A rapid enantiospecific synthesis of the (6,6,5)-tricyclic ring system of the elisabethane diterpenes

Article abstract of DOI:10.1016/j.tetlet.2007.04.005

A rapid enantiospecific stereoselective synthesis of the 6,6,5-ring system of the novel tricyclic elisabethin diterpenes, starting from (R)-carvone, employing a ROM-RCM sequence as the key step, has been accomplished.

Full text of DOI:10.1016/j.tetlet.2007.04.005

Tetrahedron Letters 48 (2007) 4087–4090
A rapid enantiospecific synthesis of the (6,6,5)-tricyclic ring
system of the elisabethane diterpenes
A. Srikrishna,* Vijendra H. Pardeshi and G. Satyanarayana
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 27 February 2007; revised 27 March 2007; accepted 4 April 2007
Available online 11 April 2007
Abstract—A rapid enantiospecific stereoselective synthesis of the 6,6,5-ring system of the novel tricyclic elisabethin diterpenes, start-
ing from (R)-carvone, employing a ROM-RCM sequence as the key step, has been accomplished.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Gorgonian corals have attracted considerable attention
as a result of their wealth of bioactive secondary metab-
olites.1 Specifically, the West Indian sea whip Pseudo-
pterogorgia elisabethae, collected in deep waters near
San Andreas Island (Colombia), has been a goldmine
for novel diterpenoids with unusual carbon-skeleton
architectures. The structural variety found among the
many terpenoid natural products isolated from P. elis-
abethae, as well as the ample spectrum of biological
activities exhibited by many of these compounds, is
indeed quite remarkable. Rodriguez and co-workers
have reported the isolation of a series of structurally
related novel metabolites, elisabethins, colombiasins,
cumbiasins and elisapterosins, for example 1–4, from
P. elisabethae, collected from the waters near San
Andreas Island, Colombia.2 Many members of this
super family display anti-inflammatory, anticancer and
antitubercular activities, and/or general antibacterial
properties. Elisabethanes stand out among these diter-
penoids for their interesting anti-inflammatory, anti-
bacterial, analgesic and cytotoxic activities. The more
intricate members of the family, elisapterosins, cumbai-
sins and colombiasins, were suggested to be biosynthe-
sized from elisabethin A, which in turn arises from
geranylgeranyl pyrophosphate via a serrulatane precur-
sor. It was also shown that colombiasin A 4 readily
isomerises to elisapterosin B 2.
The 6,6,5-ring system (tricyclo[7.4.0.01,5]tridecane) of
elisabethin A 1 embodies a fully substituted enedione
functionality and six contiguous stereogenic centres, of
which one, at the junction of the three rings, is quater-
nary. The structural complexity and interesting biologi-
cal activity has made these terpenes interesting and
novel targets for chemical synthesis.3,4 To date, only
two research groups have tackled the total synthesis of
elisabethin A 1 with limited success.4 In continuation
of our interest in the enantiospecific synthesis of polycy-
clic sesquiterpenes and diterpenoids from the readily
and abundantly available monoterpene (R)-carvone,5
herein we report a rapid and efficient enantiospecific ap-
proach to the 6,6,5-tricyclic ring system (comprising the
C 1–9 and C 14–19 carbons of elisabethanes) of the elis-
abethin diterpenoids, which is also present as part of the
H
H
H
H
Me
OH
H
Me
H
O
Me
Me
H
H
O
H
O
O
O
O
O
O
OH
Me
Me
Me
OH
Me
OH
Me
OH
Elisabethin A (1)
Elisapterosin B (2)
cumbiasin A (3)
Colombiasin A (4)
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.005

4088
A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 4087–4090
19
8
5
2
6
7
4
3
O
1
9
18
14
15
17
16
10
11
O
12
13
20
(
R
)-carvone (5)
6
Elisabethane
Scheme 1.
structure of the tetracyclic diterpenes colombiasins,
cumbiasins and elisapterosins, employing a ROM-
RCM reaction as the key step.
Thus, kinetic allylation of carvone 5 with lithium diiso-
propylamide and allyl bromide7 generated a 1:5 cis–
trans mixture of 6-allylcarvone 8 in 95% yield, which
on second allylation using the same conditions furnished
6,6-bisallylcarvone 7 in 87% yield. An alkylative 1,3-en-
one transposition8 was adopted for the introduction of
the third allyl group. Thus, sonochemically accelerated
Barbier reaction with zinc and allyl bromide trans-
formed bisallylcarvone 7 into trisallylcarveol 9 in quan-
titative yield, which on oxidation with pyridinium
Carvone 5 was identified as the A-ring precursor of elis-
abethins, Scheme 1. Initially two simultaneous RCM
reactions6 in a single step were contemplated for the
construction of the B- and C-rings, and pentaenone 6
was identified as a suitable precursor, which could be
obtained from carvone 5 via 6,6-bisallylcarvone 7.
a
a
b
H
100%
95%
87%
OH
O
O
O
5
8
7
9
c
d
79%
40%
H
O
O
H
X
OH
6
10
Scheme 2. Reagents and conditions: (a) LDA, THF, ꢀ15 ꢁC, 45 min, CH2@CHCH2Br, rt, 12 h; (b) Zn, CH2@CHCH2Br, THF,))), 45 min; (c) PCC,
silica gel, CH2Cl2, rt, 24 h; (d) Cl2Ru(PCy3)2@CHPh (5 mol %), CH2Cl2, reflux, 24 h.
H
a
b
d
99%
100%
76%
OH
OH
O
O
7
10
78%
11
X
12
c
e
78%
O
H
H
O
O
14
14
13
Scheme 3. Reagents and conditions: (a) Cl2Ru(PCy3)2@CHPh (5 mol %), CH2Cl2, reflux, 4 h. (b) Zn, CH2@CHCH2Br, THF,))), 45 min; (c) PCC,
silica gel, CH2Cl2, rt, 24 h; (d) Cl2Ru(PCy3)2@CHPh (10 mol %), CH2Cl2, reflux, 12 h; (e) PCC, silica gel, CH2Cl2, rt, 1 h.

A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 4087–4090
4089
chlorochromate (PCC) and silica gel in methylene chlo-
ride furnished 3,4,4-trisallylcarvone 6 in 79% yield.
Attempted RCM reaction of trisallylcarvone 6 with
the first generation Grubbs’ catalyst, contrary to our
expectation, furnished a complex mixture. On the other
hand, RCM reaction of trisallylcarveol 9 with Grubbs’
first generation catalyst furnished the targeted tricyclic
system 10, albeit in low yield, whose structure was estab-
lished from spectral data (Scheme 2).
11 in 99% yield. Sonochemically accelerated Barbier
reaction of spiroenone 11 with zinc and allyl bromide
generated tert-alcohol 12, in quantitative yield, which
on oxidation with PCC and silica gel furnished enone
13. Although reaction of enone 13 was found to be
unsuccessful, alcohol 12 underwent a smooth ROM-
RCM reaction. Thus, refluxing a 0.01 M methylene
chloride solution of alcohol 12 and 10 mol % of the
Grubbs’ first generation catalyst for 12 h furnished the
targeted tricyclic system 10 in 76% yield. Oxidation with
PCC and silica gel transformed alcohol 10 into enone
14 in 78% yield, whose structure was established from
spectral data (Scheme 3).
It was then conceived that a two stage metathesis
sequence might control the reaction and improve the
formation of the tricyclic compound 10. Accordingly,
a ROM-RCM strategy was explored via spiroenone
11. Thus, RCM reaction of bisallylcarvone 7 with
Grubbs’ first generation catalyst furnished spiroenone
In summary, we have developed an efficient enantiospec-
ific methodology for the synthesis of the tricyclic ring
system present in the elisabethin diterpenes (which is
also present in colombiasins, cumbiasins and elisaptero-
sins), starting from the readily and abundantly available
monoterpene (R)-carvone. A ROM-RCM sequence was
employed for the simultaneous generation of the B- and
C-rings. Currently, we are investigating the extension of
the methodology for the total synthesis of the elisabe-
thin natural products and their analogues for evaluating
their biological potential.
Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
HRMS) consistent with their structures. Selected spectral data for
26
(5R)-3,4,4-trisallyl-5-isopropenyl-2-methylcyclohex-2-enone 6: ½aꢁD
+91.2 (c 2.5, CHCl3); IR (neat): mmax/cmꢀ1 1668, 1635, 1606, 912;
1H NMR (300 MHz, CDCl3+CCl4) d 5.88–5.57 (3H, m), 5.20–5.00
(6H, m), 4.93 (1H, br s), 4.85 (1H, br s), 3.20–3.00 (2H, m), 2.79 (1H,
dd, J 9.0 and 6.0 Hz), 2.65–2.30 (6H, m), 1.85 (3H, s), 1.74 (3H, s);
13C NMR (75 MHz, CDCl3+CCl4): d 197.6 (C), 157.3 (C), 145.1 (C),
135.3 (C), 135.0 (CH), 134.6 (CH), 134.3 (CH), 118.4 (CH2), 117.8
(CH2), 117.5 (CH2), 115.9 (CH2), 47.2 (CH), 46.6 (C), 42.5 (CH2),
39.7 (CH2), 39.2 (CH2), 35.7 (CH2), 23.2 (CH3), 12.1 (CH3); HRMS:
m/z calcd for C19H26ONa (M+Na): 293.1881; found, 293.1873.
Acknowledgement
25
(10R)-10-Isopropenyl-7-methylspiro[4.5]dec-2,7-dien-6-one 11: ½aꢁD
We thank the Council of Scientific and Industrial
Research, New Delhi, for the award of research fellow-
ships to V.H.P. and G.S.
ꢀ179.2 (c 1.3, CHCl3); IR (neat): mmax/cmꢀ1 1670, 895; 1H NMR
(300 MHz, CDCl3+CCl4): d 6.52 (1H, br s), 5.60 and 5.49 (2H, 2 · dt,
J 6.0 and 2.1 Hz), 4.76 (1H, s), 4.62 (1H, s), 2.90–2.25 (7H, m), 1.79
(3H, s), 1.64 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): d 200.9 (C),
146.4 (C), 140.8 (CH), 134.0 (C), 129.4 (CH), 127.0 (CH), 114.0
(CH2), 54.5 (C), 51.8 (CH), 41.8 (CH2), 37.8 (CH2), 29.0 (CH2), 22.0
(CH3), 16.9 (CH3); HRMS: m/z calcd for C14H18ONa (M+Na):
225.1255; found, 225.1257. (6S,10R)-6-Allyl-10-isopropenyl-7-meth-
References and notes
1. Rodriguez, A. D. Tetrahedron 1995, 51, 4571, and refer-
ences cited therein.
24
ylspiro[4.5]deca-2,7-dien-6-ol 12: ½aꢁD +2.96 (c 2.7, CHCl3); IR
(neat):
m
max/cmꢀ1 3573, 1633, 893; 1H NMR (300 MHz,
2. Rodriguez, A. D.; Gonzalez, E.; Huang, S. D. J. Org.
Chem. 1998, 63, 7083; Rodriguez, A. D.; Ramirez, C. Org.
Lett. 2000, 2, 507; Rodriguez, A. D.; Ramirez, C.; Rodri-
guez, I. I.; Barnes, C. L. J. Org. Chem. 2000, 65, 1390;
Rodriguez, A. D.; Ramirez, C.; Medina, V.; Shi, Y.-P.
Tetrahedron Lett. 2000, 41, 5177; Rodriguez, A. D.;
Ramirez, C.; Shi, Y.-P. J. Org. Chem. 2000, 65, 6682;
Rodriguez, A. D.; Shi, Y.-P. Tetrahedron 2000, 56, 9015;
Shi, Y.-P.; Rodriguez, I. I.; Rodriguez, A. D. Tetrahedron
Lett. 2003, 44, 3249; See also: Ata, A.; Win, H. Y.; Holt,
D.; Holloway, P.; Segstro, E. P.; Jayatilake, G. S. Helv.
Chim. Acta 2004, 87, 1090.
3. For approaches as well as total syntheses of elisapterosins,
cumbiasins and colombiasins, see: Kraus, G. A.; Kim, J.
Tetrahedron Lett. 2006, 47, 7797; Davies, H. M. L.; Dai, X.;
Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485; Boezio, A.
A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2005, 44, 6046; Jarvo, E. R.; Lawrence, B.
M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6043;
Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne,
H. O. Angew. Chem., Int. Ed. 2005, 44, 1221; Chaplin, J. H.;
Edwards, A. J.; Flynn, B. L. Org. Biomol. Chem. 2003,
1842; Kim, A. I.; Rychnovsky, S. D. Angew. Chem., Int.
Ed. 2003, 42, 1267; Nicolaou, K. C.; Vassilikogiannakis, G.;
Magerlein, W.; Kranich, R. Chem. Eur. J. 2001, 7,
5359; Harrowven, D. C.; Tyte, M. J. Tetrahedron Lett.
2001, 42, 8709; Nicolaou, K. C.; Vassilikogiannakis, G.;
CDCl3+CCl4): d 5.93 (1H, ddt, J 16.8, 9.0 and 7.2 Hz), 5.68–5.60
(1H, m), 5.60–5.50 (1H, m), 5.34 (1H, br s), 5.17–5.10 (2H, m), 4.72
(1H, s), 4.70 (1H, s), 2.77 (1H, dd, J 11.1 and 6.6 Hz), 2.60–2.20 (8H,
m), 2.05–1.94 (1H, m), 1.71 (3H, s), 1.69 (3H, s); 13C NMR (75 MHz,
CDCl3+CCl4): d 147.2 (C), 139.8 (C), 135.7 (CH), 130.9 (CH), 129.9
(CH), 121.9 (CH), 117.9 (CH2), 114.3 (CH2), 78.0 (C), 52.6 (C), 47.3
(CH), 44.6 (CH2), 37.9 (CH2), 36.5 (CH2), 28.6 (CH2), 20.6 (CH3),
20.0 (CH3); HRMS: m/z calcd for C17H24ONa (M+Na): 267.1725;
found, 267.1721. (1R,5S,9S)-4,8-Dimethyltricyclo[7.4.0.01,5]trideca-3,
24
7,11-trien-9-ol 10: ½aꢁD ꢀ124.0 (c 2.0, CHCl3); IR (neat): mmax/cmꢀ1
3490, 1660, 889; 1H NMR (300 MHz, CDCl3+CCl4): d 5.65 (2H, br
s), 5.45 (1H, m), 5.18 (1H, s), 2.55–1.78 (10H, m), 1.77 (3H, s), 1.64
(3H, s); 13C NMR (75 MHz, CDCl3+CCl4): d 143.4 (C), 143.1 (C),
125.8 (CH), 124.4 (CH), 122.9 (CH), 121.4 (CH), 74.7 (C), 51.1 (C),
50.1 (CH), 44.7 (CH2), 37.0 (CH2), 35.9 (CH2), 26.4 (CH2), 19.0
(CH3), 15.5 (CH3); HRMS: m/z calcd For C15H20ONa (M+Na):
239.1412; found, 239.1404. (1R,5S)-4,8-Dimethyltricy-
26
clo[7.4.0.01,5]trideca-3,8,11-trien-7-one 14: ½aꢁD ꢀ168.3 (c 1.2,
CHCl3); IR (neat): mmax/cmꢀ1 1670, 1622; 1H NMR (300 MHz,
CDCl3+CCl4): d 5.90–5.60 (2H, m, H-11 and 12), 5.21 (1H, br s, H-
3), 3.11 and 2.91 (2H, 2 · d, J 21 Hz), 2.56–2.16 (7H, m), 1.75 (3H, s)
and 1.68 (3H, s) [2 · olefinic-CH3]; 13C NMR (75 MHz,
CDCl3+CCl4): d 197.8 (C), 154.5 (C), 141.4 (C), 129.2 (C), 126.0
(CH), 124.7 (CH), 122.1 (CH), 51.8 (CH), 46.7 (C), 43.1 (CH2), 39.1
(CH2), 38.0 (CH2), 30.0 (CH2), 14.9 (CH3), 11.4 (CH3); HRMS: m/z
calcd for C15H18ONa (M+Na): 237.1255; found, 237.1250.

4090
A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 4087–4090
Magerlein, W.; Kranich, R. Angew. Chem., Int. Ed. 2001,
40, 2482; Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.;
Sugita, K. Angew. Chem., Int. Ed. 2001, 40, 2145.
yana, G. Tetrahedron: Asymmetry 2005, 16, 3992; Sri-
krishna, A.; Satyanarayana, G. Tetrahedron 2005, 61,
8855.
4. Zanoni, G.; Franzini, M. Angew. Chem., Int. Ed. 2004, 43,
4837; For approaches to elisabethin A, see: Waizumi, N.;
Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc. 2003,
125, 13022; Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc.
2003, 125, 4680, and 9538; For the synthesis of a seco
elisabethin, see: Miyaoka, H.; Honda, D.; Mitome, H.;
Yamada, Y. Tetrahedron Lett. 2002, 43, 7773.
6. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413;
(b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013; (c)
¨
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18;
(d) Grubbs, R. H.. In Handbook of Metathesis; Wiley-VCH,
2003; Vol. 2.
7. Gesson, J.-P.; Jaquesy, J.-C.; Renoux, B. Tetrahedron 1989,
45, 5853.
5. Srikrishna, A.; Kumar, P. R.; Gharpure, S. J. Indian J.
Chem. 2006, 45B, 1909; Srikrishna, A.; Satyanarayana, G.
Tetrahedron Lett. 2006, 47, 367; Srikrishna, A.; Satyanara-
8. Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021;
Srikrishna, A.; Hemamalini, P. Indian J. Chem. 1990,
29B, 152.