STEREOSELECTIVE SYNTHESIS OF β-LACTAMS

Article abstract of DOI:10.1016/S0040-4039(00)93462-2

An efficient method for the preparation of chiral cis-3,4-disubstituted β-lactams, based on reaction between imines from homochiral protected lactaldehydes and furfurylamine and phenyl dichlorophosphate activated carboxylic acid derivatives, is reported.

Full text of DOI:10.1016/S0040-4039(00)93462-2

Tetra,he&on Letters, Vol.32, No.38, pp 5187-5190, 1991
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S T I ~ E L E C T I V I ~
~
I
S
OF 8-LACThMS
Alan D. Brown and Ernest W. Colvin*
Department of Chemistry, University of Glasgow
Glasgow GI2 8QQ, U.K.
Abstract:
An efficient method for the preparation of chiral cis-3,4-disubstituted
8-1actams, based on reaction between imines from homochiral protected lactaldehydes
and furfurylamine and phenyl dichlorophosphate activated carboxylic acid derivatives,
is reported.
The ketene-imine cycloaddition process (Staudinger reaction) has provided one of the
most fruitful routes I to 8-1actams.
in terms of cis/trans product ratios, can depend2 on the size of the imine nitrogen
substituent. Additionally, when the imine is derived from homochiral amine and an
However, the degree of stereoselectivity observed,
a
achiral aldehyde, the level of diastereoselectivity 3 in the cis product can also vary.
On the other hand, extremely high diastereoselectivities are observed4 with imines from
achiral amines and homochiral aldehydes, such as D-glyceraldehyde acetonide.
A
recent communication 5 on the preparation of chiral 8-1actams using homochiral
lactaldehyde-derived imines prompts us to report our results on 8-1actam formation using
the imines derived from furfurylamine and protected (S)-lactaldehydes. Furfurylamine was
chosen not only as furylmethyl protective group for nitrogen, but also because the
furan ring can be cleaved oxidatively 6 to carboxyl function, so generating
synthetically useful acetic acid substituent on the 8-1actam nitrogen; the lactaldehyde-
derived portion can be converted into 4-acetoxy substituent. These two substituents
are then ideally positioned for further elaboration to bicyclic ring system. The
a
a
a
a
a
ketene precursors were phenoxyacetic acid and the Dane salt of glycine, 7 activation being
achieved in each case using phenyl dichlorophosphate. 8
(S)-(-)-Methyl lactate, protected as its O-t-butyldimethylsilyl ether, was reduced
with di-isobutylaluminium hydride to the corresponding protected lactaldehyde 9 (i).
Reaction of this with freshly distilled furfurylamine gave the homochiral imine (2).
Reaction of imine (2) with phenoxyacetic acid in the presence of phenyl dichloro-
phosphate and Et3N yielded cis-8-1actam I0'II (3) in 86% yield; no trans-8-1actam was
detected, and capillary g.c. analysis indicated
a
diastereoisomeric excess (d.e.) of 83%.
Ruthenium dioxide/sodium periodate mediated oxidation 8 of 8-1actam (3), followed by
esterification with diazomethane, gave ester (4) in an overall yield of 83% (Scheme i).
5187

5188
OS, iMe2Bu t
OH
O,SiMe2But
I
i
I
I
~NH2
IButMe2SiCt
./K..,
CHO
COOMe
i
2.Bu2AIH
(I)
(2)
H, H, ..~Me2But
P h O - . ~
H
H
OSiM%But
~
PhOCH2COOH ~,
P
h
O
I. RuO~ ..,
o N-]
PhOP(O)CI.2, Ef3N
" ~ ' -
(3)
'
~
~
d
o"
"
2.CH2N2
COOMe
(~)
Scheme
1
Reaction of imine (2) with the Dane salt (5) in the presence of phenyl dichloro-
phosphate and Et3N gave cis-8-1actam (6) in 86% yield; capillary g.e. analysis indicated
a
d.e. of 91~.
Selective cleavage of the amino protective group was achieved by brief
Reaction of the product amine hydrochloride with
treatment with anhydrous HCI/MeOH.
phenoxyacetyl chloride in the presence of DMAP/Et3N gave the phenoxyacetamide (7).
oxidative cleavage and esterification, followed by fluoride-induced desilylation and
oxidation 12 gave methyl ketone (8), which was then converted cleanly into acetoxy- 8-
lactam (9), in an overall yield of 40~ from imine (2) (Scheme 2).
Furan

5189
OSiMe2 But
" ~ ]
. , , ~ iOEf
(5) HCOOK
H
H OSiMe2But
H H OSiMe2But
RNH-~
vC_.
I. HCI, MeOH
2.PhOCH 2C0C[,
PhOP(OICI 2,
Ef3N
Ef3N, DMAP
(2)
(6)
(7)
H H
HHO
V ~ "JL"
m-CPBA
)
~
O">- N ~I
COOHe
COOMe
(8)
(9)
Scheme
2
The O-t-butyldiphenylsilyl protected imine (i0) reacted with even higher
diastereoselectivity. Treatment with phenoxyacetic acid under the above conditions gave
B-lactam (ii) in 84% yield, with d.e. of 95%. Reaction with Dane salt (5) gave
B-laetam (12) in 85% yield, as single diastereoisomer (Scheme 3).
a
>
a
In conclusion, O-protected imines (2) and (I0) represent excellent starting
materials for the synthesis of 3,4-disubstituted cis-B-lactams of high optical purity.
Since both enantiomers of methyl lactate are available, 8-1actams of either chirality
can be accessed readily.

5190
H H OSiPh2But
PhO~@,"
PhOCHzCOOH
O,SiPh2But
/
a
i
/
(11)
R NHHH~OSiPh2But
0" '~'0
""9
(10)
(12)
Scheme
3
Acknowledgement:
We thank the Carnegie Trust for the Universities of Scotland for
a
studentship (A.D.B.).
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I.
2.
3.
4.
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4
12.
(Received in UK 9 July 1991)