1501
J. Am. Chem. SOC.1981, 103, 1501-1513 eterization of the potential functions used by the different groups may explain the difference in their predictions, especially since these compounds are sterically hindered and sensitive to choice of van der Waals parameters. The structures of the two tripeptides Boc-Leu-Aib-Pro-OX ( X = H , Bzl) and the published tetra~ e p t i d e (Z)-Aib-Pro-Aib-Ala-OMe, ,~ provide three examples of Aib residues preceding a proline. Theoretical calculations (Moore and Marshall, in preparation) suggest only a slight preference for the positive values of 4 and J. for Aib residues preceding a proline and both combinations are observed experimentally. Systematic calculation of the possible conformers of acetyl-Aib-Ala-Aib methylamide a t 1 1.2S0 increments gave four conformers within 0.5 kcal/mol of the minimum as shown in Table X. Conformer R,L-A is very similar to the crystal structure observed for the fragment-Aib-Ala-Aib of the tetrapeptide, averaging only 8' deviation from the observed structure. This further supports the conclusion that the primary determinants of conformation in these molecules are intramolecular with crystal-packing forces selecting between energetically similar conformers. It should, therefore, be feasible to apply the constraints introduced by Aib residues to limit the possible conformations available to the alamethicin molecule. In addition, other antibiotics such as a n t i a m ~ e b i n , ~ ~
e m e r i m i ~ i nand , ~ ~ s ~ z u k a c i l l i nhave ~ ~ been shown to contain Aib residues. The name of peptaibophol antibiotics has been proposed3* for this class which contains phenylalaninol as well as several residues of Aib. The unique properties associated with a-methyl substitution have been recognized by natural selection and have resulted in this class of compounds with unique membrane properties.
Acknowledgment. This investigation was supported in part by Grant No. GM-19684 from the National Institute of General Medical Sciences, D H E W (G.D.S. and W.L.D.), Grant No. PCM(74-03059) from the National Science Foundation (F.S.M. and E.W.C.), and Grant No. RR-00396 and Grant No. 5ROlAI16182-02 from the National Institute of Allergy and Infectious Diseases (G.R.M. and T.M.B.). Supplementary Material Available: Listings of atomic coordinates, bond distances and angles for the nonhydrogen and hydrogen atoms, and a tabulation of observed and calculated structure factors (71 pages). Ordering information is given on any current masthead page. (33)
R. C. Pandey, J. C. Cook, Jr., and K. C. Rinehart, Jr., J. Am. Chem.
SOC.,99, 5205 (1977). (32)
R. C. Pandey, H. Meng, J. C. Cook, Jr., and K. C. Rinehart, Jr., J .
Am. Chem. SOC.,99, 5203 (1977).
(34) G. Jung, W. A. Konig, D. Leibfritz, T.Ooka, K. Janko, and G. Boheim, Biochim. Biophys. Acta, 433, 164 (1976).
Synthesis and Reactions of Simple 3( 2H)-Furanones Amos B. Smith, III,*l Patricia A. Levenberg, Paula J. Jerris, Robert M. Scarborough, Jr., and Peter M. Wovkulich Contribution from the Department of Chemistry, The Laboratory for Research on the Structure of Matter, and The Monell Chemical Senses Center, The University of Pennsylvania, Philadelphia, Pennsylvania 19104. Received June 27, 1980
Abstract: Interest in the total synthesis of natural product antitumor agents which have as a central structural element the 3(2H)-furanone ring system has led to the development of an efficient general synthesis of a variety of simple 3(2H)-furanones. The strategy involves aldol condensation of aldehydes with the enolate derived from 3-methyl-3-(trimethyIsiloxy)-2-butanone (35) followed by Collins oxidation to afford the 1,3-diketone. Acid-catalyzed cyclization-dehydration then leads to the corresponding 3(2H)-furanones. The availability of this facile approach to the 3(2H)-furanone ring system provided the opportunity to explore the chemistry of this increasingly important heterocycle. Three reactions were selected for initial study; they were (a) alkylation, (b) conjugate addition of organocuprate reagents, and (c) reaction with sulfur nucleophiles. The results of the latter vis-&vis the mode of action of 3(2H)-furanone antitumor agents is discussed.
Introduction and Background During the course of studies directed a t devising a viable synthetic approach to jatrophone2 (1) and related antitumor agents such as the e r e m a n t h ~ l i d e s(A, ~ B, and C) (2) and geiparvarin4 (3), each of which possesses as a central structural element the (1) Camille and Henry Dreyfus Teacher-Scholar, 1978-1983, and National Institutes of Health (National Cancer Institute) Career Development Awardee, 1980-1985. (2) S. M. Kupchan, C. W. Sigel, M. J. Matz, C. J. Gilmore, and R. F. Bryan, J. Am. Chem. SOC.,98, 2295 (1976). For the first total synthesis of normethyljatrophone see: A. B. Smith, 111, M. A. Guaciaro, S. R. Schow, P. M. Wovkulich, B. H. Todu, and T.W. Hall, J . Am. Chem. SOC.,103,219 (1981). (3) P. W. Le Quesne, S.B. Levery, M. D. Menachery, T.F.Brennan, and R. F. Raffauf, J. Chem. SOC.,Perkin Trans. I , 1572 (1978). (4) (a) F.N. Lahey and J. K. MacLeod, Aust. J. Chem., 20, 1943 (1967); (b) R. M. Carman, F.N. Lahey, and J. K. MacLeod, ibid., 20, 1957 (1967); (c) D. L. Dreyer and A. Lee, Phytochemistry, 11, 763 (1972). (d) For the
first total synthesis and assignment of olefinic configuration see P. J. Jerris and A. B. Smith, 111, Tetrahedron Lett., 21, 711 (1980).
3(2H)-furanone ring, we have had occasion to explore the synthesis and chemistry of a number of simple 3(2H)-furanones. We report here the results of that study.
f OH Jatrophone 1
O n f O Y O
Eremantholide
2a: R = i.Pr Zb: R = sec-Bu 2c: R = CMe-CH,
Geiparvarin
3
Our interest in simple 3(2H)-furanones was threefold. First, selection of the above synthetic targets demanded the availability of an efficient and hopefully general strategy for construction of
0002-7863/81/1503-1501$01.25/0 0 1981 American Chemical Society
1502 J . Am. Chem. SOC.,Vol. 103, No. 6, 1981
Smith et al.
the 3(2H)-furanone ring; no such approach was available at the outset of our work.5 In fact the chemistry of this increasingly important heterocycle had been little explored. Finally, it appeared that simple 3(2H)-furanones would be ideal substrates to model the mode of biological action of antitumor agents which possessed this structural element. In this regard, jatrophone and eremantholide A were reported, respectively by KupchanZand Le Q ~ e s n e , ~ to undergo facile conjugate addition of propanethiol to yield monoadducts 4 and 5. Details of similar reactions with simple
Scheme I
19 17a
I
0
0
17b 4
5
3(2H)-furanones, however, had not been investigated. Furthermore, the recent discovery in our laboratory of bis-&@'-conjugate addition6 of organocuprate reagents to substrates such as 6' suggested that 3(2H)-furanones such as budlein As or goyazen~ o l i d eeach , ~ of which possesses a potential leaving group in the
+
process in vivo would permit cross-linking, a process that has been suggested to enhance activity of many antitumor agents.' With these considerations in mind, we expanded the initial scope of our investigation to include the synthesis and chemistry of simple 5-vinyl-3(2H)-furanones 9-1 1.
0
AcO
RzCuLi
R
9: R = CH=CH, 10: R = CMe=CH,
R
6
4
11: R
= C(CH,OHI=CH,
Results and Discussion Synthesis of Simple 3(2H)-Furanones. In 1971 MargarethaI2 reported that the sodium hydride catalyzed acylation of hydroxy ketone 12 with ethyl formate follwed by an acid-promoted dehydration afforded furanone 13 in 50% yield. Unfortunately, all n Budlein A
Goyazensolide
#-position, could undergo bis-6,b'-conjugate addition with an appropriate bionucleophile.10 That is, budlein A and goyazensolide are vinylogues of enone 6. Conjugate addition of propanethiol followed by loss of H 2 0 would lead to a new furanone (i.e., 7), which in a subsequent step could accept a second equivalent of propanethiol to afford 8 via 1,6-conjugate addition. Such a
7
OH
0
0
HCOOEt OH
12
13
attempts to exploit this transformation, for elaboration of 5substituted 3(2H)-furanones, through utilization of an alkyl ester in place of ethyl formate proved fruitless. Further consideration suggested that an intramolecular version of the Margaretha transformation might offer a general solution. In this regard L e h m a ~ m as ' ~ early as 1965 reported that a-acyloxy ketones such as 14, when treated with sodium dimsyl in Me,SO,
8
( 5 ) For a recent elegant approach to a chiral 3(2H) and furanone see B. Fraser-Reid and T. F. Tam, J. Org. Chem., 45, 1344 (1980). For the syntheis of specific 3(2H)-furanone derivatives see: F. Sher, J. L. Isidor, H. R. Taneja, and R. M. Carlson, Tetrahedron Lett. 577 (1973); W. Ried and A. Marhold, Chem. Ber., 107, 1714 (1974); R. M. Carlson, R. W. Jones, and A. S. Hatcher, Tetrahedron Lett. 1741 (1975); A. S . Medvedeva, M. M. Demina, and V. I. Kaigorodova, Zh. Org. Khim., 10, 2280 (1974); P. K. Gupta, J. G. L. Jones, and E. Caspi, J . Org.Chem., 40 1420 (1975). (6) A. B. Smith, 111, B. A. Wexler, and J. S.Slade, Tetrahedron Lett., in press. (7) M. A. Guaciaro, P. M. Wovkulich, and A. B. Smith, 111, Tetrahedron Lett., 4661 (1978). (8) A. R. de Vivar, C. Guerrero, E. Diaz, and A. Ortega, Tetrahedron, 26, 1657 (1970). (9) W. Vichnewski, S. J. Sarti, B. Gilbert, and W. Herz, Phytochemistry, 15, 191 (1976). (10) Conjugate addition at the a-methylene functionality would also be expected.
14
15
16
afford a mixture of a-hydroxyfuranone 15 and butenolide 16, with (11) S . M.Kupchan, D. C. Fessler, M. A. Eakin, and T. J. Giacobbe,
a . -176 -.qripnrp .--,-l --. . - 11970) ,--
. - I .
(12) P. Margaretha, Tetrahedron Lett., 4891 (1971). (13) H. G. Lehmann, Angew. Chem., Int. Ed. Engl., 4, 783 (1965). For additional examples of this reaction see: G. W. Moersch, D. E. Evans, and G. S.Lewis, J . Med. Chem., 10, 254 (1967); T. L. Popper, J. N. Gardner, R. Neri, and H. L. Herzog, ibid., 12,393 (1969);N. H. Dyson, J. A. Edwards, and J. H. Fried, Tetrahedron Lett., 1841 (1966) S.J. Halkes, J. Hartog, L. Morsink, and A. M.de Wachter, J. Med. Chem., 15, 1288 (1972);G. Teutsch, L. Weber, G. Page, E. L. Shapiro, H. L. Herzog, R. Neri, and E. J. Collins, ibid., 16, 1370 (1973); J. R. Bull and A. Tuinman, Tetrahedron Lett. 4349 (1973); H. A. C. M. Keuss and J. Lakemann, Tetrahedron, 32,1541 (1976).
J. Am. Chem. SOC.,Vol. 103, No. 6,1981 1503
Reactions of Simple 3(2H)-Furanones Scheme I1
one hydrogen in the d-position of the ester substituent, to dimsyl sodium. As illustrated in Table I, 3(2If)-furanones 26-28 were obtained as the sole product in good to excellent yield. Particularly noteworthy here is the facile, highly efficient synthesis of bullatenone 27, a natural 3(2H)-furanone isolated from blistered leaf myrtle (Myrtus bullata), a shrub endemic to New Zealand.16 Alternatively, if the a-position of the ester substituent possesses more than one hydrogen or does so through the principle of vinylology (Le., 17 and 25, respectively), the corresponding butenolides 18 and 30 result. Thus, while we had succeeded in devising an efficient intramolecular cyclization-dehydration strategy for the synthesis of selected 3(2H)-furanones, the lack of generality of this approach left much to be desired. Convinced that the most efficient general approach to the 3(2H)-furanone ring system would involve the acid-catalyzed cyclization4ehydration of an appropriately substituted a‘-hydroxy 1,3-diketone 31, we reexamined the intermolecular acylation of
*=4%& 0
21
0
It 0
\
“
II
0
M
4 J&
0
Table I. Synthesis of 3(2~Y)-Furanonesfrom a-Acyloxy Ketones
4 0
NaCH,{Me 0
‘yo
31 DMSO
hydroxy ketone 12, employing kinetic deprotonation under aprotic conditions. To this end, treatment of the dianions of 12 and 32 (2.3 equiv of L D A / T H F , -78 “ C ) with the standard acylating agents EtOAc, Ac,O, and AcCl again led only to complex mixtures. However, when the imidazole acyl transfer reagent” acetyl
aAcyloxy ketone
Product (percent yield/
R CHMe, Ph
22 23
26 27
(64)
b
(88)
-
c
t-Bu
24
28
(79)
-
a
0
or
0 En try
0
d
Me
17
-
e
CH=CMe,
25
-
18
(20)
30
(75)
31
$
the latter being the major product. The predominance of 16 was, however, troublesome in view of the well-known difference in acidity of ketones vs. esters (ca. 4-5 pK, units).14 T o explore the Lehmann transformation in detail, we subjected a-acyloxy ketone 17 to the N a H / M e 2 S 0 reaction conditions; the result, albeit in low yield, was butenolide 18. Even kinetic de-
(70%)
HO
12
0 18
19
protonation ( L D A / T H F at -78 “C) followed by an acidic workup did not afford the desired furanone (i.e., 19) in useful amounts. Instead, a complex mixture containing both 18 and 19 along with a number of unidentified components resulted. Collectively these results suggest (see Scheme I) that a n equilibrium is established between the ketone and ester enolates (17a and 1%) at a rate that is fast relative to addition of the ketone enolate to the ester carbonyl. Furthermore, the greater facility with which ketones are known to undergo nucleophilic addition relative to ester carbonyl^'^ leads to the prediction that butenolide 18 should in fact be the major product. However, if the system is so constructed (see Scheme 11) such as to prevent elimination of water from the favored intermediate (20), the course of the reaction is expected to shift to formation of the 3(2H)-furanone ring system. That this rationale is correct was demonstrated by subjecting a-acyloxy ketones 22-24, each of which bear a t most ~~
~
~
~
~~
(14) H. 0. House, “Modern Synthetic Reactions”, 2nd ed., W. A. Benjamin, Menlo Park, Calif., 1972, p 494. (15) Consider the ease with which ketones vs. esters react with HCN (Le., cyanohydrin formation); see, for example, D. T. Mowry, Chem. Reu., 42 ( 1948).
‘0
/y
19 (1) 2’ eq LDAITHF, -78O C
32
17
-J
(11 2 ea LDAITHF. -78’C (2) Acetylimidazolide (3) H+
33
imidazolide was employed, 3(2H)-furanones 19 and 33 accompanied only by starting hydroxy ketone were obtained. Although these tranformations were quite clean, conversions were only in the range of 3 0 4 % . Presumably, the low conversions result from the acidic nature of the initially derived 1,3-diketone (e.g., 31). Unfortunately, all attempts to increase the conversion either by inverse addition or by employing greater than 2 equiv (ca. 3-5 equiv) of base were counterproductive. The latter result is presumably due to the known base-catalyzed self-condensation of acetyl imidazolide.” Thwarted by low conversions, we turned our attention to an alternative strategy. While our previous approach involved an electrophile in the oxidation state of a carboxylic acid, there appeared to be no reason that an aldehyde could not be employed for the initial carbon-carbon bond formation step (ca. a n aldol condensation). Subsequent oxidation of the resultant @-hydroxy ketone 34 would then afford the desired 1,3-diketone (31).’* n
12
OH
0
34
0
0
31
(16) (a) T. Brandt and W. I. Taylor, J. Chem. SOC.,3425 (1954); (b) W. Parker, R. A. Raphael, and D. I. Wilkinson, ibid., 3871 (1958). (17) H. A. Staab, Angew. Chem., Internat. Ed. Engl., 1, 351 (1962).
1504 J . Am. Chem. SOC., Vol. 103, No. 6,1981
Smith et al.
Table 11. Synthesis of Simple 3(2H)-Furanones Aldol
En try
Ketone
Aldehyde RCHO
(36)
P
1,3-Diketone
R
Me,SiO
&R Me,SiO
(34) (percent yield)
R&
(311
(percent yield)
(percent yield)
57
9
50
60
10
60
90
11
43
35
Me,SiO b
J(2HI-Furanone
35
CH,=C(Me)CHO
9Za
d
35
PhCHO
1008
95
27
78
e
35
ECHO
818
86 79 80
37
66
38
45
39
62
67
40 50
93
42
f
35
n-BuCHO
776
g
35
Me(CH,I,CHO
h
35
PhCH,CHO
936 86b
PhCH,CHO
828
0
i
Lithium enolate employed.
20
Zinc enolate employed.
Furthermore, if the oxidation were carried out under acidic conditions, it might be possible in “one pot” to effect direct cyclization to the desired 3(2H)-furanone. Indeed, treatment of 35 (see Table 11) with 1.1 equiv of LDA, followed by condensation a t low temperature with a variety of aldehydes (Le., 36a-h), led to the desired @-hydroxyketones 34. Yields, in general, were good to excellent, except in the case of easily enolizable aldehydes (36e-h), where conversions were only modest (ca. 58%). Marked improvement here was realized by exploiting the zinc enolate prepared according to the method of Ho~se.’~-~~ Subsequent oxidation of the aldol products with Jones reagent2l8 resulted both in formation of the diketone and in cyclizationdehydration to the 3(2H)-furanone. Best results, however, were obtained when oxidations were effected using Collins’ reagent?lb followed in a subsequent step by treatment of the derived 1,3diketone with mild aqueous acid to effect cyclization4ehydration. This two-step protocol for the elaboration of 1,3-diketones holds considerable promise, we believe, as a general synthetic method. Several additional comments are in order. First, the generality of this approach to 3(2H)-furanones disubstituted in the 2-position is illustrated by the variety of systems prepared. Even the very unstable 3(2H)-furadienones (Table 11; entries a-c) could be prepared via this strategy in useful, albeit modest, yields. Furthermore, the method depends only on the availability of the appropriate aldehyde. In this regard, we note that tert-butyldi(18) The oxidation of @-hydroxyketones to 1,3-diketones, while not unprecedented, has not been widely exploited, presumably because of the enolic nature of the derived diketone and the potential of oxidative cleavage. Studies in our laboratory with simple @-hydroxyketones and esters indicate that the latter is not a serious problem when Collins’ or Swern’s oxidation conditions are employed. (unpublished results of P. Levenberg). (19) H. 0. House, D. S. Crumrine, A. Y.Teranishi, and H. D. Olmstead, J. Am. Chem. SOC.,95, 3310 (1973). (20) It is of interest that the lithium enolate derived from ketone 41, unlike that of 35, afforded an excellent conversion to aldol Mi. Presumably, the added methyl group decreases the basicity of the lithium enolate such that proton transfer in this case is not a serious problem. (21) (a) K. Bowden, I. M. Heilbroon, E. R. H. Jones, and B. C. L. Weedon, J. Chem. Soc.,39 (1946); (b) J. C. Collins and W. W. Hess, Org. Synrh., 52, 5 (1972).
methylsiloxymethacrolein (36c) was previously an unknown compound. Its synthesis, modeled after previous work of Ficini22 and that of this laboratory,’ is depicted below.23 I l l Br2/H,02‘ 156%)
B r z “ t
I21 IEtO1,CH. NH,NO,’S 177%)
Illn-BuLi, -7tPC7.”
12) HCHO lgl 172%) 43
Ill TBDMSCI, imidazole/DMF26 191%) 121 Oxalic acid, CH,C12/H,0 187%) 44
36c
With a general approach to the 3(2H)-furanone ring system secure, we next turned our attention to the study of the chemistry of this heterocycle. Three reactions were selected; they were alkylation, conjugate addition of organocuprate reagents, and reaction with sulfur nucleophiles. Alkylation of the 3(2H)-Fura”e Ring SystentZ7 We initiated this study by examining the alkylation of a number of simple substituted 3(2H)-furanones. Our results are illustrated in Table 111. As predicted, treatment of the kinetic lithium enolate of 2,5-dimethyl-3(2H)-furanone(45) with alkyl halides resulted in exclusive alkylation at the &-position. On the other hand, reaction of a‘,a‘-disubstituted derivatives 19, 22, 46, and 47 afforded excellent yields of only y-alkylation. Of interest here is the fact that the reactivity of these furanones is not affected by the degree (22) J. Ficini and J. C. Depezay, Tetrahedron Lerr., 4797 (1969). (23) It is significant that the stability of 36c differed considerably from that of a-hydroxymethylacrolein, the latter known to polymerize rapidly in the neat state; see: J. E. Vik, Acra Chem. S c a d . , 27, 239 (1973). (24) R. H.Baker, S. W. Tinsley, Jr., D. Butler, and B. Riegel, J . Am. Chem. Soc., 72, 393 (1950). (25) H. 0. L. Fischer and E. Baer, Helu. Chim. Acra, 18, 514 (1935). (26) E. J. Corey and A. Venkateswarlu, J. Am. Chem. SOC.,94, 6190 ( 19i2j. (27) For a preliminary account of this work see: R. M.Scarborough, Jr., and A. B. Smith, 111, Tetrahedron Lerr., 4193 (1978).
J. Am. Chem. SOC.,Vol. 103, No. 6, 1981 1505
Reactions of Simple 3(2H)-Furanones
Table 111. Alkylation of 3(2H)-Furanones and P-Alkoxya,p-unsaturated Carbonyl Compounds Alkylation distribution Fntry
Substrate
Alkyl halide
fpercentl
a 100 ( a ’ )
Product 7
fpercentl
0
19
73
lOO(a’)
0
54
81
100 ( a ’ )
0
46
71
0
100
37
85
0
100
39
80
0
100
28
93
0
100
55
92
0
100
56
83
0
100
57
75
0
100
47
74
PhSeBr
0
100
58
84
Me1
0
100
59
58
Me I
100
0
60
61
61.62
74
63
91
45
19 335
4 22
A
q 4 ,
46
48
49
MeOOC
J-J
34
66
100
0
33
67
64,65
86
100
0
66
88
50 EtOOC 938
E tO
b 51
52
of either a or y substitution. Furthermore, the utility of this process can be expanded to yield an alternative route to the furandienone system. For example, y-alkylation of 3(2H)furanones 22 and 47 with phenylselenenyl chloride followed by
~xidative-elimination~’ affords furadienones 10 and 67 in 5040% overall yield. Interestingly, the intermediate selenoxides displayed no propensity toward [2,3]-sigmatropic rearrangement, a known reaction of allylic s e l e n ~ x i d e s . ~ ~
1506 J. Am. Chem. Soc., Vol. 103, No. 6, 1981
&
(11 LDAITHF
22
do 47
Smith et al.
& 10
R = H or Me
Addition of Organocuprate Reagents to Simple 3(2H)Furanones.@ The second area investigated was that of addition
( 1 ) LDAITHF (2) PhSeBr
87
To our knowledge, selective y-alkylation of lithium dienolates is unprecedented.28 Indeed, the only other reported example of selective y-alkylation of a @-alkoxy-a,@-unsaturated carbonyl compound is that reported for 2,6-dimethyl-y-pyrone 48.z9,30 However, this vinylogous ester is exceptional in view of its aromatic nature. It is interesting in this regard to note that a wide variety of copper dienolates, derived from simple a,@-unsaturatedesters, were recently observed to undergo selective y - a l k y l a t i ~ n . ~ ~ To evaluate the factors which determine the observed regiochemistry, we examined alkylation of a number of related ,L?alkoxy-a,P-unsaturated carbonyl substrates. Ideal candidates for this purpose appeared to be P-alkoxy-a,@-unsaturatedesters since a’-alkylation would no longer be a concern. In the event, kinetic deprotonation of derivatives 49, 51, and 53, employing the LDA-HMPA complex of Rathke” and Schlessinger4’ followed by reaction with alkyl halides afforded 10096 a-alkylation, while similar treatment of substrates 50 and 52 led to a mixture of aand y-alkylated products, with the y adduct predominating 3:2 in each case. Although no definitive statement can, as yet, be made concerning the factors that govern a vs. y selectivity, one consistent observation was noted. In those cases where the dienolate incorporates an exocyclic double bond, y-alkylation is the preferred mode. Conversely, dienolates possessing an endocyclic olefin yield exclusively a adducts. Clearly, further structurereactivity studies are required before the subtle features governing CY vs. y selectivity in the alkylation of P-alkoxy-a,P-enones can be fully appreciated.
(28) (a) H. E. Zimmerman in “Molecular Rearrangements”,P. de Mayo, Ed., Interscience, New York, 1963, p 345; (b) A. C. Cope, H. L. Holmes, and H. 0. House, Org. React., 9, 102 (1957); (c) H. 0. House, “Modern Synthetic Reactions”, 2nd ed., W. A. Benjamin, Menlo Park, Calif., 1972, Chapter 9; (d) M. W. Rathke and D. Sullivan, Tetrahedron Lett., 4249 (1972); (e) J. L. Hermann, G. R. Kieczykowski,and R. H. Schlessinger,ibid., 2433 (1973); (f) S.A. G. de Graaf, P. E. R. Osterhoff, and A. van der Gen, ibid., 1653 (1974). (29) M. Yamamoto and N. Sugiyama, Bull. Chem. SOC.Jpn., 48, 508 (1975). (30) Regioselective y-alkylation has been reported for vinylogous amides; see: M. Yoshimoto, N. Ishida, and T. Hiraoka, TetrahedronLett., 39 (1973); T. A. Bryson and R. B. Gammill, ibid., 3963 (1974). (31) (a) H. J. Reich, I. L. Reich, and J. M. Renga, J . Am. Chem. SOC., 95, 5813 (1973); (b) K. B. Sharpless, R. F. Lauer, and A. Y. Teranishi, ibid., 95, 6137 (1973); (c) D. L. J. Clive, J. Chem. SOC.,Chem. Commun., 695 (1973). (32) H. J. Reich, J. M. Renga, and I. L. Reich, J . Am. Chem. SOC.,97, 5434 (1975). (33) C. Venture110 and R. D’Aloisio, Synthesis, 754 (1977). (34) Prepared by alkylation of 45. For earlier preparation see I. I. Nazarova, B. P. Gusev, and V. F. Kucherov, Isu.Akad. Nauk USSR, 729 (1965). (35) J. A. Rampes, S. Hoff, P. Montijn, L. Brandsma, and J. F. Arens, R e d . Trav. Chim. Pays-Bas, 88, 1445 (1969). (36) Ae. de Groot and B. J. M. Jansen, Recl. Trau. Chim. Pays-Bas, 93, 153 (1974). (37) F. Korte and H. Machleidt, Chem. Ber., 90, 2137 (1957). (38) Prepared by the method of Stork and Kraus; see G. Stork and G. A. Kraus, J. Am. Chem. SOC.,98, 2351 (1976). (39) J. A. Katzenellenbogen and A. L. Crumrine, J . Am. Chem. Soc., 96, 5662 (1974); also see J. A. Katzenellenbogen and A. L. Crumrine, ibid., 98, 4925 (1976). (40) M. W. Rathke and D. Sullivan, Tetrahedron Lett., 4249 (1972). (41) J. L. Herrmann, G. R. Kieczykowski, and R. H. Schlessinger, Tetrahedron Lett., 2433 (1973).
of ~ r g a n o c u p r a t e sto~ ~3(2H)-furanones. Such a study was anticipated not only to evaluate the reactivity of simple furanones with respect to conjugate addition but also to provide a test of the Baldwin rules for ring closure.44 That is, if retro-Sendotrigonal reactions are indeed disfavored processes as postulated by Baldwin, reaction of 3(2H)-furanones with excess cuprate should lead only to the mono-@-alkylatedadduct, since expulsion of the @-alkoxysubstituent by the initially formed enolate entails a retro-5-endo-trigona1 process.45 In the event, treatment of 2,2-dimethyl-3(2H)-furanone(13) with 2.5 equiv of lithium dimethyl-, di-n-butyl-, and diphenylcuprates led in each case only to the monoalkylated adduct. Similarly, furadienone 10 afforded monoadduct 71 as the sole product. Me,CuLi,
Et,O.
ODC
172%)
68
13 n-Bu,CuLi. Et,O,
0°C
(7W)
n.Bu
4 E9
-25’ Ph,CuLi, to -23’C Et,O (57%)
4
Ph
seO, P
d
27
70
10
h
71
Two experimental findings suggest that the a’-hydroxy enone is not formed. First, if such an intermediate were present, one would expect in the presence of excess reagent at least partial conversion to the @,@-dialkylatedhydroxy ketone;46 no such products (
