Double stereodifferentiation in the "acetate-type" aldol reaction with Garner's aldehyde. Stereocontrolled synthesis of polyhydroxylated γ-amino carbonyl compounds

Article abstract of DOI:10.1021/ol0487433

(Chemical Equation Presented) The aldol reaction of acetamide enolates with protected chiral α-amino-β-hydroxy aldehyde 1 (Garner's aldehyde) has been performed in a stereocontrolled way under double stereodifferentiation conditions using pseudoephedrine

Full text of DOI:10.1021/ol0487433

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3171-3174
Double Stereodifferentiation in the
“Acetate-Type” Aldol Reaction with
Garner’s Aldehyde. Stereocontrolled
Synthesis of Polyhydroxylated γ-Amino
Carbonyl Compounds
Jose L. Vicario, Mo´nica Rodriguez, Dolores Bad´ıa,* Luisa Carrillo, and
Efraim Reyes
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, UniVersidad del Pa´ıs
Vasco-Euskal Herriko Unibertsitatea, P.O. Box E-644, 48080 Bilbao, Spain
qopbaurm@lg.ehu.es
Received July 2, 2004
ABSTRACT
The aldol reaction of acetamide enolates with protected chiral r-amino-â-hydroxy aldehyde 1 (Garner’s aldehyde) has been performed in a
stereocontrolled way under double stereodifferentiation conditions using pseudoephedrine as the additional chiral information source attached
to the enolate reagent. In addition, the obtained adduct has been transformed into other valuable chiral building blocks such as γ-amino-
â,δ-dihydroxy acids, esters, and ketones.
The stereoselective construction of molecules containing
sequences of contiguous heterosubstituted stereocenters is a
challenging task for the synthetic organic chemist. The
significance of this structural motif relies upon the fact that
it is widespread in natural products and synthetic drugs.
An easy and direct approach to some of these targets
consists of the nucleophilic addition of different nucleophiles
to R-heterosubstituted chiral aldehydes, in which the chiral
information present at the aldehyde should exert the required
degree of stereocontrol.1 In this context, many differently
protected R-amino and R-alkoxy aldehydes have been tested
in reactions with several nucleophiles, normally proceeding
with good levels of diastereoselection.2 Despite this, the
particular case in which an R-unsubstituted enolate is
subjected to addition to this kind of aldehydes, also known
as “acetate-type” aldol addition (Scheme 1), has not attracted
so much attention, mainly because of the low diastereo-
selectivities usually obtained,3 although in some particular
Scheme 1. Diastereoselective “Acetate-Type” Enolate Addition
on R-Heterosubstituted Chiral Aldehydes
(1) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191. See also:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
10.1021/ol0487433 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004

cases this problem has been circumvented by protective
group tuning.
the particular case of R-unsubstituted enolate nucleophiles,
it is difficult to find examples in which the reaction proceeded
with a complete degree of diastereoselection, and mixtures
of the two possible diastereoisomers have been usually
obtained. In fact, only two papers can be found in the
literature for this reaction, both reporting moderate dia-
stereoselectivities.7 A convenient way of resolving this
problem in other cases has consisted of the introduction of
additional chiral information, under typical double stereo-
differentiation conditions.8 However, as far as we know, this
approach has never been applied to the acetate aldol reaction
with aldehyde 1.
In this context and in connection with our ongoing program
directed toward the development of new procedures for the
asymmetric synthesis of natural products and new drugs, we
have been pursuing a procedure for the stereocontrolled
synthesis of polyhydroxylated amino acids and ketones. In
particular, the asymmetric synthesis of γ-amino-â-hydroxy
acids is of key relevance because they are peptide compo-
nents that act as protease inhibitors of aspartic acid,4 which
activity has been shown to be highly dependent upon the
configuration of the stereogenic centers present in the
molecule.5
With these precedents in mind we thought about the
possibility of carrying out this “acetate” aldol reaction under
double asymmetric induction conditions using the chiral
amino alcohols (S,S)-(+)- or (R,R)-(-)-pseudoephedrine
incorporated at the enolate reagent as second stereodiffer-
entiating chiral component (Scheme 2). This amino alcohol
has been successfully used by our group in aldol reactions
with substituted enolates (propionamide enolates).9 Remark-
able features of the use of this auxiliary rely upon the fact
that it is a cheap reagent, commercially available in both
enantiomeric forms. Additional advantages of the use of this
auxiliary are related to the unique reactivity of the amide
function present in the obtained adducts, which allows the
preparation of a wide range of other interesting chiral
building blocks.10
An easy and direct approach to these targets (Scheme 2)
Scheme 2. Diastereoselective Addition of Acetamide Enolates
on Chiral Aldehyde 1
We therefore subjected aldehyde 1 to aldol addition with
the lithium enolate of (R,R)-(-)- and (S,S)-(+)-pseudo-
ephedrine acetamides (R,R)-2a and (S,S)-2a (Scheme 2),
obtaining the expected â-hydroxyamide adducts (R,R)-3 and
(S,S)-3 in good yields and in 96% and 12% de, respectively.11
To test the degree of simple asymmetric induction exerted
by the aldehyde, we also tested the reaction using N,N-
diethylacetamide 2b as the enolate source. As expected, the
diastereoselectivity observed was much lower in this case
(see Scheme 2). These results indicate that a double
asymmetric induction process was operating, allowing us to
establish that (R,R)-2a and aldehyde 1 constitute the matched
consists of the nucleophilic addition of enolates to an
R-heterosubstituted chiral aldehyde 1,1-dimethylethyl 4-formyl-
2,2-dimethyloxazolidine-3-carboxylate, 1 (also known as
Garner’s aldehyde),6 which is commercially available in
highly enantioenriched form and configurationally stable.
Although this reaction has been studied by some groups, in
(6) Review: Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin
Trans. 1 2001, 2136. Some additional examples from past years: (b)
Nakagawa, M.; Uchida, H.; Ono, K.; Kimura, Y.; Yamabe, M.; Watanabe,
T.; Tsuji, R.; Akiba, M.; Terada, Y.; Nagaki, D.; Ban, S.; Miyashita, N.;
Kano, T.; Theeraladanon, C.; Hatakeyama, K.; Arisawa, M.; Nishida, A.
Heterocycles 2003, 59, 721. (c) Starkmann, B. A.; Young, D. W. J. Chem.
Soc., Perkin Trans. 1 2002, 725. (d) Ma, D.; Yieng, J. J. Am. Chem. Soc.
2001, 123, 9706
(7) Acetate aldol additions with aldehyde 1: (a) Dondoni, A.; Merino,
P. J. Org. Chem. 1991, 56, 5294. (b) Garner, P.; Ramakanth, S. J. Org.
Chem. 1986, 51, 2609. For other examples of acetate aldol addition to N-Boc
R-amino aldehydes, see: (c) Palomo, C.; Oiarbide, M.; Garcia, J. M.;
Gonzalez, A.; Pazos, R.; Odriozola, J. M.; Ban˜uelos, P.; Tello, M.; Linden,
A. J. Org. Chem. 2004, 69, 4126 and references therein.
(8) Reviews: (a) Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953. (b)
Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int.
Ed. 1985, 24, 1.
(9) (a) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Tetrahedron: Asymmetry
2003, 14, 489. (b) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez,
M.; Carrillo, L. J. Org. Chem. 2000, 65, 3754.
(2) For some reviews, see: (a) Gryko, D.; Chalko, J.; Jurczak, J. Chirality
2003, 15, 514. (b) Alcaide, B.; Almendros, P. Chem. Soc. ReV. 2001, 30,
226. (c) Reetz, M. T. Chem. ReV. 1999, 99, 1121. (d) Juczak, J.;
Golebiowski, A. Chem. ReV. 1989, 89, 149.
(3) Reviews on the asymnetric aldol reaction: (a) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem. Soc. ReV. 2004, 33, 65. (b) Palomo, C.; Oiarbide,
M.; Garcia, J. M. Chem. Eur. J. 2002, 8, 37. (c) Alcaide, B.; Almendros,
P. Eur. J. Org. Chem. 2002, 1595. (d) Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352. (e) Arya, P.; Quin, H. Tetrahedron
2000, 56, 917. (f) Mahrwald, R. Chem. ReV. 1999, 99, 1095. (g) Carreira,
E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 3, p 997. (h)
Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. (i) Braun, M. In
StereoselectiVe Synthesis, Houben-Weyl; Helmchen, G., Hoffmann, R.,
Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. E21/3, p
1603. (j) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. For an excellent
discussion about the problems of the acetate-type aldol reaction, see: (k)
Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. See also ref 3a and
b.
(10) See, for example: (a) Myers, A. G.; Yang, B. H.; Chen, H.;
McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997,
119, 6496. See also ref 9b.
(11) Diastereomeric excesses were determined by HPLC analysis of crude
reaction mixtures (see Supporting Information).
(4) (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. See also:
(b) Cooke, J. W. B.; Davies, S. G.; Naylor, A. Tetrahedron 1993, 49, 7955
and references cited therein.
(5) Liu, W.-S.; Smith, S. C.; Glover, G. I. J. Med. Chem. 1979, 22, 577.
3172
Org. Lett., Vol. 6, No. 18, 2004

combination of reagents and (S,S)-2a and 1 are the mis-
matched couple.
One of the most significant features of pseudoephedrine
amides is that the amide moiety is able to undergo fast and
clean 1,2-addition of organolithium reagents, affording the
corresponding ketones after aqueous workup.13 This moiety
has shown a behavior comparable in this context to that of
Weinreb amides. Therefore, we proceeded to apply these
conditions to the adduct (Scheme 5), observing that, to our
We proceeded next to the transformation of the obtained
enantiopure adducts into the target γ-amino carbonyl com-
pounds. The first transformation performed was the removal
of the chiral auxiliary by base hydrolysis, which proceeded
in excellent yield and no racemization, regardless the
configuration of the auxiliary (Scheme 3). Remarkably, both
Scheme 5
Scheme 3
delight, this densely highly functionalized compound behaved
as we expected, thus opening a direct way for the preparation
of many enantiopure γ-amino-â,δ-dihydroxy ketones 9, in
excellent yields (Table 1).
chiral auxiliaries (S,S)-(+) and (R,R)-(-)-pseudoephedrine
could be easily recovered after this hydrolysis step by
standard acid-base workup, which allowed their recycling
for further uses. Next, the acids 5 were esterified with
TMSCHN2,12 furnishing methyl esters 6.
At this point, to determine the absolute configuration of
the new stereogenic center created in the aldol addition step,
we converted amide (R,R)-3 into the cyclic derivative 7 by
first performing a selective N,O-acetal cleavage followed by
protection of the diol moiety in the form of a cyclic acetal
(Scheme 4). Unfortunately, NMR spectra of cyclic derivative
Table 1. Synthesis of γ-Amino-â,δ-dihydroxy Ketones 9a-f
entry
ketone
R
yield (%)a
1
2
3
4
5
6
9a
9b
9c
9d
9e
9f
Me
Et
i-Pr
n-Bu
t-Bu
Ph
94
88
87
89
71
68
a Yield of product after flash column chromatography purification.
As can be observed in Table 1, a wide range of organo-
lithium reagents are acceptable regardless of their structure,
and therefore primary, secondary, and even tertiary alkyl-
lithium reagents, as well as phenyllithium, underwent clean
1,2-addition, with no evidence of competitive aldolization
at the two highly acidic R-protons of the substrates under
these extremely basic conditions. It has also to be pointed
out that, again, the chiral auxiliary (R,R)-(-)-pseudo-
ephedrine could be easily recovered after standard acid-
base work up and was recycled for further uses.
Scheme 4
In conclusion, the amino alcohol pseudoephedrine has been
shown to be an excellent auxiliary for the asymmetric acetate
reaction with chiral R-amino-â-hydroxy aldehyde 1 under
double stereodifferentiation conditions, which otherwise
furnishes low diastereoselectivities if achiral enolates are
employed. We have found that (R,R)-(-)-pseudoephedrine
amide enolate and aldehyde 1 constitute the corresponding
matched combination of reagents, furnishing the aldol adducts
in excellent yield and diastereoselectivity. In addition, the
pseudoephedrine amide moiety remaining at the aldol ad-
dition product has been demonstrated to be an extremely
7 was too complicated for any structural elucidation experi-
ment because of the presence of the amide moiety, and
therefore this derivative was subjected to a hydrolysis/
esterification sequence in order to afford the ester 8. NOESY
experiments on this derivative indicated the anti relative
configuration of the â-hydroxy-γ-amino moiety.
(12) Hashimoto, N. Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475.
(13) See refs 9b and 10. See also Vicario, J. L.; Badia, D.; Carrillo, L.
Tetrahedron: Asymmetry 2002, 13, 745.
Org. Lett., Vol. 6, No. 18, 2004
3173

versatile functionality for its conversion into many interesting
densely functionalized chiral building blocks such as γ-amino-
â,δ-dihydroxy acids esters and ketones. An additional advan-
tage of the use of this auxiliary was found in the recyclability
of the amino alcohol after cleavage from the adducts.
Note Added after ASAP Posting. Scheme 3 was inad-
vertently duplicated as Scheme 4 in the version posted ASAP
July 30, 2004; the corrected version was posted August 5,
2004.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and characterization of
γ-amino-â,δ-dihydroxy amide (R,R)-3, acid 5, ester 6, and
ketones 9a-f. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank the University of
the Basque Country (Subvencio´n General a Grupos de
Investigacio´n, UPV 170.310-13546/2001 and a fellowship
to E.R.) and the Spanish Ministerio de Ciencia y Tecnolog´ıa
(Project BQU2002-00488 and a fellowship to M.R.) for
financial support.
OL0487433
3174
Org. Lett., Vol. 6, No. 18, 2004