LETTER
2343
Rhodium Carbenoid Mediated C–H Activation of a Tertiary Methyl Group:
An Enantiospecific Approach to the Angular Triquinanes Norsilphiperfolane
and Norcameroonanes
Ap roachtotheAngular TriquSrikrishna,*
A.
ina esNorsilphiperfolaneandNorcamero nanes
Vishal M. Sheth, Gopalasetty Nagaraju
Abstract: An enantiospecific synthesis of the angular triquinane
system present in the sesquiterpenes cameroonanes and silphiperfolanes has been accomplished, starting from 5-isopropenyl-2methylcyclopent-1-ene-1-methanol [readily available in three steps
from (R)-limonene] employing an intramolecular rhodium carbenoid insertion into the C–H bond of a tertiary methyl group for the
construction of the triquinane system.
Key words: angular triquinanes, silphiperfolane, cameroonane,
enantiospecific synthesis, rhodium carbenoid C–H insertion
tertiary methyl group for the construction of the angular
triquinanes. With this background, in continuation of our
interest in the chiral-pool-based enantiospecific synthesis
of natural products starting from the readily available
monoterpene (R)-limonene,5 herein we report an intramolecular rhodium carbenoid C–H-insertion-based approach
for the construction of the angular triquinanes norcameroonane and norsilphiperfolanes.
8
10
The polyquinane natural products have aroused a great
deal of interest among synthetic chemists in the last three
decades. In particular, triquinane sesquiterpenes have
triggered the activity and provided the thrust for the development of new strategies for cyclopentannulations.1 The
sesquiterpene natural products containing an angular
triquinane moiety 1, isolated so far, fall into five different
skeletal types 2–6 on the basis of the arrangement of the
four carbon substituents on the tricyclo[6.3.0.01,5]undecane (1, Figure 1).1 In addition, di- and sesterterpene natural products, like laurenene, crinipellenes, and
retigeranic acid also incorporate an angular triquinane
unit in their core structures. Among the angular triquinane
sesquiterpenes
2–6,
silphiperfolane2
(5)
and
3
cameroonane (6) are very closely related (by a 1,2-methyl migration). Cameroonane (6) is the latest angular
triquinane sesquiterpene group to be isolated from the
nature,3 and it is postulated to be an intermediate in the
biogenetic formation3 of silphiperfolane from presilphiperfolane.
The main challenge in the synthesis of angular triquinanes
is the stereocontrolled construction of the tricyclic system
1. In general, functionalisation of a methyl group, in particular a methyl located on a quaternary carbon atom, is
difficult in a synthetically useful manner. Since the rhodium carbenoids, derived from the corresponding diazoketones, are known to insert into a suitably oriented C–H
bond of a g-carbon atom (Equation 1) leading to cyclopentanones,4 it was contemplated to explore the suitability
of the regiochemical rhodium carbenoid insertion into a
SYNLETT 2011, No. 16, pp 2343–2346xx. 201
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260308; Art ID: D19311ST
© Georg Thieme Verlag Stuttgart · New York
5
1
3
1
isocomane (2)
pentalenane (3)
silphinane (4)
silphiperfolane (5)
cameroonane (6)
Figure 1
H
α
H
H
γ H
β
H
H
'Rh'
O
H
O
Equation 1
It was conceived (Scheme 1) that the angular triquinane 7
could be generated via the insertion of the rhodium carbenoid derived from the diazoketone 8 into a g-C–H bond.
Since the diazoketone moiety in 8 is exo-oriented (to the
diquinane system), only two g-C–H positions (C-4 methylene and methyl on the C-1 carbon) are geometrically accessible for the insertion reaction. Of the two, the
secondary C–H of C-4 methylene would lead to a strained
bridged system {bicyclo[2.2.1]heptane} and is hence less
preferred, whereas the primary C–H of the methyl group
at the ring junction would lead to the angular triquinane 7,
which could be further transformed into norcameroonane
and norsilphiperfolane. It was readily identified that the
diazoketone 8 could be obtained by modification of the
isopropenyl group present in the diquinane 9, whose syn-
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Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)3600683; E-mail: askiisc@gmail.com
Received 21 June 2011
Dedicated to Professor Vishwakarma Singh on the occasion of his 60th birthday
LETTER
A. Srikrishna et al.
thesis from limonene 10 via the ester 11 and the allyl alcohol 12 has already been developed by us5c en route to
the sesquiterpene cucumin-H.
OH
γ
norcameroonane
norsilphiperfolane
X
γ
O
O
7
O
9
12
O
11
O
O
d
e
c
X
H
85%
OH
b
67%
COOEt
10
11
γ
8
N2
OEt
80%
12
10
X
H
O
a
15
13 R = OH
14 R = CHN2
92%
9
Scheme 1
O
f
O
86%
O
O
O
The synthetic sequence is depicted in Scheme 2. The synthesis of the diquinane 9 was carried out employing the
methodology reported earlier by us.5c,j The requisite allyl
alcohol 12 was obtained from (R)-limonene 10 in three
steps viz. controlled ozonolysis, intramolecular aldol condensation, and Luche reduction.5a Johnson’s orthoester
Claisen rearrangement6 of the cyclopentenylmethanol 12
with triethyl orthoacetate in the presence of a catalytic
amount of propionic acid furnished the ester 11 creating
the first quaternary carbon atom in a highly stereoselective manner. An anhydrous copper sulfate–copper catalysed intramolecular diazoketone cyclopropanation7 of the
diazoketone 14, derived from the acid 13, generated the
tricyclic ketone 15 in a regio- and stereospecific manner,
which on regiospecific cyclopropane ring cleavage8 with
lithium in liquid ammonia furnished the key intermediate
of the sequence, the diquinane 9. To avoid regiochemical
problems at a later stage, the ketone in the diquinane 9 was
protected by reacting with ethylene glycol and a catalytic
amount of p-toluenesulfonic acid (PTSA) in refluxing
benzene under Dean–Stark conditions to furnish the ketal
16 in 92% yield. Ozonolytic cleavage of the olefin of the
isopropenyl group in 16 followed by reductive workup
with dimethyl sulfide furnished the ketone 17 in 86%
yield.9 For efficient generation of a diazoketone, the
acetyl group in 17 was transformed into a b-keto ester by
reacting with lithium hexamethyldisilazide and ethyl
chloroformate to furnish the b-keto ester 18 in 88% yield.
A diazo transfer reaction was carried on the b-keto ester
18 with p-toluenesulfonyl azide and triethylamine to furnish the precursor for the key reaction, the a-diazo-b-keto
ester9 19 in 84% yield.
Treatment of the a-diazo-b-keto ester 19 with a catalytic
amount of rhodium acetate in refluxing CH2Cl2 for two
hours furnished an epimeric mixture of the triquinane 20
in 87% yield in a highly regioselective manner. Krapcho’s
dealkoxycarbonylation10 of the b-keto ester 20 with
DMSO, lithium chloride, and water, followed by acidic
workup furnished the triquinane dione9 21 in 82% yield.
Synlett 2011, No. 16, 2343–2346
© Thieme Stuttgart · New York
16
17
g
88%
O
O
i
O
H
O
87%
O
O
X
COOEt
EtOOC
18 X = H, H
20
j
h 84%
82%
19 X = N2
k
O
71%
H
O
21
H
22
Scheme 2 Reagents and conditions: (a) MeC(OEt)3, EtCO2H (cat.),
sealed tube, 180 °C, 48 h; (b) i. 5% NaOH, H2O, MeOH, reflux, 8 h;
ii. (COCl)2, C6H6, r.t., 3 h; iii. CH2N2, Et2O, 0 °C, 2 h; (c) Cu, anhyd
CuSO4, W lamp, c-C6H12, reflux, 4 h; (d) Li, liq. NH3, THF, –33 °C,
0.25 h; (e) (CH2OH)2, PTSA, C6H6, reflux (Dean–Stark), 2 h; (f) O3/
O2, CH2Cl2–MeOH (4:1), –70 °C; Me2S, r.t., 4 h; (g) LiHMDS, THF,
–70 °C; ClCO2Et, r.t., 6 h; (h) TsN3, Et3N, MeCN, r.t., 2 h; (i)
Rh2(OAc)4, CH2Cl2, reflux, 2 h; (j) LiCl, DMSO, H2O, sealed tube,
180 °C, 1.5 h, (acidic workup); (k) t-AmOK, Ph3P+MeBr–, THF, r.t.,
4 h.
The structure of the dione 21 was established from its
spectral data. Presence of a strong carbonyl absorption
band at 1736 cm–1 due to cyclopentanones in the IR spectrum and the presence of only one methyl singlet at d =
1.14 ppm in the 1H NMR spectrum revealed the structure
of the triquinane 21. Presence of four quaternary carbon
resonances at d = 220.7, 217.0, 57.3 and 50.2 ppm (of
which, two are due to typical cyclopentanone ketone carbons), one methine resonance at d = 58.7 ppm and in particular only one methyl resonance at d = 21.5 ppm in
addition to the six methylene resonances in the 13C NMR
spectrum confirmed the structure of the angular triquinane
dione 21. Finally, double Wittig reaction of the dione 21
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2344
Approach to the Angular Triquinanes Norsilphiperfolane and Norcameroonanes
with an excess of methyltriphenylphosphonium bromide
and potassium tert-amyloxide in anhydrous THF furnished the diene 22, in 71% yield, whose structure was established from its spectroscopic data.9 The diene 22
represents both a norsilphiperfolane and a norcameroonane.
In conclusion, we have developed an enantiospecific approach to the angular triquinane system of silphiperfolane
and cameroonanes employing the diquinane 9, obtained
from the monoterpene (R)-limonene 10, as the key intermediate. The key reaction is the highly regioselective insertion of a rhodium carbenoid into the C–H bond of a
tertiary methyl group at the ring-junction position of a
diquinane for the generation of the angular triquinane system. Extension of the strategy for the enantiospecific synthesis of silphiperfol-6-ene and other cyclopentanoid
natural products is in progress.
(6)
(7)
(8)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the CSIR, New Delhi for the award of a research fellowship to GN.
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Yields refer to isolated and chromatographically pure
compounds. All the compounds exhibited spectroscopic data
(IR, 1H and 13C NMR, and HRMS) consistent with their
structures.
Selected Spectral Data
1-{(1S,2R,5S)-1,5-Dimethylbicyclo[3.3.0]octanespiro[7.2¢]-1,3-dioxolan-2-yl}ethanone (17)
[a]D22 –69.6 (c 2.1, CHCl3). IR (neat): nmax = 2959, 2879,
1708 (C=O), 1452, 1354, 1331, 1238, 1161, 1114, 1091,
1070, 1040, 1019, 946, 894, 820, 727 cm–1. 1H NMR (400
MHz, CDCl3): d = 3.95–3.65 (4 H, m, OCH2CH2O), 3.15 (1
H, dd, J = 9.2, 8.0 Hz), 2.24 (1 H, d, J = 14.4 Hz), 2.09 (3 H,
s, CH3C=O), 2.10–1.45 (7 H, m), 0.94 (3 H, s), 0.74 (3 H, s,
2 × tert-CH3). 13C NMR (100 MHz, CDCl3): d = 209.9 (C,
C=O), 116.3 (C, C-7), 64.0 (CH2), 63.7 (CH2) [OCH2CH2O],
61.0 (CH, C-2), 52.1 (C), 51.4 (C), 50.7 (CH2), 49.6 (CH2,
C-4), 37.8 (CH2), 31.3 (CH3, CH3C=O), 24.4 (CH2, C-3),
23.4 (CH3), 18.5 (CH3). HRMS: m/z calcd for C14H22O3Na
[M + Na]: 261.1467; found: 261.1465.
Ethyl 2-Diazo-3-{(1S,2R,5S)-1,5-dimethylbicyclo[3.3.0]octane-spiro[7.2¢]-1,3-dioxolan-2-yl}-3oxopropanoate (19)
[a]D25 –50.9 (c 3.0, CHCl3). IR (neat): nmax = 2960, 2878,
2136 (N=N), 1715 (OC=O), 1652 (C=O), 1470, 1455, 1378,
1334, 1301, 1206, 1116, 1092, 1043, 1020 cm–1. 1H NMR
(400 MHz, CDCl3): d = 4.29 (2 H, q, J = 7.1 Hz, OCH2CH3),
4.02 (1 H, dd, J = 7.8, 7.1 Hz), 3.95–3.75 (4 H, m,
OCH2CH2O), 2.21 (1 H, d, J = 14.2 Hz), 2.15–2.06 (1 H, m),
1.98 (1 H, d, J = 14.1 Hz), 1.92 (1 H, d, J = 14.9 Hz), 1.90–
1.66 (4 H, m), 1.32 (3 H, t, J = 7.1 Hz, OCH2CH3), 1.01 (3
H, s), 0.91 (3 H, s, 2 × tert-CH3). 13C NMR (100 MHz,
CDCl3): d = 195.0 (C, C=O), 161.3 (C, OC=O), 116.4 (C,
OCO), 64.1 (C, C=N2), 64.0 (CH2), 63.8 (CH2, OCH2CH2O],
61.2 (CH2, OCH2CH3), 56.4 (CH), 53.6 (C), 52.3 (CH2),
51.2 (C), 49.9 (CH2), 39.9 (CH2), 26.7 (CH2), 23.1 (CH3),
19.9 (CH3), 14.4 (CH3, OCH2CH3). HRMS: m/z calcd for
C17H24N2O5Na [M + Na]: 359.1583; found: 359.1579
(1S,5R,8S)-8-Methyltricyclo[6.3.0.01,5]undecane-4,10dione (21)
mp 147–149 °C; [a]D22 +62.6 (c 2.5, CHCl3). IR (neat):
nmax = 2961, 2875, 1736 (C=O), 1405, 1272, 1227, 1178,
Synlett 2011, No. 16, 2343–2346
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LETTER
2346
LETTER
A. Srikrishna et al.
(400 MHz, CDCl3): d = 4.82 (1 H, s), 4.76 (1 H, s), 4.75 (1
H, s), 4.72 (1 H, s, 2 × C=CH2), 2.51 (1 H, d, J = 8.8 Hz),
2.40 (1 H, d, J = 15.4 Hz), 2.37–2.29 (2 H, m), 2.25 and 2.18
(2 H, 2 × d, J = 16.4 Hz), 2.10–1.88 (1 H, m), 1.68 (1 H, td,
J = 12.4, 8.4 Hz), 1.65–1.35 (5 H, m), 1.00 (3 H, s, tert CH3).
13
C NMR (100 MHz, CDCl3): d = 159.0 (C, C-4), 151.4 (C,
C-10), 105.1 (CH2), 104.4 (CH2, 2 × C=CH2), 62.9 (C, C-1),
56.2 (CH, C-5), 51.3 (C, C-8), 47.5 (CH2), 46.2 (CH2), 39.9
(CH2), 35.2 (CH2), 33.5 (CH2), 31.6 (CH2), 23.3 (CH3).
HRMS: m/z calcd for C14H20Na [M + Na]: 211.1463; found:
211.1475.
(10) Krapcho, A. P. Synthesis 1982, 893.
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735 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.61 (1 H, d, J =
18.7 Hz), 2.50–2.27 (4 H, m), 2.24 (2 H, s), 2.20–1.95 (2 H,
m), 1.94–1.55 (4 H, m), 1.14 (3 H, s, tert CH3). 13C NMR
(100 MHz, CDCl3 + CCl4): 220.7 (C, C=O), 217.0 (C, C=O),
58.7 (CH, C-5), 57.3 (C, C-1), 51.2 (CH2), 50.2 (C, C-8),
50.1 (CH2), 39.8 (CH2), 37.7 (CH2), 29.2 (CH2), 26.7 (CH2),
21.5 (CH3, tert CH3). HRMS: m/z calcd for C12H16O2Na [M
+ Na]: 215.1060; found: 215.1048
(1S,5S,8S)-4,10-Bismethylene-8-methyltricyclo[6.3.0.01,5]dodecane (22)
[a]D24 –35.7 (c 1.0, CHCl3). IR (neat): nmax = 3072, 2947,
2862, 1654, 1464, 1456, 1375, 1210, 879 cm–1. 1H NMR
Synlett 2011, No. 16, 2343–2346
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