General approach for the stereocontrolled construction of the beta-lactam ring in amino acid-derived 4-alkyl-4-carboxy-2-azetidinones.

Article abstract of DOI:10.1021/jo025571j

The first general approach toward the asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived from amino acids is described. The stereoselective construction of the beta-lactam ring was achieved through base-mediated intramolecular cyclization of the corresponding N(alpha)-chloroacetyl derivatives bearing (+)- or (-)-10-(N,N-dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up to 82%).

Full text of DOI:10.1021/jo025571j

J . Org. Chem. 2002, 67, 3953-3956
3953
Ch a r t 1. 4-Alk yl-4-ca r boxy-2-a zetid in on es
Der ived fr om Am in o Acid s
Gen er a l Ap p r oa ch for th e Ster eocon tr olled
Con str u ction of th e â-La cta m Rin g in
Am in o Acid -Der ived
4-Alk yl-4-ca r boxy-2-a zetid in on es
Guillermo Gerona-Navarro,
M. Teresa Garc´ıa-Lo´pez, and Rosario Gonza´lez-Mun˜iz*
Instituto de Qu´ımica Me´dica (CSIC), J uan de la Cierva 3,
28006 Madrid, Spain
suitable position for the appendage of the asymmetric
inductor. Among the carboxylate bearing auxiliaries, we
selected the 10-(N,N-dicyclohexylsulfamoyl)isoborneol
that was described to be a practical stereoface-directing
moiety in Diels-Alder additions,7 R-acetoxylation, and
R-amination reactions,8 2 + 2 cycloadditions,9 and C-C
bond formation at both CR or Câ positions of carbox-
ylates.10 In this respect, a few papers described its
application to the diastereoselective alkylation of cyano
esters that, after convenient elaboration, afforded both
enantiomers of the same R,R-dialkylamino acid.11 To the
best of our knowledge, only one example describes the
use of this auxiliary for the direct asymmetric alkylation
of amino acid derivatives.12
iqmg313@iqm.csic.es
Received J anuary 31, 2002
Abstr a ct: The first general approach toward the asym-
metric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived
from amino acids is described. The stereoselective construc-
tion of the â-lactam ring was achieved through base-
mediated intramolecular cyclization of the corresponding
NR-chloroacetyl derivatives bearing (+)- or (-)-10-(N,N-
dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up
to 82%).
In connection with our current interest in conforma-
tionally constrained amino acid and peptide derivatives,
we have recently reported the first concise and versatile
route to the preparation of 3-unsubstituted 4-alkyl-4-
carboxy-2-azetidinones II (Chart 1).1,2 The synthetic
strategy involves, as the key step, the formation of the
C3-C4 bond of the â-lactam ring through base-promoted
intramolecular alkylation of the corresponding easily
available NR-benzyl-NR-chloroacetyl-substituted amino
acid derivatives I.2 While modest selectivity was found
in the intramolecular cyclization of Trp, Phe, and Leu
derivatives (ee up to 56%), no stereoselectivity at all was
observed for Ala, Glu, and Orn analogues.2 It was
suggested that, in the particular cases of â-ramified
amino acids, the cyclization reaction proceeded by way
of planar enolate intermediates, which possess axial
chirality, according to the recently proposed concept of
the memory of chirality.3
Due to the moderate or null enantioselectivity of the
intramolecular cyclization, the application of other asym-
metric protocols to this convenient procedure needs to
be addressed. It was expected that the chiral auxiliary-
based methodologies commonly used for the asymmetric
synthesis of R-alkyl R-amino acid derivatives4 could result
in a general strategy to facilitate the preparation of these
â-lactams enantiomerically pure. In related amino acid
templates the chiral auxiliary can be borne either at the
amino or at the carboxylate functions.5,6 In the case of
structure I, the carboxylate moiety appears to be the most
In this paper, we wish to present our preliminary study
on the asymmetric synthesis of 1,4,4-trisubstituted 2-aze-
tidinones resulting from N-chloroacetyl Phe and Ala
derivatives, bearing the chiral auxiliary 10-(N,N-dicy-
clohexylsulfamoyl)isoborneol at the carboxylic function.
To synthesize the required N-chloroacetyl derivatives
10-12, we first investigate the incorporation of the
alcoholic chiral auxiliary into Z-Phe-OH by DCC/DMAP-
mediated esterification.13 However, after several at-
(5) For some selected reviews, see: (a) Duthaler, R. O. Tetrahedron
1994, 50, 1540-1650. (b) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 225-227. (c) Abella´n, T.; Chinchilla, R.; Galindo, N.; Na´jera, C.;
Sansano, J . M. Eur. J . Org. Chem. 2000, 2689-2697.
(6) For chiral auxiliaries at the carboxylate function used for the
asymmetric synthesis of R-amino acids, including esters, amides and
imides, see: (a) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Maroto, R.; Quiroga,
M. L. J . Org. Chem. 1995, 60, 7934-7940. (b) Tanaka, K.; Ahn, M.;
Watanabe, Y.; Fuji, K. Tetrahedron: Asymmetry 1996, 7, 1771-1782.
(c) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30,
6009-6010. (d) Karoyan, P.; Sagan, S.; Clodic, G.; Lavielle, S.;
Chassaing, G. Bioorg. Med. Chem. Lett. 1998, 8, 1369-1374. (e) Myers,
A. G.; Gleason, J . L.; Yoon, T.; Kung, D. W. J . Am. Chem. Soc. 1997,
119, 656-673. (f) Guillena, G.; Na´jera, C. J . Org. Chem. 2000, 65,
7310-7322. (g) Reyes, A.; J uaristi, E. Tetrahedron: Asymmetry 2000,
11, 1411-1423.
(7) (a) Oppolzer, W.; Chapuis, C.; Kelly, M. J . Helv. Chim. Acta 1983,
66, 2358-2361. (b) Oppolzer, W.; Chapuis, C.; Bernardinelli, G.
Tetrahedron Lett. 1984, 25, 5885-5888. (c) Oppolzer, W.; Kelly, M. J .;
Bernardinelli, G. Tetrahedron Lett. 1984, 25, 5889-5892.
(8) (a) Opplolzer, W.; Dudfield, P. Helv. Chim. Acta 1985, 68, 216-
219. (b) Opplolzer, W.; Moretti, R. Tetrahedron 1988, 44, 5541-5552.
(9) (a) Hart, D. J .; Lee, C.-S. J . Am. Chem. Soc. 1986, 108, 6054-
6056. (b) Georg, G. I.; Cheruvallath, Z. S.; Harriman, G. C. B.;
Hepperle, M.; Park, H. Bioorg. Med. Chem. Lett. 1993, 3, 2467-2470.
(10) Oppolzer, W.; Dudfield, P.; Stevenson, T.; Godel, T. Helv. Chim.
Acta 1985, 68, 212-215.
(11) (a) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J . A. J . Org.
Chem. 1994, 59, 2497-2505. (b) Cativiela, C.; Diaz-de-Villegas, M. D.;
Galvez, J . A. Tetrahedron 1995, 51, 5921-5928. (c) Cativiela, C.; Diaz-
de-Villegas, M. D.; Galvez, J . A.; Lapen˜a, I. Tetrahedron 1997, 53,
5891-5898.
(12) Genet, J . P.; Kopola, N.; Ruiz-Montes, J .; Antunes, O. A. C.;
Tanier, S. Tetrahedron Lett. 1990, 31, 3133-3136.
(13) (a) Vowinkel, E. Chem. Ber. 1967, 100, 16. (b) Hassner, A.;
Alexanian, V. Tetrahedron Lett. 1978, 4475-4478. (c) Neises, B.;
Sterlich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522-524. (d)
Tennant-Eyles, R. J .; Fairbanks, A. J . Tetrahedron: Asymmetry 1999,
10, 391-401.
(1) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcı´a-Lo´pez,
M. T.; Gonza´lez-Mun˜iz, R. Synlett 2000, 1249-1252.
(2) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garcı´a-Lo´pez,
M. T.; Gonza´lez-Mun˜iz, R. J . Org. Chem. 2001, 66, 3538-3547.
(3) For some leading references on the memory of chirality, see: (a)
Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J . Am. Chem.
Soc. 1994, 116, 10809-10810. (b) Fuji, K.; Kawabata, T. Chem. Eur.
J . 1998, 4, 373-376. (c) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K.
Angew. Chem., Int. Ed. 2000, 39, 2155-2157.
(4) (a) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517-3599. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2000, 11, 645-732.
10.1021/jo025571j CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/26/2002

3954 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Sch em e 1. Syn th esis of
Sch em e 2. Asym m etr ic Syn th esis of
4-Alk yl-4-ca r boxy-2-a zetid in on esa
N-p-Meth oxyben zyl-N-ch lor oa cetyl Der iva tivesa
a
Reagents and conditions: (a) base/solvent (see Table 1).
Ta ble 1. In tr a m olecu la r Cycliza tion of
10-(N,N-Dicycloh exylsu lfa m oyl)isobor n eol-Der ived
Am in o Acid s
starting
compd
time final yielda ratio
R1
R* base solvent (d) compd (%) a /bb
10
10
10
10
11
12
CH2Ph (+) Cs2CO3 MeCN
CH2Ph (+) Cs2CO3 DMF
CH2Ph (+) BTPP MeCN
CH2Ph (+) BTPP CH2Cl2
CH2Ph (-) Cs2CO3 MeCN
10
2
1
1
10
2
22
22
22
22
23
24
72 85:15
55 81:19
77 71:29
60 73:27
70 16:84
71 91:9
CH3
(+) Cs2CO3 MeCN
a
Yield of isolated compounds. b Measured by HPLC of the crude
reaction mixture.
bearing (+)-N,N-dicyclohexylisoborneol-10-sulfonamide
as the chiral auxiliary, gave compound 22a as the major
isomer, in a 70% diastereoisomeric excess (Table 1). In
this case, both the yield and the diastereoselectivity of
the reaction was higher using MeCN as solvent than
DMF. On the other hand, the use of the strong soluble
base BTPP resulted in lower diastereomeric excesses
than those obtained in the Cs2CO3-mediated cyclization.
As expected, the use of the (-)-10-(N,N-dicyclohexylsul-
famoyl)isoborneol derivative, as in compound 11, allowed
us the preparation of compound 23b in 68% de. These
results pointed out that the topicity of the intramolecular
alkylation was exclusively governed by the chirality of
the isoborneol derivative and not by the memory of
chirality, as previously observed for the corresponding
methyl and tert-butyl ester derivatives.2 Still better
diastereoselectivity was obtained in the alkylation of the
Ala derivative 12, which afforded a 91:9 mixture of
azetidinones 24a and 24b (82% de). The observed differ-
ence in the diastereoisomeric ratio between the Phe and
Ala derivatives was similar to those previously reported
in the intermolecular R-alkylation of amino acids bearing
the camphor sultam auxiliary,15 and in the phase-transfer
catalytic alkylation of aldimine Schiff bases derived from
different amino acids.16
a
Reagents and conditions: (a) R*OH/DMAP/CH2Cl2; (b) H2/Pd-
C/MeOH; (c) (1) (4-OMe)C6H5CHO/MeOH, (2) NaBH4; (d) ClCH2-
COCl/propylene oxide/THF; (e) C6H5CH2OCOCl/propylene oxide/
CH2Cl2; (f) 4 M HCl/EtOAc.
tempts, compound 3 was obtained in very low yield (10-
20%), due to extensive Phe-derived N-acylurea formation.13
This side reaction was avoided by using amino acid
fluorides 1 and 2, previously generated by “in situ”
treatment of Z-Phe-OH and Z-Ala-OH, respectively, with
cyanuric fluoride,14 as the acylating agent for the prepa-
ration of compounds 3 and 4. Removal of the Z group from
3 and 4 followed by treatment with anisaldehyde and
reduction with NaBH4 afforded the expected p-methoxy-
benzyl derivatives 7 and 9. Alternatively, esterification
of the fully N-protected Phe and Ala derivatives 17 and
18 resulted in satisfactory yields of compounds 19-21
(Scheme 1). Careful monitoring of the H2/Pd-C-mediated
Z removal, to avoid simultaneous hydrogenolysis of the
p-methoxybenzyl group (Pmb), afforded compounds 7-9
in almost quantitative yield. Finally, N-chloroacetyl
derivatives 10-12 were also quantitatively prepared by
reaction of derivatives 7-9 with chloroacetyl chloride,
using propylene oxide as HCl scavenger.
As shown in Scheme 3, the absolute configuration at
C4 in 2-azetidinones 22a (23a ) and 22b (23b) was initially
established by measuring the chemical shifts of the â-H
1
protons of the Ala residue in the H NMR spectra of the
corresponding dipeptide derivatives 26a and 26b17,18 and
their respective retention times in the HPLC chromato-
(15) Ayoub. M.; Chassaing, G.; Loffet, A.; Lavielle, S. Tetrahedron
Lett. 1995, 36, 4069-4072.
(16) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J . Am. Chem.
Soc. 2000, 122, 5228-5229.
(17) 1H NMR studies on stereoisomeric dipeptides composed by one
aromatic amino acid and one aliphatic amino acid, showing that the
methyl or methylene protons of the aliphatic residue are more shielded
in the heterochial (D-L and L-D) dipeptides than in the homochiral
(L-L and D-D) analogues: (a) Deber, C. M.; J oshua, M. Biopolymers
1972, 11, 2493-2503. (b) Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.;
Molinero, M. T. Del R´ıo, J . J . Med. Chem. 1988, 31, 295-300. (c)
Gonza´lez-Mun˜iz, R.; Cornille, F.; Bergeron, F.; Ficheux, D.; Pothier,
J .; Durieux, C.; Roques, B. P. Int J . Peptide Protein Res. 1991, 37, 331-
340.
On the basis of our previous results,2 Cs2CO3 was
initially chosen as base to promote the cyclization of the
NR-chloroacetyl derivatives 10-12 to the corresponding
â-lactams (Scheme 2). The reaction of compound 10,
(14) Granitza, T.; Beyermann, M.; Wenschuh, H.; Haber, H.; Car-
pino, L. A.; Truran, G.; Bienert, M. J . Chem. Soc., Chem. Commun.
1995, 2223-2224.

Notes
Sch em e 3. Syn th esis of Dip ep tid e Der iva tivesa
J . Org. Chem., Vol. 67, No. 11, 2002 3955
a
Reagents and conditions: (a) (1) 2 N NaOH/MeOH/THF
F igu r e 1. Possible transition states for the intramolecular
alkylation using (+)-10-(N,N-dicyclohexylsulfamoyl)isoborneol
as the chiral auxiliary.
(2:1), (2) HCl (pH 3); (b) H-L-Ala-OMe/BOP/TEA; (c) 12 N HCl/
85 °C.
grams.19 Thus, the chemical shift of the C-terminal
R-methyl hydrogens of isomer 26a appeared at slightly
lower field (∆δ ≈ 0.1 ppm) than that of the isomer 26b
(Scheme 3), while this latter compound is 0.7 min. more
retained in the HPLC chromatogram with respect to
isomer 26a .20 This assignment was then unambiguously
confirmed by conversion of compound 25a into the known
(S)-R-benzyl aspartic acid 27a .21 The configuration of Ala
derivatives 24a and 24b was assigned by comparison of
highly effective chiral auxiliary in the intramolecular
NR-CR-cyclization of N-(p-methoxy)benzyl-N-chloroacetyl
Phe and Ala derivatives, making this an attractive
procedure for the stereocontrolled preparation of amino
acid-derived 2-azetidinones. The diastereoselectivity seems
to be governed by the E geometry of the enolate and by
the intramolecular alkylation opposite to the SO2 func-
tion. The broader conceptualization of this asymmetric
alkylation process, both by further optimization of the
procedure described here or by a search for other ap-
propriate chiral auxiliaries, and its application to the
construction of new optically active â-lactams may be
anticipated.
1
the H NMR data and the sign of the optical rotations
with those of the corresponding Phe analogues 22a and
22b.22
In the present study, the observed asymmetric induc-
tion could be explained by preferential formation of a
chelated E enolate, as the reactive intermediate, and
approach of the electrophile (COCH2Cl) by the opposite
face of the SO2N(Chx)2 moiety (Figure 1). A similar
asymmetric induction was observed in the intermolecular
alkylation of related camphorsultam-derived amino acids,
different from Gly.15 In our case, all attempts to stereo-
selectively prepare the corresponding 2-azetidinones
derived from the N-chloroacetyl Phe derivative bearing
(+)-2,10-camphorsultam as the chiral auxiliary failed.23
In conclusion, we have shown that the 10-(N,N-
dicyclohexylsulfamoyl)isoborneol can be utilized as a
Exp er im en ta l Section
For general experimental procedures regarding the prepara-
tion of N-(p-methoxy)benzyl- and N-(p-methoxy)benzyl-N-chlo-
roacetyl derivatives see ref 2. Z-Phe-F and Z-Ala-F derivatives
1 and 2 were synthesized by reaction of the corresponding Z
amino acid with cyanuric fluoride in pyridine.24
Gen er a l P r oced u r es for t h e Syn t h esis of t h e 10-(N,-
N-Dicycloh exylsu lfa m oyl)isob or n eol-Der ived 2-Azet id i-
n on es. A solution of the corresponding N-chloroacetyl-N-p-
methoxybenzyl derivative 10-12 (2.02 mmol) in dry CH3CN or
(23) Reaction of compound 28 with Cs2CO3 or BTPP resulted in
partial O-alkylation to morpholine derivative 29,2 with the concomitant
release of camphorsultam. The nucleophilic attack of the free sultam
to compound 28 furnished the bis-sultam derivative 30 as the major
product in these reactions. Compound 30: HPLC: tR ) 20.51 min
(A/B ) 55:45). ES MS: 738.5 (M + 1)+, 760.5 (M + Na)+. 1H NMR
(300 MHz, DMSO-d6, 80 °C): δ 1.08, 0.96, 0.92, 0.87 (4s, 3H, Me
camphorsultam).
(18) In our previous publication (ref 2) the assignment of homochiral
and heterochiral 2-azetidinone-containing dipeptide derivatives 26 was
erroneously made. In that case, the 4R,1′S isomer was mistakenly
correlated to an L-L homochiral dipeptide derivative, by considering
that the benzyl group at C4 position in the 4R isomer showed the same
spatial disposition that the amino acid side chain in the L-Phe, instead
of just considering the absolute configuration at this position, indicating
that the 4R,1′S isomer is the heterochiral one.
(19) In dipeptides and retrodipeptides, it was shown that hetero-
chiral derivatives are more retained than homochiral analogues:
Fournie´-Zaluski, M. C.; Lucas-Soroca, E.; Devin, J .; Roques, B. P. J .
Med. Chem. 1986, 29, 751-757.
(20) Isomer (R,S)-26a : HPLC: tR ) 9.58 min (A:B ) 35:65). Isomer
(S,S)-26b: HPLC: tR ) 10.28 min (A/B ) 35:65). A: MeCN. B: H2O
(0.05% TFA).
(21) 27a [R]D ) +48.60 (described [R]D ) +50.00): J uaristi, E.;
Lo´pez-Ruiz, H.; Madrigal, D.; Ram´ırez-Quiro´s, Y.; Escalante, J . J . Org.
Chem. 1998, 63, 4706-4710.
(22) The signal corresponding to the low field 1-CH2 proton of 4S
isomers (22b and 24b) is shielded (0.3-0.4 ppm) with respect to the
same proton in the 4R-configured analogues (22a and 24a ). 22a
[R]D ) +66.86; 24a [R]D ) +21.79.
(24) Carpino, L. A.; Mansour, E. M. E.; Sadat-Aalaee, D. J . Org.
Chem. 1991, 56, 2611-2614.

3956 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
DMF (50 mL) was treated with Cs2CO3 or BTPP (4.04 mmol)
and stirred at room temperature until disappearance of the
starting material. After evaporation of the solvent, the residue
was partitioned between EtOAc and H2O, and the phases were
separated. The organic layer was dried over Na2SO4 and
evaporated, leaving a residue that was purified on a silica gel
column, using the solvent system specified in each case.
(4S)-P m b-r-Bzl-Azn -OR*(+) (22a ). Yield: 61% (from 10, Cs2-
CO3/CH3CN), 44% (from 10, Cs2CO3/DMF), 55% (from 10, BTPP/
CH2Cl2), 43% (from 10, BTPP/CH3CN). Eluent: EtOAc/hexane
3H), 0.84 (s, 3H). 13C NMR (75 MHZ, CDCl3): δ 170.51, 165.48,
159.03, 129.94, 127.66, 113.81, 79.47, 58.60, 57.39, 55.09, 54.08,
49.37, 49.21, 49.08, 44.16, 44.10, 39.48, 32.89, 32.77, 30.78, 26.82,
26.25, 24.94, 20.81, 20.17, 19.87. MS (ES, positive mode): 629.3
(M + 1)+. Anal. Calcd for C35H52N2O6S: C, 66.85; H, 8.33; N,
4.45; S, 5.10. Found: C, 66.62; H, 8.20; N, 4.54; S, 5.07.
(4R)-P m b-r-Bzl-Azn -OR*(+) (24b). Yield: 6.6% (from 12).
Eluent: CH2Cl2/MeOH (99:1). Foam. HPLC: tR ) 15.55 min
(A/B ) 65:35). 1H NMR (300 MHz, CDCl3): δ 7.30 (d, 2H, J )
8.6), 6.89 (d, 2H, J ) 8.6), 4.96 (m, 1H), 4.16 (d, 1H, J ) 12.7),
4.02 (d, 1H, J ) 12.7), 3.80 (s, 3H), 3.33 (d, 1H, J ) 14.2), 3.18
(d, 1H, J ) 13.4), 3.17 (m, 2H), 2.78 (d, 1H, J ) 14.2), 2.67 (d,
1H, J ) 13.4), 1.94 (m, 2H), 1.60 (m, 18H), 1.37 (s, 3H), 1.27 (m,
7H), 1.03 (s, 3H), 0.87 (s, 3H). 13C NMR (75 MHZ, CDCl3): δ
168.93, 166.70, 159.37, 130.02, 127.55, 114.30, 79.68, 59.19,
57.46, 55.28, 54.12, 49.58, 49.48, 48.50, 44.35, 44.67, 39.11, 33.21,
32.69, 30.18, 27.06, 26.39, 25.15, 21.19, 20.41, 20.10. MS (ES,
positive mode): 629.3 (M + 1)+. Anal. Calcd for C35H52N2O6S:
C, 66.85; H, 8.33; N, 4.45; S, 5.10. Found: C, 66.66; H, 8.27; N,
4.61; S, 5.15.
Rem ova l of th e Ch ir a l Au xilia r y fr om th e Isobor n eol-
Der ived 2-Azetid in on es. A solution of the corresponding 10-
(N,N-dicyclohexylsulfamoyl)isoborneol-derived 2-azetidinone (0.43
mmol) in MeOH (6 mL) was treated with 2 N NaOH (0.32 mL,
0.64 mmol), and the mixture was stirred overnight at room
temperature. After evaporation of the MeOH, the remaining
aqueous mixture was diluted with H2O (5 mL) and extracted
with EtOAc to recover up to 90% of the corresponding isoborneol
chiral auxiliary. The remaining aqueous layer was acidified with
1 N HCl to pH 3 and extracted again with EtOAc. The extract
was dried (Na2SO4) and evaporated. The resulting residue was
purified on a silica gel column as specified.
(4S)-P m b-r-Bzl-Azn -OH (25a ). Yield: 89% (from 22a ).
Eluent: CH2Cl2/MeOH (98:2). Foam. HPLC: tR ) 6.03 min
(A/B ) 65:35). [R]D ) +41.38 (c ) 1.13, CHCl3). 1H NMR (200
MHz, CDCl3): δ 7.28 (d, 2H, J ) 8.4), 7.23 (m, 3H), 7.02 (m,
2H), 6.86 (d, 2H, J ) 8.4), 4.56 (d, 1H, J ) 15.3), 4.30 (d, 1H,
J ) 15.3), 3.78 (s, 3H), 3.24 (d, 1H, J ) 14.8), 3.22 (d, 1H, J )
14.1), 2.95 (d, 1H, J ) 14.8), 2.92 (d, 1H, J ) 14.1). 13C NMR
(50 MHZ, CDCl3): δ 175.18, 166.79, 159.31, 134.52, 130.28,
129.80, 128.75, 128.18, 127.47, 114.07, 63.29, 55.35, 54.46, 45.44,
44.91, 39.58. MS (ES, positive mode): 326.4 (M + 1)+. Anal.
Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.03;
H, 5.85; N, 4.22.
(4R)-P m b-r-Bzl-Azn -OH (25b). Enantiomer of 25a Yield:
80% (from 23b). Eluent: CH2Cl2/MeOH (98:2). [R]D ) -43.76
(c ) 0.52, CHCl3). MS (ES, positive mode): 326.4 (M + 1)+. Anal.
Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 69.97;
H, 5.93; N, 4.04.
(1:15). Foam. HPLC: tR ) 12.76 min (A/B ) 75:25). [R]D
)
+66.86 (c ) 1.24, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.32
(d, 2H, J ) 8.7), 7.18 (m, 3H), 6.96 (m, 2H), 6.86 (d, 2H, J )
8.7), 5.03 (m, 1H), 4.73 (d, 1H, J ) 15.3), 4.26 (d, 1H, J ) 15.3),
3.79 (s, 3H), 3.23 (d, 1H, J ) 14.4), 3.21 (m, 2H), 3.20 (d, 1H,
J ) 13.9), 3.11 (d, 1H, J ) 13.3), 2.92 (d, 1H, J ) 14.4), 2.73 (d,
1H, J ) 13.9), 2.63 (d, 1H, J ) 13.3), 1.85 (m, 2H), 1.71 (m, 16H),
1.60 (m, 2H), 1.34 (m, 5H), 1.11 (m, 2H), 0.89 (s, 3H), 0.82 (s,
3H). 13C NMR (75 MHZ, CDCl3): δ 169.46, 165.67, 158.97,
134.72, 130.06, 129.82, 128.99, 128.42, 127.14, 113.88, 79.40,
63.31, 57.49, 55.22, 54.46, 49.54, 47.18, 45.01, 44.36, 44.26, 40.59,
39.10, 33.25, 32.26, 31.25, 26.94, 26.25, 26.15, 25.09, 20.27, 19.78.
MS (ES, positive mode): 705.4 (M + 1)+. Anal. Calcd for
C
41H56N2O6S: C, 69.85; H, 8.01; N, 3.97; S, 4.55. Found: C,
69.79; H, 7.99; N, 4.03; S, 4.62.
(4R)-P m b-r-Bzl-Azn -OR*(+) (22b). Yield: 11% (from 10),
11% (from 10, Cs2CO3/DMF), 22% (from 10, BTPP/CH2Cl2), 19%
(from 10, BTPP/CH3CN). Eluent: EtOAc/CH2Cl2 (1:15). Foam.
HPLC: tR ) 10.73 min (A/B ) 75:25). [R]D ) -15.04 (c ) 1.04,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.24 (d, 2H, J ) 8.7),
7.15 (m, 3H), 6.88 (m, 2H), 6.81 (d, 2H, J ) 8.7), 4.97 (m, 1H),
4.44 (d, 1H, J ) 15.1), 4.17 (d, 1H, J ) 15.1), 3.77 (s, 3H), 3.32
(d, 1H, J ) 14.5), 3.17 (d, 1H, J ) 14.5), 3.13 (m, 2H), 3.11 (d,
1H, J ) 13.4), 3.02 (d, 1H, J ) 14.5), 2.76 (d, 1H, J ) 14.5), 2.60
(d, 1H, J ) 13.4), 1.84 (m, 2H), 1.69 (m, 16H), 1.50 (m, 2H),
1.17 (m, 5H), 0.98 (m, 2H), 0.88 (s, 3H), 0.82 (s, 3H). 13C NMR
(75 MHZ, CDCl3): δ 169.82, 166.45, 159.17, 134.76, 130.42,
129.96, 128.68, 128.43, 126.98, 113.96, 79.94, 62.70, 57.49, 55.28,
54.17, 49.56, 49.21, 44.78, 44.46, 44.26, 39.27, 38.15, 33.21, 32.24,
30.98, 26.95, 26.29, 25.03, 20.31, 20.07. MS (ES, positive
mode): 705.4 (M + 1)+. Anal. Calcd for C41H56N2O6S: C, 69.85;
H, 8.01; N, 3.97; S, 4.55. Found: C, 69.81; H, 8.10; N, 3.90; S,
4.58.
(4S)-P m b -r-Bzl-Azn -OR *(-) (23a ). Enantiomer of 22b .
Yield: 60% (from 11). Eluent: EtOAc/hexane (1:15). [R]D
)
+14.78 (c ) 0.76, CHCl3). MS (ES, positive mode): 705.6 (M +
1)+. Anal. Calcd for C41H56N2O6S: C, 69.85; H, 8.01; N, 3.97; S,
4.55. Found: C, 69.73; H, 7.82; N, 4.09; S, 4.66.
(4R)-P m b -r-Bzl-Azn -OR *(-) (23b ). Enantiomer of 22a .
Yield: 12% (from 11). Eluent: EtOAc/hexane (1:15). [R]D
)
-68.30 (c ) 1.07, CHCl3). MS (ES, positive mode): 705.5 (M +
1)+. Anal. Calcd for C41H56N2O6S: C, 69.85; H, 8.01; N, 3.97; S,
4.55. Found: C, 69.70; H, 7.85; N, 4.12; S, 4.70.
Ack n ow led gm en t. We thank the Comisio´n Inter-
ministerial de Ciencia y Tecnolog´ıa (SAF 2000-0147) for
financial support. G.G.-N. is a predoctoral fellow from
the Ministerio de Ciencia y Tecnolog´ıa, Spain.
(4S)-P m b-r-Bzl-Azn -OR*(+) (24a ). Yield: 67.3% (from 12).
Eluent: gradient from 5 to 15% of AcOEt in CH2Cl2. Mp ) 173-
174 °C (CH2Cl2). HPLC: tR ) 13.80 min (A:B ) 65:35). [R]D
)
+21.79 (c ) 1.32, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.20
(d, 2H, J ) 8.5), 6.81 (d, 2H, J ) 8.5), 4.93 (m, 1H), 4.65 (d, 1H,
J ) 14.9), 4.17 (d, 1H, J ) 14.9), 3.76 (s, 3H), 3.34 (d, 1H, J )
14.2), 3.16 (m, 2H), 3.09 (d, 1H, J ) 13.3), 2.74 (d, 1H, J ) 14.2),
2.61 (d, 1H, J ) 13.3), 1.98 (dd, 1H, J ) 6.7, 14.6), 1.89 (m, 1H),
1.73 (m, 15H), 1.57 (m, 3H), 1.25 (s, 3H), 1.13 (m, 7H), 0.90 (s,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical and spectroscopic data of compounds
3, 4, 7-12, 19-21, 28, and 30. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O025571J