Enantioselective synthesis of α-amino acids from chiral 1,4-benzodiazepine-2,5-diones containing the α-phenethyl group

Full text of DOI:10.1021/jo980777z

2914
J . Org. Chem. 1999, 64, 2914-2918
En a n tioselective Syn th esis of r-Am in o
Acid s fr om Ch ir a l
1,4-Ben zod ia zep in e-2,5-d ion es Con ta in in g
th e r-P h en eth yl Gr ou p
Eusebio J uaristi,* J ose´ Luis Leo´n-Romo, and
Yara Ram´ırez-Quiro´s
Departamento de Quı´mica, Centro de Investigacio´n y de
Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado 14-740, 07000 Me´xico, D.F., Mexico
Received April 24, 1998
Because of their fundamental importance in physi-
ological events and because of their increasing use in
pharmaceutical, agricultural, and food products, R- and
â-amino acids are receiving extraordinary attention in
biology, chemistry, and medicine.1 In particular, an
unprecedented degree of activity has been recorded in
the field of enantioselective synthesis of chiral amino
acids.2,3
F igu r e 1. X-ray crystallographic structure and conformation
of 1-methyl-4-N-[(S)-R-phenylethyl]-1,4-benzodiazepine-2,5-di-
one, (S)-1.7
Sch em e 1
Among the various methods available for the prepara-
tion of enantioenriched R-amino acids, those employing
chiral glycine derivatives4 have been particularly suc-
cessful. On the other hand, (R)- and (S)-R-phenylethyl-
amines are simple, yet efficient, chiral auxiliaries in
asymmetric synthesis.5 In the present work, a novel
chiral glycine derivative was developed by incorporation
of (S)-R-phenylethylamine [(S)-R-PEA] into 1,4-benzodi-
azepine-2,5-dione, (S)-1. 1,3-Stereoinduction in alkylation
reactions of enolate (S)-1-Li was, as anticipated, signifi-
cantly higher than the 1,4-stereoinduction achieved
several years ago by Decorte et al.6 in the related
substrate (S)-2-Li (Scheme 1).
Sch em e 2
Resu lts a n d Discu ssion
A. Syn th esis of En a n tiop u r e Ben zod ia zep in ed i-
on e, (S)-1. As outlined in Scheme 2, N-methylisatoic
* To whom correspondence should be addressed. Tel: (525) 747-
7000. Fax: (525) 747-7113. E-mail juaristi@relaq.mx.
(1) In addition to a substantial number of monographs, a periodical
journal, Amino Acids, Springer-Verlag, has been dedicated to the
subject since 1994.
(2) (a) O’Donnell, M. J ., Ed. R-Amino Acid Synthesis (Tetrahedron
Symposium-in-Print) Tetrahedron 1988, 44, 5253-5614. (b) Williams,
R. M. Synthesis of Optically Active R-Amino Acids; Pergamon Press:
Oxford, 1989. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650.
(3) (a) J uaristi, E., Ed. Enantioselective Synthesis of â-Amino Acids;
Wiley-VCH: New York, 1997. (b) J uaristi, E.; Quintana, D.; Escalante,
J . Aldrichim. Acta 1994, 27, 3-11. (c) Cole, D. C. Tetrahedron 1994,
50, 9517-9582. (d) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996,
25, 117-128.
anhydride was treated with (S)-R-PEA to give benzamide
(S)-3 in excellent yields (92% isolated). N-(Chloroacetyl)-
N-methyl derivative (S)-4 was obtained (88% yield) from
the reaction of (S)-3 with chloroacetyl chloride in triethyl-
amine, and exposure to methanolic sodium methoxide
provided (S)-1 in 73% yield, after recrystallization. Thus,
(S)-1 was obtained in 57% overall yield (Scheme 2).
(4) See, for example: (a) Schoellkopf, U. Tetrahedron 1983, 39,
2085-2091. (b) Seebach, D.; J uaristi, E.; Miller, D. D.; Schickli, C.;
Weber, T. Helv. Chim. Acta 1987, 70, 237-261. (c) Williams, R. M.;
Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem. Soc. 1988, 110, 1547-
1557. (d) Belokon, Y. N.; Sagyan, A. S.; Djamgaryan, S. M.; Bakhmutov,
V. I.; Belikov, V. M. Tetrahedron 1988, 44, 5507-5514. (e) Orena, M.;
Porzi, G.; Sandri, S. J . Org. Chem. 1992, 57, 6532-6536. (f) J uaristi,
E.; Anzorena, J . L.; Boog, A.; Madrigal, D.; Seebach, D.; Garc´ıa-Baez,
E. V.; Garc´ıa-Barradas, O.; Gordillo, B.; Kramer, A.; Steiner, I.;
Zurcher, S. J . Org. Chem. 1995, 60, 6408-6415. (g) Chinchilla, R.;
Falvello, L. R.; Galindo, N.; Na´jera, C. Angew. Chem., Int. Ed. Engl.
1997, 36, 995-997.
B. Con for m a tion a l F ea tu r es of (S)-1. Recrystalli-
zation of benzodiazepinedione (S)-1 from diethyl ether
afforded suitable crystals of the heterocycle, whose
crystallographic structure is presented in Figure 1.7
Salient features in the crystallographic structure are the
anticipated8 boat conformation of the ring and the
orientation of the phenethyl group. As pointed out in the
(5) J uaristi, E.; Escalante, J .; Leo´n-Romo, J . L.; Reyes, A. Tetrahe-
dron: Asymmetry 1998, 9, 715-740.
(7) Atomic coordinates for all the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Centre, 12 Union Road, Cambridge CB2
IEZ, U.K.
(6) Decorte, E.; Toso, R.; Sega, A.; Sunjic, V.; Ruzic-Toroz, Z.; Kojic-
Prodic, B.; Bresciani-Pahor, N.; Nardin, G.; Randaccio, L. Helv. Chim.
Acta 1981, 64, 1145-1149.
10.1021/jo980777z CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/26/1999

Notes
J . Org. Chem., Vol. 64, No. 8, 1999 2915
Ta ble 1. Dia ster eoselectivity of En ola te (S)-1-Li
Alk yla tion s
diastereomer yielda
entry
RX
CH3I
CH3I
CH3I
additive
products
ratio (l:u)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5
5
5
5
6
6
6
6
7
7
7
8
8
8
9
10
19:81
33:67
43:57
10:90
85:15
75:25
62:38
91:9
63
74
89
82
74
79
82
91
78
75
77
55
64
73
71
84
F igu r e 2. X-ray crystallographic structure and conformation
of (1,3R)-dimethyl-4-N-[(S)-R-phenylethyl]-1,4-benzodiazepine-
2,5-dione, (3R,1′S)-5.7
1 equiv of LiCl
6 equiv of LiCl
6 equiv of HMPA
CH3I
PhCH2Br
PhCH2Br 1 equiv of LiCl
PhCH2Br 6 equiv of LiCl
PhCH2Br 6 equiv of HMPA
EtI
EtI
EtI
n-BuI
n-BuI
n-BuI
n-PrI
of salt effects on structure and aggregation state of Li
enolates is more advanced.13
26:74
31:69
17:83
27:73
33:67
19:81
21:79
23:77
In contrast, use of hexamethylphosphoric triamide
(HMPA)14 is known to activate the reactions of lithium
carbanions with electrophiles15 and often to dramatically
alter regio- and/or stereoselectivity.16 In the present
study, both the yields and diastereoselectivities of the
alkylation reactions (entries 4, 8, 11, and 14, Table 1)
improved significantly in the presence of 6 equivalents
of HMPA.17 Therefore, yields rose to 73-91%, with
diastereoselectivities (de) as high as 82%.
10 equiv of LiCl
6 equiv of HMPA
10 equiv of LiCl
6 equiv of HMPA
6 equiv of HMPA
CH2dCH- 6 equiv of HMPA
CH2Br
a
Combined yield after purification.
D. Assign m en t of Con figu r a tion of th e Dia ster eo-
isom er ic P r od u cts 5-10. In the case of the methylated
and benzylated main products, crystals suitable for X-ray
crystallographic analysis were obtained. The resulting
structures (Figures 2 and 3,7 respectively) show an unlike
relative configuration in the major product 5 but a like
relative configuration in the predominant diastereomer
of product 6.18 Thus, the configurations for the newly
created stereogenic center at C(3) are R and S, respec-
tively.
The absolute configuration of C(3) in the major dia-
stereomeric products u-5, l-6, u-7, u-8, and u-9 was also
ascertained by acid hydrolysis to the known R-amino
acids 11-15 (Table 2).19 Although hydrolysis of 5-9 was
not successful upon treatment with 6 N HCl,4b,f excellent
results were achieved with 57% HI.4e Under these condi-
tions, both amide groups were cleaved, and the phenethyl
group was removed to give the desired amino acids in
excellent yields (94-100% yield of the free amino acid
after ion exchange purification). Finally, the configura-
tion of product 10 was assigned by hydrogenation of the
olefinic side chain to give the n-propyl analogue u-9.
literature,9 A1,3 strain10 favors the conformation in which
the C-H bond eclipses the adjacent carbonyl group.
C. Dia ster eoselectivity of Alk yla tion of Ch ir a l
En ola te (S)-1-Li. The results of alkyl halide addition
(at -78 °C) to enolate (S)-1-Li, generated by metalation
of the corresponding benzodiazepinedione with LDA, are
summarized in Table 1. Moderate diastereoselectivities
(diastereomeric excess ) % of major diastereomer - %
of minor diastereomer11) in the 46-70% range (entries
1, 5, 9, and 12) were found in the absence of additives as
1
indicated by integration of the H and 13C NMR spectra
of the crude products. Chemical yields were also moder-
ate under these conditions (55-78%).
Recently,12 addition of “inert” salts to reaction media
has been found to affect the stereoselectivity of alkylation
reactions. Thus, Table 1 includes data obtained in the
presence of 1 or more equiv of lithium chloride. Disap-
pointingly, diastereoselectivities (de) fell to the 14-38%
range in the presence of 6-10 equiv of LiCl. Nevertheless,
it was found that the chemical yields did improve
substantially under these conditions (compare entries 3,
7, 10, and 13 with entries 1, 5, 9, and 12, Table 1). It is
to be expected that seemingly contrasting observations
as those reported here will be understood as knowledge
(13) J uaristi, E.; Beck, A. K.; Hansen, J .; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271-1290 and references
therein.
(14) Normant, H. Bull. Soc. Chim. Fr. 1968, 791-826.
(8) (a) Gilli, G.; Bertolasi, V.; Sacerdoti, M.; Borea, P. A. Acta
Crystallogr. B 1977, 33, 2644-2667. (b) Sunjic, V.; Sega, A.; Lisini,
A.; Kovac, T.; Kajfez, F.; Ruscic, B. J . Heterocycl. Chem. 1979, 16, 757-
761.
(9) Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. Tetrahedron
1987, 43, 2505-2512. (b) Cardillo, G.; Tomasini, C. In Enantioselective
Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New York,
1997; pp 219-221.
(10) (a) J ohnson, F. Chem. Rev. 1968, 68, 375-413. (b) Hoffmann,
R. W. Chem. Rev. 1989, 89, 1841-1860.
(11) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; p 1196.
(12) (a) Loupy, A.; Tchoubar, B.; Astruc, D. Chem. Rev. 1992, 92,
1141-1165. (b) Seebach, D.; Beck, K. A.; Studer, A. Modern Synthetic
Methods, 1995; VCH Publishers: Basel, 1995; pp 1-178. (c) Anaya de
Parrodi, C.; J uaristi, E.; Quintero-Corte´s, L.; Amador, P. Tetra-
hedron: Asymmetry 1996, 7, 1915-1918.
(15) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65,
385-391 and references therein. (b) See also: J uaristi, E.; Madrigal
D. Tetrahedron 1989, 45, 629-636.
(16) (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A.
Benjamin: New York, 1972; pp 527-530. (b) J ackman, L. M.; Lange,
B. C. J . Am. Chem. Soc. 1981, 103, 4494-4499.
(17) The idea behind the use of 6 equiv of the cosolvent is that this
will lead to tetrasolvated lithium cation and an essentially free anion
instead of a contact ion pair or aggregate thereof: (a) Reich, H. J .; Borst,
J . P. J . Am. Chem. Soc. 1991, 113, 1835-1837. See, however: (b)
J ackman, L. M.; Chen, X. J . Am. Chem. Soc. 1992, 114, 403-411.
(18) For a discussion on the like/unlike stereochemical descriptors,
see: (a) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982,
21, 654-660. (b) See also: J uaristi, E. Introduction to Stereochemistry
and Conformational Analysis; Wiley: New York, 1991; pp 52-54.
(19) The major isomer was separated prior to hydrolysis, so that
enantiopure amino acids may be obtained.

2916 J . Org. Chem., Vol. 64, No. 8, 1999
Notes
F igu r e 4. Global energy minimum geometry of enolate
(S)-1-Li at the Becke3LYP/6-31G (d,p) level. HF energy:
-956.730 405 8 hartrees (annotated distances in angstroms).
F igu r e 3. X-ray crystallographic structure and conformation
of 1-methyl-(3S)-benzyl-4-N-[(S)-R-phenylethyl]-1,4-benzodi-
azepine-2,5-dione, (3S,1′S)-6.7
phenylethyl group that is usually favored by allylic A1,3
strain (see section B).
Ta ble 2. Hyd r olysis of P r od u cts 5-9 to th e
r-Su bstitu ted r-Am in o Acid s 11-15 w ith 57% HI a t ca .
100 °C
It can be appreciated in Figure 4 that because of Li+
bridging to the phenyl ring it is the Re face of the reactive
enolate that should be better exposed to addition to the
electrophile, as is observed with alkyl halides (Table 1).
In contrast, benzyl bromide may compete for lithium
bridging, so that approach of this electrophile would be
directed to the Si face of the enolate segment. Neverthe-
less, as pointed out by one reviewer, against this expla-
nation stands the observation that best diastereoselec-
tivities were obtained upon addition of 6 equiv of HMPA,
an additive that is likely to compete for chelation of Li+.17
Thus, Figure 4 may not correspond to a proper repre-
sentation of the enolate in solution.
starting
material
R
product
yield (%)
[R]exptl
[R]20
lit
u-5
l-6
u-7
u-8
u-9
CH3
(R)-11
(S)-12
(R)-13
(R)-14
(R)-15
96
100
94
97
93
-14.0
-31.9
-7.9
-14.2
-32.7
-7.9
In summary, chiral benzodiazepinedione (S)-1 was
prepared in good yield from N-methylisatoic anhydride
and (S)-R-phenylethylamine. Enolate (S)-1-Li was alky-
lated in high yield and with good diastereoselectivity with
various electrophiles and in the presence of HMPA as
cosolvent. Hydrolysis of the main products u-5, l-6, u-7,
u-8, and u-9 with 57% HI proceeded in excellent yield to
afford enantiopure R-substituted R-amino acids (R)-11,
(S)-12, (R)-14, and (R)-15.
PhCH2
CH3CH2
n-Bu
-21.0
-23.1
-21.2
-24.0
n-Pr
E. In ter p r eta tion of th e Ster eoch em ica l P a th -
w a ys for Alk yla tion of (S)-1-Li. Complete geometry
optimization (without symmetry constrains) was per-
formed on the complete structure of enolate (S)-1-Li
(Figure 4) at the ab initio level and within the frame of
density functional theory (DFT) at the Becke3LYP/6-31G-
(d,p) level with the Gaussian 94 program (G94).20 Per-
haps the most interesting finding is that the global
energy minimum for (S)-1-Li shows that lithium is
bridged both to the enolate δ-C,C,Oδ- segment and to
the phenyl ring in a bridged structure that resembles
allyllithium21 and that overcomes the conformation of the
Exp er im en ta l Section 22
2-(Meth yla m in o)-N-[(S)-r-p h en yleth yl]ben za m id e, (S)-
3. In a 25-mL round-bottom flask provided with a magnetic
stirrer was placed 0.50 g (2.82 mmol) of N-methylisatoic
anhydride in 5.0 mL of ethyl acetate, before the dropwise
addition of 0.40 mL (3.20 mmol) of (S)-R-phenylethylamine. The
reaction mixture was heated to 35 °C with stirring, until
complete dissolution of the suspension. (TLC analysis, eluent
hexane-AcOEt 70:30, indicated that the reaction was complete
at this point.) Concentration in a rotatory evaporator gave the
crude product, which was recrystallized from ether-hexane-
ethyl acetate (30:55:15) to afford 0.66 g (92% yield) of benzamide
(S)-3: mp 110-111 °C. [R]28D ) -144.0 (c ) 10, CHCl3); 1H NMR
(CDCl3, 270 MHz) δ 1.57 (d, J ) 6.6 Hz, 3H), 2.83 (s, 3H), 5.24
(dq, J 1 ) 6.6 Hz, J 2 ) 5.2 Hz, 1H), 6.26 (b, 1H), 6.56 (t, J ) 7.9
Hz, 1H), 6.66 (d, J ) 8.6 Hz, 1H), 7.2-7.4 (m, 7H), 7.50 (b, 1H);
(20) Frisch, M. J .; Trucks G. W.; Schelegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith. T. A.; Peterson,
G. A.; Montgomery, J . A.; Raghavachai, K.; Al-Laham, M. A.; Zarrze-
wski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .; Stefanov, B.
R.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen,
W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts, R.; Martin,
R. L.; Fox, D. J .; Binkley, J . S.; Defreess, D. J .; Baker, J .; Stewart, J .
P.; Head-Gordon, M.; Gonzales, C.; Pople, J . A. GAUSSIAN 94 (revision
C.2); Gaussian: Pittsburgh, 1995.
(21) (a) Streitwieser, A.; Bachrach, S. M.; Dorigo, A.; Schleyer, P. v.
R. In Lithium Chemistry; Sapse, A.-M., Schleyer, P. v. R., Eds.; Wiley:
New York, 1995; Chapter 1. (b) Lambert, C.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1129. (c) See also: Ghera, E.; Kleiman,
V.; Hassner, A. J . Org. Chem. 1999, 64, 8. (d) See also: Posner, G. H.;
Lentz, C. M. J . Am. Chem. Soc. 1979, 101, 934.
(22) (a) For general experimental procedures, see: J uaristi, E.;
Lo´pez-Ruiz, H.; Madrigal, D.; Ram´ırez-Quiro´s, Y.; Escalante, J . J . Org.
Chem. 1998, 63, 4706. (b) For a detailed description of the computa-
tional method, see: Cuevas, G.; J uaristi, E. J . Am. Chem. Soc. 1997,
119, 7545.

Notes
J . Org. Chem., Vol. 64, No. 8, 1999 2917
13C NMR (CDCl3, 67.8 MHz) δ 22.0, 29.6, 48.9, 111.2, 114.4,
114.9, 126.1, 127.1, 127.3, 128.7, 132.9, 143.4, 150.6, 169.0.
Anal. Calcd for C16H18N2O: C, 75.59; H, 7.09. Found: C, 75.94;
H, 7.14.
1-Meth yl-(3S)-ben zyl-4-[(S)-r-p h en yleth yl]-1,4-ben zod i-
a zep in e-2,5-d ion e, (3S,1′S)-6, l-6. The general procedure was
followed with 0.50 g (1.70 mmol) of (S)-1 in 10 mL of THF, 1.8
mL (6.08 mmol) of HMPA, 0.26 mL (0.18 g, 1.83 mmol) of (i-
Pr)2NH, 0.90 mL (1.70 mmol) of 1.9 M n-BuLi, and 0.30 mL (0.43
g, 2.53 mmol) of benzyl bromide. The isolated product (0.59 g,
91% yield) consisted of a 91:9 mixture of (3S,1′S)-6 and (3R,1′S)-6
diastereomeric products, which were separated by flash column
chromatography (hexane-AcOEt 90:10) to give 0.40 g (61%
yield) of the major product, l-6: mp 160-161 °C; [R]28D ) -117.2
2-[N-(Ch lor oa cetyl)m eth yla m in o]-N-[(S)-r-p h en yleth yl]-
ben za m id e, (S)-4. In a 500 mL round-bottom flask was placed
3.60 g (14.16 mmol) of (S)-3 and 180 mL of triethylamine before
the addition of 30 mL of CH2Cl2. The resulting solution was
cooled to 0 °C, and then 1.50 mL (18.4 mmol) of chloroacetyl
chloride was added dropwise. The reaction mixture was stirred
at 0 °C for 1.5 h and at ambient temperature for an additional
hour. Solvent removal at reduced pressure afforded the crude
product, which was washed with three 20-mL portions of 15%
K2CO3 solution. Extraction with CH2Cl2 (3 × 20 mL) and
concentration gave 4.2 g (90% yield) of crude product, which was
purified by flash chromatography (hexane-AcOEt 90:10) to give
1
(c ) 5.8, CHCl3); H NMR (CDCl3, 400 MHz) δ 0.95 (d, J ) 7.2
Hz, 3H), 2.43 (dd, J 1 ) 9.9 Hz, J 2 ) 13.2 Hz, 1H), 2.60 (dd, J 1
)
7.3 Hz, J 2 ) 13.2 Hz, 1H), 3.20 (s, 3H), 4.12 (dd, J 1 ) 9.9 Hz, J 2
) 7.3 Hz, 1H), 6.16 (q, J ) 7.2 Hz, 1H), 6.91-8.06 (m, 14 H);
13C NMR (CDCl3, 100 MHz) δ 15.0, 35.7, 53.3, 61.8, 120.9, 125.6,
127.3, 127.4, 127.9, 128.0, 128.4, 128.6, 128.7, 129.2, 129.8, 130.9,
132.3, 136.4, 139.6, 140.0, 166.7, 170.3.
4.1 g (88% yield) of pure (S)-4: mp 91-93 °C. [R]28 ) -34.0 (c
D
1
Anal. Calcd for C25H24N202: C, 78.12; H, 6.25. Found: 78.50;
H, 6.22.
) 10, CHCl3); H NMR (400 MHz; 100 °C; DMSO-d6) δ 1.46 (d,
J ) 6.9 Hz, 3H), 3.11 (b, 3H), 3.94 (b, 2H), 5.09 (dq, J 1 ) 6.9 Hz,
J 2 ) 5.3 Hz, 1H), 7.2-7.58 (m, 9H), 8.54 (b, 1H); 13C NMR
(CDCl3, 100 MHz) δ 21.5, 37.8, 41.6, 49.5, 126.3, 126.2, 127.7,
127.8, 128.8, 128.9, 129.0, 129.1, 129.2, 131.9, 168.8, 182.2.
Anal. Calcd for C18H19ClN2O2: C, 65.35; H, 5.79. Found: C,
65.89; H, 5.74.
1-Meth yl-(3R)-eth yl-4-[(S)-r-p h en yleth yl]-1,4-ben zod ia z-
ep in e-2,5-d ion e, (3R,1′S)-7, u -7. The general procedure was
followed with 0.25 g (0.85 mmol) of (S)-1 in 5.0 mL of THF and
0.9 mL of HMPA, 0.13 mL (0.09 g, 0.93 mmol) of diisopropyl-
amine, 0.49 mL (0.93 mmol) of 1.9 M n-BuLi, and 0.10 mL (0.195
g, 1.25 mmol) of ethyl iodide. The isolated product (0.21 g, 77%
yield) consisted of a 83:17 mixture of (3R,1′S)-7 and (3S,1′S)-7
diastereomeric products, which were separated by flash chro-
matography (hexanes-ethyl acetate 95:5) to give 0.13 g (47%
yield) of the major product, u-7, and 36 mg (13% yield) of the
minor product, l-7.
(3R,1′S)-7: mp ) 90-91 °C; [R]28D ) +100.0 (c ) 0.35, EtOAc);
1H NMR (CDCl3, 400 MHz) δ 0.25 (t, J ) 7.7 Hz, 3H), 0.61-
1.05 (m, 2H), 1.61 (d, J ) 7.1 Hz, 3H), 3.38 (s, 3H), 3.88 (dd, J 1
) 9.9 Hz, J 2 ) 6.7 Hz, 1H), 6.31 (q, 7.1 Hz, 1H), 7.09-7.91 (m,
9H); 13C NMR (CDCl3, 100 MHz) δ 10.7, 15.9, 23.2, 35.9, 53.2,
60.9, 120.6, 125.5, 128.0, 128.3, 128.6, 129.4, 130.1, 130.9, 132.1,
139.6, 139.7, 166.1, 171.4.
1-Met h yl-4-N-[(S)-r-p h en ylet h yl]-1,4-b en zod ia zep in e-
2,5-d ion e, (S)-1. In a three-necked, round-bottom flask provided
with a magnetic stirrer was placed 3.6 g (10.90 mmol) of (S)-4,
which was dissolved with 40 mL of dry methanol under nitrogen
before the addition of 150 mL of 0.1 M CH3ONa (15.0 mmol).
The reaction mixture was heated to reflux for 3 h, allowed to
cool to ambient temperature, washed with brine solution,
extracted with four 25-mL portions of CH2Cl2, and concentrated
to give the crude product, which was recrystallized from diethyl
ether to afford 2.60 g (73%, yield) of crystalline (S)-1: mp ) 150-
151 °C; [R]28 ) +22.0 (c ) 6, CH3OH); 1H NMR (DMSO-d6; 70
D
°C; 270 MHz) δ 1.56 (d, J ) 7.2 Hz, 3H), 3.31 (b, 3H), 3.45 (d, J
) 16.6 Hz, 1H), 3.71 (d, J ) 16.6 Hz, 1H), 5.96 (q, J ) 7.2 Hz,
1H), 7.17-7.95 (m, 9H); 13C NMR (CDCl3, 27 °C; 67.8 MHz) δ
16.0, 16.4, 34.6, 34.7, 46.2, 46.3, 52.3, 52.4, 120.7, 125.4, 125.6,
127.2, 128.5, 128.8, 130.8, 132.0, 139.7, 140.9, 167.0, 169.2, 169.8.
Anal. Calcd for C18H18N2O2: C, 73.46; H, 6.12. Found: C,
73.24; H, 6.27.
Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88. Found: C,
74.55; H, 6.98.
(3S,1′S)-7: mp ) 128-130 °C; [R]28 ) +27.0 (c ) 1, AcOEt);
D
1H NMR (CDCl3, 400 MHz) δ 0.75 (t, J ) 7.7 Hz, 3H), 1.27 (m,
2H), 1.60 (d, J ) 6.95 Hz, 3H), 3.20 (s, 3H), 3.87 (t, J ) 8.4 Hz,
1H), 6.34 (q, J ) 7.0 Hz, 1H), 7.06-7.91 (m, 9H); 13C NMR
(CDCl3, 100 MHz) δ 11.0, 16.2, 23.7, 35.7, 53.0, 61.2, 120.3, 125.3,
127.4, 128.0, 128.5, 129.4, 130.8, 132.1, 139.6, 139.7, 166.5, 170.7.
Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88. Found: C,
74.99; H, 6.95.
Gen er a l P r oced u r e for th e Rea ction of Ben zod ia z-
ep in ed ion e En ola te. [(S)-1-Li] w ith Electr op h iles. A solu-
tion of (i-Pr)2NH (0.25 mL, 1.83 mmol) in 15 mL of dry THF
was cooled to 0 °C before the slow addition of 1.0 equiv of n-BuLi
(ca. 1.9 M in hexane). The resulting solution was stirred at 0 °C
for 40 min and then cooled to -78 °C before the dropwise
addition of 0.50 g (1.70 mmol) of (S)-1 in 10 mL of dry THF.
Stirring was continued for 1 h at -78 °C in order to secure the
complete formation of the enolate. The alkylating agent (2.50
mmol, 1.5 equiv) was added dropwise, and then 1.0 mL of dry
THF was added via syringe. The reaction mixture was stirred
at -78 °C until the reaction was complete (TLC monitoring). At
this point, the reaction was quenched by the addition of
saturated aqueous NH4Cl solution and extracted with four
portions of CH2Cl2. The combined extracts were dried over anhyd
Na2SO4, filtered, and concentrated. Final purification was ac-
complished by flash chromatography.
1-Meth yl-(3R)-n -bu tyl-4-[(S)-r-p h en yleth yl]-1,4-ben zod i-
a zep in e-2,5-d ion e, (3R,1′S)-8, u -8. The general procedure was
followed with 0.70 g (2.38 mmol) of (S)-1 in 13 mL of THF and
2.54 mL of HMPA, 0.35 mL (0.26 mg, 2.56 mmol) of diisopro-
pylamine, 1.23 mL (2.28 mmol) of 1.9 M n-BuLi, and 0.30 mL
(0.48 mg, 2.63 mmol) of n-butyl iodide. The isolated product (0.61
g, 73% yield) consisted of a 81:19 mixture of (3R,1′S)-8 and
(3S,1′S)-8 diastereomeric products, which were separated by
flash chromatography (hexanes-ethyl acetate 100:0 f 90:10)
to give 0.31 g (52% yield) of the major product, u-8, and 0.09 g
(11% yield) of the minor product, l-8.
(3R,1′S)-8: mp 108-109 °C; [R]28D ) +85.1 (c ) 0.47, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.26 (t, J ) 7.2 Hz, 3H), 0.55-
1.21 (m, 6H), 1.63 (d, J ) 7.3 Hz, 3H), 3.36 (s, 3H), 3.90 (dd, J 1
) 9.9 Hz, J 2 ) 6.5 Hz, 1H), 6.34 (q, J ) 7.2 Hz, 1H), 7.10-7.92
(m, 9H); 13C NMR (CDCl3, 100 MHz) δ 10.6, 15.8, 23.2, 29.7,
35.7, 35.8, 53.2, 60.8, 120.5, 125.4, 128.0, 128.2, 128.5, 130.0,
130.8, 132.0, 139.5, 139.7, 166.1, 171.3.
(1,3R)-Dim eth yl-4-[(S)-r-ph en yleth yl]-1,4-ben zodiazepin e-
2,5-d ion e, (3R,1′S)-5, u -5. The general procedure was followed
with 0.30 g (1.02 mmol) of (S)-1 in 7.0 mL of THF, 1.1 mL of
HMPA (6.19 mmol), 0.09 mL (1.10 mmol) of (i-Pr)2NH, 0.62 mL
(1.1 mmol) of 1.9 M n-BuLi, and 0.10 mL (0.23 g, 1.60 mmol) of
methyl iodide. The isolated product (0.26 g, 82% yield) consisted
of a 90:10 mixture of (3R,1′S)-5 and (3S,1′S)-5 diastereomeric
products, which were separated by flash column chromatography
(hexanes-ethyl acetate, 95:5 f 90:10) to give 0.15 g (48% yield)
Anal. Calcd for C22H26N2O2: C, 75.43; H, 7.43. Found: C,
75.48; H, 7.46.
(3S,1′S)-8: mp 130-131 °C; [R]28D ) +36.2 (c ) 0.65, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 0.69 (t, J ) 6.9 Hz, 3H), 0.98-
1.30 (m, 6H), 1.60 (d, J ) 6.9 Hz, 3H), 3.19 (s, 3H), 3.94 (dd, J 1
= J 2 ) 7.3 Hz, 1H), 6.31 (q, J ) 6.9 Hz, 1H), 7.06-7.91 (m, 9H);
13C NMR (CDCl3, 100 MHz) δ 13.6, 16.2, 22.1, 28.6, 30.2, 35.7,
53.1, 59.9, 120.6, 125.3, 127.4, 127.9, 128.5, 129.5, 130.8, 132.1,
139.6, 139.7, 166.6, 170.7.
of the major product, u-5: mp 101-102 °C. [R]28 ) -91.0 (c )
D
1, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.52 (d, J ) 7.2 Hz,
3H), 1.62 (d, J ) 7.2 Hz, 3H), 3.37 (s, 3H), 4.11 (q, J ) 7.2 Hz,
1H), 6.32 (q, J ) 7.2 Hz, 1H), 7.10-7.94 (m, 9H); 13C NMR
(CDCl3, 400 MHz) δ 15.4, 15.8, 35.9, 53.0, 54.8, 120.7, 125.4,
127.9, 127.9, 128.5, 130.0, 130.9, 132.0, 139.4, 139.8, 166.0, 171.8.
Anal. Calcd for C19H20N2O2: C, 74.05; H, 6.53. Found: C,
74.39; H, 6.68.
Anal. Calcd for C22H26N2O2: C, 75.43; H, 7.43. Found: C,
75.24; H, 7.36.

2918 J . Org. Chem., Vol. 64, No. 8, 1999
Notes
1-Meth yl-(3R)-n -p r op yl-4-[(S)-r-p h en yleth yl]-1,4-ben zo-
d ia zep in e-2,5-d ion e, (3R,1′S)-9, u -9. The general procedure
was followed with 1.4 g (4.76 mmol) of (S)-1 in 28 mL of THF
and 5.08 mL of HMPA, 0.72 mL (0.56 g, 5.5 mmol) of diisoprop-
ylamine, 2.9 mL (5.5 mmol) of 1.9 M n-BuLi, and 0.55 mL (0.97
g, 5.71 mmol) of n-propyl iodide. The isolated product (0.61 g,
73% yield) consisted of a 79:21 mixture of (3R,1′S)-9 and
(3S,1′S)-9 diastereomeric products, which were separated by
monitoring). The solution was then allowed to cool to ambient
temperature and extracted four times with EtOAc. The aqueous
phase was evaporated to afford the crude amino acid chloride,
which was adsorbed to acidic ion-exchange resin Dowex 50W ×
8. The resin was washed with distilled H2O until the washings
came out neutral, and then the free amino acid was recovered
with 1 N aqueous NH3. Evaporation afforded the crystalline
amino acid, which was dried under vacuum at 40 °C.
flash chromatography (hexanes-ethyl acetate, 97.5:2.5
f
(R)-Ala n in e, (R)-11. Derivative (3R,1′S)-5 (0.20 g, 0.65 mmol)
was hydrolyzed according to the general procedure to afford 55.2
mg (0.62 mmol, 96% yield) of pure free amino acid (R)-5: mp
90:10) to give 0.153 g (13% yield) of the minor product, l-9, and
0.576 g (69% yield) of the major product, u-9.
(3S,1′S)-9: mp 159-160 °C; [R]28 ) -19.6 (c ) 0.94, CH2-
291 °C dec (lit.23a mp 291 °C dec); [R]28 ) -14.0 (c ) 6, 1 N
D
D
Cl2); 1H NMR (CDCl3, 270 MHz) δ 0.68 (t, J ) 5.9 Hz, 3H), 1.11-
1.25 (m, 4H), 1.58 (d, J ) 7.2 Hz, 3H) 3.17 (s, 3H), 3.93 (dd, J 1
= J 2 ) 8.17 Hz, 1H), 6.80 (q, J ) 7.2, 1H), 7.05 (d, J ) 8.4 Hz,
1H), 7.2-7.4 (m, 6H), 7.47 (td, J 1 ) 7.91 Hz, J 2 ) 1.73 Hz, 1H),
7.89 (dd, J 1 ) 7.91 Hz, J 2 ) 1.73 Hz, 1H); 13C NMR (CDCl3,
67.5 MHz) δ 13.7, 16.3, 20.0, 32.8, 35.7, 53.2, 59.8, 120.4, 125.3,
127.4, 128.0, 128.5, 130.9, 132.1, 139.7, 166.6, 170.8.
HCl) [lit.23a [R]28D ) -14.2 (c ) 6, 1 N HCl)]; 1H NMR (D2O, 400
MHz) δ 1.44 (d, J ) 7.3 Hz, 3H), 3.74 (q, J ) 7.3 Hz, 1H).
(S)-P h en yla la n in e, (S)-12. Derivative (3S,1′S)-6 (0.25 g, 0.65
mmol) was hydrolyzed according to the general procedure to
afford 106 mg (quantitative yield) of pure, free amino acid (S)-
12: mp 270-274 °C (lit.23d mp 270-275 °C); [R]28D ) -31.9 (c )
1
2, H2O) [lit.23d [R]28 ) -32.7 (c ) 2, H2O)]; H NMR (D2O, 400
D
Anal. Calcd for C21H24N2O2: C, 75.13; H, 7.14. Found: C,
74.93; H, 7.33.
MHz) δ 3.07 (dd, J 1 ) 14.3 Hz, J 2 ) 8.1 Hz, 1H), 3.24 (dd, J 1
)
14.3 Hz, J 2 ) 5.1 Hz, 1H), 3.94 (dd, J 1 ) 14.3 Hz, J 2 ) 5.1 Hz,
1H), 7.27-7.38 (m, 5H).
(3R,1′S)-9: mp 129-131 °C; [R]28D ) -43.4 (c ) 1.1, CH2Cl2);
1H NMR (CDCl3, 270 MHz) δ 0.38 (t, J ) 6.9 Hz, 3H), 0.8-0.9
(m, 4H), 1.65 (d, J ) 7.2 Hz, 3H), 3.35 (s, 3H), 3.35 (s, 3H), 3.98
(dd, J 1 ) 10.6 Hz, J 2 ) 10.1 Hz, 1H), 6.37 (q, 7.2 Hz, 1H), 7.14
(d, J ) 7.9 Hz, 1H), 7.26-7.54 (m, 7H), 7.92 (t, J ) 7.8 Hz, 1H);
13C (CDCl3, 67.5 MHz) δ 11.4, 16.8, 20.5, 32.2, 34.3, 52.9, 58.4,
120.9, 125.8, 127.1, 128.2, 128.4, 130.5, 132.4, 139.1, 165.8, 169.1.
1-Meth yl-(3R)-(2-pr open yl)-4-[(S)-r-ph en yleth yl]-1,4-ben -
zod ia zep in e-2,5-d ion e, (3R,1′S)-10, u -10. The general proce-
dure was followed with 0.25 g (0.85 mmol) of (S)-1 in 5 mL of
THF, 0.9 mL (3.04 mmol) of HMPA, 0.26 mL (0.18 g, 1.83 mmol)
of (i-Pr)2NH, 0.45 mL (0.85 mmol) of 1.9 M n-BuLi, and 0.084
mL (0.118 g, 1.02 mmol) of allyl bromide. The isolated product
(0.211 g, 74.3% yield) consisted of a 77:23 mixture of (3R,1′S)-
10 and (3S,1′S)-10 diastereomeric products, which were sepa-
rated by flash chromatography (hexanes-ethyl acetate 100:0 f
90:10) to give 44.3 mg (0.132 mmol, 22% yield) of the minor
product, l-10, and 141.4 mg (0.423 mmol, 67% yield) of the major
product, u-10.
(R)-2-Am in obu tyr ic Acid , (R)-13. Derivative (3R,1′S)-7 (230
mg, 0.71 mmol) was hydrolyzed according to the general
procedure to afford 68.7 mg (94% yield) of pure, free amino acid
(R)-6: mp > 298 °C (lit.23b mp > 300 °C); [R]28 ) - 7.8 (c ) 4,
D
H2O) [lit.23b [R]D ) -7.9 (c ) 4, H2O)]; H NMR (D2O, DCl, 400
1
MHz) δ 0.93 (t, J ) 7.7 Hz, 3H), 1.84 (m, 2H), 3.67 (t, J ) 5.8
Hz, 1H).
(R)-Nor leu cin e, (R)-14. Derivative (3R,1′S)-8 (208 mg, 0.59
mmol) was hydrolyzed according to the general procedure to
afford 75 mg (97% yield) of pure, free amino acid (R)-14: mp >
300 °C (lit.23c mp > 300 °C); [R]D ) -21.0 (c ) 4.7, 6 N HCl)]
[lit.23c [R]28 ) - 21.2 (c ) 4.7, 6 N HCl)]; 1H NMR (D2O, DCl
D
400 MHz) δ 0.90 (t, J ) 7.4 Hz, 3H), 1.27-1.50 (m, 6H), 1.78-
2.00 (m, 2H), 3.82 (t, J ) 6.2 Hz, 1H).
(R)-Nor va lin e, (R)-15. Derivative (3R,1′S)-9 (300 mg, 0.59
mmol) was hydrolyzed according to the general procedure to
afford 97.3 mg (93% yield) of pure, free amino acid (R)-15: mp
>300 °C (lit.23e mp >300 °C); [R]D ) -23.1 (c ) 10, 5 N HCl)]
(3S,1′S)-10: mp 102-104 °C; [R]28D ) -123.33 (c ) 0.3, CH2-
Cl2); 1H NMR (CDCl3, 270 MHz) δ 1.54 (δ, J ) 6.6 Hz, 1H), 1.91-
1.98 (m, 2H), 3.14 (s, 3H), 3.98 (dd, J 1 = J 2 ) 9.2 Hz, 1H), 4.67
[lit.23e [R]28 ) -24.0 (c ) 10, 5 N HCl)]; 1H NMR (D2O, 300
D
MHz) δ 0.77 (t, J ) 7.3 Hz, 3H), 1.17-1.34 (m, 2H), 1.56-1.75
(m, 2H), 3.57 (t, J ) 6.6 Hz, 1H).
(dd, J 1 ) 1.32, J 2 ) 17.2 Hz, 1H), 4.91 (dd, J 1 ) 1.32 Hz, J 2
)
Deter m in a tion of th e Absolu te Con figu r a tion of th e
Ma jor P r od u ct in Com p ou n d s 10. Ca ta lytic Hyd r ogen a -
tion of u -10 To Give u -9. To determine the absolute configu-
ration of allylic products 10, a chemical correlation was carried
out. Thus, 400 mg (1.19 mmol) of the major diastereomeric
product 10, 4 mL of dry methanol, and 32 mg (10% w/w) of Pd/C
10% were suspended in a hydrogenation flask vessel and reduced
in a hydrogen atmosphere (50 psi) during 30 min. The resulting
mixture was filtered off on a Celite bed, and the filtrate was
concentrated on a rotatory evaporator to give 390 mg (97% yield)
of the reduced compound u-9.
9.9 Hz, 1H), 5.9 (ddd, J 1 ) 7.2 Hz, J 2 ) 9.9 Hz, J 3 ) 17.2 Hz,
1H), 7.04 (d, J ) 9.2 Hz, 1H), 7.21-7.31 (m, 6H), 7.47 (t, J )
7.3 Hz, 1H), 7.89 (d, J ) 9.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 16.4, 34.8, 35.6, 53.1, 59.3, 118.7, 120.5, 125.4, 127.4, 128.0,
128.5, 129.4, 130.9, 132.1, 132.4, 139.6, 166.5, 170.1.
Anal. Calcd for C21H22N2O2: C, 75.45; H, 6.57. Found: C,
75.55; H, 6.75.
(3R,1′S)-10: mp 139-141 °C; [R]28 ) -29.7 (c ) 0.3, CH2-
D
Cl2); H NMR (CDCl3, 400 MHz) δ 1.27 (ddd, J 1 ) 10.28, J 2
)
1
10.6, J 3 ) 7.3 Hz, 1H), 1.60 (d, J ) 7.3 Hz, 3H), 1.61 (m, 1H),
3.34 (s, 3H), 4.01 (dd, J 1 ) 10.3, 10.6 Hz, 1H), 4.35 (dd, J 1
)
16.8 Hz, J 2 ) 1.3, 1H), 4.65 (dd, J 1 ) 9.88 Hz, J 2 ) 1.3 Hz, 1H),
4.91 (ddt, J 1 ) 16.8 Hz, J 2 ) 9.88, J 3 ) 6.9 Hz, 1H), 6.30 (q, J
) 7.3 Hz, 1H), 7.1 (d, J ) 8.08 Hz, 1H), 7.24-7.42 (m, 6H), 7.48
Ack n ow led gm en t. We are grateful to H. Lo´pez-
Ruiz and V. M. Gonza´lez for the recording of several
NMR spectra and to CONACYT for financial support
via grant 211085-5-L0006E. We also are indebted to Dr.
A. Vela for his assistance with the computational
calculations and to the reviewers for useful comments.
(dd, J 1 ) 8.0 Hz, J 2 ) 7.3 Hz, 1H), 7.90 (dd, J 1 ) 7.7 Hz, J 2
)
1.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.4, 34.8, 35.6, 53.1,
59.3, 118.7, 120.5, 125.4, 127.4, 128.0, 128.5, 129.4, 130.9, 132.1,
132.4, 139.6, 166.5, 170.1.
Gen er a l P r oced u r e for th e Hyd r olysis of th e Alk yla ted
Ben zod ia zep in ed ion es 11-15. A suspension of 1 mmol of
adduct in 5 mL of 57% HI was heated in a sealed ampule to
95-100 °C until the starting material was consumed (TLC
J O980777Z
(23) Aldrich Chemical Catalogue, 1994-1995; Aldrich: Milwaukee,
1994; (a) p 37; (b) p 61; (c) p 1064; (d) p 1115; (e) p 1102.