in THF at low temperature afforded a mixture of crystalline b-
hydroxyphosphine oxides, which were subjected to syn elimina-
tion by treatment with NaH in DMF at 0 °C to give a mixture of
isomeric vinyl ethers 11. Direct chromatographic purification of
this mixture on silica gel resulted in chemoselective hydrolysis
of the vinyl ether moiety and consecutive opening of the
epoxide, providing the desired unsaturated hydroxy aldehyde 12
cleanly and efficiently (77% overall yield from epoxy ketone
10).† Methylenation of 12 under Wittig conditions then gave
dienol 13 in 85% yield, which was transformed into the
propargyl ether 14 in very high yield by reaction with propargyl
bromide under phase-transfer conditions. Sequential treatment
of compound 14 with BuLi and methyl cyanoformate in the
presence of added HMPA provided 15 in 87% yield, which
underwent a smooth IMDA cycloaddition upon heating in a
sealed tube at 105 °C overnight in anhydrous toluene. The
reaction takes place very cleanly to give the tricyclic system 16
in nearly quantitative yield.14
After successfully accomplishing the synthesis of the CD ring
fragment, attention was turned towards the construction of the
AB rings, for which we followed a parallel route to that
previously used by us for the preparation of a related system
(Scheme 2).12c Removal of the aldehyde acetal function of 16
with PPTS in aqueous acetone afforded the aldehyde 17 in 87%
yield. Wittig reaction of 17 with (a-formylethylidene)triphenyl-
phosphorane provided the chain-extended aldehyde 18, which
by subsequent standard Wittig methylenation afforded the
compound 19 in 78% overall yield. Heating a solution of this
compound in toluene and a small amount of propylene oxide in
a sealed tube at 185 ºC for 6 days afforded the pentacyclic
compound 20, with the expected trans–anti–trans fused ABC
ring system of the scalarane framework, in 85% yield after
column chromatography.
synthesis of the more representative scalaranes. Work is
currently in hand to further elaborate this intermediate towards
scalaradial.§
Financial support from DGICYT (Grant PB95-1088) is
gratefully acknowledged. Special thanks are due to Dr Roberto
M. Sotelo (Programa Intercampus América Latina/España 1997
from Universidad Tecnológica Nacional de Avelladena, Argen-
tina) for the repetition of some reactions.
Notes and references
† Alternative procedures to effect the same transformation using different
mild acidic conditions also promoted hydrolysis of the acetal moiety.
‡ All new compounds give satisfactory analytical and spectral data. Selected
data for 16: [a]2D1 221.3 (c 2.8, CHCl3); dH(300 MHz, CDCl3) d 5.75 (1H,
dd, J 6.9, 1.8), 4.82 and 4.72 (1H each, each br s), 4.78 (1H, dd, J 15.5, 2.7),
4.58 (1H, dd, J 15.5, 3.8), 4.4 (1H, dd, J 5.3, 5.2), 4.17 (1H, dd, J 8.6, 4.5),
3.71 (3H, s), 3.61 and 3.44 (2H each, each m), 3.28 (1H, dd, J 20.7, 6.9),
2.73 (1H, m), (3H, s), 1.16 (6H, t, J 6.5), 1.11 (3H, s), 1.06 (3H, s). For 20:
[a]2D1 244.7 (c 3.3, CHCl3); mp 159–160 °C (from EtOH); dH(400 MHz,
CDCl3), 5.65 (1H, dd, J 6.5, 1.5), 5.27 (1H, br s), 4.96 (1H, dd, J 14, 2.4),
4.31 (1H, dd, J 14, 3.5), 3.92 (1H, dd, J 4.5, 1.7), 3.74 (3H, s), 3.34 (1H, dd,
J 20.7, 6.5), 2.65 (1H, dddd, J 20.7, 3.5, 2.4, 1.5), 1.61 (3H, br s), 1.19 (3H,
s), 1.107 (3H, s), 0.786 (3H, s). For 22: [a]2D1 +82 (c 2.8, CHCl3); mp
217–220 °C (from EtOH–acetone); dH(400 MHz, CDCl3) 5.73 (1H, dd, J
4.6, 2.9), 4.93 (1H, dd, J 3.0, 2.2), 4.82 (1H, ddd, J 16.5, 3.3, 1.5), 4.48 (1H,
ddd, J 16.5, 2.4, 2.3), 2.96 (1H, m), 2.82 (2H, m), 1.95 (3H, s), 1.42 (3H, s),
1.25 (3H, s), 0.98 (3H, s), 0.8 (1H, m), 0.82 (3H, s), 0.55 (1H, m), 0.44 (1H,
dd, J 9.5, 4), 0.35 (1H, ddd, J 18.8, 12.7, 6.9), 20.03 (1H, dd, J 5.3,
4.0).
§ This transformation requires the establishment of a trans CD ring fusion.
An initial experiment showed that the hydrogenation of the C14–C15
double bond of the alcohol resulting from hydrolysis of the acetate group of
22, with [Ir(cod)(py)(PCy3)]PF6 takes place chemo- and stereo-selectively
to give the required trans CD ring fusion.
Completion of the synthesis of compound 22 was effected as
follows. First 20 was submitted to Simmons-Smith cyclopropa-
nation conditions to chemo- and stereoselectively cyclopropa-
nate the ring A double bond, an indirect way of introducing the
geminal dimethyl group at C-4 of the natural scalaranes.
Finally, cleavage of the dihydrofuran ring of 21 occurred
smoothly and cleanly by treatment with Ac2O and zinc iodide,
being accompanied by simultaneous lactonisation to give the
scalarane-type compound 22‡ in 86% overall yield for the last
two steps.
1 J. D. Connolly and R. A. Hill, in Dictionary of Terpenoids, 1st edn.,
Chapman and Hall, London, 1991, vol. 3, p. 1110; D. J. Faulkner, Nat.
Prod. Rep., 1997, 14, 259 and previous reviews of this series.
2 R. P. Walker, J. E. Thompson and D. J. Faulkner, J. Org. Chem., 1980,
45, 4876.
3 K. B. Glaser, M. L. Sung, Y. W. Lock, J. Bauer, D. Kubrak and A. Kreft,
Bioorg. Med. Chem. Lett., 1994, 4, 1873, and references cited therein.
4 A. Rueda, E. Zubía, M. J. Ortega, J. L. Carballo and J. Salvá, J. Org.
Chem., 1997, 62, 1481 and references cited therein.
5 B. Terem and P. J. Scheuer, Tetrahedron, 1986, 42, 4409; M. A.
Becerro, V. J. Paul and J. Starmer, Marine Ecology Progress Series,
1998, 168, 187.
6 N. Tsuchiya, A. Sato, T. Hata, N. Sato, K. Sasagawa and T. Kobayashi,
J. Nat. Prod., 1998, 61, 468.
The synthesis of 22 from (S)-(+)-carvone is thus completed in
15 synthetic operations in 17% overall yield. We believe that
this compound constitutes an attractive intermediate for the
7 G. R. Pettit, Z. A. Cichacz, R. Tan, M. S. Hoard, N. Melody and R. K.
Petitt, J. Nat. Prod., 1998, 61, 13.
8 W. Herz and J. S. Prasad, J. Org. Chem., 1982, 47, 4171; V. Ragoussis
and M. Liapis, J. Chem. Soc., Perkin Trans. 1, 1990, 2545; N. Ungur, M.
Gavagnin and G. Cimino, Nat. Prod. Lett., 1996, 8, 275.
9 M. González-Sierra, R. M. Cravero, M. A. Laborde and E. A. Rúveda,
J. Chem. Soc., Perkin Trans. 1, 1985, 1227.
10 T. Nakano, M. I. Hernández, A. Martín and J. D. Medina, J. Chem. Soc.,
Perkin Trans. 1, 1988, 1349.
17
i
O
O
CO2Me
CO2Me
iii
R
H
H
11 E. J. Corey, G. Luo and S. Lin, J. Am. Chem. Soc., 1997, 119, 9927.
12 (a) A. Abad, C. Agulló, M. Arnó, A. C. Cuñat, B. Meseguer and R. J.
Zaragozá, J. Org. Chem., 1998, 63, 5100; (b) A. Abad, C. Agulló, M.
Arnó, M. L. Marín and R. J. Zaragozá, Synlett, 1997, 573; (c) A. Abad,
C. Agulló, M. Arnó, A. Cantín, A. C. Cuñat, B. Meseguer and R. J.
Zaragozá, J. Chem. Soc., Perkin Trans. 1, 1997, 1837.
H
20
18 R = O
ii
19 R = CH2
iv
13 For previous works which use carvone and an IMDA reaction for the
construction of other polycyclic natural products, see: V. H. Rawal and
S. Iwasa, Abstracts of Papers, 204th National Meeting of the American
Chemistry Society, Washington, DC, American Chemical Society,
Washington, 1992, ORGN 35; T. K. M. Shing, Q. Jiang and T. C. W.
Mak, J. Org. Chem., 1998, 63, 2056. For reviews of the intramolecular
Diels–Alder reaction, see: W. R. Roush, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol.
5 (ed. L. A. Paquette), ch. 4.4, p. 513 and references cited therein.
14 A related strategy has been previously used for the synthesis of the AB
rings of the labdane diterpene forskolin, see: M. I. Colombo, J. Zinczuk
and E. A. Rúveda, Tetrahedron, 1992, 48, 963.
O
OAc
O
O
v
CO2Me
H
H
H
H
22
21
Scheme 2 Reagents and conditions: i, Ph3PNCMeCHO, benzene, reflux,
87%; ii, Ph3PNCH2, THF, 220 °C, 90%; iii, toluene, 185 °C, 85%; iv,
Et2Zn, CH2I2, toluene, room temp., 89%; v, ZnI2, (MeCO)2O, room temp.,
96%.
Communication 9/00081J
428
Chem. Commun., 1999, 427–428