New C-glycosylated α-amino acid synthesis by addition reaction of an amino acid organozinc reagent on carbohydrate-derived aldehydes

Article abstract of DOI:10.1080/00397911.2010.540698

Two unreported C-glycosylated amino acid structures could be prepared by addition of an amino acid organozinc on carbohydrates bearing an aldehyde function. For this purpose, a new iodinated amino acid bearing a four-carbon side chain was conveniently prepared in two steps. Conversion into the corresponding organozinc reagent was optimal in acetonitrile using zinc/copper activated with 1,2-dibromoethane and trimethylsilyl chloride. A protocol was developed for the addition of this organozinc compound to simple aldehydes in acetonitrile using BF₃ · OEt₂ as a Lewis acid. When applied to riboside and glucoside aldehyde derivatives, this protocol led to new C-glycosylated amino acids in acceptable yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.540698

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New C-Glycosylated α-Amino Acid
Synthesis by Addition Reaction of an
Amino Acid Organozinc Reagent on
Carbohydrate-Derived Aldehydes
Nicolas Boutard a , Frédéric Labéguère a , Yves Vidal a , Jean-Pierre
Lavergne a & Jean Martinez a
a Institut des Biomolécules Max Mousseron, Université Montpellier
II , Montpellier , France
Accepted author version posted online: 17 Nov 2011.Published
online: 25 Jan 2012.
To cite this article: Nicolas Boutard , Frédéric Labéguère , Yves Vidal , Jean-Pierre Lavergne &
Jean Martinez (2012) New C-Glycosylated α-Amino Acid Synthesis by Addition Reaction of an Amino
Acid Organozinc Reagent on Carbohydrate-Derived Aldehydes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:10, 1461-1471,
DOI: 10.1080/00397911.2010.540698
To link to this article: http://dx.doi.org/10.1080/00397911.2010.540698
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Synthetic Communications1, 42: 1461–1471, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.540698
NEW C-GLYCOSYLATED a-AMINO ACID SYNTHESIS
BY ADDITION REACTION OF AN AMINO ACID
ORGANOZINC REAGENT ON CARBOHYDRATE-
DERIVED ALDEHYDES
´ ´
Nicolas Boutard, Frederic Labeguere, Yves Vidal,
Jean-Pierre Lavergne, and Jean Martinez
´
`
´
Institut des Biomolecules Max Mousseron, Universite Montpellier II,
Montpellier, France
´
GRAPHICAL ABSTRACT
Abstract Two unreported C-glycosylated amino acid structures could be prepared by
addition of an amino acid organozinc on carbohydrates bearing an aldehyde function.
For this purpose, a new iodinated amino acid bearing a four-carbon side chain was con-
veniently prepared in two steps. Conversion into the corresponding organozinc reagent
was optimal in acetonitrile using zinc/copper activated with 1,2-dibromoethane and tri-
methylsilyl chloride. A protocol was developed for the addition of this organozinc compound
to simple aldehydes in acetonitrile using BF3 ꢀ OEt2 as a Lewis acid. When applied to ribo-
side and glucoside aldehyde derivatives, this protocol led to new C-glycosylated amino acids
in acceptable yields.
Keywords Amino acid; C-glycosylated amino acid; organozinc
INTRODUCTION
Glycoproteins and glycopeptides are molecules bearing a carbohydrate and a
peptidic domain linked by glycosidic bonds. In most cases, those bonds are N-glyco-
sidic (through an asparagine residue) or O-glycosidic (through serine, threonine, or
tyrosine residues).[1] Glycoproteins are present in every living organisms and play
important roles in biological events such as intercellular communication, molecular
recognition, microbial virulence,[2] inflammation processes,[3] and immune
responses.[4] However, N- and O-glycosidic linkages are sensitive to enzymatic
Received November 1, 2010.
Address correspondence to Jean Martinez, Institut des Biomolecules Max Mousseron, UMR 5247,
´
´
Faculte de Pharmacie, 15 avenue Charles Flahault, B.P. 14 491 34 093, Montpellier cedex 5, France.
E-mail: jean.martinez@univ-montp1.fr
1461

1462
N. BOUTARD ET AL.
cleavages by glycosidases, or to acidic and basic media, complicating the synthesis
and biological evaluation of glycopeptidic drugs.
Over the past 20 years, increasing efforts have been involved in the synthesis of
amino acids linked by their a-carbon to carbohydrate units by carbon–carbon bonds,
either directly or through a carbon tether. Synthetic approaches used for the syn-
thesis of these compounds cover a wide range of carbon–carbon bond-forming meth-
odologies (phosphorus and sulfur ylide chemistry, use of metallated nucleophiles,
radical chemistry, Strecker reaction, Claisen rearrangement, Ramberg–Ba¨cklund
reaction, or palladium cross coupling) and have been extensively reviewed.[5] Those
more stable C-glycosylated amino acids could lead to drugs with improved pharma-
cokinetic properties.[6]
As part of our ongoing program on new C-glycosylated amino acid syntheses,
our group already showed that this type of compounds could be obtained by
addition of glycine enolates on sugars bearing a carbonyl group.[7] Our research
efforts led us to consider the possibility of installing a carbon tether between the
amino acid and the carbohydrate moieties. This could be achieved by addition of
a suitable carbanionic nucleophile equivalent, located at the end of the side chain
of an amino acid, on an electrophilic function, such as an aldehyde, localized on
the carbohydrate moiety (Scheme 1).
Protected lithiated alaninol prepared from serine has been shown to react on
electrophiles such as aldehydes and ketones to give addition products in good
yields.[8] However, this approach required subsequent deprotection and reoxidation
of the alcohol function to recover the amino acid functionality of the target com-
pounds. In spite of their low reactivity, organozinc reagents display a high selectivity,
especially in the presence of highly functionalized substrates.[9] Amino acid organo-
zinc compounds, prepared by zinc insertion reaction on amino esters iodinated on
their side chain, have been extensively studied by Jackson et al.[10] These reagents
could be synthesized and used with conservation of the carboxyl functionality. This
0
group reported a synthesis of C-glycosylated amino acids by conjugate SN2 reaction
of various zinc=copper reagents derived from amino acids on glucals bearing a leav-
ing group on position 3.[11] Stimulated by those results, we decided to explore the
unprecedented addition of amino acid organozinc reagents on aldehydes for its
application to C-glycosylated amino acid synthesis.
Scheme 1. Synthetic strategy.

C-GLYCOSYLATED a-AMINO ACID
1463
Scheme 2. Synthesis of amino acid organozinc 4.
We report herein a proof of concept study concerning the preparation of amino
acid organozinc reagent 4 (Scheme 2) and its subsequent ‘‘one-pot’’ addition on alde-
hydes, more particularly on riboside and glucoside derivatives bearing an aldehyde
function, leading to new C-glycosyl amino acid structures.
RESULTS AND DISCUSSION
To explore amino acid organozinc addition on aldehydes, we decided to use
tert-butyl 2-(dibenzylamino)-6-iodohexanoate 3 (Scheme 2) as a readily available
iodinated precursor. This previously unreported iodinated derivative was prepared
from tert-butyl bromoacetate 1 in a two step sequence consisting in reaction with
dibenzylamine[12] and alkylation of the resulting glycine derivative 2 with 1,4-diiodo-
butane after conversion into its lithium enolate with lithium diisopropylamide
(LDA, Scheme 2).[13] LDA was prepared in situ by reaction of diisopropylamine
and butyllithium. Better alkylation yields were obtained using butyllithium prepared
in diethyl ether instead of commercially available hexane solutions. The use of an
excess of 1,4-diiodobutane (4 equiv.) reduced the formation of the double substi-
tution by-product. Iodinated precursor 3 was obtained in good overall yield (88%)
and could be prepared on a large scale (up to 20 mmol). Attempts to use 1,3-diiodo-
propane or 1,2-diiodoethane to access shorter iodinated amino acid analogs were
unsuccessful. In the case of 1,3-diiodopropane, amine quaternarization occurred
instantaneously after alkylation, leading exclusively to the favored five-member cyc-
lic salt. Interestingly, such reaction was not observed on compound 3 even after
prolonged storage periods. The use of 1,2-diiodoethane invariably yielded mixtures
of unchanged starting material and vinylglycine arising from LDA-mediated elimin-
ation after alkylation. The use of longer linear diiodoalkanes (>C4) was not
considered because it would lead to compounds losing bio-isosterism with natural
N- and O-glycosylated amino acids.
Formation of the organozinc reagent 4 depended on the zinc activation
method[14] and the solvent employed. Different procedures for the activation of zinc
powder were first examined in dry tetrahydrofuran (THF) (Table 1) before the zinca-
tion reaction of compound 3 was performed at 40 ꢁC. The reaction was monitored by
liquid chromatography–mass spectroscopy (LC-MS) analysis of an aliquot hydro-
lyzed with D2O. Conversion was calculated as the ratio between starting iodinated
material and hydrolyzed product. The ratio of protonated versus deuterated
compound shown by MS analysis allowed us to evaluate the effective quantity of
organozinc compound in the reaction mixture.
The use of catalytic quantities of iodine crystals or 1,2-dibromoethane
(10 mol%) as activating agents failed to give the expected organozinc compound.

1464
N. BOUTARD ET AL.
Table 1. Influence of the zinc activation method and the solvent on the formation of organozinc reagent 4
Activation method of the zinc powder
Solvent
Time (h)
Conversion (%) to 4
I2
1,2-Dibromoethane
THF
THF
THF
15
15
15
15
15
4
0
0
Rieke Zinc
TMSCl
Zn=Cu
44
62
THF
THF
68
80
Zn=Cu þ ultrasound
THF
THF
1,2-Dibromoethane þ TMSCl
Zn=Cu þ 1,2-dibromoethane þ TMSCl
Zn=Cu þ 1,2-dibromoethane þ TMSCl
Zn=Cu þ 1,2-dibromoethane þ TMSCl
Zn=Cu þ 1,2-dibromoethane þ TMSCl
Zn=Cu þ 1,2-dibromoethane þ TMSCl
2.5
2
87
Quant.
0
THF
Et2O
15
2.25
1.5
1
Toluene=DMA 9=1
DMF
MeCN
Quant.
Quant.
Quant.
The use of commercial Rieke zinc[15] as a suspension in THF (Aldrich) was trouble-
some as it led to large amounts of the corresponding hydroxylated compound, pre-
sumably because of the presence of peroxides in the THF suspension. Activation
with TMSCl (0.06 equiv.) and Zn=Cu (prepared from zinc powder according to Sim-
mons and Smith[16]) led to 4 in respectively 62% and 68% conversion after 15 h.
When Zn=Cu couple was employed under ultrasound activation,[17] the reaction time
was dramatically reduced to 4 h with 80% conversion to 4. Knochel’s activation
method (TMSCl 0.06 equiv. þ 1,2-dibromoethane 0.22 equiv.)[18] on zinc powder
led to 4 in 87% conversion in 2.5 h. Combined with the use of Zn=Cu, the reaction
time was further decreased to 2 h. Use of diethyl ether with the optimized conditions
completely inhibited the reaction. A 9=1 toluene=dimethylacetamide (DMA) mix-
ture[19] gave results similar to THF. Finally, dimethylformamide (DMF) and MeCN
led quantitatively to 4 with respective reaction times of 1.5 h and 1 h.
Addition of organozinc 4 on aldehydes was first examined using cyclohexane
carbaldehyde as a simplified model for hexose substrates. In early attempts,
two transmetalation protocols known to enhance reactivity with aldehydes were
investigated. According to Knochel’s procedure,[18] 4 was first converted into the
zinc=copper reagent 5, which reacted with cyclohexane carbaldehyde in the presence
of BF3 ꢀ OEt2 to give the addition compound 7a in 33% isolated yield (Scheme 3). In
the second protocol, 4 was prepared in a toluene=DMA 9=1 mixture. The organozinc
compound was then transferred to a chlorotriisopropoxytitanium(IV) solution in dry
dichloromethane (DCM) and cyclohexane carbaldehyde was added to give 7a after
15 h at 0 ꢁC in 25% yield. In the latter case, the reaction is believed to proceed
through the formation of organotitanium 6.[19a,20]
Direct reaction of 4 on cyclohexane carbaldehyde mediated by BF3 ꢀ OEt2 in
MeCN in a one-pot process gave better results (Scheme 4). Preparation of 4 was first
performed in MeCN using optimized conditions for zinc activation (Zn=Cu þ 1,2-
dibromoethane þ TMSCl). After cooling the reaction mixture to ꢂ40 ꢁC, cyclohex-
ane carbaldehyde (0.5 equiv.) and BF3 ꢀ OEt2 (2 equiv.) were successively added.
The reaction mixture was allowed to slowly reach room temperature, and stirring
was pursued for 15 h. After aqueous workup and column chromatography isolation,
7a was obtained in 55% yield.

C-GLYCOSYLATED a-AMINO ACID
1465
Scheme 3. Synthesis of 7a from 4 by transmetalation.
These latter conditions were also tested using aromatic aldehydes (Scheme 4).
Benzaldehyde and 2-formylpyridine led to addition products 6b and 6c in 60% and
32% yields respectively. 2-Formylthiophene and 2-formylpyrrole failed to give the
expected addition compounds but yielded complex reaction mixtures presumably
due to the sensitivity of these substrates to BF3 ꢀ OEt2.
We performed the addition of 4 on ribose and glucose derivatives bearing an
aldehyde function to prepare unreported C-glycosylated a-amino acids (Scheme 5).
Riboside 8a was prepared from D-ribose by simultaneous protection of positions 1,
2, and 3[21] followed by oxidation of the hydroxyl group with iodoxybenzoic acid
(IBX).[22] Glucoside 8b was obtained in four steps from D-glucose according to a
procedure published by our group.[23] We used our optimized conditions for prep-
aration of 4 and its direct addition on 8a and 8b mediated by BF3 ꢀ OEt2 gave the
expected compounds 9a and 9b in 51% and 38% yields respectively. Compound 9a
was obtained with 50% diastereoisomeric excess, as determined by 1H NMR analysis
at 400 MHz of the crude mixture (signals for protons on position 40 of the ribose
moiety at 4.24 and 4.29 ppm were used for diagnosis). Preparation of compound
9b did not lead to any diastereoisomeric excess (as determined by 1H NMR analysis
at 400 MHz, observing signals for protons on the carbon bearing the hydroxyl func-
tion at 3.35 and 3.38 ppm). In both cases, attempts to isolate the different diastereoi-
somers by column chromatography were unsuccessful, and the compounds were
characterized as mixtures of diastereoisomers.
In summary, we developed a simple method for the addition of an amino acid
organozinc reagent to various aldehydes. Choosing an organozinc reagent as
Scheme 4. Optimized protocol for the synthesis of 4 and its addition on aldehydes.

1466
N. BOUTARD ET AL.
Scheme 5. C-glycosylated amino acid synthesis.
nucleophile allowed us to use an amino acid precursor in a commonly protected
form, without further modification of its amino and acid functions. This method
was used to synthesize three new amino acids and two novel C-glycosylated a-amino
acid structures in acceptable yields. The four-carbon tether between the carbo-
hydrate to the amino acid moieties could potentially mimic linkage through an
asparagine residue. Work is currently carried out to extend this methodology to
L-amino acids with different side-chain lengths and amine deactivating protecting
groups. These results will be reported in due course.
EXPERIMENTAL
General Methods
Zinc powder was purchased from Strem Chemical Inc. (Newburyport, MA,
USA, 99.9% purity, 325 mesh, ref. 93–3060). The Zn=Cu was prepared according
to Simmons and Smith and was kept under argon.[16] Anhydrous solvents were
obtained by distillation over drying agents: sodium-benzophenone (THF, Et2O),
calcium hydride þ phosphorus pentoxide (MeCN), and calcium hydride (DCM).
DMA was dried by storing it over 4-A molecular sieves. 1H NMR and 13C
˚
NMR spectra were recorded on a Brucker AC 400-MHz spectrometer with chemi-
cal shift values in ppm relative to residual chloroform (dH 7.26 & dC 77.2) and
1
C6D5H (dH 7.16 & dC 128.4). Assignments of H NMR and 13C NMR signals were
made possible, using correlation spectroscopy (COSY), heteronuclear multiple
quantum correlation (HMQC) and distortionless enhancement by polarization
transfer (DEPT) experiments. High-resolution mass spectrometry (HRMS) analyses
were performed on a FAB (fast atom bombardment) Jeol JSM DX300-SX 102
spectrometer in positive mode (FABþ) using 3-nitrobenzylic alcohol (NBA) or a
glycerol=thioglycerol (50=50) mixture (GT) matrices. RP-HPLC-MS analyses were
performed on a Waters (Milford, MA, USA) Millenium system coupled with a
Platform II Micromass-Waters spectrometer in electrospray positive ionization
mode (ESþ). A C18 Nucleosil column (Waters, 5 lm, 4.6 mm ꢃ 250 mm) was used
with mixtures of MeCN and water (þ0.1% formic acid) as eluent at a flow of
0.5 mL per min. Melting points were determined on a Gallenkamp digital melting
point apparatus and are uncorrected.

C-GLYCOSYLATED a-AMINO ACID
1467
tert-Butyl N,N-Dibenzylaminoethanoate 2
tert-Butyl bromoacetate (5 mL, 29.87 mmol, 1 equiv.) was added to a dibenzy-
lamine (12.6 mL, 65.72 mmol, 2.2 equiv.) solution in a EtOH=dioxane 5=4 mixture
(22 mL). A white precipitate rapidly formed, and the mixture was refluxed for 8 h.
After solvent evaporation, the white residue was taken up in diethyl ether, and the
white suspension was washed with NaOH 1 N (4 ꢃ 60 mL). The aqueous layers were
extracted with diethyl ether (2 ꢃ 100 mL). The combined organic layers were washed
with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and con-
centrated in vacuo to yield an oil, which solidified on standing. Compound 2 was pur-
ified by successive crystallizations from petroleum ether (5.70 g). Evaporation of the
filtrates and purification by column chromatography (petroleum ether=EtOAc 9=1)
yielded more 2 (white crystals, total weight: 8.75 g, 94%). Rf (petroleum ether=
DCM 1=1): 0.42; MSHR (FABþ) for C20H26O2N: calculated: 312.1964, found:
1
312.1977; mp 65–67 ꢁC (lit.[24] 68 ꢁC); H NMR (CDCl3, 400 MHz) d ppm: 1.45 (s,
9H, tBu), 3.16 (s, 2H, CH2a), 3.79 (s, 4H, CH2-Ph), 7.20–7.41 (m, 10H, Harom.);
13C NMR (CDCl3, 100 MHz) d ppm: 27.20 (CH3 tBu), 53.42 (CH2a), 56.59 (CH2-
Ph), 79.72 (Cquat tBu), 125.99, 126.19, 126.98, 127.22, 127.30, 127.66, 127.86 (Carom.),
=
138.05 (C1 arom.), 169.76 (C O).
n-Butyllithium in Et2O
A dry, 100-mL, round-bottom flask under argon sweeping was charged with
finely cut lithium (1.6 g, 228.57 mmol, 1 equiv.) and anhydrous diethyl ether
(33 mL). A solution of n-butyl bromide (10.5 mL, 98.29 mmol, 0.4 equiv.) in anhy-
drous diethyl ether (18 mL) was added dropwise with a dropping funnel. The first
10 drops were added at room temperature, and addition was continued for 6 h at
ꢂ10 ꢁC. After 15 h reaction at this temperature, the butyllithium solution was
titrated with diphenylacetic acid.[25] Concentrations usually ranged between 1.2 M
and 1.5 M. The solution could be kept for a few weeks at ꢂ20 ꢁC in the tightly sealed
round-bottom flask under argon.
tert-Butyl 2-(Dibenzylamino)-6-iodohexanoate 3
Diisopropylamine (2.81 mL, 20.1 mmol, 1.25 equiv.) in dry THF (250 mL) was
cooled to ꢂ25 ꢁC under argon, and butyllithium (1.2 M in Et2O, 15.4 mL, 18.5 mmol,
1.15 equiv.) was added. The mixture was left with stirring at ꢂ25 ꢁC for 45 min and
was cooled to ꢂ40 ꢁC. A solution of 2 (5 g, 16.1 mmol, 1 equiv.) in dry THF (5 mL)
was added by syringe over 2 min. The reaction mixture took a characteristic deep
purple color over a few minutes. After 30 min at ꢂ40 ꢁC, the mixture was cooled
to ꢂ78 ꢁC, and 1,4-diiodobutane (8.47 mL, 6.2 mmol, 4 equiv.) was added. The reac-
tion mixture was allowed to come back to room temperature slowly and was left with
stirring for 15 h. The reaction was quenched with saturated aqueous ammonium
chloride (100 mL). The two phases were separated, and the aqueous layer was
extracted with diethyl ether (2 ꢃ 100 mL). The combined organic layers were washed
with 15% aqueous sodium thiosulfate (100 mL) and brine (100 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo. Compound 3 was purified

1468
N. BOUTARD ET AL.
by silica-gel column chromatography (petroleum ether=DCM 8=2) and was isolated
as a clear yellow oil (7.29 g, 92%). It was stored over copper turnings, under argon,
away from light, at ꢂ20 ꢁC. Rf (petroleum ether=DCM 85=15): 0.19; MSHR
1
(FABþ) for C24H33IO2N: calculated: 494.1558, found: 494.1556; RMN H NMR
(CDCl3, 400 MHz) d ppm: 1.18–1.66 (m, 6H, Hb þ c þ e), 1.49 (s, 9H, tBu), 3.02 (t,
2H, CH2I, Jdꢂe ¼ 6.8 Hz), 3.09 (t, 1H, CHa, Jaꢂb ¼ 6.0 Hz), 3.47 (d, 2H, CH2-Ph,
J ¼ 13.9 Hz), 4.82 (d, 2H, CH2-Ph, J ¼ 13.9 Hz), 7.11–7.33 (m, 10H, Harom.); RMN
13C (CDCl3, 100 MHz) d ppm: 7.35 (CH2 e), 27,43 (CH2 c), 28.76 (CH2 b), 28.92
(CH3 tBu), 33.39 (CH2 d), 54.89 (CH2-Ph), 56.72 (CHa), 81.46 (Cquat. tBu), 127.41,
=
128.67, 129.32, 140.18 (Carom.), 172.61 (C O).
Representative Procedure of Optimized Zinc Activation in MeCN,
Zincation of 3, and Direct Addition on Aldehydes: tert-Butyl
2-(Dibenzylamino)-7-hydroxy-7-cyclohexylheptanoate 7a
Zn=Cu powder (0.239 g, 3.65 mmol, 6 equiv.)[16] was placed under argon sweep-
ing in a dry, 10-mL, round-bottom flask, gently heated under vacuum with a heat
gun, and allowed to cool down to room temperature under argon. Dry MeCN
(3 mL) was added, followed by 1,2-dibromethane (12 mL, 0.13 mmol, 0.22 equiv.),
and the resulting slurry was heated with a heat gun with stirring until reflux and
cooled back to room temperature (three times). While still warm, TMSCl (5 mL,
0.04 mmol, 0.06 equiv.) was added. After 15 min, neat 3 (0.3 g, 0.61 mmol, 1 equiv.)
was added dropwise by syringe, and the resulting suspension was warmed up to
40 ꢁC. The mixture was stirred at this temperature under an argon atmosphere for
1 h, at which point all of the iodide had been consumed as judged by thin layer chro-
matography (TLC; petroleum ether=Et2O 95=5, Rf ¼ 0.5). The mixture was cooled to
ꢂ40 ꢁC, and cyclohexane carbaldehyde (40 mL, 0.3 mmol, 0.5 equiv.) was added by
syringe, followed by BF3 ꢀ OEt2 (154 mL, 1.22 mmol, 2 equiv.). After 15 h stirring,
during which time the mixture was allowed to reach room temperature, saturated
aqueous NH4Cl (10 mL) was added and mixture was extracted with EtOAc
(3 ꢃ 10 mL). The organic phase was washed with brine (10 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (petroleum ether=Et2O 8=2) to give 7a as a colorless
oil (0.161 g, 55%). Rf (EP=EtOAc 8=2): 0,41; MSHR (FABþ) for C31H46NO3: calcu-
1
lated: 480.3478, found: 480.3485; H NMR (CDCl3, 400 MHz) d ppm: 1.44 (s, 9H,
CH3 tBu), 1.65 þ 1.18 (2 m, 19H, Hcyclohexyl and Hb,c,d,e), 3.10 (m, 1H, CHOH),
0
0
3.46 (d, 2H, CH2-Ph, JH-H ¼ 13.8 Hz), 3.87 (d, 2H, CH2-Ph, JH-H ¼ 13.8 Hz), 4.16
(d, 1H, Ha, Ja–b ¼ 6.3 Hz), 7.27 (m, 10H, Harom.); 13C NMR (CDCl3, 100 MHz) d
ppm: 25.88 (CH2 3 cyclohexyl), 26.37 (CH2 4 cyclohexyl), 26.48 (CH2 c), 26.95 (CH2 d),
28.56 (CH2 2 cyclohexyl), 28.89 (CH3 tBu), 29.80 þ 29.75 (CH2 b), 34.29 þ 34.26 (CH2 e),
42.66 (CH2 1 cyclohexyl), 53.57 (CH2-Ph), 66.67 (CHa), 76.69 (CH-OH), 81.37 (Cquat.
=
tBu), 127.28, 128.82, 128.95, 140.36 (Carom.), 173.05 (C O).
tert-Butyl 2-(Dibenzylamino)-7-hydroxy-7-phenylheptanoate 7b
Compound 7b was prepared from compound 3 on a 4.06-mmol scale according
to the representative optimized procedure (vide supra). The addition compound was

C-GLYCOSYLATED a-AMINO ACID
1469
isolated as a colorless oil after silica-gel column chromatography (petroleum ether=
Et2O 8=2, 576 mg, 60%). Rf (petroleum ether=EtOAc 8=2): 0.38; MSHR (FABþ) for
1
C31H46NO3: calculated: 474.3008, found: 474.2997; H NMR (CDCl3, 400 MHz) d
0
ppm: 1.42 (s, 9H, CH3 tBu), 3.48 (d, 2H, CH2-Ph, JH-H ¼ 13.5 Hz), 3.79 (d, 2H,
0
CH2-Ph, JH-H ¼ 13.5 Hz), 4.22 (s, 0.5H, Ha,), 4.24 (s, 0.5H, Ha,), 4.57 (t, 1H, CH-
OH, J ¼ 4.2 Hz), 7.35 (m, 15H, Harom.); 13C NMR (CDCl3, 100 MHz) d ppm:
25.43 (Cc), 26.16 (Cd), 28.74 (CH3 tBu), 29.65 (Cb), 35.24 (Ce), 53.42 (CH2-Ph),
66.45 (Ca), 78.02 (CH-OH), 81.48 (Cquat. tBu), 128.26, 128.70, 128.93, 129.28,
=
129.62, 129.85, 140.34; 144.66 (Carom), 172.75 (C O).
tert-Butyl 2-(Dibenzylamino)-7-hydroxy-7-(pyridin-2-yl)heptanoate 7c
Compound 7c was prepared from compound 3 on a 1.01 mmol scale according
to the representative optimized procedure (vide supra). The addition compound was
isolated as a colorless oil after silica gel column chromatography (petroleum ether=
Et2O 8=2, 58 mg, 30%). Rf (EP=EtOAc 8=2): 0,15; MSHR (FABþ) for C30H39N2O3:
calculated: 475.2934, found: 475.2946; RMN 1H (CDCl3, 400 MHz) d ppm: 1.29 (m,
0
0
0
0
3H, Hd þcþc ), 1.36 (m, 1H, Hd), 1.45 (s, 9H, CH3 tBu), 1.57 (m, 3H, He þbþb ), 1.68
0
(m, 1H, He), 3.08 (t, 1H, Ha, Ja-b ¼ 7.5 Hz), 3.46 (d, 2H, CH2 Benzyl., JH -H ¼ 13.9 Hz),
0
3.83 (d, 2H, CH2 Benzyl., JH-H ¼ 13.9 Hz), 4.58 (t, 1H, HCH-OH, JH-e ¼ 4.0 Hz), 7.12
(m, 2H, H3þ5 Py), 7.25 (m, 10H, Harom. Benzyl.), 7.59 (m, 1H, H4 Py), 8.44 (m, 1H,
H
6 Py); RMN 13C NMR (CDCl3, 100 MHz) d ppm: 25.10 (CH2 c), 26.11 (CH2 d),
28.48 (CH3 tBu), 29.45 (CH2 b), 38.50 (CH2 e), 54.47 (CH2 Benzyl.), 61.23 (CHa),
72.70 (CH C-OH), 80.82 (Cquat. tBu), 120.37 (C3 Py), 122.23 (C5 Py), 126.87 (Carom.
Bn), 128.19 (Carom. Bn), 128.64 (Carom. Bn), 136.61 (C4 Py), 139.97 (C1
Bn),
arom.
=
148.19 (C6 Py), 162.17 (C2 Py), 172.45 (C O).
tert-Butyl 2-(Dibenzylamino)-7-(1’-O-methyl-2’,3’-O-isopropylidene-
b-D-ribofuranos-5’-yl)-heptanoate 9a
Compound 9a was prepared from compound 3 and compound 8a on a
2.63-mmol scale according to the representative optimized procedure (vide supra).
The addition compound was isolated as a colorless oil after silica-gel column chro-
matography (petroleum ether=Et2O 9=1, 458 mg, 51%, ee 50%). Two diastereoi-
somers could be distinguished in NMR spectroscopy in C6D6 at 400 MHz (1H)
and 100 MHz (13C); signals accounting for the minor isomer are underlined. Rf (pet-
roleum ether=EtOAc 8=2): 0.41; MSHR (FABþ) for C33H48NO7: calculated:
1
570.3431, found: 570.3448; RMN H (C6D6, 400 MHz) d ppm: 1.07 (s, 3H, CH3 IP),
1.22 (m, 6H, Hcþdþe), 1.35 (m, 2H, Hb), 1.38 (s, 3H, CH3 IP), 2.84 (s, 3H, CH3
0
OMe), 3.29 (m,1H, Ha), 3.51 (m,1H, H5 ), 3.61 (d, 2H, CH2-Ph., J ¼ 13.8 Hz), 3.95 (2
0
0
d, 2H, CH2-Ph, J ¼ 13.8 Hz), 4.24 (m, 0.33H, H4 ), 4.29 (dd, 0.66H, H4 , J ¼ 8.3 Hz,
0
0
0
0
0
0
J ¼ 2.3 Hz), 4.51 (d, 0.33H, H2 , J2 -3 ¼ 6.0 Hz), 4.63 (d, 0.66H, H2 , J2 -3
¼
0
0
0
0
0
0
6.0 Hz), 4.72 (d,0.66H, H3 , J2 -3 ¼ 6.0 Hz), 4.82 (d, 0.33H, H3 , J2 -3 ¼ 6.0 Hz), 4.90
(s,1H, H1 ), 7.32 (m, 10H, Harom.); 13C NMR (C6D6, 100 MHz) d ppm: 26.19 (CH2
c), 26.75 (CH2 d), 28.58 (CH3 tBu), 30.02 (CH2 b), 33.38 (CH2 e), 55.25 (CH2-Ph.),
0
0
55.44 (CH3 OMe), 61.75 (CHa), 72.12 (CH5 ), 72.58 (CH5 ), 80.39 (CH3 ), 80.77 (Cquat.
0
0
0
tBu), 83.37 (CH3 ), 86.37 (CH2 ), 86.71 (CH2 ), 91.06 (CH4 ), 92.53 (CH4 ), 110.62
0
0
0
0

1470
N. BOUTARD ET AL.
=
(CH1 ), 112.25 (Cquat. IP), 127.73; 128.05; 129.45; 140.67 (Carom.), 172.22 (C O), 172.28
0
=
(C O).
tert-Butyl 2-(Dibenzylamino)-7-hydroxy-7-(2’,3’,4’,6’-tetra-O-benzyl-
b-D-glucopyranos-1’-yl)-heptanoate 9b
Compound 9b was prepared from compound 3 on a 0.709-mmol scale accord-
ing to the representative optimized procedure (vide supra). The addition compound
was isolated as a colorless oil after silica gel column chromatography (petroleum
ether=Et2O 9=1, 124 mg, 38%). Rf (petroleum ether=EtOAc 8=2): 0.17; (FABþ)
for C59H70NO8: calculated: 920.5101, found: 920.5114; 1H NMR (CDCl3,
400 MHz) d ppm: 1.34 (m, 8H, Hb,c,d,e), 1.38 (s, 9H, CH3 tBu), 3.31 (m, 1H, H5),
3.35 (m, 0.5H, CH-OH), 3,38 (m, 0.5H, CH-OH), 3.47 (m, 1H, H4), 3.51 (m, 1H,
0
H2), 3.53 (m, 1H, H6 ), 3.55 (m, 1H, H6), 3.66 (m, 1H, H3), 3.92 (m, 12H, CH2 Benzyl.),
4.14 (s, 0.5H, H ), 4.17 (s, 0.5H, Ha), 7.21 (m, 30H, Harom.); 13C NMR (CDCl3,
a
100 MHz) d ppm: 26.39 (CH2 e), 26.84 (CH2 d), 28.23 (CH3 tBu), 29.61 þ 29.72
0
(CH2 b), 34.21 þ 34.18 (CH2 e), 53.31 (N-CH2-Ph), 66.47 (CHa), 69.32 (CH2 6 ),
74.02 (O-CH2-Ph.), 74.38 (O-CH2-Ph.), 74.51 (O-CH2-Ph.), 74.68 (O-CH2-Ph.),
0
0
0
76.32 þ 76.56 (CH-OH), 76.41 (CH1 ), 78.84 (CH5 ), 79.82 (CH2 ), 81.41 (Cquat. tBu),
0
82.52 (CH4 ), 86.87 (CH3 ), 128.08, 128.14, 128.60, 129.15; 129.49; 129.71; 129.84;
0
129.96; 130.40; 130.44; 130.57; 130.78; 130.89; 130.95; 130.99; 139.21; 139.61;
=
139.63; 139.90;140.51 (Carom.), 172.84 (C O).
ACKNOWLEDGMENTS
`
This work was supported Ministere de l’Education Nationale, de l’Enseigne-
ment Superieur et de la Recherche, as well as the Fondation Recherche Medicale.
´
´
´
We are grateful to Pierre Sanchez and Maryse Bejaud for performing LC-MS and
NMR analyses, respectively. We thank Pr William D. Lubell for constructive
comments on the manuscript.
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