DOI: 10.1039/C4CC05765A
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highly efficient route to the synthesis of these important bio-active
compounds.
Acknowledgments
We gratefully acknowledge the Herbert C. Brown Center for
Borane Research for funding this project.
Scheme 3 Proposed intramolecular proton transfer mechanism
To further probe the mechanism, we designed a competitive
isotopic distribution experiment (Scheme 4). Piperidine was added to Notes and references
Department of Chemistry, Purdue University
West Lafayette, IN, USA 47907-2084
E-mail: chandran@purdue.edu
a 1:1 mixture of 35 and 36 (the γ-deuterio analog of
wherein three outcomes were possible. First, piperidine could simply
react with the ‘better' Michael acceptor 35. In this case (k >k or k ), it
1) in ethanol,
3
1
2
Electronic Supplementary Information (ESI) available: Full experimental
and characterization data. See DOI: 10.1039/c000000x/
would be necessary that little deuterium incorporation into the
product mixture be observed. The second possibility was for 36 to be
converted into the deuterated lactone 37 in situ, followed by a
1
(a) D. Enders, C. Wang and J. X. Liebich, Chem. Eur. J. 2009, 15,
1058; (b) J. L. Vicario, D. Badía, L. Carrillo, J. Etxebarria, E. Reyes
2 1 3
conjugate addition (k >k or k ). Were this occurring, a buildup of 37
1
would occur, and piperidine would undergo a subsequent addition
and N. Ruiz, Org. Prep. Proced. Int. 2005, 37, 513; (c) L. -W. Xu
and C. –G. Xia, Eur. J. Org. Chem. 2005, 633.
onto both of the isotopically differentiated lactones, giving a nearly
1
1
:1 ratio of 38
:
5
, and a ≈50% deuterium incorporation by H NMR. In
2
E. Juaristi, in Enantioselective Synthesis of β-Amino Acids Wiley-
VCH, Weinheim, 1997.
the third scenario, an aza-Michael reaction onto 36 would occur
rapidly, followed by the lactonization reaction (k >k or k ). Were this
1
2
3
3
4
P. A. Magriotis, Angew. Chem. Int. Ed. 2001, 40, 4377.
S. Neelakantan, S. Nasim, M. L. Guzman, C. T. Jordan and P. A.
Crooks, Bioorg. Med. Chem. Lett. 2009, 19, 4346.
pathway correct, it would necessitate a near-complete incorporation
of deuterium into the product. After 30 min, the volatile components
1
2
were removed from the reaction mixture; H and H NMR analysis
5
6
M. Kawatsura and J. F. Hartwig, Organometallics 2001, 20, 1960.
(a) G. Bartoli, M. Bosco, E. Marcantoni, M. Petrini, L. Sambri and E.
Torregiani, J. Org. Chem. 2001, 66, 9052; (b) G. Jenner, Tetrahedron
Lett. 1995, 36, 233.
indicated a>99% incorporation of deuterium into the γ-position of the
resulting aminolactone, indicating that 38 had formed instead of 5,
thereby supporting our postulation.
7
8
N. Azizi and M. R. Saidi, Tetrahedron 2004, 60, 383.
P. V. Ramachandran, D. Pratihar, H. N. G. Nair, M. Waters, S.
Smith, M. T. Yip-Schneider, H. Wu and C. M. Schmidt, Bioog. Med.
Chem. Lett. 2010, 20, 6620.
9
1
P. V. Ramachandran, D. R. Nicponski, H. N. G. Nair, M. A. Helppi,
P. D. Gagare, C. M. Schmidt and M. T. Yip-Schneider, Bioorg. Med.
Chem. Lett. 2013, 23, 6911.
0 Only limited H-bonding typically exists in γ-hydroxycarbonyl
compounds. L. L. McCoy and D. Mal, J. Org. Chem. 1984, 49, 939.
Scheme 4 Isotopic competition experiment.
11 The anti-diastereomer was the major product, as determined by
comparison with reported values: O. Prien, K. Rölfing, M. Thiel and
H. Künzer, Synlett 1997, 325.
1
1
2 Many examples appear in the literature. For one such case, see Ref 4.
3 Such interactions with the vinylic ether are unlikely, as the Bürgi-
Dunitz angle of attack necessitates a dihedral angle approaching a
gauche conformation. H. B. Bürgi, J. D. Dunitz, J. M. Lehn and G.
Wipff, Tetrahedron 1974¸ 30, 1563.
While it cannot be definitively ruled out, the fact that the reaction
proceeds in excellent diastereoselectivity even in aprotic solvents such
as CH2Cl2 and toluene (Table 1, entries 5 and 7) as well as that the
reaction of 33 resulted only in uncyclized product 34 suggests that the
solvent might not be involved in the direct protonation of the enolate.
If present, a role played by the acidic ammonium proton in scheme 3
may or may not be immaterial. However, our postulated mechanism
satisfactorily clarifies the observed diastereoselectivities (see
electronic supplementary information).
1
4 R. M. Beesley, C. K. Ingold and J. F. Thorpe, J. Chem. Soc. 1915,
1
07, 1080.
In conclusion, we have developed a remarkably mild and efficient
procedure for the synthesis of α-(aminomethyl)-γ-butyrolactones.
This novel reaction, which occurs in nearly quantitative yields and with
readily predictable and consistent diastereomeric outcomes, offers a
4
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