Total synthesis of the supposed structure of (-)-sclerophytin A and an improved route to (-)-7-deacetoxyalcyonin acetate.

Article abstract of DOI:10.1021/ol006236p

[reaction: see text]Stereoselective acid-catalyzed rearrangement of 15-->16 is the central step in total syntheses of (-)-7-deacetoxyalcyonin acetate (1) and the compound with the alleged structure of sclerophytin A (2). Since tetracyclic diether 2 is not identical to sclerophytin A, the structure of this antineoplastic marine diterpene must be revised. The conversion of 15-->16 demonstrates for the first time that tetrahydrofurans containing (Z)-1-methylalkenyl side chains can be prepared by Prins-pinacol rearrangements.

Full text of DOI:10.1021/ol006236p

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2683-2686
Total Synthesis of the Supposed
Structure of (−)-Sclerophytin A and an
Improved Route to
(−)-7-Deacetoxyalcyonin Acetate
Larry E. Overman* and Lewis D. Pennington
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
Received June 21, 2000
ABSTRACT
Stereoselective acid-catalyzed rearrangement of 15 f 16 is the central step in total syntheses of (−)-7-deacetoxyalcyonin acetate (1) and the
compound with the alleged structure of sclerophytin A (2). Since tetracyclic diether 2 is not identical to sclerophytin A, the structure of this
antineoplastic marine diterpene must be revised. The conversion of 15 f 16 demonstrates for the first time that tetrahydrofurans containing
(Z)-1-methylalkenyl side chains can be prepared by Prins−pinacol rearrangements.
Marine invertebrates are a rich source of structurally novel
oxacyclic diterpenes.1 One large family is derived from
cembrane precursors by C2-C11 bond formation and
includes the cladiellins (e.g., 1 and 2), the briarellins (e.g.,
3), the asbestinins (e.g., 4) and the sarcodictyins, (e.g.,
eleuthrobin). The cladiellins, briarellins, and asbestinins have
in common a rare oxatricyclic ring system composed of
hydroisobenzofuran (2-oxabicyclo[4.3.0]-nonane) and oxa-
cyclononane units as well as the six stereogenic centers
indicated by asterisks in structure 1.1
In 1995, we reported an enantioselective total synthesis
of (-)-7-deacetoxyalcyonin acetate (1), which was the first
total synthesis of a 2,11-cyclized cembranoid ether.2 The
(1) For recent reviews, see: (a) Coll, J. C. Chem. ReV. 1992, 92, 613-
631. (b) Wahlberg, I.; Eklund, A.-M. In Progress in the Chemistry of
Organic Natural Products; Springer-Verlag: New York, 1992; Vol. 60,
pp 1-141. (c) Bernardelli, P.; Paquette, L. A. Heterocycles 1998, 49, 531-
derived dienyl diol 5 with a trans-R,â-unsaturated aldehyde,
556.
central step in this synthesis was condensation of (S)-carvone-
(2) (a) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,
117, 10391-10392. (b) MacMillan, D. W. C. Ph.D. Dissertation, University
of California, Irvine, CA, 1996.
(3) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am. Chem. Soc.
1991, 113, 5354-5365.
10.1021/ol006236p CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/01/2000

(E)-6, to generate the hexahydroisobenzofuran ring and five
stereogenic centers of (E)-9 (Figure 1). A potentially valuable
chromatography on AgNO3-impregnated silica gel. Conver-
sion of 12 to the corresponding vinyllithium species followed
by formylation with DMF provided isomerically pure 13.
A two-step procedure for combining enal 13 and dienyl
diol 142 to produce hexahydroisobenzofuran 16 was devel-
oped (Scheme 2). Condensation of 13 with 14 under carefully
Scheme 2
Figure 1.
extension of this strategy, which we anticipated might be of
particular utility in addressing the additional structural
complexity of the asbestinins and briarellins, would be
realized if bicyclic ethers 9 containing a (Z)-1-methylalkenyl
side chain could be prepared from condensation of 5 and
(Z)-R,â-unsaturated aldehydes. It was unclear at the outset
of this investigation whether such an extension could be
achieved, since conjugated oxocarbenium ion 7, a presumed
intermediate in this Prins cyclization-pinacol rearrangement
sequence,3 might undergo ready stereomutation. We chose
to first pursue this issue in the context of a total synthesis of
sclerophytin A, a marine diterpene whose structure, although
depicted with some ambiguity in the original accounts,4 was
most reasonably construed to be 2.5 This cladiellin was
chosen since it was reported to exhibit notable in vitro
toxicity against the L1210 leukemia cell line (0.001 µg
mL-1).4a Moreover, selection of this target would provide
an opportunity for us to demonstrate that our total synthesis
strategy could readily address natural products of this group
that contain exocyclic as well as endocyclic unsaturation in
the cyclohexane ring.6
optimized conditions generated acetal 15 as a mixture of
diastereomers in 76% yield. Prins-pinacol rearrangement
of 15 proceeded efficiently in the presence of catalytic SnCl4
to give 16 in 88% yield. Salient features of the pivotal
transformation of 13 and 14 to 16 are as follows: no
stereomutation of the alkene substituent is observed and all
of the carbon atoms of the target molecule are installed.
The extraneous carbon and protecting groups were re-
moved from 16, and the tertiary hydroxyl group was installed
stereoselectively as outlined in Scheme 3. Photolytic de-
formylation8 of 16 furnished hexahydroisobenzofuran 17 in
Scheme 3
Our studies began with the synthesis of (Z)-R,â-unsaturated
aldehyde 13 (Scheme 1). Silylation of commercially available
Scheme 1
3-buten-1-ol (10) followed by ozonolysis and stereoselective
Wittig olefination of the derived aldehyde with phosphonium
ylide 117 furnished isomerically pure Z iodide 12, after
removal of a trace of the E stereoisomer by flash column
2684
Org. Lett., Vol. 2, No. 17, 2000

66% yield after removal of ∼10% of the ∆1,12a-tetrasubsti-
tuted alkene regioisomer by medium-pressure liquid chro-
matography. Bis-desilylation of 17, followed by homoallylic
alcohol-directed epoxidation of 18 with (t-BuO)3Al/t-
BuO2H,9 provided a separable 7:1 mixture of epoxides 19
and 20 in good yield.
in two high-yielding steps to crystallographically character-
ized (-)-7-deacetoxyalcyonin acetate (1).2
Completion of the synthesis of the presumed structure of
sclerophytin A (2) required formation of the bridging
tetrahydropyran ring (Scheme 5). Desilylation of 23 provided
A series of transformations to elaborate the side chains of
19 set the stage for the formation of the oxonane ring
(Scheme 4). Regioselective opening of epoxide 19 with
Scheme 5
Scheme 4
diol 24,2b which upon sequential treatment with Hg(OAc)2
and NaBH4 furnished the single tetracyclic diether 25 in 47%
yield (66% based upon consumed 24).12 At short irradiation
times in the presence of acetic acid, light-induced isomer-
ization of 25 was realized in high yield to give 2 and 25 in
a 4:1 ratio.6,13 Spectral data for 2 did not match those reported
for sclerophytin A.4 To pursue the possibility that sclero-
phytin A was the alcohol epimer, 2 was oxidized to ketone
26,14 which underwent reduction from the less-hindered
â-face with high selectivity to generate 27. NMR data for
this product were again distinctly different from those
reported for sclerophytin A. Our results are in accord with
independent investigations of Paquette and co-workers,15 who
after reinvestigating the natural isolate have proposed a
revised structure for sclerophytin A.16
LiAlH4 followed by differential protection of the primary
and tertiary alcohols produced 21. Selective iodoboration of
the alkyne moiety of 21 with B-iodo-9-borabicyclo[3.3.1]-
nonane10 (B-I-9-BBN) and subsequent cleavage of the
pivaloyl group and oxidation of the resulting primary alcohol
generated the known iodoaldehyde 22.2 As previously
demonstrated,2 Nozaki-Hiyama-Kishi cyclization11 of 22
proceeded with high stereoselectivity to deliver 23 in good
yield. This latter intermediate had been converted previously
(4) (a) Sharma, P.; Alam, M.J. Chem. Soc., Perkin Trans. 1 1988, 2537-
2540. (b) Alam, M.; Sharma, P.; Zektzer, A. S.; Martin, G. E.; Ji, X.; van
der Helm, D. J. Org. Chem. 1989, 54, 1896-1900.
(5) Hochlowshi, J. E.; Faulkner, D. J. Tetrahedron Lett. 1980, 21, 4055-
4056.
In conclusion, these studies demonstrate that (Z)-R,â-
unsaturated aldehydes are viable reaction partners in the
Prins-pinacol synthesis of cyclic ethers. Using this approach,
a formal total synthesis (-)-7-deacetoxyalcyonin acetate (1),
(6) Kropp, P. J. In Organic Photochemistry; Padwa, A., Ed.; Marcel
Dekker: New York, 1979; Vol. 4, pp 1-142.
(7) Wang, J. C. T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827-2828.
(8) Baggiolini, E.; Hamlow, H. P.; Schaffner, K. J. Am. Chem. Soc. 1970,
92, 4906-4921.
(12) Bordwell, F. G.; Douglass, M. L. J. Am. Chem. Soc. 1966, 88, 993-
999.
(13) Marshall, J. A.; Hochstetler, A. R. J. Am. Chem. Soc. 1969, 91,
648-657.
(14) The minor endocyclic alkene isomer was easily removed at this
stage by flash chromatography.
(15) Paquette, L. A.; Moradei, O. M.; Bernardelli, P.; Lange, T. Org.
Lett. 2000, 2, 1875-1878.
(16) Friedrich, D.; Doskotch, R. W.; Paquette, L. A. Org. Lett. 2000, 2,
1879-1882.
(9) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 1657-
1660.
(10) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983,
24, 731-734.
(11) (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050. (b) Kress, M. H.;
Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999-
6002.
Org. Lett., Vol. 2, No. 17, 2000
2685

which is two steps shorter than our original route,2 was
achieved and an enantioselective total synthesis of the alleged
structure 2 of (-)-sclerophytin A was accomplished. The
synthesis of 2 was realized in 15 steps and 3% overall yield
from (Z)-R,â-unsaturated aldehyde 13 and dienyl diol 14.
mass spectra were obtained at UCI using instrumentation
acquired with the assistance of NSF and NIH Shared
Instrumentation programs. We are grateful to Professor Leo
A. Paquette for exchange of information regarding the actual
and supposed structures of (-)-sclerophytin A.
Supporting Information Available: Experimental pro-
cedures and characterization data for the preparation of
compounds 15, 16, 19, 25, and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was financed by NIH
Grant NS-12389, while L.D.P. was supported in part by a
Pharmacia & Upjohn Graduate Fellowship in Synthetic
Organic Chemistry. The authors thank Dr. John Greaves and
Dr. John Mudd for mass spectrometric analyses. NMR and
OL006236P
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Org. Lett., Vol. 2, No. 17, 2000