An enantioselective synthesis of nitrogen protected 3-arylserine esters

Article abstract of DOI:10.1016/j.tetasy.2004.10.005

A method for the preparation of (2R,3S) nitrogen protected arylserine esters is described. The method consists of rhodium mediated insertion of tert-butylcarbamate into the corresponding 3-keto-2-diazoester, affording the N-protected α-amino-β-ketoester, followed by asymmetric reduction/dynamic resolution to afford the corresponding N-protected 3-arylserine esters in good chemical yield, and in most cases high enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2004.10.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3485–3487
An enantioselective synthesis of nitrogen protected
3-arylserine esters
Lisa H. Bourdon, David J. Fairfax,* Gregory S. Martin,
Casey J. Mathison and Pavel Zhichkin
Albany Molecular Research Inc., 21 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
Received 30 March 2004; revised 17 May 2004; accepted 7 October 2004
Abstract—A method for the preparation of (2R,3S) nitrogen protected arylserine esters is described. The method consists of rho-
dium mediated insertion of tert-butylcarbamate into the corresponding 3-keto-2-diazoester, affording the N-protected a-amino-b-
ketoester, followed by asymmetric reduction/dynamic resolution to afford the corresponding N-protected 3-arylserine esters in good
chemical yield, and in most cases high enantiomeric excess.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
As part of an ongoing research project, a direct route to
a variety of chiral threo 3-arylserine derivatives of gen-
eral structure 3 was required. It was envisioned that
these compounds could be derived from the asymmetric
reduction/dynamic resolution1,2 of the corresponding a-
amino-b-ketoester derivative 2. Although several meth-
ods for the preparation of a-amino-b-ketoesters are
known,3 all of the reported methods employed strongly
basic or acidic conditions, which limits the scope of the
method. Pearson and Zigmantas4 reported the synthesis
of ethyl 3-(4-chlorophenyl)-2-tert-butyloxycarbonylami-
nopropionate via an asymmetric aminohydroxylation
protocol, which gave excellent enantioselectivity but
relatively poor yields. This compound was used to intro-
duce the C-ring of ristocetin A as well as served as the
linchpin in the construction of the key macrocyclic link-
age. We envisioned the substrates of general formula 2
could be readily obtained under neutral conditions via
the insertion of a rhodium carbenoid, derived from diazo-
esters of structure 1 into the N–H bond of tert-butyl
carbamate, as outlined in Scheme 1.
Moody and co-workers5,6 have reported the rhodium-
mediated variant of this reaction with alcohols, amines,
amides and thiols, with these reactions working well.
The requisite a-diazo-b-ketoesters 1a–g were readily
synthesized from the corresponding b-ketoesters using
mesyl azide and triethylamine under standard
conditions.7
In turn, the b-ketoester starting materials were either
commercially available or synthesized via the tin(II)
mediated condensation of ethyl diazoacetate and the
corresponding benzaldehyde derivative.8
After some experimentation it was discovered that the
rhodium(II) octanoate was a superior catalyst for the
insertion reaction and results are outlined in Table 1.
The reaction appears to be applicable to both electron
donating and electron withdrawing substituents on the
aromatic ring with a variety of functional groups
tolerated.
With the required a-amino-b-ketoester intermediates in
hand we began to study the asymmetric reduction/ki-
netic resolution step. Noyori et al.1 have described this
procedure using a BINAP/ruthenium system, though
the method employs high pressure hydrogenation. A
more recent report has described this transformation un-
der hydrogen transfer conditions,2 although the number
of examples reported was very limited and the chiral
*
Corresponding author. Fax: +1 518 867 4379; e-mail: david.fairfax@
albmolecular.com
Intern student, June–August 2001.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.005

3486
L. H. Bourdon et al. / Tetrahedron: Asymmetry 15 (2004) 3485–3487
O
O
O
O
tBuOC(O)NH2
Ar
OEt
OtBu
Ar
OEt
HN
Rh2(octanoate)4, CH2Cl2
N2
1a-g
O
2a-g
OH
O
Et3N HCO2H, i-PrOH
Ar
OEt
OtBu
HN
(RuCl2C6H6)2
(+)-Pseudoephedrine
O
3a-g
Scheme 1.
Table 1. Rhodium-mediated insertion of tert-butyl carbamate into
diazoesters 1a–g
Table 2. Asymmetric reduction/dynamic resolution of 2a–g
Product Yielda Diastereomeric Enantiomeric Rotation
Product
Ar
R
Yielda (%)
(%)
excessb (%)
excessc (%)
(EtOH, 25°C)d
2a
2b
2c
2d
2e
2f
Phenyl
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
63
56
57
82
70
65
46
70
3a
3b
3c
3d
3e
3f
78
50
77
72
52
76
66
45
>95
>95
>95
87
85
81
84
42
83
84
87
85
+20.4 (c 1.1)
+16.6
+29.7
3-Trifluoromethylphenyl
4-Nitrophenyl
2-Furyl
+9.1
+15.9
3-Methoxyphenyl
4-Chlorophenyl
3,4-Methylenedioxyphenyl
4-(2-Phthalimido)ethoxy
>95
>95
87
+26.3
+15.8
+20.9
2g
2h
3g
3h
91
a All compounds were determined pure by 1H NMR and mass spectral
analysis.
a All compounds were >95% HPLC purity and had consistent 1H
NMR and mass spectra.
b Determined by NMR analysis of the corresponding deprotected
hydrochloride salt. In most cases the NMR resonances for the C-3
methine protons of the erythro isomer were 0.05–0.08ppm upfield
relative to the corresponding threo isomer. The two exceptions were
the salts derived from compounds 3c and 3e and which had reso-
nances of 0.04 and 0.06ppm downfield, respectively.
ligands of choice were based on NoyoriÕs C-2 symmetric
diamines. Although the diamine precursors to these lig-
ands are commercially available, the cost was envisioned
as somewhat prohibitive, especially if the reduction were
to be run on larger scale, and the method necessitated
the synthesis of the catalyst. With these factors in mind,
our efforts focused on the use of ephedrine and pseudo-
ephedrine derived ligands, as these ligands have been
reported to give excellent enantioselectivities in the
reduction of aromatic ketones.9 Furthermore, they are
inexpensive, and can be potentially used directly without
further chemical modification. An initial ligand screen,
using 1a as the reduction substrate, revealed that while
most ephedrine and pseudoephedrine derived ligands
did afford some degree of enantioselection, (+)-pseudo-
ephedrine gave superior enantioselectivities. Results from
the (+)-pseudoephedrine mediated asymmetric reduc-
tion/dynamic resolution of substrates 1a–g are outlined
in Table 2.
c Determined by NMR analysis of the corresponding Mosher ester.
d c 0.5, unless otherwise indicated.
enantioselectivity being observed. Following the analy-
sis method of Dale and Mosher,10 an (S)-configuration
was assigned at the 3-position for products derived from
(+)-pseudoephedrine mediated chiral reduction. As the
ruthenium catalyzed transfer hydrogenation of pro-
tected a-amino-b-ketoesters has been reported to be
threo selective,2 this translates to an (R)-configuration
at the 2-centre to give an absolute configuration of
2R,3S. However, a discrepancy was observed in the
comparison of the observed rotation of +20.4 (c 1.1,
EtOH) for 1a to the reported value11 of +8.5 (c 1.1,
EtOH). The exact reason for this discrepancy was un-
clear and further efforts to corroborate our stereochem-
ical assignment were made. Thus, 2a was converted to
ethyl (2R,3S)-2-amino-3-hydroxy-3-phenylpropionate
hydrochloride, readily obtained by treatment with 4M
hydrogen chloride in dioxane. This material was found
to have a specific rotation of +32.6 (25°C, c 1.0,
H2O), which corresponded well to the literature value12
of À30.0 (18°C, c 2.0, H2O) for the 2S,3R antipode.
Further treatment of this compound with 2equivalents
of lithium hydroxide in water at 0°C afforded (2R,3S)-
2-amino-3-hydroxy-3-phenylpropionic acid. The specific
rotation of this material was found to be +50.0 (25°C,
The reduction reaction appears quite diverse and a vari-
ety of functionality was tolerated.
Diastereoselectivity was generally excellent, with little of
the erythro isomer being observed in most cases by H
1
NMR analysis of either the initial reduction product
or the deprotected amino-ester hydrochloride salt. The
enantioselectivity of the reduction was also high, with
enantiomeric excesses greater than 90% being observed
in virtually all cases. An exception to this was the furyl
derivative 2d, with good diastereoselectivity but modest

L. H. Bourdon et al. / Tetrahedron: Asymmetry 15 (2004) 3485–3487
3487
3. (a) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y.
Tetrahedron: Asymmetry 2001, 12, 1757–1762; (b) Singh,
J.; Gordon, T. D.; Early, W. G.; Morgan, B. A.
Tetrahedron Lett. 1993, 34, 211–214; (c) Hara, O.; Ito,
M.; Hamada, Y. Tetrahedron Lett. 1998, 39, 5537–5540;
(d) Nakatsuka, T.; Miwa, T.; Mukaiyama, T. Chem. Lett.
1981, 279–282.
c 2.0, 6M HCl), which is also in good agreement with
the reported11,13 literature values of +52.0 (c 0.8, 6M
HCl) and +50.2 (20°C, c 2.0, 6M HCl). These obser-
vations further corroborated our initial assignment of
2R,3S based on Mosher ester analysis.
4. Pearson, A. J.; Zigmantas, S. Tetrahedron Lett. 2001, 42,
8765–8768.
3. Conclusion
5. Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody,
C. J. J. Org. Chem. 1995, 60, 4449–4460.
6. Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh,
D.; Moody, C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem.
Soc., Perkin Trans. 1 1996, 2879–2884.
7. Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org.
Chem. 1993, 58, 4646–4655.
8. Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org.
Chem. 1990, 55, 5297–5299; Holmquist, C. R.; Roskamp,
E. J. J. Org. Chem. 1989, 54, 3258–3260.
In conclusion, we have reported a general synthesis of
threo-aryl serine derivatives that appears applicable to
a variety of substrates. The method gives a rapid entry
into threo-3-arylserine derivatives with a high degree of
diastereoselectivity and enantioselectivity. As both
enantiomers of pseudoephedrine are readily available,
both antipodes of the final compounds should be
attainable.
9. Everaere, K.; Mortreux, A.; Carpentier, J.-F. Adv. Synth.
Catal. 2003, 345, 67–77.
References
10. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512–519.
1. Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36–56.
11. Bold, G.; Duthaler, R. O.; Riediker, M. Angew. Chem.,
Int. Ed. 1989, 28, 497–498.
2. Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.;
Wagner, A.; Mioskowski, C. J. Chem. Soc., Chem.
Commun. 2001, 2572–2573.
12. Vogler, K. Helv. Chim. Acta 1950, 33, 2111–2117.
13. Davies, F. A.; Srirajan, V.; Fanelli, D. L.; Portonova, P.
J. Org. Chem. 2000, 65, 7663–7666.