Table 1. Highly Enantioselective Mannich Reactions with
R-Aryl SKAs 3 and 6
time
yield
ee
dr (%)
entry
R
R0
SKA (h) product (%)
Figure 1. Examples of bioactive compounds possessing an R-aryl,
β-aminocarbonyl substructure.
1
2
3
Ph
p-CF3C6H4
3
3
3
3
3
3
6
4
1
2
48
20
2.5
5a
5b
5c
5d
5b
5e
5f
77 >20:1 97
PhCH2CH2 Ph
i-PrCH2
89
86
70
74
91
79
5:1 95
4:1 95
9:1 99
13:1 94
5:1 82
4:1 95
Ph
p-CF3C6H4
starting point for the present investigation. Indeed, it was
quickly found that SKA 3 (prepared and employed as
a 13:1 Z/E mixture) reacts smoothly with the silane 1/
hydrazone 4a complex to give syn-Mannich product 5a.
Optimization was straightforward, and by performing the
reaction in CH2Cl2 at ambient temperature for 4 h, 5a
could be isolated in 77% yield as a single diastereomer in
97% ee.
4a i-Pr
5b PhCH2CH2 Ph
6c CO2i-Pr
PhCH2CH2 Ph
p-MeOC6H4
7
1
a This reaction was run at 0 °C. b This reaction was run with 1.5 equiv
of (R,R)-1 and 3 equiv of SKA 3 in PhCF3 at 0 °C. c This reaction was run
with 2.4 equiv of SKA 3 in PhCF3.
and although the enantiopurity of the product (5e) was
somewhat lower with this substrate, this reaction never-
theless provides a useful and direct entry into systems such
as the Merck DPP IV inhibitor5,6 (see Figure 1). Finally,
the use of a substituted aryl group (p-bromophenyl) on the
SKA (6, prepared and employed as a 6:1 Z/E mixture) was
demonstrated withhydrazone 4b, whichled tothe isolation
of 5f (R=PhCH2CH2, R0 =Ph, Ar=p-Br-C6H4) in 79%
yield (4:1 dr) and 95% ee (entry 7).
Scheme 1
As an additional demonstration of the power of this
method to allow direct and efficient access to medicinally
relevant structures, hydrazone 7 was prepared and sub-
jected to the reaction conditions described in Table 1
(Scheme 2). Prior to isolation, the unpurified Mannich
productwas treated with basic alumina resulting insmooth
cyclization to give 8 in 78% overall yield (5:1 dr) and
95% ee. Reductive cleavage of the N-N bond was accom-
7
Summarized in Table 1 is a brief survey of the scope
of the reaction with respect to the hydrazone substrate.
Optimization focused on the nature of the group (R0) on
the hydrazone, as we have found that this can have a
significant effect on reaction performance. The use of both
aromatic and aliphatic aldehyde-derived hydrazones re-
sulted in excellent levels of enantioselectivity (entries 1-4),
albeit with only moderate diastereoselectivity for unhin-
dered aliphatic substrates (entries 2 and 3). As shown in
entry 5, however, this moderate diastereoselectivity may be
significantly improved simply by performing the reaction
in PhCF3. Although the reaction is slower and required a
higher silane loading, the product 5b was isolated with 13:1
dr and 94% ee. Glyoxylate-derived hydrazone 4e (R =
CO2i-Pr, R0=p-MeOC6H4) was employed as well (entry 6),
plished with SmI2 and led to the isolation of erythro-
(2R,20S)-methylphenidate 9 as the major product of a 5:1
mixture of diastereomers in 76% yield.
Structures such as tilidine8 and spirotryprostatin A9
(Figure 1), and more generally the challenge of establishing
quaternary carbon stereocenters in the context of complex
β-amino acid derivatives, led us to examine R-aryl-R-alkyl
(5) Edmondson, S. D.; Mastracchio, A.; Mathvink, R. J.; He, J.;
Harper, B.; Park, Y.-J.; Beconi, M.; Di Salvo, J.; Eiermann, G. J.; He,
H.; Leiting, B.; Leone, J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.;
Patel, S. B.; Petrov, A.; Scapin, G.; Shang, J.; Sinha Roy, R.; Smith, A.;
Wu, J. K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E. J. Med.
Chem. 2006, 49, 3614.
(6) The Merck Research Laboratories Department of Process Re-
search has also reported a Mannich reaction based approach to the
synthesis of these bioactive compounds. See: Janey, J. M.; Hsiao, Y.;
Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390.
(7) Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetra-
hedron 1994, 50, 4399.
(8) (a) Satzinger, G. Liebigs Ann. Chem. 1969, 728, 64. (b) Satzinger,
G. Liebigs Ann. Chem. 1972, 758, 43.
(9) (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832. (b)
Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651.
(3) Notte, G. T.; Leighton, J. L. J. Am. Chem. Soc. 2008, 130, 6676.
(4) Silane 1 is isolated and employed as a 2.2:1 mixture of diaster-
eomers. We have previously provided evidence that, upon reaction with
a hydrazone, the diastereomers converge upon a single complex prior to
the C-C bond-forming event. See ref 3.
Org. Lett., Vol. 13, No. 4, 2011
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