Stereoselective synthesis of a novel natural carbasugar and analogues from hydroxymethylated cycloalkenone scaffolds

Article abstract of DOI:10.1016/j.tetasy.2012.03.001

Novel carbasugars from Streptomyces lincolnensis have been synthesized from an enantiomerically pure 5-hydroxymethyl-cyclohex-2-enone scaffold via a stereoselective approach. Several structural analogues of those carbasugars have also been synthesized in a stereoselective manner from hydroxymethylated cycloalkenone derivatives.

Full text of DOI:10.1016/j.tetasy.2012.03.001

Tetrahedron: Asymmetry 23 (2012) 364–372
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of a novel natural carbasugar and analogues
from hydroxymethylated cycloalkenone scaffolds
⇑
Rohan Rej, Navendu Jana, Shantasree Kar, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 February 2012
Accepted 2 March 2012
Novel carbasugars from Streptomyces lincolnensis have been synthesized from an enantiomerically pure 5-
hydroxymethyl-cyclohex-2-enone scaffold via a stereoselective approach. Several structural analogues of
those carbasugars have also been synthesized in a stereoselective manner from hydroxymethylated
cycloalkenone derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
tional scaffolds, which can be successfully applied for the
asymmetric synthesis of natural products7 and designed cyclitols.8
Nature has been a great source of therapeutic agents for many
decades and continues to be a rich supplier of novel chemotypes
and pharmacophores. With only 5–15% of the approximately
250,000 species of higher plants thoroughly investigated,1 and
the potential of the marine environment scarcely tapped, these
areas remain an essential resource for the discovery of new bioac-
tive compounds. Less than 1% of bacterial and 5% of fungal species
have been explored, and the probability of finding novel microbial
sources, predominantly in extreme environments, seems limit-
less.2 It is thus obvious that Nature can offer novel multifunctional
chemical scaffolds for synthetic manipulation by combinatorial ap-
proaches (chemical and biochemical), leading to agents that have
been optimized on the basis of their pharmacological activities.3
The proven natural product guided drug discovery programme,
coupled with the enduring threat to biodiversity through the
destruction of terrestrial and marine ecosystems and the current
low number of new chemical entities in pharmaceutical industry
pipelines, provides undeniable argument in favor of expanded
multidisciplinary and international collaboration in the explora-
tion of nature as a source of new lead molecules for the develop-
ment of drugs and other precious medicinally active ingredients.
Streptomyces lincolnensis is well known to produce antibiotics
and other secondary metabolites under normal cultivation condi-
tions.4 Recently novel carbasugars (hydroxy skipped at the 4-posi-
tion; 1 and 2; Fig. 1) have although isolated from S. lincolnensis.5
Simple carbasugars are usually not abundant in Nature, however
they are often present as a subunit of natural products exhibiting
a wide array of biological activities.6 In our recent work in the area
of SOS (scaffold oriented synthesis), we have identified hydrox-
ymethylated cycloalkenone derivatives as potential multifunc-
Herein we report the synthesis of two carbasugars isolated from
S. lincolnensis 1 and 2 and a few of its structural analogues. We
have also synthesized novel carbasugars based on a cyclopentane
framework from 5-hydroxymethyl-2-cyclopentenone and some
cyclopropane based carbasugars in a stereoselective manner. The
main highlight of our synthetic strategy was the stereoselective
reduction of the carbonyl functionality of the core hydroxymethy-
lated cycloalkenone scaffolds, substrate directed asymmetric
epoxidation/cyclopropanation, and stereoselctive dihydroxylation
(Scheme 1).
2. Results and discussion
2.1. Synthesis of natural carbasugars 1 and 2, their analogues
and related cyclopropane carbasugars from 5-hydroxymethyl-
ated cyclohex-2-enone
The parent scaffold was synthesized by adopting a known liter-
ature procedure.9 However, we found that the procedure was inef-
fective in terms of chemical yield. Hence we decided to adopt a
new strategy for synthesizing both the scaffolds (cyclopentane
and cyclohexane based) from the same starting material. We
started by using 2-allyl-1,3-propane diol. Selective monoprotec-
tion with NaH and TBDPS-Cl afforded the mono TBDPS protected
alcohol 7 in 90% yield. Enzymatic kinetic resolution (EKR) of 7 with
lipase PS-D and vinyl acetate as acyl donor afforded (R)-acetate 8
and (S)-alcohol 9 with excellent enantioselectivity. Compound 9
was oxidized under Swern’s conditions10 to afford aldehyde 10 in
92% yield. Vinylmagnesium bromide addition onto aldehyde 10
at ꢀ78 °C afforded alcohol 11 in 78% yield as a diastereomeric mix-
ture. The alcohol functionality in 11 was oxidized to compound 12
in 88% yield. The ring closing metathesis (RCM) reaction of com-
pound 12 with G-I catalyst11 in DCM as the solvent afforded the
⇑
Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.001

R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
365
RO
68% yield. Deprotection of the TBDPS group was achieved as before
to afford the cyclopropane based carbasugar 4 in 80% yield (overall
yield = 44% from 19; Scheme 3).
RO
Compound 19 upon reduction with L-selectride16 at ꢀ78 °C
afforded compound 24 as a single product in 72% yield. The sub-
strate directed cyclopropanation afforded compound 25 in 80%
yield as a single diastereomer. Deprotection of the TBDPS group
with TBAFꢁTHF afforded cyclopropane carbasugar 5 in 88% yield
(overall yield = 50% from 19). The substrate directed epoxidation
of 24 with mCPBA afforded epoxide 26 as a single diastereomer
in 78% yield. The ring opening of epoxide17 26 was achieved with
0.2 M H2SO4 to afford triol 27 (71% yield), which upon deprotection
of the TBDPS group afforded carbasugar 3 in 84% yield (overall
yield = 33% from 19; Scheme 3).
RO
OR
RO
OR
OR
OR
1
2
R = H
Figure 1. Novel carbasugars from S. lincolnensis.
5-hydroxymethyl-2-cyclopentenone scaffold 13 in 76% yield. The
other enantiomer of compound 13 can easily be synthesized by
applying the same procedure starting from acetate 8.
For the synthesis of 5-hydroxymethyl-2-cyclohexenone, we
started with(R)-acetate 8, which was transformed into the corre-
sponding mesylate 14 in 93% yield by deacetylation followed by
treatment with methanesulfonyl chloride (MsCl) and triethyl
amine. Treatment of compound 14 with NaCN in refluxing DMSO
as a solvent afforded compound 15 in 90% yield. Compound 15
on DIBAL-H reduction at ꢀ78 °C afforded the aldehyde 16 in 82%
yield.12 Vinylmagnesium bromide addition onto aldehyde 16
yielded compound 17 in 80% yield. After Swern oxidation of com-
pound 17, respective ketone 18 was obtained in 90% yield. The
RCM with compound 18 with the G-I catalyst afforded the parent
cyclohexane based scaffold 19 in 90% yield. The other enantiomer
of 19 can also be synthesized by adopting a similar strategy start-
ing from alcohol 9 (Scheme 2).
For the synthesis of carbasugar analogue 6, the secondary hy-
droxyl group in 20 was protected as its TBS ether by treatment
of TBSꢁCl in the presence of imidazole to afford compound 28 in
82% yield. Epoxidation of compound 28 was achieved with mCPBA
to yield the epoxide 29 as the sole product in 79% yield. The reac-
tion outcome in favor of the formation of 29, was attributed mainly
due to the steric parameters imposed by the TBDPS and TBS
groups. The selective deprotection of the TBS group was achieved
with PPTS/MeOH to afford the epoxy alcohol 30 in 76% yield. The
epoxide opening of compound 30 was achieved by applying similar
condition as described earlier to afford triol 31 in 70% yield. Finally
removal of the TBDPS group afforded the carbasugar 6 in 87% yield
(overall yield = 25% from 19; Scheme 3).
After the successful synthesis of both scaffolds 13 and 19 (in
both enantiomeric forms) we turned our attention toward the syn-
thesis of natural carbasugars 1 and 2 and their analogues. The syn-
thetic route for the cyclohexane based carbasugars 1 and 2 has
started from compound 19. Reduction of the carbonyl functionality
with an NaBH4ꢁCeCl3 reagent system13 afforded compound 20 as a
single diastereomer in 82% yield. Dihydroxylation of 20 with OsO4
followed by deprotection with TBAF/THF at room temperature
afforded the carbasugar 2 in 60% overall yield (in two steps). A sim-
ilar type of stereoselective hydroxylation has already been demon-
strated in our earlier work. The substrate directed epoxidation14 of
compound 20, with mCPBA (meta-chloro per-benzoic acid) affor-
ded epoxide 21 as the major diastereomer (20:1 in favor of 21)
in 75% yield. The acid catalyzed epoxide ring opening of 21 fur-
nished compound 22 as a single product in 65% yield. Deprotection
of the TBDPS group with TBAF–THF afforded carbasugar 1 in 83%
yield (overall yield = 33% from 19; Scheme 3).
2.2. Synthesis of carbasugar analogues and related
cyclopropane carbasugars from 5-hydroxymethylated
cyclopent-2-enone
For the synthesis of carbasugars based on the cyclopentane
scaffolds, we started from the parent 5-hydroxymethyl-2-cyclo-
pentenone 13. Reduction with NaBH4ꢁCeCl3 afforded compounds
32 and 33 in equimolar ratio and they could be separated by chro-
matography. At this point we are unsure about the absolute config-
urations of 32 and 33, hence both compounds were subjected to
next round of reaction. The substrate directed epoxidation of syn-
diastereomer 32 with mCPBA afforded two epoxides 34 (substrate
directed) and 35 (directed by steric factors) in a 4:1 ratio. The
epoxidation of 33 under similar conditions afforded epoxide 36
as a single product. The formation of the single epoxide diastereo-
mer 36 from 35 can be attributed to the combined effort of the di-
rected reaction as well as the steric effects caused by the bulky
OTBDPS groups on the cyclopentane ring that indirectly correlates
to the fact that 33 is an anti-diastereomer. Epoxides 34 and 35
Compound 20, when treated with a Zn–Cu couple15 and CH2Br2,
afforded the cyclopropane derivative 23 as a single diastereomer in
O
OH
OH
H
HO
HO
OTBDPS
OTBDPS
OH
OH
H
carbasugars 1-2 and analogues
cyclopropane carbasugars
OH
OH
O
OH
OH
H
HO
HO
H
cyclopentane based carbasugars
Scheme 1. 5-Hydroxymethyl-cycloalkenones as starting materials for carbasugar synthesis.

366
R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
OTBDPS
OH
OTBDPS
OH
OTBDPS
a
b
+
OH
OH
OAc
7
(R)-8, ee = 96%
9
(S)- , ee = 94%
c
O
OP
OTBDPS
O
OTBDPS
OTBDPS
f
d
e
CHO
13
OH
10
12
11
P = TBDPS
OTBDPS
OMs
OTBDPS
CN
OTBDPS
CHO
g
h
j
i
8
14
16
15
O
O
OTBDPS
OH
k
l
OTBDPS
OTBDPS
17
18
19
Scheme 2. Reagents and conditions: (a) NaH, TBDPS-Cl, THF, rt, 90%; (b) Lipase PS-D; vinyl acetate, DIPE; (c) (COCl)2, Me2SO, Et3N, ꢀ78 °C, 92%; (d) CH2@CHMgBr, THF,
ꢀ78 °C, 78%; (e) same as c, 88%; (f) G-I, DCM, rt, 90%; (g) (i) K2CO3, MeOH, rt, (ii) Et3N, Ms-Cl, DCM, rt, 93%; (h) NaCN, DMSO, reflux, 90%; (i) DIBAL-H, ꢀ78 °C, 82%; (j) same as
conditions d; 80%; (k) same as conditions c, 90%; (l) same as conditions f; 78%.
were treated separately with 0.2 M H2SO4 in dioxane to afford the
epoxide cleaved triol products 37 and 38. Cleavage of the OTBDPS
groups under standard conditions afforded the cyclopentane based
carbasugars 40 and 41. A similar reaction sequence was performed
with epoxide 36 to give carbasugar 42 (overall yield = 27% from 13,
Scheme 4).
Compound 32 was subjected to a cyclopropanation reaction un-
der standard Simmon–Smith conditions to afford cyclopropane
derivatives 43 and 44 in a 6:1 ratio, which could be separated by
chromatography. Deprotection of the OTBDPS group with
TBAFꢁTHF afforded cyclopropane based carbasugars 45 and 46. A
similar reaction sequence was performed with 33 to afford cyclo-
propane based carbasugars 48 (Scheme 4, overall yield = 57% from
13).
Lipase PS-D (Burkholderia cepacia, immobilized on diatomite),
was purchased from Amano, Japan. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel plates (Merck) with UV light, ethanolic anisaldehyde and phos-
phomolybdic acid/heat as developing agents. Silica gel 100–200
mesh was used for column chromatography. Concentrations were
performed on a Buchi rotary evaporator at a temperature below
40 °C. Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. NMR spectra
were recorded on Bruker 200 and 400 MHz spectrometers at
25 °C in CDCl3 using TMS as the internal standard. Chemical shifts
are shown in d. 13C NMR spectra were recorded with a complete
proton decoupling environment. The chemical shift value is listed
as dH and dC for 1H and 13C, respectively. For NMR spectra in deu-
terated solvents, the solvent peak was used as the reference
(CDCl3: d = 7.26 for 1H, 76.93 for 13C). Optical rotations were mea-
sured on a JASCO P-1020 digital polarimeter. Mass spectroscopic
analysis was performed at IACS-Kolkata. Chiral HPLC was per-
formed using Chiral OJ-H and OD-H column (0.46 ꢂ 25 cm, Daicel
industries) with a Shimadzu Prominence LC-20AT chromatograph
coupled with a UV–Vis detector (254 nm). Eluting solvent used
had different ratios of hexane and 2-propanol.
3. Conclusion
In conclusion, we have described stereoselective synthetic
strategies for the synthesis of a few natural cyclohexane based car-
basugars 1 and 2 isolated from Streptomyces lincolnensis. The syn-
thetic strategy described herein is a unified and general one, and
was successfully applied to the synthesis of several carbasugar
analogues based on cyclohexane and cyclopentane scaffolds.
4.1.1. 2-(tert-Butyldiphenylsilanyloxymethyl)-pent-4-en-1-ol 7
At first, NaH (60% dispersion in mineral oil, 0.45 g, 11.2 mmol)
was taken in 50 mL of dry THF. Then, 2-allyl-1,3-propane diol
(1.3 g, 11.2 mmol) was added to it portionwise at 0 °C. The reaction
mixture was stirred at 0 °C for 1 h. Next, TBDPSꢁCl (2.9 mL,
11.2 mmol) was added to the reaction mixture. The reaction mix-
ture was stirred overnight at room temperature. Water was added
carefully to the reaction mixture to quench any excess NaH. The
reaction mixture was then extracted with a large volume of diethyl
ether. The organic solution was washed with water and brine.
Evaporation and purification by means of silica gel chromatogra-
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethylether were distilled from sodium benzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF) and dimeth-
ylsulfoxide (DMSO) were distilled from calcium hydride. Diisopro-
pyl ether (DIPE) was refluxed over P2O5 and distilled prior to use.

R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
367
OH
O
OH
HO
HO
a
i
OP
OP
OH
2
20
19;
P = TBDPS
g
b
e
OTBS
OH
OH
OH
f
19
OP
O
OP
OP
OP
28
24
23
21
b
d
c
b
e
OTBS
OH
OH
OH
OH
HO
HO
O
OP
O
OP
OH
OP
OP
29
22
4
25
26
d
h
d
c
OH
OH
OH
OH
HO
HO
HO
HO
O
OH
OP
OH
OP
1
30
27
5
c
d
OH
OH
HO
HO
HO
HO
OP
OH
31
3
d
OH
HO
OH
HO
6
Scheme 3. Stereoselective synthesis of cyclohexane based carbasugars; Reagents and conditions: (a) CeCl3ꢁ7H2O, NaBH4, MeOH, 0 °C to rt, 3 h; (b) mCPBA, NaHCO3, DCM, 0 °C
to rt, 2 h; (c) 0.2 M H2SO4/dioxan (1:1), rt, 6 h; (d) TBAF, THF, 0 °C, rt, 5 h; (e) CH2Br2, Zn–Cu couple, diethylether, 30 h, reflux; (f) L-selectride, ꢀ78 °C, THF, 2 h; (g) TBS-Cl,
imidazole, DCM, rt, 6 h; (h) PPTS, MeOH, rt, 4 h; (i) AD mix-b, MeSo2NH2, TBAF, THF.
phy (50:1, petroleum ether/EtOAc) afforded the compound 7 in
90% yield. dH (200 MHz, CDCl3): 7.75–7.71 (m, 4H), 7.45–7.43 (m,
6H), 5.86–5.65 (m, 1H), 5.9–4.99 (m, 2H), 3.87–3.67 (m,4H), 3.01
(broad s,1H), 2.15–2.08 (t, 2H, J = 6.8 Hz), 1.96–1.91 (m, 1H), 1.12
(s, 9H). dC (50 MHz, CDCl3): 136.4, 135.6, 133.2, 129.9, 127.8,
116.4, 66.1, 65.0, 42.3, 32.4, 26.9, 19.3.
4.1.2. (R)-Acetic acid 2-diphenylsilanyloxymethyl-pent-4-enyl
ester 8
Compound 7 (2.7 g, 7.3 mmol) was taken in 50 mL of dry anhy-
drous diisopropyl ether (DIPE) on 4 Å molecular sieves. Then li-
pase-AK enzyme (1 g) was added to it followed by the addition
of vinyl acetate (1.4 mL, 15 mmol) to the reaction mixture at

368
R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
O
OH
OH
OH
a
OTBDPS
OH
b
+
OTBDPS
OH
OTBDPS
OTBDPS
OTBDPS
OH
O
13
32
33
36
c
+
OH
OTBDPS
OTBDPS
O
O
HO
34
35
HO
c
c
39
d
OH
OH
HO
HO
OH
OTBDPS
OTBDPS
HO
HO
38
HO
37
d
HO
d
42
OH
OH
OH
HO
HO
OH
H
OH
e
OTBDPS
33
HO
HO
+
41
40
47
H
OH
H
OH
H
d
e
OTBDPS
OTBDPS
32
OH
44
43
H
H
H
d
d
OH
OH
48
OH
H
H
H
OH
OH
46
H
45
H
Scheme 4. Reagents and conditions: (a) CeCl3ꢁ7H2O, NaBH4, MeOH, 0 °C to rt, 3 h; (b) mCPBA, NaHCO3, DCM, 0 °C to rt, 19 h; (c) 0.2 M H2SO4/dioxane (1:1); rt, 6 h; (d) TBAF,
THF, rt; (e) CH2Br2, Zn–Cu couple, diethylether, 30 h, reflux.
25 °C. The reaction mixture was stirred at 25 °C for 3 h. The reac-
tion mixture was then filtered on a Celite pad. Evaporation and
purification by means of silica gel chromatography (20:1, petro-
leum ether/EtOAc) afforded acetate 8 (1.34 gm) and alcohol 9
(1.264 g) in 95% yield. dH (200 MHz, CDCl3): 7.68–7.64 (m, 4H),
7.41–7.36 (m, 6H), 5.84–5.64 (m, 1H), 5.08–4.99 (m, 2H), 4.4 (d,
J = 6.0 Hz, 2H), 3.66–3.63 (m, 2H), 2.24–2.08 (m, 2H), 2.08 (s, 3H),
2.0–1.92 (m, 1H), 1.06 (s, 9H). dC (50 MHz, CDCl3): 171.1, 135.9,
135.6, 133.6, 129.6, 127.6, 116.7, 64.2, 62.9, 40.1, 26.8, 20.9, 19.3.
ture was extracted with DCM. The organic extract was washed
with water, NaHCO3 solution, and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography afforded aldehyde 10 in 92% yield. dH (200 MHz, CDCl3):
9.77–9.75 (d, 1H, J = 1.4 Hz), 7.66–7.62 (m, 4H), 7.45–7.36 (m,
6H), 5.81–5.61 (m, 1H), 5.23–5.0 (m, 2H), 3.99–3.83 (m, 2H),
2.54–2.44 (m, 2H), 2.44–2.23 (m, 1H), 1.07 (s, 9H). dC (50 MHz,
CDCl3): 203.7, 135.6, 134.9, 133.1, 129.9, 127.8, 117.2, 62.0, 53.6,
29.6, 26.8, 19.3. ½a D28
¼ þ18:45 (c 1.0, CHCl3).
ꢃ
½
a 2D8
ꢃ
¼ þ12:4 (c 1.0, CHCl3).
4.1.4. 4-Diphenylsilanyloxymethyl-hepta-1,6-dien-3-ol 11
Aldehyde 10 (0.6 g, 1.7 mmol) was taken in 10 mL of dry THF. A
freshly prepared solution of vinyl magnesium bromide (3.8 mmol)
in dry THF was then added to it at ꢀ78 °C. The reaction mixture
was stirred for a further 2 h at room temperature, after which a sat-
urated NH4Cl solution was added to it. The solution was extracted
with diethyl ether, and the organic layer was washed with water
and brine. The organic layer was dried (MgSO4) and evaporated,
purification by silica gel chromatography (20:1, petroleum ether/
EtOAc) afforded alcohol 11 in 78% yield. dH (200 MHz, CDCl3, mix-
4.1.3. (R)-2-Diphenylsilanyloxymethyl-pent-4-enal 10
Oxalyl chloride (0.47 mL, 5.4 mmol) was taken in anhydrous
DCM (25 mL). Then DMSO (0.8 mL, 10.7 mmol) was added to the
solution and kept at ꢀ78 °C. After 15 min, alcohol 9 (1.264 g,
3.6 mmol) was added, and the solution was stirred at the same
temperature for a further 45 min. After this time Et3N (3 mL,
21.4 mmol) was added slowly to the reaction mixture at the same
temperature. The reaction mixture was allowed to return to room
temperature. Water was then added to the solution, and the mix-

R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
369
ture of diastereomers): 7.72–7.67 (m, 4H), 7.49–7.38 (m, 6H), 5.96–
5.84 (m, 1H), 5.83–5.64 (m, 1H), 5.42–5.33 (m, 1H), 5.29–5.20 (m,
1H), 5.05–4.93 (m, 2H), 4.84–4.78 (m, 1H), 4.46–4.42 (m, 0.5H),
4.38–4.31 (m, 0.5H), 3.97–3.91 (m, 0.5H), 3.76–3.63 (m, 2H),
3.51–3.41 (m, 1H), 2.32–1.67 (m, 3H), 1.08 (s, 9H). dC (50 MHz,
CDCl3, mixture of diastereomer): 139.9, 138.4, 136.7, 136.5,
135.6, 135.4, 132.7, 129.9, 127.8, 116.6, 116.4, 115.5, 75.4, 74.7,
65.3, 64.8, 44.7, 32.6, 30.4, 26.9, 19.1.
was washed with water and brine. Evaporation and purification by
means of silica gel chromatography (20:1, petroleum ether/EtOAc)
afforded compound 15 in 90% yield. dH (200 MHz, CDCl3): 7.72–
7.68 (m, 4H), 7.52–7.31 (m, 6H), 5.79–5.59 (m, 1H), 5.16–5.07
(m, 2H), 3.79–3.59 (m, 2H), 2.56–2.46 (d, J = 6.0 Hz, 2H), 2.31–
2.11 (m, 2H), 2.11–1.97 (m, 1H), 1.12 (s, 9H). dC (50 MHz, CDCl3):
135.6, 134.6, 133.1, 129.0, 127.8, 118.6, 118.0, 64.7, 37.9, 34.5,
26.9, 19.3, 18.7. ½a D28
¼ ꢀ11:25 (c 1.0, CHCl3).
ꢃ
4.1.5. (R)-4-Diphenylsilanyloxymethyl-hepta-1,6-dien-3-one 12
Oxalyl chloride (0.16 mL, 1.8 mmol) was taken in anhydrous
DCM (10 mL). Then DMSO (0.3 mL, 3.6 mmol) was added to the
solution and kept at ꢀ78 °C. After 15 min, alcohol 11 (0.45 g,
1.183 mmol) was added to it, and the solution was stirred at the
same temperature for a further 45 min. After this time, Et3N
(1 mL, 7.1 mmol) was added slowly to the reaction mixture at
the same temperature. The reaction mixture was allowed to return
to room temperature. Water was then added to the solution, and
the mixture was extracted with DCM. The organic extract was
washed with water, NaHCO3 solution, and brine. The organic layer
was dried (MgSO4) and evaporated. Purification by silica gel chro-
matography yielded ketone 12 (0.385 g) in 88% yield. dH (200 MHz,
CDCl3): 7.66–7.62 (m, 4H), 7.44–7.28 (m, 6H), 6.54–6.40 (m, 1H),
6.29–6.18 (m, 1H), 5.83–5.56 (m, 2H), 5.03–4.94 (m, 2H), 3.92–
3.71 (m, 2H), 3.22–3.08 (m, 1H), 2.48–2.09 (m, 2H), 1.02 (s, 9H).
dC (50 MHz, CDCl3): 202.2, 136.7, 135.7, 135.3, 133.3, 129.9,
4.1.9. (R)-3-Diphenylsilanyloxymethyl-hex-5-enal 16
Compound 15 (0.7 g, 1.93 mmol) was taken in 80 mL of dry
DCM and cooled to ꢀ78 °C. Then 4 mL of 1 M DIBAL-H solution
was added slowly to the reaction mixture at the same temperature.
The reaction mixture was stirred for 2 h at ꢀ78 °C. A saturated
solution of Na2SO4 was then added dropwise to the reaction mix-
ture to precipitate aluminum hydroxide. The reaction mixture
was then filtered on a Celite pad. The organic solution was washed
with water and brine. Evaporation and purification by means of sil-
ica gel chromatography (20:1, petroleum ether/EtOAc) afforded
compound 16 in 82% yield. dH (200 MHz, CDCl3): 9.78 (1H), 7.67–
7.64 (m, 4H), 7.49–7.40 (m, 6H), 5.80–5.59 (m, 1H), 5.05–4.99 (d,
J = 12.6 Hz, 2H), 3.69–3.50 (m, 2H), 2.52–2.46 (m, 1H), 2.37–2.01
(m, 4H), 1.07 (s, 9H). dC (50 MHz, CDCl3): 202.5, 136.0, 135.7,
133.5, 129.9, 127.8, 117.3, 66.2, 45.9, 36.1, 35.7, 29.8, 27.0, 19.4.
½
a 2D8
ꢃ
¼ ꢀ4:6 (c 1.0, CHCl3).
128.3, 127.8, 116.9, 64.7, 51.1, 32.5, 26.9, 19.3. ½a D28
ꢃ
¼ þ31:9 (c
4.1.10. 5-Diphenylsilanyloxymethyl-octa-1,7-dien-3-ol 17
Aldehyde 16 (0.5 g, 1.4 mmol) was taken in 10 mL of dry THF. A
freshly prepared solution of vinyl magnesium bromide (2.8 mmol)
in dry THF was then added to it at ꢀ78 °C. The reaction mixture
was stirred for a further 2 h at room temperature, after which a sat-
urated NH4Cl solution was added to it. The solution was extracted
with diethyl ether, and the organic layer was washed with water
and brine. The organic layer was dried (MgSO4) and evaporated;
purification by silica gel chromatography (20:1, petroleum ether/
EtOAc) afforded alcohol 17 in 80% yield. dH (200 MHz, CDCl3, mix-
ture of diastereomers): 7.69–7.67 (m, 4H), 7.52–7.27 (m, 6H), 5.93–
5.59 (m, 2H), 5.29–4.93 (m, 4H), 4.17–4.15 (m, 1H), 3.63–3.54 (m,
2H), 2.36–2.25 (m, 2H), 1.90–1.65 (m, 1H), 1.58–1.54 (m, 2H), 1.07
(s, 9H). dC (50 MHz, CDCl3, mixture of diastereomers): 141.7, 136.9,
136.7, 135.9, 133.6, 129.9, 127.9, 116.6, 114.4, 71.9, 70.9, 67.2,
66.5, 40.0, 39.2, 38.2, 37.0, 36.5, 27.1, 19.5.
1.0, CHCl3).
4.1.6. (R)-5-Diphenylsilanyloxymethyl-cyclopent-2-enone 13
Ketone 12 (0.1 g, 0.2643 mmol) was taken in 50 mL of dry DCM.
A small amount of 1st generation Grubbs’ catalyst was then added
to it. The reaction mixture was stirred overnight at room tempera-
ture. After that time, the organic solvent was evaporated and the
crude reaction product was purified by silica gel chromatography
(10:1, petroleum ether/EtOAc) to afford compound 13 (0.085 g)
in 90% yield. dH (200 MHz, CDCl3): 7.78–7.76 (m, 1H), 7.66–7.63
(m, 4H), 7.42–7.40 (m, 6H), 6.26–6.22 (m, 1H), 4.09–4.02 (dd,
J = 9.8, 4.8 Hz, 1H), 3.88–3.76 (dd, J = 9.8, 3.6 Hz, 1H), 2.82–2.8
(m, 2H), 2.51–2.31 (m, 1H), 1.01 (s, 9H). dC (50 MHz, CDCl3):
210.4, 135.6, 134.4, 133.5, 133.1, 129.7, 127.7, 63.0, 47.1, 32.9,
26.8, 19.3. ½a 2D8
¼ þ22:8 (c 1.0, CHCl3).
ꢃ
4.1.7. (S)-Methanesulfonic acid 2-diphenylsilanyloxymethyl-
pent-4-enyl ester 14
4.1.11. (R)-5-Diphenylsilanyloxymethyl-octa-1,7-dien-3-one 18
Oxalyl chloride (0.12 mL, 1.33 mmol) was taken in anhydrous
DCM (10 mL). Then DMSO (0.2 mL, 2.67 mmol) was added to the
solution and kept at ꢀ78 °C. After 15 min, alcohol 17 (0.35 g,
0.9 mmol) was added to it, and the solution was stirred at the same
temperature for a further 45 min. After this time, Et3N (0.7 mL,
5.3 mmol) was added slowly to the reaction mixture at the same
temperature. The reaction mixture was then allowed to return to
room temperature. Water was added to the solution, and the mix-
ture was extracted with DCM. The organic extract was washed
with water, NaHCO3 solution and brine. The organic layer was
dried (MgSO4) and evaporated. Purification by silica gel chroma-
tography yielded ketone 18 in 90% yield. dH (200 MHz, CDCl3):
7.66–7.62 (m, 4H), 7.46–7.25 (m, 6H), 6.32–6.14 (m, 2H), 5.81–
5.76 (m, 2H), 5.03–4.95 (m, 2H), 3.60–3.57 (m, 2H), 2.82–2.71
(dd, J = 16.6, 6.4 Hz, 1H), 2.57–2.46 (dd, J = 16.6, 6.0 Hz, 1H),
2.33–2.05 (m, 3H), 1.05 (s, 9H). dC (50 MHz, CDCl3): 200.2, 136.9,
136.3, 135.6, 133.6, 129.6, 127.6, 116.7, 65.6, 40.7, 36.5, 35.5,
Alcohol ent-9 (1 g, 2.7 mmol) was taken in 20 mL dry DCM.
Then, Et3N (0.6 mL, 4.12 mmol) was added to it portionwise at
0 °C. Next, a small portion of DMAP was added. Then MsCl
(0.3 mL, 3.3 mmol) was added slowly to the reaction mixture at
the same temperature. The reaction mixture was stirred for a 2 h
at room temperature. The reaction mixture was extracted with a
large volume of diethyl ether. The organic solution was washed
with water and brine. Evaporation and purification by means of sil-
ica gel chromatography (20:1, petroleum ether/EtOAc) afforded
compound 14 in 93% yield. dH (200 MHz, CDCl3): 7.72–7.68 (m,
4H), 7.49–7.39 (m, 6H), 5.84–5.64 (m, 1H), 5.13–5.05 (m, 2H),
4.32 (d, J = 9.8 Hz, 2H,), 3.79–3.63 (m, 2H), 2.98 (s, 3H), 2.25–2.18
(t, J = 6.7 Hz, 2 H), 2.14–1.98 (m, 1H), 1.11 (s, 9H). dC (50 MHz,
CDCl3): 135.6, 135.1, 133.2, 129.8, 127.7, 117.4, 69.4, 62.3, 40.5,
37.0, 31.9, 26.9, 19.3. ½a D28
¼ ꢀ6:7 (c 1.0, CHCl3).
ꢃ
4.1.8. (R)-3-Diphenylsilanyloxymethyl-hex-5-enenitrile 15
Compound 14 (1.07 g, 2.5 mmol) was taken in 30 mL dry DMSO.
Then NaCN (0.5 g, 8.5 mmol) was added and reaction mixture was
stirred overnight at room temperature. The reaction mixture was
extracted with a large volume of diethyl ether. The organic solution
26.9, 19.3. ½a 2D8
¼ ꢀ44:2 (c 0.8, CHCl3).
ꢃ
4.1.12. (R)-5-Diphenylsilanyloxymethyl-cyclohex-2-enone 19
Ketone, compound 18 (0.1 g, 0.2643 mmol) was taken in 50 mL
of dry DCM. A small amount of 1st generation Grubbs’ catalyst

370
R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
(0.027 mmol) was then added to it. The reaction mixture was stir-
red overnight at room temperature. Evaporation and purification
by means of silica gel chromatography (10:1, petroleum ether/
EtOAc) afforded compound 19 in 78% yield. The spectroscopic data
were similar to those reported earlier.8
and filtered. The ether solution was extracted with hydrochloric
acid (3 mL) to remove the dissolved zinc iodide, aqueous sodium
bicarbonate (5 mL) and saturated aqueous sodium chloride. The
combined ether extract was evaporated. The product was purified
by flash chromatography (1:5; hexane/EtOAc) to afford the com-
pounds in 75% yield.
4.1.13. General procedure for the NaBH4/CeCl3 reduction
To a cooled (0 °C) solution of enones (0.1 mmol) in MeOH,
CeCl3ꢁ7H20 (0.12 mmol) was added. The mixture was stirred at
0 °C for 10 min, and then NaBH4 was added. The resulting mixture
was stirred for 3 h at ambient temperature until the reaction was
complete (monitored by TLC). The solution was diluted with EtOAc
(20 mL), washed with brine (2 mL), dried over Na2SO4, and concen-
trated in vacuo to give the crude product. The residue was purified
by flash column chromatography (1:5, hexane/EtOAc) to afford the
alcohols in 95% yield.
4.1.17. (1R,5R)-5-(tert-Butyldiphenylsilyloxymethyl)-cyclohex-
2-enol 20
dH (200 MHz, CDCl3): 7.70–7.65 (m, 4H), 7.48–7.32 (m, 6H),
5.82–5.66 (m, 2H), 4.3 (br, 1H), 3.57 (d, J = 5.6 Hz, 2H), 2.23–1.91
(m, 3H), 1.34–1.23 (m, 2H), 1.1 (s, 9H). dC (50 MHz, CDCl3):
135.6, 133.8, 131.0, 129.6, 128.4, 127.7, 68.2, 67.8, 35.9, 35.8,
28.3, 26.9, 19.3. ½a D28
¼ ꢀ19:5 (c 0.6, CHCl3).
ꢃ
4.1.18. (1R,2R,3R,5R)-5-(Hydroxymethyl)cyclohexane-1,2,3-triol
2
4.1.14. General procedure for the substrate directed epoxidation
with mCPBA
At first, tBuOH (2 mL), H2O (2 mL) and AD-mix b (550 mg) were
mixed and the mixture was stirred for 15 min. Methane sulfon-
amide (28 mg, 0.3 mmol) was then added and the stirring was con-
tinued for a further 15 min. Compound 20 (100 mg, 0.3 mmol) was
then added in one portion. The slurry was stirred vigorously at
20 °C for 24 h. After that time, sodium sulfite (750 mg) was added
and stirring was continued for a further 1 h. The reaction mixture
was extracted with EtOAc (4 ꢂ 10 mL). The organic layer was dried
(Na2SO4) and evaporated in vacuo. The diol was purified by flash
chromatography (1:1; hexane/EtOAc) followed by TBDPS deprotec-
tion by TBAF in THF to afford compound 2 in 75% yield. dH
(200 MHz, CDCl3): 4.19–4.12 (m, 1H), 3.98–3.86 (m, 1H), 3.43 (d,
J = 5.6 Hz, 2H), 3.41–3.37 (m, 1H), 2.16–2.10 (m, 2H), 1.98–1.91
(m, 1H), 1.5–1.42 (m, 2H). dC (50 MHz, CDCl3): 76.6, 70.2, 70.0,
Unsaturated alcohols (0.31 mmol) were dissolved in dichloro-
methane (5 mL) along with sodium hydrogencarbonate (52 mg,
0.62 mmol). To the stirred suspension, meta-chloroperoxybenzoic
acid (108 mg, 0.62 mmol) was added at room temperature. The
resulting suspension was stirred vigorously for 19 h. Next a 20%
aqueous solution of sodium sulfite (10 mL) was added and the
resulting two-phase mixture was stirred vigorously for 15 min.
The two layers were separated and the aqueous layer was ex-
tracted with dichloromethane (30 mL). The combined organic lay-
ers were washed with a 20% aqueous solution of sodium sulfite
(10 mL) and a 5% aqueous solution of sodium hydrogencarbonate
(5 mL), dried (Na2SO4) and evaporated under reduced pressure.
The residue was purified by flash column chromatography (1:3,
hexane/EtOAc) to afford the compound in 88–90% yield.
68.1, 35.9, 33.9, 33.1. ½a D28
¼ þ17:0 (c 1.0, H2O). HRMS (ESI) calcu-
ꢃ
lated for C7H14O4Na: 185.0790; observed: 185.0796.
4.1.15. General procedure for the acid induced epoxide ring
opening
4.1.19. (1R,2R,4S,6S)-4-(tert-Butyldiphenylsilyloxymethyl)-7-
oxa-bicyclo[4.1.0]heptan-2-ol 21
Epoxide compounds (0.085 mmol) were added to a 1:1 mixture
of 0.2 M sulfuric acid/1,4-dioxane (5 mL) and the reaction mixture
was stirred at room temperature for 0.5 h. The reaction was then
diluted with a saturated solution of sodium hydrogencarbonate
(5 mL) and extracted with ethyl acetate (30 mL). The organic layers
were combined, dried (MgSO4), and concentrated in vacuo. The
residue was purified by flash column chromatography (1:1, hex-
ane/EtOAc) to afford the diols in 80% yield.
dH (200 MHz, CDCl3): 7.65–7.51 (m, 4H), 7.47–7.38 (m, 6H),
4.06–3.98 (m, 1H), 3.43 (d, J = 5.6 Hz, 2H), 3.37–3.31 (m, 2H),
2.01–1.49 (m, 5H), 1.09 (s, 9H). dC (50 MHz, CDCl3): 135.7, 133.8,
129.8, 127.8, 69.3, 67.8, 56.4, 54.8, 36.4, 31.0, 27.0, 26.2, 19.4.
½
a 2D8
ꢃ
¼ þ4:4 (c 0.5, CHCl3).
4.1.20. (1R,2S,3R,5S)-5-(tert-Butyldiphenylsilyloxymethyl)cyclo-
hexane-1,2,3-triol 22
dH (200 MHz, CDCl3): 7.75–7.68 (m, 4H), 7.50–7.36 (m, 6H), 4.09
(br, 2H), 3.81 (br, 1H), 3.55 (d, J = 5.4 Hz, 2H), 2.92 (br, 3H, –OH),
2.06–1.50 (m, 5H), 1.15 (s, 9H). dC (50 MHz, CDCl3): 135.6, 133.6,
129.7, 127.7, 73.4, 69.7, 68.6, 68.3, 33.5, 31.6, 30.9, 26.9, 19.3.
4.1.16. General procedure for the cyclopropanation reaction
To a hot, rapidly stirred solution of (126 mg, 0.7 mmol) cupric
acetate monohydrate in 1 mL of glacial acetic acid was added zinc
dust (800 mg, 12 mmol). After about 0.5 min, all of the copper
had deposited on the zinc. The couple was allowed to settle for
10 min, then the acetic acid was decanted while taking care to
not lose the silt-like couple. The dark reddish gray couple was
then washed with one portion (2 mL) of acetic acid followed by
three portions (10 mL) of ether. The moist couple was then ready
for use.
Methylene bromide (124 mg, 72 mmol) and iodine (0.15 g,
0.06 mmol) in anhydrous ether (5 mL) were added to the mixture
of zinc–copper couple. The iodine color disappeared immediately;
the initial gray-colored mixture was then refluxed for 30 min. Dur-
ing this period the mixture turned darker; the color change was
accompanied by a gentle exothermic reaction. External heating
was discontinued and the compound (60 mg, 18 mmol, in anhy-
drous ether 2 mL) was added dropwise over 30 min. During the
addition, the mixture continued to reflux. Heating was resumed
and the mixture refluxed for 30 h. The reaction mixture was cooled
4.1.21. (1R,2S,3R,5S)-5-(Hydroxymethyl)cyclohexane-1,2,3-triol
1
dH (200 MHz, CDCl3): 4.1–4.01 (br, 2H), 3.8–3.73 (br, 1H), 3.51
(d, J = 5.6 Hz, 2H), 2.90–2.2 (br, 3H, –OH), 2.06–1.48 (m, 5H). dC
(50 MHz, CDCl3): 71.4, 70.1, 67.8, 66.6, 32.5, 30.6, 29.4. ½a D28
¼
ꢃ
ꢀ8:8 (c 1.0, H2O). HRMS (ESI) calculated for C7H14O4Na:
185.0790; observed: 185.0796.
4.1.22. (1S,2R,4R,6R)-4-(tert-Butyldiphenylsilyloxymethyl)bi-
cyclo[4.1.0]heptan-2-ol 23
dH (400 MHz, CDCl3): 7.67–7.65 (m, 4H), 7.46–7.38 (m, 6H),
4.26–4.24 (m, 1H), 3.43–3.40 (m, 2H), 2.02–2.0 (m, 1H), 1.9–1.87
(m, 1H), 1.59–1.54 (m, 2H), 1.3–1.24 (m, 2H), 1.1 (s, 9H), 0.78–
0.7 (m, 2H), 0.28 (m, 1H). dC (50 MHz, CDCl3): 135.6, 133.8,
129.6, 127.6, 68.7, 68.0, 37.9, 32.2, 26.8, 26.5, 19.3, 18.5, 12.3,
8.5. ½a 2D8
¼ ꢀ22:1 (c 0.6, CHCl3).
ꢃ

R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
371
4.1.23. (1S,2R,4R,6R)-4-(Hydroxymethyl)bicyclo[4.1.0]heptan-2-
ol 4
dH (200 MHz, CDCl3): 4.26–4.15 (m, 1H), 3.38–3.34 (m, 2H),
4.1.31. (1S,2R,4S,6R)-2-Methoxy-4-(methoxymethyl)-7-oxa-
bicyclo[4.1.0]heptanes 29
dH (200 MHz, CDCl3): 7.67–7.63 (m, 4H), 7.43–7.35 (m, 6H),
3.97–3.89 (m, 1H), 3.51–3.47 (m, 2H), 3.3 (br, 1H), 3.06 (d, J = 6.8
Hz, 1H), 2.17–2.11 (m, 1H), 1.93–1.83 (m, 1H), 1.61–1.3 (m, 3H),
1.1 (s, 9H), 0.95 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H). dC (50 MHz,
CDCl3): 135.6, 133.7, 129.6, 127.7, 67.9, 67.5, 57.7, 54.1, 35.0,
2.06–1.98 (m, 1H), 1.92–1.5 (m, 4H), 1.1–1.0 (m, 1H), 0.6–0.5 (m,
2H), 0.3–0.25 (m, 1H). dC (50 MHz, CDCl3): 68.7, 67.5, 38.1, 32.2,
26.6, 18.5, 12.4, 8.8. ½a D28
¼ ꢀ12:5 (c 1.0, CHCl3). HRMS (ESI) calcu-
ꢃ
lated for C8H14O2Na: 165.0891; observed: 165.0894.
29.7, 28.0, 26.8, 25.8, 19.3, 18.2, ꢀ4.6, ꢀ4.8. ½a D28
¼ ꢀ31:9 (c 1.0,
ꢃ
CHCl3).
4.1.24. (1S,5R)-5-(tert-Butyldiphenylsilyloxymethyl)cyclohex-2-
enol 24
4.1.32. (1S,2R,3R,5R)-5-(Hydroxymethyl)cyclohexane-1,2,3-triol
6
dH (200 MHz, CDCl3): 7.70–7.66 (m, 4H), 7.42–7.36 (m, 6H),
5.96–5.72 (m, 2H), 4.23 (br, 1H), 3.63–3.57 (m, 2H), 2.37–1.42
(m, 5H), 1.1 (s, 9H). dC (50 MHz, CDCl3): 135.8, 134.0, 131.1,
129.8, 128.4, 127.8, 68.3, 64.3, 34.4, 31.6, 28.8, 27.1, 19.5.
dH (200 MHz, CDCl3): 4.18–4.12 (m, 1H), 4.0–3.95 (m, 1H), 3.57–
3.53 (m, 2H), 3.44–3.40 (m, 1H), 1.94–1.42 (m, 5H). dC (50 MHz,
CDCl3): 82.9, 71.1, 70.6, 68.5, 33.4, 32.8, 30.2. ½a D28
¼ þ7:4 (c 1.0,
ꢃ
½
a 2D8
ꢃ
¼ ꢀ18:8 (c 0.3, CHCl3).
H2O). HRMS (ESI) calculated for C7H14O4Na: 185.0790; observed:
185.0796.
4.1.25. (1S,2S,4S,6R)-4-(tert-Butyldiphenylsilyloxymethyl)-7-
oxa-bicyclo[4.1.0]heptan-2-ol 26
4.1.33. (1R,5R)-5-(tert-Butyldiphenylsilyloxymethyl)cyclopent-
2-enol 32
dH (200 MHz, CDCl3): 7.69–7.59 (m, 4H), 7.48–7.35 (m, 6H),
4.15–4.08 (m, 1H), 3.46 (d, J = 5.4 Hz, 2H), 3.38–3.32 (m, 2H),
2.26–1.34 (m, 5H), 1.09 (s, 9H). dC (50 MHz, CDCl3): 135.7, 133.8,
129.8, 127.8, 67.8, 64.0, 55.8, 54.4, 33.7, 28.8, 27.4, 27.0, 19.4.
dH (200 MHz, CDCl3): 7.71–7.65 (m, 4H), 7.48–7.38 (m, 6H),
5.98–5.87 (m, 2H), 4.95 (br, 1H), 3.90 (d, J = 6.4 Hz, 2H), 2.79–
2.38 (m, 3H), 1.15 (s, 9H). dC (50 MHz, CDCl3): 135.5, 135.4,
134.3, 133.1, 133.0, 132.8, 129.8, 129.7, 127.7, 127.6, 76.6, 64.1,
½
a 2D8
ꢃ
¼ ꢀ17:3 (c 1.0, CHCl3).
42.6, 33.7, 26.6, 19.1. ½a D28
¼ þ2:25 (c 1.0, CHCl3).
ꢃ
4.1.26. (1S,2S,3S,5S)-5-(tert-Butyldiphenylsilyloxymethyl)cyclo-
hexane-1,2,3-triol 27
4.1.34. (1S,5R)-5-(tert-Butyldiphenylsilyloxymethyl)cyclopent-
2-enol 33
dH (200 MHz, CDCl3): 7.65–7.63 (m, 4H), 7.44–7.35 (m, 6H), 4.14
(br, 1H), 3.87–3.83 (m, 1H), 3.56–3.50 (m, 2H), 3.48–3.46 (m, 1H),
2.12–1.89 (m, 3H), 1.42–1.28 (m, 2H), 1.08 (s, 9H). dC (50 MHz,
CDCl3): 135.7, 133.7, 129.9, 127.9, 77.4, 70.4, 69.8, 67.9, 35.8,
33.8, 33.1, 27.0, 19.5.
dH (200 MHz, CDCl3): 7.70–7.65 (m, 4H), 7.48–7.38 (m, 6H),
5.89–5.75 (m, 2H), 4.80 (br, 1H), 3.82–3.63 (m, 2H), 2.6–2.38 (m,
2H), 2.0–1.88 (m, 1H), 1.15 (s, 9H). dC (50 MHz, CDCl3): 135.6,
133.6, 133.4, 132.8, 129.7, 127.7, 80.8, 66.0, 50.4, 34.0, 26.9, 19.2.
½
a 2D8
ꢃ
¼ þ5:3 (c 1.0, CHCl3).
4.1.27. (1S,2S,3S,5S)-5-(Hydroxymethyl)cyclohexane-1,2,3-triol
3
4.1.35. (1S,2S,3R,5R)-3-(tert-Butyldiphenylsilyloxymethyl)-6-
oxa-bicyclo[3.1.0]hexan-2-ol 34
dH (200 MHz, CDCl3): 4.14–4.1 (br, 2H), 3.87–3.83 (m, 1H),
3.56–3.50 (m, 2H), 2.82 (br, 4H, –OH), 1.8–1.4 (m, 5H). dC
(50 MHz, CDCl3): 76.4, 70.1, 69.6, 66.2, 35.4, 33.5, 32.4.
dH (400 MHz, CDCl3): 7.67–7.64 (m, 4H), 7.46–7.37 (m, 6H),
4.54–4.52 (m, 1H), 4.15–4.10 (m, 1H), 4.02 (m, 1H), 3.61 (br, 1H),
3.52–3.49 (m, 1H), 3.40 (br, 1H), 2.39–2.35 (m, 1H), 1.91–1.85
(m, 1H), 1.4 (m, 1H), 1.05 (s, 9H). dC (100 MHz, CDCl3): 135.4,
132.9, 129.8, 127.7, 74.9, 67.2, 60.8, 55.4, 38.2, 29.5, 26.7, 18.9.
½
a 2D8
ꢃ
¼ ꢀ6:2 (c 0.5, CHCl3).
HRMS (ESI) calculated for C7H14O4Na: 185.0790; observed:
185.0796.
½
a 2D8
ꢃ
¼ þ12:3 (c 1.0, CHCl3).
4.1.28. (1R,2S,4R,6S)-4-(tert-Butyldiphenylsilyloxymethyl)bi-
cyclo[4.1.0]heptan-2-ol 25
4.1.36. (1R,2S,3R,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-6-
oxa-bicyclo[3.1.0]hexan-2-ol 35
dH (200 MHz, CDCl3): 7.70–7.64 (m, 4H), 7.44–7.27 (m, 6H),
4.51–4.37 (m, 1H), 3.48 (d, J = 5.8 Hz, 2H), 1.89–1.45 (m, 7H), 1.1
(s, 9H), 0.55–0.38 (m, 2H). dC (50 MHz, CDCl3): 135.8, 134.1,
129.7, 127.8, 68.2, 64.3, 34.3, 30.4, 27.1, 26.1, 19.5, 17.1, 12.6,
dH (400 MHz, CDCl3): 7.68–7.64 (m, 4H), 7.47–7.40 (m, 6H), 4.45
(br, 1H), 3.99–3.96 (m, 1H), 3.80–3.75 (m, 1H), 3.55 (br, 1H), 3.49
(br, 1H), 2.08–2.0 (m, 1H), 1.97–1.85 (m, 1H), 1.7–1.6 (m, 1H),
0.99 (s, 9H). dC (100 MHz, CDCl3): 135.4, 132.7, 129.9, 127.8,
5.0. ½a 2D8
¼ ꢀ34:2 (c 1.0, CHCl3).
ꢃ
72.6, 62.8, 58.3, 56.7, 40.0, 27.6, 26.7, 19.0. ½a D28
¼ þ22:1 (c 1.0,
ꢃ
CHCl3).
4.1.29. (1R,2S,4R,6S)-4-(Hydroxymethyl)bicyclo[4.1.0]heptan-2-
ol 5
4.1.37. (1R,2R,3R,5S)-3-(tert-Butyldiphenylsilyloxymethyl)-6-
oxa-bicyclo[3.1.0]hexan-2-ol 36
dH (200 MHz, CDCl3): 4.44–4.37 (m, 1H), 3.48 (d, J = 5.8 Hz, 2H),
1.92–1.43 (m, 7H), 0.50–0.38 (m, 2H). dC (50 MHz, CDCl3): 68.7,
dH (400 MHz, CDCl3): 7.65–7.63 (m, 4H), 7.46–7.37 (m, 6H), 4.17
(t, J = 6.4 Hz, 1H), 3.81–3.77 (m, 1H), 3.65–3.63 (m, 1H), 3.54 (1H),
3.46 (1H), 2.14–2.09 (m, 2H), 1.80–1.6 (m, 1H), 1.09 (s, 9H). dC (100
MHz, CDCl3): 135.5, 133.1, 129.8, 127.7, 76.4, 64.3, 58.4, 54.5, 41.8,
64.8, 34.2, 30.8, 27.1, 17.1, 12.6, 5.0. ½a D28
¼ ꢀ9:8 (c 1.0, CHCl3).
ꢃ
HRMS (ESI) calculated for C8H14O2Na: 165.0891; observed:
165.0894.
31.8, 29.6, 26.8. ½a D28
¼ þ22:0 (c 1.0, CHCl3).
ꢃ
4.1.30. (3R,5R)-3-tert-Butyldimethylsilyloxy-5-(tert-
butyldiphenylsilyloxymethyl)cyclohex-1-ene 28
4.1.38. (1S,2R,3S,4R)-4-(Hydroxymethyl)cyclopentane-1,2,3-triol
40
dH (200 MHz, CDCl3): 7.74–7.71 (m, 4H), 7.52–7.44 (m, 6H), 5.8–
5.62 (m, 2H), 4.4 (br, 1H), 3.61 (d, J = 5.2 Hz, 2H), 2.15–1.42 (m, 5H),
1.15 (s, 9H), 1.02 (s, 9H), 0.2 (s, 6H). dC (50 MHz, CDCl3): 135.6,
133.9, 132.3, 129.6, 127.7, 127.4, 68.6, 68.3, 36.1, 36.0, 28.3, 26.9,
dH (400 MHz, CDCl3): 4.48–4.14 (m, 3H), 3.52–3.44 (m, 2H),
3.40–2.92 (br, 4H, –OH), 1.91–1.45 (m, 3H). dC (100 MHz, CDCl3):
77.2, 72.3, 71.9, 68.4, 38.2, 33.5. ½a D28
¼ þ8:35 (c 1.0, H2O). HRMS
ꢃ
26.0, 19.4, 18.3, ꢀ4.4, ꢀ4.6. ½a D28
¼ ꢀ44:2 (c 1.0, CHCl3).
ꢃ
(ESI) calculated for C6H12O4Na: 171.0633; observed: 171.0628.

372
R. Rej et al. / Tetrahedron: Asymmetry 23 (2012) 364–372
4.1.39. (1R,2S,3S,4R)-4-(Hydroxymethyl)cyclopentane-1,2,3-triol
41
1.67–1.49 (m, 3H), 0.45–0.41 (m, 2H). dC (50 MHz, CDCl3): 77.3,
68.5, 43.3, 32.8, 27.6, 18.7, 8.9. ½a D28
¼ þ1:2 (c 1.0, CHCl3). HRMS
ꢃ
dH (400 MHz, CDCl3): 4.42–4.08 (m, 3H), 3.46–3.40 (m, 2H),
3.20–2.92 (br, 4H, –OH), 1.88–1.40 (m, 3H). dC (100 MHz, CDCl3):
(ESI) calculated for C7H12O2Na: 151.0735; observed: 151.0739.
77.6, 72.7, 71.5, 67.2, 38.7, 32.5. ½a D28
¼ þ12:1 (c 1.0, H2O). HRMS
ꢃ
Acknowledgements
(ESI) calculated for C6H12O4Na: 171.0633; observed: 171.0628.
Financial support from DST-India is gratefully acknowledged
(Grant: SR/S1/OC-55/2009, IRPHA for NMR instrument). Two of
the authors R.R. and N.J. are thankful to CSIR-India for providing
a research fellowship.
4.1.40. (1R,2S,3R,4R)-4-(Hydroxymethyl)cyclopentane-1,2,3-
triol 42
dH (400 MHz, CDCl3): 4.52–4.34 (m, 1H), 4.26–4.20 (m, 1H),
4.12–4.06 (m, 1H), 3.48–3.42 (m, 2H), 3.12–2.90 (br, 4H, –OH),
1.80–1.45 (m, 3H). dC (100 MHz, CDCl3): 77.7, 72.3, 70.9, 66.4,
37.3, 30.8. ½a 2D8
¼ ꢀ6:9 (c 1.0, H2O). HRMS (ESI) calculated for
ꢃ
References
C6H12O4Na: 171.0633; observed: 171.0628.
1. (a) Fallarino, M. Herbalgram 1994, 31, 38–44; (b) Chang, H.-M.; But, H. H.-P.
Pharmacology and Application of Chinese Materia Medica; World Scientific
Publishing: Singapore, 1986; (c) Kappor, L. D. CRC Handbook of Ayurvedic
Medicinal Plants; CRC Press: Boca Raton, 1990; (d) Iwu, M. M. Handbook of
African Medicinal Plants; CRC Press: Boca Raton, Florida, 1993; (e) Jain, S. K.
Medicinal Plants of India; Reference publications: Algonac, MI, 1991; (f) Arvigo,
R.; Balick, M. Rainforest Remedies; Lotus Press: Twin Lakes, 1993; (g) Ayensu, S.
E. Medicinal Plants of West Indies; Reference Publications: Algonac, MI, 1981; (h)
Schules, R. E.; Raffauf, R. F. The Healing Forest; Dioscorides Press: Portland,
1990; (i) Farnsworth, N. R.; Akerele, R. O.; Bingel, A. S.; Soejarto, D. D.; Guo, Z.
Bull. WHO 1985, 63, 965–981; (j) De Smet, P. A. G. M. Drugs 1997, 54, 801–840.
2. (a) Buss, A. D.; Waigh, R. D. In Burgers Medicinal Chemistry and Drug Discovery;
Wlf, M. E., Ed.; John Wiley: NY, 1995; Vol. 1, pp 983–1033. fifth ed.; (b) Mann, J.
Murder Magic and Medicine; Oxford University Press: NY, 1994. pp 164–170.
3. (a) Shang, S.; Tan, D. Curr. Opin. Chem. Biol. 2005, 9, 245–258; (b) Reayi, A.; Arya,
P. Curr. Opin. Chem. Biol. 2005, 9, 240–247; (c) Breinbauer, R.; Vetter, I. R.;
Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 2879–2890; (d) Ecker, D. J.;
Crooke, S. T. Biotechnology 1995, 13, 351–360; (e) Rich, J. O.; Michels, P. C.;
Khmelnitsky, Y. L. Curr. Opin. Chem. Biol. 2002, 6, 161–167; (f) Altreuter, D. H.;
Clark, D. S. Curr. Opin. Biotechnol. 1999, 10, 130–136; (g) Michels, P. C.;
Khmelnitsky, Y. L.; Dordick, J. S.; Clark, D. S. Trends Biotechnol. 1998, 16, 210–
215; (h) Goodnow, R. A.; Guba, W.; Haap, W. Comb. Chem. High Throughput
Screen. 2003, 6, 649–690; (i) Ramstrom, O.; Lehn, J. M. Nat. Rev. Drug. Discov.
2002, 1, 26–36; (j) Krstenansky, J. L.; Khmelnitsky, Y. L. Bioorg. Med. Chem. 1999,
7, 2157–2162; (k) Yu, H.-L.; Xu, J.-H.; Wang, Y.-X.; Lu, W.-Y.; Lin, G.-Q. J. Comb.
Chem. 2008, 10, 79–87; (l) Secundo, F.; Carrea, G.; De Amici, M.; Di Ventimiglia,
S. J.; Dordick, J. S. Biotechnol. Bioeng. 2003, 81, 391–396.
4.1.41. (1R,2R,3R,5R)-3-(tert-Butyldiphenylsilyloxymethyl)bi-
cyclo[3.1.0]hexan-2-ol 43
dH (200 MHz, CDCl3): 7.68–7.63 (m, 4H), 7.45–7.36 (m, 6H),
4.88–4.79 (m, 1H), 3.76–3.53 (m, 2H), 2.59–2.49 (m, 1H), 2.12–
2.0 (m, 1H), 1.67–1.60 (m, 1H), 1.44–1.38 (m, 2H), 1.1 (s, 9H),
0.63–0.60 (m, 2H). dC (50 MHz, CDCl3): 135.4, 133.6, 129.7, 127.7,
75.5, 65.3, 46.0, 30.9, 26.7, 26.1, 19.0, 17.5, 9.8.
4.1.42. (1S,2R,3R,5S)-3-(tert-Butyldiphenylsilyloxymethyl)bi-
cyclo[3.1.0]hexan-2-ol 44
dH (200 MHz, CDCl3): 7.69–7.61 (m, 4H), 7.47–7.38 (m, 6H),
4.80–4.72 (m, 1H), 3.81–3.67 (m, 2H), 2.50–2.44 (m, 1H), 2.09–
2.0 (m, 1H), 1.64–1.57 (m, 1H), 1.40–1.28 (m, 2H), 1.09 (s, 9H),
0.60–0.55 (m, 2H). dC (50 MHz, CDCl3): 135.6, 133.2, 129.9, 127.4,
75.9, 65.8, 46.6, 31.5, 26.8, 26.4, 19.8, 17.6, 9.2.
4.1.43. (1R,2R,3R,5R)-3-(hydroxymethyl)bicyclo[3.1.0]hexan-2-
ol 45
dH (200 MHz, CDCl3): 4.84–4.79 (m, 1H), 3.70–3.58 (m, 2H), 2.9
(br, 2H, –OH), 2.56–2.48 (m, 1H), 2.04–2.0 (m, 1H), 1.6–1.38 (m,
3H), 0.55–0.50 (m, 2H). dC (50 MHz, CDCl3): 76.8, 67.4, 44.8, 31.5,
4. (a) Hoeksema, H.; Bannister, B.; Birkenmeyer, R. D.; Kagan, F.; Magerlein, B. J.;
MacKellar, F. A.; Schroeder, W.; Slomp, G.; Herr, R. R. J. Am. Chem. Soc. 1964, 86,
4223; (b) Rajeswaran, M.; Srikrishnan, T. Carbohydr. Res. 2004, 339, 2111; (c)
26.8, 17.5, 9.2. ½a D28
¼ ꢀ2:3 (c 1.0, CHCl3). HRMS (ESI) calculated
ꢃ
ˇ
Spízek, J.; Rezanka, T. Appl. Microbiol. Biotechnol. 2004, 65, 510; (d) Argoudelis,
for C7H12O2Na: 151.0735; observed: 151.0739.
A. G.; Fox, J. A.; Eble, T. E. Biochemistry 1965, 4, 698; (e) Argoudelis, A. G.; Fox, J.
A.; Mason, D. J. Biochemistry 1965, 4, 710.
5. Sedmera, P.; Halada, P.; Pospisil, S. Magn. Reson. Chem. 2009, 47, 509.
6. (a) Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem. Rev. 1919, 2007, 107;
(b) Zhao, C. S.; Zhang, W. H.; Zeng, X.; Feng, Y. Q. Prog. Chem. 2007, 19, 1357; (c)
Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 22; (d) Ogawa, S.;
Hirai, K.; Odagiri, T.; Matsunaga, N.; Yamazaki, T.; Nakajima, A. Eur. J. Org. Chem.
1998, 1099.
7. (a) Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2009, 20, 610; (b)
Mahapatra, T.; Bhunya, R.; Nandas, S. Tetrahedron Lett. 2009, 50, 5392.
8. (a) Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2010, 21, 2199; (b)
Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2011, 22, 406.
9. (a) Barral, K.; Courcambeck, J.; Pepe, G.; Balzarini, J.; Neyts, J.; De Clercg, E.;
Camplo, M. J. Med. Chem. 2005, 48, 450; (b) Hatcher, M. A.; Peleg, S.; Dolan, P.;
Kensler, T. W.; Sarjeant, A.; Posner, G. H. Bioorg. Med. Chem. 2005, 13, 3964; (c)
Yu, S.-H.; Chung, S.-K. Tetrahedron: Asymmetry 2004, 15, 581; (d) Smith, A. B.;
Hale, K. J.; Laakso, L. M.; Chen, K.; Riera, A. Tetrahedron Lett. 1989, 30, 6963; (e)
Linde, R. G.; Egbertson, M.; Coleman, R. S.; Jones, A. B.; Danishefsky, S. J. J. Org.
Chem. 1990, 55, 2771.
4.1.44. (1S,2R,3R,5S)-3-(Hydroxymethyl)bicyclo[3.1.0]hexan-2-
ol 46
dH (200 MHz, CDCl3): 4.72–4.64 (m, 1H), 3.65–3.52 (m, 2H), 2.94
(br, 2H, –OH), 2.50–2.36 (m, 1H), 2.0–1.92 (m, 1H), 1.64–1.45 (m,
3H), 0.48–0.42 (m, 2H). dC (50 MHz, CDCl3): 77.1, 68.2, 43.9, 32.3,
27.4, 18.2, 8.8. ½a D28
¼ ꢀ8:2 (c 1.0, CHCl3). HRMS (ESI) calculated
ꢃ
for C7H12O2Na: 151.0735; observed: 151.0739.
4.1.45. (1S,2S,3R,5S)-3-(tert-
Butyldiphenylsilyloxymethyl)bicyclo[3.1.0]hexan-2-ol 47
dH (200 MHz, CDCl3): 7.68–7.60 (m, 4H), 7.44–7.35 (m, 6H),
4.84–4.76 (m, 1H), 3.83–3.69 (m, 2H), 2.52–2.48 (m, 1H), 2.12–
2.05 (m, 1H), 1.64–1.57 (m, 1H), 1.42–1.32 (m, 2H), 1.09 (s, 9H),
0.62–0.55 (m, 2H). dC (50 MHz, CDCl3): 135.7, 133.5, 129.3, 127.6,
75.5, 66.2, 46.1, 31.7, 26.7, 26.1, 19.5, 17.3, 9.1.
10. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148.
11. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
12. Enders, D.; Plant, A.; Backhaus, D.; Reinhold, U. Tetrahedron 1995, 51, 10699.
13. Lannou, M. I.; Hélion, F.; Namy, J.-L. Synlett 2007, 2707.
14. (a) Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1958, 1957; (b) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307.
15. LeGoff, E. J. Org. Chem. 1964, 29, 2048.
16. Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159.
17. Ahmad, S.; Thomas, L. H.; Sutherland, A. Org. Biomol. Chem. 2011, 9, 2801.
4.1.46. (1S,2S,3R,5S)-3-(Hydroxymethyl)bicyclo[3.1.0]hexan-2-ol
48
dH (200 MHz, CDCl3): 4.67–4.61 (m, 1H), 3.68–3.59 (m, 2H),
2.90–2.8 (br, 2H, –OH), 2.42–2.31 (m, 1H), 2.04–1.92 (m, 1H),