Asymmetric synthesis of 2-alkyl-perhydroazepines from [5,3,0]-bicyclic lactams

Article abstract of DOI:10.1021/jo001548r

The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the cyclodehydration of (R)-phenylglycinol with ω-keto acids, lactams 4-6 were obtained as separable diastereomeric mixtures.(～2:1) in low yields (～40%). Higher chemical yield (up to 61%) was realized via an alternate route involving ring closure metathesis of 2-allyl-N-acroyl oxazolidines, 8. Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a, occurred with the use of alane or lithiumaluminum hydride, affording azepine alcohols, 11a and 15a, of the R configuration at the 2-position, in good to moderate yields (50-88%). High selectivity was also observed in the diisobutylaluminum hydride reduction of the epimeric anti lactams, 4b and 5b, affording, azepine alcohols, 11b and 15b, of the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiety afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric excesses (84-94%).

Full text of DOI:10.1021/jo001548r

J . Org. Chem. 2001, 66, 1413-1419
1413
Asym m etr ic Syn th esis of 2-Alk yl-P er h yd r oa zep in es fr om
[5,3,0]-Bicyclic La cta m s
A. I. Meyers,* Susan V. Downing, and Michael J . Weiser
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
aimeyers@lamar.colostate.edu
Received November 1, 2000
The synthesis and utility of a novel class of [5,3,0]-bicyclic lactams are described. Produced by the
cyclodehydration of (R)-phenylglycinol with ω-keto acids, lactams 4-6 were obtained as separable
diastereomeric mixtures (∼2:1) in low yields (∼40%). Higher chemical yield (up to 61%) was realized
via an alternate route involving ring closure metathesis of 2-allyl-N-acroyl oxazolidines, 8.
Stereoselective reductions of the syn-bicyclic lactams, 4a and 5a , occurred with the use of alane or
lithiumaluminum hydride, affording azepine alcohols, 11a and 15a , of the R configuration at the
2-position, in good to moderate yields (50-88%). High selectivity was also observed in the
diisobutylaluminum hydride reduction of the epimeric anti lactams, 4b and 5b, affording azepine
alcohols, 11b and 15b, of the S configuration at C-2. Hydrogenolytic cleavage of the N-benzyl moiety
afforded chiral 2-substituted perhydroazepines, (R)- and (S)-12, in good yields and good enantiomeric
excesses (84-94%).
Seven-membered nitrogen heterocycles are constitu-
ents of a number of compounds with interesting phar-
macological properties. For example, Balanol, the subject
of several synthetic efforts,1 is known to be a potent
inhibitor of the protein kinase C enzyme, while imino-
homopiperidinium salts are known to be selective inhibi-
tors of inducible nitric oxide synthase2 and are therefore
potential therapeutic agents for inflammatory conditions
such as osteo or rheumatoid arthritis. Additionally,
substituted seven-membered lactams have been studied
as potential peptide turn mimetics,3 and 7,5-fused bicyclic
lactams have been used as conformationally restricted
dipeptide surrogates.4
obtained from the trialkylaluminum-mediated Beckman
rearrangement of cyclohexanone oxime sulfonates5 and
the alkylation of dipole stabilized carbanions.6 Given our
earlier successes in the construction of chiral pyrrolidines
and piperidines from [3,3,0]- and [4,3,0]-bicyclic lactams,7
we felt that the [5,3,0]-bicyclic lactam scaffold 1a could
provide access to chiral 2-substituted azepines 3 in a
relatively straightforward fashion. We have elected to
name the [3,3,0] lactams as “5,5-”, the [4,3,0] lactams as
“5,6-”, and the [5,3,0] lactams as “5,7-”. This trivial
nomenclature will be used throughout this paper.
Previous methods for accessing the versatile bicyclic
lactam template consisted of cyclodehydration of a γ- or
δ-keto acid and a chiral amino alcohol by simply heating
the two in toluene overnight with azeotropic removal of
water.7 For the synthesis of N-heterocycles, (R)- or (S)-
phenylglycinol was commonly employed as the chiral
auxiliary. Employing this protocol with 6-oxooctanoic
(5) (a) Hattori, K.; Matsumura, Y.; Miyazaki, T.; Maruoka, K.;
Yamamoto, H. J . Am. Chem. Soc. 1981, 103, 7368-7370. (b) Maruoka,
K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.;
Yamamoto, H. J . Am. Chem. Soc. 1983, 105, 2831-2843.
General methods for the direct synthesis of 2-substi-
tuted perhydroazepines are few. Racemic products are
(6) (a) Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey, T. R. J .
Am. Chem. Soc. 1984, 106, 3270-3276. (b) Beak, P.; Lee, W. K. J . Org.
Chem. 1993, 58, 1109-1117.
(1) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1,
615-617, and references therein.
(7) The extensive chemistry of the 5,5- and 5,6-bicyclic lactam
systems has been thoroughly reviewed: (a) Romo, D.; Meyers, A. I.
Tetrahedron 1991, 47, 9503-9569. (b) Meyers, A. I. In Stereocontrolled
Organic Synthesis; Trost, B. M., Ed.; Blackwell Scientific Publica-
tions: Cambridge, MA, 1994; pp 145-161. (c) Meyers, A. I.; Brengel,
G. P. Chem. Commun. 1997, 1-8. (d) Meyers, A. I.; Andres, C. J .;
Resek, J . E.; Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D.
A. Tetrahedron 1999, 55, 8931-8952. (e) For a recent review on this
subject, see: Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, in press.
(2) Hansen, D. W., J r. et al. J . Med. Chem. 1998, 41, 1361-1366.
(3) (a) Lindstro¨m, U. M.; Somfai, P. J . Am. Chem. Soc. 1997, 119,
8385-8386. (b) Nadin, A.; Derrer, S.; McGeary, R. P.; Goodman, J .
M.; Raithby, P. R.; Holmes, A. B.; O’Hanlon, P. J .; Pearson, N. D. J .
Am. Chem. Soc. 1995, 117, 9768-9769.
(4) (a) Robl, J . A. Tetrahedron Lett. 1994, 35, 393-396. (b) Colombo,
L.; Di Giacomo, M.; Papeo, G.; Carugo, O.; Scolastico, C.; Manzoni, L.
Tetrahedron Lett. 1994, 35, 4031-4034.
10.1021/jo001548r CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/24/2001

1414 J . Org. Chem., Vol. 66, No. 4, 2001
Meyers et al.
Sch em e 1
acid8 furnished the 5,7-bicyclic lactam diastereomers 5a
and 5b, as a 2:1 mixture, in very low (11%) yield (5a ,b;
R ) Et). After extending the reaction time to 5 days, the
yield of the angular ethyl lactams 5a b was improved to
40%, with the remainder of the material consisting of
several uncharacterized products.9 A reaction time of 3
days was then set as the standard, which facilitated
purification (fewer side products) without compromising
the yield of the desired products. In this way, the angular
methyl lactams 4a b were also obtained in 38% yield (2:
1). The keto acid 6-oxo-8-methylnonanoic acid provided
a 5:1 mixture of angular isobutyl lactams 6a b in very
low yield (8%).
accommodate the trans ring fusion. Products A and B
are both formed as a 4-10:1 mixture, respectively,11 with
k2 > k4. For the “5,7-bicyclic lactams” (n ) 3), the ring
fusion in B is even more accommodated as a result of
the increased flexibility of the larger ring size. However,
neither k2 or k4 are very fast, and a prior equilibrium
k1,k-1 and k3,k-3 to oxazolidines is established, with very
little preference in the latter for 2,4-trans versus 2,4-cis
geometry.13 The mixture of lactam 5a or 5b could not be
altered when heated in wet toluene, but addition of
1
p-TsOH caused an enriched sample of 5a (96% de by H
NMR) to be reduced to 33% de within 24 h.
Efforts to enhance the chemical yield and diastereo-
selection of 4-6 included the examination of different
amino alcohols14 (valinol, tert-leucinol, and gem-dimeth-
ylphenylglycinol), different solvents that form azeotropes
with water, and additives reported to aid in amide bond
formation,15 to name a few. However, these efforts did
not lead to any improvements in yield and stereochem-
istry.
A new approach to these lactams was investigated
(Scheme 2) using ring closure metathesis (RCM), to form
a 5,7-bicyclic lactam from the bisolefinated oxazolidine
8. First, azeotropic condensation of 5-hexene-2-one 7 with
(R)-phenylglycinol formed the 2-butenyl substituted 1,3-
oxazolidine, which was immediately treated with acryloyl
chloride and triethylamine to afford the bisolefinated
oxazolidine 8 in a combined yield of 84% with a diaste-
riomeric ratio of 3:1 at the C-2 center. The syn and anti
diastereomers of 8 were separated, and the major dias-
tereomer 8b10 was then subjected to RCM using 5 mol %
of Grubbs’ ruthenium catalyst16 to provide the unsatur-
ated 5,7-bicyclic lactam (98%) as a single product, which
was reduced without further purification (H2-Pd(OH)2)
to afford the 5,7-bicyclic lactam 4b in 99% yield. The
overall yield of 4b from (R)-phenylglycinol was 61%.
Thus, the RCM route to 5,7-bicyclic lactam systems
appear to be much improved over the classical cyclode-
hydration of a keto acid and amino alcohol. However, the
major product 4b contained the anti configuration with
respect to the angular methyl and phenyl groups. This,
therefore, corresponded to the minor diastereomer of 4
The absolute stereochemistry of the aminal center in
lactam diastereomer 4a was determined from its crystal
structure.10 While assignment of the other lactam prod-
ucts might rest on analogy with 4a , it was observed for
each of the phenylglycinol-derived 5,7-bicyclic lactams
(4a -6a ) that the chemical shift of the benzylic proton in
the major lactam diastereomers (5a , 6a ) was found
downfield (5.29 ( 0.04 ppm) from that for the minor
epimers (5.19 ( 0.02 ppm). This distinction has also been
observed on related bicyclic lactams derived from 4-acetyl-
butyric acid and phenylglycinol (syn-alkyl; 5.38 ppm,
anti-alkyl; 4.96 ppm), whose stereochemistry has been
confirmed to be 4:1 favoring the syn methyl.11
The rationale to account for the above mixtures of
bicyclic lactams of (a,b) products is based upon their
mechanism of formation,12 which is depicted in Scheme
1. In synthesis of the “5,5-bicyclic lactam” (A, n ) 1), k2
. k4, leading to the syn-alkyl product A to the exclusion
of the very strained anti-alkyl product B. For the “5,6-
bicyclic lactam” (A, n ) 2), closure to B is more likely to
occur since the bicyclic structure can now more easily
(13) Amat, M.; Llor, N.; Bosch, J . Tetrahedron Lett. 1994, 35, 2223-
2226.
(14) (a) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J . Am. Chem.
Soc. 1985, 107, 7974-7978. (b) Dickman, D. A.; Meyers, A. I.; Smith,
G. A.; Gawley, R. Organic Syntheses; Wiley: New York, 1990; Collect.
Vol. VII, p 530. (c) Meyers, A. I.; McKennon, M. J . J . Org. Chem. 1993,
58, 3568-3571. (d) Corey, E. J .; Ishihara, K. Tetrahedron Lett. 1992,
33, 6807.
(15) (a) Yamada, S.; Wagatsuma, M.; Takkeuchi, Y.; Terashima, S.
Chem. Pharm. Bull. 1971, 19, 2380-2388. (b) Steliou, K.; Poupart,
M.-A. J . Am. Chem. Soc. 1983, 105, 7130. (c) Nadin, A. I. et al. Mater.
Sci. Eng. C 1996, 4, 59.
(8) (a) White, R. H. J . Am. Chem. Soc. 1980, 102, 6605-6607. (b)
Kaga, H.; Miura, M.; Orito, K. Synthesis 1989, 864-866.
(9) Starting material was recovered only in very low yields.
(10) Susie Miller of this department is gratefully recognized for
solving the X-ray crystal structures of compounds 4a , 8b, and 10a .
(11) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7084-
7085.
(16) For a review on ring closing metathesis, see: Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413.
(12) Fu¨lo¨p, F.; Pihlaja, K. Tetrahedron 1993, 6701-6706.

Asymmetric Synthesis of 2-Alkyl-Perhydroazepines
J . Org. Chem., Vol. 66, No. 4, 2001 1415
Sch em e 2
Sch em e 3
Ta ble 1. Hyd r id e Red u ction s of syn - a n d
a n ti-5,7-Bicyclic La cta m s 4, 5, a n d 10
Sch em e 4
hydride
source
yield of amino
alcohol (%)
diastereomeric
purity (a :b)
entry
lactam
a
b
c
d
e
f
g
h
i
4a
4a
4a
4a
5a
5a
10a
4b
4b
4b
LiAlH4
AlH3
i-Bu2AlH
BH3
LiAlH4
AlH3
LiAlH4
LiAlH4
AlH3
i-Bu2AlH
i-Bu2AlH
i-Bu2AlH
88b (11a )
80 (11a )
93b (11a )
89b (11a )
83 (15a )
51c (15a )
50 (13a )
70b (11b)
51 (11b)
95 (11b)
61 (15b)
53 (13b)
94.3:5.7d
95.7:4.3d
1:1e
a
3:1e
88.6:11.4f
92.0:8.0f
95:5g
2:1e
1:1e
j
k
l
4.5:95.5d
3.2:96.8f
3:97g
5b
10b
a
b
Generated in situ from AlCl3 and LiAlH4. Yield is crude.
c Reaction did not go to completion; partial reduction product
obtained. From HPLC of derivative 14; value is (0.5. e From
d
integration of 1H NMR signals (methyl doublets) at 1.17 and 0.97
ppm, respectively; values are approximate as a result of signal-
obscuring impurity in samples. f From HPLC of derivative 15c;
(4b) obtained by azeotropic condensation of the 6-oxo-
carboxylic acids and (S)-phenylglycinol. As mentioned,
the stereochemistry of 4b was based upon the X-ray data
taken for 8b.
value is (0.5. From integration of 1H NMR signals (methyl
g
doublets) at 0.78 and 0.72 ppm, respectively; value is (2%.
It was next decided to employ a conformational re-
straint in the keto acid backbone (cisoid double bond) to
assess if seven-membered ring closure via azeotropic
condensation would be facilitated. In this regard, the keto
acid, 9, when subjected to azeotropic condensation with
(S)-phenylglycinol in toluene, gave the benzo-fused lac-
tams 10a and 10b in 65-87% chemical yield as a 1.5:1
mixture, respectively (Scheme 3). Once again, the ben-
zylic proton of the chiral auxiliary in 10a appeared
downfield in the major diastereomer (5.42 ppm) compared
to that for the minor epimer 10b (4.99 ppm), and when
both epimers are available, this trend may serve as a
diagnostic tool for diastereomer identification for other
phenylglycinol-derived 5,7-bicyclic lactams. For further
structure proof, the stereochemistry of 10a was confirmed
from a crystal structure.10
and alane, with both reductions showing good selectivity
(retention) and affording predominantly epimer 11a
(entries a and b). Unfortunately, the resulting amino
alcohol diastereomers 11a ,b could not be totally freed
from the minor amounts of the other epimer. In this
regard, conversion of the hydroxyl in 11a ,b to various
esters (acyl, naphthoyl), which was a successful remedy
in the separation of piperidine-derived amino alcohols,11
did little to solve the problem. It was, therefore, decided
to reductively remove the chiral remnant in 11 and 15
using Pd(OH)2-H2 and convert the resulting amines 12
(R ) Me) to the p-bromobenzoyl amides, (R)-14, using
p-bromobenzoyl chloride. This could be cleanly separated
and allowed accurate ratio data to be obtained. The
enantiomeric hydrochloride salts [(R)-12, (S)-12; R ) Me]
could also be separated by HPLC (Regis (R,R) Whelk-02
Pirkle covalent chiral column).17 The absolute stereo-
Hydride reduction of each of the purified bicyclic
lactam diastereomers 4a , 4b, 10a , and 10b was then
undertaken (Scheme 4) and these results are summarized
in Table 1. Screening of hydride reagents was performed
on syn-methyl lactam 4a with lithium aluminum hydride
(17) While an [R]D value was not recorded for enantiomers (S)-12
or (S)-17, the proton NMR spectra for each of these were identical to
those for compounds (R)-12 and (R)-17, respectively.

1416 J . Org. Chem., Vol. 66, No. 4, 2001
Meyers et al.
chemistry at the C-2 methyl group of the major product
(12), obtained from the hydride reduction of lactam 4a ,
was determined to be R from a crystal structure solved
for azepine hydrochloride salt (R)-12, R ) Me.18
For the 2-ethyl compound 5 (a and b), the p-bromoben-
zoyl derivative of azepines 15a and 15b could not be
separated after acylation of the amino group as was done
previously for 14. However, the urea derivative 15c from
(S)-R-methylbenzylisocyanate (50% yield) allowed sepa-
ration of the diastereomers of 15a and 15b by HPLC
(CHIRACEL OD column). Again, lactam reduction of 5a
with alane (entry f) was slightly more selective than with
lithium aluminum hydride (entry e). However, in this
case, the reaction with alane was much slower, and 20%
of starting material was obtained wherein only carbonyl
reduction in the lactam had occurred (not shown).
F igu r e 1. Circular dichroism (CD) spectra of amino alcohols
11a , 15a , and 15b in CH3CN.
The reduction was found to occur with the same stere-
ochemical sense on each of the anti-bicyclic lactams
studied. This was determined from comparison of the
circular dichroism spectra of amino alcohols 11a and 15a
and 15b. Because there are two stereo centers in 11a and
15a , the spectrum of 15b from DIBAL reduction of endo-
lactam 5b was also obtained to ascertain that the CD
characteristics weren't simply due to the stereochemistry
at the aryl group of the chromophore. As observed in
Figure 1, the Cotton effects of 11a and 15a are quite
similar, while that for 15b is quite consistent with its
enantiomer.
Rationalization for the stereochemical outcome in
hydride reductions of the syn-5,7-bicyclic lactams follows
directly from retention, which was reported for the
reduction of 5,5- and 5,6-bicyclic lactams with alane.11,20
Following reduction of the carbonyl group, complexation
of the Lewis acidic aluminum reagent to the sterically
less congested R-face weakens the angular C-O bond and
promotes formation of the iminium ion species, 18.
Hydride delivery from aluminum, in an intramolecular
sense, follows prior to formation of a discreet, planar
intermediate. The observed result is that hydrogen
occupies the site previously held by the oxygen, and
retention of the stereochemistry predominates. For the
anti-lactams, the â-face is the more accessible one, and
reaction in the above manner, as in 19, accounts for the
retention of the orientation of the angular alkyl group.
To restate, the derivatives (R)-14 and 15c derived from
the cyclodehydration condensation were formed primarily
to establish accurate enantiomer ratios, which could not
be determined from proton NMR shift reagents because
of signal overlapping or the presence of impurities that
were not removed by flash chromatography, and not for
the purpose of obtaining stereochemically pure product.
The ratio of amino alcohols 13a ,b, obtained from reduc-
tion of benzo-fused lactam 10a with LAH, was easily
discerned by proton NMR, and the products, therefore,
need not be derivatized for HPLC separation.
Prior to this study, the stereochemistry of hydride
reductions of anti-bicyclic lactam diastereomers (4b, 5b)
had not been investigated. In view of the fact that the
ring closure metathesis gave good yields of the anti-
bicyclic lactams, 4b, several hydride reagents were
screened, and it was found that diisobutylaluminum
hydride provided selectivity far superior to that of alane
or LAH (Table 1, entries h-j). That the stereochemistry
at C-2 in 15b was found to be opposite of that obtained
from reduction of syn-lactam 4a was verified once the
N-substituent was removed by hydrogenolysis. The prod-
ucts, 12, from each lactam 4a and 4b were found to be
enantiomers.19
Some comments on the stereoselectivity of the hydride
reductions of the lactams 4-6 and 10 are appropriate.
In summary, stereoselective reductions of the 5,7-
bicyclic lactams 4a , 4b, 10a , and 10b proceeded smoothly
with the use of alane or lithium aluminum hydride,
affording the corresponding perhydroazepines with R
configuration at C-2 in good to moderate yields (50-88%)
from the syn epimers. Good selectivity was also observed
in the diisobutylaluminum hydride reduction of the anti
lactam epimers, 4b, 5b, and 10b, affording perhy-
droazepines of the opposite configuration at C-2. Hydro-
genolytic cleavage of the N-benzyl moiety then produced
(18) Agnete la Cour is gratefully recognized for solving the X-ray
crystal structure of compound (R)-12‚HCl (R ) Me), for which the
absolute structure parameter is 0.00 ( 0.19. After refinement of the
structure as the (S)-enantiomer, the flack parameter was 1.20 ( 0.18.
Designation of C-5 as nitrogen and N as C-5 resulted in an unreliable
temperature factor and a rise of the conventional R-factor from 0.0764
to 0.0839. Upon refinement of the crystal structure as a racemic twin,
the data converged to 100% of the (R)-enantiomer of 12 (R ) Me), with
a confidence level of 95%.
(19) (a) Meyers, A. I.; Burgess, L. E. J . Org. Chem. 1991, 56, 2294-
2296. (b) Burgess, L. E.; Meyers, A. I. J . Org. Chem. 1992, 57, 1656-
1662.
(20) Beugelmans, R.; Ginsburg, H. Heterocycles, 1985, 23, 1197.

Asymmetric Synthesis of 2-Alkyl-Perhydroazepines
J . Org. Chem., Vol. 66, No. 4, 2001 1417
as an epimeric mixture (5a /5b 2.3:1). Recrystallization from
Et2O provided purified anti-ethyl 5b, as a 12:1 mixture, as long
colorless needles. While under aspirator pressure during
collection of 5b, syn-ethyl 5a precipitated from the mother
liquor as a white solid, essentially free from the minor
diastereomer. 5a : mp 137-138 °C; Rf ) 0.34 (hexanes/EtOAc
1:1); [R]23D ) -49.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 1.01 (t, J ) 7.3 Hz, 3H), 1.63-2.04 (m, 6H), 2.13-2.31 (m,
2H), 2.48-2.67 (m, 2H), 3.94 (dd, J ) 5.9 and 9.0 Hz, 1H),
4.34 (dd, J ) 7.2 and 9.2 Hz, 1H), 5.29 (dd, J ) 5.9 and 7.2
Hz, 1H), 7.22-7.36 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 8.6,
23.7, 24.2, 29.3, 35.3, 37.1, 61.7, 70.1, 98.0, 126.5, 127.4, 128.7,
140.3, 171.6; IR (neat) 1634 cm-1; MS m/z 259. Anal. Calcd
for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.20;
H, 8.10; N, 5.43. 5b: mp 92-94 °C; Rf ) 0.30 (hexanes/EtOAc
1:1); [R]23D ) -4.67 (c 0.3, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 0.93 (t, J ) 7.5 Hz, 3H), 1.50-1.67 (m, 2H), 1.74-2.09 (m,
4H), 2.26-2.35 (m, 2H), 2.50-2.54 (m, 2H), 3.88 (dd, J ) 2.1
and 9.1 Hz, 1H), 4.25 (dd, J ) 6.9 and 9.1 Hz, 1H), 5.19 (dd,
J ) 1.9 and 6.7 Hz, 1H), 7.16-7.37 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 8.4, 21.2, 24.3, 26.9, 35.8, 38.2, 61.6, 70.5, 97.6,
126.8, 127.4, 128.6, 142.2, 171.0; IR (neat) 1637 cm-1; MS m/z
259. Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40.
Found: C, 73.65; H, 8.19; N, 5.26.
chiral 2-substituted perhydroazepines in good yields and
good enantiomeric excesses (84-94%).
Exp er im en ta l Section
Gen er a l. (R)-Phenylglycinol was generously provided by
The Pharmacia Company. The synthesis of 8-methyl-6-ox-
ononanoic acid was adapted from Koga;8b 6-oxooctanoic acid8a
and benzo-fused keto acid 920 were synthesized according to
literature procedures. All other reagents were commercially
available (Aldrich) and used without further purification.
8-Meth yl-6-oxon on a n oic Acid . Isovaleryl chloride (9.3
mL, 76.4 mmol) in CH2Cl2 (15 mL) was added dropwise
(addition funnel) over the course of 30 min to a solution of
1-morpholinocyclopentene (10.4 mL, 65.3 mmol) and Et3N
(10.9 mL, 78.4 mmol) in CH2Cl2 (35 mL) at 0 °C. This mixture
was allowed to warm to room temperature, and stirring was
maintained for 4 days. Then, 6 M HCl (35 mL) was added,
the mixture was heated to reflux for 5 h, and then it was cooled
to room temperature. The phases were separated, and the
organic one was washed with brine and dried (Na2SO4).
The crude diketone was dissolved in water (15 mL), NaOH
(9.0 g, 225 mmol) was added, and the solution was heated to
reflux for 1 h. The mixture was poured into ice water (70 mL),
acidified to pH 3 with concentrated HCl, and extracted with
CH2Cl2 (2 × 35 mL). The organic extracts were washed with
brine, dried (Na2SO4), and triturated with hexanes to provide
3.6 g (29%) of 8-methyl-6-oxononanoic acid as a light tan solid,
mp 37.5-39.5 °C. The aqueous material was further acidified
to pH 2, saturated with solid NaCl, and extracted with EtOAc.
The organic phase was dried (Na2SO4) and concentrated to
provide an additional 5.0 g (41%) of the keto acid as an impure
oil: 1H NMR (CDCl3, 300 MHz) δ 0.93 (d, J ) 6.5 Hz, 6H),
1.64 (apt s, 4H), 2.15 (m, 1H), 2.30 (d, J ) 7.4 Hz, 2H), 2.39-
2.43 (m, 4H), 11.73 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ
22.8, 22.8, 23.2, 24.4, 24.9, 34.0, 43.0, 52.1, 179.8, 210.7; IR
(neat) 1698 cm-1; HRMS (FAB+) calcd for C10H18O3 (M + H)+
187.1334, found 187.1338. This material was used without
further purification.
2-(R)-N-Acr oyl Oxa zolid in e 8b. A solution of (R)-(-)-
phenylglycinol (8.88 g, 64.7 mmol) and 5-hexene-2-one 7 (7.50
mL, 64.7 mmol) in toluene (200 mL) was heated to reflux
through
a Dean Stark trap for 24 h. The solution was
concentrated without workup to a yellow oil. The crude oil was
then taken up in 200 mL of dichloromethane and placed in an
ice bath. Triethylamine (18.0 mL, 129 mmol) and acryloyl
chloride (5.28 mL, 65.0 mmol) were subsequently added. After
10 min, the ice bath was removed, and the solution was stirred
at room temperature for 2 h. The reaction was quenched by
the addition of saturated (aqueous) NH4Cl (20 mL), and the
phases were separated. The organic phase was washed with
brine, and the combined aqueous layers were extracted with
dichloromethane. The organics were then dried (Na2SO4) and
concentrated to a tan oil. Flash column chromatography (40:
60, ether/hexanes) provided 14.75 g of 8a and 8b (84%)
containing 11.06 g of the (2R)-diastereomer 8b as a yellow
solid, and 3.69 g of the crude (2S)-diastereomer 8b as a yellow
Gen er a l P r oced u r e for th e Azeotr op ic Syn th esis of
5,7-Bicyclic La cta m s. An gu la r Meth yl La cta m s 4. 6-Oxo-
heptanoic acid (2.0 g, 13.7 mmol) and (R)-phenylglycinol (1.9
g, 13.7 mmol) were combined in 137 mL of toluene, heated to
reflux with azeotropic removal of water for 3 days, cooled, and
concentrated, and the residue was dissolved in EtOAc (100
mL). The solution was washed with 2 M NaOH (25 mL), 1 M
HCl (25 mL), and saturated (aqueous) NaHCO3 (25 mL) and
then dried (MgSO4). Flash chromatography of the residue
(hexanes/EtOAc 2:1) provided 630 mg of syn-methyl 4a as a
yellow oil that solidified upon standing (19%), 285 mg of anti-
methyl 4b as a pale yellow solid (8%), and 61 mg (2%) of 4a /
oil (dr ) 3:1). (2R)-8b: mp 65-67 °C; [R]23 ) -29.9 (c 1.05,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.64 (s, 3H), 2.06 (m,
1H), 2.22 (dd, J ) 6.6 Hz, 7.5 Hz, 2H), 2.62 (m, 1H), 3.90 (dd,
J ) 3.0 Hz, 3.0 Hz, 1H), 4.36 (dd, J ) 6.6 Hz, 6.6 Hz, 1H),
4.95 (m, 3H), 5.41 (dd, J ) 2.1 Hz, 1.5 Hz, 1H), 5.82 (m, 1H),
6.04 (dd, J ) 10.2 Hz, 10.2 Hz, 1H), 6.25 (dd, J ) 2.4 Hz, 1.5
Hz, 1H), 7.29 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 20.9, 28.8,
37.1, 61.0, 71.6, 114.5, 125.9, 127.7, 127.8, 128.8, 129.8, 138.1;
IR (neat) 1653, 1613, 1418, 1361 cm-1. Anal. Calcd for C17H21
-
NO2: C, 75.25; H, 7.80. Found: C, 75.43; H, 7.78. The minor
diastereomer, 8a , was not characterized further because of
impurities.
4b as an epimeric mixture (1:1.4). 4a : mp 96-98 °C; Rf ) 0.21
1
(hexanes/EtOAc 1:1); [R]23 ) -65.7 (c 1.0, CHCl3); H NMR
D
(CDCl3, 300 MHz) δ 1.66-2.11 (m, 9H), 2.57-2.68 (m, 2H),
4.03 (dd, J ) 5.2 and 9.0 Hz, 1H), 4.38 (dd, J ) 7.0 and 9.0
Hz, 1H), 5.33 (dd, J ) 5.0 and 6.9 Hz, 1H), 7.26-7.40 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 24.2, 24.4, 37.3, 39.7, 62.0, 70.3,
95.7, 126.6, 127.5, 128.7, 140.5, 171.39; IR (neat) 1643, 1403
cm-1; MS m/z 245. Anal. Calcd for C15H19NO2: C, 73.44; H,
7.81; N, 5.71. Found: C, 73.34; H, 7.79; N, 5.71. 4b: mp 103-
An gu la r Meth yl 5,7-Bicyclic La cta m 4b. A solution of
the (2R)-diastereomer of 8b (3.25 g, 12.0 mmol) in toluene (1.6
L) was heated to reflux. The high dilution was necessary as a
result of dimerization at higher concentrations. A solution of
Grubbs’ catalyst,16 Cy2Ru(PPh3)2CHPh, (493 mg, 0.60 mmol)
in toluene (10 mL) was added through the condenser via a
syringe pump set at a rate of 0.397 mL/h. TLC (EtOAc,
KMnO4) confirmed completion after 25 h. The cooled solution
was washed with brine, and the combined aqueous layers were
extracted with EtOAc. The organics were dried (Na2SO4) and
concentrated to a light brown solid. Flash column chromatog-
raphy (EtOAc) afforded 2.87 g of the unsaturated lactam (98%)
as a white crystalline solid. R,â-u n sa t u r a t ed la ct a m : mp
128-130 °C; [R]23D ) +92.9 (c 1, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 1.47 (s, 3H), 2.27 (m, 2H), 2.45 (m, 2H), 3.98 (dd, J )
8.1 Hz, 8.1 Hz, 1H), 4.39 (dd, J ) 6.6 Hz, 6.6 Hz, 1H), 5.12
(dd, J ) 6.6 Hz, 6.6 Hz, 1H), 5.85 (m, 1H), 6.14 (m, 1H), 7.15-
7.38 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 20.6, 26.1, 36.5,
61.5, 70.3, 93.2, 126.2, 126.5, 127.1, 128.1, 139.9, 141.5; IR
(neat) 1653, 1592 cm-1. Anal. Calcd for C15H17NO2: C, 74.05;
H, 7.04. Found: C, 74.02; H, 7.18. To a solution of the R,â-
104 °C; Rf ) 0.14 (hexanes/EtOAc 1:1); [R]23 ) 1.18 (c 1.1,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.61-2.08 (m, 8H), 2.25-
2.31 (m, 1H), 2.60-2.64 (m, 2H), 4.05 (dd, J ) 1.5 and 9.2 Hz,
1H), 4.41 (dd, J ) 6.7 and 9.0 Hz, 1H), 5.21 (br d, J ) 6.1 Hz,
1H), 7.25-7.44 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 22.5,
24.4, 24.9, 38.2, 40.1, 61.5, 70.3, 95.3, 126.8, 127.5, 128.7, 142.2,
171.0; IR (neat) 1629, 1412 cm-1; MS m/z 245. Anal. Calcd for
C
15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.37; H,
7.81; N, 5.74.
An gu la r Eth yl 5,7-Bicyclic La cta m s 5. Prepared from
6-oxooctanoic acid8a (500 mg, 3.16 mmol) and (R)-phenylgly-
cinol (434 mg, 3.16 mmol) in 50 mL of toluene using the
general procedure described above. Flash chromatography of
the residue (hexanes/EtOAc 5:2) provided 330 mg (40%) of 5

1418 J . Org. Chem., Vol. 66, No. 4, 2001
Meyers et al.
unsaturated lactam (500 mg, 2.06 mmol) in ethanol (10 mL)
was added Pd(OH)2 (20% on carbon) (21.9 mg, 0.0411 mmol).
A balloon of H2 gas was fitted to the reaction flask, and the
solution was allowed to stir at room temperature. Reaction
progress was monitored by NMR because of TLC co-spotting.
After 24 h, NMR indicated completion. The reaction solution
was filtered directly through a Celite pad and concentrated to
a white solid. The crude solid was passed through a plug of
silica to afford 498 mg of 4b (99%) as a colorless crystalline
solid. 4b: mp 99-101 °C. This proved to be identical to 4b
obtained by the cyclodehydration route.
phases were washed with 1 M NaOH (10 mL, back extracted
with 10 mL of CH2Cl2) and brine (10 mL) and then dried (Na2-
SO4). Flash chromatography of the residue (hexanes/EtOAc
10:1, then EtOAc) provided 59 mg (68%) of 15a , shown to be
a mixture of diastereomers (11.5:1) by HPLC analysis of its
1
urea derivative, 15c. 15a : H NMR (300 MHz) δ 0.90 (t, J )
7.4 Hz, 3H), 1.31-1.81 (m, 10H), 2.49-2.57 (m, 1H), 2.86-
2.93 (m, 2H), 3.45 (br s, 1H), 3.68 (dd, J ) 5.0 and 10.1 Hz,
1H), 3.93 (apt t, 1H), 4.04 (dd, J ) 5.0 and 10.1 Hz, 1H), 7.25-
7.40 (m, 5H); 13C NMR (75 MHz) δ 11.4, 23.9, 26.4, 29.4, 30.3,
31.1, 45.1, 61.0, 61.1, 65.8, 127.8, 128.4, 128.8, 138.4; MS m/z
247; HRMS (FAB+) calcd for C16H25NO (M + H)+ 248.2014,
found 248.2021. This material was used without further
purification.
Ben zo-F u sed 5,7-Bicyclic La cta m s 10. Synthesized from
keto acid 920 (300 mg, 1.19 mmol) and (R)-phenylglycinol (163
mg, 1.19 mmol) in 50 mL of toluene using the general
procedure for azeotropic cyclocondensation. Flash chromatog-
raphy of the residue, after solvent evaporation, (hexanes/
EtOAc 1:1) provided 166 mg (39%) of the syn-diastereomer 10a
and 109 mg (26%) of the anti-diastereomer 10b as solids. 10a :
mp 138-139 °C; Rf ) 0.19 (hexanes/EtOAc 1:1); [R]23D ) -48.5
(c 1.2, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 3H), 3.17
(d, J ) 14.8 Hz, 1H), 3.43 (d, J ) 15.0 Hz, 1H), 3.80-3.93 (m,
9H), 4.47 (t, J ) 8.7 Hz, 1H), 5.42 (apt t, 1H), 6.72 (s, 1H),
6.75 (s, 1H), 7.16-7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
14.4, 21.3, 25.4, 42.9, 43.8, 56.3, 60.9, 69.2, 94.6, 112.9, 113.7,
125.6, 125.8, 126.5, 127.3, 128.8, 140.6, 148.3, 167.4; IR (neat)
1639 cm-1; MS m/z 353. Anal. Calcd for C21H23NO4: C, 71.37;
H, 6.56; N, 3.96. Found: C, 70.68; H, 7.12; N, 3.60. 10b: mp
N-(1′-(R)-P h en yl-2′-h yd r oxy-eth yl)-2-(R)-m eth yl-ben za -
zep in e 13a . To a stirred solution of lactam 10a (70 mg, 0.20
mmol) in THF (5 mL) at 0 °C was added LiAlH4 (27 mg, 0.71
mmol) as a solid in one portion. The heterogeneous mixture
was allowed to reach room temperature, stirred for 29 h, and
then heated to reflux for 15 min. The mixture was cooled to 0
°C, quenched by the careful addition of 1 M HCl (3.0 mL), and
made alkaline (pH 11) by the addition of 2 M NaOH. The
phases were separated, and the aqueous phase was extracted
with EtOAc. The combined organic phases were washed with
1 M NaOH (10 mL, back extracted with 10 mL of EtOAc) and
brine (10 mL) and dried (Na2SO4). Flash chromatography of
the residue (hexanes/EtOAc 10:1, then EtOAc) provided 34 mg
(50%) of pure 13a as an oil and a 20:1 mixture of diastereo-
mers. 13a :13b: 1H NMR (400 MHz) δ 0.78 (d, J ) 6.1 Hz, 3H),
2.56 (dd, J ) 6.1 and 15.0 Hz, 1H), 2.64 (dd, J ) 7.0 and 14.0
Hz, 1H), 2.68-2.76 (m, 1H), 2.89 (br dd, J ) 8.7 and 14.0 Hz,
1H), 3.01 (br dd, J ) 9.3 and 11.0 Hz, 1H), 3.10 (apt d, J )
13.9 Hz, 1H), 3.17 (apt t, J ) 5.5 Hz, 1H), 3.73 (dd, J ) 5.1
and 10.5 Hz, 1H), 3.80 (s, 6H), 3.90 (apt t, J ) 9.2 Hz, 1H),
3.99 (dd, J ) 4.7 and 7.7 Hz, 1H), 6.51 (s, 1H), 6.55 (s, 1H),
7.24-7.37 (m, 5H); 13C NMR (100 MHz) δ 16.3, 36.9, 43.2, 45.8,
52.2, 56.2, 56.3, 61.4, 66.9, 112.9, 114.2, 128.0, 128.5, 128.7,
131.0, 133.3, 139.3, 147.0, 147.2; HRMS (FAB+) calcd for
147-148 °C; Rf ) 0.11 (hexanes/EtOAc 1:1); [R]23 ) +79.6 (c
D
1
1.3, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.60 (s, 3H), 3.29
(d, J ) 15.4 Hz, 1H), 3.42 (d, J ) 15.2 Hz, 1H), 3.50 (d, J )
15.5 Hz, 1H), 3.72-3.84 (m, 5H), 3.92 (s, 3H), 4.38 (dd, J )
7.4 and 9.1 Hz, 1H), 4.99 (dd, J ) 1.9 and 7.4 Hz, 1H), 6.67 (s,
1H), 6.80-6.83 (m, 3H), 7.07-7.09 (m, 3H); 13C NMR (CDCl3,
75 MHz) δ 25.7, 42.9, 44.4, 56.2, 56.3, 60.3, 70.6, 94.0, 112.8,
113.8, 125.7, 126.5, 127.2, 127.3, 128.4, 141.8, 148.1, 148.2,
167.4; IR (neat) 1652 cm-1; MS m/z 353. Anal. Calcd for C21H23
-
NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.17; H, 6.60; N,
3.95.
N-(1′-(R)-P h en yl-2′-h ydr oxy-eth yl)-2-(R)-m eth yl-h exah y-
d r ozep in e 11a . Alane was generated as follows. THF (4 mL)
was added slowly to AlCl3 (48 mg, 0.36 mmol) at 0 °C. After
stirring for5 min, a solution of LiAlH4 (41 mg, 1.07 mmol) in
1 mL of THF was added slowly via syringe. The mixture was
stirred at room temperature for 20 min and then cooled to -78
°C. To the alane solution was added a precooled (-78 °C)
solution of lactam 4a (73 mg, 0.30 mmol) in 3 mL of THF via
cannula. After 45 min, the solution was warmed to room
temperature, stirred an additional 1 h, and then recooled to 0
°C. The mixture was quenched by the careful addition of 1 M
HCl (5 mL), the phases were separated, and the aqueous was
extracted with CH2Cl2. The combined organic phases were
washed with 2 M NaOH (10 mL, back extracted with 10 mL
of CH2Cl2) and brine (10 mL) and then dried (Na2SO4). Flash
chromatography of the residue (hexanes/EtOAc 10:1, then
EtOAc) provided 76 mg (80%) of 11a shown to be a mixture of
diastereomers (22.0:1) by HPLC analysis of derivative (R)-14.
11a : 1H NMR (300 MHz) δ 1.17 (d, J ) 6.3 Hz, 3H), 1.30-
1.46 (m, 2H), 1.56-1.74 (m, 6H), 2.42-2.50 (m, 1H), 2.87-
2.95 (m, 1H), 3.16-3.22 (m, 1H), 3.38 (br s, 1H), 3.69 (dd, J )
5.2 and 10.3 Hz, 1H), 3.92 (appt t, 1H), 4.06 (dd, J ) 5.0 and
10.3 Hz, 1H), 7.25-7.40 (m, 5H); 13C NMR (100 MHz) δ 20.5,
23.7, 29.3, 31.7, 35.6, 44.9, 54.1, 61.0, 65.0, 127.8, 128.5, 128.8,
138.3; MS m/z 233; HRMS (FAB+) calcd for C15H23NO (M +
H)+ 234.1858, found 234.1856. This material was used without
further purification.
C
21H27NO3 (M + H)+ 342.2069, found 342.2071. This material
was used without further purification in the next step.
Gen er a l P r oced u r e for th e Red u ction of a n ti-Bicyclic
Lactam s with DIBAL. N-(1′-(R)-P h en yl-2′-h ydr oxy-eth yl)-
2-(S)-m eth yl-h exa h yd r oa zep in e 11b. To a solution of anti-
bicyclic lactam 4b (82 mg, 0.33 mmol) in THF (5 mL) at -78
°C was added diisobutylaluminum hydride (0.60 mL, 3.34
mmol) dropwise. The solution was stirred, with gradual
warming to room temperature, for 12 h. The mixture was
cooled to 0 °C and quenched by the careful addition of 1 M
HCl (5.0 mL). It was made alkaline (pH 11) by the addition of
2 M NaOH and stirred for 0.5 h with warming to room
temperature. The phases were separated, and the aqueous
phase was extracted with EtOAc. The combined organic phases
were washed with 1 M NaOH (10 mL, back extracted with 10
mL EtOAc) and brine (10 mL) and dried (Na2SO4). The crude
residue was purified by chromatography (hexanes/EtOAc 10:
1, then EtOAc) to provide 73 mg (95%) of 11b, shown to be a
mixture of diastereomers (21.2:1) by HPLC analysis of the
N-(p-bromobenzyoyl) derivative (S)-14, obtained from (S)-12
(R ) Me). 11b: 1H NMR (300 MHz) δ 1.00 (d, J ) 6.4 Hz, 3H),
1.26-1.50 (m, 4H), 1.51-1.80 (m, 4H), 2.52-3.08 (bs, 1H),
2.76-2.89 (m, 2H), 3.17-3.30 (m, 1H), 3.78 (apt t, J ) 6.2 Hz,
2H), 3.95 (dd, J ) 8.1 and 14.6 Hz, 1H), 7.26-7.38 (m, 5H).
This material was used without further purification in the next
step.
N-(1′-(R)-P h en yl-2′-h yd r oxy-eth yl)-2-(S)-eth yl-h exa h y-
d r oa zep in e 15b. Prepared from lactam 5b (47 mg, 0.18 mmol)
using the general procedure for DIBAL reduction. Flash
chromatography of the crude product (hexanes/EtOAc 10:1,
then EtOAc) provided 27 mg (61%) of 15b shown to be a
mixture of diastereomers (30.5:1) by HPLC analysis of the urea
derivative 15c. 15b: 1H NMR (300 MHz) δ 0.84 (t, J ) 7.4 Hz,
3H), 1.30-1.81 (m, 10H), 2.78-2.95 (m, 3H), 3.70-3.85 (m,
2H), 4.0 (apt t, J ) 6.8 Hz, 1H), 7.31-7.45 (m, 5H); 13C NMR
(100 MHz) δ 11.6, 24.3, 26.3, 29.2, 29.6, 32.9, 45.2, 61.7, 62.7,
68.6, 127.6, 128.5, 128.9, 140.7; MS m/z 247; HRMS (FAB+)
N-(1′-(R)-P h en yl-2′-h yd r oxy-eth yl)-2-(R)-eth yl-h exa h y-
d r ozep in e 15a . Alane was prepared as described for com-
pound 11a . To a solution of alane (0.43 mmol) in THF (5.2
mL) at -78 °C was added lactam 5a (92 mg, 0.35 mmol) as a
solution in THF (3.5 mL). This mixture was stirred for 1 h,
warmed to -40 °C and stirred for 14 h, and then warmed to
-20 °C and stirred for an additional 4 h. The reaction was
quenched by the careful addition of 1 M HCl (3 mL), brine (1
mL) was added, the phases were separated, and the aqueous
phase was extracted with CH2Cl2. The combined organic

Asymmetric Synthesis of 2-Alkyl-Perhydroazepines
J . Org. Chem., Vol. 66, No. 4, 2001 1419
calcd for C16H25NO (M + H)+ 248.2014, found 248.2013. This
material was used without further purification in the next
step.
N-(p -Br om oben zoyl)-2-(S)-m et h yl-h exa h yd r oa zep in e
(S)-14. Prepared from 11b (after hydrogenolysis) as described
for compound (R)-12 (R ) Me). HPLC analysis ((R,R) Whelk-
02 Pirkle covalent, hexanes/2-propanol 90:10, 1 mL/min)
N-(1′-(R)-P h en yl-2′-h yd r oxy-eth yl)-2-(S)-m eth yl-ben za -
zep in e 13b. Prepared from anti-lactam 10b (77 mg, 0.22
mmol) using the general procedure for DIBAL reduction. Flash
chromatography of the crude product (hexanes/EtOAc 10:1,
then 1:1) provided 40 mg (53%) of 13b as an oil and a 30:1
mixture of diastereomers: 1H NMR (300 MHz) δ 0.72 (d, J )
6.6 Hz, 3H), 2.56 (dd, J ) 6.6 and 14.7 Hz, 1H), 2.63-2.77 (m,
2H), 2.98-3.10 (m, 2H), 3.32 (apt d, J ) 14.9 Hz, 1H), 3.37-
3.44 (m, 1H), 3.68 (dd, J ) 5.1 and 10.9 Hz, 1H), 3.83-3.90
(m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.99 (dd, J ) 5.2 and 8.2
Hz, 1H), 6.59 (s, 1H), 6.64 (s, 1H), 7.31-7.38 (m, 5H); 13C NMR
(100 MHz) δ 13.9, 37.0, 42.4, 43.2, 55.2, 56.2, 56.3, 62.1, 70.3,
113.0, 114.3, 127.9, 128.7, 129.0, 131.0, 133.5, 140.1, 147.0,
147.1; MS m/z 341; HRMS (FAB+) calcd for C21H27NO3 (M +
H)+ 342.2069, found 342.2078. This material was used without
further purification in the next step.
Gen er a l P r oced u r e for Hyd r ogen olysis of th e P h en -
eth yl Moiety. 2-(R)-Meth yl-h exa h yd r oa zep in e Hyd r o-
ch lor id e (R)-12 (R ) Me). A solution of amino alcohol 11a
(25 mg, 0.11 mmol) in EtOH (2 mL) was hydrogenated over 5
mg of Pd(OH)2. After 4 h, the mixture was filtered over Celite,
and the pad was rinsed with Et2O. Concentrated HCl (5 drops)
was added to the filtrate prior to concentration. The crude solid
was triturated with Et2O to provide 13 mg (85%) of (R)-12 (R
) Me) as a white solid that was used without further
purification: [R]23D ) -1.8 (c 1.3, CH2Cl2); 1H NMR (300 MHz)
δ 1.56 (d, J ) 6.4 Hz, 3H), 1.63-2.13 (m, 8H), 3.18 (br s, 1H),
3.31 (br s, 1H), 3.43 (br s, 1H), 9.30 (br s, 1H), 9.65 (br s, 1H);
13C NMR (100 MHz) δ 20.6, 25.0, 25.2, 27.0, 33.8, 44.9, 55.1.
2-(R)-Eth yl-h exa h yd r oa zep in e Hyd r och lor id e (R)-12
(R ) Et). Prepared from 15a (37 mg, 0.15 mmol) in 86% yield
using the general procedure for hydrogenolysis: [R]23D ) -5.8
(c 1.0, CH2Cl2); 1H NMR (300 MHz) δ 1.07 (t, J ) 7.2 Hz, 3H),
1.55-2.13 (m, 10H), 3.17 (m, 2H), 3.31 (br s, 1H), 9.26 (br s,
1H), 9.57 (br s, 1H); 13C NMR (100 MHz) δ 10.7, 25.1, 25.2,
27.2, 27.2, 30.3, 45.3, 60.5. This material was used without
further purification in the next step.
showed (S)-14 to be a 21.2:1 mixture of enantiomers: [R]23
+29.8 (c 1.1, CH2Cl2).
)
D
N-(1′-(S)-Met h yl-b en zyla m in o-ca r b on yl)-2-(R)-et h yl-
h exa h yd r oa zep in e 15c. Azepine salt (R)-12 (R)Et) (20 mg,
0.12 mmol) was dissolved in CH2Cl2 (5 mL), washed with 2 M
NaOH (2.5 mL, back extracted with CH2Cl2), and dried (Na2-
SO4). The filtered solution was cooled to 0 °C, and (S)-R-
methylbenzyl isocyanate (0.03 mL, 0.21 mmol) was added. The
mixture was stirred for 6 h with gradual warming to room
temperature and was quenched with brine. The phases were
separated, and the aqueous one was extracted with CH2Cl2.
The combined organic phases were dried (Na2SO4), and the
crude solid was purified by flash chromatography (hexanes,
then hexanes/EtOAc 10:1) to provide 21 mg (64%) of 15c as
an off-white waxy solid. HPLC analysis (Chiracel OD, hexanes/
2-propanol 97.5:2.5, 1 mL/min) showed 15c to be an 11.5:1
mixture of diastereomers: mp 72-75 °C; [R]23D ) -17.4 (c 1.1,
CH2Cl2); 1H NMR (300 MHz) δ 0.92 (t, J ) 7.3 Hz, 3H), 1.15-
1.36 (m, 4H), 1.40-1.66 (m, 4H), 1.53 (d, J ) 6.5 Hz, 3H),
1.66-1.92 (m, 4H), 2.09-2.19 (m, 1H), 2.82-2.97 (m, 1H), 3.53
(br s, 1H), 4.01 (br s, 1H), 4.64 (br d, J ) 6.3 Hz, 1H), 5.10
(quintet, J ) 7.0 Hz, 1), 7.26-7.38 (m, 5H); 13C NMR (100
MHz) δ 11.0, 14.3, 23.1, 25.0, 28.1, 28.9, 30.1, 34.4, 41.4, 50.2,
126.2, 127.1, 128.7, 145.2, 157.4; IR (neat) 3344, 1617, 1528,
1494 cm-1; MS m/z 274; HRMS (FAB+) calcd for C17H26N2O
(M + H)+ 275.2123, found 275.2120.
N-(1′-(S)-Met h yl-b en zyla m in o-ca r b on yl)-2-(S)-et h yl-
h exa h yd r oa zep in e (S)-15c. Prepared from 15b (after hy-
drogenolysis) in 50% yield (two steps) as described for com-
pound (R)-12 (R ) Et). HPLC analysis (Chiracel OD, hexanes/
2-propanol 97.5:2.5, 1 mL/min) showed (S)-15c to be a 30.5:1
mixture of diastereomers: mp 97-102 °C; [R]23 ) +30.8 (c
D
1
0.5, CH2Cl2); H NMR (400 MHz) δ 0.84 (t, J ) 6.8 Hz, 3H),
1.16-1.82 (m, 12H), 1.46 (d, J ) 6.8 Hz, 3H), 2.08 (m, 1H),
2.82 (m, 1H), 4.52 (br d, 1H), 5.05 (m, 1H), 7.19-7.34 (m, 5H);
13C NMR (100 MHz) δ 11.1, 14.4, 23.0, 25.1, 28.2, 28.9, 30.1,
34.6, 41.4, 50.0, 126.3, 127.2, 128.8, 145.2, 157.4; IR (neat)
3333, 1622, 1528, 1494 cm-1; MS m/z 274; HRMS (FAB+) calcd
for C17H26N2O (M + H)+ 275.2123, found 275.2120.
2-(S)-Meth yl-ben za zep in e Hyd r och lor id e (S)-17. Pre-
pared from 13a (40 mg, 0.15 mmol) in 65% yield using the
general procedure for hydrogenolysis: [R]23 ) - 4.7 (c 1.3,
D
CH2Cl2). Anal. Calcd for C13H20ClNO2: C, 60.58; H, 7.82; N,
5.43. Found: C, 58.66; H, 7.55; N, 5.03.
N -(p -B r o m o b e n zo y l)-2-(R )-m e t h y l-h e x a h y d r o a ze -
p in e (R)-14. To a solution of 4-bromobenzoyl chloride (29 mg,
0.13 mmol) in CH2Cl2 (1 mL) at 0 °C was added azepine
hydrochloride (R)-12 (R ) Me) (13 mg, 0.09 mmol) as a solution
in CH2Cl2 (5 mL) and 2 M NaOH (2 mL), dropwise. The
mixture was stirred vigorously for 4 h with gradual warming
to room temperature. The phases were separated, and the
aqueous one was extracted with CH2Cl2. The combined organic
phases were washed with brine and dried (Na2SO4). The crude
material was purified by flash chromatography (hexanes, then
hexanes/EtOAc 10:1) twice to provide 16 mg (60%) of (R)-14
as a mixture of rotamers. HPLC analysis ((R,R) Whelk-02
Pirkle covalent, hexanes/2-propanol 90:10, 1 mL/min) showed
(R)-14 to be a 20:1 mixture of enantiomers, with the major
N-(p-Br om oben zoyl)-2-(R)-m eth yl-ben za zep in e 16. Pre-
pared from (R)-17 (8 mg, 0.02 mmol) in 33% yield, as a mixture
of rotamers, as described for compound (R)-14: [R]23D ) -38.4
1
(c 1.6, CH2Cl2); H NMR (400 MHz) δ 1.06-1.50 (br d, 3H),
2.65-3.12 (m, 4.6H), 3.24 (br t, 0.4H), 3.61 (br d, 0.4H), 3.81
(s, 2.4H), 3.86 (s, 3.6H), 3.96 (br s, 0.6H), 4.62 (br d, 0.6H),
5.14 (br s, 0.4H), 6.49 (s, 0.6H), 6.57 (s, 0.4H), 6.64 (s, 0.4H),
6.69 (s, 0.6H), 6.99 (d, J ) 6.8 Hz, 1.2H), 7.18 (d, J ) 7.2 Hz,
0.8H), 7.47 (d, J ) 7.6 Hz, 1.2H), 7.52 (d, J ) 7.6 Hz, 0.8H);
13C NMR (100 MHz) δ 16.4, 17.6, 30.0, 35.0, 36.5, 37.4, 41.3,
41.7, 43.1, 46.9, 53.3, 56.2, 56.4, 113.3, 113.6, 114.0, 114.4,
123.5, 128.1, 128.6, 128.8, 132.0, 136.2, 147.8, 170.7; IR (neat)
1628, 1518, 1429 cm-1; HRMS (FAB+) calcd for C20H2279BrNO3
(M + H)+ 404.0861, found 404.0852.
one eluting as the second peak: [R]23 ) -28.4 (c 1.6, CH2-
D
Cl2); 1H NMR (400 MHz) δ 1.02 (d, J ) 6.9 Hz, 2H), 1.15-
1.40 (m, 5H), 1.52-1.60 (m, 0.4H), 1.71-1.98 (m, 4H), 2.03-
2.13 (m, 0.4 H), 2.73-2.92 (m, 0.6 H), 2.99 (dd, J ) 11.8 and
14.9 Hz, 0.4H), 3.40 (br d, J ) 15.0 Hz, 0.4H), 3.55-3.67 (m,
0.6H), 4.21 (br d, J ) 13.1 Hz, 0.6 H), 4.62-4.66 (m, 0.4 H),
7.17-7.24 (m, 2H), 7.50-7.53 (m, 2H); 13C NMR (75 MHz) δ
19.6, 21.0, 25.0, 25.3, 27.0, 29.1, 31.1, 30.8, 35.3, 36.3, 40.0,
43.4, 50.4, 53.6, 122.7, 127.6, 127.7, 131.6, 131.7, 136.6, 136.8,
170.0; IR (neat) 1628, 1589, 1422 cm-1; MS m/z 295 (M - 1),
297 (M + 1); HRMS (FAB+) calcd for C14H1879BrNO (M + H)+
296.0650, found 296.0637.
Ack n ow led gm en t. The authors are indebted to the
National Institutes of Health and the National Science
Foundation for financial support of this work.
Su p p or tin g In for m a tion Ava ila ble: X-ray data and
selected 1H and 13C spectra and CD curves. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O001548R