A general approach to cyathin diterpenes. Total synthesis of allocyathin B3

Article abstract of DOI:10.1021/ol006026c

matrix presented The synthesis of allocyathin B₃ from an advanced intermediate possessing the ring system and relative stereochemistry but lacking the isopropyl and hydroxymethyl groups is reported. The isopropyl group was introduced by radical

Full text of DOI:10.1021/ol006026c

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2125-2127
A General Approach to Cyathin
Diterpenes. Total Synthesis of
Allocyathin B3
Dale E. Ward,* Yuanzhu Gai, and Qi Qiao
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon, SK S7N 5C9 Canada
dale.ward@usask.ca
Received May 8, 2000
ABSTRACT
The synthesis of allocyathin B3 from an advanced intermediate possessing the ring system and relative stereochemistry but lacking the
isopropyl and hydroxymethyl groups is reported. The isopropyl group was introduced by radical cyclization of a methyl propargyl acetal of
an r-bromo ketone, and the hydroxymethyl group was generated by Pd-catalyzed carbonylation of a vinyl triflate. The route provides functionalized
intermediates that could allow access to more complex members of the cyathin family of diterpenes.
The cyathins are a unique family of diterpenoids first isolated
by Ayer et al. from cultures of bird’s nest fungi of the genus
Cyathus.1 With the exception of allocyathin B2 (3),1g all
cyathins possess a trans 6-7 ring fusion as illustrated by
cyathin A3 (1) and differ only in the degree of oxidation
around the five-membered2 and seven-membered3 rings.
(1) (a) Allbutt, A. D.; Ayer, W. A.; Brodie, H. J.; Johri, B. N.; Taube,
H. Can. J. Microbiol. 1971, 17, 1401. (b) Ayer, W. A.; Taube, H.
Tetrahedron Lett. 1972, 19, 1917. (c) Ayer, W. A.; Taube, H. Can. J. Chem.
1973, 51, 3842. (d) Ayer, W. A.; Carstens, L. L. Can. J. Chem. 1973, 51,
3157. (e) Ayer, W. A.; Browne, L. M.; Mercer, J. R.; Taylor, D. R.; Ward,
D. E. Can. J. Chem. 1978, 56, 717. (f) Ayer, W. A.; Yoshida, T.; Van
Schie, D. M. J. Can. J. Chem. 1978, 56, 2113. (g) Ayer, W. A.; Lee, S. P.
J. Can. J. Chem. 1979, 57, 3332.
(2) For example, ∆,1,2, 3,4-epoxide, C-1 ketone, C-2 ketone, C-1 â-OH,
C-19 OH, C-19 acid.
(3) For example, C-15 aldehyde, C-14 â-OH.
More recently, several fungal metabolites with structures
closely related to those of the cyathins have been reported.
For example, the striatins4 and erinacines5 are carbohydrate
conjugates of cyathins (e.g., 4), the sarcodonins6 are cyathins
with a C-19 alcohol, and the scabronines7 are cyathins with
a C-17 carboxylic acid. Several cyathins1a show strong
antibiotic activity, and both the erinacines5 and scabronines7
stimulate the synthesis of nerve growth factor. The unique
5-6-7 ring system and biological activities associated with
this ever growing family of natural products has attracted
the attention of synthetic chemists.8-10 To date, total
(4) Hecht, H.-J.; Ho¨fle, G.; Steglich, W.; Anke, T.; Oberwinkler, F. J.
Chem. Soc., Chem. Commun. 1978, 665.
(5) (a) Kawagishi, H.; Shimada, A.; Shirai, R.; Okamoto, K.; Ojima, F.;
Sakamoto, H.; Ishiguro, Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569.
(b) Kawagishi, H.; Shimada, A.; Shizuki, K.; Mori, H.; Okamoto, K.;
Sakamoto, H.; Furukawa, S. Heterocycl. Commun. 1996, 2, 51. (c)
Kawagishi, H.; Shimada, A.; Hosokawa, S.; Mori, H.; Sakamoto, H.;
Ishiguro, Y.; Sakemi, S.; Bordner, J.; Kojima, N.; Furukawa, S. Tetrahedron
Lett. 1996, 37, 7399.
(6) Shibata, H.; Tokunaga, T. Karasawa, D.; Hirota, A. Nakayama, M.;
Nozaki, H.; Tada, T. Agric. Biol. Chem. 1989, 53, 3373.
(7) (a) Ohta, T.; Kita, T.; Kobayashi, N.; Obara, Y.; Nakahata, N.;
Ohizumi, Y.; Takaya, Y.; Oshima, Y. Tetrahedron Lett. 1998, 39, 6229.
(b) Kita, T.; Takaya, Y.; Oshima, Y.; Aizawa, K.; Hirano, T.; Inakuma, T.
Tetrahedron 1998, 54, 11877.
10.1021/ol006026c CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

syntheses of both (()-39,10 and 49 have been reported;
however, modifications of these routes to provide targets with
the much more common trans 6-7 ring fusion have not been
demonstrated and are far from certain. In this paper we report
the first synthesis of a cyathin diterpene with the trans 6-7
ring fusion and fully functionalized seven-membered ring.11
Several years ago we reported the synthesis of 10,8c an
intermediate possessing the ring system and relative stereo-
chemistry present in cyathin diterpenes (cf. 1). The prepara-
tion of 10 was efficient, proceeding in >10% overall yield
from 2,5-dimethylbenzoquinone (5) in 17 operations of which
only 6 required purification beyond normal workup including
only 4 chromatographic separations (Scheme 1).
were less obvious. After considerable experimentation, a
method was established to introduce a 3-carbon side chain
based on radical cyclization (Scheme 2). Treatment of 10
Scheme 2a
Scheme 1a
a Reagents: (a) MeOH, HCl, (MeO)3CH, toluene, reflux. (b)
NBS, propargyl alcohol, CH2Cl2, -78 °C. (c) Ph3SnH, AIBN, C6H6,
reflux (60% from 10). (d) H2, Pd-C, EtOAc (90%). (e) 10% HCl,
THF (85%). (f) NaBH4, EtOH (85%).
a Reagents: (a) i. 5 + 6, 140 °C (92%); ii. allene, hν; iii. TFA;
iv. mCPBA; v. 9-BBN; vi. PhSH, NaOH (50% from 5). (b) i.
PhCOOH, DEAD, Ph3P; ii. NaBH4, CH2Cl2, MeOH, -78 °C; iii.
NaOH, MeOH; iv. RaNi; v. NaOH, MeOH, reflux; vi. BzCl, Et3N,
DMAP (60% from 7). (c) i. MsCl, pyridine, 50 °C, then DBU,
toluene reflux (75%); ii. H2, RhCl(Ph3P)3 (90%). (d) i. O3, Sudan
III, then Me2S; ii. TsOH, toluene; iii. MeI, Ag2O (50% from 9).
with trimethyl orthoformate and methanolic HCl in toluene
followed by azeotropic distillation of MeOH produced the
dienol ether 11. Cohalogenation12 of 11 with N-bromosuc-
cinimide (NBS) and propargyl alcohol gave the somewhat
unstable 12 as a single diastereomer (1H NMR) which
cyclized13 to 13 (60% overall yield from 10) on treatment
with Ph3SnH and AIBN in refluxing benzene.14,15
Unmasking the isopropyl group present in 13 proved to
be difficult. Treatment with protic or Lewis acids led to loss
of MeOH and formation of the corresponding furan deriva-
tive.16 Hydrogenation of 13 gave 1417 which on exposure to
10% aqueous HCl slowly (ca. 14 h) produced the isomerized
hemiacetal 1518 without evidence of an intermediate (by
TLC). Although various attempts to trap the hydroxy ketone
tautomer of 15 by formation of acyl, xanthate, or dithioacetal
For conversion of 10 into a cyathin diterpene (cf. 1), a
number of methods can be envisaged to generate the required
vinyl hydroxymethyl group at C-12 (cyathin numbering);
however, strategies to introduce the isopropyl group at C-3
(8) (a) Ayer, W. A.; Browne, L. M.; Fernandez, S.; Ward, D. E.; Yoshida,
T. ReV. Latinoamer. Quim. 1978, 9, 177. (b) Ayer, W. A.; Ward, D. E.;
Browne, L. M.; Delbaere, L. T. J.; Hoyano, Y. Can. J. Chem. 1981, 59,
2665. (c) Ward, D. E. Can. J. Chem. 1987, 65, 2380. (d) Dahnke, K. R.;
Paquette, L. A. J. Org. Chem. 1993, 59, 885. (e) Piers, E.; Cook, K. L.
Chem. Commun. 1996, 1879. (f) Magnus, P.; Shen, L. Tetrahedron 1999,
55, 3553. (g) Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga,
I.; Frey, D. A. Org. Lett. 1999, 1, 1535.
(9) (a) Snider, B. B.; Vo, N. H.; O′Neil, S. V.; Foxman, B. M. J. Am.
Chem. Soc. 1996, 118, 7644. (b) Snider, B. B.; Vo, N. H.; O’Neil, S. V. J.
Org. Chem. 1998, 63, 4732.
(10) Tori, M.; Toyoda, N. Sono, M. J. Org. Chem. 1998, 63, 306.
(11) After this paper was submitted, the synthesis of (()-sarcodonin G,
which has a trans 6-7 ring fusion and a C-19 hydroxyl group, was reported.
Piers, E.; Gilbert, M.; Cook, K. L. Org. Lett. 2000, 2, 1407.
(12) Rodriguez, J.; Dulcere, J.-P. Synthesis 1993, 1177.
(16) Sirkrishna, A.; Pullaiah, K. C. Tetrahedron Lett. 1987, 28, 5203.
(17) The relative configuration of 14 was assigned on the basis of the
3JHH coupling constants between H2C-19 and HC-18 (4, <1 Hz), which
are consistent with the dihedral angles (44°, -81°) determined for 14 by
molecular mechanics (CaChe, version 3.9), and on the apparent shielding
of the C-20 methyl group (δ 0.83) by the alkene. This relative configuration
at C-18 (cyathin numbering) is the same as that in the sarcodonins A and
G (refs 6 and 11) and possibly the cyathins A4 and C5 (ref 1e).
(13) Giese, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. L.; Trach,
F. Org. React. 1996, 48, 301.
(18) The relative configuration of 15 was assigned on the basis of the
3
(14) The relative configuration of 13 was assigned on the basis of a
positive NOE for HC-3 and H3C-9 on irradiation of the C-2 methoxy group.
(15) Several examples of this route to 3-methylenetetrahydrofurans can
be found in ref 13. For early examples, see: (a) Okabe, M.; Abe, M.; Tada,
M. J. Org. Chem. 1982, 47, 1775. (b) Moriya, O.; Okawara, M.; Ueno, Y.
Chem. Lett. 1984, 1437.
large changes in the JHH coupling constants between H2C-19 and HC-18
(8, 10.5 Hz) and chemical shift of the C-20 methyl group (δ 1.32) compared
to those of 14 (and 18a). These coupling constants are consistent with the
dihedral angles (-36°, -161°) for 15 determined by molecular mechanics
(CaChe, version 3.9) which also indicated that 15 was 1.3 kcal/mol more
stable than 18a.
2126
Org. Lett., Vol. 2, No. 14, 2000

derivatives failed, the diol 17 was readily prepared by
reaction of 15 with NaBH4. Unfortunately, all efforts to
deoxygenate one or both the alcohol groups in 17 were
unsuccessful, and several attempts at derivatization led to
the tetrahydrofuran 16.19 The serendipitous observation that
under very mild conditions hydrolysis of 14 would occur
without isomerization was crucial for our solution of this
problem (Scheme 3).
18 has functionality that potentially can provide access to
any of the various oxidation patterns present on the A (i.e.,
five-membered) ring of cyathin and related diterpenes.2 For
many of the possible synthetic targets, deoxygenation of the
C-19 alcohol group is required; this was readily accomplished
by reaction of 18 with Ph2PCl followed by I2 and reduction
of the resulting iodide20 19 with H2 over Pd-C to give 20
(65% overall from 18).
Treatment of 20 with NaOH in MeOH served to hydrolyze
the benzoate ester with concomitant isomerization of the
C-4,5 double bond into conjugation with the ketone, thereby
reestablishing the desired trans 6-7 ring fusion.21 To avoid
unnecessary protection/deprotection schemes, the resulting
alcohol was directly oxidized to ketone 21 with NMO/
TPAP22 (85% from 20). Selective deoxygenation of the
cyclopentenone carbonyl was achieved by reaction of 21 with
triflic anhydride (Tf2O) in the presence of the hindered base
2,6-di-tert-butyl-4-methylpyridine23 to give the dienol triflate
which was reduced to cyclopentadiene 22 by Pd-catalyzed
reaction with Bu3SnH (50% from 21).24,25 Finally, introduc-
tion of the vinyl hydroxymethyl group was achieved by Pd-
catalyzed carbonylation26 of the vinyl triflate derived from
22 followed by DIBAL-H reduction of the resulting 23 to
give (()-24 (50% from 22). Spectral data (1H and 13C NMR,
UV, MS) for (()-24 closely matched that previously
reported1c,27 for (-)-24. Hydrolysis of 24 to allocyathin B3
(2; a mixture of hydroxy ketone and hemiacetal tautomers)
proceeds readily in THF solution on exposure to aqueous
HClO4.1e
In conclusion, the synthesis of allocyathin B3 (2) was
achieved by introduction of the required isopropyl and vinyl
hydroxymethyl groups onto an advanced intermediate (10)
already possessing the correct ring system and relative
stereochemistry. This is the first synthesis of a cyathin
diterpene incorporating the trans 6-7 ring fusion and a fully
functionalized seven-membered ring. Although introduction
of the isopropyl group proved difficult (i.e. 10 f 21; 8 steps,
35% yield), the reported solution provides intermediates with
potentially useful functionality. Indeed, simple modifications
of the route reported herein can be contemplated that might
lead to any of the known cyathin diterpenes and several
related natural products.
Scheme 3a
a Reagents: (a) PPTS, acetone, H2O, rt, 12 d (75%; quantitative
based on conversion). (b) i. Ph2PCl, pyridine, toluene. ii. I2. (c)
H2, Pd-C (65% from 18. (d) i. NaOH, MeOH, reflux; ii. NMO,
TPAP (85%). (e) i. Tf2O, 2,6-di tert-butyl-4-methylpyridine; ii.
Bu3SnH, LiCl, Pd(Ph3P)4, THF (50%). (f) i. NaN(TMS)2, THF,
-78 °C; ii. PhNTf2; iii. CO, DIEA, Pd(Ph3P)4, THF (50%); iv.
DIBAL-H (50%). (g) 1 N HClO4, THF (80%; see ref 1e).
Reaction of 14 with pyridinium 4-methylbenzenesulfonate
(PPTS) in aqueous acetone for 12 days gave 18 (75%) along
with recovered 14 (25%) (Scheme 3). In contrast to 15, H
and 13C NMR (in CDCl3) of 18 indicated a 1.5:1 mixture of
the hydroxy ketone (18b) and hemiacetal (18a) tautomers,
respectively. Importantly, esters of the hydroxy ketone
tautomer 18b could be prepared in good yield. Intermediate
1
(19) For an example of unusually facile cyclization of a 1,4-diol, see:
Schlessinger, R. H.; Schultz, J. A. J. Org. Chem. 1983, 48, 407.
(20) Classon, B.; Liu, Z. J. Org. Chem. 1988, 53, 6126.
(21) The presence of the transannular acetal within the seven-membered
ring makes the cis-fused diastereomer impossibly strained.
(22) For a review on oxidation with tetrapropylammonium perruthenate/
N-methylmorpholine N-oxide, see: Ley, S. V.; Norman, J.; Griffith, W.
P.; Marsden, S. P. Synthesis 1994, 639.
Acknowledgment. Financial support from the Natural
Sciences and Engineering Research Council of Canada and
the University of Saskatchewan is gratefully acknowledged.
We thank Prof. W. A. Ayer for samples of cyathins and for
his continuing interest in this work.
(23) Stang, P. J.; Treptow, W. Synthesis 1980, 283.
(24) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(25) For a review on the preparation and reactions of enol triflates, see:
Ritter, K. Synthesis 1993, 735.
(26) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109.
(27) Ayer, W. A.; Nakashima, T. T.; Ward, D. E. J. Can. J. Chem. 1978,
56, 2197.
Supporting Information Available: Spectroscopic data
for 11-24. This material is available free of charge via the
Internet at http://pubs.acs.org.
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