Stereoselective Formal Synthesis of (+)- and (-)-Cyclophellitol and (-)-Conduritol-B and Synthesis of (-)-Conduramine-B Derivative Using a Sulfinyl Moiety for C-O Bond Formation and α-Chloro Sulfide for C-C Bond Formation

Article abstract of DOI:10.1021/acs.joc.6b00616

The formal total synthesis of both the enantiomers of cyclophellitol and conduritol-B and synthesis of conduramine-B derivative have been achieved from a common intermediate, obtained by regio- and stereoselective vicinal functionalization of a diene utilizing an intramolecular sulfinyl group as a nucleophile, followed by stereoselective preparation of an allylic sulfide by reaction of vinylzinc bromide with an electrophilic α-chloro sulfide, and last by ring-closing metathesis reaction as the key steps. The sulfoxide, sulfilimine, and sulfur ylid prepared from this common intermediate have been transformed into derivatives of conduritol-B, conduramine-B, and (-)-cyclophellitol, respectively. The silyl sulfide was converted via sila-Pummerer rearrangement, hydrolysis, and reduction in an one-pot operation to a hydroxymethyl group. [2,3]-Wittig-Still rearrangement was employed for the synthesis of (+)-cyclophellitol. The potential utility of sulfur intermediates as nucleophilic and electrophilic partners in total synthesis is elegantly demonstrated.

Full text of DOI:10.1021/acs.joc.6b00616

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Article
Stereoselective Formal Synthesis of (+)- and (–)-Cyclophellitol, (–)-Conduritol-
B and Synthesis of (–)-Conduramine-B derivative Using a Sulfinyl Moiety
for C–O Bond Formation and alpha-Chloro Sulfide for C–C bond formation
Sadagopan Raghavan, Ravi Kumar Chiluveru, and Sankaran Ganapathy Subramanian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00616 • Publication Date (Web): 20 Apr 2016
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Stereoselective Formal Synthesis of (+)ꢀ and (–)ꢀCyclophellitol, (–
)ꢀConduritolꢀB and Synthesis of (–)ꢀConduramineꢀB derivative
Using a Sulfinyl Moiety for C–O Bond Formation and αꢀChloro
Sulfide for C–C Bond Formation
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Sadagopan Raghavan*, Ravi Kumar Chiluveru, S. Ganapathy Subramanian
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Hyderabad-
500007, India.
sraghavan@iict.res.in
Abstract: The formal total synthesis of both the enantiomers of cyclophellitol, conduritolꢀB
and synthesis of conduramineꢀB derivative has been achieved from a common intermediate,
obtained by regioꢀ and stereoselective vicinal functionalization of a diene utilizing an
intramolecular sulfinyl group as a nucleophile followed by stereoselective preparation of an
allylic sulfide by reaction of vinylzinc bromide with an electrophilic αꢀchloro sulfide and
lastly by ringꢀclosing metathesis reaction as the key steps. The sulfoxide, sulfilimine and
sulfur ylid prepared from this common intermediate have been transformed into derivatives
of conduritolꢀB, conduramineꢀB and (–)ꢀcyclophellitol respectively. The silyl sulfide was
converted via silaꢀPummerer rearrangement, hydrolysis and reduction in an oneꢀpot operation
to a hydroxymethyl group. [2,3]ꢀWittigꢀStill rearrangement was employed for the synthesis
of (+)ꢀcyclophellitol. The potential utility of sulfur intermediates as nucleophilic and
electrophilic partners in total synthesis is elegantly demonstrated.
Introduction
(+)ꢀCyclophellitol (1, Figure 1) was isolated1 in 1990 from the mushroom Phellinus
sp., and shown to possess potent βꢀglucosidase inhibitory activity and activity against HIV.2
Glycosidase inhibitors, in addition to providing insight into glycoprotein processing also find
applications in immunology, diabetes, virology and cancer. Cyclophellitol has been the target
of several total syntheses due to its potent biological activity. However, most syntheses start
with chiral pool starting materials, notably carbohydrates,3 and are frequently lengthy as a
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consequence of manipulating functionality using protecting groups. Also these strategies
provide access to one enantiomer of the natural product only, in contrast to asymmetric
synthesis strategies4 whereby both enantiomers can be synthesized and are more often
efficient. Conduritols (5ꢀcyclohexeneꢀ1,2,3,4ꢀtetrols) are precursors for the synthesis of
cyclitols,5 pseudosugars and conduritol derivatives have interesting biological activities.
Herein, we report the asymmetric synthesis of both the enantiomers of cyclophellitol taking
advantage of the sulfinyl moiety as an intramolecular nucleophile for C–O bond formation
and an αꢀchloro sulfide as an intermediate for C–C bond formation.
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OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
OH
OH
O
O
NH2
OH
OH
OH
(+)ꢀCyclophellitol 1
(–)ꢀCyclophellitol 2
(–)ꢀConduritolꢀB 3 (–)ꢀConduramineꢀB 4
Figure 1. Cyclophellitol, ConduritolꢀB, ConduramineꢀB.
Results/Discussion
Our retrosynthesis of the targets 1ꢀ4 is shown in Scheme 1. As depicted,
cyclophellitol, conduritol B and conduramine B were envisaged to be obtained from a
common intermediate 5 via [2,3] sigmatropic rearrangement of a sulfur ylid/ sulfoxide/
sulfilimine. Sulfide 5 would come from the metathesis of the diene 6 which in turn can be
obtained from αꢀchloro sulfide derived from sulfide 7. Compound 7 would result from the
diene sulfoxide 8, a compound prepared in the group using ethyl sorbate 10 and (S)ꢀmethyl pꢀ
tolyl sulfoxide 9 as starting materials.
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OH
OH
4
5
6
7
OH
OH
HO
HO
O
O
8
9
Intermolecular
SN2 displacement
OH
OH
1
2
OP
OP
OP
KirmseꢀDoyle rearrangement
followed by
silaꢀPummerer reaction
WittigꢀStill
rearrangement
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S
OP
Tol
S
Tol
Br
OH
OH
OH
OP
5
6
OH
OH
Reaction with
αꢀchloro sulfide
Ringꢀclosing metathesis
OH
NH2
OH
4
3
[2,3] sigmatropic shift
MislowꢀEvans
rearrangement
of sulfilimine
Stereoselective reduction
O
O
OH
OP
OP
+
S
S
S
EtO2C
Tol
Me
Tol
Tol
9
10
7
Br
8
Vicinal heteroꢀ
functionalization
P = Protecting group
Scheme 1. Retrosynthetic disconnection of (–)ꢀcyclophellitol, (+)ꢀcyclophellitol, (–)ꢀ
conduritol B and (–)ꢀconduramine B.
The diene sulfoxide 8, prepared as reported earlier6 from ethyl sorbate, in two steps
and in 77% overall yield, was reacted with freshly recrystallized Nꢀbromosuccinimide in
dichloromethane in the presence of water to furnish bromodiol 11, regioꢀ and
stereoselectively. The hydroxyl groups in 11 were protected as their TBSꢀethers 12 under
standard conditions and subsequent reduction of the sulfinyl moiety employing trifluoroacetic
anhydride and sodium iodide7 afforded sulfide 7 (P = TBS).8 Treatment of 7 with Nꢀ
chlorosuccinimide furnished the αꢀchloro sulfide 13, which without isolation was reacted
with vinylzinc bromide,9 to yield diene sulfide 6 (P = TBS) as the sole product.10,11 Ringꢀ
closing metathesis of 6 using Grubbs’first generation catalyst afforded allylic sulfide 14. The
synthetic sequence called for the nucleophilic displacement of bromide in 14 by a suitable
oxygen nucleophile. Toward this end, compound 14 was subjected to oxidation with mꢀ
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CPBA to furnish a diastereomeric mixture of sulfoxides, which without isolation on warming
in toluene in the presence of a thiophile, underwent MislowꢀEvans rearrangement12 to furnish
the bromotriol derivative 15, Scheme 2.
O
S
OH
O
S
OH
OH
TBSꢀCl, Imidazole
DCM, 4 h, 90%
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NBS
Tol
Tol
Tol
Tol
H2O, DCM, 0 oC,
1 h, 70%
Br
8
11
O
S
OTBS OTBS
OTBS OTBS
TFAA, NaI
Acetone, ꢀ20 oC,
1 h, 85%
NCS, Benzene
30 min
S
Tol
Br
Br
12
7
OTBS OTBS
OTBS OTBS
Grubbs 1st cat.
S
S
MgBr,ZnBr2
Tol
DCM, 8 h, 80%
THF, 0 oC, 4 h, 80%
Br
Cl
Br
6
13
Br
OTBS
Br
OTBS
Br
Cy3P
Cl
H
1. mCPBA, CHCl3,
ꢀ40 oC, 30 min
S
H
S
OTBS
Ru
Tol
TolS
TBSO
Cl
Ph
H
2.
PCy3
OTBS
OTBS
HN NMe
H
Grubbs 1st gen. cat.
Toluene, 70 oC,
4 h, 75% (Two steps)
14
14
OH
15
Scheme 2: Synthesis of bromotriol derivative 15 from diene sulfoxide 8
SN2 displacement of bromide in compound 15 would provide (–)ꢀconduritol B
derivative. Toward this end, the hydroxyl group in 15 was protected as its acetate 16 and was
further subjected to reaction with potassium acetate as the oxygen nucleophile in DMF at 100
oC. Unfortunately, instead of the desired tetrol derivative, the unsaturated ketone 1713 was
only obtained. E2 elimination of HBr from 16 under the mildly basic conditions followed by
hydrolysis of the silyl enol ether probably during column chromatography would account for
the formation of 17. In another trial, the MOMꢀether 18, prepared from alcohol 15, on
reaction with potassium superoxide14 in DMSO furnished the hydroquinone derivative 19.15
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The MOM derivative related to 17 probably suffers elimination and tautomerization to yield
compound 19.16 Having been unsuccessful in preparing conduritolꢀB derivative by
nucleophilic displacement on a cyclic compound, the same was attempted on the acyclic
sulfide 6. Reaction of 6 with an excess of potassium acetate/sodium nitrite17 in DMF or
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DMSO at 80ꢀ120 oC for extended periods of time led to only recovered starting materials.
O
OTBS
OAc
O
OTBS
Br
H
Br
H
OTBS
KOAc, DMF
AcO
TBSO
100 oC, 6 h, 70%
H
OAc
OTBS
OTBS
OTBS
H
OAc
OP
17
Ac2O, Et3N, DMAP
DCM, 2 h, 90%
15
, P = H
MOMꢀCl, DIPEA
DCM, 2 h, 90%
16, P = Ac
18, P = MOM
OH
O
KO2, 18C6, DMSO
0 oC, 30 min, 70%
18
OTBS
OMOM
OMOM
OMOM
19
1. NaNO2, BHT
OTBS OTBS
OR
OR
DMSO, 24 h,
85 oC, 75%
CSA, MeOH
rt, 4 h
S
S
Tol
Tol
2. Ac2O, Et3N
DMAP, DCM,
2 h, 90%
Br
Br
6
Ac2O, Et3N
DMAP, DCM
2 h, 85% (two steps)
20 R= H
21 R= Ac
OAc
OAc
OAc OAc
1. mCPBA, CHCl3,
ꢀ40 oC 30 min, 90%
OAc
OAc
S
OAc
OAc
Grubbs 1st cat.
DCM, 8 h, 80%
S
Tol
Tol
S
2.
OAc
HN
NMe
OH
22
Toluene, 70 oC,
4 h, 75%
23
24
(ꢀ)ꢀConduritolꢀB
derivative
Scheme 3. Attempted displacement of bromide and synthesis of (–)ꢀconduritolꢀB derivative.
Assuming steric hindrance of the silyl groups to be the cause for the failure, the silyl groups
were deprotected under acidic conditions to furnish the bromodiol 20. Acetylation furnished
the diacetate 21, which on reaction with an excess of sodium nitrite in the presence of BHT,18
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furnished a mixture of diacetates as a consequence of migration. The crude reaction mixture
was therefore subjected to acetylation to yield the triacetate 22. Ringꢀclosing metathesis
furnished the allylic sulfide 23. Oxidation of sulfide to an epimeric mixture of sulfoxides
followed by warming in toluene yielded (–)ꢀconduritolꢀB derivative 24, Scheme 3.
The synthesis of (–)ꢀcyclophellitol was envisioned by a KirmseꢀDoyle rearrangement
of the ylid obtained by the reaction of 23 with trimethylsilyl diazomethane. Indeed, the
reaction proceeded cleanly in the presence of Rh2(OAc)419 and excess TMSꢀdiazomethane to
yield an epimeric mixture of sulfides 25. Oxidation of sulfide with mꢀCPBA and warming the
reaction mixture resulted in the silaꢀPummerer rearrangement,20 hydrolysis followed by
reduction of the ensuing aldehyde with sodium borohydride furnished a very polar
compound, probably resulting from the hydrolysis of the acetate groups, which however,
could not be isolated. The strategy, thus called for a protecting group that would be stable to
the conditions of Pummerer followed by reduction reactions. Therefore, the acetate groups in
23 were hydrolysed and the resulting triol 27 protected as its benzyl ethers 28. The structures
assigned to compounds 28 and therefore compounds 22 and 23 is supported by the J values
observed for C2H and C3H resonating at δ 3.76 (dd, J = 9.9 Hz, 7.9 Hz) and δ 3.65 (dd, J =
9.9 Hz, 8.6 Hz) in 28. The J value can be rationalized only if all the methine protons are
axially oriented. SN2 displacement of the bromide in compound 21 is thus proven beyond
doubt. Reaction of 28 with TMSꢀdiazomethane and Rh(II) catalyst yielded an epimeric
mixture of sulfides 29. Oxidation of the sulfide to an epimeric mixture of sulfoxides and
warming in THF led to Pummerer rearrangement. Hydrolysis of the intermediate with aq.
sodium bicarbonate and reduction of the resulting aldehyde in the same pot resulted in
alcohol 3 (P = Bn), Scheme 4. Stereoselective epoxidation completed the formal synthesis of
(–)ꢀcyclophellitol 2.
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OH
OAc
OH
OH
5
6
7
8
OAc
OAc
1. mCPBA, CHCl3,
ꢀ
Rh2(OAc)4, TMSCHN2
40 oC, 30 min.
23
Toluene, 50 oC,
12 h, 75%
2. THF, reflux, 30 min,
aq NaHCO3, NaBH4,
30 min, 75%
9
Tol
OH
S
TMS
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26
25
Not isolated
H
3
OR
OBn
H
1
OBn
S
OR
OR
OBn
OBn Rh2(OAc)4, TMSCHN2
K2CO3, MeOH,
Tol
4
5
23
TolS
BnO
2
rt, 2 h
Toluene, 50 oC,
12 h, 75%
H
OBn
TMS
H
28
BnBr, NaH,
TBAI, THF,
27 R= H
28 R=Bn
Tol
S
0 oC ꢀ rt, 6 h,
85% (two steps)
29
OBn
OBn
OBn
OBn
OBn
mCPBA, CHCl3
ꢀ40 oC, 30 min.
aq NaHCO3, NaBH4
rt, 10 min, 75%
THF, reflux
30 min
OBn
TMS
Tol
Tol
S
S
OTMS
O
OBn
OH
OBn
OBn
OH
OBn
OBn
mCPBA, CHCl3
0 oCꢀ rt, 16 h, 80%
Ref. 4b
O
O
OBn
OH
OH
OH
OH
(ꢀ)ꢀCyclophellitol, 2
3
30
Scheme 4. Formal synthesis of (–)ꢀcyclophellitol.
The formal synthesis of (+)ꢀcyclophellitol was completed following the sequence of
reactions reported in the literature4b using compound 31 as the building block, as depicted in
Scheme 5. Oxidation of 28 with mꢀCPBA followed by MislowꢀEvans rearrangement yielded
(–)ꢀconduritolꢀB derivative 31. Deprotonation of 31 with potassium hydride followed by
reaction with iodomethyltributyltin21 yielded the tin derivative 32. Treatment of 32 with nꢀ
BuLi led to homoallylic alcohol ent-3 via WittigꢀStill rearrangement.22 Epoxidation of the
homoallylic alcohol completed the formal synthesis of (+)ꢀcyclophellitol.
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OBn
OBn
OBn
1. mCPBA, CHCl3,
S
OBn
OBn
ꢀ40 oC, 30 min
OBn
OBn
KH, Bu3SnCH2I
OBn
Tol
THF, 0 oCꢀrt,
4 h, 80%
S
2.
HN
NMe
8
OBn
9
28
Toluene, 70 oC,
4 h, 75%
OH
O
SnBu3
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13
14
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16
17
18
19
20
21
22
23
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32
OBn
OBn
OBn
OBn
nꢀBuLi, THF, ꢀ78 oC
mCPBA, CHCl3
HO
HO
(+)ꢀCyclophellitol, 1
0 oCꢀrt, 16 h, 80%
Ref. 4b
1 h, 85%
OBn
OBn
O
33
entꢀ3
Scheme 5. Formal synthesis of (+)ꢀcyclophellitol.
The synthesis of (–)ꢀconduramineꢀB derivative was achieved by rearrangement of the
sulfilimine prepared from sulfide 28. Thus, treatment of 28 with NꢀchloroꢀNꢀtertꢀbutyloxy
carbamate23 at 0 oC and warming to rt led to allylic amino derivative which without isolation
on treatment with sodium borohydride in methanol led to the cleavage of the NꢀS bond to
furnish carbamate 34 and thus completing the synthesis of (–)ꢀconduramineꢀB derivative,
Scheme 6.
Scheme 6. Synthesis of (–)ꢀconduramineꢀB derivative via a sulfilimine intermediate.
In conclusion, we have disclosed an asymmetric route to (–)ꢀ and (+)ꢀcyclophellitol.
The key steps of the strategy include utilization of an intramolecular sulfinyl group as the
nucleophile for vicinal heterofunctionalization of a diene, αꢀchloro sulfide intermediate for
stereoselective C–C bond formation, ringꢀclosing metathesis, MislowꢀEvans reaction for the
synthesis of conduritol derivative, KirmseꢀDoyle rearrangement and WittigꢀStill
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rearrangement for the introduction of the hydroxymethyl substituent of cyclophellitol and
preparation of conduramine derivative again by a [2,3] sigmatropic rearrangement. A
characteristic feature of the synthesis is the utilisation of a single allylic sulfide 28 for the
synthesis of all the target molecules by C–O, C–N and C–C bond formations. The potential
utility of sulfur intermediates as nucleophilic and electrophilic partners in total synthesis is
elegantly demonstrated.
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Experimental
Dry reactions were performed under an inert atmosphere using argon or nitrogen. All glassware
apparatus used for reactions are perfectly oven dried. Anhydrous solvents were distilled prior to use:
THF from Na and benzophenone; CH2Cl2, Toluene from CaH2 ; MeOH from Mg cake; CHCl3 from
P2O5, Acetone from KMnO4 and K2CO3. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel (100−200 mesh). Analytical thinꢀlayer
chromatography (TLC) was run on silica gel 60 F254 precoated plates (250 ꢁm thickness). Optical
rotations [α]D were measured on a polarimeter and given in 10−1 deg cm2 g−1. Infrared spectra were
recorded in neat / KBr (as mentioned) and reported in wavenumber (cm−1). Mass spectral data were
obtained using MS (EI) ESI, HRMS mass spectrometers. Highꢀresolution mass spectra (HRMS)
1
[ESI+] were obtained using either a TOF or a double focusing spectrometer. H NMR spectra were
recorded at 300 or 400 or 500 MHz and 13C NMR spectra at 75 or 100 or 125 MHz in CDCl3 with the
residual solvent signal as internal standard unless otherwise mentioned, chemical shifts are in ppm
downfield from tetramethylsilane, and coupling constants (J) are reported in hertz (Hz). The following
abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad.
(S,3E,5E)ꢀ1ꢀ((S)ꢀpꢀTolylsulfinyl)heptaꢀ3,5ꢀdienꢀ2ꢀol (8): To a solution of anhydrous ZnCl2 (10.88 g,
80 mmol) in anhydrous THF (150 mL) was added a solution of keto sulfoxide6 (9.9 g, 40 mmol) in
THF (50 mL) dropwise over 5 min. The reaction mixture was stirred at r.t for 30 min and then cooled
to ꢀ78 °C. After 5 min, DibalꢀH (38 mL, 1.6 M in toluene, 60 mmol) was added dropwise over 5 min.
After 30 min, MeOH (5 mL) was added slowly to the reaction mixture and allowed to warm to rt. The
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volatiles were evaporated under reduced pressure and the residue was dissolved by adding aq. 5%
HCl (100 mL) at 0 °C. Then EtOAc (100 mL) was added, the layers were separated and the aqueous
layer extracted with EtOAc (2X100 mL). The combined organic layers were washed with water, brine
and dried over Na2SO4. The solvent was evaporated under reduced pressure to afford the crude
product which was purified by column chromatography using 40% EtOAc/petroleum ether (v/v) to
give pure hydroxy sulfoxide 8 (8.2 g, 32.8 mmol) in 82% yield as a gummy oil. TLC: Rf 0.25 (40%
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EtOAc/hexane). [α]25 = –194.0 (c 1.02, CHCl3); IR (neat): 3417, 2925, 2856, 1727, 1085, 994, 810
D
cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.20 (dd, J =
15.1 Hz, 10.4 Hz, 1H), 5.98 (dd, J = 14.9 Hz, 10.4 Hz, 1H), 5.75ꢀ5.63 (m, 1H), 5.51 (dd, J = 15.1 Hz,
6.4 Hz, 1H), 4.73ꢀ4.66 (m, 1H), 3.04 (dd, J = 13.0 Hz, 8.9 Hz, 1H), 2.77 (dd, J = 13.0 Hz, 3.6 Hz,
1H), 2.41 (s, 3H), 1.74 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 141.6, 140.7, 131.8, 130.8,
130.6, 130.0, 129.9, 124.1, 68.9, 63.1, 21.5, 18.2; MS (ESI): m/z 273 [M+Na]+. HRMS (ESI): calcd
for C14H18NaO2S: 273.0925, Found: 273.0921.
(2R,3S,4S,E)ꢀ3ꢀBromoꢀ1ꢀ((R)ꢀpꢀtolylsulfinyl)heptꢀ5ꢀeneꢀ2,4ꢀdiol (11): To a solution of the diene 8
(7.5 g, 30 mmol) in DCM (120 mL) was added water (0.65 mL, 36 mmol) and the mixture stirred at 0
°C for 5 min. To the above solution, freshly recrystallised NBS (5.34 g, 30 mmol) was added portion
wise over a period of 1 h. The reaction mixture was stirred for another 30 min when TLC examination
revealed consumption of the starting material. The solvent was evaporated under reduced pressure and
the residue was purified by column chromatography using 35%ꢀ50% EtOAc/petroleum ether (v/v) to
give pure bromohydrin 11 (7.26 g, 21 mmol) in 70% yield as a colorless viscous oil. TLC: Rf 0.25
(50% EtOAc/hexane). [α]25D= +75.8 (c 0.5, MeOH). IR (neat): 3423, 3020, 2922, 2856, 1730, 1641,
1492, 1251, 1085, 970, 807, 761, 494 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.2 Hz, 2H),
7.34 (d, J = 8.2 Hz, 2H), 5.78ꢀ5.66 (m, 1H), 5.47 (dd, J = 15.7 Hz, 6.8 Hz, 1H), 5.13 (br s, OH), 4.49ꢀ
4.38 (m, 1H), 4.35ꢀ4.26 (m, 1H), 4.05 (dd, J = 6.8 Hz, 6.1 Hz, 1H), 3.68 (br s, OH), 3.19 (dd, J = 12.9
Hz, 2.0 Hz, 1H), 3.08 (dd, J = 12.9 Hz, 9.5 Hz, 1H), 2.44 (s, 3H), 1.69 (d, J = 5.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 141.8, 138.6, 130.2, 130.1, 129.5, 124.0, 73.5, 67.9, 62.1, 59.8, 21.3, 17.7; MS
(ESI): m/z 347/349 [M+H]+, 369/371 [M+Na]+ HRMS (ESI): calcd for C14H19BrO3SNa: 369.0130,
.
Found: 369.0149.
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1ꢀ((R)ꢀ((2R,3S,4S,E)ꢀ3ꢀBromoꢀ2,4ꢀbis(2,3,3ꢀtrimethylbutanꢀ2ꢀyloxy)heptꢀ5ꢀenyl)sulfinyl)ꢀ4ꢀ
methylbenzene (12): To a solution of the bromohydrin 11 (7.26 g, 21 mmol) in DCM (84 mL) cooled
at 0 °C was added imidazole (5.7 g, 84 mmol) and then TBSꢀCl (7.0 g, 46.2 mmol). The reaction
mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was quenched by the
addition of water and diluted with DCM (100 mL). The layers were separated and the organic layer
was washed with water, brine and dried over Na2SO4. The solvent was evaporated under reduced
pressure to afford the crude product which was purified by column chromatography using 10%
EtOAc/petroleum ether (v/v) to give pure TBS ether 12 (10.8 g, 18.7 mmol) in 90% yield as a
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gummy oil. TLC: Rf 0.5 (20% EtOAc/hexane). [α]25 = +35.2 (c 0.5, CHCl3). IR (neat): 3019, 2973,
D
2924, 1709, 1492, 1211, 1094, 806, 756, 495 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.5 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.3 Hz, 2H), 5.70ꢀ5.52 (m, 1H), 5.46 (dd, J = 15.8 Hz, 7.5 Hz, 1H), 4.60 (dt, J = 9.8
Hz, 2.3 Hz, 1H), 4.19 (t, J = 6.7 Hz, 1H), 4.12ꢀ4.03 (dd, J = 6.7 Hz, 2.3 Hz, 1H), 3.13 (dd, J = 12.8
Hz, 2.3 Hz, 1H), 2.89 (dd, J = 12.8 Hz, 9.8 Hz, 1H), 2.38 (s, 3H), 1.70 (d, J = 5.3 Hz, 3H), 0.95 (s,
9H), 0.77 (s, 9H), 0.24 (s, 3H), 0.14 (s, 3H), 0.02 (s, 3H), ꢀ0.05 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
141.7, 140.8, 131.5, 129.7, 129.4, 123.6, 75.8, 65.6, 65.3, 64.5, 25.7, 25.6, 21.3, 18.0, 17.8, 17.4, –4.1,
–4.73, –4.75, –4.9; MS (ESI): m/z 597/599 [M+Na]+. HRMS (ESI): calcd for C26H47O3BrSSi2Na:
599.1834, Found: 599.1835.
((2R,3S,4S,E)ꢀ3ꢀBromoꢀ2,4ꢀdimethoxyheptꢀ5ꢀenyl)(pꢀtolyl)sulfane (7): To a stirred solution of a
mixture of TBS ether 12 (10.3 g, 18 mmol) and NaI (10.8 g, 72 mmol) in acetone (72 mL) cooled at ꢀ
20 °C was added TFAA (5 mL, 36 mmol) dropwise. The reaction mixture was stirred for 1 h at ꢀ20 °C
and then quenched by adding an aq. saturated Na2SO3 solution (20 mL). Acetone was evaporated
under reduced pressure and the aq phase was extracted with dichloromethane (2x50 mL). The
combined organic extracts were successively washed with aq saturated NaHCO3 solution, water, brine
and dried over Na2SO4. Evaporation of the solvent under reduced pressure furnished the crude
compound which was purified by column chromatography using 5ꢀ10% EtOAc/petroleum ether (v/v)
to give pure sulfide 7 (8.55 g, 15.3 mmol) in 85% yield as a gummy oil. TLC: Rf 0.5 (10%
EtOAc/hexane). [α]20 = +85.8 (c 1.0, CHCl3). IR (neat): 3015, 2960, 2924, 1729, 1452, 1211, 1094,
D
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806, 756, 495 cmꢀ1.1H NMR (300 MHz, CDCl3): δ 7.29 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H),
5.72ꢀ5.57 (m, 1H), 5.39 (dd, J = 15.8 Hz, 7.5 Hz, 1H), 4.36 (t, J = 6.0 Hz, 1H), 4.17ꢀ4.09 (m, 2H),
3.35 (dd, J = 13.5 Hz, 3.0 Hz, 1H), 3.20 (dd, J = 13.5 Hz, 7.54 Hz, 1H), 2.32 (s, 3H), 1.7 (d, J = 6.7
Hz, 3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 135.7, 133.5, 131.5, 129.8, 129.5, 128.9, 75.0, 71.1, 64.5, 39.9, 25.9, 25.8, 20.9,
18.2, 18.1, 17.5, –4.0, –4.2, –4.8; MS (ESI): m/z 581/583 [M+Na]+. HRMS (ESI): calcd for C26H47
BrNaO2SSi2: 581.1911, Found: 581.1906.
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(5S,6S,7R)ꢀ6ꢀBromoꢀ2,2,3,3,9,9,10,10ꢀoctamethylꢀ5ꢀ((E)ꢀpropꢀ1ꢀenyl)ꢀ7ꢀ((R)ꢀpꢀ
tolylsulfinylmethyl)ꢀ4,8ꢀdioxaꢀ3,9ꢀdisilaundecane (6): To a solution of vinylmagnesium bromide
(30 mL, 30 mmol, 1M in THF) cooled at 0 °C was added ZnBr2 (24 mL, 36 mmol, 1.5 M in THF) and
stirred for 30 min. To the resulting vinylzinc bromide maintained at 0 °C was added the solution of
chloro sulfide (10 mmol) in benzene (100 mL) prepared by the dropwise addition of a solution of the
sulfide 7 (5.6 g, 10 mmol) in anhydrous benzene (50 mL) to the solution of Nꢀchlorosuccinimide (1.4
g, 10.5 mmol) in benzene (50 mL) at ambient temperature and stirring for a period of 30 min. The
reaction mixture was stirred and gradually allowed to warm to rt, and stirred for a period of 4 h when
TLC examination indicated complete consumption of the chloro sulfide. The reaction mixture was
cooled to 0 °C and quenched by the addition of an aq saturated NH4Cl solution. It was allowed to
warm to rt and diluted with Et2O (25 mL), the layers were separated and aq layer extracted with Et2O
(2X50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over
Na2SO4 and the solvent evaporated under reduced pressure to afford a crude compound which was
purified by column chromatography using hexanes as the eluent to afford the pure product 6 (4.68 g, 8
mmol) in 80% yield as a colorless viscous liquid. TLC: Rf 0.55 (10% EtOAc/hexane). [α]20D = –55.1
1
(c 0.72, CHCl3). IR (neat): 2954, 2929, 2857, 1466, 1363, 1254, 1095, 838, 776, 684 cmꢀ1. H NMR
(300 MHz, CDCl3): δ 7.31 (d, J = 7.5 Hz, 2H), 7.07 (d, J = 7.5 Hz, 2H), 5.97ꢀ5.82 (m, 1H), 5.78ꢀ5.62
(m, 1H), 5.42 (dd, J = 15.1 Hz, 6.0 Hz, 1H), 4.99 (dd, J = 10.5 Hz, 1.5 Hz, 1H), 4.93 (dd, J = 16.6 Hz,
1.5 Hz, 1H), 4.54 (dd, J = 6.0 Hz, 5.3 Hz, 1H), 4.38 (t, J = 5.3 Hz, 1H), 4.20ꢀ4.12 (m, 2H), 2.31 (s,
3H), 1.73 (d, J = 6.7 Hz, 3H), 0.97 (s, 9H), 0.92 (s, 9H), 0.18 (s, 3H), 0.15 (s, 3H), 0.10 (s, 3H), 0.06
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(s, 3H); 13C NMR (75 MHz, CDCl3): δ 136.9, 136.5, 133.1, 130.7, 129.4, 128.8, 116.8, 75.3, 72.1,
63.8, 59.4, 26.1, 25.9, 21.0, 18.6, 18.2, 17.7, –3.71, –3.89, –3.97, –4.56; MS (ESI): m/z 607/609
[M+Na]+. HRMS (ESI): calcd for C28H49O2BrNaSSi2: 607.20674, Found: 607.20673.
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((1R,2S,3S,6S)ꢀ2ꢀBromoꢀ6ꢀ(pꢀtolylthio)cyclohexꢀ4ꢀeneꢀ1,3ꢀdiyl)bis(oxy)bis(tertꢀ
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butyldimethylsilane) (14): To a solution of the compound 6 (275 mg, 0.47 mmol) in dry DCM (1
mL) maintained under an atmosphere of N2 at ambient temperature was added Grubbs 1st generation
catalyst (20 mg, 0.02 mmol). The reaction was heated at 40 °C for 8 h. The solution was concentrated
under vacuum to afford a crude compound which was purified by column chromatography using 5ꢀ
15% EtOAc/petroleum ether (v/v) to afford the pure product 14 (205 mg, 0.38 mmol) in 80% yield as
a colorless oil. TLC: Rf 0.3 (10% EtOAc/hexane). [α]20 = +33.7 (c 0.72, CHCl3). IR (neat): 2960,
D
2924, 1729, 1452, 1211, 1094, 806, 756, 495 cmꢀ1. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, J = 8.1 Hz,
2H), 7.10 (d, J = 8.1 Hz, 2H), 5.72 (dt, J = 10.3 Hz, 2.4 Hz, 1H), 5.40 (dq, J = 10.2 Hz, 1.8 Hz, 1H),
4.43ꢀ4.33 (m, 2H), 3.89ꢀ3.82 (m, 1H), 3.75 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 2.33 (s, 3H), 0.94 (s, 9H),
0.91 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
137.2, 132.3, 130.8, 129.6, 129.5, 127.9, 72.2, 68.2, 63.1, 51.7, 25.8, 25.7, 21.0, 18.2, 18.1, –4.4, –4.6,
–4.7; MS (ESI): m/z 565/567 [M+Na]+. HRMS (ESI): calcd for C25H43O2BrNaSSi2:
565.1597/567.1578, Found: 565.1599/567.1577.
(1R,4R,5R,6S)ꢀ5ꢀBromoꢀ4,6ꢀbis(tertꢀbutyldimethylsilyloxy)cyclohexꢀ2ꢀenol (15): To a solution of
sulfide 14 (90 mg, 0.16 mmol) in anhydrous CHCl3 (1 mL) cooled at –40 oC was added mCPBA (26
mg, 0.16 mmol). The reaction mixture was stirred for 30 min at the same temperature when TLC
examination revealed complete transformation of sulfide to sulfoxide. A solution of 2ꢀmercaptoꢀ1ꢀ
methyl imidazole (38 mg, 0.33 mmol) in toluene (2 mL) was added and the reaction mixture was
gradually allowed to warm to rt and then heated at 70 °C for 4 h. The reaction mixture was cooled to
rt and quenched by the addition of saturated sodium sulfite solution (5 mL). The layers were separated
and the aq layer was extracted with dichloromethane (2X10 mL). The combined organic layers were
washed with aq saturated NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to furnish the crude product. Purification of the crude residue via flash
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chromatography on silica gel using 8ꢀ15% EtOAc/hexane (v/v) as the eluent afforded 15 as a
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colourless oil (52 mg, 0.12 mmol) in 75% overall yield. TLC: Rf 0.15 (10% EtOAc/hexane). [α]20
=
D
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–15.1 (c 0.1, CHCl3). IR (neat): 3446, 3015, 2960, 2924, 1728, 1452, 1211, 1054, 806, 756, 495 cmꢀ1.
1H NMR (300 MHz, CDCl3): δ 5.69 (dt, J = 10.5 Hz, 2.2 Hz, 1H), 5.49 (dd, J = 10.5 Hz, 1.5 Hz, 1H),
4.55ꢀ4.46 (m, 2H), 4.33ꢀ4.28 (m, 1H), 3.62 (dd, J = 7.5 Hz, 3.0 Hz, 1H), 0.95 (s, 9H), 0.93 (s, 9H),
0.14 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 130.8, 128.0,
74.6, 71.8, 68.6, 62.3, 25.7, 25.6, 18.2, 18.0, 1.01, –4.5, –4.71, –4.7; MS (ESI): m/z 459/461 [M+Na]+.
HRMS (ESI): calcd for C18H37 BrNaO3Si2: 459.1357, Found: 459.1330.
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(1R,4R,5R,6S)ꢀ5ꢀBromoꢀ4,6ꢀbis(tertꢀbutyldimethylsilyloxy)cyclohexꢀ2ꢀenyl acetate (16): To a
stirred solution of compound 15 (50 mg, 0.11 mmol) in anhydrous DCM (1 mL) cooled at 0 °C,
DMAP (2 mg, 0.01 mmol), Et3N (0.05 mL, 0.33 mmol), and Ac2O (0.02 mL, 0.17 mmol) were
sequentially added. After stirring this mixture for 2 h at rt it was quenched by addition of aq saturated
NaHCO3 solution and extracted with DCM (2X10 mL). The organic layers were washed with water,
brine, dried over Na2SO4 and evaporated to furnish the crude acetate which was purified by column
chromatography using 5ꢀ10% EtOAc/petroleum ether (v/v) to afford the pure product 16 (49.3 mg,
0.1 mmol) in 90% yield as a viscous oil. TLC: Rf 0.25 (10% EtOAc/hexane). [α]20 = –29.9 (c 0.1,
D
CHCl3). IR (neat): 2960, 2924, 1725, 1452, 1094, 856, 715, 495 cmꢀ1. 1H NMR (600 MHz, CDCl3): δ
5.61 (dt, J = 10.5 Hz, 2.1 Hz, 1H), 5.58ꢀ5.53 (m, 2H), 4.52ꢀ4.48 (m, 1H), 4.30ꢀ4.28 (m, 1H), 3.87 (dd,
J = 7.5 Hz, 2.6 Hz, 1H), 2.07 (s, 3H), 0.93 (s, 9H), 0.91 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s,
6H); 13C NMR (75 MHz, CDCl3): δ 170.1, 132.3, 125.0, 74.9, 71.4, 68.3, 62.4, 25.7, 25.5, 21.1, 18.2,
17.9, –4.6, –4.7, –4.8; MS (ESI): m/z 501/503 [M+Na]+. HRMS (ESI): calcd for C20H39BrNaO4Si2:
501.1463, Found: 501.1459.
(1R,6R)ꢀ6ꢀ(tertꢀButyldimethylsilyloxy)ꢀ4ꢀoxocyclohexꢀ2ꢀenyl acetate (17): To a stirred solution of
bromo acetate 16 (35 mg, 0.07 mmol) in dry DMF (0.7 mL) was added KOAc (68 mg, 0.7 mmol) and
the mixture heated at 100 °C for 6 h when TLC examination revealed complete consumption of
starting material. The reaction mixture was cooled to rt, quenched by the addition of water and
extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to
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furnish the crude compound which was purified by column chromatography using 10ꢀ20%
EtOAc/petroleum ether (v/v) to afford the pure product 17 (16 mg, 0.05 mmol) in 70% yield as a
viscous oil. TLC: Rf 0.25 (20% EtOAc/hexane). 1H NMR (500 MHz, CDCl3): δ 6.7 (dd, J = 9.6 Hz,
1H), 6.05 (dd, J = 9.6 Hz, 1H), 5.5 (m, 1H), 4.21ꢀ4.10 (m, 1H), 2.75 (dd, J = 16.4 Hz, 6.0 Hz, 1H),
2.51 (dd, J = 16.4 Hz, 3.2 Hz, 1H), 2.12 (s, 3H), 0.89 (s, 9H), 0.01 (s, 6H).
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((1S,2R,3R,6R)ꢀ2ꢀBromoꢀ6ꢀ(methoxymethoxy)cyclohexꢀ4ꢀeneꢀ1,3ꢀdiyl)bis(oxy)bis(tertꢀ
butyldimethylsilane) (18): To a stirred solution of compound 15 (50 mg, 0.11 mmol) in anhydrous
DCM (1 mL) cooled at 0 °C, DIPEA (0.06 mL, 0.34 mmol), and MOMꢀCl (0.014 mL, 0.165 mmol)
were sequentially added. After stirring this mixture for 2 h at rt the reaction was quenched by addition
of aq saturated NaHCO3 solution and extracted with DCM (2X10 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and evaporated to furnish the MOM ether which was
purified by column chromatography using 5ꢀ10% EtOAc/petroleum ether (v/v) to afford the pure
product 18 (49 mg, 0.1 mmol) in 90% yield as a gummy liquid. TLC: Rf 0.45 (10% EtOAc/hexane).
1H NMR (500 MHz, CDCl3): 5.6 (dt, J = 10.2 Hz, 2.2 Hz, 1H), 5.39 (dd, J = 10.2 Hz, 2.6 Hz, 1H),
4.71 (d, J = 6.7 Hz, 1 H), 4.58 (d, J = 6.7 Hz, 1H), 4.40ꢀ4.32 (m, 1H), 4.27ꢀ4.20 (m, 1H), 4.20ꢀ4.15
(m, 1H), 3.61 (dd, J = 7.5 Hz, 2.6 Hz, 1H), 3.30 (s, 3H), 0.82 (s, 18H), 0.01 (s, 6H), ꢀ0.01 (s, 6H).
4ꢀ(Methoxymethoxy)phenol (19): 18ꢀcrownꢀ6 (26 mg, 0.1 mmol) and potassium superoxide (30 mg,
0.4 mmol) were added to a solution of the compound 18 (50 mg, 0.10 mmol) in anhydrous
dimethylsulfoxide (1 mL) cooled at 0 oC. After 30 min the reaction mixture was diluted with diethyl
ether (5 mL) and poured into brine. The organic phase was separated and the aq phase was extracted
with diethyl ether (2X5 mL). The organic layers were washed with aq 1N HCl, water, dried with
Na2SO4 and evaporated. The resulting crude compound was purified by column chromatography using
10ꢀ20% EtOAc/petroleum ether (v/v) to afford the pure product 19 (10 mg, 0.07 mmol) in 70% yield
1
as a liquid. TLC: Rf 0.15 (20% EtOAc/hexane). H NMR (300 MHz, CDCl3): δ 6.92 (d, J = 9.0 Hz,
2H), 6.75 (d, J = 9.0 Hz, 2H), 5.10 (s, 2H), 3.48 (s, 3H).
(3S,4R,5S,6S,E)ꢀ5ꢀBromoꢀ3ꢀ(pꢀtolylthio)nonaꢀ1,7ꢀdieneꢀ4,6ꢀdiyl diacetate (21): To a stirred
solution of bromo compound 5 (4.1 g, 7 mmol) in MeOH (25 mL) was added (±)ꢀcamphorsulfonic
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acid (90 mg, 0.4 mmol) at rt and the mixture stirred for 4 h. The reaction mixture was concentrated
under reduced pressure and the residue diluted with DCM (25 mL). DMAP (35 mg, 0.28 mmol), Et3N
(4 mL, 28 mmol), and Ac2O (1.4 ml, 14 mmol) were sequentially added at 0 °C. After stirring this
mixture for 2 h at rt it was quenched by the addition of aq saturated NaHCO3 solution and extracted
with DCM (2X50 mL). The organic layers were washed with brine, dried over Na2SO4 and evaporated
to furnish the crude diacetate which was purified by column chromatography using 5ꢀ15%
EtOAc/petroleum ether (v/v) to afford the pure product 21 (2.66 g, 5.95 mmol) in 85% yield as a
gummy oil. TLC: Rf 0.3 (20% EtOAc/hexane). [α]20D = –20.2 (c 0.56, CHCl3). IR (neat): 2977, 1748,
1492, 1371, 1224, 1021, 966, 810, 606, 499 cmꢀ1..1H NMR (300 MHz, CDCl3): δ 7.34 (d, J = 8.3 Hz,
2H), 7.09 (d, J = 8.3 Hz, 2H), 5.85ꢀ5.63 (m, 1H), 5.62ꢀ5.51 (m, 1H), 5.41 (dd, J = 7.5 Hz, 3.7 Hz,
1H), 5.35 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 5.08 (d, J = 3.0 Hz, 1H), 5.03 (d, J = 2.2 Hz, 1H), 4.77 (dd, J =
9.0 Hz, 3.0 Hz, 1H), 4.14 (dd, J = 8.3 Hz, 3.0 Hz, 1H), 2.32 (s, 3H), 2.10 (s, 6H), 1.73 (d, J = 6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 169.5, 169.2, 137.7, 134.7, 133.6, 133.5, 129.9, 129.6, 124.8,
117.4, 74.2, 72.9, 56.7, 54.9, 21.1, 21.0, 20.7, 17.9; MS (ESI): m/z 458/460 [M+NH4]+. HRMS (ESI):
calcd for C20H29 BrNO4S: 458.0995, Found: 458.0986.
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(3S,4S,5R,6S,E)ꢀ3ꢀ(pꢀTolylthio)nonaꢀ1,7ꢀdieneꢀ4,5,6ꢀtriyl triacetate (22): To a stirred solution of
bromo compound 21 (872 mg, 2 mmol) in dry DMSO (8 mL) was added BHT (45 mg, 0.2 mmol),
NaNO2 (1.38 g, 20 mmol) and the mixture heated at 85 °C for 24 h in the dark. The reaction mixture
was cooled to rt and quenched by the addition of water and extracted with CHCl3 (2X20 mL). The
organic layer was washed with brine, dried over Na2SO4 and evaporated to furnish the crude
compound which was purified by column chromatography using10ꢀ20% EtOAc/petroleum ether (v/v)
to afford the triol derivative as a mixture of diacetates (567 mg, 1.5 mmol) in 75% yield as a viscous
liquid. To the purified mixture of diacetates (567 mg, 1.5 mmol) in dry DCM (6 mL) cooled at 0 °C,
DMAP (6 mg, 0.05 mmol), Et3N (0.43 mL, 3 mmol) and Ac2O (0.14 mL, 1.5 mmol) were
sequentially added. After stirring the mixture for 2 h at rt it was quenched by the addition of aq
saturated NaHCO3 solution and extracted with DCM (2X20 mL). The organic layer were washed with
brine, dried over Na2SO4 and evaporated to furnish the crude triacetate which was purified by column
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chromatography using 10ꢀ15% EtOAc/petroleum ether (v/v) to afford the pure product 22 (567 mg,
1.35 mmol) in 90% yield as a viscous liquid. TLC: Rf 0.5 (20% EtOAc/hexane). [α]20D = +61.3 (c 0.5,
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CHCl3). IR (neat): 2924, 1748, 1372, 1217, 1027, 962, 810, 601, 500 cmꢀ1. H NMR (500 MHz,
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CDCl3): δ 7.3 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 5.82ꢀ5.71 (m, 1H), 5.70ꢀ5.60 (m, 1H),
5.40 (dd, J = 6.2 Hz, 2.7 Hz, 1H), 5.36 (dd J = 10.5 Hz, 3.2 Hz, 1H), 5.31 (dd, J = 7.1 Hz, 2.7 Hz,
1H), 5.23 (dd J = 7.1 Hz, 3.3 Hz, 1H), 5.03 (d, J = 10.2 Hz, 1H), 4.89 (d, J = 16.3 Hz, 1H), 3.71 (dd, J
= 8.4 Hz, 7.7 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 1.68 (d, J = 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 169.8, 169.7, 169.4, 137.6, 133.6, 133.1, 133.0, 129.7, 129.5, 124.2,
118.0, 73.1, 72.2, 71.7, 54.3, 21.0, 20.8, 20.6, 20.6, 17.7; MS (ESI): m/z 438 [M+NH4]+. HRMS
(ESI): calcd for C22H32O6SN: 438.1929, Found: 438.1945.
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(1S,2R,3S,6S)ꢀ6ꢀ(pꢀTolylthio)cyclohexꢀ4ꢀeneꢀ1,2,3ꢀtriyl triacetate (23): To a solution of the
compound 22 (210 mg, 0.5 mmol) in dry DCM (1 mL) maintained under an atmosphere of N2 at
ambient temperature was added Grubbs 1st generation catalyst (45 mg, 0.05 mmol). The reaction was
heated at 40 °C for 8 h. The solution was concentrated under vacuum to afford a crude compound
which was purified by column chromatography using 10ꢀ15% EtOAc/petroleum ether (v/v) to afford
the pure product 23 (150 mg, 0.4 mmol) in 80% yield as a viscous liquid. TLC: Rf 0.3 (20%
EtOAc/hexane). [α]20 = +146.8 (c 1.0, CHCl3). IR (neat): 2926, 1751, 1371, 1222, 1045, 964, 811,
D
769, 601 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.83
(dt, J = 10.2 Hz, 2.2 Hz, 1H), 5.48 (dt, J = 10.2, Hz, 2.4 Hz, 1H), 5.38ꢀ5.32 (m, 1H), 5.24ꢀ5.19 (m,
2H), 3.77ꢀ3.72 (m, 1H), 2.3 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 170.1, 170.0, 169.7, 138.9, 135.0, 129.8, 129.7, 126.9, 126.0, 72.4, 71.3, 71.2, 49.3, 21.1,
20.8, 20.5; MS (ESI): m/z 396 [M+NH4]+. HRMS (ESI): calcd for C19H26O6SN: 396.1475, Found:
396.1470.
(1S,2S,3R,6R)ꢀ6ꢀHydroxycyclohexꢀ4ꢀeneꢀ1,2,3ꢀtriyl triacetate (24): To a solution of sulfide 23 (50
o
mg, 0.13 mmol) in anhydrous CHCl3 (1 mL) cooled at ꢀ40 C was added mCPBA (22 mg, 0.13
mmol). The reaction mixture was stirred for 30 min at same temperature when TLC examination
revealed complete transformation of sulfide to sulfoxide. A solution of 2ꢀmercaptoꢀ1ꢀmethyl
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imidazole (23 mg, 0.2 mmol) in toluene (2 mL) was added and the reaction mixture was gradually
allowed to warm to rt and then heated at 70 °C for 4 h. The reaction mixture was cooled to rt and
quenched by the addition of saturated sodium sulfite solution (5 mL). The layers were separated and
the aq layer was extracted with dichloromethane (2X10 mL). The combined organic layers were
washed with NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to furnish the crude product. Purification of the crude residue via flash chromatography on
silica gel using 8ꢀ15% EtOAc/hexane (v/v) as the eluent afforded 24 as a colourless oil (26.3 mg,
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0.097 mmol) in an overall 75% yield. TLC: Rf 0.25 (30% EtOAc/hexane). [α]20 = –116.3 (c 0.5,
D
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CHCl3). {Lit.:{4c} –111.8 (c 0.1, CHCl3)}. IR (neat): 3448, 2922, 2852, 1633, 1021, 763 cmꢀ1. H
NMR (500 MHz, CDCl3): δ 5.81 (dt, J = 10.3 Hz, 2.13 Hz, 1H), 5.62 (dt, J = 10.3 Hz, 2.6 Hz, 1H),
5.57 (dq, J = 8.0 Hz, 2.6 Hz, 1H), 5.29 (dd, J = 11.1 Hz, 8.0 Hz, 1H), 5.04 (dd, J = 10.9 Hz, 7.7 Hz,
1H), 4.45ꢀ4.41 (m, 1H), 2.11 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.3,
170.2, 170.0, 131.0, 125.4, 75.5, 71.8, 71.1, 70.6, 20.8, 20.7, 20.6; MS (ESI): m/z 290 [M+NH4]+.
HRMS (ESI): calcd for C12H20O7N: 290.1234, Found: 290.1228.
(1S,2S,3R,6R)ꢀ6ꢀ(pꢀTolylthio(trimethylsilyl)methyl)cyclohexꢀ4ꢀeneꢀ1,2,3ꢀtriyl triacetate (25):
Trimethylsilyl diazomethane (0.2 mL, 2 M in hexanes, 0.4 mmol) was added to a solution of allyl
sulphide 23 (30 mg, 0.08 mmol) and rhodium (II) acetate dimer (3 mg, 0.006 mmol) in toluene (1.5
mL). After stirring for 12 h at 50 °C the solvent was removed under reduced pressure and the residue
was purified by flash chromatography eluting with 2% EtOAc/petroleum ether (v/v) to give as a
mixture of epimeric sulfide 25 (27 mg, 75%) as a colourless liquid..TLC: Rf 0.5 (10%
EtOAc/hexane). [α]25 = –69.1 (c 0.5, CHCl3). IR (neat): 2963, 2954, 1723, 1456, 1211, 1094, 806,
D
756, 695 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 7.10
(d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.02 (dt, J = 10.2 Hz, 2.2 Hz, 1H), 5.65ꢀ5.61 (m, 3H),
5.60ꢀ5.50 (m, 4H), 5.23ꢀ5.11 (m, 2H), 3.05ꢀ3.0 (m, 1H), 2.85ꢀ2.79 (m, 1H), 2.53 (d, J = 2.2 Hz, 1H),
2.51 (d, J = 1.8 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.98 (s,
3H), 1.97 (s, 3H), 1.91 (s, 3H), 0.22 (s, 9H), 0.16 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 170.3, 170.2,
170.0, 169.2, 136.7, 136.6, 133.2, 132.5, 131.3, 130.2, 129.8, 129.77, 129.70, 129.0, 126.0, 124.2,
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73.4, 72.7, 72.16, 72.11, 71.8, 71.6, 45.4, 43.4, 36.1, 35.4, 21.0, 20.9, 20.8, 20.6, 20.5, –0.8, –1.7; MS
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(ESI): m/z 482 [M+NH4]+. HRMS (ESI): calcd for C23H36O6NSSi: 482.2027, Found: 482.2009.
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pꢀTolyl((1S,4S,5R,6S)ꢀ4,5,6ꢀtris(benzyloxy)cyclohexꢀ2ꢀenyl)sulfane (28): To a stirred solution of
triacetate compound 23 (200 mg, 0.52 mmol) in MeOH (3 mL) was added K2CO3 (20 mg, 0.14 mmol)
at rt, and the mixture stirred for 2 h. The mixture was filtered and the filtrate evaporated to furnish the
crude triol 27 which was used in the next step without further purification.
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The suspension of the sodium hydride (70 mg, 1.75 mmol, 60% dispersion in Nujol was
washed twice with dry petroleum ether) in anhydrous THF (2.5 mL), cooled at 0 °C was added nꢀ
tetrabutylammonium iodide (20 mg, 0.05 mmol) followed by dropwise addition of a solution of the
triol 27 (l30 mg, 0.5 mmol) in anhydrous THF (2.5 mL) under nitrogen atmosphere. After stirring at
room temperature for l h, benzyl bromide (0.21 mL, 1.75 mmol) was added dropwise and the resulting
mixture stirred for 6 h. The reaction was then quenched by the addition of ice pieces and the mixture
extracted with ethyl acetate (3x10 mL). The combined organic layers were washed successively with
water and brine. The organic extracts were dried over Na2SO4 and the solvent was removed under
reduced pressure to afford the crude product which was purified by column chromatography using 3ꢀ
8% EtOAc/petroleum ether (v/v) to give compound 28 (234 mg, 0.44 mmol, 85%) as a colourless oil.
TLC: Rf 0.35 (10% EtOAc/hexane). [α]20 = +196.8 (c 1.0, CHCl3). IR (neat): 2923, 2856, 1493,
D
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1454, 1355, 1138, 1070, 1026, 807, 739, 697 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.41ꢀ7.27 (m,
15H), 7.37 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.75 (dt, J = 10.1 Hz, 2.2 Hz, 1H), 5.66 (dt, J
= 10.1 Hz, 2.0 Hz, 1H), 4.94 (d, J = 10.3 Hz, 1H), 4.91 (d, J = 10.3 Hz, 1H), 4.90 (d, J = 10.8 Hz,
1H), 4.88 (d, J = 10.8 Hz, 1H), 4.69 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.13ꢀ4.08 (m,
1H), 3.85ꢀ3.79 (m, 1H), 3.76 (dd, J = 9.9 Hz, 7.9 Hz, 1H), 3.65 (dd, J = 9.9 Hz, 8.6 Hz, 1H), 2.34 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 138.5, 138.4, 138.2, 137.7, 133.5, 129.7, 129.6, 128.8, 128.34,
128.33, 128.2, 128.1, 127.9, 127.7, 127.6, 127.5, 127.2, 84.6, 81.7, 79.8, 75.9, 75.5, 72.3, 52.5, 21.0;
MS (ESI): m/z 545 [M+Na]+. HRMS (ESI): calcd for C34H34NaO3S: 545.2121, Found: 545.2109.
Trimethyl(pꢀtolylthio((1R,4R,5S,6S)ꢀ4,5,6ꢀtris(benzyloxy)cyclohexꢀ2ꢀenyl)methyl)silane
(29):
Trimethylsilyl diazomethane (0.15 mL, 2 M in hexanes, 0.3 mmol) was added to a solution of allyl
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sulphide 28 (30 mg, 0.057 mmol) and rhodium (II) acetate dimer (3 mg, 0.005 mmol) in toluene (1.5
mL). After stirring for 12 h at 50 °C the solvent was removed under reduced pressure and the residue
was purified by flash chromatography eluting with 2% EtOAc/petroleum ether (v/v) to give as a
mixture of epimeric sulfide 29 (26 mg, 75%) as a colourless liquid. TLC: Rf 0.5 (10%
EtOAc/hexane). [α]25D = –87.1 (c 0.25, CHCl3). IR (neat): 2923, 2855, 1733, 1638, 1459, 1257, 1079,
757, 698 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.40ꢀ7.24 (m, 30H),7.23 (d, J = 8.0 Hz, 2H), 7.10 (d, J
= 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.90 (dt, J = 10.2 Hz, 2.1 Hz, 1H),
5.81 (dt, J = 10.2 Hz, 2.1 Hz, 1H), 5.70 (dt, J = 10.2 Hz, 2.1 Hz, 1H), 5.56 (dt, J = 10.2 Hz, 2.1 Hz,
1H), 5.02 (d, J = 11.4 Hz, 1H), 4.88 (d, J = 10.8 Hz, 2H), 4.84 (d, J = 11.7 Hz, 1H), 4.79 (d, J = 11.9
Hz, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.72 (d, J = 11.9 Hz, 2H), 4.68 (d, J = 11.7 Hz, 2H), 4.66 (d, J =
11.9 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 4.26ꢀ4.18 (m, 2H), 3.74 (dd, J = 9.7 Hz, 8.2 Hz, 1H), 3.68
(dd, J = 9.7 Hz, 8.2 Hz, 1H), 3.58 (dd, J = 9.6 Hz, 5.7 Hz, 1H), 3.54 (dd, J = 9.7 Hz, 5.1 Hz, 1H), 2.94
(d, J = 2.2 Hz, 1H), 2.9ꢀ2.85 (m, 1H), 2.85 (d, J = 2.2 Hz, 1H), 2.83ꢀ2.78 (m, 1H), 2.32 (s, 3H), 2.23
(s, 3H), 0.19 (s, 9H), 0.08 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 138.6, 138.4, 136.4, 135.5, 135.4,
133.2, 132.4, 131.3, 130.8, 129.7, 129.6, 129.0, 128.9, 128.7, 128.36, 128.33, 128.3, 128.0, 127.7,
127.6, 127.5, 127.4, 127.0, 126.5, 125.7, 124.4, 123.9, 85.7, 85.4, 81.0, 80.9, 80.5, 79.9, 75.4, 75.3,
74.7, 73.8, 72.1, 71.9, 47.4, 46.0, 38.7, 36.6, 23.7, 22.9, –0.3, –1.5; MS (ESI): m/z 631 [M+Na]+.
HRMS (ESI): calcd for C38H44NaO3SSi: 631.2673, Found: 631.2703.
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((1S,4R,5S,6S)ꢀ4,5,6ꢀTris(benzyloxy)cyclohexꢀ2ꢀenyl)methanol (3): To a solution of sulphide 29
(25 mg, 0.04 mmol) in anhydrous CHCl3 (1 mL) cooled at ꢀ40 °C was added mCPBA (7 mg, 0.04
mmol). The reaction mixture was stirred for 30 min at same temperature. After complete
transformation of sulfide to sulfoxide, dry THF (2 mL) was added and the reaction mixture was
refluxed for 30 min. After the reaction mixture was cooled to rt aq NaHCO3 (33 mg, 1 mL) and
NaBH4 (15.5 mg, 0.4 mmol) were added and the mixture stirred for 10 min. The reaction mixture was
quenched by the addition of water and extracted with CHCl3 (3X5 mL). The combined organic layers
were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. Chromatography on
silica gel using 10ꢀ25% EtOAc/petroleum ether (v/v) as the eluent provided the homoallylic alcohol 3
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(15 mg, 0.03 mmol) in 75% yield as a colorless oil. TLC: Rf 0.2 (20% EtOAc/hexane). [α]20 = –
D
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106.1 (c 1.0, CHCl3). {lit.:{4b} For the enantiomer +104.5 (c 1.92, CHCl3)}.IR (neat): 3442, 3030,
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2878, 1454, 1359 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.4ꢀ7.25 (m, 15H), 5.76 (dt, J = 10.0 Hz, 2.4
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Hz, 1H), 5.55 (dt, J = 10.0 Hz, 1.9 Hz, 1H), 5.0 (d, J = 11.1 Hz, 1H), 4.95 (d, J = 11.1 Hz, 1H), 4.92
(d, J = 10.9 Hz, 1H), 4.70 (s, 2H), 4.66 (d, J = 11.1 Hz, 1H), 4.26ꢀ4.21 (m, 1H), 3.85 (dd, J = 9.9 Hz,
7.6 Hz, 1H), 3.68ꢀ3.63 (m, 3H), 2.52ꢀ2.45 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 138.7, 138.3,
138.2, 128.4, 128.37, 128.34, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5, 85.0, 80.7, 78.5, 75.1, 75.0,
72.0, 63.2, 45.7; MS (ESI) m/z 453 [M+Na]+. HRMS (ESI): calcd for C28H30NaO4: 453.2036, Found:
453.2041.
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((1S,2S,3S,4R,5S,6S)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ7ꢀoxabicyclo[4.1.0]heptanꢀ2ꢀyl)methanol
(30):
mCPBA (10 mg, 0.052 mmol) was added to a solution of the alkene 3 (15 mg, 0.034 mmol) in CHCl3
o
(1 mL) cooled at 0 C. The mixture was warmed to rt and stirred for overnight. The mixture was
diluted with CHCl3 (10 mL) and washed with 1N NaOH (2X10 mL) and brine. The aqueous layer was
back extracted with CHCl3 (10 mL). The combined organic layers were washed with brine, dried with
Na2SO4 and concentrated in vacuo. Chromatography on silica gel using 25ꢀ45% EtOAc/petroleum
ether (v/v) as the eluent provided epoxy alcohol 30 (12 mg, 0.02 mmol, 80%) as a crystalline white
o
solid. TLC: Rf 0.2 (40% EtOAc/hexane). M.p. 93ꢀ95 C, [α]20 = –69.3 (c 1.0, CHCl3). {Lit.:{4b} for
D
the enantiomer +71.0 (c 0.9, CHCl3)}. IR (neat): 3314, 3030, 2891, 1454, 1359, 1064 cmꢀ1. 1H NMR
(400 MHz, CDCl3): δ 7.4ꢀ7.27 (m, 15H), 4.93 (d, J = 10.8 Hz, 1H), 4.88 (d, J = 11.0 Hz, 1H), 4.84 (d,
J = 11.1 Hz, 1H), 4.80 (d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.3 Hz, 1H), 4.55 (d, J = 11.0 Hz, 1H), 3.96
(dd, J = 10.7 Hz, 4.4 Hz, 1H), 3.89ꢀ3.83 (m, 2H), 3.59 (dd, J = 10.0 Hz, 8.0 Hz, 1H), 3.46 (t, J = 10.0
Hz, 1H), 3.34 (d, J = 3.6 Hz, 1H), 3.16 (d, J = 3.7 Hz, 1H), 2.20ꢀ2.14 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ 138.5, 138.0, 137.5, 128.53, 128.51, 128.3, 128.1, 127.9, 127.8, 127.7, 127.5, 84.9, 79.8,
75.5, 75.3, 73.1, 62.7, 55.8, 52.9, 43.9; MS (ESI): m/z 469 [M+Na]+. HRMS (ESI): calcd for
C28H30NaO5: 469.1985, Found: 469.1992.
(1R,4R,5S,6S)ꢀ4,5,6ꢀTris(benzyloxy)cyclohexꢀ2ꢀenol (31): Compound 31 was prepared following
the procedure detailed for the preparation of allylic alcohol 24 from 23 (50 mg, 0.13 mmol). TLC: Rf
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0.2 (20% EtOAc/hexane). [α]20D = –103.8 (c 1.0, CHCl3). {Lit.:{4b} –116.0 (c 1.87, CHCl3)}. IR (neat):
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3448, 3087, 3062, 3030, 2864, 1469, 1453, 1202, 1088, 1073, 1027, 952, 910, 735, 697 cmꢀ1. H
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9
NMR (500 MHz, CDCl3): δ 7.4ꢀ7.27 (m, 15H), 5.72 (dt, J = 10.3 Hz, 2.1 Hz, 1H), 5.67 (dt, J = 10.3
Hz, 1.8 Hz, 1H), 5.02 (d, J = 11.4 Hz, 1H), 4.91 (s, 2H), 4.71 (d, J = 11.4 Hz, 1H), 4.70 (s, 2H), 4.34ꢀ
4.29 (m, 1H), 4.28ꢀ4.23 (m, 1H), 3.78 (dd, J = 10.3 Hz, 7.6 Hz, 1H), 3.53 (dd, J = 10.2 Hz, 7.9 Hz,
1H), 2.17 (d, J = 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 138.5, 138.1, 129.3, 128.5, 128.4, 128.3,
127.9, 127.8, 127.7, 127.6, 126.9, 84.2, 83.2, 80.5, 75.2, 72.2, 71.8; MS (ESI): m/z 439 [M+Na]+.
HRMS (ESI): calcd for C27H28NaO4: 439.188, Found: 439.1902.
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Tributyl(((1R,4R,5S,6S)ꢀ4,5,6ꢀtris(benzyloxy)cyclohexꢀ2ꢀenyloxy)methyl)stannane
(32):
Potassium hydride (10 mg, 0.24 mmol, 30% suspension in mineral oil) was washed with anhydrous
hexane (2X1 mL) and suspended in THF (2.5 mL) at 0 °C. The alcohol 31 (50 mg, 0.12 mmol) was
added slowly as a solution in THF (1 mL) and the mixture was warmed to rt. After 30 min, the
o
mixture was cooled to 0 C and iodomethyltributyltin (80 mg, 0.18 mmol) was added. The mixture
was warmed to rt. After 4 h, aq ammonium chloride (3 mL) was added and the mixture was extracted
with diethyl ether (2X15 mL). The combined organic layers were washed with brine (10 mL), dried
over Na2SO4 and concentrated in vacuo. Chromatography on silica gel using 2ꢀ5% EtOAc/petroleum
ether (v/v) provided the tributylstannylmethylether 32 (70 mg, 80%) as a colorless oil. TLC: Rf 0.4
(5% EtOAc/hexane). [α]20D = –86.8 (c 1.0, CHCl3). {Lit.:{4b} –83.9 (c 1.32, CHCl3)}. IR (neat): 2924,
1454, 1368, 1221, 1067, 952, 910, 735 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.4ꢀ7.25 (m, 15H), 5.79
(dt, J = 10.3 Hz, 1.9 Hz, 1H), 5.72 (dt, J = 10.2 Hz, 1.8 Hz, 1H), 4.94 (d, J = 11.0 Hz, 1H), 4.88 (d, J
= 11 Hz, 1H), 4.83 (d, J = 10.5 Hz, 2H), 4.73 (d, J = 11.6 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.23ꢀ
4.17 (m, 1H), 3.97ꢀ3.91 (m, 1H), 3.93 (d, J = 9.6 Hz, 1H), 3.77 (d, J = 9.6 Hz, 1H), 3.72 (dd, J = 10.3
Hz, 7.7 Hz, 1H), 3.64 (dd, J = 10.3 Hz, 7.4 Hz, 1H), 1.56ꢀ1.46 (m, 6H), 1.36ꢀ1.23 (m, 6H), 0.95ꢀ0.90
(m, 6H), 0.88 (t, J = 7.3 Hz, 9H); 13C NMR (75 MHz, CDCl3): δ 138.9, 138.8, 138.4, 128.3, 128.25,
128.22, 127.9, 127.79, 127.78, 127.6, 127.45, 127.41, 127.3, 85.1, 83.4, 83.0, 80.0, 75.5, 75.2, 72.4,
59.9, 29.1, 27.2, 13.6, 8.9; MS (ESI): m/z 743 [M+Na]+. HRMS (ESI): calcd for C40H56NaO4Sn:
743.3093, Found: 743.3109.
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((1R,4S,5R,6R)ꢀ4,5,6ꢀTris(benzyloxy)cyclohexꢀ2ꢀenyl)methanol (entꢀ3): nꢀButyl lithium (0.10 mL,
2.0 M in hexanes, 0.2 mmol) was added to a solution of the stannylmethyl ether 32 (50 mg, 0.07
mmol) in THF (1.5 mL) cooled at –78 °C. After 1 h, the reaction was quenched with aq saturated
ammonium chloride (3 mL), warmed to room temperature, and extracted with diethyl ether (3X10
mL). The organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in
vacuo. Chromatography on silica gel 10ꢀ25% EtOAc/petroleum ether (v/v) provided the homoallylic
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alcohol entꢀ3 (25 mg, 85%) as a colorless oil. TLC: Rf 0.2 (20% EtOAc/hexane). [α]20 = +106.3 (c
D
1
1.0, CHCl3). {Lit.:{4b} +104.5 (c 1.92, CHCl3)}. IR (neat): 3442, 3030, 2878, 1454, 1359 cmꢀ1. H
NMR (400 MHz, CDCl3): δ 7.4ꢀ7.25 (m, 15H), 5.76 (dt, J = 10 Hz, 2.4 Hz, 1H), 5.55 (dt, J = 10 Hz,
1.9 Hz, 1H), 5.0 (d, J = 11.1 Hz, 1H), 4.95 (d, J = 11.1 Hz, 1H), 4.92 (d, J = 10.9 Hz, 1H), 4.70 (s,
2H), 4.66 (d, J = 11.1 Hz, 1H), 4.26ꢀ4.21 (m, 1H), 3.85 (dd, J = 9.9 Hz, 7.6 Hz, 1H), 3.68ꢀ3.63 (m,
3H), 2.52ꢀ2.45 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 138.7, 138.3, 138.2, 128.4, 128.37, 128.34,
128.2, 128.1, 127.86, 127.82, 127.6, 127.5, 85.0, 80.7, 78.5, 75.1, 75.0, 72.0, 63.2, 45.7; MS (ESI):
m/z 453 [M+Na]+. HRMS (ESI): calcd for C28H30NaO4: 453.2036, Found: 453.2041.
((1R,2R,3R,4S,5R,6R)ꢀ3,4,5ꢀTris(benzyloxy)ꢀ7ꢀoxabicyclo[4.1.0]heptanꢀ2ꢀyl)methanol (33)
:
Compound 33 was prepared following the procedure detailed for the preparation of compound 30
from 3 (15 mg, 0.034 mmol). TLC: Rf 0.2 (40% EtOAc/hexane). M.p. 93ꢀ95 oC, [α]20D = +69.3 (c 1.0,
CHCl3). {Lit.:{4b} +71.0 (c 0.9, CHCl3)}.
tertꢀButyl (1R,4R,5S,6S)ꢀ4,5,6ꢀtris(benzyloxy)cyclohexꢀ2ꢀenylcarbamate (34): To
a stirred
suspension of NaNBocCl (35 mg, 0.19 mmol) in dry acetonitrile (0.5 mL) was added a solution of the
sulfide 28 (20 mg, 0.038 mmol) in dry acetonitrile (0.5 mL) at rt and the mixture stirred at rt for 6 h.
The reaction mixture was diluted with EtOAc (10 mL), washed with water, brine and dried over
Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product which was
used for next step without purification.
To a stirred solution of the above crude compound (20 mg, 0.03 mmol) in MeOH (1
mL) was added NaBH4 (10 mg, 0.3 mmol) at 0 oC under nitrogen atmosphere. After being stirred for
30 min the reaction mixture was quenched with water and extracted with EtOAc (2X10 mL). The
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organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo.
Chromatography on silica gel using 5ꢀ15% EtOAc/petroleum ether (v/v) as the eluent provided the
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compound 34. TLC: Rf 0.33 (20% EtOAc/hexane). [α]20 = –30.1 (c 0.62, CHCl3). IR (neat): 3448,
D
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3029, 2924, 2855, 1685, 1526, 1251, 755, 696 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.37ꢀ7.27 (m,
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15H), 5.70 (dt, J = 10.2 Hz, 2.3 Hz, 1H), 5.60 (dt, J = 10.2 Hz, 1.8 Hz, 1H), 4.89 (d, J = 10.6 Hz, 1H),
4.88 (d, J = 10.6 Hz, 1H), 4.83 (d, J = 11.1 Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.69 (d, J = 10.2 Hz,
1H), 4.66 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 8.5 Hz, ꢀNH), 4.34ꢀ4.25 (m, 1H), 4.2ꢀ4.16 (m, 1H), 3.81
(dd, J = 9.5 Hz, 7.3 Hz, 1H), 3.53 (t, J = 9.2 Hz, 1H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): δ
155.3, 138.5, 138.2, 129.2, 128.39, 128.36, 128.1, 127.9, 127.8, 127.7, 127.6, 126.9, 83.4, 81.1, 81.0,
79.4, 75.1, 74.8, 72.1, 28.3; MS (ESI): m/z 538 [M+Na]+. HRMS (ESI): calcd for C32H37NNaO5:
538.2564, Found: 538.2556.
Acknowledgements
Ravi Kumar Ch. is thankful to CSIR for SRF fellowship. S.R. acknowledges funding from
DST (SR/S1/OCꢀ5/2011) and CSIR, New Delhi as a part of the XII five year plan programme
under the title ORIGIN (CSCꢀ108).
1
Supporting Information: Copies of H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(3) (a) Li, K. Y.; Jiang, J.; Witte, M. D.; Kallemeijn, W. W.; Elst, H. V. D.; Wong, C. S.;
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to compound 5 is further supported by the J value observed for CHSPh resonating at δ 3.75
(dd, J = 8.5 Hz, 2.4 Hz) in compound 13 resulting from ringꢀclosing metathesis. The
preferred halfꢀchair conformation of 13, depicted in Scheme 2, would explain the 8.5 Hz
diaxial coupling observed with CHOTBS and 2.4 Hz coupling observed with the olefinic
proton resonating at δ 5.72 (dt, J = 10.3 Hz, 2.4 Hz). Alternately, if the diastereomeric anti βꢀ
siloxy sulfide were obtained in lieu of diene 5 from sulfide 6, the observed J values for
CHSPh in 13 cannot be rationalized since an axialꢀequatorial coupling (3ꢀ4 Hz) with
CHOTBS only would be expected.
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(16) In yet another experiment an intramolecular displacement of bromide by the anion
derived from the malonate derivative was attempted only to recover unreacted starting
material. For a precedent see: (a) Begley, M. J.; Madeley, J. P.; Pattenden, G.; Smith, G. F. J.
Chem. Soc. Perkin Trans. 1, 1992, 57. (b) Corey, E. J.; Das, J. S. Tetrahedron Lett. 1982, 23,
4217. (c) Corey, E. J.; Das, J. S. J. Am. Chem. Soc. 1982, 104, 5551.
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(18) Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org. Lett. 2007, 9, 4603. It is
noteworthy that the rearrangement in the absence of BHT afforded the rearranged primary
allylic sulfide.
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(19) (a) Aggarwal, V. K.; Ferrara, M.; Hainz, R.; Spey, S. E. Tetrahedron Lett. 1999, 40,
8923. (b) Carter, D. S.; Van Vranken, D. L. Tetrahedron Lett. 1999, 40, 1617. c) Carter, D.
S.; Van Vranken, D. L. Org. Lett. 2000, 2, 1303.
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(20) Kocienski, P. Tetrahedron Lett. 1980, 21, 1559.
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(21) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(22) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927.
(23) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1980, 45, 2710.
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