Figure 2. Possible transition states for lithium- and titanium-mediated acetate aldol reaction.
To understand the stereochemical implications, ab initio
molecular orbital calculations were carried out using basis
set B3LYP/STO-3G levels on a Gaussian03 program
package,12 and the most stable conformation wasidentified
(Figure 1) for each of the chiral auxiliaries 6aꢀe. This was
extrapolatedto the corresponding acetate derivatives7aꢀe.
The proposed transition states for the reaction between 7a
and benzaldehyde, analogous to the transition states com-
puted by Shinisha et al.,13 are depicted in Figure 2. Lithium
coordinates with the carbonyl groups of the acetyl sub-
stituent on N1 and the aldehyde allowing a six membered
open transition state, similar to boron enolate.2,14a The
transition state TS-Li-1 is favored over TS-Li-2 due to com-
paratively less steric repulsion on the CR-si face of aldehyde,
affording the anti acetate aldol as the major product.
Contrary to this, titanium forms the chlorotitanium
enolate, which is expected to proceed through a closed
transition state as a result of chelation promoted by the
oxophilicity.8a A six-membered transition state TS-Ti-1
involving carbonyl groups of the auxiliary, acetyl substi-
tuent at N1 and aldehyde,8a,14 is favored over TS-Ti-2 due
to comparatively less steric repulsion on the CR-re face
of aldehyde affording the syn acetate aldol as the major
product. This validates our inferences on the additional
directive influence of the N3-R-Me-Bn group of 7a and 7b,
which is geared to favor a CR-si face attack over CR-re face
attack on the electrophile in an open transition state, while
it would be the reverse in the case of a closed transition
state. The lower selectivity observed with 7c, 7d, and 7e
may be due to the lack of this gearing effect.
The lithium enolate of 7a was examined for acetate aldol
reactions with various aryl/heteroaryl aldehydes (iꢀix), and
excellent selectivity toward the anti acetate aldol adducts was
obtained (Table 2). Reaction with trans-cinnamaldehyde (x)
at ꢀ78 °Caffordedhighdiastereoselectivity (02:98, syn:anti),
whereas isobutyraldehyde (xi) gave moderate selectivity
(30:70, syn:anti). To improve the selectivity, the reaction
temperature was reduced to ꢀ90 °C, and we found appreci-
able enhancement in diastereoselectivity (11:89, syn:anti).
This optimized reaction condition was utilized in the acetate
aldol reactions with other aliphatic aldehydes such as iso-
valeraldehyde (xii), pivaldehyde (xiii), and phenylacetalde-
hyde (xiv) (entries12ꢀ14, Table 2). The reversal of selectivity
observed with the Lewis acid TiCl4 was further assessed with
various aldehydes (iꢀxiv), affording the syn acetate aldol
adducts in good yields and selectivities.
The acetate aldol reaction was then explored for the
stereoselective formation of (S)- and (R)-fluoxetine. The
fluoxetine racemate (Prozac) is marketed as a potent
selective serotonin reuptake inhibitor (SSRI), but the
enantiomers exhibit different pharmacological proper-
ties.15 (R)-Fluoxetine is used for treating depression,
while (S)-fluoxetine is envisaged for migraine treatment.
Chirality has been introduced in fluoxetine synthesis
through enantioselective hydroxylation,16 epoxidation,17
chemical18 and enzymatic19 reduction of ketones and
(12) All calculations were performed using the Gaussian 03 program
package: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. In Gaussian03, Revision E.01; Gaussian, Inc.:
Wallingford CT, 2004.
(15) (a) Robertson, D. A.; Krushinski, J. H.; Fuller, R. W.; Leander,
J. D. J. Med. Chem. 1988, 31, 1412. (b) Robertson, D. W.; Jones, N. D.;
Swartzendruber, J. K.; Yang, K. S.; Wong, D. T. J. Med. Chem. 1988, 31,
185.
(16) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett.
2002, 43, 4425.
(17) (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081.
(b) Kakei, H.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2004, 43, 317. (c) Mitchell, D.; Koenig, T. M. Synth. Commun.
1995, 25, 1231.
(13) Shinisha, C. B.; Sunoj, R. B. J. Am. Chem. Soc. 2010, 132, 12319.
(14) (a) Nerz-Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56,
2489. (b) Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299. (c) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y.
J. Am. Chem. Soc. 1993, 115, 2613.
2444
Org. Lett., Vol. 14, No. 10, 2012