Use of lithium (α-methylbenzyl)allylamide for a formal asymmetric synthesis of thienamycin

Article abstract of DOI:10.1039/a700216e

The highly stereoselective conjugate addition of lithium (αR)-(α-methylbenzyl)allylamide 3 to (E)-tert-butyl penta-2,4-dienoate 4, followed by a stereoselective aldol reaction with acetaldehyde, are the key steps in the synthesis of the known β-lactam int

Full text of DOI:10.1039/a700216e

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Use of lithium (a-methylbenzyl)allylamide for a formal asymmetric synthesis of
thienamycin
Stephen G. Davies* and David R. Fenwick
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, UK OX1 3QY
The highly stereoselective conjugate addition of lithium
(aR)-(a-methylbenzyl)allylamide 3 to (E)-tert-butyl penta-
2,4-dienoate 4, followed by a stereoselective aldol reaction
with acetaldehyde, are the key steps in the synthesis of the
known b-lactam intermediate, (3S,4R)-3-[(R)-1-(tert-butyl-
dimethylsilyloxy)ethyl]-4-vinylazetidin-2-one 2, for elabora-
tion to thienamycin and its derivatives.
observed (Scheme 2). Analysis of the 500 MHz 1H NMR
spectrum of the crude addition product showed the dia-
stereoselectivity (ds) to be 99:1. Treatment of the adduct (3S,
aR)-5 with LDA in THF at 0 °C for 2 h followed by cooling to
278 °C and quenching with acetaldehyde gave only two of the
four possible diastereomeric aldol products, (2S,3S,aR,2AR)-6
and (2R,3S,aR,2AS)-7, in a 4:1 ratio by analysis of the 500 MHz
1H NMR spectrum of the crude reaction mixture. To improve
the stereoselectivity of the aldol reaction a series of trans-
metallating reagents were investigated. The best selectivity was
achieved using trimethyl borate, giving the same two diaster-
eomers but with an improved ratio of 91:9 (Scheme 2), in
accordance with the results from Asao et al. using lithium
(a-methylbenzyl)benzylamide,7 attesting to the structural sim-
ilarity of the intermediate enolates. These were separable by
flash chromatography to give (2S,3S,aR,2AR)-6 as a single
diastereomer in 75% yield.
The carbapenems are an important class of b-lactam antibiotics
with broad-spectrum potency and stability to b-lactamases.
(+)-Thienamycin 1, the first member of the family to be
discovered,1 has been the subject of numerous syntheses, with
the trans stereochemistry of the protons in the b-lactam ring and
the 3-[(R)-1-hydroxyethyl] side chain presenting a considerable
synthetic challenge.2 This key b-lactam framework is also
found in the 1b-methylcarbapenems3 and the tribactams,4
antibiotics of current interest due to their enhanced chemical
and metabolic stabilities.
A concise approach to this b-lactam framework is via a
conjugate addition-aldol condensation strategy. Yamamoto
et al. have used lithium N-benzyltrimethylsilylamide to give a
key b-lactam intermediate as a single diastereomer,5 but with
the wrong absolute stereochemistry, and lithium (a-methyl-
benzyl)benzylamide,6 developed in our laboratories, to give a
b-lactam with the correct absolute stereochemistry but, due to
the requirement of removing the N-benzyl groups by hydro-
genation, without the possibility of incorporating an unsaturated
side chain necessary for further synthetic elaboration.7
The absolute stereochemistry of (2S,3S,aR,2AR)-6 was deter-
mined by treatment with tris(triphenylphosphine)rhodium(i)
chloride in toluene under anhydrous conditions. This gave
cyclisation to a 19:1 mixture of the perhydro-1,3-oxazines,
(2S,4R,5S,6R,aR)-8 and (2R,4R,5S,6R,aR)-9, diastereomeric at
the newly formed C2 aminol centre, in 90% yield (Scheme 3).
The cyclisation presumably occurs by intramolecular trapping
of an intermediate imminium species, in equilibrium with the
enamine generated in the isomerisation of the allyl double bond,
by the 2A-hydroxy group.‡ Analysis of the coupling constants in
1
the 500 MHz H NMR spectrum of the major diastereomer
We have recently developed lithium (aR)-(a-methylben-
zyl)allylamide 3 specifically for the synthesis of homochiral
b-amino acids and b-lactams8 and its application to the
synthesis of carbapenem intermediates has already been
demonstrated.9 In particular, the use of this reagent to generate
b-lactams with unsaturated side chains suggested its application
in the synthesis of the known b-lactam intermediate, (3S,4R)-
3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-vinylazetidin-2-
one 210,11 for the synthesis of thienamycin, via a conjugate
addition–aldol condensation approach (Scheme 1).
Addition of lithium (a-methylbenzyl)allylamide (R)-3 to
(E)-tert-butyl penta-2,4-dienoate 4,† followed by quenching
with aqueous ammonium chloride, gave the b-amino adduct
(3S,aR)-5 in 87% yield with no 1,2- nor 1,6-addition being
Me
Me
i, ii
Ph
N
Ph
N
Li
CO2But
(3S, αR)-5, ds 99:1
iii–vi
Me
Me
Ph
N
Ph
N
H
H
H
H
CO2But
OH
CO2But
OH
+
Me
Me
(2S, 3S, αR, 2′R)-6
(2R, 3S, αR, 2′S)-7
ds 91:9
HO
NH2
Scheme 2 Reagents and conditions: i, CH2NCHCHNCHCO2But 4, ii, aq.
NH4Cl, 87%; iii, LDA, iv, B(OMe)3, v, MeCHO, vi, aq. NH4Cl, 82%
H
H
N
Me
S
Me
Me
Et
Me
Et
O
Me
CO2H
1
i
Ph
N
Ph
N
O
Ph
N
O
(R)-3
+
H
H
Ph
N
Li
CO2But
O H
ButMe2SiO
Me
Me
CO2But
Me
CO2But
H
H
N
CO2But
4
Me
H
O
H
(2S, 3S, αR, 2′R)-6
(2S, 4R, 5S, 6R, αR)-8
(2R, 4R, 5S, 6R, αR)-9
(3S, 4R, 3′R)-2
Me
O
ds 19:1
Scheme 1
Scheme 3 Reagents and conditions: i, (PPh3)3RhCl, 90%
Chem. Commun., 1997
565

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(2S,4R,5S,6R,aR)-8 allowed determination of the two stereo-
centres formed in the aldol reaction (HB-HC, J 10.9 Hz, ax–ax
coupling; HC-HD J 6.2 Hz, ax–eq coupling) and NOE analysis
verified the expected equatorial stereochemistry of the ethyl
group at the aminol centre (HA–HB, 16.4%) (Fig. 1).
two steps. Since the conjugate addition of the lithium amide has
been shown to be highly selective to a wide range of a,b-
unsaturated esters this methodology can be applied to the
synthesis of the key b-lactam frameworks of a variety of
carbapenems.
We thank the EPSRC, FMC Ltd and Oxford Asymmetry Ltd
for support (to D. R. F.) through a CASE award.
Although treatment of this mixture of perhydro-1,3-oxazines
with aqueous hydrochloric acid gave only the desired b-amino
acid (2S,3S,aR,2AR)-10 in 92% yield, verifying that they were
diastereomeric only at C2, it proved more efficient to first
remove the allyl group from the aldol product (2S,3S,aR,2AR)-6
with tetrakis(triphenylphosphine)palladium(0) and N,N-di-
methylbarbituric acid12 to give the deallylated product in 98%
yield. Since the deprotection proceeds via a p-allyl cation there
is no opportunity for cyclisation to a perhydro-1,3-oxazine.
Hydrolysis of the tert-butyl ester with trifluroacetic acid then
gave the b-amino acid (2S,3S,aR,2AR)-10 in 97% yield (Scheme
4). Despite its polar nature and the possibility of a zwitterionic
form the acid was readily extracted into ethyl acetate,
presumably because of its ability to intramolecularly hydrogen
bond.
Treatment of b-amino acid (2S,3S,aR,2AR)-10 with 2,2A-di-
pyridyl disulfide and triphenylphosphine13 gave cyclisation to
the b-lactam (3S,4R,aR,3AR)-11 in 98% yield (Scheme 4).
Protection of the hydroxy group with tert-butyldimethylsilyl
chloride proceeded in 98% yield and was followed by removal
of the N-a-methylbenzyl group using sodium in liquid ammo-
nia14 to give the known intermediate (3S,4R,3AR)-2 in 95%
yield. The specific rotation, [a]2D2 225.9 (c 1.06, CHCl3), of
(3S,4R,3AR)-2, was in excellent agreement with the literature
value, [a]2D5 224.5 (c 1.05, CHCl3), as was the spectroscopic
data.§
Footnotes
† (E)-penta-2,4-dienoic acid was prepared by the Knoevenagel-type
reaction of malonic acid with acrolein in the presence of pyridine, see:
P. J. Jessup, C. B. Petty, J. Roos and L. E. Overman, Org. Synth., 1988, Coll.
Vol. 6, 95. The tert-butyl ester 4 was preapred from the acid using
isobutylene and a catalytic amount of concentrated sulfuric acid. This bulky
ester group prevents 1,2-addition of the lithium amide.
‡ An analagous cyclisation to form acetals has been observed in the
isomerisation of allyl ethers to prop-1-enyl ethers using tris(triphenyl-
phosphine)rhodium(i) chloride, R. Gigg and C. D. Warren, J. Chem. Soc. C,
1968, 1903.
§
(3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-vinylazetidin-
2-one 2 was isolated as a white crystalline solid; mp 62–63 °C; [a]2D1225.9
(c 1.06, CHCl3); (Found: C, 61.24; H, 9.85; N, 5.17. C13H25NO2Si requires
C, 61.13; H, 9.87; N, 5.48%); nmax(CHCl3/cm21 3415m (N–H), 2957m
(C–H), 1762s (CNO); dH (300 MHz; CDCl3) 6.02 (1 H, br s, NH), 5.96 (1
H, ddd, J 17.1, 10.3 and 6.8, CHNCH2), 5.32 (1 H, d, J 17.1, trans CHNCH2),
5.17 (1 H, d, J 10.3, cis CHNCH2), 4.10–4.30 (2 H, m, CHOSi, NCHCH),
2.89 (1 H, dd, J 4.4 and 2.4, NCHCH), 1.22 (3 H, d, J 6.3, CH3CO), 0.88 [9
H, s, (CH3)3CSi], 0.08 [6 H, s, (CH3)2Si]; dC (50 MHz) 169.1 (CNO), 137.8
(CHNCH2), 116.5 (CHNCH2), 65.8, 65.3 (CHOSi, NCH), 52.2 (CHCO),
25.6 [C(CH3)3], 22.2 (CH3CO), 17.8 [C(CH3)3], 24.4, 25.2 [Si(CH3)2];
m/z (CI, NH3) 256 (MH+, 100%). For comparative data see ref. 11. All other
compounds exhibited satisfactory analytical and spectroscopic data.
In summary, the key b-lactam intermediate (3S,4R,3AR)-2 for
the synthesis of thienamycin and its derivatives has been
synthesised in seven steps and 58% overall yield from lithium
(a-methylbenzyl)allylamide (R)-3 and (E)-tert-butyl penta-
2,4-dienoate 4. The highly diastereoselective conjugate addition
of the lithium amide (R)-3 to the unsaturated ester 4, followed
by a selective aldol reaction with acetaldehyde, constructed all
three stereocentres with the correct absolute stereochemistry in
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HA
HB
J / Hz NOE
(%)
Et
Me
CO2But
O
HA-HB
HB-HC 10.9
HC-HD 6.2
–
16.4
2.0
7.0
N
HD
Ph
(2S, 4R, 5S, 6R, αR)-8
Fig. 1
HC
Me
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H
H
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OH
CO2H
OH
Me
Me
H
(2S, 3S, αR, 2′R)-6
(2S, 3S, αR, 2′R)-10
iii
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ButMe2SiO
HO
H
H
N
H
H
N
iv, v
Me
Me
Ph
O
H
O
Me
(3S, 4S, αR, 3′R)-11
(3S, 4R, 3′R)-2
Scheme 4 Reagents and conditions: i, Pd(PPh3)4, NDMBA, 98%, ii, TFA,
97%; iii, (PyS)2–PPh3, 98%; iv, ButMe2SiCl, 98%; v, Na, NH3 (1), 95%
Received, 9th January 1997; Com. 7/00216E
566
Chem. Commun., 1997