Use of diphenyliodonium bromide in the synthesis of some N-phenyl-amino acids

Article abstract of DOI:10.1080/00397910903051259

The N-phenyl methyl esters 4 of glycine, alanine, valine, leucine, isoleucine, phenylalanine, methionine, proline, serine, threonine, tyrosine, aspartic acid, and glutamic acid have been synthesized in good to excellent yields using diphenyliodonium bromide, AgNO₃, and a catalytic amount of CuBr starting from the relevant amino acid ester. The chiral integrity of the amino acids 5 was maintained during these reactions, which were confirmed by the synthesis of dipeptide for each N-phenyl amino acid. The structures of the new compounds were confirmed by the analysis of their IR, ¹H, and ¹³C NMR spectra in addition to CHN microanalysis or high-resolution mass spectrometry for the new N-phenyl amino acids 5 and the esters 4.

Full text of DOI:10.1080/00397910903051259

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Use of Diphenyliodonium Bromide in the
Synthesis of Some N-Phenyl α-Amino
Acids
Jason D. McKerrow a , Jasim M. A. Al-Rawi a & Peter Brooks b
a School of Pharmacy and Applied Science, La Trobe University,
Bendigo, Australia
b Faculty of Science, Health, and Education, University of the
Sunshine Coast, Maroochydore, Australia
Available online: 12 Mar 2010
To cite this article: Jason D. McKerrow, Jasim M. A. Al-Rawi & Peter Brooks (2010): Use
of Diphenyliodonium Bromide in the Synthesis of Some N-Phenyl α-Amino Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 40: 1161–1179, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903051259
USE OF DIPHENYLIODONIUM BROMIDE IN THE
SYNTHESIS OF SOME N-PHENYL a-AMINO ACIDS
Jason D. McKerrow,1 Jasim M. A. Al-Rawi,1 and
Peter Brooks2
1School of Pharmacy and Applied Science, La Trobe University, Bendigo,
Australia
2Faculty of Science, Health, and Education, University of the Sunshine Coast,
Maroochydore, Australia
The N-phenyl methyl esters 4 of glycine, alanine, valine, leucine, isoleucine, phenylalanine,
methionine, proline, serine, threonine, tyrosine, aspartic acid, and glutamic acid have been
synthesized in good to excellent yields using diphenyliodonium bromide, AgNO3, and a cata-
lytic amount of CuBr starting from the relevant amino acid ester. The chiral integrity of the
amino acids 5 was maintained during these reactions, which were confirmed by the synthesis
of dipeptide for each N-phenyl amino acid. The structures of the new compounds were con-
firmed by the analysis of their IR, 1H, and 13C NMR spectra in addition to CHN microanalysis
or high-resolution mass spectrometry for the new N-phenyl amino acids 5 and the esters 4.
Keywords: a-Amino acids; diphenyliodonium bromide; esters; N-phenylation
INTRODUCTION
The synthesis of N-aryl amino acids is an area of research that has gained
momentum in recent times.[1] These compounds find application as structural
components of antimicrobial, antiviral, and pharmacologically active molecules.[1a,b]
They are also important core structures of synthetically challenging and medicinally
important agents, such as protein kinase C activators,[2] indolactam-V10,[2] and its
analog benzolactam-V8.[3]
Early work on the synthesis of these compounds used achiral starting materials,
resulting in a racemic mixture that required several steps to isolate the enantiomeri-
cally pure form.[4] A method that allows for the direct synthesis of enantiomerically
pure N-phenyl-a-amino acids is therefore of great interest. Ma and coworkers[1a,b]
were able to use an Ullmann-type reaction to prepare N-phenyl amino acids directly
from the amino acid and an aryl halide.
This method, while relatively simple, requires long reaction times (48 h) and was
limited to only amino acids bearing nonpolar side chains. Recently, Rottger et al.[1g]
developed a protocol for the N-arylation of free and protected amino acids in water
Received January 30, 2009.
Address correspondence to Jasim M. A. Al-Rawi, School of Pharmacy and Applied Science, La
Trobe University, P. O. Box 199, Bendigo 3552, Australia. E-mail: j.al-rawi@latrobe.edu.au
1161

1162
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
using a microwave-enhanced copper-catalyzed method. However, the method was
used only with phenylalanine, leucine, t-leucine, and proline. a-Diazo-compounds
were used with copper complexes of chiral spirobisoxazolines to synthesize a limited
number of chiral N-aryl a-amino acids esters.[1j,k] Diaryliodonium salts have long
been used as arylating electrophiles[5] to carbanions, alcohols, amines, Grignard
reagents, alkoxides, and phenoxides. The use of diaryliodonium salts in the synthesis
of 11 N-phenyl amino acid esters commencing from the parent L-amino acid, with
chirality being maintained, are reported for the first time.
RESULTS AND DISCUSSION
Because of the possibility of the acid group of the amino acid interfering in the
reactions, the amino acids were first converted into the corresponding methyl ester
HCl salt using thionyl chloride in anhydrous methanol. These were prepared in
excellent yields (85–99% only, tyrosine was 61%).
Removal of HCl was via triethylamine in chloroform. Except for the serine
methyl ester (ME) (41%), threonine ME (82%), and tyrosine ME (80%) derivatives,
this was essentially a quantitative reaction. All amino acid ester free amines were
1
characterized by infrared (IR), H NMR, and 13C NMR spectroscopy. Structural
assignments were made by comparison of the spectroscopic data with the amino
ester hydrochloride spectra.[6]
The amino ester was generally carried directly through to N-phenylation
because prolonged standing of the amino esters can lead to polymerization.
Optimum N-phenylation (Scheme 1) was achieved in refluxing acetonitrile using
2 equivalents of amino ester, 1 equivalent of diphenyliodonium bromide, 1 equivalent
of silver nitrate, and a catalytic amount of cuprous bromide. The silver cation precipi-
tates the bromide anion as AgBr, which otherwise competes as a nucleophile. The
nitrate caused no side reactions. The second equivalence of amino ester acts as a mild
base, absorbing the acid (Hþ) released during the coupling of the amine and aryl group.
Triethylamine and pyridine were tested as alternate bases, but both resulted in
considerably lower yields. Purification was via column chromatography, grading
from hexane to ethyl acetate.
The optimum condition of N-phenylation of a-amino acid ester were used
on a-amino acid (glycine and valine), which gave back the a-amino acid used,
bromobenzene, and iodobenzene. However, no N-aryl a-amino acid was identified.
Poor N-phenylation yields were obtained for the glycine ester (7%), because of
competing polymerization, and the proline ester (60%), because of the steric hin-
drance of the secondary amine. The remaining N-phenyl amino esters were obtained
in good yields (see Experimental). All of the N-phenyl amino esters were light
orange=brown color. The leucine, tyrosine, and valine derivatives were solids,
whereas the remaining eight were oils. The structures of products 4 were confirmed
1
using H and 13C NMR spectroscopy in addition to the CHN microanalysis or
high-resolution mass spectrometry (HRMS).
The N-phenyl a-amino acid esters 4 were then hydrolyzed to the corresponding
acids 5 using dilute NaOH solution under mild conditions to keep the chirality
unchanged, and good to excellent yields (see Experimental) of the acids were
obtained. The structures of products 5 were confirmed using P NMR, 13C NMR,

N-PHENYLATION OF a-AMINO ACIDS
1163
Scheme 1. Synthesis of N-phenyl amino acid starting from amino acid 1, converting to its methyl amino
acid ester 2, neutralization to 3, N-phenyl substitution to 4, and then hydrolysis to N-phenyl amino acid 5.
and CHN microanalysis or HRMS. Physical and spectroscopy data agreed with
previously reported data (for references, see Experimental).
Chirality and Anisochrony (Magnetic Nonequivalence)
As a result of chirality, some of amino acid esters 3, N-phenyl amino acid esters
4, and the corresponding N-phenyl amino acids 5 showed magnetic nonequivalent
protons and carbon-13 chemical shift for the chemically equivalent groups.[9]
L-Valine derivatives 3, 4, 5c, and 5cꢀ (ꢀ indicates the DL mixture) showed two
different proton and carbon-13 chemical shifts for the 4- and 5-methyl groups.
Similarly, the methyl groups 5 and 6 in leucine derivatives 3, 4, 5d, and 5dꢀ showed
two different proton and carbon-13 chemical shifts.
However, the CH2 protons of C4 in isoleucine derivatives 3e, 4e, 5e, and 5eꢀ
showed that the two protons of the CH2 are nonequivalent. Similarly, the C3H2
protons in phenylalanine derivatives 3f, 4f, 5f, and 5fꢀ, C3H2 protons in methionine
derivatives 3 g, 4 g, 5 g, and 5gꢀ, tyrosine derivatives 3k, 4k, 5k, and 5kꢀ, aspartic
derivatives 3 l, 4 l, 5 l, and 5lꢀ, and glutamic derivatives 3 m, 4 m, and 5 m showed that
the two protons of the C3H2 are nonequivalent.
Chiral Integrity and Structural Assignment of N-Aryl Amino Acid
Dipeptide Methyl Esters 6
Chiral analysis was undertaken by preparing the chiral dipeptide derivative of
each product to determine if single compounds or diastereoisomers existed.[7] The

1164
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
Scheme 2. Dipeptide formation by coupling of N-phenyl a-amino acid with L-alanine or L-phenylalanine
amino acid methyl ester. NHS, N-hydroxysuccinimide; EDC, N-(3-dimethylaminopropyl)-N0-ethylcarbo-
diimide.
N-phenyl-L-amino acids 5 were coupled with L-phenylalanine methyl ester HCl (2f)
or L-alanine methyl ester HCl (2b) to yield the respective chiral dipeptides 6 using
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide (EDC) as the coupling reagent
(Scheme 2). The two carboxylic acid functions on N-phenyl-L-aspartic acid (5l)
resulted in the formation of the chiral tripeptide 7 (Fig. 1).
Analysis of the 1H NMR of the crude and recrystallized coupling product using
L-N-phenyl amino acids showed the presence of only one isomer, whereas analysis of
the crude and recrystallized coupling product using racemic D, L-N-phenyl amino
acids clearly showed two isomers to be present (see experimental). The individual
1H NMR spectra of the components were relatively unchanged in product 6 com-
pared with those of compound 5, except that the chiral carbon (C10H) of L-alanine
ME was shifted downfield as result of amide formation from d 3.74 to d 4.50. The
system no longer showed as a first-order spectrum and became very complicated.
1
The H NMR of the N-phenyl-L-alanine-L-phenylalanine ME 6b clearly showed
the presence of a single isomer of the dipeptide (see Experimental). Only one signal
was observed for the OCH3 d 3.63 ppm (s) and C3H3 at d 1.37 ppm (d), whereas for
LL and DL-mixture 6bꢀ, two signals equal integration for OCH3 at d 3.63
(LL-product) and 3.80 ppm (s) (DL-product) and C3H3 at d1.47 and 1.38 ppm (d).
13
In the C NMR of the LL-derivatives [d: 174.1 (C11), 171.8 (C2), 146.8 (C10),
136.3 (C16), 129.5 (C14,18), 129.4 (C30,50), 128.8 (C15,17), 127.3 (C16), 119.5
Figure 1. Structure of N-phenyl-L-aspartic acid di-(L-alanine methyl ester).

N-PHENYLATION OF a-AMINO ACIDS
1165
(C40), 114.23 (C20,60), 55.6 (C3), 53.1 (C1), 52.5 (OCH3), 38.0 (C5), 19.8 (C3)], only a
single peak was observed for each carbon environment.
The 13C NMR of the LL and LD derivatives showed two sets of signals, one for
LL- and one for LD-N-phenyl-L-alanine-L-phenylalanine ME 6bꢀ [d: 174.2, 174.0
(C11), 172.0, 171.8 (C2), 146.8, 146.7 (C10), 136.3, 135.7 (C13), 129.7, 129.6 (C15,17),
129.5, 129.4 (C30,50), 128.9, 128.8 (C14, 18), 127.3, 127.2 (C16), 119.5, 119.4 (C40),
114.23, 113.8 (C20,60), 55.6, 55.2 (C3), 53.1, 53.0 (C1), 52.5, 52.4 (OCH3), 38.3, 38.0
1
(C12), 19.9, 19.8 (C3)]. The H NMR of N-phenyl-L-valine-L-phenylalanine ME
and DL are in good agreement with previously reported P NMR.[1a,b]
1
The same findings were observed in the H NMR and 13C NMR of the crude
and recrystallized dipeptide 6c, d compared with 6cꢀ, dꢀ, which confirms the reten-
tion of amino acid chirality after N-phenylation using diphenyliodonium bromide.
EXPERIMENTAL
All solvents and reagents were purchased and used without further purification
unless otherwise stated. Dichloromethane was distilled from CaH2 and stored over
type 3A molecular sieve. Acetonitrile was dried over type 4A molecular sieve; diethyl
formamide and dimethyl formamide were both dried over type 3A molecular sieve
and distilled under reduced pressure before use. Melting points (mp) were determined
using a Stuart SMP3 melting-point apparatus. Optical rotation measurements were
conducted on Bellingham and Stanley polarimeter no. 582129 using a 10-cm cell.
IR spectra were recorded on a Perkin-Elmer 1720-X FT. NMR measurement was
performed on a Bruker AC 200 spectrometer. Proton NMR (1H NMR) spectra were
acquired at 200 MHz. 13C NMR were acquired at 50 MHz. Chemical shifts (d) are
expressed in parts per million (ppm) relative to the internal standard (tetramethylsi-
lane in CDCl3 and solvent peak of acetone d6 and d6 dimethylsulfoxide). GC-MS was
performed on a Shimadzu GC-17A gas chromatograph coupled with a Shimadzu
QP-5000 mass spectrometer with 70-eV electron impact (EI) ionization. HRMS
was conducted by Dr. Sally-Ann Poulsen and coworkers at Griffith University on
a Bruker Daltronics Apex III 4.7e Fourier transform mass spectrometer, fitted with
an Apollo API source. Microanalysis was performed by E. Mocellin and coworkers
from Chemical and MicroAnalytical Services Pty. Ltd. in Belmont, Victoria.
Preparation of Diaryliodonium Bromide[5]
Diaryliodonium bromide was prepared according to the published procedure.[5]
The product was obtained as long white needles (60%), mp 208–210 ꢁC (lit.[5]
1
208–209 ꢁC). H NMR (d6-DMSO) d: 8.22 (d, 4H, J ¼ 8.0 Hz, ArH2,6,20,60), 7.64
(t, 2H, J ¼ 8.0 Hz, ArH4,40), 7.50 (t, 4H, J ¼ 8.0 Hz, ArH3,5,30,50). 13C NMR
(d6-DMSO) d: 135.8 (C20,60), 132.3 (C30,40,50), 120.3 (C10).
Amino Acid Methyl Ester Hydrochloride Salts 2: General Method A
Amino acid salts were prepared following the procedure of Gmeiner and
coworkers.[8] The products were recrystallized from an appropriate solvent (solvent=
yield %): 1a acetonitrile=89, 1b acetonitrile=78, 1c acetonitrile=85, 1d ethyl acetate=99,

1166
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
1dꢀ ethyl acetate=99, 1e methanol–ether=88, 1f chloroform=89, 1 g chloroform–
ether=90, 1i methanol–ether=88, 1k acetonitril=61, 1 l methanol–ether=90, and 1 m
ethyl acetate=98, whereas compounds 1 h (99%) and 1j (58%) gave clear oils that
solidified on standing at room temperature. The purified products were character-
1
ized by melting point, IR, H NMR, and 13C NMR and compared with reported
spectroscopy data.[6]
Amino Acid Methyl Ester Free Amine (3): General Method B
The amino acid ester hydrochloride salt 2 (14 mmol) was mixed with chloro-
form (10 mL) in a 50-mL, round-bottom flask. A solution of triethylamine (14 mmol)
in chloroform (10 mL) was added dropwise to the stirred solution and the mixture
then stirred for 4 h at room temperature. The mixture was heated at 70 ꢁC for 1 h,
then cooled to room temperature and concentrated in vacuo to a white solid. The
solid was diluted with 50 ml ether, filtered, and washed with 10 mL of ether. Con-
centration of the ether filtrate in vacuo yielded the amino acid ester free amine 3.
Glycine methyl ester 3a. The free amine 3a was isolated as yellow oil (1.25 g,
1
100%). The IR, H, and 13C NMR data are in good agreement with the previously
reported values.[8]
L-Alanine methyl ester 3b. The free amine 3b was isolated as a light yellow
1
oil (1.47 g, 100%). The IR, H, and 13C NMR data are in good agreement with the
previously reported values.[9]
DL-Alanine methyl ester 3bꢀ. The free amine 3bꢀ was isolated as a light
1
yellow oil (1.47 g, 100%). The IR, H, and 13C NMR data are in good agreement
with the previously reported values.[10]
L-Valine methyl ester 3c. The free amine 3c was isolated as a light yellow oil
1
(1.84 g, 100%). The IR, H, and 13C NMR data are in good agreement with the
previously reported values.[10]
DL-Valine methyl ester 3cꢀ. The free amine 3cꢀ was obtained as a light yel-
1
low oil (1.84 g, 100%). The IR, H, and 13C NMR data are in good agreement with
the previously reported values.[10]
L-Leucine methyl ester 3d. The free amine 3d was obtained as a clear yellow
liquid (2.02 g, 100%). The IR, 1H, and 13C NMR data are in good agreement with the
previously reported values.[10]
DL-Leucine methyl ester 3dꢀ. The free amine 3dꢀ was isolated as a clear
yellow liquid (2.03 g, 100%). The IR, 1H, and 13C NMR data are in good agreement
with the previously reported values.[10]
L-Isoleucine methyl ester 3e. The free amine 3e was isolated as a clear
1
yellow oil (2.03 g, 100%). The IR, H, and 13C NMR data are in good agreement
with the previously reported values.[11]

N-PHENYLATION OF a-AMINO ACIDS
1167
L-Phenylalanine methyl ester 3f. The free amine 3f was isolated as a clear
1
yellow oil (2.51 g, 100%). The IR, H, and 13C NMR data are in good agreement
with the previously reported values.[12]
L-Methionine methyl ester 3g. The free amine 3g was isolated as a clear
yellow oil (2.20 g, 96%). The IR, 1H, and 13C NMR data are in good agreement with
the previously reported values.[9]
L-Proline methyl ester 3h. The free amine 3h was isolated as a clear oil
1
(1.80 g, 100%). The IR, H, and 13C NMR data are in good agreement with the
previously reported values.[11]
L-Serine methyl ester 3i. The free amine 3i was isolated as a clear yellow oil
1
(0.70 g, 41%). The IR, H, and 13C NMR data are in good agreement with the
previously reported values.[9]
L-Threonine methyl ester 3j. Prepared from 2j (4.13 g, 24 mmol) and Et3N
(3.4 mL, 24 mmol) in tetrahydrofuran (30 mL). The mixture was stirred for 1 h at
25 ꢁC, the triethylamine hydrochloride was removed by filtration, and the filtrate
was concentrated in vacuo. The free amine 3j was isolated as a clear oil (2.66 g,
1
82%). The IR, H, and 13C NMR data are in good agreement with the previously
reported values.[8]
L-Tyrosine methyl ester 3k. The light yellow solid was obtained, which was
recrystallized from ethyl acetate to afford 3k as clear yellow crystals (2.18 g, 80%).
The IR, 1H, and 13C NMR data are in good agreement with the previously reported
values.[13]
L-Aspartic acid dimethyl ester 3l. The free amine 3l was isolated as a clear
1
yellow oil (2.26 g, 100%). The IR, H, and 13C NMR data are in good agreement
with the previously reported values.[9]
L-Glutamic acid diethyl ester 3m. Prepared via general procedure B using
absolute ethanol instead methanol. The free amine 3m was isolated as a clear yellow
oil (2.82 g, 100%). 1H NMR (CDCl3) d: 4.18 (q, 2H, J ¼ 7.0 Hz, OCH2), 4.14 (q, 2H,
J ¼ 7.0 Hz, OCH2), 3.42 (dd, X part of ABM2X system, 1H, JAX ¼ 5.0 Hz,
JBX ¼ 8.0 Hz, C1H), 2.40 (t, M2 part of ABM2X system, 2H, J ¼ 7.0 Hz, C4H2),
2.06 and 1.85 (m, 1H and m, 1H, unresolved AB part of ABM2X system, C3H2),
1.61 (bs exchanges with D2O, 2H, NH2), 1.28 (t, 3H, J ¼ 7.0 Hz, CH2CH3), 1.26
(t, 3H, J ¼ 7.0 Hz, CH2CH3). 13C NMR (CDCl3) d: 175.8 (C2), 173.4 (C5), 61.2
(OCH2), 60.6 (OCH2), 54.0 (C1), 30.9 (C4), 30.0 (C3), 14.0 (CH2CH3 ꢂ 2).
N-Phenylation: General Procedure C
The amino acid ester free amine 3 (10 mmol) was combined with diphenyliodo-
nium bromide (5 mmol), AgNO3(5.1 mmol), CuBr (0.1 mmol), and anhydrous acet-
onitrile (25 mL) in a 100-mL, round-bottom flask equipped with stirrer bar and fitted
with a condenser. The system was flushed with N2, sealed with a latex balloon,
heated at 90 ꢁC for 3 h, and protected from light. The reaction was cooled to room
temperature, Na2CO3(0.5 g) was added, the mixture was gravity filtered, and the

1168
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
filtrate was concentrated to an oil. Purification of the product was achieved by flash
chromatography on a silica-gel column using hexane=ethyl acetate.
N-Phenyl glycine methyl ester 4a. Prepared from 3a (1.25 g, 14 mmol) via
general procedure C. The product 4a was isolated as a viscous yellow oil (0.32 g,
1
28%). H NMR (CDCl3) d: 7.18 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.74 (t, 1H, J ¼ 8.0 Hz,
ArH40), 6.61 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.32 (bs, exchanges with D2O, 1H, NH),
3.97 (s, 2H, C1H2), 3.73 (s, 3H, OCH3). 13C NMR (CDCl3) d: 173.1 (C2), 147.3
(C10), 129.5 (C30), 118.6 (C40), 113.5 (C20), 52.1 (OCH3), 46.0 (C1). Data are consis-
tant with literature values.[1k] MS m=z: 165 (24), 106 (100), 91 (49), 77 (32).
N-Phenyl-L-alanine methyl ester 4b. Prepared from 3b (1.44 g, 14 mmol) via
general procedure C to yield a viscous yellow oil, which was distilled under vacuum
22
to afford 4b as a light yellow oil (1.01 g, 80%). Bp 72 ꢁC at 0.02 mmHg. ½aꢃD ꢄ57.8 (c
1
1.7, CHCl ). H NMR (CDCl3) d: 7.18 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.74 (t, 1H,
3
J ¼ 8.0 Hz, ArH40), 6.61 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.15 (q, 1H, J ¼ 7.0 Hz, C1H),
4.14 (bs, exchanges with D2O, 1H, NH), 3.73 (s, 3H, OCH3), 1.47 (d, 3H, J ¼ 7.0 Hz,
C3H3). 13C NMR (CDCl3,) d: 175.0 (C2), 146.5 (C10), 129.2 (C30), 118.2 (C40), 113.3
(C20), 52.1 (OCH3), 51.8 (C1), 18.8 (C3). MS m=z: 179 (68), 120 (100), 104 (26), 91
(17), 77 (44). Data are consistant with literature values.[1k] Found: C, 66.97; H 7.40;
N, 7.88. C10H13NO2 requires C, 67.02; H, 7.31; N, 7.82.
N-Phenyl-DL-alanine methyl ester 4bꢀ. Prepared from 3bꢀ (2.75 g, 27 mmol)
via general procedure C. The product 4bꢀ was isolated as a viscous yellow oil (1.81 g,
1
76%). H NMR (CDCl3) d: 7.17 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.74 (t, 1H, J ¼ 8.0 Hz,
ArH40), 6.60 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.14 (bs exchanges with D2O, 1H, NH), 4.12
(q, 1H, J ¼ 7.0 Hz, C1H), 3.73 (s, 3H, OCH3), 1.47 (d, 3H, J ¼ 7.0 Hz, C3H3). 13C
NMR (CDCl3) d: 175.0 (C2), 146.5 (C10), 129.2 (C30), 118.2 (C40), 113.3 (C20),
52.1 (OCH3), 51.8 (C1), 18.8 (C3). MS m=z: 179 (68), 120 (100), 104 (26), 91 (17),
77 (44). Data are consistant with literature values.[11]
N-Phenyl-L-valine methyl ester 4c. Prepared from 3c (2.49 g, 19 mmol) via
general procedure C. The product 4c was isolated as a bright yellow oil (1.54 g,
22
80%), which solidified to a light yellow solid on cooling at 0 ꢁC. Mp 26–27 ꢁC. ½aꢃD
1
ꢄ75.8 (c 1.9, CHCl3). H NMR (CDCl3) d: 7.16 (dd, 2H, J ¼ 7.0 Hz, J ¼ 8.0 Hz,
ArH30), 6.72 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.62 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.11 (bs
exchanges with D2O, 1H, NH), 3.86 (d, 1H, J ¼ 6.0 Hz, C1H), 3.69 (s, 3H, OCH3),
2.11 (m, 1H, C3H), 1.04 (d, 3H, J ¼ 7.0 Hz, C4=5H3), 1.00 (d, 3H, J ¼ 7.0 Hz, C4=
13
5H3). C NMR (CDCl3) d: 174.1 (C2), 147.3 (C10), 129.3 (C30), 118.2 (C40), 113.5
(C20), 62.4 (C1), 51.7 (OCH3), 31.6 (C3), 19.0, 18.6 (C4, 5). MS m=z: 207 (19), 164
(34), 148 (100), 104 (45), 77 (28). Data are consistant with literature values.[14] Found:
C, 69.61; H, 8.31; N, 6.71. C12H17NO2 requires: C, 69.54; H, 8.27; N, 6.76.
N-Phenyl-DL-valine methyl ester 4cꢀ. Prepared from 3cꢀ (1.83 g, 14 mmol)
via general procedure C. The product was isolated as a yellow solid which was
recrystallised from hexane=ethyl acetate to afford 4cꢀ as light yellow crystals
22
1
(1.17 g, 81%). Mp 52–53 ꢁC. ½aꢃD 0.0 (c 1.0, CHCl3). H NMR (CDCl3) d: 7.17 (dd,
2H, J ¼ 7.0 Hz, J ¼ 8.0 Hz, ArH30), 6.73 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.63 (d, 2H,
J ¼ 8.0 Hz, ArH20), 4.09 (bs exchanges with D2O, 1H, NH), 3.87 (d, 1H, J ¼ 6.0 Hz,

N-PHENYLATION OF a-AMINO ACIDS
1169
C1H), 3.71 (s, 3H, OCH3), 2.11 (m, 1H, C3H), 1.05 (d, 3H, J ¼ 7.0 Hz, C4=5H3), 1.01
13
(d, 3H, J ¼ 7.0 Hz, C4=5H3). C NMR (CDCl3) d: 174.5 (C2), 147.6 (C10), 129.6
(C30), 118.5 (C40), 113.8 (C20), 62.7 (C1H), 52.1 (OCH3), 31.9 (C3), 19.4, 19.0
(C4,5). Data are consistant with literature values.[15] MS m=z: 207 (74), 164 (74),
148 (100), 104 (74), 77 (50).
N-Phenyl-L-leucine methyl ester 4d. Prepared from 3d (2.03 g, 14 mmol) via
general procedure C. The product was initially isolated as a viscous oil, which slowly
formed opaque crystals on standing at 0 ꢁC. The solid was dissolved in hexane and
22
slowly evaporated to yield 4d as needle crystals (1.26 g, 81%). Mp 50–51 ꢁC. ½aꢃD
ꢄ
62.0 (c 1.0, CHCl3). 1H NMR (CDCl3) d: 7.17 (dd, 2H, J ¼ 7.0 Hz, J ¼ 8.0 Hz,
ArH30), 6.73 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.61 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.09 (t,
1H, J ¼ 7.0 Hz, C1H), 3.97 (bs exchanges with D2O, 1H, NH), 3.70 (s, 3H,
OCH3), 1.77 (m, 1H, C4H), 1.65 (m, 2H, C3H2), 0.99 (d, 3H, J ¼ 6.0 Hz, C5=
6H3), 0.94 (d, 3H, J ¼ 6.0 Hz, C5=6H3). 13C NMR (CDCl3) d: 175.5 (C2), 147.3
(C10), 129.6 (C30), 118.6 (C40), 113.7 (C20), 55.4 (C1), 52.3 (OCH3), 42.7 (C4), 25.2
(C3), 23.0, 22.5 (C5, 6). MS m=z: 221 (78), 162 (100), 120 (77), 104 (49), 91 (14),
77 (49). Found: C, 70.54; H, 8.60; N, 6.28. C13H19NO2 requires C, 70.56; H, 8.65;
N, 6.33.
N-Phenyl-DL-leucine methyl ester 4dꢀ. Prepared from 3dꢀ (2.03 g, 14 mmol)
via general procedure C. The product 4dꢀ was initially isolated as a viscous orange
1
oil (1.30 g, 84%), which solidified on prolonged cooling at 0 ꢁC. Mp 46–47 ꢁC. H
NMR (CDCl3) d: 7.17 (dd, 2H, J ¼ 7.0 Hz, J ¼ 8.0 Hz, ArH30), 6.73 (t, 1H,
J ¼ 7.0 Hz, ArH40), 6.61 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.09 (t, 1H, J ¼ 7.0 Hz, C1H),
3.95 (bs exchanges with D2O, 1H, NH), 3.69 (s, 3H, OCH3), 1.79 (m, 1H, C4H),
1.64 (m, 2H, C3H2), 0.99 (d, 3H, J ¼ 6.0 Hz, C5=6H3), 0.94 (d, 3H, J ¼ 6.0 Hz,
13
C5=6H3). C NMR (CDCl3) d: 175.5 (C2), 147.3 (C10), 129.6 (C30), 118.6 (C40),
113.7 (C20), 55.4 (C1), 53.3 (OCH3), 42.7 (C4), 25.2 (C3), 23.0, 22.5 (C5,6).
N-Phenyl-L-isoleucine methyl ester 4e. Prepared from 3e (1.45 g, 10 mmol)
via general procedure C. The product 4e was isolated as clear colorless oil (0.84 g,
22
1
76%). ½aꢃD ꢄ47.4 (c 0.61, CHCl3). H NMR (CDCl3) d: 7.17 (t, 2H, J ¼ 8.0 Hz,
ArH30), 6.72 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.62 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.13 (bs
exchanges with D2O, 1H, NH), 3.95 (d, 1H, J ¼ 6.0 Hz, C1H), 3.70 (s, 3H,
OCH3), 1.85 (m, 1H, C3H), 1.63 and 1.29 (m, 1H and m, 1H, C4H2), 0.97 (d, 3H,
J ¼ 6.0 Hz, C6H3), 0.95 (t, 3H, J ¼ 7.0 Hz, C5H3). 13C NMR (CDCl3) d: 174.4
(C2), 147.4 (C10), 129.6 (C30), 118.4 (C40), 113.7 (C20), 61.4 (C1), 52.1 (OCH3),
38.3 (C3), 25.9 (C6), 15.8 (C4), 11.8 (C5). MS m=z: 221 (19), 162 (100), 132 (12),
104 (52), 77 (30). Found: C, 70.43; H, 8.61; N, 6.43. C13H19NO2 requires C, 70.56;
H, 8.65; N, 6.33.
N-Phenyl-L-phenylalanine methyl ester 4f. Prepared from 3f (2.30 g,
13 mmol) via general method C. The product was isolated as dark orange oil, which
was distilled under vacuum to isolate 4f as light orange oil (1.30 g, 80%). Bp 130 ꢁC at
22
1
0.024 mmHg. ½aꢃD þ44.7 (c 1.4, CHCl3). H NMR (CDCl3,) d: 7.30–7.10 (m, 7H,
ArH5–9,30), 6.72 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.58 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.36
(t, X part of ABX system, 1H, J ¼ 6.0 Hz, C1H), 4.13 (bs exchanges with D2O,
1H, NH), 3.67 (s, 3H, OCH3), 3.11 (AB part of ABX system, 2H, J ¼ 13.5 Hz,

1170
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
C3H2). 13C NMR (CDCl3) d: 173.5 (C2), 146.2 (C10), 136.2 (C4), 129.2 (C6, 8), 129.1
(C30), 128.4 (C7), 126.9 (C5, 9), 118.3 (C40), 113.4 (C20), 57.6 (C1), 51.9 (OCH3), 38.5
(C3). MS m=z: 255 (12), 196 (20), 164 (100), 104 (56), 77 (30). Data are consistant
with literature values.[16] Found: C, 75.38; H, 6.75; N, 5.58. C16H17NO2 requires
C, 75.27; H, 6.71; N, 5.49.
N-Phenyl-L-methionine methyl ester 4g. Prepared from 3 g (1.96 g,
12 mmol) via general procedure C. The product 4 g was isolated as clear light brown
22
1
oil (0.98 g, 68%). Bp 122 ꢁC at 0.02 mmHg. ½aꢃD ꢄ50.8 (c 0.80, CHCl3). H NMR
(CDCl3) d: 7.18 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.75 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.65
(d, 2H, J ¼ 8.0 Hz, ArH20), 4.26 (dd, X part of ABM2X system, 1H, JAX ¼ 5.0 Hz,
JBX ¼ 7.0 Hz, C1H), 4.17 (bs exchanges with D2O, 1H, NH), 3.73 (s, 3H, OCH3),
2.63 (t, M2 part of ABM2X system, 2H, J ¼ 7.0 Hz, C4H2), 2.20–1.90 (unresolved
AB part of ABM2X system, 2H, C3H2), 2.10 (s, 3H, SCH3). 13C NMR (CDCl3) d:
174.1 (C2), 146.7 (C10), 129.3 (C30), 118.5 (C40), 113.6 (C20), 55.5 (C1), 52.2
(OCH3), 32.3 (C4), 30.2 (C3), 15.4 (SCH3). MS m=z: 239 (23), 180 (62), 132 (52),
104 (19), 77 (24), 61 (100). Found: C, 60.06; H, 7.21; N, 5.90; S, 13.35. C12H17NO2S
requires C, 60.22; H, 7.16; N, 5.85; S, 13.40.
N-Phenyl-L-proline methyl ester 4h. Prepared from 3 h (1.80 g, 14 mmol)
via general procedure C. The product 4 h was isolated as a viscous yellow oil
22
(0.83 g, 60%). ½aꢃD ꢄ110.6 (c 2.2, CHCl3). 1H NMR (CDCl3) d: 7.21 (dd, 2H,
J ¼ 7.0 Hz, 8.0 Hz, ArH30), 6.70 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.54 (dd, 2H, J ¼ 1.0 Hz,
8.0 Hz, ArH20), 4.24 (dd, 1H, J ¼ 2.0 Hz, 8.0 Hz, C1H), 3.70 (s, 3H, OCH3), 3.56 and
3.34 (m, 1H and m, 1H, C5H2), 2.15 (m, 4H, C3H2 and C4H2). 13C NMR (CDCl3) d:
174.9 (C2), 146.6 (C10), 129.1 (C30), 116.6 (C40), 111.9 (C20), 60.7 (C1), 52.0 (OCH3),
48.2 (C5), 30.8 (C3), 23.8 (C4). Data are consistant with literature values.[12] MS
m=z: 205 (12), 146 (100), 104 (18), 77 (23). Found: C, 70.20; H, 7.40; N, 6.78.
C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82.
N-Phenyl-L-serine methyl ester 4i. Prepared from 3i (0.70 g, 6 mmol) via
general procedure C. The product 4i was isolated as clear yellow oil (0.30 g, 51%).
22
1
½aꢃD ꢄ22.5 (c 1.3, CH2Cl2). H NMR (CDCl3) d: 7.20 (dd, 2H, J ¼ 7.0 Hz, 8.0 Hz,
ArH30), 6.79 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.69 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.21 (t,
1H, J ¼ 4.0 Hz, C1H), 3.96 (AB part of ABX system, 2H, J ¼ 11.0 Hz, C3H2), 3.79
(s, 3H, OCH3), 2.25 (bs exchanges with D2O, 2H, OH and NH). 13C NMR (CDCl3)
d: 172.9 (C2), 146.8 (C10), 129.7 (C30, 50), 119.3 (C40), 114.2 (C20, 60), 63.2 (C3), 58.8
(C1), 52.9 (OCH3).
N-Phenyl-L-threonine methyl ester 4j. Prepared from 3j (2.66 g, 20 mmol)
via general procedure C. The product 4j was isolated as a thin, clear yellow oil
22
(0.98 g, 47%). ½aꢃD ꢄ56.3 (c 4.1, CHCl3). 1H NMR (CDCl3) d: 7.19 (dd, 2H,
J ¼ 7.0 Hz, 8.0 Hz, ArH30), 6.78 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.69 (d, 2H, J ¼ 8.0 Hz,
ArH20), 4.44 (bs exchanges with D2O, 1H, OH), 4.13 (m, 1H, C3H), 3.96 (bs
exchanges with D2O, 1H, NH), 3.78 (m, 1H, C1H), 3.74 (s, 3H, OCH3), 1.32 (d,
13
3H, J ¼ 6.0 Hz, C4H3). C NMR (CDCl3) d: 173.6 (C2), 147.4 (C10), 129.6 (C30),
119.3 (C40), 114.4 (C20), 68.7 (C3), 62.9 (C1), 52.6 (OCH3), 20.0 (C4). MS m=z:
165 (36), 106 (100), 77 (56). HRMS: Found: M þH, 210.112005. C11H16NO3
requires M þ H, 210.11247.

N-PHENYLATION OF a-AMINO ACIDS
1171
N-Phenyl-L-tyrosine methyl ester 4k. Prepared from 3k (2.73 g, 14 mmol)
via general procedure C. The product was isolated as a brown solid. This was recrys-
tallized from ether=hexane to yield 4k as long, straw-colored, needle crystals (1.60 g,
22
85%). Mp 125–126 ꢁC. ½aꢃD þ46.0 (c 1.0, CHCl 3). 1H NMR (CDCl3) d: 7.17 (t, 2H,
J ¼ 8.0 Hz, ArH30), 7.02 (d, 2H, J ¼ 8.0 Hz, ArH5,9), 6.74 (t, 1H, J ¼ 8.0 Hz, ArH40),
6.73 (d, 2H, J ¼ 8.0 Hz, ArH6,8), 6.59 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.84 (bs exchanges
with D2O, 1H, OH), 4.32 (t, X part of ABX system, 1H, J ¼ 6.0 Hz, C1H), 4.13 (bs
exchanges with D2O, 1H, NH), 3.67 (s, 3H, OCH3), 3.06 (AB part of ABX system,
13
2H, J ¼ 14.0 Hz, C3H2). C NMR (CDCl3) d: 174.1 (C2), 154.9 (C7), 146.6 (C10),
130.8 (C5, 9), 129.7 (C30), 128.6 (C4), 118.8 (C40), 115.7 (C6, 8), 113.9 (C20), 58.1
(C1), 52.4 (OCH3), 38.1 (C3). MS m=z: 271 (53), 212 (37), 164 (100), 132 (23), 104
(80), 77 (52). Found: C, 70.98; H, 6.22; N, 5.09. C16H17NO3 requires C, 70.83; H,
6.32; N, 5.16.
N-Phenyl-L-aspartic acid dimethyl ester 4l. Prepared from 3 l (1.13 g,
7 mmol) via general procedure C. The product 4 l was isolated as a viscous, bright
22
1
yellow oil (0.60 g, 72%). ½aꢃD þ7.0 (c 2.6, CH2Cl2). H NMR (CDCl3) d: 7.19 (dd,
2H, J ¼ 7.0 Hz, J ¼ 8.0 Hz, ArH30), 6.77 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.66 (dd, 2H,
J ¼ 1.0 Hz, J ¼ 8.0 Hz, ArH20), 4.46 (t, 1H, J ¼ 6.0 Hz, C1H), 4.45 (bs exchanges with
D2O, 1H, NH), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 2.88 (d, 2H, J ¼ 6.0 Hz,
13
C3H2). C NMR (CDCl3) d: 173.0 (C2), 171.2 (C4), 146.4 (C10), 129.6 (C30),
119.0 (C40), 114.0 (C20), 53.6 (C1), 52.8 (OCH3), 52.2 (OCH3), 37.4 (C3). MS m=z:
237 (19), 178 (90), 146 (24), 104 (100), 77 (29), 59 (20). Found: C, 60.81; H, 6.42;
N, 5.87. C12H15NO4 requires C, 60.75; H, 6.37; N, 5.90.
N-Phenyl-L-glutamic acid diethyl ester 4m. Prepared from 3 m (1.42 g,
7 mmol) via general procedure C. The product 4 m was isolated as a brown oil
22
(0.65 g, 67%). ½aꢃD ꢄ21.6 (c 2.8, CHCl). 1H NMR (CDCl3) d: 7.16 (dd, 2H,
J ¼ 7.0 Hz, J ¼ 8.0 Hz, ArH30), 6.74 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.62 (d, 2H,
J ¼ 8.0 Hz, ArH20), 4.71 (dd, X part of ABM2X system, 1H, J ¼ 3.0 Hz, J ¼ 8.0 Hz,
C1H), 4.19 (q, 2H, J ¼ 7.0 Hz, OCH2), 4.13 (q, 2H, J ¼ 7.0 Hz, OCH2), 2.50 (bs
exchanges with D2O, 1H, NH), 2.47 (t, M2 part of ABM2X system, 2H, J ¼ 7.0 Hz,
C4H2), 2.30–2.13 (unresolved AB part of ABM2X system, 2H, C3H2), 1.25 (t, 3H,
J ¼ 7.0 Hz, CH2CH3), 1.24 (t, 3H, J ¼ 7.0 Hz, CH2CH3). 13C NMR (CDCl3,) d:
173.8 (C2), 173.2 (C5), 147.0 (C10), 129.6 (C30), 118.7 (C40), 113.8 (C20), 61.6
(OCH2), 60.9 (OCH2), 56.3 (C1), 30.7 (C4), 28.2 (C3), 14.5 (CH2CH3 ꢂ 2). MS
m=z: 279 (10), 234 (8), 206 (76), 160 (100), 132 (48), 104 (34), 77 (37).
Hydrolysis of N-Phenyl Amino Acid Esters 4 and Preparation of
N-Phenyl Amino Acids 5: General Procedure D
The N-phenyl amino acid ester 4 (1 mmol) was dissolved in anhydrous meth-
anol (5 mL=mmol of ester), and 1 M NaOH (1.1 mmol) was added dropwise to this
solution. The hydrolysis was monitored by thin-layer chromatography (TLC). When
the hydrolysis was deemed complete, the solution was concentrated to 5 mL; the
resulting mixture was then extracted between 10% Na2CO3 and dichloromethane.
The aqueous layer was acidified with 1 M HCl; the precipitate was collected and

1172
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
washed with a 50=50 mixture of hexane=dichloromethane. The collected solid was
then recrystallized from a suitable solvent.
N-Phenyl-L-alanine 5b. Prepared from 4b (0.63 g, 3.5 mmol) via general
procedure D. Hydrolysis was complete in 12 h. The product was initially collected
as a bright orange solid and recrystallized from toluene to yield 5b as small off-white
22
25
crystals (0.47 g, 81%). Mp 138–139 ꢁC. ½aꢃD ꢄ52.0 (c 1.0, CH3COCH3 [lit.[1b] ½aꢃD
ꢄ
44.8 (c 0.84, CH3COCH3]. 1H NMR (CDCl3) d: 7.20 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.79
(t, 1H, J ¼ 8.0 Hz, ArH40), 6.63 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.20 (bs exchanges with
D2O, 2H, OH and NH), 4.13 (q, 1H, J ¼ 7.0 Hz, CHCH3), 1.54 (d, 3H, J ¼ 7.0 Hz,
13
CHCH3) C5H3. C NMR (CD3COCD3) d: 176.5 (C2), 149.3 (C10), 130.5 (C30),
118.7 (C40), 114.5 (C20), 53.0 (C1), 19.6 (C3). Data are consistant with literature
values.[1b] Found: C, 65.38; H, 6.67; N, 8.51. C9H11NO2 requires C, 65.44; H,
6.71; N, 8.48.
N-Phenyl-DL-alanine 5bꢀ. Prepared from 4bꢀ (1.50 g, 8.4 mmol) via general
procedure D. Hydrolysis was complete in 12 h. The product was initially collected
as a light brown powder and recrystallized from toluene to yield 5bꢀ as small white
22
crystals (1.10 g, 80%). Mp 157–159 ꢁC. ½aꢃD 0.0 (c 1.0, CH3COCH3) 1H NMR
(CD3COCD3) d: 7.12 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.65 (t, 1H, J ¼ 8.0 Hz, ArH40),
6.60 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.03 (q, 1H, J ¼ 7.0 Hz, C1H), 3.70 (bs exchanges
with D2O, 2H, NH and OH), 1.48 (d, 3H, J ¼ 7.0 Hz, C3H3). 13C NMR
(CD3COCD3) d: 176.5 (C2), 149.3 (C10), 130.5 (C30), 118.7 (C40), 114.5 (C20), 53.0
(C1), 19.6 (C3) data is consistant with literature values.[12]
N-Phenyl-L-valine 5c. Prepared from 4c (1.34 g, 6.5 mmol) via general
procedure D. Hydrolysis was complete in 15 h. The product was initially collected
as an orange solid and recrystallized from hexane to yield 5c as short white needles
22
25
(1.06 g, 85%). Mp 108–109 ꢁC. ½aꢃD ꢄ47.0 (c 1.0, CHCl3) [lit.[1b]½aꢃD ꢄ49.5 (c 0.84,
CHCl3). 1H NMR (CDCl3) d: 7.19 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.78 (t, 1H, J ¼ 8.0 Hz,
ArH40), 6.65 (d, 2H, J ¼ 8.0 Hz, ArH20), 3.86 (d, 1H, J ¼ 5.0 Hz, C1H), 2.90 (bs
exchanges with D2O, 2H, OH and NH), 2.22 (m, 1H, C3H), 1.06 (d, 6H, J ¼ 7.0 Hz,
13
C4H3 and C5H3. C NMR (CDCl3) d: 177.4 (C2), 147.0 (C10), 129.4 (C30), 118.8
(C40), 113.7 (C20), 62.6 (C1), 31.3 (C3), 19.1, 18.3 (C4,5). Data are consistant with
literature values.[1b] Found: C, 68.32; H, 7.78; N, 7.30. C11H15NO2 requires C,
68.37; H, 7.82; N, 7.25.
N-Phenyl-DL-valine 5cꢀ. Prepared from 4cꢀ (1.12 g, 5.4 mmol) via general
procedure D. Hydrolysis was complete in 16 h. The product was initially collected
as a brown solid and recrystallized from hexane to yield 5cꢀ as flat white crystals
22
1
(0.94 g, 90%). Mp 125–127 ꢁC. ½aꢃD 0.0 (c 1.0, CHCl3). H NMR (CDCl3,) d: 7.36
(bs exchanges with D2O, 2H, OH and NH), 7.18 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.76
(t, 1H, J ¼ 8.0 Hz, ArH40), 6.64 (d, 2H, J ¼ 8.0 Hz, ArH20), 3.87 (d, 1H, J ¼ 5.0 Hz,
C1H), 2.18 (m, 1H, C3H), 1.06 (d, 6H, J ¼ 7.0 Hz, C4H3 and C5H3). 13C NMR
(CDCl3,) d: 179.1 (C2), 147.3 (C10), 129.7 (C30), 119.1 (C40), 114.0 (C20), 62.8
(C1), 31.7 (C3), 19.4, 18.6 (C4, 5). Data are consistant with literature values.[1b]
N-Phenyl-L-leucine 5d. Prepared from 4d (0.73 g, 3.3 mmol) via general
procedure D. Hydrolysis was complete in 20h. The product was initially collected as

N-PHENYLATION OF a-AMINO ACIDS
1173
a white solid and recrystallized from toluene to yield 5d as flat white crystals (0.59g,
22
20
86%). Mp 156–157 ꢁC. ½aꢃD ꢄ63.9 (c 0.54, CHCl3), lit. [1g]½aꢃD ꢄ45.0 (c 1.08, acetone).
1H NMR (CD3COCD3) d: 7.10 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.67 (d, 2H, J ¼ 8.0 Hz,
ArH20), 6.61 (t, 1H, J ¼ 8.0Hz, ArH40), 4.04 (t, 1H, J ¼ 7.0 Hz, C1H), 2.87 (bs
exchanges with D2O, 2H, OH and NH), 1.95–1.80 (m, 1H, (C4H), 1.69 (t, 2H,
J ¼ 7.0 Hz, C3H2), 0.98 (d, 3H, J ¼ 7.0 Hz, C5=6H3), 0.94 (d, 3H, J ¼ 7.0 Hz, C5=
13
6H3). C NMR (CDCl3,) d: 179.3 (C2), 146.5 (C10), 129.4 (C30), 118.9 (C40), 113.6
(C20), 55.4 (C1), 42.1 (C4), 24.9 (C3), 22.7, 21.9 (C5,6). Data are consistant with litera-
ture values.[12] Found: C, 69.58; H, 8.24; N, 6.80. C12H17NO2 requires C, 69.54; H,
8.27; N, 6.76.
N-Phenyl-DL-leucine 5dꢀ. Prepared from 4dꢀ (0.92 g, 4.1 mmol) via general
procedure D, Hydrolysis was complete in 20 h. The product was initially collected
as a white solid and recrystallized from toluene to yield 5dꢀ as fine white crystals
1
(0.70 g, 81%). Mp 163–165 ꢁC. H NMR (CD3COCD3) d: 7.10 (t, 2H, J ¼ 8.0 Hz,
ArH30), 6.67 (d, 2H, J ¼ 8.0 Hz, ArH20), 6.61 (t, 1H, J ¼ 8.0 Hz, ArH40), 4.04 (t,
1H, J ¼ 7.0 Hz, C1H), 2.23 (bs exchanges with D2O, 2H, OH and NH), 1.95–1.80
(m, 1H, C4H), 1.69 (t, 2H, J ¼ 7.0 Hz, C3H2), 0.98 (d, 3H, J ¼ 7.0 Hz, C5=6H3),
0.94 (d, 3H, J ¼ 7.0 Hz, C5=6H3). 13C NMR (CD3COCD3) d: 176.6 (C2), 149.7
(C10), 130.5 (C30), 118.7 (C40), 114.5 (C20), 56.2 (C1), 43.4 (C4), 26.3 (C3), 23.9,
23.0 (C5,6). Data are consistant with literature values.[12]
N-Phenyl-L-isoleucine 5e. Prepared from 4e (1.11 g, 5.0 mmol) via general
procedure D. Hydrolysis was complete in 21 h. The product was initially collected
as a light brown solid and recrystallized from hexane to yield 5e as fine white needles
22
(0.80 g, 77%). Mp 115–116 ꢁC. ½aꢃD ꢄ43.2 (c 1.0, CDCl3). 1H NMR (CDCl3,) d: 7.82
(bs exchanges with D2O, 2H, OH and NH), 7.17 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.75 (t,
1H, J ¼ 7.0 Hz, ArH40), 6.63 (d, 2H, J ¼ 8.0 Hz, ArH20), 3.94 (d, 1H, J ¼ 5.0 Hz,
C1H), 1.90 (m, 1H, C3H), 1.63 and 1.31 (m, 1H and m, 1H, C4H2), 1.01 (d, 3H,
J ¼ 7.0 Hz, C6H3), 0.95 (t, 3H, J ¼ 7.0 Hz, C5H3). 13C NMR (CDCl3) d: 179.2
(C2), 146.8 (C10), 129.4 (C30), 118.6 (C40), 113.6 (C20), 61.2 (C1), 37.8 (C3), 25.4
(C6), 15.5 (C4), 11.4 (C5). Found: C, 69.60; H, 8.24; N, 6.80. C12H17NO2 requires
C, 69.54; H, 8.27; N, 6.76.
N-Phenyl-L-phenylalanine 5f. Prepared from 4f (1.14 g, 4.5 mmol) via
general procedure D. Hydrolysis was complete in 16 h. The product was initially
collected as a white solid and recrystallized from toluene to yield 5f as small white
22
20
crystals (0.89 g, 89%). Mp 176–177 ꢁC. ½aꢃD þ3.0 (c 1.0, CH3COCH3) [lit.[1g] ½aꢃD
1
þ2.1 (c 1.0, CH3COCH3)]. H NMR (CD3SOCD3) d: 7.42–7.13 (m, 5H,ArH5–9),
7.04 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.56 (d, 2H, J ¼ 8.0 Hz, ArH20), 6.54 (t, 1H,
J ¼ 8.0 Hz, ArH40), 4.10 (t, X part of ABX system, 1H, J ¼ 6.0 Hz, C1H),
3.27–3.00 (AB part of ABX system, 2H, J ¼ 14.0 Hz, C3H2), 2.90 (bs exchanges with
13
D2O, 2H, OH and NH). C NMR (CD3SOCD3) d: 174.9 (C2), 147.8 (C10), 138.3
(C4), 129.1 (C30), 128.7 (C6,8), 127.9 (C5,9), 126.0 (C7), 115.9 (C40), 112.4 (C20),
57.8 (C1), 37.7 (C3). Data are consistant with literature values.[1b] HRMS: found
M þ H, 242.116893. C15H16NO2 requires M þ H, 242.117555.
N-Phenyl-L-methionine 5g. Prepared from 4 g (0.77 g, 3.2 mmol) via general
procedure D. Hydrolysis was complete in 20 h. The product was initially collected as

1174
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
a brown solid, which was recrystallized from hexane to yield 5 g as small white crys-
22
tals (0.43 g, 60%). Mp: 141–143 ꢁC. ½aꢃD ꢄ46.3 (c 1.0, CH3COCH3). 1H NMR
(CDCl3) d: 7.17 (t, 2H, J ¼ 8.0 Hz, ArH30), 6.74 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.68
(d, 2H, J ¼ 8.0 Hz, ArH20), 6.15 (bs exchanges with D2O, 2H, OH and NH), 4.26
(dd, X part of ABM2X system, 1H, JAX ¼ 5.0 Hz, JBX ¼ 7.0 Hz, C1H), 2.68 (t,
M2 part of ABM2X system, 2H, J ¼ 7.0 Hz, C4H2), 2.30–2.00 (unresolved AB part
of ABM2X system, 2H, C3H2), 2.11 (s, 3H, SCH3). 13C NMR (CDCl3) d: 179.3 (C2),
146.7 (C10), 129.8 (C30), 119.4 (C40), 114.1 (C20), 56.0 (C1), 32.4 (C4), 30.6 (C3), 15.7
(SCH3). Data are consistant with literature values.[1b] HRMS: found M þ H,
226.088805. C11H16NO2S requires M þ H, 226.089628.
N-Phenyl-L-proline 5h. Prepared from 4 h (1.02 g, 5.0 mmol) via general
procedure D. Hydrolysis was complete after 20 h. The product was initially obtained
as yellow oil, which was diluted with hexane and cooled at ꢄ20 ꢁC. After 2 days,
clusters of large clear plate crystals of 5 h were collected (0.81 g, 85%). Mp:
22
22
1
90–91 ꢁC. ½aꢃD ꢄ47.1 (c 1.0, CHCl3) [lit.[1b] ½aꢃD ꢄ46.8 (c 1.1, CHCl3)]. H NMR
(CDCl3) d: 10.68 (bs exchanges with D2O, 1H, OH), 7.24 (dd, 2H, J ¼ 8.0, 7.0 Hz,
ArH30), 6.76 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.58 (d, 2H, J ¼ 8.0 Hz, ArH20), 4.21 (dd,
1H, J ¼ 8.0, 3.0 Hz, C1H), 3.59 and 3.33 (m, 1H and m, 1H, C5H2), 2.26 (m, 2H,
13
C3H2), 2.07 (m, 2H, C4H2). C NMR (CDCl3) d: 180.3 (C2), 146.9 (C10), 129.6
(C30), 117.7 (C40), 112.67 (C20), 61.3 (C1), 48.9 (C5), 31.3 (C3), 24.2 (C4) (compared
well with the reported spectra[17] of N-phenyl-L-proline). Found: C, 68.41; H, 6.50;
N, 7.19. C11H13NO2 requires C, 69.09; H, 6.85; N, 7.32.
N-Phenyl-L-tyrosine 5k. Prepared from 4k (1.00 g, 3.7 mmol) via general
procedure D. Hydrolysis was complete after 25 h. The product was initially obtained
as a green solid, which was dissolved in acetone and decolorized with activated
charcoal. The off-white powder was then dissolved in hot ether and allowed to
22
slowly evaporate to yield 5k as a white powder, mp 167–168 ꢁC. ½aꢃD þ21.7 (c, 1.0
25
1
CH3OH) [lit.[1b] ½aꢃD þ23.9 (c, 1.0 CH3OH)]. H NMR (CD3COCD3) d: 7.13 (d,
2H, J ¼ 8.5 Hz, ArH5,9), 7.09 (dd, 2H, J ¼ 8.0 Hz, 7.0 Hz, ArH30), 6.75 (d, 2H,
J ¼ 8.5 Hz, ArH6,8), 6.67 (d, 2H, J ¼ 8.0 Hz, ArH20), 6.61 (t, 1H, J ¼ 7.0 Hz, ArH40),
4.27 (dd, X part of ABX system, 1H, JAX ¼ 6.0 Hz, JBX ¼ 7.0 Hz, C1H), 3.05 (AB
part of ABX system, 2H, J ¼ 14.0 Hz, C3H2), 2.12 (bs exchanges with D2O, 2H, OH
13
and NH). C NMR (CD3COCD3) d: 175.3 (C2), 157.7 (C7), 149.2 (C10), 131.9
(C5,9), 130.5 (C30), 129.7 (C4), 118.8 (C40), 116.6 (C6,8), 114.7 (C20), 59.3 (C1),
39.0 (C3). Data are consistant with literature values.[1b] HRMS: found M þ H,
258.11171. C15H16NO3 requires M þ H, 258.112472.
N-Phenyl-L-aspartic acid 5l. Prepared from 4 l (0.67 g, 2.8 mmol) and 1 M
NaOH (6 mL, 6 mmol) via general procedure D. Hydrolysis was complete after
20 h. The product was initially collected as an orange solid and recrystallized from
22
ether=hexane to yield 5 l as clear flat crystals (0.50 g, 85%). Mp 146–147 ꢁC. ½aꢃD
ꢄ17.5 (c 1.0, CH3COCH3). 1H NMR (CD3COCD3) d: 7.13 (t, 2H, J ¼ 8.0 Hz,
ArH30), 6.74 (d, 2H, J ¼ 8.0 Hz, ArH20), 6.65 (t, 1H, J ¼ 8.0 Hz, ArH40), 4.49 (dd,
X part of ABX system, 1H, JAX ¼ 6.0 Hz, JBX ¼ 7.0 Hz, C1H), 2.88 (AB part of
ABX system, 2H, J ¼ 16.0 Hz, C3H2).13C NMR (CD3COCD3) d: 174.6 (C2), 172.8

N-PHENYLATION OF a-AMINO ACIDS
1175
(C4), 149.0 (C10), 130.6 (C30), 119.2 (C40), 115.0 (C20), 54.5 (C1), 38.2 (C3). HRMS:
found: M þ H, 210.075763. C10H12NO4 requires M þ H, 210.076085.
Synthesis of Chiral Dipeptides 6: General Procedure E
N-Phenyl amino acid 5 (1 mmol), L-alanine, or L-phenylalanine amino acid methyl
ester hydrochloride 2b or 2f (1 mmol), triethylamine (1 mmol), N-hydroxysuccinimide
(1 mmol), and CH2Cl2 (20 mL) were mixed in a 50-mL, round-bottom flask and stirred
at 0 ꢁC for 1 h. EDC (1 mmol) was added to the stirred mixture, which was allowed to
slowly warm to room temperature, and stirring continued for 30 h. The clear solution
was concentrated to dryness in vacuo, dissolved in ethyl acetate, and washed with
10% Na2CO3 and water before drying over MgSO4 and evaporated to dryness. The
residue was dissolved in minimal CH2Cl2, diluted with hexane, and slowly evaporated.
The product was obtained as a white precipitate, which was recrystallized from a suitable
solvent.
N-Phenyl-L-alanine-L-phenylalanine methyl ester 6b. Prepared from 5b
(0.10 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The product
was collected as a white solid and recrystallized from CH2Cl2=hexane to yield 6b
as small white crystals (0.14 g, 71%). Mp 131–133 ꢁC. 1H NMR (CDCl3,) d:
7.32–7.02 (m, 7H, ArH14–18, 30,50), 6.79 (t, 1H, J ¼ 7.5 Hz, ArH40), 6.57 (d, 2H,
J ¼ 8.0 Hz, ArH20,60), 4.84 (m, X part of ABX system,1H, C3H), 3.76 (bs exchanges
with D2O, 2H, NH), 3.75 (m, 1H, C1H), 3.63 (s, 3H, OCH3), 3.27–2.94 (AB part of
ABX system, 2H, J ¼ 14.0 Hz, C12H2), 1.37 (d, 3H, J ¼ 7.0 Hz, C3H3). 13C NMR
(CDCl3) d: 174.1 (C11), 171.8 (C2), 146.8 (C10), 136.3 (C16), 129.5 (C14,18), 129.4
(C30,50), 128.8 (C15,17), 127.3 (C16), 119.5 (C40), 114.23 (C20,60), 55.6 (C3), 53.1
(C1), 52.5 (OCH3), 38.0 (C5), 19.8 (C3).
N-Phenyl-DL-alanine-L-phenylalanine methyl ester 6bꢀ. Prepared from
5bꢀ (0.10 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The product
was collected as an off white-solid and recrystallized from CH2Cl2=hexane to yield
1
6bꢀ as a white crystalline solid (0.12 g, 62%). Mp: 116–118 ꢁC. H NMR (CDCl3)
d: 7.33–7.02 (m, 14H, ArH15–17,30,50), 6.79 (t, 2H, J ¼ 7.5 Hz, ArH40), 6.58 (d,
2H, J ¼ 7.5 Hz, ArH20, 60, DL), 6.57 (d, 2H, J ¼ 7.5 Hz, ArH20 LL), 4.84 (m, 2H,
C12H), 3.75 (bs exchanges with D2O, 4H, NH), 3.74 (m, 2H, C1H), 3.63 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.27–2.93 (m, 4H, C12H2), 1.47 (d, 3H, J ¼ 7.0 Hz,
C3H3, DL), 1.38 (d, 3H, J ¼ 7.0 Hz, C3H3, LL). 13C NMR (CDCl3) d: 174.2,
174.0 (C11), 172.0, 171.8 (C2), 146.8, 146.7 (C10), 136.3, 135.7 (C13), 129.7, 129.6
(C15,17), 129.5, 129.4 (C30,50), 128.9, 128.8 (C14, 18), 127.3, 127.2 (C16), 119.5,
119.4 (C40), 114.23, 113.8 (C20,60), 55.6, 55.2 (C3), 53.1, 53.0 (C1), 52.5, 52.4
(OCH3), 38.3, 38.0 (C12), 19.9, 19.8 (C3).
N-Phenyl-L-valine-L-phenylalanine methyl ester 6c. Prepared from 5c
(0.12 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The crude
product was collected as an off-white solid and recrystallized from CH2Cl2=hexane
to yield 6c as small white crystals (0.18 g, 84%). Mp 107–109 ꢁC. 1H NMR (CDCl3,)
d: 7.30–6.97 (m, 7H, ArH14–18, 30,50), 6.79 (t, 1H, J ¼ 8.0 Hz, ArH40), 6.61 (d, 2H,
J ¼ 8.0 Hz, ArH20,60), 4.88 (dt, X part of ABX system, 1H, JAX ¼ 6.0 Hz,

1176
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
JBX ¼ 8.0 Hz, C10H), 3.78 (bs exchanges with D2O, 1H, NH), 3.62 (s, 3H, OCH3),
3.52 (d, 1H, J ¼ 5.0 Hz, C1H), 3.22–2.92 (AB part of ABX system, 2H, J ¼ 14.0 Hz,
C12H2), 2.23 (m, 1H, C3H), 1.91 (bs exchanges with D2O, 1H, NH), 0.93 (d, 3H,
J ¼ 7.0 Hz, C4=5H3), 0.80 (d, 3H, J ¼ 7.0 Hz, C4=5H3) (in good agreement with
the reported spectra[1b] of N-phenyl-L-valine-L-phenylalanine methyl ester). 13C
NMR (CDCl3) d: 173.0 (C11), 171.9 (C2), 147.7 (C10), 136.4 (C13), 129.6
(C15,17), 129.4 (C30), 128.8 (C14,18), 127.3 (C116), 119.4 (C40), 114.4 (C2), 65.5
(C10), 53.2 (C1), 52.5 (OCH3), 38.2 (C12), 31.4 (C3), 19.8, 17.8 (C4,5).
N-Phenyl-DL-valine-L-phenylalanine methyl ester 6cꢀ. Prepared from 5cꢀ
(0.12 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The crude
product was collected as an off-white solid and recrystallized from CH2Cl2=hexane
1
to yield 6cꢀ as small white crystals (0.18 g, 84%). Mp 95–97 ꢁC. H NMR (CDCl3,)
d: 7.32–6.97 (m, 14H, ArH14–18, 30, 50), 6.78 (m, 2H, ArH40), 6.49 (m, 4H,
ArH20,60), 4.90 (m, 2H, C10H), 4.02 (bs exchanges with D2O, 4H, NH), 3.70 (s,
3H, OCH3), 3.62 (s, 3H, OCH3), 3.57 (d, 1H, J ¼ 5.0 Hz, C1H, DL), 3.52 (d, 1H,
J ¼ 5.0 Hz, C1H,LL), 3.23–2.87 (m, 4H, C12H2), 2.41–2.12 (m, 2H, C3H), 1.02 (d,
3H, J ¼ 7.0 Hz, C4=5H3, DL), 0.97 (d, 3H, J ¼ 7.0 Hz, C4=5H3, DL), 0.92 (d, 3H,
J ¼ 7.0 Hz, C4=5H3, LL), 0.80 (d, 3H, J ¼ 7.0 Hz, C4=5H3, LL) (in good agreement
with the reported spectra[1b] of N-phenyl-DL-valine-L-phenylalanine methyl ester).
13C NMR (CDCl3) d: 173.1, 172.9 (C11), 172.1, 171.9 (C2), 147.7, 147.4 (C10),
136.3, 135.6 (C13), 129.7, 129.5 (C15, 17), 129.4, 129.3 (C30,50), 128.9, 128.8
(C14,18), 127.3, 127.2 (C16), 119.4, 119.3 (C40), 114.4, 114.0 (C20,60), 65.5, 64.8
(C10), 53.2, 53.2 (C1), 52.5, 52.5 (OCH3), 38.2, 38.1 (C112), 31.4, 31.3 (C12), 20.0,
19.8, 17.8, 17.6 (C13,14).
N-Phenyl-L-leucine-L-phenylalanine methyl ester 6d. Prepared from 5d
(0.13 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The crude
product was collected as a white solid and recrystallized from CH2Cl2=hexane to
yield 6d as a white crystalline solid (0.18 g, 81%). Mp 120–122 ꢁC. 1H NMR (CDCl3)
d: 7.30–7.00 (m, 7H, ArH14–18, 30, 50), 6.78 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.58 (d, 2H,
J ¼ 7.0 Hz, ArH20,60), exchanges with D2O, 2H, NH), 3.68 (m, 1H, C1H), 3.62 (s, 3H,
OCH3), 3.10 (AB part of ABX system, 2H, J ¼ 14.0 Hz, C12H2), 1.70 (m, 2H, C3H2),
1.40 (m, 1H, C4H), 0.95 (d, 3H, J ¼ 6.0 Hz, C5=6H3), 0.86 (d, 3H, J ¼ 6.0 Hz, C5=
13
6H3). C NMR (CDCl3) d: 174.2 (C11), 171.8 (C2), 147.1 (C10), 136.3 (C3), 129.6
(C15,17), 129.5 (C30,50), 128.8 (C14,18), 127.3 (C16), 119.4 (C40), 114.1 (C20,60),
58.6 (C10), 53.1 (C1), 52.5 (OCH3), 43.0 (C4), 38.0 (C12), 25.4 (C3), 23.4, 22.0 (C5,6).
N-Phenyl-DL-leucine-L-phenylalanine methyl ester 6dꢀ. Prepared from
5dꢀ (0.13 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The crude
product was collected as an off-white solid and recrystallised from CH2Cl2=hexane
to yield 6dꢀ as small white crystals (0.15 g, 68%). Mp 133–134 ꢁC. 1H NMR (CDCl3)
d: 7.30–6.98 (m, 14H, ArH14–18,30,50), 6.77 (m, 2H, ArH40), 6.56 (m, 4H, ArH20,60),
4.85 (m, 2H, C10H), 3.93 (bs exchanges with D2O, 4H, NH), 3.71 (m, 2H, C1H),
3.68 (s, 3H, OCH3, DL), 3.60 (s, 3H, OCH3, LL), 3.25–2.86 (m, 4H, C12H2), 1.70
(m, 4H, C3H2), 1.41 (m, 2H, C13H), 0.95 (d, 3H, J ¼ 6.0 Hz,C5=6H3,), 0.94 (d,
3H, J ¼ 6.0 Hz, C5=6H3,), 0.87 (d, 3H, J ¼ 6.0 Hz, C5=6H3,), 0.85 (d, 3H, J ¼ 6.0 Hz,
C5=6H3). 13C NMR (CDCl3) d: 174.2, 174.1 (C11), 172.0, 171.9 (C2), 147.1, 147.0

N-PHENYLATION OF a-AMINO ACIDS
1177
(C10), 136.3, 135.7 (C14), 129.6, 129.5 (C15,117), 129.4, 129.3 (C30,50), 128.8, 128.7
(C14,18), 127.2, 127.1 (C16), 119.4, 119.3 (C40), 114.1, 113.7 (C20,60), 58.5, 58.1
(C10), 53.1, 52.5 (C1), 52.5, 52.4 (OCH3), 43.0, 42.8 (C4), 38.3, 38.0 (C12), 25.5,
25.4 (C3), 23.4, 23.3, 22.0, 21.8 (C5,6).
N-Phenyl-L-phenylalanine-L-alanine methyl ester 6f. Prepared from 5f
(0.15 g, 0.6 mmol) and 2b (0.09 recrystallized from CH2Cl2=hexane to yield 6f as fine
1
white crystals (0.16 g, 80%). Mp 95–97 ꢁC. H NMR (CDCl3) d: 7.40–7.05 (m, 7H,
ArH7–12,30,50), 6.79 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.58 (d, 2H, J ¼ 8.0 Hz, ArH20,60),
4.59 (m, 1H, C3H), 4.00 (dd, X part of ABX system, 1H, JAX ¼ 5.0 Hz,
JBX ¼ 8.0 Hz, C1H), 3.87 (bs exchanges with D2O, 1H, NH), 3.65 (s, 3H, OCH3),
3.19 (AB part of ABX system, 2H, J ¼ 14.0 Hz, C6H2), 1.36 (d, 3H, J ¼ 7.0 Hz,
13
C5H3). C NMR (CDCl3) d: 173.0 (C4), 172.8 (C2), 146.8 (C10), 136.7 (C7),
129.6 (C8,10), 129.5 (C30,50), 129.2 (C7,11), 127.5 (C9), 119.7 (C40), 114.6 (C20,60),
60.5 (C3), 52.5 (OCH3), 48.2 (C1), 38.9 (C6), 18.4 (C5).
N-Phenyl-L-methionine-L-phenylalanine methyl ester 6g. Prepared from
5 g (0.14 g, 0.6 mmol) and 2f (0.13 g, 0.6 mmol) via general procedure E. The crude
product was collected as an off-white solid and recrystallized from CH2Cl2=hexane
1
to yield 6 g as off-white crystals (0.21 g, 89%). Mp: 97–99 ꢁC. H NMR (CDCl3) d:
7.24 (m, 3H, ArH15,17), 7.18 (t, 2H, J ¼ 8.0 Hz, ArH30,50), 7.07 (m, 2H,
ArH14,18), 6.79 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.60 (d, 2H, J ¼ 8.0 Hz, ArH20,60), 4.86
(dt, X part of ABX system, 1H, JAX ¼ 6.0 Hz, JBX ¼ 8.0 Hz, C10H), 4.17 (bs
exchanges with D2O, 1H, NH), 3.86 (bs exchanges with D2O, 1H, NH), 3.86 (dd,
X part of ABM2X system, 1H, JAX ¼ 5.0 Hz, JBX ¼ 8.0 Hz, C1H), 3.65 (s, 3H,
OCH3), 3.10 (AB part of ABX system, 2H, J ¼ 14.0 Hz, C12H2), 2.51 (t, 2H,
J ¼ 7.0 Hz, C5H2), 2.10 and 1.90 (m, 1H and m, 1H, AB part of ABM2X system,
C3H2), 2.06 (s, 3H, SCH3). 13C NMR (CDCl3) d: 173.0 (C11), 171.8 (C2), 146.8
(C10), 136.2 (13), 129.6 (C30,50), 129.4 (C15,17), 128.9 (C14,18), 127.4 (C16), 119.6
(C40), 114.3 (C20,60), 59.2 (C10), 53.2 (C1), 52.6 (OCH3), 38.1 (C12), 32.2 (C4),
31.0 (C12), 15.7 (SCH3).
N-Phenyl-L-tyrosine-L-alanine methyl ester 6k. Prepared from 5k (0.27 g,
1.0 mmol) and 2b (0.14 g, 1.0 mmol) via general procedure E. The crude product
was collected as a yellow solid and recrystallized from ether=hexane to yield 6k as
1
a white solid (0.21 g, 61%). H NMR (CDCl3) d: 7.16 (t, 2H, J ¼ 8.0 Hz, ArH30,50),
7.06 (d, 2H, J ¼ 8.5 Hz, ArH5,9), 6.80 (t, 1H, J ¼ 7.0 Hz, ArH40), 6.78 (d, 2H,
J ¼ 8.5 Hz, ArH6,8), 6.57 (d, 2H, J ¼ 8.0 Hz, ArH20,60), 4.59 (d, 1H, J ¼ 7.0 Hz,
C10H), 3.92 (dd, X part of ABX system, 1H, JAX ¼ 5.0 Hz, JBX ¼ 8.0 Hz, C1H),
3.87 (bs exchanges with D2O, 1H, OH=NH), 3.65 (s, 3H, OCH3), 3.10 (AB part of
ABX system, 2H, J ¼ 14.0 Hz, C3H2), 1.68 (bs exchanges with D2O, 2H, OH=
NH), 1.36 (d, 3H, J ¼ 7.0 Hz, C12H3). 13C NMR (CDCl3) d: 173.3 (C11), 173.0
(C2), 155.4 (C7), 146.9 (C10), 130.7 (C5,9), 129.6 (C30,50), 128.3 (C4), 119.8 (C40),
116.1 (C6,8), 114.7 (C20,60), 60.7 (C1), 52.6 (OCH3), 48.2 (C10), 38.1 (C6), 18.4 (C12).
N-Phenyl-L-aspartic acid di-(L-alanine methyl ester) 7. Prepared from 5 l
(0.13 g, 0.6 mmol) 2b (0.17 g, 1.2 mmol), triethylamine (0.20 mL, 1.2 mmol), EDC
(0.22 mL, 1.2 mmol), and N-hydroxysuccinimide (0.14 g, 1.2 mmol) via general
procedure E. The crude product was collected as an off-white solid and recrystallized

1178
J. D. MCKERROW, J. M. A. AL-RAWI, AND P. BROOKS
1
from ether=hexane to yield 7 as a white solid (0.20 g, 88%). Mp 146–148 ꢁC. H
NMR (CDCl3) d: 7.20 (t, 2H, J ¼ 8.0 Hz, ArH30,50), 6.79 (t, 1H, J ¼ 8.0 Hz, ArH40),
6.71 (d, 2H, J ¼ 8.0 Hz, ArH20,60), 4.56 (m, 2H, C3H,C8H), 3.73 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 2.75 (AB part of ABX system, 2H, J ¼ 14.0 Hz, C6H2), 1.41 (d, 3H,
J ¼ 7.0 Hz, C5=10H3), 1.39 (d, 3H, C5=10H3). 13C NMR (CDCl3) d: 173.9, 173.6,
172.3, 170.9 (C2,4,7, 9), 146.3 (C10), 129.7 (C30,50), 119.3 (C40), 114.5 (C20,60), 56.1
(C1), 52.9, 52.7 (OCH3), 48.6, 48.5 (C3,8), 38.2 (C6), 18.1, 17.9 (C5,10).
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N-PHENYLATION OF a-AMINO ACIDS
1179
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