Aitken, R. Alan

Lefker, Bruce A.

Meyers, A. I.

Wanner, Klaus Th.

English

Universität München: Elektronischen Publikationen

1936 ,J. Org. Chem. 1986, 51 ,  1936-1938 
An oil suspension of potassium hydride, transferred to a 
flask, was allowed to settle and most of the oil decanted 
with a double-ended needle. Then the potassium hydride 
was washed with pentane (3 x 100 mL). 'To this oil-free 
potassium hydride (12 g, 300 mmol) suspended in THF 
(150 mL) was added a THF solution (250 mL) of 3 (76 g, 
200 mmol) slowly via a double-ended needle with vigorous 
stirring. The reaction became slightly exothermic after 
a 10-30-min induction period. The reaction was monitored 
both by hydrolysis of centrifuged aliquots and by IlB 
NMR. It was complete within 2 h, producing the addition 
compound, K 9-O-DIPGF-9-BBNH, 4 (0.48 M, 96% yield): 
"B NMR 6 1.33 (br, s): IR Y 2038 cm (s). Hydride and 
potassium were determined as H2 and KOH following 
hydrolysis; boron was estimated as 1,5-cycloctanediol 
following oxidation by alkaline hydrogen peroxide: [ H] 
= 0.48 M; [K] = 0.48 M; [B] = 0.50 M. Therefore, a 
stoichiometry of K:B:H of 1:l:l was established. 
The following procedure for the reduction of pivalo- 
phenone to (R)-(+)-2,2-dimethyl-l-phenylpropanol is 
representative of the asymmetric reductions. The THF 
solution (1.0 M, 10 mL) of pivalophenone (10 mmol), 
precooled to -78 "C, was added to the solution (0.48 M, 
23 mL) of the reagent 4 (11 mmol) at 78 "C via a dou- 
ble-ended needle. After 40 h, unreacted hydride was 
quenched by injecting anhydroris IICl in ee precooled to 
-78 "C. Then the mixture was raised to 26 'C, and the 
reduction product was extracted with pentane after hy- 
drolysis by dilute HC1 followed by conversion of the borinic 
acid moiety into the "ate" complex4a using aqueous NaOH. 
The pentane layer was washed with brine, dried (MgSO,), 
and filtered, and the solvent was evaporated. IXstillation 
of the residue provided 1.42 g of (R)-(C)-2.2-dimethyl-l- 
phenylpropanol (92% yield, hp 114-118 OC:/16 torr, [lit 
bp 130-140 "C ia0  torr] containing a small amount of 
starting ketone). The alcohol product was further purified 
by preparative GLC (20% Carbowax 20M, 6 f t  x ' / 2  in. 
column, 150 "0, and the rotation was measured: [ ( Y ] ~ ~ ~  
+25.96" (c 2.2, benzene), 100% ee based on the maximum 
reported rotation [ ~ j ~ , ~ ~ ~ ~  +25.9' IC 2.2, benzene).' Ca- 
pillary GLC analysis (Supelcowax, 15 m) of MT'PA estersY 
of the product alcohol revealed a composition of 98.4% R 
-t 1.6% S ( i t , ,  96.8% ee). in close agreement with optical 
rotation measurement. 
In conclusion, the present study provides a convenient 
and simple synthesis of an effective chiral borohydride 
reagent containing a single hydride per molecule and 
consisting of a single characterized reducing species. The 
new reagent reduces prochiral alkyl phenyl ketones and 
relatively hindered aliphatic ketones, effectively providing 
high optical yields of the corresponding alcohols consist- 
ently enriched in their R enantiomers. This study can be 
extended to the synthesis of a variety of simple, stable, and 
characterized chiral borohydride reagents incorporated 
with various chiral auxiliaries. Consequently, one should 
be able to design improved chiral borohydride reagents by 
systematic studies of the effect of the chiral moiety on the 
asymmetric induction. Such systematic studies are un- 
derway. 
Acknowledgment, We are grateful to the United 
States Army Research Office for the financial assistance 
(ARO DAAG 29-85-K-0062) which made this investigation 
possible. B. T. Cho also thanks the Korean Science and 
(7)  MacLeod, R.; Welch. F. J.; Mosher, 11. S. J .  Am. Chem. Soc. 1960, 
(8) Nasipuri, D.; Sarker, G. J .  Indian Chem. SOC. 1967, 44, 165. 
(9) Ilale, J. A,: Mosher, H. S. J .  Am. Chem. Sor. 1973. P15, 512. 
82, 876. 
Engineering Foundation for the postdoctorate fellowship 
which enabled him to perform this research. 
Herbert C. Brown,* Won Suh  Park,  Ryung Tae Cho 
Richard R. Wetheril l  Laboratory 
Purdue University 
W m t  Lafayette,  Indiana 47907 
Received Dewmber 30, 1985 
An Asymmetric Synthesis of Chiral 
4,CDisubstituted Cyclohexenones in High 
Enantiomeric Purity 
Summary:  An efficient approach to the title compounds 
in >95% ee has been accomplished by metalation and 
alkylation of chiral bicyclic lactams derived frorn &keto 
acids and (1S,2S)-2-amino-l-phenyl-1,3-propanediol. 
Sir: Our recent successes in reaching chiral compounds 
containing a quaternary stereocenter' has led to 3,3-di- 
substituted cyclopentenones 3.2 Thus, dialkylation of the 
readily available bicyclic lactam 1 by successive treatment 
with LDA and two different alkyl halides to 2, followed 
by reduction and hydrolysis, gave 3 in >99% ee. It was 
Me 
R 
- y - - - P R R  ",: ;-A' - Q  
H 
R 
"_ 2 3 
assumed that the homologated bicyclic lactam 4, under 
similar conditions, would provide the chiral cyclohexenone, 
5.  However this was not to be the case since all attempts 
to reduce the lactam carbonyl to aldehyde gave unwanted 
side products, the major one being the piperidone 6. The 
6 - 4 - 5 __ 
(R=CH,CH,OH) 
Red-AI  
- 7 (R) 1-1 & 
latter arises from reductive cleavage of the oxazolidine ring. 
(1) Meyers, A. I.; Harre, M.; Garland, R .  J .  Am. Cheni. SOC. 1984, 106, 
(2) Meyers, A. I.; W-anner, K. T. Tetrahedron Let t .  1985, 26, 2047. 
1146. 
Meyers, A I.; Lefker, B. A. J. Org. Chem., in press. 
1986 American Chemical Society 
Communications J. Org. Chem., Vol. 51, No. 10, 1986 1937 
Scheme I 
Scheme I1 
Ph 
P h q o H  6 
(14%) 
&%R ~ Red-AI 
Ph R' 
14 
B ~4 NH, PO4 \ 
g& LDA-HMPA 
R -  
R 'X 
Ph 0 R' 
1 3 ,  R =  Me, R'=PhCH, 
l a ,  R=PhCH,, R'=Me 
l a ,  R =  PhCH,,R'=Allyl 
r Me 1 
g+ 
Ph 0 
(84%) 
LDA - RX I 
Ph gb 0 R 
12, R=Me,PhCH,,Allyl 
L R' 
E 
During the course of this work, it was observed that bi- 
cyclic lactams, containing a hydroxyethyl or aminoethyl 
substituent, 4 (R = CH,CH,OH) were readily reduced to 
the keto aldehyde precursor 7 and hydrolyzed to the cy- 
clohexenone 8 in 75% yield and in >99% ee.3 This may 
be attributed to the intermediate aluminum salt acting as 
a "hinge" to rapidly deliver hydride in an intramolecular 
fashion. If this conclusion is accurate, then the asymmetric 
synthesis of chiral 4,4-disubstituted cyclohexenones is 
presently limited only to those cases where a hydroxyl or 
amino group is suitably placed in the molecule. On the 
other hand, if the chiral bicyclic lactams were to possess 
a hydroxyl group to allow carbonyl reduction to readily 
occur (A) then hydride deliver via the "hinge effectn4 (B) 
would furnish the keto aldehyde precursor (C) and ulti- 
mately lead after hydrolysis to the cyclohexenones 5 
(Scheme I). Using the process in Scheme I as a working 
model, it  was decided to evaluate the commercially 
available amino diol g5 as the chiral auxiliary. Treatment 
of the latter with 1.0 equiv of 4-acetylbutanoic acid5 
(benzene, reflux, 16 h) gave the bicyclic lactams 10 and 11 
in a 14234 ratio with approximately 2% of another lactam 
(3) Meyen, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. SOC. 1985, 
107, 7776. 
(4) For an excellent example of the hinge effect on stereo- and re- 
gioselective reductions with aluminum hydrides-alkoxy ate complexes, 
see: Thompson, H. W.; McPherson, E. J.  Org. Chem. 1977, 42, 3350. 
(5 )  Aldrich Chemical Co., Milwaukee, WI. 
1 
A 
<>'\ 
R' R 
&, R=Me,R'=PhCH, 
5b, R =  PhCH-, R'= Me 
s, R PhCH,, R'= Allyl 
isomer of 11 (Scheme 11). Recrystallization (EtOAc-Hex) 
gave pure 11 (mp 98-99 "C) in 60-65% yield. I t  was 
believed that 11 would provide the crucial test outlined 
in Scheme I, and to this end, metalation (2.5 equiv of LDA, 
THF, -78 "C) of 11 followed by alkyl halides (3.0 equiv, 
-78 "C) gave 12 in 7040% yields as a mixture of endo-exo 
isomers. The latter mixture is of no consequence since 
repeating the metalation (2.5 equiv of LDA, 20% 
HMPA-THF, -78 "C, followed by 2.0 equiv of RX) gave 
13a (97:3), 13b (75:25), and 13c (82:18) with the diaste- 
reomer from endo entry predominating. Thus, as noted 
alkylation of the lactam enolate proceeds mainly 
from the bottom face. Chromatography (silica gel, 1:l 
EtOAc-hexane) gave pure 13 in 50-80% yields.'jv7 To 
confirm the stereochemistry, an X-ray structure was per- 
formed on 13a and showed the stereochemistry of the 
bicyclic lactam and the two alkyl substituents are correct 
as shown. 
When the dialkylated bicyclic lactams were subjected 
to reductions with Red-A1 (1.2 equiv, toluene, -60 to 25 
"C, 24 h) the tricyclic aminals 14 were obtained and 
treated, in their crude form, with an aqueous 1 M solution 
of tetrabutylammonium dihydrogen phosphate in ethanol 
(l:l,  2 h a t  25 "C, 16 h at  reflux). The intermediate keto 
~ ~ 
(6) Alkylations were carried out with methyl iodide, benzyl bromide, 
or allyl bromide. The highest diastereoselectivity was noted when the 
larger electrophile was added in the second alkylation step. 
1938 J .  Org. Chem., Vol. 51, No. 10, 6986 Communications 
aldehyde 15 was bypassed during the hydrolysis, giving 
only the 4,4-dialkylcyclohexenones 5a-c. Both enantiom- 
ers were thus formed ( [ a ] D  for Sa, -65.58'; [aID for 5b, 
+64.83') along with 5c (["ID +48.98').7 Presumably, the 
acid-catalyzed hydrolysis of 14 also provided the proper 
conditions for the aldol cyclizations. 
As an extension of this methodology, we prepared the 
bicyclic lactam 16 from 9 and 5-oxoheptanoic acid (toluene, 
reflux 1 2  h). The lactam 16 was isolated pure, after re- 
crystallization, in 68% yield (mp 83-85 'C). Double al- 
- 16 
Ph gQM* - M4 
I Me Ph 
Ph 
- 17 (97: 3) 
- 18 
kylation (2.5 equiv of sec-BuLi, THF, -78 "C, 3.0 equiv 
of MeI; 2.5 equiv of sec-BuLi, 4:l THF-HMPA, 4.0 equiv 
of benzyl bromide) gave 17 as a 97:3 mixture of endo-exo 
(7) Physical data. 13a: yield, 67%; IR (CC1,) 3350 br, 2950, 1620, 
1460, 1425 cm-': 'H NMR (CDC1,) 6 7.10-7.50 (m, 10 H), 4.68 (d. J = 8.4 
- Hz, 1 H), 4.20 (br s, 1 H), 4.03 (dt, J = 2.2, 8.6 Hz, 1 H), 3.88 (dd, J = 
2.2. 11.3 Hz. 1 H). 3.77 (dd. J = 8.8. 11.3 Hz. 1 H). 3.38 (d. J = 13.0 Hz. 
1 H), 2.10 (k, 1 H), 1.75 (k, 2 H), i.48 (s,3 H), 1.36 (s,3 H), 1.05 (m, 1 
H). 13b: yield, 60%; IR (CC14) 3400 br, 2950,1620,1460,1420 cm-'; 'H 
NMR (CDCL) 6 7.10-7.50 (m, 10 H), 4.81 (dd, J = 2.4, 7 9 Hz, 1 H), 4 65 
(d, J = 8.6 Hz, 1 H), 4.05 (dt, J = 2.0, 8.1 Hz, 1 H), 3.86 (ddd, J = 2.0, 
7.9, 10.1 Hz, 1 H), 3.61 (ddd, J = 2.4, 10.1, 8.1 Hz, 1 H), 3.41 (d, J = 13.0 
Hz, 1 H), 2.48 (d, J = 13.0 Hz, 1 H), 1.50-2.00 (m, 4 H), 1.41 (s, 3 H), 0.77 
(s,3 H). 13c: yield, 72%; IR (CC14) 3350 br, 2910,1620, 1440,1410 cm-?; 
'H NMR (CDC1,) 6 7.15-7.60 (m, 10 H), 6.90 (m, 1 H), 5.20 (m, 2 H), 4.89 
(dd, J = 2.4, 7.9 Hz, 1 H), 4.64 (d, J = 6.1 Hz, 1 H), 1.05 (dt, J = 1.9, 8.2 
Hz, 1 H), 3.85 (ddd, J = 1.9, 7.9, 10.1 Hz, 1 H), 3.61 (ddd, J = 2.4, 8.2, 
10.1 Hz, 1 H), 3.35 (d, J = 12.9 Hz, 1 H), 2.75 (dd, J = 7.2, 13.6 Hz, 1 H), 
2.48 (d, J = 12.9 Hz, 1 H), 2.38 (dd, J = 8.1, 12.9 Hz, 1 H), 1.90 (m, 4 H), 
0.63 (s,3 H). 5a: yield, 53%; [aID -65.58' (e  1.04, EtOH); IR (film) 3040, 
2935, 2885, 1680, 1605, 1490, 1450, 1415 cm''; 'H NMR (CDC1,) 6 
7.10-7.40 (m, 5 H), 6.69 ( d , J  = 10.2 Hz, 1 H), 5.90 (d, J =  10.2 Hz, 1 H), 
2.75 (s, 2 H), 2.44 (t, J = 6.9 Hz, 2 H), 1.96 (d, J = 6.7 Hz, 1 H), 1.79 (m, 
1 H), 1.13 (s, 3 H). Anal. Calcd for CI4Hl6O: C, 83.95; H, 8.05. Found 
C, 83.84; H, 8.01. 5b: yield, 68%; [oilD +64.83' (e  1.02, EtOH); 'H NMR 
(CDCI,) 6 [same as above]. Anal. Calcd for CI4HI6O: C, 83.95; H, 8.05. 
Found: C, 83.84; H, 8.20. 5c: yield, 47%; [a]D +48.98' (c 1.03, EtOH); 
IR (film) 3080,3040,2940,2875,1690,1650,1610,1500,1460,1395 cm-'; 
'H NMR (CDC1,) 6 7.10-7.40 (m, 5 H), 6.68 (d, J = 10.2 Hz, 1 H), 5.96 
(d, J = 10.2 Hz, 1 H), 5.80 (m, 1 H), 5.13 (m, 2 H), 2.80 (AB q, J = 13.4 
Hz, 2 H), 2.40 (m, 1 H), 2.20 (t, J = 6.6 Hz, 1 H), 1.90 (m, 2 H). 16: yield, 
71%; mp 83-85 OC (1:4 EtOAc-hexane); [a]D +12.61° (c  2.1, EtOH); IR 
(film) 1625 cm-'; 'H NMR (CDC13) 6 7.36 (m, 5 H), 5.18 (br, 1 H, ex- 
changeable with D,O), 4.64 (d, J = 8.6 Hz, 1 H), 3.97-4.10 (m, 1 H), 336 
(dd. J = 11.2. 2.2 Hz. 1 H). 3.72 (dd. J = 11.2. 8.7 Hz. 1 H). 2.3G2.63 (m. -, ~ ~~ < ~ ~ ,, ~ 
2-~H): 1.50-2.05 (m, 6 H), 0.94 it, 3 = 7.4 H z ,  3 Hj. Anal. Calcd for 
C16H21N03: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.82; H, 7.62; N, 5.37. 
17 (pure endo-benzyl): yield, 81.2%; 'H NMR (CDCIJ 6 7.0-7.45 (m, 5 
H),5.55 (dd, J = 6.9,1.2 Hz, 1 H, exchangeable with D,O), 4.56 (d, J = 
8.4 Hz, 1 H), 3.93-4.05 (m, 1 H), 3.67-3.90 (m, 2 H), 3.41 (d, J = 13 Hz, 
1 H), 2.53 (d, J = 13 Hz, 1 H), 1.50-2.10 (m, 6 H), 1.35 (s, 3 H), 0.85 (t, 
J = 7.4 Hz, 3 H). 18: yield, 66%; [a]D -39.70' ( c  0.99, EtOH); IR (film) 
1680,1635 cm-'; 'H NMR (CDCl,) 6 7.05-7.37 (m, 5 H), 6.45 (br d, 1 H), 
2.73 (s, 2 H), 2.45 (t, J = 6.8 Hz, 2 H), 1.85-2.00 (m, 1 H), 1.76 (d, J = 
1.4 Hz, 3 H), 1.65-1.79 (m, 1 H), 1.10 (s, 3 H). Anal. Calcd for C15H180: 
C, 84.07; H, 8.47. Found C, 84.19; H, 8.43. 21: yield, 47%; l a l m D  122.2" 
(c  0.32, EtOH); IR (film) 1665 cm-'; 'H NMR (CDCI,) 6 7.25-7.45 (m, 5 
H), 6.94 (d, J = 10.2 Hz, 1 H), 6.13 (d, J = 10.2 Hz, 1 H), 2.10-2.50 (m, 
4 H), 1.57 (s, 3 H). Anal. Calcd for CI3Hl40: C, 83.83; H, 7.58. Found: 
C, 83.56; H, 7.59. 
diastereomers. Flash chromatography (silica gel, 1:1 Et- 
OAc-hexane) provided pure 17 in 81 ?& yield. Reduction 
and hydrolysis to the cyclohexenone 18 was accomplished, 
as above, furnishing the enantiomerically pure product in 
We also examined the asymmetric route to (a)-(+)-4- 
phenyl-4-methylcyclohexenone, prepared earlier by Ya- 
madas in 40-50% ee via the proline-derived enamine 
addition to methyl vinyl ketone. Our sequence began by 
condensing 9 with racemic 2-phenyl-5-oxohexanoic acid 
(19)9 (benzene, reflux, 16 h), proddcing 20 (80%) along with 
an isomer similar to IO (20%). Due to difficulty in sep- 
aration, the mixture of lactams was metalated (2.5 equiv 
of LDA, THF, -78 'C) and alkylated with methyl iodide 
(1.8 equiv) and chromatographed (silica gel 3070, Et- 
OAc-hexane) to remove the isomeric lactam. The desired 
lactam (53% yield, mp 122-123 'C) was reduced with 
Red-AI and hydrolyzed with Bu4NH2P04 to give the cy- 
65% yield [ a ] ~  - 39.70°).7 
n 
(s,s)-9 + o%ph - 
HO,C 
(+)-E! 
al LDA - Me1 
ph blRed-AI 
Me Ph cl H0 
Ph 0 
20 - 21 -
clohexenone (R)-(+)-21, [aIz0D 122.2' (lit.lo [aIz5D 122.5') 
in 99.8% ee. 
In summary, we have described an efficient route to 
4,4-disubstituted cyclohexenones in high enantiomeric 
excess using readily available materials, and work is in 
progress to extend this to more elaborate systems. 
Acknowledgment. Financial support was provided by 
the National Institutes of Health, and K.T.W. acknowl- 
edges a postdoctoral Fellowship from the Deutsche For- 
schungsgemeinschaft. We also thank Professor 0. P. An- 
derson and Joe Reibenspies for providing the X-ray 
structure of 13a. 
Supplementary Material Available: X-ray data for 13a (9 
pages). Ordering information is given on any current masthead 
Page. 
(8) Yamada, S.; Otani, G. Tetrahedron Lett. 1969,48,4237. Soue, T.; 
Hiroi, K.; Yamada, S. Chem. Pharm. Bull. 1973,23, 2331. Schuster, D. 
I.; Brown, R. H.; Resnick, B. M. J .  Am. Chem. SOC. 1978, 100, 4504. 
(9) Prepared in a manner similar to that reported in ref 3 above. 
(10) The optical purity given in ref 8 was determined by conversion 
to 2-methyl-2-phenylglutaric anhydride and reported to be 130 f 2'. 
However, a recent report (Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J .  
Org. Chem. 1985,50,2557) has challenged the rotation by Yamada et al. 
as being too high and has revised the rotation, on the basis of enantiom- 
eric purity determined by chiral shift reagents, to 122.2O. Our results, 
based on the lactam precursor to 21 (HPLC, 270MHz, 'H NMR) showed 
that it was homogeneous with less than 0.3% of the other diastereomers. 
A. I. Meyers,* Bruce A. Lefker 
Klaus Th. Wanner, R. Alan Aitken 
Department of Chemistry 
Colorado State University 
Fort Collins, Colorado 80523 
Received February 3, 1986 


An asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones in high enantiomeric purity

Meyers, Albert I.

Lefker, B. A.

Wanner, Klaus T.

Aitken, R Alan

University of St. Andrews - Pure

An Asymmetric Synthesis of Chiral 4,4-Disubstituted Cyclohexenones in High Enantiometric Purity

Open Access LMU ( Ludwig-Maximilians-Univ. München)

1936 ,J. Org. Chem. 1986, 51 ,  1936-1938 An oil suspension of potassium hydride, transferred to a flask, was allowed to settle and most of the oil decanted with a double-ended needle. Then the potassium hydride was washed with pentane (3 x 100 mL). 'To this oil-free potassium hydride (12 g, 300 mmol) suspended in THF (150 mL) was added a THF solution (250 mL) of 3 (76 g, 200 mmol) slowly via a double-ended needle with vigorous stirring. The reaction became slightly exothermic after a 10-30-min induction period. The reaction was monitored both by hydrolysis of centrifuged aliquots and by IlB NMR. It was complete within 2 h, producing the addition compound, K 9-O-DIPGF-9-BBNH, 4 (0.48 M, 96% yield): "B NMR 6 1.33 (br, s): IR Y 2038 cm (s). Hydride and potassium were determined as H2 and KOH following hydrolysis; boron was estimated as 1,5-cycloctanediol following oxidation by alkaline hydrogen peroxide: [ H] = 0.48 M; [K] = 0.48 M; [B] = 0.50 M. Therefore, a stoichiometry of K:B:H of 1:l:l was established. The following procedure for the reduction of pivalo- phenone to (R)-(+)-2,2-dimethyl-l-phenylpropanol is representative of the asymmetric reductions. The THF solution (1.0 M, 10 mL) of pivalophenone (10 mmol), precooled to -78 "C, was added to the solution (0.48 M, 23 mL) of the reagent 4 (11 mmol) at 78 "C via a dou- ble-ended needle. After 40 h, unreacted hydride was quenched by injecting anhydroris IICl in ee precooled to -78 "C. Then the mixture was raised to 26 'C, and the reduction product was extracted with pentane after hy- drolysis by dilute HC1 followed by conversion of the borinic acid moiety into the "ate" complex4a using aqueous NaOH. The pentane layer was washed with brine, dried (MgSO,), and filtered, and the solvent was evaporated. IXstillation of the residue provided 1.42 g of (R)-(C)-2.2-dimethyl-l- phenylpropanol (92% yield, hp 114-118 OC:/16 torr, [lit bp 130-140 "C ia0  torr] containing a small amount of starting ketone). The alcohol product was further purified by preparative GLC (20% Carbowax 20M, 6 f t  x ' / 2  in. column, 150 "0, and the rotation was measured: [ ( Y ] ~ ~ ~  +25.96" (c 2.2, benzene), 100% ee based on the maximum reported rotation [ ~ j ~ , ~ ~ ~ ~  +25.9' IC 2.2, benzene).' Ca- pillary GLC analysis (Supelcowax, 15 m) of MT'PA estersY of the product alcohol revealed a composition of 98.4% R -t 1.6% S ( i t , ,  96.8% ee). in close agreement with optical rotation measurement. In conclusion, the present study provides a convenient and simple synthesis of an effective chiral borohydride reagent containing a single hydride per molecule and consisting of a single characterized reducing species. The new reagent reduces prochiral alkyl phenyl ketones and relatively hindered aliphatic ketones, effectively providing high optical yields of the corresponding alcohols consist- ently enriched in their R enantiomers. This study can be extended to the synthesis of a variety of simple, stable, and characterized chiral borohydride reagents incorporated with various chiral auxiliaries. Consequently, one should be able to design improved chiral borohydride reagents by systematic studies of the effect of the chiral moiety on the asymmetric induction. Such systematic studies are un- derway. Acknowledgment, We are grateful to the United States Army Research Office for the financial assistance (ARO DAAG 29-85-K-0062) which made this investigation possible. B. T. Cho also thanks the Korean Science and (7)  MacLeod, R.; Welch. F. J.; Mosher, 11. S. J .  Am. Chem. Soc. 1960, (8) Nasipuri, D.; Sarker, G. J .  Indian Chem. SOC. 1967, 44, 165. (9) Ilale, J. A,: Mosher, H. S. J .  Am. Chem. Sor. 1973. P15, 512. 82, 876. Engineering Foundation for the postdoctorate fellowship which enabled him to perform this research. Herbert C. Brown,* Won Suh  Park,  Ryung Tae Cho Richard R. Wetheril l  Laboratory Purdue University W m t  Lafayette,  Indiana 47907 Received Dewmber 30, 1985 An Asymmetric Synthesis of Chiral 4,CDisubstituted Cyclohexenones in High Enantiomeric Purity Summary:  An efficient approach to the title compounds in >95% ee has been accomplished by metalation and alkylation of chiral bicyclic lactams derived frorn &keto acids and (1S,2S)-2-amino-l-phenyl-1,3-propanediol. Sir: Our recent successes in reaching chiral compounds containing a quaternary stereocenter' has led to 3,3-di- substituted cyclopentenones 3.2 Thus, dialkylation of the readily available bicyclic lactam 1 by successive treatment with LDA and two different alkyl halides to 2, followed by reduction and hydrolysis, gave 3 in >99% ee. It was Me R - y - - - P R R  ",: ;-A' - Q  H R "_ 2 3 assumed that the homologated bicyclic lactam 4, under similar conditions, would provide the chiral cyclohexenone, 5.  However this was not to be the case since all attempts to reduce the lactam carbonyl to aldehyde gave unwanted side products, the major one being the piperidone 6. The 6 - 4 - 5 __ (R=CH,CH,OH) Red-AI  - 7 (R) 1-1 & latter arises from reductive cleavage of the oxazolidine ring. (1) Meyers, A. I.; Harre, M.; Garland, R .  J .  Am. Cheni. SOC. 1984, 106, (2) Meyers, A. I.; W-anner, K. T. Tetrahedron Let t .  1985, 26, 2047. 1146. Meyers, A I.; Lefker, B. A. J. Org. Chem., in press. 1986 American Chemical Society Communications J. Org. Chem., Vol. 51, No. 10, 1986 1937 Scheme I Scheme I1 Ph P h q o H  6 (14%) &%R ~ Red-AI Ph R' 14 B ~4 NH, PO4 \ g& LDA-HMPA R -  R 'X Ph 0 R' 1 3 ,  R =  Me, R'=PhCH, l a ,  R=PhCH,, R'=Me l a ,  R =  PhCH,,R'=Allyl r Me 1 g+ Ph 0 (84%) LDA - RX I Ph gb 0 R 12, R=Me,PhCH,,Allyl L R' E During the course of this work, it was observed that bi- cyclic lactams, containing a hydroxyethyl or aminoethyl substituent, 4 (R = CH,CH,OH) were readily reduced to the keto aldehyde precursor 7 and hydrolyzed to the cy- clohexenone 8 in 75% yield and in >99% ee.3 This may be attributed to the intermediate aluminum salt acting as a "hinge" to rapidly deliver hydride in an intramolecular fashion. If this conclusion is accurate, then the asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones is presently limited only to those cases where a hydroxyl or amino group is suitably placed in the molecule. On the other hand, if the chiral bicyclic lactams were to possess a hydroxyl group to allow carbonyl reduction to readily occur (A) then hydride deliver via the "hinge effectn4 (B) would furnish the keto aldehyde precursor (C) and ulti- mately lead after hydrolysis to the cyclohexenones 5 (Scheme I). Using the process in Scheme I as a working model, it  was decided to evaluate the commercially available amino diol g5 as the chiral auxiliary. Treatment of the latter with 1.0 equiv of 4-acetylbutanoic acid5 (benzene, reflux, 16 h) gave the bicyclic lactams 10 and 11 in a 14234 ratio with approximately 2% of another lactam (3) Meyen, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. SOC. 1985, 107, 7776. (4) For an excellent example of the hinge effect on stereo- and re- gioselective reductions with aluminum hydrides-alkoxy ate complexes, see: Thompson, H. W.; McPherson, E. J.  Org. Chem. 1977, 42, 3350. (5 )  Aldrich Chemical Co., Milwaukee, WI. 1 A <>'\ R' R &, R=Me,R'=PhCH, 5b, R =  PhCH-, R'= Me s, R PhCH,, R'= Allyl isomer of 11 (Scheme 11). Recrystallization (EtOAc-Hex) gave pure 11 (mp 98-99 "C) in 60-65% yield. I t  was believed that 11 would provide the crucial test outlined in Scheme I, and to this end, metalation (2.5 equiv of LDA, THF, -78 "C) of 11 followed by alkyl halides (3.0 equiv, -78 "C) gave 12 in 7040% yields as a mixture of endo-exo isomers. The latter mixture is of no consequence since repeating the metalation (2.5 equiv of LDA, 20% HMPA-THF, -78 "C, followed by 2.0 equiv of RX) gave 13a (97:3), 13b (75:25), and 13c (82:18) with the diaste- reomer from endo entry predominating. Thus, as noted alkylation of the lactam enolate proceeds mainly from the bottom face. Chromatography (silica gel, 1:l EtOAc-hexane) gave pure 13 in 50-80% yields.'jv7 To confirm the stereochemistry, an X-ray structure was per- formed on 13a and showed the stereochemistry of the bicyclic lactam and the two alkyl substituents are correct as shown. When the dialkylated bicyclic lactams were subjected to reductions with Red-A1 (1.2 equiv, toluene, -60 to 25 "C, 24 h) the tricyclic aminals 14 were obtained and treated, in their crude form, with an aqueous 1 M solution of tetrabutylammonium dihydrogen phosphate in ethanol (l:l,  2 h a t  25 "C, 16 h at  reflux). The intermediate keto ~ ~ (6) Alkylations were carried out with methyl iodide, benzyl bromide, or allyl bromide. The highest diastereoselectivity was noted when the larger electrophile was added in the second alkylation step. 1938 J .  Org. Chem., Vol. 51, No. 10, 6986 Communications aldehyde 15 was bypassed during the hydrolysis, giving only the 4,4-dialkylcyclohexenones 5a-c. Both enantiom- ers were thus formed ( [ a ] D  for Sa, -65.58'; [aID for 5b, +64.83') along with 5c (["ID +48.98').7 Presumably, the acid-catalyzed hydrolysis of 14 also provided the proper conditions for the aldol cyclizations. As an extension of this methodology, we prepared the bicyclic lactam 16 from 9 and 5-oxoheptanoic acid (toluene, reflux 1 2  h). The lactam 16 was isolated pure, after re- crystallization, in 68% yield (mp 83-85 'C). Double al- - 16 Ph gQM* - M4 I Me Ph Ph - 17 (97: 3) - 18 kylation (2.5 equiv of sec-BuLi, THF, -78 "C, 3.0 equiv of MeI; 2.5 equiv of sec-BuLi, 4:l THF-HMPA, 4.0 equiv of benzyl bromide) gave 17 as a 97:3 mixture of endo-exo (7) Physical data. 13a: yield, 67%; IR (CC1,) 3350 br, 2950, 1620, 1460, 1425 cm-': 'H NMR (CDC1,) 6 7.10-7.50 (m, 10 H), 4.68 (d. J = 8.4 - Hz, 1 H), 4.20 (br s, 1 H), 4.03 (dt, J = 2.2, 8.6 Hz, 1 H), 3.88 (dd, J = 2.2. 11.3 Hz. 1 H). 3.77 (dd. J = 8.8. 11.3 Hz. 1 H). 3.38 (d. J = 13.0 Hz. 1 H), 2.10 (k, 1 H), 1.75 (k, 2 H), i.48 (s,3 H), 1.36 (s,3 H), 1.05 (m, 1 H). 13b: yield, 60%; IR (CC14) 3400 br, 2950,1620,1460,1420 cm-'; 'H NMR (CDCL) 6 7.10-7.50 (m, 10 H), 4.81 (dd, J = 2.4, 7 9 Hz, 1 H), 4 65 (d, J = 8.6 Hz, 1 H), 4.05 (dt, J = 2.0, 8.1 Hz, 1 H), 3.86 (ddd, J = 2.0, 7.9, 10.1 Hz, 1 H), 3.61 (ddd, J = 2.4, 10.1, 8.1 Hz, 1 H), 3.41 (d, J = 13.0 Hz, 1 H), 2.48 (d, J = 13.0 Hz, 1 H), 1.50-2.00 (m, 4 H), 1.41 (s, 3 H), 0.77 (s,3 H). 13c: yield, 72%; IR (CC14) 3350 br, 2910,1620, 1440,1410 cm-?; 'H NMR (CDC1,) 6 7.15-7.60 (m, 10 H), 6.90 (m, 1 H), 5.20 (m, 2 H), 4.89 (dd, J = 2.4, 7.9 Hz, 1 H), 4.64 (d, J = 6.1 Hz, 1 H), 1.05 (dt, J = 1.9, 8.2 Hz, 1 H), 3.85 (ddd, J = 1.9, 7.9, 10.1 Hz, 1 H), 3.61 (ddd, J = 2.4, 8.2, 10.1 Hz, 1 H), 3.35 (d, J = 12.9 Hz, 1 H), 2.75 (dd, J = 7.2, 13.6 Hz, 1 H), 2.48 (d, J = 12.9 Hz, 1 H), 2.38 (dd, J = 8.1, 12.9 Hz, 1 H), 1.90 (m, 4 H), 0.63 (s,3 H). 5a: yield, 53%; [aID -65.58' (e  1.04, EtOH); IR (film) 3040, 2935, 2885, 1680, 1605, 1490, 1450, 1415 cm''; 'H NMR (CDC1,) 6 7.10-7.40 (m, 5 H), 6.69 ( d , J  = 10.2 Hz, 1 H), 5.90 (d, J =  10.2 Hz, 1 H), 2.75 (s, 2 H), 2.44 (t, J = 6.9 Hz, 2 H), 1.96 (d, J = 6.7 Hz, 1 H), 1.79 (m, 1 H), 1.13 (s, 3 H). Anal. Calcd for CI4Hl6O: C, 83.95; H, 8.05. Found C, 83.84; H, 8.01. 5b: yield, 68%; [oilD +64.83' (e  1.02, EtOH); 'H NMR (CDCI,) 6 [same as above]. Anal. Calcd for CI4HI6O: C, 83.95; H, 8.05. Found: C, 83.84; H, 8.20. 5c: yield, 47%; [a]D +48.98' (c 1.03, EtOH); IR (film) 3080,3040,2940,2875,1690,1650,1610,1500,1460,1395 cm-'; 'H NMR (CDC1,) 6 7.10-7.40 (m, 5 H), 6.68 (d, J = 10.2 Hz, 1 H), 5.96 (d, J = 10.2 Hz, 1 H), 5.80 (m, 1 H), 5.13 (m, 2 H), 2.80 (AB q, J = 13.4 Hz, 2 H), 2.40 (m, 1 H), 2.20 (t, J = 6.6 Hz, 1 H), 1.90 (m, 2 H). 16: yield, 71%; mp 83-85 OC (1:4 EtOAc-hexane); [a]D +12.61° (c  2.1, EtOH); IR (film) 1625 cm-'; 'H NMR (CDC13) 6 7.36 (m, 5 H), 5.18 (br, 1 H, ex- changeable with D,O), 4.64 (d, J = 8.6 Hz, 1 H), 3.97-4.10 (m, 1 H), 336 (dd. J = 11.2. 2.2 Hz. 1 H). 3.72 (dd. J = 11.2. 8.7 Hz. 1 H). 2.3G2.63 (m. -, ~ ~~ < ~ ~ ,, ~ 2-~H): 1.50-2.05 (m, 6 H), 0.94 it, 3 = 7.4 H z ,  3 Hj. Anal. Calcd for C16H21N03: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.82; H, 7.62; N, 5.37. 17 (pure endo-benzyl): yield, 81.2%; 'H NMR (CDCIJ 6 7.0-7.45 (m, 5 H),5.55 (dd, J = 6.9,1.2 Hz, 1 H, exchangeable with D,O), 4.56 (d, J = 8.4 Hz, 1 H), 3.93-4.05 (m, 1 H), 3.67-3.90 (m, 2 H), 3.41 (d, J = 13 Hz, 1 H), 2.53 (d, J = 13 Hz, 1 H), 1.50-2.10 (m, 6 H), 1.35 (s, 3 H), 0.85 (t, J = 7.4 Hz, 3 H). 18: yield, 66%; [a]D -39.70' ( c  0.99, EtOH); IR (film) 1680,1635 cm-'; 'H NMR (CDCl,) 6 7.05-7.37 (m, 5 H), 6.45 (br d, 1 H), 2.73 (s, 2 H), 2.45 (t, J = 6.8 Hz, 2 H), 1.85-2.00 (m, 1 H), 1.76 (d, J = 1.4 Hz, 3 H), 1.65-1.79 (m, 1 H), 1.10 (s, 3 H). Anal. Calcd for C15H180: C, 84.07; H, 8.47. Found C, 84.19; H, 8.43. 21: yield, 47%; l a l m D  122.2" (c  0.32, EtOH); IR (film) 1665 cm-'; 'H NMR (CDCI,) 6 7.25-7.45 (m, 5 H), 6.94 (d, J = 10.2 Hz, 1 H), 6.13 (d, J = 10.2 Hz, 1 H), 2.10-2.50 (m, 4 H), 1.57 (s, 3 H). Anal. Calcd for CI3Hl40: C, 83.83; H, 7.58. Found: C, 83.56; H, 7.59. diastereomers. Flash chromatography (silica gel, 1:1 Et- OAc-hexane) provided pure 17 in 81 ?& yield. Reduction and hydrolysis to the cyclohexenone 18 was accomplished, as above, furnishing the enantiomerically pure product in We also examined the asymmetric route to (a)-(+)-4- phenyl-4-methylcyclohexenone, prepared earlier by Ya- madas in 40-50% ee via the proline-derived enamine addition to methyl vinyl ketone. Our sequence began by condensing 9 with racemic 2-phenyl-5-oxohexanoic acid (19)9 (benzene, reflux, 16 h), proddcing 20 (80%) along with an isomer similar to IO (20%). Due to difficulty in sep- aration, the mixture of lactams was metalated (2.5 equiv of LDA, THF, -78 'C) and alkylated with methyl iodide (1.8 equiv) and chromatographed (silica gel 3070, Et- OAc-hexane) to remove the isomeric lactam. The desired lactam (53% yield, mp 122-123 'C) was reduced with Red-AI and hydrolyzed with Bu4NH2P04 to give the cy- 65% yield [ a ] ~  - 39.70°).7 n (s,s)-9 + o%ph - HO,C (+)-E! al LDA - Me1 ph blRed-AI Me Ph cl H0 Ph 0 20 - 21 -clohexenone (R)-(+)-21, [aIz0D 122.2' (lit.lo [aIz5D 122.5') in 99.8% ee. In summary, we have described an efficient route to 4,4-disubstituted cyclohexenones in high enantiomeric excess using readily available materials, and work is in progress to extend this to more elaborate systems. Acknowledgment. Financial support was provided by the National Institutes of Health, and K.T.W. acknowl- edges a postdoctoral Fellowship from the Deutsche For- schungsgemeinschaft. We also thank Professor 0. P. An- derson and Joe Reibenspies for providing the X-ray structure of 13a. Supplementary Material Available: X-ray data for 13a (9 pages). Ordering information is given on any current masthead Page. (8) Yamada, S.; Otani, G. Tetrahedron Lett. 1969,48,4237. Soue, T.; Hiroi, K.; Yamada, S. Chem. Pharm. Bull. 1973,23, 2331. Schuster, D. I.; Brown, R. H.; Resnick, B. M. J .  Am. Chem. SOC. 1978, 100, 4504. (9) Prepared in a manner similar to that reported in ref 3 above. (10) The optical purity given in ref 8 was determined by conversion to 2-methyl-2-phenylglutaric anhydride and reported to be 130 f 2'. However, a recent report (Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J .  Org. Chem. 1985,50,2557) has challenged the rotation by Yamada et al. as being too high and has revised the rotation, on the basis of enantiom- eric purity determined by chiral shift reagents, to 122.2O. Our results, based on the lactam precursor to 21 (HPLC, 270MHz, 'H NMR) showed that it was homogeneous with less than 0.3% of the other diastereomers. A. I. Meyers,* Bruce A. Lefker Klaus Th. Wanner, R. Alan Aitken Department of Chemistry Colorado State University Fort Collins, Colorado 80523 Received February 3, 1986 

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An asymmetric synthesis of chiral 4,4-disubstituted cyclohexenones in high enantiomeric purity

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