Novel synthesis of the C1-C15 polyether domain of the thyrsiferol and venustatriol natural products.

Article abstract of DOI:10.1021/ol990648k

[formula: see text] A convergent construction of the C1-C15 domain of the thyrsiferol-related natural products has been developed. This involved the separate construction of C1-C7 and C8-C15 fragments, their organochromic-mediated coupling, and subsequent

Full text of DOI:10.1021/ol990648k

ORGANIC
LETTERS
1999
Vol. 1, No. 2
319-322
Novel Synthesis of the C1−C15
Polyether Domain of the Thyrsiferol and
Venustatriol Natural Products
Isabel C. Gonza´lez and Craig J. Forsyth*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
forsyth@chem.umn.edu
Received May 7, 1999
ABSTRACT
A convergent construction of the C1−C15 domain of the thyrsiferol-related natural products has been developed. This involved the separate
construction of C1−C7 and C8−C15 fragments, their organochromic-mediated coupling, and subsequent reductive closure of the B ring. This
synthetic A−B−C ring construct will be useful for the total synthesis of the biologically active polyether squalenoid natural products, as well
as their non-natural analogues.
The marine algae metabolites thyrsiferol (1),1,2 venustatriol
(4),2 and congeners3-7 represent a biogenetically unique class
of squalene-derived polyether natural products that display
a range of potent biological activities (Figure 1). Chief among
these are venustatriol’s potent antiviral activity2 and thyr-
siferyl 23-acetate’s (2) in vitro cytotoxicity toward P388
murine leukemia (ED50 ) 0.3 ng/mL, 0.5 nM)4 and selective
inhibition of the protein serine/threonine phosphatase 2A
(IC50 ) 4-16 µM).8 The polyether structures of these
squalenoid natural products are characterized by a bromotet-
(1) Blunt, J. W.; Hartshorn, M. P.; McLennan, T. J.; Munro, M. H. G.;
Robinson, W. T.; Yorke, S. C. Tetrahedron Lett. 1978, 69-72.
(2) Sakemi, S.; Higa, T.; Jefford, C. W.; Bernardinelli, G. Tetrahedron
Lett. 1986, 27, 4287-4290.
(3) Gonzalez, A. G.; Arteaga, J. M.; Fernandez, J. J.; Martin, J. D.; Norte,
M.; Ruano, J. Z. Tetrahedron 1984, 40, 2751-2755.
Figure 1. Structures of thyrsiferol and venustatriol.
(4) Suzuki, T.; Suzuki, M.; Furusaki, A.; Matsumoto, T.; Kato, A.;
Imanaka, Y.; Kurosawa, E. Tetrahedron Lett. 1985, 26, 1329-1332.
(5) Suzuki, T.; Takeda, S.; Suzuki, M.; Kurosawa, E.; Kato, A.; Imanaka,
Y. Chem. Lett. 1987, 361-364.
rahydropyranyl A ring appended directly to a trans-fused 2,7-
dioxabicyclo-[4.4.0]decane B-C ring system and a side
chain-linked tetrahydrofuran D ring. X-ray analyses of
thyrsiferyl 18-acetate (3)1 and 42 revealed that the B-C rings
adopt a chair-twist-boat conformation that is phenotypic of
this class, to avoid 1,3-diaxial interactions between the
(6) Norte, M.; Fernandez, J. J.; Souto, M. L.; Garvin, J. A.; Garcia-
Gravalos, M. D. Tetrahedron 1997, 53, 3173-3178.
(7) Norte, M.; Fernandez, J. J.; Garcia-Gravalos, M. D. Tetrahedron Lett.
1996, 37, 2671-2674.
(8) Matsuzawa, S.; Suzuki, T.; Suzuki, M.; Matsuda, A.; Kawamura,
T.; Mizuno, Y.; Kikuchi, K. FEBS Lett. 1994, 356, 272-274.
10.1021/ol990648k CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999

epoxy alcohol opening, and brominative cyclization, respec-
tively. Broka innovated the use of intramolecular oxymer-
curations to sequentially close the C and B rings, followed
by bromoetherification to access the A ring. The combined
yields for the three key etherification steps in each of these
approaches range from 4 to 16%. This is largely due to the
low yielding formation of the desired bromotetrahydropy-
ranyl A ring via intramolecular bromoetherification (22-
36% yield).13-15 Here, the problematic A ring is constructed
independently and at the outset, and then joined in the form
of C1-C7 aldehyde 6 to a fragment containing the preformed
C ring and representing C8-C15 (7). Subsequent annulation
to close the B ring completes the synthetic sequence.
The synthesis of aldehyde 6 began with (S)-(+)-linalool
(8) which was prepared from geraniol in 95% ee (Mosher
ester analysis) by sequential Sharpless asymmetric epoxi-
dation,16 tosylation, and Te-assisted reduction (Scheme 2).17
Figure 2. X-ray conformation of the C1-C15 domain of thyrsiferyl
18-acetate, highlighting the C10-C14 twist-boat.1
angular methyl group at C10 and the C15 side chain (Figure
2). The distinct structural features of the A-B-C ring system
have motivated the synthetic strategies that have been devised
toward these natural products.9-15 Reported here is a novel
assembly of the A-B-C ring system of thyrsiferol and
venustatriol.
A convergent synthetic approach to these natural products
involves the separate construction of two fragments repre-
senting C1-C15 (5) and C16-C24 domains (Scheme 1).
Scheme 2. Synthesis of the C1-C7 A-Ring (6)
Scheme 1. Retrosynthesis of the C1-C15 Domain of the
Thyrsiferol and Venustatriol Natural Products
Tertiary alcohol 8 was treated with TBCO18 in CH3NO2 at
0 °C to give a mixture of bromotetrahydrofurans 9 (17%
yield) and tetrahydropyrans 10 (38%) and 11 (24%).19
Although the direct yield of the desired tetrahydropyran 11
was comparable to those reported for similar bromoetheri-
fications,13-15 far less of the 5-exo tetrahydrofuran products
(9) were obtained. The mild diastereoselectivity reflects the
preferential axial orientation of the terminal alkene in the
transition state leading to 10. Isomers 9 and 10 could be
reverted to 8 by treatment with Zn in AcOH-EtOH,14,15 but
separation of 10 and 11 was difficult. Subjection of the
mixture of 10 and 11 to alkene oxidation allowed facile
chromatographic separation to provide epimeric bromo
The aldehyde corresponding to 5 was an advanced interme-
diate used in Corey’s total synthesis of 4,14 whereas Shira-
hama9 and Broka15 have also prepared A-B-C ring
constructs related to 5. In the total syntheses of 1, 2, and 4,
Shirahama assembled these rings in the order B-C-A,
highlighting the use of epoxy alcohol opening/ring expansion
strategies for the B and C rings, and a brominative cyclization
to close the A ring. Corey’s concise synthesis of 4 featured
a C-B-A ring closure sequence involving cyanohydrin
formation, distal hydroxyl-directed asymmetric epoxidation-
(9) Hashimoto, M.; Kan, T.; Yanagiya, M.; Shirahama, H.; Matsumoto,
T. Tetrahedron Lett. 1987, 28, 5665-5668.
(10) Broka, C. A.; Hu, L.; Lee, W. J.; Shen, T. Tetrahedron Lett. 1987,
28, 4993-4996.
(11) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. Tetrahedron Lett. 1988, 29, 1143-1144.
(12) Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron
Lett. 1988, 29, 5417-5418.
(13) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.;
Matsumoto, T. J. Org. Chem. 1990, 55, 5088-5107.
(14) Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174.
(15) Broka, C. A.; Lin, Y.-T. J. Org. Chem. 1988, 53, 5876-5885.
(16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masumune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(17) Dittmer, D. C.; Discordia, R. P.; Zhang, Y.; Murphy, C. K.; Kumar,
A.; Pepito, A. S.; Wang, Y. J. Org. Chem. 1993, 58, 718-731.
(18) 2,4,4,6-Tetrabromocyclohexa-2,5-dienone: Kato, T.; Ichinose, I.;
Hosogai, T.; Kitahara, Y. Chem. Lett. 1976, 1187-1190. Also see: Jung,
M. E., D’Amico, D. C.; Lew, W. Tetrahedron Lett. 1993, 34, 923.
(19) All new compounds gave satisfactory characterization data (1H
NMR, IR, MS) consistent with the structures assigned.
320
Org. Lett., Vol. 1, No. 2, 1999

Scheme 3. Synthesis of the C8-C15 C-Ring (7)
aldehydes 12 and 6. Bromooxane 12 showed unique NOEs
conveniently induced both desilylation and monodehydrode-
that were absent in 6 (Scheme 2). Executing the bromo-
etherification early in the synthesis and the opportunity to
revert the undesired bromo ether isomers to 8 ameliorates
the low yield.
bromination to yield the hydroxyalkynyl epoxide 19.
Upon treatment of 19 with catalytic CSA, a 76:24 ratio
of THP:THF isomers was obtained in 98% combined yield.
In contrast, a highly regio- and stereoselective etherification
was effected by treatment of the propargylic epoxide with
BF3‚OEt2 at -10 °C, which resulted in tetrahydropyran 20
as the essentially exclusive product. Hence, the presence of
the methyl substituent at the propargylic position stabilizes
incipient positive charge destiny leading to 6-endo etherifi-
cation. The secondary hydroxyl at C11, which would soon
serve as the B ring heteroatom, was temporarily masked as
a TES ether to complete the synthesis of the C-ring
intermediate 7.
The bromoalkyne 7 was targeted to serve as a C-ring
coupling partner to the A-ring aldehyde 6. The strategy for
the synthesis of 7 was to perform an intramolecular epoxide
opening of a trisubstituted, trans γ,δ-epoxy alcohol. Hanaoka
and co-workers had found that trans propargylic epoxides
bearing electron-withdrawing substituents at the alkyne
terminus favored 5-exo etherification upon treatment with
BF3‚OEt2.20 A δ-hydroxy disubstituted acetylenic cis-epoxide
was reported to also give nearly exclusively the 5-exo ring-
opening product upon treatment with catalytic CSA.21 The
presence of both a methyl and an alkyne substituent on the
distal position of the trans epoxide was anticipated to direct
regioselective 6-endo ring formation. To test this hypothesis
the requisite epoxy alcohol was prepared from lactone 13,
which in turn was obtained from D-glutamic acid in two steps
(Scheme 3).22,23 Acid-catalyzed benzylation of 13 followed
by reduction with DIBAL and direct treatment of the lactol
with (carbethoxyethylene)triphenylphosphorane afforded the
R,â-unsaturated ester 15. The resulting free hydroxyl group
was silylated, and the ester was reduced with DIBAL to
furnish the corresponding allylic alcohol. A Sharpless
asymmetric epoxidation16 using D-(-)-diethyl tartrate pro-
vided the epoxy alcohol 17.24 Subsequent oxidation with SO3‚
pyr gave the epoxy aldehyde, which was converted25,26 into
dibromoalkene 18 in high yield. Treatment of 18 with TBAF
The final B ring could be assembled in four steps via the
convergent coupling of A and C rings. An organochromic-
mediated coupling27,28 of the C8-C15 alkynyl bromide 7
with the C1-C7 aldehyde 6 provided a moderate yield of
propargylic alcohols 21 nonstereoselectively (Scheme 4). It
is noteworthy that the secondary alkyl bromide of 6
withstands this mild carbon-carbon bond-forming process,
as well as the subsequent chemistry en route to 5. Initial
attempts to saturate the alkyne of 21 were accompanied by
premature liberation of the primary and secondary hydroxyl
groups. Semi-hydrogenation (H2, Pd/CaCO3/Pb) of alkyne
21 gave the corresponding (Z)-allylic alcohols without
cleavage of the benzyl or TES ethers, but subsequent
oxidation to the enone was problematic. However, 21 was
converted efficiently into ynone 22, which upon Pd(OH)2-
mediated hydrogenation yielded hemiketal 23, as a result of
triple bond saturation and liberation of both silyl- and benzyl-
masked hydroxyls at C11 and C15, respectively.29 Efficient
and stereoselective axial delivery of hydride to the oxonium
(20) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M. Tetrahedron Lett.
1994, 35, 2179-2182.
(21) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330-5334.
(22) Ravid, U.; Silverstein, R. U.; Smith, L. R. Tetrahedron 1978, 34,
1449-1452.
(27) Takai, K.; Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1985, 5585-5588.
(23) Herdeis, C. Synthesis 1986, 232-233.
(24) The diastereomer of the aldehyde derived from 17 was prepared
previously from L-glutamic acid: Nicolaou, K. C.; Reddy, K. J.; Skokotas,
G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem. Soc. 1993, 115,
3558-3575.
(25) Corey, E. J.; Fuchs, P. Tetrahedron Lett. 1972, 3769-3772.
(26) McIntosh, M. C.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4823-
4832.
(28) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1-36.
(29) The spontaneous acid-induced ketalization of a δ,δ′-dihydroxy
ketone was observed previously in similar hydrogenation conditions:
Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am. Chem. Soc. 1998, 120,
2523-2533.
(30) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978.
Org. Lett., Vol. 1, No. 2, 1999
321

Scheme 4. Synthesis of the C1-C15 Domain (5) of the Thyrsiferol and Venustatriol Natural Products
natural and unique non-natural products will be reported in
due course.
species generated from 23 upon treatment with TMSOTf and
Et3SiH30 then completed the synthesis of the B ring, as well
as the entire C1-C15 system 5. The stereochemistry of 5
was confirmed by NOE studies, summarized in Scheme 4.
Acknowledgment. We thank the Ministerio de Educacio´n
y Cultura of Spain (I.C.G.), the NIH (CA62195), Zeneca
Pharmaceuticals, and Bristol-Myers Squibb (C.J.F.) for
financial support.
This novel and convergent construction of the A-B-C
system of the thyrsiferol natural products provides the C1-
C15 domain in 15 steps in the longest linear sequence from
the glutamic acid derivative 13. The combined yield is 21%
for the bromoetherification, hydroxy epoxide opening, and
hemiketal reductive ring-forming steps. Application of this
convergent approach to the total synthesis of thyrsiferol-type
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 5-7 and 9-23
and their full characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL990648K
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Org. Lett., Vol. 1, No. 2, 1999