Novel bicyclic lactams as XaaPro type VI β turn mimics: Design, synthesis, and evaluation

Article abstract of DOI:10.1021/jo960012w

The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI β turn is described. The mimics duplicate the conformation of the backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. ¹H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational characteristics of the six-membered ring of the lactam; X-ray crystallographic analysis confirmed the conformational and stereochemical assignment. Examination of the crystal structure of lactam 6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of the amide bond was attributed to angle strain resulting from the presence of the sp²-hybridized nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylformamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine 11, a mimic of an L-Phe L-Pro dipeptide in the type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure-function studies.

Full text of DOI:10.1021/jo960012w

3138
J . Org. Chem. 1996, 61, 3138-3144
Novel Bicyclic La cta m s a s Xa a P r o Typ e VI â Tu r n Mim ics: Design ,
Syn th esis, a n d Eva lu a tion
Kyonghee Kim, J ean-philippe Dumas, and J uris P. Germanas*
Department of Chemistry, University of Houston, Houston, Texas 77204-5641
Received J anuary 2, 1996X
The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as
peptide mimics of the type VI â turn is described. The mimics duplicate the conformation of the
backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly
L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2′-propenyl)proline.
1H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational
characteristics of the six-membered ring of the lactam; X-ray crystallographic analysis confirmed
the conformational and stereochemical assignment. Examination of the crystal structure of lactam
6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of
the amide bond was attributed to angle strain resulting from the presence of the sp2-hybridized
nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylfor-
mamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine
11, a mimic of an L-Phe L-Pro dipeptide in the type VI turn conformation. The efficient synthetic
route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide
structure-function studies.
Sch em e 1. Isom er ism in P r olin e-Con ta in in g
P ep tid es
In tr od u ction
Of the 20 common amino acids, proline is unique by
virtue of its secondary amino group, a feature that has a
significant effect on its conformational properties (Scheme
1). For instance, the difference in free energy between
the trans and cis isomers of amides involving proline is
small (∆G° ) 0.5 kcal/mol), in contrast to amides involv-
ing the primary amino acids, where the trans configu-
rational isomer is substantially more stable than the cis
isomer (∆G° ) 2.6 kcal/mol).1 Hence both cis and trans
isomers of proline-containing peptides may be present in
significant amounts under physiological conditions.2
enzymes termed peptidyl-prolyl isomerases (PPIases),
which greatly accelerate the rate of interconversion of
prolyl peptide bond isomers.8 The PPIases have become
the object of significant research focus due to their roles
in modulating immunosuppression9 and HIV infectivity.10
A common peptide conformational feature that incor-
porates a cis proline residue is the type VI â turn.11 This
conformation is characterized by a cis peptidyl linkage
between the central two residues of the four amino acids
that constitute the turn (Figure 1). The type VI turn is
often found in peptides and proteins containing the
sequence ArProAr, where Ar represents an amino acid
with an aryl side chain; in these cases the prolyl pyrro-
lidine ring is sandwiched between the aryl rings of the
neighboring amino acids.12 The type VI turn has at-
tracted a great deal of attention as a result of its unique
structure and biological importance. For instance, the
Cis-trans isomerism of proline-containing peptides has
been implicated in a number of biologically important
processes. Due to the substantial barrier to intercon-
version of the isomers at room temperature (∆Gq ) 18-
21 kcal/mol),3 the rate-determining step of folding of
many proteins is the isomerization of specific prolyl
peptide bonds from “non-native” to “native” states.4
Isomerization of prolyl amide bonds has also been
proposed to modulate the biological activity of certain
peptide hormones,5 to control the activities of membrane-
spanning polypeptides,6 and to influence peptide suscep-
tibility to protease degradation.7 It has recently become
evident that all cells contain considerable amounts of
X Abstract published in Advance ACS Abstracts, April 15, 1996.
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Nicholson, B. J . Nature 1993, 365, 847-849. (d) Wellner, M.; Monden,
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Structure and the Principles of Protein Conformation; Fasman, G. D.,
Ed.; Plenum Press: New York; 1989, pp 48-53.
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P. E.; Dyson, H. J . J . Mol. Biol. 1994, 243, 736-753. (b) Yao, J .;
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116, 12051-12052.
S0022-3263(96)00012-6 CCC: $12.00 © 1996 American Chemical Society

Bicyclic Lactams as XaaPro Type VI â Turn Mimics
J . Org. Chem., Vol. 61, No. 9, 1996 3139
Sch em e 2
F igu r e 1. Conformation of the type VI â turn and general
structure of the type VI â turn mimic.
type VI turn conformation appears to be a basic recogni-
tion feature for peptide binding to PPIases13 and is also
found in the solution conformation of biologically active
peptide hormones.14
The correlation between a polypeptide’s structure and
its biological activity can often be clarified by assessing
the biological properties of peptides constrained to spe-
cific conformations.15 Such constrained molecules, some-
times termed peptidomimetics, are highly desirable as
therapeutic agents, since they generally do not possess
the pharmacological drawbacks of peptides, such as low
oral availability and rapid proteolytic turnover.16 Pep-
tidomimetics of the type VI turn conformation would find
considerable utility in probing the structure-function
relationships of proline-containing peptides. Herein we
report the design, stereo- and enantioselective synthesis,
and structural evaluation of a series of substituted
bicyclic lactams that represent the central two residues
of an XaaPro dipeptide unit constrained to the type VI
turn conformation (Figure 1).17 A unique feature of the
described synthetic method is the ease of construction of
variants of the parent structure with functional groups
that represent the side chain of the Xaa residue, a vital
consideration for combinatorial chemical applications.
II displayed a planar lactam amide bond and a pseudo-
chair conformation for the six-membered ring with the
amino group assuming a pseudoequatorial disposition.
The starting material for the preparation of the mimic
was (R)-2-(2-propenyl)proline (1), which was readily
available as a single enantiomer from (S)-proline follow-
ing the elegant protocol of Seebach.19 Protection of the
amino and carboxyl functionalities as (benzyloxy)car-
bamates and methyl esters, respectively, furnished the
ester 2 (Scheme 2). Oxidative cleavage of the double bond
with periodate and osmium tetroxide afforded the alde-
hyde 3 in good yield. Introduction of a glycyl anion
equivalent was achieved by coupling aldehyde 3 with the
anion of the phosphonate reagent N-(tert-butyloxycarbo-
nyl)-R-phosphonoglycine dimethyl ethyl ester;20 an equimo-
lar mixture of alkenes 4E and 4Z was obtained after
silica gel chromatography. Exposure of the isomeric
mixture of alkenes to hydrogen in the presence of a
palladium catalyst effected concomitant reduction of the
double bond and hydrogenolysis of the benzyloxycarbonyl
group to provide the amino ester 5 as a mixture of
enantiomers at the chiral center of the pendant alkyl
chain. Thermolysis of the amino ester 5 in refluxing
toluene afforded two products, presumably the bicyclic
lactams 6 and 7. The lactams 6 and 7 could also be
prepared in racemic form, starting from racemic ester 2,
obtained by allylation of the enolate of N-(benzyloxycar-
bonyl)proline methyl ester.
Resu lts a n d Discu ssion
Syn th esis a n d Str u ctu r a l Ch a r a cter iza tion of
GlyP r o An a logs 6 a n d 7. The bicyclic skeleton for the
dipeptide mimic was suggested by a structural homology
search algorithm, using the coordinates of the type VI
turn found in residues 92 and 93 of the RNase A as the
template (Figure 1).18 Conceptually the five-membered
ring of the bicycle II represents the pyrrolidine ring of
the proline residue, the R group represents the side chain
of the i + 1 amino acid residue, and the carboxyl and
amino groups represent the carboxyl and amino groups
of the i + 2 and i + 1 amino acid residues, respectively.
According to molecular mechanics calculations, cis-bicycle
(13) (a) Kallen, J .; Wlakinshaw, M. D. FEBS Lett. 1992, 300, 286.
(b) Orozco, M.; Tirado-Rives, J .; J orgensen, W. L. Biochemistry 1993,
32, 12864-12874. (c) Fischer, S.; Michnick, S.; Karplus, M. Ibid. 1993,
32, 13830-13837.
(14) (a) Freidinger, R. M.; Perlow, D. S.; Randall, W. C.; Saperstein,
R.; Arison, B. H.; Veber, D. F. Int. J . Pept. Protein Res. 1984, 23, 142-
150. (b) Eggleston, D. S.; Baures, P. W.; Peishoff, C. E.; Kopple, K. D.
J . Am. Chem. Soc. 1991, 113, 4410-4416.
(15) (a) Hruby, V. J . Life Sci. 1982, 31, 189-199. (b) Toniolo, C. Int.
J . Pept. Protein Res. 1990, 35, 287-300. (c) Rizo, J .; Gierasch, L. M.
Ann. Rev. Biochem. 1992, 61, 397-418.
(16) (a) Ball, J . B.; Alewood, P. F. J . Mol. Recognit. 1990, 3, 55-64.
(b) Kemp, D. S. Trends Biol. Sci. 1990, 8, 249-255. (c) Gante, J . Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699-1720.
The thermolysis products were separated by silica gel
chromatography and individually characterized. The
similarities of their NMR spectral characteristics sup-
ported the hypothesis that these compounds were the
isomeric lactams 6 and 7. The relative stereochemistry
of the substituents on the six-membered ring and the
conformation of the bicyclic skeleton of each lactam
isomer were investigated in detail, since these features
would determine the structural similarity of the lactams
to the native peptide conformation. The bicyclic lactams
(17) Portions of this work were described in a previous note. See:
Dumas, J .-P.; Germanas, J . P. Tetrahedron Lett. 1994, 35, 1493-1496.
The synthesis of a structurally similar compound was simultaneously
reported by another group; see Gramberg, D.; Robinson, J . A. Tetra-
hedron Lett. 1994, 35, 861-864.
(19) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am. Chem.
Soc. 1983, 105, 5390-5398.
(20) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1984, 53-
(18) Germanas, J . P., in preparation.
60.

3140 J . Org. Chem., Vol. 61, No. 9, 1996
Kim et al.
incorporated the 5(6H)-indolizidinone ring system, as in
III, for which synthetic procedures had been described
previously.21 Since the precise conformational charac-
teristics of this ring system had not been reported,
however, detailed analysis of the conformational proper-
ties of lactams 6 and 7 was carried out by NMR
spectroscopy as well as X-ray crystallography.
F igu r e 2. X-ray crystal structure of bicyclic lactam 6.
The relative stereochemistry of the substituents and
solution phase conformation of the six-membered ring of
each isomer were first elucidated by analysis of their
NMR spectral characteristics. COSY was used to define
the pyrrolidine and piperidinone ring spin systems of the
1H spectrum of each lactam. Stereospecific assignments
of the 1H resonances were then carried out as far as
possible by 1-D NOE difference spectroscopy and NOESY.
The coupling constant values of each resolved signal were
then obtained by inspection or by spectral simulation. For
delineation of the splitting patterns of the C6 protons,
spectra of samples that had been incubated in D2O were
utilized, since the absence of the carboxamide hydrogen
in such samples greatly simplified spectral analysis.
The values of the coupling constants for the six-
membered ring protons of the more polar isomer were
consistent with hydrogens that occupied pseudoaxial or
pseudoequatorial positions on a flattened chair.22 For
example the C6 proton displayed large (13.0 Hz) and
medium (7.3 Hz) couplings to the two C7 protons,
compatible with pseudoaxial-pseudoaxial and pseudo-
axial-pseudoequatorial couplings, respectively.22 The
magnitudes of the C6-C7 1H-1H coupling constants
were indicative of a pseudoaxial C6 hydrogen. On the
basis of the coupling constants, the more polar lactam
was assigned the cis stereochemistry, as in 6, with the
angular carboxy group assuming a pseudoaxial disposi-
tion and the amido group a pseudoequatorial disposition
on the six-membered ring.
Although amides generally adopt conformations in
which the six atoms of the functional group are copla-
nar,25 in unusual cases, such as in strained ring systems,
amide bonds may adopt conformations where the amide
bond is distorted from planarity.26 In the case of the
lactam 6, the value of ω, or the dihedral angle incorpo-
rating the atoms C6-C5-N4-C8a, was found to be
-14.6 ( 0.5°. In contrast the value of ω for the crystal-
lographically characterized, unstrained amide caprolac-
tam, which also contains a cis-lactam bond, was -4.2 +
0.4°.27 A more precise description of amide bond distor-
tion is obtained from an analysis of atom positions by
the method of Dunitz and Winkler.28 The Dunitz pa-
rameters øN and τ′ reflect the N-atom pyramidalization
and rotation about the N-C(O) bond, respectively. De-
viations of the values for these parameters from 0° signify
distortion of a cis amide function. For the lactam bond
of compound 6, the values of øN and τ′ are 6.8 ( 0.5°
and -5.9 ( 0.5°, respectively. The values for øN and τ′
for the cis amide bond of caprolactam are -1.6° and 2.6°,
respectively. Thus the amide bond of lactam 6 displays
a distorted conformation relative to analogous monocyclic
lactam bonds; the degree of nonplanarity of the amide
function of lactam 6 is similar in magnitude to that seen
for the amide bond in cis-caprylolactam (øN ) -6.4° and
τ′ ) 4.3°),28 one of the more strained monocyclic amides.
The origin of the angle strain of the indolizidinone ring
system of lactam 6 was analyzed through comparison of
the conformation of its six-membered ring with that of
cyclohexene. In the absence of strain, the conformation
of the six-membered ring of lactam 6 should resemble
that of cyclohexene, with the CN bond corresponding to
the double bond. Differences in conformation between
these structures were noted, however, in the values for
The less polar isomer’s six-membered ring 1H splittings
were significantly different from those of the more polar
isomer. In particular no large pseudoaxial-pseudoaxial
or small pseudoequatorial-pseudoequatorial coupling
constants could be discerned. The spectral characteris-
tics of this isomer suggested its six-membered ring
adopted a twisted chair or boat conformation, a confor-
mation seen in certain monocyclic piperidinones.23 Hence
the structure of the less polar isomer was assigned the
trans stereochemistry.
The structure of the more polar lactam 6 was unequivo-
cally confirmed by X-ray crystallography (Figure 2).24 In
the crystalline state the six-membered ring of the bicycle
indeed adopted a pseudochair conformation with the
amido substituent oriented pseudoequatorially, as sug-
gested by NMR spectroscopy. Furthermore the X-ray
structure of lactam 6 revealed appreciable distortion of
the lactam amide bond from a planar conformation.
(24) The racemic derivative of the lower Rf lactam crystallized from
ethyl acetate as flat plates as the monohydrate. The space group was
determined to be Pbca. Crystallographic data, including the fractional
atomic coordinates, together with distances and angles of covalent
bonds involving non-hydrogen atoms have been deposited with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(25) The Chemistry of Amides; Zabicky, J ., Ed.; Wiley: London, 1970.
(26) For strained bicyclic amides, see: (a) Somayaji, V.; Brown, R.
S. J . Org. Chem. 1986, 51, 2676-2686. (b) Wang, Q.-P.; Bennet, A. J .;
Brown, R. S.; Santarsiero, B. D. J . Am. Chem. Soc. 1991, 113, 5757-
5765. For strained monocyclic lactams, see: Dunitz, J . D.; Winkler, F.
K. Acta Crystallogr. 1975, B31, 251-263. (c) For strained acyclic
amides, see: Yamada, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1113-
1115 and references therein. (d) For amides in which the nitrogen atom
is incorporated into an aziridine ring, see: Shao, H.; J iang, X.; Gantzel,
P.; Goodman, M. Chem. Biol. 1994, 1, 231-234.
(21) Aube, J .; Milligan, G. L. J . Am. Chem. Soc. 1991, 113, 8966-
8967.
(22) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Sterochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994; p 729.
(23) Meguro, H.; Konno, T.; Tuzimura, K. Tetrahedron Lett. 1975,
1309-1312.
(27) Winkler, F. K.; Dunitz, J . D. Acta Crystallogr. 1975, B31, 268-
270.
(28) Winkler, F. K.; Dunitz, J . D. J . Mol. Biol. 1971, 59, 169-182.

Bicyclic Lactams as XaaPro Type VI â Turn Mimics
J . Org. Chem., Vol. 61, No. 9, 1996 3141
Ta ble 1. X-r a y Cr ysta l Str u ctu r e-Der ived Tor sion An gle
Va lu es for Bon d s of La cta m 6 a n d An a logou s Bon d s of
Cycloh exen e
Sch em e 3
lactam 6 torsion
angle (deg)
cyclohexene torsion
angle (deg)
bond
bond
C5-C6
C6-C7
C7-C8
C8-C8a
C8a-N4
N4-C5
17.7
40.0
58.7
54.1
33.4
14.6
C1-C2
C2-C3
C3-C3′
C2-C3
C1-C2
C1-C1′
15.2
45.0
60.0
45.0
15.2
0.0
the intraring torsion angles. While the values for the
torsions for the dihedral angles incorporating C5-C6,
C6-C7, and C7-C8 of compound 6 were similar to those
for the analogous bonds of cyclohexene,29 the values for
the remaining angles (C8-C8a, C8a-N4, and N4-C5)
deviate significantly from those for cyclohexene (Table
1). These torsion angles all involve C8a and N4, the
atoms common to both the six- and five-membered rings.
Thus strain is introduced into the piperidinone ring of
lactam 6 in order to accommodate fusion with the five-
membered ring.
To assess the conformational similarity between mimic
6 and a typical type VI turn, a superimposition of the
main-chain and side-chain atoms of 6 with the corre-
sponding atoms of the type VI turn from RNase (Tyr92-
Pro93) was carried out using the molecular similarity
algorithm of the QUANTA software package that mini-
mizes the deviation between the positions of analogous
atoms of the two structures. The two structures dis-
played exceptional similarity, with 0.15 Å rms overall
deviation in backbone and five-membered ring atom
positions.17
The difference in free energy between the isomeric
lactams 6 and 7 was investigated by NMR spectroscopy.
Incubation of either lactam in CD3OD in the presence of
CD3ONa at room temperature in an NMR tube resulted
in the appearance of the other stereoisomer, without
appreciable decomposition. The reaction was judged to
have reached equilibrium after a period of 7 days, when
no further change in the ratio of isomers was noted. The
ratio of the integral of the C-8R proton resonance of the
cis isomer at 1.95 ppm, which was unobscured, to the
integral of the multiplet at 2.3 ppm, which contained two
non-exchangeable hydrogens of the trans isomer and one
of the cis isomer, gave a thermodynamic equilibrium
composition for 6 to 7 of 3:1. Incubation of the lactams
in benzyl alcohol in the presence of sodium benzyloxide
afforded a 4:1 cis:trans mixture of benzyl esters 8 and 9.
The benzyl esters will find particular utility in coupling
reactions with amino acids due to the ease of unmasking
the free carboxyl function (Scheme 3).
Ster eoselective Rou te to Xa a P r o An a logs a n d
Descr ip tion of th e Syn th esis of P h eP r o An a log 11.
The lactam 6 is a mimic for the dipeptide GlyPro
constrained to the type VI turn conformation. Stereospe-
cific replacement of the C-6 hydrogen atom of compound
6 with a functional group R would result in a new lactam
whose structure mimics a constrained XaaPro dipeptide,
where Xaa is the amino acid at the i + 1 position of the
turn, as in II (Figure 1). The selection of the specific
functional group R would be made to duplicate the side
chain of the Xaa residue. In view of the importance of
amino acid side-chain-receptor interactions in determin-
ing the selectivity and affinity of biologically active
peptides, the development of an efficient synthetic route
to such compounds became a prime objective.
Alkylation of the enolate of the lactam 6 was consid-
ered to be the most expedient route to XaaPro analogs.
The alkylation reaction would be most straightforward
if the acidic carboxamide hydrogen of compound 6 were
masked during the deprotonation of the hydrogen of C-6.
Vedejs and co-workers have shown that enolates of N,N-
dimethylformamidino amino acid esters can be treated
with various alkyl halides to generate R-substituted N,N-
dimethylformamidino amino acid esters.30 The forma-
midine functionality could be later removed under mild
conditions to generate the free amino analog of the
alkylated amino acid.30 Inspired by these results, we
endeavored to prepare the formamidine derivatives of
lactams such as 6 and attempt their alkylation.
Removal of the carbamate function of lactam 6 was
achieved with trifluoroacetic acid in CH2Cl2. The crude
amine salt was then treated with an excess of N,N-
dimethylformamide dimethyl acetal under reflux for 6 h
(29) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Sterochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994; p 727.
(30) Vedejs, E.; Fields, S. C.; Schrimpf, M. R. J . Am. Chem. Soc.
1993, 115, 11612-11613.

3142 J . Org. Chem., Vol. 61, No. 9, 1996
Kim et al.
to afford a single formamidine product, according to the
characteristics of the H NMR spectrum. The spectrum
L-Pro dipeptide. It is anticipated that other electrophiles
would afford alkylated lactams with identical stereo-
chemistry, yielding an unlimited series of constrained
XaaPro dipeptide mimics. The formamidine functionality
is easily removed under mildly acidic or basic conditions
that are compatible with many common protecting
groups.
In summary the outlined stereoselective synthetic
scheme will afford access to a host of novel, highly
functionalized dipeptide mimics for analysis of peptide
conformation-activity relationships. The evaluation of
the biological properties of several of these mimics is
currently under investigation.
1
of the product displayed a double doublet at δ 4.02 ppm
(J ) 11.4 and 6.9 Hz), a signal consistent with an axial
C-6 hydrogen of the cis formamidine derivative 10
(Scheme 3). The absence of the isomeric trans formami-
dine in the reaction mixture signified that epimerization
at C-6 did not take place during the sequence of trans-
formations. The configuration of the amidine imine bond
was not determined, but was assumed to be trans.
Treatment of the potassium enolate of amidine 10 in
THF with benzyl bromide afforded a single product,
1
1
according to the crude H NMR spectrum. The H NMR
spectrum of the product isolated after chromatography
lacked a signal for the C-6 proton; in addition, an
unusually shielded signal, whose splitting pattern was
consistent with a pseudoaxial hydrogen on the six-
membered ring, was detected at 1.01 ppm. The 13C NMR
spectrum of the product displayed a total number of
carbons equal to that expected for the alkylation product.
The spectral characteristics of the alkylation product
were in accord with an R-benzylindolizidinone, whose six-
membered ring assumed a pseudochair conformation, as
in cis-lactam 6.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all starting materials
and solvents were obtained from commercial suppliers and
used without further purification. Dimethylformamide (DMF)
was distilled from CaH2 under reduced pressure directly before
use. Tetrahydrofuran (THF) and ether (Et2O) were distilled
just prior to use from sodium/benzophenone, and dichlo-
romethane (CH2Cl2) was distilled from P2O5. Benzene was
distilled from sodium, and methanol was distilled from mag-
nesium. Reactions were carried out under a dry nitrogen
atmosphere in glassware that had been flame- or oven-dried
(T > 100 °C) overnight.
The stereochemical course of the benzylation was
determined through analysis of the COSY and NOESY
spectra of the alkylation product. First the 1H resonances
of the product were assigned to the five- or six-membered
ring spin systems using through-bond connectivities
revealed in the COSY spectrum. Through-space connec-
1H and 13C NMR spectra were recorded at 300 or 600 MHz,
using (CH3)4Si as an internal standard. COSY and NOESY
spectra were recorded with 2048 by 512 data points and were
zero filled to 2K × 2K sizes. A mixing time of 350 ms was
used for the NOESY spectra.
Column chromatography was performed on silica gel (Merck
reagents silica gel 60, 230-400 mesh ASTM). Thin layer
chromatography (TLC) was carried out on Analtech Uniplate
silica gel plates with a 0.25 mm coating containing fluorescent
indicator. Spots were visualized using ninhydrin, phospho-
molybdic acid, iodine, or UV light.
1
tivities between the H resonances were then extracted
from the NOESY spectrum, and stereospecific assign-
ments consistent with the distance restraints were made.
For instance a strong NOE crosspeak was observed
between the upfield signal at 1.01 ppm and the signal at
1.44 ppm, assigned to one of the C-1 protons of the five-
membered ring. The upfield signal was thus assigned
to the C-8â proton, because the C-8 hydrogens are the
only six-membered ring hydrogens sufficiently close to
C-1 to display NOEs, and due to its splitting pattern.
According to the crystal structure of lactam 6, the
distance between the C-8â proton and the C-1â proton
is 2.45 Å (Figure 2); hence the 1.47 ppm resonance was
ascribed to the C-1â proton.
The 1.01 ppm signal also displayed a NOESY cross-
peak to a multiplet at 3.33 ppm, assigned to the benzyl
hydrogens on the basis of strong NOEs to the phenyl
hydrogens. In the structure of the (6S,8aR) stereoisomer
of the alkylation product, the distance between the C-8â
hydrogen and the benzyl methylene carbon is 2.58 Å; in
the structure of the alternative (6R,8aR) stereoisomer,
the analogous distance is 4.10 Å. The NOE between
these sets of signals is more consistent with a compound
with (6S,8aR) stereochemistry, as in compound 11
(Scheme 3), than with (6R,8aR) stereochemistry. The
absence of NOE crosspeaks between the 1.01 ppm
resonance and the formamidine resonances further con-
firmed the stereochemical assignment. The shielding
properties of the aromatic ring would also explain the
significant upfield shift of the C-8â proton of lactam 11
relative to the analogous hydrogen of lactam 10 (∆δ )
1.6 ppm).
Molecular mechanics calculations and theoretical and struc-
tural analyses were performed with the Quanta package using
the CHARMM force field.
(R )-(-)-N -(Be n zyloxyca r b on yl)-2-(2′-p r op e n yl)p r o-
lin e. To an ice-cooled solution of amino acid hydrochloride
119 (6.54 g, 34.2 mmol) and triethylamine (14.25 mL, 102.7
mmol) in 40 mL of CH3CN/H2O (1:1) was added dropwise a
solution of triethylamine (4.75 mL) and benzyl chloroformate
(9.8 mL, 68.5 mmol). The reaction mixture was then stirred
at room temperature for 4 days. The acetonitrile was removed
under reduced pressure, and the remaining aqueous solution
was adjusted to pH 8-9 with saturated sodium bicarbonate,
washed three times with ether, acidified to pH 1 with 6 N HCl,
and then extracted with three portions of ether. The organic
extracts were washed with brine, dried over anhydrous Na2-
SO4, and evaporated under reduced pressure to give 6.6 g
(67%) of the acid as a dark orange oil: [R]25 ) -18.0° (c 0.9,
D
CHCl3); IR (KBr) 3470, 3070, 2980, 2881, 2600, 1707, 1415,
1357, 1215, 1176, 1116, 920, 698 cm-1; 1H NMR (CDCl3) cis +
trans rotomers (1:1) δ 7.32 (m, 5H), 5.67 (m, 1H), 5.12 (m, 4H),
3.68, 3.78 (2 × m, 1H), 3.43 (m, 1H), 2.92, 3.02 (2 × m, 1H),
2.6, 2.72 (2 × m, 1H), 1.85, 2.05, 2.20, 2.35 (4 × m, 4H); 13C
NMR (CDCl3) cis + trans rotomers (1:2) δ 176.4, 155.8, 136.21
(C Ar), 132.63, 132.1, 128.5, 128.4, 128.1, 127.9, 127.8, 127.6,
127.5, 126.9, 119.8, 119.4, 69.0, 67.5, 67.3, 49.2, 48.8, 39.0, 37.9,
35.0, 22.9, 22.5.
(R )-(-)-N -(Be n zyloxyca r b on yl)-2-(2′-p r op e n yl)p r o-
lin e Meth yl Ester (2). A fresh solution of diazomethane was
made by adding 30 mL of a 50% KOH solution to a solution of
nitrosomethylurea (10 g, 136.8 mmol) in 100 mL of ether. The
reaction was stirred for 30 min. The ether layer was separated
and added dropwise to an ice-cooled solution of crude acid from
the previous procedure (6.6 g, 22.8 mmol) in 60 mL of ether
until the color of the reaction mixture turned from orange to
yellow. The solution was then stirred at room temperature
for an additional 15 min, the reaction was quenched with acetic
Exclusive formation of the (6S,8aR) stereoisomer of
lactam 11 resulted from stereoelectronically favored
pseudoaxial attack of the electrophile onto the planar
enolate of formamidine 10. The stereochemistry of the
alkylation product is analogous to that of a natural L-Phe

Bicyclic Lactams as XaaPro Type VI â Turn Mimics
J . Org. Chem., Vol. 61, No. 9, 1996 3143
acid to destroy excess diazomethane, and the solution was
washed three times with water and evaporated under reduced
pressure to give a brown oil. Chromatography of the oil on
silica gel eluting with hexane/ethyl acetate (3:1) gave 6.0 g
(87%) of ester 2 as a yellow oil: [R]25D ) -19.2° (c 0.7, CHCl3);
153.2, 136.6, 136.0, 130.3, 129.5,128.6, 128.4, 128.2, 127.8,
127.6, 80.7, 80.5, 67.9, 67.2, 66.9, 52.5, 52.3, 52.2, 49.0, 48.2,
37.7, 36.3, 34.2, 32.8, 28.1, 22.9, 22.6. 4E: 0.08 g (20%); Rf
0.21; [R]25 ) -18.2° (c 0.8, CHCl3); IR (CHCl3) 3667, 3541,
D
3423, 3040, 2984, 2955, 1726, 1707, 1693, 1512, 1437, 1356,
1
1
IR (KBr) 3059, 2955, 2883, 1737, 1701, 1410, 1356 cm-1; H
1249, 1163, 908 cm-1; H NMR (CDCl3) δ 7.35 (m, 5H), 6.54
NMR (CDCl3) cis + trans rotomers (1:2) δ 7.34 (m, 5H), 5.71
(m, 1H), 5.13 (m, 4H), 3.70, 3.47 (2 × s, 3H), 3.70, 3.47 (2 ×
m, 2H) 2.90, 3.11 (2 × m, 1H), 2.64 (m, 1H), 1.85, 2.09 (2 × m,
4H); 13C NMR (CDCl3) cis + trans rotomers (1:2) δ 174.5, 154.2,
136.9, 136.3, 133.2, 132.9, 128.4, 128.3, 128.1, 128.0, 127.7,
127.5, 119.1, 119.0, 68.0, 67.0, 66.5, 52.3, 52.1, 49.1, 48.2, 39.3,
38.0, 37.0, 35.5, 23.0, 22.5. Anal. Calcd for C17H21NO4: C,
64.59; H, 7.00; N, 4.12. Found: C, 64.19; H, 6.70; N, 3.74.
(R,S)-N-(Ben zyloxyca r b on yl)-2-(2′-p r op en yl)p r olin e
Meth yl Ester (2). To a solution of N-(benzyloxycarbonyl)-
proline methyl ester (21.1 g, 80.0 mmol) and allyl iodide (30.0
g, 178.0 mmol) in THF (500 mL) was added dropwise with
stirring a solution of potassium hexamethyldisalizide (25.0 g,
125 mmol) in toluene (250 mL) at -78 oC. A cloudy yellow
solution formed immediately. After the mixture was stirred
at this temperature for 1 h, the reaction was quenched with
water (300 mL) the solution was and allowed to warm to room
temperature. The crude reaction mixture was extracted with
three portions of ether (150 mL), and the organic extracts were
combined and washed with saturated brine and dried over
MgSO4. After filtration and removal of solvent, the crude
product was distilled in a Kugelrohr apparatus to afford the
racemic ester 2 as an oil (20.4 g, 84%).
(m, 1H), 5.23-4.89 (m, 2H), 3.81, 3.76, 3.71, 3.45 (4 × s, 6H),
3.57 (m, 2H), 3.40 (m, 1H), 3.25 (dd, J ) 15 Hz, J ) 8 Hz, 1H),
2.16 (m, 2H), 1.92 (m, 2H), 1.45 (s, 9H); 13C NMR (CDCl3) cis
+ trans rotomers (1:1) δ 174.3, 174.2, 164.6, 164.4, 154.2, 152.9,
137,5, 136.9, 128.8, 127.7, 127.6, 127.4, 127.1, 123.9, 123.8,
80.6, 80.5, 68.4, 67.7, 66.6, 52.2, 52.1, 49.1, 48.3, 37.4, 36.3,
33.6, 32.5, 28.1, 23.0, 22.5. Anal. Calcd for C25H34N2O8: C,
58.99; H, 7.00; N, 5.71. Found: C, 58.79; H, 6.65; N, 6.21.
(2R,3′R,S)-2-(3′-(N-(ter t-Bu toxyca r bon yl)a m in o)-3′-ca r -
boeth oxyp r op yl)p r olin e Meth yl Ester (5). The E/Z mix-
ture of alkenes 4E and 4Z (0.0525 g, 0.11 mmol) was dissolved
in 2.0 mL of methanol and nitrogen was bubbled through. To
this was added Pd/C (10%, 0.008 g), and the mixture was
flushed again with nitrogen. The solution was stirred for 45
min under
a hydrogen atmosphere before being filtered
through Celite to remove the catalyst. The solvent was then
removed under reduced pressure to give 0.0355 g (93%) of
amine 5 as a clear oil: [R]25
D ) -17.2° (c 0.6, CHCl3); 1H NMR
(CDCl3) δ 5.85, 5.57 (2 × d, J )12 Hz, 1H), 4.15 (m, 1H), 3.69
(s, 6H), 2.92 (m, 2H), 2.48 (m, 1H), 2.09 (m, 1H), 1.81-1.51
(m, 6H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 177.1, 172.6, 155.5,
105.3, 68.8, 68.7, 61.2, 53.3, 52.4, 46.6, 46.5, 36.2, 34.9, 28.3,
25.2, 14.1.
(6R,8a R)- a n d (6S,8a R)-N-(ter t-Bu t oxyca r b on yl)-6-
a m in o-8a -ca r boxyin d olizid in -5-on e Meth yl Ester (6 a n d
7). A solution of amine 5 (0.550 g, 1.54 mmol) in 20 mL of
toluene and 0.8 mL of triethylamine was refluxed for 48 h
under a nitrogen atmosphere. The solvent was removed under
reduced pressure to give 0.5 g of a yellow oil. Chromatography
on silica gel eluting with hexane/ethyl acetate (1:2) provided
the bicyclic lactams 6 and 7 as crystalline solids. 6: 0.07 g
(R )-(-)-N -(Be n zyloxyca r b on yl)-2-(2′-oxoe t h yl)p r o-
lin e Meth yl Ester (3). To a solution of methyl ester 2 (1.0
g, 3.3 mmol) in 60 mL of methanol/water (2:1) was added 0.25
mL of a solution of OsO4 in tert-butyl alcohol (2.5% w/w). The
mixture was stirred for 30 min until a dark brown color
developed and then was treated with sodium periodate (2.06
g, 9.9 mmol) in small portions over a period of 30 min under
vigorous stirring, resulting in a white precipitate. After an
additional stirring period of 2 h, the solution was poured onto
150 mL of water and extracted five times with ethyl acetate.
The organic extracts were dried over anhydrous MgSO4,
(50%); Rf 0.31; mp 89-92 °C; [R]25 ) -20.0° (c 0.6, CHCl3);
D
IR (CHCl3), 3672, 3428, 2979, 2897, 1735, 1698, 1651, 1494,
1440, 1160 cm-1; 1H NMR (CDCl3) δ 5.22 (br s, 1H), 4.06 (ddd,
J )13.0, 6.7, 7.3 Hz, 1H), 3.75 (s, 3H), 3.63 (m, 1H), 3.54 (dt,
J ) 11.0 Hz and J ) 3 Hz, 1H), 2.58 (ddd, J ) 13.8, 3.3, 3.3
Hz, 1H), 2.50 (m, 1 H), 2.40 (dd, J ) 14.0, 5.3 Hz, 1H), 1.92
(dddd, J ) 11.3, 7.3, 3.3, 3.3 Hz, 1H), 1.80-1.65 (m, 3H), 1.49,
(m, 1H), 1.44 (s, 9H); 13C NMR (CDCl3) δ 173.7, 167.7, 156.1,
79.5, 70.1, 52.9, 51.8, 45.0, 37.6, 30.7, 28.2, 26.8, 20.6. Anal.
Calcd for C15H24N2O5‚H2O: C, 54.52; H, 7.95; N, 8.48.
Found: C, 54.78; H, 7.80; N, 8.38.
filtered through
a layer of anhydrous MgSO4, and then
evaporated under reduced pressure to give 0.8 g (80%) of
aldehyde 3 as a brown oil: [R]25 ) -20.6° (c 1.0, CHCl3); IR
D
(KBr) 2955, 2883, 1739, 1705, 1410, 1356, 1216, 1170, 1053
cm-1; 1H NMR (CDCl3) cis + trans rotomers (1:2) δ 9.80, 9.71
(s, 1H), 7.26 (m, 5H), 5.12 (m, 2H), 3.71, 3.56, 3.47 (3 × m,
5H), 3.30-2.97 (m, 2H), 2.29, 1.96 (2 × m, 4H); 13C NMR
(CDCl3) δ 199.5, 199.3, 173.5, 173.3, 154.5, 153.7, 136.4, 135.8,
128.7, 128.5, 128.4, 128.3, 127.9, 127.8, 127.6, 67.4, 67.0, 66.5,
65.7, 52.7, 52.5, 48.9, 48.5, 48.2, 47.7, 38.2, 37.0, 23.1, 22.6.
(R)-(-)-(E a n d Z)-N-(Ben zyloxyca r bon yl)-2-(3′-(N-(ter t-
bu toxyca r bon yl)a m in o-3′-ca r boeth oxy-2′-p r op en yl)p r o-
lin e Meth yl Ester (4E, 4Z). To a solution of LDA (1.51 mmol)
in 4.0 mL of THF/hexane (1:3) was added dropwise a solution
of N-(tert-butoxycarbonyl)-1-amino-1-(carboxymethyl)phospho-
nic acid dimethyl ethyl ester (0.537 g, 1.47 mmol) in 3.0 mL
of THF. The temperature was allowed to warm to -10 °C to
dissolve the precipitate. The resulting orange solution was
again cooled to -78 °C and then treated with a solution of
aldehyde 3 (0.440 g, 1.44 mmol) in 3.0 mL of THF. The
mixture was warmed to room temperature and stirred for an
extra 2 h. The solvent was evaporated under reduced pressure
and the residue dissolved in ethyl acetate. The organic layer
was then washed with water, dried over Na2SO4, filtered, and
evaporated under reduced pressure to give a crude brown oil.
Chromatography column on silica eluting with hexane/ethyl
acetate (3:1) afforded the alkene as Z/E isomers (2:1) in 60%
yield. 4Z: 0.16 g (40%); Rf 0.13; [R]25D ) -18.8° (c 0.7, CHCl3);
IR (CHCl3) 3670,3545, 3423, 3040, 2984, 2955, 2885, 1726,
7: 0.140 g (20%); Rf 0.47; [R]25 ) -18.2° (c 1.0, CHCl3); IR
D
(CHCl3) 3695, 3433, 2984, 2957, 1736, 1709, 1649, 1495, 1442,
1
1167 cm-1; H NMR (CDCl3) δ 5.63 (br s, 1H), 3.95 (ddd, J )
7.6, 7.6, 5.6 Hz, 1H), 3.75 (s, 3H), 3.71 (dt, J ) 11.0, 3.0 Hz,
1H), 3.50 (m, 1H), 2.53 (ddd, J ) 14.0, 7.3, 7.3 Hz, 1H), 2.48
(m, 1H), 2.36 (dddd, J ) 14.0, 7.6, 7.6, 7.6 Hz, 1H), 1.95-1.76
(m, 4H), 1.60 (dddd, J ) 14.0, 7.6, 7.6, 7.6 Hz, 1H), 1.44 (s,
9H); 13C NMR (CDCl3) δ 173.8, 168.7, 155.6, 79.5, 67.9, 53.0,
49.3, 45.7, 39.3, 29.8, 28.3, 26.4, 21.6.
(6R,8a R)- a n d (6S,8a R)-N-(ter t-Bu t oxyca r b on yl)-6-
a m in o-8a -ca r boxyin d olizid in -5-on e Ben zyl Ester (8 a n d
9). To a solution of ester 7 (1.00 g, 3.4 mmol) in benzyl alcohol
(50 mL) was added a piece of sodium metal (0.01 g, 0.5 mmol).
The mixture was stirred for 24 h at rt, then poured into 10%
aqueous NH4Cl, and then extracted with CHCl3. The organic
layer was washed with water and saturated NaCl and dried
with MgSO4. Excess benzyl alcohol and other volatile liquids
were removed under reduced pressure to afford a yellow oil of
a mixture of benzyl esters 8 and 9. Chromatography on silica
gel eluting with hexanes:ethyl acetate (3:1) afforded esters 8
and 9 as oils. 8: 0.79 g (60%); [R]25 ) -18.0° (c 0.5, CHCl3);
D
1709, 1691,1483, 1454,1437, 1354, 1259, 1163, 910 cm-1; H
IR (CHCl3) 3650, 2980, 1738, 1700, 1650 cm-1
;
1H NMR
1
NMR (CDCl3) cis + trans rotomers (1:1) δ 7.35 (m, 5H), 6.49,
6.36 (2 × t, J ) 10 Hz, 1H), 5.23-4.88 (m, 2H), 3.76, 3.72,
3.42 (3 × s, 6H), 3.54 (m, 2H), 3.17 (dd, J ) 14 Hz, J ) 8 Hz,
1H), 2.92 (dd, J ) 14 Hz, J ) 8 Hz, 1H), 2.12-2.09 (m, 2H),
1.92-1.85 (m, 2H), 1.45 (s, 9H); 13C NMR (CDCl3) cis + trans
rotomers (1:1) δ 174.0, 173.8, 165.2, 165.0, 154.8, 154.1, 153.4,
(CDCl3) δ 7.21-7.23 (m, 5H), 5.10 (s, 2H), 5.03 (br s, 1H), 3.96
(ddd, J ) 11.4, 5.7, 5.7 Hz, 1H), 3.40-3.55 (m, 2H), 2.52 (ddd,
J ) 13.0, 3.3, 3.3 Hz, 1H), 2.43 (dd, J ) 12.0, 6.9 Hz, 1H),
1.90 (m, 1H), 1.65-1.72 (m, 4H), 1.43 (s, 9H), 0.83 (m, 1H);
13C NMR (CDCl3) δ 173.5, 168.2, 156.5, 135.6, 129.1, 129.0,
128.6, 80.1, 70.5, 68.0, 52.2, 45.5, 38.1, 31.2, 28.7, 27.2, 21.1.

3144 J . Org. Chem., Vol. 61, No. 9, 1996
Kim et al.
9: 0.077 g (20%); [R]25 ) -20.0° (c 0.5, CHCl3); IR (CHCl3)
to the solution. After 1 h, the reaction was quenched with 0.2
mL of an aqueous 10% NH4Cl solution. Volatile material was
removed under reduced pressure to give an oil that was
subjected to flash colum chromatography, eluting with CH2-
Cl2 to afford 0.11 g (43%) of formamidine 11 as a white foam:
D
3700, 3430, 2982, 1732, 1710, 1659 cm-1; H NMR (CDCl3) δ
1
7.23-7.33 (m, 5H), 5.59 (br s, 1H), 5.18 (d, J ) 12.3 Hz, 1H),
5.12 (d, J ) 12.3 Hz, 1H), 3.94 (m, 1H), 3.70 (m, 1H), 3.52 (m,
2H), 2.30-2.52 (m, 3H), 1.53-1.87 (m, 4H), 1.43 (s, 9H); 13C
NMR (CDCl3) δ 173.0, 168.7, 155.6, 135.1, 128.5, 128.6, 128.2,
79.5, 68.0, 67.6, 49.4, 45.7, 39.2, 29.7, 28.3, 26.4, 21.5.
(6R,8a R)-6-(((N,N-Dim eth yla m in o)m eth ylen e)a m in o)-
8a -ca r boxyin d olizid in -5-on e Meth yl Ester (10). To a
solution of ester 6 (0.090 g, 0.31 mmol) in CH2Cl2 (10 mL) was
added trifluoroacetic acid (0.18 mL, 2.44 mmol), and the
solution was stirred at rt. After 2 h, CH2Cl2 and trifluoroacetic
acid were removed under reduced pressure to give a yellowish
oil. The crude amine salt was suspended in dimethylforma-
mide dimethyl acetal (0.5 mL, 3.76 mmol) and the solution
refluxed under N2 for 6 h. Columm chromatography on silica
eluting with a solution of CH2Cl2 and MeOH (9:1) afforded
0.074 g of a colorless oil of 10 (65%): IR (CHCl3) 2980, 1730,
1650 cm-1; 1H NMR (CDCl3) δ 7.47 (s, 1H), 3.75 (s, 3H), 3.66-
3.39 (m, 3H), 2.90 (s, 6H), 2.63 (ddd, J ) 13.8, 3.3, 3.3 Hz,
1H), 2.40 (dd, J ) 10.8, 5.8 Hz, 1H), 2.09 (m, 1H), 1.95 (m,
1H), 1.82-1.72 (m, 4H); 13C NMR (CDCl3) δ 173.2, 166.3, 156.6,
70.1, 56.8, 53.3, 45.5, 37.6, 30.9, 25.6, 20.7.
1
IR (CHCl3) 2985, 1734, 1647, 1595 cm-1; H NMR (CDCl3) δ
7.60 (s, 1H), 7.26-7.21 (m, 5H), 3.74 (m, 1H), 3.65 (s, 3H), 3.58
(m, 1H), 3.33 (d, J ) 12.9 Hz, 2H), 2.84 (s, 6H), 2.25 (dd, J )
12.1, 6.7 Hz, 1H), 2.17 (ddd, J ) 14.4, 4.7, 4.7 Hz, 1H), 1.97
(ddd, J ) 14.4, 4.3, 4.3 Hz, 1H), 1.83 (m, 1H), 1.66-1.62 (m,
2H), 1.47 (ddd, J ) 12.6, 12.6, 7.8 Hz, 1H), 1.01 (ddd, J ) 13.3,
12.7, 3.6, 1H); 13C NMR (CDCl3) δ174.5, 172.5, 154.32, 138.2,
130.5, 127.8, 126.2, 69.0, 63.5, 52.4, 47.3, 45.4, 38.6, 34.1, 29.5,
20.8.
Ack n ow led gm en t. We are grateful to the R. A.
Welch Foundation, the American Heart Associations
Texas Affiliate (Grant 95G-448), American Cyanamid,
and the University of Houston for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
3, 5, 7, 8, and 9, 13C spectra of 10 and 11, and COSY and
NOESY spectra of the benzyl derivative of 11 (9 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of this journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(6S,8a R)-6-Ben zyl-6-(((N,N-d im eth yla m in o)m eth ylen e-
)a m in o)-8a -ca r boxyin d olizid in -5-on e Meth yl Ester (11).
Formamidine 10 (0.20 g, 0.78 mmol) and benzyl bromide (0.46
mL, 3.92 mmol) were dissolved in dry THF (15 mL) and cooled
to -78 °C under N2. A solution of potassium hexamethyl-
disilazide (0.18 g in 1 mL of THF) was then added dropwise
J O960012W