3099
J. Am. Chem. SOC. 1981,103,3099-3111
Stereoselective Aldol Condensations via Boron Enolates’ D. A. Evans,* J. V. Nelson,2 E. Vogel, and T. R. Taber2 Contribution No. 6279from the Laboratories of Chemistry, California Institute of Technology, Pasadena, California 91125. Received August 25, 1980
Abstract: A detailed investigation of the enolization of a variety of ketones and carboxylic acid derivatives with dialkylboryl triflates in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The stereochemistry of the enolates formed from acyclic ketones was found to be dependent on the structure of the ketone, the dialkylboryl triflate, and the tertiary amine. A mechanism for the enolization involving initial coordination of the boryl triflate to the ketone carbonyl with subsequent deprotonation by the amine is proposed to explain the results. The boron enolates derived from these acyclic ketones undergo aldol condensation with a number of aldehydes in good yield. Consistently good correlation was observed between the enolate geometry and the product aldol stereochemistry for these acyclic ketones regardless of the structure of the ketone or the boron ligands. However, for the boron enolate derived from cyclohexanone the aldol stereoselectivity was dependent on the boron ligands and the solvent. In this case, the use of the cyclopentylthexylboron enolate in tetrahydrofuran as solvent resulted in complete stereocontrol in the condensation. Although simple esters and amides cannot be enolized with the triflate reagents, tert-butyl thiopropionate was readily converted to the trans enolate. The stereoselectivity of the aldol condensations of this enolate is also dependent on the boron ligands and the solvent; again, the proper choice of these parameters allowed total stereocontrol of the condensation. It was found that carboxylic acids could be converted to the dialkylboryl enediolates, and the aldol condensations of these species were used to probe the relative reactivity of cis and trans enolates. Chiral boron enolates were studied for possible asymmetric induction in the aldol condensation. Methyl ketone enolates exhibited moderate levels of chirality transfer, while cis enolates gave only one detectable diastereoisomer. The sense of chirality transfer was proven by determination of the absolute configurations of newly created centers of asymmetry. A transition state model based on steric interactions is proposed for chirality transfer. Scheme I
Introduction The aldol condensation is a reaction of fundamental importance in the biosynthesis of a broad range of biologically significant natural products. The recognition of both the macrolide and ionophore antibiotics as attainable targets for synthesis has been instrumental in focusing renewed interest toward the development of stereoregulated variants of this process in the l a b ~ r a t o r y . ~ Ideally, it would be signifcant to reveal those stereochemical issues which deal with the control of both reaction diastereoselection (El E2vs. T1 T2)and enantioselection (El vs. E2 or TIvs. T2) for a range of reaction substrates (eq 1).
+
+
R,CHO t
#
H
1“ RzCHO
In 1957, in conjunction with a stereochemical study of the Ivanov and Reformatsky reactions, Zimmerman and Traxler accounted for the observed aldol diastereoselection by advancing the hypothesis that the reaction proceeded via a preferred chairlike transition state involving cooperative metal ion ligation of both the enolate and carbonyl substrates (cf. Scheme I)! Subsequent investigations by Duboiss and more recently by Heathcock6 on (1) Aspects of this work have been previously disclosed: (a) Evans, D. A. 15th Eurochem Conference on Stereochemistry, Burgenstock, Switzerland, April 29,1979. (b) Evans, D. A.; Vogel, E.; Nelson, J. V. J . Am. Chem. Soc. 1979,101,6120-6123. (c) Evans, D. A,; Taber, T. R. Tetrahedron Lett. 1980, 4675-4678. (2) Abstracted from the Ph.D. Theses of J. V. Nelson and T. R. Taber. (3) For a review of early efforts in this area see: Nielson, A. T.; Houlihan, W. J. Org. React. 1968.16, 1-438. (4) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Sot. 1957, 79, 1920- 1923. ( 5 ) (a) Dubois, J. E.; Fort, J. F. Tetrahedron 1972, 28, 1653-1663, 1665-1675, and references cited therein. (b) Dubois, J. E.; Fellman, P. C. R. Acad. Sci. 1972, 274, 1307-1309. (c) Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225-1228. (6) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A,; Pirrung, M. C.;Sohn, J. E.; Lampe, J. J . Org. Chem. 1980,45, 1066-1081, and citations to earlier
work.
0002-7863/81/1503-3099$01.25/0
threo
erythro
t
t 9
c-t
R2CHO
+ OM ‘ R , v H 3 H
Y
preformed lithium enolates have unambiguously shown that kinetic aldol diastereoselection is, in part, defined by enolate geometry. With regard to the pericyclic chair transition states illustrated in Scheme I, both “trans” and “cis” lithium enolates (M = Li) exhibit excellent kinetic threo and erythro product selection, re0 - 198 1 American Chemical Societv
3100 J. Am. Chem. SOC., Vol. 103, No. 11, 1981
Evans et al. Table I. Kinetic Enolate Formation with Triflates 4a and 4 b (Ecl 2)
Scheme I1 [G O j !
1*
[Boat]'
entry
ratio
1. R. =
A B C D E F G H I J
D
spectively, when the enolate ligand, R I , is sterically demanding such as tert-butyl. The observation that the steric bulk of Rl (t-C4H, > GC3H7> C2H5> OCH3 > H) and the attendant aldol diastereoselections*6are directly coupled is consistent with the elaborated Zimmerman model (Scheme I).4 For example, for trans enolates transition state B is destabilized relative to A owing to Rl * R2 interactions. Related trends in aldol stereoselection have been noted for magnesium,' zinc,8 and aluminumg enolates. At the outset of the present study the decision was made to explore the role of "metal-centered steric effects" in the kinetic aldol process.' Within the context of the diastereoisomeric chair transition states illustrated in Scheme I, the pseudo- 1,3-diaxial L interactions in transition states B and C might confer Rz enhanced aldol diastereoselection from either enolate geometry. Given the assumption that the chair transition state geometry is preferred, it follows that both the enolate ligand, RI, and the metal ligand, L, will contribute in a complementary fashion to enhanced aldol diastereoselection. It was also felt that an examination of metal ligand steric effects in the aldol process might also provide direct evidence pertaining to the actual transition state geometry (boat vs. chair). If one examines the four diastereoisomeric transition states for a given enolate geometry (Scheme 11), it is projected that in the chair transition state geometries, R1 R 2 and L R2,steric parameters will contribute in a Complementary fashion to destabilize B relative to A. However, for the diastereoisomeric boat transition states E and F, the enolate ligand, Rl, and the metal ligand, L, control elements will operate in a noncomplementary fashion. Consequently, an examination of the effects of structural variation a t the metal center (ML,) a n d enolate ligand, RI, might reveal the actual transition geometries in question. For the reasons outlined in our earlier communication,Ib dialkylboryl enolates appeared to be excellent candidates for study. A limited number of literature cases indicated that good levels of aldol diastereoselection might be anticipated.l0 This paper reports the full details of our initial investigations into the generation of stereochemically homogeneous boron enolates and their stereoselective aldol condensations with aldehydes. The parallel investigations of Masamune' I and Mukaiyama', are in accord with those made in the present study.
-
-
-
Results and Discussion Selective Generation of Boron Enolates. A variety of published methods exist for the generation of dialkylboryl en01ates.l~ (7) Fellmann, P.; Dubois, J. E. Tetrahedron 1978, 34, 1349-1357. (8) House, H. 0.;Crumrine, D. S.; Teranishi, A. Y . ;Olmstead, H. D. J . Am. Chem. SOC.1973, 95, 331CL3324. (9) (a) Jeffrey, E. A,; Meisters, A.; Mole, T. J . Organomet. Chem. 1974, 74, 365-372, 373-384. (b) Maruoka, K.; Hashimoto, S.; Kitagawa, Y . ; Yamamoto, H.; Nozaki, H.J . Am. Chem. SOC.1977, 99, 7705-7707. (IO) (a) Mukaiyama, T.; Inomata, K.; Muraki, M. J . Am. Chem. SOC. 1973, 95, 967-968. (b) Fenzl, W.; KBster, R. Justus Liebigs Ann. Chem. 1975, 1322-1338. (c) Fenzl, W.; Koster, R.; Zimmerman, H. J. Ibid. 1975, 2201-2210. (1 1) (a) Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. Tetrahedron Lett. 1979, 1665-1668. (b) Hirama, M.; Masamune, s. Ibid. 1979, 2225-2228. (c) Van Horn, D. E.; Masamune, S.Ibid. 1979, 2229-2232. (d) Hirama, M.; Garvey, D. S.; Lu, L. D.-L.; Masamune, S. Ibid. 1979, 3937-3940. (12) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980,53, 174-178.
Et Et Et Et Me,CH Me,CH Me,CH Me,CH Me,CH Me,C K Me,C L MeiCHCH, M C,H, N Me,CS
4. L =
basea
n-C,H, n-C,H, n-C,H, c-C,H, n-C,H, n-C,H, n-C,H, c-C,H, c-C,H, nC,H, n-C,H, n-C,H, n-C,H, n-C,H. - ,
DPEA Lut Lut DPEA DPEA Lut Lut Lut DPEA DPEA DPEA DPEA DPEA DPEA
conditionsb
2c:2tcvd
>97:3 -78 "C, 30 min 69:31 -78 'C, 30 min (86:14) -1-77 "C, 3 he 82:18 0 'C, 30 min 45:55 -78 "C, 30 min 56:44 -78 'C, 30 min (73:27) +77 "C, 30 mine O°C, 30min 42:58 19:81 0 "C, 30 min 25:75 0 'C, 30 minf +35 "C, 2 h (>97:3) >97:3 -78 "C, 30 min >97:3 25"C, 1 h 0 "C, 30 min 97:3 69:31 >97:3 >97:3 >97:3 >97:3 82:18
>97:3 72: 28 >97:3 >97:3 92:8 93:7 84:16
77 76 65 61 68 65 (86)
>99: 1
>97:3 84:16
82 (85)
44:56 18:82
65 (87)
C, H,-CHO C,H,-CHO n-C, H ,-CHO i-C,H,-CHO CH,=C(CH,)-CHO (E)-CH ,CH=C(CH, )-CH 0 C, H,-CHO
nC,H, n-C,H,e n-C,H, n-C,H, nC4H9 n-C,H, @C,H,
-78 -78 -78 -78 -78 -78
C,H,-CHO C,H,-CHO
n-C,H, G H ,
-78
C,H,-CHO C,H,-CHO
n-C,H, G H 9
-78
C, H&HO
n-C,H,
+35
>99: 1
>97:3
65
C,H,-CHO
n-C,H,
+25
99: 1
>97:3
82
C,H,-CHO
n-C,H,
-78
>97:3
70
iC,H,-CHO i-C, H ,-CHO
n-C,H, 45H9f
t 25
C,H,-CHO C,H,CHO
n-C, H,
-78
C,H,-CHO C,H ,-CHO n-C, H,-CHO i-C,H,-CHO CH,=C(CH,)-CHO (E)-CH,CH=C(CH,)-CHO
n-C,H, G H 9 n-C,H, n-C,H, n-C,H9 n-C, H,
I t -EOC 0 P
L,BOTF
0 0
4555 19:81
0
90: 10
+ 25
87:13
60 57
19:81 35:65
53 (68)
10:90 5:95 10:90 9:91 12:88 18:82
75 (90) 67 63 65 61
Ts
Q R
Me34
S T U V W X
t - BUS
6
4
3
0
9
0 0 0 0 0
loo%) of unpurified trimethylsilyl enol ether. A sharp quartet for the vinyl proton appeared at 6 5.25 in the 'HNMR spectrum for the trans enolate 2t. In samples containing cis enolate 2c, an additional signal appeared at 6 5.21 (9). Assignments were made by comparison with known mixtures generated by trapping the enolates formed using lithium diisopropylamide in analogy to the work of Ireland" et al. erytbro-1-Hydroxy-2-methyl-l-phenyl-3-pentanone (Table 11, Entry A). Kinetic enolization of 0.52 g (6.0 mmol) of 3-pentanone with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of di-nbutylboryl triflate in 15 mL of ether at -78 "C for 30 min was followed by aldol condensation and hydrogen peroxide workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.01 g (88%) of colorless oil. No threo aldol adduct 12T was detected by 'H NMR of the unpurified product; vide infra. The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 8 : l ) to afford 0.89 g (77%) of erythro aldol adduct 12E as a colorless oil: IR (CC14, 5%) 3605, 3500, 2985, 2969, 1705, 1695, 696 cm-I; 'H NMR (CC14) 6 7.17 (s, 5, aromatic), 4.80 (d, J = 3 Hz, 1, erythro CHOH), 3.19 (s, 1 , OH), 2.65 (m,1, COCH-), 2.21 (m,2, -COCH2-), 0.98 (d, 3, -CHCH3), 0.89 (t, 3, -CH2CH3). Authentic6 threo adduct gave rise to an additional signal at 6 4.48 (d, J = 8 Hz, threo CHOH). These spectra are identical with those reported in the literature6 for this compound. eryth-5-Hydroxy-4methyl-3-octanone (Table 11, Entry C). Kinetic enolization of 0.17 g (2.0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 mL of ether at -78 "C for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of n-butyraldehyde to yield 0.22 g (69%) of a colorless oil. No threo aldol adduct 12T was detected by 'H NMR of the unpurified product; vide infra. The product was bulbto-bulb distilled (130 OC (1 mm)) to afford 0.20 g (65%) of erythro aldol adduct 12E as a colorless oil: IR (neat) 3480, 2960, 1700, 1455, 975 cm-'; IH NMR (CDCIJ 6 3.89 (m,1 , erythro CHOH), 2.92-2.38 (m,4, -COCHz-, -COCH-, OH), 1.65-0.82 (m,13, aliphatic). Preparative gas-liquid chromatographic separation of a mixture of aldol products generated by lithium enolate condensation provided compounds for which assignments for the 'H NMR spectra were made by a comparison of the carbinol protons: erythro 6 3.89 (m,J = 3 Hz) and threo 6 3.65 (m,J = 7 Hz). The coupling constants were determined by an analysis of the signal of the proton on carbon 4. Exact mass: Calcd for C9HI8O2: 158.131. Found: 158.132. erytbro-5-Hydroxy-4,6-dimethyl-3-heptanone (Table 11, Entry D). Kinetic enolization of 0.17 g (2.0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 mL of ether at -78 OC for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of isobutyraldehyde to yield 0.21 g (65%) of a colorless oil. No threo aldol adduct 12T was detected by 'H NMR of the unpurified product; vide infra. The product was bulb-to-bulb distilled (130 OC (1 mm)) to afford 0.19 g (61%) of erythro aldol adduct 12E as a colorless oil: IR (neat) 3490, 2970,1700, 1455,973 cm-I; IH NMR (CDClJ 6 3.48 (d of d, J = 3 and 8 Hz, 1, erythro CHOH), 2.95 (s, 1, OH), 2.71 (d of q, J = 3 and 7 Hz, 1, COCH-), 2.50 (q, 2, C W H z - ) , 1.61 (m.1, -CH(CHJ2), 1.294.80 (m, 1 2 , 4 CHp's). Threo aldol adduct, prepared via the lithium enolate, gave rise to an additional signal at 6 3.41 (t, J = 7 Hz, threo CHOH). Exact mass: Calcd for C9Hl8OZ:158.131. Found: 158.134. erytbro- and tbreo-5-Hydroxy-4,6-dimethyl-~hepten-3-one (Table 11, Entry E). Kinetic enolization of 0.17 g (2.0 "01) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 mL of ether at -78 OC for 30 min was followed by aldol condensation and MoOPH workup with 0.21 g (3.0 mmol) of methacrolein to yield 0.23 g (72%) of a yellow oil. The ratio of erythro:threo aldol adducts, 12E:12T, in the unpurified product was determined by 'H NMR to be 92:8. The product was bulb-to-bulb distilled (150 OC (1 mm)) to afford 0.21 g (68%) of a colorless oil: IR (neat) 3480, 3100, 2980, 1705, 1650, 1457, 977, 900 cm-I; IH NMR (CDC13) 6 4.98 (m,2, olefin), 4.36 (d, J = 3 Hz, 0.92, erythro CHOH), 4.17 (d, J = 8 Hz, 0.08, threo CHOH), 2.90 to 2.39 (m,4, -COCH, COCHz-, and OH), 1.69 (s, 3, =CCH3), 1.20 to 0.95 (m,6, 2 CH,'s). Exact mass: Calcd for C9HI6O2:156.115. Found: 156.116.
3108 J . Am. Chem. SOC.,Vol. 103, No. 11, 1981 erytbro- and tlueo-5-Hydroxy-4,6-dimethyl-(E)-&-octen-J-one(Table 11, Entry F). Kinetic enolization of 0.17 g (2.0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol)
Evans et al.
erytbro- 1-( 1-tert-ButyloxycarbonyI-l-azacyclopenta-~4-dien-2-yl)-3hydroxy-2-methyl-3-phenyl-l-propanone (Table 11, Entry N). Kinetic enolization of 0.446 g (2.0 mmol) of 1-(1-tert-butyloxycarbonyl-1-azaof di-n-butylboryl triflate in 5 mL of ether at -78 OC for 30 min was cyclopenta-2,4-dien-2-y1)-1-propanone#with 0.310 g (2.4 mmol) of difollowed by aldol condensation and MoOPH workup with 0.25 g (3.0 isopropylethylamine and 0.603 g (2.2 mmol) of di-n-butylboryl triflate mmol) of tiglic aldehyde to yield 0.24 g (70%) of a yellow oil. The ratio in 5 mL of ether at -78 "C for 45 min was followed by aldol condensation of erythro:threo aldol adducts, 12E:12T,in the unpurified product was and MoOPH workup with 0.22 g (2.0 mmol) of benzaldehyde to yield determined by IH NMR to be 93:7. The product was bulb-to-bulb 0.723 g (>loo%) of a light yellow oil. No threo aldol adduct 12T was distilled (150 "C (1 mm)) to afford 0.22 g (65%) of a colorless oil: IR detected by IH NMR of the unpurified product; vide infra. The product (neat) 3490,2970,1700, 1667, 1450,970,825 cm-'; 'H NMR (CDCI,) was chromatographed at medium pressure over silica gel (hexane, ethyl 6 5.47 (m, 1, olefin), 4.58 (s, 1, OH), 4.24 (d, J = 5 Hz, 0.93, erythro acetate) to give 0.47 g (70%) of erythro aldol adduct 12E as a colorless CHOH), 4.11 (d, J = 9 Hz, 0.07, threo CHOH), 2.92 to 2.32 (m, 3, oil: IR (CC14) 3500,2980,2940, 1750, 1700, 1650, 1440, 1410, 1370, -COCH- and -COCH2-), 1.60 and 1.55 (d and s, 6, =CHCHg and 1310, 1150,945,845,695 cm-I; 'H NMR (CDC1,) 6 7.30 (broad s, 5, =CCHg), 1.22 (m, 6, 2 CH,'s). phenyl), 7.28-7.1 5 (m, 1, pyrrole), 6.78-6.70 (m, 1, pyrrole), 6.15-6.05 (m, 1, pyrrole), 5.19 (d, J = 4 Hz, 1, -CHCHOH), 3.64 (broad s, 1, Exact mass: Calcd for CloHlsOz: 170.131. Found: 170.131. OH), 3.40 (d of q, J = 7, 4 Hz, 1, CHjCHCHOH), 1.57 (s, 9, t-Bu erytbro-l-Hydroxy-55-dimethyI-l-phenyl-3-~~~ (Table 11, Entry CH,'s), 1.13 (d, J = 7 Hz, 3, CH3CH-). In the threo aldol adduct" the H). Kinetic enolization of 0.68 g (6.0 mmol) of 2-methyl-4-hexanone signal for CH3CHCHOH (carbinol center proton) appears at 6 4.90 (d, with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) J = 8 Hz). These spectra are identical with those reported in the literof di-n-butylboryl triflate in 15 mL of ether at -78 OC for 30 min was ature# for this compound. followed by aldol condensation and hydrogen peroxide workup with 0.64 erytbro- and tbreo-3-Hydroxy-3-phenyl-2-methyl-l-trimethylsilyl-lg (6.0 mmol) of benzaldehyde to yield 1.44 g (>loo%) of a pale yellow propanone (Table II, Entry Q). Kinetic enolization of 0.13 g (1.0 mmol) oil. No threo aldol adduct 12T was detected by IH NMR of the unpuof propionyltrimethylsilane with 0.16 g (1.2 mmol) of diisopropylethylrified product; vide infra. The product was chromatographed at medium amine and 0.30 g (1.1 mmol) of di-n-butylboryl triflate in 5 mL of ether pressure over silica gel (hexane:ethyl acetate, 8:l) to afford 1.09 g (82%) at -78 OC for 30 min was followed by aldol condensation and MoOPH of erythro aldol adduct 12E as a colorless oil: IR (CCl,, 5%) 3605,3510, workup with 0.1 1 g (1.0 mmol) of benzaldehyde to yield 0.16 g (66%) 2958, 1707, 1694, 1098, 1078, 698 cm-I; 'H NMR (CC14) 6 7.23 (s, 5, of a yellow oil. The ratio of erythro:threo aldol adducts, 12E12T, in the aromatic), 4.88 (d, J = 4 Hz, 1, erythro CHOH), 3.0 (s, 1, OH), 2.64 unpurified product was determined by 'H NMR to be 19:81. The (m, 1, COCH-), 2.3-1.75 (m, 3, COCH2CH-), 0.98 (d, 3, -CHCHg), product was bulb-to-bulb distilled (150 OC (1 mm)) to afford 0.12 g 0.83 (d, 6, -CH(CHg)J. Threo aldol adduct, from reactions using di(53%) of a colorless oil: IR (neat) 3460, 3030, 2960, 1635, 1450, 1250, cyclopentylboryl triflate, gave rise to an additional signal at 6 4.64 (d, 843, 755, 699 cm-'; IH NMR (CDC13) 6 7.31 (s, 5, aromatic), 5.03 (d, J = 9 Hz, threo CHOH). J = 3 Hz, 0.23, erythro CHOH), 4.72 (d, J = 8 Hz, 0.77, threo CHOH), Exact mass: Calcd for C14H2002:220.146. Found: 220.146. erytbro- and tbreo-l-Hydroxy-2,4-dimethyI-l-phenyl-3-pentanone 3.31 (m, 1, -COCH-), 2.8 (b, 1, OH), 0.83 (two d, 3, -CHCHg), 0.19 (s, 9, -Si(CH,),). Distillation resulted in a slight enrichment in the (Table 11, Entry J). Kinetic enolization of 0.60 g (6.0 mmol) of 2erythro adduct. These spectra are identical with those reported in the methyl-3-pentanonewith 0.85 g (6.6 mmol) of diisopropylethylamineand literature6 for this compound. 1.81 g (6.6 mmol) of di-n-butylboryl triflate in 15 mL of ether at -78 erytbro- and tbreo-S-(1,l-Dimethylethyl)3-Hydroxy-2-methyl-3OC for 30 min was followed by aldol condensationand hydrogen peroxide phenylpropanethioate (Table 11, Entry S). Kinetic enolization of 0.29 g workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.10 g (89%) (2.0 mmol) of S-tert-butyl propanethioate with 0.31 g (2.4 mmol) of of a pale yellow oil. The ratio of erythro:threo aldol adducts, 12E:12T, diisopropylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in the unpurified product was determined by 'H NMR to be 44:56. The in 5 mL of ether at 0 OC for 30 min was followed by aldol condensation product was chromatographed at medium pressure over silica gel (hexand MoOPH workup with 0.21 g (2.0 mmol) of benzaldehyde to yield ane:ethyl acetate, 12:l) to afford 0.80 g (65%) of a colorless oil: IR 0.40 g (80%) of a yellow oil. The ratio of erythro:threo aldol adducts, (CC4, 5%) 3480, 3030, 2970, 1707, 1450, 1100, 1005, 698 cm-I; 'H 12E:12T, in the unpurified product was determined by IH NMR to be NMR (CC14) 6 7.30 (s, 5, aromatic), 4.91 (d, J = 5 Hz, 0.44, erythro 10:90. The product was bulb-to-bulb distilled (150 "C (0.5 mm)) to CHOH), 4.70 (d, J = 8 Hz, 0.56, threo CHOH), 3.40 (s, 1, OH), 3.22 afford 0.31 g (75%) of a colorless oil: IR (neat) 3450, 3030, 2960, 1675, to 2.46 (m, 2, -COCHCH and -COCH(CH3)2), 1.19 to 0.89 (m, 9, 3 1450, 1365, 960, 700 cm-'; 'H NMR (CDCI,) 6 7.22 (s, 5, aromatic), CHis). These spectra are identical with those reported in the literature6 5.03 (d, J = 4 Hz, 0.10, erythro CHOH), 4.74 (d, J = 8 Hz, 0.90, threo for this compound. CHOH), 2.85 (m, 1, -COCH-), 2.5 (b, 1, OH), 1.48 (s, 9, -S(CH,),), erytb~-l-Hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (Table 11, 1.03 (two d, 3, CHg). Entry L). Enolization and equilibration of 0.68 g (6.0 mmol) of 2,2Exact mass: Calcd for C14H2002S:252.118. Found: 252.119. dimethyl-3-pentanone with 0.85 g (6.6 mmol) of diisopropylethylamine erytbro - and tbreo- S - (1,l-Dimethylethyl) 3-Hydroxy-2-methyland 1.81 g (6.6 mmol) of di-n-butylboryl triflate in 15 mL of refluxing hexanethioate (Table 11, Entry U). Kinetic enolization of 0.29 g (2.0 ether for 2 h were followed by aldol condensation and hydrogen peroxide mmol) of S-tert-butyl propanethioate with 0.31 g (2.4 mmol) of diisoworkup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.01 g (76%) propylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 of a yellow oil. No threo aldol adduct 12T was detected by IH NMR mL of ether at 0 OC for 30 min was followed by aldol condensation and of the unpurified product; vide infra. The product was chromatographed MoOPH workup with 0.17 g (2.4 mmol) of n-butyraldehyde to yield 0.31 at medium pressure over silica gel (hexane:ethyl acetate, 8:l) to afford g (70%) of a pale yellow oil. The ratio of erythro:threo aldol adducts, 0.86 g (65%) of erythro aldol adduct 12E as a colorless oil: IR (CC14, 12E:12T, in the unpurified product was determined by 'H NMR to be 5%) 3620,3500,2970, 1695, 1685,982,698 cm-I; IH NMR (CC14) 6 10:90. The product was bulb-to-bulb distilled (150 OC (1 mm)) to afford 7.25 (s, 5, aromatic), 4.76 (d, J = 4 Hz, 1, erythro CHOH), 3.32-2.97 0.29 g (67%) of a colorless oil: IR (neat) 3450, 2960, 1675, 1455, 1365, (m, 1, COCH-), 3.18 (s, 1, OH), 1.02 (s, 9, -C(CH,),), 0.99 (s, 3, 960 cm-I; IH NMR (CDCIg) 6 4.8 (b, 1, OH), 3.89 (m, 0.10, erythro -CHCH3). Authentic6 threo adduct gave rise to an additional signal at CHOH), 3.64 (m, 0.90, threo CHOH), 2.61 (m, 1, -COCH-), 1.49 (s, 6 4.60 (d, J = 7 Hz, threo CHOH). These spectra are identical with 9, -S(CH,),), 1.27 to 0.75 (m, 10, aliphatics). Preparative gas-liquid those reported in the literature6 for this compound. chromatographic separation of a mixture of aldol products generated by erytbro-3-Hydroxy-2-methyl-1,3-diphenyl-l-propanone (Table II, Enlithium enolate condensation provided compounds for which assignments try M). Kinetic enolization of 0.80 g (6.0 mmol) of propiophenone with for the 'H NMR spectra were made by a comparison of the carbinol 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of protons: erythro, 6 3.89 (m, J = 3 Hz); threo, 6 3.64 (m, J = 6 Hz). The di-n-butylboryl triflate in 15 mL of ether at room temperature for 1 h coupling constants were determined by an analysis of the signal of the was followed by aldol condensation and hydrogen peroxide workup with proton on carbon 2. 0.64 g (6.0 mmol) of benzaldehyde to yield 1.60 g (>100%) of a yellow Exact mass: Calcd for C10H2202S:218.134. Found: 218.133. oil. No threo aldol adduct 12T was detected by IH NMR of the unpuerytbro - and tbreo-S-( 1,l -Dimethylethyl) 3-Hydroxy-2,4-dimethylrified product; vide infra. The product was chromatographed at medium pentanethioate (Table 11, Entry V). Kinetic enolization of 0.29 g (2.0 pressure over silica gel (hexane:ethyl acetate, 9:l) to afford 1.12 g (78%) mmol) of S-tert-butyl propanethioate with 0.31 g (2.4 mmol) of diisoof erythro aldol adduct 12E as a viscous oil: IR (CC14,4%) 3605, 3520, propylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 1670, 1662, 1211,970,698 cm-I; IH NMR (CC14) 6 7.95-7.75 (m, 2, mL of ether at 0 "C for 30 min was followed by aldol condensation and aromatic), 7.55-7.0 (m, 8, aromatic), 5.05 (d, J = 3 Hz, 1, erythro MoOPH workup with 0.17 g (2.4 mmol) of isobutyraldehyde to yield CHOH), 3.53 (m, 1, COCH-), 3.4 (s, 1, OH), 1.1 (d, 3, CHg). Authentic6 threo adduct gave rise to an additional signal at 6 4.92 (d, J = 9 Hz, threo CHOH). These spectra are identical with those reported in (44) Sacks, C. E. Ph.D. Thesis, California Institute of Technology, 1980, the literature6 for this compound. pp 119-120.
Stereoselective Aldol Condensations via Boron Enolates 0.29 g (66%) of a pale yellow oil. The ratio of erythro:threo aldol adducts, 12E12T, in the unpurified product was determined by 'H NMR to be 9:91. The product was bulb-to-bulb distilled (150 OC (1 mm)) to afford 0.26g (63%) of a colorless oil: IR (neat) 3500,2960, 1650,1455, 1365,960cm-'; 'H NMR (CDC1,) 6 3.51 (d of d, J = 3 and 8 Hz, 0.09, erythro CHOH), 3.30 (t, J = 7 Hz, 0.91,threo CHOH), 2.82 (s, 1, OH), 2.69 (m, J = 7 Hz, -COCH-), 1.70 (m,J = 7 Hz, 1, -CH(CH3)2), 1.48 (s, 9,-S(CH,),), 1.18 (d, 3, CHS), 0.89 (two d, 6,-CH(CH,),). Exact mass: Calcd for CllH2202S:218.134. Found: 218.133. e r y t h - and theo-S-(1,l-Dimethylethyl) 3-Hydroxy-2,4-dimethyl-4 pentenethioate (Table 11, Entry W). Kinetic enolization of 0.29 g (2.0 mmol) of S-tert-butyl propanethioate with 0.31 g (2.4mmol) of diisopropylethylamine and 0.60g (2.2mmol) of di-n-butylboryl triflate in 5 mL of ether at 0 "C for 30 min was followed by aldol condensation and MoOPH workup with 0.21 g (3.0mmol) of methacrolein to yield 0.29 g (66%) of a yellow oil. The ratio of erythro:threo aldol adducts, 12E:12T, in the unpurified product was determined by 'H NMR to be 12:88. The product was bulbto-bulb distilled (150OC (1 mm)) to afford 0.28 g (65%) of a pale yellow oil: IR (neat) 3460, 3080, 2960, 1675, 1455,1365,960,900,745 cm-I; 'H NMR (CDCI,) 6 4.92 (m,2,olefins), 4.37 (d, J = 4 Hz, 0.12,erythro CHOH), 4.14 (d, J = 9 Hz, 0.88,threo CHOH), 2.76 (m, 1,-COCH-), 2.49 (s, 1, OH), 1.73 (s, 3,=CCH3), 1.50 (s, 9,-S(CH,),), 1.13 (d, 3, CH,). Exact mass: Calcd for CllH2,,02S: 216.118. Found: 216.119. e r y h - and tlueo-S-(l,l-Dimethylethyl)3-Hydroxy-2,4-dimethyl-4hexenethioate (Table 11, Entry X). Kinetic enolization of 0.29 g (2.0 mmol) of S-tert-butyl propanethioate with 0.31 g (2.4mmol) of diisopropylethylamine and 0.60g (2.2mmol) of di-n-butylboryl triflate in 5 mL of ether at 0 OC for 30 min was followed by aldol condensation and MoOPH workup with 0.25 g (3.0mmol) of tiglic aldehyde to yield 0.31 g (71%) of a yellow oil. The ratio of erythro:threo aldol adducts, 12E:12T, in the unpurified product was determined by 'H NMR to be 18:82. The product was bulbto-bulb distilled (150"C (1 m))to afford 0.28 g (68%) of a colorless oil: IR (neat) 3480,1680, 1455, 1370,960, 830,740 cm-'; 'H NMR (CDCI,) 6 5.47 (m,1, olefin), 5.03 (b, 1, OH), 4.19 (d, J = 5 Hz, 0.18,erythro CHOH), 4.10 (d, J = 9 Hz, 0.82,threo CHOH), 2.72 (m, 1, -COCH-), 1.59 and 1.53 (d and s, 6,=CHCH,, =CUI,), 1.48 (s, 9,-S(CH3)3), 1.03 (two d, 3, CH3). Exact mass: Calcd for C12H2202S:230.134. Found: 230.134. tho-2-Phenylhydroxymethyl-1-cyclohexanone(Table 111, Entry F). Kinetic enolization of 0.98g (10mmol) of cyclohexanone with 1.42g (1 1 mmol) of diisopropylethylamine and 1 1 mmol of cyclopentylthexylboryl triflate (Zc), generated in situ, in 20 mL of tetrahydrofuran at -78 OC for 30 min was followed by aldol condensation and hydrogen peroxide workup with 1.06 g (10.0 mmol) of benzaldehyde to yield 1.92 g (94%) of a pale yellow oil. No erythro aldol adduct 14E was detected by 'H NMR of the unpurified product; vide infra. The product was chromatographed on 40 g of silica gel (hexancethyl acetate, 1:l) to afford 1.49 g (73%) of threo aldol adduct 14T as a white crystalline solid, mp 73.5-76 OC: IR (CC14) 3540,2943,1697, 1450, 1129, 1043,698 cm-I; 'H NMR (CDCl,) 6 7.2 (s, 5, aromatic), 4.6 (d, J = 8 Hz, 1, threo CHOH), 3.6 (b, 1, OH), 2.6-1.0 (m,9,cyclohexyl). Authentic6 erythro adduct gave rise to an additional signal at 6 5.31 (d, J = 3 Hz, erythro CHOH). The melting point and spectra of this compound are identical with those reported in the literature.8 e r y t h - and tlueo-3-Hydroxy-2-methyl-3-phenylpropanoic Acid ( 18% 1%). To a stirred solution of 0.57g (4.4mmol) of diisopropylethylamine and 1.15 g (4.2mmol) of di-n-butylboryl triflate in 15 mL of ether at 0 OC under an argon atmosphere was added 0.15 g (2.0mmol) of propanoic acid dropwise. A white precipitate appeared immediately. After 45 min the white slurry was cooled to -78 OC and 0.21 g (2.0mmol) of benzaldehyde was added. The mixture was stirred for 30 min at -78 OC and 1 h at 0 OC. The reaction mixture was then added to saturated aqueous sodium bicarbonate and ether. After separation of the layers the organic phase was extracted with additional saturated aqueous sodium bicarbonate. The combined aqueous solution was successively acidified to pH 2 with 6 N hydrochloric acid, saturated with sodium chloride, extracted twice with ether, and dried (Na2S04). Concentration of the ether solution in vacuo gave 0.31 g (87%) of clear oil: IR (neat) 3420,2980,1710,1450,1200,1010,700 cm-I; 'H NMR (CDCl,) 6 7.33 (s, 5, aromatic), 5.42 (s, 2, OH and C02H), 5.16 (d, J = 4 Hz, 0.35, erythro CHOH), 4.73 (d, J = 9 Hz, 0.65,threo CHOH), 2.79 (m, 1, XOCH-), 1.10 and 0.98 (two d, 3, CHI). 'H NMR integration afforded a ratio 18a:19a = 35:65. The spectra of this compound are identical with those reported in the literature.6 tlueo-3Hydroxy-3-phenyl-2-phenylmethoxypropanoic Acid (19b). To a stirred solution of 0.32g (2.4mmol) of diisopropylethylamineand 0.60 g (2.2mmol) of di-n-butylboryl triflate in 5 mL of ether at 0 OC under an argon atmosphere was added 0.17g (1 mmol) of phenylmethoxyethanoic acid dropwise. A white precipitate appeared immediately. After
J . Am. Chem. SOC.,Vol. 103, No. 11, 1981 3109 1 h the white slurry was cooled to -78 OC and 0.11 g (1.0mmol) of benzaldehyde was added. The mixture was stirred for 30 min at -78 OC and 1 h at 0 OC. The reaction mixture was then added to saturated aqueous sodium bicarbonate and ether. After separation of the layers the organic phase was extracted with additional saturated aqueous sodium bicarbonate. The combined aqueous solution was successively acidified to pH 2 with 6 N hydrochloric acid, saturated with sodium chloride, extracted twice with ether, and dried (Na80,). Concentration of the ether solution in vacuo gave 0.23g (85%) of a viscous colorless oil: IR (neat) 3400,3020,2860,1730,1495,1455,1100,910,735,700cm-I; 'H NMR (CDC13) 6 7.27 (s and m,10,aromatic), 6.77 (s, 2, OH and C02H), 4.92 (d, J = 7 Hz, 1, threo CHOH), 4.41 (AB q, J = 12 and 28 Hz, 2,-OCH2C6HS),4.03 (d, J = 7 Hz, 1, -CHC02H). The stereochemistry of this product was confirmed by dehydrativedecarboxylation; vide infra. The product was characterized by conversion to a dicyclohexylammonium salt: mp 175-176 "C after recrystallization from ethyl acetate. Anal. (C28H39N04):C, H, N. (2)-2-Phenylmethoxy-l-pbenylethene(21b). A solution of 0.25 g (0.92 mmol) of threo-3-hydroxy-3-phenyl-2-phenylmethoxypropanoic acid (vide supra) and 0.66g (5.5 m o l ) of dimethylformamide dimethyl acetal in 10 mL of chloroform under a nitrogen atmosphere was stirred for 1 h at rmm temperature and was then heated at reflux for 7 h. The reaction mixture was concentrated in vacuo to afford an oil which was dissolved in hexane. The hexane solution was washed successively with water and brine, dried (Na2S04),and concentrated in vacuo to yield 0.18 g of a yellow oil. The product was bulb-to-bulb distilled (150 OC (0.1 mm)) to afford 0.16 g (81%) of a colorless oil: IR (neat) 3030,2940, 1645,1487,1445,1365,1090,775,690cm-I; 'H NMR (CDCI,) 6 7.33 (s and m,10, aromatic), 6.22 (d, J = 7 Hz, 1, (Z)-CH=CHO-), 5.23 (d, J = 7 Hz, 1, (Z)-CH=CH(T), 4.92 (s, 2,-0CH2C6HS). Exact mass: Calcd for CI5Hl40:210.104. Found: 210.105. Condensations of 3-Methyl-2-pentanone (22). Lithium Aldols. The lithium enolate of 22 (1.00g, 10 mmol) was prepared and condensed with freshly distilled propionaldehyde (0.58g, 10 mmol) according to the literature proced~re.'~The product was purified by distil la ti or^'^ to give 1.04g (65%) of a colorless oil: IR (film) 3460,2970,2940,2880,1700, 1410, 1380 cm-'; 'H NMR (CC14) 6 3.80 (m, J = 6 Hz, 1 H, -CH2CHOH), 3.10 (broad s, 1 H, OH), 2.60-2.20 (m, 3 H, -OCCH2, -CH2CHCO-), 1.88-1.15 (m,4 H, 2 CH3CH2),1.10-0.70 (m, 9 H, 3 CH,'s); "C NMR (CH2C12)6 69.1,48.5,47.6,29.9, 25.9,15.5, 11.5,9.9. These spectral data are identical with those reported in the literat~re.,~ Anal. (C9HI8O2):C, H. Boron Aldols. Kinetic enolization of 0.20g (2 mmol) of 3-methyl-2pentanone (22) with 0.31 g (2.4mmol) of diisopropylethylamine and 0.60 g (2.2mmol) of di-n-butylboryl triflate in dichloromethane at -78 OC for 30 min (pentane, 60 min at 0 OC; ether, 30 min at -78 "C) was followed by aldol condensation and MoOPH workup with 0.13 g (2.2 mmol) of freshly distilled propionaldehyde to give 263 mg (83%) of a light yellow oil. A portion of the mixture was purified by distillation to give a colorless oil: IR (film) 3460,2960,2940,2880, 1700,1455,1410, 1380 cm-l; 'H NMR (CDCI,) 6 3.97 (m, J = 6 Hz, 1 H, -CH2CHOH), 3.20 (broad s, 1 H, OH), 2.60-2.30 (m, 3 H, -OCCH,-, -CH2CHCO), 1.88-1.23(m,4 H, 2 CH3CH2),1.20.80(m,9 H, 3 CH,'s); 13CNMR (CH2C12)6 69.2,48.5,47.6,29.8,25.9,15.5, 11.5, 9.8. These spectra are identical with the spectra above and those reported in the literat~re.'~ It is an interesting sidelight that the mixture of diastereoisomers does not display any difference in the I3C NMR spectrum. Thus, the diastereoisomeric ratios were determined by analytical HPLC (DuPont Zorbax Sil, 4.6 mm X 25 cm, 15% ether-hexane): kA (major, 24)= 6.08; ke (minor, 25) = 6.70. The ratio was obtained by integration of the corresponding peaks after one recycle to obtain complete separation. In this manner, the purified lithium aldol adduct was shown to be a 55:45 mixture of 2425. The unpurified boron aldol adducts were determined to be a mixture of 2425 as indicated: pentane (64:36),dichloromethane (63:37),and ether (57:43). Finally, the lithium aldol condensation was repeated under "kinetic" conditions6 at -78 OC and the ratio of 24:25 was found to be 53:47 (Table V). (S)-(-)-N-4-Toluenesulfonylproline (35). The title compound was prepared from L-(-)-proline (20.0g, 0.17 mol) and p-toluenesulfonyl chloride (39.0g, 0.20mol) according to the published proced~re.'~ The oily, white solid was purified by a modification of the reported recrystallization from benzene4" to ensure complete removal of water. The solid was over-layered with benzene and the suspension refluxed for 3 h with removal of water via a Dean-Stark trap. The hot suspension was filtered and the filtrate cooled to room temperature to precipitate 35.0 g (66%) of 35 (as a benzene solvate) as a white crystalline solid: mp
(45)(a) Izumiya, N.Bull. Chem. SOC.Jpn. 1953,26, 53-56. (b) Pravda, Z.; Rudinger, J. Collect. Czech. Chem. Commun. 1955, 20, 1-12.
3110 J. Am. Chem. SOC.,Vol. 103, No. 11. 1981
Evans et al.
Table VI11 shift reagent, mg
0 1.5 3.0
racemic ketone 26a CH,
methineH
2.31, s 3.96, d of d 2.80,~;2.87,s 4.78,m (1:l ratio) 3.73,s;3.90,9 6.504.06,m (1:1 ratio)
opt active ketone 26a CH,
methineH
2.30, s 2.93, s
3.96, d of d 4.92, d of d
3.78,s
6.21,dofd
92-96 O C ; lit.'S*mp 95-98 O C ; IR (CH2C12)3540-2400 (broad), 1760, 1720, 1595, 1475, 1345, 1195, 1160, 1090, 1010, 810, 660 cm-I; 'H NMR (CDCl3) 6 10.87 (s, 1 H, COZH), 7.78 (d, J = 8 Hz, 2 H, aromatic H's), 7.35 (benzene solvate, 13.2%by integration), 7.32 (d, J = 8 Hz, 2 H, aromatic H), 4.40-4.20 (d of d, J = 4.5, 7 Hz, 1 H, >NcHC02H), 3.65-3.10 (m, 2 H, -CHzN
