Regio- and stereoselective synthesis of key 1-methyl carbapenem intermediates via hydroformylation using a zwitterionic rhodium catalyst

Article abstract of DOI:10.1021/ja993080j

The asymmetric hydroformylation of a 4-vinyl β-lactam catalyzed by a rhodium catalyst with a chiral phosphine ligand was investigated. The catalytic system consisting of a zwitterionic rhodium catalyst, (NBD)Rh⁺(C₆H₅B

Full text of DOI:10.1021/ja993080j

J. Am. Chem. Soc. 1999, 121, 11697-11703
11697
Regio- and Stereoselective Synthesis of Key 1-Methyl Carbapenem
Intermediates via Hydroformylation Using a Zwitterionic Rhodium
Catalyst
H. S. Park, E. Alberico, and H. Alper*
Contribution from the Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
ReceiVed August 24, 1999
Abstract: The asymmetric hydroformylation of a 4-vinyl â-lactam catalyzed by a rhodium catalyst with a
chiral phosphine ligand was investigated. The catalytic system consisting of a zwitterionic rhodium catalyst,
(NBD)Rh+(C6H5B-Ph3) 4, and (S,S)-2,4 bis(diphenylphosphino)pentane, (S,S)-BDPP, gave branched aldehydes
in high regio- and stereoselectivity. The hydroformylated products are key intermediates in the synthesis of
1-methylcarbapenem antibiotics. Using (3S,4R)-3-[(R)-1-(tert-butyldimethyl-silyloxy)ethyl]-4-vinyl-2-azetidinone
(5a) as the reactant afforded aldehydes in a 97:3 branched-to-linear ratio and 91:9 to â- to R-branched isomers.
The regio (branched/linear)- and stereoselectivity (â/R) was >99:1 when (3S,4R)-1-N-BOC-3-[(R)-1-
methoxyethyl]-4-vinyl-2-azetidinone was used as the substrate (5q).
Introduction
In 1996, Nozaki and co-workers12 reported the synthesis of
the 1-methylcarbapenem intermediate 2 by hydroformylation
of the 4-vinyl â-lactam, (3S,4R)-3-[(R)-1-(tert-butyldimethyl-
silylolxy)ethyl]-4-vinyl-2-azetidinone 5a, using Rh(acac)(CO)2
and a chiral bidentate phosphorous ligand based on BINAPHOS.
While the diastereoselectiveity was good, the regioselectivity
of the reaction was low with the ratio of branched/linear
aldehydes being 76/24.
Previous studies by one of us have demonstrated that
zwitterionic rhodium complexes such as 4 are useful catalysts
for a variety of carbonylation reactions. Complex 4,13 either by
itself or in the presence of 1,4-bis(diphenylphosphino)butane,
can effect the highly regioselective hydroformylation of aryl
and 1,1-disubstituted alkenes,14 allyl acetates,15 vinyl ethers,16
vinyl silanes,17 vinyl sulfones18 and sulfoxides,19 as well as R,â-
unsaturated esters.20 These results prompted us to apply 4 to
the hydroformylation of 4-vinyl â-lactams 5 as shown in Scheme
1. Two branched (6â and 6R)-chain and one linear (7) aldehyde
are possible reaction products, with the desired aldehyde
precursor to 2 being 6â.
As unnatural antibiotics, 1-methylcarbapenems (1) are among
the most extensively investigated â-lactams in the last two
decades.1 1-Methylcarbapenem has a wide range of biological
properties including strong antibacterial activity, resistance to
â-lactamase, and metabolic stability.2 Of particular note is the
resistance to renal dehydropeptidase.3 Furthermore as 1 contains
4-chiral centers, many organic chemists have been interested
in the synthesis of 1, key intermediates,4 or related derivatives,5
since the first discovery of its activities and structure by Merck
researchers. The monocyclic â-lactam 2, one of the most
valuable intermediates of 1, is usually derived form 4-acetoxy-
2-azetidinone7 3 by alkylation,8 Reformatsky reaction,9 or by
asymmetric hydrogenation.10 Recently the diastereoselective
radical cyclization of an N-vinyl R-bromoamide was reported
as another strategy to generate 2 without involvement of the
acetoxy compound 3.11
(1) Kumagai, T.; Tamai, S.; Abe, T.; Matsunaga, H.; Hayash, K.; Kishi,
I.; Shiro, M.; Nagao, Y. J. Org. Chem. 1998, 63, 8145 and references therein.
(b) Yasuda, N.; Huffaman, M. A.; Ho, G. J.; Xavier, L. C.; Yang, C.;
Emerson, K. M.; Tsay, F. J. Org. Chem. 1998, 63, 5438. (c) Kume, M.;
Ooka, H.; Ishttobi, H. Tetrahedron 1997, 53, 1635.
(2) Oda, K.; Yyoshida, A. Tetrahedron Lett. 1997, 38, 5687. (b) Berks,
A. H. Tetrahedron 1996, 52, 331 and references therein.
(3) Shih, D. H.; Cama, L.; Christensen, B. G. Tetrahedron Lett. 1985,
26, 587.
Herein we report the hydroformylation of a variety of 4-vinyl
â-lactams (5) catalyzed by the zwitterionic rhodium complex 4
and chiral phosphine ligands. Steric and electronic effects of
substrates at several positions of the â-lactam were investigated.
This research has resulted in the determination of the substituent
(4) Seki, M.; Miyake, T.; Izukawa, T.; Ohmizu, H. Synthesis 1997, 47.
(b) Choi, W. B.; Lee, J.; Volante, R. P.; Reider, P. J.; Reamer, R. A. J.
Chem. Soc. Chem. Commun. 1998, 1817. (c) Murayama, T.; Yoshida, A.;
Kobayashi, T.; Miura, T. Tetrahedron Lett. 1994, 35, 2271.
(5) Hu, X. E.; Thomas, P. D. J. Org. Chem. 1998, 63, 1719. (b) Osamu,
S.; Horikawa, H. Tetrahedron Lett. 1996, 37, 7811.
(6) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles
1984, 21, 587.
(7) Nagao, Y.; Kumagai, T.; Matsunaga, H.; Oshimada, O.; Hayashi,
T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243.
(8) Shira, F.; Nakai, T. J. Org. Chem. 1987, 52, 5491.
(9) Kendo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki, T. J. Org.
Chem. 1997, 62, 2877.
(10) Kitamura, M.; Nagai, K.; Hsiao, Y.; Noyori, R. Tetrahedron Lett.
1990, 31, 549.
(11) Ishibash, H.; Kameoka, C.; Kodamo, K.; Kawanami, H.; Hadada,
M.; Ikeda, M. Tetrahedron 1997, 53, 9611.
(12) Nozaki, K.; Li, W.; Horiuch, T.; Takaya, H.; Saito, T.; Yoshida,
A.; Matsumura, K.; Kato, Y.; Imai, T.; Miura, T.; Kumobayashi, H. J. Org.
Chem. 1996, 61, 7658.
(13) Schrock, R. R.; Osborn, J. Inorg. Chem. 1970, 9, 2339.
(14) Amer, I.; Alper, H. J. Am. Chem. Soc. 1990, 112, 3674. (b) Zhou,
J. Q.; Alper, H. J. Chem. Soc. Chem. Commun. 1993, 233.
(15) Alper, H.; Zhou, J. Q. J. Org. Chem. 1992, 57, 3729.
(16) Zhou, J. Q.; Alper, H. J. Org. Chem. 1996, 57, 3328.
(17) Alper, H.; Zhou, J. Q. J. Chem. Soc., Chem. Commun. 1993, 316.
(18) Totland, K.; Alper, H. J. Org. Chem. 1993, 58, 3326.
(19) Crudden, C. M.; Alper, H. J. Org. Chem. 1994, 59, 3091.
(20) Lee, C. W.; Alper, H. J. Org. Chem. 1995, 60, 449. (b) Zhou, Z.;
James, B. R.; Alper, H. Organometallics 1996, 14, 4209.
10.1021/ja993080j CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/03/1999

11698 J. Am. Chem. Soc., Vol. 121, No. 50, 1999
Park et al.
Table 2. Hydroformylation of 5a Catalyzed by 4 and (S,S)-BDPPa
Scheme 1
cat./
T
time CO/H2 conv.b
entry solvent lig. (°C) (h)
(psi)
(%)
6/7c 6â/6Rc
1
2
3
4
5
6
7
8
9
PhH
PhH
PhH
PhH
PhH
THF
THF
THF
1/2
1/2
1/2
1/1
1/4
2/4
2/4
2/8
70
70
70
70
70
90
70
70
70
90
70
70
70
24
24
12
24
24
24
24
24
24
24
12
24
48
1200
700
1200
1200
1200
700
1200
1200
1200
1200
1200
1200
1200
100 97/3 91/9
100 97/3 90/10
87 92/8 89/11
100 87/13 80/20
80 94/6 90/10
100 66/34 44/56
100 75/25 36/64
100 77/23 40/60
40 60/40 77/23
100 83/17 35/65
100 76/24 32/68
50 80/20 95/5
70 93/7 92/8
CH2Cl2 2/4
10 DME
11 DME
12 DME
13 DME
2/2
2/4
2/8
2/8
a Reactions were carried out using 5 mol % of catalyst and 1/1 CO/
H2. b The % conversion was determined by GC and by 1H NMR
1
spectroscopy. c The ratio was determined by H NMR spectroscopy.
results of Nozaki and co-workers who used Rh(CO)(acac)2 as
the catalyst (entry 11 in Table 1).12 Two stereoisomers of 2,4
bis(diphenylphosphino)pentane (BDPP)s(S,S)-BDPP and (R,R)-
BDPPsafforded excellent regioselectivities of branched/linear
aldehydes (92/8 and 93/7) using 5 mol % of 4, 1200 psi of
CO/H2, at 60 °C for 24 h in benzene (Table 1, entries 12/13).
The stereoselectivity was opposite for (S,S)- and (R,R)-BDPP,
with the desired â- form as the major product in a 85/15 ratio
with (S,S)-BDPP, and the undesired R-form as the dominant
stereoisomer using (R,R)-BDPP (90/10). These chiral ligand
effects are different from those of (R)- and (S)-BINAP which
gave similar ratios of 6/7 and especially 6â/6R.
To increase the regio- and stereoselectivity of the hydro-
formylation of the vinyl â-lactam 5a, we examined the influence
of temperature, solvent, amount of catalyst, reaction time, and
pressure on the (S,S)-BDPP reaction system, and the results
are summarized in Table 2. Increasing the temperature from 60
to 70 °C for the reaction in benzene enhanced the regio and
stereoselectivity (97/3 6/7; 91/9 6â/6R) of the reaction (compare
Table 2, entry 1 and Table 1, entry 12). The reaction proceeds
essentially as well at 700 psi as it does at 1200 psi (Table 2,
entries 1 and 2), but reducing the reaction time (12 h) or the
chiral ligand/4 ratio to 1/1 is deleterious for the process (entries
3 and 4). Increasing the chiral ligand/4 ratio to 4/1 is not
beneficial in terms of conversion, regio- or stereoselectivity
(entry 5). Lower regio- and stereoselectivities or conversions
resulted using THF, CH2Cl2, or DME as the solvent (entries
6-13).
The nature and effective bulk of substituents at nitrogen, and
at the C-3 position of the â-lactam, play an important role in
the reaction. As noted previously,12 the bulky OTBS group of
5a protects one side of the olefin, and the Rh complex should
approach from the other side of the olefin. According to
computational modeling (CS Chem3D Pro), the rhodium
complex must approach from the side of the OTBS group in
order to give the â-isomer. This suggests that the high
stereoselectivity resulted from rotation of the olefin of 5a.
Consequently, the hydrogen of NH was replaced by other groups
to assess the influence of such substrates in the regio- and
stereoselectivity of the hydroformylation reaction. It was
reasoned that since the NH group is closer to the double bond
than the OTBS group, the steric effect of the substituent at
nitrogen may be significant for the process. The electron density
of the N of the lactam is also a factor on the hydroformylation
reaction. The conversion of NH to a variety of alkylated,
acylated, and silylated NR compounds was achieved by simple
methods as shown in Figure 1. The N-Me (5b) and N-Bn
Table 1. Hydroformylation of 5a Catalyzed by 4 in Benzenea
cat./
T
time
p
conv.b
entry
ligand
lig. (°C) (h) (psi) (%)
6/7c 6â/6Rc
1
2
3
4
5
6
7
8
9
PPh3
(S,S)-DIOP
(S,R)-BPPFA
(S,S)-Me-DUPHOS 1/2 70 24 1200
NORPHOS
(S,S)-BPPM
(S,S)-CHIRAPHOS 1/2 95 24
(S)-BINAP
(R)-BINAP
1/1 50 24 1400 100 58/42 53/47
1/1 50 45 1400
1/1 80 24 700
60 48/52 39/61
98 38/62 48/52
61 68/32 35/65d
46 77/33 55/45
95 76/24 41/59
96 81/19 41/59
1/2 70 24 1200
1/2 50 45 1400
700
1/2 50 48 1400 100 82/18 33/87
1/2 50 40 1400 100 90/10 36/64
10 JOCIPHOS 1/2 70 24 1200
11 (R,S)-BINAPHOS 1/4 50 24 1400
30 86/14 49/51
98 61/39 92/8
12 (S,S)-BDPP
13 (R,R)-BDPP
1/2 60 24 1200 100 92/8 85/15
1/2 60 24 1200 100 93/7 10/90
a Reactions were carried out using 5 mol % of 4 and 1:1 CO/H2.
1
b The % conversion was determined by GC or H NMR. c The ratio
was determined by 1H NMR spectroscopy. d The reaction was carried
out in THF solution.
groups needed to achieve hydroformylation with complete regio-
and stereoselectivity.
Result and Discussion
We first examined the effect of different types of chiral
phosphine ligands on the regio- and stereoselectivity of the
hydroformylation reaction of 5a catalyzed by 4. Various chiral
bidentate phosphorus ligands which were used for the hydro-
formylation of simple olefins,21 including (S,S)-DIOP, (S,S)-
BPPM, (R)- and (S)-BINAP, Joshiphos, (S,S)-Me-Duphos,
Norphos, (S,S)-BDPP, (R,R)-BDPP, and BINAPHOS were
applied to the reaction and the results are summarized in Table
1. When triphenylphosphine was used as a monodentate ligand,
the ratio of b/l and R/â was in the range of 1:1(Table 1, entry
1). Though (R)- or (S)-BINAP gave good regioselectivity, the
major branched aldehyde was 6a R (Table 1, entries 8/9). The
same observations were made (S,S)-CHIRAPHOS (Table 1,
entry 7) and Joshiphos (Table 1, entry 10). In addition, Joshiphos
gave low conversions due to low solubility.
High stereoselectivity (92/8) was obtained using BINAPHOS
but the regioselectivity was low (61/39), consistent with the
(21) Ungvary, F. Coord. Chem. ReV. 1997, 160, 129 and references
therein. (b) Amatore, C.; Jutand, A. Coord. Chem. ReV. 1997, 178-180,
129 and references therein.

Synthesis of Methylcarbapenem Intermediates
J. Am. Chem. Soc., Vol. 121, No. 50, 1999 11699
Scheme 2
stereoselectivity in the case of 5e. The N-silylated derivatives
5f and 5g gave low regio- and stereoselectivity.
Appreciative of the impact of the R group at nitrogen, we
next investigated replacing the OTBS function at 5a by OAc,
BOC, and OCH3 functionalities. The preparation of the N-methyl
and N-benzyl methoxy-â-lactams (5k and 5l) required two steps:
desilylation and alkylation as shown in Scheme 2. Transforma-
tion of the OTBS group to OH was effected with tetrabutyl-
ammonium fluoride in THF to give 5h and 5i. The t-BOC
derivative 5j was obtained from 5h by standard methods.
Alkylation of 5h and 5i using NaH and methyl iodide afforded
5k and 5l, respectively.
N-BOC derivatives were synthesized in several steps as
shown in Scheme 3. The TBS group of 5a was removed by
tetrabutylammonium fluoride to give 5m in good yield. The
N-BOC lactam 5n was generated by treatment of 1 equiv of
5m with di-(tert-butyl)dicarbonate, DMAP, and triethylamine,
while the N,O-DiBOC lactam 5o was obtained using 2 equiv
of di-(tert-butyl)dicarbonate. The acylated product (5p) was
easily obtained by acylation of 5n. Because simple methylation
of 5m with NaH and methyl iodide gave the N-methylated
product, we used 5n as a substrate to obtain the O-methyl
product. Unfortunately, the O-methyl product was minor with
epimerization as the principal pathway. Therefore, another
methylation method was used involving NaOH, dimethyl sulfate,
and tetrabutylammonium iodide24 in reaction with 5n, to form
the O-methylated product 5q in 75% yield. The results for the
hydroformylation of 5j, 5k, 5l, 5o, 5p, and 5q are summarized
in Table 4.
Lactam 5j has a structure similar to that of 5b, and gave low
regio- and stereoselectivity in the hydroformylation reaction.
The BOC group in 5j does not fully protect one side of the
olefin, and thus the selective approach of the rhodium complex
might be difficult. Poor regio- and stereoselectivity was observed
in the case of 5k and 5l which have electron-donating substit-
uents at the nitrogen atom. The lower stereoselectivity may be
due to the similar steric environment of both faces of the olefin.
The more bulky benzyl derivative 5l gave higher stereoselec-
tivity than the methyl derivative (5k). In comparison with 5k
and 5l, the electron deficient derivatives (5o and 5p) afforded
moderate regio- and appreciably higher stereoselectivities. The
large difference of stereoselectivity between 5o and 5k resulted
from the difference in steric effects. In the case of 5o, the bulky
BOC group protects both sides of olefin; therefore, it is difficult
to induce high regioselectivity though the stereoselectivity is
excellent. A significant result was obtained when we used 5q
as the starting material. We examined the hydroformylation of
5q with (S,S)-BDPP and (R)-BINAP as the chiral ligand. In
Figure 1.
Table 3. Hydroformylation of 5 Catalyzed by 4 in Benzenea
conv.b
(%)
substrates
ligands
6/7c
6â/6Rc
5b
5c
5c
5d
5d
5e
5e
5f
(S,S)-BDPP
(S,S)-BDPP
(R)-TolBINAP
(S,S)-BDPP
(R)-BINAP
(S,S)-BDPP
(R)-BINAP
(S,S)-BDPP
(S,S)-BDPP
(R)-BINAP
95
98
100
100
60
100
30
64
63/37
85/15
75/25
50/50
60/40
13/87
36/64
43/57
50/50
60/40
>99/1
67/33
85/15
80/20
84/16
>99/1
94/6
84/16
80/20
84/16
5g
5g
100
100
a Reactions were carried out by using 5 mol % of 4 under 1200 psi
of CO/H2 at 70 °C for 24 h (ligand/catalyst ) 2/1). b The ratios were
determined by GC or 1H NMR. c The ratio was determined by 1H NMR
spectroscopy.
(5c) lactams were synthesized in good yields by simple
alkylation reactions with NaH which proceeded without epimer-
ization. The N-acetyl derivative (5d) was generated by using
acetic anhydride and triethylamine, and the t-BOC lactam (5e)
was obtained in excellent yield by using a weak base,22 while
triphenylsilyllactam (5f) and tert-butyldimethylsilyllactam (5g)
were prepared with triethylamine in DMF.23 Lactams 5b-5g
were hydroformylated using 4 and a chiral bidentate ligand, and
results are presented in Table 3.
The regioselectivities for the hydroformylation of the N-
alkylated â-lactams 5b and 5c, by 4 and (S,S)-BDPP, were
inferior to 5a. Stereoselectivity occurred in the N-CH3 case
(Table 3, entry 1). Note that the methyl group increases the
basicity at nitrogen. This factor, together with the bulky OTBS
group protecting one side of the olefin, may be responsible for
the selective approach of 4 from the less hindered side.
Compared to 5b, 5c gave moderate stereoselectivity because
the larger benzyl group also protects the other side of olefin.
Substrates containing an electron deficient N atom, gave a
substantial proportion of the linear aldehyde with excellent
(22) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem., 1983, 48,
2424.
(23) Murayama, T.; Yoshida, A.; Kobayashi, T.; Miura, T. Tetrahedron
Lett. 1994, 35, 2271.
(24) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.

11700 J. Am. Chem. Soc., Vol. 121, No. 50, 1999
Park et al.
Scheme 3
Table 4. Hydroformylation of 5j-l, 5o-q Catalyzed by 4 in
prior to use. Methylene chloride was distilled using CaH2 as drying
agent. The rhodium zwitterionic catalyst (4) was prepared according
to the literature procedure.13 The 4-vinyl lactam 5a was obtained from
the Takasago International Corp. Spectral measurements were deter-
mined by use of the following instruments: Bomem MB-100 (FT-IR),
Varian XL 300 or 200 MHz (NMR), VG 7070E (MS).
Benzenea
substrates
ligands
conv.b (%)
6/7c
6â/6Rc
5j
5k
5l
5o
5o
5p
5q
5q
(S,S)-BDPP
(S,S)-BDPP
(S,S)-BDPP
(S,S)-BDPP
(R)-BINAP
(S,S)-BDPP
(S,S)-BDPPd
(R)-BINAP
100
95
98
98
82
100
70
30
55/45
57/43
47/53
76/24
60/40
82/18
>99/1
60/40
60/40
50/50
76/24
>99/1
72/28
92/8
Preparation of 5b. To a solution of NaH (55 mg, 2.2 mmol) in 10
mL of THF was added 5a (51 mg, 2 mmol) in THF (3 mL) at 0 °C.
The reaction mixture was stirred for 30 min until no further gas
evolution occurred, followed by slow addition of MeI (283.8 mg, 2.2
mmol) in THF (3 mL) at -78 °C. The reaction mixture was quenched
after 6 h by saturated NH4Cl solution and was extracted with ether (40
mL) and methylene chloride (20 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuum. Purification of the
residue by flash chromatography on silica gel, with hexanes/ether
>99/1
>99/1
a Reactions were carried out by using 5 mol % of 4 under 1200 psi
of CO/H2 at 70 °C for 24 h (Cat/L ) 1/2, CO/H2 ) 1/1). b The ratios
1
were determined by GC and H NMR. c The ratios were determined
1
by H NMR spectroscopy. d Note that use of Rh(CO)2acac instead of
1
4 results in olefin hydrogenation as the major pathway, and the ratio
of the byproducts 6/7 was 1/1.
(1:9) as the eluant, gave 511 mg (95%)of 5b as a liquid. H NMR: δ
0.032 (s, 6H), 0.82 (s, 9H), 1.13-1.16(d, 3H, J ) 6 Hz), 2.69(s, 3H),
2.78-2.81 (m, 1H), 3.93-3.97(dd, 1H, J ) 1.4, 7.0 Hz), 4.11-4.20-
(m, 1H), 5.15-5.35(m, 2H), 5.70-5.87(m, 1H); 13C NMR: δ 17.87,
22.45, 25.69, 52.01, 58.07, 67.11, 67.16, 118.59, 136.30, 167.97; IR
(CH2Cl2): 1740 (CdO) cm-1; HRMS calcd for C14H27NO2Si 269.1811,
found 254.1592 (M+ - 15).
the case of (R)-BINAP, we obtained moderate regioselectivity
and complete stereoselectivity. We were gratified to observe
that the use of (S,S)-BDPP afforded only one regio- and
stereoisomer in the hydroformylation of 5q. It is conceivable
that the large difference in size of the substituent at O and N
accounts for the high stereoselectivity. In the event, the bulky
N-substituent, being closer to the olefin than the OCH3 group,
sterically impacts the hydroformylation process. That is, the
bulky N-BOC protects one side of the olefin, and it is only
possible to approach the rhodium catalyst from the less hindered
OMe side.
Preparation of 5c. To a solution of NaH (55 mg, 2.2 mmol) in
THF (10 mL) was added 5a (510 mg, 2 mmol) in THF (3 mL) at 0 °C.
The reaction mixture was stirred for 30 min, and then benzyl bromide
(342 mg, 2.2 mmol) in THF (3 mL) was added at -78 °C. The reaction
mixture was stirred and, after 6 h, was treated with saturated NH4Cl
and then extracted with ether (40 mL) followed by methylene chloride
(20 mL) The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuum. Purification of the residue, effected
by flash chromatography on silica gel, with hexanes/ether (1:9) as the
Conclusions
1
eluant, gave 655 (96%)mg of 5c as a liquid. H NMR: δ -0.01 (s,
3H), 0.03 (s, 3H), 0.80 (s, 9H), 1.13-1.16(d, 3H, J ) 6.2 Hz), 2.84-
2.87(dd, 1H, J ) 2.2, 4.2 Hz), 3.9-4.1(m, 2H), 4.08-4.30(m, 1H),
4.47-4.59(d, 1H, J ) 16 Hz), 5.10-5.30(m, 2H), 5.61-5.82(m, 1H),
7.10-7.41(m, 5H); 13C NMR: δ 17.89, 22.39, 25.70, 44.43, 55.83,
64.64, 65.29, 118.93, 127.40, 128.41, 135.87, 136.26, 167.46; IR (CH2-
Cl2): 1757 (CdO) cm-1; HRMS calcd for C19H31NO2Si 345. 2124,
found 330.1925 (M+ - 15).
In conclusion, the zwitterionic rhodium complex 4 and (S,S)-
BDPP catalyzed the hydroformylation of 5a to give the
â-aldehyde in excellent regio- and diastereoselectivity. This
procedure provides a more efficient method to synthesize one
of the key intermediates of 1-methylcarbapenem than using the
[Rh(I)(acac)(CO)2]-chiral phosphite ligand.12 While the hydro-
formylation of a variety of â-lactams indicates that the stereo-
selectivity is principally affected by the chiral ligand and steric
hindrance, the regioselectivity depends on the nature of the chiral
ligand, as well as steric and electronic effects of the substituents.
The results for the hydroformylation of 5q are impressive
indeed. These excellent results for the synthesis of 1-methyl-
carbapenem intermediates, afforded a better understanding of
the nature of the hydroformylation of key 4-vinyl-â-lactams.
Preparation of 5d. To a solution of 5a (255 mg, 1 mmol) in
methylene chloride (10 mL) was added triethylamine (280 µL, 2.2
mmol). After 10 min, acetic anhydride (125 mg, 1.1 mmol) in methylene
chloride (2 mL) was added slowly at 0 °C. The reaction mixture was
stirred for 4 h and then quenched with saturated NH4Cl solution and
extracted with ethyl acetate (40 mL) and then with methylene chloride
(20 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo. Purification of the residue by flash chromatog-
raphy on silica gel, with hexanes/ether (1:10) as the eluant, gave 279
1
mg (94%) of 5d as a liquid. H NMR: δ 0.015(s, 3H), 0.040(s, 3H),
Experimental Section
0.79(s, 9H), 1.15-1.22(d, 3H, j)6), 2.31(s, 3H), 2.89-2.91(dd, 1H, J
) 3.2, 3.15 Hz), 4.19-4.22(m, 1H), 4.60-4.61(dd, 1H, J ) 3.2, 6.8
Hz), 5.22-5.45(m, 2H), 5.84-6.01(m, 1H); 13C NMR: δ 17.75, 21.95,
23.92, 53.59, 64.53, 64.80, 118.05, 134.84, 166.31, 167.63; IR (CH2-
General. Unless otherwise noted materials were obtained from
commercial suppliers and were used without further purification. THF,
DME, and benzene were distilled from sodium benzophenone ketyl

Synthesis of Methylcarbapenem Intermediates
J. Am. Chem. Soc., Vol. 121, No. 50, 1999 11701
Cl2): 1710 (CdO, aldehyde), 1790 (CdO, ester) cm-1; HRMS calcd
for C14H27NO3Si 297.1760, found 282.1483 (M+-15)
eluant, gave 230 mg (92%) of 5i as a liquid. 1H NMR: δ 0.03-0.04-
(d, 6H, J ) 1.4 Hz), 0.09(s, 9H), 1.21-1.24(d, 3H, J ) 2.4 Hz), 2.80-
2.84(m, 1H), 4.0-4.4(m, 3H), 4.6-4.8(d, 1H), 5.2-5.4(m, 2H), 5.8-
5.9(m, 1H); 13C NMR: δ 21.18, 44.61, 55.72, 64.10, 64.55, 119.33,
127.54, 128. 24, 128.62, 135.71, 136.78, 167.73; IR (CH2Cl2): 1731
(CdO), 3415 (OH) cm-1; HRMS calcd for C14H17NO2 231.1259, found
231.1278.
Preparation of 5e. To the mixture of di-(tert-butyl)dicarbonate (436
mg, 1.1 mmol), 5a (255 mg, 1 mmol), and DMAP (123.4 mg, 1.1 mmol)
in methylene chloride (10 mL) was added triethylamine (140 µL, 1.1
mmol). The reaction mixture was stirred for 6 h at room temperature
and then quenched by saturated NH4Cl and extracted with methylene
chloride (40 mL) followed by extraction with ethyl acetate (20 mL).
The combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Purification of the residue by flash chromatog-
raphy on silica gel, with hexanes/ether (1:10) as the eluant, gave 324
Preparation of 5j. To a mixture of di-(tert-butyl)dicarbonate (436
mg, 1 mmol), 5h (142 mg, 0.9 mmol) , and DMAP (123 mg, 1 mmol)
in methylene chloride (10 mL) was added triethylamine (140 µL, 1.1
mmol). The reaction mixture was stirred for 6 h at room temperature.
Saturated NH4Cl was added, and the product was extracted with
methylene chloride (40 mL) and then with ethyl acetate (20 mL). The
combined organic layers were dried (MgSO4) and concentrated in vacuo.
Purification of the residue by flash chromatography on silica gel, with
ethyl acetate/hexanes (1:3) as the eluant, afforded 208 mg (86%) of 5j
1
mg (91%) of 5e as a liquid. H NMR: δ 0.039(s, 3H), 0.049(s, 3H),
0.83(s, 9H), 1.15-1.19(d, 3H, J ) 6), 1.46(s, 9H), 2.81-2.87 (dd, 1H,
J ) 3.2, 3.2 Hz), 4.21-4.32(m, 1H), 4.47-4.52(dd, 1H, J ) 3.2, 7.4
Hz), 5.21- 5.40 (m, 2Η), 5.83-6.00(m, 1H); 13C NMR: δ 17.81, 22.05,
25.66, 27.99, 54.59, 63.61, 64.77, 82.90, 117.09, 135.42, 147.82, 165.64;
IR (CH2Cl2): 1725 (CdO, lactam), 1812 (CdO, carbamate) cm-1
;
as a liquid. H NMR: 1.35-1.38(d, 3H, J ) 1.2 Hz), 1.45(s, 9H),
1
HRMS calcd for C17H33NO4Si 355.2179, found 298.1083 (M+ - 57).
Preparation of 5f. To the mixture of triphenylchlorosilane (323 mg,
1.1 mmol) and 5a (255 mg, 1 mmol) in DMF (10 mL) was added
triethylamine (280 µL, 2.2 mmol). The reaction mixture was refluxed
for 12 h. The reaction mixture was treated with saturated NH4Cl and
extracted with methylene chloride (40 mL) and ethyl acetate (20 mL).
The combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the residue, attained by flash chromatography
on silica gel, with hexanes/ether (1:15) as the eluant, gave 410 mg
(80%) of 5f as a white solid 1H NMR: δ 0.025(s, 3H), 0.089 (s, 3H),
0.8(s, 9H), 1.19-1.22(d, 3H), 3.03-3.07(dd, 1H, J ) 3.0, 4.8 Hz),
4.12-4.18(dd, 1H, J ) 0.8, 8.6 Hz), 4.23-4.35(p, 1H, J ) 11 Hz),
4.62-4.80(m, 2H), 5.62-5.78(m, 1H), 7.3-7.5(m, 10H), 7.6-7.8(m,
5H); 13C NMR: δ 17.85, 23.28, 25.70, 52.14, 54.69, 65.41, 116.37,
117.30, 127.78, 129.90, 130.22, 131.69, 134. 87, 135.42, 135.90, 137.44,
137.87, 173.01; IR (CH2Cl2): 1749 (CdO) cm-1; HRMS calcd for
C30H39NO2Si2 543.2625, found: 456.1810 (M+ - 57).
2.73(s, 3H), 2.95-2.99(m, 1H), 3.96-4.01(dd, 1H, J ) 2.0, 8.2 Hz),
4.97-5.11(p, 1H, J ) 12.4 Hz), 5.2-5.4(m, 2H), 6.7-6.9(m, 1H); 13
C
NMR: δ 18.64, 27.72, 59.08, 63.37, 68.48, 70.24, 82.29, 119.71,
135.16, 152.82, 167.06; IR (CH2Cl2): 1750 (CdO, lactam), 1815
(CdO, carbamate) cm-1; HRMS calcd for C13H21NO4 269.1811, found
269.1519.
Preparation of 5k. To a solution of NaH (28 mg, 1.1 mmol) in
THF (10 mL) was added 5h (158 mg, 1.0 mmol) in THF (2 mL) at 0
°C. The reaction mixture was stirred for 30 min, and MeI (141.9 mg,
1.1 mmol) in THF (2 mL) was then added slowly to the reaction mixture
at -78 °C. The reaction mixture was quenched after 6 h using saturated
NH4Cl solution, and extracted with ether (40 mL) and then with
methylene chloride (20 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel, with ethyl acetate/hexanes (1:4) as the
eluant, gave 150.4 mg (89%) of 5k as a liquid. 1H NMR: δ 1.1-1.3-
(d, 3H, J ) 6.2), 2.72(s, 3H), 2.86-2.87(m, 1H), 3.31(s, 3H), 3.57-
3.69(p, 1H, J ) 11.6 Hz), 3.86-3.90(dd, 1H, J ) 2.2, 8.2 Hz), 5.17-
5.34(m, 2H), 5.69-5.83(m, 1H); 13C NMR: δ 17.43, 56.46, 57.94,
63.33, 73.72, 77.57, 119.02, 135.82, 167.64; IR (CH2Cl2): 1731
(CdO) cm-1; HRMS calcd for C9H15NO2 169.1103, found 169.1098.
Preparation of 5l. To a solution of NaH (28 mg, 1.1 mmol) in THF
(10 mL) was added 5i (229 mg, 0.99 mmol) in THF (2 mL) at 0 °C.
The reaction mixture was stirred for 30 min, and MeI (141.9 mg, 1.1
mmol) in THF (2 mL) was then added slowly to the reaction mixture
at -78 °C. The reaction mixture was quenched after 6 h by aqueous
NH4Cl and extracted with ether (40 mL) and then with methylene
chloride (20 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated in vacuo. Purification of the residue
effected by flash chromatography on silica gel, with ethyl acetate/
hexanes (1:4) as the eluant, gave 214.02 mg (87%) of 5l as a liquid
Preparation of 5 g. To a mixture of tert-butyl(dimethyl)chlorosilane
(165 mg, 1.1 mmol) and 5a (255 mg, 1 mmol) in DMF was added
triethylamine (280 µL, 2.2 mmol). The reaction mixture was refluxed
for 12 h. The reaction mixture was quenched with saturated NH4Cl
and extracted with methylene chloride (40 mL) and then ethyl acetate
(20 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel, with hexanes/ether (1:15) as the eluant,
gave 306 mg (83%) of 5g as a liquid. 1H NMR: δ 0.036(s, 3H), 0.049-
(s, 3H), 0.149(s, 3H), 0.162(s, 3H), 0.85(s, 9H), 0.90(s, 9H) 1.12-
1.15(d, 3H, J ) 6.2 Hz), 2.85-2.88 (dd, 1H, J ) 3.0, 4.6 Hz), 4.01-
4.07(dd, 1H, J ) 2.8, 9.0 Hz), 4.11-4.22(p, 1H, J ) 10.4 Hz), 5.07-
5.30(m, 2H), 5.75-5.93(m, 1H); 13C NMR: δ 17.97, 18.11, 22.23,
25.83, 26.27, 54.48, 65.56, 65.70, 117.16, 139.92, 173.00; IR (CH2-
Cl2): 1724 (CdO) cm-1; HRMS calcd for C18H39NO2Si2 369.2519,
found: 354.2290 (M+ - 15).
1
(214.02 mg, 87% isolated yield). H NMR: δ 1.18-1.19(d, 3H, J )
2.4 Hz), 2.90-2.94(dd, 1H, J ) 1.8 Hz, J ) 6 Hz), 3.32(s, 3H), 3.65-
3.73(p, 1H, J ) 11.4 Hz), 3.9-4.0(m, 2H), 4.65-4.73(d, 1H, J ) 15.4
Hz), 5.14-5.29(m, 2H), 5.6-5.8(m, 1H), 7.2-7.4(m, 5H); 13C NMR:
δ 17, 44, 56.4, 56.8, 63.2, 73.9, 119.5, 127, 128.4, 128.8, 136.1, 136.2,
168; IR (CH2Cl2): 1755 (CdO) cm-1; HRMS calcd for C15H19NO2
245.1416, found 245.1416.
Preparation of 5h. To a solution of 5b (538.4 mg, 2 mmol) in THF
(10 mL) was added 1 N (Bu)4NF in THF (3 mL, 3 mmol). The reaction
mixture was stirred for 4 h and followed by the addition of a saturated
solution of NH4Cl. The crude product was extracted with ethyl acetate
(40 mL) and then methylene chloride (20 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purification of
the residue by flash chromatography on silica gel, with ethyl acetate/
Preparation of 5m. To a solution of 5a (1280 mg, 5 mmol) in THF
(15 mL) was added 1 N (Bu)4NF in THF (6 mL). The reaction mixture
was stirred for 8 h and then quenched by a solution of NH4Cl. The
crude product was extracted by ethyl acetate (90 mL) and then with
methylene chloride (30 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel, with ethyl acetate/hexanes (2:1 f 4:1)
as the eluant, afforded 634 mg (90%) of 5m as a white solid. 1H
NMR: δ 1.26-1.29(d, 3H, J ) 6.4 Hz), 1.78(s, 1H, OH), 2.94-2.95-
(dd, 1H, J ) 2.4 Hz), 4.1-4.3(m, 2H), 5.14-5.36(m, 2H), 5.85-6.10-
(m, 1H) 6.11 (br, 1H, OH); 13C NMR: δ 21.23, 52.26, 64.68, 65.35,
116.95, 137.44, 168.48; IR (CH2Cl2): 1731 (-NH), 1738 (CdO), 3288
(-OH) cm-1; HRMS calcd for C7H11NO2 141.0790, found: 123.9054
(M+ - 18).
1
hexanes (1:1) as the eluant, gave 282 mg (91%) of 5h as a liquid. H
NMR: δ 1.20-1.25(d, 3H, J ) 6.4 Hz), 2.5-2.6(br, 1H), 2.72(s, 3H),
2.8-2.9(dd, 1H, J ) 0.4, J ) 2 Hz), 3.90-4.00(dd, 1H, J ) 6, 8.2
Hz), 4.1-4.3(m, 2H), 5.2-5.4(m, 2H), 5.7-5.8(m, 1H); 13C NMR: δ
21.18, 52.18, 57.21, 64.26, 64.40, 119.12, 135.69, 168.17; IR (CH2-
Cl2): 1734 (CdO), 3397 (OH) cm-1 ; HRMS calcd for C8H13NO2
155.0946, found 155.0919.
Preparation of 5i. To a solution of 5c (375 mg, 1.08 mmol) in
THF (10 mL) was added 1N (Bu)4NF in THF (1.5 mL). The reaction
mixture was stirred for 4 h, saturated NH4Cl was added, and the crude
product was extracted with ethyl acetate (40 mL) and then methylene
chloride (20 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. Purification of the residue by flash
chromatography on silica gel, with ethyl acetate/hexanes (1:1) as the
Preparation of 5n. To a mixture of di-(tert-butyl)dicarbonate (1308
mg, 3 mmol), 5m (423 mg, 3 mmol), and DMAP (370 mg, 3 mmol)

11702 J. Am. Chem. Soc., Vol. 121, No. 50, 1999
Park et al.
in methylene chloride (10 mL) was added triethylamine (420 µL, 3.3
mmol), The reaction mixture was stirred for 6 h at room temperature,
quenched with saturated NH4Cl, and extracted with methylene chloride
(40 mL) and then with ethyl acetate (20 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purification of
the residue by flash chromatography on silica gel, with ethyl acetate/
hexanes (1:3 f 1:1) as the eluant, gave 607 mg (84%) of 5n as a
three times with carbon monoxide and subsequently pressurized with
carbon monoxide and hydrogen. The autoclave was heated in an oil
bath; at the end of the reaction time, it was cooled to room temperature,
the gas was vented, and the reaction mixture was filtered through
Flurosil to remove the catalyst. The conversion of the starting material
was determined by gas chromatography. After evaporation of the
solvent, the branched/linear ratio of the isomeric aldehydes and the
stereoselectivity were determined by 1H NMR by integration of the
resonances corresponding to the aldehyde protons.25
1
white solid. H NMR: δ 1.12-1.19(d, 3H, J ) 4 Hz), 1.39(s, 9H),
1.72(s, 1H, OH), 2.81-2.85(m, 1H), 4.08-4.20(m, 1H), 4.35-4.45-
(m, 1H), 5.1-5.3(m, 1H), 5.7-5.9(m, 1H); 13C NMR: δ 22.09, 28.67,
56.45, 64.12, 64.12, 64.93, 83.87, 119.02, 136.91, 148.43, 166.82; IR
(CH2Cl2): 1725 (CdO, lactam), 1808 (CdO, carbamate), 3503 (OH)
cm-1; HRMS calcd for C12H19NO4 241.1314, found 241.1418.
Preparation of 5o. To the mixture of di-(tert-butyl)dicarbonate (872
mg, 2 mmol), 5m (141 mg, 1 mmol), and DMAP (246.8 mg, 2 mmol)
in methylene chloride (10 mL) was added triethylamine (280 µL, 2.2
mmol). The reaction mixture was stirred for 6 h at room temperature,
quenched with saturated NH4Cl, and extracted with methylene chloride
(40 mL) and then with ethyl acetate (20 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purification of
the residue effected by flash chromatography on silica gel, with ethyl
acetate/hexanes (1:7) as the eluant, afforded 272 mg (80%) of 5n as a
6ar: 1H NMR: δ 0.01 (s, 3H). 0.04(s, 3H), 0.85(s, 6H), 1.18-1.23-
(m, 6H), 2.4-2.6(m, 1H), 2.75-2.85(dd, 1H), 3.61-3.62(d, 1H, J )
2 Hz), 4.10-4.20(m, 1H), 6.1-6.2(br, 1H), 9.67(s, 1H); 13C NMR: δ
10.74, 17.56, 22.33, 25.68, 51.02, 52.13, 63.60, 65.49, 167.86, 202.96;
IR (CH2Cl2): 1692 (CdO, aldehyde), 1746 (CdO, lactam) cm-1; HRMS
calcd for C14H27NO3Si 285.1760, found 228.1052 (M+ - 57).
1
6aâ: H NMR: δ 0.01 (s, 3H), 0.02 (s, 3H), 0.88(s, 6H), 1.14-
1.19(m, 6H), 2.53-2.72(m, 1H), 2.94-2.98(dd, 1H, J ) 2.6, J ) 5.2
Hz), 3.88-3.92(dd, 1H, J ) 2.4, 3.6 Hz), 4.10-4.20(m, 1H), 6.1(br,
1H), 9.727-9.731(d, 1H, J ) 1.2 Hz); 13C NMR: δ 9.14, 17.90, 22.64,
25.71, 49.25, 61.91, 65.64, 168.14, 202.27; IR (CH2Cl2): 1692 (CdO,
aldehyde), 1746 (CdO, lactam) cm-1; HRMS calcd for C14H27NO3Si
285.1760, found 228.2171 (M+ - 57).
1
1
white solid. H NMR: δ 1.35-1.38(d, 3H, J ) 7 Hz), 1.44(s, 9H),
6bâ: H NMR: δ 0.003(s, 3H), 0.018(s, 3H), 0.81(s, 9H), 1.12-
1.47(s, 9H), 2.98-3.04(dd, 1H, J ) 1.5, 7.0 Hz), 4.43-4.47 (dd, 1H,
J ) 1.6, 6.8 Hz), 5.03-5.15(p, 1H, J ) 11.8 Hz), 5.23-5.38(m, 2H),
5.78-5.95(m, 1H); 13C NMR: δ 18.55, 27.73, 27.97, 57.14, 61.16,
70.48, 82.67, 83.52, 118.94, 134.55, 147.58, 151.62, 163.61; IR (CH2-
Cl2): 1736 (CdO, lactam), 1818 (CdO, carbamate) cm-1; HRMS calcd
for C17H27NO6 341.1838, found 224.9302 (M+ - 117).
1.12(m, 6H), 2.8-1.9(m, 1H), 3.80-3.82(m, 1H), 4.01-4.10(m, 1H),
9.762-9.768(d, 1H, J ) 1.2 Hz); 13C NMR: δ 8.74, 17.76, 23.86,
25.63, 47.64, 60.70, 63.27, 65.41, 167.58, 202.25; IR cm-1 1698
(CdO, aldehyde), 1731 (CdO, lactam); HRMS calcd for C15H24NO3-
Si 299.1917, found 242.1208 (M+ - 57).
1
6cr: H NMR: δ 0.003(s, 3H), 0.018(s, 3H), 0.79 (s, 9H), 0.90-
Preparation of 5p. To a mixture of 5n (241 mg, 1 mmol) and
triethylamine (140 µL, 1.1 mmol) in methylene chloride (10 mL) was
added acetic anhydride (125 mg, 1.1 mmol) in methylene chloride (3
mL) at 0 °C. After stirring for 6 h at room temperature, the reaction
mixture was quenched with saturated NH4Cl and extracted with
methylene chloride (40 mL) and then ethyl acetate (20 mL). The
combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. Purification of the residue by flash chromatog-
raphy on silica gel, with ethyl acetate/hexanes (1:3) as eluant, gave
247 mg (87%) of 5p as liquid. 1H NMR: δ 1.30-1.33(d, 3H, J ) 6.6
Hz), 1.46(s, 9H), 2.00(s, 3H), 2.98-3.03(dd, 1H, J ) 3.2, 7.0 Hz),
4.33-4.37(dd, 1H, J ) 1.2, 7.4 Hz), 5.21-5.40(m, 3H), 5.78-5.95-
(m, 1H); 13C NMR: δ 13.9, 17.9, 20.5, 27.5, 56.4, 60.6, 67.0, 83.0,
118.3, 134.2, 147.1, 163.1, 169.3; IR (CH2Cl2): 1726 (CdO, lactam),
1809 (CdO, carbamate) cm-1; HRMS calcd for C14H21NO5 283.1420,
found 283.1433.
1.01(d, 3H, J ) 1.0 Hz), 1.19-1.28(d, 3H, J ) 2 Hz), 2.40-2.50(m,
1H), 2.80-2.90(m, 1H), 3.80-3.90(m, 1H), 4.00-4.48(m, 2H), 7.19-
7.50(m, 5H), 9.415(s, 1H); 13C NMR: δ 10.41, 17.90, 22.87, 25.77,
45.16, 49.02, 54.11, 60.74, 65.56, 65.56, 126.78, 127.43, 128.34, 128.56,
132.72, 167.52, 202.19; IR (CH2Cl2): 1675 (CdO, aldehyde), 1724
(CdO, lactam) cm-1 ; HRMS calcd for C20H32NO3Si 375. 2230, found
360.1976 (M+ - 15).
6câ: 1H NMR: δ0.01 (s, 3H), 0.02(s, 3H), 0.80 (s, 9H), 0.90-1.01-
(d, 3H, J ) 1.0 Hz), 1.22-1.30(d, 3H, J ) 2 Hz), 2.51-2.58(m, 1H),
2.92-3.02(m, 1H), 3.81-3.98(m, 1H), 4.05-4.52(m, 2H), 7.20-7.33-
(m, 5H), 9.49-9.50(d, 1H, J ) 1.0); 13C NMR: δ 8.88, 17.90, 22.87,
25.77, 44.55, 45.53, 54.27, 60.47, 65.86, 126.81, 127.23, 128.54, 128.56,
132.72, 167.52, 202.46; IR (CH2Cl2): 1675 (CdO, aldehyde), 1724
(CdO, lactam) cm-1 ; HRMS calcd for C20H32NO3Si 375.2230, found
360.1976 (M+ - 15).
7c: 1H NMR: δ 0.01 (s, 3H), 0.02(s, 3H), 0.79-0.83(d, 9H, J )
6.4 Hz), 1.13-1.16(d, 3H, J ) 1.2 Hz), 1.58-1.78(m, 1H), 1.83-
2.01(m, 1H), 2.32-2.40(t, 2H, J ) 7.3 Hz), 2.69-2.70(d, 1H, J ) 1.2
Hz), 3.47-3.55(m, 1H), 4.01-4.20(m, 1H), 4.42-4.57(2H), 7.20-
7.33(m, 5H), 9.61-9.65(t, 1H, J ) 2.0 Hz); 13C NMR: δ 17.90, 22.87,
25.77, 39. 74, 47.37, 53.96, 53.96, 63.03, 65.74, 126.81, 127.23, 128.54,
129.36, 132.72, 167.52, 200.34; IR (CH2Cl2): 1675 (CdO, aldehyde),
1724 (CdO, lactam) cm-1 ; HRMS calcd for C20H32NO3Si 375. 2230,
found 360.1976 (M+ - 15).
Preparation of 5q. To the reaction mixture of 5n (303.5 mg, 1.19
mmol) and tetrabutylammonium iodide (13.3 mg) in petroleum ether
(15 mL) was added 50% aqueous NaOH (160 mg, 4 mmol). The
reaction mixture was stirred at reflux for 30 min. After cooling to below
45 °C, dimethyl sulfate (229.3 mg, 1.75 mmol) in 5 mL of H2O was
added, the reaction mixture was stirred for 3 h, and then 3 mL of NH4-
OH solution was added. After more stirring for 30 min, the reaction
mixture was extracted with ether (40 mL) and washed with H2O (10
mL). The combined organic layers were dried (MgSO4) and concen-
trated in vacuo. Purification of the residue by flash chromatography
on silica gel, with ethyl acetate/hexanes (1:4) as the eluant, gave 227
6dr: 1H NMR: δ 0.01 (s, 3H),0.03(s, 3H), 0.90(s, 9H), 1.10-1.31-
(m, 6H), 2.87-2.95(m, 2H), 4.00-4.17(m, 2H), 9.69-9.70(d, 1H, J
) 2.4 Hz); 13C NMR: δ 10.52, 17.90, 22.87, 44.53, 49.42, 54.26,
167.53, 177.80, 201.93; IR (CH2Cl2): 1654 (CdO, aldehyde), 1702
(CdO, lactam), 1790 (CdO, ester) cm-1; HRMS calcd for C15H28-
NO4Si 327.1866, found 270.1145 (M+ - 57)
1
mg (75%) of 5q as a white solid. H NMR: δ 1.15-1.18(d, 3H, J )
6.0 Hz), 1.43(s, 9H), 2.5-2.6(dd, 1H, J ) 3.0, 9.0 Hz), 3.62(s, 3H),
3.8-3.9(m, 1H), 4.6-4.7(m, 1H), 5.1-5.4(m, 2H), 5.6-5.8(m, 1H);
13C NMR: δ 20.75, 27.10, 28.26, 50.28, 51.44, 57.32, 80.54, 115.48,
135.88, 157.16, 172.93; IR (CH2Cl2): 1726 (CdO, lactam), 1830
(CdO, carbamate) cm-1; HRMS calcd for C13H21NO4 255.1471, found
255.1512.
6dâ: 1H NMR: δ 0.01 (s, 3H),0.03(s, 3H), 0.90(s, 9H), 1.10-1.31-
(m, 6H), 2.88-3.00(m, 2H), 4.03-4.22(m, 2H), 9.706 (s, 1H); 13C
NMR: δ 8.93, 17.92, 22.22, 23.89, 25.52, 45.78, 52.51, 59.89, 64.92,
165.55, 168.29, 201.53; IR (CH2Cl2): 1654 (CdO, aldehyde), 1702
(CdO, lactam), 1790 (CdO, ester) cm-1; HRMS calcd for C15H28-
NO4Si 327.1866, found 270.1144 (M+ - 57).
General Procedure for the Hydroformylation of 5. The hydro-
formylation reaction was carried out in a 45 mL Parr autoclave fitted
with a glass liner and a stirring bar. The 4-vinyl â-lactam (0.25 or 0.5
mmol), catalyst (5 mmol % to the substrate), and phosphorus ligand
(10 mmol % to the substrate) were placed in the glass liner which was
then protected with a septum. Carbon monoxide was bubbled through
a needle for several minutes prior to the addition of solvent. The glass
liner was transferred into the autoclave, and the system was purged
7d: 1H NMR: δ 0.01 (s, 3H),0.03(s, 3H), 0.90(s, 9H), 1.10-1.31-
(m, 6H), 1.78-2.00 (m, 1H), 2.10-2.30 (m, 1H), 2.59-2.72 (t, 2H),
2.85-2.92 (m, 1H), 4.03-4.25(m, 2H), 9.75-9.76(t, 1H, J ) 1.0 Hz);
1
(25) The ratios of â to R were determined by H NMR, by integration
of the resonances corresponding to the aldehyde protons.12

Synthesis of Methylcarbapenem Intermediates
J. Am. Chem. Soc., Vol. 121, No. 50, 1999 11703
13C NMR: δ 17.92, 22.22, 23.51, 25.18, 40.52, 52.32, 62.72, 64.88,
167.44, 168. 29, 200.55; IR (CH2Cl2): 1654 (CdO, aldehyde), 1702
(CdO, lactam), 1790 (CdO, ester): cm-1; HRMS calcd for C15H28-
NO4Si 327.1866, found 270.1145 (M+ - 57).
6eâ:1H NMR: δ 0.01 (s, 3H),0.03(s, 3H), 0.80(s, 9H), 1.10-1.20-
(d, 3H, J ) 3 Hz), 1. 47 (s, 9H), 2.70-2.87(m, 1H), 3.90-4.48(m,
1H), 4.29-4.38(m, 1H), 9.689-9.702(d, 1H, J ) 2.6 Hz); 13C NMR:
δ 8.26, 16.72, 22.26, 25.60, 27.84, 46.81, 52.97, 60.12, 64.90, 83.62,
147.92, 164.80, 201.64; IR (CH2Cl2): 1694 (CdO, aldehyde), 1724
(CdO, lactone), 1809 (CdO, carbamate) cm-1;; HRMS: calcd
371.2492, found 328.1700 (M+ - 57).
7e 1H NMR: δ 0.01 (s, 3H),0.03(s, 3H), 0.80(s, 9H), 1.10-1.30(d,
3H, J ) 6 Hz), 1.49(s, 9H), 1.77-2.01(m, 1H), 2.20-2.30(m, 1H),
2.50-2.60(t, 2H, J ) 5.8 Hz), 2.51-2.60(m, 1H), 4.00-4.10(m, 1H),
4.20-4.30(m, 1H), 9.763-9.772(t, 1H, J ) 0.9 Hz); 13C NMR: δ
16.72, 22.26, 25.02, 25.60, 27.93, 40.09, 52.63, 62.44, 64.76, 82.90,
148.10, 165.44, 200.38; IR (CH2Cl2): 1694 (CdO, aldehyde), 1724
(CdO, lactam), 1809 (CdO, carbamate) cm-1; HRMS calcd for C17H33-
NO4Si 543.2625, found 586. 2437 (M+ - 57).
aldehyde), 1738 (CdO, lactam) cm-1; HRMS calcd for C10H17NO3
199.1208, found 199.1232.
7k: 1H NMR: δ 1.20-1.24 (d, 3H, J ) 6 Hz), 1.63-1.69 (m, 1H),
2.06-1.13 (m, 1H), 2.50-2.58 (t, 2H, J ) 7.2), 2.75 (s, 3H), 2.87-
2.90 (m, 1H), 3.28 (s, 3H), 3.6-3.7 (m, 1H), 3.5-3.6 (m, 1H), 9.757
(s, 1H); 13C NMR δ 17.46, 23.86, 26.49, 39.55, 56.28, 61.89, 74.57,
73.64, 167.20, 200.59; IR (CH2Cl2): 1658 (CdO, aldehyde), 1738
(CdO, lactam) cm-1; HRMS calcd for C10H17NO3 199.1208, found
199.1232
6lr: 1H NMR: δ 1.02-1.05(d, 3H, J ) 7.2 Hz), 2.50-2.60(m, 1H),
3.77-3.85(m, 1H), 3.40-3.50(m, 1H), 3.70-3.80(dd, 1H), 4.01-4.19-
(d, 1H), 4.50-4.59(d, 1H), 7.22-7.52(m, 5H), 9.45-9.46(d, 1H, J )
1.8 Hz); 13C NMR: δ 10.34, 17.46, 45.34, 44.98, 48.82, 54.37, 59.01,
76.48, 127, 129, 167.62, 202.39; IR (CH2Cl2): 1702 (CdO, aldehyde),
1746 (CdO, lactam) cm-1; HRMS calcd for C16H20NO3 275.1521,
found 275.1524.
6lâ: 1H NMR: δ 1.02-1.05(d, 3H, J ) 7.2 Hz), 2.70-2.80(m, 1H),
2.90-3.00(m, 1H), 3.285(s, 3H), 3.40-3.50(m, 1H), 3.81-3.89 (dd,
1H, J ) 1.4 Hz), 4.01-4.20(d, 1H), 4.61-4.70(m, 1H), 7.22-7.52(m,
5H), 9.530-9.535(d, 1H, J ) 1.0 Hz); 13C NMR: δ 8.83, 17.46, 44.98,
45.34, 47.52, 54.30, 58.89, 74.01, 127.13, 167.62, 202.24; IR (CH2-
Cl2): 1702 (CdO, aldehyde), 1746 (CdO, lactam) cm-1; HRMS calcd
for C16H20NO3 275.1521, found 275.1524.
7l: 1H NMR: δ 1.233-1.26(d, 3H, J ) 2.8 Hz), 1.52-1.70(m,
1H), 1.90-2.10(m, 1H), 2.37-2.41(t, 2H, J ) 3.5 Hz), 2.71-2.72(dd,
1H, J ) 2.2 Hz), 3.272(s, 3H), 3.40-3.50(m, 1H), 3.50-3.70(m, 1H),
4.64-4.73(d, 1H), 7.21-7.35(m, 5H), 9.653-9.657(t, 1H, J ) 1.4 Hz);
13C NMR: δ 17.50, 24.21, 44.39, 39.62, 44.39, 54.67, 61.54, 74.35,
127, 129, 167.32, 200.58; IR (CH2Cl2): 1702 (CdO, aldehyde), 1746
(CdO, lactam) cm-1; HRMS calcd for C16H20NO3 275.1521, found
275.1524.
6or: 1H NMR: δ 1.10-1.20(d, 3H, J ) 6 Hz), 1.46(s, 9H), 1.47-
(s, 9H), 2.80-2.90(m, 1H), 3.11-3.19(m, 1H), 4.40-4.50(m, 1H),
5.00-5.10(m, 1H), 9.635 (s, 1H); 13C NMR: δ 9.88, 18.75, 27.87,
27.96, 50.54, 55.42, 59.95, 70.79, 82.80, 84.35, 147.80, 155.27, 163.25,
200.67; IR (CH2Cl2): 1690 (CdO, aldehyde), 1724 (CdO, lactam),
1825 (CdO, carbamate) cm-1; HRMS calcd for C18H28NO7 387.2257,
found 270.1147 (M+ - 101).
6oâ: 1H NMR: δ 1.10-1.20(d, 3H, J ) 6 Hz), 1.46(s, 9H), 1.47(s,
9H), 2.80-2.90(m, 1H), 3.11-3.19(m, 1H), 4.40-4.50(m, 1H), 4.90-
5.00(m, 1H), 9.690-9.695(d, 1H, J ) 2.4); 13C NMR: δ 7.91, 18.75,
27.87, 27.96, 48.67, 55.42, 59.95, 70.79, 82.80, 84.32, 147.80, 155.27,
163.25, 202.13; IR: 1690 (CdO, aldehyde), 1724 (CdO, lactam), 1825
(CdO, carbamate) cm-1; HRMS calcd for C18H28NO7 371.1944, found
270.1147 (M+ - 101).
7o: 1H NMR: δ 1.46-1.48(m, 18H), 1.8-1.9(m, 9H), 2.5-2.6(m,
1H), 2.5-2.6(t, 2H, J ) 3.8 Hz), 2.7-2.8(dd, 1H), 3.8-4.0(m, 1H),
4.8-5.0(m, 1H), 9.773(s, 1H); 13C NMR: δ 19.75, 24.73, 27.87, 27.67,
39.54, 57.63, 59.95, 70.91, 83.57, 82.66, 145.77, 152.45, 162.72, 200.04;
IR: 1690 (CdO, aldehyde), 1724 (CdO, lactam), 1825 (CdO,
carbamate) cm-1; HRMS calcd for C18H28NO7 371.1944, found
270.1147 (M+ - 101).
6pâ: 1H NMR: δ 1.21-1.32(m, 6H), 1.424(s, 9H), 2.32(s, 3H),
2.52-2.56(m, 1H), 2.98-3.01(m, 1H), 4.2-4.44(m, 2H), 4.5-4.6(m,
1H), 9.75-9.75(d, 1H, J ) 1.2 Hz); 13C NMR: δ 8.38, 18.36, 20.91,
27.80, 50.00, 55.35, 57.44, 67.83, 84.32, 145.71, 165.98, 169.81, 201.10;
IR (CH2Cl2): cm-1; HRMS calcd for C15H22NO6 313.1525, found
312.9783.
6fâ: 1H NMR: δ -0.01(s, 3H), 0.00 (s, 3H), 0,8(s, 9H), 1.19-1.28-
(d, 2H), 2.52-2.62(m, 1H), 3.01-3.6(m, 1H), 3.8-3.84(m, 1H), 4.10-
4.20(m, 1H), 7.25-7.72(m, 15H), 9.504-9.508(d, 1H, J ) 1.2 Hz);
13C NMR: δ 8.80, 17.92, 22.63, 25.78, 46.00, 53.80, 60.88, 64.31,
127.87, 130.04, 134.97, 168.10, 201.80; IR (CH2Cl2): cm-1 1693
(CdO, aldehyde), 1719, 1728(CdO, lactam), 1738; HRMS calcd for
C32H41NO3 543.2625, found 466.9739 (M+ - 57).
7f: 1H NMR: δ -0.01 (s, 3H), 0.00 (s, 3H), 0,8(s, 9H), 1.19-1.28-
(d, 2H), 2.52-2.62(m, 1H), 3.01-3.6(m, 1H), 3.8-3.84(m, 1H), 4.10-
4.20(q, 1H), 7.25-7.72(m, 15H), 9.504-9.508(t, 1H, J ) 1.0 Hz); 13
C
NMR: δ 17.92, 20.71, 22.63, 41.31, 46.00, 53.80, 60.88, 64.31, 127,
130, 134, 168.10, 199.97; IR (CH2Cl2): 1693 (CdO, aldehyde), 1719,
1728(CdO, lactam), 1738 cm-1; HRMS calcd for C32H41NO3 543.2625,
found 466.9739 (M+-57).
6gâ: 1H NMR: 0.01 (s, 6H), 0.03 (s, 3H), 0.034 (s, 3H), 0.045 (s,
3H 0.825(s, 9H), 0.925(s, 9H), 1.08-1.11(d, 3H), 2.70-2.81(m, 1H),
2.90-3.00(m, 1H), 3.76-3.80(m, 1H), 3.95-4.05(m, 1H), 9.385-
9.843(d, 1H, J ) 1.2 Hz); 13C NMR: δ 8.90, 17.90, 22.95, 26.20, 25.83,
49.20, 51.28, 54.23, 61.33, 173.01, 201.72; IR (CH2Cl2): 1675 (CdO,
aldehyde), 1748 (CdO, lactam) cm-1; HRMS calcd for C19H40NO3Si2
399.2625, found 384.2411 (M+ - 15).
7g: 1H NMR: 0-0.05(d, 6H), 0.123(s, 6H), 0.825(s, 9H), 0.925(s,
9H), 1.21-1.23(d, 3H), 1.5-1.7(m, 1H), 2.05-2.25(m, 1H), 2.61-
2.68(m, 1H), 3.40-3.50(m, 1H), 3.90-4.10(q, 1H), 9.75-9.77(t, 1H,
J ) 1.0); 13C NMR: δ 17.90, 22.95, 25.61, 26.20, 25.83, 40.19, 52.44,
64.50, 66.55, 172.88, 200.51; IR (CH2Cl2): 1675 (CdO, aldehyde),
1748 (CdO, lactam) cm-1; HRMS calcd for C19H40NO3Si2 399.2625,
found 384.2411 (M+ - 15).
6jâ: 1H NMR: 1.117-1.168 (dd, 3H, J ) 2.8, 7.4 Hz), 1.370-
1.407(dd, J ) 1.2, 6.4 Hz), 1.439 (s, 9H), 2.6-3.2 (m, 2H), 2.74-
2.8(d, 1H, J ) 0.8), 3.9-4.0(m, 1H), 4.8-5.0(m, 1H), 9.83-9.85(d,
1H, J ) 1.4); 13C NMR: δ 8.42, 18.66, 27.72, 47.40, 57.68, 58.18,
62.46, 71.31, 82.40, 152.83, 165.55, 201.65; IR (CH2Cl2): 1675
(CdO, aldehyde), 1740 (CdO, lactam) cm-1 HRMS calcd for C14H22-
NO5 285.1576, found 285.1576.
7j: 1H NMR : δ 1.117-1.168 (dd, 3H, J ) 2.8, 7.4 Hz), 1.36-
1.39(d, 3H, J ) 6.4), 1.439 (s, 9H), 1.51-1.68 (m, 1H), 2.70-3.00(m,
1H), 3.38-3.50(m, 1H), 4.80-5.00(m, 1H), 9.74-9.76(t, 1H, J ) 1.1
Hz);13C NMR: δ18.80, 26.72, 27.69, 40.08, 49.20, 56.72, 60.74, 82.32,
152.95, 166.31, 200.15; IR (CH2Cl2): 1675 (CdO, aldehyde), 1740
(CdO, lactam) cm-1 HRMS calcd for C14H22NO5 285.1576, found
285.1576.
6qâ: 1H NMR: δ 1.12-1.20(m, 6H,), 1.45(s, 9H), 2.5-2.6(m, 1H),
3.5-3.6 (m, 1H), 4.0-4.2(m, 1H), 4.5-4.6(m, 1H), 9.625-9.630(d,
1H, J ) 1.0); 13C NMR: δ 9.32, 20.27, 28.16, 51.91, 54. 04, 65. 33,
70.43, 80.13, 148.51, 165.91, 201.10; IR (CH2Cl2): 1694 (CdO,
aldehyde), 1737 (CdO, lactam), 1830 (CdO, carbamate) cm-1; HRMS
calcd for C14H23NO5 285.1576, found 285.1570.
6kr: 1H NMR: δ 1.12-1.42(m, 6H), 2.58-2.62(m, 1H), 2.73(s,
3H), 2.87-2.94(m, 1H), 3.31(s, 3H), 3.60-3.70(m, 1H), 9.725 (s, 1H);
13C NMR δ 9.96, 17.46, 28.05, 47.69, 56.15, 59.11, 74.12, 74.31,
167.29, 201.06; IR (CH2Cl2): 1658 (CdO, aldehyde), 1738 (CdO,
lactam). cm-1; HRMS calcd for C10H17NO3 199.1208, found 199.1232.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada and to Takasago
International Corp, for support of this research.
1
6kâ: H NMR: δ 1.12-1.42(m, 6H), 2.58-2.62(m, 1H), 2.73(s,
3H), 2.87-2.89(m, 1H), 3.31(s, 3H), 3.60-3.70(m, 1H), 9.74-9.75-
(d, 1H, J ) 1.0 Hz); 13C NMR δ 8.49, 17.46, 27.68, 48.83, 56.28,
59.41, 74.39, 74.48, 167.29, 202.23; IR (CH2Cl2): 1658 (CdO,
JA993080J