A highly enantioselective synthesis of 5- ( I-menthyloxy ) -4-substituted-3-chloro-

2( 5 H ) -furanones

Recently, theR is an incmwingly large lesearch on deveioping synthetic mutea to satwakd and unsaturated 7-butymlactones, which was caused by considerable interests in the occurrence of these substructure in a wide variety of bioactive natural products.’ Optically active Y-substituted butenolides were alS0 remadably useful as the chiral synthons for syntheses of teqenolicbd lactone + m n e s 2 , antileukaemic lignans3 and other biologically active natural Due to the incmsing intemt in the high versatility of butenolides as described above, there have been many reports on the preparation both from natural resomes and from synthetic compounds. Among the previous methods, most of hem are tediousor it seema difEcult to prepam in a large scale for practical use. However, several important approaches to the syntheses and pmpehes of a c h i r a l 5 - m e t h o ~ y - 2 ( 5 H ) - f , ~ chiral5-menthyloxy- 2(5H>-furanones6 and 5-akyl-2(5H)-furanon~’ have recently attracted much sttention owing to their utility as valuable synthetic intermediates in o e c synthesis and asymmetric reactions to prepare some

hetenxyclic cOmpOunds and some biohgidy active nahual products conveniently. As a part of our

Received July 28,1998; revised Nwemba 16, 1998. hj& (No. 29132036) wqrported by the National N d Science F d m of China.

tCurrentaddrese: ac;partmCntofChan&y, GpitdNormalUnkmity, €&nglooO37, chino. C O m a p h author’s Email: qi&uac@h.edU.cn

190 Chinese J o d of Chemistry Vol. 17 No. 2 1999

research programs, we have accomplished the studies of highly stereoselective synthesis for enantiomeridy pure chiral 7-substituted-2 ( 5H )-furanones and their rehted asymrnetxic meactions . Several preliminary communications have been recently reported concerning efficient synthesis of novel ch id sources, 5-( ~-menthyloxy)-3,4-dihalc+2(5H)-furanones and 5 - ( endo-ls-bornyloxy)-3,4-dihalo-2 (5H)-furanones as well as their s t e m n t d e d tandem Michael addition-elimination reaction to obtain various S-alkyloxy4substitut~-3-~~2(SH)-furanones in good yields with d . e. 298% .'

r 1

Results and discussion

An earlier pape2b by Farina et al , showed that 5-methoxy4hd0-2( SH)-furanona reacted easily with amines and thiols to give the products of a nucleophilic vinylic substitution of the bhalogen atom in very good yields. These and especially the 4-halogenated furanones appeared suitable substractes for the induct ion of other functional groups into the b o n e nucleus by nucleophilic substitution of the halogen. AII efficient synthesis of enantiomeridy pure 5-menthyloxy-4-substituted-3-chloro-2 ( 5H )- furanones(2a-2d, 3a-3e) via the stereocontmlled tandem Michael addition-elimination reaction of 1 with various thiols and amines under mild conditions is reported here ( Scheme 1 ) .

The c h d 5- ( 1 ) -menthyloxy-3,4-dichloro-2( 5 H ) -furanone ( 1 ) reacted with an equhnolar amount of various thiols at room temperature in CH2C12 with a catalytic amount of triethylamine to &,ord the

GENG et al. Tandem Michael addition-elimination 191

cctmponding products of iandem Michael addition-elimination reaction, the novel chiral compounds, 5- ( 1)-menthyloxy4substituted-3-chlom-2( 5H)-fUranone~ (2a-2d) , in 42-68% yields with d . e . 2 98%. Under similar experimental conditions, some simple primary and secondary aaines were found to

react with chiral s o w 1 in DMF in a Michael fashion followed by HC1 elimination to yield novel chid compounds, the various 5-( I )-menthyloxy-4-substituted-3-chloIo-2(5H 3a-3e in 50-82% yields with d. e. 298%.

most probably the stereoselective attack of the nucleophile occurs preferentially from opposite to the mnthyloxy p u p , sterically less hindered face. And after

elimination of a mol of HC1, the chiral compounds, 2 ~ 2 d , 3a-%, were obtained in high stereoselectivities ( d . e . 2 98% ) . The absolute configuration at the aced carbon of these compounds were proved to be S by means of X-ray structure analyses of 3a.8b

In conclusion, the novel chiral sources, 5- ( Z ) -menthylo~y-3, bdichloro-2- ( 5 H) - furanones ( i ) was obtained from the cheap furfural and natural chiral awilaryl-menthol. The various enantiomeridy pure 5- ( Z ) -menthyloxy4substituted-3-chloro-2( 5H )-furanones 2a-2d and 3a-3e were prepared efficiently in good yields with d. e . 298% via stereocontrolled tandem Michael addition-elimination reaction of 1 with thiols and amines under mild conditions. Application of this strategy to substituted chid butenolides in asymmetric synthesis is currently under investigation.

On the basis of literature

Experimental

Y&mp5Ob melting point apparatus ( uncorrected) ; Shimazu LJV-760 Ultraviolet ahsorption detector; Hitachi 260-50 and Nicolet IT 170-5x fourier idrated spectrophotometexs; Few hWT 4500 Mass spectrometer; Perkii-Elmer 2.41-C polarimeter; Perkin-Elmer 240-C elementary analysis instnunent; Enraf -N~ni~~ CAD4 X-ray *tometer we= used. 'H NMR spectra were recorded on V&an 300 MIG; and Jeol PMX-60 M H Z nuclear magnetic mnance spectmmetexs (TMS as intemal standad) and 13C NMR spectra on Varian-300 (at 75 MHz) spectrometer in CDC13 and chemical shifts were reported in ppm. Silica gel H ( 10-40 p) was used for flash column chmatography . AU solvents were purified by distillation.

5- ( GMenthyEoxy ) -3,4- dichloo-2( 5 H) -f;.no.e ( 1)

Compound 1 was p repad f b m 5-hydroxy-3,4-dichlom2(5H)-furanone9 and Z-menthol according to the procedure described previously.8b

5-( Z-Menthylmy)4phenylthw-3-chloro-2( 5 H)-+ne (2a)

0.11 g ( 1 mmol) of phenylthiol and 2 dmp of Et3N were added to 0.31 g ( 1 mmol) of 1 in anhydmus CH$& ( 5 mL) . The mixture was SM at mom temperatue for 2.4 h. ?he solvent was

192 Chinese J o d of Chemistry Vol. 17 No. 2 1999

removed under educed pressure, and the remaining mixture was purified by flash column chnwrratagraphy togivepure2aasaw)litesolid: 0.23g(61%). mp108-109OC (frompetrOl-AcOEt). [a]$ -112.02(c, l.40,CHC13). A,-(%% &H50H): 209 nm ( lg=4 .17) , 250 nm (IgE=3.71), 287 nm(lg~=4.07) . u,(KBr): 2949, 2918(CH), 1761(C=O), 1636(C=C), 15%, 14150(Ar), 1132(C-O--C,u,) ~ m ' . &(6OMHZ, CCb): 7.37-7.33(m, 5H, ArH), 5 .89 (~ , lH, 5-H), 3.50-7.33(m, lH, 6-H), 2.26--0.66(m, 18H, M*H)ppm. m / z ( % ) : 382(M' +2,30), 380 (M+, lOO), 225(M+ -C10H19, 30), 138(CloH18+ ,20). A d . hHzSQc1. Calcd.: C , 63.06; H , 6.61. Found: C, 63.08; H, 6.69.

5- ( I - Menthybxy ) 4 bemylho-3- chlonw, -2( 5 H ) -furanone (2b )

As similar as the procedure described for the synthesis of 2a, 2b was obtained fmm 1 and benzylthiolasawhite solid: 0.22g(56%). mp88-89T (hmpetrol-AcOEt). [a]g-38.33(c, 2.03, CHC13). A,-(%% &H50H): 208(1g=4.03), 288(1~=4.86) nm. u,(KBr): 29.54, 2919 (CH), 177O(C=O), 15sri(C=C), 1452(Ph) cm". 6 H ( 3 0 0 MHz, CDCL,): 7.36-7.34 (s, 5H, hH),5.78(s , lH, 5-H), 4.53(d, J = 12.9 Hz, lH, PhCH*), 4.42(d, J = 12.9 Hz, l H , PhCH,), 3.70--3.56(bt, J=10.8, 5.2Hz, lH, 6-H),2.27-2.22(m, 3H, M*H), 1.70-1.64 (m, 2H, M"H), 1.40-1.35(m, 2H, M'H), 1.14-1.06(m,2H, M*H),0.!?2(d, J=6.6Hz, 6H, M'CH,), 0 .78(d ,J=7 .2 Hz, 3H, M*CH3)ppm. aC(75 M H z , CDCl3): 164.08, 154.07, 134.82, 128.82, 128.62, 128.03, 101.80, 101.76, 82.73, 48.06, 42.17, 34.90, 3m3.90, 31.61, 25.18, 22.80, 22.09, 20.99, 15.83 ppm. d t ( % ) : 394(M+, 20), 303(M+ - q H 7 ,

30), 238(M' - M * O H , 20), 91(C7H7+, 100). Anal. CqIHnaCl . Calcd.: C, 63.86; HI, 6.89. Found: C, 63.94; H, 6.88.

As similar as the pmedure described for the synthesis of 2a, 2c was obtained from 1 and furlurylthiol as a whte solid: 0.16 g (42%). mp 83--84"r: ( h m petrol- AcOEt). [a]% - 35.88(c, 1.99, CHC13). &(95% GH50H): 216(1~=3.86) , 286(1ge=3.73)nm. u,(KBr): 2941, 2918 ( C H ) , 1771(C=O), 1588(C=C) ern-'. &(60 M H z , CCb): 7.32-7.27(m, l H , Funuz-H), 6.29-6.24(m, 2H, Furan-H), 5.83(s, lH, 5-H), 4.40(s, 2H, furfuryl-CHz), 3.70-3.40(m, lH, 6-H) , 2.48--0.65(m, 18H, M' H) ppm. m/z( %): 384(M' , lo) , 303(M+ - C-jHsO, lo), 2 4 5 ( M + - M' , 20), 81(GH50' , 100). Anal. C,9HZSO,Cl. Calcd. : C, 59.29; H, 6.54. Found: C , 59.31; H, 6.53.

As similar as the procedure described for the synthesis of 2a, 2d was obtained from 1 and pentylthiol as awhitewlid: 0.22g(58%). mp64-65 C (bmpetrol-AcOEt). [a]Fg+2.98(c, 1 , CHCI,).

GENG et d. Tandem Michael addition-elimination 193

&(95% GH50H): 192 (lgs=3.55), 288(1ge=4.17)nm. u-(KBr): 2950, 2910(CH), 1760(C = 0) ,1600( C = C)cm-'. &(6OMEG, CQ) : 5.70( s , 1H,5H) , 3.60-3.40(m, l H , 6-H) , 3.20-3.12(m, 2H, pentyl-H), 2.48-0.78(m, 27H, M"H, pentyl-H)ppm. rn / z (%) : 376(M+ +2, 30), 374(M+.85), 237(C1.&1@', loo), 95(&H44Cz', 5 5 ) , 71(GHll+ 40). Anal. C19H31S@c1. Cdcd.: C, 60.86; H, 8.33. Found: C, 61.12; H, 8.60.

5- ( 1 - M d y l m y ) 4pylTolid;lo-3-&m-2(5 H ) -fiarwne (3a)

0.31 g (1 mmol) of 1( 1 m l ) and 0.1 mL (0.12 mmol) of pymlidine dissolved in anhydmus DMF ( 5 mL) , stirred at room tempemhue for 24 h . The solvent was removed under reduced pressure and the residue was chmnatographed to give pure 3a as a white solid: 0.24 g (71%). mp 127-128t (h peml- AcOEt). [a]g+85.65(c, 1.77, CHC13). &(%% GH50H): 200 (IgE=3.08), 289(b=3.95) nm. u,(KBr): 2982, 2931(CH), 1753(C=O), 1633(C= C) , 1123(C--O-C, u,)cm-'. &(300 MHz, CDC13>: 5.75(s, lH, 5-H), 3.*3.70(m, 4H, py~mlidine-H), 3.58 (bt, J=l0.8, '4.2Hz, lH, 6-H), 2.21-2.15(m, 3H, M"H), 1.97-1.93(m,4H, p l i d i n e H ) ,1.66-1.63( m,2H,M* H) ,1.36-1.28(m,2H,M" H) , l .16-1.10(m,2H, M" H) , 0.92 (d, J=6.6Hz, 6H, M"CHs), 0.77(d, J=7 .2 Hz, 3H, M"CH3) ppm. 6 ~ ( 7 5 MHz, CD- C13): 168.19, 154.87, %.97, 85.91, 80.13, 48.94, 48.16, 42.24, 33.91, 31.65, 25.08, 24.

168(C1,HmO+ , l oo ) , 129( G&NCI+ ,90) .Anal. C18HaNQCl. Cdcd. : C,63.34; H , 8.21 ; N, 98, 22.69, 22. 18, 21. 19, 15. 17 ppm. m / z ( % ) : 341 (M', a), 203(M+ - M", 40),

4.10, Found: C, 63.23; H, 8.25; N, 4.05.

5- ( 1 - M d y h y ) 4 p + ~ i d i n 0 -3- chloro-2( 5 H)-*M (3b)

As similar as the pmcedure described for the synthesis of 3a,3b was obtained fmm 1 and piperidine asawhitesolid: 0 .23g (64%). mp 160-161"c (hpetml-AcOEt). [a]g-67.12(c, 1.68, CHCl3). &(95% &HsOH): m ( b = 3 . 3 9 ) , 281(1@=4.12). u,(KBr): 2948, 2925(CH), 1747( C = 0) ,1628( C = c ) ,1120( c-o-c, V,)Cm-'. &( ~ O O M H Z , m 3 ) :5.76( 9 , l H , 5-H), 3.69-3.51(m, 5H, 6-H, pipridindH), 2.27-2.15(m, 3H, M"H), 1.70-1.68(m, 6H, pipridine-H), 1.64-1.62(m, 2H, M*H), 1.35-1.31(m, 2H, M"H), 1.14-1.10(m, 2H, M*H), 0.92(d, J = 5.7 Hz, 6H, M" C H 3 ) , 0.76(d, J = 6.9 Hz, 3H, M" (333) p p . &(75 MHz, CDC13): 168.20, 154,97, 97.15, 86.58, 80.73, 49.02, 48.08, 42.42, 33.90, 31.65, 26.09, 25.02, 23.88, 22.72, 22. 18, 21. 17, 15.71 ppm. m / z ( % ) : 355(M+, lo), 135 (&€&NO+ , 95), 39( &H3+ ,100). Anal. C19HxNQCl. Cdcd. : C, 64.22; H, 8.45; N, 3.94. Found: C, 64.28; H, 8.49; N, 3.88.

5-( 1 - Menhyhy) -4- m ~ b h - 3 - chloro-2( 5 H) -f;...m (3~)

A s similar as the procedure described for the synthesis of 3a, 3c was obtained from 1 and

194 Chinese J o d of Chemistry Vol. 17 No. 2 1999

morpholineas awhitesolid: 0.28g (78%). mp147-148% (frornpetrol-AcOEt). [ a ] g - . 3 4 . 5 ( c

( C H I , 1760(C=O), 164O(C=C), llU)(C-O-C,u,) crn-I. & ( 6 O M H z , CC4): 5.71(s, lH, 5- H), 3.@-3.60(m, 9H, 6-H, mo1pholine-8H), 2.32-0.68(m, 18H, M*H)ppm. m / z ( % ) :

1.45, CHCl3). &(95% GHsOH): 201(&=3.55), 280(& =3.13)nm.~-(KBr): 2950, 2850

358(M' + I , 30), 357 (M', loo), 202(M+-M"OH, 30), 145(C&NOCl+, 30). Anal. ClsHB- NOdCI. Calcd.: C, 60.41; HJ.89, N ; 3.91. Found: C , 60.12; H, 8.28; N , 3.98.

5-( 1- Menthrlozy ) 4 beqkmizw-3- &r0-2( 5 H )-f;....e (3d)

As similar as the p d m described for the synthesis of 3a, 3d was obtained from 1 and benzylamineasawhitesolid: 0.31 g (82%). mp 121-122T (hpetrol-AcOEt). [a]g+58.77 ( c , 1.87, CHCl3). &(95% GH5OH): 204(lge=3.93), 275(&=4.23)m. u,,(Kl31?): 3300 (NH), U)90(AKH), 2950(CH), 1740(C= O ) , 164O(C= C), 1450(Ar), 114O(C+-C,u,) cm-]. &(60 M H z , CCb): 7.15-7.10(rn, 5H, ArH), 6.2€)-5.%(m, lH, NH), 5.66(s, lH, 5- H). 4.70-4.60(rn, 2H, P h C H 2 ) , 3.60-3.40(m, lH, H-6), 2.33-0.65(rn, 18H.M"IH) pprn. m / ~ ( % ) : 379(M' + 2 , 201, 377(M+, 60), 91(phCH2, 80), 43(C3H7+, 100). Anal. (&Ha- NQC1. Calcd.: C, 66.74; H, 7.47; N, 3.71. Found: C, 66.83; H, 7.66; N, 4.13.

5-( Z-Menthyluxy ) 4 R-( + )-a- mthyt%erq--3- chloro-2( 5 H) -fwanone (3e)

As similar as the procedure described for the synthesis of 3a, 3e was obtained fnwn 1 and R-( + )- a-methylbenzylamine as a white solid: 0.19 g ( 5 0 % ) . mp 167-168t (fmm petrol - AcOEt). [ a ] E

(KBr): 3272(NH), 2955, 2865(CH), 1783(C=O), 1632(C= C), 1455(Ar), 1122(C--O-C, u,) cm". 6 ~ ( 3 0 0 MHz, cDc13): 7.38-7.34(rn, 5H, Ar-H), 5.55 (5, IH, 5-H), 5.15-5.10 (br, lH, NH), 4.%-4.90(m, lH, methylbenzylamine-CH), 3.52(bt, J=10.8, 5.2Hz, lH, 6- H ) , 2.30-2.10(rn, 3H, M " H ) , 1.69-1.63(m, 2H, M"H), 1.59(d, J = 6 . 9 IHZ, 3H, methylbeqhe-CH3), 1.38-1.32(m, 2H, M * H ) , 1.16-1.01(m, 2H, M"H), O.!X?(d, J =

?iC(75 MHz, CDC13>: 166.99, 155.71, 142.45, 128.93, 127.73, 125.02, 97.58, 82.02, 77.09,

+84.40(~, 1.68, CHC13). & ( 9 5 % GH5OH): 24E( lg~=3.55) , 277(lg~=4.91)tm1. U,

5.7 Hz, 3H, M"CH3), 0.90 ( d , 5 = 6 . 3 Hz, M*CH-,), 0.79(d, 5 ~ 7 . 2 Hz, 3H, M"CIH3)ppm.

52.85, 47.97, 42.17, 33.88, 31.54, 25.52, 24.11, 22.80, 22.04, 20.99, 15.83 pptn. m/z ( % ) : 391(M+, lo), 105(PhCHCH3+, 100). Anal. CpHwNQCI. Calcd: C, 67.42; H, 7.72; N, 3.57. Found: C, 67.37; H , 7.88; N, 3.79.

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GENG r t nl. Tandem Michael addition-elimination 195

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