Enantio- And Regioselective Synthesis of a (Z)-Alkene czs-Proline Mimic

Full text of DOI:10.1021/jo981387f

7580
J . Org. Chem. 1998, 63, 7580-7581
En a n tio- a n d Regioselective Syn th esis of a
(Z)-Alk en e cis-P r olin e Mim ic
Scott A. Hart, Michal Sabat, and Felicia A. Etzkorn*
University of Virginia, Department of Chemistry, McCormick
Road, Charlottesville, Virginia 22901
Received J uly 16, 1998
F igu r e 1. cis-Pro mimics and cis-/trans-Pro equilibrium.
Proline is the unique dialkylated member of the 20
common natural amino acids, resulting in cis/trans amide
bond isomerization. Isomerization of proline has profound
effects on peptide and protein structure1 and results in
structural issues for every peptide containing a proline.
Several bioactive peptides contain cis-Pro,2-5 a type-VI
â-turn,6 though it is not always known whether the bioactive
conformation is trans- or cis-Pro.7-12 We have synthesized
an isosteric mimic of a cis-Pro dipeptide that will be useful
in rational drug design and protein folding studies, Figure
1. Our mimic is suitable for stabilizing the bioactive con-
formation of peptides and proteins. The cis-Pro mimic will
be incorporated into substrate analogues for the peptidyl-
prolyl isomerase enzymes, cyclophilin and FK506 binding
protein (FKBP), that preferentially bind cis-Pro substrates.13
The peptide Ac-Ala-cis-Pro-NHMe and the corresponding
mimic, 1a (Figure 1), were subjected to a MonteCarlo
conformational search and minimized using the Amber force
field with water solvation in MacroModel v. 3.5a. The lowest
energy structure of the mimic overlayed with the peptide
on the bonds marked with vectors with root-mean-square
deviation of 0.17 Å, Figure 1. The vectors14 in this case are
part of the peptide backbone, giving direction to attached
peptide chains.
Sch em e 1
Sch em e 2
The conformationally rigid (Z)-alkene isostere of Ala-cis-
Pro was synthesized in
a form suitably protected for
alkene trans isosteres have been made.19 Stereoselective
routes to trans-alkene dipeptide isosteres16,20,21 and trans-
Pro mimics are known.22
incorporation into peptidomimetics. The (Z)-alkene mimic
is a very good isostere for the cis-amide bond and does not
introduce additional functionality that could interfere with
peptide structure. Surprisingly, this simple dipeptide mimic
has not yet been synthesized. Other cis-proline mimics have
been reviewed.5,15 Nonproline cis-amide alkene isosteres
have been made,16 some as E/Z mixtures.17,18 The fluoro-
The synthetic challenges associated with the cis-Pro mimic
were as follows: (1) versatility for introducing a variety of
amino acid side chains to mimic the residue N-terminal to
Pro, (2) enantiospecific synthesis of the key S,R enantiomer
of the mimic, and (3) formation of the (Z)-alkene exocyclic
to a cyclopentyl ring to mimic the cis-amide. The R-amino
acid starting material permits introduction of a wide variety
of amino acid side chains into the mimic and is the origin of
stereoselectivity for the synthesis, Scheme 1. A Still-Wittig
[2,3]-sigmatropic rearrangement introduced the (Z)-alkene
and transferred chirality to the cyclopentyl ring.23
The enantio- and regioselective synthesis of the dipep-
tide mimic of L-Ala-cis-L-Pro is shown in Schemes 2 and 3.
Beginning with L-Ala, the Weinreb amide 2 was prepared
according to published procedures.24 The reaction of 2 with
cyclopentenyllithium25,26 gave the desired ketone 3 in 93%
* To whom correspondence should be addressed. Tel.: (804) 924-3135.
Fax: (804)-924-3567. E-mail: fae8m@virginia.edu.
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Llina´s, M. Biochemistry 1991, 30, 1663-1672.
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10.1021/jo981387f CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/08/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7581
Sch em e 3
reduction; however, J ones oxidation of the resulting alcohol
gave decomposition. Instead, oxidation of alcohol 8 with the
doubly protected amine proceeded in high yield to give acid
9 from which the benzyl group was easily removed via Na/
NH3 reduction to give the target 1b. Concerns about â,γ-
unsaturated acid or amide isomerization to the R,â-unsat-
urated compound proved unfounded.31 The (E)-alkene
dipeptide isosteres are also stable toward isomerization.20,21
We have synthesized 1b, a new (Z)-alkene isostere of a
cis-Pro dipeptide. This route uses a single chiral precursor
for the enantio- and regioselective synthesis. The Ala-cis-
Pro mimic was prepared in eight steps and 49% overall yield
from the Weinreb amide of dibenzyl-Ala. These results
demonstrate the ease of preparing the (Z)-alkene mimic
starting with a chiral amino acid in a quantity required for
peptide synthesis. The Ala-cis-Pro mimic has been incorpo-
rated into a cyclophilin substrate analogue (Hart, S. A.;
Etzkorn, F. A., unpublished results).
yield.27,28 Simple LiAlH4 reduction of ketone 3 resulted in
greater than 95% diastereoselectivity of the Felkin-Ahn
product 4.29
The tributyltin intermediate 5 was prepared and Still-
Wittig rearrangement gave the desired (Z)-alkene 6, with
transfer of chirality to the cyclopentyl ring to give a single
diastereomer in the NMR. (Z)-Alkene regiochemistry was
confirmed by NOE (see the Supporting Information). Alcohol
6 crystallized after evaporation of ethyl acetate. X-ray
crystallographic analysis provided definitive evidence for the
desired isomer (see the Supporting Information). Similar
steric features of the five-membered ring that induce cis/
trans isomerization in Pro peptides appear to be responsible
for the high (Z)-stereoselectivity obtained in this case.17
Protection of the amine in a form suitable for peptide
synthesis and oxidation of the alcohol to the acid were
intertwined synthetic steps, Scheme 3. Didebenzylation via
dissolving metal reduction (Na or Li in NH3/THF) failed. One
of the two benzyl groups could be removed by catalytic
transfer hydrogenolysis in formic acid on Pearlman’s cata-
lyst.30 Protection of benzylamine 7 with tert-butoxycarbonyl
(Boc) facilitated removal of the second benzyl via Na/NH3
Ack n ow led gm en t. This work was supported in part
by J effress Foundation Grant J -355 to F.A.E. We thank
J eremy Travins for preliminary results and helpful dis-
cussions. We thank Ben Brooks, Scott Meiere, and Profes-
sor W. Dean Harman (University of Virginia) for elemental
analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures for all compounds, 1H NMR spectrum of an oxazolidinone
derivative of compound 4, 1D NOE spectrum of compound 6, X-ray
crystallographic data for compound 6, and the 1H and 13C NMR
spectra of compound 7 (24 pages).
J O981387F
(27) Boutin, R. H.; Rapoport, H. J . Org. Chem. 1986, 51, 5320-5327.
(28) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(29) Only one diastereomer of alcohol 4 was observed by 1H and 13C NMR.
The absolute configuration was determined from the 1H NMR 6 Hz coupling
constant between the two ring protons of an oxazolidinone derivative as
previously described. (Williams, T. M.; Crumbie, R.; Mosher, H. S. J . Org.
Chem. 1985, 50, 91-97.) In the case of trityl-protected amine, the best
observed diastereomeric ratio was only 2:1 (Hart, S. A.; Etzkorn, F. A.,
unpublished results).
(30) Hiskey, R. G.; Northrop, R. C. J . Am. Chem. Soc. 1961, 83, 4798-
4800.
(31) The double bond was inert to isomerization both under conditions
of amide coupling to the activated ester and toward heating with tertiary
amine base. Acid 1b was coupled to L-Phe-p-nitroanilide using standard
solution-phase methods (Hart, S. A.; Etzkorn, F. A., unpublished results).
No migration of the alkene was observed in the product. This product was
treated with 2.5 equiv of Et3N at 80 °C for 16 h, and no isomerization was
observed by 1H NMR.