Diastereoselective allylation of a chiral imine with allylzinc reagents: Diastereoselective synthesis of a novel broad spectrum carbapenem

Article abstract of DOI:10.1055/s-2001-18100

Diastereoselective allylation of chiral imine with allyl-metal reagents was applied to prepare β-amino acid derivative as a key intermediate for the synthesis of a novel carbapenem 1. Combination of the allylzinc reagents and chiral imine, which was derived from L-valine methyl ester as a chiral auxiliary afforded a homoallylamine in good yield with excellent diastereoselectivity.

Full text of DOI:10.1055/s-2001-18100

LETTER
1747
Diastereoselective Allylation of a Chiral Imine with Allylzinc Reagents:
Diastereoselective Synthesis of a Novel Broad Spectrum Carbapenem
D
iastereoselective
u
A
llylation of
i
a
Chir
c
al Imine hi Sugimoto,* Hideaki Imamura, Hiroki Sakoh, Koji Yamada, Hajime Morishima
Banyu Tsukuba Research Institute, Okubo-3, Tsukuba 300-2611, Ibaraki, Japan
Fax +81(298)772027; E-mail: sugmtoyt@banyu.co.jp
Received 31 August 2001
however, cost-effectiveness of these were low because
considerable amounts of expensive chiral amine was used
in the Michael addition, half of the substrate used was lost
in enzymatic resolution, and so on. Accordingly, we in-
Abstract: Diastereoselective allylation of chiral imine with allyl-
metal reagents was applied to prepare -amino acid derivative as a
key intermediate for the synthesis of a novel carbapenem 1. Combi-
nation of the allylzinc reagents and chiral imine, which was derived
from L-valine methyl ester as a chiral auxiliary afforded a homoal- vestigated an alternative approach using diastereoselec-
tive allylation of chiral imine9a,b to construct the -alanine
lylamine in good yield with excellent diastereoselectivity.
moiety of the side chain of 1. Herein, we disclose a highly
diastereoselective allylation of chiral imine derived from
-amino acid9c–h and following conversion to 1.
Key words: diastereoselective allylation, chiral imine, homoally-
lamine, 1- -methylcarbapenem
Retrosynthetic analysis of 1 is outlined in Scheme 1. Con-
version of protected thiol intermediate 2 to the final prod-
uct 1 was reported in our previous paper.7 Carbamoyl
function of 2 was formed from carboxylic acid 3, which
was obtained by oxidative cleavage of homoallylamine 4.
Diastereoselective allylation of chiral aldimine 5 and re-
placement of the substituent on nitrogen gave chiral ho-
moallylamine 4.
Recently, we reported that a novel 1- -methylcarbapenem
11 has an ultra-broad antimicrobial spectrum covering me-
thicillin-resistant Staphylococcus aureus (MRSA) and
Pseudomonas aeruginosa. Although the known carbapen-
ems such as meropenem,2 S-4661,3 E1010 (ER-35786),4
ertapenem5 and lenapenem6 have cis-3,5-disubstituted
pyrrolidin-3-ylthio side chains at the C-2 position of the
carbapenem nucleus, 1 has a trans-3,5-disubstituted pyr-
rolidin-3-ylthio side-chain which afforded such unique bi-
ological activities.
There are many efficient asymmetric allylmetalation pro-
cedures using N-masked aldimines with chiral allylmetal
reagents,9l–n however, we initially examined the addition
reaction of allylmetal reagents with aldimines bearing
chiral auxiliary such as -amino acid,9c–k since high ste-
reoselectivity would be expected by convenient proce-
dures. In this paper, our attention was focused on the
development of an efficient method for the construction of
In order to stereoselectively construct the -alanine moi-
ety of the side chain of 1, we previously described two
strategies as follows: 1) asymmetric Michael addition of
chiral amine to cinnamate ester7 and 2) enzymatic resolu-
tion of diastereomeric mixture of 3-aryl-3-hydroxy propi-
onate ester.8 These methods were effective and practical,
OH
H
H
N
AcS
HO
S
N
N
Boc
O
Boc
COOH
CONH2
NHBoc
N
H
COOH
NHBoc
1
2
3
CONH2
NH2
TBSO
TBSO
TBSO
H2N
R*
M
N
Boc
N
Boc
N
Boc
CHO
5
6
4
N
NHBoc
R*
R*: chiral auxiliary group
Scheme 1
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1747,1750,ftx,en;Y16001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1748
Y. Sugimoto et al.
LETTER
TBSO
TBSO
H2N
COOMe
TBSO
ZnBr
N
Boc
N
Boc
N
Boc
H
N
COOMe
N
COOMe
CHO
6
7
8
R
Br
Zn
O
N
OMe
Scheme 2
(S)-homoallylamine 4 using valine as a chiral auxiliary, which was oxidized with sodium periodate forming alde-
which is inexpensive and can be supplied in bulk quanti- hyde and sequentially with sodium chlorite17 to provide
ties.
N-Boc- -aryl- -amino acid 11. After removal of the t-bu-
tyldimethylsilyl (TBS) group by using tetrabutylammoni-
um fluoride (TBAF), hydroxy acid 3 was treated with
methanesulfonyl chloride (MsCl) in the presence of Et3N
at –20 °C, and successively with ammonia water to form
carbamoyl derivative 12 (46% from diol 10). Finally, a
thiol function was introduced by the substitution reaction
The Schiff base 7 was readily derived from aldehyde 610
and L-valine methyl ester. First, allylation of imine 7 by
the allyl Grignard reagent was carried out, and afforded
the desired homoallylamine with excellent diastereoselec-
tivity (> 99% diastereomeric excess).11 However, chemi-
cal yield was moderate (48%), and byproducts formed
were unseparable by column chromatography. On the oth-
er hand, Barbier-type allylation using allyl bromide and
zinc powder combination resulted in acceptable yield and
selectivity9c–h (Table). Althoug the Zn-promoted reaction
of allyl bromide did not proceed below ambient tempera-
ture (entry 1, 2), allylation product was obtained at 60 °C
in THF (entry 3). The yield was significantly increased by
using DMF as a solvent (entry 11),12 while the presence of
CeCl3 did not influence the yield (entry 4, 5). The reason
why the reaction readily proceeds using DMF as a solvent
is not clear. We propose that the reaction proceeds
Table Reaction of Allylzinc Reagent under various Conditions.a
ZnBr
7
8
Solvent Additive
Temp.
Entry Solvent Additive
Temp.
Yieldc
n.r.d
1
2
THF
THF
THF
THF
THF
Et2O
none
0 °C r.t.
CeCl3 7 H2O (x 0.1) 0 °C
r.t.
n.r.d
through
a plausible cyclic chair transition state
3
none
60 °C
60 °C
~ 40%
20%
39%
n.r.d
(Scheme 2), where Zn is coordinated by ester group and
the bulky isopropyl group is disposed externally.9f Under
the optimized conditions, Zn-promoted allylation took
place smoothly to provide multi grams of the desired (S,S)
diasteromer 8 (77%, Scheme 3).13
4
CeCl3b (x 0.8)
5
CeCl3 7 H2O (x 0.8) 60 °C
6
none
reflux
reflux
60 °C
60 °C
60 °C
60 °C
60 °C
Stereoselectivities of the diastereoselective allylation re-
action were determined after conversion of 8 to the pro-
tected primary homoallylamine
7
CH2Cl2 none
Benzene none
Dioxane none
trace
n.r.d
4
by sequential
8
manipulation. According to the reported procedures,9f 8
was reduced with LiAlH4 (85%), and the resulting amino
alcohol 914 was oxidatively cleaved by using HIO4 to form
a primary amino group which was then protected with a
Boc group to afford 4 in quantitative yield. Enantiomeric
purity of 4 (> 98% diastereomeric excess)15 was deter-
mined by HPLC analysis with comparison of a standard
sample.16
9
n.r.d
10
11
12
MeCN
DMF
none
none
n.r.d
69%
n.r.d
DMSO none
a Conditions: 7 50 mg (0.096 mmol), Zn 60 mg (10 equiv), Allylbro-
mide 170 mL (20 equiv), solvent 3 mL.
b Anhydrous beads, purchased from ALDRICH.
c Isolated yield.
Oxidation of homoallylamine 4 by the combination of os-
mium tetroxide and 4-methylmorpholine N-oxide (NMO)
at room temperature afforded vicinal diol 10 (74%),
d No reaction.
Synlett 2001, No. 11, 1747–1750 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Allylation of a Chiral Imine
1749
TBSO
TBSO
TBSO
a,b, c
f
d, e
6
N
Boc
N
Boc
N
Boc
H
N
OH
OH
9
4
10
OH
NHBoc
NHBoc
TBSO
MsO
AcS
i, j
g, h,
k
N
Boc
N
Boc
N
Boc
1
COOH
CONH2
NHBoc
CONH2
NHBoc
11
NHBoc
12
2
Scheme 3 Reagents and conditions: (a) L-Val-OMe HCl, Et3N, MgSO4, THF, r.t., quant.; (b) Allyl bromide, Zn, DMF, 60 °C, 77%; (c) LAH,
THF, 0 °C, 85%; (d) H5IO6, MeNH2, MeOH–H2O, 0 °C; (e) Boc2O, NaOH, Dioxane–H2O, 0 °C, quant. in 2 steps; (f) OsO4, NMO, Acetone–
H2O, r.t., 74%; (g) NaIO4, THF–H2O, r.t.; (h) NaClO2, NaH2PO4, 2-metyl-2-butene, t-BuOH–H2O, rt.; (i) TBAF, THF, r.t.; (j) MsCl, Et3N,
THF, –20 °C –10 °C then NH4OH, r.t., 46% in 4 steps; (k) AcSK, DMF, 70 °C, 67%.
(2) Sunagawa, M.; Matsumura, H.; Inoue, T.; Fukasawa, M.;
of mesylate 12 with potassium thioacetate in DMF to
yield enantiomerically pure thioacetate 2 (67%, > 99% di-
astereomeric excess).18 No appreciable decrease of the
enantiomeric purity was observed in the above transfor-
mation of 4 to 2.
Kato, M. J. Antibiot. 1990, 43, 519.
(3) Iso, Y.; Irie, T.; Nishio, Y.; Motokawa, K.; Nishitani, Y. J.
Antibiot. 1996, 49, 199.
(4) Ohba, F.; Nakamura-Kamijo, M.; Watanabe, N.; Katsu, K.
Antimicrob. Agents Chemother. 1997, 41, 298.
(5) Gill, C. J.; Jackson, J. J.; Gerckens, L. S.; Pelak, B. A.;
Thompson, R. K.; Sundelof, J. G.; Kropp, H.; Rosen, H.
Antimicrob. Agents Chemother. 1998, 42, 1996.
(6) (a) Ohtake, N.; Okamoto, O.; Mitomo, R.; Kato, Y.;
Yamamoto, K.; Haga, Y.; Fukatsu, H.; Nakagawa, S. J.
Antibiot. 1997, 50, 598. (b) Nakagawa, S.; Hashizume, T.;
Matsuda, K.; Sanada, M.; Okamoto, O.; Fukatsu, H.;
Tanaka, N. Antimicrob. Agents Chemother. 1993, 37, 2756.
(7) Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.;
Sakuraba, S.; Nakajima, S.; Abe, S.; Miura, K.; Nishimura,
I.; Yamada, K.; Morishima, H. Tetrahedron 2000, 56, 7705.
(8) Sugimoto, Y.; Imamura, H.; Shimizu, A.; Nakano, M.;
Nakajima, S.; Abe, S.; Yamada, K.; Morishima, H.
Tetrahedron: Asymmetry 2000, 11, 3609.
In conclusion, aldehyde 6 was converted to the enantio-
merically pure 2 in 11 steps and the overall yield was 15%
with > 99% diastereomeric excess. These procedures
were practical by using economical reagents without
cryogenic conditions and provided complete stereoselec-
tivity. Thus, we successfully demonstrated the efficiency
of diastereoselective allylation of valine-derived aldimine
for constructing the -alanine amide structure of side
chain of 1- -methylcarbapenem 2.
Acknowledgement
(9) (a) Kleinman, E. F.; Volkamnn, R. A. In Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M.; Fleming, I.;
Heathcock, C. H., Eds.; Pergamon: Oxford, 1991, 975.
(b) Yamamoto Y., Asao N.; Chem. Rev.; 1993, 93: 2207.
(c) Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.;
Torii, S. Tetrahedron Lett. 1990, 31, 3023. (d) Bocoum, A.;
Boga, C.; Savoia, D.; Umani-Ronchi, A. Tetrahedron Lett.
1991, 32, 1367. (e) Bocoun, A.; Savoia, D.; Umani-Ronchi,
A. J. Chem. Soc., Chem. Commun. 1993, 1542. (f) Basile,
T.; Bocoun, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem.
1994, 59, 7766. (g) Alvaro, G.; Boga, C.; Savoia, D.;
Umani-Ronchi, A. J. Chem. Soc., Perkin Trans. 1 1996,
875. (h) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.; Villa,
M. . (i) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883.
(j) Chen, L.; Trilles, R. V.; Tilley, J. W. Tetrahedron Lett.
1995, 36, 8715. (k) Yanagisawa, A.; Ogasawara, K.; Yasue,
K.; Yamamoto, H. Chem. Commun. 1996, 367. (l) Eddine,
J. J.; Chergaoui, M. Tetrahedron: Asymmetry 1995, 6, 1225.
(m) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 4242. (n) Chen, G.-M.;
We are indebted to Mr. Hirokazu Ohsawa for FAB-HRMS analyses
and to Ms. Aya Shimizu for optical rotation measurements. We are
also grateful to Ms. Kimberley Marcopul, Merck & Co. Inc., for her
critical reading of this manuscript.
References
(1) (a) Imamura, H.; Ohtake, N.; Shimizu, A.; Jona, H.; Sato, H.;
Nagano, R.; Ushijima, R.; Yamada, K.; Hashizume, T.;
Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 109.
(b) Imamura, H.; Ohtake, N.; Shimizu, A.; Sato, H.;
Sugimoto, Y.; Sakuraba, S.; Kiyonaga, H.; Suzuki-Sato, C.;
Nakano, M.; Nagano, R.; Yamada, K.; Hashizume, T.;
Morishima, H. Bioorg. Med. Chem. Lett. 2000, 10, 115.
(c) Imamura, H.; Ohtake, N.; Shimizu, A.; Sato, H.;
Sugimoto, Y.; Sakuraba, S.; Nagano, R.; Nakano, M.; Abe,
S.; Suzuki-Sato, C.; Nishimura, I.; Kojima, H.; Tsuchiya, Y.;
Yamada, K.; Hashizume, T.; Morishima, H. Bioorg. Med.
Chem. 2000, 8, 1969. (d) Nagano, R.; Shibata, K.; Adachi,
Y.; Imamura, H.; Hashizume, T.; Morishima, H. Antimicrob.
Agents Chemother. 2000, 44, 489. (e) Shibata, K.; Nagano,
R.; Hashizume, T.; Morishima, H. J. Antimicrob.
Ramachandran, P. V.; Brown, H. C. Angew. Chem. Int. Ed.
1999, 38, 825.
(10) Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.;
Sakuraba, S.; Nagano, R.; Yamada, K.; Hashizume, T.;
Morishima, H. J. Antibiot. 2000, 53, 314.
Chemother. 2000, 45, 379. (f) Hashizume, T.; Morishima,
H. Drugs of the Future 2000, 25, 833.
Synlett 2001, No. 11, 1747–1750 ISSN 0936-5214 © Thieme Stuttgart · New York

1750
Y. Sugimoto et al.
LETTER
TBSO
TBSO
TBSO
TBSO
n, o
m
l
N
Boc
N
Boc
N
Boc
N
Boc
CHO
6
13
OH
14
N3
15
NHBoc
Scheme 4 Reagents and conditions: (l) Allylmagnesium bromide, THF, 0 °C, 92%; (m) MsCl, Et3N, THF, –50 °C
–30 °C then NaN3,
DMF, r.t., 46%; (n) PPh3, H2O, THF, 60 °C; (o) Boc2O, NaOH, Dioxane–H2O, 0 °C, 72% in 2 steps.
(11) The diastereomeric excess (de) of 8 was determined by
HPLC analysis after converting to the corresponding 4. See
ref15 about the HPLC condition of 4.
(12) Shono, T.; Ishifune, M.; Kashimura, S. Chem. Lett. 1990,
449.
J = 8.1 Hz), 7.21 (2 H, d, J = 8.1 Hz); 13C NMR (100 MHz,
CDCl3) = –5.1, 17.7, 18.7, 19.4, 25.5, 27.9, 29.2, 29.5,
42.6, 44.4, 54.6, 59.4, 59.7, 59.9, 61.0, 69.9, 79.2, 117.0,
125.9, 126.5, 135.2, 141.6, 143.7, 154.3; HRMS–FAB: m/z
[M + H]+ calcd for C30H53N2O4Si, 533.3774; found
533.3759.
(13) A typical experimental procedure for the synthesis of 8 is as
follows: To a mixture of 7 (6.57 g, 12.67 mmol)and Zn
powder (8.06 g, 123.3 mmol) in DMF (100 mL) was added
allyl bromide (21.3 mL, 246.1 mmol) at r.t. The reaction
mixture was stirred at 60 °C overnight (ca. 12–18 h). The
mixture was poured into H2O and the whole was extracted
EtOAc. The organic layer was washed with brine, dried over
anhyd MgSO4, and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane/EtOAc = 10:1) to give 8 (5.47 g, 77%) as a pale
yellow oil; [ ]25D –39.4 (c 1.0, CHCl3); IR (KBr): 2931,
1734, 1697, 1396, 1157, 1092, 837, 777; 1H NMR (400
MHz, CDCl3) = –0.04 (3 H, s), 0.05 (3 H, s), 0.82 (9 H, s),
0.83 (3 H, d, J = 7.0 Hz), 0.88 (3 H, d, J = 7.0 Hz), 1.14 (9
H, s), 1.80 (2 H, m), 1.92 (1 H, m), 2.35 (2 H, m), 2.51 (1 H,
m), 2.77 (1 H, m), 3.47 (2 H, m), 3.70 (3 H, s), 3.87 (1 H, m),
4.38 (1 H, m), 4.69 (1 H, m), 5.08 (2 H, m), 5.71 (1 H, m),
7.17 (2 H, d, J = 8.4 Hz), 7.20 (2 H, d, J = 8.4 Hz); 13C NMR
(100 MHz, CDCl3) = –5.0, 17.9, 18.6, 19.4, 25.6, 28.1,
28.4, 31.7, 43.8, 44.6, 51.2, 54.7, 60.1, 60.5, 64.3, 70.0, 79.3,
117.5, 125.9, 127.2, 135.3, 141.5, 143.8, 154.5, 176.2;
HRMS–FAB: m/z [M + H]+ calcd for C31H53N2O5Si,
561.3724; found 561.3736.
(15) Selected data for compound 4: [ ]25D –4.8 (c 1.0, CHCl3); IR
(KBr): 2931, 2347, 1697, 1508, 1396, 1173, 1093, 837, 777;
1H NMR (400 MHz, CDCl3) = –0.03 (3 H, s), 0.04 (3 H, s),
0.81 (9 H, s), 1.14 (9 H, s), 1.40 (9 H, s), 1.89 (1 H, m), 2.50
(3 H, m), 3.42 (1 H, m), 3.82 (1 H, m), 4.37 (1 H, m), 4.69 (2
H, m), 4.87 (1 H, br s), 5.07 (2 H, m), 5.65 (1 H, m), 7.16 (2
H, d, J = 8.1 Hz), 7.21 (2 H, d, J = 8.1 Hz); 13C NMR (100
MHz, CDCl3) = –5.1, 17.7, 25.5, 27.9, 28.2, 29.5, 41.1,
44.5, 53.6, 54.5, 59.9, 69.8, 79.3, 117.9, 125.7, 126.0, 133.8,
143.6, 154.3; HRMS–FAB: m/z [M + Na]+ calcd for
C30H50N2O5SiNa, 569.3386; found 569.3365. Analytical
HPLC condition: column, Chiralcel OD-H (Daicel, 4.6 mm
I. D. 250 mm); eluent, n-hexane:i-PrOH = 98:2; flow rate,
0.5 mL/min; column temp., 40 °C; detection, UV 230 nm;
retention time, 10.9 min [4, (S)-isomer] and 12.2 min [(R)-
isomer].
(16) Diastereomeric mixture of homoallylamine 15 was prepared
as illustrated above (Scheme 4). Allylation of aldehyde 6
with allylmagnesium bromide afforded homoallyl alcohol
13 (92%). Mesylation of 13 with MsCl and Et3N at –50 °C,
followed by treatment with NaN3 gave azide 14 (46%).
Reduction of 14 with triphenylphosphine in the presence of
water and subsequent protection with Boc2O provided the
mixture of (R)- and (S)-homoallylamine (ca. 1:1, 72%) 15.
(17) Hase, T.; Wähälä, K. In Handbook of Reagents for Organic
Synthesis: Oxidizing and Reducing Agents; Burke, S. D.;
Danheiser, R. L., Eds.; John Wiley & Sons: Chichester,
1999, 400.
(14) Selected data for compound 9: [ ]25D +16.8 (c 1.0, CHCl3);
IR (KBr): 3047, 2926, 1684, 1404, 1092, 837, 777; 1H NMR
(400 MHz, CDCl3) = –0.04 (3 H, s), 0.05 (3 H, s), 0.81 (9
H, s), 0.81 (3 H, d, J = 6.6 Hz), 0.86 (3 H, d, J = 6.6 Hz), 1.15
(9 H, s), 1.69 (1 H, ddd, J = 6.6, 6.6, 20.2 Hz), 1.91 (1 H,
ddd, J = 5.9, 7.0, 12.7 Hz), 2.08 (1 H, br s), 2.23 (1 H, m),
2.40 (1 H, m), 2.48 (2 H, m), 3.39 (1 H, dd, J = 3.3, 10.6 Hz),
3.46 (1 H, dd, J = 4.9, 10.4 Hz), 3.61 (1 H, dd, J = 3.9, 10.8
Hz), 3.69 (1 H, t, J = 7.0 Hz), 3.83 (1 H, m), 4.39 (1 H, m),
4.72 (1 H, m), 5.02 (2 H, m), 5.68 (1 H, m), 7.15 (2 H, d,
(18) Compound 2 was in agreement with all reported analytical
data and the enantiomeric purity was determined by HPLC
analysis. See ref7.
Synlett 2001, No. 11, 1747–1750 ISSN 0936-5214 © Thieme Stuttgart · New York