CHAPTER III

SYNTHESIS O F N O V E L F U R A N O N E TYPE CHIRAL MOLECULES

111.1 Introduction

Chlral y-butyrolactones (furanones) form structural unit of many naturally 141.157 l60.167 occurring cli~t~al n~olecules Such optically active natural products

include alkaloiiis. macrocycl~c antibiotics, antileukem~cs, lignan lactones,

pheromones. atltlf'ung;~l agents, flavour components, rare metabolites etc

(Fig. 111.1 ). The pharmacology of chiral substituted y-butyrolactones are well ',

documented" The chemistry of y-butyrolactones h&e been reviewed168 as early , TJ

as 1955 'l'lie renewed interest in these class of compounds is evidenced by the

increase in puhl~cat~ons related to the preparation of various substituted versions.

Though dlstr~huted widely in nature as sub-units of several compounds, synthetic

strategies I I I V O ~ V I ~ ~ the d~rec t use of chiral y-butyrolactone unit for the synthesis

of such molecules are rare.

( + i Pmiargolac1one (ti-trans-cognac lactone (-)-Phaseol~n~c acid

011 Vlrginiae butanol~de Methyl butenolide

Caproladc~ne Quercus lactone Blastmyc~none

Approps~atclv substituted chiral y-butyrolactones are even used as

interrned~ates fool the :syntheses of certain natural products, which do not bear any

lactone moret,' '"" (Sche:me 111. I )

/ I ,H - Y > , , m ' ~ ~ ~ s e ~ r a l ..... steps .D

Sulcatol (Frorn Glutarilc acid1

n-Od

several steps CONH, ..--. * 0

(From Tartarlcacld) Tetrahydrocerulenln

?[x0 / several ..... steps *

jkrorr [I- hdannltol) (-)-lpsdlenol

Scheme 111.1

As inosr of'the ~nolecules tilscussed are present in small quantities in nature

and cons~dering their wide-ranging applications, total synthesis of such

compounds arc often ]required 111 this background optically pure y-butyrolactone

based ch~ral synthons play a sign~ficant role in the syntheses of natural products

bearing y-l~iityrolactone sub-un~ts

11 I S evident tiom the l~terature that enantiomerically pure and appropriately

functlonallscd y-hutyrolactones are often synthesised from molecules obtained

from natural sources The usual starting points for such syntheses are

carbohydrates amlno acids, hjdroxy acids e t ~ . ' , ~ , ~ (Scheme 111.1 and 111.2). Other

methods f i ) i the prep,aration of' chiral y-butyrolactones involve the use of chiral

sulphox~des. cpoxides or substituted acetylinic acids15''.

COOH sewral steps W\>OC /\I ..... *

" " LOJ"" \i seeral .-..- steps * oq8&

C)H OH L) Klbvse

i lilt32 sewral steps

/ "'-'COOH ----- -

I J Leuc~ne H2C

Scheme 111.2

In t h ~ s context it i:s expected that the title compound, (2S,3S)-Tetrahydro-3-

hydroxy-S-oxo-1.3-t'urandicarboxyl1~ acid, 127 (Garcinia acid) could find limitless

applications in the broad area of asymmetric synthesis as the molecule is available

in nature, in the o [~ t~ca l ly pure fol-m, in plenty. This molecule is yet another

valuable addluon to the plethora of chiral synthons from the chiral pool as the

absolute corif~gur;lt~on of the molecule matches with several naturally occurring

ones. It has to be noted that by using 127 quite a few steps may be saved in the

synthetic scheme tbl the stereoselect~ve syntheses of y-butyrolactone moiety.

111.2 Results and l~iscussion

'To make use of unique chlral y-butyrolactone moiety of (2S,3S)-

Tetrahydro-3-hydroxy-5-o.to-2,3-furandicarboxyl1c acid (127), in any demanding

synthesis. ~t must be en:jur-ed that the mo~ety must be intact during the course of

any chemical manipi~lation For tnsttlnce, the attempted preparation of dimethyl

ester (129) followrng the pr~cedure" '~ reported by Lewis et ul resulted in a mixture

of cyclic d~methvi estei- and the ;liycllc trimethylester formed by openlng up of the

lactone rlns

To a\old the cleavage of tlie lactone ring, it was proposed to carry out the

esterification 111 a softel- mannel T h ~ s can be done in two ways.

129 was the only product, totally free from acyclic triester, obtained upon

treatment of' 127 with diazomethane (Chapter 11). Any other method for the

esterificatlon leads to the formation of a mixture of diester and triester. However

this method i s limltetl to the preparat~on of methyl ester and use of diazomethane

is not advisable

In thls hackground attentron was focussed on the preparation of diacid

chloride (132) f h e i n ~ t ~ a l attempts employing thionyl chloride for the purpose

res~llted in tlie open~ng-up of the lactone ring. Efforts were made to prepare the

disodium salt (131) from 127 for the reaction with thionyl chloride to yield 132.

This method docs not generate HCI during the reaction and thus minimises the

possibility of the rupture of lactone ring

There 1s no mention in the i~terature regarding the formation of 131. Initial

experiments ccsulted in the cleavage of lactone ring lead~ng to the formation of

very hygroscopic trisod~.um salt of 127. It was fortunate to observe the formation

of 131 by ti~catlng 127 .with aqueous sodium bicarbonate at Oo C (Scheme 111.3).

Unlrke 127 or 115, rr~sodium salt, this compound was not hygroscopic and the white

crystalline sol~ii could be stored tbr long periods. Though the conversion is a

simple one. 131 1.; a v;iluable ~nterrnediate as it is smoothly giving the diacid

chloride

The 11< spectrum (Fig. 111 ?a) of 13 1 shows the characteristic absorption

bancls at 3500 ( 0 1 1, sharp), 1800 (y-lactone) and 1600 cm-I (carboxylate anion).

'The band corlespontling to the hydroxyl group is sharp and indicative of the

I : I I I I I I I ~ I I I I I I I ~ I t3 and "C X31K spectra (FI: 111 2 h

, . a i i i Ill 2 i 1 . ! ,ilso colif11111r llie h l ~ r n a t i i ~ i i ot' disodi i~m salt "C N R l R

spr:ctruili I : I peaks n l~ i . r i -boxyl~c a c ~ d salts at 6 170 4 and 177 4

I ls111i. i i \ k , i i ~ ~ ~ ~ ~ i st~lt. n l t ~ . i i l ~ t s \\ere made to p lqal -e the d~ac ld cl~lol-lde by

I I I t l I I I I \ s~~spellsiol i o f 131 111 etlier \\.as treated \vitli

. ; ~ ~ I C ~ I I ~ I I I I ~ ~ I I ~ . .11i,111tlt\ of t l11i i i : i i chlc>r~de to exclusi\el\ \ ~ e l d 132 as a f u r n ~ t ~ ~

s o l ~ d (SC~ICIIIL, I l l 4 1 ( ' l iarncte~ls.itlon o f t l i e coli ipo~ind \vas d ~ f f ~ c u l t due to the

l i ~ g l i leacti\ II\ I l i ) \ \c\ei- the cc~ii- pound \\)as foulid to hc optically actlve ( [ a ] =

7 - 1 1 -- , , ;inJ Ill ,; i~~,~.t lul i i (PIS i l l 1 ) shows the charactelnstlc band IS00 cm-I,

~ ~ I I ~ C S ~ O I ~ L ~ I I I ~ i , ~ < I \ , I ~ cl i lo~-~cie

l l l c ~ L ~ I ~ I I ; I ~ I L ~ I I o f the diiiclJ chloride was further establ~slied b\. preparlny

o f d i~soplop\ I VXICI 1,133). by aiiclilig the requ~red iluantlty o f tli ionyl chloride to a

suspensloli 0 1 I31 I I I 133 was cliaracterlsed by IR, 'H and "C

1 I I s t - ( I I 1 - In fact t h ~ s method is a yelieral entry

to\xiariis t i l e l i ~ c j x i ~ ; ~ t ~ ~ ~ i o f aliv die.,ter o f 127

I I :l,,li<:,.,, 0

127 g , ~~+. .( :]LiF - s o c k oyyyl 3 Ether

31 "'c00Na 132 "',COCI

F c . 1 ROH

1

0 I I

y 1 ; ~ C OOR

Scheme 111.3

131

Fig. IU.2a -~ -~ ~ ~ -

!

-~ ._T_-___(_ _ P 6 5 4 3 Fig. III.2b

/ Fig. 111.3

1 Fig. III.4d

With the ol~lect~ve of preparing chiral synthons of the type 134-137, useful

precursors for the syntheses of natural products and chiral catalysts,

chemoselect~ve reduct~on of the carboxyl groups of 127 and subsequent oxidative

cleavage of I,?-diol moiety of 134 to give 135 were planned. 135 could be a

potential ch~ral precursor for syntheses of various natural products and catalysts

(Scheme 11 1 4 )

Scheme III.4

The select~vit~ of borane reagents, like BH,.THF, BH3SMe2, for the

reduction of carhoxyl groups in presence of lactone carbonyl is well known169.

However thc reduct~on of 127 using Borane-methyl sulphide complex (BMS)

failed to give the expected product Though the TLC of the reaction mixture was

indicative of the complete consumption of 127 and the formation of an

intermed~ate, repeated attempts for the isolation of the product were in vain. Other

borane reagents l ~ k e BH3.THF were also tried without success. The reactions were

carried out in diglyme as we11 as THF. In all the cases, alkaline or acidic work-up

resulted in intractable mixtures. No meaningful reaction was observed during the

attempted reduction of 1;32 with NaBH4/diglyme.

Cons~der~ng the unique structure of 127 which bears two carboxyl groups

along with a hydroxyl group, it is possible to explain the failure of the reduction

reaction. It 1s know11 that dicarboxylic acids and hydroxy acids occasionally react

with borane reagents to give insoluble polymeric intermediates with the inevitable

result of ~ncotnplete reaction170. Formation of lactones due to the partial reduction

of dicarboxyl~c a c ~ d s have also been reported17' (Scheme 111.5). The laxity of the

reaction could also bc due to the formation of stable acyloxyborane complexes.

NaBH4- BF, -a

diglyme C H3

Scheme 111.5

The known for countering such problems associated with the

reduction of d~car-boxylic or hydroxy acids include

(a) carry out the react.ion in the presence of trimethyl borate,

(b) In s r t i r gencrdtion of BH, by the use of sodlum borohydrlde and lodlne

(c) effect the reduct~c~n of carboxyl group after protection of hydroxyl group

Trimethyl borate is known to facilitate the dissolution of polymers formed

during borane reductions. However the reduction reactions of 127 employing

borane reagents in presence of trimethyl borate were carried out and no

improvement was found.

Sodium borollydride-iodine method, described by Periasamy el al, as most

suitable for the chernoselective reduction of dicarboxylic acids and hydroxy acids

in presence of several other functional groups170 also failed to achieve the desired

reduction.

To fi~rther explol-e the poss~bility of achieving the reduction, by protecting

the hydroxyl group, the following scheme was worked out (Scheme 111.6).

Scheme III.6

The attempted acylation of 127 was not successful probably because the

hydroxyl group 1s tert~ary. The use of NBS, the specific reagent recommended for

the bromination of tertiary hydroxyl groups, also did not succeed17'. Again, direct

preparation of M T M ether (130) of a molecule like 127 is not possible. However

the dimethyl ester 129 smoothly underwent the reaction leading to the formation

of 130(chapter 11) Hov~ever the protected ester decomposed on regeneration of the

acid from the methyl ester and hence could not be of use in borane reductions.

It is well known that chloral is employed to protect a-hydroxy carboxylic

acids17'. The protection was attempted with 127. However the major product

obtained upon isolation as methyl ester, was identified as acyclic 139 or 140 and

not 138 (Scheme 111.7) on the basis of available spectroscopic data (Fig. II1.5a-d).

Though 139 or140 do not bear any lactone moiety, its synthetic utility for the

preparation of acycllc chiral synthons is noteworthy.

Scheme III.7

Though the reduction of 127 with borane reagents was not successful,

reduction of 141 (prepared from L-Glutamic acid) with BMS, proceeded with ease

to furnish the expected product (Scheme 111.8). This clearly points to the structural

features of 127. responsible for the failure of borane reagents in effecting the

reduction.

Scheme III.8

Attempts to effect the direct conversion of 127 to 136 by decarboxylation

using concentrated H,>S04 also d ~ d not materia~isel'~. This could be attributed to

the opening u p of the lactone rlng and subsequent fragmentation (Scheme 111.9).

Scheme 111.9

~~~~ ~ ..

- -- --.--.- 7 Fig. m.5b

~- I-~.~

Fig. 111.5d

111.3 Experimental

To an aqueous solution of 127 (2.0 g, 10.5 mmol, in 10 ml water), saturated

aqueous solution of sodium bicarbonate was added till the pH of the reaction

mixture became neutral ( ca 15 ml NaHC03 solution was consumed). The residue

obtained after evaporatlon of the reaction mixture under reduced pressure, was

triturated and washed wi,th dry acetone (5 x 20 ml). The product was finally dried

under vacuum

Yield 2 0 g (82 %)

[alD +81 837'(c 163, H20)

IR (KBr) 3400 (OH, sharp), 1800 (y-lactone) and 1600 cm-I (COO')

'H NMR (D20) : 6 4 . 8 4 ( s , IH) ,3 .19(d , J=17 .8Hz, 1H),2.83 ( d , J = 17.8 Hz., 1 H), 2.27 (s, I H) ppm.

"C NMR (D,O) 6 179.4, 1774, 174.6, 89.1,81.5,42.7ppm.

To a suspens~on of 131(1 0 g, 4.4 mmol) in ether (10 ml), thionyl chloride (

0.7 ml, 10 mmol) was added. The mixture was stirred for two hours at room

temperature F~ltrat~on followed by evaporatlon of the reaction mixture yielded

132 as fum~ng solid

Yield : 0.75 g ((15 %)

[aII, : -2 3' (c 5 74, Acetone)

IR (1KBr) 3450 (OH), 1800 (-COCI), 1750 (y-lactone) and 1725 cm-' (ester).

To a precooled (-5 - 0" C') suspension of 131(1.0 g, 4.4 mmol) in dry

isopropyl alcohol ( 1 0 ml), th~onyl chloride ( 0.7 ml, 10 mmol) was added. The

mixture was then stirred for 48 hours at room temperature. After filtration of the

reaction rnlxture, pH of the filtrate was adjusted to 7.0, by adding saturated

aqueous soliltloil of sodium bicarbonate and was extracted with chloroform (3 x

10 rnl). The combined extract upon drying followed by evaporation furnished an

olly residue The residue was extracted two times wlth 5 ml portions of hexane

and concentratlon of the extract y~elded 134

Yield : 0.5 3 (41 Yo)

[aJD : 1 3 2 0 " (c 1 0 , (IHCI,)

IR (film) : 3500 (OH), 1800 (y-lactone) and 1740 ern-' (ester).

I H NMR (CDCI,) 6 5.10-5.18 (m, IH), 4.94-5.01(m, IH), 3.96 (s, IH), 2.98 ( d , J = 16.3 Hz, lH), 2.93 (d, J = 16.3 Hz, IH), 1.18-1.32 (m, 1i:H) ppm~

' 3 ~ ~ ~ ~ ( ~ ~ l ( ' l . r ~ : 6 171.5, 170.1, 169.2, 74.6, 71.7, 71.1, 69.9, 40.0, 21.6, 2 1.5 ppm.

Mass s p e c t r ~ ~ n ~ rn/z 274 (M+) (7 4) 246 (60 3), 232 (34.2), 216 (21 8), 204 (37 I), 190 (15 8), 174 (23), 162 (523), 144 (58.7), 132 (43 6), 117 (12), 98(15), 76 (52), and 42 (100).

(2S,3S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylicaciddioxolane derivative (1391140):

127 ( 2 0 g, 10 5 mmol) was reacted with anhydrous chloral (1.6g,

10.9 mmol) in presence: of concentrated sulphuric acid (2.5 ml, 26 mmol) at 0 - 5'

C, under anhydrous conditions fbr two hours. After keeping the reaction mixture

overnight, it was quenched by pouring over crushed ice followed by extraction

with ether (4 x 10 ml). The combined extract was dried and treated with slight

excess of an ether~al solution of diazomethane. The mixture was conceritrated and

purified by chromatography (eluent-chloroform : acetone 9: I ) to yield 140.

Yield 0.6 g (16 %).

IR (film) 3450, 1820, 1740 and 1650 crn-I

'H NMR (CDC'l,+OMSO-d,) 6 5.98 (s, IH), 4.56 (s, lH), 3.7 (s, 6 H), 3.41 (d, . I= 18 Hz, lff),3.33 ( d , J = ISHz, 1H)ppm.

"cNMR(cD('I,+DMsO-~~) 6 169.8, 168.9, 168.2, 103.2, 95.1, 83.2, 72.5, 51 8 , 51.6, 36.6 ppm.

Mass spectrum : m/z 365 (M+) (6.6), 335 (14.8), 308 (10.6), 276 (33.8), 201 (5.1) 187 (10.4), 159 (43.8), 141 (12.4), 131 (16.2), 113 (:26.7), 99 i67.2), 83 (26), 74 (29), 59 (loo), 44 (86.7).