Total synthesis of (-)-kendomycin

Article abstract of DOI:10.1021/ol801499s

(Chemical Equation Presented) An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide

Full text of DOI:10.1021/ol801499s

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3813-3816
Total Synthesis of (-)-Kendomycin
Jason T. Lowe and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Metcalf Center for Science and Engineering, Boston UniVersity,
590 Commonwealth AVenue, Boston, Massachusetts 02215
panek@bu.edu
Received July 2, 2008
ABSTRACT
An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation
strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type
reaction) is employed to afford the protected macrocycle.
Kendomycin [(-)-TAN 2162] was originally isolated from
Streptomyces Violaceuber in 1996 by Funahashi and co-
workers.1 Initial screens of the compound revealed potent
endothelin receptor antagonist activity1 as well as its potential
as an antiosteoporotic agent.2 Subsequent reports indicated
that kendomycin exhibited effective antibacterial activity
against both Gram-positive and Gram-negative strains as well
as having enhanced cytotoxic activity toward several human
tumor cell lines (average GI50 < 0.10 µM).3 Recently, it has
been suggested that kendomycin mediates its cytotoxic
effects, in part, through proteasome inhibition.4
Kendomycin is a 16-membered conformationally restricted
macrocycle comprising a densely functionalized pyran ring
system and unique quinone methide chromophore through
a pseudo C-glycosidic bond and further tethered by an
aliphatic ansa system. The relative and absolute stereochem-
istry of kendomycin was confirmed by both single crystal
X-ray and advanced Mosher’s ester analysis.3
The biological profile of kendomycin crosses several
therapeutic areas, and its unique molecular architecture has
led to considerable interest by the synthetic community,
which culminated with two total syntheses5,6 in addition to
several fragment syntheses.7 Herein, we report an enanti-
oselective synthesis of kendomycin.
The synthetic plan for constructing kendomycin in-
tended to utilize an underdeveloped macrocyclization
involving an intramolecular Barbier-type reaction of 3
(5) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720–
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Soc. 2005, 127, 6948–6949. (b) Smith, A. B., III; Mesaros, E. F.; Meyer,
E. A. J. Am. Chem. Soc. 2006, 128, 5292–5299
.
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japan Patent
08231551 [A2960910], 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi,
Y.; Kawamura, N.; Ishimaru, T. Japan Patent 08231552, 1996; Chem. Abstr.
1996, 125, 326518.
(7) (a) Sengoku, T.; Uemura, D.; Arimoto, H. Chem. Lett. 2007, 36,
726–727. (b) Williams, D. R.; Shamim, K. Org. Lett. 2005, 7, 4161–4164.
(c) White, J. D.; Smits, H. Org. Lett. 2005, 7, 235–238. (d) Mulzer, J.;
Pichlmair, S.; Green, M. P.; Marques, M. M. B.; Martin, H. J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11980–11985. (e) Sengoku, T.; Arimoto, H.;
Uemura, D. Chem. Commun. 2004, n/a, 1220–1221. (f) Pichlmair, S.;
Marques, M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003,
5, 4657–4659. (g) Marques, M. M. B.; Pichlmair, S.; Martin, H. J.; Mulzer,
J. Synthesis 2002, n/a, 2766–2770. (h) Martin, H. J.; Drescher, M.; Ka¨hlig,
H.; Schneider, S.; Mulzer, J. Angew. Chem., Int. Ed. 2001, 40, 3186–3188.
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5728727 [A 980317], 1998; Chem. Abstr. 1998, 128, 239489.
(3) (a) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000,
n/a, 323–328. (b) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1
2000, n/a, 2665–2670.
(4) Elnakady, Y. A.; Rohde, M.; Sasse, F.; Backes, C.; Keller, A.;
Lenhof, H. P.; Weissman, K. J.; Mueller, R. ChemBioChem. 2007, 8, 1261–
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10.1021/ol801499s CCC: $40.75
Published on Web 08/13/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis of Kendomycin 1
Scheme 2. Synthesis of Aromatic Core 8
phenol 9.14 This material was chemoselectively protected as
its benzyl ether furnishing 10.15 Oxidation of the remaining
benzylic alcohol using pyridinium chlorochromate (PCC)
provided aromatic aldehyde 8 in high yield and completed
the preparation of the aromatic annulation partner.16
Use of crotylsilane 7 in a [4 + 2]-annulation with aldehyde
8 gave the desired 2,5-syn dihydropyran 11 in 87% isolated
yield (dr > 20:1; Scheme 3). The resulting trisubstituted
Scheme 3. Synthesis of the C1a-C10 Subunit
(Scheme 1).8 In that regard, few examples of samarium(II)
iodide-catalyzed macrocyclizations have been described.9
Disconnection of the C14-C15 trisubstituted olefin of 3
provides an intermediate vinyl iodide and primary alkyl
iodide 6.10 In the forward sense, this bond construction
will be installed through palladium-catalyzed Negishi
cross-coupling. The C10-C11 bond was our next discon-
nection and was accessed via a Wittig olefination using
previously described phosphonium salt 411 and fully
functionalized tetrahydropyran 5. Our convergent approach
to the pyran portion of kendomycin is highlighted by a
stereoselective [4 + 2]-annulation12 between crotylsilane
713 and aldehyde 8.
double bond was treated with m-CPBA in methylene chloride
at 0 °C to provide the desired ꢀ-epoxide as the major isomer
(R:ꢀ 1:3, 82%). The resulting diastereomers could be
separated via column chromatography or taken forward as a
mixture of isomers.17 Epoxide ring opening occurred in the
presence of potassium carbonate in methanol to give second-
ary alcohol 12. This substrate underwent catalytic hydroge-
nation in which both the aryl benzyl ether and R,ꢀ-
unsaturated ester were reduced. Masking the resident hydroxyl
The synthesis of the aromatic fragment 8 (Scheme 2)
began with a regioselective hydroxymethylation of known
(8) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307–338.
(9) (a) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.;
Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003,
42, 1753–1758. (b) Nicolaou, K. C.; Huang, X.; Giuseppone, N.; Rao, P. B.;
Bella, M.; Reddy, M. V.; Snyder, S. A. Angew. Chem., Int. Ed. 2001, 40,
4705–4709.
(10) Fujita, K.; Mori, K. Biosci. Biotechnol. Biochem. 2001, 65, 1429–
1433.
(14) Obtained in two steps starting from commercial 2,6-dimethoxy-
toluene: (a) Knolker, H.-J.; Frohner, W.; Reddy, K. R. Synthesis 2002, 4,
557–564.
(11) Gaeta, F. C. A.; Lehman de Gaeta, L. S.; Kogan, T. P.; Or, Y. S.;
Foster, C.; Czarniecki, M. J. Med. Chem. 1990, 33, 964–972.
(12) For recent examples of allyl and crotylsilane reagents utilized in
natural product synthesis see: (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005,
7, 3231–3234. (b) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44,
1223–1225. (c) Su, Q; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425–
2430. (d) Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991–1993.
(13) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 1529–1532. (b)
Lowe, J. T.; Panek, J. S. Org. Lett. 2007, 9, 2753–2753.
(15) Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181–
2184.
(16) Nakahara, S.; Kubo, A. Heterocycles 2003, 60, 2717–2725.
(17) The C7 epimer (or isomeric mixture) of 12 could be oxidized under
Swern conditions to provide an intermediate ketopyran, which was
selectively reduced under Luche conditions (99%, 15:1 ꢀ:R) to provide 12
in 50% yield over three steps. See Supporting Information for details.
3814
Org. Lett., Vol. 10, No. 17, 2008

groups as their TBS ethers furnished 13 in two steps with
84% yield as a single diastereomeric pyran. Bromination of
the aromatic ring system followed by a Stille cross-coupling
with tri-n-butyl(vinyl)stannane provided styrene 14 (two
steps, 82%). Oxidative cleavage of the resulting styrene
functionality followed by a reductive workup (O3, NaBH4)
gave an intermediate benzyl alcohol that was protected as
its MOM ether. Finally, reduction of the methyl ester using
DIBAL-H provided aldehyde 5.
Scheme 5
.
Installation of the ansa-Bridging System
The synthesis of fragment 6 was carried out through the
alkylation of Myers’ pseudoephedrine-derived auxiliary 1518
with primary iodide 1619 to provide the desired product 17
containing a 1,3-anti relationship between C16 and C18
methyl groups (Scheme 4). Cleavage of the auxiliary was
Scheme 4. Synthesis of the C15-C19 Subunit
t
iodide 6. Treatment of the alkyl iodide with BuLi and
trapping of the resulting anion with anhydrous ZnCl2
generated an intermediate alkyl zinc species. Coupling of
the in situ prepared zinc intermediate with the vinyl iodide
20 in the presence of Pd(PPh3)4 provided the advanced
fragment 21 in 92% yield. This reaction introduced the
remaining chiral centers and carbon atoms en route to
kendomycin.
carried out as previously described using a borane-ammonia
complex to give a primary alcohol.20 This material was
directly converted to the primary iodide 6 by treatment with
I2/PPh3 in 83% yield (over two steps).
Generation of the ylide from phosphonium salt 4 by
treatment with n-butyllithium at 0 °C followed by addition
of aldehyde 5 gave a 10:1 (Z:E) selectivity of the resulting
Wittig adduct (Scheme 5). Hydrogenation of the olefin and
deprotection of the benzyl ether gave the primary alcohol,
which was subsequently oxidized under Swern conditions21
to give aldehyde 18. This material was immediately con-
verted to the internal alkyne 19 using conditions developed
by Corey and Fuchs (86% over two steps).22 Formation of
vinyl iodide 20 was initially found to be problematic. In that
regard, we found that the alkyne undergoes a palladium(0)-
mediated hydrostannation with useful levels of regioselec-
tivity (E:Z 10:1). Conversion of this material to the vinyl
iodide (NIS, CH3CN/CCl3CN) completed the preparation of
the electrophilic cross-coupling partner.23
The final stages of the synthesis began with the removal
of MOM ether of 21 using MgBr2·OEt2 and ethane thiol
initiated (Scheme 6).25 This transformation was followed by
Scheme 6. Synthesis of the Kendomycin Macrocycle
Introduction of the ansa-system was brought about through
a Negishi cross-coupling24 with vinyl iodide 20 and alkyl
(18) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(19) Friestad, G. K.; Marie, J. C.; Deveau, A. M. Org. Lett. 2004, 6,
3249–3252. Or Marshall, J. A.; Grote, J.; Audia, J. E. J. Am. Chem. Soc.
1987, 109, 1186–1194.
(20) Myers, A.; Yang, B.; Kopecky, D. Tetrahedron Lett. 1996, 37,
3623–3626.
(21) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
introduction of a benzylic bromide, which eventually will
become the nucleophilic site in the macrocyclization step.26
Selective removal of the primary TBS ether using CSA in a
(22) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
(23) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996,
37, 8647–8650.
(24) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298–3299. (b) For a recent example, see: Organ, M. G.; Wang,
J. J. Org. Chem. 2003, 68, 5568–5574, and references therein.
(25) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, n/a, 183–
184.
Org. Lett., Vol. 10, No. 17, 2008
3815

CH2Cl2/MeOH mixture followed by oxidation of the alcohol
gave 3 in 74% over four steps, which was used without
purification. Immediate exposure of the bromide to a dilute
solution of freshly prepared samarium(II) iodide27 in THF
resulted in the production of a secondary alcohol 2 in a single
stereochemical configuration.28 Removal of the aromatic silyl
ether with TBAF29 was followed by oxidation of the C19
secondary alcohol, and the aromatic system using hypervalent
iodide provided the ortho-quinone 22.30
Scheme 7. Completion of the Synthesis
The final deprotection sequence to access kendomycin
involved the removal of the secondary silyl ether and
formation of the quinone methide portion of the molecule.6
Interestingly, however, when the reported conditions were
applied, only minute amounts of 1 were obtained (<20%
isolated yield). The spectroscopic data of the major product
isolated was consistent with compound 23. Resubjecting this
material (or 22) to slightly modified conditions (100 equiv
of aq HF, CH3CN, 2 h, RT) and purification over silica gel
provided pure kendomycin as a yellow solid. A plausible
mechanistic pathway has been outlined in Scheme 7. Initial
Michael-type addition of water to ortho-quinone 22 and
elimination of methanol (I) would provide a reasonable
explanation of the formation of structure 23. The silyl ether
eventually lost to arrive at an intermediate product assumed
to be 23-OH (C7). At this point, a number of paths leading
to kendomycin may be operative.31 Initial formation of the
enol tautomer (II f III) could be followed by a reorganiza-
tion to provide R,ꢀ-unsaturated ketone IV, which cyclizes
to form 1. Alternatively, hemiketal formation to access V,
which precedes tautomerization to kendomycin through
intermediate VI, may also be an operative pathway. Though
the mechanism of a similar system has been proposed,32 the
sequence as applied to kendomycin has only been inferred.6b
In summary, the total synthesis of the bacterial metabolite
kendomycin has been achieved in 26 steps with a 1.51%
overall yield starting from 7. The approach relied on the
application of a silane reagent bearing a fully substituted
carbon center to construct the pyran ring. In addition, a SmI2-
promoted macrocyclization strategy was demonstrated to
form the macrocycle of the natural product. Future studies
to explore the scope and limitation of this strategy are
currently underway.
(26) Kim, H. M.; Sendzik, M.; Spencer, J. R.; Zhang, P. PCT Int. Appl.
2005, 117 pp. WO 2005-US18504 20050526.
Acknowledgment. Financial support for this research is
obtained from the NIH CA56304. J.S.P. is grateful to Amgen,
Johnson & Johnson, Merck Co., Novartis, Pfizer, and GSK
for financial support. J.T.L. acknowledges a Merck Graduate
Fellowship and ACS Graduate Fellowship sponsored by
Bristol-Myers Squibb Pharmaceuticals.
(27) Freshly prepared in THF from samarium and diiodoethane, see
Supporting Information for details.
(28) Several attempts to determine the stereochemistry through the use
of chiral derivatizing agents and NMR were unsuccessful.
(29) (a) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003,
125, 5095–5106. (b) For selective deprotection review see: Crouch, R. D.
Tetrahedron 2004, 60, 5833–5871.
(30) (a) Ozanne, A.; Pouyse´gu, L.; Depernet, D.; Franc¸ois, B.; Quideau,
S. Org. Lett. 2003, 5, 2903–2906. (b) Magdziak, D.; Rodriguez, A. A.;
Van De Water, R. W.; Pettus, T. R. R. Org. Lett. 2002, 4, 285–288.
(31) A second Michael-type addition of water to C20a carbon of II could
provide a ꢀ-hydroxy alcohol, which upon loss of water and hemiketalization
would also provide kendomycin. See reference 3a for details.
(32) Ling, T.; Poupon, E.; Rueden, E. J.; Theodorakis, E. A. Org. Lett.
2002, 4, 819–822.
Supporting Information Available: Experimental details
and selected spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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