Total syntheses of depsipeptide elastase inhibitors YM-47141 and YM- 47142 with use of ylide protection and coupling methods [12]

Full text of DOI:10.1021/ja9840302

J. Am. Chem. Soc. 1999, 121, 1401-1402
1401
Scheme 1a
Total Syntheses of Depsipeptide Elastase Inhibitors
YM-47141 and YM-47142 with use of Ylide
Protection and Coupling Methods
Harry H. Wasserman,* Jyun-Hung Chen, and Mingde Xia
Department of Chemistry, Yale UniVersity
P.O. Box 208107
New HaVen, Connecticut 06520-8107
ReceiVed NoVember 23, 1998
Interest in molecules containing the vicinal tricarbonyl system
has been heightened in recent years with the discovery of the
potent immunosuppressant activity of the macrolide lactones FK-
506 and rapamycin.1,2 Both of these substances incorporate the
tricarbonyl system in the form of intramolecular hemiketals.
Elegant total syntheses of these metabolites have been reported3
along with extensive studies directed at the formation of
substructural units considered to be of importance in connection
with the biological activity of the natural products.4
Very recently, two novel elastase inhibitors isolated from
Flexibacter sp. Q 17897 have been characterized as the dep-
sipeptides YM-47141 (1a) and YM-47142 (1b).5 The structures,
elucidated by MS and NMR spectroscopic analysis, are notewor-
thy in that they contain the vicinal tricarbonyl aggregate in the
form of hydrated R,â-diketo amides. The stereochemistry at C-4
of the unnatural amino acid 2,3-dioxo-4-amino-6-methylheptanoic
acid (Dah) was not determined.
tricarbonyls in a natural product. This work establishes the
stereochemistry at C-4 as that derived from L-leucine, and
demonstrates the generality of the phosphoranylidene ylide
activation and protection methodology that we have employed
in earlier syntheses of R-keto amides.6-8 The advantages of this
procedure (eq 1) are the facile coupling of carboxylic acids with
phosphoranes to form stable ylide intermediates which contain
highly electrophilic carbonyl groups in protected form. The
tricarbonyl units may then be easily unmasked by oxidative
cleavage of the carbon phosphorus double bond, affording pure
products in high yields.
An important element in planning our synthesis involved the
initial formation of the ylide fragment (4) containing the Dah
residue with the central carbonyl group of the vicinal tricarbonyl
protected in ylide form. We were confident that this unit would
be stable under the varied deprotection conditions employed in
the elaboration of the depsipeptide. Because of the strongly
electrophilic activity of the central carbonyl which predisposes
the aggregate to cleavage reactions9 or benzilic acid type
rearrangements,10 we deferred the deprotection of this group until
the last step in the sequence.
We began the synthesis by coupling L-leucine benzyl ester with
bromoacetic acid to form 2, which was then converted to the
phosphonium salt 3 and then to the ylide 4 by sequential treatment
We now report the total syntheses of these macrocyclic
tricarbonyl depsipeptides, the first examples of hydrated vicinal
(1) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto,
T.; Hahimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031.
(4) (a) Egbertson, M.; Danishefsky S. J. J. Org. Chem. 1989, 54, 11. (b)
Villalobos, A.; Danishefsky S. J. J. Org. Chem. 1989, 54, 12. (c) Schreiber,
S. L.; Sammakia, T.; Uehling, D. E. J. Org. Chem. 1989, 54, 15. (d) Jones,
A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J. A.; Smith, D.
B.; Schreiber, S. L. J. Org. Chem. 1989, 54, 17. (e) Schreiber, S. L.; Smith,
D. B. J. Org. Chem. 1989, 54, 9. (f) Batchelor, M. J.; Gillespie, R. J.; Golec,
J. M. C.; Hedgecock, C. J. R. Tetrahedron Lett. 1993, 34, 167. (g) Wasserman,
H. H.; Rotello, V. M.; Williams, D. R.; Benbow, J. W. J. Org. Chem. 1989,
54, 2785. (h) Rama Rao, A. V.; Desibhatla, V. Tetrahedron Lett. 1993, 34,
7111.
(5) (a) Yasumuro, K.; Suzuki, Y.; Shibazaki, M.; Teramura, K.; Abe, K.;
Orita, M. J. Antibiot. 1995, 48, 1425. (b) Orita, M.; Yasumuro, K.; Kokubo,
K.; Shimizu, M.; Abe, K.; Tokunaza, T.; Kaniwa, H. J. Antibiot. 1995, 48,
1430.
(2) (a) FK-506: Kino, T.; Hatanaka, H.; Hashimoto, M.; Nishyama, M.;
Goto, T.; Okuhara, M.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1987,
40, 1249. (b) FR-900525: Hatanaka, H.; Kino, T.; Asano, M.; Goto, T.;
Tanaka, H.; Okuhara, M. J. Antibiot. 1989, 42, 620. (c) FR-900520 and FR-
900523: Hatanaka, H.; Kino, T.; Miyata, S.; Inamura, N.; Kuroda, A.; Goto,
T.; Tanaka, H.; Okuhara, M. J. Antibiot. 1988, 41, 1592. (d) Rapamycin:
Swindelly, D.; White, P.; Findlay, J. Can. J. Chem. 1978, 56, 2491. Martel,
R.; Klicius, J.; Galet, S. Can. J. Physiol. Pharmacol. 1977, 55, 48.
(3) (a) Jones, T. K.; Reamer, R. A.; Desmond, R.; Mills, S. G. J. Am. Chem.
Soc. 1990, 112, 2998. (b) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A.
D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. (c) Romo,
D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993,
115, 7906. (d) Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 9345. (e) (i) Smith, A. B., III; Condon, S. M.; McCauley, J.
A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc.
1995, 117, 5407-5408. (ii) Smith, A. B., III; Condon, S. M.; McCauley, J.
A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc.
1997, 119, 947-961 and 962-973. (f) For a recent total synthesis of FK-506
and other references to synthetic work in this field, see: Ireland, R. E.; Liu,
L.; Roper, T. D. Tetrahedron 1997, 53, 13221. Ireland, R. E.; Liu, L.; Roper,
T. D.; Gleason, J. L. Tetrahedron 1997, 53, 13257.
(6) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59, 4364.
(7) Wasserman, H. H.; Petersen, A. K. Tetrahedron Lett. 1997, 38, 953.
(8) Wasserman, H. H.; Petersen, A. K. J. Org. Chem. 1997, 62, 8972.
(9) (a) Luengo, J. I.; Rozamus, L. W.; Holt, D. A. Tetrahedron Lett. 1993,
34, 4599. (b) Fisher, M. J.; Chow, K.; Villalobos, A.; Danishefsky, S. J. J.
Org. Chem. 1991, 56, 2900.
(10) Luengo, J. I.; Konialian, A. L.; Holt, D. A. Tetrahedron Lett. 1993,
34, 991.
10.1021/ja9840302 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/02/1999

1402 J. Am. Chem. Soc., Vol. 121, No. 6, 1999
Communications to the Editor
Scheme 2
to introduce the remaining threonine, alanine, and aspargine
residues by the 2+2+1 approach leading to 7 as shown in Scheme
2.
Depsipeptide 5, derived from L-threonine and D-alanine, was
allowed to react (EDCI) with the free amine resulting from HCl
removal of the Boc group from 4, yielding 6. Removal of the
Fmoc group of 6 with piperidine was followed by coupling
(EDCI) with N-Cbz asparagine, the primary amido group of which
was protected as the 4,4′-dimethoxybenzhydryl (Mbh) derivative.11
The differentially protected product 7 containing five amino acids
was then cyclized to the depsipeptide precursor (8), after Pd/C
hydrogenolysis of the Cbz and Bn groups, by treatment with
DPPA/NaHCO3 in dilute DMF. Installation of each side chain
was accomplished by TFA deprotection of both Boc and Mbh
groups followed by EDCI coupling with the substituted phenyl-
alanyl threonine to form 9a (R ) COCH2Ph) or 9b (R ) COCH2-
CH(CH3)2).
The resulting macrocyclic ylides 9a and 9b represent precursors
which could easily be converted to the desired natural products
by oxidative cleavage of the carbon-phosphorus double bonds.12
The final conversion of 9a,b to 1a,b under the mild conditions
of ozonolysis (-78 °C, 2 min) took place without complication,
forming the natural products in excellent yields (89 and 92%,
respectively). The only side product, Ph3PO, was easily removed
by CH2Cl2 washing. The 1H and 13C NMR spectra of both
synthetic products YM-47141 and YM-47142 were identical in
every respect with the corresponding spectra of the natural
products. Since L-leucine was used in the preparation of the Dah
fragment, we assign the corresponding L-leucine configuration
to the C-4 chiral center. There was no evidence of any epimer-
ization of this center in our synthetic product.13
Acknowledgment. This work was supported by grants from the
National Institutes of Health and the National Science Foundation. We
are grateful to Dr. Masaya Orita, Yamanouchi Pharmaceutical Company,
Japan, for samples and spectra of natural YM-47141 and YM-47142.
Supporting Information Available: Experimental procedures for
preparation of all compounds in Schemes 1 and 2 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA9840302
(11) (a) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 2041. (b) Evans, D.
A.; Watson, P. S. Tetrahedron Lett. 1996, 37, 3251.
(12) We were mindful of possible side reactions in this last step: sensitivity
of the primary amide group and secondary alcohol group toward oxidation,
â-elimination of the free threonine hydroxyl in the conversion of 9 to 1. These
concerns were allayed by model studies of primary amide units and threonine
residues in small peptides, which were stable to the conditions of low-
temperature ozonolysis.
(13) The 1H NMR peaks corresponding to the methine and methylene
protons at the γ and δ positions of Dah were indistinguishable from the
corresponding absorptions in the natural products. There were no additional
peaks in the synthetic product to indicate any epimerization.
with Et3N followed by reaction with N-Boc-L-leucine (Scheme
1). In the further progression to the 18-membered ring, we chose