Synthesis of some carbahexopyranoses using Mn/CrCl3 mediated domino reactions and ring closing metathesis

Article abstract of DOI:10.1016/j.tet.2016.02.044

An efficient and common method for the synthesis of 5a-carba-α-D-mannopyranose 5, 5a-carba-β-D-mannopyranose 6, (+) methyl shikimate 9, (+) methyl-5-epi-shikimate 10, validamine analogue 15 and valiolamine analogue 16 from D-mannose, formal synthesis of T

Full text of DOI:10.1016/j.tet.2016.02.044

Tetrahedron xxx (2016) 1e12
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Synthesis of some carbahexopyranoses using Mn/CrCl3 mediated
domino reactions and ring closing metathesis
*
Bejugam Santhosh Kumar, Girija Prasad Mishra, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and common method for the synthesis of 5a-carba-a-D-mannopyranose 5, 5a-carba-b-D-
Received 14 December 2015
Received in revised form 28 January 2016
Accepted 19 February 2016
Available online xxx
mannopyranose 6, (þ) methyl shikimate 9, (þ) methyl-5-epi-shikimate 10, validamine analogue 15 and
valiolamine analogue 16 from -mannose, formal synthesis of Tamiflu 17 from -ribose and also synthesis
of 5a-carba- -glucopyaranose 1, 5a-carba- -glucopyaranose 2, 5a-carba- -altropyranose 7 and 5a-
carba- -altropyranose 8 from -xylose is described using NozakieHiyamaeKishi (NHK) condition and
D
D
a-
D
b-
D
b-L
a
-L
D
ring closing metathesis (RCM). In this transformation 5-deoxy-5-halo-manno/ribo/xylo furanoside un-
dergoes reductive elimination in the presence of Mn/CrCl3 to give corresponding olefin-aldehyde which
was trapped by nucleophile under the same condition to afford diolefinic species which on metathesis
reaction with appropriate Grubbs catalyst produced required carbocycles.
Keywords:
Carbasugars
Aminocarbasugars
Reductive elimination
NozakieHiyamaeKishi reaction
Ring closing metathesis
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Some of the important aminocarbasugars are depicted in Fig. 2.
These are valienamine 11, validamine 12 and valiolamine 13, which
Carbasugars or pseudosugars are carbocyclic analogues of
monosaccharides in which the ring oxygen is replaced by methy-
lene.1 If C-1 OH in carbasugars is replaced by amino group then they
are called as aminocarbasugars. These compounds are excellent
glycosidase inhibitors and shows interesting biological activity
such as anti-cancer, anti-diabetic, anti-HIV, etc.1,2
are secondary metabolites of various microorganisms showing
glycosidase inhibitory activity. Valiolamine 13 shows activity
against maltase and sucrase.9 Voglibose 14 is the chemical modi-
fication of valiolamine currently used for the treatment of di-
abetes.10 Tamiflu 17 is related to aminocarbasugar structure and is
widely used for the treatment of H5N1 influenza as well as H1N1
influenza.11
Some of the important carbasugars and their derivatives are
depicted in Fig. 1. Racemic pseudo-
a
-
D
-glucopyranose 1 shows in-
In continuation of our efforts towards the synthesis of carbo-
hibition of glucose stimulated-insulin release and islet glucokinase
hydrate mimics such as carbasugars,12 aminocarbasugars13 and
activity.3 (ꢀ) Carbasugar 2 is a substrate of the cellobioside phos-
iminosugars,14 herein we report the synthesis of 5a-carba-
a-D-
phorylase of cellvibro gilvuse,4 and also the taste of (ꢀ) carba-
b
-
DL
-
mannopyranose 5,15 5a-carba-
b
-
D
-mannopyranose 6,15b,c,d,h (þ)
glucopyranose
2
is same as that of
D
-glucose.5 Carba-
methyl shikimate 9,16 (þ) methyl-5-epi-shikimate 10,16 validamine
glucotropaeolin 3 is a 5a-carba analogue of
b
-D
-glucopyranose
analogue 1513b,17a,b and valiolamine analogue 1613b,17c,d from
D-
and is a good inhibitor of myrosinase.6 Pseudo-sergliflozin 4 is
a carba analogue of sergliflozin, a phase II drug and is a potent and
selective inhibitor of sodium-dependent glucose cotransporter 2
(SGLT2) for the treatment of Type 2 diabetes and its IC50¼2.45 nm.7
Shikimic acid is a key intermediate in the synthesis of aromatic
amino acids by plants, fungi and microorganisms. Shikimic acid and
their derivatives such as methyl shikimate 9 and methyl-5-epi-
shikimate 10 are biologically important compounds.8 Moreover
several carbasugars and aminocarbasugars have been synthesised
starting from shikimic acid and their intermediates.1a
mannose and formal synthesis of Tamiflu18 from
present here synthesis of 5a-carba-
-glucopyaranose 1,15a,b,c,19
5a-carba- -altropyr-
-glucopyaranose 2,9c,9e,15a,19g 5a-carba-
anose 719d,20 and 5a-carba- -altropyranose 821 from
-xylose. The
D-ribose. Also we
a-D
b
-D
b-L
D
a
-L
key step in the synthesis of above molecules is one pot reductive
ring opening of 5-deoxy-5-iodomanno/ribo/xylo furanoside and
CeC bond formation using allyl bromide under NHK22 condition to
get the diene precursor for RCM reaction.23
2. Results and discussions
Reductive elimination of 5-deoxy-5-halofuranosides under
Bernet-Vasella24 protocol giving chiral 4-pentenals, has many
* Corresponding author. E-mail address: venky@iict.res.in (B.V. Rao).
http://dx.doi.org/10.1016/j.tet.2016.02.044
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
Fig. 1. Carbasugars and their derivatives.
The 5-deoxy-5-iodo furanosides can be obtained from re-
spective sugar such as mannose, ribose and xylose. The nucleo-
philes 18, 19 and 20 required for the NHK reaction are prepared
from methyl/ethyl acrylate28 (Scheme 2).
Scheme 2. Allyl nucleophiles for NHK reaction.
Fig. 2. Some important aminocarbasugars.
synthetic applications.25 The reductive elimination can be carried
out with different metallic reagents such as Zn,24a,b In,25d CrCl2,26a
SmI2,26b Mn/PbCl2,26c BuLi24a,b and acetyliron.24g Reductive ring
opening of 5-deoxy-5-halofuranosides followed by intermolecular
CeC bonding coupling in one pot have been performed by using
Zn25cef and In25d under ultrasonication. Our group has earlier de-
veloped CrCl3/Zn condition for the generation of olefin-aldehyde in
which Zn is used for the conversion of CrCl3 to CrCl2 and the al-
dehyde was trapped by vinyl chromium (NHK reaction) to form
diene precursor for the RCM, which was carried further for the
synthesis of carbafuranoses.12a Later for this purpose,12b we utilized
Furstner’s modified NHK condition for the generation of CrCl2 from
CrCl3 using Mn as reductant which remains inert throughout the
reaction.27 Herein we wish to describe the synthetic utility of our
domino NHK and RCM strategy for the synthesis of various carba-
pyranoses from 5-deoxy-5-halo manno/ribo/xylo furanosides. The
retrosynthetic analysis was depicted in Scheme 1.
For the synthesis of (þ) methyl shikimate 9, (þ) methyl-5-epi-
shikimate 10, pseudo-a-D-mannopyranose 5 and pseudo-b-D-
mannopyranose 6 (Scheme 3), the iodo compound 2129 obtained
from -mannose was treated with Mn/CrCl3 (20:1) for 8 h in THF/
D
DMF. The change in colour from violet to pale blue confirmed the
formation of CrCl2. After the consumption of starting iodo com-
pound (confirmed by TLC), catalytic amount of NiCl2, methyl 2-
(bromomethyl)acrylate 18 followed by TMSCl at 50 ꢁC were added
to carry out the NHK reaction. The reaction completed in 5 h and
gave an inseparable mixture of diastereomers 22 and 23 in 1:1 ratio
in 75% yield (over 2 steps). Mixture of 22 and 23 were reacted with
Hoveyda-Grubbs second generation catalyst to afford compounds
24 and 25 in 96% yield which were separated using column chro-
matography. The compound 24 on oxidation with DesseMartin
periodinane followed by stereo selective reduction with NaBH4
produced compound 25 exclusively. Though NHK reaction gave two
diastereomeric alcohols in 1:1 ratio, the oxidation and reduction
strategy provided a way for obtaining the single diastereomeric
compound 25. Deprotection of 24 and 25 independently using
aqueous TFA afforded (þ) methyl shikimate 9 and (þ) methyl-5-
epi-shikimate 10, respectively. The physical and spectral data of
compound 916i,j and 1016h are in accordance with the reported
values. For the synthesis of pseudo-
a-D-mannopyranose 5 and
pseudo- -mannopyranose 6, first the ester functionalities in
b-D
compounds 24 and 25 were reduced using DIBALH to furnish al-
cohols 26 and 29, respectively. Next the compounds 26 and 29 on
stereoselective hydroboration/oxidation afforded triol compounds
27 and 30, respectively. Deprotection of acetonide functionality in
Scheme 1. Retrosynthetic analysis.
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B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
3
Scheme 3. Synthesis of (þ) methyl shikimate (9), (þ) methyl-5-epi-shikimate (10), 5a-carba-
a
-D-mannopyranose (5) and 5a-carba-
b
-D-mannopyranose (6). Reagents and condi-
tions: (a) Mn/CrCl3 (20:1), THF:DMF (5:1), 8 h then NiCl2 (cat), 18, TMSCl, 50 ꢁC, 5 h, TBAF, rt, 5 h, 75%; (b) Hoveyda-Grubbs second generation catalyst, 1,2 dichloroethane, reflux, 3 h,
96%; (c) (i) DesseMartin periodinane, DCM, rt, 1 h (ii) NaBH4, MeOH, 0 ꢁC, 1 h; (d) 50% aqueous CF3COOH, rt, 4 h, 95% for (5) and (6), 98% for (9) and (10) (e) DIBAL-H, DCM, 0 ꢁC, 2 h,
78%; (f) BH3.DMS, THF 0 ꢁC to rt, 2 h, then NaOH, H2O2, 0 ꢁC, 2 h, 65%; (g) pyridine, Ac2O, DMAP, 24 h, 70%.
compounds 27 and 30 using 50% aqueous TFA afforded pseudo-
a
-
D
-
compound 36, which on deprotection with 50% aqueous TFA gave
valiolamine analogue 16. The crude compound on acetylation
afforded peractylated compound 37 in 90% yield over 2 steps,
whose physical and spectral data are in accordance with reported
values.17c,d
mannopyranose 5 and pseudo- -mannopyranose 6, respectively.
b-D
Compound 5 was converting to its acetate derivative 28 for further
confirmation. The physical and spectral data of compounds 5,15c
2815c,g and 615d are in good agreement with the reported values.
For the synthesis of validamine analogue 15 and valiolamine
analogue 16 (Scheme 4), compounds 24 and 25 were treated with
DesseMartin periodinate to furnish unstable keto compound,
which on reaction with hydroxylamine hydrochloride salt in eth-
anol and pyridine (1:1) afforded oxime 31. Stereoselective re-
duction of oxime 31 with NaBH4 in presence of MoO3 afforded
amine.18a The crude amine was treated with di-tert-butyl dicar-
bonate to furnish Boc protected amine compound 32, which on
reduction with DIBAL-H afforded 33. Regio- and stereoselective
reduction of 33 in presence of BH3.DMS followed by NaOH/H2O2
afforded alcohol 34 exclusively. Deprotection of 34 using 50%
aqueous TFA gave validamine analogue 15. For the sake of proper
characterization, the crude product 15 was peracetylated with
acetic anhydride to give 35 in 90% yields over 2 steps, whose
spectral data was in accordance with the reported values.13b The
compound 33 on reaction with OsO4 afforded trihydroxy
After successfully applying our strategy on mannose (Scheme 3),
we designed an approach for the formal synthesis of Tamiflu from
D-ribose (Scheme 5). Earlier synthesis for the Tamiflu reported with
the use of Zn and In metal mediated reductive ring opening of 5-
deoxy-5-halo-ribofuranoside followed by CeC bond formation us-
ing ethyl 2-(bromomethyl)acrylate 1918 to give 39 and 40 under
ultrasonication. The above reaction also gave bi products18a posing
problem in isolation of the product in pure form, and also ultra-
sonication condition is not practical for higher scale synthesis. To
study the product formation in our condition, we carried the re-
ductive elimination of 38 and allylation using substituted allyl ha-
lide 19. 5-deoxy-5-iodo-ribosyl compound 38 obtained from D-
ribose18a was treated with ethyl 2-(bromomethyl)acrylate 19 under
standard Mn/CrCl3 mediated domino NHK condition. The reaction
completed in 5 h and yielded diastereomeric mixture of com-
pounds 39 and 40 in 1:1 ratio without any visible impurities on the
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4
B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
Scheme 4. Synthesis of validamine analogue 15 and valiolamine analouge 16. Reagents and conditions: (a) (i) DesseMartin periodinane, DCM, rt, 1 h (ii) NH2OH$HCl, EtOH, Py, rt,
2 h, 70% (over 2 steps); (b) (i) MoO3, NaBH4, MeOH, 0 ꢁC, 1 h, di-tert-butyl diocarbonate, 2 h, 70% (over 2 steps); (c) DIBAL-H in toluene, DCM, 0 ꢁC, 2 h, 78%; (d) BH3.DMS, THF 0 ꢁC to
rt, 2 h, then NaOH, H2O2, 0 ꢁC, 2 h, 65% (e) (i) 50% aqueous CF3COOH, rt, (ii) Ac2O, Py, rt, 2 h, 90%; (f) OsO4, NMO, acetone: water (4:1), 0 ꢁC, 2 h, 90%.
Scheme 5. Formal synthesis of Tamiflu. Reagents and conditions: (a) Mn/CrCl3 (20:1), THF:DMF (5:1), 8 h then NiCl2 (cat), 19, TMSCl, 50 ꢁC, 5 h, TBAF, rt, 2 h, 75%; (b) Hoveyda-
Grubbs second generation catalyst, 1,2 dichloroethane, reflux, 3 h, 92%; (c) DesseMartin periodinane, DCM, rt, 1 h, NH2OH$HCl, Py, rt, 2 h, 70%.
TLC, the products were well purified by simple column chromato-
graphic technique. This method is useful for the scaling up of in-
termediate compounds 39 and 40 for the synthesis of Tamiflu 17,
which doesn’t require any ultrasound assistance. Ring closing me-
tathesis of diolefinic compounds 39 and 40 using Hoveyda-Grubbs
catalyst second generation gave products 41 and 42, respectively.
Oxidation of secondary alcohol in 41 and 42 using DesseMartin
periodinane gave unstable ketone which on reaction with hy-
droxylamine hydrochloride salt in pyridine solvent afforded oxime
43 required for the synthesis of Tamiflu 17.18a
Most of the carbasugars have pendant hydroxymethyl group in
their structure. Generally in the carbasugar synthesis the hydrox-
ymethyl group was introduced by reduction of corresponding ester.
To avoid the reduction step and to get directly hydroxymethyl on
carbasugar core structure, we prepared NHK precursor 20 as a nu-
altropyranose (7) and 5a-carba-
a
-
L
-altropyranose (8) starting from
D
-xylose (Scheme 6). The 5-deoxy-5-iodo xylofuranose compound
44 was prepared from
-xylose in 3 steps.30 The compound 44 on
D
reaction with allyl nucleophile 20 under standard domino re-
ductive ring opening, followed by allylation under Mn/CrCl3 (NHK
reaction) conditions afforded compounds 45 and 46 in 1:1 ratio. In
the Fursntner’s modified NHK condition27 one has to use TBAF to
deprotect the OTMS to get OH. Here in this case, TBAF will deprotect
both the OTMS and OTBS groups. Therefore here we used 1N HCl for
work up which could deprotect the OTMS group selectively giving
rise to compounds 45 and 46. The stereochemistry of the newly
generated chiral centre in 45 and 46 were assigned after cyclisation
in presence of Grubbs second generation catalyst which afforded
compounds 47 and 48. The stereochemistry of the newly created
centre C-1 of 47 was ascertained by analyzing coupling constants
for 6a-H (2.05,1H, m, major couplings J¼9.4 Hz,17.0 Hz), 6e-H (2.40,
dd, 1H, J¼5.9 Hz, 17.0 Hz) and 1a-H (3.76, m, 1H, one of coupling
cleophile, and utilized this for the synthesis of pseudo-
a-D-gluco-
pyranose (1), pseudo- -glucopyranose (2), 5a-carba-b-L-
b
-D
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B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
5
Scheme 6. Synthesis of 5a-carba-
a
-D-glucopyaranose 1, 5a-carba-
b
-D-glucopyaranose 2, 5a-carba-
b
-L-altropyranose 7 and 5a-carba-
a
-L-altropyranose 8. Reagents and conditions:
(a) Mn/CrCl3 (20:1), THF:DMF (5:1), 8 h then NiCl2 (cat), 20, TMSCl, 50 ꢁC, 5 h, 1N HCl, rt, 2 h, 75%; (b) Grubbs second generation catalyst, toluene, reflux, 3 h, 90%; (c) BH3.DMS, THF
0
ꢁC to rt, 2 h, then NaOH, H2O2, 0 ꢁC, 2 h, 70%; (d) 6N MeOH (HCl), reflux, 1 h, 95% quantitative; (e) pyridine, Ac2O, DMAP, 12 h, 95%.
J¼9.4 Hz) suggesting the orientation of hydroxyl group in equitorial
in six membered skeleton. Similarly the stereochemistry at C-1 of
48 was ascertained by analyzing the coupling constants for 6a-H
(2.11, dd, 1H, J¼7.1, 17.3), 6e-H (2.28, dd, 1H, J¼4.8 Hz, 17.3 Hz) and
1e-H (3.77, dd, 1H, J¼2.2 Hz, 4.8 Hz) suggesting the orientation of
hydroxyl group is axial. Hydroboration-oxidation of olefin com-
pound 47 using BH3.DMS followed by NaOH/H2O2 afforded 49 and
3. Conclusions
We have developed an efficient method for the synthesis of
various carbasugars and aminocarbasugars using domino reductive
ring opening of 5-deoxy-5-halo furanosides followed by allylation
for getting diolefinic species under NHK condition followed by
RCM. This method is highly useful and convenient for the synthesis
of different carbapyranoses and their analogues from cheaply
available sugars in a short possible route in good overall yields.
50 in 6:1 ratio. Deprotection of 49 afforded pseudo-
anose 2 whose data was in good accordance with the reported
values.9c Deprotection of 50 afforded pseudo-
-altropyranose 8,
b-D-glucopyr-
a-L
which was confirmed by converted to peracetyl derivative 53,
whose data was in good agreement with the literature values.21a
Hydroboration-oxidation of olefin compound 48 using BH3.DMS
followed by NaOH/H2O2 treatment gave 51 and 52 in 6:1 ratio.
4. Experimental
4.1. General information
Deprotection of 51 afforded pseudo-b-L-altropyranose 7 which was
All reactions are carried under nitrogen atmosphere in oven
dried glassware equipped with magnetic stirrer and rubber septum
unless otherwise indicated. All solvents are freshly distilled before
use; THF over sodium and benzophenone; DCM over calcium hy-
dride. All other commercial reagents were used without further
purification, unless otherwise noted. Reactions were monitored by
thin layer chromatography (TLC) of aliquots using glass sheets
coated (0.25 mm layered thickness) with silica gel F254 (Merck
converted to peracetyl derivative 54, whose data are also in good
agreement with the reported values.20b Deprotection of 52 afforded
pseudo-a-D-glucopyranose 1, the physical and spectral data of 1 are
in good accordance with the reported values.15c Here, noteworthy
to mention is the facial selectivity of BH3.DMS reduction of olefin,
which was decided by the chirality at C-1 position. Major product
being formed is anti to the existing C-1 hydroxy chiral centre.
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6
B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
Kiesel gel 60). TLC plates are viewed under UV light and charred
with phosphomolybdic acid. Column chromatographies were car-
ried out with silica gel 60e120 mesh or 100e200 mesh (Merck).
NMR spectra were recorded in deuterated solvents on 300 MHz or
400 or 500 MHz or 600 MHz spectrometer at ambient temperature.
29.3, 52.1, 68.7, 72.2, 77.8, 109.6, 130.5, 133.9, 166.5; HRMS (ESI,
Orbitrap) m/z: calcd for C11H16O5Na 251.0889, found 251.0886.
4.2.2. (3aS,7R,7aR)-Methyl 7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetra-
hydrobenzo[d][1,3]dioxole-5-carboxylate (25). [
a
]
20: ꢂ21.2ꢁ (c 1.1,
D
Chemical shifts
d
is given in ppm, coupling constant J are in Hz. The
CHCl3) {lit.15d
[
a
]D: ꢂ23.93ꢁ (c 1.1, MeOH); IR (Neat) nmax: 3434,
chemical shifts are reported in ppm on scale downfield from TMS as
internal standard and signal patterns are indicated as follows: s,
singlet; d, doublet; t, triplet; m, multiplet; br, broad peak. FTIR
recorded as neat. Optical rotations were measured on polarimeter
using a 1 mL cell with a one dm path length. For High (HRMS)
resolution, m/z ratios are reported as values in atomic mass units.
2987, 2952, 2851, 1712, 1651, 1438, 1376, 1297, 1238, 1094, 742 cmꢂ1
,
1H NMR, (300 MHz, CDCl3):
d 1.39 (s, 3H), 1.41 (s, 3H), 2.25 (br s,
-OH), 2.51 (m, 1H), 2.65 (dd, 1H, J¼4.5 Hz, 16.6 Hz), 3.78 (s, 3H), 3.95
(m, 1H), 4.42 (dd, 1H, J¼2.2 Hz, 3.0 Hz), 4.73 (br s, 1H), 6.78 (s, 1H);
13C NMR (75 MHz, CDCl3):
d 25.9, 27.3, 27.7, 52.0, 66.8, 72.8, 75.4,
109.9, 129.1, 134.7, 166.7; HRMS (ESI, Orbitrap) m/z: calcd for
11H16O5Na 251.0889, found 251.0883.
C
4.1.1. (S)-Methyl 4-((4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
4-hydroxy-2-methylenebutanoate (22) and (R)-methyl 4-((4R,5S)-
2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-4-hydroxy-2-
methylenebutanoate (23). To a flame dried two-necked round
bottom flask, CrCl3 (0.603 g, 3.81 mmol) and powdered activated
Mn (4.19 g, 76.2 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 21 (0.8 g, 2.54 mmol) in
THF (9 mL) was slowly added to it and stirred for 8 h. When TLC
showed the absence of starting material, NiCl2 (32 mg, 0.25 mmol)
was added to the reaction mixture and stirred for 30 min. Then allyl
bromo compound 18 (0.76 mL, 6.35 mmol) followed by TMSCl
(0.48 mL, 3.18 mmol) were added. The reaction mixture was
allowed to stir for an additional 5 h at 50 ꢁC and diluted with diethyl
ether (70 mL). Next, n-Bu4NF (5 mL, 1M in THF, 5.08 mmol) was
added and stirred at rt for 2 h. The reaction mixture was filtered
through a pad of Celite using sintered funnel, concentrated and
purified by column chromatography using ethyl acetate/hexane
(2:8) to afford a mixture of 22 and 23 (489 mg, 75%) in a 1:1 ratio
4.2.3. Conversion compound 24 to compound 25. To a solution of 24
(50 mg, 0.21 mmol) in DCM (5 mL) were added DesseMartin
periodinane (186 mg, 3.5 mmol) at rt for 1 h. After consumption of
the starting material, the reaction was being quenched by adding
saturated hypo solution (2 mL) followed by saturated NaHCO3
(2 mL). The organic layer was extracted with DCM (3 mLꢃ3), the
combined fractions were collected and dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give crude
product. The crude ketone was unstable and proceeded for next
reaction without further purification. To the ketone dissolved in
MeOH (2 mL) was added NaBH4 (15.8 mg, 0.42 mmol) at 0 ꢁC and
stirred for 1 h. The reaction quenched by adding saturated NH4Cl
(2 mL) and the MeOH was removed using rotavapor followed by
extraction of the aqueous layer with EtOAc (10ꢃ3 mL). The com-
bined organic fractions were collected and dried over Na2SO4 to
give crude 25. Purification by column chromatography using ethyl
acetate: hexane (1:5) as eluent gave 25 (35 mg, 70%) as an oil.
(by 1H NMR) as a yellow oil, [
a
]
D
20: þ21ꢁ (c 1.1, CHCl3); IR (Neat)
4.2.4. (þ)Methyl shikimate (9). To the compound 24 (20 mg,
0.1 mmol) was added aqueous CF3COOH (3 mL, 1:1 v/v) at ice-cold
temperature and stirred at room temperature for 4 h. After com-
pletion of the reaction, the solvent was evaporated under reduced
pressure to give crude compound 9 which was purified by column
chromatography using MeOH:CHCl3 (0.3:9.7) to afford pure com-
pound 9 as a white solid (19 mg, 95%), mp 107e108 ꢁC (lit.16i,j
113e115 ꢁC). The physical and spectroscopic data of compound 9
were in exact agreement with the reported literature values.16i,j
nmax: 3395, 2989, 2929, 1719, 1632, 1511, 1211, 750 cmꢂ1, 1H NMR,
(400 MHz, CDCl3): d 1.37 (s, 3H),1.40 (s, 3H),1.50 (s, 3H),1.53 (s, 3H),
2.34e2.46 (m, 2H), 2.55 (dd, 1H, J¼3.2 Hz, 14.2 Hz), 2.87 (dd, 1H,
J¼2.9 Hz, 14.1 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 3.75e3.81 (m, 2H), 3.97
(dd, 1H, J¼6.2 Hz, 8.5 Hz), 4.07 (dd, 1H, J¼4.2 Hz, 6.8 Hz), 4.62 (t, 1H,
J¼7.2 Hz), 4.68 (t, 1H, J¼6.6 Hz) 5.26e5.44 (m, 4H), 5.71 (s, 1H), 5.75
(s, 1H), 5.99e6.11 (m, 2H), 6.27 (d, 1H, J¼1.4 Hz), 6.28 (d, 1H,
J¼1.4 Hz); 13C NMR (75 MHz, CDCl3):
d 24.8, 25.3, 27.1, 27.6, 36.6,
36.9, 51.8, 52.1, 68.1, 69.1, 78.6, 79.0, 80.0, 80.0, 108.5, 108.6, 117.7,
119.5, 127.9, 128.4, 133.8, 134.0 136.4, 136.6, 167.5, 168.7; HRMS (ESI,
Orbitrap) m/z: calcd for C13H20O5Na 279.1202, found 279.1199.
[
a
]
20: þ137ꢁ (c 0.84, MeOH) {lit.16j
[
a
]D: þ139ꢁ (c 0.4, MeOH); IR
D
(Neat) nmax: 3394, 2924, 2853, 1714, 1654, 1438, 1375, 1251,
1066 cmꢂ1
,
1H NMR, (300 MHz, CD3OD):
d
2.2 (dd, 1H, J¼4.7 Hz,
17.9 Hz), 2.69 (dd, 1H, J¼4.3 Hz, 17.9 Hz), 3.69 (m, 1H), 3.74 (s, 3H),
4.2. Experimental procedure for ring closing metathesis
reaction
3.99 (dd, 1H, J¼5.2 Hz, 11.7 Hz), 4.37 (br s, 1H), 6.8 (br s, 1H); 13C
NMR (75 MHz, CD3OD):
d 31.5, 52.4, 67.2, 68.4, 72.5, 130.2, 139.1,
168.7; HRMS (ESI, Orbitrap) m/z: calcd for C8H12O5Na 211.0576,
To the diastereomeric mixture of compounds 22 and 23
(470 mg, 1.83 mmol) in anhydrous 1,2 dichloro ethane (15 mL)
under a nitrogen atmosphere, was added Hoveyda-Grubbs second
generation catalyst (22 mg, 0.036 mmol) and the reaction mixture
was refluxed for 2 h. After completion of the reaction, the reaction
mixture was evaporated at reduced pressure to give a crude resi-
due, which was purified by column chromatography using
100e200 silica gel mesh eluated by ethyl acetate/hexane (1.5:8.5:
to 3:7) to give compounds 24 (200 mg, 47.8%) and 25 (200 mg,
47.8%) as yellow oils.
found 211.0580.
4.2.5. (þ)Methyl 5-epi-shikimate (10). Experimental procedure is
similar to compound 9 synthesis. The crude product is purified by
column chromatography eluated by using MeOH:CHCl3 (0.3:9.7) to
give pure 10 as a white solid (95%) mp 120e121 ꢁC (lit.,16h
122e123 ꢁC), [
a
]
20: þ51.5ꢁ (c 0.75, EtOH) {lit.16h
[
a
]D: þ53.7ꢁ (c
D
0.88, EtOH) the physical and spectral properties are in accordance
with the literature values.;16h IR (Neat) nmax: 3409, 2923, 2853,
1708, 1651, 1438, 1375, 1249, 1238, 1151, 1034 cmꢂ1 1H NMR,
,
(500 MHz, acetone-d6):
17.2 Hz), 3.7 (s, 3H), 3.86 (m, 1H), 3.94 (m, 1H), 4.30 (br s, 1H), 6.65
(br s, 1H); 13C NMR (125 MHz, CD3COCD3):
31.3, 52.9, 69.9, 70.2,
72.7, 130.2, 140.9, 168.3; HRMS (ESI, Orbitrap) m/z: calcd for
C8H12O5Na 211.0576, found 251.0576.
d
2.38 (m, 1H), 2.49 (dd, 1H, J¼5.4 Hz,
4.2.1. (3aS,7S,7aR)-Methyl 7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetra-
hydrobenzo[d][1,3]dioxole-5-carboxylate (24). [
a
]
20: þ122.5ꢁ (c 1.0,
d
D
CHCl3); IR (Neat) nmax: 3499, 2988, 2921, 2310, 1715, 1656, 1511,
1438, 1245, 1216, 1053, 770 cmꢂ1, 1H NMR, (300 MHz, CDCl3):
d
1.33
(s, 3H), 1.38 (s, 3H), 2.18 (dd, 1H, J¼7.9 Hz, 16.9 Hz), 2.73 (dd, 1H,
J¼4.5 Hz, 16.9 Hz), 3.7 (s, 3H), 3.84 (m, 1H), 4.03 (t, 1H, J¼6.9 Hz),
4.2.6. (3aR,4S,7aS)-6-(Hydroxymethyl)-2,2-dimethyl-3a,4,5,7a-tet-
rahydrobenzo[d][1,3]dioxol-4-ol (26). To the compound 24 (100 mg,
4.68 (br s, 1H), 6.85 (s, 1H); 13C NMR (125 MHz, CDCl3):
d
25.7, 27.9,
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
7
0.438 mmol) in DCM (5 mL) was added DIBAL-H (0.62 mL,
1369, 1217, 1042, 720 cmꢂ1
,
1H NMR, (500 MHz, CDCl3):
1.09 mmol) 25% w/v in toluene at ꢂ5 ꢁC and stirred for 2 h. After
completion of the reaction MeOH (1 mL) was added to quench the
excess DIBAL-H followed by saturated potassium sodium tartarate
(10 mL) and saturated NH4Cl (5 mL). Mixture is extracted using
ethylacetate (3ꢃ20 mL), all the organic fractions were collected and
dried over Na2SO4, solvent was removed under reduced pressure
using rotavapour. The crude product was purified by column
chromatography using as ethylacetate: hexane (7.5:2.5) as eluent to
d 1.81e1.92 (m, 2H), 1.96 (s, 3H), 2.02 (s, 3H), 2.05 (s, 3H), 2.10 (s,
3H), 2.12 (s, 3H), 2.23 (m, 1H), 3.93 (dd, 1H, J¼3.8 Hz, 11.4 Hz),
4.09 (dd, 1H, J¼5.6 Hz, 11.4 Hz), 5.01 (dd, 1H, J¼3.0 Hz, 6.4 Hz),
5.16e5.23 (m, 2H), 5.29 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 20.9,
20.9, 21.0, 21.1, 21.2, 27.7, 35.8, 63.9, 68.5, 69.2, 69.5, 71.0, 169.5,
169.5, 170.2, 170.3, 171.0; HRMS (ESI, Orbitrap) m/z: calcd for
C
17H24O10Na 411.1261, found 411.1247.
give 26 as an oil, (67 mg, 78%). [
a
]
20: þ84.5ꢁ (c 1.42, CHCl3); IR
4.2.10. (3aR,4R,7aS)-6-(Hydroxymethyl)-2,2-dimethyl-3a,4,5,7a-tet-
D
(Neat) nmax: 3609, 3394, 2922, 2852, 1679, 1657, 1458, 1376, 1216,
rahydrobenzo[d][1,3]dioxol-4-ol (29). Experimental procedure for
20
1050, 772 cmꢂ1, 1H NMR, (600 MHz, CDCl3):
d
1.40 (s, 3H), 1.48 (s,
the preparation of 29 is similar to compound 26 preparation. [a] :
D
3H), 2.05 (dd, J¼6.0 Hz, 16.9 Hz), 2.35 (dd, 1H, J¼4.1 Hz, 16.9 Hz),
ꢂ2.0ꢁ (c 1.38, CHCl3); IR (Neat) nmax: 3611, 3395, 2922, 2852, 1691,
3.84 (dd, 1H, J¼8.6 Hz, 13.5 Hz), 4.01 (t, 1H, J¼7.9 Hz), 4.07 (s, 2H),
1550, 1514, 1214, 1041, 749 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d 1.39
4.66 (br s, 1H), 5.84 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
25.8, 28.2,
(s, 3H), 1.42 (s, 3H), 2.18 (dd, J¼4.4 Hz, 16.2 Hz), 2.32 (dd, 1H,
J¼8.2 Hz, 16.2 Hz), 2.82 (br s, -OH), 3.92e3.96 (m, 1H), 4.05 (s, 2H),
4.35 (dd, 1H, J¼2.7 Hz, 6.1 Hz), 4.64 (s, 1H), 5.72 (s, 1H); 13C NMR
31.2, 65.5, 69.3, 72.6, 79.1, 109.3, 118.1, 140.8; HRMS (ESI, Orbitrap)
m/z: calcd for C10H16O4Na 223.0940, found 223.0936.
(125 MHz, CDCl3):
d 25.8, 27.2, 29.2, 65.6, 66.7, 72.7, 75.5, 109.3,
4.2.7. (3aS,4R,7S,7aR)-5-(Hydroxymethyl)-2,2-dimethylhexa
119.5, 138.2; HRMS (ESI, Orbitrap) m/z: calcd for C10H16O4Na
hydrobenzo[d][1,3]dioxole-4,7-diol (27). To the compound 26
(60 mg, 0.3 mmol) in THF (5 mL), BH3$Me2S (0.08 mL, 0.9 mmol)
was added drop wise at 0 ꢁC, stirring continued for 2 h at rt. Then
NaOH (3N, 0.5 mL) followed by H2O2 (30%, 0.5 mL) solution were
added at 0 ꢁC and stirring continued for 30 min at the same tem-
perature. The reaction mixture was diluted with EtOAc, washed
with water, brine, dried (Na2SO4), purified by column chromatog-
raphy using MeOH: CHCl3 (0.2: 9.8) as the eluent to give 27 as an oil
223.0940, found 223.0936.
4.2.11. (3aS,4R,5R,7R,7aR)-5-(Hydroxymethyl)-2,2-dimethylhexa
hydrobenzo[d][1,3]dioxole-4,7-diol (30). Experimental procedure
for preparation of compound 30 is similar to compound 27 prep-
aration [
a]
20: ꢂ6.8ꢁ (c 0.92, MeOH); IR (Neat) nmax: 3419, 2924,
D
2854, 1463, 1379, 1264, 1220, 1072 cmꢂ1
,
1H NMR, (500 MHz,
CD3OD):
d 1.36 (s, 3H), 1.46 (m, 1H), 1.51(s, 3H), 1.58 (q, 1H,
(42 mg, 65%). [
a]
20: ꢂ16.2ꢁ (c 0.86, MeOH); IR (Neat) nmax: 3668,
J¼12.0 Hz), 1.82 (m, 1H), 3.48e3.57 (m, 2H), 3.72 (dd, 1H, J¼4.2 Hz,
D
3439, 2922, 2852, 1377, 1166, 1066, 722 cmꢂ1, 1H NMR, (500 MHz,
10.6 Hz), 3.89 (dd, 1H, J¼5.1 Hz, 7.4 Hz), 3.93 (m, 1H), 4.33 (t, 1H,
CD3OD):
d
1.35 (s, 3H), 1.47 (s, 3H), 1.64 (m, 1H), 1.76 (m, 1H), 1.83
J¼4.5 Hz); 13C NMR (100 MHz, CD3OD):
d 26.5, 28.5, 31.1, 42.0, 64.3,
(m, 1H), 3.52 (dd, 1H, J¼7.6 Hz, 10.5 Hz), 3.62 (dd, 1H, J¼5.6 Hz,
10.8 Hz), 3.67 (dd, 1H, J¼4.5 Hz, 10.8 Hz), 4.0 (dd, 1H, J¼5.9 Hz,
7.6 Hz), 4.04 (dd, 1H, J¼3.5 Hz, 8.0 Hz), 4.11 (dd, 1H, J¼3.6 Hz,
68.9, 74.3, 78.5, 83.3, 110.5; HRMS (ESI, Orbitrap) m/z: calcd for
C10H18O5Na 241.1046, found 241.1045.
5.0 Hz); 13C NMR (100 MHz, CD3OD):
d
26.6, 28.4, 31.1, 38.8, 64.2,
4.2.12. Pseudo- -mannopyranose (6). Experimental procedure
b-D
67.7, 73.9, 80.2, 81.9, 109.9; HRMS (ESI, Orbitrap) m/z: calcd for
10H18O5Na 241.1046, found 241.1042.
for the preparation of compound 6 is similar to the compound 5
C
preparation to give solid compound 6 (95%), mp 218e219 ꢁC, {lit.15d
223 ꢁC} [
a
]
20: þ12.5 (c 0.42, MeOH), {lit.15e
[
a
]D: þ11.9ꢁ (c 0.65,
D
4.2.8. Pseudo-
a
-D-mannopyranose (5). To the compound 25
MeOH) the physical and spectral data are in good agreement with
(30 mg, 0.13 mmol) was added aqueous CF3COOH (3 mL, 1:1 v/v)
at ice-cold temperature and stirred at room temperature for 4 h.
After completion of the reaction, the solvent was evaporated
under reduced pressure to give compound 5 as an oil (23 mg,
the reported values.15d; IR (Neat) nmax: 3362, 2922, 2855, 1461,
1376, 1219, 1220, 1048 cmꢂ1, 1H NMR, (500 MHz, D2O):
d
1.52 (m,
2H), 1.75 (m, 1H), 3.41e3.50 (m, 2H), 3.59 (m, 1H), 3.73e3.79 (m,
2H), 4.0 (s, 1H); 13C NMR (125 MHz, D2O):
29.3, 41.0, 63.2, 69.4,
d
95%), The physical and spectroscopic data of compound 5 were in
70.6, 73.6, 74.8; HRMS (ESI, Orbitrap) m/z: calcd for C7H14O5Na
201.0733, found 201.0732.
20
exact agreement with the reported literature values.15c
[
a
]
:
D
þ2.5ꢁ (c 0.75, MeOH) {lit.15c
[
a
]D: þ1.9ꢁ (c 1.08, MeOH); IR (Neat)
nmax: 3389, 2922, 2853, 1461, 1219, 1120, 1048, 722 cmꢂ1, 1H NMR,
4.2.13. (3aS,7aR)-Methyl 7-(hydroxyimino)-2,2-dimethyl-3a,6,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (31). To a solution of
24 and 25 (400 mg, 1.7 mmol) in DCM (20 mL) were added
DesseMartin periodinane (1.48 g, 3.5 mmol) at rt for 1 h. After
consumption of the starting material, the reaction is being
quenched by adding saturated hypo solution (5 mL) followed by
saturated NaHCO3 (5 mL). The organic layer is extracted using DCM
(10 mLꢃ3) the combined fractions are collected and dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
give the crude product. The crude ketone is unstable and proceeded
for next reaction without further purification. To the crude ketone
(1.7 mmol) in EtOH (2 mL) was added hydroxylamine hydrochlo-
ride (245 mg, 3.53 mmol) followed by pyridine (1 mL). The reaction
mixture was stirred at room temperature for 2 h. The solution was
poured into water and extracted with CH2Cl2 (3ꢃ50 mL). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude oxime 31 was
purified by ethyl acetate: hexane (1:9) to give 31 (295 mg, 70%, over
two steps) as a yellow oil. IR (Neat) nmax: 3588, 3543, 2988, 2928,
2853, 1716, 1660, 1438, 1339, 1226, 1046, 938, 772 cmꢂ1, 1H NMR,
(300 MHz, D2O):
3.58e3.73 (m, 3H), 3.89 (br s, 1H), 3.96 (br s, 1H); 13C NMR
(125 MHz, D2O): 28.9, 39.3, 63.1, 69.6, 70.8, 72.9, 73.2; HRMS
(ESI, Orbitrap) m/z: calcd for C7H14O5Na 201.0733, found
201.0729.
d
1.61e1.85 (m, 3H), 3.51 (t, 1H, J¼9.8 Hz),
d
4.2.9. (1S,2R,3S,4R,5R)-5-(Acetoxymethyl)cyclohexane-1,2,3,4-tetrayl
tetraacetate (28). To a solution of compound 5 (10 mg, 0.05 mmol)
in pyridine (2 mL) were added acetic anhydride (0.05 mL,
0.56 mmol) and a few crystals of DMAP (cat) and the reaction
mixture was stirred for 24 h at room temperature. After com-
pletion of the reaction 1 mL of aqueous NH4Cl was added. The
aqueous phase is extracted with DCM (3ꢃ5 mL). The combined
organic layers were collected dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give a residue. The res-
idue was purified on a column (ethyl acetate: hexane¼1:4) to
afford 28 as a white solid (15 mg, 70%) mp 77 oC (lit.,15c 80 ꢁC).
[
a
]
20: þ29ꢁ (c 1.0, CHCl3) {lit.15c
[
a
]D: þ27.1ꢁ (c 3.95, CHCl3). The
D
physical and spectral properties are in accordance with the re-
ported values.15g; IR (Neat) nmax: 3610, 2956, 2925, 1738, 1514,
(500 MHz, CDCl3): d 1.39 (s, 3H), 1.42 (s, 3H), 3.02e3.08 (dt, 1H,
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

8
B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
J¼2.3 Hz), 3.75e3.81 (m, 4H), 4.66 (d, 1H, J¼4.9 Hz), 4.83 (m, 1H),
6.8 (s, 1H); 13C NMR (125 MHz, CDCl3):
21.1, 26.6, 27.9, 52.2, 73.4,
73.8, 110.6, 126.7, 135.7, 152.5, 166.4 HRMS (ESI, Orbitrap) m/z: calcd
CDCl3): d 26.4, 28.3, 39.9, 48.1, 66.2, 75.5, 79.7, 81.6, 109.6, 155.2; ESI
(MS) m/z: [MþNa] 340.
d
for C11H16O5N 242.1023, found 241.1019.
4.2.17. (1R,2S,3R,4R,6R)-4-Acetamido-6-(acetoxymethyl)cyclohex-
ane-1,2,3-triyl triacetate (35). Aqueous CF3COOH {(1:1 v/v) 2 mL}
was added to the compound 34 (15 mg, 0.004 mmol) at ice-cold
temperature, the mixture was stirred at rt for 3 h. After comple-
tion of the reaction the solvent was removed under reduced pres-
sure to give crude amine. To the crude amine were added pyridine
(2 mL), Ac2O (0.2 mL) and catalytic amount of DMAP at rt and
stirred overnight. The solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
with 5% MeOH in CHCl3 to afford pentaacetate 35 (16 mg, 90% from
34) as a white solid. Mp 173e175 ꢁC {lit.13b 175e178 ꢁC}. The
physical and spectral data are in accordance with the literature
4.2.14. (3aS,7R,7aR)-Methyl 7-(tert-butoxycarbonylamino)-2,2-
dimethyl-3a,6,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate
(32). To a mixture of oxime 31 (280 mg, 1.16 mmol) and MoO3
(250 mg, 1.74 mmol) in MeOH (8 mL) was added NaBH4 (439 mg,
11.61 mmol) portionwise. An exothermic reaction occurred with
vigorous gas evolution. The reaction mixture was stirred at room
temperature for 50 min. To the reaction mixture was added brine
and the precipitate was filtered off. The filtrate was extracted with
EtOAc (3ꢃ10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure to
give amine. To the crude amine taken MeOH (3 mL) was added
Boc2O (379 mg, 1.74 mmol) and stirred at room temperature for
3 h. The solvent was removed under reduced pressure. The crude
product was purified by column chromatography using ethyl ac-
etate: hexane (1:9) to afford 32, 265 mg, 70% yield, as a syrup.
values.13b
[a
]
20: þ16.0ꢁ (c 0.52, CHCl3); IR (Neat) nmax: 3394, 2923,
D
2852, 1738, 1676, 1460, 1369, 1122, 1073, 772 cmꢂ1
,
1H NMR,
(500 MHz, CDCl3): d 1.56e163 (m, 1H),1.97 (s, 6H),1.97e2.1 (m, 2H),
2.04 (s, 3H), 2.06 (s, 3H), 2.21 (s, 3H), 3.97 (dd,1H, J¼3.6 Hz,11.3 Hz),
4.05 (dd, 1H, J¼6.1 Hz, 11.3 Hz), 4.27 (m, 1H), 4.94 (dd, 1H, J¼2.8 Hz,
10.8 Hz), 5.17 (t, 1H, J¼10.5 Hz), 5.45 (t, 1H, J¼2.9 Hz), 5.49 (d, 1H,
[
a
]
20: ꢂ38.5ꢁ (c 1.3, CHCl3); IR (Neat) nmax: 3744, 3610, 2981,
D
2926, 2853, 1783, 1715, 1659, 1514, 1368, 1246, 1168, 772 cmꢂ1, 1H
J¼8.5 Hz); 13C NMR (125 MHz, CDCl3):
d 20.5, 20.7, 20.9, 23.2, 28.7,
NMR, (500 MHz, CDCl3):
d
1.31 (s, 3H), 1.36 (s, 3H), 1.44 (s, 9H),
37.9, 46.7, 63.7, 68.9, 71.5, 72.6, 169.2, 169.7, 170.1, 170.3, 170.7;
HRMS (ESI, Orbitrap) m/z: calcd for C17H25O9NNa 410.1415, found
410.1410.
2.20 (m, 1H, major couplings J¼16.8 Hz, 10.8 Hz), 2.67 (dd, 1H,
J¼5.2 Hz, 16.8 Hz), 3.75 (s, 3H), 3.95 (m, 1H, one of coupling
J¼10.8 Hz), 4.33 (d, 1H, J¼4.3 Hz), 4.72 (m, 1H), 5.0 (d, 1H,
J¼9.2 Hz), 6.71 (m, 1H); 13C NMR (125 MHz, CDCl3):
d
25.5, 26.3,
4.2.18. tert-Butyl
(3aR,4R,6S,7S,7aS)-6,7-dihydroxy-6-(hydrox-
27.6, 28.3, 47.5, 52.0, 73.0, 74.6, 79.7, 109.8, 129.8, 134.9, 155.1,
166.6 HRMS (ESI, Orbitrap) m/z: calcd for C16H25O6NNa 350.1574,
found 350.1566.
ymethyl)-2,2-dimethylhexahydrobenzo[d][1,3]dioxol-4-ylcarbamate
(36). To an ice cooled, stirred solution of compound 33 (50 mg,
0.016 mmol) in acetone/water (4:1) (1 mL) were added NMO
(50 mg, 0.048 mmol) and OsO4 (0.06 mL from 0.25 g in 20 mL
toluene). The reaction was allowed to return to room temperature
and stirred for another 2 h. The reaction mixture was quenched
with solid Na2S2O3. The solvent was removed under reduced
pressure and extracted with ethyl acetate (2ꢃ15 mL). The combined
organic extracts were washed with brine, separated, and dried over
anhydrous Na2SO4. The solvent was removed on a rotary evaporator
and the residue was purified by column chromatography on silica
gel using ethyl acetate: hexane (3:2) as the eluent to give pure
4.2.15. tert-Butyl
(3aR,4R,7aS)-6-(hydroxymethyl)-2,2-dimethyl-
3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-ylcarbamate (33). To the
compound 32 (200 mg, 0.06 mmol) in DCM (10 mL) was added
DIBAL-H (0.8 mL, 1.55 mmol) 25% w/v in toluene at ꢂ5 ꢁC and
stirred for 2 h. After completion of the reaction MeOH (1 mL) was
added to quench excess DIBAL-H followed by saturated sodium,
potassium tartarate (10 mL) and saturated NH4Cl (5 mL). Com-
pound is extracted using ethylacetate (3ꢃ20 mL), all the organic
fractions were collected and dried over Na2SO4, solvent was re-
moved under reduced pressure using rotavapour, the crude
product is purified by column chromatography using ethyl-
acetate: hexane (1:4) as eluent to give 33 as an oil (142 mg, 78%
compound 30 (50 mg, 90%) as a colourless liquid. [
a
]
20: ꢂ8.0ꢁ (c 1.1,
D
MeOH); IR (Neat) nmax: 3447, 3407, 3360, 2925, 1696, 1510, 1459,
1369, 1219, 1049 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d 1.37 (s, 3H),
1.45 (s, 9H), 1.50 (s, 3H), 1.50e1.52 (m, 1H), 1.91 (m, 1H), 3.51 (d, 1H,
J¼11.2 Hz), 3.62 (d, 1H, J¼6.7 Hz), 3.69 (d, 1H, J¼11.1 Hz), 4.17 (m,
1H), 4.28e4.39 (m, 2H), 5.01 (d, 1H, J¼8.9 Hz); 13C NMR (125 MHz,
yield). [
a
]
20: þ3.5ꢁ (c 1.7, CHCl3); IR (Neat) nmax: 3395, 2980, 2929,
D
1639, 1513, 1367, 1219, 1168, 772 cmꢂ1
;
1H NMR, (500 MHz,
CDCl3):
d
1.36 (s, 6H), 1.44 (s, 9H), 1.79 (br s, -OH), 2.06e2.21 (m,
CDCl3): d 26.2, 28.1, 28.3, 33.0, 44.6, 68.8, 73.2, 75.0, 75.1, 79.9, 80.0,
2H), 3.91 (s, 1H), 4.03 (s, 2H), 4.31 (dd, 1H, J¼2.3 Hz, 5.8 Hz), 4.65
109.4, 155.4; HRMS (ESI, Orbitrap) m/z: calcd for C15H28O7N
334.1860, found 334.1858.
(s, 1H), 5.02 (d, 1H, J¼9.1 Hz), 5.65(s, 1H); 13C NMR (125 MHz,
CDCl3):
d 26.4, 27.2, 27.5, 28.4, 47.9, 65.7, 73.8, 74.8, 79.6, 109.2,
119.8, 139.2, 155.3 HRMS (ESI, Orbitrap) m/z: calcd for
15H25O5NNa 322.1624, found 322.1616.
4.2.19. (1R,2R,3S,4S,6R)-6-Acetamido-4-(acetoxymethyl)-4-
C
hydroxycyclohexane-1,2,3-triyl
triacetate
(37). An
aqueous
CF3COOH (1:1 v/v) 2 mL was added to the compound 36 (20 mg,
0.06 mmol) at ice-cold temperature and the mixture was stirred at
rt for 3 h. After completion of the reaction, the solvent was removed
under reduced pressure to give crude amine. To the crude amine
were added pyridine (2 mL), Ac2O (0.2 mL), and catalytic amount of
DMAP at rt and stirred for overnight. The solvent was removed
under reduced pressure. The crude product was purified by column
chromatography with 5% MeOH in CHCl3 to afford pentaacetate 37
(24 mg, 90% from 36) as a white solid mp 269 ꢁC {lit17c 273 ꢁC}.;
4.2.16. tert-Butyl (3aR,4R,6R,7R,7aS)-7-hydroxy-6-(hydroxymethyl)-
2,2-dimethylhexahydrobenzo[d][1,3]dioxol-4-ylcarbamate (34). To
the compound 33 (50 mg, 0.016 mmol) in THF (2 mL), BH3$Me2S
(0.038 mL, 0.5 mmol) was added drop wise at 0 ꢁC. Stirring con-
tinued for 2 h at rt. Then NaOH (3N, 0.5 mL) followed by H2O2 (30%,
0.7 mL) solution were added at 0 ꢁC and stirring continued for
30 min at the same temperature. The reaction mixture was diluted
with EtOAc, washed with water, brine, dried (Na2SO4) and purified
by column chromatography using ethyl acetate: hexane (2:3) to
[
a
]
20: -17.0ꢁ (c 0.52, CHCl3) {lit.17c
[
a
]
20: ꢂ15.6ꢁ} the physical and
D
D
give 22 as an oil (34 mg, 65%). [
a]
20: þ5.0ꢁ (c 0.89, MeOH); IR (Neat)
spectral data are in accordance with the literature values;13b,17c IR
(Neat) nmax: 2957, 2925, 2854, 1732, 1464, 1368, 1283, 1222, 1122,
D
nmax: 3367, 2921, 2852, 1697, 1661, 1504, 1368, 1219, 861 cmꢂ1
;
1H
NMR, (400 MHz, CDCl3): (D2O exchanged)
d
1.30 (m, H), 1.37 (s, 3H),
1074 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d
1.78 (t, 1H, J¼12.9 Hz), 1.96
1.45 (s, 9H),1.51 (s, 3H),1.60 (m,1H),1.75 (m,1H) 3.57e3.76 (m, 3H),
(s, 6H),1.99e2.08 (m,1H), 2.09 (s, 6H), 2.2 (s, 3H), 3.92 and 4.0 (ABq,
2H, J¼11.4 Hz), 4.63e4.70 (m, 1H), 5.26 (d, 1H, J¼10.2 Hz), 5.33 (dd,
3.92e3.99 (m, 2H), 4.27 (t, 1H, J¼4.4 Hz); 13C NMR (125 MHz,
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
9
1H, J¼2.1 Hz, 10.2 Hz), 5.4 (d, 1H, J¼8.3 Hz), 5.5 (s, 1H); 13C NMR
(m, 4H), 2.24 (m, 1H), 2.78 (dd, 1H, J¼4.5 Hz, 17.2 Hz), 3.92 (m, 1H),
4.12 (t, 1H, J¼7.0 Hz), 4.23 (q, 2H, J¼7.1 Hz), 4.77 (m, 1H), 6.94 (m,
(125 MHz, CDCl3): d 20.5, 20.6, 20.7, 20.9, 23.3, 34.0, 43.7, 67.3, 69.8,
70.3, 71.5, 72.0, 169.2, 169.7, 169.8, 170.3, 170.5; HRMS (ESI, Orbi-
trap) m/z: calcd for C17H26O10N 404.1550, found 404.1537.
1H); 13C NMR (125 MHz, CDCl3):
d 7.8, 8.5, 14.1, 29.1, 29.3, 29.6, 61.0,
68.9, 72.2, 77.8, 113.6, 130.4, 134.0, 166.1; Mass (ESI) m/z [MþNa]:
293.
4.2.20. Experimental procedure for the reductive elimination and
NHK on 38. To a flame dried two-necked round bottom flask, CrCl3
(347 mg, 2.19 mmol) and powdered activated Mn (2.41 g,
43.85 mmol) were taken in THF/DMF (12 mL/3 mL) and stirred for
2 h at rt under an inert atmosphere until the colour changed from
violet to green. Compound 38 (500 mg, 1.46 mmol) in THF (3 mL)
was slowly added to it and stirred for 8 h. When TLC showed the
absence of starting material, NiCl2 (19 mg, 0.14 mmol) was added to
the reaction mixture and stirred for 30 min. Then allylbromo
compound 19 (0.3 mL, 2.19 mmol) was added to it followed by the
addition of TMSCl (0.27 mL, 2.19 mmol). The reaction mixture was
allowed to stir for an additional 5 h at 50 ꢁC, and diluted with
diethyl ether (70 mL). Next, n-Bu4NF (2.2 mL,1M in THF, 2.19 mmol)
was added and stirred at rt for 2 h. The reaction mixture was fil-
tered through a pad of Celite using sintered funnel, concentrated
and purified by column chromatography using ethyl acetate/hex-
ane (0.5:9.5) to afford a mixture of 39 (163 mg, 37.5%) and 40
(163 mg, 37.5%) in a 1:1 ratio as oils.
4.2.25. (3aR,7S,7aS)-Ethyl 2,2-diethyl-7-hydroxy-3a,6,7,7a-tetrahy-
20
drobenzo[d][1,3]dioxole-5-carboxylate (42). [
a
]
:
þ45.2ꢁ (c 1.0,
D
CHCl3) {(lit.18 þ43.4)}; IR (Neat) nmax: 3442, 2974, 2937, 1711, 1651,
1463, 1373, 1237, 1171, 1058, 1017, 925 cmꢂ1 1H NMR, (500 MHz,
,
CDCl3):
d
0.85 (t, 3H, J¼7.4 Hz), 0.92 (t, 3H, J¼7.4 Hz), 1.30 (t, 3H,
J¼7.1 Hz), 1.57e1.71 (m, 4H), 2.42 (m, 1H), 2.68 (dd, 1H, J¼5.0 Hz,
16.6 Hz), 3.92 (m, 1H), 4.21 (q, 2H, J¼7.1 Hz), 4.43 (dd, 1H, J¼2.7 Hz,
5.9 Hz), 4.75 (m, 1H), 6.78 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 7.9,
8.4, 14.1, 27.6, 29.9, 60.9, 67.6, 72.9, 75.4, 113.7, 129.4, 134.7, 166.3;
Mass (ESI) m/z [MþNa]: 293.
4.2.26. (3aR,7aS)-Ethyl 2,2-diethyl-7-(hydroxyimino)-3a,6,7,7a-tet-
rahydrobenzo[d][1,3]dioxole-5-carboxylate (43). To a solution of 41
or 42 (100 mg, 0.37 mmol) in DCM (6 mL) were added DesseMartin
periodinane (392 mg, 0.92 mmol) at rt for 1 h. After consumption of
the starting material, the reaction is being quenched by adding
saturated hypo solution (2 mL) followed by saturated NaHCO3
(2 mL). The organic layer is extracted using DCM (5 mLꢃ3), all the
fractions are collected and dried over anhydrous Na2SO4 and con-
centrated under reduced pressure to give crude product. The crude
ketone is unstable and proceeded for next reaction without further
purification. To the crude ketone (0.37 mmol) in EtOH (1 mL) was
added hydroxylamine hydrochloride (251 mg, 0.74 mmol) followed
by pyridine (0.5 mL). The reaction mixture was stirred at room
temperature for 2 h. The solution was poured into water and
extracted with CH2Cl2 (3ꢃ10 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude oxime 43 was purified by ethylacetate: hexane
(1:9) to give 43 (72 mg, 70%, over two steps) as yellow oil. 3395,
4.2.21. (S)-Ethyl 4-((4S,5R)-2,2-diethyl-5-vinyl-1,3-dioxolan-4-yl)-4-
hydroxy-2-methylenebutanoate (39). [
a
]
20: ꢂ18.8ꢁ (c 0.95, CHCl3);
D
IR (Neat) nmax: 2974, 2931, 2311, 1766, 1713, 1630, 1550, 1464, 1217,
1172, 1075, 932, cmꢂ1 1H NMR, (300 MHz, CDCl3):
; d 0.84 (t, 3H,
J¼7.4 Hz), 0.9 (t, 3H, J¼7.5 Hz), 1.23 (t, 3H, J¼7.1 Hz), 1.59 (q, 2H,
J¼7.5 Hz), 1.69 (q, 2H, J¼7.5 Hz), 2.34e2.5 (m, 1H), 3.72 (m, 1H), 4.0
(dd, 1H, J¼4.3 Hz, 7.3 Hz), 4.14 (q, 2H, J¼7.1 Hz), 4.54 (dd, 1H,
J¼7.3 Hz, 7.5 Hz), 5.23 (d, 1H, J¼11.1 Hz), 5.28 (d, 1H, J¼17.1 Hz), 5.62
(d, 1H, J¼1.5 Hz), 6.0 (m, 1H), 6.2 (d, 1H, J¼1.5 Hz); 13C NMR
(125 MHz, CDCl3):
d 7.9, 8.6, 14.1, 28.2, 29.2, 37.1, 60.7, 68.3, 79.1,
79.9, 112.3, 119.4, 127.5, 134.4, 136.9, 167.1; HRMS (ESI, Orbitrap) m/
z: calcd for C13H26O5Na 321.1672, found 321.1675.
2976, 2934, 1713, 1645, 1498, 1464, 1240, 1216, 1172, 1071, 926 cmꢂ1
1H NMR, (500 MHz, CDCl3):
,
d
0.85 (t, 3H, J¼7.5 Hz), 0.93 (t, 3H,
4.2.22. (R)-Ethyl 4-((4S,5R)-2,2-diethyl-5-vinyl-1,3-dioxolan-4-yl)-
J¼7.5 Hz), 1.33 (t, 3H, J¼7.5 Hz), 1.58e1.72 (m, 4H), 3.0 (d, 1H,
J¼21.9 Hz), 3.82 (d, 1H, J¼21.9 Hz), 4.25 (q, 2H, J¼6.8 Hz), 4.67 (d,
1H, J¼5.2 Hz), 4.85 (m, 1H), 6.8 (s, 1H); 13C NMR (125 MHz, CDCl3):
4-hydroxy-2-methylenebutanoate (40). [
a
]
20: þ2.8ꢁ (c 0.48, CHCl3)
D
{lit.18
[a
]
24: þ3.75ꢁ (c 1.70, CH2Cl2)}; IR (Neat) nmax: 2973, 2928,
D
1767, 1713, 1630, 1550, 1512, 1462, 1275, 1172, 932 cmꢂ1
;
1H NMR,
d 8.1, 8.3, 14.1, 20.8, 29.6, 30.4, 61.1, 73.5, 73.6, 114.4, 126.8, 135.6,
(500 MHz, CDCl3):
d
0.89 (t, 3H, J¼7.6 Hz), 0.95 (t, 3H, J¼7.6 Hz), 1.3
152.7, 166.0; HRMS (ESI, Orbitrap) m/z: calcd for C22H14O5N
284.1492, found 284.1491.
(t, 3H, J¼7.1 Hz), 1.63 (q, 2H, J¼7.6 Hz), 1.70 (q, 2H, J¼7.6 Hz), 2.44
(dd, 1H, J¼9.1 Hz, 14.1 Hz), 2.87 (dd, 1H, J¼3.9 Hz, 14.1 Hz), 3.76 (m,
1H), 3.96 (dd, 1H, J¼6.7 Hz, 8.6 Hz), 4.22 (m, 2H), 4.69 (m, 1H), 5.27
(d, 1H, J¼10.3 Hz), 5.41(d, 1H, J¼17 Hz), 5.72 (s, 1H), 6.04 (m, 1H),
4.3. Experimental procedure for reductive elimination and
NHK on compound 44
6.28 (s, 1H); 13C NMR (125 MHz, CDCl3):
d 8.0, 8.6, 14.1, 28.6, 29.7,
36.7, 61.2, 69.3, 78.7, 79.9, 112.5, 117.8, 128.3, 134.4, 137.0, 168.4;
HRMS (ESI, Orbitrap) m/z: calcd for C13H26O5Na 321.1672, found
321.1670.
To a flame dried two-necked round bottom flask, CrCl3 (320 mg,
2.07 mmol) and powdered activated Mn (2.27 g, 41.1 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 44 (500 mg, 1.38 mmol) in THF (9 mL) was slowly added
to it and stirred for 8 h. When TLC showed the absence of starting
material, NiCl2 (17 mg, 0.13 mmol) was added to the reaction
mixture and stirred for 30 min. Then allylbromo compound 20
(910 mg, 3.42 mmol) in DMF (3 mL) was added to it followed by the
addition of TMSCl (0.91 mg, 3.45 mmol). The reaction mixture was
allowed to stir for an additional 5 h at 50 ꢁC, and diluted with
diethyl ether (30 mL). Next the reaction mixture was filtered
through a pad of Celite using sintered funnel, to it 1N HCl (5 mL)
was added and further stirred for 2 h at 0 ꢁC and the reaction
mixture was washed with water. The organic fraction was con-
centrated and dried over Na2SO4, purified by column chromatog-
raphy using ethyl acetate: hexane (1:9) to afford 45 and 46 (404 mg,
75%) in a 1:1 ratio as oils.
4.2.23. Experimental procedure for ring closing metathesis re-
action. To a solutions of 39 or 40 (140 mg, 0.46 mmol) in anhydrous
1,2 dichloro ethane (8 mL) under a nitrogen atmosphere, was added
Hoveyda-Grubbs second generation catalyst (6 mg, 0.009 mmol)
and the reaction mixture was refluxed for 2 h. After completion of
the reaction, the solvent was evaporated at reduced pressure to
give a crude residue, which was purified by column chromatogra-
phy using ethyl acetate: hexane (1.2:8.8) to give compound 41 or 42
(116 mg, 92%) as an oils.
4.2.24. (3aR,7R,7aS)-Ethyl 2,2-diethyl-7-hydroxy-3a,6,7,7a-tetrahy-
20
drobenzo[d][1,3]dioxole-5-carboxylate (41). [
a
]
:
ꢂ67ꢁ (c 0.64,
D
CHCl3); IR (Neat) nmax: 3670, 3396, 2975, 2934, 1712, 1655, 1464,
1366, 1245, 1172, 1070 cmꢂ1; 1H NMR, (500 MHz, CDCl3):
3H, J¼7.4 Hz), 0.92 (t, 3H, J¼7.4 Hz), 1.30 (t, 3H, J¼7.1 Hz), 1.65e1.70
d 0.89 (t,
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

10
B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
4.3.1. (5S,6S,7R)-6-(Methoxymethoxy)-12,12,13,13-tetramethyl-9-
Stirring continued for 2 h at rt. To it NaOH (3N, 0.5 mL) followed by
30% H2O2 (0.7 mL) solution were added at 0 ꢁC and stirring con-
tinued for 30 min at the same temperature. The reaction mixture
was diluted with ethylacetate, washed with water, brine, dried
Na2SO4, purified by column chromatography using ethyl acetate:
hexane (1:4) as the eluent in case of 47 to give 49 (62 mg, 59.61%)
and 50 (10 mg, 9.6%) in 6:1 ratio as oils. In case of 48 the solvent
mixture was MeOH:CHCl3 (0.2:9.8) for purification to give 51
(62 mg, 59.61%) and 52 (10 mg, 9.6%) in 6:1 ratio as oils.
20
methylene-5-vinyl-2,4,11-trioxa-12-silatetradecan-7-ol (45). [a] :
D
þ8.5ꢁ (c 1.0, CHCl3); IR (Neat) nmax: 3454, 2924, 2853, 1739, 1650,
1464, 1363, 1254, 1152, 1101, 1029 cmꢂ1, 1H NMR, (300 MHz, CDCl3):
d
0.07 (s, 6H), 0.9 (s, 9H), 2.16 (dd, 1H, J¼10.0 Hz, 14.3 Hz), 2.50 (d,
1H, J¼14.3 Hz), 3.39 (s, 3H), 3.42 (s, 3H), 3.55 (t, 1H, J¼4.9 Hz), 3.85
(m, 1H), 4.12 (s, 2H), 4.31 (dd, 1H, J¼4.72 Hz, 7.3 Hz), 4.59e4.78 (m,
4H), 4.96 (s, 1H), 5.14 (s, 1H), 5.31 (d, 1H, J¼10.3 Hz), 5.34 (d, 1H,
J¼17.3 Hz), 5.82 (m, 1H); 13C NMR (125 MHz, CDCl3):
d
ꢂ5.4, 18.3,
25.8, 36.7, 55.7, 56.1, 66.3, 69.8, 77.4, 84.3, 94.2, 98.3, 112.4, 118.9,
134.7, 145.7; HRMS (ESI, Orbitrap) m/z: calcd for C1H38O6NaSi
413.2329, found 413.2320.
4.5.1. (1R,2S,3S,4R,5R)-5-((tert-Butyldimethylsilyloxy)methyl)-2,3-
20
bis(methoxymethoxy)cyclohexane-1,4-diol (49). [
a
]
D
:
ꢂ25.5ꢁ (c
0.53, CHCl3); IR (Neat) nmax: 3440, 2925, 2854, 1466, 1377, 1253,
4.3.2. (5S,6S,7S)-6-(Methoxymethoxy)-12,12,13,13-tetramethyl-9-
1212, 1095, 1025 cmꢂ1 1H NMR, (500 MHz, CDCl3):
; d 0.06 (s, 6H),
20
methylene-5-vinyl-2,4,11-trioxa-12-silatetradecan-7-ol (46). [
a
]
D
:
0.88 (s, 9H), 1.55e1.68 (m, 2H), 1.98 (dt, 1H, J¼4.15 Hz), 3.19 (t, 1H,
J¼8.9 Hz), 3.31 (t, 1H, J¼8.9 Hz), 3.4 (dd, 1H, J¼8.9 Hz, 11.8 Hz), 3.45
(s, 3H), 3.46 (s, 3H), 3.54 (m, 1H), 3.74 (d, 2H, J¼4.8), 3.98 (s, -OH),
4.02 (s, -OH), (D2O exchanged), 4.78e4.84 (m, 4H); 13C NMR
þ21.5ꢁ (c 0.76, CHCl3); IR (Neat) nmax: 2924, 2853, 1465, 1254, 1217,
1152, 1102, 1029 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d 0.08 (s, 6H), 0.9
(s, 9H), 2.28e2.43 (m, 2H), 3.38 (s, 3H), 3.45 (s, 3H), 3.47 (dd, 1H,
J¼3.39 Hz, 6.04 Hz), 3.9 (m, 1H), 4.13 (s, 2H), 4.32 (t, 1H, J¼6.6 Hz),
4.58 (d, 1H, J¼6.6 Hz), 4.71 (d, 1H, J¼6.6 Hz), 4.78 (d, 1H, J¼6.6 Hz),
4.89 (d, 1H, J¼6.6 Hz), 4.97 (s, 1H), 5.14 (s, 1H), 5.29e5.40 (m, 2H),
(125 MHz, CDCl3):
72.9, 86.2, 88.1, 98.6, 98.7; HRMS (ESI, Orbitrap) m/z: calcd for
17H36O7NaSi 403.2122, found 403.2132.
d
ꢂ5.3, 18.2, 25.8, 31.0, 40.1, 55.8 (2C), 64.4, 70.5,
C
5.58 (m, 1H); 13C NMR (125 MHz, CDCl3):
38.1, 55.7, 56.3, 66.3, 69.3, 78.2, 82.5, 94.0, 98.4, 112.5, 119.3, 134.8,
145.5; HRMS (ESI, Orbitrap) m/z: calcd for C1H38O6NaSi 413.2329,
found 413.2319.
d
ꢂ5.4, -5.3, 18.3, 25.8,
4.5.2. (1R,2S,3S,4S,5S)-5-((tert-Butyldimethylsilyloxy)methyl)-2,3-
bis(methoxymethoxy)cyclohexane-1,4-diol (50). [
a
]
20: þ38.4 (c 0.19,
D
CHCl3); IR (Neat) nmax: 3461, 2928, 2855, 1467, 1254, 1215, 1148,
1103, 1033 cmꢂ1, 1H NMR, (400 MHz, CDCl3):
d 0.08 (s, 6H), 0.9 (s,
4.4. Procedure for RCM
9H), 1.64 (m, 1H), 1.79 (m, 1H), 2.14 (m, 1H), 3.40 (s, 3H), 3.43 (s, 3H),
3.62e3.81 (m, 4H), 3.80e3.97 (m, 2H), 4.67e4.80 (m, 4H); 13C NMR
To the compound 45 or 46 (180 mg, 0.46 mmol) in anhydrous
toluene (18 mL) under a nitrogen atmosphere, was added Grubbs
second generation catalyst (39 mg, 0.0046 mmol) and the reaction
mixture was refluxed for 2 h. After completion of the reaction, the
solvent was evaporated at reduced pressure to give a crude residue,
which was purified by column (ethyl acetate: hexane¼1.5:8.5) to
give compounds 47 or 48 (150 mg, 92%) as oils.
(100 MHz, CDCl3):
71.1, 77.1, 78.7, 97.2, 97.5; HRMS (ESI, Orbitrap) m/z: calcd for
17H36O7NaSi 403.2122, found 403.2136.
d
ꢂ5.5, -5.5, 18.1, 25.8, 36.7, 55.7, 55.9, 65.9, 68.9,
C
4.5.3. Pseudo-b-D-glucopyranose (2). To the compound 49 (30 mg,
0.078 mmol) in methanol (1 mL) was added HCl (6N, 1 mL) and the
reaction mixture was refluxed for 30 min. After completion of the
reaction, solvent was removed under reduced pressure to give
crude compound which on purification with column chromatog-
raphy using MeOH:CHCl3 (1:4) as eluent gave pure compound 2
(13 mg, 95%) as an oil. The physical and spectroscopic data of
compound 9 were in exact agreement with the reported literature
4.4.1. (1R,5S,6S)-3-((tert-butyldimethylsilyloxy)methyl)-5,6-
20
bis(methoxymethoxy)cyclohex-3-enol (47). [
a
]
D
:
ꢂ28ꢁ (c 1.0,
CHCl3); IR (Neat) nmax: 3453, 2952, 2929, 2851, 2892, 2855, 1466,
1443, 1254, 1150, 1100, 838 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d 0.06
(s, 6H), 0.9 (s, 9H), 2.05 (m, 1H, major couplings J¼9.4 Hz and
17.0 Hz), 2.40 (dd, 1H, J¼5.9 Hz, 17.0 Hz), 3.39 (s, 3H), 3.46 (s, 3H),
3.50 (dd, 1H, J¼7.3 Hz, 9.6 Hz), 3.76 (m, 1H, one of coupling
J¼9.4 Hz), 3.90 (s, -OH), 4.02 (s, 2H), 4.00 and 4.04 (ABq, 2H,
J¼14.4 Hz), 4.18(d, 1H J¼7.3 Hz), 4.73 (d, 1H, J¼6.8 Hz), 4.76 (d, 1H,
J¼6.8 Hz), 4.80 (d, 1H, J¼6.5 Hz), 4.82 (d, 1H, J¼6.5 Hz), 5.61 (s, 1H);
values.9c
[a
]
20: þ8.1ꢁ (c 0.16, MeOH) {lit.9c
[
a
]
D
20: þ6.7ꢁ (c 0.15,
D
MeOH); IR (Neat) nmax: 3389, 2922, 2853,1461,1219 cmꢂ1; 1H NMR,
(400 MHz, CD3OD):
d
1.18 (q, 1H, J¼12.9 Hz), 1.52 (m, 1H), 1.96 (ddd,
1H, J¼3.6 Hz, 4.6 Hz, 12.9 Hz), 3.08e3.23 (m, 3H), 3.42 (ddd, 1H,
J¼4.7 Hz, 8.6 Hz, 12.9 Hz), 3.58 (dd, 1H, J¼6.1 Hz, 10.7 Hz), 3.74 (dd,
1H, J¼4.0 Hz, 10.7 Hz); 13C NMR (100 MHz, CD3OD):
d 33.7, 42.2,
13C NMR (125 MHz, CDCl3):
d
ꢂ5.4, -5.4, 18.2, 25.8, 32.6, 55.4, 55.9,
64.2, 72.9, 74.8, 78.9, 79.0; HRMS (ESI, Orbitrap) m/z: calcd for
65.3, 68.2, 77.5, 87.0, 96.4, 98.4, 119.8, 137.1; ESI (MS) m/z: [MþNa]:
C17H14O5Na 201.0733, found 201.0730.
385.
4.5.4. (1R,2S,3S,4S,5S)-5-(Acetoxymethyl)cyclohexane-1,2,3,4-tetrayl
tetraacetate (53). To the compound 50 (8 mg, 0.021 mmol) in
methanol (1 mL) was added HCl (6N, 1 mL) and the reaction mix-
ture was refluxed for 30 min. After completion of the reaction,
solvent was removed under reduced pressure to give crude com-
pound. To the crude compound dissolved pyridine(1 mL), acetic
anhydride (0.3 mL) and few crystal of DMAP were added and stirred
for overnight at rt. Aqueous NH4Cl was added to the reaction
mixture and the organic fraction was extracted with ethylacetate
(2ꢃ10 mL). The collected organic fractions were combined and
solvent was removed under reduced pressure to give oily com-
pound, which on column chromatography with ethyl acetate:
hexane (1:4) afforded pure 53 (7 mg, 95% from 50). The physical
and spectroscopic data of compound 53 were in exact agreement
4.4.2. (1S,5S,6S)-3-((tert-Butyldimethylsilyloxy)methyl)-5,6-
20
bis(methoxymethoxy)cyclohex-3-enol (48). [
a]
:
þ44ꢁ (c 0.73,
D
CHCl3); IR (Neat) nmax: 3424, 2924, 2898, 2851, 2827, 1687, 1465,
1444, 1213, 1148, 1099, 1029 cmꢂ1 1H NMR, (500 MHz, CDCl3):
,
d
0.05 (s, 6H), 0.88 (s, 9H), 2.11 (dd, 1H, J¼7.1 Hz, 17.3 Hz), 2.28 (dd,
1H, J¼4.8 Hz, 17.3 Hz), 3.38 (s, 3H), 3.41 (s, 3H), 3.77 (dd, 1H,
J¼2.2 Hz, 4.8 Hz), 4.03 (s, 2H), 4.08 (m, 1H), 4.24 (s, 1H), 4.70e4.78
(m, 4H), 5.68 (s, 1H); 13C NMR (125 MHz, CDCl3):
d
ꢂ5.4, -5.4, 18.2,
25.8, 31.3, 55.4, 55.7, 65.7, 66.5, 74.3, 80.9, 96.0, 97.1, 118.1, 139.0;
[MþNa]: 385.
4.5. Experimental procedure for hydroboration/oxidation
reaction
with the reported literature values.21a
[
a
]
D
20: ꢂ15.1ꢁ (c 0.3, CHCl3);
To the compounds 47 or 48 (100 mg, 0.27 mmol) in THF (5 mL),
BH3$Me2S (0.08 mL, 0.85 mmol) was added drop wise at 0 ꢁC.
IR (Neat) nmax: 2919, 2851, 1737, 1715, 1462, 1374, 1242, 1184,
1079 cmꢂ1, 1H NMR, (400 MHz, CDCl3):
d 1.93e1.99 (m, 2H), 2.01 (s,
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
11
3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.40 (q, 1H,
References and notes
J¼5.7), 4.10 (dd, 1H, J¼6.2 Hz, 11.4 Hz), 4.14 (dd, 1H, J¼6.2 Hz,
ꢀ
ꢀ
1. (a) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919
11.4 Hz), 4.99 (m, 1H), 5.13 (dd, 1H, J¼3.0 Hz, 7.5 Hz), 5.23e5.28 (m,
ꢀ
ꢀ
and references cited there in; (b) Plumet, J.; Gomez, A. M.; Lopez, J. C. Mini-Rev.
Org. Chem. 2007, 4, 201.
2H); 13C NMR (100 MHz, CDCl3):
d 20.6, 20.7, 20.8, 20.8, 20.9, 27.6,
34.2, 63.5, 69.0, 69.1, 69.3, 70.2, 169.5, 169.7, 169.8, 169.8, 170.6;
2. (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229; (b) Ferrero, M.; Gotor, V. Chem.
Rev. 2000, 100, 4319; (c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedg, R. Tetrahedron 1994, 50, 10611; (d) Borthwick,
A. D.; Biggadicke, K. Tetrahedron 1992, 48, 571.
HRMS (ESI, Orbitrap) m/z: calcd for
C
17H28O10
N
[MþNH4]þ
406.1707, found 406.1721.
3. Miwa, I.; Hara, H.; Okuda, J.; Suami, T.; Ogawa, S. Biochem. Int. 1985, 11, 809.
4. Kitaoka, M.; Ogawa, S.; Taniguchi, H. Carbohydr. Res. 1993, 247, 355.
5. Suami, T.; Ogawa, S.; Toyokuni, T. Chem. Lett. 1983, 611.
6. Lefoix, M.; Tatibouet, A.; Cottaz, S.; Driguez, H.; Rollin, P. Tetrahedron Lett. 2002,
43, 2889.
4.5.5. (1S,2S,3S,4S,5S)-5-((tert-Butyldimethylsilyloxy)methyl)-2,3-
bis(methoxymethoxy)cyclohexane-1,4-diol (51). [
a
]
20: þ22.3 (c 0.65,
D
€
CHCl3); IR (Neat) nmax: 3440, 2950, 2928, 2890, 2856, 1467, 1391,
1253, 1148, 1102, 1029, 916, 834, 776 cmꢂ1
CDCl3):
;
1H NMR, (400 MHz,
0.07 (s, 6H), 0.9 (s, 9H), 1.37 (q, 1H, J¼12 Hz), 1.75 (m, 1H),
7. (a) Shing, T. K. M.; Ng, W.-L.; Chan, J. Y.-W.; Lau, C. B.-S. Angew. Chem., Int. Ed.
2013, 52, 8401; (b) Ohtake, Y.; Sato, T.; Matsuoka, H.; Kobayashi, T.; Nishimoto,
M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Higuchi, T.; Murakata, M.;
Morikawa, K.; Shimma, N.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.;
Kato, M.; Ikeda, S. Bioorg. Med. Chem. 2012, 20, 4117; (c) Ohtake, Y.; Sato, T.;
Matsuoka, H.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.;
Higuchi, T.; Murakata, M.; Kobayashi, T.; Morikawa, K.; Shinma, N.; Suzuki, M.;
Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Bioorg. Med. Chem. 2011,
19, 5334; (d) Yao, C.-H.; Song, J.-S.; Chen, C.-T.; Yeh, T.-K.; Hung, M.-S.; Chang,
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Med. Chem. 2011, 54, 166; (e) Rosenstock, J.; Vico, M.; Wei, L.; Salsali, A.; List, J. F.
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D. M. Annu. Rev. Biochem. 1988, 57, 627; (C) Haslam, E. Shikimic Acid: Metabolism
and Metabolites; John Wiley and Sons: Chichester, 1993; (d) Campbell, M. M.;
Sainsbury, M.; Searle, P. A. Synthesis 1993, 179.
9. (a) Suami, S. T.; Ogawa, S.; Nakamoto, K.; Kasahara, I. Carbohydr. Res. 1977, 58,
240; (b) Ogawa, S.; Kashara, I.; Suami, T. Bull. Chem. Soc. Jpn. 1979, 52, 118; (c)
Yoshikawa, M.; Murakami, N.; Yokokawa, Y.; Inoue, Y.; Kuroda, Y.; Kitagawa, I.
Tetrahedron 1994, 50, 9619; (d) Shing, T. K. M.; Tai, V. W. F. J. Org. Chem. 1995, 60,
5332; (e) Tatsuta, K.; Mukai, H.; Takahashi, M. J. Antibiot. 2000, 53, 430; (f)
Suzuki, Y.; Ogawa; Sakakibara, Y. Perspect. Med. Chem. 2009, 3, 7.
d
1.89 (m, 1H), 3.42 (s, 3H), 3.43 (s, 3H), 3.7 (d, 2H, J¼5.7 Hz), 3.76 (m,
1H), 3.88 (m, 1H), 3.93 (m, 1H), 4.70e4.78 (m, 4H); 13C NMR
(125 MHz, CDCl3):
67.0, 70.1, 80.2, 81.3, 98.0, 98.05; HRMS (ESI, Orbitrap) m/z: calcd for
17H36O7NaSi 403.2122, found 403.2133.
d
ꢂ5.5, -5.5, 18.2, 25.8, 30.3, 38.8, 55.8, 55.9, 66.0,
C
4.5.6. (1S,2S,3S,4R,5R)-5-((tert-Butyldimethylsilyloxy)methyl)-2,3-
bis(methoxymethoxy)cyclohexane-1,4-diol (52). [
CHCl3); IR (Neat) nmax
1029 cmꢂ1, 1H NMR, (400 MHz, CDCl3):
a
]
20: ꢂ17.8 (c 0.75,
D
:
3741, 2923, 2852, 1513, 1454, 1219,
d
0.06 (s, 6H), 0.89 (s, 9H),
1.40 (t, 1H, J¼12.7 Hz), 1.86 (ddd, 1H, J¼3.6 Hz, 7.3 Hz, 14.5 Hz), 2.01
(m, 1H), 3.37e3.49 (m, 8H), 3.60e3.67 (m, 2H), 3.84 (dd, 1H,
J¼4.4 Hz, 9.9 Hz), 4.12 (m, 1H), 4.7e4.9 (m, 4H); 13C NMR (125 MHz,
CDCl3):
d
ꢂ5.5, 18.2, 25.9, 29.3, 37.8, 55.6, 55.8, 63.9, 68.0, 72.7, 79.7,
84.4, 96.5, 98.6; HRMS (ESI, Orbitrap) m/z: calcd for C17H36O7NaSi
403.2122, found 403.2135.
10. (a) Chen, X.; Zheng, Y.; Shen, Y. Curr. Med. Chem. 2006, 13, 109; (b) Negishi, M.;
Shimomura, K.; Proks, P.; Shimomura, Y.; Mori, M. Br. J. Clin. Pharmacol. 2008,
66, 318.
4.5.7. (1S,2S,3S,4S,5S)-5-(Acetoxymethyl)cyclohexane-1,2,3,4-tetrayl
tetraacetate (54). Experimental procedure is similar to compound
53 preparation, to give 54 as a solid mp 103e104 ꢁC, {lit.20d
11. (a) Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P.
A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451; (b)
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chofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J.
Am. Chem. Soc. 1997, 119, 681; (c) Hurt, A. C.; Selleck, P.; Komadina, N.; Shaw, R.;
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Rao, B. V. Tetrahedron: Asymmetry 2010, 21, 930; (d) Mishra, G. P.; Ramana, G. V.;
Rao, B. V. Chem. Commun. 2008, 3423; (e) Ramana, G. V.; Rao, B. V. Tetrahedron
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3049; (g) Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5103.
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B. V. Tetrahedron: Asymmetry 2009, 20, 1217; (d) Chandrasekhar, B.; Madhan, A.;
Rao, B. V. Tetrahedron 2007, 63, 8746.
105e106.5 ꢁC }, [
a
]
D
20: þ8ꢁ (c 0.5, CHCl3), {lit.20b
[a
]
20: þ7ꢁ (c 0.75,
D
CHCl3); IR (Neat) nmax: 2924, 2853, 1738, 1433, 1367, 1214,
1032 cmꢂ1, 1H NMR, (500 MHz, CDCl3):
d
1.75 (q,1H, J¼11.5 Hz),1.94
(m, 1H), 1.96 (s, 6H), 2.01 (s, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.30 (m,
1H), 4.01 and 4.03 (ABq, 2H, J¼11.4 Hz), 5.03 (dd, 1H, J¼2.9 Hz,
10.5 Hz), 5.14 (m, 1H), 5.22 (m, 1H), 5.28 (dd, 1H, J¼3.0 Hz, 4.8 Hz);
13C NMR (125 MHz, CDCl3):
d 20.7, 20.8, 20.9, 27.0, 34.35, 63.9, 67.9,
68.3, 68.6, 68.7, 169.2, 169.3, 170.0 (2C), 170.8; HRMS (ESI, Orbitrap)
m/z: calcd for calcd for C17H28O10N 406.1707, found 406.1720.
4.5.8. Pseudo-a-D-glucopyranose (1). Experimental procedure is
similar to the preparation of compound 2. Compound 1 obtained as
a white solid mp 144e145 ꢁC, {lit.15c 146e147 ꢁC}, [
a
]
20: þ61ꢁ (c 0.3,
D
MeOH), {lit.15c
[
a]
20: þ63ꢁ (c 0.6, MeOH); IR (Neat) nmax: 3610, 2926,
15. (a) Sudha, A. V. R. L.; Nagarajan, M. Chem. Commun. 1998, 925; (b) Shing, T. K.
M.; Cui, Y.-X.; Tang, Y. J. Chem. Soc., Chem. Commun. 1991, 756; (c) Shing, T. K. M.;
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47, 4571; (e) Paulsen, H.; von Deyn, W.; Roben, W. Liebigs Ann. Chem. 1984, 433;
(f) Paulsen, H.; von Deyn, W. Liebigs Ann. Chem. 1987, 133; (g) Pingli, L.; Van-
D
2850, 1368, 1220, 1032, 772 cmꢂ1, 1H NMR, (300 MHz, D2O):
d 1.40
(td, 1H, J¼15.0 Hz, 18.0 Hz), 1.78e1.90 (m, 2H), 3.23 (t, 1H, J¼9.8 Hz),
3.38 (dd, 1H, J¼3.0 Hz, 9.8 Hz), 3.53 (t, 1H, J¼9.8 Hz), 3.60e3.70 (m,
2H), 4.03 (m, 1H); 13C NMR (125 MHz, D2O):
d 30.7, 38.6, 62.9, 69.4,
ꢀ
ꢀ
devalle, M. Tetrahedron 1994, 50, 7061; (h) Gomez, A. M.; Danelon, G. O.;
ꢀ
Moreno, E.; Valverde, S.; Lopez, J. C. Chem. Commun. 1999, 175.
73.6, 74.4, 75.0; HRMS (ESI, Orbitrap) m/z: calcd for C17H14O5Na
201.0733, found 201.0730.
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Acknowledgements
B.S.K. and G.P.M. thanks to CSIR-New Delhi for fellowship. Au-
thors also thank the CSIR New Delhi for financial support as part of
XII Five Year plan programme under the title ORIGINE (CSC-0108)
and DENOVA (CSC-0205).
~
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Supplementary data
18. (a) Chuanopparat, N.; Kongkathip, N.; Kongkathip, B. Tetrahedron 2012, 68,
6803 and references cited therein; (b) review on TamfluÒ Magano, J.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.02.044.
Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044

12
B.S. Kumar et al. / Tetrahedron xxx (2016) 1e12
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Please cite this article in press as: Kumar, B. S.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.044