Stereoselective Synthesis of Freidinger Lactams Using Oxaziridines Derived from Amino Acids

Article abstract of DOI:10.1021/jo961670j

Conformationally restrained dipeptidyl lactams are building blocks for the synthesis of peptidomimetics, including Freidinger lactams (Figure 1). Few synthetic methodologies toward such moieties allow for incorporation of a stereodefined substituent on the ring nitrogen (i.e., corresponding to an amino acid side chain). Enantiopure Freidinger lactams were obtained by (1) condensation of (S)-tert-butoxycarbonyl (Boc)-protected 2-aminocycloalkanones with commercially available α-amino esters, (2) oxidation of the resulting imines with m-CPBA to give spirocyclic oxaziridines, and (3) photorearrangement. Conformational analyses of seven- and eight-membered dipeptidyl lactams by NMR and by X-ray crystallography are described. The utility of this chemistry was illustrated by the synthesis of potential inhibitors of angiotensin converting enzyme (ACE).

Full text of DOI:10.1021/jo961670j

654
J . Org. Chem. 1997, 62, 654-663
Ster eoselective Syn th esis of F r eid in ger La cta m s Usin g
Oxa zir id in es Der ived fr om Am in o Acid s
Michael S. Wolfe,† Dinah Dutta, and J effrey Aube´*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506
Received August 29, 1996X
Conformationally restrained dipeptidyl lactams are building blocks for the synthesis of peptido-
mimetics, including Freidinger lactams (Figure 1). Few synthetic methodologies toward such
moieties allow for incorporation of a stereodefined substituent on the ring nitrogen (i.e., corre-
sponding to an amino acid side chain). Enantiopure Freidinger lactams were obtained by (1)
condensation of (S)-tert-butoxycarbonyl (Boc)-protected 2-aminocycloalkanones with commercially
available R-amino esters, (2) oxidation of the resulting imines with m-CPBA to give spirocyclic
oxaziridines, and (3) photorearrangement. Conformational analyses of seven- and eight-membered
dipeptidyl lactams by NMR and by X-ray crystallography are described. The utility of this chemistry
was illustrated by the synthesis of potential inhibitors of angiotensin converting enzyme (ACE).
Endogenous peptide hormones and neurotransmitters
represent an important and still largely untapped res-
ervoir of diverse lead molecules for drug development.1
Problems such as poor solubility, poor gastrointestinal
absorption, multiple physiological effects, and short
biological half-lives have limited the direct clinical utility
of most endogenous peptides.2 The design and synthesis
of conformationally restricted peptidomimetics is an
important approach toward improving the potency, se-
lectivity, and metabolic stability of peptide hormones and
neurotransmitters.3 Among the numerous strategies
toward the conformational restriction of peptides, incor-
porating the backbone into a “Freidinger” lactam struc-
ture4 (Figure 1) has proven useful in the design of a
variety of medicinally relevant targets5 but especially
peptidase/protease inhibitors.6 Such cyclization of the
peptide backbone7 fixes the amide bond in the trans
rotameric form, places severe limitations on ψ1 rotation,
and would be expected to bias neighboring φ1 and φ2
torsional angles.
F igu r e 1. Conformational restriction of the peptide backbone
via a Freidinger lactam.
stereoselective methods that allow control over the C-3
center (amino substituent) or the glycyl side chain (R1
in Figure 1).4-6,8 However, no one method has proved
completely facile for the stereoselective synthesis of
Freidinger lactams of various ring sizes containing a
spectrum of C-terminal amino acid residues. An ideal
method would (1) be applicable to lactams of various
sizes, (2) allow the installation of potentially expensive
and/or scarce amino acid moieties late in the scheme,
permitting divergence to a number of amino acid substi-
tutions (and obviously relevant to combinatorial ap-
(6) In addition to monocyclic lactams of various ring sizes, the
following list contains some lead references to derivatives of Freidinger
lactams bearing heteroatom substituents. Selected references to related
compounds containing additional cyclizations (fused or spiro) are
included as well. (a) Thorsett, E. D.; Harris, E. E.; Aster, S.; Peterson,
E. R.; Taub, D.; Patchett, A. A. Biochem. Biophys. Res. Commun. 1983,
111, 166-171. (b) Thorsett, E. D.; Harris, E. E.; Aster, S. D.; Peterson,
E. R.; Tristram, E. W.; Snyder, J . P.; Springer, J . P.; Patchett, A. A.;
Ulm, E. H., In Peptides: Structure and Function; Hruby, V. J ., Rich,
D. H., Ed.; Pierce Chemical Co.: Rockford, IL, 1983; pp 555-558. (c)
Watthey, J . W. H.; Stanton, J . L.; Desai, M.; Babiarz, J . E.; Finn, B.
M. J . Med. Chem. 1985, 28, 1511-1516. (d) Thorsett, E. D.; Harris, E.
E.; Aster, S. D.; Peterson, E. R.; Snyder, J . P.; Springer, J . P.;
Hirshfield, J .; Tristram, E. W.; Patchett, A. A.; Ulm, E. H.; Vassil, T.
C. J . Med. Chem. 1986, 29, 251-260. (e) Yanagisawa, H.; Ishihara,
S.; Ando, A.; Kanazaki, T.; Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi,
K.; Matsushita, Y.; Hata, T. J . Med. Chem. 1987, 30, 1984-1991. (f)
Flynn, G. A.; Giroux, E. L.; Dage, R. C. J . Am. Chem. Soc. 1987, 109,
7914-7915. (g) Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.;
Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi, K.; Matsushita, Y.; Hata,
T. J . Med. Chem. 1988, 31, 422-428. (h) Burkholder, T. P.; Huber, E.
W.; Flynn, G. A. Bioorg. Med. Chem. Lett. 1992, 3, 231-234. (i) Robl,
J . A.; Cimarusti, M. P.; Simpkins, L. M.; Barown, B.; Ryono, D. E.;
Bird, J . E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J . Med.
Chem. 1996, 39, 494-502.
Several different synthetic strategies have been devel-
oped toward Freidinger lactams (loosely defined to en-
compass monocyclic γ-, δ-, and ꢀ-lactams), including some
† Current address: Department of Pharmaceutical Sciences, Uni-
versity of Tennessee; Room 327C, Faculty Building; 847 Monroe St.,
Memphis, TN 38163.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) For
a general review, see: Hruby, V. J .; Mazmierski, W.;
Kawasaki, A. M.; Matsunaga, T. O. In Peptide Pharmaceuticals:
Approaches to the Design of Novel Drugs; Ward, D. J ., Ed.; Open
Univerisity: Buckingham, England, 1991; pp 135-184.
(2) Plattner, J . J .; Norbeck, D. J ., In Drug Discovery Technologies;
Clark, C. R., Moos, W. H., Eds.; J ohn Wiley & Sons: New York, 1990;
pp 92-126.
(3) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bo¨s, M.; Cook, C. M.;
Fry, D. C.; Graves, B. J .; Hatada, M.; Hill, D. E.; Kahn, M.; Madison,
V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J .; Vincent, G. P.; Voss,
M. E. J . Med. Chem. 1993, 36, 3039-3049.
(4) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J . R.;
Saperstein, R. Science 1980, 210, 656-658. (b) Freidinger, R. M.;
Perlow, D. S.; Veber, D. F. J . Org. Chem. 1982, 47, 104-109. (c)
Freidinger, R. M., In Peptides: Synthesis, Structure, Function; Rich,
D. H., Gross, E., Eds.; Pierce Chemical Co.: Rockford, IL, 1981; pp
673-683. (d) Veber, D. F.; Freidinger, R. M. Trends Neurosci. 1985,
392-396.
(5) (a) Samanen, J .; Hempel, J . C.; Narindray, D.; Regoli, D. In
Chemistry and Biology: Proceedings of the Tenth American Peptide
Symposium; Marshall, G. R., Ed.; ESCOM: Leiden, 1988; pp 123-
125. (b) Samanen, J .; Cash, T.; Narindray, D.; Brandeis, E.; Adams,
W., J r.; Weideman, H.; Yellin, T. J . Med. Chem. 1991, 34, 3036-3043.
(c) Ede, N. J .; Rae, I. D.; Hearn, M. T. W. Tetrahedron Lett. 1990, 31,
6071-6074.
(7) Review: Toniolo, C. Int. J . Pept. Protein Res. 1990, 35, 287-
300.
(8) (a) Garvey, D. S.; May, P. D.; Nadzan, A. M. J . Org. Chem. 1990,
55, 936-940. (b) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett.
1994, 36, 191-194. (c) Robl, J . A.; Cimarusti, M. P.; Simpkins, L. M.;
Weller, H. N.; Pan, Y. Y.; Malley, M.; DiMarco, J . D. J . Am. Chem.
Soc. 1994, 116, 2348-2355. (d) Robl, J . A.; Karanewsky, D. S.; Asaad,
M. M. Tetrahedron Lett. 1995, 36, 1593-1596. (e) Miller, S. J .; Grubbs,
R. H. J . Am. Chem. Soc. 1995, 117, 5855-5856. (f) Acton, J . J ., III;
J oesn, A. B. Tetrahedron Lett. 1996, 37, 4319-4322.
S0022-3263(96)01670-2 CCC: $14.00 © 1997 American Chemical Society

Stereoselective Synthesis of Freidinger Lactams
J . Org. Chem., Vol. 62, No. 3, 1997 655
Ta ble 1. Ster eoch em istr y of Oxa zir id in e F or m a tion
F r om Cycloh exa n on e a n d Selected r-Am in o Ester s
Sch em e 1
oxaziridines
yield
entry
R
amino ester
L-Phe-OMe
L-Leu-OMe
L-Val-OMe
products (%)
ratio
79 >95:5a,b
80 88:12
1
2
3
4
5
CH2Ph
4a /5a
4b/5b
4c/5c
i-Bu
i-Pr
proaches), (3) incorporate protection schemes consonant
with standard peptide chemistry, and (4) allow control
over relative and absolute stereochemistry. The stereo-
selective synthesis of chiral lactams from cyclic ketones
using spirocyclic oxaziridines has become established as
a potent tool in ring-expansion chemistry.9 We thought
an oxaziridine-mediated approach to Freidinger lactams
could potentially address all of the above criteria.
80 >95:5a,b
CH2CO2Me L-Asp(OMe)-OMe 4d /5d
CH2OCH2Ph L-Ser(OBn)-OMe 4e/5e
80
67
54:46a,b,c
60:40b,c
Ratios were determined by 500 MHz 1H-NMR examination of
a
b
the crude reaction mixture. Approximate ratios were determined
by isolation of pure isomers. c Stereochemical assignments not
made.
The results of these experiments (Table 1) clearly indicate
a preference for like stereochemistry when the R-amino
ester side chain is an unfunctionalized hydrophobic group
(entries 1-3; the direction of attack was assigned in
analogy to experiments carried out with (R)-3-methyl-
cyclohexanone, as described below). High stereochemical
preferences were seen using phenylalanine and valine
methyl esters (entries 1 and 3), in which only one
diastereomer was observed within the limits of 1H-NMR
detection. Oxaziridine formation via leucine methyl ester
(entry 2) was slightly less selective although the dia-
stereomeric ratio was still acceptably high. The high
preference for like stereochemistry is similar to that
observed with R-methylbenzylamine.12 In sharp contrast,
stereochemical preferences of oxaziridine formation were
essentially absent when the functionized aspartate and
serine methyl esters were employed (entries 4 and 5). The
reasons for the differences between functionalized and
unfunctionalized amino ester side chains are probably
related to the diminished size differential between
CH2CO2Me/CO2Me vs CH2Ph/CO2Me. Whatever the
reason, similar differences were also observed in analo-
gous experiments with protected 2-aminocyclohexanone
1 (vide infra).
Our general synthetic strategy is depicted in Scheme
1. Condensation of enantiopure (S)-tert-butoxycarbonyl
(Boc)-protected 2-aminocycloalkanones 1 with commer-
cially available R-amino esters and subsequent oxidation
of the imines with m-CPBA should form oxaziridines 2
in which the N-substituent is oriented trans to the more
highly substituted carbon for steric reasons. Oxaziridines
are known to rearrange to lactams under photochemical
conditions so that the carbon anti to the nitrogen lone
pair of electrons migrates predominantly.9 Therefore, the
stereochemical relationship of oxaziridines 2 should
dictate the formation of the desired regioisomeric lactams
3 upon photorearrangement. No other kind of known
nitrogen insertion process could be expected to reliably
provide lactams of this regiochemical type. In a prelimi-
nary communication, we reported the formation of stereo-
defined Freidinger lactams 3 utilizing a variety of
R-amino esters.10 Here we (1) describe this chemistry in
detail, (2) discuss the stereochemistry of the oxidation
of amino ester-derived imines in general, (3) provide
X-ray crystallographic structures for seven- and eight-
membered Freidinger lactams, and (4) illustrate the
utility of this chemistry in the synthesis of potential
angiotensin-converting enzyme (ACE) inhibitors.
The preferential formation of like-configured oxaziri-
dines was established by analyzing reactions of the imine
derived from Phe-OMe and (R)-3-methylcyclohexanone
(Scheme 2). Oxaziridine formation with L-phenylalanine
methyl ester under the standard conditions provided
predominantly one diastereomer of 6 (ratio ca. 7:1). This
major diastereomer photorearranged to 4-methylcapro-
lactam 7; hence, the nitrogen lone pair of electrons of 6
is oriented trans to the migrating C-8 carbon. This
Resu lts a n d Discu ssion
Ster eoch em ica l P r efer en ces of Oxa zir id in e F or -
m a tion Usin g r-a m in o ester s. In order to establish
some general principles governing the oxidation of imines
derived from R-amino esters, we examined oxaziridine
formation using cyclohexanone and (R)-3-methylcyclo-
hexanone. Condensation of L-R-amino methyl esters with
cyclohexanone in the presence of catalytic dibutyltin
dichloride11 and subsequent oxidation of the imines with
m-CPBA provided oxaziridines 4 and 5 in good yields.
(12) The unlike product is preferred when R-methylbenzylamine is
employed.9 However, the preference for like stereochemistry using
phenylalanine methyl ester (Phe-OMe) is probably a consequence of
the rules for prioritizing substituents in the Cahn-Prelog-Ingold
system; hence, L-Phe-OMe (i.e., (S)-Phe-OMe) can be super-
imposed onto (R)-R-methylbenzylamine better than it can be super-
imposed onto (S)-R-methylbenzylamine (see structures below). The use
of either of these two amines results in a preference for S stereochem-
istry at N-2 of the resulting oxaziridine.
(9) (a) Lattes, A.; Oliveros, E.; Rivie`re, M.; Belzecki, C.; Mostowicz,
D.; Abramskj, W.; Piccinni-Leopardi, C.; Germain, G.; Van Meerssche,
M. J . Am. Chem. Soc. 1982, 104, 3929-3934. (b) Aube´, J .; Wang, Y.;
Hammond, M.; Tanol, M.; Takusagawa, F.; Vander Velde, D. J . Am.
Chem. Soc. 1990, 112, 4879-4891. (c) Aube´, J .; Hammond, M.;
Gherardini, E.; Takusagawa, F. J . Org. Chem. 1991, 56, 499-508.
Correction: Idem., Ibid. J . Org. Chem. 1991, 56, 4086.
(10) Aube´, J .; Wolfe, M. S. Bioorg. Med. Chem. Lett. 1992, 2, 925-
928.
(11) Stetin, C.; de J eso, B.; Pommier, J . C. Synth. Commun. 1982,
12, 495-499.

656 J . Org. Chem., Vol. 62, No. 3, 1997
Wolfe et al.
Sch em e 2
Ta ble 2. Oxa zir id in e F or m a tion fr om (S)-Boc-2-Am in ocycloh exa n on e a n d r-Am in o Ester s
entry
amino ester
L-Phe-OMe
D-Phe-OMe
L-Leu-OMe
D-Leu-OMe
L-Val-OMe
L-Asp(OMe)-OMe
R1
CH2Ph
R2
products
yield (%)
ratio
1
2
3
4
5
6
H
10a
72
61
62
60
66
70
>95:5aa
93:7c
H
CH2Ph
12b/13bb
10c/11c
10d /12d
10e/11e/12e
10f + 12f/11f or 13f
CH2CH(CH3)2
H
CH(CH3)2
CH2CO2Me
H
77:23c
CH2CH(CH3)2
50:50a
H
H
48:39:13a,c
57:43a,c
Ratio estimated by 1H NMR. Note that 12b is ent-11a and 13b is ent-10a . c Ratio estimated by separation of isomers.
a
b
information, in combination with the known9,13 preference
for equatorial approach of oxidant to imines derived from
enantiopure 3- and 4-substituted cyclohexanones, pro-
vided a complete stereochemical assignment to 6. In
contrast, condensation of (R)-3-methylcyclohexanone with
D-phenylalanine methyl ester afforded oxaziridine 8 as
the major diastereomer, with photorearrangment yield-
ing 5-methylcaprolactam 9. The clear stereochemical
assignments of oxaziridines 6 and 8 allowed us to assign
the configurations of the oxaziridines in Table 1 by
analogy. The experiments using (R)-3-methylcyclohex-
anone demonstrated that the use of R-amino esters is
compatible with both oxaziridine formation and photo-
rearrangment, providing the desired products in good
yields. Furthermore, no compromise of the amino ester
stereocenter was noted during oxaziridine formation
under the conditions employed. This was evident by the
formation of compounds 6 and 8 as single diastereo-
mers: if the R-center had epimerized, some of the same
products would have been obtained in the two different
experiments. Retention at this stereocenter is essential
for obtaining enantiopure Freidinger lactams.
Condensation between ketone 1a and L-phenylalanine
methyl ester and oxidation via m-CPBA occurred smoothly
to afford a single diastereomeric oxaziridine 10a (Table
2, entry 1). The standard conditions entailed the use of
20 mol % dibutyltin dichloride,11 2 equiv of sodium
bicarbonate, and a high proportion of pulverized 5 Å
molecular sieves. This protocol was found to be impor-
tant both for optimizing the yield of the reaction and for
preventing epimerization of the C-4 (BocNH substituted)
stereocenter. For instance, performing the oxaziridine
synthesis under toluene reflux and without tin catalyst
or bicarbonate led to the formation of diastereomers 10a
and 11a in an essentially 1:1 ratio.
The stereochemical assignments of oxaziridines 10a
and 11a were made by several considerations. One is
that 10a and 11a photorearranged to diastereomeric
lactams 14a and 15a , respectively (Table 3, entries 1 and
2). Therefore, for both 10a and 11a , the lone pair of
electrons on the oxaziridine ring nitrogen is anti to the
migrating C-8 methylene group, and the amino ester
moiety is trans to the bulky Boc-protected amino sub-
stituent as expected. This notion was corroborated by
13C-NMR analysis: the C-8 peaks of both 10a and 11a
have chemical shift values of ca. 27 ppm. Chemical shifts
in this region correlate with carbons anti to the nitrogen
lone pair electrons.15
F or m a tion of F r eid in ger -Typ e Dip ep tid yl La c-
ta m s. We have previously detailed the synthesis of
enantiopure (S)-tert-butoxycarbonyl (Boc)-protected 2-ami-
nocycloalkanones 1 from cycloalkene oxides.14 The key
step of the route is cycloalkene oxide ring opening with
(R)-R-methylbenzylamine and chromatographic separa-
tion of the resulting diastereomeric amino alcohols.
The stereochemical assignment of oxaziridine 11a was
additionally supported by the observation of an unusually
upfield proton (0.42 ppm) in the 1H-NMR spectrum of this
compound. Coupling constants and data from COSY and
(13) Oliveros, E.; Rivie`re, M.; Lattes, A. J . Heterocycl. Chem. 1980,
17, 107-112.
(14) Aube´, J .; Wolfe, M. S.; Yantiss, R. K.; Cook, S. M.; Takusagawa,
F. Synth. Commun. 1992, 22, 3003-3012.
(15) J ordan, G. J .; Crist, D. R. Org. Magn. Reson. 1977, 9, 322-
324.

Stereoselective Synthesis of Freidinger Lactams
J . Org. Chem., Vol. 62, No. 3, 1997 657
F igu r e 2. Proposed conformation of oxaziridine 11a .
HETCOR NMR experiments were consistent with the
notion that this signal comes from the proton bonded to
C-8. This peak is an apparent doublet of triplets, with
two large and coincidentally identical coupling constants
of 12.8 Hz (one axial-axial coupling and one geminal
coupling) and one small coupling constant of 3.7 Hz
(axial-equatorial coupling). In addition, decoupling
experiments revealed that H-4 is axial and, by elimina-
tion, the carbamate substituent is equatorial (the overall
spectrum is consistent with the cyclohexane ring being
in a well-behaved chair conformation). Molecular models
show that only diastereomer 11a , which is expected to
exist largely with the R-H occupying the inside position
shown, can obtain a conformation where the axial H-8 is
shielded via a ring current effect of the phenyl group
(Figure 2). We have previously observed similar shifts
due to anisotropy in a series of oxaziridines derived from
substituted benzylamines.16
F igu r e 3. Stereochemical results of imine oxidation on
substrates derived from D- vs L-phenylalanine.
Ta ble 3. P h otor ea r r a n gem en t of Oxa zir id in es to
F r eid in ger La cta m s
In contrast to oxaziridine formation from ketone 1a
and L-phenylalanine methyl ester, the D-isomer of this
amino ester gave lower yields and some compromise of
the stereocenter at C-3 (Table 2, entry 2; the assignments
were facilitated by the fact that the minor isomer formed
in this experiment was the enantiomer of 10a ). The
model experiments with cyclohexanone and (R)-3-methyl-
cyclohexanone established a clear preference for like
stereochemistry when phenylalanine methyl ester is
employed (Scheme 2). We hypothesize that oxaziridine
formation using ketone 1a and the D-isomer of this amino
ester is disadvantaged by the fact that equatorial attack
(â attack) occurs from the opposite face as like attack (R
attack); i.e., the two stereocontrolling events are mis-
matched (Figure 3a). In contrast, oxaziridine formation
with 1a and L-Phe-OMe methyl ester represents a case
of matched stereocontrol as both equatorial attack and
like attack occur from the â face (Figure 3b). This
mismatching of stereochemistry leads to a lower yield and
compromise of the C-3 stereocenter compared with the
same reaction with the L amino ester.
We drew similar conclusions from analogous experi-
ments with L- versus D-leucine methyl ester. Oxaziri-
dines derived from L-leucine methyl ester were formed
in somewhat lower yields and with considerable compro-
mise of C-3 stereointegrity in comparison with L-phenyl-
alanine methyl ester (Table 2, cf. entries 1 and 3).17
Nevertheless, one major diastereomer formed which
could be readily separated by flash chromatography, and
photorearrangement of the purified 10c provided lactam
14c (Table 3, entry 4). In contrast to L-leucine methyl
yield
entry oxaziridinea
R1
CH2Ph
CH2Ph
H
CH2CH(CH3)2
H
CH(CH3)2
CH(CH3)2
CH2CO2Me
R2
lactamb (%)
1
2
3
4
5
6
7
8
9
10a
11a
12b
10c
H
H
14a
15a
14b
14c
72
63
68
61
59
59
55
44
52
CH2Ph
H
CH2CH(CH3)2 14d
10d /12d
10e/12e
11e
H
H
H
H
14e
15e
15f
14f/15f
10f or 12fc
10f or 12f/11fd CH2CO2Me
a
b
Refer to Table 2 for structures. Except where noted, a single
lactam stereoisomer was obtained, even when mixtures of oxaziri-
dines were reacted (entries 5, 6, and 8). c Minor isomer from Table
d
2, entry 6; N-2 and C-3 configurations not determined. This 2:1
mixture of oxaziridines was inseparable; a 2:1 ratio of lactams
resulted from the photolysis of the mixture.
ester, when the antipodal D-Leu-OMe was used, a 1:1
mixture of diastereomeric oxaziridines was isolated
(Table 2, entry 4). Photorearrangement of this 1:1
mixture (Table 3, entry 5) led to convergence on one
diastereomeric lactam: therefore, the two oxaziridine
diastereomers differ in N-2/C-3 stereochemistry. It ap-
pears that the intrinsic preference of leucine to direct
like attack (Table 1, entry 2) is less able to compete with
this imine’s preference for equatorial attack relative to
the competition observed in the phenylalanine ex-
amples.
(16) Usuki, Y.; Wang, Y.; Aube´, J . J . Org. Chem. 1995, 60, 8028-
8035.
(17) The stereochemical assignment of these other oxaziridines
(Table 2, entries 3-6) was not determined as rigorously as those
derived from L- and D-phenylalanine methyl ester. The assignments
were determined using the following information: (1) the predominance
of one diastereomer, (2) the convergence of some to identical lactams,
and (3) analogy with results from L-Phe-OMe.
As previously observed with cyclohexanone, oxaziridine
formation from 1a and L-aspartate dimethyl ester dis-
played no clear stereochemical preference (Table 2, entry
6). While a minor diastereomer could be chromatographi-

658 J . Org. Chem., Vol. 62, No. 3, 1997
Wolfe et al.
Sch em e 3
cally purified and photorearranged to a single diastereo-
meric lactam (Table 3, entry 8), the bulk of the oxaziri-
dines could not be separated and gave a mixture of two
diastereomeric lactams upon photorearrangement (Table
3, entry 9). Hence, the C-4 stereocenter was almost
completely compromised during oxaziridine synthesis
from this functionalized amino ester. It should be
mentioned that glycine esters gave atypical (and, thus
far, uninterpretable) results when oxaziridine syntheses
from 1a were attempted. However, the synthesis of the
corresponding lactams of various ring sizes have been
previously reported. Because of the absence of stereo-
chemistry in glycine, such substituents can be easily
incorporated into Freidinger lactams by coupling N-
unsubstituted lactams with R-haloacetate esters (e.g., see
Thorsett et al.6d).
F igu r e 4. Ball-and-stick depictions of X-ray crystallographic
structures of (a) 14a and (b) 17.
Condensation of L-phenylalanine methyl ester and
enantiopure cycloheptanone 1b (Scheme 3) required
larger amounts of tin catalyst to form the imines needed
for the subsequent oxidation (almost a full equivalent was
used). Even still, the oxaziridines 16 were isolated in
only modest yield, although most of the remaining ketone
1b could be recovered. The 2:1 ratio of diastereomeric
oxaziridines converged onto a single lactam (17) upon
photorearrangement. Therefore, the oxaziridines differ
in N-2/C-3 stereochemistry, and the oxidant approach is
less selective compared with the corresponding reaction
using cyclohexanone 1a (cf. Table 2, entry 1). Neverthe-
less, the formation of these oxaziridines and their photo-
rearrangement to ú-lactam 17 is significant because
lactams of this size are difficult to obtain by other
methods.18 All attempts to form oxaziridines from cyclo-
octanone 1c and L-phenylalanine methyl ester failed,
even under forcing conditions (toluene reflux in the
presence of tin catalyst).
Overall, photorearrangement of the dipeptidyl oxaziri-
dines to Freidinger-type lactams proceeds in moderate
to good yields, resulting in essentially one regioisomer
(i.e., 3-substituted lactams). In many cases racemic
ketone can be used, and subsequent separation of the
resultant diastereomeric oxaziridines and photo-
rearrangement provides stereodefined dipeptidyl lactams.
Con for m a tion a l An a lysis of Dip ep tid yl La cta m s
14a a n d 17. The conformation of ꢀ-lactam 14a was
investigated by NMR and X-ray crystallography. 1H-
NMR decoupling experiments revealed that H-3 prefers
the axial position in solution (CDCl3), indicating that the
F igu r e 5. Effect of CR stereochemistry on ACE inhibition.
BocNH substituent is oriented equatorially and that the
caprolactam is a well-behaved chairlike entity. Other
coupling information gleaned from a COSY spectrum was
consistent with this assumption. Unfortunately, 2-D
NOESY experiments did not show any proximity between
protons on the phenylalanine substructure and those of
the lactam ring. Such information would have been
useful in determining the preferred rotamer about the
N-CR bond (φ2). However, an X-ray crystallographic study
of 14a revealed φ2 ) +61°, φ1 ) +139°, and ψ1 ) -175°
(Figure 4a). Similarly, crystallographic studies on ú-lac-
tam 17 confirmed a “lawn-chair” conformation for the
eight-membered ring and indicated φ2 ) +63°, φ1
)
+142°, and ψ1 ) -158° (Figure 4b). It is interesting that
both molecules adopted such similar conformations with
respect to the side chains.
F or m a tion of P oten tia l ACE In h ibitor s. ACE is a
proven target for the treatment of hypertension and
congestive heart failure.19 Like many clinically used ACE
inhibitors (e.g., captopril and enalapril), Freidinger-type
lactams such as 18 inhibit ACE well into the nanomolar
range.6b As shown in Figure 5, the potency of derivatives
bearing methyl substitution at CR (19 and 20) depend
on the configuration of that stereocenter.6b The original
syntheses of compounds 18-20 led to mixtures of stereo-
isomers which were resolved to isolate the bioactive
diastereomers in racemic form. Resolution of the eight-
(18) Evans, P. A.; Holmes, A. B.; Russell, K. Tetrahedron Lett. 1992,
33, 6857-6858.
(19) Kostis, J . B.; DeFelice, E. A. Angiotensin-Converting Enzyme
Inhibitors; Alan R. Liss: New York, 1987.

Stereoselective Synthesis of Freidinger Lactams
J . Org. Chem., Vol. 62, No. 3, 1997 659
Sch em e 4
Con clu sion s. The synthetic methodology described
here is useful for obtaining seven- and eight-membered
Freidinger lactams. Although the synthesis of the chiral
spirocyclic oxaziridine intermediates often leads to the
formation of more than one diastereomer, in many cases
chromatographic separation provides
a single dia-
stereomer that can undergo photorearrangement to a
stereodefined lactam. In some cases, the diastereomeric
oxaziridines need not be separated since they converge
upon the same lactam. A variety of substituents can be
installed adjacent to the ring nitrogen by the simple
expedient of using the appropriate R-amino ester in the
oxaziridine formation.
Exp er im en ta l Section
Gen er a l Meth od s. Chemical shifts are expressed in parts
per million (δ) relative to tetramethylsilane with either TMS
or residual solvent as an internal reference. Optical rotations
were measured at ambient temperature; concentrations are
reported in g/100 mL. Melting points were taken on a Thomas-
Hoover melting point apparatus and are uncorrected. Ele-
mental analyses were performed in-house. Column chroma-
tography was carried out with 230-400 mesh silica gel.
Except where noted, all starting materials were purchased
from Aldrich or Sigma Chemical Co. and used as received. The
(S)-tert-butoxycarbonyl (Boc)-protected 2-aminocycloalkanones
(1a -c) were prepared as previously reported.14
Gen er a l P r oced u r e for th e Syn th esis of Oxa zir id in es.
To a solution of ketone (1.0 equiv) in 5 mL of toluene (stored
over 5 Å molecular sieves) was added 2.0 equiv of NaHCO3,
crushed 5 Å molecular sieves (250 mg/100 mg ketone), amino
ester (4.2 equiv), and 20 mol % of Bu2SnCl2. The suspension
was sealed under N2, stirred for 3-20 h at room temperature,
and then transferred via a wide-bore cannula to a -78 °C
suspension of m-CPBA (1.5 equiv) in toluene. After 30 min
the suspension was allowed to warm to ambient temperature,
whereupon it was quenched with 10% aqueous Na2S2O3
solution, diluted with Et2O, and washed with saturated
NaHCO3 solution and saturated NaCl solution. After drying
over Na2SO4 and concentration, the oil was chromatographed
using flash silica gel and ethyl acetate/hexane mixtures
ranging from 5:1 to 3:1 as eluent.
membered lactam corresponding to 18 identified the S,S
isomer as the better inhibitor (IC50 ) 2 nM).6b The
additional sterogenic center in 19 and 20 makes the task
of stereoselective synthesis more challenging. To il-
lustrate the utility of our chemistry toward the synthesis
of new stereodefined Freidinger-type lactams of potential
biological interest, we synthesized new CR-substituted
lactams (R ) i-Bu or Bn). These particular substituents
were chosen as prototypes to address the question of
whether adding a hydrophobic group would increase
potency by improving interaction with the S2′ binding
site of the enzyme.
The synthesis of these compounds from lactams 14a -d
was accomplished according to the method of Attwood
et al. as depicted in Scheme 4.20 After deprotection of
14 with TFA, the 3-amino group was alkylated with the
triflate derivative of ethyl (R)-2-hydroxy-4-phenyl-
butyrate to form 21 as a single diastereomer in 52-66%
yield. Ester hydrolysis under basic conditions afforded
the final compounds 22.
These compounds were tested for their ability to inhibit
purified ACE isolated from rabbit lung.21 The IC50 value
for 22c was 165 nM, while those for compounds 22a , 22b,
and 22d were >200 nM. The benzyl-substituted com-
pounds 22a and 22b were completely ineffective at the
highest concentration tested (200 nM); isobutyl-substi-
tuted 22d displayed 16% inhibition at this concentration
(two experiments). It is clear that the additional steric
bulk at the CR adjacent to the ring nitrogen has a
detrimental effect on inhibitory activity: compounds
22a -d are all significantly less active than 18-20, and
the four-carbon isobutyl group is tolerated better than
the seven-carbon benzyl group. This finding is consistent
with a recent report for a series of closely related
(mercaptoacetyl)-3-amino-ꢀ-lactams.6i Whereas methyl
substitution at CR adjacent to the ring nitrogen with S
stereochemistry was well-tolerated, benzyl or isopropyl
substitution resulted in a 20- to 40-fold increase in the
IC50 value. In addition, our finding that 22c is more
active than 22d confirms the observation made with
methyl-substituted compounds 19 and 20 that S stereo-
chemistry at the CR position is preferred over R stereo-
chemistry for ACE binding.6b
(2R,rS)-1′-(P h en ylm eth yl)-1-oxa -2-a za spir o[2.5]octa n e-
2-a cetic Acid Meth yl Ester (4a ). According to the general
procedure, cyclohexanone (0.500 g, 5.1 mmol) was allowed to
react with L-phenylalanine methyl ester (3.76 g, 21 mmol),
followed by m-CPBA (1.29 g, 7.58 mmol). Column chroma-
tography with 40% ethyl acetate/hexane afforded the title
compound as an oil (1.08 g, 79%): [R]D ) -54.7 (c 1.1, CHCl3);
IR (neat) 2910, 2840, 1745, 1490 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 0.71 (m, 1H), 1.08 (m, 1H), 1.39-1.67 (m, 8H), 3.12
(dd, J ) 9.0, 16 Hz, 1H), 3.15 (dd, J ) 5.1, 16 Hz, 1H), 3.53
(dd, J ) 5.2, 9.0 Hz, 1H), 3.78 (s, 3H), 7.18-7.30 (m, 5H); 13
C
NMR (125.8 MHz, CDCl3) δ 23.7, 24.4, 25.0, 27.5, 35.5, 37.2,
52.4, 65.6, 86.5, 127.1, 128.5, 129.4, 136.3, 170.0; MS (CI) m/ e
276 (M+ + 1). Anal. Calcd for C16H21NO3: C, 69.79; H, 7.68;
N, 5.08. Found: C, 69.78; H, 7.89; N, 5.00.
(2R,rS)-1′-(2-Meth ylpr opyl)-1-oxa-2-azaspir o[2.5]octan e-
2-a cetic Acid (4b) a n d (2S,rS) d ia ster eom er (5b). Ac-
cording to the general procedure, cyclohexanone (1.0 g, 10.02
mmol) was allowed to react with L-leucine methyl ester (6.09
g, 42.8 mmol) followed by m-CPBA (2.63 g, 15.3 mmol).
Column chromatography with 40% ethyl acetate/hexane af-
forded a major isomer (1.2 g, 50%, Rf ) 0.60) and a minor
isomer (0.15 g, 6%, Rf ) 0.65), both as oils. Major isomer (4b):
[R]D ) -38.7 (c 3.6, CHCl3); IR (neat) 2930, 2840, 1740, 1640
(20) Attwood, M. R.; Hassall, C. H.; Kro¨hn, A.; Lawton, G.; Redshaw,
S. J . Chem. Soc., Perkin Trans. 1 1996, 1011-1019.
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H),
(21) (a) Performed according to: Cushman, D. W.; Cheung, H. S.
Biochem. Pharmacol. 1971, 20, 1637-1648. (b) ACE isolated from
rabbit lung, substrate hippuryl-His-Leu, and captopril were obtained
from Sigma (St. Louis, MO). Due to the insolubility of 8a -d in water,
ethanol was used as a cosolvent (final concentration 0.2%). The IC50
value for captopril was determined to be 38 nM without ethanol and
48 nM with 0.2% ethanol (lit. value21a ) 23 nM).
0.94 (d, J ) 6.5 Hz, 3H), 1.37-1.5 (m, 2H), 1.55-1.84 (m, 10H),
1.88-1.95 (m, 1H), 3.36 (dd, J ) 4.5, 9.5 Hz, 1H), 3.79 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 22.1, 23.3, 24.0, 24.8, 25.2, 25.2,
27.9, 36.1, 39.2, 52.2, 63.6, 85.8, 171.8; MS (CI) m/ e 242 (M+
+ 1). Anal. Calcd for C13H23NO3: C, 64.70; H, 9.60; N, 5.80.
Found: C, 64.31; H, 9.89, N, 6.10. Minor isomer (5b): IR

660 J . Org. Chem., Vol. 62, No. 3, 1997
Wolfe et al.
(neat) 2920, 2840, 1745, 1660 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.91 (d, J ) 6.9 Hz, 3H), 0.93 (d, J ) 6.3 Hz, 3H), 1.25-2.01
(m, 13H), 3.35 (t, J ) 6.0 Hz, 1H), 3.74 (s, 3H); 13C NMR (74.5
MHz, CDCl3) δ 22.4, 23.2, 24.4, 25.0, 25.1, 25.6, 28.5, 36.3,
42.5, 52.3, 64.0, 85.0, 171.7; MS (EI) m/ e 242 (M+ + 1). Anal.
Calcd for C13H23NO3: C, 64.70; H, 9.60; N, 5.80. Found: C,
64.40; H, 10.00; N, 5.98.
(2R,rS)-1′-(1-Meth yleth yl)-1-oxa -2-a za sp ir o[2.5]octa n e-
2-a cetic Acid Meth yl Ester (4c). According to the general
procedure, cyclohexanone (0.250 g, 2.5 mmol) was allowed to
react with L-valine methyl ester (1.37 g, 10.5 mmol), followed
by m-CPBA (0.64 g, 3.75 mmol). Column chromatography
with 40% ethyl acetate/hexane afforded the title compound
(0.466 g, 82%) as an oil: [R]D ) -63.5 (c 2.2, CHCl3); IR (neat)
2920, 2840, 1745, 1660, 1430 cm-1; 1H NMR (500 MHz, CDCl3)
δ 0.99 (d, J ) 9.9 Hz, 3H), 1.01 (d, J ) 9.9 Hz, 3H), 1.39 (m,
2H), 1.58-1.85 (m, 8H), 2.22 (m, 1H), 3.13 (d, J ) 7.6 Hz, 1H),
3.79 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 19.0, 19.5, 23.8,
24.5, 25.1, 28.6, 30.6, 35.6, 51.9, 69.5, 86.7, 170.8; MS (CI) m/ e
228 (M+ + 1). Anal. Calcd for C12H21NO3: C, 63.40; H, 9.31;
N, 6.15. Found: C, 63.28; H, 9.50; N, 6.08.
J ) 7.10 Hz, 1H), 3.70 (s, 3H), 3.73 (m, 1H), 5.00 (brs, 1H),
7.17-7.34 (m, 5H); 13C NMR (74.5 MHz, CDCl3) δ 23.4, 23.7,
27.4, 28.3, 32.1, 37.4, 52.3, 65.6, 79.2, 85.3, 127.2, 128.7, 129.2,
135.7, 156.3, 170.2; MS (EI) m/ e 391 (M+ + 1). Anal. Calcd
for C21H30N2O5: C, 64.59; H, 7.74; N, 7.17. Found: C, 64.30;
H, 8.00; N, 6.78.
(2R,3R,4S,rR)-4-[[(1,1-Dim eth yleth oxy)car bon yl]am in o]-
r-(p h en ylm et h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e-2-a cet ic
Acid Meth yl Ester (12b). According to the general proce-
dure, 1a (0.906 g, 4.25 mmol) was allowed to react with
D-phenylalanine methyl ester (3.18 g, 17.8 mmol) followed by
m-CPBA (1.08 g, 6.37 mmol). Column chromatography with
25% ethyl acetate/hexane provided 12b (0.940 g, 57%): [R]D
) -44.8 (c 1.5, CHCl3); IR (CHCl3) 3415, 3000, 2990, 2940,
1795, 1700 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.42 (app td, J
) 12.8, 3.7, 1H), 1.20-1.46 (m, 4H), 1.50 (s, 9H), 1.69 (m, 2H),
2.01 (m, 1H), 3.01-3.19 (m, 2H), 3.50 (dd, J ) 4.6, 9.2 Hz,
1H), 3.6 (m, 1H), 3.81 (s, 3H), 4.63 (d, J ) 8.4 Hz, 1H), 7.20-
7.50 (m, 5H); 13C NMR (75.4 MHz, CDCl3) δ 24.4, 24.5, 27.5,
28.8, 31.8, 37.3, 51.1, 52.5, 65.9, 77.3, 85.8, 127.5, 127.6, 129.0,
130.0, 156.4, 171.1; MS (EI) m/ e 391 (M+ + 1). Anal. Calcd
for C21H30N2O5: C, 64.59; H, 7.74; N, 7.17. Found: C, 64.30;
H, 7.89; N, 7.30. Another isomer (13b) was also isolated in
4% yield with spectra identical to 10a (i.e., 13b is the antipode
of 10a ).
(2S,3S,4S,rS)-4-[[(1,1-Dim eth yleth oxy)car bon yl]am in o]-
r-(2-m e t h y lp r o p y l)-1-o x a -2-a z a s p i r o [2.5]o c t a n e -2-
a cetic Acid Meth yl Ester (10c) a n d Isom er 11c. According
to the general procedure, 1a (0.602 g, 2.8 mmol) was allowed
to react with L-leucine methyl ester (1.69 g, 11.76 mmol),
followed by m-CPBA (0.722 g, 4.2 mmol). Column chroma-
tography with 1:5 ethyl acetate/hexane provided 10c (0.475
g, 49%) as an oil: [R]D ) -22.1 (c 1.7, CHCl3); IR (neat) 3450,
2920, 2840, 1740, 1700, 1600 cm1; 1H NMR (300 MHz, CDCl3)
δ 0.94 (d, J ) 4.2 Hz, 3H), 0.95 (d, J ) 4.2 Hz, 3H), 1.12-2.30
(m, 11H), 1.42 (s, 9H), 3.37 (dd, J ) 3.6, 10.5 Hz, 1H), 3.72 (br
d, 1H), 3.79 (s, 3H), 5.07 (d, J ) 6.9 Hz, 1H); 13C NMR (74.5
MHz, CDCl3) δ 22.3, 23.8, 24.2, 24.9, 25.8, 27.9, 28.8, 33.1,
39.9, 52.6, 52.7, 63.5, 79.6, 85.2, 156.0, 171.6; MS (EI) m/ e
357 (M+ + 1). Anal. Calcd for C18H32N2O5: C, 60.64, H; 8.97;
N, 7.86. Found: C, 60.30; H, 9.18; N, 7.48. The minor isomer
11c was also isolated (0.142 g, 14%) as an oil: 1H NMR (300
MHz, CDCl3) δ 0.91 (br d, 6H), 1.28-2.15 (m, 11H), 1.44 (s,
9H), 3.35 (dd, J ) 5.0, 9.1 Hz, 1H), 3.78 (m, 4H), 4.59 (br d, J
) 7.2 Hz, 1H); 13C NMR (74.5 MHz, CDCl3) δ 22.2, 23.1, 24.2,
24.4, 25.1, 27.6, 28.3, 31.1, 38.7, 51.6, 52.1, 63.3, 79.0, 84.8,
156.2, 171.5.
1′-[1-Oxa -2-a za sp ir o[2.5]oct-2-yl]bu ta n ed ioic Acid Di-
m eth yl Ester (4d /5d ). According to the general procedure,
cyclohexanone (0.500 g, 5.1 mmol), was allowed to react with
L-aspartic acid dimethyl ester (0.850 g, 10 mmol) followed by
m-CPBA (1.29 g, 7.5 mmol). Column chromatography with
40% ethyl acetate/hexane afforded a less polar isomer 1 (Rf )
0.70, 0.687 g, 52%) and a more polar isomer 2 (Rf ) 0.44, 0.597
g, 45%). Isomer 1: [R]D ) -33.2 (c 0.7, CHCl3); IR (neat) 2935,
1
2800, 1745, 1695 cm-1; H NMR (300 MHz, CDCl3) δ 1.29-
2.01 (m, 10H), 2.87 (dd, J ) 4.9, 16.4 Hz, 1H), 3.04 (dd, J )
7.3, 16.4 Hz, 1H), 3.72 (s, 3H) 3.78 (s, 3H), 3.76-3.80 (m, 1H);
13C NMR (75.4 MHz, CDCl3) δ 24.3, 24.7, 25.5, 28.5, 36.2, 36.5,
52.4, 53.0, 61.2, 87.2, 169.4, 171.5; MS (EI) m/ e 258 (M+ + 1).
Anal. Calcd for C12H19NO5: C, 56.01; H, 7.44; N, 5.44.
Found: C, 56.07; H, 7.80; N, 5.28. Isomer 2: [R]D ) -24.1 (c
1
1.0, CHCl3); IR (neat) 2940, 2835, 1740, 1695 cm-1; H NMR
(300 MHz, CDCl3) δ 1.29-1.88 (m, 10H), 2.69 (dd, J ) 5.4,
16.4 Hz, 1H), 2.99 (dd, J ) 8.0, 16.4 Hz, 1H), 3.71 (s, 3H),
3.73 (m, 1H), 3.82 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 25.1,
25.4, 25.5, 28.3, 35.2, 36.1, 52.6, 53.1, 60.9, 86.3, 170.4, 170.7;
MS (CI) m/ e 258 (M+ + 1). Anal. Calcd for C12H19NO5: C,
56.01; H, 7.44; N, 5.44. Found: C, 55.89; H, 7.19; N, 5.09.
1′-[(Ben zyloxy)m eth yl]-1-oxa -2-a za sp ir o[2.5]octa n e-2-
a cetic Acid Meth yl Ester (4e/5e). According to the general
procedure, cyclohexanone (0.100 g, 1.02 mmol) was allowed
to react with O-benzyl-L-serine methyl ester (0.84 g, 4.42
mmol) followed by m-CPBA (0.263 g, 1.53 mmol). Column
chromatography with 25% ethyl acetate/hexane provided the
less polar isomer 1 (Rf ) 0.60, 0.083 g, 27%) and the more
polar isomer 2 (Rf ) 0.48, 0.124 g, 40%) as yellow oils. Isomer
1: IR (neat) 2910, 2850, 1740, 1447 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.25-1.85 (m, 10H), 3.48 (t, J ) 4.5 Hz, 1H), 3.76 (s,
3H), 3.89 (m, 2H), 4.65 (AB q, J ) 12.3 Hz, Dn ) 42.6 Hz,
2H), 7.26-7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 24.0,
24.5, 25.1, 27.8, 35.8, 52.2, 65.4, 69.7, 73.5, 85.5, 127.6, 127.7,
128.3, 137.7, 168.9; MS (CI) m/ e 306 (M+ + 1), HRMS calcd
for (M+ + 1) C17H24NO4: 306.1705, found 306.1715. Isomer 2:
[R]D -22.9 (c 0.9, CHCl3), IR (neat) 2920, 2840, 1740, 1445
(2SR,3SR,4S,rR )-4-[[(1,1-Dim et h ylet h oxy)ca r b on yl]-
a m in o]-r-(2-m eth ylp r op yl)-1-oxa -2-a za sp ir o[2.5]octa n e-
2-a cetic Acid Meth yl Ester (10d /12d ). According to the
general procedure, 1a (1.0 g, 4.6 mmol) was allowed to react
with D-leucine methyl ester (2.75 g, 19.3 mmol) followed by
m-CPBA (1.20 g, 6.9 mmol). Column chromatography with
40% ethyl acetate/hexane afforded the title compound as a
1
mixture of diastereomers as determined by H-NMR integra-
tion (ca. 1:1 ratio of isomers, 1.02 g, 60%). Isomer 1: For
analytical purposes, a pure sample of this isomer could be
obtained by careful chromatography. IR (neat) 3451, 2910,
2820, 2840, 1740, 1700, 1600 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.91 (d, J ) 6.6 Hz, 3H), 0.95 (d, J ) 6.0 Hz, 3H), 1.21-2.23
(m, 11H), 1.44 (s, 9H), 3.36 (m, 1H), 3.73 (s, 3H), 3.80 (m, 1H),
4.60 (d, 3.6 Hz, 1H): 13C NMR (74.5 Hz, CDCl3) δ 22.0, 22.8,
23.9, 24.3, 24.6, 25.1, 27.8, 28.2, 31.2, 51.2, 52.0, 63.1, 78.8,
84.7, 155.9, 171.5. Anal. Calcd for C18H32N2O5: C, 60.64; H,
8.97; N, 7.86. Found: C, 60.29; H, 8.70; N, 7.48. Isomer 2:
1H NMR (diagnostic peaks only, 300 MHz, CDCl3) δ 0.90 (d, J
) 6.6 Hz, 3H), 0.94 (d, J ) 6.3 Hz, 3H), 1.42 (s, 9H), 3.78 (s,
3H): 13C NMR (74.5 MHz, CDCl3) δ 22.2, 23.1, 24.2, 24.3, 24.5,
25.3, 27.8, 31.0, 51.5, 52.2, 63.2, 78.8, 84.1, 156.0, 170.3; MS
(CI) m/ e 357 (M+ + 1).
1
cm-1; H NMR (500 MHz, CDCl3) δ 1.25-1.89 (m, 10H), 3.65
(dd, J ) 4.8, 7.4 Hz, 1H), 3.79 (s, 3H), 3.81-3.83 (m, 2H), 4.53
(s, 2H), 7.29-7.35 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 23.7,
24.1, 24.9, 28.2, 35.6, 52.3, 64.3, 68.3, 73.3, 86.1, 127.5, 127.6,
128.1, 137.1, 169.3; MS (CI) m/ e 306 (M+ + 1); HRMS calcd
for (M+ + 1) C17H24NO4: 306.1705, found: 306.1688.
(2S,3S,4S,rS)-4-[[(1,1-Dim eth yleth oxy)car bon yl]am in o]-
r-(p h en ylm et h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e-2-a cet ic
Acid Meth yl Ester (10a ). According to the general proce-
dure, 1a (0.250 g, 1.15 mmol) was allowed to react with
L-phenylalanine methyl ester (0.800 g, 4.92 mmol), followed
by m-CPBA (0.290 g, 1.71 mmol). Column chromatography
with 25% ethyl acetate/hexane provided the title compound
(0.180 g, 72%): [R]D ) -50.8 (c 1.5, CHCl3); IR (CHCl3) 3420,
(2S,3S,4S,rS)-4-[[(1,1-dim eth yleth oxy)car bon yl)am in o]-
r-(1-m et h ylet h yl)-1-oxa -2-a za sp ir o[2.5]oct a n e-2-a cet ic
Acid Meth yl Ester (10e), th e (2S,3S,4R,rS) d ia ster eom er
11e, a n d th e (2R,3R,4S,rS) Dia ster eom er 12e. According
to the general procedure, 1a (0.500 g, 2.3 mmol) was allowed
to react with L-valine methyl ester (1.26 g, 9.6 mmol) followed
3000, 2950, 1790, 1700 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.01-1.21 (m, 2H), 1.44 (s, 9H), 1.45-2.39 (m, 6H), 3.05 (dd,
J ) 6.8, 13.6 Hz, 1H), 3.26 (dd, J ) 7.3, 13.2 Hz, 1H), 3.56 (t,

Stereoselective Synthesis of Freidinger Lactams
J . Org. Chem., Vol. 62, No. 3, 1997 661
by m-CPBA (0.593 g, 3.4 mmol). Column chromatography
with 40% ethyl acetate/hexane afforded a less polar isomer
11e (Rf ) 0.65, 0.208 g, 26%) and a more polar, inseparable
mixture of isomers 10e and 12e (Rf ) 0.53, 0.312 g, 40%, ratio
of isomers 10e:12e ca. 4-5:1) as oils. 11e: [R]D ) -12.0 (c
[2R ,3S ,5R ,rR ]-5-Me t h yl-r-(p h e n ylm e t h yl)-1-oxa -2-
a za sp ir o[2.5]octa n e-2-a cetic Acid Meth yl Ester (8) a n d
Isom er . (R)-3-Methylcyclohexanone (1.1 g, 10 mmol) was
allowed to react with D-phenylalanine methyl ester (2.52 g,
14 mmol). Column chromatography with 40% ethyl acetate/
hexane afforded the title compound (Rf ) 0.60 (20% ethyl
1
2.5, CDCl3); IR (neat) 3390, 2910, 2840, 1730, 1700 cm-1; H
NMR (300 MHz, CDCl3) δ 0.96 (d, J ) 9.0 Hz, 3H), 0.99 (d, J
) 9.1 Hz, 3H), 1.20-2.30 (m, 9H), 3.12 (d, J ) 7.2 Hz, 1H),
3.77 (s, 3H), 3.82-3.87 (m, 1H), 4.62 (br d, J ) 9.0 Hz, 1H);
13C NMR (74.5 MHz, CDCl3) δ 19.1, 19.4, 19.6, 24.4, 24.6, 24.7,
31.1, 31.5, 51.6, 52.3, 69.7, 79.4, 86.3, 156.7, 171.2; MS (EI)
m/ e 343 (M+ + 1). Anal. Calcd for C17H30N2O5: C, 59.62; H,
8.83; N, 8.18. Found: C, 59.96; H, 9.20; N,7.80. 10e: IR (neat)
3410, 3000, 2900, 1740, 1700 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.02 (d, J ) 13.8 Hz, 3H), 1.12-2.30 (m, 9H), 1.43 (s, 9H),
1.70 (d, J ) 14.1 Hz, 3H), 3.17 (d, J ) 7.2 Hz, 1H), 3.76 (s,
3H), 3.81 (m, 1H), 5.09 (d, J ) 7.2 Hz, 1H); 13C NMR (74.5
MHz, CDCl3) δ 19.5, 19.7, 24.8, 28.8 (2C), 31.1, 31.6, 51.9, 52.2,
69.2, 79.2, 85.1, 155.6, 169.7; MS (CI) m/ e 343 (M+ + 1). Anal.
Calcd for C17H30N2O5: C, 59.62; H, 8.83; N, 8.18. Found: C,
60.00, H, 8.83; N, 8.23. 12e (diagnostic peaks only): 1H NMR
(300 MHz, CDCl3): δ 3.14 (d, J ) 5.1 Hz, 1 H), 3.72 (s, 3 H);
13C NMR (74.5Hz, CDCl3) δ 18.7, 24.2, 27.7, 50.2, 70.3.
(2S,3S,4S,rS)-4-[[(1,1-Dim eth yleth oxy]car bon yl]am in o]-
1-oxa -2-a za sp ir o[2.5]oct-2-yl]-bu ta n ed ioic a cid d im eth yl
ester (10f), th e (2R,3R,4S,rS) Dia ster eom er (12f), a n d a
(4R,rS) Dia ster eom er (11f or 13f). According to the general
procedure, 1a (0.500 g, 2.3 mmol) was allowed to react with
L-aspartic acid dimethyl ester (1.55 g, 9.6 mmol) followed by
m-CPBA (0.593 g, 3.4 mmol). Column chromatography with
40% ethyl acetate/hexane afforded a less polar, inseparable
mixture of 10f and 40% ethyl acetate/hexane (Rf ) 0.41, 0.471
g, 55%, isomer 1:2 ca. 2-3:1) and a more polar isomer 3 (Rf )
0.25, 0.083 g, 9%) as oils. 10f and 12f: IR (neat) 3460, 3440,
2940, 2820, 1740, 1720 cm-1; MS (EI) m/ e 373 (M+ + 1) HRMS
calcd for (M+ + 1) C17H28N2O7: 373.1915, found 373.1967. 10f:
1H NMR (300 MHz, CDCl3) δ 1.24-2.14 (m, 8H), 1.42 (s, 9H),
2.74-3.12 (m, 2H), 3.67-3.86 (m, 2H), 3.71 (s, 3H), 3.78 (s,
3H), 4.49 (d, J ) 7.3 Hz, 1H); 13C NMR (74.5 MHz, CDCl3,
diagnostic peaks only) δ 23.4, 24.0, 28.3, 32.0, 36.2, 52.1, 52.6,
60.1, 155.7, 169.0, 170.9. 12f (diagnostic peaks only): 1H NMR
(300 MHz, CDCl3) δ 1.40 (s, 9H), 3.76 (s, 3H), 4.52 (br d, 1H);
13C NMR (74.5 MHz, CDCl3) δ 23.9, 24.3, 31.3, 35.9, 60.6,
156.0, 168.2, 171.1. 11f or 13f: IR (neat) 3440, 3330, 2930,
acetate/hexane), 2.62 g, 93%) as an oil: [R]D +83.1 (c 2.4,
)
1
CDCl3); IR (neat) 3100, 2940, 1700, 1600 cm-1; H NMR (300
MHz, CDCl3) δ 0.90 (d, J ) 6.6 Hz, 3H), 1.02 (m, 1H), 1.18-
1.81 (m, 8H), 3.09 (dd, J ) 7.3, 13.6 Hz, 1H), 3.21 (dd, J )
13.6, 6.5), 3.50 (t, J ) 7.10 Hz, 1H), 3.73 (s, 3H), 7.12-7.30
(m, 5H); 13C NMR (74.5 MHz, CDCl3) δ 21.9, 22.7, 30.9, 33.3,
35.5, 35.9, 37.9, 52.6, 66.8, 86.8, 127.5, 129.0, 129.7, 136.6,
171.1; MS (EI) m/ e 290 (M+ + 1); HRMS calcd for C17H24NO3:
290.1756, found 290.1763. A m in or isom er was obtained as
an oil (Rf ) 0.68 (20% ethyl acetate/hexane), 0.260 g, “9%”,
neither purified nor fully characterized): 1H NMR (300 MHz,
CDCl3) δ 0.95 (d, J ) 6.5 Hz, 3H), 1.00 (m, 1H), 1.22-1.90 (m,
8H), 3.25 (apparent d, 2H), 3.46 (t, J ) 6.8 Hz, 3H), 3.65 (s,
3H), 7.22-7.32 (m, 5H).
(2SR,3SR,4S,rS)-4-[[(1,1-Dim et h ylet h oxy)ca r b on yl]-
a m in o]-r-(p h en ylm eth yl)-1-oxa -2-a za sp ir o[2.5]n on a n e-2-
a cetic Acid (16). According to the general procedure, ketone
1b (0.262 g, 0.65 mmol) was reacted with L-phenylalanine
methyl ester (0.800 g, 2.60 mmol) with dibutyltin dichloride
(173 mg, 0.57 mmol, 87 mol %), followed by m-CPBA (0.262 g,
0.65 mmol). Column chromatography with 40% ethyl acetate/
hexane afforded 16, as an inseparable mixture of diastereo-
mers (major:minor 1.8:1, 0.120 g, 46%). Major isomer: 1H
NMR (300 MHz, CDCl3) δ 1.00-1.41 (m, 2H), 1.42 (s, 9H),
1.43-2.10 (m, 8H), 3.04 (dd, J ) 6.9, 13.5 Hz, 1H), 3.22 (m,
1H), 3.56 (t, J ) 6.9 Hz, 1H), 3.71 (s, 3H), 3.81 (m, 1H), 5.15
(d, J ) 3.9 Hz, 1H), 7.15-7.40 (m, 5H); 13C NMR (74.5 MHz,
CDCl3) δ 22.6, 23.4, 26.7, 28.3, 29.7, 32.1, 37.1, 52.3, 53.6, 65.4,
79.1, 86.1, 128.1, 129.3, 129.6, 135.6, 158.2, 170.4; MS (CI)
m/ e 405 (M+ + 1). Anal. Calcd for C22H32N2O5: C, 65.32; H,
7.97; N, 6.93. Found: C, 65.03; H, 8.30; N, 6.80. Minor isomer
(diagnostic peaks only): 1H NMR (300 MHz, CDCl3) δ 3.30
(dd, J ) 6.9, 13.5 Hz, 1H), 3.15 (dd, J ) 6.3, 15.6 Hz, 1H),
3.49 (t, J ) 6.6 Hz, 1H), 3.64 (s, 3H), 4.90 (d, J ) 6.0 Hz, 1H).
Gen er a l P r oced u r e for La cta m Syn th esis. The oxaziri-
dine was dissolved in benzene (0.05-0.10 M) and placed in a
quartz photolysis tube. The solution was degassed by bubbling
nitrogen through it for 45 min and then photolyzed in a
Rayonet (merry-go-round) chamber at 254 nm for 2-4 h.
(3S ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -r-(p h e n y lm e t h y l)-2-o x o -1H -a z e p i n e -1-
a cetic Acid Meth yl Ester (14a ). Oxaziridine 10a (0.260 g,
0.66 mmol) was photolyzed for 4 h. Concentration followed
by column chromatography with 40% ethyl acetate/hexane
yielded 14a as a white solid (0.187 g, 72%): mp 108 °C; [R]D
) -57.0 (c 0.52, CHCl3); IR (CHCl3) 3400, 3000, 2900, 1740,
1
2440, 1740, 1720 cm-1; H NMR (300 MHz, CDCl3) δ 1.20-
2.20 (m, 8H), 1.42 (s, 9H), 2.70 (dd, J ) 5.1, 16.7 Hz, 1H), 3.70
(dd, J ) 8.3, 16.6 Hz, 1H), 3.68-3.72 (m, 2H), 3.70 (s, 3H),
3.80 (s, 3H), 4.89 (d, J ) 7.8 Hz, 1H); 13C NMR (74.5 MHz,
CDCl3) δ 23.2, 24.1, 27.1, 28.1, 32.1, 35.1, 51.9, 52.0, 52.5, 59.7,
79.0, 84.6, 155.6, 169.4, 169.8; MS (EI) m/ e 373 (M+ + 1)
HRMS calcd for (M+ + 1) C17H29N2O7: 373.1975, found:
373.1970.
1
1700, 1640 cm-1; H NMR (300 MHz, CDCl3) δ 0.99 (m, 1H),
[2S ,3S ,5R ,rS ]-5-Me t h y l-r-(p h e n y lm e t h y l)-1-ox a -2-
a za sp ir o[2.5]octa n e-2-a cetic Acid Meth yl Ester (6) a n d
Isom er . (R)-3-Methylcyclohexanone (1.10 g, 9.8 mmol) was
allowed to react with L-phenylalanine methyl ester (2.52 g,
14 mmol) followed by m-CPBA (2.52 g, 14 mmol). Column
chromatography with 40% ethyl acetate/hexane afforded the
title compound (Rf ) 0.44 (20% ethyl acetate/hexane), 2.44 g,
86%) as an oil: [R]D ) -49.2 (c 2.8, CDCl3); IR (neat) 2956,
1.42 (s, 9H), 1.5-1.9 (m, 5H), 3.08 (dd, J ) 9.8, 14 .2 Hz, 1H),
3.31 (m, 3H), 3.72 (s, 3H), 4.20 (dd, J ) 5.8, 10.3 Hz, 1H), 5.14
(dd, J ) 6.3, 9.8 Hz, 1H), 5.89 (d, J ) 5.5 Hz, 1H), 7.23-7.36
(m, 5H); 13C NMR (74.5 MHz, CDCl3) δ 26.9, 27.7, 28.4, 32.2,
35.1, 47.3, 52.2, 53.6, 61.0, 79.3, 126.9, 128.6, 129.1, 137.0,
155.1, 171.1, 173.4; MS (EI) m/ e 390 (M+ + 1). Anal. Calcd
for C21H30N2O5: C, 64.59; H, 7.74; N, 7.17. Found: C, 64.80;
H, 7.69; N, 7.50.
1
1739, 1600, 1560 cm-1, H NMR (300 MHz, CDCl3) δ 0.92 (d,
J ) 6.6 Hz, 3H), 1.10 (m, 2H), 1.51 (m, 7H), 3.10 (dd, J ) 6.9,
13.5 Hz, 1H), 3.21 (dd, J ) 6.9, 13.5 Hz, 1H), 3.51 (apparent
t, J ) 6.9 Hz, 1H), 3.72 (s, 3H), 7.12-7.30 (m, 5H); 13C NMR
(74.5 MHz, CDCl3) δ 21.7, 22.8, 27.4, 31.1, 33.2, 37.8, 43.9,
52.7, 67.0, 86.8, 127.5, 129.1, 129.7, 136.5, 171.1; MS (EI) m/ e
290 (M+ + 1); HRMS calcd for C17H24NO3: 290.1756, found
290.1761. Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N,
4.83. Found: C, 70.20, H, 8.38; N, 4.61. A minor isomer was
also isolated (Rf ) 0.56 (20% ethyl acetate/hexane), 0.34 g,
12%) as an oil: IR (neat) 2950, 1742 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.94 (d, J ) 6.2 Hz, 3H), 1.00 (m, 1H), 1.48-1.87 (m,
8H), 3.25 (m, 2H), 3.47 (t, J ) 6.6 Hz, 1H), 3.63 (s, 3H), 7.22-
7.31 (m, 5H); 13C NMR (74.5 MHz, CDCl3) δ 21.9, 23.3, 31.2,
33.5, 35.6, 35.8, 39.0, 51.8, 67.7, 85.5, 126.7, 128.3, 129.3, 136.6,
170.0; MS (EI) m/ e 290 (M+ + 1).
(3S ,rR )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -r-(p h e n y lm e t h y l)-2-o x o -1H -a z e p i n e -1-
Acetic Acid Meth yl Ester (14b). Oxaziridine 12b (0.269 g,
0.68 mmol) was photolyzed for 3 h. Column chromatography
with 40% ethyl acetate/hexane yielded 14b (0.182 g, 68%): [R]D
) +48.3 (c 0.20, CDCl3); IR (CHCl3) 3400, 3000, 2900, 1745,
1
1700, 1645 cm-1, H NMR (300 MHz, CDCl3) δ 1.27-1.41 (m,
2H), 1.47 (s, 9H), 1.52-1.90 (m, 4H), 2.92 (dd, J ) 4.0, 15.3
Hz, 1H), 3.20 (m, 2 H), 3.43 (dd, J ) 5.0, 14.4 Hz, 1H), 3.75 (s,
3H), 4.34 (dd, J ) 6.2, 9.8 Hz, 1H), 4.83 (dd, J ) 4.9, 10.5 Hz,
1H), 6.00 (d, J ) 5.9 Hz, 1H); 13C NMR (74.5 MHz, CDCl3) δ
26.7, 27.7, 28.2, 35.0, 40.0, 48.8, 52.2, 53.4, 62.1, 79.1, 126.6,
128.4, 128.7, 137.2, 155.0, 170.6, 173.2; MS (EI) m/ e 391 (M+
+ 1). Anal. Calcd for C21H30N2O5: C, 64.59; H, 7.74; N, 7.17.
Found: C, 64.63; H, 8.00; N, 7.22.

662 J . Org. Chem., Vol. 62, No. 3, 1997
Wolfe et al.
(3S ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h exa h yd r o-r-(2-m et h ylp r op yl)-2-oxo-1H-a zep in e-1-a ce-
tic Acid Meth yl Ester (14c). Oxaziridine 10c (0.400 g, 1.12
mmol) was photolyzed for 4 h. Column chromatography with
15% ethyl acetate/hexane afforded 14c as a white solid (0.244
g, 61%): mp 122 °C; [R]D ) -42.0 (c 0.3, CHCl3), IR (KBr) 3390,
2980, 2940, 2900, 1740, 1795, 1630 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.89 (d, J ) 6.3 HZ, 3H), 0.91 (d, J ) 6.9 Hz, 3H),
1.44 (s, 9H), 1.45-2.10 (m, 9H), 3.36 (m, 2H), 3.71 (s, 3H), 4.34
(m, 1H), 5.37 (dd, J ) 6.0, 9.6 Hz, 1H), 6.00 (br d, J ) 6.0 Hz,
1H); 13C NMR (74.5 MHz, CDCl3) δ 21.7, 23.1, 24.9, 27.8, 27.9,
28.3, 32.6, 37.9, 46.1, 52.3, 53.7, 56.4, 79.2, 155.1, 171.9, 173.8;
MS (EI) m/ e 356 (M+ + 1). Anal. Calcd for C18H32N2O5: C,
60.64; H, 9.05; N, 7.85. Found: C, 60.39; H, 9.45; N, 7.60.
(3S ,rR )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -r-(2-m e t h y lp r o p y l)-2-o x o -1H -a ze p in e -1-
a cetic Acid Meth yl Ester (14d ). A 1:1 mixture of oxaziri-
dine diastereomers 10d and 12d (0.30 g, 0.84 mmol) was
photolyzed for 3 h. Column chromatography with 40% ethyl
acetate/hexane afforded a single lactam 14d (0.177 g, 59%):
[R]D ) +41.5 (c 0.6, CHCl3). IR (CHCl3) 3400, 2930, 1740, 1730,
27.7, 28.3, 32.3, 34.5, 49.1, 52.0, 52.6, 53.7, 58.0, 79.4, 155.1,
170.2, 171.3, 173.4; MS (CI) m/ e 373 (M+ + 1). Anal. Calcd
for C17H28N2O7: C, 54.82; H, 7.57; N, 7.52. Found: C, 54.80;
7.63, H, 7.96; N, 7.10.
(3SR,rS)-3-[[(1,1-Dim et h ylet h oxy)ca r b on yl]a m in o]-
h e xa h yd r o-r-(1-m e t h yle t h yl)-2-oxo-1H -a ze p in -1-yl]-
bu ta n ed ioic Acid Dim eth yl Ester (14f/15f). A mixture of
two diastereomeric oxaziridines (11f and either 10f or 12f, ca.
2:1, 0.200 g 0.53 mmol) was photolyzed for 4 h. Column
chromatography with 40% ethyl acetate/hexane afforded a
mixture of distereomers 14f and 15f (ca. 2:1 ratio, 0.104 g,
52%) which were difficult to separate by chromatography.
1
14f: IR (CHCl3) 3400, 3000, 1730, 1700, 1650 cm-1, H NMR
(300 MHz, CDCl3) δ 1.42 (s, 9H), 1.53-2.00 (m, 6H), 2.88 (dd,
J ) 8.5, 17.1 Hz, 1H), 3.20 (dd, J ) 5.2, 17.1 Hz, 1H), 3.36 (m,
1H), 3.57 (dd, J ) 7.8, 15.6 Hz, 1H), 3.69 (s, 3H), 3.72 (s, 3H),
4.35 (m, 1H), 4.71 (dd, J ) 5.3, 8.4 Hz, 1H), 5.88 (m, 1H); 13C
NMR (74.5 MHz, CDCl3) δ 26.6, 27.7, 28.4, 32.2, 34.7, 50.4,
52.1, 52.6, 53.3, 59.3, 79.4, 155.0, 169.9, 171.5, 173.3. Anal.
Calcd for C17H28N2O7: C, 54.82; H, 7.57; N, 7.52. Found: C,
1
54.80; H, 7.96; N, 7.10. Peaks for the minor isomer in the H
1700, 1640 cm-1
,
1H NMR (300 MHz, CDCl3) δ 0.96 (d, J )
NMR (300 MHz, CDCl3) and 13C NMR (74.5 MHz, CDCl3)
matched spectra for 15f above.
6.6 Hz, 3H), 0.99 (d, J ) 6.6, Hz, 3H), 1.22-2.10 (m, 9H), 1.43
(s, 9H), 3.23 (dd, J ) 4.8, 15.3 Hz, 1H), 3.46 (dd, J ) 11.7,
15.6 Hz, 1H), 3.69 (s, 3H), 4.41 (dd, J ) 6.0, 9.6 Hz, 1H), 5.21
(dd, J ) 4.5, 9.9 Hz, 1H), 6.10 (d, J ) 5.7 Hz, 1H); 13C NMR
(74.5 MHz, CDCl3) δ 21.8, 23.1, 24.9, 27.8, 28.3, 29.6, 32.6,
37.9, 46.0, 52.2, 53.7, 56.4, 79.2, 155.0, 171.8, 173.8; MS (EI)
m/ e 356 (M+ + 1). Anal. Calcd for C18H32N2O5: C, 60.64; H,
9.05; N, 7.85. Found: C, 60.59; H, 8.71; N, 7.68.
(3R,rS)-Hexa h yd r o-4-m eth yl-r-(p h en ylm eth yl)-2-oxo-
1H-a zep in e-1-a cetic Acid Meth yl Ester (7). Oxaziridine
6 (0.400 g, 1.3 mmol) was photolyzed in benzene for 2 h.
Column chromatography with 40% ethyl acetate/hexane af-
forded 7 (0.350 g, 88%): [R]D ) -80.9 (c 2.4, CHCl3); IR (CHCl3)
2930, 2910, 1730, 1635 cm-1 1H NMR (300 MHz, CDCl3) δ
;
0.85 (d, J ) 6.8 Hz, 3H), 1.19-1.30 (m, 2H), 1.57-1.82 (m,
4H), 2.20 (dd, J ) 9.5, 13.6 Hz, 1H), 2.40 (br d, J ) 13.6 Hz,
1H), 3.06 (dd, J ) 10.3, 14.3 Hz, 1H), 3.21 (m, 1H), 3.33 (dd,
J ) 5.8, 14.5 Hz, 1H), 3.71 (s, 3H), 5.25 (dd, J ) 5.8, 10.3 Hz,
1H), 7.12-7.35 (m, 5H); 13C NMR (74.5 MHz, CDCl3) δ 21.9,
26.4, 28.7, 35.2, 37.9, 44.4, 47.6, 52.1, 59.7, 126.6, 128.4, 129.0,
137.2, 171.6, 174.7; MS (EI) m/ e 290 (M+ + 1). Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.01; N, 4.83. Found: C, 70.41;
H, 8.38; N, 4.68.
(3S ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -r-(1-m e t h y le t h y l)-2-o x o -1H -a z e p i n e -1-
a cetic Acid Meth yl Ester (14e). A mixture of oxaziridine
diastereomers 10e and 12e (ca. 4-5:1, 0.200 g, 0.58 mmol)
was photolyzed for 4 h. Column chromatography with 40%
ethyl acetate/hexane afforded 14e (0.110 g, 59%) as a single
isomer: [R]D ) -99.8 (c 0.7, CDCl3); IR (CHCl3) 3420, 3000,
2900, 1740, 1700, 1640 cm-1 1H NMR (300 MHz, CDCl3) δ
,
0.96 (dd, J ) 6.6 Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H), 1.22-2.21
(m, 7H), 1.43 (s, 9H), 3.35 (dd, J ) 11.4, 15.9 Hz, 1H), 3.58
(dd, J ) 5.4, 15.6 Hz, 1H), 3.69 (s, 3H), 4.37 (dd, J ) 4.2, 4.8
(6R,rR)-Hexa h yd r o-4-m eth yl-r-(p h en ylm eth yl)-2-oxo-
1H-a zep in e-1-a cetic Acid Meth yl Ester (9). Oxaziridine
8 (0.600 g, 2.07 mmol) was photolyzed in benzene for 2 h.
Column chromatography with 40% ethyl acetate/hexane af-
Hz, 1H), 4.69 (d, J ) 9.9 Hz, 1H), 6.01 (d, J ) 5.4 Hz, 1H); 13
C
NMR (74.5 MHz, CDCl3) δ 20.0, 20.2, 27.9, 28.4, 28.5, 28.8,
33.0, 46.7, 52.3, 54.2, 64.4, 79.7, 155.5, 171.3, 174.3; MS (CI)
m/ e 343 (M+ + 1). Anal. Calcd for C17H30N2O5: C, 59.62; H,
8.83; N, 8.18. Found: C, 59.74; H, 9.22; N, 7.98.
forded 9 (0.495 g, 82%) as a white solid: mp 107 °C. [R]D
)
-83.1 (c 2.4, CHCl3), IR (KBr) 3100, 2900, 2820, 1735, 1630
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.81 (d, J ) 6.9 Hz, 3H),
1.11-1.81 (m, 6H), 2.30 (dd, J ) 1.5, 13.8 Hz, 1H), 2.43 (m,
1H), 3.10 (m, 2H), 3.29 (dd, J ) 6.0, 14.1 Hz, 1H), 3.70 (s, 3H),
5.13 (dd, J ) 6.3, 9.9 Hz, 1H), 7.15-7.32 (m, 5H); 13C NMR
(74.5 MHz, CDCl3) δ 20.9, 23.0, 33.7, 35.7, 37.4, 38.7, 52.4,
54.8, 60.7, 127.0, 128.8, 129.5, 137.7, 172.0, 176.1; MS (EI)
m/ e 290 (M+ + 1). Anal. Calcd for C17H23NO3: C, 70.56; H,
8.01; N, 4.83. Found: C, 70.42; H, 8.18; N, 4.71.
(3S ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -2-o x o -r-(p h e n y lm e t h y l)-1(2H )-a zo c in e -
a cetic Acid Meth yl Ester (17). Oxaziridine 16 (0.100 g, 0.24
mmol) was photolyzed for 4 h. Concentration followed by
column chromatography with 40% ethyl acetate/hexane af-
(3R ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e x a h y d r o -r-(1-m e t h y le t h y l)-2-o x o -1H -a z e p i n e -1-
a cetic Acid Meth yl Ester (15e). Oxaziridine 11e (0.220 g,
0.64 mmol) was photolyzed for 4 h. Column chromatography
with 40% ethyl acetate/hexane afforded 15e (0.130 g, 59%)
along with an unseparable isomer (ca.7-8:1). 15e: IR (CHCl3)
3400, 3000, 2900, 1790, 1695, 1645 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.80 (d, J ) 6.6 Hz, 3H), 0.97 (d, J ) 6.6 Hz, 3H),
1.22-2.21 (m, 7H), 1.44 (s, 9H), 3.29 (dd, J ) 11.4, 15.3 Hz,
1H), 3.53 (dd, J ) 5.1, 14.7 Hz, 1H), 3.72 (s, 3H), 4.37 (m, 1H),
4.94 (d, J ) 8.0 Hz, 1H), 6.01 (d, J ) 5.7 Hz, 1H); 13C NMR
(74.5 MHz, CDCl3) δ 18.6, 19.5, 23.3, 27.4, 28.3, 28.4, 32.5,
43.5, 52.0, 53.5, 61.5, 79.4, 155.1, 171.3, 173.7. Anal. Calcd
for C17H30N2O5: C, 59.62; H, 8.83; N, 8.18. Found: C, 60.00;
H, 8.89; N, 8.14. Minor isomer (diagnostic peaks only): 1H
NMR (300 MHz, CDCl3) δ 1.02 (d, J ) 6.9 Hz, 3H), 1.05 (d, J
) 6.9 Hz, 3H), 1.43 (s, 9H), 3.76 (s, 3H); 13C NMR (74.5 MHz,
CDCl3) δ 23.8, 27.6; MS (CI) m/ e 373 (M+ + 1).
forded 17 as a white solid (0.048 g, 48%): mp 118 °C; [R]D
)
-76.2 (c 0.3, CHCl3); IR (KBr) 3380, 2985, 2970, 2930, 1735,
1700, 1635 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.40-1.79 (m,
6H), 1.43 (s, 9H), 1.99 (m, 1H), 3.04 (dd, J ) 8.1, 14.1 Hz, 1H),
3.38 (m, 3H), 3.68 (s, 3H), 3.72 (m, 1H), 4.60 (m, 1H), 5.10 (t,
J ) 7.8 Hz, 1H), 5.54 (d, J ) 7.6 Hz, 1H), 7.15-7.30 (m, 5H);
13C NMR (74.5 MHz, CDCl3) δ 23.3, 24.6, 28.3, 29.7, 34.9, 36.7,
45.0, 50.3, 52.1, 59.2, 79.3, 126.7, 128.4, 129.0, 137.0, 154.9,
171.2, 173.5; MS (CI) m/ e 405 (M+ + 1). Anal. Calcd for
C22H32N2O5: C, 65.32; H, 7.97; N, 6.93. Found: C, 65.28; H,
8.18; N, 6.68.
(3R ,rS )-3-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]a m in o]-
h e xa h yd r o-r-(1-m e t h yle t h yl)-2-oxo-1H -a ze p in -1-yl]-
bu ta n ed ioic Acid Dim eth yl Ester (15f). Oxaziridine 10f
or 12f (0.050 g, 13 mmol) was photolyzed for 4 h. Column
chromatography with 40% ethyl acetate/hexane afforded 15f
(0.022 g, 44%): [R]D ) -30.6 (c 0.9, CHCl3); IR (CHCl3) 3400,
Gen er al P r ocedu r e for N-Depr otection an d Side Ch ain
In stallation . (3S,rS)-3-[N-[1(S)-(Eth oxycar bon yl)-3-ph en -
ylp r op yl]a m in o]-h exa h yd r o-r-(p h en ylm eth yl)-2-oxo-1H-
a zep in e-1-a cetic Acid Meth yl Ester (21a ). According to the
literature procedure,20 to a solution of lactam 14a (0.260 g,
0.67 mmol) in 10 mL of CH2Cl2 was added 5 mL of TFA
dropwise. After stirring at room temperature for 2 h, concen-
tration afforded the crude amino lactam as its trifluoroacetate
3000, 1740, 1690, 1650 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.42 (s, 9H), 1.51-2.00 (m, 6H), 2.75 (dd, J ) 7.4, 16.6 Hz,
1H), 3.13 (dd, J ) 6.5, 16.6 Hz, 1H), 3.31 (dd, J ) 3.3, 15.2
Hz, 1H), 3.57 (dd, J ) 11.3, 15.2 Hz, 1H), 3.69 (s, 3H), 3.72 (s,
3H), 4.32 (dd, J ) 6.1, 9.6 Hz, 1H), 5.00 (t, J ) 7.1 Hz, 1H),
5.89 (d, J ) 5.50 Hz, 1H); 13C NMR (74.5 MHz, CDCl3) δ 27.6,

Stereoselective Synthesis of Freidinger Lactams
J . Org. Chem., Vol. 62, No. 3, 1997 663
salt. The free amine was obtained by forming a slurry with
an excess of solid NaHCO3 in CH2Cl2 and allowing to stir for
1 h, at which time the reaction was filtered, the solids were
washed with CH2Cl2, and the filtrate was concentrated. The
resulting residue in CH2Cl2 (15 mL) was reacted with the
triflate of ethyl (R)-2-hydroxy-4-phenylbutyrate (0.0.248 g, 0.73
mmol) and triethylamine (0.1 mL) at room temperature. The
reaction was concentrated, partitioned between ethyl acetate
and water, and dried over MgSO4. Concentration followed by
column chromatography with 1:1 EA/cyclohexane afforded the
title compound (0.140 g, 43% overall): [R]D ) -86.8 (c 0.16,
CHCl3); IR (neat) 2920, 2800, 1730, 1640 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.07 (m, 1H), 1.27 (t, J ) 6.9 Hz, 3H), 1.44-
1.90 (m, 7H), 2.68 (t, J ) 7.4 Hz, 2H), 2.82 (m, 1H) 2.99-3.37
(m, 6H), 3.73 (s, 3H), 4.17 (q, J ) 6.9 Hz, 2H), 5.28 (m, 1H),
7.21-7.31(m, 10H); 13C NMR (74.5 MHz, CDCl3) δ 14.5, 27.1,
27.7, 31.6, 31.7, 34.6, 35.1, 46.7, 52.1, 58.7, 59.1, 60.4, 60.6,
125.8, 126.7, 128.3, 128.4, 129.1, 137.2, 147.7, 171.5, 174.5,
175.5; MS (EI) m/ e 481 (M+ + 1). Anal. Calcd for
C28H36O5N2: C, 69.97; H, 7.55; N, 5.82. Found: C, 69.60; H,
7.68; N, 5.60.
25.1, 25.9, 26.2, 28.5, 31.1, 31.6, 34.1, 46.7, 58.5, 61.4, 67.0,
126.0, 126.4, 128.2, 128.3, 128.4, 129.1, 137.8, 141.0, 171.6
(signal-to-noise ratio not high enough to observe the two
unaccounted carbonyl peaks); MS (EI) m/ e 439 (M+ + 1);
HRMS calcd for (M+ + 1) C25H31N2O5: 439.2233; found:
439.2241.
1-[1(S)-(P h en ylm eth yl)ca r boxym eth yl]-3(S)-[[1(R)-ca r -
boxy-3-ph en ylpr opyl]am in o]-per h ydr oazepin -2-on e (22b).
According to the general procedure, compound 21b (0.100 g,
0.21 mmol) was converted to the title compound as a white
solid (0.035 g, 38%): mp 127 °C; IR (KBr) 3800, 3200, 2900,
2820, 1740, 1730, 1650 cm-1; 1H NMR (300 MHz, DMSO-d6) δ
1.17-2.30 (m, 8H), 2.51 (br s, 1H), 2.61-2.75 (m, 2H), 2.91-
3.28 (m, 4H), 3.48 (br s, 1H), 3.78 (d, J ) 5.1 Hz, 1H) 4.80 (m,
1H), 7.19-7.31 (m, 10H), 10.2 (center of very br s, 2H); 13C
NMR (124.8 MHz, DMSO-d6) δ 26.2, 26.4, 28.9, 31.3, 32.7, 34.2,
48.4, 58.8, 58.9, 62.3, 126.0, 126.3, 128.3 (2), 128.4, 128.9,
138.1, 141.2, 171.5, 171.9, 172.5; MS (EI) m/ e 439 (M+ + 1);
HRMS calcd for (M+ + 1) C25H31N2O5: 439.2233; found:
439.2247.
(3S,rR)-3-[N-1(S)-(E t h oxyca r b on yl)-3-p h en ylp r op yl]-
a m in o]-h exa h yd r o-r-(p h en ylm eth yl)-2-oxo-1H-a zep in e-
1-a cetic Acid Meth yl Ester (21b). According to the general
procedure, lactam 14b (0.300 g, 0.77 mmol) was converted to
the title compound (0.309 g, 84%): [R]D ) +54.6 (c 0.16,
CHCl3); IR (neat) 2920, 2940, 1740, 1730, 1640 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.29 (t, J ) 7.2 Hz, 3H), 1.24-2.08 (m,
8H), 2.74 (t, J ) 7.3 Hz, 2H), 2.92-3.42 (m, 6H), 3.73 (s, 3H),
4.20 (m, 2H), 4.80 (dd, J ) 5.2, 10.5 Hz, 1H), 7.18-7.31 (m,
10H); 13C NMR (74.5 MHz, CDCl3) δ 14.3, 27.1, 27.9, 31.6, 31.8,
34.8, 35.1, 48.8, 52.2, 59.1, 59.2, 60.5, 125.8, 126.5, 128.3, 128.4,
128.5, 128.9, 137.6, 141.5, 171.0, 174.6, 175.2; MS (EI) m/ e
480 (M+).
1-[1(S)-(P h en ylm eth yl)ca r boxym eth yl]-3(S)-[[1(S)-ca r -
boxy-2-m eth ylpr opyl]am in o]-per h ydr oazepin -2-on e (22c).
According to the general procedure, compound 21c (0.85 g, 0.19
mmol) was converted to 22c (0.30 g, 39%): mp 105 °C dec; IR
(KBr) 3400, 3100, 2900, 2830, 1740, 1735, 1650 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 0.78 (d, J ) 6.2 Hz, 3H), 0.85 (d, J )
6.3 Hz, 3H), 1.26 (m, 4H), 1.64 (m, 5H), 1.90 (m, 2H), 2.33 (m,
2H), 3.18-3.50 (m, 3H), 3.42 (m, 1H), 3.94 (m, 1H), 5.05 (dd,
J ) 4.90, 15.2 Hz, 1H), 7.21 (m, 5H); 13C NMR (124 MHz,
DMSO-d6) δ 21.2, 22.3, 24.3, 26.7, 29.3, 30.8, 33.4, 35.8, 43.2,
59.3, 60.0, 68.9, 125.8, 128.2, 128.3, 141.5, 172.2, 172.7, 173.5;
MS (EI) m/ e 405 (M+ + 1); HRMS calcd for (M+ + 1)
(3S,rS)-3-[N-[1(S)-(Eth oxyca r bon yl)-3-p h en ylp r op yl]-
a m in o]-h exa h yd r o-r-(2-m eth ylp r op yl)-2-oxo-1H-a zep in e-
1-a cetic Acid Meth yl Ester (21c). According to the general
procedure, lactam 14c (0.150 g, 0.42 mmol) was converted to
C
22H33N2O5: 405.2389; found: 405.2414.
1-[1(S)-(P h en ylm eth yl)ca r boxym eth yl]-3(S)-[[1(R)-ca r -
boxy-2-m eth ylpr opyl]am in o]-per h ydr oazepin -2-on e (22d).
According to the general procedure, compound 21d (0.059 g,
0.13 mmol) afforded 22d as a white solid (0.032 g, 61%): mp
21c (0.155 g, 83%): IR (neat) ; 2960, 2830, 1730, 1640 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.92 (d, J ) 7.1 Hz, 3H), 0.94 (d,
J ) 6.6 Hz, 3H), 1.29 (t, J ) 7.1Hz, 3 H), 1.62-1.70 (m, 6 H),
1.90-2.10 (m, 6H), 2.74 (m, 2H), 3.20 (m, 1H), 3.32 (t, J ) 8.7
Hz, 1H), 3.47 (m, 2H), 3.70 (s, 3H), 4.17 (m, 2H), 5.37 (dd, J )
6.3, 9.2Hz, 1 H), 7.26 (m, 5H); 13C NMR (74.5 MHz, CDCl3) δ
14.3, 21.6, 23.2, 24.9, 26.5, 27.4, 31.7, 32.1, 35.1, 37.6, 43.5,
51.9, 55.1, 59.8, 60.2, 60.6, 125.8, 128.3, 128.4, 141.4, 172.4,
174.5, 175.3; MS (EI) m/ e 446 (M+), 447 (M+ + 1). Anal.
Calcd for C25H38O5N2: C, 67.23; H, 8.57; N, 6.27. Found: C,
66.88; H, 8.90; N, 5.98.
110 °C; IR (KBr): 3400, 2940, 2820, 1740, 1730, 1650 cm-1
;
1H NMR (500 MHz, DMSO-d6) δ 0.84 (d, J ) 6.1 Hz, 3H), 0.90
(d, J ) 10.7 Hz, 3H), 1.22-2.15 (m, 11H), 2.63 (m, 1H), 2.79
(m, 1H), 3.30 (m, 1H), 3.57(m, 2H), 4.24 (d, J ) 10.6 Hz, 1H),
4.86 (br t, J ) 5.2 Hz, 1H), 7.17-7.31 (m, 5H); 13C NMR (124.8
MHz, DMSO-d6) δ 21.7, 23.0, 24.5, 26.3, 26.7, 28.0, 30.7, 32.0,
37.5, 57.2, 59.0, 59.1, 126.0, 128.2, 128.3, 140.8, 170.6, 172.1;
MS (CI) m/ e 405 (M+ + 1); HRMS calcd for (M+ + 1)
C
22H33N2O5: 405.2389; found: 405.2401.
(3S,rR)-3-[N-[1(S)-(Eth oxyca r bon yl)-3-p h en ylp r op yl]-
a m in o]-h exa h yd r o-r-(2-m eth ylp r op yl)-2-oxo-1H-a zep in e-
1-a cetic Acid Meth yl Ester (21d ). According to the general
procedure, lactam 14d (0.100 g, 0.28 mmol) afforded the title
compound (0.059 g, 47%): [R]D ) +13.2 (c 1.00, CHCl3); IR
(neat) 2900, 2940, 2830, 1730, 1640 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H), 0.96 (d, J ) 6.3, 3H), 1.41
(m, 1H), 1.52-2.01 (m, 11H), 2.74 (m, 2H), 3.30 (m, 4H), 3.68
(s, 3H), 4.15 (m, 2H), 5.29 (dd, J ) 4.5, 10.2 Hz, 1H), 7.26 (m,
5H); 13C NMR (74.5 MHz, CDCl3) δ 14.7, 22.2, 23.5, 25.4, 27.7,
28.3, 32.4, 33.0, 35.4, 38.6, 45.8, 52.4, 56.8, 60.4, 60.9, 61.0,
126.2, 128.7, 128.8, 141.9, 172.7, 174.9; MS (EI) 446 (M+) 447
(M+ + 1). Anal. Calcd for C25H38O5N2: C, 67.23; H, 8.57; N,
6.27. Found: C, 66.73; H, 8.74, N, 6.18.
Gen er a l P r oced u r e for Sa p on ifica tion to th e Dia cid .
1-[1(S)-(P h en ylm et h yl)ca r b oxym et h yl]-3(S)-[[1(S)-ca r -
boxy-3-ph en ylpr opyl]am in o]-per h ydr oazepin -2-on e (22a).
Compound 21a (0.080 g, 0.16 mmol) was dissolved in MeOH
(2 mL) and THF (10 mL). NaOH (1 N) (10 mL) was added
and the reaction stirred for 48 h at room temperature. The
reaction was adjusted to pH 3 using 1 N HCl. Extraction with
chloroform, concentration, and recrystallization with n-hexane
afforded 22a (0.039 g, 57%): mp 127 °C; IR (KBr) 3400, 3000,
2900, 2820, 1720, 1730, 1650 cm-1; 1H NMR (500 MHz, DMSO-
d6) δ 0.95 (m, 1H), 1.16 (m, 1H), 1.37-1.94 (m, 4H), 1.87 (m,
3H), 2.53 (m, 1H), 2.67 (m, 1H), 3.04-3.38 (m, 6H), 5.00 (m,
1H), 7.14-7.30 (m, 10H); 13C NMR (125.7 MHz, DMSO-d6) δ
Ack n ow led gm en t . The National Institiutes of
Health and the American Heart Association, Kansas
Affiliate, are gratefully acknowledged for support of this
work. The AHA-KA is additionally thanked for a
postdoctoral fellowship to M.S.W. J .A. acknowledges the
receipt of an Eli Lilly Granteeship (1989-91), an Alfred
P. Sloan Fellowship (1993-1995), and an American
Cyanamid Faculty Award (1994) during the tenure of
this project. We also thank Dr. Fusao Takasagawa for
carrying out X-ray crystallographic determinations of
14a and 17, and Dr. David Vander Velde for assistance
with 2-D NMR studies.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 4e or 5e (isomers 1 and 2), 8,
10f + 12f, 11f or 13f, and 22a -d (18 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O961670J