Full text of DOI:10.1016/S0040-4020(01)00554-3

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 6641±6650
Enantiomeric enrichment of a-amino acid derivatives:
recrystallization of N-Fmoc a-amino acid tert-butyl esters
Martin J. O'Donnellp and Francisca Delgado
Department of Chemistry, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202,USA
Received 12 March 2001; revised 22 March 2001; accepted 4 April 2001
AbstractÐThe optical purity of products derived from enantioselective reactions of the benzophenone imine of glycine tert-butyl esters can
often be improved by conversion to the N-Fmoc a-amino acid tert-butyl esters followed by simple recrystallization. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
acetate 3, which is readily prepared from 1, can be reacted
with various neutral or charged nucleophiles 3e.g. organo-
copper reagents, organoboranes/ArOK, active methylene
anions/Pd30), vinyl organometallics/Pd30), active aromatics/
TiCl4, vinyl silanes/TiCl4).7,8 Products containing the
benzophenone imine group are typically more stable to
hydrolysis and chromatography than their aldimine counter-
parts.1 However, since the benzophenone imine is removed
under mildly acidic aqueous conditions, care must be taken
to avoid acids or long residence times on chromatography
columns.
New methods for the synthesis of natural and unnatural
a-amino acids have been developed by numerous research
groups over the past quarter century.1,2 Since 1978 we have
been interested in the use of Schiff bases for the synthesis of
a-amino acids by Phase-Transfer Catalysis 3PTC)3±5 and
other synthetic routes. The use of benzophenone imines of
a-amino acid esters for the synthesis of ®rst racemic and
then of optically active a-amino acids will be reviewed and
then a new method for the enantiomeric enrichment of these
products will be described.
The solid-phase synthesis of unnatural a-amino acids and
peptides, termed `Unnatural Peptide Synthesis' 3`UPS'),
using the benzophenone imines of resin-bound glycinates,
was reported in 1996 as a part of our academic-industrial
collaboration with the laboratory of Dr William L. Scott at
the Lilly Research Laborarories.9 UPS involves the room-
temperature introduction of an amino acid side-chain by a
three-step sequence during a normal solid-phase peptide
synthesis 3SPPS) 3Scheme 2). The resin-bound N-terminal
glycine residue 37) is activated as the benzophenone imine
to form 8, the side-chain is introduced by deprotonation and
reaction with an electrophile to yield 9, and then the imine is
The benzophenone imines of glycine alkyl esters can serve
as either glycine anion or glycine cation equivalents in the
preparation of a-monoalkyl amino acid derivatives 3Scheme
1). Thus, reaction of 1 with base and an electrophile
yields the monoalkyl derivative 5 via the Schiff base ester
enolate. A key feature of this methodology is the selective
monoalkylation of the starting benzophenone imine
substrates, which is due to the considerable decrease in
acidity of the monoalkylated product [5, RˆMe, pKa,
3DMSO)ˆ22.8] in comparison with the starting substrate
[1, pKa 3DMSO)ˆ18.7].6 The complementary Schiff base
Scheme 1. Glycine anion and cation equivalents for the synthesis of a-amino acids.
p
Corresponding author. Tel.: 11-317-274-6887; fax: 11-317-274-4701; e-mail: odonnell@chem.iupui.edu
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00554-3

6642
M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
Scheme 2. Unnatural amino acid and peptide synthesis.
selectively removed by hydrolysis or transimination to give
the resin-bound product 10. Product 10 can then either be
subjected to another UPS cycle or it can be cleaved from the
resin.10
As noted in Scheme 2, a number of different types of amino
acid- or peptide-derived products are available by UPS
methodology. Relatively unreactive alkylating agents can
be used by increasing the stoichiometry of the base and
alkyl halide or by using an in situ Finkelstein reaction for
conversion to the more reactive alkyl halide.9c a,a-Dialkyl-
ation can be accomplished either by alkylation of an aldi-
mine-activated monoalkylated substrate9b or by a tandem
procedure involving normal UPS monoalkylation of the
benzophenone imine of a glycine substrate followed by a
direct second alkylation with stronger base 3KHMDS) under
anhydrous conditions.9d Michael addition of substrates 8
leads to various glutamic acid derivatives.9e Different resins
can be used for the preparation of amino amides or peptide
amides 3Rink resin)9g or amino aldehydes, amino ketones,
peptide aldehydes or peptide ketones 3Weinreb amide
resin).9f A resin-bound glycine cation equivalent 39,
UnˆOAc) can be reacted with organoboranes to give a
variety of a-substituted amino acid derivatives.7h
Since solid-phase synthesis already involves a second
phase, use of normal PTC-type reaction conditions with a
heterogeneous base was expected to be problematic. The
neutral, organic-soluble Schwesinger bases, BEMP 311)
and BTPP 312) 3Scheme 3),11 employed in the alkylation
step, function similar to typical PTC base systems. Because
these sterically hindered bases do not react with alkyl
halides at an appreciable rate, both the electrophile and
the base can be present from the beginning of the alkylation
step.
The preparation of optically active a-alkyl amino acids
from the benzophenone imines of glycine derivatives has
been accomplished in three major ways: enzymatic resolu-
tion, the use of chiral auxiliaries, and enantioselective
Scheme 3. Schwesinger bases: strong, neutral, organic-soluble bases.
Scheme 4. Enzymatic resolution of alkylation products.

M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
6643
The groups of Imperiali,15 Pirrung,16 Long,17 and others18
have reported enzymatic resolutions of various amino acid
derivatives 313, 16, and 17). Groups at DSM Research and
the University of Amsterdam have used enzymatic reso-
lution of a-amino amides as a route to the enriched 3S)-14
and unreacted 3R)-18.2j,19
Scheme 5. Products from the alkylation of benzophenone imines containing
chiral auxiliaries.
Use of either an ester or an amide chiral auxiliary in
conjunction with nitrogen activation with the benzophenone
imine has been reported by a number of groups. Two of
these systems, which have been used with considerable
success 319 and 20), will be discussed here 3Scheme 5).
Alkylation of substrate 19 3RˆH), which contains the
Oppolzer sultam auxiliary, to give products 19, has been
reported by the groups of Chassaing20 and Roques.21 Palla-
dium-catalyzed allylations of 19 3RˆH) were accomplished
by the de Meijere22 and SalauÈn groups.22a Pleixats reported
use of phase-transfer catalyzed conditions, which avoid the
use of the normal low-temperature, anhydrous conditions
that often require use of HMPA or another additive, for
synthesis involving a chiral catalyst or reagent. Each of
these methods will be discussed below.
Although classical resolutions12 can and certainly have been
used for the preparation of optically active a-amino acids
from derivatives prepared by various synthetic routes from
compounds such as 1 or 3, the use of enzymatic resolution
Ê
È
will be the focus of this discussion. Langstrom and co-
workers prepared 11C-labeled l-amino acids for positron
emission tomography 3PET) studies by racemic alkylation
of the benzophenone imine of glycine tert-butyl ester 32)
followed by hydrolysis to the amino acid and then selective
destruction of the d-amino acid using d-amino acid
oxidase.13 Because of the short half-life of 11C 320.4 min),
syntheses involving this isotope need to be both very rapid
and ef®cient. In 1989 the Whitesides group reported the
kinetic resolution of unnatural amino acid derivatives
prepared by racemic alkylation of 1 and other amino acid
anion equivalents 3Scheme 4).14 Enantioselective hydrolysis
of racemic N-acyl amino acids 313) was accomplished using
acylase I. Such enzymatic resolutions provide access to each
of the enantiomers of the amino acid, the hydrolyzed
product 3S)-14 and the unreacted starting substrate 3R)-15.
the alkylation of 19 3RˆH).23 More recently, the Najera
Â
group has made use of substrate 20 3RˆH), which contains
an ephedrine-derived imidazolidinone chiral auxiliary,
for both alkylations and Michael additions using several
different base systems as a route to products 20.24
The ®nal major route to prepare optically active a-amino
acids from the benzophenone imines of glycine alkyl esters
involves enantioselective reactions, in which the chiral
control is used either as a catalyst or a reagent 3Scheme
6). In 1989 we reported the catalytic enantioselective alkyl-
ation of imine 2 using the pseudoenantiomeric catalysts, 21a
3from cinchonine, CnOH) or 22a 3from cinchonidine,
Scheme 6. Enantioselective phase-transfer catalysis.

6644
M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
Scheme 7. Enantioselective reactions of a resin-bound glycine derivative.
CdOH), derived from the Cinchona alkaloids 3Scheme 6).25
Even though only modest enantioselectivities 3up to 66%
ee) by today's standards were achieved using these ®rst
generation catalysts, it was possible to increase the optical
purity of some of these products by a simple recrystalli-
zation or by enzymatic resolution of the partially enriched
derivatives 3see beginning of Results and Discussion
Section). A second generation of catalysts 321b and 22b),
in which the free hydroxyl group of the original Cinchona-
quat catalysts were O-alkylated, gave enantioselectivities of
up to 81%.26
enantioselective alkylations29 and Michael additions31under
homogeneous reaction conditions by using the Schwesinger
bases BEMP 311) or BTPP 312) together with Cinchona-
derived quats 21d or 22d. In this case, the highest enantio-
selectivity 397% ee) was obtained using isobutyl bromide.
The Maruoka group recently reported use of a BINAP-
derived catalyst 323) for the catalytic enantioselective alkyl-
ation of substrate 2.32 Excellent enantioselectivity 396% ee)
was obtained with only 1 mol% of catalyst at 08C in 30 min
for the model benzylation reaction. Recently this group has
reported a dramatic rate enhancement of the alkylation reac-
tion using ultrasonic irradiation 3methylation in 8 h with
stirring or in 1 h with ultrasound).32c
A further major improvement in catalyst design was
reported simultaneously in late 1997 by the Lygo27 and
Corey28 groups. Enantioselectivites of 91±94% were
obtained for the model benzylation reaction by introduction
of the N-9-anthracenylmethyl group into either the catalysts
containing a free hydroxyl group 321c and 22c),27 which are
converted to the active O-alkylated catalysts in situduring
the PTC alkylation reaction, or the O-allylated catalysts
322d28 or 21d29). The highest enantioselectivities reported
for these two related catalyst systems were 94% ee using the
Lygo catalyst 22c 3with benzyl bromide)27 and 99.5% ee
using the Corey catalyst 22d 3with either n-hexyl iodide
or benzhydryl bromide).28 Reactions developed using
these catalyst systems include: alkylations,27,28a,b,30 Michael
additions,28b,c and aldol reactions.28d
The solid-phase enantioselective alkylation33 and Michael
addition31 of resin-bound glycinate 24 was accomplished
using the Cinchona-derived reagents 21d and 22d together
with the Schwesinger bases BEMP 311) and BTPP 312)
3Scheme 7). In this case the model benzylation with 22d
gave product in 76% ee. The highest enantioselectivity
achieved was 89% using methallyl bromide.
Polymer-supported Cinchona-derived catalysts similar in
structure to catalysts 21a and 22a have recently been
34
reported by the Najera group. Alkylation of the benzo-
Â
phenone imine of glycine isopropyl ester gave up to 90%
ee for the alkylation with benzyl bromide. Other active
alkylating agents gave enantioselectivites from 24±64%.
We showed that it was possible to carry out catalytic
Scheme 8. Catalytic enantioselective allylic substitution using Pd30) and a chiral ligand.

M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
6645
problem in these syntheses is the need to enrich product
enantiomers to optically pure products. The Imperiali
group15 and others18b have used enantioselective PTC
reactions followed by enzymatic resolution of product
derivatives to achieve this goal.
We7g,25 and others15b,38,39 have shown that in some cases it is
possible to recrystallize a partially enriched product to an
optically pure one. Two notable successes in this regard as
well as one failure are shown in Scheme 10. Enantioselective
PTC alkylation of 2 with 4-chlorobenzyl bromide using the
®rst generation catalyst 21a yielded 3R)-6 in 66% ee. A single
recrystallization gave racemic crystals and nearly optically
pure product in the ®ltrate.25 In the complementary catalytic
enantioselective synthesis involving palladium-catalyzed
coupling of malonate anion with the glycine cation equivalent
4 3Scheme 9), the initial product was obtained in 79% ee.
Again a single recrystallization gave a highly enriched
product, in this case as crystalline product 3S)-6.7g Unfortu-
nately, not all cases work so well! As noted by Pirrung and
Krishnamurthy, phenylalanine analogs with unsymmetrical
substitutions are often non-crystalline.16b An example is
shown in Scheme 10; the benzophenone imine of 3-iodo-
phenylalanine tert-butyl ester 3S)-6b is an oil, so it is not
possible to enrich this product by simple recrystallization.
Scheme 9. Catalytic enantioselective reaction of a glycine cation equivalent
with malonate anion.
The catalytic enantioselective allylic substitutions of 2 using
Pd30) and a chiral phosphine ligand have been studied by a
number of groups. With the exception of the two cases
discussed below 3Scheme 8), the enantioselectivites have
only been modest with this type of reaction. The Williams
group reported the allylation of 2 with a diphenyl-substi-
tuted allylic acetate in the presence of the phosphorous-
containing oxazole ligand 30 as a route to allylated product
29 397% ee).35 Considerably lower enantioselectivites with
the parent allyl acetate imply that the choice of the electro-
philic partner is important in obtaining high inductions in
these reactions. Recently, the groups of Hou and Dai have
shown that allylic allylation of the alanine-derived imine 6a
using a ferrocene ligand with planar chirality 332) gives
75% ee of the a,a-dialkylated product 31.36 These results
are promising since such optically active a,a-dialkylated
systems are typically dif®cult to prepared from benzo-
phenone imine-containing starting substrates.
We now report that it is often possible to achieve enantio-
meric enrichment by recrystallization of the N-Fmoc
a-amino acid tert-butyl esters 333). These products are
readily prepared from the benzophenone derivatives 6 by
mild hydrolysis with aqueous citric acid followed by
N-acylation with FmocCl 3Scheme 11 and Table 1).
Enantiomeric excesses were determined by chiral HPLC.40
We reported a catalytic enantioselective synthesis involving
a glycine cation equivalent in conjunction with a novel
32-aza-p-allyl)palladium intermediate as a route to optically
active b-carboxyaspartic acid derivatives 3Scheme 9).7g,37
Reaction of 4 with malonate anion for one hour at room
temperature in the presence of catalytic Pd30) and the chiral
bisphosphine ligand BINAP gave product
6
[Rˆ
Several representative products 6 obtained by catalytic
enantioselective alkylation 36a±6e) or Michael addition
36g±6j) of the benzophenone imine of glycine tert-butyl
ester 32) as well as the product 6f, derived from glycine
cation equivalent 4, were chosen for recrystallization studies
3Table 1). Following conversion into the Fmoc tert-butyl
esters 6, the products were recrystallized. In many cases
the crystals obtained were highly enriched in the major
enantiomer 36a±6c, 6f, 6h, and 6j). In other cases the
enriched major enantiomer was contained in the ®ltrate
36d and 6e). The mixed glutamate ester 36g) was an oil,
so its optical purity could not be improved. In one case
36i), the crystals obtained on repeated recrystallization
were of constant %ee.
CH3CO2Me)2] in 79% ee 3see beginning of Results and
Discussion Section for the use of recrystallization to
improve the optical purity of this product). The reaction
was optimized for substrate ester, imine, and leaving
group; base, solvent, counterion, and additive; and steric
factors in the nucleophilic partner. The level of induction
was shown to be sensitive to the nature of the nucleophile.
2. Results and discussion
The enantioselective syntheses outlined above demonstrate
that it is now possible to prepare a variety of types of
unnatural a-amino acid derivatives with moderate to high
enantioselectivities from substrates 2 and 4. One potential
The orthogonal nature of the Fmoc and tert-butyl ester
Scheme 10. Enantiomeric enrichment by recrystallization of Schiff base tert-butyl esters.

6646
M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
Scheme 11. Imine hydrolysis of 6 followed by conversion to the N-Fmoc a-
amino acid tert-butyl esters 333).
Scheme 12. Hydrolysis of 3S)-33b to yield N-Fmoc-3-iodophenylalanine
334).
groups allows for differential deprotection of derivatives 33.
For example, the Fmoc tert-butyl ester of 3-iodophenyl-
alanine [3S)-33b] was converted into Fmoc-3-iodophenyl-
alanine [3S)-34] in 93% yield by treatment with TFA
3Scheme 12).
prepared from 2.40 Product 6f was prepared from 4.41
NMR analyses were performed on a GE 300 MHz spectro-
meter; d is in ppm relative to TMS as internal standard in the
indicated solvent. Elemental analyses were performed by
Midwest Microlab of Indianapolis, IN. High resolution
mass spectrometry data were obtained with a Kratos
MS80 high resolution mass spectrometer with chemical
ionization.
The benzophenone imines of glycine esters are proving to
be important starting materials for the synthesis of optically
enriched a-amino acid derivatives. The new method for the
enantiomeric enrichment of the Fmoc tert-butyl derivatives
reported here provides another option for the preparation of
optically active a-amino acid derivatives of high purity.
3.2. General procedure for the hydrolysis of the
alkylated benzophenone imine -6)
3. Experimental
3.1. General methods
The alkylated product 6 3150±300 mg) was dissolved in
THF 36 mL) and 15% aqueous citric acid 33 mL) was
added. The reaction mixture was stirred at room temperature
The starting alkylated products 6a±6e and 6g±6j were
Table 1. Enantioselectivities of substrates 6 and recrystallized products 33

M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
Table 2. Initial %ee of Products 3S)-6 and recrystallization yields and %ee of Products 3S)-33
Yield 3%ee) of 3S)-33 following recrystallization
1st recrystallization 2nd recrystallization
6647
3rd recrystallization
Product 3R Group)
%ee 3S)-6
Filtratea
Crystalsa
Filtratea
Crystalsa
Filtratea
Crystalsa
6a 3Me)
83
63
71
84
80
92
82
76
65
70
12 324)
26 322)
12 316)
80 3.98)
40 393)
14 346)
±
19 312)
18 365)
22 324)
88 391)
74 393)
88 393)
20 326)
60 371)
86 3.99)
±
81 391)
82 365)
78 383)
8 334)
7 314)
9 332)
±
92 396)
93 3.98)
91 3.99)
±
10 360)
90 3100)
6b 33-I-PhCH2)
6c 32-Naphthylmethyl)
6d 3Allyl)
±
±
±
±
±
±
±
365)
±
±
±
±
±
±
±
±
365)
±
6e 3n-Octyl)
±
±
±
±
±
±
6f 3Cyclohexyl)
6gb 3CH2CH2CO2Me)
6h 3CH2CH2CN)
6i 3CH2CH2COEt)
6j 3CH2CH2SO2Ph)
20 378)
365)
±
80 395)
365)
±
a
Yield 3ee).
Oil.
b
overnight, then made basic with saturated aqueous K2CO3
and extracted with ethyl acetate 33£10 mL) followed by
drying of the extracts 3MgSO4). Concentration under
reduced pressure gave the crude amino acid tert-butyl
esters, which were used in the next step without further
puri®cation.
C6H4CH2): Pentane/Et2O, Mp. 86±888C; 1H NMR
3CDCl3, d) 1.43 3s, 9 H); 3.04 3d, 2 H, Jˆ5.1 Hz); 4.22 3t,
1 H, Jˆ7.0 Hz); 4.34 3dd, 1 H, Jˆ10.3 and 7.4 Hz); 4.44±
4.53 3m 2 H); 5.32 3d, 1H, Jˆ8.1 Hz); 7.02 3t, 1 H,
Jˆ7.4 Hz); 7.11 3d, 1 H, Jˆ7.4 Hz); 7.33 3td, 2 H, Jˆ7.4
and 1.5 Hz); 7.41 3t, 2 H, Jˆ7.4 Hz); 7.54±7.59 3m, 4 H);
7.77 3d, 2 H, Jˆ8.1 Hz); 13C NMR 3CDCl3, d): 27.9, 37.9,
47.2, 55.0,.9, 82.7, 94.2, 119.9, 125.1, 127.0, 16138.6,
141.3, 143.8, 155.4, 170.1. Anal. calcd for C28H28INO4: C
59.06, H 4.96, N 2.46; found: C 59.00, H 4.95, N 2.39.
Chiracel OD, hexane/i-PrOH 370:30), 1.0 mL/min,
254 nm, retention times: R 3minor) 7.68 min, S 3major)
23.47 min.
3.3. General procedure for the conversion of the amino
tert-butyl esters to the N-Fmoc amino acid tert-butyl
esters -33)
The crude amino ester was dissolved in THF 36 mL) and
10% aqueous Na2CO3 36 mL) was added, followed by
FmocCl 39-¯uorenylmethyl chloroformate) 31.0 equiv).
The reaction mixture was stirred at room temperature over-
night. The aqueous layer was then extracted with EtOAc
33£10 mL), and the combined organic extracts were dried
3MgSO4) and concentrated under reduced pressure to give
the crude product, which was puri®ed by ¯ash chroma-
tography to remove benzophenone and excess of reagents.
The puri®ed product was then crystallized from the
indicated solvent 3Table 2). The enantiomeric excess was
determined by chiral HPLC 3isocratic) using the conditions
speci®ed in each case: column, mobile phase 3ranges used),
¯ow rate 3ranges used), detection wavelength, retention
times. Table 2 lists the initial %ee of products 3S)-6 and
the recrystallization yields and %ee of products 3S)-33.
3.3.3. 1,1-Dimethylethyl -aS)-[[-9H-¯uoren-9-ylmethoxy)-
carbonyl]amino]-2-naphthalenepropanoate 33c. 3Rˆ
2-Naphthylmethyl): Pentane/Et2O, Mp. 104±1058C; 1H
NMR 3CDCl3, d) 1.41 3s, 9 H); 3.27 3d, 2 H, Jˆ5.9 Hz);
4.203t, 1 H, Jˆ7.0 Hz); 4.32 3dd, 1 H, Jˆ10.3 and 6.6 Hz);
4.43 3dd, 1 H, Jˆ10.3 and 7.4 Hz); 4.65 3q, 1 H, Jˆ5.9 Hz);
5.32 3d, 1H, Jˆ8.1 Hz); 7.24±7.32 3m, 3 H); 7.39 3t, 2 H,
Jˆ7.4 Hz); 7.44±7.47 3m, 2 H); 7.56 3t, 2 H, Jˆ6.6 Hz);
7.62 3s, 1 H); 7.75±7.83 3m 5 H); 13C NMR 3CDCl3, d):
27.9, 38.5, 47.1, 55.2, 66.8, 82.3, 119.9, 124.9, 125.0, 125.6,
125.8, 126.0, 126.9, 127.4, 127.6, 128.0, 128.1, 132.4,
133.3, 133.6, 141.2, 143.7, 143.8, 155.5, 170.5. Anal.
calcd for C32H31NO4: C 77.87, H 6.33, N 2.84; found: C
77.92, H 6.37, N 2.92. Chiracel OD, hexane/i-PrOH 375:25),
1.0 mL/min, 254 nm, retention times: R 3minor) 9.15 min, S
3major) 21.52 min.
3.3.1. 1,1-Dimethylethyl N-[9H-¯uoren-9-ylmethoxy)-
carbonyl]-l-alaninate 33a. 3RˆMe): Pentane/Et2O, Mp.
1
89±908C; H NMR 3CDCl3, d) 1.40 3d, 3 H, Jˆ6.6 Hz);
3.3.4. 1,1-Dimethylethyl -2S)-[[-9H-¯uoren-9-ylmethoxy)-
carbonyl]amino]-4-pentenoate 33d. 3RˆAllyl): Pentane/
1.48 3s, 9 H); 4.20±4.30 3m, 2 H); 4.38 3d, 2 H,
Jˆ7.4 Hz); 5.37 3d, 1H, Jˆ6.6 Hz); 7.32 3td, 2 H, Jˆ7.4
and 1.5 Hz); 7.40 3t, 2 H, Jˆ7.4 Hz); 7.61 3d, 2 H, Jˆ
7.4 Hz); 7.77 3d, 2 H, Jˆ7.4 Hz); 13C NMR 3CDCl3, d):
18.8, 27.9, 47.1, 50.1, 66.8, 81.8, 119.8, 125.0, 126.9,
127.6, 141.2, 143.8, 143.9, 155.5, 172.2. Anal. calcd for
C22H25NO4: C 71.91, H 6.86, N 3.81; found: C 72.07, H
6.89, N 3.77. Chiracel OD, hexane/i-PrOH 385:15),
1.0 mL/min, 254 nm, retention times: R 3minor) 8.53 min,
S 3major) 20.83 min.
1
Et2O, Mp. 81±828C; H NMR 3CDCl3, d) 1.48 3s, 9 H);
2.46±2.62 3m, 2 H); 4.23 3t, 1H, Jˆ7.0 Hz); 4.32±4.40
3m, 3 H); 5.15 3d, 2 H, Jˆ12.5 Hz); 5.36 3d, 1H, Jˆ
8.1 Hz); 5.67±5.78 3m, 1 H); 7.31 3t, 2 H, Jˆ7.0 Hz); 7.40
3t, 2 H, Jˆ7.4 Hz); 7.60 3d, 2 H, Jˆ7.4 Hz); 7.77 3d, 2 H,
Jˆ7.4 Hz); 13C NMR 3CDCl3, d): 27.8, 36.8, 47.0, 53.5,
66.8, 81.9, 118.7, 119.7, 124.9, 126.8, 127.4, 132.2, 141.1,
143.7, 143.8, 155.5, 170.6. Anal. calcd for C24H27NO4: C
73.26, H 6.92, N 3.56; found: C 73.00, H 6.87, N 3.33.
Chiracel OD, hexane/i-PrOH 385:15), 1.0 mL/min, 254 nm,
retention times: R 3minor) 6.84 min, S 3major) 12.89 min.
3.3.2. 1,1-Dimethylethyl N-[-9H-¯uoren-9-ylmethoxy)-
carbonyl]-3-iodo-l-phenylalaninate
33b.
3Rˆ3-I-

6648
M. J. O'Donnell, F. Delgado / Tetrahedron 57 -2001) 6641±6650
3.3.5. 1,1-Dimethylethyl -2S)-[[-9H-¯uoren-9-ylmethoxy)-
carbonyl]amino]decanoate 33e. 3Rˆn-Octyl): Hexane,
Mp. 61±638C; 1H NMR 3CDCl3, d) 0.88 3t, 3 H, Jˆ
6.6 Hz); 1.27±1.83 3m, 23 H); 4.21±4.29 3m, 2 H); 4.38
3d, 2 H, Jˆ7.4 Hz); 5.30 3d, 1H, Jˆ8.1 Hz); 7.31 3t, 2 H,
Jˆ7.4 Hz); 7.40 3t, 2 H, Jˆ7.4 Hz); 7.60 3d, 2 H, Jˆ7.4 Hz);
7.77 3d, 2 H, Jˆ7.4 Hz); 13C NMR 3CDCl3, d): 14.0, 22.6,
24.9, 27.9, 29.1, 29.2, 29.3, 31.7, 32.7, 47.2, 54.3, 66.8,
81.8, 119.9, 125.0, 126.9, 127.6, 141.2, 143.8, 143.9,
155.8, 171.8. Anal. calcd for C29H39NO4: C 74.81, H 8.44,
N 3.01; found: C 74.65, H 6.36, N 3.11. Chiracel OD, hex-
ane/i-PrOH 385:15), 1.0 mL/min, 254 nm, retention times: R
3minor) 6.94 min, S 3major) 15.48 min.
Jˆ7.4 Hz); 7.40 3t, 2 H, Jˆ7.7 Hz); 7.58±7.61 3m, 2 H);
7.77 3d, 2 H, Jˆ8.1 Hz); 13C NMR 3CDCl3, d): 7.5, 26.3,
27.7, 35.6, 37.7, 46.9, 53.7, 66.6, 81.8, 119.7, 124.8, 126.7,
127.4, 141.8, 143.5, 143.7, 155.8, 171.0, 209.9. Anal. calcd
for C26H31NO5: C 71.37, H 7.14, N 3.20; found: C 71.35, H
7.21, N 3.13. Chiracel OD, hexane/i-PrOH 380:20), 1.0 mL/
min, 254 nm, retention times: R 3minor) 9.92 min, S 3major)
19.66 min.
3.3.10. 1,1-Dimethylethyl -2S)-[[-9H-¯uoren-9-ylmethoxy)-
carbonyl]amino]-4-phenylsulfonyl)butanoate 33j. 3Rˆ
CH2CH2SO2Ph): Pentane/Et2O, Mp. 91±928C; 1H NMR
3CDCl3, d) 1.44 3s, 9 H); 1.99±2.11 3m, 1 H); 2.28±2.40
3m, 1 H); 2.99±3.10 3m, 1 H); 3.14±3.25 3m, 1 H); 4.18 3t, 1
H, Jˆ6.6 Hz); 4.24±4.31 3m, 1 H); 4.37 3d, 2 H, Jˆ7.4 Hz);
5.37 3d, 1H, Jˆ7.4 Hz); 7.31 3td, 2 H, Jˆ7.4 and 2.2 Hz);
7.40 3t, 2 H, Jˆ7.4 Hz); 7.53±7.58 3m, 4 H); 7.66 3t, 1 H,
Jˆ7.4 Hz); 7.77 3d, 2 H, Jˆ8.1 Hz); 7.90 3d, 2 H,
Jˆ7.4 Hz); 13C NMR 3CDCl3, d): 26.1, 27.9, 47.1, 52.5,
52.9, 67.1, 83.2, 119.9, 125.0, 127.1, 127.6, 128.0, 129.3,
133.8, 138.9, 141.3, 143.6, 143.7, 155.8, 169.9. Anal. calcd
for C29H31NO6S: C 66.77, H 5.99, N 2.69; found: C 66.57, H
6.03, N 2.73. Baker Bond DNBPG 3Covalent), hexane/
i-PrOH/EtNMe2 397:3:0.2), 1.0 mL/min, 254 nm, retention
times: S 3major) 50.26 min, R 3minor) 53.27 min.
3.3.6. 1,1-Dimethylethyl -aS)-[[-9H-¯uoren-9-ylmethoxy)-
carbonyl]amino]cyclohexaneacetate 33f. 3RˆCyclo-
1
hexyl): Pentane/Et2O, Mp. 104±1058C; H NMR 3CDCl3,
d) 1.01±1.28 3m, 6 H); 1.48 3s, 9 H); 1.60±1.78 3m, 5 H);
4.15±4.25 3m, 2 H); 4.34±4.45 3m, 2 H); 5.30 3d, 1H,
Jˆ8.8 Hz); 7.32 3t, 2 H, Jˆ7.4 Hz); 7.40 3t, 2 H, Jˆ
7.4 Hz); 7.61 3d, 2 H, Jˆ7.4 Hz); 7.77 3d, 2 H, Jˆ7.4 Hz);
13C NMR 3CDCl3, d): 26.0, 27.9, 28.0, 29.3, 41.3, 47.2,
59.0, 66.8, 81.9, 119.9, 125.0, 127.0, 127.6, 141.3, 143.8,
143.9, 156.1, 171.1. Anal. calcd for C27H33NO4: C 74.45, H
7.64, N 3.22; found: C 74.10, H 7.94, N 3.13. Chiracel OD,
hexane/i-PrOH 385:15), 1.0 mL/min, 254 nm, retention
times: R 3minor) 6.33 min, S 3major) 8.99 min.
3.4. Hydrolysis of the benzophenone imine of 3-iodo-
phenylalanine tert-butyl ester -4b) to form N-[-9H-
¯uoren-9-ylmethoxy)carbonyl]-3-iodo-l-phenylalanine
-34)
3.3.7. 1,1-Dimethylethyl 5-methyl N-[-9H-¯uoren-9-yl-
methoxy)carbonyl]-l-glutamate 33g. 3RˆCH2CH2CO2Me):
1
Hexane and Hexane/Et2O; H NMR 3CDCl3, d) 1.46 3s, 9
H); 1.81±2.42 3m, 4 H); 3.68 3s, 3 H); 4.18±4.31 3m, 2 H);
4.39 3d, 2 H, Jˆ7.0 Hz); 5.42 3d, 1H, Jˆ7.5 Hz); 7.28±
7.7.44 3m, 4 H); 7.60 3d, 2 H, Jˆ7.3 Hz); 7.76 3d, 2 H,
Jˆ7.3 Hz); 13C NMR 3CDCl3, d): 27.3, 27.5, 29.7, 46.8,
51.2, 53.5, 66.6, 81.7, 119.5, 124.7, 126.6, 127.3, 140.9,
143.4, 143.6, 155.7, 170.7, 172.7. HRMS m/z calcd for
C25H30NO6 440.2073 for 3M1H1), found 440.2088.
Chiracel OD, hexane/i-PrOH 385:15), 1.0 mL/min,
254 nm, retention times: R 3minor) 12.41 min, S 3major)
19.35 min.
TFA 30.5 mL) was added to the Fmoc-ester product 33b
3240 mg, 0.42 mmol) and the reaction mixture was stirred
at room temperature overnight. Concentration under
reduced pressure gave the crude Fmoc-protected amino
acid 334), which was recrystallized from ethyl acetate.
1
Yield 3200 mg, 0.39 mmol, 93%). H NMR 3CDCl3, d)
3.02±3.22 3m, 2 H); 4.22 3t, 1 H, Jˆ6.6 Hz); 4.36±4.51
3m, 2 H); 4.50±4.65 3m, 1 H); 5.22 3d, 1H, Jˆ7.4 Hz);
7.03 3t, 1 H, Jˆ7.4 Hz); 7.12 3d, 1 H, Jˆ7.4 Hz); 7.32
3app.t, 2 H, Jˆ7.4 Hz); 7.41 3t, 2 H, Jˆ7.4 Hz); 7.54±
7.62 3m, 4 H); 7.78 3d, 2 H, Jˆ7.4 Hz); 13C NMR 3CDCl3,
d): 34.9, 45.3, 53.6, 64.5, 92.6, 118.3, 123.7, 125.5, 126.0,
127.1, 128.6, 133.7, 136.4, 138.9, 139.3, 142.2, 154.5,
171.5. HRMS m/z calcd for C24H20INO4 513.0396, Found
513.0440.
3.3.8. 1,1-Dimethylethyl 4-cyano--2S)-[[-9H-¯uoren-9-
ylmethoxy)carbonyl]amino]butanoate
33h.
3Rˆ
CH2CH2CN): Pentane/Et2O, Mp. 61±628C; 1H NMR
3CDCl3, d) 1.48 3s, 9 H); 1.92±2.01 3m, 1 H); 2.21±2.40
3m, 3 H); 4.22 3t, 1 H, Jˆ6.3 Hz); 4.25±4.54 3m, 3 H); 5.38
3d, 1H, Jˆ6.6 Hz); 7.33 3t, 2 H, Jˆ7.0 Hz); 7.42 3t, 2 H,
Jˆ7.4 Hz); 7.59 3d, 2 H, Jˆ7.4 Hz); 7.77 3d, 2 H, Jˆ
8.1 Hz); 13C NMR 3CDCl3, d): 13.5, 27.9, 28.9, 47.2,
53.3, 66.9, 83.3, 120.0, 124.9, 125.0, 127.1, 127.7, 141.3,
143.5, 143.7, 155.9, 169.8. Anal. calcd for C24H26N2O4: C
70.92, H 6.45, N 6.89; found: C 70.20, H 6.44, N 6.83.
Chiracel OD, hexane/i-PrOH 360:40), 1.0 mL/min,
254 nm, retention times: R 3minor) 8.46 min, S 3major)
14.33 min.
Acknowledgements
We gratefully acknowledge the National Institutes of Health
3GM 28193) for support of this research.
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