Total synthesis of siphonazoles by the use of a conjunctive oxazole building block

Article abstract of DOI:10.1021/ol900455m

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 the new b

Full text of DOI:10.1021/ol900455m

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2389-2392
Total Synthesis of Siphonazoles by the
Use of a Conjunctive Oxazole Building
Block
Jianmin Zhang and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received March 4, 2009
ABSTRACT
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 the new building block.
Siphonazole, 1, and its methylated congener, 2 (Scheme 1),
are structurally novel natural products isolated from a Gram-
negative filamentous gliding bacterium of the Herpetosiphon
genus.1 Their uniqueness derives from the fact that they
incorporate a pair of oxazole subunits connected by a two-
carbon tether. As of yet, no information is available concern-
ing the bioactivity of 1-2, which we propose to distinguish
with the names siphonazole A, 1, and siphonazole B, 2.
The unusual structure of siphonazoles has not escaped the
attention of the synthetic community, and efforts in this field
have recently culminated in Moody’s landmark syntheses
of 1-2.2 This successful route to the target molecules
demonstrates yet another application of elegant oxazole-
forming processes, which rely on the reaction of a ketocar-
benoid with an amide3 or a nitrile.4 On the other hand,
siphonazoles provide ample opportunity for further meth-
odology development. To illustrate (Scheme 1), an alternative
avenue could be envisioned based on the iterative use of
oxazole nucleophile 3. This synthon would enable both the
olefination of aldehyde 4 (bond-forming step a), resulting
in formation of a 1,2-diarylethylene motif and the condensa-
tion with an ester, yielding a (2-oxazolyl)methyl ketone (step
b). The product of C-C bond-forming steps a and b would
Scheme 1
.
Structure and Retrosynthetic Disconnection of
Siphonazoles A and B
¨
(1) Nett, M.; Erol, O; Kehrhaus, S.; Ko¨ck, M.; Krick, A.; Eguereva, E.;
Neu, E.; Ko¨nig, G. M. Angew. Chem., Int. Ed. 2006, 45, 3863.
(2) (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.
(3) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron Lett. 2004,
60, 3967 See refs 2 for a thorough bibliography.
then be advanced to the ultimate 1 or 2 by condensation with
amine 5 (step c).
(4) Connell, R. D.; Tebbe, M.; Helquist, P.; Åkermark, B. Tetrahedron
Lett. 1991, 32, 17 See also refs 2.
10.1021/ol900455m CCC: $40.75
Published on Web 04/27/2009
 2009 American Chemical Society

Precedent foreshadowed numerous difficulties with the
strategy depicted in Scheme 1. Briefly, the oxazole C-4
carboxy substituent opposes the formation of anion 3. As
shown in Scheme 2, metalation of 2-methyloxazole-4-
In principle, the foregoing ills could be cured by activating
the C-2 Me with an appropriate anion-stabilizing unit. A
sulfonyl group would be a logical choice, given that the
acylation of a 2-(arylsulfonyl)methyl oxazole, in a fashion
reminiscent of step b in Scheme 1, finds precedent in the
work of Fujita,6 and that a sulfonyl group should permit the
execution of step a in a Julia10 mode.
In practice, such a remedy creates a new set of problems.
The exiguous volume of literature on the chemistry of
2-(sulfonyl)methyloxazole-4-carboxylates11 suggests that the
anions of these species are exceedingly poor nucleophiles.
To wit, the anion of 14 (Scheme 3) fails to add to
Scheme 2
.
Problematic Behavior of Oxazole-4-carboxylic Acid
Derivatives
Scheme 3. Problematic Behavior of
2-(Sulfonyl)methyloxazole-4-carboxylic Acid Derivatives
aldehydes,12 preventing the occurrence of Julia reactions.
Once again, the peculiar behavior of these compounds is
attributable to the effect of the 4-COOR functionality in that
analogues lacking a 4-carbonyl group, e.g., 15, do participate
in Julia-type processes,13 though not very efficiently. Indeed,
Wittig technology is superior for olefination reactions involv-
ing 2-methyloxazole donors.12-14 Clearly, in order to reach
1-2 by the intended route, it was necessary to circumvent
the unfavorable reactivity profile of 2-(sulfonyl)methylox-
azole-4-carboxylates.
carboxylic acid5 or the corresponding tert-butyl ester6 (6)
occurs exclusively at the unsubstituted C-4 ring position (7).
Deprotonation of 2,4-dimethyloxazole-4-carboxylic acid or
ester (8) takes place preferentially (ca. 2:1) at the C-4 methyl
group (9),7,2b while the corresponding diethylamide is
metalated exclusively there.7 Finally, and in accord with
Moody,2b we found that deprotonation of 10, followed by
capture of the intermediate organometallic species with
aldehyde 4, resulted in a complex mixture of products from
which adduct 11 was isolated in 4% yield.8 The behavior of
2-methyloxazole-4-carboxylic acid derivatives thus deviates
from that of analogues lacking the 4-carboxy group. The
latter, e.g., 12, are smoothly deprotonated at the C-2 Me
group, and the ensuing anions 13 perform well in nucleo-
philic processes, including olefination reactions.9
Scheme 4. Preparation of Building Block 22
(5) (a) Meyers, A. I.; Lawson, J. P. Tetrahedron Lett. 1981, 22, 3163.
(b) Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Lindermann, R. J. J. Org.
Chem. 1986, 51, 5111.
(6) (a) Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24,
2287. (b) Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24,
2291.
(7) Cornwall, P. Dell, C. P. Knight, D. W. J. Chem. Soc., Perkin Trans.
1 1991, 2417. These authors report that under particular conditions it is
possible to generate a 1:1 mixture C-2 and C-4 lithiomethyl derivatives of
the oxazole 4-carboxylic acid.
(8) These difficulties may be ascribed to the unfavorable positioning of
the 4-COOR substituent: the 5-COOR isomer is smoothly deprotonated at
the C-2 Me group (ref 7), arguably because of good mesomeric stabilization
of the resulting anion. In a later step of the synthesis of 1 and 2 (ref 2),
Moody bypassed the problem by employing an organozinc reagent prepared
from the 2-(iodomethyl) analogue of oxazole 8.
The first goal of this study was oxazole conjunctive agent
22 (Scheme 4). The synthesis of this material relied on an
oxazole-forming reaction developed in this laboratory.15
Accordingly, addition of 2-(phenylthio)acetamide 16 to ethyl
(9) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett.
1999, 1, 87.
2390
Org. Lett., Vol. 11, No. 11, 2009

glyoxylate provided 17, which was then converted into
chloride 18 in excellent yield. The action of alkynylaluminum
reagent 19 on 18 resulted in formation of an alkynylglycinate
intermediate, which is isolable, but that in the present case
was more conveniently allowed to cyclize in situ to oxazole
20. The desired 22, a white solid of mp 154-155 °C,
emerged upon desilylation and m-CPBA oxidation of 20.
Both 21 and 22 underwent facile deprotonation of the
activated C-2 substituent upon exposure to LDA (21) or NaH
(22).16 While the anion of 21 added to aldehydes to form
the anticipated adducts in modest yield,17 that of sulfone 22
failed to undergo the same reaction. This is in accord with
the observations of Hoffmann.12 Fortunately, it transpired
that the combination of TiCl4 and Et3N promotes a smooth
Knoevenagel-type condensation of 22 with aldehydes, lead-
ing to alkylidene derivatives in excellent yield, albeit as
mixtures of geometric isomers. This is exemplified in Scheme
5 by the conversion of aldehydes 23 and 24 into olefinic
A potential drawback of the above process is that the
release of the sulfonyl group from the olefinic products may
be difficult. However, such a concern proved to be un-
founded: efficient reduction of 25-26 to olefins 27-28 was
readily achieved by treatment with Zn and aqueous saturated
NH4Cl solution in THF. This technique for the desulfony-
lation of olefinic sulfones such as 25-26 appears to be
undocumented. When the reaction was carried out at room
temperature for 30 min, the emerging 27-28 were obtained
as mixtures of E- and Z-isomers, but conduct of the same
step in refluxing THF for 6 h afforded exclusively (within
the limits of 300 MHz 1H NMR spectroscopy) the E-isomer
of the products. The chemistry of Scheme 5 had thus resolved
all the reactivity issues outlined earlier.
The weak nucleophilicity of the anion of 22 precluded a
direct condensation with esters 27-28. Therefore, the
corresponding carboxylic acids 29-30, prepared by the
customary LiOH saponification of the esters, were activated
with EtOCOCl/Et3N, and the resulting mixed anhydrides
were intercepted in situ with sodiated 22, which had been
generated separately by deprotonation of the parent com-
pound with NaH. The ensuing Fujita-like reaction6 resulted
in the formation of R-sulfonyl ketones 31-32, which 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 derivatives (CDI).26 Desulfonylation
of 31-32 was once again best carried out by treatment with
Scheme 5. Preparation of Key Intermediates 29 and 30
(10) (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.
(11) Comprehensive bibliography beyond refs 6 and 12: (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. In addition, the following patents describe the preparation of some
2-(arylsulfonyl)methyloxazole-4-carboxylic esters: (d) Jpn. Kokai Tokkyo
Koho (1984) JP 59108772 A 19840623 Showa (Taiho Pharmaceutical Co.,
Ltd.), CAN 101:171238. (e) Dehmlow, H.; Kuhn, B.; Masciadri, R.; Panday,
N.; Ratni, H.; Wright, M. B. U.S. Pat. Appl. Pub. (2005), US 2005215577
A1 20050929, CAN 143:347051.
(12) (a) Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron
Lett. 1999, 40, 4527. (b) Wolbers, P.; Misske, A. M.; Hoffmann, H. M. R.
Synlett 1999, 1808.
(13) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999, 40, 2291.
(14) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185.
(15) (a) Coqueron, P. Y. Didier, C. Ciufolini, M. A. Angew. Chem.,
Int. Ed. 2003, 42, 1411. See also: (b) Sano, S. Shimizu, H. Kim, K. Lee,
W. S. Shiro, M. Nagao, Y. Chem. Pharm. Bull. 2006, 54, 196. Reference
a above contains an extensive bibliography of oxazole-forming reactions.
Subsequent representative examples of oxazole construction via the cy-
clization of N-propargylamide intermediates. (c) Wipf, P. Aoyama, Y.
Benedum, T. E. Org. Lett. 2004, 6, 3593. (d) Hashmi, A. S. K. Weyrauch,
J. P. Frey, W. Bats, J. W. Org. Lett. 2004, 6, 4391. (e) Milton, M. D. Inada,
Y. Nishibayashi, Y. Uemura, S. Chem. Commun. 2004, 2712. (f) Hashmi,
A. S. K. Rudolph, M. Schymura, S. Visus, J. Frey, W. Eur. J. Org. Chem.
2006, 4905. (g) Kang, J.-E. Kim, H.-B. Lee, J.-W. Shin, S. Org. Lett. 2006,
8, 3537. (h) Merkul, E. Grotkopp, O. Mu¨ller, T. J, J. Synthesis 2009, 502.
It is important to note that among these methods only the chemistry of refs
a and b permits access to the 2,5-dialkyloxazole-4-carboxylate series.
(16) The deprotonation of 22 with NaH is in accord with ref 6.
(17) These results shall be detailed in a forthcoming full paper.
(18) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 2183.
(19) Nikolae, A.; Florea, S.; Rudorf, W.-D.; Perjessy, A. ReV. Chim.
2005, 56, 524; CAN 144:412344.
sulfones 25 (1:5 mixture of E- and Z-isomers) and 26 (4:5
mixture of E- and Z-isomers), respectively. These conditions
are reminiscent of the Masamune-Roush variant of the
Wadsworth-Emmons olefination reaction.18 However, we
are unable to find literature precedent for the application of
a similar protocol in the Knoevenagel-like condensation of
sulfones with aldehydes. The closest recorded example
involves the reaction of an activated sulfone with PhCHO
in the presence of piperidine.19 With less reactive sulfones,
bases such as BuLi,20 LiHMDS,21 NaH,22 tBuOK,23 or
NaOH24 are necessary, though in one case, the weaker base,
TBAF,25 did promote condensation in modest yield.
Org. Lett., Vol. 11, No. 11, 2009
2391

Zn/NH4Cl. Contrary to the case of 25-26, the desulfony-
lation of R-sulfonyl ketones by this method finds precedent
in the work of Holton.27 Reductants like Na/Hg amalgam
or SmI2 performed poorly in the present case. Ketones 33-34
and derivatives thereof, including the ultimate 1-2, existed
in equilibrium with the relative enols, the proportion of which
once again varied as a function of experimental parameters
(solvent, temperature, etc.).
influence of EDCI to deliver fully synthetic 1 and 2,
1
respectively. The H and 13C NMR spectra of siphonazoles
A and B thus obtained (mostly keto tautomers)29 were
identical to the published spectra of the natural products.1,2
Synthetic siphonazoles were tested for antibiotic activity
against representative pathogens. However, a standard paper
disk assay (10 µg/mL) showed no activity against typical
Gram-positive [methycillin-sensitive Staphylococcus aureus
(MSSA)] or Gram-negative (Escherichia coli, Pseudomonas
aeruginosa) bacteria, as well as fungi (Candida albicans).
In summary, a straightforward synthesis of siphonazoles
has been completed by the iterative use of the oxazole
conjunctive reagent 22. Additional aspects of the chemistry
of this reagent and of the synthesis of siphonazoles will be
discussed in detail in a forthcoming full paper.
The synthesis of siphonazoles was completed as delineated
in Scheme 6. Compound 33 was debenzylated (BCl3) to
Scheme 6. Total Synthesis of Siphonazoles A and B
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, CFI, BCK-
DF, NSERC, CIHR, and MerckFrosst Canada for financial
support. We are grateful to Dr. Elena Polishchuk and the
staff of the Chemistry Department’s Biological Services for
testing the siphonazoles for bioactivity.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds, plus
hardcopy NMR (1H and 13C) spectra of several molecules.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900455M
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Information.
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