Stereoselective Synthesis of Pyrans from Epoxyalkenes: Dual Catalysis with Palladium and Br?nsted Acid

Article abstract of DOI:10.1021/acs.joc.8b00026

We describe regio- and stereoselective cycloisomerizations of alcohols tethered to epoxyalkenes, to construct alkene-substituted pyrans. These transformations are best catalyzed by Pd(PPh₃)₄ in the presence of phosphite ligands, and with diphenylphosphinic acid as an essential Br?nsted acid cocatalyst for activation of the epoxyalkene.

Full text of DOI:10.1021/acs.joc.8b00026

Subscriber access provided by Kaohsiung Medical University
Article
Stereoselective Synthesis of Pyrans from Epoxyalkenes:
Dual Catalysis with Palladium and Brønsted Acid
Noah A. Setterholm, and Frank E. McDonald
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00026 • Publication Date (Web): 17 May 2018
Downloaded from http://pubs.acs.org on May 17, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
Stereoselective Synthesis of Pyrans from Epoxyalkenes:
Dual Catalysis with Palladium and Brønsted Acid
7
8
9
Noah A. Setterholm and Frank E. McDonald*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
email: frank.mcdonald@emory.edu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
H
Pd(PPh3)4 (5 mol %)
P(O-i-Pr)3 (30 mol %)
Ph2P(O)OH (10 mol %)
OAc
OAc
O
O
HO
CH2Cl2, 20 oC
OTBDPS
OTBDPS
HO Me
Me
ABSTRACT: We describe regio- and stereoselective cycloisomerizations of alcohols tethered to
epoxyalkenes, to construct alkene-substituted pyrans. These transformations are best catalyzed
by Pd(PPh3)4 in the presence of phosphite ligands, and with diphenylphosphinic acid as an
essential Brønsted acid co-catalyst for activation of the epoxyalkene.
INTRODUCTION
The stereoselective synthesis of cyclic ethers has been a long-standing interest of our
laboratory.1 As a new strategy for the synthesis of polycyclic ethers, we considered regioselective
and stereospecific cycloisomerizations of epoxyalkenes to form highly functionalized pyrans. In
this approach, the pendant hydroxyl group of 1 would undergo vinylogous addition onto the alkene
terminus of an epoxyalkene, with the stereochemical information of the epoxide transferred to the
new chiral center formed in the pyran 2 (Figure 1). Our goal was the stereocontrolled synthesis
of the three chiral centers of compound 2, corresponding to several natural product substructures
3, including yessotoxin (R1=Me) and gambierol (R1=H).2
H
H
H
O
OR2
OR2
this work
4
4
5
8
O
5
1
R1
O
HO
O
H
H
8
OPG
H
OPG
O
HO R1
1
R1
2
3
Figure 1. Proposed stereoselective synthesis of a substructure 2 commonly found in fused
polycyclic ether natural products
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 40
1
2
3
4
5
6
7
8
®
Despite the straightforward nature of the proposed transformation 1
2 (Figure 1), the
literature has provided very few examples in which an alcohol has added to the alkene terminus
of an epoxyalkene.3 Trost reported a single example of a Pd-catalyzed oxacyclization of such a
substrate, converting epoxyalkene 4 into the oxepane isomer 5, arising from regioselective
addition to the alkene terminus (eq 1).4
9
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Pd (catalytic)
BOMO
BOMO
(1)
4:1 i-PrOH/THF
(52% yield)
O
HO
#
4
5, E/Z 3:1
More recently, Uenishi has described Pd-catalyzed dehydrative oxacyclizations of allylic
alcohols 6 and 7 with tethered hydroxyl groups, observing stereospecificity in the formation of the
pyrans 10 and 11 corresponding to the stereochemistry of the allylic alcohols (Figure 2).5 Aponick
has subsequently demonstrated stereospecific Au-catalyzed cyclizations of trans-8 and cis-9 to
the respective enantiomers of pyran 12.6
H
H
OTBDPS
OTBDPS
PdCl2(MeCN)2
(10 mol %)
S
R
S
O
HO
THF
(93% yield)
H
R
Me
HO
Me
H
10
6
H
H
OTBDPS
OTBDPS
PdCl2(MeCN)2
(10 mol %)
S
S
S
O
HO
HO
HO
THF
(96% yield)
H
S
Me
HO
HO
Me
H
11
7
8
Ph3PAuCl (1 mol %)
AgOTf (1 mol %)
R
O
CH2Cl2, 4Å MS
(91% yield)
H
R
Ph
Ph
(R)-12
H
Ph3PAuCl (1 mol %)
AgOTf (1 mol %)
H OH
S
R
O
H
CH2Cl2, 4Å MS
(94% yield)
Ph
Ph
9
(S)-12
Figure 2. Intramolecular additions of alcohols tethered to allylic alcohols, with stereospecificity
corresponding to alcohol and alkene stereochemistry of substrates 6 - 9
In this Article, we describe the development of a catalytic process for stereoselective
cycloisomerizations of epoxyalkenes 1 into cyclic ethers 2.
2
ACS Paragon Plus Environment

Page 3 of 40
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
Stereoselective preparations of epoxyalkenes tethered to hydroxyl groups: Each
substrate in this study was synthesized by a cross-metathesis strategy. The epoxyalkene
diastereomers 20 or 21 were obtained from the corresponding Z- or E-dienyl alcohols 15 or 17
(Scheme 1). Specifically, Cu-catalyzed carbomagnesiation of propargyl alcohol (13) with
methylmagnesium bromide followed by quenching with elemental iodine provided (Z)-3-iodo-2-
methylprop-2-en-1-ol (14),7,8 and subsequent Pd-catalyzed Kumada coupling with
vinylmagnesium bromide gave (Z)-2-methyl-2,4-pentadien-1-ol (15).9,10 A complementary
sequence of steps, namely Sonogashira coupling of propargyl alcohol and vinyl bromide to pent-
4-en-2-yn-1-ol (16),11 followed by Cu-catalyzed carbomagnesiation yielded exclusively (E)-2-
methyl-2,4-pentadien-1-ol (17).12,13 Sharpless asymmetric epoxidation of each dienyl alcohol 15
or 17 provided the corresponding epoxyalkenyl alcohols 18 or 19.14 The primary alcohols were
then blocked as TBDPS ethers, completing the synthesis of epoxyalkene diastereomers 20 and
21.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Stereoselective syntheses of epoxyalkenes 20 and 21
1) CuI (10 mol %)
MeMgBr (2 equiv)
THF, 0 ˚C, 45 min
Pd(PPh3)4 (1.1 mol %)
I
(2.7 equiv)
MgBr
OH
OH
PhMe, 0 ˚C - rt, 12 h
(45% yield)
2) I2 (0.99 equiv)
Et2O, 30 min
(50% yield)
Me
15
Me
14
OH
PdCl2(PPh3)2 (0.4 mol %)
CuI (4.5 mol %)
i-Pr2NH (2.1 equiv)
13
MeMgBr (3.1 equiv)
CuI (13 mol %)
Br
(1.01 equiv)
Me
OH
THF, rt, 16 h
(81% yield)
Et2O/THF, 0 ˚C - rt, 20 h
(93% yield)
OH
16
17
Ti(O-i-Pr)4 (5 mol %)
D
-(-)-DIPT (8 mol %)
t-BuOOH (2.1 equiv)
TBDPSCl (1.0 equiv)
Imidazole (1.1 equiv)
S
S
H
15
H
OH
R
OTBDPS
R
O
O
3Å MS (55% by mass)
CH2Cl2, -35 ˚C, 24 h
(80% yield, er 80:20)
DMF, 0 ˚C - rt, 12 h
(76% yield)
Me
Me
20
18
Ti(O-i-Pr)4 (5 mol %)
TBDPSCl (1.1 equiv)
Et3N (1.6 equiv)
DMAP (11 mol %)
D
-(-)-DET (6 mol %)
t-BuOOH (2.0 equiv)
R
R
Me
Me
H
H
17
R
R
O
O
4 Å MS (53% by mass)
CH2Cl2, -20 ˚C, 2 h
CH2Cl2, 0 ˚C - rt, 3.5 h
(88% yield)
OTBDPS
OH
(41% yield, er > 95:5)
19
21
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 40
1
2
3
4
5
6
7
8
9
For the other alkene components, trimethylsilyl ethers 22 - 24 (Figure 3) were prepared
from the corresponding alkenyl alcohols,15 using hexamethyldisilazane and catalytic N-
bromosuccinimide, under conditions that did not require aqueous workup.16 For the differentially
O-protected alkenyl diol synthon 28 (Scheme 2), enzyme-catalyzed resolution of the racemic
allylic alcohol 2517 in the presence of isopropenyl acetate18 provided a separable mixture of the
(S)-acetate 26 and recovered (R)-25. Chemoselective deprotection of the TBS ether afforded
primary alcohol 27, which was reprotected as the more labile TMS ether 28.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMSO
TMSO
TMSO
23
24
22
Figure 3. Structures of O-trimethylsilyl ethers 22 - 24 from alkenyl alcohols
Scheme 2. Kinetic resolution of racemic 25, forming differentially O-protected 28
CAL-B (5% by mass)
H
H
OH
OAc
OH
(1.7 equiv)
S
R
OAc
+
TBSO
TBSO
TBSO
K3PO4 (1.05 equiv)
PhMe, rt, 3.25 h
(±)-25
(R)-25
26
(43% yield, er 96:4)
(41% yield, er 96:4)
H
H
TMS2NH (1 equiv)
NBS (6 mol %)
AcCl (0.28 equiv)
MeOH
OAc
S
OAc
S
26
TMSO
HO
neat, 50 ˚C, 1 h
(86% yield)
0 ˚C, 20 min
(65% yield)
28
27
Cross-metathesis experiments with the epoxyalkene 20 were initially conducted with the
TBS-ether-alkene 26, catalyzed by Grubbs II catalyst19 (29, Figure 4). However, the TBS ether
of the product was difficult to remove due to side-reactions of the epoxyalkene, and metathesis
reactions proceeded with poor yields with the primary alcohol 27. Therefore, the labile TMS-
ether-alkenes 22 - 24 and 28 were preferred. The nitro-substituted Grela metathesis catalyst
(30)20 generally gave the best trans-selectivity with relatively low catalyst loading. Typically, a
two- to four-fold excess of the less valuable alkene 22 - 24 or 28 was combined with epoxyalkene
20 or 21 in CDCl3 solution (to facilitate reaction monitoring by 1H NMR of aliquots) and the Grela
o
catalyst 30 (2 - 4 mol %), and warmed to 35 C. After 30 minutes, the reaction mixture was
concentrated under vacuum to remove ethylene and solvent, affording the corresponding
epoxyalkenes 32 - 33 and 35 - 39 (Figure 5 and Table 1, entries 1 - 2 and 4 - 8). The cis-
epoxyalkene 34 was prepared using the Grubbs Z-catalyst 31 (Table 1, entry 3).21 When the
Grela catalyst was used for cross-metathesis between two chiral non-racemic components,
epoxyalkenes 20 or 21 and allylic acetate 28, the diastereomer ratio of products 35 and 36 was
typically higher than expected from statistical analysis (Table 1, entries 4 - 5). This unexpected
enhancement of stereoselectivity suggested a mismatch between the minor enantiomer of one
component with the major enantiomer of the other chiral alkene.
4
ACS Paragon Plus Environment

Page 5 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N
N
N
N
N
N
Mes
Mes
Mes
Mes
Mes
Cl
Cl
Ru
Ru
Ru
O
Cl
Cy3P
Cl
i-PrO
O
N
O
NO2
i-PrO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Grubbs II catalyst (29)
Grela catalyst (30)
Grubbs Z-catalyst (31)
Figure 4. Catalysts for cross-metathesis (Table 1)
TMSO
TMSO
R
Me
H
R
S
Me
H
H
TMSO
H
OTBDPS
R
R
R
O
O
O
32
Me
33
34
OTBDPS
OTBDPS
H
OAc
OAc
S
S
TMSO
TMSO
R
S
Me
H
H
OTBDPS
R
R
O
O
35
Me
36
OTBDPS
Me
TMSO
TMSO
R
R
H
R
Me
Me
Me
H
H
R
R
R
O
O
O
37
38
39
OTBDPS
OTBDPS
OTBDPS
Figure 5. Products arising from cross-metathesis (Table 1)
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 40
1
2
3
4
5
6
Table 1. Cross-metathesis for syntheses of substrate precursors 32 - 39
alkene, equiv
(er)
epoxyalkene
(er)
catalyst
(loading)
isolated trans:cis
yield
entry
product
(dr)b
7
8
9
a
1
2
3
4
22, 4 equiv
22, 3 equiv
22, 3 equiv
20 (80:20)
21 (95:5)
21 (95:5)
20 (80:20)
30 (5 mol %)
30 (2 mol %)
31 (4.4 mol %)
30 (4 mol %)
32
33
34
35
90:10
89:11
10:90
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24%
61%
28, 2 equiv
>98:2
(96:4)
(86:14)b
28, 2 equiv
97:3
5
21 (95:5)
30 (4 mol %)
36
54%
(96:4)
(91:9)b
6
7
8
1-hexene, 8 equiv
23, 3 equiv
21 (95:5)
21 (95:5)
21 (95:5)
30 (2.5 mol %)
30 (3.5 mol %)
30 (3 mol %)
37
38
39
94%
45%
72%
88:12
90:10
89:11
24, 2 equiv
a The product was not isolated until after the deprotection step (see Table 2). The dr for products
35 and 36 arises from coupling the chiral allylic acetate 28 with the chiral epoxyalkenes 20 or
21.
b
Chemoselective deprotections of the cross-metathesis products revealed the hydroxyl
groups of epoxyalkene substrates 40 - 48 (Figure 6). We observed that the TMS ethers were
removed by methanolysis promoted by either K2CO3 (Table 2, entries 1, 2, and 9) or NH4Cl
(entries 3 and 8), affording epoxyalkene substrates 40 - 42 and 47 - 48. K2CO3-promoted
methanolysis removed both the trimethylsilyl ether and acetate ester protective groups from
compounds 35 and 36, providing diols 43 and 44 (entries 4 - 5), whereas NH4Cl-promoted
methanolysis exclusively removed the primary trimethylsilyl ethers to furnish the corresponding
monoacetates 45 and 46 (entries 6 - 7).
6
ACS Paragon Plus Environment

Page 7 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
HO
HO
R
S
R
Me
Me
7
8
9
H
H
H
OTBDPS
HO
R
R
R
O
O
O
Me
41
40
42
OTBDPS
OTBDPS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
OR
OR
S
S
HO
HO
R
S
Me
H
H
OTBDPS
R
R
O
O
Me
R = H, 43
R = Ac, 45
R = H, 44
OTBDPS
R = Ac, 46
HO
HO
R
R
Me
Me
H
H
R
R
O
O
48
47
OTBDPS
OTBDPS
Figure 6. Deprotected epoxyalkene substrates (Table 2)
Table 2. Deprotections of hydroxyl groups providing epoxyalkene substrates 40 - 48 (Figure 6)
entry
reactant product
conditions
isolated yield
70%a
41%a
83%
1
2
3
4
5
6
7
8
9
32
33
34
35
36
35
36
38
39
40
41
42
43
44
45
46
47
48
K2CO3, MeOH, 1 h
K2CO3, MeOH, 1 h
NH4Cl, MeOH, 5 h
K2CO3, MeOH, 3.5 h
K2CO3, MeOH, 3.5 h
NH4Cl, MeOH, 3 h
NH4Cl, MeOH, 3 h
NH4Cl, MeOH, 5 h
K2CO3, MeOH, 1 h
53%
55%
80%
44%
88%
99%
a Isolated yield after cross-metathesis (Table 1) and desilylation (2 steps)
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 40
1
2
3
4
5
6
7
8
Brønsted acid-catalyzed cycloisomerizations: Prior to our first successful palladium-
catalyzed cyclizations (vide infra), we serendipitously discovered an analogous process catalyzed
exclusively by Brønsted acids. In an attempt to deprotect a silyl ether from an epoxyalkene
substrate with pyridinium p-toluenesulfonate (PPTS) in ethanol,22 a mixture of compounds was
1
obtained exhibiting the H NMR resonances expected for a pyran. Reactions of epoxyalkenes
with p-toluenesulfonic acid monohydrate were complicated by epoxide ring-opening side
reactions with water, but the reaction of (S,R)-epoxyalkene substrate 40 with anhydrous
benzenesulfonic acid in THF produced a mixture of pyranyl alcohols 49 and 50 (Table 3, entry 1).
The corresponding reaction with the (R,R)-epoxyalkene diastereomer 41 exhibited slight
preference for one diastereomer, subsequently characterized as the (R,S)-diastereomer 50 (entry
2). Both diastereomers 49 and 50 were exclusively formed as trans-alkenes. In CDCl3 solvent,
the diastereoselectivities of the PhSO3H-catalyzed process were higher. Thus the epoxyalkene
40 was rapidly converted primarily to the pyranyl alcohol diastereomer 49 (entry 3), and the
corresponding transformation with epoxyalkene 41 produced the complementary diastereomer
50 (entry 4), demonstrating a modest level of stereospecificity arising from epoxide
stereochemistry. PhSO3H catalyst loading and reaction conditions were optimized in CDCl3 for
the cyclization of an 89:11 mixture favoring the trans-alkene of the (R,R)-epoxide substrate 41,
giving an 82:18 mixture of diastereomers favoring (R,S)-pyranyl alcohol 50 (entry 5). To test for
stereospecificity arising from alkene stereochemistry, a 90:10 mixture favoring the cis-alkene 42
with (R,R)-epoxide stereochemistry identical to substrate 41 underwent cycloisomerization to
provide the (S,S)-pyranyl alcohol 49 (entry 6). These experiments revealed that the cyclizations
in CDCl3 were highly but not completely stereospecific, as in all cases the diastereomer ratios of
pyranyl alcohols 49 : 50 were measurably lower than the trans:cis ratios of epoxyalkene
substrates 40 - 42.23
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 40
The Journal of Organic Chemistry
1
2
3
4
Table 3. Stereoselectivity of PhSO3H-catalyzed cycloisomerizations of epoxyalkenes 40 - 42
5
6
7
8
9
trans
HO
S
S
O
trans
H
OTBDPS
R
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
40
41
S
O
Me
OTBDPS
PhSO3H
(3 - 10 mol %)
HO
Me
49
trans
R
CDCl3
HO
Me
R
H
H
R
O
O
trans
S
H
OTBDPS
OTBDPS
cis
R
HO
Me
50
Me
OH
R
O
42
OTBDPS
epoxyalkene
(trans:cis)
isolated yield
(conversion)
entry
PhSO3H
10 mol %
10 mol %
10 mol %
10 mol %
3 mol %
3 mol %
solvent
THF
time
dr, 49:50
52:48
36:64
70:30
24:76
18:82
83:17
1
2
3
4
5
6
40
4.5 h
4.5 h
(>90%)
(>90%)
(>90%)
(>90%)
87%
(86:14)a
41
THF
(85:15)a
40
CDCl3
CDCl3
CDCl3
CDCl3
5 min
10 min
2.5 h
(86:14)a
41
(85:15)a
41
(89:11)
42
3.5 h
90%
(10:90)
a For these experiments, epoxyalkenes 40 and 41 were produced and tested prior to optimizing
the trans:cis stereoselectivity in the cross-metathesis step of substrate synthesis.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 40
1
2
3
4
5
6
The stereochemistry of the pyran chiral center was established by ozonolysis of product
50 (dr 85:15) and reductive workup, affording the known tetrahydropyranmethanol 51 (eq 2). The
optical rotation of our synthetic 51 exhibited the opposite sign from the (R)-enantiomer of 51
arising from deoxygenation of D-galactose.24
7
8
9
1. O3
CH2Cl2, MeOH
-78 oC, 5 min
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
R
S
compare with
(2)
O
O
O
H
H
H
2. NaBH4
0 oC, 2 h
S
OH
OH
OTBDPS
(R)-51
[α]23D = -3.4
(CHCl3, c = 0.68)
(S)-51
[α]23D = +11.0
(CHCl3, c = 1.00)24
HO
Me
50
To gain insights into the mechanism, the PhSO3H-catalyzed cycloisomerizations of
substrates 41 and 42 were monitored by 1H NMR (Figures 7 - 10). We calibrated integrals with
the TBDPS tert-butyl group, and acquired data at five-minute intervals. These experiments
showed nearly linear formation of the pyran products over time, along with a linear decrease of
the concentration of the epoxyalkene substrates. This work also revealed that the trans-alkene
substrate 41 was considerably more reactive than the cis- substrate 42. For instance, with an
89:11 mixture of 41:42 favoring the trans-alkene substrate 41 (Figures 7, 8), the concentration of
the minor cis-alkene 42 remained relatively constant until all of the trans-alkene 41 had been
consumed. Conversely, with a 90:10 mixture favoring the cis-alkene substrate 42 (Figures 9, 10),
the minor trans-alkene isomer 41 was rapidly consumed in the first hour of the reaction.
10
ACS Paragon Plus Environment

Page 11 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
trans
R
PhSO3H (3 mol %)
O
HO
+ 49
+ 42
H
R
Me
S
CDCl3, rt, 2.5 h
87% isolated
dr 82:18 (50:49)
OTBDPS
H
R
O
HO Me
OTBDPS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
41
trans:cis 89:11
50
Figure 7. Normalized NMR conversion of species in PhSO3H-catalyzed cycloisomerization of
epoxyalkene mixture favoring trans-alkene 41
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 40
1
2
3
4
5
6
7
8
9
a
h2
f
c2
b
PhSO3H (3 mol %)
O
OTBDPS
HO
+ 49
iH
j2
Me
g
CDCl3, rt, 2.5 h
87% isolated
dr 82:18 (50:49)
e
H
O
HO Me
50
d2
OTBDPS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
41
trans:cis 89:11
Figure 8. NMR time course, showing disappearance of trans-alkene 41 and appearance of
pyranyl alcohol 50, at five minute intervals
12
ACS Paragon Plus Environment

Page 13 of 40
The Journal of Organic Chemistry
1
2
3
4
cis
PhSO3H (3 mol %)
+ 41
S
5
6
7
8
+ 50
R
O
Me
CDCl3, rt, 3.5 h
90% isolated
dr 83:17 (49:50)
H
H
HO
R
S
O
OTBDPS
OTBDPS
HO Me
9
42
cis:trans 90:10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
49
Figure 9. Normalized NMR conversion of species in cyclization of substrate mixture favoring
cis-alkene 42
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
a
4
5
6
7
8
9
b
PhSO3H (3 mol %)
h2
+ 50
f
O
OTBDPS
Me
d2
CDCl3, rt, 3.5 h
90% isolated
dr 83:17 (49:50)
H
H
HO
i
c
j2
O
g
e2
OTBDPS
HO Me
49
42
cis:trans 90:10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 10. NMR time course, showing disappearance of cis-alkene 42 and appearance of
pyranyl alcohol 49, at five minute intervals
14
ACS Paragon Plus Environment

Page 15 of 40
The Journal of Organic Chemistry
1
2
3
1
In both studies (Figures 7, 9), we also observed an intermediate in the H NMR spectra
with a normalized concentration consistent with the acid catalyst loading (ca. 3%), suggesting the
possibility of an allylic sulfonate intermediate. To gain better insight into the nature of this
intermediate, the PhSO3H-promoted reaction of epoxyalkene 37 was studied, as this compound
was incapable of cyclization. With 40 mol % of benzenesulfonic acid, the epoxyalkene 37 gave
a mixture of two diastereomers of a metastable product 52 in a relatively high concentration
(Figure 11). This compound could not be isolated, but the chemical shift of the methine hydrogen
at 4.97 ppm was similar to the literature value for the methylene hydrogens of allyl tosylate (4.5
ppm).25 Allylic benzenesulfonate 52 was accompanied by formation of the diene 53, which may
have arisen from elimination of intermediate 52. NOE correlations were observed in intermediate
52 between Ha on the benzensulfonate and Hb, Hc and Hd, providing strong evidence for our
assignment of the allylic benzenesulfonate intermediate.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
Me
PhSO3H
(40 mol %)
5 h
PhSO2O
H
CDCl3, rt
Me
OTBDPS
OTBDPS
H
O
HO Me
HO Me
37
53
65:35 (E,E):(Z,E)
52
OTBDPS
65:35 dr
1D-TOCSY & COSY
Selected NOESY
1.28 ppm
m
0.86 ppm
H
H
t
Me
H
1.28 ppm
m
HMQC 13C Shifts
83.99 ppm (major)
84.32 ppm (minor)
1.75 & 1.63 ppm H
m
Ha
H
O
H
5.62 ppm
app. ddd
Hc
C
S
O
(two diastereomers)
H
H
Hb
O
Ha
Hd
OTBDPS
7.85 ppm
m
O
Me
4.97 ppm
app. q
He
5.54 ppm
app. dd
2.38 ppm (major)
2.44 ppm (minor)
(two diastereomers)
Figure 11. Reaction of epoxyalkene 37 with benzenesulfonic acid, and NMR evidence for allylic
benzenesulfonate intermediate 52
From PhSO3H-catalyzed cycloisomerizations of the more complex substrates 43 - 44, we
established that cyclizations were slower in THF than in CDCl3, as we had observed with
epoxyalkenes 40 and 41. Moreover, cyclizations of either epoxyalkene diastereomer 43 or 44 in
THF favored the same pyranyl diol diastereomer 55 (Table 4, entries 1, 2). In contrast,
complementary stereoselectivity was exhibited for PhSO3H-catalyzed cyclizations in CDCl3, with
epoxyalkene 43 leading predominantly to pyranyl diol 54 (entry 3), and the diastereomeric
epoxyalkene 44 giving higher stereoselectivity for pyranyl diol 55 (entry 4). As the pyranyl diols
54 and 55 were unstable upon prolonged exposure to the reaction conditions,26 the cyclizations
of the corresponding allylic acetates 45 and 46 were also studied with PhSO3H catalysis,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 40
1
2
3
4
5
6
producing the respective pyrans 56 and 57 (entries 5, 6). The stereochemistry of each pyran was
assigned from the coupling constants between the hydrogens at the adjacent chiral centers, with
the trans-configuration of (S,R)-pyran 56 consistent with a larger coupling constant for the axial
hydrogens at the adjacent chiral centers than observed for the (S,S)-diastereomer 57.
7
8
9
Table 4. Brønsted acid-catalyzed cycloisomerizations of epoxyalkenes 43 - 46
3JHH 9.1 Hz
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
OR
OR
S
S
R
O
HO
H
S
S
H
OTBDPS
OTBDPS
PhSO3H
R
O
HO
Me
Me
43 R = H
45 R = Ac
54 R = H
56 R = Ac
(10 mol %)
H
H
solvent, time
20 oC
OR
OR
S
S
S
O
HO
H
R
3JHH 1.7 Hz
S
Me
H
OTBDPS
R
O
HO
Me
OTBDPS
solvent
THF
44 R = H
46 R = Ac
55 R = H
57 R = Ac
epoxyalkene
(dr)
products
(dr)
entry
time
22 h
22 h
2 h
conversion
(>90%)
1
2
3
4
5
6
43
(86:14)
54 + 55
(38:62)
44
(89:11)
54 + 55
(37:63)
THF
(>90%)
43
(86:14)
CDCl3
CDCl3
CDCl3
CDCl3
54 + 55
(63:37)
(ca. 50%)
(>90%)
44
(89:11)
2 h
54 + 55
(15:85)
45
2.5 h
2.5 h
56 + 57
(74:26)
(>90%)
(83:17)a
46
56 + 57
(>90%)
(95:5)
(17:83)
a In this experiment, substrate 45 was produced and tested prior to optimizing its synthesis.
16
ACS Paragon Plus Environment

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Overall, these results indicate that the PhSO3H-catalyzed cycloisomerization involves two
steps: stereoselective addition of benzenesulfonic acid to the epoxyalkene in an SN' fashion,
followed by intramolecular substitution of the primary alcohol, displacing the allylic
benzenesulfonate with inversion of configuration. This mechanism is consistent with the
complementary sense of stereoinduction arising from substrates 40 - 46 in forming the
corresponding pyran products 49 - 50 and 54 - 57 (Tables 3, 4). However, the Brønsted acid-
catalyzed process was limited with regard to yields and diastereoselectivities, and could not be
extended to preparing seven-membered ring products from substrate 47. With the mechanistic
insights on the role of Brønsted acids on epoxide opening, we returned to the study of palladium
catalysis for this transformation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 40
1
2
3
4
5
6
7
8
9
Palladium-catalyzed cycloisomerizations: With an aim to improving on the Brønsted
acid-catalyzed process, we investigated the cyclization of substrate 41 with Pd(PPh3)4 and P(O-
i-Pr)3,27 in the presence of various Lewis and Brønsted acids (Table 5). This work revealed that
acidic additives were essential to the success of palladium-catalyzed cycloisomerizations.
Diphenylphosphinic acid (Ph2P(O)OH) was the best additive for these Pd-catalyzed cyclizations,
rapidly furnishing the pyran product 50 with good diastereoselectivity (Table 5, entry 9).28 This
reaction went to completion with identical diastereoselectivity in CDCl3, CH2Cl2 and THF, although
the reaction progress was slightly slower in THF.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. An acidic additive is required for Pd-catalyzed cycloisomerizations of epoxyalkene 41
Pd(PPh3)4 (10 mol %)
P(O-i-Pr)3 (60 mol %)
additive
R
+ 49
HO
O
H
CDCl3
R
S
Me
H
OTBDPS
R
41
O
HO
Me
OTBDPS
50
trans:cis 89:11
entry
additive (equiv)
(none)
time
3 h
conversion
(no reaction)
80%a
dr (50:49)
-
1
2
Zn(OTf)2 (1.1)
3 h
64:36
63:37
58:42
NDc
3
Zn(OTf)2 (1.1)
6 d
52%b
4
Cu(OTf)•(MeCN)4 (1.3)
Cu(OTf)•(MeCN)4 (1.3)
Ti(O-i-Pr)4 (0.9)
Ti(O-i-Pr)4 (0.9)
ClTi(O-i-Pr)3 (0.9)
Ph2P(O)OH (0.9)
AcOH (82)d
3 h
86%a
5
6 d
50%b
6
6 d
38%a
77:23
80:20
80:20
83:17
85:15
7
15 d
17 h
1 h
24 h
>95%
8
>95%
9
>95%
10
76%e
a
b
The remainder was epoxyalkene 41.
Epoxyalkene 41 was completely consumed; the
c
remaining material was identified as a spiroketal derived from the pyran products.
The
diastereomer ratio could not be determined because of line broadening induced by paramagnetic
copper species. d In THF solvent. e The remaining 24% corresponded to addition of acetic acid
instead of cycloisomerization.
18
ACS Paragon Plus Environment

Page 19 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
In optimizing the ligands for the Pd-catalyzed process, we determined that P(O-i-Pr)3 was
required for the cycloisomerization of 41 to 50 (Table 6, entry 3). The best yield and highest
diastereoselectivity were obtained with both P(O-i-Pr)3 and PPh3 (entry 4).
7
8
Table 6. Ligand investigations of Pd-catalyzed cycloisomerizations of epoxyalkene 41
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd2(dba)3•CHCl3 (5 mol %)
R
+ 49
HO
O
phosphine (catalyst)
phosphite (catalyst)
Ph2P(O)OH (50 mol %
THF, rt, 24 h
H
R
S
Me
H
OTBDPS
)
R
41
O
HO
Me
OTBDPS
50
trans:cis 89:11
entry
phosphine
(none)
phosphite
(none)
conversion
(no reaction)
trace
dr (50:49)
-
1
2
3
4
5
6
PPh3 (50 mol %)
(none)
(none)
-
P(O-i-Pr)3 (80 mol %)
P(O-i-Pr)3 (40 mol %)
P(O-i-Pr)3 (40 mol %)
P(O-i-Pr)3 (40 mol %)
92%
83:17
85:15
85:15
81:19
PPh3 (50 mol %)
PCy3 (50 mol %)
dppp (25 mol %
100%
78%
44%
This transformation was further optimized in CH2Cl2 solvent and generalized with several
substrates, using Pd(PPh3)4 as the source of both palladium and the triphenylphosphine ligand,
and decreasing the loading of the phosphite ligand and the Brønsted acid catalyst (Table 7).
Under identical conditions, the epoxyalkene substrates 40 and 41 produced the corresponding
pyranyl alcohol diastereomers 49 and 50 (entries 1, 2). The allylic alcohol substrate 43 gave
modest isolated yield of the pyranyl diol 54 under the Pd-catalyzed conditions (entry 3),
accompanied by substantial formation of an acyclic enone byproduct 58 (eq 3).29 We
hypothesized that the enone 58 may have arisen from hydride migration from the secondary
carbinol of 43. This side reaction was effectively suppressed with the corresponding acetate ester
45 and its diastereomer 46, which were converted into the corresponding pyranyl alcohol
diastereomers 56 and 57, respectively (entries 4, 5). The chemoselectivity of these cyclizations
was notable, as oxidative addition of the epoxyalkene with Pd(0) was favored over the reaction of
the allylic acetates 56 and 57. In all cases, the Pd-catalyzed method proceeded with the same
sense of stereoinduction as observed with the PhSO3H-catalyzed process, but with uniformly
higher diastereoselectivities, consistent with a greater degree of stereospecificity linking chirality
and mechanism.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 40
1
2
3
4
Table 7. Optimized conditions for Pd-catalyzed cycloisomerizations of epoxyalkenes
5
6
H
H
X
X
7
8
9
HO
O
H
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
OTBDPS
OTBDPS
Pd(PPh3)4 (5 mol %)
R
O
HO
Me
Me
40 X = H
43 X = OH
45 X = OAc
49 X = H
54 X = OH
56 X = OAc
P(O-i-Pr)3 (30 mol %)
Ph2P(O)OH (10 mol %)
H
X
H
X
CH2Cl2, 20 oC
HO
O
H
R
H
Me
OTBDPS
R
O
HO
Me
OTBDPS
41 X = H
46 X = OAc
50 X = H
57 X = OAc
epoxyalkene substrate
pyran product
entry
trans:cis
dra
isolated yield
84%
dr
1
2
3
4
5
40
41
43
45
46
90:10
89:11
>98:2
95:5
n/a
n/a
49
50
54
56
57
88:12
85:15
94:6
88%
86:14
85:15
93:7
45%b
61%
81:19
92:8
>95:5
62%
a The diastereomer ratios refer to the ratio of the secondary allylic alcohol or acetate (X = OH or
OAc) to both stereoisomers of the epoxide. b Acyclic enone 58 was also isolated in 31% yield (eq
3).
Pd(PPh3)4 (5 mol %)
P(O-i-Pr)3 (30 mol %)
Ph2P(O)OH (10 mol %)
O
HO
43
54 (45%) +
(3)
CH2Cl2, 20 oC
OTBDPS
HO
Me
58 (31%)
20
ACS Paragon Plus Environment

Page 21 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Initial efforts to apply Pd-catalysis to the cycloisomerization of epoxyalkene substrate 47
gave only partial conversion and low yield of seven-membered ring oxepane 59, even with higher
catalytic loading and prolonged reaction time (Table 8, entry 1). However, the conformationally
restricted substrate 48 provided more promising results, giving high conversion within two hours
to provide benzooxepane 60 (entry 2). We subsequently observed better results in the
cycloisomerization of epoxyalkene 47 using trimethylolpropane phosphite 61 (EtCage),30 a ligand
known to enhance the rates of other Pd-catalyzed processes, achieving greater than 90%
conversion to the oxepane 59 (entry 3). An additional benefit of the EtCage ligand was that the
oxepane product 59 was produced with diastereoselectivity very close to the trans:cis ratio of
epoxyalkene 47.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 8. Syntheses of oxepanes by palladium-catalyzed cycloisomerizations
HO
O
H
R
Me
H
OTBDPS
Pd(PPh3)4 (10 - 18 mol %)
phosphite (catalyst)
R
O
HO Me
59
47
OTBDPS
Ph2P(O)OH (16 - 20 mol %)
CDCl3, 20 oC
HO
O
H
R
Me
H
OTBDPS
R
O
HO Me
48
60
OTBDPS
epoxyalkene
phosphite ligand
oxepane product a
conversion
(isolated yield)
entry
trans:cis
dr
1
2
47
48
88:12
P(O-i-Pr)3 (120 mol %)
P(O-i-Pr)3 (120 mol %)
59
60
ca. 58% conversion
(21% yield)b
ND
>90% conversion
(42% yield)
89:11
83:17
87:13
82:18
Et
O
>90% conversion
(25% yield)c
3
47
(60 mol %)
59
P
O
O
61 (EtCage)
a The stereochemical assignments for the major diastereomers of 59 and 60 were not determined.
b In addition to ca. 42% of 47 still present, byproducts included an acyclic diene (ca. 20%) and
c
incorporation of diphenylphosphonite (ca. 17%). The low isolated yield may be due to the small
scale of this experiment.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 40
1
2
3
4
5
6
In the conversion of epoxyalkene 40 to pyranyl alcohol 49, the reaction rate was
considerably slower with EtCage ligand 61 relative to P(O-i-Pr)3 (eq 4), but now the
diastereoselectivity of 49 matched the trans:cis ratio of epoxyalkene reactant 40.
7
8
9
Pd(PPh3)4 (10 mol %)
EtCage 60 (60 mol %)
Ph2P(O)OH (20 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OTBDPS
HO
O
(4)
H
CDCl3, 20 oC, 22 h
>95% conversion
S
H
OTBDPS
R
O
HO
Me
Me
49
dr 90:10
40
trans:cis 90:10
Based on these results, we propose a mechanism for the dual catalytic process with
palladium and Brønsted acid, depicted for the conversion of allylic acetate epoxyalkene 45 to
pyran 56 (Figure 12). The catalytic cycle begins with coordination of Pd(0) to the alkene of the
epoxyalkene 45 along with protonation of the epoxide, to give 62. The protonated epoxide is now
activated for oxidative addition of Pd, furnishing p-allyl complex 63. Intramolecular addition of the
alcohol to the p-allylpalladium intermediate and regeneration of diphenylphosphinic acid
generates the product as the p-complex 64. Dissociation of palladium from 64 closes the catalytic
cycle and releases the pyran product 56.
H
H
OAc
H
OAc
H
O
HO
H
H
H
OTBDPS
H
OTBDPS
O
HO Me
OAc
PdLn
Ph2P(O)OH
Me
45
56
H
H
H
OAc
H
O
HO
H
LnPd
LnPd
H
OTBDPS
OTBDPS
O
H
Ph2P(O)OH
HO Me
Ph2PO2
Me
H
OAc
62
64
oxidative
addition
alcohol addition
H
HO
H
to Pd π-allyl
LnPd
H
OTBDPS
Ph2PO2
HO Me
63
Figure 12. Working hypothesis for catalytic cycle
22
ACS Paragon Plus Environment

Page 23 of 40
The Journal of Organic Chemistry
1
2
3
4
CONCLUSION
In summary, we have developed palladium-catalyzed conditions for the stereoselective
formation of either pyran diastereomer, corresponding to the choice of epoxyalkene diastereomer.
The addition of Ph2P(O)OH as a Brønsted acid co-catalyst is essential for these cyclizations.
Brønsted acid-catalyzed cycloisomerizations give the same sense of stereospecificity as the Pd-
catalyzed transformations, but with lower stereoselectivity and a greater propensity for acid-
catalyzed product decomposition pathways. Future activities along these lines will include
applications to the stereoselective synthesis of fused polycyclic ethers.31,32
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General experimental: Proton and carbon NMR spectra were recorded on MERCURY
300 (300 MHz), INOVA-400 (400 MHz), VNMRS 400 (400 MHz), INOVA-500 (500 MHz), INOVA-
600 (600 MHz), Unity-600 (600 MHz) or a BRUKER 600 (600 MHz) instrument equipped with
cryogen probe. NMR spectra were recorded in solutions of deuterated chloroform (CDCl3) with
the residual chloroform (7.27 ppm for 1H NMR and 77.23 ppm for 13C NMR) taken as the internal
standard, deuterated methanol (CD3OD) with residual methanol (3.31 ppm for 1H-NMR and 49.3
ppm for 13C-NMR) taken as the internal standard, or deuterated benzene with residual benzene
1
(7.16 ppm for H NMR and 128.23 ppm for 13C NMR) taken as the internal standard, and were
reported in parts per million (ppm). With the exception of the diastereomeric ratios of the
epoxyalkene cross metathesis products, all drs, ers (of Mosher esters) and trans:cis ratios were
determined by NMR integration of isolated peaks with an uncertainty of ±2%. Abbreviations for
signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet;
ddd, doublet of doublet of doublet; dt, doublet of triplet; m, multiplet. IR spectra were collected on
a Nicolet iS10 from Thermo Scientific and reported in units of cm-1. Mass spectra (high resolution
ESI and APCI) were recorded on a Thermo LTQ (linear quadrupole ion trap) FTMS (Fourier
transform mass spectrometer) based on ion cyclotron resonance mass spectrometry (ICR-MS).
Optical rotations were measured using a Perkin-Elmer 341 polarimeter (concentration in
g/100mL). Thin layer chromatography (TLC) was performed on pre-coated glass-backed plates
purchased from Whatman (silica gel 60F254; 0.25mm thickness). Preparative TLC was performed
on pre-coated glass-backed plates purchased from Analtech (20 x 20 cm, Silica gel GF UV254,
1.0 mm thickness). Flash column chromatography was carried out with silica gel 60 (230-400
mesh ASTM) from Silicycle. All reactions were carried out with anhydrous solvents in oven dried
or flame dried and argon-charged glassware unless otherwise specified. All anhydrous solvents
were dried with 4Å molecular sieves purchased from Sigma-Aldrich and tested for trace water
content with Coulometric KF titrator from Denver instruments. All solvents used in extraction
procedures and chromatography were used as received from commercial suppliers without prior
purification. All metathesis catalysts were purchased from Sigma Aldrich, except for the nitro-
Grela catalyst, which was purchased from Strem Chemical.
Mosher (MTPA) ester derivatives were prepared in the following fashion:33 the secondary
alcohol (2 - 10 mg) was dissolved in dry CDCl3 (1.2 mL). From a freshly opened ampule of d5-
pyridine, 12 drops was added to this solution. The mixture was then partitioned between two new
NMR tubes sparged with Ar. To each tube was added one drop (as dispensed from a short
Pasteur pipette using thumb pressure) of one enantiomer of the MTPA acid chloride. The NMR
tubes were inverted several times to mix and then allowed to stand for 24 h before NMR analysis.
For primary alcohols, the reaction was much faster. Substrates containing epoxides were prone
to degradation upon standing, thus were analyzed within an hour of adding the MTPA acid
chloride.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 40
1
2
3
4
5
6
Preparation of (Z)-3-iodo-2-methylprop-2-en-1-ol 14: CuI (2.77 g, 14.5 mmol) was
suspended in THF (150 mL) at 0,oC and MeMgBr (100 mL, 300 mmol, 3 M in Et2O) was added
by cannula. Propargyl alcohol (13, 9.0 mL, 8.55 g, 152.5 mmol) was added slowly to this solution
o
(Caution! vigorous gas evolution). The mixture was stirred at 0 C for 45 min, whereupon a
7
solution of I2 (38.3 g, 150.9 mmol) in Et2O (250 mL) was added slowly. The mixture was removed
from the cooling bath, stirred for 30 min and poured directly into a separatory funnel charged with
sat. NH4Cl (150 mL) and brine (150 mL). Solid Na2S2O3 was added in portions to remove
unreacted iodine from the organic layer (turning it from brown to yellow). The layers were
separated and the blue aqueous layer (likely due to formation of copper ammine) was extracted
with Et2O (3 x 250 mL). The combined organic layers were dried over MgSO4 and concentrated
under reduced pressure to give a yellow oil (15.95 g). Crude NMR showed the oil to be 93.5%
(Z)-3-iodo-2-methylprop-2-en-1-ol 14 by weight (14.91 g, 75.3 mmol, 50% yield), the remaining
mass being 2-methyl-2-propen-1-ol. The oil of this experiment was carried on directly to the next
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
step, but may be purified via short path distillation (bp 72 C, 7 torr) if desired. Spectral data
matched that reported in the literature.8
Preparation of (Z)-2-methyl-2,4-pentadien-1-ol 15: A solution of vinyl iodide 14 (15.95 g,
93.5% by weight, 75.3 mmol) in PhMe (250 mL) was degassed with argon for 20 minutes and
cooled to 0. oC. Pd(PPh3)4 (1.00 g, 0.86 mmol) was added, and the solution aged for 20 minutes,
whereupon a solution of vinylmagnesium bromide (200 mL, 200 mmol, 1 M in THF) was added
slowly (Caution! Vigorous gas evolution) via addition funnel over 10 minutes. The reaction mixture
was allowed to warm to room temperature overnight, and quenched with saturated NH4Cl (200
mL). The solution was further diluted with water (200 mL), the layers were separated, and the
aqueous layer was extracted with Et2O (3 x 300 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo (the water bath temperature was kept between 10 and
20 oC) to give an orange oil with some red solids. The oil was filtered though a small pad of cotton
with Et2O and distilled under reduced pressure to give (Z)-2-methyl-2,4-pentadien-1-ol 15 as a
o
clear liquid (3.35 g, 34.1 mmol, 45% yield, bp 49–51 C at 7 torr). Spectral data matched that
reported in the literature.10
Preparation of pent-4-en-2-yn-1-ol 16: To a 1 M solution of vinyl bromide (84 mL, 84 mmol)
in THF was added CuI (728 mg, 3.8 mmol), PdCl2(PPh3)2 (247 mg, 0.35 mmol) and i-Pr2NH (25
o
mL, 178 mmol). The mixture was cooled to 0 C, and propargyl alcohol (13, 4.8 mL, 83 mmol)
was added dropwise over 5 minutes, whereupon the cooling bath was removed. After aging for
20 h at rt, the reaction mixture was poured into a mixture of saturated aqueous NH4Cl (100 mL)
and Et2O (50 mL). The layers were separated, and the aqueous layer was extracted with Et2O (3
x 50 mL; for the last extraction, the aqueous layer was diluted with 20 mL water). The combined
organics were dried over MgSO4 and concentrated in vacuo in a fume hood to give pent-4-en-2-
yn-1-ol 16 as a dark red oil (5.55 g, 81% yield). Spectral data matched that reported in the
literature.11b
o
Preparation of (E)-2-methyl-2,4-pentadien-1-ol 17: To a 0 C suspension of CuI (1.68 g,
8.8 mmol) in THF (20 mL) was added MeMgBr (3 M in Et2O, 70 mL, 210 mmol). To the yellow
suspension was added dropwise a solution of enynol 16 (5.55 g, 67.6 mmol) in THF (20 mL) over
10 minutes (Caution! vigorous CH4 evolution). The reaction mixture was allowed to warm to rt
over 20 h, and then was quenched slowly at 0 oC via addition of a 1:1 mixture of water:saturated
NH4Cl (100 mL). The mixture was further diluted with water (200 mL) and extracted with Et2O (3
x 100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo (the
water bath temp was kept < 20 oC) to afford (E)-2-methyl-2,4-pentadien-1-ol 17 as a red-orange
oil (6.18 g, 93% yield). Spectral data matched that reported in the literature.13
24
ACS Paragon Plus Environment

Page 25 of 40
The Journal of Organic Chemistry
1
2
3
4
5
Preparation of (S,R)-epoxyalkenyl alcohol 18: To a suspension of ground activated 3Å
molecular sieves (1.86 g) in CH2Cl2 (150 mL) at -20 C was added titanium isopropoxide (0.50
o
mL, 1.7 mmol) and D-(-)-diisopropyl tartrate (0.55 mL, 2.6 mmol). Tert-butyl hydroperoxide (5.5
M in decane, 13.0 mL, 71.5 mmol) was then added to this mixture over 5 min, and the mixture
was aged for 30 min. After cooling to -35 oC, a solution of dienyl alcohol 15 (3.35 g, 34 mmol) in
CH2Cl2 (30 mL) was added slowly. The reaction mixture was stirred at -35 ˚C for 24 h and then
warmed to -20 oC, whereupon it was quenched via addition of a 10% NaOH solution in saturated
NaCl (2.7 mL). After adding Et2O (20 mL), the mixture was allowed to warm to 10 ˚C over 2 h,
whereupon MgSO4 (2.7 g) and Celite (380 mg) were added, and the mixture stirred for 10 min
before filtering through a pad of Celite with Et2O (~500 mL). The eluant was concentrated in
vacuo, and the resulting oil was purified by column chromatography eluting with 30/70
EtOAc/Hexanes to give (S,R)-epoxyalkenyl alcohol 18 as a clear liquid (3.12 g, 80% yield, 80:20
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
1
a
er by analysis of the corresponding Mosher esters). [ ]D = +7.0 (CH2Cl2, c = 0.91); H-NMR
(400 MHz; CDCl3): d 5.85 (ddd, J = 17.3, 10.4, 7.1 Hz, 1H), 5.50 (ddd, J = 17.2, 1.4, 0.9 Hz, 1H),
5.38 (ddd, J = 10.5, 1.4, 0.8 Hz, 1H), 3.69 (d, J = 6.1 Hz, 2H), 3.35 (d, J = 7.2 Hz, 1H), 1.60 (t, J
= 5.2 Hz, 1H), 1.45 (s, 3H); 13C-NMR (101 MHz; CDCl3): d 132.5, 121.1, 64.64, 64.56, 64.0, 20.02,
19.97; IR (neat) 3418, 2974, 2935, 1740, 1640, 1448, 1377, 1044, 1027 cm–1; HRMS (NSI)
calculated for C6H10O2Na+ [M+Na]+ 137.0573, found 137.0572.
o
Preparation of (R,R)-epoxyalkenyl alcohol 19: To a cooled (-20 C) suspension of
powdered 4Å molecular sieves (3.27 g) in CH2Cl2 (200 mL) was added Ti(Oi-Pr)4 (0.93 mL, 3.1
mmol) and D-(-)-diethyl tartrate (0.68 mL, 3.9 mmol). t-BuOOH (5.5 M in decane, 23 mL, 127
mmol) was added dropwise over the course of 5 min. After aging for 45 min at -20 oC, a solution
of (E)-2-methyl-2,4-pentadien-1-ol 17 (6.18 g, 63 mmol) in CH2Cl2 (15 mL) was added portionwise
over 15 min. After 2 h at -20 oC, the reaction mixture was quenched via addition of a 10% NaOH
solution in saturated NaCl (8 mL). After allowing the mixture to warm to 0 ˚C over 30 min, Et2O
(40 mL) was added followed by MgSO4 (5.5 g) and Celite (0.76 g), and the mixture allowed to
warm to 10 oC over 30 min. The solution was filtered through a pad of Celite, and concentration
of the crude gave a yellow oil whose NMR showed it to be approximately 2:1 epoxide:diene. The
crude oil was purified via flash column chromatography to give (R,R)-epoxyalkenyl alcohol 19 as
a colorless oil (2.97 g, 41% yield, 54% brsm, er > 95:5 by analysis of the corresponding Mosher
esters). Some of the starting diene 17 (1.37 g, 22%) was also recovered. [ ]D20 = +9.4 (CH2Cl2,
a
c = 0.60); 1H-NMR (400 MHz; CDCl3): d 5.77 (ddd, J = 17.2, 10.5, 7.3 Hz, 1H), 5.50 (ddd, J = 17.2,
1.5, 0.8 Hz, 1H), 5.40 (ddd, J = 10.5, 1.5, 0.8 Hz, 1H), 3.74 (dd, J = 12.4, 4.3 Hz, 1H), 3.65 (dd, J
= 12.4, 8.9 Hz, 1H), 3.57 (d, J = 7.3 Hz, 1H), 1.83 (dd, J = 8.9, 4.3 Hz, 1H), 1.30 (s, 3H); 13C-NMR
(101 MHz; CDCl3): d 132.6, 121.2, 64.9, 62.9, 60.2, 14.4; IR (neat) 3408, 2932, 1638, 1451, 1384,
1067, 986, 924, 871, 805, 696, 649 cm–1; HRMS (NSI) calculated for C6H11O2 [M+H]+ 115.0754,
found 115.0753.
Preparation of (S,R)-epoxyalkenyl TBDPS ether 20: Epoxy alcohol 18 (2.31 g, 20.3 mmol)
o
and imidazole (1.51 g, 22.1 mmol) were dissolved in dry DMF (20 mL) and cooled to 0 C, and
TBDPSCl (5.20 mL, 5.51 g, 20.3 mmol) was added. The reaction mixture was allowed to warm
to rt overnight, diluted with water (100 mL) and extracted with Et2O (5 x 50 mL). The combined
organic layers were back-extracted with water (5 x 50 mL), washed with brine (50 mL), dried over
Na2SO4 and concentrated under reduced pressure. The crude oil was subjected to column
chromatography eluting with 5/95 Et2O/Hexanes to give silyl ether 20 as a white, amorphous,
waxy solid (5.47 g, 15.5 mmol, 76% yield). [ ]D20 = +10.7 (CH2Cl2, c = 0.65); 1H-NMR (400 MHz;
a
CDCl3): d 7.71-7.66 (m, 4H), 7.47-7.37 (m, 6H), 5.60 (ddd, J = 17.2, 10.4, 6.8 Hz, 1H), 5.37 (ddd,
J = 17.1, 1.5, 0.8 Hz, 1H), 5.22 (ddd, J = 10.5, 1.5, 0.7 Hz, 1H), 3.68 (dd, J = 17.2, 10.9 Hz, 2H),
3.29 (d, J = 6.9 Hz, 1H), 1.51 (s, 3H), 1.08 (s, 9H); 13C-NMR (101 MHz; CDCl3): d 135.85, 135.80,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 40
1
2
3
4
5
6
133.5, 133.3, 132.6, 129.9, 127.9, 120.2, 65.2, 64.09, 64.07, 63.0, 27.0, 20.1, 19.5; IR (CH2Cl2):
3071, 3049, 2959, 2931, 2891, 2858, 1589, 1487, 1428, 1111, 823, 701 cm-1; HRMS (NSI)
calculated for C22H28O2NaSi+ [M+Na]+ 375.1751, found 375.1749.
7
8
9
Preparation of (R,R)-epoxyalkenyl TBDPS ether 21: Epoxy alcohol 19 (2.64 g, 23.2 mmol)
was dissolved in CH2Cl2 (80 mL), and cooled to 0 oC. Et3N (5 mL, 36 mmol) was added followed
by TBDPSCl (6.5 mL, 25 mmol) and DMAP (311 mg, 2.5 mmol). The mixture was allowed to
warm to rt over 3.5 h, and was quenched with saturated aqueous NH4Cl (100 mL). The aqueous
layer was extracted with CH2Cl2 (3 x 50 mL), the combined organic layers were washed with
water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude oil was
purified via column chromatography eluting with 5/95 Et2O/Hexanes to give silyl ether 21 as a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
clear oil (7.18 g, 88% yield). [ ]D20 = -3.8 (CH2Cl2, c = 0.95); 1H-NMR (400 MHz; CDCl3): d 7.71-
a
7.68 (m, 4H), 7.47-7.37 (m, 6H), 5.75 (ddd, J = 17.3, 10.4, 7.1 Hz, 1H), 5.44 (ddd, J = 17.2, 1.6,
0.8 Hz, 1H), 5.36 (ddd, J = 10.5, 1.6, 0.7 Hz, 1H), 3.72-3.65 (dd, J = 16.1, 11.3 Hz, 2H), 3.35 (d,
J = 7.2 Hz, 1H), 1.32 (s, 3H), 1.07 (s, 9H); 13C-NMR (151 MHz, CDCl3): d 135.9, 135.8, 133.6,
133.5, 133.2, 129.95, 127.94, 127.93, 120.5, 77.4, 77.2, 77.0, 68.0, 63.0, 61.2, 27.0, 19.5, 14.5;
IR (neat) 3071, 2959, 2931, 2858, 1589, 1471, 1427, 1113, 702 cm–1; HRMS (NSI) calculated for
C22H28NaO2Si+ [M+Na]+ 375.1751, found 375.1744.
Preparation of trimethylsilyl ether 22: 5-hexen-1-ol (7.0 mL, 52 mmol) was mixed with
hexamethyldisilazane (8.5 mL, 40.7 mmol) without solvent, and NBS (461 mg, 2.6 mmol) was
added. The mixture was heated to 50 oC for 1.5 h, diluted with pentane and filtered through a pad
of SiO2 (20 g), washing with pentane (200 mL). The eluant was concentrated in vacuo at 20 oC
1
to give trimethylsilyl ether 22 as a colorless liquid (8.89 g, 51.6 mmol, 99% yield). H-NMR (600
MHz, CDCl3): d 5.82 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.01 (ddt, J = 17.1, 2.1, 1.6 Hz, 1H), 4.95
(ddt, J = 10.2, 2.2, 1.1 Hz, 1H), 3.59 (t, J = 6.6 Hz, 2H), 2.08 (q, J = 7.1 Hz, 2H), 1.58-1.53 (m,
2H), 1.46-1.41 (m, 2H), 0.12 (s, 9H); 13C-NMR (151 MHz, CDCl3): d 139.1, 114.6, 62.7, 33.8, 32.4,
25.4, -0.2; IR (neat): 3078, 2934, 2861, 1641, 1439, 1386, 1250, 1095, 835 cm–1; HRMS (APCI)
calculated for C9H21OSi+ [M+H]+ 173.1356, found 173.1353.
Preparation of trimethylsilyl ether 23: 6-hepten-1-ol (1.71 g, 14.9 mmol) was mixed with
hexamethyldisilazane (2.5 mL, 12.0 mmol) without solvent, and NBS (158 mg, 0.9 mmol) was
added. The mixture was heated to 50 ˚C for 70 min, diluted with pentane and filtered through a
pad of SiO2 (10 g), washing with pentane (200 mL). The eluant was concentrated in vacuo at 20
oC to give trimethylsilyl ether 23 as a colorless liquid (2.42 g, 13.0 mmol, 87% yield). 1H-NMR
(600 MHz, CDCl3): d 5.82 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.01 (ddt, J = 17.1, 2.1, 1.6 Hz, 1H),
4.94 (ddt, J = 10.2, 2.2, 1.1 Hz, 1H), 3.58 (t, J = 6.7 Hz, 2H), 2.06 (q, J = 7.3 Hz, 2H), 1.55 (dt, J
= 14.6, 7.1 Hz, 2H), 1.44-1.38 (m, 2H), 1.37-1.32 (m, 2H), 0.12 (s, 9H); 13C-NMR (151 MHz,
CDCl3): d 139.2, 114.5, 62.9, 34.0, 32.8, 29.0, 25.6, -0.2; IR (neat): 3078, 2931, 2859, 1641, 1437,
1387, 1250, 1095, 836 cm-1; HRMS (APCI) calculated for C10H23OSi+ [M+H]+ 187.1513, found
187.1509.
Preparation of trimethylsilyl ether 24: (2-(But-3-en-1-yl)phenyl)methanol (168 mg, 1.03
mmol; prepared from o-toluic acid in 2 steps15b) was mixed with hexamethyldisilazane (0.25 mL,
1.2 mmol) without solvent, and NBS (9 mg, 0.05 mmol) was added. The mixture was heated to
50 oC for 1 h, diluted with hexanes and filtered through a pad of SiO2 washing with hexanes. The
eluant was concentrated in vacuo to give trimethylsilyl ether 24 (204 mg, 0.87 mmol, 84% yield)
1
as a colorless oil. H-NMR (600 MHz, CDCl3): d 7.39 (d, J = 7.0 Hz, 1H), 7.24-7.18 (m, 3H), 5.91
(ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.08 (dquintet, J = 17.1, 1.7 Hz, 1H), 5.01 (dquintet, J = 10.2,
1.3 Hz, 1H), 4.72 (s, 2H), 2.73 (dd, J = 8.6, 7.4 Hz, 2H), 2.37 (q, J = 7.4 Hz, 2H), 0.17 (s, 9H);
26
ACS Paragon Plus Environment

Page 27 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
13C-NMR (126 MHz, CDCl3): d 139.6, 138.5, 138.4, 129.2, 127.9, 127.6, 126.2, 115.1, 62.9, 35.2,
31.8, -0.2; IR (CH2Cl2): 3078, 3021, 2956, 2871, 1640, 1605, 1490, 1454, 1379, 1251, 1068, 878,
840, 753 cm-1; HRMS (NSI) calculated for C14H23OSi+ [M+H]+ 235.1513, found 235.1512.
7
8
9
Preparation of chiral non-racemic allylic acetate 26: Racemic alcohol 25 17 (22.2 g, 96.3
mmol) was dissolved in PhMe (250 mL), and powdered K3PO4 (22.4 g, 101 mmol), CAL-B resin
(980 mg) and isopropenyl acetate (18.0 mL, 163 mmol) were added. The mixture was stirred for
3.25 hours (1H NMR showed ~50% conversion), filtered through Celite washing with Et2O, and
the eluant concentrated in vacuo to give an orange oil. Column chromatography of the crude
eluting with 20/80 Et2O/Hexanes -> 50/50 Et2O/Hexanes gave the acetate 26 as a clear oil (10.71
g, 41% yield, er 96:4 by analysis of the Mosher ester after hydrolysis of the acetate), and the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
alcohol (R)-13 as a yellow oil (9.46 g, 43% yield, er 96:4 by analysis of the Mosher ester derivative).
20
The spectra and sign of the optical rotation of 26 matched that reported in the literature.18a [ ]D
a
= -3.2 (CH2Cl2, c = 0.69), literature value [ ]D29 = -2.7 (MeOH, c = 1.00);18a 1H-NMR (600 MHz;
a
CDCl3): d 5.78 (ddd, J = 17.2, 10.6, 6.5 Hz, 1H), 5.27-5.22 (m, 2H), 5.17 (dt, J = 10.5, 1.2 Hz, 1H),
3.65-3.59 (m, 2H), 2.07 (s, 3H), 1.68 (q, J = 7.3 Hz, 2H), 1.61-1.50 (m, 2H), 0.90 (s, 9H), 0.05 (s,
6H); IR (CH2Cl2) 2930, 2954, 2858, 1742, 1472, 1371, 1239, 1099, 835, 776 cm-1.
A sample of (S)-25 was generated by hydrolyzing a sample of acetate 26 (100 mg, 0.37 mmol)
o
with K2CO3 (5 mg) in methanol (0.3 M), and heating this mixture to 35 C on the rotovap bath,
monitoring by TLC until acetate 26 was consumed, within 2 h. The mixture was concentrated in
vacuo, the resulting residue was triturated with Et2O, and filtered through a small plug of silica gel,
providing (S)-25 with 1H NMR spectra identical to rac-25. Mosher esters were prepared from (S)-
25 using the general procedure (vide supra).
Preparation of (S)-allylic acetate-primary alcohol 27: The silyl ether 26 (4.0 g, 17.3 mmol)
o
was dissolved in MeOH (30 mL), cooled to 0 C, and acetyl chloride (AcCl, 0.35 mL, 4.9 mmol)
was added dropwise. After 20 min, saturated aqueous NaHCO3 (10 mL) was added, and the
resulting suspension was concentrated in vacuo to remove the MeOH. The remaining solution
was extracted with Et2O (3 x 20 mL), the combined organic layers were washed with brine (20
mL), dried over Na2SO4 and concentrated in vacuo to give a pale yellow oil. The oil was purified
via column chromatography eluting with 70/30 Et2O/Hexanes to give alcohol 27 as a pale yellow
oil (1.77 g, 65% yield). [ ]D20 = -11.3 (CH2Cl2, c = 0.78); 1H-NMR (400 MHz; CDCl3): d 5.78 (ddd,
a
J = 17.1, 10.6, 6.5 Hz, 1H), 5.29-5.24 (m, 2H), 5.18 (dt, J = 10.5, 1.1 Hz, 1H), 3.67 (q, J = 5.1 Hz,
2H), 2.07 (s, 3H), 1.77-1.54 (m, 5H); 13C-NMR (101 MHz; CDCl3): d 170.7, 136.4, 117.1, 74.7,
62.6, 30.7, 28.3, 21.5; IR (neat) 3398, 2945, 2871, 1736, 1647, 1373, 1242 cm–1; HRMS (NSI)
calculated for C8H14O3Na+ [M+Na]+ 181.0835, found 181.0833.
Preparation of (S)-allylic acetate trimethylsilyl ether 28: The alcohol 27 (646 mg, 4.1 mmol)
was mixed with hexamethyldisilazane (0.85 mL, 4.1 mmol) without solvent, and NBS (44 mg, 0.25
o
mmol) was added. The mixture was heated to 50 C for 1 h, diluted with pentane and filtered
through a pad of SiO2 (10 g) with 5/95 Et2O/pentane (100 mL). The eluant was concentrated in
vacuo to give trimethylsilyl ether 28 as a colorless oil (813 mg, 86% yield). [ ]D20 = -2.8 (CH2Cl2,
a
c = 0.58); 1H-NMR (600 MHz; CDCl3): d 5.78 (ddd, J = 17.2, 10.6, 6.5 Hz, 1H), 5.28-5.23 (m, 2H),
5.18 (dt, J = 10.5, 1.2 Hz, 1H), 3.61-3.57 (m, 2H), 2.07 (s, 3H), 1.68-1.66 (m, 2H), 1.59-1.54 (m,
2H), 0.11 (s, 9H); 13C-NMR (125 MHz; CDCl3): d 170.6, 136.7, 116.9, 74.8, 62.3, 30.8, 28.4, 21.5,
-0.3; IR (neat) 2956, 1741, 1371, 1249, 1095, 841 cm–1; HRMS (NSI) calculated for C11H22O3NaSi+
[M+Na]+ 253.1230, found 253.1224.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 40
1
2
3
4
5
6
7
8
9
Preparation of (R,R)-epoxy-cis-alkenyl trimethylsilyl ether 34: To a stirred solution of
(R,R)-epoxyalkene 21 (366 mg, 1.04 mmol) and alkene trimethylsilyl ether 22 (550 mg, 3.2 mmol)
in THF (2 mL) was added Grubbs Z catalyst 31 (15.4 mg, 0.024 mmol). The solution was heated
o
at 35 C for 5 h whereupon a solution of additional Grubbs Z catalyst (13.6 mg, 0.021 mmol) in
THF (1 mL) was added. The solution was stirred at 35 oC for another 19 h and then concentrated
in vacuo. Chromatography of the resulting oil eluting with 5/95 Et2O/hexanes gave (R,R)-epoxy-
cis-alkenyl trimethylsilyl ether 34 as a colorless oil (124 mg, 0.25 mmol, 24% yield, cis:trans 90:10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[ ]D20 = -10.5 (CH2Cl2, c = 0.84); 1H-NMR (600 MHz, CDCl3): d 7.70-7.66 (m, 4H), 7.46-7.42 (m,
a
2H), 7.42-7.38 (m, 4H), 5.77 (dtd, J = 11.1, 7.6, 1.0 Hz, 1H), 5.29 (ddt, J = 11.2, 8.2, 1.5 Hz, 1H),
3.71-3.67 (m, 2H), 3.65 (dd, J = 8.1, 0.9 Hz, 1H), 3.59 (t, J = 6.5 Hz, 2H), 2.27-2.14 (m, 2H), 1.59-
1.54 (m, 2H), 1.50-1.43 (m, 2H), 1.33 (s, 3H), 1.08 (s, 9H), 0.11 (s, 9H); 13C-NMR (151 MHz,
CDCl3): d 137.2, 135.86, 135.80, 133.56, 133.48, 129.9, 127.93, 127.92, 124.7, 68.0, 62.69, 62.62,
56.7, 32.5, 27.9, 27.0, 26.1, 19.5, 15.1, -0.2; IR (CH2Cl2): 3071, 3049, 2999, 2931, 2896, 2858,
1590, 1473, 1428, 1250, 1113, 841, 702 cm-1; HRMS (NSI) calculated for C29H45O3Si2 [M+H]+
+
497.2902, found 497.2898.
Preparation of (S,S,R)-epoxyalkenyl trimethylsilyl ether 35: (S,R)-Epoxyalkene 20 (350
mg, 0.99 mmol) and the alkene-trimethylsilyl ether-acetate 28 (464 mg, 2.01 mmol) were
dissolved in CDCl3 (2 mL). The Grela catalyst 30 (24.3 mg, 0.036 mmol) was added. The solution
was stirred at 35 oC for 0.5 h, then concentrated in vacuo (~7 torr) at 35 oC for another 0.5 h. The
crude oil was chromatographed on SiO2 eluting with 20/80 Et2O/Hexanes to furnish the
epoxyalkene-trimethylsilyl ether-acetate 35 as a colorless oil (335 mg, 0.60 mmol, 61% yield).
[ ]D20 = +0.1 (CH2Cl2, c = 0.48); 1H-NMR (600 MHz; CDCl3): d 7.70-7.65 (m, 4H), 7.46-7.38 (m,
a
6H), 5.75 (ddd, J = 15.6, 6.7, 0.9 Hz, 1H), 5.49 (ddd, J = 15.6, 6.8, 1.1 Hz, 1H), 5.22 (q, J = 6.3
Hz, 1H), 3.66-3.62 (m, 2H), 3.53-3.48 (m, 2H), 3.27 (d, J = 6.7 Hz, 1H), 2.00 (s, 3H), 1.61-1.43
(m, 7H), 1.07 (s, 9H), 0.10 (s, 9H); 13C-NMR (151 MHz; CDCl3): d 170.3, 135.85, 135.78, 134.4,
133.5, 133.3, 130.0, 127.93, 127.91, 126.9, 73.5, 65.2, 63.16, 63.14, 62.2, 30.9, 28.3, 27.0, 21.4,
20.1, 19.5, -0.3; IR (neat) 2956, 2859, 1740, 1473, 1428, 1373, 1239, 1110, 841, 703 cm–1; HRMS
(NSI) calculated for C31H47O5Si2 [M+H]+ 555.2957, found 555.2955.
+
Preparation of (S,R,R)-epoxyalkenyl trimethylsilyl ether 36: To a solution of (R,R)-
epoxyalkene 21 (260 mg, 0.74 mmol) and the alkene-trimethylsilyl ether-acetate 28 (341 mg, 1.48
mmol) in CDCl3 (2 mL) was added Grela catalyst 30 (18.7 mg, 0.028 mmol). The solution was
stirred at 35 oC for 0.5 h, then concentrated in vacuo (~7 torr) at 35 oC for another 0.5 h. NMR of
the crude mixture showed complete consumption of the epoxide. The crude oil was
chromatographed on SiO2 eluting with 20/80 Et2O/Hexanes to furnish the epoxyalkene-
20
a
trimethylsilyl ether-acetate 36 as a colorless oil (223 mg, 0.40 mmol, 54% yield). [ ]D = -9.7
1
(CH2Cl2, c = 0.59); H-NMR (600 MHz; CDCl3): d 7.69-7.67 (m, 4H), 7.46-7.43 (m, 2H), 7.41-7.38
(m,4H), 5.80 (ddd, J = 15.6, 6.6, 0.8 Hz, 1H), 5.61 (ddd, J = 15.6, 6.9, 1.1 Hz, 1H), 5.32 (q, J =
6.3 Hz, 1H), 3.68 (dd, J = 16.9, 11.4 Hz, 2H), 3.60 (td, J = 6.4, 1.6 Hz, 2H), 3.36 (d, J = 6.9 Hz,
1H), 2.07 (s, 3H), 1.72-1.68 (m, 2H), 1.64-1.50 (m, 2H), 1.27 (s, 3H), 1.06 (s, 9H), 0.12 (s, 9H);
13C-NMR (151 MHz; CDCl3): d 170.4, 135.9, 135.8, 134.3, 133.5, 133.4, 130.0, 127.94, 127.93,
127.5, 73.7, 67.5, 63.2, 62.3, 59.9, 31.8, 31.0, 28.4, 27.0, 21.4, 19.5, -0.3; IR (neat) 2956, 2859,
+
1740, 1473, 1429, 1372, 1239 cm–1; HRMS (NSI) calculated for C31H47O5Si2 [M+H]+ 555.2957,
found 555.2959.
Preparation of (R,R)-epoxyalkene 37: To a solution of (R,R)-epoxyalkene 21 (352 mg, 1.0
mmol) and 1-hexene (1.00 mL, 8.0 mmol) in CDCl3 (1 mL) was added Grela catalyst 30 (17.2 mg,
0.026 mmol). The solution was concentrated in vacuo (~7 torr) at 50 oC for 1 h. The resulting oil
was passed through a plug of SiO2 (10 g) eluting with 5/95 Et2O/hexanes (100 mL) and the eluent
28
ACS Paragon Plus Environment

Page 29 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
concentrated in vacuo to give (R,R)-epoxyalkene 37 as a thick oil (385 mg, 0.94 mmol, 94% yield,
trans:cis 88:12). [ ]D20 = +6.5 (CH2Cl2, c = 1.03); 1H-NMR (600 MHz, CDCl3): d 7.71-7.66 (m, 4H),
a
7.46-7.42 (m, 2H), 7.42-7.38 (m, 4H), 5.88 (dt, J = 15.4, 6.9 Hz, 1H), 5.34 (ddt, J = 15.4, 7.9, 1.5
Hz, 1H), 3.67 (app. q, J = 11.2 Hz, 2H), 3.30 (d, J = 7.9 Hz, 1H), 2.11 (qd, J = 7.3, 1.2 Hz, 2H),
1.43-1.31 (m, 7H), 1.07 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H); 13C-NMR (151 MHz, CDCl3): d 138.1,
135.68, 135.60, 133.39, 133.35, 129.7, 127.70, 127.68, 124.4, 68.0, 62.6, 61.1, 32.3, 31.2, 26.8,
22.2, 19.3, 14.5, 13.9; IR (CH2Cl2): 2071, 2049, 2998, 2957, 2929, 2857, 1665, 1589, 1472, 1428,
1112, 823, 701 cm-1; HRMS (NSI) calculated for C26H37O2Si+ [M+H]+ 409.2568, found 409.2559.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of (R,R)-epoxyalkene trimethylsilyl ether 38: To a solution of (R,R)-
epoxyalkene 21 (379 mg, 1.07 mmol) and the alkene trimethylsilyl ether 23 (611 mg, 3.3 mmol)
in CDCl3 (3 mL) was added Grela catalyst 30 (14.9 mg, 0.022 mmol). The solution was heated
to 35 oC for 2 h, whereupon NMR of a small aliquot indicated ca. 60% conversion to the desired
product. Additional metathesis catalyst (10.3 mg, 0.054 mmol) was then added and the reaction
o
heated another 1.5 h at 35 C. The reaction mixture was then concentrated in vacuo and the
resulting oil chromatographed eluting with 5/95 Et2O/Hexanes to furnish compound (R,R)-
epoxyalkene trimethylsilyl ether 38 as a colorless oil (247 mg, 0.48 mmol, 45% yield, trans:cis
90:10). [ ]D20 = +7.4 (CH2Cl2, c = 0.49); 1H-NMR (600 MHz, CDCl3): d 7.69-7.68 (m, 4H), 7.45-
a
7.42 (m, 2H), 7.41-7.37 (m, 4H), 5.87 (dtd, J = 15.4, 6.9, 0.5 Hz, 1H), 5.34 (ddt, J = 15.4, 7.8, 1.5
Hz, 1H), 3.67 (app. q, J = 10.8 Hz, 2H), 3.58 (t, J = 6.7 Hz, 2H), 3.30 (d, J = 7.8 Hz, 1H), 2.11 (q,
J = 6.8 Hz,2H), 1.57-1.52 (m, 2H), 1.46-1.40 (m, 2H), 1.38-1.33 (m, 2H), 1.33 (s, 3H), 1.07 (s,
9H), 0.12 (s, 9H); 13C-NMR (151 MHz, CDCl3): d 138.1, 135.9, 135.8, 133.61, 133.56, 129.9,
127.92, 127.90, 124.7, 68.1, 62.83, 62.81, 61.2, 32.79, 32.77, 29.1, 27.0, 25.6, 19.5, 14.7, -0.2;
IR (CH2Cl2): 3071, 3049, 2998, 2956, 2931, 2858, 1590, 1473, 1250, 1106, 840, 702 cm-1; HRMS
+
(NSI) calculated for C30H47O3Si2 [M+H]+ 511.3058, found 511.3054.
Preparation of (R,R)-epoxyalkene trimethylsilyl ether 39: To a solution of (R,R)-
epoxyalkene 21 (151 mg, 0.43 mmol) and alkenyl silyl ether 24 (197 mg, 0.84 mmol) in CDCl3 (1
mL) was added Grela catalyst 30 (3.9 mg, 0.0058 mmol). The solution was stirred for 1 h
whereupon NMR of a small aliquot indicated ca. 60% conversion to the desired product. An
additional amount of Grela catalyst (4.9 mg, 0.0073 mmol) was then added and the reaction stirred
at rt for another 2 h. NMR of the crude reaction mixture then showed high (>90%) conversion to
the desired cross metathesis product. The reaction mixture was concentrated in vacuo and the
resulting oil chromatographed eluting with 5/95 Et2O/hexanes to give (R,R)-epoxyalkene
trimethylsilyl ether 39 as a colorless oil (173 mg, 0.31 mmol, 72%, trans:cis 89:11). [ ]D20 = +5.1
a
(CH2Cl2, c = 0.48); 1H-NMR (600 MHz, CDCl3): d 7.70-7.67 (m, 4H), 7.46-7.42 (m, 2H), 7.42-7.37
(m, 5H), 7.24-7.19 (m, 2H), 7.18-7.16 (m, 1H), 5.95 (dtd, J = 15.4, 6.8, 0.5 Hz, 1H), 5.40 (ddt, J =
15.4, 7.8, 1.5 Hz, 1H), 4.71 (s, 2H), 3.69 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.3 Hz, 1H), 3.30 (d,
J = 7.8 Hz, 1H), 2.80-2.70 (m, 2H), 2.44-2.39 (m, 2H), 1.32 (s, 3H), 1.07 (s, 9H), 0.17 (s, 9H); 13C-
NMR (151 MHz, CDCl3): d 139.4, 138.5, 137.1, 135.9, 135.8, 133.58, 133.55, 129.9, 129.3, 128.1,
127.93, 127.91, 127.7, 126.4, 125.4, 68.1, 62.93, 62.88, 61.1, 34.0, 31.9, 27.0, 19.5, 14.7, -0.2;
IR (CH2Cl2): 3071, 3049, 3021, 2957, 2931, 2896, 2858, 1737 (weak), 1589, 1487, 1428, 1251,
1113, 1074, 873, 841, 742, 702 cm–1; HRMS (NSI) calculated for C34H47O3Si2 [M+H]+ 559.3058,
+
found 559.3027.
Preparation of (S,R)-epoxyalkenyl alcohol 40: To a solution of (S,R)-epoxyalkene 20 (349
mg, 0.99 mmol) and the alkene trimethylsilyl ether 22 (683 mg, 3.96 mmol) in CDCl3 (2 mL) was
added Grela catalyst 30 (21 mg, 0.051 mmol). The solution was stirred at rt under active argon
o
flow for 1 h, then concentrated in vacuo at 35 C for 0.5 hours. The resulting oil was
chromatographed on SiO2 eluting with 5/95 Et2O/hexanes to furnish the trimethylsilyl-protected
29
ACS Paragon Plus Environment