Enantioselective synthesis of β-amino alcohols and α-amino acids via a copper catalyzed addition of diorganozinc reagents to N-phosphinoylimines

Article abstract of DOI:10.1016/j.tet.2005.03.113

Enantioenriched β-amino alcohols were prepared via an asymmetric addition of diethylzinc, catalyzed by the BozPHOS·Cu(I) complex, on in situ formed N-phosphinoylimines. The nature of the hydroxyl protecting groups was found to affect the enantioselectivities. Subsequent deprotection and oxidation of N-phosphinoyl β-amino alcohols afforded optically active α-amino acids (97% ee).

Full text of DOI:10.1016/j.tet.2005.03.113

Tetrahedron 61 (2005) 6186–6192
Enantioselective synthesis of b-amino alcohols and a-amino acids
via a copper catalyzed addition of diorganozinc reagents
to N-phosphinoylimines
*
ˆ ´ ´
Jean-Nicolas Desrosiers, Alexandre Cote and Andre B. Charette
´
´
´
Departement de Chimie, Universite de Montreal, PO Box 6128, Station Downtown, Montreal, Que., Canada H3C 3J7
Received 8 November 2004; revised 4 February 2005; accepted 4 March 2005
Available online 20 April 2005
Abstract—Enantioenriched b-amino alcohols were prepared via an asymmetric addition of diethylzinc, catalyzed by the BozPHOS$Cu(I)
complex, on in situ formed N-phosphinoylimines. The nature of the hydroxyl protecting groups was found to affect the enantioselectivities.
Subsequent deprotection and oxidation of N-phosphinoyl b-amino alcohols afforded optically active a-amino acids (97% ee).
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
reagents to N-phosphinoylalkylimines (2) substituted with
a b-alkoxy functionality. Subsequent oxidation of the
deprotected b-amino alcohol will afford a-amino acid (3).
The N-diphenylphosphinoyl protecting group was used
due to its facile cleavage under mildly acidic conditions
with no racemization. Diastereoselective methodologies
were developed to generate b-amino alcohols.3 One
powerful method for preparing b-amino alcohols was
a one-pot catalytic enantioselective reaction developed
by Hoveyda and Snapper.4 Excellent ee values were
obtained, but this procedure suffered from use of an
excess of diorganozinc reagents and a N-aryl pro-
tecting group that can be cleaved only under oxidizing
conditions.
The synthesis of b-amino alcohols is of considerable current
interest as they are important sub-units commonly found
in natural products, biologically active molecules, ligands,
and chiral auxiliaries, or simply used as building blocks.1
b-Amino alcohols are also potential precursors for the
synthesis of non-proteinogenic a-amino acids. Incorpo-
ration of these unnatural compounds into proteins can lead
to conformational changes, non-scissile peptide mimics and
biologically active molecules with novel properties.2
The method we chose to synthesize b-amino alcohols
(1, Scheme 1) was a nucleophilic addition of diorganozinc
Scheme 1. Strategy to generate N-phosphinoylalkylimines, b-amino alcohols and a-amino acids.
Keywords: b-Amino alcohols; a-Amino acids; Enantioselective synthesis; Imines; Copper; Diorganozinc reagents.
*
Corresponding author. Tel.: C1 514 343 6283; fax: C1 514 343 5900; e-mail: andre.charette@umontreal.ca
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.113

J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
6187
One drawback of using N-phosphinoylalkylimines with
a-enolizable protons was the difficulty to isolate them due to
their instability. Two strategies were used to solve this
problem. The first one (path A) was a one-pot procedure
involving generation of the imine from an in situ
condensation of the aldehyde and the amide, using the
diorganozinc reagent as a dehydrating agent. This approach
led to excellent ee values but low conversions. The second
(path B), was an in situ formation of the imine from a stable
precursor 4 containing a leaving group (–OMe,5 –SO2Ph,6
benzotriazoyl,7 –OTMS,8 or succinimyl9) on the a-position
of the N-protected amine.
product precipitated from the reaction mixture. The
synthesis of the sulfinic acid adduct 7d was problematic
because it did not lead to any precipitation of the desired
product. Consequently, the latter needed to be purified from
the crude mixture by flash chromatography and it decom-
posed upon isolation.
With these compounds 7 in hand, we studied the effect of
protecting groups (PG) on the level of enantiocontrol in the
Cu-catalyzed diethylzinc addition (Table 2). The sulfinic
acid adducts 7 were submitted to the optimized reaction
conditions recently developed.11 As the data summarized in
Table 2 illustrate, the BozPHOS$Cu catalyzed addition of
diethylzinc was strongly affected by the protecting group. It
was found that the bulky trityl group 8b (entries 4–7)
provided best isolated yields (81–92%) and best ee values
(75–97%).
Recently, we reported an efficient methodology to generate
the N-phosphinoylalkylimines in situ, from sulfinic acid
(LGZ–SO2Tol) adducts, which was compatible with
the BozPHOS (5)$Cu asymmetric catalyzed addition of
diorganozinc reagents (Fig. 1).10,11 Because it afforded
excellent yields and ee values, we planned to use this
strategy (path B) to generate optically active b-amino
alcohols (1) and a-amino acids (3).
Table 2. Enantioselective addition of diethylzinc to sulfinic acid adducts 7
Entry
PG
Bn
Product
Temperature
(8C)
Yield
(%)
eea
(%)
1b
2
8a
K20
K40
K60
95
96
83
84
86
89
3
4
5
6
7
Tr
8b
0
92
81
84
89
93
95
97
75
K40
K60
K78
Figure 1. Structure of (R,R)-BozPHOS, ((R,R)-MeDuPHOS monoxide).
2. Results and discussion
8
9
10
Piv
8c
10
0
K20
49
51
69
79
92
87
We initially identified which hydroxyl protecting group
(PG) was the most suitable for the BozPHOS$Cu catalyzed
asymmetric addition. Thus, sulfinic acid adducts 7 were
prepared with several hydroxyl protecting groups (PG) by
mixing the aldehyde 6, diphenylphosphinic amide and
p-toluenesulfinic acid in diethyl ether. The benzyl protected
substrate 7a was produced in the highest yield of 97%
(Table 1, entry 1). It was found that strictly anhydrous
conditions were mandatory to generate the adduct 7b
bearing the trityl moiety. Otherwise, acidic traces of water
deprotected the a-trityloxyacetaldehyde 6b and no desired
11
12
TBDMS
8d
0
K60
79
67
75c
79c
a Enantiomeric excesses were determined by HPLC on a chiral stationary
phase unless otherwise stated.
b Results determined after 48 h.
c Enantiomeric excesses were determined by SFC on a chiral stationary
phase.
The temperature was another parameter that considerably
affected the enantiomeric excesses. The most striking
example was a 13% ee difference for a variation of 10 8C
with the pivaloyl adduct 8c (entries 8 and 9). In addition, a
temperature of K60 8C was required to reach 97% ee with
substrate 8b. Finally, we changed the sulfinate leaving
group by a benzotriazoyl substituent (4, LGZBt). Com-
parable ee values were obtained but, owing to its low
solubility, modest yields were obtained.
Table 1. One-pot synthesis of sulfinic acid adducts 7
Removal of both the trityl and the N-diphenylphosphinoyl
groups from 8b was possible using HCl/MeOH, affording
the free b-amino alcohol in quantitative yield (Scheme 2).
However, our goal was to develop reaction conditions to
access monoprotected a-amino acids 10 and 13, which
could be more useful in peptidic synthesis. Several
conditions were screened for selective trityl deprotection
(hydrogenolysis,12 ZnBr2,13 BCl3,14 BBr3, BBr3$DMS,
TFA,15 TFA and TFAA followed by Et3N16 and acetyl
chloride17) but the best procedure was a reductive
Entry
PG
Product
Time (h)
Yield (%)
1
Bn
Tr
Piv
TBDMS
7a
7b
7c
7d
20
15
26
15
97
70
54
38b
2a
3
4
a Required strictly anhydrous conditions.
b Determined after flash chromatography.

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J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
Scheme 2. Synthesis of a-amino acids from 8b.
demercuration reported by Maltese.18 A 10-fold excess of
HgCl2 was required to afford the b-amino alcohol 9 in 98%
yield and 97% ee.
3. Conclusion
In summary, based on the BozPHOS$Cu catalyzed addition
of diorganozinc reagents, we have developed a practical
procedure for the synthesis of enantioenriched (97% ee)
b-amino alcohols.
The next challenge was the oxidation of the b-amino alcohol
9 (Scheme 2). The complexity of this step resided in the
presence of the protic acid sensitive N-phosphinoyl group
and the possibility of the chiral center to racemize.
Unsuccessful procedures tried included TEMPO free radical
with sodium chlorite19 or with trichloroisocyanuric acid,20
IBX and 2-hydroxypyridine21 or PDC22 and all afforded
total or partial degradation of the starting material or of the
desired amino acid. The most successful procedure was the
Sharpless oxidation23 with RuCl3 and NaIO4 which
generated the a-amino acid 10 in 60% yield without erosion
in enantiomeric purity and 10% of the side-product 11
caused by over oxidation. Subsequent esterification with
diazomethane and straightforward deprotection of the
N-phosphinoyl group in mildly acidic conditions afforded
the enantioenriched (97% ee) methyl ester hydrochloride
derivative 13 of ethylglycine in 89% yield over two steps.
The latter was an excellent framework for the catalytic
enantioselective synthesis of optically active a-amino acids
from a nucleophilic addition on imines. This method
allowed generation of both enantiomers of a-amino acids,
since both enantiomers of the BozPHOS ligand can be
prepared, from the two commercially available enantiomers
of Me-DuPHOS. We have also previously reported that the
reaction was compatible with different dialkylzinc (Me2Zn,
n-Bu2Zn and i-Pr2Zn) or functionalized reagents.10
4. Experimental
4.1. General
All non-aqueous reactions were run under an inert
atmosphere (argon) with rigid exclusion of moisture from
reagents and glassware by using standard techniques for
manipulating air-sensitive compounds. All glassware was
stored in the oven and/or was flame-dried before use under
an inert atmosphere of gas. Anhydrous solvents were
obtained either by filtration through drying columns
(ether, toluene, acetonitrile, dichloromethane) on a Glass-
Contour system (Irvine, CA) or by distillation over
sodium/benzophenone (toluene). Analytical TLC was
performed on precoated, glass-backed silica gel (Merck 60
F254). Visualization of the developed chromatogram was
performed by UV absorbance, aqueous cerium molybdate,
ethanolic phosphomolybdic acid, ninhydrine, p-anisalde-
hyde or aqueous potassium permanganate. Flash column
chromatography was performed by using 230–400 mesh
An alternative approach toward a-amino acids was to start
from the addition product 14 of the N-phosphinoylimine
derived from 2-furaldehyde (Scheme 3).24 The enantio-
selective synthesis of the latter substrate from the Boz-
PHOS$Cu catalyzed addition of diorganozinc reagents was
reported by our research group.10 By treating compound 14
with the same oxidation conditions mentioned above
(Scheme 2), a similar yield of the a-amino acid 10 was
obtained.
´
silica [EM Science or Silicycle (Quebec City, QC, Canada)]
of the indicated solvent system according to standard
technique. Melting points were obtained on a Buchi (Flawil,
Switzerland) melting point apparatus and are uncorrected.
NMR spectra (1H, 13C, 31P) were recorded on Bruker AV
300, AMX 300, AV 400 or ARX 400 spectrometers.
Scheme 3. Oxidative cleavage of the N-phosphinoylimine 14 derived from
2-furaldehyde.

J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
6189
1
Chemical shifts for H NMR spectra are recorded in ppm
acid (1.56 g, 10 mmol, 1.5 equiv) was added in one portion
at room temperature. The reaction mixture was allowed to
stir (200 rpm) under closed atmosphere for a specific period
of time, during which a white precipitate was slowly
formed. The mixture was filtered through a sintered glass
funnel and the white solid was washed with diethyl ether
and dried under vacuum to afford the sulfinic acid adduct 7.
with the solvent resonance as the internal standard (CDCl3,
d 7.27 ppm, DMSO-d6, d 2.50 ppm or D2O d 4.80 ppm).
Data are reported as follows: chemical shift, multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; qn, quintet; sept,
septet; oc, octet; m, multiplet; br, broad), coupling constant
in Hz, and integration. Chemical shifts for 13C NMR spectra
are recorded in ppm from tetramethylsilane by using the
central peak of deuterochloroform (77.00 ppm) or deuter-
ated DMSO (39.52 ppm) as the internal standard.
All spectra were obtained with complete proton decoupling.
Infrared spectra were taken on a Perkin–Elmer Spectrum
One FTIR and are reported in reciprocal centimeters
(cmK1). Optical rotations were determined with a Perkin–
Elmer 341 polarimeter at 589 or 546 nm. Data are reported
as follows: [a]tDemp, concentration (c in g/100 mL) and
solvent. Combustion analyses were performed by the
4.2.1. N-{2-(Benzyloxy)-1-[(4-methylphenyl)sulfonyl]-
ethyl}-P,P-diphenylphosphinic amide (7a). The general
procedure was followed (specific conditions: 20 h). The
crude compound (white powder) was used without purifi-
cation for the next step. Yield: 97%. Mp 125.0–126.0 8C
(dec); Rf 0.45 (100% EtOAc); 1H NMR (300 MHz, DMSO-
d6) d 2.34 (s, 3H), 3.80 (dd, JZ10.4, 7.5 Hz, 1H), 3.87 (dd,
JZ10.4, 3.5 Hz, 1H), 4.38 (d, JZ11.7 Hz, 1H), 4.44 (d, JZ
11.8 Hz, 1H), 4 .78 (m, 1H), 6.49 (t, JZ11.7 Hz, 1H), 7.11–
7.65 (m, 19H); 13C NMR (100 MHz, DMSO-d6) d 21.2,
67.9, 71.6, 72.3, 127.6, 127.7, 128.1 (d, JC–PZ13.0 Hz),
128.2 (d, JC–PZ13.2 Hz), 128.2, 129.1, 129.5, 131.2 (d,
´
Elemental analysis Laboratory of the Universite de
´
Montreal.
Analytical HPLC was performed on a Hewlett–Packard
analytical instrument (model 1100) equipped with a diode
array UV detector. Data for determination of the enantio-
meric excess are reported as follows: column type, eluent,
flow rate, and retention time (tr). Analytical Supercritical
Fluid Chromatography was performed on a Berger SFC
Analytical Instrument equipped with a diode array UV
detector. Data are reported as follows: column type, eluent,
flow rate: retention time (tr). Analytical gas chromatography
was carried out on a Hewlett–Packard 5880A gas chro-
matograph equipped with a splitless mode capillary injector
and a flame ionization dectector. Unless otherwise noted,
the injector and detector temperatures were set to 250 8C
and hydrogen was used as the carrier gas (63 psi). Data are
reported as follows: column type, column length, initial
temperature, initial time, rate, final temperature, final time:
retention time (tr).
JC–PZ10.1 Hz), 131.4 (d, JC–PZ10.0 Hz), 131.6 (d, JC–P
10.0 Hz), 131.6 (d, JC–PZ10.2 Hz), 132.3 (d, JC–P
77.1 Hz), 134.0, 134.5 (d, JC–PZ73.3 Hz), 137.6, 144.4;
31P NMR (121 MHz, DMSO-d6) d 25.3; IR (Neat) 3065,
2877, 1595, 1435, 1289, 1191, 1125, 1085, 865, 725, 692,
666, 583 cmK1. LRMS (APCI) m/z calcd for C21H20NO2P
[MKSO2Tol]C: 350.1 found: 350.1.
Z
Z
4.2.2. N-[1-[(4-Methylphenyl)sulfonyl]-2-(trityloxy)-
ethyl]-P,P-diphenylphosphinic amide (7b). The general
procedure was followed, except that reagents and glassware
were dried, anhydrous ether was used and the reaction was
run under inert atmosphere (specific conditions: 15 h). The
crude compound (white powder) was used without purifi-
cation for the next step. Yield: 70%. Mp 99.5–100.0 8C
1
(dec); H NMR (400 MHz, DMSO-d6) d 2.35 (s, 3H), 3.41
(dd, JZ8.1, 6.8 Hz, 1H), 3.51 (dd, JZ9.8, 4.1 Hz, 1H),
4.74–4.78 (m, 1H), 6.61 (dd, JZ12.5, 12.3 Hz, 1H), 7.20–
7.30 (m, 17H); 7.40–7.43 (m, 4H), 7.47–7.54 (m, 6H); 7.70
(dd, JZ11.8, 7.3 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
d 22.2, 63.3, 73.2, 87.9, 128.0, 128.0, 128.9–129.1 (m),
129.2, 130.1 (d, JC–PZ8.2 Hz), 132.3 (dd, JC–PZ11.8,
Cu(OTf)2 and RuCl3$H2O were purchased from Strem
Chemicals (Newburyport, MA). Diazomethane was pre-
pared from Diazaldw. p-Toluenesulfinic acid was formed by
dissolving its hydrated sodium salt in a minimum of hot
10% vol/vol HCl (the resulting pH must be lower than 3)
and crystallization at 4 8C. Further filtration and drying
under vacuum led to white crystals. Diethylzinc was
purchased neat from Akzo Nobel and used without
purification. All others starting materials were purchased
from Aldrich or Alfa Aesar (Ward Hill, MA). Unless
otherwise stated, commercial reagents were used without
purification. Racemic samples for HPLC analysis were
prepared by addition of Et2Zn/CuCN in toluene to the
sulfinic acid adducts. Ligand (R,R)-BozPHOS was prepared
according to literature procedure.10
11.4 Hz), 132.5 (d, JC–PZ9.5 Hz), 135.0, 135.0 (dd, JC–P
Z
125, 59 Hz), 144.0, 145.3; 31P NMR (161 MHz, DMSO-d6)
d 27.0; IR (Neat) 3058, 2879, 1314, 1299, 1185, 1154, 1125,
1062, 702, 689 cmK1. Elemental analysis calcd for
C39H34NO4PS: C, 72.77; H, 5.32; N, 2.18; S, 4.98 found:
C, 72.75; H, 5.55; N, 2.24; S, 4.97.
4.2.3. 2-[(Diphenylphosphoryl)amino]-2-[(4-methyl-
phenyl)sulfonyl]ethyl pivalate (7c). The general procedure
was followed(specific conditions:26 h). Thecrudecompound
(white powder) was used without purificationfor the next step.
Yield: 54%. Mp 134.0–135.0 8C (dec); 1H NMR (400 MHz,
DMSO-d6) d 0.93 (s, 9H), 2.39 (s, 3H), 4.21 (dd, JZ13.0,
7.5 Hz, 1H), 4.52 (dd, JZ11.5, 4.3 Hz, 1H), 4.77–4.80 (m,
1H), 6.64 (dd, JZ12.0, 11.8 Hz, 1H), 7.33 (d, JZ7.9 Hz, 2H),
7.37–7.55 (m, 4H), 7.44–7.55 (m, 4H), 7.66–7.71 (m, 4H);13C
NMR (100 MHz, DMSO-d6) d 22.2, 27.6, 39.1, 62.9, 71.6,
129.2 (dd, JC–PZ27.0, 12.5 Hz), 130.4 (d, JC–PZ22.0 Hz),
132.1 (dd, JC–PZ19.9, 10.3 Hz), 132.6 (d, JC–PZ22.0 Hz),
134.4, 134.7 (dd, JC–PZ125.7, 42.7 Hz), 145.8, 178.2; 31P
NMR (161 MHz, DMSO-d6) d 26.7; IR (Neat) 3061, 2976,
4.2. General procedure for preparation of sulfinic acid
adducts 7
A round-bottomed flask equipped with a magnetic stirring
bar, was charged with P,P-diphenylphosphinic amide
(1.43 g, 6.6 mmol, 1 equiv). Diethyl ether (70 mL,
w0.1 M) was then added to the flask. The resulting
suspension was stirred for 5 min and the aldehyde 6
(10 mmol, 1.5 equiv) was added, then p-toluenesulfinic

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J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
2949, 1729, 1438, 1302, 1291, 1279, 1192, 1165, 1135, 1126,
972, 668 cmK1. LRMS (APCI) m/z calcd for C19H22NO3P
[MKSO2Tol]C: 344.1 found: 344.1.
7.4 Hz, 3H), 1.69 (oc, JZ7.0 Hz, 2H), 3.05–3.20 (m, 1H),
3.27 (dd, JZ10.4, 7.0 Hz, 1H), 3.57 (d, JZ3.8 Hz, 2H),
4.47 (d, JZ12.0 Hz, 1H), 4.52 (d, JZ12.0 Hz, 1H), 7.20–
7.30 (m, 5H), 7.30–7.50 (m, 6H), 7.84–7.94 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 10.4, 15.2, 27.0 (d, JC–P
6.2 Hz), 52.5, 72.6 (d, JC–PZ4.1 Hz), 73.1, 127.5, 127.6,
128.2, 128.4, 131.6 (d, JC–PZ2.3 Hz), 132.0 (d, JC–P
Z
4.2.4. N-{2-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(4-methyl-
phenyl)sulfonyl]ethyl}-P,P-diphenylphosphinic amide
(7d). The general procedure was followed, but the product
did not precipitate (specific conditions: 15 h). The reaction
mixture was evaporated under reduced pressure, and the
crude mixture was purified by flash chromatography (70%
EtOAC in hexanes). A white foam was obtained (Yield:
38%) and decomposed upon isolation, so it had to be used
Z
7.0 Hz), 132.1 (d, JC–PZ7.0 Hz), 133.7 (d, JC–PZ10.1 Hz),
138.2; 31P NMR (121 MHz, CDCl3) d 23.5; IR (Neat) 3058,
2841, 1435, 1183, 1108, 1049, 998, 721, 691, 573 cmK1
.
LRMS (ACPI) m/z calcd for C23H26NO2P [MCH]C: 380.1
found: 380.1. Elemental analysis calcd for C23H26NO2P: C,
72.81; H, 6.91; N, 3.69 found: C, 72.71; H, 7.13; N, 3.72.
1
immediately for the next step. Rf 0.50 (100% EtOAc); H
NMR (400 MHz, DMSO-d6) d 0.05 (s, 6H), 0.77 (s, 9H),
2.36 (s, 3H), 3.96 (dd, JZ7.5, 6.6 Hz, 1H), 4.15 (dd, JZ8.4,
4.6 Hz, 1H), 4.53–4.62 (m, 1H), 6.36 (dd, JZ11.9, 11.8 Hz,
1H), 7.29 (d, JZ8.0 Hz, 2H), 7.35–7.45 (m, 4H), 7.48–7.53
(m, 4H), 7.62 (d, JZ8.0 Hz, 2H), 7.71 (dd, JZ12.1, 7.9 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) d K4.6, 18.9, 21.9,
26.8, 62.7, 74.8, 125.5, 129.1 (dd, JC–PZ17.2, 12.7 Hz),
130.2 (d, JC–PZ45.9 Hz), 132.2–132.6 (m), 132.5, 134.8
(dd, JC–PZ148.0, 24.3 Hz), 145.3; 31P NMR (161 MHz,
DMSO-d6) d 26.6.
4.3.2. P,P-Diphenyl-N-{1-[(trityloxy)methyl]propyl}-
phosphinic amide (8b). The general procedure was
followed (specific conditions: K60 8C) to afford 8b as a
white solid. Yield 84%, enantiomeric excess (97% ee) was
determined by HPLC analysis (Chiralpak AD-H, 90:10
hexanes–i-PrOH, 1.0 mL/min: (S)-8b trZ10.8 min, (R)-8b
trZ13.6 min). [a]D20ZK8.1 (c 1.00, CH2Cl2); mp 67.5–
68.5 8C; Rf 0.35 (70% EtOAc in hexanes); 1H NMR
(300 MHz, CDCl3) d 0.86 (t, JZ7.4 Hz, 3H), 1.86 (dqn,
JZ34.5, 7.4 Hz, 2H), 3.08–3.16 (m, 1H), 3.21–3.33 (m,
2H), 3.28 (dd, JZ3.7, 3.7 Hz, 1H), 7.25–7.51 (m, 21H),
7.79–7.93 (m, 4H); 13C NMR (75 MHz, CDCl3) d 10.8,
28.1, 53.4, 65.7, 86.8, 127.5, 128.3, 128.9 (d, JC–PZ12,
5 Hz), 129.1, 132.1 (dd, JC–PZ8.8, 2.5 Hz), 132.6 (dd,
JC–PZ33.6, 9.4 Hz), 133.4 (d, JC–PZ71.9 Hz), 144.4; 31P
NMR (121 MHz, CDCl3) d 22.5; IR (Neat) 3056, 2928,
1437, 1189, 1089, 1068, 1029, 722, 693 cmK1. Elemental
analysis calcd for C35H34NO2P: C, 79.07; H, 6.45; N, 2.63
found: C, 78.90; H, 6.63; N, 2.77.
4.3. General procedure for the asymmetric addition on
sulfinic acid adducts 7
A flame-dried round-bottomed flask equipped with a
magnetic stirring bar was charged with Cu(OTf)2 (6.5 mg,
0.018 mmol, 4.5 mol%) and (R,R)-BozPHOS (6.4 mg,
0.02 mmol, 5 mol %) under argon. Anhydrous toluene
(1.5 mL) was added to the flask at room temperature via a
syringe. The resulting dark green heterogeneous solution
was stirred for 1 h at room temperature and neat diethylzinc
(102 mL, 1 mmol, 2.5 equiv) was added at room temperature
under argon via a gas-tight syringe (Caution: pyrophoric).
The resulting dark brown suspension was stirred for 20 min
at room temperature. The mixture was cooled to the
temperature described in Table 2 and stirred 10 min at
that temperature. Substrate 7 (0.4 mmol, 1 equiv) in
anhydrous toluene (1.5 mL) was added via a teflon cannula
(heterogeneous mixture) under argon. The flask was rinsed
with 1 mL, and 0.5 mL of toluene. The reaction mixture was
allowed to stir 20 h at the temperature mentioned above
under argon. Aqueous saturated ammonium chloride (5 mL)
was then added dropwise. The mixture was brought to room
temperature and poured into a separatory funnel containing
aqueous saturated ammonium chloride (20 mL). The
biphasic mixture was extracted with dichloromethane (3!
20 mL). The combined extracts were dried over Na2SO4,
filtered and evaporated under reduced pressure. The crude
product was purified by flash chromatography with ethyl
acetate 100% to afford compound 8.
4.3.3. 2-[(Diphenylphosphoryl)amino]butyl pivalate (8c).
The general procedure was followed (specific conditions:
0 8C) to afford 8c as a white solid. Yield 51%, enantiomeric
excess (92% ee) was determined by HPLC analysis
(Chiralpak AD-H, 80:20 hexanes–i-PrOH, 1.0 mL/min:
(R)-8c trZ6.6 min, (S)-8c trZ7.8 min). [a]2D1ZK23.3 (c
0.63, CH2Cl2); mp 95.5–96.5 8C; Rf 0.18 (70% EtOAc in
hexanes); 1H NMR (400 MHz, CDCl3) d 0.92 (t, JZ7.4 Hz,
3H), 1.19 (s, 9H), 1.61–1.66 (m, 2H), 3.01 (dd, JZ10.9,
6.4 Hz, 1H), 3.20–3.30 (m, 1H), 4.13 (d, JZ3.0 Hz, 1H),
4.14 (d, JZ2.6 Hz, 1H), 7.42–7.48 (m, 6H), 7.88–7.91 (m,
4H); 13C NMR (100 MHz, CDCl3) d 10.0, 26.9, 27.0, 38.7,
51.6, 66.5, 128.4 (dd, JC–PZ12.5, 6.4 Hz), 131.7, 131.9 (dd,
JC–PZ9.4, 2.8 Hz), 133.1 (d, JC–PZ21.1 Hz), 178.1; 31P
NMR (121 MHz, CDCl3) d 23.5; IR (Neat) 2966, 2933,
2873, 1725, 1437, 1282, 1182, 1159, 1121, 1108, 722,
693 cmK1; LRMS (APCI) m/z calcd for C21H28NO3P [MC
H]C: 374.2 found: 374.2. Elemental analysis calcd for
C21H28NO3P: C, 67.54; H, 7.56; N, 3.75 found: C, 67.24; H,
7.87; N, 3.82.
4.3.1. N-{1-[(Benzyloxy)methyl]propyl}-P,P-diphenyl-
phosphinic amide (8a). The general procedure was
followed, except that the reaction was run 48 h (specific
conditions: K60 8C) to afford 8a as a white solid. Yield
83%, enantiomeric excess (89% ee) was determined by
HPLC analysis (Chiralpak AD-H, 80:20 hexanes–i-PrOH,
1.0 mL/min: (S)-8a trZ9.52 min, (R)-8a trZ11.83 min).
[a]2D1ZK32.2 (c 1.30, CH2Cl2); mp 89.0–91.0 8C; Rf 0.20
(100% EtOAc); 1H NMR (300 MHz, CDCl3) d 0.89 (t, JZ
4.3.4. N-[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)pro-
pyl]-P,P-diphenylphosphinic amide (8d). The general
procedure was followed (specific conditions: K60 8C) to
afford 8d as a colorless oil. Yield 67%, enantiomeric excess
(79% ee) was determined by SFC analysis (Chiralpak AD,
10% MeOH, 1.5 mL/min: (S)-8d trZ16.1 min, (R)-8d trZ
18.9 min). [a]2D2ZK20.0 (c 1.40, CH2Cl2); Rf 0.42 (100%
EtOAc); 1H NMR (400 MHz, CDCl3) d 0.03 (d, JZ7.7 Hz,

J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
6191
6H), 0.86 (s, 9H), 1.54–1.71 (m, 2H), 2.97–3.07 (m, 1H),
3.20 (dd, JZ10.5, 7.1 Hz, 1H), 3.67 (d, JZ4.1 Hz, 2H),
7.42–7.47 (m, 6H), 7.87–7.97 (m, 4H); 13C NMR
(100 MHz, CDCl3) d K5.6, 10.3, 18.1, 25.7, 26.4, 53.7,
65.2, 128.2 (dd, JC–PZ12.5, 4.7 Hz), 131.5, 131.9 (dd,
JC–PZ20.3, 9.4 Hz), 133.1 (dd, JC–PZ129.1, 11.2 Hz); 31P
NMR (121 MHz, CDCl3) d 22.6; IR (Neat) 2954, 2928,
80 mL). Combined extracts were dried over Na2SO4,
filtered and evaporated under reduced pressure to afford
106 mg of the title compound as a white solid (60% yield).
The crude compound was used without purification for the
next step. Analytically pure product can be obtained by flash
chromatography with 1% AcOH in EtOAc. Enantiomeric
excess (97% ee) was determined by SFC analysis
(Chiralpak AD, 20% MeOH, 1.5 mL/min: (S)-10 trZ
36.9 min, (R)-10 trZ41.3 min). [a]2D0ZK49.5 (c 1.00,
CH2Cl2); mp 130.0–131.0 8C; Rf 0.47 (1% AcOH in
EtOAc); 1H NMR (400 MHz, CDCl3) d 0.95 (t, JZ
7.3 Hz, 3H), 1.77 (qn, JZ7.2 Hz, 2H), 3.73 (dq, JZ21.5,
5.0 Hz, 1H), 3.91 (dd, JZ10.7, 3.9 Hz, 1H), 7.43–7.56 (m,
6H), 7.90–7.97 (m, 4H), 12.57–12.79 (br s, 1H); 13C NMR
2856, 1438, 1253, 1190, 1106, 835, 723, 697, 630 cmK1
;
LRMS (APCI) m/z calcd for C22H34NO2PSi [MCH]C:
404.2 found: 404.2.
4.3.5. N-[1-(Hydroxymethyl)propyl]-P,P-diphenylphos-
phinic amide (9). A flame-dried round-bottomed flask
equipped with a magnetic stirring bar was charged with
compound 8b (270 mg, 0.50 mmol, 1 equiv) and HgCl2
(1.37 g, 5.07 mmol, 10 equiv) under argon. Anhydrous
MeCN (25 mL, 0.02 M) was added to the flask. The
colorless solution was stirred for 30 min at room tempera-
ture under argon. Small solid portions of NaBH4 were added
to the stirred solution and a dark grey precipitate was
formed (gas formation). Additions of NaBH4 were stopped
when the precipitate formed 3/4 of the solution and no gas
was formed. The mixture was stirred 5 min at room
temperature, then was brought to 0 8C. Small portions of
H2O (total of 100 mL) were added (gas formation). The
mixture was warmed to room temperature and stirred
25 min. The mixture was extracted with DCM (3!80 mL).
The combined extracts were dried over Na2SO4, filtered and
evaporated under reduced pressure. The crude product was
purified by flash chromatography with 100% DCM to
remove the trityl moiety, then with 5% MeOH in DCM to
afford 145 mg of the title compound as a white solid (98%
yield). Enantiomeric excess (97% ee) was determined by
SFC analysis (Chiralpak AD, 15% MeOH, 1.5 mL/min:
(S)-9 trZ29.3 min, (R)-9 trZ32.1 min). [a]2D0ZK39.3
(c 1.00, CH2Cl2); mp 139.5–141.0 8C; Rf 0.34 (10%
MeOH in DCM); 1H NMR (300 MHz, CDCl3) d 1.00
(t, JZ7.4 Hz, 3H), 1.44–1.59 (m, 2H), 2.90–3.10 (m, 2H),
3.46 (dd, JZ11.6, 6.7 Hz, 1H), 3.65 (d, JZ11.2 Hz, 1H),
4.55–4.60 (br s, 1H), 7.44–7.54 (m, 6H), 7.54–7.97 (m, 4H);
13C NMR (75 MHz, CDCl3) d 11.3, 26.9, 57.5, 67.7, 129.0
(d, JC–PZ12.3 Hz), 132.0 (dd, JC–PZ130.9, 118.5 Hz),
132.6 (dd, JC–PZ74.1, 9.4 Hz), 132.5 (dd, JC–PZ9.7,
2.7 Hz); 31P NMR (121 MHz, CDCl3) d 26.4; IR (Neat)
3253, 2961, 2913, 2871, 1436, 1169, 1142, 1112, 1092, 995,
723, 694 cmK1; LRMS (APCI) m/z calcd for C16H20NO2P
[MCH]C: 290.1 found: 290.1.
(100 MHz, CDCl3) d 9.0, 27.4, 54.3, 130.6 (dd, JC–P
Z
133.1, 107.1 Hz), 131.9 (dd, JC–PZ79.1, 9.8 Hz), 132.1 (dd,
JC–PZ3.1, 3.1 Hz), 174.4; 31P NMR (161 MHz, CDCl3) d
26.6; IR (Neat) 2877, 2458, 1714, 1438, 1123, 1106, 891,
724, 692 cmK1. Elemental analysis calcd for C16H18NO3P:
C, 63.36; H, 5.98; N, 4.62 found: C, 63.50; H, 6.15; N, 4.67.
4.3.7. Methyl 2-[(diphenylphosphoryl)amino]butanoate
(12). A flame-dried round-bottomed flask equipped with a
magnetic stirring bar was charged with the amino acid 10
(89 mg, 0.2934 mmol, 1 equiv) under argon. Anhydrous
DCM (5 mL) was added via a syringe and the colorless
solution was cooled to 0 8C. Excess of diazomethane in
Et2O was added at 0 8C under argon until the yellow color
persisted. The resulting yellow solution was stirred 5 min
under argon at 0 8C and 5 min at room temperature. The
solution was evaporated under reduced pressure to afford
93 mg of the title compound as a white solid (99% yield).
The crude compound was used without purification for
the next step. Analytically pure product can be obtained by
flash chromatography with 70–100% EtOAc in hexanes.
Enantiomeric excess (97% ee) was determined by HPLC
analysis (Chiralpak AD-H, 90:10 hexanes–i-PrOH, 1.0 mL/
min: (R)-12 trZ14.3 min, (S)-12 trZ24.5 min). [a]2D2Z
K16.8 (c 1.00, CH2Cl2); mp 91.0–92.0 8C; Rf 0.30 (100%
EtOAc); 1H NMR (400 MHz, CDCl3) d 0.91 (t, JZ7.4 Hz,
3H), 1.77 (sept, JZ1.0 Hz, 2H), 3.62–2.67 (m, 1H), 3.68 (s,
3H), 3.77–3.86 (m, 1H), 7.41–7.47 (m, 6H), 7.49–7.90 (m,
4H); 13C NMR (100 MHz, CDCl3) d 9.0, 28.1, 52.0, 54.3,
128.3 (dd, JC–PZ12.6, 5.6 Hz), 131.8, 131.8 (dd, JC–P
127.6, 55.6 Hz), 131.9 (dd, JC–PZ20.9, 9.7 Hz), 173.9; 31
NMR (121 MHz, CDCl3) d 23.4; IR (Neat) 3110, 2936,
2877, 1732, 1436, 1197, 1184, 1106, 903, 721, 691 cmK1
Z
P
.
Elemental analysis calcd for C17H20NO3P: C, 64.35; H,
6.35; N, 4.41 found: C, 64.01; H, 6.45; N, 4.39.
4.3.6. 2-[(Diphenylphosphoryl)amino]butanoic acid (10).
A round-bottomed flask equipped with a magnetic stirring
bar was charged with compound 9 (170 mg, 0.5876 mmol,
1 equiv). The amino alcohol was dissolved in a 2:2:3
mixture of MeCN (3.6 mL), CCl4 (3.6 mL) and H2O
(4.8 mL). Solid NaIO4 (502 mg, 2.35 mmol, 4 equiv), then
RuCl3$H2O (4 mg, 0.017 mmol, 0.03 equiv) were added in
one portion to the reaction mixture. The dark brown mixture
was vigorously stirred for 2.5 h at room temperature. The
mixture was diluted with DCM (20 mL) and washed with
H2O (20 mL). The aqueous layer was extracted twice with
DCM (2!20 mL). The crude product was dissolved in
EtOAc (15 mL) and extracted with NaHCO3 sat. (3!
40 mL). Combined basic extracts were acidified (pH 1–2)
with HCl 10% v/v and extracted quickly with DCM (3!
4.3.8. Methyl 2-aminobutanoate hydrochloride (13).
A round-bottomed flask equipped with a magnetic stirring
bar was charged with substrate 12 (67 mg, 0.211 mmol,
1 equiv). A mixture of methanol (1.7 mL) and aqueous
concentrated HCl (0.38 mL) was added to the flask. The
resulting bright clear yellow solution was allowed to stir at
room temperature under closed atmosphere for 24 h. The
reaction mixture was evaporated under reduced pressure
and the residue was dissolved in aqueous HCl 10% v/v
(4 mL). The precipitate (diphenylphosphinic acid) was
removed by filtration on a sintered glass funnel. The acidic
filtrate was extracted with diethyl ether (3!10 mL), the
acidic layer was then evaporated under reduced pressure or

6192
J.-N. Desrosiers et al. / Tetrahedron 61 (2005) 6186–6192
Chem. 2003, 68, 9948–9957. (d) Foresti, E.; Palmieri, G.;
Petrini, M.; Profeta, R. Org. Biomol. Chem. 2003, 1,
4275–4281. (e) Giri, N.; Petrini, M.; Profeta, R. J. Org.
Chem. 2004, 69, 1290–1297. (f) Schwardt, O.; Veith, U.;
lyophilized to afford 29 mg of the title compound as an off-
white solid (90% yield). Analytically pure product can be
obtained by triturating in Et2O, then in EtOAc or by flash
chromatography with 10% DCM in MeOH. Enantiomeric
excess (97% ee) was determined by GC analysis (Cyclodex
b, 30 m, 30 8C, 0 min, 5 8C/min, 220 8C, 5 min: (R)-13 trZ
12.8 min, (S)-13 trZ13.0 min). The absolute configuration S
of 13 was determined by comparison of the optical rotation
with that of the literature data. [lit.25 [a]D20ZC14.1 (c 1.00,
95% AcOH)]. [a]2D0ZC13.4 (c 0.32, 95% AcOH); Rf 0.42
(20% MeOH in DCM); The physical and spectroscopic
properties were in accordance with those described in the
literature.25
¨
Gaspard, C.; Jager, V. Synthesis 1999, 1473–1490.
(g) Ishimaru, K.; Tsuru, K.; Yabuta, K.; Wada, M.;
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13137–13144. (h) Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895–1946.
4. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
J. Am. Chem. Soc. 2001, 123, 10409–10410.
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Acknowledgements
8. Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003,
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This work was supported by NSERC, Merck Frosst Canada,
´
Boehringer Ingelheim (Canada), and the Universite de
Montreal. J. N. D. is grateful to NSERC (ES M), F.Q.R.N.T.
9. Kohn, H.; Sawhney, K. A.; Robertson, D. W.; Leander, J. D.
J. Pharm. Sci. 1994, 83, 689–691.
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´
´
(B1) and to the Universite de Montreal for graduate
fellowships. A. C. is grateful to NSERC (ES D) for graduate
fellowship.
ˆ ´
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Charette, A. B. J. Am. Chem. Soc. 2003, 125, 14260–14261.
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