Indian Journal of Chemistry
Vol. 50B, January 2011, pp. 73-76
Rapid Communication
Enantiospecific approach to AB-ring system
of the diterpenes fusicoccanes
A Srikrishna* & Gopalasetty Nagaraju
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
E-mail: ask@orgchem.iisc.ernet.in
Received 30 September 2010
Enantiospecific synthesis of the AB ring system of 5-8-5
tricyclic diterpenes fusicoccanes has been accomplished, starting
from the readily available monoterpene (R)-limonene employing
an RCM reaction as the key step.
Keywords: Fusicoccanes, ophiobolins, limonene, bicyclo[6.3.0]undecanes, RCM reaction
Interest in the synthesis of cyclooctanoid compounds
remained low until the past two decades, perhaps due
to the fact that unfavorable entropic and enthalpic
factors coupled with the possibility of transannular
reactions, precluded the adaptation of traditional
methods of ring annulations for their construction1. In
the past two decades, the number of carbocyclic
skeletons in which a cyclooctane forms a part of the
polycyclic system have proliferated rapidly. The
cyclooctane bearing carbon skeletons have now been
located among lignans, sesqui-, di-, sester-, and
triterpenes. Presently, well over 100 natural products
constitute the structurally diverse and interesting
family of cyclooctanoid natural products. Fusicoccane
diterpenoids and ophiobolin sesterterpenes share a
common 5-8-5 tricyclic ring system (1,4,8trimethyltricyclo[9.3.0.03,7]tetradecane 1, with either
an isopropyl or a 6-methylhept-2-yl moiety at the C12 carbon). Members of the fusicoccane family have
been isolated from a variety of sources ranging from
liverworts, fungi and plants2,3. Some of the
representative examples are depicted in Chart I. A
number of synthetic approaches including a few total
syntheses to fusicoccanes have been reported in the
literature4. Recently, research groups of Wicha and
Patrick described their efforts towards the synthesis of
AB-ring system of fusicoccanes4.
The presence of an interesting cyclooctanoid
framework coupled with the identification of the cis
orientation of the C-1 methyl and C-12 isopropyl
groups prompted us to investigate new strategies to
fusicoccanes. In continuation of our interest in the
chiral pool based enantiospecific synthesis of natural
products starting from the readily available monoterpene (R)-limonene5, herein we report a ring-closing
metathesis6 (RCM) based approach to the AB-ring
system of fusicoccanes and ophiobolins.
It was contemplated that a RCM reaction based
cyclooctannulation of the cyclopentylacetate 2, via the
diene 3, would lead to the AB ring system of fusicoccanes 4, which also contains the C-1 methyl and the
isopropyl groups cis to each other, Scheme I. Synthesis
of the cyclopentylacetate 2 from the readily and
abundantly available monoterpene limonene 5 has
already been well established7 via the Johnson’s orthoester Claisen rearrangement of the allyl alcohol 6.
The synthetic sequence for the construction of the
AB ring system of fusicoccanes is depicted in
Scheme II. To begin with (R)-limonene 5 has been
converted into the allyl alcohol 6 by a four step
sequence, namely Wilkinson catalyst mediated
regioselective hydrogenation of the isopropenyl
group; ozonolytic cleavage of the cyclohexene
moiety; intramolecular aldol condensation of the
resultant keto aldehyde 7; followed by reduction of
the cyclopentenealdehyde with sodium borohydride in
methanol. Johnson’s orthoester Claisen rearrangement8 of the allyl alcohol 6 with triethyl orthoacetate
and a catalytic amount of propionic acid in a sealed
tube at 180ºC furnished the ester 2. For the conversion
of the ester 2 into the diene system 3, it was
contemplated that cleavage of the exomethylene,
conversion of the ester to the corresponding aldehyde
and nucleophilic addition of two allyl groups to the
resultant keto aldehyde 8 was appropriate. Thus,
reduction of the ester 2 with lithium aluminum
hydride (LAH) in ether furnished the alcohol 9 in
quantitative yield. Ozonolytic cleavage of the
exomethylene moiety in the alcohol 9 followed by
reductive work-up with dimethyl sulfide generated the
hydroxy ketone 10, which on oxidation with
pyridinium dichromate (PDC) in methylene chloride
at RT furnished the keto aldehyde 8 in 67% overall
yield. Grignard reaction of the keto aldehyde 8 with
an excess of allylmagnesium chloride in dry THF
furnished a diastereomeric mixture of the diol 11 in
INDIAN J. CHEM., SEC B, JANUARY 2011
74
MeO
O
HO
HO
O
OH
H
AcO
H
glu O
H
Fusicoccin
Anadensin
Fusicoauritone
HO
OH
H
H
OH
O
O
H
CHO
H
H
O
HO
H
O
H
CHO
H
H
Periconicin A
Fusicogigantone B
Ophiobolin B
Chart I
C
A
B
fusicoccanes 1
A
B
4
RCM
3
COOEt
OH
5
6
of the secondary alcohol 16 with IBX in DMSO
furnished the ketone 17 in 90%, whose structure was
established from its spectral data. The ketone 17
represents the AB-ring system of the fusicoccanes and
ophiobolins.
In conclusion, we have developed an enantiospecific approach to the AB-ring system of the 5-8-5
tricyclic diterpenes fusicoccanes, starting from the
readily available monoterpene (R)-limonene employing an RCM reaction as the key step. Further
extension of the strategy for the synthesis of
fusicoccanes is currently under progress.
2
Scheme I
57% yield9. The stereochemistry at the tertiary alcohol
was assigned on the basis of the preferred approach of
the Grignard reagent from the less hindered face of
the molecule, i.e. opposite to the isopropyl group. As
the RCM reaction7 of the diol 11 was found to be
inefficient, the alcohols were protected. Thus,
treatment of the diol 11 with acetic anhydride in
pyridine in the presence of a catalytic amount of 4N,N-dimethylaminopyridine (DMAP) furnished the
monoacetate 12. The hydroxyacetate 12 on treatment
with methoxymethyl (MOM) chloride, ethyldiisopropylamine and a catalytic amount of DMAP in
methylene chloride furnished the MOM ether 13 in
90% yield. As the RCM reaction of the diene 13 with
Grubbs' first generation catalyst was inefficient, it was
carried out with the second generation catalyst 14.
Thus, treatment of a 0.01 M methylene chloride
solution of the diastereomeric mixture of the diene 13
with 5 mol% of the catalyst 14 at RT furnished the
bicyclic compound 15 in near quantitative yield.
Hydrolysis of the acetate 15 with potassium carbonate
in methanol at RT furnished the alcohol 16. Oxidation
Experimental Section
1-[(1S,2R,3S)-2-Allyl-2-methoxymethoxy-3-isopropyl-1-methylcyclopentyl]pent-4-en-2-yl acetate
13. [α] 26
D : +7.0 (c 2.2, CHCl3); IR (neat): 3077, 2953,
2873, 1738 (OC=O), 1455, 1374, 1243, 1157, 1030,
917 cm-1; 1H NMR (400 MHz, CDCl3+CCl4, signals
due to the major isomer): δ 6.04-5.84 (1 H, m,
CH=CH2), 5.80-5.58 (1 H, m, CH=CH2), 5.18-4.88 (5
H, m, 2 × CH=CH2 & CH-OAc), 4.83 and 4.63 (2 H,
2 × d, J = 6.7 Hz, OCH2O), 3.38 (3 H, s, OCH3), 2.66
(1 H, dd, J = 14.6 Hz, 5.0 Hz), 2.26 (2 H, t, J = 6.4
Hz), 2.30-2.00 (1 H, m), 2.00 (3 H, s, COCH3), 1.961.12 (9 H, m), 1.08-0.82 (5 H, m), 0.9 (3 H, s,
tert.CH3); 13C NMR (100 MHz, CDCl3+CCl4, signals
due to the major isomer): δ 170.2 (C, OC=O), 135.3
(CH), 133.6 (CH), 118.1 (CH2), 117.4 (CH2), 91.9
(CH2), 89.4 (C), 71.5 (CH), 55.9 (CH3), 53.2 (CH),
49.3 (C), 41.1 (CH2), 41.0 (CH2), 40.0 (CH2), 36.5
(CH2), 28.3 (CH), 23.9 (CH2), 23.7 (CH3), 21.5 (CH3),
20.8 (CH3), 20.3 (CH3); HRMS: m/z Calcd for
C21H36O4Na (M+Na): 375.2511. Found: 375.2514.
(1S,8R,9S)-9-Isopropyl-8-(methoxymethoxy)-1methylbicyclo[6.3.0]undec-5-en-3-yl acetate 15.
[α] 26
D : +29.3 (c 2.9, CHCl3); IR (neat): 3028, 2955,
2875, 2822, 1734 (OC=O), 1465, 1376, 1317, 1247,
1151, 1088, 1025, 950, 918, 808, 761 cm-1; 1H NMR
(400 MHz, CDCl3+CCl4, signals due to the major
isomer): δ 5.96-5.54 (2 H, m, olefinic), 5.00-4.78 (1
H, m, CH-OAc), 4.97 and 4.60 (2 H, 2 × d, J = 7.4
Hz, OCH2O), 3.36 (3H, s, OCH3), 2.91 (1 H, dd, J =
13.1 and 9.0 Hz), 2.60-2.40 (2 H, m), 2.35-2.20 (1H,
m), 2.00 (3 H, s, COCH3), 2.1-1.22 (8 H, m), 1.06 (3
H, s, tert.CH3), 1.05 (3 H, d, J = 6.3 Hz) and 0.89 (3
H, d, J = 6.2 Hz) [CH(CH3)2]; 13C NMR (100 MHz,
CDCl3+CCl4, signals due to the major isomer): δ
169.7 (C, OC=O), 130.8 (CH), 126.9 (CH), 91.9
(CH2, O-CH2-O), 90.5 (C, C-8), 74.1 (CH, C-3), 55.7
COMMUNICATIONS
COOEt
O
a,b
85%
75
c,d
e
OH
CHO 63%
96%
2
6
7
5
f
99%
CHO
OH
h
O
O
95%
8
OH
g
70%
9
10
i 57%
OAc
OAc
OH
k
j
91%
90%
OMOM
OH
OH
11
13
12
96%
O
OR
N
m,n
17
N
Cl Ru
Ph
Cl PCy3
89%
OMOM
l
OMOM
14
15. R = Ac
16. R = H
Scheme II — Reagents and Conditions: (a) H2 (1 atm), (Ph3P)3RhCl, MeOH, RT, 48 hr; (b) O3/O2, CH2Cl2-MeOH (4:1), NaHCO3, –
70°C; Me2S, RT, 4 hr; (c) piperidine, AcOH, C6H6, reflux, 1 hr; (d) NaBH4, MeOH, 0°C, 20 min; (e) CH3C(OEt)3, EtCOOH, sealed tube,
180°C, 48 hr; (f) LiAlH4, Et2O, 0°C, 1 hr; (g) O3/O2, CH2Cl2-MeOH (4:1), NaHCO3, –70°C; Me2S, RT, 4 hr; (h) PDC, CH2Cl2, RT, 3 hr;
(i) CH2=CHCH2MgCl, RT, THF, 1 hr; (j) Ac2O, py, DMAP, RT, 3 hr; (k) MOMCl, iPr2NEt, CH2Cl2, DMAP, RT, 48 hr; (l) 14 (5 mol%),
CH2Cl2, RT, 8 hr; (m) K2CO3, MeOH, RT, 6 hr; (n) IBX, DMSO, RT, 2.5 hr.
(CH3, OCH3), 52.2 (C), 50.4 (CH), 42.0 (CH2), 40.9
(CH2), 31.2 (CH2), 29.2 (CH), 28.9 (CH2), 25.2 (CH2),
22.6 (CH3), 22.0 (CH3), 21.4 (CH3), 21.3 (CH3);
HRMS: m/z Calcd for C19H32O4Na (M+Na):
347.2198. Found: 347.2198.
(1S,8R,9S)-9-Isopropyl-8-(methoxymethoxy)-1methylbicyclo[6.3.0]undec-5-en-3-ol 16.
[α] 25
D :
+17.5 (c 4.5, CHCl3); IR (neat): 3402 (OH), 3024,
2952, 2874, 2822, 1470, 1464, 1382, 1316, 1216,
1150, 1087, 1031, 920, 758 cm-1; 1H NMR (400 MHz,
CDCl3+CCl4, signals due to the major isomer): δ 5.765.56 (2 H, m, CH=CH), 4.98 and 4.60 (2 H, 2 × d, J =
7.3 Hz, OCH2O), 3.95-3.78 (1 H, m, CH-OH), 3.37 (3
H, s, OCH3), 2.92 (1 H, dd, J = 12.8 and 8.3 Hz),
2.75-2.18 (3 H, m), 2.12-1.10 (9 H, m), 1.09 (3 H, s,
tert. CH3), 1.04 (3 H, d, J = 6.5 Hz) and 0.89 (3 H, d,
J = 6.2 Hz) [CH(CH3)2]; 13C NMR (100 MHz,
CDCl3+CCl4, signals due to the major isomer): δ
130.1 (CH), 127.7 (CH), 91.9 (CH2, OCH2O), 90.3
(C, C-OMOM), 72.0 (CH, C-3), 55.7 (CH3. OCH3),
51.9 (C, C-1), 51.0 (CH), 46.5 (CH2), 40.6 (CH2), 35.2
(CH2), 31.5 (CH2), 29.2 (CH), 25.5 (CH2), 24.2 (CH3),
22.8 (CH3), 21.9 (CH3); HRMS: m/z Calcd for
C17H30O3Na (M+Na): 305.2093. Found: 305.2106.
(1S,8R,9S)-9-Isopropyl-8-methoxymethoxy-1methylbicyclo[6.3.0]undec-5-en-3-one 17.
[α] 24
D :
+67.0 (c 1.4, CHCl3); IR (neat): 3033, 2954, 2875,
1698 (C=O), 1465, 1380, 1311, 1223, 1176, 1148,
1088, 1029, 918, 755 cm-1; 1H NMR (400 MHz,
CDCl3+CCl4): δ 6.06-5.85 (1 H, m) and 5.76-5.56 (1
H, m) [CH=CH], 4.81 and 4.50 (2 H, 2 × d, J = 7.7
Hz, OCH2O), 3.33 (3 H, s, OCH3), 3.07 (1 H, d, J =
76
INDIAN J. CHEM., SEC B, JANUARY 2011
19.1 Hz), 2.95-2.84 (2 H, m), 2.66 (1 H, dd, J = 14.0
and 7.8 Hz) and 2.38 (1 H, dd, J = 14.0 and 9.8 Hz)
[H-7], 2.12-1.18 (7 H, m), 1.03 (3 H, s, tert. CH3),
1.08 and 0.95 (6 H, 2 × d, J = 6.6 Hz, CH(CH3)2); 13C
NMR (100 MHz, CDCl3+CCl4): δ 210.6 (C, C=O),
130.9 (CH) and 124.5 (CH) [CH=CH], 92.0 (CH2, OCH2-O), 89.8 (C, C-8), 55.6 (CH3, OCH3), 52.7 (C),
50.2 (CH2), 50.0 (CH), 44.0 (CH2), 40.1 (CH2), 29.5
(CH2), 28.9 (CH), 25.1 (CH2), 22.1 (CH3), 22.0 (CH3),
21.2 (CH3); HRMS: m/z Calcd for C17H28O3Na
(M+Na): 303.1936. Found: 303.1934.
4
5
Acknowledgement
The authors thank the Council of Scientific and
Industrial Research, New Delhi for the award of a
research fellowship to GN.
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In addition varying amount (10-20%) of easily separable
another isomer of the diol 11, perhaps epimeric at the tertiary
alcohol, was also obtained.