Total synthesis of kendomycin: A macro-C-glycosidation approach

Article abstract of DOI:10.1021/ja0447154

Kendomycin, also known as (-)-TAN 2162, is a novel polyketide-derived ansamycin isolated from Streptomyces sp., which exhibits potent antagonist and agonist activities at the endothelin and calcitonin receptors, respectively. This bacterial metabolite als

Full text of DOI:10.1021/ja0447154

Published on Web 10/27/2004
Total Synthesis of Kendomycin: A Macro-C-Glycosidation Approach
Yu Yuan, Hongbin Men, and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544-1009
Received September 1, 2004; E-mail: cblee@princeton.edu
Scheme 2. Synthesis of the Tetrahydropyran Domaina
Kendomycin (1), also known as (-)-TAN 2162, is a novel
ansamycin isolated from various Streptomyces species.1,2 It is a
potent antagonist of the endothelin receptor and a calcitonin receptor
agonist that functions as an anti-osteoporotic agent.1 In addition to
these modulatory roles on cellular receptors, this bacterial metabolite
also displays strong antibiotic activities against a wide range of
bacteria, including MRSA strains.2 Furthermore, kendomycin
possesses remarkable cytostatic effects on the growth of several
human cancer cell lines with a potency higher than or comparable
to that of some clinically used drugs.2 Structurally, kendomycin
represents a unique ansa system in which a densely substituted
tetrahydropyran ring is directly attached to the quinone methide
chromophore within a macrocyclic scaffold. This fully carbogenic
a Reagents and conditions: (a) ref 7; (b) (i) CBr4, PPh3, Zn, DCM, 83%,
ansa framework is unprecedented among all of the ansamycins
(ii) n-BuLi, MeI, THF, 99%, (iii) TBAF, THF, 99%, (iv) Dess-Martin,
isolated so far.3 Thus, the novel molecular architecture, along with
DCM, 85%; (c) Sn(OTf)2 TEA, DCM, -78 °C, 82% (dr ) 7:1); (d) (i)
the impressive biological profile, renders kendomycin an important
subject of bio-2 and chemical4,5 synthetic studies. Described herein
is the first enantioselective total synthesis of kendomycin (1).
From a synthetic viewpoint, the C13-C14 bond offers an
attractive handle for macrocyclization by a ring-closing olefin
metathesis (RCM) reaction. However, the trisubstitution and (E)-
geometry of this alkene cast uncertainties as to the efficacy of this
approach. Moreover, Mulzer and co-workers have noted a hindered
rotation about the C4a-C5 bond in their advanced synthetic
intermediates,4 which might prove prohibitive for an RCM strategy.
Our approach is based on the idea that the very C4a-C5 bond that
causes atropisomerism might be formed by a ring closure, thereby
avoiding complications arising from the conformational issues
(Scheme 1). Hence, the challenge of constructing a macrocycle and
the ansa bridge could be simultaneously reduced to a potentially
more manageable problem of an aryl C-glycoside synthesis.6 Our
synthetic plan projects a late stage fashioning of the ansa core by
an oxidative hydration of benzofuran (3 f 2 f 1). The secomac-
rocycle 4 is envisioned to be assembled by the union of two
subunits, 5 and 6, of roughly equal complexity, which in turn can
be prepared from readily available building blocks.
NaBH(OAc)3, AcOH, 5 °C, 84% (dr ) 20:1), (ii) DBU, DCM, 90%; (e)
(i) cat. Pd(OAc)2-PCy3, n-Bu3SnH, hexanes-THF, (ii) I2, DCM, 83% (dr
) 7-10:1).
Scheme 3. Synthesis of the Benzofuran Domaina
a Reagents and conditions: (a) (i) TBSCl, imidazole, DCM, (ii) Dibal-
H, DCM, -78 °C, 95%; (b) Ph3P‚HBr, CH3CN, 78%; (c) DCC/DMAP,
DCM, then TEA, toluene, reflux, 93%; (d) (i) 10 mol % Pd/C, H2, EtOAc-
CH3OH, 99%, (ii) I2/PPh3, imidazole, DCM, 96%.
(Scheme 2). The route commenced with the alkylation of Myers’
amide 7 with iodide 8, which set the C12 stereocenter.7 After
reductive detachment of the chiral auxiliary, the resulting aldehyde
9 was advanced to 10 by alkynylation8 of the aldehyde and
oxidation9 of the desilylated alcohol. The THP ring, adorned with
contiguous stereogenic centers, was then constructed through a
sequence involving stereoselective aldolation, reduction, and lac-
tonization.10 The sequential hydrostannylation-iodination of 13 was
carried out with high regioselectivity to afford subunit 5.11
Scheme 1. Structure and Retrosynthetic Analysis of Kendomycin
Having defined a route to 5, we turned to the synthesis of the
benzofuranyl domain using a two-stage condensation approach
(Scheme 3).12 Thus, the phenolic phosphonium bromide 16 was
prepared from the known aldehyde 1413 by selective silylation,
reduction, and addition of HBr‚PPh3.14 The sequential esterification
and Wittig processes merged 16 and 1715 smoothly to give
benzofuran 19 in high yield.12 Finally, removal of the benzyl group
The synthesis of the tetrahydropyranyl subunit 5 employed chiral
enolate chemistry to establish the key bonds and stereogenic centers
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10.1021/ja0447154 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Suzuki-Miyaura Merger of the Key Fragments, Macroglycosidation, and Completion of the Total Synthesis of Kendomycin (1)a
a Reagents and conditions: (a) 4% PdCl2(dppf), 3 M aq K3PO4, Et2O-THF-DMF, 86%; (b) Dibal-H, toluene, then Ac2O, pyridine, 79%; (c) TBAF,
THF, 91%; (d) SnCl4, 4 Å MS, CHCl3, 40-70%; (e) (i) MeONa/MeOH, 87%, (ii) TESOTf, Et3N, DCM, 98%; (f) IBX, DMF, 62% (g) aq HF, CH3CN, 50%.
Supporting Information Available: Experimental details and
spectral data for all new compounds. This material is available free of
change via Internet at http://pubs.acs.org.
followed by iodination of the exposed hydroxyl group furnished
the desired alkyl iodide 20.
With the procurement of the two fragments, the feasibility of
their union through C14-C15 bond formation was probed (Scheme
4). Under the Pd-catalyzed conditions,16 boranate 6, which was
prepared from 20 by lithiation and transmetalation (t-BuLi, ether,
then B-OMe-9-BBN), participated well in the cross-coupling
reaction with iodide 5 to provide alkene 21 in excellent yield. To
this intermediate containing all of the carbon atoms of kendomycin
was imparted a glycosyl donor function by converting it into
anomeric acetate 22, thus setting the stage for the macro aryl
C-glycosidation. Our initial attempts to cyclize 22 under a variety
of Friedel-Crafts conditions were unsuccessful, mainly leading to
hydrolysis of the anomeric acetate.17 In contrast, the reaction
employing phenol 23 as the substrate occurred smoothly to afford
the desired macrocycle 25 as a single stereoisomer in 40-70%
yield. As a nonpolar product was produced rapidly at -5 °C, which
turned into 25 at room temperature over 12 h, this reaction appeared
to proceed through facile formation of O-glycoside 24 and
subsequent rearrangement to C-glycoside 25.18 After exchange of
the C7 protecting groups, oxidative fashioning of the aryl core was
achieved by careful treatment of 26 with IBX, which formed the
unstable diketone 30.19 Monitoring this reaction by 1H NMR
revealed the intermediacy of mixed ketal 28, which underwent slow
hydrolysis to 29 and eventually to 30. The removal of the TES
group and hydration of the ortho-quinone by the action of aqueous
HF finally produced kendomycin (1). Synthetic kendomycin
exhibited physical and spectroscopic characteristics (Rf, mp, [R]D,
References
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. JP Patent 08231551
[A296090], 1996. (b) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston,
T. L. US Patent 5728727 [A980317], 1998.
(2) (a) Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 323. (b)
Bode, H. B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 2665.
(3) Funayama, S.; Cordell, G. A. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: New York, 2000; Vol. 23, pp 51-106.
(4) (a) Martin, H. J.; Drescher, M.; Ka¨hlig, 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, 2766. (c) Pichlmair, S.;
Marques, M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett.
2003, 5, 4657. (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.
(5) Sengoku, T.; Arimoto, H.; Uemura, D. Chem. Commun. 2004, 1220.
(6) For reviews, see: (a) Jaramillo, C.; Knapp, S. Synthesis 1994, 1. (b)
Postema, M. H. D. C-Glycoside Synthesis; CRC: Boca Raton, FL, 1995.
(7) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361. (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry,
L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(8) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(10) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866. (b) Evans, D. A.; Cee, V. J.;
Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000, 39,
2533. (c) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am.
Chem. Soc. 2000, 122, 10033. (d) Ref 4b,d.
(11) Semmelhack, M. F.; Hooley, R. J. Tetrahedron Lett. 2003, 44, 5737.
(12) Hercouet, A.; Lecorre, M. Tetrahedron Lett. 1979, 20, 2145.
(13) Siddiqi, S. A.; Heckrodt, T. J. Z. Naturforsch. B 2003, 58, 328.
(14) Hercouet, A.; Lecorre, M. Tetrahedron 1981, 37, 2867.
1
IR, H, 13C NMR, and HRMS) identical to those reported for the
(15) See Supporting Information for the synthesis acid 17. Vong, B. G.;
Abraham, S.; Xiang, A. X.; Theodorakis, E. A. Org. Lett. 2003, 5, 1617.
natural product.
(16) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Marshall, J.
A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(17) For a rare example of macrocyclization via a Friedel-Crafts acylation
reaction, see: (a) Chen, M.; Guzei, I.; Rheingold, A. L.; Gibson, H. W.
Macromolecules 1997, 30, 2516. For a macro-O-glycosidation to prepare
cyclodextrins, see: (b) Stoddart, J. F.; Nepogodiev, S. A.; Gattuso, G.
Chem. ReV. 1998, 98, 1919.
In summary, the first total synthesis of kendomycin has been
achieved. Notable features of the synthesis are high levels of
convergence and stereocontrol in the assembly of key subunits,
efficient establishment of the structural core by a macroglycosi-
dation, and a novel oxidative hydration strategy to construct the
ansa chromophore.
(18) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988, 29, 6935.
(19) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus, T. R.
R. Org. Lett. 2002, 4, 285. (b) Ozanne, A.; Pouyse´gu, L.; Depernet, D.;
Franc¸ois, B.; Quideau, S. Org. Lett. 2003, 5, 2903.
Acknowledgment. The authors gratefully acknowledge Prince-
ton University for startup funding. Y.Y. thanks FMC corporation
for a graduate fellowship.
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