Towards colombiasin A

Article abstract of DOI:10.1016/S0040-4039(01)01885-8

A synthetic route to an unnatural diastereoisomer of colombiasin A is described. Key features are an arene alkylation with a γ-methylene-γ-butyrolactone and an intramolecular Diels-Alder cycloaddition.

Full text of DOI:10.1016/S0040-4039(01)01885-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8709–8711
Towards colombiasin A
David C. Harrowven* and Melloney J. Tyte
Department of Chemistry, The University of Southampton, Southampton SO17 1BJ, UK
Received 29 August 2001; revised 26 September 2001; accepted 5 October 2001
Abstract—A synthetic route to an unnatural diastereoisomer of colombiasin A is described. Key features are an arene alkylation
with a g-methylene-g-butyrolactone and an intramolecular Diels–Alder cycloaddition. © 2001 Elsevier Science Ltd. All rights
reserved.
Colombiasin A 1 is a structurally complex diterpene,
recently isolated from the Caribbean sea whip Pseu-
dopterogorgia elisabethae.1 Though modest in size, its
carbon frame contains three six-membered rings that
share a common carbon to carbon bond. To this ‘pro-
pellane’ is fused a further cyclopentane ring. Six con-
tiguous stereogenic centres are present within its unique
tetracyclic skeleton, including two adjacent quaternary
centres at its core (Fig. 1). Earlier this year, Nicolaou et
al. reported the first total synthesis of colombiasin A.2
Herein we report an alternative approach leading to an
unnatural diastereoisomer of this challenging target.
Our synthesis began with 2,6-dimethoxytoluene 2 which
was converted into phenol 4 using a known sequence.3
A Pechmann reaction with ethyl acetoacetate and medi-
ated by triflic acid then gave coumarin 5.4 Reduction of
the alkene and saponification of the lactone in the
presence of dimethyl sulfate next furnished ester 7, a
precursor to aldehyde 9. Union of aldehyde 9 and
phosphonate 10 led to a separable 3:2 mixture of (Z)-
and (E)-alkenes 11.5 Each of these materials underwent
a diastereoselective aromatic alkylation on exposure to
triflic acid giving spirolactone 12 as the major product.
This was accompanied by traces of its diastereoisomeric
partner and the cyclopentadienone 13 (Scheme 1).
H
At this juncture we attempted to effect a simultaneous
alkene hydrogenation and ester hydrogenolysis under
neutral conditions in order to establish the C-6 and C-7
stereogenic centres of colombiasin A. Unfortunately,
even under forcing conditions we were unable to
accomplish the second of these tasks, the product given
being a single diastereoisomer of spirolactone 14 with
the C-7 stereocentre installed with the correct relative
stereochemistry. When the reaction was conducted in
acidic media, reduction of the lactone was accom-
plished at room temperature and pressure, but pro-
ceeded with complete retention of configuration to give
16! This was shown to be due to the formation of
g,d-unsaturated ester 17 as an intermediate, with the
pseudo-axial C-18 methyl group dictating the stereo-
chemical course of the reduction (Scheme 2). Reduction
of spirolactone 12 to 16 could also be effected in good
yield using these conditions.
O
OH
O
H
Colombiasin A 1
4
18
3
5
6
19
2
7
17
16
1
12
15
20
8
9
14
11
10
13
Figure 1. Colombiane numbering.
Though disappointed by our failure to establish the C-6
stereogenic centre correctly, we decided to progress
ester 16 towards an unnatural colombiasin diastereoiso-
mer. Thus, it was smoothly transformed into aldehyde
Keywords: cyclisation; lactones; natural products; terpenes and ter-
penoids.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01885-8

8710
D. C. Harrow6en, M. J. Tyte / Tetrahedron Letters 42 (2001) 8709–8711
MeO
MeO
MeO
POCl3, DMF
MCPBA, DCM
Ethyl acetoacetate
CHO
OH
2 h, 105 °C, 68%
TfOH, 70 °C, 3 h
60%
reflux, 20 h then
KOH, MeOH
RT, 1 h, 96%
OMe
OMe
3
OMe
4
2
MeO
MeO
MeO
CO2Me
H2, Pd-C, EtOAc
RT, 4 days, 98%
Me2SO4, KOH
acetone, 16 h, 89%
O
O
O
O
OMe
OMe
OMe
OMe
5
6
7
Dess-Martin
periodinane
MeO
CH2OH
MeO
CHO
LiAlH4, THF
EtO
+
EtO
O
-78 °C → 0 °C
40 min, 99%
DCM, 0 °C
30 min, 96%
P
O
OMe
OMe
O
OMe
OMe
8
9
10
O
H
5:1
MeO
KOtBu, THF
TfOH, PhMe
MeO
MeO
MeO
MeO
+
O
O
O
0 °C → RT
24 h, 62%
80 °C, 72 h
12, 59%; 13, 26%
O
MeO
O
O
O
11
12
13
Scheme 1.
intramolecular Diels–Alder cycloaddition leading to a
single diastereoisomer of dione 24 (Scheme 3).
19 allowing a diene unit to be introduced by standard
Wittig chemistry. Attempts to effect aromatic oxidation
of 20 to a quinone led to a complex product mixture,
many components seemingly derived from oxidation of
the diene. Such a problem had been overcome by
Nicolaou et al.,2 through protection of the diene moiety
as its sulfur dioxide adduct. Their tactic proved simi-
larly effective in our hands, though oxidation of 21 to
quinone 22 with silver oxide and nitric acid was still
low yielding. Finally, heating a toluene solution of 22 in
the dark at 180°C in a sealed tube induced the
At this time we must add a cautionary note on the
stereochemistry of 24 as it has yet to be established with
rigour. Our assignment is based on a knowledge of the
stereochemistry of the precursor 22, an assumption that
no epimerisation of the transient diene 23 occurs and
that the Diels–Alder cycloaddition to 24 proceeds
though an endo-cyclic transition state. All concur with
the findings of Nicolaou et al. Moreover, epimerisation
H
H2, Pd-C, PtO2
MeO
MeO
MeO
MeO
MeO
CO2R
O
O
O
EtOAc, RT
1 h, 86%
O
O
MeO
O
O
12
14
15
H2, Pd-C
AcCl, MeOH
PtO2, AcCl
RT, 2 days, 92%
MeOH, RT 2 days, 85%
H
H2, Pd-C
MeO
MeO
MeO
MeO
EtOAc, RT
3 h, 94%
O
CO2Me
O
CO2Me
16
17
Scheme 2.

D. C. Harrow6en, M. J. Tyte / Tetrahedron Letters 42 (2001) 8709–8711
8711
Dess-Martin
periodinane
H
H
H
LiAlH4, THF
MeO
MeO
MeO
MeO
MeO
MeO
-78 °C → 0 °C
20 min, 99%
DCM, 0 °C
30 min, 99%
O
CO2Me
O
CH2OH
MeO
O
CHO
16
18
19
MeO
MeO
MeO
PPh3
liquified SO2
AgO, HNO3
H
H
O
O
H
THF, 0 °C → RT
-78 °C → RT
dioxane, RT
5 min, 25%
S
MeO
MeO
40 min., 60%
4 h, 71%
20
21
O
MeO
O
H
H
H
180 °C, toluene
H
O
OMe
O
H
O
S
sealed tube
dark, 7 h, 64%
O
OMe
O
O
22
23
24
Scheme 3.
at the C-6 stereocentre in 23 would have provided us
with the methyl ether of colombiasin A. Data reported
for that material differs from that attained for 24, again
suggesting the outcome depicted.6
2. Nicolaou, K. C.; Vassilikogiannakis, G.; Ma¨gerlein, W.;
Kranich, K. Angew. Chem., Int. Ed. 2001, 40, 2482.
3. Godfrey, I. M.; Sargent, M. V.; Elix, J. A. J. Chem. Soc.,
Perkin Trans. 1 1974, 1353.
4. Sethna, S.; Phadke, R. Org. React. 1953, 7, 1.
5. Harrowven, D. C.; Wilden, J. D.; Tyte, M. J.; Hurst-
house, M. B.; Coles, S. J. Tetrahedron Lett. 2001, 42,
1193.
In conclusion, we have developed a route to an unnatu-
ral diastereoisomer of colombiasin A. Key features are
the arene alkylation with a g-methylene-g-butyrolac-
tone, viz. 11“12, and the intramolecular Diels–Alder
cycloaddition 23“24. We are presently seeking a more
efficient protocol for effecting the aromatic oxidation
21“22 and exploring other routes to 15, from which
the natural colombiasin A diastereoisomer should be
accessible.
6. Data for 24: IR (film) wmax 2931 m, 1673 s, 1626 w, 1457
1
m, 1230 w, 1127 s cm−1; H NMR (400 MHz, CDCl3) lH
5.67 (1H, br. s, ꢀCH), 3.89 (3H, s, OCH3), 3.09 (1H, m,
ꢀCHCH), 2.99 (1H, m, CCHCH3), 2.33–1.97 (7H, m),
1.97 (3H, s, CH3CꢀC-CꢀO), 1.44 (3H, s, CH3CꢀCH),
1.44–1.10 (3H, m), 1.10 (3H, d, J 7.7, CH3CHC), 0.94
(3H, d, J 6.9, CH3CHCH); 13C NMR (100 MHz, CDCl3)
lC 203.1 (s, C-14), 198.6 (s, C-17), 155.2 (s, C-16), 131.7
(s, C-11), 129.9 (s, C-15), 125.7 (d, C-10), 64.8 (s, C-1),
60.2 (q, OCH3), 52.6 (s, C-2), 48.1 (d, C-7), 44.6 (d, C-6),
39.4 (t, C-12), 38.1 (d, C-9), 34.0 (d, C-3), 33.3 (t, C-8),
29.8 (t, C-5), 28.9 (t, C-4), 22.7 (q, C-13), 16.1 (q, C-19),
15.6 (q, C-18), 10.4 (q, C-20) assigned with reference to
those data reported for 1 and colombiasin A methyl
ether;1,2 LRMS (CI) m/z 329 (100%, MH+), 301 (18%,
[M−CO]+), 109 (42%); HRMS (EI) m/z Found M+:
328.2038, C21H28O3 requires 328.2038.
Acknowledgements
The authors thank EPSRC for a Quota Studentship to
M.J.T.
References
1. Rodr´ıguez, A. D.; Cam´ırez, C. Org. Lett. 2000, 2, 507.