4452 J. Org. Chem., Vol. 43, No. 23, 1978
Kingsbury, Hutton, and Durham
hydroxy acids of oppositc?configuration,28the condensation of ( - m n t h y l or (tkbornyl acetates with aryl ketones gave @-hydroxyacids of the sam c o n f i g u r a t i ~ n , *and ~ ~ the ~ ~ Darzens reaction of (-)-menthyl or (+)-bornyl chloroacetate with acetophenone gave glycidates in which the @-chiral centers had the same c ~ n f i g u r a t i o n . ~ ~ (28)M. H. Palmer and J. A. Reid, J. Chem. SOC.,931 (1960). (29)K. Sisido, K. Kumazawa, and H. Nozaki, J. Am. Chem. SOC.,82, 125
(1960). (30) S.Mitsui and Y. Kudo, 7etrahedron. 23, 4271 (1967). (31)K. Sisido, 0.Nakanisi, and H. Nozaki, J. Org. Chem., 26, 4878 (1961). (32)F. C. Whitmore and J. H. Olewine, J. Am. Chem. Soc., 60, 2569 (1938). (33)J. L. Simonsen. "The Terpenes", Vol. 1. 2nd ed., Cambridge University Press, Cambridge, 1947,p 236 (no solvent listed.)
(34)J. Clark and J. Read, J. Chem. SOC.,1775 (1934). (35)Reference 33,p 359. (36)(a) R. Q. Brewster, C. A. VanderWerf, and W. E. McEwen, "Unitized Experiments in Organic Chemistry", 3rd ed.,Van Nostrand-Reinhold, New York, 1970,p 168;(b) R. N. Keller and H. D. Wycoff. "Inorganic Synthesis", Vol. 11, W. C. Fernelius, Ed., McGraw-Hill, New York, 1946,p 1. (37)J. N. Huffman and J. T. Charles, J. Am. Chem. SOC.,90, 6486 (1968). (38)R . H. Pickard and W. 0. Littlebury, J. Chem. SOC.,91, 1973 (1907). (39)For comparison: C11H18N302,224.1398;C12H22N30,224.1762. (40)H.M. Walborsky and L. Plonsker, J. Am. Chem. Soc., 83, 2138 (1961). (41)C. H. DePuy, G. M. Dappen, K. L. Eilers. and R. A. Klein, J. Org. Chem., 29,
2813 (1984). (42)R. S.Ratney and J. English, Jr., J. Org. Chem., 25, 2213 (1960).
Configuration and Conformation of Acyclic Keto Diesters Charles A. Kingsbury,' Ronald F. Hutton, and Dana Durham University of Nebraska-Lincoln,
Lincoln, Nebraska 68588
Received August 26, 1977 Conformational preferences in molecules such as 4,4-dicarbomethoxy-l,3-diphenyl-l-butanone are reported with special emphasis on the effect of the dicarbomethoxy group in comparison to other disubstituted carbon substituents on an ethanic skeleton. The diesters of interest are characterized by a low degree of conformational purity, especially in the threo isomers. The configuration of the keto diesters was proved by conversion into cyclopropanes, or into cyclic hemiacetals. The hemiacetals were characterized by a facile epimerization. The results of NMR determinations of conformation are compared to the usual 1H determinations; the two forms are in reasonable agreement. 7'1 measurements, however, were insensitive to segmental motion.
In the 191O's, Kohler and co-workers published convenient methods of synthLesizing keto diesters of general structure 2.1 More important, methods for separating the pairs of diastereomers were given, usually a difficult task. The configuration of these diastereomers (e.g., 4 and 5) remained unknown until the present study. These molecules are of interest with regard to their conformational preferences. In other work, compounds with the groups RzCH or RR'CH (e.g., isopropyl, cyclohexyl, cyclopentyl, Ph(CH3)CH, etc.) have been thoroughly investigated.2J These groups have a strong tendency to adopt a (certain preferred conformation, and furthermore, they impart a strong degree of conformational purity elsewhere in the molecule. A possible exception is the benzhydryl group, which, despite a larger overall size, was not strongly determinative in the conformational sense.4 Since benzhydryl has relatively few hydrogens at the periphery of the group which could interact with other vicinal substituents, the question arises as to the effect of a RzCH group where R lacks interacting hydrogens a l t ~ g e t h e rThe . ~ diester function (CH302C)ZCH is ideal for this investigation. CH,OIC,
0 Ph--CH=C-C-R
11
I
,CO?CH, :CH,
CH,(CO,CH,), - -oOCH
I Ph--,CH-CH-,C-R
6 7 8
0
I
R 2
1
5
II
'I
3
ri, compd 3 4
0
Hz indicate gauche protons. Intermediate values suggest weighted means of trans and gauche conformers. The lH NMR data will be compared to 13Ccoupling constants to lH. A greater uncertainty prevails with regard to the 3 Jdata, ~ ~ as relatively few cases have been studied. The 13C data, in theory, are more useful, however, since many combinations of nuclei can be ~ t u d i e d For . ~ anti 13C(sp3)and lH nuclei, Chertkov and Sergeyev have found 3 J c to ~ be 8 Hz, in a cyclohexane derivative, whereas for gauche nuclei 3 J cis~ca. 2 Hz.8 However, work in more complex systems by Perlin and co-workerssb and otherssCtd(including this study) appeared to be consistent with smaller values. For sp2hybridized nuclei (e.g., COOH), 3 Jmay ~be ~ as high as 12 Hz.'le,gLemieux has warned of substantial variations in 3 J c ~ due to stereoelectronic effects,7bas well as due to the usual torsional variations. Thus, the lH--lH data are regarded as the more important criteria in arriving at a decision with regard to molecular conformation. Configuration of 4-8. The configuration of the low melting isomer of 2-bromo-4,4-dicarbornethoxy-1,3-diphenyl-l-b~tanone (4) was proved by base catalyzed conversion to the trans-cyclopropane 9 ( J a b = 7.8 Hz). The high-melting bromide 5 formed the cis-cyclopropane 10 (3J,b = 10 Hz). A
isomer threo erythro threo erythro erythro
R' H Br Br CH3 CH3 Ph
R Ph Ph Ph Ph Ph CH3
mp, "C 106-107 96-98 108-109 88-90 91-93 118-119
In this study, NMR coupling constants will be used as a qualitative guide to conformation.6 lH coupling constants of 11-13 Hz are indicative of trans protons, whereas values of 1-3
9
0
10
0022-326317811943-4452$01.00/0 0 1978 American Chemical Society
J. Org. Chem., Vol. 43, No. 23, 1978 4453
Configuration of Acyclic Keto Diesters
Table I. 'H NMR Chemical Shifts (ppm) and Coupling Constants (Hz) CH,O,C-CH,-CO,CH,
0
Ph-
CHb-CHa-
I
II
C-R
R' compd. 3 4 (threo) 5 (erythro)
6 b (threo) 7 (erythro) 8 (erythro)
R
R'
Ph Ph Ph Ph Ph CH3
Ha.Q Br Br CH3 CH3 Ph
= 3.55 ppm, :IJa,i,= 8.9; 'Jaa'
6a
6b
6,
3.48 6.16 6.16 4.06 4.23 4.75
4.21 4.32 4.37 3.67 3.98 4.31
3.88 4.15 4.33 3.89 3.99 3.52
3Jab
Other
3Jbc
4.8 1.8 11.5 7.6 7.9
9.4 8.2 5.8 8.3 8.8 6.3
11.5
6CH3 1.01 6CH3 1.22
~ C 1.88 H ~
= 9.1 Hz. = -12.0 Hz. In acetone-& as solvent, 3 J a b = 5.4; 3J13c
search of Bothner-By's compilation of authenticated coupling constants revealed no case in which a trans-cyclopropane had a larger 3 5 value than the cis isomer (in the cis isomer, the dihedral angle between vicinal protons is ca. O", whereas in the trans isomer, this angle is ca. l2Oo).9J0 Thus, 4 must be the threo isomer, and 5 the erythro isomer. With regard to the a-methyl compounds 6 and 7, it was hoped that configuration could be proved by reductive cyclization. The low-melting isomer 6 gave a hemiacetal 11 upon treatment with BH4- rather than the expected lactone." The l H NMR coupling constants of 11 were very large (10-12 Hz), except for 35ae,12 indicating several sets of trans diaxial hydrogens. The major substituents must therefore be equatorial. The configuration of 6 is thus threo. The high-melting isomer 7 gave the lactone 12, as well as the hemiacetal, 13, upon reduction. The configuration of the lactone 12 was unclear, perhaps due to conformational averaging.13 However, the hemiacetal 13 exhibited a strong preference for the conformation indicated in Chart I. In 13, C4CH3 has the opposite configuration as 11, consistent with the erythro configuration of 7. In the coupled 13C spectrum, the methyl group of 13 was split into a rough quartet of quartets. This pattern is explicable in terms of a roughly equivalent coupling of CH3 to H,, Hd, and Hb of ca. 5 H[z. The splitting by Hi, and Hd, though rather smaller than expected, is consistent with CH3 trans to Hb and Hd. In 11, the CH3 was split into a doublet of quartets pattern (2 X 4). The doublet was due to 2 J ~ ~ (ca. 3 - 4.4 ~ ,Hz). Additional splittings of this resonance by Hb and Hd were barely visible, and of the same magnitude as the error in data Chart I
collection, f0.3 Hz. These small couplings are consistent with the gauche arrangement of CH3 with Hb and Hd. Lack of solubility precluded the use of sufficiently high sample concentration to achieve better data collection statistics. By a similar procedure, 5,5-dicarbomethoxy-3,4-diphenyl-2-pentanone (8) was reductively cyclized to form the
14
Jae= 8.0 Jab =
12.9
J b c = 4.7 Jcd = 2.8
hemiacetal 14, which is similar to 13. Thus 8 is also an erythro isomer. The threo isomer could not be isolated. The hemiacetals 11,13, and 14 each showed the presence of a second material in the lH and 13C spectra. In neutral solvents, this second substance increased from an initial low level to ca. 20% of the overall quantity, and thereafter remained at a constant level. These minor components are believed to be the anomers (OH axial) of the parent compounds (OH equatorial). Attempts to isolate the anomers were unsuccessful. The 3Jae= 3 Hz observed for the anomer of 14 is consistent with equatorial He and an axial OH group. The low concentration of the presumed anomers is notable. In certain carbohydrates, the a anomer (OR axial) is dominant in many cases.14 The reasons for the dominance of a seemingly sterically hindered axial OR group (the anomeric effect) have been extensively reviewed.15 Eliel and co-workers, and others, have interpreted the anomeric effect in terms of a hyperconjugative interaction (i.e., as in 15).16 However, such stabilization is not apparent in the anomers of 11, 13, and 14. Molecular models suggest that the hydrogen bond between hydroxyl and the C2-carbomethoxy group is more stable for an equatorial hydroxyl. The orientation of the carbonyl group (eclipsed with the Cl-C2 bond) is favorable in such a case.I7 The orientation of carbonyl (not eclipsed) is less favorable, if hydrogen is bonded to an axial OH.
doR-pJ -OR
15 12
13 J,, = 7 . 8
Jab = 1 2 . 3
Jbc = 4 . 0
Jc,j = 2.3
Acyclic Keto Diesters. Table I lists the lH NMR data, and Table I1 gives the 13C data for 3-8. Of these compounds, 3 alone lacks a substituent a t C2. Compound 3, however, is the most conformationally pure compound of this study with re-
4454 J. Org. Chem., Vol. 43, No. 23, 1978
Kingsbury, Hutton, and Durham
Table 11. 13C NMR Chemical Shifts (ppm)e and Coupling Constants (Hz) CH,O?C, ,CO,CH,
0
4CH‘
I
Ph- ,CHb--,CH,--,C-R
II
I
R compd
~61 82
63
64
8R’
6COd
168.4 167.8 167.8 167.2 168.2 168.3 167.9 169.2 167.8 168.2 167.9
3
197.0
42.0
40.6
57.1
4
191.4
52.5
46.8
55.2
5
6
191.5 201.7
47.9 42.9
46.9 46.7
54.9 55.1
15.0
7
201.7
43.5
46.9
54.3
15.4
8‘
205.7
61.8
46.8
54.8
3Jcz-~,
3J~4-~a
3JCO-Hbd
2.8 3.4?
2.6 -7.5 3.2 8.0 a -3 -8
1.2
-1
