A new stereocontrolled approach to 1β-methylcarbapenem: Asymmetric hydroformylation of 4-vinyl β-lactams catalyzed by Rh(I) complexes of chiral phosphine - phosphites and phosphine - phosphinites

Full text of DOI:10.1021/jo961689m

7658
J . Org. Chem. 1996, 61, 7658-7659
A New Ster eocon tr olled Ap p r oa ch to
1â-Meth ylca r ba p en em : Asym m etr ic
Hyd r ofor m yla tion of 4-Vin yl â-La cta m s
Ca ta lyzed by Rh (I) Com p lexes of Ch ir a l
P h osp h in e-P h osp h ites a n d
P h osp h in e-P h osp h in ites
ligands was carried out under the conditions shown in
eq 1. The representative results are summarized in
Kyoko Nozaki,* Wen-ge Li, Toshihide Horiuchi, and
Hidemasa Takaya*,†
Department of Material Chemistry, Graduate School of
Engineering, Kyoto University, Yoshida,
Sakyo-ku, Kyoto 606-01, J apan
Takao Saito,* Akifumi Yoshida,
Kazuhiko Matsumura, Yasushi Kato, Takashi Imai,
Takashi Miura, and Hidenori Kumobayashi
Takasago International Corporation, Central Research
Laboratory, Nishi-Yawata, Hiratsuka 254, J apan
Table 1. The ligands used for this reaction are drawn in
Chart 1 along with their abbreviations. As shown in run
1, the desired product 4â, its epimer 4R, and their linear
isomer 5 were obtained using Rh(I)-PPh3 as a catalyst.
The iso/ normal (4/5) and the â/R (4â/4R) selectivities
were 51/49 and 45/55, respectively. The use of a con-
ventional bidentate bisphosphine ligand, (R)-BINAP,
gave 4â, 4R, and 5 in the lower total yield (run 2). The
4â/4R selectivity was slightly improved. When a phos-
phine-phosphite (R,S)-BINAPHOS was employed as a
ligand, a higher catalytic activity was observed. Satis-
factory â/R selectivity, 93/7, was obtained, and the i/ n
ratio was comparable to (R)-BINAP (run 3). With
another phosphine-phosphite ligand, (R)-BIPPHOS, the
i/ n ratio was improved but the â/R selectivity was rather
low (run 4). The use of a phosphine-phosphinite, (R)-
BIPNITE, resulted in a slightly higher i/ n than that of
(R,S)-BINAPHOS, while the high level of â/R was main-
tained (run 5). The low catalytic activity of (R)-BIPNITE
was overcome by changing the phenyl groups in the
phosphine site to 2-naphthyls (run 6). As shown in run
7, the catalytic activity was remarkably advanced by the
introduction of an electron-withdrawing fluoro group into
the phosphinite moiety of 2-Nap-BIPNITE. In this case,
the electronic properties did not affect on the selectivities.
Hence, the best result, a 95% total yield, i/ n ) 74/26,
and â/R ) 96/4, has been achieved using 2-Nap-BIPNITE-
p-F (run 7). The last ligand shows high crystallinity,
which is convenient for industrial treatment.
Received September 4, 1996
Since the discovery of 1â-methylcarbapenem antibiot-
ics,1 which possess an excellent antibacterial profile as
well as enhanced chemical and metabolic stability,
intensive studies have been reported on the stereoselec-
tive synthesis of a 1â-methyl intermediate 1â. Many of
these syntheses include the nucleophilic addition of an
ester enolate or its derivative to 4-acetoxy-2-azetidinone
2 as a key step.2,3 On the other hand, we have recently
developed a highly enantioselective hydroformylation of
various olefins using a rhodium complex of a chiral
phosphine-phosphite ligand, (R,S)-BINAPHOS [) (R)-
2-(diphenylphosphino)-1,1′-binaphthalen-2′-yl (S)-1,1′-bi-
naphthalene-2,2′-diyl phosphite], as a catalyst.4 The
highest stereoselectivity and the versatility obtained by
this hydroformylation prompted us to apply this reaction
to the 1â-methylcarbapenem synthesis. We describe here
the first example of the synthesis of the key intermediate
1â via rhodium-catalyzed asymmetric hydroformylation.
In addition to the phosphine-phosphite, a new class of
chiral ligands, phosphine-phosphinites, have been syn-
thesized and used for this purpose. A 4-vinyl-â-lactam,
(3S,4R)-3-[(R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-vinyl-
2-azetidinone (3),5 was the substrate of choice.6
Hydroformylation of the 4-vinyl â-lactam 3 catalyzed
by the Rh(I) complexes of chiral bidentate phosphorus
† Deceased on Oct 4, 1995.
(1) (a) Shih, D. H.; Baker, F.; Cama, L. D.; Christensen, B. G.
Heterocycles 1984, 21, 29. (b) Shih, D. H.; Cama, L. D.; Christensen,
B. G. Tetrahedron Lett. 1985, 26, 587.
(2) Recent references for this approach: (a) Shirai, F.; Nakai, T. J .
Org. Chem. 1987, 52, 5491 and references cited therein. (b) Nagao, Y.;
Nagase, Y.; Kumagai, T.; Matsunage, H.; Abe, T.; Shimada, O.;
Hayashi, T.; Inoue, Y. J . Org. Chem. 1992, 57, 4243 and references
cited therein.
The oxidation of the aldehydes 4â and 4R proceeded
without epimerization to produce the corresponding
carboxylic acids 1â and 1R in excellent yields. Thus, a
new synthetic route toward 1â-methylcarbapenem anti-
biotics has been developed.
(3) Other recent approaches: Tsukada, N.; Shimada, T.; Gyoung,
Y. S.; Asao, N.; Yamamoto, Y. J . Org. Chem. 1995, 60, 143 and
references cited therein.
(4) (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, H. J . Am. Chem.
Soc. 1993, 115, 7033. (b) Sakai, N.; Nozaki, K.; Takaya, H. J . Chem.
Soc., Chem. Commun. 1994, 395. (c) Higashizima, T.; Sakai, N.; Nozaki,
K.; Takaya, H. Tetrahedron Lett. 1994, 35, 2023. (d) Nanno, T.; Sakai,
N.; Nozaki, K.; Takaya, H. Tetrahedron: Asymmetry 1995, 6, 2583.
(e) Horiuchi, T.; Ohta, T.; Nozaki, K.; Takaya, H. Chem. Commun.
1996, 155.
(5) The 4-vinyl-â-lactam 3 was prepared from 4-acetoxy-2-azetidi-
none 2 by addition of vinyl Grignard reagent. Kobayashi, T.; Ishida,
N.; Hiraoka, T. J . Chem. Soc., Chem. Commun. 1980, 736.
(6) We previously reported the synthesis of 2 using asymmetric
hydrogenation as a key step. Mashima, K.; Kusano, K.; Sato, N.;
Matsumura, Y.; Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.;
Ishizaki, T.; Akutagawa, S.; Takaya, H. J . Org. Chem. 1994, 59, 3064.
The i/ n ratio observed in the hydroformylation of 3 is
much higher than simple olefins, such as 1-hexene (i/ n
) 26/74, 75% ee for the iso-aldehyde)4a and 3-methyl-1-
S0022-3263(96)01689-1 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7659
Ta ble 1. Asym m etr ic Hyd r ofor m yla tion of 4-Vin yl â-La cta m 3 Ca ta lyzed by Rh (I)-Ch ir a l Liga n d sa
run
ligand
S/Cb
time (h)
total CHO yieldc (%)
i/ nc (4â + 4R)/5
â/Rc 4â/4R
1
2
3
4
5
6
7
PPh3
(R)-BINAP
(R,S)-BINAPHOS
(R)-BIPPHOS
(R)-BIPNITE
200
200
1000
200
500
500
500
48
17
6
6
6
86
51/49
52/48
55/45
71/29
64/36
74/26
74/26
45/55
67/33
93/7
60/40
95/5
24d
95
92
58d
76
(R)-2-Nap-BIPNITE
(R)-2-Nap-BIPNITE-p-F
6
6
95/5
96/4
95
a
b
In decane, substrate/solvent ) 2 g/mL. Substrate/catalyst. c The yield and the (4â + 4R)/5 and 4â/4R ratios were determined by
d
HPLC using 4-acetoxy-2-azetidinone 2 as an internal standard (Inertsil ODS-2, CH3CN/H2O ) 65/35). Starting material was recovered.
Low conversion is the reason for the low yield.
Ch a r t 1
regioselectivity, (4r + 4â)/5. In addition, the i/n ratios
with (R)-6, which is still higher than with simiple olefins,
suggests that the high i/n with 3 (52/48-74/26) may also
be attributed to the â-lactam framework itself. In other
words, the electron-withdrawing nature of the â-lactam,
which can be effectively transmitted through the 4-mem-
bered ring sp3 carbon to the adjacent alkene, probably
does play an important role in favoring the branched
regioselectivity. The fact that (S)-6 resulted in higher
i/n than 3 proves that the substituent at the 3-carbon of
3 was unfavorable for the isoaldehyde formation probably
due to some steric repulsion. The matching of the chiral
ligands with the S configuration at the 4-carbons of 3
should have elevated the â-methyl selectivity.
In our previous study, we proposed that the hydride
and the phosphite occupy the apical sites of Rh in
trigonal-bipyramidal RhH(CO)2[(R,S)-BINAPHOS] based
on the magnitude of J {P-H} (21.3 Hz for phosphine and
butene (8/92, 84% ee).7 This result may be attributed to
(1) the â-lactam framework itself, (2) the absolute con-
figuration of the 4-carbon, or (3) the substituent at the
3-position. In order to investigate the factors that
induced the high i/ n ratio as well as the high â-methyl
selectivity obtained above, 4-vinyl-2-azetidinone (6), an
unsubstituted analog of 3, was prepared and then
subjected to hydroformylation. A racemic mixture of 6
was treated under the same conditions as 3.
The regio- and stereoselectivity from each enantiomer
was calculated from the product distribution.8 The
general features are as follows: (1) much high i/n ratio
was observed with (S)-6 (76/24-92/8) than with (R)-6 (48/
52-56/44) when (R,S)-BINAPHOS or (R)-2-Nap-BIPNITE
was used as a ligand, and (2) the absolute configuration
of the newly formed chiral center was R from both
enantiomers, but the selectivity was higher with (S)-6.
From these results, it is manifested that the absolute
configuration at the 4-carbon of 3 is essential for the high
1
158.7 Hz for phosphite).4a,8 With (R)-BIPNITE, the H
and 31P NMR of the corresponding complex showed a
similar trend of J {P-H} with BINAPHOS complex (12.0
Hz for phosphine and 135.0 Hz for phosphinite).9 Thus,
it is probable to assume that the RhH(CO)2(ligand)
complexes have similar structures between (R,S)-BINA-
PHOS and (R)-BIPNITEs. Further mechanistic studies
are now in progress.
Su p p or tin g In for m a tion Ava ila ble: Detailed results on
hydroformylation of 6, experimental procedures, and refer-
ences for the experiments (6 pages).
J O961689M
(8) Detailed results on hydroformylation of 6 are given in the
supporting information.
(9) Merkin, P.; Muetterties, E. L.; J esson, J . P. J . Am. Chem. Soc.
1972, 94, 5271.
(10) 31P[1H] NMR (CDCl3) data for (R)-BIPNITE are as follows. Free
ligand: δ -13.0 (d, J P-P ) 6 Hz, for phosphine), 111.3 (d, for
phosphinite). RhH(CO)2[(R)-BIPNITE]: δ 23.7 (dd, J P-Rh ) 127.0 Hz,
J P-P ) 28.0 Hz, for phosphine), 163.0 (J P-Rh ) 40.0 Hz, for phosphinite).
(7) Sakai, N. Highly stereoselective organic synthesis by use of
transition-metal catalyzed reactions of carbon monoxide and olefins,
Kyoto University, 1994.