C O M M U N I C A T I O N S
Table 1. Synthesis of â3- and â2,3-Amino Acids
facile stereoselective syntheses of a variety of â-amino acids. Simply
by choosing different combinations of three readily available starting
materials - an oxime, a chiral allylic alcohol, and a nucleophile -
the reaction sequence can be extended to the synthesis of either
enantiomer of a wide range of â-amino acid structural types. Finally,
this approach is unique in that it can be used to synthesize
previously inaccessible, sterically encumbered â3,3- and â2,3,3-amino
acids. Studies of the structural properties of oligomers of this amino
acid class are underway and will be reported in due course.
substratea
R
1
R
2
dr (% yield)b
yield of 11
7b
7c
7d
7e
7f
Et
i-Pr
H
H
H
H
Et
7:1c (44)
7:1d (64)
70%
76%
59%e
72%
67%
10:1d (40)
15:1c (54)
12:1d (63)
Acknowledgment. A.K.M. is grateful for financial support from
the NIH (GM65330), the Burroughs Wellcome Fund, and the March
of Dimes. A.R.M. was supported by the Chemistry/Biology
Interface Training Program (GM09597).
Ph
Et
a Yield of isoxazolines: 7b (69%), 7c (96%), 7d (69%), 7e (85%), 7f
(50%). b Combined yield of diastereomers; only 8 was carried on to the
1
oxidative cleavage. c Determined by H NMR spectral integration prior to
separation. d Due to poorly dispersed resonances, determined by comparison
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
of the isolated components. e NaIO4 followed by NaClO2 provided 11d.
Table 2. Synthesis of Highly Substituted â-Amino Acids
References
(1) Recent reviews on â-amino acids applications: (a) Steer, D. L.; Lew, R.
A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. I. Curr. Med. Chem. 2002,
9, 811-822. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. ReV. 2001, 101, 3893-4011. (c) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173-180. (d) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219-3232. (e) Gademann, K.;
Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905-925.
(f) Juaristi, E., Ed. EnantioselectiVe Synthesis of â-Amino Acids; Wiley-
VCH: New York, 1997. (g) Seebach, D.; Matthews, J. L. Chem. Commun.
1997, 2015-2022.
(2) Griffith, O. W. Annu. ReV. Biochem. 1986, 55, 855-878.
(3) See: (a) Juaristi, E.; Lo´pez-Ruiz, H. Curr. Med. Chem. 1999, 6, 983-
1004. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035. (c)
Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1-15. (d) Cole, D. C.
Tetrahedron 1994, 50, 9517-9582 and references therein.
product
R
R
R
3
yield of 13
dre,f
9:1
10:1
18:1
1
2
13a
13b
13c
13di
i-Bu
Et
i-Bu
Et
H
H
H
Ph
allyl
allyl
benzyl
allyl
90%
95%
90%g,h
81%g
>20:1
(4) The nomenclature of Seebach in which the superscript after “â” describes
the substitution pattern of a â-amino acid is used throughout. According
to this system, for example, a â2,3,3-amino acid has a single substituent at
the C2 position and two substituents at the C3 position. See ref 3c.
(5) For a discussion of this point, see ref 3c.
a R3MgCl, BF3‚OEt2, THF, -78 f 0 °C. b (i) LiAlH4, Et2O; (ii) Boc2O.
c NaIO4. d NaClO2, 2-methyl-2-butene. e The facial selectivity of addition
was confirmed by NOE difference experiments; see the Supporting
Information for details. f Determined by 1H NMR analysis of the crude
reaction mixture. g Isolated as the HCl salt. h N-O bond reduction was
accomplished with 10% Pd/C, NH4O2CH. i Prepared in 67% yield.
(6) For elegant approaches in which R1 and R2 are sterically dissimilar, see:
(a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819-7832. (b)
Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12-13. (c) Kobayashi,
K.; Matoba, T.; Irisawa, S.; Takanohashi, A.; Tanmatsu, M.; Morikawa,
O.; Konishi, H. Bull. Chem. Soc. Jpn. 2000, 73, 2805-2809. (d) Ishitani,
H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180-8186.
(7) (a) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J. Am. Chem.
Soc. 1994, 116, 2324-2339. (b) Bode, J. W.; Fraefel, N.; Muri, D.;
Carreira, E. M. Angew. Chem., Int. Ed. 2001, 40, 2082-2085.
(8) For a rare exception, see the example in: Espino, C. G.; Wehn, P. M.;
Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935-6936.
(9) For a recent example, see: Hamuro, Y.; Schneider, J. P.; DeGrado, W.
F. J. Am. Chem. Soc. 1999, 121, 12200-12201.
selectivity is dictated by steric constraints, with the C5 substituent
blocking the top face of the ring. The resulting isoxazolidines 13
are readily transformed into the corresponding â3,3- and â2,3,3-amino
acids by N-O bond reduction, protection of the free amine, and
oxidative cleavage of the diol. In preliminary experiments, we have
also found that nonstabilized organometallic reagents add to
isoxazolines such as 7a in good yields and excellent diastereo-
selectivity (PhLi: 78%, 20:1 dr; MeLi: 63%, 10:1 dr) upon masking
of the side chain hydroxyl as a silyl ether, increasing the range of
accessible substitution patterns.
(10) Good selectivity has only been observed when steric hindrance is also a
contributing factor: (a) Ja¨ger, V.; Buss, V.; Schwab, W. Tetrahedron Lett.
1978, 3133-3136. (b) Ja¨ger, V.; Mu¨ller, I.; Paulus, E. F. Tetrahedron
Lett. 1985, 26, 2997-3000. (c) Ja¨ger, V.; Schwab, W.; Buss, V. Angew.
Chem., Int. Ed. Engl. 1981, 20, 601-603.
(11) (a) Williams, D. R.; Benbow, J. W.; Sattleberg, T. R.; Ihle, D. C.
Tetrahedron Lett. 2001, 42, 8597-8601. (b) Williams, D. R.; Osterhout,
M. H. J. Am. Chem. Soc. 1992, 114, 8750-8751. (c) Feuer, H.; Vincent,
B. F., Jr.; Bartlett, R. S. J. Org. Chem. 1965, 30, 2877-2880. (d) Zhu,
Q.-C.; Hutchins, R. O. Org. Prep. Proced. Int. 1994, 26, 193-236.
(12) El Marini, A.; Roumestant, M. L.; Viallefont, P.; Razafindramboa, D.;
Bonato, M.; Follet, M. Synthesis 1992, 1104-1108.
The highly selective addition of carbon nucleophiles provides
access to a class of â-amino acids not readily prepared by existing
methods, those in which the â-substituents are sterically similar.
In addition, the allyl group can be readily transformed by oxidation14
or reduction, for example, to access additional functional group
diversity within the final â-amino acid product. Furthermore,
isoxazolidines 13 contain four contiguous stereocenters, one of
which is a quaternary stereogenic center,15 and will thus serve as
useful intermediates for a variety of synthetically challenging
structures such as amino alcohols, amino alkenes, and â-lactams.1f,3a,b,d
In summary, we have demonstrated that the high yields and
selectivities of 1,3-dipolar cycloadditions can be translated into
(13) For a rare example of an organometallic addition to an isoxazoline, see:
Huang, K. S.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem.
2000, 65, 499-503.
(14) 13a was subjected to reductive ozonolysis to introduce a hydroxyethyl
side chain in 77% yield, for example. See the Supporting Information for
details.
(15) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388-401.
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