Efforts toward the total synthesis of (-)-kendomycin

Article abstract of DOI:10.1021/ol051512r

(Chemical Equation Presented) The synthesis of an advanced component leading to (-)-kendomycin is described. The synthetic scheme features the application of asymmetric conjugate addition methodology for the early generation of the C13-C14 (E)-trisubstitu

Full text of DOI:10.1021/ol051512r

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4161-4164
Efforts toward the Total Synthesis of
)-Kendomycin
(−
David R. Williams and Khalida Shamim
Department of Chemistry, Indiana UniVersity, 800 E. Kirkwood AVenue,
Bloomington, Indiana 47405
williamd@indiana.edu
Received June 28, 2005
ABSTRACT
The synthesis of an advanced component leading to (
conjugate addition methodology for the early generation of the C13
chain. Condensation reactions probe two strategies for attachment of the aromatic system.
−)-kendomycin is described. The synthetic scheme features the application of asymmetric
−C14 (E)-trisubstituted olefin, providing an efficient assembly of the ansa
Kendomycin (1) is a structurally unique polyketide originally
isolated from two different Streptomyces species and shown
to exhibit potent activity as an endothelin antagonist and as
an antiosteoporotic agent.1 In 2000, Zeeck and co-workers
reisolated kendomycin from Streptomyces Violaceruber
(strain 3844-33C) and established the structure via X-ray
crystallographic analysis.2
(-)-Kendomycin demonstrates notable antibacterial activ-
ity against both Gram-positive and Gram-negative bacteria,
particularly against multiresistant Staphylococcus aureus
(MRSA) strains, including vancomycin-resistant S. aureus
(MU50).2a Cytotoxicity studies of 1 have been investigated
with stomach adenocarcinoma (HMO2), hepatocellular car-
cinoma (HEPG2), and breast adenocarcinoma (MCF7) cell
lines. These studies show potency comparable to that of
doxorubicin and increased growth inhibition (GI50) compared
to that of cisplatin.2a
methide chromophore. A substituted ansa chain tethers these
components in a conformationally restricted macrocyclic
system. In 2004, Lee and co-workers3 disclosed the first total
synthesis of 1. However, these challenging structural features
have stimulated numerous synthesis studies adopting a ring-
closing strategy of olefin metathesis.4,5 Although ring-closing
metathesis (RCM) has generally proven to be ineffective,
Smith and co-workers have recently described conditions for
16-membered macrocyclization by RCM, albeit with forma-
tion of the undesired Z-olefin.6 Subsequently, kendomycin
was obtained by epoxidation and inversion of olefin geom-
(2) (a) Bode, H. B.; Zeeck, A. J. J. Chem. Soc., Perkin Trans. 1 2000,
323. (b) Bode, H. B.; Zeeck, A. J. J. Chem. Soc., Perkin Trans. 1 2000,
2665.
(3) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720.
(4) (a) Martin, H. J.; Drescher, M.; Kahlig, H.; Schneider, S.; Mulzer, J.
Angew. Chem., Int. Ed. 2001, 40, 3186. (b) Marques, M. M. B.; Pichlmair,
S.; Martin, H. J.; Mulzer, J. Synthesis 2002, 18, 2766. (c) Pichlmair, S.;
Marques, M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003,
5, 4657. (d) Green, M. P.; Pichlmair, S.; Marques, M. M. B.; Martin, H. J.;
Diwald, O.; Berger, T.; Mulzer, J. Org. Lett. 2004, 6, 3131. (e) Mulzer, J.;
Pichlmair, S.; Green, M. P.; Marques, M. M. B.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11980.
The structure of kendomycin (1) features a novel C-aryl
glycoside substructure as conceptualized by the direct linkage
of a fully substituted tetrahydropyran and the quinone
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japanese Patent
08231551 [A2960910], 1996; Chem. Abstr. 1996, 126, 6553. (b) Funahashi,
Y.; Kawamura, N. Japanese Patent 08231552, 1996; Chem. Abstr. 1996,
126, 326518. (c) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L.
U.S. Patent 5728727, 1998; Chem. Abstr. 1998, 128, 239489.
(5) For other approaches, see: (a) Sengoku, T.; Arimoto, H.; Uemura,
D. Chem. Commun. 2004, 1220. (b) White, J. D.; Smits, H. Org. Lett. 2005,
7, 235. (c) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529.
(6) Smith, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2005,
127, 6948.
10.1021/ol051512r CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/24/2005

Scheme 1. Retrosynthetic Analysis of Kendomycin
Scheme 2. Formation of the (E)-Trisubstituted Olefin
etry. Owing to our interest in atropisomerism of this C-aryl
glycoside system, we have chosen to examine a pathway
for late-stage introduction of the quinone methide component.
Herein, we present a concise and efficient route for the
stereocontrolled synthesis of the fully elaborated ansa chain
of kendomycin (1) as a prelude to ring-closure studies.
The synthesis of the ansa chain began with the construction
of the 1,3-anti dimethyl substitution in the C14-C19
component (Scheme 2).7 N-Enoyl oxazolidinone 48 was
treated with the Yamamoto organocopper species derived
from the nonracemic bromide 5,9 providing the 1,3-anti
stereochemistry of 6 with high diastereoselectivity (dr >17:
1). Reductive cleavage of the chiral auxiliary of 6 gave a
primary alcohol for oxidation under Swern conditions,10 and
high yielding homologation to the terminal alkyne 7 was
effected upon subsequent treatment with the Bestmann acyl-
DAMP reagent.11
Stereocontrolled formation of the E-trisubstituted C13-
C14 alkene was undertaken by initial syn-carboalumination
using Negishi conditions.12 The intermediate alkenylalane
was transformed by the addition of the cyano cuprate 8,13
and in situ formation of a new organometallic reagent
facilitated reactivity for conjugate addition. In the event, the
introduction of nonracemic oxazolidinone 9 resulted in 70%
yield of 10 (dr 7:1) after purification by flash chromatog-
raphy. Preliminary attempts to use CuCN‚LiCl for trans-
metalation of the alkenylalane resulted in significant amounts
of product arising from methyl conjugate addition that
originated from the trimethylalane.14 Overall the process
leading to 10 was particularly gratifying, since it effected
the stereoselective olefin synthesis and stereocontrol at C12
in a single operation.
Removal of the chiral auxiliary of 10 and conversion of
the resultant alcohol to aldehyde 11 proceeded in a straight-
forward fashion (Scheme 3). Asymmetric aldol condensation
of 11 with the Z(O)-enolate of the ethyl ketone 12 under
Paterson conditions using (-)-(Ipc)2BOTf provided the
â-hydroxy ketone adduct 13 in good yield and high diaste-
reoselectivity (dr 9:1).15 Advantageously, this reagent-
controlled process utilizes chirality in the propionate-derived
ethyl ketone 12 for diastereofacial discrimination in the aldol
transition state, which is fully incorporated in 13. Internally
directed hydride reduction via the Evans protocol16 gave the
expected 1,3-anti-diol, which was protected as the corre-
sponding acetonide 14. Hydrogenolysis of the C19-OBn
protecting group in the presence of the C5-OPMB ether was
readily achieved using W-2 Raney nickel,17 and the resulting
primary alcohol was replaced under Mitsunobu conditions18
to yield the benzothiazolyl sulfide 15. Oxidative cleavage
of the C5-OPMB ether with buffered DDQ19 and oxidation
(14) Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56, 5761.
(15) (a) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (b) Paterson,
I.; Lister, M. A. Tetrahedron Lett. 1988, 29, 585. (c) Paterson, I.; Norcross,
R. D.; Ward, R. A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116,
11287. (d) For preparation of (-)-(Ipc)2BH precursor, see: Joshi, N. K.;
Brown, H. C. J. Org. Chem. 1988, 53, 4059.
(7) (a) Williams, D. R.; Kissel, W. S.; Li, J. J. Tetrahedron Lett. 1998,
39, 8593. (b) Williams, D. R.; Kissel, W. S.; Li, J. J.; Mullins, R. J.
Tetrahedron Lett. 2002, 43, 3723.
(8) For introduction of 4-phenyl-1,3-oxazolin-2-ones: Nicolas, E.; Rus-
sell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766.
(9) (a) White, J. D.; Johnson, A. T. J. Org. Chem. 1994, 59, 3347. (b)
Williams, D. R.; Li, J. Tetrahedron Lett. 1994, 35, 5113.
(10) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(11) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
1996, 521. (b) Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois,
R. G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540.
(12) Negishi, E. I.; Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
167, 6639.
(13) (a) Ireland, R. E.; Wipf, P. J. Org. Chem. 1990, 55, 1425. (b) Wipf,
P.; Smitrovich, J. H.; Moon, C. W. J. Org. Chem. 1992, 57, 3178.
(16) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560. (c) Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993, 115,
1608. (d) Paterson, I.; Yeung, K. S.; Watson, C.; Ward, R. A.; Wallace, P.
A. Tetrahedron 1998, 54, 11935.
(17) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(18) (a) Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem.
Soc., Perkin Trans. 1 1999, 955. (b) Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563.
4162
Org. Lett., Vol. 7, No. 19, 2005

Scheme 3. Elaboration of 10 to the Advanced Aldehyde 2
of the resulting alcohol under Parikh-Doering conditions20
able decomposition. Studies of halogen-metal exchange with
aryl bromides 17 and 18, featuring different protecting groups
for the benzylic alcohol, gave significant amounts of reduc-
tion product resulting from simple protonation.22,23 On the
other hand, the dimethyl acetal 19 cleanly afforded the
advanced intermediate 20 in 68% yield as a mixture of
benzylic alcohols (dr 2:1).24 No attempt has been made to
secure better stereocontrol in this event since our plan for
pyran ring closure supports elimination and subsequent
intramolecular capture of a quinone methide intermediate.
provided aldehyde 2 as an advanced component for studies
of macrocycle formation. The acyclic aldehyde 2 represents
the entire C5-C19 ansa bridge of kendomycin with inclusion
of the E-trisubstituted alkene and seven additional stereogenic
centers.
Preliminary investigations have explored several options
for the introduction of the aromatic nucleus. Benzoic acid
derivative 16 (Scheme 4) provided for directed deprotonation
To explore the feasibility of the Julia olefination reaction
as a technique for initial attachment of the aromatic system,
the benzothiazolyl sulfide 15 (from Scheme 3) was oxidized
to the corresponding sulfone 21 using hydrogen peroxide in
the presence of ammonium molybdate hydrate (Scheme 5).25
This procedure led to 21 with high yield (87%) while
avoiding competing oxidation of the trisubstituted alkene.
Scheme 4
Scheme 5
(sBuLi/TMEDA) and moderate yields of condensation
products with model aldehydes, which resulted in the
expected isolation of five-membered lactones.21 However,
the corresponding reactions with aldehyde 2 led to consider-
(19) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.
(20) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(21) (a) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem.
1994, 59, 4042. (b) Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J. L.
J. Chem. Soc., Perkin Trans. 1 1995, 1265.
Org. Lett., Vol. 7, No. 19, 2005
4163

Subsequent treatment of 21 with LDA at -78 °C and the
addition of aldehyde 22 exclusively yielded the E-olefin 23
upon warming to room temperature (80%).
In summary, a fully functionalized ansa chain of kendo-
mycin has been prepared with excellent overall stereoselec-
tivity. Two techniques have been examined for successful
introduction of the aromatic moiety. Efforts are underway
to advance this strategy for synthesis of kendomycin.
(22) (a) Parham, W. E.; Sayed, Y. E. Synthesis 1976, 116. (b) Parham,
W. E.; Montgomery, W. C. J. Org. Chem. 1974, 39, 2048. (c) Schmidt, R.
R.; Frick, W. Tetrahedron 1988, 44, 7163. The halogen metal exchange
was observable by TLC as well as isolation of the protonated compound
Acknowledgment. We acknowledge the National Insti-
tutes of Health (GM42897) for their generous support of this
work.
1
by H NMR after workup.
(23) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed
2004, 43, 1239.
(24) For examples of the metalation of similarly substituted aryl bromides
and condensation with aldehydes, see: (a) Sugahara, M.; Moritani, Y.;
Terakawa, Y.; Ogiku, T.; Ukita, T.; Iwasaki, T. Tetrahedron Lett. 1998,
39, 1377. (b) Kusama, H.; Hara, R.; Kawahra, S.; Nishimori, T.; Kashima,
H.; Nakamura, N.; Morihira, K.; Kuwajima, I. J. Am. Chem. Soc. 2000,
122, 3811. (c) Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi,
H. J. Chem. Soc., Perkin Trans. 1 1997, 4, 443.
(25) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140. For example, see: Williams, D. R.; Cortez, G. S.; Bogen, S. L.;
Rojas, C. M. Angew. Chem., Int. Ed. 2000, 39, 4612.
Supporting Information Available: Experimental pro-
cedures and spectral chracterizations for compounds 2, 7,
10, 11, 13-15, and 20-23. This material is available free
of charge via the Internet at http://pubs.acs.org.
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