Asymmetric allylation of α-ketoester-derived N-benzoylhydrazones promoted by chiral sulfoxides/N-oxides lewis bases: Highly enantioselective synthesis of quaternary α-substituted α-allyl-α-amino acids

Article abstract of DOI:10.1002/chir.22159

Chiral sulfoxides/N-oxides (R)-1 and (R,R)-2 are effective chiral promoters in the enantioselective allylation of α-keto ester N-benzoylhydrazone derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g to generate the corresponding N-benzoylhydrazine derivatives 4a, 4b, 4c, 4d, 4e, 4f, 4g, with enantiomeric excesses as high as 98%. Representative hydrazine derivatives 4a, 4b were subsequently treated with SmI₂, and the resulting amino esters 5a, 5b with LiOH to obtain quaternary α-substituted α-allyl α-amino acids 6a, 6b, whose absolute configuration was assigned as (S), with fundament on chemical correlation and electronic circular dichroism (ECD) data. 2013 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22159

CHIRALITY 25:529–540 (2013)
Asymmetric Allylation of a-Ketoester-Derived N-Benzoylhydrazones
Promoted by Chiral Sulfoxides/N-Oxides Lewis Bases: Highly
Enantioselective Synthesis of Quaternary a-Substituted a-Allyl-a-
Amino Acids
1
GLORIA REYES-RANGEL,1 YAMIR BANDALA,1,2 FRED GARCÍA-FLORES,1 AND EUSEBIO JUARISTI
*
1Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F., México
2Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México
ABSTRACT
Chiral sulfoxides/N-oxides (R)-1 and (R,R)-2 are effective chiral promoters in
the enantioselective allylation of a-keto ester N-benzoylhydrazone derivatives 3a-g to generate
the corresponding N-benzoylhydrazine derivatives 4a-g, with enantiomeric excesses as high
as 98%. Representative hydrazine derivatives 4a-b were subsequently treated with SmI2, and
the resulting amino esters 5a-b with LiOH to obtain quaternary a-substituted a-allyl a-amino
acids 6a-b, whose absolute configuration was assigned as (S), with fundament on chemical
correlation and electronic circular dichroism (ECD) data. Chirality 25:529–540, 2013. © 2013
Wiley Periodicals, Inc.
KEY WORDS: Asymmetric allylation; chiral sulfoxides; a-allyl-a-amino acids; quaternary
carbons; Lewis bases
INTRODUCTION
dimethylpyridine N-oxide.80 In this procedure, both chiral
monosulfoxide (R)-1 and C2-symmetric bis-sulfoxide (R,R)-2
are obtained (Scheme 1). In particular, bis-sulfoxide (R,R)-2
proved to be an efficient chiral organocatalyst in the asymmetric
allylation of prochiral N-benzoyl hydrazones derived from both
aldehydes and ketones (Scheme 2).80
The enantioselective allylation of prochiral aldehydes and
ketones, imines, or hydrazones is a reaction of fundamental
importance in organic synthesis owing to its capacity to gener-
ate new C–C bonds in the synthesis of complex molecules.1
For example, enantiopure homoallylic amines are useful
intermediates for the preparation of several valuable nitrogen-
containing compounds.2–12 In this regard, allyl organometallics
On the other hand, the stereoselective formation of chiral
quaternary centers remains
a challenging subject in
asymmetric synthesis87–93; thus, we deemed it of interest to ex-
amine the applicability of chiral bis-sulfoxide/N-oxide (R,R)-2
in the enantioselective allylation of hydrazones derived from
a-keto esters. If successful, this protocol will create a new
quaternary center in the product, which can be derivatized to
biologically active a-allyl a-amino acids (Scheme 3).94–109
Herein, we describe the allylation of N-benzoyl hydrazones
derived from a-keto esters employing sulfoxide/N-oxides (R)-1
and (R,R)-2 as chiral organocatalysts, according to the reaction
conditions recommended by Kobayashi et al.38 Subsequent
chemical manipulation of the enantioenriched hydrazine
products allowed for the enantioselective synthesis of 6a-b,
two a-allyl a-amino acids derived of L-phenylglycine.
have been used with success in imine addition reactions13–16
;
however, metal-free organocatalyzed allylation reactions are
most attractive in terms of reagent stability and environmental
concerns (so-called “green” chemistry).17–30
A major problem encountered in the addition of allylmetals to
imines is competitive a-deprotonation.31–33 This complication
can be solved by the use of allylsilanes; nevertheless, their
relatively low reactivity usually requires the use of catalysts. In
particular, allyltrichlorosilanes are essentially inert to electrophilic
imines in the absence of added promoters. Thus, activation of the
addition reaction is usually accomplished in two ways: (1) by
the use of Lewis acid catalysis, including asymmetric variants
using chiral Lewis acids, which activate the imine,34–41 and (2)
by means of a Lewis base, which activates the nucleophile via
coordination to the silicon atom of the allyltrichlorosilanes to
generate more reactive hypervalent silicon intermediates.41
Particularly effective Lewis bases include N,N-dimethylfo-
rmamide (DMF),42,43 hexamethylphosphoramide (HMPA),42,43
N-oxides,44–48 P-oxides,49,50 and ureas,51 including their
enantiopure chiral derivatives for asymmetric catalysis.37 It is
worth mentioning that the allylation of a-hydrazo esters with
BINAP dioxides is particularly efficient.36 Furthermore, chiral
sulfoxides52–67 and C2-symmetric bis-sulfoxides68–76 have been
used as Lewis base promoters in the enantioselective allylation
of aldehydes and hydrazones with allyltrichlorosilane, which is
of particular relevance in the present work.77–86
MATERIALS AND METHODS
Materials
Optical rotations were measured with a Perkin-Elmer 241 polarimeter.
Melting points were measured with a Melt-Temp ‘Electrothermal’ appara-
tus and are uncorrected. NMR spectra were recorded with a Jeol ECA 500
(500 MHz) spectrometer. IR spectra were recorded with a Varian model
640 apparatus. Mass spectra were registered with a Thermo Electron
Trace-DSQ spectrometer, at 20 eV. HRMS were recorded with Jeol
*Correspondence to: Eusebio Juaristi, Departamento de Química, Centro de
Investigación y de Estudios Avanzados del Instituto Politécnico Nacional,
Apartado Postal 14–740, 07000 México, D.F., México. E-mail: juaristi@relaq.mx;
Received for publication 25 June 2012; Accepted 4 January 2013
DOI: 10.1002/chir.22159
Published online 11 July 2013 in Wiley Online Library
(wileyonlinelibrary.com).
Recently, we reported the synthesis of novel enantiomerically
pure sulfoxides according to the Andersen protocol with
(S)-menthyl p-tolyl sulfinate and the dilithium derivative of 2,6-
© 2013 Wiley Periodicals, Inc.

530
REYES-RANGEL ET AL.
Scheme 1. Synthesis of chiral sulfoxides (R)-1 and (R,R)-2.
the literature protocols.110,111 Racemic hydrazines (4a-e), amino esters
(5a-b), and amino acids (6a-b) were prepared as reference samples in
order to establish the optical purity of the corresponding enantioenriched
chiral products by HPLC.
Substrate Synthesis
(R)-2-Methyl-6-(p-tolylsulfinylmethyl)pyridine-1-oxide, (R)-1, and
6-bis(p-tolylsulfinylmethyl))-pyridine-1-oxide, (R,R)-2. To a solution
of 2,6-dimethylpyridine N-oxide (0.166 g, 1.35 mmol) in 5 ml of THF at
0
ꢀC was added dropwise a solution of n-BuLi in hexane (2.5 M, 1.0
ml, 2.70 mmol). The resulting mixture was stirred at 0 ꢀC for 1 h and
then transferred via cannula to
a
flask containing (S)-(À)-menthyl
p-tolylsulfinate (1.0 g, 3.34 mmol) in 5.0 ml of THF at 0 ꢀC. The reaction
mixture was stirred for 1 h at 0 ꢀC before quenching with aqueous sat-
urated ammonium chloride solution. The product mixture was extracted
with ethyl acetate, dried over anhydrous sodium sulfate, concentrated at
reduced pressure, and purified by silica gel column chromatography
(EtOAc–CH2Cl2-i-PrOH, 4:4:1).
Scheme 2. Asymmetric allylation of prochiral N-benzoyl hydrazones cata-
lyzed for bis-sulfoxide (R,R)-2.
(R)-1, Rf = 0.44 (tlc 4 times) followed by crystallization from hexane
to afford 0.23 g (68% yield) of monosulfoxide, mp 71–72 ꢀC. [a]D25
+295.0 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) d: 2.39 (s, 3H),
2.52 (s, 3H), 4.05 (d, J = 12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H),
7.137.14 (m, 1H), 7.22–7.30 (m, 4H), 7.60–7.61 (m, 2H). 13C NMR
(125.76 MHz, CDCl3) d: 18.2, 21.5, 61.7, 123.9, 125.0, 126.0, 126.3,
130.1, 141.0, 141.8, 142.8, 149.3. HRMS (ESI-TOF) calcd. for
C
14H16NO2S + H+: 262.0896; found: 262.0895.
(R,R)-2, Rf = 0.54 (tlc 4 times) followed by crystallization from CH2Cl2-
hexane to afford 0.12 g (22% yield) of bis-sulfoxide, mp 175–176 ꢀC. [a]D25
+320.0 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3) d: 2.39 (s, 6H), 4.08
(d, J = 12.3 Hz, 2H), 4.49 (d, J = 12.2 Hz, 2H), 7.14–7.18 (m, 1H), 7.29–7.34
(m, 6H), 7.57-7.60 (m, 4H). 13C NMR (125.76 MHz, CDCl3) d: 21.6, 60.8,
123.9, 124.7, 128.2, 130.1, 140.5, 142.1, 142.9. HRMS (ESI-TOF) calcd. for
Scheme 3. Allylation of various N-benzoylhydrazones 3a-g with
allyltrichlorosilane under catalysis by bis-sulfoxide/N-oxide (R,R)-2.
C
21H21NO3S2 + H+: 400.1038; found: 400.1036.
(Z)-Methyl 2-(2-benzoylhydrazono)-2-phenylacetate, (3a)112
JMS-SX 102a and Agilent-MSD-TOF1069A spectrometers. Elemental
analyses were obtained using a Thermo-Finnigan CHNS/O 1112 appara-
tus. HPLC analyses were carried out with a Waters 600 E equipment
fitted with a UV/Visible Waters 2487 detector and Chiralpack AD-H and
Chiralcel OD-H (Daicel Chemical Ind., 0.46 x 25 cm) columns, employing
hexane-i-PrOH mixture as mobile phase. Experimental CD spectra were
recorded with a Jasco-815 spectropolarimeter using the following param-
eters: 1 cm quartz cells, 5 mM in MeCN or MeOH, 20 ꢀC, data pitch 1 nm,
data points 201, bandwidth 1 nm, response 1 sec, high sensitivity, scan
speed 100 nm/min, 400–200 nm measurement range, and the baselines
correspond to the spectra of the solvent under the same conditions.
Methyl benzoylformate, ethyl glyoxalate, and ethyl pyruvate were
commercially available. Methyl 2-(naphthalene-2-yl)-2-oxoacetate, methyl
2-oxo-2-(p-tolyl)acetate, methyl 2-(4-bromophenyl)-2-oxoacetate, and
methyl 2-(4-methoxyphenyl)-2-oxoacetate were prepared according to
Benzoic hydrazine (2.48 g, 18.2 mmol) was added to a
stirred solution of methyl benzoylformate (3 g, 18.2 mmol)
in 70 ml of a mixture of methanol-acetic acid (4:1). The
resulting solution was heated to reflux for 12 h, during which
time all solid dissolved. The reaction mixture was allowed to
cool to room temperature, concentrated, and the residue was
dissolved in ethyl acetate and washed several times with satu-
rated aqueous sodium and potassium tartrate solution, dried
(Na2SO4), filtered, and concentrated. The crude product was
recrystallized from ethyl acetate-hexane to afford 3.5 g
(68% yield) of 3a: mp 128–129 ꢀC. 1H NMR (500 MHz, CDCl3)
d: 7.96 (d, 2H, ArH), 7.67 (br, 2H, ArH), 7.59 (m, 1H, ArH),
7.51 (m, 2H, ArH), 7.417.39 (m, 2H, ArH), 3.94 (s, 3H, CH3).
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE SYNTHESIS OF QUATERNARY AMINO ACIDS
531
13C NMR (125.76 MHz, CDCl3) d: 163.9, 163.5, 139.4, 134.5,
135.4, 132.7, 132.6, 129.6, 129.2, 128.9, 128.3, 127.8, 52.9.
This same procedure was followed for the preparation of
N-benzoylhydrazones 3b-e.
MS (EI) m/z (%): 361 (0.52) (M+), 303 (89), 302 (25), 301
(100), 105(25). HRMS (ESI-TOF) calcd. for C16H14BrN2O3 +
H+: 361.0182; found: 361.0180.
(Z)-Ethyl 2-(2-benzoylhydrazono)propanoate, (3f)
(Z)-Methyl 2-(2-benzoylhydrazono)-2-(4-methoxyphenyl)
Benzoic hydrazine (3.52 g, 25.8 mmol), ethyl pyruvate (3 g,
25.8 mmol), and 60 ml of ethanol were heated to reflux for 18
h. The reaction mixture was allowed to cool to room temper-
ature, concentrated, and the residue was purified by flash
chromatography on silica gel CH2Cl2-ethyl acetate (95:5).
Two products were detected, the less polar corresponding
to the desired product (3 g, 57% yield), mp 81–82 ꢀC. 1H
NMR (500 MHz, CDCl3) d: 7.88 (d, J = 7.5 Hz, 2H, ArH),
7.53-7.41(m, 3H, ArH), 4.30 (q, J = 7.1 Hz, 2H, CH2), 2.27
(s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (125.76
MHz, CDCl3) d: 163.9, 163.2, 138.1, 132.6, 128.9, 127.6, 62.2,
20.3, 14.1. IR (cm-1): 3238, 2997, 2360, 1682, 1576, 1518,
1486, 1269, 1181, 1141, 1024, 917. MS (EI) m/z (%): 235
(0.56) (M++1), 161 (100), 105 (13). HRMS (ESI-TOF) calcd.
for C12H14N2O3 + H+: 235.1077; found: 235.1077.
acetate, (3b)
This compound was obtained from benzoic hydrazine and
methyl 2-(4-methoxyphenyl)-2-oxoacetate, purified by flash
chromatography on silica gel [hexane-ethyl acetate (6:4)],
and recrystallized from ethyl acetate-hexane (68% yield), mp
1
ꢀ
129–130 C. H NMR (500 MHz, CDCl3) d: 7.95 (d, J = 7.45
Hz, 2H, ArH), 7.637.49 (m, 6H, ArH), 6.91 (d, J = 6.75 Hz,
1H, ArH), 3.94 (s, 3H, CH3), 3.83 (s, 3H, CH3). 13C NMR
(125.76 MHz, CDCl3) d: 163.6, 160.8, 139.4, 132.8, 132.6,
130.6, 129.0, 127.7, 127.3, 126.7, 113.7, 55.4, 52.9. IR (cm-1):
3267, 1690, 1604, 1505, 1478, 1239, 1175, 1141, 1027, 831.
MS (EI) m/z (%): 312 (7.5) (M+), 254 (17), 253(100). Calcd.
for C17H16N2O4 (312.32): C 65.38, H 5.16, N 8.97; found:
C 65.71, H 5.17, N 9.20.
(Z)-Methyl 2-(2-benzoylhydrazono)-2-(naphthalen-2-yl)
(Z)-Ethyl 2-(2-benzoylhydrazono)acetate, (3g)113
acetate, (3c)
Benzoic hydrazine (5.75 g, 42.2 mmol), ethyl glyoxalate
50% in toluene (10 g, 9.73 ml, 49.2 mmol) and 50 ml of ethanol
were heated to 80 C for 90 min. The reaction mixture was
This compound was obtained from benzoic hydrazine and
methyl 2-(naphthalen-2yl-)-2-oxoacetate, purified by flash
chromatography on silica gel [hexane-ethyl acetate (9:1)],
and recrystallized from ethyl acetate-hexane (55% yield), mp
115–116 ꢀC. 1H NMR (500 MHz, CDCl3) d: 8.17 (br, 1H, ArH),
7.99-7.97 (m, 2H, ArH), 7.91-7.79 (m, 5H, ArH), 7.61-7.56 (m,
1H, ArH), 7.52-7.50 (m, 4H, ArH), 3.16 (s, 3H, CH3). 13C NMR
(125.76 MHz, CDCl3) d: 163.9, 163.6, 139.5, 133.7, 132.9,
132.7, 132.6, 131.9, 129.2, 129.0, 128.8, 127.9, 127.7, 127.1,
126.5, 126.0, 53.1. IR (cm-1): 3243, 3053, 1714, 1682, 1548,
1508, 1481, 1435, 1254, 1145, 907. MS (EI) m/z (%): 332 (0.78)
(M+), 287(13), 272(71), 207(15), 153(100), 105(13). Calcd. for
C20H16N2O3 (332.35): C 72.28, H 4.85, N 8.43; found: C 72.29,
H 4.83, N 8.55.
ꢀ
allowed to cool to room temperature, and the precipitated
hydrazone was filtered and washed with ethanol (30 ml),
toluene (300 ml), and hexane (500 ml), to give 4.7 g (43%
yield) of 3g, that was recrystallized from CH2Cl2-hexane,
mp 141–142 ꢀC (lit.113 mp = 140–141 ꢀC). 1H NMR (500
MHz, CDCl3) d: 11.80 (br, 1H, COH), 8.04-7.93 (m, 3H,
ArH, NH), 7.52-7.47 (m, 1H, ArH), 7.42-7.36 (m, 2H, ArH),
4.31 (q, J = 6.7 Hz, 2H, CH2), 1.21 (t, J = 6.6 Hz, 3H, CH3).
13C NMR (125.76 MHz, CDCl3) d: 165.8, 163.8, 138.8, 132.5,
131.9, 128.5, 128.0, 61.5, 14.0. IR (cm-1): 3127, 3041, 1736,
1660, 1598, 1555, 1344, 1213, 1133, 1084, 1031, 932. MS (EI)
m/z (%): 220 (0.01) (M+), 148 (9.0), 147 (100), 105 (15).
HRMS (ESI-TOF) calcd. for C12H12N2O3 + Na+: 243.0740;
found: 243.0741.
(Z)-Methyl 2-(2-benzoylhydrazono)-2-p-tolylacetate, (3d)
This compound was obtained from benzoic hydrazine and
methyl-2-oxo-2-p-tolylacetate, purified by flash chromatogra-
phy on silica gel [hexane-ethyl acetate (8:2)], and
recrystallized from ethyl acetate-hexane (72% yield), mp
General Procedure for the Enantioselective Allylation of
Hydrazones 3a-g
To a solution of 35 mg of N-benzylhydrazone and bis-
sulfoxide/N-oxide (R,R)-2 (3 equiv.) in 2 ml of anhydrous
1
130–131 ꢀC. H NMR (500 MHz, CDCl3) d: 7.95 (d, J = 7.3
ꢀ
Hz, 2H, ArH), 7.65-7.45 (m, 5H, ArH), 7.20 (d, J = 8.0 Hz, 2H,
ArH), 3.93 (s, 3H, CH3), 2.38 (s, 3H, CH3). 13C NMR
(125.76 MHz, CDCl3) d: 163.6, 139.8, 132.7, 131.7, 129.0,
127.7, 52.9, 21.5. IR (cm-1): 3256, 3036, 1697, 1683, 1536,
1502, 1444, 1236, 1141, 825. MS (EI) m/z (%): 296 (0.72)
(M+), 237(100), 105(3). Calcd. for C17H16N2O3 (296.32): C
68.91, H 5.44, N 9.45; found: C 68.60, H 5.19, N 9.68.
CH2Cl2 at À78 C was added dropwise 0.1 ml of 2-methyl-2-
butene and 0.1 ml of allyltrichlorosilane. After stirring at
À50ꢀC for 48 h, the reaction mixture was quenched with
saturated aqueous solution of NaHCO3 (2 ml) and warmed
to room temperature. Three additional milliliters of saturated
aqueous solution of NaHCO3 were added, the CH2Cl2 solvent
was evaporated, the aqueous phase was extracted with ethyl
acetate (3 x 15 ml), and the combined organic phase was
dried with anhydrous Na2SO4 and concentrated. The residue
was purified by column chromatography with hexane-ethyl
acetate-CH2Cl2 (3:1:1).
(Z)-Methyl 2-(2-benzoylhydrazono)-2-(4-bromophenyl)
acetate, (3e)
This compound was obtained from benzoic hydrazine and
methyl 2-(4-bromophenyl)-2-oxoacetate, purified by flash
chromatography on silica gel [hexane-ethyl acetate (8:2)],
and recrystallized from ethyl acetate-hexane (75% yield), mp
(S)-Methyl 2-(2-benzoylhydrazinyl)-2-phenylpent-4-enoate,
(S)-4a112
1
132–133 ꢀC. H NMR (500 MHz, CDCl3) d: 7.94 (d, J = 7.5
Yield 31%, pale yellow oil. [a]2D5 = +35.9 (c 1.02, CHCl3)
[Lit.112 [a]D25 = À36.0 (c 1.15, CHCl3) for the (R)-enantiomer].
1H NMR (500 MHz, CDCl3): d = 7.82 (s, 1H, NH), 7.59-7.55
(m, 2H, ArH), 7.47-7.43 (m, 3H, ArH), 7.40-7.26, (m, 5H,
ArH), 5.92-5.82 (m, 1H, CH), 5.64 (br, 1H, NH), 5.21 (dd,
Chirality DOI 10.1002/chir
Hz, 2H, ArH), 7.62-7.47 (m, 7H, ArH), 3.94 (s, 3H, CH3). 13C
NMR (125.76 MHz, CDCl3) d: 163.1, 133.5, 132.8, 132.4,
131.4, 130.7, 129.0, 127.8, 124.0, 53.1. IR (cm-1): 3582, 3256,
1697, 1678, 1582, 1497, 1472, 1436, 1230, 1141, 1071, 984.

532
REYES-RANGEL ET AL.
J = 1.1, 17 Hz, 1H, CH2), 5.15 (dd, J = 1.0, 10.1 Hz, 1H, CH2),
3.8 (s, 3H, CH3), 3.02 (dd, J = 7.3, 14.2 Hz, 1H, CH2), 2.95
(dd, J = 6.9, 14.3 Hz, 1H, CH2). 13C NMR (125.76 MHz,
CDCl3): d = 174.0, 166.2, 138.6, 132.9, 132.6, 131.7, 128.6,
128.4, 128.2, 126.8, 126.6, 119.5, 71.1, 52.5, 41.1. IR (cm-1):
3278, 3070, 2950, 1728, 1637, 1578, 1523, 1431, 1229, 916,
692. MS (EI) m/z (%): 324 (0.85) (M+), 283 (100), 265 (17),
223 (22), 105 (44). HRMS (ESI-TOF) calcd. for C19H20N2O3 +
H+: 325.1546; found: 325.1549. Enantiomeric ratio 1:99, deter-
mined by HPLC (Chiralpak AD-H, Hexane-i-PrOH (90:10),
254 nm, 1 ml/min): tr = 30.1 min (minor, R enantiomer); 35.3
min (major, S enantiomer).
166.2, 138.0, 135.7, 133.0, 132.8, 131.7, 129.3, 128.7, 126.9, 126.6,
119.5, 71.0, 52.6, 41.0, 21.1. IR (cm-1): 3283, 3065, 2919, 1731,
1640, 1513, 1432, 1228, 918, 708, 691. MS (EI) m/z (%):
338 (0.96) (M+), 297 (76), 279 (18), 237 (100), 105 (38). HRMS
(ESI-TOF) calcd. for C20H22N2O3 +H+: 339.1703; found:
339.1706. Enantiomeric ratio 98:2, determined by HPLC
(Chiralpak AD-H, Hexane-i-PrOH (90:10), 254 nm, 1 ml/min): tr =
23.7 min (major, S enantiomer); 26.3 min (minor, R enantiomer).
(S)-Methyl-2-(2-benzoylhydrazinyl)-2-(4-bromophenyl)
pent-4-enoate, (S)-4e
Yield 18%, pale yellow oil. [a]2D5 = +13.3 (c 0.6, CHCl3). H
1
NMR (500 MHz, CDCl3): d = 7.8 (d, J = 6 Hz, 1H, NH), 7.61-
7.57 (m, 2H, ArH), 7.51-7.45 (m, 3H, ArH), 7.42-7.37 (m, 2H,
ArH), 7.37- 7.33 (m, 2H, ArH), 5.87-5.76 (m, 1H, CH), 5.61
(d, J = 6.4 Hz, 1H, NH), 5.20 (dd, J = 1.6, 17 Hz, 1H, CH2),
5.16 (dd, J = 0.8, 10.2 Hz, 1H, CH2), 3.8 (s, 3H, CH3), 2.97
(dd, J = 7.4, 14.5 Hz, 1H, CH2), 2.88 (dd, J = 7.0, 14.3 Hz, 1H,
CH2). 13C NMR (125.76 MHz, CDCl3): d = 173.5, 166.4,
137.8, 132.8, 132.2, 131.9, 131.6, 128.8, 128.6, 126.9, 122.4,
120.0, 70.8, 52.8, 41.2. IR (cm-1): 3277, 3067, 2950, 2921,
1731, 1641, 1488, 1432, 1228, 1009, 920, 709, 691. MS (EI)
m/z (%): 402 (0.62) (M+-1), 370 (35), 281 (18), 207 (26), 105
(100). HRMS (ESI-TOF) calcd. for C19H19BrN2O3 + H+:
403.0651; found: 403.0652. Enantiomeric ratio 1:99, deter-
mined by HPLC (Chiralpak AD-H, Hexane-i-PrOH (90:10),
254 nm, 1 ml/min): tr = 32.1 min (minor, R enantiomer); 35.5
min (major, S enantiomer).
(S)-Methyl-2-(2-benzoylhydrazinyl)-2-(4-methoxyphenyl)
pent-4-enoate, (S)-4b
Yield 50%, pale yellow oil. [a]2D5 = +26.5 (c 1.08, CHCl3). H
1
NMR (500 MHz, CDCl3): d = 7.87 (s, 1H, NH), 7.60-7.56 (m,
2H, ArH), 7.48-7.43 (m, 1H, ArH), 7.40-7.34, (m, 4H, ArH),
6.89-6.84 (m, 2H, ArH), 5.92-5.82 (m, 1H, CH), 5.60 (br, 1H,
NH), 5.20-5.12 (m, 2H, CH2), 3.78 (s, 3H, CH3), 3.79 (s, 3H,
CH3), 2.99 (dd, J = 7.3, 14.3 Hz, 1H, CH2), 2.92 (dd, J = 7.0,
14.2 Hz, 1H, CH2). 13C NMR (125.76 MHz, CDCl3):
d = 174.2, 166.2, 159.3, 133.0, 132.8, 131.7, 130.6, 128.7,
128.0, 126.9, 119.5, 113.8, 70.7, 55.3, 52.6, 41.1. IR (cm-1):
3278, 3069, 2919, 1730, 1640, 1609, 1512, 1433, 1249, 1180,
1028, 919, 692. MS (EI) m/z (%): 355 (0.57) (M+ + 1), 322 (7),
253 (100), 105 (15). HRMS (ESI-TOF) calcd. for C20H22N2O4 +H+:
355.1652; found: 355.1653. Enantiomeric ratio 98:2, determined
by HPLC (Chiralpak AD-H, Hexane-i-PrOH (90:10), 254 nm,
1 ml/min): tr = 41.2 min (major, S enantiomer); 45.2 min (minor,
R enantiomer).
Ethyl 2-(2-benzoylhydrazinyl)-2-methylpent-4-enoate, 4f
Yield 64%, pale yellow oil. [a]2D5 = +17.1 (c 1.08, CHCl3). H
1
NMR (500 MHz, CDCl3): d = 7.96 (s, 1H, NH), 7.76-7.72
(m, 2H, ArH), 7.53-7.49 (m, 1H, ArH), 7.46 -7.41 (m, 2H,
ArH), 5.89- 5.78 (m, 1H, CH), 5.19 (dd, J = 1.4, 12.6 Hz, 1H,
CH2), 5.16 (dd, J = 1.6, 5.7 Hz, 1H, CH2), 5.05 (br, 1H, NH),
4.27-4.16 (m, 2H, CH2), 2.58 (dd, J = 7.0, 14.0 Hz, 1H, CH2),
2.52 (dd, J = 7.7, 13.9 Hz, 1H, CH2), 1.40 (s, 3H, CH3), 1.30
(t, J = 7.23 Hz, 3H, CH3). 13C NMR (125.76 MHz, CDCl3):
d = 174.9, 166.7, 132.9, 132.1, 131.7, 128.6, 126.8, 119.6, 64.8,
61.3, 41.5, 21.2, 14.2. IR (cm-1): 3275, 3073, 2980, 1726, 1640,
1448, 1302, 1217, 1150, 1024, 918, 709, 691. MS (EI) m/z
(%): 276 (0.18) (M+), 235 (100), 203 (16), 105 (24). HRMS
(ESI-TOF) calcd. for C15H20N2O3 + H+: 277.1546; found:
277.1552. Enantiomeric ratio 79:21, determined by HPLC
(Chiralpak AD-H, Hexane-i-PrOH (90:10), 210 nm, 1 ml/min):
tr = 18.5 min (major); 19.3 min (minor).
(S)-Methyl-2-(2-benzoylhydrazinyl)-2-(naphthalen-2-yl)-
pent-4-enoate, (S)-4c
Yield 25%, pale yellow oil. [a]2D5 = +13.5 (c 1.0, CHCl3). H
1
NMR (500 MHz, CDCl3): d = 7.94 (s, 1H, NH), 7.86-7.75 (m,
4H, ArH), 7.60-7.54 (m, 3H, ArH), 7.51-7.46 (m, 2H, ArH),
7.46-7.42 (m, 1H, ArH), 7.38-7.33 (m, 2H, ArH), 5.95-5.85
(m, 1H, CH), 5.82 (d, J = 6.6 Hz, 1H, NH), 5.22 (dd, J = 1.3,
17 Hz, 1H, CH2), 5.15 (dd, J = 1.0, 10.2 Hz, 1H, CH2), 3.81 (s,
3H, CH3), 3.11 (dd, J = 7.4, 14.3 Hz, 1H, CH2), 3.04 (dd,
J = 6.7, 14.3 Hz, 1H, CH2). 13C NMR (125.76 MHz, CDCl3):
d = 173.8, 166.4, 136.2, 133.1, 133.0, 132.9, 132.7, 131.7,
128.7, 128.4, 128.3, 127.6, 126.9, 126.5, 126.4, 125.9, 124.5,
119.6, 71.2, 52.7, 40.9. IR (cm-1): 3284, 3058, 2921, 1731,
1659, 1432, 1226, 917, 817, 749, 709, 692. MS (EI) m/z (%):
374 (12) (M+), 355 (17), 315 (18), 281 (45), 272 (36), 207
(100), 153 (19), 105 (17), 83 (30). HRMS (ESI-TOF) calcd. for
C23H22N2O3 + H+: 375.1703; found: 375.1704. Enantiomeric ra-
tio 1:99, determined by HPLC (Chiralcel OD-H, Hexane-i-PrOH
(90:10), 254 nm, 1 ml/min): tr = 5.5 min (minor, R enantiomer);
6.0 min (major, S enantiomer).
Ethyl 2-(2-benzoylhydrazinyl)pent-4-enoate, 4g
Yield 93%, pale yellow oil. [a]2D5 = À14.42 (c 1.04, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 8.0 (s, 1H, NH), 7.76-7.72 (m,
2H, ArH), 7.54-7.47 (m, 1H, ArH), 7.44-7.39, (m, 2H, ArH),
5.84-5.88 (m, 1H, CH), 5.16-5.23 (m, 2H, CH2), 5.10 (s, 1H,
NH), 4.23-4.18 (m, 2H, CH2), 3.83-3.81 (m, 1H, CH), 2.65-2.60
(m, 1H, CH2), 2.50-2.44 (m, 1H, CH2), 1.27 (t, J = 7 Hz, 3H,
CH3). 13C NMR (125.76 MHz, CDCl3): d = 172.7, 167.0, 133.0,
132.6, 132.0, 128.8, 127.0, 119.0, 62.1, 61.2, 35.3, 14.3. IR
(cm-1): 3213, 3064, 2982, 1727, 1644, 1452, 1317, 1188,
1016, 989, 913, 849, 697. MS (EI) m/z (%): 262 (0.64) (M+),
222 (14), 221 (100), 189 (21), 150 (50). HRMS (ESI-TOF)
calcd. for C14H18N2O3 + H+: 263.1390; found: 263.1391. Enan-
tiomeric ratio 32:68, determined by HPLC (Chiralpak AD-H,
Hexane-i-PrOH (90:10), 210 nm, 1 ml/min): tr = 17.20 min
(minor); 18.35 min (major).
(S)-Methyl 2-(2-benzoylhydrazinyl)-2-p-tolylpent-4-enoate,
(S)-4d
1
Yield 35%, pale yellow oil. [a]2D5 = +29.3 (c 0.87, CHCl3). H
NMR (500 MHz, CDCl3): d =7.81 (s, 1H, NH), 7.60-7.56 (m, 2H,
ArH), 7.49-7.44 (m, 1H, ArH), 7.40-7.35, (m, 2H, ArH), 7.35-7-30
(m, 2H, ArH), 7.18-7-13 (m, 2H, ArH), 5.82-5.93 (m, 1H, CH),
5.63 (d, J= 4.9 Hz, 1H, NH), 5.20 (dd, J=1.1, 17 Hz, 1H, CH2),
5.15 (dd, J= 0.86, 10.2 Hz, 1H, CH2), 3.7 (s, 3H, CH3), 3.00 (dd,
J= 7.4, 14.3 Hz, 1H, CH2 ), 2.93 (dd, J= 6.9, 14.3 Hz, 1H, CH2),
2.31 (s, 3H, CH3). 13C NMR (125.76 MHz, CDCl3): d = 174.1,
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE SYNTHESIS OF QUATERNARY AMINO ACIDS
533
(S)-Methyl 2-amino-2-phenylpent-4-enoate, (S)-5a
determined by HPLC (Chirobiotic T, MeOH-H2O (50:50),
210 nm, 0.7 ml/min): tr = 6.4 min (major S enantiomer); 9.6
min (minor R enantiomer).
To a solution of hydrazine (S)-4a (120 mg, 0.37 mmol) in
MeOH (0.3 ml) was added 11.1 ml (448 mg, 1.1 mmol) of
SmI2 (0.1 M in THF) at ambient temperature. The dark
blue-green SmI2 solution turned yellow. The reaction mixture
was stirred for 30 min at room temperature and the solvent
was removed under vacuum. The residue was treated with
1N HCl (15 ml) and diethyl ether (30 ml), the aqueous phase
was neutralized with 1M NaOH, and extracted with ethyl
acetate. The organic phase was washed with water and brine,
dried over NaSO4, filtered, and concentrated under vacuum.
The residue was purified by flash chromatography on silica
gel with CH2Cl2-ethyl acetate (8:2) to afford the desired
amino ester (S)-5a in 26% yield (20 mg) as a pale yellow oil,
[a]2D5 = À13.5 (c 2, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 7.53-7.51 (m, 2H, ArH), 7.36-7.33 (m, 2H, ArH), 7.29-7.25
(m, 1H, ArH), 5.75-5.40 (m, 1H, CH), 5.22-5.13 (m, 2H,
CH2), 3.71 (s, 3H, CH3), 2.98 (dd, J = 6.7, 13.6 Hz, 1H, CH2),
(S)-2-Amino-2-(4-methoxyphenyl)pent-4-enoic acid, (S)-6b
The procedure described above was followed with 45 mg
(0.19 mmol) of (S)-5b, 2 ml mixture THF Á H2O (3:1 v/v)
and 18.45 mg (0.44 mmol) of LiOH Á H2O to afford the desired
amino acid 6b in 54% yield (23 mg) as a white solid, mp
190–191 ꢀC (EtOH-diethyl ether), [a]2D5 = À13.75 (c 0.8, 1N
HCl). 1H NMR (500 MHz, CD3OD): d = 7.48-7.46 (m, 2H,
ArH), 6.94-6.92 (m, 2H, ArH), 5.83-5.77 (m, 1H, CH), 5.32-
5.28 (m, 1H, CH2), 5.24-5.22 (m, 1H, CH2), 3.78 (s, 3H,
CH3), 3.08-3.04 (m, 1H, CH2), 2.98-2.94 (m, 1H, CH2). 13C
NMR (125.76 MHz, CD3OD): d = 173.0, 159.8, 131.6, 130.2,
127.3, 120.1, 113.6, 65.4, 54.4, 40.5. IR (cm-1): 3734, 3127,
3039, 2936, 2360, 2340, 1582, 1516, 1375, 1256, 1032, 930,
827. HRMS (ESI-TOF) calcd. for C12H15NO3 + H+: 222.1124;
found: 222.1126. Enantiomeric ratio 98:2, determined by HPLC
(Chirobiotic T, MeOH-H2O (50:50), 210 nm, 0.7 ml/min): tr =
7.3 min (major S enantiomer); 13.2 min (minor R enantiomer).
2.66 (dd, J = 7.8, 13.6 Hz, 1H, CH ). 13C NMR (125.76 MHz,
2
CDCl3): d = 175.8, 142.8, 133.0, 128.5, 127.6, 125.5, 120.1,
63.2, 52.6, 44.7. IR (cm-1): 2951, 2923, 2849, 2363, 1729,
1434, 1215, 1143, 921, 697. MS (EI) m/z (%): 206 (0.05)
(M++1), 164 (94), 146 (100), 104 (3). HRMS (ESI-TOF) calcd.
for C12H15NO2 + H+: 206.1175; found: 206.1180.
General Procedure for the Nonasymmetric Allylation of the
Prochiral Hydrazones, in Order to Prepare Racemic
Standards
A solution of 1 mmol of hydrazone and 0.2 mmol of InCl3
(dried 2 h under vacuum at 100 C) in 5 ml of anhydrous
(S)-Methyl 2-amino-2-(4-methoxyphenyl)pent-4-enoate,
(S)-5b
ꢀ
THF was stirred for 15 min at room temperature, then
allyltributylstannane (1.3 mmol) was added dropwise via
syringe and stirred for 18 h at room temperature. Saturated
aqueous NH4Cl (15 ml) was added and the resulting solution
was extracted with ethyl acetate (3 x 20 ml). The combined
organic layers were dried (NaSO4), filtered, concentrated,
and purified by flash chromatography on silica gel with
hexane-ethyl acetate-dichloromethane (3:1:1).
The procedure described above was followed with 368 mg
(1.04 mmol) of hydrazine (S)-4b, 0.84 ml methanol, and
31.15 ml (1.26 g, 3.1 mmol) of SmI2 (0.1 M in THF) to afford
the desired amino ester (S)-5b in 21% yield (51 mg) as a pale
yellow oil, [a]2D5 = À16.8 (c 1.01, CHCl3). H NMR (500 MHz,
1
CDCl3): d = 7.44-7.43 (m, 2H, ArH), 6.88-6.86 (m, 2H, ArH),
5.72-5.63 (m, 1H, CH), 5.20-5.14 (m, 2H, CH2), 3.7 (s, 3H,
CH3), 2.97 (dd, J = 6.7, 13.6 Hz, 1H, CH2), 2.65 (dd, J = 7.9,
13.6 Hz, 1H, CH2). 13C NMR (125.76 MHz, CDCl3):
d = 176.0, 159.0, 134.9, 133.1, 126.7, 120.0, 113.8, 62.7, 55.3,
52.6, 44.8. IR (cm-1): 3387, 3001, 2951, 1728, 1509, 1248,
1214, 1177, 1031, 829. MS (EI) m/z (%): 235 (0.03) (M++1),
194 (100), 176 (88), 134 (5). HRMS (ESI-TOF) calcd. for
C13H17NO3 + H+: 236.1281; found: 236.1282.
Methyl 2-(2-benzoylhydrazinyl)-2-phenylpent-4-enoate,
rac-4a
Yield 44%, mp 78–79 ꢀC (hexane). 1H NMR (500 MHz,
CDCl3): d = 7.81 (d, J = 6.61 Hz, NH), 7.25-7.56 (m, 9H, ArH),
5.83-5.89 (m, 1H, CH), 5.63 (d, J = 6.6 Hz, 1H, CH), 5.13-5.22
(m, 2H, CH2), 3.8 (s, 3H, CH3 ), 3.0 (dd, J = 7.3, 14.3 Hz, 1H,
CH2), 2.93 (dd, J = 7.0, 14.3 Hz, 1H, CH2). 13C NMR (125.76
MHz, CDCl3): d = 174.0, 166.2, 138.7, 133.0, 132.7, 131.7,
128.5, 128.3, 126.8, 126.7, 119.6, 71.2, 52.7, 41.1. IR (cm-1):
3373, 3248, 1711, 1662, 1580, 1535, 1472, 1293, 1250, 1025,
691. MS (EI) m/z (%): 324 (0.68) (M+), 283 (100), 265 (16),
223 (16), 105 (20). HRMS (ESI-TOF) calcd. for C19H22N2O2 +
H+: 325.1546; found: 325.1543. HPLC: Chiralpak AD-H, Hexane-
i-PrOH (90:10), 254 nm, 1 ml/min, tr = 30.2 and 36.2 min.
(S)-2-Amino-2-phenylpent-4-enoic acid, (S)-6a
In a 50 ml round-bottom flask was placed 20 mg (0.097
mmol) of amino ester (S)-5a, 1.5 ml of mixture THF-H2O
(3:1 v/v), and 9.4 mg (0.22 mmol) of LiOH Á H2O, and the
reaction mixture was stirred for 24 h at room temperature.
The THF was evaporated and the aqueous residue was
acidified to pH 2 with 1N HCl. The H2O was removed under
vacuum and the residue was purified by flash chromatogra-
phy on silica gel with i-PrOH-MeOH-NH4OH (7:2:0.5 v/v) to
afford the desired aꢀmino acid 6a in 54% (10 mg) as a white
solid, mp 180–181 C, [a]2D5 = +5.88 (c 0.51, 1N HCl). 98%
ee (determined by HPLC, Scheme 4) [Lit.114 mp = 223–225
ꢀC, [a]2D5 = +12.6 (c 0.4, 1N HCl)]. 1H NMR (500 MHz,
CD3OD): d = 7.60-7.53 (m, 2H, ArH), 7.44-7.32 (m, 3H,
ArH), 5.86-5.74 (m, 1H, CH), 5.32-5.21 (m, 2H, CH2), 3.10-
2.96 (m, 2H, CH2). 13C NMR (125.76 MHz, CD3OD):
d = 173.0, 138.5, 131.7, 128.4, 128.0, 125.9, 120.1, 65.8, 40.7.
IR (cm-1): 3080, 2977, 2360, 2341, 1658, 1587, 1538, 1363,
910, 738, 693. HRMS (ESI-TOF) calcd. for C11H13NO2 + H+:
192.10191; found: 192.10216. Enantiomeric ratio 99:1,
Methyl 2-(2-benzoylhydrazinyl)-2-(4-methoxyphenyl)pent-
4-enoate, rac-4b
Yield 69%, colorless oil. 1H NMR (500 MHz, CDCl3):
d = 7.80 (d, J = 6.5 Hz, 1H, NH), 7.58-7.56 (m, 2H, ArH,),
7.46-7.44 (m, 1H, ArH), 7.38-7.35 (m, 4H, ArH), 6.86 (d, 2H,
ArH), 5.89-5.82 (m, 1H, CH), 5.58 (d, J = 6.8 Hz, 1H, NH),
5.21-5.13 (m, 2H, CH2), 3.79 (s, 3H, CH3), 3.78 (s, 3H, CH3),
2.98 (dd, J = 7.5, 14.25 Hz, 14.25, 1H, CH2) 2.91 (dd, J = 7.0,
14.3 Hz, 1H, CH2). 13C NMR (125.76 MHz, CDCl3):
d = 174.2, 166.2, 159.3, 132.7, 131.7, 128.7, 127.9, 126.9,
119.6, 117.0, 114.1, 113.8, 70.5, 55.3, 52.6, 41.1. IR (cm-1):
3282, 3073, 2952, 2923, 2360, 1731, 1639, 1610, 1511, 1433,
Chirality DOI 10.1002/chir

534
REYES-RANGEL ET AL.
Scheme 4. Assignment of the absolute configuration in chiral hydrazines 4a-b by chemical correlation with quaternary a-allyl-a-aryl-a-amino acids 6a-b.
1250, 1180, 1032, 691. MS (EI) m/z (%): 354 (1) (M+), 312 (8),
253 (100), 207 (5), 105 (17). HRMS (ESI-TOF) calcd. for
C20H22N2O4 + H+: 355.1652; found: 355.1651. HPLC: Chiralpak
AD-H, Hexane-i-PrOH (90:10), 254 nm, 1 ml/min, tr = 41.3 and
44.9 min.
5.22-5.13 (m, 2H, CH2), 3.78 (s, 3H, CH3), 2.99 (dd, J = 7.2,
14.3 Hz, 1H, CH2), 2.92 (dd, J = 7.1, 14.2 Hz, 1H, CH2), 2.31
(s, 3H, CH3). 13C NMR (125.76 MHz, CDCl3): d = 174.1,
166.2, 138.0, 135.7, 132.8, 131.7, 129.3, 128.7, 126.9, 126.6,
119.5, 70.9, 52.6, 41.0, 21.1. IR (cm-1): 3276, 3072, 2951,
2920, 1731, 1639, 1513, 1431, 1227, 1136, 707, 691. MS (EI)
m/z (%): 338 (0.08) (M+), 297(100), 279(22), 237(62), 203
(19), 181(11), 145(13), 105 (69). HRMS (ESI-TOF) calcd. for
C20H23N2O3 + H+: 339.1703; found: 339.1706. HPLC:
Chiralpak AD-H, Hexane-i-PrOH (90:10), 254 nm, 1ml/min,
tr = 23.8 and 26.6 min.
Methyl 2-(2-benzoylhydrazinyl)-2-(naphthalen-2-yl)pent-4-
enoate, rac-4c
Yield 61%, colorless oil. 1H NMR (500 MHz, CDCl3): d = 7.94
(s, 1H, NH), 7.84-7.76 (m, 4H, ArH), 7.58-7.55 (m, 3H, ArH),
7.49-7.42 (m, 3H, ArH), 7.36-7-33 (m, 2H, ArH), 5.96-5.87
(m, 1H, CH), 5.81 (d, J = 6.8 Hz, 1H, NH), 5.24-5.14 (m, 2H,
CH2), 3.80 (s, 3H, CH3), 3.11 (dd, J = 7.5, 14.4 Hz, 1H, CH2),
3.04 (dd, J = 6.7, 14.3 Hz, 1H, CH2). 13C NMR (125.76 MHz,
CDCl3): d = 173.8, 166.4, 136.2, 133.1, 133.0, 132.9, 132.7,
131.8, 128.7, 128.4, 128.3, 127.6, 126.9, 126.5, 126.4, 125.9,
124.5, 119.6, 71.2, 60.5, 52.8, 40.9. IR (cm-1): 3276, 3058, 2950,
2923, 1730, 1639, 1530, 1431, 1275, 1226, 1134, 918, 708, 691.
MS (EI) m/z (%): 374 (4) (M+), 315 (31), 282 (14), 281 (48),
273 (41), 272 (28), 207 (100), 153 (18), 105 (22). HRMS
(ESI-TOF) calcd. for C23H22N2O3 + H+: 375.1703; found:
375.1704. HPLC: Chiralcel OD-H, Hexane-EtOH (90:10), 254
nm, 1 ml/min, tr = 5.46 and 6.06 min.
Methyl 2-(2-benzoylhydrazinyl)-2-(4-bromophenyl)pent-4-
enoate, rac-4e
Yield 80%, colorless oil. 1H NMR (500 MHz, CDCl3):
d = 7.80 (d, J = 6.35 Hz, 1H, NH), 7.58-7.57 (m, 2H, ArH),
7.49-7.45 (m, 3H, ArH), 7.40-7.33 (m, 2H, ArH), 5.84-5.78
(m, 1H, CH), 5.60 (d, J = 6.8 Hz, 1H, NH), 5.20-5.14 (m, 2H,
CH2), 3.79 (s, 3H, CH3), 2.96 (dd, J = 7.2, 14.3 Hz, 1H, CH2),
2.87 (dd, J = 6.9, 14.3 Hz, 1H, CH2). 13C NMR (125.76 MHz,
CDCl3): d = 173.5, 166.4, 137.8, 132.7, 132.2, 131.9, 131.6,
128.8, 128.6, 126.9, 122.4, 120.0, 70.8, 52.8, 41.2. IR (cm-1):
3272, 3071, 2951, 2920, 1731, 1640, 1488, 1432, 1228, 1075,
1009, 708, 691. MS (EI) m/z (%): 402 (1.58) (M+-1), 372
(30), 371(11), 370 (36), 303 (38), 302(16), 301 (44), 281(20),
207 (40), 105 (100). HRMS (ESI-TOF) calcd. for
C19H19N2O3Br + H+: 403.0651; found: 403.0645. HPLC:
Chiralpak AD-H, Hexane-i-PrOH (90:10), 254 nm, 1ml/min,
tr = 32.2 and 35.8 min.
Methyl 2-(2-benzoylhydrazinyl)-2-p-tolylpent-4-enoate, rac-4d
Yield 66%, colorless oil. 1H NMR (500 MHz, CDCl3):
d = 7.79 (d, J = 6.4 Hz, 1H, NH), 7.58-7.56 (m, 2H, ArH,),
7.47-7.44 (m, 1H, ArH), 7.39-7.31 (m, 4H, ArH), 7.15 (m, 2H,
ArH), 5.89-5.84 (m, 1H, CH), 5.61 (d, J = 6.5 Hz, 1H, NH),
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE SYNTHESIS OF QUATERNARY AMINO ACIDS
535
Ethyl 2-(2-benzoylhydrazinyl)-2-methylpent-4-enoate,
rac-4f
Compounds rac-6a and rac-6b were obtained according to the
procedure described for the preparation of (S)-6a (see above).
Yield 57%, colorless oil. 1H NMR (500 MHz, CDCl3): d = 8.0
(s, 1H, NH), 7.75-7.73 (m, 2H, ArH), 7.51-7.49 (m, 1H, ArH),
7.45-7.42 (m, 2H, ArH), 5.86-5.79 (m, 1H, CH), 5.19-5.15 (m,
2H, CH2), 5.06 (br, 1H, NH), 4.27-4.18 (m, 2H, CH2), 2.58
(dd, J = 7.0, 14.0 Hz, 1H, CH2), 2.52 (dd, J = 7.7, 14.0 Hz, 1H,
CH2), 1.40 (s, 3H, CH3), 1.30 (t, J = 7.0 Hz, 3H, CH3). 13C
NMR (125.76 MHz, CDCl3): d = 174.8, 166.6, 132.9, 132.1,
131.7, 128.6, 126.8, 119.5, 64.8, 61.3, 41.5, 21.2, 14.2. IR
(cm-1): 3278, 2980, 2957, 2930, 1723, 1641, 1449, 1287,
1271, 1150, 1024, 920, 711, 692. MS (EI) m/z (%): 276
(0.25) (M+), 235 (39), 203 (21), 161 (7), 105 (100), 77(42).
HRMS (ESI-TOF) calcd. for C15H20N2O3 + Na+: 299.1366;
found: 299.1367. HPLC: Chiralpak AD-H, Hexane-i-PrOH
(90:10), 210 nm, 1ml/min, tr = 20.4 and 21.4 min.
2-Amino-2-phenylpent-4-enoic acid, rac-6a
With 41 mg (0.19 mmol) of rac-5a, 19.2 mg (0.46 mmol) of
LiOH Á H2O and 2 ml of a THF-H2O (3:1) mixture, to afford 23 mg
ꢀ
(60% yield) of rac-6a, mp 177–179 C (EtOH-diethyl ether).
1H NMR (500 MHz, CD3OD): d = 7.60-7.53 (m, 2H, ArH),
7.42-7.32 (m, 2H, ArH), 7.35-7.30 (m, 1H, ArH), 5.82-5.74
(m, 1H, CH), 5.34-5.26 (m, 1H, CH2), 5.25-5.18 (m, 1H,
CH2), 3.11-3.04 (m, 1H, CH2), 3.02-2.95 (m, 1H, CH2).
13C NMR (125.76 MHz, CD3OD): d = 173.0, 138.5, 131.7,
128.4, 128.0, 125.9, 120.1, 65.8, 40.7. IR (cm-1): 3080,
2977, 2360, 2341, 1587, 1538, 1500, 1363, 910, 738, 693.
HRMS (ESI-TOF) calcd. for C11H13NO2 + H+: 192.1019;
found: 192.1017. HPLC: Chirobiotic T, MeOH-H2O (50:50),
210 nm, 0.7 ml/min. tr =6.6 and 9.5 min.
Ethyl 2-(2-benzoylhydrazinyl)pent-4-enoate, rac-4g
Yield 42%, colorless oil. 1H NMR (500 MHz, CDCl3) d: 8.18
(s, 1H, NH), 7.76-7.70 (m, 2H, ArH), 7.52-7.47 (m, 1H, ArH),
7.44-7.38 (m, 2H, ArH), 5.92-5.80 (m, 1H, CH), 5.23-5.07 (m,
3H, CH2, NH), 4.23-4.12 (m, 2H, CH2), 3.82 (t, J = 6.1 Hz,
1H, CH), 2.66-2.56 (m, 1H, CH2), 2.50-2.40 (m, 1H, CH2),
1.26 (t, J =7.1 Hz, 3H, CH3). 13C NMR (125.76 MHz, CDCl3):
d = 172.7, 167.0, 133.0, 132.7, 132.0, 128.7, 127.0, 119.0, 62.2,
61.2, 35.3, 14.3. IR (cm-1): 3285, 3066, 2980, 2932, 1731,
1640, 1526, 1463, 1295, 1192, 1025, 917, 692. MS (EI) m/z
(%): 260 (0.93) (M+-2), 221 (17), 121 (14), 105 (100), 77 (66),
68 (39). HRMS (ESI-TOF) calcd. for C14H18N2O3 + Na+:
285.1209; found: 285.1210. HPLC: Chiralpak AD-H, Hexane-
i-PrOH (90:10), 210 nm, 1ml/min, tr = 17.2 and 18.4 min.
Compounds rac-5a and rac-5b were obtained according
to the procedure described for the preparation of (S)-5a
(see above).
2-Amino-2-(4-methoxyphenyl)pent-4-enoic acid, rac-6b
100 mg (0.43 mmol) of rac-5b, 41 mg (0.98 mmol)
LiOH Á H2O and 3 ml mixture THF-H2O (3:1), to afford 46
mg (49% yield) of rac-6b, mp 186–188 ꢀC (EtOH-diethyl ether).
1H NMR (500 MHz, CD3OD): d = 7.48-7.46 (m, 2H, ArH), 6.94-
6.92 (m, 2H, ArH), 5.83-5.75 (m, 1H, CH) 5.33-5.23 (m, 2H,
CH2), 3.78 (s, 3H, CH3), 3.09-3.05 (m, 1H, CH2), 3.00-2.96 (m,
1H, CH2). 13C NMR (125.76 MHz, CD3OD): d = 173.9, 159.8,
131.4, 128.8, 127.3, 120.4, 113.7, 65.2, 54.5, 40.5. IR (cm-1):
3379, 3110, 3043, 2359, 1613, 1592, 1518, 1378, 1264, 1185, 821,
603. HRMS (ESI-TOF) calcd. for C12H15NO3 +H+: 222.1124;
Found: 222.1126. HPLC: Chirobiotic T, MeOH-H2O (50:50),
210 nm, 0.7 ml/min. tr = 7.1 and 12.9 min.
RESULTS AND DISCUSSION
Asymmetric Allylation of Prochiral Hydrazones 3a-g
Methyl 2-amino-2-phenylpent-4-enoate, rac-5a
Initially, the asymmetric allylation of the N-benzoyl
hydrazone 3a with allyltrichlorosilane was attempted in tꢀhe
presence of 3 equivalents of bis-sulfoxide (R,R)-2 at À78 C
in CH2Cl2. However, under these reaction conditions the
desired product 4a was not observed by TLC even after
48 h (Table 1, entry 1). To obtain the desirꢀed N-benzoyl
hydrazine, the temperature was raised to À50 C, which led
to the formation of product 4a in 31% yield with excellent
enantioselectivity, 98% ee (Table 1, entry 2). Motivated by this
result, we next examined the scope of the reaction with a va-
riety of a-keto ester derived N-benzoyl hydrazones 4b-g, and
the results are collected in Table 1.
With 200 mg (0.61 mmol) of rac-4a, 0.5 ml of methanol and
18.5 ml (747 mg, 1.83 mmol) of SmI2 (0.1 M in THF), to afford
80 mg (63% yield) of rac-5a as colorless oil. 1H NMR (500 MHz,
CDCl3): d = 7.52-7.51 (m, 2H, ArH), 7.36-7.34 (m, 2H, ArH),
7.29-7.25 (m, 1H, ArH), 5.72-5.65 (m, 1H, CH), 5.22-5.14 (m, 2H,
CH2), 3.71 (s, 3H, CH3), 3.10-2.95 (m, 1H, CH2), 2.67-264 (m,
1H, CH2). 13C NMR (125.76 MHz, CDCl3): d = 175.8, 142.8,
133.0, 128.5, 127.6, 125.5, 120.1, 63.2, 52.6, 44.7. IR (cm-1): 2951,
2916, 1729, 1434, 1214, 921, 697. MS (EI) m/z (%): 205 (0.08)
(M+), 164 (100), 146 (81), 104 (82). HRMS (ESI-TOF) calcd. for
C12H15NO2 + H+: 206.1175; found: 206.1181.
As shown in Table 1, the anticipated products 4a-g were
obtained in 18 to 93% yield and with enantiomeric excesses
ranging from 36–98%. In those cases proceeding in low
yield, the starting material was recovered unchanged. The
best enantioselectivities (ee = 96–98%) were obtained with
hydrazones derived from methyl aryl-glyoxylates (Table 1,
entries 2–6). The configuration of the major enantiomer of
the N-benzoyl hydrazine 4a was assigned as (S) by compar-
ison of its optical rotation with that already assigned in the
literature for the (R)-enantiomer.112 By contrast, substrates
3f and 3g, which do not present an aromatic substituent at
the imine carbon, afforded products 4f and 4g of low
enantiopurity, probably because the steric hindrance intro-
duced by the aryl substituent has a beneficial effect on the
stereodifferentiation process at the transition state (Table 1,
entries 7 and 8).
Methyl 2-amino-2-(4-methoxyphenyl)pent-4-enoate, rac-5b
With 664 mg (1.87 mmol) of rac-4b, 1.51 ml of methanol,
and 56.2 ml (2.27g, 5.62 mmol) of SmI2 (0.1 M in THF), to af-
1
ford 132 mg (30% yield) of rac-5b as colorless oil. H NMR
(500 MHz, CDCl3): d = 7.44-7.43 (m, 2H, ArH), 6.88-6.86
(m, 2H, ArH), 5.72-5.64 (m, 1H, CH), 5.20-5.13 (m, 2H,
CH2), 3.79 (s, 3H, CH3), 3.70 (s, 3H, CH3), 2.97-2.93 (m 1H,
CH2), 2.65-2.62 (m, 1H, CH2). 13C NMR (125.76 MHz,
CDCl3): d = 175.9, 158.9, 134.8, 133.1, 126.7, 120.0, 113.8,
62.7, 55.3, 52.6, 44.8. IR (cm-1): 3386, 3001, 2951, 1727, 1509,
1248, 1214, 1173, 1031, 829. MS (EI) m/z (%): 235 (0.03)
(M+ +1), 194 (100), 176 (88), 134 (5). HRMS (ESI-TOF) calcd.
for C13H17NO3 + H+: 236.1281; found: 236.1284. HPLC:
Chiralcel OD-H, Hexane-i-PrOH (95:5), 220 nm, 1 ml/min, tr =
15.9 and 17.7 min.
Chirality DOI 10.1002/chir

536
REYES-RANGEL ET AL.
TABLE 1. Allylation of N-benzoylhydrazones 3a-g with allyltrichlorosilane under (R,R)-2 catalysis
Entry
Product
R
R1
Yield (%)
% eea
1b
2
3
4
5
6
7
8
4a
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
4-MeOPh
2-Naphtyl
4-MePh
4-BrPh
Me
—
31
50
25
35
18
64
93
—
98c
96
98
96
98
58
36
4g
Et
H
aThe enantiomeric excess was determined by chiral HPLC.
bAt À78 ꢀC.
cThe absolute configuration of compound 4a was assigned as (S) with base on literature precedent (Ref. 112).
In an attempt to improve the observed yields, reaction
times were increased using N-benzoylhydrazone 3a as a
model substrate. Indeed, entries 6–8 in Table 2 show a direct
correlation between reaction time andꢀyield. Best results were
found after 6 days of reaction at À50 C.
Electronic Circular Dichroism
Electronic circular dichroism (ECD) is regarded as one of
the most powerful techniques for the assignment of the abso-
lute configuration (AC) of chiral compounds, principally be-
cause of its high sensitivity to the tridimensional orientation
of the chromophores present in the chiral molecule.118,119 In
principle, chiral compounds with the same or similar chromo-
phores and stereochemical environment exhibit similar ECD
spectra, which is the basis for the assignment of the AC of a
new chiral molecule that can be compared with those whose
absolute configuration is known.119,120 For example, Aimi
and coworkers established the AC of several oxoindoles by
comparison of their ECD spectra with those of known
oxytryptophan derivatives.121 In similar fashion, Tomasini
and coworkers were able to establish the absolute configura-
tion of a group of aromatic ring-substituted chiral isatins by
comparison of their ECD spectra with those from known
hydroxytryptophan derivatives.122–124
In this context, in 2004 Leighton and coworkers synthesized
compound 4a of (R) configuration and reported an optical
rotation equal to À36.0 ([a]D = À36.0; c 1.15, CHCl3),112 which
is opposite in sign to that obtained by us. Therefore, it is
concluded that we had obtained (S) configured allylated
a-allyl benzoylhydrazinyl keto ester derivative (S)-4a. Further-
more, one can anticipate that derivatives presenting similar
ECD spectra should have the same configuration. Indeed,
compounds 4b-e were analyzed by ECD spectroscopy in
MeCN and MeOH and the resulting spectra were compared
with the ECD spectra of (S)-4a. Spectra of similar shape were
recorded in both solvents (Figure 1). Allylated derivatives 4a-c
and 4e exhibit similar negative Cotton effects in the long-wave
region (300–230 nm) and a positive effect in the short-wave re-
gion (230–200 nm) in methanol, which suggests that all of
them have the same stereochemistry; i.e., an (S) configuration.
With these precedents, monosulfoxide (R)-1 was then eval-
uated as chiral promoter, under the best reaction conditions
discovered for bis-sulfoxide (R,R)-2 (Table 2). Nevertheless,
six equivalents of (R)-1 were required to achieve good yield
(47%), while maintaining good enantiomeric excess (Entry
17 in Table 2).
When hydrazone 3a was treated with allyltrichlorosilane in
the presence of chiral sulfoxide (R)-1 in 10 ml of anhydrous
solvent (that is, under more diluted conditions) the desired
product was not observed (Entry 11 in Table 2). Interestingly,
decreasing the amount of solvent to 3 ml afforded the desired
product in 70% yield and 76% ee (Entry 12 in Table 2).
With respect to the recyclability of bis-sulfoxide/N-oxide
(R,R)-2, it is worth mentioning that this promoter can be re-
covered (75–85% recovery) and reused up to six times with
no loss of enantiomeric purity.
On the other hand, enantiomerically pure a-allyl a-amino acids
have previously been prepared by enzymatic resolution97,115 or
by diastereoselective alkylation of chiral a-iminoesters.116,117 In
this work, (S)-N-benzoyl hydrazines 4a-b were converted to
the corresponding amino esters 5a-b by treatment with excess
SmI2. Finally, the (S)-amino esters 5a-b were hydrolyzed with
LiOH to obtain the desired a-allyl a-amino acids 6a-b related to
L-phenylglycine in 54–55% yield and with very high enantiopurity
(Scheme 4). The levorotatory optical activity of 6a agrees in sign
(although not in magnitude) with that reported in the literature
for the (S)-enantiomer.114 Thus, chemical correlation (conver-
sion of (S)-4a to (S)-6a with retention of configuration,
Scheme 4) confirms the assignment of configuration for the
major product of the asymmetric allylation reported herein.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE SYNTHESIS OF QUATERNARY AMINO ACIDS
537
TABLE 2. Allylation of N-benzoylhydrazone 3a with allyltrichlorosilane in the presence of (R)-1 and (R,R)-2 catalysts and under
different reaction conditions
Promoter
equivalents
Temp.
(ꢀC)
Allylsilane/butene
equivalents
CH2Cl2 volume
(ml)
Time
(days)
Yield
(%)
eea
(%)
Entry Promoter
c
1b
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R,R)-2
(R)-1
1
1
3
3
3
3
3
3
3
3
3
3
1
3
1
3
6
À50
À50
À50
À50
À24
À50
À50
À50
À50
À24
À50
À50
À50
À50
À50
À50
À50
2/6
2/6
2/6
2/6
5/7
5/7
5/7
5/7
5/7
5/7
5/7
5/7
2/6
2/6
5/7
5/7
5/7
2
3
2
5
2
2
2
2
2
2
10
3
3
3
2
2
2
3
3
3
3
3
2
3
6
8
3
6
6
3
3
3
3
3
—
—
91
—
95
—
98
96
98
98
—
—
76
85
87
88
90
94
2b
15
—
c
3b
4b
17
e
5d
—
31
37
45
6d
7d
8d
9d
39
e
10d
11b
12b
13b
14b
15d
16d
17d
—
—
70
61
40
20
45
47
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
aThe enantiomeric excess was determined by chiral HPLC.
bThese reactions were carried out with 0.65 mmol of hydrazone.
cIt is observed low solubility of the promoter under these conditions.
dThese reactions were carried out with 0.13 mmol of hydrazone.
eDecomposition of the promoter was observed at this temperature.
Fig. 1. Superimposed CD spectra of compounds 4a-e. a) 5 mM in MeCN, 20 ꢀC; b) 5 mM in methanol, 20 ꢀC.
Chirality DOI 10.1002/chir

538
REYES-RANGEL ET AL.
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ACKNOWLEDGMENTS
24. Mukherjee S, Yang JW, Hoffmann S, List B. Asymmetric enamine catal-
The authors are grateful to Consejo Nacional de Ciencia y
Tecnología (CONACyT, México) for financial support via
grant No. 130826. Y. Bandala is also indebted to the Consejo
Técnico de la Investigación Científica and to Instituto de
Biotecnología (UNAM) for his postdoctoral fellowship. We
are indebted to Rodrigo González-Olvera for technical
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