A new route to functionalised π-allyltricarbonyliron lactam complexes from aziridines and their use in stereoselective synthesis and oxidative conversion to β-lactams

Article abstract of DOI:10.1039/a806236f

Aziridinyl enones can be converted in good yield into π-allyltricarbonyliron lactam complexes bearing ketone functionality in the side chain; addition of a variety of nucleophiles into the side chains of these complexes proceeds in good yield and excellen

Full text of DOI:10.1039/a806236f

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A new route to functionalised p-allyltricarbonyliron lactam complexes from
aziridines and their use in stereoselective synthesis and oxidative conversion to
b-lactams
Steven V. Ley*† and Ben Middleton
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW
Br
Aziridinyl enones can be converted in good yield into
Bn
R1
R2
i
N
CO2Me
p-allyltricarbonyliron lactam complexes bearing ketone
functionality in the side chain; addition of a variety of
nucleophiles into the side chains of these complexes proceeds
in good yield and excellent ( > 95%) de to afford secondary
and tertiary alcohols which on treatment with trimethyl-
amine N-oxide form the corresponding b-lactams in good
yield.
R3
Br
4a R1 = H, R2 = CH3, R3 = CO2Me
b R1 = CH3, R2 = H, R3 = CO2Me
3
ii, iii
5a R1 = H, R2 = CH3, R3 = CHO
b R1 = CH3, R2 = H, R3 = CHO
p-Allyltricarbonyliron lactam complexes have been previously
investigated as precursors to stereodefined b- and d-lactams,1
and have been utilised in the synthesis of several natural
products in our laboratory.2 Previous preparation of these
complexes involved the treatment of p-allyltricarbonyliron
lactone complexes with a primary amine3 or the sonochemical
reaction of an alkenyl carbamate with Fe2(CO)9.2a In an isolated
example, Aumann has also shown that UV irradiation of the
vinyl aziridine 1 in the presence of Fe(CO)5 leads to the
formation of a p-allyltricarbonyliron lactam complex 2 in 71%
yield (Scheme 1).4
iv
O
Fe(CO)3
R2
Bn
v
O
R1
N
BnN
R1
O
R2
6a R1 = H, R2 = CH3
b R1 = CH3, R2 = H
7a R1 = CH3, R2 = H
b R1 = H, R2 = CH3
Scheme 2 Reagents and conditions: i, BnNH2, benzene, reflux, 16 h, then
chromatographic separation, 35% (4a), 35% (4b); ii, LiAlH4, Et2O, 0 °C,
2 h; iii, (COCl)2, Me2SO, NEt3, CH2Cl2, 270 °C, 3 h, 63% (5a), 56% (5b)
(over 2 steps); iv, (EtO)2P(O)CH2COMe, NaH, THF, 0 °C, 10 min, 91%
(6a), 83% (6b); v, Fe2(CO)9, benzene, sonication, 30 °C, 3 h, 68% (dr 14:1)
(7a), 77% (dr 10:1) (7b)
O
(OC)3Fe
i
NCO2Me
NCO2Me
1
2
being formed (dr 14:1). Similarly, treatment of enone 6b under
the same conditions yielded a 10:1 ratio of 7b and 7a in 77%
yield.
Scheme 1 Reagents and conditions: i, Fe(CO)5, benzene, hn, 71%
We have additionally demonstrated that ketone function-
alised p-allyltricarbonyliron lactone complexes, available from
epoxy enone precursors, are versatile chiral templates for
organic synthesis.5 Here we show that the corresponding
p-allyltricarbonyliron lactam complexes may be prepared from
functionalised alkenyl aziridines by treatment with Fe2(CO)9
under ultrasonication.6 This allows the rapid, large scale
synthesis of p-allyltricarbonyliron lactam complexes bearing
carbonyl functionality in the side chains and facilitates
investigation into the potential of these lactam-tethered
p-allyltricarbonyliron units as chiral templates. We also show
that oxidative decomplexation of the stereodefined alcohols
generated by diastereoselective addition of nucleophiles to
ketone-bearing p-allyltricarbonyliron lactam complexes can be
effected by treatment with trimethylamine N-oxide, providing
an efficient route to highly functionalised b-lactams.
O
O
(R3)–
Fe(CO)3
Fe(CO)3
OH
R3
O
BnN
BnN
R1 R2
R1 R2
11a–13a R1 = CH3, R2 = H
11b–13b R1 = H, R2 = CH3
14 R1 = CH3, R2 = H
7a R1 = CH3, R2 = H
7b R1 = H, R2 = CH3
10 R1 = CH3, R2 = H
Enantiomerically enriched exo complex 10 could be syn-
thesised in five steps from enantiomerically enriched methyl
ester 9 (Scheme 3), accessible via cyclisation of the known
L
-threonine derivative 8.11 Reaction as above afforded exo
Racemic enones 6a,b were synthesised in a four step
sequence from a known common precursor, dibromo ester 37
(Scheme 2). Treatment of 3 with excess BnNH2 in boiling
benzene8 afforded a 1:1 mixture of methyl esters 4a,b which
were separated by flash column chromatography. Reduction
with LiAlH4 and Swern oxidation9 of the crude product yielded
the aldehydes 5a,b. Horner–Wadsworth–Emmons coupling
with diethyl (2-oxopropyl)phosphonate10 afforded 6a,b re-
spectively in good yield. Sonication of 6a in benzene in the
presence of nonacarbonyldiiron afforded the exo-lactam com-
plex 7a in good yield, with only a small proportion of the
chromatographically separable isomeric endo complex 7b
O
Bn
Fe(CO)3
ii, iii, iv, v
i
N
BnNH
O
OH
CO2Me
BnN
MeO2C
H
8
9
10
Scheme 3 Reagents and conditions: i, PPh3, CCl4, MeCN, 25 °C, 16 h, 83%;
ii, LiAlH4, Et2O, 0 °C, 2 h; iii, (COCl)2, Me2SO, NEt3, CH2Cl2, 270 °C,
3 h, 59% (over 2 steps); iv, (EtO)2P(O)CH2COMe, NaH, THF, 0 °C, 10 min,
83%; v, Fe2(CO)9, benzene, sonication, 30 °C, 3 h, 68% (dr 18:1)
Chem. Commun., 1998
1995

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O
O
Table 2 Decomplexation of functionalised p-allyltricarbonyliron lactam
complexes to b-lactams
Fe(CO)3
H
Fe(CO)3
H
0%
Starting material
R1
R2
R3
Product
Yield (%)a
O
CH3
BnN
H
BnN
H
11a
11b
12a
12b
13a
13b
Me
H
Me
H
Me
H
H
Me
H
Me
H
Me
H
H
Et
Et
allyl
allyl
15a
15b
16a
16b
17a
17b
63
65
61
65
54
69
X
H
CH3
H
O
2.7%
4.6%
Figure 1 Selected NOE enhancements of complex 7b
a Isolated yield after treatment with excess Me3NO in THF at 0 °C for 2 h,
followed by chromatography on Florisil.
Table 1 Reaction of nucleophiles with p-allyltricarbonyliron lactam
complexes bearing methyl ketone functionality in the side chain
Starting
material Conditions
Yield
(%)b
has given markedly lower yields of b-lactams with this type of
substrate.15
R3
H
Producta
11a
In summary, a convenient route to racemic and homochiral
p-allyltricarbonyliron lactam complexes bearing ketone func-
tionality in the side chain has been developed. It has been shown
that the tethered tricarbonyliron moiety is able to direct
nucleophilic attack on an appended methyl ketone group,
affording complexes bearing secondary and tertiary alcohol
functionality in good yield and with excellent diastereoselectiv-
ity. A novel oxidative decomplexation method allows the
generation of highly functionalised b-lactams bearing ster-
eodefined secondary and tertiary alcohol centres. These results
should extend further the utility of p-allyltricarbonyliron
complexes for natural product synthesis.
7a
NaBH4, MeOH–CH2Cl2,
77
65
76
270 °C
7b
10c
NaBH4, MeOH–CH2Cl2,
270 °C
H
11b
NaBH4, MeOH–CH2Cl2,
270 °C
H
14d
7a
7b
7a
7b
7a
AlBui3, CH2Cl2, 0 °C
AlBui3, CH2Cl2, 0 °C
AlEt3, CH2Cl2, 0 °C
AlEt3, CH2Cl2, 0 °C
H
H
Et
Et
11a
11b
12a (11a)
12b (11b)
13a
77
70
52 (26)
62 (32)
86
Allyltributyltin, BF3·OEt2, allyl
CH2Cl2, 0 °C
Allyltributyltin, BF3·OEt2, allyl
CH2Cl2, 0 °C
7b
13b
89
We gratefully acknowledge financial support from the
EPSRC, the Isaac Newton Trust and Zeneca Pharmaceuticals
(to B. M.) and the BP Endowment and the Novartis Research
Fellowship (to S. V. L.).
a De determined by 600 MHz 1H NMR, determined to be > 95%. b Figures
in parentheses refer to isolated yield of reduction side product. c Ee > 95%
[determined by 200 MHz 1H NMR analysis in the presence of Pr(hfc)3].
d
Ee
>
95% [determined by 600 MHz 1H NMR analysis of the
corresponding (S)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl ester].
Notes and References
† E-mail: svl1000@cus.cam.ac.uk
1
complex 10 in > 95% ee [determined by 200 MHz H NMR
spectroscopy in the presence of the chiral shift reagent
1 For a general review on the synthetic utility of p-allyltricarbonyliron
lactone complexes see: S. V. Ley, L. R. Cox and G. Meek, Chem. Rev.,
1996, 96, 423 and references cited therein.
(+)-Pr(hfc)3].12
In order that the addition of nucleophiles to the ketone group
in the sidechain proceeds with high diastereocontrol, it is
necessary that the tricarbonyliron group blocks one face of the
carbonyl group, thus forcing approach of the nucleophile to
occur from the opposite side, and that the ketone adopts only
one reactive conformation. The solution conformation of
complex 7b was investigated by the use of NOE experiments.
These results clearly show that the s-cis conformation is
adopted preferentially (Fig. 1). These results are consistent with
earlier studies carried out on p-allyltricarbonyliron lactone
complexes.5a Reaction of complexes 7a,b with a variety of
nucleophiles (Table 1) afforded the addition products 11a–13a
and 11b–13b in good yield and excellent diastereoselectivity
(de > 95%).13 Reduction of enantiomerically enriched 10 with
NaBH4 to form alcohol 14 proceeded in 76% yield without loss
of enantiopurity, as determined by 600 MHz 1H NMR analysis
2 (a) S. V. Ley and J. G. Knight, Tetrahedron Lett., 1991, 7119; (b) S. V.
Ley, S. T. Hodgson and D. M. Hollinshead, Tetrahedron, 1985, 5871;
(c) S. V. Ley, S. T. Hodgson, D. M. Hollinshead, C. M. R. Low and
D. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1985, 2375.
3 S. V. Ley, G. D. Annis, E. M. Hebblethwaite, S. T. Hodgson and D. M.
Hollinshead, J. Chem. Soc., Perkin Trans. 1, 1983, 2851.
4 R. Aumann, K. Fröhlich and H. Ring, Angew. Chem., Int. Ed. Engl.,
1974, 13, 275.
5 (a) S. V. Ley, L. R. Cox, G. Meek, K.-H. Metten, C. Piqué and J. M.
Worral, J. Chem. Soc., Perkin Trans. 1, 1997, 3299; (b) S. V. Ley and
L. R. Cox, J. Chem. Soc., Perkin Trans. 1, 1997, 3315; (c) S. V. Ley and
L. R. Cox, Chem. Commun., 1998, 227
6 S. V. Ley, A. M. Horton and D. M. Hollinshead, Tetrahedron, 1984,
1737.
7 T. Hudlicky, L. Radesca and H. L. Rigby, J. Org. Chem., 1987, 52,
4397.
8 M. Prostetnik, N. P. Salzman and H. E. Carter, J. Am. Chem. Soc., 1955,
77, 1856.
9 D. Swern and K. Omura, Tetrahedron, 1978, 1651.
10 W. S. Wadsworth Jr., Org. React., 1977, 25, 73.
11 H. Rapoport, K. J. Shaw and J. R. Luly, J. Org. Chem., 1985, 50,
4521.
of
the
ester
formed
with
(S)-(+)-a-methoxy-
a-(trifluoromethyl)phenylacetyl chloride.14
Furthermore, it was discovered that treatment of complexes
11–13 with excess Me3NO in THF at room temperature affords
the functionalised b-lactams 15–17 in good yield (Table 2). This
result is an improvement over the published method of
oxidative decomplexation with ceric ammonium nitrate3 which
12 D. Parker, Chem. Rev. 1991, 91, 1441.
13 Only one diastereoisomeric product could be observed via 600 MHz 1H
NMR analysis, thus the quoted 95% de is a conservative estimate of
selectivity.
O
O
14 H. S. Mosher and J. A. Dale, J. Am. Chem. Soc., 1973, 95, 512.
15 Treatment of a solution of complex 11a in MeCN with CAN (6.5 equiv.)
at 220 °C in the dark for 2 h afforded b-lactam 15a in 31% isolated
yield after chromatography on Florisil.
H
Fe(CO)3
Me3NO
OH
R3
OH
R3
BnN
R1
BnN
R1
THF, 0 °C, 2 h
R2
R2
11–13
15–17
Received in Liverpool, UK, 8th July 1998; 8/06236F
1996
Chem. Commun., 1998