Synthesis of (S)- and (R)-1-(2-furyl)alkylamines and (S)- and (R)-α- amino acids through the addition of organometallic reagents to imines derived from (S)-Valinol

Article abstract of DOI:10.1055/s-1998-2227

(S)-1-(2-Furyl)alkylamines were prepared through the addition of organometallic reagents to the imine derived from 2-furaldehyde and (S)- valinol, previous protection of the auxiliary hydroxy group as trimethylsilyl ether, followed by removal of the auxiliary. Then, protection of the primary amine as tosylamide or benzamide and oxidation of the furan ring gave the N- derivatives of (S)-α-amino acids. (R)-N-Benzoylphenylglycine was prepared from the benzaldimine, where the hydroxy group was protected as the tert- butyldimethylsilyl ether, through addition of 2-furyllithium.

Full text of DOI:10.1055/s-1998-2227

SYNTHESIS
December 1998
1773
Synthesis of (S)- and (R)-1-(2-Furyl)alkylamines and (S)- and (R)-α-Amino Acids
Through the Addition of Organometallic Reagents to Imines Derived from (S)-Valinol
Giuseppe Alvaro, Gianluca Martelli, Diego Savoia,* Andrea Zoffoli
Dipartimento di Chimica “G. Ciamician”, Università degli Studi di Bologna, via Selmi 2, I-40126 Bologna, Italy
Fax: +(0)51-259456; E-mail: savoie@ciamsow.ciam.unibo.it
Received 23 April 1998; revised 22 May 1998
Abstract: (S)-1-(2-Furyl)alkylamines were prepared through the
addition of organometallic reagents to the imine derived from 2-
furaldehyde and (S)-valinol, previous protection of the auxiliary
intermediate 2-hydroxy-1,2-dihydropyridin-5-ones.5
hydroxy group as trimethylsilyl ether, followed by removal of the
1-(2-furyl)alkylamines are also useful precursors of sub-
stituted piperidines, alkaloids and azasugars through the
auxiliary. Then, protection of the primary amine as tosylamide or
benzamide and oxidation of the furan ring gave the N-derivatives
chiral 2-furylimines,6 we found that the reaction of the
of (S)-α-amino acids. (R)-N-Benzoylphenylglycine was prepared
By literature survey of organometallic additions to homo-
imine 1 with benzylmagnesium chloride (5 equiv, THF,
45–50°C, 5–8 h) was previously described, giving dia-
stereoselectively the (S,S)-secondary amine, but removal
of the auxiliary was not accomplished.6a A few other anal-
ogous reactions have exploited (R)-phenylglycinol
(MeLi, THF, –55°C, d.e. 90%)6b and (1R,2S)- or (1S,2R)-
2-amino-1,2-diphenylethanol (RMgX, CeCl3, THF, 0–
20°C, d.e. 84–99.6%)6c as auxiliaries. In the latter case,
removal of the auxiliary by selective hydrogenolysis was
performed in a single example with unreported yield.
from the benzaldimine, where the hydroxy group was protected as
the tert-butyldimethylsilyl ether, through addition of 2-furyllith-
ium.
Key words: α-amino acids, asymmetric synthesis, furfuryl-
amines, organometallics, valinol
Continuing our studies directed to the synthesis of enan-
tiopure amines through the addition of organometallic re-
agents to homochiral amines,1 we have recently introduced
the use of (S)-valinol trimethylsilyl ether as a highly effi-
cient and easily removable auxiliary for the preparation of
(S)-1-(2-pyridyl)alkylamines through the diastereoselec-
tive addition of organolithiums, Grignard and triorganozin-
cate reagents to the imine derived from pyridine-2-carbal-
dehyde.1h These reactions lead sometimes to tertiary
amines as the main products (by addition of primary alkyl-
magnesium halides to the nitrogen atom of the imine) or to
unexpected byproducts, mainly ketimines.1h The use of (S)-
O-(tert-butyldimethylsilyl)phenylglycinol as auxiliary for
the addition of Grignard reagents to 2-pyridyl ketimines in
the presence of magnesium bromide in dichloromethane
has been recently described.2
The hydroxy-imine 1, readily prepared by condensation
of 2-furaldehyde and (S)-valinol, was immediately con-
verted to the imine 2 by protection of the hydroxy function
as the trimethylsilyl ether with >95% overall yield
(Scheme 1). The addition of a slight excess of allylzinc
bromide to the solution of 2 in anhydrous tetrahydrofu-
ran (THF) at –78°C gave the secondary homoallylic
amine 3 with excellent yield and complete diastereoselec-
tivity, as determined by GC-MS analysis of a sample pre-
pared by basic quenching, which allowed preservation of
the silyl protection. Notably, the amine 3 could be pre-
pared directly from 1 by using an excess of allylzinc bro-
mide and allowing the temperature to reach 20°C, but
consistent epimerization at the newly formed stereocenter
occurred with time,1b,c as the d.r. progressively decreased
to the value 92:8 while the reaction went to completion.
We now describe the preparation of (S)- or (R)-1-(2-fur-
yl)alkylamines by an analogous method, properly choos-
ing the starting imine and organometallic reagent, and the
subsequent conversion to (S)- or (R)-α-amino acids3 by a
three-step sequence, exploiting in the last step the oxida-
tion of the furan ring to a carboxy group.4 Homochiral
Removal of the auxiliary from 3 was accomplished by ox-
idative cleavage with periodic acid and methylamine,1c,d,f
Scheme 1

SYNTHESIS
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1774
followed by acidic hydrolysis and basic treatment, afford- bound to nitrogen and to C5 of the furan ring, and were
ing the primary homoallylic amine 4, which was convert- likely formed through silyl transfer from oxygen to meta-
ed to the benzamide 5 and tosylamide 6. The latter amide lated nitrogen and furan-C5 carbon atoms. Consistently
has been recently prepared by kinetic resolution of the ra- with the structure assignment, no byproduct was present
cemic compound by asymmetric dihydroxylation,4d and in significant amounts in the reaction mixture (GC-MS
was then converted to (2S,4S)-2-(benzyloxycarbonylamino)- and 1H NMR) after acidic quenching.
4-(hydroxymethyl)butanoic acid γ-lactone 7,4j precursor
The auxiliary was removed as usually and the crude (S)-
of the β-lactam antibiotic clavalanine 8,7 as well as to the
1-(2-furyl)alkylamines 9 and 10 were immediately con-
diastereomer (2S,4R)-7.
verted to the N-benzoyl derivatives (S)-11 and (S)-12 with
Methyl- and phenyllithium reacted smoothly with the imi- satisfactory yields after chromatography on a short silica
ne 2 at –10°C in THF and the additions were complete gel column. Oxidation of the furan ring with sodium perio-
after 0.5 h. After quenching and subsequent desilylation date in the presence of a catalytic amount of ruthenium
in acidic aqueous solution, followed by basic treatment, dioxide4b,d gave (S)-N-benzoylalanine [(S)-13] and (S)-N-
the β-amino alcohols (S,S)-9 and (S,S)-10 were isolated. A benzoylphenylglycine [(S)-14] with good yields and excel-
single diastereomer of 9 was revealed by GC-MS analysis lent optical purity, as determined by comparison with au-
of the crude product after basic quenching of the reaction thentic compounds. Hence, in this route to α-amino acids
mixture, which preserved the silyl ether; in fact, the dia- the imine 2 behaves as an (S)-glycine cation equivalent.3
stereomers of analogous O-trimethylsilyl β-amino alco-
(R)-Arylglycines2 can be obtained by interchanging the
hols are usually well separated by GC.1h The perfect dia-
organic groups of the imine and the organometallic re-
stereoselectivity was then confirmed by 1H NMR analysis
agent.8 For example, we prepared (R)-N-benzoylphenyl-
of the desilylated products 9, since the of analogous dia-
glycine exploiting the addition of 2-furyllithium (3 equiv)
stereomeric β-amino alcohols gave different absorptions
to the benzaldimine 16, obtained by protecting the hy-
of the CHN protons.1b–d On the other hand, trace amounts
droxy group of the imine 15 as the tert-butyldimethylsilyl
of (R,S)-10 (<3%) were detected by either GC-MS and 1H
ether (Scheme 3). The organometallic reaction proceeded
NMR analyses; notably, the spectra of (S,S)- and (R,S)-10
slowly and was incomplete even at 0–20°C giving the ex-
differed only for the absorption of a furan proton.
pected C=N adduct. However, the subsequent attack of
2-furyllithium to the silyloxy group of the adduct, and
probably of the imine 16, occurred leading in situ to the
β-amino alcohol (R,S)-10 and 2-(tert-butyldimethyl-
silyl)furan. After basic quenching, the complete desilyla-
tion of the primary reaction product was achieved by
treatment with tetrabutylammonium fluoride in THF/H2O
mixture, then the β-amino alcohol (R,S)-10 was separated
from the byproducts and the starting imine by column
1
chromatography on silica gel. The H NMR analysis
showed the presence of only one diastereomer for 10. (R)-
N-Benzoylphenylglycine [(R)-14] was then prepared from
(R)-12 with good yield by the routine two-step procedure.
Scheme 2
Byproducts were formed in these reactions, as observed
by GC-MS analysis of the O-silyl products obtained by
basic quenching of reaction samples. In the reaction with
methyllithium, minor amounts of unreacted imine and
(S)-(E)- and (S)-(Z)-N-[1-(2-furyl)ethylidene]valinol tri-
methylsilyl ether (8%), analogous to the ketimines pro-
duced in the organometallic reactions of aromatic imi-
nes,1e,h were identified by their mass spectral fragmenta-
tion pattern (GC-MS analysis). These byproducts were
decomposed by acidic quenching of the reaction mixtures
and eliminated by the usual workup procedure. On the
other hand, two minor products were observed in the re-
action mixture of phenyllithium and considered (MS) as
isomers of the main product 10. In fact, they presumably
Scheme 3
differed for the position of the silyl group, which was

SYNTHESIS
December 1998
1775
(S)-N-Benzylidenevalinol tert-Butyldimethylsilyl Ether (16):
The imine 15 was prepared in quantitative yield by the same proce-
dure previously described for the imine 1. The crude imine 15 was
dissolved in anhyd CH2Cl2 (10 mL) and imidazole (0.752 g,
11 mmol) and t-BuMe2SiCl (1.65 g, 11 mmol) were added to the
magnetically stirred solution. After stirring for 3 h, the solid was fil-
tered off and the solution was concentrated in vacuo. The residue was
taken with anhyd Et2O/cyclohexane (1:1, 50 mL) and the solid phase
filtered off. The organic solution was concentrated in vacuo to leave
the imine 16, which was used in subsequent reactions without purifi-
cation; yield: 2.89 g (95%); [α]D20 +36.7 (c = 1.2, CHCl3).
It should be also stressed that the use of the tert-butyldi-
methylsilyl protection for the hydroxy group of the imine
is necessary for the successful reaction with 2-furyllithi-
um. In fact, we preliminarily observed that the addition of
2-furyllithium to the O-trimethylsilyl derivative of 15 ex-
clusively gave desilylation to 15. Moreover, 2-furyllithi-
um (5 equiv) added very slowly to the unprotected imine
15 (25°C, 2 d) gave the β-amino alcohol 10 with 66% iso-
lated yield, but low stereocontrol (d.r. 80:20).
1H NMR (CDCl3, 200 MHz): δ = 8.22 (s, 1 H, CH=N), 7.73 (m, 2 H,
Ph), 7.42 (m, 3 H, Ph), 3.90 (dd, J = 4.1 and 10.0 Hz, 1 H, CH2O),
3.68 (dd, J = 8.2 and 10.0 Hz, 1 H, CH2O), 3.0 (m, 1 H, CHN), 1.95
(m, 1 H, CHMe2), 0.95 (d, J = 7.4 Hz, 6 H, CHMe2), 0.85 (s, 9 H,
SiBu-t), 0.03 and –0.04 (2 s, 6 H, SiMe2).
A comparison of this procedure with other methods for
the preparation of optically pure α-furylamines and α-
amino acids is opportune. Homochiral 1-(2-furyl)alkyl-
amines have been prepared by resolution of racemic com-
pounds or by asymmetric synthesis. N-Benzoyl-1-(2-fur-
yl)ethylamine was resolved by crystallization of the dias-
tereomeric tartrates, and the (–)-N-benzoyl derivative was
oxidized to (–)-(R)-N-benzoylalanine by treatment with
potassium permanganate.4a Moreover, 1-(2-furyl)-N-(to-
syl)alkylamines were obtained with 90–100% ee by kinet-
ic resolution using a modified Sharpless asymmetric ep-
oxidation reagent, and the subsequent oxidation of the fu-
ran ring using ozone4d,f or NaIO4/RuCl3 (cat.)4f gave the
N-tosyl-α-amino acids with moderate to good optical pu-
rity. The synthesis of (R)-furfurylamines has been recent-
ly accomplished by the reaction of 2-furylboronic acid
with iminium intermediates derived from (S)-phenylmor-
pholinone.10 The enantioselective reduction of oxime
benzyl ethers of 2-furyl ketones with reagents derived
MS: m/z (%) = 160 (100, M+ – CH2OSiMe2Bu-t), 248 (68, M+ – Bu-t),
73 (24), 162 (16), 59 (14), 161 (14), 249 (14), 75 (13), 91 (11), 93 (11).
Addition of Allylzinc Bromide to the Imine 2. Preparation of (S)-
N-[(S)-1-(2-Furyl)but-3-enyl]valinol (3):
Allylzinc bromide was prepared by stirring allyl bromide (1.31 mL,
15 mmol) and zinc powder (1.63 g, 25 mmol) in anhyd THF (20 mL)
for 3 h, then the mixture was cooled to –78°C and the imine 2 (2.53 g,
10 mmol) dissolved in THF (5 mL) was added while the mixture was
stirred magnetically. After 2 h, 4 N HCl (10 mL) was added and the
mixture was stirred overnight at rt. Et2O (20 mL) was added and the
aqueous phase was separated and washed with Et2O (20 mL). NaOH
pellets were added to the aqueous phase until pH 11, and the amine
was extracted with Et2O (3 × 20 mL). The Et2O layers were collected,
dried (Na2SO4) and concentrated to leave the crude amine 3 in pure
state; yield: 2.22 g (99.5%); [α]D25 –47.8 (c = 2.2, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 7.38, 6.32 and 6.15 (3 m, 3 H, Ar),
5.84–5.68 (m, 1 H, CH=CH2), 5.17–5.03 (m, 2 H, CH=CH2), 3.78 (t,
1 H, ArCH), 3.59 (dd, J = 4.0 and 10.9 Hz, 1 H, CH2O), 3.43 (dd, J =
4.7 and 10.9 Hz, 1 H, CH2O), 2.55 (m, 2 H, ArCHCH2), 1.68 (m, 1 H,
CHMe2), 1.43 (s, 1 H, NH), 0.85 (d, J = 6.8 Hz, 6 H, CHMe2).
MS: m/z (%) = 182 (100, M+ – CH2OH), 96 (60, ArCHNH2), 121 (52,
ArCHC3H5), 103 (32), 91 (29), 77 (24), 93 (24), 81 (17), 72 (12).
•
from BH3 THF and (–)-norephedrine was also described,
then N-benzoyl (S)- or (R)-α-amino acids were prepared
through the ozonolysis of the furan ring (28–55% overall
yield, five steps, ee 87–96%).4k Another route involves
alkylation of the 2-azaallyl anions of the N-(2-furylmeth-
yl)imines prepared from (+)- or (–)-2-hydroxy-3-pi-
nanone (44–67% overall yield, 91–>98% ee) and (–)-3-
hydroxy-2-caranone (36% yield, 81% ee).11
Addition of Organolithium Reagents to the Imine 2. Preparation
of the Amines (S,S)-9 and (S,S)-10:
1 M MeLi in THF/cumene (12 mL, 12 mmol) or 2 M PhLi in benzene/
Et2O (6 mL, 12 mmol) was slowly added to the solution of the imine
2 (2.53 g, 10 mmol) in anhyd THF (15 mL) cooled at –15°C under N2.
The mixture was stirred for 30 min at –10°C, then quenched by addi-
tion of 4 N HCl (20 mL) and stirred overnight at rt. Et2O (20 mL) was
added and the aqueous phase was separated and washed with Et2O
(20 mL). NaOH pellets were added to the aqueous phase until pH 11,
and the amine was extracted with Et2O (3 × 20 mL). The Et2O layers
were collected, dried (Na2SO4) and concentrated to leave the crude β-
amino alcohol, which was purified by column chromatography (silica
gel, 10 g, cyclohexane/Et2O 80:20).
General methods and instrumentation were as previously described.1
(S)-N-[(2-Furyl)methylene]valinol Trimethylsilyl Ether (2):
Anhyd MgSO4 (5 g) and 2-furaldehyde (0.96 g, 10 mmol) were added
to a solution of (S)-valinol (1.03 g, 10 mmol) in CH2Cl2 (10 mL) at
0°C, and the mixture was stirred magnetically for 2 h. The solid phase
was filtered off and the organic solvent was evaporated under reduced
pressure to leave the crude (E)-imine 15 in almost quantitative yield.12
The imine 1 was dissolved in anhyd CH2Cl2 (10 mL) and Et3N
(1.12 g, 11 mmol) and Me3SiCl (1.16 g, 11 mmol) were added to the
magnetically stirred solution. The mixture was stirred for 3 h, the sol-
id was filtered off and the solution was concentrated in vacuo. The
residue was taken up in anhyd Et2O/cyclohexane (1:1, 50 mL) and the
solid phase filtered off. The organic solution was concentrated in vac-
uo to leave the imine 2, which was used in subsequent reactions with-
out purification; yield: 2.40 g (95%); [α]D20 +1.7 (c = 2.1, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 7.99 (s, 1 H, CH=N), 7.49, 6.71 and
6.45 (3 m, 3 H, Ar), 3.88 (dd, J = 4.0 and 10.3 Hz, 1 H, CH2O), 3.61
(dd, J = 8.1 and 10.3 Hz, 1 H, CH2O), 2.86 (m, 1 H, CHN), 1.95 (m,
1 H, CHMe2), 0.93 and 0.89 (2 d, 6 H, J = 7.4 Hz, CHMe2), 0.03 (s, 9
H, SiMe3).
(S)-N-[(S)-1-(2-Furyl)ethyl]valinol [(S,S)-9]: yield: 87%.
1H NMR (CDCl3, 200 MHz): δ = 7.34 (m, 1 H, Ar), 6.30 (m, 1 H, Ar),
6.12 (m, 1 H, Ar), 3.70 (q, 1 H, CHMe), 3.58 (dd, J = 4.2 and 10.8 Hz,
1 H, CH2O), 3.37 (dd, J = 5.2 and 10.8 Hz, 1 H, CH2O), 2.33 (m, 1 H,
CHN), 2.20 (broad, 2 H, NH and OH), 1.42 (d, J = 7.4 Hz, 3 H,
CHMe), 0.87 and 0.85 (2 d, J = 4.7 Hz, 6 H, CHMe2).
(S)-N-[(S)-α-(2-Furyl)benzyl]valinol [(S,S)-10]: yield: 77%.
1H NMR (CDCl3, 200 MHz): δ = 7.47–7.24 (m, 6 H, Ar), 6.31 (m, 1
H, Ar), 6.10 (m, 1 H, Ar), 4.98 (s, 1 H, CHAr2), 3.54 (dd, J = 6.6 and
16.2 Hz, 1 H, CH2O), 3.39 (dd, J = 9.2 and 16.2 Hz, 1 H, CH2O), 2.42
(m, 1 H, CHCH2), 2.20–1.50 (broad, 2 H, NH and OH), 1.90 (m, 1 H,
CHMe2), 0.96 and 0.92 (2 d, J = 4.7 Hz, 6 H, CHMe2).
MS: m/z (%) = 253 (5, M+), 150 (100, M+ – CH2OSiMe3), 73 (29), 55
(11), 238 (6, M+ – Me).

SYNTHESIS
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1776
Addition of 2-Furyllithium to the Imine 16. Preparation of the
(S)-N-[(R)-α-(2-Furyl)benzyl]valinol [(R,S)-10]:
(R)-N-[α-(2-Furyl)benzyl]benzamide [(R)-12]: yield: 66%; [α]D20
+29.91 (c = 1, CHCl3).
2.5 M BuLi (6 mL, 15 mmol) was added to the magnetically stirred
solution of furan (1.02 g, 15 mmol) in anhyd THF (10 mL) cooled at
–78°C under N2, then the mixture was stirred at 0°C for 2 h. A solu-
tion of the imine 16 (1.99 g, 6.55 mmol) in THF (10 mL) was added
at 0°C. Stirring was continued at 0°C for 8 h, then the mixture was
allowed to reach 20°C overnight, quenched at 0°C with water
(10 mL), and extracted with Et2O (3 × 10 mL). The collected Et2O
layers were concentrated at reduced pressure. The residue was dis-
solved in THF/H2O (1:1, 14 mL), then 1 M Bu4NF in THF (7.5 mL,
7.5 mmol) was added, and the mixture was stirred overnight. The or-
ganic bases were extracted with Et2O (3 × 10 mL), and the collected
etheral layers dried (Na2SO4) and concentrated in vacuo. The residue
was chromatographed (silica gel, 10 g, cyclohexane/Et2O 4:1) to give
(R,S)-10; yield: 1.20 g (74%); [α]D20 +1 (c = 1.0, CHCl3); the 1H NMR
spectrum was identical to that of (S,S)-10.
Preparation of N-Protected α-Amino Acids by Oxidation of the
Furan Ring; (S)-N-Benzoylphenylglycine [(S)-14]; Typical Proce-
dure:
•
RuO2 H2O (0.010 g, 0.066 mmol) was added to the mixture of NaIO4
(6.38 g, 29.8 mmol), water (13 mL), MeCN (19 mL) and CCl4 (13
mL), and the mixture was stirred magnetically for 0.5 h. The amide
(S)-12 (0.52 g, 1.87 mmol) was added and the mixture was stirred for
2 h. The organic phase was separated and the aqueous phase was
washed with CH2Cl2 (5 × 20 mL), and the collected organic layers
were washed with sat. NaHSO3(20 mL) and sat. brine (20 mL), dried
(Na2SO4) and concentrated in vacuo. The residue was dissolved in
EtOAc (20 mL) and filtered through a small pad of Celite, the solvent
was evaporated in vacuo to leave (S)-14 as a solid residue, which was
recrystallized (CH2Cl2); yield: 0.36 g (75%); mp 196–197°C; [α]D20
+114.3 (c = 1.2, EtOH).
Oxidative cleavage of N-Protected â-Amino Alcohols with Peri-
odic Acid. Preparation of Amides 5, 6, 11, and 12; General Proce-
dure:
IR (Nujol): ν = 3600–1800, 3440, 1720, 1630 cm–1.
1H NMR (200 MHz, CDCl3): δ = 11.4 (br, 1 H, CO2H), 7.79 (m, 2 H,
Ar), 7.55–7.20 (m, 9 H, Ar and NH), 5.75 (d, J = 7 Hz, 1 H, CHN).
1H NMR (200 MHz, MeOD): δ = 7.81 (m, 2 H, Ar), 7.52–7.25 (m, 8
H, Ar), 5.65 (s, 1 H, CHN).
To a magnetically stirred solution of the β-amino alcohol 4, 9, or 10
(4 mmol) in MeOH (20 mL) was added 40% aq MeNH2 (5 mL) and
then a solution of H5IO6 (3.40 g, 15 mmol) in water (5 mL). The
progress of the reaction was monitored by TLC (EtOAc/MeOH 95:5),
then the solid was filtered off, water (5 mL) was added, and the aque-
ous phase was extracted with Et2O (3 × 15 mL). The collected organic
layers were concentrated to a volume of 10 mL, then 2 N HCl (10 mL)
was added and the mixture was stirred overnight. Most of the solvent
was removed at reduced pressure and the aqueous phase was extract-
ed with Et2O (2 × 10 mL), then NaOH pellets were added until pH 11
and the organic phase was extracted with Et2O (3 × 10 mL). The col-
lected Et2O layers were dried (MgSO4) and concentrated at reduced
pressure to leave the crude primary amine as an oil. This was dis-
solved in CH2Cl2 (8 mL), then Et3N (1.01 g, 10 mmol) and BzCl
(0.98 g, 7 mmol), or p-toluenesulfonyl chloride (1.33 g, 7 mmol) were
added to the stirred solution. The mixture was stirred for 3 h, the solid
was filtered off, and the solution was washed with 2 N HCl (2 × 10
mL), dried (Na2SO4) and concentrated. The residue was chromato-
graphed (silica gel, 10 g, cyclohexane/Et2O 4:1) to obtain the pure
amide.
(R)-N-Benzoylphenylglycine [(R)-14]: yield: 75%; mp 196–197°C
(Lit.13 mp 196.5–198°C); [α]D20 –110 (c = 0.7, EtOH) (Lit.13 [α]D20
–119.3 (c = 1.2, EtOH)).
(S)-N-Benzoylalanine [(S)-13]: yield: 88%; mp 148–149°C (CH2Cl2/
cyclohexane) (Lit.4a mp 143–144°C, Lit.14 mp 150–15°C); [α]20
D
+33 (c = 1.0, 0.73 M KOH) (Lit.4a [α] +32.6.(KOH in H2O); Lit.14 [α]
+37.13.(c = 10, KOH in H2O); [α] –37.4 for (R)-13).
IR: ν = 3400–2200, 3510, 3485, 1725, 1710, 1635 cm–1.
1H NMR (300 MHz, CDCl3): δ = 11.5 (s, 1 H, CO2H), 7.80 (m, 2 H),
7.60–7.40 (m, 3 H), 6.82 (d, J = 6.9 Hz, 1 H, NH), 4.81 (m, 1 H,
NHCHMe), 1.59 (d, J = 7.1 Hz, 3 H, CHMe).
Financial support from the Ministero dell'Università e della Ricerca
Scientifica e Tecnologica, Roma, and the University of Bologna
(National Project "Stereoselezione in Sintesi Organica. Metodologie
ed Applicazioni") is gratefully acknowledged.
(S)-N-[1-(2-Furyl)but-3-enyl]benzamide (5): yield: 0.723 g (75%);
[α]D20 –59.8 (c = 2.75, CHCl3).
(1) (a) Boga, C.; Savoia, D.; Umani-Ronchi, A. Tetrahedron:
Asymmetry 1990, 1, 291.
1H NMR (CDCl3, 200 MHz): δ = 7.78 (m, 2 H, Ph), 7.53–7.36 (m, 4
H, Ar), 6.46 (br, 1 H, NH), 6.33 (m, 1 H, Ar), 6.24 (m, 1 H, Ar), 5.86–
5.70 (m, 1 H, ArCHCH2), 5.42 (m, 1 H, CH=CH2), 5.22–5.09 (m, 2
H, CH=CH2), 2.71 (m, 2 H, ArCHCH2).
(b) Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Chem. Soc.,
Chem. Commun. 1993, 1542.
(c) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A.
J. Org. Chem. 1994, 59, 7766.
(d) Alvaro, G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7,
2083.
(e) Alvaro, G.; Savoia, D.; Valentinetti, M. R. Tetrahedron
1996, 52, 12571.
MS: m/z (%) = 241 (M+, 1), 105 (100, PhCO), 200 (60, M+ – C3H5),
77 (41).
(S)-N-[1-(2-Furyl)but-3-enyl]-4-toluenesulfonamide (6): yield:
0.908 g (78%); the product was identical to the authentic compound.5d
(f) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3,
726.
(g) Alvaro, G.; Grepioni, F.; Savoia, D. J. Org. Chem. 1997, 62,
4180.
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1998, 775.
(S)-N-[1-(2-Furyl)ethyl]benzamide [(S)-11]: yield: 60%; [α]D20 –52 (c
= 1.11, CHCl3).
1H NMR (CDCl3, 200 MHz): δ = 7.80 (m, 2 H, Ar), 7.60–7.35 (m, 4
H, Ar), 6.42 (br, 1 H, NH), 6.36 (m, 1 H, Ar), 6.26 (m, 1 H, Ar), 5.46
(m, 1 H, CHMe), 1.61 (d, J = 7.4 Hz, 3 H, CHMe).
MS: m/z (%) = 215 (M+, 25), 105 (100), 77 (40).
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Chem. USSR 1964, 34, 516.
(S)-N-[α-(2-Furyl)benzyl]benzamide [(S)-12]: yield: 70%; [α]D20 –31.1
(c = 1.56, CHCl3).
1H NMR (CDCl3, 200 MHz): δ = 7.84 (m, 2 H, Ph), 7.55–7.25 (m, 9
H, Ar), 6.85 (d, J = 7.8 Hz, NH), 6.52 (d, J = 7.8 Hz, 1 H, NHCH),
6.36 (m, 1 H, Ar), 6.25 (m, 1 H, Ar).
MS: m/z (%) = 277 (M+, 55), 105 (100), 77 (39).

SYNTHESIS
December 1998
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