C-glycosphingolipid precursors via iodocyclization of homoallyic trichloroacetimidates

Article abstract of DOI:10.1016/j.carres.2015.02.005

The iodocyclization of homoallylic trichloroacetimidates derived from α-C-allyl galactoside were investigated. In line with the stereochemical trend observed for less substituted non-glycosylated frameworks, E and Z substrates delivered stereoselectively

Full text of DOI:10.1016/j.carres.2015.02.005

Carbohydrate Research 407 (2015) 148e153
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
C-glycosphingolipid precursors via iodocyclization of homoallyic
trichloroacetimidates
,
, b, *
Ahmad S. Altiti a b, David R. Mootoo a
a Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10065, USA
b The Graduate Center, CUNY, 365 5th Avenue, New York, NY 10016, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The iodocyclization of homoallylic trichloroacetimidates derived from a-C-allyl galactoside were inves-
Received 18 December 2014
Received in revised form
10 February 2015
Accepted 12 February 2015
Available online 21 February 2015
tigated. In line with the stereochemical trend observed for less substituted non-glycosylated frameworks,
E and Z substrates delivered stereoselectively the 1,3-anti and 1,3-syn amino alcohol motifs, respectively.
These products are advanced precursors to C-glycosides of the potent immunostimulatory glycolipid
KRN7000.
© 2015 Elsevier Ltd. All rights reserved.
Keywords:
Glycomimetic
C-Glycoside
Glycolipid
KRN7000
Imidate
Oxazine
Iodocyclization
1. Introduction
intramolecular nitrogen delivery strategy (Scheme 1). Our initial
execution of this plan utilized the iodocyclization of a homoallylic
The involvement of glycosphingolipids in a variety of biological
pathways has created a demand for unnatural analogs for use as
mechanistic probes.1e8 A popular subset thereof are C-glycosides,
which are of interest because of their greater hydrolytic stability
and conformational mobility compared to their parent O-glyco-
sides.9e13 However, the synthesis of these materials are not trivial,
with a major challenge being the stereoselective fabrication of the
pseudoanomeric bond, which is exacerbated for structures with
highly substituted aglycone segments, as in the case of C-glyco-
sphingolipids. One solution to this problem is to elaborate simple C-
glycosides in which the pseudoanomeric configuration is ‘pre-
set’.14e24 In this vein C-allyl glycosides of a variety of different
monosaccharides are available in either pseudoanomeric config-
uration,25e29 and new approaches for their transformation to more
functionalized C-glycosides are of interest.
carboimidothioate 3.30 Herein, we describe our results on the
cyclization of related trichloroacetimidates 4. These studies were
directed at C-glycosides of the potent immunostimulatory glyco-
lipid KRN7000 9 (Scheme 2).31
2. Results and discussion
2.1. Synthetic design
The specific templates 6 and 7, chosen for this study were of
interest because of their easily availability from known precursors,
and their potential as versatile relay compounds to C-glycosides of
KRN7000 and related sphingolipids (Scheme 2). Studies on the
iodocyclization of simple homoallylic tricloroacetimidates suggest
that the stereochemistry of this cyclization depends primarily on
alkene geometry and the configuration at the allylic position.32e34
Thus, the reaction of E-alkene 6 is expected to favor the 1,3-anti
amino alcohol motif (cf. 22 vide infra), which would lead to the
‘unnatural’ stereochemistry in C-KRN7000 (i.e., 8a), because of
stereoelectronic factors due to the allylic oxygen. In contrast, the
reaction of the Z-isomer 7 is predicted to give the 1,3-syn amino
Towards this end, we have recently reported a strategy in which
C-allylglycosides 1 are converted to homoallylic alcohol derivatives
2, which serve as templates to C-glycosphingolipids 5 via an
* Corresponding author. Tel.: þ212 772 4356; fax: þ212 772 5332.
E-mail address: dmootoo@hunter.cuny.edu (D.R. Mootoo).
http://dx.doi.org/10.1016/j.carres.2015.02.005
0008-6215/© 2015 Elsevier Ltd. All rights reserved.

A.S. Altiti, D.R. Mootoo / Carbohydrate Research 407 (2015) 148e153
149
Scheme 1. C-glycosphingolipids via intramolecular nitrogen delivery.
alcohol derivative (cf. 23, vide infra), because A(1,3) strain overrides
the directing effect of the allylic substituent. However, because of
the highly substituted nature of 6 and 7, and the conformational
rigidity imposed by the cyclic acetal framework, neither the ex-
pected stereoselectivity nor chemoselectivity in these reactions
was assured. With regards to the latter, to reduce the likelihood of
deleterious THF formation involving the C2-oxygen on the sugar
ring, the 2-OH on the sugar segment was protected as an ace-
tate15,23,35 Schemes 3e5.
Scheme 3. Cross metathesis strategy for homoallylic trichloroacetimidates.
synthesis as benzyl and p-methoxybenzyl ethers were found to give
appreciable amounts of the tetrahydrofuran product resulting from
nucleophilic attack by the C2-oxygen, during the iodination
step.15,23 Aldehyde 20 was obtained from 12 after alcohol benzy-
lation and ozonolysis of the alkene. Treatment of 18 in a mixture of
THF and dichloromethane at ꢀ78 ꢁC with NaHMDS, followed by
addition of 20 to the resulting ylide, provided alkene 21 in 46% yield
from 18, as exclusively the Z isomer within the limits of 1H NMR
detection. The solvent mixture for this reaction was critical as pure
THF gave lower Z:E ratios. This result may be due to a higher
effective concentration of the metal cation in the reaction with pure
THF, which facilitates oxaphosphetane reversion, and consequently
2.2. Synthesis
We envisaged that a cross metathesis (CM) strategy would
provide the desired E and Z frameworks in a single step, with the
former as the major isomer.17,30,36 Accordingly, CM on known al-
kenes, C-allyl galactoside 1135 and the glucose derived alkene 1237
(6 equiv), using Grubbs II catalyst, produced an E:Z mixture of
homoallylic alcohols 13 and 14 in 90% yield from 12, as an
approximately 3:1 E:Z mixture, as determined by 1H NMR analysis.
stereochemical drift.38,39 That the relative configuration at the
a-
carbon in 20 was unaffected by epimerization under the conditions
of the Wittig reaction, was confirmed by correlation of the Wittig
J
vic values of 15.7 and 11.0 Hz for 13 and 14, respectively, supported
the assigned alkene geometry. Treatment of 13 and 14 with DBU
and trichloroacetonitrile provided the respective tri-
chloroacetimidates 6 and 7.
A more stereoselective synthesis of the Z-homoallylic alcohol 14
was performed using a Wittig olefination strategy. Thus, C-allyl
glycoside 10 was converted to alcohol 16 through standard pro-
cedures for alcohol silylation and alkene processing. Trans-
formation of 16 to the iodide 17 and reaction of the latter with
triphenylphosphine provided phosphonium salt 18. The use of the
tert-butyldimethylsilyl protecting group was important for this
Scheme 2. Homoallylic trichloroacetimidate precursors for C-glycosides of KRN7000.
Scheme 4. Wittig strategy for Z-homoallylic trichloroacetimidate.

150
A.S. Altiti, D.R. Mootoo / Carbohydrate Research 407 (2015) 148e153
applications to the synthesis of C-glycosides of KRN7000 and
related glycosphingolipids are underway.
4. Experimental
4.1. Synthesisegeneral
Solvents were purified by standard procedures or used from
commercial sources as appropriate. Petroleum ether refers to the
fraction of petroleum ether boiling between 40 and 60 ꢁC. Ether
refers to diethyl ether. Unless otherwise stated thin layer chroma-
tography (TLC) was done on 0.25 mm thick precoated silica gel 60
(HF-254, Whatman) aluminium sheets and flash column chroma-
tography (FCC) was performed using Kieselgel 60 (32e63 mesh,
Scientific Adsorbents). Elution for FCC usually employed a stepwise
solvent polarity gradient, correlated with TLC mobility. Chromato-
grams were observed under UV (short and long wavelength) light,
and/or were visualized by heating plates that were dipped in a
solution of ammonium (VI) molybdate tetrahydrate (12.5 g) and
cerium (IV) sulfate tetrahydrate (5.0 g) in 10% aqueous sulphuric
acid (500 mL), or a solution of 20% sulfuric acid in ethanol. NMR
spectra were recorded using a Varian Unity Plus 500 instrument. 1H
and 13C spectra were recorded at 500 and 125 MHz, respectively in
CDCl3 or C6D6 solutions with residual CHCl3 or C6H6 as internal
standard (dH 7.27, 7.16 and dC 77.2, 128.4 ppm). Optical rotations
Scheme 5. Iodocyclization of E- and Z-homoallylic trichloroacetimidates.
product 21 with the Z-alkene 14 from the CM route, and by NMR
analysis of 23, the oxazine subsequently obtained from 14 (vide
infra). Thus, exchange of the protecting group at the C2eOH of the
sugar residue in 21 from the silyl ether to the acetate, followed by
DDQ promoted removal of the p-methoxybenzyl ether afforded 14
in 93% overall yield from 21.
([
a]
D were recorded using a Jasco P-1020 polarimeter and are given
-line). Chemical shifts
in units of 10ꢀ1 degcm2g at 589 nm (sodium
D
Treatment of
a
solution of the E-homoallylic tri-
are quoted in ppm relative to tetramethysilane (dH 0.00) and
coupling constants (J) are given in Hertz. First order approximations
are employed throughout. High resolution mass spectrometry was
performed on Ultima Micromass Q-TOF or Waters Micromass LCT
Premier mass spectrometers.
chloroacetimidate 6 in dry propionitrile with IBr, in the presence of
anhydrous K2CO3 at ꢀ78 / ꢀ25 ꢁC, gave oxazine 22 in approxi-
mately 62% yield. Under similar conditions the Z-tri-
chloroacetimidate 7 gave oxazine 23 in 70% yield. In contrast to the
iodocyclizations of related carboimidothioate substrates where
iodonium dicollidine perchlorate (IDCP) was favored as the pro-
moter over IBr, the more reactive IBr was preferred here because of
the apparently lower reactivity of the trichloroacetimidate sub-
strates. The structures of 22 and 23 were assigned from 2D COSY,
HSQC and NOESY experiments. The stereochemistry of the newly
4.2. E Homoallylic trichloroacetimidate (6)
To a solution of 13 (150 mg, 0.215 mmol) in dry CH3CH2CN
(3.0 mL) at ꢀ25 ꢁC was added DBU (100
mL, 0.70 mmol) and CCl3CN
mL, 0.99 mmol). The reaction mixture was stirred at this
0
0
0 0
(100
formed oxazine ring in 22 was deduced from J2 ,3 and J3 4 values of
7.0 and 10.3 Hz, respectively, and a H30/50 NOE. That the J2 3 is
7.0 Hz and not much lower, suggests that six membered ring adopts
0
0
temperature for 20 min, then diluted with water and extracted with
EtOAc. The organic phase was washed with brine and dried
(Na2SO4), filtered, and concentrated in vacuo. The crude residue
was purified by FCC to give 6 (185 mg, 92%): Rf¼0.35 (20% EtOAc/
0
0
0 0
a distorted half chair conformation. Similarly, J2 ,3 and J3 4 values of
8.8 and 10 Hz, respectively, and H20/H40 and H30/50 nOes supported
hexane); 1H NMR (CDCl3)
d 8.39 (s, 1H), 7.43e7.17 (m, 20H), 5.75 (m,
0
0
the structure of 23. In this case the relatively large J2 3 of 8.8 Hz
1H), 5.56 (dd, J¼6.7, 15.6 Hz, 1H), 5.49 (s, 1H), 4.97 (m, 1H), 4.89 (m,
1H), 4.62e4.40 (m, 7H), 4.22 (dd, J¼6.8, 9.4 Hz, 1H), 4.09 (m, 1H),
3.94 (m, 1H), 3.85 (m, 1H), 3.82 (dd, J¼3.0, 5.0 Hz, 1H), 3.67e3.62
suggests a less distorted conformation of the oxazine ring.
(m, 3H), 2.33e2.05 (m, 2H), 1.95 (s, 3H). 13C NMR (CDCl3)
d 170.3,
3. Conclusion
161.6, 138.7, 138.3, 138.2, 137.5, 131.1, 129.3, 128.8, 128.6, 128.5,
128.0, 127.9, 127.8, 126.5, 101.5, 79.8, 77.7, 76.8, 75.0, 74.0, 73.5, 73.4,
73.1, 72.5, 71.0, 70.6, 67.5, 66.6, 32.5, 21.2. HRMS (ESI, MNaþ) m/z
calcd for C44H46Cl3NNaO9 860.2136, found 862.2098.
Thus, the iodocyclizations of homoallylic trichloroacetimidates
6 and 7 showed opposite facial selectivity, resulting in the 1,3-syn
and 1,3-anti aminoalcohol motifs, respectively. This stereochemical
trend is line with results reported for less substituted non-
glycosylated substrates, but differs to our earlier result for related
carboimidothioates, in which the E and Z substrates showed the
same facial selectivity.30,32,33 However, since the tri-
chloroacetimidates in the present study are conformationally
restrained by the cyclic acetal framework, whereas the analogous
carboimidothioates were not, it is unclear whether the contrasting
stereochemical trends are a consequence of the different imidate
nucleophiles or the greater rigidity of the trichloroacetimidate
substrates. It is also unclear whether highly substituted sugar ring
impacts on the stereoselectivity of these iodocyclizations. More
systematic are needed for a clearer understanding of the stereo-
chemistry of these complex imidate cyclizations. These and
4.3. Z Homoallylic trichloroacetimidate (7)
To a solution of 14 (120 mg, 0.173 mmol) in dry CH3CH2CN
(2 mL) at ꢀ25 ꢁC was added DBU (100
ml, 0.70 mmol), and CCl3CN
(100 ml, 0.99 mmol). The reaction was processed as described for
the synthesis of the E-trichloroacetimidate 6, and the crude ma-
terial purified by FCC to give 7 (100 mg, 70%): Rf¼0.50 (20% EtOEt/
hexane); 1H NMR (CDCl3) 8.39 (s, 1H), 7.43e7.17 (m, 20H), 5.66 (m,
1H), 5.52 (m, 2H), 4.93 (m, 1H), 4.89 (dt, J¼5.2, 9.8 Hz, 1H),
4.61e4.43 (m, 8H), 4.15 (m,1H), 3.93 (m, 2H), 3.78 (dd, J¼3.0, 5.4 Hz,
1H), 3.65 (m, 3H), 2.40e2.27 (m, 2H), 1.93 (s, 3H). 13C NMR (CDCl3)
d
170.3, 161.8, 138.7, 138.3, 138.2, 137.4, 131.8, 129.4, 128.6, 128.5,
128.0, 127.9, 127.4, 126.5, 101.5, 77.5, 75.6, 74.7, 74.5, 73.4, 73.2, 71.2,

A.S. Altiti, D.R. Mootoo / Carbohydrate Research 407 (2015) 148e153
151
71.0, 67.6, 66.4, 28.9, 21.2. HRMS (ESI, MNaþ) m/z calcd for
44H46Cl3NNaO9 860.2136, found 862.2118.
HRMS (ESI, MHþ) m/z calcd for C36H49O5Si 589.3349, found
589.3346.
C
4.7. 1-(20-O-tert-butyldimethylsilyl-30,40,60-tri-O-benzyl-
a-D-
galactopyranosyl)-2-ethanol (16)
4.4. 1-(20-O-acetyl-30,40,60-tri-O-benzyl-
a-D-galactopyranosyl)-2-
propene (11)
A stream of O3/O2 was passed through a solution of 15 (1.0 g,
1.7 mmol) in CH2Cl2 (150 mL) at ꢀ78 ꢁC for 10 min. The reaction
mixture was then purged with nitrogen, PPh3 (500 mg, 1.9 mmol)
added and stirring continued at rt for 2 h. At this point the mixture
was concentrated in vacuo. FCC of the residue afforded the derived
aldehyde (0.85 g, 85%): Rf¼0.50 (20% EtOAc/hexane); 1H NMR
To a solution of 10 (250 mg, 0.53 mmol) in EtOAc (9 mL) at rt,
was added DMAP (6.5 mg, 0.053 mmol) and Ac2O (100 l,
m
0.97 mmol). The reaction mixture was stirred for 20 min, then
concentrated in vacuo, and the residue purified by FCC to give 11
(250 mg, 92%): Rf¼0.45 (20% EtOEt/hexane); 1H NMR (CDCl3)
d
7.22e7.19 (m, 15H), 5.65 (m, 1H), 5.00e4.95 (m, 3H), 4.64e4.45
(CDCl3) d 9.75 (s,1H), 7.32e7.30 (m,15H), 4.73e4.5 (m, 7H), 4.03 (m,
(m, 6H), 4.16 (m, 1H), 3.95 (m, 2H), 3.83 (dd, J¼3.0, 5.2 Hz, 1H), 3.68
(m, 2H), 2.27e2.09 (m, 2H), 1.97 (s, 3H). 13C NMR (CDCl3)
d
170.2,
1H), 4.00 (m, 1H), 3.96 (m, 1H), 3.86 (t, J¼10.3 Hz, 1H), 3.68 (dd,
J¼10.6, 4.5 Hz, 1H), 3.54 (dd, J¼6.7, 2.5 Hz, 1H), 2.62 (m, 2H), 0.83 (s,
138.5, 138.2, 138.1, 134.0, 128.4, 127.8, 127.7, 127.6, 127.5, 117.3, 74.7,
74.0, 73.3, 73.1, 73.0, 72.1, 70.8, 68.7, 66.2, 33.9, 21.0.
9H), 0.00 (s, 3H), ꢀ0.05 (s, 3H). 13C NMR (CDCl3)
d 201.3, 138.5,
128.6, 128.5, 128.0, 127.9, 127.8, 127.7, 78.2, 73.7, 73.4, 73.3, 70.1,
68.2, 67.3, 42.9, 26.0, 18.2, ꢀ4.5, ꢀ4.7. HRMS (ESI, MHþ) m/z calcd
for C35H46O6Si 591.3142, found 591.3146.
4.5. CM of 11 and 12: E- and Z-homoallylic alcohols (13) and (14)
NaBH4 (125 mg, 3.5 mmol) was slowly added to a solution of the
material from the previous step in methanol (20 mL) at 0 ꢁC. The
reaction mixture was stirred for 30 min, then diluted with satu-
rated aqueous NH4Cl and evaporated under reduced pressure. The
residual syrup was taken up in EtOAc and washed with saturated
aqueous NaHCO3 and brine. The organic extract was dried (Na2SO4),
filtered and concentrated in vacuo. FCC of the residue provided 16
as a colorless oil (730 mg, 86%): Rf¼0.25 (20% EtOAc/hexane); 1H
Ethylene gas was bubbled through a mixture of 11 (250 mg,
0.49 mmol) and 12 (600 mg, 2.9 mmol) in dry dichloromethane
(50 mL) for 1 h. Grubbs II catalyst (42 mg, 0.04 mmol) was then
added and the reaction mixture heated at reflux for 2 h. The solvent
was concentrated in vacuo and the crude mixture was subjected to
FCC to give a mixture of E alkene 13, Z alkene 14 (305 mg, 90% based
on 11; E:Z ca. 3:1). Repeat FCC afforded partial separation of E and Z
alkenes, 13 and 14.
NMR (CDCl3) d 7.32e7.30 (m, 15H), 4.71e4.50 (m, 6H), 4.09 (m, 2H),
For 13: Rf¼0.22 (40% EtOAc/hexane); 1H NMR (CDCl3)
3.98 (t, J¼10.05 Hz, 1H), 3.89 (m, 2H), 3.75 (m, 2H), 3.55 (dd, J¼6.6,
d
7.25e7.15 (m, 20H), 5.62 (m, 1H), 5.43 (m, 1H), 5.39 (dd, J¼8.4,
2.8 Hz, 1H), 3.51 (dd, J¼10.7, 3.5 Hz, 1H), 1.90 (m, 1H), 1.61 (m, 1H),
0.83 (s, 9H), 0.00 (s, 3H), ꢀ0.05 (s, 3H). 13C NMR (CDCl3)
d 138.7,
15.7 Hz, 1H), 4.89 (m, 1H), 4.61e4.41 (m, 6H), 4.23 (m, 2H), 4.04 (t,
J¼10.6 Hz, 1H), 3.90 (m, 1H), 3.85 (t, J¼8.6 Hz, 1H), 3.79 (dd, J¼3.0,
5.8 Hz, 1H), 3.64e3.52 (m, 3H), 3.43 (m, 1H), 3.03 (d, J¼4.4 Hz, 1H),
138.5, 138.3, 128.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 78.4, 74.0, 73.4, 73.0, 72.4, 70.8, 67.8, 61.7, 30.0, 26.2, 26.0,
25.9, 25.8, 18.2, ꢀ4.6, ꢀ4.7. HRMS (ESI, MNaþ) m/z calcd for
2.34 (m, 1H), 2.13 (m, 1H), 2.02 (s, 3H). 13C NMR (CDCl3)
d 171.3,
138.5,138.1, 138.0, 137.9, 131.6, 130.1, 128.9, 128.4, 128.3,127.9, 127.8,
127.7, 127.6, 126.2, 101.0, 83.9, 76.8, 74.5, 73.1, 73.0, 70.7, 70.4, 64.8,
33.4, 21.1. HRMS (ESI, MNaþ) m/z calcd for C42H46NaO9 717.3040,
found 717.3039.
C35H48NaO6Si 615.3118, found 615.3112.
4.8. 1-(20-O-tert-butyldimethylsilyl-30,40,60-tri-O-benzyl-
a-D-
galactopyranosyl)-2-iodoethane (17)
For 14: Rf¼0.26 (40% EtOAc/hexane); 1H NMR (CDCl3)
d
7.38e7.20 (m, 20H), 5.57 (dt, J¼11.0, 4.7 Hz, 1H), 5.47 (m, 2H), 5.00
I2 (673 mg, 2.65) was added to a mixyure of alcohol 16 (630 mg,
1.06 mmol), Ph3P (837 mg, 3.48 mmol) and imidazole (289 mg,
4.24 mmol) in toluene (20 mL). The reaction mixture was stirred at
rt for 30 min, then quenched with 10% aqueous Na2S2O3 and
extracted with EtOAc. The organic phase was washed with brine,
dried (Na2SO4) and concentrated in vacuo. FCC of the residue gave
17 as a colorless oil (691 mg, 93%): Rf¼0.6 (10% EOAc/hexane); 1H
(m, 1H), 4.66e4.40 (m, 7H), 4.25 (m, 2H), 4.17 (m, 1H), 4.02 (d,
J¼10.5 Hz, 1H), 3.95 (t, J¼11 Hz, 1H), 3.84 (dd, J¼17.9, 5.25 Hz, 1H),
3.70 (dd, J¼5.1, 3.0 Hz, 1H), 3.56 (m, 3H), 3.38 (dt, J¼9.5, 5.4 Hz, 1H),
2.50 (m, 1H), 1.98 (m, 4H). 13C NMR (CDCl3)
d 170.5, 138.3, 138.2,
138.9, 137.9, 131.4, 129.7, 129.2, 128.6, 128.5, 128.1, 128.0, 127.9,
126.4, 101.0, 78.6, 74.3, 73.6, 73.3, 72.4, 72.0, 71.0, 65.1, 29.2, 21.2.
HRMS (ESI, MNaþ) m/z calcd for C42H46NaO9 717.3040, found
717.3037.
NMR (CDCl3)
d 7.30e7.23 (m, 15H), 4.70e4.45 (m, 6H), 3.99 (ddd,
J¼10.6, 6.9, 3.5 Hz, 1H), 3.93e3.89 (m, 2H), 3.67 (dd, J¼10.4, 4.1 Hz,
1H), 3.49 (dd, J¼6.9, 2.6 Hz, 1H), 3.27 (m, 1H), 3.18 (m, 1H), 2.05 (m,
1H), 1.92 (m, 1H), 0.82 (s, 9H), 0.00 (s, 3H), ꢀ0.06 (s, 3H). 13C NMR
4.6. 1-(20-O-tert-butyldimethylsilyl-30,40,60-tri-O-benzyl-
a-D-
galactopyranosyl)-2-propene (15)
(CDCl3) d 138.7, 138.6, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9,
127.8, 127.7, 78.8, 74.1, 73.6, 73.2, 72.9, 70.4, 68.1, 31.8, 26.2, 26.0,
TBSCl (1.4 g, 9.2 mmol) and NaH (212 mg, 8.9 mmol) were added
to a solution of alcohol 10 (1.4 g, 2.95 mmol) in dry THF (10 mL). The
reaction mixture was stirred at rt for 1 h. The reaction was diluted
with water and extracted with EtOAc. The organic phase was
washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo The residue was purified by FCC to give 15 (1.74 g, 98%):
25.9, 25.8, 18.2, 3.6, ꢀ4.6, ꢀ4.7. HRMS (ESI, MNaþ) m/z calcd for
C35H47INaO5Si 725.2135, found 725.2131.
4.9. 1-(20-O-tert-butyldimethylsilyl-30,40,60-tri-O-benzyl-
a-D-
galactopyranosyl)-2-triphenylphosphoniumethyl iodide (18)
Rf¼0.47 (10% EtOAc/hexane); 1H NMR (CDCl3)
d
7.32e7.30 (m, 15H),
A mixture of 17 (691 mg, 0.984 mmol) and PPh3 (2.24 g,
8.5 mmol) was fused at 80 ꢁC for 3 h. The mixture was then cooled
to rt and purified by FCC to give 18 (845 mg, 88%): Rf¼0.16 (10%
5.78 (m, 1H), 5.00 (m, 2H), 4.68e4.41 (m, 6H), 3.97 (m, 1H), 3.90 (m,
2H), 3.86 (ddd, J¼9.8, 9.0, 4.1 Hz, 1H), 3.77 (t, J¼10.5 Hz, 1H), 3.62
(dd, J¼10.6, 4.7 Hz, 1H), 3.50 (dd, J¼7.0, 2.7 Hz, 1H), 2.27 (m, 2H),
acetone/CH2Cl2); 1H NMR (CDCl3)
d 7.75 (m, 15H), 7.65 (m, 15H),
0.83 (s, 9H), 0.00 (s, 3H), ꢀ0.06 (s, 3H). 13C NMR (CDCl3)
d
138.8,
4.61e4.47 (m, 6H), 4.13 (m, 2H), 4.04 (m, 1H), 3.86 (m, 1H), 3.75 (m,
1H), 3.69 (1H), 3.65 (d, J¼7.6 Hz, 1H), 3.62 (dd, J¼5.7, 2.8 Hz, 1H),
3.43 (m, 1H), 2.07e1.83 (m, 2H), 0.60 (s, 9H), ꢀ0.20 (s, 3H), ꢀ0.28 (s,
138.7, 135.7, 128.5, 128.5, 128.1, 127.9, 127.8, 127.7, 127.6, 116.7, 78.5,
74.2, 73.4, 73.2, 73.2, 72.7, 70.3, 67.7, 32.0, 26.0, 18.2, ꢀ4.5, ꢀ4.7.

152
A.S. Altiti, D.R. Mootoo / Carbohydrate Research 407 (2015) 148e153
3H). 13C NMR (CDCl3)
d
139.0, 138.5, 135.2, 134.0, 133.9, 130.8, 130.7,
The reaction mixture was warmed to rt, stirred at this temperature
for 2 h, then diluted with water and extracted with EtOAc. The
organic phase was washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was dissolved in EtOAc (2 mL)
and treated with Ac2O (0.2 mL) and DMAP (5 mg). After stirring for
10 min at rt. the organic solvent was concentrated in vacuo, and the
crude product was purified by FCC to give a homogeneous product
(330 mg, 98%): Rf¼0.25 (30% EtOAc/hexane). DDQ (190 mg,
0.80 mmol) was added to a mixture of this material (330 mg,
0.40 mmol), CH2Cl2 (4.5 mL) and saturated aqueous NaHCO3
(0.5 mL). The reaction mixture was stirred at rt for 30 min, then
concentrated in vacuo. FCC of the residue gave 14 (160 mg, 95%
brsm). This material was identical by TLC, 1H and 13C NMR to a
sample of 14 prepared via the CM route.
128.6, 128.5, 128.1, 128.0, 127.9, 127.7, 127.6, 118.4 (JCeP¼85.8 Hz),
73.9, 73.6, 73.5, 73.0, 72.4, 70.3, 68.1, 25.9, 23.2, 19.5 (JCeP¼52.4 Hz),
18.0, ꢀ4.6, ꢀ4.9. HRMS (ESI, MꢀI) m/z calcd for C53H62O5PSi
837.4104, found 837.4102.
4.10. (2R,4S,5R)-5-((4-Methoxybenzyl)oxy)-2-phenyl-4-vinyl-1,3-
dioxane (19)
To a solution of 12 (1.0 g, 4.9 mmol) in dry DMF (20 mL) at 0 ꢁC
was added NaH (213 mg, 5.3 mmol). The mixture was stirred at this
temperature for 15 min, at, which time PMBCl (1.0 mL, 7.2 mmol)
was added slowly, and stirring continued at rt for 2 h. The mixture
was then quenched with methanol (0.5 mL), diluted with water and
extracted with EtOAc. The organic phase was washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. FCC of the
residue provided 19 (1.4 g, 86%): Rf¼0.55 (20% EtOAc/hexane); 1H
4.14. C-Glycoside oxazine (22)
NMR (CDCl3)
d
7.48 (d, J¼1.8 Hz, 2H), 7.32 (m, 3H), 7.23 (d, J¼9.2 Hz,
To a solution of 6 (165 mg, 0.197 mmol) in dry CH3CH2CN (4 mL)
at ꢀ25 ꢁC was added anhydrous K2CO3 (55 mg, 0.80 mmol) and IBr
(243 mg, 1.18 mmol). The reaction was stirred at this temperature
for 2 h, then diluted with aqueous Na2S2O3 and extracted with
EtOAc. The organic phase was washed with brine and dried
(Na2SO4), filtered, and concentrated in vacuo. The crude material
was purified by FCC to give an inseparable mixture of 22 and an
unidentified impurity (139 mg). The purity of 22 was estimated at
ca. 85 mol % by 1H NMR, corresponding to a yield of 62% of 22 from
7. Repeated FCC gave a pure sample of 22: Rf¼0.18 (0.5% EtOH/
2H), 6.86 (d, J¼8.6 Hz, 2H) 6.03 (ddd, J¼17.3, 10.8, 5.8 Hz, 1H), 5.35
(dd, J¼95.8, 16.8 Hz 2H), 4.45 (m, 2H), 4.25 (dd, J¼10.9, 5.1 Hz, 1H),
4.12 (dd, J¼9.2, 5.9 Hz, 1H), 3.79 (s, 3H), 3.62 (t, J¼10.4, 1H) 3.42 (dt,
J¼9.5, 5.1 Hz, 1H). 13C NMR (CDCl3)
d 159.7, 137.9, 135.2, 130.1, 129.8,
129.6, 129.1, 128.4, 126.4, 101.0, 81.5, 72.8, 72.7, 69.9, 55.5. HRMS
(ESI, MNaþ) m/z calcd for C20H22NaO5 349.1416, found 349.1413.
4.11. (2R,4R,5R)-5-((4-Methoxybenzyl)oxy)-2-phenyl-1,3-dioxane-
4-carbaldehyde (20)
CH2Cl2); [
a
]
18 47 (c 1.5, CH2Cl2); 1H NMR (C6D6)
d
7.70 (dd, J¼1.3 Hz,
D
Alkene 19 (1.00 g, 3.06 mmol) was subjected to the standard
ozonolysis procedure described in the preparation of 16. FCC of the
crude reaction product afforded 20 (500 mg, 50%): Rf¼0.17 (20%
EtOAc/hexane); 1H NMR (CDCl3) 9.72 (d, J¼1.0 Hz, 1H), 7.46 (m, 2H),
7.35 (m, 3H), 7.25 (m, 2H), 6.88 (d, J¼8.7 Hz, 2H), 5.51 (s, 1H), 4.55
(ABq, Dd¼0.04 ppm, J¼11.3 Hz, 2H), 4.29 (dd, J¼5.1, 10.8 Hz, 1H),
2H), 7.50 (m, 2H), 7.42 (m, 2H), 7.33e7.18 (m,14H), 5.47 (m,1H), 5.19
(s, 1H), 5.11 (m, 1H), 4.77 (m, 2H),4.70 (apparent d, J¼11.5 Hz, 1H),
4.61 (ABq, J¼11.0 Hz, Dd¼0.06 ppm, 2H), 4.54 (m, 3H), 4.40 (m, 2H),
4.27 (dd, J¼4.5, 7.0 Hz,1H), 4.07 (m, 2H), 3.96 (dd, J¼3.0, 5.2 Hz,1H),
3.87 (dd, J¼3.0, 5.3 Hz, 1H), 3.45 (dd, J¼6.9, 10.3 Hz, 1H), 3.28 (t,
J¼10.2 Hz, 1H), 2.57 (m, 1H), 2.35 (m, 1H), 1.73 (s, 3H). 13C NMR
4.18 (d, J¼9.7 Hz, 1H), 3.78 (s, 3H), 3.74 (m, 1H), 3.65 (m, 1H). 13
C
(C6D6) d 169.7, 152.5, 139.5, 139.0, 137.8, 129.7, 129.0, 128.9, 128.8,
NMR (CDCl3)
d
197.3, 159.9, 137.0, 130.1, 129.5, 128.6, 126.4, 114.2,
128.5, 128.0, 127.1, 103.2, 76.6, 75.7, 75.1, 74.3, 74.2, 73.2, 72.6, 72.0,
101.1, 83.0, 72.7, 69.6, 67.9, 55.5. HRMS (ESI, MNaþ) m/z calcd for
19H20NaO5 351.1208, found 351.1209.
68.6, 68.2, 66.6, 59.0, 38.0, 30.5, 20.8. HRMS (ESI, MKþ) m/z calcd for
C
C44H45Cl3IKNO9 1002.0842, found 1004.0811.
4.12. Z-p-Methoxybenzyl ether (21)
4.15. C-Glycoside oxazine (23)
NaHMDS (0.57 mL of a 2M solution in THF, 1.14 mmol) was
added at ꢀ78 ꢁC to a solution of 18 (1.10 g, 1.14 mmol) in anhydrous
2:1 THF/CH2Cl2 (24 mL). The resulting bright orange solution was
stirred for 1 h at this temperature, at, which time a solution of 20
(450 mg, 1.37 mmol) in THF (10 mL) was added dropwise. The
resulting mixture was warmed to rt over 5 h, then poured into
saturated aqueous NH4Cl and extracted with EtOAc. The organic
phase was washed with brine, dried (Na2SO4), filtered, and evap-
orated under reduced pressure. FCC of the residue gave 21 (385 mg,
To a solution of 7 (85 mg, 0.1 mmol) in dry CH3CH2CN (2.0 ml)
at ꢀ78 ꢁC was added anhydrous K2CO3 (56 mg, 0.4 mmol) and IBr
(150 mg, 0.7 mmol). Processing of the reaction as described for the
iodocyclization of E-trichloroacetimidate 6, and FCC of the crude
product gave 23 (68 mg, 70%): Rf¼0.43 (20% EtOAc/hexane); [
a]
18 11
D
(c 0.8, CH2Cl2); 1H NMR (C6D6)
d
7.40e7.18 (m, 20H), 5.51 (m, 1H),
5.33 (s, 1H), 5.10 (t, J¼6.2 Hz,1H), 4.73 (m, 2H), 4.60 (ABq, J¼11.0 Hz,
Dd¼0.05 ppm, 2H), 4.52 (m, 3H), 4.35 (m, 2H), 4.08 (m, 1H), 4.02
(dd, J¼5.3, 10.3 Hz, 1H) 3.96 (m, 2H), 3.90 (m, 1H), 3.78 (dt, J¼5.5,
10.0 Hz, 1H), 3.42 (dd, J¼1.8, 8.8 Hz, 1H), 3.36 (t, J¼10.3 Hz, 1H),
46%): Rf¼0.23 (10% EtOAc/hexane); 1H NMR (CDCl3)
d 7.38e7.20 (m,
22H), 6.8 (m, 2H), 5.8 (m, 1H), 5.6 (t, J¼9.6 Hz, 1H), 5.45 (s, 1H),
4.75e4.40 (m, 10H), 4.20 (m, 1H), 4.04 (m, 1H), 3.94 (m, 3H), 3.89
(m, 1H), 3.32 (m, 1H), 3.79 (s, 3H), 3.64 (m, 1H), 3.57 (m, 1H), 3.47
(m, 1H), 3.42 (m, 1H), 2.6e2.4 (m, 2H), 0.86 (s, 9H), ꢀ0.02 (s,
2.76e2.61 (m, 2H), 1.73 (s, 3H), 13C NMR (C6D6)
d 169.8, 153.0, 139.7,
139.1,139.0,137.7, 130.0,129.6,129.0,128.9,127.9,127.1,126.9,102.4,
77.7, 75.7, 74.7, 74.2, 74.0, 73.2, 72.7, 72.0, 69.9, 68.3, 67.9, 61.6, 37.6,
30.6, 20.8. HRMS (ESI, MNaþ) m/z calcd for C44H45Cl3INNaO9
986.1102, found 988.1075.
3H), ꢀ0.08 (s, 3H). 13C NMR (CDCl3)
d 159.6, 139.0, 138.5, 135.2,
134.0, 133.9, 130.8, 130.7, 128.6, 128.5, 128.1, 128.0, 127.9, 127.7,
127.6, 114.0, 101.1, 78.9, 77.5, 74.3, 73.5, 73.2, 72.5, 72.3, 68.1, 55.5,
26.1, 18.3, ꢀ4.5, ꢀ4.6. HRMS (ESI, MNaþ) m/z calcd for C54H66NaO9Si
909.4374, found 909.4373.
Acknowledgments
This work was supported by the National Science Foundation
(#1301330). A Research Centers in Minority Institutions Program
grant from the National Institute of Health Disparities (MD007599)
of the National Institutes of Health (NIH), which supports the
infrastructure at Hunter College, and a Clinical Translational Sci-
ence Center award (TR000457) from the NIH are also
4.13. Z-Homoallylic alcohol 14 from Wittig reaction
To a solution of 21 (370 mg, 0.4 mmol) in THF (10 mL) at 0 ꢁC was
added dropwise a 1M solution of Bu4NF in THF (0.8 mL, 0.8 mmol).

A.S. Altiti, D.R. Mootoo / Carbohydrate Research 407 (2015) 148e153
153
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acknowledged. We thank Dr. Matthew Devany and Ms. Rong Wang
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Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.carres.2015.02.005.
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