (1 H, s), 3.57 (3 H, s), 3.23 and
2.71 (2 H, 2 × d, J ) 16.5 Hz), 2.70-2.45 (2 H, m), 1.90-1.75
(2 H, m), 1.25 (3 H, s), 1.24 (3 H, s), 1.21 (3 H, s). 13C NMR:
δ 212.8 (C), 171.4 (C), 159.6 (C), 108.6 (CH2), 51.4 (CH3), 51.3
(C), 44.1 (CH2), 35.7 (C), 35.5 (CH2), 34.5 (CH2), 31.4 (CH3),
30.3 (2 C, CH3). MS: m/z 224 (M+, 83), 193 (44), 165 (85), 151
(26), 137 (37), 123 (42), 109 (100), 95 (42).
78%) as an oil. [R]D26: +32.7 (c 1.65, CHCl3). IR: νmax (cm-1
)
1
1741, 1622, 901. H NMR: δ 5.04 (1 H, s), 4.79 (1 H, s), 3.64
(3 H, s), 2.30-2.00 (3 H, m), 1.85-1.65 (1 H, m), 1.60-1.20 (6
H, m), 1.12 (3 H, s), 1.11 (3 H, s), 1.05 (3 H, s). 13C NMR: δ
174.4 (C), 159.2 (C), 109.5 (CH2), 51.4 (CH3), 41.5 (CH2), 40.5
(CH2), 39.2 (C), 36.5 (C), 35.0 (CH2), 32.7 (CH3), 30.0 (CH2),
29.7 (CH3), 29.6 (CH3), 18.6 (CH2).
(-)-(1R ,3S ,7R )-7,11,11-Tr im e t h ylt r icyclo[5.4.0.01,3]-
u n d eca n -4-on e (4). Hydrolysis of the ester 6 (20 mg, 0.089
mmol) in 1 mL of methanol using 10% aqueous NaOH solution
(1 mL) for 12 h, as described in the previous experiment,
furnished the acid8b 5 (17 mg, 91%) as an oil. Reaction of the
acid 5 (17 mg, 0.08 mmol) with oxalyl chloride (0.07 mL, 0.8
mmol) in dry benzene (1 mL) for 2 h at rt furnished the acid
(-)-Meth yl (1R)-1,3,3-Tr im eth yl-2-m eth ylen ecycloh ex-
a n e-1-a ceta te (20). A solution of the ketone 19 (112 mg, 0.5
mmol), ethanedithiol (0.12 mL, 1.5 mmol), and BF3·OEt2 (0.06
mL, 0.5 mmol) in dry benzene (0.5 mL) was magnetically

7106 J . Org. Chem., Vol. 66, No. 21, 2001
Srikrishna and Anebouselvy
chloride, which on treatment with an excess of an ethereal
solution of diazomethane (3 mL) followed by purification of
the product, as described in the previous reaction, furnished
the diazo ketone 25 (17 mg, 90%) as a yellow oil. IR (neat):
1H NMR: δ 2.52 (1 H, ddd, J ) 18.9, 13.5, and 7.2 Hz), 2.12 (1
H, ddd, J ) 18.9, 6.3, and 1.8 Hz), 2.00-1.50 (2 H, m), 1.75-
1.45 (4 H, m), 1.22 (3 H, s), 1.40-1.10 (4 H, m), 1.14 (3 H, s),
0.99 (1 H, dd, J ) 10.5 and 5.1 Hz), 0.63 (3 H, s). 13C NMR:
δ 209.4 (C), 40.2 (CH2), 38.9 (C), 35.2 (CH2), 35.0 (CH2), 33.8
(C), 33.0 (CH2), 32.9 (C), 32.5 (CH), 28.6 (CH3), 28.5 (CH3),
27.3 (CH3), 18.9 (CH2), 13.2 (CH2).
ν
max (cm-1) 2102, 1641, 902. The diazo ketone 25 was taken in
dry cyclohexane (4 mL) and added dropwise to a magnetically
stirred, refluxing (using two 100 W tungsten lamps) suspen-
sion of Cu powder (50 mg) and anhydrous CuSO4 (40 mg) in 4
mL of dry cyclohexane, the resulting mixture was refluxed for
4 h. The reaction mixture was then cooled, and the catalyst
was filtered off. Evaporation of the solvent and purification of
the residue over a silica gel column using ethyl acetate-
hexane (1:20 to 1:10) as eluent furnished dihydromayurone4e,8
4 (6 mg, 36% from the acid 5), which was recrystallized from
hexanes.
Ack n ow led gm en t. We thank the Department of
Science and Technology, New Delhi, for financial sup-
port and the Council of Scientific and Industrial Re-
search, New Delhi, for the award of a research fellow-
ship to K.A.
Alternatively,8a a solution of the diazo ketone 25 (9 mg,
0.0385 mmol) and rhodium acetate (1 mg) in benzene (5 mL)
was magnetically stirred at room temperature for 12 h.
Evaporation of the solvent followed by purification as above
furnished dihydromayurone 4 (5 mg, 57% from the acid 5).
Mp: 105-106 °C (lit.5 mp: 106-108 °C). [R]D22: -71.0 (c
1.0, CHCl3), [lit.5 for (+)-4, [R]D: +75.4]. IR: νmax (cm-1) 1681.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 4, 6, 7, 11, 13, 14, 19, 20, 22, and 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0105484