A ring closing metathesis strategy for carbapyranosides of xylose and arabinose

Article abstract of DOI:10.1016/j.carres.2016.05.010

The synthesis of β-carba-xylo and arabino pyranosides of cholestanol is described. The synthetic strategy, which is analogous to the Postema approach to C-glycosides, centers on the ring closing metathesis of an enol ether-alkene precursor to give a cycli

Full text of DOI:10.1016/j.carres.2016.05.010

Carbohydrate Research 429 (2016) 143–147
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A ring closing metathesis strategy for carbapyranosides of xylose and
arabinose
Clayton E. Mattis, David R. Mootoo *
Department of Chemistry, Hunter College and The Graduate Center of the City University of New York, 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:
Received 20 January 2016
Received in revised form 29 February 2016
Accepted 2 March 2016
Available online 25 May 2016
The synthesis of β-carba-xylo and arabino pyranosides of cholestanol is described. The synthetic strat-
egy, which is analogous to the Postema approach to C-glycosides, centers on the ring closing metathesis
of an enol ether–alkene precursor to give a cyclic enol ether that is elaborated to a carba-pyranoside via
hydroboration–oxidation on the olefin. The method, which is attractive for its modularity and
stereoselectivity, may find wider applications to carba-hexopyranosides and other complex cycloalkyl
ether frameworks.
Keywords:
Glycomimetic
Carbasugar
Cycloalkyl ether
Arabinose
Xylose
© 2016 Elsevier Ltd. All rights reserved.
RCM
1. Introduction
Carbohydrate residues are present on a wide range of bioactive
molecules and invariably, impact on potency and, or specificity.1–4
Thus, glycodiversification is a popular strategy in the develop-
ment of carbohydrate-based therapeutics.5–9 In this context,
nonhydrolyzable sugar analogues such as carbasugars, in which the
ring oxygen is replaced with a “CH2”, have attracted attention as po-
tentially metabolically stable therapeutic agents and for mechanistic
studies.10 The nuanced conformational properties of carbasugars rel-
ative to their parent O-glycosides are of additional relevance to
structure activity studies.11 Consequently, there is much interest in
the synthesis and properties of carbasugars. While several methods
have been developed for carbasugars in which the pseudo sugar ring
is linked to relatively simple alcohol segments or to the primary
alcohol oxygen of a sugar, structures with more complex alcohol
segments are not as easily accessible because of the challenges as-
sociated with fabricating the pseudoglycosidic ether bond.10,12–14 We
Fig. 1. OSW-1 and carbasugar analogues.
Chemical compounds studied in this article: Methyl 2,3-O-isopropylidene-beta-d-
ribofuranoside (PubChem CID: 96666); Methyl alpha-d-arabinofuranoside
(PubChem CID: 11389582); Cholestanol (PubChem CID: 6665); Methyl
(triphenylphosphoranylidene)acetate (PubChem CID: 17453); Tebbe reagent
(PubChem CID: 91617563); Grubbs catalyst 2nd generation (PubChem CID:
11147261); Dimethyl sulfide borane (PubChem CID: 9833925)
envisaged an RCM-based approach to carbasugars that may address
this issue and that has further appeal because of its modularity. This
strategy is illustrated herein in the synthesis of β-carba-arabino and
xylo pyranosides of cholestanol. We were drawn to these frame-
works because of the existence of the parent sugars in several
antitumor steroidal and triterpenoid saponins, of which OSW-1 1
is a notable example (Fig. 1).15–18 β-Xylopyranosides also comprise
the capsular polysaccharide of fungal pathogens associated with
*
Corresponding author. Department of Chemistry, Hunter College and The
Graduate Center of the City University of New York, New York, NY 10016, USA. Tel.:
212-772-4356; fax: 212-772-5332.
E-mail address: dmootoo@hunter.cuny.edu (D.R. Mootoo).
http://dx.doi.org/10.1016/j.carres.2016.05.010
0008-6215/© 2016 Elsevier Ltd. All rights reserved.

144
C.E. Mattis, D.R. Mootoo / Carbohydrate Research 429 (2016) 143–147
Scheme 1. RCM strategies to C- and carba-pyranosides.
AIDS. Carbaxylosides thereof may be of interest to vaccine devel-
opment in this area.19
7. Through the use of C-branched sugar acids, this method has been
applied to C-di- and higher order C-glycosides. An analogous strat-
egy for carbasugars calls for an RCM on an enolether alkene 10 to
give the cyclic enol ether 9, which differs from 4, the correspond-
ing enol ether in the C-glycoside synthesis, in that the enol ether
oxygen is exocyclic and not endocyclic. However, while RCMs on
enol ether–alkenes like 5 have been successful on a variety of highly
substituted substrates, to the best of our knowledge, RCMs on vari-
ants like 10, in which the ether oxygen is exocyclic to the eventual
ring, have only been tested on silyl or simple alkyl enol ethers.21–25
Our approach builds on the C-glycoside synthesis from the
Postema group, in which the pivotal reaction is the RCM on an enol
ether–alkene 5 to give the C1-substituted glycal 4 (Scheme 1).20
Stereoselective hydroboration–oxidation on 5 leads to the 1,2-trans/
2,3-trans C-glycoside 3. An attractive feature of this strategy is the
modular assembly from “glycone” and “aglycone” precursors 6 and
2. Results and discussion
Synthesis of “glycone” segments. The unsaturated acid precursor
15 for carba-arabinoses was obtained by hydrolysis of the known
ester 14, which in turn was prepared from 5-deoxy-5-iodo-d-ribo-
furanoside 13, via a known procedure (Scheme 2).26 The carba-
xyloside precursor 19, which was previously prepared from L-tartaric,
was prepared here via a more concise route, using a strategy similar
to that used for 14.27 Thus, zinc mediated reductive opening on the
5-deoxy-5-iodo-d-arabinofuranoside 16 afforded enal 17.28,29 Treat-
ment of 17 with methyl(triphenylphosphoranylidene)acetate
provided 18 as a single E-isomer. Selective hydrogenation of the con-
jugated alkene followed by hydrolysis of the ester led to 19.
The feasibility of the key RCM reaction was tested using
cholestanol 20 as a model steroidal segment (Scheme 3). Accord-
ingly, DCC promoted esterification of 20 and alkenoic acids 15 and
19 produced esters 21 and 25 in 98% and 90% yields respectively.
Next, olefination on 21 and 25 using the Tebbe and Takai reagents
afforded the respective enol ethers 22 and 26 in 70% and 66%
yields.30,31 These materials were sensitive to acid and silica gel pu-
rification required the presence of triethylamine in the mobile phase.
Treatment of 22 and 26 with 10 mole % Grubbs II catalyst in
Scheme 2. Synthesis of “glycone” precursors.
Scheme 3. Synthesis of carba-3β-cholestanyl pentopyranosides.

C.E. Mattis, D.R. Mootoo / Carbohydrate Research 429 (2016) 143–147
145
dichloromethane at 60 °C led to the cyclic enol ethers 23 and 27
3.3. (2S,3R)-2,3-Bis(benzyloxy)pent-4-enal (17)
in 75% and 80% yields respectively. Finally, a hydroboration–
oxidation sequence on 23 and 27 afforded the β-carba-arabinoside
and xyloside 24 and 28 respectively, as the only observed diaste-
reomers, in 80% and 63% yields. The stereochemistry of 24 and 28
was assigned from 1H NMR analysis of their acetates 24-OAc
(J1′,2′ = 9.5, J2′,3′ = 9.9, J3′,4′ = 5.1 Hz) and 28-OAc (J1′,2′ = J2′,3′ = J3′,4′ = 9.5–
9.6 Hz, see Supporting Information for selected 1H NMR assignments).
NOEs between H1′–H3′ and H2′–H4′ supported the structure of
28-OAc.
Activated zinc dust (5.14 g, 79.7 mmol) was added to a solu-
tion of 16 (3.62 g, 7.97 mmol) in EtOH (30 mL). 1,2-Dibromoethane
(0.2 mL) was introduced and the mixture stirred for 2 h then fil-
tered over a bed of Celite. The filtrate was concentrated in vacuo
and the residue purified by FCC to give 17 (2.22 g, 94%) as a color-
less oil: Rf = 0.6 (20% EtOAc: petroleum ether); 1H NMR (500 MHz,
CDCl3) δ 3.76 (dd, 1H, J = 1.5, 4.5 Hz), 4.10 (dd, 1H, J = 4.5, 8.0 Hz),
4.48 (ABq, 2H, Δδ = 0.36 ppm, J = 12.0 Hz), 4.62 (ABq, 2H,
Δδ = 0.11 ppm, J = 12.0 Hz), 5.29 (m, 2H), 5.87 (m, 1H), 7.19–7.29 (m,
10H), 9.6 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 70.7, 73.5, 79.9, 85.2,
119.9, 127.8, 127.9, 128.1, 128.2, 128.4, 128.5, 133.8, 137.1, 137.5,
202.6; ESILRMS (M + Na)+ calculated for C19H20O3Na 319.1, found
319.1.
3. Conclusion
In summary, this RCM approach to cholestanol carba-
pentopyranosides 24 and 28 illustrates a potentially general strategy
for the synthesis of β-carba-arabino and xylo-pyranosides with
complex aglycone segments. The methodology, which constitutes
a synthesis of stereochemically complex cycloalkyl-ethers, is at-
tractive for its modularity and stereoselectivity. The synthesis of
carba-hexopyranosides is an obvious direction for future study and
application to other groups of cycloalkyl ether frameworks is also
envisaged.
3.4. Methyl (4R, 5R, E)-4,5-bis(benzyloxy)hepta-2,6-dienoate (18)
A mixture of 17 (2.0 g, 6.76 mmol) and Ph3P = CHCO2Me (4.52 g,
13.52 mmol) in dry CH3CN (40 mL) was heated at reflux for 2 h. After
cooling to rt, the mixture was filtered and the filtrate concen-
trated under reduced pressure. FCC of the residue afforded 18 (2.38 g,
98%) as a colorless oil: Rf = 0.8 (20% EtOAc: petroleum ether); 1H NMR
(500 MHz, CDCl3) δ 3.78 (s, 3H), 3.96 (dd, 1 H, J = 5.5, 6.5 Hz), 4.14
(dt, 1H, J = 1.0, 5.5 Hz), 4.45 (app d, 1 H, J = 12.0 Hz), 4.54 (app d,
1H, J = 12.0 Hz), 4.67 (app d, 2H, J = 12.0 Hz), 5.35 (m, 2H), 5.80 (m,
1H), 6.11 (dd, 1H, J = 1.5, 16.0 Hz), 6.96 (dd, 1H, J = 6.0, 16.0 Hz), 7.30–
7.35 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 51.6, 70.7, 71.9, 79.9, 81.7,
119.6, 122.8, 127.6, 127.7, 128.3, 128.4, 134.3, 137.9, 138.2, 145.1,
166.5; ESILRMS (M + Na)+ calculated for C22H24O4Na 375.2, found
375.2.
3.1. Synthesis—general
Solvents were purified by standard procedures or used from com-
mercial 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 chromatography
(TLC) was done on 0.25 mm thick precoated silica gel 60 (HF-254,
Whatman) aluminum sheets and flash column chromatography (FCC)
was performed using Kieselgel 60 (32–63 mesh, Scientific
Adsorbents). Elution for FCC usually employed a stepwise solvent
polarity gradient, correlated with TLC mobility. Chromatograms were
observed under UV (short and long wavelength) light, and/or were
visualized by heating plates that were dipped in a solution of am-
monium (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 re-
corded using Varian Unity Plus 500 and Bruker Ultra Shield Plus
600 MHz instruments, in CDCl3 or C6D6 solutions with residual CHCl3
or C6H6 as internal standard (δH 7.27, 7.16 and δC 77.2, 128.4 ppm).
Optical rotations ([α]D were recorded using a Jasco P-1020 polar-
imeter and are given in units of 10−1 degcm2g at 589 nm (sodium
D-line). Chemical shifts are quoted in ppm relative to
tetramethysilane (δH 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.
3.5. (4R,5R)-4,5-Bis(benzyloxy)hept-6-enoic acid (19)
Conjugated ester 18 (1.20 g, 3.40 mmol) was dissolved in MeOH
(30 mL) and CuCl (40 mg, 0.34 mmol) was added and the reaction
mixture was cooled to −78 °C. NaBH4 (646 mg, 17.1 mmol) was then
added in one portion to the reaction. The brown slurry was stirred
vigorously at −78 °C until the color changed from brown to black
over a period of 2 h. The reaction was then slowly warmed to rt,
filtered and concentrated in vacuo to give a crude oil. FCC of the re-
sidual oil gave the dihydroderivative as a pale yellow oil (1.18 g, 99%):
Rf = 0.7 (10% EtOAc: petroleum ether). 1H NMR (500 MHz, CDCl3) δ
1.77 (m, 1H), 1.96 (m, 1H), 2.40 (m, 1H), 3.55 (m, 1H), 3.63 (s, 3H),
3.94 (t, 1H, J = 6.7 Hz), 4.43 (app d, 1H, J = 12.0 Hz), 4.55 (app d, 1H,
J = 11.4 Hz), 4.67 (app d, 1H, J = 12.0 Hz), 4.78 (app d, 1H, J = 12.0 Hz),
5.36 (m, 2H), 5.85 (m, 1H), 7.29–7.36 (m, 10H); 13C NMR (125 MHz,
CDCl3) δ 26.2, 30.2, 51.5, 70.6, 73.3, 80.0, 82.6, 119.1, 127.5, 127.6,
127.7, 128.0, 128.3, 128.3, 128.4, 135.0, 138.5, 138.6, 174.1; ESILRMS
(M + Na)+ calculated for C22H26O4Na 377.2, found 377.2.
The material from the previous step (1.10 g, 3.11 mmol) was trans-
formed to 19 (1.05 g, 99%) following the hydrolysis procedure that
1
3.2. (4S,5R)-4,5-O-Isopropylidene-hept-6-enoic acid (15)
was used for 15. For 19: Rf = 0.6 (30% EtOAc: petroleum ether). H
NMR (500 MHz, CDCl3) δ 1.67 (m, 1H), 1.86 (m, 1H), 2.33 (m, 2H),
3.48 (m, 1H), 3.85 (t, 1H, J = 6.7 Hz), 4.45 (ABq, 2H, Δδ = 0.36 ppm,
J = 12.0 Hz), 4.58 (ABq, 2H, Δδ = 0.23 ppm, J = 11.5 Hz), 5.27 (m, 2H),
5.74 (m, 1H), 7.20–7.26 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 23.6,
27.8, 68.3, 71.1, 77.6, 80.2, 117.0, 125.3, 125.4, 125.5, 125.8, 126.1,
132.5, 136.0, 136.1, 175.9; ESILRMS (M-H)− calculated for C21H23O4
339.17, found 339.15.
Methyl ester 14 (1.21 g, 5.65 mmol) was dissolved in 5:1 THF:H2O
(12 mL) and 3N NaOH (6 mL) was added. The mixture was stirred
vigorously for 16 h, then brought to pH 5 by the addition of 1N HCl
(15 mL), and extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated in vacuo. FCC
of the residual oil afforded 15 (1.12 g, 98%): Rf = 0.4 (20% EtOAc: pe-
troleum ether); 1H NMR (600 MHz, CDCl3) δ 1.38 (s, 3H), 1.49 (s, 3H),
1.76 (m, 2H), 2.46 (m, 1H), 2.55 (m, 1H), 4.19 (m, 1H), 4.57 (t, 1H,
J = 6.9 Hz), 5.29 (d, 1H, J = 10.4 Hz), 5.37 (d, 1H, J = 17.2 Hz), 5.85 (m,
1H), 11.51 (bs, 1H); 13C NMR (150 MHz, CDCl3) δ 25.6, 25.8, 28.1, 30.6,
79.5, 108.6, 118.9, 133.6, 179.5; ESIHRMS (M + H)− calculated for
C10H15O4 199.0970, found 199.0977.
3.6. 3β-Cholestanyl (4S, 5R)-4,5-O-isopropylidene-hep-6-enoate
(21)
Cholestanol 21 (972 mg, 2.50 mmol) was added to a mixture of
15 (500 mg, 2.50 mmol), DCC (516 mg, 2.50 mmol) and DMAP

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C.E. Mattis, D.R. Mootoo / Carbohydrate Research 429 (2016) 143–147
(31 mg, 0.25 mmol) in DCM (10 mL). The reaction mixture was stirred
for 1 h then diluted with ether and filtered. The filtrate was suc-
cessively washed with 0.1 N aqueous HCl and brine, dried (Na2SO4),
filtered, and evaporated in vacuo. FCC of the residue gave ester 21
(1.40 g, 98%): Rf = 0.7 (10% EtOAc: petroleum ether); 1H NMR
(600 MHz, C6D6) δ 0.47 (t, 1H, J = 11.8 Hz), 0.65 (s, 3H, H-18), 0.68
(s, 3H, H-19), 0.78–0.95 (m, buried 5H), 0.93 (bd, 6H, J = 6.5 Hz, H-26,
27), 1.02 (d, 3H, J = 6.4 Hz), 1.15–1.63 (m, 22H), 1.28 (s, buried, 3H),
1.47 (s, buried, 3H), 1.68 (m, 1H), 1.74 (m, 1H), 1.86 (m, 2H), 1.98
(bd, 1H, J = 12.8 Hz), 2.45 (m, 1H), 2.55 (m, 1H), 4.01 (m, 1H), 4.33
(t, 1H, J = 6.7 Hz), 4.93 (m, 1H), 5.00 (d, 1H, J = 10.4 Hz), 5.18 (d, 1H,
J = 17.0 Hz), 5.70 (m, 1H); 13C NMR (150 MHz, C6D6) δ 12.1 (two
peaks), 18.8, 21.3, 22.6, 22.8, 24.1, 24.3, 25.5, 26.6, 27.8, 28.2, 28.5,
28.7, 31.4, 32.0, 34.2, 34.3, 35.4, 35.5, 36.0, 36.5, 36.7, 39.7, 40.2, 42.7,
44.5, 54.1, 56.4, 56.5, 73.4, 77.3, 79.4, 108.2, 117.3, 134.7, 172.2;
ESIHRMS (M + H)+ calculated for C37H63O4 571.4726, found
571.4717.
3.9. β-Carba-arabinoside (24-OAc)
BH3.Me2S (0.20 mL of a 90% solution in dimethyl sulfide) was
added at 0 °C, under a nitrogen atmosphere to a solution of 23
(120 mg, 0.222 mmol) in THF (7 mL) and cooled to 0 °C. The mixture
was warmed to rt, stirred for an additional 1 h at this tempera-
ture, then recooled to 0 °C and treated with a mixture of 3N NaOH
(0.5 mL) and 30% aqueous H2O2 (0.5 mL) for 30 min. The mixture
was then extracted with ether and the organic phase was washed
with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered
and evaporated under reduced pressure. FCC of the residue pro-
vided 24 as a colorless oil (100 mg, 85%): Rf = 0.6 (20% EtOAc:
petroleum ether); 1H NMR (500 MHz, C6D6) δ 0.70 (bt, 1H, J = 11.0 Hz),
0.81 (s, 3H), 0.85 (s, 3H), 0.90–1.84 (m, 30H), 1.05 (d, buried, 6H,
J = 6.4 Hz), 1.15 (d, buried, 3H, J = 6.2 Hz), 1.46 (s, buried, 3H), 1.63
(s, buried, 3H), 1.89 (m, 1H), 2.02 (m, 2H), 2.09 (m, 1H), 2.16 (m,
1H), 2.81 (s, 1H), 3.12 (dt, 1H, J = 4.0, 9.8 Hz), 3.38 (m, 1H), 3.93 (dd,
1H, J = 7.5, 9.8 Hz), 4.08 (m, 1H), 4.12 (dd, 1 H, J = 5.0, 7.5 Hz); 13C
NMR (125 MHz, C6D6) δ 12.2, 12.3, 18.8, 21.4, 22.6, 22.8, 24.0, 24.2,
24.4, 24.7, 26.5, 28.2, 28.4, 28.5, 29.0, 30.0, 32.3, 35.3, 35.6, 35.7, 36.0,
36.5, 37.3, 39.7, 40.3, 42.7, 44.9, 54.6, 56.5, 56.6, 73.7, 77.0 (two peaks),
77.8, 80.8, 108.6.
3.7. (3R)-(((5S,6R)-5,6-O-Isopropylidene-octa-1,7-dien-
2-yl)oxy)-cholestane (22)
Tebbe reagent (5.71 mL, 0.5M in THF) was added under an argon
atmosphere, at −78 °C, to a mixture of 21 (200 g, 0.35 mmol), pyri-
dine (0.10 mL) and 3:1 anhydrous toluene:THF (6 mL). The reaction
mixture was warmed to rt, maintained at this temperature for 1 h,
then poured into 1N aqueous NaOH at 0 °C. The resulting suspen-
sion extracted with ether and the combined organic phase washed
with brine, dried (Na2SO4), filtered and concentrated in vacuo. FCC
of the crude material over basic alumina afforded 22 (140 mg, 70%
based on recovered starting material) as light yellow oil: Rf = 0.7
(basic alumina, 10% EtOAc: petroleum ether: 2% TEA); 1H NMR
(500 MHz, C6D6) δ 0.64 (dt, 1H, J = 3.8. 11.0 Hz), 0.78 (s, 3H), 0.82
(s, 3H), 0.85–1.10 (m, 5H), 1.06 (d, 6H, J = 6.6 Hz), 1.15 (d, 3H,
J = 6.6 Hz), 1.20–1.80 (m, 19H), 1.42 (s, buried, 3H), 1.62 (s, buried,
3H), 1.74 (m, 2H), 1.90 (m, 2H), 2.01 (m, 2H), 2.13 (m, 2H), 2.43 (m,
1H), 2.64 m, 1H), 4.08 (m, 1H), 4.17 (s, 1H), 4.23 (m,1H), 4.25 (s, 1H),
4.51 (t, 1H, J = 6.4 Hz), 5.15 (d, 1H, J = 10.4 Hz), 5.32 (bd, 1H,
J = 16.6 Hz), 5.92 (m, 1H); 13C NMR (125 MHz, C6D6) δ 12.7 (two
peaks), 19.4, 21.9, 23.1, 23.4, 24.7, 24.9, 26.2, 28.3, 28.8, 28.9, 29.0,
29.3, 29.6, 32.8, 33.4, 34.8, 36.0, 36.2, 36.6, 37.0, 37.4, 40.3, 40.8, 43.3,
45.2, 54.9, 57.1 (two peaks), 75.8, 78.3, 80.3, 81.9, 108.6, 117.6, 135.9,
161.8; ESIHRMS (M + H)+ calculated for C38H65O3 569.4934, found
569.4951.
A portion of the material from the previous step (40 mg,
0.07 mmol) was dissolved in ethyl acetate (2.0 mL) and treated with
acetic anhydride (0.02 mL, 0.2 mmol) and DMAP (8 mg, 0.07 mmol)
for 10 min. CH3OH (0.1 mL) was then added to the reaction mixture,
and the solvent evaporated in vacuo. FCC of the residue afforded 24-
OAc as a colorless oil (42 mg, 99%): Rf = 0.7 (15% EtOAc: petroleum
ether); [α]D20-13 (c 0.1, CHCl3); 1H NMR (500 MHz, C6D6) δ 0.72 (bt,
1H, J = 11.0 Hz), 0.80 (s, 3H, CH3-18/19), 0.84 (s, 3H, CH3-18/19), 1.05
(d, buried, 6H, J = 6.5 Hz, CH3-26,27), 1.13 (d, buried, 3H, J = 6.5 Hz,
CH3-21), 0.94–1.83 (m, 30H), 1.42 (s, buried 3H), 1.80 (s, buried, 3H),
1.85–2.08 (m, 3H), 2.02 (s, buried, 3H), 2.14 (m, 1H), 3.22 (dt, 1H,
J = 4.0, 10.2 Hz, H1′), 3.37 (m, 1H, H3), 4.04 (m, 2H, H3′, 4′), 5.64 (dd,
1H, J = 7.5, 10.2 Hz, H2′); 13C NMR (125 MHz, C6D6) δ 12.4 (two peaks),
19.0, 21.0, 21.6, 22.8, 23.1, 23.7, 24.4, 24.6, 26.5, 26.8, 28.2, 28.4, 28.7,
29.3, 30.0, 32.6, 35.7, 35.9 (two peaks), 36.2, 36.7, 37.5, 39.9, 40.5,
42.9, 45.3, 54.8, 56.7, 56.8, 74.1, 75.9, 77.0, 78.3, 79.2, 109.4, 169.3.
ESIHRMS (M + Na)+ calculated for C38H64O5Na 623.4651, found
623.4642.
3.10. Cholestanyl (4R,5R)-4,5-bis(benzyloxy)hept-6-enoate (25)
The reaction of acid 19 (1.0 g, 2.94 mmol) and 20 (1.14 g,
2.94 mmol) following the esterification procedure described for the
synthesis of 21 provided 25 (1.80 g, 90%) as a colorless oil: Rf = 0.8
(20% EtOAc: petroleum ether); 1H NMR (500 MHz, CDCl3) δ 0.36 (bt,
1H, J = 10.6 Hz), 0.53 (s, 3H), 0.56 (s, 3H), 0.62-0.1.60 (m, 27H), 0.81
(d, buried, 6H, J = 6.2 Hz), 0.90 (d, 3H, J = 6.0 Hz), 1.73–1.88 (m, 4H),
2.04 (m, 1H), 2.40 (m, 2H), 3.50 (m, 1H), 3.78 (t, 1H, J = 6.9 Hz), 4.30
(ABq, 2H, δΔ = 0.26 ppm, J = 12.0 Hz), 4.50 (ABq, 2H, δΔ = 0.23 ppm,
J = 11.5 Hz), 4.79 (m, 1H), 5.00 (d, 1H, J = 10.5 Hz), 5.08 (d, 1H,
J = 17.0 Hz), 5.65 (m, 1H), 6.97–7.10 (m, 6H), 7.22 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 12.3 (two peaks), 19.0, 21.5, 22.8, 23.0, 24.4, 24.5,
26.8, 28.0, 28.4, 28.7, 28.9, 31.2, 32.3, 34.6, 35.6, 35.7, 36.2, 36.7, 37.0,
39.9, 40.4, 42.9, 44.7, 54.4, 56.7 (two peaks), 70.8, 73.4, 73.5, 80.4,
82.9, 118.5, 127.6 (two peaks), 127.9, 128.1, 128.3, 128.5, 128.6, 135.5,
139.3, 139.6, 172.8; ESIHRMS (M + Na)+ calculated for C48H70O4Na
733.5160, found 733.5172.
3.8. (3R)-(((1S,2R)-1,2-O-Isopropylidene-cyclohex-3-ene-
4-yl)oxy)-cholestane (23)
Nitrogen was bubbled through a solution of enol ether 22
(200 mg, 0.351 mmol) in anhydrous benzene (12 mL) for 30 min.
Grubbs (ll) catalyst (104 mg, 0.122 mmol) was then introduced the
reaction mixture heated under nitrogen at 60 °C for 1 h. Addition-
al catalyst (52 mg, 0.061 mmol) was then added and heating
continued for 1 h, at which time the solvent was removed under
reduced pressure. FCC of the residue provided 23 (150 mg, 78%) as
a light brown oil: Rf = 0.6 (on alumina, 10% EtOAc: petroleum ether:
2% TEA); 1H NMR (500 MHz, C6D6) δ 0.66 (dt, 1H, J = 3.6, 11.5 Hz),
0.77 (s, 3H), 0.80 (s, 3H), 0.85–1.78 (m, 1H), 0.94–1.0 (m, 27H), 1.06
(d, buried, J = 6.8 Hz, 6H), 1.15, (d, 3H, buried J = 6.6 Hz), 1.55 (s,
buried, 3H), 1.71 (s, buried, 3H), 1.91 (m, 1H), 1.97–2.15 (m, 5H),
2.54 (m, 1H), 4.08 (m, 1H), 4.20 (m, 1H), 4.81 (t, 1H, J = 5.1 Hz), 4.95
(d, 1H, J = 3.9 Hz); 13C NMR (125 MHz, C6D6) δ 12.7, 19.4, 21.9, 23.1,
23.4, 24.7, 24.9, 25.3, 26.6, 27.2, 28.5, 28.8, 29.0, 29.1, 29.3, 32.8, 34.8,
36.0, 36.2, 36.6, 37.0, 37.4, 40.3, 40.8, 43.3, 45.1, 54.9, 57.1 (two peaks),
73.4, 74.2, 75.3, 94.1, 108.7, 157.3.
3.11. (3R)-(((5R,6R)-5,6-bis(benzyloxy)octa-1,7-dien-2-yl)oxy)-
3-cholestane (26)
A solution of titanium tetrachloride (0.09 mL, 2 M in CH2Cl2,
0.176 mmol) was added to THF (3 mL) at 0 °C. The mixture was
stirred for 30 min at which point TMEDA (0.05 mL, 0.363 mmol) was

C.E. Mattis, D.R. Mootoo / Carbohydrate Research 429 (2016) 143–147
147
added in one portion. The resulting yellow-brown suspension was
allowed to warm to rt and stirred for 30 min. At this point, zinc dust
(0.02 g, 0.03 mmol) and lead (ll) chloride (0.3 mg, 1.0 μmol) were
added in one portion, and stirring was continued at rt for 10 min.
A solution of 25 (110 mg, 0.155 mmol) and dibromomethane
(0.05 mL) in THF (1 mL) was then added via cannula to the reac-
tion flask. The mixture was stirred at 60 °C for 1 h, cooled to 0 °C,
then quenched by addition of saturated aqueous K2CO3 (2 mL). The
resulting mixture was warmed to rt and stirred at this tempera-
ture for 30 min, then diluted with ether (2 mL), stirred vigorously
for an additional 15 min, and filtered through basic alumina using
3% triethylamine-ether as the eluent. The greenish-blue residue was
triturated with diethyl ether (3–5 mL) and the combined ethereal
extract was concentrated in vacuo. FCC over basic alumina af-
forded 26 as a yellow oil (72 mg, 66%): Rf = 0.7 (10% EtOAc: petroleum
ether: 1% TEA); 1H NMR (500 MHz, C6D6) δ 0.65 (bt, 1H, J = 10.8 Hz),
0.78 (s, 3H), 0.82 (s, 3H), 0.84–1.76 (m, 27H), 1.05 (d, buried, 6H,
J = 6.5 Hz), 1.15 (d, 3H, J = 6.5 Hz), 1.98–2.05 (m 2H), 2.14 (m, 2H),
2.28 (m, 1H), 2.53 (m, 1H), 2.65 (m, 1H), 3.79 (m, 1H), 4.08 (m, 2H),
4.17 (s, 1H), 4.22 (s, 1H), 4.44 (app d, 1H, J = 12.1 Hz), 4.70 (m, 2H),
4.91 (app d, 1H, J = 11.6 Hz), 5.28 (d, 1H, J = 10.5 Hz), 5.36 (d, 1H,
J = 17.4 Hz), 5.97 (m, 1H), 7.16–7.36 (m, 6H, J = 7.1 Hz), 7.48 (m, 4H);
13C NMR (125 MHz, C6D6) δ 12.3, 12.4, 19.0, 21.6, 22.8, 23.0, 24.4,
24.6, 27.9, 28.4, 28.7, 29.0, 29.3, 32.4, 34.5, 35.7, 35.9, 36.2, 36.7, 37.1,
39.9, 40.5, 42.9, 45.0, 54.6, 56.7, 56.8, 70.8, 73.3, 75.4, 80.8, 81.5, 82.9,
118.2, 127.5, 127.6 (two peaks), 127.7, 127.9, 128.1, 128.3, 128.4, 128.5,
128.6, 135.9, 139.4, 139.9, 161.8; ESILRMS (M + Na)+ calculated
C49H72O3Na 731.55, found 731.54.
3), 4.80 (app d, 1H, J = 11.0 Hz, PhCH), 4.85 (t, 1H, J = 9.5 Hz, H2′),
7.19–7.25 (m, 10H, ArH); 13C NMR (125 MHz, CDCl3) δ 12.1, 12.3, 18.7,
21.2, 22.6, 22.8, 23.8, 24.2, 26.4, 27.5, 28.0, 28.3, 28.9, 29.4, 32.1, 35.4,
35.5, 35.7, 35.8, 36.2, 37.1, 39.5, 40.1, 42.6, 45.0, 54.4, 56.3, 56.5, 72.6,
75.1, 76.7, 77.0, 79.0, 80.9, 83.5, 127.5, 127.6, 127.7, 127.8 (two peaks),
128.0, 128.3, 128.4 (two peaks), 138.7, 138.8, 170.0; ESIHRMS
(M + Na)+ calculated C49H72O5Na 763.5307, found 763.5277.
Acknowledgment
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 in-
frastructure at Hunter College, and a Center for Clinical and
Translational Science award (TR000457) from the NIH are also ac-
knowledged. We thank Dr. Matthew Devany and Ms. Rong Wang
for their help with NMR and mass spectrometry measurements,
respectively.
Supplementary material
Supplementary data to this article can be found online at
doi:10.1016/j.carres.2016.03.002.
References
1. La Ferla B, Airoldi C, Zona C, Orsato A, Cardona F, Merlo S, et al.. Nat Prod Rep
2011;28:630–48.
2. Bhattacharya C, Yu Z, Rishel MJ, Hecht SM. Biochemistry 2014;53:3264–6.
3. Wojtkielewicz A, Dlugosz M, Maj J, Morzycki JW, Nowakowski M, Renkiewicz
J, et al.. J Med Chem 2007;50:3667–73.
3.12. (3R)-(((1R,2R)-1,2-di-O-benzyl-cyclohex-3-ene-4-
yl)oxy)-cholestane (27)
4. Lorent JH, Quetin-Leclercq J, Mingeot-Leclercq M-P. Org Biomol Chem
2014;12:8803–22.
5. Shukla RK, Tiwari A. Crit Rev Ther Drug Carrier Syst 2011;28:255–92.
6. El Alaoui A, Saha N, Schmidt F, Monneret C, Florent JC. Bioorg Med Chem
2006;14:5012–9.
7. Goff RD, Thorson JS. Medchemcomm 2014;5:1036–47.
8. Cai H, Wang H-YL, Venkatadri R, Fu D-X, Forman M, Bajaj SO, et al.. ACS Med Chem
Lett 2014;5:395–9.
Treatment of 26 (65 mg, 0.092 mmol) following the RCM pro-
cedure described for the synthesis of 23 provided 27 (50 mg, 80%)
as a light brown oil: Rf = 0.8 (20% EtOAc: petroleum ether: 1% TEA);
1H NMR (500 MHz, C6D6) δ 0.45 (bt, 1H, J = 10.5 Hz), 0.58 (s, 3H),
0.63 (s, 3H), 0.64–1.60 (m, 25H), 0.84 (d, buried, 6H, J = 6.5 Hz), 0.95
(d, buried, 3H, J = 6.5 Hz), 1.66–1.83 (m, 4H), 1.93 (m, 3H), 2.10 (m,
1H), 2.34 (m, 1H), 3.68 (m, 1H), 3.93 (m, 1H), 4.27 (bt, 1H, J = 4.2 Hz),
4.40 (ABq, 2H, Δδ = 05 ppm, J = 12.0 Hz), 4.56 (ABq, 2H, Δδ = 03 ppm,
J = 12.0 Hz), 4.86 (d, 1H, J = 4.0 Hz), 7.03–7.14 (m, 6H), 7.26 (d, 2H,
J = 7.5 Hz), 7.32 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, C6D6) δ 12.3,
12.4, 19.0, 21.6, 22.8, 23.0, 24.3, 24.4, 24.6, 26.1, 28.1, 28.4, 28.7, 29.0,
32.4, 34.7, 35.7, 35.9, 36.2, 36.7, 37.1, 39.9, 40.5, 42.9, 44.9, 54.6, 56.7,
56.8, 71.1, 71.2, 75.1, 77.1, 77.5, 94.0, 126.9, 127.5, 127.6, 127.8, 127.9,
128.1, 128.3 128.5, 128.9, 139.7, 140.1, 156.5; ESILRMS (M + Na)+ cal-
culated C47H68O3Na 703.52, found 703.51.
9. Beale TM, Taylor MS. Org Lett 2013;15:1358–61.
10. Arjona O, Gómez AM, López JC, Plumet J. Chem Rev 2007;107:1919–2036.
11. Alonso M, Cañada FJ, Jiménez-Barbero J, Solís D, Gabius H-J, Cheng X, et al. Eur
J Org Chem 2004;1604–13.
12. Sakairi N, Kuzuhara H. Tetrahedron Lett 1982;23:5327–30.
13. Ogawa S, Hirai K, Odagiri T, Matsunaga N, Yamazaki T, Nakajima A. Eur J Org Chem
1998;1099–109.
14. Cheng X, Khan N, Kumaran G, Mootoo DR. Org Lett 2001;3:1323–6.
15. Podolak I, Galanty A, Sobolewska D. Phytochem Rev 2010;9:425–74.
16. Mana S, Gao W, Zhang Y, Huang L, Liu C. Fitoterapia 2010;81:703–14.
17. Dinda B, Debnath S, Mohanta BC, Harigaya Y. Chem Biodivers 2010;7:2327–580.
18. Zhou Y, Garcia-Prieto C, Carney DA, Xu R-H, Pelicano H, Kang Y, et al. J Natl Cancer
Inst 2005;97:1781–5.
19. Guazzelli L, Ulc R, Rydner L, Oscarson S. Org Biomol Chem 2015;13:6598–610.
20. Postema MHD, Piper JL, Betts RL. J Org Chem 2005;70:829–36.
21. Okada A, Ohshima T, Shibasaki M. Tetrahedron Lett 2001;42:8023–6.
22. Arisawa M, Theeraldanon C, Nishida A, Nakagawa M. Tetrahedron Lett
2001;42:8029–32.
23. Aggarwal VK, Daly AM. Chem Commun 2002;2490–1.
24. Smith AB III, Kim D-S. Org Lett 2005;7:3247–50.
25. Ceccon J, Danoun G, Greene AE, Poisson J-F. Org Biomol Chem 2009;7:2029–31.
26. Baird LJ, Timmer MSM, Teesdale-Spittle PH, Harvey JE. J Org Chem 2009;74:2271–
7.
27. Prasad KR, Penchalaiah K. Tetrahedron 2011;67:4268–76.
28. Hyldtoft L, Madsen R. J Am Chem Soc 2000;122:8444–52.
29. Gurjar MK, Nagaprasad R, Ramana CV. Tetrahedron Lett 2002;43:7577–9.
30. Pine SH, Pettit RJ, Geib GD, Cruz SG, Gallego CH, Tijerina T, et al.. J Org Chem
1985;50:1212–6.
3.13. β-Carba-xyloside (28-OAc)
Application of the hydroboration oxidation that was used for the
synthesis of 24, to 27 (50 mg, 0.073 mmol) and acetylation of the
crude reaction product (following the procedure used for 24-
OAc), afforded β-carba-xyloside 28-OAc as a colorless oil (43 mg,
80% over two steps): Rf = 0.8 (20% EtOAc: petroleum ether); 1H NMR
(500 MHz, CDCl3) δ 0.51 (m, 1H), 0.57 (s, 3H, CH3-18/19), 0.68 (s,
buried 3H, CH3-18/19), 0.80 (bd, buried, 6H, J = 6.8 Hz, CH3-26, 27),
0.65–1.75 (m, 31H), 0.82 (d, buried 3H, J = 6.8 Hz, CH3-21), 1.87 (m,
2H), 1.90 (s, 3H), 1.98 (m, 1H), 3.17 (m, 1H, H3), 3.23 (m, 1H, H1′),
3.33 (t, 1H, J = 9.0 Hz, H3′), 3.43 (m, 1H, H4′), 4.58 (m, 3H, PhCH x
31. Takai K, Kakiuchi T, Kataoka Y, Utimoto K. J Org Chem 1994;59:2668–70.