J. Org. Chem., Vol. 41, No. 26, 1976
a-Methylene Lactone Synthesis Using Itaconic Acid Derivatives
4065
Direct Methods for a-Methylene Lactone Synthesis Using Itaconic Acid Derivatives Robert M. Carlson* a n d Alan R. Oyler
Department of Chemistry, University of Minnesota, Duluth, Minnesota 55812 Received J u n e 18, 1976 Anions of itaconic acid derivatives [R02CFHC(=CH2)C02] are versatile intermediates for the synthesis of u methylene lactones. The addition of these anionic species to aldehydes or ketones and subsequent lactonization and hydrolysis have been utilized for the synthesis of a variety of compounds including protolichesterinic acid, nephrosterinic acid, and canadensolide. a-Methylene lactones have recently attracted much synthetic effort] owing to the isolation of several cytotoxic and/or antitumor agents t h a t possess this characteristic system.2 Although several direct procedures have been developed for t h e synthesis of a-methylene lactones, t h e current m e t h o d ology rests primarily upon techniques for the introduction and subsequent elimination of a heteroatom attached t o t h e (3 carbon.' Structural analysis of several naturally occurring 6-carboxy-a-methylene lactones such as protolichesterinic acid," nephrosterinic acid,4 and c a n a d e n ~ o l i d esuggested ~ t h a t these compounds could be obtained by the addition of a n itaconic acid derivative to an aldehyde6 (Scheme I). This synthesis would offer the advantages of broad scope a n d t h e ready availability of starting material^.^
Results and Discussion Stable enolate anions could not be generated from dimethyl itaconate (1, R1 = R2 = CH:J even a t reduced temperatures (-78 oC).HT h e polymeric products t h a t resulted from such attempts appeared to be derived from a Claisen condensation of the desired anion with the carboxymethyl not directly involved in the resonance stabilized system. Therefore, in order to avoid nucleophilic addition to the affected carbonyl carbon a carboxylate anion was used as a convenient protecting group (1, Rz = Li).!j 0
Attempts to generate t h e trianion of itaconic acid (1, R1 = R l = Li) a n d t o a d d i t t o carbonyl compounds were only moderately successful. T h u s , treatment of itaconic acid with
3 equiv of lithium diisopropylamide1° (LDA) a t -78 OC in tetrahydrofuran ( T H F ) followed by the addition of 1 equiv of aldehyde or ketone gave, upon acidification, low yields (-30%) of the desired a-methylene lactone 2 (RI = H).ll T h e use of higher reaction temperatures and/or hexamethylphosphoramide ( H M P A ) decreased the yield of 2. In contrast, the dianions derived from monoesters of itaconic acid 1 (RI = CH3, ArCH2; R2 = Li) were generated a n d observed to be viable nucleophiles in addition reactions t o both aldehydes and ketones (Table I). For example, treatment of methyl itaconate (prepared by the addition of methanol to itaconic anhydride7J2) with 2 equiv of LDA'O gave the dianion which upon addition to cyclohexanone a n d acid-catalyzed cyclization provided a 71% yield of the desired a-methylene lactone 2 [ R I = CH:,; R.3R4 = (-CH2-)6]. However, t h e use of methyl itaconate in t h e synthesis of protolichesterinic acid and its carboxy analogues 3 was precluded by the inability to hydrolyze the methyl ester without isomerization to the butenolide (Scheme 11). T h e problem of selective hydrolysis vs. isomerization in this overall scheme was overcome by utilizing the dianion of p methoxybenzyl itaconate (1, R1 = ArCH2; R2 = Li).]3 H y drolysis of the ester without concurrent isomerization was then effected with trifluoroacetic acid. T h e overall sequence of addition, cyclization, and hydrolysis successfully generated a number of a-methylenebutyrolactones 3, including protolichesterinic a n d nephrosterinic acids (Table I).
Scheme I
0
II
RIOC-
CH,
II
X
CH -CCOOR,
I X =OH X = ('I
1
/
R, = CH,; R, = CH, R, = Li;R, = Li R, = CH,$;R, = Li
R, = CH,C,>H.,OCH,E CH2Ar;R2=Li
3
RT = fCH,),,CH,;
2
R, = H
(protolichesterinic acid) R, = fCH,),&H ,;R, = H (nephmterinic acid)
7
R, = H R , = f C H I ) , C H , ; R,,=H R, = CH, (canadensol ide) R , = CH2Ar R,=H;R,,=(CHJICH, ( epz-canademolide)
5
6
4066 J . Org. Chem., Vol. 41, No. 26, 1976
Carlson and Oyler
Table 1.0 Compounds Prepared from Monoesters of Itaconic Acid
H
_____
Compd (registry no.) -
2 and 3
__
-___-_.____
%
Rl
--
R,
R4
54.51 . 2 2 ( 3 H , s ) , 1 . 5 5 ( 3 H , s ) , 3.72 (1 H, t ) , 3.81 5E1.5~ ( 3 H, s), 5.19 ( 2 H, s), 5.85 (1 H , d , J = 2.5 Hz), 6.48 (1H, d , J = 2.5 Hz), 6.95 ( 2 H, m), 7.32 ( 2 H, m)' 1501.37 ( 3 H , s ) , 1.55 ( 3 H , s ) , 3.85 (1 H, t ) , 5.90 151.86 (1h, d , J = 2.2 Hz), 6.05 (1 H , broad), 6.30 (1 H, d , J = 2.8 Hz)d e 1.7 (8 H, m), 3.78 ( 3 H , s ) , 3.90 (1 H, t ) , 5 . 1 2 ( 2 H, s ) , 5.75 (1 H , d , J = 2.2 Hz), 6.32 (1 H, d , J = 2.8 Hz), 6.9 ( 2 H , m ) , 7.3 ( 2 H, m)C 1071.9 (8 H, m ) , 3.92 (1 H, t ) , 5.90 (1 H, d, J = 109b 2.2 Hz), 6.47 (1 H, d , J = 2.5 Hz), 8.5 (1 H,
2a (60427-56-7)
p-CH,OC,H,CH,
CH,
CH,
780
3a (60427-57-8)
H
CH,
CH3
69a
ab (60427-58-9)
p-CH,OC,H,CH,
-CH,CH,CH,CH,-
730
3b (60427-59-0)
H
-CH,CH,CH,CH,-
540
2c (60427-60-3)
p-CH,OC,H,CH,
CH,CH,
CH,CH,
3Oa e
H
CH,CH,
CH,CH,
17a 74-756
p-CH,OC,H,CH,
H
CH,(CH,),,
25f
p-CH,OC,H,CH,
CH,(CH,), , H
16.f 3839.5h
3C
s)c
(60427-61- 4 )
2d (60427-62-5) 2e ( 604 2 7 -6 3-6)
53.554.5b
3d (51260-32-3)
H
H
CH,(CH,),,
2Og 91926
3e (60478-54-8)
H
CH,(CH,)i,
H
134 87-
2f (604 27-64-7)
p-CH,OC,H,CH,
H
CH,(CH,),,
13.f
P-CH,OC,H,CH,
CH,(CH,),o
H
13.f 34-35h
CH,(CH,),,
llb
83.584.5h
5R
81.582.56
2g
88h
46.84 76
( 604 27 -65-8)
3f (604 27-66-9)
H
H
3g (60427-10-0)
H
CH3(CH2)10
2h (60427-67-0)
CH,
-CH,CH,CH,CH,CH,-
7la
NMR, 6
Mp,"C
yield
63-6.56
0.9 (6 H, m), 1.7 ( 4 H, m ) , 3.8 ( 2 H, s ) , 3.8 (lH,rn),5.15(2H,s),5.8(1H,d,J=2.5 Hz), 6.4 (1 H, d , J = 2.5 Hz), 6.9 ( 2 H, m ) , 7.28 ( 2 H, m)" 1.0 ( 6 H, m), 1.85 ( 4 H, m ) , 3.9 (1 H, t), 5.95 (1 H, d , J = 2.5 Hz), 6.52 (1 H, d , J = 2.5 Hz), 8.5 (1 H, s ) C 0.91 ( 3 H, t ) , 1.28 ( 2 4 H , m ) , 3.65 (1 H, m ) , 3.90 ( 3 H, s), 4.83 (1 H, m ) , 5.28 ( 2 H, s ) , 5.98 (1 H , d , J = 2.1 Hz), 6.50 (1 H, d , J = 2.5 Hz), 7.1 ( 2 H, m ) , 7.4 ( 2 H , m)c 0.89 ( 3 H, t ) , 1 . 2 5 ( 2 4 H, m), 3.9 ( 3 H , s ) , 4.08 (1 H, d , t , J = 8 and 1 Hz), 4.7 (1 H, m), 5.25 ( 2 H, s ) , 5.9 (1 H, d , J = 2 Hz), 6.5 (1 H, d , J = 2 Hz), 7.08 ( 2 H, m), 7.4 ( 2 H, m)c 0.9 ( 3 H, t ) , 1.3 ( 2 4 H, m ) , 3.7 (1 H, m ) , 4 . 8 5 (1 H, m), 6.1 (1 H, d , J = 2.1 Hz), 6.55 (1 H, d , J = 2.8 Hz), 8.3 (1 H, s ) C 0.9 ( 3 H, t ) , 1.25 (24 H, m ) , 4.08 (1 H, d , t, J = 7 . 6 a n d 2 H z ) , 4 . 7 (1 H, m), 6.0 (1 H, d , J = 2 Hz), 6.55 (1 H , d , J = 2 Hz), 9.75 ( 1 H, slc 0.88 ( 3 H, t ) , 1 . 2 5 ( 2 0 H , m ) , 3 . 5 8 (1 H , m ) , 3.8 ( 3 H , s ) , 4 . 7 5 (1 € I , m ) , 5.13 ( 2 H , s ) , 6.83 (1 H, d, J = 2.3 Hz), 6.37 (1 H, d , J = 3 Hz), 6.9 ( 2 H, m), 7.3 ( 2 H, m)C 0.89 ( 3 H, t ) , 1.23 ( 2 0 H, m ) , 3.8 ( 3 H, s ) , 3.95 (1 H, d , t , J = 7.6 and 2 Hz), 4.55 (1 H, m), 5.12 ( 2 H, s), 5.78 (1H, d , J = 2.1 Hz), 6.38 (1H, d , J = 2.5 Hz), 6.9 ( 2 H, m ) , 7.2 ( 2 H, m)C 0.88 ( 3 H, t ) , 1 . 2 8 ( 2 0 H, m), 3.65 (1 H, m ) , 4.8 (1 H, m), 6.0 (1 H, d , J = 2.7 Hz), 6.49 (1 H, d, J = 2.8 Hz), 9.5 (1 H, s ) C 0.9 ( 3 H, t ) , 1 . 2 8 ( 2 0 H, m ) , 4 . 0 5 (1H, d, t, J = 8 and 2.1 Hz), 4.65 (1 H, m), 5.92 (1 H, d , J = 1.9 Hz), 6.5 (1H, d, J = 2.1 Hz), 9.3 (1 H, s ) C 1.6 (10 H, m), 3.62 (1 H, t , J = 2.1 Hz), 3.88 ( 3 H, s), 5.86 (1 H, d , J = 2.8 Hz), 6.58 (1 H, d, J = 2.5 Hz)c
UInitial yield based o n itaconic acid ester; > 9 0 % pure by NMR a n d / o r HPLC. b A satisfactory elemental analysis ( * 0.3%) was obtained for this compound. C Solvent: CDCI,. d Solvent: acetone-d,. e This compound gave satisfactory mass spectral analysis. fYield of single diastereomer, based o n itaconic ester, after separation and purification by HPLC. RYield based on itaconic acid ester; includes separation of intermediate ester diastereomers by HPLC and subsequent hydrolysis. Lit. i"(i )-trans-Nephrosterinic a ~ i d " . ~ ? ' ~ mp of (t )-protolichesterinic acid is 92-93.5 "C. I ( ? )-Alloprotolichesterinic acid. k"( t )-cis-Nephrosterinic a ~ i d " . ~ , ~ ~ 38916
1
R,= ArCH, RL= Li
"),.=,, K, A
mild d
2
R, = m H , -
CF:,WH
- 3
c6H,
T h e synthesis of canadensolide a n d related bislactones 7 (Table 111) could be visualized as emanating from the previously developed synthetic sequence by t h e use of aldehydes 4 possessing a n a-hydroxyl equivalent (Scheme I). Symmetrically substituted a-chloro aldehydes were found
J . Org. Chem., Vol. 41, No. 26,1976
a-Methylene Lactone Synthesis Using Itaconic Acid Derivatives
4067
Table 11. Physical Properties of Compounds Prepared from Symmetrical a-Chloro Aldehydes and Methyl Itaconate
O RB N
RS
0
7 Compd (registry n o . ) la (60451 -45-8)
7b (60427-68-1) 7c (60427-69-2)
R6
MP, " C
NMR, 6 (CDCL,)
-CH,CH,CH,CH,CH,-
174-1750
-CH,CH,CH,CH,CH,CH,-
148-1510
CH,CH,CH,
80.5-820
1 . 7 ( m , 1 0 H), 4 . 2 ( d , t , 1 H , J = 7 , 2 Hz), 5.0 ( d , 1 H , J = 7 Hz), 6 . 4 ( d , 1 H, J = 2 Hz), 6.7 (d, 1 H , J = 2 Hz) 1.7 ( m , 1 2 H ) , 4 . 2 5 ( d , t , 1 H , J = 7 , 2 Hz), 5 . 0 ( d . 1 H, J = 7 Hz), 6.3'(d, 1 H, J = 2 Hz), 6.65 ( d , 1 H, J = 2 H z ) 1.0 ( t , 3 H), 1 . 6 ( m , 8 H), 4.15 (d, t , 1 H , J = 7 , 2 Hz), 5 ( d , 1
R,
CH,CH,CH,
a A satisfactory elemental analysis
(t 0.3%) was
H , J = ~ H Z ) , ~ . ~ ~ ( ~ , ~ H , J = Z H Z ) , ~ . ~ ~ ( ~ , ~ H ,
obtained for this c o m p o u n d . Scheme I11
Q
Ho2c+fCH:i I R,R,CCHO
+oAo
+
1
R, = CH,; & = Li
+oAo
t o provide a n e n t r y into t h e desired bislactone system by t h e addition of methyl itaconate dianion, the formation of t h e cis chloro lactone 5 (contaminated with 0-2096 of the trans lactone 6) by treatment with acid, a n d the generation of the bislactone by t h e silver ion promoted solvolysis of t h e tertiary halide (Scheme 111, T a b l e 11). However, t h e synthesis of canadensolide itself from achlorovaleraldehyde could not be accomplished utilizing this procedure since t h e requisite cis chloro lactone 5 was n o t formed during t h e initial addition step. T h e successful synthesis of canadensolide involved t h e addition of t h e itaconic acid trianion (1, R1 = Rz = Li)I4 t o a-hydroxyvaleraldehyde protected as t h e ethoxyethyl e t h e r 14, R.5 = CH:j(CHz):j; Re = H ; X = OCH(OCH&H:%)CH3]. Moreover, t h e ease of isolation of t h e canadensolide isomers by the extraction of the uncyclized acidic products 6 (R1 = H ) from t h e itaconic acid trianion addition provided significant consolation for t h e relatively low yields. Separation of t h e isomers by liquid chromatography (HPLC) gave pure samples of canadensolide a n d epi-canadensolide.
?CH,CH:,
I
OCHCH,,
CH,(CH,),-~K-C
=N
I
CH,,(CH,),,-~H-
CHO
4
8
Experimental Section General. Melting points (uncorrected) were obtained on a Thomas-Hoover capillary apparatus. Infrared spectra were recorded
4
Ut
0 '
A
R,.
Ri
c1."Ag+ 5
CH,OH
-fl0/ "
Ri &,
7 on a Beckman IR-33. NMR spectra were obtained with a Varian EM-360 instrument using Me4Si as an internal standard. Preparative liquid chromatography (HPLC) was carried out on Waters Associates equipment using two 610 X 9.5 mm columns packed with Porasil A. In most cases ether-hexane mixtures were used at a flow rate of 9.9 ml/min. The THF (Aldrich Gold Label,
