Enantiospecific total synthesis of 15-hydroxy-5-(methoxymethoxy) crinipellin-9-one

Article abstract of DOI:10.1016/j.tet.2012.02.018

Enantiospecific total synthesis of the crinipellin mentioned in the title was accomplished. In the present synthesis cyclopentane ring in campholenaldehyde was identified as the B-ring, two intramolecular rhodium carbenoid CH insertion reactions were empl

Full text of DOI:10.1016/j.tet.2012.02.018

Tetrahedron 68 (2012) 3046e3055
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantiospecific total synthesis of 15-hydroxy-5-(methoxymethoxy)crinipellin-
9-one
*
A. Srikrishna , V. Gowri
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 January 2012
Received in revised form 5 February 2012
Accepted 8 February 2012
Available online 21 February 2012
Enantiospecific total synthesis of the crinipellin mentioned in the title was accomplished. In the present
synthesis cyclopentane ring in campholenaldehyde was identified as the B-ring, two intramolecular
rhodium carbenoid CH insertion reactions were employed for the construction of the A and C rings, and
an intramolecular Michael addition reaction was utilized for the construction of the D-ring of crinipellin.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Crinipellins
Tetraquinanes
Intramolecular rhodium carbenoid CH
insertion
Enantiospecific synthesis
Campholenaldehyde
Intramolecular Michael addition
1. Introduction
Crinipellis stipitaria is a fungus that grows on both the dead
Last 3 decades had witnessed a rapid growth in the de-
velopment of synthetic methodologies for generating poly-
condensed cyclopentane rings, commonly known as polyquinanes.1
During the second half of the last century, several polyquinane
natural products have been encountered among plant, marine and
microbial sources.2 So far, natural products containing up to four
fused cyclopentanes, 1e5, have been revealed. Triquinanes 2,3 are
the most commonly encountered polyquinanes in sesquiterpenes.
Among the tetraquinanes, only tetracyclo[6.6.0.01,11.03,7]tetrade-
cane 5, comprising of both a linear cis, anti, cis-triquinane and an
angular triquinane, was found to present in natural products.
and living parts of grasses. In 1979, research groups of Anke and
Steglich3a reported the isolation of an antibiotic from the sub-
merged cultures of the basidiomycete C. stipitaria (Agaricales)
strain no.7612, and named it as ‘crinipellin’, later identified as O-
acetyl crinipellin A. Although structure of crinipellin was not
elucidated at that time, its biological properties were evaluated
against a variety of bacteria and fungi. Subsequent investigations
by Anke and co-workers3b on several strains of this fungus led to
the isolation of five related crinipellins, namely crinipellin A 6,
crinipellin B 7, O-acetyl crinipellin A 8, dihydrocrinipellin B 9 and
tetrahydrocrinipellin A 10. Structures of the crinipellins 6e10
H
H
H
H
H
H
H
H
H
H
H
H
1
2
3
4
5
were deduced on the basis of the 1 and 2D NMR spectra. Further
confirmation was obtained by single crystal X-ray diffraction
analysis of crinipellin B 7. The absolute configuration of
* Corresponding author. Fax: þ91 80 23600529; e-mail address: askiisc@
gmail.com (A. Srikrishna).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.018

A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
3047
crinipellins 6e10 was assigned by comparing the CD-curves with
those of ent-3 -hydroxy-5 -androstan-17-one and the linear cis,
2. Results and discussion
b
a
anti, cis-triquinane sesquiterpene hypnophilin.3b Recently, in
2010 Shen and Li4 reported the isolation of four new crinipellins,
namely dihydrocrinipellin A 11, tetrahydrocrinipellin B 12, cri-
nipellin C 13 and crinipellin D 14 (Fig. 1), in addition to the
earlier reported crinipellins 9 and 10 from the fungal strain C.
stipitaria 113 obtained from Zhujiangyuan in Yunnan Province,
China.
After successfully demonstrating the suitability of the strategy
for the synthesis of a 20-nor-crinipellin 15 in the optically pure
form with the hydroxy group masked as its methyl ether, it was
decided to extend the strategy to a crinipellin with a more ac-
ceptable protecting group, such as a methoxymethyl (MOM) group.
The retrosynthetic strategy is depicted in Scheme 1. Extrapolating
the earlier approach,7 it was readily identified (Scheme 1) that the
HO
H
O
O
HO
O
O
O
O
O
RO
H
OH
O
O
O
HO
OH
9
5
O
A
7
3
C
D
1
B
11
H
H
H
H
H
20
H
15
13
6 R = H
9
10
7
8 R = Ac
O
HO
O
O
O
O
O
O
OH
OH
HO
HO
HO
OH
OH
OH
H
H
13
14
12
11
Fig. 1. Natural crinipellins.
Crinipellin is the first group of natural products to contain
a tetraquinane framework. From the synthetic perspective, crini-
pellins have several interesting features, viz. the unique tetra-
quinane system comprising of both a linear cis, anti, cis-triquinane
(ABC) as well as an angular triquinane (BCD) system; contains
three contiguous all carbon quaternary centres (C-1, C-8 and C-
11); contains eight to ten stereogenic centres, of which upto nine
are in contiguous manner; and posses interesting biological
properties. As a consequence, a few innovative approaches have
been developed for the synthesis of crinipellins. Only model
studies5 and total synthesis6 of crinipellin B 7 in racemic form
were reported in the literature prior to the initiation of the work
described here. Recently,7 we have reported an enantiospecific
approach to a 20-nor-crinipellin 15 starting from camphole-
naldehyde 16 (Eq. 1), employing a combination of rhodium car-
benoid CH insertion and intramolecular Michael addition as key
reactions. In continuation of our interest in the enantiospecific
synthesis of natural products employing the readily available
campholenaldehyde 16,7,8 herein, we report the extension of
the strategy for the total synthesis of the crinipellin mentioned in
the title.
cyclopentane ring in (S)-campholenaldehyde 16 would serve as the
B-ring of crinipellins, and the D-ring of crinipellin 17 could be re-
alized through an intramolecular Michael addition of an ester onto
an enone in the C-ring, e.g., 18. The enone ester 18 could be ob-
tained from the triquinane 19 via the enone 20. The triquinane 19
could be obtained from (S)-campholenaldehyde 16 via the diqui-
nane 21 by employing two rhodium carbenoid CH insertion re-
actions9 for the construction of the A and C rings, a strategy
developed earlier in our laboratory.8a,i
The synthetic sequence is depicted in Schemes 2 and 3. To begin
with synthesis of the bicyclic alcohol 22 has been carried out as
described earlier.8b Thus, reaction of campholenic acid 23 with
oxalyl chloride followed by treatment of the resultant acid chloride
with an excess of ethereal diazoethane furnished the diazo ketone
24. Treatment of the diazo ketone 24 with a catalytic amount of
rhodium acetate in methylene chloride furnished the diquinane 21
in highly regio- and stereoselective manner, which on stereo-
selective reduction with sodium borohydride generated the alcohol
22. The stereochemistry of the alcohol 22 has already been well
established.8b Reaction of the alcohol 22 with ethyldiisopropylamine
(DIPEA), methoxymethyl chloride and a catalytic amount of DMAP in
O
H
H
OMe
(eqn. 1)
CHO
H
16
20-nor-crinipellin 15

O
O
O
H
H
H
OMOM
OMOM
OMOM
A
C
D
B
H
H
H
R
EtOOC
HO
20
18
crinipellin 17
H
H
H
OMOM
O
CHO
H
21
O
H
H
16
19
Scheme 1.
H
H
H
a
a
b
O
OH
X
16
O
H
21
H
22
23 X = OH
24 X = C(Me)=N
c or d
2
H
H
H
H
OHC
OR
e
OHC
f,g
OR
OBz
H
H
H
26 R = MOM
28 R = Bz
25 R = MOM
27 R = Bz
29x α-H
29n β-H
h
EtO2C
X
H
H
H
R
j
EtO2C
OBz
OBz
O
O
H
H
30 X = H2
31 X = N2
32 R = H
33 R = SePh
i
k
H
H
OBz
EtO2C
OBz
l
O
O
H
H
O
H
H
35
34
m
H
H
OMOM
OH
c
O
H
H
19
H
H
36
Scheme 2. (a) Ref. 8b; (b)NaBH4, MeOH; (c)MOMCl, EtN(iPr)2, DMAP, CH2Cl2, 98%; (d) PhCOCl, Et3N, CH2Cl2, DMAP, 96%; (e) SeO2, PhBr, 77%; (f)H2,10% Pd/C, EtOAc, 99%; (g) DBU, CH2Cl2, 65%;
(h) N2CHCOOEt, SnCl2$2H2O, CH2Cl2, 95%; (i) TsN3, NEt3, CH3CN, 91%; (j) Rh2(OCOCF3)4, CH2Cl2, 93%; (k) PhSeCl, py; 30%H2O2, CH2Cl2, 65%; (l) LiCl, DMSO, H2O, 84%; (m) K2CO3, MeOH, 93%.

A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
3049
H
H
OMOM
b
OMOM
a
19
HO
O
H
H
38
37
c
O
O
H
H
OMOM
d
OMOM
H
H
H
CHO
40
e
39
O
H
O
H
OMOM
OMOM
f
H
EtOOC
g,h
COOEt
41
18
O
O
H
H
OMOM
OMOM
OMOM
OMOM
+
H
42n
i
H
42x
i
EtOOC
EtOOC
O
O
H
H
H
H
HO
HO
17n
17
Scheme 3. (a) LDA, THF; allyl bromide, 81%; (b) MeLi, THF, 91%; (c) PDC, CH2Cl2, 93%; (d) O3/O2, MeOH/CH2Cl2, 84%; Me2S; (e) NaH, (EtO)2P(O)CH2COOEt, THF, 94%; (f) (Ph3P)3RhCl,
EtOAc, H2, 97%; (g) LDA, THF, 65% (42n/42x 17:3); (h) DBU, C6H6, 65% (42n/42x 7:9); (i) MeMgCl, Et2O, 86 (17) and 78% (17n).
methylene chloride furnished the MOM ether 25. Selenium dioxide
mediated oxidation of the olefinic methyl group in the MOM ether
25 under a variety of conditions, however, failed to produce the
requisite aldehyde 26. To circumvent the problems, although not
suitable to the reactions in the later part of the sequence, benzoate
group was chosen as the protecting group with an intention to ex-
change it with an MOM group in the later stages of the sequence.
Accordingly, the bicyclic alcohol 22 was transformed into the ben-
zoate 27 by treating with benzoyl chloride and triethylamine in
methylene chloride in the presence of a catalytic amount of DMAP in
96% yield. Reaction of the benzoate 27 with 2 equiv of selenium
dioxide in refluxing bromobenzene10 furnished the aldehyde 28 in
77% yield. Hydrogenation of the olefin in the aldehyde 28 in ethyl
acetate at 1 atm pressure of hydrogen using 10% palladium over
carbon as the catalyst furnished the saturated endo aldehyde 29n
(containing about 10% of exo isomer 29x) via the approach of the
hydrogen from the sterically preferred exo face of the diquinane 28.
Equilibration of the aldehyde 29n with DBU in methylene chloride
furnished, exclusively, the exo aldehyde 29x in 65% yield. Coupling of
the aldehyde 29x with ethyl diazoacetate in the presence of a cata-
lytic amount of stannous chloride11 generated the
95% yield, which was found (by NMR) to exist as a mixture of the keto
and enol forms. Reaction of the -keto ester 30 with p-toluene-
sulfonyl azide and triethylamine in acetonitrile furnished the -di-
azo- -keto ester 31 in 91% yield. Treatment of the diazo ester 31 with
b-keto ester 30 in
b
a
b
a catalytic amount of rhodium trifluoroacetate in refluxing methy-
lene chloride furnished an epimeric mixture (by NMR) of the tri-
quinane esters 32 along with its enol form in 93% yield.

3050
A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
Reaction of the
b
-keto ester 32 with phenylselenyl chloride in
15-hydroxy-5-(methoxymethoxy)-crinipellin-9-one 17 in 86% yield.
Presence of an absorption band at 3488 due to the hydroxy group
and a carbonyl absorption band at 1730 cmꢁ1 due to the ketone in
the IR spectrum and presence of the sodiated molecular ion at m/z
387.2515 (C22H36O4Na) in the HRMS revealed the formation of
the presence of pyridine12 in methylene chloride furnished a 1:5
mixture of the selenide 33 and the unsaturated keto ester 34 in 77%
yield, which were separated by column chromatography on silica
gel. Oxidation of the selenide 33 with 30% hydrogen peroxide at
0e5 ꢀC furnished the unsaturated keto ester 34 in 71% yield, whose
structure was established from its spectral data. Krapcho’s deal-
koxycarbonylation13 of the keto ester 34 in DMSO and lithium
chloride in the presence of water furnished the triquinane enone 35
in 84% yield.
crinipellin 17. Presence of two doublets at
d 4.61 and 4.54 (OCH2O)
and a singlet at 3.34 (OCH3) due to the MOM group, a multiplet at
4.05e3.95 due to the MOM ether bearing methine, a doublet at 2.73
(J 17.8 Hz) due to one of the diastereotopic methylene protons
a to
the ketone group and, in particular, four singlets at 1.31, 1.22, 1.17
and 1.10 due to four tertiary methyls and a doublet at 0.95 ppm due
to the secondary methyl group along with other resonances in the
1H NMR spectrum established the structure of crinipellin 17. In the
22 lines 13C NMR spectrum, presence of resonance due to a qua-
It was felt that the benzoate group may not be suitable for
subsequent sequence, hence it was exchanged to a methoxymethyl
group via the alcohol 36. Hydrolysis of the benzoate 35 with po-
tassium carbonate in methanol at rt furnished the alcohol 36 in 93%
yield. Treatment of the alcohol 36 with methoxymethyl chloride,
ethyldiisopropylamine (DIPEA) and a catalytic amount of DMAP in
methylene chloride at rt gave the MOM ether 19 in 98% yield.
Next, conversion of the triquinane 19 into the keto ester 18 via
addition of a suitable side chain at the C-6 position followed by
alkylative 1,3-enone transposition14 was carried out. Accordingly,
generation of the enolate of the enone 19 with LDA in THF at ꢁ70 ꢀC
and alkylation with allyl bromide furnished the 6-allyl triquinane
enone 37 in 81% yield. Regioselective 1,2-addition of methyllithium
to the enone 37 in THF furnished the allylic tertiary alcohol 38 in
a highly stereoselective manner, which on oxidation with PDC in
methylene chloride furnished the transposed enone 39 in 93% yield.
Presence of the sodiated molecular ion at m/z 327.1931 (C19H28O3Na)
in the HRMS and presence of a carbonyl absorption band at
1704 cmꢁ1 due to the enone in the IR spectrum revealed the for-
ternary carbon at
d 225.9 due to the ketone carbon, a methylene at
96.1 (OCH2O) and a methyl at 55.3 (OCH3) due to the MOM carbons,
a methine at 79.5 due to the MOM ether bearing carbon, four
quaternary carbons at 73.1 (CeOH), 65.6, 60.9 and 49.8, four
methines at 57.3 (C-12), 54.1 (C-7), 46.6 (C-3) and 40.3 (C-4), four
tertiary methyls at 31.2, 30.0, 18.8 and 17.6 and a secondary methyl
at 11.4 ppm along with other resonances confirmed the structure of
crinipellin 17.
In a similar manner, Grignard reaction of the endo ester 42n
with an excess of methylmagnesium chloride in dry ether at 0 ꢀC
furnished 12-epicrinipellin 17n in 78% yield, which exhibited
spectral data very similar to that of crinipellin 17. Presence of two
absorption bands at 3482 and 1731 cmꢁ1 due to the hydroxy and
ketone groups, respectively, in the IR spectrum and presence of the
sodiated molecular ion at m/z 387.2508 (C22H36O4Na) in the HRMS
revealed the formation of 12-epicrinipellin 17n. Presence of two
mation of the transposed enone 39. Presence of a singlet at
to the ring olefinic proton and a singlet at 2.00 ppm due to the methyl
group on the
-carbon of the enone in the 1H NMR spectrum and
presence of resonances due to two quaternary carbons at 213.5 and
at 180.5 and a methine at 130.1 ppm due to the ketone, and ole-
d 5.89 due
doublets at
methylene protons
d
3.20 and 2.08 (J 17.1 Hz) due to the diastereotopic
to the ketone group, four singlets at 1.33, 1.25,
b
a
d
1.24 and 1.02 ppm due to four tertiary methyls along with other
signals in the 1H NMR spectrum established the structure of the 12-
epicrinipellin 17n, which was further confirmed by the 22 lines 13C
NMR spectrum.
b
a
finic carbons, respectively, of the enone along with other resonances
in the 13C NMR spectrum confirmed the structure of the enone 39.
The enone 39 was then transformed into the keto ester 18 via the
conversion of the allyl group into a butanoate. Thus, ozonolysis of
the olefin of the allyl group in 39 at ꢁ70 ꢀC followed by reductive
workup with dimethyl sulfide furnished the aldehyde 40 in 84%
yield, in a regioselective manner. Reaction of the aldehyde 40 with
triethyl phosphonoacetate and sodium hydride in dry THF at rt
furnished, predominantly, the trans-2-butenoate 41 in 94% yield.
Regioselective hydrogenation of the double bond of the butenoate
in 41 at rt with Wilkinson’s catalyst in ethyl acetate at 1 atm pres-
sure of hydrogen (balloon) for 24 h furnished the saturated ester 18
in 97% yield, whose structure was established from its spectral data.
Intramolecular Michael addition reaction of the keto ester 18 with
LDA in THF at ꢁ70 ꢀC furnished a 3:17 mixture (by NMR) of the exo
and endo tetraquinane esters 42x and 42n. Generation of the cis ring
junction of the C and D rings was obvious as the Michael addition is
possible only via the syn approach. The stereochemistry of the ester
group in the major isomer 42n was assigned as endo based on the
assumption that the lithium cation will interact with both the
enolate and enone oxygens in the transition state during the
intramolecular Michael addition reaction. Since the isopropyl side
chain in crinipellins is exo oriented to CD-ring system, the ester
group was isomerized. Equilibration of a 3:17 mixture of the esters
with DBU in a sealed tube at 110 ꢀC for 24 h gave a 9:7 mixture of the
exo 42x and endo ester 42n in 81% yield, which were separated by
chromatography on an alumina column. The structures of the esters
42x and 42n were established from their spectral data. The endo and
exo stereochemistry of the ester group in 42n and 42x was assigned
in analogy to 20-nor-crinipellins.7
3. Conclusions and summary
An enantiospecific approach to the tetraquinane diterpenes
crinipellins has been described. Crinipellins contain three all car-
bon contiguous quaternary centres and eight to 10 stereogenic
centres (upto nine of them in contiguous manner) making them
challenging synthetic targets. Cyclopentene in campholenaldehyde
was utilized as the B-ring of crinipellins. A rhodium carbenoid in-
sertion into an allylic CeH bond was employed for the construction
of the A-ring. Rhodium carbenoid mediated CH activation of a ter-
tiary methyl group was developed for the construction of the C-ring
of crinipellins. An intramolecular Michael addition reaction was
employed for the construction of the D-ring of crinipellins. Starting
from campholenaldehyde 16, crinipellin 17 and 12-epicrinipellin
17n were obtained in 26 steps with overall yields of 1.9 and 1.7%,
respectively.
4. Experimental section
4.1. General
IR spectra were recorded on Jasco FTIR 410 and PerkineElmer
FTIR spectrum BX and GX spectrophotometers. 1H (300 and
400 MHz) and 13C (75 and 100 MHz) NMR spectra were recorded on
JNM
l-300 and Brucker Avance 400 spectrometers, using a 1:1
mixture of CDCl3 and CCl4 as solvent. The chemical shifts (
d
ppm)
and coupling constants (Hz) are reported in the standard fashion
with reference to either internal tetramethylsilane (for 1H) or the
central line (77.0 ppm) of CDCl3 (for 13C). In the 13C NMR spectra,
Finally, reaction of the exo ester 42x with an excess of
methylmagnesium chloride in dry ether at
0
ꢀC furnished

A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
3051
the nature of the carbons (C, CH, CH2, or CH3) was determined by
recording the DEPT-135 spectra, and is given in parentheses. High
resolution mass spectra were recorded on a Micromass Q-TOF mi-
cro mass spectrometer using electron spray ionization mode. Op-
tical rotations were measured using a Jasco DIP-370 and Jasco P-
8.3 Hz, H-50), 2.58 (1H, td, J 9.6 and 4.8 Hz, H-10), 2.48 (1H, sextet, J
7.1 Hz, H-40), 2.12e2.02 (2H, m, H-20), 1.25 (3H, s) and 1.23 (3H, s)
[2ꢂ tert-CH3], 1.12 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz,
CDCl3þCCl4):
d 189.3 (CH, HC]O), 165.6 (C, OC]O), 153.4 (CH, C-
60), 152.7 (C, C-70), 132.8 (CH), 130.2 (C), 129.4 (2C, CH), 128.3 (2C,
CH), 78.4 (CH, C-30), 53.5 (CH), 53.1 (CH), 46.5 (C, C-8), 41.4 (CH),
33.6 (CH2, C-20), 30.2 (CH3) and 22.3 (CH3) [2ꢂ tert-CH3], 11.5 (CH3,
sec-CH3); HRMS: m/z calcd for C19H22O3Na (MþNa): 321.1467;
found: 321.1474.
1020 polarimeters and
[a
]
values are given in units of
D
10ꢁ1 deg cm2 gꢁ1. Hydrogenation reactions at 1 atm pressure were
carried out using a balloon filled with hydrogen. Analytical thin-
layer chromatography (TLC) was performed on glass plates
(7.5ꢂ2.5 and 7.5ꢂ5.0 cm) coated with Acme’s silica gel G containing
13% calcium sulfate as binder and various combinations of ethyl
acetate/hexane and methylene chloride/hexane were used as elu-
ent. Visualization of spots was accomplished by exposure to iodine
vapour. Acme’s silica gel (100e200 mesh) was used for column
chromatography (approximately 15e20 g per 1 g of the crude
product). All small-scale dry reactions were carried out using
standard syringe-septum technique. Low temperature reactions
were carried out using a bath made of sodium chloride and ice, or
alcohol and liquid nitrogen. Dry THF was obtained by distillation
over sodium/benzophenone ketyl. Dry ether was obtained by dis-
tillation over sodium and stored over sodium wire. Dry dichloro-
methane was prepared by distillation over phosphorous pentoxide
or calcium hydride.
4.1.3. (1R,2R,3S,5R,7S)-7-Formyl-2,6,6-trimethylbicyclo[3.3.0]oct-3-
yl benzoate (29n). To a solution of the unsaturated aldehyde 28
(1.12 g, 3.76 mmol) in ethyl acetate (3 mL) was added activated 10%
Pd/C (150 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 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 (1:9) as an eluent furnished a w10:1 epimeric
mixture of the aldehyde 29n (1.12 g, 99%) as an oil. ½a D23
þ4.2 (c 5.5,
ꢃ
CHCl3); IR (neat): nmax/cmꢁ1 3064, 2964, 2936, 2878, 2717 (H-C¼O),
1716 (HC]O and OC]O), 1602, 1584, 1452, 1382, 1368, 1314, 1275,
1176, 1112, 1070, 1026, 981, 936, 713; 1H NMR (400 MHz,
CDCl3þCCl4): (signals due to the mixture of epimers)
d 9.74 (1H, d, J
4.1.1. (1R,3S,4R,5R)-4,7,8,8-Tetramethylbicyclo[3.3.0]oct-6-en-3-yl
benzoate (27). To a magnetically stirred, cold (0e5 ꢀC) solution of
the alcohol 22 (880 mg, 4.89 mmol) in CH2Cl2 (5 mL) were added
DMAP (298 mg, 2.44 mmol), triethylamine (2.06 mL, 14.67 mmol)
and benzoyl chloride (1.15 mL, 9.78 mmol), and stirred for 10 h at rt.
Water (8 mL) was added to the reaction mixture and extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic extract was washed with
brine (8 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using CH2Cl2/
hexane (3:7) as an eluent furnished the benzoate 27 (1.2 g, 96%) as
2.2 Hz, HeC]O), 8.03 and 7.93 (2H, d, J 7.9 Hz, H-2 and 6),
7.56e7.50 (1H, m, H-4), 7.49e7.38 (2H, m, H-3 and 5), 5.36 (1H, td, J
6.3 and 3.8 Hz, H-30), 2.74e1.97 (6H, m), 1.84e1.73 (2H, m), 1.25 and
1.17 (3H, s, tert-CH3), 1.05 (3H, d, J 7.2 Hz, sec-CH3), 0.93 and 0.99
(3H, s, tert-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d (signals due to
the major isomer) 204.1 (CH, HC]O), 166.1 (C, OC]O), 132.9 (CH),
130.5 (C), 129.5 (2C, CH), 128.5 (2C, CH), 79.8 (CH, C-30), 63.3 (CH, C-
70), 54.3 (CH, C-50), 47.3 (CH, C-10), 44.5 (C, C-60), 39.4 (CH, C-20),
32.9 (CH3, tert-CH3), 32.7 (CH2, C-40), 26.8 (CH2, C-80), 21.9 (CH3,
tert-CH3), 11.0 (CH3, sec-CH3); HRMS: m/z calcd for C19H24O3Na
(MþNa): 323.1623; found: 323.1627.
an oil. Rf (1:1 CH2Cl2/hexane) 0.4; ½a D26
þ94.9 (c 5.7, CHCl3); IR
ꢃ
(neat): nmax/cmꢁ1 3064, 3034, 2958, 2935, 2875, 1716 (OC]O),
1603, 1854, 1451, 1377, 1360, 1314, 1273, 1176, 1115, 1069, 1027, 898,
4.1.4. (1R,2R,3S,5R,7R)-7-Formyl-2,6,6-trimethylbicyclo[3.3.0]oct-3-
yl benzoate (29x). To a magnetically stirred solution of a w10:1
epimeric mixture of the aldehyde 29n (683 mg, 2.28 mmol) in dry
CH2Cl2 (2 mL) was added DBU (0.19 mL, 1.26 mmol) and stirred for
10 h at rt. The reaction mixture was then diluted with CH2Cl2
(15 mL), washed with 3 N HCl solution (3 mL) and brine (10 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 eluent furnished the exo aldehyde 29x (443 mg, 65%) as an oil. Rf
847, 711, 688; 1H NMR (400 MHz, CDCl3þCCl4):
d 7.98 (2H, d, J
7.8 Hz, H-2 and 6), 7.51 (1H, t, J 7.4 Hz, H-4), 7.40 (2H, t, J 7.7 Hz, H-3
and 5), 5.31 (1H, s, H-60), 5.27 (1H, q, J 4.9 Hz, H-30), 3.26e3.18 (1H,
m, H-50), 2.45 (1H, q, J 7.6 Hz), 2.30 (1H, sextet, J 7.2 Hz), 2.01e1.95
(2H, m), 1.65 (3H, s, olefinic-CH3), 1.05 (3H, s) and 0.94 (3H, s) [2ꢂ
tert-CH3], 1.03 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz,
CDCl3þCCl4): 165.8 (C, OC]O), 146.2 (C, C-70), 132.5 (CH), 130.8 (C),
129.6 (2C, CH), 128.1 (2C, CH), 123.6 (CH, C-60), 79.0 (CH, C-30), 51.7
(CH), 51.3 (CH), 47.9 (C, C-80), 40.9 (CH, C-40), 33.8 (CH2, C-20), 29.8
(CH3) and 22.6 (CH3) [2ꢂ tert-CH3], 12.6 (CH3, olefinic-CH3), 11.5
(CH3, sec-CH3); HRMS: m/z calcd for C19H24O2Na (MþNa): 307.1674;
found: 307.1686.
(1:9 EtOAc/hexane) 0.5; ½a D25
ꢃ
þ8.4 (c 2.0, CHCl3); IR (neat): nmax
/
cmꢁ1 3064, 3034, 2965, 2936, 2875, 2819, 2717 (HeC]O), 1715
(HC]O and OC]O), 1602, 1584, 1452, 1387, 1370, 1314, 1274, 1200,
1176, 1112, 1070, 1056, 1026, 973, 713; 1H NMR (400 MHz,
CDCl3þCCl4):
d 9.76 (1H, d, J 2.1 Hz, HeC]O), 7.95 (2H, d, J 7.2 Hz,
4.1.2. (1R,3S,4R,5R)-7-Formyl-4,8,8-trimethylbicyclo[3.3.0]oct-6-en-
3-yl benzoate (28). To a solution of the benzoate 27 (650 mg,
2.29 mmol) in bromobenzene (5 mL) was added SeO2 (564 mg,
5.08 mmol) and refluxed for 1 h. The reaction mixture was cooled
and filtered through filter paper. Water (8 mL) was added to the
filtrate and extracted with CH2Cl2 (3ꢂ10 mL). The combined or-
ganic extract was washed with brine (8 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 eluent furnished
the aldehyde 28 (526 mg, 77%) as an oil. Rf (1:9 EtOAc/hexane) 0.4;
H-2 and 6), 7.55 (1H, t, J 7.3 Hz, H-4), 7.43 (2H, t, J 7.8 Hz, H-3 and 5),
5.34 (1H, t, J 5.6 Hz, H-30), 2.80e2.60 (2H, m), 2.36e2.08 (4H, m),
2.02 (1H, ddd, J 13.7, 9.1 and 4.6 Hz), 1.90e1.70 (1H, m), 1.19 (3H, s)
and 1.01 (3H, s) [2ꢂ tert-CH3], 1.08 (3H, d, J 7.1 Hz, sec-CH3); 13C
NMR (100 MHz, CDCl3þCCl4):
d 204.4 (CH, HC]O), 165.8 (C, OC]
O), 132.8 (CH), 130.4 (C), 129.3 (2C, CH), 128.5 (2C, CH), 79.5 (CH, C-
30), 58.7 (CH, C-70), 56.9 (CH, C-50), 45.4 (C, C-60) 45.2 (CH, C-10), 41.5
(CH, C-20), 34.7 (CH2), 25.2 (CH3) and 24.2 (CH3) [2ꢂ tert-CH3], 23.9
(CH2), 11.2 (CH3, sec-CH3); HRMS: m/z calcd for C19H24O3Na
(MþNa): 323.1623; found: 323.1623.
½
a 2D5
ꢃ
þ23.8 (c 5.4, CHCl3); IR (neat): nmax/cmꢁ1 3064, 3037, 2970,
2879, 2710 (CHO), 1716 (OC]O), 1682 (HC]O), 1617, 1603, 1452,
4.1.5. Ethyl 3-[(1R,3R,5R,6R,7S)-7-benzoyloxy-2,2,6-trimethylbicyclo
[3.3.0]oct-3-yl]-3-oxopropanoate (30). To a magnetically stirred
solution of the aldehyde 29x (600 mg, 2.00 mmol) and ethyl
diazoacetate (0.26 mL, 2.47 mmol) in dry CH2Cl2 (3 mL) was added
SnCl2$2H2O (100 mg, 0.44 mmol) over a period of 30 min and
1382, 1360, 1315, 1271, 1176, 1118, 1070, 1062, 1026, 984, 788; 1H
NMR (400 MHz, CDCl3þCCl4):
d 9.80 (1H, s, HeC]O), 7.87 (2H, d, J
7.6 Hz, H-2 and 6), 7.52 (1H, t, J 7.4 Hz, H-4), 7.39 (2H, t, J 7.7 Hz, H-3
and 5), 6.79 (1H, s, H-60), 5.35 (1H, q, J 4.8 Hz, H-30), 3.47 (1H, t, J

3052
A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
stirred for 2.5 h at rt. Solvent was evaporated under reduced
pressure and the residue was purified on a silica gel column using
ethyl acetate/hexane (1:19) as an eluent to furnish the b-keto ester
and pyridine (0.16 mL, 1.96 mmol) in dry CH2Cl2 (2 mL) was added
drop wise a solution of the keto ester 32 (377 mg, 0.98 mmol) in dry
CH2Cl2 (2 mL) and stirred for 1 h at the same temperature. 3 N HCl
(4 mL) was added to the reaction mixture and extracted with
CH2Cl2 (3ꢂ10 mL). The combined CH2Cl2 extract was washed with
brine (10 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate/
hexane (1:9) as an eluent furnished first an epimeric mixture of the
30 (730 mg, 95%) as oil, which was found to exist as a mixture of
keto and enol forms. ½a D21
ꢃ
þ18.8 (c 3.8, CHCl3); IR (neat): nmax/cmꢁ1
2969, 2936, 2876, 1744, 1715, 1641, 1620, 1452, 1367, 1314, 1275,
1175, 1154, 1112, 1070, 1026, 713; 1H NMR (400 MHz, CDCl3þCCl4):
d
(signals due to the keto form) 7.98e7.93 (2H, m) and 7.57e7.38
(3H, m) [AreH], 5.38e5.30 (1H, m, H-70), 4.11e4.05 (2H, m,
OCH2CH3), 3.35 and 3.30 (2H, 2ꢂd, J 15.0 Hz, H-2), 2.99 (1H, dd, J 9.6
and 8.9 Hz, H-30), 2.72e1.72 (7H, m), 1.21 (3H, t, J 7.2 Hz, OCH2CH3),
1.15 (3H, s) and 0.93 (3H, s) [2ꢂ tert-CH3], 1.05 (3H, d, J 7.2 Hz, sec-
CH3); (important signals due to the enol form) 12.23 (1H, s, enolic-
OH), 4.88 (1H, s, H-2), 4.16 (2H, q, J 7.0 Hz, OCH2CH3), 1.27 (3H, t, J
7.0 Hz, OCH2CH3), 1.03 (3H, s) and 0.94 (3H, s) [2ꢂ tert-CH3]; 13C
selenide 33 (63 mg, 12%) as colourless oil. ½a D23
ꢁ24.4 (c 2.0, CHCl3);
ꢃ
IR (neat): nmax/cmꢁ1 2969, 2934, 2877, 1736, 1716, 1583, 1459, 1451,
1381, 1365, 1314, 1275, 1176, 1160, 1112, 1070, 1025, 974, 743, 713,
692. 1H NMR (400 MHz, CDCl3þCCl4):
d (signals due to the major
isomer) 8.02e7.96 (2H, m) and 7.70e7.26 (8H, m) [AreH],
5.41e5.35 (1H, m, H-10), 4.14e4.06 (2H, m, OCH2CH3), 2.68e1.76
(10H, m), 1.20 (3H, t, J 7.2 Hz, OCH2CH3), 1.09 (3H, s, tert-CH3), 1.02
NMR (100 MHz, CDCl3þCCl4):
d
(signals due to the keto form) 204.1
(3H, d, J 7.0 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d (sig-
(C, C]O), 166.9 (C) and 165.9 (C) [2ꢂOC]O], 132.9 (CH), 130.6 (C),
129.4 (2C, CH), 128.5 (2C, CH), 79.6 (CH, C-70), 61.0 (CH2, OCH2CH3),
58.8 (CH, C-30), 57.3 (CH, C-10), 50.4 (CH2, C-2), 45.3 (C, C-20), 44.4
(CH, C-50), 41.5 (CH, C-60), 34.8 (CH2), 26.8 (CH2), 25.5 (CH3) and
24.9 (CH3) [2ꢂ tert-CH3], 14.2 (CH3, OCH2CH3), 11.2 (CH3, sec-CH3);
(signals due to the enol form) 179.3 (C, C-3), 166.9 (C) and 165.9 (C)
[2ꢂOC]O],132.8 (CH), 130.6 (C),129.6 (2C, CH),128.5 (2C, CH), 89.9
(CH, C-2), 79.5 (CH, C-70), 59.8 (CH2, OCH2CH3), 56.1 (CH, C-30), 51.9
(CH, C-10), 45.4 (C, C-20), 44.2 (CH, C-50), 41.3 (CH, C-60), 34.6 (CH2),
26.5 (CH2), 25.4 (CH3) and 24.3 (CH3) [2ꢂ tert-CH3], 14.3 (CH3,
OCH2CH3), 11.2 (CH3, sec-CH3); HRMS: m/z calcd for C23H30O5Na
(MþNa): 409.1991; found: 409.1991.
nals due to the major isomer) 211.0 (C, C]O),170.5 (C) and 166.0 (C)
[2ꢂOC]O], 137.4 (2C, CH), 134.4 (C), 132.9 (CH), 129.7 (CH), 129.4
(2C, CH), 128.9 (2C, CH), 128.5 (2C, CH), 127.7 (C), 79.2 (CH, C-10),
62.2 (CH2, OCH2CH3), 59.6 (CH, C-6), 58.4 (C, C-4), 55.3 (CH, C-1),
48.5 (CH, C-8), 48.4 (C, C-1), 47.3 (CH2), 40.2 (CH, C-5), 34.6 (CH2),
30.8 (CH2), 25.2 (CH3, tert-CH3), 14.0 (CH3, OCH2CH3), 11.2 (CH3, sec-
CH3); HRMS: m/z calcd for C29H32O5SeNa (MþNa): 563.1314; found:
563.1312.
Further elution of the column with ethyl acetate/hexane (1:4)
furnished the conjugated keto ester 34 (244 mg, 65%) as oil. Rf (1:6
EtOAc/hexane) 0.3; ½a D21
ꢃ
ꢁ29.0 (c 6.5, CHCl3); IR (neat): nmax/cmꢁ1
2971, 2935, 2878, 1748, 1716, 1620, 1452, 1368, 1333, 1314, 1300,
1276, 1178, 1113, 1070, 1026, 974, 919, 715; 1H NMR (400 MHz,
4.1.6. Ethyl (1R,2S,6R,8R,9R,10S)-10-benzoyloxy-2,9-dimethyl-5-
CDCl3þCCl4):
d 8.09 (1H, s, H-3), 8.00 (2H, d, J 7.6 Hz), 7.56 (1H, t, J
oxotricyclo[6.3.0.02,6]undecane-4-carboxylate (32). To a magneti-
7.5 Hz) and 7.44 (2H, t, J 7.6 Hz) [AreH], 5.45 (1H, td, J 7.6 and 4.6 Hz,
H-10), 4.29 (2H, q, J 7.2 Hz, OCH2CH3), 2.59 (1H, d, J 9.1 Hz),
2.55e2.40 (5H, m), 2.05e1.95 (1H, m), 1.83 (1H, ddd, J 14.4, 6.6 and
4.8 Hz), 1.35 (3H, t, J 7.2 Hz, OCH2CH3), 1.31 (3H, s, tert-CH3), 1.01
cally stirred solution of the b-keto ester 30 (443 mg, 1.15 mmol) in
acetonitrile (3 mL) were added tosyl azide (250 mg, 1.27 mmol) and
triethylamine (0.32 mL, 2.31 mmol), and stirred at rt for 5 h.
Evaporation of the solvent under reduced pressure and purification
of the residue on a silica gel column using ethyl acetate/hexane
(3H, d, J 7.1 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 205.6
(C, C]O), 178.5 (CH, C-3), 165.9 (C) and 161.8 (C) [2ꢂOC]O], 134.7
(C, C-4), 133.0 (CH), 130.4 (C), 129.5 (2C, CH), 128.5 (2C, CH), 78.1
(CH, C-10), 61.0 (CH2, OCH2CH3), 59.0 (CH, C-6), 52.8 (C, C-2), 49.4
(CH, C-1), 48.1 (CH, C-8), 40.0 (CH, C-9), 34.7 (CH2), 30.7 (CH2), 20.8
(CH3, tert-CH3), 14.3 (CH3, OCH2CH3), 11.2 (CH3, sec-CH3); HRMS: m/
z calcd for C23H26O5Na (MþNa): 405.1679; found: 405.1674.
(1:19) as an eluent furnished the a-diazo-b-keto ester 31 (430 mg,
91%) as an oil. [IR (neat): nmax/cmꢁ1 2966, 2936, 2876, 2129 (N]N),
1715 (OC]O), 1642 (C]O), 1597, 1451, 1371, 1298, 1276, 1190, 1170,
1114, 1087, 815, 748, 714, 662.]
To a magnetically stirred, refluxing solution of Rh2(OCOCF3)4
(3 mg) in CH2Cl2 (20 mL) was added a solution of the a-diazo-b-
keto ester 31 (430 mg, 1.04 mmol) in dry CH2Cl2 (15 mL) 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 (1:19) as an eluent furnished an epimeric mixture
of the triquinane 32 (377 mg, 93%) as an oil. Rf (1:9 EtOAc/hexane)
4.1.8. Oxidative elimination of selenide 33. To a magnetically stirred
cold (0e5 ꢀC) solution of the selenide 33 (63 mg, 0.12 mmol) in
CH2Cl2 (4 mL) was added 30% aq H2O2 (0.5 mL) and stirred for 0.5 h
at the same temperature. It was then diluted with water (3 mL) and
extracted with CH2Cl2 (3ꢂ5 mL). The combined organic extract was
washed with brine (3 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
ethyl acetate/hexane (1:4) as an eluent furnished the conjugated
keto ester 34 (32 mg, 71%) as an oil.
0.5; ½a 2D2
ꢃ
þ5.9 (c 2.7, CHCl3); IR (neat): nmax/cmꢁ1 2965, 2877, 1750,
1716, 1661, 1622, 1452, 1370, 1314, 1276, 1176, 1112, 1070, 1026, 714;
1H NMR (400 MHz, CDCl3þCCl4):
d (signals due to the major iso-
mer) 7.95 (2H, d, J 7.5 Hz), 7.55 (1H, t, J 7.6 Hz) and 7.44 (2H, d, J
7.5 Hz) [AreH], 5.40e5.33 (1H, m, H-10), 4.28e4.10 (2H, m,
OCH2CH3), 3.43 (1H, dd, J 8.0 and 5.1 Hz), 2.75 (1H, t, J 8.4 Hz),
2.66e1.80 (9H, m), 1.29 (3H, t, J 7.1 Hz, OCH2CH3), 1.13 (3H, s, tert-
4.1.9. (1S,2R,4S,5R,6R,8R)-1,5-Dimethyl-9-oxotricyclo[6.3.0.02,6]un-
dec-10-en-4-yl benzoate (35). A solution of the keto ester 34
(50 mg, 0.13 mmol) and LiCl (16 mg, 0.39 mmol) in DMSO (0.5 mL)
and water (0.01 mL) was placed in a Carius tube and heated to
180 ꢀC for 6 h. The reaction mixture was cooled to rt, diluted with
ether (10 mL), washed with water (5 mL) and brine (5 mL) and
dried (NaSO4). 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 enone 35 (34 mg, 84%) as an oil. Rf (1:4 EtOAc/
CH3), 1.05 (3H, d,
CDCl3þCCl4): (signals due to the major isomer) 213.0 (C, C]O),
J
7.2 Hz, sec-CH3); 13C NMR (100 MHz,
d
169.5 (C) and 166.0 (C) [2ꢂOC]O], 132.9 (CH), 130.5 (C), 129.5 (2C,
CH), 128.5 (2C, CH), 79.1 (CH, C-10), 61.3 (CH2, OCH2CH3), 58.7 (CH,
C-4), 54.7 (CH, C-6), 49.3 (C, C-2), 49.2 (CH, C-1), 47.9 (CH, C-8), 40.7
(CH, C-9), 39.5 (CH2), 34.9 (CH2), 29.2 (CH2), 22.8 (CH3, tert-CH3),
14.3 (CH3, OCH2CH3), 11.2 (CH3, sec-CH3); HRMS: m/z calcd for
C23H28O5Na (MþNa): 407.1835; found: 407.1837.
hexane) 0.6; ½a 2D1
ꢃ
ꢁ6.4 (c 1.3, CHCl3); IR (neat): nmax/cmꢁ1 3071,
2964, 2929, 2878, 1713 (C]O and OC]O), 1588, 1452, 1314, 1276,
4.1.7. Ethyl (1R,2S,6R,8R,9R,10S)-10-benzoyloxy-2,9-dimethyl-5-
oxotricyclo[6.3.0.02,6]undec-3-ene-4-carboxylate (34). To a magneti-
cally stirred cold (0e5 ꢀC) solution of PhSeCl (207 mg, 1.08 mmol)
1177, 1113, 1071, 1026, 971, 836, 796, 714; 1H NMR (400 MHz,
CDCl3þCCl4):
d 8.02 (2H, d, J 7.6 Hz), 7.57 (1H, t, J 7.3 Hz) and 7.46
(2H, t, J 7.8 Hz) [AreH], 7.45 (1H, d, J 5.5 Hz, H-110), 6.07 (1H, d, J

A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
3053
5.5 Hz, H-100), 5.46 (1H, td, J 7.7 and 4.9 Hz, H-40), 2.50e2.35 (3H,
m), 2.34e2.15 (3H, m), 1.93e1.87 (1H, m), 1.82 (1H, ddd, J 14.5, 9.7
(3ꢂ10 mL). The combined organic extract was washed with brine
(8 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 alkylated enone 37 (90 mg,
and 4.7 Hz), 1.28 (3H, s, tert-CH3), 1.02 (3H, d, J 7.2 Hz, sec-CH3); 13
C
NMR (100 MHz, CDCl3þCCl4):
d
212.9 (C, C]O), 172.5 (CH, C-110),
166.0 (C, OC]O), 132.9 (CH), 131.6 (CH, C-100), 130.5 (C), 129.5 (2C,
CH), 128.5 (2C, CH), 78.3 (CH, C-40), 57.4 (CH, C-80), 55.4 (C, C-10),
49.7 (CH, C-20), 47.9 (CH, C-60), 39.9 (CH, C-50), 34.8 (CH2), 30.3
(CH2), 21.3 (CH3), 11.2 (CH3); HRMS: m/z calcd for C20H22O3Na
(MþNa): 333.1467; found: 333.1467.
81%) as an oil. Rf (1:3 EtOAc/hexane) 0.6; ½a D22
ꢁ38.6 (c 1.7, CHCl3);
ꢃ
IR (neat): nmax/cmꢁ1 3076, 2931, 1705 (C]O), 1595, 1459, 1380,
1342, 1216, 1152, 1100, 1039, 916 (CH]CH2), 833; 1H NMR
(400 MHz, CDCl3þCCl4):
d 7.32 (1H, d, J 5.6 Hz, H-3), 6.03 (1H, d, J
5.6 Hz, H-4), 5.84 (1H, ddt, J 17.2, 10.2 and 7.0 Hz, CH]CH2), 5.02
(1H, d, J 17.2 Hz) and 5.01 (1H, d, J 10 Hz) [CH]CH2], 4.60 and 4.52
(2H, 2ꢂd, J 6.7 Hz, OCH2O), 4.05 (1H, q, J 7.2 Hz, H-10), 3.33 (3H, s,
OCH3), 2.26 (2H, d, J 7.0 Hz, H-10), 2.20e1.60 (7H, m),1.18 (3H, s, tert-
CH3), 0.90 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz,
4.1.10. (1R,2S,6R,8R,9R,10S)-10-Hydroxy-2,9-dimethyltricyclo
[6.3.0.02,6]undec-3-en-5-one (36). To a magnetically stirred solution
of the tricyclic benzoate 35 (88 mg, 0.29 mmol) in MeOH (0.5 mL)
was added K2CO3 (158 mg, 1.14 mmol) and stirred for 12 h at rt.
Water (3 mL) was added to the reaction mixture and extracted with
ether (2ꢂ5 mL). The combined organic extract was washed with
brine (5 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate/
hexane (1:4) as eluent furnished the alcohol 36 (54 mg, 93%) as an
CDCl3þCCl4):
d 214.6 (C, C]O), 172.4 (CH, C-3), 134.8 (CH, HC]
CH2), 130.4 (CH, C-4), 117.4 (CH2, HC]CH2), 95.9 (CH2, OCH2O), 80.2
(CH, C-10), 60.2 (C, C-6), 57.1 (C, C-2), 55.2 (CH3, OCH3), 50.9 (CH, C-
1), 44.9 (CH, C-8), 39.7 (CH, C-9), 38.7 (CH2), 37.2 (CH2), 34.8 (CH2),
18.1 (CH3, tert-CH3), 11.3 (CH3, sec-CH3); HRMS: m/z calcd for
C18H26O3Na (MþNa): 313.1780; found: 313.1782.
oil. Rf (1:3 EtOAc/hexane) 0.45; ½a D23
ꢁ73.2 (c 2.7, CHCl3); IR (neat):
ꢃ
nmax/cmꢁ1 3449 (OH), 2961, 2929, 1698 (C]O), 1584, 1458, 1342,
4.1.13. (1R,2S,5S,6R,8R,9R,10S)-6-Allyl-10-(methoxymethoxy)-2,5,9-
trimethyltricyclo[6.3.0.02,6]undec-3-en-5-ol (38). To a cold (0e5 ꢀC)
solution of the enone 37 (43 mg, 0.15 mmol) in anhydrous THF
(2 mL) was added a solution of MeLi (1 M in ether, 0.74 mL,
0.74 mmol) and stirred for 10 h at rt. The reaction was then
quenched with saturated aq NH4Cl (2 mL) solution and extracted
with ether (3ꢂ5 mL). The combined organic layer was washed with
brine (5 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 eluent furnished the tertiary alcohol 38 (41 mg,
1076, 986, 838, 800; 1H NMR (400 MHz, CDCl3þCCl4):
d 7.40 (1H, d, J
5.5 Hz, H-3), 6.00 (1H, d, J 5.5 Hz, H-4), 4.24 (1H, q, J 7.2 Hz, H-10),
2.34 (1H, d, J 9.3 Hz, H-6), 2.24e2.04 (5H, m), 1.96 (1H, s, OH),
1.76e1.62 (2H, m), 1.26 (3H, s, tert-CH3), 0.94 (3H, d, J 7.1 Hz, sec-
CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 213.6 (C, C]O), 172.9 (CH,
C-3), 131.3 (CH, C-4), 75.6 (CH, C-10), 57.5 (CH, C-6), 55.3 (C, C-2),
49.2 (CH, C-1), 47.8 (CH, C-8), 40.4 (CH, C-9), 36.6 (CH2), 30.5 (CH2),
21.3 (CH3, tert-CH3), 10.7 (CH3, sec-CH3); HRMS: m/z calcd for
C13H18O2Na (MþNa): 229.1204; found: 229.1200.
91%) as an oil. Rf (1:4 EtOAc/hexane) 0.5; ½a D25
þ3.8 (c 4.3, CHCl3); IR
ꢃ
4.1.11. (1R,2S,6R,8R,9R,10S)-10-(Methoxymethoxy)-2,9-
dimethyltricyclo[6.3.0.02,6]undec-3-en-5-one (19). To a magnetically
stirred cold (0e5 ꢀC) solution of the secondary alcohol 36 (27 mg,
0.13 mmol) in CH2Cl2 (1 mL) were added DMAP (16 mg, 0.13 mmol),
DIPEA (0.07 mL, 0.39 mmol) and MOMCl (0.03 mL, 0.39 mmol)
successively and stirred for 3 h at rt. Water (2 mL) was added to the
reaction mixture and extracted with CH2Cl2 (3ꢂ4 mL). The com-
bined organic extract was washed with brine (3 mL) and dried
(Na2SO4). 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 MOM ether 19 (32 mg, 98%) as an oil. Rf (3:7 EtOAc/
(neat): nmax/cmꢁ1 3482 (OH), 3072, 3035, 2954, 2931, 2883, 1636,
1457, 1376,1168,1151, 1099, 1039, 934, 916 (CH]CH2), 779; 1H NMR
(400 MHz, CDCl3þCCl4):
d 6.00 (1H, ddt, J 17.2, 8.9 and 7.0 Hz, CH]
CH2), 5.45 and 5.33 (2H, 2ꢂd, J 5.7 Hz, H-3 and 4), 5.11 (1H, d, J
17.2 Hz) and 5.07 (1H, d, J 8.9 Hz) [HC]CH2], 4.62 and 4.54 (2H,
2ꢂd, J 6.7 Hz, OCH2O), 4.09e4.03 (1H, m, H-10), 3.35 (3H, s, OCH3),
2.50 (1H, dd, J 14.1 and 7.2 Hz), 2.28e2.00 (5H, m), 1.88e1.79 (1H,
m), 1.71e1.58 (2H, m), 1.47 (1H, s, OH), 1.36 (3H, s) and 1.02 (3H, s)
[2ꢂ tert-CH3], 0.99 (3H, d, J 6.9 Hz, sec-CH3); 13C NMR (100 MHz,
CDCl3þCCl4):
d 140.2 (CH, C-4), 136.9 (CH, C-3), 136.0 (CH, HC]
CH2), 116.9 (CH2, HC]CH2), 95.7 (CH2, OCH2O), 87.0 (C, C-5), 81.4
(CH, C-10), 59.9 (C, C-6), 57.9 (C, C-2), 55.2 (CH3, OCH3), 46.3 (2C,
CH), 41.2 (CH, C-9), 40.6 (CH2), 34.5 (CH2), 33.3 (CH2), 27.7 (CH3) and
18.2 (CH3) [2ꢂ tert-CH3], 11.5 (CH3, sec-CH3); HRMS: m/z calcd for
C19H30O3Na (MþNa): 329.2093; found: 329.2095.
hexane) 0.55; ½a D23
ꢃ
ꢁ42.9 (c 2.8, CHCl3); IR (neat): nmax/cmꢁ1 2953,
2930, 2822, 1706 (C]O), 1588, 1457, 1378, 1341, 1271, 1211, 1150,
1097, 1043, 917, 835, 797; 1H NMR (400 MHz, CDCl3þCCl4):
d 7.40
(1H, d, J 5.5 Hz, H-3), 6.02 (1H, d, J 5.5 Hz, H-4), 4.61 and 4.55 (2H,
2ꢂd, J 6.7 Hz, OCH2O), 4.10e4.04 (1H, m, H-10), 3.35 (3H, s, OCH3),
2.35 (1H, d, J 9.2 Hz, H-6), 2.21e2.05 (5H, m),1.80e1.65 (2H, m),1.27
(3H, s, tert-CH3), 0.95 (3H, d, J 6.6 Hz, sec-CH3); 13C NMR (100 MHz,
4.1.14. (1R,2S,6S,8R,9R,10S)-6-Allyl-10-(methoxymethoxy)-2,5,9-
trimethyltricyclo[6.3.0.02,6]undec-4-en-3-one (39). To
a magneti-
CDCl3þCCl4):
d
214.3 (C, C]O), 172.7 (CH, C-3), 131.3 (CH, C-4), 95.8
cally stirred solution of the alcohol 38 (41 mg, 0.13 mmol) in dry
CH2Cl2 (1 mL) was added PDC (151 mg, 0.40 mmol) and stirred
vigorously for 3 h at rt. The reaction mixture was then filtered
through a small silica gel column with an excess of CH2Cl2. Evap-
oration of the solvent and purification of the residue on a silica gel
column using ethyl acetate/hexane (1:9) as an eluent furnished the
(CH2, OCH2O), 80.3 (CH, C-10), 57.5 (CH, C-6), 55.3 (C, C-2), 55.2
(CH3, OCH3), 49.3 (CH, C-1), 47.8 (CH, C-8), 39.9 (CH, C-9), 34.7
(CH2), 30.2 (CH2), 21.3 (CH3, tert-CH3), 11.2 (CH3, sec-CH3); HRMS:
m/z calcd for C15H22O3Na (MþNa): 273.1467; found: 273.1467.
4.1.12. (1R,2S,6R,8R,9R,10S)-6-Allyl-10-(methoxymethoxy)-2,9-
enone 39 (38 mg, 93%) as an oil. Rf (1:4 EtOAc/hexane) 0.4; ½a D25
ꢃ
dimethyltricyclo[6.3.0.02,6]undec-3-en-5-one
(37). To
a
cold
ꢁ7.7 (c 3.8, CHCl3); IR (neat): nmax/cmꢁ1 3076, 2921, 1704 (C]O),
(0e5 ꢀC), magnetically stirred solution of diisopropylamine
(0.32 mL, 2.30 mmol) in anhydrous THF (2 mL) was added a solu-
tion of n-BuLi (2.4 M in hexane, 0.8 mL, 1.92 mmol) over a period of
5 min and stirred for 10 min. The LDA thus formed was cooled to
ꢁ70 ꢀC, a solution of the enone 19 (96 mg, 0.38 mmol) in THF (2 mL)
was added drop wise over a period of 10 min and stirred for 30 min
at the same temperature. The enolate was then treated with allyl
bromide (0.27 mL, 3.07 mmol) and stirred for 6 h at rt. The reaction
mixture was diluted with water (4 mL) and extracted with ether
1623, 1458, 1376, 1281, 1217, 1152, 1099, 1039, 917 (CH]CH2); 1H
NMR (400 MHz, CDCl3þCCl4):
d 5.89 (1H, s, H-4), 5.61 (1H, ddt, J
17.0, 10.2 and 7.0 Hz, HC]CH2), 5.04 (1H, d, J 17.0 Hz) and 4.98 (1H,
d, J 10.2 Hz) [HC]CH2], 4.59 and 4.52 (2H, 2ꢂd, J 6.6 Hz, OCH2O),
4.00 (1H, q, J 7.1 Hz, H-10), 3.33 (3H, s, OCH3), 2.42 and 2.37 (2H,
2ꢂdd, J 17.4 and 8.8 Hz, H-10), 2.26 (1H, q, J 7.4 Hz), 2.17e2.08 (2H,
m), 2.00 (3H, s, olefinic-CH3), 1.96e1.86 (1H, m), 1.79 (1H, t, J
12.4 Hz), 1.70e1.55 (2H, m), 1.05 (3H, s, tert-CH3), 0.93 (3H, d, J
7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 213.5 (C, C]O),

3054
A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
180.5 (C, C-5),134.9 (CH, HC]CH2), 130.1 (CH, C-4),117.4 (CH2, HC]
CH2), 95.7 (CH2, OCH2O), 80.1 (CH, C-10), 61.2 (C, C-2), 59.4 (C, C-6),
55.2 (CH3, OCH3), 50.9 (CH, C-1), 45.0 (CH, C-8), 39.8 (CH, C-9), 39.4
(CH2), 35.1 (CH2), 34.5 (CH2), 15.7 (CH3), 15.5 (CH3), 11.4 (CH3, sec-
CH3); HRMS: m/z calcd for C19H28O3Na (MþNa): 327.1935; found:
327.1931.
HRMS: m/z calcd for C22H32O5Na (MþNa): 399.2147; found:
399.2146.
4.1.17. Ethyl 4-[(1R,2S,6S,8R,9R,10S)-10-(methoxymethoxy)-2,5,9-
trimethyl-3-oxotricyclo[6.3.0.02,6]undec-4-en-6-yl]butanoate (18). To
a solution of the a,b-unsaturated ester 41 (36 mg, 0.10 mmol) in
ethyl acetate (1 mL) was added Wilkinson’s catalyst (12 mg) and the
reaction mixture was stirred at 1 atm pressure of hydrogen, created
by evacuative displacement of air (balloon), for 24 h. The reaction
mixture was then 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 (1:9) as
an eluent furnished the saturated ester 18 (35 mg, 97%) as an oil. Rf
4.1.15. [(1R,2S,6R,8R,9R,10S)-10-(Methoxymethoxy)-2,5,9-trimethyl-
3-oxotricyclo[6.3.0.02,6]undec-4-en-6-yl]ethanal (40). Dry ozone in
oxygen was passed through a cold (ꢁ70 ꢀC) solution of the enone 39
(80 mg, 0.26 mmol) and a catalytic amount of NaHCO3 in 1:4
MeOH/CH2Cl2 (5 mL) for
3 min. Dimethyl sulfide (0.1 mL,
1.32 mmol) was added to the reaction mixture and stirred for 3 h at
rt. Water (2 mL) was added to the reaction mixture and extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic layer was washed
with brine (5 mL) and dried (Na2SO4). Evaporation of the solvent
and purification of the residue on a silica gel column using ethyl
acetate/hexane (1:4) as an eluent furnished the aldehyde 40
(1:4 EtOAc/hexane) 0.5; ½a D25
ꢃ
þ2.6 (c 5.2, CHCl3); IR (neat): nmax
/
cmꢁ1 2943, 1734 (OC]O), 1703 (C]O), 1622, 1458, 1376, 1270, 1252,
1209, 1184, 1151, 1098, 1044, 918; 1H NMR (400 MHz, CDCl3þCCl4):
d
5.93 (1H, s, H-40), 4.60 and 4.52 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.10
(2H, q, J 7.2 Hz, OCH2CH3), 3.99 (1H, td, J 6.9 and 4.2 Hz, H-100), 3.34
(3H, s, OCH3), 2.32e2.19 (3H, m), 2.12e2.02 (2H, m), 2.04 (3H, s,
olefinic-CH3), 2.00e1.89 (1H, m), 1.80e1.30 (7H, m), 1.25 (3H, t, J
7.2 Hz, OCH2CH3), 1.06 (3H, s, tert-CH3), 0.93 (3H, d, J 7.2 Hz, sec-
(68 mg, 84%) as an oil. Rf (3:7 EtOAc/hexane) 0.3; ½a D22
þ4.6 (c 3.9,
ꢃ
CHCl3); IR (neat): nmax/cmꢁ1 2942, 2824, 2733 (HeC]O), 1722
(HC]O), 1699 (C]O),1623, 1458, 1378, 1280, 1216, 1152, 1098, 1041,
917; 1H NMR (400 MHz, CDCl3þCCl4):
d
9.71 (1H, s, HeC]O), 5.97
CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 213.4 (C]O), 180.1 (C, C-
(1H, s, H-40), 4.61 and 4.54 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.05 (1H, td, J
7.2 and 4.1 Hz, H-100), 3.34 (3H, s, OCH3), 2.67 (2H, d, J 1.8 Hz,
OHCeCH2), 2.40e2.10 (3H, m), 2.05 (3H, s, olefinic-CH3), 2.05e1.88
(2H, m), 1.85e1.75 (1H, m), 1.66e1.57 (1H, m), 1.03 (3H, s, tert-CH3),
0.94 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
50),172.8 (C, OC]O),130.3 (CH, C-40), 95.6 (CH2, OCH2O), 80.2 (CH, C-
100), 62.0 (C, C-20), 60.2 (CH2, OCH2CH3), 58.6 (C, C-60), 55.2 (CH3,
OCH3), 51.2 (CH, C-10), 45.1 (CH, C-80), 39.7 (CH, C-90), 35.7 (CH2),
34.5 (CH2), 34.2 (CH2), 34.1 (CH2), 21.0 (CH2), 15.2 (CH3), 15.1 (CH3),
14.3 (CH3), 11.4 (CH3, sec-CH3); HRMS: m/z calcd for C22H34O5Na
(MþNa): 401.2304; found: 401.2304.
d
212.2 (C, C]O), 200.4 (CH, HC]O),178.5 (C, C-50), 130.2 (CH, C-40),
95.8 (CH2, OCH2O), 79.9 (CH, C-100), 59.8 (C), 59.4 (C), 55.3 (CH3,
OCH3), 50.7 (CH, C-10), 48.5 (CH2, C-2), 45.1 (CH, C-80), 40.3 (CH, C-
90), 35.7 (CH2), 35.0 (CH2),16.3 (CH3),15.4 (CH3),11.4 (CH3, sec-CH3);
HRMS: m/z calcd for C18H27O4 (MþH): 307.1909; found: 307.1903.
4.1.18. Ethyl
(1S,3R,4R,5S,7R,8S,11S,12R)-5-(methoxymethoxy)-
4,8,11-trimethyl-9-oxo-tetracyclo[6.6.0.01,11.03,7]tetradecane-12-
carboxylate (42x) and ethyl (1S,3R,4R,5S,7R,8S,11S,12S)-5-(methox-
ymethoxy)-4,8,11-trimethyl-9-oxo-tetracyclo [6.6.0.01,11.03,7]tetrade-
cane-12-carboxylate (42n). To a cold (0e5 ꢀC), magnetically stirred
solution of diisopropylamine (0.21 mL, 1.52 mmol) in anhydrous
THF (3 mL) was slowly added a solution of n-BuLi (2.4 M in hexane,
0.48 mL, 1.14 mmol) over a period of 5 min and stirred for 10 min.
The LDA thus formed was cooled to ꢁ70 ꢀC, a solution of the ester
18 (72 mg, 0.19 mmol) in THF (5 mL) was added drop wise over
a period of 10 min and stirred for 30 min at the same temperature
and for 5 h at rt. Water (3 mL) was then added to the reaction
mixture and extracted with ether (3ꢂ5 mL). The combined organic
extract was washed with brine (3 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
a 17:3 epimeric mixture of the tetraquinane esters 42n and 42x
(47 mg, 65%) as an oil.
4.1.16. Ethyl (E)-4-[(1R,2S,6S,8R,9R,10S)-10-(methoxymethoxy)-2,5,
9-trimethyl-3-oxotricyclo[6.3.0.02,6]undec-4-en-6-yl]but-2-enoate
(41). A suspension of sodium hydride (18 mg, 0.46 mmol, 60%
dispersion in oil) in hexanes under nitrogen atmosphere was
magnetically stirred for 10 min and the solvent was syringed out.
The oil free sodium hydride was then suspended in dry THF (1 mL)
and cooled to 0 ꢀC. Triethyl phosphonoacetate (0.11 mL, 0.55 mmol)
was added drop wise and stirred for 40 min at rt. A solution of the
aldehyde 40 (14 mg, 0.05 mmol) in dry THF (2 mL) was added drop
wise to the reaction mixture at 0 ꢀC and stirred at the same tem-
perature for 1 h, and for 7 h at rt. The reaction was then quenched
by careful addition of saturated aq NH4Cl solution (1 mL) and
extracted with ether (3ꢂ3 mL). The combined organic extract was
washed with brine (2 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
A solution of a 17:3 epimeric mixture of the esters 42n and 42x
(27 mg, 0.07 mmol) and DBU (0.05 mL, 0.36 mmol) in C6H6 (0.5 mL)
was placed in a Carius tube and heated to 110 ꢀC for 24 h. The re-
action mixture was cooled to rt, diluted with ether (5 mL), washed
with water (3 mL) and brine (5 mL) and dried (NaSO4). Evaporation
of the solvent and purification of the residue on an alumina column
using CHCl3/C6H6 (1:1) as an eluent furnished first the exo ester 42x
ethyl acetate/hexane (3:17) as an eluent furnished the
a,b-un-
saturated ester 41 (16 mg, 94%) as an oil. Rf (1:4 EtOAc/hexane) 0.5;
½
a 2D3
ꢃ
ꢁ28.9 (c 3.9, CHCl3); IR (neat): nmax/cmꢁ1 2939, 2823, 1715
(OC]O), 1704 (C]O), 1651, 1622, 1456, 1370, 1269, 1183, 1153, 1097,
1040, 982, 918; 1H NMR (400 MHz, CDCl3þCCl4):
d 6.78 (1H, dt, J
15.5 and 7.8 Hz, H-3), 5.94 (1H, s, H-40), 5.84 (1H, d, J 15.5 Hz, H-2),
4.60 and 4.53 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.15 (2H, q, J 7.1 Hz,
OCH2CH3), 4.03 (1H, dt, J 7.1 and 4.1 Hz, H-100), 3.34 (3H, s, OCH3),
2.56 (1H, dd, J 15.0 and 6.6 Hz) and 2.50 (1H, dd, J 15.0 and 8.0 Hz)
[H-3], 2.29 (1H, q, J 6.4 Hz), 2.25e2.10 (2H, m), 2.03 (3H, s, olefinic-
CH3), 2.00e1.80 (2H, m), 1.71 (1H, dd, J 12.4 and 6.2 Hz), 1.66e1.58
(1H, m), 1.28 (3H, t, J 7.1 Hz, OCH2CH3), 1.04 (3H, s, tert-CH3), 0.95
(12 mg, 44%) as an oil. Rf (1:4 EtOAc/hexane) 0.39; ½a D23
þ48.8 (c 1.8,
ꢃ
CHCl3); IR (neat): nmax/cmꢁ1 2962, 2933, 1732 (C]O and OC]O),
1462, 1455, 1371, 1348, 1226, 1179, 1153, 1099, 1041, 917; 1H NMR
(400 MHz, CDCl3þCCl4): 4.58 and 4.52 (2H, 2ꢂd, J 6.6 Hz, OCH2O),
d
4.15 and 4.09 (2H, 2ꢂdq, J 10.8 and 7.2 Hz, OCH2CH3), 4.05e3.95
(1H, m, H-5), 3.32 (3H, s, OCH3), 2.79 (1H, d, J 17.9 Hz, H-10A), 2.43
(1H, t, J 9.7 Hz, H-12), 2.25e2.10 (4H, m), 2.05e1.92 (3H, m),
1.91e1.80 (3H, m),1.76e1.67 (1H, m),1.62e1.52 (1H, m),1.25 (3H, t, J
7.1 Hz, OCH2CH3), 1.08 (3H, s) and 1.01 (3H, s) [2ꢂ tert-CH3], 0.94
(3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 213.8
(C, C]O), 179.4 (C, C-50), 165.7 (C, OC]O), 145.1 (CH, C-3), 130.5
(CH, C-40), 123.8 (CH, C-2), 95.6 (CH2, OCH2O), 79.8 (CH, C-100), 60.9
(C, C-20), 60.3 (CH2, OCH2CH3), 59.7 (C, C-60), 55.2 (CH3, OCH3), 50.8
(CH, C-10), 45.1 (CH, C-80), 40.1 (CH, C-90), 38.0 (CH2), 35.1 (CH2),
34.7 (CH2), 16.0 (CH3), 15.6 (CH3), 14.3 (CH3), 11.4 (CH3, sec-CH3);
(3H, d, J 7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d 223.8
(C, C]O), 173.0 (C, OC]O), 96.0 (CH2, OCH2CH3), 79.4 (CH, C-5),
64.6 (C, C-8), 61.4 (C, C-1), 60.3 (CH2, OCH2CH3), 55.2 (CH3, OCH3),

A. Srikrishna, V. Gowri / Tetrahedron 68 (2012) 3046e3055
3055
54.5 (CH, C-12), 54.0 (CH, C-7), 50.53 (CH2, C-10), 50.47 (C), 46.6
(CH, C-3), 40.5 (CH, C-4), 36.2 (CH2), 35.6 (CH2), 33.9 (CH2), 24.7
(CH2, C-13), 18.3 (CH3) and 17.5 (CH3) [2ꢂ tert-CH3], 14.4 (CH3,
OCH2CH3), 11.4 (CH3, sec-CH3); HRMS: m/z calcd for C22H34O5Na
(MþNa): 401.2304; found: 401.2303.
(OH), 2958, 2930, 2877, 1731 (C]O), 1465, 1378, 1215, 1152, 1099,
1042, 918; 1H NMR (400 MHz, CDCl3):
d
4.63 and 4.56 (2H, 2ꢂd, J
6.6 Hz, OCH2O), 4.01 (1H, td, J 6.5 and 5.0 Hz, H-5), 3.36 (3H, s, OCH3),
3.20 (1H, d, J 17.1 Hz, H-10A), 2.49 (1H, q, J 8.6 Hz), 2.23e2.13 (2H, m),
2.08 (1H, d, J 17.1 Hz, H-10B), 2.05e1.89 (2H, m), 1.80e1.55 (6H, m),
1.55e1.40 (2H, m), 1.33 (3H, s), 1.25 (3H, s), 1.24 (3H, s) and 1.02 (3H,
s) [4ꢂ tert-CH3], 0.96 (3H, d, J 6.6 Hz, sec-CH3); 13C NMR (100 MHz,
Further elution of the column with CHCl3/C6H6 (7:3) furnished
the endo ester 42n (10 mg, 37%) as oil. Rf (1:4 EtOAc/hexane) 0.4;
½
a 2D6
ꢃ
þ10.9 (c 0.8, CHCl3); IR (neat): nmax/cmꢁ1 2961, 2930,1734 (C]
CDCl3): d 223.8 (C, C]O), 95.7 (CH2, OCH2O), 80.5 (CH, C-5), 72.8 (C,
O), 1460, 1370, 1226, 1179, 1154, 1100, 1041, 918; 1H NMR (400 MHz,
CeOH), 64.9 (C, C-8), 59.3 (C, C-1), 59.3 (CH, C-12), 55.3 (CH3, OCH3),
50.6 (CH, C-7), 47.1 (C), 47.0 (2C, CH2 and CH), 39.8 (CH, C-4), 38.3
(CH2), 35.2 (CH2), 34.1 (CH2), 31.6 (CH3), 30.6 (CH3) and 27.2 (CH3)
[3ꢂ tert-CH3], 27.16 (CH2, C-13), 17.0 (CH3, tert-CH3), 11.2 (CH3, sec-
CH3); HRMS: m/z calcd for C22H36O4Na (MþNa): 387.2511; found:
387.2508.
CDCl3þCCl4):
d
4.60 and 4.53 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.17 and
4.09 (2H, 2ꢂdq, J 10.8 and 7.2 Hz, OCH2CH3), 4.00 (1H, td, J 6.7 and
5.0 Hz, H-5), 3.34 (3H, s, OCH3), 2.60 (1H, d, J 17.2 Hz, H-10A), 2.51
(2H, dd, J 10.6 and 7.1 Hz), 2.25e1.90 (6H, m), 1.86e1.58 (4H, m),
1.54e1.45 (1H, m), 1.26 (3H, t, J 7.2 Hz, OCH2CH3), 1.26 (3H, s) and
1.03 (3H, s) [2ꢂ tert-CH3], 0.94 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR
(100 MHz, CDCl3þCCl4):
d 221.2 (C, C]O), 173.3 (C, OC]O), 95.7
Acknowledgements
(CH2, OCH2O), 80.2 (CH, C-5), 63.2 (C, C-8), 60.2 (C, C-1), 60.2 (CH2,
OCH2CH3), 55.2 (CH3, OCH3), 55.1 (CH, C-12), 50.0 (CH, C-7), 48.1
(C), 47.2 (CH2, C-10), 47.0 (CH, C-3), 40.0 (CH, C-4), 38.4 (CH2), 35.7
(CH2), 34.2 (CH2), 27.7 (CH2, C-13), 24.5 (CH3) and 17.5 (CH3) [2ꢂ
tert-CH3], 14.4 (CH3, OCH2CH3), 11.2 (CH3, sec-CH3); HRMS: m/z
calcd for C22H34O5Na (MþNa): 401.2304; found: 401.2302.
We thank Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to V.G. We are grateful
to M/s Organica Aromatics (Bangalore) Pvt. Ltd. for the generous
gift of campholenaldehyde.
References and notes
4.1.19. 2-[(1S,3R,4R,5S,7R,8S,11S,12R)-5-(Methoxymethoxy)-4,8,11-
trimethyl-9-oxotetracyclo[6.6.0.01,11.03,7]tetradec-12-yl]propan-2-ol
(17). To a cold (0e5 ꢀC) magnetically stirred solution of the exo
ester 42x (12 mg, 0.03 mmol) in dry ether (1 mL) was added a so-
lution of MeMgCl (3 M in THF, 0.13 mL, 0.39 mmol) and stirred for
1.5 h at rt. The reaction was then quenched with saturated aq NH4Cl
solution (2 mL) and extracted with ether (3ꢂ3 mL). The combined
organic layer was washed with brine (2 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
gel column using ethyl acetate/hexane (1:4) as an eluent furnished
1. (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671; (b) Singh, V.; Thomas, B.
Tetrahedron 1998, 54, 3647; (c) Paquette, L. A. Top. Curr. Chem. 1979, 79, 41; (d)
Trost, B. M. Chem. Soc. Rev. 1982, 11, 141; (e) Paquette, L. A. Top. Curr. Chem. 1984,
119, 1; (f) Ramaiah, M. Synthesis 1984, 529; (g) Paquette, L. A.; Doherty, A. M.
Recent Synthetic Developments in Polyquinane Chemistry; Springer: New York,
NY, 1987; (h) Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89, 1467.
2. (a) Asakawa, Y. In; Herz, W., Kirby, W. B., Moore, R. E., Steglich, W., Tamm, Ch,
Eds. Progress in the Chemistry of Organic Natural Products; Springer: Wien, New
York, NY, 1995; Vol. 65, pp 1e296; (b) Fraga, B. M. Nat. Prod. Rep. 2011, 28, 1580
and earlier parts in the series.
3. (a) Kupka, J.; Anke, T.; Oberwinkler, F.; Schramm, G.; Steglich, W. J. Antibiot.
1979, 32, 130; (b) Anke, T.; Heim, J.; Knoch, F.; Mocek, U.; Steffan, B.; Steglich, W.
Angew. Chem., Int. Ed. Engl. 1985, 24, 709.
crinipellin 17 (10 mg, 86%) as an oil. Rf (1:3 EtOAc/hexane) 0.3; ½a D21
ꢃ
þ73.6 (c 1.0, CHCl3); IR (neat): nmax/cmꢁ1 3488 (OH), 2964, 2934,
2881, 1730 (C]O), 1471, 1463, 1456, 1374, 1218, 1152, 1100, 1044,
4. Li, Y. Y.; Shen, Y. M. Helv. Chim. Acta 2010, 93, 2151.
5. (a) Mehta, G.; Rao, K. S. J. Chem. Soc., Chem. Commun. 1987, 1578; (b) Mehta, G.;
Rao, K. S.; Reddy, M. S. Tetrahedron Lett. 1988, 29, 5025; (c) Mehta, G.; Rao, K. S.;
Reddy, M. S. J. Chem. Soc., Perkin Trans. 1 1991, 693.
6. (a) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11; (b) Piers, E.; Renaud, J.; Rettig,
S. J. Synthesis 1998, 590; (c) Wender, P. A.; Dore, T. M. Tetrahedron Lett. 1998, 39,
8589.
917; 1H NMR (400 MHz, CDCl3):
d
4.61 and 4.54 (2H, 2ꢂd, J 6.6 Hz,
OCH2O), 4.05e3.95 (1H, m, H-5), 3.34 (3H, s, OCH3), 2.73 (1H, d, J
17.8 Hz, H-10A), 2.25e1.50 (14H, m), 1.31 (3H, s), 1.22 (3H, s), 1.17
(3H, s) and 1.10 (3H, s) [4ꢂ tert-CH3], 0.95 (3H, d, J 7.2 Hz, sec-CH3);
7. Srikrishna, A.; Gowri, V. Synlett 2011, 2652.
13C NMR (100 MHz, CDCl3):
d 225.9 (C, C]O), 96.1 (CH2, OCH2O),
8. (a) Srikrishna, A.; Beeraiah, B.; Satyanarayana, G. Tetrahedron: Asymmetry 2006,
17, 1544; (b) Srikrishna, A.; Gowri, V. G. Tetrahedron: Asymmetry 2007, 18, 1663;
(c) Srikrishna, A.; Beeraiah, B. Tetrahedron: Asymmetry 2007, 18, 2587; (d)
Srikrishna, A.; Beeraiah, B. Indian J. Chem. 2007, 46B, 1999; (e) Srikrishna, A.;
Beeraiah, B.; Babu, R. R. Tetrahedron: Asymmetry 2008, 19, 624; (f) Srikrishna, A.;
Beeraiah, B. Tetrahedron: Asymmetry 2008, 19, 884; (g) Srikrishna, A.; Beeraiah,
B.; Gowri, V. Tetrahedron 2009, 65, 2649; (h) Srikrishna, A.; Neetu, G. Tetrahe-
dron: Asymmetry 2010, 21, 2067; (i) Srikrishna, A.; Gowri, V.; Neetu, G. Tetra-
hedron: Asymmetry 2010, 21, 202; (j) Srikrishna, A.; Neetu, G. Tetrahedron 2011,
67, 7581.
79.5 (CH, C-5), 73.1 (C, CeOH), 65.6 (C, C-8), 60.9 (C, C-1), 57.3 (CH,
C-12), 55.3 (CH3, OCH3), 54.1 (CH, C-7), 52.6 (CH2, C-10), 49.8 (C),
46.6 (CH, C-3), 40.3 (CH, C-4), 36.0 (CH2), 35.8 (CH2), 33.4 (CH2), 31.2
(CH3) and 30.0 (CH3) [2ꢂ tert-CH3], 24.8 (CH2, C-13), 18.8 (CH3) and
17.6 (CH3) [2ꢂ tert-CH3], 11.4 (CH3, sec-CH3); HRMS: m/z calcd for
C22H36O4Na (MþNa): 387.2511; found: 387.2515.
9. (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091; (b) Doyle, M. P. In; He-
gedus, L. S., Ed. Comprehensive Organometallic Chemistry II; Pergamon: Oxford,
1995; Vol. 12, Chapter 5.2.2; (c) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: from Cyclopro-
panes to Ylides; John Wiley: New York, NY, 1998, Chapter 3.
4.1.20. 2-[(1S,3R,4R,5S,7R,8S,11S,12S)-5-(Methoxymethoxy)-4,8,11-
trimethyl-9-oxotetracyclo[6.6.0.01,11.03,7]tetradec-12-yl]propan-2-ol
(17n). To a cold (0e5 ꢀC) magnetically stirred solution of the endo
ester 42n (8 mg, 0.02 mmol) in dry ether (1 mL) was added a solu-
tion of MeMgCl (3 M in THF, 0.11 mL, 0.33 mmol) and stirred for 1.5 h
at rt. The reaction was then quenched with saturated aq NH4Cl so-
lution (2 mL) and extracted with ether (3ꢂ3 mL). The combined
organic layer was washed with brine (2 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate/hexane (1:4) as an eluent
furnished 12-epicrinipellin 17n (6 mg, 78%) as an oil. Rf (3:7 EtOAc/
10. Tobe, Y.; Yamashita, D.; Takahashi, T.; Inata, M.; Sato, J.-I.; Kakiuchi, K.; Kobiro,
K.; Odaira, Y. J. Am. Chem. Soc. 1990, 112, 775.
11. (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258; (b) Holmquist,
C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33, 1131.
12. Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar, H. S. J. Org. Chem.
1981, 46, 2920.
13. (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 215;
(b) Krapcho, A. P. Synthesis 1982, 805; (c) Krapcho, A. P. Synthesis 1982, 893.
14. (a) Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021; (b) Srikrishna, A.; Hema-
malini, P. Indian J. Chem. 1990, 29B, 152; (c) Srikrishna, A.; Sharma, G. V. R.;
Danieldoss, S.; Hemamalini, P. J. Chem. Soc., Perkin Trans. 1 1996, 1305.
hexane) 0.4; ½a 2D5
ꢃ
þ11.0 (c 0.5, CHCl3); IR (neat): nmax/cmꢁ1 3482