Application of the Doetz reaction to construction of a major portion of the ansa macrocycle (-)-kendomycin

Article abstract of DOI:10.1021/ol047779s

(Chemical Equation Presented) A Doetz reaction employing a terminal alkyne and a Fischer-type alkenylchromium carbenoid led to a pentasubstituted benzene from which a major portion of the Streptomyces metabolite (-)-kendomycin was synthesized.

Full text of DOI:10.1021/ol047779s

ORGANIC
LETTERS
2005
Vol. 7, No. 2
235-238
Application of the Do
Construction of a Major Portion of the
1tz Reaction to
Ansa Macrocycle (−)-Kendomycin
James D. White* and Helmars Smits
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@oregonstate.edu
Received October 28, 2004
ABSTRACT
A Do
1
tz reaction employing a terminal alkyne and a Fischer-type alkenylchromium carbenoid led to a pentasubstituted benzene from which a
)-kendomycin was synthesized.
major portion of the Streptomyces metabolite (
−
The announcement in a 1996 patent by scientists at Takeda
Pharmaceutical Company of a substance, (-)-TAN 2162,
isolated from Streptomyces Violaceoruber (strain 3844-33C)
brought to light a novel ansamycin with pronounced endot-
helin receptor antagonist and antiosteoporotic activity.1-3 The
same substance was isolated later from a different Strepto-
myces strain by Zeeck and co-workers and was named
kendomycin. Zeeck’s group established the structure, includ-
ing absolute configuration, of kendomycin as 1 and reported
that it possessed antibacterial and cytostatic activity.4,5
The unique structure of kendomycin, in which an ansa
macrocycle incorporating a fully substituted tetrahydropyran
bridges a quinone methide core, presents a challenging target
for synthesis.6 Toward that goal, we have laid down a route
to a major portion of 1 that comprises all but C11-C14 of
the macrocycle as well as a hexasubstituted benzene that will
serve as the progenitor of the quinone methide nucleus of
this structure. A key component of our strategy is a Do¨tz
annulation7 that creates the benzenoid system 2 by addition
of R,â-unsaturated chromium carbenoid 3 to a terminal
alkyne 4 (Scheme 1). In his studies of Fischer-type car-
benoids, Do¨tz has shown that alkenylchromium carbenes
undergo addition to terminal alkynes accompanied by car-
bonyl insertion to yield substituted phenols in which the
position of substituents on the aromatic ring is highly
predictable.8 Wulff has made elegant use of this feature of
the Do¨tz benzannulation process in the synthesis of natural
products.9
The first task in our plan for the acquisition of 2 was
synthesis of the previously unknown chromium carbene 3,10
and this was accomplished as shown in Scheme 2. 1-Meth-
(6) (a) Martin, H. J.; Drescher, M.; Ka¨hlig, H.; Schneider, S.; Mulzer, J.
Angew. Chem. 2001, 113, 3287. (b) Marques, M. M. B.; Pichlmair, S.;
Martin, H. J.; Mulzer, J. Synthesis 2002, 18, 276. (c) Pichlmair, S.; Marques,
M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003, 24,
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. (e) Sengoku, T.;
Arimoto, H.; Uemura, D. Chem. Commun. 2004, 1220. (f) Yuan, Y.; Men,
H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720.
(7) (a) Dotz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644. (b) Dotz,
K. H.; Dietz, R.; von Imhof, A.; Lorenz, H.; Huttner, G. Chem. Ber. 1976,
109, 2033.
(1) Funahashi, Y.; Kawamura, N.; Ishimaru, T. Jpn. Patent 08231551
[A2960910], 1996; Chem. Abstr. 1996, 126, 6553.
(2) Funahashi, N.; Kawamura, N. Jpn. Patent 08231552, 1996; Chem.
Abstr. 1996, 126, 326518.
(3) Su, M. H.; Hosken, M. I.; Hotovec, B. J.; Johnston, T. L. U.S. Patent
5728727, 1998; Chem. Abstr. 1998, 128, 239489.
(4) Bode, H. B.; Zeeck, A. J. J. Chem. Soc., Perkin Trans. 1 2000, 323.
(5) Bode, H. B.; Zeeck, A. J. J. Chem. Soc. Perkin Trans. 1 2000, 2665.
(8) (a) Dotz, K. H.; Dietz, R. Chem. Ber. 1978, 111, 2517. (b) Dotz, K.
H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. (c) de Meijere, A.; Schrimer,
H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964.
(9) (a) Wulff, W. D.; Tang, P.-C. J. Am. Chem. Soc. 1984, 106, 434. (b)
Wulff, W. D.; Xu, Y. C. J. Am. Chem. Soc. 1988, 110, 2312. (c) Manish,
R.; Wulff, W. D. Org. Lett. 2004, 6, 329.
10.1021/ol047779s CCC: $30.25
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Published on Web 12/30/2004

1-octyne derivative 7. The synthesis of 7 began with
alkylation of Myers’ (1R,2R)-(+)-N-propionylpseudo-
ephedrine (8)13 with (R)-iodo compound 9,14 which led to
1015 as the sole detectable diastereomer but as a mixture of
rotamers according to its proton NMR spectrum (Scheme
3). Reductive cleavage of the auxiliary13 from 10 gave
alcohol 11,16 which was oxidized to the corresponding
aldehyde and then subjected to Brown asymmetric allyla-
tion.17 The resulting homoallylic alcohol was protected as
its methoxymethyl (MOM) ether 12, from which it was
deduced by proton NMR that the dr of allylation was 95:5.
Ozonolytic cleavage of terminal alkene 12 furnished aldehyde
13, which, upon exposure to the Seyferth-Gilbert diazo-
phosphonate 1418 in the presence of base, afforded alkyne
7.
Scheme 1. Retrosynthetic Analysis of the Quinone Methide
Core of Kendomycin
Scheme 3. Synthesis of Alkyne 7 for Do¨tz Reaction with 3
oxypropyne (5), prepared from chloroacetaldehyde dimethyl
acetal,11 was reacted with trimethylsilyl bromide and metha-
nol to give (E)-1-bromo-1-methoxypropene (6).12 Halogen-
metal exchange of 6 with tert-butyllithium followed by
exposure of the lithioalkene to chromium hexacarbonyl
yielded a carbene complex that was methylated in situ with
trimethyloxonium tetrafluoroborate. The resultant (Z)-
unsaturated chromium carbene 3 was obtained as a dark red
oil that is easily oxidized but can be preserved indefinitely
as a solution in benzene.
Scheme 2. Synthesis of Chromium Carbenoid 3
The Do¨tz reaction of 3 with 7 was initiated in deoxygen-
ated THF at 50 °C, after which workup involving the passage
of air through the mixture gave the 2,3,4,6-tetrasubstituted
phenol 15 as the sole isomer (Scheme 4). Methylation of 15
produced the trimethyl ether 16, and bromination of the open
benzenoid site in the latter led to the hexasubstituted benzene
17. This aryl bromide was advanced to aldehyde 18 in the
hope that the second alkyl chain of kendomycin could be
attached at this site. In practice, the aldehyde carbonyl of
The efficient preparation of 3 persuaded us to explore its
application toward the synthesis of a hexasubstituted benzene
derivative bearing ortho-oriented side chains that could serve
as the core subunit of 1. For this purpose, a reaction partner
for 3 was identified that possesses the structural features of
the C15-C18 portion of kendomycin. In practical terms, the
component required for our projected Do¨tz reaction was the
(13) (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.
(14) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290.
(15) White, J. D.; Xu, Q.; Lee, C.-S.; Valeriote, F. A. Org. Biomol. Chem.
2004, 2, 2092.
(16) Abiko, A.; Moriya, O.; Filla, S. A.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 793.
(17) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(18) (a) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(b) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379.
(10) Wulff, W. D.; Chan, K.-S.; Tang, P.-C. J. Org. Chem. 1984, 49,
2293.
(11) (a) Farnum, D. G.; Heybey, M. A. T.; Webster, B. J. Am. Chem.
Soc. 1964, 86, 673. (b) Nooi, J. R.; Arens, J. F. Rec. TraV. Chim. Pays-Bas
Belg. 1959, 78, 284.
(12) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840.
236
Org. Lett., Vol. 7, No. 2, 2005

Scheme 4. Do¨tz Reaction and Further Elaboration of the Product Toward Kendomycin
18 was too sterically hindered for reactions intended to install
a precursor to the tetrahydropyran segment of 1. These
included asymmetric crotylation19 as well as Evans’ anti-
selective aldol process.20 Oppolzer’s sultam methodology21
was only slightly more successful, but the reaction of
aldehyde 18 with the dicyclohexylborinate of propionate 19
bearing Masamune’s chiral auxiliary22 led smoothly to
hydroxy ester 20 in high diastereomeric excess. After
protection of secondary alcohol 20 as its triethylsilyl (TES)
ether, the auxiliary was cleaved by reduction to yield primary
alcohol 21. This was oxidized to an aldehyde that was
subjected to Brown asymmetric crotylation19 to give homo-
allylic alcohol 22.
Scheme 5. Synthesis of the Tetrahydropyran Segment of
Kendomycin
At this stage, we were presented with an opportunity to
establish that the structural features of 22, including the
Figure 1. ORTEP representation of the X-ray crystal structure of
24. Ellipsoids are drawn at the 50% level.
Org. Lett., Vol. 7, No. 2, 2005
237

configuration of its seven stereogenic centers, were correctly
assigned, since cleavage of the triethylsilyl (TES) ether and
esterification of the resulting diol 23 with 3,5-dinitrobenzoyl
chloride yielded crystalline bis-dinitrobenzoate 24. X-ray
crystallographic analysis of 24 (Figure 1) not only confirmed
the structure of its parent substance 22 but also established
that 24 exists as the (R)-atropisomer around the alkyl-aryl
bond.
Continuation of the synthesis from 22 necessitated an
interchange of protecting groups, for which alcohol 22 was
converted to its trimethylsilylethoxymethyl (SEM) ether and
the TES ether was cleaved to afford alcohol 25. Several
attempts were made to cyclize the hexenyl substituent of 25
toatetrahydropyranusingpalladium(II)-mediatedalkoxycarbon-
ylation methodology that has been successful in other
contexts,23 but this plan failed. Mercuration of 25 did lead
to cyclization; however, a stereoisomeric mixture of tetra-
hydropyrans was produced, and oxidative cleavage of the
alkylmercury species resulted in decomposition. However,
iodocyclization of 25 led rapidly and cleanly to tetrahydro-
pyran 26,24 which was found by NMR to exist as a 3.7:1
mixture of atropisomers. The observation of atropisomerism
in a similar structure has been noted by Mulzer.6a
In summary, we have completed the synthesis of a major
portion of (-)-kendomycin, including seven of its nine
stereogenic centers. Our route illustrates the utility of the
Do¨tz reaction for the construction of a heavily substituted
benzene ring, from which elaboration of the quinone methide
nucleus of 1 is envisioned through a deprotection-oxidation
sequence.
Acknowledgment. We are grateful to Professor Alexan-
dre F.T. Yokochi of our department for the X-ray crystal
structure of 24. Financial support was provided by the
National Institute of General Medical Sciences through Grant
GM50574.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds and X-ray
crystallographic data for 24. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(20) Evans, D. A.; Downey, W. C.; Shaw, J. T. Org. Lett. 2002, 4, 1127.
(21) Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G.
Tetrahdron Lett. 1991, 32, 61.
(22) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119,
2586.
OL047779S
(23) (a) White, J. D.; Hong, J.; Robarge, L. A. Tetrahedron Lett. 1999,
40, 1463. (b) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett.
2001, 3, 4003.
(24) Bernard, N.; Chemla, F.; Ferreira, F.; Mostefai, N.; Normant, J.-F.
Chem. Eur. J. 2002, 8, 3139.
238
Org. Lett., Vol. 7, No. 2, 2005