Diastereoselective radical addition to dehydroalanine derivatives of pantolactone

Article abstract of DOI:10.1016/S0957-4166(02)00135-0

The diastereoselective synthesis of α-amino acids by radical addition to dehydroalanine derivatives of pantolactone using the stannane method both in the presence and absence of Lewis acid catalysts is reported. The absolute configuration of the newly-generated stereogenic center is highly dependent on the nature of the added radical. Acid hydrolysis afforded the amino acids with excellent yields and without racemization. This approach constitutes a novel method for the asymmetric synthesis of α-amino acids by a radical pathway.

Full text of DOI:10.1016/S0957-4166(02)00135-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 503–510
Diastereoselective radical addition to dehydroalanine derivatives
of pantolactone
Anne-Marie Yim, Yves Vidal,* Philippe Viallefont and Jean Martinez
Laboratoire des Aminoacides, Peptides et Prote´ines, UMR-CNRS 5810, Universite´s Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier cedex 5, France
Received 14 February 2002; accepted 12 March 2002
Abstract—The diastereoselective synthesis of a-amino acids by radical addition to dehydroalanine derivatives of pantolactone
using the stannane method both in the presence and absence of Lewis acid catalysts is reported. The absolute configuration of the
newly-generated stereogenic center is highly dependent on the nature of the added radical. Acid hydrolysis afforded the amino
acids with excellent yields and without racemization. This approach constitutes a novel method for the asymmetric synthesis of
a-amino acids by a radical pathway. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
stannane method, indicating the Re attack of tributyltin
hydride on the intermediate radical. However, the
preparation of the chiral substrate is long and tedious.
Chai5 demonstrated that addition to chiral
methylenepiperazine-2,5-diones using the organomer-
cury method produces only the disubstituted cis-iso-
mer, but with low yields of 46–49%.
The purpose of this study was to develop a method for
the synthesis of unnatural a-amino acids by radical
addition to a,b-dehydroamino acids in homogeneous
phase. The use of free radicals to create CꢀC bonds has
aroused considerable interest in this area.1 Conjugate
addition to a,b-unsaturated systems is a fundamental
process in organic chemistry, and chiral auxiliary-con-
trolled diastereoselective synthesis based on free-radical
additions is emerging as an important route to enan-
tiomerically enriched compounds. However, little has
been done concerning the diastereoselective conjugate
addition of radicals to acyclic systems in solution.2 In
connection with this, we present herein the results that
we have obtained on radical additions to dehydroala-
nine derivatives of pantolactone.
Beckwith6 realized an enantioselective synthesis of C-
glycosyl amino acids (yields: 67–88%) by radical addi-
tion of glycosyl halides to (2R)-4-methyleneoxa-
zolidin-5-one (d.e.: 100%). The high stereoselectivity of
this addition is due to the double asymmetric induction
induced by the chiral auxiliary and anomeric stereoelec-
tronic control7 from the carbohydrate radical. It was
also found that when the reaction was performed using
the stannane method, the best diastereoisomeric
excesses were obtained, whereas the organomercury
method provided the best yields.
One advantage of addition to dehydroamino acids is
the possibility of adding a sterically hindered alkyl or
carbohydrate radical to generate non-proteogenic a-
amino acids or glycosyl a-amino acids, respectively.
Research into radical additions to chiral dehydroamino
acids were originally initiated by Crich.3
Pyne’s8 original approach for preparing optically active
homoserine derivatives has been achieved via photoin-
duced radical additions of alcohols and ethers to the
chiral 4-methyleneoxazolidin-5-ones. These reactions
proceed with moderate yields (17–48%) and low to
excellent diastereoselectivities (d.e.: 10–96%), but the
photoadducts are prone to epimerization and fail to
release the desired amino acids.
Diastereoselective radical addition (d.e.: 40–92%) to a
chiral nickel(II) complex of a Schiff base derivative of
dehydroalanine was achieved by Belokon4 using the
Chiral oxazolidinones prepared from lactamide and
2-bromobenzaldehyde followed by N-alkylation with
* Corresponding author. E-mail: yvidal@univ-montp2.fr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00135-0

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A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
ethyl bromoacetate and ethyl 2-propionate are suitable
for the generation of glycinyl and alaninyl radicals. The
control of the stereochemistry proceeds via a 1,5-hydro-
gen atom transfer mechanism, and in this work
Renaud9 brilliantly introduced the innovative notion of
the PRT (protecting-radical translocating group) where
the protecting group plays both the role of a radical
precursor and a secondary source of chirality. Allyl-
ation of these oxazolidinones proceeds with satisfactory
yields (59–85%) and diastereoselectivities (d.e.: 32–
96%).
Lewis acids in radical additions to dehydroamino
esters.
The N-phthaloyl dehydroalanine (R)-pantolactonyl
ester 3 was easily prepared in two steps from DL-serine.
A
mixture of DL-serine, phthalic anhydride and
triethylamine18 heated in refluxing toluene with
azeotropic elimination of water yielded a mixture of
N-phthaloyl serine 1 (16%) and N-phthaloyl dehy-
droalanine 2 (50%). Esterification of the mixture of 1
and 2 with (R)-pantolactone using DCC/DMAP pro-
duced the desired product 3 (61%). During the esterifi-
cation step, spontaneous dehydration of 2 into 3
occurred (Scheme 1).
Furthermore Naito10 demonstrated that it is also possi-
ble to realize highly diastereoselective syntheses of a-
amino acids by radical addition to the Oppolzer’s
camphor sultam derivative of glyoxylic oxime ether.
High chemical yields (57–86%) and diastereoselectivities
(80–96%) were observed in the presence of Lewis acids.
Reductive cleavage releases the enantiomerically pure
a-amino acid of (R)-configuration.
In a typical experiment, a solution of the chiral dehy-
droamino acid 3, Bu3SnH and AIBN in benzene was
slowly added (90 min) to a refluxing solution of the
alkyl halide or glycosyl halide, following the conditions
of Vogel and co-workers,19 according to Scheme 1.
After disappearance of the starting material as shown
by TLC analysis (1–4 h), chromatography of the crude
product, free from organotin residues after treatment
with acetonitrile/hexane, yielded a mixture of the
diastereoisomeric adducts 5a–c and 6a–c.
The results of these investigations showed that the
diastereoselectivity of the reaction depends both on the
nature of the nitrogen protecting group and the hydro-
gen atom transfer to the a-carbon-centered intermedi-
ate radical. The use of sterically hindered secondary or
tertiary halides is generally recommended to improve
both yields and diastereoisomeric excesses.
The compounds 5a,6a, 5b,6b and 5c,6c, resulting from
addition of tert-butyl iodide 11, cyclohexyl iodide 12
and 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide
13 (TA-glc-Br) onto N-phthaloyl dehydroalanine (R)-
pantolactonyl ester 3, respectively, were isolated as
colorless powders in 54–60% yields (Table 1; entries
1–3). In all cases, the mixtures of these diastereoisomers
were separated, but only by analytical HPLC on a
chiral reverse-phase column, as the usual methods
failed.
2. Results and discussion
We studied the stereoselective radical addition to the
chiral N-phthaloyl dehydroalanine pantolactonyl ester
using the stannane method, both in the presence and
absence of Lewis acid catalysts, with a view to its
development as a possible synthesis of a-amino acids.
Spectral and chemical analysis of the compounds
1
enabled their structural characterization. COSY H/1H
The N-phthaloyl group was selected because of its
strong electron-withdrawing properties, which counter-
balance the deactivating effects of the amino group.
This was shown by Renaud11 in the addition of the
tert-butyl radical to benzyl 2-N-phthaloyl-2-butenoate
which gave a 41% yield of a 2.3:1 mixture of anti:syn
isomers. The stereoselectivity of the reaction could be
explained by the effect of 1,3-allylic strain.12 The 1,3-
allylic strain model is in complete accordance with the
pioneering ESR experiments on ester-substituted radi-
cals of Giese,13 who showed that allylic strain effects
are responsible for the 1,2-stereoinduction in acyclic
radicals, where the attack of the entering radical on the
preferred conformation of the a-prochiral radical center
occurs anti to the more sterically hindered group.
1
and H/13C correlation experiments were required for
the assignments of the protons and the carbons in the
adducts. Diastereoisomeric excesses were determined
via the 250 MHz 1H NMR spectrum (C6D6) of the
crude products (Table 1). For 5a,6a (R: tert-Bu), the
integration of the tert-Bu singlet found at 0.95 ppm for
the major diastereoisomer was compared to the signal
of the minor diastereoisomer at 1.00 ppm, and gave a
ratio of 78:22 (entry 1). Integration of the protons of
the pantolactonyl moiety for 5b,6b and 5c,6c resulted in
a ratio major/minor of 68:32 with cyclohexyl iodide 12
and only of 52:48 in the case of glycosyl bromide 13,
respectively (entries 2 and 3).
To confirm the hypothesis of a mismatched addition in
this last reaction, where the configuration of the chiral
auxiliary of the (R)-pantolactone was counterbalanced
by the induction from the carbohydrate radical, we
carried out the radical addition of 13 to N-phthaloyl
dehydroalanine (S)-pantolactonyl ester 4, using the
same protocol as for 3, but from DL-serine and (S)-pan-
tolactone (60% yield). The yields of the radical addition
to 4 (63%) and 3 were comparable (60%), in contrast
the ratio was successfully improved to 78:22, as
expected (entries 3 and 4).
The pantolactonyl group was chosen since Helmchen14
demonstrated that Lewis acids such as TiCl4 induce a
stable bidentate coordination complex with panto-
lactonyl acrylate, which amplifies diastereofacial dis-
crimination in pericyclic reactions. By analogy to these
reactions, it is expected that Lewis acids will strongly
influence the outcome of radical reactions, both in their
reactivity as well as their stereoselectivity.15–17 These
results guided our approach to study the effects of

A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
505
Scheme 1. Reagents and conditions: (i) phthalic anhydride, Et3N, toluene, 5 h/D; (ii) (R)- or (S)-2-hydroxy-3,3-dimethyl-g-butyro-
lactone (pantolactone), DCC/DMAP, CH2Cl2, 15 h, rt; (iiia) RX (tert-BuI 11, c-C6H11I 12, TA-glc-Br 13), Bu3SnH, AIBN, C6H6,
1–4 h, 80°C; (iiib) RX (tert-BuI 11), Bu3SnH (2.0 equiv.), Et3B (2.0 equiv.), CH2Cl2/THF (4/1), 5.5 h, −78 to −20°C; Lewis acids
(1.1–2.1 equiv.): TiCl4, Sm(OTf)3, MgI2·Et2O; (iv) HCl (6 M)/glacial acetic acid, 5 h/D.
Table 1. Radical additions to dehydroalanine derivatives of pantolactone
Entry
Substrate
RX
Lewis acids (equiv.)
Yield of the diastereoisomers (%)
Maj./min.c
1a
2a
3a
4a
5b
6b
7b
8b
3
3
3
4
3
3
3
3
11
12
13
13
11
11
11
11
–
–
–
–
5a,6a (54)
5b,6b (60)
5c,6c (60)
7c,8c (63)
5a,6a (65)
5a,6a (71)
5a,6a (70)
5a,6a (48)
78:22
68:32
52:48
78:22
68:32
75:25
83:17
79:21
TiCl4 (2.2)
TiCl4 (1.1)
Sm(OTf)3 (1.1)
MgI2·Et2O (1.1)
a See (iiia) and (iiib) in Scheme 1.
b See (iiia) and (iiib) in Scheme 1.
c Determined by 1H NMR (250 MHz).
diastereoisomer (Table 2). Enantiomeric excesses mea-
sured agreed with diastereoisomeric excesses established
by NMR before deprotection.
Next, to determine the configuration of the predomi-
nant newly-generated stereogenic center, we simulta-
neously deprotected the amino and acid functions.
Non-racemizing acid hydrolysis20 of compounds 5a,6a
and 5b,6b in refluxing HCl/glacial acetic acid quantita-
tively released the mixtures of enantiomers 9a,10a and
9b,10b in 90 and 86% yields, respectively. The
hydrochlorides 9a,10a were converted into amino acids
9a%,10a% using propylene oxide. Comparison of the spe-
cific rotation of the product mixture to the value for the
pure enantiomer from the literature, allowed the deduc-
tion of the configuration of the predominant product
enantiomer and thereby the corresponding predominant
Surprisingly, the additions with tert-butyl iodide and
cyclohexyl iodide led to opposite configurations of the
major isomers, (S) and (R), respectively. It appeared
that the radical hydrogen is added to the conformation
which minimized 1,3-allylic strain effects12 of the first
radical obtained by addition of the alkyl group. This
particular conformation was dependent upon the bulki-
ness of the alkyl group introduced and was different for
the cyclohexyl and tert-butyl groups.

506
A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
Table 2. Deprotected amino acids
Entry
RX
Yield (%)
[h]2D0 lit.
[h]2D0 exp.
Configuration of the major
enantiomer
Enantiomers
Diastereoisomers
Maj./min.a
Maj./min.b
1
2
tert-BuI
c-C6H11
9a%,10a%
(90)
9b,10b
(86)
(S): −12.621
(R): −1122
−5.0
−3.8
(S)
(R)
10a%:9a%
70:30
9b:10b
68:32
6a:5a
78:22
5b:6b
68:32
I
a Enantiomeric excesses determined by measurement of the specific rotation, [h]2D0
.
b Diastereoisomeric excesses determined by 1H NMR (250 MHz).
Hydrolysis of the diastereoisomers 5c,6c and 7c,8c
resulting from the addition of carbohydrate radical
were not performed because of the thermal sensitivity
of these compounds, and therefore the configurations
of the major diastereoisomers were not established.
used as received. Thin-layer chromatography was car-
ried out on silica gel 60 F254 Merck aluminum sheets.
Column chromatography was performed using silica gel
Geduran Si 60 (0.63–0.200 mm) supplied by Merck.
Capillary melting points were determined with an Elec-
1
trothermal 9200 apparatus and are uncorrected. H and
Lewis acids were then used in an attempt to increase
the diastereoselectivity in these radical additions.
Among the variety of Lewis acids evaluated: titanium
tetrachloride (TiCl4), samarium triflate (Sm(OTf)3) and
magnesium iodide–diethylether (MgI2·Et2O), which
have been reported to give the best results,16,25 were
preferred.
13C NMR spectra were recorded on Bruker AC-250 or
AC-400 machines. Data are reported as follow: chemi-
cal shifts (l) in ppm with respect to TMS, multiplicity
(s: singlet, d: doublet, t: triplet, m: multiplet, br: broad),
coupling constants (J) in Hz. Diastereoisomeric
excesses were determined on the crude products. IR
spectra were recorded with a Perkin–Elmer paragon
1000. Optical rotations were measured for the sodium
D line (589 nm) at 20°C with a Perkin–Elmer 141
polarimeter. Mass spectra were recorded on a SX 102
or DX 3200 type spectrometer (JEOL). The matrices
used were glycerol or meta-nitrobenzyl alcohol.
Reverse-phase analytical and preparative HPLC was
carried out with a Nucleosil C18 column; HPLC: (fast
gradient H2O/ACN (CH3CN): 10–100% ACN in 30
min), (Nucleosil column 5 C 18; 250×4.6 mm; flow: 1
mL/min, T column: 30°C). Reverse phase chiral analyt-
ical HPLC was carried out with a Nucleosil C18
column (column Chiracel OD, 250×4.6 mm, flow: 1
mL/min, detector 484 Waters, u=214 nm, hexane/iso-
propanol). A flow rate of 1 mL/min of the solvent,
using ACN/H2O/TFA as eluent, was applied with a
Waters Associates pump (Model 510). Elemental analy-
ses were performed by the Service Central d’Analyse,
De´partement Analyse Ele´mentaire de Vernaison
(CNRS-Lyon).
In a standard procedure,26 tert-butyl iodide, tributyltin
hydride and triethylboron were successively added to a
solution containing the chiral dehydroamino ester 3
and a Lewis acid, at low temperature and under a
saturated atmosphere of oxygen (Scheme 1). In this
reaction, the tandem triethylboron/oxygen plays acts as
the radical initiator.23,24 After purification of the
residue, the diastereoisomers 5a,6a were isolated with
acceptable yields (48–71%; Table 1, entries 5–8).
Moderate increases in the yields (54–71%; Table 1,
entries 1 and 6) and diastereoselectivities (78:22–83:17;
entries 1 and 7) were observed. Furthermore, these
results suggested, that it was preferable to use 1.1 equiv.
instead of 2.2 equiv. of Lewis acid for optimization of
the reaction conditions (entries 5 and 6). Moreover, we
can report that the best result was obtained in the
presence of Sm(OTf3) (yield: 70%; ratio: 83:17).
3. Conclusion
4.1. Preparation of N-phthaloyl serine 1 and N-
In conclusion, Lewis acid-catalyzed diastereoselective
radical additions onto dehydroamino acid pantolac-
tonic esters were carried out and gave satisfactory
diastereoisomeric excesses. The absolute configuration
of the predominant product isomer depended greatly
on the nature of the entering alkyl radical. Acid hydrol-
ysis released the amino acids in high yields and without
racemization.
phthaloyl dehydroalanine 2
A mixture of DL-serine (5 g, 47.61 mmol), phthalic
anhydride (7 g, 47.29 mmol) and triethylamine (0.7 mL)
in toluene (250 mL) was heated under reflux under
nitrogen atmosphere for 4 h with azeotropic elimination
of water with a Dean–Stark apparatus.18 After removal
of the solvent under reduced pressure, ethyl acetate was
added and the organic phase was washed with dilute
HCl (1 M) to eliminate the unreacted serine, then dried
over MgSO4 and filtered and concentrated to give a
yellow oil. This oil was purified by column chromatog-
raphy and the elution with petroleum ether/EtOAc
(7/3) afforded N-phthaloyl serine 1 and N-phthaloyl
dehydroalanine 2 as colorless powders.
4. Experimental
Solvents were purified in the usual way. Pantolactone
was purchased from Fluka Chemical Co. All other
chemicals were commercially pure compounds and were

A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
507
4.2. N-Phthaloyl serine 1
4.6. N-Phthaloyl dehydroalanine (S)-pantolactonyl ester
4
1.78 g (colorless powder); 16% yield; Rf=0.1 (CH2Cl2/
EtOAc: 1/1+m AcOH); mp 70–72°C; MS (FAB): [M+
H]+=236; HPLC (isocratic, H2O/ACN: 52/48) tR=9.47
Following the general procedure, from N-phthaloyl
dehydroalanine 2 (1.51 g, 6.96 mmol), 4 (1.37 g, 60%
yield) was obtained as a colorless solid; Rf=0.54
(petroleum ether/EtOAc: 5/5); mp 122°C (EtOAc/
CH2Cl2: 5/5); MS (FAB): [M+H]+=330; HRMS (FAB)
calcd for C17H16NO6 [M+H]+=330.0978, found:
330.1024; [h]2D0=+20 (c=1; CHCl3); HPLC (isocratic,
H2O/ACN: 55/45) tR=13.51 min; IR (KBr) w (cm−1):
1793 (CꢁO, lactone), 1739 (CꢁO, imide), 1726 (CꢁO,
ester),1637 (CꢁC); 1H NMR (250 MHz, CDCl3) l
(ppm): 1.10 (s, 3H, Me); 1.27 (s, 3H, Me); 4.05 (s, 2H,
Hb+Hb%); 5.45 (s, 1H, Ha); 6.13 (d, Jbb%=0.8 Hz, 1H,
Hb); 6.78 (d, Jbb%=0.8 Hz, 1H, Hb%); 7.79–7.94 (m, 4H,
ArH); 13C NMR (100 MHz, CDCl3) l (ppm): 20.21,
23.40, 41.04, 76.47, 76.63, 124.12, 124.22, 128.47,
129.49, 132.08, 134.81, 135.10, 161.75, 166.55, 171.99.
1
min; H NMR (250 MHz, CDCl3) l (ppm): 4.90 (dd,
J=11.6 Hz, J=9.2 Hz, 1H, Hb); 5.14 (dd, J=11.6 Hz,
J=4.7 Hz, 2H, Hb%); 5.38 (dd, J=9.2 Hz, J=4.7 Hz,
1H, Ha); 7.72 (m, 2H, ArH); 7.86 (m, 2H, ArH); 8.05
(br s, 1H, OH).
4.3. N-Phthaloyl dehydroalanine 2
5.13 g (colorless powder); 50% yield; Rf=0.26 (CH2Cl2/
EtOAc: 1/1+ m AcOH); mp 74–75°C (EtOAc); MS
(FAB): [M+H]+=218; HPLC (isocratic, H2O/ACN: 52/
48) tR=8.47 min; IR (KBr) w (cm−1): 1739 (CꢁO,
1
imide), 1712 (CꢁO, acid); H NMR (250 MHz, CDCl3)
l (ppm): 6.03 (s, 1H, CꢁC-H); 6.74 (s, 1H, CꢁC-H);
7.70 (m, 2H, ArH); 7.81 (m, 2H, ArH); 8.60 (br s, 1H,
CO2H). Anal. calcd for C11H17NO4 (217): C, 60.80; H,
3.28; N, 6.44; O, 29.47; found: C, 60.63; H, 3.43; N,
6.37; O, 29.45.
4.7. Radical addition onto N-phthaloyl dehydroalanine
(R)- and (S)-pantolactonyl esters 3 and 4: general
procedure
A 0.5 M solution of alkyl iodide 11 or 12 (1.50 mmol)
or 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide
4.4. Preparation of N-phthaloyl dehydroalanine (R)- or
(S)-pantolactonyl esters 3 or 4: general procedure
13 (1.50 mmol) in anhydrous benzene was heated under
reflux. Chiral dehydroamino ester 3 or 4 (0.75 mmol),
Bu3SnH (0.97 mmol) and AIBN (0.06 mmol) in anhy-
drous benzene (5 mL) was added through an automatic
syringe in 90 min.19 The mixture was then heated under
reflux for between 1 and 4 h and allowed to cool to
20°C. The solvent was evaporated under vacuum. The
residue was dissolved in acetonitrile (10 mL) and
washed with hexane (5×5 mL). The acetonitrile phase
was dried over MgSO4, filtered and concentrated under
vacuum. The crude product was purified by column
chromatography and the elution with petroleum ether/
EtOAc (8/2) afforded a mixture of two diastereoisomers
5a–c, 6a–c or 7c,8c which were separated on an analyt-
ical HPLC equipped with a chiral reverse-phase column
(column Chirasphere Merck, 25 cm×4 mn, flow: 1
mL/min, hexane/isopropanol: 85/15).
To a mixture of N-phthaloyl dehydroalanine 2 (1
mmol), (R)- or (S)-pantolactone (1.1 mmol) and 4-
dimethylaminopyridine (0.1 mmol) in CH2Cl2 (6 mL)
was added dicyclohexylcarbodiimide (1.2 mmol) at 0°C.
The mixture was stirred at room temperature for 12 h.
Dicyclohexylurea was removed by filtration and the
solution was concentrated under vacuum. The residue
was diluted into ethyl acetate (5 mL) and allowed to
stand for 1 h at −15°C and again, the remaining
dicyclohexylurea was filtered off. The solution was
dried over MgSO4 and evaporated under vacuum. The
crude oil was purified by column chromatography
(petroleum ether/EtOAc: 7/3).
4.5. N-Phthaloyl dehydroalanine (R)-pantolactonyl
ester 3
4.8. N-Phthaloyl (R)- and (S)-g-methylleucine (R)-pan-
tolactonyl esters 5a,6a
Following the general procedure, from N-phthaloyl
dehydroalanine 2 (4.06 g, 18.7 mmol), 3 (3.74 g, 61%
yield) was obtained as a colorless solid; Rf=0.54
(petroleum ether/EtOAc: 5/5); mp 122°C (EtOAc/
CH2Cl2: 5/5); MS (FAB): [M+H]+=330; [h]D20=−20
(c=1, CHCl3); HPLC (isocratic, H2O/ACN: 52/48)
tR=21.64 min; IR (KBr) w (cm−1): 1793 (CꢁO, lactone),
Following the general procedure (t=1 h), from N-
phthaloyl dehydroalanine (R)-pantolactonyl ester 3
(250 mg, 0.75 mmol), a mixture of 5a,6a (157 mg, 54%
yield) was obtained as a colorless solid; Rf=0.60
(petroleum ether/EtOAc: 6/4); mp 144°C (benzene/hep-
tane: 1/9); MS (FAB): [M+H]+=388; HRMS (FAB)
calcd for C21H26NO6 [M+H]+=388,1760, found:
388,1777; chiral HPLC (isocratic, hexane/iPrOH: 85/15)
1
1739 (CꢁO, imide), 1726 (CꢁO, ester), 1638 (CꢁC); H
NMR (250 MHz, CDCl3) l (ppm): 1.05 (s, 3H, Me);
1.21 (s, 3H, Me); 4.01 (s, 2H, Hb+Hb%); 5.40 (s, 1H, Ha);
6.08 (d, Jbb%=0.8 Hz, 1H, Hb); 6.72 (d, Jbb%=0.8 Hz,
1H, Hb%); 7.75–7.88 (m, 4H, ArH); 13C NMR (100
MHz, CDCl3) l (ppm): 19.92, 23.05, 40.96, 76.86,
77.04, 124.05, 128.43, 129.56, 132.30, 134.47, 161.71,
166.51, 171.99. Anal. calcd for C17H15NO6 (329): C,
62.00; H, 4.59; N, 4.25; O, 29.15; found: C, 62.00; H,
4.41; N, 4.12; O, 29.47%.
t
R1=10.88 min, tR2=13.83 min; IR (KBr) w (cm−1):
1788 (CꢁO, lactone), 1759 (CꢁO, imide), 1712 (CꢁO,
ester); H NMR (250 MHz, C6D6) l (ppm): 0.6 (s, 3H,
1
Me min.); 0.65 (s, 3H, Me maj.); 0.70 (s, 3H, Me min.);
0.95 (s, 9H, tert-Bu maj.); 1.00 (s, 9H, tert-Bu min.);
2.55–2.70 (m, Jbb%=7.5 Hz maj., Jbb%=7.0 Hz min.,
Jab=3.8 Hz, 4H, Hb+Hb% maj. and Hb+Hb% min.); 2.90–
3.11 (AB syst., Jbb%=8.9 Hz, 2H, Hb+Hb% maj.); 2.92–

508
A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
3.15 (AB syst., Jbb%=8.7 Hz, 2H, Hb+Hb% min.); 5.11 (s,
1H, Ha min.); 5.26 (s, 1H, Ha maj.); 5.51 (dd, Jab=8.8
Hz, Jab%=3.8 Hz, 2H, Ha maj.+ Ha min.); 6.87 (m, 2H,
ArH min.); 6.92 (m, 2H, ArH maj.); 7.56 (m, 2H, ArH
maj.); 7.66 (m, 2H, ArH min.); 13C NMR (100 MHz,
C6D6) l (ppm): 19.91, 20.23, 23.44, 23.05, 29.53, 29.58,
30.78, 30.82, 41.62, 42.02, 49.62, 49.93, 76.43, 76.45,
76.52, 76.70, 123.97, 132.06, 132.15, 134.65, 134.78,
167.94, 169.06, 171.80. Anal. calcd for C21H25NO6
(387): C, 65.17; H, 6.51; N, 3.51; O, 24.81; found: C,
64.93; H, 6.56; N, 3.97; O, 24.54%.
1H NMR (250 MHz, C6D6) l (ppm): 0.40 (s, 6H, 2Me,
Me maj.+Me min.); 0.55 (s, 3H, Me min.); 0.66 (s, 3H,
Me maj.); 1.71 (s, 6H, OAc maj.+OAc min.); 1.76 (s,
6H, OAc maj.+OAc min.); 1.78 (s, 6H, OAc maj.+OAc
min.); 1.99 (s, 6H, OAc maj.+OAc min.); 3.10 (AB
syst., Jbb%=8.8 Hz, 4H, Hb+Hb% maj. and Hb+Hb% min.);
3.01–3.22 (m, Jbb%=15.7 Hz; Jab%=11.4 Hz; Jab=3.4 Hz,
4H, Hb+Hb% maj. and Hb+Hb% min.); 3.86–3.92 (m,
J4-5=9.1 Hz, J5-6%=5.1 Hz, J5-6=2.4 Hz, 2H, H5 maj.+
H5 min.); 4.20 (dd, J6-6%=12.2 Hz, J5-6=2.4 Hz, 2H, H6
maj.+H6 min.); 4.42–4.48 (m, J1-2=5.7 Hz, 2H, H1
maj.+H1 min.); 4.50 (dd, J6-6%=12.2 Hz, J5-6%=5.1 Hz,
2H, H6% maj.+H6% min.); 5.25 (s, 2H, Ha maj.+Ha min.);
5.30 (dd, J2-3=9.0 Hz; J1-2=5.7 Hz, 2H, H2 maj.+H2
min.); 5.31 (t, J4–5=9.1 Hz; J3–4=9.0 Hz, 2H, H4
maj.+H4 min.); 5.61 (dd, Jab%=11.4 Hz; Jab=3.4 Hz,
2H, Ha maj.+Ha min.); 5.73 (t, J2-3=J3-4= 9.0 Hz, 2H,
H3 maj.+H3 min.); 6.90 (m, 2H, ArH); 7.48 (m, 2H,
ArH); 13C NMR (100 MHz, C6D6): 17.81, 18.03, 18.61,
18.68, 18.75, 18.81, 18.86, 19.03, 19.73, 20.63, 21.03,
23.78, 47.17, 60.69, 67.32, 67.65, 68.67, 68.87, 69.20,
73.66,75.25, 122.12, 122.16, 130.51, 130.83, 132.57,
132.74, 166.19, 167.58, 167.78, 167.83, 167.97, 168.09,
168.17, 168.52, 165.98, 168.80, 1693. Anal. calcd for
C31H35NO15 (661): C, 56.28; H, 5.29; N, 2.92; O, 35.05;
found: C, 56.28; H, 5.29; N, 2.13; O, 36.30%.
4.9. N-Phthaloyl (R)- and (S)-cyclohexylalanine (R)-
pantolactonyl esters 5b,6b
Following the general procedure (t=1 h), from N-
phthaloyl dehydroalanine (R)-pantolactonyl ester 3
(250 mg, 0.75 mmol), a mixture of 5b,6b (182 mg, 59%
yield) was obtained as a colorless solid; Rf=0.67
(petroleum ether/EtOAc: 6/4); mp 61°C (benzene/hep-
tane: 1/9); MS (FAB): [M+H]+=414; HRMS (FAB)
calcd for C23H28NO6 [M+H]+=414.1917, found:
414.1866; chiral HPLC (isocratic, hexane/iPrOH: 85/15)
t
R1=11.78 min, tR2=13.95 min; IR (KBr) w (cm−1):
1792 (CꢁO, lactone), 1730 (CꢁO, imide), 1717 (CꢁO,
ester); 1H NMR (250 MHz, C6D6) l (ppm): 0.62 (s, 3H,
Me maj.); 0.73 (s, 3H, Me maj.); 0.79 (s, 3H, Me min.);
0.86 (s, 3H, Me min.); 0.90–1.20 (m, 12H, Chx maj.+
Chx min.); 1.30–1.50 (m, 2H, Hg maj.+Hg min.); 1.50–
1.75 (m, 8H, Chx maj.+ Chx min.); 2.26–2.36 (ddd,
Jbb%=14.2 Hz, Jbg=9.5 Hz, Jab=4.8 Hz, 1H, Hb min);
2.36–2.45 (ddd, Jbb%=14.9 Hz, Jbg=9.5 Hz, Jab=4.8
Hz, 1H, Hb maj.); 2.55–2.66 (m, 2H, Hb% maj.+Hb%
min.); 3.09 (d, Jbb%=8.8 Hz, 1H, Hb min.); 3.11 (d,
Jbb%=8.8 Hz, Hb maj.); 3.20 (d, Jbb%=8.8 Hz, 1H, Hb%
maj.); 3.30 (d, Jbb%=8.8 Hz, 1H, Hb% min.); 5.21 (s, 1H,
Ha maj.); 5.33 (s, 1H, Ha min.); 5.49 (dd, Jab=10.6 Hz,
Jab%=4.8 Hz, 1H, Ha maj.); 5.50 (dd, Jab=11.0 Hz,
Jab%=4.8 Hz, 1H, Ha min.); 6.90 (m, 2H, ArH min.);
6.93 (m, 2H, ArH maj.); 7.54 (m, 2H, ArH maj.); 7.55
(m, 2H, ArH min.); 13C NMR (100 MHz, C6D6) l
(ppm):19.47, 19.70, 22.27, 22.66, 26.36, 26.74, 26.57,
26.59, 32.14, 32.18, 33.88, 34.01, 34.86, 34.98, 36.73,
37.01, 39.86, 40.28, 50.38, 50.60, 75.26, 76.34, 76.65,
123.57, 123.63, 132.25, 132.33, 134.08, 134.23, 167.80,
167.91, 169.48, 167.91, 171.22, 171.28. Anal. calcd for
C23H27NO6 (413): C, 66.81; H, 6.58; N, 3.38; O, 23.21;
found: C, 66.95; H, 6.60; N, 3.51; O, 22.94%.
4.11. (2R)- and (2S)-(S)-Pantolactonyl 2-N-phthaloyl-
3-(2,3,4,6-tetra-O-acetyl)-a-D-glucopyranosyl
propanoate 7c,8c
Following the general procedure (t=4 h), from N-
phthaloyl dehydroalanine (S)-pantolactonyl ester 4
(250 mg, 0.75 mmol), a mixture of 7c,8c (312 mg, 63%
yield) was obtained as a colorless solid; Rf=0.10
(petroleum ether/EtOAc: 5/5); mp 92°C (petroleum
ether); MS (FAB): [M+H]+=662; HRMS (FAB) calcd
for C31H36NO15 [M+H]+=662.2085, found: 662.2033;
chiral HPLC (isocratic, hexane/iPrOH: 15/85) tR1=7.61
min, tR2=20.65 min; IR (KBr) w (cm−1): 1794 (CꢁO,
lactone), 1752 (CꢁO, imide), 1721 (CꢁO, ester); 1H
NMR (250 MHz, C6D6) l (ppm): 0.71 (s, 3H, Me); 0.76
(s, 3H, Me); 1.77 (s, 3H, OAc); 1.79 (s, 6H, 2OAc); 1.99
(s, 3H, OAc); 3.16 (ddd, J=7.0 Hz, J=4.1 Hz, J=12.1
Hz, 1H, Hb); 3.18 (AB syst., J=8.9 Hz, 2H, Hb+Hb%);
3.25 (ddd, J=12.1 Hz, J=11.4 Hz, J=7.3 Hz, 1H,
Hb%); 4.09 (ddd, J=8.6 Hz, J=5.2 Hz, J=2.6 Hz, 1H,
H5); 4.24 (dd, J=12.1 Hz, J=2.6 Hz, 1H, H6); 4.47
(dd, J=12.1 Hz, J=5.2 Hz, 1H, H6%); 4.42–4.51 (m, 1H,
H1); 5.17 (s, 1H, Ha); 5.30 (t, 1H, H4, J=8.8 Hz); 5.32
(dd, J=5.7 Hz, J=8.8 Hz, 1H, H2); 5.66 (dd, J=11.4
Hz, J=4.0 Hz, 1H, Ha); 5.74 (t, J=8.8 Hz, 1H, H3);
6.94 (m, 2H, ArH); 7.53 (m, 2H, ArH); 13C NMR (100
MHz, C6D6): 19.57, 20.25, 20.37, 20.41, 20.57, 22.47,
25.36, 40.02, 49.02, 62.56, 68.96, 69.30, 70.40, 70.70,
70.94, 75.39, 76.94, 123.78, 132.40, 134.28, 168.04,
169.05, 169.60, 169.68, 169.95, 170.81, 171.28.
4.10. (2R)- and (2S)-(R)-Pantolactonyl 2-N-phthaloyl-
3-(2,3,4,6-tetra-O-acetyl)-a-D-glucopyranosyl
propanoate 5c,6c
Following the general procedure (t=4 h), from N-
phthaloyl dehydroalanine (R)-pantolactonyl ester 3
(250 mg, 0.75 mmol), a mixture of 5c,6c (298 mg, 60%
yield) was obtained as a colorless solid; Rf=0.10
(petroleum ether/EtOAc: 5/5); mp 95–97°C (petroleum
ether); MS (FAB): [M+H]+=662; HRMS (FAB) calcd
for C31H36NO15 [M+H]+=662.2085, found: 662.2033;
4.12. Hydrolysis of N-phthaloyl pantolactonyl esters
5a,6a or 5b,6b: general procedure
chiral HPLC (isocratic, hexane/iPrOH: 85/15) tR1
=
16.89 min, tR2=20.65 min; IR (KBr) w (cm−1): 1782
(CꢁO, lactone), 1743 (CꢁO, imide), 1723 (CꢁO, ester);
A mixture of N-phthaloyl pantolactonyl esters 5a,6a or
5b,6b (0.5 mmol), acetic acid (1.4 mL) and 6 M aqueous

A.-M. Yim et al. / Tetrahedron: Asymmetry 13 (2002) 503–510
509
HCl solution (14 mL) was heated under reflux until
4.16. Radical addition of tert-butyl iodide to N-
completion of the hydrolysis20 (6 h). The reaction was
monitored by TLC (hexane/EtOAc 5/5). The solution
was allowed to cool to room temperature and the
volatile products were eliminated under reduced pres-
sure. Water (15 mL) was added to the residue and
the aqueous phase was washed with EtOAc (3×15
mL). Evaporation under vacuum of the aqueous layer
gave the free amino acids as enantiomers 9a,10a or
9b,10b.
phthaloyl dehydroalanine (R)-pantolactonyl ester 3 cat-
alyzed by Lewis acids: general procedure
To a 0.04 M solution of 3 (250 mg, 0.75 mmol) in
CH2Cl2/THF (4/1) at −78°C under a blanket of oxy-
gen was added the Lewis acid† (1.1–2.2 equiv.). tert-
Butyl iodide (0.45 mL, 3.75 mmol), Bu3SnH (0.4 mL,
1.50 mmol) and triethylborane (1 M in hexane, 1.5
mL, 1.5 mmol) were successively added dropwise to
the solution.26 The reaction mixture was stirred at
−78°C for 5.5 h. After completion of the reaction, the
crude residue was diluted with Et2O (30 mL), washed
with 10% HCl (2×15 mL) and brine. The organic
layer was dried over MgSO4 and concentrated under
vacuum. The residue was purified by column chro-
matography (petroleum ether/EtOAc: 4/1) and gave a
mixture of the diastereoisomers 5a,6a (Table 1, entries
5–8) whose characteristics were previously given.
4.13. (S)- and (R)-g-Methylleucine hydrochlorides
9a,10a
Following the general procedure, from N-phthaloyl
pantolactonyl esters 5a,6a (427 mg, 1.10 mmol),
9a,10a (180 mg, 90% yield) were obtained as colorless
solids; mp (scalemic 70/30) >300°C (petroleum ether);
MS (ESI): [M+H]+=146; HPLC (fast gradient) tR=
4.11 min; IR (KBr) w (cm−1): 3348 (NH3 ); 3204–2636
+
1
(OH, acid); 1743 (CꢁO); H NMR (250 MHz, D2O) l
(ppm): 0.99 (s, 9H, tert-Bu); 1.68 (dd, J=14.9 Hz,
J=6.3 Hz, 1H, Hb); 2.20 (dd, J=14.9 Hz, J=5.3 Hz,
1H, Hb%); 4.41 (dd, J=6.3 Hz, J=5.3 Hz, 1H, Ha).
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