Total synthesis of the antiviral marine natural product (-)-hennoxazole A.

Article abstract of DOI:10.1021/ol000305i

[structure:see text] The marine natural product hennoxazole A was synthesized by a convergent approach. The diastereoselective Mukaiyama aldol reaction with beta-alkoxy aldehyde was used to construct the tetrahydropyran segment, and the preparation of the

Full text of DOI:10.1021/ol000305i

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4169-4172
Total Synthesis of the Antiviral Marine
Natural Product (−)-Hennoxazole A
Fumiaki Yokokawa,* Toshinobu Asano, and Takayuki Shioiri
Faculty of Pharmaceutical Sciences, Nagoya City UniVersity,Tanabe-dori, Mizuho-ku,
Nagoya 467-8603, Japan
yokokawa@phar.nagoya-cu.ac.jp
Received October 9, 2000
ABSTRACT
The marine natural product hennoxazole A was synthesized by a convergent approach. The diastereoselective Mukaiyama aldol reaction with
â-alkoxy aldehyde was used to construct the tetrahydropyran segment, and the preparation of the nonconjugated triene moiety was accomplished
via SN2 displacement of allylic bromide with vinyllithium and Takai’s iodoolefination followed by palladium-catalyzed cross coupling with
MeMgBr. The final steps involve an amide coupling using DEPC and oxazole synthesis via a oxidation/cyclodehydration process.
Hennoxazole A (1) was isolated from the marine sponge
Polyfibrospongia sp. by Scheuer, Higa, and co-workers.1 It
has been found to be active against herpes simplex virus
type 1 (IC50 ) 0.6 µg/mL) and displays peripheral analgesic
activity. The most unique feature of its structure is a directly
linked bisoxazole core, which is only found in the complex
polycyclic marine alkaloid diazonamide A-B,2 cyanobac-
terium-derived muscoride A,3 and hennoxazole A.4 Other
unique structural features of hennoxazole A are a highly
functionalized tetrahydropyranyl ring moiety and a noncon-
jugated triene unit. The unique structural features and
interesting biological activity of hennoxazole A have attracted
the attention of several synthetic research groups. Wipf and
Lim have accomplished the total synthesis of the (+)-
enantiomer of 1, and their synthesis has elucidated the
absolute configuration of 1 and relative stereochemistries at
C8 and C22.5 Recently, the total synthesis of (-)-hennoxazole
A has been reported by Williams and co-workers.6 In our
program concerning the total synthesis of marine natural
products,7 we have also embarked on the total synthesis of
hennoxazole A.8,9 In this Letter, we wish to report our
synthetic studies leading to the total synthesis of (-)-
hennoxazole A (1).
Our strategy is a convergent approach that combines
tetrahydropyran segment 2 and triene unit 3 via Wipf’s
oxidation/cyclodehydration process. The tetrahydropyran
segment 2 could be obtained by acid-catalyzed ketalization
of the methyl ketone 4, which could be synthesized by the
diastereoselective Mukaiyama aldol reaction. The triene unit
(1) (a) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T. J. Am. Chem.
Soc. 1991, 113, 3173-3174. (b) Higa, T.; Tanaka, J.; Kitamura, A.; Koyama,
T.; Takahashi, M.; Uchida, T. Pure Appl. Chem. 1994, 66, 2227-2230.
(2) Lindquist, N.; Fenical, W.; Van Duyne, G. D. J. Am. Chem. Soc.
1991, 113, 2303-2304.
(3) Nagatsu, A.; Kajitani, H.; Sakakibara, J. Tetrahedron. Lett. 1995,
36, 4097-4100.
(4) Linked trisoxazole units have been found in some marine macrolides.
(a) Ulapualides A and B (Roesener, J. A.; Scheuer, P. J. J. Am. Chem. Soc.
1986, 108, 846-847). (b) Halichondramides (Kernan, M. R.; Molinski, T.
F.; Faulkner, J. D. J. Org. Chem. 1988, 53, 5014-5020). (c) Kabiramides
A-E (Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Koseki, K.; Noma, M.;
Noguchi, H.; Sankawa, U. J. Org. Chem. 1989, 54, 1360-1363). (d)
Jaspisamides A-C (Kobayashi, J.; Murata, O.; Shigemori, H. J. Nat. Prod.
1993, 56, 787-791). (e) Mycalolides (Matsunaga, S.; Sugawara, T.;
Fusetani, N. J. Nat. Prod. 1998, 61, 1164-1167, and references therein).
(5) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558-559. (b)
Wipf, P.; Lim, S. Chimia 1996, 50, 157-167.
(6) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc.
1999, 121, 4924-4925.
(7) For recent examples of our work, see: Sugiyama, H.; Yokokawa,
F.; Shioiri, T. Org. Lett. 2000, 2, 2149-2152.
(8) For our preliminary synthetic studies on hennoxazole A, see: (a)
Cheng, Z.; Hamada, Y.; Shioiri, T. Synlett 1997, 109-110. (b) Shioiri, T.;
McFarlane, N.; Hamada, Y. Heterocycles 1998, 47, 73-76.
(9) For other synthetic studies on hennoxazole A, see: Barrett, A. G.
M.; Kohrt, J. T. Synlett 1995, 415-416.
10.1021/ol000305i CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/01/2000

3 could be constructed by SN2 displacement of allylic
bromide 6 with vinyllithium 5 (Scheme 1).
Scheme 2a
Scheme 1
The synthesis of the tetrahydropyran segment 2 was started
(Scheme 2) by treatment of commercially available (R)-
glycidyl tosylate (7) with lithiated 1,3-dithiane followed by
copper-catalyzed Grignard addition to afford the alcohol 8
in 63% yield. Protection of the alcohol 8 as its p-methoxy-
benzyl (PMB) ether 9 and removal of the 1,3-dithiane
provided the aldehyde 10 in 64% yield. The BF3‚OEt2-
mediated Mukaiyama aldol reaction between the trimethyl-
silyl enol ether 12 derived from benzalacetone (11) and the
aldehyde 10 provided the aldol adduct 13 in 89% yield with
good diastereoselectivity (88:12 anti:syn).10 This transforma-
tion establishes the C6 stereocenter with a good level of 1,3-
anti induction.12 Subsequent chelation-controlled reduction13
of the C8 ketones from the aldol reaction afforded the
corresponding syn diols. Protection of the syn diols as
acetonides followed by separation on silica gel gave the
desired isomer 14 (59%),14 the minor isomer 15 (9%),14 and
recovered starting diol (31%). The terminal olefin of 14 was
converted to the methyl ketone 4 by the modified Wacker
oxidation16 in 77% yield. Mild acidic treatment of 4 caused
cleavage of the acetonide and intramolecular ketalization
simultaneously to produce the tetrahydropyran 16 in 85%
a (a) n-BuLi, 1,3-dithiane, THF; (b) vinylmagnesium bromide,
CuI, THF, 63%; (c) KH, PMBCl, n-Bu4NI, THF, 86%; (d) MeI,
CaCO3, aq. CH3CN, 74%; (e) TMSOTf, Et3N, CH2Cl2, 96%; (f)
BF3‚OEt2, CH2Cl2, -78 °C, 89% (88:12); (g) Et2BOMe, NaBH4,
THF; (h) 2,2-dimethoxy propane, PPTs; (i) silica gel column
chromatography 14; 59%, 15; 9%; (j) PdCl2, Cu(OAc)2‚H2O,
AcNMe2/H2O (7:1), 77%; (k) PPTs, MeOH, 85%; (l) NaH, MeI,
THF, 98%; (m) OsO4, NMO, aq. acetone; (n) NaIO4, pH 7
phosphate buffer, THF; (o) Cp2TiCH2AlClMe2, THF, 72%; (p)
OsO4, NMO, aq. acetone; (q) DPSCl, Et3N, DMAP, CH2Cl2, 94%;
(r) MsCl, Et3N, DMAP, CH2Cl2; (s) n-Bu4NN3, DMF, 100 °C, 68%;
(t) Ph3P, aq. THF, 55 °C, 68%.
yield. After O-methylation of 16, oxidative cleavage of the
styryl group in 17 followed by Tebbe olefination17 afforded
18 in 71% yield. Dihydroxylation of terminal olefin 18 with
osmium tetroxide and N-methylmorpholine N-oxide (NMO)
and selective protection of the primary alcohol led to the
mono-tert-butyldiphenylsilyl (DPS) ether 19 in 94% yield.
Treatment of the resulting alcohol with methanesulfonyl
chloride (MsCl) and displacement with n-Bu4NN3 provided
the azide 20 in 68% yield. Mild reduction of the azide 20
with Ph3P/H2O completed the C1-C10 tetrahydropyran seg-
ment 2 in 68% yield.
(10) The configuration of the newly formed hydroxyl stereogenic center
of the aldol adduct 13 was established by NOE analysis of the corresponding
p-methoxybenzylidene acetal, which was produced by treatment of the aldol
adduct 13 under anhydrous condition with DDQ (see Supporting Informa-
tion).11
(11) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron. Lett. 1982,
23, 889-892.
(12) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322-4343.
(13) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 1923-1926.
(14) The 1,3-syn relationships of the acetonides 14 and 15 were supported
by analysis of their 13C NMR spectra.15
(15) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron. Lett. 1990,
31, 945-948. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron.
Lett. 1990, 31, 7099-7100. (c) Rychnovsky, S. D.; Rogers, B.; Yang, G.
J. Org. Chem. 1993, 58, 3511-3515.
(16) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998,
39, 8765-8768.
The synthesis of the triene unit (Scheme 3) was initiated
by protection of methyl (S)-3-hydroxy-2-methylpropionate
(21) as its DPS ether to give 22 in 95% yield. Diisobutyl-
aluminum hydride (DIBAL) reduction of 22 afforded the
(17) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613.
4170
Org. Lett., Vol. 2, No. 26, 2000

Scheme 3a
a (a) DPSCl, imidazole, DMF, 95%; (b) DIBAL, Et2O, -78 °C; (c) (CF3CH2O)2P(O)CH(CH3)CO2CH3 (23), KHMDS, 18-crown-6,
THF, -78 °C, 48%; (d) DIBAL, Et2O, -78 °C, 94%; (e) CBr4, Ph3P, CH3CN, 99%; (f) 26, t-BuLi, HMPA, THF, -78 °C, 53%; (g) TBAF,
THF, 90%; (h) Py‚SO3, DMSO, Et3N, CH2Cl2; (i) CrCl2, CHI3, THF, 68%; (j) MeMgBr, Pd(Ph3P)4, THF, quant.; (k) aq. HCl, MeOH,
THF, 83%; (l) PDC, DMF, 72%; (m) DEPC, HCl‚H-(S)-Ser-OMe, Et3N, DMF, 91%; (n) Deoxo-fluor, CH2Cl2, -20 to -30 °C; (o) BrCCl3,
DBU, CH2Cl2, 80%; (p) aq. LiOH, THF, quant.
corresponding aldehyde, which was directly treated with the
phosphonate 23 under (Z)-selective Still-Horner olefination
conditions18 to provide the (Z)-ester 24 in 48% yield as a
single isomer. Reduction of the methyl ester 24 with DIBAL
and bromination of the resulting allylic alcohol 25 using CBr4
and Ph3P gave the allylic bromide 6 in 93% yield.19 After
considerable experimentation,20 SN2 displacement of the
allylic bromide 6 with vinyllithium derived from the vinyl
iodide 2621 cleanly afforded the skipped diene 27 in 53%
yield.22 After deprotection of the DPS group, the resulting
primary alcohol 28 was oxidized by the Parikh-Doering
oxidation23 to furnish the corresponding aldehyde, which was
immediately subjected to the Takai’s CrCl2-mediated
iodoolefination process24 to give the (E)-vinyl idodide 29 in
61% yield. Cross coupling of the vinyl iodide 29 with
MeMgBr in the presence of palladium catalyst25 constructed
the nonconjugated tiene unit 30 in quantitative yield.
Removal of the methoxymethyl group (MOM), oxidation
using pyridinium dichromate (PDC), followed by coupling
with (S)-serine methyl ester using diethyl phosphorocyanidate
(DEPC)26 afforded the amide 33 in 54% yield. According
to the Wipf and Williams’ methodology,27 dehydrative
cyclization of the â-hydroxy amide 33 with bis(2-methoxy-
ethyl)aminosulfur trifluoride (Deoxo-fluor) to the oxazoline
followed by oxidation with BrCCl3 and 1,8-diazabicyclo-
[5.4.0]-7-undecene (DBU) provided the oxazole 34 in 80%
(18) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-
4408. (b) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16, 1285-
1295. (c) Rathke, M. W.; Bouhlel, E. Synth. Commun. 1990, 20, 869-875.
(19) Cheng, Z.; Nakao, R.; Hamada, Y.; Shioiri, T. Unpublished results.
We thank Dr. Z. Cheng and Mr. R. Nakao for their preliminary studies on
the preparation of the triene unit.
(20) Stille coupling of allylic bromide or acetate with vinyl stannane
caused the loss of the C20-C21 double bond stereochemistry to give the
inseparable E/Z mixture.
Scheme 4a
(21) MOM ether 26 was preparaed by MOMCl, i-Pr2NEt in CH2Cl2 from
the known alcohol. Yamada, H.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1991, 65, 4569-4574.
(22) The Z-configuration of the C20-C21 double bond in 27 was
confirmed by NOE analysis.
(23) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(24) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(25) Review: Negishi, E.-I.; Liu, F. Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998;
pp 1-47.
a (a) DEPC, Et3N, DMF; (b) TBAF, THF, 86%; (c) Dess-Martin
periodinane, CH2Cl2; (d) BrCCl2CCl2Br, Ph3P, 2,6-di-tert-butylpy-
ridine, CH2Cl2, 0 °C; (e) DBU, CH3CN, 60%; (f) DDQ, pH 7
phosphate buffer, CH2Cl2, 36%.
(26) Takuma, S.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30,
3147-3153, and references therein.
(27) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165-1168.
Org. Lett., Vol. 2, No. 26, 2000
4171

yield.28 Saponification of the methyl ester 34 completed the
construction of the C11-C25 triene unit 3 in quantitative yield.
The final steps of the synthesis (Scheme 4) began with
the condensation of 2 and 3 using DEPC,26 and removal of
the DPS group provided the amido alcohol 35 in 86% yield.
Oxazole synthesis via the oxidation/cyclodehydration pro-
cess5,29 was performed through intermediary bromo-oxazoline
under Wipf’s conditions to afford the bisoxazole 36 in 60%
yield. The final oxidative removal of the C4 PMB group with
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)30 provided
(-)-hennoxazole A (1) in 36% yield. The synthetic hennox-
azole A was identical in all respects with spectra provided
for the natural product.
In summary, we have developed an efficient, convergent
strategy for the preparation of the structurally and biologically
attractive marine natural product hennoxazole A.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Research in Nagoya City
University (to F.Y.) and Grant-in-Aids from the Ministry of
Education, Science, Sports and Culture, Japan. Helpful
comments by Prof. Y. Hamada of Chiba University at the
early stage of this work are greatly acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds of the
synthesis. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) We thank Professor Wipf for physical data of the enantiomer of 34
for our comparisons.
(29) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606.
(30) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888.
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