Lithium N-trityl-N-(R)-1-phenethylamide, a readily available and useful base for the enantioselective formation of chiral enolates from achiral ketones

Article abstract of DOI:10.1016/S0040-4039(00)01185-0

Lithium N-trityl-N-(R)-1-phenylethylamide (6) is a readily available and useful reagent for the enantio-selective (20:1) conversion of 4-t-butylcyclohexanone to the corresponding (S)-enolate. This reaction provides access to numerous useful chiral compoun

Full text of DOI:10.1016/S0040-4039(00)01185-0

Tetrahedron Letters 41 (2000) 6941±6944
Lithium N-trityl-N-(R)-1-phenethylamide, a readily available
and useful base for the enantioselective formation of chiral
enolates from achiral ketones
Jakub Busch-Petersen and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Received 14 July 2000; accepted 17 July 2000
Abstract
Lithium N-trityl-N-(R)-1-phenylethylamide (6) is a readily available and useful reagent for the enantio-
selective (20:1) conversion of 4-t-butylcyclohexanone to the corresponding (S)-enolate. This reaction
provides access to numerous useful chiral compounds. # 2000 Elsevier Science Ltd. All rights reserved.
We recently reported a convenient one-step synthesis of trityl-t-butylamine (1) and the application
of the corresponding lithium amide to highly stereoselective enolate formation from a variety of
ketones.1 The ease of preparation and recovery of 1 and the e€ectiveness of the lithio derivative
as a superhindered base prompted us to investigate a chiral analog, N-trityl-N-(R)-1-phenylethyl
23
amine (2), ‰ꢀŠ +114 (c 1.0, in CH2Cl2), which is also available in one step by N-tritylation of
D
commercial (R)-1-phenylethylamine (Aldrich).1 In this note we describe a few illustrative
applications of 2 in enantioselective synthesis which build on previous observations involving the
chiral amines 3 (Koga2) and 4 (Simkins3).4 The focus of the present study with 2 was on the
substrate 4-t-butylcyclohexanone (5) since this is the most intensively studied reactant with
respect to enantioselective enolate formation with bases such as 3 and 4.4
After several screening experiments to determine optimum conditions for the enantioselective
deprotonation of 5 by 6, the N-lithio derivative of 2, it was determined that excellent results could
be obtained using 2 equivalents of lithium bromide, i.e. 6 and LiBr in a ratio of 1:2, in the
presence of trimethylchlorosilane5 in tetrahydrofuran (THF) as solvent at ^100ꢀC (liq. N2±Et2O
bath). Removal of THF and evaporative distillation of the reaction mixture in vacuo a€orded the
trimethylsilyl enol ether 7 in 89% yield and 91% enantiomeric excess (ee).6,7 Reaction of 7 with
1,4-benzoquinone in the presence of Pd(OAc)2 in CH3CN solution at 23ꢀC a€orded the chiral
23
D
enone 8, ‰ꢀŠ +50.0 (c 0.02 in CHCl3), of 91% enantiomeric purity in 83% isolated yield. The
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01185-0

6942
conversion of 5 to 7 by 6 is considerably less enantioselective in the absence of LiBr or using 6
plus a coordinating diamine such as tetramethylethylenediamine (TMEDA) in THF (Scheme 1).
Scheme 1.
The enantioselectivity of the deprotonation of 5 by 6±2LiBr to form the silyl enol ether 7 is
comparable with the best results reported for the bases 3 and 4 which appear to be the most
e€ective of those described in the literature.4
We have also examined the application of the hindered chiral base 6 to the enantioselective
Robinson annulation of 4-t-butylcyclohexanone. Deprotonation of 5 by 6±2LiBr, in the THF as
described above, and subsequent reaction with methyl cyanoformate and 2 equivalents of
TMEDA at ^100ꢀC for 2 h a€orded the b-keto ester 9 in ca. 70% yield.8,9 Treatment of 9 with
diisopropylethylamine and methyl vinyl ketone (slow addition) in methanol at ^78ꢀC produced
the Michael adduct 10 which upon heating with p-toluenesulfonic acid and 4 A mol. sieves in
benzene at re¯ux yielded the bicyclic a,b-enone 11 as a colorless oil in 69% overall yield after
24
D
column chromatography on silica gel. The enantiomeric purity of 11, ‰ꢀŠ +74.1 (c 0.01 in
CHCl3), was determined to be 89% by HPLC analysis using a Chiralpak AD-RH column with
3:1 CH3CN:H2O for elution (retention times: major enantiomer, 6.6 min; minor enantiomer, 8.0
min) (Scheme 2).10
b-Keto ester 9 is a versatile intermediate for the synthesis of many other types of compounds.
For example, in connection with a project on enantioselective hydroxylation by lead tetraacetate
we needed a supply of the chiral ligand 13. This chiral b-hydroxy acid was readily synthesized

6943
Scheme 2.
from 9 by a two-step sequꢀence. Diastereoselective carbonyl reduction using 2.8 equivalents of
SmI2 in aqueous THF at 0 C,11 and recrystallization from hexane a€orded colorless crystals of
24
D
12, mp 83ꢀC, ‰ꢀŠ +11.3 (c 0.015 in CHCl3), of 92% ee by H NMR analysis of the Mosher
1
ester.12 Saponi®cation of hydroxy ester 12 using 1:1 THF:1N aqueous LiOH at 0ꢀC for 2 h
provided, after recrystallization from EtOAc, colorless crystals of hydroxy acid 13, mp 161±
24
D
162ꢀC, ‰ꢀŠ +21.6 (c 0.052 in EtOH), of ee >98% by 1H NMR analysis of the Mosher ester.
The enantioselective generation of the chiral enolate 14 from 5 by asymmetric deprotonation
using 6±2LiBr can also obviously be applied to aldol coupling reactions. Treatment of the chiral
enolate thus formed with benzaldehyde at ^100ꢀC in THF produced after chromatography on
silica gel the major product 15 (58% yield, 89% ee by HPLC analysis using a Chiralpak AD-RH
with 3:1 acetonitrile:water for elution13).14 Recrystallization of 15 from EtOAc±heptane gave 15
24
D
of 98.5% ee, ‰ꢀŠ ^49.7 (c 0.05 in EtOH), mp 74±74.5ꢀC (Scheme 3).
Reaction of the chiral enolate 14 in THF solution at ^100ꢀC with a solution of monomeric
formaldehyde in THF15 a€orded, as major product after silica gel chromatography, the hydroxy
1
ketone 16 as a colorless oil (ca. 50% yield); 89% ee by H NMR analysis of the Mosher ester.
Reduction of 16 with sodium triacetoxyborohydride in CH3CN±HOAc at 23ꢀC for 6 h produced
the trans diol 17 cleanly as a colorless solid (from heptane), mp 86±87ꢀC.16
Scheme 3.

6944
The basis of the observed ca. 20:1 enantioselectivity of deprotonation of 5 by 6 and LiBr to
form the (S)-enolate 14 is a matter of conjecture at this time. One reasonable transition state
model involves an eight-membered transition state with the ring members: a-H (axial), C(a),
CˆO, Li±Br and LiNR2 with the lone pair on nitrogen attacking a-H (axial).
In summary, the chiral amine 2, which is readily available in one step from inexpensive
commercial precursors, and the N-lithio derivative 6 are promising synthetic reagents. The utility
of 6 in enantioselective enolate formation has been demonstrated by the conversion of 4-t-butyl-
cyclohexanone (5) via the chiral enolate 14 to several interesting transformation products.
Acknowledgements
This work was supported by grants from the National Science Foundation and the National
Institutes of Health.
References
1. Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 2000, 41, 2515. In this paper we inadvertently omitted
referencing two earlier publications which were relevant: Brander, M. M. Recl. Trav. Chim. Pays-Bas. 1918, 37,
67 mentions, but provides no further information on trityl-t-butylamine. Maender, O. W.; Janzen, E. G. J. Org. Chem.
1969, 34, 4072 also mention this compound and describe it as a colorless liquid (solid, mp 90±91ꢀC in our hands).
2. Shirai, R.; Tanaka, M.; Koga, K. J. Am. Chem. Soc. 1986, 108, 543.
3. Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simkins, N. S. Tetrahedron 1990, 46, 523.
4. For a recent review on enantioselective deprotonation by chiral bases, see: O'Brien, P. J. Chem. Soc., Perkin
Trans. 1 1998, 1439.
5. Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
6. Enantiomeric excess of 7 was determined by transformation to 8 and analysis of 8 by HPLC using a Chiral
Technologies Inc. Chiralpak AD column with 5% isopropyl alcohol in hexane for elution; retention times: minor
enantiomer 6.3 min, major enantiomer 8, 7.3 min; ¯ow rate, 1 mL/min at 23ꢀC.
7. Extractive work-up of the residue remaining from the distillation of silyl enol ether 7 allowed ecient recovery of
the chiral amine 2.
8. (a) Crabtree, S. R.; Mander, L. N.; Sethi, S. Org. Synth. 1991, 70, 256. (b) Mander, L. N.; Sethi, P. Tetrahedron
Lett. 1983, 24, 5425.
9. The enol methoxycarboxyl ester of 5 was produced as a byproduct of the conversion 5!9 in ca. 7% yield under
these conditions; in the absence of TMEDA more of this byproduct was formed.
10. The relative stereochemistry of 11 follows from previously known diastereoselective Robinson annulations. See,
for example: Turner, R. B.; Lee Jr., R. E.; Hildenbrand, E. G. J. Org. Chem. 1961, 26, 4800.
11. (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187. (b) See also: Beeson, C.; Pham,
N.; Dix, T. A. Tetrahedron Lett. 1992, 33, 2925.
12. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543. (b) Dale, J. A.; Mosher, H. S. J. Am.
Chem. Soc. 1973, 95, 112.
13. Retention times: minor enantiomer, 7.1 min; major enantiomer, 8.3 min.
14. The assignment of absolute con®guration of 15 follows from data reported above for the enolate 14. The
1
equatorial arrangement of the a-hydroxybenzyl substituent is indicated by the 500 MHz H NMR spectrum of
15 which shows an 8.9 Hz coupling constant between the a-methine proton and one of the b-methylene protons.
Finally, the con®guration at the a-hydroxybenzyl stereocenter follows from the pericyclic chair ring transition
state preference for the lithium enolate aldol reaction with aldehydes; see: House, H. O.; Crumrine, D. S.;
Teranishi, A. Y.; Olmstead, H. D. J. Am. Chem. Soc. 1973, 95, 3310.
15. Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
16. Compounds 7±9, 11±13, and 15±17 described above were characterized by infrared, 1H NMR, 13C NMR and high
resolution mass spectra using chromatographically puri®ed or recrystallized samples.