Diastereoselective conjugate reduction and enolate trapping with glyoxylate imines. A concise approach to β-lactams that involves a ternary combination of components

Full text of DOI:10.1021/jo981574d

J . Org. Chem. 1999, 64, 1693-1698
1693
Dia ster eoselective Con ju ga te Red u ction
a n d En ola te Tr a p p in g w ith Glyoxyla te
Im in es. A Con cise Ap p r oa ch to â-La cta m s
th a t In volves a Ter n a r y Com bin a tion of
Com p on en ts
Claudio Palomo,* J esu´s Ma Aizpurua, and
J ose J avier Gracenea
F igu r e 1.
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica,
Universidad del Pais Vasco, Apdo 1072,
20080 San Sebastia´n, Spain
Received August 4, 1998
The development of efficient approaches to the stereo-
controlled synthesis of â-lactams continues to be of crucial
importance within the context of the most widely em-
ployed class of antimicrobial agents, the â-lactam anti-
biotics.1 The most commonly used strategy to access to
these systems lies, Figure 1, in the prior construction of
a monocyclic â-lactam such as 2 followed by chemical
manipulations at N-1 and C-4 positions of the azetidinone
nucleus and ring closure at a later stage in the synthesis.2
Besides this significance, 3-alkyl-4-alkoxycarbonylazeti-
din-2-ones 2 are also excellent candidates for the devel-
opment of synthetic inhibitors of elastase enzymes.3
Three representative examples, Figure 2, of the latter are
the L-652117 3,4 compound 4,5 and L-680,833 5.6 There-
fore, it is not surprising that a vast number of methods
are now available for the stereoselective synthesis of
monocyclic â-lactams.7 With few exceptions, the majority
of these methods involve a combination of two reactants
that provide the required â-lactam framework in a single
F igu r e 2.
synthetic step. Special attention has been put on the use
of the metal ester enolate-imine condensation because
of the easy availability of the starting materials and the
high levels of asymmetric induction often attained through
the use of either chiral carboxylic acid esters or chiral
imines.8 We report here a conceptually different, but in
practice equivalent, strategy to access to â-lactams that
is based on a ternary combination of components. Namely,
the conjugate addition of hydride reagents to enoates or
related systems and subsequent condensation of the
resulting enolate with an imine.
Prior to the present investigation, very few studies
concerning the coupling reaction of three reactants to
furnish â-lactams have been described. All of these cases
have dealt with the addition of nitrogen nucleophiles to
enoates followed by enolate trapping with an electro-
phile.9 The resulting intermediate â-amino acid and/or
ester, upon cyclization at a separate step, led to the
corresponding â-lactam product. Contemporary to these
studies, we have also reported on the addition of the
higher order Fleming’s cyanosilylcuprate reagent to
methyl crotonate followed by condensation with glyoxy-
late imines.10 In these instances, the resulting â-amino
ester intermediate cyclized spontaneously to give the
desired â-lactam product in a single pot operation albeit
in its recemic form. As an extension of this work and in
(1) For reviews on this subject, see: (a) Southgate, R.; Elson, S. In
Progress in the Chemistry of Organic Natural Products; Herz, W.,
Grisebach, H., Kirby, G. W., Tamm, C., Eds.; Springer: Vienna, 1985;
Vol. 47, p 1. (b) Southgate, R.; Branch, C.; Coulton, S.; Hunt, E. In
Recent Progress in the Chemical Synthesis of Antibiotics and Related
Microbial Products; Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2, p
621. (c) Southgate, R. Contemp. Org. Synth. 1994, 1, 417. (d) The
Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and Hall: London,
1992.
(2) For strategies on the synthesis of bicyclic â-lactams, see: (a)
Palomo, C. In Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbial Products; Lukacs, G., Ohno, M. Eds.; Springer:
Berlin, 1990; Vol. 1, p 565. (b) Kant, J .; Walker, D. G. In The Organic
Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; p
121.
(3) For reviews, see: (a) Edwards, P. D.; Bernstein, P. R. Med. Res.
Rev. 1994, 14, 127. (b) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G.
O.; Mata, E. G.; Roveri, O. A. Current Med. Chem. 1995, 1, 441.
(4) Firestone, R. A.; Barker, P. L.; Pisano, J . M.; Ashe, B. M.;
Dahlgren, M. E. Tetrahedron 1990, 46, 2255.
(5) Shah, S. K.; Finke, P. E.; Brause, K. A.; Chandler, G. O.; Ashe,
B. M.; Weston, H.; Maycock, A. L.; Mumford, R. A.; Doherty, J . B.
Bioorg. Med. Chem. Lett. 1993, 3, 2295.
(8) For reviews, see: (a) Hart, D. J .; Ha, D. C. Chem. Rev. 1989, 89,
1447. (b) Brown, M. J . Heterocycles 1989, 29, 2225. (c) Georg, G. I. In
Studies in Natural Product Chemistry; Rahman, A.-ur., Ed.; Elsevier:
Amsterdam, 1989; Vol. 4, p 431. (d) Fujisawa, T.; Shimizu, M. Rev.
Heteroatom. Chem. 1996, 15, 203. (e) Cainelli, G.; Panunzio, M.;
Giacomini, D.; Martelli, G.; Spunta, G.; Bandini, E. In Chemical
Synthesis, Gnosis to Prognosis; Chatgilialoglu, C., Snieckus, V., Eds.;
Kluwer Academic: Amsterdam, 1996; p 25.
(6) Kuo, D.; Weidner, J .; Griffin, P.; Shah, S. K.; Knight, W. B.
Biochemistry 1994, 33, 8347.
(7) For general reviews on â-lactam synthesis, see: (a) Koppel, G.
A. In Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York,
1983; Vol. 42, p 219. (b) Backes, J . In Houben-Weyl, Methoden der
Organischen Chemie; Muller, E., Bayer, O., Eds.; Thieme: Stuttgart,
1991; Band E 16B, p 31. (c) Dekimpe, N. In Comprehensive Heterocyclic
Chemistry II; Padwa, A., Ed.; 1996; Vol. 1B, p 507. For recent reviews
on asymmetric synthesis of â-lactams, see: (d) Thomas, R. C. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno,
M., Eds.; Springer: Berlin, 1990; Vol. 1, p 533. (e) Ternansky, R. J .;
Morin, J . M., J r. In The Organic Chemistry of â-Lactams; Georg, G. I.,
Ed.; VCH: New York, 1993; p 257. (f) Ghosez, L.; Marchand-Brynaert,
J . In Comprehensive Organic Synthesis; Trost, B., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, p 85.
(9) (a) Yamamoto, Y.; Asao, N.; Uyehara, T. J . Am. Chem. Soc. 1992,
114, 5427. (b) Asao, N.; Uyehara, T.; Tsukada, N.; Yamamoto, Y. Bull.
Chem. Soc. J pn. 1995, 68, 2103. (c) Davies, S. G.; Fenwick, D. R. J .
Chem. Soc., Chem. Commun. 1997, 565. For a comprehensive review
on conjugate addition-enolate trapping, see: (d) Hulce, M.; Chapde-
laine, M. J . In Comprehensive Organic Synthesis; Semmelhack, M. F.,
Ed.; Pergamon: Oxford, 1991; Vol. 4, p 237. For another approach to
â-lactams involving a one-pot reaction of an amine, an aldehyde, and
silyl ketene thioacetals, see: (e) Annunziata, R.; Cinquini, M.; Cozzi,
F.; Molteni, V.; Schupp, O. J . Org. Chem. 1996, 61, 8293.
(10) (a) Palomo, C.; Aizpurua, J . M.; Urchegui, R. J . Chem. Soc.,
Chem. Commun. 1990, 1390. (b) Palomo, C.; Aizpurua, J . M.; Urchegui,
R.; Iturburu, M. J . Org. Chem. 1992, 57, 1571.
10.1021/jo981574d CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/06/1999

1694 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Sch em e 1a
Ta ble 1. Con ju ga te Red u ction of 6a -g F ollow ed by
En ola te Tr a p p in g w ith Im in e 7a
yield
c
entry
R
M
product (%)b cis:trans
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
Me
Me
Me
Ph
Ph
Ph
Et
Li
K
Na
Li
K
Na
Li
K
Na
Na
Na
Na
8a
8a
8a
8b
8b
8b
8c
8c
8c
8d
8e
8f
52
40
55
72
50
70
54
35
40
60
60
55
50
73:27
88:12
98:2
72:28
98:2
98:2
72:28
98:2
75 (97)e
g99
g99
97
g99
g99
82
g99
g99
98
98
98
85:15
95:5
a
Reagents and conditions: (a)M-Selectride (2.2 equiv).CuBr‚SMe2
n-Bu
4-MeC6H4
4-MeOC6H4 Na
99:1
(1.1 equiv), SMe2 (17 equiv), THF, -78 °C, 1 h; (b) PMP-Nd
CH-CO2-t-Bu 7, -78 °C to rt, 16 h; (c) F3CCO2H (40 equiv), CH2Cl2,
rt, 4 h; 73-91%; (d) CH2N2, Et2O, 0 °C. PMP: 4-MeOC6H4.
g99:5f
g99:5f
8g
96
a
Reactions carried out in THF on 1 mmol scale, see Experi-
mental Section, using the following molar ratio of reagents:
N-enoylsultam (0.25 M)/M-Selectride (1.0 M)/CuBr‚SMe2/SMe2
1:2.2:1.1:17. The reduction step was performed at -78 °C for 30
min and the trapping with the imine 7 (0.5 M in THF) from -78
°C to 25 °C for 16 h. For entries 12 and 13, the reduction step
Sch em e 2a
b
was performed at -50 °C for 2.5 h. Yields of the pure isolated
cis isomers. c The cis:trans ratio measured by GC-MS analysis
(major isomers gave longer retention times than minor ones). The
cis:trans ratio was also confirmed by 1H NMR. Values related
d
to major cis-(3S,4S) isomers after derivatization to the cis-3-alkyl-
4-(methoxycarbonyl)-â-lactams 9. The ee values were determined
by chiral stationary phase HPLC analysis (column: Chiralpak-
AS 250 × 4.6 mm; eluant: i-PrOH/hexane; flow 50/50 to 70/30
mL/min). e Value in parentheses indicates ee after a single crystal-
lization from cyclohexane. f Determined by 1H NMR.
a
(THF-HMPA, toluene, or diethyl ether) and/or temper-
ature conditions for enolate trapping all met with fail-
ure.14 The finding was that copper halide complexes
(CuX‚SMe2) in a molar ratio 1:2 (complex:M-Selectride)
along with dimethyl sulfide as cosolvent efficiently
promoted both the conjugate reduction and the enolate
trapping, resulting in a clean formation of â-lactams 8a -
g. In every case, after the addition of the imine 7, the
latter step of the reaction was carried out by leaving off
the cooling of the mixture from -78 °C to room temper-
ature during 16 h. Noticeably, when the whole process
was performed entirely at -78 °C overnight, no â-lactam
product was formed. Likewise, trapping of the enolate
at 0 °C did not lead to the formation of the expected
â-lactam. As the results in Table 1 show, L-Selectride,
under the established conditions, afforded â-lactams
8a -c (entries 1, 4, and 7) in reasonable yields, but the
cis:trans selectivity was poor. K-Selectride (entries 2, 5,
and 8) provided better stereochemical control and enan-
tiomeric purity for the corresponding cis-(3S,4S) isomers.
However, in these cases, the yields were only moderate.
The best results were achieved by the use of N-Selectride
as the reducing agent. On the other hand, although the
choice of the halide in the copper additive was unimpor-
tant (CuCl‚SMe2 and CuI‚SMe2 gave similar results to
CuBr‚SMe2), the nature of the ligand used appeared to
be critical as shown by the fact that dicoordinated CuX‚
TMEDA complex15 gave only 20% yield of 8b from 6b and
N-Selectride. Increasing the SMe2:CuX molar ratio from
an equimolar amount to an excess (typically, 15 equiv of
SMe2 per mol of CuX), raised the yield of isolated 8a from
20 to 55% (entry 3). In a similar way, 8b and 8c were
Reagents and conditions: (a) CAN, MeCN; (b) (Boc)2O; (c)
4-MeOC6H4MgBr, THF, -40 °C; (d) L-Selectride, THF, -78 °C;
(e) nicotinic acid CrO3 (NDC), pyridine, toluene. PMP: 4-MeOC6H4.
view of the existing precedents on asymmetric conjugate
reductions,11 we thought that this approach would also
be valuable for the synthesis of nonracemic â-lactams
both as intermediates of â-lactam antibiotics and elastase
inhibitors.
For the study, we elected to use N-enoylsultams 6a -g
which have proven to be good acceptors in conjugate
reductions.12 Initially, the approach (Scheme 1) was
examined under established conditions13 by the addition
of either L-Selectride or K-Selectride to each N-enoyl-
sultam 6a -g in THF at -78 °C. After 1 h at the same
temperature, the glyoxylate imine 7 was added. Unfor-
tunately, only the N-acylsultams from the reduction of
6a -g were obtained in each case tested along with traces
of the expected â-lactam products. Increasing the tem-
perature of the enolate trapping step from -78 °C to
room-temperature did not improve the results. Under the
above conditions, N-Selectride also proved to be effective
for the conjugate reduction but not for the carbon-carbon
bond-forming step. Variations on the reaction solvent
(11) For reviews on asymmetric conjugate additions, including
conjugate reductions, see: (a) Rossiter, B. E.; Swingle, N. M. Chem.
Rev. 1992, 92, 771. (b) Schmalz, H.-G. In Comprehensive Organic
Synthesis; Semmelhack, M. F., Ed.; Pergamon: Oxford, 1991; Vol. 4,
p 199. (c) Leonard, J . Contemp. Org. Synth. 1994, 1, 387. (d) Perlmut-
ter, P. Conjugate Addition Reactions in Organic Synthesis; Perga-
mon: Oxford, 1992.
(12) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27, 4717.
(13) For conjugate reductions of enones and enoates with K- and
L-Selectride, see: (a) Reference 12. (b) Fortunato, J . M.; Ganem, B. J .
Org. Chem. 1976, 41, 2194. (c) Bell, R. A.; Turner, J . V. Tetrahedron
Lett. 1981, 22, 4871. (d) Cativiela, C.; Diaz-de-Villegas, D.; Galvez, J .
A. Bull. Chem. Soc. J pn. 1992, 65, 1657. For an extensive list of
references concerning conjugate reductions, see: (e) Kawakami, T.;
Miyatake, M.; Shibata, I.; Baba, A. J . Org. Chem. 1996, 61, 376.
(14) In general, glyoxylate imines do not react well with enolates,
particularly with lithium enolates, to give â-lactams, see: Georg, G.
I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 109, 1129.
(15) J ohnson, C. R.; Marren, T. J . Tetrahedron Lett. 1987, 28, 27.

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1695
F igu r e 3.
produced in substantially lower yields when the process
was carried out in the absence of the SMe2 cosolvent. In
general, the method affords â-lactams either from 2-alkyl-
1-enoyl- or 2-aryl-1-enoylsultams 6 in moderate to good
yields and with remarkable diastereo- and enantioselec-
tivity. N-Cinnamoylsultams 6f,g bearing electron-donat-
ing substituents required temperatures of -50 °C to give
a complete conjugate reduction with N-selectride (entries
12 and 13). In particular, the enolate resulting from 6g
(entry 13) gave the â-lactam 8g only if the trapping step
was carried out by warming the reaction mixture from
-78 to 25 °C during a period not exceeding for 3 h. As a
final remark, a change of the CuBr‚SMe2:M-Selectride
molar ratio from 1:2 to 1:1 rendered the reaction sluggish,
affording traces of the expected â-lactams toghether with
undefined byproducts.
For each compound 8a -e, the cis relative disposition
of the vicinal methine protons at C-3 and C-4 positions
was easily established on the basis of the 1H NMR
coupling constants (J 3,4 ≈ 5.9 Hz), and the enantiomeric
purity was determined by comparative chiral stationary
phase HPLC analysis of 4-methoxycarbonylazetidinones
9a -e, derivatized from 8a -e, and their equivalent
racemic â-lactams.16 Obviously, by simply changing the
N-enoylsultams employed in this strategy to their enan-
tiomers, the corresponding enantiomers of both 8 and 9
would be equally available. The enantiomer of 9b would
be the precursor of either the antibiotic (+)-PS-517 or the
elastase inhibitors 3-5, while the â-lactams 9c and 9g
constitute valuable precursors of inhibitors of prostate
specific antigen.18 Besides this significance, ring opening
of these â-lactam products by oxygen and nitrogen
nucleophiles is expected to give â-alkyl aspartic acid
derivatives.19 Product 9a , on the other hand, can be
transformed into the amino lactone 11, Figure 3, the
cyclized form of the N-terminal amino acid residue found
F igu r e 4. Enantiomeric excess determination by chiral
stationary phase HPLC analysis for the aminolactone 11 by
comparison with the racemic mixture (()-11: column Chiral-
pak-AS 250 x 4.6 mm; eluant i-PrOH/hexanes 50/50. The
enantiomeric purity of the â-lactams 9a -g was determined
in the same way by comparison with the corresponding racemic
compounds (see ref 16).
in the antibiotic family of nikkomycins (10).20 For ex-
ample, N-dearylation of 9a according to the Kronenthal
procedure21 and subsequent Boc introduction afforded 12
in 60% yield over the two steps. Ring opening of 12 with
the corresponding Grignard reagent led to the â-amino
ketone 13. As expected by our previous work on racemic
nikkomycin,22 the L-Selectride reduction of 13 provided
aminolactone 11 along with 14. The latter, after chro-
matographic separation, was transformed into 11 in 76%
overall yield. A comparative chiral HPLC analysis of 11
with the equivalent racemic compound, Figure 4, showed
its enantiomeric purity, and the comparison of the optical
rotation of 11 with the reported values confirmed its
absolute configuration. The configuration of the â-lactam
products was established by analogy and by assuming a
uniform mechanism for the present three-component
coupling reaction.23
In summary, the examples described here demonstrate
that N-Selectride in combination with CuX2‚SMe2 halides
efficiently promote both conjugate reduction and enolate
trapping with glyoxylate imines leading to important
â-lactam intermediates with remarkable enantioselec-
tivity.
Exp er im en ta l Section
Melting points were determined with capillary apparatus and
are uncorrected. 1H NMR (300 MHz) spectra and 13C NMR
(16) 4-tert-Butoxycarbonyl-â-lactams 8a -c showed very deficient
chromatographic peak resolution in comparison with â-lactams 9a -
c, which were prepared in their racemic form by the ketene-imine [2
+ 2] cycloaddition reaction of the corresponding alkanoyl chlorides with
the imine derived from p-anisidine and methyl glyoxylate, according
to our previously reported procedure: Palomo, C.; Ontoria, J . M.;
Odriozola, J . M.; Aizpurua, J . M.; Ganboa, I., J . Chem. Soc., Chem.
Commun. 1990, 248.
(17) Cainelli, G.; Panunzio, M.; Giacomini, D.; Martelli, G.; Spunta,
G. J . Am. Chem. Soc. 1988, 110, 6879. For a review on (+)-PS-5, see:
Palomo, C. In Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer-Verlag: Berlin, 1990; p 565.
(18) Adlington, R. M.; Baldwin, J . E.; Chen, B.; Cooper, S. L.;
McCoull, W.; Pritchard, G. J .; Howe, T. J .; Becker, G. W.; Hermann,
R. B.; McNulty, A. M.; Neubauer, B. L. Bioorg. Med. Chem. Lett. 1997,
7, 1689.
(20) For some recent examples on synthesis of the N-terminal amino
acid of nikkomycins, see: (a) Barrett, A. G. M.; Lebold, S. A. J . Org.
Chem. 1991, 56, 4875. (b) Barluenga, J .; Viado, A. L.; Aguilar, E.;
Fustero, S.; Olano, B. J . Org. Chem. 1993, 58, 5972. (c) Mukai, C.;
Miyakawa, M.; Hanaoka, M. Synlett 1994, 165. (d) Akita, H.; Chen,
C. Y.; Uchida, K. Tetrahedron: Asymmetry 1995, 6, 2131. (e) Mandville,
G.; Ahmar, M.; Bloch, R. J . Org. Chem. 1996, 61, 1122. (f) Aggarwal,
V. K.; Monteiro, N.; Tarver, G. J .; Lindell, S. D. J . Org. Chem. 1996,
61, 1192. (g) Tamura, O.; Mita, N.; Kusaka, N.; Suzuki, H.; Sakamoto,
M. Tetrahedron Lett. 1997, 38, 429.
(21) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J . Org. Chem. 1982,
47, 2765.
(22) Palomo, C.; Aizpurua, J . M.; Garc´ıa, J . M.; Iturburu, M.
Odriozola, J . M. J . Org. Chem. 1994, 59, 5184.
(19) Palomo, C.; Aizpurua, J . M.; Ontoria, J . M.; Iturburu, M.
Tetrahedron Lett. 1992, 33, 4823. For a recent review on â-lactams as
building blocks of â-amino acids and their derivatives, see: Palomo,
C.; Aizpurua, J . M.; Ganboa, I. In Enantioselective Synthesis of â-Amino
Acids; J uaristi, E., Ed.; Wiley-VCH: New York, 1997, p 279.
(23) Another paper will deal with conjugate additions of carbon
nucleophiles and enolate trapping with glyoxylate imines, see: Palomo,
C.; Aizpurua, J . M.; Gracenea, J . J .; Garcia-Granda, S.; Pertierra, P.
Eur. J . Org. Chem. 1998, 2201, 1.

1696 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
spectra (75 MHz) were recorded at room temperature for CDCl3
solutions, unless otherwise stated. All chemical shifts are
reported as δ values (ppm) relative to, respectively, residual
CHCl3 δH (7.26 ppm) and CDCl3 δC (77.0 ppm) as internal
standards. Mass spectra were obtained with a mass spectrometer
(70 eV), equipped with ion-trap, and using GC-MS coupling
(column of fused silica, 15 m, 0.25 mm, 0.25 µm phase SPB-5).
Optical rotations were measured at 25 ( 0.2 °C in methylene
chloride unless otherwise stated. HPLC analyses were performed
on a preparative column (25 cm, 3.0 cm, 7 µm phase Lichrosorb-
Si60) with flow rates of 10 mL/min and using a UV detector (254
nm). Flash chromatography was performed on silica gel (230-
400 mesh) using mixtures of ethyl acetate and hexane as eluants.
Tetrahydrofuran was distilled over sodium and benzophenone
(indicator). Methylene chloride was shaken with concentrated
sulfuric acid, dried over potassium carbonate, and distilled.
Commercially available compounds were used without further
purification. The N-enoylsultams 6a 24 and 6b-g25 were prepared
by literature procedures. Nicotinic acid CrO3 complex (NDC) was
prepared as described.26
Gen er a l P r oced u r e for th e Th r ee-Com p on en t Syn th esis
of â-La cta m s 8a -g. M-Selectride, 1 M in THF, (2.2 mL, 2.2
mmol) was dropped over a solution of CuBr‚SMe2 (0.23 g, 1.1
mmol) and SMe2 (1.4 mL) in THF kept under nitrogen at -78
°C, and the mixture was stirred for 30 min at the same
temperature. A solution of N-enoylsultam 6 (1 mmol) in THF (4
mL) was added dropwise, and the mixture was stirred for 1 h
at the same temperature. A solution of the imine 7 (0.47 g, 2
mmol) in THF (4 mL) was then added, and the mixture was
allowed to reach room temperature during 16 h. After this time,
the reaction mixture was diluted in CH2Cl2 (30 mL), washed
with saturated NH4Cl (3 × 30 mL), and dried over MgSO4.
Evaporation of the solvents yielded a crude containing cis and
trans isomers from which the cis isomer was purified by column
chromatography (230-400 mesh silica gel; eluant EtOAc/hexane
1/14). Analytical samples were obtained by crystallization from
cyclohexane.
(100.0); 1H NMR (CDCl3, δ ppm) 7.36-7.19 (m, 7H, J ) 9.0 Hz),
6.86 (d, 2H, J ) 9.0 Hz), 4.55 (d, 1H, J ) 6.0 Hz), 3.89 (dt, 1H,
J ) 8.2, 6.0 Hz), 3.78 (s, 3H), 3.24 (dd, 1H, J ) 15.5, 7.4 Hz),
3.03 (dd, 1H, J ) 15.5, 8.4 Hz), 1.46 (s, 9H); 13C NMR (CDCl3,
δ ppm) 167.8, 165.1, 156.2, 137.8, 131.1, 128.7, 128.5, 126.6,
117.8, 114.3, 83.2, 56.2, 55.4, 52.9, 30.7, 27.8. Anal. Calcd. for
C22H25NO4 (367. 44): C, 71.91; H, 6.86; N, 3.81. Found: C, 71.60;
H, 6.63; N, 3.73.
(3S,4S)-4-ter t-Bu toxyca r bon yl-1-(4-m eth oxyp h en yl)-3-n -
p r op yla zetid in -2-on e (8d ). The general procedure was fol-
lowed using N-Selectride, 1 M in THF, (2.2 mL, 2.2 mmol) and
(1S) N-(E)-pentenoyl-2,l0-camphorsultam (0.30 g, 1 mmol): yield
0.18 g (60%); mp 52-54 °C (EtOAc/hexane); [R]2D5 ) -122.1 (c )
0.7, CH2Cl2); IR (KBr, υ cm-1) 1751 (CdO); MS(m/z, rel intensity)
1
134 (21.9), 162 (67.1), 263 (100.0), 319 (18.4); H NMR (CDCl3,
δ ppm) 7.24 (d, 2H, J ) 9.0 Hz), 6.85 (d, 2H, J ) 9.0 Hz), 4.45
(d, 1H, J ) 6.0 Hz), 3.78 (s, 3H), 3.51 (dt, 1H, J ) 6.0, 7.4 Hz),
l.90-1.42 (m, 4H), 1.46 (s, 9H), 1.32-1.28 (m, 4H), 0.89 (t, 3H,
J ) 6.4 Hz); 13C NMR (CDCl3, δ ppm) 168.0, 166.0, 156.1, 131.2,
117.8, 114.2, 82.9, 56.0, 55.5, 52.8, 28.0. 27.5, 20.8, 13.9. Anal.
Calcd for C18H25NO4 (319.40): C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.67; H, 8.02; N, 4.62.
(3S,4S)-4-ter t-Bu toxyca r bon yl-1-(4-m eth oxyp h en yl)-3-n -
p en tyla zetid in -2-on e (8e). The general procedure was followed
using N-Selectride, 1 M in THF, (2.2 mL, 2.2 mmol) and (1S)-
N-(E)-heptenoyl-2,10-camphorsultam (0.32 g, 1 mmol): yield
0.21 g (60%); mp 52-54 °C (EtOAc/hexane); [R]2D5 ) -76.1 (c )
0.7, CH2Cl2); IR (KBr, υ cm-1) 1749, 1725 (CdO); MS(m/z, rel
intensity) 347 (16.1), 291 (100.0), 219 (48.0); 1H NMR (CDCl3, δ
ppm) 7.23 (d, 2H, J ) 9.l Hz), 6.85 (d, 2H, J ) 9.l Hz), 4.45 (d,
1H, J ) 6.0 Hz), 3.78 (s, 3H), 3.52 (dt, 1H, J ) 7.8, 6.0 Hz),
1.87-1.68 (m, 4H), 1.46 (s, 9H), 0.92 (t, 3H, J ) 7.0 Hz); 13C
NMR (CDCl3, δ ppm) 168.0, 166.0, 156.1, 131.1, 117.8, 114.2,
82.9, 56.1, 55.4, 53.0, 31.7. 28.0, 27.2, 25.5, 22.4, 14.0. Anal. Calcd
for C20H29NO4 (347.45): C, 69.14; H, 8.41; N, 4.03. Found: C,
69.35; H, 8.35; N, 3.98.
(3S,4S)-4-ter t-Bu t oxyca r b on yl-1-(4-m et h oxyp h en yl)-3-
[(4-m eth ylp h en yl)m eth yl]a zetid in -2-on e (8f). The general
procedure was followed using N-Selectride, 1 M in THF, (2.2
mL, 2.2 mmol) and (1S)-N-(p-methylcinamoyl)-2,10-canphorsul-
tam (0.36 g, 1 mmol); yield 0.21 g (55%); [R]2D5 ) -64.0 (c ) 1.0,
(3S,4S)-4-tert-Butoxycarbonyl-3-methyl-1-(4-methoxyphen-
yl)a zetid in -2-on e (8a ). The general procedure was followed
using N-Selectride, 1 M in THF, (2.2 mL, 2.2 mmol) and (1S)-
N-(acryloyl)-2,10-camphorsultam (0.27 g, 1 mmol): yield: 0.16
g (55%); mp 94-95 °C (cyclohexane); [R]2D5 ) -132.3 (c ) 1.0,
CH2Cl2); IR (KBr, υ cm-1) 1734 (CdO); MS (m/z, rel intensity)
1
CH2Cl2); IR (KBr, υ cm-1) 1751, 1734 (CdO); H NMR (CDCl3,
δ ppm) 7.25 (d, 2H, J ) 9.0 Hz), 7.17 (d, 2H, J ) 6.3 Hz), 7.12
(d, 2H, J ) 6.3 Hz), 6.86 (d, 2H, J ) 9.0 Hz), 4.53 (d, 1H, J )
6.0 Hz), 3.85 (dt, 1H, J ) 7.9, 6.0 Hz), 3.78 (s, 3H), 3.18 (dd, 1H,
J ) 15.0, 7.3 Hz), 2.98 (dd, 1H, J ) 15.0, 8.2 Hz), 2.32 (s, 3H),
1.38 (s, 9H); 13C NMR (CDCl3, δ ppm) 167.9, 165.2, 156.2, 136.1,
134.7, 131.1, 129.2, 128.4, 117.8, 114.3, 83.2, 56.3, 55.5, 53.2,
30.4, 27.9, 21.0. Anal. Calcd for C23H27NO4 (381.46): C, 72.42;
H, 7.13; N, 3.67. Found: C, 72.32; H, 7.15; N, 3.71.
1
291 (10.3), 235 (40.7), 163 (100.0), 134 (66.2); H NMR (CDCl3,
δ ppm) 7.24 (d, 2H, J ) 9.0 Hz), 6.85 (d, 2H, J ) 9.0 Hz), 4.46
(d, 1H, J ) 6.2 Hz), 3.78 (s, 3H), 3.63 (dq, 1H, J ) 7.5, 6.2 Hz),
1.46 (s, 9H), 1.32 (d, 3H, J ) 7.3 Hz); 13C NMR (CDCl3, δ ppm)
167.9, 166.3, 156.2, 131.2, 117.9, 114.3, 83.0, 56.2, 55.4, 47.6,
28.1. Anal. Calcd for C16H21NO4 (291.35): C, 65.96; H, 7.26; N,
4.81. Found: C, 65.50; H, 6.43; N, 4.71.
(3S ,4S )-4-t er t -Bu t oxyca r b on yl-3-e t h yl-1-(4-m e t h oxy-
p h en yl)a zetid in -2-on e (8b). The general procedure was fol-
lowed using N-Selectride, 1 M in THF, (2.2 mL, 2.2 mmol) and
(1S)-N-crotyl-2,10-camphorsultam (0.28 g, 1 mmol): yield 2.1 g
(70%); mp 74-76 °C (cyclohexane); [R]2D5 ) -113.5 (c ) 1.0,
CH2Cl2); IR (KBr, υ cm-1) 1730, 1734 (CdO); MS (m/z, rel
(3S,4S)-4-ter t-Bu t oxyca r b on yl-1-(4-m et h oxyp h en yl)-3-
[(4-m eth oxyp h en yl)m eth yl]a zetid in -2-on e (8g). The general
procedure was followed using N-Selectride, 1 M in THF, (2.2
mL, 2.2 mmol) and (1S)-N-(4-methoxycinamoyl)-2,10-camphor-
sultam (0.38 g, 1 mmol): yield 0.2 g (50%); mp 110-112 °C
(cyclohexane); [R]D25 ) -80.2 (c ) 1.0, CH2Cl2); IR (KBr, υ cm-1
)
1
1756, 1735 (CdO). 1H NMR (CDCl3, δ ppm) 7.26 (m, 2H, J )
9.0 Hz), 7.22 (m, 2H, J ) 9.0 Hz), 6.87 (d, 4H, J ) 9.0 Hz),
4.54 (d, 1H, J ) 6.0 Hz), 3.84 (dt, 1H, J ) 7.9, 6.0 Hz), 3.80 (s,
3H), 3.78 (s, 3H), 3.16 (dd, 1H, J ) 15.2, 7.8 Hz), 2.96 (dd,
1H, J ) 15.2, 7.9 Hz), 1.40 (s, 9H); 13C NMR (CDCl3, δ ppm)
167.9, 165.2, 158.2, 156.2, 129.8, 129.5, 117.7, 114.3, 114.0, 113.8,
83.1, 56.2, 55.4, 53.3, 30.0, 27.9. Anal. Calcd for C23H27NO5
(397.46): C, 69.50; H, 6.85; N, 3.52. Found: C, 69.42; H, 6.77;
N, 3.63.
intensity) 222 (0.5), 149 (29.3), 134 (70.6), 57 (100.0); H NMR
(CDCl3, δ ppm) 7.24 (d, 2H, J ) 9.0 Hz), 6.86 (d, 2H, J ) 9.0
Hz), 4.47 (d, 1H, J ) 6 Hz), 3.78 (s, 3H), 3.46 (dt, 1H, J ) 6.0,
8.0 Hz), 1.87-1.68 (m, 2H), 1.46 (s, 9H), 1.12 (t, 3H, J ) 7.5
Hz); 13C NMR (CDCl3, δ ppm) 168.0, 165.9, 156.1, 131.1, 117.8,
114.2, 82.8, 55.9, 55.4, 54.4, 27.9, 18.8, 12.1. Anal. Calcd. for
C
17H23NO4 (305.37): C, 66.86; H, 7.59; N, 4.59. Found: C, 66.67;
H, 8.18; N, 5.05.
(3S,4S)-3-Benzyl-4-tert-butoxycarbonyl-1-(4-methoxyphen-
yl)a zetid in -2-on e (8c). The general procedure was followed
using N-Selectride, 1 M in THF, (2.2 mL, 2.2 mmol) and (1S)-
N-cinamoyl-2,10-camphorsultam (0.35 g, 1 mmol): yield 0.15 g
(40%); [R]2D5 ) -72.0 (c ) 1.0, CH2Cl2); IR (KBr, υ cm-1) 1751,
1728 (CdO); MS (m/z, rel intensity) 367 (2.0), 149 (16.8), 134
Typ ica l P r oced u r e for th e Syn th esis of â-La cta m s 9a -
g. A solution of â-lactam (1.0 mmol) in CH2Cl2 (15 mL) was
treated with trifluoroacetic acid (2.97 mL, 40 mmol) at room
temperature for 4 h. The organic layer was washed with water
(4 × 15 mL) and dried over MgSO4, and the solvents were
evaporated. To the resulting crude material was added Et2O (5
mL), and the resulting mixture was treated with a solution of
0.6-0.7 M CH2N2 in Et2O (8.0 mL, 5.0 mmol). The Et2O was
evaporated, and the resulting crude material was purified by
column chromatography (230-400 mesh silica gel; eluant EtOAc/
hexane 1:14).
(24) Lee, J . Y.; Chung, J .; Kim, B. H. Synlett 1994, 197.
(25) Oppolzer, W.; Chapuis, C.; Bernardelli, G. Helv. Chim. Acta
1984, 67, 1397.
(26) Cossio, F. P.; Lopez, M. C.; Palomo, C. Tetrahedron 1987, 43,
3963.

Notes
(3S,4S)-3-Meth yl-4-(m eth oxycar bon yl)-1-(4-m eth oxyph en -
J . Org. Chem., Vol. 64, No. 5, 1999 1697
procedure was followed using 8g (0.40 g, 1 mmol): yield 0.32 g
(91%); mp 172-174 °C (cyclohexane); [R]2D5 ) -41.2 (c ) 1.0,
CH2Cl2); IR (KBr, υ cm-1) 1736, 1727 (CdO); MS(m/z, % int.)
355 (73.1), 327 (29.9), 268 (100.0), 193 (7.82), 134 (27.6); 1H NMR
(CDCl3, δ ppm) 7.19 (d, 2H, J ) 9.0 Hz), 7.15 (d, 2H, J ) 9.0
Hz), 6.85 (d, 2H, J ) 9.0 Hz), 6.84 (d, 2H, J ) 9.0 Hz), 4.58 (d,
1H, J ) 5.9 Hz), 3.84 (dt,1H,J ) 5.9, 7.1 Hz), 3.78 (s, 3H), 3.77
(s, 3H), 3.67 (s, 3H), 3.16 (dd, 1H, J ) 7.1, 15.0 Hz), 2.88 (dd,
1H, J ) 9.0, 15.0 Hz); 13C NMR (CDCl3, δ ppm) 169.3, 165.0,
158.3, 156.4, 130.8, 129.5, 128.8, 117.8, 114.4, 113.9, 55.4, 55.2,
53.9, 52.4, 30.2. Anal. Calcd for C20H21NO5 (355.14): C, 67.59;
H, 5.96; N, 3.94. Found: C, 69.80; H, 6.01; N, 4.33.
yl)a zetid in -2-on e (9a ). The general procedure was followed
using 6a (0.29 g, 1 mmol): yield 0.21 g (85%); mp 80-82 °C
(cyclohexane); [R]D25 ) -175.6 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1746 (CdO); MS(m/z, rel intensity) 249 (11.5), 149 (27.9),
1
134 (100.0); H NMR (CDCl3, δ ppm) 7.25 (d, 2H, J ) 9.1 Hz),
6.89 (d, 2H, J ) 9.1 Hz), 4.61 (d, 1H, J ) 6.1 Hz), 3.80 (s, 3H),
3.78 (s, 3H), 3.67 (dq, 1H, J ) 6.1, 7.6 Hz), 1.28 (d, 3H, J ) 7.6
Hz); 13C NMR (CDCl3, δ ppm) 167.8, 165.1, 156.2, 137.8, 131.1,
128.7, 128.5, 126.6, 117.8, 114.3, 83.2, 56.2, 55.4, 52.9, 30.7, 27.8.
Anal. Calcd for C13H15NO4 (249.27): C, 62.64; H, 6.07; N, 5.62.
Found: C, 63.01; H, 6.32; N 5.75.
(3S,4S)-3-Eth yl-4-(m eth oxyca r bon yl)-1-(4-m eth oxyp h en -
yl)a zetid in -2-on e (9b). The general procedure was followed
using 6b (0.37 g, 1 mmol): yield 0.19 g (73%); mp 102-104 °C
(cyclohexane); [R]D25 ) -136.3 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1732 (CdO); MS(m/z, rel intensity) 263 (16.3), 149 (44.6),
(3S,4S)-1-(ter t-Bu t oxyca r b on yl)-3-m et h yl-4-(m et h oxy-
ca r bon yl)a zetid in -2-on e (12). A solution of (NH4)2Ce(NO3)6
(16.4 g, 30 mmol) in water (120 mL) was added dropwise to a
solution of the â-lactam 9a (2,49 g, 10 mmol) in acetonitrile (125
mL) at -10 °C. The mixture was stirred at this temperature for
30 min. Water (400 mL) was then added, and this mixture was
treated again with EtOAc (3 × 150 mL) and washed with a
saturated solution of NaHCO3 (350 mL). The aqueous layer of
NaHCO3 was extracted again with EtOAc (60 mL), and the
combined organic layers were washed with NaHSO3 (40%) (4 ×
300 mL) and saturated solutions of NaHCO3 (70 mL) and NaCl
(70 mL). The organic layer was dried over MgSO4, and the
solvents were removed in vacuo. The crude â-lactam was
dissolved in acetonitrile (10 mL) and di-tert-butyl dicarbonate
(1.4 mL, 10 mmol) and DMAP (0.12 g, 1.0 mmol) were added,
and the reaction was stirred for 16 h. The organic layer was
diluted in CH2Cl2 (25 mL) and washed with HCl (25 mL) and
NaHCO3 (10 mL), and the solvents were evaporated. The
resulting crude was purified by column chromatography (230-
400 mesh silica gel; eluant EtOAc/hexane 1:10): yield 1.46 g
(60%); colorless oil; [R]2D5 ) -95.3 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1808, 1743, 1723 (CdO); MS(m/z, rel intensity) 187 (10.8),
1
134 (100.0); H NMR (CDCl3, δ ppm) 1.11 (d, 3H, J ) 6.8 Hz),
1.56-1.98 (m, 2H), 3.54 (dt, 1H, J ) 6.0, 8.0 Hz), 3.81 (s, 3H),
3.83 (s, 3H), 4.63 (d, 1H, J ) 6.0 Hz), 6.89 (d, 2H, J ) 9.0 Hz),
7.26 (d, 2H, J ) 9.0 Hz); 13C NMR (CDCl3, δ ppm) 169.5, 165.6,
156.2, 131.0, 117.8, 114.4, 55.5, 55.3, 54.7, 52.4, 19.0. Anal. Calcd
for C14H17NO4 (263.29): C, 63.87; H, 6.51; N, 5.32. Found: C,
63.50; H, 6.60; N, 5.23.
(3S,4S)-3-Ben zyl-4-(m eth oxycar bon yl)-1-(4-m eth oxyph en -
yl)a zetid in -2-on e (9c). The general procedure was followed
using 6c (0.30 g, 1 mmol): yield 0.29 g (90%); mp 112-114 °C
(cyclohexane); [R]D25 ) -63.3 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1736, 1727 (CdO); MS(m/z, rel intensity) 325 (22.7), 149
(59.3), 134 (100.0); 1H NMR (CDCl3, δ ppm) 2.96 (dd, 1H, J )
9.3, 15.0 Hz), 3.25 (dd, 1H, J ) 6.8, 15.0 Hz), 3.65 (s, 3H), 3.78
(s, 3H), 3.96 (dt, 1H, J ) 6.6, 9.2 Hz), 4.60 (d, 1H, J ) 6.0 Hz),
6.86 (d, 2H, J ) 9.0 Hz), 7.22-7.34 (m, 7H); 13C NMR (CDCl3,
δ ppm) 169.1, 164.7, 156.2, 137.2, 130.7, 128.7, 128.4, 126.5,
1
142 (57.5), 100 (77.0), 57 (100.0); H NMR (CDCl3, δ ppm) 4.50
117.6, 114.2, 55.2, 54.9, 53.4, 52.2, 30.8. Anal. Calcd for C19H19
-
(d, 1H, J ) 6.8 Hz), 3.80 (s, 3H), 3.54 (m, 1H), 1.50 (s, 9H), 1.20
(d, 3H, J ) 7.6 Hz); 13C NMR (CDCl3, δ ppm) 168.3, 165.9, 54.7,
52.3, 47.3, 27.8, 9.0.
NO4 (325.36): C, 70.14; H, 5.89; N, 4.31. Found: C, 69.80; H,
6.01; N, 4.33.
(3S,4S)-4-(Meth oxyca r bon yl)-1-(4-m eth oxyp h en yl)-3-n -
p r op yla zetid in -2-on e (9d ). The general procedure was fol-
lowed using 8d (0.35 g, 1 mmol): yield 0.22 g (80%); mp 84-86
°C (cyclohexane); [R]D25 ) -148.7 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1748 (CdO), 1734 (CdO); 1H NMR (CDCl3, δ ppm) 0.96
(t, 3H, J ) 6.8 Hz), 1.42-1.80 (m, 4H), 3.58 (dt, 1H, J ) 6.0, 7.4
Hz), 3.79 (s, 3H), 3.80 (s, 3H, OMe), 4.60 (d, 1H, J ) 6.0 Hz),
6.86 (d, 2H, J ) 9.0 Hz), 7.24 (d, 2H, J ) 9.0 Hz); 13C NMR
(CDCl3, δ ppm) 13.9, 20.6, 27.5, 52.4, 53.0, 53.4, 55.4, 55.5, 114.4,
117.8, 131.0, 156.2, 165.8, 169.6; MS (m/z, % intensity) 277 (8.4),
149 (34.8), 134 (l00.0). Anal. Calcd for C15H19NO4 (277.33): C,
64.97; H, 6.91; N, 5.05. Found: C, 65.07; H, 6.60; N, 5.13.
(3S,4S)-4-(Meth oxyca r bon yl)-1-(4-m eth oxyp h en yl)-3-n -
p en tyla zetid in -2-on e (9e). The general procedure was followed
using 8e (0.37 g, 1 mmol): yield 0.21 g (73%); mp 50-52 °C
(cyclohexane); [R]D25 ) -110.9 (c ) 1.0, CH2Cl2); IR (KBr, υ
cm-1) 1738 (CdO), 1728 (CdO); 1H NMR (CDCl3, δ ppm) 0.88
(t, 3H, J ) 6.4 Hz), 1.24-1.77 (m, 8H), 3.55 (dd, 1H, J ) 6.0,
7.9 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 4.58 (d, 1H, J ) 6.0 Hz), 6.84
(d, 2H, J ) 9.0 Hz), 7.21 (d, 2H, J ) 9.0 Hz); 13C NMR (CDCl3,
δ ppm) 13.9, 22.3, 25.4, 26.9, 31.6, 52.3, 53.1, 55.3, 55.4, 114.3,
117.7, 130.9, 156.2, 165.7, 169.5; MS (m/z, % intensity) 305 (7.2),
149 (39.1), 134 (l00.0). Anal. Calcd for C17H23NO4 (305.37): C,
66.86; H, 7.59; N, 4.59. Found: C, 65.07; H, 6.60; N, 5.13.
(3S,4S)-3-[(4-Meth ylph en yl)m eth yl]-4-(m eth oxycar bon yl)-
1-(4-m eth oxyp h en yl)a zetid in -2-on e (9f). The general proce-
dure was followed using 8f (0.38 g, 1 mmol): yield 0.23 g (88%);
mp 94-96 °C (cyclohexane); [R]2D5 ) -53.4 (c ) 1.0, CH2Cl2); IR
(KBr, υ cm-1) 1736, 1727 (CdO); MS (m/z, % intensity) 339
(87.8), 311 (40.5), 252 (100.0), 134 (35.2); 1H NMR (CDCl3, δ ppm)
2.32 (s, 3H), 2.90 (dd, 1H, J ) 9.3, 15.0 Hz), 3.19 (dd, 1H, J )
6.9, 15.0 Hz), 3.66 (s, 3H), 3.77 (s, 3H), 3.92 (dt,1H,J ) 6.0, 9.2
Hz), 4.59 (d, 1H, J ) 6.0 Hz), 6.85 (d, 2H, J ) 9.0 Hz), 7.11 (sb,
5H), 7.23 (d, 2H, J ) 9.0 Hz); 13C NMR (CDCl3, δ ppm) 169.3,
165.0, 156.4, 136.3, 134.3, 130.8, 129.2, 128.4, 117.8, 114.4, 55.5,
55.2, 53.9, 52.4, 30.6, 21.0. Anal. Calcd for C20H21NO4 (339.15):
C, 70.78; H, 6.24; N, 4.13. Found: C, 70.75; H, 6.11; N, 4.23.
(3S,4S)-3-[(4-Meth oxyp h en yl)m eth yl]-4-(m eth oxyca r bo-
n yl)-1-(4-m eth oxyp h en yl)a zetid in -2-on e (9g). The general
(2S,3S)-Meth yl 2-(ter t-Bu toxyca r bon yla m in o)-4-(4-m eth -
oxyp h en yl)-3-m eth yl-4-oxobu ta n oa te (13). Over a solution
of 12 (0.24 g, 1.0 mmol) in THF (3 mL) a solution of 4-methoxy-
phenylmagnesium bromide 1 M in THF (1.3 mL, 1.3 mmol) was
added at -78 °C. The reaction mixture was stirred at -40 °C
for 1 h, and the reaction was quenched at this temperature with
a saturated solution of NH4Cl. The organic layer was stracted
with CH2Cl2 (10 mL) and dried over MgSO4, and the solvents
were evaporated. The crude was purified by column chromatog-
raphy (230-400 mesh silica gel; eluant EtOAc/hexane 1:5): yield
0.26 g (75%); colorless oil; [R]2D5 ) +15.7 (c ) 0.75, CH2Cl2); IR
(KBr, υ cm-1) 3335 (NH), 1735, 1708 (CdO); MS (m/z, rel
intensity) 295 (2.7), 136 (9.2), 135 (100.0); 1H NMR (CDCl3, δ
ppm) 7.96 (d, 2H, J ) 9.0 Hz), 6.95 (d, 2H, J ) 9.0 Hz), 5.31 (d,
1H, J ) 8.1 Hz), 4.59 (dd, 1H, J ) 5.9, 8.3 Hz), 4.07 (m, 1H),
3.87 (s, 3H), 3.74 (s, 3H), 1.42 (s, 9H), 1.28 (d, 3H, J ) 7.3 Hz);
13C NMR (CDCl3, δ ppm) 199.3, 171.7, 163.6, 155.2, 130.6, 113.8,
79.9, 55.6, 55.4, 52.3, 42.7, 28.1, 13.8.
(2S,3S,4R)-2-(ter t-Bu toxyca r bon yla m in o)-3-m eth yl-4-(4-
m eth oxyp h en yl)bu tyr ola cton e (11). To solution of 13 (0.35
g, 1.0 mmol) in THF (6 mL) at -78 °C a solution of L-Selectride,
1 Μ in THF, was added, and the reaction mixture was stirred
for 1 h at the same temperature. The reaction was then
quenched with a saturated solution of NH4Cl (6 mL), extracted
with Et2O (15 mL), and filtered through Celite to give an organic
solution which was dried over MgSO4 and evaporated in vacuo
to afford a 63:37 mixture of 11 and 14 as a colorless oil.
Separation by column chromatography (230-400 mesh silica gel;
eluant EtOAc/hexane 1:10 and then 1:5) gave compounds 11 and
14. A solution of 14 (89 mg, 0.28 mmol) in toluene (0.5 mL) was
added to a suspension of NDC (320 mg, 0.70 mmol) and pyridine
(0.45 mL, 5.57 mmol) in the same solvent (1 mL), and the
mixture was stirred at room temperature for 4 h. Afterward,
the suspension was filtered through a pad of silica gel, and the
organic solution was washed with 6 N HCl (1 mL) and NaHCO3
(1 mL), dried over MgSO4, and evaporated to give 11 as a viscous
oil. Yield from 14: 074 mg (83%). Overall yield of 11: 0.23 g
(73%). [R]2D5 ) +20.1 (c ) 0.8, CDCl3); lit18b [R]2D5 ) +20.1 (c )

1698 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
0.82, CDCl3); lit18g [R]D25 ) +20.6 (c ) 1.17, CDCl3). IR (KBr, υ
cm-1): 1781, 1707 (CdO). MS (m/z, rel intensity): 321 (1.1), 176
(36.4), 160 (100.0), 135 (48.1). 1H NMR (CDCl3, δ ppm): 7.28
(d, 2H), 6.92 (d, 2H), 5.10 (d, 1H, J ) 7.6 Hz), 4.83 (d, 1H, J )
10.3 Hz), 4.26 (dd, 1H, J ) 11.5, 7.6 Hz), 3.82 (s, 3H), 2.34 (m,
1H), 1.47 (s, 9H), 1.17 (d, 3H, J ) 6.4 Hz). 13C NMR (CDCl3, δ
ppm): 174.2, 160.2, 155.5, 136.0, 128.1, 114.1, 84.7, 80.5, 57.9,
55.3, 46.8, 28.2, 13.6.
Ack n ow led gm en t. Financial support of this work
by Gobierno Vasco (projects EX-1997/108, Aquitania-
Euskadi) and by Universidad del Pa´ıs Vasco (UPV
170.215-G47/98). A grant from Gobierno Vasco to J .J .G.
is gratefully acknowledged.
J O981574D