Synthesis of β-C-galactosyl d- and l-alanines

Article abstract of DOI:10.1039/c2ob26078f

Synthesis of β-C-d-galactosyl d- and l-alanines is carried out via a highly stereoselective Grignard reaction of glycosyl iodides, Sharpless dihydroxylation and S_N2 displacement of the corresponding mesylate or tosylate. Alternatively, attempted triflation of the intermediate alcohols triggers a stereoselective debenzylative cyclization leading to interesting bicyclic trans-fused compounds.

Full text of DOI:10.1039/c2ob26078f

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PAPER
Synthesis of β-C-galactosyl D- and L-alanines†‡
V. Narasimharao Thota,a Jacquelyn Gervay-Hagueb and Suvarn S. Kulkarni*a
Received 4th June 2012, Accepted 16th August 2012
DOI: 10.1039/c2ob26078f
Synthesis of β-C-D-galactosyl D- and L-alanines is carried out via a highly stereoselective Grignard
reaction of glycosyl iodides, Sharpless dihydroxylation and SN2 displacement of the corresponding
mesylate or tosylate. Alternatively, attempted triflation of the intermediate alcohols triggers a
stereoselective debenzylative cyclization leading to interesting bicyclic trans-fused compounds.
A few syntheses of C-glycosylated alanines have been
Introduction
reported using a variety of methods. The majority of the syn-
thesized C-glycosylated amino acids are α-linked pyranosides.
For example, Kessler and co-workers12 employed Bu3SnH pro-
moted free radical coupling of per-acetylated glycosyl bromides
(D-Glc, D-Gal, D-Lac) and urethane protected dehydroalaninate
derivatives to obtain α-linked C-glycopyranosyl DL-alanines.
Alternatively, reductive ring opening of 1,2-anhydro sugars with
titanocene(III) chloride and trapping of the so formed free radical
with Boc protected dehydroalaninate derivative led to α-C-glu-
copyranosyl DL-alanines.13 Yet another free radical coupling
method, to access α-linked C-glycopyranosyl D-alanine, involves
Bu3SnH/NaCNBH3 promoted coupling of per-acetylated glyco-
syl iodides (D-Glc, D-Gal) and a chiral methyleneoxazolidinone
derived from L-alanine itself.14 Conversion of the known α-C-
allyl glucopyranoside into α-C-glucopyranosyl D- and L-alanines
via Sharpless AD reaction and subsequent SN2 displacement of
the secondary sulfonate by azido group is reported.15 A similar
strategy has been employed to access the corresponding β-D-
GalNAc analogs starting from 2-nitro substituted β-C-allyl
D-galactopyranoside.16 Other methods involve asymmetric
Strecker synthesis of α-C-glycosyl L-alanines (D-Glc, L-fuc),17
and a sequential olefin cross-metathesis followed by Hg(II)
mediated cyclization18 to obtain α-D-glucopyranosyl D-alanine.
Claisen–Ireland [3,3] sigmatropic rearrangement of exo-methy-
lene glycals bearing a C-2 glycine ester has been shown to afford
glycosylated DL alanine mixture which was transformed into
racemic β-D-glucosamine derivative.19 Likewise, a Wittig reac-
tion of a 2-deoxy D-galactosyl phosphorane with Garner alde-
hyde and its concomitant hydrogenation afforded 2-deoxy β-C-
D-galactosyl D-alanine.20 Dondoni’s proline catalyzed electrophi-
lic α-amination of C-glycosyl acetaldehydes21 gives direct
access to various α- and β-linked C-glycosyl D- and L-alanines.
However, to the best of our knowledge the synthesis of β-C-D-
galactopyranosyl L-alanine 1a and its corresponding D-alanine
analog 1b has not been previously disclosed. Herein, we report a
short synthesis of β-C-D-galactopyranosyl D- and L-alanines 1a
and 1b using an allyl Grignard reaction of per-O-benzyl galacto-
syl iodides as one of the key steps.
Cell surface carbohydrates in the form of glycoconjugates play
important roles in various life processes.1,2 Glycoproteins
present key components of cellular recognition processes, signal-
ing pathways and the immune response. Over the past few years,
small glycopeptides have been emerging as valuable vaccine
candidates and therapeutics.3–6 One of the factors that limits the
utility of glycopeptides as drugs is their chemical and enzymatic
instability under physiological conditions. Incorporation of
C-glycosyl amino acids in such glycopeptides could provide
stable glycopeptide analogs which are resistant to cleavage by
O or N-glycosidases as well as acidic hydrolysis.7–11
In native glycoproteins, the sugar is linked to the protein
either through the OH group of L-serine or L-threonine (O-glyco-
proteins) or through the NH2 group of L-asparagine (N-glyco-
proteins). Consequently, most of the efforts in this area have
been focused on devising syntheses of C-glycosyl analogs of
serine/threonine and asparagine.10 In order to access C-glyco-
peptide mimics wherein the sugar is closer to the peptide back-
bone, we were interested in the synthesis of the chain-shortened
C-glycosyl alanines 1 (Fig. 1).
Fig. 1 Structures of β-C-D-galactopyranosyl alanines.
aDepartment of Chemistry, Indian Institute of Technology Bombay,
Mumbai 400076, India. E-mail: suvarn@chem.iitb.ac.in
bDepartment of Chemistry, University of California Davis, One Shields
Avenue, Davis, California 95616, USA
†Dedicated to Prof. M. S. Wadia on the occasion of his 75th birthday.
‡Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for all new compounds and 2D spectra for compounds 9
and 10. See DOI: 10.1039/c2ob26078f
8132 | Org. Biomol. Chem., 2012, 10, 8132–8139
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0 °C under neat conditions. To our delight, the reaction cleanly
generated a single product as judged by TLC. Column chromato-
graphy of the crude product afforded the desired β-C-allyl com-
pound 6 (85% over two steps) as a single isomer. No α-isomer
was encountered, suggesting that the reaction follows a SN2-type
pathway. Formation of a single isomer avoided tedious column
chromatography to separate the α/β isomers. Compound 6 has
been earlier prepared by Kishi and co-workers using a stereo-
selective Grignard addition to 2,3,4,6-tetra-O-benzyl galactopyr-
ano-lactone followed by triethylsilane reduction of the formed
hemiketal in the presence of BF3·OEt2 (76%, α : β = 1 : 10).23
Arya and co-workers utilized a Grignard reaction of in situ gen-
erated 2,3,4,6-tetra-O-benzyl galactosyl chloride from the corre-
sponding hemiacetal to obtain 6 in 48% yield.7 More recently,
Miller and Gardiner employed direct allylation of methyl glyco-
sides using an allylTMS, TMSOTf, MeCN combination to
obtain 6 in 57% yield and in a 1 : 9 α : β ratio.24 The characteriz-
ation data for compound 6 matched the reported data7 and the
stereochemistry of 6 was independently confirmed by NOESY
analysis.
Sharpless AD reaction of 6 using AD mix-β furnished a non-
separable diastereomeric mixture, which, upon selective TBDPS
protection of the primary alcohol,25 could be readily separated
by silica gel column chromatography, to obtain alcohols 7 and 8
in 54% and 38% yields, respectively. The stereochemistry of the
faster running major isomer 7 was tentatively assigned as R at
this stage using Sharpless’s mnemonic.26 In order to confirm the
assignment, another reaction was conducted on olefin 6 with AD
mix-α. As expected, this reaction afforded 7 as a minor isomer
and the slower running 8 as a major isomer in a ratio of 1 : 4.
Thus the stereochemistry of 7 and 8 was assigned as 7 (R) and 8
(S). This exercise also provided access to both diastereomeric
alcohols in acceptable yields.
Results and discussion
The retrosynthetic strategy is outlined in Scheme 1. According to
previous studies by Gurjar and co-workers, reported in the
course of their synthesis of α-D-glucopyranosyl alanines,15 the
target molecule 1a could be synthesized from secondary alcohol
2a by nucleophilic displacement of the corresponding sulfonate
by azide, followed by functional group inter-conversions. Com-
pound 2a could be obtained by Sharpless asymmetric dihydroxy-
lation (AD) of the terminal olefin 3 using AD mix-β. It was
envisaged that the β-C-glycoside could be accessed via a stereo-
selective Grignard reaction of galactosyl iodide 4 with allyl mag-
nesium halide. The same sequence of reactions using AD mix-α
would give entry to D-alanine analog 1b through the intermedi-
acy of alcohol 2b.
The synthesis began with preparation of the key β-C-galacto-
pyranoside 6. As shown in Scheme 2, treatment of the known
and easily accessible 2,3,4,6-tetra-O-benzyl β-D-galactopyranosyl
acetate 522 with iodotrimethylsilane in CH2Cl2 at 0 °C cleanly
furnished the corresponding α-iodide. The reaction was com-
pleted in 1 h and the formed TMSOAc side product was evapor-
ated by repeated benzene azeotrope. The crude iodide was
treated with a 2 M THF solution of allyl magnesium chloride at
In order to synthesize the L-alanine derivative, alcohol 7 was
subjected to triflation using Tf2O and pyridine in CH2Cl2
(Scheme 3). The reaction was completed in 15 min, however, 1H
and 13C NMR analysis of the product indicated peaks corres-
ponding to only 3 benzyl groups along with loss of the OTf
group. Further the H-2 proton moved downfield indicating that
the 2-OBn group might have been cleaved. MS data showed m/z
peak at 729 corresponding to (M + 1) peak of the debenzylated
product. Detailed NMR analysis (see ESI‡) revealed a trans-
fused bicyclic structure 9. 1H–1H COSY analysis allowed
Scheme 1 Retrosynthetic strategy.
Scheme 2 Stereoselective preparation of β-C-allyl glycoside 6 and its
Sharpless AD reaction. Reagents and conditions: (a) TMSI (1.1 equiv),
CH2Cl2, 0 °C, 1 h; (b) 2.0 M allylmagnesium chloride in THF (3 equiv),
0 °C to rt, 2 h, 85% over two steps; (c) AD mix-α or AD mix-β,
t-BuOH : H2O (1 : 1), cat. K2OsO4·2H2O, 0 °C, 3 d; (d) TBDPSCl
(2 equiv), pyridine (13 equiv), rt, 1 d.
Scheme 3 Triflation leading to serendipitous debenzylative cycloether-
ification. Reagents and conditions: (a) pyridine (6 equiv), Tf2O
(2 equiv), CH2Cl2, 0 °C, 15 min, 57% for 9 and 76% for 10.
This journal is © The Royal Society of Chemistry 2012
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Fig. 2 Key NOESY correlations in 9 and 10.
assignment of the H1–H6 sugar and side chain protons. A
NOESY spectrum of 9 clearly showed correlation between the
proton at the newly formed stereocenter and the anomeric proton
H1 (and no correlation with the H2 proton) unambiguously
confirming the absolute stereochemistry of the bicyclic structure
(Fig. 2). Likewise, triflation of the other isomer 8 under identical
conditions afforded the corresponding bicyclic product 10.
NOESY analysis showed a correlation between the proton of the
newly formed stereocenter and the H2 ring proton (and no corre-
lation with the H1 proton) confirming the absolute structure of
the diastereomer 10.
Formation of bicyclic compounds 9 and 10 presumably
occurred via neighboring group participation by the benzyl
group during intramolecular displacement of triflate anion, for
example in 11, forming a benzyloxonium ion 12, which probably
undergoes attack by a nucleophile, perhaps pyridine, to release
the latent benzylic carbocation (Scheme 4).27 Such cyclizations
are well precedented in the literature and are commonly encoun-
tered when the reacting groups are in a 1,4 relationship.27–32
Similar debenzylative cycloetherifications have been observed in
epoxides33 and allylic systems,34,35 and in iodoetherification36,37
reactions. The trans-fused bicyclic compounds 9 and 10 could
serve as valuable intermediates in the synthesis of the Ezomycin
group of antibiotics and related analogs.38
Scheme 5 Synthesis of C-β-D-galactosyl-L-alanine 1a. Reagents and
conditions: (a) p-TsCl (1.5 equiv), pyridine (6 equiv), CH2Cl2, 0 °C to
100 °C, 36 h; (b) NaN3, DMF, 120 °C, 8 h, 65% over two steps; (c) 1 M
TBAF in THF, rt, 7 h, 91%; (d) cat. TEMPO, NaBr, 15% NaHCO3, tri-
chloroisocyanuric acid, acetone, 0 °C, 1 h; (e) SOCl2, MeOH, 0 °C to rt,
90 min, 78% over two steps; (f) PPh3, THF, H2O, 80 °C, 20 min; (g)
Boc2O (3.5 equiv), Et3N, CH2Cl2, 10 h, 90% over two steps; (h) 20%
Pd(OH)2, H2 (1 atm), MeOH : CH2Cl2 (4 : 1), 8 h, 84%.
Removal of the TBDPS group using TBAF revealed the primary
alcohol 14 (91%), which upon TEMPO oxidation39 and con-
comitant esterification using SOCl2 in MeOH40 delivered the
azido ester 15 (78%, 2 steps). Rapid reduction of the azide to an
amino group under modified Staudinger conditions (80 °C,
20 min) and subsequent Boc-protection afforded the fully protected
amino acid derivative 16 (90% over two steps). Hydrogenolysis
catalyzed by Degussa type Pd(OH)2 reagent41 using a hydrogen
balloon cleanly furnished the desired β-C-D-galactosyl-L-alanine
1a (84%) in good overall yield.
Although quite interesting, the cyclization was an obvious
obstacle in the planned synthesis of C-glycosyl amino acids.
After some experimentation, it was realized that, the adventitious
cyclization could be circumvented by using tosylates or mesy-
lates in place of triflates (Scheme 5). Thus, tosylation of the R
alcohol 7 followed by sodium azide nucleophilic displacement
afforded the desired azido derivative 13 (65% over two steps)
with no trace of the earlier encountered cyclized product 9.
Scheme 6 Synthesis of C-β-D-galactosyl-D-alanine 1b. Reagents and
conditions: (a) MsCl (2.2 equiv), pyridine (6 equiv), CH2Cl2, 0 °C to rt,
3 h; (b) NaN3, DMF, 120 °C, 7 h, 74% over two steps; (c) 1 M TBAF in
THF, rt, 7 h, 80%; (d) cat. TEMPO, NaBr, 15% NaHCO3, trichloroiso-
cyanuric acid, acetone, 0 °C, 1 h; (e) SOCl2, MeOH, 0 °C to rt, 90 min,
82% over two steps; (f) PPh3, THF, H2O, 80 °C, 20 min; (g) Boc2O
(3.5 equiv), Et3N, CH2Cl2, 10 h, 90% over two steps; (h) 20% Pd(OH)2,
H2 (1 atm), MeOH, 3 h, 85%.
Scheme 4 Proposed mechanism of debenzylative cyclization.
8134 | Org. Biomol. Chem., 2012, 10, 8132–8139
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The D-alanine analog 1b was prepared under more or less
identical conditions. Although tosylation of 8 required reflux
conditions and afforded the corresponding chloride (perhaps via
concomitant SN2 displacement of the in situ generated tosylate),
no conversion was observed at RT. Advantageously, mesylation
of S alcohol 8 cleanly delivered the corresponding mesylate and
subsequent SN2 displacement by azide afforded 17, which was
transformed to 1b in a similar manner in good overall yield via
the intermediacy of 18–20 (Scheme 6).
aqueous layer was extracted using ethyl acetate (30 mL × 2) and
the combined organic layer was washed with saturated aq.
Na2S2O3 (15 × 2 mL) and brine (15 × 2 mL), dried over anhy-
drous Na2SO4, concentrated, and dried under vacuum to obtain
an oily residue, which was purified by silica gel column chrom-
atography (6% ethyl acetate/pet ether) to afford 6 as a viscous
liquid (172 mg, 85% over two steps): [α]2D5 +8.8 (c 1.31,
1
CHCl3); IR (CHCl3) ν 3066, 3032, 1642, 1028, 911 cm−1; H
NMR (400 MHz, CDCl3) δ 7.5–7.1 (m, 20H, ArH), 5.97–5.87
(m, 1H, Allylic CH), 5.09 (dd, J = 1.5, 17.3 Hz, 1H, Allylic
CH2), 5.03 (d, J = 10.3 Hz, 1H, Allylic CH2), 4.94 (d, J =
10.7 Hz, 1H, PhCH2), 4.93 (d, J = 12.4 Hz, 1H, PhCH2), 4.73,
4.66 (ABq, J = 11.7 Hz, 2H, PhCH2), 4.64 (d, J = 10.7 Hz, 1H,
PhCH2), 4.63 (d, J = 12.4 Hz, 1H, PhCH2), 4.46, 4.40 (ABq,
J = 11.8 Hz, 2H, PhCH2), 3.98 (d, J = 2.5 Hz, 1H, H-4), 3.72 (t,
J = 9.3 Hz, 1H, H-2), 3.59 (dd, J = 2.5, 9.3 Hz, 1H, H-3),
3.56–3.50 (m, 3H, H-5, H-6 and H-6′), 3.31 (ddd, J = 2.9, 8.5,
9.3 Hz, 1H, H-1), 2.63–2.58 (m, 1H, CHa), 2.32 (ddd, J = 4.9,
8.5, 14.4 Hz, 1H, CHb); 13C NMR (100 MHz, CDCl3) δ 138.9,
138.6, 138.5, 138.1, 135.3, 128.54, 128.51, 128.3, 128.22,
128.18, 128.0, 127.84, 127.80, 127.74, 127.65, 116.8, 84.1,
79.5, 78.7, 76.9, 75.5, 74.5, 73.8, 73.6, 72.3, 69.1, 36.3; HRMS
calcd for C37H41O5 [M + H]+ 565.2954, found 565.2942.
Conclusion
In conclusion, we have carried out the first synthesis of β-C-D-
galactosyl D- and L-alanines via a highly stereoselective Grignard
reaction of glycosyl iodides, Sharpless AD and SN2 displace-
ment of mesylate or tosylate. Glycosyl iodide42 mediated
Grignard reaction allowed direct access to the key β-C-glycoside
6 in a highly stereoselective fashion. This protocol could be
employed for the synthesis of other sugar analogs of alanines.
During our explorations, we also encountered a stereoselective
debenzylative cyclization leading to interesting trans-fused bicyclic
compounds with potential application in natural product synthesis.
Experimental section
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(2R)-ol-3-tert-
butyl-diphenylsilyloxy-propane (7). A solution of AD mix-β
(1.5 g) in 1 : 1 tert-butyl alcohol and water (6 mL) was added to
a stirred solution of 6 (610 mg, 1.07 mmol) in 1 : 1 tert-butyl
alcohol and water (4 mL) at 0 °C. Potassium osmate dihydrate
(7.2 mg, 0.02 mmol) was added and the reaction was stirred at
0 °C for 3 d. The reaction was stopped by adding sodium sulfite
(1.6 g) and kept at rt for 20 min. It was diluted with CH2Cl2
(40 mL), washed with water (10 mL) and brine (5 mL), dried
over anhydrous Na2SO4. The combined organic layer was con-
centrated on rotary evaporator. To this crude product, pyridine
(951 μL, 11.81 mmol) and TBDPSCl (471 μL, 1.82 mmol) were
sequentially added and stirred at rt for 1 d, concentrated on a
rotary evaporator and co-evaporated with toluene several times.
The residue was dissolved in CHCl3 (50 mL), washed with water
(10 mL) and dried over anhydrous Na2SO4. The chloroform
layer was concentrated to get a residue which upon column chro-
matographic purification on silica gel (11% ethyl acetate/pet
ether) afforded (2R)-alcohol 7 as a viscous liquid (486 mg, 54%
over two steps) and (2S)-alcohol 8 (343 mg, 38% over two
steps): Compound 7 [α]D25 +5.0 (c 1.14, CHCl3); IR (CHCl3) ν
General methods
All reactions were conducted under a dry nitrogen atmosphere.
Solvents (CH2Cl2 >99%, THF 99.5%, Acetonitrile 99.8%, DMF
99.5%) were purchased in capped bottles and dried under
sodium or CaH2. All other solvents and reagents were used
without further purification. All glasswares used were oven dried
before use. TLC was performed on pre-coated aluminium plates
of silica gel 60 F254 (0.25 mm, E. Merck). Developed TLC
plates were visualized under a short-wave UV lamp and by
heating plates that were dipped in ammonium molybdate/cerium(IV)
sulfate solution. Silica gel column chromatography was per-
formed using silica gel (100–200 mesh) and employed a solvent
polarity correlated with TLC mobility. NMR experiments were
conducted on 400 MHz instrument using CDCl3 (D, 99.8%) or
CD3OD (D, 99.9%) or (CD3)2SO (D, 99.9%) as solvents.
Chemical shifts are relative to the deuterated solvent peaks and
are in parts per million (ppm). 1H–1H COSY was used to
confirm proton assignments. High resolution mass spectra were
acquired under ESI mode using Q-TOF analyzer. Melting points
were determined by capillary apparatus. Specific rotation exper-
iments were measured at 589 nm (Na) and 25 °C. IR spectra
were recorded on an FT-IR spectrometer using CsCl plates.
3497, 3019, 1219, 1107 cm−1 1H NMR (400 MHz, CDCl3)
;
δ 7.72–7.63 (m, 4H, ArH), 7.41–7.23 (m, 26H, ArH), 4.93 (d,
J = 11.3 Hz, 2H, PhCH2), 4.74, 4.68 (ABq, J = 11.7 Hz, 2H,
PhCH2), 4.66 (d, J = 10.6 Hz, 1H, PhCH2), 4.60 (d, J =
11.7 Hz, 1H, PhCH2), 4.42, 4.37 (ABq, J = 11.8 Hz, 2H,
PhCH2), 3.97–3.93 (m, 2H, H-4 and CHOH), 3.72 (t, J =
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-2-propene (6).
TMSI (61.3 μL, 0.43 mmol) was added dropwise to a stirred
solution of 5 (209 mg, 0.36 mmol) in anhydrous CH2Cl2
(3.5 mL) at 0 °C. After 1 h, dry benzene (5 mL) was added at
0 °C and the solvent was evaporated on a rotary evaporator
under N2 atmosphere; azeotroping was repeated twice. To the
crude yellowish compound, a solution of allylmagnesium chlor-
ide (2.0 M in THF, 0.54 mL) was added dropwise at 0 °C and
the reaction was stirred at rt for 2 h. It was quenched by adding
ethyl acetate (5 mL) and saturated aq. NH4Cl (5 mL). The
9.3 Hz, 1H, H-2), 3.64 (dd,
J = 5.5, 10.0 Hz, 1H,
CH2O(CH3)3CSi), 3.62–3.38 (m, 7H, H-1, H-3, H-5, H-6a,
H-6b, OH and CH2O(CH3)3CSi), 2.32–2.29 (m, 1H, CHa), 1.65
(dt, J = 5.0, 9.4 Hz, 1H, CHb), 1.03 (s, 9H, (CH3)3CSi); 13C
NMR (100 MHz, CDCl3) δ 138.6, 138.34, 138.25, 137.8,
135.70, 135.68, 133.6, 133.5, 129.8, 128.58, 128.56, 128.50,
128.4, 128.3, 128.2, 128.1, 127.9, 127.82, 127.79, 127.7, 84.5,
80.0, 78.9, 76.9, 75.7, 74.6, 73.7, 72.4, 71.9, 69.0, 67.7, 35.2,
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27.0, 19.3; HRMS calcd for C53H60O7SiNa [M + Na]+
859.4006, found 859.3976.
4.36–4.32 (m, 1H, CHCH2O(CH3)3CSi), 3.99 (t, J = 9.3 Hz,
1H, H-2), 3.97 (s, 1H, H-4), 3.80 (dd, J = 3.5, 11.0 Hz, 1H,
CH2O(CH3)3CSi), 3.72–3.66 (m, 4H, H-3, H-5, H-6a and
CH2O(CH3)3CSi), 3.58 (dd, 1H, H-6b), 3.47 (app. q, J = 8.8,
9.1, 9.3 Hz, 1H, H-1), 3.56–3.44 (m, 1H, CHa), 1.89 (app. q,
J = 10.5 Hz, 1H, CHb), 1.08 (s, 9H, (CH3)3CSi); 13C NMR
(100 MHz, CDCl3) δ 138.9, 138.7, 138.0, 135.9, 135.73,
135.68, 133.70, 133.6, 129.9, 129.8, 128.58, 128.56, 128.5,
128.3, 128.1, 127.94, 127.86, 127.82, 127.7, 127.6, 82.6, 80.4,
80.3, 79.5, 78.5, 75.5, 73.7, 72.3, 69.2, 66.2, 30.8, 27.0, 19.5;
HRMS calcd for C46H53O6Si [M + H]+ 729.3611, found
729.3593.
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl-(2S)-ol-3-tert-
butyl-diphenylsilyloxy-propane (8). The same procedure as
described above was followed for AD reaction of alkene 6
(343 mg, 0.61 mmol) using AD mix-α (0.85 g) to afford 8
(314 mg, 62% over two steps) and 7 (76 mg, 16% over two
steps). Compound 8 [α]D25 −0.3 (c 1.02, CHCl3); IR (CHCl3)
1
ν 3242, 3015, 1217, 1160 cm−1; H NMR (400 MHz, CDCl3)
δ 7.65–7.62 (m, 4H, ArH), 7.43–7.23 (m, 26H, ArH), 4.93 (d,
J = 11.0 Hz, 1H, PhCH2), 4.92 (d, J = 11.7 Hz, 1H, PhCH2),
4.74, 4.66 (ABq, J = 12.5 Hz, 2H, PhCH2), 4.63 (d, J =
13.3 Hz, 2H, PhCH2), 4.41, 4.38 (ABq, J = 11.8 Hz,
2H, PhCH2), 3.98 (d, J = 2.3 Hz, 1H, H-4), 3.98–3.97 (m, 1H,
CHOH), 3.69–3.58 (m, 3H), 3.56–3.46 (m, 5H), 2.73 (br s, 1H,
OH), 2.06 (ddd, J = 2.2, 9.2, 14.3 Hz, 1H, CHa), 1.56 (ddd, J =
3.0, 9.8, 14.3 Hz, 1H, CHb), 1.03 (s, 9H, (CH3)3CSi); 13C NMR
(100 MHz, CDCl3) δ 138.9, 138.4, 138.0, 137.8, 135.7, 133.4,
129.9, 128.6, 128.5, 128.40, 128.36, 128.2, 128.0, 127.92,
127.87, 127.76, 127.73, 127.69, 84.9, 78.8, 77.5, 76.9, 76.8,
75.5, 74.6, 73.6, 72.4, 68.9, 68.8, 68.2, 35.1, 27.0, 19.4; HRMS
calcd for C53H60O7SiNa [M + Na]+ 859.4006, found 859.3994.
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(2S)-azido-3-
tert-butyl-diphenylsilyloxy-propane (13). To a stirred solution
of 7 (323 mg, 0.39 mmol) in CH2Cl2 (3.4 mL) was successively
added pyridine (0.47 mL, 5.78 mmol) and p-TsCl (111 mg,
0.58 mmol) at 0 °C and the reaction was refluxed (100 °C) for
36 h. It was quenched by adding aq. NH4Cl (5 mL) and
extracted with EtOAc (30 mL), washed with H2O (10 mL) and
brine (5 mL), and dried over anhydrous Na2SO4. The organic
layer was concentrated on a rotary evaporator and the obtained
residue was purified using column chromatography on silica gel
(10% ethyl acetate/pet ether) to afford the corresponding tosy-
late. It was dissolved in DMF (3.3 mL), NaN3 (46 mg,
0.694 mmol) was added and stirred for 8 h at 120 °C. Reaction
mixture was diluted with CHCl3 (30 mL), washed with H2O
(10 mL) and brine (5 mL), and dried over anhydrous Na2SO4.
The organic layer was concentrated and column chromatographic
purification of the residue on silica gel (7% ethyl acetate/pet
ether) gave compound 13 as a viscous liquid (216 mg, 65% over
two steps): [α]2D5 −7.0 (c 0.96, CHCl3); IR (CHCl3) ν 3032,
Bi-cyclic compound (9). To a stirred solution of 7 (132 mg,
0.16 mmol) in CH2Cl2 (2.0 mL) and pyridine (80 μL,
0.95 mmol), was added trifluoromethanesulfonic anhydride
(53 μL, 0.32 mmol) in a slow dropwise manner at 0 °C, over a
period of 15 min. After the addition was over, the reaction
mixture was diluted with CH2Cl2 and successively washed with
aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL), and
dried over anhydrous Na2SO4. The organic layer was concen-
trated on a rotary evaporator and the crude product was purified
by column chromatography on silica gel (10% ethyl acetate/pet
ether) to obtain compound 9 as a viscous liquid (65 mg, 57%):
[α]2D5 −4.4 (c 0.95, CHCl3); IR (CHCl3) ν 2930, 1471, 1382,
2931, 2111, 1261 cm−1
;
1H NMR (400 MHz, CDCl3)
δ 7.68–7.64 (m, 4H, ArH), 7.44–7.22 (m, 26H, ArH), 4.92 (d,
J = 11.6 Hz, 1H, PhCH2), 4.91 (d, J = 10.8 Hz, 1H, PhCH2),
4.73 (d, J = 11.6 Hz, 1H, PhCH2), 4.66 (d, J = 9.3 Hz, 1H,
PhCH2), 4.63 (d, J = 9.3 Hz, 1H, PhCH2), 4.59 (d, J = 10.8 Hz,
1H, PhCH2), 4.44, 4.42 (ABq, J = 11.7 Hz, 2H, PhCH2), 4.0 (s,
1H, H-4), 3.72 (m, 2H, H-3 and CHN3), 3.69–3.51 (m, 6H, H-2,
H-5, H-6a, H-6b, CH2O(CH3)3CSi), 3.43 (m, 1H, H-1), 1.98 (m,
1H, CHa), 1.41 (ddd, J = 2.3, 11.3, 14.3 Hz, 1H, CHb), 1.05 (s,
9H, (CH3)3C); 13C NMR (100 MHz, CDCl3) δ 138.8, 138.43,
138.35, 138.1, 135.8, 135.7, 133.19, 133.17, 129.9, 128.6,
128.5, 128.48, 128.39, 128.2, 128.0, 127.95, 127.91, 127.81,
127.79, 127.7, 84.9, 79.0, 77.5, 76.3, 75.5, 74.7, 73.7, 73.6,
72.5, 68.8, 67.8, 60.4, 33.1, 26.8, 19.3; HRMS calcd for
C53H60N3O6Si [M + H]+ 862.4251, found 862.4260.
1
1103 cm−1; H NMR (400 MHz, CDCl3) δ 7.74–7.72 (m, 4H,
ArH), 7.40–7.26 (m, 21H, ArH), 4.99 (d, J = 11.6 Hz, 1H,
PhCH2), 4.97 (d, J = 12.5 Hz, 1H, PhCH2), 4.72 (d, J =
12.2 Hz, 1H, PhCH2) 4.60 (d, J = 11.3 Hz, 1H, PhCH2), 4.53,
4.43 (ABq, J = 11.9 Hz, 2H, PhCH2) 4.37–4.30 (m, 1H,
CHCH2O(CH3)3CSi), 4.03 (t, J = 9.3 Hz, 1H, H-2), 3.95 (s, 1H,
H-4), 3.77–3.62 (m, 5H, H-3, H-5, H-6a and CH2O(CH3)3CSi),
3.54 (dd, J = 6.0, 9.0 Hz, 1H, H-6b), 3.40–3.34 (m, 1H, H-1),
2.27 (dt, J = 6.9, 11.2 Hz, 1H, CHa), 1.89 (app. q, J = 8.9,
11.0 Hz, 1H, CHb), 1.06 (s, 9H, (CH3)3CSi); 13C NMR
(100 MHz, CDCl3) δ 138.9, 138.6, 137.8, 135.7, 135.6, 133.5,
133.4, 129.6, 128.4, 128.1, 127.9, 127.7, 127.4, 127.3, 82.4, 80.2,
79.7, 78.0, 76.7, 75.4, 75.2, 73.5, 72.0, 69.1, 66.3, 31.0, 19.2;
HRMS calcd for C46H53O6Si [M + H]+ 729.3611, found 729.3587.
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(2S)-azido-3-
propanol (14). To a solution of 13 (210 mg, 0.24 mmol) in THF
(2.5 mL) was added a solution of 1.0 M TBAF in THF
(0.49 mL, 0.49 mmol) at rt and the reaction stirred for 8 h. It
was diluted with CH2Cl2 (30 mL), washed with H2O (10 mL)
and brine (5 mL), and dried over anhydrous Na2SO4. The
organic layer was concentrated and column chromatographic
purification of the crude residue on silica gel (30% ethyl acetate/
pet ether) yielded compound 14 as a viscous liquid (138 mg,
91%): [α]2D5 −2.5 (c 0.94, CHCl3); IR (CHCl3) ν 3432, 3020,
Bi-cyclic compound (10). The same procedure as described
earlier for triflation of 7 was used for alcohol 8 (209 mg,
0.25 mmol) to obtain 10 (138 mg, 76% over two steps) as a
white solid: [α]2D5 −9.8 (c 1.53, CHCl3); mp 112–113 °C; IR
1
(CHCl3) ν 3069, 3032, 1472, 1112 cm−1; H NMR (400 MHz,
CDCl3) δ 7.77–7.72 (m, 4H, ArH), 7.46–7.26 (m, 21H, ArH),
5.00 (d, J = 11.0 Hz, 1H, PhCH2), 4.98 (d, J = 12.2 Hz, 1H,
PhCH2), 4.73 (d, J = 12.2 Hz, 1H, PhCH2) 4.61 (d, J = 11.0 Hz,
1H, PhCH2), 4.54, 4.46 (ABq, J = 11.9 Hz, 2H, PhCH2)
;
2105, 1216, cm−1 1H NMR (400 MHz, CDCl3) δ 7.37–7.20
8136 | Org. Biomol. Chem., 2012, 10, 8132–8139
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(m, 20H, ArH), 4.95 (d, J = 11.0 Hz, 1H, PhCH2), 4.92 (d, J =
11.6 Hz, 1H, PhCH2), 4.74, 4.67 (ABq, J = 11.8 Hz, 2H,
PhCH2), 4.63 (d, J = 11.0 Hz, 1H, PhCH2), 4.62 (d, J = 11.6 Hz,
1H, PhCH2), 4.43, 4.42 (ABq, J = 11.8 Hz, 2H, PhCH2), 3.97
(d, J = 2.3 Hz, 1H, H-4), 3.68–3.52 (m, 6H, H-2, H-3, H-5,
H-6a, H-6b and CHN3), 3.49–3.45 (m, 2H, CH2O(CH3)3CSi),
3.39 (m, 1H, H-1), 2.36 (br s, 1H, OH), 2.02 (m, 1H, CHa), 1.71
(ddd, J = 4.8, 9.6, 14.0 Hz, 1H, CHb); 13C NMR (100 MHz,
CDCl3) δ 138.6, 138.3, 138.2, 137.9, 128.6, 128.55, 128.45,
128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 84.8, 78.7, 77.5, 76.6,
75.5, 74.7, 73.64, 73.60, 72.4, 68.9, 65.5, 61.3, 33.4; HRMS
calcd for C37H42N3O6 [M + H]+ 624.3074, found 624.3057.
CH2Cl2 (2.2 mL) and Et3N (31 μL) and Boc2O (85 μL,
0.37 mmol) added dropwise and the reaction stirred for 10 h.
Reaction mixture was concentrated in vacuo, diluted with EtOAc
(30 mL), washed with H2O (10 mL) and brine (5 mL), and dried
over anhydrous Na2SO4. The organic layer was concentrated and
column chromatographic purification of the residue on silica gel
(16% ethyl acetate/pet ether) yielded compound 16 as a white
solid (69 mg, 90% over two steps): [α]2D5 −0.2 (c 0.33, CHCl3);
mp 113–114 °C; IR (CHCl3) ν 3019, 1742, 1712, 1423,
1
1216 cm−1; H NMR (400 MHz, CDCl3) δ 7.36–7.23 (m, 20H,
ArH), 5.64 (d, J = 8.6 Hz, 1H, NH), 4.93 (d, J = 10.9 Hz, 1H,
PhCH2), 4.92 (d, J = 11.6 Hz, 1H, PhCH2), 4.73 (d, J = 11.6 Hz,
1H, PhCH2), 4.64 (d, J = 11.6 Hz, 1H, PhCH2), 4.61 (d, J =
11.6 Hz, 2H, PhCH2), 4.53–4.50 (m, 2H, PhCH2 and CHCOO),
4.41 (d, J = 11.8 Hz, 1H, PhCH2), 3.95 (s, 1H, H-4), 3.68 (s,
3H, CO2Me), 3.66 (t, J = 9.2 Hz, 1H, H-2), 3.58–3.47 (m, 4H,
H-3, H-5, H-6a, H-6b), 3.29 (t, J = 9.20, 9.28 Hz, 1H, H-1),
2.26 (m, 1H, CHa), 1.91 (ddd, J = 3.6, 10.4 Hz, 12.1 Hz, 1H,
CHb), 1.38 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3)
δ 173.2, 155.8, 138.6, 138.3, 138.2, 138.0, 128.6, 128.55, 128.4,
128.39, 128.2, 128.1, 128.0, 127.9, 127.86, 127.8, 127.7, 84.8,
79.6, 78.3, 76.9, 75.6, 74.7, 73.6, 72.6, 68.9, 52.3, 51.7, 33.4,
28.4; HRMS calcd for C43H52NO9 [M + H]+ 726.3642, found
726.3616.
Methyl 3C-(β-2,3,4,6-tetra-O-benzyl-galactopyranosyl)-(2S)-
azido propionate (15). To a stirred solution of alcohol 14
(128 mg, 0.21 mmol) in acetone (2.0 mL) was sequentially
added 15% NaHCO3 (0.62 mL), NaBr (4.0 mg, 0.04 mmol) and
TEMPO (6.4 mg, 0.04 mmol) at 0 °C. Subsequently, trichloro-
isocyanuric acid (95 mg, 0.4 mmol) was added portion-wise
over 5 min and the reaction was allowed to stir at 0 °C for 1 h.
Isopropanol (120 μL) was added to it and reaction mixture was
filtered through Celite-545, washed with acetone (50 mL), and
the solution was concentrated. The white residue was partitioned
between EtOAc (30 mL) and H2O (10 mL) and organic layer
was treated with 2.0 M HCl (0.98 mL), washed with brine
(5 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was taken in dry MeOH (2.2 mL) and
SOCl2 was added dropwise (22 μL, 0.31 mmol) at 0 °C over a
period of 5 min. It was stirred at 0 °C and gradually allowed to
warm up to rt over a period of 90 min. The reaction mixture was
concentrated and the residue was dissolved in CH2Cl2 (30 mL),
washed with NaHCO3 (15 mL), water (15 mL) and brine
(15 mL) and dried over anhydrous Na2SO4. The organic layer
was concentrated and column chromatographic purification of
the residue on silica gel (7% ethyl acetate/pet ether) afforded
compound 15 as a white solid (104 mg, 78% over two steps):
[α]2D5 −16.8 (c 0.60, CHCl3); mp 58–59 °C; IR (CHCl3) ν 3016,
Methyl β-D-galactopyranosyl-N-tert-butoxycarbonyl-L-alanine
(1a). To a solution of 16 (83 mg, 0.11 mmol) in anhydrous
MeOH–CH2Cl2 (4 : 1), was added vacuum dried Degussa type
Pd(OH)2/C (70 mg, 20%). It was stirred at rt for 8 h under a
hydrogen atmosphere using a H2 balloon (1 atm). It was filtered
through celite-545 and washed with 50% MeOH and CHCl3
solution. The organic layer was concentrated in vacuo. Column
chromatographic purification of the residue on silica gel (12%
MeOH–CH2Cl2) afforded compound 1a as a viscous liquid
(35 mg, 84% yield): [α]D25 +4.7 (c 0.58, CHCl3); IR (CHCl3)
ν 3406, 3020, 1736, 1700, 1216 cm−1 1H NMR (400 MHz,
;
CDCl3 + CD3OD) δ 4.13–4.09 (m, 1H), 3.90 (s, 1H, H-4), 3.82
(dd, J = 6.8, 11.6 Hz, 1H), 3.75 (s, 3H, CO2Me), 3.67 (dd, J =
4.4, 11.6 Hz, 1H), 3.45–3.4 (m, 3H), 3.21–3.16 (m, 1H),
2.24–2.17 (m, 1H, CHa), 1.96 (ddd, J = 3.6, 10.8, 14.4 Hz, 1H,
CHb), 1.27 (s, 9H, (CH3)3C); 13C NMR (100 MHz, CDCl3)
δ 174.1, 156.2, 80.3, 78.7, 76.3, 75.2, 71.4, 69.8, 62.0, 52.7,
50.7, 34.1, 28.4; HRMS calcd for C15H28NO9 [M + H]+
366.1764, found 366.1773.
2110, 1742, 1215 cm−1
;
1H NMR (400 MHz, CDCl3)
δ 7.36–7.23 (m, 20H, ArH), 4.95 (d, J = 11.0 Hz, 1H, PhCH2),
4.94 (d, J = 11.6 Hz, 1H, PhCH2), 4.75, 4.67 (ABq, J = 11.8 Hz,
2H, PhCH2), 4.63 (d, J = 11.6 Hz, 2H, PhCH2), 4.44, 4.43
(ABq, J = 11.7 Hz, 2H, PhCH2), 4.14 (dd, J = 3.2, 11.3 Hz, 1H,
CHN3), 4.01 (d, J = 2.4 Hz, 1H, H-4), 3.73 (s, 3H, CO2Me),
3.67 (t, J = 9.3 Hz, 1H, H-2), 3.62 (dd, J = 2.4, 9.3 Hz, 1H,
H-3), 3.58–3.53 (m, 3H, H-5, H-6a, H-6b), 3.42 (m, 1H, H-1),
2.15 (ddd, J = 2.0, 11.7, 11.9 Hz, 1H, CHa), 1.93 (ddd, J = 3.3,
10.7 Hz, 1H, CHb); 13C NMR (100 MHz, CDCl3) δ 171.3,
138.6, 138.24, 138.19, 137.9, 128.5, 128.46, 128.3, 128.1,
128.0, 127.9, 127.8, 127.7, 127.66, 84.7, 78.5, 76.9, 75.4, 75.3,
74.7, 73.6, 73.5, 72.4, 68.7, 58.6, 52.6, 33.9; HRMS calcd for
C38H42N3O7 [M + H]+ 652.3023, found 652.3022.
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(2R)-azido-3-
tert-butyldiphenylsilyloxy propane (17). To a stirred solution of
8 (185 mg, 0.22 mmol) in CH2Cl2 (2.2 mL) at 0 °C was sequen-
tially added pyridine (0.11 mL, 1.33 mmol) and MsCl
(0.037 mL, 0.486 mmol). The reaction was allowed to warm up
to rt over 3 h. It was diluted with CH2Cl2 (30 mL), washed with
NaHCO3 (15 mL), H2O (10 mL) and brine (5 mL), and dried
over anhydrous Na2SO4. The organic layer was concentrated
in vacuo and the crude product was purified by column chrom-
atography on silica gel (10% ethyl acetate/pet ether) to afford the
corresponding mesylate. This was dissolved in DMF (2.2 mL),
NaN3 (29 mg, 0.442 mmol) was added and the reaction mixture
was heated overnight at 120 °C. It was diluted with CHCl3
(30 mL), washed with H2O (10 mL) and brine (5 mL), and dried
Methyl 3C-β-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-N-
tert-butoxycarbonyl-L-alanine (16). To a stirred solution of 15
(69 mg, 0.11 mmol) in THF (2.4 mL) was added triphenylphos-
phine (56 mg, 0.21 mmol) and H2O (10 μL, 0.55 mmol) at rt
and the reaction mixture was heated at 80 °C. After 20 min, sol-
vents were evaporated and residue was co-evaporated with
toluene several times in vacuo. The residue was dissolved in dry
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8132–8139 | 8137

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over anhydrous Na2SO4. The organic layer was concentrated on
a rotary evaporator and the residue was purified by column
chromatography on silica gel (7% ethyl acetate/pet ether) to
afford compound 17 as a viscous liquid (141 mg, 74% over two
steps): [α]2D5 +0.8 (c 1.36, CHCl3); IR (CHCl3) ν 3018, 2960,
2105, 1216, cm−1; 1H NMR (400 MHz, CDCl3) δ 7.74–7.63 (m,
4H, ArH), 7.43–7.21 (m, 26H, ArH), 4.93 (d, J = 10.9 Hz, 1H,
PhCH2), 4.91 (d, J = 11.6 Hz, 1H, PhCH2), 4.73 (d, J = 11.8 Hz,
1H, PhCH2), 4.65 (s, 2H, PhCH2), 4.61 (d, J = 11.6 Hz, 1H,
PhCH2), 4.38, 4.37 (ABq, J = 11.8 Hz, 2H, PhCH2), 3.95 (d, J =
2.3, 1H, H-4), 3.73 (dd, J = 2.3, 10.2 Hz, 1H, H-3), 3.69–3.58
(m, 3H, H-5, H-6a and CHN3), 3.51–3.46 (m, 2H, H6b and
H-2), 3.41 (dd, J = 5.3, 9.0 Hz, 1H, CH2O(CH3)3CSi), 3.32 (dd,
J = 5.84, 7.08 Hz, 1H, CH2O(CH3)3CSi), 3.12 (td, J = 4.0,
9.1 Hz, 1H, H-1), 2.05 (ddd, J = 2.9, 7.8, 14.1 Hz, 1H, CHa),
1.67 (ddd, J = 5.2, 9.0, 14.1 Hz, 1H, CHb), 1.04 (s, 9H,
(CH3)3C); 13C NMR (100 MHz, CDCl3) δ 138.8, 138.4, 138.37,
138.0, 135.9, 135.8, 133.3, 133.3, 129.9, 128.6, 128.5, 128.4,
128.3, 128.28, 128.1, 128.05, 128.0, 127.9, 127.85, 127.8,
127.75, 127.7, 127.6, 84.8, 78.8, 77.1, 76.6, 75.5, 74.7, 73.62,
73.55, 72.3, 68.8, 66.4, 60.8, 32.8, 26.9, 19.3. HRMS calcd for
C53H60N3O6Si [M + H]+ 862.4251, found 862.4238.
138.2, 138.18, 137.9, 128.5, 128.49, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8, 127.6, 84.8, 78.2, 75.7, 75.3, 74.7, 73.6, 73.5,
72.2, 68.5, 59.0, 52.5, 33.9; HRMS calcd for C38H42N3O7
[M + H]+ 652.3023, found 652.3019.
Methyl 3C-β-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-N-
tert-butoxycarbonyl-D-alanine (20). The same procedure as
described for 16 was followed for reduction followed by Boc
protection of azido ester 19 (79 mg, 0.12 mmol) to afford 20
(79 mg, 90% over two steps) as a viscous liquid: [α]2D5 −10.6
(c 1.72, CHCl3); IR (CHCl3) ν 3020, 1746, 1707, 1498,
1
1217 cm−1; H NMR (400 MHz, CDCl3) δ 7.35–7.26 (m, 20H,
ArH), 5.42 (d, J = 6.3 Hz, 1H, NH), 4.93 (d, J = 11.4 Hz, 2H,
PhCH2), 4.74 (d, J = 11.7 Hz, 1H, PhCH2), 4.66 (d, J = 11.6 Hz,
1H, PhCH2), 4.64 (d, J = 11.5 Hz, 1H, PhCH2), 4.61 (d, J =
11.9 Hz, 1H, PhCH2), 4.43 (m, 3H, PhCH2 and CHCOO), 4.00
(d, J = 1.9 Hz, 1H, H-4), 3.67 (t, J = 9.7, 18.1 Hz, 1H, H-2),
3.66 (s, 3H, CO2Me), 3.59 (dd, J = 2.0, 9.2 Hz, 1H, H-3), 3.5
(m, 3H, H-5, H-6a and H-6b), 3.36 (app. t, J = 9.2 Hz, 1H,
H-1), 2.36 (m, 1H, CHa), 1.87 (m, 1H, CHb), 1.40 (s, 9H,
(CH3)3C); 13C NMR (100 MHz, CDCl3) δ 173.1, 155.3, 138.9,
138.4, 138.3, 137.9, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1,
127.9, 127.86, 127.8, 127.7, 84.8, 79.8, 78.4, 76.7, 76.5, 75.54,
74.7, 73.7, 73.6, 72.3, 68.5, 52.2, 51.6, 34.1, 28.5. HRMS calcd
for C43H52NO9 [M + H]+ 726.3642, found 726.3616.
1-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(2R)-azido-3-
propanol (18). The same procedure as described for 14 was fol-
lowed for de-silylation of compound 17 (180 mg, 0.21 mmol) to
afford 18 (104 mg, 80%) as a white solid: [α]2D5 −8.9 (c 0.96,
CHCl3); mp 81.7–82.7 °C; IR (CHCl3) ν 3463, 3065, 2106,
1454, 1216 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.37–7.21 (m,
20H, ArH), 4.96 (d, J = 11.7 Hz, 1H, PhCH2), 4.93 (d, J = 12.2
Hz, 1H, PhCH2), 4.74 (d, J = 11.6 Hz, 1H, PhCH2), 4.66 (d, J =
11.6 Hz, 2H, PhCH2), 4.61 (d, J = 11.7 Hz, 1H, PhCH2), 4.43,
4.41 (ABq, J = 11.8 Hz, 2H, PhCH2), 3.94 (d, J = 2.3 Hz, 1H,
H-4), 3.70 (t, J = 9.3 Hz, 1H, H-2), 3.66–3.51 (m, 6H, H-3, H-5,
H-6a, H-6b, CH2O(CH3)3CSi and CHN3), 3.41 (m, 2H,
CH2O(CH3)3CSi and H-1), 2.59 (br s, 1H, OH), 2.06 (m, 1H,
CHa), 1.82 (ddd, J = 4.4, 9.0, 14.5 Hz, 1H, CHb); 13C NMR
(100 MHz, CDCl3) δ 138.5, 138.2, 138.17, 137.8, 128.6,
128.58, 128.4, 128.3, 128.33, 128.1, 128.0, 127.9, 127.8, 127.7,
84.9, 78.1, 77.5, 76.3, 75.5, 74.7, 73.7, 73.6, 72.4, 69.1, 64.1,
60.9, 32.7; HRMS calcd for C37H42N3O6 [M + H]+ 624.3074,
found 624.3068.
Methyl β-D-galactopyranosyl-N-tert-butoxycarbonyl-D-alanine
(1b). The same procedure as described for 1a was followed for
de-benzylation of 20 (96 mg, 0.13 mmol) in anhydrous methanol
(3 mL) to afford 1b (41 mg, 85%) as a viscous liquid: [α]D25
−24.3 (c 0.58, CHCl3); IR (CHCl3) ν 3393, 2929, 1767, 1695,
1
1217 cm−1; H NMR (400 MHz, DMSO) δ 7.15 (d, J = 7.2 Hz,
1H, NH), 4.80 (d, J = 4.8 Hz, 1H), 4.66 (s, 1H), 4.34 (t, J = 4.8,
5.2 Hz, 1H), 4.27 (d, J = 4.4 Hz, 1H), 4.16 (app. q, J = 5.2, 7.2,
7.6 Hz, 1H), 3.66 (s, 1H), 3.58 (s, 3H, CO2Me), 3.46–3.34 (m,
2H), 3.24–3.14 (m, 3H), 3.09–3.05 (m, 1H), 2.14 (dd, J = 8.0,
12.4 Hz, 1H, CHa), 1.66–1.59 (m, 1H, CHb), 1.37 (s, 9H,
(CH3)3C); 13C NMR (100 MHz, CDCl3) δ 174.4, 155.9, 80.5,
78.5, 76.7, 75.2, 71.4, 69.8, 62.2, 52.8, 51.3, 29.9, 28.5; HRMS
calcd for C15H28NO9 [M + H]+ 366.1738, found 366.1754.
Acknowledgements
Methyl 3C-(β-2,3,4,6-tetra-O-benzyl-galactopyranosyl)-(2S)-
azido propionate (19). The same procedure as described for 15
was followed for oxidation followed by esterification of azido
alcohol 18 (90 mg, 0.14 mmol) to afford 19 (79 mg, 82% over
two steps) as a viscous liquid: [α]2D5 −2.2 (c 0.39, CHCl3); IR
This work was supported by the Council of Scientific and Indus-
trial Research (Grant No. 01(2376)/10/EMR-II) and Department
of Science and Technology (Grant No. SR/S1/OC-40/2009).
(CHCl3) ν 3019, 2928, 2109, 1745, 1216 cm−1 1H NMR
;
References
(400 MHz, CDCl3) δ 7.41–7.26 (m, 20H, ArH), 5.0 (d, J =
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(d, J = 11.7 Hz, 1H, PhCH2), 4.70 (d, J = 11.7 Hz, 1H, PhCH2),
4.69 (d, J = 11.8 Hz, 1H, PhCH2), 4.66 (d, J = 11.8 Hz, 1H,
PhCH2), 4.46, 4.48 (ABq, J = 11.7 Hz, 2H, PhCH2), 4.13 (dd,
J = 5.3, 7 Hz, 1H, CHN3), 4.05 (d, J = 2.1 Hz, 1H, H-4), 3.76
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14 Hz, 1H, CHb); 13C NMR (100 MHz, CDCl3) δ 170.7, 138.8,
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