PDF Copyright INTRODUCTION TO SYNTHESIS OP beta-LACTAMS IIT Kharagpur

INTRODUCTION TO SYNTHESIS OP beta-LACTAMS

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/2>-lactam or 2-azetidinone (I) was a relatively obscure family of synthetic products until the beginning of World War II. Attention was drawn to earlier sporadic study of this heterocycle, when the fused thiazolidine |S -lactam

structure was proposed for penicillin (ll)^c The study gained further impetus when another fi-lactam antibiotic family, cephalosporins (ill), was discovered2. Within the last ten to fifteen years, ft-lactam containing

0 CH2OAc

III NH. C0oH

I 2 I 2 eH2CH2CHC0NHCHCH0HCH, HO-

m

alkaloids (17) have been found in a family of higher plant

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called pa schyt ermine^,, A 6-lactam substituted peptide ( V )

has been identified as Wildfire toxin that blights tobacco leaves1*. The bleomycin^5, a /i-lactam containing antibiotic family has been discovered to be effective against certain types of cancer* More recently clavulanic acid (VI), an oxa analog of penicillin has been isolated from streptomyces clavaligerus. Undoubtedly more p-lactams will be found in nature in future years <,

Owing to various physiological properties of

£ -lactam containing compounds, numerous routes to the synthesis of both monocyclic and fused /^lactamshave been developed within last three decades. Much effort has been directed towards the synthesis of simple /s-lactams because of their potential medicinal importance such as antimicrobial .,

rj Q 0\v antidepressaht,sedative and antiinflamatoxy properties. ’ *

A rev ie w ^ of literature by Sheehan and Corey.

contains different synthetic routes developed upto 1952.

1 n 11 10 *i 7 41. Recently reviews on the synthesis * ’ , reactions * of

1 *5 1 fi

-lactams and chemistry of (^-lactam antibiotics have appeared in the literature.

There are various methods for constructing a -lactam ring. In principle the synthesis might be

accomplished by the formation of one, two, three or all four bonds of the ring during the cyclization step. Of these four possibilities all but the last have been realised, also the formation of C 2 - C y ‘bond in the route to the /^-lactam in

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been realised*

A large number of 2-azetidinone derivatives

have been synthesized by cyclization of /5-aminopropionie acid derivatives in presence of such reagents as acetic anhydride1^, acetyl chloride1^, thionyl chloride1^,

*1ft PO

phosphorous trichloride # benzesulfonyl chloride 6 This method of synthesis is capable of yielding a high variety of alkyl and aryl derivatives with upto five substituents in the ^-lactam ring.

-RJ R £

S 5-NH

R¹ COgH

R- R ‘ sr

r5-n

R 0

1

It is noteworthy that simple heating of /9-aminoacids fail to afford p-lactams as a result of deamination through

/}> — elimination^o Carbodiimides have been successfully

employed as a cyclization reagent in the synthesis of hi cyclic /^-lactams sueh as penicillin (II) 91 cephalosporin analog (VI)22 and the compound2*^ (VII)

HO^O, HN DGCD

R.

‘N

M C0 2CH3 ^X

QT ^■ C0 2CH3

VI VII

R sl&thalimido

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4

.The treatment of B- a minoesters with G-rignard

17 R OK

reagents leads t o ;the f or ma ti o n of 2-azetidinones ’ ’ „ The ft-aminoesters required for the latter synthesis are conveniently prepared by Michael addition of a carbanion to

n c o CL

an imine , or of amine to an acrylic ester derivative

• B o th o f :these syntheses permit retention of stereochemistry at 4^-and p-carbons and inc orporation of chiral centres, at and - of the lactam' r i n g 0

The bicyclic ft-lactam (IX), a n intermediate used in the total synthesis of cephalosporin G has been prepared by cyclization of appropriate p - a m i n o e s t e r (VIII) with tr iisobutyl a lu mi ni um „27

HO 0C NH„ ° -Y~NH

c-\ \ d

0 j— y __ 0 vj—

t - C ^ O C - N ^ S t - G ^ O C - N ^ S

VIII -IX

' F o r m a t i o n of 0- l a c t a m by ring closure at

can be achieved .by internal displacement of h a l o g e n by amide n i t r o g e n of p - h a l o a m i d e s in presence of bases such

28 29

as l it h i u m carbonate , sodium hydride , amines in di methyl formamide , p o t a s s i u m t-butoxide in 30 D oM„S„0 and alkali metal

32 33

amides in-liquid ammonia 0 K n unyant et al have extensively used alkali me ta l in liquid ammonia for the synthesis of large n um b e r 2-azetidinone derivatives,, Recently it h a s b e e n shown that even we a k e r bases could bring out c y c l i z ation at h i g h e r

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temperature^* It has been observed that substitution at the amide nitrogen atom does not play any role in the

I H

R 1 - CH * --tN - R2* R¹ H

R* C = 0 R 2

R 0

R- R-

cyclization. ?he 1-alkoxy-2-azetidinone(X) was prepared by

this method 35 R'

R 1

BrGH2 - C - GOG1 + HgNOBz R"

Pyridine

I

B z O — N-

■R‘

rO X •, Bz = benzyl The formation of bond by ring closure

has been achieved by base treatment of haloacetamidomalonates (XIa) and this affords p-lactam* (Xlla)"^’^ in high yield*.

The bond formation can be accomplished if there is a leaving group at one end and potential carbanionic centre at the

other. This method, initially developed by Sheehan and Bose, has been extended by Chatterjee’^ " ’^ and coworkers. The

-haloamides having various activating functions have been successfully cyclized to -lactams (XII). The nature of the bases that have been used for cyclization depends upon the the activating groups (X and Y in XI).

XIa could be cyclized in high yield in the presence of triethylamine but strong base such as alcoholic KOH had to be employed for cyclization of (Xlb) and(XIc). Other bases that have been used for cyclization include d i e t h y l a m i n e ^ ,

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ion exchange resin^, dimethylformamide^, fused sodium acetate1^ and sodium azide*4-^.

XI XII

R = Aryl , L * Halogen XIa, X = Y = C02Et

b, X = GOPh , Y = H c, X = Ph , Y = C02Et

d, X sa 2,4 - dinitrophenyl, Y = H.

It has been observed that 2 mols of alcoholic KOH, can bring oat cyclization of(XIa)with hydrolysis of an

ester function® Cyclization always precedes saponifipation.

The ester groups of(Xlla)have been functionalised to build up a spirobarbiturate derivative 1|i and a thiazolidine derivative*1"-*.

It is noteworthy that attempts to synthesize N-unsubstituted 2-azetidinones by this intramolecular alkylation method met with failure.

It has been observed that the amide(XIe)on treatment with base gives either p-laetam(XIIe)or dihydro 1,4-oxazine (XIII),according to the nature of the substituents present on

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the two phenyl rings^*"^. An electron withdrawing

R 1 — p C O c T

El- O f -

■R‘

Xlle CH2C°-W

0=C— CHgCl XI e

group on the N-phenyl ring (R1 = COCH^, R 2 = H) yields f*-lactam(XIIe>whereas(XIII)is obtained when electron withdrawing group is placed on the phenacyl moiety

(R1 = H, R 2 = N 0 2). '

Recently Bose-Sheehan cycladehydrohalogenation has been successfully employed in the synthesis of azeto

quinoxaline - 1,3 - diones (XIV) and (XV)

OOgEt

r 0

H XT (E = H .C H j) A new synthesis of 2-azetidinones using intra­

molecular Michael addition of suitable acrylamides (XVI) under influence of piperidine has been reported*^.

XIV (X « H,0H)

C6H 5-N— CH(C02Et)2 0=0 CH t= CH ** R

R = p-nitrophenyl XVI

•7

or

,co2Et

•C02Et

■^CH2R XVII

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Cyclodehydration of N-methyl glycolic acid amides have "been shown to give 2-azetidinone derivatives(XVIII). .62.

R R OH

CONR1Me ^{H 2S04}

R

R = Substituted phenyl R 1 = H 1 Me

O' XVIII

-N— R¹

Reformatsky reaction of Schiff bases with -bromoesters yields the cis isomer of 2-azetidinone

r-z

derivatives as the major product' . The cis trans ratio, however, depends upon the nature of the substituents on the

ester as well as the polarity of the solvent.

R 1 - N = GH - R 2 + R3 CHBr-C02C2H 5 2 n R 1 - N ---*

OtsC

■ R-

H R- The reaction of <* —haloacetic and propionic acids with schiff bases in DMF in presence of phosphorous

oxychloride yields (i-lactams via an amide intermediate^*

Stsfodinger et a l ^ in 1907 obtained the first

synthetic 2-azetidinone by interaction of diphenylketene with benzalaniline. Since then a large number of structually

different keteneshave been employed in the synthesis of

q 10

2 - a z e t i d i n o n e s . The synthetic ketene is either employed in the reaction or it is generated in situ* Ketenes obtained from thermal decomposition of diazoketone have been employed

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in -the synthesis of p-lactams5 6 . At elevated temperature aeetylinic ethers such as 1-ethoxypropyne reacts with imines

c ry via ketene intermediate to form 2-azetidinones (XIV) 0

C 2H 5° C = C - R¹ R ‘ R- R^{1 ..}

> R 1 - CH = C = 0

Mr

R

RX = N - R1

H XIV

In the ketene - imine interaction, different

products have been obtained besides the expected P-lactams

of Q

depending upon the nature^ ketene and imine . lor example, piperidinedione derivative (XX) is obtained by the reaction,.

of one mole of imine with 2 moles of dimethyl ketene. It has been suggested that the ketene dimer instead of ketene

condenses with imine to form (XX) .CO

0

CH, CH

CH-

D

. 0 S'

3

\

0

R - N = CH - C 6H 5 - > CIV

CH- ^0A

CH, CH-

'T-R 6 5 CH, XX

The mechanism of ketene - imine reaction has been extensively studied. It has been suggested that this non­

concerted eycloaddition reaction is initiated by attack of

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10

imine nitrogen on the carbonyl group resulting in

steroselective formation of the dipolar intermediate (XXI) following by stereospecifie cyclization to p>-lactam (XIII)

R 1- NH ss CH - CHR2 ^R R^

t>3 .0

R 2 - f ” J< R 1

H R

XXI R-

R ‘

- p o N - R^

4-Imino-azetidinones (XXIII) were,obtained on

interaction of ketenes with earbodiimides^® (XXII). Ketenes have also been found to react with conjugated schiff base

sueh as (XXIY) to give (b-laetam derivative (XXV) .

R - N=C = N - R + XXII

CH, CH,i 3 I J

R 2.

R

R -N-

1

■ NR

0 -R-

R ‘

Ph - N = C - XXIV

C = N = Ph + R 2C=£-0

Ph - N =C, --->

CH, t 3

XXIII

E'

N - P h i-,o R

XXXV

Even bicyclic £ -lactams such as the penam derivatives (XXVII) j&epre successfully synthesized from appropriate i m i n e s ^ * ^ (XXVI).

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R _•s .S N

Ph B

+ Ph2G=C=0 Ph.

r

S7 -N-

XXVI °' XXVII

Spiro 2-azetidinones (XXIX) along with

spirooxazolidinones (XXX) are formed when^dimethyl ketene is reacted with N-(fluoroen-9-ylidene)-alkylamine-N-oxide (XXVIII)62.

0 R

XXVIII

Interaction of ketene with azidocarboxylate has led to the formation of a bicycle ft-lactam (XXXI) ^ .

R 1

-„ > - C = 0 + R2C> C - N=N-C0oR 2. . d- ’ d

C02R 2

R 1— I J - R 1

R R

Formationjsf 2-azetidinones by addition of acid chlorides to imines in presence of a base such as

triethylamine may be treated as an extension of ketene - imine interaction. This method has been extensively used in the synthesis of large number of monocyclic and fused

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£ -lactam derivatives,, The acid chlorides that have been used successfully in this reaction include j^halimidoacetyl

chloride^’ , cyanoacetyl chloride , substituted malonyl

cc c.n

chloride , dichloroacetyl chloride , azidoacetyl chloride , phenoxyacetyl chloride*^, methoxy acetyl chloride^®’ and a few heterocyclically substituted acetyl chlorides . The 71

reaction of azidoacetyl chloride with appropriate

t,3-thiazoline in presence of triethylamine afforded b.icyclic -lactam (XXXII) which on catalytic reduction and acylation with phenoxyacetyl chloride yielded the penicillin ( X X X I I l ) ^

g

1) V Ni

P h Q C I U C Q M s

^ ^ 2) PhOCH2COCi/NEt3 'j— f ^

Cr ---- - CG„CH, 2 3 r\4 ^-K. _C02CH3

XXXIII

The bicyclic p-lactam (XXXY) has been prepared by the reaction of a substituted aeetylchloride with 2-phenyl-1,3- thiazine (XXXIV) in presence triethylamine^4’,'^<>

I E h ,

Ph S R * * -s

0

R aPHthalimido XXXI? XXXV

Azacephams(XXXYIl) were prepared by treating

tetrahydropyrimidines (XXXVI) with an acid chloride in presence of triethylamine^.

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A certain amount of steric control can be R

El A

XXXVI S » Hj R 1= SMej XXXVII

H * - OPh, ■ „ OMe; * ‘ a 0(!B2C0I II30H200

2 CH^OCHgCO .

ex<fcercised on the product of reaction by changing the

sequence of addition of the reactants «> The structures'of rO imines^ and acid chloride?®’^ also influence the course of the reaction. Thus additionjof acid chloride to a mixture of imine and triethylamine gave more eis than trans product. But when triethylamine was added to a mixture of imine and acid chloride, the major product obtained was trans isomer. But pjfoialimidoacetyl chloride takes precedence over other

factors and produces trans-2-azetidinone exclusively. It / should be noted that the reaction proceeds through either ketene 01* non-ketene route. As ketene addition in all cases

so far has led to trans- -lactams, formation of eis

^-lactam would indicate existence of non-ketene pathway.

4-Mereapto-2-azetidinone (XXXIX) has been synthe­

sized fromAppropriate /imine component^6 (XXXVIII)

1)NEt, r ou

CMe„ ' 3 K v SH

I 2 2) Hg(OAp)0 ^

Ph,— CSCH = N - C':4-C0oMe + R GH^COGl 2

3 ) d d

SMe 3) 0

XXXVIII XXXIX

COgMe

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3-Hydroxy-2-azetidinone derivatives (XII) have been conveniently synthesized according to following scheme .77

OAC OAC NEt, H ' 1—

_ ' 3 H T CaCl„

> = K - P h + P h - C H C O C l ---- > , ______

Ph. q J— N- Ph MeOH

OH R H -t---h F h

0

XL XLI, R = OMe, SMe

Reaction of iminomalonic ester with appropriate acid chlorides gave f*®laetams (XLII)^®.

Recently isocyanoketene obtained in situ, by base treatment of isocyanoaeetyl chloride bas been successfully

R = OMe

NEtj -- (CO 0E t )

NEt R

2 'i O P h XLI I

R - N = CRg + Q R = Ph

r 'i/k o b u* ^

N CHgCOCl - - R R C = N-

3 C = N | R O' ■N - R

XLI 11 R

0 / — N - R XLIY , R =-CH3 ,-CH2P h employed in synthesis of 3-isocyano-2-azetidinone (XLIII) which could be alkylated at o( -position in presence of

strong base to form (XLIV)^.

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H H

r 'c h = n-r ’ + r - c h2c o c i NEt, _{£— R} N - R

XLV R » PhCH20C0NH-, (p)-02N-C6H^0C0NH-

R* « OMe

Recently Merck group has achieved the synthesis of cephalosporin derivative (XLVIl) from the imine (XLVI) using 1acidchloride-imine reaction⁸¹

NjCHRCOCl NEt, C0„R'

XLVI

Imines react directly with dichloroacetic anhydride to afford dichloro ^-lactams (XL VIII)

GHMe| Urn C6H 5GH = N-CH-COgMe

(C12CHC0)20 gi

---

Cl

~ C A6 5

XLVIII C02Me Cycloaddition of isocyanate to olefins is a versatile method for the synthesis of 2-azetidinones.

Arylisocyanat'e can react only with activated olefin sueh as (XLIX) to form ^ - l a c t a m ^ ( L ) . However, photo-cycloaddition of phenylisocyanate to stilbene leads to stereospecific

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formation of 2-azetidinone. Trans stilbene yields the trans isomer (LI) and vice v e r s a ^ .

C H X OMe CH^

= c' + Ph-N=C=0' ____ >

GUj, OMe MeO

c h3

.0

P h - I = C = 0 + P h

P h

— N-Ph QMe

L P h - N — r— P h

P - » 0 ^

LI The addi t ion of trichloroacetyl isocyanate to

Or O/r Or?

dienes , phenyl isocyanate to enamines and dienes , and p-nitr op h en yl isocyanate to styrene 88 leads to the f o r m a t i o n of 2-azetidinone derivatives. Various aroyl and arene

sulfonyl isocyanates h av e been reacted with alkenes 8Q and v inyl ethers^ to give ^ - l a c t a m derivatives.90

Chlorosulfonyl isocyanate reacts w i t h a great variety of olefinic species, leading to the fo rma t i o n of

p - l a c t a m s in mo derate to h ig h y i e l d ^ 1 . M o n o c y c l i c ^ ,

Qii Q5

bjcyclic-^ and spxro p> -lactams have been convenie ntl y synthesized employing appropriate olefins. The initial product, a 1-chloro-sulfonyl-2-azetidinone can readily be h ydroly s e d to N-unsubstituted az etidinone derivative. V i n y l -

e ster (LII) undergo cycloa dd it i on re a c t i o n w i t h c h l o r o s u l f o n y l

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isocyanate to form l+-acyloxy-2-azetidinone derivative (LIII). The synthetic importance of this reaction arises from the fact that the acyloxy group can be readily replaced by variety of nucleophiles such as RSO“, N^, R0“, RS“ to form corresponding 2-azetidinone derivative (LIV). The displacement occurs with recemization . Recently this reaction has "been extended to synthesis of bicyclic system

92

C1S0, N=C=0 +

,1 R*

r — c-o - ch c

car ■,

B?

CSI

Na9S«G 'G — ■ > HN- B 1C00*

ClSO^-N-

t?2 -R-

=0

R 1C00

(LV) 93

/ HH-

R ‘

■R- s0

LIII L1Y

1,2-Dimethylcyclobutene and methylenecyclobutane

ACO

T

HN- 0

SH

+ MegGH - CHCOgMe

0 N 0Me

iLY

readily react' with CSI to give hicyclic 2-azetidinone^ (LYI) and spiroazetidinone^ (LVII).

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1 8

3 1)CSI

CH3 2)Na2S203-H20

CH,

/ ^ ° H 3 0

NH LVI

) CSI

ii) Na2S203-H20

^ 0 m

1VII

Cyclopropanone has "been shown to react with

-amino ester and tf-cyanohydroxylamine to form the adduct (LYIIl) and (LX')which on treatment with suitable reagents

undergo ring expansion to form p-lactam ( L I X ) ^ and ( L X l ) ^ respectively.

Q NH»

I 2

+ R-CHCOgEt

-78° H0\ m CHRCOpEt

\ / i)t-:

CHRC0oEt _{i £}

c h2c i2 ii)Ag+ ,

LTIII LIX

0 HO N(0H)CHRCN

+ RCH(CN)NH0H ---->

X

^P“MeC6H^S02Cl

|

--- ■" : ^ JL . -K

LX ⁰

-- N- CHRCN LXI

Aziridine carboxylate on treatment with thionyl chloride undergoes rearrangement to form 3-chloro-2- azetidionone (LXII)98 in high yield. This reaction is

stereospecific.

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t-Bu N

G 0 2Na SOCl,

t-Bur N

t-BuI 4

" V

— c'n' Cl— > v. j* ( * \4 ~ x***0 Cl* N

ClL_

? Bu"6 LXII Oxidative ring contraction of (LXIIl) by sodium

yield q q

periodate at pH7 lias been shown tcy bj'cyclic P-lactanr^

(LXIY).

o( -Diazoamider (LXV) on photolysis generates carbene species which can abstract hydrogen from the carbon atom

adjacent to amide nitrogen and simaltaneously couple to afford bicyclic p-lactam (LXII)

h V 0 C02Me

LXV

Ph

0 — N,^{r s v} COgMe LXVI

Several similar photochemical cyclizationp^ ik7 to build up 2-azetidinone ring are known. The dibromide

(LXVII) afforded 6- -bromopenicillate(LXVIII) in low yield through the masked carbene intermediate101.

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Br Br S

0^& COgMe

BrHg B r g,

• ₀^{K -}

Br.

"COgMt ^JL -COgMe LXVIII

Photolytic Woulfe rearrangement of Pyrrolidinone derivative (LXIX) in presnece of t-butyl carbazate gave

p>-lactam (LXX)102. Similarly penicillin derivative (LXXII) was obtained from (LXXIJ? ' , These ring contraction reactions afford stereoselective product in high overall yield.

h ~v t-BuOCONHOC Me

t-BuOCONHNH,

m

N-Isopropyl allenimine (LXXIlD have been shown to react with azidoearboxylate and t> -toluenesulfonyl azide to give i^-imino p- -lactam (LXXIV)10<4'.

■n

LXXIII

;NR

OCXIV H == -fG02Et,

p - CHjCgH^SO"

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interest exhibited by various groups of wc$cers throughout the world on the chemistry of beta,-lactams, it was decided to under t ak e the present investigation w ith the a i m of synthesiz­

ing p olycyclic and N-unsubstituted ft -lactams.

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