Asymmetric Synthesis of (-)-Isolaurallene

Full text of DOI:10.1021/ja005892h

J. Am. Chem. Soc. 2001, 123, 1533-1534
1533
Scheme 1
Asymmetric Total Synthesis of (-)-Isolaurallene
Michael T. Crimmins* and Kyle A. Emmitte
Venable and Kenan Laboratories of Chemistry
The UniVersity of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599-3290
ReceiVed December 15, 2000
Medium-ring ethers of various structural types have been
isolated from marine organisms.1 While medium-ring ethers such
as the ladder ether toxins have important implications with regard
to their biological impact, it is the exquisite structures of naturally
occurring medium-ring ethers that has provoked the imagination
of synthetic chemists. Because eight-membered cyclic ethers are
more prevalent, many unique and interesting approaches to their
construction have been designed.2 Nine-membered ethers are
perhaps less common, but are present in the ladder toxins
brevetoxin A,3 ciguatoxin,4 gambieric acid A,5 the eunicellins,6
and the simpler metabolites obtusenyne,7 neolaurallene,8 and
isolaurallene.9 Synthetic approaches to nine-membered ethers have
been limited not only because of their infrequent occurrence, but
also because of the challenges associated with their stereoselective
assembly.10 Isolaurallene, which contains a nine-membered cyclic
ether, as well as a bromoallene-substituted tetrahydrofuran, was
isolated by Kurata from laurencia nipponica yamada collected
in Izumihama near Hiroo on the Pacific Coast of Hokkaido. The
structure of isolaurallene was proposed based on spectroscopic
information and later confirmed by a single-crystal X-ray study.9
The closely related metabolite, neolaurallene, was subsequently
isolated and its structure was also elucidated by X-ray crystal-
lography.8
As part of our continuing program directed toward the
development of flexible strategies for the asymmetric construction
of medium-ring ether metabolites,2 we designed an approach to
the synthesis of isolaurallene that focused on construction of the
core nine-membered ether through a ring-closing metathesis
without the assistance of a cyclic conformational constraint
(Scheme 1).11 A similar asymmetric alkylation-olefin metathesis
approach was employed in our recent laurencin synthesis.12 It was
anticipated that diene 3 would undergo rapid closure to the ∆5-
oxonene because of the gearing effect created by two synergistic
gauche effects at C6-C7 and C12-C13.13 The assembly of diene
3 would be completed by an asymmetric glycolate alkylation14
of oxazolidinone 4 followed by additional functionalization. The
implementation of this plan culminating in the first total synthesis
of isolaurallene is the subject of this report.
The oxazolidinone 4 was prepared from the glycolic acid
derivative as described for the antipode.12 Exposure of 4 to NaN-
(SiMe3)2 and iodide 515 produced the alkylation product 6 in high
yield with excellent (97:3) diastereoselectivity (Scheme 2).14 The
auxiliary was reductively removed with sodium borohydride to
provide the alcohol 7 in 88% yield.16 Oxidation of the alcohol 7
under Swern conditions17 gave the aldehyde 8, which was
immediately exposed to Brown’s asymmetric allylation18 to
generate a 96:4 mixture of the two diastereomeric secondary
alcohols in 93% yield. The major isomer was subsequently
converted to the corresponding acetate 9. Removal of the benzyl
ethers of 9 under oxidative conditions19 also resulted in oxidation
of the allylic alcohol to the aldehyde. The aldehyde was
immediately reduced with sodium borohydride to provide diol
10, which was readily converted to the bis silyl ether 11 upon
treatment with Et3SiOTf (67% for 3 steps). The allylic alcohol
12 was prepared by selective removal of the primary silyl ether
with catalytic PPTS in ethanol and dichloromethane. Epoxidation
of the allylic alcohol 12 under Sharpless conditions20 led to
exclusive formation of the desired epoxyalcohol which was
immediately exposed to the Grubbs catalyst [(Cy3P)2Cl2Rud
(1) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155-198. Faulkner, D. J.
Nat. Prod. Rep. 1998, 15, 113-158. Faulkner, D. J. Nat. Prod. Rep. 1997,
14, 259-302. Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75-125 and earlier
reviews in the same series. Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93,
1897-1909.
(2) For recent approaches to the synthesis of eight-membered-ring ethers
see: Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473-
5476 and references therein.
(3) Pawlak, J.; Tempesta, M. S.; Golik, J.; Zagorski, M. G.; Lee. M. S.;
Nakanishi, K.; Iwashita, T.; Gross, M. L.; Tomer, K. B. J. Am. Chem. Soc.
1987, 109, 1144-1150.
(11) For a discussion of conformational effects on rates of ring closing
metathesis of medium-ring ethers see: Crimmins, M. T.; Emmitte, K. A.
Synthesis 2000, 899-903. Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc.
1999, 121, 5653-5660. Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997,
62, 7548-7549. For other applications of ring-closing metathesis in the
synthesis of medium-ring ethers see: Maier, M. C. Angew. Chem., Int. Ed.
2000, 39, 2073-2077. Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-
3043. Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372-374
and references therein.
(4) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T. J. Am. Chem.
Soc. 1989, 111, 8929-8931. Murata, M.; Legrand, A. M.; Ishibashi, Y.; Fukui,
M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386.
(5) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, T.; Hirota,
H. J. Am. Chem. Soc. 1992, 114, 1102-1103. Nagai, H.; Murata, M.; Torigoe,
K.; Satake, M.; Yasumoto, T. J. Org. Chem. 1992, 57, 5448-5453.
(6) Uchio, Y.; Kodama, M.; Usui, S.; Fukazawa, Y. Tetrhedron Lett. 1992,
33, 1317-1320.
(7) King, T. J.; Imre, S.; Oztunc, A.; Thomson, R. H.; Tetrahedron Lett.
1979, 1453-1454. Howard, B. M.; Schulte, G. R.; Fenical, W.; Solheim, B.;
Clardy, J. Tetrahedron 1980, 36, 1747-1751. Norte, M.; Gonzalez, A. G.;
Cataldo, F.; Rodriguez, M. L.; Brito, I. Tetrahedron 1991, 47, 9411-9418.
(8) Notaro, G.; Piccialli, V.; Sica, D.; Mayol, L.; Giordano, F. J. Nat. Prod.
1992, 55, 626-632.
(12) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-2032.
(13) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley and Sons: New York, 1994; pp 609-610.
(14) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165-2167.
(15) Prepared from 2-butyne-1,4-diol as follows: (1) BnBr, NaH, THF;
(2) LiAlH4, Et2O; (3) MsCl, Et3N, CH2Cl2; (4) NaI, THF. Sugiyama, H.;
Yokokawa, F.; Shioiri, T.; Katagiri, N.; Oda, O.; Ogawa, H. Tetrahedron Lett.
1999, 40, 2569-2572.
(16) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067-7070.
(17) Swern, D.; Mancuso, A. J.; Huang, S.-L. J. Org. Chem. 1978, 43,
2480-2482.
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U. S. J. Am. Chem. Soc. 1990, 112, 2389-2392.
(9) Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T. Chem.
Lett. 1982, 1031-1034.
(10) For approaches to nine-membered-ring ethers see: Fujiwara, K.;
Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org.
Chem. 1999; 64, 2616-2617 and references therein.
(19) Schreiber, S. L.; Ikemoto, N. J. Am. Chem. Soc. 1992, 114, 2524-
2536.
(20) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
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10.1021/ja005892h CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/27/2001

1534 J. Am. Chem. Soc., Vol. 123, No. 7, 2001
Communications to the Editor
Scheme 2
Scheme 3
addition of ethynylmagnesium bromide to the aldehyde derived
from diol 14 was nonselective. The bromoallene was introduced
by conversion of the propargylic alcohol to the trisylate 19
followed by its SN2′ displacement through exposure to LiCuBr2.23
The desired regioisomer 20 was obtained as an 8:1 mixture of
isomeric bromoallenes and was accompanied by 9% of the product
from direct SN2 displacement. Finally, conversion of bromoallene
20 to isolaurallene was achieved by removal of the silyl ether
and treatment of the secondary alcohol with CBr4-trioctylphos-
phine24 to give synthetic (-)-isolaurallene in 58% overall yield.
The structure of synthetic (-)-isolaurallene was confirmed by
CHPh, CH2Cl2, 40 °C]21 to provide the oxonene 13 in 94% yield
in 6 h. The rapid and efficient metathesis formed the nine-
membered ring without the aid of a cyclic conformational
constraint. Hydrolysis of the acetate 13 with potassium carbonate
in methanol resulted in concomitant closure of the tetrahydrofuran
ring. The basic skeleton incorporating both the oxonene and the
tetrahydrofuran had been completed in just 11 steps from
oxazolidinone 4.
Completion of the synthesis required incorporation of the C12
secondary bromide and stereoselective installation of the bromo-
allene unit. To this end, diol 14 was converted to the allylic
alcohol 15 by oxidative cleavage of the diol to the aldehyde,
condensation of the aldehyde with carbethoxy-methylenetri-
phenylphosphorane, and subsequent reduction of the unsaturated
ester with i-Bu2AlH to give the alcohol 15 (Scheme 3). Since a
highly stereocontrolled introduction of a propargylic alcohol was
required for stereoselective construction of the allene, we once
again called on the Sharpless epoxidation20 to produce the epoxy
alcohol 16 with essentially complete control of stereochemistry.
Conversion of the epoxy alcohol to the chloride 17 set the stage
for the elimination of the chloroepoxide to the propargylic alcohol
18 according to the method of Yadav.22 The propargylic alcohol
18 was produced in >98:2 diastereoselectivity. In contrast,
1
comparison of 13C, H NMR, IR, and [R]D to authentic spectra
of the natural product.9
Acknowledgment. This work was supported by a grant from the
National Institutes of Health (GM 60567). We are grateful to Dr. Kazuya
Kurata for providing spectra of natural (-)-isolaurallene and we thank
Professor Akio Murai for his gracious assistance in obtaining the authentic
spectra.
Supporting Information Available: Spectral data and experimental
procedures for compounds 1, 6-20 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA005892H
(23) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem.
1985, 50, 364-367. Montmury, M.; Gore´, J. Synth. Commun. 1980, 873.
Grese, T. A.; Hutchinson, K. D.; Overman, L. E. J. Org. Chem. 1993, 58,
2468-2477.
(21) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(22) Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990,
55, 4235-4237.
(24) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.