T. D. Owens et al. / Tetrahedron Letters 42 (2001) 6271–6274
6273
Acknowledgements
1:1.2, confirming retention of the original chirality and
formation of one diastereomeric pair at the newly-cre-
ated a-hydroxy center.8e,f Base-catalyzed Fmoc-depro-
tection of 10a led, via a smooth O- to N-acyl
migration, to 11 in high yield.17 Hydrolysis of 11 and
subsequent hydrogenolysis afforded advanced interme-
diate 12, which constitutes the entire acyclic skeleton of
the eurystatins. Deprotection–migration of 10b fol-
lowed by global hydrogenolysis provided a more direct
route to 12. Macrocyclization of the v-amino acid 12
occurred under standard high dilution conditions and
delivered the 13-membered macrocycle 13 in respectable
yields. Finally, 13 was elaborated to the target eury-
statin A 1a by sequential N-Boc deprotection, acylation
with (E)-6-methyl-2-heptenoic acid, and oxidation to
the a-ketoamide. Physical properties of our sample
agreed with literature values.18 It is of interest to note
that solubility issues with both 13 and the N-acylated
penultimate intermediate precluded the use of typical
Swern-type oxidation conditions in dichloromethane
solvent. However, the oxidation was efficiently and
reproducibly executed via the Parikh–von Doering
protocol19 in DMSO.
Stimulating discussions with T. K. Brunck, K. E. Pryor,
J. E. Reiner and O. A. Moreno are gratefully
acknowledged.
References
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Our approach to eurystatin A 1a via the key Passerini
reaction–deprotection–acyl migration strategy is con-
vergent and highly efficient. Proceeding over nine to ten
steps in 20–26% overall yield from commercially avail-
able leucine esters, it compares quite favorably to other
current routes.18,20 Although Wasserman’s elegant acyl
cyanophosphorane oxidation approach to 1a proceeded
concisely over ten steps, the base-labile a-ketoamide
functionality is revealed early in the synthesis
sequence.18 Our experience,1,2,10 as well as literature
precedent,2c,21 indicates that a-ketoamide racemization
issues may arise during completion of such a synthesis.
Schmidt’s simple Passerini–acyl cleavage method to 1a
proceeded in 14 steps and utilized benzoic acid for
adduct formation.20 The benzoyl moiety was subse-
quently cleaved and discarded, producing a simpler
a-hydroxyamide derivative akin to 4. We contrast these
approaches with our method, whereby a suitably pro-
tected ornithine derivative is used as the carboxylic acid
component in the key Passerini reaction and is retained
throughout the succeeding deprotection–migration
stages, ultimately shortening the synthesis of this target
by several steps.
6. HCMV protease inhibitors: LaPlante, S. R.; Bonneau, P.
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tion: Toda, S.; Kotake, C.; Tsuno, T.; Narita, Y.;
Yomasaki, T.; Konishi, M. J. Antibiot. 1992, 45, 1580.
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Isonitrile Chemistry, Ugi, I., Ed.; Academic Press: New
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Chim. Acta 1983, 66, 1618.
In conclusion, the utility of this technology for the
rapid assembly of relatively complex a-ketoamide
amide-containing natural products is highlighted by a
concise total synthesis of eurystatin A (1a). The key
Passerini reaction, deprotection and acyl migration
steps proceed in moderate to high yields and under
mild conditions. Other noteworthy features of our
methodology include high atom-economy and very late
stage oxidation to the reactive a-ketoamide moiety,
which minimizes potential stability and racemization
issues. Numerous applications to the synthesis of a-
ketoamide natural products and protease inhibitors are
envisioned and will form the basis of forthcoming
publications from our laboratories.
9. Semple, J. E.; Levy, O. E. PCT Int. Appl. WO 0035868
A2, June, 2000.
10. Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E.
Org. Lett. 2000, 2, 2769.
11. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000,
985.
12. All new compounds were characterized by full spectro-
scopic (NMR, low/high resolution MS) analysis. Yields
refer to spectroscopically and chromatographically
homogenous (]95% by HPLC, TLC) materials.
13. (a) Skorna, G.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1977,
16, 259; (b) Urban, R.; Marquarding, D.; Seidel, P.; Ugi,
I. Chem. Ber. 1977, 110, 2012; (c) Giesemann, G.; von
Hinrichs, E.; Ugi, I. J. Chem. Res. (S) 1982, 79.