Enantioselective syntheses of diquinane and (cis, anti, cis)-linear triquinanes

Article abstract of DOI:10.1016/j.tetasy.2010.01.014

The enantioselective syntheses of diquinane and cis, anti, cis-linear triquinanes, starting from the readily available (S)-campholenaldehyde, employing an intramolecular rhodium carbenoid CH insertion reaction, are described.

Full text of DOI:10.1016/j.tetasy.2010.01.014

Tetrahedron: Asymmetry 21 (2010) 202–207
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective syntheses of diquinane and (cis, anti, cis)-linear triquinanes
*
A. Srikrishna , Vijayendran Gowri, Ghodke Neetu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 November 2009
Accepted 21 January 2010
The enantioselective syntheses of diquinane and cis, anti, cis-linear triquinanes, starting from the readily
available (S)-campholenaldehyde, employing an intramolecular rhodium carbenoid CH insertion reac-
tion, are described.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
industrially (flavors and fragrance) important monocyclic com-
pounds.4 However, the use of campholenaldehyde 7 as a chiral
Over the last three decades polycondensed cyclopentane rings,
commonly known as polyquinanes, have attracted the attention
of synthetic chemists, both in the context of natural product syn-
thesis1 and aesthetically appealing molecules such as dodecahed-
rane.2 Polyquinane natural products were revealed to chemists
only in the second half of 20th century. The structure determina-
tion of the first ‘authentic’ polyquinane natural product, hirsutic
acid-C3 was accomplished in 1966. Despite this belated discovery,
during the second half of the last century, several polyquinane nat-
ural products have been encountered among plant, marine, and
microbial sources. So far, natural products containing up to four
fused cyclopentanes, 1–5, have been revealed, whereas the aes-
thetically appealing dodecahedrane 6 has 12 cyclopentanes.
starting material in the synthesis of polycyclic compounds in nat-
ural product synthesis is relatively unexplored.5 In continuation of
our interest6 in the enantiospecific synthesis of polycyclic com-
pounds starting from (S)-campholenaldehyde 7, we have explored
its utility in the enantioselective synthesis of diquinane and cis,
anti, cis-triquinanes, which do not contain
a gem-dimethyl
grouping.
H
H
O
O
ð1Þ
H
H
7
8
H
H
H
H
H
H
H H
H
H
5
H
H
1
2
3
4
6
The polyquinane natural products have attracted a great deal of
interest amongst synthetic chemists over the last three decades.1
Among the polyquinanes, triquinanes are the most commonly
encountered in sesquiterpenes and are classified according to ring
fusion as linear 2, angular 3 or propellane 4. The linear triquinanes
bearing thermodynamically favored cis, anti, cis-tricy-
clo[6.3.0.02,6]undecane 2 moiety as the fundamental ring system
are the most abundant among natural polyquinanes.
Recently, we have reported an efficient route for the enantio-
specific conversion of (S)-campholenaldehyde 7 into diquinane 8
(Eq. 1), which retains the gem-dimethyl grouping of campholenal-
dehyde.6a Of the three methyl groups in campholenaldehyde 7, the
olefinic methyl group can be easily functionalized, for example, via
allylic oxidation. However, the remaining two tertiary methyl
groups are difficult to functionalize, and to the best of our knowl-
edge, there is no report in the literature on the utility of these
methyl groups for further elaboration (other than as a dimethyl
grouping in the targets). We conceived that it could be possible
to utilize tertiary methyl carbon for ring construction via an intra-
(S)-Campholenaldehyde 7, readily available from
a-pinene
epoxide, is a commonly available cyclopentane-based chiral start-
ing material, and has been employed in the synthesis of a variety of
molecular rhodium carbenoid
c
-CH insertion reaction.7 In this
direction, it was contemplated that the olefinic methyl group could
* Corresponding author. Fax: +91 80 23600529.
be linked to one of the tertiary methyl groups via an extra carbon
E-mail address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.014

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 202–207
203
and a cyclopentannulation could be affected, with the product con-
taining only one methyl group (Eq. 2). Based on this concept, we
herein report the synthesis of diquinane and cis, anti, cis-linear
triquinanes.
genation of the olefin in the acid 15 in ethyl acetate with 10% pal-
ladium on carbon as the catalyst at one atmospheric pressure of
hydrogen generated the acid 12 in a highly stereoselective manner
via the addition of hydrogen from the opposite face of the
methoxyethyl side chain.6c The reaction of acid 12 with oxalyl
chloride followed by the treatment of the resultant acid chloride
with an excess of ether diazomethane furnished diazoketone 10
in 89% yield. The reaction of the diazoketone 10 with a catalytic
amount of rhodium acetate in refluxing methylene chloride fur-
nished diquinane 9 in 59% yield, via regio- and stereospecific inser-
tion7 of the intermediate rhodium carbenoid in the CH bond of the
cis-methyl group. The structure of the diquinane 9 was established
from its spectroscopic data, in particular, the presence of a car-
bonyl absorption band at 1737 cmꢀ1 in the IR spectrum, the pres-
ence of only one tertiary methyl group at d 1.34 in the 1H NMR
spectrum, and the presence of a typical cyclopentanone ketone car-
bon resonance at d 221.5 ppm in the 13C NMR spectrum.
X
X
ð2Þ
'C'
7 X = CHO
2. Results and discussion
Initially, the synthesis of the diquinane 9 was investigated in or-
der to test the feasibility of the concept. It was contemplated
(Scheme 1) that the diquinane 9 could be obtained by intramolec-
ular insertion of the rhodium carbenoid derived from the diazoke-
tone 10 in the CH bond of one of the gem dimethyl groups, as the
After successfully accomplishing the synthesis of diquinane 9,
the synthesis of a cis, anti, cis-triquinane 17 was investigated start-
ing from the diquinane 8 (Scheme 3). The diquinane 8 was prepared
as described earlier.6a Thus, the oxidation of campholenaldehyde 7
with Jones’ reagent generated acid 18, which was converted into
the diazoketone 19 via the corresponding acid chloride. The reac-
tion of diazoketone 19 with a catalytic amount of rhodium acetate
in refluxing methylene chloride furnished diquinane 8, via regio-
and stereospecific insertion of the intermediate rhodium carbenoid
in the allylic CH bond. In order to avoid regiochemical problems at
a later stage, the ketone in diquinane 8 was masked. Reduction of
the ketone in 8 with sodium borohydride in methanol furnished
alcohol 20 in a highly stereoselective manner, which on etherifica-
tion with sodium hydride and methyl iodide furnished the methyl
ether 21. Oxidation of diquinane 21 with selenium dioxide in
refluxing aqueous dioxane furnished aldehyde 22. Hydrogenation
of the olefin in 22 in ethyl acetate at one atmospheric pressure of
hydrogen using 10% palladium over carbon as the catalyst fur-
nished the saturated endo-aldehyde 23 in a stereoselective manner
via the delivery of the hydrogen from the exo face of the molecule.
It was obvious that for the generation of the cis, anti, cis-triquinane,
the carboxyl group needed to be in the exo orientation, for which
the aldehyde group in 23 needs to be isomerized. The treatment
of aldehyde 23 with diazabicyclo[5.4.0]undec-7-ene (DBU) in
methylene chloride furnished exo-aldehyde 24. For the construc-
tion of the third ring, an intramolecular rhodium carbenoid inser-
other two possible
c-CH bonds lead to strained bridged com-
pounds. Allylic oxidation of the olefinic methyl group in the readily
available campholenyl methyl ether8 11 was conceived for the gen-
eration of acid 12.
γ
H
H
γ
γ
OMe
H
OMe
γ
X
OMe
α
O
O
10 X = CHN2
9
11
12 X = OH
Scheme 1.
The synthetic sequence is depicted in Scheme 2. The reduction
of campholenaldehyde 7 with sodium borohydride in methanol,
followed by Williamson’s etherification of the resultant alcohol
13 with sodium hydride and methyl iodide generated the requisite
starting material 11.8 Allylic oxidation of the methyl ether 11 with
selenium dioxide in refluxing aqueous dioxane furnished the
unsaturated aldehyde 14 in a highly regioselective manner. Further
oxidation of aldehyde 14 with sodium chlorite in tertiary butyl
alcohol generated the acid 15, which was purified as its methyl es-
ter 16. Since the rhodium carbenoid derived from the acid 15, in
principle, could insert into either of the two gem dimethyl groups
leading to regioisomers, it was decided to saturate the olefin in 15.
Accordingly, the hydrolysis of the ester 16 with sodium hydroxide
in aqueous methanol furnished the acid 15, mp 106–09 °C. Hydro-
tion of an
a-diazo-b-keto ester was chosen. Accordingly, the
treatment of aldehyde 24 with methyl diazoacetate in the presence
H
H
H
a
98%
b
92%
OH
OMe
51%
CHO
13
7
11
c
H
H
H
H
f
d
ROOC
OHC
OMe
OMe
OMe
97%
HOOC
OMe
99%
60%
16. R = Me
15. R = H
12
14
e
g
89%
H
H
OMe
h
N2
59%
H
10
H
9
O
O
Scheme 2. Reagents: (a) NaBH4, MeOH; (b) NaH, MeI, TBAI, THF; (c) SeO2, dioxane–H2O; (d) (i) NaClO2, tBuOH, CH2@CMe2, NaH2PO4, (ii) CH2N2, Et2O; (e) NaOH, MeOH–H2O;
(f) H2, 10% Pd/C, EtOAc; (g) (i) (COCl)2, C6H6, (ii) CH2N2, Et2O; (h) Rh2(OAc)4, CH2Cl2.

204
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 202–207
H
H
H
a
c
d
7
O
OH
O
93%
X
H
8
H
20
18 X = OH
b
19 X = CHN2
e
88%
OMe
H
H
H
H
H
g
f
OHC
OMe
OMe
100%
63%
OHC
H
22
H
21
23
91%
h
N2
H
H
H
MeOOC
OHC
MeOOC
OMe
OMe
OMe
j
i
O
O
H
H
H
H
25
H
24
88%
H
26
82%
k
79%
H
H
H
OMe
OMe
l
82%
MeOOC
H
O
O
H
H
17
27
Scheme 3. Reagents: (a) Jones’ reagent, acetone; (b) (i) (COCl)2, C6H6, (ii) CH2N2, Et2O; (c) Rh2(OAc)4, CH2Cl2; (d) NaBH4, MeOH; (e) NaH, MeI, TBAI, THF; (f) SeO2, dioxane–
H2O; (g) H2, 10% Pd/C, EtOAc; (h) DBU, CH2Cl2; (i) N2CHCOOMe, SnCl2ꢃ2H2O, CH2Cl2; (j) TsN3, Et3N, MeCN; (k) Rh2(OCOCF3)4, CH2Cl2; (l) LiCl, DMSO-H2O.
of a catalytic amount of stannous chloride generated the b-keto es-
ter 25.9 The diazo transfer reaction of the b-keto ester 25 with tol-
uenesulfonyl azide and triethylamine in acetonitrile furnished the
parentheses. High resolution mass spectra were recorded on a
Micromass Q-TOF micro mass spectrometer using electron spray
ionization mode. Optical rotations were measured using a Jasco
DIP-370 digital polarimeter and a Jasco P-1020 polarimeter and
a-diazo-b-keto ester 26. The rhodium carbenoid reaction of 26 was
found to be inefficient with rhodium acetate, hence it was carried
out with rhodium trifluoroacetate. Thus, the treatment of the diazo
ester 26 with a catalytic amount of rhodium trifluoroacetate in
refluxing methylene chloride furnished an epimeric mixture of
the triquinane 27 in 79% yield. Finally, Krapcho decarboxylation10
of the b-keto ester 27 in DMSO and lithium chloride in the pres-
ence of water furnished the triquinane ketone 17, whose structure
was deduced from its spectroscopic data.
[a]
values are given in units of 10ꢀ1 deg cm2 gꢀ1. Analytical
D
thin-layer chromatography (TLC) were performed on glass plates
(7.5 ꢁ 2.5 and 7.5 ꢁ 5.0 cm) coated with Acme’s silica gel G con-
taining 13% calcium sulfate as binder and various combinations
of ethyl acetate and hexane were used as an eluent. Visualization
of spots was accomplished by exposure to iodine vapor. Acme’s sil-
ica gel (100–200 mesh) was used for column chromatography
(approximately 15–20 g per 1 g of the crude product).
3. Conclusion
4.1. (4S)-4-(2-Methoxyethyl)-5,5-dimethylcyclopent-1-ene-1-
carboxaldehyde 14
In conclusion, we have accomplished enantioselective synthesis
of diquinane 9 and cis, anti, cis-linear triquinane 17, starting from
(S)-campholenaldehyde 7, employing an intramolecular rhodium
carbenoid insertion reaction in an iterative manner. An extension
of the methodology for the enantioselective synthesis of tri- and
tetraquinane based natural products is currently under investi-
gation.
To a magnetically stirred solution of the methyl ether8 11
(500 mg, 2.97 mmol) in dioxane–H2O (4:1) (5 mL) was added
SeO2 (660 mg, 5.95 mmol) and the reaction mixture was refluxed
for 1 h. The reaction mixture was then cooled and filtered. Aqueous
ammonium chloride (5 mL) was added to the filtrate and extracted
with ether (10 mL). The ether extract was washed with brine
(5 mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using ethyl acetate/hex-
ane (1:19) as an eluent furnished the aldehyde 14 (280 mg, 51%)
4. Experimental
as an oil. ½a 2D7
ꢂ
¼ ꢀ3:6 (c 9.0, CHCl3); IR (neat):
m
max/cmꢀ1 3040,
Melting points are recorded using a Buchi melting point appara-
tus in capillary tubes and are uncorrected. IR spectra were recorded
on Jasco FTIR 410 and Perkin–Elmer FTIR spectrophotometers. 1H
(300 and 400 MHz) and 13C (75 and 100 MHz) NMR spectra were
recorded on JNM k-300 and Brucker AMX 400 spectrometers using
either CDCl3 or a 1:1 mixture of CDCl3 and CCl4 as a solvent. The
chemical shifts (d ppm) and coupling constants (Hz) are reported
in the standard fashion with reference to either internal tetrameth-
ylsilane (for 1H) or the central line (77.0 ppm) of CDCl3 (for 13C). In
the 13C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3)
was determined by recording the DEPT-135 spectra, and is given in
2932, 2869, 2829, 2709, 1683, 1610, 1459, 1433, 1388, 1362,
1342, 1326, 1212, 1146, 1118, 994, 975, 914, 834, 805, 732; 1H
NMR (300 MHz): d 9.65 (1H, s, HC@O), 6.68 (1H, dd, J 6.0 and
3.0 Hz, H-2), 3.50–3.33 (2H, m, OCH2), 3.31 (3H, s, OCH3), 2.62
(1H, dq, J 18.6 and 3.3 Hz), 2.20–1.90 (2H, m), 1.85–1.70 (1H, m),
1.55–1.35 (1H, m), 1.37 (3H, s) and 1.24 (3H, s) [2 ꢁ tert-CH3];
13C NMR (75 MHz): d 189.3 (CH, CHO), 154.8 (CH, C-2), 151.2 (C,
C-3), 71.9 (CH2, C-20), 58.5 (CH3, OCH3), 48.0 (CH, C-4), 45.5 (C, C-
5), 36.9 (CH2), 29.0 (CH2), 25.6 (CH3), 20.1 (CH3); HRMS: m/z calcd
for C11H18O2Na (M+Na): 205.1204; found: 205.1203.

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 202–207
205
4.2. Methyl (4S)-4-(2-methoxyethyl)-5,5-dimethylpent-1-ene-
(CH3), 23.8 (CH2), 16.4 (CH3); HRMS: m/z calcd for C11H20O3Na
1-carboxylate 16
(M+Na): 223.1310; found: 233.1318.
To a magnetically stirred solution of the aldehyde 14 (500 mg,
2.75 mmol) in tert-butyl alcohol (10 mL) and 2-methyl-2-butene
(10 mL) was added a solution of sodium chlorite (994 mg, 11.0
mmol) and sodium dihydrogen phosphate (2.1 g, 13.7 mmol) in
water (10 mL). The reaction mixture was stirred at rt for 24 h.
The volatile components were removed in vacuo, and the residue
was dissolved in water (10 mL) and then extracted with CH2Cl2
(3 ꢁ 10 mL). The organic layer was washed with brine (8 mL), dried
(Na2SO4), and concentrated to give the acid 15 (510 mg, 94%). To an
ice cold solution of the acid 15 (500 mg, 2.5 mmol) in ether was
added an ethereal solution of diazomethane [prepared from 1.5 g
of N-nitroso-N-methylurea, 60% aq KOH solution (30 mL), and
ether (20 mL)] and stirred at the same temperature for 10 min.
Careful evaporation of the excess diazomethane and solvent on a
hot water bath and purification of the residue over a silica gel col-
umn using ethyl acetate/hexane (1:20) as an eluent furnished the
4.5. (1S,5R,6S)-6-(2-Methoxyethyl)-5-methylbicyclo[3.3.0]-
octan-2-one 9
To a magnetically stirred solution of the acid 12 (135 mg,
0.67 mmol) in dry benzene (2 mL) was added oxalyl chloride
(0.2 mL, 2.0 mmol) and stirred for 4 h. Evaporation of the excess
oxalyl chloride and solvent under reduced pressure gave the acid
chloride, which was taken in dry ether (3 mL), and added to a cold
(0 °C), magnetically stirred ethereal solution of diazomethane [ex-
cess, prepared from N-nitroso-N-methylurea (300 mg), 60% aq KOH
solution (15 mL), and ether (5 mL)] and the reaction mixture was
stirred for 3 h. Careful evaporation of the excess diazomethane
and solvent on a hot water bath and purification of the residue over
a silica gel column using ethyl acetate/hexane (1:9) as an eluent
furnished diazoketone 10 (125 mg, 89%) as an oil. IR (neat): mmax
/
cmꢀ1 3089, 2962, 2934, 2872, 2102, 1729, 1639, 1466, 1370,
1323, 1156, 1121.
ester 16 (350 mg, 65%) as an oil. ½a D26
¼ ꢀ10:0 (c 1.9, CHCl3); IR
ꢂ
(neat):
m
max/cmꢀ1 2931, 2868, 1719, 1620, 1456, 1435, 1325,
To a magnetically stirred refluxing solution of rhodium acetate
(2 mg) in dry CH2Cl2 (5 mL) was added a solution of the diazoke-
tone 10 (125 mg, 0.56 mmol) in CH2Cl2 (25 mL) dropwise over a
period of 30 min and refluxed for 3.5 h. Evaporation of the solvent
and purification of the residue on a silica gel column using ethyl
acetate/hexane (1:9) as an eluent furnished the diquinane ketone
1259, 1242, 1198, 1119, 1062, 759; 1H NMR (400 MHz): d 6.66
(1H, t, J 2.2 Hz, H-2), 3.69 (3H, s, COOCH3), 3.50–3.30 (2H, m, H-
20), 3.31 (3H, s, OCH3), 2.48 (1H, ddd, J 17.2, 7.2 and 3.2 Hz),
2.06–1.55 (3H, m), 1.53–1.42 (1H, m), 1.21 (3H, s) and 0.96 (3H,
s) [2 ꢁ tert-CH3]; 13C NMR (100 MHz): d 165.0 (C, OC@O), 144.2
(C, C-1), 141.8 (CH, C-2), 72.0 (CH2, C-20), 58.4 (CH3), 50.8 (CH3),
47.0 (CH, C-4), 46.2 (C, C-5), 36.0 (CH2), 29.2 (CH2), 25.9 (CH3),
20.3 (CH3); HRMS: m/z calcd for C12H20O3Na (M+Na): 235.1310;
found: 235.1308.
9 (64 mg, 59%) as an oil. ½a D26
¼ þ1:4 (c 13.3, CHCl3); IR (neat):
ꢂ
m
max/cmꢀ1 2950, 2870, 1737 (C@O), 1455, 1414, 1387, 1275,
1
1180, 1120, 935; H NMR (400 MHz): d 3.50–3.30 (2H, m, H-20),
3.27 (3H, s, OCH3), 2.40–2.25 (1H, m, H-1), 2.25–2.10 (2H, m),
1.95–1.24 (9H, m), 1.34 (3H, s, tert-CH3); 13C NMR (100 MHz): d
221.5 (C, C@O), 72.0 (CH2, C-20), 59.2 (CH, C-1), 58.4 (CH3, OCH3),
49.7 (C, C-5), 47.7 (CH, C-6), 38.0 (CH2, C-3), 31.0 (CH2, C-4), 28.7
(CH2), 28.4 (CH2), 27.5 (CH2), 25.6 (CH3); HRMS: m/z calcd for
C12H20O2Na (M+Na): 219.1361; found: 219.1361.
4.3. (4S)-4-(2-Methoxyethyl)-5,5-dimethylcyclopent-1-ene-1-
carboxylic acid 15
To a magnetically stirred solution of the ester 16 (100 mg,
0.47 mmol) was added 5% aq methanolic NaOH solution (5 mL)
and refluxed for 4 h. The reaction mixture was cooled, neutralized
with 10% HCl, and extracted with CH2Cl2 (3 ꢁ 5 mL). The organic
layer was washed with brine (5 mL), dried (Na2SO4), and concen-
trated to give acid 15 (90 mg, 97%), which was recrystallized from
4.6. (1R,3R,5R)-7,8,8-Trimethylbicyclo[3.3.0]oct-6-en-3-ol 20
To a cold (0 °C), magnetically stirred solution of the ketone6a
8
(400 mg, 2.44 mmol) in methanol (2 mL) was added NaBH4
(278 mg, 7.32 mmol) in batches and stirred for 10 min at the same
temperature. Methanol was evaporated under reduced pressure.
Water (2 mL) followed by 3 N HCl (3 mL) was added to the reaction
mixture and extracted with ether (3 ꢁ 5 mL). The combined ether
extract was washed with brine (5 mL) and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silica gel
column using ethyl acetate/hexane (1:9) as an eluent furnished
hexane. Mp 106–109 °C; IR (KBr): m
max/cmꢀ1 2933 (br), 1674, 1614,
1420, 1263, 1114, 1048, 974, 942; 1H NMR (400 MHz): d 6.85 (1H,
s, H-2), 3.65–3.35 (2H, m, H-20), 3.30 (3H, s, OCH3), 2.53 (1H, dd, J
17.0 and 5.8 Hz), 2.20–1.65 (3H, m), 1.65–1.38 (1H, m), 1.24 (3H, s)
and 0.98 (3H, s) [2 ꢁ tert-CH3]; 13C NMR (100 MHz): d 170.2 (C,
OC@O), 144.8 (C, C-1), 144.0 (CH, C-2), 72.0 (CH2, C-20), 58.5
(CH3, OCH3), 47.1 (CH, C-4), 46.0 (C, C-5), 36.1 (CH2), 29.2 (CH2),
25.8 (CH3), 20.2 (CH3); Anal. Calcd for C11H18O3: C, 66.64; H,
9.15. Found: C, 66.92; H, 8.87.
alcohol 20 (376 mg, 93%) as a colorless oil. ½a D22
¼ ꢀ23:3 (c 5.9,
ꢂ
CHCl3); IR (neat): m
max/cmꢀ1 3345, 3028, 2954, 2868, 1439, 1360,
1346, 1115, 1090, 1065, 1012, 827; 1H NMR (300 MHz): d 5.16
(1H, br s, H-6), 4.07 (1H, quintet, J 6.3 Hz, H-3), 3.10–2.90 (1H,
m, H-5), 2.26 (1H, q, J 8.4 Hz), 2.00 (1H, dt, J 12.9 and 7.8 Hz),
1.85–1.70 (1H, m), 1.65–1.45 (2H, m), 1.56 (3H, s, olefinic-CH3),
1.39 (1H, dt, J 12.9 and 5.4 Hz), 0.98 (6H, s, 2 ꢁ tert-CH3); 13C
NMR (75 MHz): d 146.0 (C, C-7), 128.5 (CH, C-6), 74.9 (CH, C-3),
52.3 (CH, C-1), 47.7 (C, C-8), 45.0 (CH, C-5), 40.6 (CH2), 37.7
(CH2), 29.2 (CH3), 22.6 (CH3), 12.5 (CH3); HRMS: m/z calcd for
C11H19O (M+H): 167.1436; found: 167.1442.
4.4. (1S,3S)-3-(2-Methoxyethyl)-2,2-dimethylcyclopentane-1-
carboxylic acid 12
To a solution of the acid 15 (90 mg, 0.45 mmol) in ethyl acetate
(1.5 mL) was added activated 10% Pd/C (20 mg) and the reaction
mixture was stirred at 1 atm. pressure of hydrogen, created by
evacuative displacement of air (balloon), for 3 h. The reaction mix-
ture was passed through a short silica gel column to remove the
catalyst. Evaporation of the solvent furnished the acid 12 (90 mg,
99%) as an oil. ½a D26
ꢂ
¼ ꢀ5:2 (c 2.0, CHCl3); IR (neat):
m
max/cmꢀ1
4.7. (1R,5R,7R)-7-Methoxy-3,4,4-trimethylbicyclo[3.3.0]oct-2-
ene 21
3000 (br), 2962, 2873, 2743, 1702, 1464, 1456, 1418, 1390, 1371,
1
1239, 1177, 1122; H NMR (400 MHz): d 3.50–3.35 (2H, m, H-20),
3.31 (3H, s, OCH3), 2.49 (1H, t, J 9.4 Hz, H-1), 2.20–1.20 (7H, m),
1.14 (3H, s) and 0.70 (3H, s) [2 ꢁ tert-CH3]; 13C NMR (100 MHz):
d 180.1 (C, OC@O), 72.0 (CH2, C-20), 58.4 (CH3, OCH3), 55.2 (CH,
C-1), 47.8 (CH, C-3), 44.5 (C, C-2), 29.6 (CH2), 28.0 (CH2), 26.4
To an ice cold magnetically stirred suspension of NaH (60% dis-
persion in oil, 350 mg, 8.77 mmol, washed with dry hexane) and
TBAI (8 mg, catalytic) in THF (2 mL) was added a solution of the
alcohol 20 (485 mg, 2.92 mmol) in THF (5 mL) and stirred for

206
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 202–207
30 min at rt. To the alkoxide thus formed was added methyl iodide
(0.60 mL, 9.64 mmol) and the reaction mixture was stirred for 12 h
at rt. Water (3 mL) was added to the reaction mixture and ex-
tracted with ether (3 ꢁ 5 mL). The combined ether extract was
washed with brine (5 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue over a silica gel column
using hexane as an eluent furnished the methyl ether 21
4.10. (1R,3R,5S,7R)-7-Methoxy-2,2-dimethylbicyclo[3.3.0]-
octane-3-carboxaldehyde 24
To a magnetically stirred solution of a ꢄ10:1 epimeric mixture
of the aldehydes 23 and 24 (263 mg, 1.33 mmol) in dry CH2Cl2
(2 mL) was added DBU (0.04 mL, 0.27 mmol) and stirred for 10 h
at rt. The reaction mixture was then diluted with CH2Cl2 (15 mL),
washed with 3 M HCl solution (3 mL) and brine (4 mL), and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate/hexane (1:19) as an elu-
ent furnished the exo aldehyde 24 (239 mg, 91%) as an oil.
(455 mg, 88%) as an oil. ½a D23
¼ ꢀ20:3 (c 10.7, CHCl3); IR (neat):
ꢂ
m
max/cmꢀ1 2954, 2924, 2871, 2854, 1668, 1653, 1464, 1365,
1109; 1H NMR (300 MHz): d 5.11 (1H, br s, H-2), 3.79–3.60 (1H,
m, H-7), 3.28 (3H, s, OCH3), 3.00–2.85 (1H, m, H-1), 2.28–2.12
(2H, m), 1.87 (1H, dt, J 11.7 and 6.3 Hz), 1.57 (3H, s, olefinic-
CH3), 1.38 (2H, q, J 11.4 Hz), 1.30–1.15 (2H, m), 0.99 (3H, s) and
0.97 (3H, s) [2 ꢁ tert-CH3]; 13C NMR (75 MHz): d 144.5 (C, C-3),
127.9 (CH, C-2), 83.1 (CH, C-7), 57.1 (CH3, OCH3), 51.9 (CH, C-5),
47.2 (C, C-4), 43.4 (CH, C-1), 36.7 (CH2), 33.8 (CH2), 28.7 (CH3),
22.0 (CH3), 12.4 (CH3); HRMS: m/z calcd for C12H20ONa (M+Na):
203.1413; found: 203.1406.
½
a 2D1
ꢂ
¼ ꢀ21:2 (c 9.8, CHCl3); IR (neat):
m
max/cmꢀ1 2956, 2872,
2822, 2713, 1718, 1463, 1387, 1370, 1264, 1190, 1120, 1095,
1001, 965; 1H NMR (300 MHz): d 9.76 (1H, d, J 2.1 Hz, H-C@O),
3.64–3.52 (1H, m, H-7), 3.30 (3H, s, OCH3), 2.69–1.90 (6H, m),
1.50 (1H, ddd, J 13.5, 8.4 and 2.1 Hz), 1.33–1.12 (2H, m), 1.17
(3H, s) and 0.92 (3H, s) [2 ꢁ tert-CH3]; 13C NMR (75 MHz): d
204.7 (CH, C@O), 82.2 (CH, C-7), 57.9 (CH, C-3), 57.1 (CH3, OCH3),
54.2 (CH, C-1), 44.9 (C, C-2), 40.2 (CH2), 36.6 (CH, C-5), 34.5
(CH2), 32.3 (CH2), 24.7 (CH3), 24.3 (CH3); HRMS: m/z calcd for
C12H20O2Na (M+Na): 219.1362; found: 219.1366.
4.8. (1R,5R,7R)-7-Methoxy-4,4-dimethylbicyclo[3.3.0]oct-2-
ene-3-carboxaldehyde 22
To a solution of methyl ether 21 (317 mg, 1.79 mmol) in diox-
ane and water (4:1) was added SeO2 (596 mg, 5.37 mmol) and
refluxed for 3 h. The reaction mixture was cooled, filtered, and
the residue was washed with ether (5 mL). Aq NH4Cl solution
(3 mL) was added to the filtrate and extracted with ether
(3 ꢁ 5 mL). The combined organic phase was washed with brine
(4 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column using ethyl acetate/
hexane (1:19) as an eluent furnished the aldehyde 22 (217 mg,
4.11. Methyl 3-[(1R,3R,5S,7R)-7-methoxy-2,2-dimethylbicyclo-
[3.3.0]oct-3-yl]-3-oxopropanoate 25
To a magnetically stirred solution of the aldehyde 24 (203 mg,
1.06 mmol) and methyl diazoacetate (0.34 mL, 3.17 mmol) in dry
CH2Cl2 (2 mL) was added SnCl2ꢃ2H2O (24 mg, 0.11 mmol) in
batches over a period of 30 min and stirred for 2.5 h at rt. The sol-
vent was evaporated under reduced pressure and the residue was
purified over a silica gel column using ethyl acetate/hexane (1:9)
as an eluent to furnish the b-keto ester 25 (229 mg, 88%) as oil,
which was found to exist as a mixture of keto and enol forms.
63%) as an oil. ½a D20
ꢂ
¼ ꢀ33:8 (c 4.8, CHCl3); IR (neat):
m
max/cmꢀ1
2958, 2927, 2862, 2824, 2706, 1682, 1608, 1458, 1365, 1111,
1032; 1H NMR (300 MHz): d 9.70 (1H, s, HC@O), 6.55 (1H, s, H-
2), 3.78–3.64 (1H, m, H-7), 3.28 (3H, s, OCH3), 3.30–3.15 (1H,
m, H-1), 2.38–2.21 (2H, m), 2.05–1.88 (1H, m), 1.54–1.40 (2H,
m), 1.26 (3H, s) and 1.17 (3H, s) [2 ꢁ tert-CH3]; 13C NMR
(75 MHz): d 190.0 (CH, CHO), 155.8 (CH, C-2), 151.1 (C, C-3),
82.4 (CH, C-7), 57.1 (CH3, OCH3), 53.5 (CH, C-5), 45.9 (C, C-4),
45.4 (CH, C-1), 35.5 (CH2), 33.7 (CH2), 29.1 (CH3) and 21.8
(CH3); HRMS: m/z calcd for C12H18O2Na (M+Na): 217.1204;
found: 217.1204.
½
a 2D2
ꢂ
¼ ꢀ21:5 (c 3.4, CHCl3); IR (neat):
m
max/cmꢀ1 2955, 2824,
1751, 1710, 1646, 1622, 1447, 1406, 1370, 1316, 1242, 1225,
1155, 1118, 1095, 1024; 1H NMR (300 MHz): d (peaks due to the
keto form) 3.71 (3H, s, CO2CH3), 3.55–3.40 (1H, m, H-70), 3.28
(3H, s, OCH3), 2.91 (2H, dd, J 11.7 and 7.5 Hz, H-2), 2.50–1.70
(6H, m), 1.55–1.51 (1H, m), 1.30–1.07 (2H, m), 1.13 (3H, s) and
0.85 (3H, s) [2 ꢁ tert-CH3]; (select peaks due to the enol form)
12.11 (1H, s, enolic-OH), 4.91 (1H, s, H-2), 3.69 (3H, s, CO2CH3),
3.41 (3H, s, OCH3), 1.01 (3H, s) and 0.83 (3H, s) [2 ꢁ tert-CH3].
13C NMR (75 MHz): d (peaks due to the keto form) 203.9 (C,
C@O), 167.4 (C, OC@O), 82.1 (CH, C-70), 57.6 (CH, C-30), 57.2
(CH3), 54.2 (CH3), 52.2 (CH, C-10), 50.5 (CH2, C-2), 44.8 (C, C-20),
40.2 (CH2, C-40), 35.8 (CH, C-50), 35.0 (CH2), 34.7 (CH2), 24.8 (2
C, CH3); (peaks due to the enol form) 179.0 (C, C-1), 167.4 (C,
OC@O), 89.7 (CH, C-2), 82.0 (CH, C-70), 57.2 (CH3), 53.0 (CH3),
51.0 (CH, C-10), 50.6 (CH), 44.7 (C, C-20), 40.2 (CH2, C-40),
35.6 (CH, C-50), 34.8 (CH2), 34.2 (CH2), 24.9 (CH3), 24.2 (CH3);
HRMS: m/z calcd for C15H24O4Na (M+Na): 291.1573; found:
291.1570.
4.9. (1R,3S,5S,7R)-7-Methoxy-2,2-dimethylbicyclo[3.3.0]octane-
3-carboxaldehyde 23
To
a solution of the unsaturated aldehyde 22 (261 mg,
1.35 mmol) in ethyl acetate (2 mL) was added activated 10% Pd/C
(60 mg) and the reaction mixture was stirred at 1 atm pressure
of hydrogen atmosphere, created by evacuative displacement of
air (balloon), for 2 h. The reaction mixture was passed through a
short silica gel column to remove the catalyst. Evaporation of the
solvent and purification of the residue on a silica gel column using
ethyl acetate/hexane (1:19) as an eluent furnished a ꢄ10:1 epi-
meric mixture of the aldehydes 23 and 24 (263 mg, 100%) as an
4.12. Methyl 3-[(1R,3R,5S,7R)-7-methoxy-2,2-dimethylbicyclo-
[3.3.0]oct-3-yl]-2-diazo-3-oxopropanoate 26
oil. IR (neat):
m
max/cmꢀ1 2956, 2868, 2822, 2714, 1719, 1464,
1370, 1243, 1222, 1188, 1120; 1H NMR (300 MHz): d (peaks due
to 23) 9.70 (1H, d, J 2.7 Hz, HC@O), 3.66 (1H, tt, J 8.7 and 6.3 Hz,
H-7), 3.23 (3H, s, OCH3), 2.50–2.25 (2H, m), 2.25–1.70 (4H, m),
1.35–1.12 (3H, m), 1.12 (3H, s) and 0.93 (3H, s) [2 ꢁ tert-CH3];
13C NMR (75 MHz): d (peaks due to 23) 203.9 (CH, C@O), 84.0
(CH, C-7), 64.1 (CH, C-3), 56.9 (CH3, OCH3), 53.0 (CH, C-1), 44.3
(C, C-2), 39.1 (CH, C-5), 38.8 (CH2), 32.0 (CH2), 31.9 (CH2), 31.1
(CH3), 21.2 (CH3); HRMS: m/z calcd for C12H20O2Na (M+Na):
219.1362; found: 219.1357.
To a magnetically stirred solution of the b-keto ester 25
(360 mg, 1.43 mmol) in acetonitrile (2 mL) were added tosyl azide
(283 mg, 1.71 mmol) and NEt3 (0.4 mL, 2.86 mmol), and stirred at
rt for 5 h. The solvent was then evaporated under reduced pressure
and the residue was purified on a silica gel column using ethyl ace-
tate/hexane (1:19) as an eluent to furnish the
a-diazo-b-keto ester
26 (326 mg, 82%) as an oil. IR (neat):
m
max/cmꢀ1 2956, 2823, 2137
(N@N), 1724 (OC@O), 1649 (C@O), 1463, 1438, 1372, 1307, 1208,
1119, 840, 777, 768, 741.

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 202–207
207
4.13. Methyl (1R,2S,6R,8S,10R)-10-methoxy-2-methyl-5-oxotri-
(CH, C-1), 51.1 (C, C-2), 40.8 (CH, C-8), 39.1 (CH2), 36.6 (CH2),
36.3 (CH2), 34.7 (CH2), 34.6 (CH2), 22.3 (CH3); HRMS: m/z calcd
for C13H20O2Na (M+Na): 231.1361; found: 231.1351.
cyclo[6.3.0.02,6]undecane-4-carboxylate (27)
To a magnetically stirred, refluxing solution of Rh2(OCOCF3)4
(8 mg) in anhydrous CH2Cl2 (20 mL) was added a solution of the
Acknowledgments
a-diazo-b-keto ester 26 (352 mg, 1.27 mmol) in dry CH2Cl2
(15 mL, 0.01 M) over a period of 30 min and refluxed for 3.5 h.
Evaporation of the solvent and purification of the residue over a sil-
ica gel column using ethyl acetate/hexane (1:19) as an eluent fur-
nished an epimeric mixture of the triquinane 27 (250 mg, 79%) as
We thank the Department of Science and Technology, New Del-
hi, for the financial support, Council of Scientific and Industrial Re-
search, New Delhi, and University Grants Commission, New Delhi,
for the award of research fellowships to V.G. and G.N., respectively.
We are grateful to M/s Organica Aromatics (Bangalore) Pvt. Ltd, for
the generous gift of campholenaldehyde.
an oil. ½a 2D4
ꢂ
¼ ꢀ40:0 (c 1.7, CHCl3); IR (neat):
m
max/cmꢀ1 2953, 2874,
2824, 1751, 1728, 1662, 1623, 1446, 1365, 1287, 1264, 1235, 1198,
1142, 1114; 1H NMR (300 MHz): d (peaks due to the major isomer)
3.90–3.60 (1H, m), 3.75 (3H, s), 3.50–3.30 (1H, m), 3.30 (3H, s),
2.80–2.50 (2H, m), 2.45–1.90 (5H, m), 1.87–1.70 (1H, m), 1.50–
1.20 (3H, m), 1.12 (3H, s); 13C NMR (75 MHz): d (peaks due to
the major isomer) 212.0 (C, C@O), 170.0 (C, OC@O), 82.8 (CH, C-
10), 58.5 (CH), 57.0 (CH3), 54.1 (CH3), 52.8 (CH), 52.4 (CH), 49.5
(C, C-2), 40.5 (CH), 39.1 (CH2), 38.6 (CH2), 35.7 (CH2), 34.8 (CH2),
22.1 (CH3); HRMS: m/z calcd for C15H22O4Na (M+Na): 289.1417;
found: 289.1406.
References
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Synthetic Developments in Polyquinane Chemistry; Springer: New York, 1987;
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4.14. (1R,2S,6R,8S,10R)-10-Methoxy-2-methyltricyclo[6.3.0.02,6]-
undecan-5-one 17
A solution of the keto ester 27 (34 mg, 0.14 mmol) and LiCl
(23 mg, 0.54 mmol) in DMSO (0.5 mL) and water (0.01 mL) was
placed in a Carius tube and heated to 180 °C for 10 h. The reaction
mixture was cooled to rt, diluted with ether (3 mL), washed with
water (2 mL) and brine, and dried (Na2SO4). Evaporation of the sol-
vent and purification of the residue on a silica gel column using
ethyl acetate/hexane (1:19) as an eluent furnished the ketone 17
(23 mg, 82%) as an oil. ½a D25
¼ ꢀ45:5 (c 1.6, CHCl3); IR (neat):
ꢂ
m
max/cmꢀ1 2950, 2872, 2822, 1738 (C@O), 1456, 1365, 1262,
1195, 1114; 1H NMR (400 MHz): d 3.67 (1H, quintet, J 7.2 Hz, H-
10), 3.29 (3H, s, OCH3), 2.60–2.45 (1H, m), 2.40–2.25 (3H, m),
2.25–2.20 (2H, m), 2.05–1.85 (2H, m), 1.81–1.70 (3H, m), 1.50–
1.20 (2H, m), 1.11 (3H, s, tert-CH3); 13C NMR (100 MHz): d 221.2
(C, C@O), 83.0 (CH, C-10), 59.1 (CH, C-6), 57.0 (CH3, OCH3), 52.5