Stereoselective formal synthesis of (-)-fumagillol

Article abstract of DOI:10.1016/j.tet.2017.05.090

A formal synthesis of fumagillol, a congener of fumagillin that possesses varied biological activity, is disclosed. Initial attempts at preparing an allylic sulfide via an α-chloro sulfide met with failure. The successful route involves a carbonyl-ene reaction, one-pot stannyl cupration, methylation of resulting alkenyl copper and further Stille-coupling of the alkenyl stannane as the key steps.

Full text of DOI:10.1016/j.tet.2017.05.090

Accepted Manuscript
Stereoselective formal synthesis of (-)-fumagillol
Sadagopan Raghavan, Mahesh Kumar Rao Yelleni
PII:
S0040-4020(17)30599-9
10.1016/j.tet.2017.05.090
TET 28756
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 April 2017
Revised Date: 29 May 2017
Accepted Date: 30 May 2017
Please cite this article as: Raghavan S, Yelleni MKR, Stereoselective formal synthesis of (-)-fumagillol,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.090.
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ACCEPTED MANUSCRIPT
Graphics for TOC
H
O
O
H
O
MOMO
H
OTBDPS
O
O
H
H
OMe
OMOM
OMe
OMe
O
O
OH
A stereoselective formal synthesis of fumagillol is disclosed. The key steps include stereoselective
carbonyl-ene reaction, Barton-McCombie radical deoxygenation, one-pot stannyl cupration of an
alkyne, methylation of the resultant alkenyl copper and further Stille-coupling of the alkenyl stannane.

ACCEPTED MANUSCRIPT
Stereoselective Formal Synthesis of (-)-Fumagillol
Sadagopan Raghavan*a,b, Mahesh Kumar Rao Yellenia,b
aNatural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, India,
bAcademy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India.
Email:sraghavan@iict.res.in
Abstract: A formal synthesis of fumagillol, a congener of fumagillin that possesses varied biological
activity, is disclosed. Initial attempts at preparing an allylic sulfide via an α-chloro sulfide met with
failure. The successful route involves a carbonyl-ene reaction, one-pot stannyl cupration, methylation
of resulting alkenyl copper and further Stille-coupling of the alkenyl stannane as the key steps.
Introduction
Fumagillin 1 was isolated in 1949 by Elbe and Hanson1 from the fungus Aspergillus fumigatus. It
was originally shown to display antibiotic activity, later it was found to be useful for the treatment of
nosema disease in honey bees, amoebiasis in humans,2 microsporidial keratoconjunctivitis3 of the eye,
malaria, leishmania4 and microsporidiosis in HIV-infected patients.5 Folkmann and co-workers
discovered the notable capacity of fumagillin 1 to inhibit angiogenesis in tumor cells.6 This activity was
hypothesized to be related to the inhibition of endothelial cell proliferation as a result of binding and
inhibiting methionine aminopeptidase type 2 (metAP-2).7, 8
1
O
2
H
3
O
7
5
H
OMe
OR
O
OH
R =
R =
Fumagillin (1)
Fumagillol (2)
4
O
H
Figure 1. Structure of Fumagillin and its Congener, Fumagillol.
1

ACCEPTED MANUSCRIPT
Fumagillin has a highly functionalized cyclohexane ring and five contiguous chiral centers. Due
to its varied biological activity and its rare carbon skeleton a number of synthetic studies have been
reported both for fumagillin and fumagillol.9 Herein, we describe initially, our frustrated attempts to
prepare an allylic sulfide from an α-chloro sulfide, envisioned as a key intermediate to fumagillol and
later a successful route taking advantage of an intramolecular carbonyl-ene reaction resulting in the
formal synthesis of fumagillol. The original retrosynthetic disconnection is depicted in Scheme 1.
Me3Si
X
2
O
H
4
8
O
H
OMe
6
PhS
PhS
O
OMe
OMe
OH
OP
OP
2
3
4
I
SnBu3
SiMe3
MgBr
4
O
+
6
+
PO
PO
OH
OH
5
8
6
7
X = Leaving group
P = Protecting group
Scheme 1. Retrosynthetic Disconnection of Fumagillol.
Fumagillol was envisioned to be obtained from allylic sulfoxide 3 by [2,3] sigmatropic
rearrangement to introduce the hydroxyl at C3 (fumagillol numbering) followed by introduction of the
epoxide moieties. The cyclohexene 3 was expected to be obtained by a ring-closing metathesis of
tetraene 4. Compound 4 was envisaged to be obtained by the regioselective opening of epoxide 5 at C4
(fumagillol numbering) by Grignard reagent 6 and eventually from the chloro sulfide derived from the
primary hydroxyl at C7 in the ensuing product. Epoxide 5 itself was imagined to be obtained by
coupling stannane 7 and iodo alkene 8 followed by Sharpless' asymmetric epoxidation.
2

ACCEPTED MANUSCRIPT
The synthesis began with the preparation of stannane 7, from aldehyde 9 in four steps, following
the procedure reported in the literature,10 without incident. The enyne 12, obtained by a copper catalyzed
addition11 of lithio propyne with prenyl bromide, on regioselective hydrozirconation12 followed by
iodine quench yielded iodo alkene 8. Stille-coupling13 of stannane 7 and iodo alkene 8 proceeded in
good yield to afford the trienol 13. Attempted Sharpless' epoxidation14 however, failed to yield any of
o
o
the desired epoxide 5, no reaction was observed at -20 C and on rising the temperature to 0 C, a
complex mixture resulted after an extended period of time, Scheme 2. It is reasonable to assume that the
adjoining trisubstituted alkene probably hinders the approach of the reagent to the substrate at low
temperature and probably, after the epoxide was formed at higher temperature, Lewis acid promoted
opening of the epoxide results in a complex mixture. Having been unsuccessful in preparing the epoxide
5, it was decided to introduce the side chain at C4 late in the synthesis. By a revised analysis, the retron
24, resembling 4, possessing a hydroxymethyl residue in the place of the dienyl side chain was
envisaged as the key intermediate.
SnBu3
O
Ref. 10
PMBO
PMBO
H
OH
9
7
BuLi, CuI, THF
Br
Cp2ZrHCl, THF
I
10
Then I2 quench
70%
12
8
86%
SnBu3
Pd(PPh3)4
Ti(OiPr)4,
tBuOOH,
(-)-DET
Complex
mixture
CsF, DMF
RT, 73%
PMBO
+
PMBO
I
7
8
13
OH
OH
DCM
Scheme 2. Attempted Synthesis of Diene Epoxide 5.
3

ACCEPTED MANUSCRIPT
The synthesis following a revised strategy began with (D)-glyceraldehyde acetonide15 14 which
was converted by a two step sequence into alcohol 16. Sharpless asymmetric epoxidation afforded
epoxide 1715 that on treatment with 2-propenylmagnesium bromide16 in the presence of CuBr.Me2S
yielded diol 18, Scheme 3. Selective protection of the primary hydroxyl as its silyl ether afforded
compound 19. Deprotection of the acetonide using CuCl217 yielded the triol 20 which was converted to
tosylate 21. Protection of diol as its acetonide furnished compound 22. Displacement of the tosylate by
sodium thiophenoxide in anhydrous DMF afforded sulfide 23.18 Reaction of sulfide 23 with N-
chlorosuccinimide in benzene yielded the α-chloro sulfide which without isolation was reacted with
vinylzinc bromide only to obtain a complex mixture of products and none of the desired diene 24.
BrMg
(-)-DET
Ti(O Pr)
O
O
O
CuBr.Me2S
PPh3CHCO2Et
i
4
O
OH
Ether, -30 oC,
87%
O
O
H
PhH, 80 oC, 83%
tBuOOH
M.S 4Å
DCM, 79%
R
O
O
15, R = CO2Et
16, R = CH2OH
17
14
DIBAL-H
DCM, 92%
OMe
OMe
O
OTBDPS
O
OH
PO
CuCl2.2H2O
CH3CN, 0 oC
O
OP
OTBDPS
P
CSA, DCM
92%
79%
OH
OH
O
18, P = H
Imidazole,
TBDPSCl,
DCM, 98%
20, P = H
21, P = Ts
Et3N, TsCl
22, P = OTs
23, P = SPh
DBTO,
DCM
19, P = TBDPS
PhSH, NaH
DMF, 82%
87%
Complex Mixture
NCS, PhH
ZnBr THF
OTBDPS
PhS
O
O
24
Scheme 3. Attempted Synthesis of Allylic Sulfide 24.
4

ACCEPTED MANUSCRIPT
A subsequent attempt was made to prepare the allylic sulfide following Takeda's protocol19 by a
Ni(0)-catalysed reaction of an allylic acetate with thiophenol. The requisite substrate was prepared as
detailed in Scheme 4. Acetonide 19 was converted to the methyl ether 25 under standard conditions.
Deprotection of the acetonide afforded diol 26 that was converted to the MOM ether 27 in a one-pot
operation by selective protection of the primary hydroxyl using TBSOTf and further treatment of the
ensuing silyl ether with MOM-Cl in the presence of Hunig's base. Selective deprotection of the primary
TBS ether with TBAF buffered with acetic acid afforded alcohol 28, that was oxidized to aldehyde 29
using DMP.20 Reaction of aldehyde 29 with vinylmagnesium bromide proceeded with poor
diastereoselectivety to furnish allylic alcohols 30 and 31 in nearly equimolar ratio. The structure was
assigned to alcohols 30 and 31 following Trost’s protocol21 by preparation of α-methoxyphenylacetic
esters. We decided to address the issue of poor stereoselectivety in the addition to the aldehyde after
securing the allylic sulfide 33. Thus alcohol 31 was converted to acetate 32 and subjected to treatment
with PhSH in the presence of Ni[P(OEt)3]4 in the presence of 2,6-di-tert-butyl phenol. The allylic sulfide
33 was not obtained, after prolonged reaction time, only the hydrolyzed alcohol 31 could be isolated.
Thus our attempts at securing the allylic sulfide were frustrated again.
P2O
O
MOMO
R
TBAF, AcOH
THF, 89%
P1O
OTBDPS
CuCl2.2H2O
CH3CN, 0 oC
84%
OTBDPS
O
OTBDPS
OMe
OMe
OP
19, P = H
TBSOTf, DCM
2,6-Lutidine
28, R = CH2OH
29, R = CHO
26, P1 = P2 = H
DMP, NaHCO3
DCM, 92%
NaH, MeI
THF, 92%
-78o C
DIPEA, MOMCl
TBAI, -78 oC - RT
89%
25, P = Me
27, P1 = TBS, P2 = MOM
, THF
MOMO
MgBr
0 oC
MOMO
HO
MOMO
Ni[P(OEt)3] 4
OTBDPS
OTBDPS
OTBDPS
OMe
+
OMe
43%
OMe
HO
THF+DMF (2:1) PhS
40%
31, P = H
33
30
Ac2O
Not obtained
Et3N, DMAP,
DCM, rt, 94%
32, P = Ac
Scheme 4. Attempted Route for the Synthesis of Allylic Sulfide 33.
5

ACCEPTED MANUSCRIPT
In our attempts to improve the selectivity in the preparation of allylic alcohol 31, MgBr2 was
introduced to chelate the aldehyde carbonyl and the MOM ether groups. Addition of vinylmagnesium
bromide to aldehyde 29 in the presence of MgBr2 did not afford the alcohol 31 but the cyclohexenol 34
by an intramolecular carbonyl-ene reaction thus opening a way to fumagillol quite by an accident.
Although a single isomer was obtained, the structure of 34 was not rigorously established since the
carbinol stereocenter was to be destroyed subsequently.22 The alcohol was converted to xanthate 35 and
radical deoxygenation23 with nBu3SnH and catalytic AIBN afforded cyclohexene 36. Deprotection of
silyl ether using TBAF furnished alcohol 37, Scheme 5. Hydroxyl directed epoxidation with mCPBA
proceeded stereoselectively24 to furnish epoxide 38. Oxidation of alcohol to aldehyde 39 using DMP
proceeded cleanly. Subjecting aldehyde 39 to reaction with Ohira-Bestmann reagent25 in the presence of
NaOMe furnished alkyne 40 cleanly. Attempted carboalumination using Negishi’s protocol26 did not
yield the desired product but the chlorohydrin 41.
MOMO
H
MgBr2
THF, 0 oC, 89%
OTBDPS
OP
Bu3SnH, AIBN
OTBDPS
Toluene, reflux
84%
PO
OMe
OMOM
OMe
OMOM
OMe
29
O
36, P = TBDPS
34, P = H
NaH, CS2, MeI,
THF, 0 oC-RT,
86%
TBAF,
THF, 94%
37, P = H
35, P = C(S)SMe
Cl
O
O
O
H
O
OH
H
P(OMe)2
R
mCPBA, DCM,
0 oC, 87%
N2
Me3Al, Cp2ZrCl2
DCE, 55%
NaOMe, THF
-78 oC - RT, 75%
OMe
OMe
OMOM
40
OMe
OMOM
OMOM
41
38, R = CH2OH
DMP, NaHCO3
DCM, 93%
39, R = CHO
Scheme 5. Attempted Synthesis of a Trisubstituted Alkene by Carboalumination.
Stannyl cupration could however, be effected by the Lipshutz protocol,27 treatment of the
resulting alkenyl copper with MeI afforded the trisubstituted alkenyltin derivative which was subjected
6

ACCEPTED MANUSCRIPT
28
to Stille-coupling with allyl bromide in the presence of Pd(PPh3)4 to yield the diene 42 in 71% yield.
Deprotection of MOM ether, achieved using TMS-Br at low temperature, followed by treatment of the
crude product with K2CO3 afforded alcohol 43 which has been prepared by Kim and co-workers29 en
route to fumagillol and thus completing the formal synthesis of fumagillol, Scheme 6.
O
H
Me
O
CuCN, BuLi
Me
O
i) TMSBr, DCM, -
78 oC, 30 min
Bu3SnH, THF
-78 oC, MeI, DMPU
ref 29
(-)-2
then add allyl
bromide, (PPh3)4Pd
rt, 3d, 71%
OMe
ii) K2CO3, MeOH,
0 oC, 76%
OMe
OMe
OMOM
40
OMOM
42
OH
43
Scheme 6. Formal Synthesis of Fumagillol.
Conclusion
In summary, a stereoselective route to fumagillol was developed. The key steps of the synthesis
include the C-C bond formation using intramolecular carbonyl-ene reaction to construct cyclohexane
framework, Ohira-Bestmann reaction, stannyl cupration, methylation and Stille-coupling reaction to
introduce the side chain. Attempts to prepare an allylic sulfide from an allylic acetate by a Ni-catalyzed
reaction and from a sulfide via the chloro sulfide did not fructify.
Experimental procedure
The stannane 7 was prepared following a reported procedure.10
(S,E)-Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (15): To a stirred solution of diacetonide
derivative of D-Mannitol (2 g, 8 mmol) in DCM (40 mL) cooled to 0 oC was added NaHCO3 (1.3 g, 16
mmol) and NaIO4 (3.4 g, 16 mmol). The reaction mixture was stirred for 2 h at the same temperature, the
solids were filtered and the filtrate was washed with water. The aq layer was extracted with DCM (3x20
mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude aldehyde 14 (2 g,
16 mmol) was reacted with (ethoxycarbonylmethyl)triphenylphosphonium bromide (6.78 g, 16 mmol)
in refluxing benzene (53 mL) for 12 h. The solvent was evaporated and the crude mixture was washed
7

ACCEPTED MANUSCRIPT
with 15% ethyl acetate/hexane (v/v) to precipitate triphenylphosphine oxide. The filtrate was evaporated
in vacuo and the residue was purified by column chromatography using 10% ethyl acetate/hexane (v/v)
to give pure compound 15 (2.64 g, 13.2 mmol) in 83% yield as a liquid. TLC: Rf 0.6 (8:2, hexanes:ethyl
acetate). IR (neat): 2986, 2934, 1720, 1261, 1216, 1061 cm-1. 1H NMR (500 MHz, CDCl3): δ 6.86 (dd, J
= 15.5, 5.6 Hz, 1H), 6.08 (dd, J = 15.5, 1.4 Hz, 1H), 4.67-4.62 (m, 1H), 4.21-4.15 (m, 3H), 3.66 (dd, J =
13
8.2, 7.1 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ
165.7, 144.4, 122.1, 109.9, 74.7, 68.5, 60.3, 26.2, 25.5, 13.9. MS (ESI): m/z 223 [M+Na]+.
(S,E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)prop-2-en-1ol (16): To a solution of ester 15 (2.6 g, 13
mmol) in DCM (43 mL) cooled to -78 oC was added DIBAL-H (1.2 M in toluene, 23.8 mL, 28.6 mmol).
The reaction mixture was stirred at the same temperature for 1h and then quenched with aq saturated
sodium potassium tartarate (25 mL). The temperature was warmed to rt and stirring continued for 1 h.
The layers were separated and the aq layer was extracted with DCM (3x25 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography
using 20% ethyl acetate/hexane (v/v) to give pure compound 16 in 92% yield (1.89 g, 12 mmol) as a
pale yellow liquid. TLC: Rf 0.3 (8:2, hexanes:ethyl acetate). IR (neat): 3413, 2988, 2934, 2875, 1154,
1
1099, 1058 cm-1. H NMR (500 MHz, CDCl3): δ 5.98-5.9 (m, 1H), 5.73-5.66 (m, 1H), 4.55-4.48 (m,
1H), 4.14 (d, J = 5.0 Hz, 2H), 4.08 (dd, J = 8.1, 6.2 Hz, 1H), 3.5 (dd, J = 8.1, 7.1 Hz, 1H), 2.0-1.88 (brt,
1H), 1.41 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 133.3, 127.3, 108.8, 76.0, 68.7, 61.4,
26.1, 25.3; MS (ESI):m/z 181 [M+Na]+. HRMS (ESI): calcd for C8H14O3Na: 181.0835, found: 181.0829.
((2R,3S)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)oxiran-2-yl)methanol (17): A suspension of finely
powdered activated molecular sieves (4Å, 1.9 g) in anhydrous DCM (80 mL) maintained under nitrogen
atmosphere was cooled to -20 oC. Neat Ti(OiPr)4 (3.57 mL, 11.8 mmol) and a solution of D-(-)-diethyl
tartrate (2.2 mL, 13 mmol) in anhydrous DCM (13 mL) were added successively. The mixture was
stirred for 20 min and allylic alcohol 16 (1.86 g, 11.8 mmol) in anhydrous DCM (12 mL) was added
8

ACCEPTED MANUSCRIPT
over 15 min. After stirring for 30 min a solution of tert-butyl hydroperoxide (5 M in toluene, 3.5 mL,
o
17.7 mmol) was added dropwise. The mixture was maintained at -20 C overnight. The reaction was
quenched by adding an aq solution of FeSO4.7H2O (2 g) and tartaric acd (1.2 g) in water (20 mL) at 0
oC. After stirring for 10 min the mixture was filtered and the residue was washed with DCM (25 mL).
The filtrate was separated and the aq layer was extracted with DCM (3x50 mL). The combined organic
layers were stirred at 0 oC for 1 h with 30% NaOH (w/v) solution in saturated brine (10 mL), after which
the layers were separated and the aq layer was washed with ether (3x20 mL). The combined organic
layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography
using 30% ethyl acetate/hexane (v/v) to give pure compound 17 (1.6 g, 9.3 mmol) in 79% yield as a pale
yellow liquid. TLC: Rf 0.3 (7:3, hexanes:ethyl acetate). IR (neat): 3449, 2988, 2927, 1152, 1060 cm-1.
1H NMR (500 MHz, CDCl3): δ 4.12 (dd, J = 8.2, 6.2 Hz, 1H), 3.98-3.93 (m, 2H), 3.9 (dd, J = 8.2, 5.6
Hz, 1H), 3.67 (ddd, J = 12.5, 6.2, 4.1 Hz, 1H), 3.12-3.07 (m, 2H), 1.89 (br, 1H), 1.44 (s, 3H), 1.36 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 109.6, 75.0, 66.5, 60.9, 57.0, 55.1, 26.2, 24.9; MS (ESI): m/z 197
[M+Na]+. HRMS (ESI): calcd for C8H14O4Na: 197.0784, found: 197.0777.
(1S,2S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(prop-1-en-2-yl)propane-1,3-diol (18): A freshly
prepared solution of isopropenylmagnesium bromide in THF (1.0 M, 78.3 mL) was added over a period
of 20 min to a slurry of CuBr.Me2S (6.4 g, 31.2 mmol) in anhydrous ether (120 mL) cooled to -50 °C.
The mixture was stirred for 10 min at -20 °C, after which time a solution of the epoxide 17 (1.56 g, 9
mmol) in anhydrous ether (37 mL) was added over a period of 10 min. The mixture was stirred at -20 °C
for 36 h. The reaction mixture was quenched by adding aq saturated aqueous NH4Cl (37 mL) and brine
(18 mL). The layers were separated and the aq layer was extracted with ether (3x30 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column
chromatography to yield the diol 18 as white crystals (1.69 g, 7.83 mmol) in 87% yield. TLC: Rf 0.25
(7:3, hexanes:ethyl acetate). [α]25D = +21 (c, 1, CHCl3); mp 50-51oC; IR (neat): 3413, 2984, 2926, 1156,
9

ACCEPTED MANUSCRIPT
1064 cm-1. 1H NMR ( 500 MHz, CDCl3): δ 4.94-4.92 (brs, 1H), 4.84-4.82 (brs, 1H), 4.16-4.06 (m, 2H),
3.98-3.94 (m, 2H), 3.92 (dd, J = 9.1, 8.0 Hz, 1H), 3.71-3.65 (m, 1H), 2.23-2.17 (m, 1H), 1.73 (s, 3H),
1.43 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 142.3, 114.2, 108.7, 76.5, 71.9, 64.3, 63.5,
50.7, 26.2, 25.0, 20.9; MS (ESI): m/z 239 [M+Na] +. HRMS (ESI): calcd for C11H20O4Na: 239.1253,
found: 239.1242.
(1S,2S)-2-((tert-Butyldiphenylsilyloxy)methyl)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
methylbut-3-en-1-ol (19): To a solution of compound 18 (1.66 g, 7.7 mmol) in anhydrous DCM (30
mL) cooled to 0 °C was added imidazole (1.04 g, 15.4 mmol) followed by TBDPS-Cl (2 mL, 7.7 mmol).
The reaction mixture was warmed to rt and stirred for 10 h. The reaction mixture was quenched by the
addition of water (10 mL) and diluted with DCM (20 mL). The layers were separated and the organic
layer was washed with water (20 mL), brine (20 mL) and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford the crude product which was purified by column
chromatography using 10% ethyl acetate/hexane (v/v) to give pure TBDPS ether 19 (3.42 g, 7.54
mmol) in 98% yield as a gummy oil. TLC: Rf 0.4 (9:1 hexanes:ethyl acetate). [α]25 = +42 (c, 0.6,
D
CHCl3), IR (neat): 3485, 3071, 2932, 2860, 1157, 1109, 1061 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.7-
7.64 (m, 4H), 7.45-7.36 (m, 6H), 4.89 (s, 1H), 4.84 (s, 1H), 4.15-4.05 (m, 2H), 4.2 (ddd, J = 8.3, 4.1, 3.0
Hz, 1H), 3.98-3.92 (m, 2H), 3.87 (dd, J = 10.2, 5.8 Hz, 1H), 3.0 (d, J = 2.9 Hz, 1H), 2.2-2.16 (m, 1H),
1.7 (s, 3H), 1.42 (s, 3H), 1.32 (s, 3H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 143.3, 135.6, 133.1,
129.7, 127.6, 114.1, 108.7, 76.9, 71.0, 64.4, 64.4, 50.5, 26.8, 26.4, 25.3, 21.3, 19.1; MS (ESI): m/z 477
[M+Na]+. HRMS (ESI): calcd for C27H38O4NaSi: 477.2431, found: 477.2405.
tert-Butyl((S)-2-((S)-2-((S)-((R)-2,2-dimethyl-1,3-dioxalan-4-yl)(methoxy)methyl)-3-methylbut-3-
enyloxy)diphenylsilane (25): A solution of compound 19 (2.95 g, 6.5 mmol) in anhydrous THF (13
mL) was added dropwise to a suspension of NaH (60% in Nujol, 312 mg, 7.8 mmol) in anhydrous THF
(13 mL) maintained at 0 oC. After stirring at rt for 1 h the mixture was cooled to 0 oC and MeI (0.8 mL,
10

ACCEPTED MANUSCRIPT
13 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 12 h. The reaction
mixture was quenched with aq saturated NH4Cl solution (10 mL). The layers were separated and the aq
layer was extracted with EtOAc (3x10 mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was purified by column chromatography using 8% ethyl acetate/hexane (v/v)
to give pure compound 25 (2.8 g, 6 mmol) in 92% yield as a liquid. TLC: Rf 0.5 (9:1 hexanes:ethyl
1
acetate). [α]25 = +35 (c, 0.5, CHCl3), IR (neat): 3070, 2932, 2859, 1106 cm-1. H NMR (500 MHz,
D
CDCl3): δ 7.7-7.64 (m, 4H), 7.44-7.34 (m, 6H), 4.9 (s, 1H), 4.79 (s, 1H), 4.17 (td, J = 7.0, 3.2 Hz, 1H),
3.94-3.87 (m, 2H), 3.84 (d, J = 5.6 Hz, 2H), 3.63 (dd, J = 8.8, 3.2 Hz, 1H), 3.45 (s, 3H), 2.15 (dt, J =
8.8, 5.6 Hz, 1H), 1.67 (s, 3H), 1.42 (s, 3H), 1.27 (s, 3H), 1.2 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
143.8, 135.5, 133.5, 129.4, 127.4, 113.8, 108.4, 79.2, 77.3, 64.3, 62.9, 60.7, 51.4, 26.8, 26.1, 25.4, 21.4,
19.1; MS (ESI): m/z 491 [M+Na] +. HRMS (ESI): calcd for C28H40O4NaSi: 491.2588, found: 491.2564.
(2R,3S,4S)-4-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-5-methylhex-5-ene-1,2-diol
(26):
Acetonide 25 (2.76 g, 5.9 mmol) was deprotected following the same procedure detailed for the
preparation of 20 to afford diol 26 (2.12 g, 4.96 mmol) in 84% yield. [α]25D = +5 (c, 0.4, CHCl3), TLC:
1
Rf 0.3 (7:3 hexanes:ethyl acetate). IR (neat): 3448, 3071, 2930, 2857, 1108, 1038 cm-1. H NMR (400
MHz, CDCl3): δ 7.7-7.64 (m, 4H), 7.46-7.36 (m, 6H), 4.88-4.85 (brs, 1H), 4.77-4.74 (brs, 1H), 3.92 (dd,
J = 10.0, 5.7 Hz, 1H), 3.8-3.67 (m, 4H), 3.52 (dd, J = 7.2, 4.4 Hz, 1H), 3.42 (s, 3H), 2.41 (dt, J = 7.5, 5.6
13
Hz, 1H), 1.72 (s, 3H), 1.05 (s, 9H); C NMR (125 MHz, CDCl3): δ 143.9, 135.6, 133.1, 129.7, 127.6,
113.7, 83.0, 71.9, 63.4, 62.9, 60.7, 50.3, 26.8, 21.8, 19.1. MS (ESI): m/z 451 [M+Na]+. HRMS (ESI):
calcd for C25H36 NaO4Si: 451.2275, found: 451.2294.
(6R,7S,8S)-7-Methoxy-6-(methoxymethoxy)-2,2,3,3,12,12-hexamethyl-11,11-diphenyl-8-(prop-1-
en-2-yl)-4,10-dioxa-3,11-disilatridecane (27): To a solution of compound 26 (2.11 g, 4.94 mmol) in
o
anhydrous DCM (25 mL) cooled to -78 C was added 2,6-lutidine (1.14 mL, 10 mmol) and TBSOTf
(1.14 mL, 5 mmol). The solution was stirred at the same temperature for 30 min subsequently, DIPEA
11

ACCEPTED MANUSCRIPT
(1.74 mL, 10 mmol), MOMCl (0.43 mL, 6 mmol) and TBAI (157 mg, 0.49 mmol) in DCM (0.5 mL)
were added at the same temperature. The reaction mixture was warmed to rt, stirred for 12 h and
quenched by the addition of water (10 mL). The reaction mixture was diluted with DCM (10 mL). The
layers were separated and the organic layer was washed with water (10 mL), brine (10 mL) and dried
over Na2SO4. The solvent was evaporated under reduced pressure to afford the crude product which was
purified by column chromatography using 1% ethyl acetate/hexane (v/v) to give pure compund 27 (2.57
g, 4.4 mmol) in 89% yield as a gummy oil. TLC: Rf 0.7 (9.5:0.5 hexanes:ethyl acetate). [α]25D = -50 (c,
0.6, CHCl3), IR (neat): 3071, 2930, 2857, 1108, 1038 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.7-7.64 (m,
4H), 7.44-7.34 (m, 6H), 4.95-4.93 (brs, 1H), 4.86-4.84 (brs, 1H), 4.74 (d, J = 6.5 Hz, 1H), 4.67 (d, J =
6.5 Hz, 1H), 3.84-3.81 (m, 2H), 3.77-3.72 (m, 3H), 3.6-3.56 (m, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 2.36-
2.31 (m, 1H), 1.77 (s, 3H), 1.04 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
144.1, 135.6, 133.7, 129.4, 127.4, 114.1, 96.8, 81.4, 80.1, 63.2, 62.7, 60.0, 55.2, 51.2, 26.8, 25.9, 21.2,
19.2, 18.2, -5.3, -5.4; MS (ESI): m/z 609 [M+Na]+. HRMS (ESI): calcd for C33H54NaO5Si2: 609.3402,
found: 609.3394.
(2R,3S,4S)-4-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(methoxymethoxy)-5-methylhex-5-
en-1-ol (28): To a solution of compound 27 (2.46 g, 4.2 mmol) in THF (2.1 mL) cooled to 0 oC, TBAF
(1M in THF, 4.2 mL, 4.2 mmol) in acetic acid (0.24 mL, 4.2 mmol) was added. The reaction mixture
was allowed to warm to rt and stirred for 12 h. The solvent was evaporated under reduced pressure to
afford a crude compound, which was purified by column chromatography using 15% ethyl
acetate/hexane (v/v) to give pure compund 28 (1.76 g, 3.72 mmol) in 89% yield as a gummy oil. TLC:
Rf 0.25 (9:1 hexanes:ethyl acetate). [α]25 = -10 (c, 0.4, CHCl3), IR (neat): 3457, 3065, 2934, 1104,
D
1
1042 cm-1. H NMR (500 MHz, CDCl3): δ 7.69-7.63 (m, 4H), 7.45-7.34 (m, 6H), 4.95-4.92 (brs, 1H),
4.84-4.82 (brs, 1H), 4.7 (d, J = 6.8 Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 3.87-3.7 (m, 4H), 3.68-3.64 (m,
1H), 3.6 (dd, J = 9.5, 2.5 Hz, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 2.34 (ddd, J = 9.5, 6.4, 4.1 Hz, 1H), 1.74
12

ACCEPTED MANUSCRIPT
(s, 3H), 1.04 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 143.8, 135.6, 133.6, 129.5, 127.5, 114.2, 96.7,
82.2, 81.5, 62.9, 62.0, 60.5, 55.5, 51.2, 26.8, 21.4, 19.2; MS (ESI): m/z 495 [M+Na]+. HRMS (ESI):
calcd for C27H40NaO5Si: 495.2357, found: 495.2557.
(2S,3S,4S)-4-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(methoxymethoxy)-5-methylhex-5-
enal (29): To a solution of alcohol 28 (1.7 g, 3.6 mmol) in anhydrous DCM (14 mL) was added Dess-
Martin periodinane (1.9 g, 4.3 mmol). After being stirred at rt for 30 min, the reaction mixture was
quenched with aq saturated Na2S2O3 (5 mL) and aq saturated NaHCO3 solution (5 mL). The aq phase
was extracted with DCM (3x10 mL), the combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using
5% ethyl acetate/hexane (v/v) to afford compound 29 (1.55 g, 3.3 mmol) in 92% yield as a liquid. TLC:
Rf 0.65 (9:1 hexanes:ethyl acetate). [α]25 = +10 (c, 0.6, CHCl3), IR (neat): 3071, 2932, 2892, 1729,
D
1109, 1040 cm-1. 1H NMR (500 MHz, CDCl3): δ 9.58 (d, J = 0.9 Hz, 1H), 7.69-7.63 (m, 4H), 7.44-7.35
(m, 6H), 5.02-4.99 (brs, 1H), 4.94-4.92 (brs,1H), 4.72 (s, 2H), 4.19-4.17 (m, 1H), 3.86 (dd, J = 9.9, 6.7
Hz, 1H), 3.8 (dd, J = 9.9, 3.5 Hz, 1H), 3.75 (dd, J = 10.5, 1.6 Hz, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 2.62
(ddd, J = 10.5, 6.7, 3.5 Hz, 1H), 1.7 (s, 3H), 1.04 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 201.1, 143.5,
135.6, 133.6, 129.5, 127.5, 116.0, 96.9, 83.1, 82.3, 62.7, 58.8, 55.7, 49.4, 26.8, 21.6, 19.2; MS (ESI):
m/z 493 [M+Na]+. HRMS (ESI): calcd for C27H38O5NaSi: 493.2380, found: 493.2368.
(1R,2R,3S,4S)-4-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(methoxymethoxy)-5-
methylenecyclohexanol (34): A solution of aldehyde 29 (1.3 g, 2.8 mmol) in anhydrous THF was
added to magnesium bromide (1M in diethyl ether, 2.8 mL, 2.8 mmol) at 0 oC. The reaction mixture was
stirred for 30 min at 0 oC. The reaction was quenched by the addition of an aq saturated NH4Cl solution
(10 mL), allowed to warm to rt and diluted with Et2O (10 mL). The layers were separated and the aq
layer was extracted with Et2O (3x10 mL). The combined organic layers were washed with H2O (10 mL),
brine (10 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a
13

ACCEPTED MANUSCRIPT
crude compound which was purified by column chromatography using 10% ethyl acetate/hexane (v/v)
to yield compound 34 (1.18 g, 2.5 mmol) in 89% yield. TLC: Rf 0.3 (9:1 hexanes:ethyl acetate). [α]25
=
D
-20 (c, 0.4, CHCl3), IR (neat): 3447, 3070, 2930, 2890, 1647, 1110 cm-1. 1H NMR (500 MHz, CDCl3): δ
7.7-7.64 (m, 4H), 7.46-7.36 (m, 6H), 4.99-4.97 (brs, 1H), 4.97-4.95 (brs, 1H), 4.84 (d, J = 6.8 Hz, 1H),
4.75 (d, J = 6.8 Hz, 1H), 3.93-3.91 (m, 1H), 3.85-3.8 (m, 3H), 3.72-3.69 (m, 1H), 3.45 (s, 3H), 3.37 (s,
3H), 2.74 (q, J = 5.6 Hz, 1H), 2.41 (dd, J = 13.7, 6.4 Hz, 1H), 2.31 (dd, J = 13.7, 3.0 Hz, 1H), 1.07 (s,
9H). 13C NMR (100 MHz, CDCl3): δ 140.1, 135.6, 133.3, 129.7, 127.6, 115.1, 96.1, 80.6, 75.3, 69.7,
62.5, 57.4, 55.6, 47.4, 39.4, 26.8, 19.2; MS (ESI): m/z 493 [M+Na]+.
O-(1R,2R,3S,4S)-4-((tert-Butyldiphenylsilyloxy)methyl)-3-methoxy-2-(methoxymethoxy)-5-
methylenecyclohexyl S-methyl carbonodithioate (35): To a suspension of NaH (60% in Nujol, 192
o
mg, 4.8 mmol) in anhydrous THF (10 mL) cooled to 0 C was added alcohol 34 (1.13 g, 2.4 mmol)
dissolved in anhydrous THF (10 mL) under nitrogen atmosphere, the mixture was stirred for 30 min at
room temperature. To the above alkoxide carbon disulfide (0.24 mL, 3.6 mmol) was added at 0 °C, and
the mixture was stirred for 30 min. Methyl iodide (0.26 mL, 4.3 mmol) was added, and the mixture was
gradually warmed to room temperature and stirred for 2 h. The reaction was quenched with ice pieces at
0 °C and diluted with ethyl acetate (25 mL) and water (10 mL). The layers were separated and the aq
layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with H2O (10
mL), brine (10 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford
a crude compound which was purified by column chromatography using 8% ethyl acetate/hexane (v/v)
to yield compound 35 (1.15 g, 2.06 mmol) in 86% yield. TLC: Rf 0.5 (9:1 hexanes:ethyl acetate). IR
(neat): 3070, 3048, 2929, 2890, 2856, 1648, 1211, 1147, 1112, 1063 cm-1. 1H NMR (500 MHz, CDCl3):
δ 7.7-7.65 (m, 4H), 7.46-7.36 (m, 6H), 5.48 (ddd, J = 11.9, 4.8, 2.5 Hz, 1H), 5.07 (s, 1H), 5.01 (s,1H),
4.76 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 6.8 Hz, 1H), 4.57-4.53 (m, 1H), 4.07 (dd, J = 10.3, 4.5 Hz, 1H),
3.98 (dd, J = 10.3, 1.8 Hz, 1H), 3.44 (s, 3H), 3.31 (s, 3H), 3.3-3.26 (m, 1H), 2.8-2.72 (m, 1H), 2.59 (s,
14

ACCEPTED MANUSCRIPT
3H), 2.57-2.48 (m, 2H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 215, 139.8, 135.6, 133.4, 129.4,
127.5, 112.9, 96.7, 80.8, 78.9, 70.3, 60.2, 56.5, 55.5, 44.0, 35.3, 26.9, 19.3,19.0. MS (ESI): m/z
583 [M+Na]+. HRMS (ESI): calcd for C29H40O5SiS2: 561.2159, found: 561.2185.
tert-Butyl(((1S,2S,3R)-2-methoxy-3-(methoxymethoxy)-6-methylenecyclohexyl)methoxy)
diphenylsilane (36): To a solution of compound 35 (1.13 g, 2.01 mmol) in toluene (15 mL), Bu3SnH
(914 mg, 3.0 mmol), catalytic amount of AIBN (33 mg, 0.2 mmol) were added under a nitrogen
atmosphere and the mixture was heated at reflux for 8 h. Toluene was removed under reduced pressure
and the residual product was purified by column chromatography using 8% ethyl acetate/hexane (v/v) to
yield compound 36 (771 mg, 1.7 mmol) in 84% yield. TLC: Rf 0.4 (9:1 hexanes:ethyl acetate). [α]25D = -
5 (c, 0.6, CHCl3), IR (neat): 2925, 1219, 1105, 1043, 771, 699 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.7-
7.66 (m, 4H), 7.46-7.36 (m, 6H), 4.84 (s, 1H), 4.8 (s, 1H), 4.74 (d, J = 6.9 Hz, 1H), 4.7 (d, J = 6.9 Hz,
1H), 3.96 (dt, J = 9.0, 3.2 Hz, 1H), 3.83-3.77 (m, 2H), 3.61 (dd, J = 5.4, 2.6 Hz, 1H), 3.4 (s, 3H), 3.39
(s, 3H), 2.75 (q, J = 5.8 Hz, 1H), 2.27 (ddd, J = 13.8, 6.2, 4.7 Hz, 1H), 2.07 (ddd, J = 13.8, 9.9, 4.7 Hz,
1H), 1.96-1.88 (m, 1H), 1.64-1.61 (m, 1H), 1.08 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 144.7, 135.6,
133.5, 129.6, 127.6, 111.7, 95.1, 79.8, 72.4, 62.9, 57.0, 55.2, 47.8, 30.1, 27.6, 26.8, 19.2; MS (ESI): m/z
477 [M+Na]+. HRMS (ESI): calcd for C27H38O4Si: 455.2612, found: 455.2629.
((1S,2S,3R)-2-Methoxy-3-(methoxymethoxy)-6-methylenecyclohexyl)methanol (37): To a solution
o
of compound 36 (726 mg, 1.6 mmol) in THF (1.6 mL) cooled to 0 C, TBAF (1M in THF, 1.6 mL, 1.6
mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 12 h. The solvent was
evaporated under reduced pressure to afford a crude compound, which was purified by column
chromatography using 30% ethyl acetate/hexane (v/v) to give pure compund 37 (324 mg, 1.5 mmol) in
94% yield as a gummy oil. TLC: Rf 0.3 (7:3 hexanes:ethyl acetate). [α]25 = +15 (c, 0.6, CHCl3), IR
D
(neat): 3450, 2927, 1149, 1100, 1037 cm-1. 1H NMR (500 MHz, CDCl3): δ 4.85 (s, 1H), 4.76 (d, J = 6.8
Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.65 (s, 1H), 4.11-4.08 (m, 1H), 3.9 (dd, J = 10.9, 4.7 Hz, 1H), 3.84
15

ACCEPTED MANUSCRIPT
(dd, J = 10.9, 6.7 Hz, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.24 (dd, J = 6.5, 2.7 Hz, 1H), 2.8-2.74 (m, 1H),
2.42-2.34 (m, 1H), 2.1 (dt, J = 13.6, 4.7 Hz, 1H), 2.05-1.98 (m, 1H), 1.47-1.39 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 145.8, 108.7, 95.2, 84.6, 70.5, 62.8, 56.6, 55.2, 45.3, 30.1, 28.6; MS (ESI): m/z 239
[M+Na]+. HRMS (ESI): calcd for C11H20NaO4: 239.1254, found: 239.1270.
((3R,4S,5S,6R)-5-Methoxy-6-(methoxymethoxy)-1-oxaspiro[2.5]octan-4-yl)methanol (38): To a
solution of compound 37 (302 mg, 1.4 mmol) in DCM (7 mL) cooled to 0 ºC was added mCPBA (393
mg, 1.6 mmol). The reaction mixture was stirred at the same temperature for another 30 min and then
quenched by adding aq saturated Na2SO3 (3 mL). The mixture was diluted with DCM (10 mL) and the
layers separated. The combined organic layers were washed successively with aq saturated NaHCO3 (10
mL), water (10 mL), brine (10 mL), dried over Na2SO4 and the solvent was evaporated under reduced
pressure to furnish the crude compound which was purified by column chromatography using 40% ethyl
acetate/hexanes (v/v) as the eluent to afford the product 38 (283 mg, 1.22 mmol) in 87% yield as a
liquid. TLC: Rf 0.2 (7:3 hexanes:ethyl acetate). [α]25 = -50 (c, 0.6, CHCl3), IR (neat): 3447, 2929,
D
1
1148, 1102, 1036 cm-1. H NMR (500 MHz, CDCl3): δ 4.77 (d, J = 6.8 Hz, 1H), 4.75 (d, J = 6.8 Hz,
1H), 4.27-4.24 (m, 1H), 3.75 (dd, J = 11.9, 3.3 Hz, 1H), 3.64 (dd, J = 11.9, 3.0 Hz, 1H), 3.58 (dd, J =
10.8, 2.7 Hz, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 3.19 (d, J = 3.8 Hz, 1H), 2.65 (d, J = 3.8 Hz, 1H), 2.36 (dt,
J = 10.8, 3.3 Hz, 1H), 2.23 (td, J = 13.5, 4.4 Hz, 1H), 2.04-1.98 (m, 1H), 1.75-1.67 (m, 1H), 1.11 (dt, J =
14.0, 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 95.6, 79.5, 69.9, 61.1, 58.9, 57.2, 55.3, 51.2, 40.4,
28.4, 25.5; MS (ESI): m/z 255 [M+Na]+. HRMS (ESI): calcd for C11H20NaO5: 255.1203, found:
255.1226.
(3R,4S,5S,6R)-5-Methoxy-6-(methoxymethoxy)-1-oxaspiro[2.5]octane-4-carbaldehyde (39): To a
solution of alcohol 38 (259 mg, 1.12 mmol) in DCM (5.6 mL) was added Dess-Martin periodinane (560
mg, 1.23 mmol). After being stirred at rt for 30 min, the reaction mixture was quenched with aq
saturated Na2S2O3 (2 mL) and aq saturated NaHCO3 solution (2 mL). The aq phase was extracted with
16

ACCEPTED MANUSCRIPT
DCM (3x4 mL), the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chromatography on silica gel using 30% ethyl
acetate/hexane (v/v) to afford compound 39 (239 mg, 1.04 mmol) in 93% yield as a liquid. TLC: Rf 0.5
(7:3 hexanes:ethyl acetate). [α]25D = -35 (c, 0.6, CHCl3), IR (neat): 2932, 1726, 1150, 1096, 1036 cm-1.
1H NMR (500 MHz, CDCl3): δ 9.42 (d, J = 3.6 Hz, 1H), 4.74 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 6.8 Hz,
1H), 4.3-4.27 (m, 1H), 3.97 (dd, J = 10.3, 2.7 Hz, 1H), 3.44 (s, 3H), 3.41 (s, 3H), 2.94 (dd, J = 10.3, 3.6
Hz, 1H), 2.72 (d, J = 3.8 Hz, 1H), 2.63 (d, J = 3.8 Hz, 1H), 2.18-2.1 (m, 1H), 2.07-2.0 (m, 1H), 1.82-
1.74 (m, 1H), 1.17 (dt, J = 14.0, 4.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 201.7, 95.5, 79.2, 68.8,
58.0, 56.9, 55.4, 52.3, 51.2, 27.9, 25.5; MS (ESI): m/z 253 [M+Na]+. HRMS (ESI): calcd for
C11H18NaO5: 253.1046, found: 253.1050.
(3R,4S,5S,6R)-4-Ethynyl-5-methoxy-6-(methoxymethoxy)-1-oxaspiro[2.5]octane (40): To a solution
of Ohira-Bestmann reagent (422 mg, 2.2 mmol) in anhydrous THF (2 mL) cooled to -78 oC was added
NaOMe (5.4 M in Methanol, 0.37 mL, 2 mmol) in anhydrous THF (2 mL). The mixture was stirred for
10 min and then the solution of aldehyde 39 (230 mg, 1 mmol) in anhydrous THF (1 mL) was added
o
o
slowly at -78 C. The reaction mixture was gradually warmed to 0 C and stirred for 12 h at the same
temperature and then warmed to rt. The reaction was quenched by adding aq saturated NH4Cl solution
(2 mL) at 0 oC. It was allowed to warm to rt and diluted with Et2O (5 mL), the layers were separated and
the aq layer was extracted with Et2O (3x5 mL). The combined organic layers were washed with H2O (5
mL), brine (5 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a
crude compound which was purified by column chromatography using 20% ethyl acetate/hexane (v/v)
to yield compound 40 (169 mg, 0.75 mmol) in 75% yield. TLC: Rf 0.3 (8:2 hexanes:ethyl acetate).
1
[α]25 = -25 (c, 0.6, CHCl3), IR (neat): 2927, 2855, 2101, 1735, 1251, 1110, 1033 cm-1. H NMR (300
D
MHz, CDCl3): δ 4.75 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.22-4.19 (m, 1H), 3.52-3.5 (m, 1H),
3.48 (s, 3H), 3.4 (s, 3H), 3.16 (dd, J = 8.8, 1.6 Hz, 1H), 3.07 (d, J = 4.7 Hz, 1H), 2.66 (d, J = 4.7 Hz,
17

ACCEPTED MANUSCRIPT
1H), 2.12 (d, J = 2.4 Hz, 1H), 2.0-1.9 (m, 2H), 1.8-1.72 (m, 1H), 1.54-1.46 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 95.6, 82.0, 80.2, 71.5, 70.6, 58.0, 57.5, 55.3, 52.5, 36.1, 26.8, 25.6; MS (ESI): m/z 249
[M+Na]+. HRMS (ESI): calcd for C12H18NaO4: 249.1097, found: 249.1088.
(1R,2S,3S,4R)-1-(Chloromethyl)-2-ethynyl-3-methoxy-4-(methoxymethoxy)cyclohexanol (41): To a
o
solution of Cp2ZrCl2 (27 mg, 0.09 mmol) in DCE (0.5 mL) cooled to 0 C was added Me3Al (2 M in
toluene, 0.15 mL, 0.3 mmol) slowly. After stirring for 15 min, alkyne 40 (22.6 mg, 0.1 mmol) was
added at the same temperature and stirring was continued for 30 min. Prenyl bromide (0.01 mL, 0.1
mmol) followed by solution of Pd (PPh3)4 (0.005 mmol, 5 mg) in DCE (0.2 mL) was added. The
reaction was stirred for 6 h at rt, there upon quenchend by the addition of an aq saturated citric acid
o
solution (1 mL) at 0 C. It was allowed to warm to rt and diluted with DCM (3 mL), the layers were
separated and aq layer extracted with DCM (3x3 mL). The combined organic layers were washed with
H2O (3 mL), brine (5 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to
afford a crude compound which was purified by column chromatography using hexane to yield a
1
chloron alcohol 41 (14 mg, 0.055 mmol) in 55% yield. TLC: Rf 0.2 (8:2 hexanes:ethyl acetate). H
NMR (400 MHz, CDCl3): δ 4.72 (d, J = 6.8 Hz, 1H), 4.7 (d, J = 6.8 Hz, 1H), 4.15-4.12 (m, 1H), 3.7 (d,
J = 11.0 Hz, 1H), 3.63 (d, J = 11.0 Hz, 1H), 3.5 (s, 3H), 3.44 (dd, J = 10.5, 2.6 Hz, 1H), 3.4 (s, 3H), 3.14
(dd, J = 10.5, 2.2 Hz, 1H), 2.4 (d, J = 2.2 Hz, 1H), 2.16-2.14 (brs, 1H), 1.95-1.8 (m, 2H) 1.74-1.65 (m,
2H). MS (ESI): m/z 285 [M+Na]+.
(3R,4S,5S,6R)-4-((E)-Hexa-2,5-dien-2-yl)-5-methoxy-6-(methoxymethoxy)-1-oxaspiro[2.5]octane
o
(42): To a solution of CuCN (36 mg, 0.4 mmol) in anhydrous THF (1 mL) cooled to -78 C was added
o
n-BuLi (2.5 M in THF, 0.32 mL, 0.8 mmol). The reaction mixture was warmed to -65 C to get clear
solution. After 15 min cooled to -78 oC and tributyltinhydride (0.21 mL, 0.8 mmol) was added slowly,
the reaction mixture became yellowish and bubbles of hydrogen gas were evolved. After 10 min alkyne
40 (45 mg, 0.2 mmol) in THF (0.5 mL) was added, stirring was continued for 30 min followed by MeI
18

ACCEPTED MANUSCRIPT
(0.06 mL, 2 mmol) and DMPU (0.2 mL) were added. The reaction mixture was slowly warmed to 0 oC
then allyl bromide (0.035 mL, 0.4 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) were added. The reaction
o
mixture was stirred at rt for 3 days and quench with aq saturated NH4Cl solution (1 mL) at 0 C. It was
allowed to warm to rt and diluted with Et2O (2 mL), the layers were separated and aq layer extracted
with Et2O (3x2 mL). The combined organic layers were washed with H2O (2 mL), brine (2 mL), dried
over Na2SO4 and the solvent was evaporated under reduced pressure to afford a crude compound which
was purified by column chromatography using 20% ethyl acetate/hexane (v/v) to yield diene 42 (40 mg,
0.14 mmol) in 71% yield. TLC: Rf 0.25 (8:2 hexanes:ethyl acetate). [α]25 = -55 (c, 0.6, CHCl3), IR
D
1
(neat): 2953, 2924, 2855, 1434, 1152, 1100, 1035 cm-1. H NMR (400 MHz, CDCl3): δ 5.83-5.72 (m,
1H), 5.27 (t, J = 8.0 Hz, 1H), 5.02 (d, J = 17.1 Hz, 1H), 4.94 (d, J = 10.1 Hz, 1H), 4.77 (d, J = 6.7 Hz,
1H), 4.74 (d, J = 6.7 Hz, 1H), 4.32-4.28 (m, 1H), 3.51 (dd, J = 11.2, 2.7 Hz, 1H), 3.42 (s, 3H), 3.38 (s,
3H), 2.97 (d, J = 11.2 Hz, 1H), 2.86-2.72 (m, 2H), 2.66 (d, J = 5.0 Hz, 1H), 2.45 (d, J = 5.0 Hz, 1H),
2.23 (td, J = 13.7, 4.4 Hz, 1H), 2.04-1.96 (m, 1H), 1.72 (tdd, J = 13.9, 4.4, 2.2 Hz, 1H), 1.57 (d, J = 3.3
Hz, 3H), 1.1 (ddd, J = 13.7, 4.4, 2.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 136.9, 130.4, 127.7,
114.4, 95.8, 80.6, 69.5, 56.7, 55.3, 51.3, 48.6, 37.9, 32.2, 28.6, 26.0, 21.4. MS (ESI): m/z 305 [M+Na]+.
HRMS (ESI): calcd for C16H26NaO4: 305.1729, found: 305.1730.
(3R,4S,5S,6R)-4-((E)-Hexa-2,5-dien-2-yl)-5-methoxy-1-oxaspiro[2.5]octan-6-ol (43): To a solution
o
of compound 42 (28.2 mg, 0.1 mmol) in DCM (1 mL) cooled to -78 C, TMSBr (0.03 ml, 0.3 mmol)
was added. The reaction mixture was stirred for 30 min and quenched with aq saturated NaHCO3
solution (0.5 mL). It was allowed to warm to rt and diluted with DCM (2 mL), the layers were separated
and aq layer extracted with DCM (3x2 mL). The combined organic layers were washed with H2O (2
mL), brine (2 mL), dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a
crude bromo compound. TLC: Rf 0.15 (8:2 hexanes:ethyl acetate). To the solution of crude compound
in methanol (5 mL) at room temperature was added solid potassium carbonate (27 mg, 0.2 mmol). After
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ACCEPTED MANUSCRIPT
stirring for 1 h at the same temperature, methanol was removed in vacuo. The residue was partitioned
between brine (2 mL) and ethyl acetate (6 mL). The organic layer separated and the aqueous phase was
extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with H2O (2 mL),
dried over Na2SO4 and the solvent was evaporated under reduced pressure to afford a crude compound
which was purified by column chromatography using 30% ethyl acetate/hexane (v/v) to yield
compound 43 (18 mg, 0.076 mmol) in 76% yield. TLC: Rf 0.2 (8:2 hexanes:ethyl acetate). IR (neat):
1
3464, 2930, 2362, 1638, 1445, 1377, 1324, 1214, 1103 cm-1. H NMR (400 MHz, CDCl3): δ 5.86-5.76
(m, 1H), 5.42-5.26 (brs, 1H), 5.05 (d, J = 17.0 Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.28-4.26 (m, 1H),
3.7-3.5 (m, 2H), 3.37 (s, 3H), 3.32 (d, J = 10.0 Hz, 1H), 2.9-2.8 (m, 2H), 2.52 (d, J = 5.0 Hz, 1H), 2.27-
2.22 (brs, 1H), 1.93-1.75 (m, 3H), 1.7-1.66 (m, 1H), 1.57 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 136.7,
132.7, 127.0, 114.5, 80.9, 64.4, 60.7, 56.9, 51.2, 47.9, 32.1, 29.7, 27.8, 26.6. MS (ESI): m/z 261
[M+Na]+. HRMS (ESI): calcd for C14H23O6: 239.1647, found: 239.1633.
Acknowledgements
M.K.R.Y. is thankful to Council of Scientific and Industrial Research (CSIR)-New Delhi for a
fellowship. S.R. is grateful to the Department of Science and Technology, New Delhi for funding the
project (SR/S1/OC-5/2011) and CSIR, New Delhi for funding under the XII five year plan programme
entitled ORIGIN (CSC-108).
References
1. (a) Hanson, F. R.; Elbe, T. E. J. Bacteriol. 1949, 58, 527-529; (b) Elbe, T. E.; Hanson, F. R. Antibiot.
Chemother. 1951, 1, 54-58.
2. (a) McCowen, M. C.; Callender, M. E.; Lawlis, Jr. J. F. Science. 1951, 112, 202-203; (b) Katznelson,
H.; Jamieson, C. A. Science. 1952, 115, 70-71; (c) Killough, J. H.; Magill, G. B.; Smith, R. C. Science.
1952, 115, 71-72.
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ACCEPTED MANUSCRIPT
3. Wilkins, J. H.; Joshi, N.; Margolis, N, T. P.; Cevallos, V.; Dawson, C. R. Eye. 1994, 8, 703-704.
4. Zhang, P.; Nicholson, D. E.; Bujnicki, J. M.; Su, X.; Brendle, J. J.; Ferdig, M.; Kyle, D. E.; Milhous,
W. K.; Chiang, P. K. J. Biomed. Sci. 2002, 9, 34-40.
5. (a) Molina, J- M.; Derouin, F. PCT. Int. Appl. WO 9630010, CA. 125, 309073; (b) Coyle, C.; Kent,
M.; Tanowitz, H. B.; Wittner, M.; Weiss, L. M. J. Infect. Dis. 1998, 177, 515-518; (c) Molina, J- M.;
Goguel, J.; Sarfati, C.; Michiels, J- F.; Desportes-Livage, I.; Balkan, S.; Chastang, C.; Cotte, L.; Maslo,
C.; Struxiano, A.; Derouin, F.; Decazes, J- M. AIDS. 2000, 14, 1341-1348
.
6. (a) Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kanamaru, T.; Brem, H.; Folkman, J. Nature.
1990, 348, 555-557; (b) Folkman, J. New Engl. J. Med. 1995, 333, 1757-1763.
7. Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. G.; Crews, C. M. Proc. Natl. Acad.
Sci., U.S.A. 1997, 94, 6099-6103.
8. Griffith, E. C.; Su, Z.; Turk, B. E.; Chen, S.; Chang, Y.-H.; Wu, Z.; Biemann, K.; Liu, J. O. Chem.
Biol. 1997, 4, 461-471.
[9] J. S. Yadav, P. Sreedhar, P. Srihari, G. Dattatreya Sarma and B. Jagadeesh, Synthesis, 2008, 1460-
1466 and references cited therein.
[10] Y. Kitano, T. Matsumoto and F. Sato, Tetrahedron, 1988, 44, 4073-4086.
[11] E. Davin, M. Giongo and M. Riocci, Org. Prep. Proceed. Int., 1995, 27, 586-590.
[12] Z. Huang and E. Negishi, Org. Lett., 2006, 8, 3675-3678.
13. (a) Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J. Tetrahedron
Lett. 1995, 36, 9533-9536; (b) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds, K.; Sarma,
P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc. Perkin Trans. 1. 2002, 13, 69-79.
14. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136-6137.
15. Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68, 7768-7771.
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16. Attempts at opening the epoxide 17 with Grignard reagent 6 in the presence of CuBr.Me2S to secure
compound ii met with failure, unreacted epoxide being recovered. The allylic silane iii was prepared
from compound 22 by a three step sequence involving, (a) chlorination using Ca(OCl)2, (b) introduction
of the silyl residue and (c) displacement of the tosylate by sodium thiophenoxide.
Cl
TMS
OTBDPS
Ca(OCl)2
OTBDPS
OTBDPS
Si2Me6
TsO
O
TsO
O
Dry ice, DCM
H2O, 84%
TsO
O
MeLi.LiBr, CuCN
HMPA, THF
72%
O
O
O
ii
i
22
TMS
PhS
OTBDPS
PhSH, NaH
DMF, 84%
O
O
iii
For chlorination see: (a) Hegde, S. G.; Vogel, M. K.; Saddler, J.; Hrinyo, T.; Rockwell, N.; Haynes, R.;
Oliver, M.; Wolinsky, J. Tetrahedron Lett. 1980, 21, 441-444; (b) Hegde, S. G.; Wolinsky, J. J. Org.
Chem. 1982, 47, 3148-3150. For introduction of the silyl group see: Smith, J- G.; Drozda, S. E.;
Petraglia, S. P.; Quinn, N. R.; Rice, E. M.; Taylor, B. S.; Viswanathan, M. J. Org. Chem. 1984, 49,
4112-4120.
17. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tetrahedron Lett. 1998, 39, 3091-
3092.
18. The readily prepared sulfide 23 was used to prepare the corresponding chloro sulfide for reaction
with vinylzinc bromide. Once conditions were standardized it was proposed to employ sulfide iii (see
ref. 16. above).
19. Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org. Lett. 2007, 9, 4603-4606.
20. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287; (b) Dess, D. B.; Martin, J.
C. J. Org. Chem. 1983, 48, 4155-4156.
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21. Trost, B. M.; Belletire, J. L.; Godleski, S.; Mcdougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy,
M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370-2374.
22. The tentative structure assigned to alcohol 34 is based on the observed coupling constants for C7H
in the xanthate ester 35 (11.9, 4.9 and 2.6 Hz). The large 11.9 Hz coupling can be explained only if C7H
is axially oriented.
23]. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1. 1975, 1574-1585.
24. Mazitschek, R.; Huweb, A.; Giannis, A. Org. Biomol. Chem. 2005, 3, 2150-2154.
25. (a) Ohira, S. Synth. Commun. 1989, 19, 561-564; (b) Muller, S.; Liepold, B.; Roth, G. J.;
Bestmann, H. J. Synlett. 1996, 521-522.
26. (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252-2254; (b) Negishi, E.; Wang,
G.; Rao, H.; Xu, Z. J. Org. Chem. 2010, 75, 3151-3182.
27. Lipshutz, B. H.; Amorelli, B. J. Am. Chem. Soc. 2009, 131, 1396-1397.
28. (a) Adlington, R. M.; Barrett, A. G. M. J. Chem. Soc., Perkin Trans. 1. 1981, 2848-2863; (b) Corey,
E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915-8918; (c) Amano, S.; Ogawa, N.;
Ohtsuka, M.; Chida, N. Tetrahedron. 1999, 55, 2205-2224.
29. Kim, D.; Ahn, S. K.; Bae, H.; Kim, H. S. Arch. Pharm. Res. 2005, 28, 129-141.
23