A concise synthesis of globotriaosylsphingosine

Article abstract of DOI:10.1002/ejoc.201001690

Globotriaosylsphingosine (lysoCTH) is produced in the cell by deacylation of the globo-sphingolipid globotriaosylceramide. The latter compound is the major storage material encountered in Fabry patients, an inherited lysosomal storage disorder characteriz

Full text of DOI:10.1002/ejoc.201001690

FULL PAPER
DOI: 10.1002/ejoc.201001690
A Concise Synthesis of Globotriaosylsphingosine
Henrik Gold,[a] Rolf G. Boot,[b] Johannes M. F. G. Aerts,[b] Herman S. Overkleeft,[a]
Jeroen D. C. Codée,*[a] and Gijs A. van der Marel*[a]
Keywords: Sphingolipids / Glycosylation / Glycolipids / Protecting groups
Globotriaosylsphingosine (lysoCTH) is produced in the cell
by deacylation of the globo-sphingolipid globotriaosylcer-
amide. The latter compound is the major storage material en-
countered in Fabry patients, an inherited lysosomal storage
disorder characterized by partially impaired α-galactosid-
ase A (GLA) activity. Recent findings suggest that lysoCTH,
next to its acylated precursor, is an important causative of
Fabry disease symptoms. The glycolipid is thus a relevant
synthetic target, and we here report on its efficient synthesis.
Key to our strategy is the use of 4,6-O-di-tert-butylsilylene-
protected D-galactose donors to yield D-Gal-α-D-Gal linkages
with high stereoselectivity. In our optimized route we make
use of acyl protecting groups to mask most of the hydroxy
functions in the carbohydrate building blocks to facilitate
straightforward global deprotection.
Introduction
Glycosphingolipids (GSLs) are a ubiquitous class of the cell membrane. The galabiose disaccharide is an impor-
cellular components that partake in many biological pro- tant recognition site for both toxins and adhesive proteins,
cesses. Glycosphingolipids that belong to the globo series including bacterial lectins.[1,2] Moreover, some globo glyco-
have the d-Gal-α-d-Gal linkage as a characteristic substruc- sphingolipids have been identified as tumor-specific anti-
ture (Figure 1). This galabiose moiety is located in the hy- gens,[3] as is exemplified by the observed elevated glo-
drophilic part of the glycosphingolipid that protrudes from botriaosylceramide levels in Burkitt’s lymphoma.[4]
Figure 1. Globotriaosylceramide (R = fatty acid) and globotriaosylsphingosine (R = H).
The metabolism of glycosphingolipids is a tightly con-
trolled process, and disruption of any of the metabolic
transformations is at the basis of several human diseases
that belong to the family of lysosomal storage disorders.[5]
For example, an inherited defect in gene encoding for the
lysosomal hydrolase α-galactosidase A (GLA) is the under-
lying cause of Fabry disease.[6] This genetic defect results in
[a] Leiden Institute of Chemistry, Gorlaeus Laboratories,
Einsteinweg 55, 2300 RA Leiden, The Netherlands
E-mail: jcodee@chem.leidenuniv.nl
marel_g@chem.leidenuniv.nl
[b] Department of Medical Biochemistry, Academic Medical
Center, University of Amsterdam,
Amsterdam, The Netherlands
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001690.
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A Concise Synthesis of Globotriaosylsphingosine
reduced GLA activity, with a concomitant accumulation of
In the development of a robust and high-yielding syn-
its substrate globotriaosylceramide (CTH).[7] Although the thetic route towards lysoCTH, both a high degree of stereo-
deficiency in enzyme activity is the undisputed cause of the selectivity in the glycosylation reactions and minimal pro-
disease, correlation between CTH levels and disease mani- tecting group manipulations are of importance. With these
festations has yet to be observed. Recent findings have considerations in mind, we first turned our attention to the
shown that another glycosphingolipid, namely, globotriaos- stereoselective formation of the d-Gal-α-d-Gal linkage. Re-
ylsphingosine (lysoCTH), which is the deacylated form of cent literature demonstrates that 4,6-O-di-tert-butylsilylene-
CTH, may be the actual storage material that causes disease protected d-galactose donors can be condensed with vari-
manifestations in Fabry patients.[8,9] With the aim to get ous acceptor molecules in a highly stereoselective fashion
more insight in the physiological role of LysoCTH in Fabry to provide the 1,2-cis-linked products.[17] It appears that the
disease we decided to embark on the development of an steric influence of the bulky tert-butyl groups (positioned
efficient synthesis of this glycosphingolipid. In this paper above the anomeric position) overrules the trans-directing
we report on our results in the development of a concise properties of participating groups at the C2-OH of a donor
synthesis of globotriaosylsphingosine.
galactoside, with a high α-selectivity as a result. We rea-
soned that the use of the silylene protecting group would
present an attractive alternative to the existing routes, which
almost without exceptions employ a nonparticipating group
Results and Discussion
Dating back to the first reported synthesis of globotriose (benzyl) at the C2-OH of the galactose donor to achieve
(Gb3) by Cox et al.[10] and globotriaosylceramide by Sha- high, or in some cases complete, α-selectivity.
piro and Acher[11] in 1978, a handful of approaches towards
As the first research objective we set out to investigate
the synthesis of Gb3 have been reported.[12] The most com- the α-directing effect of 4,6-O-di-tert-butylsilylene-pro-
monly used strategy for the assembly of Gb3 is to attach a tected d-galactose donors in the condensation with a
galactose donor to a lactose acceptor, although condensa- number of galactose and lactose acceptors under a variety
tion of a d-Gal-α-d-Gal disaccharide with a glucose ac- of glycosylation conditions. Donors 2–7 and acceptors 9,
ceptor has also been reported.[13] One-pot procedures[14] 10, and 13 used in these studies were prepared from readily
using either the “armed–disarmed” concept or in situ re- available starting materials as depicted in Scheme 1.
movable protecting groups have been utilized. Expeditious
routes using fluorous protecting groups[15] to minimize the complished starting from known[17] phenyl 1-thio-4,6-O-di-
total assembly time have also been published.[16]
tert-butylsilylene-thiogalactoside (1) as the common precur-
The synthesis of the target donor galactosides was ac-
Scheme 1. Reagents and conditions: (a) TBDMSOTf, pyridine, DMAP, DMF, –40 °C, 45 min (93%); (b) BzCl, pyridine, 3 h (97%);
(c) 1. NIS, TFA, CH2Cl2, 0 °C, 3 h, 2. Et3N, 0 °C, 20 h (67%); (d) NIS, TFA, CH2Cl2, 0 °C, 3 h (78%); (e) ClC(NPh)CF3, Cs2CO3,
acetone, 0 °C, 2 h, (83%); (f) ClC(NPh)CF3, Cs2CO3, acetone, 0 °C, 3 h, (83%); (g) TBDPSCl, imidazole, DMF, 0 °C to r.t. (80%);
(h) BzCl, pyridine, 0 °C, 1 h (70%); (i) 1. NaOMe, MeOH, r.t., 20 h, 2. PhCH(OMe)2, p-TsOH·H2O, MeCN, r.t., 20 h, 3. BzCl, pyridine,
r.t., 20 h (66%); (j) 1. TFA, H2O, CH2Cl2, 0 °C, 1 h (92%), 2. HOBt, BzCl, Et3N, CH2Cl2, 0 °C, 5 h (63%).
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J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
sor. The tert-butyldimethylsilyl ether groups in 2 were intro- ated donor 5 with otherwise the same reaction conditions.
duced by using TBSOTf in pyridine with DMAP as the Imidate donor 7 gave, upon activation with trifluorometh-
catalyst. Benzoylation of the diols in 1 afforded thio donor anesulfonic acid[20] and subsequent addition of acceptor 10,
3.[17c] Hydrolysis of the thioacetals in 2 and 3 by using con- disaccharide 15 in 75% yield. In contrast to these results,
ditions we previously[18] disclosed [N-iodosuccinimide condensation of persilylated imidate 6 with acceptor 10 (ac-
(NIS), trifluoroacetic acid (TFA), dichloromethane] pro- tivating system triflic acid) proved unproductive. The same
vided hemiacetals 4 and 5,[19] respectively, which in turn holds true when thioglycosides 2 or 3 (Ph2SO, Tf2O) was
were transformed into acetimidate derivatives 6 and 7 by condensed with acceptor 10.[26] Acceptor 9 featuring a
using standard conditions.[20] It should be noted that the bulky TBDPS substituent at O-6 proved resistant to galac-
NIS/TFA-mediated hydrolysis of 2 proceeded through the tosidation, and condensation with thiogalactoside 2, hemi-
formation of the rather stable anomeric α-trifluoroacetate, acetal 4 (in both cases, activating system Ph2SO/Tf2O), or
which was hydrolyzed to the desired product after addition imidate 6 (activated by triflic acid) failed to give the disac-
of triethylamine.
charide. In the glycosylation experiments we performed that
Acceptors 9 and 10 were synthesized from phenyl 2,3-di- involved acceptor lactoside 13, we observed productive cou-
O-benzoyl-1-thiogalactoside (8).[21] Regioselective protec- plings, again with exclusive formation (at least in isolated
tion of the C6-OH in 8 as the TBDPS ether or the benzoyl form) of the desired d-Gal-α-d-Gal linkage, employing
ester produced galactose acceptors 9 and 10,[22] respectively. hemiacetal 4, hemiacetal 5, or imidate donor 7, in conjunc-
Acceptor lactoside 13[23] was prepared from peracetylated tion with the appropriate activator systems. The most ef-
thiolactoside 11[24] in the following five-step sequence: ficient glycosylation in these series proved to be the one
(1) deacetylation, (2) installment of the O-4Ј-O-6Ј benzyl- involving imidate 7, providing trisaccharide 17 in 90%
idene, (3) benzoylation of the remaining five hydroxy func- yield.
tions, (4) removal of the benzylidene protecting group, and
(5) selective benzoylation of the primary alcohol.
The final stages of our synthesis of the title compound
are depicted in Scheme 3. Requisite partially protected d-
With the set of donor and acceptor galactosides/lactos- erythro-sphingosine derivative 20 was prepared in two steps
ides in hand we turned our attention to the construction of (benzoylation followed by liberation of the primary hy-
the desired d-Gal-α-d-Gal linkage. To this end, we investi- droxy) from known[27] sphingosine derivative 19. It should
gated the use of different donor–acceptor pairs and glycos- be noted that in the final deprotection step we could not
ylation conditions. The fruitful reactant/reagent combina- avoid partial migration of the benzoyl group from the sec-
tions, with respect to productive coupling (isolated yields) ondary hydroxy group to the primary one, with 62% yield
and anomeric selectivity, are listed in Scheme 2. Hemiacetal as a result.[28] Triflic acid mediated condensation of azido-
donors 4 and 5 were both successfully condensed with sphingosine 20 with trisaccharide 18, prepared from 17 by
phenyl 2,3,6-tri-O-benzoyl-1-thiogalactoside (10) under the hydrolysis of the thioacetal and ensuing installation of the
agency of diphenyl sulfoxide and triflic anhydride to yield imidate group, provided the title compound in fully pro-
disaccharides 14 and 15, respectively.[25] Both reactions tected form 21 in 80% yield and with no detectable forma-
yielded exclusively the d-Gal-α-d-Gal linkage, as evidenced tion of the α-anomer. Condensation of thioglycoside 17
by the observed 1Ј-H coupling constants (J1Ј,2Ј ≈ 3.5 Hz). (Ph2SO, Tf2O) with acceptor 20 provided the same product
The important difference in these two experiments is the far in much lower (32%) yield, whereas dehydrative condensa-
more (90% as opposed to 30%) efficient glycosidation of tion of the intermediate hemiacetal, obtained after hydroly-
acceptor 10 by silylated donor 4 in comparison to benzoyl- sis of the thioacetal in 17, provided 21 in 26% yield. Glo-
Scheme 2. Reagents and conditions: (a) Ph2SO, Tf2O, TTBP, DCM, –60 °C to r.t., (b) TfOH, DCM, 0 °C.
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A Concise Synthesis of Globotriaosylsphingosine
Scheme 3. Reagents and conditions: (a) 1. NIS, TFA, CH2Cl2, 0 °C, 3 h (86%), 2. ClC(NPh)CF3, Cs2CO3, acetone, 0 °C, 2 h (92%);
(b) 1. BzCl, pyridine, r.t. (93%), 2. TBAF, AcOH, THF, 0 °C, 1 h (62%); (c) TfOH (cat.), 0 °C, 1 h (80%); (d) 1. NaOMe, MeOH, r.t.,
·
3 h, 2. H2S, pyridine, AcOH, Et3N, THF, r.t., 3 h, 3. (HF)3 Et3N, pyridine, r.t., 20 h, 72%.
moisture-sensitive reactions were performed under an argon atmo-
sphere. Molecular sieves (3 Å) were flame dried prior to use. Liquid
column chromatography was performed using forced flow of the
indicated solvent systems on Screening Devices Silica gel 60 (40–
63 μm mesh). Analytical TLC was performed on aluminium sheets,
precoated with silica gel (Merck, silica gel 60, F254). Compounds
were visualized using UV absorption (245 nm) or by spraying with
20% H2SO4 in ethanol, ammonium molybdate/cerium sulfate solu-
tion [(NH4)6Mo7O24·4H2O (25 g/L), (NH4)4Ce(SO4)6·2H2O (10 g/
L), 10% sulfuric acid in ethanol], or phosphomolybdic acid in
EtOH (150 g/L) followed by charring (≈150 °C) or by spraying with
potassium permanganate (1.6% in conc. sulfuric acid). IR spectra
were recorded with a Shimadzu FTIR-8300. Optical rotations were
measured with a Propol automatic polarimeter (sodium d line, λ =
589 nm). 1H and 13C NMR spectra were recorded with a Bruker
AV 400 MHz spectrometer at 400.2 (1H) and 100.6 (13C) MHz or
botriaosylsphingosine 22 was finally obtained after the fol-
lowing three-step sequence of events. (1) Global debenzo-
ylation was performed using Zemplén conditions. (2) The
partially deprotected Gb3 was purified by column
chromatography prior to reduction of the azide with hydro-
gen sulfide to avoid acylation of the free amine. (3) The di-
tert-butylsilylene protecting group was then removed with
hydrogen fluoride in pyridine to give globotriaosylsphingo-
sine 22 in 72% yield after HPLC purification.
Conclusions
In conclusion, we have described a straightforward syn-
thesis of globotriaosylsphingosine. The optimized route of
synthesis uses an α-directing galactosyl imidate bearing a with a Bruker AV 600 MHz spectrometer at 600.0 (1H) and 150.1
(13C) MHz, respectively. Chemical shifts are reported as δ values
4,6-di-tert-butylsilylene protecting group for the formation
(ppm) and directly referenced to TMS (δ =0.00 ppm) in CDCl3 or
of the d-Gal-α-d-Gal glycosidic linkage, giving access to
to the solvent residual peak (D2O). Coupling constants (J) are
phenyl 1-thioglobotrioside. The globotriaosyl donor was
then transformed into the corresponding N-phenyl trifluo-
roimidate donor to achieve optimal yield in the condensa-
tion with an azidosphingosine acceptor. The protected glo-
given in Hz and all 13C spectra are proton decoupled. NMR assign-
ments were made using COSY and HSQC and in some cases
TOCSY experiments. LC–MS analyses were performed with a
LCQ Advantage Max (Thermo Finnigan) equipped with a Gemini
C18 column (Phenomenex, 50ϫ4.6 mm, 3μ), utilizing the following
botriaosyl sphingosine was assembled in 57% yield over
four steps from the 4,6-di-tert-butylsilylene galactosyl imid-
ate. A mild deprotection sequence produced the desired glo-
botriaosylsphingosine in 72% yield.
buffers: A: H2O, B: acetonitrile, and C: 1.0% TFA (aq.).
General Procedure for the Dehydrative Glycosylations: 1-Hydroxy-
donor (0.12 mmol, 1.2 equiv.), diphenyl sulfoxide (0.26 mmol,
2.6 equiv.),
and
2,4,6-tris-tert-butylpyrimidine
(0.12 mmol,
1.2 equiv.), were dissolved in anhydrous DCM (3 mL) under an at-
mosphere of argon. Activated molecular sieves (3 Å) were added,
and the mixture was stirred for 1 h at ambient temperature. The
solution was then cooled to –60 °C and trifluoromethanesulfonic
anhydride (0.130 mmol, 1.3 equiv.) was added. The mixture was
warmed to –40 °C and stirred at this temperature for 1 h. The reac-
tion was then cooled to –60 °C and the acceptor (0.10 mmol,
1.0 equiv.) was added as a solution in anhydrous DCM (2 mL).
The reaction was stirred going to room temperature and was then
quenched by addition of anhydrous triethylamine (1.0 mmol,
Experimental Section
General: Commercially available reagents and solvents (Acros,
Fluka, or Merck) were used as received unless stated otherwise.
Dichloromethane and THF were freshly distilled before use from
P2O5 and Na/benzophenone, respectively. Triethylamine was dis-
tilled from calcium hydride and stored over potassium hydroxide.
Trifluoromethanesulfonic anhydride was distilled from P2O5.
Traces of water were removed from the starting compounds by co-
evaporation with dichloroethane, dioxane, and/or toluene. All
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J. D. C. Codée, G. A. van der Marel et al.
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10 equiv.). The mixture was transferred to an extraction funnel
using EtOAc, and the organics were washed with sat. aq. NaHCO3
and brine. The water layers were extracted with EtOAc, and the
combined organics were dried (Na2SO4), filtered, and concentrated
in vacuo.
(dd, J = 12.2, 1.9 Hz, 1 H, 6a-H), 4.15 (dd, J = 12.2, 2.0 Hz, 1 H,
6b-H), 4.01 (t, J = 8.9 Hz, 1 H, 2-H), 3.52 (dd, J = 8.6, 2.8 Hz, 1
H, 3-H), 3.33 (m, 1 H, 5-H), 1.12 (s, 9 H, CH3-tBu-Si), 1.04 (s, 9 H,
CH3-tBu-Si), 0.96 (s, 9 H, CH3-tBu-Si), 0.95 (s, 9 H, CH3-tBu-Si), 0.26
(s, 3 H, CH3-TBS), 0.15 (s, 3 H, CH3-TBS), 0.12 (s, 3 H, CH3-TBS),
0.10 (s, 3 H, CH3-TBS) ppm. 13C NMR (101 MHz, CDCl3): δ =
135.8 (Cq-arom), 131.6, 128.6, 126.9 (3 CHarom), 90.5 (C-1), 77.9 (C-
3), 74.7 (C-5), 74.5 (C-4), 70.0 (C-2), 67.3 (C-6), 27.8, 27.4, 26.50,
26.46 (4 CH3-tBu-Si), 23.4, 20.7, 18.29, 18.28 (4 Cq-tBu-Si), –2.0,
General Procedure for the Imidate Glycosylations: The imidate do-
nor (0.12 mmol, 1.2 equiv.) and acceptor (0.1 mmol, 1 equiv.) were
coevaporated two times in toluene and were then dissolved in anhy-
drous DCM (2 mL) and cooled to 0 °C before addition of a cata-
lytic amount of TfOH (0.01 mmol, 0.1 equiv.). The reaction was
stirred until TLC showed complete conversion of the acceptor. The
reaction was then quenched by addition of triethylamine
(1.0 mmol, 10 equiv.). The organics were transferred to an extrac-
tion funnel using EtOAc, and the organics were washed with sat.
aq. NaHCO3 and brine. The water layers were extracted with
EtOAc, and the combined organics were dried (Na2SO4), filtered,
and concentrated in vacuo.
–3.39, –3.42, –3.7 (4 CH3-TBS) ppm. IR (neat): ν = 2932, 2856, 1473,
˜
1254, 1080, 839, 772 cm–1. HRMS: calcd. for [C32H60O5SSi3
H]+ 641.3542; found 641.3542.
+
Phenyl
2,3-Di-O-benzoyl-4,6-O-di-tert-butylsilanediyl-1-thio-β-D-
galactopyranoside (3): Phenyl 4,6-O-di-tert-butylsilanediyl-1-thio-β-
d-galactopyranoside (3.30 g, 8.0 mmol, 1.0 equiv.) was dissolved in
pyridine (20 mL) and benzoyl chloride (2.23 mL, 19.2 mmol,
2.4 equiv.) was added at room temperature. The reaction was stirred
until TLC showed full conversion to a higher running product and
was then quenched with MeOH (1 mL) and concentrated under
reduced pressure. The residue was dissolved in EtOAc (50 mL) and
washed with 1 n HCl (50 mL), sat. aq. NaHCO3 (50 mL), and brine
(40 mL). The aqueous layers were extracted with EtOAc (50 mL),
and the combined organics were dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by silica gel column chromatog-
raphy (10% EtOAc in petroleum ether) afforded the title compound
as a white solid (4.80 g, 7.7 mmol, 97%). Rf = 0.25 (10% EtOAc
in petroleum ether). [α]2D2 = +121 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.03–7.96 (m, 4 H, Harom), 7.55–7.45 (m,
4 H, Harom), 7.42–7.35 (m, 4 H, Harom), 7.28–7.24 (m, 3 H, Harom),
5.92 (t, J = 10.0 Hz, 1 H, 2-H), 5.21 (dd, J = 9.6, 3.2 Hz, 1 H, 3-
H), 4.95 (d, J = 10.0 Hz, 1 H, 1-H), 4.88 (d, J = 3.2 Hz, 1 H, 4-
H), 4.40–4.30 (m, 2 H, 6a-H and 6b-H), 3.65 (br. s, 1 H, 5-H),
1.16 (s, 9 H, CH3-tBu-Si), 0.96 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR
(101 MHz, CDCl3): δ = 166.1, 165.4 (2 C=OBz), 133.8 (Cq-arom),
133.22, 133.15, 132.4, 129.79 (4 CHarom), 129.77, 129.6 (2 Cq-arom),
129.4, 128.9, 128.4, 128.3, 127.8 (5 CHarom), 87.5 (C-1), 75.4
(C-3), 75.0 (C-5), 70.4 (C-4), 68.1 (C-2), 67.1 (C-6), 27.5, 27.4 (2
Phenyl 4,6-O-Di-tert-butylsilanediyl-1-thio-β-D-galactopyranoside
(1): Phenyl 1-thio-β-d-galactopyranoside (10.9 g, 40.0 mmol,
1.05 equiv.) was dried by coevaporation with anhydrous DMF
(100 mL) and then dissolved in anhydrous DMF (160 mL). The
mixture was cooled to –40 °C before dropwise addition of di-tert-
butylsilyl bis(trifluoromethanesulfonate) (12.3 mL, 38.1 mmol,
1.0 equiv.). The reaction was stirred at –40 °C for 30 min followed
by addition of pyridine (9.24 mL, 114 mmol, 3.0 equiv.). The reac-
tion was stirred for an additional 15 min and then transferred to
an extraction funnel with diethyl ether (400 mL). The organics were
washed with water (2ϫ400 mL) and brine (300 mL). The aqueous
layers were extracted with diethyl ether (300 mL), and the com-
bined organics were dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by silica gel column chromatography (5–20%
acetone in DCM) afforded the title compound as a clear viscous
oil (14.6 g, 35.4 mmol, 93%). Rf = 0.15 (20% EtOAc in petroleum
1
ether). [α]2D2 = –63 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ = 7.56–7.51 (m, 2 H, Harom), 7.33–7.24 (m, 3 H, Harom), 4.56 (d,
J = 9.8 Hz, 1 H, 1-H), 4.42 (dd, J = 3.5, 1.1 Hz, 1 H, 4-H), 4.26
(dd, J = 12.5, 1.9 Hz, 1 H, 6a-H), 4.22 (dd, J = 12.5, 2.2 Hz, 1 H,
6b-H), 3.76 (dd, J = 9.8, 9.0 Hz, 1 H, 2-H), 3.55 (dd, J = 9.0,
3.5 Hz, 1 H, 3-H), 3.45 (m, 1 H, 5-H), 3.08 (br. s, 2 H, OH), 1.05 (s,
9 H, CH3tBu-Si), 1.04 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR (101 MHz,
CDCl3): δ = 133.2 (Cq-arom), 132.3, 128.8, 127.7 (CHarom), 88.8 (C-
1), 75.1 (C-5), 75.0 (C-3), 72.5 (C-4), 70.5 (C-2), 67.0 (C-6), 27.5,
CH3-tBu-Si), 23.2, 20.7 (2 Cq-tBu-Si) ppm. IR (neat): ν = 2934, 2858,
˜
1720, 1273, 1169, 1084, 978, 826, 746 cm–1. HRMS: calcd. for
[C34H40O7SSi + H]+ 621.2337; found 621.2340.
2,3-Di-O-(tert-butyldimethylsilyl)-4,6-O-di-tert-butylsilanediyl-α/β-
D-galactopyranose (4): Phenyl 2,3-di-O-(tert-butyldimethylsilyl)-4,6-
O-di-tert-butylsilanediyl-1-thio-β-d-galactopyranoside (1.90 g,
2.96 mmol, 1.0 equiv.) was dissolved in DCM (30 mL). N-iodosuc-
cinimide (1.33 g, 5.93 mmol, 2.0 equiv.) was added at 0 °C, before
addition of trifluoroacetic acid (0.23 mL, 2.96 mmol, 1.0 equiv.).
The reaction was left stirring at 0 °C under exposure to the atmo-
27.3 (2 CH3-tBu-Si), 23.2, 20.5 (Cq-tBu-Si) ppm. IR (neat): ν = 3398,
˜
2934, 2858, 1473, 1162, 1063, 826, 732, 649, 442 cm–1. HRMS:
calcd. for [C20H32O5SSi + Na]+ 435.1632; found 435.1629.
Phenyl 2,3-Di-O-(tert-butyldimethylsilyl)-4,6-O-di-tert-butylsilane-
diyl-1-thio-β-D-galacto-pyranoside (2): Phenyl 4,6-O-di-tert-butylsil- sphere. Initially TLC showed full conversion to a higher running
anediyl-1-thio-β-d-galactopyranoside (1.73 g, 4.2 mmol, 1.0 equiv.)
and DMAP (51 mg, 0.42 mmol, 0.1 equiv.) were dissolved in pyr-
idine (20 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate
(2.5 mL, 10.9 mmol, 2.6 equiv.) was added at 0 °C. The reaction
was stirred at 0 °C for 15 min and then at room temperature over-
night. The reaction was concentrated in vacuo, diluted with EtOAc
product (anomeric TFA adduct, which could be isolated). Triethyl-
amine (1.25 mL, 8.89 mmol, 3.0 equiv.) was added, and the reac-
tion showed full conversion to a lower running product after 5 h.
The mixture was then transferred to an extraction funnel with
EtOAc (70 mL). The organics were washed with sodium thiosulfate
(20% aq., 100 mL), sat. aq. NaHCO3 (100 mL), and brine (80 mL).
(80 mL) and washed with 1 n HCl (100 mL), sat. aq. NaHCO3 The aqueous layers were extracted with EtOAc (100 mL), and the
(100 mL), and brine (80 mL). The aqueous layers were extracted
with EtOAc (80 mL), and the combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by silica
gel column chromatography (0–40% DCM in petroleum ether) af-
forded the title compound as a clear oil (2.22 g, 3.46 mmol, 83%).
Rf = 0.33 (40% DCM in petroleum ether). 1H NMR (400 MHz,
CDCl3): δ = 7.48 (m, 2 H, Harom), 7.29–7.19 (m, 3 H, Harom), 4.56
(d, J = 9.4 Hz, 1 H, 1-H), 4.32 (dd, J = 2.8, 1.0 Hz, 1 H, 4-H), 4.19
combined organics were dried (Na2SO4), filtered, and concentrated
in vacuo. Purification by silica gel column chromatography (5–20%
EtOAc in petroleum ether) afforded the title compound as a clear
oil (1.09 g, 1.99 mmol, 67%). Rf = 0.30 (10% EtOAc in petroleum
ether). NMR assignment of major isomer (α): 1H NMR (400 MHz,
CDCl3): δ = 5.18 (d, J = 3.5 Hz, 1 H, 1-H), 4.30 (d, J = 2.9 Hz, 1
H, 4-H), 4.23 (dd, J = 12.4, 1.7 Hz, 1 H, 6a-H), 4.17 (dd, J = 12.4,
1.7 Hz, 1 H, 6b-H), 4.07 (dd, J = 9.3, 3.5 Hz, 1 H, 2-H), 3.89 (br.
1656
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1652–1663

A Concise Synthesis of Globotriaosylsphingosine
s, 1 H, 5-H), 3.79 (dd, J = 9.3, 2.9 Hz, 1 H, 3-H), 2.99 (br. s, 1 H, 5.25 mmol, 1.5 equiv.), and the reaction was stirred at 0 °C for 2 h.
OH), 1.04 (br. s, 18 H, 2 CH3tBu-Si), 0.94 (s, 9 H, CH3tBu-Si), 0.92
(s, 9 H, CH3tBu-Si), 0.13 (s, 3 H, CH3-TBS), 0.11 (s, 3 H, CH3-TBS), fication by silica gel column chromatography, using silica gel that
0.10 (s, 6 H, 2 CH3-TBS) ppm. 13C NMR (101 MHz, CDCl3): δ =
was neutralized by running an eluent of 3% NEt3 in petroleum
94.0 (C-1), 74.6 (C-3), 71.3 (C-4), 70.1 (C-5), 67.9 (C-2), 67.4 (C- ether (100 mL) through the column (0–5% EtOAc, 20% DCM in
The reaction mixture was filtered and concentrated in vacuo. Puri-
6), 27.42, 27.35, 26.04, 25.99 (4 CH3-tBu-Si), 23.4, 20.7, 18.07, 18.05
petroleum ether) produced the title compound as a white solid
(4 Cq-tBu-Si), –4.0, –4.1, –4.3, –4.8 (4 CH3-TBS) ppm. IR (neat): ν =
(1.90 g, 2.72 mmol, 78 %). Rf = 0.64 (0.58 for β-anomer; 10 %
EtOAc and 20% DCM in petroleum ether). H NMR (400 MHz,
CDCl3): δ = 8.06–7.98 (m, 4 H, Harom), 7.61–7.50 (m, 2 H, Harom),
˜
1
2932, 2858, 1472, 1253, 1102, 833, 774, 648 cm–1. HRMS: calcd.
for [C26H56O6Si3 + H]+ 549.3458; found 549.3453. Data for the
anomeric TFA adduct trifluoroacetyl 2,3-di-O-(tert-butyldimethyl- 7.46–7.35 (m, 4 H, Harom), 7.12 (t, J = 7.7 Hz, 2 H, Harom-NPh),
silyl)-4,6-O-di-tert-butylsilandiyl-1-thio-α-d-galacto-pyranoside: Rf
= 0.95 (10 % EtOAc in petroleum ether). 1H NMR (400 MHz,
CDCl3): δ = 6.38 (d, J = 3.3 Hz, 1 H, 1-H), 4.45 (d, J = 2.2 Hz, 1
H, 4-H), 4.34 (dd, J = 9.5, 3.3 Hz, 1 H, 2-H), 4.27 (d, J = 12.7 Hz,
7.00 (t, J = 7.7 Hz, 1 H, Harom-NPh), 6.87 (br. s, 1 H, 1-H), 6.40 (br.
s, 2 H, Harom-NPh), 6.02 (br. d, J = 9.2 Hz, 1 H, 2-H), 5.65 (dd, J
= 10.6, 3.3 Hz, 1 H, 3-H), 5.00 (s, 1 H, 4-H), 4.40–4.26 (m, 2 H,
6a-H and 6b-H), 4.15 (br. s, 1 H, 5-H), 1.13 (s, 9 H, CH3-tBu-Si),
1 H, 6a-H), 4.20 (d, J = 12.7 Hz, 1 H, 6b-H), 3.91 (dd, J = 9.5, 0.98 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR (101 MHz, CDCl3): δ =
2.7 Hz, 1 H, 3-H), 3.85 (br. s, 1 H, 5-H), 1.09 (br. s, 18 H, 166.1, 165.6 (2 C=OBz), 143.0 (C=NNPh), 133.5, 133.3, 129.8, 129.7
2 CH3tBu-Si), 0.98 (s, 9 H, CH3tBu-Si), 0.90 (s, 9 H, CH3tBu-Si), 0.15 (4 CHarom), 129.5, 129.0 (2 Cq-arom), 128.6, 128.5, 128.4 (3 CHarom),
(s, 3 H, CH3-TBS), 0.14 (s, 6 H, 2 CH3-TBS), 0.13 (s, 3 H, 124.2, 119.1 (2 CHarom-NPh), 93.4 (br., C-1), 70.74 (C-3), 70.65 (C-
CH3-TBS) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.2 (q, J = 4), 69.8 (C-5), 67.2 (C-2), 66.6 (C-6), 27.5, 27.2 (2 CH3-tBu-Si), 23.3,
42.5 Hz, C=O), 114.6 (q, J = 286.1 Hz, CF3), 98.0 (C-1), 74.2 (C-
20.8 (2 Cq-tBu-Si) ppm. IR (neat): ν = 2948, 2862, 1732, 1276, 1208,
˜
3), 71.11 (C-5), 71.06 (C-4), 68.0 (C-2), 66.6 (C-6), 27.4, 27.3, 26.1, 1119, 994, 786, 707, 443 cm–1. HRMS: calcd. for [C36H40F3NO8Si
25.8 (4 CH3tBu-Si), 23.4, 20.8, 18.1, 17.8 (4 Cq-tBu-Si), –4.2, –4.4, + H]+ 700.2548; found 700.2549.
–4.5, –4.7 (4 CH3-TBS) ppm.
Phenyl 2,3-Di-O-benzoyl-β-D
-galactopyranoside (8):[21] Phenyl 2,3-
2,3-Di-O-benzoyl-4,6-O-di-tert-butylsilanediyl-α/β-
D
-galacto-
di-O-benzoyl-4,6-O-benzylidene-1-thio-β-d-galactopyranoside
(2.12 g, 3.92 mmol, 1.0 equiv.) was dissolved in acetic acid (40 mL)
and heated to 80 °C. The reaction was stirred until TLC showed
full conversion to a lower running product (≈3 h) and was then
concentrated in vacuo. Purification by silica gel column chromatog-
pyranose (5): Phenyl 2,3-di-O-benzoyl-4,6-O-di-tert-butylsilanediyl-
1-thio-β-d-galactopyranoside (5.49 g, 8.85 mmol, 1.0 equiv.) was
dissolved in DCM (85 mL). N-iodosuccinimide (3.98 g, 17.7 mmol,
2.0 equiv.) was added at 0 °C, before addition of trifluoroacetic acid
(0.68 mL, 8.85 mmol, 1.0 equiv.). The reaction was left stirring un- raphy (20–40% EtOAc in petroleum ether) afforded the title com-
der exposure to the atmosphere until TLC showed full conversion.
The mixture was then transferred to an extraction funnel with
EtOAc (150 mL) and washed with sodium thiosulfate (20% aq.,
200 mL), sat. aq. NaHCO3 (200 mL), and brine (150 mL). The
aqueous layers were extracted with EtOAc (150 mL), and the com-
bined organics were dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by silica gel column chromatography (0–10%
ethyl ether, 40% DCM in petroleum ether) afforded the title com-
pound as a white solid (3.67 g, 6.9 mmol, 78%). Rf = 0.25 (20%
EtOAc in petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 8.04–
7.97 (m, 4 H, CHarom), 7.56–7.49 (m, 2 H, CHarom), 7.42–7.35 (m,
pound as a white solid (1.33 g, 2.8 mmol, 74%). Rf = 0.35 (50%
EtOAc in petroleum ether). [α]2D2 = +105 (c = 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.99–7.90 (m, 4 H, Harom), 7.59–
7.49 (m, 4 H, Harom), 7.40–7.24 (m, 7 H, Harom), 5.81 (dd, J = 10.0,
9.9 Hz, 1 H, 2-H), 5.33 (dd, J = 9.9, 3.0 Hz, 1 H, 3-H), 4.98 (d, J
= 10.0 Hz, 1 H, 1-H), 4.43 (d, J = 2.8 Hz, 1 H, 4-H), 4.02 (dd, J
= 11.9, 5.9 Hz, 1 H, 6a-H), 3.93 (dd, J = 11.9, 4.5 Hz, 1 H, 6b-H),
3.82 (t, J = 5.1 Hz, 1 H, 5-H), 2.65 (br. s, 2 H, OH) ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.8, 165.3 (2 C=OBz), 133.4, 133.2,
132.4, 129.83, 129.77 (5 CHarom), 129.3 (Cq-arom), 129.0 (CHarom),
128.9 (Cq-arom), 128.42, 128.35, 128.1 (3 CHarom), 86.6 (C-1), 78.1
4 H, CHarom), 5.77 (dd, J = 10.5, 3.5 Hz, 0.7 H, 2α-H), 5.72 (m, (C-5), 75.5 (C-3), 68.4 (C-4), 67.9 (C-2), 62.7 (C-6) ppm. IR (neat):
0.7 H, 1α-H), 5.66 (m, 1 H, 3α-H and 2β-H), 5.31 (dd, J = 10.2,
3.2 Hz, 0.3 H, 3β-H), 4.91–4.85 (m, 1 H, 4α-H and 1β-H), 4.83 (d,
J = 3.0 Hz, 0.3 H, 4β-H), 4.38–4.31 (m, 1.3 H, 6a-α-H, 6a-β-H, and
6b-α-H), 4.22 (dd, J = 12.6, 1.6 Hz, 0.7 H, 6b-β-H), 4.19 (m, 0.7 H,
5α-H), 3.68 (m, 0.3 H, 5β-H), 3.63 (d, 0.3 H, OHβ), 2.81 (s, 0.7 H,
OHα), 1.15 (s, 2.7 H, CH3-tBu-Si-β), 1.13 (s, 9 H, CH3-tBu-Si-α/β), 0.98
(s, 6.3 H, CH3-tBu-Si-α) ppm. 13C NMR (101 MHz, CDCl3): δ =
167.4, 166.21, 166.15, 166.10 (4 C=OBz), 133.5, 133.33, 133.29,
133.1, 129.9, 129.8, 129.74, 129.71 (8 CHarom), 129.42, 129.40,
129.1 (3 Cq-arom), 128.43, 128.37 (2 CHarom), 96.3 (C-1β), 91.2 (C-
1α), 73.4 (C-3β), 71.9 (C-2β), 71.7 (C-5β), 71.3 (C-4α), 70. 6 (C-3α),
70.5 (C-4β), 68.9 (C-2α), 67.04 (C-6α), 67.03 (C-5α), 66.9 (C-6β),
27.5, 27.43, 27.36, 27.2 (CH3, 4 CH3-tBu-Si-α/β), 23.28, 23.26, 20.8,
ν = 3470, 3063, 2942, 2878, 1718, 1275, 1093, 1069, 1027, 734, 708,
˜
691 cm–1. HRMS: calcd. for [C26H24O7S + H]+ 481.1316; found
481.1313.
Phenyl 2,3-Di-O-benzoyl-6-O-tert-butyldiphenylsilyl-β-D-galactopyr-
anoside (9): Phenyl 2,3-di-O-benzoyl-1-thio-β-d-galactopyranoside
(1.79 g, 3.73 mmol, 1.0 equiv.) and imidazole (0.38 g, 5.59 mmol,
1.5 equiv.) were dissolved in anhydrous DMF (20 mL) and cooled
to 0 °C. tert-Butyldiphenylchlorosilane (1.13 g, 4.10 mmol,
1.1 equiv.) was dissolved in anhydrous DMF (10 mL) and added to
the cooled solution. The reaction was stirred, going to ambient
temperature overnight and was then quenched with methanol
(1 mL). The mixture was transferred to an extraction funnel with
EtOAc (100 mL) and washed with water (2ϫ100 mL) and brine
(80 mL). The aqueous layers were extracted with EtOAc (100 mL),
and the combined organics were dried (Na2SO4), filtered, and con-
centrated in vacuo. Purification by silica gel column chromatog-
20.7 (4 Cq-tBu-Si-α/β) ppm. IR (neat): ν = 3473, 2935, 2860, 1719,
˜
1267, 1100, 1073, 997, 708, 441 cm–1. HRMS: calcd. for
[C28H36O8Si + H]+ 529.2252; found 529.2249.
2,3-Di-O-benzoyl-4,6-O-di-tert-butylsilanediyl-α-D-galacto- raphy (5–10% EtOAc in petroleum ether) afforded the title com-
pyranoside N-Phenyl-2,2,2-trifluoroacetimidate (7): 2,3-Di-O-ben-
zoyl-4,6-O-di-tert-butylsilanediyl-α/β-d-galactopyranose (1.85 g,
3.5 mmol, 1.0 equiv.) was dissolved in acetone (20 mL) and cooled
to 0 °C. Cesium carbonate (1.71 g, 5.25 mmol, 1.5 equiv.) was
pound as a white solid (2.15 g, 2.99 mmol, 80%). Rf = 0.60 (20%
EtOAc in petroleum ether). [α]2D2 = +70 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.02–7.95 (m, 4 H, Harom), 7.77–7.68 (m,
4 H, Harom), 7.52–7.29 (m, 10 H, Harom), 7.26–7.19 (m, 2 H, Harom),
added followed by chloro N-phenyl-trifluoroimidate (1.09 g, 5.83 (t, J = 9.9 Hz, 1 H, 2-H), 5.33 (dd, J = 9.9, 2.9 Hz, 1 H, 3-
Eur. J. Org. Chem. 2011, 1652–1663
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1657

J. D. C. Codée, G. A. van der Marel et al.
H), 4.95 (d, J = 9.9 Hz, 1 H, 1-H), 4.49 (br. s, 1 H, 4-H), 4.05 (dd, (200 mL) and brine (200 mL). The aqueous layers were extracted
FULL PAPER
J = 10.9, 5.0 Hz, 1 H, 6a-H), 4.00 (dd, J = 10.9, 4.7 Hz, 1 H, 6b-
H), 3.80 (t, J = 4.7 Hz, 1 H, 5-H), 3.02 (br. d, J = 3.7 Hz, 2 H,
OH), 1.08 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR (101 MHz, CDCl3):
δ = 165.9, 165.2 (2 C=OBz), 135.6, 135.5, 134.7, 133.3, 133.1 (5
with EtOAc (200 mL), and the combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. The crude phenyl 4-
O-(4,6-benzylidene-β-d-galactopyranosyl)-1-thio-β-d-glycopyrano-
side was dissolved in anhydrous pyridine (150 mL) followed by ad-
CHarom), 132.71, 132.65, 132.42 (3 Cq-arom), 132.38, 129. 9, 129.8, dition of benzoyl chloride (16.0 mL, 138 mmol, 6.0 equiv.) at ambi-
129.7 (4 CHarom), 129.5, 129.1 (2 Cq-arom), 128.8, 128.33, 128.28, ent temperature. The reaction was stirred overnight, quenched by
127.82, 127.80, 127.6 (6 CHarom), 86.7 (C-1), 77.9 (C-5), 75.7 (C-
addition of MeOH (2 mL), and concentrated in vacuo. Crystalli-
3), 68.5 (C-4), 67.9 (C-2), 64.0 (C-6), 26.8 (CH3-tBu-Si), 19.1 zation from DCM/petroleum ether produced the title compound as
(Cq-tBu-Si) ppm. IR (neat): ν = 3483, 3078, 2930, 2856, 1720, 1275, a white cotton like solid (10.6 g, 10.2 mmol, 44%). The mother
˜
1105, 1093, 1069, 1026, 740 cm–1. HRMS: calcd. for [C42H42O7SSi liquor was then purified by silica gel column chromatography (0–
+ Na]+ 741.2313; found 741.2312.
10% EtOAc, 40% DCM in petroleum ether) for additional product
(5.2 g, 5.0 mmol, 22%) in a total yield of 66% over three steps. Rf
= 0.80 (50% EtOAc in petroleum ether). [α]2D2 = +107 (c = 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.97–7.86 (m, 10 H,
Harom), 7.60 (t, J = 7.4 Hz, 1 H, Harom), 7.51 (t, J = 7.4 Hz, 1 H,
Phenyl 2,3,6-Tri-O-benzoyl-β-D-galactopyranoside (10): Phenyl 2,3-
di-O-benzoyl-1-thio-β-d-galactopyranoside (4.81 g, 10 mmol,
1.0 equiv.) was dissolved in pyridine (30 mL) and cooled to 0 °C
followed by addition of benzoyl chloride (1.28 mL, 11.0 mmol,
1.1 equiv.). The reaction was stirred for 1 h at 0 °C and was then
quenched with methanol (1 mL). The mixture was concentrated in
vacuo and transferred to an extraction funnel with EtOAc
(100 mL). The organics were washed with 1 n HCl (100 mL), sat.
aq. NaHCO3 (100 mL), and brine (80 mL). The aqueous layers
were extracted with EtOAc (100 mL), and the combined organics
were dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by silica gel column chromatography (10–20% EtOAc in petro-
leum ether) afforded the title compound as a white solid (4.10 g,
7.01 mmol, 70 %). Rf = 0.64 (40 % EtOAc in petroleum ether).
[α]2D2 = +90 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
8.06–8.00 (m, 2 H, Harom), 7.99–7.93 (m, J = 7.3 Hz, 4 H, Harom),
7.58 (m, 1 H, Harom), 7.53–7.41 (m, 6 H, Harom), 7.40–7.28 (m, 4
H, Harom), 7.23 (m, 1 H, Harom), 7.18–7.12 (m, 2 H, Harom), 5.84
(t, J = 9.9 Hz, 1 H, 2-H), 5.41 (dd, J = 9.9, 3.0 Hz, 1 H, 3-H), 5.00
(d, J = 10.1 Hz, 1 H, 1-H), 4.70 (dd, J = 11.7, 5.3 Hz, 1 H, 6a-H),
4.64 (dd, J = 11.7, 6.6 Hz, 1 H, 6b-H), 4.43 (m, 1 H, 4-H), 4.15 (br.
t, J = 6.1 Hz, 1 H, 5-H), 2.78 (br. d, J = 5.2 Hz, 2 H, OH) ppm.
13C NMR (101 MHz, CDCl3): δ = 166.4, 165.8, 165.3 (3 C=OBz),
133.5, 133.3, 133.2 (3 CHarom), 132.9 (Cq-arom), 132.2, 129.81,
129.76, 129.75 (4 CHarom), 129.5, 129.3, 128.84 (3 Cq-arom), 128.82,
128.41, 128.40, 128.3, 127.9 (5 CHarom), 86.8 (C-1), 76.3 (C-5), 75.2
Harom), 7.47–7.41 (m, 4 H, Harom), 7.40–7.35 (m, 4 H, Harom), 7.34–
7.26 (m, 10 H, Harom), 7.21–7.13 (m, 3 H, Harom), 7.04 (m, J =
7.6 Hz, 2 H, Harom), 5.84 (t, J = 9.1 Hz, 1 H, 3-H), 5.78 (dd, J =
10.4, 7.9 Hz, 1 H, 2Ј-H), 5.31 (t, J = 9.7 Hz, 1 H, 2-H), 5.28 (s, 1
H, CHbenzylidene), 5.16 (dd, J = 10.4, 3.6 Hz, 1 H, 3Ј-H), 4.91 (d, J
= 10.0 Hz, 1 H, 1-H), 4.83 (d, J = 7.9 Hz, 1 H, 1Ј-H), 4.66 (dd, J
= 11.9, 1.9 Hz, 1 H, 6a-H), 4.39 (dd, J = 11.9, 5.1 Hz, 1 H, 6b-H),
4.31 (d, J = 3.3 Hz, 1 H, 4Ј-H), 4.13 (dd, J = 9.7, 9.1 Hz, 1 H, 4-
H), 3.89 (ddd, J = 9.7, 5.1, 1.9, Hz, 1 H, 5-H), 3.71 (d, J = 11.5 Hz,
1 H, 6Јa-H), 3.56 (d, J = 11.5 Hz, 1 H, 6Јb-H), 2.99 (m, 1 H, 5Ј-
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.1, 165.5, 165.3,
165.0, 164.8 (5 C=OBz), 137.4 (Cq-arom), 133.3, 133.2, 133.1, 133.03,
133.01 (5 CHarom), 131.6 (Cq-arom), 129.88, 129.86, 129.7, 129.6 (4
CHarom), 129.5, 129.3, 128.92, 128.87 (4 Cq-arom), 128.8, 128.7,
128.32, 128.26, 128.1, 127. 9, 126.3 (7 CHarom), 101.5 (C-1Ј), 100.6
(CHbenzylidene), 85.6 (C-1), 76.8 (C-4 and C-5), 75.0 (C-3), 73.0 (C-
4Ј), 72.6 (C-3Ј), 70.8 (C-2), 69.5 (C-2Ј), 67.9 (C-6Ј), 66.5 (C-5Ј),
62.6 (C-6) ppm. IR (neat): ν = 3070, 2942, 2862, 1717, 1452, 1276,
˜
1113, 1027, 706 cm–1. HRMS: calcd. for [C60H50O15S + Na]+
1065.2763; found 1065.2765.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-β-
D-galactopyr-
anosyl)-1-thio-β- -glycopyranoside: Phenyl 2,3,6-tri-O-benzoyl-4-O-
D
(C-3), 67.9 (C-4), 67.6 (C-2), 63.5 (C-6) ppm. IR (neat): ν = 3483,
˜
(2,3-di-O-benzoyl-4,6-benzylidene-β-d-galactopyranosyl)-1-thio-β-
d-glycopyranoside (6.8 g, 6.5 mmol, 1.0 equiv.) was dissolved in
DCM (250 mL) and cooled to 0 °C. Trifluoroacetic acid (2.50 mL,
3078, 2930, 2856, 1720, 1275, 1105, 1093, 1069, 1026, 740 cm–1.
HRMS: calcd. for [C42H42O7SSi + Na]+ 741.2313; found 741.2312.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-4,6-benzylidene- 32.5 mmol, 5.0 equiv.) was added followed by water (1 mL). The
β- -galactopyranosyl)-1-thio-β- -glycopyranoside (12): Phenyl reaction was run until TLC showed full conversion to a lower run-
D
D
2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galacto- ning spot. The reaction mixture was transferred to an extraction
pyranosyl)-1-thio-β-d-glycopyranoside[2] (16.8 g, 23.0 mmol,
1.0 equiv.) was dissolved in methanol (250 mL) and sodium meth-
funnel and washed with sat. aq. NaHCO3 (200 mL) and brine
(150 mL). The aqueous layers were extracted with EtOAc
oxide (30 % in methanol, 0.64 mL, 4.60 mmol, 0.2 equiv.) was (200 mL), and the combined organics were dried (Na2SO4) and
added at ambient temperature. The reaction was run overnight giv-
ing full conversion to a lower running product (TLC; 30% MeOH
in EtOAc, Rf = 0.32). The reaction was neutralized with Amberlite
H+, filtered, and concentrated in vacuo, producing a white solid
that was used without further purification. The solids were dried
by means of a vacuum pump overnight. The crude phenyl 4-O-(β-
d-galactopyranosyl)-1-thio-β-d-glucopyranoside was then sus-
pended in anhydrous acetonitrile (300 mL) and placed under an
atmosphere of argon. Benzaldehyde dimethylacetal (5.18 mL,
34.5 mmol, 1.5 equiv.) was added followed by p-TsOH·H2O
concentrated under reduced pressure. Purification by column
chromatography (5–20% EtOAc, 40% DCM in petroleum ether)
produced the title compound as a white solid (5.7 g, 5.97 mmol,
92%). Rf = 0.35 (50% EtOAc in petroleum ether). [α]2D2 = +78 (c =
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.01–7.97 (m, 2 H,
Harom), 7.96–7.92 (m, 4 H, Harom), 7.92–7.88 (m, 4 H, Harom), 7.61
(tm, J = 7.4 Hz, 1 H, Harom), 7.56–7.50 (m, 2 H, Harom), 7.49–7.43
(m, 3 H, Harom), 7.42–7.36 (m, 6 H, Harom), 7.34–7.28 (m, 3 H,
Harom), 7.23–7.15 (m, 3 H, Harom), 7.06 (tm, J = 7.6 Hz, 1 H,
Harom), 5.76 (t, J = 8.9 Hz, 1 H, 3-H), 5.73 (t, J = 10.4, 7.9 Hz, 1
(0.219 g, 1.15 mmol, 0.05 equiv.). The reaction was left stirring at H, 2Ј-H), 5.39 (t, J = 9.6 Hz, 1 H, 2-H), 5.09 (dd, J = 10.4, 3.1 Hz,
ambient temperature overnight, giving a clear solution (TLC; 10%
MeOH in EtOAc, Rf = 0.33). The reaction was quenched by ad-
dition of triethylamine (1.62 mL, 11.5 mmol, 0.5 equiv.) and was
then concentrated under reduced pressure. The residue was dis-
solved in EtOAc (200 mL) and washed with sat. aq. NaHCO3
1 H, 3Ј-H), 4.92 (d, J = 9.9 Hz, 1 H, 1-H), 4.78 (d, J = 7.9 Hz, 1
H, 1Ј-H), 4.65 (dd, J = 11.9, 1.9 Hz, 1 H, 6a-H), 4.43 (dd, J = 11.9,
5.7 Hz, 1 H, 6b-H), 4.20 (d, J = 3.1 Hz, 1 H, 4Ј-H), 4.10 (dd, J =
9.4, 8.9 Hz, 1 H, 4-H), 3.89 (ddd, J = 9.4, 5.7, 1.9, Hz, 1 H, 5-H),
3.41–3.33 (m, 2 H, 5Ј-H and 6Јa-H), 3.26 (dd, J = 11.8, 5.0 Hz, 1
1658
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1652–1663

A Concise Synthesis of Globotriaosylsphingosine
H, 6Јb-H), 1.70 (br. s, 2 H, 2 OH) ppm. 13C NMR (101 MHz,
CDCl3): δ = 165.82, 165.75, 165.4, 165.2, 165.0 (5 C=OBz), 133.5,
(dd, J = 12.2, 7.6 Hz, 1 H, 6b-H), 4.36 (d, J = 1.4 Hz, 1 H, 4-H),
4.31 (dd, J = 12.6, 1.5 Hz, 1 H, 6aЈ-H), 4.27 (d, J = 2.3 Hz, 1 H,
133.32, 133.25, 133.2, 133.0 (5 CHarom), 131. 8 (Cq-arom), 129.85, 4Ј-H), 4.20 (dd, J = 7.8, 3.1 Hz, 1 H, 5-H), 4.11–4.05 (m, 2 H, 2Ј-
129.81, 129.74 (3 CHarom), 129.70 (Cq-arom), 129.64, 129.55 (2 H and 6bЈ-H), 3.94 (dd, J = 9.7, 2.8 Hz, 1 H, 3Ј-H), 3.58 (br. s, 1
CHarom), 129.2, 129.0, 128.80 (3 Cq-arom), 128.77, 128.6, 128.42, H, 5Ј-H), 1.06 (s, 9 H, CH3-tBu-Si), 0.97 (s, 18 H, CH3-tBu-Si), 0.83
128.39, 128.38, 128.36, 128.1 (7 CHarom), 101.3 (C-1Ј), 85.8 (C-1), (s, 9 H, CH3-tBu-Si), 0.21 (s, 3 H, CH3-TBS), 0.18 (s, 3 H, CH3-TBS),
76.9 (C-5), 76.5 (C-4), 74.6 (C-3), 74.3 (C-5Ј), 74.2 (C-3Ј), 70. 5 (C- 0.05 (s, 3 H, CH3-TBS), 0.00 (s, 3 H, CH3-TBS) ppm. 13C NMR
2), 69.7 (C-2Ј), 68.1 (C-4Ј), 62.9 (C-6), 62.4 (C-6Ј) ppm. IR (neat):
(101 MHz, CDCl3): δ = 166.0, 165.9, 164.9 (3 C=OBz), 133.8, 133.4,
133.14, 133.07 (4 CHarom), 131.7 (Cq-arom), 130.1 (CHarom), 130.0
(Cq-arom), 129.81, 129.73 (2 CHarom), 129.4 (Cq-arom), 129.2
(CHarom), 128.7 (Cq-arom), 128.5, 128.44, 128.37, 128.28, 127.9,
127.6 (6 CHarom), 101.3 (C-1Ј), 85.6 (C-1), 77.5 (C-5), 76.1 (C-4),
74.9 (C-4Ј), 74.7 (C-3), 70.9 (C-3Ј), 70.3 (C-2Ј), 68.9 (C-5Ј), 67.7
(C-2), 67.1 (C-6Ј), 64.9 (C-6), 27.5, 27.3, 26.2 (4 CH3-tBu-Si), 23.4,
20.7, 18.3, 18.2 (4 Cq-tBu-Si), –3.9, –4.2, –4.3, –4.7 (4 CH3-TBS) ppm.
ν = 3490, 3064, 2948, 2872, 1722, 1269, 1069, 1027, 707 cm–1
.
˜
HRMS: calcd for [C53H46O15S + Na]+ 977.2450; found 977.2448.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-(2,3,6-tri-O-benzoyl-β-
D-galacto-
pyranosyl)-1-thio-β-
D
-glycopyranoside (13):[23] Benzoyl chloride
(0.51 mL, 4.4 mmol, 1.1 equiv.) was added dropwise to a solution
of hydroxybenzotriazole (0.60 g, 4.4 mmol, 1.1 equiv.) and triethyl-
amine (0.62 mL, 4.4 mmol, 1.1 equiv.) in anhydrous DCM (16 mL).
When TLC showed full conversion to the activated ester. Phenyl
2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-β-d-galactopyranosyl)-
1-thio-β-d-glycopyranoside (3.82 g, 4.00 mmol, 1.0 equiv.), dis-
solved in DCM (5 mL) was added followed by triethylamine
(0.62 mL, 4.4 mmol, 1.1 equiv.). The reaction was stirred until no
more conversion to product was seen and transferred to an extrac-
tion funnel with EtOAc (80 mL). The organics were washed with
sat. aq. NaHCO3 (100 mL) and brine (80 mL). The aqueous layers
were extracted with EtOAc (100 mL), and the combined organics
were dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by silica gel column chromatography (5–15 % EtOAc, 40 %
DCM in petroleum ether) produced the title compound as a white
solid (2.68 g, 2.53 mmol, 63%). Rf = 0.12 (20% EtOAc in petro-
leum ether). [α]2D2 = +55 (c = 1.0, CHCl3). NMR spectroscopic data
IR (neat): ν = 3070, 2932, 2857, 1729, 1270, 1093, 1069, 837,
˜
709 cm–1. HRMS: calcd. for [C59H82O13SSi3 + Na]+ 1137.4676;
found 1137.4676.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-4,6-O-di-tert-but-
ylsilanediyl-α-D-galactopyranosyl)-1-thio-β-D-glucopyranoside (15)
Method A: Galactose hydroxy donor 5 (63 mg, 0.12 mmol,
1.2 equiv.), diphenyl sulfoxide (53 mg, 0.26 mmol, 2.6 equiv.), and
2,4,6-tris-tert-butylpyrimidine (30 mg, 0.12 mmol, 1.2 equiv.) were
dissolved in anhydrous DCM (3 mL) under an atmosphere of ar-
gon. Activated molecular sieves (3 Å) were added, and the mixture
was stirred for 1 h at ambient temperature. The solution was then
cooled to –60 °C and trifluoromethanesulfonic anhydride (22 μL,
0.13 mmol, 1.3 equiv.) was added. The mixture was warmed to
–40 °C and stirred at this temperature for 1 h. The reaction was
then cooled to –60 °C and galactose acceptor 10 (59 mg,
0.10 mmol, 1.0 equiv.) was added as a solution in anhydrous DCM
(2 mL). The reaction was stirred for 3 h going to room temperature
and was then quenched by addition of anhydrous triethylamine
(140 μL, 1.0 mmol, 10 equiv.). The mixture was transferred to an
extraction funnel using EtOAc (40 mL), and the organics were
washed with sat. aq. NaHCO3 (40 mL) and brine (40 mL). The
water layers were extracted with EtOAc (40 mL), and the combined
organics were dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by silica gel column chromatography (5–20% EtOAc
in petroleum ether) produced the title compound as a white solid
(33 mg, 30 μmol, 30%).
are identical to those previously reported.[3] IR (neat): ν = 3487,
˜
3062, 2950, 2868, 1722, 1265, 1093, 1069, 1026, 706 cm–1. HRMS:
calcd. for [C60H50O16S + Na]+ 1081.2712; found 1081.2709.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-(2,3-bis-O-tert-butyldimethylsilyl-
4,6-O-di-tert-butylsilanediyl-α-D-galactopyranosyl)-1-thio-β-D-
glucopyranoside (14): Galactose hydroxy donor 4 (66 mg,
0.12 mmol, 1.2 equiv.), diphenyl sulfoxide (53 mg, 0.26 mmol,
2.6 equiv.), and 2,4,6-tris-tert-butylpyrimidine (75 mg, 0.300 mmol,
3.0 equiv.) were dissolved in anhydrous DCM (4 mL) under an at-
mosphere of argon. Activated molecular sieves (3 Å) were added,
and the mixture was stirred for 1 h at ambient temperature. The
solution was then cooled to –60 °C and trifluoromethanesulfonic
anhydride (22 μL, 0.13 mmol, 1.3 equiv.) was added. The mixture
was warmed to –40 °C and stirred at this temperature for 1 h. The
reaction was then cooled to –60 °C and galactose acceptor 10
(59 mg, 0.10 mmol, 1.0 equiv.) was added as a solution in anhy-
drous DCM (2 mL). The reaction was stirred for 3 h going to room
temperature and was then quenched by addition of anhydrous tri-
ethylamine (140 μL, 1.0 mmol, 10 equiv.). The mixture was trans-
ferred to an extraction funnel using EtOAc (40 mL), and the or-
ganics were washed with sat. aq. NaHCO3 (40 mL) and brine
(40 mL). The water layers were extracted with EtOAc (40 mL), and
the combined organics were dried (Na2SO4), filtered, and concen-
trated in vacuo. Purification by silica gel column chromatography
(10–30% ethyl ether in petroleum ether) produced the title com-
pound as a white solid (100 mg, 90 μmol, 90%). Rf = 0.31 (15%
EtOAc in petroleum ether). [α]2D2 = +54 (c = 1.0, CHCl3). 1H NMR
Method B: Galactoside imidate donor 7 (105 mg, 0.15 mmol,
1.5 equiv.) and galactose acceptor 10 (59 mg, 0.10 mmol, 1.0 equiv.)
were coevaporated twice with anhydrous toluene (4 mL) and then
dissolved in anhydrous DCM (3 mL). The solution was cooled to
0 °C and trifluoromethansulfonic acid (0.9 μL, 10 μmol, 0.1 equiv.)
was added. The reaction was stirred for 2 h at 0 °C and was then
quenched by addition of triethylamine (140 μL, 1.0 mmol,
10 equiv.). The organics were transferred to an extraction funnel
using EtOAc (40 mL), and the organics were washed with sat. aq.
NaHCO3 (40 mL) and brine (40 mL). The water layers were ex-
tracted with EtOAc (40 mL), and the combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by silica
gel column chromatography (5–20% EtOAc in petroleum ether)
produced the title compound as a white solid (82 mg, 75 μmol,
75%). Rf = 0.18 (15% EtOAc in petroleum ether). [α]2D2 = +51 (c =
(400 MHz, CDCl3): δ = 8.14–8.09 (m, 2 H, Harom), 8.07–8.02 (m, 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.09–8.05 (m, 2 H,
2 H, Harom), 7.95–7.91 (m, 2 H, Harom), 7.61 (m, 1 H, Harom), 7.54– Harom), 8.05–8.02 (m, 2 H, Harom), 7.96–7.91 (m, 4 H, Harom), 7.78–
7.45 (m, 7 H, Harom), 7.38–7.31 (m, 4 H, Harom), 7.16 (br. t, J =
7.3 Hz, 2 H, Harom), 5.57 (t, J = 9.9 Hz, 1 H, 2-H), 5.47 (dd, J = H, Harom), 7.44–7.30 (m, 12 H, Harom), 7.22 (br. t, J = 7.7 Hz, 2
10.2, 2.3 Hz, 1 H, 3-H), 4.90 (d, J = 10.2 Hz, 1 H, 1-H), 4.89 (d, J H, Harom), 5.73 (dd, J = 10.7, 3.6 Hz, 1 H, 2Ј-H), 5.51 (dd, J =
= 3.2 Hz, 1 H, 1Ј-H), 4.77 (dd, J = 12.2, 3.3 Hz, 1 H, 6a-H), 4.69 10.7, 3.1 Hz, 1 H, 3Ј-H), 5.50–5.44 (m, 2 H, 2-H and 3-H), 5.37 (d,
7.74 (m, 2 H, Harom), 7.67–7.63 (m, 2 H, Harom), 7.54–7.47 (m, 4
Eur. J. Org. Chem. 2011, 1652–1663
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1659

J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
J = 3.6 Hz, 1 H, 1Ј-H), 4.89 (d, J = 8.3 Hz, 1 H, 1-H), 4.86 (dd, J
26.22, 26.16 (4 CH3-tBu-Si), 23.4, 20.7, 18.2, 18.1 (4 Cq-tBu-Si), –4.0,
= 11.1, 6.3 Hz, 1 H, 6a-H), 4.75 (d, J = 3.1 Hz, 1 H, 4Ј-H), 4.42 –4.2, –4.5, –4.6 (4 CH3-TBS) ppm.
(dd, J = 11.1, 6.5 Hz, 1 H, 6b-H), 4.26 (br. s, 1 H, 4-H), 4.21 (dd,
Phenyl 2,3,6-Tri-O-benzoyl-4-O-[2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-
J = 13.1, 1.7 Hz, 1 H, 6aЈ-H), 4.10 (t, J = 6.5 Hz, 1 H, 5-H), 3.98
(dd, J = 13.1, 2.2 Hz, 1 H, 6bЈ-H), 3.41 (br. s, 1 H, 5Ј-H), 1.07 (s, 9
H, CH3-tBu-Si), 0.99 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR (101 MHz,
CDCl3): δ = 166.3, 166.0, 165.9, 165.6, 164.8 (5 C=OBz), 135.6,
133.5, 133.3, 133.2, 133.04, 133.02, 130.2 (7 CHarom), 123.0, 129.9
(2 Cq-arom), 129.73, 129.70, 129.67, 129.6 (4 CHarom), 129.4, 129.2,
128.8 (3 Cq-arom), 128.70 (CHarom), 128.67 (Cq-arom), 128.5, 128.39,
128.35, 128.34, 128.2 (5 CHarom), 98.7 (C-1Ј), 84.8 (C-1), 76.7 (C-
4), 76.3 (C-5), 74.4 (C-3), 71.1 (C-4Ј), 70.5 (C-3Ј), 69.5 (C-2Ј), 67.9
(C-5Ј), 67.6 (C-2), 66.7 (C-6Ј), 62.2 (C-6), 27.5, 27.2 (2 CH3-tBu-Si),
benzoyl-4,6-O-di-tert-butylsilanediyl-α-
D-galactopyranosyl)-β-D-ga-
lactopyranosyl]-1-thio-β- -glucopyranoside (17)
D
Method A: Galactose hydroxy donor 5 (63 mg, 0.12 mmol,
1.2 equiv.), diphenyl sulfoxide (53 mg, 0.26 mmol, 2.6 equiv.), and
2,4,6-tri-tert-butylpyrimidine (30 mg, 0.12 mmol, 1.2 equiv.) were
dissolved in anhydrous DCM (3 mL) under an atmosphere of ar-
gon. Activated molecular sieves (3 Å) were added, and the mixture
was stirred for 1 h at ambient temperature. The solution was then
cooled to –60 °C and trifluoromethanesulfonic anhydride (22 μL,
0.13 mmol, 1.3 equiv.) was added. The mixture was warmed to
–40 °C and stirred at this temperature for 1 h. The reaction was
then cooled to –60 °C and lactose acceptor 13 (106 mg, 0.10 mmol,
1.0 equiv.) was added as a solution in anhydrous DCM (3 mL). The
reaction was stirred for 3 h going to room temperature and was
then quenched by addition of anhydrous triethylamine (140 μL,
1.0 mmol, 10 equiv.). The mixture was transferred to an extraction
funnel using EtOAc (40 mL), and the organics were washed with
sat. aq. NaHCO3 (40 mL) and brine (40 mL). The water layers were
extracted with EtOAc (40 mL), and the combined organics were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification
by silica gel column chromatography (2–8% EtOAc, 20% DCM in
petroleum ether) produced the title compound as a white solid
(32 mg, 20 μmol, 20%).
23.3, 20.7 (2 Cq-tBu-Si) ppm. IR (neat): ν = 3072, 2935, 2858, 1718,
˜
1269, 1093, 1070, 1027, 707 cm–1. HRMS: calcd. for [C61H62O15SSi
+ Na]+ 1117.3471; found 1117.3477.
Phenyl 2,3,6-Tri-O-benzoyl-4-O-[2,3,6-tri-O-benzoyl-4-O-(2,3-bis-
O-(tert-butyldimethylsilyl)-4,6-O-di-tert-butylsilanediyl-α-
D-
galactopyranosyl)-β- -galactopyranosyl]-1-thio-β- -glucopyranoside
D
D
(16): Galactose hydroxy donor 4 (66 mg, 0.12 mmol, 1.2 equiv.),
diphenyl sulfoxide (53 mg, 0.26 mmol, 2.6 equiv.) and 2,4,6-tris-
tert-butylpyrimidine (75 mg, 0.30 mmol, 3.0 equiv.) were dissolved
in anhydrous DCM (4 mL) under an atmosphere of argon. Acti-
vated molecular sieves (3 Å) were added, and the mixture was
stirred for 1 h at ambient temperature. The solution was then co-
oled to –60 °C and trifluoromethanesulfonic anhydride (22 μL,
0.13 mmol, 1.3 equiv.) was added. The mixture was warmed to
–40 °C and stirred at this temperature for 1 h. The reaction was
then cooled to –60 °C and lactose acceptor 13 (106 mg, 0.10 mmol,
1.0 equiv.) was added as a solution in anhydrous DCM (2 mL). The
reaction was stirred for 3 h going to room temperature and was
then quenched by addition of anhydrous triethylamine (140 μL,
Method B: Imidate donor 7 (1.78 g, 2.6 mmol, 1.5 equiv.) and lac-
tose acceptor 13 (1.80 g, 1.7 mmol, 1.0 equiv.) were coevaporated
two times with toluene (10 mL) and then dissolved in anhydrous
DCM (17 mL) and cooled to 0 °C before addition of a catalytic
amount of TfOH (15 μL, 0.17 mmol, 0.1 equiv.). The reaction was
1.00 mmol, 10 equiv.). The mixture was transferred to an extraction stirred until TLC showed complete conversion of the lactose ac-
funnel using EtOAc (40 mL), and the organics were washed with
sat. aq. NaHCO3 (40 mL) and brine (40 mL). The water layers were
extracted with EtOAc (40 mL), and the combined organics were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification by
silica gel column chromatography (10–30% ethyl ether in petroleum
ether) produced the title compound as a white solid (53 mg,
33 μmol, 33%). Rf = 0.28 (15% EtOAc in petroleum ether). 1H
ceptor (≈4 h). The reaction mixture was then transferred to an ex-
traction funnel with EtOAc (30 mL) and washed with sat. aq.
NaHCO3 (50 mL) and brine (40 mL). The aqueous layers were then
extracted with EtOAc (40 mL), and the combined organics were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification
by size exclusion column chromatography, followed by silica gel
column chromatography (2–8% EtOAc, 20% DCM in petroleum
NMR (400 MHz, CDCl3): δ = 8.01 (br. d, J = 7.9 Hz, 2 H, Harom), ether) produced the title compound as a white solid (2.46 g,
7.98 (br. d, J = 8.0 Hz, 2 H, Harom), 7.89 (br. d, J = 7.6 Hz, 6 H, 1.57 mmol, 92 %). Rf = 0.41 (20 % EtOAc in petroleum ether).
Harom), 7.75 (br. d, J = 7.9 Hz, 2 H, Harom), 7.58–7.49 (m, 3 H,
[α]2D2 = +49 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
Harom), 7.46–7.28 (m, 12 H, Harom), 7.24–7.06 (m, 6 H, Harom), 7.02 8.14 (br. d, J = 7.9 Hz, 2 H, Harom), 8.05 (br. d, J = 8.0 Hz, 2 H,
(br. t, J = 8.0 Hz, 2 H, Harom), 5.80 (t, J = 9.2 Hz, 1 H, 3-H), 5.61 Harom), 8.01 (br. d, J = 7.9 Hz, 2 H, Harom), 7.95 (br. d, J = 8.0 Hz,
(dd, J = 10.7, 8.0 Hz, 1 H, 2Ј-H), 5.32 (dd, J = 10.7, 2.3 Hz, 1 H, 2 H, Harom), 7.90 (br. d, J = 7.9 Hz, 2 H, Harom), 7.88 (br. d, J =
3Ј-H), 5.25 (t, J = 9.5 Hz, 1 H, 2-H), 4.95–4.88 (m, 2 H, 1Ј-H and 8.0 Hz, 2 H, Harom), 7.68 (br. d, J = 7.9 Hz, 2 H, Harom), 7.58–7.51
1ЈЈ-H), 4.78 (d, J = 9.9 Hz, 1 H, 1-H), 4.71–4.62 (m, 2 H, 6a-H and (m, 4 H, Harom), 7.50–7.43 (m, 4 H, Harom), 7.42–7.16 (m, 19 H,
6aЈ-H), 4.51 (dd, J = 11.9, 5.5 Hz, 1 H, 6b-H), 4.38 (d, J = 11.4 Hz,
1 H, 6aЈЈ-H), 4.33 (m, 1 H, 4ЈЈ-H), 4.29–4.21 (m, 2 H, 4Ј-H and
6bЈЈ-H), 4.09–4.03 (m, 2 H, 5ЈЈ-H and 2ЈЈ-H), 3.94 (m, 1 H, 5-H),
Harom), 7.14–7.05 (m, 4 H, Harom), 5.78 (t, J = 9.2 Hz, 1 H, 3-H),
5.72 (dd, J = 10.7, 3.7 Hz, 1 H, 2ЈЈ-H), 5.61 (dd, J = 10.8, 7.8 Hz,
1 H, 2Ј-H), 5.50 (dd, J = 10.7, 3.1 Hz, 1 H, 3ЈЈ-H), 5.39 (t, J =
3.85 (m, 2 H, 5Ј-H and 3ЈЈ-H), 1.03 (s, 9 H, CH3-tBu-Si), 0.97 (s, 9 9.7 Hz, 1 H, 2-H), 5.36 (d, J = 3.6 Hz, 1 H, 1ЈЈ-H), 5.27 (dd, J =
H, CH3-tBu-Si), 0.90 (s, 9 H, CH3-tBu-Si), 0.73 (s, 9 H, CH3-tBu-Si), 10.7, 2.1 Hz, 1 H, 3Ј-H), 5.09 (d, J = 3.0 Hz, 1 H, 4ЈЈ-H), 4.89 (d,
0.04 (s, 3 H, CH3-TBS), 0.03 (s, 3 H, CH3-TBS), –0.05 (s, 3 H, CH3- J = 10.0 Hz, 1 H, 1-H), 4.80 (d, J = 7.8 Hz, 1 H, 1Ј-H), 4.59 (dd,
TBS), –0.07 (s, 3 H, CH3-TBS) ppm. 13C NMR (101 MHz, CDCl3): J = 12.1, 2.1 Hz, 1 H, 6a-H), 4.52 (dd, J = 12.9, 1.8 Hz, 1 H, 6aЈЈ-
δ = 165.9, 165.8, 165.72, 165.65, 165.2, 165.0 (6 C=OBz), 133.4,
H), 4.48–4.41 (m, 2 H, 6b-H and 6bЈЈ-H), 4.36 (br. s, 1 H, 5ЈЈ-H),
133.3, 133.19, 133.16, 132.8 (5 CHarom), 131.9 (Cq-arom), 129.84, 4.11–4.05 (m, 2 H, 4-H and 4Ј-H), 3.95 (dd, J = 10.9, 5.5 Hz, 1 H,
129.81, 129.64, 129.61, 129.59 (5 CHarom), 129.53, 129.49, 129.2, 6aЈ-H), 3.87 (ddd, J = 10.0, 5.4, 2.0 Hz, 1 H, 5-H), 3.76 (dd, J =
128.9 (4 Cq-arom), 128.8 (CHarom), 128.7 (Cq-arom), 128.6, 128.38, 10.9, 7.7 Hz, 1 H, 6bЈ-H), 3.57 (dd, J = 7.7, 5.5 Hz, 1 H, 5Ј-H),
128.36, 128.3, 128.0 (5 CHarom), 101.2 (C-1ЈЈ), 94.2 (C-1Ј), 85.7 (C-
1), 77.0 (C-5), 76.3 (C-4), 75.1 (C-4Ј), 74.2 (C-4ЈЈ), 74.1 (C-5Ј), 72.7 (101 MHz, CDCl3): δ = 166.2, 166.0, 165.8, 165.7, 165.14, 165.05,
1.06 (s, 9 H, CH3-tBu-Si), 0.99 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR
(C-3), 71.0 (C-3Ј), 70.4 (C-2), 69.7 (C-3ЈЈ), 68.9 (C-5ЈЈ), 67.7 (C-
2Ј), 67.2 (C-2ЈЈ), 66.7 (C-6ЈЈ), 62.7 (C-6Ј), 61.8 (C-6), 27.4, 27.3,
164.83, 164.77 (8 C=OBz), 133.4, 133.2, 133.16, 133.13, 133.08,
133.0, 132.9 (7 CHarom), 131.7 (Cq-arom), 130.1, 129.98 (2 CHarom),
1660
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1652–1663

A Concise Synthesis of Globotriaosylsphingosine
129.94 (Cq-arom), 129.8, 129.66, 129.62 (3 CHarom), 129.60, 129.56
2 H, Harom), 8.08–8.02 (m, 4 H, Harom), 7.98 (br. d, J = 7.5 Hz, 2
(2 Cq-arom), 129.52, 129.4 (2 CHarom), 129.2, 129.0 (2 Cq-arom), 128.7 H, Harom), 7.93 (br. d, J = 7.9 Hz, 4 H, Harom), 7.69 (br. d, J =
(CHarom), 128.64, 128.56, 128.52 (3 Cq-arom), 128.46, 128.43, 128.36, 7.8 Hz, 2 H, Harom), 7.57–7.51 (m, 4 H, Harom), 7.50–7.43 (m, 4 H,
128.32, 128.18, 128.09 (6 CHarom), 101.5 (C-1Ј), 98.7 (C-1ЈЈ), 85.7 Harom), 7.42–7.25 (m, 16 H, Harom), 7.12 (br. t, J = 7.8 Hz, 2 H,
(C-1), 76.95 (C-5), 76.84 (C-4), 76.3 (C-4Ј), 74.2 (C-3), 72.78 (C-
3Ј), 72.72 (C-5Ј), 71.2 (C-3ЈЈ), 71.0 (C-4ЈЈ), 70.4 (C-2), 69.7 (C-2Ј),
H
arom), 7.05 (br. t, J = 7.8 Hz, 2 H, Harom-NPh), 6.94 (br. t, J =
7.4 Hz, 1 H, Harom-NPh), 6.71 (br. s, 1 H, C-1), 6.36 (br. s, 2 H,
69.6 (C-2ЈЈ), 68.3 (C-5ЈЈ), 66.9 (C-6ЈЈ), 62.6 (C-6), 60.5 (C-6Ј), 27.5, Harom-NPh), 6.14 (t, J = 9.2 Hz, 1 H, 3-H), 5.75 (dd, J = 10.7,
27.2 (2 CH3-tBu-Si), 23.2, 20.7 (2 Cq-tBu-Si) ppm. IR (neat): ν = 3070,
3.6 Hz, 1 H, 2ЈЈ-H), 5.69 (dd, J = 10.8, 7.8 Hz, 1 H, 2Ј-H), 5.54
(dd, J = 10.7, 3.0 Hz, 1 H, 3ЈЈ-H), 5.49 (m, 1 H, 2-H), 5.40 (d, J =
3.6 Hz, 1 H, 1ЈЈ-H), 5.30 (dd, J = 10.9, 2.1 Hz, 1 H, 3Ј-H), 5.11 (d,
J = 3.1 Hz, 1 H, 4ЈЈ-H), 4.90 (d, J = 7.8 Hz, 1 H, 1Ј-H), 4.64–4.35
(m, 5 H, 6a-H, 6b-H, 6aЈЈ-H, 6bЈЈ-H and 5ЈЈ-H), 4.31–4.21 (m, 2 H,
4-H, 5-H), 4.15–4.09 (m, 1 H, 4Ј-H), 4.05 (dd, J = 10.9, 5.1 Hz, 1
H, 6aЈ-H), 3.81 (m, 1 H, 6bЈ-H), 3.55 (dd, J = 8.0, 5.4 Hz, 1 H),
1.07 (s, 9 H, CH3-tBu-Si), 1.01 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR
(101 MHz, CDCl3): δ = 166.2, 166.0, 165.7, 165.6, 165.4, 164.80,
164.77, 164.7 (8 C=OBz), 142.8 (C=N), 133.6, 133.4, 133.2, 133.14,
133.10, 133.06, 132.95, 132.87, 130.1, 129.94 (10 CHarom), 129.91
(Cq-arom), 129.89, 129.63, 129.59, 129.57, 129.5 (5 CHarom), 129.4
(Cq-arom), 129.3 (CHarom), 129.0, 128.6 (2 Cq-arom), 128.53, 128.50
(2 CHarom), 128.48 (Cq-arom), 128.44, 128.40, 128.36, 128.35, 128.3,
128.1, 128.0 (7 CHarom), 124.2, 119.0 (2 CHarom-NPh), 115.8 (q, J =
285.7 Hz, CF3), 101.8 (C-1Ј), 98.8 (C-1ЈЈ), 92.1 (C-1, br.), 76.4 (C-
4), 76.1 (C-4Ј), 72.9 (C-3Ј), 72.7 (C-5Ј), 71.3 (C-3ЈЈ), 71.2 (C-5),
71.0 (C-4ЈЈ), 70.2 (C-2 and C-3), 69.8 (C-2Ј), 69.5 (C-2ЈЈ), 68.3 (C-
5Ј), 66.9 (C-6ЈЈ), 61.7 (C-6), 60.1 (C-6Ј), 27.5, 27.2 (2 CH3-tBu-Si),
˜
2934, 2860, 1722, 1266, 1069, 706 cm–1. HRMS: calcd. for
[C88H84O23SSi + Na]+ 1591.4786; found 1591.4795.
2,3,6-Tri-O-benzoyl-4-O-[2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-
benzoyl-4,6-O-di-tert-butylsilanediyl-α-
D-galactopyranosyl)-α-D-
galactopyranosyl]-β- -glucopyranoside N-Phenyl-2,2,2-Trifluoroace-
D
timidate (18): Phenyl thioglycotrioside 17 (2.24 g, 1.43 mmol,
1.0 equiv.) was dissolved in DCM (30 mL) and cooled to 0 °C. N-
Iodosuccinimide (0.35 g, 1.57 mmol, 1.1 equiv.) was added followed
by addition of trifluoroacetic acid (0.12 mL, 1.57 mmol, 1.1 equiv.).
The reaction was left stirring under exposure to the atmosphere
until TLC showed full conversion (≈3 h). The mixture was then
transferred to an extraction funnel with EtOAc (50 mL) and
washed with sodium thiosulfate (20 % aq., 70 mL), sat. aq.
NaHCO3 (70 mL), and brine (60 mL). The aqueous layers were
extracted with EtOAc (70 mL), and the combined organics were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification
by silica gel column chromatography (0–10% acetone, 40% DCM
in petroleum ether) afforded the title compound as a white solid
(1.82 g, 1.23 mmol, 86%). Rf = 0.55 and 0.60 (20% acetone in pe-
troleum ether). NMR assignment for the major isomer (α): 1H
NMR (400 MHz, CDCl3): δ = 8.22 (br. d, J = 7.6 Hz, 2 H, Harom),
23.2, 20.7 (2 Cq-tBu-Si) ppm. IR (neat): ν = 3069, 2936, 2860, 1718,
˜
1452, 1266, 1093, 1070, 907, 730, 705 cm–1. HRMS: calcd. for
[C90H84F3NO24Si + Na]+ 1670.4997; found 1670.5009.
8.10–8.03 (m, 4 H, Harom), 8.02–7.88 (m, 6 H, Harom), 7.76–7.70 2-Azido-3-O-benzoyl-
D-erythro-sphingosine-1-yl 2,3,6-Tri-O-
(m, 2 H, Harom), 7.62–7.26 (m, 22 H, Harom), 7.26–7.19 (m, 2 H, benzoyl-4-O-[2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-4,6-O-di-
Harom), 7.16 (br. t, J = 7.8 Hz, 2 H, Harom), 6.17 (t, J = 9.6 Hz, 1
H, 3-H), 5.75 (dd, J = 10.6, 3.5 Hz, 1 H, 2ЈЈ-H), 5.68 (m, 1 H, 2Ј-
H), 5.63 (d, J = 3.5 Hz, 1 H, 1-H), 5.55 (dd, J = 11.0, 3.3 Hz, 1 H,
3ЈЈ-H), 5.41 (d, J = 3.5 Hz, 1 H, 1ЈЈ-H), 5.32 (d, J = 10.1 Hz, 1 H,
tert-butylsilanediyl-α-
D-galactopyranosyl)-α-D-galactopyranosyl]-β-
D-glucopyranoside (21): Globotriaosylimidate donor 18 (180 mg,
0.11 mmol, 1.2 equiv.) and sphingosine acceptor 20 (39 mg,
0.09 mmol, 1.0 equiv.) were coevaporated twice with toluene (5 mL)
3Ј-H), 5.23 (dd, J = 10.2, 3.5 Hz, 1 H, 2-H), 5.11 (m, 1 H, 4ЈЈ-H), and then dissolved in anhydrous DCM (3 mL). Activated molecu-
4.90 (d, J = 7.8 Hz, 1 H, 1Ј-H), 4.60–4.30 (m, 6 H, 6a-H, 6b-H, lar sieves (3 Å) were added, and the mixture was stirred for 1 h at
6aЈЈ-H, 6bЈЈ-H, 5-H and 5ЈЈ-H), 4.23–4.07 (m, 3 H, 4-H, 4Ј-H and ambient temperature and then cooled to 0 °C before addition of a
6aЈ-H), 3.87 (m, 1 H, 6bЈ-H), 3.58 (m, 1 H, 5Ј-H), 1.09 (s, 9 H, catalytic amount of trifluoromethanesulfonic acid (0.8 μL,
CH3-tBu-Si), 1.03 (s, 9 H, CH3-tBu-Si) ppm. 13C NMR (101 MHz, 9.1 μmol, 0.1 equiv.). The reaction was stirred at 0 °C until TLC
CDCl3): δ = 166.3, 166.1, 165.99, 165.98, 165.8, 165.1, 164.9 (2) (8
C=OBz), 133.5, 133.4, 133.2, 133.1, 133.01, 132.96, 130.1, 129.9,
129.68, 129.66, 129.5, 129.4 (12 CHarom), 129.1, 129.0, 128.9, 128.7,
128.6 (5 Cq-arom), 128.49, 128.45, 128.40, 128.37, 128.3, 128.1 (6
showed complete conversion of the sphingosine acceptor (≈2 h).
The reaction was quenched by addition of triethylamine (0.13 mL,
0.91 mmol, 10 equiv.). The organics were then transferred to an
extraction funnel with EtOAc (40 mL) and washed with sat. aq.
CHarom), 101.5 (C-1Ј), 98.7 (C-1ЈЈ), 90.2 (C-1), 76.9 (C-4), 76.1 (C- NaHCO3 (40 mL) and brine (30 mL). The aqueous layers were ex-
4Ј), 73.0 (C-3Ј), 72.7 (C-5Ј), 72.2 (C-2), 71.2 (C-3ЈЈ), 71.1 (C-4ЈЈ),
70.3 (C-3), 69.9 (C-2ЈЈ), 69.6 (C-2Ј), 68.4 (C-5ЈЈ), 68.3 (C-5), 66.9
tracted with EtOAc (40 mL), and the combined organics were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by silica
(C-6ЈЈ), 62.3 (C-6), 60.5 (C-6Ј), 27.6 27.3 (2 CH3-tBu-Si), 23.3, 20.8 gel column chromatography (10–20% EtOAc and 10% DCM in
(2 Cq-tBu-Si) ppm. IR (neat): ν = 3070, 2934, 2855, 1722, 1452, 1266, petroleum ether) produced the title compound as an amorphous
˜
1093, 1069, 1027, 706 cm–1. HRMS: calcd. for [C82H80O24Si + solid (138 mg, 0.07 mmol, 80%). Rf = 0.35 (20% EtOAc in petro-
Na]+ 1499.4701; found 1499.4707. The protected globotriaosyl
hemiacetal (1.80 g, 1.22 mmol, 1.0 equiv.) was dissolved in acetone
(30 mL) and cooled to 0 °C. Cesium carbonate (0.60 g, 1.83 mmol,
1.5 equiv.) was added followed by chloro N-phenyl-trifluoroimidate
(0.38 g, 1.83 mmol, 1.5 equiv.), and the reaction was stirred at 0 °C
for 2 h. The reaction mixture was filtered and concentrated in
vacuo. Purification by silica gel column chromatography, which ini-
tially was neutralized by running an eluent of 3% NEt3 in petro-
leum ether (200 mL) through the column (0–10 % EtOAc, 20 %
DCM in petroleum ether) produced the title compound as a white
solid (1.85 g, 1.12 mmol, 92%). Rf = 0.47 and 0.42 (10% EtOAc
and 20% DCM in petroleum ether). NMR assignment of major
leum ether). [α]2D2 = +29 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.17 (br. d, J = 7.2 Hz, 2 H, Harom), 8.07–7.99 (m, 4
H, Harom), 7.97 (br. d, J = 7.6 Hz, 4 H, Harom), 7.89 (br. d, J =
7.4 Hz, 4 H, Harom), 7.69 (br. d, J = 7.2 Hz, 2 H, Harom), 7.57 (br.
d, J = 7.2 Hz, 2 H, Harom), 7.54–7.42 (m, 8 H, Harom), 7.41–7.27
(m, 15 H, Harom), 7.21 (br. t, J = 7.6 Hz, 2 H, Harom), 7.11 (br. t,
J = 7.7 Hz, 2 H, Harom), 5.78 (t, J = 9.1 Hz, 1 H, 3-H), 5.73 (dd,
J = 10.7, 3.6 Hz, 1 H, 2ЈЈ-H), 5.67 (m, 1 H, 5Sp-H), 5.62 (dd, J =
11.2, 7.7 Hz, 1 H, 2Ј-H), 5.55–5.48 (m, 2 H, 3ЈЈ-H and 3Sp-H),
5.47–5.38 (m, 2 H, 2-H and 4Sp-H), 5.38 (d, J = 3.4 Hz, 1 H, 1ЈЈ-
H), 5.28 (dd, J = 10.9, 2.1 Hz, 1 H, 3Ј-H), 5.10 (d, J = 2.8 Hz, 1
H, 4ЈЈ-H), 4.83 (d, J = 7.8 Hz, 1 H, 1Ј-H), 4.71 (d, J = 7.6 Hz, 1
H, 1-H), 4.57–4.48 (m, 2 H, 6a-H and H6aЈЈ), 4.46–4.39 (m, 2 H,
1
isomer: H NMR (400 MHz, CDCl3): δ = 8.22 (br. d, J = 7.2 Hz,
Eur. J. Org. Chem. 2011, 1652–1663
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1661

J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
6b-H and H6bЈЈ), 4.37 (br. s, 1 H, 5ЈЈ-H), 4.21 (t, J = 9.4 Hz, 1 H,
4-H), 4.09 (br. s, 1 H, 4Ј-H), 3.98 (dd, J = 10.9, 5.4 Hz, 1 H, 6aЈ-
H), 3.91–3.77 (m, 4 H, 1a–Sp-H, 2Sp-H, 5-H and 6bЈ-H), 3.58–3.48
(m, 2 H, 5Ј-H and 1b–Sp-H), 1.87 (m, 2 H, 6Sp-H), 1.33–1.12 (m,
22 H, 7Sp-H to 17Sp-H), 1.06 (s, 9 H, CH3-tBu-Si), 1.00 (s, 9 H,
CH3-tBu-Si), 0.88 (t, J = 6.8 Hz, 3 H, 18Sp-H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 166.2, 166.0, 165.8, 165.7, 165.1, 165.0,
164.9, 164.81, 164.78 (9 C=OBz), 138.9 (C-5Sp), 133.4, 133.2, 133.1,
133.04, 132.98, 132.9, 130.1, 130.0 (8 CHarom), 129.93, 129.89 (2
(C-18Sp) ppm. IR (neat): ν = 3344 (br., s), 2925, 2855, 1674, 1202,
˜
1134, 1067, 1027, 974, 801, 721 cm–1. HRMS: calcd for
[C36H67NO17 + H]+ 786.4482; found 786.4485.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all new compounds.
Acknowledgments
C
q-arom), 129.8, 129.7, 129.63, 129.56, 129.51 (5 CHarom), 129.46
We thank the Netherlands Ministry of Economic Affairs, the B-
Basic Partner Organizations through B-Basic, and The Netherlands
Organization of Scientific Research (NWO) for financial support.
(Cq-arom), 129.4 (CHarom), 129.3, 129.1, 128.6, 128.53, 128.50
(5 Cq-arom), 128.48, 128.4, 128.3, 128.2, 128.1 (5 CHarom), 122.3 (C-
4Sp), 101.4 (C-1Ј), 100.6 (C-1), 98.7 (C-1ЈЈ), 76.7 (C-4), 76.2 (C-4Ј),
74.8 (C-3Sp), 73.1 (C-3), 73.0 (C-5), 72.8 (C-3Ј), 72.7 (C-5Ј), 71.7
(C-2), 71.2 (C-3ЈЈ), 71.0 (C-4ЈЈ), 69.7 (C-2Ј), 69.5 (C-2ЈЈ), 68.6 (C-
5ЈЈ), 68.1 (C-1Sp), 66.9 (C-6ЈЈ), 63.4 (C-2Sp), 62.2 (C-6), 60.5 (C-6Ј),
32.2 (C-6Sp), 31.9, 29.64, 29.61 (2), 29.59, 29.5, 29.31, 29.30, 29.1,
28.5 (10 CH2-Sp), 27.5, 27.2 (2 CH3-tBu-Si), 23.2 (Cq-tBu-Si), 22.7
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21 (70 mg, 0.04 mmol, 1.0 equiv.) was dissolved in DCM/MeOH
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title compound (TFA-salt) as a white powder after lyophilization
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7.8 Hz, 1 H, 1-H), 4.32 (ddd, J = 6.8, 4.7, 1.3 Hz, 1 H, 3Sp-H), 4.25
(ddd, J = 7.1, 5.2, 1.3 Hz, 1 H, 5ЈЈ-H), 4.01–3.96 (m, 2 H, 4Ј-H
and 1a–Sp-H), 3.94 (dd, J = 11.9, 2.6 Hz, 1 H, 6a-H), 3.93–3.91 (m,
2 H, 4ЈЈ-H and 1b–Sp-H), 3.89 (dd, J = 7.7, 4.1 Hz, 1 H, 6b-H),
3.88–3.81 (m, 3 H, 6aЈ-H, 6bЈ-H and 2ЈЈ-H), 3.77 (dd, J = 10.2,
3.2 Hz, 1 H, 3ЈЈ-H), 3.74 (dd, J = 11.1, 7.1 Hz, 1 H, 6aЈЈ-H), 3.71–
3.66 (m, 2 H, 5Ј-H and 6bЈЈ-H), 3.58–3.51 (m, 4 H, 4-H, 3-H, 3Ј-
H and 2Ј-H), 3.47 (m, 1 H, 5-H), 3.40 (ddd, J = 8.5, 4.7, 3.6 Hz, 1
H, 2Sp-H), 3.30 (t, J = 7.7 Hz, 1 H, 2-H), 2.10 (q, J = 7.0 Hz, 2 H,
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Received: December 16, 2010
Published Online: February 11, 2011
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