Organic Letters
Letter
JBIR-04, JBIR-05: Izumikawa, M.; Ueda, J.-Y.; Chijiwa, S.; Takagi, M.;
Shin-ya, K. J. Antibiot. 2007, 60, 640−644. (c) Prunustatin A and SW-
163A: Umeda, Y.; Furihata, K.; Sakuda, S.; Nagasawa, H.; Ishigami, K.;
Watanabe, H.; Izumikawa, M.; Takagi, M.; Doi, T.; Nakao, Y.; Shin-ya,
K. Org. Lett. 2007, 9, 4239−4242 and references therein. (d) Neo-
antimycin: Cagliote, L.; Misiti, D.; Selva, A.; Arcamone, F.; Cassinelli, G.
Tetrahedron 1969, 25, 2193−2221.
available 3-nitro-salicylic acid gave nitro-aryl compound 26 in
74% yield over two steps. Conveniently, 26 serves as a single
intermediate for completing the synthesis of both natural
product targets enabling an alternative approach to install
amino-salicylic acid components characteristic of this natural
product class. Hydrogenation of the nitro-group of 23 afforded 1
in 83% yield, thus completing the first total synthesis of the
cytotoxic natural product kitastatin 1 in 7.9% overall yield in 12
linear steps and only 9 chromatographic purifications from N-
Boc-L-leucinal. Finally, reaction of 1 under neutral conditions
with the recently disclosed N-formylsaccharin reagent20
converted the aniline of kitastatin into the target formamide of
2 to complete the total synthesis of respirantin in 5.9% yield over
13 linear steps and 10 chromatographic purifications.
In conclusion, we have completed the total syntheses of the
potent depsipeptide neo-antimycin cytotoxic agents kitastatin 1
and respirantin 2 in a convergent and scaleable manner.
Importantly, the application of a prenylation strategy solved
the issues associated with decarboxylation of gem-dimethyl-β-
keto-acids and validated the use of prenyltrifluoroborate
aldehyde additions to α-chiral gem-dimethyl-β-keto-ester units
and related prenyl-alcohol derivatives. Work is currently
underway to use this synthetic process to generate analogues
of both the amino-salicylic acid and macrocycle components and
to evaluate the clinical potential of this class of compounds.
(4) Pettit, G. R.; Tan, R.; Pettit, R. K.; Smith, T. H.; Feng, S.; Doubek,
D. L.; Richert, L.; Hamblin, J.; Weber, C.; Chapuis, J.-C. J. Nat. Prod.
2007, 70, 1069−1072.
(5) The neo-antimycin natural product JBIR-05 also contains a des-
formamide 3-amino-salicylic acid unit. See ref 3b.
(6) Pettit, G. R.; Smith, T. H.; Feng, S.; Knight, J. C.; Tan, R.; Pettit, R.
K.; Hinrichs, P. A. J. Nat. Prod. 2007, 70, 1073−1083.
(7) The synthesis of kitastatin 1 is claimed in a patent; however, no
experimental details or yields were included regarding its preparation.
Pettit, G. R.; Smith, T. H.; Feng, S. U.S. Pat. Appl. 065991, 2008.
(8) Decarboxylation observed during a preliminary attempt to access
the southern fragment in the ketone oxidation state:
(9) Configurational stability study: Rittle, K. E.; Homnich, C. F.;
Ponticello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47, 3016−3018.
(10) BF3·OEt2 conditions: (a) Batey, R. A.; Thadani, A. N.; Smil, D. V.
Tetrahedron Lett. 1999, 40, 4289−4292. (b) Batey, R. A.; Thadani, A. N.;
Smil, D. V. Synthesis 2000, 990−998. (c) Li, S.-W.; Batey, R. A. Chem.
Commun. 2004, 1382−1383. (d) Nowrouzi, F.; Batey, R. A. Angew.
Chem., Int. Ed. 2013, 52, 892−895. (e) Ramadhar, T. R.; Bansagi, J.;
Batey, R. A. J. Org. Chem. 2013, 78, 10362−10368. Phase-transfer
catalyzed conditions: (f) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4,
3827−3830. (g) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44,
8051−8055. Montmorillonite K10 catalyzed conditions: (h) Nowrouzi,
F.; Thadani, A. N.; Batey, R. A. Org. Lett. 2009, 11, 2631−2634. Indium
catalyzed conditions: (i) Nowrouzi, F.; Janetzko, J.; Batey, R. A. Org.
Lett. 2010, 12, 5490−5493.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
1
compounds including H and 13C NMR, and comparison of
spectral data of 1 and 2 with reported data. This material is
AUTHOR INFORMATION
Corresponding Author
■
(11) The only related example of potassium prenyltrifluoroborate
carbonyl-like reactivity is an interesting Rh-catalyzed enantioselective
reaction with cyclic sulfonyl-imines; see: Luo, Y.; Hepburn, H. B.;
Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309−8313.
(12) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.-I.; Mizuno,
Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063−1066.
(13) In the course of this work we have examined numerous coupling
conditions for the various ester formations and have found MNBA
(“Shiina’s Reagent”) to be generally optimal: (a) Shiina, I.; Miyao, R.
Heterocycles 2008, 76, 1313−1328. (b) Shiina, I.; Kubota, M.; Oshiumi,
H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822−1830.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the University of Toronto and the Natural
Science and Engineering Research Council of Canada (NSERC)
for financial support. R.E.B. is grateful to the University of
Toronto for an Edwin Walter Warren Scholarship and to the
Ontario Ministry of Education for an Ontario Graduate
Scholarship. We thank Dr. Matthew Forbes (Toronto) for MS
analysis and Dr. Alan Lough (Toronto) for X-ray structure
determination of 18. Frontier Scientific Inc. is gratefully
acknowledged for their generous donation of B2Pin2.
(14) Ishiyama, T.; Ahiko, T.-A.; Miyaura, N. Tetrahedron Lett. 1996,
37, 6889−6892.
(15) Used within 3 h of preparation according to: Rich, D. H.; Sun, E.
T.; Boparai, A. S. J. Org. Chem. 1978, 43, 3624−3626.
(16) The major isomer 18 was determined to be syn by X-ray
crystallography; see Supporting Information.
(17) Prenylation of α-aminoaldehydes: (a) Rubsam, F.; Seck, S.;
Giannis, A. Tetrahedron 1997, 53, 2823−2834. (b) Hanessian, S.; Park,
H.; Yang, R.-Y. Synlett 1997, 353−354.
(18) (a) Triprenylborane: Bubnov, Y. N.; Zhun, I. V.; Klimkina, E. V.;
Ignatenko, A. V.; Starikova, Z. A. Eur. J. Org. Chem. 2000, 3323−3327.
(b) Prenyl-9-BBN: Kramer, G. W.; Brown, H. C. J. Organomet. Chem.
1977, 132, 9−27.
(19) (a) Breitfelder, S.; Schlapbach, A.; Hoffmann, R. W. Synthesis
1998, 468−478. (b) Hoffmann, R. W.; Schlapbach, A. Tetrahedron
1992, 48, 1959−1968.
(20) Cochet, T.; Bellosta, V.; Greiner, A.; Roche, D.; Cossy, J. Synlett
2011, 1920−1922.
REFERENCES
■
(1) For a review of the total synthesis of selected antimicrobial and
antitumor cyclic depsipeptides, see: Li, W.; Schlecker, A.; Ma, D. Chem.
Commun. 2010, 46, 5403−5420.
(2) Antimycin A synthesis reviews: (a) Kiyota, H. Top. Heterocycl
Chem. 2006, 6, 181−214. (b) Yang, Y.-Q.; Wu, Y. Org. Prep. Proced. Int.
2007, 39, 135−152. (c) A recent asymmetric total synthesis of 14
antimycin A family members: Inai, M.; Nishi, T.; Tanaka, A.; Kaku, H.;
Horikawa, M.; Tsunoda, T. Eur. J. Org. Chem. 2011, 2719−2729.
(3) In addition to kitastatin and respirantin, there are six other known
neo-antimycins: (a) JBIR-06: Ueda, J.-Y.; Nagai, A.; Izumikawa, M.;
Chijiwa, S.; Takagi, M.; Shin-ya, K. J. Antibiot. 2008, 61, 241−244. (b)
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