Stereoselectivity of electrophile-promoted oxacyclizations of 1,4-dihydroxy-5-alkenes to 3-hydroxytetrahydropyrans Dedicated to Professor Paul A. Wender with heartiest congratulations on his receipt of the 2012 Tetrahedron Prize for Creativity in Organic

Article abstract of DOI:10.1016/j.tet.2013.04.138

Stereoinduction from the allylic hydroxyl group of 1,4-dihydroxy-5-alkenes has been systematically explored with various alkene substitution patterns and electrophilic reagents. For formation of erythro-diastereomers of 2-substituted 3-hydroxytetrahydropy

Full text of DOI:10.1016/j.tet.2013.04.138

Tetrahedron 69 (2013) 7746e7758
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journal homepage: www.elsevier.com/locate/tet
Stereoselectivity of electrophile-promoted oxacyclizations of
1,4-dihydroxy-5-alkenes to 3-hydroxytetrahydropyrans
*
Frank E. McDonald , Kento Ishida, Jessica A. Hurtak
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoinduction from the allylic hydroxyl group of 1,4-dihydroxy-5-alkenes has been systematically
explored with various alkene substitution patterns and electrophilic reagents. For formation of erythro-
diastereomers of 2-substituted 3-hydroxytetrahydropyrans, mercuric trifluoroacetate-promoted cycli-
zations of cis- and (Z)-alkenyldiols generally give the highest diastereoselectivities. For the corresponding
1,4-dihydroxy-5-alkyne, mercuric triflate-catalyzed cyclization followed by triethylsilane reduction af-
fords an alternative route to the erythro-diastereomer.
Received 28 February 2013
Received in revised form 29 April 2013
Accepted 30 April 2013
Available online 9 May 2013
Dedicated to Professor Paul A. Wender with
heartiest congratulations on his receipt of
the 2012 Tetrahedron Prize for Creativity in
Organic Chemistry
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alcohol
Alkene
Alkyne
Cyclic ether
Diastereoselectivity
Oxacyclization
1. Introduction
focused on mechanistic design to favor endo-mode cyclization mo-
tifs.5 On the other hand, a few strategies for fused polycyclic ether
transesynetrans Polycyclic ether natural products have long
been the subject of considerable interest by the synthetic commu-
nity,1 both in terms of target-directed total synthesis and de-
velopment of synthetic methods inspired by the common
stereochemistry of the ring fusions, exemplified by the structure of
brevanal (1, Fig.1).2 Our laboratory has explored several approaches
tothese compounds, including iterative alkynol cycloisomerizations
and polyepoxide cyclizations.3,4 These synthetic methods have
structures from other laboratories have utilized exo-cyclizations
(2/3, 5/6, Fig. 2) followed by solvolytic ring expansion to prod-
ucts corresponding to endo-mode cyclization (i.e., 4, 7).6,7
Fig. 2. exo-Mode cyclization followed by stereospecific ring expansion.
Fig. 1. Structure of brevenal.
Herein we describe preliminary studies toward a variation on
this approach, in which 1,4-dihydroxy-5-alkenes 8 bearing an al-
lylic alcohol in the tether will undergo 6-exo-mode cyclization with
stereoinduction from the chiral allylic alcohol, so that the ether
* Corresponding author. Tel.: þ1 404 727 6102; fax: þ1 404 727 6586; e-mail
address: fmcdona@emory.edu (F.E. McDonald).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.138

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
7747
oxygen in product structures 9 or 10 will be erythro or threo, re-
2. Results and discussion
spectively, with reference to the chiral alcohol (Fig. 3). In this new
approach, subsequent rearrangement will not be required if the
regio- and stereoselectivity are properly controlled. Although ex-
tensive studies of 5-exo-mode cyclizations have been reported,
especially for electrophile-promoted lactonizations,8,9 fewer stud-
ies have been described for 6-exo-mode cyclizations to forming 3-
hydroxytetrahydropyrans. The most relevant studies utilized
compounds bearing additional substituents and chiral centers in
the tether, so that stereoinduction from the chiral allylic alcohol
was not isolated from other factors.10,11
2.1. Preparation of 1,4-dihydroxy-5-alkene substrates
By design, all substrates had an additional oxygen protected as
a benzyl or silyl ether, to mimic the presence of additional oxygens
as a model system for future tandem cyclization processes. Most of
the required substrates were prepared by nucleophilic addition to
4-silyloxybutanal (11).12 For instance, the terminal alkyne of 12 was
deprotonated with n-butyllithium,13 followed by addition to alde-
hyde 11 to provide the propargylic alcohol 14, with deprotection of
the silyl ether affording the 1,4-dihydroxy-5-alkyne substrate 15.
P2-nickel hydrogenation14 afforded reduction to give the cis-alkene
predominantly, whereas the trans-alkene isomer 17 was prepared
by hydroxyl-directed reduction with Red-Al (Fig. 5).15 The 1,1-
disubstituted alkene of 21 was synthesized from halogen-metal
exchange of 19,16 with addition to tetrahydro-2-furanol (20,
Fig. 6).17
H
H
H
OH
R3
X+
OH
R3
OH
R3
and/or
X
X
HO
R1
O
O
R1
R1
R2
R2
R2
9
10
threo
8
erythro
Fig. 3. Oxacyclization with stereoinduction from the chiral allylic alcohol.
O
TBSO
H
OH
Chamberlin and Hehre have proposed a reactive conformational
model for a variety of cyclization reactions with stereoinduction
from allylic alcohol substituents.9 The essential features of this
model predict that intramolecular electrophilic additions generally
11
RO
M
OBn
OBn
14 R = TBS (64%)
15 R = H (73%)
Bu4NF
THF
occur via conformation A, in which the electrophile forms a
p-
12 M = H
13 M = Li
n-BuLi
THF, 0 o
C
complex on the face syn- to the carbinol hydrogen, with the allylic
hydroxyl in the plane of the alkene (Fig. 4). In contrast to in-
termolecular electrophilic additions, the internal nucleophile will
1. Ni(OAc)2-4H2O / NaBH4
H2NCH2CH2NH2, EtOH
OBn
OH
add to the electrophile-activated alkene before the p-complex can
H2 (1 atm)
HO
14
transform into an onium ion. Applying this model to the formation
of six-membered rings from 1,4-dihydroxy-5-alkenes 8 predicts the
formation of the threo-diastereomer 10. However, the synthetic
application of this transformation to the trans-fused polycyclic
ethers will require the opposite erythro-diastereomer 9. To this end,
the ChamberlineHehre model predicts that the erythro-di-
astereomer 9 will arise from 1,4-dihydroxy-5-alkene 8 with a cis-
alkene (R3sH), in which the hydroxyl-in-plane conformer A is
destabilized by steric interaction with R3. The alternate conformer
B has the sterically small carbinol hydrogen in the plane of the
alkene, so that intramolecular nucleophilic addition occurs on the
opposite face of the activated alkene. In this paper, we will sys-
tematically report the patterns of stereoinduction in cyclizations
with a variety of di- and trisubstituted 1,4-dihydroxy-5-alkenes as
well as a related transformation with a dihydroxyalkyne congener,
with the goal of finding generally applicable methods to prepare
the erythro-diastereomers required for the synthesis of trans-fused
polycyclic ether natural products.
2. Bu4NF, THF
16
1. Red-Al
OH
Et2O, 0 o to 20 o
C
HO
14
OBn
2. Bu4NF, THF
17
Fig. 5. Preparation of dihydroxyalkyne substrate 15, and the cis- and trans-1,2-
disubstituted dihydroxyalkenes 16 and 17.
n-BuLi
OH
Et2O, -78 oC; then
I
OR
HO
OTBS
O
OH
(20)
TBSCl
imidazole
DMF
21 (44%)
18 R = H
19 R = TBS (94%)
Fig. 6. Preparation of 1,1-disubstituted dihydroxyalkene 21.
X+
OH
HO
X+
OH
H
R3
R2
R3
R2
8
To avoid the difficulty of selectively deprotecting only one of two
TBS ethers in subsequent substrates, the trisubstituted dihydrox-
yalkenes 24 and 30 were protected as the triisopropylsilyl (TIPS)
ethers. Thus the known vinylic iodide 2218 underwent halogen-
emetal exchange and addition of the vinyllithium intermediate 23
to the TBS-protected aldehyde 11, from which the TBS ether was
selectively deblocked under acidic conditions to afford the (Z)-al-
kene substrate 24 (Fig. 7). For the (E)-isomer 30, the (E)-vinylic
iodide 26 was prepared by hydrotitanationeiodination of 2-butyn-
1-ol (25).19,20 After protection as the TIPS ether 27, the same se-
quence of halogenemetal exchange and addition to aldehyde 11
followed by selective hydrolysis of the TBS ether provided com-
pound 30 (Fig. 8).
R1
R1
H
X+
OH
favored if R3 = H
A
B
favored if R3 ≠ H
H
H
OH
R3
OH
R3
X
X
O
O
R1
R1
R2
R2
9
10
erythro
threo
Fig. 4. Conformational models for oxacyclizations with stereoinduction from a chiral
allylic alcohol.

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F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
1. 11, THF
OTIPS
these conditions, iodocyclization of cis-alkene 16 provided the six-
OTIPS
OH
-78 oC to 0 o
C
membered cyclic iodoether product structures, but without ap-
preciable diastereoselectivity, providing both diastereomers 31a
and 34a (Table 1, entry 1). Stereochemical assignments were con-
firmed by conversion of each iodoether into the corresponding al-
kenes 35 and 37 and comparing the coupling constants for the
hydrogens at the adjacent chiral centers. Thus the coupling con-
stant of 8.4 Hz21 was consistent with the erythro-stereochemistry of
35 (depicted as the diequatorial conformer), whereas the coupling
constant of 1.2 Hz indicated the threo-stereochemistry assigned to
37(Fig. 9). Moreover, the structure of the threo-diastereomer 34a
was unambiguously confirmed by X-ray crystallography (Fig. 10).
In contrast, the mercury-promoted cyclization of 16 more
closely followed the ChamberlineHehre model (Fig. 4),9 to provide
primarily the desired erythro-diastereomer (81:19 ratio before
separation), which was isolated as compound 36 after reduction of
M
HO
2. cat. PPTs
CH3OH
Me
24 (39%)
Me
22 M = I
t-BuLi (2 equiv)
THF, -78 oC
23
M = Li
Fig. 7. Preparation of (Z)-trisubstituted dihydroxyalkene 24.
Me
(2.4 equiv)
MgCl
Cp2TiCl2 (cat.)
Me
OH
I
OR
Me
Et2O, 0 o to 20 oC; then
I2, 0 o to 20 o
Me
25
C
TIPSCl
imidazole
DMF
26 R = H (31%)
27 R = TIPS (86%)
the organomercury intermediate (Table 1, entry 2). Our 1H and 13
C
NMR data for compound 36 closely matched the tabulated data
11, THF
previously reported for this compound.22
OH
-78 oC to 0 o
C
The corresponding phenylselenium-mediated cyclization of 16
proceeded with somewhat lower diastereoselectivity and yield
(Table 1, entry 3), and was best evaluated after oxidation and
elimination giving a mixture of the same alkenes 35 and 37 ob-
tained from the iodocyclization and elimination protocol. Iodo-
cyclization of the trans-alkene 17 afforded only the threo-
diastereomer 33a (Table 1, entry 4), consistent with the Chamber-
lineHehre stereoinduction model. The mercury- and selenium-
promoted cyclizations of the trans-alkene 17 proceeded with poor
diastereoselectivity and could not be optimized to favor the desired
erythro-diastereomer (Table 1, entries 5 and 6).
OTIPS
M
RO
OTIPS
Me
Me
t-BuLi (2 equiv)
27 M = I
28 M = Li
29 R = TBS (91%)
30 R = H (62%)
cat. PPTs
CH3OH
THF, -78 o
C
Fig. 8. Preparation of (E)-trisubstituted dihydroxyalkene 30.
2.2. Stereoselectivity of electrophile-promoted oxacycliza-
tions of 1,2-disubstituted alkenes
We began our studies by evaluating typical conditions for
iodocyclizations of the cis- and trans-alkenes 16 and 17, as well as
mercury- and selenium-promoted cyclizations. The first experi-
ments with iodine in dichloromethane or in acetonitrile afforded
dehydrative cyclization to the 2-alkenyltetrahydrofuran. As this
undesired reaction pathway was presumably acid-catalyzed, we
added sodium bicarbonate but failed to inhibit the dehydrative
cyclization, until we changed the solvent to tetrahydrofuran. Under
At this stage, we can only speculate on the reasons for superior
diastereoselectivity with the mercury-promoted procedure when
compared with iodocyclization, but the predicted hydrogen-in-
plane conformation B may be complemented by chelation or
electrostatic attraction between the Lewis acidic mercuric ion and
a non-bonding electron pair from the allylic hydroxyl (B0, Fig. 11),
thus providing a higher degree of conformational organization than
might be expected from the conformational model B depicted in
Table 1
Oxacyclization of 1,2-disubstituted alkenes 16 and 17
H
H
H
H
H
H
H
OH
OH
OH
X
OH
OH
X
OBn
step 1
step 2
HO
+
+
OBn
OBn
OBn
OBn
O
O
O
O
16: cis-alkene
17: trans-alkene
H
a: X = I
b: X = HgCl
c: X = SePh
31: β-X
32: α-X
33: β-X
34: α-X
35: alkene
36: alkane
37: alkene
38: alkane
threo:
threo:
erythro:
erythro:
Entry
1a
Alkene
(Steps) Reagents and conditions
(1) I2, NaHCO3, THF, 0ꢀ to 20 ꢀC
(2) DBU, CH2Cl2, 20 ꢀC
(1) Hg (O2CCF3)2, THF, 20 ꢀC; then satd aq KCl, 20 ꢀC
(2) Bu3SnH, cat. AIBN, toluene, 74 ꢀC
(1) PhSeNPhth, p-TsOHeH2O, CH2Cl2, 20 ꢀC
(2) H2O2, HOAc, THF, 0 ꢀC
(1) I2, NaHCO3, THF, 0ꢀ to 20 ꢀC
(2) DBU, CH2Cl2, 20 ꢀC
(1) Hg (O2CCF3)2, THF, 20 ꢀC; then satd aq KCl, 20 ꢀC
(2) then Bu3SnH, cat. AIBN, toluene, 77 ꢀC
(1) PhSeNPhth, p-TsOHeH2O, CH2Cl2, 20 ꢀC
(2) H2O2, HOAc, THF, 0 ꢀC
erythro-Product, isolated yield
threo-Product, isolated yield
16
31a, X¼I, 26%
34a, X¼I, 30%
35, 33%c
37, 46%d
2b
3b
4
16
16
17
17
17
36:38 [81:19 ratio], 65% combined yield (two steps)e
35:37 [70:30 ratio], 41% combined yield (two steps)f
(Not observed)
33a, X¼I, 69%
37, 60%
5
36:38 [34:66 ratio], 50% combined yield (two steps)e
6
35:37 [56:44 ratio], 62% combined yield (two steps)f
a
Compound 16 was used as the pure cis-isomer.
Compound 16 was used as an 88:12 mixture of cis- and trans-isomers.
Starting material was also recovered.
Starting material was also recovered, contaminated by an enol ether isomer of 37.
The organomercury intermediates were not isolated. Pure samples of 36 and 38 could be obtained by careful chromatographic separation.
b
c
d
e
f
The organoselenium intermediates were not isolated. However, crude NMR showed the erythro-selenoethers 31c (entry 3) and 32c (entry 6) mixed with threo-alkene 37 at
the conclusion of step 1. Mixtures of diastereomeric alkenes 35 and 37 were inseparable.

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
BnO
7749
in the presence of triflic acid (which was probably also responsible
for catalytic turnover of the initial vinylmercury intermediate), we
quenched the cycloisomerization reaction mixture with excess
triethylsilane.25 This protocol provided compound 36 in excellent
yield and high selectivity for the erythro-diastereomer; in fact the
threo-diastereomer 37 was not observed when the triethylsilane
reduction stage was conducted at ꢁ15 ꢀC.26 Compound 36 gener-
ated by this method was indistinguishable from the product de-
scribed earlier, from mercuric trifluoroacetate-promoted
cyclization of cis-alkene 16 followed by tributyltin hydride (Table 1,
entry 2).
J = 8.4 Hz
OH
H
H
O
OH
OH
O
O
BnO
H
H
BnO
37
35
J = 1.2 Hz
Fig. 9. Coupling constants for diastereomers 35 and 37.
The cycloisomerization stage of this transformation (15/39)
involved protiodemercuration of the initial mercury-containing
exocyclic enol ether, providing a mechanism for catalytic turnover
of the mercuric triflate catalyst. Moreover, hydride delivery to the
oxonium ion 40 proceeded with axial addition, consistent with
many literature precedents.4,25,27 However, addition of triethylsi-
lane to the reaction mixture immediately reduced mercuric triflate
to Hg(0), so that its activity for cycloisomerization was destroyed in
the reduction step, and thus the mercuric triflate-catalyzed cyclo-
isomerization could not be conducted in the presence of trie-
thylsilane. Nonetheless, this one-pot procedure gave superior yield
and diastereoselectivity when compared with the corresponding
cyclizations of the 1,4-dihydroxy-5-alkene substrates.
Fig. 10. Thermal ellipsoid map for threo-34a.
HgII
2.4. Stereoselectivity of electrophile-promoted oxacyclization
of 1,1-disubstituted 1,4-dihydroxy-5-alkene
H
H
HO
H
OH
CH2CH2OBn
HgX
HgII
H
CH2CH2OBn
H
cis-16
For the formation of the cyclic ether bearing a methyl sub-
stituent at the reactive carbon, we first envisioned an approach, in
which the 1,1-disubstituted dihydroxyalkene 21 would undergo
cyclization via the generally favored hydroxyl-in-plane confor-
mation A (Fig. 13). The ChamberlineHehre model would predict
formation of the threo-diastereomer, but if the carbon bearing the
X group were transformed into the methyl group and the R1
substituent was the ethanyl ether structure mimicking a longer-
chain substituent, this would also provide a cyclic ether sub-
structure with the desired stereochemistry. Iodocyclization of 21
gave stereoselective formation of the iodoether as a mixture of the
diol 42a and silyl ether 43a, which was desilylated to maximize
the isolated yield of 42a (Table 2, entry 1). Compound 42a was
isolated in crystalline form and unambiguously characterized by
X-ray crystallography (Fig. 14). Radical deiodination of 42a affor-
ded compound 44 with the axial methyl group at the quaternary
center, corresponding to the relative stereochemistry of C11 and
C12 of brevenal (Fig. 1). Mercury- and phenylselenium-promoted
cyclizations of 21 proceeded without loss of the silyl ether to
provide predominantly 45, albeit with poorer yields (Table 2, en-
tries 2, 3). The identity of 45 was confirmed by desilylation to
provide the diol 44.
O
H
OH
B' (chelate)
31b, erythro
Fig. 11. Conformational model for Hg(O2CCF3)2-promoted oxacyclization of cis-16,
giving erythro-31b as the major diastereomer.
Fig. 4. Moreover, the different diastereoselectivities observed could
arise from different degrees of
mation, depending on the choice of electrophile.
p-complex versus onium ion for-
2.3. Mercury-catalyzed reductive cyclization of 1,4-
dihydroxy-5-alkyne
We then explored oxacyclizations of the 1,4-dihydroxy-5-alkyne
15, followed by reduction of the cyclization product. Mercuric tri-
fluoroacetate was poorly reactive with the dihydroxyalkyne 15, but
substoichiometric mercuric triflate induced the rapid reaction of
dihydroxyalkyne 15.23,24 We could not isolate the expected cyclo-
isomerization product 39, but instead recovered a compound with
structural characteristics consistent with the cyclic hemiacetal 41
(Fig. 12). Recognizing the likely intermediacy of the oxonium ion 40
OH
H
OH
I+
Hg(OTf)2 (20 mol %)
H
OH
H
CH2Cl2, -15 oC;
OH
OH
21
HOCH2CH2
H
I
HO
O
OBn
then Et3SiH (3 equiv)
CH2CH2OH
H
O
OBn
H
I
15
42a
A
36 (94% yield, > 95 : 5 dr)
Hg(OTf)2
OH
Et3SiH
OH
Fig. 13. Conformational model for iodine-promoted oxacyclization of 21, giving threo-
42a as the major diastereomer.
OH
HOTf
H2O
2.5. Stereoselectivity of electrophile-promoted oxacycliza-
tions of trisubstituted 1,4-dihydroxy-5-alkenes
OBn
OBn
OBn
O
O
O
OH
H
H
H
39
40
41 (90% yield)
With the Z-trisubstituted alkene 24, iodocyclization favored
formation of the threo-diastereomer 49a (Table 3, entry 1), but the
Fig. 12. Reductive oxacyclization of dihydroxyalkyne 15.

7750
F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
Table 2
corresponding reaction with mercuric trifluoroacetate gave only
Oxacyclization of 1,1-disubstituted alkene 21
the desired erythro-diastereomer 46b, which was further con-
firmed upon reductive demercuration to 50 (Table 3, entry 2). The
erythro-stereochemistry of 46b was confirmed by observing NOE
interactions between a side-chain hydrogen and the carbinol hy-
drogen (Fig.15), whereas the O-acetyl derivative 52 (from the threo-
compound 49a) exhibited NOE interactions showing the methyl
substituent on the ether ring cis- to the carbinol hydrogen. More-
over, desilylation of erythro-50 provided compound 44, equivalent
to the product arising from iodocyclization and deiodination of the
1,1-disubstituted alkene 21, thus demonstrating an alternative
synthetic approach to the relative stereochemistry at C11 and C12 of
brevenal. However, the selenium-mediated reaction of 24 provided
ca. 1:1 mixture of erythro-46c and threo-49c (confirmed by desi-
lylation and O-acetylation to afford the separable diastereomers 53
and 54, which were analyzed for NOE interactions, Fig. 15). The
corresponding reactions of the (E)-alkene 30 with iodine, mercury
and selenium reagents uniformly favored formation of the threo-
diastereomers (i.e., threo-48a, Fig. 15) and were not further opti-
mized (Table 3, entries 4e6).
OH
step 1
H
HO
OTBS
21
H
OH
OH
step 2
O
O
OR
OR
Me
X
a: X = I
b: X = HgCl
c: X = SePh
Bu4NF, THF
(86%)
42 R = H
43 R = TBS
44 R = H
45 R = TBS
Entry
1
(Steps) Reagents and conditions
Products, isolated
yield
(1) I2, NaHCO3, THF, 0 ꢀCe20 ꢀC; then cat.
PPTS, MeOH
42a, 70%
44, 74%
(2) Bu3SnH, cat. AIBN, toluene, 80 ꢀC
(1) Hg(O2CCF3)2, THF, 20 ꢀC; then satd aq
KCl, 20 ꢀC
2
45, 38% (two steps)a
(2) Bu3SnH, cat. AIBN, toluene, 74 ꢀC
(1) PhSeNPhth, p-TsOH, CH2Cl2, 0 ꢀC
(2) Bu3SnH, cat. AIBN, toluene, 70 ꢀC
3
43c, 23%
45, 90%
NOE
a
Compound 45 was accompanied by 7% of the diastereomer. The organomercury
HO
H
intermediates were not isolated.
H
Me
H
I
H
O
H
OTIPS
H
O
OH
NOE
H
H
Me
H
H
TIPSO
HgCl
NOE
48a, threo
46b, erythro
NOE
Me
AcO
O
AcO
O
NOE
H
H
H
NOE
H
H
H
H
OTIPS
H
H
H
OAc
H
O
OAc
H
SePh
Me
I
H
Me
H
H
H
H
AcO
H
SePh
NOE
NOE
52, threo
from acetylation of 49a
53, erythro
54, threo
from desilylation and
from desilylation and
acetylation of 46c
acetylation of 49c
Fig. 15. Assignments of relative stereochemistry by NOE interactions in erythro- and
threo-diastereomers.
Fig. 14. Thermal ellipsoid map for 42a.
Table 3
Oxacyclizations of trisubstituted alkenes 24 and 30
H
H
H
H
OTIPS
OH
X
OH
OH
OH
X
OH
step 1
step 2
+
+
HO
O
O
OTIPS
-X
O
OR
O
OTIPS
-X
OTIPS
Me
Me
Me
Me
Me
a: X = I
b: X = HgCl
c: X = SePh
46:
β
α
48:
β
threo: 51
Bu4NF
THF
24: Z-alkene
30: E-alkene
erythro: 50, R = TIPS
44, R = H
threo:
erythro:
α
49: -X
47: -X
Entry
1
Alkene
(Steps) Reagents and conditions
(1) I2, NaHCO3, THF, 0ꢀ to 20 ꢀC
(2) Bu3SnH, cat. AIBN, toluene, 70 ꢀC
erythro-Product, isolated yield
threo-Product, isolated yield
49a, 51%a
(not conducted from 49a)
(Not observed)
24
46a, X¼I, 11%a
50, 67% (from minor isomer 46a)
46b, X¼HgCl, 54%
50, 90%
2
24
(1) Hg(O2CCF3)2, THF, 20 ꢀC; then satd aq KCl, 0ꢀ to 20 ꢀC
(2) Bu3SnH, cat. AIBN, toluene, 70 ꢀC
(1) PhSeNPhth, p-TsOHeH2O, CH2Cl2, 0 ꢀC
(1) I2, NaHCO3, THF, 20 ꢀC
3
4
24
30
46c:49c [X¼SePh, 47:53 ratio], 78% combined yieldb
(Not observed)
48a, X¼I, 76%
(2) Bu3SnH, cat. AIBN, toluene, 70 ꢀC
51, 99%
5
6
30
30
(1) Hg(O2CCF3)2, THF, 0 ꢀC, 30 min; then satd aq KCl, 0 ꢀ
(2) Bu3SnH, cat. AIBN, toluene, 75 ꢀC
C
50, 13% (two steps)
50, 8% (two steps)c
51, 48% (two steps)
(1) PhSeNPhth, p-TsOHeH2O, CH2Cl2, 0ꢀ to 20 ꢀC
(2) Bu3SnH, cat. AIBN, toluene, 75 ꢀC
51, 50% (two steps)c
a
Pure samples of 46a and 49a were obtained by careful chromatographic separation.
Diastereomers 46c and 49c were inseparable. Due to the low diastereoselectivity, the reduction (step 2) was not conducted.
A pure sample of 51 was obtained by careful chromatographic separation.
b
c

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
7751
Thus the behavior of (Z)-24 was similar to that of the cis-alkene
16, so that only the mercuric trifluoroacetate-promoted cyclization
afforded the erythro-diastereomer predicted by the Chamber-
lineHehre model. The divergent behavior observed between
iodocyclization and mercuriocyclization may be explained by Hg(II)
doublet of doublet of triplets; dtd, doublet of triplet of doublets;
tdd, triplet of doublet of doublets; dddd, doublet of doublet of
doublet of doublets; m, multiplet; br, broad. IR spectra were col-
lected on a Mattson Genesis II FT-IR spectrometer, with samples as
neat films. Mass spectra (high resolution FAB) were recorded on
a VG 70-S Nier Johason Mass Spectrometer or a Thermo Finnigan
LTQ FT spectrometer. Optical rotations were recorded at 23 ꢀC with
a PerkineElmer Model 341 polarimeter (concentration in g/
100 mL). Melting points were recorded on Fisher-Johns melting
point apparatus. Analytical thin layer chromatography (TLC) was
performed on precoated glass backed plates purchased from
Whatman (silica gel 60 F254; 0.25 mm thickness). Flash column
chromatography was carried out with silica gel 60 (230e400 mesh
ASTM) from EM Science. All reactions were conducted with anhy-
drous solvents in oven-dried or flame-dried and argon-charged
uniquely interacting with the allylic hydroxyl oxygen in the
p-
complex B0 (Fig. 16).
HgII
H
HO
H3C
OH
CH2OTIPS
HgX
HgII
H
CH2OTIPS
H
(Z)-24
O
H3C
H
OH
B' (chelate)
46b, erythro
ꢀ
ꢀ
glassware. All anhydrous solvents were dried over 3 A or 4 A mo-
lecular sieves, and trace water content was tested with Coulometric
KF Titrator from Denver Instruments. Solvents used in workup,
extraction and column chromatography were used as received from
commercial suppliers without prior purification. All reagents were
purchased from SigmaeAldrich.
Fig. 16. Conformational model for Hg(O2CCF3)ꢁ2 promoted oxacyclization of (Z)-24,
giving erythro-46b as the major diastereomer.
3. Conclusions
4.2. Preparation of 1,4-dihydroxy-5-alkene substrates
In summary, these results have demonstrated several oxacycli-
zation pathways to the desired erythro-stereochemistry required
for transesynetrans polypyran structures:
4.2.1. Alkynyldiol 15
4.2.1.1. Preparation of alkynyl alcohol 14. The terminal alkyne 12
(5.76 g, 36.0 mmol)13 was dissolved in THF (90 mL), cooled to 0 ꢀC,
and n-butyllithium (1.55 M in hexane, 21.3 mL, 33.0 mmol) was
added slowly. The reaction mixture was stirred at 0 ꢀC for 5 min,
and then a solution of aldehyde 11 (6.06 g, 30.0 mmol)12 in THF
(30 mL) was added. The reaction mixture was stirred for 2 h at 0 ꢀC,
and then quenched with pH 7 buffer solution. The mixture was
extracted with ethyl acetate (three times), the combined organic
layers were washed with brine and dried over magnesium sulfate,
and solvent was removed by rotary evaporation. The residue was
purified by silica gel flash chromatography (hexanes/ethyl
acetate¼90/10 to 80/20) to give the propargylic alcohol 14 (6.94 g,
19.2 mmol, 64% yield); nmax (liquid film) 3427, 3031, 2953, 2928,
2858, 2238, 1740, 1471, 1389, 1362, 1254, 1101, 1028, 836, 777,
(a) Hg(O2CCF3)-promoted cyclizations are generally consistent
with the ChamberlineHehre model, so that the cis-alkene 16
and the (Z)-alkene 24 both favor the erythro-diastereomers 36
and 50, respectively.
(b) The Hg(OTf)2-catalyzed cyclization of the 1,4-dihydroxy-5-
alkyne 15 coupled with acid-catalyzed hydride reduction also
favors the erythro-diastereomer 36.
(c) Although the iodocyclization of the 1,1-disubstituted alkene 21
is formally threo-selective, the product is easily transformed by
deiodination into the same diastereomer produced by erythro-
selective mercuriocyclization of the (Z)-alkene 24.
Generally, iodocyclizations of 1,4-dihydroxy-5-alkenes to the
six-membered cyclic ethers generally exhibit a preference for
producing the threo-diastereomers, regardless of the substitution
pattern of the alkene. Although the threo-selectivity is diminished
for the cis-alkene 16 and (Z)-alkene 24, the conformer B predicted
by the ChamberlineHehre model is apparently not favored for
iodocyclizations of these substrates. Although the mechanistic
significance of these findings awaits more thorough experimental
and/or theoretical study, this work does establish the viability of
several oxacyclization pathways to produce the relative stereo-
chemistry of hydroxyl and side-chain substituents corresponding
to the stereochemistry of many fused polycyclic ether natural
products.
737 cmꢁ1
; dH (CDCl3, 600 MHz) 7.37e7.26 (5H, m), 4.55 (2H, s),
4.44e4.38 (1H, m), 3.71e3.62 (2H, m), 3.58 (2H, t, J¼7.2 Hz), 3.00
(1H, d, J¼6.0 Hz (OH)), 2.53 (2H, t, J¼7.2 Hz), 1.82e1.73 (3H, m),
1.71e1.62 (1H, m), 0.90 (9H, s), 0.07 (6H, s); dC (CDCl3, 150 MHz)
138.0, 128.4, 127.7 (2C), 82.4, 81.6, 72.9, 68.4, 63.2, 62.2, 35.5, 28.6,
25.9, 20.1, 18.3, ꢁ5.4 (2C); HRMS (APCI) calcd for C21H35O3Si
[MþH]þ 363.23500, found 363.23523.
4.2.1.2. Desilylation of 14 to alkynyldiol 15. Compound 14
(6.76 g, 17.8 mmol) was dissolved in THF (180 mL), cooled to 0 ꢀC,
and tetrabutylammonium fluoride (1
M in THF, 26.75 mL,
26.75 mmol) was added dropwise. The resulting solution was
allowed to warm to room temperature. After 2 h, the reaction
mixture was quenched with saturated aqueous ammonium chlo-
ride. The mixture was extracted with ethyl acetate (five times), the
combined organic layers were washed with brine and dried over
magnesium sulfate, filtered, and solvent was removed by rotary
evaporation. The residue was purified by silica gel flash chroma-
tography (hexanes/ethyl acetate¼30/70) to give the alkynyldiol 15
(3.21 g, 13.0 mmol, 73% yield) as a pale yellow oil; nmax (liquid film)
4. Experimental section
4.1. General information
1H and 13C NMR spectra were recorded on an Inova-400 spec-
trometer (400 MHz for 1H, 100 MHz for 13C), or an Inova-600
spectrometer (600 MHz for 1H, 150 MHz for 13C). NMR spectra
were reported in deuterated solvents with the following reference
peaks for 1H NMR: CDCl3, 7.26 ppm; C6D6, 7.16 ppm; (CD3)2C]O,
2.05 ppm; and for 13C NMR: CDCl3, 77.00 ppm; C6D6, 128.39 ppm;
(CD3)2C]O, 206.68 or 29.92 ppm. Abbreviations for signal cou-
plings are as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd,
doublet of doublets; dt, doublet of triplets; td, triplet of doublets;
qt, quartet of triplets; ddd, doublet of doublet of doublets; ddt,
3345, 2930, 2865, 1453, 1363, 1093, 1027, 735, 697 cmꢁ1
; dH (CDCl3,
600 MHz) 7.38e7.29 (5H, m), 4.53 (2H, s), 4.38 (1H, m), 3.92 (1H,
broad (OH)), 3.64e3.58 (2H, m), 3.56 (2H, t, J¼6.8 Hz), 3.17 (1H,
broad (OH)), 2.50 (2H, td, J¼6.9, 2.0 Hz), 1.90e1.51 (4H, m); dC
(CDCl3, 100 MHz) 137.9, 128.5, 127.8 (2C), 82.4, 81.9, 72.9, 68.4, 62.3,
62.0, 35.0, 28.4, 20.1; HRMS (ESI) calcd for C15H20O3Na [MþNa]þ
271.13047, found 271.13043.

7752
F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
4.2.2. cis-Alkenyldiol 16. Ni(OAc)2$4H2O (179.0 mg, 0.719 mmol)
was suspended in ethanol (3 mL), and NaBH4 (26.7 mg, 0.705 mmol)
was added to give a black suspension. The flask was purged with
washed with brine and dried over magnesium sulfate, and the sol-
vent was removed by rotary evaporation. The residue was purified
by silica gel flash chromatography (hexanes/ethyl acetate¼90/10) to
give the silyl ether 19 (881 mg, 2.82 mmol, 94% yield); nmax (liquid
hydrogen gas. Ethylenediamine (100
mL, 1.50 mmol) was added
followed by a solution of propargylic alcohol 14 (2.20 g, 6.08 mmol)
in ethanol (4 mL). The reaction mixture was stirred under a balloon
pressure of H2 for 3 h. The reaction mixture was filtered through
filter paper, and washed with dichloromethane. The organic layer
was washed with brine, dried over magnesium sulfate, and the
solvent was removed by rotary evaporation. The residue was diluted
with THF (60 mL). Tetrabutylammonium fluoride (1 M in THF, 9 mL,
9 mmol) was added to the solution. The reaction mixture was stirred
overnight at room temperature, and quenched by addition of satu-
rated aqueous ammonium chloride. The product mixture was
extracted with ethyl acetate (three times), the combined organic
layers were washed with brine and dried over magnesium sulfate,
and solvents were removed under rotary evaporation. The residue
was purified by silica gel flash chromatography (hexanes/ethyl
acetate¼50/50 to 0/100 with 1% Et3N) to give cis-alkenyldiol 16
(876.1 mg, 3.50 mmol, 58% yield (two steps)); nmax (liquid film)
film) 2954, 2929, 2857, 1617, 1255, 1108, 836, 776 cmꢁ1
; dH (CDCl3,
400 MHz) 6.08 (1H, q, J¼1.2 Hz), 5.76 (1H, d, J¼1.2 Hz), 3.72 (2H, t,
J¼6.4 Hz), 2.59 (2H, td, J¼6.4, 0.8 Hz), 0.89 (9H, s), 0.07 (6H, s); dC
(CDCl3, 100 MHz) 127.4, 107.6, 61.7, 48.4, 25.9, 18.3, ꢁ5.2; HRMS
(APCI) calcd for C10H22OISi [MþH]þ 313.04792, found 313.04810.
4.2.4.2. Preparation of the alkenyldiol 21. Compound 19 (3.12 g,
10.0 mmol) was dissolved in ether (30 mL) and cooled to ꢁ78 ꢀC,
and a 1.6 M hexane solution of n-butyllithium (6.3 mL, 10 mmol)
was added slowly. The reaction mixture was stirred at ꢁ78 ꢀC for
45 min.
A solution of the lactol 20 and ethyl acetate
(20:EtOAc¼78:22, ca. 450 mg of 20, 4.0 mmol, prepared from
butyrolactone)17 in Et2O (20 mL) was added slowly, the reaction
mixture gradually warmed to 0 ꢀC, and was stirred for 3.5 h. The
reaction mixture was quenched by addition of saturated aqueous
ammonium chloride. The mixture was extracted with diethyl ether
(three times), the combined organic layers were washed with brine
and dried over magnesium sulfate, and the solvent was removed by
rotary evaporation. The residue was purified by silica gel flash
chromatography (hexanes/ethyl acetate¼70/30 to 60/40) to give
the alkenyldiol 21 (438 mg, 1.77 mmol, 44% yield). nmax (liquid film)
3365, 2939, 2864, 1454, 1362, 1096, 1005, 739 cmꢁ1
; dH (CDCl3,
600 MHz) 7.37e7.26 (5H, m), 5.62 (1H, ddd, J¼10.8, 8.4, 1.2 Hz),
5.58e5.52 (1H, m), 4.52 (2H, s), 4.43 (1H, q, J¼6.6 Hz), 3.72e3.57
(2H, m), 3.55 (1H, dt, J¼9.0, 5.4 Hz), 3.43 (1H, td, J¼9.0, 4.2 Hz),
2.61e2.51 (1H, m), 2.30e2.24 (1H, m), 1.74e1.55 (4H, m); dC (CDCl3,
150 MHz) 137.6, 135.2, 128.61, 128.63, 128.5, 127.8, 73.2, 68.8, 66.6,
62.9, 34.0, 29.2, 28.4; HRMS (APCI) calcd for C15H23O3 [MþH]þ
251.16417, found 251.16420. A separate run on similar scale (1.8 g of
14) produced an inseparable 88:12 mixture of 16 and 17.
3351, 2953, 2930, 2858, 1646, 1255, 1095, 836 cmꢁ1
; dH (CDCl3,
600 MHz) 5.05 (1H, s), 4.91 (1H, s), 4.12e4.08 (1H, m), 3.82 (1H, dt,
J¼10.8, 5.4 Hz), 3.74e3.62 (3H, m), 2.41 (1H, ddd, J¼14.4, 9.0,
5.4 Hz), 2.24 (1H, dt, J¼14.4, 4.8 Hz), 1.71e1.62 (4H, m), 0.90 (9H, s),
0.079 (3H, s), 0.076 (3H, s); dC (CDCl3, 150 MHz) 149.7, 112.8, 75.0,
64.3, 62.9, 34.6, 33.4, 29.5, 25.8, 18.3, ꢁ5.48, ꢁ5.53; HRMS (ESI)
calcd for C14H30O3NaSi [MþNa]þ 297.18564, found 297.18570.
4.2.3. trans-Alkenyldiol 17. The propargylic alcohol 14 (1.76 g,
4.86 mmol) was dissolved in Et2O (25 mL), and cooled to 0 ꢀC. Red-
AlÒ (sodium bis(2-methoxyethoxy)aluminate, >65% in toluene,
4.4 mL, 14.7 mmol) was slowly added, and the reaction mixture
stirred at 0 ꢀC for 2 h, then gradually warmed to room temperature
and stirred overnight. The reaction mixture was cooled to 0 ꢀC, and
was quenched with saturated aqueous Rochelle’s salt. The mixture
was extracted with ethyl acetate (four times), the combined organic
layers were washed with brine and dried over magnesium sulfate,
and solvents were removed by rotary evaporation. Without further
purification, the crude allylic alcohol was dissolved in THF (50 mL),
and tetrabutylammonium fluoride (1 M in THF, 7.3 mL, 7.3 mmol)
was added. The reaction mixture was stirred overnight, and then
quenched with saturated aqueous ammonium chloride. The mixture
was extracted with ethyl acetate (three times), the combined or-
ganic layers were washed with brine and dried over magnesium
sulfate, and solvents were removed by rotary evaporation. The
residue was purified by silica gel flash chromatography (ethyl ace-
tate with 1% Et3N) to give the trans-alkenyldiol 12 (1.08 g,
4.32 mmol, 89% yield (two steps)); nmax (liquid film) 3364, 2934,
4.2.5. (Z)-Trisubstituted alkenyldiol 24. The iodoalkene 22 (1.06 g,
2.99 mmol)18 was dissolved in THF (15 mL), cooled to ꢁ78 ꢀC, and
tert-butyllithium (1.59 M in pentane, 3.8 mL, 6.0 mmol) was added
slowly. The reaction mixture was stirred at ꢁ78 ꢀC for 75 min, and
then a solution of aldehyde 11 (512 mg, 2.53 mmol)12 in THF
(15 mL) was added. The reaction mixture gradually warmed to 0 ꢀC
over 2 h, and was stirred at 0 ꢀC for 40 min. The reaction was then
quenched with saturated aqueous ammonium chloride. The mix-
ture was extracted with ether (three times), the combined organic
layers were washed with brine and dried over magnesium sulfate,
and solvent was removed by rotary evaporation. Without further
purification, the residue was dissolved in methanol (60 mL), and
pyridinium p-toluenesulfonate (73.9 mg, 0.294 mmol) was added.
The reaction mixture was stirred at room temperature for 5 h, and
then quenched by addition of saturated aqueous sodium bi-
carbonate. The mixture was extracted with ethyl acetate (three
times), the combined organic layers were washed with brine and
dried over magnesium sulfate, and solvent was removed by rotary
evaporation. The residue was purified by silica gel flash chroma-
tography (hexanes/ethyl acetate¼70/30 to 60/40) to give the alke-
nyldiol 24 (310.4 mg, 0.980 mmol, 39% yield); nmax (liquid film)
2860, 1737, 1454, 1362, 1095, 1077, 1062, 971, 738 cmꢁ1
; dH (CDCl3,
600 MHz) 7.38e7.26 (5H, m), 5.69 (1H, dt, J¼15.6, 6.6 Hz), 5.58 (1H,
dd, J¼15.6, 6.6 Hz), 4.51 (2H, s), 4.15e4.10 (1H, m), 3.70e3.62 (2H,
m), 3.52 (2H, t, J¼6.6 Hz), 2.36 (2H, q, J¼6.6 Hz), 2.00 (1H, broad),
1.96 (1H, broad),1.70e1.58 (4H, m); dC (CDCl3,150 MHz) 138.3,134.8,
128.4,128.0,127.7,127.6, 72.8, 72.6, 69.6, 62.8, 34.2, 32.6, 28.8; HRMS
(APCI) calcd for C15H23O3 [MþH]þ: 251.16417, found 251.16428.
3351, 2943, 2866, 1463, 1381, 1059, 1011, 883, 774 cmꢁ1
; dH (CDCl3,
600 MHz) 5.49 (1H, t, J¼6.6 Hz), 4.49 (1H, dd, J¼7.8, 4.2 Hz), 4.32
(1H, ddd, J¼12.6, 6.6, 1.2 Hz), 4.21 (1H, ddd, J¼12.6, 6.6, 1.2 Hz), 3.71
(1H, dt, J¼11.4, 5.4 Hz), 3.66 (1H, dt, J¼11.4, 6.0 Hz), 1.74 (3H, s),
1.73e1.60 (4H, m), 1.15e1.04 (21H, m); dC (CDCl3, 150 MHz) 140.2,
126.5, 70.2, 62.7, 59.0, 32.0, 29.5, 18.1, 17.9, 11.9; HRMS (APCI) calcd
for C17H37O3Si [MþH]þ 317.25065, found 317.25081.
4.2.4. 1,1-Disubstituted alkenyldiol 21
4.2.4.1. Preparation of vinylic iodide 19. The iodoalcohol 18
(597 mg, 3.00 mmol, prepared from 3-butyn-1-ol)16 was dissolved
in DMF (15 mL) and cooled to 0 ꢀC, imidazole (542 mg, 7.96 mmol)
and TBSCl (600 mg, 3.98 mmol) were added, and the reaction
mixture gradually warmed to room temperature. After the mixture
was stirred for 8 h, water was added. The mixture was extracted
with ethyl acetate (two times), the combined organic layers were
4.2.6. (E)-Trisubstituted alkenyldiol 30
4.2.6.1. Preparation of vinylic iodide 27. Isobutylmagnesium
chloride (0.75 M in ether, 64 mL, 48 mmol) was cooled to 0 ꢀC, and
titanocene dichloride (257 mg, 1.03 mmol) was added. The reagent

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
7753
mixture was stirred for 10 min at 0 ꢀC, and then 2-butyn-1-ol (25,
1.42 g, 20.3 mmol) in ether (6 mL) was added. The reaction mixture
was gradually warmed to room temperature, and was then stirred
for 4 h. The reaction mixture was then cooled to 0 ꢀC, iodine (13.2 g,
52.0 mmol) was added, and the mixture was stirred overnight
while gradually warming to room temperature.19 The reaction was
quenched by addition of saturated aqueous sodium thiosulfate. The
mixture was extracted with ethyl acetate (three times), the com-
bined organic layers were washed with brine (twice) and dried over
magnesium sulfate, and the solvent was removed by rotary evap-
oration. The residue was purified by silica gel flash chromatography
(hexanes/ethyl acetate¼90/10 to 80/20) to give (E)-3-iodobut-2-en-
1-ol (26, 1.25 g, 6.31 mmol) in 31% yield. The spectral data matched
the literature values.20 Compound 26 (1.25 g, 6.31 mmol) was
dissolved in DMF (6 mL), cooled to 0 ꢀC, and imidazole (752 mg,
11.0 mmol) and TIPSCl (1.4 mL, 6.5 mmol) were added. The reaction
mixture was stirred at 0 ꢀC for 3 h, and then quenched by addition
of pH 7 buffer solution. The mixture was extracted with ether (three
times), the combined organic layers were washed with brine and
dried over magnesium sulfate, and solvents were removed by ro-
tary evaporation. The residue was purified by silica gel flash chro-
matography (hexanes/ethyl acetate¼100/0 to 95/5) to give silyl
ether 27 (1.92 g, 5.42 mmol, 86% yield). nmax (liquid film) 2942,
29.2, 18.0, 12.0; HRMS (ESI) calcd for C17H36O3NaSi [MþNa]þ
339.23259, found 339.23267.
4.3. Oxacyclizations of 1,2-disubstituted alkenes 16 and 17
4.3.1. Iodocyclization of cis-alkenyldiol 16
4.3.1.1. Formation of 31a and 34a. The cis-alkenyldiol 16
(70.0 mg, 0.280 mmol) was dissolved in THF (3 mL), the solution
was cooled to 0 ꢀC, and sodium bicarbonate (70.7 mg, 0.842 mmol)
and iodine (214.4 mg, 0.845 mmol) were added. The reaction
mixture gradually warmed to room temperature while stirring for
24 h. The reaction was quenched with saturated aqueous sodium
thiosulfate. The mixture was extracted with ethyl acetate (three
times), the combined organic layers were washed with brine and
dried over magnesium sulfate, and the solvent was removed by
rotary evaporation. The residue was purified by silica gel flash
chromatography (hexanes/ethyl acetate¼90/10 to 80/20) to give
the erythro-product 31a (27.9 mg, 0.0742 mmol, 26% yield), and
threo-product 34a (31.3 mg, 0.0832 mmol, 30% yield).
4.3.1.1.1. Data for 31a. nmax (liquid film) 3427, 2937, 2856, 2228,
1692, 1454, 1364, 1270, 1095, 945, 739 cmꢁ1
; dH (CDCl3, 600 MHz)
7.37e7.26 (5H, m), 4.76 (1H, ddd, J¼9.6, 4.8, 1.8 Hz), 4.55 (1H, d,
J¼12.0 Hz), 4.51 (1H, d, J¼12.0 Hz), 3.99 (1H, dd, J¼11.4, 4.8 Hz),
3.67e3.58 (3H, m), 3.39 (1H, td, J¼11.4, 2.4 Hz), 2.35 (1H, tq, J¼9.6,
4.8 Hz), 2.15 (1H, dd, J¼8.4, 1.8 Hz), 2.15e2.04 (2H, m), 1.77 (1H, qt,
J¼13.2, 4.2 Hz), 1.70e1.63 (1H, m), 1.58e1.50 (1H, m); dH (acetone-
d6, 600 MHz) 7.38e7.24 (5H, m), 4.88 (1H, dd, J¼10.2, 5.4 Hz), 4.52
(2H, s), 3.90e3.84 (1H, m), 3.68e3.58 (2H, m), 3.51e3.44 (1H, m),
3.44e3.37 (1H, m), 2.31e2.24 (1H, m), 2.14 (1H, d, J¼7.8 Hz),
2.12e2.03 (2H, m), 1.67e1.59 (2H, m), 1.59e1.49 (1H, m); dC (CDCl3,
150 MHz) 138.3, 128.4, 127.8, 127.6, 83.6, 73.1, 71.4, 69.2, 67.9, 37.8,
35.2, 32.3, 25.3; dC (acetone-d6, 150 MHz) 140.3, 129.6, 128.9, 128.7,
85.0, 73.9, 71.8, 70.5, 68.7, 39.6, 37.9, 33.8, 26.7; HRMS (APCI) calcd
for C15H22O3I [MþH]þ 377.06082, found 377.06098. The unusual
chemical shifts for the proton resonances of the iodoether were
confirmed by HMQC spectroscopy (values in acetone-d6):
2866, 1638, 1463, 1381, 1370, 1254, 1108, 1042, 882, 771 cmꢁ1
; dH
(CDCl3, 600 MHz) 6.32 (1H, tq, J¼6.0, 1.2 Hz), 4.20 (2H, dd, J¼6.0,
0.6 Hz), 2.41 (3H, s), 1.13e1.04 (2H, m); dC (CDCl3, 150 MHz) 141.0,
95.4, 61.0, 28.2, 17.9, 12.0; HRMS (APCI) calcd for C13H28OISi
[MþH]þ 355.09487, found 355.09476.
4.2.6.2. Preparation of 29. The iodoalkene 27 (886 mg,
2.50 mmol) was dissolved in THF (12.5 mL), cooled to ꢁ78 ꢀC, and
tert-butyllithium (1.59 M in pentane, 3.1 mL, 4.9 mmol) was added
slowly. The reaction mixture was stirred at ꢁ78 ꢀC for 85 min, and
then a solution of aldehyde 11 (425 mg, 2.10 mmol)12 in THF
(12.5 mL) was added. The reaction mixture gradually warmed to
0 ꢀC, and was stirred at 0 ꢀC for 3 h. The reaction was then quenched
with saturated ammonium chloride. The mixture was extracted
with ether (three times), the combined organic layers were washed
with brine and dried over magnesium sulfate, and solvent was
removed by rotary evaporation. The residue was purified by silica
gel flash chromatography (hexanes/ethyl acetate¼90/10) to give
the alcohol 29 (982 mg, 2.28 mmol, 91% yield); nmax (liquid film)
H
OH
31a
OBn
O
3396, 2947, 2865, 1463, 1386, 1254, 1102, 1058, 1011, 836, 776 cmꢁ1
;
4.3.1.1.2. Data for 34a. Mp 81e89 ꢀC (recrystallized from tolu-
ene/hexanes); nmax (liquid film) 3475, 2940, 2854, 1720, 1453, 1357,
dH (CDCl3, 600 MHz) 5.58 (1H, t, J¼5.4 Hz), 4.34e4.26 (2H, m),
4.04e4.00 (1H, m), 3.65 (2H, t, J¼6.0 Hz), 2.31 (1H, d, J¼3.0 Hz
(OH)), 1.70e1.53 (4H, m), 1.61 (3H, s), 1.14e1.04 (21H, m), 0.90 (9H,
s), 0.06 (6H, s); dC (CDCl3, 150 MHz) 137.8, 126.3, 76.9, 63.2, 60.2,
32.0, 29.0, 25.9, 18.3, 18.0, 12.0, 11.9, ꢁ5.4; HRMS (ESI) calcd for
C23H50NaO3Si2 [MþNa]þ 453.31962, found 453.31922; HRMS (ESI)
calcd for C23H50KO3Si2 [MþK]þ 469.29356, found 469.29317.
1206, 1131, 1096, 1061, 999, 883, 738, 697 cmꢁ1
; dH (CDCl3,
400 MHz) 7.38e7.26 (5H, m), 4.54 (1H, d, J¼11.6 Hz), 4.51 (1H, d,
J¼11.6 Hz), 4.37 (1H, td, J¼9.2, 3.2 Hz), 4.12e4.05 (1H, m), 4.04 (1H,
broad), 3.76 (1H, dt, J¼10.0, 5.6 Hz), 3.66 (1H, ddd, J¼9.2, 7.2,
5.6 Hz), 3.50 (1H, dd, J¼12.0, 2.0 Hz), 3.44 (1H, d, J¼9.2 Hz),
2.20e1.80 (4H, m), 1.62e1.51 (1H, m), 1.36e1.44 (1H, m); dC (CDCl3,
100 MHz) 138.2, 128.4, 127.7, 127.6, 84.1, 73.1, 69.9, 69.2, 64.8, 34.8,
34.4, 30.6, 20.1; HRMS (APCI) calcd for C15H22O3I [MþH]þ
377.06082, found 377.06081. The structure of 34a was confirmed by
X-ray crystallography, as described in the Supplementary data.
4.2.6.3. Preparation of 30. Compound 29 (167 mg, 0.388 mmol)
was dissolved in methanol (8 mL) and cooled to 0 ꢀC, and pyr-
idinium p-toluenesulfonate (12.2 mg, 0.0485 mmol) was added.
The reaction mixture was stirred at 0 ꢀC for 8 h, and then quenched
by addition of saturated aqueous sodium bicarbonate. The mixture
was extracted with ethyl acetate (three times), the combined or-
ganic layers were washed with brine and dried over magnesium
sulfate, and solvent was removed by rotary evaporation. The resi-
due was purified by silica gel flash chromatography (hexanes/ethyl
acetate¼80/20 to 50/50) to give the alkenyldiol 30 (76.0 mg,
0.240 mmol, 62% yield); nmax (liquid film) 3345, 2941, 2865, 1670,
4.3.1.2. Dehydrohalogenation of 31ae35. The iodoether 31a
(20.5 mg, 0.0545 mmol) was dissolved in CH2Cl2 (1 mL), and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 16
mL, 0.11 mmol) was
added. After stirring for 2 days, the solvent was removed by rotary
evaporation, and the residue was purified by silica gel flash chro-
matography (hexanes/ethyl acetate¼85/15 to 75/25) to give the
alkene 35 (4.5 mg, 0.018 mmol, 33% yield), along with 46% re-
covered 31a (9.3 mg, 0.025 mmol); nmax (liquid film) 3429, 3030,
1463, 1384, 1258, 1115, 1083, 1057, 1011, 882, 779 cmꢁ1
; dH (CDCl3,
600 MHz) 5.58 (1H, t, J¼6.0 Hz), 4.32e4.25 (2H, m), 4.06e4.02 (1H,
m), 3.70e3.61 (2H, m), 1.68e1.59 (4H, m), 1.61 (3H, s), 1.14e1.03
(21H, m); dC (CDCl3, 150 MHz) 138.0, 126.2, 77.0, 62.8, 60.1, 31.9,
2936, 2854, 1724, 1454, 1361, 1264, 1208, 1093, 972, 739 cmꢁ1
; dH
(CDCl3, 600 MHz) 7.37e7.26 (5H, m), 5.97 (1H, dtd, J¼15.6, 5.4,
0.6 Hz), 5.81 (1H, ddt, J¼15.6, 7.2, 1.2 Hz), 4.53 (2H, s), 4.07 (2H, dd,

7754
F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
J¼5.4, 1.2 Hz), 3.94 (1H, ddt, J¼10.8, 3.6, 1.8), 3.51 (1H, br t,
J¼8.4 Hz), 3.39 (1H, td, J¼10.8, 3.6 Hz), 3.33 (1H, ddd, J¼10.8, 8.4,
4.8 Hz), 2.18e2.10 (1H, m), 1.80e1.66 (2H, m), 1.50e1.38 (1H, m); dC
(CDCl3, 100 MHz) 138.1, 131.3, 130.3, 128.4, 127.72, 127.65, 83.0, 72.4,
70.0, 69.7, 67.4, 31.6, 25.4; HRMS (APCI) calcd for C15H21O3 [MþH]þ
249.14852, found 249.14856.
CH2Cl2 (3 mL), the solution was cooled to 0 ꢀC, and toluenesulfonic
acid (5.7 mg, 0.030 mmol) and N-phenylselenophthalimide
(75.8 mg, 0.251 mmol) were added. The reaction mixture gradually
warmed to 20 ꢀC over 6.5 h. The mixture was then diluted with
chloroform, the organic phase was washed with 0.2 M aqueous
KOH (three times) followed by brine, dried over magnesium sulfate,
and the solvent was removed by rotary evaporation. The crude
NMR spectrum at this stage showed that the phenylselenyl com-
pound 31c was present, along with elimination product 37. Without
separating these compounds, the mixture was dissolved in THF
4.3.1.3. Dehydrohalogenation of 34ae37. The iodoether 34a
(17.5 mg, 0.0466 mmol) was dissolved in CH2Cl2 (1 mL), and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 14
mL, 0.094 mmol) was
added. After stirring for 2 days, the solvent was removed by rotary
evaporation, and the residue was purified by silica gel flash chroma-
tography (hexanes/ethyl acetate¼85/15 to 75/25) to give the alkene
37 (5.4 mg, 0.022 mmol, 47% yield), along with a trisubstituted enol
ether byproduct (9.4 mg, contaminated with 34a); nmax (liquid film)
3452, 3030, 2927, 2852, 1723, 1454, 1361, 1101, 1081, 1056, 999, 970,
(2 mL) and cooled to 0 ꢀC, acetic acid (64
mL) and 30% hydrogen
peroxide (0.27 mL) were added. The reaction mixture was stirred
for 45 min, and then quenched with saturated aqueous sodium
bicarbonate (20 mL). The mixture was extracted with diethyl ether
(three times), the combined organic layers were washed with brine
and dried over magnesium sulfate, and solvents were removed by
rotary evaporation. The residue was purified by silica gel flash
chromatography (hexanes/ethyl acetate¼70/30 to 60/40) to give an
inseparable mixture of 35 and 37 (70:30, 20.6 mg, 41% combined
yield). The mixture exhibited spectroscopic characteristics consis-
tent with 35 and 37 arising from dehydrohalogenation of the cor-
responding iodoethers 31a and 34a, respectively.
895, 737 cmꢁ1
; dH (CDCl3, 600 MHz) 7.36e7.26 (5H, m), 5.94 (1H, dtd,
J¼15.6, 5.4,1.2 Hz), 5.80 (1H, dd, J¼15.6, 4.8 Hz), 4.52 (2H, s), 4.06 (2H,
dt, J¼4.8, 1.2 Hz), 4.07e4.02 (1H, m), 3.95 (1H, dt, J¼4.8, 1.2 Hz), 3.73
(1H, br m), 3.53 (1H, td, J¼11.4, 2.4 Hz), 2.04e1.92 (2H, m), 1.74e1.66
(1H, m), 1.43e1.37 (1H, m); dC (CDCl3, 100 MHz) 138.2, 130.2, 129.1,
128.4, 127.7, 127.6, 79.3, 72.2, 70.1, 68.3, 66.9, 30.0, 19.9; HRMS (APCI)
calcd for C15H21O3 [MþH]þ 249.14852, found 249.14849.
4.3.4. Iodocyclization of trans-alkenyldiol 17
4.3.2. Mercury-promoted cyclization of cis-alkenyldiol 16 to form 36
and 38. The alkenyldiol 16 (53.0 mg, 0.212 mmol) was dissolved in
THF (2 mL), the solution was cooled to 0 ꢀC, and a solution of
mercuric trifluoroacetate (139.8 mg, 0.328 mmol) in THF (2 mL)
was added slowly. The reaction mixture gradually warmed to room
temperature while stirring for 2 h. Saturated aqueous potassium
chloride (0.14 mL) was added, and the mixture was stirred for 1.5 h
at room temperature. The reaction mixture was diluted with ethyl
acetate, the organic layer was washed with water (twice) and brine,
dried over magnesium sulfate, and the solvent was removed by
rotary evaporation. The residue was diluted with toluene (6 mL),
tributyltin hydride (0.26 mL, 0.97 mmol) and AIBN (5.6 mg) were
added, and the reaction mixture was heated at 74 ꢀC for 2 h. The
reaction mixture cooled to room temperature, the solvent was re-
moved by rotary evaporation, and the residue was purified by flash
chromatography on silica gel support mixed with 10% KF (hexanes/
ethyl acetate¼90/10 to 50/50) to give pure samples of di-
astereomers 36 and 38 along with fractions containing both di-
astereomers, which in total corresponded to an 81:19 mixture of
diastereomers 36 and 38 (34.2 mg, 0.137 mmol, 65% combined
yield). The data for compound 36 closely matched the tabulated
data previously reported for this compound.22
4.3.4.1. Formation of 33a. The trans-alkenyldiol 17 (104.4 mg,
0.418 mmol) was dissolved in THF (4 mL), the solution was cooled
to 0 ꢀC, and sodium bicarbonate (100.8 mg, 1.20 mmol) and iodine
(303.8 mg, 1.20 mmol) were added. The reaction mixture gradually
warmed to room temperature while stirring for 7.5 h. The reaction
was quenched with saturated aqueous sodium thiosulfate. The
mixture was extracted with ethyl acetate (three times), the com-
bined organic layers were washed with brine and dried over
magnesium sulfate, and the solvent was removed by rotary evap-
oration. The residue was purified by silica gel flash chromatography
(hexanes/ethyl acetate¼90/10 to 80/20) to give the threo-product
33a (108.2 mg, 0.288 mmol, 69% yield); nmax (liquid film) 3346,
2943, 2854, 1454, 1365, 1210, 1093, 998, 892, 736 cmꢁ1
; dH (CDCl3,
600 MHz) 7.38e7.25 (5H, m), 4.53 (2H, s), 4.37 (1H, td, J¼9.0,
3.0 Hz), 4.29 (1H, dt, J¼9.6, 3.0 Hz), 3.98 (1H, dd, J¼11.4, 4.8 Hz),
3.69 (1H, ddd, J¼9.0, 6.6, 4.2 Hz), 3.62 (1H, ddd, J¼9.0, 7.8, 5.4 Hz),
3.44 (1H, d, J¼9.0 Hz), 3.46e3.40 (1H, m), 2.47 (1H, dddd, J¼15.0,
7.8, 6.6, 3.0 Hz), 2.03e1.94 (2H, m), 1.89 (1H, d, J¼9.6 Hz), 1.87 (1H,
qt, J¼13.8, 4.2 Hz), 1.67 (1H, tdd, J¼13.8, 4.8, 3.0 Hz), 1.36e1.31 (1H,
m); dC (CDCl3, 150 MHz) 138.4, 128.3, 127.7, 127.5, 82.9, 73.0, 69.7,
69.1, 66.3, 35.4, 32.0, 30.9, 19.9; HRMS (APCI) calcd for C15H22O3I
[MþH]þ 377.06082, found 377.06085.
4.3.2.1. Data for 36. nmax (liquid film) 3433, 2935, 2853, 1720,
4.3.4.2. Dehydrohalogenation of 33a to 37. The iodoether 33a
(47.3 mg, 0.126 mmol) was dissolved in CH2Cl2 (1.5 mL), and 1,8-
1454, 1361, 1270, 1205, 1095, 940, 737 cmꢁ1
;
dH (CDCl3, 400 MHz)
7.36e7.24 (5H, m), 4.51 (2H, s), 3.91e3.84 (1H, m), 3.51 (2H, t,
J¼6.0 Hz), 3.34e3.24 (2H, m), 3.00 (1H, td, J¼8.8, 2.8 Hz), 2.11e2.03
(1H, m), 2.03e1.80 (3H, m), 1.74e1.61 (2H, m), 1.55e1.44 (1H, m),
1.43e1.31 (1H, m); dC (CDCl3, 150 MHz) 138.5, 128.3, 127.7, 127.5,
82.1, 72.8, 70.4, 70.2, 67.5, 32.7, 28.6, 25.6, 25.3; HRMS (APCI) calcd
for C15H23O3 [MþH]þ 251.16417, found 251.16425.
diazabicyclo[5.4.0]undec-7-ene (DBU, 36 mL, 0.241 mmol) was
added. After stirring for 1 day, the solvent was removed by rotary
evaporation, and the residue was purified by silica gel flash chro-
matography (hexanes/ethyl acetate¼70/30) to give the alkene 37
(18.9 mg, 0.0762 mmol, 60% yield). Spectroscopic data matched
that of compound 37 obtained by dehydrohalogenation of 34a.
4.3.2.2. Data for 38. nmax (liquid film) 3452, 2942, 2852, 1718,
4.3.5. Mercury-promoted cyclization of trans-alkenyldiol 17 to form
36 and 38. The alkenyldiol 17 (53.1 mg, 0.212 mmol) was dissolved
in THF (2 mL), the solution was cooled to 0 ꢀC, and a solution of
mercuric trifluoroacetate (139.9 mg, 0.328 mmol) in THF (2 mL)
was added slowly. The reaction mixture gradually warmed to room
temperature while stirring for 2 h. Saturated aqueous potassium
chloride (0.14 mL) was added, and the mixture was stirred for 1.5 h
at room temperature. The reaction mixture was diluted with ethyl
acetate, the organic layer was washed with water (twice) and brine,
dried over magnesium sulfate, and the solvent was removed by
1496, 1454, 1362, 1275, 1206, 1095, 992, 907, 738 cmꢁ1
; dH (CDCl3,
400 MHz) 7.37e7.24 (5H, m), 4.50 (2H, s), 4.00e3.92 (1H, m), 3.63
(1H, broad), 3.54e3.38 (3H, m), 3.28 (1H, t, J¼6.2 Hz), 2.12e1.80 (3H,
m), 1.80e1.50 (4H, m), 1.44e1.34 (1H, m); dC (CDCl3, 150 MHz) 138.5,
128.3, 127.6, 127.5, 79.8, 72.8, 70.2, 68.5, 66.6, 30.6, 28.5, 25.7, 20.2;
HRMS (APCI) calcd for C15H23O3 [MþH]þ 251.16417, found 251.16425.
4.3.3. Selenium-promoted cyclization of cis-alkenyldiol 16 to form 35
and 37. The alkenyldiol 16 (50.1 mg, 0.200 mmol) was dissolved in

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
7755
rotary evaporation. The residue was diluted with toluene (6 mL),
tributyltin hydride (0.26 mL, 0.97 mmol) and AIBN (6.0 mg) were
added, and the reaction mixture was heated at 77 ꢀC for 2 h. The
reaction mixture cooled to room temperature, the solvent was re-
moved by rotary evaporation, and the residue was purified by flash
chromatography on silica gel support mixed with 10% KF (hexanes/
ethyl acetate¼90/10 to 50/50) to give pure samples of di-
astereomers 36 and 38 along with fractions containing both di-
astereomers, which in total corresponded to a 34:66 mixture of
diastereomers 36 and 38 (26.3 mg, 0.105 mmol, 50% combined
yield). Compounds 36 and 38 exhibited spectroscopic characteris-
tics consistent with compounds arising from mercury-promoted
cyclization of 16 followed by reductive demercuration.
compound 36 (50.7 mg, 94% yield). Spectroscopic data matched
that of compound 36 produced by mercuric trifluoroacetate-
promoted cyclization of cis-16 followed by tributyltin hydride
demercuration.
4.5. Oxacyclizations of 1,1-disubstituted alkene 21
4.5.1. Iodocyclization of 21
4.5.1.1. Formation of 42a. The alkenyldiol 21 (54.7 mg,
0.199 mmol) was dissolved in THF (2 mL), the solution was cooled to
0
ꢀC, and sodium bicarbonate (50.7 mg, 0.604 mmol) and iodine
(150.0 mg, 0.591 mmol) were added. The reaction mixture gradu-
ally warmed to room temperature while stirring overnight. The
reaction was quenched with saturated aqueous sodium thiosulfate.
The mixture was extracted with ethyl acetate (three times), the
combined organic layers were washed with brine and dried over
magnesium sulfate, and the solvent was removed by rotary evap-
oration. As TLC and crude NMR analysis of the product mixture
revealed that the silyl ether 43a was largely deprotected under the
iodocyclization conditions, the residue was diluted with MeOH
(4 mL), pyridinium p-toluenesulfonate (7.0 mg, 0.028 mmol) was
added, and the mixture was stirred at room temperature for 20 h, to
complete the desilylation process. The reaction was quenched with
saturated aqueous sodium bicarbonate. The mixture was extracted
with ethyl acetate (three times), the combined organic layers were
washed with brine and dried over magnesium sulfate, and the
solvent was removed by rotary evaporation. The residue was
purified by silica gel flash chromatography (hexanes/ethyl
acetate¼70/30 to 60/40) to give the iododiol 42a (39.9 mg,
0.139 mmol, 70% yield). The product was recrystallized from hex-
anes and ethyl acetate to provide crystals suitable for X-ray anal-
ysis; mp 119e120 ꢀC (decomposed); nmax (liquid film) 3235, 3155,
4.3.6. Selenium-promoted cyclization of trans-alkenyldiol 17 to form
35 and 37. The alkenyldiol 17 (49.0 mg, 0.196 mmol) was dissolved
in CH2Cl2 (3 mL), the solution was cooled to 0 ꢀC, and toluene-
sulfonic acid (3.1 mg, 0.016 mmol) and N-phenylselenophthalimide
(73.8 mg, 0.244 mmol) were added. The reaction mixture gradually
warmed to 20 ꢀC over 14.5 h. The mixture was then diluted with
chloroform, the organic phase was washed with 0.2 M aqueous
KOH (three times) followed by brine, dried over magnesium sulfate,
and the solvent was removed by rotary evaporation. The crude
NMR spectrum at this stage showed that the phenylselenyl com-
pound 32c was present, along with elimination product 37. With-
out separating these compounds, the mixture was dissolved in THF
(2 mL) and cooled to 0 ꢀC, acetic acid (64 mL) and 30% hydrogen
peroxide (0.27 mL) were added. The reaction mixture was stirred
for 25 min, and then quenched with saturated aqueous sodium
bicarbonate (20 mL). The mixture was extracted with diethyl ether
(three times), the combined organic layers were washed with brine
and dried over magnesium sulfate, and solvents were removed by
rotary evaporation. The residue was purified by silica gel flash
chromatography (hexanes/ethyl acetate¼70/30 to 60/40) to give an
inseparable mixture of 35 and 37 (56:44, 30.2 mg, 62% combined
yield). The mixture exhibited spectroscopic characteristics consis-
tent with 35 and 37 arising from dehydrohalogenation of the cor-
responding iodoethers 31a and 33a/34a, respectively.
2931, 2871, 1425, 1335, 1073, 1064, 1046, 998, 785, 705 cmꢁ1
; dH
(CDCl3, 600 MHz) 3.86 (1H, ddd, J¼8.4, 5.4, 3.6 Hz), 3.84e3.75 (2H,
m), 3.79 (1H, d, J¼12.0 Hz), 3.69e3.64 (1H, m), 3.47 (1H, d,
J¼12.0 Hz), 3.39 (1H, td, J¼12.0, 4.2 Hz), 2.03 (1H, ddd, J¼15.0, 5.4,
2.4 Hz), 1.95e1.88 (2H, m), 1.74e1.54 (4H, m); dC (CDCl3, 150 MHz)
76.3, 70.0, 60.7, 58.3, 41.4, 27.2, 24.8, 9.8; HRMS (APCI) calcd for
C8H16O3I [MþH]þ 287.01387, found 287.01396.
4.4. Mercury-catalyzed oxacyclizations of 15
4.5.1.2. Reductive deiodination of 42a to 44. The iodide 42
(29.5 mg, 0.103 mmol) was dissolved in toluene (3 mL), tributyltin
hydride (0.10 mL, 0.37 mmol) and AIBN (3.1 mg) were added, and
the reaction mixture was heated at 80 ꢀC for 3.5 h. The reaction
mixture cooled to room temperature, solvent was removed by ro-
tary evaporation, and the residue was purified by flash chroma-
tography on silica gel support mixed with 10% KF (eluted with ethyl
acetate) to give the diol 44 (12.3 mg, 0.0768 mmol, 74% yield); nmax
(liquid film) 3376, 2940, 2871, 1666, 1443, 1376, 1082, 1058,
4.4.1. Mercury-catalyzed
oxacyclization
and
hydration
to
41. Mercuric triflate (508 mg, 1.01 mmol) was dissolved in CH2Cl2
(8 mL) and the solution was cooled to ꢁ20 ꢀC. A solution of the
alkynyldiol 15 (505 mg, 2.03 mmol) in CH2Cl2 (2 mL) was added
dropwise to the catalyst solution. After stirring for 15 min, the re-
action mixture was quenched with triethylamine (100 mL) and fil-
tered through a pad of silica gel. Solvents were removed by rotary
evaporation, and the crude off-white powder was purified by silica
gel flash chromatography (hexanes/ethyl acetate¼90/10) to afford
compound 41 as a white powder (452 mg, 90% yield); dH (CDCl3,
600 MHz) 7.41e7.17 (5H, m), 4.52 (2H, s), 3.93 (1H, t, J¼3.0 Hz), 3.86
(1H, dd, J¼11.7, 5.0 Hz), 3.63 (1H, td, J¼12.5, 2.6 Hz), 3.53 (2H, t,
J¼6.2 Hz), 2.00e1.67 (8H, m), 1.26 (1H, broad (OH)), 1.20 (1H, m); dC
(CDCl3, 100 MHz) 138.5, 128.2, 127.5, 127.4, 95.1, 72.6, 70.5, 64.5,
63.9, 29.3, 26.2, 22.1, 19.1.
987 cmꢁ1
; dH (CDCl3, 600 MHz) 3.86e3.76 (2H, m), 3.63e3.51 (3H,
m), 3.34 (1H, broad, (OH)), 3.29 (1H, broad, (OH)), 1.89e1.80 (3H,
m), 1.71e1.54 (3H, m), 1.22 (3H, s); dC (CDCl3, 150 MHz) 78.2, 72.0,
60.4, 59.0, 42.4, 27.5, 25.4, 14.3; HRMS calcd for C8H17O3 [MþH]þ
161.11722, found 161.11707.
4.5.2. Mercury-promoted cyclization of 21
4.4.2. Mercury-catalyzed reductive cyclization to 36. Mercuric tri-
flate (19 mg, 0.038 mmol) was dissolved in CH2Cl2 (2 mL) and the
solution was cooled to ꢁ20 ꢀC. A solution of the alkynyldiol 15
(54.1 mg, 0.21 mmol) in CH2Cl2 (1 mL) was added dropwise to the
catalyst solution. After stirring for 15 min, the reaction mixture was
4.5.2.1. Formation of 45. The alkenyldiol 21 (48.1 mg,
0.194 mmol) was dissolved in THF (2 mL), the solution was cooled to
0
ꢀC, and a solution of mercuric trifluoroacetate (137.0 mg,
0.321 mmol) in THF (2 mL) was added slowly. The reaction mixture
gradually warmed to room temperature while stirring for 2 h.
Saturated aqueous potassium chloride (0.14 mL) was added, and
the mixture was stirred for 1.5 h at room temperature. The reaction
mixture was diluted with ethyl acetate, the organic layer was
washed with water (twice) and brine, dried over magnesium
quenched with triethylsilane (130
mL, 0.81 mmol) and filtered
through a pad of silica gel. Solvents were removed by rotary
evaporation, and the crude oil was purified by silica gel flash
chromatography (hexanes/ethyl acetate¼90/10 to 80/20) to afford

7756
F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
sulfate, and the solvent was removed by rotary evaporation. The
residue was diluted with toluene (6 mL), tributyltin hydride
(0.26 mL, 0.97 mmol) and AIBN (5.3 mg) were added, and the re-
action mixture was heated at 74 ꢀC for 2 h. The reaction mixture
cooled to room temperature, the solvent was removed by rotary
evaporation, and the residue was purified by flash chromatography
on silica gel support mixed with 10% KF (hexanes/ethyl acetate¼90/
10 to 70/30) to give the cyclic ether 45 (20.4 mg, 0.0743 mmol, 38%
yield), and a minor diastereomer (3.6 mg, 0.013 mmol, 7% yield).
4.5.2.1.1. Data for 45. nmax (liquid film) 3433, 2953, 2858, 1471,
4.6. Oxacyclizations of trisubstituted alkenes 24 and 30
4.6.1. Iodocyclization of (Z)-alkenyldiol 24
4.6.1.1. Formation of 46a and 49a. The Z-alkenyldiol 24
(113.4 mg, 0.358 mmol) was dissolved in THF (3.6 mL), the solution
was cooled to 0 ꢀC, and sodium bicarbonate (91.4 mg, 1.09 mmol)
was added. Iodine (184.1 mg, 0.725 mmol) was then added in
several portions. The reaction mixture was stirred at 0 ꢀC for 4 h,
and at room temperature for 20.5 h. The reaction was quenched
with saturated aqueous sodium thiosulfate. The mixture was
extracted with ethyl acetate (three times), the combined organic
layers were washed with brine and dried over magnesium sulfate,
and the solvent was removed by rotary evaporation. The residue
was purified by silica gel flash chromatography (hexanes/ethyl
acetate¼95/5 to 80/20) to give pure samples of diastereomers 46a
and 49a along with fractions containing both diastereomers, which
in total corresponded to a 17:83 mixture of diastereomers 46a and
49a (97.7 mg, 0.221 mmol, 62% combined yield).
1254, 1089, 1003, 836, 777 cmꢁ1
; dH (CDCl3, 400 MHz) 4.46 (1H, d,
J¼3.2 Hz, OH), 3.81 (1H, ddd, J¼10.8, 5.2, 4.0 Hz), 3.71 (1H, ddd,
J¼11.2, 9.2, 2.8 Hz), 3.52e3.63 (2H, m), 3.47 (1H, ddd, J¼10.8, 4.4,
2.8 Hz), 1.88e1.47 (6H, m), 1.17 (3H, s), 0.90 (9H s), 0.10 (3H, s), 0.09
(3H, s); dC (CDCl3, 100 MHz) 72.2, 60.4, 59.5, 45.6, 26.7, 25.8, 25.5,
25.2, 18.2, 13.8, ꢁ5.5, ꢁ5.6; HRMS (APCI) calcd for C14H31O3Si
[MþH]þ 275.20370, found 275.20378.
4.5.2.1.2. Partial data for the minor diastereomer. dH (CDCl3,
400 MHz) 3.82e3.64 (4H, m), 3.44 (1H, td, J¼6.4, 2.8 Hz), 2.15 (1H,
ddd, J¼14.4, 10.0, 4.4 Hz), 1.94e1.80 (2H, m), 1.80e1.69 (1H, m), 1.64
(1H, ddd, J¼14.8, 4.8, 3.2 Hz), 1.54e1.44 (1H, m), 1.27 (3H, s), 0.91
(9H, s), 0.10 (3H, s), 0.09 (3H, s).
4.6.1.1.1. Data for 46a. nmax (liquid film) 3428, 2943, 2866, 1463,
1381, 1276, 1257, 1087, 986, 822, 782 cmꢁ1
; dH (CDCl3, 600 MHz)
4.95 (1H, d, J¼3.6 Hz, OH), 4.30 (1H, dd, J¼11.4, 3.6 Hz), 4.26 (1H, dd,
J¼9.6, 3.0 Hz), 4.04 (1H, dd, J¼11.4,10.2 Hz), 3.69e3.63 (1H, m), 3.61
(1H, dt, J¼10.2, 4.2 Hz), 3.50 (1H, dt, J¼12.0, 7.2 Hz), 1.94e1.87 (1H,
m), 1.66e1.53 (3H, m), 1.29 (3H, s), 1.20e1.02 (21H, m); dC (CDCl3,
150 MHz) 78.4, 70.2, 67.3, 61.1, 49.1, 28.1, 25.1, 17.80, 17.76, 13.0, 11.8;
HRMS (APCI) calcd for C17H36O3ISi [MþH]þ 443.14730, found.
443.14752.
4.5.2.2. Desilylation of 45 to 44. The silyl ether 45 (15.8 mg,
0.0638 mmol) was dissolved in THF (0.6 mL), and tetrabutylammo-
nium fluoride (1 M in THF, 0.10 mL, 0.10 mmol) was added. The re-
action mixture was stirred for 6.5 h, after, which the solvent was
removed by rotary evaporation. The residue was purified by silica gel
flash chromatography (eluted with ethyl acetate) to give the diol 44
(8.8 mg, 0.055 mmol, 86% yield). The spectroscopic data matched
that of compound 44 obtained by reductive deiodination of 42a.
4.6.1.1.2. Data for 49a. nmax (liquid film) 3415, 2941, 2866, 1463,
1383, 1262, 1214, 1116, 1089, 1058, 1032, 995, 882, 799 cmꢁ1
; dH
(CDCl3, 600 MHz) 4.72 (1H, dd, J¼9.0, 3.0 Hz), 4.27 (1H, dd, J¼11.4,
3.0 Hz), 4.01 (1H, dd, J¼11.4, 9.0 Hz), 3.95 (1H, d, J¼7.2 Hz (OH)),
3.75e3.64 (3H, m), 1.96e1.84 (2H, m), 1.84e1.77 (1H, m), 1.49e1.42
(1H, m), 1.38 (3H, s), 1.20e1.11 (3H, m), 1.11e1.04 (18H, m); dC
(CDCl3, 150 MHz) 77.4, 68.8, 67.3, 61.3, 43.5, 27.5, 21.9, 20.3, 17.9,
11.8; HRMS (APCI) calcd for C17H36O3ISi [MþH]þ 443.14730, found
443.14850.
4.5.3. Selenium-promoted cyclization of 21
4.5.3.1. Formation of 43c. The alkenyldiol 21 (49.1 mg,
0.198 mmol) was dissolved in CH2Cl2 (3 mL), the solution was cooled
to 0 ꢀC, and toluenesulfonic acid (5.3 mg, 0.028 mmol) and N-phe-
nylselenophthalimide (74.3 mg, 0.246 mmol) were added. The re-
action mixture was stirred for 8 h at 0 ꢀC. The mixture was then
diluted with chloroform, the organic phase was washed with 0.2 M
aqueous KOH (three times) followed by brine, dried over magne-
sium sulfate, and the solvent was removed by rotary evaporation.
The crude product contained many compounds, but the principal
component was isolated by silica gel flash chromatography (hex-
anes/ethyl acetate¼95/5 to 90/10) to give selenoether 43c (19.2 mg,
0.0447 mmol, 23% yield); nmax (liquid film) 3396, 3071, 3057, 2953,
4.6.1.2. Reductive deiodination of 46a to 50. Iodide 46a (9.6 mg,
0.0217 mmol) was dissolved in toluene (3 mL), tributyltin hydride
(0.10 mL, 0.37 mmol) and AIBN (3.2 mg) were added, and the re-
action mixture was heated at 70 ꢀC for 2 h. The reaction mixture
then cooled to room temperature, solvent was removed by rotary
evaporation, and the residue was purified by flash chromatography
on silica gel support mixed with 10% KF (hexanes/ethyl acetate¼90/
10) to give compound 50 (4.6 mg, 0.015 mmol, 67% yield); nmax
(liquid film) 3420, 2941, 2866, 1463, 1380, 1089, 997, 883, 729 cmꢁ1
;
2933, 2858,1579,1475,1437,1256,1081,1057, 837, 779, 736 cmꢁ1
; dH
dH (CDCl3, 600 MHz) 4.59 (1H, d, J¼3.0 Hz, OH), 3.88 (1H, ddd,
J¼10.8, 5.4, 3.6 Hz), 3.83 (1H, td, J¼10.8, 2.4 Hz), 3.62e3.54 (2H, m),
3.51 (1H, ddd, J¼10.8, 4.2, 2.4 Hz), 1.88e1.81 (2H, m), 1.76e1.71 (1H,
m), 1.68e1.62 (2H, m), 1.58e1.50 (1H, m), 1.19 (3H, s), 1.18e1.04
(21H, m); dC (CDCl3, 150 MHz) 72.2, 60.4, 59.8, 45.9, 26.7, 25.6, 25.2,
17.88, 17.86, 13.8, 11.8; HRMS (APCI) calcd for C17H37O3Si [MþH]þ
317.25065, found 317.25056.
(CDCl3, 400 MHz) 7.55e7.50 (2H, m), 7.30e7.20 (3H, m), 4.95 (1H, d,
J¼2.4 Hz, OH), 3.80 (1H, ddd, J¼11.2, 5.2, 4.0 Hz), 3.76e3.68 (2H, m),
3.68e3.58 (2H, m), 3.52e3.44 (1H, m), 3.16 (1H, d, J¼12.8 Hz), 2.18
(1H, ddd, J¼15.2, 4.8,1.6 Hz),1.94e1.86 (1H, m),1.80 (1H, ddd, J¼14.0,
10.4, 2.0 Hz),1.72e1.56 (3H, m), 0.89 (9H, s), 0.10 (3H, s), 0.07 (3H, s);
dC (CDCl3, 100 MHz) 132.6, 130.6, 129.0, 126.7, 78.4, 72.5, 61.0, 59.6,
42.9, 28.0, 26.5, 25.8, 25.2, 18.2, ꢁ5.5, ꢁ5.7; HRMS (ESI) calcd for
C20H33O3SeSi [MꢁH]þ 429.13587, found. 429.13623.
4.6.1.3. Acetylation of 49a to 52. Iodide 49a (23.0 mg,
0.0520 mmol) was dissolved in dichloromethane (2 mL), and acetic
anhydride (49 mL, 0.52 mmol), pyridine (84 mL, 1.0 mmol), and
dimethylaminopyridine (1.4 mg, 0.011 mmol) were added succes-
sively. The mixture was stirred at room temperature for 20.5 h, the
solvent was removed by rotary evaporation, and the residue was
purified by silica gel chromatography (hexanes/ethyl acetate¼90/
10) to provide the acetate ester 52 (24.9 mg, 0.0514 mmol, 99%
yield); nmax (liquid film) 2942, 2866, 1741, 1463, 1373, 1236, 1090,
4.5.3.2. Reductive deselenylation of 43c to 45. Compound 43
(17.7 mg, 0.0412 mmol) was dissolved in toluene (3 mL). Tributyltin
hydride (0.10 mL, 0.37 mmol) and AIBN (3.9 mg) were added, and
the reaction mixture was heated to 70 ꢀC for 2 h, after which the
solvent was removed by rotary evaporation. The residue was pu-
rified by flash chromatography on silica gel support mixed with 10%
KF (hexanes/ethyl acetate¼90/10) to give the product 45 (10.2 mg,
0.0372 mmol) in 90% yield. The spectroscopic data matched that of
45 obtained by mercury-promoted cyclization of 21 followed by
reductive demercuration.
883, 807 cmꢁ1
;
dH (benzene-d6, 600 MHz) 5.00 (1H, dd, J¼4.8,
3.0 Hz), 4.74 (1H, dd, J¼7.8, 4.2 Hz), 4.05 (1H, dd, J¼12.0, 4.2 Hz),
3.95 (1H, dd, J¼12.0, 7.8 Hz), 3.46 (1H, dt, J¼11.4, 3.0 Hz), 3.30 (1H,

F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
7757
td, J¼11.4, 3.0 Hz), 1.69 (3H, s), 1.63e1.57 (1H, m), 1.55e1.46 (1H, m),
1.46e1.35 (1H, m), 1.20 (3H, s), 1.17e1.07 (21H, m), 0.82 (1H, dt,
J¼13.2, 3.6 Hz); dC (benzene-d6, 100 MHz) 169.5, 75.3, 70.8, 66.5,
61.3, 47.8, 25.2, 21.4, 21.1, 20.3, 18.7, 12.7; HRMS (APCI) calcd for
C19H38O4ISi [MþH]þ 485.15787, found 485.15816.
(0.56H, d, J¼7.6 Hz), 4.01e3.50 (6H, m), 2.01e1.51 (4H, m), 1.37
(1.68H, s), 1.30 (1.32H, s), 0.96e0.84 (21H, m); dC (CDCl3, 150 MHz)
136.2,135.9, 129.2,129.0,128.8,128.7, 128.05,127.98, 79.8, 78.6, 72.2,
71.1, 64.4, 64.1, 61.2, 60.8, 58.7, 53.0, 27.4, 27.1, 25.1, 22.7, 19.2, 17.73,
17.69, 11.6, 11.5, 11.4; HRMS (ESI) calcd for C23H39O3SeSi [MꢁH]þ
471.18282, found 471.18316.
4.6.2. Mercury-promoted cyclization of (Z)-alkenyldiol 24
4.6.2.1. Formation of 46b. The (Z)-alkenyldiol 24 (31.4 mg,
0.0992 mmol) was dissolved in THF (1 mL), the solution was cooled
to 0 ꢀC, and a solution of mercuric trifluoroacetate (69.0 mg,
0.162 mmol) in THF (1 mL) was added slowly. The reaction mixture
gradually warmed to room temperature while stirring for 1.5 h.
Saturated aqueous potassium chloride (69 mL) was added, and the
mixture was stirred for 2 h at room temperature. The reaction
mixture was diluted with ethyl acetate, the organic layer was
washed with water (twice) and brine, dried over magnesium sul-
fate, and the solvent was removed by rotary evaporation. The res-
idue was purified by silica gel flash chromatography (hexanes/ethyl
acetate¼90/10 to 80/20) to provide the erythro-product 46b
(29.5 mg, 0.0535 mmol, 54% yield); melting point 100e103 ꢀC; nmax
(liquid film) 3260, 2939, 2863, 1459, 1082, 1063, 1001, 982, 882, 791,
4.6.3.2. Desilylation and acetylation of 46c and 49c to provide 53
and 54. The mixture of 46c and 49c (37.4 mg, 0.0793 mmol) was
dissolved in THF (0.8 mL), and tetrabutylammonium fluoride (1 M
in THF, 0.12 mL, 0.12 mmol) was added. The reaction was stirred for
1.5 h. The solvent was then removed by rotary evaporation, and the
residue was purified by silica gel flash chromatography (hexanes/
ethyl acetate¼50/50 to 0/100) to give an inseparable mixture of diol
diastereomers (22.9 mg, 0.0726 mmol, 92% combined yield). This
mixture was dissolved in dichloromethane (4 mL), and acetic an-
hydride (103 mL, 1.09 mmol), pyridine (0.18 mL, 2.23 mmol), and
dimethylaminopyridine (3.6 mg, 0.029 mmol) were added succes-
sively. The mixture was stirred for 17 h. The solvent was then re-
moved by rotary evaporation, and the residue was purified by silica
gel flash chromatography (hexanes/ethyl acetate¼90/10) to provide
the erythro-product 53 (10.4 mg, 0.0260 mmol, 36% yield), and the
threo-product 54 (12.7 mg, 0.0318 mmol, 44% yield).
681, 671, 654, 640 cmꢁ1
;
dH (CDCl3, 600 MHz) 4.18 (1H, d, J¼2.4 Hz
(OH)), 4.09 (1H, dd, J¼11.4, 4.8 Hz), 4.04 (1H, t, J¼10.8 Hz),
3.67e3.62 (1H, m), 3.57e3.52 (1H, m), 3.47 (1H, ddd, J¼11.4, 4.2,
2.4 Hz), 3.06 (1H, dd, J¼10.8, 4.8 Hz), 1.93e1.86 (1H, m), 1.67e1.58
(2H, m), 1.56e1.46 (1H, m), 1.26 (3H, s), 1.17e1.04 (21H, m); dC
(CDCl3, 150 MHz) 79.7, 73.8, 70.1, 62.0, 61.3, 28.0, 25.6, 18.0, 15.7,
11.8; HRMS (ESI, negative) calcd for C17H35Cl2HgO3Si [MþCl]ꢁ
587.14388, found 587.14507.
4.6.3.2.1. Data for 53. nmax (liquid film) 3056, 2959, 2872, 1731,
1746, 1578, 1477,1438,1373,1234,1079, 1038, 990, 894, 742 cmꢁ1
; dH
(CDCl3, 400 MHz) 7.62e7.56 (2H, m), 7.29e7.22 (3H, m), 5.55 (1H, dd,
J¼10.0, 4.4 Hz), 4.65 (1H, dd, J¼12.0, 6.4 Hz), 4.40 (1H, dd, J¼12.0,
6.4 Hz), 3.68 (1H, br d, J¼11.6 Hz), 3.55 (1H, td, J¼11.6, 2.8 Hz), 3.39
(1H, t, J¼6.4 Hz), 2.15e2.05 (1H, m),1.97 (3H, s),1.91 (3H, s),1.84e1.56
(3H, m), 1.40 (3H, s); dC (CDCl3, 150 MHz) 170.8, 170.0, 134.7, 130.3,
129.0,127.5, 76.6,72.7, 65.1, 61.1, 53.8, 24.4,24.2,21.2, 20.8,16.2;HRMS
(ESI) calcd for C18H24O5NaSe [MþNa]þ 423.06812, found. 423.06834.
4.6.3.2.2. Data for 54. nmax (liquid film) 3071, 3056, 2955, 2869,
1746, 1731, 1578, 1477, 1438, 1373, 1234, 1093, 1081, 1049, 1022, 912,
4.6.2.2. Reductive demercuration of 46b to 50. Compound 46b
(17.7 mg, 0.0412 mmol) was dissolved in toluene (3 mL), tributyltin
hydride (0.10 mL, 0.37 mmol) and AIBN (2.8 mg) were added, and
the reaction mixture was heated at 70 ꢀC for 2 h. After the reaction
mixture had cooled to room temperature, the solvent was removed
by rotary evaporation, and the residue was purified by flash chro-
matography on silica gel support mixed with 10% KF (hexanes/ethyl
acetate¼90/10) to give 50 (15.0 mg, 0.0474 mmol, 90% yield).
Spectroscopic characteristics were identical to those of 50 arising
from reductive deiodination of 46a.
742 cmꢁ1
; dH (benzene-d6, 600 MHz) 7.71e7.66 (2H, m), 6.97e6.90
(3H, m), 4.89 (1H, t, J¼3.0 Hz), 4.75 (1H, dd, J¼12.0, 6.0 Hz), 4.49
(1H, dd, J¼12.0, 7.8 Hz), 4.05 (1H, dd, J¼7.8, 6.0 Hz), 3.55 (1H, br d,
J¼12.0 Hz), 3.33 (1H, td, J¼12.0, 2.4 Hz), 1.78 (3H, s), 1.77e1.70 (1H,
m), 1.66e1.56 (1H, m), 1.60 (3H, s), 1.45e1.39 (1H, m), 1.11 (3H, s),
0.85e0.79 (1H, m); dC (benzene-d6, 100 MHz) 170.4, 170.0, 135.3,
131.2, 129.6, 127.9, 77.1, 71.8, 65.9, 61.6, 53.6, 24.5, 21.3, 20.80, 20.77,
18.4; HRMS (ESI) calcd for C18H24O5NaSe [MþNa]þ 423.06812,
found 423.06842.
4.6.2.3. Desilylation of 50 to 44. The silyl ether 50 (19.3 mg,
0.0610 mmol) was dissolved in THF (1 mL), and tetrabutylammo-
nium fluoride (1 M in THF, 0.10 mL, 0.10 mmol) was added. The re-
action mixture was stirred for 4 h, after which the solvent was
removed by rotaryevaporation. The residue was purified bysilica gel
flash chromatography (eluted with ethyl acetate) to give the diol 44
(6.1 mg, 0.038 mmol, 38% yield). The spectroscopic data matched
that of compound 44 obtained by reductive deiodination of 42a.
4.6.4. Iodocyclization of (E)-alkenyldiol 30
4.6.4.1. Formation of 48a. The (E)-alkenyldiol 30 (31.2 mg,
0.0985 mmol) was dissolved in THF (1 mL), the solution was cooled
to 0 ꢀC, and sodium bicarbonate (25.5 mg, 0.304 mmol) and iodine
(74.2 mg, 0.292 mmol) were added. The reaction mixture gradually
warmed to room temperature while stirring for 3 h. The reaction
was quenched with saturated aqueous sodium thiosulfate. The
mixture was extracted with ethyl acetate (three times), the com-
bined organic layers were washed with brine and dried over
magnesium sulfate, and the solvent was removed by rotary evap-
oration. The residue was purified by silica gel flash chromatography
(hexanes/ethyl acetate¼95/5 to 90/10) to give the threo-product
48a (33.2 mg, 0.0750 mmol, 76% yield); mp 108e110 ꢀC; nmax (liquid
film) 3298, 2914, 2864, 1461, 1380, 1215, 1096, 1053, 1036, 994, 882,
4.6.3. Selenium-promoted cyclization of (Z)-alkenyldiol 24
4.6.3.1. Formation of 46c and 49c. The (Z)-alkenyldiol 24
(32.8 mg, 0.104 mmol) was dissolved in CH2Cl2 (1.5 mL), the solution
was cooled to 0 ꢀC, and toluenesulfonic acid (2.4 mg, 0.013 mmol)
and N-phenylselenophthalimide (38.8 mg, 0.128 mmol) were added.
The reaction mixture was stirred at 0 ꢀC for 7 h. The mixture was
then diluted with chloroform, the organic phase was washed with
0.2 M aqueous KOH (three times) followed by brine, dried over
magnesium sulfate, and the solvent was removed by rotary evapo-
ration. The residue was purified by silica gel flash chromatography
(hexanes/ethyl acetate¼90/10) to give an inseparable mixture of 46c
and 49c (47:53, 30.8 mg, 78% combined yield); Data for the mixture:
nmax (liquid film) 3395, 3070, 3057, 2941, 2866, 2240, 1579, 1463,
804, 685, 639 cmꢁ1
;
dH (CDCl3, 400 MHz) 4.40 (1H, dd, J¼8.4,
3.2 Hz), 4.04 (1H, dd, J¼10.8, 3.2 Hz), 3.92 (1H, dd, J¼10.8, 8.4 Hz),
3.86 (1H, dt, J¼7.6, 3.6 Hz), 3.74 (1H, br dd, J¼11.2, 4.0 Hz), 3.65 (1H,
td, J¼11.6, 2.8 Hz), 2.05 (1H, d, J¼7.6 Hz, OH), 2.02e1.76 (3H, m),1.36
(3H, s), 1.33e1.20 (1H, m), 1.20e1.00 (21H, m); dC (CDCl3, 150 MHz)
76.3, 69.4, 64.8, 62.5, 44.6, 25.9, 19.5, 18.1, 16.0, 12.0; HRMS (APCI)
calcd for C17H36O3ISi [MþH]þ 443.14730, found 443.14764.
1382, 1257, 1082, 1024, 883, 801, 740 cmꢁ1
7.68e7.63 (2H, m), 7.34e7.23 (3H, m), 5.10 (0.44H, d, J¼3.2 Hz), 4.63
; dH (CDCl3, 400 MHz)

7758
F.E. McDonald et al. / Tetrahedron 69 (2013) 7746e7758
4.6.4.2. Reductive deiodination of 48a to 51. Iodide 48a
supported by the National Science Foundation under CHE-
1151304. We thank Dr. John Bacsa (Emory University X-ray
Crystallographic Center) for structural determinations of com-
pounds 34a and 42a.
(20.3 mg, 0.0459 mmol) was dissolved in toluene (3 mL), tributyltin
hydride (0.10 mL, 0.37 mmol) and AIBN (3.5 mg) were added, and
the reaction mixture was heated at 70 ꢀC for 2 h. The reaction
mixture then cooled to room temperature, solvent was removed by
rotary evaporation, and the residue was purified by flash chroma-
tography on silica gel support mixed with 10% KF (hexanes/ethyl
acetate¼90/10) to give compound 51 (16.9 mg, 0.0534 mmol, 99%
yield); nmax (liquid film) 3433, 2941, 2866, 2721, 1463, 1382, 1088,
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.138.
995, 883, 731 cmꢁ1
;
dH (CDCl3, 600 MHz) 3.86 (1H, dt, J¼10.8,
4.2 Hz), 3.83e3.78 (2H, m), 3.66 (2H, t, J¼5.4 Hz), 3.47 (1H, td, J¼6.6,
3.0 Hz), 2.20 (1H, ddd, J¼14.4, 9.6, 4.2 Hz), 1.91e1.82 (2H, m),
1.77e1.70 (1H, m), 1.64 (1H, ddd, J¼15.0, 5.4, 3.6 Hz), 1.53e1.45 (1H,
m), 1.28 (3H, s), 1.16e1.05 (21H, m); dC (CDCl3, 150 MHz) 76.3, 70.9,
60.9, 59.7, 38.4, 26.9, 22.8, 22.1, 17.9, 11.8; HRMS (APCI) calcd for
C17H37O3Si [MþH]þ 317.25065, found 317.25054.
References and notes
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3. Bowman, J. L.; McDonald, F. E. J. Org. Chem. 1998, 63, 3680.
4.6.5. Mercury-promoted cyclization of (E)-alkenyldiol 30 to 50 and
51. The (E)-alkenyldiol 30 (33.9 mg, 0.107 mmol) was dissolved in
THF (1 mL), the solution was cooled to 0 ꢀC, and a solution of
mercuric trifluoroacetate (66.3 mg, 0.155 mmol) in THF (1 mL) was
added slowly. The reaction mixture was stirred at 0 ꢀC for 30 min.
Saturated aqueous potassium chloride (69 mL) was added, and the
mixture was stirred for 2 h at 0 ꢀC. The reaction mixture was diluted
with ethyl acetate, the organic layer was washed with water (twice)
and brine, dried over magnesium sulfate, and the solvent was re-
moved by rotary evaporation. The residue was diluted with toluene
(3 mL), tributyltin hydride (0.13 mL, 0.48 mmol) and AIBN (4.3 mg)
were added, and the reaction mixture was heated at 75 ꢀC for 2 h.
After the reaction mixture cooled to room temperature, the solvent
was removed by rotary evaporation, and the residue was purified
by flash chromatography on silica gel support mixed with 10% KF
(hexanes/ethyl acetate¼95/5 to 80/20) to give the erythro-di-
astereomer 50 (4.5 mg, 0.0142 mmol, 13% yield), and the threo-di-
astereomer 51 (16.3 mg, 0.0515 mmol, 48% yield). The spectroscopic
data matched that observed for compounds 50 and 51 arising from
reductive deiodinations of 46a and 48a, respectively.
4. Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816.
5. See also: (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J. Am.
Chem. Soc. 1989, 111, 5330; (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Hwang, C. K. J. Am. Chem. Soc. 1989, 111, 5335; (c) Morimoto, Y.; Nishizawa, Y.;
Ueba, C.; Tanaka, T. Angew. Chem., Int. Ed. 2006, 45, 810; (d) Tanuwidjaja, J.; Ng,
S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 12084; (e) Van Dyke, A. R.; Ja-
mison, T. F. Angew. Chem., Int. Ed. 2009, 48, 4430.
6. Bartlett, P. A.; Ting, P. C. J. Org. Chem. 1986, 51, 2230.
7. Morimoto, M.; Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996, 37, 6365.
8. (a) Tamaru, Y.; Hojo, M.; Kawamura, S.; Sawada, S.; Yoshida, Z. J. Org. Chem.
1987, 52, 4062; (b) Reitz, A. B.; Nortey, S. O.; Maryanoff, B. E.; Liotta, D.; Mon-
ahan, R. J. Org. Chem. 1987, 52, 4191; (c) Williams, D. R.; White, F. H. J. Org. Chem.
1987, 52, 5067; (d) Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron
1985, 41, 4835.
9. Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc.
1987, 109, 672.
10. (a) Boschetti, A.; Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1988, 53, 4181; (b)
Gruttadauria, M.; Aprile, C.; Riela, S.; Noto, R. Tetrahedron Lett. 2001, 42, 2213;
(c) Albert, B. J.; Koide, K. Org. Lett. 2004, 6, 3655; (d) Nolen, E. G.; Donahue, L. A.;
Greaves, R.; Daly, T. A.; Calabrese, D. R. Org. Lett. 2008, 10, 4911.
11. Review: Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron 2008, 64, 2683.
~
ꢁ
ꢁ
12. Pena-Lopez, M.; Martinez, M. M.; Sarandeses, L. A.; Perez Sestelo, J. Org. Lett.
4.6.6. Selenium-promoted cyclization of (E)-alkenyldiol 30 to 50 and
51. The (E)-alkenyldiol 30 (63.7 mg, 0.201 mmol) was dissolved in
CH2Cl2 (3 mL), the solution was cooled to 0 ꢀC, and toluenesulfonic
acid (4.2 mg, 0.022 mmol) and N-phenylselenophthalimide
(78.5 mg, 0.260 mmol) were added. The reaction mixture gradually
warmed to 20 ꢀC over 15 h. The mixture was then diluted with
chloroform, the organic phase was washed with 0.2 M aqueous
KOH (three times) followed by brine, dried over magnesium sulfate,
and the solvent was removed by rotary evaporation. The residue
was dissolved in toluene (6 mL), tributyltin hydride (0.26 mL,
0.97 mmol) and AIBN (7.6 mg) were added. The reaction mixture
was heated at 70 ꢀC for 2 h, additional tributyltin hydride (0.52 mL,
1.93 mmol) and AIBN (14.3 mg) were added, and the reaction
mixture was heated at 70 ꢀC for two additional hours. The mixture
was allowed to cool to room temperature, solvents were removed
by rotary evaporation, and the residue was purified by flash chro-
matography on silica gel support mixed with 10% KF (hexanes/ethyl
acetate¼90/10 to 80/20) to give primarily the threo-diastereomer
51 (24.1 mg, 0.0761 mmol, 38% yield), and mixture fractions con-
taining both erythro-50 and threo-51 (40:60 ratio, 13 mg total, 20%
combined yield). The spectroscopic data matched that observed for
compounds 50 and 51 arising from reductive deiodinations of 46a
and 48a, respectively.
2010, 12, 852.
13. Michaelides, I. N.; Darses, B.; Dixon, D. J. Org. Lett. 2011, 13, 664.
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C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226.
15. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C.; Saucy, G. J. Org. Chem. 1976,
41, 3497.
16. Sugiyama, H.; Yokokawa, F.; Shioiri, T. Tetrahedron 2003, 59, 6579.
17. Barrett, A. G. M.; Broughton, H. B.; Attwood, S. V.; Gunatilaka, A. A. L. J. Org.
Chem. 1986, 51, 495.
18. Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamura, T.; Imai, H.; Nishi-
gaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew. Chem., Int. Ed. 2008, 47, 6657.
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8507.
20. Hayes, M. E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7, 3917.
21. The magnitude of the JHH coupling observed for compound 35 is consistent
3
with the presence of the electronegative oxygen substituents. See: Haasnoot, C.
A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783.
22. Miura, K.; Hondo, T.; Okajima, S.; Nakagawa, T.; Takahashi, T.; Hosomi, A. J. Org.
Chem. 2002, 67, 6082.
23. (a) Nishizawa, M.; Takemoto, T.; Sasaki, I.; Nakano, M.; Ho, E.; Namba, K.; Ya-
mamoto, H.; Imagawa, H. Synlett 2009, 1175; (b) Nishizawa, M.; Imagawa, H.;
Yamamoto, H. Org. Biomol. Chem. 2010, 8, 511.
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25. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
26. In our hands, cyclizations with a Hg(OTf)2-etetramethylurea complex pro-
ceeded much more slowly than Hg(OTf)2 alone: (a) Imagawa, H.; Fujikawa,
Y.; Tsuchihiro, A.; Kinoshita, A.; Yoshinaga, T.; Takao, H.; Nishizawa, M.
Synlett 2006, 639; (b) Imagawa, H.; Kotani, S.; Nishizawa, M. Synlett 2006,
642.
27. (a) Bennek, J. A.; Gray, G. R. J. Org. Chem. 1987, 52, 892; (b) Zheng, W.; DeMattei,
J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc.
1996, 118, 7946; (c) Smith, A. B.; Sfouggatakis, C.; Risatti, C. A.; Sperry, J. B.; Zhu,
W.; Doughty, V. A.; Tomioka, T.; Gotchev, D. B.; Bennett, C. S.; Sakamoto, S.;
Atasoylu, O.; Shirakami, S.; Bauer, D.; Takeuchi, M.; Koyanagi, J.; Sakamoto, Y.
Tetrahedron 2009, 65, 6489.
Acknowledgements
K.I. thanks the Uehara Memorial Foundation for a postdoctoral
fellowship. Later stages of this project are based upon work