Indian Journal of Chemistry
Vol. 51B, March 2012, pp. 481-485
Rapid Communication
An enantiospecific synthesis of a crinipellin
A Srikrishna* & V Gowri
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
E-mail: askiisc@gmail.com
Received 9 December 2011; accepted (revised) 3 February 2012
An enantiospecific synthesis of a crinipellin has been
accomplished, starting from the readily available (S)-campholenaldehyde employing two intramolecular rhodium carbenoid CH
insertions and an intramolecular Michael addition reaction as key
steps.
Keywords: Crinipellins, tetraquinanes, enantiospecific
synthesis, campholenaldehyde, intramolecular Michael
addition
Crinipellins 1-9 (Chart I) are a small group of
diterpenes containing a tetraquinane carbon framework 10, whose first member 12-acetoxycrinipellin A,
1 was isolated1 in 1979 by the research groups of
Anke and Steglich from the submerged cultures of
basidomycete Crinipellis stipitaria, strain No. 7612,
which was found to be very active against Grampositive bacteria. Subsequently, further investigations
by Steglich and coworkers2 on several strains of C.
stipitaria and by Shen and Li3 from the fungal strain
Crinipellis sp. 113. led to the isolation of several
related crinipellins 2-9, of which 2 and 3 were found
to exhibit antibiotic activity, whereas 4 and 5 were
found to be nonantibiotic. Structure elucidation
revealed the new diterpene skeleton containing a
tetraquinane
carbon
framework
(tetracyclo[6.6.0.01,11.03,7]tetradecane 10), which was confirmed
by the single crystal X-ray diffraction analysis of
crinipellin B, 3. The absolute configuration of crinipellins was assigned by comparing the CD-curves
with those of linear triquinane sesquiterpene hypnophilin and ent-3β-hydroxy-5α-androstan-17-one,
which is yet to be confirmed. Crinipellin is the first
group of natural products to contain a tetraquinane
framework, which incorporates both a linear cis, anti,
cis-triquinane (ABC-rings) as well as an angular
triquinane (BCD-rings) system (both are known to be
present in a number of sesquiterpenes) as integral
parts4.
The interesting tetraquinane framework coupled
with potential biological activity made the crinipellin
group of diterpenes interesting synthetic targets.
Although a few model studies and one total synthesis
of crinipellin-B in racemic form has been reported
earlier5, there is no report in the literature on the
enantioselective synthesis of crinipellins. Recently, as
a part of the interest in the enantiospecific synthesis of
natural products6 starting from the readily available
campholenaldehyde 11, the first enantiospecific
approach to crinipellins has been developed, and its
utility demonstrated in the enantiospecific synthesis
of 20-norcrinipellins6i. In continuation, herein is
reported the enantiospecific synthesis of a crinipellin.
Extrapolating the earlier approach, it was readily
identified (Scheme I) that the cyclopentane ring in
(S)-campholenaldehyde 11 would serve as the B-ring
of crinipellins, and the D-ring of crinipellins could be
realized through an intramolecular Michael addition
of an ester onto an enone in the C-ring, e.g. 12. The
enone ester 12 could be obtained from the triquinane
13 via the enone 14. The triquinane 13 could be
obtained from (S)-campholenaldehyde 11 via the
diquinane 15 by employing two rhodium carbenoid
CH insertion reactions7 for the construction of the A
and C rings, a strategy developed earlier by this
research group6a,g.
The synthetic sequence for the construction of the
ABC ring system of crinipellins is depicted in
Scheme II. To begin with, the diquinane 15 was
prepared6b via regiospecific CH insertion reaction of
the rhodium carbenoid derived from the diazoketone
16. The diquinane 15 was then transformed into the
methyl ether 17 via sodium borohydride reduction
followed by Williamson's etherification. The stereochemistry at the methoxy and secondary methyl
groups in 17 has already been confirmed earlier6c.
Reaction of the diquinane 17 with 3 equivalents of
selenium dioxide in refluxing acetic acid8 furnished
the aldehyde 18 in 63% yield. Hydrogenation of the
olefin in the aldehyde 18 in ethyl acetate at one
atmospheric pressure of hydrogen using 10%
palladium over carbon as the catalyst furnished a 9:1
(by NMR) mixture of the saturated endo and exo
aldehydes 19n and 19x in a stereoselective manner,
which on equilibration with DBU in methylene
INDIAN J. CHEM., SEC B, MARCH 2012
482
H
H
R
R'
OR
O
O
O
H
O
OH
HO
O
O
OH
3 R,R' = O (crinipellin B)
4 R = OH; R' = H
1 R = Ac
2 R = H (crinipellin A)
5
D
3
5
H
H
13
O
B1
A
7
10
H
11
C
9
HO
HO
OH
O
HO
O
R R'
6 R,R' = O
7 R = H; R' =OH
OH
HO
O
O
8 (crinipellin C)
O
O
9 (crinipellin D)
Chart I
ROOC
D
B
C
A
H
crinipellin
R
H
H
MeH
O
12
H
O
CHO
H
OR
OR
O
H
Me H
14
H
H
O
OR
H
Me H
15
11
13
Scheme I
chloride furnished a 1:7 mixture of the endo and exo
aldehydes 19n and 19x. The epimeric mixture of the
aldehyde 19 was then coupled9 with methyl
diazoacetate in the presence of a catalytic amount of
stannous chloride to generate an epimeric mixture of
the β-ketoester 20, which was then converted into the
α-diazo-β-ketoester 21 by diazo transfer reaction with
tosyl azide and triethylamine. Regiospecific insertion
of the rhodium carbenoid derived from the diazo ester
21 into the corresponding cis methyl group furnished
a mixture of cis, anti, cis- and cis, syn, cis-triquinanes
22a and 22s. Introduction of an olefin group by
selenation-deselenation sequence, followed by
Krapcho's dealkoxycarbonylation11 of the resultant
enone ester 23 transformed the keto esters 22a and
22s into the triquinanes 24a and 24s. As the attempted
separation of the isomers at various stages (19 to 24)
was found to be unsuccessful, an alternative strategy
was explored for the generation of the stereoselective
generation of the triquinane 24a (Scheme III) from
the aldehyde 18. Thus, reaction of the aldehyde 18
with methylmagnesium iodide in ether at 0°C
furnished a 3:2 diastereomeric mixture (by NMR) of
secondary alcohol in 96% yield, which on oxidation
with pyridinium dichromate (PDC) in methylene
chloride generated the enone 25 in 98% yield.
Hydrogenation of the olefin in 25 in ethyl acetate at
one atmospheric pressure of hydrogen using 10%
palladium over carbon as the catalyst followed by
equilibration of the endo isomer with DBU in benzene
at 110°C furnished a 1:19 mixture of the endo and
exo-ketones 26n and 26x, which were separated by
chromatography on an alumina column. Reaction of
the ketone 26x with LDA in THF at ‒70°C, followed
by treatment of the resultant kinetic enolate with ethyl
chloroformate furnished the β-keto ester 20x in 90%
yield. The diazo transfer reaction of the β-keto ester
20x with toluenesulfonyl azide and triethylamine in
COMMUNICATIONS
N2
Me
H
H
a
a
11
483
a
O
O
H
H
16
15
OMe
H
17
b
(α:β 1:7)
H
O H
OMe
X
MeOOC
H
H
H
20 X = H2
21 X = N2
e
H
OHC
OMe
c,d
OHC
OMe
H
19n α−H
19x β-H
f
H
18
g
O
EtOOC
H
H
O
H
H
h,i
Me H
22
OMe
R
Me H
23a R = COOEt
24a R = H
O
+
OMe R
H
H
Me H
OMe
23s R = COOEt
24s R = H
Scheme II — Reagents and Conditions: (a) ref. 6b; (b) SeO2, AcOH, reflux, 1.5 hr, 63%; (c) 10% Pd/C, EtOAc, H2 (1 atm), 2 hr, 90%;
(d) DBU, C6H6, sealed tube, 110°C, 10 hr, 39%; (e) SnCl2.H2O, CH2Cl2, N2CHCOOEt, 2.5 hr, 70%; (f) TsN3, Et3N, CH3CN, RT, 5 hr,
87%; (g) Rh2(OCOCF3)4 (catalytic), CH2Cl2, reflux, 4 hr, 76%; (h) i. PhSeCl, py, CH2Cl2, 0°C, 1 hr; ii. 30%H2O2, CH2Cl2, 0°C, 0.5 hr;
73%; (i) LiCl, DMSO, H2O, 180°C, 10 hr, 70%.
acetonitrile furnished the α-diazo-β-keto ester 21x in
93% yield. Treatment of the diazo ester 21x with a
catalytic amount of rhodium trifluoroacetate in
refluxing methylene chloride furnished an epimeric
mixture (by NMR) of the triquinane esters 22a along
with its enol form in 70% yield. Reaction of the βketo ester 22a with phenylselenyl chloride in the
presence of pyridine11 in methylene chloride followed
by oxidation of the selenide with hydrogen peroxide
furnished the unsaturated keto ester 23a in 72% yield.
Krapcho dealkoxycarbonylation10 of the keto ester
23a in DMSO and lithium chloride in the presence of
water furnished the triquinane enone 24a in 71%
yield, which was then transformed into crinipellin
following the sequence that was employed6i for
norcrinipellin. Generation of the dienolate of the
enone 24a with LDA in THF at ‒70°C and alkylation
with allyl bromide furnished the allylated enone 27 in
71%
yield.
Regioselective
1,2-addition
of
methyllithium to the enone 27 in THF furnished the
allylic tertiary alcohol 28 in a stereoselective manner,
which on oxidation with PCC and silica gel in
methylene chloride furnished the transposed enone
29, whose structure was established from its spectral
data. Ozonolysis of the olefin in the allyl group 29 at
‒70°C followed by reductive workup with dimethyl
sulfide furnished the aldehyde 30 in 67% yield in a
regioselective manner. Horner-Wadsworth-Emmons
reaction of the aldehyde 30 with triethyl
phosphonoacetate and sodium hydride in dry THF at
RT furnished exclusively the trans 2-butenoate 31 in
92% yield, which on regioselective hydrogenation
with Wilkinson’s catalyst in dry ethyl acetate at one
atmospheric pressure of hydrogen (balloon) furnished
the saturated ester 32 in 96% yield. Intramolecular
Michael addition of the keto ester 32 with LDA in
THF at ‒70°C, followed by equilibration of the
resultant tetraquinane ester with DBU in a sealed tube
at 110°C gave a 5:4 mixture of the exo 33x and endo
esters 33n, which were separated by chromatography
on an alumina column. Structures of the esters 33x
and 33n were established from their spectral data. The
endo and exo stereochemistry of the ester group in
33n and 33x was assigned in analogy to
norcrinipellins6i. Finally, reaction of the exo ester 33x
with an excess of methylmagnesium chloride in dry
ether at 0°C furnished 15-hydroxy-5-methoxycrinipellin-9-one 34x, in 79% yield. In a similar
manner, Grignard reaction of the endo ester 33n with
an excess of methylmagnesium chloride in dry ether
at 0°C furnished 12-epicrinipellin 34n in 91% yield,
whose structure was established from its spectral data.
INDIAN J. CHEM., SEC B, MARCH 2012
484
H
18
O
a,b
H
OMe
O
H
e,f
OMe
H
26x (
OMe
X
MeOOC
H
(α,β 1:19)
25
H
O
c,d
H)
g
Y
O
H
H
H
O
H
H
h
j
X
H
20x X = H2
21x X = N2
R
OMe
Me H
27 X,Y = O
k
28 X = CH3, Y = OH
OMe
Me H
23a R = COOMe
24a R = H
MeOOC
Me H
22a
OMe
i
l
MeOOC
X
Me
H
MeOOC
H
Me
o
n
O
OMe
Me H
29 X = H2
30 X = O
O
31
Me
+
q
OMe
Me H
O
(4:5)
33n
H
Me
OMe
Me H
p
(10:1)
MeOOC
H
O
33x
OMe
Me H
32
Me
Me H
33
OMe
r
r
OH
O
MeOOC
H
O
OMe
Me H
m
MeOOC
H
Me
OH
H
H
Me
+
O
Me H
Me
OMe
O
34n
Me H
OMe
34x
Scheme III — Reagents and conditions: (a) MeMgI, Et2O, 0.5 hr, 96%; (b) PDC, CH2Cl2, 3 hr, 98%; (c) 10% Pd/C, EtOAc, H2 (1 atm), 2
hr, 99%; (d) DBU, C6H6, sealed tube, 110°C, 24 hr, 70%; (e) LDA, THF, ‒70ºC; ClCOOEt, RT, 6 hr, 90%; (f) TsN3, Et3N, CH3CN, RT,
5 hr, 93%; (g) Rh2(OCOCF3)4 (catalytic), CH2Cl2, reflux, 5 hr, 70%; (h) i. PhSeCl, py, CH2Cl2, 0°C, 1 hr; ii. 30%H2O2, CH2Cl2, 0°C, 0.5
hr, 72% (i) LiCl, DMSO, H2O, 180°C, 24 hr, 71%; (j) LDA, THF; CH2=CHCH2Br, ‒70°C→RT, 6 hr, 71%; (k) MeLi, THF, Et2O,
0°C→RT, 10 hr, 89%; (l) PCC, silica gel, CH2Cl2, RT, 1 hr, 88%; (m) O3/O2, CH2Cl2-MeOH (4:1), ‒70°C; Me2S, RT, 3 hr. 67%; (n)
(EtO)2P(O)CH2CO2Et, NaH, THF, 0°C→RT, 7 hr, 92%; (o) H2 (1 atm), (Ph3P)3RhCl, EtOAc, RT, 24 hr, 96%; (p) LDA, THF,
‒70°C→RT, 5 hr, 71%; (q) DBU, C6H6, sealed tube, 180°C, 24 hr, 85%; (r) 3 M CH3MgCl, Et2O, 0°C→RT, 3 hr, 80%.
In conclusion, an enantiospecific synthesis of the
tetraquinane diterpene crinipellin has been accomplished, starting from the readily available (S)-campholenaldehyde 11. Identifying the cyclopentane in
campholenaldehyde as the B-ring of crinipellins, two
intramolecular rhodium carbenoid CH insertions and
an intramolecular Michael addition reactions were
employed as key steps for the construction of the A, C
and D rings, respectively.
Experimental Section
2-[(1S,3R,4R,5S,7R,8S,11S,12R)-5-Methoxy4,8,11-trimethyl-9-oxotetracyclo[6.6.0.01,11.03,7]tetradec-12-yl]propan-2-ol (15-hydroxy-5-methoxy-
COMMUNICATIONS
crinipellin-9-one 34x): m.p. 108-109°C; [α] 23
D :
+103.3° (c 0.9, CHCl3); IR (KBr): 3507 (OH), 2976,
2956, 2918, 2876, 1715 (C=O), 1475, 1450, 1410,
1375, 1259, 1193, 1153, 1103, 1092, 951, 933, 844,
826, 606 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.693.60 (1 H, m, H-5'), 3.28 (3 H, s, OCH3), 2.75 (1 H, d,
J 17.8 Hz, H-10A), 2.30-1.40 (14 H, m), 1.33 (3 H, s),
1.23 (3 H, s), 1.20 (3 H, s) and 1.13 (3 H, s) [4 × tertCH3], 0.96 (3 H, d, J 7.1 Hz, sec-CH3); 13C NMR (100
MHz, CDCl3): δ 226.0 (C, C=O), 83.7 (CH, C-5'),
73.1 (C, C-OH), 65.5 (C, C-8'), 60.9 (C, C-1'), 57.7
(CH3, OCH3), 57.3 (CH, C-12'), 53.9 (CH, C-7'), 52.6
(CH2, C-10'), 49.7 (C, C-11'), 46.4 (CH, C-3'), 40.2
(CH, C-4'), 36.1 (CH2), 34.7 (CH2), 33.3 (CH2), 31.2
(CH3) and 30.0 (CH3) [2 × tert-CH3], 24.7 (CH2, C13'), 18.7 (CH3) and 17.5 (CH3) [2 × tert-CH3], 11.1
(CH3, sec-CH3); HRMS: m/z Calcd for C21H34O3Na
(M+Na): 357.2406; Found: 357.2400.
2-[(1S,3R,4R,5S,7R,8S,11S,12S)-5-Methoxy-4,8,
11-trimethyl-9-oxotetracyclo[6.6.0.01,11.03,7]tetradec-12-yl]propan-2-ol (34n): m.p. 79-80°C; [α] 24
D :
+15.0° (c 1.0, CHCl3); IR (KBr): 3464 (OH), 2982,
2960, 2888, 1714 (C=O), 1460, 1377, 1261, 1213,
1170, 1108, 1094, 945 cm-1; 1H NMR (400 MHz,
CDCl3): δ 3.61 (1 H, td, J 6.8 and 5.6 Hz, H-5'), 3.28
(3 H, s, OCH3), 3.20 (1 H, d, J 17.0 Hz, H-10A), 2.49
(1 H, q, J 8.5 Hz), 2.30-2.10 (2 H, m), 2.10 (1 H, d, J
17.0 Hz, H-10B), 2.00-1.40 (10 H, m), 1.34 (3 H, s),
1.26 (3 H, s), 1.24 (3 H, s) and 1.02 (3 H, s) [4 × tertCH3], 0.95 (3 H, d, J 6.5 Hz, sec-CH3); 13C NMR (100
MHz, CDCl3): δ 224.0 (C, C=O), 85.0 (CH, C-5'),
72.7 (C, C-OH), 65.1 (C, C-8'), 59.2 (CH, C-12), 59.1
(C, C-1'), 57.5 (CH3, OCH3), 50.4 (CH, C-7'), 47.0 (C,
C-11'), 46.9 (CH2, C-10'), 46.6 (CH, C-3'), 39.5 (CH,
C-4'), 38.2 (CH2), 35.0 (CH2), 32.7 (CH2), 31.6 (CH3),
30.5 (CH3) and 27.4 (CH3) [3 × tert-CH3], 27.1 (CH2,
C-13'), 16.8 (CH3, tert-CH3), 10.8 (CH3, sec-CH3);
HRMS: m/z Calcd for C21H34O3Na (M+Na):
357.2406; Found: 357.2399.
485
Acknowledgement
The authors thank the Council of Scientific and
Industrial Research, New Delhi for the award of a
research fellowship to VG. The authors are grateful to
M/s Organica Aromatics (Bangalore) Pvt. Ltd. for the
generous gift of campholenaldehyde.
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