Lactam Synthesis Peter Quayle Doctor of Philosophy of the University of London

Home , Shapiro reaction

THE USE OF CARBANIONS IN ^-LACTAM SYNTHESIS

A Thesis presented

PETER QUAYLE

In Partial Fulfilment of the Requirements

for the Degree of

DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON

DEPARTMENT OF CHEMISTRY IMPERIAL COLLEGE OF SCIENCE & TECHNOLOGY LONDON SW7 2AY. OCTOBER, 1981. 2.

To my Parents "It pays to speculate as widely and wildly as possible; people only remember when you are right!"

Derek H.R. Barton, FRS.

(Gordon Research Conference> 19£>4) 4.

ACKNOWLEDGEMENTS

I wish to thank my supervisor, Dr. A.G.M. Barrett, for his advice, insight and encouragement throughout the duration of this project.

I wish to thank all my colleagues, past and present, for their stimulating lunch-time discussions. I would specially like to thank Az and Shabaht, Chris and Greg, Elizabeth and Dave, Carmen and

Pagona for their unfailing friendship.

I am indebted to the technical staff at Imperial College for their invaluable assistance.

I thank the Science Research Council for financial support throughout my studies.

I would also like to thank Maria Serrano-Widdowson for typing this thesis.

Peter Quayle 15th October, 1981. The synthesis of carbapenem ring systems is reviewed.

The phenylethynolate anion has been shown to undergo a novel cycloaddition reaction with electron defficient Schiff's bases to afford highly substituted azetidin-2-ones,in good yields, in a stereoselective fashion. Attempts to react the phenylethynolate anion with less activated Schiff's bases were unsuccessful. The reaction of several related species is described.

The Shapiro reaction has been successfully applied to the synthesis of a-methylene-3-lactams.

The preparation of l-benzyl-3-phenylazetidin-2-one, from the readily available N-benzyl-3-hydroxy-3-phenylpropanamide, is described. Competing elimination reactions limit the general applicability of this methodology.

The facile preparation of the synthetically important 4-(arylcarbonyl- methyl)azetidin-2-ones and related compounds from 4-acetoxy-l-trimethylsilylazetidin-2-one and various silylenol ethers is described. The use of trimethylsilyl trifluoromethanesulphonate as catalyst in these C-4 displacement reactions was found to give optimum results. 6.

LIST OF CONTENTS

page

ACKNOWLEDGEMENTS 4

ABSTRACT 5

REVIEW: SYNTHESIS OF CARBAPENEM RING SYSTEMS 7

Introduction 8

Structure Activity Relationships 12

Synthesis of Carbapenem Ring Systems 14

A. Synthesis of the carbapenem nucleus 14 B. Total Synthesis of Thienamycin and Related Compounds 38

References 65

RESULTS AND DISCUSSION: 72

Introduction 73

The Use of Ynolate Anions in the Synthesis of Azetidin-2-ones 73

Reaction of the phenylethynolate anion (17) with Schiff's bases 79

Miscellaneous reactions of the phenylethynolate anion (17) and the thiolate anion (14) 93 Aminoalkylation reactions of C-6 penicillanate enolate anions 97 C-4 Displacement Reactions 101 Preparation of cx-Methylene-3-lactams 128 Preparation of 3-Unsubstituted Azetidin-2-ones 141 EXPERIMENTAL: 153 Section 1: Ynolate Chemistry 156 Section 2: C-4 Displacement Reactions 170 Section 3: Shapiro Reactions 180 Section 4: Other N1-C4 Cyclisation Reactions 191

REFERENCES 201 REVIEW

SYNTHESIS OF CARBAPENEM RING SYSTEMS 8.

INTRODUCTION

Nature continues to provide us with products containing new structural 1,2 variations, the class of 3-lactam antibiotics being no exception . In

1976, it was disclosed by Merck scientists that a novel B-lactam antibiotic had been isolated from the culture broths of a previousl3 y unrecognized species, subsequently designated Streptornycca cattleya . This natural product was the first member of a family of antibiotics containing the des-thiacarbapen- t

2-em nucleus, from which the name thienamycin was derived . Intense interest

in these compounds results from their exceptional biological activity and unique structure.

In the first part of this review, the structure and activity will be

briefly discussed. The remainder will be concerned with the approaches to,

and syntheses of the carbapenem systems.

The assignment of the structure of thienamycin (1) was achieved by a

combination of nmr, mass spectral fragmentation patterns, degradative

t Throughout, the nomenclature adopted is based on the assignment of the

term carbapen-2-em as: 9.

4 experiments and finally X-ray analysis . The absolute stereochemistry of 4 thianamycin was determined as 5R, 8R .

Thienamycin contains several unique structural features:-

(i) the carbapenem nucleus was hitherto unknown,

(ii) the relative stereochemistry of the 5,6 protons is trans-, in contrast

to the cis- relationship found in the penicillins and cephalosporins,

(iii) the incorporation of a 1'-R-hydroxyethyl group in place of the customary

amide side chains found in penicillins and cephalosporins.

Thienamycin was found to be a potent antibiotic, with broad spectrum activity. Of particular importance was its activity against isolates 2 5 exhibiting resistance to other drugs ' . Its aerobic spectrum included most gram- negative bacilli tested, including E. ooli.j Pseudomonasj and S. aureus. Excellent activity was also exhibited against anaerobic bacteria 6. 2 A detailed account of the biological activity of thienamycin has appeared .

Subsequent work by the Merck group indicated that at least six other closely related compounds, the epithienamycins (A-F), could be isolated 7 from a large number of strains of Sbreptomyces flavogri-esus .

A Beecham group independently isolated three novel (3-lactams from

Streptomyoes olivaceUQ,m\ 4550, MM 13902 and MM 17880. Subsequently, four

new metabolites, MM 22380, MM 22381, MM 22382 and MM 22383 were also iso-

lated. Collectively, these metabolites were designated as olivanic acids.

It has been suggested that the olivanic acids and epithienamycins

correspond to the same structures (Table 1). More recently, other metabo-

10 11 11 12 3 lites including 1PS-54 , PS-6 f • PS-7 , NS-5 , C-19393 S„£ , C-19393 AH* ,

and PA-31088-IV have been isolated (Table 1). It is interesting that

the olivanic acids differ from thienamycin by virtue of the opposite configuration at C-8. 10.

Tabic 1

R = H, R MM 22380 CH2CH2NHC0Me n = 0 ETM A (2)

R = H, R1 = CH = CHNHCOMe MM 22382 n = 0 ETM B (3)

1 R = H0S02, R = CH = CHNHCOMe MM 13902 n = 0 ETM E

R = HOSO , R1 = CH = CHNHCOMe MM 4450 n = 1

R = HOSO , R = CH CH NHCOMe MM 17880 A £ n = 0 ETM F

R = H, R = CHCH NHCOMe m 22381 ETM C

R = H, R1 = CH = CHNHCOMe MM 22383 ETM D

/continued. 11.

Table 1/continucd...

S(CH2)2NHR S(CH2)2NHAC

CO2H COOH

R = Ac PS-5

R = H NS-5 PS-6

0© OR

o' NHAc

CO2H C0ZH

C-19393 S2, R = SOgNa PS-7

C-19393 H2, R = S03H

0© CJGH)M

S-(CH2)2N-CH o NHAc A—N HN COoH COoH

PA-31088-IV MK-0787 12.

STRUCTURE-ACTIVITY RELATIONSHIPS

Structure-activity relationships will only be briefly mentioned here, 2 15 as further details can be obtained elsewhere ' . The factors affecting

in vitro activity may be summarized as follows.

(i) Stereochemistry at C-5, C-6 and C-8

Thienamycin, with the tra.ns -5R, 6S^, 8R stereochemistry, is the most

potent natural antibiotic. The potency of the non-sulphated series appears

to be trans-R > cis-S > trans-S^'. The trans-R series has the best peni- 9 cillanase resistance, trans-S moderate and that of the cis-S series is low . 2 Some metabolites (e.g. PS-5) are 3-lactamase inhibitors . The sulphated 9 compounds have an enhanced penicillanase inhibitory capacity .

(ii) Effect of substructures

Carbapen-2-em-2-carboxylic acid has the same potency as clinically used 15 penicillins . The presence of the basic function at C-3 in thienamycin

maximizes antipseudomonal activity1^' . Various derivatives of thienamycin

have been prepared and their activity evaluated. MK-0787 is being tested 15 clinicallt • n y in• man

An important factor which has had to be considered in relation to

both their clinical use and attempted synthesis is that the carbapen-2-em

system in particular was found to be a highly reactive substrate towards 3 17

nucleophiles ' . In fact, the instability of thienamycin in solution has

been ascribed to a bimolecular reaction, in which the nucleophilic nitrogen of one molecule attacks the 3-lactam moiety of a second 3 . Generally, the

trans- or cis- refers to the relative stereochemistry of the C-5 and C-6 protons. R or S refers to the C-8 stereochemistry. 13.

3 carbapen-2-cms are also only stable over a narrow pH range . ' This instabi= 6 lity renders thienamycin itself unsuitable as a clinical agent .

The inherent instability of the carbapen-2-em system has been attributed 18 to the departure from coplanarity of the 3-lactam N-l atom from the plane containing C-2, C-5 and C-7. The altitude h, of the apex N-l, from the base of the trigonal pyramid containing N-l, C-2, C-5 and C-7 is used as a convenient factor relating to the strain in such systems (4). Values of h have been computed from X-ray data. A qualitative agreement has been observed between 18 the values of h and the lability of the respective B-lactams , i.e. the

larger the value of h, the greater the lability of the 3-lactam.

On this basis, Woodward argued that the carbapen-3-em system should be more reactive towards nucleophiles than the carbapen-2-ems, as a reflection of the greater degree of distortio3 n within the molecule. Curiously, this was not found to be the case. A -Thienamycin was found to be chemically more stable than the A 2 -isomer 17 . Other factors, e.g. electronic effects, may be of importance in determining the reactivity of such systems, as in the case 2 3 19 of the A - and A -cephems 14.

SYNTHESIS OF CARBAPENEM RING SYSTEMS

Duo to the chemical lability of the intact carbapen-2-em nucleus

(vide supra), the formation of the bicyclic system is carried out in the latter stages of synthetic schemes*. In view of this, the methods which have been developed to effect ring closure will be discussed first, followed by their use as illustrated in the total synthesis of thienamycin and its analogues.

A. SYNTHESIS OF THE CARBAPENEM NUCLEUS

To our knowledge, three methods have been utilised in the synthesis of the carbapenem nucleus. They can be summarized as involving an (i) intramolecular Wittig reaction, (ii) intramolecular aldol, nucleophilic displacement or other condensation reaction or, (iii) a carbene insertion reaction.

(i) Intramolecular Wittig reactions 18 20 21 This method has enjoyed the most attention ' ' . Both 3-unsubstituted and 3-substituted carbapen-2-ems have been made accessible by this methodology. Ring closure is accomplished with concomitant formation of the 2

A -double bond. In general terms, an intermediate of type (5) is required

in order to effect cyclisation.

Throughout, the following abbreviations will be used: Bz = benzyl 0 = phenyl NB = o-nitrobenzyl PNB= p-nitrobenzyl 15.

0 •R&3 /

CO2R

(5) R = H, alkyl, aryl, S-alkyl, S-aryl

R1 = alkyl, aryl

(a) Prep a r a tion of 3-unsubstituted, 3-alkyl and 3-aryl substituted carbapen^2-ems.- Several strategies, including the cycloaddition of chloro- 22 sulphonyl isocyanate with olefins and Lowe syntheses have been utilised in the preparation of intermediates such as the phosphorane (5). A method of great synthetic potential, involving the direct formation of the C-4 to

C-5 bond has also been described in relation to these studies. 22 The Beecham group prepared 4-allylazetidin-2-one (6) from penta-1,4- 23 diene and chlorosulphonyl isocyanate . Treatment of the B-lactam (6) with benzyl glyoxalate, afforded the hydroxy-acetate (7), which was readily converted to the chloride (8) on treatment with thionyl chloride and a base. Treatment of the chloride (8) with triphenylphosphine and base afforded the 21 phosphorane (9) . Ozonolysis of the ylid (9), in the presence of trifluo- roacetic acid selectively oxidized the alkene moiety. Regeneration of the phosphorane with aqueous base afforded the intermediate (10) which spon- o r 22 taneously cyclised at 0 C, to the carbapenem (11) I Scheme lj . Cyclisa- tions involving aldehydes, as above, were usually found to go in good op yields . Competing intermolecular processes have not been observed.

Cyclisation of the di-aldehyde (12) gave the carbapenem (13) as the only product"". 16.

1. csr CHOCO?BZ •NH 2 Nq S ' 2 2°B <> (6) A

SOCI2 L : N : // B o B /JR—U 6> O o P03 ^OH CI

C02BZ C02BZ C02BZ (7) (8) (9)

// N- 0 (9 pd>3

C02BZ C02BZ (11) (10) Scheme 1

H H

0 N\ 0 a

CO^z

C02BZ

(12) (13) 17.

24 The Merck group have utilised this methodology in the synthesis of the sodium salt of the carbapenem nucleus (19). The acetoxy compound

(14a) was obtained in several steps from 1-acetoxybuta-l,3-diene and chlorosulphonyl isocyanate. Conversion of the 3-lactam (14a) into the phosphorane

(15) and deprotection of the acetoxy- group afforded the alcohol (16).

Oxidation of the intermediate (16) to the aldehyde (17) resulted in spontaneous cyclisation to the carbapenem (18) (Scheme 2).

OAc /h-m <9 (14) a; R=0Ac b; R=0H •OH

a <9

(15) C0 NB 2 (16) C02NB H

•Nx 0 (9 (9 >P03 CO2NB (17) C02NB (18)

NAHCO-

Scheme 2 18.

The sensitivity of the carbapen-2-em system towards hydrogenolysis is 24 adequately portrayed at this point . Attempted hydrogenolysis of the benzyl- or 4-nitrobenzy1 esters of the carbapenem (19) resulted in very low yields 25 of the desired product. A photolytic method of deblocking the 2-nitrobenzy1 ester (18) in the presence of sodium hydrogencarbonate was found to be the 24 method of choice

26 An alternative route to the intermediates similar to the B-lactan

(14b) has been developed from the tetrahydro-1,3-oxazine (20). Reaction of 27 the amine (20) with diketen afforded the amide (21) whereupon azide transfer 28 followed by photolytic or rhodium (II) acetate carbene insertion gave the 26 trans- 3-lactam (22) in good yield . Deprotection of the ketone (22) under mild conditions to the alcohol (23) was observed (Scheme 3).

0 to N 0 TSN3

0 d H hv>

@ H3O (22)

(23)

Scheme 3 19.

Workers at Shionogi have published details of the synthesis of the 29 carbapen-2-em system from penicillins . Degradation of penicillin afforded 30 the chloro-azetidin-2-one (24) . An uncommon C-4 carbon-carbon bond formation reaction using a displacement reaction with the allylcopper reagent

(25) afforded the 8-lactam (26) in moderate yield. Conversio29 n of the 3- lactam (26) to this ylid (27) was achieved in <2ight steps . Spontaneous cyclisation of the ylid was observed at ambient temperature (Scheme 4).

Deprotection of the carbapenem (28) by catalytic hydrogenolysis was unsuccessful. The phthalidyl ester (29) was prepared in the hope that in2 4vitr o deprotection would occur. However, unlike the sodium salt (19) , the ester

(29) exhibited low activity 20' . 20.

CO2CH02

(2 8)

Scheme 4

A second example of a displacement reaction of this type has recently 31 appeared Treatment of 4-acetoxyazetidin-2-one (30) with the aluminium enolate of acetophenone afforded the 4-substituted B-lactam (31) in moderate 31 yield" Cyclisation of the benzyl-phosphorane (32) to the carbapenem (33) proceeded in good yield. Deprotection of the carbapenem (33) by catalytic 32 hydrogenation was unsuccessful (Scheme 5).

OAc 0AIE+2 Ph •Ph 0 / NH NH (9' <2 (30) (31) Ph

Jr- N 0 (9 P 0 3 > C02BZ C02BZ (32) (33) Scheme 5 21.

Cyclisation of the ylid (34), which was prepared from 4,-allylazetidin-

2-one (6), proceeded at a slower rate than the analogous cyclisation of 22 ylid (10) .

SPh

•N 0 O P0 3

C02BZ CO2NB (34) (35)

The ketones (36) have been prepared from the ylid (35)3 3 . Cyclisation

to the carbapenems (37) proceeded in low yields. In this case, photolytic

deblocking of the esters (37) was found to be unsatisfactory, as low yields

R A 0

CO^IB CO2NB (36) a R= Ph (37) aR=Ph b R.= Me b R=Me

h9 NaHCO'

rne M @ C02 Na (3 ft) a R=Ph b R=Me 22.

33 of the desired sodium salts (38) were obtained . The carbapenem (38b) was

found to be especially unstable. The 3-phenyl 3-lactam (38a), exhibited 33 biological activity in vitro

The cyclisation of ketones in this manner generally affords poorer

yields than in the case of aldehydes.

(b) Synthesis of 3-thio substituted carbapen-2-ems.- Analogous intra- 34 35 molecular Wittig reactions of thioesters have been studied. Southgate

showed that, cyclisation of the ylid (39) took place after prolonged heating

(toluene, three days, 53%).

Me SPh A Nv 0

CO2PNB (39)

The following generalisations can be drawn from Southgate's results in 35 relation to the simple alkylthio- and arylthioesters (41) :

(i) the presence of a 4-methyl group leads to greater product stability

(R1 = Me), 2 (ii) when R = PNB, the thioester becomes activated towards cyclisation 2 (relative to R = Ph), 3 (iii) when R = PNB, the phosphorane becomes deactivated towards cyclisation 3 (relative to R = Bz),

(iv) when R 2 = alkyl, R 1 = H, cyclisation does not occur to any appreciable extent, 2 1 (v) when R = alkyl, R = Me, cyclisation proceeds in low yields,

(vi) in cases (i)-(iii) yields are generally low. 23.

Similar electronic effects in intramolecular Wittig reactions have 36 been observed elsewhere . The unreactivity of simple alkylthioestors has 31 37 subsequently been observed by other groups

(41) 38 The use of 2-pyrimidinylthioesters (42) has been found to greatly

enhance the rate of cyclisation and improve product yields [(42), 39 R1 = R2 = Me, X = N, R = Bz or PNB Pyridinylthioesters (42), X = 39,40 CH, R = Bz, PNBJ and ethenylthioesters (43) R = NHCOMe, CO^t, Ph, H,

—Nx 0

esters (43) the reactions are again slow compared to aldehyde substra-

tes and go in low yields. In conclusion, the intramolecular Wittig reaction has been used with

good effect to produce a range of carbapen-2-ems. However, the low yields

observed in some cases (thioesters in particular) has meant that other

methods of introducing such substituents have had to be developed. 24.

(iia) Intramolecular aldol and other condensation reactions .

2- Several variations of this approach have led to the synthesis of A and A^-carbapenems.

2 41 (a) A -carbapenems: Initial studies used the a-disubstituted substrate

(44), in order to prevent undesirable competing reactions. Treatment of aldehyde-ester (44) with lithium hexamethyldisilazide at -78°C afforded the bicyclic 3-lactam (45a) in moderate yield, as the only isomer.

H LiN(SiMe3)2

- 78°/ THF

C02BZ

C02BZ a R=H (44) (45) b R=Ms

The relative stereochemistry about C-2, C-3 and C-5 was assigned on

the basis of nOe experiments. Later work has shown that the exo- 42 orientation of the ester moiety in such systems was preferred . Such a

stereochemical preference has also been noted in the case of the clavulanic 43 acids

Mesylation, either in situ or after isolation of the alcohol (45a)

gave the mesylate (45b). Dehydromesylation to the carbapenem (46) was

achieved in good yield using 3,3,6,9,9-pentamethyl-2,10-diazobicyclo[4,4,o]

1-decene, while DBU gave poor yields. Dehydromesylation of the related 44 3-lactam (47) was unsuccessful

45 In reality , the presence of the a-blocking groups in the aldehyde

(44) was found not to be an essential requirement for a successful outcome

of this reaction. Treatment of the aldehyde 45 (48) in a similar manner to 25.

CO^Bz

(46) (47)

the 3-lactam (44) for short reaction times, afforded the carbapenam (49) in

moderate yield. Conversion of the alcohol (49) to the mesylate, followed by

dehydromesylation produced the carbapenem (50). Interestingly, dehydromesyl-

ation of the carbapenam (51) led to the formation of the alkene (52), which

had an exocyclic double bond. Isomerisation to the carbapen-2-em (53) 43 occurred in the presence of triethylamine (Scheme 6) eO H MeO MeO

/i—Nv 0 O "OH

CO2PNB CO2PNB CO2PNB (48) (49) (50)

CO2CH2OM (23)

Scheme 3 26.

46 Once more, deprotection by catalytic hydrogenolysis proved difficult , the ester (50) was destroyed on attempted deprotection. The biologically 45 46 labile ester (54) did not exhibit any antibacterial activity '

(b) A -carbapenems: An analogous procedure to that described above has 3 47 been employed in the synthesis of A -carbapenems . Treatment of the 3-lactam

(55) (Scheme 7) with sodium hydride and allyl bromide afforded the bis-alkene

(56), which on ozonolysis and reductive work-up afforded the di-aldehyd48 e (57). Treatment of the intermediate (57) with acetic acid-piperidine furnished the unstable aldehyde (58). Subsequent reduction to the alcohol, protection and decarboxylation produced the carbapen-2-em (59).

RF^ 1. NaH 2. <9 CO2PNB CO2PNB

C02PNB c O2PNB

(57)

(59 > COOPN2 B • Scheme 7 27.

The relative stereochemistry at C-2 and C-5 was established by X-ray analysis of the carbapenem (59). Interestingly, although the X-ray analysis 18 indicated that the carbapenem (59) was as highly strained as thienamycin

(h * 0.5 X in both cases), the free acid derived from (59) exhibited no biological activity. Similar observations have been made elsewhere regarding 17 3 the lack of reactivity of the carbapen-3-em system . As suggested, the A - 19 2 system may not be as good an "electron sink" as the A -isomer. Similar 3 19 observations have been made in the case of A -cephems

A "one-pot" condensation-elimination sequence has been reported by 49

Durst (Scheme 8). 1,4-Addition of the 1-lithio anion (60) to a range of phosphonates (61) proceeded in good yield; subsequent ozonolysis afforded aldehydes (62), which on treatment with sodium hydride produced the carbapen-

3-ems (63) in reasonable overall yields. The relative stereochemistry of the

2 .R

+ / N© -N.

NaH

P(0Et)? II (6 2) o (23) Scheme 3 28.

carbapcncms (G3) was not established. Notably, reaction of the 1-lithio r 1 2 n 49 B-lactam (60) with phosphonate [(Gl), R = Ph, R = SMe) was unsuccessful

(iib) Intramolecular nucleophilic displacement reactions

Two approaches have been investigated (Scheme 9).

-SMe

COoBz C02BZ (65) (64)

Scheme 9

50 (a) Cyclisation via the C-3 carbanion (64): Initial attempts to generate

the carbanion (64) by direct metalation were unsuccessful. Proton transfer

from other acidic centres in the molecule being a possible explanation.

However, even on blocking the a-site in the chloro-ester (64) as in the case of the malonate (66a), the desired products were not obtained 50 . Interest- 50 ingly, the malonate (66b) was isolated from such reactions

•SM+ e N O SMe X-^7 "X02Bz

C02BZ (66) a X-Cl b X^H 29.

(b) Cyclisation via the C-2 carbanion (65): Attempts to form the a-bromo thioethers 50 |(65) (a) Z = II, (b) Z = CO Bz] from the dithioacetals (67a, b) followed by cyclisation in situ resulted instead in the formation of the 51 50 thienol ethers (68a,b) respectively . Bromination of the thioenolether

(68b) gave an isomeric mixture of bromides (69) which on treatment with sodium hydride afforded the bicyclic product (70).

-SMe

N SMe <9 -X

CO2BZ CO2BZ (67) a X=H (65) a X-H

b X=C02BZ b X=C02BZ

SHG

C02BZ C02BZ

(69) (70) 3

The bromide (70) underwent dehydrobromination to the A -carbapenem (71)

on reaction with DBU in dimethyl sulphoxide. Surprisingly, initial decarboxyl-

ation studies on the carbapenem (71), suggested that only one product, the ~ 50

AJ-carbapenem (72), having the exo-ester stereochemistry, was formed

Partial isomerisation of the carbapenem (72) to the A2-isomer (73) could be 30.

50 achieved when using DBU as base . Under such equilibration conditions, i 50 poor yields (25%) of the desired A2-isomer (73) were obtained (Scheme 10)

Lil collidine

^ / ^02BZ C0 BZ C0 Bz 2 (71) 2 (72)

DBU o'

C02Bz (73)

Scheme 10

Subsequent investigations indicated that the A2-isomer (73) was unstable to

the decarboxylation conditions employed and could not, therefore, be isolated ,. ,, 50,51 directly

Although the decarboxylation and isomerisation procedures described

above are synthetically unattractive, this methodology was employed in the 52 first total synthesis of (±) thienamycin The isomerisation procedures 17 constituted a means of preparing the A^-isomer for biological investigation

The N1-C2 cyclisation as depicted in Scheme 11 has been reported by 53 DiNinno . Subsequent work has revealed that DiNinno's original findings 54

were incorrect , the (3-lactam (74) was shown by X-ray analysis, to be the

correct structure. However, the underlying principle behind this reaction

may find application in the synthesis of carbapen-2-em systems. N1-C2 Cycli-

sation has been achieved by way of a carbene insertion reaction. 31.

/S^SMe SMe z^-N© (9' Br C02PNB CO PNB COOPNB 2

,Me

Scheme 11

(iii) Carberie insertion reactions

The synthesis of carbapenams and hence carbapenems by way of a Nl-

C2 carbene insertion reaction is the method of choice. This methodology was 42 31 reported independently by the Merck and Sankyo research groups. In the 42

Merck route, the aldehyde (75) was condensed with the lithium enolate of

benzyl acetate to afford an epimeric mixture of the alcohols (76), which on

deprotection, oxidation and diazo transfer produced the B-keto-a-diazoester

(77) (Scheme 12). Photolysis of the diazoester (77) gave a mixture of the

insertion (78) and rearranged (79) products. However, thermolysi55 s of the diazoester (77) in the presence of rhodium (II) acetate afforded a near

quantitative yield of the insertion product, the carbapenam (78). The relative stereochemistry at C-2 and C-5 was confirmed by X-ray analysis 42 . The exo-isomer was also suggested to be the more favoured 42 isomer from computer modelling studies

Conversion of the ketone (78) into the vinyl tosylate (80) was accomplished by reaction with di-iso-propylethylamine and toluene-4-sulphonic 42 anhydride . The thienamycin side chain was readily introduced on treatment © 32 U 0 H © OBz 0 o' N

(75)

n-oBz. o o o A—NH o'

C02BZ m (78)

C02BZ

Scheme 12 of the vinyl tosylate (80) with N-(4-nitrobenzyloxycarbonyl)cysteamine in the presence of di-iso-propylethylamine giving the carbapenem (81) in good 42 yield

(80) C°2Bz (81) C°2Bz 33.

5(3 Recently, conversion of the ketone (80) into the vinyl phosphate (82)

using diphcnyl chlorophosphonate, and subsequent reaction as above has bean

shown to give optimal yields (80%) for the introduction of the cysteamine 56 moiety into the carbapen-2-em system. The use of diethyl chlorophosphonate

gave lower yields.

Interestingly, reaction of cysteamine with ketone (78) afforded the amide 42 (83) in high yield . Curiously, nucleophilic attack on the 3-lactam moiety was not observed,4 2

0P(0Ph)? II z 0

C02BZ C02BZ (82) (83)

31 The Sankyo group prepared the 3-keto ester (85a) in low yield from

4-acetoxyazetidin-3-one (30) via a displacement reaction using the aluminium 57 enolate (84) . Diazo transfer and subsequent carbene insertion into the

OMe QAlEt2

(30)

a X= H2

b X= N2 (84) (85)

Nl-H bond gave the ketoester (86) . Reaction of the ketoester (86) with tri-

phenylphosphine and diphenyl disulphide gave poor yields of the A3-carba-

penem (87a) and the ketal (88) . Isomerisation to the A2-system was not 31 reported . Surprisingly, the ester (87a) was found to be relatively stable

to base, reaction with one equivalent of sodium hydroxide afforded the sodium 31 salt (87b) in good yield 34.

/>-N 7 O O

CC^Me CO2R C02Me

(86) (87) (88) a R=Me b R=Na©

(iv) Other methods of introducing the C-3 sulphur substituents

The reaction of thiols with the carbapenem (11) has been shown by the 58 Beecham group to be a general reaction . N-Acetylcysteamine reacted with the carbapenem (11) in the presence of potassium carbonate in N-dimethylformamide at ambient temperatures to afford a mixture of isomeric products

(89), (90) and (91). The stereochemistry at C-2, C-3 and C-5 was proven by 58 39, X-ray analysis . The isomer ratio was dependent on the nature of the thiol 58 and on the substitution at C-6. Isomerisation of the 3-lactam (91) to the more stable isomer (90) occurred in.the presence of DBU.

Oxidation of the two major products, the thioesters (89) and (90) with 59 iodobenzene dichloride in the presence of pyridine and water proceeded

in a regiospecific and stereospecific manner, to afford the a-chloro- 39, 58 sulphoxides (92) and (93) respectively . As before, the structures of 58 the sulphoxides was determined by,X-ray analysis . Dehydrochlorination of

the a-chlorosulphoxides (92) and (93) produced the carbapenems (94) and (95) 39,58 respectively

39 Deoxygenation of the sulphoxides (94) and (95) proved unsuccessful ,S(CH2)2NHAI

S(CH2)2NHAC

(89) C02Bz (90) C02BZ

S(CH2)2NHAC

C02BZ

©S(CH 2)2NHAC

(92) 'C02Bz C02BZ

0© 0© S(CH2)2NHAC S(CH2)2NHAC

C02BZ 02BZ (93)

A modified method for the direct introduction of the C-3 sulphenyl 39,60 group has been described . Reaction of the carbapenem (96) with ethane- thiol as above afforded the thioether (97) as a mixture of isomers. Subse- quent reaction of the thioether (97) with iodobenzene dichloride under strictly anhydrous conditions in the presence of pyridine led to the direct formation of the A3-carbapenem (98) in 50% yield. Interestingly, it was observed that in acyclic model systems similar reactions led to the direct 39 formation of the conjugated product 36.

" >SET" • O P ,96, (97) ®2 NB

(98) (99)

Isomerisation of the A3-carbapenem (98) to the A2-isomer (99) was 39,60 achieved in low yields, using DBU as base .Of note is the fact

61 that pyridine was ineffective in this transformation A variety of 39 ethanethiols have been studied in these reactions-". The 1,4-addition of ethenylthiolates to such systems has not been reported.

62 Corbett has recently shown that the thione (101) can be prepared from the ester (100). Reaction of the thione (101) with a series of 37.

alkylating agents was observed. It was also shown that the thione (101) underwent 1,4-addition reactions with ethyl propiolate affording the ester (102). Hence, isomers of thienamycin are now accessible from the appropriate olivanic acids. The preparation of the thiones (103a) from the bicyclic ketones (103b) would be a useful synthetic goal.

AcO

NHAC CO2PNB (100)

•N-y (9 CO R C02PNB 2 (102) (10 3) a X=S

bX=0 Generally, the Merck method is preferable for the introduction of the 3-thio-substituents into the carbapen-2-em system. The Beecham approach however has made it possible for a large number of 3-sulphenyl and 3-sulphinyl q 39 A^-carbapenems to be tested for biological activity

It is interesting to note that the cleavage of the highly reactive

A2-carbapenem system was not reported by the Beecham group during the course of these reactions.

B_. TOTAL SYNTHESIS OF THIENAMYCIN AND RELATED COMPOUNDS

(i) Merck approach

50 Initial Merck studies were concerned with a non-stereospecific introduction of the 6-(l'-hydroxyethyl) function, arguably in order to evaluate the biological activity of each of the isomers so formed. This objective was readily achieved on alkylation of the N^, O-protected 3-lactam (104) with acetaldehyde (Scheme 13). Originally, only the trans-8R*(105a) and trans-8S* (105b) isomers were observed (SjJ* % 3 Protection of the epimeric mixture of alcohols (105) as the 4-nitrobenzyl carbonate and subsequent hydrolysis of the acetonide moiety afforded the alcohols (107a,b).

The pure 8S* isomer (107b) could be obtained at this stage by fractional crystallisation. Oxidation of the epimeric mixture (107a,b) gave the aldehydes (108a,b) which were converted to the dithioacetals (109a,b) . 64 Cyclisation of the dithioacetals (109a,b) was effected in a similar 50 manner to that previously described for the dithioacetal (67b) . Conden-

sation of the intermediate (109a,b) with bis-(4-nitrobenzyl)mesoxalate and subsequent transformation of the hydroxy-malonates (110a,b) to the malonates 39.

OH OH

1.LDA J^L N n 0 a. NXOZCH3OHO H0dHxp * HQO^K (104) I y (105a) I trl (106a)

RO ^-NxL + m. r O NX? (105b) (106b) 0C02PNB OCO2PNB

(107a, b) (10M QCO?PNB

. ijJH

-NK C02PNB S(CH2)2NHC02PNB HO'Y—C0 PNB (109ab) 2

CO2PNB (110a,b) HL Br NHC02PN3 Jy-N o C02PNB CO2PNB CO2PNB CO2PNB

(111 a,b) (112a, b)

Scheme 13/continued 40.

OCO2PNB CO2PNB H H

•s— S^NHCO2PNB <7 o C02PNB o C02PNB

COOPNB CO2PNB

(113a, b) (114a)

OCO2PNB OH

(114b) (115)

Scheme 13 41.

(111a,b) was achieved by standard methodology. Treatment of the malonates

64 (111a,b) with bromine followed by triethylamine afforded the carbapenams

(112a,b). Attempted dehydrobromination of the bromides (112a,b) using DBU as the base led to the formation of side products. Silver fluoride-pyridine was found to be the reagent of choice for this transformation. The 8j?*- epimer (113a), on decarboxylation and isomerisation afforded the protected

(±)thienamycin (114a). Di-iso-propylamine gave optimal yields in the iso- . «.. + 52,64 merisation step

Deprotection of the carbapenem (114a) was accomplished in low yields by

52, 64 catalytic hydrogenolysis . This is to be compared with the relative

17 stability of A3-thienamycin under similar reaction conditions

The synthesis of (±)-8-epithienamycin (115) was accomplished as outlined

52,64 above, starting from the 8S*-epimer (105b) . This 3-lactam (115) was

64 found to have diminished in vitro activity compared to (±)-thienamycin

Intermediates (105a,b) have also been prepared as a 1:1 mixture by

reduction of the ketone (22) with sodium borohydride followed by mild hydro-

26 lysii •s

Subsequent studies have shown that alkylation of the 3-lactam (104)

with acetaldehyde also produced the cis-R* isomer (I06a)> 9% and the cis-R*

isomer (106b), present only in trace amounts. The preference to form the

cis-R* isomer over the cis-S* isomer has been noted in similar studies oil the alkylation of penicillins 65

Several facets of the above scheme have to be considered if a stereo-

specific synthesis of thienamycin were sought:

(i) the introduction of the 6-(lT-hydroxyethyl) group affords a mixture

of products, mainly consisting of the trans-R* and trans-S* epimers,

(ii) the decarboxylation and isomerisation steps go in low yields (45 and

48% respectively), even after recycling recovered starting materials, 42.

(iii) the mode of cyclisation may limit the synthetic usefulness of the

scheme.

A stereospecific synthesis of (+)-thienamycin has subsequently appeared in which the above problems have, to a degree, been resolved.

As described previously , a method has been developed for the construc- tion of the 3-substituted carbapen-2-em nucleus. The major problem to be addressed therefore was the introduction of the hydroxylated side-chain in a stereospecific manner.

Model studies indicated that the 3-lactam (104) could be efficiently acylated by employing a two step procedure. Silylation of the B-lactam

(104) was accomplished on reacting sequentially with lithium di-iso-propylamide and chlorotrimethylsilane. The product (116) had exclusive trans- stereochemistry. Regeneration of the 3-lactam enolate, using two equivalents of lithium di-iso-propylamide, followed by reaction with acetyl imidazole afforded the enolate (117). Aqueous work up afforded the trans-6-acyl

3-lactam (118). Stereoselective reduction of the ketone (118) was observed when hindered borohydride reagents such as K-Selectride and L-Selectride

67 were employed . The product stereochemistry was dependent on the solvent polarity and the counter cation in the reagent. K-Selectride gave mainly the 8R*-isomer (R*:S* = 88:12), whereas L-Selectride reversed the isomer distribution (R*:S* = 8:92)67. These observations have been rationalised67 on the basis of the formation of a syn-chelate (119) in the case of the potassium counterion, which underwent stereospecific reduction due to steric approach control.

Stereospecific reductions using K-Selectride on this and similar compounds has been observed by other workers^**'^. Interestingly, reduction of the ketone (120) using zinc borohydride led to almost exclusive formation

69 of the 8S* isomer (121) . Stereospecific reductions of 3-ketoesters using 43. Li o© TMS

N ^NxO {7 O (117) (116)

W' (105a) (119) M*=K

(120)

70 zinc borohydride have recently been reported

With a stereospecific method of introducing the 6-(l'-hydroxyethyl)-

group at hand, a stereospecific synthesis of (+)-thienamycin has subsequently 66

been accomplished . The chiral 3-lactam (122) was readily accessible from

L-aspartic acid (Scheme 14). Conversion to the iodide (123) was accomplished

using standard methodology, which was reacted with the masked acid synthon

(124), affording the 3-lactam (125). Generation of the 3-lactam enolate,

using two equivalents of lithium di-iso-propylamide, followed by trapping

with N-acetylimidazole produced the ketone (126) in good overall yields.

The product (126) had exclusive trans-stereochemistry. Stereospecific reduction of the ketone (126) with K-Selectride 67 produced a separable mixture of the 44.

02H

OC OH II -^-NH NH^ C> 0 © (122)

+ ^ \ Li® —Si SiMe

(124) (123)

—Si (125) OH OH H Ul

^ -N •N O'

OHC127) (128) OH (129) |

M ^V^VOPNB NH 0 0 o' <2 CO2PNB C02PNB (130) (131)

Schomc 14 45.

epimeric alcohols (127), 8R and (128), 8S (with a ratio- of 8R: 8£ =

9:1).

Treatment of the dithiane (127) with a mixture of mercury (II) oxide and mercury (II) chloride followed by hydrogen peroxide afforded the acid

71 (129) which was converted to the 3-ketoester (130) . The carbene insertion methodology 42 was now used to effect cyclisation. Subsequent elabora- 4: tion of the carbapenem so formed afforded the bis-protected thienamycin (131)

Deprotection, by way of catalytic reduction, afforded (+)-thienamycin in low yield (20%) (Scheme 14).

An interesting observation was noted during this work. Oxidation of the mixture of alcohols (105a,b) and (106a,b) afforded the thermodynamically more

72 stable trans- 3-lactam (118) . A similar finding has recently been reported

by Kametani 69

An alternative approach to the stereochemical problems presented in the

synthesis of thienamycin has been presented by another Merck group . The

functionalised 3-lactam (142), having the 5R*, 6S*, 8S* relative stereo-

chemistry was readily obtainable from 1,3-diethyl acetone-1,3-dicarboxylate

(133) . The crucial step in this synthetic scheme was the stereospecific

reduction of enamine (134). It was argued that because of the very strong

hydrogen bonding present in (134), reduction with sodium cyanoborohydride in

acetic acid would give one product,(135). This was observed. The lactone

(136), derived from the alcohol (135), was debenzylated and the resulting

amino acid upon reacting with benzyl alcohol afforded the ester (137) . Cycli-

sation of the amino-acid (137) to the 3-lactam (138) was achieved in high

yield using dicyclohexylcarbodiimide. Silylation of the 3-lactam (138)

followed by catalytic debenzylation enabled the formation of the imidazolide

(139) which reacted with Meldrum's acid to afford the malonate (140). On

heating the malonate (140) in the presence of 4-nitrobenzyl alcohol and

subsequent desilylation, the B-ketoester (141) was obtained. 46 /f-k Q BzN o

NaCNBH3 HOAc Etnc COoEf Et02C C02Et 7 (133) z (134) BzNH OH

EfCkC C02Et NHBz (135) 0^(136) DCC li COoBz OBz 0 NH °=C NHo-HCl

6H n 37 > (138)

(139)

OPNB

(141) 17.

73,74,75 Inversion of stereochemistry at C-8 was accomplished by reacting

(141) with triphenylphosphine in the presence of di-iso-propyl azodicarboxylate and

formic acid, affording an intermediate formate ester which was readily hydro-

lysed to alcohol (142) having the required 5 R *, 6£3* , 8IV*, relative stereochem-

73 •istry (Scheme 15) .

Conversion of the intermediate (142) to (±)-thienamycin was accomplished by 42 way of the carbene insertion methodology . The overall yield for the synthesis

was ^ 10% 73 76

In a later paper ,the inversion of configuration of the alcohol stereochem-

istry at C-8 was carried out at an earlier stage in the synthesis. Cyclisation

of the hydroxy-diester (135) under milder conditions gave the lactone (143), 76 which on hydrolysis afforded the hydroxy-ester (144) . Relactonisation was

achieved by a reverse activation procedure . Treatment of the intermediate (144)

with triphenylphosphine and diethyl azodicarboxylate afforded a new lactone (145)

in which the C-8 stereochemistry was inverted.

Hydrolysis of the ester function, followed by solvolysis, as before, afford— 77 ed the amino-acid (146), which was transformed into (±)-thienamycin as described

73 for the intermediate (137) . It was observed that (D, ^-protection was unnecessary

76 in the chain elongation step (Scheme 16)

Scheme 16 48.

(ii) Kamotani Approach

Kametani also tried to construct an acyclic precursor with the correct

relative stereochemistry at C-5, C-6 and C-8, which could then be transformed

by a number of routes to the carbapenem system.

Catalytic reduction of isoxazoline (147) , prepared from a 1,3-dipolar

cycloaddition of the nitrile oxide (148) with methyl crotonoate, afforded an

epimeric mixture of the esters (149) which on hydrolysis and subsequent

cyclisation with dicyclohexylcarbodiimide produced a separable mixture of the 78 3-lactams (150) and (151), both in low yields (22 and 0.8% respectively)

Remarkably, the 3-lactam (150) was found to have the wrong stereochemistry

78 at C-8 (S*), as confirmed by X-ray analysis of a derivative . Extensive

epimerisation at C-6 had occurred. When hydrolysis of the ester (149) was

79 carried out under milder conditions followed again by cyclisation as above,

an inseparable mixture of the 3-lactams (150) and (152) was produced in poor

79,80 yields (20-40%). Trace amounts of 3-lactam (151) were again observed

80 Prior hydrolysis of the ester (147) followed by hydrogenolysis again

afforded a mixture of the 3-lactams (150) and (152) [(150) : (152) = 1:2.5] 81

on cyclisation as above. However, cyclisation of the pure amino acid

derived from (153), itself prepared from (147) in poor yields by reduction

with nickel chloride-sodium borohydride, gave the 3-lactam (152) in 81 reasonable yields, as a single isomer

It was concluded that a considerable degree of epimerisation occurred,

even under mild conditions, in the transformation of intermediates (149) to 80 (152) . The formation of the trans-8S* isomer (150) was rationalised on the

grounds that the formation of this product was thermodynamically more favour- 80 able than the formation of the cis-8R* isomer (151)

Other methods of cyclising amino-ester (149) were investigated in order 49.

80,81 to circumvcnt these problems . Direct cyclisation of the epimeric esters 80 81 81 C149) using Grignard reagents ' or tri-isobutyl aluminium selectively produced 3-lactam (152) in low yields.

OoMe OMe

—C=N-0 Me C02He MeO

OMe (147) (148) OH 0HuNH2 OMe OMe OMe

C02Me OMe (149) (150)

OMe OMe

OMe OMe (151) (152)

OH NH2 OMe

OMe

C02Me (153) 50.

In order to prepare starting materials which contained more of the desired epimer having the 5R* stereochemistry, the t^-butyl ester (154)

80 82 was used in the cycloaddition reaction ' . Hydrogenation of (155) produced a 1:1 mixture (156) of the 80two, 82epimer s at C-5 compared with a 3:2 (£*

R*) mixture previously obtained . Selective silylation of the alcohol group in the epimeric mixture (149), followed by treatment with excess ethylmagnesium bromide again selectively produced, after deprotection, the desired trans-product (152) (21%) and the cis- B-lactam (151) 38% (Scheme

17) 81,82 . Remarkably, in the case of the t-butyl ester (156), silylation,

cyclisation followed by deprotection afforded the trans-8R* B-lactam (152) 81,82 in 41% yield, as the only identifiable product

This reaction sequence has subsequently been extended to cover a range

83 of substrates . The use of optically active esters in the cycloaddition

reaction followed by the established procedure in preparing the 3-lactams

84 afforded a small degree of asymetric induction in the product

Having arrived at a method of preparing the isomers (150), (151) and

(152) in low yields, a range of carbapenems have subsequently been prepared.

The Merck routes leading to the introduction of the correct 5R*, 6S*, 8R*

relative stereochemistry, as found in thienamycin, are far superior to

Kametani's efforts in this area.

The 3,3-dimethoxy group in intermediate (152) is of course equivalent

to an aldehyde. Hence on unmasking this functionality, and conversion to

the protected acid (157), a synthesis of the protected (±)-thienamycin 85 3V 3d (158) was accomplished ' using the Merck methodology in the ring closing

step and in the introduction of the C-3 protected side chain (Scheme 18).

The synthesis of the bis-protected (±)-decysteaminyl-8-epithienamycin

(159) was accomplished by way of an intramolecular Wittig reaction (Scheme 80,86 19) .In this case, the Wittig reaction afforded a 39% yield of the 51.

(154)

C02Bu

(156) /SiMe3/SiMe3 NHo OMe 0 NH OMe ' z r EI-BN-TMSCI I C T

OMe Me-^^^^^OMe

C02Me C02Me

Me3Si0

EtMqSr

.y^-N HF0 \ OMe

SiMe3

(151) (15 2)

Scheme 17 52.

0C02PNB OMe

COOPNB OH

f>-S^NHC02PNB o NH 0 (157) (158) CO2PNB

Scheme 18

OCO2PNB OCO2PNB

(150) OMe ^AJ

O OMe

OCO2PNB C02NB H

C02PNB

(159)

Scheme 19 53.

80.86 carbapcncm (159)

80,81 As the cis- 3-lactam (151) was readily available , a synthesis of the protected (±)-epithienamycin A (161) and (i)-epithienamycin B (162) have also

87 been reported by the same author The key intermediate in these syntheses was the vinyl phosphate (160), which was transformed to the epithienamycins

87 (161) and (162) upon reaction with the appropriate thiolate The vinyl

0C02PNB H H

0Ph)2 NHAc

C02PNB C02PNB (161)

NHAc

(162f02PNB

phosphate was prepared using the Merck method as outlined in the synthesis

of the protected thienamycin (158). Deprotection of the esters (161) and

(162) afforded (±)-epithienamycin A (2) and B (3) respectively.

It is interesting to note that the difficulties experienced by Kametani

in the formation of the 3-lactam system without loss of stereochemical inte-

73 grity were not experienced by Melillo

An interesting model study has appeared , in which the desired 5R*,

6S*, 8R* relative stereochemistry is produced in one step, again in a

dipolar cyclo-addition reaction. Reaction of the nitrone (163) with methyl

crotonate afforded the bicyclic ester (164) in excellent yield (Scheme 20).

Hydrogenolysis of the bicyclic intermediate (164), followed by treatment 54.

Scheme 20

with excess ethylmagnesium bromide afforded the 3-lactam (165) in moderate yield. More functionlised systems have not yet been studied.

The ability to equilibrate a mixture of cis- and trans- 3-lactams to the more favoured trans-isomer has been utilised in the synthesis of a

89 chiral intermediate of use in the preparation of thienamycin

Preparation of the 3-lactam (167) was readily accomplished from the

acid chloride (166) (Scheme 21). The di-ester (167) was converted to the

epimeric phenylthiomethylketones (168a,b) in five steps. On treatment of

the mixture (168a,b) with base, the thermodynamically favoured trans-

isomer (168a) was isolated as the only product. Intermediate (168a) was

89 then converted to the thioenolether (169) by a lengthy procedure

The Merck group have prepared (±)-decysteaminylthienamycin from the al-

24 cohols (105a,b) . The two epimers of the alcohol (170a,b) could be

separated, the 8R* isomer was converted to the aldehyde-phosphorane (171) 21 by usual methodology , which cyclised to the carbapenem (172). Deprotection

25 of the carbapenem (172) by a photolytic method , afforded the sodium salt

39 of (±)-decysteaminylthienamycin (173) (Scheme 22). The Beecham group OAc 55, H H W* COCl C02Et N <9 (166) (167) OAc C02BZ

- s f* <9 (168a,b)

(168a) (169) Scheme 21 have found that attempted deprotection of the benzyl- or 4-nitrobenzy1 esters of (173) could not be achieved without concomitant reduction of the A2- double bond.

(105a,b)

(170 ,A)

C0 NB 2 C02Na (172) (173) Scheme 22 56

0 H ri (s N (9 NH OH

(22) OCO2PNB (174) H S NHAc

(175) CO2PNB

(X02 PNB H

NHAc

4 C02PNB (176 ) OH. OH

NHAc NHAc r . .© C02Na CO?Na® (MM 2283) (177)

Scheme 23 These workers employed the use of the phthalidyl ester which is deprotected in vitro. This parallels the results of the Shionogi

29 group in the synthesis of the carbapen-2-em-2-carboxylic acid skele- ton, where such a protecting group was also used, due to the instability of the carbapen-2-em system.

The Beecham group have described the total synthesis of (±)-

MM 2233 and (±)-N-acetyl-dehydrothienamycin, starting from the 68

3-lactam (22) . This key intermediate, on reduction with sodium borohydride and deprotection gave an epimeric 1 : 1 mixture of the alcohols (174) . Conversion of the alcohols (174) to the phosphorane (175) was achieved by standard methodology. Cyclisation to the carbapenem (176a, b) was observed in low yield. Deprotection of the 3S* epimer (176a) afforded (±)-MM 2283 whereas the 8R*

isomer (176b) gave (l')-N-acetyldehydrothienamycin (177) (Scheme 23) .

The stability of the phosphorane (9) towards strong bases has

22 39 been utilised in a synthesis of (±)-MM 22381 benzylester (180) '

Alkylation of the phosphorane (9) with acetaldehyde, afforded

a single cis-isomer (178), and a single trans-isomer (179). The rel-

ative stereochemistry of the cis- and trans-isomers (178) and (179) was

22 39

assigned as 5R*, 6 R*, 8R* , and 5R*, OS*, 8S* respectively '

The trans-isomer (179) was converted to (±)-MM 22381 benzyl ester

(180) by standard methodology (Scheme 24). (178) / ' 3 OH • C°2Bz

//-S-^^NHAc o N\ . (179)/ ^3 (180) C02BZ

C02BZ

Scheme 24

(iii) Synthesis of PS-5 derivatives

Alkylation of the N-protected 3-lactam (181) afforded the trans- 60 product (182) . Desilylation of the intermediate (182), followed by the usual Wittig sequence furnished the carbapenem (183). Introduction of the

39 60

C-3 side chain was accomplished as previously described ' to give the protected (±)-PS-5 derivative (184). Deprotection of the carbapenem (184) to the sodium salt of PS-5 (185) was achieve6 0 d by hydrogenolysis in the presence of sodium hydrogencarbonate (Scheme 25).

A synthesis of (±)-6-epi-PS-5 has also been described by the same 60 workers

The instability of carbapenems such as (184) towards catalytic hydrogenolysis has brought about the introduction of the 4-methoxycarbonylbenzyl ester as a protecting group for the carboxylic acid moiety in such systems.

39 90 Deblocking is achieved electrochemically '

An interesting synthesis of (±)-PS-5 benzyl- and t-butyl esters has 59.

— Si (181)

S^N/NHAC

(183) C02PNB (184) C02PNB

H rv NHAc //-N-Z

0 Ccf2^a (185)

Scheme 25 LIV 60. 0 /-OAc o,^-N H N 2 (186) (187) R=Bz or fBu

r0R Rh2(0Ac)4 0 0

(188)

S^^NHAc

CO2R C02R (189) (190)

1 © > N u

(191)

Scheme 26 61.

91 appeared . Displacement of the 4-acetoxy- group in the 3-lactam (186) occurred in poor yields on reacting with the enolate (187) , affording the substituted 3-lactam (188). The 3-lactam (188) had exclusive trans-

42 stereochemistry. Carbene insertion into the Nl-H bond was observed in quantitative yield on refluxing the diazo-compound (188) in the presence of rhodium (II) acetate. The carbapenam (190) so formed was converted to the

(±)-PS-5 benzyl- and t-butyl esters (190) by standard methodology.

A "1,4-additionM of the enolate (187) to the intermediate (191) was invoked in order to explain the stereochemical course of the displacement

91 reaction (Scheme 26) .

39 The stereospecific reduction of the ene-lactam (192) has been observed '

Catalytic hydrogenation of the 3-lactam (192) gave mainly the cis- isomer (193), whereas reduction of (192) with sodium borohydride gave the trans- 3-lactam (194). Thus, the 6-epi-PS-5 derivatives (193) have become available by such methodology (Scheme 27).

39 The addition of thiols to the ene-lactam (192) have also been observed ,

92 93 again leading to the thermodynamic product (195) ' . The 8R*/8S* ratio in the product (195) was not disclosed. Such compounds exhibited biological activity.

A synthesis of the ring expanded analogue (-)-homothienamycin (196) has

94 been reported . The starting material in this synthesis was the chiral iodide (197), which after displacement with the dianion (198) afforded the substituted 3-lactam (199). Cyclisation to the bicyclic system (200) was accomplished by way of the carbene insertion methodology. Conversion of the enol (200) to the vinyl tosylate (201) and subsequent alkylation with acetaldehyde gave the alcohol (202). The alcohol (202) was then con- 42 verted to (-)-homothienamycin (196) by standard methodology (Scheme 28).

(-)-Homothienamycin (196) was biologically inactive. 62.

(193)

H2/PT02

0 '(19 2)

C02R<

RSH/ K2C03

C02R (195)

Scheme 27 63.

If® v® U 00 U 06

NH u

(197) (19 ft)

(199) OH M /?— OH ^ OTs O t, t C02'BU C02 Bu " CO^BU (200) (201) (20 2) OH

/M NH (9

(196)

Scheme 28 CONCLUSIONS

Since the isolation of thienamycin was disclosed in 1976, a number of

structurally related compounds have been isolated.

The inherent biological activity of these compounds has been attributed

to high degree of strain (h ^ 0.5 X) present in the carbapen-2-em nucleus.

The infrared absorption frequency of the carbonyl group in the A -

carbapen-2-em systems is usually in the range 1750-1785 cm 1, a similar

range to that found in penicillins, again indicative of a strained system.

Delocalisation of the lone pair on the N-l atom into the A2-double bond may

be important in determining the biological activity of the A2-carbapenem

system. Infra-red data is in accord with such a charge delocalisation.

Although the A3-system is as highly strained as the A2-carbapenems, such

delocalisation of charge is not possible in this case. A3-Carbapenems are

biologically inactive. Ring strain is important however, as homothienamycin

is inactive. Further studies into the factors affecting biological activity

are required, especially in view of thienamycin's unusual broad spectrum

activity.

Synthetic methodology has improved immensely since the first attempts

at the total synthesis of these compounds. The inefficient step still

remaining in such syntheses is concerned with the formation of the bicyclic

system. Facile formation of the bicyclic ring system from readily available

starting materials could be achieved if Kametani's C-4 displacement reactions

were extended.

A thienamycin derivative, MK-0787 is in clinical trials. 65.

REFERENCES

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72 Ref. 67, footnote 10.

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1980, 1193. RESULTS AND DISCUSSION 73.

INTRODUCTION

Activity in the field of 3-lactam antibiotics has continued at a high level in recent years due to the isolation of the nocardicins^,

2 3 clavulanic acids , olivanic acids and more recently the monobactamic acids!1 Our own interest lay in the development of new methodologies for the synthesis of substructures related to the carbapenem antibiotics.

The work described herein can be categorised as follows:

(i) the use of ynolate anions in the synthesis of azetidin-2-ones;

(ii) the functionalisation at C-4 in monocyclic 3-lactams;

(iii)the application of the Shapiro reaction in the synthesis of a-methylene

3-lactams; and

(iv) the preparation of monocyclic 3-lactams from acyclic amides.

(i) The Use of Ynolate Anions in the Synthesis of Azetidin-2-ones

From a retrosynthetic viewpoint, the 3-lactam moiety and the 6-(l'-hydroxyethyl)-side-chain present in thienamycin (1) could be derived via the cycloaddition of the metalated lceten (2) to the imine (3), followed by trapping of the intermediate 3-lactam eriolate (4) with acetaldehyde in situ

(Scheme 1).

The 1,2-cycloaddition reactions of ketens and imines has been used 5 extensively in the preparation of azetidin-2-ones . Likewise, the alkyl-

ation and hydroxyalkylation of 3-lactam enolates has also received attention 6

m recent years . Our initial aim, therefore, was to prepare a number of ynolate anions (5) in the hope that these would react with imines (3),

affording the 3-lactam enolate (6) which could subsequently be reacted with 74.

V CH:

:0 H © 0 M® (4)

2 M© R © o + N: / H R1 (2) (3)

SCHEME 1

other electrophiles in situ.

\ o M® 9" •R2 % + N R- ©0x Ki R1 R1 M® (5) M® (6) There were, at the onset of our investigations several reports in the literature on the preparation of ynolates (5) and related species. For 75.

example, it had been observed that carbon monoxide reacted with a number of reactive metals to produce species such as the ynediolate (7), which has been

7 characterised by X-ray crystallography .

C® E 0 — = — O9 CS® (7) More recently , lithiation of the triazole (8) at -60 C afforded the

o intermediate (9a) on allowing to warm up to 40 C. Interestingly, in the case

1 i®

Ijj-Ph R-E —N—Ph

R R=PH(8) (9) a. R= p)-| R-H (10) B. R= H of the triazole (10), proton transfer from the initially formed intermediate g (9b) was observed, affording the starting material (10) and the dianion (11) .

LI ©

Ph H—=—N—Ph © © (9b) H LI

I © LI © =—N—PH e

(11) Li®

A similar intermediate (12), has recently been prepared from the metal-

o 9 lation of the ketenimine (13) with potassium t-butoxide at -60 C . 76. 'Ph —P h © Kcfeu K® NPh N

(13) Ph_=-NPh K® (12)

The thiolate analogue (14) has also been prepared, either by treatment of the lithium acetylide (15) with elemental sulphur10, or via metalation of the isothiadiazole** (16) (Scheme 2).

n BljLi Rh-E-H - - Ph—E ©Li®

(15)

Ph—E-S

Li (14)

IA ^ / Ph Ph (16) SCHEME 2

12 It was not until 1975, that Schtillkopf reported the preparation of

the phenylethynolate anion (17). It was observed that metalation of 3,4-

diphenylisoxazole (18) with n-butyllithium at -78 C afforded the phenyl-

ethynolate anion (17), with concomitant formation of benzonitrile. The inter-

mediate phenylethynolate anion (17) underwent reactions with a number of

electrophiles, including aldehydes and ketones, affording the 3-lactone 77.

PHCN N-BULI +

PH -78/THF PH-E-O0 LI® (18) (17)

O Li®

R •d E®=R2R360,R4X R1 (19)

SCHEME 3 enolates (19) which could be reacted further with other electrophiles, E 12 (Scheme 3)

13 The precursor, 3,4-diphenylisoxazole (18) was readily available from

the enamine (20) via the oxazoline (21) (Scheme 4). Huisgen has shown that

such 1,3-dipolar cycloaddition reactions are highly regio- and stereo-

selective processes. In our hands, treatment of the isoxazole (18) with H PH H

0 A

@ © PHC=N-0 HCl

(21) (18) 78.

one equivalent of n-butyllithium at -78 C in tetrahydrofuran, afforded an

intensely blue coloured solution. The colour of the solution was found to be stable over a long period of time ( ^ 20 hours), even at higher temperatures

(-20°C). The mechanism for the ring fragmentation process has not been established, but the intense blue colouration may be indicative of an electron transfer mechanism, affording the radical anion (22). Rh

Schttllkopf assumed that the ring fragmentation of the intermediate (23)

was very rapid since trapping experiments with chlorotrimethylsilane gave the

keten (24) in 47% yield. None of the 5-trimethylsilylisoxazole (25) was

isolated.

SiMe3 SiHG3 (24) (25)

Other workers have recently shown that C-5 metalation in isoxazoles is

followed by rapid ring fragmentation . We observed that metalation of the

isoxazole (18), followed by quenching with deuterium oxide gave benzonitrile

(tic) and trace amounts of the undeuteriated starting material (ms). The

formation of keten intermediates such as (26) in similar ring fragmentation 16 reactions have been postulated elsewhere (Scheme 5). 79.

R H

(26)

SCHEME 5

Curiously, Shttllkopf observed that metalation of the oxazole (27) did not result in ring fragmentation.

(27) PH

The preparation of the silylated isoxazole (25) has recently been report-

ed , such substrates may themselves be useful intermediates in the prepara-

tion of other ynolates. 18

Since the completion of our work in this area, Rathke has reported the

preparation of the ynolate (29) by low temperature metalation of the silyl-

keten (28) with n-butyllithium. Curiously, the intermediate (29) was colour-

less, and was found to be surprisingly unreactive towards a number of electro- 18 philes, with the exception of chlorotrimethylsilane

(a) Reaction of the phenylethynolate anion (17) with Schiff's bases.-

Reaction of the intense blue coloured solutions of the phenylethynolate

anion (17) with electron defficient Schiff's bases led to the formation of

the highly substituted azetidinones (30-33) (Table 1), in good yields. 80.

R2 Ph R f^NH o-

(30- 36)

TABLE 1

PRODUCT (Yield) R1 R2

(37) -C6H4-4-N02 -Ph 30 (66%) II (38) -CgH4-4-N02 31 (89%)

(39) it -C-H -3-Me 32 (58%) 6 4

(40) -C6II4-4-C02Et -C6H4-4-N02 33 (79%)

(41) C 4 N -C„H -4—OMe 34 (*) - 6V - °2 6 4 II (42) -C6H4-4-Cl 35 (*)

(43) -C JI -4-CN -C6H4-4-N02 36 (*) o 4

* Could not be obtained analytically pure

The products in some cases proved difficult to purify, although they were considered to be 3-lactams, as inferred from the high carbonyl stretching

frequency (ca 1760 cm "S in the infrared spectrum. Generally, the reaction

to form the 3-lactams was quite rapid (/u 30 minutes at -78°C to -60°C), and was marked by the appearance of a red-orange coloured reaction mixture.

In the case of the Schiff's bases (44) and (45), and the sulphenamide

(46), the formation of 3-lactamic products was not observed, even after prolonged reaction times at higher reaction temperatures [e.g. 3 hours at

-40°C in the case of the sulphenamide (46)]. 81.

(4 4) N02 (46)

PhCH=N C02Et

(45)

From the initial experiments with the phenylethynolate anion (17), several generalisations could be made as to its reactivity pattern:

(i) the phenylethynolate anion reacted only with electron deficient

Schiff's bases;

(ii) a powerfully electron withdrawing group on the azomethine nitrogen atom

was an essential prerequisite for 3-lactam formation;

(iii) the 3-lactam enolate (47) was always alkylated by a second molecule of

the Schiff's base; attempted trapping of the enolate (47) with other

electrophiles was unsuccessful; and

(iv) the high field (220 MHz) 1H nmr spectra of the products (30-33) indicated

that the aminoalkylation reaction of the 3-lactam enolate (47) was

highly stereoselective (vide infra).

The requirement for a strongly electron withdrawing group attached to

the azomethine nitrogen atom in the Schiff's base is indicative of the poor nucleophilicity of the phenylethynolate anion, and that charge stabilisation on nitrogen in the initial adduct (43) (Scheme 6) is an important factor in determining the path of the reaction. Similar effects have been noted in 82.

Li® Ph—E-0 6 CHR2 (17) / Ph N—-Li —o R^-C

Li® Ph' Ch ,1 n 2 1 F?" © R , R (4 8) (47) R2 Ph 2 ® X R H30 RN (30 - 36) © ^N-rI

SCHEME 6

19 the reactions of ester enolates with imines to form 3-lactams

The stereochemistry observed in the product formation may be explained by invoking steric approach control of the Schiff's bases to the chelated

3-lactam enolate (47) (Scheme 6) . Similar observations relating to the 20 stereoselective alkylation of 3-lactam enolates have been observed by Durst 21 (eg. as in Scheme 7) and by Di Ninno . Such reactions have recently been

22 used extensively in approaches towards the total synthesis of thienamycin

23 and 6-(1 '-hydroxyalkyl)-penems

In the hope of investigating further the stereochemical outcome of the aminoalkylation of 3-lactam enolates, the reaction of the parent ethynolate anion (56) with Schiff's bases was also investigated. 83.

i/CO H Ph ^>0 •Ph

e />—N L ®i 0 / N Ph <2 'Ph

SCHEME 7

The required intermediate, 3-phenylisoxazole (49) was prepared by two

24 methods (Scheme 8). Cycloaddition of benzonitrile oxide with acetylene

led to the direct formation of 3-phenylisoxazole in moderate yield (58%).

25 Alternatively, formylation of the dianion (50) derived from acetophenone

oxime, with N_,N-dimethylformamide at -40 C, and subsequent refluxing of the

intermediate (51) in an aqueous acid and THF mixtures, afforded the desired

isoxazole (49) in a lower yield (26%) (Scheme 8).

® © PhCEN-0 H- = -H

(49)

Li© N-OH N~0 9 n-BuLi DMF

Ph 6 10 CH3 -25' Prnh I 0 " (50)

l eLl © q o @ ,4"v0H N~0 H30 •(49) Ph' A (52) Ph SCHEME 8 84.

Curiously, attempted formylation of the analogous dianiori (53) derived from deoxybenzoin oxime (52) in a similar manner resulted in recovery of deoxybenzoin in low yields.

12 The metalation of 3-phenylisoxazole has also been studied by Schtillkopf

He reported that treatment of the isoxazole (49) with two equivalents of

o lithium 2,2,6,6-tetramethylpiperidide at -78 C led to the formation of the dianion (54). This was captured by chlorotrimethylsilane to afford the 12 keten (55) in moderate yield (47%) . The preparation of the keten (28) was not described.

® © Li ©E-OLi® (54)

CISiMe 3

In an attempt to prepare the monoanion (56), 3-phenylisoxazole (49) was reacted with one equivalent of n-butyllithium at -78°C and a deep purple coloured solution was obtained. Attempted trapping of any carbon nucleophiles present with the Schiff's base (43) afforded a product which contained a

v 1 3-lactam moiety ( max 1760 cm ), which could not be obtained analytically pure. (49) JhBuLi _ H-E-06 Li®

THF/-78° (56) 85.

It was argued that the di-anion (54) would be more reactive than the phenylethynolate anion. If this were the case, reaction with unactivated

Schiff's bases may be possible. Trapping of the intermediate (57) with an

aldehyde or ketone could then lead to the intermediate keten (58) which on preferential 3-lactam formation would afford a 3-lactam (59) with a 3-(l'-

hydroxalkyl)-side-chain (Scheme 9). Treatment of the isoxazole (49) with

two equivalents of n-butyllithium afforded intensely brown coloured reaction

mixtures. However, the results of trapping experiments with both unactivated

and electron deficient imines were disappointing (Table 2). In the case of

benzophenone anil, the starting imine could be recovered in good yield after

after chromatography. Notably, attempted silylation afforded none of the

bis-silylketen (55) (ms), although the starting material was consumed (nmr).

The ^"H nmr spectrum of one of the fractions of the chromatographed mixture

from the reaction of the dianion (54) with benzophenone anil contained a

singlet at 5 4.10, plausibly due to the presence of the 3-lactam (61). The

infrared spectrum of the crude reaction mixture also contained an absorption

at 1

SCHEME 9 TABLE 2

ATTEMPTED TRAPPING OF THE DIANION (54)

ENTRY REACTION SEQUENCE OBSERVATIONS

1 (1) Ph2C=NPh; -78°C a

+ (2) H30 ; -78°C

2 (1) Ph_C=NPh; -78°C a

(2) (CH3)2CO; -78°C

+ (3) H30 ; -78°C 1

! 3 (1) tBuN=/ ; -78°C b | + 0 (2) H30 ; -78 C

4 (1) Schiff's base (43); -78°C b

+ (2) 1I30

5 (1) Schiff's base (43); -78°C b

(2) (CH3)2CO; -78°C

+ (3) H30

6 Me SiCl; -78°C b

a imine recovered

b intractable mixture 87.

A reference sample of this compound (61) was prepared from dichloroketcn

26,27 and benzophenone anil The initial adduct, 3,3-dichlo-l,4,4-tripheny 1- azetidin-2-one (60) was converted in low yields (20%) to 1,4,4-triphenyl- 28 azetidin-2-one (61) on treatment with tri-n-butylstannane in the presence of a radical initiator (AIBN) (Scheme 10).

ClPh Et"3'N CK •Ph •NPh <2

(60)

(n-Bu)3SnH AIBN

SCHEME 10

Comparison of the authentic 3-lactam (61) with the product from the ynolate reaction indicated that the compounds were different. Futher reactions of the ethynolate dianion (54) and Schiff's bases were not attempted.

In an attempt to prepare the electron rich,and hence more reactive, ynolate anion (65), the synthesis of 3-pheny1-4-methoxyisoxazole (64,b) was undertaken.

29 The preparation of isoxazole (64,b) is cited once in the literature

In our hands, the cycloaddition reaction of benzonitrile oxide with

vinylene carbonate*^ (62) gave 2-oxo-4-phenyl-3a,3b-dihydro[l,3] dioxolo[4 ,5-dJ

isoxazole (63) in 20% yield. Attempted decarboxylation of (63) to the isoxazole

(64a) under a range of conditions was unsuccessful (Scheme 11). Decarboxy- 88.

91 lation with 20% aqueoussulphuric acid led to the formation of phenacyl alcohol in low yield (8%) as the only identifiable product.

Interestingly, the preparation of 4-hydroxyisoxazole has only recently been reported^.

@ © •0 PhCEN-0 + -o (62)

0 (64) N © a R=H MeO-=' b R=Me 0 Pn OR Li (63) (65)

SCHEME 11

On failing to prepare the isoxazole (64a) the synthesis of 3-phenyl-4-(3,4-

dimethoxyphenyl)isoxazole (67) , the precursor to the 3,4-dimethoxyphenyl-

ethynolate anion (66), was undertaken. The key intermediate in the synthesis

of the precursor (67) was the aldehyde (68). Oxidation of 2-(3, 4-dimetho:xy-

phenyl)ethanol (69) with Collin's reagent afforded a low yield (27%) of

the required aldehyde (68). Other oxidising agents produced unidentifiable

mixtures of products or a mixture of 3,4-dimethoxybenzaldehyde (70) and

3,4-dimethoxyphenylacetaldehyde (68) (Table 3). Attempted reduction of the 36,37 nitrostyrene (71) with titanium (III) trichloride afforded the aldehyde (70) Ph 89,

MeO +(66 ) OMe OMe

(67) PhCN

MeO

MeO (68)

CHO

MeO MeO MeO

(70) (71)

The aldehyde (68) was found to be readily available from the homologue

(70) via a Darzens reaction . Condensation of the aldehyde (68) with

pyrrolidine in the presence of toluene-4-sulphonic acid in refluxing benzene

afforded E-l-(3,4-dimethoxyphenyl)-2-pyrrolidinoethene (72) in quantitative

yield. Cycloaddition of the enamine (72) with benzonitrile oxide in dichloro-

methane at 0 C afforded the isoxazoline (73) in high yield (81%). Subse-

quent treatment of the isoxazoline (73) with refluxing ethanolic hydrochloric 90.

TABLE 5

OXIDISING AGENT (ref) COMMENTS

Collin's reagent; 15 min; 20 C; (68) (27%)

6 equivalents (32)

Dimethyl sulphide - complex mixture

N-chlorosuccinimide (33)

PDC (34) (68):(70) = 5 : lia

Collins; -78°C to + 5°C; (68):(70) = 16 : 11& 6 equivalents

Collins, 12 h; 30 equivalents (68):(70) = 7 : 13a

a Cr03/pyridine/water (35) mixture of (68) and (69)

As determined by nmr spectroscopy

acid gave the desired product, 3-phenyl-4-(3,4-dimethoxyphenyl)isoxazole

(67) in 61% yield (Scheme 12).

Again, the cycloadduct (73) had a trans-stereochemistry, as judged

13 1 from the coupling constant J = 3 Hz, in the H nmr spectrum. 91.

(68) A

(72)

(67)

MeO

(73)

SCHEME 12

Treatment of 3-phenyl(3,4-dimethoxyphenyl)isoxazole (67) with one equiv-

o alent of n-butyllithium in tetrahydrofuran at -78 C in order to form the intermediate (74), resulted in the formation of an intense blue coloured reaction mixture. Attempts to trap the ynolate anion (66) with various

? 92.

Schiff's bases are listed in Table 4. Generally, the reaction mixtures proved to be intractable, but the presence of 3-lactamic products was in-

ferred from their infrared spectra (v c.a. 1760 cm 1). Attempts to 1 max — 12

react the intermediate (66) with benzaldehyde resulted in the formation of

an oil probably containing the 3-lactone (77) in low yield (10%). This again

could not be obtained analytically pure.

It should be noted that the electron rich ynolate anion (66) was still

not reactive enough to react with the electron rich Schiff's bases (e.g. inline

75), or even with the more activated substrate (imine 76, Table 4).

As it became evident that the ynolate anions, as described above, only

underwent reaction with activated Schiff's bases to furnish 3-lactams, their

synthetic usefulness as regards to the synthesis of the carbapenem systems was

limited, hence work in this area was not continued any further.

TABLE 4

ATTEMPTED TRAPPING OF THE INTERMEDIATE (66)

3 ENTRY COMMENTS R1 R2

1 -CgH4-4-N02 -C6H4-4-N02 3-lactam formation

a 2 -CgH4-4-N02 "C6H5 a 3 -C6H5 (75) no 3-lactam formation -C6H5

4 -C6H4-4-N02 -C6H4-4-N02 3-lactam formation

a 5 -CaH -4-C0„Et -C H -4-N0 6 4 2. 6 4 2

6 -CgH4-4-Me -CgH4-4-N02 (76) no 3-lactam formation 1 a as indicated by ir spectroscopy 93.

(b) Miscellaneous reactions of the phGnyletliynolatc anion (17) and the thiolatc anion (14).- There are several reports in the literature concer-

39 ning the preparation of 2-azetin-4-ones. Henry-Logan reported the preparation.

40 of the unsaturated 3-lactam (78) from the triazene (79). Re has also

•N o "Ph (78) postulated the formation of the 2-azetin-4-one (81) from the thione (8o) on reaction with triethylamine and methyl iodide. However, a recent publication

41 by Bachi would put some doubt on the validity of the original work.

Et^N Mel

(60) C02Me 81) C02Me 42 The kinetically stable azetine (82) has been prepared by a photolytic method from the triazene (83). Arbuzov 43 has claimed that azetines can be prepared by way of a cycloaddition reaction of isocyanates with acetylenic

67 esters. Recent work would dispute these findings. Similar claims by Claup and Jensen 44mus t be viewed with a degree of caution.

N-Ad hv

(83) (8 2) 94.

Carbanions arc known to react with imidoyl halides , hence it was considered that reaction of the phenylethynolate anion (17) with an imidoyl chloride (84) could lead to the formation of the keten (85) which could then

46 cyclise to the 3-lactam (86) (Scheme 13) .

CI e Ph—EE — 0 NR R' (84) Ph

o ?

-NR R (85)

Ph •R2

(9 (86)

SCHEME 13

Reaction of the phenylethynolate anion with several imidoyl chlorides

was investigated (Table 5). Generally, the reactions were carried out at

-78°C. However, in the case of the imidoyl chloride (89) reactions were also

investigated at -100 C. Even at these temperatures, intractable mixtures

resulted, presumably due to the instability of the products if formed, or

due to competing reaction pathways. 95.

TABLE 5

(84) ENTRY COMMENTS R1 R2

a 1 -Me -C6H5 (87) 3-lactam formed ?

3 2 -Me -C6H4-4-N02 (88) complex mixture*

II H k 3 -C6H4-4-N02 -C6H4-4-N02 (89)

as indicated by ir spectroscopy

it ii tic

There have been a number of papers in the recent literature relating

47 to the preparation of azetidin-2-thiones . It was argued that reaction of the thiolate (14) with an activated Schiff's base could give rise to an azetidin-2-thione (91) (Scheme 14) in an analogous manner to the preparation Ph 2 1 Ph-E-SeLi® R CH=NR =S

(14) 2 e R © -1i . - -NR Li H Ph R2 ©

-NR1 ©S- Li® (90)

SCHEME 14 96.

of the azetidin-2-ones |(30)-(36)]. However, generation of the thiolate (14) and subsequent reaction with the activated Schiff's bases (37) and (38) afforded an intractable mixture of products.

Recently Japanese workers have shown that the thiolate (14) reacts with carbonyl compounds, to afford upon acidification, the alkenes (93)

(Scheme 15). It is unclear whether the pathway to the observed products (93) proceeds via the intermediate (92a) or (92b).

R1 (14) Q V

R' \

(92a) Ph^/H

1 R AR2

(93)

SCHEME 15 97.

(c) Aminoalkylation reactions of ponicillanatc cnolato anions.- Since tlie isolation of thienamycin, several studies have appeared on the aldol reactions 49 of C-G penicillanate enolate anions . In view of the high degree of stereochemical control observed in the aminoalkylation of monocyclic 3-lactam 50 enolates with Schiff's bases , it was decided to investigate the analogous alkylation reactions with ponicillanate enolates. 51 52 Benzhydryl 6a-chloro- (96) and benzhydryl 6a-bromopenicillanate C99) were prepared from 63-aminopenicillanic acid (94) in yields of 46% and 21% respectively. In the case of the 6a-bromopenicillanate, a small amount

53 (ca 10%) of the 6,6-dibromopenicillanate (100) was also produced (Scheme 16).

The halogen-metal exchange reactions which were investigated are

summarised in Table 6. Metal-halogen exchange was not observed with 6a-chloro- penicillanic acid (95). In the case of benzhydryl 6a-chloropenicillanate (96),

transmetalation was again unsuccessful. Deuterium incorporation studies

indicated that the deuterio compound (101) was formed in the latter case.

This product may have arisen from the removal of the 63-proton instead of

transmetalation. However, halogen-metal exchange was observed in the case of

benzhydryl 63-bromopenicillanate when using t-butyllithium or n-butyllithdum

as metalating agents. Metalation of the penicillanate (99) with n-buty1lithium,

and subsequent quenching with acetic acid afforded a reasonable yield (61^)

CI NaNO 2—- "n"sx <9 CO H 2 (95) 98.

CI (95) Ph2C>N2 R=-CHPh2 o- Ki

(96) C02R

Br NaBr """-j—r^Sy' (94) H3 0 ® ^N^A

h (97) C02H (98) ^°2

Br Br Ph2C-N2 •S Br-•—t v / :CX + A-N^ <9 \ O CO R (99) C02R (100) 2 r

D o CO R 2 CO2R

(101) (102) 99.

49b of benzhydryl penicillanato (104)

Surprisingly , methylmagnesium bromide was found to be ineffective in

these metalation reactions. Again, the analogous deuterio-compound (102) was

observed in the deuterium incorporation studies of the bromopenicillanate (99),

when n-butyllithium was employed as the metalating agent. Quenching of the

enolate (103), formed in the reaction between the penicillanate (99) and

n-butyllithium, with d^-acetic acid indicated £a 80% d-incorporation. 1H nmr

spectroscopy indicated that the cis-isomer (105) was the major product, as 54 manifested by the relatively large vicinal coupling constant, J o, o = 4 Hz

N "!x o (105) C02CHPh2

Attempted hydroxyalkylation of the enolate (103) with benzophenone led

to a product whose spectral data was consistent with the structure (106).

However, an analytically pure sample of the product could not be obtained.

The trans-disposition of the C-5 and c-G protons in the product (106) was 39 predicted on the basis of the small vicinal coupling constant, J 5,6 of 1 Hz

In this example, steric approach control can be invoked in explaining the

product stereochemistry. Attempted aminoalkylation of the enolate (103) TABLE 2

SUBSTRATE; CONDITIONS | COMMENTS • I i a ,b i (95) (1) t-BuLi;(2 eq); 90 min, -78°C ! i i j (2) HOAc

1 (96) (I) t-BuLi; -100°C (1 eq); -100°C (96) recovered (50.2%) | ! (2) HOAc i *i

(99) (1) t-BuLi; (1 eq); -100°C (104) (approx. 50% )

(2) HOAc

(96) (1) t-BuLi; (1 eq), -100°C (101) (22%)

(2) D20

(99) (1) n-BuLi; (1 eq), -78°C (104) (61%)

(2) HOAc

(99) (1) n-BuLi, (1 eq); -78°C; THF (105) (42%)

(2) d^-Acetic acid (102) (10%)

|(99) (1) RleMgBr; (1 eq) ; -78°C; EtgO a ,b

(2) HOAc j i i

a no reaction

b 1 as judged by H nmr spectroscopy 101.

with the activated Schiff's base (38) afforded a complex mixture of products, however, the spectral data (ms, ir, nmr) indicated the presence of the desired product (107). Attempted aminoalkylation with less reactive Schiff's bases, for example (37) , led to the formation of benzhydryl penicillanate (104) on work up fnmr^

Because of the intractable nature of the products formed in such reactions, this area of investigation was not pursued any further.

(ii) C-4 Displacement Reactions

With the isolation of the carbapenem family of antibiotics, synthetic

strategies towards the 7-oxo-l-azabicyclo[3.2.o]hept-2-ene ring system (108)

have been developed in order to synthesise novel compounds for biological

evaluation. Two methods, intramolecular Wittig and carbene insertion reactions, have been used extensively in the preparation of such systems, both of which

are concerned with the formation of the N1-C2 bond. From the above discussion,

the preparation of intermediates of the form (109) and (110) would be required

if such methodology were to be used to effect formation of the bicyclic system

(108). 102.

R2 ^NH U J-NH 0 O (9 Rl (108) (109) (110) It became apparent, therefore, that a method of obtaining azetidin-2-ones containing a functionalised C-4 substituent was required. Such compounds have been prepared in several ways (vide supra). We sought an approach which, hopefully, would be more general in scope, starting from readily available precursors. It was considered that a displacement reaction at C-4 of a suitably functionalised azetidin-2-one by a carbon nucleophile could be utilised in the preparation of such intermediates.

Prior to our investigations in this area, we knew of two accounts in the

literature where a formal displacement reaction at C-4 had been observed using

a carbon nucleophile. Ernest observed that the diazo-compound (111), upon

treatment with copper (II) salts afforded the tricyclic 3-lactam (112) in good yields (Scheme 17).

SCHEME 17 103 .

97 Bachi found that treatment of the thione (113) with diazoethane

followed by triphenylphosphine afforded the azetidin-2-one (114) (Scheme 18)

R R CH3CHN2 r-Jn ^-N O O

C0zMe C02Me (113)

Me R-

C02Me C02Me

(114)

SCHEME 18

In contrast, the displacement reactions of 4-acetoxyazetidin-2-one (115)

with various hetero-centered nucleophiles has been studied in some detail,

.57 by Clau3 Subsequently, a miriad of papers concerning similar displacement

58 reactions have appeared

57 An interesting stereochemical point was raised by Clau3, who found that

displacement reactions of the cis- 3-lactam (116) with various nucleophiles io4:

Me OAc Mey ^QAc © X NH NH ^—NH (9 9

(115) (116) (117)

(X = PhO , PhS , EtS , MeO , N3 ) afforded mainly the trans- product (117).

It was also found that such displacement reactions occurred with racemisa- tion at C-4. These results are in agreement with the formation of a planar intermediate (118) which is captured by the nucleophile from the less hindered face of the molecule, affording the product (119) with trans-stereo-

59 chemistry. Similar findings have been observed by Lombardi

<9 R 0 S f/'-N u RV/-Nu N /^-NH <9 <9 (9 (118) (119) (120) 57 Initial experiments-were conducted on 4-pyvalyloxyazetidin-2-one (120), as it was considered that the steric bulk of the t-butyl moiety in (120) would weaken the C4-0 bond and hence make the C-4 position more reactive towards nucleophilic attack. In addition, unwanted functionalisation of the ester carbonyl (via 121) would be prevented.

(121) 105.

57 60 4-Pivalyloxyazetidin-2-one was readily prepared from vinyl pivaloato and chlorosulphonyl isocyanate61'(Scheme 19).

0 0AC p-y / H92%SO.

:i20)

CO2H

SCHEME 19

It was originally considered that a malonate displacement at.the C-4 position in the 3-lactam (120) would furnish the functionalised 3-lactam

(122) which on conversion to the di-acid (123) would undergo facile decarboxy-

63 lation to produce the synthetically useful intermediate (124).

CO2R

CO2R NH a (122) (123) (124)

Displacement reactions of the 3-lactam (120) with the enolate derived

from di-t-butyl malonate were unsuccessful under a variety of conditions.

For example, treatment of di-t-butyl malonate with potassium t-butoxide

in t-butanol and subsequent reaction with the 3-lactam (120) afforded a

mixture of products, containing di-t-butyl malonate, but none of the desired

product (125) was observed. Polar materials were also observed in these

reactions, but they were not characterised. Reaction of diethyl malonate

with the 3-lactam (120) in the presence of sodium ethoxide, afforded a

mixture of diethyl malonate and 4-ethoxyazetidin-2-one (126) as the only

identifiable products. 106. CO 2 Bu OEt f 2 Bu NH r^-NH O <9

(125) (126)

Similar reactions were performed on 4-acetoxyazetidin-2-one (115), which again was prepared by -way of a cycloaddition reaction of chloro-

sulphonyl isocyanate with vinyl acetate. On treatment of the 3-lactam

(115) with diethyl malonate and an aqueous THF and sodium hydroxide

solution at 0°C, 3-lactam cleavage was observed. It was considered

that 3-lactam cleavage may have resulted due to the acidity of the a-

hydrogen in the product (127) from the initial displacement reaction

(Scheme 20).

-9m

(127)

SCHEME 20

In order to test this hypothesis, diethyl methylmalonate was prepared

from diethyl malonate, and the sodium enolate generated by treatment with

sodium hydride in tetrahydrofuran. On addition of the B-lactam (115) to

the enolate (129), the desired displacement reaction was observed, furni— 107 .

C02Et 02Et

(115) + 02Et Na® CO 2Et NH

(129) (12 8)

shing the 3-lactam (128) in 66% yield. If the lithium enolate of diethyl methylmalonate was employed in this reaction, lower yields (35%) of the desired product were obtained. In order to make the transformation mor«

synthetically useful, the reactions of the enolate of dibenzhydryl methylmalonate with the 3-lactam (115) was also investigated. However, the displacement reaction to form the substituted 3-lactam (132) proceeded in poor yields (25%) and this was not pursued further.

64 Kametani has recently shown that 4-acetoxyazetidin-2-one undergoes

displacement reactions with the sodium or lithium enolate of diethyl

malonate to afford the functionalised 3-lactam (133) in variable yields

(0-20%). The major product isolated in such reactions was the amide (134). 108.

04 It was also observed by the same author that attempted displacement with the Grignard reagent (135) led to the formation of 4-ethoxyazetidin-2-one (126). This is not surprising, as such compounds (135) are

65 known to readily undergo 3-elimination reactions , the ethoxide thus generated reacts with the B-lactam (115) to afford the observed product

(126).

Interestingly, Shibuya has subsequently shown that reaction of the

3-ketoesters (136) with the 3-lactam (115) afforded the substituted 3-

lactams (137) in reasonable yields (40-50%).

In order to make our initial approach more versatile, the reactions

of the substituted acetate (138) were also investigated. The ester (138)

was readily prepared from methyl dichloroacetate and sodium benzylthiolate

Treatment of the ester (138) with sodium hydride generated the sodium

enolate (139b), which was reacted with the 3-lactam (115) in tetrahydrofuran

at -78°C. However, only starting materials were isolated from the reaction

mixture. Similar results were obtained when the lithium enolate (139a)

was employed in such reactions, none of the desired product (140) was

observed. It is possible that the enolate (139) was too stable to react

in the desired manner. 109

PhCHoS I \ 0 (PhCH2S)2CHC02Me 2.

(138) PhCH2%e "OMe (139) aM®= Li®

PhCH2S SCH2Ph bM® Na® OMe

—NH 0 O (140) 68

A similar approach has recently been reported by the Pfizer group

Reaction of the 3-lactam (115) with the anion (141) or (142) afforded the products (143) and (144) in excellent yields.

SPh CO^Bu

0 ~ Na® Na © PhS-^^P(OEf) •(C02E«2 2 II 0 (141) (142)

0 SPh II PhS P(0Ef)2

C0 %u o •NH 2

(143) (144) no.

The monoanion (145) derived from resorcinol may also be considered as a masked enolate anion which could undergo displacement reaction at

C-4 in the 3-lactam (115) (Scheme 21). However, generation of the anion

(145) and subsequent reaction with the 3-lactam (115) led to a complex mixture of products.

0©M®

(115) + •X HO (145) M = Na .K

(146) (147)

SCHEME 21

From the H nmr spectrum of the reaction mixture, it appeared that

the ether (147) had been produced, as judged by the appearance of a high

field multiplet at 6 5.60 ppm, compared to that of 6 5.90 ppm in the

starting material (115) . The infrared and mass spectra were also in

accord with this finding. Nucleophilic displacement reactions involving

mono-hydroxy phenols and the 3-lactam (115), affording phenyl ethers,

57 e.g. (148),have been described elsewhere 111.

04 oAr-ti H o (148) (149)

Reaction of the 3-lactam (115) with n-butyllithium (two equivalents) in tetrahydrofuran at -73°C, gave none of the desired product (149).

64 Kametani has recently claimed that the 3-lactam (149) could be prepared in low yields (12%) if one equivalent of the alkyllithium reagent were employed.

It soon became apparent that carbanions such as malonate anions, necessarily generated under highly basic conditions, were largely unsuitable in effecting the desired displacement reactions. It was therefore decided

70 to use masked carbanions in the form of silylenol ethers , which could be used in conjunction with Lewis acid catalysts to promote the displacement reactions.

Reaction of the silylether (150) with the 3-lactam (120) was investigated as a possible route to the substituted 3-lactam (151), which could then be converted to the carbapenem (152) by known methodology.

The silylether (150) was prepared by reacting the enolate (153)

o 71 with chlorotrimethylsilane at -78 C in tetrahydrofuran solutions 112.

0 © Li@ OeLi® OSiMe 3

OMe OMe

(153) (154) (155)

OMe •SPh Me3S 0 0

(156) (157)

Interestingly, this silylation reaction afforded a pure O-silylated product

(150), in contrast to the analogous reaction of the enolate (154) which

72 has been shown to give a mixture of C- and 0- silylated products (155) and (156). However, on standing at room temperature for a period of several days at room temperature, a gradual isomerisation to the ^-silylated compound (157) was observed. This isomerisation did not appear to be appreciably accelerated in solutions of deuteriochloroform in the presence of catalytic quantities of anhydrous zinc bromide. • 73

Fleming has shown that such Lewis acids are efficient catalysts in the reactions of alkyl halides with silylenol ethers. It was also considered that complexation of the zinc counter cation, forming the species

(158) or possibly the intermediate (159) may occur, thereby promoting the 74 displacement reaction. Danishefsky has reported that silylenol ethers react with substrates similar to the intermediate (159). 113.

However, reaction of the silyl ether (150) with the 3-lactam (120) in

the presence of anhydrous zinc bromide afforded the N-silylated 3-lactam

(160) and S-phenyl thioacetate. Such trans-silylation reactions were obser-

ved to be quite rapid, as determined by experiments performed in the probe

of the nmr spectrometer. An interesting phenomenom was noticed at this

point, namely the long range coupling between Nl-H and the C3-Ha protons

(J Nn, C3-Ha ^ 1H J ) which was absent in the N-silylated compounds such as 75 (160). This long range coupling has been noted elsewhere . In order to

NH A-Nv 0 NH 0® ^ © 0 V"M ZnBr ° , SiMeq 3 (158) (159) (160

OSiMe

0 •SPh

N 0 A NH O O' SiMe3 (161) (162) (163)

circumvent the problems arising from trans-silylation reactions, the N-

silyl 3-lactam (161) was prepared in good yield (65%), from the 3-lactam

(115). This was reacted with the silyl ether (150) in the presence of a

catalytic quantity of anhydrous zinc bromide. After reacting for 3 days 114.

at ambient temperature, S-phenyl thioacetate (43%), 4-phenylthioazetidin-

2-one (162) (13%) and traces of the desired product (151) were isolated.

The reaction of the silylenol ether (163) with (161), even after refluxing 77 in anhydrous benzene using anhydrous zinc acetate as catalyst, gave none of the desired product (165) .

In the hope of regenerating the enolate anion (164) under mild condi-

tions, the silylenol ether (163) was reacted with anhydrous potassium

fluoride in the presence of the 3-lactam (161) in dry tetrahydrofuran

solutions containing a catalytic quantity of 18-crown-6. Again, after

extended periods of time at ambient temperature, none of the desired

product (165) was formed.

(163) —

(164) (165)

A similar reaction, using the silylenol ether (150) merely resulted in

the isomerisation to the C-silylated compound (157). The presence of

trace amounts of 4-phenylthioazetidin-2-one (162) was also evident from 1 the H nmr spectrum of the reaction mixture.

In a final attempt to effect the displacement of the 4-acetoxy- group

from the 3-lactam (161) using silylenol ethers as the nucleophiles, the

relatively uncommon but now fashionable Lewis acid, trimethylsilyl

trifluoromethanesulphonate was used as a catalyst.

Upon addition of a catalytic quantity (0.1 equivalent) of trimethyl-

silyl trifluoromethanesulphonate (166) in dichloromethane to an equimolar

mixture of the 3-lactam (161) and the silylenol ether (167) in dichloro- 115.

o o methane at -78 C, and allowing the reaction mixture to warm up to 0 C, the "^H nmr spectrum of the crude reaction mixture indicated that a rapid transformation had taken place. After quenching the reaction mixture with buffered (pH 7.0) water, the crude product was found to be. a mixture of the 3-lactams (115), (168) and (169). OSiMeo

Me3Si0S02CF3

(166) ' (16 7)

^NR 0 O

(168) R= SiMe3 (169) R=H

Attempted isolation of the N-silyl compound (168) merely by removal of the solvent from the reaction mixture without quenching with water led to the decomposition of the product. Attempted N-deprotection using 1 M 80 aqueous hydrochloric acid solution was unsuccessful. However, treatment of the N-silyl compound (168) with an excess of aqueous potassium

fluoride solution (10% w/v) for five minutes at ambient temperature cleanly gave the deprotected 3-lactam (169). Unfortunately, column chromatography was unsuccessful in removing traces of the starting material (115).

Fractional recrystallisation of the crude product did however give an

analytical sample of -the 3-lactam (169) in fair yield (58%).

The removal of starting material from the products in these reactions by chromatography was generally found to be unsuccessful. Fortunately,

if a slight excess (0.1-0.3 molar equivalents) of the silylenol ether -were 116.

used, then work up was greatly facilitated, giving high yields of the desired products after flash chromatography. Remarkably, reaction of

81 E,^(l-ethoxy-l-trimethylsilyloxy)prop-l-ene (170) with the 3-lactam

(161) under such conditions gave a near quantitative yield (95%) of the

3-lactam (171). The 3-lactam (171) was produced as a mixture of diastereo-

82 isomers. The isomerically pure silylenol ether (172) reacted with the

N-silyl 3-lactam (161) in high yield, to afford a diastereomeric mixture of 3-lactams (173).

Epimerisation atC-a in the product (173) during work up was discounted,

as experiments carried out in the probe of the nmr spectrometer indicated

that a mixture of products was produced in the initial reaction. Chroma-

tographic separation of the two diastereoisomers was not possible, however,

fractional recrystallisation afforded mainly one diastereoisomer.

Reaction of the silylenol ether (150) with the 3-lactam (161), in a

similar fashion, afforded the ^-phenylthioester (151) (72%) in an unoptimised

reaction. 117.

Similarly, an I2,Z-mixture of the silylenol ether (174). afforded the

3-lactam (175) in 58% yield. This product was contaminated with a small amount of starting material (115), which could not be removed by chromatography. The reaction was not optimised. Reaction of the silylenol ethers (176) and (178) with the 3-lactam (161) afforded the products (177) and (179) respectively, both in high yields after chromatography (Table 7)

Me 0SiMe U 3

O^^Ph NH 0

(174) (175)

OSiMe 3

^-NH 0 O

(176) R= Me d77)R=Me (178)R=Cl (179]R=Cl 118.

TABLE 7

SILYLENOL ETHER PRODUCT (Yield)

167 169 (89%)

172 173 (71%)

170 171 (95%)

174 175 (58%)

150 151 (72%)

176 177 (75%)

178 179 (81%)

The reaction of the 3-lactam (161) with several other silylenol ethers was briefly investigated, using trimethylsilyl trifluoromethanesulphonate as the catalyst, such reactions were not optimised.

7 The silylenol ether (18of reacted v/ithtlie 3-lactam (161) to afford an inseparable mixture of the desired product (181) and starting material

(115). Similarly, the silylenol ether (183), consisting mainly as the

OSiMe 3 (180) (181)

83 Z-isomer, prepared by trapping the sodium enolate (182) with chlorotrimethylsilane at -78°C, reacted rather sluggishly (12 hours) at ambient

temperature to produce trace amounts of the desired product (184) (ms) .

The silylenol ethers (163) and (185) also underwent displacement

reactions with the B-lactam (161) , however, chromatographic separation of

starting material (115) from the products (165) and (186) was not possible 119.

NaO© o OMe OMe 0 Me3SiO (182) (18 3)

OMe

0 o •NH (184)

If an excess of the silylenol ethers (163) and (185) were employed, aldol

reactions, forming the products (187) and (188) was observed (ms) .

OSiMe O-

R ov •NH (165) R=H (185) (186) R- Me

(187) R= H (188) R=Me 120.

84 84 The masked ketones, the trimethylsilylethers (189) and. (190) were also used as potential ^-alkylating agents. However, reaction of the silyl ether (189) with the 3-lactam (161) in the presence of trimethylsi lyl trifluoromethanesulphonate afforded a poor yield (6%) of the phenyl ether (148) after chromatography.

In contrast, reaction of the silylether (190) afforded no identifiable products other than the starting materials. Further investigation into these systems was not undertaken.

In a recent paper, Kametani reported that the enolate (191) underwent a displacement reaction with the 4-acetoxyazetidin-2-one (192) to

afford the 3-lactam (193) in low yield (11%).

H N2 o t-r^Y Vo o NH u 121.

The preparation of the silylenol ether (195), was investigated in the hope that it would undergo a facile displacement reaction with the 3-lactam (161) to furnish the diazo-3-ketoester (196), which would be a useful precursor to the carbapenam system (Scheme 21).

Q 0 Me^SiO

OMe OMeJlMi ? N2 (194) (195)

SiMe C02Me

(196)

SCHEME 21

In the event, attempted formation of the enolate C197) by reacting 86

the diazo-ester (194) with lithium di-iso-propylamide in tetrahydro-

furan at -78°C afforded a deep purple coloured reaction mixture. Attempted

trapping of the supposed intermediate (197) with chlorotrimethylsilane

afforded a complex mixture of products. Deuterium incorporation studies

were also unsuccessful. Conceivably, degradation to the carbanion (198)

had occurred during the course of the reaction. Further investigation

into this area is required. 122.

Li o© 0 © OMe Li © OMe N- N2

(197) (198)

Mechanism.- In order to explain the stereochemical outcome of the reactions of 4-substituted azetidin-2-ones with hetero-centered nucleophiles, the azetinone (118) and azetinium cations (199) have been postulated

87 88 as possible intermediates The recent claim by Wolfe of the isolation

-INK® O F? (199) of such an intermediate must be regarded with caution. An interesting

89 electronic effect has been noted by Sheehan , which is in favour of the formation of such intermediates. It was observed that treatment of the

B-lactam (200) with chlorine afforded the 4-chloroazetidin-2-one (201),

Rv •ci

V^—NH -NH CH0 o- 0 (200) (201)

R R X S\ V •sci f /jr—N ^—N (9 \ CH0 o

(202) (2 03) 123.

115 whereas the N-acylated compound (202) furnished the sulphenylchloride

(203). These observations have been rationalised in terms of the inability of the nitrogen lone pair to aid in the displacement reaction at C-4 in the case of the N-acylated compound (202). However, rigorous proof of the existance of intermediates such as (118) and (199) during the course of these reactions has not been established. A similar situation arises in the case of the displacement reactions at C-4 by carbon nucleophiles. From the few examples of such reactions known in the literature, it would appear, from a stereochemical viewpoint, that a planar intermediate is involved.

For example, the Shionogi group observed that reaction of the allylcopper reagent (205) with the 3-lactam (204), having either a 4a- or

43-chloro-substituent gave the same 43 and 4a ratio (33:67) in the product

(206).

(206) <

The Sankyo group have also published similar findings. For example,

the acetylene (208) was formed as a mixture of cis- and trans-isomers

(cis- : trans- ^ 1:2) from the sulphone (207) (Scheme 22). 124.

e Ph -E-MgBr

O (207)

^-NH O

(2 08) SCHEME 22

It was also stated by these workers that the presence of a 3-alkyl substituent in the starting material led to exclusive formation of trans— substituted products in similar reactions. 85

As noted earlier, Kametani has observed the exclusive formation of trans-substituted products in the synthesis of PS-5 derivatives, using the same methodology as described above. The intermediacy of the azetinone (118) was again invoked in order to explain the product stereochemistry.

The Sankyo group have also shown that the sulphone (209) reacts with a range of Grignard and cuprate reagents to afford the 4-substituted azetidin-2-ones (210). Of note, was the observation that 4-acetoxyazetidin-

2-one (115) gave high yields of the desired products when reacted with cuprate reagents, but the results of the reactions with Grignard reagents were less promising.

In the Lewis acid catalysed displacement reactions, we have shown that

the choice of Lewis acid appears to be of paramount importance. In the case of trimethylsily1 trifluoromethanesulphonate(166), the formation of

the intermediate (211) is postulated, which then undergoes reaction with 125.

S02Ph R

/f-NH /)—NH OSiMe O O (209) (210) (211) SiMe © CF3SO§

the appropriate silylenol ether.

The formation of a similar intermediate (212) has been postulated in

the cleavage t-butyl esters by trimethylsilyl trifluoromethanesulphonate

92 in the presence of triethylamine (Scheme 23). The driving force for

Q—SiMe3 0 © (166) CF3SO3 R^O

(212)

Et3N RC02SiMe3

SCHEME 23

the formation of these intermediates is presumably associated with the

stability of the trifluoromethanesulphonate anion.

Interestingly, we observed that treatment of the g-lactam (161) with

93 a powerful Lewis acid such as titanium (IV) chloride in the presence of o the silylenol ether (172) at -78 C afforded none of the desired product

(173); allowing the reaction mixture to warm to 0 C merely resulted in 126 the degradation of the 3-lactam. However, the use of aluminium enolates

has recently been employed in displacement reactions of 4-acetoxy- 126.

azetidin-2-one (115) (Scheme 24), affording the 3-lactam (169) in moderate yield (35%).

0AlEt2 Ph (115) + Ph oJ-N H 0 (169)

SCHEME 24

It should also be noted that when the blank reaction of the 3-lactam

(161) with trimethylsilyl trifluororaethanesulphonate was investigated, in the probe of the nmr spectrometer at ambient temperature, the presence

1 2 of the azetinium cation [(199), R = SiMe3, R = H J was not observed. In the absence of any other nucleophiles, extensive polymerisation of the starting materials had occurred after fifteen minutes.

A recent paper has described the use of trimethylsilyl trifluoromethanesulphonate as a catalyst in similar displacement reactions carried

95 out on other substrates

The preparation of azetinones, the supposed intermediates in these

96 reactions, has received scant attention in the literature. Sheehan has reported the preparation of the azetine (213) (Scheme 25).

SCHEME 25 127 .

97 Attempts to trap the azetine (214) prepared in a similar way, were unsuccessful. Various routes to the intermediate (215 ) have been invest-

97 98 igated without success. The preparation of the intermediate (216)

Ph Ck

^-N {7 N <9 (9 (9 (214) (215) (216) 99 has recently been claimed. Japanese workers have also reported the

13 97 preparation of the azetine (217) . The C nmr spectrum of the intermediate

R 2 -SMe R1 -HN N (9 (217) (218>) (219)

(217) exhibited resonances at 6 160.4, 159.1 and 156.0 ppm, indicative of 2 the presence of three different sp carbon atoms in the molecule. A syn-

100 thesis of the azetines (218) has recently appeared . It is noteworthy

that these workers claimed that the azomethine carbon atom in (218) appear-

ed at 6 213 ppm in the C nmr spectrum. The preparation of the parent

compound (219) has also been reported1^1. This compound was found to be

highly unstable and underwent a ring-opening reaction to the imine (220)

when subjected to flash vacuum pyrolysis. Interestingly, the azomethine 13 carbon atom in (219) appeared at <5 187.0 in the C nmr spectrum.

N-

(22 0) 128.

Mechanistic studies on the C-4 displacement reactions are required, in order to elucidate the nature of the intermediates present. The reaction of azetines (217) and (218) with carbon nucleophiles may prove interesting.

The trimethylsilyl trifluoromethanesulphonate mediated displacement reactions could be extended to systems of greater relevance with regards to the total synthesis of carbapenem antibiotics.

(iii) Preparation of q-Methylene-3-lactams

It has recently been reported that cc-methylene-3-lactams undergo 1,4-

102 addition reactions with a number of nucleophiles (Scheme 26, Nu = RSH,

SCHEME 26

C6-(1'-hydroxyalkyl) side-chains, commonly found in the carbapenem antibiotics .

103

Adlington and Barrett have shown that the stabilised vinyl carbanion (223) can be trapped by aldehydes, forming the hydroxy-amides (224)

in high yields. Furthermore, in situ conversion of the hydroxy-amides

(224) to the anions(225) led to the formation of the a-methylene-3-

lactams104'105 (226) (Scheme 27).

It was decided, therefore, to optimise the cyclisation step and to

extend the applicability of this synthetic scheme to include intermediates which could be further transformed into bicyclic systems which are of

current interest. This would necessarily involve the development of a 129.

© Li © ,NHS02Ar NS'OoAr tf ® N n- BuLi NH Ne Ll -78°, DME © © 0 Li 0

(221) (222)

© Li® Li HOv/R © © -78; i) RCHO N NH to ii)H30® 0 RT 0 (223) (224)

i)n-BuLi •em N© Li® ii) TsCl. -78' 0

(225)

-78 to RT

(226)

Ar- =

SCHEME 27 130 .

nitrogen protecting group, which would withstand the strongly basic con-

ditions involved in the formation of the trianion (227a) but could be

easily removed when required, without disruption of the 3-lactam moiety.

The need for such an investigation stems from the failure to prepare the

104 parent trianion (227b)

a R e Hna T:u p

b R=H

0 Li©

(227)

The initial cyclisatioii ^Cu^i-iuup Wv«iv vwuuuCbcu Lhc n-oycxohexjl

system, derived from the hydrazone (221). The precursor, (221) was prepared

from cyclohexyl isonitrile (228), which on reaction with acetyl chloride

afforded the imidoyl chloride (229). Subsequent hydrolysis furnished the

1 106 a-ketoamidfSt ' ••!« e (230) which was then converted into the hydrazone (221)

NC + VCl—VN=( 0 ^ ^o (228) 0 (229)

^-NH Af^ 1221) (230) °

S02NHNH2

Scheme 28 (231) 131 .

In such a schcmo, the a-ketoamide (230) could be prepared from the

isonitrilo (228) in 2970 yield. An alternative procedure involving the

107 reaction of pyruvyl chloride (232) with cyclohexylamine and triethylamine in etheral solutions at -78°C, afforded the desired amide (230) in higher yields (^ 50%). This methodology was adopted in the preparation 0

(232) of the more sensitive substrates (235) to (244).

r-NHS02Ar 0 N NHR NHR

0 0

R = -cycl. C6Hn (230) R = -cycl. C6Hix (221)

R = -t-C4Hg (235) R = (236)

R = (237) R = (238) -C3H5 "C3H5

R = -CPh3 (239) R = -CPh3 (240)

t t R = -SiMe2 Bu (241) R = -SiMe2 Bu (242)

R = -C6H2-2,4,6-(0Me)3 (243) R = -CgH2-2,4,6> (0Me)3 (244)

108

Ganem has recently described the use of the allyl-moiety as a nitrogen protecting group. Accordingly, the N-allylpyruvamide (237) was prepared from pyruvyl chloride,as described above, in moderate yield (50%) and then converted to the hydrazone (238). The triphenylmethyl-moiety 109 has been used as a nitrogen protecting group in 3-lactam chemistry

Hence, the preparation of triphenylmethylamine (233) was undertaken. The reaction of ammonia with chlorotriphenylmethane in etheral solutions gave a mixture of the starting material and the desired product. However, ammoniolysis of bromotriphenylmethane under similar conditions afforded 132.

Ph3CNH2 (233) a near quantitative yield (94%) of triphenylmethylamine (233). The pyruvamide (239) was prepared in good yield (76%) using pyruvyl chloride.

The use of N-silyl groups in 3-lactam chemistry has recently been described11^. There are also reports111 in the literature with regards

to the stability of N-silyl groups to the strongly basic conditions employed during the course of the Shapiro reaction. It was considered that the

N-trimethylsilyl-moiety would be too labile under these reaction conditions

Consequently, work was initiated on the use of the t-butyldimethylsilyl- 112

group in such reaction. Reaction of t-butyldimethylsilylamine with py-

ruvyl chloride in the usual way afforded the desired product (241) in only

35% yield, after flash chromatography. However, by modifying the work up

conditions, good yields of the pyruvamide were obtained (65%). The pre-

paration of the hydrazone (242) was achieved in low yield (30%) on reac-

ting the pyruvamide (241) with the hydrazide (231) in anhydrous dichloro-

methane overnight. The low yield in this reaction is due, in part, to the

instability of the product (242) on chromatography.

113

There are a number of reports in the literature describing the

2,4-dimethoxybenzyl—moiety as a nitrogen protecting group. Experience in

those laboratories however, indicated that deprotection of a-methylene-$- 105

lactams containing such a group led to the disruption of the 3-lactam. It

was decided, therefore, to investigate the use of the 2,4,6-trimethoxy-

benzyl- group in such systems in the hope that a more facile deprotection

could be achieved. The reaction of 1,3,5-trimethoxybenzene with cyanogen

, 114 .

bromide in the presence of aluminium chloride afforded an intractable

mixture of products. The use of milder Lewis acids resulted in no reac-

tion taking place. Attempted preparation of 2,4,6-trimethoxybenzoyl chlo-

ride (234) from 2,4,6-trimethoxybenzoic acid and thionyl chloride gave 133.

115 low yields of the desired product. V/halley has also shown that the preparation of 2,4,6-trimethoxybenzoyl chloride in such a manner was unsatisfactory. However, the amide (245) was prepared in high yield from 1,3,5- 116 trimethoxybenzene and chlorosulphonyl isocyanate' The initial adduct COCl MeO-y^yOMe

T (234) OMe

(246) was dissolved in refluxing aqeuous potassium hydroxide (1 equivalent),

furnishing the amide (245) in 84% overall yield (Scheme 29).

OMe OMe CSI -4M

MeO OMe MeO^J^OMe

o ^NHS02a (246)

(245) (247)

SCHEME 29

Reduction of the amide (245) with lithium aluminium hydride afforded

the amine (247) in moderate yield (36%). The amine (247) was converted to 134.

the pyruvamicie (243) and hence to the hydrazone (244) in the usual manner,

The trianion (222) was generated in 1,2-dimethoxyethane at -78°C on

104 reacting the hydrazone (221) with 3.3 equivalents of n-butyllithium

The orange-red solution of (222)was then allowed to warm up to room temperature over a period of oa 40 minutes, and on doing so, the reaction mixture became yellow in colour, indicating the formation of the vinyl carbanion (223). On re-cooling to -78°C, addition of the appropriate aldehyde and subsequent work up, afforded the hydroxy-amides (248), (249) and (250) in high yields.

Treatment of the hydroxy-amide (248) with 2.2 equivalents of n-butyllithium at -78°C, produced the dianion (251), which was reacted with toluene-

4-sulphonyl chloride (1 equivalent) at -78°C and then allowed to warm to

R= CH3 (248) R= C3H7(249)

R= C7H15(250)

(2 51)

R=-CH3 (252) R= (9 -C3H7 (25 3) R -C7H15(2 54) 135.

room temperature. Such a reaction sequence produced the 3-lactam (252) in good yield (64%). On repeating the same sequence with the hydroxy-amides

(249) and (250), lower yields (43%) and (30%) of the desired 3-lactams

(253) and (254) were obtained. Further investigation into the cyclisaticn of the hydroxy-amide (240) using toluene-4-sulphonyl chloride as above, revealed that the 3-lactam (253) was again formed in moderate yield (42%), along with the chloroamide (256) in 32% yield. Evidently, the sulphonate (255) underwent a competing intermolecular displacement reaction with the chloride anion giving rise to the observed product (256). It was not ascertained

whether the chloro-compound (256) was itself converted to the 3-lactam (253).

In order to circumvent the problems relating to the reactions of the counter

anion in these cyclisation reactions, toluene-4-sulphonic acid anhydride was employed as the cyclising agent. Hence, reaction of the dianions

(257) and (258) with toluene-4-sulphonic acid anhydride at -78°C in tetia-

hydrofuran, and then allowing to warm to room temperature afford-

ed the 3-lactams (253) and (254) in improved yields of 55% and 57%

respectively.

@ e 136.

Generation of the vinyl carbanion (259) from the hydrazone (236) was accomplished as described for the hydrazone (221). Reaction of the

dianion (259)with n-propanal afforded the hydroxy-amide (260) in only moderate yield (45%). Cyclisation of the hydroxy-amide (260) was not investigated.

Generation of the N-allyl dianion (261) and subsequent quenching with n-butanal afforded a more complex reaction mixture, containing the hydroxy-amide (262). However, repeated chromatography was unsuccessful in obtaining the product in an analytically pure state. The generation

of the N-trityl dianion (263) was less successful. Treatment of the hydra-

zone (240) with 3.3 equivalents of n-butyllithium in the usual manner

@ 0 137.

afforded a deep red coloured reaction mixture. Addition of deuterium

oxide to the reaction mixture at -78°C did not discharge this colour. Column

chromatography of the reaction mixture afforded recovered starting material

(240) (36%) with no deuterium incorporation, and a second compound, of si-

milar polarity, believed to be the hydroxylated amide (264) (6%). On

repeating the deuterium incorporation experiments, using 5.5 equivalents

of n-butyllithium, starting material (40%) was again recovered as well as

104

the hydroxy-amide (264) (14%). Similar observations have been reported

elsewhere with regards to the hydroxylation of substrates during the course

of Shapiro reactions. The bi-product (264) exhibited a fragment at m/e 329

in the probe ofthe mass spectrometer, resulting from the loss of the frag-

ment (265) from the parent ion. This is a common fragmentation in these

compounds. The infrared spectrum verified that the compound was an hydroxy-

. N=NSO2

(2 65)

amide (^max 3590, 1665 cm S , and the nmr spectrum contained a singlet

at 6 4.55 ppm, consistent with the presence of an hydroxylated methyl group

The occurrence of the hydroxy-amide (264) has not been fully explained.

The formation of the azaene (266) from a redox process involving the trianion

104 (267) has been postulated as a possible intermediate in these reactions

Li ©

QjsK Me NS02Ar Af i

Li® 0 (266) u (26 7) 138 .

The reactions of the N-t-butyldimethylsilylhydrazone (242) appear to be more promising. Treatment of the hydrazone (242) with 3.3 equivalents of n-butyllithium in the usual manner afforded a lime-green coloured reaction mixture. After allowing to warm up to room temperature, recooling to

-78°C and quenching with n-butanal, a volatile oil, believed to be the hydroxy- amide (269) was isolated.

The mass spectrum of the product was in agreement with the structure

(269). However, due to the volatility of the product, full characterisa-

tion was not achieved. It was decided therefore to react the dianion (268)

with n-octanal, in an attempt to prepare a less volatile product. Column

chromatography of the crude product from this reaction, however, afforded

an impure compound, believed to be the deprotected hydroxy-amide (270). It

would appear that the t-butyldimethylsilyl-group is too labile to survive the

work up conditions employed. The use of more hindered silicon protecting

groups is now under investigation. 139 .

The fact that the hydroxy-amide (270) was produced indicates that

the Shapiro reaction had taken place prior to doprotection. This must be

the case, as it has been shown that primary amides of the type (271) do

104 not undergo the Shapiro reaction in the usual way

Attempts to prepare a-ketoamides by alternative routes were also

briefly examined. Reaction of diethyl oxalate with cyclohexylamine afforded

ethyl N-cyclohexyloxamate (272) and the amide (273). It was hoped that

reaction of the oxamate (272), at low temperatures, with n-butyllithium would

lead to the formation of a stable tetrahedral intermediate (274), which,

when quenched, would afford the keto-amide (275) ' ' .

NHCO 2 (273) (272)

n-Bu

(274) (275)

Similar chelated intermediates (276) and (277), have been proposed

117 in the formation of ketones from S-2-pyridyl thioates and aldehydes

118

from N-formyl pyridines (Scheme 30). In the event, it was observed

that reaction of the amide (272) with two equivalents of n-butyllithiun

at -78°C in tetrahydrofuran afforded, after a low temperature quench, the

desired product (275) in poor yield (21%). The starting material (272) was lie.

0 N^ RMgX R^S

0 R O^N R hS R

R (276)

RMgX Me •Me N^N T N •H CHO (277) R

RCHO

SCHEME 30

also present in the crude reaction mixture. This reaction was not optimised, but on doing so this may provide a general route to the preparation of a-ketoamides. The low yield of product in this case may be a result of the insolubility of the chelated intermediate (274) in the solvent system employed. 141 .

(iv) Preparation of 3-Unsubstituted Azotidin-2-ones

120

In a recent paper by Frater , the stereospecific alkylation of 8- hydroxyestcrs was discussed. Treatment of the 3-hyciroxyester (278) with two equivalents of lithium di-iso-propylamide afforded the dianion (279) which reacted with a number of alkyl halides to give the ester (280) with almost exclusive threo-stereochemistry.

LDA

(2 78) (279)

(280) It would be of interest to investigate the analogous reactions of

8-hydroxyamides, with a view to the stereospecific synthesis of substituted

azetidin-2-ones (Scheme 31).

The cyclisation of 8-hydroxy-amides to 3-lactams had already been

accomplished (vide supra). The alkylation and hydroxyalkylation of primary 121 and secondary amide dianions was pioneered by Hauser , and subsequently 122 extended to B-hydroxy-tertiary amides

Reaction of acetanilide or j^-benzylacetamide with two equivalents

of n-butyllithium at 0°C produced intensely coloured reaction mixtures, 121 containing the stable dianions (281) and (282) respectively. Quenching 142.

0 n-BuLi

E® ?

t'"r2 A/ O

SCHEME 31

of the dianion (281) with acetaldehyde at -78°C afforded the hydroxy-amide

(283) in 18% yield after recrystallisation. Similarly, reaction of the dianion (282) with acetaldeliyde or benzaldehyde

123 afforded the 3-hydroxy-amide (284) and (285) in 51% and 83% yield respectively. The readily available intermediates (284) and (285) were used in model studies concerned with the development of a synthetic route to monocyclic 3-lactams such as (286) and (287).

The cyclisation of the primary and secondary 3-halo-amides (288) to

124 the monocyclic 3-lactams (289) is well documented in the literature . A variety of reaction conditions have been employed to effect this transform- 143.

0 Li® Li® © 0 Li® 0 LP^N- © NPh © © Ph NHPh

(281) (282) •OH (283)

0 O Ph Ph (286) (287) ation, however, the formation of acrylamides (290) by a competing elimi- 125 nation pathway, has until recently limited the generality of this route.

It was decided to use the same methodology in the cyclisation of the hydroxy- amides (284) and (285) as previously applied to the preparation of a-methylene-B-lactams. Hence, it was argued that trapping of the dianions (291) and (292) with toluene-4-sulphony1 chloride would lead to the jin situ formation of the tosylates (293) and (294), which would cyclise to the

3-lactams (286) and (287) respectively. In the preparation of a-methylene-

3-lactams by this route, competing elimination reactions were not possible.

However, in the cyclisation of the hydroxy-amides(284) and (285), such processes greatly limited the synthetic utility of the scheme. In situ generation of the dianion (291) from dianion (282) and reaction with toluene-

4-sulphonyl chloride afforded the sulphonamide (295) (4%) and the acrylamide 144 .

X =Cl, Br (2 88)

O (289)

0 N © Ph Li® R OTs Li©

R-Me (291) R=Me (293)

R=Ph (292) R = Ph(294)

(296) (10%) as the only identifiable products. Presumably, the formation of the sulphonamide (295) occurred via N-tosylation of the dianion (291) giving the tosamide (297). This, on work up, initially afforded the alcohol (298) which hydrolysed to the acid (299) and the observed product

(295). Generation of the dianion (291) from the hydroxy-amide (284), 1'15.

^ NH V Ph PhCH2NHTs

(295) (2 96)

0 0 N- •Ts

0 Ph 0 Ph e H Li® (297) (298)

(299)

followed by reaction with toluene-4-sulphonyl chloride afforded the tosylate

(300) and the acrylamide (296) in low yields. 1410.

In order to study the effect of the counter cation on the cyclisation reactions, the dianion (301) was prepared by reacting the hydroxy-amide

(284) with sodium hydride in a ff ,I£-dimethylformamide and dichloromethane solvent mixture. The formation of the dianion (301) was slow at room temperature, even in the presence of a phase transfer catalyst. On quenching with toluene-4-sulphonyl chloride, however, a mixture of the acrylamide (296)

(11%) and the oxazine (302) (12%) was isolated. Presumably, the formation of the oxazine (302) arose by way of the reaction of the dianion (301) with the dichloromethane present in the solvent mixture.

In a further experiment, treatment of the tosylate (300), prepared

in situ from the monoanion (303), with sodium hydride afforded the anion

(304), which on work up produced a mixture of the acrylamide (305) (9%)

and the tosylate (300) (27%). Traces of the chloro-amide (306) were also

present (ms).

0 0

N- Ph J Na 0 M© (301) Na (30 2)

In view of the difficulties encountered with the direct cyclisation of

the dianions (291) and (301), it was decided to isolate the intermediate

tosylate (300) and then attempt the cyclisation reaction to the 3-lactam

(286). Treatment of the hydroxy-amide (284) with one equivalent of n-butyl-

lithium at -78°C in tetrahydrofuran followed by quenching with toluene-

4-sulphonyl chloride furnished the tosylate (300) in good yields (78%)

after chromatography. However, treatment of the tosylate (300) with so-

dium hydride in N^N-dimethylformamide cleanly gave the acrylamide (296).

In contrast, on changing the solvent system to dimethyl sulphoxide, and

126 using sodium hydride-dimethylsulphoxide as the base, the tosylate 147 .

(300) was converted into an inseparable mixture of the acrydamide (296)

and the B-lactam (286). Further optimisation of this reaction was not

attempted. << w

Similarly, the one-pot generation of the dianion (292), followed

by treatment with toluene-4-sulphony1 chloride afforded the tosamide (295)

(22%) and the acrylamide (307) (30%). Traces of the B-lactam (287) (Scheme

32) were also observed. 0 N-Ts

TsCl (282) -78'

(292)

0 Ph PhCH NHTs + NH^Ph + 2 N- o

(295) (307) (287) PH

SCHEME 32 148.

Alternatively, generation of the dianion (292) from the hydroxy-amide

(285) followed by reaction with toluene-4-sulphonyl chloride afforded a

mixture of the tosamide (295) and the acrylamide (307).

In an attempt to isolate the tosylate (309), the monoanion (308) was

reacted with toluene-4-sulphonyl chloride at -78°C and then allowed to

warm up to room temperature. The nmr spectrum of the crude reaction

0 0 0

NH Ph NH^Ph

Ph- 0©Li© . Ph^^XU

(308) (309) (310)

mixture indicated the .presence of the tosylate (309), the chloro-compound

(310) and the acrylamide (307). Column chromatography of this reaction

mixture afforded a virtually inseparable mixture of the acrylamide (307)

and the chloroamide (310).

In an attempt to elucidate the factors affecting the formation of the

acrylamide (307), the preparation of the mesylate (311) was undertaken.

Reaction of the monoanion (308) with methanesulphonyl chloride afforded

a mixture of the chloro-compound (310) and the mesylate (311).

H ^Ph

(311) In order to irradicate the formation of the chloro-compound (310),

the monoanion (308) was reacted with methanesulphonic acid anhydride. The 1 II nmr spectrum of the crude product indicated the presence of the mesylate 149.

(311) (multiplet 5 5.95 ppm) and starting material. Little or none of the

acrylamide (307) had been produced.

124

As B-chloroamides have been cyclised to 3-lactams, attempts were

made to prepare the 3-lactam (287) from the chloroamide (310). However,

treatment of the chloroamide (310) with sodium hydride in tetrahydrofuran

resulted in the formation of the acrylamide (307). In order to prepare

more of the chloroamide (310) for such experiments, the reaction of the

dianion (282) with benzal chloride (312) was investigated (Scheme 33).

0 ? Ph + PhCHCl © W ^ 2 Li® (282 (312) I (310) Ph SCHEME 33

Unfortunately, only the presence of starting materials was observed

in the "'"H nmr spectrum of the crude reaction mixture. The addition of

1 N.jN.jN. »N.'-tetramethylethylenediamine to the dianion (282) did not promote 127 formation of the desired product (310) . It is possible that proton

transfer to the dianion (282) from benzal chloride had occurred. The 128 formation of the anion (313) has been reported elsewhere

0 Li © PhCCl® Li® ©U -Ph P (313) (314) 150.

As the mesylate (311) appeared to be more stable than .the tosylate

(309) towards the formation of the acrylamide (307), it was decided to generate the anion (314) in the hope that cyclisation rather than elimination would take place. Hence, in situ formation of the mesylate (311) at

o o -78 C, followed by treatment with n-butyllithium at -78 C and allowing the

o reaction mixture to warm up to -25 C over a period of 15 minutes and subsequently to 0°C, afforded the 3-lactam (287) in moderate yield (31%). Curiously, reaction of the mesylate (311) with sodium hydride produced the acrylamide (307).

Evidently, several factors including solvent, leaving group, counter cation and electronic effects within the substrate, are important factors in determining the reaction pathway in such cases.

Interestingly, in an attempt to generate the dianion (315), deuterium incorporation studies afforded the deuterio-amide (316) (25%) and a mixture

n 151.

of compounds inseparable by chromatography, probably containing the hydro-

+ xy-amide (317) (M*, m/e 241) and a second product, plausibly the dimer + (318) (M*, m/e 449). Repeated fractional recrystallisation afforded a sample whose combustion analysis was in accord with the structure (317), although further spectral proof for this structure could not be obtained.

As the initial aim of this work was to investigate the stereo- selectivity of the addition of electrophiles to carbanions such as (319), the generation of the trianion (319) was attempted. Treatment of the

o hydroxy-amide (284) with excess n-butyllithium at 0 C in tetrahydrofuraii led to the formation of an intensely red coloured solution. However, on quenching with deuterium oxide, starting material was recovered in low yield (30%). No deuterium incorporation was observed.

In contrast, it has been observed that the dianion (321) can be generated, and reactions of this intermediate with electrophiles such as

129 benzaldehyde have been noted

© 152.

The stereochemical outcome of such processes warrants further investigation.

130 131

In the light of recent work by Miller and Bose , who have independently reported the cyclisation of 3-hydroxy-amides to 3-lactams in good yields using an alternative methodology, the facile synthesis of monocyclic precursors is now possible. EXPERIMENTAL

SECTION 1: YNOLATE CHEMISTRY

SECTION 2: C-4 DISPLACEMENT

SECTION 3: SHAPIRO REACTIONS

^FFTTDM a- OTHER N1-C4 OLL. iuii -t. CYCLISATION REACTIONS 154 .

EXPERIMENTAL

Melting points were determined using a Kofler hot stage apparatus and are uncorrected. Ultraviolet spectra were recorded on a Unicam SP 800 B ultraviolet spectrophotometer. Infrared spectra were recorded on a Perkin

Elmer 298 or 257 grating infrared spectrophotometer. Nmr spectra were recorded on a Varian T60 or a Perkin Elmer R32 spectrometer, using• tetrametliy 1- silane as an internal reference. Analytical thin layer chromatography (tic)

was performed on Merck precoated GF254 silica or F254 (Type E) alumina plates.

Preparative layer chromatography (pic) was performed on GF254 H plates.

Medium pressure chromatography was carried out on Merck Kieselgel H (type 60) or Kieselgel 60 silica.

Solvents were purified as follows: benzene and toluene were redistilled and sodium dried; dichloromethane, ethyl acetate and light petroleum (b.p.

40-60°C) were redistilled; dichloromethane was dried over and redistilled from phosphorus pentoxide; diethyl ether (ether) was redistilled and dried if necessary over sodium wire. Tetrahydrofuran (THF) and N,N_,IT,N/-tetrame-

thylethylenediamine (TMEDA) were redistilled from potassium and benzophenone ketyl; 1,2-dimethoxyethane (DME) was redistilled from potassium; ethanol was redistilled from magnesium hydroxide; pyridine was redistilled from potassium hydroxide and stored over 4A molecular sieves; di-iso-propylamine was redistilled from 4A molecular sieves and stored over 4A molecular sieves;

N_,N-dimethylformamide (DMF) was redistilled at reduced pressure from 4A

molecular sieves onto 4A molecular sieves; chlorotrimethylsilane was freshly

redistilled from calcium hydride under a dry nitrogen atmosphere; acetone

was redistilled from phosphorous pentoxide immediately before use; acetal-

dehyde, n-butanal and n-octanal were redistilled from anhydrous calcium

sulphate.

Reactions were performed under a dry nitrogen or argon atmosphere unless 155.

otherwise stated. Low reaction temperatures were recorded as internal temperatures. Organic solutions were routinely dried over anhydrous sodium or magnesium sulphate. Solvents were evaporated at reduced pressure using a

o rotary evaporator at or below 40 C unless otherwise stated. Reagents were

132 purified according to standard procedures . Unless stated otherwise, routine medium pressure column chromatography was carried out using light petroleum and dichloromethane mixtures [commonly (1'1)-(0:1)] as eluant.

Microanalyses and mass spectral measurements were carried out by the respective laboratories at Imperial College. We thank PCMU (Harwell) for

220 MHz ^"H nmr spectra. 156.

SECTION 1: YNOLATE CHEMISTRY

Preparation of N-methyl-4-nitrobenzimidoyl chloride (88)

An intimate mixture of N-methyl-4-nitrobenzamide (5 g, 28 mmol) and phosphorus pentachloride (5.75 g, 28 mmol) was heated under an atmosphere of dry nitrogen until the phosphorus pentachloride began to melt. On doing so, the amide dissolved and a vigorous evolution of hydrogen chloride was observed.

After maintaining at 100°C for 20 minutes, the phosphorus oxychloride was removed under reduced pressure, affording a pale yellow solid on cooling.

Short path distillation (110°C, 0.05 mmHg) furnished the title compound (88)

as a pale yellow crystalline solid (4.24 g, 76%), m.p. 71-73°C, v (Nujol) max

3110, 1670 (w), 1660 (s), 1610 (s), 1535 (s), 1490 (w), 1465 (s), 1410 (m) ,

1390 (m), 1365 (s), 900 (s), 865 (s), 848 (s), 755 (m), 703 (m), 6 (CDClg)

3.33 (3H, s) and 8.08 (4H, s), m/e 198, 200 (M*) 130, 163, and 117 (Found:

C, 48.57; H, 3.74; N, 14.01. C H^Orequires C, 48.39; H, 3.55; N, 14.11%).

Preparation of 5-methoxy-N-(4-nitrobenzylidene)aniline (41)

A mixture of 4-methoxybenzaldehyde (2.99 g, 22 mmol) and 4-nitroaniline

(2.76 g, 20 mmol) were refluxed together in ethanol (50 ml) for 1 h. On cooling,

the title compound crystallised (3.66 g, 71%), m.p. 123-124 (ethanol), v ma x

(Nujol) 1625 (m), 1615 (m), 1605 (m), 1590 (m), 1510 (s), 1480 (m), 1345 (s),

1255 (m), 1170 (m) , 1110 (m) , 860 (m) , 835 (m) , 825 (m) , 810 (m), 755 (m) ,

1 and 725 (m) cm" , 5 (CDC13) 3.95 (3H, s), 7.07 (2H, d, J 9Hz), 7.37 (2H, d,

J 9 Hz), 7.92 (2H, d, J 9 Hz), 8.27 (2H, d, J 9 Hz), and 8.38 (1H, s), m/e

256 (M*) (Found: C, 65.76; H, 4.71; N, 10.89. C 4H N20 requires C, 65.62;

H, 4.72; N, 10.93%).

Preparation of 3-methyl-N-(4-nitrobenzylidene)aniline (39)

A mixture of 4-nitroaniline (1.38 g, 10 mmol) and 3-methylbenzaldehyde 157.

was heated in dry benzene under an atmosphere of nitrogen for 12 hours, using a Dean and Stark trap to remove the water formed in the reaction. Removal of the solvent in vacuo and fractional recrystallisation of the product from benzene and light petroleum afforded the title compound (39) (1.18 g, 49%), m.p. 87-88°C, v (CMC1„) 1640 (m), 1605 (m), 1590 (m), 1520 (s), 1350 (s), max o

1 1215 (m), 1170 (m), and 1115 (m) cm" , 6 (CDC13) 2.42 (3H, s), 7.23 (2H, d, J

9 Hz), 7.34-7.47 (2H, m), 7.62-7.82 (2H, m), 8.22 (2H, d, £ 9Hz), and 8.40

(1H, s), m/e 240 (M*), and 138 (Found: C, 69.88; H, 5.05; N, 11.58. C..14H JL«sN &0 a requires C, 69.99; H, 5.03; N, 11.66%).

Preparation of 4-nitro-N-(4-cyanobenzylidene)aniline (43)

A mixture of 4-cyanoaniline (1.56 g, 13.2 mmol) and 4-nitrobenzaldehyde

(2 g, 13.2 mmol) were refluxed together in benzene under nitrogen for 4 hours, using a Dean and Stark trap to collect the water formed in the reaction. Con- centration afforded the title compound (43) (2.29 g, 70%) as a crystalline material, m.p. 188.5-190°C (benzene) (lit.133 190°C), v (Nujol) 2230 max

( m), 1630 (m), 1600 (s), 1520 (s), 1505 (s), 1200 (m), 1175 (m), 900 (m),

1 860 (s), 855 (s), 830 (m) , 755 (m), and 690 (m) cm" , 6 (CDC13), 7.16 (2H, d,

J 9 Hz), 7.62 (2H, d, J 8 Hz), 7.98 (211, d, J 9 Hz), 8.26 (2H, d, £ 9 Hz), and 8.41 (1H, s) , m/e 251 (IT) , 129, and 102 (Found: C, 66.94; H, 3.57;

N, 16.71. Calculated for C 14.H yn N o 02, , C, 66.93; H, 3.61; N, 16.72%).

13 Modified preparation of 3-phenylisoxazole (49)

To a solution of acetophenone oxime (1.35 g, 10 mmol) in dry THF (50 ml)

o at -78 C, was added, under an atmosphere of dry nitrogen, n-butyllithium (13.7 ml, 1.45 M). After stirring at -78°C for 15 min, the solution was allowed to

o warm to -15 C, and maintained at this temperature for a further 15 min.

Freshly redistilled N,N-dimethylformamide (0.76 ml, 10 mmol) was then added at

-20°C, and the reaction mixture was allowed to warm to room temperature over- 158.

night. The reaction mixture was poured into a solution of concentrated sulphuric acid (11 g) in a THF and water mixture (75 ml, 4:1 v/v), and refluxod for 1 h under nitrogen. After cooling, and neutralisation (sodium hydrogencarbonate) the aqueous phase was separated and extracted with ether

(3 x 25 ml). The combined organic extracts were washed (5% NaHCO^, 25 ml;

brine 20 ml, water 20 ml) and dried (MgSO^). Concentration of the crude

product in vacuo and column chromatography (Kieselgel H, 15 g) afforded the

13 title compound (49) (373 mg, 26%) as a viscous oil, v (neat)3160 (w), max

3130 (w), 3070 (w) , 1590 (w) , 1560 (s) , 1555 (s) , 1460 (s) , 1400 (s), 900

1 (s), 880 (s), 760 (s), and 690 (s) cm" , 6 (CDC13) 7.11 (1H, d, J 1 Hz),

7.44-7.58 (3H, m), 7.80-7.90 (2H, m), and 8.48 (1H, d, J 1 Hz), m/e 145

(M*), 144, 121, and 77.

Preparation of E-l-(3,4-dimethoxyphenyl)-2-pyrrolidinoethane (72)

To a solution of (3,4-dimethoxyphenyl)acetaldehyde (1.36 g, 7.64 mmol)

and toluene-4-sulphonic acid (10 mg) in dry benzene (50 ml) at 0 C was slowly

added freshly redistilled pyrrolidine (0.54 g, 8.4 mmol). After refluxing

overnight, under an atmosphere of nitrogen, using a Dean and Stark trap to

remove the water formed in the reaction, the solvent and excess pyrrolidine

were removed in vacuo, to afford the crude product (^ 100%,) as a viscous oil .

The title compound (72) was used without purification, v (neat) 1640 (s) , max

1600 (m), 1580 (m), 1515 (s), 1420 (s), 1370 (s), 1220-1260 (s) , 1150 (s),

1025 (s), 930 (m), 880 (m), 850 (m), 805 (m), 760 (m), and 680 (s) cm"1,

6 (CDC13) 1.81-2.15 (4H, m), 3.06-3.37 (4H, m), 3.83 (3H, s), 3.88 (3H, s),

5.04 (1H, d, J 14 Hz), 6.70 (3H, s), and 6.94 (1H, d, J 13 Hz), m/e 233 (M*),

218, and 151. 159.

2 Preparation of trans-A -3-phenyl-4-(3,4-dimethoxyphenyl)-5-pyrrolidino- isoxazolinc (73)

To a solution of ci-chlorobenzaldoxime (1.19 g, 7.6 mmol) in dry ether

(50 ml) at 0°C was added a solution of the enamine (72) (1.69 g, 7.6 mmol) and dry triethylamine (1.05 ml, 7.6 mmol) in dry ether (50 ml) over a period o of 20 min. After the addition was complete, the reaction was stirred at 0 C for a further 2 h. Water (100 ml) was added, the organic layer separated and the aqueous phase extracted with ether (3 x 25 ml). The combined organic extracts were dried (MgSO^) and concentrated in vacuo. Column chromatography

[Kieselgel H, 10 g, eluant benzene-dichloromethane (1:1)] afforded the title compound (73) (2.18 g, 81%) as a white foam. A sample was purified for

microanalysis by pic (Kieselgel H, developer dichloromethane), Vmax (CHCl^)

3060 (w), 2840 (m) , 1610 (m) , 1600 (m) , 1530 (s) , 1465 (s), 1265 (s) , 1250

(s), and 910 (s) cm"1, 6 (CDC1 o) 1.60-1.73 (4H, m), 2.43-2.83 (4H, m), 3.70

(6H, s), 4.10 (1H, d, J 2 rfz), 5.12 (1H, d, J 3 Hz), 6/50-6.66 (3H, m), and

7.03-7.56 (5H, m), m/e 352 (m"5") , 350, 231, 253, and 218 (Found: C, 71.57;

H, 6.86; N, 7.95. C_.H_.N_0, requires C, 71.26; H, 7.02; N, 7.63%). Ai u

Preparation of 3-phenyl-4-(3,4-dimethoxyphenyl)isoxazole (67)

A solution of the isoxazoline (73) (2.1 g, 6.19 mmol) in a methanol-

concentrated aqueous hydrochloric acid solution (65 ml, 1:2 v/v) was refluxed

under an atmosphere of nitrogen for 90 min. On cooling, ether (50 ml) was

added. The organic layer was separated, and the aqueous phase neutralised

(saturated sodium hydrogencarbonate solution). The aqueous phase was extrac-

ted with ether (3 x 50 ml) and the combined organic extracts washed with

saturated aqueous sodium hydrogencarbonate solution (10 ml), dried (MgSO^)

and concentrated in vacuo. Column chromatography (Kieselgel H, 10 g, eluant

dichloromethane-benzene, 1:1) afforded the title compound (67) (1.01 g,

60%) as a white crystalline material, m.p. 97.5-98.5°C (ethanol), v (Nujol) max 160.

3110 (w), 28G0 (s), 1602 (m), 1590 (m), 1580 (m), 1260 (m) , 1250 (m) , 1230

(s), 1180 (m), 1145 (m), 1110 (m) , 1030 (m), 810 (s) , 775 (m) , 765 (m), 720

1 (m) , and 700 (m) cm" , 6 (CDC13> 3.42 (311, s), 3.64 (3H, s) , 6.10 (1H, m) ,

6.80 (2H, d, J 1 Hz), 7.20-7.55 (5H, m) , and 8.47 (III, s) , m/e 281 (AT) , 266,

C H N0 166, 155, and 151 (Found: C, 72.51; H, 5.35; N, 4.79. 17 15 3 requires

C, 72.58; II, 5.37; N, 4.98%).

Preparation of 3-lactams from the phenylethnolate anion (17)

The general methodology employed is exemplified in the following

experiment.

Preparation of 3- ["(4-nitroanilino) (4-nitrophenyl)methyl] -1, 4-di (4-nitropheny 1)

-3-phenylazetidin-2-one (31)

To a solution of 3,4-diphenylisOxazole (18) (552.5 mg, 2.5 mmol) in

dry THF (20 ml) at -78°C was added n-butyllithium (1.50 ml, 1.60 M) . A deep

royal blue colouration was observed on the addition of the lithium reagent.

After stirring at -78°C for 10 min, a solution of the Schiff's base (38)137

(682.5 mg, 2.5 mmol) in dry THF (5 ml) was slowly added, maintaining the

temperature at -78°C. After stirring at -78°C for 2 h, the reaction mixture

had become deep red-orange in colour. Acetic acid (150 mg, 2.5 mmol) was

added at -78°C, and the reaction mixture allowed to warm up to room temperature.

The solvent was removed in vacuo and the residue was triturated with dichloro-

methane (2 x 25 ml). The organic extracts were filtered through Celite and

concentrated in vacuo. Column chromatography (Kieselgel H, 10 g, eluant

dicliloromethane) afforded the title compound (31) (741 mg, 89%) as a bright

yellow foam. An analytical sample was prepared, by pic (Kieselgel H, developed

6 x in dichloromethane) v (CHC1„) 3410 (brd), 1765 (m), 1600 (s) , 1525 (s), max J 1520 (s), 1380 (w), 1350-1320 (brd), 1270 (s), 1115 (s), 900 (w), 860 (m), — 1 6 840 (w), 790 (w), 740 (s), and 70" (m) cm , 5 (CDC1 + d -acetone, 9/1 v/v) 161.

5.28 (III, s) , 5.52 (1H, d, J 8 Hz) , 5.90 (III, d, J 8 Hz) , 6.35 (2H, d, J

9 Hz), 6.60-7.10 (9H, m), and 7.50-7.90 (10 H, m), m/e 538, 481, 295, 279,

C H N rec u:ires 236, 221, and 162 (Found: C, 61.52; H, 3.91; N, 12.45. 34 24 6°9 l

C, 61.32; H, 3.66; N, 12.72%).

(b)Preparation of 3-[(4-ethoxycarbonylanilino)(4-nitrophenyl)]-1-(4-ethoxy- carbonylphenyl)-4-(4-nitrophenyl)-3-phenylazetidin-2-one (33)

138

The above experiment was repeated using the Schiff's base (40)

Work up and chromatography as above afforded the title compound (79%) as a pale yellow foam, v (CH CI ) 3350 (shp.), 1755 (s), 1700 (brd. s), 1605 max £ ^

(s), 1525 (s), 1370 (m), 1350 (s), 1280 (s), 1270 (s), 1175 (m), 1110 (ra) ,

1 1015 (w), 850 (m), 770 (w), 740 (s) , and 700 (m) cm" , 5 (CDC13) (220 MHz),

1.32 (3H, t, J 7 Hz), 1.38 (3H, t, J 7 Hz), 4.28 (2H, q, J 7 Hz), 4.38 (2H, q,

£ 7 Hz), 4.72 (1H, d, J 9.5 Hz), 4.97 (1H, d, J 9.5 Hz), 5.61 (1H, s), 6.12

(2H, d, J 9 Hz), 7.27 (2H, d, J 9 Hz), 7.30 (3H, m), 7.44 (2H, d, J 9 Hz) ,

7.64 (4H, m), and 8.0 (4H, m), m/e 519, 398, 369, 298, 253, and 165 (Found: .

C H N 0 C, 67.38; H, 4.93; N, 7.70. 40 34 4 9 requires C, 67.22; H, 4.79; N,

7.83%).

(c) Preparation of 4-(3-methylphenyl)-3[(3-methylphenyl)(4-nitroanilino)

methyl]-1-(4-nitrophenyl)-3-phenylazetidin-2-one (32)

On repeating the above procedure with the Schiff's base (39), the

3-lactam (32) (58%) was obtained as a foam, v (CH0C10), 3400 (m), 1755 max £ z

(s), 1600 (s), 1520'(m), 1500 (m), 1380 (m), 1320 (brd. s), 1265 (m),

1180 (w), 1110 (m) , 895 (w) , 850 (m) , 835 (w) , 790 (w) , and 750 (m) cm"1,

6 (CDC13) (220 MHz) 2.13 (3H, s), 2.27 (3H, s), 4.83 (1H, s), 5.03 (1H,

d, J 7.5 Hz), 6.0 (1H, d, J 7.5 Hz), 6.40 (2H, d, J 9 Hz), 6.67 (2H, m>,

7.0-7.10 (411, m), 7.10-7.30 (5H, m), 7.37 (2H, s), 7.85 (2H, d, J 9 Hz),

and 3.0 (2H, d, J 9 Hz), m/e 598 (M*) , 481, 358, 328, 240, and 210 162.

(Found: C, 72.26; II, 5.25; N, 9.24. C..JobI oON 'l0 _3 requires C,' 72.23; H, 5.05;

N, 9.36%).

(d) Preparation of 3-[(4-nitroanilino)phenylmethyl]-4-(4-nitrophenyl)-3,4- diphenylazetidin-2-one (30)

The title compound (30) was obtained as a foam (66%), v (CH 01_) s { max 2o 2

3410 (m), 1760 (s), 1600 (s), 1520 (s), 1502 (s), 1384 (m), 1323 (brd. s),

1180 (m), 1150 (w), 1112 (s), 1072 (w), 1030 (w), 1000 (w), 900 (m), 850 (m),

-1 and 830 (m) cm , 5 (CDC13) 4.97 (1H, s), 5.12 (1H, d, J 7 Hz), 5.97

(1H, d, J, 7 Hz, NH), 6.35 (2H, d, J 9.5 Hz), 6.80-7.65 (17 H, m), 7.77

(2H, d, J 9.5 Hz), and 7.93 (2H, d, £ 9.5 Hz), m/e 570 (M*) , 554, 432,343,

328, 315, 297, 269, 227, 180, 119, and 117 (Found: C, 71.66; H, 4.70;

N, 9.70. C34H26N405 C, 71.55; H, 4.60; N, 9.82%).

Preparation of benzhydryl 6a-chloropenicillanate (96)

134 63-Aminopenicillanic acid (94) (641 mg, 3 mmol) was dissolved in an

aqueous methanol-hydrochloric acid mixture (20 ml methanol; 5.8 ml water;

2.90 ml lOr.l hydrochloric acid). On cooling to 0 C, sodium nitrite (300 mg)

was added in one go. The resulting solution was left to stir for a period

of 1 h, during which time the reaction mixture was allowed to warm to

room temperature. After partitioning between water (100 ml) and chloro-

form (100 ml), the organic extracts were washed with brine (10 ml) and

dried (MgS04). Removal of the solvent in vacuo afforded crude 6a-chloro-

51 penicillanic acid (95) as a viscous oil (0.54 g, 73%), v max (CHC1»«j )

1 3400-2500 (brd.), 1780 (s), and 1720 (s) cm" , <5 (CDC13) 1.60 (3H, s),

1.65 (3H, s), 4.60 (1H, s), 4.90 (1H, d, J 1.5 Hz), and 5.40 (1H, d, J_

1.5 Hz). To a solution of crude 6a-chloropencillanic acid (145 mg,

0.62 mmol) in dry dichloromethane (10 ml) was added a solution of diphenyl-

diazomethane until the purple colour of the diazo compound was no longer 163.

discharged. The solvent was removed in vacuo, column chromatography

(Kieselgel II, 10 g) of the residue afforded the title compound (96)

(151 mg, 61%) as a white amorphous solid, m.p. 107-108°C, \>max (CHC13)

1785 (s), 1740 (s), 1295 (m), 1260 (m) , 1200 (m), and 1180 (m) cm"1,

6 (CDC13) 1.33 (311, s), 1.63 (3H, s) , 4.73 (1H, s) , 4.83 (1H, d, J 1.5 Hz) ,

5.43 (1H, d, J 1.5 Hz), 7.03 (1H, s), and 7.40 (10H,s), m/e 401, 403 (M^) ,

c H C1N0 S 165, 167, 152, and 114 (Found: C, 62.56; H, 5.01; N, 3.51. 2i 20 2 requires C, 62.76; H, 5.02; N, 3.49%).

Preparation of benzhydryl 6a-bromopenicillinate (99)

63-Aminopenicillanic acid (94) (6.20 g, 24.1 mmol) was dissolved in

a solution of sulphuric acid (72 ml, 2.5 M) containing sodium bromide

(14.98 g) and cooled to -10°C. A solution of sodium nitrite (3.05 g)

in water (15 ml) was slowly added to the above solution over a period of

90 min, at 0 C. After the addition was complete, the reaction mixture -was

left to stir at 0 C for a period of 60 min. The reaction mixture was pour-

ed into chloroform (100 ml), the organic layer was separated and washed

with brine (20 ml). The aqueous phase was extracted with chloroform (2 x

25 ml) and the combined organic extracts were dried (MgSO^) and concentrated

in vacuo to afford a mixture of 6a-bromopenicillanic acid (97) (^90%) and 52

6,6-dibromopenicillanic acid (98) (^10%) . To a solution of the crude

product in dichloromethane (20 ml) was added diphenyldiazomethane in

dichloromethane, until the purple colour of the diazo-compound was no

longer discharged. The solvent was removed in vacuo; column chromatography

of the crude product (Kieselgel H, 20 g) afforded a yellow oil, which oil

trituration with light petroleum afforded the title compound (99) (2.90 g,

27%) as a white amorphous solid, m.p. 106-107°C, v (Nuiol) 1770 (s), max

1740 (s), 1290 (s), ll^OO (s) , 1175 (s), 1160 (m) , 1130 (m) , 1000 (w), 960 (w),

820 (w), 780 (m), 740 (m), 730 (s), 700 (s), and 690 (m) cm"1, 6 (CDC1 ) 1.27 (3H, s), 1.60 (3H, s), 4.62 (1H, s), 4.78 (1H, d, J 1.5 Hz), 5.40 3 164.

(1H, d, J 1.5 Hz), 6.94 (III, s) , and 7.35 (10 II, s) , m/e 445, 447 (M*) ,

388, 366, 322, 234, 236, and 167 (Found: C, 56.29; H, 4.33; N, 3.16.

C H DrNO.S requires C, 56.51; H, 4.52; N, 3.14%). mJL o

Motalation studies of benzhydryl 6g-halopeniciilanates (96) and (99)

(a) To a solution of benzhydryl 6a-chloropenicillanate (96) (401 mg,

1 mmol) in dry THF (10 ml) at -100°C under a dry nitrogen atmosphere was added t-butyllithium (1 mmol) , affording a pale yellow solution. After

o o stirring at -78 C for 1 h, the reaction mixture was quenched at -100 C

with acetic acid (1 mmol). After allowing the reaction mixture to warm to

room temperature, the solvent was removed in vacuo, and the residue tri-

turated with dichloromethane (25 ml). The organic extract was filtered

through celite and concentrated in vacuo. Column chromatography (Kiesel-

gel H, 10 g, eluant light petroleum-dichloromethane) afforded benzhydryl

6a-chloropenicillanate (96) (214 mg, 50.2%) as the only identifiable

product.

(b) Deuterium incorporation studies.- On attempting the metalation

reaction as described above (0.5 mmol scale), and quenching with deuterium

oxide (2 mmol), chromatography afforded a low yield (44 mg) of impure fcenz-

hydryl 6-chloro-6-deuteriopenicillanate (101) (nmr, ms).

(c) To a solution of benzhydryl 6a-bromopenicillanate (99) (427 mg,

0.95 mmol) in dry THF (10 ml) under an atmosphere of dry nitrogen was

o added t-butyllithium (1 mmol) at -100 C. The resulting yellow solution

was stirred at -100 C for 30 min, and then quenched with acetic acid (1 mmol) .

After allowing to warm to room temperature, the solvent was removed in

vacuo and the residue was triturated with dichloromethane (2 x 25 ml).

The combined extracts were filtered through Celite and concentrated in vacuo .The ^H nmr spectrum of the crude reaction mixture indicated ^50% 165.

conversion to benzhydryl penicillanate (104).

(d) To a solution of benzhydryl 6a-bromopenicillanate (99) (440 rag,

1 mmol) in dry THF (15 ml) at -73 C was added methylmagnesium bromide

(1 mmol) in ether. After stirring at -78°C for 150 min, the reaction mixture was quenched with acetic acid (1 mmol). Work up in the usual way afforded the crude product which was essentially starting material (nmr).

(e) To a solution of benzhydryl 6a-brompenicillanate (S9) (445 mg,

1 mmol) in dry THF (20 ml) at -78°C was added n-butyllithium (0.75 ml,

1.32 M) over a period of 3 min. The resultant orange-yellow solution was

o o left to stir at -78 C for 2 h, and quenched at -78 C with acetic acid

(1 mmol, 60 mg). After allowing the reaction mixture to warm to room

temperature, the solvent was removed in vacuo and the residue triturated with dichloromethane (2 x 25 ml). The organic extracts were filtered

through Celite and concentrated in vacuo. Column chromatography (Kieselgel, 49b H, 10) afforded benzhydryl penicillanate (104) (226 mg, 61%) as a viscous

oil, v (neat) 1770 (s), 1750 (s) , 1600 (w), 1580 (w), 1490 (m), 1445 (m), max

1360 (m), 1290 (s), 1250 (m), 1200 (s), 1170 (s), 1150 (m), 1020 (m), 980

(m), 960 (m), 910 (m), 750 (m), 730 (s), 700 (s), and 640 (m) cm"1,

6 (CDC13) 1.20 (3H, s), 1.60 (3H, s), 1.60 (3H, s), 3.30 (1H, d d, J 16,

1 Hz), 3.51 (1H, dd, J 16, 4 Hz), 4.55 (1H, s), 5.29 (1H, dd, J 4, 1 Hz),

6.98 (1H, s), and 7.38 (10 H, s), m/e 367 (M*) , 325, 184, 167, 114, and

105 (Found: M* 367.1238. C H NO S requires M* 367.1242). £ JL i. o

(f) To a solution of benzhydryl 6a-bromopenicillanate (99) (445 mg,

1 mmol) in dry THF (20 ml) at -78°C was added n-butyllithium (0.71 ml,

I.4 M) . After stirring the orange coloured solution at -78°C for 15 min,

d^-acetic acid (180 mg, 3 mmol) was added at -78°C, and the reaction

mixture allowed to warm up to room temperature. The solvent was removed 166.

in vacuo and the residue triturated with dichloromethane (200 ml). The organic extract was filtered through Celite and concentrated in vacuo.

Column chromatography (Kieselgel H, 10 g) afforded benzhydryl 6-deuterio-

6-bromopenicillanate (102) (57 mg, 12%), v (CHC1 ) 1780 (s), and 1740 max J

1 (s) cm" , 6 (CDC13) 1.23 (3H, s), 1.60 (3H, s), 4.66 (1H, s), 5.68 (1H, s),

7.00 (1H, s), and 7.28 (10 H, s) , m/e 446, 448 (IT) , 375, 237, and 167, and

a more polar material, a mixture of the penicillanate (104) and benz-

hydryl-6-deuteriopenicillanate (105) (116 mg), 6 (CDC13) 1.25 (3H, s) ,

1.64 (3H, s), 2.95-3.85 (^ 1H, m), 4.60 (1H, s), 5.23 (1H, d, J 4 Hz), 7.00

(1H, s), and 7.40 (10 H, s), m/e 367, 368, 325, 167 (80% d-incorporation

by ms).

Attempted hydroxy- and amino-alkylation reactions of the anion (103)

(a) To a solution of benzhydryl 6a-bromopenicillanate (99) (445 mg,

1 mmol) in dry THF (15 ml) at -78°C was added n-butyllithium (0.71 ml,

1.4 M). After stirring at -78°C :for 20 min, benzophenone (182 mg, 1 mmol)

in dry THF (5 ml) was added to the reaction mixture at -78°C. After

stirring at -78°C for 1 h, acetic acid (60 mg, 1 mmol) was added and the

reaction mixture allowed to warm up to room temperature. After work up

in the usual way, column chromatography (Kieselgel H, 9 g; eluant di-

chloromethane) afforded a white solid (167 mg), probably the alcohol (106)

which was contaminated with an unknown compound (tic) . Pic and fractional

recrystallisation were unsuccessful in further purification of the alcohol

(106), v (CHC1 ) 3470 (brd.), 1760 (s), 1750 (s), 1600 (m) , 1490 (m) , max o

1475 (m), 1300 (brd.), 1255 (m), 1200 (m), 1180 (m), 1115 (m) , 1080 (m),

1 805 (m), and 730 (m) cm" , 6 (CDC13) 1.18 (3H, s), 1.60 (3H, s), 2.78

(1H, s), 4.35 (1H, d, J 1 Hz), 4.58 (1H, s), 5.29 (1H, d, J 1 Hz), 6.87

+ + (1H, s), and 7.20-7.50 (20 H, m), m/e 382 (M - Ph2CH), and 338 (M - PhCHCOg) .

(b) To a solution of benzhydryl 6a-bromopenicillanate (99) (445 mg, 167.

1 mmol) in dry TMF (20 ml ) at -78°C was added n-butyllithium (0.71 ml ,

1.4M). After stirring at -78°C for 15 min, a solution of the

Schiff's base (38) (271 mg, 1 mmol) in dry TIIF (5 ml ) was added.

After stirring at -78°C for 2 h, acetic acid (60 mg, 1 mmol) was added and the reaction mixture allowed to warm up to room temperature.

After the usual workup, column chromatography [Kieselgel H, 8g, eluant

dichloromethane-ether (1:20)] afforded an inseparable mixture of products

(104 mg), which contained some of the desired compound (107),v max

(CH CI )3370 (m), 1770 (s), and 1750 (s), 6(CDC10) 3.80 (m, C -H), 2 Z 3 6

4.63 (s, C -H), and 4.95-5.60 (m, C -H, NH, Ar-CH-NH-), m/e 638 (M+), o 5 —

471 (Mt - CHPh ), 427 (Mt - CO CHPh ), and 304.

Preparation of 2-oxo-4-phenyl-3a,3b-dihydro-[l,3]-dioxolo-[4,5-d]

29 isoxazole (63)

To a solution of a-chlorobenzaldoxime (5.0g, 32 mmol) (53) and

vinylene carbonate (62) (12.5 ml) in dry ether (20 ml ) at 0 C was

added a solution of dry triethylamine (4.5 ml , 35 mmol) in dry ether

(15 ml ). After the addition was complete, the reaction mixture was

stirred at 0 C for 2 h. Ether (50 ml ) was added, the triethylamine

hydrochloride was filtered off and the filtrate concentrated in. vacuo.

Excess vinylene carbonate was removed under high vacuum (0.10 mmHg),

and the solid residue triturated with light petroleum (8 x 50 ml ).

The remaining solid was recrystallised from benzene, affording the

title compound (63) (1.14g, 20.5%, Lit.29 18%), m.p. 155°C (Li^;? 158°C) , v (Nujol) 1840 (s), 1825 (s), 1600 (w), 1570 (w), 1170 (m), 1145 (m) max

1090 (s), 1060 (m), 970 (s), 855 (m), 840 (m) , 770 (m), and 755 (s) cm"1,

6 (dg-acetone) 6.88 (2H, q, J 5 h'z) , and 7.55-8.05 (511, m) , m/e 205 (M+) ,

178, and 103 (Found: C, 58.30; H, 3.44; N, 6.76. Calculated for C1QH7N04

C, 58.54; H, 3.44; N, 6.83%). 168.

Attempted preparation of 4-hydroxy-3-phenylisoxazole (G4a)

A suspension of (63) (l.Og, 5.2 mmol) in 20% aqueous sulphuric

acid (25 ml ) was heated in an oil bath at 170°C under an atmosphere of nitrogen. A vigorous evolution of carbon dioxide was observed after

a few minutes. Heating was continued ( 15 min ), and then the reaction

mixture was cooled to room temperature. The aqueous solution was

extracted with ether (3 x 20 ml ), the combined organic extracts washed

with sodium hydrogencarbonate solution (10 ml , 10% w/v), dried (MgSO^)

and concentrated in vacuo. Column chromatography (Kieselgel H, 5g, eluant

dichloromethane) afforded phenacyl alcohol (50 mg) as the only identifiable

product.

10 Reactions of the phenyl ethynthiolate anion (14)

In a typical reaction, phenylacetylene (1.33 ml , 2 mmol) in dry

THF (10 ml ) was cooled to -78°C, and n-butyllithium (1.43 ml , 1.40 M)

was added over a period of 2 min. After stirring at -78 C

for 10 min,powdered sulphur (64 mg, 2 mmol) was added at -78°C and

the solution allowed to warm to room temperature. The resultant orange

solution was re-cooled to -78°C, and a solution of the Schiff's base

(2.5 mmol) in dry THF was added. After stirring at -78°C'for 60 min,

acetic acid (150 mg, 2.5 mmol) was added and the reaction mixture allowed

to warm up to room temperature. Work up in the usual way afforded an

intractable mixture of products (tic).

Modified preparation of 1,4,4-triphenylazetidin-2-one (6l)

A solution of tri-n-butyltinhydride (1.58g, 5.44 mmol), AIBN (20 mg)

and 3,3-dichloro-l,4,4-triphenylazetidin-2-one (60) (lg, 2.72 mmol) in

dry benzene (50 ml ) was refluxed for 20 h under an atmosphere of dry

nitrogen. On addition of a further quantity of the hydride reagent

(250 mg) and refluxing for a further 4 h , clean conversion to the 169.

product was observed. Removal of the solvent in vacuo afforded the

crude product, which was partitioned between ether (50 ml ) and water (50 ml ). The organic layer was washed successively with potassium iodide

and iodine solution (20 mis) , aqueous soldium thiosulphate solution

(20 ml , 10% w/v), aqueous potassium fluoride (20 ml , 10% w/v) and water

(10 ml ). The organic layer was dried (MgSO^) and concentrated iri vacuo

to afford the crude product. Low temperature recrystallisation (-78°C,

ether) afforded a sample of the title compound (61) (200 mg, 25%), m.p.

120-122°C(Lit.135 121-123°C), v (Ccl ; 1765 (s), 1600 (m), 1500 (s), max 4

and 1360 (s) cm"1, S(CC14) 3.60 (2H,S), and 7.3 (15H,m), m/e 299 (Mt),

207, 180, and 165. 170.

SECTION 2: C-'L DISPLACEMENT REACTIONS

Preparation of 4-[l,1-bis-(ethoxycarbony1)ethyl]azetidin-2-one (128)

a. To diethyl methylmalonate (348 mg, 2 mmol) in dry TMF (20 ml )

at 0°C was added sodium hydride (57.6 mg, 2.4 mmol) and imidazole (2 mg).

After allowing to warm to room temperature, the reaction mixture was

stirred until the gas evolution had ceased ( 2 h ). The reaction o 57 mixture was cooled to -78 C and 4-acetoxyazetidin-2-one (115) (258 mg,

2 mmol) in dry THF (5 ml ) was added in one go. After stirring at -78°C

for 4 h , the reaction mixture was allowed to warm up to room temperature.

On removal of the solvent in. vacuo, the crude product was triturated with

dichloromethane (2 x 25 ml ). The organic extracts were filtered through

celite, and concentrated in vacuo. Column chromatography of the residue

[Kieselgel H, 8g, eluant dichloromethane-ethy1 acetate (5:1)]afforded the

title compound (128) (320 mg, 66%) as a viscous oil v (CHC10) 3300 max o

(brd.s), 1765 (s), 1730 (s), 1450 (m) , 1370 (s), 1270 (s), 1180 (m) ,

1115 (s), 1015 (m), and 900 (m) cm"1, 6(CDC1 ) 1.26 (3H,t,J 7Hz), 1.45 (3H,s), u

2.71-3.20 (2H,m), 4.11-4.38 (5H,m), and 6.33 (lH,s), m/e 244 (Mt +1), 215,

and 174 (Found: C, 54.56; H, 7.13; N, 5.71. C, H__NO requires C, 54.31; 1111 7 c5

H, 7.04; N, 5.76%).

b. To a solution of di-iso-propylamine (0.33 ml , 2 mmol) in dry

THF (20 ml ) at 0°C was added n-butyllithium (1.31 mis, 1.4 M). After

o o_ stirring for 30 min at 0 C, the pale yellow solution was cooled to -78 C,

and diethyl methylmalonate (348 mg, 2 mmol) in dry THF (5 ml ) was

added in one go. After stirring at -78°C for 1 hour, a solution of

4-acetoxyazetidin-2-one (115) (258 mg, 2 mmol) in dry THF (5 ml ) was

added over a period of 2 min. After stirring at -78°C for

15 min, the reaction mixture was allowed to warm up to room temperature.

Work up in the usual way and column chromatography as above afforded the 171.

title compound (128) (168 mg, 35%).

Preparation of dibenzhydryl malonate (130)

To a solution of malonic acid (500 mg, 5 mmol) in dry dichloromethane (50 ml ) was added with efficient stirring at room temperature a solution of diphenyldiazomethane (1.94 g, 5 mmol) in dichloromethane

(20 ml ). A rapid evolution of gas was observed, and after stirring at room temperature for 20 min, a quantitative conversion to the di-ester was observed. Concentration in vacuo afforded the crude product, which on elution through a silica plug and concentration in vacuo afforded the

title compound (130) (^100%) as a white crystalline material, m.p. 92-93°C,

(dichloromethane - light petroleum), v (Nuiol) 1720 (s), 1600 (w), max

1580 (w) , 1370 (m) , 1220 (m) , 1155 (m) , 1000 (m) , 980 (m) , 755 (m) , 745 (m) ,

1 700 (s), and 650 (s) cm" , 6(CDC13) 3.53 (lH,s), 6.95 (1H, s), and 7.30

(10H,s)f m/e 436 (M+), 269, 183, 167, 166, 165, 105, and 91 (Found: C,

79.64; H, 5.58. CHO requires C, 79.80; H, 5.54%).

Preparation of dibenzhydryl methylmalonate (131)

To a solution of dibenzhydryl malonate (130) (872 mg, 2 mmol) in dry

THF (20 ml ) at 0°C was added sodium hydride (50 mg, 2.1 mmol) and

imidazole (2 mg). After stirring overnight under argon at room temperature,

the colourless solution was cooled to -78°C and methyl iodide (0.4 ml )

was added in one go. After stirring at -78°C for 30 min , the

reaction mixture was allowed to warm to room temperature. The solvent

was removed iri vacuo, and the residue triturated with dichloromethane

(2 x 30 ml ). The organic extracts were filtered through Celite and

concentrated in vacuo. Recrystalisation afforded the title compound (131) ,

m.p. 131-134°, v (Film) 1725 (s) , 1490 (m) , 1460 (m) , 1340 (m) , max

1280 (m), 1180 (m), 730 (m), 690 (s), and 680 (m), S(CDC1 o ) 1.50 (3H, d,

J 9HZ), 3.70 (1H, q, J9Hz), 6.95 (211,s), and 7.30 (20 H,m), m/e 283

+ (M _ CHPh2), 183, and 167, 172.

contaminated with a small amount of the dimethyl compound.

Preparation of 4-["1,1-bis-(diphenylmethyloxycarbonyl)ethyl] azetidin-2- one (132)

To a solution of dibenzyhydry1 methylmalonate (131) (450 mg, 1 mmol) in dry THF (20 ml ) under an atmosphere of dry nitrogen was added sodium hydride (26 mg, 1.1 mmol) and imidazole (2 mg). The reaction mixture was stirred overnight at room temperature and then cooled to -65°C. A solution of 4-acetoxyazetidin-2-one (115) (129 mg, 1 mmol) in dry THF

(2 ml ) was added and after stirring at -65°C for 15 min, the reaction mixture was allowed to warm up to room temperature. The solvent was removed iri vacuo and the residue triturated with dichloromethane (2 x 30 ml ). The organic extracts were filtered through Celite and concentrated in vacuo. Column chromatography (Kieselgel H, lOg, eluant dichloromethane)

afforded the title compound (132) (122 mg, 23%) as a glass, v (CH„Cln) max 2, L

3400 (m) , 1755 (s) , 1710 (s) , and 1250 (s) , <5(CDC13) 1.50 (3H,S),

2.75 (2H, m), 4.30 (lH,m), 5.88 (lH,s), 6.95, 6.90 (2H,m), and 7.30

(20H,s), m/e 519 (M^), 352, 183, 167, and 105.

Attempted displacement reactions of the B-lactams (115) and (120) with malonate carbanions

In a typical experiment, a solution of the 3-lactam (120)

(136 mg, 0.8 mmol) and potassium t-butoxide (89 mg, 0.8 mmol) in dry

t-butanol and THF (20 ml ,1:1 v/v) was cooled to 0°C, di-t-butyl malonate

(146 mg 0.8 mmol) in dry THF (5 ml ) was added. After stirring at 0°C

for 2 h, the reaction mixture was poured into water (10 ml ) and

extracted with ether (2 x 30 ml ). The combined organic extracts were

dried (MgSO^) and concentrated iji vacuo. The nmr of the crude reaction

mixture showed only the presence of di-.t-butyl malonate. 173.

Attempted displacement reaction of the 3-lactam (120) with the 0-silyl ether (150)

To 4-pivalyloxyazetidin-2-one (8.5 mg, 0.05 mmol) (120) in dry deuteriochloroform (0.5 ml ) was added the O-silylthioacetal (150)

(11 mg, 0.05 mmol) and freshly resublimed zinc bromide (2 mg) . The ^H nmr spectrum indicated that a rapid silyl exchange, forming the 1-trimethylsi

3-lactam (160) [M+ +H, m/e 244, and M+ - (CH ) C0 , m/e 142] and o O o£ S-phenyl thioacetate (M+, m/e 152) had taken place.

Attempted preparation of 4-[methoxycarbonylmethyl(bis-benzylthio) ] azetidin-2-one (140) "

Methyl 2,2-di-(benzylthio) acetate (138) (636 mg, 2 mmol) in dry

THF (5 ml ) was added to a solution of lithium di-iso-propylamide (2 mmol) in THF (20 ml > at -78°C. After stirring at -78°C for 30 min, 4- acetoxy-l-trimethylsilylazetidin-2-one (161) (258 mg, 2 mmol) in dry THF

(5 ml ) was added at -78°C. After stirring at -78°C for 40 min, the reaction mixture was allowed to warm to room temperature. Work up in the usual way, and column chromatography (Kieselgel H, 10 g, eluant dichloromethane) afforded starting material (138) (385 mg, 60%) as the only identifiable product.

Other reactions using the sodium enolate (139b) led to similar results.

Attempted preparation of 4-(phenylthiocarbonylmethyl)azetidin-2-one (151)

To a solution of 4-acetoxy-l-trimethylsilylazetidin-2-one (161)

(258 mg, 2 mmol)in dry deuteriochloroform (5 ml ) was added the trimethylsilyl

ether (150) (448 mg, 2 mmol) and freshly resublimed zinc bromide (10 mg).

After stirring for 3 days, all of the starting material had been consumed

(nmr). The reaction mixture was poured into dilute hydrochloric acid 174.

(20 ml ) and extracted with ether (2 x 25 ml ). The organic extracts were combined, dried (MgSO^) and concentrated in vacuo. Chromatography

(pic, Kieselgel H, developer dichloromethane) afforded S-phenyl thioacetate (132 mg, 43%), identical to an authentic sample, 4-phenylthio— azetidin-2-one (162) (46 mg, 13%) (nmr, ir, ms) and trace amounts of the

+ desired product (151) (M*, m/e 221).

Preparation of E,%-1-benzyloxy-l-trimethylsilyloxyprop-l-ene (174)

To a solution of di-iso-propylamine (6.18 ml , 44 mmol) in dry THF

(50 ml ) at 0°C was slowly added n-butyllithium (34.5 ml , 1.4 M).

After stirring at 0°C for 30 min, the pale yellow solution was cooled to -78°C and benzyl propanoate (6.56g, 40 mmol) in dry THF (10 ml ) was slowly added ( 5 min ); After stirring at -78°C for 30 min, the reaction mixture was allowed to warm to 0°C. On recooling to -78°C, freshly redistilled chlorotrimethylsilane (5.62 ml , 44 mmol) was added in one go. After stirring at -78°C for 15 min, the reaction mixture was allowed to warm to room temperature. The solvent was removed in_ vacuo and the residue triturated with dry pentane (2 x 25 ml ). The organic extracts were quickly filtered and reconcentrated iii vacuo. Distillation under reduced pressure afforded the title compound (174) (3.30 g, 34%), b.p. 96-98°C (1.5 mmilc ) as a mobile liquid, v (CHC1 ) 1680(s) , max 3

1 1455 (s) , 1380 (s), 1305 (s) , 1250 (s),and 1200(s)cm" , 5 (CDC13) 1.48,

1.51 (3H, 2 x d, J 7, 7Hz), 3.48-3.77 (1H, m), 4.60, 4.75 (2H, 2 x s) ,

and 7.28 (5H, s), m/e 237 (M+ + H), 147 (M+ - OSiMe ), and 91 (Found: C, 66.18; H, 8.48, C luH MU Si requires C, 66.05; H, 8.53%)o .

Preparation of 1-phenylthio-l-trimethylsilyloxyethene (150)

To a solution of lithium di-iso-propylamide (33 mmol) in dry THF

(50 ml ) at -78°C was added a solution of S-phenyl thioacetate (4.56g,

30 mmol) in dry THF (5 ml ) over a period of 5 min- After stirring 175.

at -78°C for 15 min, the solution was allowed to warm up to 0°C.

After recooling to -78°C, chlorotrimethylsilane (4.2 ml , 33 mmol) was added in one go. After stirring at -78°C for 15 min, the reaction mixture was allowed to warm up to room temperature. Removal of the solvent jln vacuo, trituration of the residue with dry pentane (2 x 30 ml ) , filtration of the organic extracts and re-concentration in vacuo afforded the crude product. Reduced pressure distillation of the residue gave the title compound (150)(4.71 g, 70%), b.p. 60-63°C (0.1 mm Hg), as a mobile oil, v (CHOI ) 1600 (s), 1245 (m), 1165 (s), and 905 (s) , m ax

6 (CDC1 ) 0.13 (9H, s), 4.50 (2H, m) , and 7.10-7.50 (5H, m), m/e 224 o

c H 0SSi (M*), 167, 147, and 73 (Found: C, 59.09; H, 7.37. 11 16 requires

C, 58.93; H, 7.14%).

Preparation of 4-acetoxy-l-trimethylsilylazetidin-2-one (161)

To a solution of 4-acetoxyazetidin-2-one (115) (3.12 g, 24 mmol) in dry ether (50 ml ) at 0°C was added dry triethylamine (2.4 g, 24 mmol) followed by chlorotrimethylsilane (2.61 g, 24 mmol). After stirring the reaction mixture at 0°C for 30 min, the solvent was removed in vacuo, and the residue thoroughly triturated with dry pentane (100 ml ). The organic extracts were rapidly filtered and reconcentrated iii vacuo.

Fractionation of the crude product afforded the title compound (161)

(3.07 g, 65%), b.p. 89°C (1 mm Hg), v (CC1J 1755 (brd. s), 1400 (w), max 4

1370 (m), 1350 (m), 1310 (s), 1250 (s) , 1230 (s), 1200 (s), 1175 (s),

1140 (s), 1110 (s), 840 (s), and 740 (s) cm"1, 6 (CDC1 ) 0.28 (9H, s), o

2.06 (3H, s), 2.92 (1H, dd, J 16, 1Hz) , 3.37 (1H, dd,' J 16, 4HZ) , and

5.92 (1H, dd, J 4, 1.0 Hz), m/e 202 (M+ + H) , 158, 117, 86, and 75

+ (Found: (M + H) 202.0896. CoH_N0_S lb o i requires 202.0899) (Found: C,

47.20; H, 7.50; N, 7.20. C H N0oSi requires C, 47.73; H, 7.51; N, 6.36%). o 15 o 176.

Attempted preparation of 4-[l-(phenylcarbony1)ethyl]-1-trimethysilylazetidin

2-one (168)

To a solution of the silyl enol ether (167) (206 mg 1 mmol) and the 3-lactam (161) (201 mg 1 mmol) in dry dichloromethane (20 ml ) at

-78°C was added a catalytic quantity of trimethylsilyl trifluoromethanesulphonate (166) (2 ml., 1% v/v in dichloromethane). After stirring for 10 min at -78°C the reaction mixture was allowed to warm up to room temperature. After stirring for 30 minutes at room temperature, removal of the solvent in vacuo afforded a polymeric product.

Preparation of 4-(phenylcarbonylmethyl)azetidin-2-one (169)

To a solution of the silyl. cnol ether (167) (422 mg, 2.2 mmol) and the 3-lactam (161) (402 mg, 2 mmol) in dry dichloromethane (10 ml ) at -78°C was added a catalytic quantity of trimethylsilyl trifluoromethanesulphonate (166) (1 ml, 1% v/v solution in dichloromethane). After stirring at -78°C for 15 min the reaction mixture was allowed to warm up to room temperature ( 20 min ). After stirring at room temperature for 30 min the lime-green coloured reaction mixture was quenched with aqueous potassium fluoride (20 ml , 5% w/v solution). The organic layer was separated, and the aqueous phase extracted with dichloromethane (2 x

25 ml ). The combined organic extracts were dried (MgSO^) and concentrated iri vacuo. Column chromatography (Kieselgel H, lOg) afforded the title compound (169) (338 mg, 89%), m.p. 141-143°C 94 O (Lit. 141-143 C) (dichloromethane - light petroleum), v (CH CI ) max ^ a

3410 (m), 1755 (s), 1680 (s), 1595 (m), 1580 (m), 1370 (m), 1350 (m),

1 1200 (m), 1170 (m), 1000 (m), and 900 (m) cm" , 6 (CDC13) 2.70

(1H, dd, J 15, 3Hz), 3.04-3.33 (2H, m), 3.49 (1H, dd, J 18, 5Hz) ,

4.0-4.29 (1H, m), 6.35 (1H, s), and 7.25-8.09 (5H, m), m/e 189 (M*),

161 (M+ - CO), 120, 105, and 77 (Found: C, 69.81; H, 5.85; N, 7.40.

Calculated for C H NO C, 69.82; H, 5.86; N, 7.40%). XX 11 z 177.

The above methodology was employed in the preparation of the following 3-lactams:

a. 4-[(4-chlorophenyl)carbonylmethylJazetidin-2-one (179)

(363 mg, 81%) as a white crystalline solid, m.p. 130-133°C

(dichloromethane - light petroleum), v (CH CI ) 3400 (m), 1755 (s), max a

1675 (s), 1580 (m) , 1370 (m) , 1200 (m) , 1170 (m) , 1085 (m) , 990 (m) , and

1 810 (m) cm" , 5 (CDC1 O ) 2.64 (1H, dd, J 15, 2Hz), 2.93-3.20 (2H, m),

3.35 (1H, dd, J 19, 5Hz), 3.88-4.15 (1H, m), 6.40 (1H, s), 7.37 (2H, d, J

9Hz), and 7.80 (2H, d, J 9Hz), m/e 223, 225 (M+ + H), 195 (M+ - CO),

154 and 139 (Found: C, 59.02; H, 4.49; N, 6.23. C -L1H 1U C1N0 J requires

C, 59.07; H, 4.51; N, 6.26%).

b. 4-[toluene-4-carbonylmethyl]azetidin-2-one (177)

(306 mg, 75%) as a white crystalline solid, m.p. 135.5-137°C (dichloromethane - light petroleum) , v (CH CI ) 3410 (m), 1755 (s), max a ci

1670 (s), 1600 (m), 1370 (m), 1200 (m) , 1175 (m), 1110 (m), and 810 (m) cm"1, 6 (CDC1 ) 2.42 (3H, s), 2.66 (1H, dd, J 15, 3Hz), 2.97-3.58 (3H, m), o

3.98-4.26 (1H, m), 6.29 (1H, s), 7.31 (2H, d, J 8Hz), and 7.81 (2H, d, J8Hz),

1 m/e 203 (M ") , and 175 (Found: C, 70.96; H, 6.46; N, 6.89. C12H13N02 requires C, 70.92; H, 6.45; N, 6.89%).

c. 4-[l-phenylcarbonylethyl]azetidin-2-one (173)

(289 mg, 71%), as a white crystalline material, m.p. 125-129°C

(dichloromethane - light petroleum), v (CH„C1 ) 3410 (m), 1755 (s), max 2 2

1675 (s), 1595 (m), 1360 (m), 1210 (m), 1180 (m), 980 (m), and 815 (m)

1 cm" , 6 (CDC13) 1.31 (3H, d, J 7Hz), 2.62 (1H, dd, J 15, 3Hz), 3.08

(1H, ddd, J 16, 5, 2 Hz), 3.44-3.58 (1H, m), 3.91-4.11 (1H, m),

6.50 (1H, s), and 7.44-8.00 (5H, m), m/e 203 (M*), 175 (M+ - CO), 134,

105, and 77 (Found: C, 70.95, H, 6.47; N, 6.92. C 1ZH lo NO requires 178.

C, 70.92; H, 6.45; N, 6.89%).

d. 4-[(phonylthio)carbonylmethyl]azctidin-2-one (151)

(318 mg, 72%), as a white crystalline solid, m.p. 60-61°C (ether - light petroleum), v (CITC1 ) 3400 (m) , 1770 (s) , 1690 (s) , 1470 (m) , max 2, 2,

1355 (m), 1170 (m), 1110 (m), 995 (m) , and 815 (m) cm"1, 6 (CDC1 ) o

2.62 (1H, dd, J 15, 2Hz), 2.82-3.26 (3H, m), 3.77-4.07 (1H, m), 6.68 (1H, s) ,

7.40 (5H, s), m/e 221 (M*), 112, 110, 109, and 70 (Found: C, 59.42;

H, 4.96; N, 6.29. C H NO S requires C, 59.71; H, 5.01; N, 6.33%). 11 11 u e. 4-[l-(benzyloxycarbonyl)ethyl]azetidin-2-one (175)

(271 mg, 58%), as a viscous oil [contaminated with a trace of (115)],

V (CH CI ) 3410 (m), 1755 (s), 1730 (s), 1610 (s), 1610 (m), 1440 (m) max j A

1380 (m) , 1360 (m) , 1180 (s) , 1050 (m) , 950 (m) , 900 (m) , 815 (m) , and

670 (m) cm"1, 5 (CDC1 ) 1.18, 1.25 (3H, 2xd, J 7, 7Hz), 2.48-3.20 o

(3H, m), 3.58-3.91 (1H, m), 5.13 (2H, s), 6.38 (1H, brd. s), and 7.35

(5H, s), m/e 233.1052 (M*) (Calculated for C H NO 233.1047). JL o J- D f. 4-[l-(ethoxycarbonyl)ethyl]azetidin-2-one (171)

To a solution of the 3-lactam (161) (402 mg, 2 mmol) and the O-silylketen acetal (170) (452 mg, 2.6 mmol) in dry dichloromethane (7 ml ) at -78°C was added a catalytic quantity of trimethylsilyl trifluoromethanesulphonate (1 ml, 10% v/v solution in dichloromethane). The reaction mixture was stirred at -78°C for 15 min and slowly allowed to warm up to room temperature ( 20 min). After stirring at room temperature for 30 min, aqueous potassium fluoride (20 ml, 2.5% w/v solution) was added. After stirring for 10 min., the organic layer was separated, the aqueous phase extracted with dichloromethane (2 x 20 ml ) and the combined organic layers dried (MgSO^) and concentrated in

vacuo. Excess ethyl propanoate was removed under high vacuum (0.07 nrniKg, 179.

room temperature) to afford the title compound (171) (326.3 mg, 95%), as a viscous oil. A sample was purified for microanalysis by short-path distillation (120°C, 0.1 mmHg), v (CH CI ) 3400 (m), 1760 (s), 1720 max ct &

(s), 1600 (w), 1365 (m) , 1360 (m), and 1120 (s), 5 (CDC1 ) 1.18, 1.26 o

(3H, 2xd, J 6, 6Hz), 2.38-2.90 (2H, m), 3.09 (1H, ddd, J 17, 5, 1 Hz),

3.64-3.91 (1H , m), 4.19, 4.18 (2H, 2xq, J 6, 6Hz)} and 6.73, 7.00 (1H,

2 x s) ,m/e 171 (M"1"), and 143 (M+ - 28) (Found: C, 56.10; H, 7.80; N, 8.02.

C oH lo N0oo requires C, 56.13; H, 7.65; N, 8.18%). 180.

SECTION 3: SHAPIRO REACTIONS

Modified preparation of N-cyclohexylpyruvamide (230)

107

To a solution of pyruvyl chloride (232) (3.67 g, 35 mmol) in dry ether (50 ml ) at -78°C was slowly added a mixture of cyclohexylamine

(3.50 g, 35 mmol) and triethylamine (3.60 g, 36 mmol) in dry ether (10 ml ).

After allowing to warm up to room temperature, water (20 ml ) was added.

The organic layer was separated, dried (MgSO ) and concentrated iri vacuo.

Recrystallisation of the residue from dichloromethane and light petroleum afforded the title compound (230) (2.97 g, 50%), identical with an authentic sample. 104

Preparation of N-t-butylpyruvamide (235)

To a solution of pyruvyl chloride (232) (2.65 g, 25 mmol) in dry ether (20 ml ) at -78°C was slowly added a mixture of t-butylamine

(1.83 g, 25 mmol) and triethylamine (2.5 g, 25 mmol) in dry ether.

On completing the addition the reaction mixture was allowed to warm up

to room temperature and water (20 ml ) added. The organic layer was

separated, washed with 10% hydrochloric acid (5 ml ) and base (5 ml , 1 M

sodium hydroxide) and dried (MgSO^). The organic extract was concentrated

in vacuo. The title compound was obtained as a mobile oil

(1.15 g, 32%), b.p. 69°C (16 cm Hg), v (neat) 3380 (s), 1715 (s), max

1675 (s), 1510 (s), 1450 (s), 1360 (s), 1225 (s), and 1110 (s) cm"1,

6 (CDC1 ) 1.40 (9H, s), 2.45 (3H, s), and 6.80 (1H, s), m/e 143 (M*) , o

100, and 57 (Found: C, 58.75; H, 9.25; N, 9.67. C H NO requires C, i lo ^

58.72; H, 9.15; N, 9.78%).

Preparation of N-t-butylpyruvamide 2,4,6-tri-iso-propylbenzenesulphonyl-

hydrazone (236)

To a solution of J^-t-butylpyruvamide (235) (1.06 g, 7 mmol) in 181.

dichloromethane was added 2, 4,6-tri-iso-propylbenzenesulphonylhydrazine

(231)1C^* (2.20 g, 7 mmol). After stirring overnight at room temperature, water (20 ml ) was added. The organic layer was separated, dried (MgSO^) and concentrated iji vacuo. Recrystallisation afforded the title compound (236) (1.96 g, 66%), m.p. 157-158°C (dichloromethane - light petroleum), v max (Nujol) 3390 (m), 3200 (m), 1660 (s), 1600 (w),

1170 (s), 860 (s), 760 (s), 750 (s), 720 (m), and 680 (m) cm"1,

6 (CDC1 ) 1.38 (27H, m), 2.08 (3H, s) , 3.00 (1H, m), 4.36 (2H, m) , o

6.70 (1H, s), 7.33 (2H, s), and 8.49 (1H, s), m/e 424 (M+ - H), 408,

268, 251, 233, 204, 189 (Found: C, 62.45; H, 8.80; N, 9.92. C H N 0 S && o / <3 0 requires C, 62.38; H, 8.80; N, 9.92%).

Preparation of N-(triphenylmethyl)pyruvamide 2,4,6-tri-iso-propylbenzenesulphonylhydrazone (239)

To a solution of pyruvyl chloride (232) (1.42 g, 13.4 mmol) in dry ether at -78°C was added a solution of triphenylmethylamine (3.40 g,

13.4 mmol) and dry triethylamine (1.34 g, 13.4 mmol) in dry ether (20 ml ).

On working up as above, the crude product was recrystallised (dichloromethane - light petroleum) to afford _N- (triphenylmethyl)pyruvamide

(239X3.56 g, 76%), m.p. 139-140°C, vmax (CI^Cl^ 3380 (s), 1710 (sh),

1680 (s), 1595 (m), 1490 (s), 1440 (s), 1360 (m), 1250 (s), 1185 (s),

1170 (s), 760 (s), 740 (s), 700 (s), and 630 (s) cm"1, 6 (CDC1 ) 2.46 O

(3H, s), and 7.20-7.28 (15H, m), m/e 329 (ft[t), 243, 182, and 105.

_N- (triphenylmethyl)pyruvamide (239) (3.29 g, 10 mmol) was converted to

the hydrazone (240) as above (5.0 g, 80%), m.p. 181-182°C

(ethanol-water), v (CH„C10) 3570 (m), 3500 (m), 3430 (m), 1695 (m), max 2 2

1 1500 (m), and 910 (m) cm" , 5 (CDC13) 1.06-1.33 (18H, m), 1.93 (3H, s),

2.93 (1H, m), 4.13 (2H, m), 7.16 (17H, m), 8.08 (1H, s), and 8.23 (1H, s) ,

m/e 313 (M+ - NHNSO^Ar), and 243 (Found: C, 71.07; H, 7.27; N, 6.52.

C H N 0 S.H 0 requires C, 70.78; H, 7.22; N, 6.69%). 37 4u 3 3 2 182.

Prcparation of 2,4 , 6-trimothoxybcnzylamine (247)

To a solution of 2,4 ,6-trimethoxybenzamidc (245) (1 g, 4.7 mmol) in dry THF (25 ml ) was added lithium aluminium hydride (1 g) . After refluxing for 10 h, the reaction mixture was allowed to cool to room temperature, and carefully poured into ice-water (50 ml ).

The aqueous phase was extracted with ether (3 x 20 ml) and the organic extracts dried (MgSO^) and concentrated in_ vacuo to afford a low melting solid, 2,4,6-trimethoxybenzylamine (247) (340 mg, 36%), v (CHC1 ) max

3400-3000 (brd, s), 1570 (s), 1490 (m) , 1440 (brd ), 1410 (m), 1200 (s),

1180 (s), 1140 (s), 1100 (s), 1050 (s) , 1030 (s), 945 (m), 900 (brd.),

1 and 810 (s) cm" , 6 (CDC1 o ) 1.51 (1H, s), 3.77 (11H, m), and 6.11 (2H, s) , m/e 196 (M+ - H), 182, 166, 151, 136, and 121. The crude product was used without further purification.

Preparation of N-(2,4,6-trimethoxybenzyl)pyruvamide 2,4,6-tri-iso- propylbenzesulphonylhydrazone (244)

A solution of 2,4,6-trimethoxybenzylamine (247) (300 mg, 1.5 mmol) and triethylamine (170 mg, 1.7 mmol) in dry ether (5 mis) was added to dry ether (20 mis) at -78°C at the same rate as a solution of pyruvyl chloride (232) (160 mg, 1.65 mmol) in dry ether (5 mis). Work up in the usual way afforded crude JN-(2,4,6-trimethoxybenzyl)pyruvamide (243)

(200 mg, 50%), v (CH CI ) 3410 (s) , 1720 (m), 1665 (s), 1600 (s), m ax z M

1505 (m) , 1200 (m), 1165 (m), 1150 (m), 1050 (s), 1030 (m), 945 (m),

1 and 810 (m) cm" ,

~~6Hz) , 6.06 (2H, s) , and 7.15 (1H, s) , m/e 267 (M*!*) , 196, 181, 136, and~~

~~121. The crude pyruvamide (243) (190 mg, 0.71 mmol) was~~

~~converted without further purification to the hydrazone (244) as for~~

~~(235); (123 mg, 51%), m.p. 197°C (d) (dichloromethane - light petroleum), v (CH CI )3420 (m), 1665 (s), 1605 (s), 1595 (s), 1505 (s), 1530 (brd ), max 2 2,~~

~~1200 (w), 1165 (m), 1150 (s), 1130 (s), 1030 (m), and 900 (brd.) cm"1, 183.~~

~~6 (CDC13) 1.16-1.40 (18H, m) , 2.06 (3H,s), 2.96 (lH,m), 3.80 (3H, s),~~

~~3.85 (3H, s), 4.10-4.50 (2H, m) , 4.46 (2H, d, J 5Hz), 6.13 (2H, s),~~

~~7.10 <1H, s), 7.13 (2H, s), and 8.16 (1H, s), m/e 503 (M+ - 44), and 251 (Found: C, 61.29; H, 7.56; N, 7.70. C H. N_0_S requires 28 41 3 b~~

~~C, 61.40; H, 7.55; N, 7.67%).~~

~~Preparation of N-allylpyruvamide 2,4,6-tri-iso-propylbenzenesulphonylhydrazone (238)~~

~~N-allylpyruvamide (237) was prepared as described above (50%),~~

~~b.p. 120°C (20 mmHg), v (CHC10) 3410 (s), 3310 (s), 1720 (s) , max 3~~

~~1680 (s) , 1520 (s) , 1420 (m) , 1355 (s) , 1260 (m) , 1170 (s) , 900 (m) ,~~

~~and 810 (s) cm"1, 6 (CDC1 ) 2.50 (3H, s), 3.88-4.11 (2H, m), 5.11-5.44 u~~

(2H,m), 5.66-6.15 (1H, m), and 7.10 (1H, s), m/e 127 (M*) (Found: M*

~~c H N0 127.0636. 6 9 2 requires M* 127.0633). The hydrazone (238) was prepared~~

~~in the usual way (54%), m.p. 173°C, (dichloromethane - light petroleum),~~

~~v m a.x (CHC1 ) 3380 (s), 3170 (s), 1660 (s), 1620 (w), 1600 (m), 1530 (m),~~

~~1430 (m), 1330 (m), 1270 (m), 1195 (m), 1170 (s), 1095 (s), 905 (s),~~

~~820 (m), and 735 (s) cm"1, 6 (CDC1 ) 1.26 (18H, d, J 7Hz), 2.00 (3H, s), o~~

~~2.93 (1H, m), 3.86 (2H, m), 4.22 (2H, m) , 4.97-5.33 (2H, m), 5.55-6.08~~

~~(1H, m), 6.80 (1H, s), 7.17 (2H, s) , and 8.25 (1H, s), m/e 283, 265,~~

~~251, 235, 185, 175, 161, 145 (Found: C, 61.57; H, 8.11; N, 10.25.~~

~~C21H33N3S03 requires C, 61.89; H, 8.16; N, 10.31%).~~

~~Preparation of N-(t-butyldimethylsilyl)pyruvamide 2,4,6-tri-iso-~~

~~propylbenzenesulphonylhydrazone (242)~~

~~To a solution of pyruvyl chloride (232) (1.31 g, 10 mmol) in dry~~

~~diethyl ether (30 ml ) at -78°C was slowly added a solution of triethyl- 112~~

~~amine (1.10 g, 11 mmol) and t^-butyldimethylsilylamine (1.31 g, 10 mmol)~~

~~in dry ether (10 ml ). After the addition was complete, the reaction~~

~~mixture was allowed to warm up to room temperature. The triethylamine 184.~~

~~hydrochloride was filtered off and the filtrate concentrated in vacuo.~~

Very rapid column chromatography (Kieselgel 60, 30g, eluant dichloromethane) afforded N-(t-butyldimethylsilyl)pyruvamide (241) (1.32 g, 65%); m.p. 51.5-53.5°C (sublimation; 100°C, 20 cmHg), v (Nujol) 3360 (m) , max

~~3270 (m), 1720 (s), 1685 (m), 1235 (s), 1000 (m), 970 (m), 855 (m),~~

~~1 830 (s), 780 (s), 755 (m), and 720 (m) cm" , 6 (CDC13) 0.27 (6H, s) ,~~

~~0.99 (9H, s), and 2.39 (3H, s), m/e 202 (M+ + H), 186, 158, 144, 115, and~~

~~73. A solution of (241) (770 mg, 3.88 mmol) and 2,4,6-tri-iso- propylbenzenesulphonylhydrazine (1.11 g, 3.88 mmol) (231) in dry dichloromethane (20 ml) was stirred overnight at room temperature.~~

~~The solvent was removed iri vacuo, rapid column chromatography of the~~

~~residue (Kieselgel 60, 30g, eluant dichloromethane) afforded the title~~

~~compound (242) (580 mg, 30%) as a white crystalline solid, m.p. 101-103°C~~

~~(dichloromethane - light petroleum), v (Nuiol) 3380 (m), 3360 (w), max~~

~~3230 (s), 1670 (s), 1600 (m), 1250 (m) , 1160 (s), 1150 (m), 1100 (m),~~

~~1 860 (m), 850 (m), 840 (s), 785 (m), and 680 (s) cm" ,6 (CDC1 o) 0.18~~

~~(6H, s), 0.85 (9H, s), 1.20-1.38 (18H, m) , 2.02 (3H, s), 2.73-3.15 (lH,m),~~

~~4.08-4.47 (2H, m), 6.31 (1H, s), 7.24 (2H, s), and 8.38 (1H, s), m/e~~

~~457 (M+ - Me), 424, 396, 383, 367, 325, 261, 250, 233, 191, and 91~~

~~(Found: C, 60.09; H, 8.92; N, 8.77. C ZriH N O0 J SSi requires C, 59.83;~~

~~H, 9.08; N, 8.72%).~~

~~Preparation of N-cyclohexyl-3-hydroxy-2-methylenehexamide (249)~~

~~To a solution of the hydrazone (221) (449 mg, 1 mmol) in dry DME~~

~~(15 ml ) at -78°C was added n-butyllithium (3.3 mmol). The orange-red~~

~~coloured solution was allowed to warm up to room temperature (60 min),~~

~~during which time, the reaction mixture turned golden-yellow in colouration.~~

~~After stirring at room temperature for 30 min, the reaction mixture~~

~~was cooled to -78°C and freshly redistilled butanal (0.09 ml , 1 mmol)~~

~~was added. The reaction mixture was allowed to warm up to room 185.~~

~~temperature ( 15 min ), and the solvent was removed ir^ vacuo. The residue was partitioned between water (10 ml ) and ether (20 ml ).~~

~~The etheral layer was separated, dried (MgSO^) and concentrated in vacuo.~~

Column chromatography (Kieselgel H, lOg, eluant dichloromethane) afforded the title compound (249) (188 mg, 83%), as a white crystalline solid, m.p. 103-104°C (dichloromethane - light petroleum), v (Nujol) max

~~3360 (brd.), 3300 (s), 1655 (m), 1620 (s), 1540 (m), 1120 (m), 985 (m),~~

~~and 930 (m) cm"1, 6 (CDC1 ) 0.90-2.10 (17H, m), 3.66-4.11 (2H, m), o~~

~~4.22-4.53 (1H,m), 5.40 (1H, s), 5.75 (1H, s), and 6.90 (1H, d, J 8Hz),~~

~~+ m/e 225 (M*) , 207 (M - HO)dL , 182, and 126 (Found: C, 69.20; H, 10.38,~~

~~c H N0 re( uires C N, 6.10. 13 23 2 l > 69.29; H, 10.29; N, 6.22%).~~

~~Preparation of N-cyclohexyl-3-hydroxy-2-methylenedecanamide (250)~~

~~To a solution of the hydrazone (221) (898 mg, 2 mmol) in dry~~

~~DME (20 ml ) at -78°C was added n-butyllithium (6.6 mmol). The red-~~

~~coloured solution was allowed to -warm up to room temperature as above~~

~~o o and recooled to -78 C. n-Octanal (0.32 mis, 2 mmol) was added at -78 C.~~

~~Work up and column chromatography (Kieselgel H, lOg, eluant dichloromethane)~~

~~afforded the title compound (250) (395 mg, 70%), m.p. 84.5-85.5°C~~

~~(dichloromethane - light petroleum), v (CH CI ) 3300 (brd.), 1650 (s) , max & &~~

~~1610 (s), 1520 (s), 1440 (m), 1210 (m) , 1185 (s), 1125 (brd.), and 810 (m)~~

~~1 cm" , 5 (CDC13) 0.8-2.0 (25H, m), 3.62-4.04 (2H, m), 4.15-4.68 (1H, m),~~

~~5.40 (1H, s), 5.77 (1H, s), and 6.90 (1H, d, J 8Hz), m/e 263 (M+ - HO),~~

~~220, and 164 (Found: C, 72.55; H, 11.25; N, 4.87. C H ND requires 1 / ol &~~

~~C, 72.55; H, 11.10; N, 4.98%).~~

~~Preparation of N-cyclohexyl-3-hydroxy-2-methylenebutanamide (248)~~

~~To a solution of the hydrazone (221) (449 mg, 1 mmol) in dry DME~~

~~(15 ml ) at -78°C was added n-butyllithium (3.3 mmol). The red-coloured~~

~~solution was allowed to warm up to room temperature and then recooled to~~

~~-78°C. After quenching with acetaldehyde (0.1 ml , 2 mmol) and work up 186.~~

~~In the usual way, column chromatography (Kieselgel H, 8g, eluant dichloromethane) afforded the title compound (248) (146 mg, 74%), ra.p.~~

~~100-102°C (dichloromethane - light petroleum), v (Nujol) 3350 (brd.), max~~

~~3300 (s), 1660 (m), 1615 (s), 1530 (s), 1110 (s), and 930 (s) cm"1,~~

~~6 (CDC1 ) 1.10-2.05 (13H, m) , 3.40-3.93 (1H, m), 4.04-4.26 (1H, m),~~

~~4.46-4.77 (1H, m), 5.42 (1H, s), 5.72 (1H, s), and 6.90 (1H, s), m/e~~

~~197 (M*) , 182 (M+ - Me), 179, 136, and 98 (Found: C, 67.01; H, 9.84;~~

~~N, 6.94. C JL JHL lb/NO & requires C, 66.97; H, 9.71; N, 7.10%).~~

~~Preparation of l-cyclohexyl-3-methylene-4-n-propylazetidin-2-one (253)~~

~~a. To a solution of the hydroxy-amide (249) (112 mg, 0.5 mmol) in dry~~

~~THF (10 ml ) at -78°C was added n-butyllithium (1.1 mmol). The reaction~~

o mixture was allowed to warm up to 0 C (15 min) and then recooled to -78°C. Toluene-4-sulphonic anhydride (220 mg) in dry THF (2 ml ) was added at -78°C. After allowing to warm up to room temperature overnight, the reaction mixture was poured into water (10 ml ) and extracted with ether (2 x 15 ml ). The combined organic extracts were dried

(MgSO^) and concentrated in vacuo. Chromatography (pic , Kieselgel H, developer dichloromethane) afforded the title compound (55.6 mg, 55%), as a viscous oil, v (CH C1J 1730 (s), 1700 (s), 1370 (s), 1250 (brd.), max 2 2

~~1105 (m) , 1070 (m) , 985 (m) , 950 (m) , 920 (s) , and 890 (s) cm"1,~~

~~6 (CDC13) 0.85-2.05 (17H, m), 3.33-3.73 (1H, m), 3.97-4.25 (1H, m),~~

~~5.06 (1H, m), and 5.27 (1H, m), m/e 207 (M*), 164, and 126, (Found:~~

~~C, 74.86; H, 10.39; N, 6.72. C H NO requires C, 75.32; H, 10.21;~~

~~N, 6.70%). b. To a solution of the hydroxyamide (249) (225 mg, 1 mmol) in dry THF~~

~~(10 ml ) at -78°C was added n-butyllithium (2.2 mmol), after allowing to warm up to 0°C and recooling to -78°C, toluene-4-sulphonyl chloride~~

~~(480 mg) in dry THF (2 ml ) was added. After allowing to warm up to~~

~~room temperature overnight, the reaction mixture was poured into water 187.~~

(10 ml ) and extracted with ether (2 x 25 ml ). The combined organic extracts were dried (MgSO^) and concentrated iri vacuo. Column chromatography of the residue [Kieselgel H, 15 g, eluant light petroleum - dichloromethane (2:1)] afforded N-cyclohexyl-3-chloro-2 methylenehexanamide

~~(256) (79.8 mg, 32%), m.p. 92-94°C (dichloromethane -light petroleum),~~

~~V 3410 (s), 1650 (s), 1620 (s), 1490 (m), 1445 (s), 1200 (brd.), and m ax~~

~~1100 (brd.) cm"1, 6 (CDC1 ) 0.85-2.10 (17H, m), 3.60-4.06 (1H, m), u~~

~~4.82 (1H, t, J 6Hz), 5.57 (1H, s), 5.68 (1H, s), and 6.05 (1H, brd. d,£~~

~~10Hz), m/e 243, 245 (M*) , 208, 162, and 126 (Found: C, 64.18; H, 9.24;~~

~~N, 5.70. C H C1N0 requires C, 64.05; H, 9.09; N, 5.75%) and the JLo ZZ~~

~~3-lactam (253) (88 mg, 42%), with spectral data as before.~~

~~Preparation of 1-cyclohexyl-4-n-heptyl-3-methyleneazetidin-2-one (254)~~

~~To a solution of the hydroxy-amide (250) (295.5 mg, 1.12 mmol) in dry THF (15 ml ) at -78°C was added n-butyllithium (2.46 mmol), after~~

~~o o allowing to warm up to 0 C and recooling to -78 C, toluene-4-sulphonic~~

~~anhydride (456»4 mg) in dry THF (5 ml ) was added. After allowing to~~

~~warm up to room temperature overnight and workup in the usual way,~~

~~chromatography ( pic , Kieselgel H, developer dichloromethane) afforded~~

~~the title compound (254) (147.5 mg, 57%), v (CH CI ) 1730 (s), max Z. /~~

~~1 1700 (m), 1450 (brd.), 1360 (brd.), 920 (s), and 890 (m) cm" , 6 (CDC13)~~

~~0.80-2.05 (25H, m) , 3.31-3.71 (1H, m) , 4.04-4.18 (1H, m), 5.04 (1H, s),~~

~~and 5.60 (1H, s), m/e 263 (M^),173,164, and 138 (Found: C, 77.14; H, 11.33;~~

~~N, 5.25; m"* 263.2257. C H NO requires C, 77.51; H, 11.10; N, 5.23%, I~~

~~M* 263.2249).~~

~~Preparation of l-cyclohexyl-4-methyl-3-methyleneazetidin-2-one (252)~~

~~To the hydroxy-amide (248) (81 mg, 0.41 mmol) in THF (10 ml ) at~~

~~-78°C was added n-butyllithium (0.91 mmol). The reaction mixture was~~

~~allowed to warm up to 0°C and then recooled to -78°C. Toluene-4-~~

~~sulphonyl chloride (100 mg) in dry THF (5 ml ) was added and the reaction 188.~~

mixture allowed to warm up to room temperature overnight. Work up and chromatography (pic , Kieselgel H, developer dichloromethane) afforded the title compound (252) (47.6 mg, 64%) as a viscous oil, v (CH CI ) 1730 (s), 1700 (m) , 1510 (brd.), 1370 (s), 1250 (brd.), max A A

~~1100 (s), 1030 (m) , 980 (m) , 920 (s) , and 890 (s) cm""1, 6 (CDC1 ) o~~

~~1.10-2.05 (13H, m), 3.31-3.93 (1H, m), 3.93-4.36 (1H, m), 5.00 (1H, s), and 5.53 (1H, s), m/e 197 (M*) , 136, and 98. (Found: C, 74.03; H, 9.70;~~

~~N, 7.98, Mt 179.1310. C^-^^0 requires C, 73.74; H, 9.50; N, 7.82%,~~

~~M* 179.130).~~

~~Attempted preparation of the dianion (263)~~

~~a. To a solution of the hydrazone (240) (609 mg, 1 mmol) in dry~~

DME (15 ml ) at -78°C was added n-butyllithium (3.3 mmol). The deep red coloured solution was stirred at -78°C for 20 min, and allowed to warm up to room temperature. The brown coloured reaction mixture was recooled to -78°C, and deuterium oxide (3 mmol) added. The red-brown colouration was not discharged. On allowing to warm up to room temperature, the

~~reaction mixture was poured into water (10 ml ) and extracted with ether~~

~~( 2 x 25 ml ). The combined organic extracts were dried (MgSO^) and~~

~~concentrated iii vacuo. Column chromatography (x 3) (Kieselgel H, 10 g )~~

~~afforded starting material (233 mg, 36%) (240), with little or no~~

~~deuterium incorporation (nmr) and a foam probably the hydroxy-hydrazone~~

~~(264)(36 mg, 6%), v (CH Cl0) 3590 (m) , 3400 (m) , 3220 (brd. m) , max 2 2~~

~~1665 (s), 1600 (m), 1490 (m), 1420 (brd.), 1330 (m), 1160 (m), 1100 (m),~~

~~1030 (m), 900 (m), and 830 (m), 5 (CDC1 ) 1.11, 1.15 (18H, 2xd, J 9, 9Kz), o~~

~~2.70-3.10 (1H, m), 3.80-4.20 (2H, m) , 4.55 (1H, s), 7.10-7.40 (17H, m) ,~~

~~and 8.11 (1H, s), m/e 512, and 329 (M+ - N = NHSO Ar). Ci~~

~~b. On repeating the above experiment using 5.5 equivalents of n-butyl-~~

~~lithium, on the same scale, starting material (267 mg) (240) and the~~

~~hydroxy-amide (264) (88 mg) were isolated. 189.~~

~~Attempted trapping of the ciianion (268)~~

~~a. To a solution of the hydrazone (242) (240 mg, 0.5 mmol) in dry DME~~

(15 ml ) at -78°C was added n-butyllithium (3.3 mmol). The lime-yellow reaction mixture was allowed to warm up to room temperature (^60 min) and recooled to -78°C. Freshly redistilled butanal (0.05 m] ) was added. After allowing the reaction mixture to warm up to room temperature,, the solvent was removed jln vacuo and the residue partitioned between water (10 ml ) and ether (20 ml ). The organic layer was dried (MgSO^); concentration jin vacuo and column chromatography [Kieselgel H, 8g, eluant diethylether - dichloromethane (1:5)] afforded a volatile liquid, probably containing the desired product,(269) m/e 258 (M+ + 1).

~~Attempts to isolate the material were unsuccessful.~~

~~b. The di-anion (268) was quenched with n-octanal. Chromatography as~~

~~above afforded an impure polar fraction (94 mg), probably containing~~

~~3-hydroxy-2-methylenedecanamide (270), v (CH CI ) 3550 (m), 3530 (m) , * max z ct~~

~~3500 (m), 3410 (m), 3370 (m), 1680 (s), 1635 (s), and 1590 (s) ,~~

~~6 (CDC1 ) 0.85 (3H, m), 1.20-1.80 (15H, m), 3.0 (1H, s), 4.35 (1H, t, o~~

~~J 6Hz), 5.50 (1H, s), and 5.88 (IE, s), m/e 181 (M+ - HO), and 100.~~

~~Preparation of N-cyclohexyl ethyl oxamate (272)~~

~~To diethyl oxalate (7.3 g, 50 mmol) in ethanol (20 ml) was added~~

~~cyclohexylamine (5 g, 50 mmol). After stirring at room temperature for~~

~~10 min, a white solid was precipitated, (2 g), identified as N, N'-~~

~~dicyclohexyloxamate (273), m.p. >230°C (ethanol), v (Nuiol) 3300 (s), max~~

~~1650 (s), and 1520 (s), 5 (CDC13) 1.15-2.05 (10H, m), 3.75 (1H, m), and~~

~~7.40 (1H, s), m/e 252 (M*) , and 126 (Found: C, 66.61; H, 9.61; N, 11.12.~~

~~C14H24N2°2 recluires c> 66.63; H, 9.59; N, 11.10%). The mother liquor~~

~~was concentrated iri vacuo, the resultant oil was triturated with light~~

~~petroleum (20 ml), affording the title compound (.272) (2.5 g, 25%), 190.~~

~~o m.p. 62-63 C (dichloromcthane - light petroleum), v (Nujol) 3280 (s), max~~

~~1730 (m) , 1660 (s) , 1530 (m) , 1240 (s) , 1200 (s) , and 1115 (s) cm"1,~~

~~5 (CDC13) 1.08-2.08 (13H, m), 3.78 (1H, m), 4.25 (2H, q, J 7Hz), and~~

~~6.92 (1H, s), m/e 199 (M.+ ) , 118, and 83 (Found: C, 60.07; H, 8.60;~~

~~N, 6.99. C i.UH -L /ND O requires C, 60.28; H, 8.60; 7.07%).~~

~~Preparation of N-cyclohexyl-2-oxo-pentanamide (275)~~

~~To a solution of the oxamide (272) (597 mg, 3 mmol) in dry THF (20 ml) at -78°C was added n-butyllithium (6.6 mmol). The resulting white~~

~~o o suspension was stirred at -78 C for 3 h and quenched at -40 C with~~

~~6M hydrochloric acid (10 ml). On warming up to room temperature, ether~~

~~(20 ml) was added, and the organic layer separated and dried (MgSO^).~~

~~Concentration in vacuo afforded the crude product, column chromatography~~

~~(Kieselgel H, 10 g) afforded the title compound (275) (131 mg, 21%) as a low melting solid, v (CH C1 ) 3310 (m), 1715 (m), 1650 (s), and 1420 max 20 02~~

~~(m), 5 (CDC1 ) 0.90-2.30 (17H, m), 2.75 (2H, t, J 6Hz), 3.90 (1H, m) , o and 7.00 (1H, brd. s), m/e 211 (M*) and 83.~~

~~Preparation of N-(t-butyl)-3-hydroxy-2-methylenepentanamide (260)~~

~~To a solution of the hydrazone (236) (425 mg, 1 mmol) in dry DME ,v~~

~~(20 ml) at -78°C was added n-butyllithium (2.35 ml, 1.4 M). The lime- yellow coloured solution was slowly allowed to warm up to room temperature~~

~~(1 h) and then recooled to -78°C. Freshly redistilled n-propanal~~

~~(66 mg, 1.1 mmol) was added and the reaction mixture allowed to warm up to room temperature (15 min ). Work up in the usual way and chromatography~~

~~[pic, silica, developer ether-dichloromethane (1:9)1 afforded the title compound (260) (83 mg, 45%), as a viscous oil, v (CH„C1„) 3300 (s), max 2 2~~

~~1715 (s), 1620 (s), and 1500 (s), 6 (CDC13) 0.93 (3H, t, J 7Hz),~~

~~1.36 (9H, s), 1.4-1.8 (2H, m) , 4.15 (2H, m), 5.28 (1H, m) ,~~

~~5.68 (1H, m) , and 6.8 (1H, s) , m/e 185 (M**) , 167, 156, 100, and 58~~

~~+ + (Found: M 185.1416. C10H19N02 requires M 185.1416). 191.~~

~~SECTION L\: OTHER N1-C4 CYCLISATION REACTIONS~~

~~Preparation of N-benzyl-3-hydroxybutanamide (284)~~

~~To N-benzylacetamide (600 mg, 4 mmol) in dry THF (20 ml) at -10°C was added n—butyllithium (6.5 ml, 1.40 M), over a period of ten min.~~

After stirring at -10°C for 30 min the resulting red-brown coloured solution was cooled to -78°C, and acetaldehyde (0.22 ml, 4 mmol) in dry THF (5 ml) was added in one go. After stirring at -78°C for one mia acetic acid (0.6 ml, 4 mmol) was added and the reaction mixture allowed to warm up to room temperature. After removing the solvent iji vacuo, the resulting residue was triturated with dichloromethane (2 x 25 ml) and filtered. The combined filtrate was concentrated in vacuo.

~~Column chromatography (Kieselgel H, 8g, eluant dichloromethane) afforded the title compound (284) (391 mg, 51%), m.p. 62-63.5°C (ether), v " m cix~~

~~(Nujol) 3300 (s), 1645 (s), 1560 (s), 1435 (s), 1215 (w), 1200 (w),~~

~~1140 (s), 1100 (w), 1085 (w), 1075 (w), 1035 (m), 950 (m), 850 (m), 745~~

~~(m) , 725 (m), and 700 (iii) , 6 (CDC13) 1.20 (3H, d, J 6Hz) , 2.33 (2H, m) ,~~

~~3.68 (1H, brd.s), 4.06-4.35 (1H, m) , 4.44 (2H, d, J 5Hz), 6.48 (1H, brd. s),~~

~~and 7.35 (5H, s), m/e 192 (M+ - H), 148, 106, 91 and 71 (Found: C, 68.37;~~

~~H, 7.86; N, 7.31. CH^NO^ requires C, 68.37; H, 7.32; N, 7.25%). 11 15 2,~~

~~Preparation of N-phenyl-3-hydroxybutanamide (283)~~

~~To a solution of _N-phenylacetamide (540 mg, 4 mmol) in dry THF~~

~~(20 ml) at 0°C was added n-butyllithium (6.0 ml, 1.4 M). The resulting~~

~~o o dianion was stirred at 0 C for 20 min and then cooled to -78 C.~~

~~Freshly redistilled acetaldehyde (176 mg, 4 mmol) in dry THF (5 ml)~~

~~was then added. After stirring at -78°C for 15 min , the reaction~~

~~o o mixture was allowed to warm up to 0 C. After recooling to -78 C, acetic~~

~~acid (0.6 ml, 4 mmol) was added, and the mixture allowed to warm up~~

~~to room temperature. The reaction mixture was poured into water (20 ml)~~

~~and extracted with dichloromethane (2 x 25 ml). The combined organic 192.~~

~~extracts wore dried (MgSO^) and concentrated iri vacuo. Recrystallisation~~

~~from light petroleum and dichloromethane afforded the title compound (283)~~

~~(130 mg, 18%), m.p. 105°C, v (Nujol) 3300 (m), 3250 (m), 3200 (m), max~~

~~3140 (m), 3100 (m), 1685 (s), 1670 (s), 1625 (m), 1615 (s), 1605 (s),~~

~~1560 (s), 1500 (s), 1325 (m), 1260 (m) , 1140 (s), 1065 (m), 980 (m) ,~~

~~940 (m), 900 (m), 870 (m) , 760 (s) , and 695 (m), 6 (CDC1 o ) 1.26 (3H, d,~~

~~J 6Hz), 2.45 (2H, m), 3.45 (1H, s) , 4.29 (1H, m), 7.05-7.60 (5H, m),~~

~~and 8.10 (1H, brd. s), m/e 179 (Mt), and 93 (Found: C, 66.81; H, 7.27;~~

~~N, 7.95. C H NO requires C, 67.02; H, 7.31; N, 7.82%). 10 15 2~~

~~Preparation of N-benzyl-3-(toluene-4-sulphonyloxy)butanamide (300)~~

~~To a solution of hydroxy-amide (284) (193 mg, 1 mmol) in dry THF~~

~~(20 ml) at -78°C was added n-butyllithium (0.7 ml, 1.47 M) . After~~

~~allowing to warm up to 0°C, the pale yellow solution was recooled to -78°C~~

~~and toluene-4-sulphonyl chloride (0.212 g) in THF (5 ml) was added.~~

~~After allowing to warm up to room temperature (30 min ) , work, up and~~

~~chromatography in the usual way afforded the title compound (300)~~

~~(251 mg, 78%), as a viscous oil, v (CHC1 ) 3420 (m), 1655 (s) , 1595 (m) , max 3~~

~~1350 (m), and 890 (s), 6 (CDC1 ) 1.30 (2H, d, J 7Hz), 2.50 (5H, m), 4.11 o~~

~~(2H, d, J 6Hz), 5.13 (1H, q, J 6Hz), 6.60 (1H, brd. s), 7.50 (7H, m),~~

~~and 8.00 (2H, d, J 8Hz), m/e 347' (M*) , 175, 160, 106, and 91.~~

~~Attempted preparation of l-benzyl-4-methylazetidin-2-one (286)~~

~~a. JN-benzylacetamide (600 mg, 4 mmol) was dissolved in dry THF (20 ml)~~

~~and the resulting solution cooled to 0°C. n-Butyllithium (5.9 ml, 1.47 M)~~

~~was added over a period of 10 min. at 0°C, affording a deep red coloured~~

~~solution. On cooling to -78°C, freshly redistilled acetaldehyde~~

~~(0.2 ml, 4 mmol) was added in one go. The pale yellow coloured reaction~~

~~mixture was allowed to warm up to 0°C (10 min ) and then recooled to -78°C.~~

~~Toluene-4-su1phony1 chloride (960 mg) in dry THF (5 ml) was added at -78°C. 193.~~

~~After allowing to warm up to room temperature overnight, the reaction mixture was poured into water (20 ml) and extracted with ether (2 x 25 ml) .~~

~~The combined organic extracts were dried (MgSO^) and concentrated iii vacuo~~

~~to afford the crude product. Column chromatography (Kieselgel H, 8g,~~

~~eluant dichloromethane) afforded N-benzyltoluene-4-sulphonamide (295)~~

~~o 136 o (45 mg, 4.3%, m.p. 112 C) (Lit. m.p. 114 C) , v (Nujol) 3270 (m) , max~~

~~1600 (m) , 1175 (m) , 1160 (s) , 1090 (m) , 1080 (m) , 1055 (m) , 870 (m) ,~~

~~1 810 (m), 740 (m), and 700-660 (multiplet, m) cm" , 5 (CDC1 O ) 2.33 (3H, s) ,~~

~~4.16 (2H, d, J 6Hz), 5.41 (1H, m), 7.30-7.56 (7H, m), and 7.93 (2H, d, J~~

~~+ 9Hz), m/e 261 (M«), 106, and 91, identical with an authentic sample,~~

~~and E-N-benzylbut-2-enamide (296) (175 mg, 10%), v (Nuiol) 3420 (m) , max~~

~~3270 (s), 1670 (s), 1630 (s), 1550 (s), 1260 (m), 1230 (m), 1080 (m), 1045~~

~~1 (m), 1030 (m), 970 (m), 730 (s), 700 (s), and 685 (s) cm" , 6 (CDC1 J )~~

~~1.82 (3H, d d, J_ 7 j 2 Hz), 4.49 (2H, d, J 7Hz) , 5.84-6.13 (1H, m) ,~~

~~6.50 (1H, brd. s) , 6.75-7.15 (1H, m) , and 7.37 (5H, s) , m/e 175 (MO ,~~

~~160. 106, 91, and 69, identical with an authentic sample.~~

~~b. Hydroxy-amide (284) (193 mg, 1 mmol) was dissolved in dry dichloro-~~

~~methane and DMF (20 ml, 1:1 v/v); on cooling to 0°C sodium hydride~~

~~(52 mg), imidazole (5 mg) and tetra-n-butylammonium iodide (10 mg) were~~

~~added. The reaction mixture was stirred overnight at room temperature~~

~~and toluene-4-sulphonyl chloride (190 mg) in dry DMF (5 ml) was added.~~

~~After 60 h. all the starting material had been consumed. The reaction~~

~~mixture was carefully poured into ice-water (20 ml) and extracted with~~

~~dichloromethane (2 x 30 ml). The combined organic extracts were dried~~

~~(MgSO^) and concentrated in vacuo. Chromatography (pic, Kieselgel H,~~

~~developer ether) afforded amide (296) (20 mg, 11%) and an oil, probably~~

~~containing compound (302) (25 mg, 12%), v max (CH CI z ) 1645 (s), 1490 (m)~~

~~1470 (m), 1355 (s), 1140 (s), 1120 (s), 1060 (m), 945 (m), 930 (m), 900 (s)~~

~~and 835 (m) cm"1, 5 (CDC1 ) 1.31 (3H, d, J 6Hz), 2.46 (2H, m), 3.80-4.20 o 194.~~

~~(1H, m), 4.41, 4.90 (2H, AB q, J 16Hz), 4.75 (2H, s), and 7.34 (5H, s) , m/e 205 (M*) , 160, 114, and 91.~~

c. Tosylate (300) (271 mg, 0.78 mmol) was dissolved in DMF (10 ml) and the solution cooled to 0°C. Sodium hydride (20 mg, 1.1 mmol) and imidazole (5 mg) were added. After stirring overnight, the reaction mixture was poured into ice-water (20 ml), extracted with dichlororaethane

~~(2 x 20 ml) and the combined organic extracts dried (MgSO^). Concentration in vacuo afforded the crude product (109 mg), which was essentially the amide (296) (nmr).~~

d. Hydroxy-amide (284) (193 mg. 1 mmol) was dissolved in dry THF (15 ml) and cooled to -78°C. n-Butyllithium (1.54 ml, 1.35 M) was added, after stirring for 10 minutes, toluene-4-sulphonyl chloride (285 mg) in dry THF

~~(5 ml) was added, and the reaction mixture allowed to warm up to room temperature overnight. After the usual workup and chromatography~~

~~(p 1 c , developer ether) afforded an inseparable mixture (50 mg) of~~

~~(300) and (296) [(296):(300) ^2:3, nmr].~~

e. Hydroxy-amide (284) (386 mg, 2 mmol) was dissolved in dry THF (15 ml) and cooled to -78°C. n-Butyllithium (1.43 ml, 1.4 M) was added at -78°C and after stirring for 10 min, toluene-4-sulphonyl chloride (475 mg) was added, and the reaction mixture allowed to warm up to 0°C. Sodium hydride (100 mg) was then added. After stirring at room temperature for

~~12 h , the usual work up followed by chromatography [Kieselgel H, lOg, eluant light petroleum - dichloromethane (2:1)] afforded~~

~~E-[N-(toluene-4-sulphonyl)]-N-benzylbut-2-enamide (305) (60 mg, 9%), as a viscous oil v (CHCl )1680 (s) , 1640 (s), 1605 (m), and 1340 (s), max 3o~~

~~6 (CDC13) 1.80 (3H, d, J 6Hz), 2.40 (3H, s), 5.40 (2H, s), 6.55-7.12~~

~~(2H, m), 7.17-7.46 (7H, m), and 7.65 (2H, d, J 8Hz), m/e 330 (M+ + H),~~

~~174, 158, 106, and 91 (Found: C, 65.72; H, 5.84; N, 4.26. C^-H-KBO,, 18 19 3 195.~~

~~requires C, 65.63; H, 5.81; N, 4.25%) and the tosylate (300) (187 mg,~~

~~27%). The chloro-amide (306) was also present in trace amounts (m/e,~~

~~M* 211, and 213).~~

f. Sodium hydride (96 mg, 4 mmol) was dissolved in dry dimethyl sulphoxide (30 ml) at 80°C under an atmosphere of dry nitrogen. On cooling to room temperature, an aliquot of this solution (6 ml) was slowly added to a solution of the tosylate (300) (187 mg, 0.54 mmol) in dry THF (5 ml) at 0°C. After allowing to warm up to room temperature, the crude reaction mixture was poured into water (20 ml) and extracted with ether (2 x 20 ml). The combined organic extracts were dried

~~(MgSO^) and concentrated iii vacuo. Column chromatography of the residue~~

~~(Kieselgel H, 8g) afforded a mixture (37 mg) of the 3-lactam (286) and the~~

~~amide (296) [(236) : (296)^ 2 :1 nmr^j. The presence of the 3-lactam(286) was inferred by the following spectral data! v max (CHC1 u ) 1730 cm \~~

~~6 (CDC1 ) 1.21 (3H, d, J 6Hz), 2.52 (1H, dd, J 14, 2Hz, C -H), 3.07 o o~~

~~(1H, dd, J 14, 5Hz, C -H), 3.60 (1H, m, C -H), 4.14 (1H, d, J 16Hz, O fx~~

~~PhCH -), and 4.63 (1H, d, J 14Hz, PhCH -), m/e 175 (M*) , and 133. £» dk~~

~~Attempted generation of the tri-anion (319)~~

~~A solution of the hydroxy-amide (284) (193 mg, 1 mmol) in dry THF~~

~~(20 ml) was cooled to 0°C and n-butyllithium (2.44 ml, 1.35 M) , was~~

~~added over 5 min.~~

~~The resulting brown coloured solution was stirred at 0°C for 30 min. ,~~

~~and deuterium oxide (0.05 ml, 2.8 mmol) was added. After allowing to~~

~~warm up to room temperature, the solvent was removed under reduced~~

~~pressure and the residue titurated with dichloromethane (2 x 25 ml).~~

~~The combined organic extracts were filtered through Celite, and concentrated~~

~~in vacuo. Chromatography (pic, Kieselgel H, eluant dichloromethane)~~

~~afforded starting material (284) (57 mg, 30%) as the major product. The H nmr indicated no deuterium incorporation.~~

~~Attempted preparation of the tosylate (309)~~

~~a. ^-benzylacetamide (600 mg, 4 mmol) in dry THF (20 ml) was cooled to~~

~~0°C and n-butyllithium (6 ml, 1.4 M) was added over a period of 5 min~~

~~followed by benzaldehyde. After stirring for 20 min at 0°C, the~~

~~reaction mixture was cooled to -78°C and acetic acid (0.24 ml, 4 mmol)~~

~~was added. After stirring at -78°C for 10 min toluene-4-sulphonyl~~

~~chloride (988 mg, 5.2 mmol) in dry THF (5 ml) was added. After work up in~~

~~the usual way, ^H nmr of the crude product indicated the presence of~~

~~the tosylate (309), the chloride (310) and the amide (307). Column~~

~~chromatography (Kieselgel H, lOg) afforded a mixture (483 mg) of the~~

~~amide (307) and the chloride (310).~~

~~123~~

~~b. Hydroxy-amide (285) (510 mg, 2 mmol) in dry THF (20 ml) was cooled to~~

~~0°C and n-butyllithium (1.4 ml, 1.47 M) was added over a period of 5 min~~

~~On cooling to -78°C, toluene-4-sulphonyl chloride (464 mg, 2.44 mmol)~~

~~was added in dry THF (5 ml). The reaction mixture was allowed to warm~~

~~up to room temperature (40 min ), and was poured into water (20 ml) and~~

~~extracted with ether (2 x 25 ml). The combined organic extracts were~~

~~dried (MgSO^) and concentrated in. vacuo. Careful column chromatography~~

~~[Kieselgel H, lOg, eluant benzene-dichloromethane (2:1)] afforded N-benzyl-~~

~~3-chloro-3-phenylpropanamide (310) (17 mg, 3.7%), m.p. 120.5-122°C~~

~~(light petroleum-ether) (lit13m.p. 116°C), v (CHC1 ) 3460 (m), max o0~~

~~1 1680 (s), and 1500 (m) cm" , 6 (CDC13) 2.91 (2H, m), 4.37 (2H, d, J 5Hz),~~

~~5.36 (a'H, d J 6Hz) , 5.44 (|H, d, J 7Hz) , 6.00 (1H, brd. s) , and 7.10-7.40~~

~~(10H, m), m/e 273, 275 (M*) , 237, 104, 106, and 91 (Found: C, 70.20,~~

~~C H C1N0 c H, 5.91; N, 5.02. Calculated for 16 16 > 70.20; H, 5.89;~~

~~N, 5.127o) and a mixture (228 mg) of the chloro-amide, (310) and the amide~~

~~(307) [(307) : (310) 1:3, nmr"]. 197.~~

~~Attempted preparation of N-benzyl-3-methanesulphonyloxy-3-phenylpropanamide (311)~~

a. To a solution of the anion (308) (1 mmol) in dry THF (15 ml) was added methanesulphonyl chloride (0.11 g, 0.08 ml) at -78°C. After allowing to warm up to room temperature, and work up in the usual way, 1 the H nmr indicated the presence of the mesylate (311) (m, 6 5.8), the chloro-amide (310) and starting material. No elimination product (307) was observed. b. To a solution of the anion (308) (1 mmol) in dry THF (20 ml) was added methanesulphonic anhydride (200 mg, 1.14 mmol) in dry THF (5 ml) at -78°C. After allowing to warm up to room temperature, and after 1 workup in the usual way, the H nmr spectrum indicated the presence of the mesylate (311) and the amide (307). Column chromatography

~~(Kieselgel H, lOg, eluant light petroleum - dichloromethane) afforded the amide (307) (31 mg, 13%).~~

~~Preparation of l-benzyl-4-phenylazetidin-2-one (287)~~

a. J^-Benzylacet amide (600 mg, 4 mmol) was dissolved in dry THF and cooled to -0°C. n-Butyllithium (5.87 ml, 1.47 M) was added at 0°C over a period of 10 min. The resulting red coloured solution was

~~stirred at 0°C for 30 min , and freshly redistilled benzaldehyde (0.4 ml,~~

~~4 mmol) was added. After stirring at 0°C for 30 min , the yellow coloured~~

~~solution was cooled to -78°C, and toluene-4-sulphonyl chloride (998 mg,~~

~~5.17 mmol) in dry THF (5 ml) was added. After allowing to warm up to~~

~~room temperature overnight the reaction mixture was worked up in the usual way. Column chromatography (Kieselgel H, 8g) afforded compound~~

~~(295) (232 mg, 22%) and the amide (307) (284 mg, 30%), identical (ir, nmr,~~

~~ms) to an authentic sample. Trace amounts of the 3-lactam (287), were~~

~~also observed in the reaction mixture (ir, \> 1735 cm . ' m o -v 198.~~

b. Hydroxy-amide (285) (255 mg, 1 mmol) was dissolved in dry THF (20 ml) and cooled to -78°C. n-Butyllithium (1.5 ml, 1.47 M) was added over a period of 2 min. After allowing to warm up to 0°C, the reaction mixture was recooled to -78°C and toluene-4-sulphonyl chloride (247 mg) in dry

THF (5 ml) was added. After allowing to warm up to room temperature overnight, and the usual work up afforded after column chromatography of the residue (Kieselgel H, 7g) compound (295) (29 mg, 11%) and the amide

~~(307) (trace) as the only identifiable compounds.~~

c. Chloro-amide (310) (50 mg, 0.18 mmol) was dissolved in dry THF (10 ml) and sodium hydride (10 mg), imidazole (1 mg) and tetra-n-butylammonium iodide (2 mg) were added. After stirring overnight at room temperature, followed by work up in the usual way, the amide (307) (20 mg) was isolated as the major product (nmr).

~~d. JN-benzylacetamide (600 mg, 4 mmol) was dissolved in dry THF (20 ml)~~

~~and cooled to 0°C. n-Butyllithium (5.9 ml, 1.40 M) was added at 0°C over a period of 5 min. After stirring at 0°C for 30 min benzaldehyde~~

~~(0.4 ml) was added. After stirring for 15 min at 0 C, the yellow~~

~~coloured solution was cooled to -78°C and acetic acid (0.24 ml, 4 mmol) was added. After a further 10 minutes at -78°C, toluene-4-sulphonyl~~

~~chloride (850 mg) in dry THF (5 ml) was added. The reaction was~~

~~maintained at -78°C for 20 min and n-butyllithium (3.5 ml, 1.4 M) was~~

~~added. On allowing to warm up to room temperature (12 h ), the reaction mixture was worked up in the usual way. Column chromatography (Kieselgel~~

~~H, lOg) afforded a mixture (157 mg) of the amide (307) and the 3-lactam~~

~~(287).~~

~~e. To a solution of anion (308) (2 mmol) in dry THF (20 ml) was added~~

~~methanesulphonyl chloride (0.15 ml, 2 mmol) at -78°C. After stirring~~

~~at -78°C for 40 min , n-butyllithium (1.43 ml, 1.4 M) was slowly added 199.~~

(5 min ). On completion of the addition, the reaction mixture was allowed to warm up to -25°C for a period of 5 min. The reaction mixture was then allowed to warm up to 0°C, quenched with water (10 ml) and worked up in the usual way. Column chromatography [Kieselgel H, lOg, eluant dichloromethane - light petroleum (2:1)'] afforded the 3-lactam 140

~~(287) (148 mg, 31%) as a viscous oil, v (CHC10) 1730 (s), 1660 (m, max 3 impurity), 1600 (m), 1450 (m), 1390 (m), 1330 (m), and 1150 (m) cm"1,~~

~~5 (CDC13) 2.83 (1H, dd, J 14, 2Hz), 3.31 (1H, dd, J 14, 5Hz), 3.73~~

~~(1H, d, J 15Hz), 4.37 (1H, dd, J 5, 2Hz), 4.75 (1H, d, J 15 Hz), and~~

~~7.10-7.30 (10 H, m) , m/e 237 (M*") , 194, 104, and 91 (Found: C, 80.78;~~

H, 6.57; N, 5.96. Calculated for C., H N0; C, 80.99; H, 6.73; N, 5.90%). lb 1C5 f. To a solution of the anion (30S) (1 mmol) in dry THF (15 ml), was added methanesulphonyl chloride (0.1 ml) at -78°C. After stirring at

~~-78°C for 1 h., the reaction mixture was transferred to a second flask containing a suspension of sodium hydride (56 mg) in THF atr-78°C.~~

~~After allowing to warm up to room temperature, the usual workup afforded, after column chromatography (Kieselgel H, lOg) the chloro-amide (310)~~

~~(74 mg), and a mixture (31 mg) of the chloro-amide (310) the amide (307)~~

~~[31 mg,(307):(310)^ 1:2, nmr] and starting material (14 mg).~~

~~Attempted preparation of the chloro-amide (310)~~

~~To a solution of N-benzylacetamide (600 mg, 4 mmol) in dry THF (50 ml)~~

~~o o was added n-butyllithium (6 ml, 1.40 M) at 0 C. On cooling to -78 C, freshly redistilled benzal chloride (0.52 ml, 4 mmol) was added.~~

After allowing to warm up to room temperature, TMEDA ( 1 ml) was added to the reaction mixture. After 45 min at 0°C, the reaction mixture was quenched at 0°C with acetic acid (240 mg, 4 mmol). Work up in the usual way afforded the crude product, which was essentially a mixture of starting materials (nmr). 200.

~~Preparation and dcutcration of the dianion (315)~~

~~N - Benzylphenylacetamide (225 mg, 1 mmol) was dissolved in dry~~

THF (20 ml) and cooled to 0°C. n-Butyllithium (1.43 ml, 1.40 M) was added at 0°C over a period of 5 min. The resulting orange solution was stirred at 0°C for 30 min , after which time, deuterium oxide (72 mg, 4 mmol) was added. After allowing to warm up to room temperature, the solvent was removed jhi vacuo. The residue was triturated with dichloromethane

~~(2 x 25 ml), the organic extracts filtered through Celite and concentrated~~

in vacuo. Column chromatography [Kieselgel H, lOg, light petroleum - dichloromethane (1:2)] afforded the deuterio-amide (316) (46.5 mg, 25%), v (Nujol) 3430 (s), 1680 (s), 1600 (w), and 1500 (s) cm"1, max

~~6 (CDC13) 3.63 (1H, brd. s), 4.43 (2H, d, J.5Hz), and 7.23-7.53 (10H, m), m/e 226 (M*) , and 91 and an inseparable mixture (130 mg), m/e 449, and~~

~~241. Repeated recrystallisation of this mixture to constant m.p. 96-97 C~~

~~(ether-light petroleum) gave a homogeneous, crystalline compound, probably~~

~~the hydroxy-amide (317) (Found: C, 74.12; H, 6.19; N, 5.89. C H NO 15 lb U requires C, 74.60; H, 6.26; N, 5.84%). 201.~~

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~~1968, 51, 2069. 401 J.C.S. CHKM. COMM., 19SI Novel Syntheses of 3-Methylene-azetidin-2-one Derivatives and Related Systems~~

~~By ROBERT M. ADLINGTON, ANTHONY G. M. BARRETT,* PETER QUAYLE, and ANDREW WALKER {Department of Chemistry, Imperial College, London SW7 2AY)~~

~~and MICHAEL J. BETTS (Imperial Chemical Industries Ltd., Pharmaceuticals Division, Mereside Aldertey Park, Macclesfield, Cheshire SKIO 4TG)~~

Summary Syntheses of the title compounds via I-lithio- Reaction of the acrylamides (3) with 2 equiv. of n-butyl- oxy-l-lithio-arnino-allene derivatives or lithium phenyl- lithium followed by toluene-4-sulphonyl chloride (TsCl) in ethynolate are described. tetrahydrofuran (THF) or 1,2-dimethoxyethane (DMK) gave the /3-lactams (5), (6), and (7) in good yields (Table and 1-LITHIO-OXY-1-LiTHio-AMINO-ALLENE derivatives (2) have Scheme 1). The intermediate toluene-4-sulphonates (4) been conveniently prepared by the reaction of secondary were isolated in some cases after brief reaction; these could a-keto-amide 2,4,6-tri-isopropylbenzenesulphonylhydra- be cyclised using sodium hydride. Since a-keto-amides are zones (1) with an excess of n-butyl-lithium.1 These readily available from isonitriles,3 a-keto-acy! chlorides,1 dianions were found to react with aldehydes to give the oxamide esters,5 etc., this synthesis of a-methylene-^- substituted acrylamides (3). Herein we report the one- lactams is highly versatile. step conversion of such amides (3) into 3-methylene-aze- Herein, we also report that the jS-lactams (10) are tidin-2-one derivatives2 (5), (6), and (7). Such j9-Iactams available from the reaction of an electron-deficient imine are relevant to the synthesis of carbabicyclic antibacterials. with lithium phenylethynolate (8) in a novel anionic cyclisa-

~~1 0H ^NH502C6H2-2J4I6-Pr'3 NR I N i / ii.iii V^R2 ii CH2=C=C 1 ^^CONHR1 - O^NHR1 (1) (2) (3)~~

~~f, NR1~~

~~(5)~~

SCHEME 1. Reagents and conditions: i, BunLi (S-2--3-4 equiv.), -78 X; 25 X in DMK; ii, RXHO, —78 X; 25 X; iii, H.O: iv. BunLi (2 equiv.), THF, -78 X; v, TsCl (1 equiv.), -78 X; 25 X. 10 min; vi, 25 C, 15 h; vn, NuH, THF. 25 X. 0

~~J.C.S. F hi.m. Comm., 1HS1 •U)f.~~

tion. Using Sihollkopf's procedure,*1 3,4-diphenylisoxa- zole7 was inetallated giving the ynolatc (8). This, as a royal blue solution in THF, reacted with the* iinines R'N^CIIR1 to give the /Madams (10) (Scheme 2, Table). The reaction was highly stereoselective. Tentatively, we assign the stereochemistry based on chelation and steric approach control. The presumed intermediate (9) could not be intercepted with an aldehyde. (6) < 7 )

TABLE. Preparation of ^-lactams (5). (6), (7), and (10). Ph Product* R1 R» Yield (%) (5) Cyclohexyl H 60 PhC=C 0 — f (5) n Me 64 (5) Et 08 n o Pr (8) (5) 54 ( 9) (5) n-C?H„ 57 (5) PhCH, Me 51 (5) „ Et 60 b (6) — — G5 — — 19b.c (7) (10) C,H4-4-NO, Ph 66 (10) » C,H4-4-NO, 89 1 (10) CgHj-3-Me 58 R NH (10) C6Hr4-C02Et C,Ht-4-NO, 79 a All new pioducts were fully characterised by microanalyses and spcctr.il data. [j3-Lactams (5; Rl = PhCH,) were not obtained microanalytically pure but exhibited the correct high , resolution A/+- in the mass spectrometer.] The acrylamides (3) (10) were prepared as described elsewhere1 or by identical routes. l n R ,R*,%: cyclohcxyl, Me, 74; cyclohexyl, Pr , 83; cyclohexyl, n b SCHEME 2. Reagents and conditions: i, Bu Li, THF, —78 to n-C,H , 70; PhCH,. Me, 57; PhCH Et, 58. 0-I.actams (6) JS 2> -GO °C; ii, R»N = CHR* (1 equiv.), THF, -78 to -50 °C; and (7) were prepared using 2,2-dimethyl-(4ft)-formyl-l,3- iii, HOAc (1 equiv.), -50 °C. dioxolan. Product (6) was obtained from the major diastereoisomer of (3); (7) from the minor. The assignment of stereochemistry is tentative but reasonable since 2,2-dimethyl-(4i?)- Clearly, the anionic reagents (2) and (8) provide routes formyl-l,3-dioxolan is erythro-selective (ref. 8) with simple carbanions. The intermediate toluene-4-sulphonates (4) correspon- to usefully functionalised /^-lactam systems. ding to the ^-lactams (6) and (7) exhibited characteristic signals We thank the S.R.C. and I.C.I. Pharmaceuticals Division in the n.in.r. spectra, respectively at 8 5-25 (1H, d, J 7 Hz) and for support. 5-20 (1H, d, J 6 Hz) for the CH-OTs protons. <= ^-Lactam prepared by the cyclisation of the isolated toluene-4-sulphonate using sodium hydride; the yield is based on the starting acrylamide. [Received, 13th February 1981; Com. 104.

1 R. M. Adlington and A. G. M. Barrett, J. Chem. Soc., Chem. Commun., 1981, 65. 1S. R. Fletcher and I. T. Kay, J. Chem. Soc., Chem. Commun., 1978, 903; M. Mori, K. Chiba, M. Okita, and Y. Ban, ibid., 1979, 698; T. Minami, M. Ishida, and T. Agawa, ibid., 1978, 12; K. Chiba, M. Mori, and Y. Ban, ibid., 1980, 770; R. Mayrhofer and H.-H. Otto, Synthesis, 1980, 247; S. Kano, T. Ebata, K. Funaki, and S. Shibaya, ibid., 1978, 746; M. Ishida, T. Minami, and T. Agawa, J. Org. Chem., 1979, 44, 2067; S. Kano, T. Ebata, Y. Yuasa, and S. Shibuya, Heterocycles, 1980, 14, 589. 4 1. Ugi and U. Fetzer, Chem. Ber., 1961, 94, 1116, and references therein. * W. Lopatin, C. Sheppard, and T. C. Owen, J. Org. Chem., 1978, 43, 4678. * L. V. Dunkerton and R. M. Ahmed, Tetrahedron Lett., 1980, 1803. * U. Schollkopf and I. Hoppe, Angew. Chem., Int. Ed. Engl., 1975, 14, 765. 1 K. Bast, M. Christl. R. Huisgen, W. Mack, and R. Sustmann, Chem. Ber., 1973, 106, 3258. * J.-C. Depezay and Y. LeMerrer, Tetrahedron Lett., 1978, 2865.