A direct and efficient stereoconservative procedure for the selective oxidation of N-protected β-amino alcohols

Article abstract of DOI:10.1055/s-2005-871947

An efficient, very simple and eco-friendly procedure has been developed for the synthesis of highly enantioenriched α-amino aldehydes by IBX-mediated oxidation of the corresponding β-amino alcohols. The procedure has been applied to a wide range of substr

Full text of DOI:10.1055/s-2005-871947

2110
LETTER
A Direct and Efficient Stereoconservative Procedure for the Selective
Oxidation of N-Protected b-Amino Alcohols
S
tereoconservative Pro
a
cedure for
r
the Selec
t
tive
O
a
xidation of N-Pro
O
tected
b
-Amino
A
c
lcohols ejo, Jose L. Vicario, Dolores Badía,* Luisa Carrillo, Efraim Reyes
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco-Euskal Herriko Unibertsitatea,
P.O. Box 644, 48080 Bilbao, Spain
Fax +34(94)6012748; E-mail: qopbaurm@lg.ehu.es
Received 6 May 2005
The main problem encountered in most of the reductive
Abstract: An efficient, very simple and eco-friendly procedure has
methods reported is the overreduction to the correspond-
ing alcohols and/or racemization. Alternatively, a wide
variety of methods have been applied to the selective oxi-
been developed for the synthesis of highly enantioenriched a-amino
aldehydes by IBX-mediated oxidation of the corresponding b-ami-
no alcohols. The procedure has been applied to a wide range of
substrates with different side chains and protecting groups showing dation of b-amino alcohols of type 5, in which the main
that the final aldehydes can be obtained in very high yields and with
drawback that has to be overcome is the racemization of
no racemization at the stereogenic center present in the starting
compounds.
the final product during the reaction or isolation. Among
the oxidation methods employed, one of the most widely
used so far has been the Swern oxidation,1,6 which has to
Key words: amino aldehydes, amino alcohols, oxidations, iodine,
green chemistry
be performed under strict adherence to the documented
reaction conditions in order to avoid racemization side
processes. Alternatively, other groups have reported the
use of TEMPO7 and Dess–Martin periodinane (DMP)8 for
Enantiomerically pure a-amino aldehydes 1 are particu-
larly important chiral intermediates in asymmetric synthe-
sis. These compounds are extremely versatile reagents
due to the presence of both the formyl group and a suitably
protected amino functionality. Furthermore, they are
readily available in both enantiomeric forms from the
corresponding a-amino acids. In particular, a-amino
aldehydes are excellent candidates to undergo diastereo-
selective C–C bond forming processes such as Grignard-
type reactions, aldol additions or hetero-Diels–Alder cy-
cloadditions, in which the stereochemistry of the newly
created stereogenic center(s) results efficiently controlled
by the chirality of the starting material, provided that the
appropriate reaction conditions are chosen.
the selective oxidation of N-protected b-amino alcohols.
With these precedents in mind, we decided to explore an
alternative methodology for the preparation of enantio-
pure a-amino aldehydes in a more simple way than the
others reported. In this context, hypervalent iodine
reagents have recently found wide applications in organic
synthesis9 and especially as highly chemoselective oxida-
tion reagents for the conversion of alcohols into aldehydes
(Dess–Martin periodinane itself has already been success-
fully employed in the oxidation of b-amino alcohols).8
Among various iodine(V) reagents, IBX (o-iodoxybenzo-
ic acid) has also found wide applications in this context
because of its high efficiency, easy availability, stability
against moisture or air and its environmentally benign
properties.10
In general, a-amino aldehydes 1 are typically prepared by
reduction of the corresponding a-amino esters 2,1a,2
Weinreb amides 3,1a,3 morpholine amides 44 or related
activated forms of carboxylic acid derivatives.1a,5 An
alternative approach consists of the selective oxidation of
the respective b-amino alcohols 5 (Scheme 1).1
We therefore subjected to several commercially available,
N-protected, enantiomerically pure b-amino alcohols
5a–m to reaction with 3.0 equivalents of IBX in refluxing
ethyl acetate (Scheme 2),11 observing that starting materi-
al was consumed in 1–2 hours. The reaction proceeded
smoothly, affording the wanted a-amino aldehydes as the
only detectable product by TLC, which were isolated as
almost pure products by 1H NMR after simple filtration of
the crude reaction mixture and evaporation of the sol-
vent.12 Nevertheless, the final a-amino aldehydes were
further purified by column chromatography for character-
ization purposes. The ee in which these compounds were
obtained was calculated by chiral HPLC analysis of the
corresponding b-amino alcohols, obtained by reduction of
samples of pure 1a–m with NaBH4 in methanol.
O
O
R1
R2
R1
R2
R1
R2
[H]
[O]
OH
H
X
N
R3
N
N
R3
R3
2 X = OR4
1
5
3 X = N(OMe)Me
4 X = N
O
Scheme 1 The most commonly used approaches to the synthesis of
enantioenriched a-amino aldehydes
As can be seen in Table 1, several b-amino alcohols with
a broad spectrum of different substitution patterns were
tested under these reaction conditions observing that in all
SYNLETT 2005, No. 13, pp 2110–2112
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871947; Art ID: G12505ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
8
.2
0
0
5

LETTER
Stereoconservative Procedure for the Selective Oxidation of N-Protected b-Amino Alcohols
2111
Table 1 Synthesis of a-Amino Aldehydes 1a–m (continued)
O
OH
I
Entry Amino alcohol 5 Product 1
Yield (%)a ee (%)b
O
O
R1
R1
2
3
4
5
82
95
73
74
92
97
98
96
O
OH
H
O
N
N
OH
NHBoc
H
R3
5a–m
R3
R2
R2
AcOEt, reflux
1–2 h
NHBoc
1a–m
5b
5c
1b
1c
1d
Scheme 2
O
OH
NHBoc
H
cases the yields were consistently high and that almost no
racemization was observed in the final products. Remark-
ably, N-Boc-phenylglycinol (5g) yielded cleanly N-Boc-
phenylglycinal (1g), which is known to be one of the most
racemization-prone a-amino aldehydes. In our case it
could be obtained in 80% yield and >99% ee (entry 7)
even after flash column chromatography purification.13
NHBoc
O
H
OH
NHBoc
NHBoc
5d
5e
O
OH
NHBoc
Concerning the protective group tolerance, all the carbam-
ate-type N-protecting groups tested (Boc, Cbz and Fmoc)
showed to be stable under the oxidation conditions. Also
the silyloxy group found in b-amino alcohol 5i and the
N,O-acetal present in amino alcohol 5l were compatible
with these reaction conditions (entries 9 and 12, respec-
tively). On the other hand, the N,N-dibenzylamino deriv-
ative 5m afforded only a complicated mixture of products
(entry 13), which indicates that the benzyl moieties are not
suitable protecting groups to be employed in this reaction.
The case of aldehyde 1l (also known as Garner’s alde-
hyde, entry 12), which is a widely employed chiral inter-
mediate in total synthesis,14 is a remarkable example of
the synthetic applicability of this methodology.
H
NHBoc
O
1e
1f
6
7
97
80
>99
>99
OH
NHBoc
H
NHBoc
5f
O
H
OH
NHBoc
NHBoc
5g
1g
8
9
74
97
99
98
OH
O
N
N
Boc
Boc
H
The main advantage of this methodology over the others
reported, especially the Swern oxidation, lies in the fact of
the simplicity of the methodology. The experimental pro-
tocol is simple, does not require special equipment, nor
strictly controlled reaction conditions, it can be performed
under open atmosphere, requiring short reaction times and
the isolation of the final product is performed by simple
filtration of the crude reaction mixture followed by evap-
oration of the solvent. Besides, it has to be pointed out that
the methodology is eco-friendly, due to the ‘green’ char-
acter of the oxidation reagent. This is an additional advan-
tage of this methodology if compared with the Swern
oxidation protocol, in which the production of malodor-
ous waste compounds precludes in most cases its utiliza-
tion on high scale. A good example of this can be found in
the preparation of Garner’s aldehyde 1l, which has been
prepared by Swern15 and TEMPO7b oxidation of 5l in
comparable yield and enantiomeric excess than those re-
ported herein, but using much more complicated experi-
mental protocols.
5h
1h
O
TBSO
OH
NHBoc
TBSO
H
5i
NHBoc
1i
10
11
12
82
95
95
96
>99
>99
O
OH
NHFmoc
H
NHFmoc
O
5j
1j
OH
NHCbz
H
5k
O
NHCbz
1k
O
O
OH
NBoc
H
NBoc
5l
1l
13
Decomp.
–
–
OH
NBn2
5m
Table 1 Synthesis of a-Amino Aldehydes 1a–m
a Yield of pure product after flash column chromatography purifica-
tion.
Entry Amino alcohol 5 Product 1
Yield (%)a ee (%)b
89 92
b Calculated by chiral HPLC of the corresponding b-amino alcohols
5a–l obtained by NaBH4 reduction of crude aldehydes (chiralcel OD
column, UV detector, hexanes–i-PrOH 9:1, flow rate 1.00 mL/min.).
1
O
OH
NHBoc
H
NHBoc
5a
1a
Synlett 2005, No. 13, 2110–2112 © Thieme Stuttgart · New York

2112
M. Ocejo et al.
LETTER
(8) (a) Wroblewski, A. E.; Piotrowska, D. G. Tetrahedron:
In conclusion, we have presented a very simple new meth-
odology for the preparation of highly enantioenriched N-
protected a-amino aldehydes using the IBX oxidation of
the corresponding b-amino alcohols. This methodology
affords excellent yields and, remarkably, proceeds with
almost no racemization in the stereogenic center present at
the starting material, which is a problem commonly found
in other methodologies reported for the synthesis of a-
amino aldehydes. In view of the wide number of com-
pounds amenable to be prepared in this way due to the
broad substrate tolerance shown by the reaction, it can be
anticipated that this methodology will be of broad interest
to the chemical community.
Asymmetry 2002, 13, 2509. (b) Myers, A. G.; Zhong, B.;
Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S.
Tetrahedron Lett. 2000, 41, 1359.
(9) Reviews: (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002,
102, 2523. (b) Nicolaou, K. C.; Baran, P. S. Angew. Chem.
Int. Ed. 2002, 41, 2678. (c) Wirth, T. Angew. Chem. Int. Ed.
2001, 40, 2812.
(10) See: (a) Moore, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
See also: (b) Moorthy, J. N.; Singhal, N.; Venkatakrishnan,
P. Tetrahedron Lett. 2004, 45, 5419. (c) Yadav, J. S.;
Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Tetrahedron
2004, 60, 2131. (d) Liu, Z.; Chen, Z.-C.; Zheng, Q.-G. Org.
Lett. 2003, 5, 3321. (e) Surenda, K.; Krishnaveni, N. S.;
Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem.
2003, 68, 2058. (f) Karthikeyan, G.; Perumal, P. T. Synlett
2003, 2249. (g) Bose, D. S.; Gurjar, S. M. K. Tetrahedron
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Santagostino, M. J. Org. Chem. 1996, 61, 9272. (i) A
polymer-supported IBX-derived reagent has also been
applied in the oxidation of alcohols: Sorg, G.; Mengel, A.;
Jung, G.; Rademann, J. Angew. Chem. Int. Ed. 2001, 40,
4395. (j) For an overview of the use of IBX in other
oxidative transformations see: Nicolaou, K. C.; Mathison, C.
J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192; and
references therein.
Acknowledgment
The authors thank the University of the Basque Country (Subven-
ción General a Grupos de Investigación, and a fellowship to M.O.
and E.R.) and the Spanish Ministerio de Ciencia y Tecnología
(Project BQU2002-00488) for financial support.
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the mixture was refluxed for 2 h opened to the atmosphere.
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Synlett 2005, No. 13, 2110–2112 © Thieme Stuttgart · New York