High diastereoselectivity in Claisen rearrangement in a sterically congested cyclopentane system. Total synthesis of (±)-β-necrodol

Article abstract of DOI:10.1016/S0040-4020(01)00019-9

Total synthesis of the monoterpene β-necrodol has been accomplished. The key step involves an ortho-ester Claisen rearrangement in a highly sterically congested cyclopentane derivative resulting in a high level of 1,3-trans diastereoselection. A novel photo-induced decarboxylation of the obtained γ,δ-unsaturated acid afforded β-necrodol.

Full text of DOI:10.1016/S0040-4020(01)00019-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2011±2014
High diastereoselectivity in Claisen rearrangement in a sterically
congested cyclopentane system. Total synthesis of (^)-b-necrodol
Susanta Samajdar, Anjan Ghatak, Shyamapada Banerjee and Subrata Ghoshp
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700-032, India
Received 3 July 2000; revised 5 December 2000; accepted 21 December 2000
AbstractÐTotal synthesis of the monoterpene b-necrodol has been accomplished. The key step involves an ortho-ester Claisen rearrange-
ment in a highly sterically congested cyclopentane derivative resulting in a high level of 1,3-trans diastereoselection. A novel photo-induced
decarboxylation of the obtained g,d-unsaturated acid afforded b-necrodol. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The key step in our synthesis is an ortho-ester Claisen
rearrangement in an appropriately constructed cyclopentane
derivative 9. It established the required trans relationship
between the 1,3-substitutents of b-necrodol with simul-
taneous generation of the exo methylene unit. The unsatu-
rated alcohol 9 was easily obtained from the cyclopentanone
derivative 5. The ketone 5 was prepared through our
previously published procedure,5 based on a methodology
The defensive spray of the red-lined carrion beetle,
Necrodes surinamensis, has been found to contain two
novel monoterpenses,1 a-necrodol 1 and b-necrodol 2.
Structurally, both the necrodols have 1,2,2,3,4-pentamethyl-
cyclopentane (necrodane) as the core structural unit with
1,3-trans disposed Me and CH2OH groups. The necrodols
exhibit strong antiinsectant activity. Owing to their fascinat-
ing structures and biological activities, these compounds
continue2to be the targets of synthetic investigations. Earlier
synthetic attempts reveal that necrodols pose a considerable
synthetic challenge. First, the construction of the sterically
congested, highly substituted cyclopentane nucleus is not
trivial, but the most dif®cult task lies in the generation of
thermodynamically unfavorable trans relationship between
the 1- and 3-substituents. The best ratio of 1,3-trans to cis-
isomers reported2c so far is 5:1. The synthesis of b-necrodol
is associated with an additional problem in generating an
exo-methylene unit through ole®nation of enolizable cyclo-
pentanone derivatives.2a Intrigued by the synthetic
challenges associated with necrodols, we undertook a
program for the synthesis of b-necrodol as part of our
interest3 in cyclopentanoid natural products. A detail
account4 of this investigation is presented here.
developed for the synthesis of vicinally substituted cyclo-
pentanones3a±e and spirocyclopentanones.
3f,g
Thus, the
diene 3 (Scheme 1) obtained from acetone, on reaction
with ethoxyvinyl lithium followed by allylation, afforded
the cyclobutane derivative 4 on irradiation in the presence
of CuOTf as catalyst. An acid induced rearrangement of the
cyclobutane derivative 4 afforded the desired cyclopenta-
none 5 in 84% yield.
The ketone 5 was then transformed to the unsaturated alde-
hyde 8 (Scheme 2), following the protocol described by
Ghatak et al.6 Toward this end, the hydroxyl group of the
hydroxyketone 5 was protected to give the silyl ether 6 in
72% yield. The ketone 6 was then converted to the b-keto-
acetal 7 as a single diastereoisomer in 79% yield using
Keywords: terpenes and terpenoids; Claisen rearrangement; decarboxyla-
tion; photochemistry.
p
Corresponding author. Tel.: 191-33-473-4971/3372; fax: 191-33-473-
2805; e-mail: ocsg@mahendra.iacs.res.in
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00019-9

2012
S. Samajdar et al. / Tetrahedron 57 (2001) 2011±2014
Scheme 2.
Mock's procedure.7 The trans-disposition of the CH2OH
and CH(OMe)2 groups could be established from compari-
son of the chemical shifts8 of the geminal Me protons at d
0.95 and 1.02 with those reported in the literature for similar
structures. The formation of the trans diastereoisomer is
also expected from addition of the dialkoxy carbonium
ion to the enolate from the face opposite to the
CH2OTBDMS group. Treatment of the keto-acetal 7 with
NaBH4 in MeOH followed by aqueous 6N HCl led to the
reduction of carbonyl group with concomitant deketaliza-
tion, dehydration and desilylation to afford the unsaturated
aldehyde 8 in 87% yield. Brief exposure of the aldehyde 8
into NaBH4±MeOH at room temperature gave the diol 9 in
62% yield.
quinoline and t-butylmercaptan led to smooth decarboxyla-
tion,10 affording b-necrodol 2 (containing a trace amount of
1
epi-b-necrodol) in 61% yield. H and 13C NMR spectral
data of this sample were identical with those reported in
the literature.2a
3. Conclusions
We have demonstrated that a high level of 1,3-trans
diastereoselection can be achieved in a sterically congested
cyclopentane
derivative
through
[3.3]-sigmatropic
rearrangement. Finally, the synthesis of b-necrodol could
be achieved through a photo-induced decarboxylation of the
corresponding g,d-unsaturated acid.
The ortho-ester Claisen rearrangement of the unsaturated
diol 9 was carried out with an excess of triethyl orthoacetate,
in the presence of mercuric acetate and propionic acid, in a
sealed tube at 2008C for 6 h. The crude rearrangement
product was directly hydrolyzed to afford the acid 10
along with its cis epimer in ca. 10:1 ratio (from integration
4. Experimental
4.1. General
1
of the geminal methyl protons in the H NMR spectrum).
Melting points were measured in open capillary tubes, in a
sulfuric acid bath, and are uncorrected. The organic extracts
were dried over anhydrous Na2SO4. Column chromato-
graphy was performed on silica gel (60±120 mesh).
Petroleum refers to fraction of petroleum ether boiling in
the range 60±808C. IR spectra were recorded as thin ®lms.
Column chromatography of the crude product followed by
crystallization, afforded the acid 10 as a white crystalline
solid, mp 688C in 40% yield. While the gross structure of the
acid was clearly evident from the 1H and 13C NMR spectra,
the stereochemical assignment to the major acid 10 was
based on comparison of the chemical shifts8 of the geminal
methyls (d 0.89 and 0.95) with those reported for b-necro-
dol (d 0.80 and 0.92). On the other hand, the chemical shifts
of the geminal methyl protons of the minor isomer (d 0.57
and 1.09) were comparable to those reported for epi-b-
necrodol (d 0.51 and 1.04). The formation of the trans
diastereomer as the major component during ortho-ester
Claisen rearrangement of the diol 9 may be attributed as
follows. During rearrangement, the hydroxymethyl group
dictated the C±C bond formation to take place from its
opposite face9 through the transition state 11. The alterna-
tive transition state 12, leading to C±C bond formation from
the side of the hydroxymethyl group, will be destabilized by
an unfavorable 1,3-diaxial interaction. Finally, irradiation of
a benzene solution of the hydroxy acid 10 in the presence of
1
Unless otherwise stated, H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, in CDCl3
solutions using TMS as internal standard.
4.1.1. 3,3-Dimethyl-4-hydroxymethylcyclopent-1-ene-car-
boxaldehyde (8). A solution of the hydroxy ketone 55
(1.09 g, 7.04 mmol), TBDMSCl (1.6 g, 10.6 mmol), tri-
ethylamine (2.1 g, 20.8 mmol), DMAP (10 mg) and imida-
zole (10 mg) in dichloromethane (20 mL) was stirred under
nitrogen for 12 h at rt. The mixture was then washed with
brine, dried and concentrated. The residue was chromato-
graphed (5% Et2O/petroleum) to afford the silyl ether 6
(1.3 g, 72%) as a colorless liquid [Found: C, 65.78;
H, 10.89. C14H28O2Si requires C, 65.57; H, 11.00%]; nmax
1741, 1467 cm21; dH 3.57±3.67 (2H, m, OCH2), 1.93±2.36

S. Samajdar et al. / Tetrahedron 57 (2001) 2011±2014
2013
(4H, m, CH2), 1.51±1.58 (1H, m, CH), 1.04 (3H, s, Me),
0.88 (3H, s, Me), 0.83 (9H, s, CMe3), 0.01 (6H, s, SiMe2); dC
223.4 (CO), 64.0 (CH2), 48.9 (CH), 47.2 (C), 35.9 (CH2),
25.8 (Me), 24.5 (Me), 22.5 (CH2), 18.2 (C), 18.0 (Me), 25.6
(Me).
Me), 0.90 (3H, s, Me); dC 140.0 (C), 136.3 (CH), 63.5
(CH2), 61.7 (CH2), 50.8 (CH), 45.4 (C), 35.6 (CH2), 28.9
(Me), 21.9 (Me).
4.2. ortho-Ester Claisen rearrangement of the allyl
alcohol 9
A solution of freshly distilled BF3´Et2O (1.7 g, 12 mmol) in
dichloromethane (10 mL) was added dropwise to freshly
distilled trimethylorthoformate (1.0 g, 9.55 mmol) with stir-
ring at 2308C under argon. The mixture was warmed to 08C
and allowed to stand at that temperature for 15 min. It was
then cooled to 2788C and a solution of the silyl ether 6
(1.24 g, 4.84 mmol) in dichloromethane (5 mL) was added
dropwise, followed by addition of N,N-diisopropylethyl-
amine (1.85 g, 14.35 mmol). The mixture was stirred at
210 to 2208C for 2 h. It was then poured into saturated
aqueous NaHCO3 solution (10 mL). The organic layer was
washed with brine (3£5 mL), dried and concentrated.
Chromatography of the residue (5% Et2O/petroleum)
afforded the ketoacetal 7 (1.26 g, 79%) as a colorless liquid
[Found: C, 61,94; H, 10.20. C17H34O4Si requires C, 61.77;
H, 10.36%]; nmax 1740, 1463 cm21; dH 4.51 (1H, d,
Jˆ3.4 Hz, CH(OMe)2), 3.59 (2H, ABX, Jˆ9.0, 6.0,
3.0 Hz, OCH2), 3.34 (3H, s, OMe), 3.33 (3H, s, OMe),
2.69±2.76 (1H, m, COCH), 2.20 (1H, dt, Jˆ13.2, 6.9 Hz),
1.99±2.03 (1H, m), 1.67±1.72 (1H, m), 1.02 (3H, s, Me),
0.96 (3H, s, Me), 0.83 (9H, s, CMe3), 0.02 (6H, s, SiMe2); dC
221.5 (CO), 105.7 (CH), 64.4 (CH2), 56.8 (Me), 55.0 (Me),
50.1 (CH), 47.9 (C), 46.9.(CH), 25.8.(Me), 24.2 (Me), 23.5
(CH2), 18.8 (Me), 18.1 (C), 25.6 (Me).
4.2.1. 2,2-Dimethyl-3a-hydroxymethyl-5-methylene-cyclo-
pent-1b-yl acetic acid (10). A mixture of the allyl alcohol 9
(154 mg, 1 mmol), triethylorthoacetate (1 mL, 5.5 mmol),
propionic acid (20 mg, 0.27 mmol) and mercuric acetate
(20 mg, 0.06 mmol) was heated in a sealed tube at 2008C
for 6 h. The crude rearrangement product was hydrolyzed
by re¯uxing its solution in MeOH (4 mL) with aqueous
NaOH (1.5 mL, 5%). The reaction mixture was then cooled
to rt, diluted with water (5 mL) and acidi®ed with HCl (6N)
(2 mL). It was then extracted with ethyl acetate (3£10 mL),
and the ethyl acetate layer was washed with saturated
NaHCO3 solution (3£1 mL). The NaHCO3 washing was
acidi®ed with cold HCl (12N) and extracted with ethyl
acetate (3£5 mL). The ethyl acetate layer was dried,
concentrated in vacuum and the residue was chromato-
graphed (30% EtOAc/petroleum). The solid mass obtained
was repeatedly crystallized (EtOAc/pentane) to afford the
hydroxy acid 10 along with a trace amount of its cis-epimer
(80 mg, 40%); mp 688C [Found: C, 66.25; H, 9.10.
C11H18O3 requires C, 66.62; H, 9.16%]; nmax 3433, 1713,
1658 cm21; dH 5.75 (2H, brs, OH), 4.90 (1H, d, Jˆ2.1 Hz,
CvCH2), 4.86 (1H, d, Jˆ2.1 Hz, CvCH2), 3.76 (1H, dd,
Jˆ1.7, 4.3 Hz, CH2OH) 3.53 (1H, dd, Jˆ8.3, 10.3 Hz,
CH2OH), 2.23±2.63 (5H, m) 1.88 (1H, m), 0.97 (3H, s,
Me), 0.90 (3H, s, Me); dC 178.7 (CO), 152.6 (C), 107.0
(CH2), 63.8 (CH2), 50.5 (CH), 48.4 (CH), 42.2 (C), 34.6
(CH2), 33.6 (CH2), 23.8 (Me), 22.8 (Me).
To a well-stirred solution of the acetal 7 (400 mg, 1.2 mmol)
in MeOH (3 mL), NaBH4 (180 mg, 4.2 mmol) was added
and the mixture was stirred for 12 h at rt. Then, the reaction
mixture was quenced with ice cold 6N HCl (4 mL) and
stirred for an additional 1.5 h. MeOH was then evaporated
in vacuum and the mixture was extracted with ether
(3£25 mL). The ether layer was dried and concentrated.
Column chromatography (5% Et2O/petroleum) of the
residual mass afforded the title compound 8 as a colorless
liquid (160 mg, 87%) [Found: C, 69.92; H, 9.22. C9H14O2
requires C, 70.10; H, 9.15%]; nmax 3407, 1677 cm21 dH 9.69
(1H, s, CHO), 6.62 (1H, s, CvCH),3.62±3.79 (2H, m,
OCH2), 2.85 (1H, brs, OH), 2.73 (1H, q, Jˆ9 Hz), 2.26
(1H, d, Jˆ9 Hz), 2.20 (1H, d, Jˆ9 Hz), 1.26 (3H, s, Me),
1.04 (3H, s, Me); dC 191.0 (CHO), 163.0 (CH), 143.3 (C),
63.3 (CH2), 50.5 (CH), 47.4 (C), 31.6 (CH2), 28.3 (Me), 21.2
(Me).
4.2.2. Decarboxylation of the acid 25. Synthesis of
b-necrodol (2). A solution of the hydroxy acid 25 (50 mg,
0.25 mmol) in benzene (6 mL) was irradiated in the
presence of quinoline (40 mg) and t-BuSH (0.3 mL) with
a medium pressure 450 W Hanovia Hg vapor lamp, with a
pyrex ®ltered light, for 3 h under Ar. The reaction mixture
was then washed successively with HCl (4 mL, 6N), satu-
rated NaHCO3 solution (3£2 mL) and brine (3 mL).
Evaporation of the solvent followed by column chromato-
graphy (25% Et2O/petroleum) afforded b-necrodol 2
(containing a trace of its cis-epimer) (23 mg, 61%) as a
clear liquid; nmax 3360, 3070, 2960, 1657, 1454, 1386,
1167, 1028, 874 cm21; dH 4.85 (1H, app. quintet,
Jˆ2.2 Hz, CvCH2), 4.79 (1H, app. quintet, Jˆ2.2 Hz,
CvCH2), 3.77 (1H, dd, Jˆ5.3, 10.3 Hz, CH2OH), 3.46
(1H, dd, Jˆ8.6, 10.3 Hz, CH2OH), 2.59 (1H, m), 2.27
(1H, m), 2.15 (1H, m), 1.85 (1H, m), 0.93 (3H, s, Me),
0.93 (3H, d, Jˆ7 Hz, CHMe), 0.82 (3H, s, Me); dC 156.0
(C), 105.1 (CH2), 64.4 (CH2), 48.9 (CH), 48.4 (CH2), 42.2
(C), 33.8 (CH2), 23.7 (Me), 23.1 (Me), 13.5 (Me). These
spectral data were identical to those reported in the
literature.2a
4.1.2. 3,3-Dimethyl-1,4-dihydroxymethyl cyclopentene
(9). NaBH4 (180 mg, 4.73 mmol) was added in small
portions to a solution of the aldehyde 8 (370 mg,
2.36 mmol) in MeOH (2 mL) with stirring at rt. Stirring
was continued for an additional 1 h. After diluting with
water (1 mL), MeOH was removed and the residue was
extracted with ether (3£5 mL). The ether layer was dried
and concentrated. The residue was chromatographed (30%
EtOAc/petroleum) to afford the title compound 9 (230 mg,
62%) as a colorless liquid [Found: C, 69.12; H, 10.20.
C9H16O2 requires C, 69.18; H, 10.33%]; nmax 3327 cm21
;
dH 5.36 (1H, s, CvCH), 4.10 (2H, s, CH2OH), 3.72±3.78
(1H, m, CH2OH), 3.55±3.61 (1H, m, CH2OH), 2.78 (2H, br,
OH), 2.46 (1H, m), 2.07±2.18 (2H, m, CH2), 1.12 (3H, s,
Acknowledgements
Financial support from DST and CSIR, New Delhi, is

2014
S. Samajdar et al. / Tetrahedron 57 (2001) 2011±2014
Chem. Commun. 1993, 783±784. (g) Patra, D.; Ghosh, S.
J. Chem. Soc., Perkin Trans. 1 1995, 2635±2641.
4. A portion of this work appeared as a preliminary communica-
tion: Samajdar, S.; Ghatak, A.; Ghosh, S. Tetrahedron Lett.
1999, 40, 4401±4402.
gratefully acknowledged. S. S. and S. B. wish to thank CSIR
for Senior and Junior Fellowships.
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