Enantioselective synthesis of neocarzinostatin chromophore aglycon

Full text of DOI:10.1021/ja9618863

10006
J. Am. Chem. Soc. 1996, 118, 10006-10007
Scheme 1a
Enantioselective Synthesis of Neocarzinostatin
Chromophore Aglycon
Andrew G. Myers,* Marlys Hammond, Yusheng Wu,
Jia-Ning Xiang, Philip M. Harrington, and Elaine Y. Kuo
DiVision of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, California 91125
ReceiVed June 5, 1996
Neocarzinostatin is the first of the “enediyne” antitumor
agents to be characterized and is further distinguished as the
first chromoprotein antibiotic.1 The DNA-cleaving properties
of the neocarzinostatin protein-chromophore complex have
been shown to reside solely within the chromophore component
(1) which, in isolation, is exceedingly unstable.2,3 The strain,
structural complexity, and, most importantly, high reactivity of
the chromophore core define an extraordinarily challenging
synthetic target. In this work, we describe an enantioselective
route that provides for the first time neocarzinostatin chro-
mophore aglycon (2), a substance which proves to be even less
stable than 1 and which, almost certainly, could not be derived
from the parent antibiotic.
a (a) LiCtCTMS, THF, -78 °C, 81%. (b) PDC, AcOH, 3A
molecular sieves, CH2Cl2, 23 °C. (c) Ph3PCH2CtCTBS+ Br-, KN(T-
MS)2, THF, -78 f -40 °C, 79% (steps b and c), 3:1 E/Z. (d) K2CO3,
CH3OH, 0 °C. (e) 1 N HCl, THF, 23 °C, separate isomers, 64% (E-
isomer, steps d and e). (f) TDSCl, Et3N, DMAP, CH2Cl2, 0 °C. (g)
(-)-DET, Ti(Oi-Pr)4, TBHP, 4A molecular sieves, CH2Cl2, -20 °C,
94% (steps f and g). (h) Et3N‚3HF, THF, 23 °C, 92%. (i) 2-Meth-
oxypropene, TsOH, DMF, 23 °C, 82%. (x) i. PhSeTMS, TMSOTf,
CH2Cl2, -78 °C; ii. HC(OCH3)3, -25 f -20 °C; iii. H2O2, Py, -20
°C, 80%.
elimination of water to produce 3. Preliminary studies had
shown that seemingly more direct approaches to the core
functionality of 1 involving intramolecular acetylide addition
within precursors such as 5 failed, presumably due to the poor
trajectory of the addition reaction. Thus, the strategy that had
been successful in our earlier work brings with it a necessary
1,3-allylic transposition stepsa step that ultimately proved to
be the undoing of this approach within the more highly
oxygenated, complex substrates necessary to produce 2. For
example, although the intermediate 6 could be prepared ef-
ficiently and in enantiomerically pure form, we were unable to
bring about the necessary 1,3-transposition reaction within this
substrate, even after much effort. Herein, we report that
modification of our earlier strategy by epoxidation of the
5-membered ring olefin avoids the allylic transposition problem,
preserves a favorable trajectory for the intramolecular acetylide
addition reaction, and, unexpectedly, defers to the final step
many of the instability issues which plagued the earlier
approaches.
The successful route to 2 involved the convergent assembly
of three components. The epoxy diyne 7 (g95% ee) was
synthesized from D-glyceraldehyde acetonide, as shown in
Scheme 1. The cyclopentenone 9 (g90% ee) was prepared from
the well-known prostaglandin intermediate 86 in one step in 75-
85% yield by a carefully optimized modification of the method
of Noyori et al.7 The third component, the naphthoic acid 10,
was prepared in six steps (31-37% yield) from 4-bromo-3-
methylanisole.8
We have previously described the preparation of compound
3, to date the only synthetic construct that bears the epoxy
diendiyne functionality of 1.4,5 The route that was developed
involved the intramolecular addition of an acetylide to an
aldehyde within the precursor 4, followed by 1,3-allylic
transposition of the tertiary (trimethylsilyl)oxy group and 1,4-
(5) For the first synthesis of the highly unstable carbocyclic skeleton of
1, see: (a) Wender, P. A.; Harmata, M.; Jeffrey, D.; Mukai, C.; Suffert, J.
Tetrahedron Lett. 1988, 29, 909. For leading references to synthetic studies
of 1, see: (b) Takahashi, T.; Tanaka, H.; Hirai, Y.; Doi, T.; Yamada, H.;
Shiraki, T.; Sugiura, Y. Angew. Chem., Int. Ed. Engl. 1993, 32, 1657. (c)
Nakatani, K.; Arai, K.; Terashima, S. Tetrahedron 1993, 49, 1901. (d)
Kawata, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1994, 35, 4595. (e)
Wender, P. A.; Tebbe, M. J. Tetrahedron 1994, 50, 1419. (f) Eckhardt,
M.; Bru¨ckner, R.; Suffert, J. Tetrahedron Lett. 1995, 36, 5167. (g) Toshima,
K.; Ohta, K.; Yanagawa, K.; Kano, T.; Nakata, M.; Kinoshita, M.;
Matsumura, S. J. Am. Chem. Soc. 1995, 117, 10825. (h) Matsumoto, Y.;
Kuwatani, Y.; Ueda, I. Tetrahedron Lett. 1995, 36, 3197. (i) Magnus, P.;
Carter, R.; Davies, M.; Elliott, J.; Pitterna, J. Tetrahedron 1996, 52, 6283.
(6) Myers, A. G.; Hammond, M.; Wu, Y. Tetrahedron Lett. 1996, 37,
3083.
(1) (a) Shoji, J. J. Antibiot. 1961, 14, 27. (b) Ishida, N.; Miyazaki, K.;
Kumagai, K.; Rikimaru, M. J. Antibiot. 1965, 18, 68. (c) Napier, M. A.;
Holmquist, B.; Strydom, D. J.; Goldberg, I. H. Biochem. Biophys. Res.
Commun. 1979, 89, 635. (d) Koide, Y.; Ishii, F.; Hasuda, K.; Koyama, Y.;
Edo, K.; Katamine, S.; Kitame, F.; Ishida, N. J. Antibiot. 1980, 33, 342.
(2) For chromophore structure, see: (a) Edo, K.; Mizugaki, M.; Koide,
Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N. Tetrahedron Lett. 1985,
26, 331. For carbohydrate stereochemistry, see: (b) Edo, K.; Akiyama, Y.;
Saito, K.; Mizugaki, M.; Koide, Y.; Ishida, N. J. Antibiot. 1986, 39, 1615.
For chromophore stereochemistry, see: (c) Myers, A. G.; Proteau, P. J.;
Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212.
(3) Kappen, L. S.; Napier, M. A.; Goldberg, I. H. Proc. Nat. Acad. Sci.
U.S.A. 1980, 77, 1970.
(4) (a) Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc.
1991, 113, 694. (b) Myers, A. G.; Harrington, P. M.; Kwon, B.-M. J. Am.
Chem. Soc. 1992, 114, 1086.
(7) Suzuki, M.; Kawagishi, T.; Noyori, R. Tetrahedron Lett. 1981, 22,
1809.
(8) Myers, A. G.; Subramanian, V.; Hammond, M. Tetrahedron Lett.
1996, 37, 587.
S0002-7863(96)01886-0 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 41, 1996 10007
Scheme 2a
as synthetic intermediates. Protective group manipulations
within 13 and introduction of the naphthoic acid 10 then afforded
the diol 14. The selection of coupling reagent and reaction
solvent in the latter step proved to be critical, with the use of
DCC in THF found to be uniquely successful. The diol 14 was
transformed into the epoxy alcohol 15 by the following
sequence: incorporation of the carbonate group, silylation of
the secondary hydroxyl and naphthol groups, elimination of the
tertiary alcohol, and removal of the silyl protecting groups.
Treatment of the epoxy alcohol 15 with a mixture of triphen-
ylphosphine, iodine, and imidazole11 led directly to the highly
unstable aglycon 2.12 The yield of carefully purified (flash
column chromatography) aglycon 2 in the latter transformation
was typically 15-30% (UV determination), which is believed
to reflect more the instability of 2 than the inherent efficiency
of the transformation.
The carbohydrate residue of 1 clearly provides a stabilizing
influence on the chromophore core, for the aglycon 2 degrades
much more rapidly than 1 both in solution and in neat form.
1
Although synthetic 2 provided good quality H NMR and CD
spectra, its half-life in solution was found to be insufficient to
acquire a 13C NMR spectrum.13 The instability of 2 also
thwarted all efforts to obtain a mass spectrum of 2 in isolation
using a variety of soft-ionization techniques. Success was
achieved in the latter effort by adopting Nature’s solution to
the stabilization of 1 in solution. Precomplexation of the
synthetic aglycon 2 with purified neocarzinostatin apoprotein
in water (pH 7) followed by electrospray mass spectral analysis
provided peaks consistent with the protein-complexed aglycon.
This finding not only establishes the molecular weight of our
synthetic material but also provides the first evidence that
neocarzinostatin chromophore aglycon (2) is capable of binding
to the apoprotein. The availability of the aglycon 2 now enables
important comparative studies that should help to elucidate the
role of the carbohydrate residue of 1 in DNA binding and
cleavage. In addition, neocarzinostatin chromophore aglycon
(2) is anticipated to serve as a platform for the preparation of 1
and analogs with modified carbohydrate residues.
a (a) LiN(TMS)2, PhCH3, -78 °C; 9, 75%. (b) Bu4NF, THF, 0 °C.
(c) TBSCl, Et3N, DMAP, CH2Cl2, 0 f 23 °C, 92% (steps b and c). (d)
TsOH, acetone, 23 °C, 90%. (e) TMSOTf, 2,6-lutidine, CH2Cl2, -78
°C, 88%. (f) DIBAL, PhCH3, -78 °C, 92%. (g) (+)-DET, Ti(O-i-Pr)4,
TBHP, 4A molecular sieves, CH2Cl2, -20 °C, 91%. (h) Dess-Martin
Periodinane, Py, CH2Cl2, 23 °C, 97%. (i) LiN(SiPh(CH3)2)2, LiCl, THF,
-78 °C, 79%. (j) (ClCH2CO)2O, Py, CH2Cl2, 0 °C, 89%. (k) Et3N‚3HF,
CH3CN, 23 °C, 81%. (l) 10, DCC, THF, 0 °C; n-PrNH2, 71%. (m)
TsOH, CH3OH, 23 °C, 67%. (n) CDI, THF, 0 f 23 °C; CSA, 2:1
CH3CN/H2O, 23 °C, 67%. (o) TESOTf, 2,6-lutidine, CH2Cl2, -78 °C,
79%. (p) Martin Sulfurane, CH2Cl2, 23 °C, 79%. (q) Et3N‚3HF, THF,
0 °C, 99%. (r) PPh3, I2, imidazole, CH2Cl2, -17 °C, 15-30% after
purification.
Acknowledgment. This manuscript is dedicated to Professor Nelson
Leonard on the occasion of his 80th birthday. This research would
not have been possible without generous financial support from the
National Institutes of Health, the David and Lucile Packard Foundation,
and Pfizer, Inc. This support is gratefully acknowledged. M.H.
acknowledges the receipt of a Glaxo summer research fellowship. We
thank Dr. Kristine Swiderek of The City of Hope (Duarte, CA) for
obtaining the mass spectrum of the NCS apoprotein-aglycon 2
complex.
Deprotonation of the epoxy diyne component 7 (1.05 equiv)
with lithium hexamethyldisilazide at -78 °C followed by
addition of the cyclopentenone 9 (1 equiv) afforded the 1,2-
adduct 11 (75%) with g20:1 diastereoselectivity (Scheme 2).
This product was transformed into the epoxy aldehyde 12 by
standard methods. In a key transformation, we found that the
epoxy aldehyde 12 underwent efficient ring closure upon
treatment with the Masamune lithium diphenyltetramethyldi-
silazide base9 at -78 °C, providing the adduct 13 as a single
diastereomer in 79% yield.10 The use of lithium chloride as an
additive proved critical in this reaction. A highly noteworthy
feature of the product 13 was its stability toward chromatog-
raphy, concentration, and routine manipulations. This stands
in marked contrast to the “olefinic” series of cyclization products
(see 6), which were found to be exceedingly difficult to handle
Supporting Information Available: Reproductions of 1H and 13
C
NMR spectra and tabulated spectroscopic data for all new synthetic
intermediates, and reproductions of 1H NMR, IR, and CD spectra of 2
(77 pages). See any current masthead page for ordering and Internet
access instructions.
JA9618863
(11) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
978.
(12) Although the iodide may be an intermediate in this reaction, it is
not observed. For related transformations, see: (a) Mori, K.; Ueda, H.
Tetrahedron 1981, 37, 2581. (b) Barluenga, J.; Ferna´ndez-Simon, J. L.;
Concello´n, J. M.; Yus, M. J. Chem. Soc., Perkin Trans. 1 1989, 77. (c)
Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett. 1991, 32,
3961.
(13) As further confirmation of structure, the treatment of the aglycon
with methyl thioglycolate (0.5 M), triethylamine (0.5 M), and 1,4-
cyclohexadiene (1.0 M) in THF at 23 °C afforded a thiol adduct in complete
analogy to 1. This adduct has been fully characterized and was obtained in
13% yield (>90% purity, isolated by reverse-phase HPLC). Full details of
this reactivity, as well as DNA cleavage by 2, are the subject of a future
manuscript.
(9) (a) Zhinkin, D. Y.; Mal’nova, G. N.; Gorislavskaya, Zh. V. Zh.
Obshch. Khim. 1968, 38, 2800. (b) Masamune, S.; Ellingboe, J. W.; Choy,
W. J. Am. Chem. Soc. 1982, 104, 5526.
(10) The stereochemistry of the addition reaction (see 13) was established
by the preparation of a cyclic disiloxane derivative, in analogy to ref 3a.