Allylic strain as a stereocontrol element in the hydrogenation of 3-hydroxymethyl-cyclohex-3-en-1,2,5-triol derivatives. Synthesis of the carbasugar pseudo-2-deoxy-α-D-glucopyranose

Article abstract of DOI:10.1016/j.tet.2018.04.078

By adaptation of a literature method developed in the glucose series and standard protecting group manipulations a 2-deoxy-D-glucose derivative is converted to a series of 1R,2R,5R-3-hydroxymethyl-cyclohexen-1,2,5-triol derivatives whose reduction to the

Full text of DOI:10.1016/j.tet.2018.04.078

Accepted Manuscript
Allylic Strain as a Stereocontrol Element in the Hydrogenation of 3-Hydroxymethyl-
cyclohex-3-en-1,2,5-triol Derivatives. Synthesis of the Carbasugar Pseudo-2-deoxy-α-
D-glucopyranose
Peng Wen, David Crich
PII:
S0040-4020(18)30483-6
10.1016/j.tet.2018.04.078
TET 29493
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 February 2018
Revised Date: 23 April 2018
Accepted Date: 24 April 2018
Please cite this article as: Wen P, Crich D, Allylic Strain as a Stereocontrol Element in the
Hydrogenation of 3-Hydroxymethyl-cyclohex-3-en-1,2,5-triol Derivatives. Synthesis of the Carbasugar
Pseudo-2-deoxy-α-D-glucopyranose, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.078.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1
Allylic Strain as a Stereocontrol Element in the Hydrogenation of 3-Hydroxymethyl-cyclohex-3-en-
1,2,5-triol Derivatives. Synthesis of the Carbasugar Pseudo-2-deoxy-α-D-glucopyranose.
Peng Wen and David Crich*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
dcrich@chem.wayne.edu
Abstract
By adaptation of a literature method developed in the glucose series and standard protecting group
manipulations a 2-deoxy-D-glucose derivative is converted to a series of 1R,2R,5R-3-hydroxymethyl-
cyclohexen-1,2,5-triol derivatives whose reduction to the corresponding diastereomeric D-gluco and L-
ido-2-deoxy carbasugars is studied. When the hydroxymethyl group is tied up in a cyclic isopropylidene
acetal with the adjacent 6-hydroxy group the cis-fused products with the ido-configuration are formed
preferentially whereas protection of the hydroxymethyl group as a methoxymethyl ether results in the
formation of the
of the minimization of allylic strain in the course of the reduction, enables the preparation of the
carbasugar pseudo-2-deoxy-α- -glucopyranose, and suggests that the conformation of the side chain is
D-gluco isomer on hydrogenation over Raney nickel. This result is rationalized in terms
D
an important control element in the chemistry of the pseudosugars as it is in the sugars themselves.
Introduction
In the course of an ongoing investigation into the synthesis of a series of carbacyclic sugar analogs1-2 and
their conjugates, we had occasion to prepare and study the catalytic hydrogenation of derivatives of
1R,2R,5R-3-hydroxymethyl-cyclohexen-1,2,5-triol. We report on the manner in which the facial
selectivity of the hydrogenation reaction, affording diastereomeric carbasugars with either the
or -ido configurations, varies as a function of the manner in which the hydroxymethyl group is
D-gluco
L

ACCEPTED MANUSCRIPT
2
protected. We demonstrate that selectivity for the gluco isomer is optimal in a monocyclic system with
the hydroxymethyl protected as a MOM ether, which we attribute to the minimization of allylic strain in
the transition state for hydrogenation. This reduction enables the completion of the first synthesis of
the carbasugar, pseudo-2-deoxy-α-D-glucose.
Results
Adapting a protocol described by Shing and coworkers for the synthesis of the gabosines and related
compounds from gluconolactone,3-5 benzyl 2-deoxy-α- -gluopyranoside 16 was treated with 2,2-
D
dimethoxypropane in DMF at room temperature in the presence of camphor-10-sulfonic acid, resulting
in the formation of the isopropylidene derivative 2 in 82% yield. Silylation with tert-butyldimethylsilyl
chloride and imidazole in DMF was followed by hydrogenolysis of the benzyl glycoside to give 86% of the
lactol 3 in the form of a mixture of anomers. Oxidation with catalytic tetrapropylammonium
perruthenate and N-methyl-morpholine N-oxide7 then afforded 88% of the lactone 4, which on
treatment with dimethyl methylphosphonate and LDA in THF at -78 oC provided the ketose 5 in 96%
yield in the form of a single unassigned anomer, presumably with the equatorial phosphonate group.
Reduction with sodium borohydride in THF have a diol 6 as an unassigned 1:2.4 mixture of anomers that
was immediately oxidized by the Swern protocol to give a dione 7 that, on stirring with potassium
carbonate and 18-crown-6 in toluene, was transformed to the enone 8 in 65% overall yield from 5. The
reduction of 5 to 6, followed by reoxidation was necessary as attempted direct conversion of 5 to the
enone 8 by the Swern protocol resulted only in the formation of elimination products. Luche reduction8
of 8 gave 74% of allylic alcohol 9, which was converted to the ester 10 in 77% yield by Mitsunobu
inversion,9 and finally to the epimeric alcohol 11 in 89% yield on exposure to sodium methoxide in
methanol (Scheme 1).

ACCEPTED MANUSCRIPT
3
Scheme 1. Synthesis of Enone 8 and Allylic Alcohol 11
Exposure of 10 to iodine in methanol at room temperature afforded the triol 12 in 26% yield along with
the desired monosilyl ether 13 in 69% yield. The same transformation could also be effected by stirring
a methanolic solution of 10 with Amberlyst 15 acidic resin when 12 and 13 were isolated in 25 and 64%
yield, respectively. Reaction of 13 with methoxymethyl chloride in the presence of Hünig’s base then
afforded 87% of the bis(methoxymethyl) ether 14, from which the ester was removed with sodium
methoxide to give the allylic alcohol 15 in 97% yield (Scheme 2).

ACCEPTED MANUSCRIPT
4
Scheme 2. Preparation of Allylic Alcohol 15
Exposure of enone 8 to 1 atmosphere of hydrogen in THF at room temperature resulted in the
formation of an approximately 1.1:1 mixture of the trans- and cis-fused ketones 16 and 17 as judged by
NMR spectroscopy of the crude reaction mixture, from which the individual compounds were isolated in
32 and 29% yield, respectively (Table 1, entry 1). Reduction of 8 by stirring with phenylsilane in the
presence catalytic hexakis(triphenylphosphino)copper hydride10-11 in toluene at room temperature for 3
days gave 30% of the cis-fused product 17 and 47% of the recovered substrate, with no indication of the
formation of the trans-fused isomer 16 from the NMR spectra of the crude reaction mixture (Table 2,
entry 2). Hydrogenation of the allylic alcohol 11 was attempted under multiple conditions, mostly
resulting in relatively complex reaction mixtures contained products derived from saturation of the
alkene, deoxygenation, loss of the acetonide, and combinations of these transformations as judged by
mass spectrometry. The only relatively clean reaction mixture arose from stirring of 11 in aqueous
ethanol under one atmosphere of hydrogen pressure in the presence of Raney nickel, resulting in the
isolation of the trans- and cis-fused saturated alcohols 18 and 19 in 41 and 29% yield, respectively (Table
1, entry 3). Attempted hydrogenation of 11 over Crabtree’s catalyst12 in dichloromethane resulted not
in reduction but migration of the alkene into the heterocyclic ring giving 20 in 66% isolated yield (Table

ACCEPTED MANUSCRIPT
5
1, entry 4). No conversion was observed on attempted hydrogenation of 11 in the presence of
Wilkinson’s catalyst13 at atmospheric pressure, just as no reaction was found on stirring 11 with
potassium azodicarboxyate and acetic acid in methanol at room temperature. Hydrogenation of the
allylic ester 13 over palladium on charcoal in ethanol at room temperature was accompanied by
hydrogenolysis of the primary allylic alcohol resulting in the formation of 21 in 56% yield along with 9%
of a second, uncharacterized isomer (Table 1, entry 5). Finally, reduction of the MOM-protected allylic
alcohol 15 over Raney nickel in aqueous ethanol gave the desired selectivity, resulting in the isolation of
22 in 92% yield with no indication of the formation of a minor isomer in the NMR spectra of the crude
reaction mixture (Table 1, entry 6).
Table 1. Reductions of Ketone 8 and Allylic Alcohols 11 and 15
Entry Substrate
Conditionsa
Products, yield
1
H2 (1 atm), Pd/C, THF
2
3
PhSiH3, [(Ph3P)CuH]6
H2, Raney Ni,
EtOH, H2O

ACCEPTED MANUSCRIPT
6
4
5
6
Ir[(cod)(Cy3P)(py)]PF6,
H2, CH2Cl2
H2, Pd/C, EtOH
H2, Raney Ni,
EtOH, H2O
a) All catalytic hydrogenations were conducted under 1 atm of hydrogen at room temperature.
Finally, gentle warming of 22 with HCl in methanol gave pseudo-α-D-glucopyranose 23 uneventfully in
99% yield (Scheme 3).
Scheme 3. Deprotection of 22 to Give Pseudo-2-deoxy-α-D-glucopyranose 23
Discussion
The unselective formation of the cis,trans-mixture of 16 and 17 from 8 (Table 1, entry 1) is consistent
with the selectivity observed on hydrogenation of Δ1,9-2-octalone 24, a carbocyclic model for the bicyclic
enone 8, over palladium and platinum catalysts.14-16 As hydrogenation of the model 24 could be
optimized for formation of the cis-fused product cis-2-decalinone 25 under acidic conditions but not for

ACCEPTED MANUSCRIPT
7
the trans-fused isomer 26 under any conditions reported,14-16 the trans-selective hydrogenation of 8 to
16 was not pursued further. As cuprates and other nucleophiles are known to add to the carbocyclic
model 24 in a highly cis-selective manner,17-19 with trans-selectivity only obtained under thermodynamic
conditions,20 the preferential formation of 17 from 8 with Stryker’s reagent (Table 1, entry 2) is
unsurprising. Following the report of Shing and coworkers on the highly selective conversion of 27 to
28,4 hydrogenation of 11 over Raney Nickel in ethanol was attempted. While the desired trans-fused
product 18 did predominate over its cis-fused isomer 19 under these conditions (Table 1, entry 3) the
degree of selectivity was inadequate for our purposes. Switching to homogeneous catalysis, attempts to
direct hydrogenation to formation of the trans-fused product with Crabtree’s catalyst21-24 resulted only
in the migration of the allylic alkene into conjugation with the ethereal oxygen (Table 1, entry 4), a well-
known process with this catalyst.25
Thwarted in our attempts to achieve the desired selectivity with the bicyclic substrates, and encouraged
by Shing’s clean and high yielding reductions of 27 and related compounds into both stereoisomers as a
function of catalyst and conditions,4,26 we turned to monocyclic substrates. Stirring of the allylic diol 13
in ethanol over palladium on carbon and under one atmosphere of hydrogen resulted in a rare example
of hydrogenolysis of an allylic C-O bond,27-28 coupled with reduction of the alkene. The product 21 was

ACCEPTED MANUSCRIPT
8
obtained as a single diastereomer in 56% isolated yield (Table 1, entry 5), albeit a minor diastereomer
was observed in the reaction mixture, and can be considered as a protected version of pseudo-2,6-
dideoxy-α-D
-glucopyranose. Finally, taking note of Shing’s successful selective reduction of 27 to 28,4
the allylic alcohol 15 was stirred in ethanol over Raney nickel under one atmosphere of hydrogen when
the desired product 22 was obtained as a single diastereomer in 92% isolated yield (Table 1, entry 6).
The highly stereoselective reduction of 15 to 22 is consistent with Shing’s reduction of 27 to 28 and is to
be contrasted with the far less selective reduction of the bicyclic analog 11 (Table 1, entry 3) when a
mixture of trans- and cis products 18 and 19 were obtained in an approximately 2:1 ratio. The
contrasting selectivity between 15 and 27 on the one hand and 11 on the other hand argues against a
hydroxyl directed mechanism as the sole stereochemical driving force. Rather, we suggest that the
change in selectivity arises from a change in conformation on replacement of the cyclic acetal by two
methoxymethyl ethers coupled with the freely rotating side chain in 15 (and 27) adopting a
perpendicular conformation to alkene. Thus, the unsaturated ring of octalin 11 adopts an approximate
half-chair conformation A in which the hydroxyl group takes up a pseudoaxial position and the siloxy
group a pseudoequatorial one (Figure 1). This conformation is largely conserved in the diol 13 after
cleavage of the isopropylidene group, but on installation of the methoxymethylethers is replaced by a
predominantly inverted half chair B in both the benzoate 14 and the alcohol 15 (Figure 1). Presumably,
conformation B is favored in 14 and 15 due to the minimization of 1,2A strain between the allylic MOM
ether on the ring and the methoxymethoxymethyl substituent and of 1,3A strain between the latter and
the olefinic hydrogen. Conformation B also minimizes dipolar repulsions between the two MOM ethers
and places the MOM and TBS ethers in pseudoaxial positions as is commonly found in cyclohexyl and
pyranosyl systems containing multiple trans-vicinal siloxy and other bulky groups.29-38

ACCEPTED MANUSCRIPT
9
Figure 1. Predominant Conformations of 11, 13, 14, and 15, with Diagnostic 3J H,H-Coupling Constants
in Hz
On this basis the facial selecivity in the reduction of 15 is readily understood in terms steric shielding of
the top face by the combination of pseudoaxial siloxy group and the methoxymethoxymethyl group in
the major conformation B. In the minor conformation A the methoxymethoxymethyl group also adopts
a perpendicular conformation so as to minimize allylic strain and in doing so shields the same face of the
alkene (Scheme 4), consistent with other well-known models for the control of stereoselectivity in
concerted additions to allylic alcohols and ethers.39-40

ACCEPTED MANUSCRIPT
10
OTBS
MOMO
MOMO
OMOM
OMOM
OH
OMOM
OTBS
HO
H
H
OMOM
HO
TBSO
22, 92%
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Raney nickel
Scheme 4. Allylic Strain Minimization-Based Model for the Selective Reduction of 15
Conclusion
We have adapted the Shing synthesis of carbasugars to the 2-deoxyglucose series and have completed a
synthesis of the previously unknown pseudo-2-deoxy-α- -glucopyranose 23 and of a protected version
D
of its 2,6-dideoxyanalog 21. In the course of this synthesis we studied the hydrogenation of several
derivatives of 1,2,5-trihydroxy-3-hydroxymethylcyclohexene and found the selectivity to depend
critically on the protection of the hydroxymethyl group. When it is tied up an isopropylidene acetal with
the 6-hydroxy group reductions are either selective for the formation of the cis-fused bicyclic derivative
with the pseudo-idose configuration or are little selective, whereas protection in the form of a MOM
ether results in the clean formation of the desired gluco-isomer. We rationalize this selectivity as arising
from minimization of allylic strain in the transition state for reduction and suggest that the conformation
of the side chain is an important control element in the chemistry of the pseudopyranoses just as it is in
that of the pyranoses themselves.41-44
Experimental Section
General information: Except for hydrogenation reactions, all reactions were performed using oven-
dried glassware under an argon atmosphere. Reagents and solvents were purchased from commercial
suppliers and were used without further purification unless otherwise specified. Reaction progress was

ACCEPTED MANUSCRIPT
11
monitored by analytical thin-layer chromatography (TLC) on pre-coated glass backed plates and
visualized by UV irradiation (254 nm) or by staining with basic potassium permanganate or ceric
ammonium molybdate (CAM) solutions. Chromatographic purifications were performed on silica gel
(230-400 mesh) columns. Specific rotations were measured on an automatic polarimeter with a path
length of 100 mm in the solvent specified; concentrations are given in g/100 mL. NMR solvents were
used without purification. Chemical shifts are given in ppm (δ) and coupling constants (J) are given in Hz.
Multiplicities are given as singlet (s), broad singlet (br s), doublet (d), triplet (t), doublet of doublets (dd),
triplet of doublets (td), multiplet (m), apparent quartet (app q), apparent pentet (app p), etc. High
resolution mass spectra (HRMS) were recorded on a mass spectrometer with an electrospray ionization
(ESI) source coupled to a time-of-flight (TOF) mass analyzer.
Benzyl 2-deoxy-4,6-O-isopropylidene-α-D-glucopyranoside (2). A mixture of 2-deoxy-D-glucose (800
mg, 4.87 mmol), benzyl alcohol (8 mL) and acetyl chloride (0.35 mL, 4.87 mmol) was heated to 50 oC for
10 min. The reaction was quenched by adding triethylamine and the excess benzyl alcohol was removed
by concentration under reduced pressure. Chromatographic purification (9%
methanol/dichloromethane) afforded benzyl 2-deoxy-α-D-glucopyranoside 1 as a white solid (1.16 g,
94%), with spectral data consistent with the literature.6 To a stirred solution of this glycoside (1.16 g,
4.56 mmol) and (1S)-(+)-10-camphorsulfonic acid (211.9 mg, 0.9 mmol) in DMF (12 mL) at room
temperature was added 2,2-dimethoxypropane (5.6 mL, 45.6 mmol). The reaction mixture was stirred
for 5 h before it was diluted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated
under reduced pressure. Chromatographic purification (30% ethyl acetate/hexanes) afforded the title
compound as a colorless oil (1.10 g, 82%): [α]D21 80.9 (c 1.08, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.39 –
7.27 (m, 5H), 4.97 (dd, J = 3.9, 1.1 Hz, 1H), 4.67 (d, J = 11.9 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H), 4.08 (ddd, J
= 11.2, 9.0, 5.2 Hz, 1H), 3.83 (dd, J = 10.0, 5.2 Hz, 1H), 3.76 (t, J = 10.0 Hz, 1H), 3.69 (ddd, J = 10.0, 9.0, 5.2
Hz, 1H), 3.52 (t, J = 9.0 Hz, 1H), 2.23 (ddd, J = 13.3, 5.2, 1.1 Hz, 1H), 1.76 (ddd, J = 13.3, 11.2, 3.9 Hz, 1H),

ACCEPTED MANUSCRIPT
12
1.52 (s, 3H), 1.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 137.4, 128.4 (2 Cs), 127.84 (2 Cs), 127.78, 99.9,
97.2, 76.4, 69.0, 66.3, 63.7, 62.4, 37.4, 29.2, 19.2. HRMS (ESI-TOF) m/z: Calcd. for C16H22O5Na ([M +
Na]+): 317.1365; found: 317.1376.
3-tert-Butyldimethylsilyl-2-deoxy-4,6-O-isopropylidene-D-glucono-1,5-lactone (4). A solution of benzyl
2-deoxyglucoside 2 (1.10 g, 3.73 mmol), tert-butyldimethylsilyl chloride (1.69 g, 11.2 mmol) and
imidazole (761 mg, 11.2 mmol) in DMF (15 mL) was stirred at room temperature for 8 h before it was
diluted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced
pressure. The crude silylated product (1.57 g) was dissolved in ethyl acetate (11 mL), treated with Pd/C
(274 mg) and stirred at room temperature under a hydrogen atmosphere (1 atm) for 4 h. The solution
was filtered through Celite and the filtrate was concentrated under reduced pressure to dryness.
Chromatographic purification (20% ethyl acetate/hexanes) afforded the hemiacetal 3 as a mixture of
anomers (1.02 g, 86%, α:β = 1.8:1). A mixture of the this product (2.18 g, 6.84 mmol), 4-
methylmorpholine N-oxide (1.20 g, 10.3 mmol) and activated 3 Å molecular siveves (829 mg) in
dichloromethane (13 mL) was stirred at room temperature for 1 h before it was cooled to 0 oC. Tetra-n-
propylammonium perruthenate (120 mg, 5 mol %) was added and the reaction mixture was stirred for a
further 2 h at room temperature before it was concentrated under reduced pressure. Ethyl acetate was
added to the residue and the mixture was then filtered through Celite. The filtrate was washed
successively with 5% aqueous Na2SO3, saturated aqueous CuSO4, and brine, dried over Na2SO4 and
concentrated under reduced pressure. Chromatographic purification (10% ethyl acetate/hexanes)
afforded the title lactone as a white solid (1.90 g, 88%): [α]D21 7.7 (c 0.93, CHCl3). 1H NMR (400 MHz,
CDCl3) δ 4.04 (td, J = 7.8, 5.8 Hz, 1H), 4.02 (dd, J = 10.4, 5.1 Hz, 1H), 3.90 (td, J = 9.9, 5.1 Hz, 1H), 3.81 (t, J
= 10.4 Hz, 1H), 3.70 (dd, J = 9.9, 7.8 Hz, 1H), 3.07 (dd, J = 18.0, 7.8 Hz, 1H), 2.58 (dd, J = 18.0, 5.8 Hz, 1H),
1.50 (s, 3H), 1.42 (s, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.0, 99.9,

ACCEPTED MANUSCRIPT
13
74.1, 69.0, 68.0, 61.6, 39.3, 28.8, 25.6 (3 Cs), 18.8, 18.0, -4.5, -5.1. HRMS (ESI-TOF) m/z: Calcd. for
C15H28O5SiNa ([M + Na]+): 339.1604; found: 339.1620.
4-tert-Butyldimethylsilyl-1,3-dideoxy-1-dimethoxyphosphinyl-5,7-O-isopropylidene-
D-gluco-2-
heptulo-2,6-pyranose (5). To a stirred solution of diisopropylamine (1.68 mL, 12.01 mmol) in THF (5.8
mL) at -78 oC was added n-butyllithium solution (2.5 M in hexanes, 4.8 mL, 12.01 mmol) dropwise. After
stirring at the same temperature for 0.5 h, dimethyl methylphosphonate (1.30 mL, 12.0 mmol) was
added dropwise. The reaction mixture was stirred for 0.5 h at -78 oC before a solution of the above
lactone 4 (1.90 g, 6.00 mmol) in THF (10 mL) was added dropwise. After completion (2 h), saturated
aqueous NH4Cl was added and the reaction mixture was allowed to warm to room temperature, and
extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4
and concentrated under reduced pressure. Chromatographic purification (50% ethyl acetate/hexanes)
afforded the title compound as a white solid (2.54 g, 96%): [α]D21 9.1 (c 0.47, CHCl3). 1H NMR (499 MHz,
CDCl3) δ 4.04 (ddd, J = 10.8, 9.0, 5.2 Hz, 1H), 3.88 (ddd, J = 10.6, 9.0, 5.2 Hz, 1H), 3.81 (dd, J = 10.3, 5.2
Hz, 1H), 3.78 – 3.67 (m, 7H), 3.41 (t, J = 9.2 Hz, 1H), 2.24 – 2.08 (m, 3H), 1.54 (dd, J = 13.0, 10.8 Hz, 1H),
1.48 (s, 3H), 1.40 (s, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 99.4, 96.5 (d,
J = 8.4 Hz), 76.1, 67.4 (d, J = 5.4 Hz), 64.9, 62.5, 53.5 (d, J = 5.7 Hz), 51.7 (d, J = 6.7 Hz), 45.4 (d, J = 15.1
Hz), 36.8 (d, J = 135.2 Hz), 29.2, 25.8 (3 Cs), 19.1, 18.2, -4.4, -4.9. 31P NMR (162 MHz, CDCl3) δ 30.51.
HRMS (ESI-TOF) m/z: Calcd. for C18H37O8PSiNa ([M + Na]+): 463.1893; found: 463.1875.
(4R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxa-Δ1,9-octalin-2-one (8). To a stirred
solution of the above phosphonate 5 (2.54 g, 5.77 mmol) in THF (15 mL) at room temperature was
added sodium borohydride (654 mg, 17.3 mmol). The reaction mixture was stirred at room temperature
for 4 h before it was concentrated to dryness, diluted with ethyl acetate and washed with water, and
brine, dried over Na2SO4 and concentrated under reduced pressure to give a crude diol 6 (2.55 g) which

ACCEPTED MANUSCRIPT
14
was directly used for next step without purification. A solution of dimethyl sulfoxide (2.46 mL, 34.6
mmol) in dichloromethane (12 mL) at -78 oC was treated dropwise with a solution of trifluoroacetic
anhydride (3.20 mL, 23.1 mmol) in dichloromethane (12 mL) and stirred at -78 oC for 2 h, before a
solution of the above diol (2.55 g) in dichloromethane (24 mL) was added dropwise. After stirring for 2 h
at the same temperature triethylamine (6.43 mL, 46.1 mmol) was added dropwise and stirring
continued at -78 oC for another 1 h, before the reaction mixture was allowed to warm to room
temperature and diluted with dichloromethane. The mixture was washed with brine, dried over Na2SO4
and concentrated under reduced pressure to give a crude diketone 7 (2.79 g), which was taken up in
toluene (20 mL), treated with 18-crown-6 (76.2 mg, 0.29 mmol) and potassium carbonate (2.39 g, 17.30
mmol), and stirred at room temperature for 18 h before it was concentrated under reduced pressure.
Chromatographic purification (7% ethyl acetate/hexanes) of the residue afforded the title compound as
a light yellow oil (1.17 g, 65%): [α]D21 -128.6 (c 1.09, CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.76 (m, 1H),
4.48 – 4.39 (m, 3H), 4.05 (ddd, J = 12.2, 8.1, 5.1 Hz, 1H), 2.68 (ddd, J = 16.4, 5.1, 1.2 Hz, 1H), 2.47 (dd, J =
16.4, 12.2 Hz, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 196.6, 159.0, 122.1, 100.4, 72.8, 71.3, 61.5, 46.2, 25.7 (4 Cs), 22.2, 18.1, -4.5, -5.0. HRMS (ESI-
TOF) m/z: Calcd. for C16H28O4SiNa ([M + Na]+): 335.1655; found: 335.1663.
(2S,4R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxa-Δ1,9-octalin-2-ol (9). To a stirred
solution of enone 8 (1.21 g, 3.87 mmol) and cerium (III) chloride heptahydrate (1.73 g, 4.65 mmol) in
MeOH (20 mL) at -20 oC was added sodium borohydride (220 mg, 5.81 mmol). After stirring at -20 oC for
1 h, the reaction was quenched by addition of saturated aqueous NH4Cl. The reaction mixture was
allowed to warm to room temperature, a mixture of water and ethyl acetate was added and the
resulting mixture was filtered through Celite. The filtrate was extracted with ethyl acetate, and the
combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced
pressure. Chromatographic purification (25% ethyl acetate/hexanes) afforded the title compound as a

ACCEPTED MANUSCRIPT
15
colorless oil (901.1 mg, 74%): [α]D21 -63.5 (c 0.48, CHCl3). 1H NMR (600 MHz, CDCl3) δ 5.50 (br s, 1H), 4.43
(dd, J = 13.8, 1.7 Hz, 1H), 4.39 (br s, 1H), 4.25 (d, J = 7.0 Hz, 1H), 4.09 (d, J = 13.8 Hz, 1H), 3.75 (ddd, J =
12.0, 7.0, 3.6 Hz, 1H), 2.20 (dddd, J = 12.3, 5.3, 3.6, 1.4 Hz, 1H), 1.64 – 1.56 (m, 1H), 1.49 (s, 3H), 1.37 (s,
3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 133.1, 124.9, 99.2, 73.3, 70.8,
66.6, 63.0, 40.4, 28.3, 25.8 (3 Cs), 20.0, 18.2, -4.5, -5.0. HRMS (ESI-TOF) m/z: Calcd. for C16H30O4SiNa ([M
+ Na]+): 337.1811; found: 337.1816.
(2R,4R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxa-Δ1,9-octalin-2-yl Benzoate (10). To a
stirred solution of 9 (125.8 mg, 0.40 mmol), triphenyl phosphine (125.9 mg, 0.48 mmol) and benzoic acid
(58.6 mg, 0.48 mmol) in THF (2 mL) at 0 oC was added a solution of diisopropyl azodicarboxylate (97.1
mg, 0.48 mmol) in THF (0.7 mL) dropwise. The reaction mixture was stirred at room temperature for 10
h before it was concentrated to dryness under reduced pressure. Chromatographic purification (5%
ethyl acetate/hexanes) afforded the title compound as a colorless oil (128.6 mg, 77%): [α]D21 137.5 (c
1.14, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz,
2H), 5.69 – 5.62 (m, 1H), 5.53 (br s, 1H), 4.42 (dd, J = 14.3, 1.7 Hz, 1H), 4.23 (d, J = 7.6 Hz, 1H), 4.19 (d, J =
14.3 Hz, 1H), 4.12 (ddd, J = 11.8, 7.6, 3.9 Hz, 1H), 2.11 (ddt, J = 14.4, 3.9, 1.8 Hz, 1H), 1.95 (ddd, J = 14.4,
11.8, 4.4 Hz, 1H), 1.51 (s, 3H), 1.41 (s, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 166.0, 138.2, 133.0, 130.2, 129.6 (2 Cs), 128.4 (2 Cs), 117.8, 99.3, 73.2, 68.4, 68.3, 62.5, 36.0,
27.8, 25.8 (3 Cs), 20.3, 18.3, -4.5, -4.8. HRMS (ESI-TOF) m/z: Calcd. for C23H34O5SiNa ([M + Na]+):
441.2073; found: 441.2056.
(2R,4R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxa-Δ1,9-octalin-2-ol (11). To a stirred
solution of ester 10 (500 mg, 1.19 mmol) in MeOH (2 mL) at room temperature was added sodium
methoxide (96.8 mg, 1.79 mmol). After stirring at room temperature for 12 h, the reaction mixture was
neutralized with Amberlyst 15 hydrogen form and then filtered. The filtrate was concentrated under

ACCEPTED MANUSCRIPT
16
reduced pressure to give a residue, chromatographic purification (25% ethyl acetate/hexanes) of which
afforded the title compound as a colorless oil (335.8 mg, 89%): [α]D21 25.8 (c 0.55, CHCl3). 1H NMR (400
MHz, CDCl3) δ 5.56 – 5.52 (m, 1H), 4.39 (dd, J = 14.2, 1.7 Hz, 1H), 4.29 (br s, 1H), 4.18 – 4.11 (m, 2H), 3.99
(ddd, J = 11.9, 7.3, 4.0 Hz, 1H), 1.98 (ddt, J = 13.9, 4.0, 1.8 Hz, 1H), 1.77 (ddd, J = 13.9, 11.9, 4.4 Hz, 1H),
1.48 (s, 3H), 1.39 (s, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 135.7, 121.5,
99.2, 73.5, 67.8, 65.2, 62.6, 38.8, 28.0, 25.8 (3 Cs), 20.2, 18.2, -4.4, -4.8. HRMS (ESI-TOF) m/z: Calcd. for
C16H30O4SiNa ([M + Na]+): 337.1811; found: 337.1822.
(1R,2R,5R)-1,2-Dihydroxy-3-(hydroxymethyl)cyclohex-3-en-5-yl Benzoate (12) and (1R,2R,5R)-1-((tert-
Butyldimethylsilyl)oxy)-2-hydroxy-3-(hydroxymethyl)cyclohex-3-en-5-yl Benzoate (13). To a solution
of 10 (1.14 g, 2.72 mmol) in MeOH (2 mL) was added a solution of iodine in MeOH (1%, 20 mL). After
stirring at room temperature for 3 h, the reaction was quenched by addition of saturated aqueous
Na2S2O3 (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated under reduce pressure. Chromatographic purification (33%
ethyl acetate/hexanes) afforded the silyl ether 13 as a colorless oil (708.7 mg, 69%) and then the triol 12
as a colorless solid (185 mg, 26%).
Silyl ether 13: [α]D21 176.7 (c 0.09, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.57 (t, J =
7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.92 – 5.86 (m, 1H), 5.61 (m, 1H), 4.34 – 4.22 (m, 2H), 4.17 (d, J = 7.0
Hz, 1H), 4.09 (ddd, J = 10.3, 7.0, 3.6 Hz, 1H), 2.13 (dtd, J = 13.9, 3.6, 1.0 Hz, 1H), 1.98 (ddd, J = 13.9, 10.3,
4.8 Hz, 1H), 0.91 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.9, 142.3, 133.0, 130.2,
129.6 (2 Cs), 128.4 (2 Cs), 122.6, 74.1, 71.0, 68.1, 64.7, 34.6, 25.8 (3 Cs), 18.1, -4.5, -4.7. HRMS (ESI-TOF)
m/z: Calcd. for C20H30O5SiNa ([M + Na]+): 401.1760; found: 401.1778.
Triol 12: [α]D21 114.6 (c 0.24, MeOH). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6
Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 5.97 – 5.90 (m, 1H), 5.63 (m, 1H), 4.26 – 4.15 (m, 2H), 4.03 – 3.95 (m,

ACCEPTED MANUSCRIPT
17
2H), 2.19 – 2.11 (m, 1H), 2.08 – 1.98 (m, 1H). 13C NMR (101 MHz, CD3OD) δ 166.0, 144.2, 132.8, 130.2,
129.0 (2 Cs), 128.1 (2 Cs), 120.2, 71.2, 69.5, 68.2, 61.8, 33.1. HRMS (ESI-TOF) m/z: Calcd. for C14H16O5Na
([M + Na]+): 287.0895; found: 287.0896.
(1R,2R,5R)-1-((tert-Butyldimethylsilyl)oxy)-2-(methoxymethoxy)-3-
((methoxymethoxy)methyl)cyclohex-3-en-5-yl Benzoate (14). A stirred solution of diol 13 (441.8 mg,
1.17 mmol) in N,N-diisopropylethylamine (5 mL) at 0 oC was treated with chloromethyl methyl ether
(1.77 mL, 23.34 mmol), and stirred at room temperature for 24 h before it was diluted with ethyl
acetate, and washed with 1 N HCl, and brine, dried over Na2SO4 and concentrated under reduced
pressure. Chromatographic purification (10% ethyl acetate/hexanes) afforded the title compound as a
colorless oil (473.8 mg, 87%): [α]D21 67.6 (c 0.46, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz,
2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 6.03 (br s, 1H), 5.73 (m, 1H), 4.82 (d, J = 6.8 Hz, 1H),
4.73 (d, J = 6.8 Hz, 1H), 4.67 (d, J = 6.5 Hz, 1H), 4.61 (d, J = 6.5 Hz, 1H), 4.22 (ddd, J = 5.6, 4.1, 2.3 Hz, 1H),
4.20 – 4.08 (m, 2H), 3.87 (d, J = 4.1 Hz, 1H), 3.43 (s, 3H), 3.37 (s, 3H), 2.20 (dt, J = 12.8, 5.6 Hz, 1H), 2.02
(ddd, J = 12.8, 8.0, 2.3 Hz, 1H), 0.90 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.0,
136.5, 132.9, 130.4, 129.6 (2 Cs), 128.3 (2 Cs), 126.5, 97.8, 95.3, 75.6, 69.3, 68.1, 67.4, 56.0, 55.4, 32.3,
25.7 (3 Cs), 18.0, -4.9 (2 Cs). HRMS (ESI-TOF) m/z: Calcd. for C24H38O7SiNa ([M + Na]+): 489.2284; found:
489.2292.
(1R,2R,5R)-1-((tert-Butyldimethylsilyl)oxy)-2-(methoxymethoxy)-3-
((methoxymethoxy)methyl)cyclohex-3-en-5-ol (15). A stirred solution of benzoate 14 (269.2 mg, 0.58
mmol) in MeOH (3 mL) at room temperature was treated with sodium methoxide (46.7 mg, 0.87 mmol)
and stirred at room temperature for 12 h. The reaction mixture was neutralized with Amberlyst 15
hydrogen form, filtered, and concentrated under reduced pressure. Chromatographic purification (33%
ethyl acetate/hexanes) afforded the title compound as a colorless oil (202.5 mg, 97%): [α]D21 3.7 (c 0.62,

ACCEPTED MANUSCRIPT
18
CHCl3). 1H NMR (400 MHz, CDCl3) δ 5.97 – 5.94 (m, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H),
4.66 (d, J = 6.5 Hz, 1H), 4.59 (d, J = 6.5 Hz, 1H), 4.42 (m, 1H), 4.17 – 4.10 (m, 2H), 4.06 (d, J = 12.8 Hz, 1H),
3.78 (d, J = 3.6 Hz, 1H), 3.41 (s, 3H), 3.37 (s, 3H), 2.08 (dtt, J = 12.6, 5.5, 1.1 Hz, 1H), 1.74 (ddd, J = 12.6,
8.7, 2.2 Hz, 1H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 133.9, 131.5, 97.6,
95.0, 75.2, 69.1, 67.5, 64.4, 55.9, 55.3, 35.6, 25.7 (3 Cs), 17.9, -4.9 (2 Cs). HRMS (ESI-TOF) m/z: Calcd. for
C17H34O6SiNa ([M + Na]+): 385.2022; found: 385.2034.
(4R,9R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxadecalin-2-one (16) and (4R,9S,10R)-
4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxadecalin-2-one (17) by Catalytic Hydrogenation of
Enone 8. A solution of enone 8 (11.7 mg, 0.04 mmol) in THF (0.5 mL) was treated with Pd/C (4.0 mg),
and stirred at room temperature under a hydrogen atmosphere (1 atm) for 8 h, then filtered through
Celite. The filtrate was concentrated under reduced pressure to dryness to give a residue (11.6 mg) that
was judged by integration of its 1H NMR spectrum to be a 1.1:1 mixture of 16 and 17. Chromatographic
purification (8% ethyl acetate/hexanes) afforded 17 (3.4 mg, 29%) as a colorless oil. Further elution
(12% ethyl acetate/hexanes) gave 16 (3.8 mg, 32%) as a colorless oil.
trans-Fused ketone 16: [α]D21 -5.0 (c 0.10, CHCl3). 1H NMR (600 MHz, CDCl3) δ 3.80 (ddd, J = 10.8, 8.9, 5.7
Hz, 1H), 3.76 (dd, J = 11.4, 4.7 Hz, 1H), 3.71 (dd, J = 10.6, 8.9 Hz, 1H), 3.67 (t, J = 11.4 Hz, 1H), 2.67 (ddd, J
= 14.7, 5.7, 2.5 Hz, 1H), 2.45 (dd, J = 14.7, 10.8 Hz, 1H), 2.15 (ddd, J = 14.3, 4.0, 2.5 Hz, 1H), 2.03 (t, J =
14.3 Hz, 1H), 1.80 – 1.69 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 205.6, 99.2, 76.4, 72.0, 64.4, 49.5, 40.5, 33.9, 29.6, 25.7 (3 Cs), 19.0, 18.2, -4.4, -5.1.
HRMS (ESI-TOF) m/z: Calcd. for C16H34O4NSi ([M + NH4]+): 332.2257; found: 332.2268.
cis-Fused ketone 17: [α]D21 4.7 (c 0.17, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.22 – 4.14 (m, 2H), 3.97 (t, J =
2.2 Hz, 1H), 3.54 (dd, J = 11.9, 1.3 Hz, 1H), 2.97 (dd, J = 14.1, 12.0 Hz, 1H), 2.75 (dd, J = 14.0, 2.8 Hz, 1H),
2.24 (dt, J = 14.0, 2.4 Hz, 1H), 2.21 – 2.06 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.05

ACCEPTED MANUSCRIPT
19
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 210.1, 98.8, 72.2, 69.2, 63.9, 44.2, 39.6, 32.4, 29.8, 25.6 (3 Cs), 19.0,
17.9, -4.9, -5.0. HRMS (ESI-TOF) m/z: Calcd. for C16H34O4NSi ([M + NH4]+): 332.2257; found: 332.2268.
Preparation of Ketone 17 by Reduction of Enone 8 with Stryker’s Reagent: To a stirred solution of
triphenylphosphinecopper (I) hydride hexamer (6.3 mg, 5 mol %) in toluene (0.25 mL) at room
temperature was added phenylsilane (11.8 μL, 0.10 mmol), followed by a solution of 8 (20.0 mg, 0.06
mmol) in toluene (0.2 mL). After stirring at room temperature for 48 h, the reaction mixture was diluted
with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
Chromatographic purification (8% ethyl acetate/hexanes) afforded 17 (6.0 mg, 30%) as a colorless oil
with spectral data identical to the above sample. Further elution (11% ethyl acetate/hexanes) gave the
recovered starting material (9.4 mg, 47%).
(2S,4R,9R,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxadecalin-2-ol (18) and
(2S,4R,9S,10R)-4-((tert-Butyldimethylsilyl)oxy-6,6-dimethyl-5,7-dioxadecalin-2-ol (19). To a stirred
solution of 11 (112.7 mg, 0.36 mmol) in EtOH (0.5 mL) at room temperature was added a suspension of
Raney nickel (20.0 mg, slurry in H2O) in EtOH (1 mL). The reaction mixture was stirred at room
temperature under a hydrogen atmosphere (1 atm) for 10 h before it was filtered through Celite and the
filtrate concentrated under reduced pressure to dryness (113.3 mg). Examination of the crude reaction
mixture by 1H NMR spectroscopy revealed a 2:1 ratio of 18 and 19. Chromatographic purification eluting
with 17% ethyl acetate in hexanes, afforded 19 (21.7 mg, 19%) as a white solid. Further elution with
20% ethyl acetate in hexanes gave 18 (46.7 mg, 41%) as a colorless oil.
trans-Fused alcohol 18: [α]D21 -9.0 (c 1.35, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.18 (app p, J = 2.9 Hz, 1H),
3.90 (ddd, J = 11.2, 8.6, 5.0 Hz, 1H), 3.67 (dd, J = 11.2, 4.9 Hz, 1H), 3.58 (t, J = 11.2 Hz, 1H), 3.35 (dd, J =
10.5, 8.6 Hz, 1H), 2.12 – 1.98 (m, 2H), 1.58 – 1.46 (m, 2H), 1.44 (s, 3H), 1.38 (s, 3H), 1.17 (td, J = 13.5, 2.9
Hz, 1H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 98.9, 78.1, 68.9, 66.5, 64.6,

ACCEPTED MANUSCRIPT
20
41.2, 32.6, 32.5, 29.8, 25.8 (3 Cs), 19.2, 18.3, -4.3, -4.9. HRMS (ESI-TOF) m/z: Calcd. for C16H33O4Si ([M +
H]+): 317.2148; found: 317.2159.
cis-Fused alcohol 19: [α]D21 21.7 (c 0.65, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.12 (dd, J = 11.7, 2.6 Hz,
1H), 4.00 (tt, J = 11.3, 4.2 Hz, 1H), 3.88 (app q, J = 3.0 Hz, 1H), 3.75 (t, J = 3.0 Hz, 1H), 3.56 (dd, J = 11.7,
1.0 Hz, 1H), 1.98 (dd, J = 11.7, 11.3 Hz, 1H), 1.90 – 1.80 (m, 1H), 1.75 – 1.52 (m, 3H), 1.45 (s, 3H), 1.39 (s,
3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 98.5, 70.6, 69.4, 65.9, 64.7, 37.5,
33.4, 30.3, 29.8, 25.7 (3 Cs), 18.9, 17.9, -4.9, -5.1. HRMS (ESI-TOF) m/z: Calcd. for C16H32O4SiNa ([M +
Na]+): 339.1968; found: 339.1975.
(5R,7S,10R)-5-((tert-Butyldimethylsilyl)oxy-3,3-dimethyl-2,4-dioxa-Δ1,9-octalin-7-ol (20). A solution of
11 (14.6 mg, 0.05 mmol) and Crabtree’s catalyst (0.8 mg, 2 mmol %) in dichloromethane (0.3 mL) was
stirred at 0 oC under a hydrogen atmosphere (1 atm) for 3 h before it was concentrated under reduced
pressure. Chromatographic purification (12% ethyl acetate/hexanes) afforded the title compound as a
colorless oil (9.7 mg, 66%): [α]D21 9.6 (c 0.49, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.29 – 6.27 (m, 1H),
4.07 (m, 1H), 3.94 – 3.82 (m, 2H), 2.23 (d, J = 14.7 Hz, 1H), 2.13 – 2.01 (m, 2H), 1.56 (ddd, J = 13.2, 10.7,
2.0 Hz, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 0.88 (s, 9H), 0.08 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 137.7, 107.0,
99.2, 74.1, 70.7, 66.3, 40.0, 34.9, 27.8, 25.8 (3 Cs), 21.3, 18.3, -4.4, -4.9. HRMS (ESI-TOF) m/z: Calcd. for
C16H30O4SiNa ([M + Na]+): 337.1811; found: 337.1816.
(1R,2R,3S,5S)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxy-3-methylcyclohexan-5-yl Benzoate (21). To a
solution of 13 (8.5 mg, 0.02 mmol) in EtOH (0.4 mL) was treated with Pd(OH)2/C (3.0 mg, 20 wt %) and
stirred at room temperature under a hydrogen atmosphere (1 atm) for 0.5 h before it was filtered
through Celite. The filtrate was concentrated under reduced pressure and chromatographic purification
of the residue (3% ethyl acetate/hexanes) afforded the title compound as a colorless oil (4.6 mg, 56%):
[α]D21 19.1 (c 0.23, CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45

ACCEPTED MANUSCRIPT
21
(t, J = 7.4 Hz, 2H), 5.34 (app p, J = 2.9 Hz, 1H), 3.88 (ddd, J = 11.6, 9.0, 6.0 Hz, 1H), 3.11 (t, J = 9.0 Hz, 1H),
2.22 (ddd, J = 14.1, 6.0, 2.9 Hz, 1H), 2.05 – 1.89 (m, 2H), 1.64 (ddd, J = 14.1, 11.6, 2.9 Hz, 1H), 1.38 (ddd, J
= 14.3, 12.2, 2.9 Hz, 1H), 1.08 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 165.6, 133.0, 130.5, 129.5 (2 Cs), 128.4 (2 Cs), 80.4, 72.8, 70.3, 37.6, 36.9, 31.9, 25.8 (3
Cs), 18. 0, 17.9, -4.2, -4.7. HRMS (ESI-TOF) m/z: Calcd. for C20H32O4SiNa ([M + Na]+): 387.1968; found:
387.1966.
(1R,2R,3R,5S)-1-((tert-Butyldimethylsilyl)oxy)-2-(methoxymethyloxy)-3-
((methoxymethoxy)methyl)cyclohexan-5-ol (22). A solution of 15 (371.7 mg, 1.03 mmol) in EtOH (2
mL) was treated with a suspension of Raney nickel (40.0 mg, slurry in H2O) in EtOH (2.5 mL), and stirred
at room temperature under a hydrogen atmosphere (1 atm) for 2 h before it was filtered through Celite.
The filtrate was concentrated under reduced pressure to dryness, and chromatographic purification
(33% ethyl acetate/hexanes) of the residue afforded the title compound as a colorless oil (343.9 mg,
92%): [α]D21 44.0 (c 1.48, CHCl3). 1H NMR (400 MHz, CDCl3) δ 4.89 (d, J = 6.7 Hz, 1H), 4.66 (d, J = 6.7 Hz,
1H), 4.62 (s, 2H), 4.14 (m, 1H), 3.99 (ddd, J = 10.1, 7.8, 4.4 Hz, 1H), 3.69 (dd, J = 9.5, 3.6 Hz, 1H), 3.61 (dd,
J = 9.5, 6.6 Hz, 1H), 3.40 (s, 3H), 3.35 (s, 3H), 3.28 (dd, J = 9.3, 7.8 Hz, 1H), 2.18 – 2.07 (m, 1H), 1.95 (dtd, J
= 13.5, 4.4, 2.4 Hz, 1H), 1.86 (dtd, J = 14.1, 4.4, 2.4 Hz, 1H), 1.61 (ddd, J = 14.1, 11.2, 3.0 Hz, 1H), 1.55
(ddd, J = 13.5, 10.1, 2.9 Hz, 1H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 98.4,
96.7, 81.2, 71.9, 68.5, 65.7, 56.1, 55.1, 40.6, 37.1, 34.8, 25.8 (3 Cs), 17.9, -4.7 (2 Cs). HRMS (ESI-TOF) m/z:
Calcd. for C17H36O6SiNa ([M + Na]+): 387.2179; found: 387.2180.
(1R,2R,3R,5S)-3-(Hydroxymethyl)cyclohexan-1,2,5-triol (Pseudo-2-deoxy-α-D-glucopyranose (23). A
solution of 22 (10.0 mg, 0.03 mmol) in MeOH (0.5 mL) at room temperature was treated with
concentrated HCl (5 μL) and stirred stirred at 60 oC for 5 h before it was concentrated under reduced
pressure. Chromatographic purification (25% methanol/dichloromethane) afforded the title compound

ACCEPTED MANUSCRIPT
22
as a colorless oil (4.4 mg, 99%): [α]D21 19.1 (c 0.22, MeOH 1H NMR (600 MHz, CD3OD) δ 4.09 (app p, J =
3.0 Hz, 1H), 3.75 (ddd, J = 11.7, 8.9, 4.9 Hz, 1H), 3.69 – 3.62 (m, 2H), 3.16 (dd, J = 10.4, 8.9 Hz, 1H), 2.03
(ddt, J = 13.5, 4.9, 3.0 Hz, 1H), 1.93 – 1.86 (m, 1H), 1.79 (dq, J = 14.1, 3.0 Hz, 1H), 1.43 – 1.34 (m, 2H). 13C
NMR (151 MHz, CD3OD) δ 76.4, 70.3, 65.5, 63.3, 38.92, 38.85, 33.7. HRMS (ESI-TOF) m/z: Calcd. for
C14H28O8Na ([2M + Na]+): 347.1682; found: 347.1689.
Acknowledgements. We thank the NIH (GM62160) for support of this work and acknowledge support
from the NSF (MRI-084043) for the purchase of the 600 MHz NMR spectrometer in the Lumigen
Instrument Center at Wayne State University.
References
(1)
Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919-2036.
Lahiri, R.; Ansari, A. A.; Vankar, Y. D. Chem. Soc. Rev. 2013, 42, 5102-5118.
Shing, T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610-6613.
(2)
(3)
(4)
Shing, T. K. M.; Ng, C. W. L. Synlett 2011, 1318-1320.
(5)
Shing, T. K. M.; Chen, Y.; Wu, H. T. Synlett 2012, 1793-1796.
(6)
Lin, C. H.; Sugai, T.; Halcomb, R. L.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem. Soc. 1992, 114, 10138-
10145.
(7)
Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639-666.
Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem. Commun. 1978, 601.
Hughes, D. L. Org. React. 1992, 42, 335-656.
(8)
(9)
(10)
(11)
(12)
(13)
Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291-293.
Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627-4630.
Crabtree, R. H.; Morris, G. E. J. Organomet. Chem. 1977, 135, 395-403.
Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem. Soc. A 1966, 1711-1732.

ACCEPTED MANUSCRIPT
23
(14)
Augustine, R. L.; Migliorini, D. C.; Foscante, R. E.; Sodano, C. S.; Sisbarro, M. C. J. Org. Chem.
1969, 34, 1075-1085.
(15)
(16)
Augustine, R. L. Adv. Catal. 1976, 25, 56-80.
Nishimura, S.-i. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis;
Wiley: New York, 2001.
(17)
(18)
(19)
(20)
Birch, A. J.; Robinson, R. J. Chem. Soc. 1943, 501-502.
Birch, A. J.; Smith, M. D. Proc. Chem. Soc. 1962, 356-356.
Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673-1675.
Utimoto, K.; Wakabayashi, Y.; Horiie, T.; Inoue, M.; Shishiyama, Y.; Obayashi, M.; Nozaki, H.
Tetrahedron 1983, 39, 967-973.
Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072-1073.
(21)
(22)
(23)
(24)
(25)
(26)
(27)
2314.
(28)
(29)
(30)
Crabtree, R. H.; Davis, M. W. Organometallics 1983, 2, 681-682.
Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 2, 2655-2661.
Evans, D. A.; Morrissey, M. M. Tetrahedron Lett. 1984, 25, 4637-4640.
Baudry, D.; Ephritikhine, M.; Felkin, H. J. Chem. Soc., Chem. Commun. 1978, 694-695.
Shing, T. K. M.; Ng, W.-L.; Chan, J. Y.-W.; Lau, C. B.-S. Angew. Chem. Int. Ed. 2013, 52, 8401-8405.
Fordred, P. S.; Niyadurupola, D. G.; Wisedale, R.; Bull, S. D. Adv. Synth. Catal. 2009, 351, 2310-
Takada, Y.; Caner, J.; Kaliyamoorthy, S.; Naka, H.; Saito, S. Chem. Eur. J. 2017, 23, 18025-18032.
Corey, E. J.; Sarakinos, G.; Axel, F. Tetrahedron Lett. 1999, 40, 7745-7748.
Marzabadi, C. H.; E., A. J.; Gonzalez-Outeirino, J.; Gaffney, P. J. R.; White, C. G. H.; Tocher, D. A.;
Todaro, L. J. J. Am. Chem. Soc. 2003, 125, 15163-15173.
(31) Okajima, K.; Mukae, T.; Imagawa, H.; Kawamura, Y.; Nishizawa, M.; Yamada, H. Tetrahedron
2005, 61, 3497-3506.

ACCEPTED MANUSCRIPT
24
(32)
Yamada, H.; Okajima, K.; Imagawa, H.; Mukae, T.; Kawamura, Y.; Nishizawa, M. Bull. Chem. Soc.
Jpn. 2007, 80, 583-585.
(33)
(34)
1576.
(35)
(36)
(37)
(38)
Okada, Y.; Nagata, O.; Taira, M.; Yamada, H. Org. Lett. 2007, 9, 2755-2758.
Okada, Y.; Mukae, T.; Okajimia, K.; Taira, M.; Fujita, M.; Yamada, H. Org. Lett. 2007, 9, 1573-
Pedersen, C. M.; Nordstrom, L. U.; Bols, M. J. Am. Chem. Soc. 2007, 129, 9222-9235.
Pedersen, C. M.; Marinescu, L. G.; Bols, M. CR Chimie 2011, 14, 17-43.
Bols, M.; Pedersen, C. M. Beil. J. Org. Chem. 2017, 13, 93-105.
Komarova, B. S.; Gerbst, A. G.; Finogenova, A. M.; Dmitrenok, A. S.; Tsvetkov, Y. E.; Nifantiev, N.
E. J. Org. Chem. 2017, 82, 8897-8908.
(39)
Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247-2255.
(40)
Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.
(41)
Jensen, H. H.; Nordstrom, M.; Bols, M. J. Am. Chem. Soc. 2004, 126, 9205-9213.
Moumé-Pymbock, M.; Furukawa, T.; Mondal, S.; Crich, D. J. Am. Chem. Soc. 2013, 135, 14249-
(42)
14255.
(43)
Kancharla, P. K.; Crich, D. J. Am. Chem. Soc. 2013, 135, 18999-19007.
Dharuman, S.; Crich, D. Chem. Eur. J 2016, 22, 4535-4542.
(44)