Synthesis of 4a-carba-β-l-lyxofuranose, 4a-carba-β-l- arabinofuranose and 2,2,5-trimethyl-3a,6a-dihydro-cyclopenta[1,3]dioxol-4-one using Mn/CrCl3 mediated domino reactions and ring closing metathesis

Article abstract of DOI:10.1016/j.tetasy.2012.07.014

A common method for the synthesis of 4a-carba-β-l-lyxofuranose and 4a-carba-β-l-arabinofuranose from d-mannose and 2,2,5-trimethyl-3a,6a- dihydro-cyclopenta[1,3]dioxol-4-one from d-ribose is described using catalytic Nozaki-Hiyama-Kishi (NHK) conditions and ring closing metathesis (RCM). In this transformation, ω-deoxy-ω-iodo manno/ribo furanoside undergoes reductive elimination in the presence of Mn/CrCl₃ to give the corresponding olefin-aldehyde which was trapped by nucleophile under the same conditions to afford the desired diolefinic species. The ring closing metathesis reaction on these diolefinic species with Grubbs second generation catalyst produced the required carbocycles.

Full text of DOI:10.1016/j.tetasy.2012.07.014

Tetrahedron: Asymmetry 23 (2012) 1161–1169
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of 4a-carba-b-L-lyxofuranose, 4a-carba-b-L-arabinofuranose and
2,2,5-trimethyl-3a,6a-dihydro-cyclopenta[1,3]dioxol-4-one using Mn/CrCl3
mediated domino reactions and ring closing metathesis
⇑
Girija Prasad Mishra, Bejugam Santhosh Kumar, B. Venkateswara Rao
Organic and biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Accepted 27 July 2012
A common method for the synthesis of 4a-carba-b-
L
-lyxofuranose and 4a-carba-b-
L
-arabinofuranose
-ribose is
described using catalytic Nozaki-Hiyama-Kishi (NHK) conditions and ring closing metathesis (RCM). In
this transformation, -deoxy- -iodo manno/ribo furanoside undergoes reductive elimination in the
from
D
-mannose and 2,2,5-trimethyl-3a,6a-dihydro-cyclopenta[1,3]dioxol-4-one from
D
x
x
presence of Mn/CrCl3 to give the corresponding olefin-aldehyde which was trapped by nucleophile under
the same conditions to afford the desired diolefinic species. The ring closing metathesis reaction on these
diolefinic species with Grubbs second generation catalyst produced the required carbocycles.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
CHO
HO
Carbasugars1 are analogues of sugars, where the ring oxygen is
replaced with a methylene.2 They belong to a broad class of com-
pounds called cyclitols. The absence of an anomeric functionality
makes them resistant to enzymatic degradation; therefore these
compounds can be viewed as excellent inhibitors of glycoprocess-
ing enzymes.3,4
Cyclitols are broadly classified into cyclohexitols and cyclopent-
itols and these are important structural units for many biologically
active compounds. Cyclopentitols exist as polyhydroxy structures
and also notably as aminocarbafuranoses and carbanucleosides.5
Some important cyclitols are caryose,6,6a calditol,6b neplanocin6e
and aristeromycin6f (Fig. 1).
OH
CH2
HO
HO
HO
O
OH
HO
OH
OH
HO
OH
calditol
HO
caryose
OH
NH2
NH2
N
N
N
N
N
The conversion of available carbohydrates into densely func-
tionalized carbocyclic derivatives is an attractive strategy that
has been adopted by many synthetic chemists.7 Over the last few
years, our group has been involved in the synthesis of glycosidase
inhibitors, iminosugars7s and carbasugars.11,12 In connection with
this, we have developed some strategies for the synthesis of car-
basugars. We utilized a Nozaki-Hiyama-Kishi (NHK)8 reaction
and ring closing metathesis (RCM)9 for the synthesis of some cyclo-
hexitols such as gabosine C, (+)-gabosine N, gabosine O, some car-
bapyranoses, (+)-pericosine B and (+)-pericosine C 7j,10a,b. We also
developed a Tebbe mediated cascade reaction for the synthesis of
N
N
N
HO
HO
OH
(-)-neplanocin
HO
OH
(-)-aristeromycin
HO
antibiotic and antitumor
antibiotic and antitumor
Figure 1. Structures of some important cyclopentitols.
in the presence of Zn/CrCl3 for the short synthesis of the cyclopent-
carbafuranoses.11 Recently we developed
involving a Bernet-Vasella reductive elimination and NHK reaction
a domino reaction
itols 4a-carba-b-
from
-ribose12. Herein we report the application of this NHK-RCM
strategy with improved reaction conditions for the synthesis of 4a-
D-arabinofuranose and 4a-carba-b-D-lyxofuranose
D
carba-b-L L
-lyxofuranose 1,13 4a-carba-b- -arabinofuranose 214 and
⇑
Corresponding author.
E-mail addresses: drb.venky@gmail.com, venky@iict.res.in (B. Venkateswara
compound 7.15 Compound 7 is a key intermediate in the synthesis
of estrone and some other natural products.
Rao).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.014

1162
G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
THPO
I
OH
OTHP
Bernet-Vasella
reductive
OP
OH
O
OMe
O
elimination
5
HO
OH
I
1
THPO
O
O
M/CrCl3
M=Zn or Mn
M/CrCl3
NHK reaction
M=Zn or Mn
O
O
O
O
4
OH
6
3
HO
OH
2
Scheme 1.
In our earlier work,
x
-iodoglycosides were treated under Zn/
First
propylidene-a-D
D
-mannose was converted into methyl-2,3:5,6-di-O-iso-
CrCl3 conditions to undergo a Bernet-Vasella reductive elimina-
tion16 to give a chiral olefin aldehyde, which upon further treat-
ment with a vinyl halide in the same pot for the NHK reaction
gave the diene precursor required for the RCM. In this reaction,
Zn is used for the conversion of CrCl3 to CrCl2 which facilitates
reductive elimination and NHK reaction. The Bernet-Vasella
reaction has been exploited very well in organic synthesis.17,18
Some alternative conditions have also been developed for this
reaction.19 The application of this reaction for the synthesis of
pentenoycin20 and carbapentofuranoses12 has also been
reported.
-mannofuranoside 10 in 95% yield.23 The 5,6-O-
acetonide functionality in 10 was cleaved in the presence of
H5IO6 in THF and the resulting diol was simultaneously cleaved
in the same reaction mixture to give an aldehyde.24 The crude
aldehyde was reduced using NaBH4 in methanol to afford com-
pound 11. The primary hydroxyl group in 11 was iodinated with
TPP, I2 and imidazole to give product 6 in 91% yield as reported
in the literature.25 The iodo compound 6 was treated with Mn/
CrCl3 (20:1 equiv) for 8 h in THF/DMF (5:1). The formation of
anhydrous CrCl2 was confirmed by a colour change from violet
to pale blue. After the generation of the aldehyde (monitored
by TLC), a catalytic amount of anhydrous NiCl2 was added to
the reaction mixture to carry out the NHK reaction. The addition
of 2.5 equiv of vinyl iodide 5 followed by 1.5 equiv of TMSCl at
50 °C for 7 h afforded an inseparable mixture of diastereomers
12 and 13 in a 1:1 ratio in 55% yield (over two steps). When
the reaction was carried out in Zn/CrCl3 (20:1), it gave the prod-
ucts in low yields (20%). Reaction of the mixture of 12 and 13
with Grubbs second generation catalyst afforded the cyclic com-
pounds 14 and 15 in 81% yield which could be separated by col-
umn chromatography. The mixture of 14 and 15 was converted
into 16 in 98% using PDC in DCM. Luche reduction26 of com-
pound 16 afforded 14 in 93%. The bicyclic [330] system in 16
probably allowed the hydride to approach exclusively from the
less hindered concave face to yield 14. The reduction of the dou-
ble bond in 14 using Pd/C under H2 afforded the saturated com-
pound 17 as the only product.27 Global deprotection of the THP
and acetonide functionality in 17 gave the required carbasugar 1
in 95% yield, whose spectroscopic and physical data were in
agreement with the reported values28 (Scheme 3).
Herein we adopted Furstner’s modified NHK conditions21 for
the generation of CrCl2 from CrCl3 using Mn as the reductant.
The development of this method is based on the fact that the use
of excess toxic CrCl2 is replaced by the easy to handle, nontoxic,
air-stable CrCl3 and inexpensive Mn metal as a reductant which re-
mains inert throughout the reaction.21 As reported earlier,12 the ra-
tio of Zn/CrCl3 was 1:1 whereas herein we used Mn/CrCl3 in a 20:1
ratio. This condition decreased the ratio of starting material to
CrCl3 from 6:1 (Zn as a reductant) to 1.5:1 and also gave the re-
quired product in better yields.
2. Results and discussion
The retrosynthetic analysis of compounds 1 and 2 is depicted in
Scheme 1. The required diene precursor 3 can be obtained from
aldehyde 4 and vinyl iodide derivative 5.22 The aldehyde 4 can in
turn be generated from compound 6, which can be easily obtained
from
D-mannose (Scheme 1). Similarly compound 7 can be pre-
pared from
D
-ribose via 8 and 9 (Scheme 2).
Br
CrCl2
Cl2CrIII
HO
O
O
O
OMe
I
CrCl2
O
O
O
O
O
O
O
O
7
8
9
20
Scheme 2.

G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
1163
HO
I
O
O
OMe
O
O
OMe
OMe
O
a
D-mannose
d
b
c
O
O
O
O
O
O
11
THPO
6
10
THPO
THPO
HO
OH
O
e
f
g
14
O
O
O
O
O
O
12
13
OH
OH
14
15
OH
OH
16
THPO
HO
OH
OH
h
i
14
O
O
HO
OH
1
17
Scheme 3. Synthesis of 4a-carba-b-
L-lyxofuranose. Reagents and conditions: (a) MeOH, acetone, H2SO4 (cat.), 0 °C to rt, 6 h, 95%; (b) (i) H5IO6, THF, 0 °C to rt, 3 h (ii) NaBH4,
MeOH, 0 °C to rt, 1 h, 65% for two steps (c) TPP, I2, imidazole, toluene, 0 °C to rt, 4 h, 91%; (d) Mn/CrCl3 (20:1), THF:DMF (1:1), 8 h then NiCl2 (cat), 4, TMSCl, 50 °C, 7 h, TBAF, rt,
2 h, 55%; (e) Grubbs 2nd gen. cat. DCM, reflux, 6 h, 81%; (f) PDC, DCM, 4 Å, MS, rt, 5 h, 98%; (g) CeCl3ꢁ7H2O, NaBH4, DCM, 6 h, ꢀ78 °C 93%; (h) Pd-C/H2, MeOH, 2 h, 98%; (i) 2 M
HCl in MeOH, 0 °C, 15 min, 95%.
Mitsunobu inversion29 of 17 gave compound 18 in 93% yield.
Complete deprotection of 18 gave the required carbasugar 2 in
95% yield whose spectroscopic data were also in good agreement
with the reported values28 (Scheme 4).
We extended this strategy to the synthesis of 2,2,5-trimethyl-
3a,6a-dihydro-cyclopenta[1,3]dioxol-4-one 7 starting from -ri-
D
bose. It is noteworthy to mention here that the methyl cyclopente-
nones 7 and ent-7 are key intermediates for the synthesis of
estrone,15a physostigmine, (ꢀ)-physovenine and (ꢀ)-aphanor-
phine.15b,c Most of the reported procedures for making 7 and ent-
7 initially involve the preparation of cyclopentenones without a
substituent on the olefin and then introduction of the methyl
group to give the desired skeleton.15b However, these methods
are lengthy, whereas our approach generates compound 7 in good
overall yield with high enantiomeric purity.
The reaction of 2-bromo propene and 20 under the above mod-
ified NHK conditions gave alcohols 21 and 22 in a 7:3 diastereo-
meric ratio (Scheme 5).
When aldehyde 9 was treated with a Grignard reaction using 2-
bromopropene and Mg in THF at ꢀ78 °C, products 21 and 22 were
obtained in a 3:7 ratio.10a,c (Scheme 6).
THPO
HO
OH
h
i
OH
17
O
O
HO
OH
2
18
Scheme 4. Synthesis 4a-carba-b-
L
-arabinofuranose. Reagents and conditions : (h)
(i) TPP, PNB, DIAD, THF, 0 °C, 12 h; (ii) LiOHꢁH2O, 5 h, 93%; (i) 2 M HCl in MeOH, 0 °C,
15 min, 95%.
O
O
O
O
OMe
OMe
HO
OH
O
I
9
O
O
O
O
O
O
Br
19
20
21
22
OH
OH
NHK conditions
Scheme 5. Reagents and conditions: (a) I2, TPP, Imidazole, DCM, 0 °C to rt, 3 h; (ii) Mn/CrCl3 (20:1), THF/DMF (1:1), 8 h then NiCl2 (cat), 2-bromopropene, TMSCl, rt, 4 h, TBAF,
2 h, 60% [21:22 = 7:3].

1164
G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
O
OMe
OH
I
OH
a
b
O
+
O
O
O
O
O
O
O
O
19
21
minor
major 22
9
3:7
Scheme 6. Reagents and conditions: (a) Mn/CrCl3 (20:1), THF:DMF (1:1), 8 h, 65%, (b) 2-bromopropene, Mg, THF, ꢀ78 °C to rt, 2 h, 75%.
ent temperature. Chemical shifts (d) are given in ppm and cou-
pling constant J is in Hertz. Chemical shifts are reported in
Mg+2
O
O
H
ppm on scale downfield from TMS as the internal standard
and signal patterns are indicated as follows: s, singlet; d, dou-
blet; t, triplet; m, multiplet; br, broad peak. FTIR spectra were
recorded as KBr thin films or neat. Optical rotations were mea-
sured on Jasco digital polarimeter using a 1 mL cell with a
1 dm path length. For low (MS) and high (HRMS) resolution,
m/z ratios are reported as values in atomic mass units. All re-
agents and solvents were of reagent grade and used without
further purification unless specified otherwise. Technical grade
ethyl acetate and petroleum ether were used for column chro-
matography and distilled prior to use. Tetrahydrofuran (THF)
when used as a solvent for reactions was freshly distilled from
sodium benzophenoneketyl. Column chromatography was car-
ried out using silica gel (60–120 mesh and 100–200 mesh)
packed in glass columns. All reactions were performed under
a nitrogen atmosphere in flame-dried or oven-dried glassware
with magnetic stirring. The 13C NMR spectra of all THP-pro-
tected compounds showed a doubling of peaks because of the
diastereomers due to the presence of a stereogenic centre in
the THP functionality.
O
H
O
O
H
O
H
Nu
Nu
Cram's
model
where
the
Felkin-Anh model where the
nucleophile is an organochromium
nucleophile is an organomagnesium
Figure 2.
The reversal of selectivity in this case can be explained as fol-
lows. Generally during an NHK reaction the nucleophile undergoes
addition via a non-chelated Felkin-Anh model,30 whereas in the
case of the Grignard addition, chelation31a,b of the magnesium
ion gave syn isomer 22 as the major product (Fig. 2).
The RCM reaction of the mixture of compounds 21 and 22 using
Grubbs second generation catalyst afforded compounds 23 and 24,
which could be easily separated by column chromatography. The
mixture of 23 and 24 was oxidized using PDC to give methyl cyclo-
pentenone 7 as the sole product; the physical and spectroscopic data
were in good agreement with the reported values15a (Scheme 7).
4.2. (S)-1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
((tetrahydro-2H-pyran-2-yloxy)methyl)prop-2-en-1-ol) 12 and
(R)-1-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
((tetrahydro-2H-pyran-2-yloxy)methyl)prop-2-en-1-ol 13
OH
O
OH
THPO
HO
O
O
O
O
O
O
24
23
OH
OH
21
22 OH
7
OH
Scheme 7. Reagents and conditions: (a) Grubbs 2nd gen. cat. DCM, reflux, 5 h, 85%;
O
O
(b) PDC, DCM, 4 Å MS, rt, 3 h, 95%.
12
OH 13
OH
3. Conclusion
To
a flame dried two-necked round bottom flask, CrCl3
In conclusion, we have developed a general strategy for the syn-
(0.345 g, 2.16 mmol) and powdered activated Mn (1.62 g,
43.2 mmol) were taken in THF/DMF (21 mL/6 mL) and stirred
for 2 h at rt under an inert atmosphere until the colour changed
from violet to green. Compound 11 (0.45 g, 1.44 mmol) in THF
(9 mL) was slowly added to it and stirred for 8 h. When TLC
showed the absence of starting material, NiCl2 (90 mg,
0.69 mmol) was added to the reaction mixture and stirred for
30 min. Then vinyl iodo compound 5 (9.7 g, 3.6 mmol) in DMF
(6 mL) was added to it followed by the addition of TMSCl
(0.234 g, 2.16 mmol). The reaction mixture was allowed to stir
for an additional 7 h at 50 °C, and diluted with diethyl ether
(70 mL). Next, n-Bu4NF (9 mL, 1 M in THF) was added and stirred
at rt for 2 h. The reaction mixture was filtered through a sintered
funnel, concentrated and purified by column chromatography
using ethyl acetate/hexane (2:8) to afford a mixture of 12 and
thesis of 4a-carba-b-L-lyxofuranose 1, 4a-carba-b-L-arabinofura-
nose 2 and 2,2,5-trimethyl-3a,6a-dihydro-cyclopenta[1,3]dioxol-
4-one 7 by using domino reductive elimination and nucleophilic
addition using modified NHK conditions and ring-closing metathe-
sis as the key steps. This strategy is helpful in making different ana-
logues of carbanucleosides. Compounds 14 and 15 can also be used
in the synthesis of neplanocin, carbasugars and their derivatives.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded either in CDCl3 or
CD3OD solvent on 200, 300 or 400 MHz spectrometer at ambi-

G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
1165
13 (240 mg, 55 %) in a 1:1 ratio (by 1H NMR) as a yellow oil.
6H), 1.41 (s, 3H), 1.38 (s, 3H). 13C NMR (75 MHz, CDCl3):
144.6, 144.1, 130.9, 130.2, 111.3, 111.2, 99.1, 98.7, 86.0, 85.9,
83.4, 83.3, 80.8, 81.615, (63.3, 65.1, 62.8, 62.4, 30.5, 30.3, 27.3,
27.2, 25.6, 25.5, 25.2, 25.1, 19.6, 19.3. The doubling of peaks is
due to the presence of diastereomers because of the THP group;
½
a 2D5
ꢂ
¼ þ4:2 (c 0.5, CHCl3) lit.13 for its enantiomer ½a 2D5
¼ ꢀ10:6
ꢂ
(c 1.18, CHCl3]; IR (KBr): mmax 3446, 2926, 2854, 1377, 1255,
1215, 1163, 1119, 1029, 909, 871, 810 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) : 6.0 (m, 1H), 5.43–5.19 (m, 4H), 4.70–4.56
(m, 2H), 4.45–3.98 (m, 4H), 3.85 (m, 1H), 3.5 (m, 1H), 2.74–
2.42 (two br s, 1H), 1.88 –1.46 (m, 6H), 1.44 (s, 3H, –CH3),
1.39 (s, 3H, –CH3); 13C NMR (75 MHz, CDCl3): 144.7, 144.4,
134.2, 119.3, 117.7, 117.0, 115.4, 108.7, 98.5, 98.0, 97.8, 79.2,
79.17, 78.8, 72.5, 71.1, 70.9, 69.1, 68.2, 67.9, 62.6, 62.4, 62.2,
30.5, 27.8, 27.2, 27.16, 25.4, 25.37, 25.3, 24.91, 24.9, 19.5, 19.3.
The extra peaks in the 13C NMR is because of the mixture of
diastereomers due to the stereogenic centre present in the
THP functionality and epimers of allylic hydroxy functionality.
HRMS (ESIMS) m/z calcd for
C14H22O5Na 293.1364, found
293.1376.
4.6. (3aR,4S,6aS)-2,2-Dimethyl-5-((tetrahydro-2H-pyran-2-yl-
oxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol 15
THPO
OH
HRMS (LC–MS) m/z calcd for
C16H26O5Na 321.1780, found
321.1714.
O
O
4.3. Procedure for ring closing metathesis reaction
15
½
a 2D0
ꢂ
¼ þ34 (c 0.5, CHCl3) {lit.13 for ent-15 ½a D20
¼ ꢀ35:8 (c 1.78,
ꢂ
To the diastereomeric mixture of compounds 12 and 13
(750 mg, 2.5 mmol) in anhydrous DCM (750 mL) under a nitro-
gen atmosphere, was added Grubbs second generation catalyst
(210 mg, 0.25 mmol) and the reaction mixture was refluxed
for 6 h. After completion of the reaction, the reaction mixture
was evaporated at reduced pressure to give a crude residue,
which was purified by column (ethyl acetate/hexane = 3:7) to
give compounds 14 (170 mg, 41%) and 15 (157 mg, 40%) as yel-
low oils.
CHCl3)}; IR (KBr): mmax 3443, 2928, 2857, 1457, 1376, 1206, 1157,
1122, 1036, 904, 864 cmꢀ1 1H NMR (300 MHz, CDCl3) : 5.82 (2s,
;
1H), 5.2 (br s, 1H), 4.71–4.58 (m, 2H), 4.51 (d, 1H, J = 5.9 Hz), 4.4
(d, 1H, J = 12.6 Hz), 4.15 (d, 1H, J = 12.6 Hz), 3.85 (m, 1H), 3.51
(m, 1H), 2.95–2.5 (br d, 1H), 1.96–1.37 (m, 6H), 1.36 (s, 3H), 1.32
(s, 3H); 13C NMR (75 MHz, CDCl3): 144.5, 144.1, 131.0, 130.3,
111.3, 111.2, 98.8, 99.2, 86.1, 85.9, 81.7, 80.9, 83.5, 65.4, 65.2,
62.8, 62.4, 30.6, 30.4, 27.34, 27.3, 25.6, 25.5, 25.2, 25.1, 19.7,
19.4. The doubling of peaks is due to the presence of diastereomers
because of the THP group. HRMS: m/z calcd for C14H22O5Na
293.1364, found 293.1376.
4.4. Procedure for the Luche reduction
To a solution of enone 16 (130 mg, 0.48 mmol) taken in DCM,
cerium trichloride heptahydrate (0.90 mL, 0.36 mmol) in metha-
nol was added, followed by the addition of sodium borohydride
(13.6 mg, 0.36 mmol) at ꢀ78 °C under a nitrogen atmosphere.
The reaction was completed in 6 h after which a saturated solu-
tion of potassium bicarbonate (2 mL) was added along with
diethyl ether (2 mL). The resulting mixture was extracted with
diethyl ether (2 ꢃ 5 mL). The combined ether layers were
4.7. (3aS,6aS)-2,2-Dimethyl-5-((tetrahydro-2H-pyran-2-yl-
oxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one 16
THPO
O
washed with
a saturated solution of sodium bicarbonate
(3 mL), followed by brine (5 mL), dried over Na2SO4, concen-
trated under reduced pressure and purified on a column (ethyl
acetate/hexane = 3:7) to give compound 14 (122 mg, 0.45 mmol)
in 93% yield.
O
O
16
To a solution of 14 and 15 (0.327 g, 0.643 mmol) in DCM
(20 mL) were added molecular sieve powder (4 Å) and PDC (pyrid-
inium dichlorochromate) (0.605 g, 1.6 mmol) at 0 °C. The reaction
mixture was then stirred at rt for 5 h. The crude reaction mixture
was filtered through Celite, washed with water, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to give a
crude brownish syrup. The syrupy liquid was purified on a column
(ethyl acetate/hexane = 2:8) to give a single product 16 (0.318 g,
4.5. (3aR,4R,6aS)-2,2-Dimethyl-5-((tetrahydro-2H-pyran-2-yl-
oxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol 14
THPO
OH
98%) as
¼ ꢀ5 (c 0.85, CHCl3)}; IR (KBr): mmax 2931, 2856, 1725, 1458,
1377, 1248, 1204, 1130, 1099, 1036, 980, 915, 864, 814 cmꢀ1 1H
a
liquid.
½
a 2D5
ꢂ
¼ þ5 (c 1.0, CHCl3) {lit.13 for ent-16
O
O
½ ꢂ
a 2D0
;
NMR (300 MHz, CDCl3): 7.49 (s, 1H), 5.21 (d, 1H, J = 5.5 Hz), 4.64
(s, 1H), 4.51 (d, 1H, J = 5.5 Hz), 4.4 (dd, 1H, J = 15.4, 1.8 Hz), 4.15
(dd, 1H, J = 15.4, 1.8 Hz), 3.85 (m, 1H), 3.51 (m, 1H), 1.90–1.45
(m, 6H), 1.41 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3):
201.4, 153.3, 153.2, 114.5, 114.4, 115.4, 98.8, 77.7, 76.6, 62.31,
62.25, 60.87, 60.81, 30.4, 27.5, 26.12, 26.07, 25.3, 19.31,19.3. The
doubling of peaks is due to the presence of diastereomers because
14
½
a 2D0
ꢂ
¼ ꢀ5 (c 1.0, CHCl3) {lit.13 for ent-14 ½a D20
¼ þ3 (c 0.57,
ꢂ
CHCl3)}; IR (KBr): mmax 3448, 2927, 2854, 1456, 1378, 1209, 1153,
1118, 1073, 1029, 974, 760 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
5.75 (s, 1H), 4.97 (d, 1H, J = 5 Hz), 4.78–4.59 (m, 2H), 4.51–4.28
(m, 2H), 4.1–4.05 (2d, 1H, J = 13.7 Hz), 3.85 (m, 1H), 3.5 (m,
1H), 2.59 (2d, 1H, J = 9.4 Hz, D2O exchanged), 1.93–1.44 (m,

1166
G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
of the THP group. HRMS: m/z calcd for C14H20O5Na, 291.1208 found
291.1210.
(m, 2H), 3.53–3.38 (m, 2H), 2.24–2.07 (m, 2H), 1.89–1.49 (m,
7H), 1.47 (s, 3H), 1.28 (s, 3H); 13C NMR (75 MHz, CDCl3): 111.9,
99.1, 98.8, 87.0, 80.5, 80.2, 78.7, 78. 6, 69.4, 62.3, 62.2, 46.5, 46.4,
32.63, 30.5, 30.4, 26.8, 25.3, 24.4, 19.5, 19.4. The doubling of peaks
is due to diastereomers because of the THP group. HRMS : m/z
calcd for C14H24O5Na 295.1521, found 295.1514.
4.8. (3aR,4R,5S,6aS)-2,2-Dimethyl-5-((tetrahydro-2H-pyran-2-
yloxy)methyl)-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol 17
THPO
4.11. (1S,2S,3R,4S)-4-(hydroxymethyl)cyclopentane-1,2,3-
triol[4a-Carba-b-
L
-lyxofuranose] 1
OH
HO
O
O
OH
17
To compound 14 (0.1 g, 0.37 mmol) in dry methanol (5 mL), Pd/
C (10 wt %, 10 mg) was added and the mixture was stirred for 2 h
under a hydrogen atmosphere. After completion of the reaction,
the reaction mixture was filtered through Celite. The filtrate was
concentrated to give compound 17 (0.099 g, 98%) as a thick syrup.
HO
OH
1
To compound 17 (50 mg, 0.18 mmol) in methanol (2 mL) was added
HCl (2 N, 0.04 mL) in methanol at ice cooled temperature and stirred for
15 min. After completion of the reaction, the reaction mixture was con-
½
a 2D0
ꢂ
¼ þ10:2 (c 0.175, CHCl3) {lit.13 for ent-17 ½a D20
¼ ꢀ10:6 (c
ꢂ
centrated and dried to give compound 1 (26 mg, 95%). ½a D20
¼ þ10 (c
ꢂ
0.175, CHCl3)}; IR (KBr): mmax 3448, 2924, 2854, 1459, 1378,
0.4, MeOH), {lit.24 ent-1 ½a D20
¼ þ10:1 (c 0.3, MeOH)}. IR (KBr): mmax
ꢂ
1262, 1209, 1121, 1074, 1029, 866, 762 cmꢀ1 1H NMR (200 MHz,
;
3445, 2925, 2858, 1640, 1454, 1218, 1031, 762, 441 cmꢀ1 1H NMR
;
CDCl3): 4.66–4.54 (m, 2H), 4.45 (dd, 1H, J = 6.8, 5.3 Hz), 4.11–3.36
(m, 5H), 2.20 (m, 1H), 1.9 (m, 1H), 1.87–1.51 (m, 7H), 1.52 (s,
3H), 1.33 (s, 3H); 13C NMR (75 MHz, CDCl3): 113.8, 113.1, 99.1,
80.9, 80.9, 79.3, 71.2, 70.6, 66.9, 66.5, 62.3, 44, 43.5, 31.8, 30.6,
26.1, 25.4, 24.2, 19.6. The doubling of peaks is due to the presence
of diastereomers because of the THP group. HRMS: m/z calcd for
(300 MHz, D2O): 4.1-4.18 (m, 2H), 3.88 (dd, 1H, J = 4.9, 4.7 Hz), 3.77
(dd, 1H, J = 10.7, 10.5 Hz), 3.62 (dd, 1H, J = 10.7, 10.5 Hz), 2.28–2.05
(m, 2H), 1.43 (ddd, 1H, J = 13.4, 8.3 Hz, 4.5 Hz); 13C NMR (75 MHz,
D2O): 74.5, 73.3, 71.4, 62.1, 40.8, 33.9; HRMS: m/z calcd for C6H12O4Na
171.0633, found 171.0625.
C14H24O5Na 295.1521, found 295.1514.
4.12. (1S,2S,3S,4S)-4-(Hydroxymethyl)cyclopentane-1,2,3-triol-
[4a-Carba-b-
L
-arabinfuranose] 2
4.9. (3aR,4S,5S,6aS)-2,2-Dimethyl-5-((tetrahydro-2H-pyran-2-
yloxy)methyl)-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol 18
HO
OH
THPO
OH
HO
OH
2
To compound 18 (50 mg, 0.18 mmol) in methanol (2 mL) was
added HCl (2 M in methanol, 0.04 mL) at ice cooled temperature and
stirred for 15 min. After completion of the reaction, the MeOH was
evaporated under reduced pressure to give compound 2 (0.026 g,
95%). The physical and spectroscopic data of compound 2 were in ex-
O
O
18
act agreement with the reported literature values. ½a D20
ꢂ
¼ ꢀ6 (c 0.55,
max 3447, 2924,
;
1H NMR (300 MHz,
4.10. Procedure for the Mitsunobu reaction
MeOH), {lit.24
½
a 2D0
ꢂ
¼ ꢀ7:9 (c 1.2, MeOH)}. IR (KBr):
m
2854, 2366, 1627, 1461, 1216, 761, 670 cmꢀ1
To a stirred solution of 17 (0.1 g, 0.64 mmol) were added tri-
phenylphosphine (0.418 g, 1.6 mmol) and 4-nitrobenzoic acid
(0.268 g, 1.6 mmol) in THF (10 mL) followed by the slow addition
of a solution of di-isopropyl azodicarboxylate (DIAD) (0.33 mL,
1.6 mmol) at 0 °C. The reaction mixture was gradually warmed to
room temperature, while being stirred and covered with alumin-
ium foil. The reaction mixture was diluted with THF (10 mL),
washed with a saturated solution of sodium bicarbonate (10 mL),
brine (10 mL) and dried over Na2SO4. The solvent was removed un-
der reduced pressure and to it, THF/H2O (10 mL, 1:1), and LiOH.-
H2O (2.5 equiv, 0.068 g, 1.6 mmol) were added at 0 °C and stirred
for 5 h. After completion of the reaction, the reaction mixture
was concentrated under reduced pressure and the crude product
was purified on a column (ethyl acetate/hexane = 1:4) to afford
D2O): 4.08 (m, 1H), 3.81–3.74 (m, 2H), 3.70 (dd, 1H, J = 10.8, 5.5 Hz),
3.55 (dd, 1H, J = 10.8, 7.6 Hz), 2.24 (ddd, 1H, J = 14.4, 9.4, 6.0 Hz),
1.98-1.9 (m, 1H), 1.34 (ddd, 1H, J = 14.4, 7.2, 3.9 Hz); 13C NMR
(75 MHz, D2O): 78.9, 77.8, 70.6, 64.7, 43.4, 32.2; HRMS: m/z calcd for
C6H12O4Na 171.0633, found 171.0627.
4.13. (S)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
methylprop-2-en-1-ol 21 and (R)-1-((4S,5R)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)-2-methylprop-2-en-1-ol 22
OH
pure product 18 in quantitative yield. ½a D20
¼ þ60:0 (c 0.2, CHCl3)
ꢂ
{lit.13 for ent-18 ½a 2D0
¼ ꢀ62 (c 0.25, CHCl3)}; IR (KBr): mmax 3448,
ꢂ
O
O
2933, 2840, 1673, 1600, 1508, 1543, 1489, 1453, 1358, 1256,
1174, 1028, 836, 770, 702, 586 cmꢀ1
;
1H NMR: (200 MHz, CDCl3):
4.65 (m, 1H), 4.58 (m, 1H), 4.37 (m, 1H), 4.0 (m, 1H), 3.88–3.75
OH
21
22
OH

G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
1167
½
a 2D0
ꢂ
¼ ꢀ14 (c 1.6, CHCl3). IR (KBr):
m
max 3456, 2923, 2854, 1461,
4.14. Procedure for the in situ NHK reaction
1396, 1217, 760 cmꢀ1; 1H NMR (300 M Hz, CHCl3): 6.10 (m, 1H), 5.42
(d, 1H, J = 17.3 Hz), 5.27 (d, 1H, J = 10.6 Hz), 5.00 (s, 1H), 4.92(s, 1H),
4.65 (t, 1H, J = 6.04 Hz), 4.12-3.99 (m, 2H), 1.8 (s, 3H), 1.45 (s, 3H),
1.35 (s, 3H); 13C NMR (75 MHz, CDCl3): 144.9, 134.1, 118.1, 114.1,
108.9, 78.8, 78.5, 73.7, 27.8, 25.4, 17.9; ESIMS: [M+Na]+ = 221.
To a flame dried two-necked round bottom flask, CrCl3 (0.115 g,
0.72 mmol) and powdered activated Mn (0.54 g, 14.5 mmol) were
taken in THF/DMF (7 mL:2 mL) and stirred for 2 h at rt under an in-
ert atmosphere until the colour changed from violet to green. Com-
pound 19 (0.15 g, 0.48 mmol) in THF (3 mL) was added slowly to it
and stirred further for 8 h. When TLC showed the absence of start-
ing material, NiCl2 (30 mg, 0.23 mmol) was added to the reaction
mixture and stirred for 30 min. Next, 2-bromo propene (1.45 g,
1.2 mmol) in DMF (2 mL) was added to it followed by the addition
of TMSCl (0.078 g, 0.72 mmol). The reaction mixture was allowed
to stir for an additional 4 h at rt, and then diluted with diethyl
ether (50 mL). Next, n-Bu4NF (3 mL, 1 M in THF) was added and
stirred at rt for 2 h. The reaction mixture was filtered through a sin-
tered funnel, concentrated and purified by column chromatogra-
phy using ethyl acetate/hexane (8:92) to afford 21 (42%) and 22
(18%) as yellow oils in a ratio of 7:3 (90 mg, 60%).
4.18. (3aS,4S,6aR)-2,2,5-Trimethyl-4,6a-dihydro-3aH-cyclo-
penta[d][1,3]dioxol-4-ol 23
OH
O
O
23
To compound 21 (0.5 g, 2.5 mmol)inanhydrousDCM(500 mL)un-
der nitrogen atmosphere, was added Grubbs second generation cata-
lyst (0.212 mg, 0.25 mmol) and the reaction mixture was allowed to
reflux for 6 h. After completion of the reaction, the reaction mixture
was evaporated at reduced pressure to give a crude residue, which
was purified by columnchromatography (ethylacetate/hexane = 1:9)
4.15. Procedure for the Grignard reaction
To a solution of isopropenyl magnesium bromide prepared from
Mg (0.384 g, 16 mmol) and 2-bromopropene (1.55 mL, 12.8 mmol)
in THF (10 mL) was added a solution of aldehyde 9 (0.5 g,
3.2 mmol) in THF over 10 min at ꢀ78 °C under nitrogen. After stir-
ring for 4 h at room temperature, the mixture was poured into sat-
urated NH4Cl (50 mL) and extracted with ethyl acetate
(3 ꢃ 50 mL). The collected organic layers were combined, washed
with water, brine, and then dried over Na2SO4, concentrated under
reduced pressure and purified by column chromatography (ethyl
acetate/hexane (8:92) to afford the corresponding alcohol 21
(22.5%) and 22 (52.5%) as yellow oils in a ratio of 3:7 (475 mg,
75% for two steps).
to give compound23 (0.36 g, 85%)asayellowoil. ½a D20
¼ ꢀ13:3 (c0.18,
ꢂ
CHCl3);IR (KBr): mmax 3433, 2985, 2927, 1448, 1377, 1245, 1210, 1161,
1048, 861, 763 cmꢀ1; 1H NMR (300 MHz, CHCl3): 5.46 (s, 1H), 4.91 (d,
1H, J = 5.66 Hz), 4.68 (dd, 1H, J = 6.04, 5.66 Hz), 4.21 (dd, 1H, J = 6.04,
9.84 Hz), 2.46 (d, 1H, J = 9.84 Hz, D2O excahnged), 1.79 (s, 3H), 1.40
(s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3): 146.0, 125.5, 111.9,
82.5, 75.7, 77.2, 26.4, 27.6, 13.6; ESIMS: [M+Na]+ = 193.
4.19. (3aS,4R,6aR)-2,2,5-Trimethyl-4,6a-dihydro-3aH-cyclo-
penta[d][1,3]dioxol-4-ol 24
4.16. (S)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
methylprop-2-en-1-ol 21
OH
OH
O
O
O
O
24
21
To compound 22 (0.4 g, 2 mmol) in anhydrous DCM (400 mL)
under a nitrogen atmosphere was added Grubbs second generation
catalyst (0.17 g, 0.2 mmol) and the reaction mixture was allowed
to reflux for 6 h. After completion of the reaction, the reaction mix-
ture was evaporated at reduced pressure to give a crude residue,
which was purified by column chromatography (ethyl acetate/hex-
ane = 1:9) to give compound 23 (0.29 g, 85 %) as a yellow oil.
½
a 2D0
ꢂ
¼ ꢀ46 (c 3.2, CHCl3); IR (KBr) : mmax 3451, 2925, 2855,
1462, 1391, 1257, 1215, 1080, 839, 764 cmꢀ1 1H NMR
;
(300 M Hz, CHCl3): 6.09 (m, 1H), 5.33 (d, 1H, J = 17 Hz), 5.27 (d,
1H, J = 10 Hz), 4.94 (s, 1H), 4.91 (s, 1H), 4.59 (t, 1H, J = 7.2 Hz),
4.20 (dd, 1H, J = 7.2 Hz), 3.94 (t, 1H, J = 4.91 Hz), 2.28 (d, –OH, 1H,
J = 6 Hz), 1.78 (s, 3H), 1.53 (s, 3H), 1.39 (s, 3H); 13C NMR
(75 MHz, CDCl3): 144.2, 133.9, 119.3, 113.2, 108.6, 79.2, 78.6,
72.9, 27.2, 24.8, 19.0; ESIMS: [M+Na]+ = 221.
½
a 2D0
ꢂ
¼ ꢀ56 (c 1.5, CHCl3). IR (KBr): mmax 3448, 2926, 1395, 1216,
1034, 761 cmꢀ1 1H NMR (300 MHz, CHCl3): 5.63 (s, 1H), 5.17 (d,
;
1H, J = 4.999 Hz), 4.53 (s, 1H), 4.53 (s, 1H), 1.81 (s, 3H), 1.41 (s,
3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3): 144.7, 128.7, 111.4,
86.7, 83.4, 83.3, 27.3, 25.6, 14.2; ESIMS: [M+Na]+ = 193.
4.17. (R)-1-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
methylprop-2-en-1-ol 22
4.20. (3aR,6aR)-2,2,5-Trimethyl-3aH-cyclopenta[d][1,3]dioxol-
4(6aH)-one 7
OH
O
O
O
O
O
22
7

1168
G. P. Mishra et al. / Tetrahedron: Asymmetry 23 (2012) 1161–1169
1620; (e) Shing, T. K. M.; Cheng, H. M. Synlett 2010, 142–144; (f)
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3179–3181; (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
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molecular sieve powder (4 Å) and PDC (pyridinium dichlorochro-
mate) (1.6 g, 4.4 mmol) at 0 °C. The reaction mixture was strirred
at rt for 5 h. After completion of the reaction, the crude reaction
mixture was filtered through Celite, washed with water, dried
over anhydrous Na2SO4 and concentrated at reduced pressure
to give a crude brownish syrup. The syrupy liquid was purified
on a column (ethyl acetate/hexane = 1:9) to give a single product
25 (0.302 g, 90 %) as a white solid. mp: 48 °C; ½a D20
ꢂ
¼ ꢀ17 (c
1.33, CHCl3) {lit.30
½
a 2D0
ꢂ
¼ ꢀ17:7 (c 0.9, CHCl3)}; IR (KBr) : mmax
3449, 2923, 2852, 1654, 1460, 1379, 1022 cmꢀ1
;
1H NMR:
(300 M Hz, CHCl3): 7.23 (m, 1H), 5.18 (m, 1H), 4.50 (d, 1H,
J = 5.665 Hz), 1.83 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H); 13C NMR
(75 MHz, CDCl3): 203.2, 153.1, 143.2, 115.2, 76.9, 76.83, 27.4,
26.03, 10.4; ESIMS: m/z calcd for C9H12O3Na 191.06814, found
191.06787.
Acknowledgements
G. P. M. and B. S. K thank CSIR (New Delhi) for fellowship. We
would like to thank Dr. J. S. Yadav and G. V. M Sharma for their con-
stant support and encouragement.
9. (a) Scholl, M.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956; (b) Grubbs,
R. H. In Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003; Vol.
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S. I., Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp 153–177. Chapter 6; (d)
Kotha, S.; Dipak, M. K. Tetrahedron 2012, 68, 397–421.
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