Synthesis of stereopure acyclic 1,5-dimethylalkane chirons: Building blocks of highly methyl-branched natural products

Article abstract of DOI:10.1016/j.tet.2013.09.020

An efficient synthetic method towards stereopure acyclic 1,5-dimethylalkane building blocks from methyl (2R)-3-hydroxy-2-methylpropionate (R)-1 (>99% ee) and methyl (2S)-3-hydroxy-2-methylpropionate (S)-1 (>99% ee) through a series of chemical transformat

Full text of DOI:10.1016/j.tet.2013.09.020

Accepted Manuscript
Synthesis of Stereopure Acyclic 1,5-Dimethylalkane Chirons: Building Blocks of
Highly Methyl Branched Natural Products
Nan-Sheng Li, Joseph A. Piccirilli
PII:
S0040-4020(13)01416-6
10.1016/j.tet.2013.09.020
TET 24795
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 August 2013
Revised Date: 6 September 2013
Accepted Date: 9 September 2013
Please cite this article as: Li N-S, Piccirilli JA, Synthesis of Stereopure Acyclic 1,5-Dimethylalkane
Chirons: Building Blocks of Highly Methyl Branched Natural Products, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.09.020.
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ACCEPTED MANUSCRIPT
TOC/Graphical Abstract
HO
HO
HO
OMe
OMe
n
n = 1, C15 Fragment of C32-MPM
n = 2, C16 Fragment of C32-MPM
C32-MPM
O
R)-1
(
Vitamin E C14-side chain
Insect pheromones etc.
*
*
OTBDPS
BnO
(
(
(
(
2R,6S)-C10 Chiron
2S,6S)-C10 Chiron
2R,6R)-C10 Chiron
2S,6R)-C10 Chiron
O
S)-1
Highly Methyl Branched
Natural Products
(

ACCEPTED MANUSCRIPT
Synthesis of Stereopure Acyclic 1,5-Dimethylalkane Chirons: Building Blocks of Highly
Methyl Branched Natural Products
Nan-Sheng Li,* and Joseph A. Piccirilli
Department of Biochemistry and Molecular Biology and Department of Chemistry, University of
th
Chicago, 929 East 57 Street, Chicago, Illinois 60637, USA
E-mail: nli@uchicago.edu; Phone: 1 773 702 5236; Fax: 1 773 702 0438
ABSTRACT: An efficient synthetic method towards stereopure acyclic 1,5-dimethylalkane
building blocks from methyl (2R)-3-hydroxy-2-methylpropionate (R)-1 (>99% ee) and methyl
(
2S)-3-hydroxy-2-methylpropionate (S)-1 (>99% ee) through a series of chemical
transformations, including Julia–Kocienski olefination and diimide reduction, is described.
Through this strategy, two fragments of -D-mannosyl phosphomycoketide (C -MPM) and four
stereopure 1,5-dimethylalkane C10 chirons are prepared. These C -MPM fragments and C
β
3
2
32
10
chirons have shown great potential application as building blocks for the synthesis of highly
methyl-branched natural products containing chiral oligoisoprenoid-like chains.
KEYWORDS: Stereopure, Acyclic, 1,5-Dimethylalkane C Chiron, Highly Methyl Branched
1
0
Natural Product, Oligoisoprenoid Chain.
INTRODUCTION
The chiral 1,5-dimethylalkane subunit is ubiquitous among many biologically active
1
,2
3
4-12
natural products (Figure 1), such as vitamins, phytol, insect pheromones , marine natural

ACCEPTED MANUSCRIPT
1
3,14
15-18
products,
phosphomycoketides).
interesting and active subject for several decades due to their structural determinations and their
archaeal lipids,
and the bacterial membrane lipids (
β-D-mannosyl
1
9,20
Total synthesis of these methyl-branched natural products has been an
2
1-28
increasing biological and biomedical applications.
For this purpose, a series of 1,5-
6
,11,18,29-34
dimethylalkane C chirons (Figure 2A)
and 1,5-dimethylalkane C10 chirons (Figure
9
1
5,18,35-39
2
B)
have been prepared. These C chirons have been used to prepare a vitamin E C -
9
14
2
9,31,34
6,11,29,33
side chain
and some insect pheromones (Figure 1, III-VI).
Not only have C10
3
7
36
chirons been used to prepare a vitamin E side chain and insect pheromones, but they have
1
5,18
also been used to prepare highly methyl-branched archaeal lipids.
Additionally, van
Summeren et al. reported the total synthesis of C -MPM using the C chiron: methyl (3R,7S)-
3
2
10
4
0
3
,7-dimethyl-8-hydroxyoctanoic ester (Figure 2B: XVIa). However, this approach yielded C -
32
4
1
mycoketide, the precursor of the final C -MPM, with only 70% stereopurity. In a recently
3
2
published report, we described a highly stereocontrolled total synthesis of C -MPM with >96%
3
2
4
2
stereopurity starting from a single chiral source, (2S)-3-hydroxy-2-methylpropionate ((S)-1).
Here, we report the synthesis of a series of stereopure 1,5-dimethylalkane acyclic chirons (Figure
C). Through a series of chemical transformations, including Julia–Kocienski olefination and
diimide reduction, we developed an alternative synthesis of the C and C fragments of C -
2
1
5
16
32
MPM beginning from (2R)-3-hydroxy-2-methylpropionate ((R)-1). We also prepared four
stereopure 1,5-dimethylalkane C10 chirons (Figure 2C) from (S)-1 and/or (R)-1. To further
evaluate the synthetic value of these chirons in natural product synthesis, we prepared the
vitamin E C -side chain (Figure 1, I) and the precursor of apple leaf miner pheromone (Figure 1,
14
III) in a straightforward fashion.

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HO
O
OH
I:1 Vitamin E
II: Phytol
3
H
O
III:4-8 Insect pheromone
IV:9,10 Insect pheromone
OCOEt
OCOEt
VI:11,12 Insect pheromone
V:11,12 Insect pheromone
O
O
3
7
11
O
O
30
3
26
7
22
11
18
XO
XO
15
(
3R, 7R, 11R)
(3R, 7R, 11S, 15S, 18S, 22S, 26R, 30R)
VIII:15 Cyclic archaeol lipid, a lipid isolated
VII:15,16 Archaeol lipid, a lipid isolated from
Methanobacterium thermoautotrophicum
from Methanococcus jannaschii
18
22
26
30
3
11
15
O
O
7
XO
O
O
OY
(
3R, 7R, 11S, 15S, 18S, 22S, 26R, 30R)
IX:17,18 Caldarchaeol, an archaeal membrane lipid isolated from Methanobacterium thermoautotrophicum
OH
OH
O
O
HO
HO
O P O
O
Na
X:19,20 β-D-mannosyl phosphomycoketide (C -MPM), a lipid isolated from Mycobacterium Tuberculosis
32
Figure 1. Examples of natural products containing 1,5-dimethylalkanesubunits.

ACCEPTED MANUSCRIPT
A) C chirons: XI-XIII
9
XO
OY XO
OY
XO
XIIIa: X = THP, Y = H
OY
XIa:1
1,29
8
X = Ac, Y = H
6
6
XIIa: X = THP, Y = H
1
18
33
XIb: X = TBS, Y = H
XIc:
XId:
XIe: X = THP, Y = TBS
XIf: X = H, Y = MOM
XIIb: X = TBS, Y = H
XIIIb: X = TBS, Y = THP
1
8,31
30
X = H, Y = TBS
XIIc: X = TBDPS, Y = H
3
0,32
30
X = H, Y = TBDPS XIId: X = TBDPS, Y = THP
3
3
33
XIIe: X = TBS, Y = THP
3
4
B) C10 chirons: XIV-XIX
O
*
*
OH
OY
OH
MeO
XVIa:
XO
AcO
XIVa:15 X = Bn, Y = TBS
XIVb: X = H, Y = TBS
XIVc:1 X = TBDPS, Y = H
XIVd:35 X = Ac, Y = H
XV35
36-39
36
(3R,7S)-C10 Chiron
XVIb: (3R,7R)-C10 Chiron
XVIc: (3S,7R)-C10 Chiron
XVId: (3S,7S)-C10 Chiron
1
8
8
36
36
C) C /C fragments of C -MPM and C chirons
15
16
32
10
*
*
OTBDPS
HO
BnO
n
(
(
(
(
2R,6S)-C10 Chiron
2S,6S)-C10 Chiron
2R,6R)-C10 Chiron
2S,6R)-C10 Chiron
n = 1, C15 Fragment of C -MPM
n = 2, C16 Fragment of C -MPM
32
32
Figure 2. Structures of 1,5-dimethylalkane chirons. A) Examples of 1,5-dimethylalkane C9
6
,11,18,29-34
chirons reported in Literature;
B) Examples of 1,5-dimethylalkane C chirons reported
10
1
8,35-39
in Literature.
C) Structures of C /C fragments of C -MPM and 1,5-dimethylalkane C
15 16 32 10
chirons synthesized.
RESULTS AND DISCUSSION
A. Synthesis of the C and C fragments of C -MPM (Scheme 1), and the C diastereomer 15
1
5
16
32
15
(Scheme 2).
(2R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropyl tosylate (2) could be prepared from
methyl (2R)-3-hydroxy-2-methylpropionate [(R)-1] in three steps (89% yield) via TBDPS

ACCEPTED MANUSCRIPT
silylation, Dibal-H reduction and tosylation (Scheme 1). Tosylate 2 was then used as the
common precursor to generate the two substrates needed in the Julia–Kocienski olefination
reaction. N-Phenyltetrazolyl sulfone 6 was obtained from 2 in four steps (63% yield), and
4
3
aldehyde (S)-7 was prepared from 2 in two steps (84% yield). The Julia–Kocienski olefination
step was carried out by slow addition of lithium hexamethyldisilazide into a solution of sulfone 6
and (S)-7 in THF at -78 ºC. Excess sulfone 6 could be used to improve the yield of olefination
followed by recovery of the unreacted sulfone 6 by silica gel chromatography during the product
purification. The reaction yielded alkene 8 in 61% yield as a mixture of (E/Z)-isomers (E/Z
~7:3). The relatively low E-selectivity of the reaction with these methyl branched substrates is
4
2
consistent with our recently report with E/Z ~75:25.
Scheme 1

ACCEPTED MANUSCRIPT
1
2
. TBDPSCl, imidazole
. Dibal-H
n-C H MgBr,
CuBr.SMe2
6
13
HO
OMe 3. TsCl, DMAP, Py
TBDPSO
OTs
TBDPSO
C H -n
7
15
89%
68%
O
R)-1
(
2
3
PT-SH,
O
O
Ph P,
3
TBAF
00%
S
m-CPBA
N
N
S
HO
DEAD
C H -n
C H -n
7 15
C H -n
N
7
15
7
15
N
1
95%
97%
N
N
N
N
Ph
Ph
4
5
6
O
NH NH ,
1
. NaCN
. Dibal-H TBDPSO
2
2
2
6, LiHMDS TBDPSO
CuSO
4
, air
H
C H -n
7 15
2
84%
61%
90%
(
S)-7
8
Dess-Martin
Periodinane
TBAF
HO
TBDPSO
C H -n
C H15-n
7
7
15
100%
77%
9
10
12
+
-
[
MePPh ] Br ,
1. 9-BBN
3
O
s-BuLi
2. NaBO
-4H O
3 2
C H -n
C H -n
7 15
7
15
6
5%
92%
11
HO
C H -n
7 15
13
Reduction of alkene 8 to compound 9 was then investigated using various reduction
conditions. The results of these investigations are summarized in Table 1. The palladium-
catalyzed hydrogenation approach afforded reduction product (67% yield) containing a 21% α-
methyl epimerization along with a 15% recovery of its starting material (entry 1). Using
platinum as a hydrogenation catalyst increased both the yield (90%) and stereopurity (ca. 9% α-
methyl epimerization) of alkane 9 (entry 2). Iridium black, and osmium powder did not catalyze

ACCEPTED MANUSCRIPT
4
4
the hydrogenation reaction (entries 3 and 4). The hydroboration/protonation procedure could
4
5
not be used to convert alkene 8 to compound 9 (entry 5). Reduction of 8 by Ashby's method
LiAlH /Nickel(II) chloride), however, yielded 9 in 33% yield but the reaction was incomplete as
(
4
4
3% of 8 was recovered (entry 6). Diimide (HN=NH) offered an attractive alternative for alkene
reduction as the proposed reaction mechanism involves a cyclic transition state that precludes
46,47
epimerization.
Three additional methods for the in situ generation of diimide (A:
4
8
49
50
NH NH /NaIO , B: TsNHNH /NaOAc, C: NH NH /CuSO ) were examined to reduce
2
2
4
2
2
2
4
alkene 8. Method A (NH NH /NaIO ) gave stereopure 9 in 33% yield along with 14% recovery
2
2
4
of 8. On the other hand, Method B (TsNHNH /NaOAc) gave no reduced product, but Method C
2
gave the best result. From the latter method, a 90% yield of the stereopure 9 was obtained when
alkene 8 was reacted with 100 equivalent of hydrazine and ~10% copper(II) sulfate in ethanol at
7
0 ºC for 15 hours (Table 1, entry 15). Stereopure C15 fragment 9 of C -MPM was then
32
obtained from (R)-1 in nine steps with 31% overall yield. Additionally, C fragment 9 could be
1
5
converted to the C fragment 13 in four steps with 46% overall yield (Scheme 1). This approach
1
6
provides an alternative route leading to the C fragment from (R)-1 in addition to our previously
1
6
4
2
reported method beginning from (S)-1. Both C and C fragments (10 and 13, respectively)
1
5
16
4
0,42
have been used as intermediates to prepare β-D-mannosyl phosphomycoketide (C -MPM).
32

ACCEPTED MANUSCRIPT
Table 1. Reduction of alkene 8 to alkane 9.
Entry
Reductive Reaction Conditions
Recovery Yield
a
b
of 8 (%)
(%)
c,d
1
10% Pd/C (0.2 equiv.), H , benzene, rt, overnight
15
67
2
c,e
2
10% Pt/C (0.2 equiv.), H , benzene, rt, overnight
0
100
100
70
43
14
84
10
0
90
0
2
3
4
5
6
7
8
9
Iridium black (0.2 equiv.), H , benzene, rt, overnight
2
Osmium powder (0.2 equiv.), H , benzene, rt, overnight
0
2
i). 9-BBN/THF, rt, 24 h; ii). CH CO H, rt, 24 h
0
3
2
NiCl (2.0 equiv.)/LiAlH (2.0 equiv.), THF, -78 ºC-rt, 24 h
33
33
0
2
4
NH NH (100 equiv.), NaIO (2.5 equiv.), 75 ºC, 2 h
2
2
4
TsNHNH (10 equiv.), NaOAc, dimethyl ethylene ether, reflux,
2
4
h
CuSO (0.5 equiv.), NH NH (140 equiv.), EtOH, rt, 63 h
64
62
63
82
73
82
90
80
68
4
2
2
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
CuSO (0.5 equiv.), NH NH (140 equiv.), EtOH, 70 ºC, 24 h
4 2 2
CuSO (0.22 equiv.), NH NH (140 equiv.), EtOH, 70 ºC, 24 h
0
4
2
2
CuSO (0.22 equiv.), NH NH (140 equiv.), EtOH, 70 ºC, 15 h
0
4
2
2
CuSO (0.22 equiv.), NH NH (70 equiv.), EtOH, 70 ºC, 15 h
5
4
2
2
CuSO (0.22 equiv.), NH NH (100 equiv.), EtOH, 70 ºC, 15 h
0
4
2
2
CuSO (0.11 equiv.), NH NH (100 equiv.), EtOH, 70 ºC, 15 h
0
4
2
2
CuSO (0.10 equiv.), NH NH (100 equiv.), EtOH, 70 ºC, 7.5 h
0
4
2
2
CuSO (0.05equiv.), NH NH (100 equiv.), EtOH, 70 ºC, 8 h
3
4
2
2
a
1
b
c
Estimated by the H NMR of the isolated product. Isolated yield. Epimerization estimated by
13
d
e
the C NMR of the isolated product. 21% α-Methyl epimerization observed. 9% α-Methyl
epimerization observed.
4
2
Aldehyde (R)-7 was prepared from (S)-1 in five steps with 81% yield. The Julia–
Kocienski olefination of aldehyde (R)-7 with sulfone 6 in the presence of lithium

ACCEPTED MANUSCRIPT
hexamethyldisilazide gave alkene 14 in 65% yield (Scheme 2). Reduction of alkene 14 with
diimide yielded O-silylated alkane 15 (a diastereomer of 9) in 89% yield. Compound 15 could be
used as an intermediate to prepare a modified C -MPM molecule with a change in chirality of
3
2
single carbon from (S) to (R). We believe the efficient synthesis of natural and unnatural C -
3
2
MPMs would allow further investigation into how the structure of C -MPM can influence its
3
2
biological functions.
Scheme 2
1
2
3
4
. TBDPSCl, imidazole
. Dibal-H
. TsCl, DMAP, Py
. NaCN
O
HO
OMe 5. Dibal-H
TBDPSO
6, LiHMDS
H
81%
65%
O
S)-1
(
(R)-7
NH NH ,
2
2
TBDPSO
CuSO , air TBDPSO
4
C H -n
C H -n
7 15
7
15
89%
14
15
B. Synthesis of C chirons (21-24)
1
0
Enantiomeric aldehydes (R)-7 and (S)-7 were converted to the corresponding N-
phenyltetrazolyl sulfones (R)-16 and (S)-16 in five steps with 60%-63% yield (Scheme 3). The
Julia–Kocienski olefinations of (R)-7 to (R)-16, (S)-7 to (R)-16, (R)-7 to (S)-16, and (S)-7 to (S)-
1
6 in the presence of lithium hexylmethyldisilazide yielded alkenes 17 (78% yield), 18 (86%), 19
(69%) and 20 (74%), respectively. Reduction of the latter set of alkenes with hydrazine in the
presence of copper(II) sulfate produced C10 chirons 21-24 in 86-97% yields. Each of these
chirons contained a benzyl and a TBDPS protective group. Compounds with these two protective
groups underwent the most common reaction conditions, such as treatment with acids, bases,

ACCEPTED MANUSCRIPT
oxidants, reductants, and organometallic reagents but they could be selectively removed either by
TBAF or by palladium-catalyzed hydrogenation to generate up to eight partially protected
alcohols. Therefore, C chirons 21-24 (Figure 2C) are expected to be more versatile and flexible
1
0
than any other of the C and C chirons previously reported (Figures 2A and 2B). These
9
10
partially protected alcohols are expected to be very useful for the synthesis of a range of methyl-
branched natural products (Figure 1). The C10 chiron, 21, has been synthesized and applied
4
2
towards the total synthesis of C -MPM.
3
2
Scheme 3

ACCEPTED MANUSCRIPT
O
S
O
Ph
N
N
1
2
3
4
5
. NaBH4
. NaH, BnBr
. TBAF
. PT-SH, Ph P, DEAD
BnO
(
(
(
R)-7
or
N
N
(R)-7 or (S)-7,
3
R)-16: 63% yield
. m-CPBA
LiHMDS
6
0-63%
69-86%
O
S
O Ph
N
BnO
(
S)-7
N
N
N
S)-16: 60% yield
OTBDPS
OTBDPS
BnO
BnO
17
18
78% yield from (R)-7 and (R)-16
86% yield from (S)-7 and (R)-16
OTBDPS
OTBDPS
BnO
BnO
19
20
69% yield from (R)-7 and (S)-16
74% yield from (S)-7 and (S)-16
NH NH ,
2
2
86-97%
CuSO , air
4
OTBDPS
1: 97% yield from 17
OTBDPS
22: 93% yield from 18
BnO
BnO
BnO
BnO
2
OTBDPS
3: 86% yield from 19
OTBDPS
24: 92% yield from 20
2
C. Application of C chirons to the synthesis of vitamin E C -side chain and the precursor of
1
0
14
apple leaf miner pheromone (III)
To further evaluate the synthetic value of these chirons, the vitamin E C -side chain (27)
1
4
was prepared from chiron 21 (Scheme 4). Removal of the benzyl group of 21 by palladium-
catalyzed hydrogenation gave 25 in 93% yield. Reaction of 25 with TsCl in pyridine gave the
tosylate 26 in 75% yield. The coupling reaction of tosylate 26 with isobutylmagnesium chloride

ACCEPTED MANUSCRIPT
in the presence of copper (I) bromide dimethyl sulfide followed by desilylation with TBAF gave
2
9,31,34
the vitamin E C -side chain (27)
in 96% yield.
14
Scheme 4
Pd-C, H2
TsCl/Py/DMAP
2
1
OTBDPS
OTBDPS
93%
HO
7
5%
TsO
2
5
26
1
. Me CHCH MgCl,
2 2
CuBr.SMe2
2
. TBAF
OH
9
6%
2
7
Chiron 23 was treated with TBAF to give alcohol 28 in 96% yield. Reaction of 28 with
TsCl in pyridine gave tosylate 29 in 72% yield. Coupling of tosylate 29 with propylmagnesium
chloride in the presence of copper (I) bromide-dimethyl sulfide complex provided 30 in 98%
yield. Finally, catalytic hydrogenation of 30 produced alcohol 31 in 91% yield. The apple
3
6
leafminer pheromone (Figure 1, III) was prepared from 31 in two steps with ~70% yield.
Scheme 5

ACCEPTED MANUSCRIPT
TBAF
6%
TsCl/Py/DMAP
23
OTs
OH
BnO
72%
9
BnO
2
8
29
n-PrMgCl,
CuBr.SMe2
Pd-C, H2
98%
BnO
91%
HO
30
31
Ref. 31
~
70%
III
In summary, through a series of classic chemical transformations, including the Julia–
Kocienski olefination and diimide reduction, we have developed an alternative synthesis of
C /C fragments of C -MPM (10 and 13 respectively) from (2R)-3-hydroxy-2-
15
16
32
4
2
methylpropionate ((R)-1) in addition to our recently reported method beginning from (S)-1. We
further prepared four stereopure 1,5-dimethylalkane acyclic C building blocks (21-24) from
1
0
(
R)-1 and (S)-1. These C chirons could be partially deprotected using either TBAF or Pd/H ,
1
0
2
and are expected to be more versatile and flexible than other C and C chirons reported (Figure
9
10
2
, A and B). The synthesis of vitamin E C -side chain, the precursor of insect pheromone, and
14
4
2
C -MPM has clearly demonstrated these 1,5-dimethyl fragments and chirons as very useful
3
2
intermediates for the efficient synthesis of highly methyl-branched natural and unnatural
products containing oligoisopenoid-like chains (Figure 1).
EXPERIMENTAL SECTION

ACCEPTED MANUSCRIPT
Methyl (2R)-3-hydroxy-2-methylpropionate (R)-1 (>99% ee) and methyl (2S)-3-hydroxy-
-methylpropionate (S)-1 (>99% ee) were purchased from TCI America. All other reagents and
2
anhydrous solvents were purchased from Aldrich; other solvents were purchased from Fisher.
(2R)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropyl p-toluenesulfonate (2): To a solution of
(R)-1 (11.8 g, 100 mmol) and imidazole (15.0 g, 220 mmol) in dry dichloromethane (100 mL) at
0
1
ºC was added dropwise TBDPSCl (28.2 mL, 110 mmol). After the mixture was stirred at rt for
h, the reaction was quenched with water (40 mL). The aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was co-evaporated with dry
toluene (2 × 10 mL) and then dried under vacuum.
To a solution of dried crude co-evaporated mixture (methyl (2R)-3-(tert-
butyldiphenylsilyloxy)-2-methylpropionate (~100 mmol)) in anhydrous dichloromethane (200
mL) under an argon atmosphere at -78 ºC was added dropwise Dibal-H (1.0 M in hexane, 270
mL, 270 mmol). After the reaction mixture was stirred at -40 ºC then warmed to -10 ºC for 1 h,
the mixture was poured into a cooled aqueous potassium sodium tartrate solution (1.0 M, 300
mL) and allowed to stir at rt overnight. The reaction mixture was extracted with diethyl ether,
then the combined organic layers were washed with brine and dried over MgSO . After filtration
4
and solvent removal, the residue was co-evaporated with dry toluene (2 × 10 mL) and dried in
vacuo.
To a solution of the dried crude (2S)-3-(tert-butyldiphenylsilyloxy)-2-methylpropanol
(~100 mmol) and DMAP (20 mg) in dry pyridine (150 mL) under argon at 0 ºC was added p-
TsCl (22.88 g, 120 mmol). After stirrirng at rt overnight, the reaction mixture was quenched with

ACCEPTED MANUSCRIPT
water (150 mL). The reaction mixture was then extracted with ether (3 × 150 mL), and the
combined organic layers were washed successively with 1 N HCl (150 mL), saturated aqueous
NaHCO (100 mL) and brine (150 mL). The organic layer was dried over MgSO . After
3
4
filtration and solvent removal, the residue was purified by silica gel chromatography, eluting
5
1,52
1
with 10% ethyl acetate in hexane to give 2:
42.8 g (89% yield). H NMR (CDCl /TMS) δ
3
7
4
2
1
.78 (d, 2H, J = 8.0 Hz), 7.60-7.55 (m, 4H), 7.45-7.25 (m, 8H), 4.12 (dd, 1H, J = 5.6, 9.2 Hz),
.00 (dd, 1H, J = 6.0, 9.2 Hz), 3.50 (dd, 1H, J = 4.8, 10.4 Hz), 3.46 (dd, 1H, J = 6.8, 10.4 Hz),
1
3
.42 (s, 3H), 2.01 (m, 1H), 0.97 (s, 9H), 0.86 (d, 1H, J = 6.8); C NMR (CDCl ) δ 144.7, 135.7,
3
35.6, 134.9, 133.49, 133.46, 129.9, 129.8, 128.1, 127.8, 72.3, 64.6, 35.8, 26.9, 21.8, 19.3, 13.4.
1
-(tert-Butyldiphenylsilyloxy)-(2S)-2-methyl-nonane (3): Under argon, hexylmagnesium
bromide (2.0 M in diethyl ether, 40 mL, 80 mmol) was added slowly over 2 h to a solution of 2
4.83 g, 10.0 mmol), copper (I) bromide-dimethyl sulfide complex (514 mg, 2.50 mmol) in
(
anhydrous THF (130 mL) at -78 ºC. After the mixture was stirred in cold for 2 h, the reaction
mixture was allowed to warm up to 0 ºC and stir overnight. The reaction was quenched with
saturated ammonium chloride, followed by extraction with ether. The organic layers were
combined, washed with brine and dried over MgSO . After filtration and solvent removal, the
4
residue was purified by silica gel chromatography, eluting with hexane to give 3 as an oil: 2.72 g
1
(
68% yield). H NMR (CDCl /TMS) δ 7.69-7.64 (m, 4H), 7.45-7.30 (m, 6H), 3.51 (dd, 1H, J =
3
6
1
1
.0, 10.0 Hz), 3.43 (dd, 1H, J = 6.4, 10.0 Hz), 1.64 (m, 1H), 1.42 (m, 1H), 1.33 -1.77 (m, 11H),
1
3
.06 (s, 9H), 0.91 (d, 3H, J = 6.8 Hz), 0.88 (d, 3H, J = 7.2 Hz); C NMR (CDCl ) δ 135.8,
3
34.3, 129.6, 127.7, 69.1, 35.9, 33.3, 32.1, 30.1, 29.5, 27.1, 27.0, 22.9, 19.5, 17.1, 14.3; HRMS
+
(
ESI/APCl) calcd for C H OSi [MH ] 397.2921, found 391.2918.
2
6
41

ACCEPTED MANUSCRIPT
(2S)-2-Methyl-1-nonanol (4): To a solution of 3 (2.72 g, 6.85 mmol) in THF (15 mL) was
added TBAF (1.0 M in THF, 10.0 mL, 10.0 mmol). After the mixture was stirred at rt overnight,
the solvent was removed, and the residue was purified by silica gel chromatography, eluting with
5
3
1
1
3
0% ethyl acetate in hexane to give 4 as an oil: 1.08 g (100% yield). H NMR (CDCl /TMS) δ
3
1
3
.44 (m, 1H), 3.36 (m, 1H), 1.56 (m, 1H), 1.40-1.15 (m, 12H), 0.90-0.85 (m, 6H); C NMR
(
CDCl ) δ 68.5, 35.8, 33.2, 32.0, 30.0, 29.4, 27.1, 22.8, 16.7, 14.2.
3
5
-[(2S)-2-Methyl-nonylsulfanyl]-1-phenyl-1H-tetrazole (5): To a solution of 4 (1.08 g, 6.85
mmol), 1-phenyl-1H-tetrazole-5-thiol (1.46 g, 8.22 mmol), PPh (2.16 g, 8.22 mmol) in
3
anhydrous THF (20 mL) under argon at 0 ºC was added DEAD (1.32 mL, 8.22 mmol). After the
mixture was warmed to rt and stirred for 1 h, the reaction was quenched with water and extracted
with diethyl ether. The organic layers were combined and the solvent was removed, the residue
was purified by silica gel chromatography, eluting with 5% ethyl acetate in hexane to give 5 as
1
an oil: 2.08 g (95% yield). H NMR (CDCl /TMS) δ 7.65-7.50 (m, 5H), 3.46 (dd, 1H, J = 6.8,
3
1
2.4 Hz), 3.26 (dd, 1H, J = 12.4, 7.6 Hz), 1.93 (m, 1H), 1.47 (m, 1H), 1.41-1.18 (m, 11H), 1.04
1
3
(
d, 3H, J = 6.5 Hz), 0.88 (t, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 154.8, 133.9, 130.1, 129.8,
3
1
23.9, 40.6, 36.0, 33.0, 31.9, 29.8, 29.3, 26.9, 22.7, 19.2, 14.2; HRMS (ESI/APCl) calcd for
+
C H N S [MH ] 319.1951, found 319.1953.
17
27
4
5
-[(2S)-2-Methyl-nonane-1-sulfonyl]-1-phenyl-1H-tetrazole (6): To a solution of 5 (1.75 g,
.48 mmol) in dichloromethane (65 mL) at 0 ºC was added m-CPBA (77%, 6.15 g, 27.4 mmol)
5
was added. After the reaction mixture was stirred at rt overnight, 10% aqueous Na S O (10 mL)
2
2
3

ACCEPTED MANUSCRIPT
and saturated aqueous sodium bicarbonate (15 mL) were added, stirred for an additional 30 min,
then extracted with dichloromethane multiple times. The organic layers were combined and
washed successively with 10% aqueous Na S O (10 mL), saturated aqueous sodium bicarbonate
2
2
3
(2 × 10 mL) and brine. After solvent removal, the residue was purified by silica gel
1
chromatography, eluting with 5% ethyl acetate in hexane to give 6 an oil: 1.87 g (97% yield). H
NMR (CDCl /TMS) δ 7.73-7.56 (m, 5H), 3.81 (dd, 1H, J = 4.8, 14.4 Hz), 3.58 (dd, 1H, J = 14.4,
3
8
.0 Hz), 2.33 (m, 1H), 1.53 (m, 1H), 1.43-1.20 (m, 11H), 1.15 (d, 3H, J = 6.8 Hz), 0.88 (t, 3H, J
13
=
6.8 Hz); C NMR (CDCl ) δ 154.2, 133.2, 131.6, 129.8, 125.3, 62.0, 36.7, 31.9, 29.5, 29.3,
3
+
2
3
8.4, 26.4, 22.7, 19.8, 14.2; HRMS (ESI/APCl) calcd for C H N O S [MH ] 351.1849, found
1
7
27
4
2
51.1855.
(3S)-4-(tert-Butyldiphenylsilyloxy)-3-methylbutanal [(S)-7)]: A solution mixture of 2 (14.6 g,
3
0.3 mmol) and sodium cyanide (1.78 g, 95%, 36.4 mmol) in DMF (35 mL) was heated and
stirred at 60 ºC for 24 h. After quenching the reaction with water (30 mL), the crude product was
extracted with hexane (4 × 35 mL). The combined organic layers were washed with brine and
dried over MgSO . Following filtration and solvent removal, the residue was purified by silica
4
gel chromatography, eluting with 5% ethyl acetate in hexane to give (3S)-4-(tert-
3
2
13
butyldiphenylsilyloxy)-3-methylbutanenitrile: 9.86 g (96% yield). C NMR (CDCl ) δ 135.67,
3
1
35.64, 133.32, 133.26, 130.0, 127.9, 119.0, 67.0, 33.4, 27.0, 21.2, 19.4, 16.0.
To a solution of (3S)-4-(tert-butyldiphenylsilyloxy)-3-methylbutanenitrile (1.14 g, 3.39
mmol) in anhydrous dichloromethane (4.0 mL) stirring at -78 ºC under argon was added
dropwise Dibal-H (1.0 M in hexane, 3.7 mL, 3.7 mmol). After stirring at -78 ºC for 1 h, the
reaction was quenched and acidified to pH 3 by slow addition of 1 N HCl. To the mixture,

ACCEPTED MANUSCRIPT
diethyl ether (10 mL) and aqueous potassium sodium tartrate solution (1.0 M, 5.0 mL) were
added, then the entire mixture was stirred at rt for an additional 2 h. The aqueous layer was
extracted with diethyl ether (3 × 10 mL) and the combined organic layers were washed with
brine then dried over MgSO . After filtration and solvent removal, the residue was purified by
4
3
2,54
silica gel chromatography, eluting with 5% ethyl acetate in hexane to give (S)-7:
1.014 g
1
(
88% yield). H NMR (CDCl /TMS) δ 9.78 (s, 1H), 7.70-7.60 (m, 4H), 7.48-7.30 (m, 6H), 3.57
3
(dd, 1H, J = 5.2, 10.0 Hz), 3.45 (dd, 1H, J = 7.2, 10.0 Hz), 2.60 (m, 1H), 2.40-2.20 (m, 2H),
1
3
1
1
.05 (s, 9H), 0.94 (d, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 202.8, 135.73, 135.71, 133.6, 129.8,
3
27.8, 68.5, 48.3, 31.4, 27.0, 19.4, 16.9.
1
-(tert-Butyldiphenylsilyloxy)-(2S,6S)-2,6-dimethyl-(Z/E)-4-tridecene (8): Standard procedure
for Julia–Kocienski olefination reaction: Under argon, LiHMDS (0.50 M in THF, 4.0 mL, 2.0
mmol) was added in a dropwise fashion over 15 min. to a solution of 6 (700 mg, 2.00 mmol) and
(S)-7 (0.448 g, 1.32 mmol) in anhydrous THF (15 mL) at -78 ºC. The resulting yellow solution
was stirred at -78 ºC for 3 h and then allowed to warm to rt overnight. The reaction was
quenched with aqueous saturated NH Cl and the aqueous layer was extracted with Et O. After
4
2
solvent removal, the residue was purified by silica gel chromatography, eluting with hexane to
1
give 8 as an oil: 0.374 g (61% yield). H NMR (CDCl /TMS) δ 7.70-7.60 (m, 4H), 7.45-7.30 (m,
3
6
1
1
2
H), 5.26 (m, 2H), 3.49 (m, 2H), 2.45-1.95 (m, 2H), 1.84 (m, 1H), 1.70 (m, 1H), 1.34-1.25 (m,
1
3
2H), 1.06 (s, 9H), 0.94-0.83 (m, 9H); C NMR (CDCl ) δ 138.3, 137.7, 135.8, 134.28, 134.25,
3
29.6, 127.7, 126.5, 126.4, 68.8, 68.5, 37.7, 37.3, 36.9, 36.8, 36.4, 36.3, 32.1, 31.8, 31.2, 30.0,
9.9, 29.5, 27.7, 27.5, 27.0, 22.8, 21.4, 21.1, 19.5, 16.8, 16.6, 14.3; HRMS (ESI/APCl) calcd for
+
C H OSi [MH ] 465.3547, found 465.3555.
31
49

ACCEPTED MANUSCRIPT
1
-(tert-Butyldiphenylsilyloxy)-(2S,6S)-2,6-dimethyl-tridecane (9): Standard procedure for
diimide reduction reaction: CuSO (1.4 mg, 0.0086 mmol) was added to a solution of 8 (40 mg,
4
0
.086 mmol) and hydrazine (0.27 mL, 8.6 mmol) in ethanol (5 mL). After the mixture was
bubbled with air and stirred at 70 ºC for 15 h, the solvent was removed, and the residue was
4
0
purified by silica gel chromatography, eluting with hexane to give product 9: 36 mg (90%
1
yield). H NMR (CDCl /TMS) δ 7.70-7.60 (m, 4H), 7.45-7.30 (m, 6H), 3.51 (dd, 1H, J = 5.6, 9.6
3
Hz), 3.43 (dd, 1H, J = 6.4, 9.6 Hz), 1.65 (m, 1H), 1.45-1.00 (m, 19H), 1.05 (s, 9H), 0.92 (d, 3H,
13
J = 6.8 Hz), 0.88 (t, 3H, J = 6.4 Hz), 0.83 (d, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 135.8, 134.3,
3
1
1
29.6, 127.7, 69.1, 37.5, 37.2, 35.9, 33.6, 32.9, 32.1, 30.1, 29.5, 27.2, 27.0, 24.5, 22.8, 19.9, 19.5,
7.1, 14.3.
(2S,6S)-2,6-Dimethyl-1-tridecanol (10): TBAF (1.0 M, 1.66 mL, 1.66 mmol) was added to a
solution of 9 (388 mg, 0.83 mmol) in THF (3.0 mL). After the mixture was stirred at rt
overnight, the solvent was removed, and the residue was purified by silica gel chromatograph,
4
0
1
eluting with 8% ethyl acetate in hexane to give product 10: 189 mg (100%). H NMR
(
CDCl /TMS) δ 3.50 (dd, 1H, J = 6.0, 10.4 Hz), 3.40 (dd, 1H, J = 6.4, 10.4 Hz), 1.72 (brs, 1H),
3
1
7
3
.60 (m, 1H), 1.45-1.17 (m, 16H), 1.17-1.00 (m, 3H), 0.92 (d, 3H, J = 6.8 Hz), 0.88 (t, 3H, J =
1
3
.2 Hz), 0.84 (d, 3H, J = 6.4 Hz); C NMR (CDCl ) δ 68.3, 37.3, 37.0, 35.8, 33.5, 32.7, 31.9,
3
0.0, 29.4, 27.1, 24.4, 22.7, 19.7, 16.6, 14.1.
(2S,6S)-2,6-Dimethyl-tridecanal (11): Under argon, Dess-Martin periodinane (662 mg, 1.56
mmol) was added to a solution of 10 (297 mg, 1.30 mmol) in dichloromethane (10 mL) at 0 ºC.
After stirring at 0 ºC to rt for 3 h, TLC showed the reaction was complete. The mixture was

ACCEPTED MANUSCRIPT
diluted with ether (100 mL), the solid filtered off, and rinsed with ether. The filtrate was washed
subsequently with 10% aqueous Na S O (20 mL), aqueous NaHCO (20 mL), brine (20 mL)
2
2
3
3
and dried over MgSO . After filtration and solvent removal, the residue was purified by silica gel
4
4
0
1
chromatography, eluting with 3% ethyl acetate in hexane to give 11: 0.228 g (77% yield). H
NMR (CDCl /TMS) δ 9.61 (m, 1H), 2.33 (m, 1H), 1.70 (m, 1H), 1.45-1.16 (m, 17H), 1.16-1.03
3
1
3
(
m, 1H), 1.09 (d, 3H, J = 8.4 Hz), 0.88 (t, 3H, J = 7.2 Hz), 0.84 (d, 3H, J = 6.4 Hz); C NMR
(
CDCl ) δ 205.5, 46.5, 37.2, 37.1, 32.8, 32.1, 31.0, 30.1, 29.5, 27.2, 24.6, 22.8, 19.8, 14.2, 13.5.
3
(3S,7S)-3,7-dimethyl-1-tetradecene (12): Under argon s-BuLi (1.4 M in cyclohexane, 2.1 mL,
3
3
1
.0 mmol) was added slowly to a suspension of triphenylmethylphosphonium bromide (1.07 g,
.00 mmol) in anhydrous THF (6 mL) at -78 ºC. After stirring at -78 ºC for 30 min, a solution of
1 (226 mg, 1.00 mmol) in anhydrous THF (3 mL) was added to the mixture under argon. The
mixture was allowed to warm to rt overnight. The reaction was quenched with saturated aqueous
ammonium chloride followed by extraction with ether, and drying the organic layers over
magnesium sulfate. After solvent removal, the residue was purified by silica gel
1
chromatography, eluting with hexane to give 12 as an oil: 146 mg (65% yield). H NMR
(
(
(
CDCl /TMS) δ 5.69 (m, 1H), 4.98-4.86 (m, 2H), 2.10 (m, 1H), 1.40-1.16 (m, 17H), 1.13-1.00
3
1
3
m, 2H), 0.97 (d, 3H, J = 5.2 Hz), 0.88 (t, 3H, J = 5.2 Hz), 0.83 (d, 3H, J = 5.2 Hz); C NMR
CDCl ) δ 145.2, 112.3, 37.9, 37.29, 37.28, 37.1, 32.9, 32.1, 30.1, 29.6, 27.3, 24.8, 22.9, 20.4,
3
+
1
9.8, 14.3; HRMS (ESI/APCl) calcd for C H [M ] 224.2499, found 224.2500.
1
6
32
(3S,7S)-3,7-Dimethyl-1-tetradecanol (13): Under argon, 9-BBN (226 mg, 0.93 mmol) was
added to a solution of 12 (104 mg, 0.46 mmol) in anhydrous THF (5 mL). After the reaction

ACCEPTED MANUSCRIPT
mixture was stirred at rt overnight, water (3 mL) and NaBO -4H O (859 mg, 5.58 mmol) were
3
2
added, the mixture was stirred at rt for an additional 2 h. The mixture was extracted with diethyl
ether (3 × 10 mL), the organic layers combined, and washed with brine. After solvent removal,
the residue was purified by silica gel chromatography, eluting with 10% ethyl acetate in hexane
4
2
1
to give 13 as an oil: 103 mg (92% yield). H NMR (CDCl /TMS) δ 3.67 (m, 2H), 1.63 (brs,
3
1
3
1
3
H), 1.59 (m, 2H), 1.42-1.00 (m, 20H), 0.92-0.82 (m, 9H); C NMR (CDCl ) δ 61.3, 40.1, 37.6,
3
7.5, 37.2, 32.9, 32.1, 30.1, 29.7, 29.5, 27.2, 24.5, 22.8, 19.84, 19.78, 14.2; HRMS (EI-GCMS)
+
calcd for C H O [M-H] 241.2531, found 241.2534.
1
6
33
1
-(tert-Butyldiphenylsilyloxy)-(2R,6S)-2,6-dimethyl-(Z/E)-4-tridecene (14): Compound 14
was prepared according to standard procedure, as described for the synthesis of 8. LiHMDS
0.50 M in THF, 3.06 mL, 1.53 mmol) was slowly added to a solution of 6 (536 mg, 1.53 mmol)
(
and (R)-7 (0369 mg, 1.08 mmol) in anhydrous THF (10 mL) at -78 ºC for 15 min. The reaction
1
afforded 14 as an oil: 0.326 g (65% yield). H NMR (CDCl /TMS) δ 7.83-7.73 (m, 4H), 7.53-
3
7
0
.42 (m, 6H), 5.45-5.20 (m, 2H), 3.70-3.50 (m, 2H), 2.51 (m, 0.3H), 2.29 (m, 1H), 2.14 (m,
1
3
.7H), 1.98 (m, 1H), 1.87 (m, 1H), 1.43-1.28 (m, 12H), 1.18 (s, 9H), 1.04-0.93 (m, 9H); C
NMR (CDCl ) δ 138.3, 137.7, 135.8, 134.26, 134.24, 129.6, 127.7, 126.5, 126.4, 69.0, 68.6,
3
3
7.8, 37.4, 37.0, 36.7, 36.5, 36.3, 32.1, 31.8, 31.2, 30.0, 29.9, 29.5, 27.7, 27.6, 27.1, 22.9, 21.4,
+
2
1.2, 19.50, 19.48, 16.84, 16.68, 14.3; HRMS (ESI/APCl) calcd for C H OSi [MH ] 465.3547,
3
1
49
found 465.3558.
1
-(tert-Butyldiphenylsilyloxy)-(2R,6S)-2,6-dimethyl-tridecane (15): Following the standard
procedure described for the synthesis of 9, compound 15 was prepared from the reaction of 14

ACCEPTED MANUSCRIPT
(
216 mg, 0.465 mmol) and hydrazine (1.46 mL, 46.5 mmol) in the presence of CuSO (7.4 mg,
4
0
.047 mmol) in ethanol (25 mL) while bubbling air flow and stirring at 70 ºC for 15 h. The
1
reaction afforded product 15 as an oil: 194 mg (89% yield). H NMR (CDCl /TMS) δ 7.70-7.62
3
(
(
(
m, 4H), 7.45-7.30 (m, 6H), 3.51 (dd, 1H, J = 5.6, 10.0 Hz), 3.44 (dd, 1H, J = 6.4, 10.0 Hz), 1.64
m, 1H), 1.45-1.00 (m, 19H), 1.06 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 0.88 (t, 3H, J = 6.4 Hz), 0.83
13
d, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 135.8, 134.3, 129.6, 127.7, 69.2, 37.5, 37.3, 35.9, 33.6,
3
3
2.9, 32.1, 30.2, 29.6, 27.3, 27.1, 24.6, 22.9, 19.9, 17.1, 14.3; HRMS (ESI/APCl) calcd for
+
C H OSi [MH ] 467.3704, found 467.3714.
31
51
5
-[(2S)-4-Benzyloxy-2-methyl-butane-1-sulfonyl]-1-phenyl-1H-tetrazole [(S)-16)]: (S)-16
was prepared from [(S)-7] in five steps with 60% overall yield according to the procedure
4
2 1
described for the synthesis of (R)-16. H NMR (CDCl /TMS) δ 7.70-7.50 (m, 5H), 7.36-7.23
3
(m, 5H), 4.48 (s, 2H), 3.98 (dd, 1H, J = 14.4, 4.4 Hz), 3.60 (dd, 1H, J = 14.4, 8.0 Hz), 3.58-3.51
1
3
(
m, 2H), 2.54 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.17 (d, 3H, J = 6.8 Hz); C NMR (CDCl )
3
δ 154.1, 138.2, 133.1, 131.5, 129.7, 128.5, 127.72, 127.71, 125.3, 73.1, 67.3, 61.8, 36.1, 26.4,
1
9.8.
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2S,6R)-2,6-dimethyl-(Z/E)-4-octene
(18):
Compound 18 was prepared according to the standard procedure described for the synthesis of 8.
4
2
LiHMDS (1.0 M in THF, 2.4 mL, 2.4 mmol) was slowly added to a solution of (R)-16 (918 mg,
2
.38 mmol) and (S)-7 (317 mg, 0.931 mmol) in anhydrous THF (10 mL) at -78 ºC for 15 min.
1
The reaction yielded 18 as an oil: 399 mg (86% yield). H NMR (CDCl /TMS) δ 7.70-7.20 (m,
3
1
5H), 5.40-5.10 (m, 2H), 4.50-4.40 (m, 2H), 3.51-3.30 (m, 4H), 2.60 (m, 0.3H), 2.30-2.10 (m,

ACCEPTED MANUSCRIPT
1
3
1
.7H), 2.00-1.40 (m, 4H), 1.06 (s, 9H), 0.97-0.85 (m, 6H); C NMR (CDCl ) δ 138.8, 138.7,
3
1
37.3, 136.6, 135.7, 134.13, 134.11, 129.6, 128.39, 128.37, 127.7, 127.53, 127.50, 127.3, 127.2,
3.03, 72.99, 68.88, 68.83, 68.7, 68.4, 37.3, 37.0, 36.5, 36.4, 36.2, 33.9, 31.1, 28.9, 27.0, 21.5,
7
+
2
1.2, 19.43, 19.41, 16.9, 16.6; HRMS (ESI/APCl) calcd for C H O Si [MNH ] 518.3449,
3
3
44
2
4
found 518.3462.
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2R,6S)-2,6-dimethyl-(Z/E)-4-octene
(19):
Compound 19 was prepared according to the standard procedure described for the synthesis of 8.
LiHMDS (1.0 M in THF, 1.5 mL, 1.5 mmol) was slowly added to a solution of (S)-16 (563 mg,
4
2
1
.46 mmol) and (R)-7 (341 mg, 1.00 mmol) in anhydrous THF (10 mL) at -78 ºC for 15 min.
1
13
The reaction yielded 19 as an oil: 345 mg (69% yield). The H and C NMR data of 18 and 19
are consistent.
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2S,6S)-2,6-dimethyl-(Z/E)-4-octene
(20):
Compound 20 was prepared according to the standard procedure described for the synthesis of 8.
LiHMDS (1.0 M in THF, 1.5 mL, 1.5 mmol) was slowly added to a solution of (S)-16 (386 mg,
1
.00 mmol) and (S)-7 (170 mg, 0.500 mmol) in anhydrous THF (5 mL) at -78 ºC for 15 min. The
1
13
reaction yielded 20 as an oil: 185 mg (74% yield). The H and C NMR data are consistent with
4
2
that of its enantiomer 17.
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2S,6S)-2,6-dimethyl-octane (22): According to
the standard procedure described for the synthesis of 9, compound 22 was prepared from 18 (397
mg, 0.793 mmol) and hydrazine (2.66 mL, 79.7 mmol) in the presence of CuSO (12.7 mg,
4
0
.0797 mmol) in ethanol (40 mL) while bubbling air and stirring at 70 ºC for 15 h. The reaction

ACCEPTED MANUSCRIPT
1
yielded 22 as an oil: 0.370 g (93% yield). H NMR (CDCl /TMS) δ 7.70-7.60 (m, 4H), 7.45-7.20
3
(m, 11H), 4.49 (s, 2H), 3.55-3.35 (m, 4H), 1.70-1.00 (m, 10H), 1.05 (s, 9H), 0.91 (d, 3H, J = 6.4
13
Hz), 0.86 (d, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 138.9, 135.8, 134.3, 129.6, 128.5, 127.73,
3
1
27.69, 127.6, 73.0, 69.1, 68.9, 37.5, 37.0, 35.8, 33.6, 30.0, 27.0, 24.4, 19.8, 19.5, 17.1; HRMS
+
(
ESI/APCl) calcd for C H NO Si [MNH ] 520.3605, found 520.3612.
3
3
50
2
4
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2R,6R)-2,6-dimethyl-octane (23): According to
the standard procedure described for the synthesis of 9, compound 23 was prepared from 19 (339
mg, 0.793 mmol) and hydrazine (2.26 mL, 67.7 mmol) in the presence of CuSO (10.8 mg,
4
0
.0677 mmol) in ethanol (35 mL) while bubbling air and stirring at 70 ºC for 15 h. The reaction
1
13
yielded 23 as an oil: 0.293 g (86% yield). The H and C NMR data of 22 and 23 are consistent.
8
-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-(2S,6R)-2,6-dimethyl-octane (24): According to
the standard procedure described for the synthesis of 9, compound 24 was prepared from 20 (178
mg, 0.355 mmol) and hydrazine (1.19 mL, 35.5 mmol) in the presence of CuSO (5.7 mg, 0.036
4
mmol) in ethanol (18 mL) while bubbling air and stirring at 70 ºC for 15 h. The reaction yielded
1
13
2
4 as an oil: 0.164 g (92% yield). The H and C NMR data are consistent with that of its
4
2
enantiomer 21.
8
-(tert-Butyldiphenylsilyloxy)-(3S,7R)-3,7-dimethyl-octyl p-toluenesulfonate (26): DMAP
4
2
(
2.0 mg) and TsCl (132 mg, 0.694 mmol) were added to a solution of 25 (191 mg, 0.463 mmol)
in pyridine (5.0 mL) at 0 ºC. After the reaction mixture was stirred at rt overnight, the reaction
was quenched with water (1.0 mL) and extracted with ether. The organic layer was washed with
1
N HCl, water, followed by saturated aqueous NaHCO , and brine, and then dried over MgSO .
3 4

ACCEPTED MANUSCRIPT
After filtration and solvent removal, the residue was purified by silica gel chromatography,
1
eluting with 5% ethyl acetate in hexane to give 26 as an oil: (197 mg, 75% yield). H NMR
(
(
(
CDCl /TMS) δ 7.79 (m, 2H), 7.70-7.62 (m, 4H), 7.45-7.28 (m, 8H), 4.10-4.00 (m, 2H), 3.48
3
dd, 1H, J = 10.0, 5.6 Hz), 3.42 (dd, 1H, J = 10.0, 6.4 Hz), 2.43 (s, 3H), 1.70-1.00 (m, 10H), 1.05
1
3
s, 9H), 0.90 (d, 3H, J = 6.4 Hz), 0.78 (d, 3H, J = 6.4 Hz); C NMR (CDCl ) δ 144.7, 135.7,
3
1
2
5
34.2, 133.4, 129.9, 129.6, 128.0, 127.7, 69.2, 68.9, 37.1, 35.81, 35.78, 33.4, 29.3, 27.0, 24.2,
+
1.8, 19.5, 19.3, 17.1; HRMS (ESI/APCl) calcd for C H O NaSiS [MNa ] 589.2778, found
3
3
46
4
89.2793.
(2R,6R)-2,6,10-Trimethyl-undecanol-1 (27): Under argon to the solution of 26 (99.0 mg, 0.175
mmol), copper(I) bromide-dimethyl sulfide complex (20 mg, 0.097 mmol) in anhydrous THF (5
mL) at -78 ºC was added isobutylmagnesium chloride (2.0 M in diethyl ether, 2.0 mL, 4.0
mmol). After stirring at -78 ºC for 2 h, the reaction mixture was allowed to warm to 0 ºC and stir
overnight. The reaction was quenched with saturated ammonium chloride, the organic layer was
separated and the aqueous layer was extracted with ether. The organic layers were combined and
washed with brine and dried over MgSO . After filtration and solvent removal, and the residue
4
was treated with a TBAF solution (1.0 M in THF, 1.0 mL, 1.0 mmol) and allowed to at rt
overnight. After solvent removal, the residue was purified by silica gel chromatography, eluting
29
1
with 10% ethyl acetate hexane to give 27: 36 mg (96% yield). H NMR (CDCl /TMS) δ 3.55-
3
3
0
2
.47 (m, 2H), 1.62 (m, 1H), 1.52 (m, 1H), 1.42-1.00 (m, 13H), 0.92 (d, 3H, J = 6.8 Hz), 0.90-
1
3
.82 (m, 9H); C NMR (CDCl ) δ 68.6, 39.5, 37.5, 37.4, 35.9, 33.6, 32.9, 28.1, 24.9, 24.6, 22.9,
3
2.8, 19.9, 16.8.

ACCEPTED MANUSCRIPT
(2R,6R)-8-Benzyloxy-2,6-dimethyloctanol-1 (28): A TBAF solution (1.0 M solution, 0.50 mL,
0
.50 mmol) was added to a solution of 23 (100 mg, 0.200 mmol) in THF (1.0 mL). After the
mixture was stirred at rt overnight, the solvent was removed, and the residue was purified by
silica gel chromatography, eluting with 15% ethyl acetate in hexane to give 28 as an oil: 51 mg
1
(
96% yield). H NMR (CDCl /TMS) δ 7.40-7.20 (m, 5H), 4.50 (s, 2H), 3.60-3.30 (m, 4H), 1.70-
3
1
3
1
1
.10 (m, 10H), 0.91 (d, 3H, J = 6.8 Hz), 0.87 (d, 3H, J = 6.8 Hz); C NMR (CDCl ) δ 138.8,
3
28.4, 127.7, 127.6, 73.0, 68.8, 68.4, 37.4, 36.9, 35.8, 33.4, 29.9, 24.4, 19.7, 16.7; HRMS
+
(
ESI/APCl) calcd for C H O [MH ] 265.2162, found 265.2162.
1
7
29
2
(2R,6R)-8-Benzyloxy-2,6-dimethyloctyl p-toluenesulfonate (29): To a solution of 28 (49.0 mg,
0
.185 mmol) in pyridine (2.0 mL) at 0 ºC were added DMAP (1.0 mg) and TsCl (71 mg, 0.372
mmol). After the reaction mixture was stirred at rt overnight, the reaction was quenched with
water then extracted with ether. The organic layer was washed successively with 1 N HCl, water,
saturated aqueous NaHCO , and brine, and then dried over MgSO . After filtration and solvent
3
4
removal, the residue was purified by silica gel chromatography, eluting with 5% ethyl acetate in
1
hexane to give 29 as an oil: 56 mg, 72% yield. H NMR (CDCl /TMS) δ 7.78 (d, 2H, J = 9.6
3
Hz), 7.40-7.20 (m, 7H), 4.49 (s, 2H), 3.87 (dd, 1H, J = 6.0, 9.2 Hz), 3.79 (m, 1H, J = 6.4, 9.2
Hz), 3.54-3.40 (m, 2H), 2.44 (s, 3H), 1.85-0.95 (m, 10H), 0.87 (d, 3H, J = 6.8 Hz), 0.84 (d, 3H, J
13
=
6.8 Hz); C NMR (CDCl ) δ 144.7, 138.8, 133.3, 129.9, 128.5, 128.0, 127.7, 127.6, 75.3,
3
7
3.0, 68.7, 37.2, 36.9, 33.0, 32.9, 29.9, 24.0, 21.7, 19.7, 16.5; HRMS (ESI/APCl) calcd for
+
C H O S [MH ] 419.2251, found 419.2259.
24
35
4

ACCEPTED MANUSCRIPT
(3R,7S)-1-Benzyloxy-3,5-dimethylundecane (30): Under argon to a solution of 29 (55 mg, 0.13
mmol), copper (I) bromide-dimethyl sulfide complex (26.7 mg, 0.13 mmol) in anhydrous THF (5
mL) at -78 ºC was added n-propylmagnesium chloride (2.0 M in diethyl ether, 1.3 mL, 2.6
mmol). After the mixture was allowed to stir at -78 ºC then warm up to 0 ºC overnight, the
reaction was quenched with saturated aqueous ammonium chloride. The organic layer was
separated, and the aqueous layer was extracted with ether. After solvent removal, the residue was
purified by silica gel chromatography, eluting with 10% ethyl acetate in hexane to give 30 as an
1
oil: 37 mg (98% yield). H NMR (CDCl /TMS) δ 7.40-7.20 (m, 5H), 4.50 (s, 2H), 3.60-3.40 (m,
3
1
3
2
7
H), 1.70-1.00 (m, 16H), 0.92-0.80 (m, 9H); C NMR (CDCl ) δ 138.8, 128.5, 127.7, 127.6,
3
3.0, 68.9, 37.6, 37.5, 36.99, 36.97, 32.9, 30.0, 29.5, 24.5, 23.2, 19.82, 19.80, 14.3; HRMS
+
(
ESI/APCl) calcd for C H O [M-H] 289.2526, found 289.2518.
2
0
33
(3R,7S)-3,5-Dimethylundecanol-1 (31): 10% Pd on carbon (5.0 mg, 0.047 mmol) was added in
a single portion to a solution of 30 (33 mg, 0.11 mmol) in ethyl acetate (5 mL). The resulting
suspension was saturated with hydrogen gas by 5 vacuum-hydrogen cycles. After stirring at rt
overnight under an H atmosphere, TLC showed the reaction was complete. The catalyst was
2
filtered off, the solvent from the filtrate was removed, and the filtrate residue was purified by
3
6
silica gel chromatography, eluting with 10% ethyl acetate in hexane to give 31 as an oil: 20 mg
1
(
91% yield). H NMR (CDCl /TMS) δ 3.80-3.60 (m, 2H), 1.58 (m, 2H), 1.43-1.02 (m, 14H),
3
1
3
0
1
.92-0.82 (m, 9H); C NMR (CDCl ) δ 61.4, 40.2, 37.6, 37.4, 37.0, 32.9, 29.6, 29.5, 24.5, 23.2,
3
9.8, 19.7, 14.3.
ACKNOWLEDGMENT: We thank A. Hernandez, K. Sundaram, H. Huang, and S. Dasgupta
for helpful discussions and critical comments on the manuscript.

ACCEPTED MANUSCRIPT
SUPPORTING INFORMATION
1
13
H and C NMR spectra for all new compounds.
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(