(3R)-chiral control of 3-alkyl-3-hydroxy-β-lactams via addition reaction of imines to enolates of 1,3-dioxolan-4-ones

Article abstract of DOI:10.1021/jo9822481

A method is described for the chiral construction of (3R)-3-alkyl-3- hydroxy-β-lactams in a versatile and predictable manner. This protocol follows Seebach's synthetic principle of self-regeneration of stereocenters and has been applied to addition reactions among a selected number of imines and (2S)-chiral enolates of 1,3-dioxolan-4-ones. These reagents are easily available from the acetalization of (S)-α-hydroxy acids (lactic, mandelic, isovaleric, malic) and pivalaldehyde or pinacolone. In several cases, the addition of the enolate to the imine, the cyclization, and the removal of the auxiliary center occur in a one-step sequence, affording the corresponding β-lactams as (3R,4S)-Z and (3R,4R)-E diastereomeric mixtures with high enantiomeric excesses. Four N-unsubstituted (3R,4S)-3-hydroxy-3-methyl-β- lactams bearing 2-furyl (4e), phenylethenyl (4h), methoxycarbonyl (4i), and 2-thienyl (41) substituents at C4 were obtained as major diastereomers and were purified by crystallization. The simultaneous presence of these substituents at C3 and C4 make these β-lactams useful intermediates for the synthesis of new taxoids with interesting structural modifications at the isoserine moiety.

Full text of DOI:10.1021/jo9822481

J . Org. Chem. 1999, 64, 4643-4651
4643
(3R)-Ch ir a l Con tr ol of 3-Alk yl-3-h yd r oxy-â-la cta m s via Ad d ition
Rea ction of Im in es to En ola tes of 1,3-Dioxola n -4-on es†
Gaetano Barbaro, Arturo Battaglia,* and Andrea Guerrini
Istituto CNR dei Composti del Carbonio Contenenti Eteroatomi “I.Co.C.E.A.”,
via Gobetti 101 40129 Bologna, Italy
Carlo Bertucci
CNR, Centro Studi Macromolecole Stereordinate ed Otticamente Attive, Dipartimento di Chimica e
Chimica Industriale, Universita` di Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received November 10, 1998
A method is described for the chiral construction of (3R)-3-alkyl-3-hydroxy-â-lactams in a versatile
and predictable manner. This protocol follows Seebach’s synthetic principle of self-regeneration of
stereocenters and has been applied to addition reactions among a selected number of imines and
(2S)-chiral enolates of 1,3-dioxolan-4-ones. These reagents are easily available from the acetalization
of (S)-R-hydroxy acids (lactic, mandelic, isovaleric, malic) and pivalaldehyde or pinacolone. In several
cases, the addition of the enolate to the imine, the cyclization, and the removal of the auxiliary
center occur in a one-step sequence, affording the corresponding â-lactams as (3R,4S)-Z and (3R,-
4R)-E diastereomeric mixtures with high enantiomeric excesses. Four N-unsubstituted (3R,4S)-3-
hydroxy-3-methyl-â-lactams bearing 2-furyl (4e), phenylethenyl (4h ), methoxycarbonyl (4i), and
2-thienyl (4l) substituents at C4 were obtained as major diastereomers and were purified by
crystallization. The simultaneous presence of these substituents at C3 and C4 make these â-lactams
useful intermediates for the synthesis of new taxoids with interesting structural modifications at
the isoserine moiety.
In tr od u ction
centers are still scarce. A few methods have been
developed for creating quaternary stereogenic centers at
the C4 and the C3 position.11 These reactions are directed
toward the synthesis of 3-heterosubstituted â-lactams,
such as 3-alkyl-3-hydroxy-â-lactams and 3-alkyl-3-amino-
The development of new approaches to the stereocon-
trolled synthesis of â-lactam intermediates has been a
subject of interest in the context of their possible use as
biologically active compounds or as versatile chiral build-
ing blocks. Biologically active targets are, for example,
the â-lactam antibiotics1 or the inhibitors of cholesterol
absorption,2 while the potential usefulness of â-lactams
as synthons has been evidenced by the development of
the “â-lactam synthon method”.3
Several methods for the synthesis of 3,4-disubstituted
â-lactams are now available. In particular, the addition
of imines to ketenes4 or to ester enolates5 has acquired
significant importance for the asymmetric synthesis of
the azetidinone ring.1a,6 Alternatively, precursors from
the “chiral pool” for the synthesis of â-lactams are, for
example, â-amino acids,7 â-amino esters,8 â-halo amides,9
and â-hydroxy amides.10 However, methods for the
construction of â-lactams with quaternary stereogenic
(3) For instance, the cleavage of the â-lactam ring at the N-C(O)
bond affords a variety of protein and nonprotein amino acids and
peptides of biological and medicinal interest, while the reductive
cleavage of the â-lactam ring affords alkanoic acid derivatives, such
as R-hydroxy- and R-amino acids. Other types of reactions specifically
involve the CdO functionality. Among various possibilities, it is worth
mentioning the chemoselective alkylation with Grignard reagents or
with cuprates yielding â-amino ketones and the selective reduction
with alanes, which provide a useful protocol of synthesis of azetidines.
Selected references: (a) Ojima, I. In The Organic Chemistry of
â-Lactams and â-Lactam Antibiotics; Georg, G. I., Ed.; VCH: New
York, 1992; Chapter 4, pp 197-255. (b) Ojima, I. Acc. Chem. Res. 1995,
28, 383-389 and references therein. (c) Ojima, I.; Delaloge, F. Chem.
Soc. Rev. 1997, 26, 377-386. (d) Ojima, I.; Suga, S.; Abe, R. Chem.
Lett. 1980, 853-856. (e) Ojima, I.; Shimizu, N. J . Am. Chem. Soc. 1986,
108, 3100-3102. (f) Palomo, C.; Aizpurua, J . M.; Garcia, J . M.;
Iturburu, M.; Odriozola, J . M. J . Org. Chem. 1994, 59, 5184-5188. (g)
Spero, D. M.; Kapadia, S.; Farina, V. Tetrahedron Lett. 1995, 36, 4543-
4546. (h) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J . Org. Chem.
1991, 56, 5263-5277.
(4) For a comprehensive review of Staudinger’s reaction see: Georg,
G. I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH: New York, 1993; pp 295-368.
† This paper is dedicated to the memory of Prof. Gaetano Maccag-
nani on the tenth anniversary of his death.
(1) (a) Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno M., Eds.; Springer-Verlag: Berlin, 1990. (b) Chem-
istry and Biology of â-Lactam Antibiotics; Morin, R. B., Gorman, M.,
Eds.; Academic Press: New York, 1982; Vols. 1-3. (c) Topics in
Antibiotic Chemistry; Sammes, P. G., Ed.; Ellis Howood Ltd.: New
York, 1980; Vol. 3. (d) O’Sullivan, J .; Abraham E. P. In Antibiotics,
Vol. IV; Springer: Berlin, 1981. (e) Bentley, P. M.; Southgate, R. In
Recent Advances in the Chemistry of â-Lactam Antibiotics; The Royal
Society of Chemistry: London, 1988. (f) Christensen, B. G. In Structure-
activity Relationships in â-Lactam Antibiotics; Salton, M. R. J .,
Shockman, G. D., Eds.; Academic: New York, 1981; p 101.
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J . Org. Chem. 1980, 45, 3413-3416. (b) Ha, D.-C.; Hart, D. J .; Yang,
T.-K. J . Am. Chem. Soc. 1984, 106, 4819-4825. (c) Hart, D. J .; Ha,
D.-C. Chem. Rev. 1989, 89, 1447-1465. (d) Kleinman, E. F. In
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Fujisawa, T. Tetrahedron Lett. 1995, 36, 729-732. (f) Fujieda, H.;
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(6) For reviews on asymmetric synthesis of â-lactams, see: (a)
Cooper, R. D. J .; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987,
59, 485-492. (b) Ghosez, L.; Marchand-Brynaert, S. In Comprehensive
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10.1021/jo9822481 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/29/1999

4644 J . Org. Chem., Vol. 64, No. 13, 1999
Barbaro et al.
â-lactams, by photoaddition of chromium-alkoxy-carbene
complexes to optically active imines12 or by stereospecific
addition of diphenylnitrone to the enantiomerically pure
(3S,4R)-3-hydroxy-3-methyl-4-furyl azetidinone.13 Ste-
reospecific R-alkylation of 3-amino- and 3-alkoxy-C3,C4-
disubstituted-â-lactams following Ojima’s protocol have
also been reported.3a,b Because of the importance of
trisubstituted â-lactams bearing heterosubstituents at a
C3 quaternary stereogenic center, both as substrates for
the “â-lactam synthon method” and for studies of biologi-
cal activity, we started to develop a new synthetic
protocol of their chiral construction in a versatile and
predictable manner. For this purpose, we believe that
R-heterosubstituted carboxylic acids, like R-hydroxy,
R-mercapto, and R-amino acids, are inexpensive natural
chiral pools that could be used for the synthesis of
trisubstituted â-lactams with absolute stereocontrol at
the C3 quaternary center bearing interesting functional
groups, such as OR, SR, and NHR. This is very important
since the biological activity of the â-lactams depends on
the type of substituent and is prevalently exhibited by
one of the enantiomers. Palomo11a clearly pointed out the
importance of understanding the reactivity of 4,4-disub-
stituted â-lactams to provide new opportunities for
studying structure-activity relationships and for the
designing new antibiotics and/or enzyme inhibitors. This
necessity has clearly been supported by some experimen-
tal findings, i.e. the superior activity of the 4,4-disubsti-
tuded â-lactam tigemonam14 by the Squibb group over
other oral â-lactam antibiotics. Similar support has also
been found in the case of 3,3-disubstituted â-lactams.
Indeed, the presence of a 3-methoxy substituent as part
of a quaternary stereogenic center at the C3 carbon atom
of the 3-methoxy-3-amino-monobactamic acid increases
the â-lactamase stability with respect to the C3-mono-
substituted-3-amino-monobactamic acid.
such as the tabtoxinine-â-lactam and its analogues.17
Moreover, these compounds with correct absolute con-
figurations serve as precursors to the corresponding
R-hydroxy-â-amino acids (isoserines), which are key
components of a large number of therapeutically impor-
tant compounds. As an example, (2R,3S)-3-amino-2-
hydroxy-5-methylhexanoic acid (norstatine) and (3R,4S)-
4-amino-3-hydroxy-5-methylheptanoic acid (statine) are
residues for peptide inhibitors of enzymes, such as renin18
and HIV-1 protease.19 Furthermore, phenylisoserine
analogues are used to synthesize new taxoids.20 To
achieve the goal of full control of stereochemistry at the
C3-alkyl-C3-hydroxy quaternary center, we have devised
a protocol that employs imines as the electrophilic
partners of enolates of acetal-type derivatives. This
strategy follows the synthetic principle called “self-
regeneration of stereocenters”, developed by Seebach,21
which has been used for EPC22 alkylations and aldol
condensations to chiral cyclic enolates. In particular, the
present paper focuses on the applicability of this protocol
for the addition reactions of lithium enolates of dioxolan-
4-ones, derived from the condensation of R-hydroxy-
substituted carboxylic acids with pivalaldehyde or pina-
colone, to imines.
Resu lts a n d Discu ssion
Rea ction s of th e En ola tes of Dioxola n on es De-
r ived fr om P iva la ld eh yd e to Im in es. The role of
peripheral substituents in the dioxolanones derived from
pivalaldehyde was studied using the diphenylimine 1 as
the non-enolizable partner and the (2S,5S)-2-(tert-butyl)-
5R-substituted-1,3-dioxolan-4-ones (2a -d ) (Figure 1)
derived from the acetalization of (S)-lactic, (S)-mandelic,
(S)-R-hydroxy-isovaleric, and (S)-malic acids. These lac-
tones can be obtained as pure homochiral material via
fractional crystallization at low temperatures. However,
suitable acetalization protocols are available which allow
their synthesis with an excellent selectivity of cyclization.
So far, compounds 2a -d were obtained, and directly
As our first target, we selected the 3-hydroxy-â-
lactams, efficient carboxylate mimics,15 that are present
in pharmacologically active monobactams, such as Sul-
fazecin and related products,16 and in enzyme inhibitors,
(7) (a) Baldwin, S. W.; Aube, J . Tetrahedron Lett. 1987, 28, 179-
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Chem. 1984, 62, 1400-1402.
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2459-2464. (b) Shono, T.; Tsubata, K.; Okinaga, N. J . Org. Chem.
1984, 49, 1056-1059. (c) Iimori, T.; Ishida, Y.; Shibasaki, M. Tetra-
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Wallace, P. M. Tetrahedron 1986, 42, 3097-3110.
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F.-S. J . Med. Chem. 1987, 30, 976-982.
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(10) (a) Miller, M. J .; Mattingly, P. G. Tetrahedron 1983, 39, 2563-
2570. (b) Bose, A. K.; Manhas, M. S.; Sahu, D. P.; Hedge, V. R. Can. J .
Chem. 1984, 62, 2498-2505. (c) Morrison, M. A.; Miller, M. J . J . Org.
Chem. 1983, 48, 4421-4423.
(11) (a) Palomo, C.; Aizpurua, J . M.; Garc`ıa, J . M.; Galarza, R.;
Legido, M.; Urchegui, R.; Roma`n, P.; Luque, A.; Server-Carrio`, J .;
Linden, A. J . Org. Chem. 1997, 62, 2070-2079. (b) Greene, A. E.;
Charbonier, F.; Luche, M.-J .; Moyano, A. J . Am. Chem. Soc. 1987, 109,
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Org. Chem. 1992, 57, 1461-1467. (b) Colson, P. J .; Hegedus, L. S. J .
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1997, 38, 2535-2538.
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1993, 26, 160-167. (b) Ojima, I.; Slater, J . C.; Michaud, E.; Kuduk, S.
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P.; Bernacki, R. J . J . Med. Chem. 1996, 39, 3889-3896. (c) Ojima, I.;
Slater, J . C.; Kuduk, S. D.; Takeuchi, C. S.; Gimi, R. H.; Sun, C.-M.,
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40, 267-278. (d) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J . M.;
Bernacki, R. J . J . Med. Chem. 1997, 40, 267-278. (e) Li, L.; Thomas,
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171.

Addition Reaction of Imines to Enolates
J . Org. Chem., Vol. 64, No. 13, 1999 4645
Sch em e 1. F or m a tion of â-la cta m s 4a -m via Ad d ition Rea ction s of En ola tes of Dioxola n on es (2S)-3a -f to
Im in es 1 a n d 8-12
In a previous paper,24 we reported a detailed study of
the optimization of the addition reaction of the enolates
3a and 3b derived from lactones 2a and 2b, respectively,
to imine 1. According to this study, best results were
obtained when the enolates were generated in situ by a
slow addition of the lactones 2a and 2b to a mixture of
LiHMDS and imine 1 at -95/-90 °C (2a ) and at -50 °C
(2b) in a THF/HMPA ) 85:15 mixed solvent (procedure
1). The condensation of the enolates with imine 1, the
subsequent cyclization, and the elimination of the aux-
iliary center occurred in a one-pot sequence (Scheme 1)
directly providing the â-lactams 4a in a 69% yield (Z/E
) 18:82)25 and the â-lactams 4b in an 82% yield (Z/E )
44:56).26 Higher reaction temperatures were required
when the imines were added to a THF solution of the
enolates in the absence of HMPA. The yields of the
â-lactams were greatly reduced.27
F igu r e 1. Dioxolanones 2a -f.
This procedure has now been extended to the reactions
of imine 1 to the enolates 3c and 3d and to the reactions
used, as diastereomeric (2S,5S)cis/(2R,5S)-trans mix-
tures: 2a 23a (R ) Me, 97:3), 2b23b (R ) C6H5, cis), 2c23b
(R ) Me2CH, 99:1), 2d 23b (R ) CH2CO2H, 98:2). The (2S,-
5S)cis/(2R,5S)-trans mixtures of dioxolanones were con-
verted into the corresponding nonracemic (2S)/ (2R)
mixtures of lithium enolates by reaction with lithium bis-
(trimethylsilyl)amide (LiHMDS). The 3-hydroxy-3-alkyl-
â-lactams were obtained via cyclization of imines to the
enolates (Scheme 1).
(24) Barbaro, G.; Battaglia, A.; Guerrini, A.; Bertucci, C. Tetrahe-
dron Asymm. 1997, 8, 2527-2531.
(25) An identical result was obtained when 1,3-dimethyl-3,4,5,6-
tetrahydro-2-(1H)-pyrimidone (DMPU), instead of HMPA, was used.
(26) In the previous communication,24 an erroneous Z/ E ) 23:76
ratio, instead of 44:56, was given for the â-lactams 4b.
(27) In the absence of HMPA, the â-lactams 4a were obtained at -
78/-50 °C as a Z/ E ) 64:36 mixture in 34% yields, 94% ee, while Z-4b
was obtained at -5/+5 °C in 65% yield, 51% ee.25 The formation of
racemic Z-4b may be due to a competitive cycloaddition of imine 1 to
the reactive phenylketene 6b (Figure 4) that is formed from the
decomposition of the enolate 3b.
(23) (a) Chapel, N.; Greiner, A.; Ortholand, J .-Y. Tetrahedron Lett.
1991, 40, 1441-1442. (b) Seebach, D.; Naef, R.; Calderari, G. Tetra-
hedron 1984, 40, 1313-1324.

4646 J . Org. Chem., Vol. 64, No. 13, 1999
Barbaro et al.
F igu r e 3. Compounds (3R,4S)-Z-14, (2S,5R)-15, and 18a
and b.
of the Z-diastereomers which have the hydroxy group in
the shielding cone of the aromatic substituents. Qualita-
tive homonuclear NOE difference spectra performed on
the â-lactams 4a and 4c-i further confirmed these
assignments.29 The E/ Z relative configuration of the
â-lactams 4b was assigned by a comparison of their
physical and spectroscopic characteristics with those
reported for the racemic forms.5a,30 A chemical correlation
of the absolute configuration (3R,4R) of the â-lactam E-4a
with the â-lactam 1,4-diphenyl-3-methylazetidinone (3S,-
4S)-Z-14 (Figure 3) has already been described.24 Ad-
ditional studies regarding the assignment of the relative
E-configuration of the â-lactam 4a and of the absolute
configuration of (3R,4S)-Z-4b by X-ray analysis together
with the assignment of the absolute configuration of the
other â-lactams from a comparison of their CD spectra
with those of (3R,4R)-E-4a and (3R,4R)-E-4b are reported
in a separate paper.31 Only in one case (Table 1, entry 9,
compound 4i), the yield was exceptionally low (24%)
because of the instability of the glyoxylic imine 11 under
the basic reaction conditions. In the other cases, the
yields ranged between moderate (41%, compound 4h ) and
high (82%, compound 4b). Major limitations are the steric
demand of the substituents in the reagents and the
instability of the cyclic enolates when long reaction times
are required. For this reason, both the presence of the
highly polar cosolvent HMPA and a slow addition of the
dioxolanone into a mixture of imine and LiHMDS is
necessary for an efficient conversion of the reagents into
â-lactams. The polarity of the mixed solvent increases
the reactivity of the substrates at low temperatures
substantially reducing the formation of self-addition
products, such as 5, the decomposition of enolates 3
leading to the ketenes 6,32 and the formation of lactone
alcohols 7 (Figure 4). The reaction of enolate 3a and bis-
(trimethylsilyl)-propargylimine (9) gave a mixture of
3-hydroxy- and 3-trimethylsilyloxy-â-lactams (4f and 4f ′)
(Figure 5).33 Similarly, the enolate 3c and the imine 9
gave a mixture of â-lactams 4g and 4g′.34 The yields
reported in entries 6 and 7 of Table 1 refer to the total
F igu r e 2. Azomethine components 1 and 8-13.
Ta ble 1. P r od u ct Distr ibu tion (yield s, % ee) of
â-La cta m s 4a -i Obta in ed via Ad d ition Rea ction of
Im in es 1 a n d 8-11 to En ola tes 3a -d (P r oced u r e 1)
enolate 3
(S/ R)
3R,4S-Z/ 3R,4R-E
(yield (%), % ee)
entry
imine
product
1
2
3
4
5
6
7
8
9
1
1
1
1
8
9
9
10
11
a (97:3)
b (S)
4a
4b
4c
4d
4e
4f
4g
4h
4i
18:82 (69, 94)a
44:56 (82, 99)b
71:29 (59, 97)c
78:22 (45, 99)d
66:33 (50, 96)a
33:66 (58, 98)a
18:82 (58, 96)a
95:5 (41, 98)a
50:50 (24, 94)a
c (99:1)
d (98:2)
a (97:3)
a (97:3)
c (99:1)
a (97:3)
a (97:3)
b
d
Expected % ee: a94. 100. c 98. 96.
of enolate 3a with other variants of the azomethine
component, i.e. the N-(trimethylsilyl)-2-furylimine (8),
bis-(trimethylsilyl)-propargylimine (9), N-(trimethylsilyl)-
cinnamylideneimine (10), N-p-methoxyphenylimino-me-
thylglyoxylate (11), and the azacumulene phenylisothio-
cyanate (13) (Figure 2 and Scheme 1). The use of the
N-trimethylsilyl and N-p-methoxyphenyl substituents in
aldimines is particularly attractive for the creation of
monocyclic N-unsubstituted (3R,4S)-3-hydroxy-3-alkyl-
â-lactams, which are useful substrates for the “â-lactam
synthon method”.3 In addition, the aromatic isothiocy-
anates, such as the phenylisothiocyanate 13, are used to
prepare thiono-malonamic esters28 from which 4-thiono-
â-lactams are obtained. Yields, product distribution, and
enantiomeric excesses (% ee) of the â-lactams 4a -i
derived from the reactions of imines 1 and 8-11 with
enolates 3a -d are collected in Table 1. The assignment
of stereostructures was based on X-ray analyses, on
chemical correlation, and on a combined NMR and
circular dichroism spectroscopic study. The E/ Z relative
configuration of the â-lactams 4a , 4c, 4d , and 4e was
established by a study of their 1H NMR spectra. The
methyl protons of E-4a and E-4e, the proton resonance
of the Me2CH group of E-4c, and the methylene protons
of E-4d are in the shielding cone of the aromatic C4-
phenyl and C4-furyl substituents. Their signals are,
therefore, more upfield than the corresponding signals
(29) In particular, the irradiation of the signals of the Z-diastere-
omers centered at 1.10 (C3-Me of 4a ), 2.25 (CH of C3-CHMe2 of 4c),
3.09 (CH2 of C3-CH2CO2H of 4d ), 1.64 (C3-Me of 4e), 1.56 (C3-Me
of 4f), 2.05 (CH of C3-CHMe2 of 4g), 1.50 (C3-Me of 4h ), 1.71 (C3-
Me of 4i), 1.63 (C3-Me of 4l), and 2.20 (CH of C3-CHMe2 of 4m )
showed a large enhancement (8.5-11%) of the neighboring C4-H
protons centered at 5.10 (4a ), 5.07 (4c), 5.52 (4d ), 4.62 (4e), 4.17 (4f),
4.18 (4g), 4.17 (4h ), 4.45 (4i), 4.83 (4l), and 4.48 (4m ), respectively,
while the corresponding E-isomers showed enhancements in the range
of 1-3%.
(30) (a) Cossio, F. P.; Palomo, C. Tetrahedron Lett. 1985, 35, 4239-
4242. (b) Bose, A. K.; Dayal, B.; Manhas, M. S.; Kapur, J . C.; Lal, B.
Tetrahedron Lett. 1974, 36, 3135-3138.
(31) Barbaro, G.; Battaglia, A.; Guerrini, A.; Bertucci, C.; Geremia,
S. Tetrahedron Asymm. 1998, 9, 3401-3409.
(28) Cainelli, G.; Giacomini, D.; Panunzio, M.; Martelli, G.; Spunta,
G. Tetrahedron Lett. 1987, 28, 3593-3596 and references therein.
(32) See also: (a) Ogawa, T.; Niwa, H.; Yamada, K. Tetrahedron
1993, 49, 1571-1578. (b) Reference 23b.

Addition Reaction of Imines to Enolates
J . Org. Chem., Vol. 64, No. 13, 1999 4647
relative ul,ul-1,3 topicity. Although the cyclic enolates
possess a clean Z-geometry, the â-lactams were obtained
with variable diastereoselectivity, this being the result
of steric and electronic effects caused by the removal of
the lithium ion by HMPA.37 In addition, it has been
shown5b that N-aryl-C3,C4-disubstituted-â-lactams easily
isomerize in the presence of HMPA under the basic
reaction conditions. This possibility cannot be excluded
in our reactions. Control experiments demonstrated that
E- and Z-4a and E- and Z-4b resist isomerization upon
treatment with 0.2 equiv of LHMDS at 0 °C for 6 h in a
THF/HMPA ) 85:15 mixed solvent.38 By contrast, a 1:1
Z/ E mixture of 4i was converted into a 1:2 mixture when
this experiment was conducted at - 40 °C in 3 h.
E-Diastereomers were preferentially formed in the reac-
tions of diphenylimine 1 with the enolates 3a and 3b and
in the reactions of propargylimine 9 with 3a and 3c. In
the other cases, the Z-diastereomers were favored. Chro-
matography allowed the isolation of pure E- and Z-â-
lactams 4a -c, and 4f and of the major isomers (3R,4S)-
Z-4d , (3R,4S)-Z-4e, (3R,4R)-E-4g, and (3R,4S)-Z-4h ,
while the minor isomers (3R,4R)-E-4d , (3R,4R)-E-4e,
(3R,4S)-Z-4g, and (3R,4R)-E-4h were isolated as variable
diastereomeric mixtures. The chromatography of the
â-lactams 4i allowed their purification but failed in
separating the product mixtures.
Rea ction s of Im in es a n d Dioxola n on es Der ived
fr om P in a colon e. The reactions so far described give
excellent 3R stereocontrol but diastereoselectivity is
generally poor (de e 64). Diastereoselectivity is particu-
larly essential when the N-unsubstituted 3-hydroxy-3-
methyl-â-lactams, with proper (3R,4S) stereochemistry,
are used as intermediates in the synthesis of taxoids.20
To improve the stereocontrol and at the same time avoid
competition between the formation of â-lactams and side-
products, such as 5 and 7, we investigated the reactivity
of two dioxolanones derived from pinacolone as the
acetalization reagent, namely, dioxolanone 2e [(2S,5S)-
cis/(2R,5S)-trans ) 96:4],39 with a small Me substituent
at C5 and the homochiral dioxolanone (2S,5S)cis-2f with
a larger Me2CH (Figure 1). Since the enolates derived
from pinacolone are more stable than the corresponding
enolates derived from pivalaldehyde, we used a different
protocol for this study (procedure 2). The imine was added
after the enolate was generated with LiHMDS in a 85:
15 THF/HMPA mixed solvent. In Table 2, the product
distribution, yields, and ee of the reactions of 2e with
imines 1 and 8-12 and of 2f with 11 are reported.
Similarly to enolate 3a , all the reactions involving enolate
3e occurred with excellent facial selectivity. We observed
remarkable differences in the yields and stereochemical
output when the results of the reactions of the enolates
3a and 3e with the same imines are compared. In several
cases, the substitution of the small proton substituent
at C2 of 3a with a larger methyl of 3e increased the yields
and the diastereoselectivity favoring the major diastere-
omer. Quite interestingly, the â-lactam 4i, derived from
the glyoxylimine 11 and enolate 3e, was obtained in good
F igu r e 4. Byproducts 5a , 6a -c, 7a , 7c, and 7d .
F igu r e 5. Compounds 4f, 4f ′, 4g, and 4g′.
amount of â-lactams 4f and 4g obtained after a selective
O-desilylation of 4f ′ and 4g′ with a 3.0 M solution of
acetic acid in methanol at 60 °C.35 The reaction of
phenylisothiocyanate 13 with 3b gave the thiono-mal-
onamic ester (2S,5R)-15 in 75% yield (Figure 3). It is
worth noting that these C4 substituents are also designed
for the synthesis of modified bicyclic penems via a step-
by-step synthesis of key cyclization precursors.36
All the reactions occurred with excellent face-selectiv-
ity. Enantioselective HPLC analysis (see Experimental
Section) showed that both diastereoisomers (3R,4S)-Z
and (3R,4R)-E of 4a were obtained as enantiomer couples
in a 97:3 ratio, 94% ee. This result indicated that the
cycloaddition occurred under total facial-diastereocontrol
since the obtained 94% ee corresponds to that expected
on the basis of the diastereomeric excess (de) of the
starting lactone. Similar results were obtained for the
other â-lactams (Table 1). The assignment of the 3R
absolute configuration at the stereogenic C3 quaternary
center of the major (3R,4S)-Z- and (3R,4R)-E-â-lactams
is in agreement with the mechanism proposed by Seebach
for the addition of electrophiles to the enolates having
(2S)-chirality. The electrophilic imine approaches the
enolate from the face opposite the tert-butyl substituent
(Scheme 1). In particular, the diastereoisomeric (3R,4S)-
Z-â-lactams are formed when the enolates having (2S)-
chirality and 1 approach with a relative lk,ul-1,3 topicity,
while (3R,4R)-E-diastereoisomers are derived from a
(33) Relevant 1H NMR spectroscopic characteristics of â-lactams 4f ′.
(3R,4R)-E-4f ′: 1H NMR (CDCl3) δ 0.17 (s, 9H), 0.18 (s, 9H), 1.53 (s,
3H), 4.10 (s, 1H), 6.25-6.35 (br s, 1H). (3R,4S)-Z-4f ′: 1H NMR (CDCl3)
δ 0.17 (s, 9H), 0.22 (s, 9H), 1.54 (s, 3H), 4. 07 (s, 1H), 6.40-6.50 (br s,
1H).
(34) Relevant 1H NMR spectroscopic characteristics of â-lactams 4g′.
(3R,4R)-E-4g′: 1H NMR (CDCl3) δ 0.17 (s, 9H), δ 0.21 (s, 9H), 1.06 (d,
3H) 1.10 (d, 3H), 2.22 (m, 1H), 4. 05 (s, 1H), 5.90-6.00 (br s, 1H). (3R,-
4R)-Z-4g′: 1H NMR (CDCl3): δ 0.18 (s, 9H), 0.95 (d, 3H) 1.01 (d, 3H),
1.90 (m, 1H), 4. 10 (s, 1H), 6.25-6.35 (br s, 1H).
(37) It is worth noting that the relative amount of the chelation-
controlled â-lactams Z-4a and Z-4b increased when the reactions of
entries 1 and 2 (Table 1) were performed in the absence of HMPA.
See refs 24 and 27.
(38) However, pure E-4b converted into a E/Z ) 4:1 mixture upon
treatment with an equimolar amount of NaH in THF under reflux for
1 h.
(35) The E/ Z diastereomeric ratios of 4f and 4f ′ and of 4g and 4g′
were identical.
(36) The conversion of the monocyclic â-lactams into bicyclic â-lac-
tams should involve the conversion of the methoxycarbonyl, 2-furyl,
propargyl, and phenylethenyl substituents into the corresponding
4-acetoxy- or the 4-(hydroxymethyl)-derivatives. See for example:
Georg, G. I.; Kant, J .; Gill, H. S. J . Am. Chem. Soc. 1987, 109, 1129-
1135 and references therein.
(39) Ortholand, Y. J .; Greiner, A. Bull. Soc. Chim. Fr. 1993, 130,
133-142.

4648 J . Org. Chem., Vol. 64, No. 13, 1999
Barbaro et al.
Ta ble 2. F or m a tion of â-La cta m s 4a , 4e, 4f, a n d 4h -m
via Ad d ition Rea ction of Im in es 1 a n d 8-12 to th e
En ola tes 3e a n d 3f (P r oced u r e 2)
Sch em e 2. P r op osed Mech a n ism for th e Ad d ition
Rea ction betw een Dioxola n on e 2e a n d
N-(Tr im eth ylsilyl)-cin n a m ylid en eim in e (10)
enolate 3
(S/ R)
3R,4S-Z/ 3R,4R-E
(yield %, % ee)
entry
imine
product
1
2
3
4
5
6
7
1
8
9
10
11
12
11
e (96:4)
e (96:4)
e (96:4)
e (96:4)
e (96:4)
e (96:4)
f (S)
4a
4e
4f
4h
4i
8:92 (87,92)a
80:20 (78, 92)a
5:95 (74, 98)a
92:8 (44, 98)a
84:16 (71, 92)a
94:6 (77, 92)a
92:8 (45, 62)b
4l
4m
b
Expected % ee: a92. 100.
yields (71%). This was probably due to the inversion of
the addition order of the reagents so that the decomposi-
tion of the unstable imine under the basic reaction
conditions was substantially reduced. The major isomer
(3R,4S)-Z-4i was isolated by chromatography or by
crystallization. However, the product distribution of 4i
was dependent on the reaction conditions. Namely, total
enantiofacial selectivity and good Z/ E diastereoselectiv-
ity (84:16) were obtained when the reaction was per-
formed at -105 °C. However, the Z/E ratio and the
enantioselectivity decreased when the reaction was car-
ried out at higher temperatures. Independent experi-
ments showed that both a Z to E epimerization and
racemization occurred when pure Z-4i was left to stand
at higher temperatures (-60 °C) under the basic reaction
conditions. The formation of amounts of byproducts was
unavoidable in some reactions. In particular, the reaction
of enolate 3e, similarly to 3a , gave a mixture of 3-hy-
droxy- (4f, 74%) and 3-trimethylsilyloxy-â-lactams (4f ′,
9%). The reaction of 2e and N-(trimethylsilyl)-cinnamylide-
neimine (10) gave the expected â-lactams 4h and byprod-
ucts deriving from the 1,4-addition of the imine to the
enolate, namely, the δ-lactam 16 (5%) and the dioxol-
anone derivatives 17a , and b (18%). The result can be
understood considering this possible reaction mechanism
(Scheme 2). A competitive addition of the enolate anion
to both the electrophilic carbon atoms of the imine (C1
and C3) leads to two acyclic aminoester intermediates I
and II, which evolve into the corresponding four- or six-
membered cyclic structures 4h and 1640 or to the open
chain 1,4-addition products 17.41,42 Finally, the reaction
of imine 11 and 2e gave the expected â-lactams 4i and a
1:1 mixture of the lactone derivatives 18a and 18b
(20%)43 (Figure 3). Similarly to the results obtained with
enolate (2S)-3e, the high diastereoselectivity (Z/ E ) 92:
8) for â-lactam 4m is probably due to the bulkiness of
the Me2CH substituent of the homochiral enolate (2S)-
3f, even if poor face-selectivity (62% ee) is observed.
Con clu sion s. Overall, this methodology appears to be
a rather direct approach to chiral 3-hydroxy-â-lactams
with full control of stereochemistry at the quaternary C3
carbon atom and a variety of substituents at C3 and C4,
which are easily available from the inexpensive starting
reagents. The diastereoselectivity is relatively low when
â-lactams are prepared from enolates 3a -d but signifi-
cantly increases when the enolate 3e is used. This allows
an easy purification of the major diastereomer by a
simple crystallization procedure. It is worth noting that
four N-unsubstituted 3-hydroxy-3-methyl-â-lactams bear-
ing 2-furyl (4e), 2-thienyl (4l), phenylethenyl (4h ), and
carbomethoxy (4i) substituents at C4, with proper (3R,-
4S) stereochemistry, were obtained in good yields, with
high diastereomeric excesses, and were easily purified
by column chromatography or by crystallization. The
simultaneous presence of these substituents at C3 and
C4 open the possibility of the synthesis of analogues of
the antitumor drugs Taxol (paclitaxel) and Taxote`re
(docetaxel) using a protocol independently developed by
Ojima and by Holton.44
(40) Relevant spectroscopic data of (3S)-3-h yd r oxy-3-m eth yl-4-
p h en yl-3,4-d ih yd r o-1H-p yr id in -2-on e (16): 1H NMR (CD3COCD3)
δ 0.99 (s, 3H), 3.90 (t, J ) 2.8 Hz, 1H), 4.2 (br s, 1H), 5.2 (m, J ) 7.8
Hz, 1H), 6.35 (m, J ) 7.8 Hz, 1H), 7.2-7.5 (m, 5H), 8.4-8.7 (br s, 1H);
13C NMR (DMSO/CDCl3) δ 18.9, 48.6, 70.4, 107.5, 124.0, 125.4, 126.3,
128.2, 137.5, 173.1; MS m/z 203 (M+), 160, 132, 115.
(41) Relevant spectroscopic data of (2S,5R,1′S a n d 2S,5R,1′R)-2-
t-b u t yl-2,5-d im et h yl-5-(3′-oxo-1′-p h en ylp r op yl)-1,3-d ioxola n -4-
on es (17a a n d 17b): MS m/z 304 (M+), 205, 172, 159; 1H NMR
(CD3COCD3) δ 0.95 (s, 9 H, 3Me of 17a ), 0.99 (s, 9H, 3Me of 17b), 1.32
(s, 3H, Me of 17b), 1.33 (s, 3H, Me of 17a ), 1.42 (s, 3H, Me of 17b),
1.57 (s, 3H, Me of 17a ), 2.92-3.20 (m, 2H, CH2 of 17b), 3.0-3.4 (m,
2H, CH2 of 17a ), 3.68 (m, J 1 ) 4.2 Hz, J 2 ) 9.5 Hz, 1H of 17b), 3.90
(m, J 1 ) 5.4 Hz, J 2 ) 8.9 Hz, 1H of 17a ), 7.2-7.4 (m, 5H of 17a and
17b), 9.59 (m, 1H, CHdO of 17b), 9.65 (m, 1H, CHdO of 17a ); 13C
NMR (CDCl3) relevant data: δ 20.3 (Me of 17a ), 21.8 (Me of 17b), 22.0
(Me of 17b), 23.0 (Me of 17a ), 24.8 (3 Me of Me3C of 17a ), 25.07 (3 Me
of Me3C of 17b), 38.8 (C of 17a ), 38.9 (C of 17b), 43.3 (CH2 of 17a ),
45.1 (CH of 17a ), 45.2 (CH2 of 17b), 47.2 (CH of 17b), 80.7 (C of 17a ),
81.6 (C of 17b), 115.0 (C of 17b), 115.1 (C of 17a ), 174.0 (C of 17b),
174.9 (C of 17a ), 199.5 (C of 17a ), 199.7 (C of 17b).
(43) Relevant spectroscopic data of (2S,5R,1′S and 2S,5R,1′R)-2-
t-bu tyl-2,5-d im eth yl-5-[1′-(4-m eth oxyp h en yla m in o)-1′-m eth oxy-
ca r bon yl-m eth yl]-1, 3-d ioxola n -4-on es (18a a n d 18b). 18a : 1H
NMR (CDCl3) δ 1.1 (s, 9H), 1.58 (s, 3H), 1.71 (s, 3H), 3.70 (s, 3H), 3.71
(s, 3H), 4.10-4.20 (m, 2H), 6.70-6.80 (m, 4H); 13C NMR (CDCl3)
relevant resonances δ 22.8, 23.0, 25.3, 38.8, 52.4, 55.7, 65.2, 81.7, 170.5,
173.1. 18b: 1H NMR (CDCl3) δ 1.0 (s, 9H), 1.61 (s, 3H), 1.67 (s, 3H),
3.70 (s, 3H), 3.73 (s, 3H), 4.10-4.20 (m, 2H) 6.75 (m, 4H); 13C NMR
(CDCl3) δ 22.2, 22.7, 24.4, 25.2, 39.0, 52.4, 55.7, 65.5, 82.5, 114.8, 116.1,
117.3, 171.1, 173.4.
(42) The hypothesis that compounds 17 are derived by the reaction
of 2e with cinnamaldehyde, which may be formed by hydrolysis of
imine 10, was ruled out in an independent experiment. In fact, the
reaction of cinnamaldehyde and the lithium enolate gave rise to
corresponding dioxolanones derived by a 1,2-aldol addition, exclusively.
An identical result has been observed in the reaction of cinnamalde-
hyde with 2a .23b

Addition Reaction of Imines to Enolates
J . Org. Chem., Vol. 64, No. 13, 1999 4649
in Tables 1 and 2. The synthesis and analytical data of E/ Z-
â-lactams 1a and 1b from dioxolanone 2a have already been
reported.24
Rea ction of Im in e 1 a n d Dioxola n on e 2e. A THF
solution of imine 1 (3.29 mmol) was added to a THF/HMPA
solution of the enolate 3c (2.03 mmol,) at -90 °C in 2 h. The
temperature was raised to -70 °C for 2 h. Chromatography
(SiO2, EtOAc/n-pentane, 2:13) gave 1.76 mmol (87%, Z/E )
8:92) of â-lactams 4a .
E- a n d Z-3-Hyd r oxy-3-isop r op yl-4-p h en yl-N-4-p h en y-
la zetid in -2-on es [(3R,4R)-E-4c a n d (3R,4S)-Z-4c]. The di-
oxolanone 2c (1.61 mmol) was added to a THF/HMPA solution
of the imine 1 (3.00 mmol) and LHMDS (2.9 mmol) at - 90 °C
in 8 h. Chromatography (SiO2, EtOAc/n-pentane, 2:13) gave
0.95 mmol (59%, Z/E ) 71:29) of â-lactams: IR νmax (CDCl3)
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded on a 200 MHz spectrometer with Me4Si or
CHCl3 (in CDCl3) as internal standards. Mass spectra were
recorded on
a ion trap spectrometer with an ionization
potential of 70 eV. Infrared spectra were recorded on a Fourier
transform IR spectrometer. The HPLC system consisted of a
J asco PU 980 pump. UV and CD detection were obtained by a
J asco MD-910 multiwavelength detector and a J asco J 710
spectropolarimeter. Chromatographic resolution was obtained
with the following columns (Daicel, 25 × 0.46 cm i.d.):
a
Chiralpack AD (compounds 4a -c, 4e), a Chiralcel OJ (com-
pounds 4d , 4f, 4g, 4h , and 4l), and a Chiralcel OD (compounds
4h , 4m ). The mobile phase was n-hexane/2-propanol/acetic acid
(75:25:1.5) in the case of 4d , while mixtures of n-hexane/2-
propanol (90:10-97.5:2.5) were used in all the other cases. The
flow was 0.8-1.0 mL/min. The dioxolanones were prepared
according to the literature and were purified by distillation
3650, 3550-3100, 1755 (N-CdO) cm-1; MS m/z 282 (M+
+
1), 264, 182, 133. (3R,4R)-E: mp 149-150 °C; [R]22D ) -64 (c
0.6, CHCl3); 1H NMR (CDCl3) δ 0.47 (d, J ) 6.6 Hz, 3H), 1.15
(d, J ) 6.6 Hz, 3H), 2.05 (m, 1H), 2.80-2.90 (br s, 1H), 5.00
(s, 1H), 7.00-7.40 (m, 10H); 13C NMR (CDCl3) δ 14.7, 16.9,
29.3, 70.0, 90.5, 118.0, 124.2, 127.7, 128.6, 128.7, 129.0, 134.3,
137.1, 168.3. Anal. Calcd for C18H19NO2: C 76.84, H 6.81, N
4.98. Found: C 76.60, H 6.86, N 5.02. (3R,4S)-Z: mp 173-
under
a vacuum. The enantiomeric excesses (ee) of the
corresponding enolates are given in Tables 1 and 2. In
particular, (2S,5S)-cis-2f was prepared for the first time
according to literature procedure.39 N-Trimethylsilylimines 8,
9, 10, and 12 were prepared according to literature proce-
dures.45
174 °C; [R]22 ) + 180 (c 0.6, CHCl3); 1H NMR (CDCl3) δ 1.13
D
(d, J ) 6.9 Hz, 3H), 1.20 (d, J ) 6.9 Hz, 3H), 2.25 (m, 1H),
2.30-2.70 (br s, 1H), 5.07 (s, 1H), 7.00-7.45 (m, 10 H); 13C
NMR (CDCl3) δ 16.7, 17.0, 33.2, 65.2, 89.1, 117.6, 124.3, 127.2,
128.8, 129.1, 129.3, 134.0, 137.1, 168.0.
(2S,5S)-cis-2-ter t-Bu tyl-2-m eth yl-5-isop r op yl-1,3-d iox-
ola n -4-on e [(2S,5S)-cis-2f]: bp 83-84 °C/14 mmHg; IR νmax
(CDCl3) 1798 (CdO) cm-1; MS m/z 200 (M+), 144; [R]22
)
D
1
+10.0 (c 2.75, CHCl3); H NMR (CDCl3) δ 4.12 (d, 1H), 2.12
(m, J ) 7.4 Hz, 1H), 1.44 (s, 3H) 1.10 (d, 3H), 1.01 (s, 9H),
1.00 (d, 3H); 13C NMR (CDCl3) δ 17.6, 18.1, 18.6, 24.3, 29.8
37.8, 77.7, 114.2, 172.5. Anal. Calcd for C11H20O3: C 65.97, H
10.07. Found: C 65.80, H 10.11.
E- a n d Z-3-Ca r boxym eth yl-3-h yd r oxy-4-p h en yl-N-p h e-
n yla zetid in -2-on es [(3R,4R)-E-4d a n d (3R,4S)-Z-4d ]. A
THF solution of dioxolanone 2d (0.12 mmol) was added at -80
°C in 8 h to a THF/HMPA solution of 1 (0.22 mmol) and
LHMDS (1 M in THF, 3.4 mL). The temperature was raised
to -20 °C in 2 h. HCl (1 M, 10 mL) was added to the reaction
mixture and extracted with ethyl acetate/CH2Cl2 ) 3:1. The
organic layer was treated with 50 mL of saturated aqueous
NaHCO3. The aqueous solution was extracted with ethyl
acetate and then with CH2Cl2 and acidified with 1 M HCl. The
mixture was extracted with ethyl acetate and then with CH2-
Cl2. The organic layer was dried (Na2SO4), and the solvent was
removed under reduced pressure. Chromatography (SiO2, CH2-
Cl2/MeOH, 9:1) gave 0.54 mmol (45%, Z/E ) 78:22) of â-lactams
4d . IR νmax (THF) 3600-3100, 1755 (N-CdO), 1720 cm-1; MS
m/z 297 (M+), 252, 251, 235, 181. (3R,4R)-E: 1H NMR (CD3-
COCD3) δ 2.52 (q, J ) 16.9 Hz, 2H), 3.60-3.90 (br s, 1H), 5.22
(s, 1H), 7.00-7.50 (m, 10H); 13C NMR (CD3COCD3) δ 35.3,
69.9, 86.6, 118.5, 124.9, 129.0, 129.1, 129.8, 129.9, 135.2, 138.5,
Gen er a l P r oced u r e for th e Syn th esis of th e â-La cta m s.
The â-lactams were prepared according to the following
procedures.
P r oced u r e 1. A THF solution of dioxolanone was added
via a syringe pump (5-7 h) to a THF/HMPA (85:15) solution
of imine and LHMDS at the selected reaction temperature
under stirring. Occasionally, the temperature was raised for
the time required. Unless otherwise stated, the reaction
mixture was treated with a saturated aqueous solution of NH4-
Cl. The organic layer was extracted two times with brine and
dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The E/ Z isomer distribution was evaluated
from 1H NMR analysis of the residue. The E/ Z-mixture of
diastereomeric â-lactams was separated by flash-chromatog-
raphy or, when possible, by crystallization. When procedure
1 was used, the N-trimethylsilylimines 8, 9, and 12 were
prepared in situ.45 A THF solution of aldehyde (1.0 equiv) was
added at -10 °C to a 1 M THF solution of LHMDS (1.2 equiv).
The resulting solution was stirred for 20 min at 0 °C, then 1.0
equiv of trimethylchlorosilane was added. After the resulting
solution was cooled to - 90 °C, a 1 M THF solution of LHMDS
(0.63-0.70 equiv) and HMPA (THF/HMPA, 85:15) were se-
quentially added. Finally, a THF solution of dioxolanone
(0.63-0.70 equiv) was added at the selected reaction temper-
ature.
166.8, 172.0. (3R,4S)-Z: mp 146-148 °C; [R]22 ) + 150 (c
D
1
0.5, THF); H NMR (CD3COCD3) δ 3.09 (q, J ) 16.0 Hz, 2H),
3.60-3.90 (br s, 1H), 5.52 (s, 1H), 7.00-7.50 (m, 10H); 13C
NMR (CD3COCD3) δ 39.8, 67.4, 84.4, 118.4, 124.7, 128.8, 129.0,
129.1, 129.8 135.6, 138.7, 167.4, 171.6. Anal. Calcd for C17H15
-
NO4: C 68.68, H 5.09, N 4.71. Found: C 68.88, H 5.13, N 4.77.
E- a n d Z-4-F u r a n -2-yl-3-h yd r oxy-3-m eth yl-a zetid in -2-
on es [(3R,4R)-E-4e a n d (3R,4S)-Z-4e]. (a ) Rea ction of
N-Tr im eth ylsilyl-2-fu r fu r a ld im in e (8) a n d Dioxola n on e
2a . The imine 8 was prepared in situ from 2-furaldehyde (4.86
mmol), 5 mL of a 1 M solution of LHMDS, and 4.86 mmol of
trimethylchlorosilane. A 1 M THF solution (3.06 mL) of
LHMDS and HMPA were sequentially added. A THF solution
of dioxolanone 2a (2.21 mmol, S/ R ) 97:3) was added in 6 h
at - 90 °C. The reaction mixture was left at -78 °C for 2 h
and then at -50 °C for 2 h. The reaction was quenched with
acetic acid, the solvent was evaporated under reduced pres-
sure, and HMPA was distilled at 10-1 Torr. Chromatographic
workup (SiO2, EtOAc/CH2Cl2, 1:3) gave the â-lactams 4e (1.10
mmol, 50%, Z/ E ) 2:1).
(b) Rea ction of N-Tr im eth ylsilyl-2-fu r fu r a ld im in e (8)
a n d Dioxola n on e 2e. A THF solution of freshly distilled
imine 8 (2.73 mmol) was added to a THF/HMPA solution of
the enolate 3e (1.70 mmol) at -78 °C. The reaction mixture
was left at -90 °C for 2 h and then at -50 °C for 2 h. The
chromatography gave 1.33 mmol (78%, Z/E ) 80:20) of
â-lactams 4e: IR νmax (THF) 3630, 3550-3100, 1770 (N-Cd
O) cm-1; MS m/z 167 (M+), 124, 110, 96. (3R,4S)-Z: mp 127-
P r oced u r e 2. A THF solution of the lactone was added to
a THF solution of lithium diisopropylamide at - 78 °C. After
30 min, solutions of HMPA and imine were sequentially added
at the selected temperature (THF/HMPA ) 85:15). Unless
otherwise stated, the reaction mixture was treated as described
in procedure 1. Overall yields, E/ Z isomer distribution, and
ee of the â-lactams (together with their expected ee) are given
(44) According to this methodology, the phenylisoserine side-chains
of paclitaxel and docetaxel are appended to the C13 of Baccatin IIIs
with proper protecting groups via ring-opening coupling of (3R,4S)-1-
acyl-3-silyloxy-4-phenyl-â-lactams with metalated baccatins. See for
example: (a) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.;
Sun, C.-M.; Brigaud, T. Tetrahedron 1992, 48, 6895-7012. (b) Holton,
R. A.; Biediger, R. J .; Boatman, P. D. In Taxol: Science and Applica-
tions; Suffness, M., Ed.; CRC: New York, 1995; pp 97-121.
(45) Colvin, E. W.; McGarry, D.; Nugent M. J . Tetrahedron 1988,
44, 4157-4172.

4650 J . Org. Chem., Vol. 64, No. 13, 1999
Barbaro et al.
1
129 °C; [R]22 ) +70 (c 0.3, CH3COCH3); H NMR (CDCl3) δ
via a syringe pump (5 h) to a THF/HMPA solution of 10 (3.65
mmol) and LHMDS (3.65 mmol) at -85 °C in 5 h. The reaction
mixture was left at - 50 °C for 3 h. The reaction mixture was
treated at -50 °C with 4 mL of a 1 N aqueous solution of HCl
D
1.64 (s, 3H), 2.90-3.00 (br s, 1H), 4.62 (s, 1H), 6.30-6.45 (m,
2H), 6.60-6.70 (br s, 1H), 7.45-7.50 (m, 1H); 13C NMR (CDCl3)
δ 20.1, 59.3, 86.2, 109.3, 110.7, 142.8, 150.3, 173.0. Anal. Calcd
for C8H9NO3: C 57.48, H 5.43, N 8.38. Found: C 57.32, H 5.38,
N 8.46. (3R, 4R)-E: 1H NMR (CDCl3) δ 1.25 (s, 3 H), 2.90-
3.00 (br s, 1H), 4.66 (s, 1H), 6.25-6.35 (m, 2H), 6.7-6.8 (br s,
1H), 7.40-7.45 (m, 1H); 13C NMR (CDCl3) δ 18.0, 60.0, 87.4,
108.4, 110.5, 143.4, 150.4, 173.2.
and neutralized with a 2 N aqueous solution of NaHCO3
. The
organic layer was extracted two times with brine and dried
(Na2SO4). Evaporation of the solvent under reduced pressure
and chromatography of the residue (SiO2, EtOAc/n-pentane,
1:2) gave 0.83 mmol of 4h (41%, Z/E ) 95:5).
E- a n d Z-3-Hyd r oxy-3-m eth yl-4-tr im eth ylsila n yleth y-
n yl-a zetid in -2-on es [(3R,4R)-E-4f a n d (3R,4S)-Z-4f]. (a )
Rea ction of Bis-tr im eth ylsilylp r op a r gylim in e (9) a n d
Dioxola n on e 2a . The imine 9 was prepared in situ from
trimethylsilylpropargylaldehyde (4.86 mmol), 5 mL of a 1 M
solution of LHMDS, and 4.86 mmol of trimethylchlorosilane.
A THF solution of LHMDS (1 M, 3.06 mL) and HMPA were
sequentially added. A THF solution of dioxolanone 2a (1.66
mmol) was added in 4 h at -85 °C. The reaction temperature
was raised to - 60 °C and left for 2 h. After the addition of a
saturated aqueous solution of NH4Cl, selective O-desilylation
of the â-lactams 4f ′ was performed by treating the reaction
mixture with MeOH/CH3CO2H (1:1) for 16 h at 25 °C. The
solution was neutralized with a 2 N aqueous solution of
NaHCO3, extracted with CH2Cl2, and dried (Na2SO4). After
evaporation of the solvent under reduced pressure, the residue
was chromatographed (SiO2, EtOAc/n-pentane, 1:4) to give the
â-lactams 4f (0.96 mmol, 58%, Z/ E ) 1:2).
(b) Rea ction of N-Tr im eth ylsilylcin n a m a ld im in e (10)
a n d Dioxola n on e 2e. The imine 10 (4.06 mmol) was added
to a THF/HMPA solution of the enolate (2.03 mmol, S/ R )
95:5) at -90 °C in 15 min. The reaction mixture was left at
-90 °C for 60 min, then at - 70 °C for 3 h, and at -50 °C for
60 min. After the workup of the reaction mixture as described
above, chromatography (SiO2, EtOAc/n-pentane, 1:2) gave the
â-lactams 4h (1.78 mmol, 44%, Z/E ) 92:8), compound 16 (0.10
mmol, 5%), and compounds 17 (0.23 mmol, 18%): IR νmax
(CDCl3) 3650, 3550-3100, 1765 (N-CdO) cm-1; MS (CI, CH4)
m/z 232 (M+ + 29), 204 (M+ + 1), 186. (3R,4R)-E: 1H NMR
(CD3COCD3) relevant resonances at δ 1.29 (s, 3H), 4.25 (d, J
) 8.0 Hz, 1H), 5.23 (br s, 1H). (3R,4S)-Z: mp 158-160 °C;
[R]22 ) +1 (c 0.5, CHCl3); 1H NMR (CD3COCD3) δ 1.50 (s,
D
3H), 2.70-2.80 (br s, 1H), 4.17 (d, J ) 7.4 Hz, 1H), 4.95 (br s,
1H), 6.4 (dd, J 1 ) 7.4 Hz, J 2 ) 16.4 Hz, 1H), 6.7 (d, J ) 16.4
Hz, 1H), 7.2-7.5 (m, 5H); 13C NMR (CD3COCD3) δ 22.2, 64.2,
86.7, 127.3, 128.4, 129.4, 133.8, 137.8, 172.1. Anal. Calcd for
(b) Rea ction w ith Dioxola n on e 2e. A THF solution of
freshly distilled imine 8 (2.30 mmol) was added to a THF/
HMPA solution of the enolate (1.70 mmol) at -90 °C. The
reaction mixture was left at -90 °C for 2 h and then at -60
°C for 2 h. Workup of the reaction as described above gave
1.24 mmol (74%, Z/ E ) 5:95) of â-lactams 4f: IR νmax (THF)
3640, 3550-3100, 1765 (N-CdO) cm-1; MS m/z 197 (M+), 182,
157, 139, 126, 116, 109, 99, 75, 73. (3R,4R)-E: mp 156-158
C
12H13NO2: C 70.92, H 6.45, N 6.89. Found: C 70.80, H 6.48,
N 6.95.
E- a n d Z-3-H yd r oxy-4-m et h oxyca r b on yl-3-m et h yl-N-
4-m eth oxyp h en yl-a zetid in -2-on es [(3R,4R)-E-4i a n d (3R,-
4S)-Z-4i]. (a ) Rea ction of Im in e 11 a n d Dioxola n on e 2a .
The dioxolanone 2a (2.03 mmol) was added to a THF/HMPA
solution of the imine 11 (3.04 mmol) and LHMDS (3.0 mmol)
at - 105 °C in 1 h. The reaction mixture was treated with 5
mL of a 1 M aqueous solution of CH3CO2H at -100 °C, with
a 1 N aqueous solution of HCl, then with NH4Cl, and then
with brine. The organic phase was dried (Na2SO4), and the
solvent was evaporated under reduced pressure. Chromatog-
raphy of the residue (SiO2, EtOAc/n-pentane, 12:8) gave 0.46
mmol (20%) of a 1:1 mixture of â-lactams 4i.
°C; [R]22 ) +97 (c 0.3, CHCl3); 1H NMR (CDCl3) δ 0.18 (s,
D
9H), 1.57 (s, 3H), 3.10-3.80 (br s, 1H), 4.22 (s, 1H), 6.10-6.20
(br s, 1H); 13C NMR (CDCl3) δ -0.27, 19.3, 53.8, 86.9, 93.8,
100.0, 172.2. (3R,4S)-Z: mp 134-136 °C; [R]22 ) -50 (c 0.3,
D
1
CHCl3); H NMR (CDCl3) δ 0.19 (s, 9H), 1.56 (s, 3H), 3.40-
3.50 (br s, 1H), 4.17 (s, 1H), 6.05-6.20 (br s, 1H); 13C NMR
(CDCl3) δ -0.31, 20.4, 53.7, 85.3, 95.4, 99.8, 171.4. Anal. Calcd
for C9H15NO2Si: C 54.79, H 7.66, N 7.10. Found: C 54.74, H
7.61, N 7.17.
(b) Rea ction of Im in e 11 a n d Dioxola n on e 2e. The imine
11 (3.04 mmol) was added to a THF/HMPA solution of the
enolate 2e (2.03 mmol) at -105 °C in 15 min. The reaction
mixture was left at -100 °C for 2 h. Workup as described above
gave the â-lactams 4i (1.44 mmol, 71.0%, Z/ E ) 5.5:1) and a
mixture of compounds 18a and 18b (0.34 mmol, 17%, a /b )
2.6): IR νmax (CHCl3) 3620, 3550-3100, 1710-1780 (N-CdO
and CO2Me) cm-1; MS m/z 265 (M+), 237, 194, 149, 134. (3R,-
E- a n d Z-3-H yd r oxy-3-isop r op yl-4-t r im et h ylsila n yl-
eth yn yl-a zetid in -2-on es [(3R,4R)-E-4g a n d (3R,4S)-Z-4g].
The imine 9 was prepared in situ from 4.5 mmol of LHMDS
and 3.74 mmol of trimethylsilylpropargylaldehyde and 3.7
mmol of trimethylchlorosilane. Then, 3.06 mL of a 1 M THF
solution of LHMDS and HMPA were sequentially added. A
THF solution of dioxolanone (2.21 mmol) was added in 6 h at
-85 °C. The reaction temperature was raised to -60 °C and
left for 2 h. After the addition of a saturated aqueous solution
of NH4Cl, selective O-desilylation of the â-lactams 4g′ was
performed by treating the reaction mixture with MeOH/CH3-
CO2H (1:1) for 16 h at 25 °C. The solution was neutralized
with a 2 N aqueous solution of NaHCO3 and extracted with
CH2Cl2. After evaporation of the solvent under reduced pres-
sure, the residue was chromatographed (SiO2, EtOAc/n-pen-
tane, 1:4) to give the â-lactams 4g (1.28 mmol, 58%, Z/ E )
4S)-Z: mp 134-136 °C; [R]22 ) +96 (c 0.7, CHCl3); 1H NMR
D
(CDCl3) δ 1.71 (s, 3H), 3.62 (br s, 1H), 3.78 (s, 3H), 3.84 (s,
3H), 4.45 (s, 1H), 6.80-7.30 (m, 4H); 13C NMR (CDCl3) δ 21.2,
52.9, 55.5, 65.5, 84.3, 114.2, 118.4, 130.3, 156.8, 166.4, 169.3.
Anal. Calcd for C13H15NO5: C 58.86, H 5.70, N 5.28. Found:
C 59.02, H 5.63, N 5.35. (3R,4R)-E: 1H NMR (CDCl3) δ 1.44
(s, 3H), 2.0-2.2 (br s, 1H), 3.77 (s, 3H), 3.83 (s, 3H), 4.52 (s,
1H), 6.80-7.30 (m, 4H); 13C NMR (CDCl3) δ 17.8, 52.6, 55.5,
66.0, 85.2, 114.4, 118.8, 130.2, 156.9, 167.5, 168.6.
18:82): IR νmax (THF) 3630, 3550-3100, 1760 (N-CdO) cm-1
;
E- a n d Z-3-Hyd r oxy-3-m eth yl-4-th ien -2-yl-a zetid in -2-
on es [(3R,4R)-E-4l a n d (3R,4S)-Z-4l]. Rea ction of N-Tr i-
m eth ylsilyl-2-th ien ylim in e (12) a n d Dioxola n on e 2e. A
THF solution of freshly distilled imine 12 (2.73 mmol) was
added to a THF/HMPA solution of the enolate 3e (1.70 mmol)
at -78 °C. The reaction mixture was left at -78 °C for 2 h
and then at -50 °C for 2 h. The reaction was quenched with
acetic acid, the solvent evaporated under reduced pressure,
and HMPA was distilled at 10-1 Torr. The chromatography
gave 1.31 mmol (77%, Z/E ) 94:6) of â-lactams 4l: IR νmax
(THF) 3630, 3550-3100, 1770 (N-CdO) cm-1; MS m/z 183
MS m/z 225 (M+), 210, 182, 167, 144, 139, 126, 98, 75, 73. (3R,-
4R)-E: mp 119-121 °C; [R]22D ) +140 (c 0.3, CHCl3); 1H NMR
(CDCl3) δ 0.17 (s, 9H), 1.12 (d, J ) 6.9 Hz, 3H) 1.17 (d, J )
6.9 Hz, 3H), 2.34 (m, 1H), 3.0-3.30 (br s, 1H), 4.16 (s, 1H),
6.20-6.30 (br s, 1H). 13C NMR (CDCl3) δ -0.5, 15.7, 16.4, 31.1,
53.2, 92.6, 93.7, 100.7, 171.4. Anal. Calcd for C11H19NO2Si: C
58.63, H 8.50, N 6.21. Found: C 58.70, H 8.44, N 6.16. (3R,-
4S)-Z: 1H NMR (CDCl3) δ 0.18 (s, 9 H), 1.01 (d, J ) 6.8 Hz,
3H) 1.09 (d, J ) 6.8 Hz, 3H), 2.05 (m, 1H), 3.10-3.25 (br s,
1H), 4.18 (s, 1H), 6.15-6.25 (br s, 1H). 13C NMR (CDCl3) δ
-0.1, 16.7, 17.14, 32.3, 50.6, 91.4, 95.6, 100.2, 171.0.
(M+), 142, 112. (3R,4S)-Z: mp 133-134 °C; [R]22 ) +70 (c
D
1
E- a n d Z-3-Hyd r oxy-3-m eth yl-4-(E)-styr yl-a zetid in -2-
on es [(3R,4R)-E-4h a n d (3R,4S)-Z-4h ]. (a ) Rea ction of
N-Tr im eth ylsilylcin n a m a ld im in e (10) a n d Dioxola n on e
2a . A THF solution of dioxolanone 2a (2.03 mmol) was added
0.8, CH3COCH3); H NMR (CDCl3) δ 1.63 (s, 3H), 3.20-3.30
(br s, 1H), 4.83 (s, 1H), 6.60-6.70 (br s, 1H), 7.00-7.50 (m,
3H); 13C NMR (CDCl3) δ 21.2, 61.6, 86.0, 126.0, 126.1, 127.7,
139.9, 172.0. Anal. Calcd for C8H9NO2S: C 52.44, H 4.95, N

Addition Reaction of Imines to Enolates
J . Org. Chem., Vol. 64, No. 13, 1999 4651
7.64. Found: C 52.22, H 5.02, N 7.56. (3R,4R)-E: 1H NMR
(CDCl3) relevant resonances at δ 1.19 (s, 3H), 4.91 (s, 1H).
E- a n d Z-3-Hyd r oxy-3-isop r op yl-4-m eth oxyca r bon yl-
N-4-m eth oxyp h en yl-a zetid in -2-on es [(3R,4R)-E-4m a n d
(3R,4S)-Z-4m ]. The imine 11 (4.00 mmol) was added to a THF/
HMPA solution of the enolate 2f (2.03 mmol, S/ R ) 95:5) at
-105 °C in 15 min. The reaction mixture was treated with 5
mL of a 1 M aqueous solution of CH3CO2H at - 100 °C,
extracted with HCl (1 N), then with NH4Cl, and then with
brine. The organic phase was dried (Na2SO4), and the solvent
was evaporated under reduced pressure. Chromatography of
the residue (SiO2, EtOAc/n-pentane, 12:8) gave 0.90 mmol
(45%, Z/ E ) 92:8) of â-lactams 4m . IR νmax (CHCl3) 3620,
3550-3100, 1710-1780 (N-CdO and CO2Me) cm-1; MS m/z
293 (M+), 194. (3R,4S)-Z: Oil; [R]22D ) +65 (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 1.07 (d, J ) 6.9 Hz, 3H), 1.45 (d, J ) 6.9 Hz,
3H), 2.20 (m, 1H), 3.78 (s, 3H), 3.83 (s, 3H), 4.48 (s, 1H), 6.80-
7.30 (m, 4H); 13C NMR (CDCl3) δ 16.4, 16.9, 32.9, 52.7, 55.4,
62.4, 90.3, 114.4, 118.3, 130.1, 156.7, 166.4, 169.3. Anal. Calcd
for C15H19NO5: C 61.42, H 6.53, N 4.78. Found: C 61.65, H
6.70, N 4.81. (3R,4R)-E: 1H NMR (CDCl3) δ 0.93 (d, J ) 6.8
Hz, 3H), 1.16 (d, J ) 6.8 Hz, 3H), 2.28 (m, 1H), 3.74 (s, 3H),
3.78 (s, 3H), 4.43 (s, 1H), 6.80-7.30 (m, 4H); 13C NMR (CDCl3)
δ 15.9, 17.0, 29.8, 52.6, 55.5, 66.0, 91.2, 114.4, 118.6, 130.2,
156.9, 166.5, 169.0.
(2S,5R)-2-t-Bu tyl-5-(ca r both ioic a cid )-5-p h en yl-N-p h e-
n yla m id e-1,3-d ioxola n -4-on e (2S,5R)-15. Phenylisothiocy-
anate (3.50 mmol) was added to a THF solution of the enolate
(S)-3b (2.72 mmol) at -78 °C in 15 min. The reaction mixture
was left at -78 °C for 3 h and then at -60 °C for 2 h. After
quenching, compound 15 was purified by crystallization (0.72
g, 1.83 mmol, 75%): mp 109-111 °C; [R]22 ) +130 (c 0.6,
D
CHCl3); IR νmax (CDCl3) 3600, 3500-3200, 1660, 1600, 1500,
1440, 1420, 1390 cm-1; MS (CI, CH4) m/z 384 (M+ + 29), 356
(M+ + 1), 314; 1H NMR (CDCl3) δ 1.06 (s, 9H), 5.6 (s, 1H),
7.20-7.80 (m, 10H), 9.00-9.20 (br s, 1H); 13C NMR (CDCl3) δ
23.5, 34.6, 88.6, 109.4, 122.9, 126.1, 127.2, 128.9, 129.0, 129.6,
134.7, 137.9, 169.0, 192.4. Anal. Calcd for C20H21NO3S:
67.58, H, 5.96, N, 3.94. Found: C 67.69, H 5.90, N 3.98.
C
J O9822481