Total synthesis of (-)-hennoxazole A [17]

Full text of DOI:10.1021/ja9904686

4924
J. Am. Chem. Soc. 1999, 121, 4924-4925
Scheme 1
Total Synthesis of (-)-Hennoxazole A
David R. Williams,* Dawn A. Brooks, and Martin A. Berliner
Department of Chemistry, Indiana UniVersity
Bloomington, Indiana 47405
ReceiVed February 15, 1999
Since 1986, there has been a dramatic increase in the number
of examples and structural complexity of bioactive natural
products containing the oxazole ring. Marine organisms are rich
sources of these novel metabolites.1 Bisoxazoles, in which the
two rings are directly linked via a single bond, are exemplified
by the hennoxazoles (1-4), first isolated from the sponge
Polyfibrospongia in 1991.2 Hennoxazole A (1) displays potency
against herpes simplex virus type 1 and peripheral analgesic
activity comparable to that of indomethacin. The absolute
configuration of 1 and the issue of relative stereochemistry at C8
and C22 have been resolved following synthesis of the (+)-
enantiomer of 1 by Wipf and Lim.3 Herein we report an efficient
strategy providing for an enantiocontrolled convergent total
synthesis of (-)-hennoxazole A.
allylation strategy was developed to yield functionalized homoal-
lylic alcohols8 based upon the pioneering efforts of E. J. Corey.9
Adaptation of this concept has expeditiously led to construction
of the C1-C17 portion of hennoxazole A as shown in Scheme 2.
Formation of the (R)-homoallylic C8 alcohol 14 was achieved
by transmetalation of optically pure stannane 12 with (R,R)-
bromoborane 139 via allylic transposition to yield an intermediate
borane for facile condensation with aldehyde 5. Stereocontrol is
induced from the 1,2-diphenylethane sulfonamide auxiliary (10.5:1
dr), and is predicted from a chairlike transition state with
minimized steric repulsions.10 Stannane 12 was conveniently
prepared via copper-catalyzed Grignard addition starting from
2-bromo-3-trimethylsilylpropene11 and nonracemic epoxide 10.12
The superior reactivity characteristics of allylstannane 12 were
required as the silane 11 failed to undergo transmetalation with
13, and direct attempts for Lewis acid mediated condensations
of 11 with aldehyde 5 were unproductive.13
Mild transketalization of 14 with bis-(trifluoroacetoxy)iodo-
benzene14 gave 15, which was converted to ketone 16 via
oxidative cleavage.15 Although ketone 16 was susceptible to
â-elimination of methanol, Terashima reduction16 using (+)-N-
methylephedrine resulted in a remarkably efficient reagent-based
hydride addition with high diastereofacial selectivity (8:1 ratio
of C6 alcohols). This new application17 of the Terashima protocol
Our plans sought the direct incorporation of a fully function-
alized tetrahydropyran segment (C1-C7) with C-linkage to the
heterocyclic core and creation of C8 chirality. Concerns for
stability of the nonconjugated triene, including the remote
stereochemistry of the C22 bis-allylic methine, suggested attach-
ment of the C18-C25 portion in the final stages.
The 2,4-disubstituted bisoxazole 5 was assembled as sum-
marized in Scheme 1. Using a mixed anhydride procedure, the
coupling of 4-(tert-butyldiphenylsiloxy)butanoic acid4 and (()-
serine methyl ester hydrochloride afforded 6. Cyclization to
oxazoline 7 occurred in a single step with diethylaminosulfur
trifluoride (DAST)5 at -78 °C. Oxidation with bromotrichlo-
romethane and DBU cleanly effected dehydrogenation to oxazole
8.6 Reiteration of this protocol illustrates a general and highly
effective synthesis of these heterocycles. Studies of the addition
of reactive nucleophiles to aldehyde 5 led to competing ring
deprotonation.7 However, the application of a mild asymmetric
(7) Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Pagel, M. Tetrahedron
Lett. 1998, 39, 8023.
(8) Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Clark, M. P. Tetrahedron
Lett. 1998, 39, 7251.
(9) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495.
(10) Preexisting C4 asymmetry does not play a significant role in the
diastereofacial addition. Model studies of the allylation reaction with achiral
Lewis-acids (TiCl4; CH2CH2; -78 °C) produced a mixture of alcohols (40:
60 ratio) favoring the corresponding C8 (S)-isomer.
(11) Nishiyama, H.; Yokoyama, H.; Harimatsu, S.; Itoh, K. Tetrahedron
Lett. 1982, 23, 1267.
(12) Synthesis of epoxide 10 proceeds via alkylation of 2-lithio-2-methyl-
1,3-dithiane with (S)-epichlorohydrin (97% ee; Aldrich) affording net inversion
at C4 (for Mosher ester analysis of 11; see Supporting Information). Seebach,
D. Synthesis 1969, 17. Braun, M.; Seeback, D. Chem. Ber. 1976, 109, 669.
(13) Common protecting units, such as esters, thioketals, silyl ethers, and
simple ethers are stable to our reaction conditions utilizing bromoborane 13,
whereas acetals and ketals do not survive. Quantitative conversion of 11 to
its corresponding bromide required the use of recrystallized N-bromosuccin-
imide with a low temperature, aqueous NaHSO3 quench to prevent hydrolysis
of the 1,3-dithiane.
(1) (a) Faulker, D. J. Nat. Prod. Rep. 1993, 10, 497; 1994, 11, 395; 1995,
12, 135; 1996, 13, 435. (b) Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993,
93, 1753.
(2) (a) Ichiba, T.; Yoshida, W.; Scheuer, P.; Higa, T. J. Am. Chem. Soc.
1991, 113, 3173. (b) Higa, T.; Tanaka, J.; Kitamura, A.; Koyama, T.;
Takahashi, M.; Uchida, T. Pure Appl. Chem. 1994, 66, 2227.
(3) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558. (b) Wipf, P.;
Lim, S. Chimia 1996, 50, 157. We thank Professor Wipf for proton and carbon
NMR spectra of authentic hennoxazole A for our comparisons.
(4) Binns, F.; Roberts, S. M.; Taylor, A.; Williams, C. F. J. Chem. Soc.,
Perkin Trans. 1 1993, 899.
(5) No evidence for the formation of an intermediate fluoride was observed,
and fluoride-induced desilylation was not encountered. Lafargue, P.; Guenot,
P.; Lellouche, J.-P. Heterocycles 1995, 41, 947.
(6) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron
Lett. 1997, 38, 331.
(14) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(15) (a) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766.
(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(16) (a) Terashima, S.; Tanno, N.; Koga, K. J. Chem Soc. Chem. Commun.
1980, 1026. (b) Terashima, S.; Tanno, N.; Koga, K. Chem Lett. 1980, 981.
(17) The use of achiral hydride sources (LiBH4, NaBH4, super hydride) or
(-)-N-methylephedrine provided selectivity slightly favoring the undesired
(S)-isomer. Interestingly, our Terashima reduction ((+)-N-methylephedrine)
of the corresponding (S)-methyl ether (C8) of ketone 16 gave predominantly
the all-syn arrangement (ratio > 20:1).
10.1021/ja9904686 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 20, 1999 4925
Scheme 2
Scheme 3
with the Grignard reagent derived from (chloromethyl)dimeth-
ylphenylsilane led to 1,2-diol 20. Syn-elimination to the trisub-
stituted Z-olefin was efficiently carried out via ketalization with
N,N-dimethylformamide dimethylacetal with subsequent addition
of acetic anhydride.21 Tamao oxidation of the phenylsilane as
described by Woerpel22 provided 21 in 90% yield. Replacement
of the primary alcohol with 1-phenyl-1H-tetrazole-5-thiol occurred
under Mitsunobu conditions. Careful oxidation of the resulting
sulfide produced a separable mixture of sulfone 22 (76%) and
the corresponding sulfoxides (24%), which were resubmitted to
the oxidation conditions to provide additional sulfone (92%
overall). Prolonged reaction times resulted in products of olefin
epoxidations.
The total synthesis of 1 (Scheme 2) was completed by
generation of the R-sulfonyl carbanion of 22 with KHMDS in
DME at -55 °C followed by addition of aldehyde 18. Spontane-
ous elimination of the intermediate â-hydroxysulfone upon
warming to ambient temperature facilitates a one-pot generation
of C17-C18 alkene with excellent E-selectivity (E:Z ratio 91:9)
in 85% yield. The Kocienski modification23 of the Julia-Lythgoe
olefination is particularly noteworthy because it provides high
trans-stereoselectivity in the absence of factors such as R-chain
branching or conjugation. Hydrolysis of the C4 pivaloate ester
(LiOH in aqueous THF/MeOH (72%)) provided synthetic hen-
presents opportunities for matched and mismatched reductions
of chiral, acyclic â-alkoxyketones. Our studies have important
implications for stereocontrolled synthesis of 1,3,5-polyols orig-
inating from acetoacetate biogenesis.18 Finally, the formation of
18 was secured upon mild acidic treatment of 17, producing a
single tetrahydropyran isomer.
The remote C22 asymmetry of the nonconjugated triene segment
was obtained through chirality transfer in a 2,3-Wittig rearrange-
ment yielding 19 (Scheme 3).19,20
noxazole A (1) as a clear, colorless oil; [R]22 -46.2° (c 1.0,
D
CHCl3), [R]22D lit. -47° (c 3.1, CHCl3),2 identical in all respects
with spectra provided for the natural product.3
Following a Sharpless asymmetric epoxidation of 19 and
protection of the secondary alcohol, nucleophilic oxirane opening
In conclusion, our convergent route to 1 has offered important
advances for asymmetric allylations, efficient oxazole prepara-
tions, and a promising new application of the Terashima reduction.
(18) For leading advances in the synthesis of 1,3,5-polyols: (a) Rychnovsky,
S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753. (b) Rychnovsky, S.
D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058.
(19) Abbott Laboratories generously supplied us with quantities of (S)-3-
butyn-2-ol resulting from enzymatic lipase resolution. The alkyne was
converted to (2S,3Z)-3-penten-2-ol by methylation and Lindlar hydrogenation.
Alkylation with methallyl chloride (NaH) afforded the substrate for Wittig
rearrangement.
(20) Midland, M.-M.; Tsai, D. J.-S. J. Am. Chem. Soc. 1985, 107, 3915.
Review: Mikami, K.; Nakai, T. Synthesis 1991, 594.
(21) Eastwood, F. W.; Harrington, K. J.; Josan, J. S.; Pura, J. L. Tetrahedron
Lett. 1970, 5223.
Acknowledgment. Dedicated in memory of Professor George H.
Bu¨chi. Financial support was provided by an award sponsored by the
National Institutes of Health (GM-41560) and Abbott Laboratories
(fellowship to D.A.B.).
Supporting Information Available: Procedures and spectral data for
all compounds of the synthesis pathway, and proton NMR spectra for 1,
and compounds 6-22 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) (a) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(b) Molander, G. A.; Nichols, P. J. J. Org. Chem. 1996, 61, 6040.
(23) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
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