M. Ordóñez et al. / Tetrahedron: Asymmetry 19 (2008) 2767–2770
2769
used in the deprotonation step. This finding can be attributed to
the counter anion and to the effects of aggregation states of the
enolates. The results presented here provide valuable guidelines
to tune the selective preparation of enantiopure compounds from
the same source of chirality.
O
O
Me
O
Me
O
(MeO)2P
(MeO)2P
1. LDA
N
H
+
1c
N
H
Ph
Ph
2. BnBr
THF, -78 o
Bn
Me Bn
2c
Me
C
(R,R)-3c
(S,R)-
LDA (2.0 equiv.), 76%
LDA (2.5 equiv.), 84%
82
27
:
18
73
Acknowledgement
:
We wish to thank CONACYT of Mexico for financial support for
this work through Grants 62271 and 44126. Two of us, EHF and
HRC, also wish to thank CONACYT for Graduate Scholarships.
Scheme 2.
nary phosphonoamides (S,R)-2c and (R,R)-3c in 76% yield and
82:18 dr, with a predominance of (S,R)-2c. A reversal in the diaste-
reoselectivity was also observed when the benzylation of 1c was
carried out using LDA (2.5 equiv), and (S,R)-2c and (R,R)-3c were
obtained in 84% yield and 27:73 dr, with a predominance of
(R,R)-3c (Scheme 2).
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On the basis of these results, the origin of the reversal of diaste-
reoselectivity observed in the alkylation of 1 by changing the
equivalents of the lithium bases can be explained in terms of
aggregation states in the enolate. We propose that enolate 4, which
is obtained by deprotonation of 1a with LDA, LiHMDS or LTMP
(2.0 equiv), adopts a conformation that is in accordance with the
literature precedent and is favoured by C@C–O–Li–O@P coordina-
tion.17,25 In addition, the C–H bond in the methylbenzyl chiral frag-
ment is oriented towards the oxygen atom, and the relative sizes of
the phenyl and methyl groups determine the preferred direction of
benzyl bromide addition.26 In this arrangement, the phenyl group
effectively blocks the Re face of enolate 4 towards alkylation, and
the addition of benzyl bromide would occur from the face that
has the methyl group (Si face) to give the (R,S)-2a diastereoisomer
as the major product. On the other hand, the addition of a further
0.5–2.0 equiv of LDA more to enolate 4 gave the aggregated state 5.
In this case, we propose that one additional molecule of LDA is
coordinated with the C@C–O and N–Li fragments, the orientation
of the C–H bond in the methylbenzyl chiral fragment is directed
towards the C@C bond in the enolate, and the phenyl group now
blocks the Si face of enolate 5. As a result, the addition of benzyl
bromide would occur at the Re face to give the (S,S)-3a diastereo-
isomer as the major product (Fig. 1).27 However, aggregate state
5 is broken down by the addition of DMPU.
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8. For the synthesis of both enantiomers from
a single chiral source via
3. Conclusion
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G.; Maroto, R.; Quiroga, M. L. J. Org. Chem. 1995, 60, 7934–7940; (b) Tomioka,
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derived from (S,S)-pseudoephedrine on changing the alkylating agents: Meyers,
A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428–2440.
In conclusion, we have found that the diastereoselectivity in the
benzylation of 1a–d depends on the number of equivalents of base
10. For reviews on this subject, see: (a) Groaning, M. D.; Meyers, A. I. Tetrahedron
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Ikuta, Y.; Tomoda, S. Tetrahedron Lett. 2003, 44, 5931–5934.
Li
O
O
Me
H
O
O
Ph
(MeO)2P
(MeO)2P
N
N
H
Ph
Si
Me
Me
Bn
Li
Me
BnBr
2a
(R,S)- ; (major)
12. Boeckman, R. K., Jr.; Boehmler, D. J.; Musselman, R. A. Org. Lett. 2001, 3, 3777–
3780.
4
13. Ordóñez, M.; Hernández-Fernández, E.; Xahuentitla, J.; Cativiela, C. Chem.
Commun. 2005, 1336–1338.
LDA, 0.5-2.0 equiv.
14. For the preparation of phosphonopropanoamides and their application in the
Horner–Wadsworth–Emmons (HWE) reaction, see: (a) Hernández-Fernández,
E.; Fernández-Zertuche, M.; García-Barradas, O.; Muñoz-Muñiz, O.; Ordóñez,
M. Synlett 2006, 440–444; (b) Ordóñez, M.; Hernández-Fernández, E.; Montiel-
Pérez, M.; Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernández-Zertuche, M.;
García-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436.
15. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415–430.
16. Typical experimental procedure for the second alkylation of 1: To a solution of the
phosphonopropanoamide 1 (1 mmol) in dry THF at À78 °C was added dropwise
2.0 or 2.5 (equivalents) of the appropriate base in dry THF. The resulting solution
was stirred for 1 h at À78 °C. The benzyl bromide (1.1 equiv) was added with
continuous stirring, and the reaction mixture was stirred at À78 °C for 3–4 h
afterwhich it was quenched with saturated aqueous NH4Clsolution. The product
O
O
Me
Li
Li
N
BnBr
(MeO)2P
O
O
(MeO)2P
Re
N
H
Ph
Li
N
Me
Bn
3a
Me
Me
(S,S)- ; (major)
H
Ph
5
Figure 1. Proposed mechanism for the benzylation of 1a.