Development of an oxazole conjunctive reagent and application to the total synthesis of siphonazoles

Article abstract of DOI:10.1021/jo9018705

(Chemical Equation Presented) The preparation of 4-carbethoxy-5-methyl-2- (phenylsulfonyl)methyloxazole and its use in the elaboration of more complex oxazoles are described. A total synthesis of the unique natural products siphonazoles A and B, illustrates an application of this building block. A discussion of the biological activity of the siphonazoles is also presented.

Full text of DOI:10.1021/jo9018705

pubs.acs.org/joc
Development of an Oxazole Conjunctive Reagent and Application to the
Total Synthesis of Siphonazoles
Jianmin Zhang,† Elena A. Polishchuk,*,‡ Jie Chen,‡ and Marco A. Ciufolini*,†
†Department of Chemistry and ‡Biological Services, Department of Chemistry, University of British
Columbia, 2036 Main Mall, Vancouver BC V6T 1Z1, Canada
ciufi@chem.ubc.ca; elena@chem.ubc.ca
Received August 21, 2009
The preparation of 4-carbethoxy-5-methyl-2-(phenylsulfonyl)methyloxazole and its use in the
elaboration of more complex oxazoles are described. A total synthesis of the unique natural products
siphonazoles A and B, illustrates an application of this building block. A discussion of the biological
activity of the siphonazoles is also presented.
Introduction
azole subunits connected by a two-carbon tether. Prior to
their discovery, only arrangements comprising directly
linked oxazoles2 (e.g., muscoride A, 3), or oxazole pairs
separated by a one-carbon bridge3 (cf. bengazole A, 4) had
been observed among polyoxazole natural products.4 We
propose to distinguish the two substances with the names
siphonazole A (1) and B (2). While the unusual structure of
these compounds provides sufficient cause to embark in a
total synthesis, lack of knowledge concerning their bioactivi-
ty adds an incentive to do so. Indeed, numerous polyoxazole
natural products, and certainly so the bengazoles, display
remarkable antibiotic and cytotoxic activity: it seemed likely
that 1 and 2 may also possess useful biological properties.
Chemical efforts in the siphonazole area culminated
in 2007 with Moody’s landmark total synthesis of 1 and
25 from advanced intermediates 5 and 6 and dienic amine
7 (Scheme 1). Key aspects of this work are the assembly of
oxazole units via the reaction of a Rh-ketocarbenoid
with an amide6 or a nitrile7 and the construction of the
central (2-oxazolyl)methyl ketone motif by acylation of
an organozinc agent derived from 4-carbomethoxy-2-
iodomethyl-5-methyloxazole. A later study by Feng
produced fragment 9 through a Wittig reaction of phos-
phorane 8.8
Siphonazole, 1, and its methylated relative 2 (Figure 1) are
structurally novel natural products isolated from a Herpeto-
siphon species.1 They are the first, and so far the only,
naturally occurring substances known that incorporate ox-
€
FIGURE 1. Structures of siphonazoles, muscoride A, and benga-
zole A.
€
(1) Nett, M.; Erol, O.; Kehrhaus, S.; Kock, M.; Krick, A.; Eguereva, E.;
€
Neu, E.; Konig, G. M. Angew. Chem., Int. Ed. 2006, 45, 3863.
9140 J. Org. Chem. 2009, 74, 9140–9151
Published on Web 11/02/2009
DOI: 10.1021/jo9018705
2009 American Chemical Society
r

Zhang et al.
JOCArticle
SCHEME 1
SCHEME 2
SCHEME 3
In 2009, we described a second total synthesis9 involving
the iterative use of a conjunctive oxazole building block
that acts as a carrier of synthon 11, as shown in Scheme 2.
This diagram captures the essence of our synthetic strategy.
At a chemical level, the solutions devised during this effort
promise to be of value beyond the siphonazole problem.
In the biological domain, our work permitted a prelimi-
nary investigation of the activity of the natural products,
whereupon moderate cytoxicity was unveiled for 1. This
paper provides full details of our chemical and biological
investigations.
(2) Representative bis-oxazoles of this type: Muscoride A (isolation):
(a) Nagatsu, A.; Kajitani, H.; Sakakibara, J. Tetrahedron Lett. 1995, 36,
4097. Synthesis: (b) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 6517.
(c) Muir, J. C.; Pattenden, G.; Thomas, R. M. Synthesis 1998, 613. (d) Ref 10.
Hennoxazole (isolation): (e) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.;
Gravalos, D. G. J. Am. Chem. Soc. 1991, 113, 3173. (f) Higa, T.; Tanaka, J.;
Kitamura, A.; Koyama, T.; Takahashi, M.; Uchida, T. Pure Appl. Chem. 1994, 66,
2227. Synthesis: (g) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(h) Wipf, P.; Lim, S. Chimia 1996, 50, 157–167. (i) Williams, D. R.; Brooks, D.
A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924. (j) Yokokawa, F.; Asano,
T.; Shioiri, T. Tetrahedron 2001, 57, 6311 as well as ref 21. Synthetic studies:
(k) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995, 415. Diazonamides (isolation):
(l) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc.
1991, 113, 2303. (n) Fernandez, R; Martin, M. J.; Rodriguez-Acebes, R.; Reyes,
F.; Francesch, A.; Cuevas, C. Tetrahedron Lett. 2008, 49, 2283. Synthesis:
(o) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2001, 40,
4765. (p) Li, J.; Burgett, A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew.
Chem., Int. Ed. 2001, 40, 4770. (q) Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.;
Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888.
(r) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.; Snyder, S. A.;
Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.; Giannakakou, P.;
O'Brate, A. J. Am. Chem. Soc. 2004, 126, 12897. For higher polyoxazoles of this
type, see the following leading references: (s) Dalisay, D. S.; Rogers, E. W.; Edison,
A. S.; Molinski, T. F. J. Nat. Prod. 2009, 72, 732. (t) Deeley, J.; Bertram, A.;
Pattenden, G. Org. Biomol. Chem. 2008, 6, 1994. (u) Hernandez, D.; Vilar, G.;
Riego, E.; Canedo, L. M.; Cuevas, C.; Albericio, F.; Alvarez, M. Org. Lett. 2007, 9,
809. (v) Petchprayoon, C.; Asato, Y.; Higa, T.; Garcia-Fernandez, L. F.; Pedpradab,
S.; Marriott, G.; Suwanborirux, K.; Tanaka, J. Heterocycles 2006, 69, 447. (w) Jin,
Z. Nat. Prod. Rep. 2006, 23, 464. (x) Doi, T.; Yoshida, M.; Shin-ya, K.; Takahashi,
T. Org. Lett. 2006, 8, 4165. (y) Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
(z) Matsunaga, S.; Fusetani, N.; Hashimoto, K. J. Am. Chem. Soc. 1986, 108, 847.
(3) Thissubstructureischaracteristicofthe bengazoles, a group ofabout 20
marinesubstanceswithremarkable bioactivity. Isolation: (a) Adamczeski, M.;
Quinoa, E.; Crews, P. J. Am. Chem. Soc. 1988, 110, 1598. (b) Rodriguez, J.;
Nieto, R. M.; Crews, P. J. Nat. Prod. 1993, 56, 2034. (c) Rudi, A.; Kashman,
Y.; Benayahu, Y.; Schleyer, M. J. Nat. Prod. 1994, 57, 829. (d) Groweiss, A.;
Newcomer, J. J.; O’Keefe, B. R.; Blackman, A.; Boyd, M. R. J. Nat. Prod.
1999, 62, 1691. (e) Fernandez, R.; Dherbomez, M.; Letourneux, Y.; Nabil, M.;
Verbist, J. F.; Biard, J. F. J. Nat. Prod. 1999, 62, 678. (f) Searle, P. A.; Richter,
R. K.; Molinski, T. F. J. Org. Chem. 1996, 61, 4073. Total syntheses:
(g) Mulder, R. J.; Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1999, 64,
4995. (h) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley, S. V.
Angew. Chem., Int. Ed. 2006, 45, 6714. () Bull, J. A.; Balskus, E. P.; Horan,
R. A. J.; Langner, M.; Ley, S. V. Chem.;Eur. J. 2007, 13, 5515. Synthetic
studies: (i) Mulder, R. J.; Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1999, 64,
4995. (j) Shafer, C. M.; Molinski, T. F. Tetrahedron Lett. 1998, 39, 2903.
(k) Shafer, C. M.; Molinski, T. F. Heterocycles2000, 53, 1167. (l) Hodges, J. C.;
Patt, W. C.; Connolly, C. J. J. Org. Chem. 1991, 56, 449. (m) Vedejs, E.;
Monahan, S. D. J. Org. Chem. 1996, 61, 5192. (n) Chittari, P.; Hamada, Y.;
Shioiri, T. Synlett 1998, 1022. (o) Chittari, P.; Hamada, Y.; Shioiri, T.
Heterocycles 2003, 59, 465.
Background. We perceived that an oxazole-forming reac-
tion devised in these laboratories (Scheme 3)10 could be
advantageously utilized in the synthesis of 1 and 2. This
chemistry relies on the condensation of an aluminum acet-
ylide, 15, with an R-chloroglycinate 14, available in high yield
from a generic primary amide 12 by Ben-Ishai addition to a
glyoxylate ester11 and SOCl2 treatment of the resultant 13.
The alkynylglycinate intermediates 16 are isolable, but they
are more conveniently allowed to cyclize in situ to oxazoles
17. The use of an organoaluminum reagent derived from
TMS-acetylene results in formation of a product 17 in which
R3 = SiMe3. Such an oxazole is amenable to desilylation
(cf. 18) or, moreinterestingly, toconversion intoanalkylidene
derivative through a Peterson reaction (cf. 19).12 Of course,
the facile cyclization of 16 to 17 is consonant with Nagao’s
observation that N-acyl alkynylglycinates isomerize easily to
oxazoles.13 The overall process embodies a special case of a
general class of oxazole-forming reactions that involve the
cycloisomerization of an N-propargylamide. Pioneering
(4) Review: (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995. See also:
(b) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,
M. R. Nat. Prod. Rep. 2006, 23, 26.
(5) (a) Linder, J.; Moody, C. J. Chem. Commun. 2007, 1508. (b) Linder, J.;
Blake, A. J.; Moody, C. J. Org. Biomol. Chem. 2008, 6, 3908.
(6) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron Lett. 2004, 60,
3967 See ref 5 for a thorough bibliography.
˚
(7) Connell, R. D.; Tebbe, M.; Helquist, P.; Akermark, B. Tetrahedron
Lett. 1991, 32, 17. See also ref 28b.
(8) Zhu, Y.; Hu, L.; Tan, W.; Feng, Y. Jingxi Huagong Zhongjianti 2008,
38, 42.
(9) Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
(10) Coqueron, P. Y.; Didier, C.; Ciufolini, M. A. Angew. Chem., Int. Ed.
2003, 42, 1411. This paper provides a thorough bibliography of oxazole-
forming reactions through early 2003.
(11) (a) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863. (b) Ben-Ishai,
D.; Sataty, I.; Bernstein, Z. Tetrahedron 1976, 32, 1571. (c) Bernstein, Z.;
Ben-Ishai, D. Tetrahedron 1977, 33, 881.
(12) Chau, J.; Zhang, J.; Ciufolini, M. A. Tetrahedon Lett. 2009, 50, 6163.
(13) (a) Nagao, Y.; Kweon, K.; Sano, S.; Kakegawa, H.; Lee, W. S.;
Shimizu, H.; Shiro, M.; Katunuma, N. Tetrahedron Lett. 1996, 37, 861.
(b) Sano, S.; Shimizu, H.; Kim, K.; Lee, W. S.; Shiro, M.; Nagao, Y. Chem.
Pharm. Bull. 2006, 54, 196.
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SCHEME 5
work by Hacksell demonstrated early instances of base-
promoted transformations of this type,14 notable exam-
ples of which were later described by Wipf.15 More
recently, transition-metal catalysis has proven to be of
value in this transformation.16
Initial efforts endeavored to reach 27 from chloride 24,
which was prepared in high yield from isoferulamide benzyl
ether, 20 (Scheme 4).17 Regrettably, 24 performed poorly in
the oxazole-forming reaction, and it afforded 27 in no more
than 15% yield. While analogous chlorides obtained from
aliphatic, aromatic, or R-amino acid-derived primary amides
generally participate in the above sequence to furnish ox-
azoles in good to excellent yield, those resulting from con-
jugated amides had never before been investigated. A control
experiment revealed that cinnamamide-derived 25 also pro-
duces oxazole 28 in an abnormally low 37% overall yield.
Evidently, conjugated amides are poor substrates for the
reaction; moreover, the protected catechol moiety present in
24 may well sequester the organometallic agent, thereby
retarding the substitution step and further diminishing the
yield.
seemed to be quite unfavorable at the onset of our investiga-
tions. To wit, the generation of nucleophiles similar to 11,
but lacking a carbonyl substituent at the oxazole C-4 posi-
tion, entails the deprotonation of a 2-methyloxazole. Nota-
ble in this respect is the work of Evans, who discovered that
lithium diethylamide is the base of choice for such a pur-
pose.18 Thus, substrates 29 are smoothly lithiated to 30
(Scheme 5), which efficiently participate in carbonyl addition
and nucleophilic substitution reactions. This chemistry per-
forms well even in complex systems, as evident from key steps
in the Evans synthesis of phorboxazole (Scheme 5, 31 f 33)19
and in the Smith synthesis of hennoxazole A (Scheme 5, 34 f
36).20
The landscape changes dramatically in the presence of a 4-
carboxy substituent on the oxazole ring. As first shown by
Meyers,21 the action of strong base upon 2-methyloxazole-4-
carboxylic acid induces exclusive deprotonation at the C-5
ring position (Scheme 6). The same is true for the corre-
sponding methyl22 or tert-butyl23 esters. This defeats all
attempts to generate a C-2 lithiomethyl intermediate by
An ultimately successful alternative materialized upon
recognition that 1 and 2 could result through the union of
an aromatic aldehyde, dienic amine 7, plus two molecules of
the same oxazole-centered nucleophile, 11 (Scheme 2), even
though the prognosis for the viability of this approach
(14) (a) Nilsson, B. M.; Hacksell, U. J. Heterocycl. Chem. 1989, 26, 269.
(b) Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem.
1992, 35, 285.
(15) (a) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63,
7132. (b) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593.
(16) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391. (b) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S.
Chem. Commun. 2004, 2712. (c) Hashmi, A. S. K.; Rudolph, M.; Schymura,
S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905. (d) Kang, J.-E.; Kim,
H.-B.; Lee, J.-W.; Shin, S. Org. Lett. 2006, 8, 3537. (e) Merkul, E.; Grotkopp,
(18) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999,
1, 87.
(19) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc.
2000, 122, 10033. See also ref 18.
(20) Smith, T. E.; Kuo, W.-H.; Bock, V. D.; Roizen, J. L.; Balskus, E. P.;
Theberge, A. B. Org. Lett. 2007, 9, 1153.
€
O.; Muller, T. J. J. Synthesis 2009, 502. It is important to note that among
these methods only the chemistry of refs 10 and 13 permits access to the
2,5-dialkyloxazole-4-carboxylate series.
(17) The preparation of this material is provided as Supporting Informa-
tion.
(21) Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1981, 22, 3163.
(22) Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Lindermann, R. J.
J. Org. Chem. 1986, 51, 5111.
(23) Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24, 2291.
9142 J. Org. Chem. Vol. 74, No. 23, 2009

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SCHEME 6
SCHEME 8
direct deprotonation. Indeed, a surrogate of the nucleophile
in question may be accessed only by lithiation of Cornforth
imidate 39 prior to oxazole ring formation.
Additional complications materialize upon the introduc-
tion of a methyl substituent at the oxazole C-5 position.
Knight determined that 2,5-dimethyloxazole-4-carboxylic
acid, 42, undergoes preferential metalation (ca. 2:1) at the
C-5 methyl group, while the corresponding diethylamide is
bond-forming sequence a (Scheme 2) entails a Wittig-type
reaction, whereas step b could proceed through an acylation-
dephosphorylation26 sequence. The pursuit of this strategy
was terminated at an early stage on the basis of the following
results. First, phosphorane 88 (Scheme 1) appears to be the
sole example recorded in the CAS database of an olefination
agent of general structure 51. By contrast, many compounds
SCHEME 7
deprotonated exclusively there (Scheme 7).24 Under parti-
cular conditions, it is possible to generate a 1:1 mixture of C-
2 lithiomethyl and C-5 lithiomethyl derivatives of the 4-
carboxylate salt. However, in Knight’s words, “this lack of
regioselectivity renders the method of little synthetic value.”
Moody and collaborators had an opportunity to reexamine
this chemistry during their synthesis of siphonazoles, but
they could only confirm Knight’s conclusions. Thus, the
Nottingham team observed poor selectivity and disappoint-
ing yields in the attempted derivatization of the C-2 methyl
group via the dianions of 2,5-dimethyloxazole-4-carboxylic
acid or of the corresponding diethyl amide, even under
Evans18,19 conditions. Further confirmation of such a pro-
blematic state of affairs is borne out of our own observation
that generation of the dianion of 2,5-dimethyloxazole-4-
carboxylic acid, addition thereof to aldehyde 10 and treat-
ment of the resultant complex mixture of products with
MeOH/SOCl2 affords 50 in a meager 4% yield after chro-
matography. In summary, the 4-COOR substituent in such
oxazoles fiercely opposes metalation at the C-2 Me group.25
In principle, one could bypass the foregoing obstacles by
activating the C-2 Me group with an appropriate anion-
stabilizing unit, logical choices for which would be a phos-
phorus- or a sulfur-centered functionality. In the first case,
FIGURE 2. Phosphorylated oxazole substructures recorded in the
CAS database.
of the type 5227 and 53 (Figure 2) are known,28 the latter
mostly in the patent literature.29 The preparation of 8
required five steps from dichloroacetonitrile and threonine.
The reaction of chloroglycinates 55 or 58 with alkynylalu-
minum agents might have offered a more direct avenue to
phosphonate 59; however, neither substrate provided any of
the desired oxazoles when treated with organoalane 47
(Scheme 9).30 No attempt was made to obtain the bromo
analogue of 56 through radical bromination of the corre-
sponding dimethyloxazole. While the radical bromination of
(27) (a) Pattenden, G.; Ashweek, N. J.; Baker-Glenn, C. A. G.; Kempson,
J.; Walker, G. M.; Yee, J. G. K. Org. Biomol. Chem. 2008, 6, 1478.
(b) Wolbers, P; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett.
1999, 40, 4527. (c) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185. (d) Crimmin, M. J.; O’Hanlon, P.; Rogers, N. H.; Walker, G. J. Chem.
Soc., Perkin Trans. 1 1989, 2047. See also literature cited therein.
(28) E.g.: (a) Schroeder, D. C.; Corcoran, P. O.; Holden, C. A.; Mulligan,
M. C. J. Org. Chem. 1962, 27, 1098. (b) Meanwell, N. A.; Rosenfeld, M. J.;
Wright, J. J. K.; Brassard, C. L.; Buchanan, J. O.; Federici, M. E.; Fleming,
J. S.; Gamberdella, M.; Hartl, K. S.; Zavoico, G. B.; Seiler, S. M. J. Med.
Chem. 1993, 36, 3871.
(29) E.g.: (a) Fischer, C.; Munoz, B.; Rivkin, A. A. PCT Int. Appl. 2008,
WO 2008097538 A1 20080814. (b) Kudo, Y.; Suzuki, M.; Suemoto, T.; Okamura,
N.; Shiomitsu, T.; Shimazu, H. PCT Int. Appl. 2005, WO 2005016888 A1
20050224. (c) Talley, J. J.; Bertenshaw, S.; Rogier, D. J., Jr.; Graneto, M.; Brown,
D. L.; Devadas, B.; Lu, H.-F.; Sikorski, J. A. PCT Int. Appl. 1996, WO 9636617
A1. (d) Hoffman, J. M., Jr.; Rooney, C. S.; Saari, W. S.; Wai, J. S.; Williams, T. M.;
Bamberger, D. L.; Jones, J. H. Eur. Pat. Appl. 1991, EP 462800 A2 19911227.
(30) Conceivably, 56 could be made by Rh(II)-mediated condensation of
diethyl cyanomethyl-phosphonate with ethyl diazoacetoacetate according to
Hoffmann, et al. (ref 27b). However, the modest yield (18%) obtained by
these authors in a similar reaction of phosphonoacetonitrile with diethyl
diazomalonate discouraged us from researching this possibility.
(24) Cornwall, P.; Dell, C. P.; Knight, D. W. J. Chem. Soc., Perkin Trans.
1 1991, 2417.
(25) This is imputable to the unfavorable positioning of the 4-COOR
substituent: the 5-COOR isomer is smoothly deprotonated at the C-2 Me
group (ref 24), presumably because of good resonance stabilization of the
ensuing anion.
(26) (a) Fox, D. J.; Parris, S.; Pedersen, D. S.; Tyzack, C. R.; Warren, S.
Org. Biomol. Chem. 2006, 4, 3102. (b) Fox, D. J.; Pedersen, D. S.; Warren, S.
Org. Biomol. Chem. 2006, 4, 3108. (c) Hawkins, M. J.; Powell, E. T.; Leo,
G. C.; Gauthier, D. A.; Greco, M. N.; Maryanoff, B. Org. Lett. 2006, 8, 3429.
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J. Org. Chem. Vol. 74, No. 23, 2009 9143

Zhang et al.
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SCHEME 9
SCHEME 11
substitutent must be responsible for such a behavior, for
Williams demonstrated that sulfonyloxazoles lacking such a
group, e.g., 65, do undergo Julia-Kocienski reactions, albeit
in only 45-50% yield.38
2-methyloxazole-4-carboxylic esters is efficient,31 that of
oxazoles incorporating multiple benzylic-type sites is notor-
iously problematic. Instructive examples appear in
Scheme 10.32
Results and Discussion
We anticipated that the reluctance of metalated sulfones of
the type 64 to add to aldehydes could be overcome by
activating the carbonyl receptor with an appropriate Lewis
acid. We thus set out to prepare sulfone 71 and study its
condensation with carbonyl compounds. Contrary to the
case of 54 and 57, R-(phenylthio)acetamide, 66, performed
well in the oxazole-forming reaction, affording 70 in 61%
overall yield. Subsequent m-CPBA oxidation produced the
desired 71, a white crystalline solid with mp 154-155 °C, in
94% yield (Scheme 12).
SCHEME 10
The sulfone alternative entails the creation of bond a in a
Julia mode33 and that of bond b through a Fujita-type
acylation,34 followed by desulfonylation.35 Precedent indi-
cated that such an approach was perilous. While a limited
volume of literature exists concerning the chemistry of
2-(sulfonyl)methyloxazole-4-carboxylates,36 the anions of
these species are known to be poor nucleophiles. For in-
stance, Hoffmann discovered that the metalated 64
(Scheme 11) fails to add to aldehydes,27b,37 precluding the
occurrence of Julia reactions. Once again, the COOMe
SCHEME 12
(31) Examples appear in ref 23 as well as in: White, J. D.; Kranemann, C.
L.; Kuntiyong, P. Org. Synth. 2003, 79, 244.
(32) For 60: (a) Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D. B.;
Hunt, J. T.; Xiao, H.-Y.; Lu, S.; Qian, L.; Han, W.-C.; Shan, W.; Mitt, T.;
Cai, Z.-W.; Poss, M. A.; Zhu, H.; Sack, J. S.; Tokarski, J. S.; Chang, C. Y.;
Pavletich, N.; Kamath, A.; Humphreys, W. G.; Marathe, P.; Bursuker, I.;
Kellar, O. K. A.; Roongta, U.; Batorsky, R.; Mulheron, J. G.; Bol, D.;
Fairchild, C. R.; Lee, F. Y.; Webster, K. R. J. Med. Chem. 2002, 45, 3905.
(b) For 62: Haffner, C. D.; Lenhard, J. M.; Miller, A. B.; McDougald, D. L.;
Dwornik, K.; Ittoop, O. R.; Gampe, R. T., Jr.; Xu, H. E.; Blanchard, S.;
Montana, V. G.; Consler, T. G.; Bledsoe, R. K.; Ayscue, A.; Croom, D.
J. Med. Chem. 2004, 47, 2010.
(33) (a) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833. Reviews:
(b) Kelly, S. E. Alkene Synthesis. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 1, pp 729-817.
(c) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(34) Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24, 2287.
See also ref 32a.
In accord with Hoffmann,27b,37 the anion of 71, generated
34
by deprotonation with NaH a la Fujita, failed to add to
ꢀ
aldehydes. More significantly, even the presumably more
reactive lithio derivative of 70, prepared by deprotonation
with LDA, added to aldehydes inefficiently, underscoring
the unfavorable influence of the 4-COOR group. However,
activation of the carbonyl receptor with TiCl4 enabled
smooth Knoevenagel-type condensations of 71 with alde-
hydes and even with ketones. Aromatic aldehydes reacted
efficiently at room temperature in THF-CH2Cl2 in the
presence of TiCl4 and Et3N (Table 1), giving rise to the
expected products 72 mostly or exclusively as the E-isomers
(shown), except in the case of cinnamaldehyde (entry h),
which reacted nonstereoselectively. The stereochemical as-
signment of the major/exclusive product of these reactions
rests on the observation of a nuclear Overhauser enhance-
ment of the signals of the ortho-protons on the PhSO2 group,
(35) Reviews: (a) Simpkins, N. Tetrahedron 1990, 46, 6951. (b) Najera,
C.; Yus, M. Tetrahedron 1999, 55, 10547.
(36) Comprehensive bibliography: refs 9, 27b, 31, and 37, as well as:
(a) Fujita, E. Heterocycles 1984, 21, 41. (b) Yokoyama, M.; Menjo, Y.;
Ubukata, M.; Irie, M.; Watanabe, M.; Togo, H. Bull. Chem. Soc. Jpn. 1994,
67, 2219. (c) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Synth 2003,
79, 244. The following patents describe the preparation of some
2-(arylsulfonyl)methyloxazole-4-carboxylic esters: (d) Jpn. Kokai Tokkyo
Koho JP 59108772 A 19840623 Showa (Taiho Pharmaceutical Co., Ltd.), 1984;
CAN 101:171238. (e) Dehmlow, H.; Kuhn, B.; Masciadri, R.; Panday, N.; Ratni,
H.; Wright, M. B. U.S. Pat. Appl. Pub. US 2005215577 A1 20050929, 2005;
CAN 143:347051.
(38) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291.
However, this study also revealed that a Wadsworth-Emmons olefination
mode is distinctly superior.
(37) Ref 27b as well as: Wolbers, P.; Misske, A.; M.; Hoffmann, H. M. R.
Synlett 1999, 1808.
9144 J. Org. Chem. Vol. 74, No. 23, 2009

Zhang et al.
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TABLE 1. Condensation of Sulfonyl Oxazole 71 with Aromatic Alde-
hydes
TABLE 2. Condensation of Sulfonyl Oxazole 71 with Enolizable
Aliphatic Aldehydes
entry
Ar
reaction time (h) E/Z ratio yield (%)
a
b
c
d
e
f
C6H5
3
3
3
3
6
6
6
6
E only
7:1
E only
E only
E only
3:1
85
93
89
88
88
83
92
76
4-MeO-C6H4
4-HO-C6H4
4-Cl-C6H4
2-Me-C6H4
2-furyl
2-thienyl
yield (%) of
entry
R
ratio 73/74
73
74
a
b
c
C6H5-CH2
Me
n-C5H11
2:1
73 only
4:1
60
87
66
30
g
h
7:1
1:1
(E)-C6H5-CHdCH
17
as well as of those on the Ar substituent, upon irradiation
of the olefinic proton. The preferential formation of the
E-isomer is consistent with the relative steric demand of an
aryl, phenylsulfonyl, and 2-oxazolyl substituent.39
TABLE 3. Condensation of Sulfonyl Oxazole 71 with Ketones
The foregoing conditions are reminiscent of the
Masamune-Roush protocol40 for Wadsworth-Emmons ole-
finations. However, the literature seems to contain no record
of like procedures for the Knoevenagel-like reaction of
sulfones. Indeed, such transformations are normally carried
out with stronger bases such as NaOH,41 tBuOK,42 NaH,43
LiHMDS,44 or BuLi,45 though in one case an activated
sulfone was successfully condensed with PhCHO in the
presence of piperidine,46 and in a second one, in the presence
of TBAF, but in modest yield.47
entry
RCOR0
acetone
2-heptanone
cyclohexanone
acetophenone
reaction time (h) isomeric ratioa yield (%)
a
b
c
24
24
24
36
81
78
85
44
5:1
4:1
d
aRatio of unassigned isomers; major product believed to be the
E-isomer.
Aliphatic aldehydes (Table 2) and ketones (Table 3) re-
acted best when exposed to the action of lithiated 71
(prepared by treatment with LHMDS) and TiCl4 in
THF-CH2Cl2 at -78 °C, followed by gradual warming to
room temperature overnight. Under these conditions, enoliz-
able aldehydes afforded mixtures of the expected 73 (major
product, E-isomer only) and its deconjugated isomer 74
(E-isomer only, Table 2), except propionaldehyde (entry b),
which delivered exclusively a product of the type 73. Com-
pounds 73 and 74 were separable (silica gel chromatography)
and wereindividually characterized. No product of either type
was formed in the absence of TiCl4. The LHMDS-based
procedure was also suitable for the condensation of 71 with
aromatic aldehydes, but it was less efficient than the
TiCl4-Et3N method detailed in Table 1. For instance, ben-
zaldehyde gave 72 (E-isomer only) in a diminished 78% yield
under these conditions (cf. 85%, Table 1). Not surprisingly,
enolizable ketones reacted more slowly than aldehydes
(24-36 h vs 12 h) but yielded exclusively conjugated sulfones
75 (Table 3). Products arising from unsymmetrical ketones
were obtained as mixtures of geometric isomers. While these
remained unassigned, the major product is believed to be the
(E)-isomer, by analogy with earlier cases. Again, no product
was formed in the absence of TiCl4.
The application of the above findings to a synthesis of
siphonazoles is subordinate to the identification of a techni-
que for the desulfonylation of compounds 72, 73, and 75
under mild conditions. Among the various reagents that
were examined for that purpose (Na/Hg, Mg/EtOH, Mg/
TMSCl, SmI2, Zn/NH4Cl), metallic Zn in the presence of
NH4Cl buffer proved to be optimal for the desulfonylation
of products 72 and 73. The latter substrates presented a
special challenge, in that they were found to isomerize easily
to allylsulfones 74.48 The combination of Zn and NH4Cl
largely suppressed this unwanted isomerization. It should be
(39) As gauged from their A values: 2.9 kcal/mol for a PhSO2 group
(Juaristi, E.; Labastida, V.; Antunez, S. J. Org. Chem. 2000, 65, 969); 2.8 kcal/
mol for a Ph group (Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; p 697); approximately 1.3 kcal/mol for
a 4-carbomethoxy-5-methyl-2-oxazolyl group (estimated by MMþ structur-
al optimization of the axial and equatorial conformer of the corresponding
2-cyclohexyl derivative).
(40) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 2183.
(41) (a) Parpani, P.; Zecchi, G. J. Org. Chem. 1987, 52, 1417. (b) Nacci, V.;
Filacchioni, G.; Porretta, G. C. Farmaco 1972, 27, 1003.
(42) Garst, M. E.; Dolby, L. J.; Esfandiari, S.; Okrent, R. A.; Avey, A. A.
J. Org. Chem. 2006, 71, 553.
(43) Cabanal-Duvillard, I.; Berrien, J.-F. Heterocycl. Commun. 1999, 5,
257.
(44) (a) Orita, A.; Hasegawa, D.; Nakano, T.; Otera, J. Chem.—Eur. J.
2002, 8, 2000. (b) Babu, G.; Orita, A.; Otera, J. Org, Lett. 2005, 7, 4641.
(45) (a) Ager, D. J. Chem. Commun. 1984, 486. (b) Ager, D. J. J. Chem.
Soc., Perkin Trans. 1 1986, 183. (c) Antelo, B.; Castedo, L.; Delamano, J.;
Gomez, A.; Lopez, C.; Tojo, G. J. Org. Chem. 1996, 61, 1188. (d) Uno, H.;
Inoue, K.; Inoue, T.; Fumoto, Y.; Ono, N. Synthesis 2001, 2255. (e) Orita, A.;
Ye, F.; Doumoto, A.; Otera, J. Chem. Lett. 2003, 32, 104. (f) Ye, F.; Orita, A.;
Doumoto, A.; Otera, J. Tetrahedron 2003, 59, 5635.
(46) Nikolae, A.; Florea, S.; Rudorf, W.-D.; Perjessy, A. Rev. Chim. 2005,
56, 524 (CAN 144:412344).
(47) Antelo, B.; Castedo, L.; Delamano, J.; Gomez, A.; Lopez, C.; Tojo,
G. J. Org. Chem. 1996, 61, 1188.
(48) For an excellent discussion of the vinylsulfone-allylsulfone isomer-
ization, see: El-Awa, A.; Noshi, M. N.; Mollat du Jourdin, X.; Fuchs, P. L.
Chem. Rev. 2009, 109, 2315 and literature cited therein. See especially
pp 2331 ff.
J. Org. Chem. Vol. 74, No. 23, 2009 9145

Zhang et al.
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TABLE 4. Desulfonylation of Vinyl Sulfones Derived from Aromatic
Aldehydesa
TABLE 6. Desulfonylation of Vinyl Sulfones Derived from Ketones
entry
Ar
C6H5
4-MeO-C6H4
4-HO-C6H4
4-Cl-C6H4
2-Me-C6H4
2-furyl
yield (%)
entry
R
R
isomeric ratio
1:1
yield (%)
a
b
c
d
e
f
100
94
57
91
93
89
93
a
b
c
Me
n-C5H11
(CH2)5
Me
Me
42
48
49
g
2-thienyl
reductant, 10% Na/Hg amalgam, which, however, pro-
moted some overreduction of the double bond. Results of
the desulfonylation of ketone-derived vinylsulfones are sum-
marized in Table 6. On the other hand, acetophenone-
derived sulfone 75d was smoothly desulfonylated with Zn/
NH4Cl to furnish 78d as the E-isomer only (Scheme 14).
aThe reaction may be carried out at rt for 30 min; however, the
product is then a mixture of E- and Z-isomers.
noted that the use of Zn/NH4Cl for the desulfonylation of
olefinic sulfones such as 72 appears to be undocumented.
Results obtained in the desulfonylation of compounds 72
are summarized in Table 4. One aspect of this chemistry
merits comment. Conducting the reaction in refluxing THF
afforded only the E- isomer of olefins 76 (within the limits of
300 MHz 1H NMR spectroscopy). By contrast, mixtures of
E- and Z-olefins were obtained when the reaction was carried
out at room temperature for 30 min. The desulfonylation of
compound 72h had to be run at room temperature for 30 min
in order to avoid overreduction of the sensitive diene 76h,
which was obtained in 45% yield (Scheme 13). Interestingly,
this product emerged substantially only as the E,Z-isomer
(shown),49 even though the starting 72h was a 1:1 mixture of
geometric isomers.
SCHEME 14
With the above results in hand, intermediates 27 and 82
were rapidly assembled in good overall yield as detailed in
Scheme 15. Thus, condensation of 71 with aldehydes 79 and 6
over 6 h provided alkylidene derivatives 80 (75%) and 81
(87%), respectively, as the E-isomers only (within the limits
SCHEME 13
SCHEME 15
Table 5 illustrates the results observed in the desulfonyla-
tion of products 73. The emerging 77 were produced as
mixtures of chromatographically separable E and Z isomers,
with the latter being dominant. Geometric isomers were thus
individually characterized. Sulfones 75 obtained from ali-
phatic ketones were resistant to desulfonylation with Zn/
NH4Cl. Conversion into 78 required the more vigorous
of 300 MHz 1H NMR spectroscopy). Conducting the reac-
tion for only 3 h had no effect on the yield, but it furnished 80
as a 5:1 mixture of E- and Z-isomers and 81 as a 4:5 mixture
of E- and Z-isomers, respectively.9 Evidently, equilibration
of the product mixture to the thermodynamically favored
isomer takes place upon prolonged contact time. Desulfo-
nylation with Zn dust in refluxing THF afforded olefins 27
and 82 as the E-isomers only.
TABLE 5. Desulfonylation of Vinyl Sulfones Derived from Enolizable
Aliphatic Aldehydes
The union of a second molecule of 71 with intermediates
27 and 82 (Scheme 16) was realized under Fujita condi-
tions,34 since the anion of 71 is insufficiently nucleophilic to
condense directly with esters. Accordingly, hydrolysis of 27
entry
R
E/Z isomeric ratio
yield (%)
a
b
c
C6H5-(CH2)2
Et
n-C6H13
1:3.5
1:3
1:3
20 (E)
23 (E)
22 (E)
70 (Z)
70 (Z)
66 (Z)
(49) Selective formation of Z-olefins in the desulfonylation of vinylsul-
fones is documented; e.g.: Bremner, J.; Julia, M.; Launay, M.; Stacino, J.-P.
Tetrahedron Lett. 1982, 23, 3265. See also ref 36a and literature cited therein.
9146 J. Org. Chem. Vol. 74, No. 23, 2009

Zhang et al.
JOCArticle
SCHEME 16
SCHEME 17
produced 1H and 13C NMR spectra54 identical to those
recorded in the literature for the natural products.1,5
The biological evaluation55 of synthetic siphonazoles re-
vealed no antibiotic activity against the following pathogens:
Candida albicans, Acinetobacter junii, Citrobacter freundii,
Bacillus cereus, Comamonas testosteroni, Enterobacter cloa-
cae, Escherichia coli 0157:H7, Klebsiella oxitoca, Mycobac-
terium neoaurum, Pseudomonas aeruginosa, Pseudomonas
cepacia, and Staphylococcus aureus. Tests were carried out
at a concentration of 10 μg/mL (in accord with the NIH
and 82 with LiOH provided the corresponding acids 83 and
84 (Scheme 16). The latter were not thoroughly character-
ized. Instead, they were directly converted into R-sulfonylke-
tones 85 and 86 by sequential reaction with EtOCOCl and
Et3N (activation as mixed anhydrides), followed by the
sodium salt of 71, which had been prepared separately by
deprotonation of the parent compound with NaH. The
resulting 85 and 86 existed as mixtures of keto (shown) and
enol tautomers in a ratio that appeared to be a function of
solvent, moisture content, time and pH. Inferior results were
obtained in this step when the acids were activated as the
corresponding acyl chlorides (SOCl2) or imidazole deriva-
tives (CDI).50 Desulfonylation of 85 and 86 was once again
best carried out by treatment with Zn/NH4Cl.
Contrary to the case of compounds 72, 73, and 75, the
desulfonylation of R-sulfonyl ketones by this method finds
precedent in the work of Holton.51 Reductants like Na/Hg
amalgam or SmI2 performed poorly in the present case.
Ketones 87 and 88 existed in equilibrium with the relative
enols, the proportion of which once again varied as a
function of solvent, temperature, etc. The same was true also
for later compounds incorporating these fragments, includ-
ing the final 1 and 2.
standard; equivalent to 2.2 ꢀ 10-5 M for 1 and 2.1 ꢀ 10-5
M
for 2) using both the paper disk and the soft agar techniques.
Compounds 1 and 2 were also tested for cytotoxic activity
using the following cell lines: human colon adenocarcinoma
(Caco-2), human hepatocellular carcinoma (hepG2), human
prostate adenocarcinoma (PC3), human breast carcinoma
(HTB-129), human acute T-cell leukemia (TIB-152), mouse
lymphoma (ML), and Chinese hamster ovarian cancer
(CHO). Both 1 and 2 exhibited cytotoxic activity against
human breast carcinoma (HTB-129) and, especially, human
acute T-cell leukemia (TIB-152) cells, but they proved to be
inactive against hepatocellular carcinoma (hepG2), prostate
cancer (PC3), colon adenocarcinoma (Caco-2), and Chinese
hamster ovarian cancer (CHO) cell lines at the same con-
centrations. The lack of activity toward hepG2 cells could be
a promising feature, indicating a probable lack of toxicity to
normal human liver cells. Compound 1 was also cytotoxic
against the mouse lymphoma cell line.
The synthesis was completed uneventfully as delineated in
Scheme 17. Compound 87 was debenzylated (BCl3) to afford
ester 89. The latter as well as its relative 88 underwent
saponification to the corresponding acids, 90 and 91, which
were condensed with dienic amine 752 in the presence of
EDCI. This delivered fully synthetic siphonazoles, which
existed mostly as the keto tautomers (NMR),53 and that
As apparent from Figures 3 and 4, siphonazole A, 1, is
significantly more cytotoxic than its congener 2. Thus,
compound 1 induced cell death in human TIB-152 leukemia
and mouse lymphoma cells with an IC50 value equal to 16 μg/
mL (3.5 ꢀ 10-5 M) and in breast carcinoma HTB-129 with
an IC50 of 20 μg/mL (4.2 ꢀ 10-5 M). Furthermore, com-
pound 1 exhibited a good dose-response curve against
human acute T cell leukemia TIB-152 (Figure 4). In conclu-
sion, the present synthesis of siphonazoles served as a vehicle
to develop the chemistry of sulfone 71 as an oxazole con-
junctive agent. The results described herein resolve the
difficulties previously experienced with the use of a similar
oxazolyl sulfone and provide a solution to the long-standing
problem of generating nucleophilic synthon 11. As indicated
(50) (a) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.
(b) Review: Armstrong, A.; Li, W. N,N'-Carbonyldiimidazole. in e-EROS
Encyclopedia of Reagents for Organic Synthesis; Wiley: New York, 2006. http://
www.mrw.interscience.wiley.com/eros/articles/rc024/frame.html; DOI 10.1002/
047084289X.rc024.pub2.
(51) Holton, R. A.; Crouse, D. J.; Williams, A. D.; Kennedy, R. M. J.
Org. Chem. 1987, 52, 2317.
(52) Grieco, P. A.; Galatsis, P.; Spohn, R. F. Tetrahedron 1986, 42, 2847.
See also ref 5.
(53) The enol tautomer of 1-2 was recognizable from a characteristic 13
C
signal at 85 ppm. See the spectra provided in the Supporting Information.
(54) The appearance of the 1H NMR spectrum of 1 depended strongly on
the nature of the solvent used. Thus, a spectrum recorded in CDCl3 solution
differed significantly from one obtained from acetone-d6. Published spectra
of 1 were recorded in the latter solvent. Accordingly, the spectra of 1 shown in
the Supporting Information were also obtained from acetone-d6 solutions.
(55) Relevant experimental protocols are provided as Supporting
Information.
J. Org. Chem. Vol. 74, No. 23, 2009 9147

Zhang et al.
JOCArticle
FIGURE 3. Cytotoxic effect of synthetic 1 and 2 on human breast carcinoma (HTB-129), prostate cancer (PC3), colon adenocarcinoma (Caco-
2), Chinese hamster ovarian cancer (CHO), human hepatocellular carcinoma (hepG2), and mouse lymphoma. Values are means ( SEM of two
independent experiments, each performed in triplicate.
SCHEME 18
steps and 53% yield from 66. Synthetic siphonazoles were
devoid of antimicrobial activity, but they showed appreci-
able and selective cytotoxicity against human breast carci-
noma HTB-129 and acute T-cell leukemia TIB-152, with 1
being significantly more active than 2.
FIGURE 4. Dose-response curve of human acute T cell leukemia
(TIB-152) against siphonazoles 1(-b-) and 2(-9-). Values are means
( SEM oftwo independentexperiments, each performed intriplicate.
Experimental Section
Experimental Protocols.56 Unless otherwise stated, H NMR
1
(300 MHz) and 13C NMR (75 MHz) spectra were recorded at room
in Scheme 18, siphonazole A was reached in eight steps and in
40% yield from 71, which in turn may be prepared in five
(56) Additional details are provided as Supporting Information.
9148 J. Org. Chem. Vol. 74, No. 23, 2009

Zhang et al.
JOCArticle
temperature from CDCl3 solutions. Chemical shifts are reported in
parts per million (ppm) on the δ scale, and coupling constants,
J, are in hertz (Hz). Multiplicities are reported as “s” (singlet), “d”
(doublet), “dd” (doublet of doublets), “ddd” (doublet of doublets
of doublets), “t” (triplet), “q” (quartet), “m” (multiplet), and
further qualified as “app” (apparent) and “br” (broad). Flash
chromatography was performed on 230-400 mesh silica gel.
Ethyl 2-Hydroxy-2-(2-(phenylthio)acetamido)acetate (67). A
solution of 2-(phenylthio)acetamide (3.3 g, 20.0 mmol) and ethyl
glyoxylate (5.2 mL, 50% in toluene, 26.0 mmol) in THF (30 mL)
was refluxed overnight, whereupon TLC (30% EtOAc/hexanes)
indicated complete conversion. The mixture was concentrated in
vacuo, and the residue was triturated with Et2O and then with
30% EtOAc in hexanes to yield 67 as a white solid (4.6 g, 86%).
Mp: 104-105 °C. IR: 3326, 1743, 1660. 1H: 8.07 (d, 1H, J = 7.8),
7.36-7.14 (m, 5H), 5.55 (d, 1H, J = 7.8), 5.03 (br, 1H), 4.17 (q,
2H, J = 7.1), 3.61 (s, 2H), 1.29 (t, 3H, J = 7.1); 13C: 169.5, 169.4,
134.4, 129.2, 129.0, 127.0, 72.0, 62.5, 37.8, 14.0. HRMS: calcd
for C12H15NO4SNa [M þ Na]þ 292.0619, found 292.0613.
Ethyl 2-Chloro-2-(2-(phenylthio)acetamido)acetate (68). A so-
lution of 67 (4.0 g, 15.0 mmol) and SOCl2 (3.3. mL, 45.0 mmol)
in CH2Cl2 (30 mL) was stirred at rt overnight, and then it was
concentrated in vacuo. The residue was dried under high
vacuum for several hours to afford 68 as a yellow foam (4.3 g,
quant), which was used for next step without purification. 1H:
7.97 (d, 1H, J = 9.8), 7.40-7.22 (m, 5H), 6.20 (d, 1H, J = 9.8),
4.31 (q, 2H, J = 7.2), 3.68 (s, 2 H), 1.33 (t, 3H, J = 7.2).
Ethyl 5-Methyl-2-(phenylthiomethyl)oxazole-4-carboxylate
(70). Commercial n-BuLi (1.6 M in hexanes, 7.9 mL, 12.6 mmol)
was added to a solution of trimethylsilylacetylene (1.8 mL, 12.6
mmol) in THF (16 mL) at -78 °C. The mixture was stirred at
-78 °C for 20 min, and then dimethylaluminum chloride (1.0 M
in hexanes, 12.6 mL, 12.6 mmol) was added. The mixture was
stirred at 0 °C for 1 h, and then a solution of 68 (3.4 g, 12.0 mmol)
in THF (16 mL) was added slowly. The resulting mixture was
stirred at rt for 3 h and then diluted with CHCl3, filtered through
silica gel (elution with EtOAc), and concentrated in vacuo. The
residue was redissolved in THF/H2O (15 mL/15 mL) and treated
with NaHCO3 (2.0 g, 24.0 mmol) at rt overnight. The reaction
mixture was diluted with H2O (30 mL) and extracted with
EtOAc (3 ꢀ 30 mL). The combined organic layers were washed
with H2O (30 mL) and brine (30 mL) and dried over MgSO4.
The solvent was removed under reduced pressure to yield a
crude oil, which was further dissolved in EtOH (20 mL) and
treated with CsF (2.0 g, 13.2 mmol). The resulting mixture was
stirred at rt for 6 h, and the solvent was removed in vacuo. The
residue was diluted with H2O (30 mL) and extracted with EtOAc
(3 ꢀ 30 mL). The combined organic layers were washed with
H2O (30 mL) and brine (30 mL), dried over MgSO4, and
concentrated in vacuo. Purification of the crude product by
flash chromatography on silica gel (30% EtOAc/hexanes) af-
forded 70 as a yellow oil (2.0 g, 61%). IR: 1713. 1H: 7.42-7.37
(m, 2H), 7.32-7.20 (m, 3H), 4.36 (q, 2H, J = 7.1), 4.17 (s, 2H),
2.57 (s, 3H), 1.37 (t, 3H, J = 7.1). 13C: 162.1, 158.9, 156.9, 134.3,
130.6, 129.1, 127.7, 127.3, 60.9, 31.0, 14.4, 12.0. HRMS: calcd
for C14H15NO3SNa [M þ Na]þ 300.0670, found 300.0667.
Ethyl 5-Methyl-2-(phenylsulfonylmethyl)oxazole-4-carboxy-
late (71). Solid m-CPBA (7.16 g, 50-60% purity, ∼41.5 mmol)
was added in portions to a cold (0 °C; ice bath) solution of
70 (2.3 g, 8.3 mmol) in CH2Cl2. The ice bath was removed, and
the suspension was stirred at rt for 6 h; The suspension was
sequentially washed with saturated NaHCO3 solution (3 ꢀ 30 mL),
H2O (30 mL), and brine (30 mL), dried (MgSO4), and evapo-
rated. The residue was purified by flash chromatography (30%
EtOAc/hexanes) to yield 71 as a white solid (2.4 g, 94%). Mp:
134.5, 129.4, 128.6, 128.4, 61.1, 55.5, 14.3, 12.1. HRMS: calcd
for C14H15NO5SNa [M þ Na]þ 332.0569, found 332.0576.
(E)-Ethyl 2-(2-(3-(Benzyloxy)-4-methoxyphenyl)-1-(phenyl-
sulfonyl)vinyl)-5-methyloxazole-4-carboxylate (80). A solution
of 71 (93 mg, 0.3 mmol), 3-(benzyloxy)-4-methoxybenzaldehyde
(79, 73 mg, 0.3 mmol), Et3N (0.2 mL, 1.5 mmol), and TiCl4
(1.0 M in CH2Cl2, 1.5 mL, 1.5 mmol) in THF (3 mL) was stirred
at rt for 6 h, and then the mixture was quenched with saturated
aq NH4Cl (10 mL) and extracted with EtOAc (15 mL). The
organic layer was sequentially washed with H2O (10 mL) and
brine (10 mL), dried (MgSO4), and evaporated in vacuo. The
residue was filtered through a plug of silica gel (50% EtOAc/
hexanes), and the eluate was concentrated to afford 80 (165 mg,
99%) as a yellow solid. Mp: 147-149 °C. IR: 1721, 1321, 1150.
1H: 8.08 (s, 1H), 7.89-7.86 (m, 2H), 7.63-7.58 (m, 1H),
7.53-7.48 (m, 2H), 7.34-7.27 (m, 5H), 6.96-6.93 (m, 2H),
6.83 (d, 1H, J = 9.0), 4.91 (s, 2H), 4.32 (q, 2H, J = 7.1), 3.87 (s,
3H), 2.57 (s, 3H), 1.32 (t, 3H, J = 7.1). 13C: 161.7, 157.7, 153.0,
152.1, 148.1, 146.2, 139.6, 136.2, 133.7, 129.1, 128.8, 128.6,
128.5, 128.0, 127.2, 126.8, 125.8, 124.0, 114.1, 111.3, 70.6,
61.1, 56.0, 14.3, 12.2. HRMS: calcd for C29H27NO7SNa [M þ
Na]þ 556.1406, found 556.1418.
(E)-Ethyl
2-(2-(3,4-Dimethoxyphenyl)-1-(phenylsulfonyl)-
vinyl)-5-methyloxazole-4-carboxylate (81). This compound was
prepared from 71 (558 mg, 1.8 mmol) and 3,4-dimethoxyben-
zaldehyde (6, 300 mg, 1.8 mmol) following the procedure
described above for 80. Yellow solid, mp 135-137 °C, 87%
after chromatography (50% EtOAc/hexanes). 1H: 8.12 (s, 1H),
7.90 (d, 2H, J = 7.4), 7.64-7.59 (m, 1H), 7.55-7.49 (m, 2H),
6.97 (dd, 1H, J = 8.3, 1.4), 6.88 (d, 1H, J = 1.4), 6.82 (d, 1H, J =
8.3), 4.35 (q, 2H, J = 7.1), 3.87 (s, 3H), 3.68 (s, 3H), 2.61 (s, 3H),
1.36 (t, 3H, J = 7.1). 13C: 161.7, 157.6, 152.4, 152.2, 148.9, 146.1,
139.6, 133.6, 129.0, 128.8, 128.6, 126.6, 125.9, 124.2, 111.8,
110.8, 61.1, 56.0, 55.6, 14.3, 12.1. HRMS: calcd for
C23H23NO7SNa [M þ Na]þ 480.1093, found 480.1103.
(E)-Ethyl 2-(3-(Benzyloxy)-4-methoxystyryl)-5-methyloxa-
zole-4-carboxylate (27). A suspension of 80 (160 mg, 0.3 mmol),
zinc dust (1.2 g, 18.0 mmol), and saturated aq NH4Cl (8 mL) in
THF (8 mL) was refluxed for 6 h, and then it was cooled to rt
and filtered through Celite. The filtrate was diluted with H2O
(10 mL) and extracted with EtOAc (15 mL). The organic layer
was washed with brine (10 mL), dried (MgSO4), and concen-
trated in vacuo. Purification of the residue by flash chromatog-
raphy (30% EtOAc/hexanes) afforded 27 as a yellow solid (88
mg, 75% over two steps). Mp: 107-109 °C. IR: 1712. 1H:
7.48-7.28 (m, 6H), 7.09 (dd, 1H, J = 8.3, 1.9), 7.05 (d, 1H,
J = 1.9), 6.90 (d, 1H, J = 8.3), 6.68 (d, 1H, J = 16.4), 5.19 (s,
2H), 4.40 (q, 2H, J = 7.1), 3.92 (s, 3H), 2.66 (s, 3H), 1.40 (t, 3H,
J = 7.1). 13C: 162.4, 159.6, 155.7, 151.0, 148.3, 136.7, 136.7,
128.7, 128.6, 128.1, 128.0, 127.2, 121.7, 111.9, 111.6, 111.1,
71.0, 61.0, 56.1, 14.4, 12.1. HRMS: calcd for C23H23NO5Na
[M þ Na]þ 416.1474, found 416.1468.
(E)-Ethyl
2-(3,4-Dimethoxystyryl)-5-methyloxazole-4-car-
boxylate (82). This compound was prepared from 81 following
the procedure described above for 27. The product, 97% yield,
was obtained as a yellow solid. Mp: 79-81 °C. IR: 1711. 1H: 7.43
(d, 1H, J = 16.4), 7.05 (dd, 1H, J = 8.3, 1.6), 7.01 (d, 1H, J =
1.6), 6.89 (d, 1H, J = 8.3), 6.75 (d, 1H, J = 16.4), 4.37 (q, 2H,
J = 7.1), 3.89 (s, 3H), 3.88 (s, 3H), 2.64 (s, 3H), 1.38 (t, 3H, J =
7.1). 13C: 162.4, 159.6, 155.7, 150.4, 149.2, 136.7, 128.6, 128.2,
121.2, 111.2, 111.1, 109.0, 60.9, 55.9, 55.8, 14.4, 12.1. HRMS:
calcd for C17H20NO5 [M þ H]þ 318.1341, found 318.1346.
(E)-2-(3-(Benzyloxy)-4-methoxystyryl)-5-methyloxazole-4-car-
boxylic acid (83). A suspension of 27 (95 mg, 0.24 mmol) and
LiOH (14 mg, 0.33 mmol) in THF/H2O (2 mL/2 mL) was stirred
at rt overnight, whereupon TLC (50% EtOAc/hexanes) indicated
complete conversion. The mixture was diluted with H2O (10 mL),
acidified to pH = 3 with aq 1 N HCl, and then extracted with
1
154-155 °C. IR: 1717. H: 7.86-7.78 (m, 2H), 7.73-7.65 (m,
1H), 7.60-7.52 (m, 2H), 4.55 (s, 2H), 4.36 (q, 2H, J = 7.1), 2.62
(s, 3H), 1.37 (t, 3H, J = 7.1). 13C: 161.6, 158.2, 151.0, 137.9,
J. Org. Chem. Vol. 74, No. 23, 2009 9149

Zhang et al.
JOCArticle
EtOAc (3 ꢀ 10 mL). The combined extracts were sequentially
washed withH2O (10mL) and brine (10mL), dried(MgSO4), and
concentrated in vacuo to afford 83 (81 mg, 92%) as a white solid.
Mp: 185-186 °C. IR: 3052, 2947, 1689. 1H (CD3OD): 7.52-7.28
(m, 6H), 7.26 (d, 1H, J = 1.3), 7.15 (dd, 1H, J = 8.3, 1.3), 6.98 (d,
1H, J = 8.3), 6.74(d, 1H, J = 16.3), 5.14 (s, 2H), 3.87 (s, 3H), 2.64
(s, 3H). 13C (CD3OD): 163.4, 160.0, 155.7, 151.4, 148.4, 137.4,
137.1, 128.2, 128.1, 127.6, 127.4, 122.0, 112.0, 111.6, 109.9, 70.7,
55.0, 10.6. HRMS: calcd for C21H19NO5Na [M þ Na]þ 388.1161,
found 388.1166.
(E)-2-(3,4-Dimethoxystyryl)-5-methyloxazole-4-carboxylic Acid (84).
The title compound was prepared from 82 (480 mg, 1.5 mmol) following
the procedure described above for 83. The product was obtained as a
white solid (390 mg, 89%). Mp 222-224 °C. IR: 3055, 2835, 1694. 1H
(CD3OD): 7.49 (d, 1H, J = 16.4), 7.23 (s, 1H), 7.16 (d, 1H, J = 8.2),
6.98 (d, 1H, J = 8.2), 6.82 (d, 1H, J = 16.4), 3.90 (s, 3H), 3.87 (s, 3H),
2.66 (s, 3H). 13C(CD3OD): 163.4, 160.0, 155.7, 150.7, 149.4, 137.5, 128.2,
121.6, 111.3, 109.9, 109.4, 55.1, 55.0, 10.6. HRMS: calcd for C15H14NO5
([M - H]-) 288.0872, found 288.0870.
(E)-Ethyl 2-(2-(2-(3-(Benzyloxy)-4-methoxystyryl)-5-methy-
loxazol-4-yl)-2-oxo-1-(phenylsulfonyl)ethyl)-5-methyloxazole-4-
carboxylate (85). A solution of 71 (495 mg, 1.60 mmol) and NaH
(211 mg, 60% dispersion in mineral oil, 5.30 mmol) in THF
(10 mL) was stirred at -10 °C for 1 h, and then it was cooled to
-25 °C. In parallel, a solution of 83 (643 mg, 1.80 mmol),
EtOCOCl (185 μL, 1.94 mmol), and Et3N (270 μL, 1.94 mmol)
in THF (10 mL) was stirred at 0 °C for 1 h, and then it was
filtered through a plug of Celite to remove precipitated
16.3), 5.19 (s, 2H), 4.50 (s, 2H), 4.38 (q, 2H, J = 7.1), 3.93 (s, 3H),
2.65 (s, 3H), 2.64 (s, 3H), 1.39 (t, 3H, J = 7.1); enol tautomer:
7.50-7.28 (m, 6H), 7.14-7.08 (m, 2H), 6.90 (d, 1H, J = 8.9), 6.68
(d, 1H, J = 16.3), 6.22 (s, 1H), 5.19 (s, 2H), 4.38 (q, 2H, J = 7.1),
3.92 (s, 3H), 2.66 (s, 3H), 2.63 (s, 3H), 1.40 (t, 3H, J = 7.1). 13
C
(mixture of tautomers): 189.4, 162.3, 162.0, 161.7, 159.6, 159.1,
157.7, 157.1, 156.4, 155.4, 153.3, 151.2, 150.9, 148.8, 148.4, 148.4,
137.1, 136.8, 136.7, 136.0, 134.4, 131.2, 128.6, 128.4, 128.0, 128.0,
127.9, 127.3, 127.3, 126.3, 121.8, 121.6, 111.9, 111.8, 111.7, 111.4,
110.8, 84.2, 71.0, 71.0, 60.8, 56.0, 39.6, 14.4, 14.3, 12.3, 12.2, 12.1,
12.0. HRMS: calcd for C29H29N2O7 [M þ H]þ, 517.1975, found
517.1979.
(E)-Ethyl 2-(2-(2-(3,4-Dimethoxystyryl)-5-methyloxazol-4-
yl)-2-oxoethyl)-5-methyloxazole-4-carboxylate (88). This com-
pound was prepared from 86 (395 mg, 0.68 mmol) following the
procedure described above for 87, and it was obtained as a
yellow oil (145 mg, 48%; keto tautomer only). IR: 1713, 1691.
1H: 7.45 (d, 1H, J = 16.3), 7.09 (dd, 1H, J = 8.2, 1.9), 7.07 (d,
1H, J = 1.9), 6.89 (d, 1H, J = 8.2), 6.75 (d, 1H, J = 16.3), 4.50
(s, 2H), 4.38 (q, 2H, J = 7.1), 3.93 (s, 3H), 3.92 (s, 3H), 2.66 (s,
3H), 2.63 (s, 3H), 1.38 (t, 3H, J = 7.1). 13C: 189.4, 162.3, 159.1,
157.2, 156.4, 155.5, 150.5, 149.3, 137.2, 134.4, 129.4, 128.1,
121.5, 111.1, 110.8, 108.9, 60.9, 56.0, 55.9, 39.6, 14.4, 12.3,
12.1. HRMS: calcd for C23H25N2O7 ([M þ H]þ) 441.1662,
found 441.1657.
(E)-Ethyl 2-(2-(2-(3-Hydroxy-4-methoxystyryl)-5-methyloxa-
zol-4-yl)-2-oxoethyl)-5-methyloxazole-4-carboxylate (89).
A
cold (-78 °C) solution of 87 (100 mg, 0.19 mmol) and BCl3
(1.0 M in CH2Cl2, 1.0 mL, 1.0 mmol) in CH2Cl2 (3 mL) was
stirred for 30 min, and then it was warmed to rt and stirred for
another 30 min. Water (5 mL) was added to quench the reaction,
and the mixture was stirred for another 15 min and then
extracted with CH2Cl2 (10 mL). The extract was washed with
brine (5 mL), dried (MgSO4), and evaporated in vacuo to yield
89 as a yellow solid (85 mg, quant), which was used in next step
without further purification. IR: 3211, 1716, 1691. 1H: 7.41 (d,
1H, J = 16.3), 7.15 (d, 1H, J = 2.0), 7.04 (dd, 1H, J = 8.4, 2.0),
6.87 (d, 1H, J = 8.4), 6.73 (d, 1H, J = 16.3), 5.67 (s, 1H), 4.50 (s,
2H), 4.38 (q, 2H, J = 7.1), 3.94 (s, 3H), 2.66 (s, 3H), 2.64 (s, 3H),
1.39 (t, 3H, J = 7.1). 13C: 189.5, 162.3, 159.1, 157.1, 156.5, 155.5,
147.9, 145.9, 137.1, 134.4, 128.8, 127.9, 120.7, 112.4, 111.2,
110.7, 60.8, 56.0, 39.6, 14.4, 12.3, 12.1. HRMS: calcd for
C22H22N2O7Na [M þ Na]þ 449.1325, found 449.1314.
Et3N HCl. The filtrate, presumed to contain the mixed anhy-
3
dride of 83, was added dropwise to the first solution. The
resulting mixture was stirred at -25 °C for 8 h, and then it
was quenched with saturated aq NH4Cl (30 mL) and extracted
with EtOAc (3 ꢀ 30 mL). The combined extracts were washed
with brine (30 mL), dried (MgSO4), and concentrated in vacuo
to yield 85 (1.12 g) as a yellow foam, which was used in next step
without further purification. 1H: 7.86-7.80 (m, 2H), 7.70-7.28
(m, 9H), 7.14-7.00 (m, 3H), 6.91 (d, 1H, J = 8.2), 6.51 (d, 1H,
J = 16.3), 5.21 (s, 2H), 4.35 (q, 2H, J = 7.1), 3.93 (s, 3H), 2.65
(s, 3H), 2.64 (s, 3H), 1.36 (t, 3H, J = 7.1). MS: 679.3 [M þ Na]þ.
(E)-Ethyl 2-(2-(2-(3,4-Dimethoxystyryl)-5-methyloxazol-4-yl)-
2-oxo-1-(phenylsulfonyl)ethyl)-5-methyloxazole-4-carboxylate:
Mixture of Keto and Enol Tautomers (86). The compound was
prepared from 71 (310 mg, 1.0 mmol) and 84 (318 mg, 1.1 mmol)
following the procedure described above for 85. The product, a
yellow foam (720 mg), was obtained as a 5:4 mixture of keto and
enol tautomers, and it was used in next step without further
(E)-2-(2-(2-(3-Hydroxy-4-methoxystyryl)-5-methyloxazol-4-yl)-
2-oxoethyl)-5-methyloxazole-4-carboxylic Acid (90). A suspension
of 89 (84 mg, 0.20 mmol) and LiOH (28 mg, 0.65 mmol) in THF/
H2O (3 mL/3 mL) was stirred at rt overnight, whereupon TLC
(50% EtOAc/hexanes) indicated complete conversion. The solvent
was removed in vacuo; the residue was diluted with H2O (10 mL),
then the solution was acidified to pH = 3 with aq 1 N HCl. The
mixture was extracted with CH2Cl2 (3ꢀ 10 mL), and the combined
extracts were washed with H2O (10 mL), dried (MgSO4), and
concentrated in vacuo to afford 90 (74 mg, 95%) as a yellow solid.
Mp: 186-188 °C. IR: 3407, 1712, 1690. 1H: 7.41 (d, 1H, J = 16.1),
7.15 (s, 1H), 7.04 (d, 1H, J = 8.3), 6.87 (d, 1H, J = 8.3), 6.73 (d,
1H, J = 16.1), 4.51 (s, 2H), 3.93 (s, 3H), 2.66 (s, 6H). 13C: 189.2,
164.6, 159.2, 158.1, 156.7, 155.6, 148.0, 145.9, 137.2, 134.4, 128.8,
127.2, 120.7, 112.4, 111.1, 110.7, 56.0, 39.5, 12.4, 12.1. HRMS:
calcd for C20H17N2O7 [M - H]- 397.1036, found 397.1028.
(E)-2-(2-(2-(3,4-Dimethoxystyryl)-5-methyloxazol-4-yl)-2-oxo-
ethyl)-5-methyloxazole-4-carboxylic Acid (91). This compound
was preparedfrom 88 (95mg, 0.22 mmol) following the procedure
described above for 90. The product was obtained as a yellow
solid (80 mg, 90%). Mp: 168-170 °C. IR: 2922, 1694, 1660. 1H:
7.46 (d, 1H, J = 16.3), 7.10 (dd, 1H, J = 8.2, 1.8), 7.08 (d, 1H, J =
1.8), 6.89 (d, 1H, J = 8.2), 6.77 (d, 1H, J = 16.3), 4.51 (s, 2H),
3.94 (s, 3H), 3.93 (s, 3H), 2.67 (s, 3H), 2.66 (s, 3H). 13C: 189.1,
164.9, 159.2, 158.2, 156.7, 155.6, 150.5, 149.3, 137.2, 134.4, 128.1,
1
purification. H keto tautomer: 7.85-7.82 (m, 2H), 7.72-7.46
(m, 3H), 7.40 (d, 1H, J = 16.3), 7.12-7.08 (m, 1H), 7.06 (d, 1H,
J = 1.7), 6.90 (d, 1H, J = 8.3), 6.62 (d, 1H, J = 16.3), 4.55 (s, 1H),
4.33 (q, 2H, J = 7.1), 3.96 (s, 3H), 3.93 (s, 3H), 2.66 (s, 3H), 2.64
(s, 3H), 1.36 (t, 3H, J = 7.1); enol tautomer: 7.83-7.79 (m, 2H),
7.72-7.46 (m, 3H), 7.43 (d, 1H, J = 16.3), 7.12-7.08 (m, 1H),
7.06 (d, 1H, J = 1.7), 7.03 (s, 1H), 6.89 (d, 1H, J = 8.3), 6.70 (d,
1H, J = 16.3), 4.37 (q, 2H, J = 7.1), 3.93 (s, 3H), 3.92 (s, 3H), 2.69
(s, 3H), 2.61 (s, 3H), 1.36 (t, 3H, J = 7.1). MS: 581.2 [M þ H]þ.
(E)-Ethyl 2-(2-(2-(3-(Benzyloxy)-4-methoxystyryl)-5-methy-
loxazol-4-yl)-2-oxoethyl)-5-methyloxazole-4-carboxylate: Mix-
ture of Keto and Enol Tautomers (87). A solution of 85 (1.1 g,
1.7 mmol), zinc dust (6.8 g, 10.5 mmol), and saturated aq NH4Cl
(100 mL) in THF (50 mL) was refluxed for 6 h, and then it was
cooled to rt and filtered through Celite. The filtrate was concen-
trated in vacuo, diluted with H2O (50 mL), and then extracted
with CH2Cl2 (100 mL). The extract was washed with brine
(50 mL), dried (MgSO4), and evaporated. Purification of the crude
(flash chromatography, 50% EtOAc/hexanes/Et3N) afforded 87
(yellow solid, 0.66 g, 80% over two steps) as a 1:3 mixture of keto
and enol tautomers. IR: 1736, 1650. 1H keto tautomer: 7.50-7.28
(m, 6H), 7.14-7.08 (m, 2H), 6.92 (d, 1H, J = 8.2), 6.68 (d, 1H, J =
9150 J. Org. Chem. Vol. 74, No. 23, 2009

Zhang et al.
JOCArticle
127.2, 121.5, 111.1, 110.8, 108.9, 56.0, 55.9, 39.5, 12.4, 12.1.
HRMS: calcd for C21H19N2O7 [M- H]- 411.1192, found 411.1198.
Siphonazole A (1). A solution of 90 (20.0 mg, 0.05 mmol), (E)-
penta-2,4-dien-1-ylamine (9.1 mg, 0.11 mmol), EDCI (21.0 mg,
0.11 mmol), HOBt (15.0 mg, 0.11 mmol), and Et3N (15.3 μL,
0.11 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The
mixture was then quenched with H2O (5 mL) and extracted with
EtOAc (10 mL). The extract was washed with H2O (10 mL),
dried (MgSO4), and evaporated. Purification of the residue by
flash chromatography (70% EtOAc/hexanes) afforded 1 as a
yellow solid (18 mg, 78%; mostly keto form). IR: 3399, 1690. 1H
(keto tautomer, acetone-d6): 7.83 (s, 1H), 7.65-7.52 (m, 1H),
7.47 (d, 1H, J = 16.4), 7.23 (d, 1H, J = 2.1), 7.16 (dd, 1H, J =
8.3, 2.1), 7.01 (d, 1H, J = 8.3), 6.85 (d, 1H, J = 16.4), 6.45-6.31
(m, 1H), 6.28-6.18 (m, 1H), 5.82 (dt, 1H, J = 15.0, 6.0),
5.21-5.15 (m, 1H), 5.05-5.02 (m, 1H), 4.44 (s, 2H),
product was obtained as a yellow solid (17 mg, 71%, mostly keto
form). IR: 1690, 1659. 1H (keto tautomer, acetone-d6): 7.56 (br,
1H), 7.50 (d, 1H, J = 16.4), 7.40 (d, 1H, J = 2.0), 7.23 (dd, 1H,
J = 8.3, 2.0), 7.01 (d, 1H, J = 8.3), 6.95 (d, 1H, J = 16.4),
6.44-6.32 (m, 1H), 6.26-6.19 (m, 1H), 5.82 (dt, 1H, J = 15.1,
5.9), 5.21-5.15 (m, 1H), 5.05-5.02 (m, 1H), 4.44 (s, 2H),
4.05-4.00 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.65 (s, 3H), 2.60
(s, 3H). 13C (acetone-d6): 190.0, 161.9, 160.0, 156.8, 155.9,
153.8, 152.0, 150.7, 138.1, 137.6, 135.3, 132.7, 131.9, 130.5,
129.1, 122.7, 117.0, 112.5, 111.5, 110.5, 56.1, 56.1, 40.7, 40.0,
12.2, 11.5. HRMS: calcd for C26H27N3O6Na [M þ Na]þ 500.1798,
found 500.1787.
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, CFI,
BCKDF, NSERC, CIHR, and MerckFrosst Canada for
financial support.
4.04-4.00 (m, 2H), 3.91 (s, 3H), 2.65 (s, 3H), 2.60 (s, 3H). 13
C
(acetone-d6): 190.1, 162.0, 160.0, 156.8, 155.9, 153.8, 150.0,
147.8, 138.2, 137.6, 135.3, 132.7, 131.9, 130.5, 129.4, 121.4,
117.0, 113.9, 112.4, 111.5, 56.3, 40.7, 40.0, 12.2, 11.5. HRMS:
calcd for C25H25N3O6Na [M þ Na]þ 486.1641, found 486.1639.
Siphonazole B (2). The title compound was prepared from 91
(21 mg, 0.05 mmol) following the procedure described for 1. The
Supporting Information Available: Experimental proce-
dures and characterization data; hardcopy NMR (1H and 13C)
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 23, 2009 9151