A simple and direct method of cyclization for the ...

0 downloads 0 Views 728KB Size Report
G. ILLUMINATI and L. MANDOLIN]. ACC. Chem. Res. 14, 95. (1981). 18. A. P. KRAPCHO, G. A. GLYNN, and B. J. GRENON. Tetrahedron. Lett. 3, 215 (1967).
A simple and direct method of cyclization for the synthesis of 10-membered rings PIERREDESLONGCHAMPS, SERGELAMOTHE,' A N D Ho-SHEN LIN Laboratoire de synthPse organique, De'partement de chirnie, Faculre' des sciences, UniversitP de Sherbrooke, Sherbrooke (Que'.), Canada J1K 2R1 Received December 4, 1986 PIERRE DESLONGCHAMPS, SERGE LAMOTHE, and Ho-SHENL ~ NCan. . J. Chem. 65, 1298 (1987).

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

Ten-membered rings containing two unsaturations are produced without the use of high dilution techniques by the intramolecular malonate anion displacement of an allylic chloride. PIERREDESLONGCHAMPS, SERGE LAMOTHE et Ho-SHENLIN.Can. J. Chem. 65, 1298 (1987). La synthkse de cycles 2 10 membres contenant deux insaturations est realisCe sans utiliser les techniques de haute dilution par dkplacement intramolCculaire d'un chlorure allylique par l'anion malonate. [Traduit par la revue]

The last decade has seen organic chemists gain interest in the synthesis of medium and large rings (1-8). The growing activity in this area was triggered by the sophistication of already existing techniques along with discovery of new ones for structure determination of organic molecules. Many naturally occurring compounds contain medium and large rings but few reliable methods for the preparation of such systems by direct cyclization involving carbon-carbon bond formation are known to this day (1-8). Moreover, most published methods require the use of high dilution techniques (either high dilution or slow additions of the substrate) to avoid polymerization. The 10-membered ring is known to be one of the most difficult rings to prepare; it combines strong enthalpy effects (Baeyer, Pitzer, and transannular strains) with a disfavorable entropy effect that keeps terminal carbon atoms from approaching within reacting distance (9). An efficient way to overcome the problems associated with medium ring closure is to replace sp3carbon atoms in the chain by sp2or sp carbons. This has the effect of lowering the number of degrees of freedom of the molecule, thereby statistically favoring encounters between the ends of the chain (10). Moreover, the proper disposition of those unsaturated carbon atoms can substantially reduce transannular interactions. With this in mind, we chose to prepare precursors l a in all possible combinations (A-A, C-A, T-A, T-C, T-T, C-C) (Scheme 1) in order to obtain monomers 2a and cyclic dimers 3a (C = cis olefin, T = trans olefin, and A = acetylene). The preparation of the different precursors l a is described in Scheme 2. We chose commercial diol4 as our starting material since it could readily be converted into all precursors but one l a . Mono protection (1 1) followed by formation of the allylic chloride using Meyers's procedure (12) afforded olefin 6 . Three sequential alkylations were then carried out starting with dimethyl malonate to give 7 , which was coupled with 1,4dichloro-2-butyne. The resulting chloride 8 was reacted with another equivalent of dimethyl malonate affording tetraester 9 . Simple deprotection (13) and chlorination of the resulting allylic alcohol 10 afforded precursor 1a [C-A] . Alkylation of 6 with tetraester 11 (obtained in 2 steps from 1,4-dibromo-2-butyne) afforded precursor l a [C-C] after the usual deprotection and chlorination sequence. For the trans series we needed to prepare chloride 16, which was easily obtained by reduction and chlorination (14) of the known aldehyde 14 (previously prepared by Corey and Suggs (15)). Again, coupling with tetraester 11 gave 17, which was 'NSERCC and FCAR predoctoral fellowships, 1983- 1987.

readily transformed into precursor l a [T-C] through alcohol 18. Introduction of a malonate moiety on chloride 16 gave 19, which could be alkylated by either trans- 1,4-dichloro-2-butene, affording precursor l a [T-TI, by the usual sequence or by 1,4-dichloro-2-butyne to give 23, which was then converted to precursor 1 a [T-A] . The last possible precursor was the one containing two triple bonds. 2-Butyne-1,4-diol was chosen as the starting material and afforded, after monochlorination (16) and alcohol protection, acetylene 28. Three subsequent alkylations transformed 28 into tetraester 31, which was readily converted to precursor l a [A-A] .2 The cyclization runs were carried out in a mixture of N,Ndimethylformamide and tetrahydrofuran with excess potassium carbonate at either 2 x l o p 2 or 2 x l o p 3 molar concentrations and without the use of high dilution techniques. The results are listed in Table 1. Monomer yields vary from 10 to 84% depending on the nature and geometry of the unsaturations, and the effect of concentration is important in most cases. Interestingly, yields as high as 42% were observed in the formation of cyclic dimers, showing that 20-membered ring cyclization is an important secondary process that can be even more important than polymerization, in some cases. Molecular model examination of the cyclization process shows that one of the carbomethoxy groups in the middle of the chain must take an orientation (e.g. pseudo-axial in the case of [A-A]) generating unfavorable steric interactions that could be stronger than the favorable gem-dimethyl effect ( 1 7 ) . ~This could be demonstrated by comparing cyclization results for decarbomethoxylated precursors l b (Scheme 1) with those obtained for tetraesters l a . The preparation of precursors 1b is detailed in Scheme 3. The previously prepared malonate 29 was alkylated with chloride 33 affording 34, which after selective deprotection was decarbomethoxylated using Krapcho's procedure (18) at a relatively low temperature. The resulting propargylic alcohol 36 was readily converted to 1 b [A-A] following the usual sequence. Decarbomethoxylation prior to alkylation of malonate 7 provided a shorter route to precursors 1 b. 1,4-Dibromo-2-

or

preparation of a similar compound see ref. 7. 3~lthoughthe gem-dimethyl effect is known (17) to be small in saturated 10-membered ring formation, we believed that it could be stronger in the case of unsaturated substrates because of a larger degree of conformational restriction.

DESLONGCHAMPS ET AL

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

=

.

Represents double bond [cis (C) or trans (T)] or acetylene (A) I SCHEME

butyne was used to alkylate monoester 40 affording bromide 41, which was converted in 3 steps to precursor l b [C-A]. The same sequence using trans malonate 19 afforded trans-acetylene precursor l b [T-A]. Alkylation of monoester 44 with trans-l,4-dibromo-2-buteneafforded allylic bromide 50, which was readily transformed into precursor l b [T-TI. Finally, partial hydrogenation of intermediate 46 with Lindlar catalyst provided direct access to precursor l b [T-C]. Triesters l b were submitted to the same reaction conditions as tetraesters l a (Table 2). The results clearly indicate that within experimental error most cyclization processes are not influenced by the removal of one carbomethoxy group. Two isolated cases (entries 2 and 10) give respectively much more monomer and dimer than the corresponding tetraesters but we found no consistent explanation to rationalize these facts. However, detailed molecular model studies could perhaps provide an explanation. The 10-membered ring is one of the most difficult to synthesize by way of direct cyclization (9, 17). The above results show that suitably functionalized precursors can provide respectable yields of cyclic monomers even without the use of high dilution techniques. It has already been proven in our laboratory that this method can be extended to the preparation of large rings ( l a , b ) . Progress is now being made in the synthesis of polycyclic molecules from macrocyclic precursors available by the above cyclization method.

TABLE1. Cyclization results for tetraesters l a

Entry

Compound

Time (h)

M

% Monomer

% Dimer

2a

3a

*K2C03/acetone,reflux. TABLE2. Cyclization results for triesters l b

Entry 1 2 3 4 5 6

Compound

Time (h)

[A-A]

16

[C-A1

24

[T-A]

24

%

90'

M

Monomer

Dimer*

2~10-, 2 x lo-3 2x10-' 2 x lo-3 2 x lo-, 2~ lo-3

26 70 53 80 29 68

42 13 27 9 48 28

Experimental .

, ... . . . ..

.. ... . . . .. . . ., . . . . . ... ....

All reactions were carried out under an argon atmosphere. The infrared spectra (ir) were taken on a Perkin-Elmer 68 1 spectrophotometer. Proton nmr spectra were recorded on a Varian EM-360, Bruker WP-60, Bruker WP-80 SY, orBruker WP-250 instrument. Carbon nmr spectra were recorded on a Bruker WP-80SY instrument. Mass spectral assays (ms m/e) and peak matching were obtained using a VG Micromass ZAB-IF spectrometer. Chromatographic separations were made using Merck Kieselgel 60 (230-400 mesh ASTM). Chemical shifts are reported in 6 values relative to tetramethylsilane. Abbreviations used are m: multiplet, s: singlet, t: triplet, d: doublet, dt: double triplets, app: apparent, br: broad, qc: quaternary carbon. No attempts were made to optimize the yields of most reactions. Mono-protected diol 5 To an ice-cooled solution of diol 4 (9.9 g; 114 mmol) and dihydropyran (9.6 g, 114 mmol) in 100 mL of methylene chloride and 250 mL of tetrahydrofuran was added p-toluenesulfonic acid (1.5 g) with vigorous stirring. After 90 min the mixture was allowed to warm up to room temperature and stirred an additional 90 min. Aqueous sodium bicarbonate (50 mL) was added to the mixture, and the water layer was separated and extracted with ether (2 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered,

* Cis-trans mixture. and concentrated to give an oily residue that was purified by column chromatography (3% acetone in dichloromethane) to afford monoprotecteddiol5 (10.4 g, 53%);ir(neat): 3400,2945, 1120, 1030 cm-'; nmr (CDC13) 6: 6.20-5.50 (2H, m, -CH=CH-), 4.90-4.60 (IH, m, 0-CH-O), 4.60-3.30 (6H, m, -CH2-CH2-0 and =C-CH2-0), 2.75 ( l H , s, -OH), 2.10-1.10(6H, m,-(CH2)3CH20); ms m/e (CI, CH,): 173 (M+ + 1). Chloride 6 (Procedure A) A stirred mixture of alcohol 5 (6.88 g, 40 mmol), syn-collidine (5.33 g, 44 mmol), and lithium chloride (1.70 g, 40 mmol) was dissolved in 60 mL of N,N-dimethylformamide. On cooling to O°C, a suspension was formed, which was treated dropwise with methanesulfonyl chloride (3.41 mL, 44 mmol). Stirring was continued at 0°C for 15 min, then at room temperature for 1 h. The yellow reaction mixture was poured over ice-water (300 mL) and extracted with

CAN. J. CHEM. VOL. 65, 1987

I

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

8 dL 9 eLIO bLla

X X = OTHP, Y = C1 X = 0THP.Y =CHE2 X = OH, Y = CHE2 [C-A] X = C1, Y = CHE2

12 X = OTHP eL13 X = O H b L l a [c-CI x = CI

14 X = = O 16 X = C1

~

2 24 L25 bLla

X 3= OTHP, Y = CI X = OTHP, Y = CHE2 X = OH, Y = CHE2 [T-A] X = C1, Y = CHE2

26

19

27 X = OH, Y = Cl j L28 X = OTHP, Y = C1 CL29 X = OTHP, Y = CHE2

E 17 X = OTHP eC18 X = O H L l a [T-CI x = CI

20 CL21 eL22 bLla

X = OTHP, Y = C1 X = OTHP, Y = CHE2 X = OH, Y = CHE2 [T-T] X = CI, Y = CHE2

30 "31 eLf2 bCla

X = OTHP, Y = C1 X =OTHP,Y =CHEl X = OH, Y = CHEa [A-A] X = CI, Y = CHE?

(a) DHP, F'TSA, CH2CI2-THF; (b) LiCI, MsCI, collidine, DMF; (c) CH2(C02Me)2,K2C03, DMF-THF; (d) K2C03, DMF-THF; (el P R S , MeOH; (f) sodium tert-amylate, benzene; (g) PCC, ACONa, CH2CI2,molecular sieves 4A; (h) DIBA-H, CH2C12; (i) SOC12, Py, benzene; (j) DHP, CF3C02H, CH2C12 SCHEME 2

DESLONGCHAMPS ET AL

E

/C1

f < ~ Ill

111

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

LOTHP

33

),3.39 (IH, t, OTHP), 4.08 (2H, t, J = 2.2Hz, -CH2-Cl), 3.76 (6H, s, J = 7.5 Hz, -CH(C02Me)?), 3.03-2.21 (6H, rn, =C-CH2-C): rns m l e (20 eV): 405 (M+(%) + I), 407 ( M + ( ~ ~+C l~) ,)ratio 3: 1. -(C02Me)2), 4.04-3.39 (2H, rn, CHI-CH2-0), 3.22-2.87 (4H, rn, -CH2-C(C02Me)2-CH2-), 2.04- 1.27 (6H, rn, -(CH2)3Chloride 23 CH20); ms m l e (10eV): 371 ( M ' ( ~ ~ c I )+ I), 373 ( M + ( ~ ~ c+ I ) l), Using procedure B, rnalonate 19 (970 rng, 3.4 rnmol) and 1,4ratio 3: 1. dichloro-2-butyne (2.1 g, 17.0 rnmol) gave, after column chrornatogTetraester 31 raphy (2% acetone in dichlorornethane), chloride 23 (927 rng, 73%); ir (neat): 1740, 1210, 1200, 1023 crn-';nrnr(CDC13)6:6.00-5.20(2H, Following procedure B , chloride 30 (2.10 g, 5.7 rnrnol) and dirnethyl rnalonate (3.74 g, 28.4 rnrnol) afforded, after column rn, -CH=CH-), 4.84-4.45 .(1H, rn, 0-CH-0), 4.09 (2H, chromatography (1% acetone in dichlorornethane), tetraester 31 t, J = 2.3 Hz, -CH2--Cl), 3.75 (6H, s, -C02Me), 4.39-3.41 (2.45 g, 93%); ir (neat): 2953, 1762, 1733, 1438, 1021 crn-I; (4H, m, CH2-CH2-0 and =C-CH2-0-), 3.12-2.57 (4H, rn, nmr (CDC13) 6: 4.75 (lH, br s, 0-CH-0), 4.20 (2H, t, J = -CH2-C(C02Me)2), 2.20-1.20 (6H, rn, -(CH2)3-CH20); rns 2.2 Hz, -CH2-OTHP), 3.77 (6H, s, R2C(CO2Me)?), 3.74 (6H, m l e (70 eV): 373 (M+ ( 3 5 ~+~ I), ) 375 (M+(37C1)+ I), ratio 3: 1 . s, -CH(C02Me)*), 3.91 -3.20 (3H, rn, -CH(C02Me)2 and CH2Malonate 24 CH2-0), 3.06-2.53 (6H, rn, =C-CH2-C), 1.94- 1.19 (6H, rn, Chloride 23 (896 mg, 2.4 mrnol) was treated according to procedure -(CH2)3-CH20); rns tnle (70 eV): 466 (M+), 465 (M+ - 1). B, affording, after column chromatography (2% acetone in dichloroAlcohol 32 methane), rnalonate 24 ( I . 1 g, 94%); ir (neat): 2955, 1760-1730, Using procedure C , tetraester 31 (2.36 g, 5.1 rnrnol) gave, after 1438, 1280-1 116, 1038, 1032, 1024 crn-'; nmr (CDC13) 6: 5.94column chromatography (2-5% acetone in dichlorornethane), alcohol 5.14 (2H, rn, -CH=CH-), 4.9 1-4.41 ( l H , rn, 0-CH-0), 3.99 32 (1.83 g, 94%); ir (neat): 3500, 1745, 1440, 1345-1 150crn-I; nmr (2H, t, J = 5.2 Hz, -CH2-Cl), 3.73 (6H, s, R2C(C02Me)2), (CDC13) 6: 4.20 (2H, dt, J = 6.1 and 2.1 Hz, -CH2-OH), 3.77 and 3.68 (6H, S, -CH(CO2Me)?), 4.36-3.22 (5H, rn, CH2-CH2-0, 3.74 (12H, boths, -C02Me), 3.53 ( l H , t, J = 7.5 Hz, -CH(C02Me)2), -CH(COrMe)2), and -CH2-OTHP), 3.07-2.32 (6H, rn, -CH23.10-2.60 (6H, m,-C-CHI-C), 1.92 (IH, t, J = 6.1 Hz, -OH); C(C02Me)2)-CH2and -CH2-CH), 2.04-0.81 (6H, rn, rns m l e (70 eV): 382 (M+), 381 (M+ - 1). -(CH2)3-CH20); rns m l e (70eV): 468 (M+).

Alcohol 25 Following procedure C, rnalonate 24 (1.02 g, 2.2 mrnol) gave, after

Precursor 1 a [A-A] Treatment of alcohol 32 (1.80 g, 4.7 mrnol) according to procedure

1304

CAN. J. CHEM.VOL. 65, 1987

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

A afforded, after column chromatography (1% acetone in dichloromethane), precursor l a [A-A] (1.74 g, 92%); ir (neat): 2960, 1740, 1440, 1210 cm-I; nmr (CDC13) 6: 4.06 (2H, t, J = 2.2 Hz, -CH2-Cl), 3.75 and 3.73 (12H, both s, -C02Me), 3.51 (lH, t, J = 7.4 Hz, -CH(C02Me)2),3.23-2.44 (6H, mC-CH2-C); ms m/e (70 eV): 401 (M+(35~1) + 1) and 403 (M' (37C1)+ l), ratio 3: 1. Chloride 33 To a stirred solution of alcohol 27 (16.4 g, 155 mrnol) and triethylarnine (17.2 g, 170 mmol) in 500 mL of dichloromethane at 0°C was added chloro-tert-butyl dimethylsilane (26.3 g, 170 mmol). The mixture was warmed to room temperature and stirred for 24 h. Water (600 mL) and ether (800 mL) were added and, after separation, the water layer was washed with 2 X 600 cm3 ether. The combined organic layers were dried over sodium sulfate and concentrated to give an oily residue that was subjected to column chromatography (1% acetone in dichlorornethane) to afford chloride 33 (23.2 g, 84%); ir (CHC13): 2960, 2930, 2860, 1260, 1145, 1080, 835 cm-I; nmr (CDCl,) 6: 4.4 and 4.0 (4H, both t, J = 2.0 Hz, -CH2-), 0.9 1 (9H, s, t-Bu), 0.12 (6H, S, -CH3). Alcohol 35 Following procedure B, rnalonate 29 (1 8.2 g, 63 rnrnol) and chloride 33 (13.3 g, 69.7 mmol) gave, after work-up, crude adduct 34, which was dissolved in tetrahydrofuran (500 mL) at O°C. To that solution was added tetra-n-butylammoniurn fluoride (60 mmol) and the resulting mixture was stirred at room temperature for 2 h. Evaporation of the solvent gave a crude oil, which was purified by column chromatography (10% acetone in dichloromethane) to afford alcohol 35 (1 1 g, 58% overall); ir (neat): 3610,3700-3100, 1740 cm-l; nmr (CDC13) 6: 4.78 (lH, m, 0-CH-O), 4.21 (4H, app t, J = 2 Hz, -CH2-O), 3.76 (6H, s, -COIMe), 3.90-3.25 (2H, m, CHI-CH2-0), 3.00 (4H, t, J = 2 Hz,=C-CH2-C), 1.90-1.25 (6H, m, -(CH2)3-CH20). Chloride 37 A solution containing diester 35 (3.12 g, 8.9 mrnol) and sodium cyanide (830 mg, 17.7 mmol) in 100 mL of dimethylsulfoxide was stirred at 100°C for 1.75 h. The cooled reaction mixture was then diluted with 400 mL of water and extracted with a mixture of ether, hexane, and rnethylene chloride 4:4:1 (4 X 200 cm3). The combined organic layers were washed with water (2 X 50 cm3) and dried over sodium sulfate. The residue was purified by column chromatography (10% acetone in dichloromethane) to afford ester 36 (58%), which was treated according to procedure A, giving, after column chromatography (1% acetone in dichloromethane), chloride 37 (1.42 g, 84%); ir (neat): 2950, 1740, 1025 cm-I; nmr (CDC13) 6: 4.79 (lH, m, 0-CH-0), 4.23 (2H, m, -CH2-OTHP), 4.1 1 (2H, m, -CHI-Cl), 3.73 (3H, s, -C02Me), 3.80-3.25 (2H, m, CHICH2-0), 3.00-2.25 (5H, rn, -CH2-CH(C0,Me)-CH2-), 1.90- 1.25 (6H, m, --(CH2)3-CH20). Alcohol 39 Using procedure B, chloride 37 (1.40 g, 4.5 mrnol) and dimethyl malonate (2.96 g, 22.4 mmol) afforded, after work-up, crude malonate 38 (1.75 g), which was treated according to procedure C to give, after column chromatography (4-10% acetone in dichloromethane), alcohol 39 (1.16 g, 82% overall); ir (neat): 3520, 2960, 1735, 1435, 1030 cm-I; nmr (CDC13) 6: 4.20 (2H, app d, J = 6.0 Hz, -CH2-OH), 3.78 (6H, s, -(C02Me),), 3.72 (3H, s, -C02Me), 3.54 (lH, m, -CH(CO,Me),), 2.90-2.25 (7H, m, --CH2-CH(C02Me)CH2- and -CH2-C(C02Me)2), 1.90 (lH, app t, J = 6.0 Hz, -OH). Precursor 1 b [A-A] Following procedure A, alcohol 39 (524 mg, 1.6 mmol) afforded, after column chromatography (2% acetone in dichloromethane), precursor 16 [A-A] (524 mg, 95%); ir (neat): 2960, 1740, 1440, 1030 cm-I ; n m (CDC13) 6: 4.1 1 (2H, m, -CH,-Cl), 3.77 (6H, s, -(C02Me)*), 3.72 (3H, s, -CH(C01Me)2), 3.55 (IH, t, J = 7.4 Hz, -CH(C02Me)2), 2.90-2.50 (7H, m, -CH2-CH(C0,Me)-CH2 and -CH2-C(C02Me)2).

Ester 40 (Procedure E) To a solution containing malonate 7 (5.0 g, 17.5 mmol) in 35 mL of dimethyl sulfoxide was added sodium cyanide (1.7 g, 35 mmol) and water (315 mg, 17.5 rnmol). The mixture was then stirred at 140145°C for 5 h, poured over 500 mL of water, and extracted with ether-hexane (1:l) (3 x 200 mL). The combined organic layers were washed with water (2 X 75 mL) and saturated aqueous bicarbonate solution (1 X 75 rnL), and dried over sodium sulfate. Column chromatography purification of the residue (2% acetone in dichloromethane) afforded ester 40 (2.1 g, 53%); ir (CHCI3): 2950, 1740, 4.62 1025 cm-I; nmr (CDC13) 6: 5.60 (2H, m, -CH=CH-), (1H, m, 0-CH-0), 4.18 (2H, m, -CHI-OTHP), 3.67 (3H, s, -C02Me), 4.00-3.20 (2H, m, CH,-CHI-O), 2.40 (4H, m, -CH2-CH2-C02Me), 1.75- 1 .OO (6H, m, -(CH2)3-CH20). Bromide 41 (Procedure F) To a stirred solution of diisopropylamine (107 mg, 1.1 mrnol) in 0.8 mL of tetrahydrofuran at O°C was added n-butyllithium (1.0 mrnol). After 30 rnin, the temperature was lowered to -78"C, ester 40 (200 mg, 0.9 rnmol) was added, and the mixture was allowed to react for 20 rnin after which 1,4-dibromo-2-butyne (373 mg, 1.8 mmol) was added rapidly. The resulting mixture was stirred at -78°C for 1.5 h and quenched with saturated aqueous ammonium chloride. Water was added and the mixture was extracted with ether (3 X 20 mL). The combined organic layers were washed with bicarbonate (10 rnL) and water (10 mL), dried over magnesium sulfate, and concentrated to give a crude oil that was subjected to column chromatography (1-2% acetone in dichloromethane) to afford bromide 41 (180 mg, 57%); ir (CHC13): 3005, 2945, 1735, 1020 cm-' ; nmr (CDCl,) 6: 5.9-5.4 (2H, rn, -CH=CH-), 4.61 (lH, rn, 0-CH-0), 3.70 (3H, s, -C02Me), 4.30-3.20 (6H, rn, -CH2-OTHP, CHI-CH2-0 and -CH,-Br), 2.80-2.30 (5H, rn, -CHI-CH(C02Me)-CH2-), 1.60 (6H, m, -(CH2)3-CH20). Malonate 42 Bromide 41 (1.40 g, 3.9 mmol) and dimethyl malonate (1.90 g, 4.4 rnrnol) were treated according to procedure B (except for temperature, which was kept at 35OC) affording, after column chromatography (2% acetone in dichlorornethane), malonate 42 (1.50 g, 94%); ir (CHC13): 3020, 2950, 1740, 1440, 1025 cm-I; nmr (CDC13) 6: 5.90-5.40 (2H, m, -CH=CH-), 4.60 (1H, m, 0-CH-0), 3.75 (6H, s, -(C02Me),), 3.69 (3H, s, C02Me), 4.30-3.35 (5H, m, -CH2-OTHP, CH2-CH2-0, and -CH(C02Me),), 2.90-2.25 (7H, m, -CH2-CH(C0,Me)-CH2and -CH2-C(C02Me),), 1.60 (6H, m, -(CH2)3-CH20). Alcohol 43 Using procedure C, malonate 42 (1.50 g, 3.7 mmol) afforded, after column chromatography (4- 10% acetone in dichloromethane), alcohol 43 (1.03 g, 87%); ir (CHC13): 3620, 3530, 3020, 2960, 1735 cm-I; n m (CDCI3) 6: 6.00-5.30 (2H, m, -CH=CH-), 4.30-4.00 (2H, m, -CH2-OH), 3.75 (6H, s, -(C02Me),), 3.68 (3H, s, -C02Me), 3.54 (lH, app t, J = 7 Hz, -CH(C02Me),), 2.90-2.20 (7H, m, -CHI-CH(C02Me)-CH2and -CH2-C(C02Me)2), 1.901.60 (lH, m, -OH). Precursor 1 b [C-A] Following procedure A, alcohol 43 (1 .O g, 3.1 mmol) afforded, after column chromatography (1% acetone in dichloromethane), chloride 16 [C-A] (956 mg, 90%); ir (CHC13): 3030, 2960, 1740, 1440 cm-I; nmr (CDC13) 6: 5.80-5.40 (2H, m, -CH=CH-), 4.10 (2H, m, -CH2-Cl), 3.75 (6H, s, -(CO2Me),), 3.68 (3H, s, -C02Me), 3.54 (lH, t, J = 7.7 Hz, -CH(C01Me)2), 2.74 (2H, dt, J = 7.7 and 2.65-2.30 (5H, m, -CHI2.3 Hz, =C-CH2-C(C02Me),), CH(C0,Me)-CH2-). Ester 44 Malonate 19 (12 g, 42 mmol) was treated according to procedure E to afford ester 44 (4.6 g, 48%); ir (neat): 2940, 1740, 1025 cm- ; nmr (CDC13) 6: 5.90-5.50 (2H, m, -CH=CH-), 4.60 (IH, m, 0-CH-0), 3.66 (3H, s, -C02Me), 4.30-3.20 (4H, m,

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

1306

CAN. 1. CHEM. 1

that was purified by column chromatography (2% acetone in dichloromethane) yielding monomer 2a [C-TI (92.8 mg, 44%; crystallized from hexane-ether); mp 119- 121"C; ir (CHCl,): 3030, 2960, 1735, 1440, 1270-1200 (br), 1180 cm-I ; nmr (CDCI,) 8: 5.57-5.07 (4H, m, -CH=CH--), 3.76, 3.75, 3.73 and 3.72 (12H, all s, -C02Me), 3.15-2.05 (8H, m including app d (3.10), J = 12.0 Hz and app t (2.14), J = 12.0 Hz, -CH2-); I3cnmr(CDC1,) 8: 172.4, 171.7 and 170.8 (C02Me), 132.9, 128.9, 125.0 and 124.1 (C=C), 56.7, 56.9 (qc), 52.7,52.4 (-OCH3), 40.1,36.3, 32.0 and 30.7 (-CH2-);ms m / e (70 eV): 368 (M'). Exact Mass calcd.: 368.1471; found: 368.1471; and dimer 3a [C-TI (52.8 mg, 25%) (crystallized from hexane-ether); mp: 155-156°C; ir (CHCI,): 3030, 2960, 1733, 1200, 1180 cm-I; nmr (CDC13) 8: 5.39-5.18 (8H, m, -CH=CH-), 3.72 (24H, s, -C02Me),2.73-2.48 (16H, m, -CH2-); I3C nmr (CDCl,) 8: 171.1 (C02Me), 128.7 and 126.5 (C=C), 57.1 (qc), 52.5 (-OCH,), 29.9 and 35.5 (-CH2-); ms m / e (70eV): 736 (M'). Exact Mass calcd.: 736.2942; found: 736.2929.

Monomer 2 a [C-A] and dimer 3 a [C-A] Following procedure G, chloride l a [C-A] (297 mg, 0.74 mmol) afforded, after column chromatography (2% acetone in dichloromethane), monomer 2a [C-A] (162 mg, 60%) (recrystallized from hexane-ether); mp 98 .5-99.S°C; ir (CHCl,): 3030,2960, 1735, 1440, 1285-1220-1 182, 1068, 1053 cm-l; nmr (CDC13) 8: 5.55-5.35 (2H, m, -CH=CH-), 3.73 (12H, s, -C02Me),3.25-2.40 (8H, m, -CH2-); 13cnmr (CDC13) 6: 170.7 (C02Me), 127.7 (C=C), 79.8 (C=C), 55.1 (qc), 52.6 (-OCH,), 31.4 (CH2-C=), 24.5 (CH2-CE); ms m / e (CI, CH4): 367 (M+ + 1). Exact Mass calcd.: 366.1315; found: 366.1315; along with dimer 3a [C-A] (46.7 mg, 17%) (recrystallized from hexane-ether); mp 163.5- 165.0°C; ir (CHCI,): 3040,2960, 1735, 1440, 1295, 1202 cm-' ; nmr (CDCI,) 8: 5.52-5.21 (4H, m, -CH=CH-), 3.74 (24H, s, -C02Me), 2.78 (8H, s, -CH2-C=), 2.97-2.77 (8H, m, -CH2-C=), 13cnmr (CDCl,) 8: 170.3 (C02Me), 127.7 (C=C), 78.1 (C=C), 57.1 (qc), 52.7 (-0CH3), 30.5 (CHr-C=), 23.5 (CH2-C=); ms tnle (70 eV): 732 (M'). Exact Mass calcd.: 732.2629; found: 732.2629. Monomer 2 a [T-TI and dimer 3 a [T-TI Using procedure G , chloride l a [T-TI (400 mg, 0.99 mmol) afforded, after column chromatography (2% acetone in dichloromethane), monomer 2a [T-TI (37 mg, 10%) contaminated with a small amount (less 10%: gc) of 2a [C-TI; ir (CHCl,): 3020, 2960, 1735, 1440, 1230, 1175 cm-I; nmr (CDC13) 8: 5.26 (4H, m, -CH=CH-), 3.79 and 3.70 (12H, both s, -C02Me), 3.05 and 2.75 (8H, app d, J = 13.2 Hz and m, -CH2-); I3cnmr (CDC1,) 8: 172.1 and 170.9 (C02Me), 132.3 (C=C), 54.0 (qc), 52.8 and 52.5 (-0CH3),39.5 (-CH2-); ms m / e (70eV): 368 (M'). Exact Mass calcd.: 368.1471; found: 368.1471; along with dimer 3a ([T-TI (154mg, 42%); ir(CHC1,): 3030,2960, 1735, 1440, 1200, 1170cm-I; nmr (CDC13) 8: 5.42-5.20 (8H, app t, J = 4.2 Hz, -CH=CH-), 3.69 (24H, s, -C02Me), 2.67-2.49 (16H, app d, J = 5.6 Hz, -CH2-); I3cnmr (CDC13)8: 170.9 (C02Me), 128.3 (C=C), 57.1 ms m / e (70 eV): 736 (M'). (qc), 52.3 (-0CH3), 35.0 (-CH2-); Exact mass calcd.: 736.2942; found: 736.2937. Monomer 2 a [T-A] and ditner 3 a [T-A] Precursor l a [T-A] (376 mg, 0.934 mrnol) was treated according to procedure G giving, after column chromatography (2% acetone in dichloromethane), monomer 2a [T-A] (59.2 mg, 17%) (recrystallized from hexane-ether); mp 101-102°C; ir (CHC13): 3035, 3025, 2960, 1732, 1440, 1250 cm-I; nmr (CDC13) 8: 5.89-5.72 (2H, m, -CH=CH-), 3.79 and 3.69 (12H, both s, -C02Me), 2.98 (2H, app d, J = 12.7 Hz, -CH2-), 2.88-2.66 (4H, m, -CH2-), 2.59-2.45 (2H, m, -CH2-); 13Cnmr(CDC1,) 8: 171.3 and 169.8 (-COzMe), 130.1 (C=C), 84.1 (C=C), 55.1 (qc), 52.9 and 52.6 (OCH,), 39.2 (CH2-C=), 25.2 (CH2-C=); ms m / e (70 eV): 366 (M'). Exact Mass calcd.: 366.1315; found: 366.1315; along with dimer 3a [T-A] (120 mg, 35%) (recrystallized hexane-ether-dichloromethane); mp 196.5- 197.0°C;ir (CHC13):3030,2960,1735,1200 cm- ; nmr (CDCI,) 8: 5.55-5.35 (4H, m, -CH=CH-), .. 3.71 (24H, s,

-C02Me),2.80-2.64 (16H, m, -CH2-); I3C nmr (CDCl,) 8: 170.2 (C02Me), 128.7 (-C=C-), 78.0 (C=C), 56.7 (qc), 52.6 (OCH,), 35.7 (CH2-C=), 22.7 (CH2-CE); ms m / e (70 eV): 732 (M'). Exact Mass calcd.: 732.2629; found: 732.2634.

Moriomer 2 a [A-A] and dimer 3 a [A-A] Following procedure G , chloride l a [A-A] (383 mg, 0.96 mmol) afforded, after column chromatography (I% acetone in dichloromethane), monomer 2a [A-A] (89 mg, 26%) (recrystallized from benzene-hexane); mp 144.5- 145.S°C);ir (CHCl,): 3040,3020,2960, 1740, 1440, 1255 cm-I; nmr(CDC13) 8: 3.77 (12H, s, -C02Me), 2.81 (8H, s, -CH2-); "C nmr (CDC13)8: 169.5 (COrMe), 80.4 ( C s C ) , 54.8 (qc), 53.0 (OCH,), 25.6 (-CH2-); ms m / e (70 eV): 364 (M'). Exact Mass calcd.: 364.1 158; found: 364.1 158; along with dimer 3a [A-A] (138 mg, 40%) (recrystallized from benzene-hexane); mp 244.5-246.0°C; ir (CHC13): 3030,2960, 1740, 1440, 1291 cm- ; nrnr (CDC1,) 6: 3.72 (24H, s, -COIMe), 2.99 (16H, s, -CH2-); 13c nmr (CDCl,) 8: 169.6 (C02Me), 78.0 (C=C), 56.0 (qc), 52.9 (OCH,), 23.3 (-CH2-); ms m / e (70 eV): 728 (M'). Exact Mass calcd.: 728.2316; found: 728.2326. Monomer 2 b [A-A] and dimer 3 b [A-A] Reaction of precursor l b [A-A] (159 mg, 0.46 mmol) in the conditions of procedure G afforded, after column chromatography (4% acetone in dichloromethane), monomer 2b [A-A] (38 mg, 27%) (recrystallized from ether-hexane); mp 102.0-102.S°C; ir (CHCl,): 3030, 3010, 2955, 1735, 1440, 1255 cm-I; nmr (CDCl,) 8 : 3.78, 3.77, and 3.7 1 (9H, all s, -C02CH3),2.95-2.60 (5H, m, -CH2C(C02Me)2--CH2 and -CH-), 2.60-2.50 (4H, m, -CH2C(C02Me)-CH2-); I3C nmr (CDC1,) 8: 173.1, 169.7, and 169.4 (C02Me), 82.0, 79.7 (C=C), 54.6 (qc), 52.8, 52.9 (OCH,), 40.8 ms m / e (70eV): 306 (M'). Exact Mass (CH), 25.5,22.1 (-CH2-); calcd.: 306.1103; found: 306.1103; along with an unseparable mixture of cis and trans dimers (54 mg, 38%) (recrystallized from etherhexane); mp 143-148°C; ir (CHCl,): 3020, 2955, 1735, 1438, 1200cm-I; nmr (CDCl,) 8: 3.72 (12H, s, (C02Me).), 3.69 and 3.68 (6H, both s, -C02Me), 2.98 (4H, br s, -CH2-), 2.63 (SH, br s, -CH2and -CH-); I3cnmr (CDC1,) 8: 1734, 169.8 (C02Me), 80.1, 76.8 (C=C), 56.3 (qc), 53.0, 52.1 (OCH,), 42.8, 42.6 (-CH-), 23.4,20.2 (-CH2-); ms m / e (70 eV): 612 (M'). Exact Mass calcd.: 612.2207; found: 612.2216. Monomer 2 b [C-A] and dimer 3 b [C-A] Precursor l b [C-A] (148 mg, 0.43 mmol) was treated under the conditions of procedure G to give, after column chromatography (2% acetone in dichloromethane), monomer 2 b [C-A] (recrystallized from ether-pentane); mp 62-63°C; ir (CHCl,): 3020, 2955, 1733, 3.76 1440 cm-I; nmr (CDC1,) 6: 5.70-5.30 (2H, m, -CH=CH-), and 3.75 (6H, both s, -(C02Me)*),3.69 (3H, s, -COrMe), 3.25-3.05 and 2.85-2.35 (9H, both m, -CH2and -CH-); 13cnmr (CDCI,) 8: 174.8, 171.1 (-COzMe), 132.6, 124.3 (C=C), 81.7,79.6 (C=C), 55.6 (qc), 52.8, 5 1.9 (OCH,), 42.1 (-CH-), 3 1 .O, 29.7, ms m / e (70eV): 309 (M' + 1). Exact Mass 23.6, 22.0 (-CH2-); calcd.: 309.1337 (M+ + 1); found: 309.1330 (M+ + 1); along with dimer 3 b [C-A] (35 mg, 27%) as an unseparable cis-trans mixture; ir (CHCl,): 3030, 3015, 1733, 1438, 1200 cm-I; nmr (CDC13) 8: 3.74, 3.72, 5.55-5.35 and 5.26-5.10 (4H, both m, -CH=CH-), 3.71, 3.70 (18H, all s, -C02Me), 3.00-2.35 (18H, m, -CH2-and -CH-); I3C nmr (CDC13) 6: 174.1, 170.4 (COrMe), 130.7, 130.5, 125.6, 125.5 (C=C), 80.0, 79.9 (C-C), 57.0 (qc), 52.7, 51.8 (OCH,), 44.1,43.7 (-CH-), 30.2, 88.6, 28.1, 23.1, 23 .O, 2 1.0, 20.7 (-CH2-);ms m / e (70 eV): (M+ + 1). Exact Mass calcd.: 616.2520; found: 616.2520. Monomer 2 b [T-A] and dimer 3 b [T-A] Using procedure G , chloride 1 b [T-A] (159 mg, 0.46 mmol) gave, after column chromatography (2% acetone in dichloromethane), monomer 2 b [T-A] (41 mg, 29%) assumed to be a mixture of conformers (4:l); ir (CHCI,): 3020, 2955, 1735, 1140 cm-I; nmr (CDCI,) 8: 5.90-5.60 (2H, m, -CH=CHminor conf.), 5.755.65 (2H, m, -CH=CHmajor conf.), 3.80,3.73, 3.70 (9H, all s,

DESLONGCHAMPS ET AL.

-C02Me minor conf.), 3.81, 3.70, 3.65 (9H, all s, -C02Me major conf.), 3.05-2.20 (9H, m, -CH2and -CHboth conf.); I3C nmr (CDCI,) 6: 174.8, 171.5, 169.9 (-C02Me), 132.9, 131.3 (C=C), 85.7, 83.4 (CEC), 55.0 (qc), 52.9, 52.7, 5 1.9 (-OCH,), 41.4, 39.2, 37.4, 25.3, 22.2 (-CH2and -CH-); ms m/e (70 eV): 308 (M+). Exact Mass calcd.: 308.1260; found: 308.1260; along with dimer 3 6 [T-A] (68 mg, 48%) as a cis-trans mixture; ir (CHCl,): 3030, 2950, 1735, 1440cm-I; nmr (CDCI,) 6 : 5.65-5.25 (4H, m, -CH=CH-), 3.71 (12H, s, -(C02Me)2), 3.67 (6H, s, -C02Me), 2.77 and 2.74 (4H, both br s, CH2-Cr), 2.60-2.30 (5H, m, -CH2-CH-CH2-); I3C nmr (CDC1,) 6: 174.1, 170.4 (C02Me), 131.6, 131.4, 126.6, 126.4 (C=C), 80.4, 76.7 (C-C), 65.8,56.9,56.8,52.6,51.7,43.9,43.6,35.5,33.4,33.2,22.7,20.2, 19.9, 15.2; ms m/e (70eV): 617 (M+ 1).

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 190.151.144.42 on 06/03/13 For personal use only.

+

Monomer 2 b [T-C] arid dimer 3 b [T-C] Following procedure G, precursor l b [T-C] (151 mg, 0.43 mmol) afforded, after column chromatography (2% acetone in dichloromethane), monomer 26 [T-C] (39.7 mg, 29%) assumed to exist as a mixture of conformers: ir (CHCI,): 3030,2955, 1730, 1440 cm-' ;nmr (CDC13) 6: (major conf.) 5.55-5.05 (4H, m, -CH=CH-), 3.76, 3.74 and 3.69 (9H, all s, -C02Me), 3.05-2.05 (9H, m, -CH2and -CH-); ms m/e (70 eV): 310 (M+). Exact Mass calcd.: 310.1416; found: 3 10.1424; along with dimer 3 6 [T-C] (56 mg, 42%) as a cis-trans mixture; nmr(CDC13) 6: 5.55-5.10 (8H, m, -CH=CH-), 3.71, 3.69 and 3.67 (18H, all s, -C02Me), 2.75-2.15 (18H, m, -CH2and -CH-); ms m/e (70 eV): 620 (M+). Exact Mass calcd.: 620.2832; found: 620.2828. Monomer 2 b [T-TI and dimer 3 b [T-TI Treatment of precursor l b [T-TI (150 mg, 0.43 mmol) according to procedure G gave, after column chromatography (2% acetone in dichloromethane), monomer 26 [T-TI (13 mg, 10%) as a mixture of conformers (6:l (nmr)); ir (CHCI,): 3020, 2950, 1730, 1435, 1180 cm-'; nrnr (CDCI,) 6: 5.40-5.10 (4H, m, -CH=CH-), 3.80, 3.72, 3.67 (9H, all s, -C02Me (major conf.)), 3.79, 3.73, 3.7 1 (9H, all s, -C02Me (minor conf.)), 3.15-3.00 and 2.90-2.40 (9H, both m, -CH2and -CH-); I3C nmr (CDC13) 6 (major conf.): 175.7, 172.3 (C02Me), 135.0, 130.7 (C=C), 54.2 (qc), 52.8, 52.5, 29.6, 37.2 (-CH2-); ms m/e 51.8 (-OCH,), 40.9 (-CH-), (70 eV): 310 (M+). Exact Mass calcd.: 310.1416; found: 3 10.1422; along with dimer 3 6 [T-TI (56 mg, 42%) as a cis-trans mixture; ir (CHCI,): 3020, 2950, 1730, 1195 cm-l; nmr (CDCl,) 6: 5.55-5.38 and 5.35-5.18 (8H, both m, -CH=CH-), 3.71, 3.67 (18H, s, -COrMe), 2.60 (8H, app d, J = 7.2 HZ, -CH2C(C02Me)2-CH2-), 2.50-2.15 (lOH, m, -CH2-CH(COZMe)-CH2-); ms m/e (70 eV): 620 (M+). Exact Mass calcd.: 620.2833; found: 620.2833.

1307

I. (a) D. BRILLON and P. DESLONGCHAMPS. Can. J. Chem. 65, 43 (1987); 6 5 , 5 6 (1987); (b) D. BRILLONand P. DESLONGCHAMPS. Tetrahedron Lett. 27, 113 1 (1986); (c) P. DESLONGCHAMPS, and H.-S. LIN. Can. J. Chem. 62, 2395 (1984); S. LAMOTHE, ( d ) P. DESLONGCHAMPS. Bull. Soc. Chim. Fr. 11, 9-10, 349 (1984); (e) P. DESLONGCHAMPS. Aldrichimica Acta, 17, 59 (1984). 2. (a) M. KODAMA,S.-I. Y o ~ o o ,H. YAMADA,and S. IT^. Tetrahedron, 34, 3121 (1978); (b) M. KODAMA, Y. MATSUKI, and S. IT^. Tetrahedron Lett. 3065 (1975); 1 12 1 (1976). 3. (a) T. TAKAHASHI, T. NAGASHIMA, and T. TSUJI.Tetrahedron H. NEMOTO,and Lett. 22, 1359 (1981); (b) T. TAKAHASHI, J. TSUJI.Tetrahedron Lett. 24, 2005 (1983); 24, 3485 (1983). 4. (a) W. C. STILL.J . Am. Chem. Soc. 99,4186(1977); (b) J. Am. Chem. Soc. 101, 2493 (1979); (c) W. C. STILL,S. MURATA, G. REVIAL,and K. YOSHIHARA. J. Am. Chem. Soc. 105, 625 Tetrahedron, 37, (1983); ( d ) W. C. STILLand I. GALYNKER. 398 1 (1981); (e) W. C. STILLand D. MOBILIO. J. Org. Chem. 48, and D. G. CLEARY. J. Org. 4786 (1983); ( f ) J. A. MARSHALL Chem. 51, 858 (1986). 5. T. KITAHARA and K. MORI.J. Org. Chem. 49, 3281 (1984). 6. M. S. FRAZZAand B. W. ROBERTS. Tetrahedron Lett. 42, 4193 (1981). 7. A. ETOURNAUD and H. WYLER.Helv. Chim. Acta, 56, 625 (1973). J. Am. Chem. Soc. 89, 8. (a) E. J. COREYand E. HAMANATA. 2758 (1976); ( b ) Y. KITAYAMA, A. ITOH,S. HASHIMOTO, H. YAMAMOTO, and H. NOZAKI.J. Am. Chem. Soc. 99, 3864 J. Am. Chem. Soc. (1977); (c) B. M. TROSTand R. W. WARNER. 104,6112 (1982); ( d ) B. M. TROSTand T. SATO.J . Am. Chem. Soc. 107, 719 (1985); (e) J. E. MCMURRYand P. KOCOVSKY. Tetrahedron Lett. 26, 2 171 (1985), and references cited therein. 9. J. SICHER.Prog. Stereochem. 3, 202 (1 962). 10. W. BAKER,J. F. MCOMIE,and W. D. OLLIS.J. Chem. Soc. 200 (1951). 11. K. F. BERNADY, M. B. FLOYD,J. F. POLETTO, and M. J. WEISS. J. Org. Chem. 44, 1438 (1979). 12. E. W. COLLINGTON and A. I. MEYERS. J. Org. Chem. 36, 3044 (1971). A. YOSHIKOSHI, and P. A. GRIECO.J. Org. 13. M. MIYASHITA, Chem. 42, 3772 (1977). 14. K. E. WILSON,R. T. SEIDER,and S. MASAMUNE. Chem. Commun. 213 (1970). and J. W. SUGGS. Tetrahedron Lett. 31,2647 (1975). 15. E. J. COREY 16. (a) A. W. JOHNSON.J. Chem. Soc. 1009 (1946); (b) W. J. J. Am. Chem. Soc. 77, 165 (1955). BAILEYand E. FUJIWARA. 17. G. ILLUMINATI and L. MANDOLIN]. ACC.Chem. Res. 14, 95 (1981). 18. A. P. KRAPCHO, G. A. GLYNN,and B. J. GRENON. Tetrahedron Lett. 3, 215 (1967).