A Novel Approach toward the Synthesis of Kendomycin: Selective Synthesis of a C-Aryl Glycoside as a Single Atropisomer

Article abstract of DOI:10.1021/ol035846x

(Matrix presented) A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S_N1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, b

Full text of DOI:10.1021/ol035846x

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4657-4659
A Novel Approach toward the Synthesis
of Kendomycin: Selective Synthesis of
a C-Aryl Glycoside as a Single
Atropisomer
Stefan Pichlmair, Maria M. B. Marques, Martin P. Green, Harry J. Martin, and
Johann Mulzer*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
johann.mulzer@uniVie.ac.at
Received September 24, 2003
ABSTRACT
A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a SN1 ring cyclization as a
key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol,
the conformation was frozen to the desired kendomycin-like atropisomer.
Kendomycin [(-)-TAN 2162] (1), a novel ansamycin
compound isolated from Streptomyces Violaceoruber (strain
3844-33C), was recently described as a potent endothelin
receptor antagonist and antiosteoperotic compound with
remarkable antibacterial and cytostatic activity.1 The structure
of kendomycin (1) features an aliphatic ansa chain with a
highly substituted tetrahydropyran ring connected to a unique
quinone methide chromophore. Its diverse pharmacological
activity and challenging structure have motivated us to
embark on a laboratory synthesis of 1.
A central issue lies in the construction of the pseudo C-aryl
glycosidic part of the molecule, which is highly sterically
congested and shows atropisomeric behavior.2 To reduce
steric hindrance, a benzofuran intermediate such as 2 was
envisaged that could then be macrocyclized in the C-9/C-11
region and oxidized to the final p-quinomethide.
The synthesis of aldehyde 4 started with a syn-aldol addi-
tion of aldehyde 3, readily available from citronellene, to
â-keto imide 6 to give ketone 7.3
After stereoselective reduction of 7 to the â-hydroxy
alcohol,4 the auxiliary was cleaved by treatment with base,
and subsequent acidification with HCl gave the lactone 8
directly. In the presence of 2,2-dimethoxypropane and a cat-
alytic amount of acid, methyl ester 9 was obtained, which
(1) (a) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Japanese patent
08231551 [A2960910], 1996; Chem. Abstr. 1997, 126, 6553. (b) Funahashi,
N.; Kawamura, N. Japanese patent 08231552, 1996; Chem. Abstr. 1996,
125, 326518. (c) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L.
US patent 5728727, 1998; Chem. Abstr. 1998, 128, 239489. (d) Bode, H.
B.; Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 323. (e) Bode, H. B.;
Zeeck, A. J. Chem. Soc., Perkin Trans. 1 2000, 2665.
(2) (a) Martin, H. J.; Drescher, M.; Ka¨hlig, H.; Schneider, S.; Mulzer, J.
Angew. Chem. 2001, 113, 3287. (b) Marques, M. B. M.; Pichlmair, S.;
Martin, J. H.; Mulzer, J. Synthesis 2002, 18, 2766.
(3) (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.; Ng. H. P.; Clark,
J. S.; Rieger, D. L. Tetrahedron 1992, 2127.
(4) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
With these considerations in mind, we reasoned that 2
might be obtained from the addition of aldehyde 4 to a carb-
anion, which could be generated by ortho-directed metalation
from 5 (Scheme 1).
10.1021/ol035846x CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/01/2003

Epoxide 15 was obtained from primary alcohol 13 first by
conversion to the iodide which was then coupled with iso-
propenylmagnesium bromide under Schlosser-Fouquet con-
ditions.7 TBDPS deprotection delivered alcohol 14 and Swern
oxidation furnished the corresponding aldehyde, which was
then transformed directly to 15 by addition of lithiated di-
bromomethane at low temperature and subsequent warming
to room temperature.8 Epoxide 17 was obtained by employ-
ing a high-yielding three-step procedure from alcohol 13
(Scheme 3).
Scheme 1. Retrosynthetic Analysis of 1
Scheme 3a
Scheme 2
a
L-Selectride ) lithium tri-sec-butylborohydride, HMPA )
hexamethyl phosphoric triamide, MCPBA ) m-chlorperbenzoic
acid, TBAF ) tetrabutylammonium fluoride.
At this stage, epoxide 15 was added to Grignard 19 and
epoxide 17 to Grignard 22 to give alcohols 20 and 23, re-
spectively.9,10 The alcohols were subjected to a Swern oxi-
dation followed by an acidic catalyzed ring closure. Benzo-
furans 5a and 24 were obtained in good yield. Phenol 24
was then reprotected to give the MOM phenol ether 5b in
nearly quantitative yield (Scheme 4).
was first reduced to primary alcohol 10 and then oxidized
to aldehyde 4 by Swern oxidation (Scheme 2).
We then tackled the syntheses of two alternative “eastern
fragments” from an identical precursor. TBDPS-protected
Roche aldehyde 11 was subjected to a Horner-Wadsworth-
Emmons olefination to afford the corresponding N-enoyl
sultam ,which was R-methylated by using Oppolzer’s 1,4-
addition/enolate-trapping protocol.5,6 We obtained 12 in 83%
yield with good stereoselectivity (97:3).
After careful experimentation, directed ortho-lithiation of
the 2-position of benzofurans 5a and 5b was performed with
(7) (a) Hegedus, L.; Lipshutz, B.; Nozaki, M.; Reets, M.; Rittmeyer, P.;
Smith, K.; Trotter, F.; Yamamoto, H. Organometallics in Synthesis: A
Manual; Schlosser, M., Ed.; John Wiley & Sons Ltd: Chichester, UK, 1994;
p 344. (b) Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1972, 42, 205.
(8) Michnick, T. J.; Matteson, D. S. Synlett 1991, 9, 631.
The sultam was removed by DIBAL-H reduction and the
crude aldehyde was reduced with NaBH4 to give alcohol 13.
(9) Suzuki, S.; Shiono, M.; Fujita, Y. Synthesis 1983, 804.
(10) For references to the preparation of 18 see: Corey, E. J.; Gin, D.
Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. For references to the
preparation of 21 see: Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc. 2003,
125, 4680.
(5) For a reference to the preparation of (S)-N-diethoxyphosphonoace-
tylcamphorsultam see: Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T.
M.; Bernardinelli, G. Tetrahedron Lett. 1988, 29 (46), 5885.
(6) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27 (39), 4717.
4658
Org. Lett., Vol. 5, No. 24, 2003

Scheme 4a
Scheme 5a
a NBS ) N-bromosuccinimide, MOMCl ) methoxymethyl
chloride.
a TMEDA ) N,N,N′,N′-tetramethylethylendiamine, MOMCl )
methoxymethyl chloride.
n-BuLi in the presence of TMEDA with n-BuLi at -30 °C.11
Addition of aldehyde 4 to these organolithium species at -78
°C gave the desired benzylic alcohols 25 and 26 in 69%
and 88% yield as mixtures of diastereomers. Removal of
the acetal protection group from 25 and subsequent heating
in warm toluene with a catalytic amount of p-TsOH resulted
in the desired SN1-type ring closure as a key step in our
synthesis (Scheme 5). In the case of 25, we were disappointed
to find that the resulting tetrahydropyran product 2a exists
as a 3:1 mixture of atropisomers favored to the undesired
isomer at room temperature.
Unfortunately, the cyclization of 26 under analogous con-
ditions was thwarted by the formation of a stable acetonide
between the oxygens at C1 and C3. Hence, we applied a
three-step procedure of acetylation, formation of the triol,
and treatment with acid, which furnished 27 in reasonable
overall yield. As before, we observed broad peaks in the 1H
NMR spectra, implying the formation of a rotameric mixture
and that the coalescence temperature is around room tem-
perature. To our delight MOM protection of the phenol 27
resulted in freezing of the conformation to the desired
kendomycin-like atropisomer 2b.
In conclusion, we have developed a convergent and ster-
eoselective route to an advanced intermediate in the synthesis
of kendomycin. A novel feature in our sequence is the
stereocontrol over the formation of C-aryl glycoside atrop-
siomers, which has been exerted by a proper choice (i.e.
MOM and OMe) of the phenolic o-hydroxyl groups. The
atropisomer thus obtained has the proper geometry for the
formation of the macrocyclic ring, which will be the next
issue to face.
Acknowledgment. This paper is dedicated to Professor
W. Steglich on the occasion of his 70th birthday. Financial
support by the Austrian Science Foundation (FWF, projects
M674 and P14729-CHE) and the Fundac¸a˜o para a Cieˆncia
e Tecnologia (SFRH/PBD/3561/2000) (Lisbon, Portugal) is
gratefully acknowledged. We also thank Hanspeter Ka¨hlig
for NMR and Sabine Schneider for HPLC support.
Supporting Information Available: Experimental pro-
cedures and NMR data for compounds 25, 26, 2a, and 2b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Dunn, B. M.; Bruice, T. C. J. Am. Chem. Soc. 1970, 92, 2410.
(b) Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S. J. Org.
Chem. 1988, 53, 3936. (c) Jeganathan, S.; Tsukamoto, M.; Schlosser, M.
Synthesis 1990, 109. (d) Parham, W. E.; Anderson, E. L. J. Am. Chem.
Soc. 1948, 70, 4187. (e) Stern, R.; English, J.; Cassidy, H. G. J. Am. Chem.
Soc. 1957, 79, 5797. (f) Townsend, C. A.; Bloom, L. M. Tetrahedron Lett.
1981, 22, 3923.
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