Crystallization-induced dynamic resolution (CIDR) and its application to the synthesis of unnatural N-substituted amino acids derived from aroylacrylic acids

Article abstract of DOI:10.1016/S0040-4039(01)00221-0

A highly stereoselective conjugate addition of chiral amino alcohols affords a simple and inexpensive access to a wide variety of N-functionalized homophenylalanine derivatives. Limitations and conditions for application of CIDR to this system were studied.

Full text of DOI:10.1016/S0040-4039(01)00221-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2579–2582
Crystallization-induced dynamic resolution (CIDR) and its
application to the synthesis of unnatural N-substituted amino
acids derived from aroylacrylic acids
Andrej Kolarovic,a Dusˇan Berkesˇ,a,* Peter Baranb,† and Frantisˇek Povazaneca
aDepartment of Organic Chemistry, Slovak Technical University, Radlinske´ho 9, SK-812 37 Bratislava, Slovakia
bDepartment of Chemistry, University of Puerto Rico, Rio Piedras, PO Box 23346, San Juan 00931-3346, Puerto Rico
Received 17 January 2001; accepted 7 February 2001
Abstract—A highly stereoselective conjugate addition of chiral amino alcohols affords a simple and inexpensive access to a wide
variety of N-functionalized homophenylalanine derivatives. Limitations and conditions for application of CIDR to this system
were studied. © 2001 Elsevier Science Ltd. All rights reserved.
Over the last decade the synthesis of non-proteinogenic
unnatural amino acids has attracted significant atten-
tion of organic chemists, who have tried to find syn-
thetic pathways with time and financial requirements as
low as possible. From this point of view, application of
the method CIDR1 seems to be an attractive alternative
since it uses easily accessible and relatively inexpensive
chiral auxiliaries to build a new stereogenic center.
R
OH
O
O
HN
*
R
*
CIDR
OH
Ar
COOH
Ar
COOH
*
NH2
IIa-d
Ia-b
IIIa-d
Scheme 1.
Table 1. Michael-type addition of amino alcohols (IIa–d) to aroylacrylic acidsa
Comp.
Ar
Amino alcohol
Solvent
Yield (%)
d.r.b
Config.
IIIa
IIIb
IIIc
IIId
4-MeO-C6H4- (Ia)
Ph (Ib)
Ph (Ib)
(R)-2-Aminobutanol (IIa)
(S)-Leucinol (IIb)
(S)-Prolinol (IIc)
CH2Cl2
CH2Cl2
CH2Cl2/Et2O
83
77
80
81
\95:5
\95:5
\95:5
\95:5
(2S,2%R)
(2R,2%S)
(2S,2%S)
(2R,2%S)
Ph (Ib)
(S)-Phenylalaninol (IId)
EtOH
a A typical procedure for preparation of IIIb is as follows: To a solution of Ib (10.00 g, 56.8 mmol) in 250 ml of CH2Cl2, aminoalcohol IIb (7.32
g, 62.4 mmol, 1.1 equiv.) was added. The resulting solution was stirred for 7 days at 25–30°C. The precipitate was then filtered off, washed with
ether and dried to afford 12.82 g (77%) of IIIb as a white solid (mp 157–159°C; d.r. >95:5). 1H NMR (300 MHz, DCl, D2O/TMS): 7.91 (m,
2H, H-arom.); 7.65 (m, 1H, H-arom.); 7.49 (m, 2H, H-arom.); 4.61 (t, 1H, J2,3A=5.3 Hz, J2,3B=5.3 Hz, H-2); 3.85–3.95 (m, 3H, H-3, H-1%A);
3.63 (dd, 1H, J1%B,2%=7.2 Hz, J1%A,1%B=12.9 Hz, H-1%B); 3.40–3.50 (m, 1H, H-2%); 1.50–1.65 (m, 3H, H-3%, H-4%); 0.88 (d, 3H, J4%,5%A=5.9 Hz,
H-5%A); 0.84 (d, 3H, J4%,5%B=5.8 Hz, H-5%B); 13C NMR (75 MHz, DCl, D2O/TMS): 201.7 (C-4); 173.8 (C-1); 137.7, 137.5, 131.8, 131.2 (C-arom.);
62.6 (C-1%); 62.2 (C-2); 56.6 (C-2%); 41.4 (C-3%); 38.4 (C-3); 27.1 (C-4%); 25.3 (C-5%A); 23.4 (C-5%B).
b d.r. values were readily determined by a reverse phase HPLC analysis on Waters Symmetry C18 5 mm column by using pH 2.5 phosphate
buffer–CH3CN=4:1 (v/v).
Keywords: amino acid derivatives; asymmetric induction; dynamic resolution; addition; amino alcohols.
* Corresponding author. E-mail: dberkes@mtf.stuba.sk
†
E-mail: baranp@adam.uprr.pr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00221-0

2580
A. Kolaro6ic et al. / Tetrahedron Letters 42 (2001) 2579–2582
O
O
Bn
Bn
OH
Ph
COOH
Ph
COOH3N
IV
NH2
IId
Ib
HO
Bn
OH
O H2N
Ph
COO
dissolution precipitation
Bn
Bn
OH
OH
O H2N
O H2N
Ph
COO
Ph
COO
IIId
the less soluble
diastereomer
Scheme 2.
Table 2. Diastereoselectivity of the addition of (R)-2-aminobutanol (IIa) to aroylacrylic acids (rt, 7 days)
Solvent
EtOH
CH2Cl2
THF
Dioxane
CH2Cl2/Et2O
a
a
b
Ar=Ph (d.r.)
Ar=4-MeO-C6H4- (d.r.)
65:35
88:12
91:9
84:16
97:3
96:4
94:6
a The product does not precipitate out of solution.
b A mixture of reagents and products falls out.
Until now, the CIDR processes for the synthesis of
g-oxo-a-amino acids have been applied in special cases
only.2,3 However, without application of CIDR, the
addition of phenylethylamine to aroylacrylic acid esters
confirms the low stereo-discriminating environment of
this chiral auxiliary in Michael-type additions.4 In con-
nection with our previous work,5 we have decided to
study the stereoselectivity of addition of easily accessible
chiral amino alcohols and to seek out the limitations of
CIDR in this reaction system (Scheme 1). The best
results are indicated in Table 1.
is as low as possible but, at the same time, high enough
to permit the equilibration processes. The example of
(R)-2-aminobutanol (IIa) shows that the ability of the
product to precipitate from solution is highly dependent
on structural modification of the aroylacrylic acid
(Table 2).
The impact of distance between asymmetric centers in
the arising adduct on the progress of the dynamic
resolution has also been studied. It is known that the
proximity of a chiral auxiliary to a labile stereocenter in
the CIDR process is sometimes not so important.1
However, this was not so in our case and shifting of an
asymmetric center by one bond had a fatal impact on
the diastereoselectivity of the process. Addition of ( )-2-
amino-1-phenylethanol to benzoylacrylic acid in various
solvents (CH2Cl2, EtOH, MeOH/H2O) led to a mixture
of diastereomers with a d.r. of approximately 1:1.
According to the nomenclature suggested by Eliel,6 this
process of equilibration can be characterized as an
asymmetric transformation of the second kind (Scheme
2). In our case, it is based on a reversible Michael-type
addition, the equilibration being catalyzed by an excess
of base (1.1 equiv.).
The solvent plays an important role when searching for
the appropriate conditions for CIDR. It is necessary to
find one in which the solubility of the arising amino acid
The asymmetric induction of primary amino alcohols
leads to (R,S)-derivatives. This stereoselectivity is
opposite to that observed when alanine benzyl ester was
3.10%
R
3.15%
H
R
O
O
HN
H
OH
.H2SO4
H2SO4
THF
O
O
O
HN
Ph
O
H
Ph
H
N
Ph
COOH
O
H
H
IIIb,d
Vb,d
Vd
Ph
Scheme 3.

A. Kolaro6ic et al. / Tetrahedron Letters 42 (2001) 2579–2582
2581
R
R
OH
OH
HN
NH2
O
HN
H2/Pd/C
1%HCl
Pb(OAc)4
MeOH
Ar
COOH
VIa-d
Ar
COOH
VIIa,b,d
Ar
COOH
IIIa-d
Scheme 4.
After removal of the activating carbonyl group, we
were able to prepare stable amino acids VIa–d with
negligible epimerization (Scheme 4).§ Derivative VIc
afforded suitable crystals of the hemihydrate and there-
after the absolute stereochemistry was assigned by
single crystal X-ray analysis (Fig. 1).¶
In the case of leucinol and aminobutanol derivatives
VIa,b the sense of asymmetric induction has been deter-
mined after their transformation to the known
homophenylalanines VIIa,b using a convenient oxida-
tive degradation with Pb(OAc)4 (Scheme 4).7 Amino
acids VIIa,b were identified and their enantiomeric
purity was determined by HPLC on a chiral CROWN-
PAK® CR(+) column.
Figure 1. ORTEP view of the molecular structure of VIc
(50% probability thermal ellipsoids).
added to ethyl benzoylacrylate.2 (S)-Prolinol (IIc), sur-
prisingly, represents a special case and forms the amino
acid IIIc with the (S,S)-configuration.
In summary, the highly stereoselective conjugate addi-
tion of chiral amino alcohols described here represents
a simple synthetic route to both antipodes of a variety
of N-functionalized homophenylalanine derivatives.
The application of this method to other conjugate
systems is currently in progress.
The absolute configuration of the adducts IIIa–d could
not be assigned by the usual spectroscopic methods. In
order to determine the configuration of the newly-built
stereogenic center in derivatives IIIa–d we therefore
used three different methods.
For the adducts it is distinctive that they are on the one
hand thermolabile, on the other unstable both in alka-
line and neutral medium. However, we succeeded in
finding mild acidic conditions for transformation of
adducts IIIb,d into the corresponding lactones (Scheme
3), leading to pure compounds via precipitation.‡ After
simple isolation of these sensitive compounds we suc-
ceeded in elucidating the absolute configuration of
adduct IIId by NOE. In the case of amino acid IIIb we
failed due to signal overlap.
§ A typical procedure for preparation of VIa is as follows: Amino acid
IIIa (2.46 g, 8.3 mmol) was dissolved in 1% HCl (75 ml) and 10%
Pd/C was added (0.50 g). The suspension was stirred under H2 (1.1
atm) for 1 day. Thereafter the catalyst was filtered off and washed
with 1% HCl (50 ml). The resulting solution was added to the
filtrate, partially concentrated under reduced pressure and its pH
adjusted to 6.5 with 1N NaOH. A precipitate was filtered off,
washed with Et2O and dried to afford 1.71 g (73%) of amino acid
VIa (d.r. >95:5) as a white solid. An analytical sample was obtained
by recrystallization from EtOH with several drops of water: mp
220–222°C, 1H NMR (300 MHz, CD3OD, DCl/TMS): 7.21 (m, 2H,
H-arom.); 6.89 (m, 2H, H-arom.); 4.12 (‘t’, 1H, J2,3A=6.3 Hz,
‡ A typical procedure for the preparation of Vd is as follows: Amino
acid IIId (980 mg, 3 mmol) was dissolved in a mixture of THF (50
ml) and 96% H2SO4 (310 mg, 3 mmol). The mixture was stirred for
3 days at room temperature. A precipitate was filtered off and dried
to afford 730 mg (60%) of Vd as a white solid (mp 185–188°C; d.r.
>95:5). 1H NMR (300 MHz, DMSO-d6/TMS): 8.05 (m, 2H, H-
arom.); 7.73 (m, 1H, H-arom.); 7.60 (m, 2H, H-arom.); 7.35 (m, 5H,
H-arom.); 4.69 (dd, 1H, J3,1%A=3.7 Hz, J3,1%B=4.4 Hz, H-3); 4.63
(dd, 1H, J6A,6B=12.1 Hz, J6A,5=12.1 Hz, H-6A); 4.45 (dd, 1H,
J
2,3B=6.3 Hz, H-2); 3.83 (dd, 1H, J1%A,2%=3.3 Hz, J1%A,1%B=12.4 Hz,
H-1%A); 3.79 (s, 3H, OMe); 3.72 (dd, 1H, J1%B,2%=5.6 Hz, J1%A,1%B
=
12.4 Hz, H-1%B); 3.15–3.25 (m, 1H, H-2%); 2.82 (m, 1H, H-3A); 2.74
(m, 1H, H-3B); 2.26 (m, 2H, H-4); 1.76 (dq, 2H, J3%,4%=7.4 Hz,
J2%,3%=7.4 Hz, H-3%); 1.01 (t, 3H, J3%,4%=7.4 Hz, H-4%); 13C NMR (75
MHz, CD3OD, DCl/TMS): 171.4 (C-1); 159.8, 133.1, 130.5, 115.1
(C-arom.); 62.4 (C-2%); 59.9 (C-1%); 58.4 (C-2); 55.8 (OMe); 33.1
(C-3); 31.3 (C-4); 21.5 (C-3%); 10.4 (C-4%).
¶ Crystal data for VIc: C30H44N2O7, M=544.67, 0.03×0.06×0.50 mm,
monoclinic, space group P21/a (No. 14), a=11.442(3), b=7.390(2),
J
6A,6B=12.1 Hz, J6B,5=2.8, Hz, H-6B); 4.17–4.29 (m, 1H, H-5);
3.99 (dd, 1H, J1%A,1%B=19.0 Hz, J3,1%A=4.4 Hz, H-1%A); 3.82 (dd,
1H, 1%A,1%B=19.0 Hz, 3,1%B=3.7 Hz, H-1%B); 3.08 (dd, 1H,
3
,
,
c=16.861(4) A, i=95.313(5)°, V=1419.6(6) A , Z=2, Dc=1.274 g
cm−3, v(Mo Ka)=0.90 cm−1, T=298 K, 2qmax=46.62°, 8169 reflec-
tions measured, 3952 unique (Rint=0.0423). The refinement (362
variables, three restrictions) based on F converged with R=0.0446,
Rw=0.0683, and GOF=0.940 using 2911 unique reflections (I>
2|(I)).
J
J
J
1¦A,1¦B=13.9 Hz, J5,1¦A=6.0 Hz, H-1¦A); 2.95 (dd, 1H, J1¦A,1¦B=
13.9 Hz, J5,1¦B=8.3 Hz, H-1¦B); 13C NMR (75 MHz, DMSO-d6/
TMS): 196.1 (C-2%); 165.9 (C-2); 135.0, 135.0, 134.5, 129.4, 129.1,
128.9, 128.5, 127.4 (C-arom.); 68.5 (C-6); 53.1 (C-5); 51.4 (C-3); 39.4
(C-1%); 33.7 (C-1¦).

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A. Kolaro6ic et al. / Tetrahedron Letters 42 (2001) 2579–2582
Acknowledgements
1143–1146.
3. Yamada, M.; Nagashima, N.; Hasegawa, J.; Takahashi, S.
Tetrahedron Lett. 1998, 39, 9019–9022.
The authors are grateful to the Slovak Grant Agency
for financial support No. 1/6269/99 and to Dr. Raphael
G. Raptis (UPR) for the access to the X-ray diffrac-
tometer.
4. Knollmu¨ller, M.; Ferencic, M.; Ga¨rtner, P.; Girreser, U.;
Klinge, M.; Gaischin, L.; Mereiter, K.; Noe, Ch. R.
Monatsh. Chem. 1999, 130, 769–782.
5. Berkesˇ, D.; Kolarovicˇ, A.; Povazˇanec, F. Tetrahedron Lett.
2000, 41, 5257–5260.
6. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; John Wiley & Sons: New York,
1994; pp. 364–365.
References
1. Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 447–456.
2. Urbach, H.; Henning, R. Tetrahedron Lett. 1984, 25,
7. Hegedus, L. S.; Schmeck, C. J. Am. Chem. Soc. 1994, 116,
9927–9934.
.
.