Highly stereocontrolled one-step synthesis of anti-β-amino alcohols from organoboronic acids, amines, and α-hydroxy aldehydes [2]

Full text of DOI:10.1021/ja981075u

11798
J. Am. Chem. Soc. 1998, 120, 11798-11799
derivatives of R-alkoxy aldehydes.16 Methods of this type,
however, often require highly reactive organometallics that involve
cumbersome experimental conditions and necessitate additional
protection-deprotection steps. Moreover, the stereoselectivity
in these cases is usually low or mixed, due to conflicting
stereoelectronic effects and chelation effects.16a
Highly Stereocontrolled One-Step Synthesis of
anti-â-Amino Alcohols from Organoboronic Acids,
Amines, and r-Hydroxy Aldehydes
Nicos A. Petasis* and Ilia A. Zavialov
Following our recently reported one-step R-amino acid syn-
thesis from organoboronic acids,17 we describe herein a new,
practical, and highly diastereocontrolled approach to a variety of
anti-â-amino alcohols. This method involves the one-step three-
component reaction of an organoboronic acid (1), an amine (2),
Department of Chemistry
Loker Hydrocarbon Research Institute
UniVersity of Southern California
Los Angeles, California 90089-1661
ReceiVed March 31, 1998
The stereocontrolled synthesis of â-amino alcohols continues
to be the focus of numerous studies.1 This highly versatile
functionality can be easily converted to many other molecules,
including amino acids2 and amino sugars.3 It is also a common
subunit of a large variety of bioactive compounds, such as many
protease inhibitors.4 â-Amino alcohols are also useful as chiral
auxiliaries1,5 and as transition metal ligands5,6 for asymmetric
synthesis and catalysis. The most common synthetic routes to
these molecules1 involve functional group interconversions,
including the reduction of amino acids7 or amino ketones,8 the
hydroboration of enamines,9 the aminohydroxylation of olefins,10
and the nucleophilic substitution of epoxides,11 diol derivatives,12
or aziridines.13 Many of these approaches, however, proceed with
low or mixed stereoselectivity, involve multiple steps, or allow
only limited types of substituents. Somewhat more versatile are
methods involving the simultaneous construction of a C-C bond,
such as the addition of various C-nucleophiles to carbonyl
derivatives,14 to N-protected R-amino aldehydes,15 or to N-
and an R-hydroxy aldehyde (3) to give directly the corresponding
â-amino alcohol (4). The reaction proceeds with a very high
degree of diastereocontrol, forming exclusively the anti products
in greater than 99% de. Moreover, when optically pure R-hydroxy
aldehydes are used, no racemization occurs, and the products are
obtained as single enantiomers, with greater than 99% ee.
Table 1 shows a number of examples of this chemistry. A
variety of organoboronic acids, including alkenyl (1b, f, and g),
2-bromoalkenyl (1a), aryl (1c and d), and heteroaryl (1e, h, and
i) participate readily in this process. The experimental procedure18
is very simple and generally involves mixing and stirring the three
components together at ambient temperature for 12-48 h. A
typical solvent is ethanol although ethanol/dichloromethane or
ethanol/water mixtures can also be used. It is noteworthy that
the reaction does not require anhydrous or oxygen-free conditions
and is readily adaptable to parallel synthesis for the construction
of combinatorial libraries.19
The use of glycolaldehyde dimer (3a) in this process gives the
primary amino alcohol products in good yields (entries 1-2).
Chiral R-hydroxy aldehydes (3b and c), readily available by a
variety of methods,20 give the corresponding â-amino alcohols
as single diastereomers (entries 3-5). The relative configuration
of the products was established to be anti by 1H NMR spectros-
copy and other techniques.21
(1) For a review see: Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV.
1996, 96, 835.
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Pergamon Press: Oxford, 1989. (b) Yokomatsu, T.; Yuasa, Y.; Shibuya, S.
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1992, 92, 889. (d) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
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Wiley-Interscience: New York, 1995.
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(18) For a typical experimental procedure see the Supporting Information.
(19) For other approaches to 1,2-amino alcohol libraries see refs 11b,c.
(20) (a) Corey, E. J.; Jones, G. B. Tetrahedron Lett. 1991, 32, 5713. (b)
Hayashi, M.; Yoshiga, T.; Nakatani, K.; Ono, K.; Oguni, N. Tetrahedron 1994,
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Hammerschmidt, S.; Kuehling, K.; Mofid, M. R.; Zimmermann, T.; Knochel,
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10.1021/ja981075u CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 45, 1998 11799
be easily obtained24 from the corresponding R-hydroxy carboxylic
acids via initial ketalization followed by DIBALH reduction.
The tolerance of hydroxy groups and aqueous media in this
reaction prompted us to examine the use of glyceraldehyde (3d).
Although the addition of organometallics to protected glyceral-
dehyde and its imine derivatives is a well-known process,16e,g,25
these reactions generally require anhydrous conditions and proceed
with variable stereocontrol. In contrast, the direct reaction of
organoboronic acids and amines with the unprotected aldehyde,
including its aqueous solutions, gave cleanly the corresponding
anti-3-amino 1,2-diol products (entries 11-16), as single dia-
stereomers (>99% de). Compounds of this type can be easily
transformed to numerous other functionalized amines,26 amino
acids,12b,16e,g,25d,27 amino epoxides,27b and peptidomimetics.4,11b
The use of enantiomerically pure glyceraldehyde (6) leads to
enantiomerically pure 3-amino 1,2-diols (e.g., 8). By using
aminodiphenylmethane (7) as the amine component, followed by
hydrogenolysis, conversion to the N-Boc derivative (9), and
Table 1. Synthesis of anti-â-Amino Alcohols (4) by the Reaction
of Organoboronic Acids (1) with Amines (2) and R-Hydroxy
Aldehydes (3)a
oxidation,16g,27a we obtained (S)-homophenylalanine (10)17a in
enantiomerically pure form (>99% ee). Comparison of 10 with
authentic material confirmed the very high degree of diastereo-
control and the anti selectivity of this process.
Overall, this new synthesis of amino alcohols is practical,
experimentally convenient, and highly versatile, and it proceeds
with very high diastereoselectivity. Further studies on mechanistic
and synthetic aspects as well as combinatorial applications of this
chemistry are currently underway.
Acknowledgment. We gratefully acknowledge the National Institutes
of Health (Grant GM 45970) for support of this research.
Supporting Information Available: Typical experimental procedure
and spectroscopic and analytical data of compounds (17 pages, print/
PDF). See any current masthead page for ordering information and Web
access instructions.
JA981075U
(22) The % ee was established by HPLC and NMR. For example, catalytic
hydrogenation of 4f followed by formation of the Mosher amide and
comparison with the amide derived from the racemic compound 4e using 19
NMR, indicated a single enantiomer.
F
(23) While these compounds are stable and can be isolated, under the
reaction conditions they presumably undergo facile fragmentation to the free
R-hydroxy aldehydes or their adducts.
a Unless otherwise indicated, reactions were performed with racemic
aldehyde in EtOH at 25 °C. All products were obtained with >99% de
and gave satisfactory spectroscopic and analytical data. b In this case,
optically pure substrate was used and the corresponding products were
obtained with >99% ee.
(24) Kim, H.-O.; Friedrich, D.; Huber, E.; Peet, N. P. Synth. Commun.
1996, 26, 3453.
(25) (a) Jurczack, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447. (b)
Matsumoto, T.; Kobayashi, Y.; Takemoto, Y.; Ito, Y.; Kamijo, T.; Harada,
H.; Terashima, S. Tetrahedron Lett. 1990, 31, 4175. (c) Veith, U.; Leurs, S.;
Jager, V. J. Chem. Soc., Chem. Commun. 1996, 329. (d) Cativiela, C.; Diaz-
de-Villegas, M. D.; Galvez, J. A. Tetrahedron: Asymmetry 1996, 7, 529.
(26) (a) Poch, M.; Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1991, 32, 6935. (b) Vidal-Ferran, A.; Moyano, A.; Pericas,
M. A.; Riera, A. J. Org. Chem. 1997, 62, 4970.
(27) (a) Poch, M.; Alcon, M.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781. (b) Castejon, P.; Moyano, A.; Pericas, M.
A.; Riera, A. Tetrahedron 1996, 52, 7063. (c) Kokotos, G.; Padron, J. M.;
Noula, C.; Gibbons, W. A.; Martin, V. S. Tetrahedron: Asymmetry 1996, 7,
857. (d) Alcon, M.; Poch, M.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron: Asymmetry 1997, 8, 2967.
Since aldehyde racemization does not occur under the reaction
conditions, enantiomerically pure (>99% ee)22 amino alcohols
can be obtained by using enantiomerically pure R-hydroxy
aldehydes.20 We have also found (entries 6-10) that this process
works very well with 4-hydroxy-1,3-dioxolanes (5),23 which can
(21) For example, catalytic hydrogenation of 4e followed by treatment of
the resulting free amino alcohol with triphosgene and Hunig’s base, gave an
oxazolidinone with a coupling constant of 8.0 Hz, corresponding to the
expected cis-isomer.14c,15f,i,16f