A flexible synthetic approach to the hennoxazoles

Article abstract of DOI:10.1055/s-2007-967978

Three advanced intermediates corresponding to the carbon skeleton of the hennoxazoles have been prepared. Central to the strategy is the synthesis of the oxazoles prior to coupling with the other fragments and a dithiane addition to allow for the generati

Full text of DOI:10.1055/s-2007-967978

LETTER
623
A Flexible Synthetic Approach to the Hennoxazoles
A
Flexible
Appr
i
the Tot
c
al Synthesis of th
J
e
H
ennox
.
s
Zylstra,1 Miles W.-L. She,1 Walter A. Salamant,1 James W. Leahy*1
Department of Chemistry, University of California, Berkeley, CA 94720-1460, USA
Fax +1(650)8378177; E-mail: jleahy@exelixis.com
Received 24 July 2006
published the synthesis of several key intermediates, cul-
minating in a total synthesis of the natural enantiomer of
hennoxazole A (1a).9 These results have prompted us to
disclose our own efforts toward a unified total synthesis of
the hennoxazoles.
Abstract: Three advanced intermediates corresponding to the car-
bon skeleton of the hennoxazoles have been prepared. Central to the
strategy is the synthesis of the oxazoles prior to coupling with the
other fragments and a dithiane addition to allow for the generation
of diastereomers of the natural product.
Key words: hennoxazole A, isopentylidene, bisoxazole, b,g-unsat-
Retrosynthetically, we disconnected the molecule at the
C7–C8 and C18–C19 bonds, leading to three disparate
fragments: epoxide 2, bisoxazole 3 and skipped diene 4
(Scheme 1). These disconnections were chosen to allow
easy variation of the stereochemistry at C8 and C22. After
introduction of C8 as a protected carbonyl, a stereoselec-
tive reduction and subsequent methylation would allow
access to either potential diastereomer. Osmylation,
periodate cleavage, and ketalization at C2 would afford
the hydropyran, while alkynylation to incorporate C18
and palladium coupling with a diene derived from 4
would complete the carbon skeleton. Ketalization with the
appropriate alcohol would provide hennoxazoles A–C
and E, while reductive deoxygenation of 1 would lead to
hennoxazole D.
urated aldehyde, skipped polyene
In 1990, Scheuer and Higa isolated a series of alkaloids
from Polyfibrospongia sp., a marine sponge collected
near the island of Miyako, Japan.2 They named these
natural products the hennoxazoles, and the most abundant
member of this family, hennoxazole A (1a, Figure 1) was
found to display antiherpetic and analgesic activity. Sub-
sequent work by Higa provided several additional hen-
noxazoles in which the only differences were within the
C1–C8 polyol region.3 The initial structural assignments
only established the relative configuration about the pyran
ring, while the absolute stereochemistry of the pyran, C8,
and C22 remained unknown.
OH
R'
OMe
13
OMe
N
8
O
OMe
O
13
N
18
8
O
O
O
N
18
OR
O
N
22
22
1a
1
Compound
Hennoxazole
R
R'
OP
1a
1b
1c
1d
1e
A
B
C
D
E
Me OH
Et OH
Bu OH
Me
H
HO
H
OH
O
Figure 1 The hennoxazoles A–E
2a P = Bn
2b P = PMB
4
N
O
This structural ambiguity and intriguing bioactivity has
prompted considerable synthetic attention.4 Wipf identi-
fied the absolute stereochemistry of the hennoxazoles by
his synthesis of ent-hennoxazole A (ent-1a),5 while Will-
iams subsequently completed the first synthesis of the
natural enantiomer.6 Barrett7 and Smith8 have described
the construction of model bisoxazoles simulating the
central portion of the hennoxazoles, while Shioiri has
S
O
S
N
OBn
3
Scheme 1 Retrosynthetic analysis of hennoxazole A (1a)
The synthesis of the epoxide fragment began from readily
available (R)-1,2,4-butanetriol (5, Scheme 2).10 Selective
1,2-ketalization11 with 3-pentanone was followed by
2,2,6,6-tetramethylpiperidinooxy
(TEMPO)-catalyzed
SYNLETT 2007, No. 4, pp 0623–0627
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967978; Art ID: S15006ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
3.
2
0
0
7
oxidation12 to give volatile aldehyde 6. Direct stereo-
chemical induction from the b-stereocenter of 6 is quite

624
E. J. Zylstra et al.
LETTER
HO
poor, but a catalytic chiral methallylation afforded 7 in
90% de.13 Protection of the alcohol as a benzyl or p-meth-
oxybenzyl ether was followed by deketalization to pro-
vide the diol 8.14 This compound served as the precursor
to epoxide 2 in a one-pot epoxidation and dithiane cou-
pling (vide infra).
O
O
a
OBn
OBn
HO
MeO2C
N
H
9
10
MeO2C
O
NH2
SPh
b–d
+
MeO2C
OBn
HO2C
N
11
12
OH OH
O
O
a, b
c
O
OH
MeO2C
MeO2C
H
N
O
f, g
e
5
6
OBn
N
PhS
O
OPMB
14
d, e
O
OH
O
O
OH
N
O
h–j
O
MeO
HO
N
OBn
7
8
15
Scheme 2 Synthesis of epoxide precursor 8. Reagents and conditi-
ons: (a) (MeO)3CH, p-TsOH, Et2CO, MeOH–CH2Cl2 (2:1), reflux,
87%; (b) TEMPO, KBr, aq NaHCO3, NaOCl, aq NaHCO3, brine,
H2O– CH2Cl2, 0 °C, 75%; (c) methallyl tributylstannane, Ti(Oi-Pr)4,
(R)-BINOL, CH2Cl2, 0 °C to –20 °C, 63%; (d) (i) NaH; (ii) PMBBr,
THF–DMF (3:1), 69%; (e) Dowex 50WX8 H+ resin, MeOH, 62%.
N
O
S
S
O
N
OBn
3
Scheme 3 Synthesis of bisoxazole dithiane 3. Reagents and condi-
tions: (a) (i) Et3N, t-BuCOCl, DMAP; (ii) serine methyl ester hydro-
chloride, CH2Cl2, 67%; (b) PPh3, CCl4, i-Pr2NEt, MeCN–CH2Cl2
(4:1), 0 °C to r.t., 70%; (c) CuBr2, DBU, HMTA, CH2Cl2, 90%; (d)
K2CO3, MeOH–H2O (4:1), 89%; (e) (i) 11, Et3N, 2,4,6-trichloro-
benzoyl chloride; (ii) 12, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 92%;
(f) (i) NCS, DMF, 0 °C to r.t.; (ii) i-Pr2NEt, DMF, r.t.; (g) (i) K2CO3,
MeOH, reflux; (ii) MeI, r.t., 72% (2 steps); (h) LiBH4, MeOH, THF,
64%; (i) Dess–Martin periodinane, CH2Cl2, 89%; (j) HS(CH2)3SH,
BF3·OEt2, CH2Cl2, –10 °C, 82%.
The central bisoxazole fragment15 was prepared from acid
9 (Scheme 3), readily available from g-butyrolactone.16
Following coupling with serine methyl ester,17 the amide
product 10 was cyclized18 and aromatized19 to give
oxazole 11. The subsequent construction of the second
oxazole ring proved to be considerably more difficult than
we had originally anticipated. While a second serine resi-
due could be added efficiently, all attempts to activate the
corresponding alcohol resulted in elimination and forma-
tion of acrylate 13 (Figure 2). Ultimately, the second ox-
azole was incorporated using methodology developed by
Shapiro.20 Amidation of 11 with malonate 12 gave 14,
which cyclized to the corresponding bisoxazole 15. Final-
ly, reduction of the ester21 and conversion to a dithiane22
yielded the central fragment 3.23
the pure Z-isomer 20. The choice of a trityl group was
critical here, as the more activated benzoate protecting
group is prone to elimination and alkene isomerization
upon oxidation to the aldehyde. Desilylation and treat-
ment with Dess–Martin periodinane28 produced the un-
stable b,g-unsaturated aldehyde,29 which was converted to
the E-alkene under Schlosser conditions.30 Acidic detrity-
lation of the inseparable mixture of isomers then gave the
desired alcohol 4.31 The Schlosser olefination, while
poorly selective in this case, was the only procedure of
many that ultimately afforded the requisite diene.32 We
exhaustively explored alternatives in which the disub-
stituted olefin was installed before the trisubstituted one.
While this did allow for a more selective introduction of
H
O
N
OBn
MeO2C
N
O
13
Figure 2
A key constraint in the synthesis of the diene fragment the E geometry, subsequent products in the pathway were
was the then-unknown stereocenter at C22. Therefore, we
chose a path that originated from a chiral pool member
that was readily available in either enantiomer; in fact,
both enantiomers of 4 were prepared by the route shown
(Scheme 4). Propionate 16 was transformed into aldehyde
1724 by standard procedures, and Horner–Emmons olefi-
nation with a-methylphosphonate 1825 gave 11:1 selectiv-
ity for the Z-alkene 19.26 Following reduction of the
isomeric mixture with DIBAL-H,27 tritylation afforded
quite volatile and provided lower overall yields.
With all three of our initial targets in hand, we set out to
study the union of these fragments to form the hennox-
azoles. Since our goal was to introduce the C22 stereo-
center as late as possible to maintain flexibility, we
explored the opening of epoxide 2 using 2-phenyl-1,3-
dithiane (21)33 as a model for the bisoxazole dithiane 3
(Scheme 5). One-pot epoxidation of 22 and ring opening
by 2134 led to dithiane alcohol 23 in good overall yield.
Synlett 2007, No. 4, 623–627 © Thieme Stuttgart · New York

LETTER
A Flexible Approach to the Total Synthesis of the Hennoxazoles
625
Li
With a method established to install the final stereocenter,
we turned our attention to the union of 2 and 3. Un-
fortunately, all attempts to use dithiane 3 were unsuccess-
ful, for the compound decomposed almost immediately
under basic conditions. A monooxazole dithiane model37
(Figure 3) survived long enough for deuteration of the
dithiane, indicating that the high base-sensitivity of 3 may
be a property specific to bisoxazoles. This conclusion was
supported by subsequent deprotonation studies of
Williams38 and Smith8 indicating the acidity of the C13
position. Their results suggest that a method of protecting
the C13 site from deprotonation must be used for success-
ful completion of this route, but Liu and Panek have
shown that excess t-BuLi can deprotonate a polyoxazole
dithiane with the appropriate selectivity.39 Despite this
challenging step, the route provides useful techniques for
the synthesis of cyclopentylidene ketals, bisoxazoles, and
b,g-unsaturated aldehydes that should be more generally
applicable.
CHO
CO2Me
O
O
a–c
+
P(OMe)2
MeO
OTBDPS
17
OH
16
18
e, f
MeO2C
d
OTBDPS
19
HO
TrO
g–j
OTBDPS
20
4
Scheme 4 Synthesis of skipped diene 4. Reagents and conditions:
(a) TBDPSCl, imidazole, CH2Cl2, 95%; (b) LiBH4, MeOH, Et2O,
0 °C to r.t., 92–98%; (c) Dess–Martin periodinane, CH2Cl2, 92%;
(d) 18 (1.2 equiv), 80% (Z/E = 11:1), Et2O–THF (6:1), –78 °C; (e)
DIBAL, toluene, 0 °C (81%); (f) TrCl, Et3N, DMAP, CH2Cl2, 90%;
(g) TBAF, THF; (h) Dess–Martin periodinane, CH2Cl2, 90% (2
steps); (i) (i) Ph3PCHMe, LiBr, MeLi, r.t. to –78 °C; (ii) 20, –30 °C;
(iii) MeLi, –30 °C; (iv) t-BuOK, t-BuOH, Et2O–THF (1:2), 62%,
(E/Z = 5:4); (j) Dowex 50WX8 H+ resin, MeOH, 61%
O
S
Ph
S
N
26
Figure 3
Acknowledgment
We gratefully acknowledge financial support from the National
Science Foundation (NSF-CHE9502507 and predoctoral fel-
lowship to E.Z.), the Research Corporation (Cotrell Scholar Award
to J.W.L.), and Pfizer for an undergraduate fellowship to M.S.
Subsequent removal of the dithiane35 gave ketone 24,
which was suitable for either directed or chelation-con-
trolled reduction. The latter was required for the natural
product, and exposure to Prasad’s conditions smoothly
afforded the desired diol 25.36
References and Notes
OBn
(1) Current addresses: E. J. Zylstra, 166 Chilton Ave, San
Francisco, CA 94131, USA; M. W.-L. She, 3952 Angelo
Ave, Oakland, CA 94619, USA; W. A. Salamant,
Department of Chemistry, University of California, Irvine,
California 92697, USA; J. W. Leahy, Exelixis
Li
a
S
Ph
+
OH
S
HO
22
21
Pharmaceuticals, Inc., 210 East Grand Ave, Box 511, South
San Francisco, CA 94083, USA.
OBn
OBn
(2) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.;
Gravalos, D. G. J. Am. Chem. Soc. 1991, 113, 3173.
(3) Higa, T.; Tanaka, J.-I.; Kitamura, A.; Koyama, T.;
Takahashi, M.; Uchida, T. Pure Appl. Chem. 1994, 66, 2227.
(4) For a review on oxazole-containing natural products, see:
Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
O
b
S S
HO
Ph
HO
Ph
23
24
(5) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(b) Wipf, P.; Lim, S. Chimia 1996, 50, 157.
OBn
(6) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am.
Chem. Soc. 1999, 121, 4924.
OH
c
(7) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995, 415.
(8) Smith, T. E.; Balskus, E. P. Heterocycles 2002, 57, 1219.
(9) (a) Cheng, Z.; Hamada, Y.; Shioiri, T. Synlett 1997, 109.
(b) Shioiri, T.; McFarlane, N.; Hamada, Y. Heterocycles
1998, 47, 73. (c) Yokokawa, F.; Asano, T.; Shioiri, T. Org.
Lett. 2000, 2, 4169. (d) Yokokawa, F.; Asano, T.; Shioiri, T.
Tetrahedron 2001, 51, 6311.
HO
Ph
25
Scheme 5 Model study for coupling of bisoxazole 3 and diol 8.
Reagents and conditions: (a) (i) 22, tosylimidazole, 0 °C to r.t.; (ii)
NaH, 0 °C to r.t.; (iii) 21, THF, –40 °C to –10 °C, 85%; (b) AgNO3,
NCS, MeCN–H2O (4:1), 69%; (c) Et2B(OMe), NaBH4, THF–MeOH
(4:1), –78 °C, 82%
(10) Hanessian, S. H.; Ugolini, A.; Dubé, D.; Glamyan, A. Can.
J. Chem. 1984, 62, 2146.
Synlett 2007, No. 4, 623–627 © Thieme Stuttgart · New York

626
E. J. Zylstra et al.
LETTER
(11) (a) This method improves upon preceding methods for
isopentylidene synthesis, for it requires only commercially
available reagents. (b) Procedure for Isopentylidene
Synthesis: To a 1-L flask under N2 were added the S-
enantiomer of triol 5 (21.01 g, 0.1980 mol), 3-pentanone (80
mL, 0.79 mol), trimethyl orthoformate (33 mL, 0.30 mol),
p-TsOH (0.44 g, 0.023 mol), anhyd MeOH (75 mL), and
distilled CH2Cl2 (150 mL). The mixture was heated to reflux
and stirred for 15 h. Et3N (1.8 mL, 0.013 mol) was added,
and the mixture was stirred for 30 min. H2O (100 mL) was
added, and the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic phases were dried over
NaSO4, filtered, and concentrated to a clear, yellow-brown
liquid. Flash chromatography (20% EtOAc–hexanes)
yielded the 1,2-isopentylidene-protected 5 as a clear,
yellow-tinged liquid (29 g, 85%). IR: 3510, 2950, 1460,
1170, 1080 cm–1. 1H NMR (300 MHz): d = 0.87–0.93 (m, 6
H), 1.59–1.69 (m, 4 H), 1.79–1.85 (m, 2 H), 2.26 (t, J = 5.0
Hz, 1 H), 3.54 (t, J = 8.0 Hz, 1 H), 3.81 (dd, J = 6.0, 12.0 Hz,
2 H), 4.10 (dd, J = 6.0, 7.9 Hz, 1 H), 4.25 (m, 1 H).
(12) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org.
Chem. 1987, 52, 2559. (b) Leanna, M. R.; Sowin, T. J.;
Morton, H. E. Tetrahedron Lett. 1992, 33, 5029.
(20) (a) Shapiro, R. J. Org. Chem. 1993, 58, 5759. (b) For best
results we suggest purifying the amine 12 shortly before
amide synthesis, as yields for the bisoxazole cyclization
dropped by as much as 30% in other cases.
(21) The reduction of the bisoxazole was a sensitive reaction;
during a repetition on larger scale, yields dropped to 30%
because of competitive decomposition.
(22) Matsuda, F.; Tomiyoshi, N.; Yanagiya, M.; Matsumoto, T.
Tetrahedron 1990, 46, 3469.
(23) Spectral data for dithiane 3: 1H NMR (300 MHz): d = 2.03–
2.18 (m, 4 H), 2.94–3.00 (m, 6 H), 3.56 (t, J = 6.1 Hz, 2 H),
4.50 (s, 2 H), 5.18 (s, 1 H), 7.26–7.32 (m, 5 H), 7.74 (s, 1 H),
8.16 (s, 1 H). 13C NMR (100 MHz): d = 24.9, 25.1, 26.8,
30.3, 41.4, 68.7, 72.8, 127.5, 127.5, 128.2, 130.0, 135.7,
138.1, 138.3, 140.5, 155.2, 165.7.
(24) We tested the enantiomeric purity of aldehyde 17’s
enantiomeric purity by reducing a sample to the alcohol and
comparing its rotation to the alcohol produced by lithium
borohydride reduction of ester 16. We observed only 1.5%
racemization, which we judged acceptable. See: Roush, W.
R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112,
6348.
(25) (a) Joe, D. Ph.D. Thesis; University of California at
Berkeley: USA, 1994. (b) The phosphonate is prepared by
Arbuzov reaction between methyl 2-bromopropionate and
trimethyl phosphite. This method is capricious and highly
sensitive to the purity of the starting materials. (c) The
lithium enolate was deprotonated with n-BuLi (1.01 equiv)
in Et2O (0.125 M) at 0 °C to r.t.
(13) (a) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org.
Chem. 1993, 58, 6543. (b) Keck, G. E.; Geraci, L. S.
Tetrahedron Lett. 1993, 34, 7827.
(14) Spectral data for diol 8: 1H NMR (300 MHz): d = 1.50 (ddd,
J = 2.9, 7.8, 14.6 Hz, 1 H), 1.62–1.76 (m, 4 H), 2.19 (dd, J =
7.6, 13.8 Hz, 1 H), 2.47 (dd, J = 5.5, 13.7 Hz, 1 H), 2.85 (s,
2 H), 3.40 (dd, J = 6.8, 11.2 Hz, 1 H), 3.56 (dd, J = 3.3, 11.2
Hz, 1 H), 3.78 (s, 3 H), 3.82–3.90 (m, 1 H), 3.91–4.02 (m, 1
H), 4.42 (d, J = 11.0 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.76
(s, 1 H), 4.81 (s, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 7.26 (d, J =
8.6 Hz, 1 H). 13C NMR (100 MHz): d = 22.8, 36.2, 42.1,
55.2, 66.9, 69.0, 70.9, 74.5, 113.3, 113.9, 129.5, 130.1,
142.2, 159.3.
(26) (a) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(b) The unusual Z selectivity is only maintained for the
olefination reagent with methyl ester and methyl
phosphonate. (c) The stereochemistry of the two isomers of
19 was corroborated by chemical shift calculations:
Silverstein, R. M.; Bassler, G. C.; Morrill, T. C.
Spectrometric Identification of Organic Compounds, 5th
ed.; John Wiley & Sons: New York, 1991, 215.
(15) For preparation of a related bisoxazole, see: Sakakura, A.;
Kondo, R.; Ishihara, K. Org. Lett. 2005, 7, 1971.
(16) (a) Szczepankiewicz, B. Ph.D. Thesis; University of
California at Berkeley: USA, 1995. (b) Lafontaine, J. A.;
Leahy, J. W. Tetrahedron Lett. 1995, 36, 6029.
(27) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443.
(28) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(29) (a) The b,g-unsaturated aldehyde could survive at room
temperature for over a day without appreciable
(17) Attempts with serine ethyl ester afforded a higher yield for
the amidation (80%) and comparable yields for the first
oxazole synthesis; however, as the ethyl ester was less
readily accessible, the methyl ester was used.
decomposition. In contrast, the benzoate-protected analogue
would decompose within hours, and it could only be
synthesized in low yield (33–56%). (b) Spectral data for the
(S)-b,g-unsaturated aldehyde: [a]D20 +135 (c = 0.54, CHCl3).
1H NMR (300 MHz): d = 1.05 (d, J = 6.9 Hz, 3 H), 1.94 (d,
J = 1.2 Hz, 3 H), 2.95–3.00 (m, 1 H), 3.58 (d, J = 10.6 Hz, 1
H), 3.68 (d, J = 10.6 Hz, 1 H), 5.07 (d, J = 9.5 Hz, 1 H), 7.21–
7.48 (m, 15 H), 9.38 (d, J = 1.3 Hz, 1 H). 13C NMR (100
MHz): d = 14.1, 22.3, 46.0, 62.7, 86.7, 123.8, 127.0, 127.7,
128.6, 137.8, 143.9, 201.2.
(18) General Procedure for Oxazoline Synthesis: To a dry 100-
mL flask under N2 was added a solution of the amide 10
(1.00 g, 3.39 mmol) in anhyd MeCN–CH2Cl2 (4:1, 15 mL),
Ph3P (1.33 g, 5.08 mmol), and DIPEA (0.94 mL, 5.47
mmol). After the mixture was cooled in an ice-bath for 90
min, CCl4 (0.50 mL, 5.16 mmol) was added slowly. After 14
min, the mixture was allowed to warm to r.t. and stirred for
5.25 h. The mixture was cooled in an ice bath. EtOAc (30
mL) and sat. aq NaHCO3 (9 mL) were added, and after 10
min, the biphasic mixture was diluted with H2O (21 mL).
The aqueous layer was extracted with EtOAc (3 × 15 mL);
the combined organic layers were washed with brine (1 × 20
mL), dried over NaSO4, filtered, and concentrated to a
yellow solid. Flash chromatography (25–50% EtOAc
gradient in hexanes) yielded the water-sensitive oxazoline as
a clear yellow oil (0.66 g, 70%). 1H NMR (300 MHz): d =
1.98 (m, 2 H), 2.47 (m, 2 H), 3.54 (t, J = 6.1 Hz, 2 H), 3.46
(dd, J = 8.8, 10.6 Hz, 1 H), 3.79 (s, 3 H), 4.46–4.50 (m, 3 H),
4.66–4.69 (m, 1 H), 7.27–7.36 (m, 5 H).
(30) (a) Schlosser, M.; Schaub, B. J. Am. Chem. Soc. 1982, 104,
5821. (b) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.;
Inners, R. R.; Almond, H. R. Jr.; Whittle, R. R.; Olofson, R.
A. J. Am. Chem. Soc. 1986, 108, 7664.
(31) (a) Spectral data for diene 4: 1H NMR (300 MHz): d = 0.99
(t, J = 5.1 Hz, 3 H), 1.61–1.68 (m, 3 H), 1.76–1.78 (m, 3 H),
3.08 (m, 1 H), 3.42–3.50 (m, 1 H), 3.96–4.18 (m, 2 H), 5.10–
5.38 (m, 3 H). (b) Spectral data for ent-(S)-20: IR: 3022,
2947, 2855, 2307, 1112, 1085, 702 cm–1. 1H NMR (300
MHz): d = 0.94 (d, J = 6.7 Hz, 3 H), 1.02 (s, 9 H), 1.89 (d,
J = 1.1 Hz, 3 H), 2.40–2.50 (m, 1 H), 3.38 (dd, J = 1.7, 9.5
Hz, 2 H), 3.48 (d, J = 10.4 Hz, 1 H), 3.75 (d, J = 10.4 Hz, 1
H), 5.10 (d, J = 9.5 Hz, 1 H), 7.24–7.63 (m, 25 H). 13C NMR
(100 MHz): d = 17.5, 19.1, 22.0, 26.7, 34.9, 62.8, 68.5, 86.4,
126.7, 127.4, 127.6, 128.6, 129.3, 131.1, 133.0, 133.8,
133.8, 135.5, 135.5, 144.3.
(19) Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W.-C.; Kissick,
T. P.; Kronenthal, D. R.; Mueller, R. H. J. Org. Chem. 1993,
58, 4494.
Synlett 2007, No. 4, 623–627 © Thieme Stuttgart · New York

LETTER
A Flexible Approach to the Total Synthesis of the Hennoxazoles
627
(32) A test reaction conducted with the aldehyde derived from
ent-20 and tetraethylphosphonium bromide did favor the E-
olefin (E/Z = 4.8:1), but in unacceptably low yield (9%).
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(37) The model 26 was prepared from racemic N-benzoyl serine
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