Synthesis of allo - And epi -inositol via the NHC-catalyzed carbocyclization of carbohydrate-derived dialdehydes

Article abstract of DOI:10.1021/jo500645z

A synthesis of carbocyclic sugars from carbohydrate-derived dialdehydes using organocatalysis has been developed. Sorbitol, mannitol, and galactitol were converted via 1,6-tritylation, perbenzylation or permethylation, detritylation, and Swern oxidation into 2,3,4,5-tetra-O-alkyl-dialdoses that were cyclized via the benzoin reaction promoted by a triazolium carbene. Manno- and galacto-configured dialdehydes gave predominantly single inosose stereoisomers in up to 75% yield if the mixture was acetylated prior to isolation while the gluco-dialdehyde afforded a mixture of three stereoisomers in 61% overall yield. The inososes were stereospecifically reduced using sodium borohydride and then deprotected to give allo- and epi-inositol in good yield that confirmed the structural and stereochemical assignments.

Full text of DOI:10.1021/jo500645z

Article
pubs.acs.org/joc
Synthesis of allo- and epi-Inositol via the NHC-Catalyzed
Carbocyclization of Carbohydrate-Derived Dialdehydes
Kieran P. Stockton,† Ben W. Greatrex,*,† and Dennis K. Taylor‡
†School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia
‡School of Agriculture, Food and Wine, The University of Adelaide, Waite Campus, Glen Osmond 5064, Australia
S
* Supporting Information
ABSTRACT: A synthesis of carbocyclic sugars from carbohy-
drate-derived dialdehydes using organocatalysis has been
developed. Sorbitol, mannitol, and galactitol were converted
via 1,6-tritylation, perbenzylation or permethylation, detri-
tylation, and Swern oxidation into 2,3,4,5-tetra-O-alkyl-
dialdoses that were cyclized via the benzoin reaction promoted
by a triazolium carbene. Manno- and galacto-configured
dialdehydes gave predominantly single inosose stereoisomers
in up to 75% yield if the mixture was acetylated prior to isolation while the gluco-dialdehyde afforded a mixture of three
stereoisomers in 61% overall yield. The inososes were stereospecifically reduced using sodium borohydride and then deprotected
to give allo- and epi-inositol in good yield that confirmed the structural and stereochemical assignments.
INTRODUCTION
■
The synthesis of natural products from inositols requires
orthogonally protected derivatives that are difficult to access
due to the numerous secondary alcohols of similar reactivity.
An attractive route to these protected inositols is the cyclization
of appropriately protected carbohydrates such as that
developed by Ferrier, which when promoted by mercury(II)
chloride or palladium(II) chloride generates cyclitols and
deoxycyclitols from glycals and 6-deoxyglycals, respectively.1,2
The Ferrier II reaction has found application in total synthesis,
notably, the synthesis of (+)-galanthamine,3 fumagillin
analogue FR65814,4 and both enantiomers of Calystegine
B2.5 The demonstrated utility of the Ferrier II reaction has been
a motivating factor in the development of alternative syntheses
of inositols from sugars. Methods include the samarium
diiodide mediated cyclizations combining a carbonyl and
reactive partner,6,7 radical cyclizations,8 as well as nitroaldol
cyclizations.2,9 We envisaged that organocatalysis would furnish
cyclic acyloins from carbohydrate-derived dialdehydes as an
alternative to the Ferrier reaction or the samarium diiodide
mediated reductive cyclization.
The use of N-heterocyclic carbenes (NHCs) as catalysts in
organic synthesis is well established.10−13 NHCs are able to
catalyze a variety of transformations including transesterifica-
tion,14 Stetter reactions,15,16 crossed benzoin condensa-
tions,17−19 and Diels−Alder chemistry.20 In particular, the
triazolium carbenes developed by Rovis formed from
precatalysts 1 and 2 by treatment with base show excellent
stability and wide applicability (Figure 1).21,22 In the case of the
benzoin condensation, thiazolium and triazolium-type NHC
catalysts show good reactivity with chiral catalysts able to
promote stereoselective transformations. Intermolecular17−19
and intramolecular23−25 variants of the reaction have been
Figure 1. NHC precatalysts.
reported, usually using aromatic aldehydes that act as the
Umpolung partner crossed with ketones or aldehydes. Enders
et al. has reported intramolecular crossed benzoin reactions
using a chiral triazolium catalyst using substochiometric
quantities of base,25 and more recently, Ema et al. reported
the synthesis of chiral α-hydroxycyclohexanones by the
cyclization of aliphatic keto-aldehydes using precatalysts 1
and 3.24 The application of organocatalysis to the cyclization of
aliphatic dialdehydes is still relatively unexplored.
There have been some recent applications of organocatalysis
in carbohydrate chemistry. The deoxygenation of hexoses and
pentoses affording 2-deoxylactones can be affected using
NHCs26 and C-glycosylation can be achieved starting with 2-
nitroglycals.27 A 1995 patent claims the synthesis of D-chiro-
inositol directly from glucodialdose using a thiazolium derived
carbene in water; however, no information on yield, stereo-
selectivity, characterization data, or even the catalyst used was
given.28,29 There has been significant interest in the synthesis of
Received: March 19, 2014
Published: April 21, 2014
© 2014 American Chemical Society
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inositols and their phosphorylated derivatives due to their
function in the cell as intracellular messengers.30 The
preparation of partially protected inositols as described herein
could lead to novel inositol phosphate isomers that may be of
biological importance.
mixture of resonances tentatively assigned to products of
hydration based upon a series of peaks in the 13C NMR
spectrum between δ 99.9 and 97.3 ppm (Scheme 2). The new
Scheme 2. Hydration of Dialdehyde 10
RESULTS AND DISCUSSION
■
Simple protocols have been established in the literature to
generate suitably protected sugar-derived 1,6-dialdehyde
substrates (Scheme 1).7,31−34 Starting with mannitol (4),
Scheme 1. Preparation of Carbohydrate-Derived 1,6-
Dialdehydes
mixture that was in equilibrium with the dialdehyde as
treatment with ethyl (triphenylphosphoranylidene)acetate
afforded diethyl (2E,8E)-4,5,6,7-tetra(benzyloxy)decan-2,8-di-
endioate as the sole product by NMR. The dialdehyde was not
stable to silica gel chromatography and was stored at −15 °C
after preparation.
As an alternative to benzyl protection on oxygen, the
tetramethyl derivative 9 was also synthesized by permethylation
of 5 using sodium hydride/methyl iodide and trityl removal.
Swern oxidation afforded the dialdehyde 1131 as the sole
product in 72% overall yield from mannitol.
The dialdehydes 18 and 1936 and 26 and 2732 were similarly
prepared from sorbitol (12) and galactitol (20), respectively.
The aldehyde groups in both 18 and 19 are chemically
nonequivalent while galactitol is meso-substituted, so 26 and 27
display symmetry in their NMR spectra. The symmetrical trityl
ethers 6, 21, and 22 had reduced solubility; thus, crystallization
without chromatography could be used for their purification.
Manno-dialdehydes 10 and 11 were chosen as initial
substrates for carbocyclization due to their symmetry that
simplifies the possibilities for cyclization, the results of which
are shown in Table 1. The dialdehyde 10 was completely
consumed within 24 h when stirred with 1, 2, or 3 and base,
and a single inosose diastereomer was isolated from the
reactions of 1 and 3 and assigned as inosose 30. The relatively
electron-rich precatalyst 2 yielded a complex mixture of
products, and so, this catalyst was excluded from further
study. Similar yields were obtained using methyl ether
protected dial 11, and the stereochemistry of the product was
found to be the same. The choice of base played an important
role in the reaction outcome for which there is ample literature
precedence,24,25 and triethylamine gave superior yields over
DBU while early attempts utilizing potassium tert-butoxide gave
complex mixtures. Analysis of the crude reaction mixtures by
NMR suggested that yields should have been higher and that
some material was decomposing during silica gel chromatog-
raphy. Acetylation of the crude reaction mixture afforded an
increased yield of cyclized material 31 that had greater stability
during isolation (entry 6).
(a) TrCl, pyr., reflux, 1.5 h; (b) BnBr, NaH, Bu4NI, THF 25 °C, 6 h,
reflux, 19 h; (c) 2:1 DCM/MeOH, TFA, 18 h; (d) MeI, NaH, THF,
25 °C, 18 h; (e) 1:1 DCM/MeOH, TsOH, 18 h; (f) (i) (COCl)2,
DMSO, DCM, −78 °C, 25 min, (ii) Et3N, −78 to 25 °C, 1.5 h; (g)
BnBr, NaH, THF, 25 °C; (h) 3:1 toluene/MeOH, TFA, 65 °C, 16 h.
The assignment of the structure, conformation, and stereo-
chemistry of the product was made on the basis of two-
dimensional (2D) NMR experiments on 30 and its acetylated
derivative 31. Greater dispersion was seen in 31, and so, its
NMR and conformation are discussed (Figure 2). The
assignment of protons around the ring in 31 was based on
the COSY spectrum and began with the assignment of α
proton H-6 that was shifted downfield to δ 5.62 ppm due to the
attached acetate group. All protons showed crosspeaks to their
selective 1,6-bis-tritylation to give 5 followed by perbenzylation
using sodium hydride/benzyl bromide afforded ether 6.35
Removal of the trityl groups under acid-catalyzed conditions
afforded the 1,6-diol 7 that was then cleanly oxidized to the 1,6-
dialdehyde 10 using Swern conditions.
Although the synthesis of 10 is known,34 the spectral data has
not been reported. The dialdehyde 10 showed characteristic
1
symmetry in the H NMR spectrum with two aliphatic broad
3
singlets and a single aldehyde resonance at δ 9.70 confirming
the structure. Over 24 h, the resonances assigned to the
dialdehyde disappeared and were replaced with a complex
neighbors. A 10.4 Hz JH5−H6 coupling was observed that
indicated a trans-diaxial relationship between these protons.
3
The 3.2 Hz JH5−H4 coupling indicated H-4 was gauche to the
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Table 1. NHC-Promoted Cyclization of 10 and 11
a
b
entry
aldehyde
base (mol %)
precatalyst (mol %)
solvent
temp
time (h)
product
yield
1
2
10
10
10
10
10
10
11
11
DBU (15)
DBU (15)
NEt3 (15)
DBU (15)
NEt3 (10)
NEt3 (15)
NEt3 (15)
NEt3 (100)
3 (20)
1 (20)
1 (20)
2 (20)
1 (15)
1 (20)
1 (20)
1 (20)
dioxane
dioxane
DCE
100
100
40
24
24
16
24
16
16
16
16
30
30
30
−
30
31
32
22
40−50
54
c
3
4
5
dioxane
DCE
25
−
55
40
d
6
DCE
40
75
7
8
DCE
40
62
DCE
40
32
59
a
b
c
Reactions were performed on 100−185 mg of dialdehyde using 50 mL/g solvent. Isolated yield by flash chromatography. Scale was 1.02 g of 10.
d
The crude mixture was acetylated prior to chromatography.
separate all stereoisomers. Of the four expected stereoisomers
from the reaction, two were produced with the other product
resulting from epimerization of an α stereocenter. Surprisingly,
one of the isomers 30 isolated from the reaction mixtures of 18
was identical to that isolated from the cyclization of manno-
dialdehyde 10. The stereochemistry of the starting materials
differ at C-2, and epimerization must occur prior to or during
the cyclization as the center is remote from the ketone moiety
in the product. Cyclization was observed for the methyl ether
analogue 19; however, decomposition occurred on silica, and
Figure 2. Conformation, ROESY interactions (dashed arrows), and
coupling constants of 31 and 33.
so, the diastereomers were not separated or characterized.
The reaction manifold for dialdehyde 18 is shown in Scheme
3. Isomer 30 results from epimerization at C-2 in the starting
material 18 generating manno-dialdehyde 10 and then
formation of the Breslow intermediate 43 at C-1 or C-6.
Cyclization occurs through a possible transition state 44 that
necessarily has two axial and two equatorial benzyl ethers and
presumably an equatorial catalyst as this also allows for
hydrogen bonding in the transition state. After proton transfer,
the cyclization leads to the intermediate 45 that eliminates the
catalyst affording observed 30. The stereoisomer 34 can be
derived directly from 18 by formation of the Breslow
intermediate at C-1 to give 46 followed by cyclization of C-1
onto C-6 generating a new equatorial stereocenter via the
possible transition state 47. The cyclized intermediate 48 then
eliminates the catalyst giving 34. The pathway to isomer 35
involves formation of the regioisomeric Breslow intermediate
49 at C-6 and then cyclization of C-6 onto C-1 through a
possible transition state 50 with three axial benzyl ethers and an
equatorial catalyst (or its ring-flipped conformer) to afford 51
that eliminates the catalyst to give 35. The observed
conformation of 35 also has these three axial benzyl ethers,
so it is reasonable to propose a transition state such as 50.
Isomer 35 was difficult to isolate analytically pure as the
compound was prone to decomposition on silica gel and several
columns were required to remove other isomers.
axial H-5 and therefore H-4 was equatorial. The 2D ROESY
NMR of 31 showed a through space interaction between H-2
and H-6 from which H-6 was assigned as cis to H-2 and axial.
This made assignment of the stereochemistry of H-2 and H-3
possible due to the 3JH2−H3 3.2 Hz coupling and confirmed that
no epimerization at other centers occurred. We also observed 4J
coupling between H-2 and H-6 across the carbonyl group in the
COSY NMR. This coupling manifested as line broadening at
1
H-2 and H-6 in the one-dimensional H NMR at 600 MHz
although a clear doublet of doublets was observed for H-2 at
4
300 MHz. Normally, J couplings are observed along an M or
W path where all elements are coplanar, but coplanarity is not
required if the hydrogens are separated by an sp2 hybridized
center, and so, this coupling could not be used to assign
stereochemistry.37 The 13C NMR spectra of 30 and 31 were
assigned using the HSQC experiment, and products exhibited
carbonyl resonances at δ 205 and 198 ppm, respectively. A
carbonyl stretching frequency was observed in the infrared
spectrum of 30 at 1732 cm−1 consistent with a cyclohexanone.
Coupling around the ring for the methyl ether analogue 33
showed identical coupling patterns and similar ROESY
interactions as depicted in Figure 2.
Sorbitol-derived dials 18 and 19 have no plane of symmetry,
and so, four possible stereoisomers can arise from the
cyclizations, the results of which are shown in Table 2. In the
best case (entry 1), a 61% yield of cyclization products was
isolated from the benzyl ether protected dialdehyde 18 using
triethylamine with extensive chromatography required to
When 30, 34, and 35 were separately resubmitted to the
reaction conditions, they were recovered unchanged indicating
that the pathways to 30, 34, and 35 are under kinetic control.
Higher temperatures improved the yield of products but did
not greatly affect isomeric ratios.
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Table 2. Carbocyclizations of Gluco-dials 18 and 19 and Galacto-dials 26 and 27
a
b
entry
aldehyde
base (mol %)
precatalyst (mol %)
solvent
temp
product
ratio
yield
c
1
18
18
18
18
18
18
18
19
26
26
26
27
27
NEt3 (15)
DBU (15)
DBU (15)
DBU (15)
NEt3 (15)
i-Pr2NEt (100)
imidazole
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
2 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
DCE
CH3CN
dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
40
40
40
25
25
40
40
25
40
40
60
60
40
30:34:35
30:34:35
−
30:34:35
30:34:35
30:34:35
30:34:35
−
32:23:45
61
25
0
d
2
3
ND
−
e
4
42:19:39
35
38
33
38
0
5
36:22:46
d
6
ND
d
7
ND
f
8
NEt3 (15)
NEt3 (15)
NEt3 (100)
DBU (15)
NEt3 (15)
NEt3 (15)
−
9
38
−
−
−
92:8
12
12
18
65
54
10
38
g
11
38
12
13
40:41
40:41
87:13
a
Reactions were performed on 100−127 mg of dialdehyde in 50 mL/g solvent and left for 16 h and products isolated by flash chromatography.
b
c
d
Ratios determined from isolated products. Scale was 1.7 g of 18. The mixture of isomers isolated from the first column was not further purified,
e
f
g
and the ratio could not be accurately determined. Reaction took 40 h to reach completion. Decomposition occurred on silica gel. Scale was 1.07 g
of 11.
Scheme 3. Reaction Manifold for Dialdehyde 18
The cyclization of benzyl ether protected galacto-dial 26
afforded a single stereoisomer 38 in low yield as well as ,
unidentified products (Table 2). Attempts to isolate the benzyl-
protected 38 free from impurities were unsuccessful due to a
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close running unidentified byproduct that lacked ketone
resonances in the 13C NMR, and so, the product was converted
to the acetate derivative 39. Due to the low yield of products, it
was not clear if small amounts of other stereoisomers were
produced in the reactions of 26. Switching protecting groups to
methyl ethers gave good yields for the cyclization reactions, and
two isomers 40 and 41 were isolated from the reaction
although the major isomer 40 was again isolated containing an
impurity that was removed upon acetylation. On the basis of
the stereochemistry of the products, it is clear that no
epimerization occurs in the reactions of 26 and the stereo-
isomers are generated in the ring-closure step. As galacto-dials
26 and 27 are meso-substituted, the products of the cyclization
are racemic, and we are yet to investigate enantioselective
versions of the reaction for 26.
assigned on the basis of the stereochemistry of the starting
material.
The major product from galacto-dials 26 and 27 were 38 and
40, respectively, with both inososes having the same stereo-
chemistry. In the acetate derivatives 39 and 42, there is a single
large trans-diaxial coupling between H-2 to H-3 with H-4
equatorial and cis to H-3. A ROESY interaction in the spectrum
of 39 between H-2 and H-6 indicated an axial H-6 allowing for
the assignment of the stereochemistry at C-6 and C-5 due to
the JH5−H6 2.6 Hz coupling.
The minor alcohol 41 is epimeric at the newly created
hydroxyl center and ring-flipped relative to the major isomer 40
(and its acetate derivative 42). Assignment of the stereo-
chemistry in 41 was made on the basis of coupling constants
supported by ROESY interactions between H-4 and H-6. The
3JH5−H6 8.5 Hz and 3JH4−H5 9.1 Hz couplings indicate that H-5 is
axial and has two axial neighbors, and the small H-3 to H-4
coupling makes H-3 equatorial and cis to the axial H-4. The
equatorial assignment of H-2 is supported by the lack of
ROESY interactions seen with other axial protons and the
stereochemistry of the starting material.
The assignment of stereochemistry in the cyclization
products 34−42 was based upon ROESY 2D NMR experi-
ments and 3J coupling constants predominantly using the
acetate derivatives (Figure 3). The gluco-dial derived acetate
In order to demonstrate the utility of the cyclization process
and to confirm the structure and stereochemistry assigned to
these products, we investigated NaBH4 reductions of
hydroxyketones 30, 34, and 38 to generate protected inositols
and ultimately inositols (Scheme 4).
Scheme 4. Synthesis of allo- and epi-Inositols from 30, 34,
and 38
Figure 3. Conformation, selected ROESY interactions (dashed
arrows), and coupling constants of 36, 37, 39, 41, and 42.
3
3
ester 36 exhibited 9.1 Hz trans-diaxial JH2−H3 and JH3−H4
couplings while the 2.3 Hz 3JH4−H5 coupling indicated that H-4
also had an equatorial neighbor. The 2D ROESY NMR showed
crosspeaks between H-2, H-4, and H-6 making H-6 axial and cis
to the other axial hydrogens. Both 35 and its acetate derivative
37 lacked characteristic trans-diaxial couplings in their 1H NMR
spectra. Furthermore, it was difficult to isolate hydroxyketone
35 in an analytically pure state as it underwent some
decomposition on silica. The ROESY spectrum of the acetate
ester 37 showed a through-space interaction between H-2 and
H-6 indicating that these atoms were cis- and axial. Coupling
constants around the ring indicated all gauche couplings (2.9−
4.7 Hz) assuming a chair structure, and H-3 and H-5 were
therefore equatorial while the remaining center at H-4 was
The reduction of hydroxyketone 30 gave a single product 52
in good yield; however, the diol 53 exhibited a broadened H
1
NMR spectrum from which it was difficult to assign resonances.
Conformations were slowly exchanging at room temperature,
and the spectrum at −100 °C gave only partially resolved
signals. Removal of the benzyl groups using PdCl2/H2 gave an
81% yield of allo-inositol 54 for the two steps from which the
stereochemistry of the reduction 30 was deduced. The allo
stereochemistry of the diol explained the NMR as there is
literature precedent for the slow conformational exchange of
allo-inositol derivatives.38 The reduction of the hydroxyketone
38 also yielded allo-inositol 54 as the final product in 65%
overall yield after removal of the benzyl groups. The
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product remained in the aqueous layer (TLC), and the combined
organic extracts were washed with a further portion of saturated
NaHCO3 before drying (Na2SO4) and concentrating under reduced
pressure. The residue was purified by flash chromatography (1:1
EtOAc/hexanes) to give the 1,6-di-O-tritylated alditols 531 (7.10 g,
97%), 1336 (3.41 g, 93%), or 2132 (3.33 g, 91%). All products had 1H
and 13C NMR spectra matching those previously reported.
intermediate diol 53 differed to diol 52 obtained from 30 in the
position on the ring of the two hydroxyl groups; however,
interpreting the NMR of the diol was again difficult due to
coalescence near ambient temperature. The sodium borohy-
dride reduction of the inosose 34 also afforded a single diol 55.
Hydrogenolysis of the benzyl groups yielded epi-inositol 56
from which the stereochemistry of the reduction could once
more be deduced.
In all three reductions using sodium borohydride, the
substrates have an axial 3-benzyloxy substituent hindering one
face of the carbonyl that has been shown to control inosose
reduction.39 It is likely that the reactive conformations match
the conformations determined by NMR as the alternative
conformers have either three or four unfavorable axial
benzyloxy groups. Furthermore, the alternative conformers
would still have one axial 3-benzyloxy substituent and an axial
2-hydroxy substituent that would direct hydride to the opposite
face to that observed.40 According to the model developed by
Cieplak41 to explain reduction of cyclohexanones, the
antibonding orbital (σ‡*) of the incipient nucleophile is more
stabilized by the C2−H axial bond than the C2−C3 bond, and
so, the axial hydride approach is preferred. It is apparent that, in
the reduction of 30, 34, and 38, the stereoelectronic
stabilization of the axial hydride approach cannot overcome
the steric hindrance encountered on this face.
In conclusion, NHC catalysis provides a novel method for
the synthesis of inosose derivatives in moderate to good yield
from readily synthesized mannitol-, sorbitol-, and galactitol-
derived 1,6-dialdehydes. While the reactions of manno- and
galacto-dials yielded mainly single isomers from the cyclization,
the reaction of gluco-dials yielded mixtures of hydroxyketone
stereoisomers. Substitution of benzyl ethers by methyl groups
dramatically improved the yield for the galacto-substituted
dialdehyde indicating the sensitivity of the cyclization to
stereochemistry and to steric effects. The inosose products of
cyclization were converted to inositols by a stereoselective
reduction using NaBH4 and protecting group removal. The
inositols were consistent with the assigned stereochemistry in
the inosose products of cyclization. The synthesis of allo-
inositol was achieved in an overall yield of 33% over six steps;
however, epi-inositol was produced in low yield due to an
unsatisfactory cyclization step. The chemistry of the inosose
derivatives is currently being examined, and their use in
synthesis will be reported in due course.
General Procedure for the Benzylation and Methylation of 1,6-
Di-O-tritylated Alditols 5, 13, and 21. To a solution of 1,6-di-O-trityl
alditol 5, 13, or 21 (1 equiv) in THF (6 mL/mmol) under N2 was
added either benzyl bromide (4.8 equiv) or methyl iodide (4.8 equiv).
A 60% oil dispersion of NaH (4.8 equiv) was added gradually, and the
mixture was stirred for 6 h and then heated under reflux overnight. If
the reaction was incomplete (1H NMR or TLC), Bu4NI (0.15 equiv)
was added, and the mixture was heated for a further hour before
careful quenching with MeOH. The solvent was removed under
reduced pressure, and the residue was partitioned between H2O/
DCM. The organic phase was collected and washed with a further
portion of H2O before being dried (Na2SO4) and concentrated under
reduced pressure. Alditol 635 (4.34 g, 90%) was recrystallized from
DCM/MeOH. Alditol 1435 (1.70 g, 85%) was purified by flash
chromatography using 9:1 hexanes/EtOAc, and 831 (0.74 g, 100%),
1636 (1.25 g, 96%), and 2432 (0.90 g, 82%) were absorbed onto a bed
of silica, washed with hexanes, and eluted with EtOAc. All products
1
had H and 13C NMR matching those previously reported.
General Procedure for Detritylation of Alditols 6, 14, and 22. To
a solution of the protected alditol 6, 14, or 22 (1 equiv) in 2:1
MeOH/DCM (15 mL/mmol) was added TFA (1.0 mL/mmol), and
the mixture was stirred overnight. The mixture was neutralized using
saturated NaHCO3 solution, and after ensuring no acid remained, the
organic phase was collected, and the aqueous phase was extracted
twice with DCM. The combined organic extracts were washed with a
further portion of saturated NaHCO3 before being dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
flash chromatography (2:3 to 13:7 EtOAc/hexane) affording 7 (510
mg, 86%), 15 (1.40 g, 79%), or 23 (199 mg, 77%). All products had
1H and 13C NMR matching those previously reported.33
General Procedure for Detritylation of Alditols 8, 16, and 24. To
a solution of the protected sugar (1 equiv) in 1:1 DCM/MeOH (24
mL/mmol) was added p-TSA·H2O (3.2 equiv), and the resulting
mixture was stirred for 18 h. Solid Na2CO3 (3.3 equiv) was added, and
the mixture was stirred for an additional 10 min before concentrating
under reduced pressure. The residue was dissolved in DCM, and
insolubles were removed by filtering through Celite. The volatiles were
removed under reduced pressure, and the residue was purified by dry
flash column chromatography (1:1 EtOAc/hexanes then 3:17 MeOH/
EtOAc) to give 931 (230 mg, 75%), 1736 (241 mg, 80%), or 2532 (594
mg, 77%). All products had 1H and 13C NMR matching those
previously reported.
General Procedure for the Swern Oxidation of 2,3,4,5-Tetra-O-
alkyl Alditols 7, 9, 15, 17, 23, and 25. To a solution of dry DMSO
(4.8 equiv) in dry DCM (2.2 mL/mmol) at −78 °C under N2 was
added a solution of (COCl)2 (2.4 equiv) in dry DCM (1.1 mL/mmol)
slowly via syringe, care being taken that, during the addition, the
temperature of the solution did not rise above −60 °C. The solution
was stirred for 10 min before a solution of diol (1 equiv) in dry DCM
(10.8 mL/mmol) was added slowly via syringe, again taking care that
solution temperature did not rise above −60 °C, and the mixture was
stirred for a further 20 min. Et3N (5 equiv) was added, and the mixture
was stirred at below −60 °C for 15 min before being allowed to come
to room temperature (ca. 1.5 h). The solvent was removed under
reduced pressure, and the residue was dissolved in diethyl ether and
then filtered. The filtrate was concentrated under reduced pressure
affording the crude dialdehydes 10, 1131 (225 mg, 99%), 18, 1936 (212
mg, 88%), 26, or 2732 (0.80 g, 81%) that were used without further
purification. Dialdehydes 11, 19, and 27 had 1H and 13C NMR
matching those previously reported.
EXPERIMENTAL SECTION
■
General Experimental. Trityl chloride was recrystallized from
acetyl chloride, NHC 1 was synthesized using a literature procedure,22
and other catalysts were purchased from Strem Chemicals, Boston,
MA, USA. Solvents were dried using literature procedures.42 All other
reagents are commercially available and were used as purchased. NMR
performed in D2O were referenced to internal 1,4-dioxane (1H δ 3.75
ppm, 13C δ 67.2 ppm), and spectra recorded in CDCl3 were referenced
to residual solvent. Melting points are uncorrected. HRMS were
recorded in positive ESI V mode (source temperature, 80 °C;
desolvation temperature, 150 °C; capillary, 2.5 kV). Ring protons in
1
the H NMR were assigned using COSY and ROESY spectra. Ring
carbons were assigned in the 13C NMR spectra using the HSQC
experiment.
General Procedure for Tritylation of 4, 12, and 20. To a solution
of the alditol 4, 12, or 20 (1 equiv) in pyridine (5.5 mL/mmol) was
added trityl chloride (2.2 equiv), and the mixture was heated under
reflux for 1.5 h. The volatiles were removed under reduced pressure,
and the residue was partitioned between DCM and saturated
NaHCO3. The aqueous phase was extracted with DCM until no
2,3,4,5-Tetra-O-benzyl-D-manno-hexodialdose (10). Pale yellow
29
1
oil (0.99 g, 99%); [α]D −2.3 (c 4.4, DCM); H NMR (300 MHz,
CDCl3) δ 9.70 (d, J = 1.3 Hz, 2H), 7.39−7.13 (m, 20H), 4.64 (d, J =
5093
dx.doi.org/10.1021/jo500645z | J. Org. Chem. 2014, 79, 5088−5096

The Journal of Organic Chemistry
Article
11.9 Hz, 2H), 4.60 (d, J = 11.4 Hz, 2H), 4.50 (d, J = 11.4 Hz, 2H),
4.42 (d, J = 11.9 Hz, 2H), 4.13 (br s, 2H), 4.05 (br s, 2H); 13C NMR
(75 MHz, CDCl3) δ 200.0, 136.6, 136.5, 127.7, 127.6, 127.3, 127.2,
127.2, 127.1, 82.6, 79.4, 72.9, 71.7; FT-IR (neat) 2858, 1721 cm−1.
2,3,4,5-Tetra-O-benzyl-D-gluco-hexodialdose (18). Pale yellow oil
(1.70, 84%); 1H NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 9.66 (d, J =
1.5 Hz, 1H), 7.37−7.14 (m, 20H), 4.82 (d, J = 11.7 Hz, 1H), 4.71 (br
d, J = 11.7 Hz, 1H), 4.57−4.43 (m, 4H), 4.53 (d, J = 11.7 Hz, 1H),
4.47 (d, J = 11.7 Hz, 1H), 4.09−4.04 (m, 2H), 4.01−3.94 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 200.7, 199.8, 137.1, 137.0, 137.0 (2C),
128.4, 128.3, 128.2, 128.2, 128.0, 127.9, 127.9, 127.7, 83.4, 81.6, 79.5,
78.7, 74, 73.6, 72.9, 72.6 (4 masked aryl C); FT-IR (neat) 3030, 2867,
1728 cm−1.
C); FT-IR (neat) 3469, 3030, 2872, 1732, 1104, 1027, 1026 cm−1; MS
(ESI) m/z 561 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C34H34O6Na 561.2253; found 561.2250.
Typical Procedure for the Acetylation of Hydroxyketones. To a
solution of the hydroxyketone (0.10−0.20 mmol) in pyridine (1 mL)
was added acetic anhydride (50 μL, 0.53 mmol), and the mixture was
stirred overnight. The solvent was removed by azeotropic distillation
with toluene, and the residue was purified by flash chromatography
(1:3 to 3:7 EtOAc/hexanes for 31, 36, 37, and 39; 4:1 EtOAc/hexanes
for 33 and 42).
(2S,3S,4S,5S,6R)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)-
23
cyclohexanone (31). Colorless syrup (90 mg, 65%); [α]D −24.2 (c
1
1.2, DCM); H NMR (600 MHz, CDCl3) δ 7.45−7.18 (m, 18H),
7.17−7.10 (m, 2H), 5.62 (dd, J = 10.4, 1.0 Hz, 1H, H6), 4.89 (d, J =
11.7 Hz, 1H), 4.74 (d, J = 12.9 Hz, 1H), 4.72 (d, J = 12.9 Hz, 1H),
4.64 (d, J = 12.3 Hz, 1H), 4.58 (d, J = 3.2, 1.0 Hz, 1H, H2), 4.52 (d, J
= 12.1 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.41 (d, J = 12.3 Hz, 1H),
4.40 (d, J = 12.3 Hz, 1H), 4.04 (dd, J = 10.4, 3.2 Hz, 1H, H5), 3.94
(dd, J = 4.1, 3.2 Hz, 1H, H3), 3.81 (dd, J = 4.1, 3.2 Hz, 1H, H4), 2.18
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.5 (C1), 169.9 (CO2),
137.9, 137.8, 137.7, 128.45, 128.4, 128.3, 127.9, 127.85, 127.8, 127.7,
81.0 (C2), 78.9 (C5), 77.7 (C3), 77.6 (C6), 75.0 (C4), 73.8, 73.7,
73.6, 72.8, 29.7 (6 masked aryl C); FT-IR (neat) 3030, 2871, 1742
(br) cm−1; MS (ESI) m/z 581 [M + H]+, 603.2 [M + Na]+; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C36H36O7Na 603.2359; found
603.2360.
1,6-Di-O-trityl-2,3,4,5-tetrakis-O-benzyl-D-galactitol (22). Pre-
pared according to the general procedure and after quenching the
reaction, water (20 mL) was added, and the precipitated solid was
collected. The solid was washed with water (50 mL) and then
triturated with methanol and dried to give a white crystalline solid
1
(1.61 g, 81%); mp 211−215 °C; H NMR (300 MHz, CDCl3) δ
7.27−7.12 (m, 50H), 4.52 (d, J = 11.7 Hz, 2H), 4.47 (d, J = 12.3 Hz,
2H), 4.42 (d, J = 12.3 Hz, 2H), 4.36 (d, J = 11.7 Hz, 2H), 4.04−3.95
(m, 2H), 3.93−3.83 (m, 2H), 3.36 (dd, J = 10.0, 4.9 Hz, 2H), 3.30
(dd, J = 10.0, 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 144.1.
138.92, 138.9, 128.7, 128.12, 128.1, 127.7, 127.6, 127.5, 127.2, 127.1,
126.9, 86.8, 79.0, 78.6, 73.5, 72.6, 63.9; FT-IR (neat) 3060, 2934,
2889, 1066 cm−1; MS (ESI) 1049.5; HRMS (ESI) m/z: [M + Na]+
calcd for C72H66O6Na: 1049.4698; found 1049.4716.
(2S,3S,4R,5R,6R)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexanone
2,3,4,5-Tetrakis-O-benzyl-D-galactitol (23).33 To a solution of 22
(0.50 g, 0.48 mmol) in toluene (30 mL) at 100 °C was slowly added
MeOH (10 mL) and then TFA (1.0 mL), and the mixture was heated
under reflux for 6 h. The mixture was cooled to room temperature,
poured onto a saturated solution of NaHCO3 (20 mL), and stirred for
15 min. The organic phase was collected, and the aqueous phase was
extracted again with toluene. The combined organic extracts were
concentrated under reduced pressure, and the residue was purified by
flash chromatography (2:3 to 1:1 EtOAc/hexane) affording 23 as a
(32). Purified by column chromatography (9:1 EtOAc/hexanes) to
32
1
give a colorless syrup (115 mg, 62%); [α]D 30.0 (c 7.1, DCM); H
NMR (600 MHz, CDCl3) δ 4.44 (d, J = 9.7 Hz, 1H, H6), 4.30 (dd, J =
3.5, 1.5 Hz, 1H, H2), 4.00 (dd, J = 4.1, 3.5 Hz, 1H, H3), 3.89 (dd, J =
4.1, 2.9 Hz, 1H, H4), 3.60 (s, 3H), 3.56 (s, 3H), 3.50 (s, 3H), 3.46 (s,
3H), 3.41 (dd, J = 9.7, 2.9 Hz, 1H, H5); 13C NMR (150 MHz, CDCl3)
δ 204.7 (C1), 84.4 (C5), 82.8 (C2), 79.3 (C3), 76.2 (C6), 75.8 (C4),
60.0, 59.9, 59.2, 58.9; FT-IR (neat) 3472, 2934, 2833, 1734 cm−1; MS
(ESI) m/z 257 ([M + Na]+); HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C10H18O6Na 257.1001; found 257.0995.
1
white powder (201 mg, 77%); H NMR (300 MHz, CDCl3) δ 7.44−
(2S,3S,4S,5S,6R)-6-Acetoxy-2,3,4,5-tetramethoxycyclohexanone
7.17 (m, 20 H) 4.81−4.63 (m, 8 H) 4.03−3.96 (m, 2H) 3.92−3.74
(m, 6H), 2.54 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 138.5, 138.4,
128.4, 128.4, 127.9, 127.9, 127.7, 80.3, 80.1, 74.3, 72.8, 66.5; (ESI-
MS): m/z 565 [M + Na]+.
30
(33). Crystalline solid (35 mg, 99%); mp 67−70 °C; [α]D 6.1 (c
0.33, DCM); 1H NMR (600 MHz, CDCl3) δ 5.46 (br d, J = 10.6 Hz,
1H, H6), 4.27 (dd, J = 3.2, 0.9 Hz, 1H, H2), 3.95 (dd, J = 4.1, 3.2 Hz,
1H, H3), 3.91 (dd, J = 4.1, 2.9 Hz, 1H, H4), 3.69 (dd, J = 10.6, 2.9 Hz,
1H, H5), 3.60 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 3.45 (s, 3H), 2.18 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 198.2 (C1), 169.9 (CO2), 83.1
(C2), 80.8 (C5), 79.1 (C3), 77.4 (C6), 75.9 (C4), 60.0, 59.9, 59.3,
59.0, 20.7 (CH3); FT-IR (neat) 2922, 2838, 1750, 1728 cm−1; MS
(ESI) m/z 299 [M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C12H20O7Na 299.1107; found 299.1100.
2,3,4,5-Tetra-O-benzyl-D-galacto-hexodialdose (26). Pale yellow
oil, (1.07 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.66 (s, 2H), 7.40−
7.10 (m, 20H), 4.66 (br d, J = 11.8 Hz, 2H), 4.49 (d, J = 11.8 Hz, 2H),
4.47 (d, J = 11.4 Hz, 2H), 4.34 (br d, J = 11.4 Hz, 2H), 4.16−4.10 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 201.6, 137.0 (2C), 128.3, 128.2,
128.1, 128.1, 127.8, 127.7, 83.3, 78.3, 73.6, 73.2; FT-IR (neat) 3027,
2907, 2872, 1731, 1026 cm−1.
(2R,3S,4R,5R,6S)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexa-
none (34). Purified by column chromatography (3:7 EtOAc/hexane
then 1:19 MeOH/toluene) to give a white solid (232 mg, 14%); mp
General Procedure for NHC-Mediated Carbocylizations of
Dialdehydes. To a suspension of precatalyst 1 (0.20 equiv) in DCE
(5 mL) under N2 was added a solution of Et3N in DCE (1.00 M, 0.15
equiv), and the mixture was stirred for 10 min. A solution of
dialdehyde (1 equiv) in DCE (50 mL/g) was then added, and the
mixture was maintained at 25−60 °C as specified in Tables 1 and 2 for
16−40 h. The solvent was removed under reduced pressure, and the
residue was taken up in a minimal volume of DCM, filtered through a
bed of silica, and washed through with 1:1 EtOAc/hexane (ca. 20 mL)
for reactions of 10, 18, and 26 or neat EtOAc for 11, 19, and 27. The
products were further purified as specified.
27
129−131 °C; [α]D −6.7 (c 1.8, DCM); 1H NMR (600 MHz,
CDCl3) δ 7.52−7.12 (m, 20H), 4.93 (d, J = 11.7 Hz, 1H), 4.90 (d, J =
10.6 Hz, 1H), 4.88 (d, J = 11.6 Hz, 1H), 4.86 (d, J = 10.6 Hz, 1H),
4.73 (d, J = 11.7 Hz, 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.7
Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.20−4.16 (m, 2H), 4.14 (dd, J =
2.3, 2.3 Hz, 1H), 4.12 (dd, J = 8.8, 1.2 Hz, 1H), 3.80 (dd, J = 9.4, 2.3
Hz, 1H), 3.41 (d, J = 6.4 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
204.2, 138.4, 138.0, 137.9, 137.3, 128.5, 128.4, 128.3, 128.2, 128.14,
128.1, 127.93, 127.9, 127.7 (2C), 127.69, 127.6, 83.6, 82.5, 79.8, 77.9,
76.1, 74.9, 74.7, 73.6, 73.2; FT-IR (neat) 3430, 3030, 2867, 1734
cm−1; MS (ESI) m/z 561 [M + Na]+, 577.2 [M + K]+; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C34H34O6Na 561.2253; found
561.2247.
(2S,3S,4R,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexa-
none (30). Purified by column chromatography (3:7 EtOAc/hexanes)
30
to give a light yellow syrup (550 mg, 54%); [α]D −35.6 (c 5.9,
DCM); 1H NMR (300 MHz, CDCl3) δ 7.57−6.96 (m, 20H), 4.86 (d,
J = 11.7 Hz, 1H), 4.85 (d, J = 12.3 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H),
4.68 (d, J = 12.3 Hz, 1H), 4.63−4.55 (m, 3H, H2 and H6), 4.48 (d, J =
11.7 Hz, 1H), 4.44 (d, J = 12.3 Hz, 1H), 4.40 (d, J = 12.3 Hz, 1H),
3.95 (dd, J = 3.8, 3.8 Hz, 1H, H3), 3.82−3.72 (m, 2H, H4 and H5),
3.53 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 205.1, 138.5, 137.9,
137.8, 137.6, 128.6, 128.5, 128.45, 128.4, 128.38, 127.9, 127.89, 127.8,
127.7, 82.5, 80.5, 77.9, 76.6, 75.2, 73.8, 73.6, 73.5, 72.7 (3 masked aryl
(2S,3S,4R,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-hydroxycyclohexa-
none (35). Purified by column chromatography (3:7 EtOAc/hexane
and 1:19 MeOH/toluene) to give a light yellow syrup (463 mg, 27%);
28
1
[α]D −40.4 (c 0.6, DCM); H NMR (600 MHz, CDCl3) δ 7.50−
7.20 (m, 18H), 7.12−7.06 (m, 2H), 4.88 (d, J = 11.7 Hz, 1H), 4.73 (d,
J = 12.3 Hz, 1H), 4.58−4.54 (m, 4H) 4.48−4.43 (m, 2H), 4.39 (d, J =
5094
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The Journal of Organic Chemistry
Article
12.3 Hz, 1H), 4.36 (d, J = 12.3 Hz, 1H), 4.25−4.20 (m, 1H), 4.18−
4.13 (m, 1H), 3.80 (dd, J = 2.8, 2.8 Hz, 1H), 3.36 (br s, 1H); 13C
NMR (75 MHz, CDCl3) δ 205.4, 138.0, 137.71, 137.7, 137.0, 128.5,
128.4, 128.3, 128.2, 128.0, 127.79, 127.75, 127.7, 127.6, 127.5, 82.2,
81.3, 80.3, 74.3, 73.6, 73.2, 73.0, 72.7, 72.3 (2 masked aryl C); FT-IR
(neat) 3429, 3030, 2871, 1731, 1069, 1026 cm−1; MS (ESI) m/z 561
[M + Na]+; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C34H34O6Na 561.2253; found 561.2261.
3H), 3.54 (s, 3H), 3.43 (s, 3H), 3.42 (dd, J = 9.1, 8.5 Hz, 1H, H5),
3.33 (s, 3H); 13C NMR (CDCl3, 150 MHz) 206.6 (C1), 84.7 (C5),
81.1 (C2), 80.3 (C4), 77.6 (C3), 76.1 (C6), 60.7, 59.0, 59.0, 58.2; FT-
IR (DCM solution) 3492, 2941 2841, 1746, 1103 cm−1; MS (ESI) 257
[M + Na]+; HRMS (ESI) m/z: [M + Na]+ calcd for C10H18O6Na
257.1001; found 257.0997.
( )-(2R,3S,4R,5S,6S)-6-Acetoxy-2,3,4,5-tetramethoxycyclohexa-
none (42). Colorless syrup (33 mg, 56%); 1H NMR (600 MHz,
CDCl3) δ 5.53 (dd, J = 3.1, 0.9 Hz, 1H, H6), 4.14 (br d, J = 10.0 Hz,
1H, H2), 3.94 (dd, J = 3.8, 3.2 Hz, 1H, H5), 3.89 (dd, J = 3.8, 3.2 Hz,
1H, H4), 3.59 (s, 3H), 3.57 (dd, J = 10.0, 3.2 Hz, 1H, H3), 3.53 (s,
3H), 3.52 (s, 3H), 3.46 (s, 3H), 2.20 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 198.5 (C1), 169.8 (CO2), 85.2 (C5), 82.1 (C3), 78.2 (C5),
76.3 (C4), 75.9 (C6), 59.8, 59.72, 59.7 (2 × C), 20.7; FT-IR (neat)
2935, 2834, 1741, 1229, 1113, 1089, 1070, 1052 cm−1; MS (ESI) 299
[M + Na]+; HRMS (ESI) m/z: calcd for C12H20O7Na [M + Na]+:
299.1107; found 299.1105.
(2R,3S,4S,5S,6S)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)-
24
cyclohexanone (36). Colorless syrup (13 mg, 81%); [α]D −15.0 (c
1
0.53, EtOH); H NMR (600 MHz, CDCl3) δ 7.44−7.17 (m, 20H),
5.15 (d, J = 1.8 Hz, 1H, H6), 4.93 (d, J = 11.1 Hz, 1H), 4.90 (d, J =
10.5 Hz, 1 H), 4.84 (d, J = 10.5 Hz, 1H), 4.81 (d, J = 12.1 Hz, 1H),
4.78 (d, J = 12.1 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.7
Hz, 1H), 4.55 (d, J = 11.1 Hz, 1H), 4.20 (dd, J = 9.1, 9.1 Hz, 1H, H3),
4.12 (dd, J = 2.3, 1.8 Hz, 1H, H5), 4.11 (br d, J = 9.1 Hz, 1H, H2),
3.84 (dd, J = 9.1, 2.3 Hz, 1H, H4), 2.17 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 197.6 (C1), 169.8 (CO2), 138.4, 137.8, 137.75, 137.5, 128.5,
128.4, 128.3, 128.2, 128.19, 128.1, 128.0, 127.9, 127.85, 127.7, 127.66,
127.6, 83.9 (C2), 82.1 (C3), 80.0 (C4), 76.1, 75.8 (C6), 75.2 (C5),
74.1, 73.7, 73.2, 20.6; FT-IR (neat) 3030, 2921, 2864, 1758, 1739,
1095, 1074, 1025 cm−1; MS (ESI) m/z 581 [M + H]+, 603.2; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C36H36O7Na 603.2359; found
603.2341.
allo-Inositol (54).43 To a solution of hydroxyketone 30 (50 mg, 93
μmol) in EtOH (2 mL) was added NaBH4 (7 mg, 0.19 mmol), and
the mixture was heated under reflux for 1 h. The solvent was removed
under reduced pressure, and the residue was filtered through a plug of
silica eluting with EtOAc. Following concentration, the residue was
purified by column chromatography (50% EtOAc/hexanes), and the
main fraction (Rf = 0.4) was collected. The purified diol was taken up
in EtOH (2 mL), PdCl2 (1 mg) was added, and the heterogeneous
mixture was stirred under an atmosphere of H2 for 16 h. The mixture
was then filtered through Celite and washed through with a small
portion of H2O. Removal of solvents gave the title compound as a
crystalline solid (13 mg, 81%); mp 280 °C (dec); lit.44 270−280 °C
(2S,3S,4S,5R,6R)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)-
34
cyclohexanone (37). Yellow syrup (13 mg, 40%); [α]D −25.0 (c
1
0.60, EtOH); H NMR (600 MHz, CDCl3) δ 7.40−7.22 (m, 18H),
7.10−7.06 (m, 2H), 5.48 (d, J = 4.7 Hz, 1H, H6), 4.92 (d, J = 11.7 Hz,
1H), 4.75 (d, J = 12.3 Hz, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.54 (d, J =
12.3 Hz, 1H), 4.54 (d, J = 12.5 Hz, 1H), 4.48 (br d, J = 4.1 Hz, 1H,
H2), 4.38 (d, J = 11.0 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.22−4.19
(m, 1H, H3), 4.18−4.15 (m, 1H, H5), 3.83 (dd, J = 2.9, 2.9 Hz, 1H,
H4), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.9 (C1), 170.0,
138.2, 137.8, 137.7,136.9, 128.6, 128.4, 128.24, 128.2, 127.9 (2 × C),
127.83, 127.8, 127.7, 127.6, 127.5, 80.9 (C3), 80.5 (C2), 80.2 (C5),
75.4 (C6), 73.5, 73.3 (C4), 73.0, 72.7, 72.5, 20.7 (1 masked aryl C);
FT-IR (neat) 3030, 2925, 2869, 1761, 1740, 1065, 1026 cm−1; MS
(ESI) m/z 581 [M + H]+, 603 [M + Na]+; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C36H36O7Na 603.2359; found 603.2369.
1
(dec); H NMR (300 MHz, D2O) δ 4.05−3.95 (m, 4H) 3.93−3.85
(m, 2H); FT-IR (neat) 3348 br, 2919 cm−1; MS (ESI) 203 [M + Na]+.
epi-Inositol (56).45 A solution of hydroxyketone 34 (65 mg, 0.12
mmol) in EtOH (2 mL) was treated with NaBH4 (8 mg, 0.21 mmol)
as per 30 to yield a crystalline solid (17 mg, 78%); mp 280 °C (dec.)
lit.46 305 °C; H NMR (300 MHz, D2O) δ 4.06 (dd, J = 3.1, 2.8 Hz,
1
2H), 3.83 (t, J = 9.9 Hz, 1H), 3.72 (t, J = 3.1 Hz, 1H), 3.47 (dd, J =
9.9, 2.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 75.1, 72.4, 70.6, 67.4;
FT-IR (neat) 3447, 3372, 3285, 3234, 2912 cm−1; MS (ESI) 203 [M +
Na]+.
( )-(2R,3S,4R,5S,6S)-6-Acetoxy-2,3,4,5-tetrakis(benzyloxy)-
cyclohexanone (39). Colorless oil (14 mg, 17% from dialdehyde 26);
1H NMR (600 MHz, CDCl3) δ 7.45−7.41 (m, 2H), 7.34−7.22 (m,
ASSOCIATED CONTENT
■
S
* Supporting Information
16H), 7.11−7.06 (m, 2H), 5.61 (d, J = 2.6 Hz, 1H, H6), 4.92 (d, J =
11.3 Hz, 1H), 4.83 (d, J = 11.9 Hz, 1H), 4.83 (d, J = 12.0 Hz, 1H),
4.62 (d, J = 11.9 Hz, 1H), 4.58 (d, J = 10 Hz, 1H, H2), 4.57 (d, J =
11.3 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H),
4.34 (d, J = 11.9 Hz, 1H), 3.98 (dd, J = 10.0, 2.9 Hz, 1H, H3), 3.91
(dd, J = 3.8, 2.6 Hz, 1H, H5), 3.84 (dd, J = 3.8, 2.9 Hz, 1H, H4), 2.19
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 198.8 (C1), 169.8 (CO2),
138.3, 137.9, 137.6, 137.3, 128.5, 128.4, 128.3, 128.29, 128.05, 128.0,
127.95, 127.92, 127.9, 127.71, 127.67, 127.66, 83.6 (C2), 80.4 (C3),
76.7 (C5), 75.9 (C6), 74.7 (C4), 74.2, 73.9, 73.8, 73.4, 20.7; FT-IR
(neat) 3030, 2869, 1741 (br), 1227, 1103, 1043, 1026 cm−1; MS (ESI)
m/z 603 [M + Na]+, 619 [M + K]+; HRMS (ESI) m/z: [M + Na]+
calcd for C36H36O7Na 603.2332; found 603.2337.
( )-(2R,3S,4S,5R,6S)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexa-
none (40). Purified by column chromatography (9:1 EtOAc/hexane)
to give a colorless syrup (76 mg, 60%); 1H NMR (600 MHz, CDCl3)
δ 4.53 (dd, J = 3.9, 0.9 Hz, 1H, H6), 4.14 (dd, J = 9.7, 0.9 Hz, 1H,
H2), 3.91 (dd, J = 3.9, 3.5 Hz, 1H, H5), 3.87 (dd, J = 3.5, 3.2 Hz, 1H,
H4), 3.57 (s, 3H), 3.52 (dd, J = 9.7, 3.2 Hz, 1H, H3), 3.52 (s, 3H),
3.51 (s, 3H), 3.43 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 205.3
(C1), 85.0 (C2), 82.6 (C3), 79.6 (C5), 76.1 (C4), 74.3 (C6), 60.1,
59.7, 59.64, 59.6; FT-IR (neat) 3459, 2932, 2832, 1736, 1111, 1092,
1062 cm−1; MS (ESI) 257 [M + Na]+; HRMS (ESI) m/z: [M + Na]+
calcd for C10H18O6Na 257.1001; found 257.0995.
1H, 13C, and selected 2D NMR data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ben.greatrex@une.edu.au.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.S. would like to thank the Australian Government for an APA
award, and we thank the University of New England for an
internal research grant.
REFERENCES
■
(1) Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455.
(2) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779.
(3) Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett. 2007, 48,
6267.
(4) Amano, S.; Ogawa, N.; Ohtsuka, M.; Chida, N. Chem. Commun.
1998, 1263.
( )−(2R,3S,4S,5R,6R)-6-Hydroxy-2,3,4,5-tetramethoxycyclohexa-
none (41). Colorless syrup (5 mg, 5%); 1H NMR (600 MHz, CDCl3)
δ 4.44 (d, J = 8.5 Hz, 1H, H6), 3.84 (d, J = 4.4 Hz, 1H, H2), 3.82 (dd,
J = 4.4, 2.6 Hz, 1H, H3), 3.77 (dd, J = 9.1, 2.6 Hz, 1H, H4), 3.63 (s,
(5) Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443.
(6) Enholm, E. J.; Trivellas, A. J. Am. Chem. Soc. 1989, 111, 6463.
5095
dx.doi.org/10.1021/jo500645z | J. Org. Chem. 2014, 79, 5088−5096

The Journal of Organic Chemistry
Article
(7) Guidot, J.; Le Gall, T.; Mioskowski, C. Tetrahedron Lett. 1994, 35,
6671.
(46) Simperler, A.; Watt, S. W.; Bonnet, P. A.; Jones, W.; Motherwell,
W. S. CrystEngComm 2006, 8, 589.
(8) Wilcox, C. S.; Thomasco, L. M. J. Org. Chem. 1985, 50, 546.
(9) Arjona, O.; Gomez, A. M.; Lop
2007, 107, 1919.
́
ez, J. C.; Plumet, J. Chem. Rev.
(10) Marion, N.; Díez-Gonzal
Ed. 2007, 46, 2988.
́
ez, S.; Nolan, S. P. Angew. Chem., Int.
(11) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(12) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606.
(13) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786.
(14) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.;
Hedrick, J. L. Org. Lett. 2002, 4, 3587.
(15) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.
(16) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta
1996, 79, 1899.
(17) Enders, D.; Henseler, A. Adv. Synth. Catal. 2009, 351, 1749.
(18) Rose, C. A.; Gundala, S.; Fagan, C.-L.; Franz, J. F.; Connon, S.
J.; Zeitler, K. Chem. Sci. 2012, 3, 735.
(19) Xu, L.-W.; Gao, Y.; Yin, J.-J.; Li, L.; Xia, C.-G. Tetrahedron Lett.
2005, 46, 5317.
(20) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418.
(21) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518.
(22) Vora, H. U.; Lathrop, S. P.; Reynolds, N. T.; Kerr, M. S.; De
Alaniz, J. R.; Rovis, T.; Chennamadhavuni, S.; Davies, H. M. L. Org.
Synth. 2010, 87, 350.
(23) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125,
8432.
(24) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett.
2009, 11, 4866.
(25) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed.
2006, 118, 1491.
(26) Wendeborn, S.; Mondier
2012, 541.
̀
e, R.; Keller, I.; Nussbaumer, H. Synlett
(27) Vedachalam, S.; Tan, S. M.; Teo, H. P.; Cai, S.; Liu, X.-W. Org.
Lett. 2011, 14, 174.
(28) Piccariello, T.; Samanaryke, G. Method for the Production of D-
Chiroinositol. U.S. Patent 5516950, February 14, 1996.
(29) Piccariello, T. Method for the Production of D-Chiroinositol.
U.S. Patent 5406005, April 11, 1995.
(30) Irvine, R. F.; Schell, M. J. Nat. Rev. Mol. Cell Biol. 2001, 2, 327.
(31) Metzke, M.; Guan, Z. Biomacromolecules 2008, 9, 208.
(32) Metzke, M.; Bai, J. Z.; Guan, Z. J. Am. Chem. Soc. 2003, 125,
7760.
(33) Ackermann, L.; El Tom, D.; Furstner, A. Tetrahedron 2000, 56,
̈
2195.
(34) Gallos, J. K.; Koftis, T. V.; Karamitrou, V. I.; Koumbis, A. E. J.
Chem. Soc., Perkin Trans. 1 1997, 2461.
(35) Mabiala-Bassiloua, C.-G.; Zwolinska, M.; Therisod, H.; Sygusch,
J.; Therisod, M. Bioorg. Med. Chem. Lett. 2008, 18, 1735.
(36) Ward, D. E.; Liu, Y.; Rhee, C. K. Can. J. Chem. 1994, 72, 1429.
(37) Sternhell, S. Quart. Rev. Chem. Soc. 1969, 23, 236.
(38) Abraham, R. J.; Byrne, J. J.; Griffiths, L.; Koniotou, R. Magn.
Reson. Chem. 2005, 43, 611.
(39) Jagdhane, R. C.; Patil, M. T.; Krishnaswamy, S.; Shashidhar, M.
S. Tetrahedron 2013, 69, 5144.
(40) Senda, Y. Chirality 2002, 14, 110.
(41) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
(42) Armarego, W.; Perrin, D. Purification of Laboratory Chemicals,
4th ed.; Butterworth-Heinemann: Oxford, U.K., 1996.
(43) Mandel, M.; Hudlicky, T. J. Chem. Soc., Perkin Trans. 1 1993,
741.
(44) Desjardins, M.; Brammer, L. E.; Hudlicky, T. Carb. Res. 1997,
304, 39.
(45) Dorman, D. E.; Angyal, S.; Roberts, J. D. J. Am. Chem. Soc. 1970,
92, 1351.
5096
dx.doi.org/10.1021/jo500645z | J. Org. Chem. 2014, 79, 5088−5096