Synthesis of 15,28-dideoxy-15,28-didehydrothyrsenol

Article abstract of DOI:10.3987/COM-12-S(N)51

The tetracyclic skeleton of thyrsenols A and B has been assembled, with the construction of ring A by exo-selective oxacyclization of an epoxybromohydrin, B ring formation by exo-selective oxacyclization of hydroxyepoxide followed by solvolytic ring expan

Full text of DOI:10.3987/COM-12-S(N)51

HETEROCYCLES, Vol. 86, No. 1, 2012
535
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 535 - 553. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 23rd June, 2012, Accepted, 18th July, 2012, Published online, 31st July, 2012
DOI: 10.3987/COM-12-S(N)51
SYNTHESIS OF 15,28-DIDEOXY-15,28-DIDEHYDROTHYRSENOL
Mary A. Smart1 and Frank E. McDonald*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA
30322 USA; E-mail: fmcdona@emory.edu
Abstract – The tetracyclic skeleton of thyrsenols A and B has been assembled,
with the construction of ring A by exo-selective oxacyclization of an
epoxybromohydrin, B ring formation by exo-selective oxacyclization of
hydroxyepoxide followed by solvolytic ring expansion of a tetrahydrofuran to
tetrahydropyran,
C
ring closure by tungsten-promoted endo-selective
oxacyclization of a hydroxyalkyne, and D ring preparation by asymmetric
dihydroxylation of an epoxyalkene accompanied by exo-selective oxacyclization.
A modified Stille coupling linked two fragments at C14-C15 to directly provide the
tetracyclic dienylether.
INTRODUCTION
Marine polyether triterpenes encompass a large class of natural products arising from oxidative
cyclizations of squalenes, exhibiting various arrangements of five, six, and even seven-membered ring
ethers.2 Pharmacologically many of these natural products display antitumor, antiinflammatory,
analgesic, antiallergy, and antiviral properties, and have been the subject of numerous biological studies.
In particular, thyrsiferol (1, Scheme 1) and especially thyrsiferyl 23-acetate (2) exhibit powerful
inhibition of cell growth against the P388 lymphoid cancer cell line,3 whereas the diastereomeric natural
product venustatriol (3) shows activity against vesicular stomatitis virus (VSV) and Herpes simples virus
type 1 (HSV-1),4 and the structurally unique dioxepandehydrothyrsiferol (4) bearing two fused
seven-membered rings is apparently inactive against several tumor cell lines.5 Thyrsenols A and B (5, 6)
represent more highly oxidized congeners of thyrsiferol, with thyrsenol B displaying much greater
cytotoxicity against than P388 cell line (IC50 = 0.016 µM) vs. thyrsenol A (IC50 = 0.40 µM).6
____________________________________________________________________________________
Dedicated in celebration of the 77th birthday of Prof. Ei-ichi Negishi.

536
HETEROCYCLES, Vol. 86, No. 1, 2012
Me OH
Me OH
Me
H
Me
Me
H
H
Me
H
Me
OR
Me
OH
Me
O
O
O
H
O
18
15
18
Me
15
10
14
10
19
23
14
19
23
O
7
Me
Br
Me Me
H
H
7
11
11
Me
Me
Br
O
HO
HO
6
O
6
3
O
H
H
H
3
Me
thyrsiferol, 1: R = H
dioxepandehydrothyrsiferol, 4
H
H
thyrsiferyl 23-acetate, 2: R = Ac
R1 R2
Me
Me
H
Me OH
Me
OH
Me
O
O
14
15
18
Me
H
Me
H
Me
OH
Me
10
O
O
19
23
18
15
H
Me Me 7
O
11
10
14
19
23
Me
HO
H
Me Me
7
11
O
6
Me
Br
O
HO
H
H
3
O
6
H
H
3
thyrsenol A, 5: R1 = CH2OH, R2 = OH
thyrsenol B, 6: R1 = OH, R2 = CH2OH
Br
venustatriol, 3
H
H
Scheme 1. Representative structures of fused polyether triterpenes
As part of our long-standing interest in the synthesis of marine polycyclic ethers including polyether
triterpenes,7 we set out to explore the preparation of thyrsiferol or one of its congeners (2 - 6) by
regioselective and stereospecific epoxide cyclizations.8 The total syntheses of thyrsiferols (1, 2),
venustatriol (3), and dioxepandehydrothyrsiferol (4) have been achieved by several different
laboratories,9-12 but to date synthetic activity directed towards the thyrsenols (5, 6) has not been reported.
In considering the synthesis of thyrsenols A and B (5, 6), we proposed that late-stage regio- and
enantioselective dihydroxylation of the dideoxydidehydrothyrsenol structure 7 would follow
cross-coupling of a tricyclic enol ether derivative 8 with tetrahydrofuranyl-containing 9, with these
sectors arising from oxidative cyclization synthetic strategies beginning with farnesol (10) and geraniol
(11), respectively (Scheme 2).
thyrsenols A, B (5, 6)
regioselective dihydroxylation
Me
H
Me
Me
OH
Me
O
D
O
14
15
H
B
C
Me Me
O
HO
Me
Br
O
A
H
H
7
cross-coupling
H
Me
Me
H
Me
OR
Me
O
14
X
O
D
15
Y
B
C
Me Me
O
H
Me
Br
RO
O
A
H
H
9
8
H
HO
Me
Me
Me
Me
OH
Me
geraniol, 11
Me
farnesol, 10
Me
Scheme 2. Retrosynthetic analysis for thyrsenols via 15,28-dideoxy-15,28-didehydrothyrsenol (7)

HETEROCYCLES, Vol. 86, No. 1, 2012
537
RESULTS AND DISCUSSION
Our synthesis began with regioselective preparation of the racemic bromohydrin 13 (Scheme 3) from
farnesyl acetate (12) as described in the literature,13 followed by regioselective and enantioselective
epoxidation utilizing the Shi ketone,14 in which the alkene bearing the allylic acetate substituent was
electronically deactivated for electrophilic epoxidation.15 As the Shi epoxidation required a buffer
system with pH 10.5, these basic reaction conditions slowly converted the bromohydrin moiety into the
undesired terminal epoxide, which was minimized only by diminishing the reaction time and thus
decreasing the conversion of 13 into monoepoxide 14. Although protective groups could be introduced
onto the tertiary alcohol of 13,16 the undesired epoxide formed upon removal of these protective groups,
so in the end we judged that our original procedure of acid-catalyzed cyclization with careful control of
temperature and conversion provided effective throughput of material into the desired
bromotetrahydropyran diastereomer 15 as the result of kinetic resolution of the diastereomers of 14.17
D
-epoxone,
Oxone
NBS
H2O, 0 oC
Me
Me
Me
Me
Br
pH 10.5, -10 oC
Me
OAc
Me
HO
OAc
Me
Me
13 (65%)
farnesyl acetate, 12
cat. CSA
Et2O, 18 oC
Me
Me
Me Me
Me
Br
Me
Br
O
H
OH
A
O
H
Me
HO
OAc
OAc
H
Me
14 (53%)
15 (50%)
Scheme 3. Synthesis of ring A
The principal challenge in constructing the B ring of thyrsenols was achieving the 6-endo-tet cyclization
of an epoxyalcohol instead of the 5-exo-tet cyclization predicted by Baldwin's rules.18 Instead, we
elected to undertake a reaction sequence in which the 5-exo-tet cyclization tetrahydrofuranyl alcohol
product would subsequently undergo isomerization to give the ring-expanded tetrahydropyranyl alcohol.
The Sharpless asymmetric epoxidation19 was conducted from the triethylsilyl ether derivative 17, as the
reaction rates and yields were diminished when the epoxidation was attempted with the corresponding
diol. The triethylsilyl ether 16 was preferred over other silyl ethers for its wider range of pH stability
and reduced tendency towards migration (Scheme 4). Upon deprotection of the silyl ether from the
epoxidation product 18, the tetrahydrofuranyl diol 19 was selectively produced in excellent yield. As a
model system for the ring expansion step, the primary alcohol was regioselectively converted into the
acetate ester 20,20 and then the remaining secondary alcohol was transformed to the chloromesylate 21.

538
HETEROCYCLES, Vol. 86, No. 1, 2012
Following optimized conditions developed by the Nakata laboratory, upon heating compound 21 in the
presence of water and zinc acetate, ring expansion provided the desired tetrahydropyran as a mixture of
acetate 23 and diol 24.21,22 As the mechanism for the Nakata rearrangement involved initial generation
of epoxonium ion 22 followed by addition of water at the tertiary C10, single inversion of each chiral
center at C10 and C11 was anticipated to provide the stereochemistry depicted for compounds 23 and 24.
10
Me
Me
O
cat. Ti(O-i-Pr)4
cat. L-(+)-DET
t-BuOOH
Me Me
Me Me
11
Me
Br
O
Me
Br
O
OR
O
A
H
H
OR'
TES OH
H
H
TESCl
DMAP
15, R = H, R' = Ac
16, R = TES, R' = Ac (85%)
17, R = TES, R' = H (96%)
18 (97%)
DIBAL
10
Zn(OAc)2-2H2O
H2O, 60 oC
Me
Bu4NF
HOAc / THF
Me Me
Me
Br
O
O
2
11
R O
OR1
H
H
19, R1 = H, R2 = H (90%)
20, R1 = Ac, R2 = H (90%)
21, R1 = Ac, R2 = ClCH2SO2
AcCl, collidine
ClCH2SO2Cl, 2,6-lutidine
Me
OH
10
10
Me
B
Me Me
Me Me
11
Me
Br
O
Me
Br
O
O
O
11
A
H
H
H
H
OR
OR
H
H
22
23, R = Ac (49%)
+
24, R = H (25%)
Scheme 4. Cyclization to form ring B
With the success of the model system, we incorporated the carbon atoms necessary for C-ring synthesis
by converting the diol 19 into epoxide 26 (Scheme 5) via intermediacy of the primary tosylate 25,23
followed by addition of lithium acetylide to provide compound 27.24 At this stage, Nakata
rearrangement converted the chloromesylate derivative 28 into the tetrahydropyranyl alcohol 29, albeit in
lower yield than we had observed in the model system in which the primary acetate had been present.
Nonetheless, basic methanolysis of the trimethylsilyl group revealed the terminal alkyne of 30. The
C-ring was then formed by endo-selective alkynol cyclization in the presence of stoichiometric tungsten
carbonyl to a cyclic Fischer oxacarbene,25 followed by reaction with triethylamine and tributyltin triflate
to install the tributyltin substituent in tricyclic compound 31 for subsequent Stille cross-coupling.

HETEROCYCLES, Vol. 86, No. 1, 2012
539
TMS
Li
TMS
BF3-THF
K2CO3
MeOH
10
10
10
Me
Me
Me
11
Me Me
Me Me
Me Me
Me
Br
O
Me
Br
O
Me
Br
O
O
O
O
11
11
H
H
H
HO
OR
O
RO H
H
H
H
TsCl
pyr.
26 (91%)
19, R = H (90%)
25, R = Ts (75%)
27, R = H (99%)
28, R = ClCH2SO2
ClCH2SO2Cl
2,6-lutidine
Me
OH
Me
O
SnBu3
Zn(OAc)2-2H2O
H2O, 60 oC
W(CO)6, h! (350 nm);
then Bu3SnOTf, Et3N
R
10
11
B
B
Me Me
O
Me Me
C
Me
Br
Me
Br
O
O
O
A
A
H
H
H
H
H
H
31 (40%)
K2CO3
MeOH
29, R = TMS (31%, 2 steps)
30, R = H (60%)
Scheme 5. Synthesis of ABC tricyclic sector
Several methods were explored for preparation of the D-ring synthon before we settled on the route
depicted (Scheme 6), in which the known epoxytetrahydrofuranyl alcohol 35 was prepared in four steps
from geraniol (11).26 Although the literature precedent had shown that asymmetric dihydroxylation27 of
the epoxytosylate 33 with stirring for three days directly afforded the epoxytetrahydrofuran 35, we
obtained better results when the dihydroxylation was quenched after five hours, followed by
acid-catalyzed cyclization for complete conversion to the tetrahydrofuranyldiol 34, which was stable to
isolation and characterization. In a separate step, basic methanolysis of 34 afforded the epoxide 35 from
which the remaining tertiary alcohol was protected as silyl ether 36. Copper-catalyzed addition of
2-methallylmagnesium chloride,28 silylation of the resulting secondary alcohol 37, and ozonolysis
afforded the methyl ketone 39,29 which was converted into enol triflate 40 via the kinetic enolate of 39.30
1. AD-mix !
2. cat. CSA
L
-DET, Ti(O-i-Pr)4
H
Me
Me
OH
Me
TsO
HO
HO
Me
Me
Me
RO
Me
Me
Me
t-BuOOH
O
D
H
O
H
TsCl
pyr.
geraniol, 11
32, R = H (98%)
33, R = Ts (81%)
34 (93%)
Me
MgCl
Me
Me
H
H
Me
Me
OR
Me
Me
OTMS
Me
K2CO3, MeOH
CuI
O
D
O
D
15
O
H
H
RO
TMSCl
imid.
TMSCl
imid.
35, R = H (87%)
36, R = TMS (72%)
37, R = H (79%)
38, R = TMS (92%)
KHMDS
PhNTf2
O3, pyridine, MeOH;
then Me2S
Me
Me
O
Me
H
H
Me
OTMS
Me
Me
OTMS
Me
O
D
15
15
O
TfO
D
H
H
TMSO
TMSO
40 (87%)
39 (67%)
Scheme 6. Synthesis of the D ring sector

540
HETEROCYCLES, Vol. 86, No. 1, 2012
Stille coupling of the stannyl enol ether 31 and enol triflate 40 proceeded with minimal homodimerization
of 31, provided that copper iodide and cesium fluoride additives were present (Scheme 7).31 As the
fluoride salt also partially removed the silyl ethers, the dienyl ether product was best isolated as the diol 7
after complete desilylation with excess tetrabutylammonium fluoride.
Me
Me
H
Me
OTMS
Me
O
SnBu3
O
D
14
15
TfO
B
+
C
Me Me
H
Me
Br
O
TMSO
O
A
H
H
40
1. Pd(PPh3)4 (2 mol%)
CuI, CsF, DMF
2. Bu4NF, THF
31
H
Me
H
Me
Me
OH
Me
O
D
O
14
15
H
B
C
Me Me
HO
Me
Br
O
O
A
H
H
7 (61%)
H
Scheme 7. Palladium-catalyzed cross-coupling of ABC and D-ring sectors
At this stage, all that remained was the regioselective dihydroxylation of the C15-alkene of 7. We were
optimistic of a favorable outcome due to our precedent of a similarly regioselective dihydroxylation of a
dienyl ether in a model system directed towards the branched C-glycoside substructure of altromycin B
(41 ! 42, Scheme 8).32 Surprisingly, the attempted dihydroxylation of compound 7 with both AD-mix
" and # gave no reaction, other than eventual decomposition of the dienyl ether after several days. The
reaction of 7 with stoichiometric osmium tetraoxide33 afforded several very polar compounds, none of
which matched the proton NMR spectra of thyrsenols A or B. The reaction of osmium tetraoxide with
the acetate derivative 43 provided a mixture of diastereomers exhibiting mass spectra consistent with the
tetraol arising from dihydroxylation of both alkenes of 43.34 It appears that the aryl ring of 41 must have
played an activating role in the regioselective dihydroxylation of the 1,1-disubstituted alkene, compared
to the corresponding C15 alkene of 7 or 43. Moreover the oxygen substituent at the allylic position of 41
may have deactivated the enol ether to dihydroxylation, whereas dihydroxylation occurred slowly but
competitively with both alkenes of 43.

HETEROCYCLES, Vol. 86, No. 1, 2012
541
HO
OH
Me
Me
O
O
AD-mix !
ref. 32
(92% yield,
dr 3.6 : 1)
O
O
O
O
Me
Me
Me
41
Me
42
R1 R2
Me
H
Me
Me
Me
Me
OH
Me
H
Me
OH
Me
O
D
O
D
O
O
14
14
15
15
H
B
C
B
C
H
HO
Me Me
Me Me
O
RO
Me
Br
O
Me
Br
O
O
A
A
H
H
H
H
H
thyrsenol A, 5: R1 = CH2OH, R2 = OH
thyrsenol B, 6: R1 = OH, R2 = CH2OH
H
7, R = H
43, R = Ac
Ac2O
pyridine
Scheme 8. Attempted conversion to thyrsenols by syn-dihydroxylation
Although the tetracyclic skeleton of the thyrsenols was produced, unfortunately the natural product was
not obtained, due to the absence of differential reactivity between the alkenes of dienyl ether 7 in the final
dihydroxylation step. However, our work has demonstrated a variety of processes for the construction
of cyclic ethers, including diastereoselective epoxyalcohol cyclization to form the A ring, ring expansion
of a tetrahydrofuranyl alcohol to the tetrahydropyranyl alcohol isomer in the presence of an alkyne
substituent, and the first example of tungsten-promoted alkynol cyclization in the presence of an alkyl
bromide.
EXPERIMENTAL
13
1
1H and C NMR spectra were recorded on a VNMR-400 spectrometer (400 MHz for H, 100 MHz for
1
13
13C) or an INOVA-600 spectrometer (600 MHz for H, 150 MHz for C). NMR spectra were recorded
1
on solutions in deuterated chloroform (CDCl3) with residual chloroform (! 7.27 ppm for H NMR and !
13
77.23 ppm for C NMR) taken as the internal standard, and were reported in parts per million (ppm).
Abbreviations for signal coupling are as follows s, singlet; b, broad; d, doublet; t, triplet; q, quartet; m,
multiplet. IR spectra were collected on a Mattson Genesis II FT-IR spectrometer as neat films. Mass
spectra (high resolution FAB) were recorded on a VG 70-S Nier Johason Mass Spectrometer.
Analytical thin layer chromatography (TLC) was performed on precoated glass backed plates purchased
from Whatman (silica gel 60 F254; 0.25mm thickness). Flash chromatography was carried out with silica
gel 60 (230-400 mesh ASTM) from EM Science. All reactions were carried out with anhydrous solvents
in oven-dried or flame-dried and argon-charged glassware. All anhydrous solvents were dried over
molecular sieves and water content assayed by Karl Fischer titration prior to use. The pH 7 buffer
solution used in aqueous workups was prepared by diluting Na2HPO4 (18.9 g, 133 mmol) and KH2PO4
(9.1 g, 67 mmol) with deionized water to a volume of 1L. All reagents were purchased from
Sigma-Aldrich or prepared as described in the cited literature.

542
HETEROCYCLES, Vol. 86, No. 1, 2012
Bromotetrahydropyranyl silyl ether (16): Chlorotriethylsilane (0.41 mL, 2.4 mmol) was added
dropwise to a solution of bromotetrahydropyranyl alcohol 15 (0.619 g, 1.6 mmol)17 and DMAP (0.0649 g,
0.5 mmol) in pyridine (4 mL). The reaction mixture was stirred overnight, diluted with Et2O (50 mL)
and washed with pH 7 buffer (50 mL). The aqueous layer was extracted with additional Et2O (3 x 50
mL). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel
column chromatography eluted with a gradient of 3% Et3N in hexanes to 9% Et3N in hexanes yielding the
silyl ether 16 (0.688 g, 85%) as a clear oil. ["]23D +23.0 (CH2Cl2, c 1.03); IR (neat) 3583, 3434, 2955,
2876, 1740, 1657, 1456, 1381, 1232, 1115, 1019, 733 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.61 (q, J = 7.6
Hz, 6H), 0.96 (t, J = 7.6 Hz, 9H), 1.17 (s, 3H), 1.26-1.36 (m, 1H), 1.28 (s, 3H), 1.42 (s, 3H), 1.49 (dt, J =
13.2, 4.4 Hz, 1H), 1.67 (t, J = 4.0 Hz, 1H), 1.70 (s, 3H), 1.81-1.89 (m, 1H), 1.99-2.30 (m, 4H), 2.07 (s,
3H), 3.25 (dd, J = 7.8, 3.0 Hz, 1H), 3.88 (dd, J = 12.6, 4.2 Hz, 1H), 4.60 (d, J = 7.2 Hz, 2H), 5.36 (dt, J =
13
7.2, 1.2 Hz, 1H); C NMR (100 MHz, CDCl3) ! 5.8, 7.3, 16.7, 19.4, 21.3, 23.8, 28.6, 30.7, 31.3, 37.1,
37.2, 59.2, 61.7, 75.3, 76.4, 81.0, 118.1, 143.1, 171.4; MS(FAB+) Calcd. for C23H44O479Br128Si1 [(M+H)+]
491.2187, found 491.2189.
Allylic alcohol (17): A solution of DIBAL (1 M in dichloromethane, 2.8 mL, 2.8 mmol) was added
slowly to a -78 °C solution of allylic acetate 16 (0.688 g, 1.4 mmol) in dichloromethane (3 mL). The
reaction mixture was stirred for 1 h, then allowed to warm to room temperature. After 3 h, sodium
sulfate decahydrate was added gradually unti a gel formed. The gel was diluted with a saturated aqueous
solution of sodium potassium tartrate (10 mL) and additional dichloromethane (10 mL). The aqueous
layer was extracted with dichloromethane (2 x 10 mL) and the combined organic layers were dried over
MgSO4. After concentration, the crude product was purified by silica gel column chromatography eluted
with Et2O : hexanes (v/v 2 : 8) resulting in allylic alcohol 17 (0.602 g, 96%) as a clear oil. ["]23D +23.2
(CH2Cl2, c 1.74); IR (neat) 3413, 2955, 2876, 2359, 2092, 1640, 1456, 1372, 1237, 1115, 1011, 733 cm-1;
1H NMR (400 MHz, CDCl3) ! 0.61 (q, J = 8.0 Hz, 6H), 0.96 (t, J = 8.0 Hz, 9H), 1.17 (s, 3H) 1.26-1.40
(m, 2H), 1.28 (s, 3H), 1.42 (s, 3H), 1.50 (dt, J = 13.2, 4.4 Hz, 1H), 1.68 (s, 3H), 1.81-1.89 (m, 1H),
1.97-2.04 (m, 1H), 2.08-2.19 (m, 2H), 2.25 (dq, J = 13.2, 3.6 Hz, 1H), 3.25 (dd, J = 7.8, 3.0 Hz), 3.88 (dd,
13
J = 12.6, 3.8 Hz, 1H), 4.17 (d, J = 6.8 Hz, 2H), 5.44 (dt, J = 6.8, 1.2 Hz, 1H); C NMR (100 MHz,
CDCl3) ! 5.8, 7.3, 16.6, 19.4, 23.8, 28.6, 30.9, 31.3, 37.2, 37.3, 59.2, 59.7, 75.3, 76.4, 81.1, 123.2, 140.7;
MS(FAB+) Calcd. for C21H41O379Br123Na128Si1 [(M+Na)+] 471.1901, found 471.1899.
Epoxy alcohol (18): 4Å powdered, activated molecular sieves (0.686 g) were suspended in a solution of
allylic alcohol 17 (0.602 g, 1.3 mmol) in dichloromethane (11 mL) with stirring. The suspension was
cooled to -20 °C and L-(+)-diethyl tartrate (0.07 mL, 0.41 mmol) followed by Ti(Oi-Pr)4 (0.09 mL, 0.30
mmol) were added. The precatalyst mixture was stirred for 30 min. An anhydrous solution of t-butyl
hydroperoxide (5.5 M in decane, 0.7 mL, 3.9 mmol) was added slowly to the mixture and stirred at -20 °C

HETEROCYCLES, Vol. 86, No. 1, 2012
543
for 1 h, then placed in the freezer (-25 °C) overnight. The reaction mixture was filtered though celite to
remove the sieves and diluted with additional dichloromethane (50 mL) and an aqueous KOH solution
(1.5 M, 50 mL). The biphasic mixture was stirred for 1 h. The aqueous layer was extracted with
dichloromethane (2 x 50 mL). The combined organic layers were dried over MgSO4, concentrated and
purified by silica gel column chromatography eluted with Et2O : hexanes (v/v 1 : 3) producing epoxy
alcohol 18 (0.605 g, 97%) as a clear oil. ["]23D +19.1 (CH2Cl2, c 1.07); IR (neat) 3435, 2955, 2876, 1641,
1456, 1382, 1237, 1116, 1017, 732 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.59 (q, J = 8.0 Hz, 6H), 0.95 (t,
J = 8.0 Hz, 9H), 1.17 (s, 3H), 1.28 (s, 3H), 1.30 (s, 3H), 1.42 (s, 3H), 1.49 (dt, J = 13.4, 4.0 Hz, 1H),
1.56-1.72 (m, 4H), 1.75-1.87 (m, 1H), 2.11 (qd, J = 13.6, 4.0 Hz, 1H), 2.25 (dq, J = 13.2, 3.6 Hz, 1H),
13
2.97 (dd, J = 7.0, 4.0 Hz, 1H), 3.25 (dd, J = 7.4, 3.4 Hz, 1H), 3.67-3.73 (m, 1H), 3.82-3.89 (m, 2H); C
NMR (100 MHz, CDCl3) ! 5.8, 7.3, 17.0, 19.4, 23.8, 28.0, 28.6, 31.3, 36.2, 37.2, 59.1, 61.7, 61.7, 62.8,
75.4, 76.4, 81.2; MS(FAB+) Calcd. for C21H42O479Br128Si1 [(M+H)+] 465.2030, found 465.2024.
Tetrahydrofuranyl diol (19): A solution of tetrabutylammonium fluoride (1 M in THF, 6 mL, 6 mmol)
was added to a solution of epoxy alcohol 18 (0.605 g, 1.3 mmol) and glacial acetic acid (0.3 mL, 5.2
mmol) in THF (1 mL). The reaction was monitored by TLC. After starting material was fully consumed,
the reaction was diluted with dichloromethane (10 mL) and washed with a saturated brine solution (3 x 10
mL). The organic layer was dried over MgSO4 and purified by silica gel column chromatography eluted
with methanol : dichloromethane (v/v 2 : 98) producing diol 19 (0.410 g, 90%) as a clear oil. ["]23D +30.7
(CH2Cl2, c 1.47); IR (neat) 3400, 2975, 2939, 2875, 2359, 2340, 1646, 1455, 1380, 1130, 1089, 1111,
1035, 901, 731 cm-1; 1H NMR (400 MHz, CDCl3) ! 1.14 (s, 3H), 1.22 (s, 3H), 1.29 (s, 3H), 1.41 (s, 3H),
1.53-1.60 (m, 2H), 1.65 (dt, J = 13.2, 4.4 Hz, 1H), 1.76-1.89 (m, 2H), 1.96-2.04 (m, 1H), 2.11 (qd, J =
13.2, 4.0 Hz, 1H), 2.26 (dq, J = 13.0, 4.0 Hz, 1H), 3.53 (dd, J = 10.2, 7.4 Hz, 1H), 3.64-3.71 (m, 3H),
13
3.88 (dd, J = 12.4, 4.0 Hz, 1H); C NMR (100 MHz, CDCl3) ! 21.7, 23.3, 23.8, 26.6, 28.1, 31.1, 33.0,
34.7, 58.6, 63.5, 74.8, 75.3, 76.7, 65.0, 88.4; MS(FAB+) Calcd. for C15H28O479Br128 [(M+H)+] 351.1166,
found 351.1166.
Primary acetate ester (20): Acetyl chloride (0.16 mL, 2.3 mmol) was added dropwise to a -78 °C
solution of tetrahydrofuranyl diol 19 (0.648 g, 1.8 mmol) and 2,4,6-trimethylpyridine (0.49 mL, 3.7
mmol) in dichloromethane (3.7 mL). The reaction mixture was stirred for 2 h at -78 °C, then placed in a
-25 °C freezer overnight. The reaction was quenched by the addition of an aqueous HCl solution (1 M, 2
mL, 2 mmol). The aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers
were dried over MgSO4, concentrated, and purified by silica gel column chromatography eluted with
1
Et2O : hexanes (v/v 1 : 1) yielding primary acetate ester 20 (0.650 g, 90%) as a clear oil. H NMR (600
MHz, CDCl3) ! 1.18 (s, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.43 (s, 3H), 1.58-1.61 (m, 3H), 1.88-1.91 (m,
2H), 2.04 (q, J = 12.0 Hz, 1.0 H), 2.11 (s, 3H), 2.12 (dq, J = 13.8, 4.2 Hz, 1H), 2.27 (dq, J = 13.0, 4.0 Hz,

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HETEROCYCLES, Vol. 86, No. 1, 2012
1H), 3.66 (t, J = 7.8 Hz, 1H), 3.76 (dd, J = 7.8, 2.4 Hz, 1H), 3.87 (dd, J = 12.6, 4.2 Hz, 1H), 4.00 (dd, J =
11.7, 8.7 Hz, 1H), 4.27 (dd, J = 12.0, 2.4 Hz, 1H).
Bistetrahydropyran diol (24): Chloromethanesulfonyl chloride (0.16 mL, 1.8 mmol) was added
dropwise to a 0 °C solution of primary acetate 20 (0.137 g, 0.35 mmol) and 2,6-lutidine (0.32 mL, 2.7
mmol) in dichloromethane (0.94 mL). The mixture was stirred for 30 min, then diluted with Et2O (10
mL) and an aqueous HCl solution (0.5 M, 5 mL). The aqueous layer was extracted with additional Et2O
(2 x 5 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude
chloromesylate ester and zinc acetate dihydrate were dissolved in 1,4-dioxane (5 mL) and water (5 mL).
The reaction mixture was heated to 72 °C and stirred for 3 h. The reaction mixture was diluted with
aqueous HCl solution (0.5 M, 5 mL) and Et2O (10 mL). The aqueous layer was extracted with
additional Et2O (2 x 10 mL). The combined organic layers were dried over MgSO4, concentrated and
purified by silica gel column chromatography eluted with a gradient of EtOAc : hexanes (v/v 1: 3 to 5 : 7)
yielding a mixture of diol 24 (0.0302 g, 25%) and the corresponding primary acetate 23 (0.0673 g, 49%).
The primary acetate was removed by treatment with LiOH (0.012 g, 0.5 mmol) in a mixture of water (1
mL) and methanol (3 mL). After monitoring the reaction by TLC, the mixture was diluted with water (1
mL) and Et2O (5 mL). The aqueous layer was extracted with additional Et2O (2 x 5 mL). The combined
organic layers were dried over MgSO4 and concentrated, and no additional purification was necessary.
1H NMR (400 MHz, CDCl3) ! 1.19 (s, 3H), 1.21 (s, 3H), 1.27 (s, 3H), 1.38-1.47 (m, 1H), 1.41 (s, 3H),
1.53-1.62 (m, 2H), 1.75-1.86 (m, 3H), 2.11 (qd, J = 13.6, 4.0 Hz, 1H), 2.26 (dq, J = 13.4, 4.0 Hz, 1H),
3.07 (dd, J = 17.2, 2.0 Hz, 1H), 3.31 (dd, J = 8.0, 6.6 Hz, 1H), 3.62 (dd, J = 17.2, 8.0 Hz, 1H), 3.78 (dd, J
= 17.2, 6.6 Hz, 1H), 3.89 (dd, 12.4, 4.0 Hz, 1H).
Primary tosylate (25): p-Toluenesulfonyl chloride (0.455 g, 2.4 mmol) was added to a 0 °C solution of
diol 19 (0.756 g, 2.2 mmol) in pyridine (31 mL). The reaction was stirred for 1 h, then placed in the
refrigerator (4 °C) for 24 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed
with aqueous saturated brine (3 x 50 mL). The organic layer was dried over MgSO4, concentrated, and
purified by silica gel column chromatography eluted with Et2O : hexanes (v/v 1 : 3) yielding primary
tosylate 25 (0.815 g, 75%) as a clear oil. ["]23D +7.6 (CH2Cl2, c 5.57); IR (neat) 3522, 3442, 2980, 2876,
1
2359, 1599, 1454, 1362, 1176, 1128, 1094, 1034, 970, 909, 835, 815, 765, 732, 662, 554 cm-1; H NMR
(400 MHz, CDCl3) ! 1.09 (s, 3H), 1.19 (s, 3H), 1.27 (s, 3H), 1.40 (s, 3H), 1.51-1.60 (m, 2H), 1.81-1.87
(m, 2H), 1.92-2.00 (m, 1H), 2.09 (qd, J = 13.6, 4.0 Hz, 1H), 2.19-2.30 (m, 1H), 2.45 (s, 3H), 2.60 (d, J =
3.2 Hz, 1H), 3.58 (t, J = 7.4 Hz, 1H), 3.72 (dt, J = 8.0, 2.8 Hz, 1H), 3.86 (dd, J = 12.4, 4.0 Hz, 1H), 3.98
(dd, J = 10.6, 8.0 Hz, 1H), 4.24 (dd, J = 10.6, 2.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz,
13
2H); C NMR (100 MHz, CDCl3) ! 21.4, 21.9, 22.7, 23.8, 26.3, 28.1, 31.1, 33.8, 35.4, 58.7, 71.9, 74.7,
74.7, 75.1, 83.8, 88.5, 128.2, 130.1, 133.0, 145.1; MS(FAB+) Calcd. for C22H34O679Br132S1 [(M+H)+]

HETEROCYCLES, Vol. 86, No. 1, 2012
545
505.1254, found 505.1254.
Terminal epoxide (26): Potassium carbonate (0.670 g, 4.8 mmol) was added to a solution of primary
tosylate 25 (0.815 g, 1.6 mmol) in methanol (16 mL) and stirred for 1 h. The reaction mixture was
concentrated, diluted with Et2O (50 mL) and washed with pH 7 buffer (3 x 50 mL). The organic layer
was dried over MgSO4, concentrated, and purified by silica gel column chromatography eluted with Et2O :
hexanes (v/v 1 : 3) producing terminal epoxide 26 (0.491 g, 91%) as a clear oil. ["]23D +23.2 (CH2Cl2, c
1
0.94); IR (neat) 3583, 2980, 2873, 2359, 1462, 1452, 1381, 1370, 1242, 1130, 1036 cm-1; H NMR (400
MHz, CDCl3) ! 1.23 (s, 3H), 1.24 (s, 3H), 1.29 (s, 3H), 1.42 (s, 3H), 1.54-1.67 (m, 2H), 1.87-1.92 (m,
2H), 2.12 (qd, J = 13.6, 4.0 Hz, 1H), 2.26 (dq, J = 13.0, 4.0 Hz, 1H), 2.58 (dd, J = 5.2, 2.8 Hz, 1H), 2.72
(t, J = 4.6 Hz, 1H), 2.97 (dd, J = 4.4, 2.8 Hz, 1H), 3.66 (t, J = 7.0 Hz, 1H), 3.89 (dd, J = 12.4, 4.0 Hz,
13
1H); C NMR (100 MHz, CDCl3) ! 20.9, 23.9, 24.0 26.5, 28.2, 31.1, 33.1, 36.1, 44.4, 57.4, 59.0, 75.1,
81.6, 88.3; MS(FAB+) Calcd. for C15H26O379Br128 [(M+H)+] 333.1060, found 333.1060.
Silyl alkynyl alcohol (27): A solution of n-butyllithium (1.6 M in hexanes, 3.5 mL, 5.6 mmol) was
added to a -78 °C solution of trimethylsilyl acetylene (0.69 mL, 4.9 mmol) in THF (10 mL). The
alkynyllithium solution was allowed to warm to -55 °C and stirred for 1 h. The mixture was cooled to
-78 °C, boron trifluoride tetrahydrofuran complex (0.69 mL, 6.3 mmol) was added and the acetylide
mixture stirred for 20 min. A solution of terminal epoxide 26 (0.491 g, 1.5 mmol) in THF (8 mL) was
added via cannula to the acetylide solution. The reaction mixture was stirred for -78 °C for 2 h, then
allowed to warm slowly to room temperature over the period of 2 h. The reaction mixture was diluted
with Et2O (75 mL) and washed with pH 7 buffer (3 x 30 mL). The organic layer was dried over MgSO4,
concentrated, and purified by silica gel column chromatography eluted with Et2O : hexanes (v/v 1 : 10)
yielding alkynyl alcohol 27 (0.634 g, 99%) as a clear oil. ["]23D +31.0 (CH2Cl2, c 3.19); IR (neat) 3436,
2973, 2898, 2877, 2175, 1642, 1456, 1381, 1250, 1132, 1076, 1034, 844, 760 cm-1; 1H NMR (400 MHz,
CDCl3) ! 0.15 (s, 9H), 1.15 (s, 3H), 1.22 (s, 3H), 1.29 (s, 3H), 1.41 (s, 3H), 1.56-1.63 (m, 2H), 1.83-1.89
(m, 2H), 1.98-2.05 (m, 1H), 2.11 (qd, J = 13.6, 4.0 Hz, 1H), 2.20-2.30 (m, 1H), 2.35 (dd, J = 16.8, 9.0 Hz,
13
1H), 2.50 (dd, J = 16.8, 3.6 Hz, 1H), 3.61-3.67 (m, 2H), 3.88 (dd, J = 12.8, 4.0 Hz, 1H); C NMR (100
MHz, CDCl3) ! 0.26, 21.2, 22.9, 23.8, 24.0, 26.6, 28.2, 31.1, 33.0, 35.7, 58.9, 74.8, 75.1, 75.2, 85.2, 86.9,
88.6, 104.5; MS(FAB+) Calcd. for C20H35O379Br123Na128Si1 [(M+Na)+] 453.1431, found 453.1432.
Alkynyl alcohol (29): Chloromethanesulfonyl chloride (0.21 mL, 2.4 mmol) was added dropwise to a
solution of alkynyl alcohol 27 (0.207 g, 0.48 mmol) and 2,6-lutidine (0.45 mL, 3.9 mmol) in
dichloromethane (1.3 mL) at 0 °C. The reaction mixture was stirred for 1 h, diluted with ethyl acetate
(10 mL) and washed with saturated aqueous brine (2 x 5 mL). The organic layer was dried over MgSO4
and concentrated. The crude chloromesylate 28 was dissolved in dioxane (6.5 mL) and water (6.5 mL).
Zinc acetate dihydrate (0.422 g, 1.9 mmol) was added to the solution and the reaction mixture was heated

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HETEROCYCLES, Vol. 86, No. 1, 2012
to 60 °C for 5 h. The reaction mixture was diluted with dichloromethane (10 mL) and pH 7 buffer (5
mL). The aqueous layer was extracted with additional dichloromethane (2 x 10 mL), the combined
organic layers were dried over MgSO4, concentrated, and purified by silica gel column chromatography
eluted with Et2O : hexanes (v/v 1 : 10) yielding bistetrahydropyranyl alcohol 29 (0.0638 g, 31%) as a clear
oil. ["]23D +40.8 (CH2Cl2, c 0.25); IR (neat) 3413, 2959, 2859, 2361, 2178, 1718, 1631, 1470, 1380, 1249,
1129, 1103, 1072, 1017, 843, 760 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.14 (s, 9H), 1.19 (s, 3H), 1.20 (s,
3H), 1.27 (s, 3H), 1.40 (s, 3H), 1.50-1.64 (m, 2H), 1.75-1.87 (m, 4H), 2.10 (qd, J = 13.6, 4.0 Hz, 1H),
2.25 (dq, J = 13.4, 4.0 Hz, 1H), 2.34 (dd, J = 17.2, 8.0 Hz, 1H), 3.04 (dd, J = 12.4, 3.6 Hz, 1H), 3.38 (dd,
J = 8.0, 6.8 Hz, 1H), 3.91 (dd, J = 12.0, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) ! 0.2, 20.2, 20.3, 21.4,
23.2, 23.9, 28.4, 29.9, 31.2, 37.2, 39.2, 59.2, 70.6, 74.6, 75.2, 82.3, 86.5, 86.9, 104.8; MS(FAB+) Calcd.
for C20H36O379Br128Si1 [(M+H)+] 431.1612, found 431.1600.
Bistetrahydropyranyl alcohol (30): Potassium carbonate (0.0984 g, 0.71 mmol) was added to a
solution of silyl alkynyl alcohol 29 (0.0638 g, 0.15 mmol) in methanol (3 mL) and stirred overnight.
The reaction mixture was concentrated, diluted with dichloromethane (10 mL) and washed with pH 7
buffer (3 x 5 mL). The organic layer was dried over MgSO4, concentrated, purified by silica gel column
chromatography eluted with methanol : dichloromethane (v/v 1 : 199) resulting in alkynyl alcohol 30
(0.0319 g, 60%) as a white solid. mp 61-62 °C; ["]23D +46.4 (CH2Cl2, c 0.83); IR (neat) 3413, 3307, 2924,
1
2856, 1462, 1381, 1265, 1128, 1103, 1072, 1028, 980, 737 cm-1; H NMR (400 MHz, CDCl3) ! 1.17 (s,
3H), 1.19 (s, 3H), 1.27 (s, 3H), 1.40 (s, 3H), 1.56 (tt, J = 13.2, 4.0 Hz, 2H), 1.74-1.87 (m, 4H), 2.00 (t, J =
2.6 Hz, 1H), 2.11 (qd, J = 13.6, 4.0 Hz, 1H), 2.19-2.30 (m, 2H), 2.49 (ddd, J = 16.8, 5.2, 2.8 Hz, 1H),
13
3.05 (dd, J = 11.6, 2.0 Hz, 1H), 3.56 (dd, J = 8.2, 5 Hz, 1H), 3.90 (dd, J = 12.2, 4.0 Hz, 1H); C NMR
(100 MHz, CDCl3) ! 19.9, 20.2, 20.2, 23.3, 23.8, 28.4, 29.9, 31.2, 37.0, 39.5, 59.2, 69.7, 70.4, 74.6, 75.1,
82.4, 82.6, 86.4; MS(FAB+) Calcd. for C17H28O379Br1 [(M+H)+] 359.1216, found 359.1218.
!-Stannyldihydropyran (31): A solution of alkynyl alcohol 30 (0.0319 g, 0.09 mmol) and tungsten
hexacarbonyl (0.163 g, 0.5 mmol) in anhydrous degassed THF (4 mL) was irradiated at 350 nm for 2 h.
The reaction mixture was stirred for 16 h, then irradiated for an additional 2 h. After stirring for an
additional 24 h, the reaction mixture was concentrated. Powdered, activated 4 Å molecular sieves (0.6 g)
and Et2O were added to the crude tungsten oxacarbene and stirred for 10 min. A solution of tributyltin
triflate35 (0.103 g, 0.24 mmol) in Et2O (0.5 mL) was added and stirred for 10 min, followed by the
addition of Et3N (0.86 mL, 6.2 mmol). After stirring overnight the mixture was filtered to remove the
sieves and concentrated. The crude yellow solid was purified by silica gel column chromatography
eluted with Et2NH : hexanes (v/v 2 : 98), producing stannyl dihydropyran 31 as an off white solid (0.0229 g,
40%). ["]23D -2.5 (CH2Cl2, c 0.49); IR (neat) 2954, 2926, 2852, 1600, 1455, 1375, 1132, 1101, 1044,
1022, 952, 903. 736 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.87-0.92 (m, satellite signals from coupling to

HETEROCYCLES, Vol. 86, No. 1, 2012
547
117/119Sn were observed, JSn-H = 26.0 Hz, 15H), 1.10, (s, 3H), 1.21 (s, 3H), 1.26-1.36 (m, 6H), 1.28 (s, 3H),
1.41 (s, 3H), 1.47-1.58 (m, 9H), 1.76-1.92 (m, 4H), 2.00-2.14 (m, 2H), 2.25 (dq, J = 13.6, 4.0 Hz, 1H),
3.08 (dd, J = 10.6, 2.6 Hz, 1H), 3.33 (dd, J =11.0, 5.6 Hz, 1H), 3.91 (dd, J = 12.0, 4.0 Hz, 1H), 4.61 (dd, J
3
13
= 5.6, 2.0 Hz, satellite signals from coupling to 117/119Sn were observed, JSn-H = 14.0 Hz, 1H); C NMR
(100 MHz, CDCl3) ! 9.8, 14.0, 15.8, 20.2, 23.2, 23.9, 26.0, 27.4, 28.4, 29.1, 29.2, 31.2, 36.9, 37.4, 59.3,
73.9, 74.5, 75.1, 86.4, 108.7, 160.0; MS(FAB+) Calcd. for C29H54O379Br1120Sn1 [(M+H)+] 649.2273, found
649.2258.
2,3-Epoxygeraniol (32):19 4Å powdered, activated molecular sieves (5.18 g) were suspended in
anhydrous dichloromethane (50 mL) in a 100 mL 3-necked round bottom flask equipped with a
thermometer. The suspension was cooled to -20 °C and L-(+)-diethyl tartrate (0.22 mL, 1.28 mmol) and
Ti(Oi-Pr)4 (0.25 mL, 0.84 mmol) were added with stirring. A solution of anhydrous TBHP (5.5M in
decane, 4.8 mL, 26.4 mmol) was added dropwise and the catalyst mixture was aged for 30 min at -20 °C.
Geraniol (11, 3 mL, 17.3 mmol) was added over a period of 20 min. The reaction mixture was stirred for
5 h at -20 °C then placed in a -25 °C freezer overnight. The cold mixture was filtered through celite and
stirred with a solution of KOH (1.5 M, 50 mL) for 1 h. The biphasic mixture was separated and the
aqueous layer was extracted with additional dichloromethane (3 x 50 mL). The combined organic layers
were dried over MgSO4 and concentrated. The resultant oil was purified by silica gel column
chromatography eluted with diethyl ether : hexanes (v/v 1 : 3) yielding 2,3-epoxygeraniol 32 (2.88 g, 98%)
as a colorless oil. ["]23D -5.8 (CH2Cl2, c 0.99) {lit.,19 ["]25D -5.3 (CHCl3, c 3.0)}; IR (neat) 3430, 2968,
2925, 2859, 1673, 1453, 1384, 1251, 1222, 1076, 1037, 865 cm-1; 1H NMR (400 MHz, CDCl3) ! 1.31 (s,
3H), 1.44-1.52 (m, 1H), 1.62 (s, 3H), 1.65-1.73 (m, 1H), 1.69 (s, 3H), 2.09 (bq, J = 7.6 Hz, 2H), 2.99 (dd,
J = 6.4, 4.4 Hz, 1H), 3.67-3.72 (m, 1H), 3.81-3.87 (m, 1H), 5.09 (tt, J = 7.0, 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) ! 17.0, 17.9, 23.9, 25.9, 38.7, 61.4, 61.7, 63.1, 123.5, 132.4; MS(FAB+) Calcd. for
C10H19O2 [(M+H)+] 171.1380, found 171.1375.
1-Tosyl-2,3-epoxygeraniol (33):26 2,3-Epoxygeraniol 32 (2.88 g, 16.9 mmol) was dissolved in pyridine
(16 mL) and cooled to 0 °C. p-Toluenesulfonyl chloride (3.56 g, 18.7 mmol) was added and stirred until
just dissolved. The reaction mixture was then placed in the freezer (-25 °C) overnight. The cold mixture
was filtered to remove the solids and the solids were rinsed with cold Et2O. The filtrate was washed with
pH 7 buffer (3 x 50 mL) and the organic layers were dried over MgSO4 and concentrated. The resultant
oil was purified by silica gel column chromatography eluted with Et2O : hexanes (v/v 1 : 10) yielding
tosylepoxygeraniol 33 (4.42 g, 81%) as a clear oil. ["]23D -4.6 (CH2Cl2, c 0.99); IR (neat) 2968, 2925,
1
2859, 1598, 1452, 1364, 1177, 1097, 966, 816 cm-1; H NMR (400 MHz, CDCl3) ! 1.21 (s, 3H),
1.40-1.47 (m, 1H), 1.60 (s, 3H), 1.60-1.68 (m, 1H), 1.68 (s, 3H), 2.04 (bq, J = 8.0 Hz, 2H), 2.46 (s, 3H),
2.98 (t, J = 5.6 Hz, 1H), 4.12 (dq, J = 11.2, 5.6 Hz, 2H), 5.04 (tt, J = 7.2, 1.4 Hz, 1H), 7.37 (d, J = 8.0 Hz,

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HETEROCYCLES, Vol. 86, No. 1, 2012
2H), 7.82 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) ! 16.9, 17.9, 21.9, 23.7, 25.9, 38.2, 58.9, 61.1,
68.8, 123.2, 128.2, 130.2, 132.6, 132.8, 145.3; MS(FAB+) Calcd. for C17H24O423Na132S1 [(M+Na)+]
347.1288, found 347.1284.
Tosyltetrahydrofuran (34): Tosylepoxygeraniol 33 (2.20 g, 6.77 mmol) was dissolved in a mixture of
t-BuOH : H2O (v/v 1 : 1, 70 mL). AD mix # (9.48 g) and methanesulfonamide (0.647 g, 6.8 mmol) were
added to the solution. After the solids had dissolved completely, the biphasic mixture was cooled to 0 °C
and stirred for 5 h. The reaction was allowed to warm to room temperature and stirred overnight.
Sodium sulfite (10.2 g, 81 mmol) was added and stirred for 1 h. The layers were separated and the
aqueous layer was extracted with dichloromethane (3 x 150 mL). The combined organic layers were
dried over MgSO4 and concentrated. The yellow oil was diluted with dichloromethane (100 mL);
camphorsulfonic acid (0.149 g, 0.6 mmol) was added and stirred for 10 min. The acid solution was
concentrated producing a yellow oil which was purified by silica gel column chromatography eluted with
MeOH : dichloromethane (v/v 2 : 98). The tosylated tetrahydrofuran 34 was obtained as a clear oil (2.26 g,
93%). ["]23D -8.8 (CH2Cl2, c 0.79); IR (neat) 3535, 3409, 2974, 2876, 1598, 1453, 1358, 1175, 1094, 968,
837, 816 cm-1; 1H NMR (400 MHz, CDCl3) ! 1.11 (s, 3H), 1.13 (s, 3H), 1.18 (s, 3H), 1.64-1.70 (m, 1H),
1.82-1.88 (m, 2H), 2.02-2.09 (m, 1H), 2.46 (s, 3H), 3.72 (dd, J = 9.0, 6.6 Hz, 1H), 3.78 (dd, J = 8.0, 2.8
Hz, 1H), 4.01 (dd, J = 10.4, 7.6 Hz, 1H), 4.25 (dd, J = 10.4, 2.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.82 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) ! 21.9, 22.9, 24.2, 26.4, 27.7, 34.3, 70.7, 71.7, 74.9, 83.8,
87.4, 128.2, 130.2, 132.9, 145.3; MS(FAB+) Calcd. for C17H27O632S1 [(M+H)+] 359.1523, found 359.1513.
Epoxytetrahydrofuranyl alcohol (35):26 Tosyltetrahydrofuran 34 (2.26 g, 6.3 mmol) was dissolved in
MeOH (30 mL) with stirring. Potassium carbonate (3.49 g, 25.2 mmol) was added and the suspension
was stirred for 15 min. The reaction mixture was concentrated to 5 mL, the residue was diluted with
dichloromethane (50 mL) followed by an aqueous solution of NH4Cl (1 M, 25 mL, 25 mmol). The
aqueous layer was diluted with pH 7 buffer (50 mL) and extracted with dichloromethane (3 x 50 mL).
The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified
by silica gel column chromatography eluted with Et3N : EtOAc : hexanes (3 : 22 : 75) yielding
epoxytetrahydrofuranyl alcohol 35 (1.03 g, 87%). ["]23D -2.7 (CH2Cl2, c 1.39) {lit.26 ["]D -2.45 (CHCl3, c
6.72)}; IR (neat) 3461, 3057, 2975, 2934, 2874, 1725, 1642, 1464, 1373, 1308, 1241, 1178, 1142, 1055,
986, 943, 915, 898, 863, 814 cm-1; 1H NMR (400 MHz, CDCl3) ! 1.13 (s, 3H), 1.23 (s, 3H), 1.28 (s, 3H),
1.61-1.64 (m, 2H), 1.82-1.87 (m, 2H), 2.59 (dd, J = 5.2, 2.8 Hz, 1H), 2.75, (t, J = 4.4 Hz, 1H), 3.04 (dd, J
13
= 4.0, 2.8 Hz, 1H), 3.78 (t, J = 7.6 Hz, 1H); C NMR (100 MHz, CDCl3) ! 24.3, 24.5, 26.4, 27.7, 32.9,
44.1, 57.3, 70.8, 81.5, 87.0; MS(FAB+) Calcd. for C10H19O3 [(M+H)+] 187.1329, found 187.1327.
Epoxytetrahydrofuranyl silyl ether (36): Trimethylsilyl chloride was added dropwise to a solution of
epoxytetrahydrofuranyl alcohol 35 (1.02 g, 5.5 mmol) and imidazole (1.51 g, 22.1 mmol) in THF (5 mL).

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The solution was stirred overnight. The reaction mixture was diluted with Et2O (50 mL) and pH 7 buffer
(50 mL). The organic layer was washed with additional pH 7 buffer (2 x 50 mL), then dried over MgSO4.
After concentration of the crude product, purification by silica gel column chromatography eluted with
Et3N : hexanes (v/v 3 : 97) yielded the silyl ether 36 (1.03 g, 72%). ["]23D -2.9 (CH2Cl2, c 1.41); IR (neat)
3436, 3052, 2974, 2897, 2874, 1632, 1462, 1382, 1369, 1250, 1174, 1101, 1063, 1044, 916, 840 cm-1; 1H
NMR (400 MHz, CDCl3) ! 0.12 (s, 9H), 1.18 (s, 3H), 1.22 (s, 3H), 1.24 (s, 3H), 1.57-1.63 (m, 1H),
1.75-1.81 (m, 1H), 1.86-1.93 (m, 2H), 2.59 (dd, J = 5.2, 2.8 Hz, 1H), 2.73 (bt, J = 4.6 Hz, 1H), 3.00 (dd, J
13
= 4.2, 3.0 Hz, 1H), 3.72 (t, J = 7.0 Hz, 1H); C NMR (100 MHz, CDCl3) ! 2.8, 24.0, 25.9, 26.7, 27.8,
33.2, 44.4, 57.4, 75.0, 81.7, 87.7; MS(FAB+) Calcd. for C13H27O328Si1 [(M+H)+] 259.1724, found
259.1721.
Alkenyl tetrahydrofuranyl alcohol (37): A solution of 2-methylallylmagnesium chloride (0.5 M in
THF, 13 mL, 6.5 mmol) was added dropwise to a -40 °C suspension of CuI (0.184 g, 0.97 mmol) in THF
(3 mL) and stirred for 10 min. A solution of epoxytetrahydrofuran 36 (1.03 g, 5.0 mmol) in THF (4 mL)
was added to the Grignard solution. The reaction was warmed to 0 °C and stirred for 30 min, then
allowed to warm to room temperature. The reaction was stirred for an additional 30 min, then diluted
with Et2O (50 mL) and pH 7 buffer (50 mL). The aqueous layer was extracted with additional Et2O (2 x
50 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was
purified by neutral alumina column chromatography eluted with Et2O : toluene (v/v 1 : 199) yielding
unsaturated alcohol 47 (0.992 g, 79%) as a clear oil. ["]23D +6.8 (CH2Cl2, c 0.27); IR (neat) 3462, 2970,
2872, 2095, 1648, 1454, 1380, 1250, 1176, 1131, 1040, 909, 883, 840 cm-1; 1H NMR (400 MHz, CDCl3)
! 0.12 (s, 9H), 1.13 (s, 3H), 1.17 (s, 3H), 1.24 (s, 3H), 1.36-1.45 (m, 1H), 1.51 (ddd, J = 11.4, 7.4, 2.0 Hz,
1H), 1.55-1.63 (m, 1H), 1.75 (s, 3H), 1.80-1.96 (m, 2H), 2.01-2.15 (m, 2H), 2.29-2.36 (m, 1H), 2.44 (t, J
= 2.0 Hz, 1H), 3.51 (dt, J = 10.8, 2.0 Hz, 1H), 3.69 (dd, J = 9.8, 5.8 Hz, 1H), 4.72-4.73 (m, 2H); 13C NMR
(100 MHz, CDCl3) ! 2.8, 22.8, 24.1, 26.5, 26.9, 27.3, 29.8, 31.1, 35.1, 74.5, 76.4, 86.3, 88.6, 110.1,
146.2; MS(FAB+) Calcd. for C17H38O3N128Si1 [(M+NH4)+] 332.2616, found 332.2614.
Unsaturated bisilyl ether tetrahydrofuran (38): Trimethylsilyl chloride (1.3 mL, 10.3 mmol) was
added dropwise to a solution of unsaturated alcohol 37 (0.992 g, 3.2 mmol) and imidazole (1.42 g, 20.9
mmol) in THF (20 mL). The reaction mixture was stirred overnight then concentrated. The resulting
yellow oil was diluted with dichloromethane (50 mL) and pH 7 buffer (50 mL). The organic layer was
washed with additional pH 7 buffer (2 x 50 mL) then dried over MgSO4. The crude product was purified
by silica gel column chromatography eluted with Et3N : hexanes (v/v 3 : 97) yielding silyl ether 38 (1.12
g, 92%). ["]23D +0.5 (CH2Cl2, c 1.26); IR (neat) 3076, 2960, 2873, 1650, 1454, 1373, 1250, 1173, 1131,
1102, 1066, 1042, 840 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.11 (s, 9H), 0.13 (s, 9H), 1.09 (s, 3H), 1.17 (s,
3H), 1.21 (s, 3H), 1.35-1.44 (m, 1H), 1.50-1.55 (m, 1H), 1.66-1.73 (m, 1H), 1.74 (s, 3H), 1.76-2.00 (m,

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HETEROCYCLES, Vol. 86, No. 1, 2012
4H), 2.14-2.21 (m, 1H), 3.52 (dd, J = 9.8, 2.6 Hz, 1H), 3.66 (dd, J = 9.0, 5.8 Hz, 1H), 4.71 (bd, J = 5.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) ! 1.2, 2.8, 22.9, 23.5, 26.2, 26.7, 27.6, 31.5, 33.6, 35.2, 74.8, 78.2, 85.9,
87.3, 109.8, 146.5; MS(FAB+) Calcd. for C20H46O3N128Si2 [(M+NH4)+] 404.3011, found 404.3011.
Methyl ketone (39): Ozone was bubbled through a -78 °C solution of alkene 38 (1.78 g, 4.6 mmol),
pyridine (9 mL), methanol (15 mL), and isopropanol (15 mL) with stirring. The reaction was monitored
by TLC. After complete consumption of alkene, dimethyl sulfide (1.4 mL, 19.1 mmol) was added and
the solution was warmed to room temperature. The reaction mixture was stirred overnight, then
concentrated. The crude product mixture was diluted with Et2O (50 mL), washed with pH 7 buffer (3 x
50 mL), then dried over MgSO4 and concentrated. Trimethylsilyl chloride (1.4 mL, 11.1 mmol) was
added dropwise to a solution of the resultant oil and imidazole (1.80 g, 26.4 mmol) in THF (7 mL). The
reaction mixture was stirred overnight then concentrated. The yellow oil was dissolved in Et2O (50 mL),
washed with pH 7 buffer (3 x 50 mL), dried over MgSO4, and concentrated. The crude product was
purified by silica gel column chromatography eluted with Et3N : hexanes (v/v 3 : 97) resulting in methyl
ketone 39 (1.20 g, 67%). ["]23D +1.1 (CH2Cl2, c 1.69); IR (neat) 2962, 2899, 2873, 1720, 1454, 1410,
1
1362, 1250, 1174, 1103, 1041, 912, 841 cm-1; H NMR (400 MHz, CDCl3) ! 0.10 (s, 9H), 0.12 (s, 9H),
1.09 (s, 3H), 1.15 (s, 3H), 1.20 (s, 3H), 1.47-1.56 (m, 2H), 1.75-1.97 (m, 4H), 2.15 (s, 3H), 2.39-2.47 (m,
13
1H), 2.57-2.65 (m, 1H), 3.52 (dd, J = 9.4, 3.4 Hz, 1H), 3.63 (dd, J = 9.0, 5.8 Hz, 1H); C NMR (100
MHz, CDCl3) ! 1.0, 2.8, 23.5, 26.2, 26.5, 27.5, 27.6, 30.1, 33.4, 41.2, 74.7, 85.9, 87.5, 209.4; MS(FAB+)
Calcd. for C19H41O428Si2 [(M+H)+] 389.2538, found 389.2539.
Enol triflate (40): A solution of KHMDS (0.5 M in toluene, 1.5 mL, 0.75 mmol) was added dropwise to
a -78 °C solution of methyl ketone 39 (0.261 g, 0.67 mmol) in THF (7 mL). The enolate solution was
stirred for 1 h. A solution of N-phenyl-bis(trifluoromethanesulfonimide) (0.362 g, 1.0 mmol) in THF (2
mL) was added dropwise to the enolate solution. The reaction was stirred at -78 °C for 10 min, then
allowed to warm to room temperature. After 1 h the reaction mixture was concentrated, diluted with
Et2O (10 mL), washed with pH 7 buffer (2 x 5 mL), and dried over MgSO4. After concentration the
crude product was purified by silica gel column chromatography eluted with Et3N : hexanes (v/v 3 : 97)
yielding enol triflate 40 (0.304 g, 87%). ["]23D +1.1 (CH2Cl2, c 0.51); IR (neat) 2962, 2900, 2873, 1670,
1419, 1252, 1213, 1176, 1146, 1101, 1066, 1041, 939, 883, 841 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.11
(s, 9H), 0.13 (s, 9H), 1.09 (s, 3H), 1.16 (s, 3H), 1.21 (s, 3H), 1.47-1.61 (m, 2H), 1.75-1.95 (m, 4H),
2.27-2.35 (m, 1H), 2.48-2.56 (m, 1H), 3.52 (dd, J = 9.4, 3.4 Hz, 1H), 3.64 (dd, J = 9.0, 5.8 Hz, 1H), 4.97
13
(d, J = 3.6 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H); C NMR (100 MHz, CDCl3) ! 1.0, 2.8, 23.0, 26.2, 26.5,
27.5, 29.9, 30.0, 31.4, 34.2, 74.6, 85.6, 87.5, 104.3, 113.9, 117.1, 120.3, 123.5, 157.4; MS(FAB+) Calcd.
for C20H39O6F323Na132S128Si2 [(M+Na)+] 543.1850, found 543.1860.
Dienyl ether (7): A solution of enol triflate 40 (39.6 mg, 76 $mol) in DMF (6 mL) was degassed by

HETEROCYCLES, Vol. 86, No. 1, 2012
551
three freeze-pump-thaw cycles, and then was transferred to a flask containing "-stannyl dihydropyran 31
(42.1 mg, 65 $mol), tetrakis(triphenylphosphine)palladium(0) (1.8 mg, 1.6 $mol), CuI36 (10.4 mg, 55
$mol), and CsF (0.02 g, 0.13 mmol). The reaction mixture was degassed an additional 2 cycles. The
mixture was heated to 50 °C and stirred for 22 h. After cooling, the solution was diluted with EtOAc (20
mL), dichloromethane (20 mL) and water (10 mL) and stirred for an additional 1 h. The biphasic mixture
was filtered through celite and diluted with saturated brine (20 mL). The aqueous layer was extracted
with a EtOAc : dichloromethane (1 : 1) solution (20 mL x 3). The combined organic layers were dried
over MgSO4, concentrated, and purified by silica gel column chromatography eluted with a gradient of
Et2O : hexanes (v/v 1 : 4 to 1 : 1) resulting in a mixture of monosilyl product and free diol. The mixture
was diluted with THF (1 mL) and a solution of tetrabutylammonium fluoride (1 M in THF, 1 mL, 1
mmol) and stirred for 1 h. The crude diol solution was concentrated and purified by silica gel column
chromatography eluted with methanol : dichloromethane (v/v 2 : 98) yielding the dienyl ether 7 (23.3 mg,
61%) as a waxy solid. mp 119-122 °C; ["]23D -7 (CH2Cl2, c 0.145); IR (neat) 3435, 2972, 2926, 2852,
1
1641, 1458, 1377, 1321, 1180, 1122, 1105, 1022, 895 cm-1; H NMR (600 MHz, CDCl3) ! 1.11 (s, 3H),
1.13 (s, 6H), 1.22 (s, 6H), 1.28 (s, 3H), 1.41 (s, 3H), 1.50-1.58 (m, 3H), 1.62-1.70 (m, 2H), 1.82-1.89 (m,
3H), 1.93-1.98 (m, 3H), 2.07-2.14 (m, 2H), 2.17-2.28 (m, 3H), 2.32 (bt, J = 1.8 Hz, 1H), 2.50-2.55 (m,
1H), 3.10 (dd, J = 11.4, 1.8 Hz, 1H), 3.36 (dd, J = 10.8, 6.0 Hz, 1H), 3.54 (bd, J = 10.2 Hz, 1H), 3.76 (dd,
13
J = 10.5, 5.7 Hz, 1H), 3.91 (dd, J = 12.6, 4.2 Hz, 1H), 4.92-4.93 (m, 2H), 5.41 (bd, J = 1.2 Hz, 1H); C
NMR (100 MHz, CDCl3) ! 15.4, 20.2, 23.0, 23.9, 24.1, 24.1, 25.2, 26.8, 28.0, 28.4, 30.1, 31.1, 31.2, 31.4,
36.7, 37.4, 59.2, 70.6, 73.5, 74.6, 75.2, 76.5, 76.7, 86.3, 86.5, 87.9, 96.0, 111.4, 142.8, 149.1; MS(FAB+)
Calcd. for C30H50O679Br1 [(M+H)+] 585.2785, found 585.2783.
ACKNOWLEDGEMENTS
This work was supported primarily by the National Science Foundation (CHE-0516793).
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34. MS(FAB+) Calcd. for C32H55O1179Br123Na1 [(M+Na)+] 717.2820, found 717.2807.
35. Tributyltin triflate was freshly prepared by dropwise addition of triflic anhydride (0.03 mL, 0.18
mmol) to neat bistributyltin oxide (0.06 mL, 0.12 mmol). The neat solution was stirred for 1 h, then
excess triflic anhydride was removed by vacuum. The white solid was used without purification.
36. Ultrapure CuI was further purified by Soxhlet extraction with THF.
37. Supporting Information is available on the Heterocycles website, http://www.heterocycles.jp/.