Organocatalytic asymmetric synthesis of α,α-disubstituted α-amino acids and derivatives

Article abstract of DOI:10.1021/ja804567h

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to α,β-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted α,β-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active α,α- disubstituted α-amino acids, α-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the α,β-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the α,β-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic α,β-unsaturated aldehydes.

Full text of DOI:10.1021/ja804567h

Published on Web 08/13/2008
Organocatalytic Asymmetric Synthesis of r,r-Disubstituted
r-Amino Acids and Derivatives
Silvia Cabrera, Efraim Reyes, Jose´ Alema´n, Andrea Milelli, Sara Kobbelgaard, and
Karl Anker Jørgensen*
Danish National Research Foundation: Center for Catalysis, Department of Chemistry, Aarhus
UniVersity, DK-8000 Aarhus C, Denmark
Received April 3, 2008; E-mail: kaj@chem.au.dk
Abstract: It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary
amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to R,ꢀ-unsaturated
aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is
demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and
different aromatic and aliphatic substituted R,ꢀ-unsaturated aldehydes, for which the stereoselective reaction
proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity.
The potential of the reaction is shown for the synthesis of optically active R,R-disubstituted R-amino acids,
R-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have
calculated by DFT-methods the transition-state structures that account for both the diastereo- and
enantioselectivity observed for the addition of oxazolones to the R,ꢀ-unsaturated aldehydes. For one class
of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of
the oxazolone with an ortho-hydroxy-phenyl substituent of the R,ꢀ-unsaturated aldehyde, whereas the
benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more
general manner for both aromatic and aliphatic R,ꢀ-unsaturated aldehydes.
Introduction
methodologies for the asymmetric synthesis of these valuable
optically active compounds. One of the challenges is to have
The synthesis of non-natural amino acids and their derivatives,
as well as the design of peptides and proteins, is an area of
great interest in biological and medicinal chemistry.1 A particular
class of non-natural amino acids, which has received consider-
able interest, is the R,R-disubstituted (quaternary) R-amino
acids.2 There are several reasons for the importance of these
R,R-disubstituted R-amino acids, such as stability toward
racemization in ViVo and restricted conformational flexibility.
The latter property is highly important for, for example, the
secondary structure of proteins, which can lead to an improve-
ment of the resistance against chemical and enzymatic degrada-
tion.3 Furthermore, R,R-disubstituted R-amino acids are also
present in many biologically active compounds and some
antibiotics, such as altemicidin.4
procedures that provide flexible and simple methods for
obtaining optically active R,R-disubstituted R-amino acids and
that, furthermore, give diversity in structural and electronic
properties.
A classical procedure for the synthesis of R-amino acid
derivatives5 is the Strecker reaction6 (eq 1, right part, Scheme
1). This reaction is well-established for the asymmetric synthesis
of chiral R-substituted amino acids starting from aldimines;
however, the synthesis of chiral R,R-disubstituted R-amino acids
using ketimines is now in progress and shows some limitations.7
These limitations are related to the lower reactivity and easy
enolization of the ketimines, as well as the difficulties to
synthesize the starting compounds. A more recent approach for
the preparation of optically active R,R-disubstituted R-amino
acids is the alkylation of imines derived from Schiff bases with
chiral phase-transfer catalysis (eq 1, left part, Scheme 1).8
The importance of R,R-disubstituted R-amino acids has
caused an increased interest in the development of efficient
(1) Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. ReV. 2001,
101, 3131.
One of the less explored methods to obtain chiral R,R-
disubstituted R-amino acids is the use of oxazolones as a masked
(2) For reviews on synthesis of R,R-disubstituted R-amino acids, see, for
example:(a) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 3517. (c) Ohfune, Y.; Shinada, T.
Eur. J. Org. Chem. 2005, 5127. (d) Vogt, H.; Bra¨se, S. Org. Biomol.
Chem. 2007, 5, 406.
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see:Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584.
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9
10.1021/ja804567h CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 12031–12037 12031

A R T I C L E S
Cabrera et al.
Scheme 1. Two Classic Different Approaches for the Synthesis of R,R-Amino Acids (eq 1) and the Alternative Organocatalytic Asymmetric
Synthesis of R,R-Disubstituted R-Amino Acids (eq 2)
amino acid fragment.9 These compounds have been applied for,
for example, the synthesis of R,R-disubstituted R-amino acids
by ring-opening reactions of chiral quaternary oxazolones,
generated by the Steglich reaction,10 as electrophile source,
whereas the application of oxazolones as nucleophiles is mainly
restricted to alkylation by metal catalysis.11
In the past few years, organocatalysis has been intensively
studied.12 During the recent rise in the development of new
organocatalytic methodologies, asymmetric 1,4-conjugate/
Michael additions have emerged as efficient and environmentally
friendly processes for the synthesis of optically active organic
compounds.13 In this field, secondary amines have demonstrated
to be one of the most successful type of organocatalysts that
allow the sequential functionalization of aldehydes or R,ꢀ-
unsaturated aldehydes, via enamine-14 or iminium-ion interme-
diates,15 in combination with electrophiles or nucleophiles,
respectively. Furthermore, two new conceptssdienamine16 and
SOMO organocatalysis17shave emerged.
Here we will demonstrate a new development in organoca-
talysis, that racemic oxazolones can act as excellent reagents
for the synthesis of chiral quaternary amino acids by nucleophilic
addition to R,ꢀ-unsaturated aldehydes.18 This new reaction leads
to R,R-disubstituted R-amino acid derivatives with two new
chiral centers in a one-step synthesis (eq 2, Scheme 1), that is,
to both control the stereocenter formed from ꢀ-carbon atom in
the R,ꢀ-unsaturated aldehyde and the C-4 carbon atom in the
racemic oxazolone. To the best of our knowledge, this is the
first organocatalytic Michael addition of oxazolones. The use
of oxazolones for these reactions adds a further potential to
organocatalysis, as the oxazolones contain orthogonal reactive
sites that make them excellent substrates for their use in diversity
oriented synthesis.19 On the basis of this concept, we will also
show that the optically active compounds formed undergo a
number of diverse transformations leading to the formation of
optically active R,R-disubstituted R-amino acids, R-quaternary
proline derivatives, amino alcohols, lactams, and tetrahydropy-
ranes. Furthermore, we will present these by using DFT-
calculations transition-state models, which account for the
(9) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. ReV. 2007, 36, 1432.
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A. Angew. Chem., Int. Ed. 2008, 47, 4638.
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Bertelsen, S.; Dine´r, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem.
Soc. 2007, 129, 1536. (b) Dine´r, P.; Nielsen, M.; Marigo, M.;
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Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Angew. Chem., Int.
Ed. 2007, 46, 4504. (e) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.;
Erikson, L.; Himo, F.; Co´rdova, A. Angew. Chem., Int. Ed. 2007, 46,
4507. (f) Maerten, E.; Cabrera, S.; Kjærsgaard, A.; Jørgensen, K. A.
J. Org. Chem. 2007, 72, 8893. (g) Gotoh, H.; Ishikawa, H.; Hayashi,
Y. Org. Lett. 2007, 9, 5307. (h) Fustero, S.; Jime´nez, D.; Moscardo,
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107, 5416.
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Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Almas¸i, D.;
Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (c)
Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065.
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Ed. 2007, 46, 609. (b) Brauman, T.; Vogt, H.; Bra¨se, S. Eur. J. Org.
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MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
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9
12032 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Synthesis of R,R-Disubstituted R-Amino Acids and Derivatives
A R T I C L E S
Table 1. Reaction of R,ꢀ-Unsaturated Aldehydes 1 with Racemic
Oxazolone rac-2aa
Table 2. Reaction of R,ꢀ-Unsaturated Aldehyde 1e with Racemic
Oxazolones 2a
yield
(%)c
ee
(%)d
entry
R1
R2/R3
drb product
entry
R1
drb
product
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
Et (1e)
Et (1e)
Et (1e)
Et (1e)
Et (1e)
Et (1e)
Et (1e)
Et (1e)
n-Pr (1f)
i-Pr/Ph (2b)
Ph/Tol (2c)
Bn/Ph (2d)
Me/Ph (2e)
Me/CHPh2 (2f)
Ph/t-Bu (2g)
i-Bu/o-ClPh (2h) 2:1
MeS(CH2)2/Ph (2i) 3:1
Me/CHPh2 (2f)
Me/CHPh2 (2f)
Me/CHPh2 (2f)
Me/CHPh2 (2f)
1.2:1 4j 81e (73) 96
7:3
3:1
5:1
4k 85
4l 75
4m 65f
93
96
93
96
91
88
94
93
94
90
94
92
94
1
2
3
4
5
6
7
8
9
Ph (1a)
1:1
3:1
>20:1 4c
3:1
4:1
7:3
3:1
4a/4a′ 46
4b
92/90
93
86
o-NO2-C6H4 (1b)
o-OH-C6H4 (1c)
Me (1d)
72
36e
82
>10:1 4n 64f
4d
4e
4f
4g
4h
4i
91
94
5:2
4o 71g
4p 54
4q 73
Et (1e)
n-Pr (1f)
91
88 (56)f
87
83 (84)f
92
Hepthyl (1g)
(Z)-n-Hex-3-enyl (1h) 2:1
BnOCH2 (1i) 2:1
>10:1 4r 40
76
93
84
53g
10 Ph (1a)
11 Me (1d)
12 Hexyl (1j)
13 (E)-Prop-1-enyl (1k) Me/CHPh2 (2f)
14 (Z)-Hex-3-enyl (1h) Me/CHPh2 (2f)
6:1
5:1
4s 47
4t 59
a All reactions were performed on a 0.2 mmol scale in 0.2 mL of
toluene. b Diastereoisomeric ratio determined by 1H NMR spectroscopy
of the crude mixture. c Overall yield of both diastereoisomers after FC.
d Determined by HPLC of the major diastereoisomer after derivatization
(see the Supporting Information). e Overall yield of the major
diastereoisomer after derivatization into 5. f Reaction performed in a 4
mmol scale. g Yield of the major diastereoisomer after FC.
>10:1 4u 52
>10:1 4v 55
>10:1 4w 38
a All reactions were performed on a 0.2 mmol scale in 0.2 mL of
toluene. b Diastereoisomeric ratio determined by 1H NMR spectroscopy
of the crude mixture. c Overall yield of both diastereoisomes after FC.
d Determined by HPLC of the major diastereoisomer after derivatization
(see the Supporting Information). e Conversion yield determined by 1H
NMR. f Yield of the major diastereoisomer after FC. g Overall yield of
both diastereoisomers after derivatization into 5.
diastereo- and enantioselectivity observed for the different
classes of R,ꢀ-unsaturated aldehydes and oxazolones applied.
control, giving the corresponding products 4d-g in high yields
and enantioselectivities in the range of 83-94% ee (entries
4-7). The reaction could also be scaled up to 4 mmol scale,
with only a slight decrease in the yield, but maintaining the
enantio- and diastereoselectivity at high levels (entry 6). The
catalytic system is also compatible with functionalized alkyl
chains containing double bond or benzyl ether functionalities
(entries 8, 9), obtaining in both cases good enantioselectivities.
Encouraged with these results we studied the addition of
different oxazolones to pentenal 1e (Table 2). The reason for
choosing different oxazolones is to show one of the potentials
of these reactions as changing the R2-substituent in the ox-
azolone to alkyl, benzyl, and aryl will give R,R-disubstituted
R-amino acid derivatives having alkyl/alkyl, alkyl/benzyl, and
alkyl/aryl groups at the quaternary stereocenter, all of them are
very difficult to obtain by only one methodology. Thus, at the
C-4 atom in the oxazolone could be placed an alkyl chain (i-
Pr, 2b) or an aromatic group (Ph, 2c), or a benzyl (2d) leading
in all cases to >90% ee (entries 1-3). In a similar manner,
different substituents could also be placed at the C-2 position
in the oxazolone, as aromatic groups (2e,h), benzhydryl (2f),
or alkyl (2g). For these oxazolones, the optically active products
were obtained with good enantioselectivities and up to >10:1
dr (entries 4-7). Furthermore, more functionalized oxazolones,
such as the methionine derivative 2i, can also be added to 1e to
obtain the corresponding product 4q in 94% ee (entry 8). It
appears from Table 2, entry 5 that the oxazolone having the
benzhydryl group (2f) increased the diastereoselectivity signifi-
cantly and this result prompted us to investigate if we can
improve the diastereoselectivity in a more general manner of
the reactions giving low diastereoselectivity.
Results and Discussion
Our initial screening showed two main observations: (a) the
best results were achieved using 10 mol% of (S)-2-[bis(3,5-
bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine 3
as the catalyst20 and toluene as solvent at room temperature
(see Table SI-1 of Supporting Information for further details);
(b) the new stereocenter created in the R,ꢀ-unsaturated aldehyde
counterpart could be completely controlled, whereas control of
the stereocenter generated in the oxazolone counterpart was
more difficult. However, these difficulties were solved by
choosing the appropriate protecting group in the oxazolone (see
below).
Thus, with the optimized conditions in hand we studied the
scope of the reaction and in Table 1 are shown the results
obtained using different R,ꢀ-unsaturated aldehydes and rac-2a
as the nucleophile. The use of cinnamaldehyde 1a gave a 1:1
mixture of separable diastereoisomers 4a/4a′ with g90% ee for
both compounds (Table 1, entry 1). The use of different ortho-
substituents at the aryl group as an electron-withdrawing group
(1b) or an electron-donating group (1c) increased the diaste-
reoselectivity up to >20:1 with an enantioselectivity up to 93%
ee (entries 2, 3). Alkyl substituted R,ꢀ-unsaturated aldehydes
also reacted giving good stereoselectivities (entries 4-7). Thus,
short alkyl chains as methyl, ethyl, and propyl or longer chains,
such as hepthyl, could be used without losing enantioselective
(20) For the first application of diarylprolinol silyl ethers as catalysts, see:
(a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem. Int. Ed 2005, 44, 794. See also: (b) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. (c) Hayashi, Y.; Gotoh, H.; Hayashi,
T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (d) Franze´n, J.;
Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 18296. (e) Palomo, C.; Mielgo,
A. Chem. Asian J. 2008, 3, 922.
We then carried out the addition of six different R,ꢀ-
unsaturated aldehydes, aryl (1a), three alkyl (1d,f,j), and two
containing a double bond in different positions (1k,h). The
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12033

A R T I C L E S
Cabrera et al.
Scheme 2. Transformation to Alkenes 5 from Oxazolones 4 and Formation of Amino Acid Derivative 6
Scheme 3. Transformation of Oxazolone Alkenes 5 to Amino Acid Esters 7 by Treatment with TMSCl
Scheme 4. Synthesis of Proline-derivatives 8 from Aldehydes 4
reason for using 1a was that this substrate gave no diastereo-
selectivity (Table 1, entry 1), whereas the other R,ꢀ-unsaturated
aldehydes were used to expand the scope and to show the ability
to control the diastereoselectivity of the reaction. We were
pleased to find that the use of oxazolone 2f gave a significant
improvement in the diastereoselectivity in all cases (Table 2,
entries 9-14); for cinnamaldehyde 1a, the diastereomeric ratio
improved from 1:1 to 6:1 and the major diastereomer was
formed with 94% ee (entry 10). For the alkyl derivatives, and
those having a double bond in the alkyl chain, 1d,f,j and 1k,h,
respectively, the obtained diastereoselectivity was improved (up
to >10:1) and excellent enantioselectivity was also obtained
(entries 9,11-14).
The results in Tables 1 and 2 show that we can control the
formation of two new stereocenters, a tertiary and a quaternary,
by the proper choice of the C2-protecting group of the
oxazolones, demonstrating the synthetic potential of this new
asymmetric organocatalytic addition of oxazolones to R,ꢀ-
unsaturated aldehydes.
Product Elaborations. The optically active products are
important starting points for different transformations leading
to a diverse number of compounds useful in various fields in
life-science. In the following, we will demonstrate some of these
transformations.
In most of the cases, the optically active major diastereoi-
somer products 4 could be isolated with Iatrobeads. For
analytical purposes it was most convenient to convert 4 into 5
(Scheme 2), as the latter compounds were much easier to
identify for enantiomeric excess determination by HPLC. One
of the oxazolones (5l) was hydrolyzed to the corresponding
protected amino acid 6 using HCl (conc.) in CH3CN in moderate
yield at room temperature.
yield, respectively, with 3 stereocenters as only one diastere-
oisomer.21 These proline derivatives, have a quaternary stereo-
center in position 2, an alkyl group in position 3 and a hydroxy
group in position 5, and are synthesized in only two steps
following this methodology (Scheme 4). Furthermore, these
types of compounds, L-glutamate semialdehydes derivatives, are
intermediates in the synthesis of carbapenem antibiotics.22
The four reactions in Schemes 2–4 show the scope of this
new organocatalytic methodology for the preparation of highly
functionalized optically active R,R-disubstituted R-amino acid
derivatives in a few steps.
To obtain a suitable crystal for X-ray analysis, we carried
out the addition of p-tosylhydrazine to the aldehyde 4f and
subsequent recrystallyzation of the resulting solid led to a 1:1
mixture of lactams 9a and 9b as aminal and hemiaminal,
respectively (Scheme 5). These types of structures, the 3-amino-
6-hydroxy-2-piperidone unit, have been found as a constituent
in more than 60 cyclic depsipeptides derived from cyanobac-
teria.23
The structures could be obtained by two presumable different
pathways. In both cases, the aldehyde and the hydrazine were
condesed to form I (Scheme 5). In path a, the corresponding
aminal is formed first (intermediate II), which proceeds by an
intramolecular attack to open the oxazolone giving 9a. In path
b, the imine opens the oxazolone to generate III by intramo-
lecular attack. The iminium intermediate III was then attacked
by another hydrazine molecule to give 9a. Finally, we believe
that aminal 9a is in equilibrium with 9b via an iminium
intermediate.
Finally, we determined the absolute configuration by X-ray
analysis of compounds 9a and 9b which were crystallized as a
To obtain the amino acid esters derived from 5, a series of
different products having alkyl chains as R1-R3 and also
aromatic as R3 were treated with TMSCl in MeOH to afford
the R,R-disubstitued N-protected R-amino acid derivatives 7 in
good yields (50-99%) without losing enaniopurity compared
to the starting material (Scheme 3).
(21) The pyrrolidines 8 were obtained as only one diastereoisomer,
determined by 1H NMR spectroscopy of the crude mixture. However
during the purification process by flash chromatography the epimer-
ization of the hemi-aminal center was observed (see Supporting
Information for more details).
(22) Stapon, A.; Li, R.; Townsend, C. A. J. Am. Chem. Soc. 2003, 125,
8486.
Direct treatment of 4f and 4p with TMSCl in MeOH afforded
the N-protected proline derivatives 8a and 8b in 71% and 90%
(23) Yokokawa, F.; Inaizumi, A.; Shioiri, T. Tetrahedron 2005, 61, 1459.
9
12034 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Synthesis of R,R-Disubstituted R-Amino Acids and Derivatives
Scheme 5. Synthesis of δ-Lactams from Aldehydes 4
A R T I C L E S
Scheme 7. Catalytic Cycle for the Addition of Oxazolones 2 to
Aldehydes 1
Figure 1. X-ray structure of compound 9b.
Scheme 6. Synthesis of Amino Alcohol Derivatives 10 and
Tetrahydropyranes 11 by Reduction of Alkenes 5
when the reduction was maintained for 24 h at room temper-
ature, the alcohol derivatives 10 undergo an intramolecular
Michael reaction to the tetrahydropyranes 11. This reaction
proceeds smoothly in good yield and the products were obtained
as only one diastereoisomer with three chiral centers without
losing enantiopurity (Scheme 6). We have shown that 10 is an
intermediate for the formation of 11, because the treatment of
10a with NaBH4 in MeOH leads to 11a in 72% yield.
mixture of 1:1. The three chiral centers in 9b were determined
as 3S,4R,6R (Figure 1).24
Mechanistic Considerations. The proposed mechanism for the
reaction course of this transformation is summarized in Scheme
7. The Michael addition follows the common path previously
reported in the literature.15 The R,ꢀ-unsaturated aldehyde 1 is
Further important transformations of the optically active
products are the reduction of the Wittig adducts 5f and 5g in
10 min by NaBH4, giving the amino alcohol derivatives 10a
and 10b in good yields (Scheme 6). A large group of important
natural products, such as carbohydrates, alkaloids, polyether
antibiotics, and pheromones contain polyfunctionalized pyran
derivatives as a subunit.25 Interestingly, it was observed that
Quayle, P.; Regan, A. C.; Urch, C. J. Tetrahedron 2005, 61, 11910.
(d) Liu, R. H.; Zhang, W. D.; Gu, Z. B.; Zhang, C.; Su, J.; Xu, X. K.
Nat. Prod. Res. 2006, 20, 866. (e) Larghi, E. L.; Kaufman, T. S.
Synthesis 2006, 2, 187. (f) Tang, Y.; Oppenheimer, J.; Song, Z.; You,
L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785. (g) Shoji,
M.; Hayashi, Y. Eur. J. Org. Chem. 2007, 3783. (h) Goddard-Boger,
E. D.; Ghisalberti, E. L.; Stick, R. V. Eur. J. Org. Chem. 2007, 3925.
(i) Brioche, J. C. R.; Goodenough, K. M.; Whatrup, D. J.; Harrity,
J. P. A. J. Org. Chem. 2008, 73, 1946. (j) Kumar, S.; Malachowski,
W. P.; DuHadaway, J. B.; LaLonde, J. M.; Carroll, P. J.; Jaller, D.;
Metz, R.; Prendergast, G. C.; Muller, A. J. J. Med. Chem. 2008, 51,
1706.
(24) CCDC 677671 contains the supplementary crystallographic data. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336-033.
E-mail: ].
(25) (a) Rahman, A.; Nasreen, A.; Akhtar, F.; Shekhani, M. S.; Clardy, J.;
Parvez, M.; Choudhary, M. I. J. Nat. Prod. 1997, 60, 472. (b) Brimble,
M. A.; Prabaharan, H. Tetrahedron 1998, 54, 2113. (c) Conway, J. C.;
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12035

A R T I C L E S
Cabrera et al.
Table 3. Electronic and Free Energies of the Transition States for
the Nucleophilic Addition of Oxazolones to R,ꢀ-Unsaturated
Aldehydes Catalysed by 3 at B3LYP/6-31G(d) Level of Theory
∆Eelec
(kcal/mol)
G
∆G
kcal/mol
entry transition state
Eelec (Hartree)a
(Hartree)a
1
2
3
4
TS-14-SS
TS-14-SR
TS-15-SS
TS-15-SR
-3677.838468
-3677.832459
-3755.026955
-3755.255542
0b
-3677.103654
-3677.096536
-3754.275416
-3754.272994
0b
3.8b
0c
4.5b
0c
0.9c
1.5c
a Absolute and free energies for calculated transition states. b Energy
are relative to TS-14-SS. c Energy are relative to TS-15-SS.
Figure 2. Two transition states leading to the two diastereoisomers in Table
1 TS-14-SS shows the hydrogen-bonding which leads to the major
diastereomer (Table 1, entry 3).
transformed by catalyst 3 and nucleophile 2 into the Michael
adduct 13. The stereocenter formed in the aldehyde is controlled
by a Re-face attack of the nucleophile on the planar iminium
ion 12. The Re-face of the ꢀ-carbon atom in the iminium-ion
intermediate is favored for approach of the nucleophile owing
to the bulk of the C2-substituent in the pyrrolidine ring of the
catalyst which shields the Si-face, as previously reported for
the use of TMS-protected prolinols as organocatalysts.15 After
the formation of the stereocenter, the catalyst is released
from the intermediate, which form the functionalized oxazolones
4. The absolute configuration of the initially formed stereogenic
center in the R,ꢀ-unsaturated aldehyde indicates that the addition
of the nucleophile approaches from the Re-face by control of
the catalyst, supported by the X-ray structure in Figure 1.
To understand the diastereo- and enantioselectivity observed
for addition of the oxazolones to the R,ꢀ-unsaturated aldehydes
a computational investigation was performed using density
functional theory (DFT) calculations.26 Geometry optimizations
were performed using the B3LYP-DFT procedure with the
6-31G(d) basis set27 and the relative energies of the different
transition-state structures were used to predict product ratios.
We started out by investigating the reaction of rac-2a with
the ortho-hydroxy-phenyl substituted R,ꢀ-unsaturated aldehyde
(1c) which proceeds with very high diastereoselectivity (>20:
1) (Table 1, entry 2). The computational study was carried out
with the assumption that it is the enolate-form of the oxazolone
which reacts with the iminium-ion (12, Scheme 7) of the catalyst
(3) and the R,ꢀ-unsaturated aldehyde (1). Our hypothesis is that
the diastereoselectivity might be controlled by hydrogen-bonding
interaction of the enolate-form of the oxazolone and the ortho-
hydroxy substituent in 1c. The two transition states leading to
the two different diastereoisomers have been located and
computational studies revealed that the transition state with
S-configuration at the carbon atom in oxazolone, TS-14-SS, was
lower in energy than the transition state TS-14-SR, leading to
the diastereoisomer with R-configuration, (Figure 2, Table 3,
entries 1, 2). As it appears from the results in entry 1, Table 3,
the formation of the (S,S)-enantiomer is favored by 3.8 kcal/
mol, relative to the (S,R)-enantiomer. Assuming a Boltzmann
distribution of the transition states at room temperature, the
calculated diastereomeric ratio is >20:1, which is in very good
agreement with the experimental result (Table 1, entry 3). The
reason for the nucleophilic approach of rac-2a to the Re-face
of 1c is due to hydrogen-bonding between the nucleophile and
the electrophile, in which the ortho-hydroxy substituent in 1c
is the hydrogen-bond acceptor and the enolized oxazolone is
the hydrogen donor as shown in Figure 2 to the left.
Figure 3. Structures of the two transition states lowest in energy accounting
for the high diastereoselectivity with oxazolone having a benzhydryl-
protecting group (hydrogen atoms deleted for clearity). The transition state
to the left is the one with the lowest energy and the one to the right shows
the steric repulsion accounting for the less-favored approach.
The role of the benzhydryl-protecting group in the oxazolone
(2f) for controlling the high diastereoselectivity in Table 2 was
unclear based on the experimental results. However, DFT-
calculations provided valuable insight to rationalize the observed
diastereoselectivity. The transition-state structures were deter-
mined using B3LYP DFT-6-31G(d) basis set and all transition-
state structures were characterized by frequency analysis. The
calculated results for the reaction between 1a and 2f via the
iminium-ion intermediate, nicely explain the experimentally
observed stereoselectivity and the role of the benzhydryl-
protecting group (Figure 3, Table 3, entries 3, 4). The relative
energy of the TS-15-SS and TS-15-SR transition states shows
an energy gap between the diastereoisomers of 0.9 kcal/mol, in
favor of TS-15-SS, which is also the major diastereoisomer
found experimentally. The diastereoisomeric ratio was calculated
to be 4.5:1, using a Boltzmann distribution, on the basis of this
difference in relative energy of TS-15-SS and TS-15-SR, which
is in agreement with the experimentally observed ratio of 6:1 (Table
2, entry 2). The diastereoselectivity originates from steric effects,
primarily due to the benzhydryl-protecting group in the oxazolone.
The bulkiness of this substituent determines the orientation of the
nucleophile, and the approach giving the S-configuration at the
carbon atom in oxazolone is favored. The C-C distance between
1a and 2f in the transition state is 0.10 Å shorter in TS-15-SS
than in TS-15-SR. If we, for the latter reaction leading to the
transition state TS-15-SR, force the oxazolone to approach even
further, steric repulsion of the benzhydryl group and the bis(3,5-
bis-trifluoromethylphenyl)trimethylsilyloxymethyl group in the
catalyst is observed (Figure 3, right). We propose that this steric
repulsion is the reason for being able to control the diastereo-
selectivity of the reaction.
The diastereo- and enantioselectivity uncovered originates
from the deformation of the basic transition structure owing to
9
12036 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Synthesis of R,R-Disubstituted R-Amino Acids and Derivatives
A R T I C L E S
the presence of certain groups in either the electrophile or
nucleophile, and the interactions giving preferentially the (S,S)-
diastereoisomer are essentially different for the two situations.
(i) The electrophile can control the selectivity by a hydrogen-
bond acceptor in the ortho-position of aromatic R,ꢀ-unsaturated
aldehydes, thus capable of directing the nucleophile via a
hydrogen-bonding to the enolate-form of oxazolone. (ii) The
nucleophile with a bulky substituent in the C-2 position of the
oxazolone, such as benzhydryl, can via steric demands orient
the nucleophile in favor of the (S,S)-enantiomer, to avoid steric
repulsion between the catalyst and nucleophile. The steric and
electrostatic effect of the substrates plays a prominent role in
controlling the proportion of the diastereomeric products. Proper
consideration of these properties of bulkiness and activation of
substituents has led to design a nucleophilic addition of
oxazolones to R,ꢀ-unsaturated aldehydes catalyzed by 3 that
will produce the (S,S)-diastereomer with high selectivity.
and tetrahydropyranes. Furthermore, we have shown by DFT
calculations of transition states that the stereoselectivity for one
class of compounds is due to hydrogen-bonding interactions
between an acceptor in the ortho-position of the aromatic R,ꢀ-
unsaturated aldehyde interacting with the enolate-form of
oxazolone, and in a more general manner, the selectivity can
be controlled by a benzhydryl-protecting group in the oxazolone.
Acknowledgment. This work was made possible by a grant
from Danish National Research Foundation and OChemSchool. S.C.
and J.A. thank the Ministerio de Educacio´n y Ciencia of Spain and
E.R. thanks the “Eusko Jaurlaritza-Gobierno Vasco” for postdoctoral
fellowships. Thanks are expressed to Dr. Jacob Overgaard for
performing X-ray analysis.
Supporting Information Available: Complete experimental
procedures and characterization and computational details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Conclusion
In conclusion, we have shown that racemic oxazolones are
excellent reagents for the synthesis of chiral quaternary amino
acids by nucleophilic addition to R,ꢀ-unsaturated aldehydes
catalyzed by diarylprolinol silyl ethers. This new organocatalytic
reaction proceeds with good diastereoselectivity and excellent
enantioselectivity for a broad range of aldehydes and oxazolones.
We have demonstrated that the optically active compounds
formed undergo a number of diverse transformations leading
to the formation of optically active R,R-disubstituted R-amino
acids, R-quaternary proline derivatives, amino alcohols, lactams,
JA804567H
(26) (a) Frisch, M. J. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh
PA, 1998. (b) Frisch, M. J.; Gaussian 03, revision B.05; Gaussian,
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M. S.; DeFrees, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654. (c)
Becke, A. D. Phys. ReV. 1988, 38, 5648. (d) Lee, C.; Yang, W.; Parr,
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J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12037