Asymmetric Total Syntheses of Two Possible Diastereomers of Gliomasolide e and Its Structural Elucidation

Article abstract of DOI:10.1021/acs.joc.6b02611

The first total syntheses of two possible diastereomers of gliomasolide E, a 14-membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was collected from the South China Sea, is reported. Highlights of the synthesis include macrolactonization through intramolecular Horner-Wadsworth-Emmons olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol synthesis as the key reactions. Detailed comparison of their ¹H and ¹³C NMR (1D and 2D NMR data) and specific rotation with those of the natural product revealed that the absolute stereochemistry of gliomasolide E should be (2E,5R,7R,9R,13R).

Full text of DOI:10.1021/acs.joc.6b02611

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Article
Asymmetric Total Syntheses of Two Possible Diastereomers
of Gliomasolide E and its Structural Elucidation
Ramidi Gopal Reddy, Ravula Venkateshwarlu, Kallaganti V. S.
Ramakrishna, Jhillu S. Yadav, and Debendra Kumar Mohapatra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02611 • Publication Date (Web): 19 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
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Asymmetric Total Syntheses of Two Possible Diastereomers of Gliomasolide E and its
Structural Elucidation
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†
,‡
†
§
Ramidi Gopal Reddy, Ravula Venkateshwarlu, Kallaganti V. S. Ramakrishna, Jhillu S.
†,‡
†,‡
Yadav, and Debendra K. Mohapatra*
†
§
Natural Products Chemistry Division, Centre for NMR and Structure Chemistry, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and
Innovative Research (AcSIR, Mathura Road, New Delhi-110 025, India; mohapatra@iict.res.in
‡
OH
OH
OBn O
Base-Induced Elimination
OTBS
Intramolecular
HWE Olefination
H
OR
O
9
PO(OEt)2
HO
O
O
+
RO
O
TBDPSO
O
OBn
Yamaguchi–Hirao
OPMB
5a
7a. R = TBDPS
alkynylation/reduction
8
ABSTRACT: The first total syntheses of two possible diastereomers of gliomasolide E, a 14-
membered macrolides isolated from the marine sponge Phakellia fusca Thiele, which was
collected from the South China Sea, is reported. Highlights of the synthesis include
macrolactonization
through
intramolecular
Horner-Wadsworth-Emmons
olefination,
Yamaguchi-Hirao alkynylation, and base-induced elimination reactions for propargyl alcohol
1
13
synthesis are the key reactions. Detailed comparison of their H and C NMR (1D and 2D NMR
data) and specific rotation with those of the natural product revealed the absolute stereochemistry
of gliomasolide E should be (2E,5R,7R,9R,13R).
______________________________________________________________________________
INTRODUCTION
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Gliomasolides A-E (1–5) (Figure 1) are 14-membered macrolides isolated from a sponge-derived
fungus Gliomastix sp. ZSDS1-F7-2 and from the South China Sea marine sponge Phakellia fusca
0
1
2
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9
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Thiele by Xu et. al. While a plethora of polyketide macrolactones resulting from the propionate
aldol reaction are known in literature, macrolactones devoid of the methyl group are rare in
nature. It was shown that gliomasolide A exhibits moderate in vitro inhibitory activity (IC50 10.1
µM) against HeLa (human epithelial carcinoma cell line) cells. While the structure and absolute
stereochemistry of gliomasolides was established by extensive NMR studies, stereochemistry of
the C9 stereocenter in gliomasolide E left unassigned. Architecturally, gliomasolide E (5)
features a 14-membered macrolactone, (E)-α,β-unsaturated ester, a lipophilic n-pentyl
substitution and four oxygenated methine carbons. The stereochemistry (2E,5R,7R,13R) of 5,
being identical with that of 3, was assumed by the biogenetic viewpoint and the proton coupling
constant of J2,3 (16.0 Hz). However, the stereochemistry at C9 position, which is a stereocenter
2
remote from the C1 and C13 positions, was left undetermined.
3c
A solitary report on the synthesis of gliomasolide C was disclosed by Reddy’s group, while
3
a handful of syntheses were reported for a closely related macrolide natural product Sch725674,
4
5
gloeosporone and others. Coupled with our own efforts in the synthesis of varied bio-active
6
macrolides, and the synthetic challenge to resolve the stereochemistry of the unassigned center
prompted us to embark on the total synthesis of gliomasolide E (5). Herein, we report the first
asymmetric total synthesis of two possible diastereomers (5a) and (5b) (Figure 1) of
gliomasolide E and comparison of their spectroscopic data with that reported for the natural
product, thus ascertaining the stereochemistry of gliomasolide E.
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Figure 1. Structure of gliomasolides A-E (1-5) and sch-725674 (6).
_________________________________________________________________________
Retrosynthetic analysis of gliomasolide E (5a) is outlined in Scheme 1. We envisaged the
formation of the macrolactone of 5a and its 9-epimer 5b by a late stage intramolecular
7
macrocyclization using Horner-Wadsworth-Emmons olefination as the key step. The precursor
8
7a could be accessible from epoxide 8 and alkyne 9 via Yamaguchi–Hirao alkynylation. The
epoxide fragment 8 could be obtained from homoallylic alchol 10 by employing Bartlett–Smith
9
iodocarbonate cyclization reaction, which in turn could be prepared from chiral epoxide 11. The
alkyne fragment 9 could be generated by utilizing base-induced protocol on corresponding epoxy
alcohol, which could be easily attainable from commercially available n-hexanal (12).
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Scheme 1. Retrosynthetic Analysis
OH
OBn O
0
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2
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7
8
9
0
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9
0
Intramolecular
HWE Olefination
H
OH
OR
O
HO
O
O
PO(OEt)2
RO
O
Yamaguchi–Hirao
7a. R = TBDPS
alkynylation/reduction
5a
Base-Induced
Elimination
TBDPSO
O
OTBS
OBn
OPMB
OPMB
8
9
OH OBn
Hexanal
1
2
1
0
O
OPMB
11
______________________________________________________________________________
RESULTS AND DISCUSSION
The synthesis commenced with the preparation of the epoxide intermediate 8 which is outlined
in Scheme 2. Enantiopure epoxide 11, prepared from commercially available L-aspartic acid in
10
three steps following literature protocol, was treated with vinylmagnesium bromide in the
o
11
presence of CuI at −78 C to furnish optically active homoallylic alcohol 13 in 93% yield.
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Scheme 2. Synthesis of the Epoxide Fragment 8
MgBr
CuI, THF
Ref. 7
O
L-Aspartic acid
OH
OPMB
o
10
11
12
13
14
15
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-
78 C-rt, 2 h
1
1
9
3%
Bn-Br, NaH
TBAI, THF
OBn
OPMB
OPMB
0 oC-rt, 12 h
95%
1
3
14
i) OsO ,1,4-
4
dioxane-H O,
2
NaIO , 2,6-lutidine
(Boc)2O, Et3N
4
OH OBn
rt, 3 h, 86%
DMAP, CH Cl2
2
OPMB
ii) Allyl(tributyl)
stannane
10
rt, 6 h, 92%
MgBr ·Et O, CH Cl
2
2
2
2
O
o
0 C, 3 h, 91%
K CO
MeOH
2
3
O
O
OBn OPMB
OBocOBn OPMB NIS, CH CN
3
o
o
-
40 C-0 C
4 h, 89%
rt, 1 h
8
16
5%
15
I
TBDPS-Cl
imidazole, DMAP O
OH OBn
OPMB
OR OBn OPMB
O
CH Cl , rt
2
2
17
5 h, 93%
8. R = TBDPS
Protection of the hydroxy group as its benzyl ether with benzyl bromide and NaH in presence
of tetra-butyl ammonium iodide (TBAI) afforded compound 14 in 95% yield. One-pot oxidative
1
2
cleavage of the terminal double bond present in 14 using Jin’s protocol afforded the
corresponding unstable aldehyde, which was immediately subjected to chelation-controlled
13
diastereoselective allylation by treatment with allyl(tributyl)stannane
MgBr ·Et O to obtain homoallyl alcohol 10 in 91% yield as the only stereoisomer. The
stereochemical assignment of the secondary hydroxy bearing center was achieved following
in presence of
2
2
14
modified Mosher’s method. Accordingly, compound 10 was converted to its (S)- and (R)-
(MTPA) ester with α-methoxy-α-(trifluoromethyl)phenyl acetic acid which showed negative
chemical shift differences (Δδ = δ
S
− δ ) for protons on C5 through C8 while protons on C1
R
through C3 showed positive differences, which is consistent with C4 bearing an R-configuration.
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After confirming the stereocenter, compound 10 was treated with di-tert-butyl carbonate in
presence of DMAP to form the homoallyl tert-butyl-carbonate 15 in 92% yield. The next
stereogenic center with the desired stereochemistry was achieved via Bartlett-Smith iodo-
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carbonate cyclization protocol. Accordingly, treatment of compound 15 with N-iodosuccinimide
o
in CH
3
CN at 0 C, produced the desired iodo-carbonate derivative 16 in 89% yield as the only
product. The iodo derivative 16 on treatment with K
2
CO in methanol at room temperature
3
underwent rapid hydrolysis and facile epoxidation to obtain the epoxy alcohol 17 in 85% yield.
2 2
The secondary alcohol was protected as its silyl ether using TBDPSCl and imidazole in CH Cl
o
at 0 C to afford epoxide fragment 8 in 93% yield.
As outlined in Scheme 3, the synthesis of the second fragment 9 started with the
16
transformation of commercially available hexanal (12) into the allylic alcohol 18 in two steps.
The first step was two carbon homologation of hexanal (12) using (ethoxycarbonylmethylene)
2 2
triphenylphosphorane in CH Cl to furnish α,ß-unsaturated ester with E-configuration in 85%
yield, followed by reduction with DIBAL-H in CH
2
Cl to obtain the corresponding allylic alcohol
2
Scheme 3. Synthesis of the Fragment 9
_
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8 in 87% yield. The Sharpless asymmetric epoxidation of (E)-2-octenol (18) using (−)-DET
i
o
18
and Ti( PrO)
4 2 2
in CH Cl
at −20 C furnished epoxy alcohol 19 in 93% yield. Compound 19 was
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converted to the corresponding (chloromethyl)oxirane using CCl
4
-Ph
3
P under reflux conditions
9
followed by Yadav’s protocol of base-induced elimination reaction to afford the chiral
19
propargylic alcohol 20 in 81% yield over two steps. The alkynol 20 was treated with TBSCl
20
and imidazole in CH
2
Cl to furnish silyl ether 9 in 94% yield.
2
Having secured both the coupling partners 8 and 9, the stage was set to examine the opening
8
of epoxide 8 with the alkyne 9 under the Yamaguchi–Hirao protocol (Scheme 4). Accordingly,
3 2
treatment of alkyne 9 with n-BuLi followed by addition to epoxide 8 with BF ·Et O (in a
separate round bottomed flask) in THF afforded the homopropargyl alcohol 21 in 85% yield. The
hydroxy functionality of homopropargyl alcohol 21 was protected as its TBDPS ether with
2 2
TBDPS-Cl and imidazole in CH Cl to obtain compound 22 in 91% yield. The TBS group in
compound 22 was selectively removed by using PPTS in methanol and subsequent diimide-
21
mediated reduction of triple bond using TsNHNH
2
furnished saturated alcohol 23a in 86%
yield over two steps. The free hydroxy group in compound 23a was then coupled with 2-
22,23
(diethoxyphosphoryl)acetic acid
using N,N′-Dicyclohexylcarbodiimide (DCC) to afford the
phosphonoester 24a in 87% yield. Oxidative removal of PMB ether by treating with ceric
ammonium nitrate (CAN) provided penultimate alcohol 25a. Oxidation of the primary alcohol
24
2
5a with Dess-Martin periodinane (DMP) furnished macrocyclization precursor phosphonate-
aldehyde 7a, which was immediately subjected to an intramolecular Horner-Wadsworth-
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Scheme 4. Synthesis of the Macrocycle 5a through Intramolecular Horner-Wadsworth-
Emmons Olefination
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
TBDPSO
OBn
O
OTBS
OPMB
n-BuLi, BF ·Et O
OTBDPS
OBn
8
+
OR
3
2
4
OPMB
o
OTBS
THF, -78 C
21, R  H
TBDPSCl, imidazole
2
h, 85%
DMAP, CH Cl , rt
2
2
22, R  TBDPS
3
h, 91%
9
OBn
i) (EtO) P(O)CH CO H
2
2
2
OPMB
i) PPTS, MeOH, rt
6 h, 94%
DCC, DMAP, CH Cl
2
2
OTBDPS
OH
rt, 12 h, 87%
ii) TsNHNH , NaOAc
2
TBDPSO
ii) CAN, CH3CN/H2O
0 oC, 30 min, 89%
o
THF, H O, 90 C
2
12 h, 92%
2
3a
OBn O
H
OBn
DMP, NaHCO3
CH Cl
OR
OTBDPS
2
2
OTBDPS
o
0 C, 1 h, 86%
TBDPSO
OCOCH PO(OEt)
2
TBDPSO
OC(O)CH P(O)(OEt)
2
2
2
7
a
24a, R = PMB
25a, R = H
OBn
OH
LiCl, DBU, CH CN
TiCl , CH Cl
4 2 2
3
OR
O
OH
rt, 1 h, 75%
rt, 12 h, 82%
RO
O
HO
O
O
2
6a R = TBDPS
5a
____________________________________________________________________________
25
Emmons reaction under Masamune−Roush conditions (LiCl, DBU, MeCN, rt, 12 h) to
establish the desired 14-membered macrolactone 26a as a sole E-olefinic isomer in 80% yield.
26
Global deprotection was achieved by treating 26a with excess TiCl
4 2 2
in CH Cl to complete the
total synthesis of 5a in 75% yield.
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After achieveing the synthesis of 5a, total syntheis of 5b was initiated. For the same, the
21
alkyne 21 was reduced to alkane 27 in 90% yield by treating excess diimide as explained
10
11
12
13
14
15
16
17
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2
7
earlier (Scheme 5). Mitsunobu inversion of the secondary alcohol (C9) group present in 27
using benzoic acid, Ph P and DIAD in THF at 0 °C followed by hydrolysis under basic
conditions (K CO , MeOH) afforded the required alcohol 28 in 70% yield over two steps.
3
2
3
Scheme 5. Synthesis of the Macrocycle 5b
_
_____________________________________________________________________________
The hydroxy group present in 28 was protected as its TBDPS ether in 93% yield and subsequent
selective deprotection of TBS group using PPTS provided phosphonate ester precursor 23b in
9
2% yield. Following similar sequence of reactions (five steps) as reported in Scheme 4 for the
synthesis of 5a, macrolactone 5b was obtained.
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Having completed the total syntheses of 5a and 5b, the structures were established by H
13
3
NMR and C NMR data (600 MHz, CD OD) and the data of 5a were found to be in full
0
1
2
3
4
5
6
7
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9
0
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13
agreement with those reported for the natural product. On the other hand, the H and C NMR
2
data of 5b were clearly different from those of the natural product. The selected chemical shift
difference between the natural product and the synthetic products 5a and 5b are described in
Table 1.
Table 1. Selected Chemical Shift Difference in ppm between Natural Gliomasolide E and
1
13
a
3
the Synthetic Products 5a and 5b in the H and C NMR (CD OD)
Position
Synthetic
a (9R)
Synthetic Synthetic Synthetic
5b (9S) 5a (9R) 5b (9S)
5
1
1
13
13
H NMR
∆δN-S
0.01
H NMR
∆δN-S
0.21
C NMR
∆δN-S
0.0
C NMR
∆δN-S
1.2
3
4
0.02
−0.20
−0.06
0.30
0.0
2.4
0
.02
0.00
.00
6
0.0
−2.9
0
7
8
0.02
0.03
0.02
0.02
−0.03
−0.17
0.1
0.0
1.8
3.2
1
0
3
−0.19
0.1
0.5
0
.02
1
0.01
0.01
0.71
0.08
0.1
0.0
0.9
17
−1.0
a
NMR spectra of the natural product and the synthetic products were recorded at 600 MHz (150 MHz). Chemical
N S
shifts are reported in ppm with reference to the residual solvent. δ and δ are chemical shifts of the natural product
and the synthetic product, respectively.
_
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Significant deviations between the natural product and the synthetic 5b were observed at the
1
C3, C4, C7, C10, and C13 positions in the H NMR data and at the C3, C4, C6, C7, C8, C10,
10
11
12
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1
3
C13, and C17 positions in the C NMR data. The measured specific rotation of the synthetic 5a,
25
[α]
D
−92.7 (c 0.15, CH OH) was consistent with the sign of the specific rotation of the natural
3
25
D
2
product, [α]
−174 (c 0.15, CH OH). The assignment of protons and carbons were made with
3
the help of 2D NMR (TOCSY, NOESY, HSQC and HMBC) experiments. In 5a, the coupling
between H2/H3 (J = 16.1 Hz) shows that these protons are anti-periplanar arrangement and the
5a
5
b
Figure 2. Energy minimized structure of 5a and 5b along with the characteristic nOe
interactions.
characteristic nOe correlation between H3/H7, H3/H5, H3/H9 and H2/H4 H2/H4' confirmed the
assigned structure where as in case of 5b, nOe correlation between H3/H9 was absent (Figure 2).
The energy minimized structure as shown in Figure 2 is also in agreement with the assigned
structures and stereochemistry proposed for the compounds 5a and 5b from NMR data.
Therefore, the absolute configuration of gliomasolide E was elucidated to be (2E,5R,7R,9R,13R)
as depicted in 5a.
CONCLUSIONS
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In summary, the total syntheses of two possible diastereomers of gliomasolide E have been
achieved following macrolactonization through intramolecular Horner-Wadsworth-Emmons
olefination, Yamaguchi-Hirao alkynylation, and base-induced elimination reaction for propargyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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0
1
13
alcohol synthesis as the key steps. Detailed comparison of their H and C NMR data and
specific rotation with those of the natural product revealed the absolute stereochemistry of
gliomasolide E should be (2E,5R,7R,9R,13R). Following the same protocol, syntheses of other
family members are in progress and will be reported in due course.
EXPERIMENTAL SECTION
General methods: Experiments which required an inert atmosphere were carried out under
argon in flame-dried glassware. Et
2
O and THF were freshly distilled from sodium/benzophenone
ketyl and transferred via syringe. Dichloromethane was freshly distilled from CaH
2
. Tertiary
amines were freshly distilled over KOH. Commercially available reagents were used as received.
Unless detailed otherwise, "work-up" means pouring the reaction mixture into brine, followed by
extraction with the solvent indicated in parenthesis. If the reaction medium was acidic (basic), an
additional washing with saturated aqueous NaHCO
3
solution (saturated aqueous NH
4
Cl
solution) was performed. Washing with brine, drying over anhydrous Na
2
SO and evaporation of
4
the solvent under reduced pressure followed by chromatography on a silica gel column (60-120
mesh) with the indicated eluent furnished the corresponding products. Where solutions were
filtered through a Celite pad, the pad was additionally washed with the same solvent used, and
1
13
the washings incorporated to the main organic layer. H and C NMR chemical shifts are
reported in ppm downfield from tetramethylsilane and coupling constants (J) are reported in
hertz (Hz). High resolution mass spectra were run by the electron impact mode (ESIMS, 70 eV)
or by the FAB mode (m-nitrobenzyl alcohol matrix), using an orbitrap mass analyzer. IR data
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were measured with oily films on NaCl plates (oils) or KBr pellets (solids). Specific optical
-1
2
-1
D
rotations [α] are given in 10 deg cm g and were measured at 20°C or otherwise mentioned.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintet, m = multiplet, br = broad.
(S)-1-((4-Methoxybenzyl)oxy)hex-5-en-3-ol (13): To a solution of chiral epoxide 11 (10.0 g,
48.01 mmol) in dry THF (150 mL), CuI (0.91 g, 4.80 mmol) was added and the mixture was
o
o
stirred at 25 C for 30 min. It was cooled to −20 C and vinyl magnesium bromide (96.03 mL,
M in THF, 96.03 mmol) was slowly added at the same temperature. It was allowed to stir for
another 2 h at the same temperature. The reaction (monitored by TLC) was quenched with
saturated aqueous NH Cl solution (100 mL) and diluted with ethyl acetate (100 mL). The two
layers were separated and aqueous layer extracted with ethyl acetate (2 × 100 mL). The
combined organic layer was washed with brine (2 × 200 mL), dried over anhydrous Na SO , and
1
4
2
4
concentrated under reduced pressure to give the crude product which was then purified by
column chromatography over silica gel (ethyl acetate/hexane = 1:9) to afford the corresponding
20
allylic alcohol 13 (10.55 g, 93%) as a colorless liquid. [α]
D
−8.5 (c 0.35, CHCl
3
); IR (neat): ν
): δ
7.25 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.88-5.78 (m, 1H), 5.13-5.06 (m, 2H), 4.45 (s,
−
1 1
3
439, 2926, 2861, 1612, 1513, 1452, 1247, 1090, 1032 cm ; H NMR (400 MHz, CDCl
3
2
1
H), 3.85 (m, 1H), 3.80 (s, 3H), 3.71-3.58 (m, 2H), 2.90 (br s, 1H), 2.24 (t, J = 6.3 Hz, 2H),
13
3
.78-1.72 (m, 2H) ppm; C NMR (100 MHz, CDCl ): δ 159.2, 134.8, 129.9, 129.2, 117.4,
20 3
113.7, 72.8, 70.4, 68.5, 55.2, 41.8, 35.7 ppm; HRMS (ESI) m/z calcd. For C14H O Na [M +
+
Na] :259.1305, found: 259.1320.
(S)-1-(((3-(Benzyloxy)hex-5-en-1-yl)oxy)methyl)-4-methoxybenzene (14): To a suspension
of NaH (5.17 g, 129.49 mmol, 60% w/v dispersion in mineral oil) in anhydrous THF (60 mL),
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5
5
5
5
5
5
5
6
was added dropwise a solution of homoallyl alcohol 13 (10.2 g, 43.16 mmol) in THF (100 mL)
o
at 0 C. To this reaction mixture, tetra-butyl ammonium iodide (catalytic) and benzyl bromide
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(7.69 mL, 64.74 mmol) were added subsequently and stirring was continued for 12 h at room
temperature. The reaction mixture was quenched by small crushed ice flakes until a clear
solution formed. The reaction mixture was extracted with ethyl acetate (3 × 100 mL). The
organic extracts were washed with water (200 mL), brine (200 mL) and dried over anhydrous
2 4
Na SO . Evaporation of solvents followed by purification of the crude product by silica gel
column chromatography (ethyl acetate/hexane = 1:19) afforded the product 14 (13.38 g, 95%) as
2
0
a colorless liquid. [α]
D
+40.5 (c 0.60, CHCl
1092, 1033 cm ; H NMR (400 MHz, CDCl
.86 (d, J = 8.6 Hz, 2H), 5.90-5.80 (m, 1H), 5.12-5.04 (m, 2H), 4.50 (q, J = 11.4 Hz, 2H), 4.40
q, J = 11.4 Hz, 2H), 3.79 (s, 3H), 3.69-3.62 (m, 1H), 3.60-3.50 (m, 2H), 2.36-2.31 (m, 2H),
3
); IR (neat): ν 3447, 2929, 2858, 1612, 1512, 1247,
−1 1
3
): δ 7.35-7.26 (m, 5H), 7.24 (d, J = 8.6 Hz, 2H),
6
(
13
1.84-1.79 (m, 2H) ppm; C NMR (125 MHz, CDCl
3
): δ 159.0, 138.7, 134.6, 130.5, 129.2,
128.2, 127.7, 127.4, 117.1, 113.7, 75.5, 72.5, 71.2, 66.4, 55.1, 38.5, 34.3 ppm; HRMS (ESI) m/z
+
26 3
calcd. For C21H O Na [M + Na] :349.1774, found: 349.1777.
(
4R,6R)-6-(Benzyloxy)-8-((4-methoxybenzyl)oxy)oct-1-en-4-ol (10): To a stirred solution
of alkene 14 (12.0 g, 36.76 mmol) in 1,4-dioxane/water (3:1; 100 mL), 2,6-lutidine (8.51 mL,
3.52 mmol), OsO (0.18 g, 0.73 mmol) followed by NaIO (31.45 g, 147.04 mmol) were
7
4
4
sequentially added at room temperature and the reaction mixture was stirred for 3 h. After
completion of the reaction (monitored by TLC), 1,4-dioxane was removed under reduced
pressure and the residue was diluted with CH
the aqueous layer extracted with CH Cl (3 × 50 mL). The combined organic layer was quickly
washed with 1N HCl (2 × 50 mL) to remove excess 2,6-lutidine followed by brine (2 × 100 mL),
2
Cl
2
(50 mL). The organic layer was separated and
2
2
dried over anhydrous Na
2
SO
4
, and concentrated under reduced pressure. The crude product was
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purified by a short flash silica gel column chromatography (ethyl acetate/hexane = 1:9) to afford
the corresponding aldehyde (10.38 g, 86%) as a colorless liquid, that was used immediately for
the next reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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60
A solution of the above aldehyde (10.38 g, 31.60 mmol) in anhydrous CH
2
Cl
2
(120 mL) was
treated with MgBr ·Et O (24.28 g, 94.82 mmol) and allyl(tributyl)stannane (12.24 mL, 37.92
2
2
mmol) at 0 °C and the mixture was stirred for 3 h. The mixture was then quenched with 2 M HCl
solution (30 mL). The resultant mixture was warmed to room temperature and extracted with
2 2 2 4
CH Cl (3 × 60 mL). The combined organic layers were dried over anhydrous Na SO and
concentrated. The residue was purified by column chromatography (ethyl acetate/hexane = 1:9)
2
D
0
to afford homoallylic alcohol 10 (10.65 g, 91%) as a colorless liquid. [α]
CHCl ); IR (neat): ν 3448, 2934, 2863, 1714, 1608, 1512, 1251, 1172, 1095, 1031 cm ; H
NMR (400 MHz, CDCl ): δ 7.35-7.27 (m, 5H), 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 5.85-5.75 (m, 1H), 5.12-5.06 (m, 2H), 4.53 (q, J = 17.1, 11.3 Hz, 2H), 4.40 (d, J = 2.0 Hz,
−5.1 (c 0.56,
−1
1
3
3
2
1
1
H), 3.97-3.87 (m, 1H), 3.80 (s, 3H), 3.58-3.48 (m, 2H), 2.23-2.18 (m, 2H), 2.04-1.95 (m, 1H),
13
.86-1.69 (m, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 159.1, 138.2, 134.8, 130.3, 129.3,
28.3, 127.9, 127.6, 117.4, 113.7, 74.4, 72.6, 71.5, 67.7, 66.3, 55.2, 42.1, 39.7, 34.0 ppm; HRMS
+
(
ESI) m/z calcd. For C23
H
30
O
4
Na [M + Na] : 393.2036, found: 393.2041.
(S)-Mosher esters of alcohol (10a): To a solution of homoallylic alcohol 10 (15 mg, 0.04
mmol) in CH Cl (2 mL) were added N,N-dicyclohexylcarbodiimide (DCC) (15 mg, 0.07 mmol),
2
2
(S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (S-MTPA) (14 mg, 0.06 mmol) and a
catalytic amount of DMAP (3 mg) simultaneously. The reaction was stirred overnight at room
3
temperature and quenched with saturated aqueous NaHCO solution (2 mL). Then the reaction
mixture was extracted with CH Cl (2 × 5 mL). The combined organic layer was dried over
2
2
anhydrous Na SO
2 4
, filtered and evaporated under reduced pressure. The crude product was
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
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4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
purified by silica gel column chromatography (ethyl acetate/hexane = 19:1) to afford (S)-MTPA
1
ester 10a (19 mg, 83%) as a colorless liquid. H NMR (500 MHz, CDCl
3
): δ 7.55 (d, J = 6.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2H), 7.39-7.27 (m, 8H), 7.22 (d, J = 8.6, 2H), 6.86 (d, J = 8.6, 2H), 5.74 (m, 1H), 5.46 (m, 1H),
5
3
.10 (m, 1H), 5.07 (m, 1H), 4.44-4.30 (m, 4H), 3.80 (s, 1H), 3.56-3.50 (m, 3H), 3.48 (m, 1H),
.46-3.40 (m, 2H), 2.47-2.41 (m, 2H), 1.84 (m, 1H), 1.79-1.69 (m, 3H).
(R)-Mosher Esters of Alcohol (10b): The reaction of (R)-(+)-α-methoxy-α-
(trifluoromethyl)phenylacetic acid (R-MTPA) with the alcohol 10 similarly afforded the (R)-
1
MTPA ester 10b. H NMR (500 MHz, CDCl
3
): δ 7.54 (d, J = 6.8, 2H), 7.40-7.26 (m, 8H), 7.22
(
d, J = 8.6, 2H), 6.85 (d, J = 8.6, 2H), 5.62 (m, 1H), 5.44 (m, 1H), 5.02 (m, 1H), 4.98 (m, 1H),
4.48-4.30 (m, 4H), 3.79 (s, 1H), 3.59 (m, 1H), 3.52 (m, 1H), 3.49-3.46 (3H), 3.43 (m, 1H), 2.46-
.30 (m, 2H), 1.90 (m, 1H), 1.84-1.71 (m, 3H).
4R,6R)-6-(Benzyloxy)-8-((4-methoxybenzyl)oxy)oct-1-en-4-yl tert-butyl carbonate (15):
To a stirred solution of alcohol 10 (7.50 g, 20.24 mmol) in anhydrous CH Cl (80 mL), di-tert-
butyl dicarbonate [(Boc) O; 13.95 mL, 60.73 mmol], followed by Et N (5.65 mL, 40.48 mmol)
and DMAP (0.24 g, 2.02 mmol) were added at room temperature. After stirring for 6 h, the
reaction was quenched with 5% aqueous KHSO solution (50 mL). The organic layer was
separated and the aqueous layer extracted with CH Cl (3 × 60 mL). The combined organic layer
was washed with brine (100 mL), dried over anhydrous Na SO and concentrated under reduced
2
(
2
2
2
3
4
2
2
2
4
pressure. The crude product was purified by column chromatography over silica gel (ethyl
acetate/hexane = 1:19) to give the Boc-protected compound 15 (8.76 g, 92%) as a colorless
20
liquid. [α]
D
−19.2 (c 0.40, CHCl
3
); IR (neat): ν 3420, 2977, 2934, 2863, 1736, 1513, 1278,
): δ 7.34-7.26 (m, 5H), 7.25 (d, J = 6.8
Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.83-5.72 (m, 1H), 5.11-4.99 (m, 2H), 4.45 (q, J = 16.1, 10.6,
−1 1
1
251, 1166, 1094, 1034 cm ; H NMR (400 MHz, CDCl
3
2
H), 4.41 (q, J = 14.0, 11.6, 2H), 3.80 (s, 3H), 3.74-3.66 (m, 1H), 3.60-3.48 (m, 2H), 2.38-2.33
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(
m, 2H), 1.91-1.79 (m, 2H), 1.77-1.73 (m, 2H), 1.47 (s, 9H) ppm; C NMR (125 MHz, CDCl
3
):
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 159.0, 153.1, 138.3, 133.3, 130.4, 129.1, 128.2, 128.0, 127.4, 117.8, 113.6, 81.5, 73.2, 73.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
38 6
72.5, 72.0, 66.1, 55.1, 39.4, 39.2, 34.5, 27.7 ppm; HRMS (ESI) m/z calcd. For C28H O Na [M +
+
Na] :493.2560, found: 493.2568.
(4S,6S)-4-((R)-2-(Benzyloxy)-4-((4-methoxybenzyl)oxy)butyl)-6-(iodomethyl)-1,3-dioxan-
2
-one (16): To a stirred solution of carbonate 15 (8.50 g, 18.06 mmol) in acetonitrile (80 mL),
o
was added N-iodosuccinimide (6.09 g, 27.09 mmol) at −40 C. The resulting mixture was
o
warmed up and stirred at 0 C for 4 h. After completion of the reaction (monitored by TLC), it
was quenched with aqueous Na
NaHCO solution (30 mL). Acetonitrile was removed under reduced pressure and the aqueous
layer extracted with CH Cl (3 × 60 mL). The combined organic layer was washed with brine
100 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The crude
2 2 3
S O solution (30 mL), followed by of saturated aqueous
3
2
2
(
2
4
product was quickly purified by flash column chromatography over silica gel (ethyl
acetate/hexane = 2:3) to furnish the desired iodo-carbonate derivative 16 (8.68 g, 89%) as a
colorless liquid, which was not very stable and used immediately.
(2S,4R)-4-(Benzyloxy)-6-((4-methoxybenzyl)oxy)-1-((S)-oxiran-2-yl)hexan-2-ol (17): To a
solution of iodocarbonate 16 (8.50 g, 18.06 mmol) in MeOH (150 mL), K CO (6.09 g, 27.09
2
3
mmol) was added and the resulting mixture was stirred at room temperature for 1 h. After
completion of the reaction (monitored by TLC), MeOH was evaporated under reduced pressure.
2
The residue was diluted with H O (40 mL) and extracted with ethyl acetate (3 × 60 mL). The
combined organic phase was washed with brine (75 mL), dried over anhydrous Na
2
SO and
4
concentrated under reduced pressure to obtain the crude product, which on purification by
column chromatography over silica gel (ethyl acetate/hexane = 3:7) afforded the desired epoxy
20
alcohol 17 (5.10 g, 85%) as a colorless liquid. [α]
D
3
+3.7 (c 0.32, CHCl ); IR (neat): ν 3449,
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
5
5
5
5
5
5
5
6
−
1 1
2
924, 2856, 1612, 1509, 1245, 1090, 1033 cm ; H NMR (400 MHz, CDCl
3
): δ 7.36-7.27 (m,
5
H), 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.54 (q, J = 16.8, 11.3 Hz, 2H), 4.40 (d, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
= 2.0 Hz, 2H), 4.16-4.10 (m, 1H), 3.95-3.89 (m, 1H), 3.79 (s, 3H), 3.59-3.49 (m, 2H), 3.09-3.04
(
m, 1H), 2.76-2.74 (m, 1H), 2.49-2.46 (m, 1H), 2.05-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.73-1.58
13
(m, 3H) ppm; C NMR (125 MHz, CDCl
3
): δ 159.1, 138.1, 130.2, 129.3, 128.4, 127.9, 127.7,
1
13.7, 74.4, 72.6, 71.6, 66.7, 66.2, 55.2, 49.9, 46.5, 40.1, 40.0, 33.9 ppm; HRMS (ESI) m/z
+
30 5
calcd. For C23H O Na [M + Na] :409.2009, found: 409.1984.
(
((2S,4R)-4-(Benzyloxy)-6-((4-methoxybenzyl)oxy)-1-((S)-oxiran-2-yl)hexan-2-
yl)oxy)(tert-butyl)diphenylsilane (8): To a stirred solution of alcohol 17 (4.50 g, 11.64 mmol)
in CH Cl (50 mL) under nitrogen atmosphere at room temperature, was added TBDPSCl (6.40
2
2
g, 23.28 mmol), imidazole (2.37 g, 34.93 mmol) and DMAP (0.14 g, 1.16 mmol). The reaction
mixture was stirred at room temperature for 5 h. After completion (monitored by TLC), the
reaction was quenched with water (50 mL). The organic layer was separated and the aqueous
layer extracted with CH
2 2 2 4
Cl (2 × 50 mL). The combined organic layer was dried over Na SO ,
filtered, and concentrated. The crude product was purified by silica gel column chromatography
20
D
over silica gel (ethyl acetate/hexane = 1:9) to give 8 (6.76 g, 93%) as a colorless liquid. [α]
−1
1
+
12.6 (c 0.63, CHCl
NMR (500 MHz, CDCl
d, J = 6.8 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.36-4.30 (m, 3H), 4.18 (d, J = 11.2 Hz, 1H), 4.13-
4.08 (m,1H), 3.79 (s, 3H), 3.64-3.58 (m, 1H), 3.48-3.36 (m, 2H), 3.08-3.03 (m, 1H), 2.64 (t, J =
.7 Hz, 1H), 2.30 (q, J = 5.0, 2.7 Hz, 1H), 1.99-1.94 (m, 1H), 1.75-1.59 (m, 5H), 1.06 (s, 9H)
3
); IR (neat): ν 3447, 2930, 2856, 1616, 1512, 1247, 1106, 770, 702 cm ; H
3
): δ 7.69-7.64 (m, 4H), 7.41-7.25 (m, 9H), 7.21(d, J = 8.5 Hz, 2H), 7.10
(
4
13
3
ppm; C NMR (100 MHz, CDCl ): δ 159.0, 138.7, 135.9, 134.0, 130.5, 129.6, 129.2, 128.1,
127.5, 127.2, 113.6, 73.5, 72.5, 70.6, 69.0, 66.3, 55.2, 48.8, 46.4, 42.3, 39.8, 34.3, 26.9, 19.3
+
ppm; HRMS (ESI) m/z calcd. For C39
H
48
O
5
NaSi [M + Na] : 647.3163, found: 647.3175.
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(
E)-Oct-2-en-1-ol (18): To a stirred solution of the commercially available hexanal (12) (6.0
g, 59.91 mmol) in CH Cl (100 mL) was added (ethoxycarbonylmethylene)
2
2
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
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39
40
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
triphenylphosphorane (31.30 g, 89.86 mmol) at room temperature and stirred for 5 h. The
reaction mixture was concentrated under reduced pressure and purified by silica gel column
chromatography using (ethyl acetate/hexane = 1:19) to give pure α,β-unsaturated ester (9.02 g,
90%) as a colorless liquid. IR (neat): ν 3422, 2927, 2861, 1721, 1655, 1267, 1171, 1044, 758
−1 1
cm ; H NMR (500 MHz, CDCl
3
): δ 6.97 (dt, J = 15.7, 7.0 Hz, 1H), 5.81 (dt, J = 15.7, 3.2 Hz,
1
H), 4.18 (q, J = 7.1 Hz, 2H), 2.19 (dq, J = 7.1, 1.5 Hz, 2H), 1.46 (qt, J = 7.4 Hz, 2H), 1.35-1.27
13
(
m, 7H), 0.89 (t, J = 6.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 166.6, 149.3, 121.1, 60.0,
18 2
32.0, 31.2, 27.6, 22.3, 14.2, 13.8 ppm; CHN analysis calcd. For C10H O : C, 70.55; H, 10.66;
Found: C, 70.43; H, 10.71.
To a stirred solution of the above α,β-unsaturated ester (8.6 g, 50.51 mmol) in anhydrous
CH Cl (75 mL) was added DIBAL-H (1.4 M solution in toluene 90.20 mL, 126.29 mmol) over
2
2
a period of 15 min at 0 °C under nitrogen atmosphere. After 30 min of stirring at the same
temperature, TLC was checked which showed complete consumption of starting material. It was
quenched by slow addition of saturated solution of sodium potassium tartrate (80 mL), diluted
with CH
separated layers. The organic layer was separated and the aqueous layer extracted with CH
2 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over
anhydrous Na SO and evaporated under reduced pressure. The crude product was purified on
2
Cl
2
(75 mL) and allowed to stir at room temperature for another 2 h to get a clear two
Cl
2 2
(
2
4
silica gel column chromatography (ethyl acetate/ hexane = 1:9) to afford the desired allylic
alcohol 18 (5.63 g, 87%) as a colorless liquid. IR (neat): ν 3383, 2925, 2859, 1457, 1085, 974
−1 1
cm ; H NMR (400 MHz, CDCl
3
): δ 5.73-5.57 (m, 2H), 4.08 (d, J = 5.6 Hz, 2H), 2.08-2.01 (m,
13
2
H), 1.42-1.24 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl ): δ 133.3,
3
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1
2
2
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2
2
2
2
2
2
2
3
3
3
3
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3
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5
5
5
5
5
5
5
5
6
1
28.7, 63.6, 32.1, 31.3, 28.7, 22.4, 13.9 ppm; CHN analysis calcd. For C
2.58; Found: C, 74.85; H, 12.49.
8
H16O: C, 74.94; H,
1
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
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7
8
9
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9
0
1
2
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7
8
9
0
((2R,3R)-3-Pentyloxiran-2-yl)methanol (19): To a freshly flame dried double necked round
bottom flask equipped with activated 4 Å molecular sieves (~13.0 g) and dry CH
2
Cl (180 mL)
2
o
at –20 C were added Ti(i-OPr)
4
(3.58 mL, 12.12 mmol), (‒)-diethyl tartrate (2.48 mL, 14.54
mmol) and the mixture was stirred for 40 min. To this reaction mixture was added allylic alcohol
18 (5.18 g, 40.40 mmol) in an interval of 30 min. and TBHP (10.77 mL, 64.60 mmol, 6.0 M
solution in toluene) were added and stirring was continued till completion of the reaction. The
o
reaction mixture was warmed to 0 C and filtered through Celite pad. The filtrate was quenched
with water (75 mL), 15% aqueous NaOH solution (15 mL) and stirred vigorously for 3 h. The
biphasic solution was separated and aqueous layer was extracted with CH
The combined organic extract was dried over anhydrous Na SO and concentrated in reduced
pressure. The crude residue was purified by column chromatography (ethyl acetate/hexane = 1:4)
2 2
Cl (2 × 100 mL).
2
4
20
to afford the pure epoxide 19 (5.41 g, 93%) as a colorless liquid. [α]
D
+17.1 (c 1.2, CHCl
neat): ν 3414, 2927, 2862, 1461, 1076, 1030, 884 cm ; H NMR (400 MHz, CDCl ): δ 3.91
dq, J = 12.6, 2.4 Hz, 1H), 3.65-3.59 (m, 1H), 2.96 (td, J = 5.6, 2.4 Hz, 1H), 2.92 (dt, J = 4.5, 2.5
O exchangeable), 1.60-1.55 (m, 2H), 1.51-1.40 (m, 2H),
3
); IR
−1
1
(
(
3
Hz, 1H), 1.91 (t, J = 5.9 Hz, 1H, D
2
13
1
.36-1.29 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 61.7, 58.6,
56.0, 31.4, 25.4, 22.4, 13.8 ppm; CHN analysis calcd. For C : C, 66.63; H, 11.18; Found:
8 16
H O
2
C, 66.75; H, 11.24.
R)-Oct-1-yn-3-ol (20): To a stirred solution of epoxyalcohol 19 (5.10 g, 35.36 mmol) in CCl
60 mL), was added Ph P (11.13 g, 42.43 mmol), NaHCO (0.65 g, 7.78 mmol) and the resulting
(
4
(
3
3
o
reaction mixture was refluxed for 6 h. The reaction mixture was then cooled to 0 C, diluted with
hexane (100 mL), and filtered through Celite pad. After evaporation of the solvent under reduced
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pressure, the crude product was purified by flash column chromatography on silica gel (ethyl
acetate/hexane = 1:19) to afford crude chloroepoxide (5.80 g) which was contaminated with
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
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
Ph P. This material was used in the next reaction without further purification.
n-BuLi (2.5 M solution in THF, 71.31 mL, 178.29 mmol) was added to a stirred solution of
above chloroepoxide (5.80 g, 35.65 mmol) in THF (60 mL) at –78 °C. The reaction mixture was
stirred at –78 °C for an additional 1 h. After completion of the reaction (monitored by TLC), it
was quenched with saturated aqueous NH
mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 60
mL). The combined organic extracts were washed with brine (70 mL), dried with Na SO , and
4
Cl solution (60 mL) and diluted with ethyl acetate (75
2
4
concentrated under reduced pressure. The crude residue was purified by column chromatography
on silica gel (ethyl acetate/hexane = 1:9) to give 20 (3.83 g, 86% over two steps) as a colourless
20
D
1
liquid. [α]
3 3
+7.2 (c 0.80, CHCl ); H NMR (400 MHz, CDCl ): δ 4.37 (dt, J = 6.6, 2.0 Hz, 1H),
2.46 (d, J = 2.2 Hz, 1H), 1.88 (br s, 1H), 1.77-1.65 (m, 2H), 1.51-1.41 (m, 2H), 1.38-1.27 (m,
1
3
4
2
1
H), 0.90 (t, J = 6.9 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 85.0, 72.6, 62.2, 37.5, 31.3,
4.6, 22.4, 13.9 ppm; CHN analysis calcd. For C
1.26.
8
H14O: C, 76.14; H, 11.18; Found: C, 76.45; H,
(R)-tert-Butyldimethyl(oct-1-yn-3-yloxy)silane (9): To a stirred solution of propargyl
o
alcohol 20 (3.70 g, 29.31 mmol) in anhydrous CH
5.98 g, 87.95 mmol), TBS-Cl (8.79 g, 58.62 mmol) and DMAP (0.35 g, 2.93 mmol)
sequentially. After stirring for 3 h at room temperature, water (50 mL) was added and diluted
with CH Cl (60 mL). The organic layer was separated and the aqueous layer extracted with
CH Cl (2 × 60 mL). The combined organic layer was washed with brine (70 mL), dried over
anhydrous Na SO and concentrated. The residue was purified by silica gel column
2 2
Cl (40 mL) at 0 C, was added imidazole
(
2
2
2
2
2
4
chromatography (ethyl acetate/hexane = 1:19) to obtain compound 9 (6.76 g, 94%) as a colorless
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
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4
4
4
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5
5
5
5
5
5
5
5
5
6
2
0
liquid. [α]
D
+14.5 (c 0.92, CHCl
cm ; H NMR (400 MHz, CDCl
1.70-1.63 (m, 2H), 1.48-1.37(m, 2H), 1.36-1.24 (m, 4H), 0.91 (s, 9H), 0.89 (t, J = 6.9 Hz, 3H),
3
); IR (neat): ν 3310, 2926, 2858, 1461, 1253, 1083, 838, 775
−1 1
3
): δ 4.33 (dt, J = 6.4, 2.0 Hz, 1H), 2.37 (d, J = 2.0 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
0
2
.13 (s, 1H), 0.11 (s, 1H) ppm; C NMR (100 MHz, CDCl
3
): δ 85.7, 71.8, 62.7, 38.5, 31.4, 25.7,
+
4.7, 22.5, 18.2, 13.9, −4.5, −5.0 ppm; ESI-MS: m/z = 242 [M + H] .
(
5R,7R,11R)-5-((R)-2-(Benzyloxy)-4-((4-methoxybenzyl)oxy)butyl)-2,2,13,13,14,14-
hexamet- hyl-11-pentyl-3,3-diphenyl-4,12-dioxa-3,13-disilapentadec-9-yn-7-ol (21): To A
flame-dried round bottom flask was charged with alkyne 9 (4.23 g, 17.60 mmol) in anhydrous
THF (40 mL) and cooled to −78 °C. To this solution, n-BuLi (2.5M in hexanes, 7.04 mL, 17.60
o
mmol) was added drop-wise via syringe, warmed slowly to 0 C. During this period, the reaction
mixture turned to dark red in color. After 30 min, epoxide 8 (5.5 g, 8.80 mmol) in dry THF (40
mL) was slowly added followed by BF
additional 1 h. After completion (monitored by TLC), the reaction was quenched with saturated
aqueous NH Cl solution (50 mL), diluted with ethyl acetate (100 mL) and warmed to room
temperature. The organic layer was separated and the aqueous layer extracted with ethyl acetate
3 2
.OEt (2.17 mL, 17.60 mmol) at −78 °C and stirred for an
4
(
3 × 75 mL). The combined organic layer was washed with brine (100 mL), dried over Na
2 4
SO ,
and concentrated under reduced pressure. Purification by flash column chromatography on silica
gel (ethyl acetate/hexane = 1:9) provided the desired secondary alcohol 21 (6.47 g, 85%) as a
20
colorless liquid. [α]
D
+11.5 (c 0.80, CHCl
3
); IR (neat): ν 3448, 2930, 2856, 1613, 1248, 1106,
): δ 7.70-7.65 (m, 4H), 7.42-7.27 (m, 7H),
.25-7.22 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),
.34-4.24 (m, 4H), 4.13-4.03 (m, 2H), 3.90-3.84 (m, 1H), 3.79 (s, 3H), 3.48-3.41 (m, 1H), 3.39-
−1 1
833, 774, 702, 505 cm ; H NMR (500 MHz, CDCl
3
7
4
3.34 (m, 1H), 3.30-3.25 ( m, 1H), 2.21 (dd, J = 6.1, 1.8 Hz, 2H), 1.89-1.55 (m, 8H), 1.43-1.23
13
(
m, 6H), 1.03 (s, 9H), 0.89 (s, 9H), 0.88 (t, J = 6.7 Hz, 3H), 0.09 (d, J = 10.9 Hz, 6H) ppm; C
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NMR (100 MHz, CDCl
3
): δ 159.0, 138.4, 135.8, 134.0, 133.7, 130.5, 129.7, 129.6, 129.1, 128.2,
127.6, 127.5, 127.4, 113.6, 84.4, 80.4, 73.9, 72.5, 70.7, 70.2, 67.6, 66.2, 63.0, 55.2, 43.4, 42.6,
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
38.8, 34.1, 31.4, 27.9, 26.9, 25.8, 24.9, 22.5, 19.2, 18.2, 14.0, -4.9, -4.4 ppm; HRMS (ESI) m/z
+
calcd. For C53
H
76
6
O NaSi
2
[M + Na] : 887.5072, found: 887.5067
(5R,9R,11S)-11-((R)-2-(Benzyloxy)-4-((4-methoxybenzyl)oxy)butyl)-9-((tert-
butyldiphenyl- silyl)oxy)-2,2,3,3,14,14-hexamethyl-5-pentyl-13,13-diphenyl-4,12-dioxa-3,13-
disilapentadec-6-yne (22): To a stirred solution of alcohol 21 (1.50 g, 1.73 mmol) in anhydrous
2 2
CH Cl (40 mL) under nitrogen atmosphere at room temperature, was added TBDPS-Cl (0.90
mL, 3.46 mmol), imidazole (0.35 g, 5.2 mmol) and DMAP (20 mg, 0.17 mmol) sequentially. The
reaction mixture was stirred at room temperature for 3 h. After completion (monitored by TLC),
the reaction was quenched with water (30 mL). The organic layer was separated and the aqueous
2 2 2 4
layer extracted with CH Cl (3 × 40 mL). The combined organic layer was dried over Na SO ,
filtered, and concentrated. The crude product was purified by silica gel column chromatography
(ethyl acetate/hexane = 1:19) to give compound 22 (1.74 g, 91%) as a colorless viscous liquid.
20
[α]
D
+5.9 (c 0.36, CHCl
3
); IR (neat): ν 3450, 2931, 2857, 1629, 1248, 1106, 772, 702, 506
): 7.63-7.57 (m, 8H), 7.41-7.27 (m, 11H), 7.25-7.22 (m, 4H),
.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.31 (q, J = 11.1,
1.6 Hz, 2H), 4.24-4.17 (m, 2H), 4.11-4.01 (m, 2H), 3.93-3.88 (m, 1H), 3.79 (s, 3H), 3.57-3.52
−1 1
cm ; H NMR (400 MHz, CDCl
3
7
2
(m, 1H), 3.40-3.35 (m, 1H), 3.31-3.26 ( m, 1H), 2.11-2.06 (m, 1H), 1.96-1.91 (m, 1H), 1.74-1.56
(m, 3H), 1.53-1.43 (m, 3H), 1.38-1.18 (m, 8H), 0.94 (s, 18H), 0.88-0.84 (m, 12H), 0.04 (d, J =
13
4
1
.2 Hz, 6H) ppm; C NMR (125 MHz, CDCl
3
): δ 159.0, 138.9, 135.9, 135.8, 135.4, 134.3,
34.2, 134.1, 133.7, 130.6, 129.5, 129.4, 129.1, 128.0, 127.5, 127.4, 127.1, 113.6, 84.0, 80.5,
73.6, 72.4, 70.6, 68.9, 68.6, 66.4, 63.1, 55.2, 44.2, 43.0, 38.9, 34.2, 31.5, 27.0, 26.9, 26.6, 25.8,
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4.9, 22.6, 19.3, 19.1, 18.2, 14.0, −4.2, −4.9 ppm; HRMS (ESI) m/z calcd. For C69
H O NaSi
94 6 3
+
[
M + Na] : 1125.6250, found: 1125.6255.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(6R,10R,12S,14R)-14-(Benzyloxy)-10,12-bis((tert-butyldiphenylsilyl)oxy)-16-((4-methoxy-
benzyl)oxy)hexadecan-6-ol (23a): Pyridinium p-toluenesulfonate (PPTS, 0.46 g, 1.83 mmol)
was added to a solution of the tri-silylether 22 (1.35 g, 1.22 mmol) in MeOH (70 mL). The
mixture was stirred at room temperature for 6 h. After completion of the reaction (TLC
3
monitoring), saturated aqueous NaHCO solution (25 mL) was added, and the solvent was
removed under reduced pressure. The residue was diluted with ethyl acetate (40 mL) and the
organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 × 30 mL).
2 4
The combined extract was dried over Na SO , concentrated under reduced pressure and purified
by flash chromatography on silica gel (ethyl acetate/hexane = 1:9) to obtain propargyl alcohol
2
0
(
1.13 g, 94%) as a colorless liquid. [α]
D
+18.0 (c 0.20, CHCl
1614, 1247, 1107, 738 cm ; H NMR (400 MHz, CDCl ): 7.67-7.62 (m, 4H), 7.59-7.51 (m, 4H),
.43-7.26 (m, 13H), 7.24-7.19 (m, 4H), 7.15 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.38-
.18 (m, 4H), 4.08-3.99 (m, 2H), 3.87-3.80 (m, 1H), 3.77 (s, 3H), 3.56-3.48 (m, 1H), 3.47-3.39
3
); IR (neat): ν 3448, 2931, 2857,
−1 1
3
7
4
(
m, 1H), 3.35-3.29 ( m, 1H), 2.75 (d, J = 5.0, 1H), 2.10 (d, J = 4.4, 1H), 2.02-1.75 (m, 4H), 1.54-
13
1
.45 (m, 4H), 1.40-1.20 (m, 6H), 1.01 (s, 9H), 0.91 (s, 9H), 0.88 (t, J = 7.3 Hz, 3H) ppm; C
): δ 159.1, 138.6, 135.8, 134.2, 134.1, 133.8, 130.0, 129.4, 128.1, 127.6,
27.5, 127.4, 127.3, 113.6, 84.1, 80.7, 73.1, 72.5, 70.6, 68.4, 66.2, 61.9, 55.1, 53.3, 43.2, 42.6,
NMR (100 MHz, CDCl
3
1
37.7, 34.1, 31.5, 26.9, 25.7, 24.9, 22.5, 19.2, 14.0 ppm; HRMS (ESI) m/z calcd. For
+
C
63 80
H O
6
NaSi
2
[M + Na] :1011.5385, found: 1011.5394.
To a flask charged with above propargylic alcohol (0.80 g, 0.80 mmol) and tetrahydrofuran
(50 mL) was added p-toluenesulfonyl hydrazide (1.5 g, 8.08 mmol) in one portion. The flask was
fitted with a reflux condensor and warmed to reflux (bath temperature 90 °C). A solution of
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9
2
NaOAc (0.99 g, 12.12 mmol) in H O (50 mL) was added by a syringe pump over 2 h and stirred
for 12 h. After completion of the reaction (monitored by TLC), the mixture was then cooled to
room temperature and diluted with ethyl acetate (50 mL). The organic layer was separated and
the aqueous layer extracted with ethyl acetate (2 × 50 mL). The combined extracts were dried
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
2
over Na SO
4
, concentrated and purified by flash chromatography on silica gel (ethyl
acetate/hexane = 1:9) to afford saturated alcohol 23a (0.74 g, 92%) as a colorless viscous liquid.
2
0
−1
1
[α]
NMR (400 MHz, CDCl
8.6 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.39-4.10 (m, 4H), 4.02-3.89
(m, 2H), 3.78 (s, 3H), 3.56-3.49 (m, 1H), 3.43-3.36 (m, 1H), 3.35-3.27 ( m, 1H), 3.21-3.14 (m,
H), 1.85-1.75 (m, 2H), 1.69-1.45 (m, 12H), 1.36-1.27 (m, 6H), 0.99 (s, 9H), 0.93 (s, 9H), 0.89
D
+10.0 (c 0.52, CHCl
3
); IR (neat): ν 3452, 2931, 2857, 1616, 1247, 1107, 741 cm ; H
3
): 7.66-7.55 (m, 8H), 7.41-7.26 (m, 12H), 7.25-7.22 (m, 3H), 7.26 (d, J
=
1
1
3
(
t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 159.0, 138.8, 135.9, 135.8, 134.7,
134.4, 134.3, 134.2, 130.5, 129.4, 129.3, 129.2, 128.1, 127.6, 127.4, 127.3, 127.2, 113.6, 73.5,
7
2
1
2.5, 71.5, 70.6, 70.3, 68.8, 66.3, 55.2, 44.0, 42.9, 37.5, 37.2, 35.5, 34.4, 31.9, 29.6, 27.0, 26.9,
+
5.3, 22.6, 20.2, 19.2, 14.0 ppm; HRMS (ESI) m/z calcd. For C63
84
H O
6
NaSi
2
[M + Na] :
015.5698, found: 1015.5702.
(
6R,10R,12S,14R)-14-(Benzyloxy)-10,12-bis((tert-butyldiphenylsilyl)oxy)-16-((4-methoxy-
benzyl)oxy)hexadecan-6-yl-2-(diethoxyphosphoryl)acetate (24a): To a stirred solution of 2-
diethoxyphosphoryl)acetic acid (0.19 g, 0.98 mmol) and DCC (0.29 g, 1.43 mmol) in CH Cl
(10 mL), was added DMAP (0.04 g, 0.32 mmol) at room temperature. The mixture was stirred
for 15 min before a solution of 23a (0.65 g, 0.65 mmol) in CH Cl (10 mL) was added at room
temperature. The mixture was stirred at room temperature for 12 h. After completion of the
reaction (TLC monitoring), the mixture was quenched with H O (20 mL). The organic layer was
separated and the aqueous layer extracted with CH Cl (3 × 25 mL). The combined organic layer
(
2
2
2
2
2
2
2
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7
8
9
1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was dried (Na
2
SO
4
), concentrated and the residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 3:7) to furnish compound 24a (0.76 g, 87%) as a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
colorless liquid. [α]
270, 1108, 1054, 1030, 738 cm ; H NMR (500 MHz, CDCl
m, 13H), 7.25-7.23 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 6.4 Hz, 2H), 6.85 (d, J = 8.6
D
+8.3 (c 0.50, CHCl
3
); IR (neat): ν 3446, 3067, 2933, 2858, 1732, 1464,
−1 1
1
3
): 7.63-7.55 (m, 8H), 7.40-7.26
(
Hz, 2H), 4.69-4.63 (m, 1H), 4.35-4.22 (m, 3H), 4.18-4.10 (m, 5H), 4.03-3.96 (m, 1H), 3.93-3.86
(m, 1H), 3.79 (s, 3H), 3.55-3.48 (m, 1H), 3.41-3.36 (m, 1H), 3.33-3.25 ( m, 1H), 2.84 (d, J = 2.1
Hz, 1H), 2.79 (d, J = 2.2 Hz, 1H ), 1.83-1.72 (m, 2H), 1.62-1.45 (m, 6H), 1.34-1.15(m, 18H),
13
0
.97 (s, 9H), 0.94 (s, 9H), 0.89 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
): δ 165.3,
165.2, 159.0, 138.8, 135.9, 135.8, 134.5, 134.2, 130.6, 129.4, 129.1, 128.1, 127.4, 127.1, 113.6,
75.7, 73.7, 72.4, 70.6, 70.5, 68.8, 66.3, 62.5, 62.4, 55.2, 44.7, 43.1, 35.9, 35.0, 34.3, 33.8, 33.6,
33.5, 31.7, 29.6, 27.0, 26.9, 24.6, 22.5, 20.4, 19.2, 16.3, 16.2, 14.0 ppm; HRMS (ESI) m/z calcd.
+
95
For C69H O
10NaPSi
2
[M + Na] :1193.6093, found: 1193.6073.
(6R,10R,12S,14S)-14-(Benzyloxy)-10,12-bis((tert-butyldiphenylsilyl)oxy)-16-
oxohexadecan-6-yl 2-(diethoxyphosphoryl)acetate (25a): To a stirred solution of 24a (0.54 g,
0
0
3 2
.46 mmol) in CH CN/H O (9:1) (20 mL) was added ceric ammonium nitrate (CAN, 0.50 g,
o
.92 mmol) at 0 C, and the mixture was stirred for 30 min. After completion (monitored by
TLC), the reaction was quenched with saturated aqueous NaHCO
mixture was filtered through Celite pad, organic layer separated and the aqueous layer extracted
with CH Cl (3 × 30 mL). The combined organic layer were washed with H O (50 mL) and brine
50 mL), dried (Na SO ), and concentrated. The residue was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:1) to afford corresponding primary alcohol 25a (0.43
3
solution (20 mL). The
2
2
2
(
2
4
20
g, 89%) as a colorless liquid. [α]
D
3
+5.3 (c 0.88, CHCl ); IR (neat) : ν 3446, 2931, 2857, 1732,
−1 1
3
1633, 1269, 1108, 1052, 1027, 7034 cm ; H NMR (400 MHz, CDCl ): δ 7.65-7.55 (m, 8H),
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.42-7.27 (m, 15H), 7.17 (dd, J = 7.9, 1.5 Hz, 2H), 4.73-4.66 (m, 1H), 4.27-4.19 (m, 2H), 4.17-
.08 (m, 6H), 4.01-3.94 (m, 1H), 3.90-3.84 (m, 1H), 3.56-3.42 (m, 2H), 2.86 (d, J = 1.5 Hz, 1H),
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2.82 (d, J = 1.5 Hz, 1H), 1.83-1.56 (m, 4H), 1.50-1.10 (m, 22H), 0.99 (s, 9H), 0.93 (s, 3H), 0.89
1
3
(
t, J = 7.1 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
): δ 165.3, 138.2, 135.8, 134.4, 134.3,
34.1, 133.9, 129.5, 129.4, 128.2, 127.6, 127.4, 75.9, 75.4, 70.6, 70.3, 68.6, 63.6, 63.5, 62.5,
2.4, 59.8, 44.2, 42.2, 36.0, 35.7, 34.9, 33.9, 33.8, 33.6, 31.6, 29.6, 27.0, 26.9, 24.6, 22.5, 20.2,
1
6
87 9 2
19.3, 19.2, 16.3, 16.2, 16.1, 16.0, 14.0 ppm; HRMS (ESI) m/z calcd. For for C61H O NaPSi [M
+
+
Na] : 1073.5518, found: 1073.5525.
(6R,10R,12S,14S)-14-(Benzyloxy)-10,12-bis((tert-butyldiphenylsilyl)oxy)-16-
oxohexadecan-6-yl 2-(diethoxyphosphoryl)acetate (7a): To a stirred solution of above alcohol
25a (0.32 g, 0.30 mmol) and solid anhydrous NaHCO
3
2 2
(0.1 g, 1.21 mmol) in CH Cl (10 mL),
o
Dess-Martin periodinane (DMP) (0.26 g, 0.60 mmol) was added at 0 C under nitrogen
o
atmosphere. The reaction mixture was stirred at 0 C for 1 h. After completion of the reaction
(
monitored by TLC), it was filtered through Celite pad and thoroughly washed with CH
mL). Organic layer was separated and the aqueous layer extracted with CH Cl (3 × 30 mL). The
combined organic layer was dried over anhydrous Na SO4, concentrated under reduced pressure
and the residue purified by flash column chromatography on silica gel (ethyl acetate/hexane =
:7) to afford aldehyde 7a (0.27, 86%) as a colorless liquid, that was immediately used in the
next step.
(6R,8S,10R,14R,E)-6-(Benzyloxy)-8,10-bis((tert-butyldiphenylsilyl)oxy)-14-pentyloxa
2 2
Cl (20
2
2
2
3
cyclotetradec-3-en-2-one (26a): The above obtained aldehyde 7a (0.25 g, 0.23 mmol) in
acetonitrile (200 mL) was added LiCl (0.15 g, 3.57 mmol) at room temperature. After 30 min, a
solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.07 mL, 0.47 mmol) in acetonitrile (100
mL) was added dropwise. After being stirred at room temperature for 12 h, the reaction was
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2
2
2
2
2
2
2
3
3
3
3
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3
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3
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4
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5
5
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5
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5
5
6
quenched with saturated aqueous NH
4
Cl solution (30 mL) and brine (30 mL). The organic
solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 4
(3 × 60 mL). The combined organic layer were dried over Na SO , filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane =
20
1
:9) to yield macrolide 26a (0.17 g, 82%) as a colorless viscous liquid. [α]
D
+6.2 (c 0.97,
1
CHCl
3
); H NMR (500 MHz, CDCl
3
): δ 7.66 (d, J = 6.7 Hz, 4H ), 7.59 (d, J = 6.7 Hz, 4H), 7.44-
7.27 (m, 15H), 7.22 (d, J = 6.8 Hz, 2H), 6.22-6.14 (m, 1H), 5.54 (d, J = 15.5 Hz, 1H), 4.76-4.69
m, 1H), 4.37(q, J = 11.7, 2.5 Hz, 2H), 4.25-4.17 (m, 1H), 4.14-4.09 (m, 1H), 3.67-3.60 (m, 1H),
.11-3.04 (m, 1H), 2.44-2.36 (m, 1H), 1.88-1.81 (m, 1H), 1.70-1.47 (m, 8H), 1.35-1.25 (m, 10H),
(
3
13
1.02 (s, 9H), 0.90 (t, J = 7.0, 3H), 0.87 (s, 9H) ppm; C NMR (100 MHz, CDCl
3
): δ 166.6,
1
1
44.1, 138.1, 135.9, 135.8, 134.5, 134.4, 134.3, 133.4, 129.8, 129.5, 129.4, 128.3, 127.6, 127.4,
25.1, 77.1, 75.6, 70.7, 69.4, 67.4, 53.3, 45.7, 41.7, 39.0, 35.2, 35.1, 34.8, 31.7, 29.6, 27.0, 26.9,
+
25.1, 22.5, 19.3, 19.1, 14.0 ppm; HRMS (ESI) m/z calcd. For for C57
17.4967, found: 917.4981.
6R,8R,10R,14R,E)-6,8,10-Trihydroxy-14-pentyloxacyclotetradec-3-en-2-one (5a): To a
stirred solution of compound 26a (100 mg, 0.11 mmol) in CH Cl (10 mL), TiCl (3.35 mL, 3.35
mmol, 1 m in CH Cl ) was added at 0 °C and the reaction mixture stirred at room temperature
for 1 h. After completion of the reaction (monitored by TLC), it was quenched with a saturated
aqueous NaHCO solution (15 mL). The organic phase was separated and the aqueous phase
extracted with CH Cl (3 x 20 mL). The combined organic layers were dried with anhydrous
Na SO and concentrated under reduced pressure to obtain the crude product which on
purification by column chromatography over silica gel (ethyl acetate/hexane = 19:1) furnished
H
74
O
5
NaSi
2
[M + Na] :
9
(
2
2
4
2
2
3
2
2
2
4
25
D
compound 5a (27 mg, 75%) as a white amorphous powder. [α]
3
−92.5 (c 0.18, CH OH); IR
−1 1
(neat): ν 3361, 2926, 2856, 1716, 1647, 1458, 1054, 861 cm ; H NMR (500 MHz, CD
3
OD): δ
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.97 (ddd, J = 16.1, 10.0, 6.5 Hz, 1H ), 5.91 (d, J = 15.7 Hz, 1H ), 4.04-3.98 (m, 1H), 3.85-3.79
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
m, 1H), 3.78-3.73 (m, 1H), 2.59-2.52 (m, 1H), 2.48-2.41 (m, 1H), 1.95-1.88 (m, 1H), 1.83-1.76
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(m, 1H), 1.75-1.67 (m, 1H), 1.66-1.50 (m, 4H), 1.49-1.38 (m, 2H), 1.34-1.23 (m, 9H), 0.88 (t, J
13
=
6.8, 3H) ppm; C NMR (75 MHz, CD OD): δ 168.3, 147.2, 125.5, 77.4, 69.9, 69.1, 68.2, 43.8,
3
4
3.2, 41.8, 36.5, 36.0, 33.6, 32.5, 25.9, 23.4, 21.7, 14.3 ppm; HRMS (ESI) m/z calcd. For for
+
C
18 32
H O
5
Na [M + Na] :351.2142, found: 351.2120.
(5R,7R,11R)-5-((R)-2-(Benzyloxy)-4-((4-methoxybenzyl)oxy)butyl)-2,2,13,13,14,14-
hexamethyl-11-pentyl-3,3-diphenyl-4,12-dioxa-3,13-disilapentadecan-7-ol (27): To a flask
charged with homopropargylic alcohol 21 (4.0 g, 4.62 mmol) and tetrahydrofuran (100 mL) was
added p-toluenesulfonyl hydrazide (8.60 g, 46.22 mmol) in one portion. The flask was fitted with
a reflux condensor and warmed to reflux (bath temperature 90 °C). A solution of NaOAc (5.68 g,
6
2
9.33 mmol) in H O (100 mL) was added by a syringe pump over 5 h and stirred for 12 h. After
completion of the reaction (TLC monitoring), the mixture was then cooled to room temperature
and diluted with ethyl acetate (100 mL). The organic layer was separated and the aqueous layer
extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were dried over
2 4
Na SO , concentration under reduced pressure and purified by flash chromatography on silica
gel (ethyl acetate/hexane = 1:9) to obtain saturated alcohol 27 (3.60 g, 90%) as a colorless
20
viscous liquid. [α]
D
+9.5 (c 0.4, CHCl
): δ 7.71-7.66 (m, 4H), 7.43-7.26 (m, 7H), 7.25-7.22 (m,
2H), 7.19 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 7.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.35-4.25 (m,
3
); IR (neat): ν 3448, 2931, 2857, 1460, 1248, 1101, 827,
−1 1
7
61 cm ; H NMR (400 MHz, CDCl
3
3
3
H), 4.13-4.03 (m, 2H), 3.80 (s, 3H), 3.75-3.67 (m, 1H), 3.62-3.54 (m, 1H), 3.41-3.30 (m, 2H),
.28-3.22 (m, 1H), 1.86-1.78 (m, 2H), 1.65-1.49 (m, 6H), 1.42-1.20 (m, 12H), 1.03 (s, 9H), 0.90-
13
0.86 (m, 12H), 0.02 (s, 6H) ppm; C NMR (100 MHz, CDCl
3
): δ 159.0, 138.3, 135.8, 134.1,
1
33.7, 130.5, 129.7, 129.6, 129.1, 128.2, 127.7, 127.6, 127.5, 127.4, 113.7, 74.1, 72.5, 72.2, 71.2,
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