upon diastereoselective protonation of chiral lactam enolates
derived from (R)-phenylglycinol.
chiral amide enolates.9 In alkylation processes, a five-
membered ring chelate between the lithium alkoxide and the
lone pair of the pyramidalized nitrogen of the lactam enolate
has been suggested to be responsible for the stereoselectivity.
In that situation, the stereochemical outcome of the alkylation
would arise from an attack of the electrophile anti to the
nitrogen lone pair (Figure 1).10 On this basis, opposite
We recently reported a diastereoselective alkylation of
chiral 1,2,3,4-tetrahydroisoquinolin-3-ones derived from (R)-
phenylglycinol.7 The synthesis of lactam 1 starts from the
readily available isochroman-3-one, which upon treatment
with HBr in ethanol gave rise to 2, which was subsequently
condensed with (R)-phenylglycinol to provide the desired
tetrahydroisoquinoline 1 in 62% overall yield. Excellent
diastereoselectivities were observed during the alkylation of
the corresponding lactam enolate under the conditions
depicted in Scheme 1. The absolute configuration at C4 of
Scheme 1a
Figure 1. Proposed stereodirecting effect of the lithium alkoxide
to account for the diastereofacial discrimination with alcohols (the
absolute configuration of phenylglycinol lactam enolates in this
figure is (S) for clarity).
diastereofacial selectivities observed in protonation reactions
could rely on a complexation of the protonating agent with
the lithium alkoxide to subsequently direct the protonation
on the opposite face of the enolate (Figure 1).11
a Reagents and conditions: i, HBr/EtOH, rt; ii, (R)-(-)-phenyl-
glycinol/EtOH, rt f reflux; iii, LHMDS/THF/-78 °C; iv,
PhCH2Br/-78 °C; v, n-BuLi/-78 °C; vi, EtOD/-78 °C.
We then applied this diastereoselective protonation to the
asymmetric synthesis of 4-phenyl-1,2,3,4-tetrahydroisoquino-
lines. The required 4-phenyl-1,2,3,4-tetrahydroisoquinolin-
3-one (4R,4S)-6 has been prepared in a manner similar to
that described for the preparation of 1. Treatment of the
readily available 2-benzylphenylmethanol 412 with n-BuLi
in THF at room temperature for 24 h followed by quenching
the reaction with methyl chloroformate afforded 4-phenyl
isochroman-3-one 513 in 54% yield. The isochroman-3-one
5 was then treated with HBr in ethanol and subsequently
the major isomer was established as (S) by X-ray analysis.
Attempts to apply that approach to the asymmetric synthesis
of 4-aryl tetrahydroisoquinolines by electrophilic arylation
of the lactam enolate with diphenyliodonium salts8 were
unsuccessful, leading in most cases to recovery of the starting
material. However, it was observed that when pure (4S)-3
was subjected to the deprotonation conditions described in
Scheme 1 and subsequently treated with EtOD, a high degree
of diastereoselectivity was retained, 90% de (Scheme 1).
Interestingly, the obtained major diastereoisomer (4S)-3-
d1 clearly indicates that protonation of the enolate intermedi-
ate occurred with diastereoselection opposite to that observed
during alkylation processes. Only a few investigations have
been reported with regard to the sense of the diastereo-
selection in both alkylation and protonation processes of
(9) This comparison has been done by Davies and Seebach in the
course of studies related to diastereoselective alkylation and protonation
of lithium enolates derived from chiral imidazolidinones or diketopiper-
azines. In both examples, whether alkyl halides or various proton sources
are used to quench the corresponding enolates, the same diastereofacial
selectivity is observed, see: Bull, S. D.; Davies, S. G.; Epstein, S. W.;
Ouzman, J. V. A. Tetrahedron: Asymmetry 1998, 9, 2795. Seebach, D.;
Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann. Chem.
1989, 1215.
(10) Micouin, L.; Jullian, V.; Quirion, J. C.; Husson, H. P. Tetrahe-
dron: Asymmetry 1996, 7, 2839.
(6) Prat, L.; Mojovic, L.; Levacher, V.; Dupas, G.; Que´guiner, G.;
Bourguignon, J. Tetrahydron: Asymmetry 1998, 9, 2509.
(7) (a) Philippe, N.; Levacher, V.; Dupas, G.; Duflos, J.; Que´guiner, G.;
Bourguignon, J. Tetrahedron: Asymmetry 1996, 7, 417. (b) This approach,
based on Husson’s methodology first developed in the piperazine series,
has been applied afterwards in the tetrahydroisoquinoline series as well.
Roussi, F.; Quirion, J. C.; Tomas, A.; Husson, H. P. Tetrahedron 1998, 54,
10363.
(8) For phenylation of enolates with diphenyliodonium salts, see: (a)
Varvoglis, A. Synthesis 1984, 709. (b) Gao, P.; Portoghese, P. S. J. Org.
Chem. 1995, 60, 2276. (c) Chen, Z. C.; Jin, Y. Y.; Stang, P. J. J. Org.
Chem. 1987, 52, 4115. (d) Ryan, J. H.; Stang, P. J. Tetrahedron Lett. 1997,
38, 5061.
(11) (a) Our results, therefore, find analogy in the work of Askin. Indeed,
alkylation of prolinol amide enolates with alkyl halides and epoxides takes
place with opposite diastereoselectivity. This finding is interpreted by the
author by an intermolecular chelation of the epoxide with the lithium
alkoxide, see: Askin, D.; Volante, R. P.; Ryan, K. M. Tetrahedron lett.
1988, 29, 4245. (b) The same phenomenon has been observed with
pseudoephedrine amide enolates. Myers, A. G.; McKinstry, L. J. Org. Chem.
1996, 61, 2428.
(12) For further preparation of 2-benzylphenylmethanol 4, see: (a) Woo,
Y. L.; Wonbo, S.; Kwang, D. C. J. Chem. Soc., Perkin Trans. 1 1992, 881.
(b) Hamon, M.; Gardent, J. Bull. Soc. Chem. Fr. 1966, 556.
(13) For further preparation of 4-phenyl isochroman-3-one, see: Azzena,
U.; Demartis, S.; Melloni, G. J. Org. Chem. 1996, 61, 4913. See ref 14b.
2186
Org. Lett., Vol. 2, No. 15, 2000
Philippe, Nicolas
