Enantioselective synthesis of anti -β-hydroxy-α-amido esters via transfer hydrogenation

Article abstract of DOI:10.1021/ol102323k

The asymmetric transfer hydrogenation of α-amido-β-keto esters to provide the corresponding anti-β-hydroxy-α-amido esters in good to excellent yields, diastereoselectivity, and enantioselectivity is reported. The procedure is operationally simple, and delicate handling of the catalyst is not necessary.

Full text of DOI:10.1021/ol102323k

Enantioselective Synthesis of anti-β-hydroxy-α-amido esters
via Transfer Hydrogenation
Brinton Seashore-Ludlow,a Piret Villo,a,b Christine Häckera and Peter Somfai a,b,
*
[a] B. Seashore-Ludlow, P.Villo, C. Häcker, and Prof. P. Somfai
Organic Chemistry, KTH Chemical Science and Engineering, Royal Institute of
Technology, 100 44 Stockholm (Sweden)
Fax: (+46) 8791-2333
E-mail: somfai@kth.se
[b] P. Villo and Prof. P. Somfai, Institute of Technology, University of Tartu,
Nooruse 1, 50411
Tartu (Estonia)
Supporting Information
General
p. 1
Synthesis of substrates 1a-h
p. 1-5
Ligand synthesis
Transfer hydrogenation and substrates
2a-h
p. 5-6
p. 6-8
Double protected 3 and 4
Determination of relative stereochemistry
NMR spectra of 1a-h, 2a-h, 3 and 4
p. 8-9
p. 9-11
p. 11 -end

General
13
1H and C NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz
spectrometer in CDCl3 using the residual peak of CHCl3 (1H NMR δ 7.26, 13C NMR δ
77.0) as internal standard. Chemical shifts are reported in the δ-scale with multiplicity
(b=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constants
(Hz) and integration. IR-spectra were recorded on an ATI Mattson Infinity Series
FTIR and only the strongest/structurally most important peaks (νmax, cm-1) are listed.
Optical rotations were determined on a Perkin Elmer Polarimeter 343 using the
sodium D line (589 nm) at the indicated temperature. Analytical thin layer
chromatography was performed on Merck silica gel 60 F254 plates; the plates were
visualized with UV light and phosphomolybdic acid/cerium sulfate staining reagent
(purchased from Aldrich as a 20 wt % solution in ethanol and diluted to ca 5 wt %
before use) or potassium permanganate stain. Enantioselectivity was determined by
HPLC analysis using a Shimadzu DGU-20As instrument (detector UV/VIS, SPD
20A, Column, Chiralcel OD-H, no: ODH0CE-EK017, mobile phase: 3% or 5% 2-
propanol in hexanes as indicated, 0.5 mL/min, λ 254 nm). Retention times are given
for S,S and R,R isomers. In the case of the S,R and R,S isomers an Agilent 1100 series
HPLC was used with a Chiracel OJ column, no: OJ00CE-IF050. Air and moisture
sensitive reactions were carried out in flame-dried, septum-capped flasks under an
atmospheric pressure of nitrogen.
O
H
N
Ot-Bu
O
Ot-Bu
O
O
O
O
H
N
!Cl
NH3
N
O
O
O
O
O
O
O
1a
S 1
S 2
S 3
Methyl 2-benzamidoacetate (S2)1
After adding a saturated solution of potassium carbonate (19 mL) and benzoyl
chloride (4.20 mL, 35.8 mmol) to a solution of glycine methyl ester (S1) (3.00 g, 23.9
mmol) in ether (10 mL) the mixture was stirred for 3 hours at 0 °C. The reaction
mixture was then transferred to a separatory funnel and the aqueous phase was
extracted three times with ether. The organic layer was washed with saturated
NaHCO3, water and brine. The aqueous phase was saturated with sodium chloride and
then it was extracted with ethyl acetate. The combined organic phases were dried over
Na2SO4 and concentrated. This crude residue could be used directly in the next
reaction to form S3.
Methyl 2-(N-(tert-butoxycarbonyl)benzamido)acetate (S 3)2
S2 (4.00 g, 20.7 mmol) was dissolved in acetonitrile (15 mL). Di-tert-butyl
dicarbonate (6.90 g, 31.8 mmol) and N,N-dimethylaminopyridine (0.30 g, 2.1 mmol)
were added successively. The mixture was stirred for 6.5 h and concentrated.
Chromatographic purification of the crude residue (Silica, Hept : EtOAc 8:1) gave S3
(6.08 g, 20.7 mmol) as a colorless oil in 100% yield.
1 (a) Nemoto, T.; Harada, T.; Matsumoto, T.; Hamada, Y. Tetrahedron Lett. 2007, 48,
6304-6307. (b) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y. Tetrahedron:
Asymmetry 2001, 12, 1757-1762.
2 Zeng, L.; Kaoudi, T.; Schiesser, C. H. Tetrahedron Lett. 2006, 47, 7911-7914.
1

1H (400 MHz, CDCl3) δ 7.48-7.47 (m, 2H), 7.43-7.42 (m, 1H), 7.41-7.39 (m, 2H),
4.56 (s, 2H), 3.79 (s, 3H), 1.16 (s, 9H). see reference 2 for further characterization.
Methyl 2-(tert-butoxycarbonylamino)-3-oxo-3-phenylpropanoate3 (1a)
DMPU (1,3-Dimethyltetrahydropyrimidin-2(1H)-one) (2.50 ml, 20.5 mmol) and
LiHMDS (Lithium bis(trimethylsilyl)azanide (1M, 25 ml, 25 mmol) were added to a
solution of S3 (3.30 g, 10.2 mmol) in THF (100 ml) at -78 °C. The mixture was
stirred for 1.5 h, quenched with saturated NH4Cl solution and extracted three times
with EtOAc. The combined organic phases were washed with water and brine, dried
over Na2SO4 and concentrated. Chromatographic purification (Silica, Hept : EtOAc
10:1, polarity increased to 3:1 during purification) gave the product 1a (2.53 g, 8.6
mmol) in 84% yield as a white solid.
1H NMR (500 MHz, CDCl3): δ 8.10 (d, 2H), 7.65-7.60 (m, 1H), 7.53-7.47 (m, 2H),
5.96 (d, J = 8.1 Hz, 1H), 5.90 (d, J = 8.1 Hz, 1H), 3.71 (s, 3H), 1.44 (s, 9H); 13C (125
MHz, CDCl3) δ 191.8, 167.6, 154.9, 134.3, 134.1, 129.4, 128.7, 80.6, 59.1, 53.0,
28.2.; IR (thin film) 3371, 2978, 1755, 1712, 1693, 1597, 1496, 1450, 1346, 1254,
1165, 1061, 1026 cm-1; HRMS (m/z) calcd for C15H19NO5 (M+H)+ 294.1336, found
294.1339; mp = 96.3-97.2 °C.
General procedure for the preparation of transfer hydrogenation substrates:
O
O
O
O
O
O
R
O
O
EtO
OEt
O
HO
OEt
O
OEt
O
EtO
OEt
HN
HN
HN
NH2
S 4
O
O
O
S 5
S 6
1b-h
Diethyl 2-(tert-butoxycarbonylamino)propandioate (S5) was synthesized according
to the known procedure from commercially available diethyl aminopropanedioate
(S4).4
2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropanoic acid (S6) was synthesized
according to known procedure from S5.5
General procedure for synthesis of the substrates 1b-h:6
To a stirred mixture of malonate S6 (1 equiv or equiv given) and MgCl2 (6 equiv) in
THF (15 mL for 0.9 mmol substrate) was added Et3N (2.5 equiv) at 0 °C. The
resulting mixture was stirred at 0 °C for an additional 2 hours. Simultaneously a
substituted benzoyl chloride was prepared by heating the corresponding benzoic acid
(3 equiv or equiv given) with SOCl2 (2.5 equiv relative to acid) for 2 hours at 80 °C.
Evaporation of excess SOCl2 yielded the substituted benzoyl chloride, which was
added to the malonate mixture in THF (1 mL) at 0 °C. Then the reaction was brought
to rt and stirred over night. After diluting with EtOAc (40 mL), the mixture was
3 Makino, K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784-5785.
4(a) Suzuki, N.; Suzuki, T.; Ota, Y.; Nakano, T.; Kurihara, M.; Okuda, H.; Yamori,
T.; Tsumoto, H.; Nakagawa, H.; Miyata, N. J. Med. Chem. 2009, 52, 2909-2922. (b)
Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J. Org. Chem. 1998, 63, 9616-9617.
5 Schmidt, U.; Griesser, H.; Lieberknecht, A.; Schmidt, J.; Gräther, T. Synthesis
1993, 1993, 765-766.
6 Tao, J.; Hu, S.; Pacholec, M.; Walsh, C. T. Org. Lett. 2003, 5, 3233-3236.
2

washed with a saturated NH4Cl solution (20 mL) and brine (20 mL). The combined
organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude
material was purified by flash chromatography on silica (10% - 20% EtOAc/Hexanes)
to give the product.
O
O
OMe
EtO
HN
Boc
1b
Ethyl 2-(tert-butoxycarbonylamino)-3-(2-methoxyphenyl)-3-oxopropanoate (1b)
Prepared from S6 (1.19 mmol) and o-anisic acid (1.14 mmol) yielding the desired
product 1b (271 mg, 0.80 mmol, 70%).
1H NMR (500 MHz, CDCl3): δ 7.70 (m, 1H), 7.48 (m, 1H), 6.99 (m, 1H), 6.94 (m,
1H), 5.91 (d, J = 8.1 Hz, 1H), 5.79 (d, J = 8.1 Hz, 1H), 4.17-4.06 (m, 2H), 3.88 (s,
13
3H), 1.40 (s, 9H), 1.07 (t, J = 7.1 Hz, 3H); C (125 MHz, CDCl3) δ 193.2, 167.4,
158.7, 155.0, 134.6, 131.2, 125.0, 120.8, 111.3, 80.1, 63.5, 61.6, 55.3, 28.1, 13.8; IR
(thin film) 3429, 3383, 2981, 2939, 1750, 1720, 1689, 1601, 1492, 1255, 1169, 1026,
cm-1; HRMS (m/z) calcd for C17H23NO6 (M+H)+ 338.1598, found 338.1602.
O
Br
O
EtO
NH
Boc
1c
Ethyl 3-(2-bromophenyl)-2-(tert-butoxycarbonylamino)-3-oxopropanoate (1c)
Prepared from S6 (0.87 mmol) and o-bromo-benzoic acid (2.62 mmol) yielding
product 1c (174 mg, 0.51 mmol, 59%).
Mixture of rotamers and enol isomers:
1H NMR (500 MHz, Tol) δ 12.93 (s, 1H enol isomer), 7.43 (d, J = 7.2 Hz, 1H enol
isomer), 7.38 – 7.32 (m, 1H major), 7.18 (d, J = 8.0 Hz, 1H enol isomer), 7.14 (d, J =
8.0 Hz, 1H major), 6.82 (t, J = 7.5 Hz, 1H enol isomer), 6.75 (t, J = 7.5 Hz, 1H
major), 6.67 – 6.55 (m, 1H major and isomer), 5.95 (d, J = 7.6 Hz, 1H major), 5.76 (d,
J = 7.7 Hz, 1H major), 5.14 (s, 1H enol isomer), 4.96 (s, 1H enol isomer), 3.93 (q, J =
7.2 Hz, 1H enol), 3.81 (dq, J = 10.7, 7.1 Hz, 1H major), 3.67 (dq, J = 10.8, 7.1 Hz, 1H
major), 1.37 (s 9H major), 1.26 (s, 9H isomer), 0.96 (t, J = 7.1 Hz, 3H isomer), 0.70
(t, J = 7.1 Hz, 3H major); 13C NMR (126 MHz, CDCl3) δ 194.6, 171.6, 171.1, 168.1,
165.8, 154.9, 154.6, 138.4, 134.8, 134.4, 134.3, 133.7, 133.3, 132.7, 132.5, 132.4,
131.9, 130.8, 123.0, 129.7, 129.5, 129.2, 127.4, 127.3, 127.2, 127.1, 122.0, 120.9,
120.6, 119.7, 102.5, 80.6, 79.8, 64.0, 62.8, 62.5, 61.4, 28.2, 28.0, 27.9, 27.9, 27.8,
27.3, 27.1, 14.1, 13.9, 13.7; IR (thin film) 3394, 2981, 2935, 1719, 1495, 1373, 1343,
1256, 1169, 1053 cm-1. HRMS (m/z) calcd for C16H20BrNO5 (M+H)+ 386.0598,
found 386.0588.
O
O
EtO
HN
Boc
1d
F
Ethyl 2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)-3-oxopropanoate (1d)
Prepared from S6 (0.29 mmol) and p-fluoro-benzoic acid (0.27 mmol) to yield the
product 1d (60 mg, 0.18 mmol, 66%)
3

1H NMR (500 MHz, CDCl3): δ 8.17-8.09 (m, 2H), 7.19-7.12 (m, 2H), 5.91-5.85 (m,
2H), 4.22-4.10 (m, 2H), 1.43 (bs, 9H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 190.4 166.9,166.4 (d, J = 257 Hz), 154.9, 132.3 (d, J = 9.6 Hz), 130.7 (d, J
= 2.6 Hz), 115.9 (d, J = 22.0 Hz), 80.6, 62.3, 59.3, 28.2, 14.0; δ; IR (CH2Cl2) 3429,
3375, 2981, 2935, 1753, 1717, 1697, 1596, 1508, 1369, 1342, 1234, 1060, 1026 cm-1;
HRMS (m/z) calcd for C16H20FNO5 (M+H)+ 326.1398, found 326.1399.
O
O
EtO
HN
Boc
Br
1e
Ethyl 3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)-3-oxopropanoate (1e)
Prepared from S6 (0.58 mmol) and p-bromo-benzoic acid (1.17 mmol) to give the
product 1e (186 mg, 0.48 mmol, 82%).
1H NMR (500 MHz, CDCl3): δ 7.96 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H),
5.87 (s, 2H), 4.22-4.07 (m, 2H), 1.44 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H); 13C (125 MHz,
CDCl3) δ 191.1, 166.7, 154.9, 133.0, 132.0, 130.8, 129.7, 80.7, 62.4, 59.3, 28.2, 13.8;
IR (thin film) 3379, 2981, 2935, 1751, 1712, 1693, 1585, 1493, 1396, 1369, 1338,
1253, 1223, 1165, 1065, 1026, 887, 837, 775, 482 cm-1; HRMS (m/z) calcd for
C16H20BrNO5 (M+H)+ 386.0597, found 386.0591.
O
O
Br
EtO
HN
Boc
1f
Ethyl 3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)-3-oxopropanoate (1f)
Prepared from S6 (0.63 mmol) and m-bromo-benzoic acid (1.89 mmol) yielding 1f
(103 mg, 0.27 mmol, 42%).
1H NMR (500 MHz, CDCl3): δ 8.21 (m, 1H), 8.02 (m, 1H), 7.73 (m, 1H), 7.37 (m,
1H), 5.87 (m, 2H), 4.23-4.10 (m, 2H), 1.43 (bs, 9H), 1.16 (t, J = 6.6 Hz, 3H); 13C (125
MHz, CDCl3) δ 190.9, 166.6, 154.9, 137.0, 136.0, 132.3, 130.2, 128.0, 122.9, 80.8,
62.5, 59.5, 28.2, 13.8; IR (CH2Cl2) 3379, 2981, 2935, 1751, 1709, 1566, 1496, 1369,
1254, 1219, 1165 cm-1; HRMS (m/z) calcd for C16H20BrNO5 (M+H)+ 386.0598, found
386.0599.
O
O
Cl
EtO
HN
Boc
1g
Ethyl 2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)-3-oxopropanoate (1g)
Prepared from S6 (0.82 mmol) and m-chloro-benzoic acid (0.39 mmol) to give 1g
(127 mg, 0.37 mmol, 95%).
1H NMR (500 MHz, CDCl3): δ 8.03 (bs, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.56 (d, J =
7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 5.92-5.83 (m, 2H), 4.21-4.08 (m, 2H), 1.42 (bs,
13
9H), 1.14 (t, J = 7.1 Hz, 3H); C (125 MHz, CDCl3) δ 191.0, 166.5, 154.8, 135.8,
134.9, 134.0, 129.9, 129.3, 127.5, 80.6, 62.4, 59.4, 28.1, 13.7; IR (CH2Cl2) 3375,
4

2981, 2935, 1751, 1693, 1496, 1165, 1061 cm-1; HRMS (m/z) calcd for C16H20ClNO5
(M+H)+ 342.1102, found 342.1106.
O
O
OMe
EtO
HN
Boc
OMe
1h
Ethyl 2-(tert-butoxycarbonylamino)-3-(3,4-dimethoxyphenyl)-3-oxopropanoate
(1h)
Prepared from S6 (0.55 mmol) and 3,4-dimethoxy benzoic acid (1.11 mmol) to give
1h (48 mg, 0.13 mmol, 24 %).
1H NMR (500 MHz, CDCl3): δ 7.81 (dd, J1 =8.4 Hz, J2 = 1.6 Hz, 1H), 7.58 (d, J = 1.6
Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.92 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 8.1 Hz, 1H),
4.20 – 4.04 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 1.43 (bs, 9H), 1.16 (t, J = 7.1 Hz, 3H);
13C (125 MHz, CDCl3) δ 189.8, 167.3, 154.9, 154.3, 149.0, 127.0, 124.7, 111.1,
110.1, 80.4, 62.1, 59.0, 56.1, 55.9, 28.2, 13.8; IR (thin film) 3417, 3359, 2978, 2939,
1747, 1712, 1681, 1593, 1516, 1269, 1161 cm-1; HRMS (m/z) calcd for C18H25NO7
(M+H)+ 368.1704, found 368.1705.
Ligand Preparation:
Pseudoephedrine and norephedrine were purchased.
NH2
NHTs
Ts-DPEN was prepared by tosylation of DPEN.7
OH
HN
(S,S)- and (R,S)-8 Bn-DPAE were prepared from commercially available 2-amino-1,2-
diphenylethanol.
OH
NHTs
(S,S)-Ts-DPAE9 was prepared by tosylation of DPAE.10
OH
HN
(1S,2S)-2-(benzylamino-1,2-diphenylethanol ((S,S)-DPAE) (S7)
7 Ikariya, T.; Hashiguchi, S.; Murata, K.; Noyori, R. Org. Syn. 2005, 82, 10-17.
8 Everaere, K.; Mortreux, A.; Bulliard, M.; Brussee, J.; van der Gen, A.; Nowogrocki,
G.; Carpentier, J.-F. Eur. J. Org. Chem. 2001, 275-291., Dinsmore, C. J.; Mercer, S.
P. Org. Lett. 2004, 6, 2885-2888., Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem.
Commun. 2007, 2977-2979.
9 Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem. 1996, 108, 449-452.
10 Hirayama, L. C.; Gamsey, S.; Knueppel, D.; Steiner, D.; DeLaTorre, K.; Singaram,
B. Tetrahedron Lett. 2005, 46, 2315-2318.
5

To a solution of (1S,2S)-2-amino-1,2-diphenylethanol (105 mg, 0.49 mmol) in ethanol
(3 mL) was added benzaldehyde (50 uL, 0.49 mmol). The mixture was stirred for 3h
at ambient temperature and after which NaBH4 (30 mg, 0.74 mmol) was added as a
solid. The reaction was stirred for an additional hour and then cooled to 0 °C. 2 mL
of 1M HCl was added to the solution and then the solution was concentrated under
reduced pressure. The residue was taken up in 1M NaOH and the aqueous phase was
extracted three times with DCM. The combined organic layers were washed with
brine and dried over Na2SO4, filtered and concentrated. The residue was subjected to
flash chromatography to yield the product (112 mg, 75 %) as a white solid.
1H NMR (500 MHz, CDCl3) δ = 7.45 7.40 (m, 2H), 7.39 – 7.29 (m, 6H), 7.26 7.25(m,
3H), 7.18 – 7.10 (m, 4H), 4.68 (d, J = 8.5, 1H), 3.81 (d, J = 13.0, 1H), 3.77 (d, J =
8.5, 1H), 3.66 (d, J = 13.0, 1H); 13C NMR (126 MHz, CDCl3) δ = 141.1, 139.8,
128.4, 128.3, 128.2, 127.9, 127.9, 127.8, 127.5, 127.4, 127.1, 126.8, 77.8, 69.63,
51.29; HRMS (m/z) calcd for C21H21NO5 (M+H)+ 304.1696, found 304.1694. mp =
76.1- 76.8 °C. [α]20D -1.8° (c 1.0, CH2Cl2). IR (thin film) 3413, 3027, 2931, 1639,
1450 cm-1
General procedure for Ru(II)-catalysed transfer hydrogenation:
First the catalyst was prepared by stirring [RuCl2(benzene)]2 (0.1 equiv) and the
ligand (S,S-Bn-DPAE) (0.2 equiv) in i-PrOH (200 uL for 0.17 mmol substrate) at +80
°C for 1 h. After letting the catalyst mixture to cool to ambient temperature over 1 h,
the catalyst was transferred to a vial containing the transfer-hydrogenation substrate
(1 equiv) using HCOOH-Et3N complex 5:2 (800 uL for 0.17 mmol substrate) and
stirred at rt for 7 days (No other solvent is used). Then the mixture was purified by
flash chromatography on silica (10% - 20% EtOAc/Hexanes) to give the product.
For the synthesis of the racemic amino alcohols for the ee assay, the TsDPEN ligand
(0.2 equiv) and [RuCl2(p-cymene)]2 (0.1 equiv) were used as the catalyst precursors
and the reaction was run at 45 °C following the procedure outlined above.
OH
O
MeO
NH
Boc
2a
(2S,3S)-methyl
(2a)
2-(tert-butoxycarbonylamino)-3-hydroxy-3-phenylpropanoate
Prepared from 1a (55 mg, 0.19 mmol) to give the product 2a (54 mg, 0.18 mmol,
95%) as a beige oil.
[α]20D +81.3° (c 1.05, CHCl3)11; 97:3 er determined by HPLC analysis (Chiralcel OD-
H, 5% 2-propanol in hexanes, 0.5 mL/min, λ=254 nm, R isomer 20.4 min, S isomer
21.3 min); 1H NMR (500 MHz, CDCl3): δ 7.37-7.22 (m, 5H), 5.27 (m, 1H), 5.19 (m,
13
1H), 4.72 (m, 1H), 3.70 (bs, 3H), 1.43 (bs, 9H); C (125 MHz, CDCl3): δ 170.3,
156.4, 139.1, 128.2, 128.0, 126.0, 80.7, 75.2, 59.6, 52.4, 28.2; IR (thinfilm) 3433,
11 a) Crich, D.; Banerjee, A. The Journal of Organic Chemistry 2006, 71, 7106-7109.
b) Lago, M. A.; Samanen, J.; Elliott, J. D. J. Org. Chem. 1992, 57, 3493-3496; c)
Kobayashi, J.; Nakamura, M.; Mori, Y.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 9192-9193.
6

2978, 2931, 1714, 1504, 1454, 1365, 1253, 1169, cm-1; HRMS (m/z) calcd for
C15H21NO5 (M+H)+ 296.1493, found 296.1495.
OMe
OH
O
EtO
NH
Boc
2b
(2S,3S)-ethyl 2-(tert-butoxycarbonylamino)-3-hydroxy-3-(2-
methoxyphenyl)propanoate (2b)
Amino alcohol (45 mg, 0.13 mmol, 83%) was obtained as a beige oil from 1b (53 mg,
0.16 mmol).
1H NMR (500 MHz, CDCl3): δ 7.31 (m, 1H), 7.26 (m, 1H), 6.95 (m, 1H), 6.84 (m,
1H), 5.36 (m, 1H), 5.27 (m, 1H), 4.67 (m, 1H), 4.18-4.03 (m, 2H), 4.00 (m, 1H), 3.81
13
(bs, 3H), 1.40 (s, 9H), 1.16 (t, J = 7.1 Hz, 3H); C (125 MHz, CDCl3): δ 170.6,
156.2, 155.8, 128.9, 127.4, 120.5, 110.1, 80.0, 71.8, 61.2, 58.6, 55.2, 28.2, 13.9; 99:1
er determined by HPLC analysis (Chiralcel OD-H, 5% 2-propanol in hexanes, 0.5
mL/min, λ=254 nm, R isomer 23.0 min, S isomer 29.4 min); IR (CH2Cl2) 3433, 2978,
2935, 1719, 1601, 1505, 1373, 1246, 1169, 1053cm-1; HRMS (m/z) calcd for
C17H25NO6 (M+H)+340.1754, found 340.1755.
OH Br
O
EtO
NH
Boc
2c
(2S, 3S)-ethyl 3-(2-bromophenyl)-2-(tert-butoxycarbonylamino)-3-
hydroxypropanoate (2c)
Amino alcohol (33 mg, 76%) was obtained as a beige oil from 1c (43 mg, 0.11
mmol), 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 7.9 Hz, 1H), 7.48 (dd, J1 = 7.9 Hz,
J2 = 1.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.15 (dt, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 5.45
(d, J = 7.3 Hz, 1H), 5.39 (bs, 1H), 4.72 (m, 1H), 4.13 – 3.94 (m, 2H), 1.41 (bs, 9H,),
13
1.08 (t, J = 6.9 Hz, 3H); C (125 MHz, CDCl3) δ 170.2, 155.5, 138.7, 132.6, 129.4,
128.3, 127.2, 122.2, 80.4, 73.7, 61.5, 57.8, 28.2, 13.7; 99:1 er determined by HPLC
analysis (Chiralcel OD-H, 5% 2-propanol in hexanes, 0.5 mL/min, λ=254 nm, R
isomer 14.9 min, S isomer 15.5 min); IR (CH2Cl2) 3429, 2978, 2931, 1724, 1694,
1504, 1369, 1169, 1053 cm-1; HRMS (m/z) calcd for C16H22BrNO5 (M+H)+ 388.0754,
found 388.0756.
O
OH
EtO
NH
Boc
F
2d
(2S,3S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-fluorophenyl)-3-
hydroxypropanoate (2d)
Amino alcohol 2d (52 mg, 89%) was obtained as a beige oil from 1d (59 mg, 0.18
mmol) 1H NMR (500 MHz, CDCl3): δ 7.24 (m, 2H), 7.01 (m, 2H), 5.31 (m, 1H), 5.17
(m, 1H), 4.65 (m, 1H), 4.20-4.10 (m, 3H), 1.43 (bs, 9H), 1.21 (t, J = 7.1 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ = 169.6, 162.5 (d, J = 246 Hz), 156.5, 135.1 (d, J = 2.8),
127.8 (d, J = 8.1), 115.1 (d, J = 21.5), 80.8, 74.7, 61.8, 59.7, 28.2, 14.0; 98:2 er
determined by HPLC analysis (Chiralcel OD-H, 3% 2-propanol in hexanes, 0.5
mL/min, λ=254 nm, R isomer 20.4 min, S isomer 22.1 min). IR (CH2Cl2) 3437, 2981,
7

2935, 1709, 1604, 1512, 1369, 1223, 1165 cm-1; HRMS (m/z) calcd for C16H22FNO5
(M+H)+ 328.1554, found 328.1557.
O
OH
EtO
NH
Boc
Br
2e
(2S,3S)-ethyl 3-(4-bromophenyl)-2-(tert-butoxycarbonylamino)-3-
hydroxypropanoate (2e)
Amino alcohol 2e (32 mg, 81%) was obtained as a beige oil from 1e (41 mg, 0.11
mmol) 1H NMR (500 MHz, CDCl3): δ 7.45 (m, 2H), 7.14 (m, 2H), 5.31 (m, 1H), 5.16
(m, 1H), 4.65 (m, 1H), 4.22 (m, 1H), 4.16 (m, 2H), 1.43 (bs, 9H), 1.21 (t, J = 7.1 Hz,
13
3H). C (125 MHz, CDCl3) δ 169.3, 156.5, 138.3, 131.2, 127.8, 121.8, 80.8, 74.7,
61.9, 59.7, 28.2, 14.0; 98:2 er determined by HPLC analysis (Chiralcel OD-H, 5% 2-
propanol in hexanes, 0.5 mL/min, λ=254 nm, R isomer 16.7 min, S isomer 17.5 min);
IR (neat) 3422, 3377, 2981, 2935, 1693, 1508, 1392, 1369, 1254, , cm-1; HRMS (m/z)
calcd for C16H22BrNO5 (M+H)+ 388.0754, found 388.0756.
O
OH
Br
EtO
NH
Boc
2f
(2S, 3S)-ethyl 3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)-3-
hydroxypropanoate (2f)
Amino alcohol 2f (16 mg, 94%) was prepared from 1f (17 mg, 0.044 mmol). 1H NMR
(500 MHz, CDCl3): δ 7.44 (bs, 1H), 7.40 (m, 1H), 7.22-7.15 (m, 2H), 5.34 (m, 1H),
5.18 (m, 1H,), 4.65 (m, 1H), 4.30 (m, 1H), 4.23-4.11 (m, 2H), 1.45 (bs, 9H,), 1.22 (t, J
13
= 7.1 Hz, 3H); C (125 MHz, CDCl3) δ 169.2, 156.5, 141.7, 130.9, 129.7, 129.3,
124.6, 122.4, 80.9, 74.7, 62.0, 59.8, 28.2, 14.0; 96:4 er determined by HPLC analysis
(Chiralcel OD-H, 5% 2-propanol in hexanes, 0.5 mL/min, λ=254 nm, R isomer 13.9
min, S isomer 14.8 min); IR (CH2Cl2) 3421, 2978, 2927, 1712, 1504, 1373, 1250 cm-
1; HRMS (m/z) calcd for C16H22BrNO5 (M+H)+ 388.0754 found 388.0747.
O
OH
Cl
EtO
NH
Boc
2g
(2S, 3S)-ethyl 2-(tert-butoxycarbonylamino)-3-(3-chlorophenyl)-3-
hydroxypropanoate (2g)
Amino alcohol 2g (43 mg, 69%) was prepared from 1g (63 mg, 0.18 mmol) 1H NMR
(500 MHz, CDCl3): δ 7.28 (m, 1H), 7.26-7.21 (m, 2H), 7.13 (m, 1H), 5.36 (m, 1H),
5.18 (m, 1H), 4.65 (m, 1H), 4.34 (m, 1H), 4.25-4.07 (m, 2H), 1.44 (bs, 9H), 1.20 (t, J
13
= 7.1 Hz, 3H); C (125 MHz, CDCl3) δ 169.3, 156.5, 141.5, 134.2, 129.4, 128.0,
126.4, 124.2, 80.9, 74.7, 61.9, 59.8, 28.2, 13.9; 66:34 er determined by HPLC
analysis (Chiralcel OD-H, 3% 2-propanol in hexanes, 0.5 mL/min, λ=254 nm, R
isomer 18.9 min, S isomer 20.7 min); IR (CH2Cl2) 3436, 2981, 2931, 1728, 1512,
1161, cm-1; HRMS (m/z) calcd for C16H22ClNO5 (M+H)+ 344.1259, found 344.1261.
8

OH
O
OMe
OMe
EtO
NH
Boc
2h
(2S,3S)-ethyl 2-(tert-butoxycarbonylamino)-3-(3,4-dimethoxyphenyl)-3-
hydroxypropanoate (1h)
Amino alcohol (25 mg, 95%) was prepared from 1h (25 mg, 0.070 mmol) and
obtained as a beige oil. 1H NMR (500 MHz, CDCl3): δ 6.85 – 6.74 (m, 3H), 5.26 (d, J
= 7.4 Hz, 1H), 5.14 (bs, 1H), 4.65 (q, J = 3.5 Hz, 1H), 4.21 – 4.10 (qd, J1 = 7.1 Hz, J2
= 2.0 Hz, 2H), 3.86 (bs, 3H), 3.86 (bs, 3H), 1.42 (bs, 9H), 1.22 (t, J = 7.1 Hz, 3H); 13C
(125 MHz, CDCl3) δ 169.8, 156.3, 148.8, 148.7, 131.7, 118.3, 110.7, 109.2, 80.58,
74.8, 61.7, 59.6, 55.8, 55.7, 28.2, 14.0; 97:3 er determined by HPLC analysis
(Chiralcel OD-H, 5% 2-propanol in hexanes, 0.5 mL/min, λ=254 nm, R isomer 39.1
min, S isomer 41.2 min); IR (CH2Cl2) 3433, 2962, 2927, 2850, 1712, 1516, 1466,
1369, cm-1. HRMS (m/z) calcd for C18H27NO7 (M+H)+ 370.1860, found 370.1860.
Double protected α-amido-β-ketoester
O
O
MeO
Boc
N
Me
3
Methyl 2-(tert-butoxycarbonyl(methyl)amino)-3-oxo-3-phenylpropanoate (3)
To a solution of methyl 2-(benzyl(tert-butoxycarbonyl)amino)ethanoate12 (234 mg,
1.15 mmol) in THF (10 mL) was added a freshly prepared LDA solution (10 mL, 1.27
mmol) at 0 °C and stirred for an additional 2 h. Then the mixture was added dropwise
to a benzoyl chloride (147 µL, 1.27 mmol) solution in THF (15 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature overnight. After
quenching with H2O (50 mL), the mixture was extracted with EtOAc (3x30 mL). The
combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo.
The crude residue was purified by flash column chromatography (EtOAc in hexanes),
the product was obtained as a clear oil (141.9 mg, 40%). 1H NMR (500 MHz, CDCl3)
mixture of rotamers: δ 12.4 (s, 1H minor), 8.00 (m, 1H, minor) 7.97 (d, 2H major and
minor), 7.58 (m, 2H major and minor), 7.47-7.40 (m, 3H major and minor), 7.40-7.32
(m, 1H major), 6.43 (s, 1H major) 5.92 (s, 1H, minor), 3.82 (bs, 3H minor), 3.79 (bs,
3H minor), 3.76 (bs, 3H major), 2.85 (bs, 3H minor), 2.80 (bs, 3H major), 2.79 (bs,
3H minor), 1.45 (s, 9H, major) 1.44 (s, 9H, minor). 13C (125 MHz, CDCl3) mixture of
rotamers δ 193.4, 192.2, 172.0, 168.8, 168.7, 168.2, 155.6, 154.3, 134.7, 134.5, 134.0,
133.0, 130.5, 128.7,128.6, 128.4, 128.2, 128.0, 127.5, 108.0, 81.5, 81.0, 80.0, 79.8,
65.0, 64.7, 62.6, 52.4, 52.2, 52.0, 36.2, 35.4, 32.3, 31.7, 28.1, 28.0, 28.0, 18.9. IR
(thin film) 3066, 2981, 1743, 1685, 1454, 1423, 1323, 1292, 1149cm-1. HRMS (m/z)
calcd for C16H21NO5 (M+H)+ 30.1493, found 308. 1496.
12 Boger, D. L.; Yohannes, D. J. Org. Chem. 1988, 53, 487-499.
9

O
OH
Me
MeO
Boc
N
4
(2R,3S)-methyl 2-(tert-butoxycarbonyl(methyl)amino)-3-hydroxy-3-
phenylpropanoate (4)
Amino alcohol (44 mg, 82%) was obtained as a yellow oil following the general
1
protocol from 3 (53 mg, 0.17 mmol). H NMR (500 MHz, CDCl3) mixture of
rotamers: δ 7.39-7.30 (m, 5H), 4.42 (m, 1H), 4.58 (bs, 1H), 4.45 (m, 1H), 3.75 (bs,
3H), 2.72 (bs, 3H), 1.37 (bs, 9H). 13C (125 MHz, CDCl3) δ 169.9, 157.2, 140.6, 128.1,
127.4, 125.9, 80.7, 73.5, 66.4, 52.3, 35.7, 28.1. 97:3 er determined by HPLC analysis
(Chiralcel OJ, 15% 2-propanol in hexanes, 0.5 mL/min, λ=210 nm, S,R isomer
(absolute configuration not determined) 25.1 min, R,S isomer 30 min). IR (neat) 3437,
2978, 2936, 1743, 1684, 1481, 1450, 1392, 1369, 1335, 1254, 1159 cm-1. HRMS
(m/z) calcd for C16H23NO5 (M+H)+ 310.1649, found 310.1651.
Determination of relative stereochemistry:
O
OH
O
HN
MeO2C
1) HCl dioxane
2) triphosgene
O
MeO
NH
Boc
2a
S 8
(4S, 5S)-methyl 2-oxo-5-phenyloxazolidine-4-carboxylate (S8)
To a solution of HCl in dioxane (4M, 3.4 mL) at 0°C was added 2a (50 mg, 0.17
mmol). The solution was warmed to ambient temperature and stirred until the
reaction was judged complete (TLC). At this point the reaction mixture was
concentrated under reduced pressure and the crude residue was taken up in saturated
NaHCO3 solution. The aqueous phase was extracted four times with EtOAc, dried
over Na2SO4, filtered and concentrated. The product was carried on to the next
reaction without further purification.
To a solution of the above product and triphosgene (79 mg, 0.27 mmol) in DCM
(1mL) at 0°C was added iPr2NEt (46 uL, 0.27 mmol). The reaction was stirred 30
min at 0°C and then stirred an additional 1 h at ambient temperature. The reaction
was quenched with saturated NaHCO3 and the aqueous phase was extracted two times
with DCM. The organic layers were dried over Na2SO4, filtered and concentrated and
then subjected to flash chromatography (1:1 Hexanes: EtOAc) to yield the desired
product S8.
1H NMR (500 MHz, CDCl3) δ 7.42 – 7.35 (m, 3H), 7.34 – 7.30 (m, 2H), 5.84 (d, J =
9.0 Hz, 1H), 5.42 (s, 1H), 4.67 (d, J = 9.0 Hz, 1H), 3.24 (s, 3H).13
Evaluation of the relevant J-coupling constants indicated the cis oxazolidine
corresponding to the anti amino alcohol.
O
OH
O
N
1) HCl dioxane
2) triphosgene
O
MeO
N
MeO2C
Boc
4
S 10
(4S,5R)-methyl 3-methyl-2-oxo-5-phenyloxazolidine-4-carboxylate (S10)
13 Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153-2156., Lago, M. A.;
Samanen, J.; Elliott, J. D. J. Org. Chem. 1992, 57, 3493-3496.
10

To a solution of HCl in dioxane (4M, 9.38 mL) stirring at 0°C was added 4 (144 mg,
0.47 mmol). The reaction was warmed to room temperature and stirred for an
additional 30 minutes. Upon completion of the reaction the solution was concentrated
under reduced pressure and the residue was then taken up in saturated NaHCO3. The
aqueous layer was extracted five times with DCM and the combined organic layers
were dried over Na2SO4. The crude residue was subjected to flash chromatography
(2:1  1:1 hexanes: EtOAc) to yield the product S9 (82 mg, 84 % yield)
Syn diastereomer: 1H NMR (500 MHz, CDCl3) δ 7.34 (m, 3H), 7.29 (m, 2H), 4.60 (d,
J = 7.6 Hz, 1H), 3.55 (s, 3H), 3.22 (d, J = 7.6 Hz, 1H), 2.38 (s, 3H).14
To a solution of S9 (82 mg, 0.39 mmol) and triphosgene (290 mg, 0.98 mmol) in
DCM (3.6 mL) at 0°C was added iPr2NEt (170 uL, 0.98 mmol). The reaction was
stirred 30 min at 0°C and then stirred an additional 1 h at ambient temperature. The
reaction was quenched with saturated NaHCO3 and the aqueous phase was extracted
two times with DCM. The organic layers were dried over Na2SO4, filtered and
concentrated and then subjected to flash chromatography (1:1 Hexanes: EtOAc) to
yield the desired product S10.
1H NMR (500 MHz, CDCl3): δ 7.44 – 7.36 (m, 5H), 5.46 (d, J = 4.9 Hz, 1H), 4.14 (d,
13
J = 4.9 Hz, 1H), 3.88 (bs, 3H), 2.98 (bs, 3H). C (125 MHz, CDCl3) δ 169.6, 157.2,
138.1, 129.1, 129.0, 125.1, 76.5, 66.7, 53.0, 30.4. IR (CH2Cl2) 2981, 2924, 1743,
+
1439, 1396, 1311, 1230 cm-1. HRMS (m/z) calcd for C12H13NO4 (M+H) 236.0917,
found 236.0917.
Evaluation of the relevant J-coupling constants indicated the trans oxazolidine
corresponding to the syn amino alcohol.
14 Seashore-Ludlow, B.; Torssell, S.; Somfai, P. Eur. J. Org. Chem. 2010, 2010,
3927-3933.
11

O
H
N
Ot-Bu
O
O
O
1a
500 MHz, CDCl3
125 MHz, CDCl3
12

O
O
OMe
EtO
HN
Boc
1b
500 MHz, CDCl3
125 MHz, CDCl3
13

O
Br
O
EtO
NH
Boc
1c
mixture of rotamers/enol isomer
500 MHz, Toluene-D6
125 MHz, CDCl3
14

O
O
EtO
HN
Boc
F
1d
500 MHz, CDCl3
125 MHz, CDCl3
15

O
O
EtO
HN
Boc
Br
1e
500 MHz, CDCl3
125 MHz, CDCl3
16

O
O
Br
EtO
HN
Boc
1f
500 MHz, CDCl3
125 MHz, CDCl3
17

O
O
Cl
EtO
HN
Boc
1g
500 MHz, CDCl3
125 MHz, CDCl3
18

O
O
OMe
OMe
EtO
HN
Boc
1h
500 MHz, CDCl3
125 MHz, CDCl3
19

OH
HN
S7
500 MHz, CDCl3
125 MHz, CDCl3
20

OH
O
MeO
NH
Boc
2a
500 MHz, CDCl3
125 MHz, CDCl3
21

OMe
OH
O
EtO
NH
Boc
2b
500 MHz, CDCl3
125 MHz, CDCl3
22

OH Br
O
EtO
NH
Boc
2c
500 MHz, CDCl3
125 MHz, CDCl3
23

O
OH
EtO
NH
Boc
F
2d
500 MHz, CDCl3
125 MHz, CDCl3
24

O
OH
EtO
NH
Boc
Br
2e
500 MHz, CDCl3
125 MHz, CDCl3
25

O
OH
Br
EtO
NH
Boc
2f
500 MHz, CDCl3
125 MHz, CDCl3
26

O
OH
Cl
EtO
NH
Boc
2g
500 MHz, CDCl3
125 MHz, CDCl3
27

OH
O
OMe
OMe
EtO
NH
Boc
2h
500 MHz, CDCl3
125 MHz, CDCl3
28

O
O
MeO
Boc
N
Me
3
mixture of rotamers
500 MHz, CDCl3
125 MHz, CDCl3
29