Solid phase synthesis of olefin and hydroxyethylene peptidomimetics

Full text of DOI:10.1021/ja962290i

12246
J. Am. Chem. Soc. 1996, 118, 12246-12247
Solid Phase Synthesis of Olefin and
Hydroxyethylene Peptidomimetics
David P. Rotella
Department of Chemistry, Cephalon, Inc.
145 Brandywine Parkway,
West Chester, PennsylVania 19380
Figure 1.
ReceiVed July 5, 1996
Scheme 1
The development of enzyme inhibitors often makes use of
peptide bond replacements to mimic the transition state for
amide hydrolysis and/or to increase the metabolic stability of
the compound. Previous reports of the preparation of enzyme
inhibitor libraries have focused on elaboration of a specific
moiety such as an hydroxyethylene,1a diol,1b or a phosphonic
ester.2 This communication outlines a flexible and potentially
more general approach to peptidomimetics3 using a resin-bound
amino acid aldehyde 1 (Figure 1) which is frequently employed
in solution for this purpose.4 This is the first published report
of the preparation and chemistry of such N-linked R-amino
aldehydes; others have described carbonyl-bound versions and
employed them in solid phase synthesis.5
The synthesis of 1 begins with acyl imidazole-modified Wang
resin 2, first reported by Hauske and Dorff6 (Scheme 1).
Reaction of 2 with an amino alcohol (5 equiv) in refluxing THF
for 18-36 h7 leads to resin-bound amino alcohols. Estimation
of the efficiency of this reaction was carried out by cleaving
the molecule from the resin using trifluoroacetic acid, followed
by NMR analysis of the crude amino alcohol. By this measure,
the yield of the reaction ranged from 75% (phenylalaninol) to
90% (alaninol). Oxidation with pyridine-sulfur trioxide com-
plex8 delivers amino aldehydes 1a-c, whose FTIR spectra show
a strong absorption at 1732 cm-1 for the aldehyde carbonyl and
a corresponding decrease in the absorption centered at 3420
cm-1. A second exposure of this material to the oxidation
conditions did not result in a further decrease in signal intensity
in the OH region of the IR spectrum. Using this approach, it
also proved possible to attach dipeptide alcohol H-Leu-Phe-
CH2OH and convert it to the corresponding aldehyde in the same
manner. Wittig olefination of 1a-c using NaHMDS and
methylene triphenylphosphonium bromide (5 equiv) in THF at
room temperature leads to allylic amines 3a-c. The aldehyde
absorption was completely absent in the FTIR spectra of these
products, suggestive of complete reaction. In order to confirm
the success of this transformation, the leucine and phenylalanine
derivatives were cleaved (TFA/CH2Cl2) and converted to known
N-Boc compounds 4a,b,9 which were isolated in 21% yield
(based on loading of the starting Wang resin). The 300 MHz
NMR spectra of these samples were identical to those originally
reported. Epoxidation of 3a with purified mCPBA in buffered
methylene chloride at reflux furnished oxirane 5, a useful
intermediate for the synthesis of hydroxyethylene peptidomi-
metics using nitrogen10 and sulfur11 nucleophiles.12 To evaluate
the stereoselectivity of the epoxidation reaction and to compare
this solid phase sequence with its solution counterpart (15:1
threo:erythro9), 5 was reduced with LiBH4 in THF (1 mol equiv)
at room temperature to secondary alcohol 6. Cleavage and
carbamate formation as with 3 (Vide supra) led to alcohols 7a,b13
as a 4.6:1 threo:erythro mixture in 65% net yield from allylic
amine 3.
The preparation of olefinic peptidomimetics is exemplified
using the phenylalanine and alanine (1b and 1c, respectively)
resin-bound aldehydes, as shown in Scheme 2. Using phos-
phorane 9a, Wittig reaction requires prolonged reflux in THF
(3-4 days) to deliver the corresponding allyl esters 8b,c. A
similar period of time is necessary for complete conversion of
3a to ester 8a (X ) Me) using 9b. The commercially available
Horner-Emmons reagent 9c14 (5 equiv) reacts with 3b,c under
milder conditions to furnish R,â-unsaturated acids 10b,c after
(1) (a) Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427-1430.
(b) Wang, G. T.; Li, S.; Wideburg, N.; Krafft, G. A.; Kempf, D. J. J. Med.
Chem. 1995, 38, 2995-3002.
(2) Campbell, D. A.; Bermak, J. C.; Burkoth, T. S.; Patel, D. V. J. Am.
Chem. Soc. 1995, 117, 5381-5382.
(3) Olefin isosteres: (a) Spatola, A. F. Chemistry and Biochemistry of
Amino Acids Peptides and Proteins; Marcel Dekker: New York, 1983; Vol.
7, pp 267-357. (b) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, H.; Mimura,
N.; Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J. Chem. Soc., Perkin
Trans. 1 1995, 1359-1371. Hydroxyethylene isosteres: (a) Abdel-Meguid,
S. Med. Res. ReV. 1993, 13, 731-778. (b) Beaulieu, P.; Wernic, D. J. Org.
Chem. 1996, 61, 3635-3645 and references therein.
(4) For examples see: (a) Baker, W. R.; Pratt, J. K. Tetrahedron 1993,
49, 8739-8756. (b) Gennari, C.; Pain, G.; Moresca, D. J. Org. Chem. 1995,
60, 6248-6249.
(5) (a) Fehrentz, J. A.; Paris, M.; Heitz, A.; Velek, J.; Liu, C. F.;
Winternitz, F.; Martinez, J. Tetrahedron Lett. 1995, 36, 7871-7874. (b)
Murphy, A. M.; Dagnino, R., Jr.; Vallar, P. L.; Trippe, A. J.; Sherman, S.
L.; Lumpkin, R. H.; Tamura, S. Y.; Webb, T. R. J. Am. Chem. Soc. 1992,
114, 3156-3157.
(6) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589-1592.
(7) See the Supplementary Information for details.
(9) Luly, J. R.; Dellaria, L. A.; Plattner, J. J.; Soderquist, J. L.; Yi, N. J.
Org. Chem. 1987, 52, 1487-1492.
(10) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.;
Talley, J. J.; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J. J.; Mueller,
R. A.; Vazquez, M. L.; Shieh, H. S.; Stallings, W. C.; Stegeman, R. A. J.
Med. Chem. 1993, 36, 288-291.
(11) Romero, S.; Rich, D. H. Tetrahedron Lett. 1993, 34, 7187-7190.
(12) Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, J. C.; Muellner, F. W.;
Weyker, C. L. Tetrahedron 1995, 51, 6397-6410.
(13) Reetz, M. T.; Rolfing, K.; Griebenow, N. Tetrahedron Lett.1994,
35, 1969-1972. [R]D values and NMR spectra for these alcohols are not
reported in this work. Ocain and Rich (J. Med. Chem. 1988, 31, 2193-
2199) also disclose this structure but give no physical characterization.
(14) Aldrich, Catalog # 27021-0.
(8) Chen, C.; Ahlberg Randall, L. A.; Miller, R. B.; Jones, A. D.; Kurth,
M. J. J. Am. Chem. Soc. 1994, 116, 2661-2662.
S0002-7863(96)02290-1 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 48, 1996 12247
Scheme 2
brief (1 h) treatment of the resin with tetrabutylammonium
fluoride to ensure complete cleavage of the labile trimethylsilyl
ester. The carbonyl region of the FTIR spectra of the products
10 again shows complete disappearance of the aldehyde
absorption and is not resolved into individual peaks for the acid
and urethane. The presence of a carboxylic acid was suggested
by broad absorbance in the region between 3400 and 3000 cm-1.
Coupling of these acids with phenylalanine methyl ester using
HATU and HOAT in the presence of N-methylmorpholine in
DMF gives dipeptides 11. FTIR of the product shows disap-
pearance of the broad OH signal; only signals attributable to
chemistry will explore other linker strategies, as well as modified
reaction conditions and/or reagents to effect these transforma-
tions.
In summary, the preparation of amino acid and dipeptide
aldehydes bound to a solid support Via the N-terminus has been
demonstrated for the first time. The synthesis of olefinic
peptidomimetics and amino acid-derived epoxides, themselves
central intermediates in hydroxyethylene peptide isostere
synthesis,3b,c,9-12 by reaction sequences similar to those em-
ployed in solution has been demonstrated. Modest stereose-
lectivity (threo > erythro) was obtained in the epoxidation of
resin-bound allylic amine 3a. This can be rationalized in part
to be due to the elevated temperature employed. Exclusive
formation of the E isomer in the Horner-Emmons reaction of
aldehydes 3b,c with phosphonate 9c was observed. These
results establish the utility of supported amino aldehydes in solid
phase approaches to peptide isosteres and further expand the
spectrum of chemistry that can be applied for the preparation
of libraries which are useful for enzyme inhibitor development.
the NH protons are observed in the region around 3400 cm-1
.
In addition, new peaks at 1682 and 1734 cm-1, indicative of
amide and ester moieties, respectively, are also present. Cleav-
age and N-terminal derivatization furnished 12a and 12b as
white solids in 21 and 25% yield, respectively, following flash
chromatography. NMR analysis of the crude reaction mixture
indicated in each case that only the E isomer was produced in
the Horner-Emmons reaction.
In both of these sequences, NMR spectra of the crude
products obtained following deriVatization with Boc anhydride
indicate that, in addition to product, the most significant
contaminant (ca. 10%) is excess di-tert-butyl dicarbonate. This
“off resin” step, used herein as a means to facilitate purification,
represents an additional site for structural diversity in the
products. Resin-derived aromatic byproducts (based on NMR
absorption in the 6.8-7.5 ppm region, <10%) can be detected
in the products prior to this reaction. The modest isolated yields
of products resulting from these sequences are most likely
associated with the instability of the urethane linker to the basic
conditions of the Wittig reactions as well as the acidic medium
of the mCPBA epoxidation.15 Mass spectral analysis of cleaved
products, e.g. 4, 7, and 11, did not detect ions associated with
starting materials for these reactions, confirming the FTIR
observations noted above. Second-generation versions of this
Acknowledgment. Drs. Iqbal Mohamed and Sankar Chatterjee
provided useful suggestions, and the support of Dr. John Mallamo was
essential in the conduct of this work.
Supporting Information Available: Listing of experimental
procedures for the syntheses of 1-12 along with physical data for 7a
and 12a,b and FTIR spectra for all of the intermediates (18 pages).
See any current masthead page for ordering and Internet access
instructions.
JA962290I
(15) Examination of the resin by FTIR following cleavage indicates that
all of the material has been cleaved in both sequences. The benzyl urethane
linker appears to be somewhat unstable to m-chlorobenzoic acid generated
as a result of olefin epoxidation of a structurally unrelated series of molecules
being studied in these laboratories, based on FTIR analysis of the resin
following the reaction and mass recovery following TFA cleavage.