1868
J. Org. Chem. 1 9 8 0 , 4 5 , 1868-1880
1740 and 1635 cm-'; 'H NMR (C&) 6 4.47 (1 H, d, J = 7 Hz), 3.18 (3 H, s), 2.29-1.40 (4 H, m), 1.34 (1 H, m), 1.20-0.94 ( 3 H, m), 1.03 (3 H, s), 0.82 (3 H, s); mass spectrum, mle 206.131 (M+; calcd for C13HlBOz 206.130). 1,3-Dimet hyl-5-isopropenyl-9-methoxytricyclo[ 4.3.1 .03s7]dec-8-en-5-01 (29). To a solution of isopropenyllithiumzZ(1 mL, 1 M in ether) a t 0 "C was added dropwise 18 mg (0.09 mmol) of 21. The reaction mixture was maintained at 0 "C for 30 min and
then was allowed to come to room temperature. After an additional 30 min, the reaction was quenched with water, and the mixture was partitioned between ether and water. The organic extract was dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was subjected to column chromatography on alumina (benzene as eluant) to give 15.3 mg (69%) of 29: 'HNMR (CDD,) 6 5.04 (1 H, br s), 4.95 (1 H, s), 4.79 (1 H, q, J = 2 Hz), 4.59 (1 H, d, J = 7 Hz), 3.28 (3 H, s), 2.47 (1 H, m), 2.14 (3 H, m), 1.78 (3 H, s), 1.86-0.92 (4 H, m), 1.26 (3 H, s), 0.89 (3 H, s); mass spectrum, mle 248 (M'). 1,3-Dimethyl-5-isopropenyltricyclo[ 4.3.1.03~']dec-4-en-9-one (31). A solution of 52 mg (0.2 mmol) of 29 in 0.3 mL of dimethyl sulfoxide was heated in an oil bath a t 150-160 "C. The course of the reaction was followed by NMR and after 11 h the reaction mixture was diluted with water and extracted with ether. The combined ethereal extracts were washed with water and brine and dried over magnesium sulfate. Removal of the solvent in vacuo gave 43 mg (94%) of virtually pure 31. A portion of the material which was subjected to column chromatography on alumina [benzenehexane (91)as eluant] afforded a sample of 31: IR (film) 1718 cm-'; 'H NMR (CDClJ 6 5.80 (1 H, s), 4.94 (1 H, br d, J = 6 Hz), 2.78 (1 H, m), 2.48 (2 H, d, J = 3 Hz), 1.92 (3 H, s), (22) E. A. Braude and E. A. Evans, J . Chem. SOC.,3333 (1956).
1.78-1.01 (4 H, m),1.12 (3 H, s), and 0.88 (3 H, s); mass spectrum,
mle 216 (M').
1,3-Dimethyl-5-isopropyl-9-oxotricyc10[4.3.1.0~~~]decan-9one (9-Pupukeanone, 3). To a prereduced suspension of 50 mg of platinum oxide in 3 mL of methanol under a hydrogen atmosphere was added 27 mg (0.13 mmol) of 31. After 46 h, the reaction mixture was diluted with ether and filtered through Celite to give 24 mg of a mixture of 3 and 32 in a 7:3 ratio (as determined
by 'H NMR). Preparative chromatography of this mixture on silver nitrate impregnated silica gel provided a sample of pure 3: 'H NMR (CDC13) 6 2.34 (2 H, d, J = 3 Hz), 1.71, 1.63, 1.56, 1.49 (br s), 1.04 (3 H, s), 0.91 (3 H, s), 0.90 (6 H, m); mass spectrum, mle 220 (M').
Acknowledgment. We are indebted to Dr. Richard Wielesek, Department of Chemistry, University of Oregon, for the high-resolution mass spectra and to Professor Hisashi Yamamoto, University of Hawaii, for providing spectra of authentic 9-pupukeanone. This research was assisted financially by a fellowship (to G.A.S.) from the Nicholas L. Tartar Foundation and by a grant from the National Science Foundation (CHE77-04379). Funds for the purchase of the Varian FT-80A NMR spectrometer were provided by the National Science Foundation. Registry No. 3, 70329-89-4; 5, 69697-76-3; 6, 73193-90-5; 7, 73193-91-6; 8, 20023-36-3; 9, 73193-92-7; 10, 73193-93-8; 12 (isomer l),73193-94-9; 12 (isomer 2), 73193-95-0; 14, 73193-96-1; 16,7319397-2; 17, 73193-98-3; 18,73193-99-4; 19,73194-00-0; 20,73194-01-1; 21, 73194-02-2; 29, 73194-03-3; 31, 70329-74-7; 32, 73194-04-4; 2,4dimethylanisole, 6738-23-4;p-cresol methyl ether, 104-93-8; diiodomethane, 75-11-6; ethyl diazoacetate, 623-73-4; vinyl bromide, 59360-2; isopropenyllithium, 6386-71-6.
Macrocyclic Lactone Formation through Sulfide Contraction. Synthesis of (A)-DiplodialideA' Robert E. Ireland* and Frank R. Brown, Jr.2 Chemical Laboratories, California Institute of Technology, Pasadena, California 91125 Received A u g u s t 20, 1979
A methodology for the synthesis of macrocyclic @-ketolactones from w-hydroxy thioamides is described. The hydroxy thioamides were esterified with chloroacetyl chloride, and the resulting chloro esters underwent Eschenmoser sulfide contraction when treated with sodium iodide, diisopropylethylamine, and triethyl phosphite in acetonitrile. The @-ketolactones were obtained in 25-58% yield. The utility of the method was demonstrated by synthesis of diplodialide A.
Recently, several procedures for macrocyclic lactone formation have appeareda3 Although a few alternate routes have been used, most of the procedures rely on the formation of the lactone bond as the ring-forming step. Existence of natural products such as narbomycin ( 1)4 and diplodialide A (2)5 which contain the P-keto lactone system suggested that such macrocycles might be synthesized
0
1
( 1 ) Contribution No. 6088. This investigation was supported by Grant CHE 74-19858 awarded by the National Science Foundation. (2) Institute fellow, 1975-76. Predoctoral fellow of the National Science Foundation, 1976-79. (3) Ishida, T.; Wada, K. J. Chem. Soc., Perkin Trans. 1 1979, 323-7, and references cited therein. (4)Corbaz, R.; Ettlinger, L.; Gaumann, E.; Keller, W.; Kradolfer, F.; Kyburz, E.; Neipp, L.; Prelog, V.; Reusser, P.; Zahner, H. Helu. Chim. Acta 1955, 38, 935-42. (5) Ishida, T.; Wada K. J. Chem. SOC.,Chem. Commun. 1975,209-10.
0022-3263/80/1945-1868$01.00/0
through formation of this grouping by some modification of the Claisen condensation. The Eschenmoser sulfide contraction,6 in which thioamide 3 was converted into 1) BrCHtC02tBu
0 1980 American Chemical Society
Synthesis of (f)-Diplodialide A Chart I. Schematic Presentation of Synthesis of p-Keto Esters through Sulfide Contraction
J. Org. Chem., Vol. 45, No. 10, 1980 1869 Scheme I. Intermolecular Sulfide Contraction" ,&c,H,
__
6a,
b,
KRZ=;"le2
NR2=pyrrolidinyl
-; a- , b, 5,
5 , h'R2=rnorpholinyl
-
NR,=NMe2 NRZ=pyrrolidinyl tm,-morphGilnyi
0
S
A
+( c H , s N ~ O C , H , 8
9
0
S c%o#N(CH~), 0
* c h o W O C z H ,
0
__
!3
12
W
d
0
N
3
a4 7- % c
B u S d O C , H ,
!4
!! a a, ICH,CO,C,H,, CH,CN; b, C,H,P[(CH,),NMe,],, CH,CN, A ; c, sihca gel.
enamino ester 4 in 75% yield, seemed to be a viable method. Macrocycle formation would be through initial carbon-sulfur bond formation rather than through more difficult carbon-carbon bond formation as in the Claisen condensation. The sulfide would then be readily converted intramolecularly into a @-ketolactone. Here we report the development of alternate conditions for the Eschenmoser sulfide contraction of thioamides, the adaptation of these conditions to macrocyclic lactone formation, and the synthesis of diplodialide A (2) through intramolecular sulfide contraction. After initial experiments with N-monoalkylthioamides proved unsatisfactory, the N,N-dialkylthioamide~~ shown were substituted (see Chart I). It was discovered that the intermediate thioimmonium salts B could be induced to undergo the sulfide contraction by treatment of the salt B with a phosphine (R3P) and an amine base (:B). A strong base such as potassium tert-butoxide6 is not necessary. Phosphine 5, developed by Eschenmoser and coPhP[(CH2)3NMe212 5
workers: proved especially convenient since it contains both phosphine and amine. Interestingly, in some cases the resulting product of sulfur extrusion with the aid of the phosphine, namely, the enamino lactone D, was isolated directly and hydrolyzed to the @-ketoester E on acid treatment. In other instances, only the end product @-keto ester E could be obtained. The facility of the reaction as compared to that of the corresponding N-alkylthioamides can be explained by the enhanced acidity of the acetate protons due to the presence of the positive charge in the thioimmonium salts B. Also, the proposed intermediate episulfide C, which is a neutral species, would provide a good intramolecular pathway for (6) (a) Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. Helu. Chirn. Acta 1971,54,710-34. (b) Laliger, P.; Fluckiger, E. Org. Synth. 1976,55, 127-33, and references cited therein. (7) Use of N,N-dialkylthioamides was first suggested to us by G. C. Gerrans, University of the Witwatersrand,Johannesburg, South Africa.
charge neutralization once deprotonation of salt B occurred. The necessary N,N-dialkylthioamides A were prepared in two general ways. Thioacylation8 of secondary amines with dithioesters was an especially convenient method when the dithioesters were readily a ~ a i l a b l e .The ~ more standard way, phosphorus pentasulfide treatment of the corresponding amide, provided a complementary route to the thioamides when the thioacylation method was inapplicable. The procedure of Rao and co-workers10was the method of choice for sulfurization of amides. Scheme I summarizes the results obtained in the modification sulfide contraction. A particularly interesting case is thioamide 14. Alkylation occurs preferentially on the thioamide sulfur rather than on the sulfide sulfur. Thus @-ketoester 15 was obtained in 47% yield. Mechanistic investigations (Scheme 11) revealed two important facts about the sulfide contraction. Two crossover experiments showed that alkylation of the thioamides with ethyl iodoacetate (17a) is reversible. Heating of thioammonium salt 16a with ester 17b in acetonitrile led to a 1:l mixture of salts 16a and 16b. Likewise, salts 18 and 16b, when heated in acetonitrile and then subjected to sulfide contraction, provided all four possible keto esters (19a, 19b, 20a, and 20b). Second, the deprotonation step appears to be irreversible and dependent on the relative acidities of the acetate and athioamide protons. Salt 21 has been reported" to give thiophene 22 when heated with triethylamine in methanol. Attempted sulfide contraction of this salt led only to the same thiophene. In contrast, thioamide 6a could not be transformed into thiophene 24 but readily underwent sulfide contraction. The phenyl ring apparently increases12 (8) Doyle, K. M.; Kurzer, F. Chern. Ind. (London) 1974, 803-9. (9)Meijer, J.; Vermeer, P.;Brandsma, L. R e d . Trau.Chirn. Pays-Bas 1973.92. 601-4. (10)Rao, C. S.;Dave, M. P.; Mody, P. N.; Pandya, A. D. Indian J. Chern. 1976,14, 999-1000. (11)Hartmann, H.; Mayer, R. 2. Chern. 1966, 6, 28.
1870 J. Org. Chem., Vol. 45, No. 10, 1980
Ireland and Brown Scheme IV. Macrocyclic Lactone Formation
0
s-CO,Et
0
o
..
b,
n=8
17b
---
B uI-& I ( C H i
-2 _0 a-.
!sa, R - E t
R-Et
b , R=iPr
b. R=iPr
>;?,
x - x = CSC x - x = t r a n s CH=CH X - x = C I S CH=CH
p, $,
>$a, b,
x-x = CIC x-x trans CH=CH
$ , x ' x = c i s CH=CH
S HO-o&$CCH3
VI.
___*
0
,?-I
CH 3
__37
24
-36-.
e.b.c VI 1.
Q o'
H&u-+
tI a, A , CH,CN; b, PhP[(CH,),NMe,],, gel; d, Et,N, MeOH; e , BrCH,COC,H,. a
CH,CN; c, silica
x-ethylene k e t a l
--5,
X'O
4Qs,
x=ethylene ketal
tl, x = o
Scheme V. Synthesis of (r )-Diplodialide Aa
Scheme 111. Formation of 5- and &Membered Lactonesa
1.
39a,
qJ9 -$9
R(#
CH H3
?Ga, R ' = C 2 H 5 , _.-
5a2-, 7c 4 %
-2 -7 _a ,
R2=H
a-c
S 23 _.
R'=C2H5, R 2 - H
b , R'=H, RZ=C2H5
b , R'=H, R 2 = C 2 H 5
I I . CsHs
d +CHl
69,63.
&R
CIHs
?.3
13
