A cation-exchange resin promoted imino aldol reaction, leading to the synthesis of 2-isocephem and 2-oxa-isocephem

Article abstract of DOI:10.1246/cl.2004.1394

Imino aldol reaction of ketene silyl acetals with the chiral imine 1 proceeds smoothly to give β-amino esters in good yields with high diasetereoselectivity under the influence of a cation-exchange resin, and the subsequent functional group transformation

Full text of DOI:10.1246/cl.2004.1394

1394
Chemistry Letters Vol.33, No.10 (2004)
A Cation-exchange Resin Promoted Imino Aldol Reaction,
Leading to the Synthesis of 2-Isocephem and 2-Oxa-isocephem
Makoto Shimizu,ꢀ Masanori Tachi, and Iwao Hachiya
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507
(Received July 21, 2004; CL-040855)
Imino aldol reaction of ketene silyl acetals with the chiral
synthesis of a key intermediate 2 for 2-isocephem (3) and 2-
oxa-isocephem (4).
The starting chiral imine 1 was prepared from (2S,3S)-1,4-
dimethoxy-2,3-butanediol in 3 steps.2b The reaction of the ke-
tene silyl acetal 5 was initially used for the optimization of the
addition reaction, and Table 1 summarizes the results.
imine 1 proceeds smoothly to giveꢀ-amino esters in good yields
with high diasetereoselectivity under the influence of a cation-
exchange resin, and the subsequent functional group transforma-
tions provide a formal synthesis of 2-isocephem and 2-oxa-
isocephem ꢀ-lactam antibiotics.
Table 1. Reaction of 5 with the chiral imine 1 in the presence of
AmberlystÒ 15 DRYa
ꢀ-Lactam antibiotics still constitute one of the most widely
utilized classes of drugs due to their highly therapeutic index in
humans.1 For the synthesis of such a class of compounds one of
the most straightforward approaches involves the ester enolate-
imine condensation. However, stereocontrolled construction of
both the C-3 and C-4 carbons does not appear to be trivial.
Our continuous interests in the stereodivergent construction of
the ꢀ-lactam rings with or without substituent at 3-position2
led us to examine the preparation of 3-alkoxy-ꢀ-lactams in a
highly stereoselective manner. During these investigations cat-
ion-exchange resins have been found to be excellent activators
for imino aldol reaction of ketene silyl acetals with imines,
which, after cyclization, would lead to the stereodivergent syn-
thesis of ꢀ-lactams. Use of ion-exchange resins offers several ad-
vantages in organic synthesis, e.g., simplification of reaction pro-
cedures, easy separation of products without discharging harmful
waste water, repeated use, and so on. In our previous report, a
cation-exchange resin, in particular AmberlystÒ 15 DRY, having
a large surface area (45 m2/g), was found to be one of the most
useful resins that promoted imino aldol type reaction, where the
addition reactions proceeded with high chemoselectivity in the
presence of two kinds of imines and/or nucleophiles.3
PMP
NH
O
O
Amberlyst ® 15 DRY
(1.0 equiv.)
OTMS
OEt
OEt
O
+
1
CH2Cl2, Temp.,14 h
MeO
OMe
5
(3S)-6
Entry
5/equiv.
Temp./ꢂC
6/%b
3S:3R
1
2
3
4
1.2
1.2
2.5
3.0
rt
11
32
76
69
97:3
97:3
94:6
94:6
ꢁ78–rt
ꢁ78–rt
ꢁ78–rt
aCarried out according to the typical procedure (Ref. 8).
bIsolated yield.
As shown in Table 1, when the reaction was carried out with
1.2 equiv. of 5 at room temperature, the desired adduct 6 was ob-
tained in low yield, where a concomitant hydrolysis of the ketene
silyl acetal was observed to some extent. The best yield was ob-
tained when the reaction was conducted with 2.5 equiv. of 5 at
ꢁ78 ꢂC–room temperature. Under these conditions a variety of
ketene silyl acetals were subjected to the addition reaction,
and Table 2 summarizes the results.
As shown in Table 2, the addition in methanol or ethanol
PMP
N
O
MeO
OSO2Me
MeO
X
Table 2. Reaction of ketene silyl acetal 7 with the chiral imine
1 in the presence of AmberlystÒ 15 DRYa
H
N
O
N
Me
CO2H
O
O
H
PMP
NH
O
MeO
OMe
3: X = S, 2-Isocephem
4: X = O, 2-Oxa-isocephem
2
1
Amberlyst® 15 DRY
(1.0 equiv.)
OTMS
R2
R2
R1
+
1
O
O
R1
Figure 1.
Solv., −78 ˚C−rt, 14 h
(1.0 equiv.)
7
(2.5 equiv.)
MeO
OMe
(2S,3S)-8
In connection with the recent interest in the semi-synthesis
of taxol4 as well as potentiality as a versatile synthon for the syn-
thesis of various important ꢀ-lactam antibiotics such as 2-isoce-
phem,5 2-oxa-isocephem,5 7-methoxycephalosporin,6 and PS-5,7
a stereodivergent synthesis of ꢀ-lactams possessing an alkoxy
group at the 3-position is one of the most useful applications
using the imino aldol reaction promoted by a cation-exchange
resin. Previous studies have already revealed the versatility of
the chiral imine 1 for the ester enolate-imine condensation
method of ꢀ-lactam synthesis.2 In the present paper we would
like to disclose a stereoselective synthesis of 3-alkoxy-ꢀ-lactams
by the ester enolate-imine condensation promoted by a cation-
exchange resin using the chiral imine 1, and application to the
Entry
R1
R2
Solvent 8/%b syn:antic de (syn)/%c
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe EtOH
21
NDd
NDd
73:27
95:5
99:1
99:1
—:—
NDd
NDd
NDd
61
OMe MeOH 22
OMe i-PrOH 82
OMe CH2Cl2 97
96
86
OTBDMS OMe CH2Cl2 90
OTBDMS OMe i-PrOH 88
14
—
NDd
NBn2
Et
OMe CH2Cl2
S-t-Bu CH2Cl2 trace
0
aCarried out according to the typical procedure (Ref. 8). Isolated
yield. cDetermined by 1H NMR and/or HPLC. Not determined.
b
d
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.10 (2004)
1395
gave the adduct in poor yield, whereas the reaction gave the ad-
duct in good yield when i-propyl alcohol was used as a solvent
(Entries 1–3). The best product yield and diastereoselectivity
were obtained when the reaction was run in dichloromethane,
where syn-adduct 8a (R1 = R2 = MeO) was formed in good di-
asteromeric excess (Entry 4). Excellent yields and syn-selectiv-
ities were observed with the TBDMSO derivative 7b, although
the diasetereomeric excess of the syn-isomer was modest (Entry
5). However, the addition did not proceed with the ketene silyl
acetal derived from a glycine derivative (Entry 7). Ketene silyl
thio acetal was not employable due to the competing hydrolysis
under the reaction conditions (Entry 8). The addition product 8a
(syn:anti = 95:5) was readily transformed into the ꢀ-lactam 9 in
93% yield on treatment with i-PrMgCl in THF, and each isomer
was readily separated on silica gel TLC. Examination of the cou-
pling constant unambiguously established the relative stereo-
chemistry.9 On the basis of the diastereoselectivity, the follow-
ing transition state was proposed. The chiral imine 1 was proto-
nated with the cation-exchange resin, and the ketene silyl acetal
approached from the sterically less hindered face in an anti-per-
iplaner fashion to give the (2S,3S)-adduct 8a as a major product.
(Figure 2)
11 was transformed into the primary alcohol 14 via the following
four step sequences in excellent overall yield of 89% (m-CPBA
oxidation, HCl treatment, cleavage with HIO4, and reduction
.
with BH3 THF). Mesylation followed by removal of the PMP
group with CAN gave the known key intermediate 25,10 to 3
and 4.
In conclusion, we have developed an efficient method
for the synthesis of ꢀ-lactams substituted at the C-3 and C-4
positions in a cis-orientation using a cation-exchange resin
promoted imino aldol reaction. Using this methodology, an easy
approach was developed to a key intermediate for the synthesis
of 2-isocephem and 2-oxa-isocephem.
References and Notes
1
W. Durckheimer, J. Blumback, R. Lattrell, and K. H. Scheunemann,
Angew. Chem., Int. Ed., 24, 180 (1985); ‘‘Chemistry and Biology of
ꢀ-Lactam Antibiotics,’’ ed. by R. B. Morin and M. Gorman, Academic
Press, New York (1982), Vols. 1–3; T. Kametani, K. Fukumoto, and
M. Ihara, Heterocycles, 17, 463 (1982).
2
a) T. Fujisawa, Y. Ukaji, T. Noro, K. Date, and M. Shimizu, Tetrahe-
dron Lett., 32, 7563 (1991). b) T. Fujisawa, Y. Ukaji, T. Noro, K. Date,
and M. Shimizu, Tetrahedron, 48, 5629 (1992). c) M. Shimizu, Y.
Ukaji, J. Tanizaki, and T. Fujisawa, Chem. Lett., 1992, 1349. d) T.
Fujisawa, R. Hayakawa, and M. Shimizu, Tetrahedron Lett., 33,
7903 (1992). e) T. Fujisawa, K. Higuchi, and M. Shimizu, Synlett,
1993, 59. f) T. Fujisawa, M. Ichikawa, Y. Ukaji, and M. Shimizu,
Tetrahedron Lett., 34, 1307 (1993). g) T. Fujisawa, D. Satou, and M.
Shimizu, Bioorg. Med. Chem. Lett., 3, 2343 (1993). h) M. Shimizu,
T. Ishida and T. Fujisawa, Chem. Lett., 1994, 1403. i) T. Fujisawa,
R. Hayakawa, and M. Shimizu, Chem. Lett., 1995, 1013. j) R.
Hayakawa, I. Fuseya, T. Konagaya, M. Shimizu, and T. Fujisawa,
Chem. Lett., 1998, 49.
Transformation into a key intermediate for the synthesis of
2-isocephem and 2-oxa-isocephem was readily carried out as
shown in Scheme 1. First, the chiral auxiliary was removed on
treatment with TfOH in refluxing 2-butanone, and the resulting
methyl ketone 10 was silylated with TMSOTf/Et3N to give
the silyl enol ether 11 in quantitative yield. The silyl enol ether
3
4
a) M. Shimizu and S. Itohara, Synlett, 2000, 1828. b) M. Shimizu, S.
Itohara, and E. Hase, Chem. Commun., 2001, 2318.
PMP
PMP
H
+
N
NH
O
O
MeO
I. Ojima, I. Habus, M. Zhao, G. I. Georg, and L. R. Jayasinghe, J. Org.
Chem., 56, 1681 (1991); I. Ojima, I. Habus, M. Zhao, M. Zucco, Y. H.
Park, C. M. Sun, and T. Brigaud, Tetrahedron, 48, 6985 (1992); G. I.
Georg, Z. S. Cheruvallath, G. C. B. Harriman, M. Hepperle, and H.
Park, Bioorg. Med. Chem. Lett., 3, 2467 (1993); J. Kant, S. Huang,
H. Wong, C. Fairchild, D. Vyas, and V. Farina, Bioorg. Med. Chem.
Lett., 3, 2471 (1993); R. A. Holton and J. H. Liu, Bioorg. Med. Chem.
Lett., 3, 2475 (1993); I. Ojima, M. Zucco, O. Duclos, S. D. Kuduk,
C. M. Sun, and Y. H. Park, Bioorg. Med. Chem. Lett., 3, 2479
(1993); M. Endo and R. Droghini, Bioorg. Med. Chem. Lett., 3, 2483
(1993).
MeO
O
O
OMe
O
H
OMe
MeO
OMe
TMSO
OMe MeO
O
(2S,3S)-8a
O
OMe
OMe
OMe
H3 H4
N
MeO
H3 H4
N
MeO
O
OMe
O
(3S,4R)-9
(3S,4S)-9
PMP
O
PMP
88% JH3-H4 = 5.61 Hz
O
5% JH3-H4 = 1.95 Hz
5
D. H. R. Barton, J. Anaya, A. Gateau-Olesker, and S. D. Gero,
Tetrahedron Lett., 33, 6641 (1992).
H. Sakai, J. Synth. Org. Chem. Jpn., 39, 243 (1981).
Figure 2.
6
7
O
C. Palomo, J. M. Aizpurua, M. C. Lopez, N. Aurrekoetxea, and M.
Oiarbide, Tetrahedron Lett., 31, 6425 (1990); C. Palomo, F. P. Cossio,
J. M. Ontoria, and J. M. Odriozola, Tetrahedron Lett., 32, 3105 (1991).
A typical experimental procedure is as follows: To a suspension of
Amberlyst 15 DRY(43.0 mg, 0.2 mmol on the sulfonic acid portion,
washed EtOH and dried in vacuo at 100 ꢂC) and the imine 1 (61.9
mg, 0.2 mmol) in CH2Cl2 (1.0 mL) was added a solution of ketene silyl
acetal 7a (R1 = R2 = MeO, 96.2 mg, 0.5 mmol) in CH2Cl2 (5.0 mL) at
ꢁ78 ꢂC under an argon atmosphere. After being stirred at ꢁ78 ꢂC for
2 h, the reaction mixture was allowed to stand at room temperature
for 12 h. The suspension was filtrated through a Celite pad. The filtrate
was concentrated in vacuo to afford a crude oil. Purification on prepa-
rative silica gel TLC (n-Hex / Et2O = 1/3, as an eluent, developed
twice) gave the adduct 8a (80.2 mg, 97%) as a pale yellow oil. Exami-
nation by HPLC indicated the formation of diastereomers in a 95:5
(syn:anti) ratio and 96% de for the syn-8a.
O
O
OMe
OMe
MeO
O
MeO
TfOH
2-Butanone
Reflux, 3 h, 95%
N
N
9
8
PMP
O
PMP
10
OTMS
TMSOTf
Et3N
1) m-CPBA, CH2Cl2
0 ˚C−rt, 4 h
MeO
CH2Cl2, 78 ˚C rt
N
2) 2 M HCl, 1 h
2 h, quant.
PMP
O
11
O
O
MeO
MeO
OH
OH
HIO4 • 2H2O
THF, 0 ˚C, 4 h
MeO
N
N
PMP
PMP
O
O
12
13
BH3 •THF
MsCl, Py
OH
THF, 0 ˚C−rt, 6 h
89%, (4 steps)
N
CH2Cl2, 0 ˚C−rt, 14 h
PMP
O
70%
MeO
14
9
Determination of the absolute stereochemistry, see Ref. 2h.
23:2
MeO
ꢁ130:2 (c 0.013, CHCl3); 1H NMR (270 MHz,
CAN
OSO2Me
10 2: Yellow oil; ½ꢁꢃD
OSO2Me
PMP
MeCN, H2O
−15 ˚C, 3 h, 72%
N
CDCl3) ꢂ 3.06 (s, 3H), 3.57 (s, 3H), 4.07–4.13 (m, 1H), 4.34 (dd,
J ¼ 11:2, 7.92 Hz, 1H), 4.46 (dd, J ¼ 11:2, 4.29 Hz, 1H), 4.63–4.66
(m, 1H), 6.24 (brs, 1H); IR (CHCl3): 3187, 3015, 1722, 1457, 1344,
1194, 1168, 990, 968, 826 cmꢁ1; MS (ESI): m=z 210 ðM þ HÞþ.
N
O
H
O
2
15
Scheme 1.
Published on the web (Advance View) September 25, 2004; DOI 10.1246/cl.2004.1394