Stereoselective conjugate addition reactions of lithium amides to α,β-unsaturated chiral iron acyl complexes [(η5-C 5H5)Fe(CO)(PPh3)(COCH=CHR)]

Journal of Organometallic Chemistry 689 (2004) 4184–4209

www.elsevier.com/locate/jorganchem

Stereoselective conjugate addition reactions of lithium amides to

a,b-unsaturated chiral iron acyl complexes

[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHR)]

*

Stephen G. Davies , Jairton Dupont, Robert J. C. Easton, Osamu Ichihara,

´

Jeﬀrey M. McKenna, Andrew D. Smith, Jose A. A. de Sousa

Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory, Mansﬁeld Road, Oxford, OX1 3TA, UK

Received 26 March 2004; accepted 26 April 2004

Available online 15 July 2004

Abstract

Conjugate addition of achiral lithium dimethylamide to the chiral iron cinnamoyl complexes (S,E)- and (S,Z)-[(g⁵-C₅H₅)Fe-

(CO)(PPh₃)(COCH@CHPh)] proceeds with high diastereoselectivity, with this protocol being used to establish unambiguously

the absolute conﬁguration of Wintersteinꢀs acid (3-N,N-dimethylamino-3-phenylpropanoic acid) as (R). The highly diastereoselec-

tive conjugate addition of lithium N-benzyl-N-trimethylsilylamide to a range of a,b-unsaturated iron acyl complexes, followed by in-

situ elaboration of the derived enolate by either alkylation or aldol reactions is also demonstrated, facilitating the stereoselective

synthesis of both cis- and trans-b-lactams. This methodology has been used to eﬀect the formal asymmetric syntheses of ( )-olivanic

acid and ( )-thienamycin. Addition of chiral lithium amides derived from primary and secondary amines to the iron crotonyl com-

plex [(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] indicates that lithium N-a-methylbenzylamide shows low levels of enantiorecogni-

tion, while lithium N-3,4-dimethoxybenzyl-N-a-methylbenzylamide and lithium N-benzyl-N-a-methylbenzylamide show high levels

of enantiodiscrimination. The high level of observed enantiorecognition was used to facilitate a kinetic resolution of (RS)-[(g⁵-

C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] with homochiral lithium (R)-N-3,4-dimethoxybenzyl-N-a-methylbenzylamide. Further

mechanistic studies show that conjugate additions of (RS)-lithium N-benzyl-N-a-methylbenzylamide to either the (RS)- or

homochiral iron crotonyl complex show 2:1 stoicheiometry, while homochiral lithium N-benzyl-N-a-methylbenzylamide shows

1:1 stoicheiometry.

Keywords: Enantiorecognition; Conjugate addition; Iron acyl auxiliary

1. Introduction

C₅H₅)Fe(CO)(PPh₃)] for a range of transformations in-

cluding alkylations, aldol reactions, conjugate addition

reactions and Diels–Alder reactions [1]. The high levels

of control observed using this auxiliary indicate that it is

able to control eﬀectively both the three dimensional

space around attached alkyl and acyl ligands and the ori-

entation of these ligands within that space. Structural and

conformational analyses of [(g⁵-C₅H₅)Fe(CO)(PPh₃)R]

complexes derived from complexation of an organic frag-

ment (R ¼ acyl, alkyl) to the iron auxiliary [(g⁵-C₅H₅)Fe

(CO)(PPh₃)] indicate that they adopt a geometry close

The iron chiral auxiliary [(g⁵-C₅H₅)Fe(CO)(PPh₃)] has

been used extensively within organic synthesis for the

asymmetric synthesis of a variety of organic molecules.

Remarkable levels of stereocontrol are observed upon re-

action of alkyl and acyl ligands attached to [(g⁵-

*

Corresponding author. Tel.: +44-1865-275695; fax: +44-1865-

275633.

E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).

doi:10.1016/j.jorganchem.2004.04.046

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4185

O

C

to octahedral [2], in which the triphenylphosphine, car-

O

C

Ph₂

P

Ph₂

P

bon monoxide and the organic ligand R occupy three ad-

jacent sites of the pseudo-octahedral structure, with each

lying approximately orthogonal to the plane formed by

the other two and the metal. The remaining three co-ordi-

nation sites on iron are occupied by the cyclopentadienyl

ligand. The iron acetyl complex [(g⁵-C₅H₅)Fe(CO)

(PPh₃)COCH₃] (1) is chiral, and adopts a conformation

that places the acetyl oxygen anti to the carbon monoxide

ligand, with one of the triphenylphosphine phenyl groups

approximately parallel to the plane of the acetyl ligand,

shielding one face of the acetyl (Fig. 1) [3,4].

(i). n-BuLi

(ii). MeI

Fe

O

2

1

n-BuLi

O

C

R

Ph₂

C

Ph₂

RX

P

Fe

O

OLi

Iron acetyl complex 1 is readily deprotonated upon

treatment with n-BuLi, and treatment of the derived en-

olate with MeI generates the corresponding propanoyl

complex 2 in essentially quantitative yield [5]. Further

deprotonation to generate the corresponding lithium en-

olate 3, and alkylation with alkyl halides generates iron

complexes 4 with high levels of diastereoselectivity (typ-

ically >96% d.e.) [6]. The high diastereoselectivity ob-

served in these transformations may be rationalised by

deprotonation of the acyl ligand being completely stere-

oselective for formation of the (E)-enolate (iron trans to

R), with alkylation occuring only from the unhindered

face (away from the triphenylphosphine) in the confor-

mation with the enolate oxygen anti to the carbon mon-

oxide ligand (Fig. 2) [7].

4, >96% d.e.

3

Fig. 2. Diastereoselective alkylation of complexes derived from the

iron acyl auxiliary.

complementary control at the b-centre may be achieved

via the corresponding copper enolate [12], demonstrat-

ing that the iron auxiliary acyls may be considered as

convenient chiral acetate and propionate enolate equiv-

alents (Fig. 3).

The high stereoselectivity observed upon reaction of

acetyl complex 1 with electrophiles has been used to dis-

criminate between the two enantiomers of racemic sub-

strates. For instance, treatment of the lithium enolate

derived from (RS)-1 with (RS)-tert-butyl 2-bromopropi-

Additions of aldehydes to the lithium enolates de-

rived from both the acetyl and propanoyl complexes 1

and 2 generate the corresponding b-hydroxy acyl com-

plexes with essentially no stereocontrol [8]. However,

transmetallation to an aluminium enolate prior to addi-

tion of the aldehyde leads to excellent stereocontrol

[9,10]. In the acetyl series, complementary stereoselectiv-

ity has been observed by Liebeskind for the correspond-

ing tin enolate [11], while in the propionyl series

O

C

O

C

PPh₃

O

PPh₃

(i) n-BuLi

R

Fe

(ii) Et₂AlCl

(iii) RCHO

O

OH

1

(i) n-BuLi

(ii) SnCl₂

(iii) RCHO

O

C

PPh₃

O

R

Fe

OH

125Þ

CO

90Þ

Fe

R

O

C

O

C

O

PPh₃

O

PPh₃

(i) n-BuLi

R

90Þ

Fe

Ph₂P

(ii) Et₂AlCl

(iii) RCHO

PPh₃

O

OH

Pseudo-octahedral

2

[(η⁵-C₅H₅)Fe(CO)(PPh₃)COMe]

[(η⁵-C₅H₅)Fe(CO)(PPh₃)R]

(i) n-BuLi

(ii) CuCN

(iii) RCHO

O

C

Ph₂

P

Ph₂

P

Fe

O

C

PPh₃

O

R

Fe

(R)-1

(S)-1

OH

Chiral iron acetyl [(η⁵-C₅H₅)Fe(CO)(PPh₃)COMe]

Fig. 1. Chiral acetyl [(g⁵-C₅H₅)Fe(CO)(PPh₃)(COMe)].

Fig. 3. Stereoselective aldol reactions of the iron acetyl and propanoyl

complexes 1 and 2.

4186

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

onate gave a 97.5:2.5 mixture of the b-methyl succinoyl

complexes (RS,SR)-5 and (RR,SS)-6, consistent with

one enantiomer of the enolate preferring to react forty

times faster with one of the enantiomers of the a-bromo-

ester than with the other [13]. Similarly, treatment of the

lithium enolate of (S)-1 with (RS)-propylene oxide in the

presence of diethyl aluminium chloride leads to the se-

lective formation of (S,R)-c-hydroxyacyl complex 7,

which upon oxidative decomplexation produces homo-

chiral (R)-4-methylbutyrolactone 8 (Fig. 4) [14].

Conjugate addition reactions to readily available (E)-

a,b-unsaturated iron acyl complexes 9 have also been

explored, with addition of a range of alkyllithium re-

agents proceeding with high stereoselectivity. The con-

ﬁguration of the newly formed b-stereogenic centre in

these reactions is consistent with the nucleophile adding

to the a,b-unsaturated acyl ligand in its cisoid confor-

mation from the unhindered face to give 10 [15].

Furthermore, addition of alkyllithiums to the (E)-a,b-

unsaturated acyl complexes and subsequent trapping

of the intermediate with alkyl halides results in the

highly stereoselective formation of two new stereogenic

centres, giving 11 in high d.e. (Fig. 5) [16].

Fig. 5. Conjugate addition of alkyllithium reagents to (E)-a,b-unsat-

urated iron acyls.

instance, conjugate addition of lithium benzylamide to

the (S)-iron crotonyl complex 12 aﬀords the (S,3S)-b-

amino complex-13 in 90% yield as a single diastereoiso-

mer, which upon oxidative decomplexation with

bromine aﬀords homochiral (S)-4-methyl-N-benzylazeti-

din-2-one 14. Furthermore, conjugate addition of

lithium benzylamide to 12 and tandem methylation gives

(S,2R,3S)-b-amino-a-methyl complex-15 in 91% yield

as a single diastereoisomer, with oxidative decomplex-

ation yielding the cis-b-lactam (3R,4S)-16 (Scheme 1)

[16–18].

In an extension of this methodology, we have demon-

strated previously that the iron crotonyl complex 12

undergoes highly diastereoselective conjugate additions

of lithium amides derived from primary amines. For

O

C

PPh₃

O

Fe

O

C

(RS)-1

(ii). Me

Ph₃P

Me

(i)

Me

Fe

t

CO₂Bu

(i). n-BuLi

90%, Ph

>98% d.e.

NH

O

Br

(S,3S)-13

(S)-12

O

C

O

C

PPh₃

O

PPh₃

O

t

CO₂Bu

+

91%

68%

Me

NBn

(S)-14

Fe

(ii)

Fe

(i, iii)

>98% d.e.

Me

O

C

Me

Ph₃P

(RS,SR) -5

(RR,SS) -6

97.5:2.5

Me

Fe

O

C

OH

O

C

Ph

NH

O

(i) n-BuLi

Ph₃P

Fe

(S,2R,3S)-15

Fe

O

(ii)

O

69%

Me

(ii)

(S,R)-7

(S)-1

(iii) Et₂AlCl

Me

O

Br₂

NBn

Me

O

(3R,4S)-16

Scheme 1. Reagents and conditions: (i) BnNHLi (1.2 eq), THF, ꢀ78

ꢁC; (ii) Br₂(2 eq), DCM, ꢀ78 ꢁC then NEt₃, ꢀ78 ꢁC to rt; (iii) MeI (4

eq), THF, ꢀ78 ꢁC to rt.

(R)-8

Fig. 4. Enantiodiscrimination reactions using the iron chiral auxiliary.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4187

O

C

As an extension of this methodology, we report here-

O

C

in our full investigations concerning the conjugate

additions of chiral and achiral lithium amides derived

from a range of primary and secondary amines to chiral

a,b-unsaturated iron acyl complexes [(g⁵-C₅H₅)Fe-

(CO)(PPh₃)(COC@CHR)], and the stereoselective in-

situ elaboration of the derived b-amino enolates. Parts

of this work have been communicated previously

[19,20].

Ph₃P

O

Ph₃P

O

(i)

Ph

Fe

82%

94% d.e.

NMe₂

(S,3R)-19

(S,E)-17

O

C

Ph₃P

O

(i)

Ph₃P

Fe

88%

97% d.e.

Ph

O

NMe₂

(S,Z)-18

2. Results and discussion

(S,3S)-20

Scheme 2. Reagents and conditions: (i) LiNMe₂, THF, ꢀ100 ꢁC.

2.1. Conjugate addition of achiral secondary lithium

amides: asymmetric synthesis of Winterstein’s acid

to their ethyl ester derivatives 21 and subsequently char-

acterized as their hydrochloride salts in 82% and 66%

yields, respectively. The e.e. of the hydrochloride salts

of (S)-21 and (R)-21 was shown to be >98% and 97%,

Wintersteinꢀs acid (3-N,N-dimethylamino-3-phenyl-

propanoic acid) has been identiﬁed as the carboxylate

side chain of the diterpene taxine B [21], and although

synthetic homochiral Wintersteinꢀs acid has been pre-

pared by resolution [22], its absolute conﬁguration is

yet to be established unambiguously. Having demon-

strated previously that high levels of asymmetric induc-

tion are observed upon conjugate addition of lithium

benzylamide to (S,E)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COC@

CHMe)] [16,17], the conjugate addition of a sec-

ondary lithium amide was investigated to probe the

generality of this procedure. Lithium dimethylamide

was chosen as the nucleophile of choice, as it was pro-

posed that stereoselectivity in this procedure would

facilitate the preparation, and allow unambiguous

assignment, of the absolute conﬁguration of Winter-

steinꢀs acid. Conjugate addition of lithium dimethyla-

mide to the diastereoisomeric iron acyl complexes

(S,E)- and (S,Z)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@

CHPh)] [23] 17 and 18 respectively at ꢀ100 ꢁC pro-

ceeded to complete conversion in each case, giving the

diastereoisomeric (S,R)- and (S,S)-b-N,N-dimethylami-

no iron complexes 19 and 20 in 82% and 88% isolated

yields and 94% and 97% d.e. respectively. In each case,

fractional crystallisation gave (S,3R)-19 and (S,3S)-20

in >97% d.e., with the conﬁguration of the b-centres

within (S,3R)-19 and (S,3S)-20 assigned relative to the

iron centre by analogy with the known sense of asym-

metric induction upon conjugate addition of lithium

dibenzylamide to the (E)-crotonoyl complex [17], and

1

respectively, by H NMR spectroscopic analysis in the

presence of (ꢀ)-2,2,2-triﬂuoro-1-(9-anthryl)ethanol and

comparison with an authentic racemic sample. These

salts were subsequently used to regenerate pure (S)-

and (R)-ethyl 3-dimethylamino-3-phenyl-propanoate

21, with measurement of the speciﬁc rotation of 21

20

{for (S)-21; [a]_D+13.9 (c 0.5, CHCl₃), [a]₄₃₆+31.5

20

(c 0.5, CHCl₃); for (R)-21; [a]₄₃₆ꢀ31.1 (c 0.5, CHCl₃)}

and comparison with the ethyl ester derived from Win-

18

20

tersteinꢀs acid {[a]_Dꢀ15.5 (neat);²²[a]_Dꢀ9.58 (c

9.0, CHCl₃)²²} unambiguously establishing the absolute

conﬁguration of Wintersteinꢀs acid as (R) (Scheme 3).

To probe further the utility of these transformations,

the tandem conjugate addition and alkylation of iron

complex (S,Z)-18 was investigated, with conjugate addi-

tion of lithium dimethylamide and alkylation of the re-

sultant enolate with MeI giving (S,2R,3S)-22 in >98%

d.e. after chromatographic puriﬁcation and recrystalli-

sation in 65% yield. The conﬁguration at C(2) within

O

C

Ph₃P

Ph

(i, ii)

66%

Ph

Fe

CO₂Et

O

NMe₂

1

(S,3R)-19

by the characteristic H NMR chemical shifts of the a-

(R)-21

protons [24]. The observed stereocontrol in these reac-

tions is consistent with a mechanism involving lithium

co-ordination to the acyl oxygen and subsequent deliv-

ery of the dimethylamide to the unhindered face of the

cinnamoyl ligand in the s-cis conformation (Scheme 2).

Oxidative decomplexation of 19 and 20 with NBS

gave, after ﬁltration through alumina and ion exchange

chromatography, the corresponding enantiomeric N,N-

dimethyl b-amino acids, which were converted directly

O

C

Ph₃P

(i, ii)

82%

Ph

Fe

CO₂Et

O

NMe₂

(S,3S)-20

(S)-21

Scheme 3. Reagents and conditions: (i) NBS, HCl, H₂O, ꢀ78 ꢁC to rt

then Dowex ion exchange chromatography; (ii) HCl, EtOH, Á.

4188

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

H

22 relative to the iron centre was assumed by analogy

with the known sense of asymmetric induction upon al-

kylation of the enolates of iron acyl complexes. Subse-

quent oxidative decomplexation with NBS and

conversion to the corresponding ethyl ester gave

(2R,3S)-23 in 82% yield and >98% d.e., which was con-

verted to its hydrochloride salt for analysis (Scheme 4).

Me

OH

N

Tandem Conjugate

Addition Aldol

CO

Fe

CO

Fe

PPh₃

O

R

O

R₁

R₂

N-Deprotection

and

decomplexation

OH

H

N

Me

2.2. Tandem conjugate addition-aldol reactions of achiral

secondary lithium amides: a formal synthesis of ( )-

olivanic acid and ( )-thienamycin

SCH₂CH₂NHAc

O

OH

O

CO₂H

H

R

olivanic acid MM22380

Me

Having demonstrated the asymmetric synthesis of

Wintersteinꢀs acid, extension of this conjugate addition

methodology to the tandem conjugate addition-aldol

manifold was investigated, as this protocol could be

used for the stereoselective preparation of b-lactam de-

rivatives with a hydroxyethyl side chain via an aldol re-

action with acetaldehyde. Such structural frameworks

have been synthesised previously for the stereoselective

synthesis of carbapenem antibiotics such as thienamycin

and olivanic acid (Fig. 6).

NH

OH

H

N

Me

SCH₂CH₂NH₂

O

CO₂H

(+)-Thienamycin

Fig. 6. Retrosynthetic analysis of olivanic acid and thienamycin.

upon conjugate addition of the lithium amide and the a-

centre upon aldol reaction with acetaldehyde, with the

mixture of diastereoisomers having diﬀerent relative

conﬁgurations at the alcohol stereocentre. The relative

conﬁguration within diastereoisomer 26 was assigned

by decomplexation with bromine at ꢀ78 ꢁC, generating

cis-b-lactam 28 in 70% yield, as indicated by the cou-

pling constant between C(3)H and C(4)H (J5.3 Hz)

[25]. Subsequent transformation of the hydroxy-b-lac-

tam to the ethylidene-b-lactam 29 via the mesylate gave

(Z)-29 exclusively in 65% isolated yield [26], with nOe

diﬀerence studies conﬁrming the (Z)-oleﬁn geometry,

consistent with the conﬁguration within syn-aldol 26.

The observed relative conﬁguration within 26 is consis-

tent with conjugate addition of LSA to the least hin-

dered face of the a,b-unsaturated acyl complex in the

anti-s-cis conformation, with subsequent approach of

acetaldehyde to the resultant (E)-enolate in the anti con-

formation, again from the unhindered face. The conﬁg-

uration within N-bis-(3,4-dimethoxybenzyl)-24 was

assigned by analogy to that of 26 (Scheme 5).

The (RS)-crotonoyl iron complex 12 was chosen for

initial studies, with conjugate addition of lithium bis-

(3,4-dimethoxybenzyl)amide followed by addition of

acetaldehyde generating an 89:11 mixture of two diaste-

reoisomers 24:25 in 78% yield, with recrystallisation of

this diastereoisomeric mixture yielding 24 as a single dia-

stereoisomer. Similarly, conjugate addition of lithium N-

benzyl-N-trimethylsilylamide (LSA) to (RS)-12 followed

by in situ reaction with acetaldehyde gave an 83:17 mix-

ture of diastereoisomers 26:27 in 81% yield, with recrys-

tallisation giving 26 as a single diastereoisomer. The

observation of only two diastereoisomers in these reac-

tions from a possible eight is consistent with the iron

auxiliary controlling both the formation of the b-centre

O

C

Me

Ph₃P

C

Ph₃P

O

(i)

Ph

Fe

65%,

>98% d.e.

Ph

O

NMe₂

With the ability of the iron auxiliary to impart high

levels of stereocontrol in the conjugate addition-aldol

manifold for the preparation of cis-b-lactams demon-

strated, the application of this strategy to natural prod-

uct synthesis was investigated. Kametani et al. [27] have

previously utilised cis-b-lactam 30 in the preparation of

( )-olivanic acid MM22380, and this product was iden-

tiﬁed as a viable target to demonstrate the synthetic util-

ity of the conjugate addition/aldol approach using the

chiral iron auxiliary. This approach necessitated the

stereoselective synthesis of d-functionalised-a,b-unsatu-

rated acyl complex 31, with conjugate addition-aldol re-

action utilised to create the required cis-b-lactam

skeleton (Fig. 7).

(S,Z)-18

(S,2R,3S)-22

(ii)

82%

Me

(iii)

Ph

CO₂Et

NMe_2.HCl

CO₂Et

NMe₂

(2R,3S)-23

Scheme 4. Reagents and conditions: (i) LiNMe₂, THF, ꢀ100 ꢁC then

MeI, ꢀ100 ꢁC to rt; (ii) NBS, HCl, H₂O, ꢀ78 ꢁC to rt then Dowex ion

exchange chromatography; (iii) HCl, EtOH, D.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4189

H

OH

O

Me

OH

N

Me

OH

N

H

N

H

OMe

CO

Fe

CO

Fe

Me

PPh₃

+

S(CH₂)₂NHAc

CO₂H

Me

R₂

Me

R₂

NH

H

O

R₁

Kametani Intermediate 30

( )-olivanic acid MM22380

24

25

Decomplexation

and

R₁=R₂=3,4-dimethoxybenzyl

deprotection

24:25 89:11

Conjugate

(i, ii)

H

78%

Addition

Aldol

Me

OH

CO

Fe

PPh₃

Me

PPh₃

OMe

Fe

O

12

O

HN

OMe

26:27 83:17

(RS)-31

(iii, ii)

81%

Ph

Fig. 7. Proposed formal synthesis of ( )-olivanic acid.

H

Me

OH

Me

NHBn

Me

OH

Me

CO

Fe

CO

Fe

PPh₃

O

+

PPh₃

CO

H

PPh₃

O

NHBn

(i, ii)

Fe

Me

SePh

Me

SePh

CO

Fe

CO

Fe

26

(iv) 70%

27

PPh₃

O

PPh₃

O

+

Me

32:33

2

(i, iii)

CO

(i, ii) 32:33 66:34, 45%

(i, iii) 32:33 9:91, 91%

PPh₃

OH

H

Fe

SePh

H

N

Me

Bn

Me

(v)

65%

O

Me

N

(iv)

75%

34

O

Bn

O

29

28

CO

PPh₃

Scheme 5. Reagents and conditions: (i) Lithium bis-(3,4-dimethoxyb-

enzyl)amide, THF, ꢀ78 ꢁC; (ii) MeCHO, THF, ꢀ78 ꢁC to rt; (iii)

Lithium N-benzyl-N-trimethylsilylamide, THF, ꢀ78 ꢁC; (iv) Br₂,

DCM, ꢀ78 ꢁC then NEt₃, ꢀ78 ꢁC to rt; (v) MsCl, NEt₃, 0 ꢁC then

NaHCO₃, D.

Fe

O

35

Scheme 6. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC, 2h; (ii)

(SePh)₂, THF, ꢀ78 ꢁC, 1 h then MeOH, ꢀ78 ꢁC to rt; (iii) MeI, THF,

ꢀ78 ꢁC to rt; (iv) mCPBA, DCM, ꢀ78 ꢁC 1 h then (iPr)₂NH, ꢀ78 ꢁC

to rt.

Although routes to functionalised a,b-unsaturated

acyl complexes have been reported previously via Peter-

son oleﬁnation or aldol-methylation-elimination [23], an

alternative tactic, via selenoxide syn-elimination, was in-

vestigated [28]. In a model system, selenenylation was

achieved following deprotonation of the propanoyl

complex 2 and addition of diphenyl diselenide, giving

the desired complex as a 66:34 mixture of diastereoiso-

mers 32:33 and in low isolated yield (45%), with ¹H

NMR spectroscopic analysis allowing assignment of

the relative conﬁguration of the two diastereoisomers.

Methylation of the selenyl complex 34 proved more suc-

cessful, giving 32:33 in an 9:91 ratio and in 91% isolated

yield. Elimination of the 9:91 mixture of selenides 32:33

through oxidation with mCPBA yielded the known iron

acryloyl complex 35 in 75% yield (Scheme 6).

to alkylation with activated electrophiles, with alkyl-

ation with allyl iodide giving a 86:14 mixture of diaste-

reoisomers

36:37

in

72%

yield.

However,

selenenylation of 38 gave a 75:25 mixture of diastereoi-

somers 39:40 in 69% yield, with subsequent syn-elimina-

tion of the diastereoisomeric mixtures 36:37 and 39:40

furnishing a,b-unsaturated complexes 41 and 31 respec-

tively in high yields (Scheme 7).

With (RS)-acceptor 31 in hand, its ability to direct the

course of asymmetric conjugate addition reactions was

assessed via reaction with lithium benzylamide, giving

b-amino iron acyl complex (RS,3RS)-42 in >96% d.e.

and in 82% yield. Furthermore, conjugate addition of

lithium benzylamide and subsequent alkylation with

MeI gave (RS,2SR,3RS)-43 in >96% d.e., and in 76% iso-

lated yield as a single diastereoisomer after puriﬁcation,

This methodology was then applied to the synthesis

of the desired d-functionalised-a,b-unsaturated acyl

complex 31. Unfortunately, the inherent reactivity of

the enolate derived from selenide 34 limited its utility

4190

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

CO

Fe

CO

Fe

isomers 45:46, but as a 1:1 mixture of diastereoisomers.

Separation via chromatographic puriﬁcation gave the

homogenous b-amino complexes 45 and 46 in 35% and

37% isolated yield respectively. In order to conﬁrm the

relative conﬁguration within each diastereoisomer, de-

complexation and N-debenzylation was undertaken.

Treatment of 45 and 46 with bromine gave cis-b-lactams

47 and 48 in 50% and 44% yield respectively, with sub-

sequent removal of the N-benzyl protecting groups

achieved by dissolving metal reduction, giving 49 and

50 in 85% and 66% yield respectively. ¹H NMR spectro-

scopic analysis conﬁrmed that b-lactam 50 had spectro-

scopic properties consistent with those described by

Kametani et al. [27] in the preparation of ( )-olivanic

acid MM22380, conﬁrming the relative conﬁguration

within complexes 45 and 46, and achieving the desired

formal synthesis (Scheme 9).

PPh₃

O

PPh₃

OMe

SePh

O

38

34

(i, ii)

69%

(i, iii)

72%

SePh

CO

PPh₃

O

PPh₃

OMe

Fe

O

(RS,SR):(RS,RS) 39:40 75:25

(RS,SR):(RS,RS) 36:37 86:14

(iv)

83%

(iv) 66%

CO

Fe

CO

PPh₃

O

PPh₃

OMe

Fe

O

The further application of this methodology for the

diastereoselective synthesis of trans-b-lactams was next

investigated. Lithium amide conjugate addition to a

(Z)-a,b-unsaturated iron acyl complex and subsequent

aldol reaction was proposed to lead, after decomplex-

41

31

Scheme 7. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC, 2h; (ii)

(SePh)₂, THF, ꢀ78 ꢁC, 1 h then MeOH, ꢀ78 ꢁC to rt; (iii) allyl iodide,

THF, ꢀ78 ꢁC to rt; (iv) mCPBA, DCM, ꢀ78 ꢁC 1 h then (iPr)₂NH,

ꢀ78 ꢁC to rt.

with decomplexation giving cis-b-lactam 44 in 75%

yield. The conﬁguration at C(3) within 42 and 43 upon

conjugate addition relative to the iron centre was as-

signed upon the basis of addition to the least hindered

face of the a,b-unsaturated acyl complex in the anti-

s-cis conformation, while that at C(2) within 43 was as-

sumed by analogy with the known sense of asymmetric

induction upon alkylation of the enolates of the iron

acyl complex (Scheme 8).

Having shown that conjugate addition and alkylation

reactions of iron acyl complex 31 proceed stereoselec-

tively, the conjugate addition of LSA to 31 and tandem

aldol reaction with acetaldehyde was investigated, giving

high conversion to the desired b-amino aldol diastereo-

CO

PPh₃

OMe

Fe

O

OMe

(RS)-31

(i, ii)

45:46 50:50

H

Me

OH

Me

OH

CO

Fe

CO

Fe

PPh₃

O

OMe

O

HN

Bn

45, 35%

(iii)

50%

OH

46, 37%

(iii)

44%

OH

CO

Fe

CO

Fe

PPh₃

O

PPh₃

O

OMe

(i)

H

OMe

Me

OMe

82%,

HN

>96% d.e.

N

(RS)-31

(RS,3RS)-42

Ph

O

Bn

O

Bn

47

48

76%,

>96% d.e.

(i, ii)

(iv) 85%

(iv) 66%

Me

CO

OH

H

N

PPh₃

O

OMe

(iii)

Me

OMe

H

Fe

OMe

Me

HN

OMe

75%

O

Bn

NH

Ph

(RS,2SR,3RS)-43

O

50

49

(3SR,4RS)-44

Scheme 8. Reagents and conditions: (i) NHBnLi, THF, ꢀ78 ꢁC; (ii)

Scheme 9. Reagents and conditions: (i) LSA, THF, ꢀ78 ꢁC; (ii)

MeCHO, THF, ꢀ78 ꢁC to rt; (iii) Br₂, DCM, ꢀ78 ꢁC then NEt₃, ꢀ78

ꢁC to rt; (iv) Na, NH₃, EtOH, ꢀ78 ꢁC.

MeI, THF, ꢀ78 ꢁC to rt; (iii) Br₂, DCM, ꢀ78 ꢁC then NEt₃, ꢀ78 ꢁC to

rt.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4191

CO

Fe

ation, to a trans-b-lactam. To facilitate conjugate addi-

PPh₃

O

SiMe₃

tion, rather than c-deprotonation, the preparation of a

(Z)-a,b-unsaturated iron acyl complex with sp²-hybridi-

sation at the c-position was investigated, which would

lead to a formal asymmetric synthesis of thienamycin

via the preparation of trans-b-lactam 51 (Fig. 8).

Following a known protocol [23], Peterson oleﬁn-

ation of the iron trimethylsilyl complex 52 with (E)-3-

trimethylsilylpropenal [29] gave a 60:40 mixture of the

separable (E,E)- and (Z,E)-dienoyl complexes 53 and

54 in 55% and 37% yield respectively. The conjugate ad-

dition of lithium benzylamide to (E,E)-53 and (Z,E)-54,

and the known dienoyl complexes (E)-55 and (Z)-56,

was next investigated. Addition of lithium benzylamide

to (E,E)-53 and (E)-55 gave (RS,3SR)-57 and

(RS,3SR)-58 in 97% d.e. in each case and in 90% and

92% yield respectively, while conjugate addition to

(Z,E)-54 and (Z)-56 gave (RS,3RS)-59 and (RS,3RS)-

60 in 98% d.e. in each case and in 54% and 66% yield re-

spectively (Scheme 10).

CO

Fe

(i)

PPh₃

SiMe₃

(2E,4E)-53, 55%

53:54

60:40

O

CO

PPh₃

O

52

Fe

SiMe₃

(2Z,4E)-54, 37%

CO

Fe

CO

(ii)

PPh₃

O

PPh₃

O

R

Fe

NHBn

R=SiMe₃, (2E,4E)-53

R=H, (E)-55

R=SiMe₃, (RS,3SR)-57, 90%, 97% d.e.

R=H, (RS,3SR)-58, 92%, 97% d.e.

CO

PPh₃

(ii)

PPh₃

R

Fe

O

NHBn

R

R=SiMe₃, (2Z,4E)-54

R=H, (Z)-56

R=SiMe₃, (RS,3RS)-59, 54%, 98% d.e.

R=H, (RS,3RS)-60, 66%, 98% d.e.

Following the high diastereoselectivity observed upon

conjugate addition of lithium benzylamide to the (Z)-die-

noyl complexes, the tandem addition of LSA to (Z)-56

followed by addition of acetaldehyde was undertaken,

giving an 89:11 mixture of only two diastereoisomers by

¹H NMR spectroscopic analysis. Chromatographic puri-

ﬁcation and subsequent recrystallisation allowed the iso-

lation of 61 as a single diastereoisomer in 62% yield.

Decomplexation of 61 with Br₂and subsequent treatment

with TBDMSCl gave O-silyl-b-lactam 62, and conﬁrmed

the trans-C(3)–C(4) conﬁguration within 62 {C(3)H–

C(4)H J2.1 Hz}. N-Debenzylation of O-silyl-b-lactam

62 using sodium in liquid ammonia gave b-lactam 63 in

83% yield and with spectroscopic properties identical to

those of the literature, further conﬁrming the relative con-

ﬁguration within 61, and completing a formal synthesis of

( )-thienamycin (Scheme 11) [30].

Scheme 10. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 ꢁC then

(E)-3-trimethylsilylpropenal, THF, ꢀ78 ꢁC to rt; (ii) NHBnLi, THF,

ꢀ78 ꢁC.

2.3. Enantiorecognition between chiral iron acyl complex

and chiral lithium amides

Having demonstrated that achiral lithium amides de-

rived from primary and secondary amines undergo eﬃ-

cient and highly diastereoselective conjugate addition to

a,b-unsaturated iron acyl complexes, and that the eno-

lates arising from these conjugate additions may react

with alkylating agents and aldehydes, further studies con-

H

Me

OH

CO

Fe

CO

Fe

PPh₃

O

(i, ii)

PPh₃

OH

TBDMSO

H

N

d.r.

89:11

H

O

NHBn

Me

S(CH₂)₂NH₂

CO₂H

61, 62%, >98% d.e.

(Z)-56

NH

O

(iii, iv)

TBDMSO

Me

43%

H

Known Intermediate 51

( )-thienamycin

Decomplexation

and

deprotection

TBDMSO

Me

H

(v)

83%

Conjugate

Addition

-Aldol

H

CO

Me

OH

N

NH

PPh₃

CO

Fe

O

Bn

O

Fe

PPh₃

51

62

O

H

O

HN

Scheme 11. Reagents and conditions: (i) LSA, THF, ꢀ78 ꢁC;

(ii) MeCHO, THF, ꢀ78 ꢁC to rt; (iii) Br₂, DCM, ꢀ78 ꢁC then NEt₃,

ꢀ78 ꢁC to rt; (iv) TBDMSCl, imidazole, DMF, rt; (v) Na, NH₃, EtOH,

ꢀ78 ꢁC.

Bn

(Z)-dienoyl iron complex

Fig. 8.

4192

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

centrated upon ascertaining the levels of chiral recogni-

tion observed in the conjugate addition of chiral lithium

amides to iron acyl complexes. The conjugate addition of

lithium (RS)-N-a-methylbenzylamide to the iron croto-

noyl complex (RS)-12 furnished a 50:50 mixture of insep-

arable diastereoisomers 63 in 72% yield. The relative

conﬁguration within these diastereoisomers was assumed

to arise from complete stereocontrol by the iron complex

in the formation of the b-stereocentre, but with no dis-

crimination observed between the enantiomers of lithium

(RS)-a-methylbenzylamide. This is consistent with the re-

action proceeding under the stereochemical dominance

of the chiral iron auxiliary, unsurprising given that

a-methylbenzylamine generally undergoes conjugate ad-

dition reactions with poor levels of stereocontrol to a,b-

unsaturated acceptors [31]. In an attempt to enhance

the observed levels of recognition, the eﬀect of the intro-

duction of a more bulky substituent to the b-position of

the iron complex was tested. Conjugate addition of lithi-

um (RS)-N-a-methylbenzylamide to (RS)-[(g⁵-C₅H₅)Fe

(CO)(PPh₃)(COCH@CHPh)] and (RS)-[(g⁵-C₅H₅)Fe

(CO)(PPh₃)(COCH@CHⁱPr)] furnished the inseparable

products of conjugate addition 64 and 65 in high yields

(91% and 89% yield respectively) but with low levels of

stereocontrol (d.r. 50:50 and 42:58, respectively), while

no addition was seen to (RS)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)-

(COCH@CH^tBu)] (Scheme 12).

aSR)-70 was unambiguously identiﬁed by separate reac-

tions of homochiral lithium amide (R)-67 with homochi-

ral (R)- and (S)-12. Addition of lithium amide (R)-67 to

(R)-12 aﬀorded (R,3R,aR)-68 as a single diastereoisomer

in 92% yield (Scheme 14).

In contrast, addition of lithium amide (R)-67 to (S)-

12 aﬀorded an inseparable 50:50 mixture of (S,3S,aR)-

69 and (S,3R,aR)-70 in 55% yield (Scheme 15).

The loss of stereocontrol observed in the reaction of

the (S)-iron auxiliary with lithium (R)-N-3,4-dimeth-

oxybenzyl-N-a-methylbenzylamide suggests that the ste-

reodirecting capabilities of the chiral iron auxiliary is

eﬀectively cancelled by the stereocontrol imposed by

the chiral lithium amide upon conjugate addition. Fur-

thermore, the 94:3:3 ratio of diastereoisomers resulting

from the reaction of the (RS)-iron auxiliary with the

(RS)-amide suggests a >15:1 rate diﬀerence between

the addition of the matched pair {lithium amide (R)-

67 and (R)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)]

12} and the mismatched pair {lithium amide (R)-67

CO

PPh₃

Me

Fe

OMe

O

N

Ph

OMe

To probe further the possibility of chiral recognition

in the iron acyl system, it was proposed that the intro-

duction of a second substituent onto the nitrogen atom

of the lithium amide would restrict the conformational

lability of the reacting species, and lead to improved lev-

els of enantiorecognition. Thus, reductive amination of

(RS)-N-a-methylbenzylamine with 3,4-dimethoxybenz-

aldehyde gave (RS)-N-3,4-dimethoxybenzyl-N-a-meth-

ylbenzylamine. Conjugate addition of two equivalents

of lithium (RS)-N-3,4-dimethoxybenzyl-N-a-meth-

ylbenzylamide to the (RS)-12 gave a crude product con-

taining three diastereoisomers 68:69:70 in a 94:3:3 ratio

(Scheme 13).

MeO

Ph

N

Li

OMe

(RS,3RS,αRS)-68

(RS)-67

CO

PPh₃

Me

Fe

O

N

Ph

CO

(i)

PPh₃

Me

Fe

MeO

83%

The conﬁguration of each of the three diastereoiso-

mers (RS,3RS,aRS)-68, (RS,3RS,aSR)-69 and (RS,3SR,

O

OMe

(RS)-12

(RS,3RS,αSR)-69

CO

PPh₃

Me

CO

Fe

CO

Fe

(i)

Fe

PPh₃

O

R

O

N

Ph

O

HN

Ph

63-65

MeO

R=Me

R=Ph

R=ⁱPr

R=^tBu

63, R=Me, 72%, d.r. 50:50

64, R=Ph, 91%, d.r. 50:50

65, R=ⁱPr, 89%, d.r. 42:58

R=^tBu, no addition

OMe

(RS,3SR,αSR)-70

Scheme 12. Reagents and conditions: (i) Lithium (RS)-N-a-meth-

ylbenzylamide (2.5 eq), THF, ꢀ78 ꢁC.

Scheme 13. Reagents and conditions: (i) Lithium (RS)-N-3,4-dimeth-

oxybenzyl-N-a-methylbenzylamide (2.0 eq), THF, ꢀ78 ꢁC.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4193

OMe

CO

Fe

(i)

92%

PPh₃

Me

PPh₃

O

Me

OMe

Fe

O

N

Ph

(R)-12

O

C

O

C

Ph

N

Li

PPh₃

O

MeO

Ph₃P

Me

Fe

OMe

Fe

O

(R,3R,αR)-68

(S)-12

(RS)-12

Conversion

Scheme 14. Reagents and conditions: (i) Lithium (R)-N-3,4-dimeth-

oxybenzyl-N-a-methylbenzylamide (2.0 eq), THF, ꢀ78 ꢁC.

SpecificRotation

(c 0.15, benzene)

+6.3

e.e (%)

(%)

4

19

42

83

>95

CO

18

34

56

70

80

+33.5

+73.8

+145.0

+181.4

Ph₃P

Me

Fe

O

(S)-12

+178.1

23

D

α

authentic (S)-12

+175.3 (c 0.15, benzene)

(i)

55%

Ph

Scheme 16. Reagents and conditions: (i) Lithium (R)-N-3,4-dimeth-

oxybenzyl-N-a-methylbenzylamide (2.0 eq), THF, ꢀ78 ꢁC.

CO

Ph₃P

O

Ph₃P

O

Me

Fe

for the conjugate addition to the (RS)-iron complex to

proceed to completion. For instance, with 0.5 equiva-

lents of lithium (RS)-amide 67 the reaction proceeds to

ꢁ25% conversion [32]; with 1.0 equivalent the conver-

sion is ꢁ50%, while with 2.0 equivalents the conversion

is >90%. To investigate further this observation, the

stoicheiometry of the addition of the related lithium am-

ide N-benzyl-N-a-methylbenzylamide 71 to the [(g⁵-

C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] iron complex

was studied in detail. Conjugate addition of lithium

Ph

N

OMe

(S,3S,αR)-69

(S,3R,αR)-70

Scheme 15. Reagents and conditions: (i) Lithium (R)-N-3,4-dimeth-

oxybenzyl-N-a-methylbenzylamide (2.0 eq), THF, ꢀ78 ꢁC.

(RS)-N-benzyl-N-a-methylbenzylamide

to

(RS)-

[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] consistently

gave a 96:2:2 diastereoisomeric mixture of (RS,3RS,-

aRS)-72, (RS,3RS,aSR)-73 and (RS,3SR,aSR)-74 inde-

pendent of the reaction conversion [33]. The reaction

proceeded to 40% conversion with 1.0 equivalent of

(RS)-lithium amide, and to >90% conversion with 2.0

equivalents of (RS)-lithium amide, indicating that the

2:1 lithium amide: acceptor stoicheiometry is observed

in this reaction pairing (Scheme 17).

The 2:1 amide:acceptor stoicheiometry was also ob-

served in the addition of lithium (RS)-71 to homochiral

(R)-iron crotonoyl 12, giving an 87:7:6 mixture of

(R,3R,aR)-72, (R,3R,aS)-73 and (R,3S,aS)-74 at 54%

conversion with 1.0 equivalent of amide, and an 89:6:5

mixture of 72:73:74 at >90% conversion with 2.0 equiv-

alents of amide (Scheme 18).

and (S)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] 12}.

This rate diﬀerence was used as the basis for a kinetic

resolution of (RS)-12 by homochiral lithium amide

(R)-67. Thus, addition of various equivalents of lithium

amide (R)-67 to (RS)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)-

(COCH@CHMe)] 12 and measurement of the reaction

conversion and speciﬁc rotation of the recovered iron

complex showed that at conversions >70% the recovered

(S)-iron complex 12 was essentially homochiral (>95%

e.e.), consistent with a stereoselectivity factor, E for

the resolution process of 15 (Scheme 16).

2.4. Probing the reaction stoicheiometry in the conjugate

addition of chiral lithium amides to the chiral iron

auxiliary

Reaction of the ꢁmatchedꢀ homochiral pair of lithium

(R)-amide 71 with (R)-12 showed 1:1 stoicheiometry, fur-

nishing (R,3R,aR)-72 as a single diastereoisomer at 46%

conversion with 0.5 equivalents of amide, and >95% con-

version with 1.0 equivalent of amide. In the ꢁmismatchedꢀ

During these investigations, the stoicheiometry of the

reaction between (RS)-lithium amide 67 and (RS)-[(g⁵-

C₅H₅)Fe(CO)(PPh₃)(COCH@CHMe)] 12 was probed,

with two equivalents of (RS)-lithium amide 67 required

4194

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

CO

Fe

slower rate than the ꢁmatchedꢀ reaction. 1:1 stoicheiome-

PPh₃

O

Me

try in this ꢁmismatchedꢀ manifold was assumed as the re-

action had proceeded to >50% conversion with 1

equivalent of amide (Scheme 19).

Ph

N

Ph

N

Li

Ph

Furthermore, conjugate addition of homochiral (R)-

lithium amide 71 to the (RS)-iron crotonyl complex 12

also showed 1:1 stoicheiometry, giving an 82:9:9 mixture

of (R,3R,aR)-72, (S,3S,aR)-73 and (S,3R,SR)-74 at 48%

conversion with 0.5 equivalents of amide, and a 55:25:20

mixture of 72:73:74 at >95% conversion with 1.0 equiv-

alent of amide (Scheme 20).

(RS)-71

(RS,3RS,αRS)-72

CO

PPh₃

Me

(i)

CO

Fe

PPh₃

O

Me

O

N

Ph

d.r.

72:73:74

96:2:2

Ph

(RS)-12

It is therefore clear that the reaction of (RS)-lithium

amide 71 with either (RS)- or homochiral iron acyl com-

plex 12 shows 2:1 stoicheiometry, while the homochiral

lithum amide 71 shows 1:1 stoicheiometry with either

(RS)- or homochiral iron acyl complex 12. The wide ap-

plicability of lithium amides within organic synthesis has

ensured that both the solid phase and solution phase

structures of lithium amides have been the subject of

many investigations, with the aim of understanding the

factors which aﬀect both the reactivity and selectivity

of these agents [34]. Studies of lithium amide complexes

in a range of solvents have shown that a variety of ag-

gregation states co-exist in solution [35], with the degree

of aggregation dependent upon solvent, temperature

(RS,3RS,αSR)-73

CO

PPh₃

Conversion(%) (RS)-71 (eq)(

Me

Fe

0.5

1.0

1.5

2.0

2.2

29

40

74

91

O

N

Ph

(RS,3SR,αSR)-74

>95

Scheme 17. Reagents and conditions: (i) Lithium (RS)-N-benzyl-N-a-

methylbenzylamide-71, THF, ꢀ78 ꢁC.

case, addition of lithium (S)-amide 71 to iron complex

(R)-12 gave, upon addition of 1.0 equivalent of lithium

(S)-amide 71 to (R)-12, 61% conversion to a 50:50 mix-

ture of (R,3R,aS)-73:(R,3S,aS)-74, consistent with, as ex-

pected, the ꢁmismatchedꢀ reaction proceeding at a much

CO

PPh₃

O

CO

Fe

Me

PPh₃

O

(i).

Fe

Me

N

Ph

"matched"

CO

PPh₃

Ph

(R,3R,αR)-72

Fe

(R)-12

O

N

Ph

Conversion(%) (R)-71 (eq)(

Ph

(R,3R,αR)-72

46

65

0.5

0.75

1.0

>95

2.0

CO

Fe

CO

PPh₃

O

(i)

PPh₃

O

CO

Fe

PPh₃

O

Me

Fe

N

Ph

N

Ph

(R)-12

Ph

(R,3R,αS)-73

CO

Fe

Ph

(R,3R,αS)-73

PPh₃

O

(ii).

"mismatched"

Me

CO

PPh₃

O

PPh₃

O

Me

Fe

(R)-12

N

Ph

N

Ph

(R,3S,αS)-74

Conversion(%)

(S)-71 (eq)(

Ratio 73:74(

Conversion(%) (RS)-71 (eq)( d.r. (72:73:74)

61

1.0

50:50

54

1.0

2.0

87:7:6

89:6:5

>90

Scheme 19. Reagents and conditions: (i) Lithium (R)-N-benzyl-N-a-

methylbenzylamide-71, THF, ꢀ78 ꢁC; (ii) Lithium (S)-N-benzyl-N-a-

methylbenzylamide-71, THF, ꢀ78 ꢁC.

Scheme 18. Reagents and conditions: (i) Lithium (RS)-N-benzyl-N-a-

methylbenzylamide 71, THF, ꢀ78 ꢁC.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4195

heterochiral [(R,S)] lithium amide dimers play an essen-

tial role in the conjugate addition reaction of the racemic

amide. Assuming that each dimeric lithium amide com-

plex can potentially react with two a,b-unsaturated ac-

ceptors, addition to both reactive sites of a homochiral

dimer upon the opposite faces of the complex will be al-

lowed, while in the case of the heterochiral lithium am-

ide dimer reacting with the extremely bulky iron acyl

acceptors, the second addition is blocked by the ﬁrst

formed complexed iron acyl enolate, as shown schemat-

ically in Fig. 9. Using homochiral (R)-amide 71, only

homochiral [(R,R)] dimers are possible, which react, in

the matched case, with the iron complex (R)-12 with

high stereoselectivity upon both reaction sites of the di-

meric complex, resulting in 1:1 stoicheiometry, giving a

single b-amino complex. Similarly, for addition of (R)-

71 to the (RS)-auxiliary 12, conjugate addition from op-

posite faces of the homochiral [(R,R)] dimer is possible,

resulting in 1:1 stoicheiometry and a loss of stereocon-

trol upon addition to the (S)-enantiomer of the chiral

iron auxiliary. With conjugate additions using racemic

(RS)-amide 71, the observed 2:1 stoicheiometry in these

reactions is consistent with the formation of a heterochi-

ral (R,S)-lithium amide dimer with a mono-complexed

iron acyl enolate that is unreactive to further conjugate

addition. In such an iron enolate-lithium amide com-

plex, the second conjugate addition is required by the

conﬁguration of the constituent amide components to

proceed on the same face of the dimer-complex as the

bound iron enolate, which will be precluded by the steric

constraints of the reaction manifold, resulting in the ob-

served 2:1 stoicheiometry upon addition to either the

(R)- or the (RS)-auxiliary 12.

Three distinct mechanistic portfolios may be con-

sidered that are compatible with the predominant

formation of an (R,S) lithium amide dimer with a

mono-complexed iron acyl enolate that is inert to further

conjugate addition. One plausible explanation is that the

lithium amides react as non-equilibrating dimers in solu-

tion, a priori homochiral dimers in the case of the homo-

chiral lithium amide, but only heterochiral dimers for

the racemic lithium amide. After one conjugate addi-

tion, the homochiral dimer-mono-enolate complex may

undergo further addition, but the heterochiral dimer-

mono-enolate complex is inert to further reaction.

Alternatively, with the (RS)-lithium amide a mixture

of rapidly equilibrating homochiral [(R,R) and (S,S)]

and heterochiral (R,S) lithium amide dimers may be

formed. If the rate of the ﬁrst conjugate addition of

the heterochiral lithium amide dimer is fast relative to

that of the homochiral dimers, the selective formation

of the required unreactive (R,S)-dimer-mono-enolate,

and thus the 2:1 stoicheiometry, may be realized (Cur-

tin–Hammett). Finally, fast mono-conjugate addition

to a mixture of rapidly equilibrating homo- and hetero-

chiral lithium amide dimers may occur to give a mixture

CO

Fe

PPh₃

O

Me

N

Ph

(R,3R,αR)-72

CO

Fe

Ph₃P

Me

PPh₃

O

(i)

Me

Fe

O

Ph

N

Ph

(RS)-12

(S,3S,αR)-73

CO

Ph₃P

Me

Fe

O

Ph

N

Ph

(S,3R,αR)-74

Conversion(%) (RS)-71 (eq)( d.r. (72:73:74)

48

>95

0.5

1.0

82:9:9

50:25:25

Scheme 20. Reagents and conditions: (i) Lithium (R)-N-benzyl-N-a-

methylbenzylamide-71, THF, ꢀ78 ꢁC.

and concentration [36], although a lithium amide dimer

is perhaps the most widely recognised aggregation state

in the literature. While the pink/red solution colouration

seen upon deprotonation of dibenzylamines has been at-

tributed to charge transfer in the unsolvated monomer

[37], the actual aggregation state of lithium N-benzyl-

N-a-methylbenzylamide 71 in THF solution has, to the

best of our knowledge, not yet been fully determined,

although in the solid phase, two groups have indepen-

dently published dimeric crystal structures of lithium

N-benzyl-N-a-methylbenzylamide [38]. The rate of de-

protonation of ketones by lithium amides have also been

investigated, with the kinetic studies of Collum et al. [39]

and Majewski et al. [40] indicating a fractional order

with respect to LDA {kꢂ[LDA]^0.5}, consistent with a di-

mer–monomer pre-equilibrium and deprotonation with

a disolvated monomer, while similar studies with

LHMDS in the presence of NEt₃implicate a dimer

based mechanism [41]. Upon the assumption that in

THF solution chiral lithium amides such as 67 and 71

react predominantly as dimeric complexes, conjugate

addition reactions involving a single enantiomer of lith-

ium amide can involve only homochiral [(R,R) or (S,S)]

dimers, while in the racemic series both homochiral

[(R,R) and (S,S)] and heterochiral [(R,S)] dimers can

be formed. The diﬀerences in the reaction stoicheiome-

try for racemic and homochiral lithium amides upon ad-

dition to the iron crotonyl complex implies that

4196

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

Diastereoselectivity

Disfavoured

Addition syn- to PPh₃

of iron acyl complex

Homochiral Dimer

Heterochiral Dimer

Fe 'exo'

matched

(R)

N

(R)

N

Li

(R)

⁽^S)N

Li

N

Li

N

Fe_(S)

Fe_(R)

N

Li

Favoured

Addition on opposite

Disfavoured

Addition on same

faces of Li amide dimer face of Li amide dimer

Favoured

Addition anti- to PPh₃

complex

Fe 'exo' Fe 'endo'

mismatch mismatch

of iron acyl complex

(R,R)-dimer and (R)-Fe complex

(R,R)-dimer and (RS)-Fe complex

(fast reaction with (R)-acceptor first)

(S,S)-dimer and (R)-Fe complex

Fe_(R)

match

Fe_(R)

match

Fe_(R)

mismatch

Fe_(R)

Li N^(R)

(S)

N

Li

(R)

N

Li

N

Li

(S)

Li

N

Fe_(R)

Fe_(S)

match

mismatch

Fe_(R)

Fe_(S)

1:1 stoicheiometry

'matched' asymmetric

induction

1:1 stoicheiometry

slow reaction

50:50 ratio of products

50% conversion, 82:9:9 ratio

100% conversion, 50:25:25 ratio

(R,S)-dimer and (R)-Fe complex

(fast reaction on (R)-amide)

(R,S)-dimer and (RS)-Fe complex

match

Fe_(S)

Fe_(R)

match

Fe_(S)

Fe_(R)

no reaction

Li N^(R)

Li

Li N^(R)

Li

(S)

N

2:1 stoicheiometry

54% conversion, 87:7:6 ratio

100% conversion, 89:6:5 ratio

2:1 stoicheiometry

high enantiorecognition

Fig. 9. Schematic representation of homo- and heterochiral lithium amides aggregates and conjugate addition to the iron crotonyl complex.

of iron acyl enolate-lithium amide dimer complexes. As-

suming that the rate of the second conjugate addition to

the dimer-mono-enolate complex is much slower than

the ﬁrst, rapid equilibration to form only the stable

(R,S)-dimer-mono-enolate complex, which is inert to

further conjugate addition, resulting in 2:1 stoicheiome-

try, may occur. With the data in hand it is not currently

possible to distinguish between these possibilities.

ation or aldol reaction facilitates the stereoselective syn-

thesis of both cis- and trans-b-lactams via addition to

the corresponding (E)- or (Z)-iron acyl complex and ox-

idative decomplexation. This methodology has been ap-

plied to the formal synthesis of ( )-olivanic acid and

( )-thienamycin. Upon conjugate addition of chiral

lithium amides to a,b-unsaturated iron acyl complexes,

lithium a-methylbenzylamide shows low levels of enan-

tiorecognition whereas homochiral secondary lithium

amides derived from a-methylbenzylamine show signiﬁ-

cant enantiodiscrimination. Conjugate additions of

(RS)-lithium amides 67 and 71 with either the (RS)- or

homochiral iron crotonyl complex 12 show 2:1 stoichei-

ometry, while homochiral lithum amides 67 and 71 show

1:1 stoicheiometry. This stoicheiometry may be ex-

plained only by the formation of a heterochiral lithium

In conclusion, conjugate addition of both primary

and secondary achiral lithium amides to a,b-unsaturated

iron acyl complexes proceed with high diastereoselectiv-

ity, with the addition of lithium dimethylamide to (S,Z)-

and

(S,E)-[(g⁵-C₅H₅)Fe(CO)(PPh₃)(COCH@CHPh)]

used to determine unambiguously the absolute conﬁgu-

ration of Wintersteinꢀs acid. In-situ elaboration of the

enolates derived from the conjugate additions via alkyl-

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4197

dimer-mono-enolate complex, which is inert to further

reaction. Further investigations from this laboratory re-

garding the application of homochiral lithium amides in

enantiorecognition protocols and further mechanistic

studies upon the aggregation state of lithium amides in

these conjugate addition protocols will be reported in

due course.

iron crotonyl complex 12 (1.0 eq) in anhydrous THF

was added dropwise via cannula and stirred at ꢀ78 ꢁC

for the speciﬁed time prior to the addition of methanol

and warmed to RT. After concentration in vacuo, the

residue was extracted with DCM, ﬁltered through alu-

mina and concentrated in vacuo before puriﬁcation by

column chromatography.

3.3. Preparation of (S,3R)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH₂CH(Ph)NMe₂(19)

3. Experimental

3.1. General experimental

n-BuLi (2.5 M, 1.3 ml, 3.3 mmol) was added dropwise

to a stirred solution of the dimethylamine (0.55 ml, 8.3

mmol) in anhydrous THF (5 ml) at ꢀ20 ꢁC under nitro-

gen. After 1 h, the solution was cooled to ꢀ78 ꢁC and

added dropwise to a solution of the iron complex

(S,E)-17 (0.9 g, 1.7 mmol) in anhydrous THF (60 ml)

at ꢀ100 ꢁC. After 1 h methanol was added and the so-

lution allowed to warm to rt. Concentration in vacuo,

dissolution of the resultant oil in DCM and ﬁltration

through alumina (grade I) and further concentration in

vacuo gave, after chromatographic puriﬁcation

(DCM:EtOAc:MeOH 60:39:1) 19 (808 mg, 81%, 94%

d.e.); C₃₅H₃₄NO₂FeP requires C, 71.6; H, 5.8; N,

All reactions involving organometallic or other mois-

ture sensitive reagents were performed under an atmo-

sphere of nitrogen and in deoxygenated solvents via

standard vacuum line techniques. All glassware was

ﬂame-dried and allowed to cool under vacuum. THF

was distilled under an atmosphere of dry nitrogen from

sodium benzophenone ketyl. n-Butyllithium was used as

a solution in hexanes at the molarity stated. All other

solvents and reagents were used as supplied (Analytical

or HPLC grade), without prior puriﬁcation. Reactions

were dried with MgSO₄. Flash chromatography was per-

formed on Kieselgel 60 silica or alumina (grade as

stated). Nuclear magnetic resonance (NMR) spectra

were recorded on a Bruker AMX 500 (¹H: 500 MHz

and ¹³C: 125.3 MHz), Bruker W-H 300 (¹H: 300

MHz), Bruker AM-250 (³¹P 100 MHz), Varian 200

(¹H: 200 MHz) and Bruker AC200 (¹H: 200 MHz and

13C 50 MHz) spectrometers in the deuterated solvent

stated. All chemical shifts (d) are quoted in ppm and

coupling constants (J) in Hz. Residual protio signals

from the solvents were used as an internal reference.

¹³C multiplicities were assigned using a DEPT sequence.

In all cases, the reaction diastereoselectivity was assessed

20

2.4%; Found C, 71.5; H, 5.9; N, 2.3%; [a]₅₄₆+129.2

(c 0.05, benzene); v_max(CH₂Cl₂) 1899 (C„O), 1611

(C@O); d_H(300 MHz, CDCl₃) 2.08 (6H, s, NMe₂),

2.67 (1H, dd, J_2A,2B16.1, J_2A,36.2, C(2)H_A), 3.41 (1H,

dd, J_2B,2A16.1, J_2B,36.2, C(2)H_B), 3.74 (1H, t, J6.2,

C(3)H), 4.37 (5H, d, J_PH1.0, C₅H₅), 7.08–7.52 (20H,

m, Ph); d_C(50 MHz, CDCl₃) 42.3, 64.6, 67.9, 85.4,

126.4, 127.7, 127.9, 128.7, 129.6, 133.3, 136.3, 140.6,

220.4; d_P(100 MHz, CDCl₃) 71.9; m/z (FAB) 587 (M⁺).

3.4. Preparation of (S,3S)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH₂CH(Ph)NMe₂(20)

1

by peak integration of the H NMR spectrum of the

crude reaction mixture. Infrared spectra were recorded

on a Perkin–Elmer 1750 IR Fourier Transform spectro-

photometer, with only the characteristic peaks quoted.

Low resolution mass spectra (m/z) were recorded on a

VG MassLab ZAB 1F using ﬁeld desorption techniques,

or VG MassLab 20–250 instrument. Optical rotations

were recorded on a Perkin–Elmer 241 polarimeter with

a water-jacketed 10 cm cell and speciﬁc rotations given

in units of 10^ꢀ1degcm²g^ꢀ1. Concentrations are quoted

in g/100 ml. Melting points were recorded on a Leica

VMTG Galen III apparatus and are uncorrected. Ele-

mental analyses were performed by the microanalysis

service of the Dyson Perrins Laboratory, Oxford.

n-BuLi (2.5 M, 1.3 ml, 3.3 mmol) was added dropwise

to a stirred solution of the dimethylamine (0.55 ml, 8.3

mmol) in anhydrous THF (5 ml) at ꢀ20 ꢁC under nitro-

gen. After 1 h, the solution was cooled to ꢀ78 ꢁC and

added dropwise to a solution of the iron complex

(S,Z)-18 (0.9 g, 1.7 mmol) in anhydrous THF (60 ml)

at ꢀ100 ꢁC. After 1 h methanol was added and the so-

lution allowed to warm to rt. Concentration in vacuo,

dissolution of the resultant oil in DCM and ﬁltration

through alumina (grade I) and further concentration in

vacuo gave, after chromatographic puriﬁcation

(DCM:EtOAc:MeOH 60:39:1) 20 (86%, >97% d.e.).

Subsequent recrystallisation (DCM:hexane) gave 20 as

a single diastereoisomer; (878 mg, 82%); C₃₅H₃₄NO₂FeP

requires C, 71.6; H, 5.8; N, 2.4%; Found C, 71.3; H, 5.8;

N, 2.1%; [a]₅₄₆²⁰+358.4 (c 0.05, benzene); v_max(CH₂Cl₂)

1900 (C„O), 1622 (C@O); d_H(300 MHz, CDCl₃) 1.95

(6H, s, NMe₂), 2.53 (1H, dd, J_2A,2B15.4, J_2A,34.0,

C(2)H_A), 3.41 (1H, dd, J_2B,2A15.4, J_2B,34.0, C(2)H_B),

3.2. Representative procedure 1

n-Butyllithium (2.5 eq) was added dropwise to a stir-

red solution of the amine (3.0 eq) in anhydrous THF at

ꢀ78 ꢁC under nitrogen. After 30 min, a solution of the

4198

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

3.74 (1H, t, J4.0, C(3)H), 4.04 (5H, d, J_PH1.0, C₅H₅),

7.18–7.59 (20H, m, Ph); d_C(50 MHz, CDCl₃) 42.5,

66.0, 67.6, 85.1, 126.5, 127.6, 127.7, 128.6, 129.4,

133.1, 136.6, 141.7, 220.5; d_P(100 MHz, CDCl₃) 71.7;

m/z (FAB) 587 (M⁺).

graphic puriﬁcation giving the free ester 21 (199 mg,

20

66%) as a colourless oil; [a]₄₃₆ꢀ31.1 (c 1.6, MeOH);

treatment with HCl (aq) and concentration in vacuo

gave the HCl salt, which was crystallised from hex-

ane:EtOH, giving 21ÆHCl as white needles;

C₁₃H₂₀ClNO₂requires C, 60.6; H, 7.8; N, 5.4%; Found

C, 60.3; H, 8.0; N, 5.3%; [a]₄₃₆[20] ꢀ22.7 (c 0.5, CHCl₃).

3.7. Preparation of (S,2R,3S)-(g⁵-C₅H₅)Fe (CO)-

(PPh₃)COCH(Me)CH(Ph)NMe₂(22)

3.5. Preparation of (S)-ethyl 3-N,N-dimethylamino-3-

phenyl-propanoate (21)

Iron complex 20 (0.8 g, 1.36 mmol), NBS (1.3 eq,

1.77 mmol) and 2.5 M HCl (2.5 eq) were combined

at ꢀ78 ꢁC in THF (100 ml) and allowed to warm to

rt. Concentration in vacuo gave a green oil, which

was extracted into water (50 ml). Filtration gave a

green solid containing (g⁵-C₅H₅)Fe(CO)(PPh₃)Br, while

concentration of the water ﬁltrate gave a yellow oil

which was puriﬁed by Dowex ion exchange chromatog-

raphy. After concentration in vacuo the intermediate

was dissolved in EtOH saturated with HCl and heated

at reﬂux for 8 h before concentration in vacuo. The res-

idue was treated with 2 M NEt₃in EtOH until basic,

with subsequent chromatographic puriﬁcation giving

the free ester 21 (247 mg, 82%) as a colourless oil;

n-BuLi (2.5 M, 1.3 ml, 3.3 mmol) was added dropwise

to a stirred solution of the dimethylamine (0.55 ml, 8.3

mmol) in anhydrous THF (5 ml) at ꢀ20 ꢁC under nitro-

gen. After 1 h, the solution was cooled to ꢀ78 ꢁC and

added dropwise to a solution of the iron complex

(S,Z)-18 (0.9 g, 1.7 mmol) in anhydrous THF (60 ml)

at ꢀ100 ꢁC. After 1 h MeI (5 eq) was added and the so-

lution allowed to warm to rt. Concentration in vacuo,

dissolution of the resultant oil in DCM and ﬁltration

through alumina (grade I) further concentration in vac-

uo gave, after chromatographic puriﬁcation (DCM:E-

tOAc:MeOH 60:39:1) 22 664 mg, (65%, >97% d.e.).

Subsequent recrystallisation (DCM:hexane) gave 22 as

a single diastereoisomer; C₃₅H₃₄NO₂FeP requires C,

72.1; H, 6.0; N, 2.3%; Found C, 72.1; H, 6.1; N, 2.1%;

20

[a]₄₃₆+31.5 (c 1.6, MeOH); d_H(300 MHz, CDCl₃)

1.11 (3H, t, J7.2, OCH₂CH₃), 2.18 (6H, s, NMe₂),

2.69 (1H, dd, J_2A,2B14.7, J_2A,36.9, C(2)H_A), 2.95 (1H,

dd, J_2B,2A14.7, J_2B,38.2, C(2)H_B), 3.86 (1H, app t,

J7.2, C(3)H), 4.01 (2H, q, J7.2, OCH₂CH₃), 7.23–7.34

(5H, m, Ph); treatment with HCl (aq) and concentra-

tion in vacuo gave the HCl salt, which was crystallised

from CHCl₃:EtOAc, giving 21ÆHCl as white needles;

m.p. 176–178 ꢁC; C₁₃H₂₀ClNO₂requires C, 60.6; H,

20

[a]₅₄₆+225.2 (c 0.05, benzene); v_max(CH₂Cl₂) 1902

(C„O), 1610 (C@O); d_H(300 MHz, CDCl₃) 0.73 (3H,

d, J4.0, C(2)Me), 2.05 (6H, s, NMe₂), 3.41 (1H, d,

J7.6, C(3)H), 3.55 (1H, m, C(2)H), 4.39 (5H, d,

J_PH1.0, C₅H₅), 6.94–7.71 (20H, m, Ph); d_C(50 MHz,

CDCl₃) 14.3, 42.7, 65.6, 71.3, 84.9, 126.3, 127.1, 127.8,

129.5, 130.0, 133.7, 137.1, 137.4, 221.5; d_P(100 MHz,

CDCl₃) 72.0; m/z (FAB) 601 (M⁺).

20

7.8; N, 5.4%; Found C, 60.3; H, 8.0; N, 5.4%; [a]₄₃₆

+23.1 (c 0.5, CHCl₃); v_max(CH₂Cl₂) 3380 (NH), 1735

(C@O); d_H(300 MHz, CDCl₃) 1.12 (3H, t, J7.2,

OCH₂CH₃), 2.69 (6H, br s, NMe₂), 3.25 (1H, dd,

J_2A,2B16.6, J_2A,34.7, C(2)H_A), 3.69 (1H, dd, J_2B,2A16.6,

J_2B,39.3, C(2)H_B), 4.04 (2H, m, OCH₂CH₃), 4.54 (1H,

m, C(3)H), 7.47–7.59 (5H, m, Ph); m/z (DCI-NH₃)

222 (M⁺).

3.8. Preparation of ethyl (2R,3S)-2-methyl-3-N,N-di-

methylamino-3-phenyl-propanoate (23)

Iron complex 22 (0.8 g, 1.33 mmol), NBS (1.3 eq, 1.73

mmol) and 2.5 M HCl (2.5 eq) were combined at ꢀ78 ꢁC

in THF (100 ml) and allowed to warm to rt. Concentra-

tion in vacuo gave a green oil, which was extracted into

water (50 ml). Filtration gave a green solid containing

(g⁵-C₅H₅)Fe(CO)(PPh₃)Br, while concentration of the

water ﬁltrate gave a yellow oil which was puriﬁed by

Dowex ion exchange chromatography. After concentra-

tion in vacuo the intermediate was dissolved in EtOH

saturated with HCl and heated at reﬂux for 8 h before

concentration in vacuo. The residue was treated with 2

M NEt₃in EtOH until basic, with subsequent chromato-

graphic puriﬁcation giving the free ester 23 (258 mg,

82%) as a colourless oil; d_H(300 MHz, CDCl₃) 0.92

(3H, d, J7.0, C(2)Me), 1.27 (3H, t, J7.1, OCH₂CH₃),

2.09 (6H, s, NMe₂), 3.16 (1H, m, C(2)H), 3.67 (1H, d,

J11.0, C(3)H), 4.19 (2H, q, J7.1, OCH₂CH₃),

7.13–7.78 (5H, m, Ph); treatment with HCl (aq) and

3.6. Preparation of (R)-ethyl 3-N,N-dimethylamino-3-

phenyl-propanoate (21)

Iron complex 21 (0.8 g, 1.36 mmol), NBS (1.3 eq, 1.77

mmol) and 2.5 M HCl (2.5 eq) were combined at ꢀ78 ꢁC

in THF (100 ml) and allowed to warm to rt. Concentra-

tion in vacuo gave a green oil, which was extracted into

water (50 ml). Filtration gave a green solid containing

(g⁵-C₅H₅)Fe(CO)(PPh₃)Br, while concentration of the

water ﬁltrate gave a yellow oil which was puriﬁed by

Dowex ion exchange chromatography. After concentra-

tion in vacuo the intermediate was dissolved in EtOH

saturated with HCl and heated at reﬂux for 8 h before

concentration in vacuo. The residue was treated with 2

M NEt₃in EtOH until basic, with subsequent chromato-

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4199

concentration in vacuo gave the HCl salt, which was

crystallised from EtOH:hexane, giving 23ÆHCl as white

needles; m.p. 166–168 ꢁC; C₁₄H₂₂ClNO₂requires C,

61.9; H, 8.1; N, 5.2%; Found C, 61.7; H, 8.3; N, 5.4%;

(3·20 ml) and ﬁltered through alumina (grade V). Con-

centration in vacuo and chromatographic puriﬁcation of

the residue on alumina (grade I) [EtOAc/CH₂Cl₂(1:9)]

gave 26:27 as a mixture of diastereoisomers (87:13;

0.490 g, 81%). Crystallisation (Et₂O:DCM) gave a single

diastereoisomer 26 as orange plates; Found: C, 70.3; H,

5.9; N, 2.2%; C₃₇H₃₈FeNO₃P requires C, 70.5; H, 6.1;

N, 2.2%); v_max(CH₂Cl₂) 1914 (C„O), 1593 (C@O);

20

[a]₄₃₆+135.0 (c 0.5, CHCl₃); v_max(CH₂Cl₂) 3320

(NH), 1732 (C@O); d_H(300 MHz, CDCl₃) 1.03 (3H,

d, J7.2, C(2)Me), 1.29 (3H, t, J7.1, OCH₂CH₃), 2.73

(6H, s, NMe₂), 3.49 (1H, m, C(2)H), 4.25 (2H, q, J7.1,

OCH₂CH₃), 4.45 (1H, br d, C(3)H), 7.44–7.63 (5H, m,

Ph); m/z (DCI-NH₃) 236 (M⁺).

d

_H(300 MHz, CDCl₃) 0.12 (3H, d, J6.2, CH(OH)CH₃),

1.18 (3H, d, J6.5, CHCH₃), 2.65 (1H, m, C(3)H), 3.15

(1H, dd, J8.7, J2.4, C(2)H), 3.44 (1H, AB, J12.6,

NCH_AHPh), 3.67 (1H, AB, J12.6, NCH_BHPh), 4.40

(5H, d, J_PH1.3, C₅H₅), 4.85 (1H, m, CH(OH)CH₃),

6.85 (1H, br s, NH), 7.10–7.69 (15H, m, PPh₃); d_C(50

MHz, CDCl₃) 17.6, 19.9, 51.0, 51.9, 67.5, 81.2, 86.4,

127.0, 128.2, 129.8, 133.3, 136.5, 139.6, 221.1, 279.9;

m/z (FAB+) 632 (MH⁺, 40%); d_P(100 MHz) 72.9.

Selected data for 27; d_H(300 MHz, CDCl₃) 0.78 (3H,

d, J6.5, CH(OH)CH₃), 1.50 (3H, d, J6.5, CHCH₃), 4.45

(5H, d, J_PH1.3, C₅H₅).

3.9. Preparation of (RS,RS,RS,RS)-(g⁵-C₅H₅)Fe

(CO)(PPh₃)COCH[CH(OH)CH₃]CH{N[CH₂Ph(3,4-

OMe)₂]₂}CH₃(24)

n-BuLi (1.50 ml, 2.40 mmol) was added to a solution

of bis-(3,4-dimethoxybenzyl)amine (0.860 g, 2.70 mmol)

in THF (10 ml) at 0 ꢁC and stirred for 1 h before cooling

to ꢀ78 ꢁC. A solution of 12 (0.480 g, 1.00 mmol) in THF

(5 ml) was added via cannula, and after 14 h a solution

of acetaldehyde (0.500 ml, 9.0 mmol) in THF (5 ml) was

added via cannula and stirred for 3 h at ꢀ78 ꢁC before

warming to rt. After concentration in vacuo, the resul-

tant oil was extracted into CHCl₃(3·20 ml) and ﬁltered

through alumina (grade V). Concentration in vacuo and

chromatographic puriﬁcation of the residue on alumina

(grade I) [EtOAc/CH₂Cl₂(1:9)] gave 24:25 as a mixture

of diastereoisomers (89:11; 0.490 g, 78%). Crystallisation

(Et₂O:hexane) gave 24 as a single diastereoisomer as or-

ange plates; Found: C, 68.55; H, 6.05; N, 2.0%;

C₄₈H₅₂FeNO₇P requires C, 68.5; H, 6.3; N, 2.1%; v_max

(CH₂Cl₂) 1900 (C„O), 1602 (C@O); d_H(300 MHz,

CDCl₃) ꢀ0.08 (3H, d, J6.6, CHCH₃), 0.44 (3H, d,

J6.5, CH(OH)CH₃), 2.83 (1H, br s, C(3)H), 3.15 (1H,

m, C(2)H), 3.50 (4H, m, NCH₂Ph), 3.84 (12H, s,

4·OMe), 4.32 (5H, d, J_PH1.1, C₅H₅), 4.92 (1H, m,

CH(OH)CH₃), 6.96–6.73 (6H, m, Ar), 7.52–7.18 (15H,

m, PPh₃); d_C(50 MHz, CDCl₃) 7.5, 17.9, 52.0, 53.0,

55.8, 68.0, 76.8, 86.2, 110.8, 113.2, 122.3, 128.1, 129.7,

131.0, 133.3, 136.6, 148.3, 149.0, 221.0; m/z (FAB+)

842 (MH⁺, 100%); d_P(100 MHz) 69.3.

3.11. Preparation of (3RS,4RS,1⁰RS)-1-benzyl-3-(1⁰-

hydroxyethyl)-4-methylazetidin-2-one (28)

To a solution of 26 (0.300 g, 0.47 mmol) in DCM (5

ml) at ꢀ78 ꢁC was added a solution of bromine (0.050

ml, 1.0 mmol) in DCM (5 ml) via cannula. The resultant

solution was stirred for 2 h at ꢀ78 ꢁC before NEt₃(0.1

ml) was added. After 1 h at ꢀ78 ꢁC the reaction was al-

lowed to warm to rt and concentrated in vacuo. The res-

idue was triturated with Et₂O, and the ﬁltrate

concentrated in vacuo to give an oil which was puriﬁed

by column chromatography on silica gel (EtOAc) to give

28 as an oil (0.072 g, 70%); v_max(ﬁlm) 1737s (C@O); d_H

(300 MHz, CDCl₃) 1.21 (3H, d, J6.5, C(4)HCH₃), 1.27

(3H, d, J6.2, CH(OH)CH₃), 2.07 (1H, br s, OH), 3.08

(1H, dd, J7.5, J5.3, C(3)H), 3.67 (1H, m, C(4)H), 4.10

(1H, AB, J_AB15.3, NCH_AHPh), 4.12 (1H, m, C(1⁰)H),

4.61 (1H, AB, J_AB15.3, CH_BHPh), 7.36–7.23 (5H, m,

Ph); d_C(50 MHz, CDCl₃) 13.6, 22.4, 43.9, 50.3, 58.5,

64.7, 127.7, 128.1, 128.8, 135.8, 168.7; 168.7 (CO), m/z

(CI, NH₃) 220 (MH⁺, 100%).

3.10. Preparation of (RS,RS,RS,RS) and (RS,RS,

RS,SR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH[CH(OH)-

CH₃]CH{NHCH₂Ph}CH₃(26 and 27)

3.12. Preparation of (Z,RS)-1-benzyl-3-ethylidene-4-

methylazetidin-2-one (29)

n-BuLi (1.60 ml, 2.40 mmol) was added to a solution

of (N-trimethylsilyl)benzylamine (0.520 g, 2.90 mmol) in

THF (5 ml) at 0 ꢁC and stirred for 1 h before cooling to

ꢀ78 ꢁC. A cooled solution of 12 (0.46 g, 0.96 mmol) in

THF (5 ml) at ꢀ95 ꢁC was added via cannula, and after

3 h a solution of acetaldehyde (0.500 ml, 9.0 mmol) in

THF (5 ml) was added via cannula and stirred for 3 h

at ꢀ95 ꢁC before the addition of methanol (1 ml) and

the reaction allowed to warm to rt. After concentration

in vacuo, the resultant oil was extracted into CHCl₃

Methanesulphonyl chloride (0.024 g, 0.18 mmol) was

added dropwise to a solution of 28 (0.040 g, 0.18 mmol)

and NEt₃(0.025 ml, 0.18 mmol) in DCM (1 ml) at 0 ꢁC.

The resulting solution was stirred for 30 min, then

washed with water, 1 M pH 3 phosphate buﬀer, sodium

hydrogen carbonate solution, brine and dried. Follow-

ing evaporation, the residue was dissolved in methanol

(5 ml), sodium hydrogen carbonate (0.090 g, 1.0 mmol)

added, and the solution heated at reﬂux for 30 min,

cooled, ﬁltered and evaporated to yield 29 as an oil

4200

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

(0.024 g, 65%); d_H(300 MHz, CDCl₃) 1.18 (3H, d, J6.1,

C(4)HCH₃), 2.01 (3H, d, J7.2, C@CHCH₃), 3.88 (1H, q,

J6.1, C(4)H), 4.18 (1H, AB, J_AB15.3, NCH_AHPh), 4.68

(1H, AB, J_AB15.3, CH_BHPh), 5.54 (1H, q, J7.2,

C@CHCH₃), 7.35–7.25 (5H, m, Ph); m/z (CI, NH₃)

202 (MH⁺, 100%).

which was puriﬁed by column chromatography on silica

gel [Et₂O/40–60 (1:4)] to give the selenide. Crystallisation

from DCM/hexane yielded 34 as red blocks (1.00 g, 75%);

Found: C, 63.2; H, 4.6%; C₃₂H₂₇FeO₂PSe requires C,

63.1; H, 4.5%; v_max(CH₂Cl₂) 1920 (C„O), 1593 (C@O);

d_H(300 MHz, CD₂Cl₂) 3.78 (1H, AB, J_AB14.4, CH_AH-

SePh), 4.30 (1H, AB, J_AB14.4, CH_BHSePh), 4.45 (5H, d,

J_PH1.1, C₅H₅), 7.55–7.23 (20H, m, Ph); d_C(50 MHz,

CDCl₃) 55.8, 85.5, 126.3, 128.4, 128.9, 129.7, 132.2,

132.3, 133.4, 136.0, 220.5, 270.0; m/z (FAB+) 611

(MH⁺, 25%), 383 (100%); d_P76.9 (PPh₃).

3.13. Preparation of (RS,SR) and (RS,RS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH(SePh)CH₃(32 and 33)

(i) To a solution of 2 (0.525 g, 1.12 mmol) in THF (10

ml) at ꢀ78 ꢁC was added n-BuLi (1.57 M, 0.800 ml,

1.26 mmol). After 2 h a solution of diphenyl disel-

enide (0.405 g, 1.30 mmol) in THF (10 ml) was

added via cannula. After 6 h at ꢀ78 ꢁC the reaction

was quenched by addition of methanol (1 ml),

warmed to rt and concentrated in vacuo. The resi-

due was extracted using DCM (2·20 ml) and ﬁl-

tered through alumina (grade V), and the ﬁltrate

evaporated to an oil which was puriﬁed by column

chromatography on alumina (grade I) yielding

starting material 2 (0.140 g, 27%) and an insepara-

ble 66:34 mixture of diastereoisomers 32 and 33

{(0.230 g, 33%), 45% based on recovered starting

material}; 32 d_H(300 MHz, CDCl₃) 0.73 (3H, d,

J6.8, C(3)H₃), 4.29 (1H, q, J6.8, C(2)H), 4.55

(5H, d, J_PH1.3, C₅H₅), 7.67–7.22 (20H, m, Ph),

33; d_H(300 MHz, CDCl₃) 1.60 (3H, d, J6.8,

C(3)H₃), 4.20 (1H, q, J7.9, C(2)H), 4.52 (5H, d,

J_PH1.3, C₅H₅), 7.68–7.18 (20H, m, Ph).

(ii) To a solution of 34 (0.610 g, 1.00 mmol) in THF

(20 ml) at ꢀ78 ꢁC was added n-BuLi (1.6 M,

0.750 ml, 1.20 mmol), before the addition of

MeI (0.100 ml, 1.52 mmol) via syringe after 1

h. The reaction mixture was allowed to warm to

rt over 4 h and the solvent removed in vacuo.

The resulting oil was extracted with DCM

(2·20 ml) and ﬁltered through alumina (grade

V). Concentration in vacuo and puriﬁcation by

column chromatography on silica gel [Et₂O/40–

60 (1:4)] aﬀorded an 9:91 mixture of 32:33

(0.570 g, 91%).

3.15. Preparation of (RS)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH@CH₂(35)

To a solution of 32:33 (9:91; 0.570 g, 0.91 mmol) in

DCM (20 ml) at ꢀ78 ꢁC was added a solution of 55%

m-chloroperbenzoic acid (0.290 g, 0.91 mmol) in DCM

(10 ml) via cannula. After 1 h, diisopropylamine (0.510

ml, 3.60 mmol) at was added using a syringe and the re-

action mixture allowed to warm to rt over 4 h, before be-

ing ﬁltered through alumina (grade V) and concentrated

in vacuo. The crude product was puriﬁed by column

chromatography on silica gel [Et₂O/40–60 (1:2)] and

crystallised from Et₂O to give 35 as yellow needles

(0.320 g, 75%) with identical spectroscopic properties

to those reported previously [23].

3.16. Preparation of (RS,SR)- and (RS,RS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH(SePh)CH₂CH@CH₂(36

and 37)

To a solution of 34 (0.500 g, 0.82 mmol) in THF (10

ml) at ꢀ78 ꢁC was added n-BuLi (1.6 M, 0.62 ml, 0.96

mmol), before the addition of allyl iodide (0.160 ml,

1.60 mmol) after 2 h. The reaction mixture was allowed

to warm to rt over 16 h, before concentration in vacuo

and the residual oil extracted with DCM (2·20 ml). Af-

ter ﬁltration of this solution through alumina (grade V)

and removal of the solvent, the crude products were pu-

riﬁed by column chromatography [Et₂O/40–60 (1:4)] to

give the title compounds as an 86:14 mixture of diastere-

oisomers 36:37. Recrystallisation of the mixture from

DCM/hexane yielded 36 as orange needles (0.400 g,

72%); Found: C, 64.4; H, 4.7%; C₃₅H₃₁FeO₂PSe re-

quires C, 64.7; H, 4.8%; v_max(CH₂Cl₂) 1919 (C„O),

1582 (C@O); d_H(300 MHz, CDCl₃) 2.48 (1H, m,

CH_AHCH@CH₂); 2.89 (1H, m, CH_BHCH@CH₂), 4.23

(1H, t, J5.4, C(2)H), 4.46 (5H, d, J_PH1.1, C₅H₅), 5.06–

5.00 (2H, m, CH@CH₂), 5.96 (1H, m, CH@CH₂),

7.12–7.58 (20H, m, Ph); d_C(50 MHz, CDCl₃) 35.0,

71.7, 85.7, 116.0, 126.6, 128.2, 129.0, 129.9, 130.7,

134.5, 136.0, 136.5, 220.6, 273.2; m/z (FAB+) 651

(MH⁺, 10%), 383 (100%); d_P74.2 (PPh₃).

3.14. Preparation of (RS)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH₂SePh (34)

To acetyl complex 1 (1.00 g, 2.20 mmol) in THF (30 ml)

at ꢀ78 ꢁC was added n-BuLi (1.6 M, 1.50 ml, 2.40 mmol),

before the addition of a solution of diphenyl diselenide

(0.825 g, 2.60 mmol) in THF (10 ml) was added via cannu-

la after 2 h. The solution was stirred for 1 h, methanol (1

ml) added and the reaction mixture warmed to rt before

being concentrated in vacuo. Extraction of the resulting

oil using DCM (3·30 ml), ﬁltration through alumina

(grade V) and further evaporation gave the crude product,

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4201

3.17. Preparation of (E,RS)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH@CHCH@CH₂(41)

removal of the solvent and puriﬁcation by column chro-

matography on silica gel [Et₂O/40–60 (3:7)] that gave

partial separation of the diastereoisomers. The less polar

fraction was obtained as a 50:50 mixture of 39:40, the

more polar fraction gave 39 as a single diastereoisomer

which was then crystallised from Et₂O to yield red

blocks (overall yield 2.63 g, 69%); 39. Found: C, 62.5;

H, 5.1%; C₃₇H₃₇FeO₄PSe requires C, 62.5; H, 5.2%; v_max

(CH₂Cl₂) 1912 (C„O), 1584 (C@O); d_H(500 MHz,

CDCl₃) 0.75, 1.12, 1.23, 1.56 (4·1H, m, CH₂CH₂),

3.11 (3H, s, OMe), 3.19 (3H, s, OMe), 3.98 (1H, t,

J5.7, CH(OMe)₂), 4.04 (1H, dd, J10.1, J3.1, C(2)H),

4.49 (5H, d, J_PH1.1, C₅H₅), 7.22–7.57 (20H, m, Ph), d_C

(50 MHz, CDCl₃) 25.4, 30.4, 51.8, 52.6, 74.1, 85.8,

104.2, 127.0, 128.1, 128.9, 129.8, 130.7, 133.4, 133.7,

136.4, 220.5, 272.1; m/z (FAB+) 713 (MH⁺, 3%), 383

(100%); d_P74.5 (PPh₃). Selected data for 40; d_H(300

MHz, CDCl₃) 3.23 (3H, s, OMe), 3.23 (3H, s, OMe),

4.47 (5H, d, J_PH1.3, C₅H₅); d_C(50 MHz, CDCl₃) 29.5,

52.4, 53.3, 85.8, 104.9.

To a mixture of 36:37 (86:14; 0.160 g, 0.25 mmol) in

DCM (5 ml) at ꢀ78 ꢁC was added a solution of 55% m-

chloroperbenzoic acid (0.080 g, 0.25 mmol) in DCM (2

ml) via cannula and after 1 h diisopropylamine (0.160

ml, 1.00 mmol) was added using syringe. After 1 h,

the reaction mixture was allowed to warm to rt over

4 h, before being ﬁltered through alumina (grade V)

and concentrated in vacuo. The crude product was pu-

riﬁed by column chromatography on silica gel [Et₂O/

40–60 (1:4)] to give the (E)-isomer 41 and some of the

less polar (Z)-isomer in the ratio (93:7). Recrystallisa-

tion of this mixture from Et₂O yielded the title com-

pound 41 as red needles (0.080 g, 66%) with identical

spectroscopic properties to those described in the liter-

ature [23].

3.18. Preparation of (RS)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

CO(CH₂)₃CH(OMe)₂(38)

3.20. Preparation of (E,RS)-(g⁵-C₅H₅)Fe(CO)(PPh₃)-

COCH@CHCH₂CH(OMe)₂(31)

To a solution of acetyl complex 1 (1.40 g, 3.08 mmol)

in THF (15 ml) at ꢀ78 ꢁC was added n-BuLi (1.5 M,

2.15 ml, 3.22 mmol), before the addition of 3-bromo-

1,1-dimethoxypropane (0.510 ml, 3.36 mmol) by syringe

after 2 h. The reaction mixture was then to warm to rt

over 6 h, methanol (1 ml) added and the solvents re-

moved in vacuo. Extraction into DCM (3·20 ml) and

ﬁltration through alumina (grade V) and subsequent pu-

riﬁcation by column chromatography on silica gel

[Et₂O/40–60 (1:2)], then crystallisation from Et₂O aﬀor-

ded 38 as orange needles (1.34 g, 78%); Found: C, 66.7;

H, 5.9%; C₃₁H₃₃FeO₄P requires C, 66.9; H, 6.0%; v_max

(CH₂Cl₂) 1914 (C„O), 1605 (C@O); d_H(300 MHz,

CDCl₃) 1.32–1.05 (4H, m, C(3)H₂C(4)H₂), 2.55 (1H,

m, C(2)H_A), 2.88 (1H, m, COCH_B), 3.24 (3H, s,

OMe), 3.26 (3H, s, OMe), 4.21 (1H, t, J5.3, CH(OMe)₂),

4.41 (5H, d, J_PH1.1, C₅H₅), 7.36–7.59 (15H, m, PPh₃);

d_C(50 MHz, CDCl₃) 20.2, 31.7, 52.1, 52.6, 65.4, 85.2,

104.5, 128.2, 129.8, 133.5, 136.6, 221.0, 277.2; m/z

(FAB+) 557 (MH⁺, 10%), 525 (100%), 383 (100%); d_P

76.2 (PPh₃).

To a mixture of 39:40 (75:25; 2.4 g, 3.4 mmol) in

DCM (10 ml) at ꢀ78 ꢁC was added a solution of 55%

m-chloroperbenzoic acid (1.1 g, 3.4 mmol) in DCM

(10 ml) via cannula and after 1 h diisopropylamine

(2.0 ml, 14.3 mmol) was added using syringe. After 1

h, the reaction mixture was allowed to warm to rt over

4 h, before being ﬁltered through alumina (grade V)

and concentrated in vacuo. The crude product was puri-

ﬁed by column chromatography on silica gel [Et₂O/40–

60 (2:5)] and subsequently crystallised from Et₂O to give

31 as red needles (1.55 g, 83%); Found: C, 67.1; H, 5.4%;

C₃₁H₃₁FeO₄P requires C, 67.2; H, 5.6%; v_max(CH₂Cl₂)

1918 (C„O), 1566 (C@O); d_H(300 MHz, CDCl₃) 2.24

(2H, app t, J6.5, CH₂) 3.31 (6H, s, 2·OMe), 4.37 (1H,

t, J5.9, CH(OMe)₂), 4.43 (5H, d, J_PH1.2, C₅H₅), 5.41

(1H, dt, J15.3, J7.2, COCH@CH), 6.50 (1H, d, J15.3,

COCH), 7.31–7.52 (15H, m, PPh₃); d_C(50 MHz, CDCl₃)

34.9, 52.6, 52.8, 85.4, 103.5, 123.0, 127.9, 129.6, 133.3,

136.3, 146.6, 220.6, 271.3; m/z (FAB+) 555 (MH⁺,

15%), 383 (100%); d_P76.9 (PPh₃).

3.19. Preparation of (RS,SR) and (RS,RS)-(g⁵-C₅H₅)-

Fe(CO)(PPh₃)COCH(SePh)CH₂CH₂CH(OMe)₂(39

and 40)

3.21. Preparation of (RS,RS)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH(NHCH₂Ph)CH₂CH(OMe)₂(42)

To a solution of 38 (3.00 g, 5.40 mmol) in THF (60

ml) at ꢀ78 ꢁC was added n-BuLi (1.5 M, 4.2 ml, 6.0

mmol) before the addition of a solution of diphenyl di-

selenide (2.0 g, 6.5 mmol) in THF (10 ml) after 2 h. The

reaction was allowed to warm to ꢀ10 ꢁC over 5 h before

the addition of methanol (1 ml). After concentration in

vacuo, the crude products were extracted into DCM

(2·20 ml) and ﬁltered through alumina (grade V) before

To benzylamine (0.580 g, 5.40 mmol) in THF (10 ml)

at ꢀ78 ꢁC was added n-BuLi (1.6 M, 2.40 ml, 3.85

mmol) at ꢀ78 ꢁC and stirred for 1 h before being added

via cannula to a solution of 31 (1.00 g, 1.80 mmol) in

THF (20 ml) at ꢀ78 ꢁC. After 5 h and then quenched

by the addition of methanol (1 ml). After warming

and evaporation of the solvent under reduced pressure

the residue was extracted into CHCl₃(2·20 ml) and

4202

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

ﬁltered through alumina (grade V). Puriﬁcation by ﬂash

chromatography on alumina (grade I) [DCM/EtOAc

(3:7)] yielded 42 which was subsequently crystallised

from Et₂O as orange needles (0.970 g, 82%); Found:

C, 69.1; H, 6.1; N, 2.0%; C₃₈H₄₀NO₄P requires C,

69.0; H, 6.1; N, 2.1%; v_max(CH₂Cl₂) 1914 (C„O),

1603 (C@O); d_H(300 MHz, CDCl₃) 1.22–1.42 (2H, m,

C(4)H₂), 2.67 (1H, dd, J16.2, J6.2, C(2)H_AH), 2.75

(1H, m, C(3)H), 3.22 (1H, dd, J16.2, J4.8, C(2)H_BH),

3.22 (3H, s, OMe), 3.25 (3H, s, OMe), 3.58 (1H, AB,

J_AB13.2, NCH_AHPh), 3.60 (1H, AB, J_AB13.2,

NCH_BHPh), 4.37 (1H, t, J5.5, CH(OMe)₂), 4.40 (5H,

d, J_PH1.1, C₅H₅), 7.51–7.17 (20H, m, Ph); d_C(50

MHz, CDCl₃) 36.9, 50.8, 50.9, 52.7, 52.8, 69.8, 85.3,

103.5, 126.7, 128.2, 129.9, 133.2, 136.6, 141.9, 220.9,

278.3; m/z (FAB+) 662 (MH⁺, 25%), 383 (100%); d_P

76.1 (PPh₃).

NEt₃(0.500 ml) was added. After 2 h at ꢀ78 ꢁC, the so-

lution was allowed to warm to rt and the solvent re-

moved in vacuo. Trituration with Et₂O, ﬁltration and

evaporation of the ﬁltrate gave an oil which was subject-

ed to column chromatography on silica gel [EtOAc/40–

60 (1:1)], giving 44 as a pale yellow oil (0.120 g, 75%);

Found: C, 68.4; H, 8.3%; C₁₅H₂₁NO₃requires C, 68.4;

H, 8.0%; v_max(ﬁlm) 1747 (C@O); d_H(300 MHz, CDCl₃)

1.21 (3H, d, J7.6, C(3)HCH₃), 1.78 (2H, m, C(4)CH₂),

3.18 (3H, s, OMe), 3.21 (3H, s, OMe), 3.27 (1H, dq,

J7.6, J5.3, C(3)H), 3.66 (1H, m, C(4)H), 4.18 (1H, AB,

J15.4, NCH_AHPh), 4.29 (1H, t, J5.6, CH(OMe)₂), 4.57

(1H, AB, J15.4, NCH_BHPh), 7.22–7.35 (5H, m, Ph);

d_C(50 MHz, CDCl₃) 9.6, 32.2, 44.5, 47.2, 51.6, 53.0,

53.4, 102.5, 127.5, 127.9, 128.7, 136.4, 171.5; m/z (CI,

NH₃) 264 (MH⁺, 100%).

3.24. Preparation of (RS,RS,RS,RS) and (RS,-

RS,RS,SR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH[CH(OH)-

CH₃]CH(NHCH₂Ph)CH₂CH(OMe)₂(45 and 46)

3.22. Preparation of (RS,2SR,3RS)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH(Me)CH(NHCH₂Ph)CH₂CH(OMe)₂

(43)

To a solution of (N-trimethylsilyl)benzylamine (1.30

g, 7.30 mmol) in THF (5 ml) at ꢀ78 ꢁC was added n-

BuLi (1.5 M, 4.30 ml, 6.45 mmol) and stirred for 1 h be-

fore being added to a solution of 31 (1.00 g, 1.80 mmol)

in THF (15 ml) at ꢀ95 ꢁC. After 4 h a solution of acet-

aldehyde (1.0 ml, 18.0 mmol) in THF (15 ml) was added

via cannula and after 3 h at ꢀ95 ꢁC methanol (1 ml) was

added. After warming to rt the reaction mixture was

concentrated in vacuo and the resultant oil extracted in-

to CHCl₃(3·20 ml), ﬁltered through alumina (grade V),

concentrated in vacuo and the residue puriﬁed by col-

umn chromatography on alumina (grade I) [EtOAc/

40–60(3:7)-EtOAc] to give 45 and 46 as a 50:50 mixture

of diastereoisomers. Further column chromatography

on silica gel [CHCl₃/MeOH/AcOH (90:4:2)] gave the less

polar diastereoisomer 45, which was subsequently crys-

tallised from DCM/Et₂O, giving 45 as orange needles

(0.450 g, 35%); Found: C, 61.2; H, 5.8; N, 1.7%;

C₄₀H₄₄FeNO₅P (1.2 CH₂Cl₂) requires C, 61.2; H, 5.8;

N, 1.7%; v_max(CH₂Cl₂) 1915 (C„O), 1591 (C@O); d_H

(500 MHz, CDCl₃) 0.54 (1H, br m, C(4)CH_AH), 0.90

(1H, br m, C(4)CH_BH), 1.23 (3H, d, J6.6, CHCH₃),

2.99 (1H, br m, C(3)H), 3.25 (3H, s, OMe), 3.28 (3H,

s, OMe), 3.35 (1H, dd, J8.7, J2.6, C(2)H), 3.52 (1H,

AB, J_AB12.6, NCH_AHPh), 3.64 (1H, AB, J_AB12.6,

NCH_BHPh), 4.26 (1H, t, J5.4, CH(OMe)₂), 4.42 (5H,

d, J_PH1.0, C₅H₅), 4.91 (1H, br m, CH(OH)Me), 6.80

(1H, br s, NH), 7.19–7.50 (20H, m, Ph), d_C(50 MHz,

CDCl₃) 20.2, 35.6, 50.8, 52.5, 53.0, 53.9, 67.6, 78.6,

86.4, 103.9, 127.0, 128.2, 128.4, 129.9, 133.3, 134.0,

136.5, 220.3 m/z (FAB+) 706 (MH⁺, 50%), 383

(100%); d_P73.3 (PPh₃). Further elution and subsequent

crystallisation (Et₂O) gave 46 as orange needles (0.465 g,

37%); Found: C, 67.8; H, 6.6; N, 2.05%; C₄₀H₄₄FeNO₅P

requires C, 68.1; H, 6.3; N, 2.0%; v_max(CH₂Cl₂) 1911

To benzylamine (0.15 g, 1.35 mmol) in THF (10 ml)

at ꢀ78 ꢁC was added n-BuLi (1.4 M, 0.8 ml, 1.12 mmol)

at ꢀ78 ꢁC and stirred for 1 h before being added via can-

nula to a solution of 31 (0.25 g, 0.45 mmol) in THF (10

ml) at ꢀ78 ꢁC. After 3 h MeI (0.150 ml, 2.40 mmol) was

added via syringe before the addition of methanol (1 ml)

after a further 3 h. After warming and evaporation of

the solvent under reduced pressure the residue was ex-

tracted into CHCl₃(2·20 ml) and ﬁltered through alu-

mina (grade V). Puriﬁcation by ﬂash chromatography

on alumina (grade I) [DCM/EtOAc (4:1)] yielded 43

which was subsequently crystallised from Et₂O as or-

ange needles (0.230 g, 76%); Found: C, 69.4; H, 6.2;

N, 1.9%; C₃₉H₄₂FeNO₄P requires C, 69.3; H, 6.3; N,

2.1%; v_max(CH₂Cl₂) 1914 (C„O), 1595 (C@O); d_H

(300 MHz, CDCl₃) 1.08 (3H, d, J7.3, C(2)CH₃) 1.36

(1H, ddd, J14.2, J7.4, J5.5, C(4)H_AH), 1.52 (1H, dt,

J14.2, J5.5, C(4)H_BH), 2.39 (1H, ddd, J7.4, J5.5, J4.8,

C(3)H), 3.13 (1H, AB, J_AB12.9, NCH_AHPh), 3.27 (3H,

s, OMe), 3.28 (3H, s, OMe), 3.28 (1H, dq, J7.3, J2.7,

C(2)H), 3.43 (1H, AB, J_AB12.9, NCH_BHPh), 4.37 (1H,

t, J5.5, CH(OMe)₂), 4.43 (5H, d, J_PH1.3, C₅H₅), 7.16–

7.55 (20H, m, Ph); d_C(50 MHz, CDCl₃) 11.7, 35.1,

51.6, 52.5, 54.1, 69.8, 85.1, 103.1, 126.3, 128.1, 129.7,

133.4, 136.9, 141.1, 221.0, 282.9; m/z (FAB+) 676

(MH⁺, 30%), 383 (100%); d_P75.7 (PPh₃).

3.23. Preparation of (3SR,4RS)-1-benzyl-4-(2⁰, 2⁰-dime-

thoxyethyl)-3-methylazetidin-2-one (44)

To a solution of 43 (0.410 g, 0.61 mmol) in DCM (10

ml) was cooled to ꢀ78 ꢁC and a solution of bromine

(0.062 ml, 1.20 mmol) in DCM (2 ml) was added drop-

wise via cannula. The reaction was stirred for 1 h then

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4203

(C„O), 1601 (C@O); d_H(500 MHz, CDCl₃) 1.40 (1H,

br m, C(4)CH_AH), 1.41 (3H, d, J6.7, CHCH₃), 1.82

(1H, br m, C(4)CH_BH), 2.63 (1H, d, J7.6, C(3)H), 2.65

(1H, d, J3.4, C(2)H), 3.24 (3H, s, OMe), 3.25 (3H, s,

OMe), 3.30 (1H, AB, J_AB12.6, NCH_AHPh), 3.69 (1H,

AB, J_AB12.6, NCH_BHPh), 4.16 (1H, dd, J7.0, J3.4,

CH(OMe)₂), 4.53 (5H, d, J_PH1.2, C₅H₅), 4.53 (1H, dq,

J10.4, J6.6, CH(OH)Me), 7.20–7.70 (20H, m, Ph); d_C

(50 MHz, CDCl₃) 24.5, 39.9, 51.6, 52.4, 53.5, 54.6,

67.8, 80.5, 86.8, 104.3, 126.6, 128.0, 128.2, 129.7,

133.4, 136.8, 140.7, m/z (FAB+) 706 (MH⁺, 40%), 383

(100%); d_P74.8 (PPh₃).

J6.6, J3.7, CH(OMe)₂), 4.62 (1H, AB, J_AB15.3,

NCH_AHPh), 7.24–7.39 (5H, m, Ph); d_C(50 MHz,

CDCl₃) 21.3, 30.6, 44.1, 51.3, 52.9, 54.9, 61.1, 63.5,

103.0, 127.8, 128.1, 128.8, 135.8, 167.3; m/z (CI, NH₃)

294 (MH⁺, 5%), 186 (100%).

3.27. Preparation of (3RS,4RS,1⁰⁰SR)-4-(2⁰,2⁰-dimeth-

oxyethyl)-3-(1⁰⁰-hydroxyethyl)azetidin-2-one (50)

NH₃(10 ml) was condensed at ꢀ78 ꢁC and sodium

(25 mg, 1.10 mmol) added. The resulting blue solution

was warmed and the dried ammonia re-condensed at

ꢀ78 ꢁC. Ethanol (0.10 ml) was added via syringe, fol-

lowed by sodium (10 mg, 0.43 mmol) and the blue solu-

tion was stirred for 5 min at ꢀ78 ꢁC before a solution of

48 (11 mg, 0.04 mmol) in THF (1 ml) was added via sy-

ringe. Following a further addition of sodium (10 mg,

0.43 mmol) the reaction mixture maintained a blue col-

our, and after stirring for a further 10 min at ꢀ78 ꢁC the

reaction was quenched by the addition of solid ammoni-

um chloride (0.10 g). On warming, and after evapora-

tion of the ammonia, the residue was dissolved in

DCM (5 ml) and ﬁltered. Concentration in vacuo, and

puriﬁcation by column chromatography on silica gel

[CHCl₃/MeOH (9:1)] gave 50 as an oil (5 mg, 66%); d_H

(300 MHz, CDCl₃) 1.42 (3H, d, J6.2, CHCH₃), 1.96

(1H, ddd, J14.4, J8.1, J5.4, C(4)CH_AH), 2.29 (1H, dt,

J14.4, J4.8, C(4)CH_BH), 3.20 (1H, ddd, J10.1, J5.2,

J1.5, C(3)H), 3.37 (3H, s, OMe), 3.39 (3H, s, OMe),

3.88 (1H, dt, J8.1, J5.0, C(4)H), 4.16 (1H, dq, J10.1,

J6.2, CH(OH)Me), 4.50 (1H, app t, J5.1, CH(OMe)₂),

5.99 (1H, br s, NH); d_C(50 MHz, CDCl₃) 22.1, 33.6,

48.2, 53.8, 54.1, 60.8, 63.9, 104.0, 167.7; m/z 189

(M+NH₄⁺-MeOH, 5%), 96 (100%); M+NH₄⁺-MeOH

exact mass calculated 189.1239, Found 189.1246.

3.25. Preparation of (3RS,4RS,1⁰⁰RS)-1-benzyl-4-(2⁰,2⁰-

dimethoxyethyl)-3-(1⁰⁰-hydroxyethyl)azetidin-2-one (47)

To a solution of 45 (0.150 g, 0.21 mmol) in DCM (5

ml) at ꢀ78 ꢁC was added a solution of bromine (0.022

ml, 0.42 mmol) in DCM (5 ml) via cannula. The resul-

tant solution was stirred for 2 h at ꢀ78 ꢁC before

NEt₃(0.1 ml) was added. After 1 h at ꢀ78 ꢁC the reac-

tion was allowed to warm to rt and concentrated in vac-

uo. The residue was triturated with Et₂O, and the ﬁltrate

concentrated in vacuo to give an oil which was puriﬁed

by column chromatography on silica gel (EtOAc) to give

47 as an oil (0.031 g, 50%); d_H(300 MHz, CDCl₃) 1.39

(3H, d, J6.4, CHCH₃), 2.00 (1H, ddd, J14.6, J7.1, J5.1,

C(4)CH_AH), 2.08 (1H, dt, J14.6, J5.8, C(4)CH_BH), 2.34

(1H, br s, Me(OH)CH), 3.19 (3H, s, OMe), 3.20 (1H,

obscured, C(1)H), 3.21 (3H, s, OMe), 3.71 (1H, dt,

J7.1, J5.4, C(3)H), 4.12 (1H, dq, J6.4, J4.4,

CH(OH)Me), 4.23 (1H, app t, J5.8, CH(OMe)₂), 4.24

(1H, AB, J_AB15.5, NCH_AHPh), 4.62 (1H, AB,

J_AB15.5, NCH_BHPh), 7.24–7.35 (5H, m, Ph), d_C(50

MHz, CDCl₃) 23.1, 32.2, 44.6, 51.5, 53.1, 53.5, 58.6,

64.5, 102.8, 127.5, 127.8, 128.7, 136.2, 168.8.

3.28. Preparation of (3RS,4RS,1⁰⁰RS)-4-(2⁰,2⁰-dimeth-

oxyethyl)-3-(1⁰⁰-hydroxyethyl)azetidin-2-one (49)

3.26. Preparation of (3RS,4RS,1⁰⁰SR)-1-benzyl-4-(2⁰,2⁰-

dimethoxyethyl)-3-(1⁰⁰-hydroxyethyl)azetidin-2-one (48)

NH₃(10 ml) was condensed at ꢀ78 ꢁC and sodium

(25 mg, 1.10 mmol) added. The resulting blue solution

was warmed and the dried ammonia re-condensed at

ꢀ78 ꢁC. Ethanol (0.10 ml) was added via syringe, fol-

lowed by sodium (10 mg, 0.43 mmol) and the blue solu-

tion was stirred for 5 min at ꢀ78 ꢁC before a solution of

47 (22 mg, 0.07 mmol) in THF (1 ml) was added via sy-

ringe. Following a further addition of sodium (10 mg,

0.43 mmol) the reaction mixture maintained a blue col-

our, and after stirring for a further 10 min at ꢀ78 ꢁC the

reaction was quenched by the addition of solid ammoni-

um chloride (0.10 g). On warming, and after evapora-

tion of the ammonia, the residue was dissolved in

DCM (5 ml) and ﬁltered. Concentration in vacuo, and

puriﬁcation by column chromatography on silica gel

[CHCl₃/MeOH (9:1)] gave 49 as an oil (13 mg, 85%);

d_H(300 MHz, CDCl₃) 1.32 (3H, d, J6.2, CHCH₃),

To a solution of 46 (105 mg, 0.15 mmol) in DCM (2

ml) at ꢀ78 ꢁC was added a solution of bromine (0.016

ml, 0.31 mmol) in DCM (5 ml) via cannula. The resul-

tant solution was stirred for 2 h at ꢀ78 ꢁC before

NEt₃(0.1 ml) was added. After 1 h at ꢀ78 ꢁC the reac-

tion was allowed to warm to rt and concentrated in vac-

uo. The residue was triturated with Et₂O, and the ﬁltrate

concentrated in vacuo to give an oil which was puriﬁed

by column chromatography on silica gel (EtOAc) to give

48 as an oil (19 mg, 44%); d_H(300 MHz, CDCl₃) 1.43

(3H, d, J6.1, CHCH₃), 1.90 (1H, dt, J14.9, J3.4,

C(4)CH_AH), 2.12 (1H, ddd, J14.9, J9.0, J6.7,

C(4)CH_BH), 3.18 (1H, dd, J10.2, J5.0, C(3)H), 3.29

(3H, s, OMe), 3.31 (3H, s, OMe), 3.71 (2H, m,

CH(OH)Me and C(4)H), 4.12 (1H, AB, J_AB15.3,

NCH_AHPh), 4.14 (1H, m, CH(OH)Me), 4.36 (1H, dd,

4204

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

1.93 (1H, ddd, J14.1, J4.1, J2.6, C(4)CH_AH), 2.11 (1H,

dd, J14.1, J10.8, J6.0, C(4)CH_BH), 3.19 (1H, app t, J5.9,

C(3)H), 3.35 (3H, s, OMe), 3.36 (3H, s, OMe), 3.85 (1H,

ddd, J10.8, J5.4, J2.6, C(4)H), 4.11 (1H, m,

CH(OH)Me), 4.47 (1H, dd, J6.0, J4.1, CH(OMe)₂),

6.19 (1H, br s, NH); d_C(50 MHz, CDCl₃) 22.7, 33.0,

47.7, 53.5, 54.0, 59.0, 64.4, 104.0, 169.3; m/z (CI, NH₃)

204 (MH⁺, 30%), 155 (100%); MH⁺exact mass calcu-

lated 204.1236, Found 204.1236.

in vacuo, the resultant oil was extracted into CHCl₃

(3·20 ml) and ﬁltered through alumina (grade V). Con-

centration in vacuo and chromatographic puriﬁcation of

the residue on alumina (grade I) [EtOAc/DCM (1:1)]

gave 58 as an orange foam (2.85 g, 90%); Found: C,

69.9, H, 6.5, N, 1.9%; C₃₉H₄₂FeNO₂PSi requires C,

69.7, H, 6.3, N, 2.1%; v_max(CH₂Cl₂) 1917 (C„O),

1604 (C@O); d_H(500 MHz, CDCl₃) 0.05 (9H, s, SiMe₃),

2.66 (1H, dd, J17.1, J2.7, C(2)H_AH), 2.98 (1H, m,

C(3)H), 3.10 (1H, dd, J17.1. J9.0, C(2)H_BH), 3.47

(1H, AB, J_AB13.3, NCH_AHPh), 3.59 (1H, AB,

J_AB13.3, NCH_BHPh), 4.40 (5H, d, J_PH1.0, C₅H₅), 5.51

(1H, d, J18.6, CH@CHSi), 5.67 (1H, dd, J18.6, J7.2,

CH@CHSi), 7.19–7.50 (20H, m, Ph); d_C(50 MHz,

CDCl₃) ꢀ1.2, 51.6, 60.9, 72.5, 85.4, 126.4, 128.0,

129.7, 130.1, 133.3, 136.3, 141.0, 148.4, 220.3, 277.3;

m/z (FAB+) 672 (MH⁺, 5%), 383 (100%); d_P75.95

(PPh₃).

3.29. Preparation of (E,E,RS)- and (Z,E,RS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH@CHCH@CHSiMe₃(53

and 54)

To a solution of trimethylsilyl complex 52 (3.10 g,

5.90 mmol) in THF (100 ml) at ꢀ78 ꢁC was added n-

BuLi (1.6 M, 4.40 ml, 7.00 mmol). After 1 h a solution

of (E)-3-trimethylsilylpropenal (1.60 g, 12.40 mmol) in

THF (10 ml) was added via cannula, and the reaction

then stirred at ꢀ78 ꢁC for 4 h before warming to rt.

The reaction mixture was evaporated to an oil which

was extracted into DCM (2·20 ml), ﬁltered through

alumina (grade V) and concentrated in vacuo before pu-

riﬁcation by column chromatography on silica gel

(DCM) giving (Z,E,RS)-54 as a red foam (1.22 g,

37%); Found: C, 68.2; H, 5.8%; C₃₂H₃₃FeO₂PSi requires

C, 68.1; H, 5.9%; v_max(CH₂Cl₂) 1917 (C„O), 1582

(C@O); d_H(300 MHz, CDCl₃) 0.02 (9H, s, SiMe₃),

4.44 (5H, d, J_PH1.1 C₅H₅), 5.13 (1H, app t, J10.8,

COCH@CH), 5.89 (1H, d, J18.4, CHSi), 6.37 (1H, d,

J11.1, COCH), 6.51 (1H, dd, J18.4, J10.8, CH@CHSi),

7.52–7.31 (15H, m, PPh₃); d_C(50 MHz, CDCl₃) ꢀ1.4,

85.5, 123.0, 128.1, 129.7, 133.2, 136.2, 139.4, 141.4,

141.5, 220.3, 273.3; m/z (FAB+) 565 (MH⁺, 5%), 383

(100%); d_P76.8 (PPh₃); further elution gave (E,E,RS)-

53 which was crystallised from Et₂O as beige needles

(1.82 g, 55%); Found: C, 67.9; H, 5.9%; C₃₂H₃₃FeO₂PSi

requires C, 68.1; H, 5.9%; v_max(CH₂Cl₂) 1917 (C„O),

1549 (C@O); d_H(300 MHz, CDCl₃) 0.09 (9H, s, SiMe₃),

4.44 (5H, d, J_PH1.1 C₅H₅), 5.80 (1H, dd, J14.9, J10.3,

COCH@CH), 6.11 (1H, d, J18.3, CHSi), 6.36 (1H, dd,

J18.3, J10.3, CH@CHSi), 6.47 (1H, d, J14.9, COCH),

7.50–7.31 (15H, m, PPh₃), d_C(50 MHz, CDCl₃) ꢀ1.4,

85.5, 127.0, 128.0, 129.7, 133.1, 136.3, 141.6, 143.1,

143.3, 220.7; m/z (FAB+) 565 (MH⁺, 5%), 383 (100%);

d_P76.8 (PPh₃).

3.31. Preparation of (RS,3SR)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃) COCH₂CH(NHCH₂Ph)CH@CH₂(57)

n-BuLi (1.6 M, 1.81 ml, 2.9 mmol) was added to a so-

lution of benzylamine (0.32 g, 3.0 mmol) in THF (5 ml)

at ꢀ78 ꢁC and stirred for 2 h. A solution of 53 (0.50 g,

1.01 mmol) in THF (15 ml) at ꢀ78 ꢁC was added via can-

nula, and after 3 h methanol (1 ml) was added and the

reaction allowed to warm to rt. After concentration in

vacuo, the resultant oil was extracted into chloroform

(3·20 ml) and ﬁltered through alumina (grade V). Con-

centration in vacuo and chromatographic puriﬁcation of

the residue on alumina (grade I) [EtOAc/DCM (1:1)] and

recrystallisation from Et₂O gave 57 as orange needles

(0.555 g, 92%); Found: C, 72.0, H, 6.0, N, 2.3%;

C₃₆H₃₄FeNO₂P requires C, 72.1, H, 5.7, N, 2.3%; v_max

(CH₂Cl₂) 1910 (C„O), 1600 (C@O); d_H(300 MHz,

CDCl₃) 2.75 (1H, dd, J17.1, J3,1, C(2)H_AH), 2.97 (1H,

m, C(3)H), 3.13 (1H, dd, J17.1, J8.6, C(2)H_BH), 3.48

(1H, AB, J_AB13.2, NCH_AHPh), 3.63 (1H, AB, J_AB13.2,

NCH_BHPh), 4.40 (5H, d, J_PH1.2, C₅H₅), 4.88–4.96

(2H, m, CH@CH₂), 5.45 (1H, ddd, J14.6, J10.3, J7.9,

CH@CH₂), 7.19–7.51 (20H, m, Ph); d_C(50 MHz, CDCl₃)

51.5, 58.4, 70.9, 85.4, 114.0, 126.0, 128.1, 128.4, 129.7,

133.2, 136.3, 140.0, 141.0, 220.3, 276.7; m/z (FAB+)

599 (M⁺, 5%), 383 (100%).

3.32. Preparation of (RS,3RS,E)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH(NHCH₂Ph)CH@CHSiMe₃(59)

3.30. Preparation of (RS,3SR,4E)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH(NHCH₂Ph)CH@CHSiMe₃(58)

n-BuLi (1.6 M, 8.1 ml, 13.0 mmol) was added to a so-

lution of benzylamine (1.64 g, 15.0 mmol) in THF (15

ml) at ꢀ78 ꢁC and stirred for 2 h. A solution of 54

(0.78 g, 1.38 mmol) in THF (25 ml) at ꢀ78 ꢁC was added

via cannula, and after 3 h methanol (1 ml) was added

and the reaction allowed to warm to rt. After concentra-

tion in vacuo, the resultant oil was extracted into

n-BuLi (11.20 ml, 18.0 mmol) was added to a solution

of benzylamine (2.03 g, 19.0 mmol) in THF (25 ml) at

ꢀ78 ꢁC and stirred for 2 h. A solution of 55 (2.67 g,

4.73 mmol) in THF (25 ml) at ꢀ78 ꢁC was added via

cannula, and after 3 h methanol (1 ml) was added and

the reaction allowed to warm to rt. After concentration

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4205

chloroform (3·20 ml) and ﬁltered through alumina

(grade V). Concentration in vacuo and chromatographic

puriﬁcation of the residue on alumina (grade I) [EtOAc/

DCM (1:1)] gave 59 as an orange foam (0.500 g, 54%);

Found: C, 69.6, H, 6.2, N, 1.9%; C₃₉H₄₂FeNO₂PSi re-

quires C, 69.7, H, 6.3, N, 2.1%; v_max(CH₂Cl₂) 1916

(C„O), 1605 (C@O); d_H(500 MHz, CDCl₃) 0.06 (9H,

s, SiMe₃), 2.85 (1H, dd, J17.0, J8.5, C(2)H_AH), 3.10

(1H, dd, J17.0, J3.5, C(2)H_BH), 3.28 (1H, ddd, J8.5,

J7.2, J3.5, C(3)H), 3.40 (1H, AB, J_AB13.0, NCH_AHPh),

3.52 (1H, AB, J_AB13.0, NCH_BHPh), 4.38 (5H, d,

J_PH1.0, C₅H₅), 5.68 (1H, d, J18.6, CH@CHSi), 5.79

(1H, dd, J18.6, J7.2, CH@CHSi), 7.16–7.48 (20H, m,

Ph); d_C(50 MHz, CDCl₃) ꢀ1.1, 51.8, 60.4, 71.0, 85.1,

126.5, 128.0, 128.0, 128.4, 129.7, 130.3, 133.2, 136.4,

140.8, 148.8, 220.3, 277.6; m/z (FAB+) 672 (MH⁺,

5%), 383 (100%); d_P76.6 (PPh₃).

a solution of acetaldehyde (5.0 ml) in THF (15 ml)

was added via cannula and stirred for 8 h at ꢀ78 ꢁC be-

fore the addition of methanol (1 ml) and the reaction al-

lowed to warm to rt. After concentration in vacuo, the

resultant oil was extracted into chloroform (3·20 ml)

and ﬁltered through alumina (grade V). Concentration

in vacuo and chromatographic puriﬁcation of the resi-

due on alumina (grade I) [EtOAc/CH₂Cl₂(1:1)] gave

61 which was crystallised (Et₂O:DCM) to give 61 as a

single diastereoisomer and as orange plates (0.60 g,

62%); Found: C, 70.7, H, 5.95, N, 2.2%; C₃₈H₃₈FeNO₃P

requires C, 70.9, H, 5.95, N, 2.2%; v_max(CH₂Cl₂) 1914

(C„O), 1600 (C@O); d_H(500 MHz, CDCl₃) 1.22 (3H,

d, J6.5, CH(OH)CH₃), 2.54 (1H, br m, CH(OH)Me);

2.70 (1H, br m, C(3)H), 2.93 (1H, br m, C(2)H), 3.32

(1H, AB, J_AB12.6, NCH_AHPh), 3.54 (1H, AB,

J_AB12.6, NCH_BHPh), 4.44 (2H, m, CH@CH₂), 4.55

(5H, d, J_PH1.0, C₅H₅), 4.65 (1H, m, CH@CH₂), 5.12

(1H, dq, J6.6, J2.0, CH(OH)Me), 7.21–7.62 (20H, m,

Ph); d_C(50 MHz, CDCl₃) 23.3, 50.4, 60.3, 68.4, 86.2,

116.1, 126.9, 128.2, 129.0, 132.0, 133.2, 136.1, 136.5,

139.5, 221.3; m/z (FAB+) 644 (MH⁺, 5%), 383 (100%);

d_P70.6 (PPh₃).

3.33. Preparation of (RS,3RS)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH(NHCH₂Ph)CH@CH₂(60)

n-BuLi (1.6 M, 43.8 ml, 70.0 mmol) was added to a

solution of benzylamine (7.7 g, 71.8 mmol) in THF

(160 ml) at ꢀ78 ꢁC and stirred for 2 h. A solution of

56 (3.50 g, 7.11 mmol) in THF (40 ml) at ꢀ78 ꢁC was

added via cannula, and after 30 h methanol (5 ml) was

added and the reaction allowed to warm to rt. After con-

centration in vacuo, the resultant oil was extracted into

chloroform (3·30 ml) and ﬁltered through alumina

(grade V). Concentration in vacuo and chromatographic

puriﬁcation of the residue on alumina (grade I) [EtOAc/

DCM (1:1)] and recrystallisation from Et₂O gave 60 as

orange needles (2.80 g, 66%); Found: C, 72.0, H, 6.05,

N, 2.3%; C₃₆H₃₄FeNO₂P requires C, 72.1, H, 5.7, N,

2.3%; v_max(CH₂Cl₂) 1910 (C„O), 1600 (C@O); d_H

(300 MHz, CDCl₃) 2.86 (1H, dd, J17.1, J8.2,

C(2)H_AH), 3.12 (1H, dd, J17.1, J3.5, C(2)H_BH), 3.25

(1H, dt, J8.2, J3.5, C(3)H), 3.41 (1H, AB, J_AB13.0,

NCH_AHPh), 3.57 (1H, AB, J_AB13.0, NCH_BHPh), 4.40

(5H, d, J_PH0.8, C₅H₅), 4.99–5.09 (2H, m, CH@CH₂),

5.57 (1H, ddd, J17.2, J10.0, J8.2, CH@CH₂), 7.16–

7.49 (20H, m, Ph); d_C(50 MHz, CDCl₃) 51.6, 58.2,

71.2, 85.1, 115.3, 126.5, 128.1, 128.4, 129.7, 133.2,

136.3, 140.7, 141.0, 220.3, 277.1; m/z (FAB+) 599 (M⁺,

5%), 383 (100%).

3.35. Preparation of (3RS,4SR,1⁰SR)-1-benzyl-3-

[(1⁰-tert-butyldimethylsilyloxy)ethyl]-4-vinylazetidin-2-

one (45)

A solution of 61 (0.230 g, 0.36 mmol) in DCM (5 ml)

was cooled to ꢀ78 ꢁC and a solution of bromine (0.040

ml, 0.72 mmol) in DCM (5 ml) was added dropwise via

cannula. The green solution was stirred for 2 h before

NEt₃(0.30 ml) was added by syringe. Stirring was con-

tinued for 1 h at ꢀ78 ꢁC and then the reaction mixture

was allowed to warm to rt. This mixture was evaporat-

ed, and the residue triturated with Et₂O. The ﬁltrate was

evaporated to an oil and subjected to puriﬁcation by

ﬂash chromatography on silica gel (EtOAc) gave (3

RS,SR,1⁰SR)-1-benzyl-3-(1⁰-hydroxyethyl)-4-vinylazeti-

din-2-one as an oil (0.042 g, 51%) contaminated 5with

triphenylphosphine (ca. 10%); v_max(ﬁlm) 1747 (C@O);

d

_H(300 MHz, CDCl₃) 1.25 (3H, d, J6.4, CH(OH)CH₃),

2.10 (1H, br s, CH(OH)CH₃), 2.97 (1H, m, C(3)H), 4.00

(2H, comprising 1H, AB, J_AB15.2, NCH_AHPh, and ob-

scured C(4)H), 4.22 (1H, br m, CH(OH)CH₃), 4.68 (1H,

AB, J_AB15.2, NCH_BHPh), 5.21 (1H, m, CH@CH_AH),

5.27 (1H, m, CH@CH_BH), 5.78 (1H, m, CH@CH₂),

3.34. Preparation of (RS,2RS,3RS,1⁰SR)-(g⁵-C₅H₅)-

Fe(CO)(PPh₃)COCH[CH(OH)CH₃]CH(NHCH₂Ph)-

CH@CH₂(61)

7.24–7.38 (5H, m, Ph). To

a

solution of (3

RS,SR,1⁰SR)-1-benzyl-3-(1⁰-hydroxyethyl)-4-vinylazeti-

din-2-one (12 mg, 0.05 mmol) in DMF (0.20 ml) was

added tert-butyldimethylsilyl chloride (35 mg, 0.23

mmol) followed by imidazole (40 mg, 0.59 mmol). After

30 h at rt the reaction mixture was partitioned between

0.1 M HCl and EtOAc. The combined organic phases

were washed with sodium hydrogen carbonate solution,

water, brine and dried. The residue was puriﬁed by col-

n-BuLi (1.6 M, 8.8 ml, 14.1 mmol) was added to a so-

lution of (N-trimethylsilyl)benzylamine (2.6 g, 14.60

mmol) in THF (5 ml) at ꢀ78 ꢁC. After 1 h, a solution

of (Z)-56 (0.74 g, 1.50 mmol) in THF (15 ml) at ꢀ78

ꢁC was added via cannula, and stirred for 30 h before

4206

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

umn chromatography on silica gel [EtOAc/40–60 (1:4)],

giving 62 as a colourless oil (15 mg, 84%; 43% over two

steps); v_max(ﬁlm) 1747 (C@O); d_H(300 MHz, CDCl₃)

0.02, 0.05 (2·3H, s, Si(CH₃)₂), 0.82 (9H, s, SiC(CH₃)₃),

1.17 (3H, d, J6.2, CH(OH)CH₃), 2.89 (1H, dd, J4.6,

J2.1, C(3)H), 4.00 (1H, dd, J8.5, J2.1, C(4)H), 4.05

(1H, AB, J_AB15.1, NCH_AHPh), 4.20 (1H, dq, J6.2,

J4.6, CH(OH)CH₃), 4.58 (1H, AB, J_AB15.1,

NCH_BHPh), 5.18 (1H, m, CH@CH_AH), 5.25 (1H, m,

CH@CH_BH), 5.75 (1H, ddd, J17.0, J10.2, J8.5,

CH@CH₂), 7.34–7.23 (5H, m, Ph); d_C(50 MHz, CDCl₃)

ꢀ4.8, ꢀ4.6, 17.9, 22.4, 25.7, 44.4, 55.8, 64.6, 65.2, 119.1,

127.4, 128.4, 128.6, 135.8, 136.2, 167.6; m/z (CI, NH₃)

346 (MH⁺, 100%); MH⁺exact mass calculated

346.2202, Found 346.2202.

1.84 (2·1H, br s, NH), 2.30 (1H, m, CH₃CHCH₂),

2.54–2.56 (3H, m, CH₃CHCH₂and CH₃CHCH₂), 2.88

(1H, dd, J_A,B17.4, J_A,CH6.7, CH₃CHCH₂), 3.20–3.27

(1H, m, CH₃CHCH₂), 3.67–3.77 (2·1H, m, C(a)H),

4.37 (2·5H, s, C₅H₅), 7.20–7.56 (2·20H, m, Ph); d_P

(100 MHz, CDCl₃) 72.4, 72.0; m/z (FAB) 602 (MH⁺,

37%).

3.38. Preparation of (RS,3RS,aRS)- and (RS,3RS,

aSR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂CH{NH[CH-

(CH₃)Ph]}Ph (64a and 64b)

Following representative procedure 1, n-BuLi (1.6

M, 3.1 ml, 4.92 mmol) and (RS)-a-methylbenzylamine

(608 mg, 5.03 mmol) in THF (10 ml) and (RS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH@CHPh (1.09 g, 2.01

mmol) in THF (10 ml) gave, after chromatography

on alumina (Et₂O), a partially separable mixture of di-

astereoisomers, arbitrarily assigned as 64a and 64b

(1.1 g, 91% overall); data for 64a: C₄₁H₃₈NO₂FeP re-

quires C, 74.2; H, 5.8; N, 2.1%; Found C, 74.1; H,

5.5; N, 1.9%; v_max(CH₂Cl₂) 1915 (C„O), 1600

(C@O); d_H(200 MHz, CDCl₃) 1.23 (3H, d, J6.5,

C(a)Me), 1.98 (1H, br s, NH), 2.78 (1H, dd, J16.9,

J3.3, PhCHCH_A), 3.30–3.72 (2H, m, C(a)H and

PhCHCH_B), 3.74 (1H, m, PhCHCH₂), 4.36 (5H, s,

3.36. Preparation of (3RS,4SR,1⁰SR)-3-[(1⁰-tert-butyl-

dimethylsilyloxy)ethyl]-4-vinylazetidin-2-one (51)

NH₃(10 ml) was condensed at ꢀ78 ꢁC and sodium

(25 mg, 1.10 mmol) added. The resulting blue solution

was warmed and the dried ammonia re-condensed at

ꢀ78 ꢁC. Ethanol (0.05 ml) was added via syringe, fol-

lowed by sodium (10 mg, 0.43 mmol) and the blue solu-

tion was stirred for 5 min at ꢀ78 ꢁC before a solution of

62 (13 mg, 0.04 mmol) in THF (1 ml) was added via sy-

ringe. After stirring for 20 min at ꢀ78 ꢁC the reaction

was quenched by the addition of solid ammonium chlo-

ride (100 mg). On warming, and after evaporation of the

ammonia, the residue was dissolved in DCM (5 ml) and

ﬁltered. Concentration in vacuo, and puriﬁcation by col-

umn chromatography on silica gel [EtOAc/40–60 (1:4)]

gave 51 as a white solid (0.008 g, 83%); d_H(lit.³¹; 300

MHz, CDCl₃) 0.08 (6H, s, Si(CH₃)₂), 0.89 (9H, s,

SiC(CH₃)₃), 1.22 (3H, d, J6.2, CH(OH)CH₃), 2.89

(1H, dd, J4.3, J2.5, C(3)H), 4.20–4.27 (2H, m, C(4)H

and CH(OH)Me), 5.18 (1H, d, J10.3, CH@CH_AH),

5.32 (1H, d, J17.1, CH@CH_BH), 5.86 (1H, br s, NH),

5.96 (1H, ddd, J17.1, J10.3, J6.9, CH@CH₂); d_C(50

MHz, CDCl₃) ꢀ5.1, ꢀ4.3, 17.9, 22.4, 25.7, 52.1, 65.2,

65.8, 116.5, 137.6, 168.4.

C

_{5 H5}), 7.07–7.53 (20H, m, Ph); d_P(100 MHz, CDCl₃)

76.2; d_C(50 MHz, CDCl₃) 21.9, 54.5, 57.2, 72.6, 85.5,

126.4, 126.6, 126.9, 127.5, 128.4, 130.0, 133.5, 133.7,

136.7, 144.5, 147.0, 220.3; m/z (electrospray) 664

(MH⁺, 100%). Data for 64b: C₄₁H₃₈NO₂FeP requires

C, 74.2; H, 5.8; N, 2.1%; Found C, 74.2; H, 6.05;

N, 2.0%; v_max(CH₂Cl₂) 1915 (C„O), 1600 (C@O);

d_H(200 MHz, CDCl₃) 1.21 (3H, d, J6.8, C(a)Me),

1.60 (1H, br s, NH), 2.78 (1H, m, PhCHCH_A),

3.06–3.14 (2H, m, C(a)H and PhCHCH_B), 3.27 (1H,

m, PhCHCH₂), 4.41 (5H, s, C₅H₅), 6.92–7.50 (20H,

m, Ph); d_P(100 MHz, CDCl₃) 75.6; d_C(50 MHz,

CDCl₃) 25.2, 55.1, 57.4, 73.0, 85.5, 126.6, 127.2,

127.8, 128.2, 129.2, 130.4, 133.6, 133.7, 135.9,

143.9, 146.0, 220.5ꢀ; m/z (electrospray) 664

(MH⁺, 100%).

3.37. Preparation of (RS,3RS,aRS)- and (RS,3RS,

aSR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂CH{NH[CH-

(CH₃)Ph]}Me (63)

3.39. Preparation of (RS,3RS,aRS)- and (RS,3RS,aSR)

-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂CH{NH[CH(CH₃)-

Ph]}ⁱPr (65a and 65b)

Following representative procedure 1, n-BuLi (1.6 M,

0.82 ml, 0.51 mmol) and (RS)-a-methylbenzylamine (60

mg, 0.52 mmol) in THF (10 ml) and (RS)-12 in THF (10

ml) gave, after chromatography on alumina (Et₂O), an

inseparable mixture of diastereoisomers 63 (90 mg,

72%) as an orange solid; C₃₆H₃₆NO₂FeP requires C,

71.9; H, 6.0; N, 2.3%; Found C, 71.8; H, 5.8; N, 2.3%;

v_max(CH₂Cl₂) 1910 (C„O), 1600 (C@O); d_H(200

MHz, CDCl₃) 0.54, 0.58 (2·3H, d, J6.2, CH₃CHCH₂),

1.23 (3H, d, J6.4, C(a)Me), 1.23 (3H, d, J6.6, C(a)Me),

Following representative procedure 1, n-BuLi (1.6

M, 2.3 ml, 3.8 mmol) and (RS)-a-methylbenzylamine

(466 mg, 3.85 mmol) in THF (10 ml) and (RS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH@CHiPr (782 mg, 1.54

mmol) in THF (20 ml) gave, after chromatography

on alumina (Et₂O), a partially separable mixture of di-

astereoisomers 65a and 65b (863 mg, 89% overall); da-

ta for 65a: C₃₈H₄₀NO₂FeP requires C, 72.5; H, 6.4; N,

2.2%; Found C, 72.7; H, 6.7; N, 2.1%; v_max(CH₂Cl₂)

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4207

1915 (C„O), 1605 (C@O); d_H(200 MHz, CDCl₃)

0.61, 0.68 (2·3H, d, J6.8, (CH₃)₂CH), 1.19 (3H, d,

J6.5, C(a)Me), 1.25 (1H, br s, NH), 1.30 (1H, m,

(CH₃)₂CH), 2.34 (1H, br s, COCH₂CH), 2.52 (1H,

dd, J16.0, J6.1, COCH_A), 3.20 (1H, dd, J16.0, J4.7,

COCH_B), 3.65 (1H, q, J6.5, C(a)H), 4.36 (5H, s, C₅

_H5), 7.18–7.55 (20H, m, Ph); d_P(100 MHz, CDCl₃)

76.2; d_C(50 MHz, CDCl₃) 17.6, 18.9, 25.2, 29.5,

55.3, 56.9, 66.6, 85.4, 126.7, 127.2, 128.2, 128.4,

129.9, 133.5, 133.7, 136.8, 147.3, 221.1; m/z (electro-

spray) 630 (MH⁺, 100%). Data for 65b: C₄₁H₃₈NO_2-

FeP requires C, 72.5; H, 6.4; N, 2.2%; Found C,

72.6; H, 6.8; N, 2.2%; v_max(CH₂Cl₂) 1910 (C„O),

1600 (C@O); d_H(200 MHz, CDCl₃) 0.47, 0.75

(2·3H, d, J6.9, (CH₃)₂CH), 1.27 (3H, d, J6.7,

C(a)Me), 1.40 (1H, m, (CH₃)₂CH), 1.65 (1H, br s,

NH), 2.74 (1H, m, COCH₂CH), 2.67 (1H, dd, J17.1,

J7.0, COCH_A), 2.78 (1H, dd, J17.1, J5.0,

COCH_B),3.70 (1H, m, C(a)H), 4.35 (5H, s, C₅H₅),

7.18–7.54 (20H, m, Ph); d_P(100 MHz, CDCl₃) 76.3;

d_C(50 MHz, CDCl₃) 17.3, 17.8, 24.9, 28.3, 55.6,

56.0, 67.5, 85.4, 126.6, 127.1, 127.2, 128.1, 128.3,

129.8, 133.4, 133.6, 136.6, 146.7, 221.0; m/z (electro-

spray) 630 (MH⁺, 100%).

CH₃CHCH_A), 2.87 (1H, d, J16.4, CH₃CHCH_B), 3.55

(2H, m, NCH₂), 3.79 (1H, q, J6.8, C(a)H), 3.88, 3.89

(2·3H, s, OMe), 4.20 (5H, s, C₅H₅), 6.78–7.00 (3H, m,

Ph), 7.23–7.68 (20H, m, Ph); d_C(63 MHz) 18.9, 19.0,

47.8, 49.8, 55.8, 56.0, 57.7, 71.4, 85.1, 111.0, 111.6,

119.9, 126.4, 127.7, 129.6, 128.0, 128.4, 133.3, 135.4,

136.6, 144.9, 147.7, 149.0, 220.5, 275.0; d_P(100 MHz,

CDCl₃) 72.4; m/z (FAB) 752 (MH⁺, 3%).

3.42. Preparation of (S,3S,aR)- and (S,3R,aR)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH₂CH{N[CH(CH₃)Ph]-

[CH₂((OMe)₂Ph)]}Me (69 and 70)

Following representative procedure 1, n-BuLi (1.6 M,

1.2 ml, 1.86 mmol) and (R)-N-3,4-dimethoxybenzyl-N-

a-methylbenzylamine (400 mg, 1.89 mmol) in THF (10

ml) and (S)-12 (300 mg, 0.63 mmol) in THF (5 ml) gave,

after chromatography on alumina (DCM:Et₂O 1:1), 69

and 70 (260 mg, 55%) as an inseparable 50:50 mixture of

diastereoisomers; C₄₅H₄₆NO₄FeP requires C, 71.9; H,

6.2; N, 1.9%; Found C, 71.6; H, 6.3; N, 2.2%; v_max

(CH₂Cl₂) 1907 (C„O), 1604 (C@O); d_H(300 MHz,

CDCl₃) 0.52 (3H, d, J6.4, CH₃CHCH₂), 0.95 (3H, d,

J6.4, CH₃CHCH₂), 1.19 (3H, d, J6.7, C(a)Me), 1.27

(3H, d, J6.7, C(a)Me), 2.36 (1H, dd, J_A,B13.4, J_A,CH9.9,

CH₃CHCH_A), 2.71 (1H, d, J13.4, CH₃CHCH_B),3.02

(1H, m, CH₃CHCH₂), 3.03-3.33 (3H, m, CH₃CHCH₂

and CH₃CHCH₂), 3.57–3.72 (2·1H, m, C(a)H), 3.85,

3.86, 3.87 (4·3H, s, OMe), 4.26, 4.32 (2·5H, s, C₅H₅),

6.99–6.77 (2·3H, m, Ph), 7.21–7.49 (2·20H, m, Ph); d_P

(100 MHz, CDCl₃) 73.1, 72.0; m/z (FAB) 602 (MH⁺, 3%).

3.40. Preparation of (RS,3RS,aRS)-, (RS,3RS,aSR)-,

and (RS,3SR,aSR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂-

CH{N[CH(CH₃)Ph]-[CH₂((OMe)₂Ph)]}Me (68, 69

and 70)

Following representative procedure 1, n-BuLi (1.6

M, 0.8 ml, 1.24 mmol) and (RS)-N-3,4-dimethoxy ben-

zyl-N-a-methylbenzylamine (267 mg, 1.26 mmol) in

THF (10 ml) and (RS)-12 (200 mg, 0.42 mmol) in

THF (5 ml) gave, after chromatography on alumina

(Et₂O), an inseparable mixture of diastereoisomers

68:69:70 (260 mg, 83%) in a 94:3:3 ratio. The ¹H

NMR spectrum of the mixture was readily assigned

by comparison with those of homochiral 68, 69 and

70 prepared separately.

3.43. Preparation of (RS,3RS,aRS)-, (RS,3RS,aSR)-,

and (RS,3SR,aSR)-(g⁵-C₅H₅)Fe(CO)(PPh₃)COCH₂-

CH{N[CH(CH₃)Ph]-[CH₂Ph]}Me (72, 73 and 74)

Following representative procedure 1, n-BuLi (1.6 M,

0.5 ml, 0.80 mmol), (RS)-N-benzyl-N-a-methylbenzyl-

amine (180 mg, 0.84 mmol) in THF (25 ml) and (RS)-

12 (200 mg, 0.42 mmol) in THF (5 ml) gave, after

chromatography on silica gel (petrol:Et₂O 4:1), an insep-

arable mixture of diastereoisomers 72:73:74 (190 mg,

3.41. Preparation of (R,3R,aR)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH{N[CH(CH₃)Ph]-[CH₂((OMe)₂-

Ph)]}Me (68)

1

67%) in a 96:2:2 ratio. The H NMR spectrum of the

mixture was readily assigned by comparison with those

of homochiral 72, 73 and 74 prepared separately.

Following representative procedure 1, n-BuLi (1.6 M,

1.2 ml, 1.86 mmol), (R)-N-3,4-dimethoxybenzyl-N-a-

methylbenzylamine (400 mg, 1.89 mmol) in THF (10

ml) and (R)-12 (300 mg, 0.63 mmol) in THF (5 ml) gave,

after work up and chromatography on alumina (DCM:E-

t₂O 1:1), 68 (430 mg, 92%) as an orange solid; C₄₅H₄₆NO_4-

FeP requires C, 71.9; H, 6.2; N, 1.9%; Found C, 72.3; H,

6.3; N, 1.8%; v_max(CH₂Cl₂) 1905 (C„O), 1600 (C@O); d_H

(300 MHz, CDCl₃) 0.50 (3H, d, J6.4, CH₃CHCH₂), 1.25

(3H, d, J6.8, C(a)Me), 2.47 (1H, dd, J_A,B16.4, J_A,CH10.0,

3.44. Preparation of (R,3R,aR)-(g⁵-C₅H₅)Fe(CO)-

(PPh₃)COCH₂CH{N[CH(CH₃)Ph]-[CH₂Ph]}Me (72)

Following representative procedure 1, n-BuLi (1.6

M, 0.28 ml, 0.46 mmol), (R)-N-benzyl-N-a-methylben-

zylamine (110 mg, 0.52 mmol) in THF (10 ml) and

(R)-12 (100 mg, 0.21 mmol) in THF (5 ml) gave, after

chromatography on alumina (DCM:Et₂O 1:1), 72 (119

4208

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

[4] S.G. Davies, J.I. Seeman, I.H. Williams, Tetrahedron Letts. 27

(1986) 619.

mg, 82%); C₄₃H₄₂NO₂FeP requires C, 74.7; H, 6.1; N,

20

2.0%; Found C, 75.0; H, 6.0; N, 1.9%; [a]_Dꢀ43.2 (c

[5] N. Aktogu, S.G. Davies, H. Felkin, G.J. Baird, O. Watts, J.

Organometal. Chem. 262 (1984) 49.

0.1, benzene); v_max(CH₂Cl₂) 1913 (C„O), 1601

(C@O); d_H(300 MHz, CDCl₃) 0.52 (3H, d, J6.6,

CH₃CHCH₂), 1.26 (3H, d, J6.9, C(a)Me), 2.48 (1H,

dd, J_A,B16.2, J_A,CH10.5, CH₃CHCH_A), 2.93 (1H, d,

J16.2, CH₃CHCH_B), 3.20 (1H, m, CH₃CHCH₂), 3.62

(2H, ABq, J16.2, NCH₂), 3.80 (1H, q, J6.8, C(a)H),

4.22 (5H, d, J_PH0.8, C₅H₅), 7.23–7.45 (25H, m, Ph);

d_C(50 MHz, CDCl₃) 19.1, 19.2 48.0, 50.3, 58.1,

71.1, 85.1, 126.4, 126.6, 127.8, 127.9, 128.1, 128.3,

129.8, 133.3, 133.5, 136.3, 137.1, 143.0, 145.0, 221.3,

276.2; d_P(100 MHz, CDCl₃) 72.5; m/z (FAB) 692

(MH⁺, 10%).

[6] S.G. Davies, N. Aktogu, H. Felkin, Chem. Commun. 1303 (1982);

G.J. Baird, S.G. Davies, J Organometal. Chem. 248 (1983) C1;

G.J. Baird, J.A. Bandy, S.G. Davies, K. Prout, Chem. Commun.

1202 (1983);

S.L. Brown, S.G. Davies, D.F. Foster, J.I. Seeman, P. Warner,

Tetrahedron Letts. 27 (1986) 623.

[7] S.G. Davies, J.I. Seeman, Tetrahedron Letts. 2 (5) (1984) 1845.

[8] See Ref. [5] L. Liebeskind, M.E. Welker, Organometallics 2

(1983) 194;

S.G. Davies, I.M. Dordor, J.C. Walker, P. Warner, Tetrahedron

Letts. 25 (1984) 2709.

[9] S.G. Davies, I.M. Dordor, P. Warner, Chem. Commun. (1984) 956;

S.G. Davies, I.M. Dordor-Hedgecock, R.H. Jones, K. Prout, P.

Warner, J. Organometal. Chem. 285 (1985) 213.

[10] P.W. Ambler, S.G. Davies, Tetrahedron Letts. 26 (1985) 2129.

[11] L.S. Liebeskind, M.E. Welker, R.W. Fengl, J. Am. Chem. Soc.

108 (1986) 6328.

3.45. Preparation of (R,3R,aS)- and (R,3S,aS)-(g⁵-

C₅H₅)Fe(CO)(PPh₃)COCH₂CH{N[CH(CH₃)Ph]-

[CH₂Ph]}Me (73 and 74)

[12] S.G. Davies, I.M. Dordor-Hedgecock, P. Warner, Tetrahedron

Letts. 26 (1985) 2125.

Following representative procedure 1, n-BuLi (1.6 M,

0.57 ml, 0.92 mmol) and (S)-N-benzyl-N-a-methylben-

zylamine (220 mg, 1.0 mmol) in THF (5 ml) and (R)-

12 (200 mg, 0.42 mmol) in THF (5 ml) gave a 50:50

mixture of diastereoisomers 73:74. Recrystallisation

from crude (petrol:DCM) gave a sample enriched in

one diastereoisomer; C₄₃H₄₂NO₂FeP requires C, 74.7;

H, 6.1; N, 2.0%; Found C, 74.5; H, 6.2; N, 1.9%; d_H

(300 MHz, CDCl₃) 0.49 (3H, d, J6.3, CH₃CHCH₂),

1.28 (3H, d, J6.8, C(a)Me), 2.40 (1H, dd, J_A,B14.8,

[13] S.P. Collingwood, S.G. Davies, S.C. Preston, Tetrahedron Letts.

31 (1990) 4067.

[14] S.G. Davies, P. Warner, Tetrahedron Lett. 26 (1985) 4815.

[15] S.G. Davies, J.C. Walker, Chem. Commun. (1985) 209;

S.G. Davies, I.M. Dordor-Hedgecock, K.H. Sutton, J.C. Walker,

Tetrahedron Letts. 27 (1986) 3787.

[16] S.G. Davies, I.M. Dordor-Hedgecock, K.H. Sutton, J.C. Walker,

R.H. Jones, K. Prout, Tetrahedron 42 (1986) 5123.

[17] S.G. Davies, I.M. Dorder-Hedgecock, K.H. Sutton, J.C. Walker,

Tetrahedron Letts. 32 (1986) 3787.

[18] For alternative synthetic routes to b-lactams using the iron acyl

auxiliary and the reaction with an imine see K. Broadley and S.G.

Davies, Tetrahedron Letts., 25 (1984) 1743 and L.S. Liebeskind,

M.E. Welker and V. Goedken, J. Am. Chem. Soc. 106 (1984) 441.

For conjugate addition to to [(g⁵-C₅H₅)Fe(CO)₂COCH@CHR]

and subsequent decomplexation as a route to b-lactams see S.G.

Davies, N.M. Garrido, P.A. McGee and J.P. Shilvock, J. Chem.

Soc. Perkin Trans 1 (1999) 3105.

J_A,CH10.0,

CH₃CHCH_A),

3.19–3.33

(2H,

m,

CH₃CHCH₂and CH₃CHCH_B), 3.62 (2H, ABq, J15.4,

NCH₂), 3.84 (1H, q, J6.8, C(a)H), 4.29 (5H, s, C₅H₅),

7.20–7.41 (25H, m, Ph); d_C(50 MHz, CDCl₃) 16.8,

19.1 48.7, 50.2, 58.2, 72.3, 85.2, 126.2, 126.3, 127.6,

127.7, 128.0, 128.4, 129.6, 133.3, 133.4, 136.3, 136.7,

142.9, 145.6, 220.5, 275.7; d_P(100 MHz, CDCl₃) 72.2;

m/z (FAB) 692 (MH⁺, 15%); selected data for other dia-

stereoisomer; d_H(300 MHz, CDCl₃) 0.94 (3H, d, J6.2,

CH₃CHCH₂), 1.16 (3H, d, J6.7, C(a)Me), 4.32 (5H, d,

J_PH0.8, C₅H₅); d_P(100 MHz, CDCl₃) 73.1.

[19] S.G. Davies, O. Ichihara, Chem. Commun. (1990) 1554.

[20] S.G. Davies, J. Dupont, R.J.C. Easton, Tetrahedron: Asymmetry

1 (1990) 279.

[21] E. Graf, S. Weinandy, B. Koch, E. Breitmaier, Liebigs Ann.

Chem. 7 (1986) 1147;

R.W. Miller, J. Nat. Prod. 43 (1980) 425.

[22] E. Graf, H. Boeddeker, Ann. Chem. 613 (1958) 111.

[23] S.G. Davies, R.J.C. Easton, J.C. Walker, P. Warner, Tetrahedron

42 (1986) 175.

[24] L.S. Liebeskind, M.E. Welker, R.W. Fengl, J. Am. Chem. Soc.

108 (1986) 6328.

Acknowledgement

[25] K.D. Barrow, T.M. Spotswood, Tetrahedron Lett. 6 (1965) 3325.

[26] F.A. Bouﬀard, D.R. Johnston, B.G. Christensen, J. Org. Chem.

45 (1980) 1130;

The authors wish to thank New College, Oxford for a

Junior Research Fellowship (A.D.S).

F. Pecquet, J. dꢀAngelo, Tetrahedron Lett. 23 (1982) 2777.

[27] T. Kametani, S.-P. Huang, T. Nagahara, M. Ihara, J. Chem.

Soc., Perkin Trans. 1 (1981) 2822;

References

T. Kametani, T. Nagahara, M. Ihara, J. Chem. Soc., Perkin

Trans. 1 (1981) 3048.

[1] For reviews see S.G. Davies, Aldrichimica Acta 23 (1990) 31;

S.G. Davies, Pure & Appl. Chem. 60 (1988) 13.

[28] H.J. Reich, S. Wollowitz, J.E. Trend, F. Chow, D.F. Wendelborn,

J. Org. Chem. 43 (1978) 1697;

[2] J.I. Seeman, S.G. Davies, Chem. Comm. 1019 (1984);

B.K. Blackburn, S.G. Davies, M. Whittaker, in: I. Bernal (Ed.),

Stereochemistry of Organometallic and Inorganic Compounds, 3,

Elsevier, Amsterdam, 1989, p. 141.

T. Hori, K.B. Sharpless, J. Org. Chem. 43 (1978) 1689.

[29] S.E. Denmark, T.K. Jones, J. Org. Chem. 47 (1982) 4595;

M.J. Carter, I. Fleming, A. Percival, J. Chem. Soc., Perkin Trans.

I (1981) 2415;

[3] B.K. Blackburn, S.G. Davies, K.H. Sutton, M. Whittaker, Chem.

Soc. Rev. 17 (1988) 147.

S. Borrelly, L.A. Paquette, J. Org. Chem. 58 (1993) 2714.

S.G. Davies et al. / Journal of Organometallic Chemistry 689 (2004) 4184–4209

4209

[30] K. Hattori, M. Miyata, H. Yamamoto, J. Am. Chem. Soc. 115

(1993) 1151;

W. Clegg, S.T. Liddle, R.E. Mulvey, A. Robertson, Chem.

Commun. 511 (1999);

Y. Ito, Y. Kobayashi, T. Kawabata, M. Takase, S. Terashima,

Tetrahedron 45 (1989) 5767;

G. Hilmersson, P.I. Arvidsson, O. Davidsson, M. Haakansson, J.

Am. Chem. Soc. 120 (1998) 8143.

For a previous synthesis of thienamycin from this intermediate

seeK. Hattori, H. Yamamoto, Synlett (1993) 239.

[31] M. Furukawa, T. Okawara, Y. Terawaki, Chem. Pharm. Bull. 25

(1977) 1319;

[35] D.B. Collum, Acc. Chem. Res. 26 (1993) 227;

J.S. De Pue, D.B. Collum, J Am. Chem. Soc. 110 (1988) 5524.

[36] For instance see P.I. Arvidsson, O. Davidsson, Angew. Chem.

Int. Edn. Engl. 39 (2000) 1467;

P. Murer, B. Rheiner, E. Juaristi, D. Seebach, Heterocycles 39

(1994) 319.

J.L. Rutherford, D.B. Collum, J. Am. Chem. Soc. 121 (1999)

10198;

[32] Reaction conversions were all determined by ¹H 500 MHz NMR

spectroscopic analysis of the crude reaction mixture.

[33] Reaction diastereoselectivities were assessed by ¹H 500 MHz

NMR spectroscopic analysis of the crude reaction mixture.

[34] For recent examples see G. Hilmersson, B. Malmros, Chem.-Eur.

J. 7 (2001) 337;

J.L. Rutherford, D.B. Collum, J. Am. Chem. Soc. 123 (2001)

199.

[37] D. Barr, W. Clegg, R.E. Mulvey, R. Snaith, Chem. Commun.

(1984) 285;

D. Barr, W. Clegg, R.E. Mulvey, R. Snaith, Chem. Commun.

(1984) 287.

P.C. Andrews, P.J. Duggan, M. Maguire, P.J. Nichols, Chem.

Commun. (2001) 53;

[38] D.R. Armstrong, K.W. Henderson, A.R. Kennedy, W.J. Kerr,

F.S. Mair, J.H. Moir, P.H. Moran, R. Snaith, J. Chem. Soc.,

Dalton Trans. (1999) 4063;

A. Johansson, A. Pettersson, O. Davidsson, J. Organomet. Chem.

608 (2000) 153;

P.C. Andrews, P.J. Duggan, G.D. Fallon, T.D. McCarthy, A.C.

Peatt, J. Chem. Soc. Dalton Trans. (2000) 1937.

[39] X. Sun, S.L. Kenkre, J.F. Remenar, J.H. Gilchrist, D.B. Collum,

J. Am. Chem. Soc. 119 (1997) 4765.

S. Pache, C. Botuha, R. Franz, E.P. Kundig, J. Einhorn, Helv.

Chim. Acta 83 (2000) 2436;

A. Kee, P. OꢀBrien, C.D. Pilgram, S.T. Watson, Chem. Commun.

(2000) 1521;

C. Sun, P.G. Williard, J. Am. Chem. Soc. 122 (2000) 7829;

[40] M. Majewski, P. Nowak, Tetrahedron Letts. 39 (1998) 1661.

[41] P. Zhao, D.B. Collum, J. Am. Chem. Soc. 125 (2003) 4008.

Article Doi

Stereoselective conjugate addition reactions of lithium amides to α,β-unsaturated chiral iron acyl complexes [(η5-C 5H5)Fe(CO)(PPh3)(COCH=CHR)]

DOI: 10.1016/j.jorganchem.2004.04.046

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.jorganchem.2004.04.046

Full text of DOI:10.1016/j.jorganchem.2004.04.046

Products guided by the article

R&D Labs maybe for 827341-87-7

Relevant to this article

Hot Product