N-heterocyclic carbene-catalyzed benzoin strategy for divergent synthesis of cyclitol derivatives from alditols

Article abstract of DOI:10.1002/adsc.201400712

A divergent synthesis of cyclitol derivatives has been developed utilizing an N-heterocyclic carbene-catalyzed benzoin-type cyclization of C₂-symmetrical dialdoses. The resulting inososes are versatile intermediates, which are readily converted

Full text of DOI:10.1002/adsc.201400712

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DOI: 10.1002/adsc.201400712
N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for
Divergent Synthesis of Cyclitol Derivatives from Alditols
Bubwoong Kang,a Toshiaki Sutou,a Yinli Wang,a Satoru Kuwano,a
Yousuke Yamaoka,a Kiyosei Takasu,a,* and Ken-ichi Yamadaa,*
a
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Phone: (+81)-(0)75-753-4573
E-mail: kay-t@pharm.kyoto-u.ac.jp or yamak@pharm.kyoto-u.ac.jp
Received: July 22, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400712.
Abstract: A divergent synthesis of cyclitol deriva- not only inositols but also amino-, deoxy-, O-methyl-
tives has been developed utilizing an N-heterocyclic and C-methyl-inositols.
carbene-catalyzed benzoin-type cyclization of C2-
symmetrical dialdoses. The resulting inososes are ver- Keywords: benzoin reaction; cyclitol derivatives; N-
satile intermediates, which are readily converted into heterocyclic carbenes
Introduction
lecular benzoin-type cyclization of dialdose should
provide a new divergent access to a variety of cyclitol
Cyclitols, which are poly-hydroxylated cycloalkanes, derivatives.
have attracted attention, especially as building blocks
Our strategy is based on the availability of various
for natural product synthesis.[1] In addition, interesting dialdoses 1 and the versatility of inososes 2 as a syn-
bioactivities of cyclitols have recently been reported.[2] thetic intermediate (Scheme 1). Benzoin-type cycliza-
Despite the utilities, cyclitols are not readily available tion of 1, which is available from the corresponding
in nature. Hence, many synthetic methods have been alditols, should give 2. Stereoselective reduction of 2
developed.[3] In addition to fermentative approaches,[4] affords cyclitols 3 and epi-3. Moreover, other deriva-
various reactions have been applied to make cycloal- tives, such as amino-, deoxy-, and O-methyl- and C-
kanes from oxygenated carbon chains, including Ferri- methylcyclitols 4, 5, 6, and 7 should also be available
er carbocyclization,[5] cyclization of malonates,[6] nitro- from 2. Herein, we report the syntheses of cyclitol de-
nate,[7] enolate,[8] or a,a-dithio carbanion,[9] Mukaiya-
ma aldol reactions,[10] Horner–Wadsworth–Emmons
reactions,[11] pinacol coupling,[12] ring-closing metathe-
sis,[13] cycloaddition,[14] and Claisen rearrangement.[15]
The benzoin condensation, which occurs between
two molecules of aldehydes to give a-hydroxy ke-
tones,[16] is a well-known N-heterocyclic carbene
(NHC)-catalyzed reaction.[17,18] Because the products
are simple homo-dimeric compounds, the original re-
action has a limited utility. Therefore, efforts have
been made to develop so-called cross-benzoin reac-
tions. In particular, an intramolecular cross-benzoin
reaction between aldehydes and ketones[19] has been
utilized for natural product synthesis.[20] In contrast,
an intramolecular benzoin reaction of dialdehydes has
been less explored,[21] probably due to difficulty in
controlling chemoselectivity[22] and the lack of atten-
tion to products derived from simple symmetrical dia-
Scheme 1. Divergent strategy for cyclitol derivatives via
ldehydes.[19c,21] However, we expected that an intramo- NHC-catalyzed benzoin-type cyclization.
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Bubwoong Kang et al.
rivatives based on this strategy using C2-symmetrical
dialdoses.[23]
Results and Discussion
NHC-Catalyzed Benzoin-Type Cyclization of C2-
Symmetric Dialdoses to give Inososes
First, tetrabenzyl dialdose 1a, which was prepared
from d-mannitol, was subjected to an NHC-catalyzed
benzoin-type cyclization reaction (Table 1). A THF
solution of 1a was added to a solution of thiazolium
salt 8[24] (Figure 1; 25 mol%) and DBU (20 mol%) in
THF. After stirring at room temperature for 4 h, TLC
monitoring indicated that 1a was completely con-
Figure 2. Determination of the stereochemistry of inososes.
sumed, and allo-2-inosose 2a was produced as a single between the carbinol and the adjacent methine pro-
diastereomer in 19% yield after purification by silica tons (H-5 and H-6; Figure 2).
gel column chromatography (entry 1).[25] The stereo-
Use of triazolium salt 9a[27] or 9b[28] instead of 8
chemistry of the newly formed hydroxy group was de- gave a complex mixture, and 2a was not obtained (en-
termined by the trans-diaxial coupling (J=9.5 Hz)[26] tries 2 and 3). Because several formyl protons were
1
observed in the H NMR spectra of the crude mix-
tures, it is speculated that aldol-type side reactions
Table 1. Optimization of the reaction conditions for 1a.[a]
occur due to the basicity of the utilized NHCs. Using
more acidic triazolium salt 9c[27] with a pentafluoro-
phenyl group suppressed the side reactions, and 2a
was obtained in 58% yield after 10 h (entry 4).
To our delight, using chiral triazolium salt 10[27]
drastically accelerated the reaction, which was com-
pleted after 2.5 h even with a lower catalyst loading
Entry NHC·HX
Solvent Time [h] Yield [%][b]
(10 mol%) and an improved yield of 2a (78%;
entry 5). Interestingly, when the antipode of 10 was
used as a catalyst, the reaction did not proceed, and
1a was recovered quantitatively after 24 h (entry 6).
Other solvents were tested for the reaction using
5 mol% of 10. In acetonitrile, the reaction proceeded
more cleanly, and 2a was obtained in a higher yield
(83% after 12 h; entry 8) than that in THF (39% after
24 h; entry 7). The reaction was much faster in di-
chloromethane, and 2a was obtained in 81% yield
after 30 min (entry 9). Among the tested solvents, tol-
uene gave the best results (88% yield after 45 min;
entry 10). It is noteworthy that the reaction with 6.0 g
1a proceeded without problems to give 5.4 g 2a
(entry 11).
Next, the reaction was conducted with another C2-
symmetrical dialdose 1b, which was derived from l-
iditol (Scheme 2). Although the reaction with 9c gave
2b in a moderate yield along with unidentified by-
products, the reaction with ent-10 (10 mol%) afforded
myo-inosose 2b as a single diastereomer in 86% yield.
In contrast to the reaction with 1a, which has the op-
posite stereochemistry at the a-positions, 1b and 10
had a mismatched stereochemistry, giving 2b in 58%
yield after 24 h along with 27% recovery of 1b. The
stereochemistry of 2b was determined based on the
coupling constant similar to that of 2a (Figure 2).
1
2
3
4
5
6
7
8
8 25 mol%[c]
9a 25 mol%
9b 25 mol%[c]
9c 25 mol%
10 10 mol%
THF
THF
THF
THF
THF
4
19
<1
<1
58
24
24
10
2.5
24
24
12
78
ent-10 25 mol% THF
0 (quant)
39 (11)
83
81
88
10 5 mol%
10 5 mol%
10 5 mol%
10 5 mol%
10 5 mol%
THF
MeCN
CH2Cl2 0.5
toluene 0.75
toluene
9
10
11[d]
1
90
[a]
20 mol% of Et3N was used in entries 1–4 and 6, while the
same amount of Et3N as NHC·HX was used in entries 5
and 7–11.
1a was completely consumed unless the recovery yield is
presented in parentheses.
DBU was used instead of Et3N.
6.0 g of 1a (11 mmol) were used.
[b]
[c]
[d]
Figure 1. Structures of the NHC precursors.
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N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
would occur from the hindered face of the enamine
moiety. This model contradicts Houkꢁs model, where
a Breslow intermediate derived from N-phenyltriazo-
lylidene prefers the E-geometry in the transition state
of a benzoin reaction.[29] Recently, however, Rovisꢁ
group also reported evidence of the Z-preference for
a Breslow intermediate derived from N-pentafluoro-
phenyltriazolylidene.[30] The preferred geometry of
Breslow intermediates likely depends on the nitrogen-
substituent of the NHC.
Scheme 2. Reaction with 1b.
The above speculation led us to envision that
changing the protective groups would alter the stereo-
chemistry in the cyclization (Scheme 4). If the 3- and
4-hydroxy groups are protected as an acetonide as
shown in 11, the reaction should proceed via chair
conformation B or C. In B, there are one repulsive
1,3-diaxial interaction and one non-minimum A1,3
strain, while C has two repulsive 1,3-diaxial interac-
tions and an unfavorable bisect allylic conformation.
If B is more stable than C, then inosose 12 with a hy-
droxy group in the S-configuration should be pro-
duced.
Scheme 3. Rationale for the stereochemical outcomes of the
reaction with 1a or 1b (ent-1b is depicted for clarity).
Thus, the reaction was performed with dialdose
11a, which has TIPSO groups at the 2- and 5-positions
with acetonide as a protective group for the 3- and 4-
The observed stereoselectivity in the benzoin-type hydroxy groups. As expected, with 9c as an NHC pre-
cyclization of dialdoses 1a and 1b can be explained as cursor, 12a was formed preferentially over epi-12a
follows (Scheme 3; for simplicity, ent-1b and 10 are (74:26), and 12a and epi-12a were produced in 53%
considered instead of 1b and ent-10). Breslow inter- combined yield (Table 2, entry 3). With 10 or ent-10,
mediate A,[18] which is generated from 10 and di- the reaction was much slower, giving an almost 1:1
ACHTUNGTRENNUNGaldose 1a or ent-1b, undergoes cyclization through the mixture of 12a and epi-12a in 13 and 7% combined
chair conformation, where the benzyloxy group next yield, respectively (entries 1 and 2). This is probably
to the nucleophilic enamine carbon is in the equatori- because the bulky NHCs enforce the A1,3 strain in
al position to minimize A1,3 strain. The nucleophilic transition state B as well as the 1,3-diaxial interaction
attack then occurs from the si-face of the aldehyde in C (Scheme 4).
moiety, which leads to hydrogen bonding between the
carbonyl and the hydroxy group, resulting in the R- significantly influence the selectivity. The product
configuration in the newly formed stereochemistry. ratio was reduced to 57:43 in the reaction with 11b,
The axially oriented substituents at the 2,5-positions
The observed stereochemical outcome and match– which has less bulky benzyloxy groups (entry 4),
mismatch with 10 and ent-10 likely indicate that the while 12c was produced with perfect selectivity
reaction better proceeds through the Breslow inter- (>99:1) when the reaction was conducted using 11c,
mediate with the Z-geometry; otherwise the reaction which bears more bulky TBDPSO groups (entry 5).
Scheme 4. Transition states B and C leading to 12 and epi-12, respectively.
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Table 2. Reactions of 11a–c protected with acetonide.
Entry
11
R
NHC·HX
12
Yield [%][a]
Ratio 12:epi-12[b]
1
2
3
4
5
6
11a
11a
11a
11b
11c
11c
TIPS
TIPS
TIPS
Bn
TBDPS
TBDPS
10
ent-10
9c
12a
12a
12a
12b
12c
12c
13 (61)
7 (47)
53 (31)
30 (3)
48:52
49:51
74:26
57:43
>99:1
>99:1
9c
9c
49 (29)
9c[c]
55[d] (4)
[a]
1
Combined yield of 12 and epi-12 determined by H NMR with Ph3CH as an internal standard. Number in parentheses is
the recovery yield of 11.
Determined by H NMR of the crude mixture.
20 mol%.
Isolated yield.
[b]
[c]
[d]
1
This observation indicates that the two 1,3-diaxial re- vestigated (Table 3). Treating 2a with NaBH4 in meth-
pulsions in C are predominant over the A1,3 strain in anol gave allo-insitol derivative allo-3a in 81% yield
B (Scheme 4). Finally, using 20 mol% of 9c, 12c was as a single diastereomer (entry 1). The stereochemis-
obtained in 55% yield as a single diastereomer try was determined by X-ray crystallography. Thus,
(entry 6). The stereochemistry of 12c was determined conditions to produce chiro-3a were examined. Al-
by the NOE experiment (Figure 2).
though neither reduction using NaBH(OAc)3 nor
BH3·THF produced chiro-3a, reduction with
BH3·SMe2 gave chiro-3a as a minor diastereomer
(entry 2). The proportion of chiro-3a in the product
Stereoselective Reduction of Inososes to Give
Inositols
increased to 30% and 56% when BH3·NH3 and t-
[31]
BuNH2·BH3
were used as hydride source, respec-
To selectively obtain allo- and chiro-inositols from 2a, tively (entries 3 and 4).
the conditions for stereoselective reduction were in-
Table 3. Selectivity in the reduction of 2a and 2c–f.[a]
Entry
2
R
HÀ source
Solvent
Yield
dr
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2c
2d
2e
2f
H
H
H
H
NaBH4
BH3·SMe2
BH3·NH3
t-BuNH2·BH3
t-BuNH2·BH3
t-BuNH2·BH3
t-BuNH2·BH3
t-BuNH2·BH3
MeOH
THF
THF
81%[b]
quant
96%
>99:1
92:8
70:30
44:56
33:67
19:81
10:90
16:84
THF
98%
TBDPS
TBDMS
TES
TMS
toluene
toluene
toluene
toluene
93%[b]
96%
87%[c]
88%
[a]
1
Yield and dr (ratio of allo- and chiro-3a) were determined by H NMR using Ph3CH as an internal standard unless other-
wise noted.
Isolated yield.
Isolated yield over two steps from 2a.
[b]
[c]
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N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
Figure 3. Rationale for stereoselectivity in Table 3.
Scheme 6. Stereoselective reduction of 12c.
The observed selectivity can be explained as fol-
lows. Hydride reduction of inososes generally occurs
from the less hindered side,[5f] due to the electronega-
tive substituents of inosose, which enhance the elec- tion from the axial direction was slightly preferred to
trophilicity of the carbonyl group and induce an early give a 75:25 mixture of neo- and allo-13c. This prefer-
transition state. Consequently, steric hindrance be- ence is attributable to the steric hindrance by the
comes a controlling factor. When an amine–borane axial TBDPSO group at the a-position. Reduction
complex is used as a hydride source, its relatively low with t-BuNH2·BH3 after TES protection gave neo-13c
reducing ability causes a later transition state. Conse- with a high diastereoselectivity (neo:allo=96:4).
quently, torsional strain becomes more important
(Figure 3).
Based on the above speculation, the a-hydroxy Synthesis of Other Cyclitol Derivatives and
group of 2a was protected with a bulky silyl group to Deprotection
increase the torsional strain. As expected, the selec-
tivity was further improved to 67–90% (entries 5–8). To show the utility of the inososes 2 as synthetic inter-
The TES group gave the best result, and chiro-3a was mediates, several transformations of 2a were demon-
obtained with a high diastereoselectivity (90:10) in strated (Scheme 7). Amino sugar 4a was obtained
87% yield after treatment with TBAF (entry 7). The along with minor diastereomer epi-4a by LiAlH4/
two epimers were easily separated by silica gel NaOMe reduction of the O-methyl oxime[32] derived
column chromatography.
from 2a. The stereoselectivity of the reduction was re-
A similar selectivity was observed in the reduction versed when the O-acetyl oxime was reduced with
of 2b (Scheme 5). Reduction by NaBH4 occurred NaBH4/NiCl2,[33] and epi-14a was obtained as a sole
preferentially from the equatorial direction to give diastereomer after acetylation. Deoxygenation of 2a
myo-3b with a slightly lower selectivity (98:2) than via thiocarbonate and subsequent reduction of the
that of 2a, probably due to the reduced steric hin- carbonyl group afforded deoxyinositol, talo-quercitol
drance of the axial side. The use of L-selectride af- derivative 5a. The stereochemistries of 4a, epi-4a, and
forded myo-3b as a single diastereomer. Protection 5a were determined after acetylation on the basis of
with a TES group and reduction using t-BuNH2·BH3 the coupling constants (14a, epi-14a, and 15a).
exclusively produced scyllo-3b after protodesilylation.
Treatment of 2a with the Meerwein reagent and
With 12c, BH3·THF was used for the reduction subsequent reduction gave O-methylinositol, epi-d-pi-
from the equatorial direction to give an allo-rich mix- nitol derivative 6a. Reaction of 2a with methyllithium
ture (89:11) of 13c in 93% yield (Scheme 6). In con- provided C-methylinositol 7a as the sole diastereo-
trast, NaBH4 gave the opposite selectivity, and reduc- mer. The stereochemistry of 6a was confirmed by the
coupling constants, while that of 7a was determined
by NOESY after conversion into acetonide 16a.
As reported with allo-3a,[23] the benzyl groups were
easily removed. Hydrogenolysis of 2a and chiro-3a
using Pd/C under a hydrogen atmosphere gave allo-2-
inosose and d-chiro-inositol in 84% and 81% yields,
respectively (Scheme 8). Deprotection of acetonide
neo-13c was reported in the literature.[12c] By analogy,
the other compounds should be deprotected in similar
manners.
Scheme 5. Stereoselective reduction of 2b.
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Bubwoong Kang et al.
BuNH2·BH3 as a hydride source with a-O-TES pro-
tection of inosose is highly effective to overcome the
inherent preference for reduction from the axial di-
rection. The inosose products are versatile intermedi-
ates, which can be converted into various cyclitol de-
rivatives. These results testify to the validity of our
strategy in Scheme 1. Future investigations include
broadening the scope of the methodology to non-C2-
symmetrical dialdoses.
Experimental Section
General Methods
All melting points are uncorrected. NMR (500 and
125 MHz for 1H and 13C, respectively) spectra were mea-
sured in CDCl3 unless otherwise mentioned. Abbreviations
are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. 13C NMR peak multiplicity assignments
were made based on DEPT. Quadrupole, double-focusing
magnetic sector, and TOF mass spectrometers were used for
EI-, FAB-, and ESI-MS, respectively. Silica gel was used for
column chromatography. Reactions were conducted under
argon atmospheres unless otherwise noted.
Materials
Triazoliums 9c, 10, and ent-10 were prepared as reported.[34]
(COCl)2, Et3N, 2,6-lutidine, TMSCl, and CH2Cl2 were pur-
chased and distilled prior to use. Other starting materials,
reagents and solvents were purchased and used as supplied
unless a literature method for the preparation is cited. Com-
mercially available anhydrous solvents were used as reaction
solvents, except that the MeOH and CH2Cl2, DMSO and
pyridine utilized in reactions were anhydrous grade.
Scheme 7. Conversion of 2a into other derivatives.
Conclusions
We have developed a divergent method to synthesize
cyclitol derivatives utilizing NHC-catalyzed benzoin-
type cyclization of C2-symmetrical dialdose. With tet-
rabenzyl-protected dialdose, the key for efficient cyc-
lization is the chiral triazolylidene catalyst. Acetonide
protection at the 3,4-positions inverts the selectivity
in the cyclization of the mannitol-derived dialdose. In
2,3,4,5-Tetra-O-benzyl-d-manno-hexodialdose (1a;
Table 1)
A solution of (COCl)2 (0.25 mL, 2.9 mmol) in CH2Cl2
(1.5 mL+0.5 mL wash) was added to a solution of DMSO
(0.21 mL, 2.9 mmol) in CH2Cl2 (4.5 mL) cooled at À788C.
After 2 min, a solution of 2,3,4,5-tetra-O-benzyl-d-manni-
tol[35] (621 mg, 1.14 mmol) in CH2Cl2 (3 mL+1 mL washꢂ2)
the
stereoselective
reduction,
employing
t-
Scheme 8. Deprotection of the products.
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N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
was added over 5 min. After 1.5 h, Et3N (1.6 mL, 11 mmol)
was added, and the mixture was stirred for additional
10 min before the cooling bath was removed. The mixture
was allowed to warm to room temperature and concentrated
under vacuum. The resulting white solids were suspended in
a 1:1 mixture of pentane and EtOAc (20 mL), filtered, and
washed with the mixed solvent (20 mLꢂ2). The combined
filtrate was concentrated under vacuum to give a 58:28:14
mixture of the title compound, EtOAc, and DMSO as
a pale yellow oil; yield: 682 mg (quant): IR (neat): n=3441,
3062, 3031, 2861, 1728, 1496, 1458, 1373, 1258, 1211, 1096,
30 min. After 1.5 h, Et3N (10 mL, 72 mmol) was added, and
the mixture was stirred for additional 15 min before the
cooling bath was removed. The mixture was allowed to
warm to room temperature and evaporated. The resulting
white solids were suspended in a 1:1 mixture of pentane and
EtOAc (20 mL), filtered, and washed with the mixed solvent
(5 mLꢂ2). The combined filtrate was concentrated under
vacuum to give a mixture of 1a and DMSO as an orange oil.
The oil was dissolved in toluene (240 mL) and added to
a
premixed suspension of triazolium salt 10 (240 mg,
0.51 mmol) and Et3N (80 mL, 0.58 mmol) in toluene
(200 mL). After 1 h, the mixture was evaporated, and the
residue was purified by column chromatography (hexane/
EtOAc 3/1) to give the title compound as a pale yellow oil;
yield: 5.4 g (90%).
1
910, 741, 702, 602, 455, 463 cmÀ1; H NMR: d=4.05 (br s,
2H), 4.12 (br s, 2H), 4.43 (d, J=12.0 Hz, 2H), 4.51 (d, J=
11.0 Hz, 2H), 4.60 (d, J=11.0 Hz, 2H), 4.65 (d, J=12.0 Hz,
2H), 7.20–7.36 (m, 20H) 9.70 (d, J=1.5 Hz, 2H); 13C NMR:
d=72.5 (CH2), 73.7 (CH2), 80.0 (CH), 83.2 (CH), 127.9
(CH), 127.97 (CH), 128.00 (CH), 128.1 (CH), 128.3 (CH),
128.4 (CH), 136.9 (C), 137.1 (C), 201.0 (C); FAB-MS: m/z=
561 (M+Na). This oil was used for the next reaction with-
out further purification.
2,3,4,5-Tetra-O-benzyl-l-ido-hexodialdose (1b;
Scheme 2)
The same procedure as 1a using 2,3,4,5-tetra-O-benzyl-l-
iditol[36] (331 mg, 0.611 mmol) in place of 2,3,4,5-tetra-O-
benzyl-d-mannitol gave a 71:29 mixture of the title com-
1
(2S,3S,4R,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-
hydroxycyclohexanone (2a) (entry 10)
pound, and DMSO as yellow oil; yield: 349 mg (quant.). H
and 13C NMR were identical to those reported.[37] This oil
was used for the next reaction, without further purification.
EtOAc was removed from the above mixture of 1a (174 mg,
0.290 mmol) by evaporation with toluene (5 mLꢂ3), and the
residue was dissolved in toluene (3 mL). To a suspension of
triazolium salt 10 (6.8 mg, 0.015 mmol) in toluene (5.5 mL),
a 1% v/v solution of Et3N in toluene (0.20 mL, 0.015 mmol)
was added, and after 30 min, the above solution of 1a was
added (1.5 mL toluene washꢂ2). After 45 min, the mixture
was concentrated under vacuum, and the residue was puri-
fied by column chromatography (toluene/EtOAc 40/1 to 20/
1) to give the title compound as a colorless oil; yield:
138 mg (88%); [a]2D5: À65.1 (c 1.00, CHCl3): IR (neat): n=
3472, 3032, 2924, 2878, 1736, 1636, 1497, 1458, 1366, 1327,
(2R,3S,4R,5S,6S)-2,3,4,5-Tetrakis(benzyloxy)-6-
hydroxycyclohexanone (2b)
To a suspension of triazolium salt ent-10 (14 mg, 30 mmol) in
toluene (6 mL), a 10% v/v solution of Et3N in toluene
(41 mL, 29 mmol) was added at room temperature. After
30 min, 1b[37] (160 mg, 0.297 mmol) in toluene (3 mL+
1.5 mL washꢂ2) was added. After 18 h, the mixture was
concentrated under vacuum. The residue was purified by
column chromatography (toluene/EtOAc 19/1) to give the
title compound as a white solid; yield: 137 mg (86%); mp
159–1618C (decomp); [a]2D5: +24.4 (c 1.00, CHCl3). IR
1211, 1111, 910, 741, 702, 463 cmÀ1 1H NMR (C6D6): d=
;
3.76 (br s, 1H), 3.86 (dd, J=3.5, 4.0 Hz, 1H), 3.96 (dd, J=
3.0, 9.5 Hz, 1H), 4.02 (t, J=4.0 Hz, 1H), 4.05 (d, J=9.5 Hz,
1H), 4.37 (d, J=12.0 Hz, 1H), 4.43 (d, J=12.0 Hz, 1H),
4.50 (d, J=12.0 Hz, 1H), 4.55 (dd, J=1.5, 3.0 Hz, 1H), 4.76
(br d, J=12.0 Hz, 3H), 4.81 (d, J=11.5 Hz, 1H), 4.95 (d, J=
12.0 Hz, 1H), 7.31–7.34 (m, 4H), 7.27–7.35 (m, 16H);
13C NMR: d=72.6 (CH2), 73.4 (CH2), 73.5 (CH2), 73.7
(CH2), 75.0 (CH), 76.5 (CH), 77.7 (CH), 80.3 (CH), 82.3
(CH), 127.6 (CH), 127.72 (CH), 127.74 (CH), 127.8 (CH),
127.9 (CH), 128.29 (CH), 128.32 (CH), 128.35 (CH), 128.40
(CH), 137.5 (C), 137.7 (C), 137.8 (C), 138.3 (C), 205.1 (C);
EIMS: m/z=538 (M+); HR-MS-FAB (m/z): m/z=561.2249
[M+Na]+, calcd. for C34H34NaO6: 561.2253. The stereo-
chemistry was determined based on the trans-diaxial cou-
pling (J=9.5 Hz) between 5-H and 6-H (3.96 and 4.05 ppm,
respectively) as shown in Figure 2.
1
(KBr): n=3435, 1730 cmÀ1; H NMR: d=3.42 (t, J=9.5 Hz,
1H), 3.47 (d, J=4.5 Hz, 1H), 3.65 (t, J=9.5 Hz, 1H), 3.89
(t, J=9.5 Hz, 1H), 4.30 (dd, J=2.0, 9.5 Hz, 1H), 4.37 (ddd,
J=2.0, 4.5, 9.5 Hz, 1H), 4.58 (d, J=11.5 Hz, 1H), 4.790 (d,
J=11.0 Hz, 1H), 4.794 (d, J=11.0 Hz, 1H), 4.86–4.91 (m,
3H), 4.91 (d, J=11.5 Hz, 1H), 4.96 (d, J=11.0 Hz, 1H),
7.20–7.40 (m, 20H); 13C NMR: d=73.5 (CH2), 75.4 (CH2),
76.1 (CH2), 77.3 (CH), 81.4 (CH), 81.7 (CH), 83.2 (CH),
83.6 (CH), 127.7 (CH), 127.78 (CH), 127.80 (CH), 127.9
(CH), 128.0 (CH), 128.09 (CH), 128.13 (CH), 128.4 (CH),
128.5 (CH), 137.0 (C), 137.9 (C), 138.0 (C), 138.1 (C), 204.1
1
(C). IR, and H and 13C NMR data were in good agreement
with those reported.[38]
3,4-O-Isopropylidene-2,5-bis-O-triisopropylsilyl-d-
manno-hexodialdose (11a; Table 2)
To a solution of DMSO (0.19 mL, 2.3 mmol) in CH2Cl2
(4 mL) cooled at À788C, a solution of (COCl)2 (0.21 mL,
2.5 mmol) in CH2Cl2 (2 mL+1 mL wash) was added. The
resulting mixture was stirred for 2 min before a solution of
3,4-O-isopropylidene-2,5-bis-O-triisopropylsilyl-d-manni-
tol[12c] (535 mg, 1.00 mmol) in CH2Cl2 (3 mL+0.5 mL washꢂ
2) was added over 5 min. After 1.5 h, Et3N (1.4 mL,
10 mmol) was added, and the mixture was stirred for addi-
(2S,3S,4R,5R,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-
hydroxycyclohexanone (2a) (entry 11)
To a solution of DMSO (2.2 mL, 31 mmol) in CH2Cl2
(60 mL) cooled at À788C, a solution of (COCl)2 (2.5 mL,
29 mmol) in CH2Cl2 (20 mL) was added over 20 min. After
2 min, a solution of 2,3,4,5-tetra-O-benzyl-d-mannitol (6.0 g,
11 mmol) in CH2Cl2 (20 mL+10 mL wash) was added over
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tional 10 min. After addition of pentane (20 mL), the cool-
ing bath was removed, and the mixture was allowed to
warm to room temperature. The resulting suspension was fil-
tered, and the filtered solids were washed with a 1:1 mixture
of pentane and EtOAc (20 mLꢂ2). The volume of com-
bined filtrate was reduced to ca. 10 mL by evaporation, and
the resulting suspension was further diluted with pentane
(10 mL). The whole was filtered, and the filtered solids were
washed with the mixed solvent (10 mLꢂ2). The combined
filtrate was concentrated under vacuum to give a 63:30:6
mixture of the title compound, EtOAc, and DMSO as
a yellow oil; yield: 570 mg (98%). IR (neat): n=2943, 2866,
1736, 1466, 1381, 1238, 1219, 1153, 1107, 1072, 1045, 1015,
compound, EtOAc, and DMSO as a pale yellow oil; yield:
1.11 g (98%). IR (neat): n=3071, 3051, 2959, 2932, 2859,
1740, 1474, 1427, 1381, 1234, 1111, 1076, 999, 822, 760,
1
741 cmÀ1; H NMR: d=1.07 (s, 18H), 1.30 (s, 6H), 3.75 (br
s, 2H), 4.27 (br s, 2H), 7.25–7.39 (m, 12H), 7.54–7.60 (m,
8H), 9.25 (s, 2H); 13C NMR: d=14.2 (C), 26.8 (CH3), 76.1
(CH), 78.5 (CH), 110.1 (C), 127.8 (CH), 127.9 (CH), 130.0
(CH), 130.2 (CH), 132.27 (C), 132.28 (C), 135.75 (CH),
135.77 (CH), 202.0 (CH); HR-MS-ESI: m/z=717.3028 [M+
Na]+, calcd. for C41H50NaO6Si2: 717.3038. The oil was used
for the next reaction without further purification.
(2S,3S,4R,5R,6S)- and (2S,3S,4R,5R,6R)-3,4-
Isopropylidenedioxy-2,5-bis(triisopropylsiloxy)-6-
hydroxycyclohexanone (12a and epi-12a) (entry 3)
1
999, 883, 760 cmÀ1; H NMR: d=1.00–1.20 (m, 42H), 1.35
(s, 6H), 4.21 (br s, 2H), 4.42 (br s, 2H), 9.68 (d, J=1.5 Hz,
2H); 13C NMR: d=12.2 (CH), 17.8 (CH3), 26.9 (CH3), 76.9
(CH), 77.8 (CH), 109.8 (C), 202.7 (CH); HR-MS-ESI: m/z=
553.3352 [M+Na]+, calcd. for C27H54NaO6Si2, 553.3351. This
oil was used for the next reaction without further purifica-
tion.
EtOAc was removed from the above mixture of 11a
(212 mg, 0.365 mmol) by evaporation with toluene (5 mLꢂ
3), and the residue was dissolved in toluene (6.5 mL). To
a suspension of triazolium salt 9c (13 mg, 37 mmol) in tolu-
ene (7 mL), a 1% v/v solution of Et3N in toluene (0.51 mL,
37 mmol) was added, and after 30 min, the above solution of
11a was added (2 mL toluene wash). After 24 h, the mixture
was concentrated under vacuum to give a crude product.
The yield (53%) and diastereomeric ratio (74:26) of the title
compounds, and the recovery yield of 11a (31%) were deter-
mined by area integration of the 1H NMR signals at 4.75
(12a), 4.13 (epi-12a), and 9.67 (11a) ppm with Ph3CH
(5.55 ppm) as an internal standard. The diastereomers were
separated by column chromatography (toluene/hexane 5:1)
to give 12a as a pale yellow solid; mp 48–508C; [a]2D5: +6.2
(c 1.0, CHCl3) and epi-12a as a pale yellow oil, containing
ca. 10% unidentified impurity. The stereochemistry was ten-
tatively assigned by analogy with that of 12c.
2,5-Di-O-Benzyl-3,4-O-isopropylidene-d-manno-
hexodialdose (11b)[12c]
To a solution of (COCl)2 (0.26 mL, 3.0 mmol) in THF
(3.5 mL) cooled at À198C, was added a 1M solution of
DMSO in THF (3.1 mL, 3.1 mmol) at such a rate that the
temperature did not rise above À188C. After 2 min, the
mixture was cooled at À788C and stirred for additional
10 min. A solution of 2,5-di-O-benzyl-3,4-O-isopropylidene-
d-mannitol[12c] (402 mg, 1.00 mmol) in THF (7 mL+1 mL
wash) was added over 5 min. After 30 min, Et3N (1.4 mL,
10 mmol) was added. After 10 min, the cooling bath was re-
moved, and the mixture was allowed to warm to room tem-
perature. After addition of pentane (10 mL), the resulting
suspension was filtered, and the filtered solids were washed
with a 1:1 mixture of pentane and EtOAc (15 mLꢂ2). The
volume of the combined filtrate was reduced by evaporation
to ca. 10 mL, and the resulting suspension was further dilut-
ed with pentane (5 mL) and filtered. The filtered solids
were washed with the mixed solvent (15 mLꢂ2). Concentra-
tion of the filtrate gave a 39:31:30 mixture of the title com-
pound, DMSO, and EtOAc as a yellow oil; yield: 510 mg
(97%). IR (neat): n=3256, 3090, 3063, 3032, 2986, 2932,
2874, 2723, 1736, 1454, 1381, 1138, 1084, 1026, 914, 868, 810,
12a: IR (KBr): n=3510, 2943, 2866, 1736, 1466, 1381,
1369, 1227, 1165, 1138, 1069, 1049, 1018, 883, 864, 849, 822,
799 cmÀ1 1H NMR: d=1.00–1.20 (m, 42H), 1.44 (s, 3H),
;
1.46 (s, 3H), 3.17 (br d, J=7.0 Hz, 1H), 3.98 (dd, J=2.5,
9.5 Hz, 1H), 4.45 (dd, J=2.0, 9.5 Hz, 1H), 4.65 (d, J=
2.5 Hz, 1H), 4.67 (dd, J=3.0, 7.0 Hz, 1H), 4.75 (dd, J=2.0,
3.0 Hz, 1H); 13C NMR: d=11.9 (CH), 12.6 (CH), 17.6
(CH3), 17.7 (CH3), 17.9 (CH3), 18.0 (CH3), 26.8 (CH3), 27.1
(CH3), 70.2 (CH), 73.7 (CH), 73.8 (CH), 74.2 (CH), 75.4
(CH), 112.5 (C), 207.2 (C); HR-MS-ESI: m/z=553.3351
[M+Na]+, calcd. for C27H54NaO6Si2: 553.3351.
epi-12a: IR (neat): n=3507, 2943, 2870, 1736, 1466, 1381,
748 cmÀ1
;
1H NMR: d=1.36 (s, 6H), 3.87 (dd, J=2.0,
1227, 1134, 1057, 1042, 1015, 883, 853, 826, 760 cmÀ1
;
3.0 Hz, 1H), 3.88 (dd, J=2.0, 3.0 Hz, 1H), 4.33 (d, J=
3.0 Hz, 1H), 4.34 (d, J=3.0 Hz, 1H), 4.57 (d, J=12.0 Hz,
2H), 4.64 (d, J=12.0 Hz, 2H), 7.27–7.37 (m, 10H), 9.58 (d,
J=2.0 Hz, 2H); 13C NMR: d=26.6 (CH3), 73.3 (CH2), 77.4
(CH), 83.0 (CH), 110.8 (C), 128.4 (CH), 128.6 (CH), 136.5
(C), 201.4 (CH); HR-MS-ESI: m/z=421.1625 [M+Na]+,
calcd. for C23H26NaO6: 421.1622. This oil was used for the
next reaction without further purification.
1H NMR: d=1.00–1.20 (m, 42H), 1.44 (s, 3H), 1.47 (s, 3H),
3.68 (d, J=8.5 Hz, 1H), 4.00 (ddd, J=1.0, 3.0, 8.5 Hz, 1H),
4.13 (dd, J=3.0, 10.0 Hz, 1H), 4.45 (d, J=3.0, 10.0 Hz, 1H),
4.49 (t, J=3.0 Hz, 1H), 4.66 (dd, J=1.0, 3.0 Hz, 1H);
13C NMR: d=12.0 (CH), 12.2 (CH), 17.5 (CH3), 17.65
(CH3), 17.68 (CH3), 17.8 (CH3), 26.9 (CH3), 27.1 (CH3), 70.6
(CH), 73.3 (CH), 74.3 (CH), 77.5 (CH), 80.5 (CH), 112.1
(C), 203.7 (C); HR-MS-ESI: m/z=553.3351 [M+Na]+,
calcd. for C27H54NaO6Si2: 553.3351.
2,5-Bis-O-tert-butyldiphenylsilyl-3,4-O-
isopropylidene-d-manno-hexodialdose (11c)[12c]
The same procedure as 11a using 3,4-O-isopropylidene-2,5-
bis-O-tert-butyldiphenylsilyl-d-mannitol[12c]
(1.02 g,
1.46 mmol) in place of 3,4-O-isopropylidene-2,5-bis-O-triiso-
propylsilyl-d-mannitol gave a 52:37:11 mixture of the title
8
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N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
24 h, the mixture was concentrated under vacuum to give
a crude product as a yellow oil; yield: 469 mg. The yield was
estimated to be 57% by area integration of the H NMR sig-
(2S,3S,4R,5R,6S)- and (2S,3S,4R,5R,6R)-2,5-
Bis(benzyloxy)-3,4-isopropylidenedioxy-6-
hydroxycyclohexanone (12b and epi-12b) (entry 4)
1
nals at 4.57–4.66 (4H) with Ph3CH (5.55 ppm) as an internal
standard. The above oil was purified by column chromatog-
raphy (DIOL silica gel, hexane to hexane/EtOAc 98:2) to
give 12c as a white solid; yield: 181 mg (55%); mp 156–
1578C; [a]25: +12.6 (c 3.03, CHCl3); IR (neat): n=3510,
3071, 3051,D2954, 2932, 2893, 2859, 1732, 1589, 1470, 1427,
1369, 1227, 1169, 1130, 1111, 1068, 1049, 968, 937, 864, 821,
EtOAc was removed from the above mixture of 11b
(148 mg, 0.280 mmol) by evaporation with toluene (5 mLꢂ
3), and the residue was dissolved in toluene (3.5 mL). To
a suspension of triazolium salt 9c (10 mg, 28 mmol) in tolu-
ene (5 mL), a 1% v/v solution of Et3N in toluene (0.39 mL,
28 mmol) was added, and after 30 min, the above solution of
11b was added (1 mL toluene wash). After 24 h, the mixture
was concentrated under vacuum to give a crude product.
The yield (30%) and diastereomeric ratio (57:43) of the title
compounds, and the recovery yield of 11b (3%) were deter-
mined by area integration of the 1H NMR signals at 4.14
(12b), 4.26–4.33 (epi-12b, 2H), and 9.58 (11b) ppm with
Ph3CH (5.55 ppm) as an internal standard. The diastereo-
mers were separated by column chromatography (hexane/
EtOAc 8/1 to 4/1). The stereochemistry was tentatively as-
signed by analogy with that of 12c.
1
799, 753, 741, 702 cmÀ1; H NMR: d=1.02 (s, 9H), 1.04 (s,
9H), 1.46 (s, 3H), 1.51 (s, 3H), 2.72 (d, J=7.5 Hz, 1H), 4.12
(dd, J=8.5, 10.0 Hz, 1H), 4.59 (dd, J=1.5, 10.0 Hz, 1H),
4.62–4.65 (m, 2H), 4.66 (d, J=2.5 Hz, 1H), 7.30–7.46 (m,
12H), 7.50 (m, 2H), 7.53 (m, 2H), 7.70 (m, 2H), 7.77 (m,
1
2H); H NMR (C6D6): d=1.09 (s, 9H), 1.18 (s, 9H), 1.41 (s,
3H), 1.45 (s, 3H), 3.02 (d, J=7.0 Hz, 1H), 4.08 (dd, J=2.5,
10.0 Hz, 1H), 4.34 (dd, J=1.0, 10.0 Hz, 1H), 4.67 (d, J=3.5,
7.0 Hz, 1H), 4.60 (dd, J=1.0, 3.5 Hz, 1H), 4.73 (d, J=
2.5 Hz, 1H), 7.13–7.28 (m, 12H), 7.61–7.69 (m, 4H), 7.77–
7.83 (m, 2H), 7.94–7.99 (m, 2H); 13C NMR: d=19.3 (C),
19.6 (C), 26.75 (CH3), 26.84 (CH3), 26.9 (CH3), 27.1 (CH3),
70.8 (CH), 73.6 (CH), 73.9 (CH), 74.6 (CH), 75.7 (CH),
112.8 (C), 127.48 (CH), 127.52 (CH), 127.7 (CH), 127.8
(CH), 129.5 (CH), 129.9 (CH), 130.0 (CH), 130.2 (CH),
131.9 (C), 132.0 (C), 132.1 (C), 134.1 (C), 135.7 (CH), 135.9
(CH), 136.7 (CH), 206.1 (C); HR-MS-FAB: m/z=717.3033
[M+Na]+, calcd. for C41H50NaO6Si2: 717.3038. The relative
configuration was determined by 2% nOe between 4-H and
6-H (4.34 and 4.67 ppm in C6D6, respectively) as shown in
Figure 2.
12b: colorless oil; [a]D20: À4.8 (c 1.4, CHCl3); IR (neat):
n=3464, 3090, 3063, 3032, 2986, 2932, 2874, 1736, 1497,
1454, 1381, 1346, 1231, 1169, 1126, 1069, 1057, 1026, 972,
1
910, 849, 802, 741 cmÀ1; H NMR: d=1.49 (s, 3H), 1.54 (s,
3H), 3.12 (br s, 1H), 4.14 (dd, J=2.5, 10.0 Hz, 1H), 4.38 (d,
J=2.5 Hz, 1H), 4.41 (dd, J=2.0, 4.0 Hz, 1H), 4.55 (dd, J=
2.0, 10.0 Hz, 1H), 4.57 (d, J=11.5 Hz, 1H), 4.60 (br d, J=
4.0 Hz, 1H), 4.69 (d, J=12.5 Hz, 1H), 4.72 (d, J=12.5 Hz,
1H), 4.87 (d, J=11.5 Hz, 1H), 7.27–7.38 (m, 10H);
13C NMR (C6D6): d=26.8 (CH3), 26.9 (CH3), 73.0 (CH2),
74.1 (CH), 74.50 (CH2), 74.54 (CH), 75.5 (CH), 75.6 (CH),
80.0 (CH), 112.4 (C), 127.76 (CH), 127.78 (CH), 127.9 (CH),
128.52 (CH), 128.53 (CH), 128.6 (CH), 137.5 (C), 138.7 (C),
205.7 (C); HR-MS-ESI: m/z=421.1622 [M+Na]+, calcd. for
C23H26NaO6: 421.1622.
(2S,3S,4S,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-(tert-
butyldiphenylsiloxy)cyclohexanone (2c; Table 3)
epi-12b: white solid; mp 121–1248C; [a]2D0: +11.5 (c 1.82,
CHCl3); IR (neat): n=3329, 3090, 3063, 3028, 2982, 2932,
2909, 2882, 1744, 1497, 1454, 1396, 1381, 1242, 1219, 1180,
1150, 1123, 1096, 1049, 1022, 968, 914, 976, 845, 795, 752,
To a solution of 2a (108 mg, 0.201 mmol), imidazole (27 mg,
0.40 mmol), and DMAP (5 mg, 0.4 mmol) in DMF (0.4 mL)
was added TBDPSCl (62 mL, 0.24 mmol) at room tempera-
ture. After 8.5 h, TBDPSCl (41 mL, 0.16 mmol) was added.
After 2.5 h, water (1 mL) was added, and the whole was ex-
tracted with toluene (8 mLꢂ3). The combined organic
layers were washed three times with water and with brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography (tolu-
ene/hexane 3:1 and then hexane/EtOAc 9:1) to give a color-
less oil. The oil was dissolved in EtOAc (2 mL), and washed
with saturated aqueous NaHCO3 (2 mL). The aqueous layer
was extracted with EtOAc, and the combined organic layers
were dried over Na2SO4 and evaporated under reduced
pressure to yield the title compound as a colorless oil; yield:
94 mg (60%); [a]25: À58.6 (c 1.35, CHCl3); IR (neat): n=
3067, 3028, 2932, D2859, 1748, 1497, 1454, 1427, 1389, 1362,
1
733 cmÀ1; H NMR: d=1.50 (s, 3H), 1.52 (s, 3H), 3.40 (br d,
J=6.5 Hz, 1H), 3.97 (dt, J=8.0, 1.5 Hz, 1H), 4.20 (br m,
1H), 4.26–4.33 (m, 2H), 4.40 (dd, J=1.5, 4.0 Hz, 1H), 4.73
(d, J=11.5 Hz, 1H), 4.74 (d, J=11.5 Hz, 1H), 4.86 (d, J=
11.5 Hz, 1H), 4.88 (d, J=11.5 Hz, 1H), 7.27–7.37 (m, 8H),
7.43 (d, J=7.5 Hz, 2H); 13C NMR (C6D6): d=26.5 (CH3),
27.2 (CH3), 72.3 (CH2), 74.3 (CH2), 74.8 (CH), 75.7 (CH),
76.8 (CH), 77.0 (CH), 81.8 (CH), 112.6 (C), 127.68 (CH),
127.74 (CH), 127.9 (CH), 128.0 (CH), 128.5 (CH), 128.6
(CH), 138.3 (C), 138.5 (C), 205.2 (C); HR-MS-ESI: m/z=
421.1622 [M+Na]+, calcd. for C23H26NaO6: 421.1622.
(2S,3S,4R,5R,6S)-2,5-Bis(tert-butyldiphenylsiloxy)-
3,4-isopropylidenedioxy-6-hydroxycyclohexanone
(12c) (entry 6)
1
1215, 1161, 1111, 1080, 1049, 822, 756 cmÀ1; H NMR: d=
1.18 (s, 9H), 3.74 (dd, J=3.0, 4.0 Hz, 1H), 3.79 (dd, J=3.0,
4.0 Hz, 1H), 3.84 (d, J=12.0 Hz, 1H), 3.91 (dd, J=3.0,
10.0 Hz, 1H), 4.08 (d, J=3.0 Hz, 1H), 4.37 (d, J=12.5 Hz,
1H), 4.43 (d, J=11.5 Hz, 1H), 4.45 (d, J=11.5 Hz, 1H),
4.56 (d, J=11.5 Hz, 1H), 4.67 (d, J=12.0 Hz, 1H), 4.69 (d,
J=12.5 Hz, 1H), 4.74 (d, J=10.0 Hz, 1H), 4.79 (d, J=
11.5 Hz, 1H), 7.04–7.14 (m, 6H), 7.21–7.38 (m, 20H), 7.72–
7.75 (m, 4H); 13C NMR: d=19.6 (C), 27.2 (CH3), 72.0
(CH2), 73.3 (CH2), 73.6 (CH2), 73.9 (CH2), 75.3 (CH), 77.6
EtOAc was removed from the above mixture of 11c
(367 mg, 0.474 mmol) by evaporation with toluene (5 mLꢂ
2), and the residue was dissolved in toluene (7.5 mL). To
a suspension of triazolium salt 9c (34 mg, 95 mmol) in tolu-
ene (9.5 mL), a 10% v/v solution of Et3N in toluene
(0.13 mL, 95 mmol) was added, and after 30 min, the above
solution of 11c was added (1 mL toluene washꢂ2). After
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(CH), 78.0 (CH), 80.5 (CH), 82.2 (CH), 127.2 (CH), 127.5
(CH), 127.57 (CH), 127.59 (CH), 127.64 (CH), 127.7 (CH),
128.0 (CH), 128.2 (CH), 128.3 (CH), 129.3 (CH), 129.4
(CH), 133.8 (C), 134.2 (C), 136.1 (CH), 136.6 (CH), 137.8
(C), 138.0 (C), 138.2 (C), 138.3 (C), 201.9 (C); FAB-MS: m/
z=799 (M+Na), 91 (Bn); HR-MS-FAB: m/z=799.3431
[M+Na]+, calcd. for C50H52NaO6Si: 799.3426.
1H), 4.59 (dd, J=1.0, 9.5 Hz, 1H), 4.65 (d, J=12.0 Hz, 1H),
4.76 (d, J=12.0 Hz, 1H), 4.81 (d, J=12.0 Hz, 1H), 4.86 (d,
J=12.0 Hz, 1H), 7.06–7.16 (m, 4H), 7.23–7.35 (m, 16H);
13C NMR: d=4.9 (CH2), 6.8 (CH3), 72.4 (CH2), 73.2 (CH2),
73.7 (CH2), 74.0 (CH2), 75.4 (CH), 77.5 (CH), 77.9 (CH),
80.6 (CH), 81.9 (CH), 127.5 (CH), 127.68 (CH), 127.69
(CH), 127.72 (CH), 127.8 (CH), 128.18 (CH), 128.24 (CH),
128.3 (CH), 137.9 (C), 138.0 (C), 138.1 (C), 138.6 (C), 203.1
(C); FAB-MS: m/z=675 (M+Na), 91 (Bn); HR-MS-ESI:
m/z=675.3118 [M+Na]+, calcd. for C40H48NaO6Si:
675.3113.
(2S,3S,4S,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-(tert-
butyldimethylsiloxy)cyclohexanone (2d)
To a solution of 2a (106 mg, 0.197 mmol) and imidazole
(74 mg, 1.1 mmol) in DMF (1 mL) was added TBDMSCl
(50 mg, 0.33 mmol) at room temperature. After 4 h,
TBDMSCl (50 mg, 0.33 mmol) was added, and the mixture
was stirred for 11 h. After addition of water (1 mL), the
whole was extracted with toluene. The organic layer was
washed with water three times and with brine, dried over
Na2SO4, and evaporated under reduced pressure. The resi-
due was purified by column chromatography (hexane/
EtOAc 15:1) to yield the title compound as a yellow oil;
yield: 118 mg (92%); [a]D25: À24.1 (c 1.20, CHCl3); IR (neat):
n=3088, 3063, 3030, 2951, 2928, 2857, 1746, 1497, 1454,
1389, 1362, 1254, 1207, 1155, 1101, 1051, 1028, 837, 781,
(2S,3S,4S,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-
(trimethylsiloxy)cyclohexanone (2f)
To a solution of 2a (87 mg, 0.16 mmol) and Et3N (90 mL,
0.64 mmol) in CH2Cl2 (0.5 mL) was added TMSCl (41 mL,
0.32 mmol) at 08C. After 1.5 h, Et3N (45 mL, 0.32 mmol) and
TMSCl (21 mL, 0.16 mmol) were added. After 1.5 h, saturat-
ed aqueous NaHCO3 (4 mL) was added, and the organic
layer was separated. The aqueous layer was extracted with
EtOAc (4 mLꢂ3). The combined organic layers were
washed with water (12 mL) and brine (12 mL), dried over
Na2SO4, and evaporated to give a crude product as a pale
yellow oil. 1H NMR: d=0.31 (s, 9H), 3.87 (dd, J=3.0,
4.0 Hz, 1H), 4.07 (dd, J=3.0, 4.0 Hz, 1H), 4.11 (dd, J=3.0,
9.5 Hz, 1H), 4.21 (d, J=12.0 Hz, 1H), 4.40 (d, J=12.0 Hz,
1H), 4.42 (d, J=12.0 Hz, 1H), 4.45 (d, J=12.0 Hz, 1H),
4.62 (dd, J=1.0, 3.0 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.76
(d, J=12.0 Hz, 1H), 4.83 (d, J=12.0 Hz, 1H), 4.88 (dd, J=
1.0, 9.5 Hz, 1H), 4.92 (d, J=12.0 Hz, 1H), 7.03–7.37 (m,
20H). Remaining EtOAc was removed by evaporation with
toluene (5 mL). The resulting pale yellow oil was used in
the reduction without purification.
1
737 cmÀ1; H NMR: d=0.05 (s, 3H), 0.17 (s, 3H), 0.96 (s,
9H), 3.70 (dd, J=3.0, 4.0 Hz, 1H), 3.83 (dd, J=3.0, 9.5 Hz,
1H), 3.85 (dd, J=3.0, 4.0 Hz, 1H), 4.37 (d, J=12.5 Hz, 1H),
4.40 (d, J=12.5 Hz, 1H), 4.42 (dd, J=1.0, 3.0 Hz, 1H), 4.47
(d, J=12.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H), 4.56 (d, J=
1.0, 9.5 Hz, 1H), 4.64 (d, J=12.5 Hz, 1H), 4.75 (d, J=
12.5 Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.85 (d, J=12.0 Hz,
1H), 7.07–7.15 (m, 4H), 7.23–7.35 (m, 16H); 13C NMR: d=
À5.2 (CH3), À4.7 (CH3), 18.6 (C), 25.8 (CH3), 72.4 (CH2),
73.2 (CH2), 73.7 (CH2), 74.0 (CH2), 75.4 (CH), 77.5 (CH),
78.0 (CH), 80.6 (CH), 81.8 (CH), 127.55 (CH), 127.63 (CH),
127.67 (CH), 127.71 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 128.27 (CH), 128.33 (CH), 128.34 (CH), 137.9 (C),
138.00 (C), 138.04 (C), 138.5 (C), 203.0 (C); FAB-MS: m/z=
675 (M+Na), 91 (Bn); HR-MS-FAB: m/z=675.3118 [M+
Na]+, calcd. for C40H48NaO6Si: 675.3113.
(1R,2S,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-
cyclohexane-1,2-diol (allo-3a) (entry 1)
To a solution of 2a (38 mg, 71 mmol) in MeOH (0.5 mL) was
added NaBH4 (4 mg, 0.1 mmol) at 08C. After 30 min, satu-
rated aqueous NaHCO3 (1 mL) was added, and the whole
was extracted with CHCl3. The organic layer was washed
with water and brine, dried over Na2SO4, and concentrated
under vacuum. The residue was purified by column chroma-
tography (hexane/EtOAc 3:1) to yield the title compound as
a colorless solid; yield: 31 mg (81%); mp 96–988C; [a]2D0:
À20.2 (c 1.00, CHCl3); IR (neat): n=3441, 3063, 3028, 2874,
(2S,3S,4S,5S,6R)-2,3,4,5-Tetrakis(benzyloxy)-6-
(triethylsiloxy)cyclohexanone (2e)
To a solution of 2a (237 mg, 0.440 mmol) and pyridine
(0.14 mL, 1.8 mmol) in CH2Cl2 (0.8 mL), was added
TESOTf (0.20 mL, 0.88 mmol) at À788C. After 2 h, saturat-
ed aqueous NaHCO3 (2 mL) was added, and the organic
layer was separated. The aqueous layer was extracted with
toluene (2 mLꢂ5). The combined organic layers were
washed with water (10 mLꢂ5) and brine (10 mL), dried
over Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography (hexane/
EtOAc 96:4) to yield the title compound as a colorless oil;
yield: 246 mg (86%); [a]20: À37.2 (c 0.445, CHCl3); IR
(neat): n=3086, 3063, 303D2, 2955, 2936, 2913, 2874, 1748,
1454, 1385, 1362, 1238, 1207, 1157, 1111, 1084, 1053, 1026,
1497, 1454, 1273, 1092, 1068, 1026, 910 cmÀ1 1H NMR
;
(558C): d=2.67 (br s, 1H), 3.47 (br s, 1H), 3.86–3.92 (br m,
5H), 4.15 (br s, 1H), 4.50–4.70 (m, 8H), 7.20–7.35 (m, 20H);
13C NMR: d=73.2 (CH2), 77.1 (CH), 78.7 (CH), 127.7 (CH),
127.8 (CH), 127.9 (CH), 128.3 (CH), 128.36 (CH), 128.44
(CH), 128.5 (CH), 137.9 (C), 138.4 (C); HR-MS-ESI: m/z=
563.2404 [M+Na]+, calcd. for C34H36NaO6: 563.2405. Re-
crystallization from hexane/EtOAc provided colorless nee-
dles suitable for X-ray crystallographic analysis; monoclinic
P21, a=11.3487(9) ꢃ, b=7.9412(6) ꢃ, c=16.2792(13) ꢃ,
a=90.00008, b=99.4718(19)8, g=90.00008, Z=2, R1 =
0.1000, wR2 =0.1548; which determined the stereochemistry.
CCDC 1009954 contains the supplementary crystallographic
data of this compound. These data can be obtained free of
1
914, 814, 737 cmÀ1; H NMR: d=0.58–0.78 (m, 6H), 0.99 (t,
J=8.0 Hz, 9H), 3.71 (dd, J=3.0, 4.0 Hz, 1H), 3.82 (dd, J=
3.0, 9.5 Hz, 1H), 3.86 (dd, J=3.0, 4.0 Hz, 1H), 4.37 (d, J=
12.0 Hz, 1H), 4.41 (d, J=12.0 Hz, 1H), 4.43 (dd, J=1.0,
3.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz,
10
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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ÝÝ
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FULL PAPERS
N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
4.75 (d, J=11.0 Hz, 1H), 4.84 (d, J=11.0 Hz, 1H), 4.85 (d,
J=10.5 Hz, 1H), 4.91 (d, J=11.0 Hz, 1H), 4.92 (d, J=
10.5 Hz, 1H), 4.95 (d, J=11.0 Hz, 1H), 7.26–7.35 (m, 20H);
13C NMR: d=69.1 (CH), 71.7 (CH), 72.7 (CH2), 75.6 (CH2),
75.7 (CH2), 75.9 (CH2), 80.0 (CH), 81.3 (CH), 81.6 (CH),
83.2 (CH), 127.6 (CH), 127.8 (CH), 127.88 (CH), 127.93
(CH), 128.0 (CH), 128.36 (CH), 128.39 (CH), 128.5 (CH),
128.6 (CH), 137.7 (C), 138.5 (C), 138.6 (C); HR-MS-ESI: m/
z=563.2404 [M+Na]+, calcd. for C34H316NaO6: 563.2404.
The melting point, specific rotation, and H and 13C NMR
were in good agreement with those reported {mp 140–
1428C; [a]2D0: À25 (c 2.7, CHCl3)}.[39]
(1S,2S,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-
cyclohexane-1,2-diol (chiro-3a) (entry 7)
To a solution of 2a (174 mg, 0.323 mmol) and pyridine
(0.11 mL, 1.3 mmol) in CH2Cl2 (0.5 mL) was added TESCl
(0.15 mL, 0.65 mmol) at À788C. After 2 h, saturated aque-
ous NaHCO3 (2 mL) was added, and the organic layer was
separated. The aqueous layer was extracted with toluene
(2 mLꢂ4), and the combined organic layers were washed
with water (8 mLꢂ5) and brine (8 mL), dried over Na2SO4,
and evaporated under reduced pressure to give crude O-
TES inosose 2e as a yellow oil (yield: 230 mg). After remov-
al of residual EtOAc by evaporation with toluene (5 mL),
the crude product was dissolved in toluene (2 mL), and
tBuNH2·BH3 (73 mg, 0.81 mmol) was added at room temper-
ature. After 30 min, 10% HCl (4 mL) and EtOAc (2 mL)
were added, and the mixture was vigorously stirred for 2 h.
The aqueous layer was separated and extracted with EtOAc
(4 mLꢂ2). The combined organic layers were washed with
saturated aqueous NaHCO3 (12 mL) and brine (12 mL),
dried over Na2SO4, and concentrated. The dr (90:10) was
(1R,2R,3S,4R,5R,6S)-3,4,5,6-Tetrakis(benzyloxy)-
cyclohexane-1,2-diol (scyllo-3b)
To a solution of 2b (38 mg, 70 mmol) and imidazole (24 mg,
0.35 mmol) in DMF (0.2 mL) cooled in an ice-water bath,
was added TESCl (29 mL, 0.17 mmol). After removal of the
cooling bath, the mixture was stirred for 2 h, and water
(1 mL) was added to the mixture. The whole was extracted
with Et2O (1 mLꢂ3), and the combined organic layers were
washed with brine, dried over Na2SO4, and evaporated
under reduced pressure. The residue was purified by column
chromatography (hexane/EtOAc 14:1) to yield O-TES ino-
sose as a white solid; yield: 42.4 mg (93%); mp 89–918C;
[a]2D0: À40 (c 0.06, CHCl3); IR (KBr): n=3032, 2955, 2920,
2878, 1736, 1458, 1408, 1385, 1366, 1261, 1238, 1211, 1134,
1
determined by the area integration of the H NMR signals
at 4.39 (chiro 2H) and 3.86–3.93 (chiro 2H+allo 5H) ppm.
The residue was purified by column chromatography
(hexane/EtOAc 5:2 to 1:1) to yield the title compound as
a colorless oil; yield: 136 mg (78%); [a]2D5: +2.0 (c 1.0,
CHCl3); IR (neat): n=3410, 3063, 3028, 2916, 2870, 1493,
1
1069, 1026, 814, 737 cmÀ1; H NMR: d=0.59–0.70 (m, 6H),
0.96 (t, J=8.0 Hz, 9H), 3.48 (t, J=10.0 Hz, 1H), 3.61 (t, J=
10.0 Hz, 1H), 3.84 (t, J=10.0 Hz, 1H), 4.14 (dd, J=1.5,
10.0 Hz, 1H), 4.34 (dd, J=1.5, 10.0 Hz, 1H), 4.55 (d, J=
11.0 Hz, 1H), 4.76 (d, J=11.0 Hz, 1H), 4.77 (d, J=11.0 Hz,
1H), 4.84 (d, J=11.0 Hz, 1H), 4.87 (d, J=11.0 Hz, 1H),
4.89 (d, J=11.0 Hz, 1H), 4.91 (d, J=11.0 Hz, 1H), 4.92 (d,
J=11.0 Hz, 1H), 7.18–7.22 (m, 2H), 7.25–7.33 (m, 16H),
7.35–7.39 (m, 2H); 13C NMR: d=4.9 (CH2), 6.8 (CH3), 73.2
(CH2), 75.9 (CH2), 75.97 (CH2), 76.04 (CH2), 78.7 (CH), 81.6
(CH), 82.2 (CH), 82.8 (CH), 83.3 (CH), 127.57 (CH), 127.62
(CH), 127.7 (CH), 127.81 (CH), 127.83 (CH), 127.9 (CH),
128.0 (CH), 128.1 (CH), 128.26 (CH), 128.31 (CH), 128.34
(CH), 128.4 (CH), 137.3 (C), 138.2 (C), 138.3 (C), 202.5 (C);
FAB-MS: m/z=675 (M+Na), 91 (Bn); HR-MS-ESI: m/z=
675.3112 [M+Na]+, calcd. for C40H48NaO6Si: 675.3113.
1454, 1273, 1096, 1057, 1026, 999, 914 cmÀ1
;
1H NMR
(558C): d=2.52 (br s, 2H), 3.68 (br d, J=7.0 Hz, 2H), 3.74
(br s, 2H), 3.91 (m, 2H), 4.39 (d, J=12.0 Hz, 2H), 4.54 (d,
J=12.0 Hz, 2H), 4.60 (d, J=12.0 Hz, 2H), 4.61 (d, J=
12.0 Hz, 2H), 7.18–7.19 (m, 4H), 7.25–7.33 (m, 16H);
13C NMR: 72.6 (CH), 72.8 (CH2), 73.1 (CH2), 74.3 (CH),
78.2 (CH), 127.70 (CH), 127.72 (CH), 127.8 (CH), 128.0
(CH), 128.3 (CH), 128.4 (CH), 138.16 (C), 138.23 (C); FAB-
MS: m/z=563 (M+Na); HR-MS-FAB: m/z=563.2411
[M+Na]+, calcd. for C34H36NaO6, 563.2404. The stereo-
chemistry was determined after the conversion into d-chiro-
inositol. allo-3a (yield: 16 mg, 9%) was also obtained as the
less polar product.
To a solution of the above solid (24.5 mg, 37.5 mmol) in
toluene (0.25 mL) was added t-BuNH2·BH3 (8 mg,
0.09 mmol) at room temperature. After 1 h, 10% HCl
(2 mL) and THF (2 mL) were added, and the mixture was
vigorously stirred for 15 min. The volume of the mixture
was reduced to ca. 2 mL by evaporation, and the mixture
was extracted with EtOAc. The organic layer was washed
with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and concentrated. The residue was purified by
column chromatography (hexane/EtOAc 2:1) to yield the
title compound as a white solid; yield: 16.3 mg (80%); mp
120–1238C; [a]20: À4 (c 0.1, CHCl3); IR (KBr): n=3372,
3275, 3063, 300D5, 2913, 1454, 1400, 1385, 1354, 1261, 1126,
(1R,2S,3S,4R,5R,6S)-3,4,5,6-Tetrakis(benzyloxy)-
cyclohexane-1,2-diol (myo-3b; Scheme 5)
To a solution of 2b (20 mg, 37 mmol) in THF (1 mL) was
added a 1M solution of L-selectride in THF (74 mL,
74 mmol) at À788C. After 30 min, water (1 mL) was added,
and the mixture was allowed to warm to room temperature.
The whole was extracted with EtOAc (2 mLꢂ3), and the
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by
column chromatography (hexane/EtOAc 2:1) to yield the
title compound as a white solid; yield: 18.7 mg (93%); mp
142–1438C; [a]2D0: À22.3 (c 1.60, CHCl3); IR (neat): n=3588,
3345, 3086, 3063, 3028, 2913, 1497, 1454, 1385, 1358, 1211,
1
1088, 1069, 1053, 1022, 802, 748 cmÀ1; H NMR: d=2.53 (br
1
1134, 1088, 1069, 1026, 729 cmÀ1; H NMR: d=2.43 (br d,
s, 2H), 3.43 (br m, 2H), 3.49 (br m, 2H), 3.58 (br m, 2H),
4.78 (d, J=11.0 Hz, 2H), 4.88 (s, 4H), 4.92 (d, J=11.0 Hz,
2H), 7.26–7.33 (m, 20H); 13C NMR: d=73.8 (CH), 75.5
(CH2), 75.9 (CH2), 82.3 (CH), 83.1 (CH), 127.7 (CH), 127.8
J=4.5 Hz, 1H), 2.52 (br s, 1H), 3.45–3.50 (m, 3H), 3.86 (t,
J=9.5 Hz, 1H), 3.97 (t, J=9.5 Hz, 1H), 4.20 (t, J=2.5 Hz,
1H), 4.70 (d, J=11.5 Hz, 1H), 4.71 (d, J=11.5 Hz, 1H),
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
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FULL PAPERS
Bubwoong Kang et al.
(CH), 127.89 (CH), 127.94 (CH), 128.4 (CH), 128.6 (CH),
138.3 (C), 138.4 (C); HR-MS-ESI: m/z=563.2404 [M+
Na]+, calcd. for C34H36NaO6: 563.2404. 1H and 13C NMR
were in good agreement with those reported.[12a,40]
19.9 (C), 26.81 (CH3), 26.84 (CH3), 27.0 (CH3), 27.2 (CH3),
71.9 (CH), 74.2 (CH), 74.6 (CH), 75.4 (CH), 75.7 (CH),
112.7 (C), 126.9 (CH), 127.3 (CH), 127.5 (CH), 127.6 (CH),
129.0 (CH), 129.5 (CH), 129.9 (CH), 130.0 (CH), 132.3 (C),
132.7 (C), 133.1 (C), 135.9 (CH), 136.2 (CH), 136.4 (CH),
136.6 (CH), 203.9 (C); HR-MS-ESI: m/z=831.3903 [M+
Na]+, calcd. for C47H64NaO6Si3: 831.3903.
(1R,2S,3R,4S,5S,6R)-3,6-Bis(tert-butyldiphenylsiloxy)-
4,5-(isopropylidenedioxy)cyclohexane-1,2-diol (allo-
13c; Scheme 6)
To a solution of the above solid (20 mg, 25 mmol) in tolu-
ene (0.15 mL), was added t-BuNH2·BH3 (6 mg, 0.06 mmol)
at room temperature. After 30 min, the mixture was evapo-
rated to give a crude material as a cloudy oil. The oil was
dissolved in a 1:1 mixture of THF/pyridine (0.8 mL) cooled
in an ice-water bath, HF·pyridine complex (0.2 mL) was
added. The cooling bath was removed and the mixture was
stirred for 45 min. The mixture was cooled in the ice-water
bath, and the reaction was quenched by the addition of satu-
rated aqueous NaHCO3 (2 mL). The whole was extracted
with EtOAc (2 mLꢂ3), and the combined organic layers
were washed with brine (6 mL), dried over Na2SO4, and
concentrated under vacuum. The residual pyridine was re-
moved by evaporation with toluene (10 mLꢂ2). The dr
To a solution of 12c (20 mg, 29 mmol) in THF (0.5 mL)
cooled in an ice-water bath, was added a 1M solution of
BH3·THF in THF (60 mL, 60 mmol). After 7 h, another por-
tion of a 1M solution of BH3·THF in THF (15 mL, 15 mmol)
was added. After 1.5 h, water (2 mL) was added, and the
whole was extracted with EtOAc (2 mLꢂ3). The combined
organic layers were washed with brine, dried over Na2SO4,
and concentrated. The borane-derived impurities were re-
moved by column chromatography (hexane/EtOAc 19:1) to
yield a mixture of the title compound with neo-13c as a col-
orless oil (yield: 19 mg, 93%); [a]2D0: À20 (c 0.74, CHCl3); IR
(neat): n=3549, 3530, 3071, 3051, 2959, 2897, 1474, 1427,
1381, 1369, 1227, 1142, 1111, 1072, 1045, 1007, 880, 849, 822,
1
(96:4) was determined by area integration of the H NMR
1
795, 760 cmÀ1; H NMR: d=1.04 (s, 9H), 1.10 (s, 9H), 1.43
signals at 4.58 and 4.71 ppm. The residue was purified by
column chromatography (hexane/EtOAc 95:5) to give
a 96:4 diastereomeric mixture of the title compound as
a white solid; yield: 16.6 mg (96%); mp 46–488C; [a]2D5: (c
0.83, CHCl3) {lit:[12c] mp 61–648C, [a]D +13.7 (c 1.0,
CHCl3)}; IR (neat): n=3549, 3071, 3051, 3013, 2986, 2969,
2932, 2859, 1427, 1381, 1369, 1219, 1157, 1111, 1042, 1007,
(s, 3H), 1.46 (s, 3H), 1.89 (d, J=10.5 Hz, 1H), 2.81 (d, J=
9.0 Hz, 1H), 3.43 (dt, J=8.5, 3.0 Hz, 1H), 3.76 (dt, J=10.0,
3.0 Hz, 1H), 4.08 (dd, J=2.0, 10.0 Hz, 1H), 4.33 (dd, J=2.5,
10.0 Hz, 1H), 4.44 (t, J=3.0 Hz, 1H), 4.71 (br t, J=3.0 Hz,
1H), 7.30–7.50 (m, 14H), 7.61 (m, 2H), 7.70–7.80 (m, 4H);
13C NMR: d=19.2 (C), 19.4 (C), 26.9 (CH3), 27.07 (CH3),
27.12 (CH3), 68.3 (CH), 69.8 (CH), 72.5 (CH), 74.1 (CH),
74.4 (CH), 75.7 (CH), 111.0 (C), 127.5 (CH), 127.6 (CH),
127.8 (CH), 127.9 (CH), 129.8 (CH), 130.0 (CH), 130.1
(CH), 132.0 (C), 132.7 (C), 133.4 (C), 133.6 (C), 135.7 (CH),
136.0 (CH), 136.1 (CH), 136.5 (CH); HR-MS-ESI: m/z=
719.3195 [M+Na]+, calcd. for C41H52NaO6Si2: 719.3195. The
dr (89:11) was determined by the integration area of
1H NMR signals at 4.71 and 4.58 ppm. The stereochemistry
was tentatively assigned as drawn.
1
837, 760 cmÀ1; H NMR: d=1.08 (s, 18H), 1.42 (s, 6H), 3.66
(br s, 2H), 4.12 (br s, 2H), 4.58 (br s, 2H), 7.33–7.45 (m,
12H), 7.66 (m, 4H), 7.78 (m, 4H); 13C NMR: d=19.6 (C),
27.06 (CH3), 27.13 (CH3), 67.0 (CH), 72.8 (CH), 74.5 (CH),
111.4 (C), 127.5 (CH), 127.7 (CH), 129.8 (CH), 129.9 (CH),
132.6 (C), 134.1 (C), 136.0 (CH), 136.5 (CH). EI-MS; m/z=
1
639 (MÀt-Bu). H and 13C NMR data were in good agree-
ment with those reported.[12c]
(1R,2R,3R,4S,5S,6R)-4,5-(Isopropylidenedioxy)-3,6-
bis(tert-butyldiphenylsiloxy)cyclohexane-1,2-diol
(neo-13c)
(1S,2R,3R,4R,5S,6R)-2-Acetamido-3,4,5,6-tetrakis-
(benzyloxy)cyclohexyl acetate (14a; Scheme 7)
To a stirred solution of 2a (161 mg, 0.299 mmol) in EtOH
(1.5 mL), were added pyridine (0.16 mL, 2.0 mmol) and
MeONH2·HCl (125 mg, 1.50 mmol) at room temperature.
After 30 min, the solution was diluted with EtOAc, washed
with H2O and brine, dried over Na2SO4, and concentrated
under vacuum. From the residue, the remaining pyridine
was removed by three-time evaporation with toluene to give
crude O-methyl oxime as a yellow oil (yield: 178 mg).
The above oil was dissolved in THF (0.5 mL+0.25 mL
washꢂ2) and added to a suspension of NaOMe (162 mg,
3.00 mmol) and LiAlH4 (170 mg, 4.48 mmol) at À788C.
After 30 min, the cooling bath was removed, and the mix-
ture was allowed to warm up to room temperature. After
30 min, the mixture was heated at 658C for 30 min and then
cooled to room temperature. To the mixture, H2O was drop-
wise added until no gas evolution occurred. The whole was
filtered through celite, which was successively washed with
CHCl3. The combined filtrate was concentrated under
vacuum to give a crude mixture of 4a and epi-4a as a yellow
oil.
To a solution of 12c (235 mg, 0.338 mmol) and 2,6-lutidine
(0.20 mL, 1.7 mmol) in CH2Cl2 (0.5 mL) cooled at À788C,
was added TESOTf (0.23 mL, 1.0 mmol). After 14.5 h, water
(2 mL) was added, and the mixture was allowed to warm to
room temperature. The aqueous layer was separated and ex-
tracted with CHCl3 (2 mLꢂ3). The combined organic layers
were washed with water (6 mLꢂ3), dried over Na2SO4, and
concentrated. The residue was purified by column chroma-
tography (hexane/EtOAc 98:2) to yield 6O-TES inosose as
a white solid; yield: 254 mg (93%); mp 78–808C; [a]2D0:
À20.5 (c 1.00, CHCl3); IR (neat): n=3075, 3051, 2955, 2932,
2878, 2859, 1751, 1474, 1462, 1427, 1381, 1369, 1231, 1180,
1
1134, 1115, 1059, 1049, 1022, 8445, 822, 741 cmÀ1; H NMR:
d=0.14 (q, J=8.0 Hz, 6H), 0.61 (t, J=8.0 Hz, 9H), 0.99 (s,
9H), 1.10 (s, 9H), 1.41 (s, 3H), 1.47 (s, 3H), 4.19 (dd, J=
2.5, 10.0 Hz, 1H), 4.53 (dd, J=2.0, 10.0 Hz, 1H), 4.58 (dd,
J=2.0, 3.5 Hz, 1H), 4.61 (d, J=2.5 Hz, 1H), 4.64 (d, J=
3.5 Hz, 1H), 7.29–7.45 (m, 12H), 7.59–7.64 (m, 4H), 7.67–
7.72 (m, 4H); 13C NMR: d=4.0 (CH2), 6.5 (CH3), 19.3 (C),
12
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FULL PAPERS
N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
The above oil was dissolved in CH2Cl2 (3 mL), and pyri-
dine (0.48 mL, 5.9 mmol), Ac2O (0.57 mL, 6.0 mmol), and
DMAP (4 mg, 0.03 mmol) were added. The mixture was
stirred at room temperature for 1.5 h and diluted with
EtOAc. The mixture was washed with 10% HCl, H2O, sat
aqueous NaHCO3, and brine, dried over Na2SO4, and con-
centrated under vacuum. The resulting oil was purified by
column chromatography (hexane/EtOAc 3:2 to 4:6) to give
the title compound as a yellow oil; yield: 127 mg (68%);
[a]2D0: +23 (c 0.33, CHCl3); IR (neat): n=3294, 3063, 3028,
2924, 2870, 1736, 1667, 1551, 1524, 1497, 1454, 1373, 1234,
H2O and brine, dried over Na2SO4, and concentrated under
vacuum to give crude epi-4a as a pale yellow oil; yield:
115 mg.
The above oil was dissolved in CH2Cl2 (2 mL), and pyri-
dine (0.16 mL, 2.0 mmol), Ac2O (0.19 mL, 2.0 mmol), and
DMAP (2 mg, 0.02 mmol) were added to the stirred solution
cooled in an ice-water bath. After 1.5 h, the reaction was
quenched by the addition of H2O (5 mL), and the whole
was extracted with CHCl3 (10 mLꢂ3). The combined organ-
ic layers were dried over Na2SO4 and concentrated under
vacuum to give crude product as a pale brown oil; yield:
128 mg. This oil was purified by column chromatography
(hexane/EtOAc 2:1) to give the title compound as a colorless
oil; yield: 64.9 mg (51%); [a]2D0: À18.2 (c 1.00, CHCl3); IR
(neat): n=3410, 3028, 3009, 2924, 2870, 1734, 1674, 1512,
1497, 1454, 1369, 1323, 1234, 1099, 1053, 1026, 914, 802,
1
1103, 1072, 1026, 756 cmÀ1; H NMR: d=1.86 (s, 3H), 2.01
(s, 3H), 3.57 (dd, J=1.5, 10.0 Hz, 1H), 3.67 (br m, 1H), 3.71
(br m, 1H), 3.90 (dd, J=2.5, 10.0 Hz, 1H), 4.32 (br d, J=
12.0 Hz, 1H), 4.36–4.42 (m, 2H), 4.45–4.57 (m, 4H), 4.67 (d,
J=12.0 Hz, 1H), 4.68 (d, J=12.0 Hz, 1H), 5.12 (t, J=
10.0 Hz, 1H), 5.12 (br s, 1H), 7.15–7.19 (m, 4H), 7.25–7.36
(m, 16H); 13C NMR: d=20.9 (CH3), 23.4 (CH3), 71.8 (CH2),
73.0 (CH), 73.1 (CH2), 73.2 (CH2), 73.5 (CH2), 73.6 (CH),
75.0 (CH), 76.5 (CH), 77.2 (CH), 127.65 (CH), 127.73 (CH),
127.8 (CH), 127.9 (CH), 128.1 (CH), 128.31 (CH), 128.34
(CH), 128.37 (CH), 128.43 (CH), 138.0 (C), 138.2 (C), 170.1
(C), 171.3 (C); HR-MS-ESI: m/z=662.2518 [M+K]+, calcd.
for C38H41KNO7: 662.2515. The stereochemistry was deter-
mined based on the trans-diaxial couplings of 1-H
(5.12 ppm) with 2-H and 6-H (both J=10 Hz) as shown in
Scheme 7. In addition, epi-14a (vide infra) was isolated as
a minor product; yield: 20 mg (11%).
1
752 cmÀ1; H NMR (À208C): d=1.81 (s, 3H), 2.04 (s, 3H),
3.78 (dd, J=3.0, 4.0 Hz, 1H), 3.84 (dd, J=3.0, 11.0 Hz, 1H),
3.86 (m, 1H), 3.94 (dd, J=3.0, 4.5 Hz, 1H), 4.36 (d, J=
11.5 Hz, 1H), 4.46 (d, J=11.0 Hz, 1H), 4.47 (d, J=12.0 Hz,
1H), 4.52 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H),
4.66 (d, J=11.5 Hz, 1H), 4.67 (d, J=11.0 Hz, 1H), 4.68 (d,
J=12.0 Hz, 1H), 5.04 (ddt, J=1.0, 9.0, 4.5 Hz, 1H), 5.22
(dd, J=4.0, 11.0 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 7.18–7.21
(m, 4H), 7.29–7.40 (m, 16H); 13C NMR: d=21.0 (CH3), 23.4
(CH3), 48.1 (CH), 70.7 (CH2), 70.8 (CH), 71.7 (CH), 73.0
(CH2), 73.5 (CH2), 74.1 (CH2), 74.5 (CH), 74.8 (CH), 79.1
(CH), 127.5 (CH), 127.57 (CH), 127.60 (CH), 127.7 (CH),
127.8 (CH), 128.1 (CH), 128.27 (CH), 128.30 (CH), 128.32
(CH), 128.5 (CH), 137.5 (C), 137.87 (C), 137.90 (C), 138.4
(C), 170.4 (C), 170.5 (C); FAB-MS: m/z=624 (M+H), 91
(Bn); HR-MS-FAB: m/z=624.2949 [M+H]+, calcd. for
C38H42NO7: 624.2956. The stereochemistry was determined
based on the trans-diaxial coupling (J=11.0 Hz) between 2-
H and 3-H (3.84 and 5.22 ppm, respectively) as shown in
Scheme 7.
(1S,2S,3R,4R,5S,6R)-2-Acetamido-3,4,5,6-tetrakis-
(benzyloxy)cyclohexyl acetate (epi-14a)
To a solution of 2a (109 mg, 0.203 mmol) in pyridine (2 mL),
was added HONH2·HCl (71 mg, 1.0 mmol), and the solution
was stirred at room temperature for 1.5 h. The solution was
diluted with EtOAc (20 mL), washed with H2O (20 mLꢂ3)
and brine, dried over Na2SO4, and concentrated under
vacuum to give crude oxime as a pale brown oil; yield:
139 mg.
The above oil was dissolved in CH2Cl2 (2 mL), and pyri-
dine (0.33 mL, 4.1 mmol), DMAP (3 mg, 0.02 mmol), and
Ac2O (0.38 mL, 4.0 mmol) were added to the stirred solu-
tion cooled in an ice-water bath. The mixture was stirred for
1 h, and the reaction was quenched by the addition of H2O
(10 mL). The whole was extracted with CHCl3 (20 mLꢂ3),
and the combined organic layers were washed with brine
(20 mL), dried over Na2SO4, and concentrated under
vacuum. The residual pyridine was removed by three-time
evaporation with toluene (10 mLꢂ3) to give crude O-acetyl
oxime as a yellow oil; yield: 131 mg.
The above oil was dissolved in EtOH (2 mL), and
NiCl2·6H2O (97 mg, 0.41 mmol) was added. To the mixture
cooled in an ice-water bath, NaBH4 (78 mg, 2.1 mmol) was
portion-wise added, and the cooling bath was removed.
After 1.5 h, the mixture was cooled in an ice-water bath,
and NaBH4 (78 mg, 2.1 mmol) was portion-wise added
again. The mixture was stirred at room temperature for 2 h
and diluted with EtOAc (20 mL). After addition of H2O
(20 mL), the whole was filtered through celite pad, which
was successively washed with EtOAc. The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(20 mLꢂ3). The combined organic layers were washed with
(1R,2R,3R,4R,5R)-2,3,4,5-Tetrakis(benzyloxy)-
cyclohexanol (5a)
To a solution of 2a (540 mg, 1.00 mmol), DMAP (18 mg,
0.15 mmol), and pyridine (0.28 mL, 3.5 mmol) in CH2Cl2
(10 mL) cooled in an ice-water bath, was added O-phenyl
chlorothioformate (0.42 mL, 3.0 mmol). After 2.5 h, MeOH
(2 mL) was added, and the mixture was stirred for another
10 min and evaporated. To the residue, EtOAc and water
were added, and the aqueous layer was separated and ex-
tracted 3 times with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrat-
ed under reduced pressure. The resulting orange oil (1.1 g),
containing O-phenoxythiocarbonyl inosose, was used in the
next reaction without purification. The crude inosose was
purified by column chromatography (hexane/EtOAc 95:5)
to provide a pale yellow solid; mp 88–908C; [a]2D0: À53.0 (c
1.21, CHCl3); IR (neat): n=3086, 3063, 3028, 2920, 2874,
1751, 1589, 1493, 1454, 1362, 1285, 1223, 1207, 1107, 1049,
1
1045, 1026, 1003, 914, 864, 818, 752 cmÀ1; H NMR: d=3.82
(dd, J=3.0, 4.0 Hz, 1H), 3.93 (dd, J=3.0, 4.0 Hz, 1H), 4.19
(dd, J=3.0, 11.0 Hz, 1H), 4.40 (d, J=12.0 Hz, 1H), 4.43 (d,
J=12.0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.53 (d, J=
12.0 Hz, 1H), 4.62 (d, J=3.0 Hz, 1H), 4.71 (d, J=12.0 Hz,
1H), 4.73 (d, J=12.0 Hz, 1H), 4.78 (d, J=12.0 Hz, 1H),
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
13
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FULL PAPERS
Bubwoong Kang et al.
4.90 (d, J=12.0 Hz, 1H), 6.15 (d, J=11.0 Hz, 1H), 7.09–7.44
(m, 25H); 13C NMR: d=72.8 (CH2), 73.7 (CH2), 73.8 (CH2),
73.9 (CH2), 74.9 (CH), 77.5 (CH), 78.8 (CH), 80.9 (CH),
85.6 (CH), 121.9 (CH), 126.6 (CH), 127.76 (CH), 127.78
(CH), 127.83 (CH), 127.9 (CH), 128.0 (CH), 128.3 (CH),
128.4 (CH), 128.5 (CH), 129.5 (CH), 137.5 (C), 137.7 (C),
153.6 (C), 194.8 (C), 197.0 (C); FAB-MS: m/z=697 (M+
Na), 91 (Bn); HR-MS-ESI: m/z=697.2233 [M+Na]+, calcd.
for C41H38NaO7S, 697.2231.
(1R,2R,3S,4R,5R)-2,3,4,5-Tetrakis(benzyloxy)cyclo-
hexyl acetate (15a)
To a solution of 5a (5.9 mg, 11 mmol), DMAP (1 mg,
8 mmol), and Et3N (0.01 mL, 0.07 mmol) in CH2Cl2 (0.1 mL)
cooled in an ice-water bath, was added Ac2O (0.01 mL,
0.1 mmol), and the mixture was stirred for 1 h. After addi-
tion of water (2 mL), the whole was extracted three times
with CHCl3. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under vacuum.
The residue was purified by column chromatography
(hexane/EtOAc 95:5) to give the title compound as a pale
yellow oil; yield: 4.0 mg (64%); [a]2D0: À3.9 (c 1.00, CHCl3);
IR (neat): n=3088, 3063, 3030, 2933, 2903, 2868, 1738, 1497,
1454, 1368, 1346, 1240, 1207, 1159, 1094, 1070, 1051, 1026,
To a solution of the above crude material in toluene
(10 mL), were added Bu3SnH (0.40 mL, 1.5 mmol) and
AIBN (16 mg, 0.097 mmol), and the solution was heated at
808C. After 2 h, another portion of AIBN (16 mg,
0.097 mmol) was added. After 1.5 h, AIBN (16 mg,
0.097 mmol) and Bu3SnH (0.40 mL, 1.5 mmol) were added
again. After 1 h, the mixture was evaporated, and the result-
ing yellow oil was purified by column chromatography
(hexane to hexane/EtOAc 95:5) to yield deoxyinosose as
a pale yellow oil; yield: 345 mg (66% in 2 steps); [a]2D0:
À61.3 (c 0.45, CHCl3); IR (neat): n=3086, 3063, 3028, 2924,
2870, 1732, 1496, 1454, 1366, 1327, 1312, 1265, 1215, 1111,
735 cmÀ1 1H NMR (608C): d=1.93–2.05 (m, 2H), 1.97 (s,
;
3H), 3.91–3.94 (m, 2H), 3.98 (dd, J=2.5, 9.0 Hz, 1H), 4.12
(br m, 1H), 4.64 (d, J=11.5 Hz, 1H), 4.66 (s, 2H), 4.67 (d,
J=11.5 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.71 (d, J=
11.5 Hz, 1H), 4.76 (d, J=11.5 Hz, 1H), 4.81 (d, J=11.5 Hz,
1H), 5.12 (ddd, J=2.5, 4.0, 11.0 Hz, 1H), 7.23–7.35 (m,
20H); 13C NMR: d=21.3 (CH3), 28.4 (CH2), 69.9 (CH), 71.6
(CH2), 72.5 (CH), 73.0 (CH2), 73.3 (CH2), 74.4 (CH2), 76.9
(CH), 79.1 (CH), 79.4 (CH), 127.45 (CH), 127.49 (CH),
127.54 (CH), 127.7 (CH), 127.82 (CH), 127.84 (CH), 128.27
(CH), 128.33 (CH), 128.4 (CH), 138.6 (C), 139.0 (C), 139.1
(C), 139.2 (C), 170.6 (C); HR-MS-ESI: m/z=605.2300 [M+
K]+, calcd. for C36H38KO6: 605.2300. The stereochemistry
was determined based on the coupling constant (2.5, 4.0,
and 11.0 Hz) of the methine proton that the AcO group at-
taches on, indicating an equatorial orientation of the AcO
group and axial orientation of the adjacent BnO groups, as
shown in Scheme 7.
1
1026, 1003, 914, 802, 752 cmÀ1; H NMR: d=2.75 (ddd, J=
1.5, 5.0, 13.0 Hz, 1H), 2.84 (dd, J=11.0, 13.0 Hz, 1H), 3.93
(ddd, J=1.5, 2.5, 5.0 Hz, 1H), 3.99 (dd, J=3.5, 5.0 Hz, 1H),
4.06 (ddd, J=2.5, 5.0, 11.0 Hz, 1H), 4.431 (d, J=12.0 Hz,
1H), 4.433 (d, J=3.5 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H),
4.47 (d, J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.55 (d,
J=12.0 Hz, 1H), 4.74 (d, J=12.0 Hz, 1H), 4.75 (d, J=
12.0 Hz, 1H), 4.87 (d, J=12.0 Hz, 1H), 7.16–7.19 (m, 4H),
7.27–7.37 (m, 16H); 13C NMR: d=42.2 (CH2), 71.4 (CH2),
72.6 (CH2), 73.4 (CH2), 73.5 (CH2), 75.7 (CH), 75.8 (CH),
78.1 (CH), 81.5 (CH), 127.5 (CH), 127.68 (CH), 127.73
(CH), 127.76 (CH), 127.79 (CH), 128.3 (CH), 128.38 (CH),
128.42 (CH), 137.8 (C), 138.0 (C), 138.05 (C), 138.14 (C),
204.6 (C); HR-MS-ESI: m/z=545.2299 [M+Na]+, calcd. for
C34H34NaO5: 545.2299.
(1R,2R,3R,4R,5R,6S)-2,3,4,5-Tetrakis(benzyloxy)-6-
To a solution of the above oil (9.0 mg, 17 mmol) in MeOH
(0.2 mL) cooled in an ice-water bath, was added NaBH4
(1.7 mg, 45 mmol), and the mixture was stirred for 40 min.
After addition of saturate aqueous NH4Cl, the whole was
extracted with EtOAc (1.5 mLꢂ4). The combined organic
layers were washed with brine (4.5 mL), dried over Na2SO4,
and evaporated. The residue was purified by column chro-
matography (hexane/EtOAc 9:2) to give the title compound
as a pale yellow solid; yield: 8.3 mg (93%); mp 91–92.58C;
[a]2D0: À24 (c 0.30, CHCl3); IR (KBr): n=3314, 3086, 3063,
3028, 2955, 2928, 2855, 2878, 2758, 2739, 2677, 1496, 1454,
1435, 1315, 1261, 1207, 1150, 1099, 1084, 1065, 1026, 1084,
methoxycyclohexanol (6a)
To a solution of 2a (107 mg, 0.198 mmol) and proton sponge
(85 mg, 0.40 mmol) in CH2Cl2 (2 mL), was added Me3O·BF4
(59 mg, 0.40 mmol) at room temperature. After 14 h, water
(8 mL) was added, and the whole was extracted with CHCl3
(8 mLꢂ2). The combined organic layers were washed with
brine (16 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (hexane/EtOAc 5:1) to yield O-methylinosose
as a colorless oil; yield: 103 mg (90%); [a]2D0: À39.0 (c 1.00,
CHCl3); IR (neat): n=3395, 3086, 3062, 3028, 3086, 3005,
2920, 2873, 1743, 1654, 1543, 1497, 1454, 1385, 1366, 1323,
1
914, 868, 802, 745 cmÀ1; H NMR (608C): d=1.85–1.95 (br s,
1026, 1150, 1111, 1026, 957, 918, 737 cmÀ1; H NMR: d=3.58
1
1H), 1.98 (ddd, J=3.5, 7.5, 11.5 Hz, 1H), 3.86–3.88 (m, 2H),
3.95 (dd, J=2.5, 7.5 Hz, 1H), 3.97 (br s, 1H), 4.09 (br s,
1H), 4.55–4.72 (m, 7H), 4.77 (br s, 1H), 7.21–7.35 (m, 20H);
13C NMR: d=32.4 (CH2), 71.5 (CH2), 72.5 (CH), 73.0
(CH2), 73.9 (CH2), 79.4 (CH), 127.6 (CH), 127.66 (CH),
127.72 (CH), 127.8 (CH), 127.9 (CH), 128.39 (CH), 128.41
(CH), 128.49 (CH), 128.51 (CH), 138.7 (C), 138.8 (C), 138.9
(C); HR-MS-ESI: m/z=547.2453 [M+Na]+, calcd. for
C34H36NaO5, 547.2455. The stereochemistry was determined
at the stage of 15a.
(s, 3H), 3.75 (dd, J=3.5, 4.0 Hz, 1H), 3.88 (dd, J=3.0,
4.0 Hz, 1H), 3.90 (dd, J=3.5, 10.0 Hz, 1H), 4.18 (dd, J=1.0,
10.0 Hz, 1H), 4.36 (d, J=12.0 Hz, 1H), 4.43 (d, J=12.0 Hz,
1H), 4.48 (dd, J=1.0, 3.0 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H),
4.53 (d, J=12.0 Hz, 1H), 4.68 (d, J=12.0 Hz, 1H), 4.73 (d,
J=12.0 Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.88 (d, J=
12.0 Hz, 1H), 7.08–7.16 (m, 4H), 7.25–7.36 (m, 16H);
13C NMR: d=59.9 (CH3), 72.5 (CH2), 73.3 (CH2), 73.7
(CH2), 74.0 (CH2), 75.3 (CH), 77.2 (CH), 80.6 (CH), 80.7
(CH), 85.7 (CH), 127.6 (CH), 127.71 (CH), 127.73 (CH),
127.8 (CH), 127.9 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 137.7 (C), 137.8 (C), 137.9 (C), 138.5 (C), 202.8 (C);
FAB-MS: m/z=575 (M+Na), 329, 136, 91 (Bn); HR-MS-
14
asc.wiley-vch.de
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
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FULL PAPERS
N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for Divergent Synthesis
FAB : m/z=575.2415 [M+Na]+, calcd. for C35H36NaO6,
575.2404.
(1R,2R,3R,4R,5S,6S)-3,4,5,6-Tetrakis(benzyloxy)-1,2-
isopropylidenedioxy-1-methylcyclohexane (16a)
To a solution of the above oil (9.7 mg, 18 mmol) in MeOH
(0.2 mL) cooled in an ice-water bath, was added NaBH4
(2 mg, 0.05 mmol). After 30 min, saturated aqueous NH4Cl
(1.5 mL) was added, and the whole was extracted with
EtOAc (1.5 mLꢂ5). The combined organic layers were
washed with brine (8 mL), dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc 2:1) to yield the
title compound as a colorless oil; yield: 8.4 mg (86%); [a]2D0:
À13 (c 0.42, CHCl3); IR (neat): n=3502, 3028, 3009, 2924,
2874, 1497, 1454, 1358, 1261, 1215, 1092, 1041, 1026, 910,
To a solution of 7a (66 mg, 0.12 mmol) in 2,2-dimethoxypro-
pane (2.0 mL, 16 mmol) was added TsOH·H2O (5 mg,
0.03 mmol) at room temperature. The mixture was stirred
for 2 h, and saturated aqueous NaHCO3 (10 mL) was added.
The whole was extracted with EtOAc (10 mLꢂ3), and the
combined organic layers were washed with brine (30 mL),
dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by column chromatography
(hexane/EtOAc 96:4) to yield the title compound as a color-
less oil; yield: 66 mg (93%); [a]2D5: À27.2 (c 1.44, CHCl3); IR
(neat): n=3086, 3062, 3028, 3005, 2982, 2932, 2889, 2878,
1497, 1454, 1377, 1308, 1258, 1242, 1211, 1188, 1115, 1088,
802, 748 cmÀ1
;
1H NMR (À208C): d=3.50 (dd, J=2.5,
10.0 Hz, 1H), 3.57 (s, 3H), 3.64 (br s, 1H), 3.66 (br s, 1H),
3.77 (br s, 1H), 3.94 (dd, J=2.0, 10.0 Hz, 1H), 4.34 (d, J=
12.0 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 4.45 (d, J=12.0 Hz,
1H), 4.47 (br s, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.58 (d, J=
12.0 Hz, 1H), 4.63 (d, J=12.0 Hz, 1H), 4.68 (d, J=12.0 Hz,
1H), 4.82 (d, J=12.0 Hz, 1H), 7.05–7.45 (m, 20H);
13C NMR (À208C): d=58.0 (CH3), 68.6 (CH), 70.4 (CH2),
72.9 (CH), 73.2 (CH2), 73.6 (CH2), 74.8 (CH), 75.7 (CH),
77.8 (CH), 79.8 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH),
127.78 (CH), 127.84 (CH), 127.9 (CH), 128.0 (CH), 128.29
(CH), 128.34 (CH), 128.4 (CH), 137.0 (C), 137.8 (C), 137.9
(C), 138.7 (C); HR-MS-ESI: m/z=577.2568 [M+Na]+,
calcd. for C35H38NaO6: 577.2561. The stereochemistry was
determined based on the trans-diaxial coupling (J=10.0 Hz)
between 5-H and 6-H (3.94 and 3.50 ppm, respectively) as
shown in Scheme 7.
1
1072, 1026, 984, 918, 864, 752, 733 cmÀ1; H NMR: d=1.36
(s, 3H), 1.38 (s, 3H), 1.39 (s, 3H), 3.65 (d, J=3.0 Hz, 1H),
3.87 (dd, J=3.0, 6.5 Hz, 1H), 4.08 (d, J=5.0 Hz, 1H), 4.10
(dd, J=3.5, 6.5 Hz, 1H), 4.19 (dd, J=3.5, 5.0 Hz, 1H), 4.57
(s, 2H), 4.65 (d, J=12.0 Hz, 1H), 4.67 (d, J=12.0 Hz, 1H),
4.68 (d, J=12.0 Hz, 1H), 4.72 (d, J=12.0 Hz, 1H), 4.74 (d,
J=12.0 Hz, 1H), 4.76 (d, J=12.0 Hz, 1H), 7.23–7.37 (m,
20H); 13C NMR: d=26.0 (CH3), 27.0 (CH3), 27.6 (CH3),
72.3 (CH2), 72.89 (CH2), 72.92 (CH2), 74.7 (CH2), 76.5 (CH),
76.9 (CH), 77.2 (CH), 81.0 (CH), 81.2 (C), 82.2 (CH), 109.7
(C), 127.31 (CH), 127.32 (CH), 127.34 (CH), 127.4 (CH),
127.49 (CH), 127.52 (CH), 127.6 (CH), 128.07 (CH), 128.11
(CH), 128.15 (CH), 128.18 (CH), 138.6 (C), 138.7 (C), 138.8
(C); FAB-MS: m/z=617 (M+Na), 329, 176, 91 (Bn); HR-
MS-FAB: m/z=617.2873 [M+Na]+, calcd. for C38H42NaO6:
617.2874. The relative configuration was determined by
NOESY correlation between angular CH3 (1.36 ppm) and H
(4.05 ppm) as shown in Scheme 7.
(1R,2R,3R,4R,5S,6S)-3,4,5,6-Tetrakis(benzyloxy)-1-
methylcyclohexane-1,2-diol (7a)
(2R,3S,4R,5S,6S)-2,3,4,5,6-Pentahydroxycyclo-
hexanone (allo-2-inosose; Scheme 8)
A
1.5M solution of MeLi·LiBr in THF (0.23 mL,
0.35 mmol) was diluted with Et2O (0.4 mL) and cooled at
À788C. A solution of 2a (62 mg, 0.12 mmol) in Et2O
(0.4 mL+0.2 mL washꢂ2) was added, and the cooling bath
was replaced with an ice-water bath. After 2 h, saturated
aqueous NH4Cl (2 mL) was added, and the whole was ex-
tracted with EtOAc (2 mLꢂ4). The combined organic layers
were washed with brine (8 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (hexane/EtOAc 3:1 to 2:1)
to yield the title compound as a colorless oil; yield: 57 mg
(89%); [a]20: +15.8 (c 1.00, CHCl3); IR (neat): n=3483,
3086, 3063,D3028, 3005, 2982, 2932, 2870, 1655, 1605, 1543,
1497, 1420, 1385, 1366, 1331, 1250, 1207, 1142, 1099, 1065,
To a solution of 2a (819 mg, 1.52 mmol) in MeOH (10 mL),
was added 10% Pd/C (wetted with 55% water, 485 mg,
0.20 mmol), and the mixture was stirred under an H2 atmos-
phere at room temperature for 24 h. After addition of H2O
(10 mL) and activated charcoal (500 mg), the mixture was
stirred for 20 min and filtered through filter paper, which
was washed with H2O (10 mLꢂ3). The combined filtrate
was concentrated under vacuum to give the title compound
as colorless blocks; yield: 228 mg (84%); mp 180–1828C
(H2O/i-PrOH); [a]D20: +75.1 (c 1.04, H2O) {lit:[41] mp 195–
1
1978C, [a]2D0: +68.6 (c 1, H2O)}; H NMR (DMSO-d6): d=
3.56 (br m, 1H), 3.82 (br s, 1H), 3.92 (br s, 1H), 4.15 (br d,
J=6.5 Hz, 1H), 4.39 (br s, 1H), 4.71 (br s, 1H), 4.91 (br s,
1H), 5.00 (br s, 1H), 5.10 (br s, 1H), 5.28 (br s, 1H);
13C NMR (DMSO-d6): d=71.1 (CH), 73.3 (CH), 73.6 (CH),
74.2 (CH), 75.7 (CH), 208.0 (C); HR-MS-ESI: m/z=
1026, 964, 914, 802, 748 cmÀ1 1H NMR: d=1.34 (s, 3H),
;
2.41 (br s, 1H), 3.49 (br s, 1H), 3.60–3.78 (m, 4H), 3.82 (br
s, 1H), 4.43–4.42 (m, 2H), 4.45–4.63 (m, 5H), 4.71 (d, J=
12.0 Hz, 1H), 7.09–7.19 (m, 4H), 7.23–7.39 (m, 16H);
13C NMR: d=22.1 (CH3), 72.9 (CH2), 73.1 (CH2), 73.2
(CH2), 73.7 (CH2), 74.2 (CH), 76.4 (CH), 77.2 (CH), 77.9
(CH), 99.8 (C), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.0
(CH), 128.1 (CH), 128.35 (CH), 128.42 (CH), 128.5 (CH),
137.1 (C), 137.7 (C), 138.2 (C), 138.5 (C); FAB-MS: m/z=
577 (M+Na), 525, 481, 437, 393, 349, 305, 243, 183, 91 (Bn);
HR-MS-FAB: m/z=577.2565 [M+Na]+, calcd. for
C35H38NaO6: 577.2561. The stereochemistry was determined
at the stage of 16a.
1
201.0378 [M+Na]+, calcd. for C6H10NaO6: 201.0370. H and
13C NMR data were in good agreement with those report-
ed.[41]
d-chiro-Inositol
To a solution of chiro-3a (195 mg, 0.361 mmol) in MeOH
(2 mL), was added 10% Pd/C (wetted with 55% water,
193 mg, 82 mmol), and the mixture was stirred under an H2
atmosphere at room temperature for 10 h. After addition of
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Bubwoong Kang et al.
H2O (5 mL), the whole was filtered through filter paper,
which was washed with H2O (5 mLꢂ3). The combined fil-
trate was concentrated under vacuum to give the title com-
pound as a slightly brown solid; yield: 53 mg (81%); mp
231–2358C (H2O/EtOH); [a]2D0: +65.2 (c 1.05, H2O) {lit:
[a]2D4: +85.5 (c 0.1, H2O);[5f] mp 238–2428C, [a]2D0: +63.2 (c 1,
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Chem. Pharm. Bull. 1988, 36, 3714.
1
H2O)[41]}; H NMR (D2O): d=3.52 (m, 4H), 3.70 (m, 4H),
3.96 (br s, 4H); 13C NMR (D2O): d=71.0 (CH), 72.3 (CH),
73.3 (CH); HR-MS-ESI: m/z=203.0532 [M+Na]+, calcd.
for C6H12NaO6: 203.0526. 1H and 13C NMR data were in
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Acknowledgements
We thank Hiroki Konegawa for his contribution in the pre-
liminary study. We thank JSPS [Grant-in-Aid for Young Sci-
entist (B)]; MEXT (Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” and Platform for Drug Design, Discovery
and Development); and Takeda Science Foundation for fi-
nancial support.
[12] a) Y. Watanabe, M. Mitani, S. Ozaki, Chem. Lett. 1987,
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18 N-Heterocyclic Carbene-Catalyzed Benzoin Strategy for
Divergent Synthesis of Cyclitol Derivatives from Alditols
Adv. Synth. Catal. 2014, 356, 1 – 18
Bubwoong Kang, Toshiaki Sutou, Yinli Wang,
Satoru Kuwano, Yousuke Yamaoka, Kiyosei Takasu,*
Ken-ichi Yamada*
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