Total synthesis and structural revision of greensporone F and dechlorogreensporone F

Article abstract of DOI:10.1021/acs.joc.0c01644

The first asymmetric total syntheses of the real isolation product (2S,5R,8R)-greensporone F and (2S,5R,8R)-dechlorogreensporone F, 14-membered resorcylic acid lactones with a cis-2,5-disubstituted tetrahydrofuran ring system, was accomplished. The synthesis features a late-stage Lewis acid-catalyzed stereoselective intramolecular oxa-Michael reaction, E-selective ring-closing metathesis, De Brabander's esterification, and Jacobsen's hydrolytic kinetic resolution as the key steps. Synthesis of both real isolation and erroneously proposed structure necessitated the revision of the absolute configuration of greensporone F and dechlorogreensporone F. The erroneous representation of (2S,5S,8S)-configuration in greensporone F and dechlorogreensporone F was assigned to be (2S,5R,8R) by comparison with the NMR data and specific rotation of the synthetic compounds with that of the reported data.

Full text of DOI:10.1021/acs.joc.0c01644

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Article
Total Synthesis and Structural Revision of
Greensporone F and Dechlorogreensporone F
Janardhan Gaddam, Aedula Vishnu Vardan Reddy, Akella V.
S. Sarma, Jhillu S. Yadav, and Debendra Kumar Mohapatra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01644 • Publication Date (Web): 02 Sep 2020
Downloaded from pubs.acs.org on September 2, 2020
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Total Synthesis and Structural Revision of Greensporone F and Dechlorogreensporone F
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Janardhan Gaddam,†,§,≠Aedula Vishnu V. Reddy,†,§,≠ Akella V. S. Sarma,‡ Jhillu S. Yadav†,§,‼ and
Debendra K. Mohapatra*†,§
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‡
†Department of Organic Synthesis and Process Chemistry and Centre for NMR and Structural
§
Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India; Academy of
Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh-201002, India. School of
Science, Indrashil University, Kadi, Gujarat, India, mohapatra@iict.res.in
‼
1
1
(S)
(S)
O
O
O
O
O
O
(S)
(S)
HO
O
HO
O
5
5
Cl
(S)
O
O
(S)
9
9
5. Greensporone F
(erroneous representation)
4. Dechlorogreensporone F
(erroneous representation)
1
1
(S)
(S)
O
O
O
O
O
O
(R)
(R)
HO
O
HO
O
5
5
Cl
O
(R)
(R)
O
9
9
4a. Dechlorogreensporone F
(revised)
5a. Greensporone F
(revised)
ABSTRACT: The first asymmetric total syntheses of the real isolation product (2S,5R,8R)-
greensporone F and (2S,5R,8R)-dechlorogreensporone F, a 14-membered resorcylic acid lactones
(RALs) with a cis-2,5-disubstituted tetrahydrofuran ring system, was accomplished. The synthesis
features a late-stage Lewis acid-catalyzed stereoselective intramolecular oxa-Michael reaction, E-
selective ring-closing metathesis (RCM), De Brabander’s esterification and Jacobsen’s hydrolytic
kinetic resolution as the key steps. Synthesis of both real isolation and erroneously proposed structure
necessitated the revision of the absolute configuration of greensporone F and dechlorogreensporone F.
The erroneous representation of (2S,5S,8S)-configuration in greensporone F and dechlorogreensporone
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F was assigned to be (2S,5R,8R) by comparison with the NMR data and specific rotation of the
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synthetic compounds with that of the reported data.
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INTRODUCTION
Fungi are known to be one of the potential sources of major antibiotic-producing organisms. These are
the most diversified kingdoms of life and 95% of these are not well investigated. The novelty of
freshwater fungi derived compounds and their wide spectrum of applications may find way in getting
solutions to many dreadful diseases like AIDS, cancer, Alzheimer’s disease and arthritis which are
difficult to be cured. Resorcylic acid lactones1 are 14-membered macrolides, exhibiting wide spectrum
of biological properties such as anti-fungal, anti-microbial, anti-malarial, anti-bacterial, estrogenic,
anti-cancer, anti-parasitic and anti-fouling activity. Oberlies et al in 2014 isolated 14 new 14-
membered resorcylic acid lactones from fresh water aquatic fungus Halenospora sp. collected in North
Carolina. During the isolation of the natural products dihydrogreensporone C (1), greensporone D (2),
dechlorogreensporone D (3), they have also isolated three new compounds dechlorogreensporone F
(4), greensporone F (5) and greensporone G (6) which are not natural products but are the artefacts
arising from the intramolecular oxa-Michael addition reaction (Figure 1).2 The absolute configuration
of the stereogenic center at the C2-position in the lactone 1 was assigned as R based on the single-
crystal X-ray diffraction analysis of the bromobenzoyl derivative of 8,9-dihydrogreensporone C 1a.
The stereochemistry at the C5-position was assigned to be S in the lactones 1-3 based on extensive
NMR analysis. While stereochemistry at the C5-position is S in the lactones 2-3, the stereochemistry at
the C5 position in the THF containing lactones 4-6 would be R owing to the change in priorities of the
substituents on the asymmetric carbon at C5. Structures of 4-6 were elucidated through various
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spectroscopic techniques. While assigning the absolute stereochemistry of the THF containing
lactones 4-6, they might have inadvertently depicted the stereocenter at C5-position as S although the
stereochemistry would be R as a consequence of the change in priorities of the substituents with the
THF formation from the lactones 2-3. Except greensporone D and greensporone F, all other isolated
cᴏmpᴏunds were tested for their in vitro activity against two cancer cell lines HT-29 (Colon) and
MDA-MB-435 (Melanoma). Among these, greensporone C was found to be potent with IC50 values of
2.9 and 7.5 μM against HT-29 and MDA-MB-435, respectively.
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Figure 1. Representative structures of 14-membered Resorcylic Acid Lactones (RALs).
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Coupled with our continuing interest in the total synthesis of resorcylic acid lactones and in THF
containing natural products, we aimed initially at the total synthesis of dechlorogreensporone F (4a)
and greensporone F (5a). Herein, we describe our efforts in the first asymmetric total synthesis of the
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greensporone F and dechlorogreensporone F and confirmation of the structure and absolute
configuration of dechlorogreensporone F and greensporone F.
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The proposed convergent retrosynthetic strategy for the synthesis of 4a and 5a is outlined in
Scheme 1. To make these two products efficiently with full control of all stereocenters, we envisioned
a late-stage diastereoselective intramolecular oxa-Michael reaction of intermediate 7 to construct the
Scheme 1. Retrosynthetic Plan
cis-2,5-disubstituted tetrahydrofuran scaffold.3 Synthesis of 7 was planned by E-selective ring-closing
metathesis (RCM) reaction of ester 9 which can be obtained by coupling of acid fragment 10 and
alcohol fragment 11 by esterification using De Brabander’s reaction conditions. Synthesis of fragment
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10 was envisaged from 12, while the alcohol fragment 11 could be synthesized from the known chiral
epoxide 13. In a similar reaction sequence, greensporone F (5) could also be synthesized via
macrolactone 8.
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RESULTS AND DISCUSSION
With the general synthetic plan in hand, regioselective opening of the enantiopure (S)-propylene
oxide 134 (prepared from corresponding racemic epoxide by treating with (S,S)-Jacobsen catalyst) with
allyl Grignard reagent and CuI at –40 oC furnished the alcohol 14 which was immediately used in the
next step without any further purification/characterization (Scheme 2). The secondary alcohol in 14
was protected with TBSCl in presence of imidazole in CH2Cl2 at 0 oC to give the TBS ether 15 in 78%
yield over two steps.5 Epoxidation of cᴏmpᴏund 13 with m-CPBA in CH2Cl2 provided 16 as a mixture
Scheme 2. Synthesis of Alcohol Fragment 12
MgBr
OH
O
CuI, THF, -40 oC to 0 o
3 h
C
14
13
TBSCl, imidazole
m-CPBA, CH2Cl2
OTBS
CH2Cl2, 0 oC to rt
6 h, 78% over
two steps
0 oC to rt, 3 h, 85%
15
(R,R)-Jacobsen
OTBS
OTBS
N
N
O
catalyst
Mn
Cl
O
AcOH, H2O, toluene
-10 oC to rt, 24 h, 45%
O
O
16
17
(dr = 99:1)
(R,R)-Jacobsen catalyst
+
17
OTBS
MgCl
CuI, THF
MOMCl, DIPEA
CH2Cl2, 0 °C to rt
5 h, 97%
OH
-40 °C, 1 h, 89%
18
TBAF
OH
OTBS
THF
0 °C to rt
4 h, 94%
OMOM
OMOM
19
11
__________________________________________________________________________________
of diastereomers (1:1) in 85% yield.6 Cᴏmpᴏund 16 was then subjected to hydrolytic kinetic resolution
using (R,R)-Jacobsen’s catalyst to yield the optically active epoxide 17 in 45% yield.7 Epoxide 17 was
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treated with allylmagnesium chloride in presence of CuI at – 40 oC to produce the requisite secondary
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alcohol fragment 18 in 89% yield. The stereochemistry of the secondary hydroxy attached at the C5
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Figure 2. (∆δ) = (δS − δR) × 103 for (S)- and (R)-MTPA ester of alcohol compound 18.
__________________________________________________________________________________
carbon was determined by following the modified Mosher’s ester method (Figure 2).8 Esterification of
the alcohol 18 with both (S)- and (R)-methoxy-(trifluoromethyl)phenylacetic acid (MTPA) revealed
negative chemical shift difference [Δδ = (δS − δR) ×103] for protons on C6 through C9 (Figure S1 in
SI), while protons on C1 through C4 showed positive chemical shift differences, which is consistent
with C5 bearing an S-configuration.
After confirming the absolute configuration at C5, the hydroxyl group in compound 18, it was
protected as MOM ether using MOMCl and N,N-diisopropylethylamine (DIPEA) to obtain cᴏmpᴏund
19 in 97% yield. The TBS group in 19 was removed smoothly using tetrabutylammonium fluoride
(TBAF)9 to provide 11 in 94% yield.
Scheme 3. Synthesis of Fragment 10
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The synthesis of cᴏmpᴏund 10 commenced from the known cᴏmpᴏund 12,10 in which the
terminal double bond was cleaved following Jin’s protocol11 of one-pot dihydroxylation-oxidation
reaction using OsO4, 2,6-lutidine, NaIO4 in 1,4-dioxane-H2O (3:1) to furnish the desired aldehyde in
86% yield which was immediately used in the next step without any further purification. Addition of
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o
Grignard reagent to the aldehyde with vinylmagnesium bromide at −40 C afforded the allyl alcohol
21 in 77% yield over two steps. The secondary alcohol group in 21 was protected as the TBS ether
using TBSCl in presence of imidazole in CH2Cl2 at 0 oC in 97% yield (Scheme 3).5
Scheme 4. Total Synthesis of the Proposed Structures of Dechlorogreensporone F and
Greensporone F
O
O
OH
OH
O
O
NaH, THF
MeI, NaH, THF
MOMO
+
O
0 oC to rt, 1 h
90%
BnO
0 oC to rt, 1 h, 89%
OMOM
BnO
TBSO
O
11
22
10
TBSO
O
O
O
O
DMP, NaHCO3
HF-Py, THF
MOMO
O
MOMO
0 oC to rt, 10 h, 82%
CH2Cl2, 0 oC to rt,
1 h, 89%
BnO
BnO
23
24
TBSO
O
HO
Hovyeda
Grubbs-II
CH2Cl2
O
O
O
O
O
TiCl4
CH2Cl2
O
MOMO
O
O
MOMO
0 o
C
reflux, 3 h
BnO
HO
O
BnO
80%
20 min, 84%
O
O
O
4a
9
7
SO2Cl2
CH2Cl2
30 min
85%
N
Cl
Ru
N
O
O
TiCl4
CH2Cl2
O
O
O
Cl
O
O
HO
O
0 oC, 20 min
83%
MOMO
BnO
Cl
O
Hovyeda Grubbs-II
Cl
O
5a
8
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The coupling of both the fragments 10 and 11 by employing De Brabander’s protocol,12 with NaH
in THF at 0 oC furnished the ester 22 in 90% yield. The free phenolic hydroxyl group in cᴏmpᴏund 22
was protected as methoxy ether using MeI and NaH to furnish the cᴏmpᴏund 23 in 89% yield.
Removal of the TBS group using HF-Py (70% v/v) in THF afforded the alcohol 24 in 82% yield.13 The
allyl alcohol 24 was oxidized to the corresponding ketone 9 with Dess–Martin periodinane14 in CH2Cl2
with 89% yield. Ring-closing metathesis reaction of a 0.001 M solution of the bis-olefin 9 with 10
mol% of Hovyeda Grubbs’ second-generation15 catalyst heating under reflux conditions for 3 h in
anhydrous, degassed CH2Cl2 provided the required 14-membered-E-lactone 7 as the sole product in
80% yield (Scheme 4).
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Global deprotection followed by acid-catalyzed intramolecular transannular oxa-Michael
cyclization was achieved by treating 7 with excess TiCl4 in CH2Cl2 to complete the total synthesis of
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4a in 84% yield.16 Pleasingly, the spectral data (1H and C NMR) of synthetic dechlorogreensporone
F (4a) matched exactly with the data reported for the natural product (see comparison of the NMR data
of natural dechlorogreensporone F and 4a in Table S1 in the Supporting Information). The specific
rotation of the synthetic dechlorosporone F (4a) was the same in sign and comparable magnitude
{[α]D20 –29.8 (c 1.0, MeOH); lit. {[α]D20 –31.0 (c 0.11, MeOH)}, confirming the synthesis of the real
isolation product. Therefore, the absolute configuration of the real isolated dechlorogreensporone F
was determined to be (2S,5R,8R) as depicted in 4a in Scheme 4 and Figure 1.
Table 1. Comparison of 13C NMR data of the Natural Products with the Synthetic Samples
Dechloro-
greensporone F
in ppm
Synthetic Prᴏduct
∆ (lit-
Greensporone F
in ppm
Synthetic
Prᴏduct 5a
in ppm
∆ (lit-
Greensporone
F 5a)a
Position
Dechlorogreen
4a
in ppm
sporone F 4a)a
1
2
3
20.9
72.7
33.0
20.8
72.6
32.9
+0.13
+0.11
+0.10
21.5
73.4
33.8
21.5
73.4
33.8
+0.04
−0.01
0.00
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31.3
79.5
31.3
79.4
+0.04
+0.12
+0.16
+0.09
+0.04
+0.04
−0.01
+0.18
+0.13
+0.05
0.00
34.7
79.3
34.7
79.3
−0.02
0.00
5
6
33.5
33.3
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31.6
31.5
+0.09
+0.03
+0.01
+0.02
−0.16
+0.02
+0.11
+0.01
−0.05
0.00
7
30.5
30.4
29.8
29.8
8
76.1
76.1
76.3
76.3
9
47.9
47.9
46.6
46.6
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207.7
49.0
207.7
48.8
203.9
48.6
204.0
48.6
134.2
109.2
157.7
98.3
134.1
109.2
157.7
98.3
132.1
113.1
153.3
99.1
132.0
113.1
153.3
99.1
0.00
159.0
117.3
167.7
56.0
159.0
117.2
167.6
55.9
−0.01
+0.09
+0.10
+0.09
157.0
119.2
166.9
56.4
157.0
119.1
166.9
56.3
+0.04
+0.14
−0.02
+0.08
With the corrected structure of dechlorogreensporone F (4a) in hand, our attention was then focused
on the synthesis of greensporone F (5a). To this end, we introduced the chlorine group in the aromatic
o
ring following regioselective electrophilic chlorination using sulfuryl chloride in CH2Cl2 at 0 C to
afford cᴏmpᴏund 8 in 85% yield.17 Global deprotection followed by acid-catalyzed intramolecular
transannular oxa-Michael cyclization of 8 with excess TiCl4 in CH2Cl2 furnished 5a in 83% yield. The
1
13
NMR spectral data (δH, δC and couplings from H and C NMR spectra) for 5a were identical with
that reported for the real isolated greensporone F (see comparison of the NMR data of natural
greensporone and 5a in Table S2 in the Supporting Information) (Table 1). The specific rotation value
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of the synthetic greensporone F {[α]D –35.2 (c 0.25, MeOH)} was quite close to that of the natural
20
product {[α]D –38.0 (c 0.01, MeOH)}. To further ascertain the correct structure of greensporone F
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and dechlorogreensporone F, we reasoned that the configuration at the THF can be cis and considered
the synthesis of erroneously represented (5S,8S)-disubstituted THF containing analogues 4 and 5.
Scheme 5. Completion of Synthetic Samples 4 and 5
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Thus, synthesis of 4 and 5 was started from the chiral alcohol 11a (fragment having inverted C5
hydroxy stereocenter which was converted into antipodal THF ring, see the Supporting Information)
following the sequence of reactions that are described in Scheme 4. However, the spectroscopic (1H
and 13C{1H} NMR spectral data) and analytical data of synthetic compound 4 and 5 (see the
comparison of NMR data in Table S3 and S4 in the Supporting Information) were found to be
different from those reported for greensporone F and dechlorogreensporone F, respectively. In
1
particular, the reported H NMR data for greensporone F contained four multiplets at 2.02 (m, 1H),
1.79 (m, 1H), 1.55 (m, 1H), 1.38 (m, 1H), whereas, for the synthesized sample, the peaks due to the
resonance of those four protons appeared at 1.66 (m, 2H), 1.48 (m, 2H) ppm, respectively (Table S4).
13
In C{1H} NMR spectra, resonances for C1 to C4, C6, C10 and C11 appeared at 21.5, 73.4, 33.8,
34.7, 31.6, 203.9 and 48.6 ppm for the reported compound, whereas, for the synthetic compound, they
appeared at 18.5, 71.0, 31.7, 31.7, 30.2, 204.9 and 47.7 ppm (Table 2). The specific rotation value of
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Table 2. Comparison of 13C{1H} NMR data of the Reported Products with the Synthetic Samples
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Dechloro-
greensporone F
in ppm
Synthetic Prᴏduct
∆ (lit-
Greensporone F
in ppm
Synthetic
Prᴏduct 5
in ppm
∆ (lit-
Greensporone
F 5)a
Position
Dechlorogreen
4
in ppm
sporone F 4)a
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1
2
20.9
72.7
18.6
70.7
+2.31
+2.02
+1.44
−0.41
+0.12
+2.99
+0.18
−1.00
+0.24
−0.83
−0.21
+0.73
+0.21
−0.14
0.00
21.5
73.4
18.5
71.0
+2.96
+2.37
+2.11
+2.96
+0.24
+1.37
+0.15
−0.55
+0.33
−1.03
+0.88
+0.79
+0.51
+0.45
+0.33
+0.90
−0.24
+0.20
0.35
3
33.0
31.6
33.8
31.7
4
31.3
31.7
34.7
31.7
5
79.5
79.4
79.3
79.1
6
33.5
30.5
31.6
30.2
7
30.5
30.3
29.8
29.6
8
76.1
77.1
76.3
76.9
9
47.9
47.7
46.6
46.3
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17
18
19
207.7
49.0
208.5
49.2
203.9
48.6
204.9
47.7
134.2
109.2
157.7
98.3
133.5
109.0
157.8
98.3
132.1
113.1
153.3
99.1
131.3
112.6
152.9
98.8
159.0
117.3
167.7
56.0
158.3
117.8
167.7
55.8
+0.70
−0.47
0.00
157.0
119.2
166.9
56.4
156.1
119.4
166.7
56.0
+0.19
20
the synthetic greensporone F (5) {[α]D +30.5 (c 0.12, MeOH)} was different from that of the
reported value {[α]D20 –38.0 (c 0.01, MeOH)}. 2D (DQF-COSY, HMBC, HSQC and NOESY) NMR
data were also not in agreement with the reported data,2 which clearly indicated that the correct
structure of the real isolation products dechlorogreensporone F and greensporone F should be 4a and
5a, respectively.
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Extensive NMR studies on synthetic compounds 5 and 5a were carried out in CDCl3 using 2D
(DQF-COSY, HMBC, HSQC and NOESY) NMR experiments. DQF-COSY and HSQC spectra
confirmed the assignment made by Oberlies et al.2 Further confirmation of the assignment was
obtained by the HMBC data. The spectra displayed the characteristic correlations; H2-6 to C-4 and C-
8, H2-7 to C-5 C-9, H2-9 to C-7, C-10 and C-11 (only with the proton with δH = 2.55 ppm), H2-11 to
C-13 and C-17, H-15 to C-13, C-17 and C-18 and O-Me to C-16 (Figure 3b). Finally, the presence of
H-5/H-8 correlation in the NOESY spectrum proved beyond doubt the cis-configuration at C-5 and C-
8 in the tetrahydrofuran ring (see Supporting Information) of all four compounds. Consequently, the
absolute configuration of the greensporone F is most likely to be (2S,5R,8R) as portrayed for 5a in
Scheme 4 and Figure 1.
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O
O
O
H
H
H
HO
O
Cl
H
O
H
H
Figure 3. (a) Energy-minimized structure of 5a. (b) Key NOE correlations in 5a.
_____________________________________________________________________________
CONCLUSIONS
In summary, the first asymmetric total synthesis of erroneously represented structures of
greensporone (5) and dechlorogreensporone F (4) as well as corrected structures of greensporone F
(5a) and dechlorogreensporone F (4a) were achieved. The key reactions such as transannular acid-
catalyzed oxa-Michael cyclization, ring-closing metathesis (RCM) reaction, and De Brabander’s
esterification were employed. The spectral and analytical data for the reported compounds were
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exactly matching with the synthetic samples 4a and 5a, led to the revision of the real isolated structure
for greensporone F and dechlorogreensporone F. The erroneously represented absolute configuration
(2S,5S,8S)-greensporone F and dechlorogreensporone were revised to (2S,5R,8R)-greensporone F and
dechlorogreensporone F, respectively. We believe that the methodologies and strategies described
herein will find wide application in the asymmetric synthesis of other natural products of this family
for further biological evaluations.
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EXPERIMENTAL SECTION
General Information: All air and/or moisture sensitive reactions were carried out in anhydrous
solvents under an inert atmosphere in flame-dried glassware. All commercially available starting
materials and reagents were used as received without further purification. Anhydrous solvents were
distilled prior to use: THF from Na and benzophenone; DMF, CH2Cl2 from CaH2; MeOH from Mg
cake. Column chromatography was carried out by using silica gel (60–120 mesh). Thin layer
chromatography (TLC) was run on plates (0.25 mm) with pre-coated silica gel GF254, for monitoring
the reactions. Specific rotations [α]D were recorded with Anton Paar MCP 200 digital polarimeter at
20 oC and reported in deg dm−1 cm3 g−1. Diastereomeric ratio was analyzed by Shimadzu LC-MS-8040
instrument. Infrared spectra were recorded in CHCl3 and reported in wave number (cm−1). HRMS
1
13
spectra were recorded by using Waters Q-TOF mass spectrometer. H and C{1H} NMR chemical
1
shifts were reported in ppm downfield from tetramethylsilane relative to the CDCl3, 7.26 ppm for H
NMR and 77.00 ppm for 13C NMR, respectively and coupling constants (J) were reported in hertz
(Hz). Structural assignments were made with additional information from gCOSY, gHSQC, and
gHMBC experiments. The following abbreviations were used to designate signal multiplicity: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
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(S)-Hex-5-en-2-ol (14): A mixture of purified epoxide 13 (10.0 g, 172.4 mmol), copper (I) iodide
−40 °C for 20 min.
(3.26 g, 17.14 mmol,) in THF (100 mL), was vigorously stirred under argon at
−40 °C and the mixture
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Allyl magnesium bromide (344.8 mL, 344.8 mmol) was added dropwise at
allowed to slowly warm to room temperature. The dark brown solution was quenched with NH4Cl
(150 mL) and diluted with ethyl acetate (200 mL). The organic layer was separated and the aqueous
layer extracted with ethyl acetate (2  200 mL). The combined organic layers were dried over Na2SO4,
filtered and the solvent evaporated under reduced pressure to give the crude product 14 which was
used immediately without further characterization.
(S)-tert-Butyl(hex-5-en-2-yloxy)dimethylsilane (15): To a cold solution (0 ºC) of crude alcohol 14
(15.0 g, 150.0 mmol), imidazole (15.3 g, 225.0 mmol), and DMAP (1.68 g, 15.0 mmol) in CH2Cl2
(200 mL) was added TBSCl (37.75 g, 225.0 mmol). The reaction mixture was warmed to room
temperature for 6 h and quenched with saturated NH4Cl solution (100 mL). The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (2 × 100 mL). The combined organic layer was
washed with brine (100 mL), dried over Na2SO4, and concentrated to leave a residue which was
purified by silica gel column chromatography (ethyl acetate/hexane = 1:49) to afford 15 (21.42 g 78%
over two steps) as a colorless liquid. [α]D20 = +15.94 (c 0.32, CHCl3); IR (neat) νmax 2922, 2854, 1629,
1
1458, 1380, 1218, 1087, 770 cm−1; H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H), 5.08–4.94 (m, 2H),
3.80 (m, 1H), 2.18–1.99 (m, 2H), 1.58–1.42 (m, 2H), 1.13 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
13
6H) ppm. C{1H} NMR (125 MHz, CDCl3) δ 138.93, 114.2, 68.1, 38.9, 30.0, 25.90, 25.9, 23.7, −4.4,
−4.7 ppm; EI-MS: m/z Calcd. for C12H27OSi [M + H]+: 215.
tert-Butyldimethyl(((2S)-4-(oxiran-2-yl)butan-2-yl)oxy)silane (16): To a stirred solution of olefin
o
15 (13.5 g, 63.06 mmol) in dry CH2Cl2 (150 mL) at 0 C, was added slowly m-chloroperbenzoic acid
(16.2 g, 94.59 mmol) as a solid and the reaction mixture was stirred for 3 h. The solution was washed
thoroughly with cold aqueous NaOH solution (6.3 g, 157.65 mmol) and the organic layer was
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separated. The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and the
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9
solvent was evaporated to obtain the crude epoxide, which on purification by silica gel column
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chromatography (ethyl acetate/hexane = 1:9) furnished 16 (12.38 g, 85%) as a viscous liquid. [α]D
=
+13.78 (c 0.37, CHCl3); IR (neat) νmax 2852, 2648, 1632, 1465, 1312, 1283, 1061, 753 cm−1; 1H NMR
(500 MHz, CDCl3) δ 3.83 (m, 1H), 2.91 (m, 1H), 2.74 (m, 1H), 2.46 (td, J = 4.7, 2.7 Hz, 1H), 1.64–
1.48 (m, 4H), 1.13 (ddd, J = 8.0, 5.1, 2.9 Hz, 3H), 0.88 (d, J = 0.8 Hz, 9H), 0.05–0.03 (m, 6H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 68.2, 68.0, 52.5, 52.3, 47.1, 47.1, 35.8, 35.4, 28.9, 28.4, 25.9,
25.8, 23.8, 23.6, 18.1, −4.4, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H26O2SiNa:
253.1600, Found: 253.1598.
tert-Butyldimethyl((S)-4-((R)-oxiran-2-yl)butan-2-yloxy)silane (17): A mixture of (R,R)-(-)-N-N’-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-diamino-cobalt-II (0.196 g, 0.32 mmol) toluene (2
mL) and acetic acid (0.15 mL, 2.5 mmol) was stirred while open to the air for 1 h at room temperature.
The solvent was removed under reduced pressure and the brown residue was dried over high vacuum.
The oxirane 16 (15 g, 65.21 mmol) was added in one portion, and the stirred mixture was cooled in an
ice water bath. Water (0.64 mL, 35.5 mmol) was slowly added and the temperature of the reaction
o
mixture was maintained in such a way that it never rises more than 20 C. After 1 h, addition was
complete. The ice bath was removed and the reaction mixture was stirred for 36 h. The crude reaction
mixture was purified by column chromatography to afford the chiral epoxide 17 (6.75 g, 45%) as
colorless oil. [α]D20 = −4.76 (c 0.9, CHCl3); IR (neat) νmax 2932, 2858, 1632, 1465, 1375, 1253, 1061,
772 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.85 (m, 1H), 2.92 (m, 1H), 2.74 (dd, J = 5.0, 4.0 Hz, 1H),
2.47 (dd, J = 5.0, 2.7 Hz, 1H), 1.59 – 1.49 (m, 4H), 1.13 (d, J = 6.1 Hz, 3H), 0.88 (s, 9H), 0.05 (d, J =
2.4 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 68.0, 52.3, 47.1, 35.4, 28.4, 25.9, 25.8, 23.6, -
4.3, -4.7 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H27O2Si: 231.1780, Found: 231.1775.
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(5S,8S)-8-(tert-Butyldimethylsilyloxy)non-1-en-5-ol (18): A mixture of purified epoxide 17 (3.0 g,
8
9
13.02 mmol), copper (I) iodide (2.64 mg, 1.3 mmol) in THF (40 mL) was vigorously stirred under
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−40 °C for 20 min. Allyl magnesium bromide (1M, 21.96 mL, 21.96 mmol) was added
argon at
dropwise and the mixture was allowed to warm room temperature slowly (ca. 1 h). The dark brown
solution was quenched with NH4Cl (30 mL) 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 organic
layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 3:17)
to afford the fragment 18 (3.16 g, 89%) as a colorless liquid. [α]D20 = +15.2 (c 0.25 CHCl3); IR (neat)
νmax 3448, 2927, 2857, 1637, 1457, 1374, 1254, 1047, 772 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.84
(m, 1H), 5.08- 4.94 (m, 2H), 3.85 (m, 1H), 3.62 (m, 1H), 2.26–2.07 (m, 2H), 1.86 (br s 1H), 1.59-1.45
(m, 6H), 1.14 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.05 (d, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
138.7, 144.6, 71.1, 68.5, 36.4, 35.0, 32.9, 30.1, 25.9, 23.5, 18.1, −4.4, −4.7 ppm; HRMS (ESI-TOF):
m/z calcd for C15H33O2Si [M + H]+ 273.2250, Found: 273.2246.
Determination of absolute stereochemistry of hydroxyl group in compound (18):
(S)-((5S,8S)-8-(tert-Butyldimethylsilyloxy)non-1-en-5-yl)-3,3,3-trifluoro-2-methoxy-2-phenyl
propanoate (18′): To a stirred solution of alcohol 18 (20 mg, 0.07 mmol) in CH2Cl2 (2 mL), were
−)
added N,N-dicyclohehylcarbodiimde (DCC) (19 mg, 0.09 mmol), (S)-( -α-methoxy-α-
(trifluoromethyl) phenylacetic acid (S-MTPA) (22 mg, 0.11 mmol) and catalytic amount of DMAP (2
mg) and the reaction was allowed to stir at room temperature for 10 h. After completion of the reaction
(monitored by TLC), it was quenched with saturated aqueous NaHCO3 solution (2 mL) and diluted
with CH2Cl2 (5 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (2
 5 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane =
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1:19) to afford (S)-MTPA ester 18′ (27 mg, 77%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ
7.57–7.53 (m, 2H), 7.42 – 7.37 (m, 3H), 5.72 (ddt, J = 16.3, 9.7, 6.6 Hz, 1H), 5.11 (m, 1H), 4.98–4.90
(m, 2H), 3.78 (m, 1H), 3.56 (d, J = 1.2 Hz, 3H), 2.02 – 1.89 (m, 2H), 1.78 (m, 1H), 1.72–1.60 (m, 3H),
1.49–1.35 (m, 2H), 1.10 (d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.03 (d, J = 5.5 Hz, 6H) ppm.
(R)-((5S,8S)-8-(tert-butyldimethylsilyloxy)non-1-en-5-yl)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate (18″): (R)-MTPA ester 18″ was obtained from the reaction of alcohol 18 with (R)-
(+)-α-methoxy-α-(trifluoromehtyl)phenylacetic acid (R-MTPA) by following the above mentioned
procedure. 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.35 (m, 5H), 5.77 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H),
5.11 (m, 1H), 5.05 – 4.95 (m, 2H), 3.71 (m, 1H), 3.55 (d, J = 0.9 Hz, 3H), 2.11 – 1.99 (m, 2H), 1.85 –
1.69 (m, 2H), 1.58 (m, 1H), 1.36 – 1.28 (m, 2H), 1.04 (d, J = 6.1 Hz, 3H), 0.86 (s, 9H), 0.02 (d, J = 2.7
Hz,6H) ppm.
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(5S,8S)-5-(But-3-en-1-yl)-8,10,10,11,11-pentamethyl-2,4,9-trioxa-10-siladodecane (19): To
a
stirred solution of alcohol 18 (1.2 g, 4.41 mmol) in CH2Cl2 (20 mL) under nitrogen atmosphere, was
added diisopropylethylamine (2.3 mL, 17.83 mmol) followed by MOMCl (0.7 mL, 8.32 mmol) at 0 oC
and allowed to stir for 5 h. After complete consumption of the starting material (monitored by TLC),
the reaction mixture was quenched with water (20 mL) and diluted with CH2Cl2 (20 mL). The organic
layer was separated and the aqueous layer extracted with CH2Cl2 (2 × 30 mL). The combined organic
layer was quickly washed with 1N HCl (40 mL) to remove excess diisopropylethylamine. The organic
layer was washed with brine (40 mL), dried over anhydrous Na2SO4 and evaporated under reduced
pressure to obtain the crude product which on purification by silica gel column chromatography (ethyl
20
acetate/hexane = 1:19) furnished the desired MOM ether 19 (1.35 g, 97%) as a colorless liquid. [α]D
1
= +2.14 (c 1.08, CHCl3); IR (neat) νmax 2930, 1453, 1219, 1042, 772 cm−1; H NMR (300 MHz,
CDCl3) δ 5.83 (m, 1H), 5.08 – 4.92 (m, 2H), 4.65 (q, J = 6.7 Hz, 2H), 3.79 (m, 1H), 3.57(m, 1H), 3.38
(s, 3H), 2.23-2.02 (m, 2H), 1.66 – 1.54 (m, 3H), 1.53 – 1.37 (m, 3H), 1.13 (d, J = 6.0 Hz, 3H), 0.08 (s,
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9H), 0.05 (d, J = 2.9 Hz, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 138.5, 114.4, 95.4, 76.9, 68.5,
8
9
−4.3, −4.7 ppm; HRMS (ESI
55.4, 34.9, 33.5, 30.0, 29.5, 25.8, 23.7, 18.0,
-TOF): m/z calcd for
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C17H36NaO3Si [M + Na]+ 339.2326, Found: 339.2341.
(2S,5S)-5-(Methoxymethoxy)non-8-en-2-ol (11): To a solution of TBS-ether 19 (1.0 g, 3.16 mmol)
o
in THF (20 mL), was added TBAF (3.79 mL of a 1 M solution in THF) at 0 C. After complete
consumption of the starting material (monitored by TLC), the reaction mixture was quenched by
addition of saturated NH4Cl solution (15 mL) and diluted with ethyl acetate (30 mL). The organic
layer was separated and the aqueous layer extracted with ethyl acetate (2 × 25 mL). The combined
organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (ethyl acetate/hexane = 1:2) gave alcohol 11 (602
20
mg, 94%) as a colorless liquid. [α]D = +12.75 (c 1.44, CHCl3); IR (neat) νmax 3412, 2950, 1638,
1371, 1052, 771 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.82 (m, 1H), 5.07 – 4.94 (m, 2H), 4.66 (s, 2H),
3.81 (m, 1H), 3.59 (m, 1H), 3.39 (s, 3H), 2.19 – 2.04 (m, 2H), 1.96 (br s, 1H), 1.68 –1.56 (m, 4H),
13
1.55-1.49 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 138.4, 114.6,
95.4, 77.0, 67.8, 55.6, 34.5, 33.3, 30.1, 29.5, 23.5 ppm; HRMS (ESI-TOF): m/z calcd for C11H22O3Na
[M + Na]+ 225.1461, Found: 225.1452.
5,7-Dihydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (20a): To a stirred solution of 2,4,6-
trihydroxybenzoic acid monohydrate (20) (15.0 g, 88.2 mmol) in 1,2-dimethoxy ethane (250 mL),
were added SOCl2 (19.2 mL, 264 mmol), DMAP (2.1 g, 17.6 mmol), and acetone (19.6 mL, 264
mmol) at 0 oC. The reaction mixture was slowly brought to room temperature and stirred for 6 h. After
completion of the reaction (monitored by TLC), volatiles were removed under reduced pressure,
poured into a saturated aqueous NaHCO3 solution (300 mL) and extracted with ethyl acetate (3  300
mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude product obtained was purified by column
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chromatography over silica gel (ethyl acetate/hexane = 1:9) to afford compound 20a (15.2 g, 82%) as
light yellow solid. Rf 0.52 (ethyl acetate/hexane = 1:4); Mp. 203–205 oC; IR (CHCl3) νmax 3765, 3182,
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2920, 1635, 1540, 1265, 1060 cm−1; H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 10.29 (s, 1H),
6.01 (d, J = 2.1 Hz, 1H), 5.94 (d, J = 2.1 Hz, 1H), 1.66 (s, 6H) ppm; C{1H} NMR (100 MHz,
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DMSO-d6): δ 166.3, 163.5, 162.1, 156.9, 106.4, 97.3, 95.3, 91.8, 25.1 ppm; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C10H11O5: 211.0601, found: 211.0601.
7-(Benzyloxy)-5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (20b): To a stirred solution
of compound 20a (8.0 g, 38.1 mmol) and benzyl alcohol (4.3 mL, 41.9 mmol) in THF (80 mL) at 0
°C, were added triphenyl phosphine (11.0 g, 41.9 mmol) and DIAD (8.2 mL, 41.9 mmol). The reaction
mixture was warmed to room temperature and stirred for 4 h. After completion of the reaction
(monitored by TLC), it was quenched with water (100 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2  100 mL). The combined organic layers were washed
with water (70 mL), brine (70 mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude mass was purified by silica gel column chromatography (ethyl acetate/hexane =
1:19) to furnish compound 20b (9.6 g, 84 %) as white solid. Rf 0.55 (ethyl acetate/hexane = 1:9); Mp.
145‒147 C; IR (CHCl3) νmax 3200, 3021, 1684, 1640, 1586, 1501, 1275, 1160, 1105 cm−1; 1H NMR
o
(500 MHz, CDCl3) δ 10.45 (s, 1H), 7.42‒7.39 (m, 4H), 7.36 (m, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.08 (d,
J = 2.3 Hz, 1H), 5.06 (s, 2H), 1.73 (s, 6H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 166.7, 165.1,
13
163.0, 156.8, 135.5, 128.7, 128.4, 127.5, 106.9, 96.5, 95.3, 93.2, 70.4, 25.6 ppm .; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C17H16O5Na: 323.0895, found: 323.0894.
2,2-Dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesulfonate (20c): Anhydrous
Et3N (12.4 mL, 90.0 mmol) and trifluolomethanesulfonic anhydride (7.5 mL, 45.0 mmol) were
successively added to a solution of compound 20b (9.0 g, 30.0 mmol) in anhydrous dichloromethane
(50 mL) and the mixture was stirred at 0 ºC for 2 h. The reaction was quenched with water (50 mL)
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and the reaction mixture was extracted with dichloromethane (3  50 mL). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography (ethyl acetate/hexane = 1:9) to afford compound
20c (11.7 g, 90%) as a white solid. Rf 0.6 (ethyl acetate/hexane = 1:4); Mp. 87–89 oC; IR (CHCl3) νmax
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3020, 1692, 1574, 1436, 1385, 1106, 1090 cm−1; H NMR (500 MHz, CDCl3) δ 7.44‒7.35 (m, 5H),
6.60 (d, J = 2.3 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 5.10 (s, 2H), 1.74 (s, 6H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 164.6, 158.8, 157.0, 149.9, 134.6, 128.9, 128.8, 127.6,123.5, 120.3, 117.1, 113.9,
106.6, 105.8, 102.0, 71.2, 25.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16F3O7S:
433.0568, Found: 433.0572.
5-Allyl-7-(benzyloxy)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (12): To a stirred solution of
triflate 21c (8.0 g, 18.51 mol) in anhydrous DMF (80 mL), LiCl (1.55 g, 36.90 mmol), Pd(PPh3)4 (1.06
g, 0.91 mmol) and allyltributyltin (8.6 mL, 25.98 mmol) were added at room temperature. The
o
resulting mixture was heated (oil bath) to 80 C and stirred for 4 h. After completion of the reaction
(monitored by TLC), it was quenched with H2O (100 mL) and extracted with ethyl acetate (3 × 100
mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude mass was purified by column
chromatography (ethyl acetate/hexane = 1:11) to obtain 12 (4.92 g, 82%) as a colorless liquid. Rf 0.7
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(ethyl acetate/hexane = 1:4); IR (neat): νmax = 2927, 1725, 1612, 1355, 1283, 1165, 1054 cm−1; H
NMR (400 MHz, CDCl3): δ 7.42-7.37 (m, 5H), 6.6 (d, J = 2.4 Hz, 1H), 6.4 (d, J = 2.4 Hz, 1H), 6.02
13
(m, 1H), 5.09‒5.05(m, 4H), 3.86 (d, J = 6.5 Hz, 2H), 1.69 (s, 6H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 164.0, 160.0, 159.0, 147.2, 136.4, 135.7, 128.7, 128.3, 127.6, 127.5, 116.3, 112.7, 105.0,
100.3, 70.4, 70.2, 38.4, 25.6 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H21O4: 325.1434,
Found: 325.1438.
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7-(Benzyloxy)-5-(2-hydroxybut-3-enyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one
(21): 2,6-
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Lutidine (2.75 mL, 25.66 mmol), OsO4 (2.1 mL, 0.21 mmol, 0.1M in toluene), and NaIO4 (9.2 g,
43.19 mmol) were added to a stirred solution of compound 12 (3.5 g, 10.8 mmol) in dioxane and water
(3:1, 60 mL) and stirred at room temperature. After completion of the reaction (monitored by TLC), it
was quenched with water (30 mL). The organic solvent was removed under reduced pressure and the
aqueous layer extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was washed with 1N
HCl (100 mL), water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The organic
solvent was removed under reduced pressure and the crude mass was purified by silica gel
chromatography (ethyl acetate/hexane = 1:5) to afford the resulting aldehyde (3.14 g, 89%) as a
colorless viscous liquid, which was used for the next reaction without characterization.
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To a stirred solution of resulting aldehyde (3.0 g, 9.2 mmol) in anhydrous THF (50 mL), was added
vinyl magnesium bromide (13.8 mL, 13.8 mmol, 1M in THF) in THF at −40 oC and stirred for 30 min.
After completion of the reaction (monitored by TLC), it was quenched with saturated ammonium
chloride solution (30 mL) and diluted with ethyl acetate (60 mL). The organic layer was separated and
the aqueous layer extracted with ethyl acetate (3  50 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (ethyl acetate/hexane = 1:4) to furnish the desired allylic alcohol 21
1
(2.83 g, 87%). IR (neat): νmax = 3451, 2933, 1717, 1410, 1202, 1162 cm−1; H NMR (400 MHz,
CDCl3) δ 7.41-7.34 (m, 5H), 6.60 (d, J = 2.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 5.97 (ddd, J = 17.1,
10.5, 5.6 Hz, 1H ), 5.26 (dt, J = 17.2, 1.5 Hz, 1H ), 5.10 (dt, J = 10.5, 1.4 Hz, 1H), 4.39 (dt, J = 8.1,
5.7 Hz, 1H), 3.33 (dd, J = 13.0, 4.5 Hz, 1H), 3.23 (dd, J = 13.0, 8.1 Hz, 1H ), 2.67 (br s, 1H), 1.69 (d, J
= 5.5 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 163.9, 161.5, 159.0, 145.1, 140.5, 135.6,
128.7, 128.4, 127.5, 114.5, 114.4, 105.8, 105.2, 101.0, 73.7, 70.3, 41.8, 25.8, 25.3 ppm; HRMS: m/z
calcd for C21H23O5 [M + H]+ 355.1545, Found 355.1561.
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7-(Benzyloxy)-5-(2-(tert-butyldimethylsilyloxy)but-3-enyl)-2,2-dimethyl-4H-enzo[d][1,3]-dioxin-
4-one (10): To a stirred solution of alcohol 21 (2.0 g, 5.64 mmol), imidazole (500 mg, 7.35 mmol),
and DMAP (34 mg, 0.27 mmol) in CH2Cl2 (40 mL), was added TBSCl (1.27 g, 8.46 mmol) at 0 ºC.
The reaction mixture was warmed to room temperature, stirred for 3 h and quenched with saturated
NH4Cl solution (30 mL). The organic layer was separated and the aqueous layer extracted with
CH2Cl2 (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (ethyl acetate/hexanes = 1:5) to afford 10 (2.57 g, 97%) as a colorless liquid.
IR (neat): νmax = 2942, 1729, 1613, 1283, 1165, 841 cm−1; 1H NMR (400 MHz, CDCl3) δ7.41-7.35 (m,
5H), 6.6 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.93 (ddd, J = 17.1, 10.4, 5.5 Hz, 1H), 5.21 (dt,
J = 17.2, 1.6 Hz, 1H), 5.08 – 5.00 (m, 3H), 4.44 (m, 1H), 3.53 (dd, J = 12.4, 3.9 Hz, 1H), 2.86 (dd, J =
12.4, 8.4 Hz, 1H), 1.69 (d, J = 9.9 Hz, 6H), 0.83 (s, 9H), −0.10 (s, 3H), −0.24 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 163.4, 160.3, 158.9, 145.8, 141.5, 135.8, 128.7, 128.3, 127.5, 115.6, 105.1,
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−4.7, −5.2 ppm; HRMS (ESI
104.9, 100.9, 73.4, 70.1, 43.7, 25.8, 25.5, 18.1,
C27H37O5Si [M + H]+ 469.2410, Found: 469.2428.
-TOF): m/z calcd for
(2S,5S)-5-(Methoxymethoxy)non-8-en-2-yl-4-(benzyloxy)-2-(2-(tert-butyldimethyl)silyloxy)-but-
3-enyl)-6-hydroxybenzoate (22): To a suspension of NaH (0.047 g, 47.52 mmol) (washed with
anhydrous hexane twice to remove mineral oil and dried under vacuum) in dry THF (10 mL), alcohol
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11 (0.4 g, 1.98 mmol) was added at 0 C under nitrogen atmosphere and stirred for 30 min. The 1,3-
benzodioxin derivative 10 (0.74 g, 1.58 mmol) was added in THF (5 mL) to the reaction mixture at 0
oC. The suspension was stirred for 1 h at room temperature. After completion of the reaction
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(monitored by TLC), it was quenched with cold water (10 mL) at 0 C and diluted with ethyl acetate
(30 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 30
mL). The combined organic layer was dried over anhydrous Na2SO4 and solvent was removed under
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reduced pressure. The crude mass was purified by silica gel chromatography (ethyl acetate/hexane =
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1:9) to obtain 22 (1.09 g, 90%) as a colorless liquid. [α]D = +17.34 (c 0.28, CHCl3); IR (neat) νmax
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3462, 2925, 1629, 1219, 1052, 771 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.32 (m, 5H), 6.43 (s,
2H), 5.93 (m, 1H), 5.80 (m, 1H), 5.34 – 5.22 (m, 2H), 5.10 (m,1H), 5.06 (d, J = 1.5 Hz, 2H), 5.01 (m,
1H), 4.96 (m, 1H), 4.67 – 4.61 (m, 2H), 4.30 (m, 1H), 3.59 (m, 1H), 3.51 (dd, J =12.9, 2.6 Hz, 1H),
3.37 (s, 3H), 3.34 (m, 1H), 2.79 (dd, J = 12.9, 9.5 Hz, 1H), 2.61 (dd, J = 12.9, 9.7 Hz, 1H), 2.15 – 2.04
(m, 2H), 1.87 (m, 1H), 1.74 – 1.60 (m, 3H), 1.39 (d, J = 6.1 Hz, 3H), 0.79 (d, 9H), −0.18 (d, 3H),
−0.38 (d, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 171.1, 171.0, 165.6, 165.3, 162.6, 143.4,
143.4, 141.4, 138.2, 136.3, 128.6, 128.1, 127.4, 114.8, 114.2, 113.9, 113.7, 105.8, 105.3, 100.5, 100.4,
95.6, 76.5, 76.5, 73.9, 73.8, 72.6, 72.5, 69.8, 55.6, 44.8, 44.4, 33.5, 33.4, 31.6, 31.4, 30.2, 30.2, 29.5,
29.4, 25.8, 25.8, 20.2, 20.2, 18.1, −4.8, −4.9, −5.4, −5.5 ppm; HRMS (ESI-TOF): m/z calcd for
C35H52O7NaSi [M + Na]+ 635.3375, Found: 635.3380.
(2S,5S)-5-(Methoxymethoxy)non-8-en-2-yl-4-(benzyloxy)-2-(2-(tert-butyldimethyl)silyloxy) but-
3-enyl)-6-methoxybenzoate (23): To a suspension of NaH (0.078 g, 3.25 mmol) (washed with hexane
twice to remove mineral oil and dried under vacuum) in anhydrous THF (5 mL), phenolic compound
22 (0.5 g, 0.81 mmol) was added in THF (5 mL) at 0 oC under nitrogen atmosphere and stirred for 30
min. Methyl iodide (0.07 mL, 0.49 mmol) was added at the same temperature. The reaction mixture
was warmed to room temperature and stirring was continued for 1 h. After completion of the reaction
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(monitored by TLC), it was quenched with cold water (15 mL) at 0 C and diluted with ethyl acetate
(25 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 20
mL). The combined organic layers were dried over anhydrous Na2SO4 and solvent was removed under
reduced pressure. The crude mass was purified by silica gel column chromatography (ethyl
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acetate/hexane = 1:15) to obtain 23 (0.455 g, 89%) as a colorless liquid. [α]D = +6.09 (c 0.4,
CHCl3); IR (neat) νmax 2926, 2856, 1717, 1598, 1457, 1155, 1038, 775 cm−1; 1H NMR (400 MHz,
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CDCl3) δ 7.44-7.30 (m, 5H), 6.47 (dd, J = 3.9, 2.2 Hz, 1H), 6.41 (d, J = 1.95 Hz, 1H), 5.87 – 5.76 (m,
2H), 5.20 – 5.12 (m, 2H), 5.09 – 4.99 (m, 4H), 4.95 (m, 1H), 4.65 (s, 2H), 4.35 (m, 1H), 3.75 (s, 3H),
3.60 (m, 1H), 3.38 (s, 3H), 2.80 (m, 1H), 2.63 (m, 1H), 2.19 – 2.04 (m, 2H), 1.82 – 1.54 (m, 6H), 1.34
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−0.11 (s, 3H), −0.21 (s, 3H) ppm; 13
(t, J = 5.0 Hz, 3H), 0.84 (s, 9H),
C{1H} NMR (100 MHz, CDCl3)
δ 167.9, 167.9, 159.7, 157.8, 141.1, 141.1, 138.5, 138.4, 136.6, 128.6, 128.1, 127.5, 114.6, 113.8,
109.1, 109.0, 97.8, 95.5, 74.0, 73.9, 71.7, 70.0, 55.8, 55.5, 42.6, 33.6, 31.4, 29.9, 29.8, 29.5, 25.9, 20.2,
20.1, 18.1, −4.9, −5.2 ppm; HRMS (ESI-TOF): m/z calcd for C36H55O7Si [M + H]+ 627.3712, Found:
627.3717.
(2S,5S)-5-(Methoxymethoxy)non-8-en-2-yl-4-(benzyloxy)-2-(2-hydroxybut-3-enyl)-6-methoxy
benzoate (24): The HF·pyridine complex (70% HF, 3.0 mL) was added dropwise to a stirred solution
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of compound 23 (300 mg, 0.48 mmol) in THF (7.0 mL, in a plastic test tube) at 0 C. The reaction
mixture was allowed to warm to room temperature. After 10 h, the mixture was partitioned between an
ice-cooled mixture of ethyl acetate (20 mL) and saturated aqueous NaHCO3 solution (15 mL). The
organic layer was separated and the aqueous layer extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1:4) to furnish
24 (201 mg, 82%) as a colorless liquid. [α]D20 = +9.1 (c 0.6, CHCl3); IR (neat) νmax 3352, 2856, 1717,
1598, 1457, 1264, 1155, 1038, 724 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 6.48 –
6.42 (m, 2H), 5.96 – 5.75 (m, 2H), 5.28 (m, 1H), 5.19 (ddd, J = 7.5, 6.2, 4.2 Hz, 1H), 5.10 (d, J = 10.4
Hz, 1H), 5.07 (s, 3H), 5.02 (m, 1H), 4.96 (d, J = 10.2 Hz, 1H), 4.65 (d, J = 2.8 Hz, 1H), 4.31 (m, 1H),
3.77 (s, 1H), 3.59 (m, 1H), 3.38 (d, J = 2.0 Hz, 1H), 2.85 (dd, J = 13.7, 4.4 Hz, 1H), 2.68 (ddd, J =
13.7, 8.8, 4.9 Hz, 1H), 2.13 (m, 1H), 1.82 – 1.62 (m, 4H), 1.59 – 1.53 (m, 2H), 1.34 (dd, J = 6.2, 4.4
Hz, 1H)ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.6, 168.5, 160.5, 158.3, 140.5, 140.5, 138.6,
138.4, 136.4, 128.6, 128.1, 127.5, 117.6, 116.8, 114.6, 114.5, 107.6, 98.1, 95.5, 73.1, 72.3, 70.1, 55.7,
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55.6, 41.5, 41.5, 33.6, 33.5, 31.5, 29.9, 29.7, 29.5, 20.3, 20.1 ppm; HRMS (ESI-TOF): m/z calcd for
C30H40NaO7 [M + Na]+ 535.2666, Found: 535.2681.
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(2S,5S)-5-(Methoxymethoxy)non-8-en-2-yl-4-(benzyloxy)-2-methoxy-6-(2-oxobut-3-enyl)
benzoate (9): To a stirred solution of allyl alcohol 24 (190 mg, 0.38 mmol) in CH2Cl2 (20 mL), was
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added Dess-Martin periodinane (230 mg, 0.57 mmol) at 0 C. The resulting reaction mixture was
stirred at same temperature for 1 h. After completion of the reaction (monitored by TLC), it was
filtered through a small bed of Celite and washed with CH2Cl2 (20 mL). The filtrate was washed with
saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The
combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification of the crude reaction mass by column chromatography on silica gel (ethyl acetate/hexane
= 3:17) afforded the ketone 9 (169 mg, 89%) as a colorless liquid. [α]D20 = +7.97 (c 0.32, CHCl3); IR
(neat) νmax 2924, 1649, 1582, 1219, 1027, 771 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.42–7.31 (m,
5H), 6.47 (d J = 2.2 Hz, 1H), 6.44 – 6.37 (m, 2H), 6.29 (dd, J = 17.3, 1.2 Hz, 1H), 5.86 – 5.77 (m, 2H),
5.13 (m, 1H), 5.04 (s, 2H), 5.01 (m, 1H), 4.95 (m, 1H), 4.64 (s, 2H), 3.89 (dd, J = 16.2 Hz, 2H), 3.78
(s, 3H), 3.59 (m, 1H), 3.37 (s, 3H), 2.17 – 2.06 (m, 2H), 1.76 – 1.57 (m, 6H), 1.30 (d, J = 6.4 Hz, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ (100 MHz, CDCl3) δ 196.6, 167.4, 160.7, 158.7, 138.4,
136.3, 135.3, 134.8, 129.0, 128.6, 128.1, 127.5, 114.6, 107.8, 98.6, 95.5, 76.6, 72.0, 70.2, 55.8, 55.6,
45.2, 33.5, 31.4, 29.8, 29.5, 20.1 ppm; HRMS (ESI-TOF): m/z calcd for C30H38NaO7 [M + Na]+
533.2510, Found: 533.2504.
(3S,6S,E)-14-(Benzyloxy)-16-methoxy-6-(methoxymethoxy)-3-methyl-3,4,5,6,7,8-hexahydro-1H-
benzo[c][1]oxacyclotetradecine-1,11(12H)-dione (7): Hovyeda Grubbs second generation catalyst
(27 mg, 0.03 mmol) was dissolved in dry, deoxygenated CH2Cl2 (80 mL) under argon atmosphere.
After the solution was heated (oil bath) to reflux, diene 9 (140 mg, 0.3 mmol) dissolved in anhydrous
and deoxygenated CH2Cl2 (30 mL) was added slowly via syringe (ca. 30 min) to the reaction mixture.
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It was then stirred under reflux conditions (oil bath) for an additional 3 h. After completion of the
reaction (monitored by TLC), solvent was evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl acetate/hexane = 1:4) to obtain macrolactone 7
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(106 mg, 80%) as a colorless liquid. [α]D = +31.1 (c 0.4, CHCl3); IR (neat) νmax 2923, 2314, 1612,
1218, 1157, 1035, 771 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.44-7.31 (m, 5H), 6.77 (m, 1H), 6.49 (d,
J = 2.2 Hz, 1H), 6.47 (d, J = 2.1, 1H), 6.10 (d, J = 15.5 Hz, 1H), 5.16 (m, 1H), 5.05 (s, 2H), 4.68 (d, J
= 6.8 Hz, 1H), 4.59 (d, J = 6.8 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 3.78 (s, 3H), 3.53 (m, 1H), 3.47 (d,
J = 15.5 Hz, 1H), 3.37 (s, 3H), 2.30 – 2.24 (m, 2H), 1.94 (m, 1H), 1.86 – 1.68 (m, 3H), 1.65-1.57 (m,
2H), 1.36 (d, J = 6.2 Hz, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 196.9, 167.7, 160.8, 159.3,
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147.5, 136.2, 135.7, 129.4, 128.6, 128.2, 127.6, 116.9, 107.7, 98.8, 95.4, 75.0, 70.4, 70.2, 56.0, 55.5,
45.4, 31.4, 30.8, 28.7, 27.7, 20.0 ppm; HRMS (ESI-TOF): m/z calcd for C28H34NaO7 [M + Na]+
505.2197, Found: 505.2173.
(2S,5R,8R)-Dechlorogreensporone F (4a) (Revised Structure):To a stirred solution of 7 (18 mg,
0.036 mmol) in CH2Cl2 (5 mL), TiCl4 (0.36 mL, 0.36 mmol, 1 M in CH2Cl2) was added at 0 °C and
the reaction mixture stirred at room temperature for 20 min. After completion of the reaction
(monitored by TLC), it was quenched with a saturated solution of NaHCO3 (5 mL) and diluted with
CH2Cl2 (10 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (2 ×
10 mL). The combined organic layer was dried with anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane
= 1:1) to afford compound 4 (11 mg, 84%) as a white amorphous solid. [α]D20 = −29.8 (c 1.0, MeOH);
IR (neat) νmax 3446, 2922, 1746, 1456, 1220, 1157, 1036, 770 cm−1; 1H NMR (500 MHz, CDCl3) δ
6.33 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.90 (br s, 1H), 5.27 (m, 1H), 4.13 (m, 1H), 4.02 (d,
J = 16.9 Hz, 1H), 3.91 (d, J = 16.9 Hz, 1H), 3.82 (m, 1H), 3.77 (s, 3H), 2.64 (dd, J = 13.7, 3.6 Hz,
1H), 2.55 (dd, J = 13.7, 8.3 Hz, 1H), 1.98 (m, 1H), 1.93 (m, 1H),1.84 (m, 2H), 1.65 (m, 1H), 1.54 (m,
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1H), 1.50 (m, 2H), 1.32 (d, J = 6.4 Hz, 3H) ppm; C{1H} NMR (125 MHz, CDCl3) δ 207.7, 167.6,
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159.0, 157.7, 134.1, 117.2, 109.2, 98.3, 79.4, 76.1, 72.6, 55.9, 48.8, 47.9, 33.3, 32.9, 31.3, 30.4, 20.8
ppm; HRMS (ESI-TOF): m/z calcd for C19H25O6 [M + H]+ 349.1651.1646, Found: 349.1652.
(3S,6S,E)-14-(Benzyloxy)-13-chloro-16-methoxy-6-methoxymethoxy)-3-methyl-3,4,5,6,7,8-hexa
hydro-1H-benzo[c][1]oxacyclo-tetradecine-1,11(12H)-dione (8): To the solution of compound 7 (40
mg, 0.08 mmol) in dry CH2Cl2 (5 mL), was added SO2Cl2 (0.01 mL, 0.13 mmol)) in CH2Cl2 (2 mL) at
0 °C. After 30 min the reaction was quenched by the addition of 5% aqueous NH4Cl solution (5 mL),
diluted with CH2Cl2 (10 mL). The organic layer was separated and washed with brine solution (10
mL), dried over anhydrous Na2SO4 concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane = 1:3) to give compound 8 (36.5 mg, 85%) as
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a colorless liquid. [α]D = +5.20 (c 2.0, CH3OH); IR (neat) νmax 2816, 2305, 1425, 1213, 1029, 735
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.32 (m, 5H), 6.78 (dt, J = 15.7, 8.0 Hz, 1H), 6.53 (s, 1H),
6.09 (d, J = 15.4 Hz, 1H), 5.20 (s, 2H), 5.11 (m, 1H), 4.66 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz,
1H), 4.14 (d, J = 16.9 Hz, 1H), 3.98 (d, J = 16.9 Hz, 1H), 3.78 (s, 3H), 3.42 (m, 1H), 3.35 (s, 3H),
2.28– 2.20 (m, 2H), 2.07 – 1.90 (m, 2H), 1.77 – 1.60 (m, 4H), 1.33 (d, J = 6.2 Hz, 1H) ppm; 13C{1H}
NMR (125 MHz, CDCl3) δ 195.0, 166.9, 156.7, 156.0, 147.2, 135.9, 133.2, 128.7, 128.3, 128.2, 127.0,
118.2, 116.7, 97.7, 95.3, 75.7, 71.4, 71.1, 56.3, 55.5, 44.0, 31.4, 31.0, 28.9, 27.9, 19.8 ppm; HRMS
(ESI-TOF): m/z calcd for C28H33O7ClNa [M + Na]+ 539.1813, Found: 539.1813.
(2S,5R,8R)-Greensporone F (5a) (Revised Structure): To a stirred solution of 8 (30 mg, 0.057
mmol) in CH2Cl2 (5 mL), TiCl4 (1.14 mL, 1.14 mmol, 1 M in CH2Cl2) was added at 0 °C and the
reaction mixture stirred at room temperature for 2 h. After completion of the reaction (monitored by
TLC), it was quenched with a saturated solution of NaHCO3 (5 mL) and diluted with CH2Cl2 (10 mL).
The organic phase was separated and the aqueous phase extracted with ethyl acetate (3 × 10 mL). The
combined organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure,
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and the residue purified by silica gel column chromatography (ethyl acetate/hexane = 1:1) to afford
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−35.2 (
= c 0.25, MeOH); IR (neat)
compound 5 (18.5 mg, 83%) as a white amorphous solid. [α]D
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νmax 3341, 2714, 1525, 1213, 1083, 1029, 735 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.57 (s, 1H), 5.87
(br s, 1H), 5.23 (m, 1H), 4.35 (m, 1H), 4.13 (d, J = 18.5 Hz, 1H), 4.0 (d, J = 18.4 Hz, 1H), 3.81 (m,
1H), 3.78 (s, 3H), 2.81 (dd, J = 13.5, 4.6 Hz, 1H), 2.55 (dd, J = 13.5, 7.1 Hz, 1H), 2.02 (m, 1H), 1.91
(m, 1H), 1.90 (m, 1H), 1.80 (m, 1H),1.75 (m, 1H),1.71 (m, 1H), 1.55 (m, 1H), 1.39 (m, 1H), 1.32 (d, J
= 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 204.0, 166.9, 157.0, 153.3, 132.0, 119.1,
113.1, 99.1, 79.3, 76.3, 73.4, 56.3, 48.6, 46.6, 34.7, 33.8, 31.5, 29.8, 21.45 ppm. HRMS (ESI-TOF):
m/z calcd for C19H23O6ClNa [M + Na]+ 405.1081, Found: 405.1088.
tert-Butyldimethyl((S)-4-((S)-oxiran-2-yl)butan-2-yloxy)silane (17a): A mixture of (S,S)-(-)-N-N’-
bis(3,5-di-tert-butyl salicylidene)-1,2-cyclohexanediamino-cobalt-II (0.131 g, 0.21 mmol) toluene (4
mL) and acetic acid (0.1 mL, 1.78 mmol) was stirred while open to the air for 1 h at room temperature.
The solvent was removed under reduced pressure and the brown residue was dried over high vacuum.
The oxirane 16 (10.0 g, 43.47 mmol) was added in one portion, and the stirred mixture was cooled in
an ice water bath. Water (0.43 mL, 23.88 mmol) was slowly added and the temperature of the reaction
mixture was maintained in such a way that it never rises more than 20 oC. After addition was complete
(1 h), the ice bath was removed and the reaction mixture was stirred at room temperature for 24 h.
The crude reaction mixture was purified by silica gel column chromatography to afford the chiral
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epoxide 17a (4.5 g, 45%) as a colorless viscous liquid. [α]D = +9.2 (c 1.2, CHCl3); IR (neat) 2962,
2633, 1647, 1435, 1389, 1057, 782 cm−1; 1H NMR (500 MHz, CDCl3) δ 3.81 (m, 1H), 2.91 (m, 1H),
2.74 (dd, J = 4.9, 4.1 Hz, 1H), 2.46 (dd, J = 5.0, 2.7 Hz, 1H), 1.66–1.48 (m, 4H), 1.14 (d, J = 6.1 Hz,
3H), 0.88 (s, 9H), 0.04 (d, J = 4.8 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 68.2, 52.5, 47.1,
35.8, 28.9, 26.0, 25.9, 23.9, 19.0, 18.1, −4.4, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H27O2Si: 231.1780, Found: 231.1778.
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(5R,8S)-8-(tert-Butyldimethylsilyloxy)non-1-en-5-ol (18a): Compound 18a (2.9 g, 89%) was
prepared from 17a by following the similar procedure described for the synthesis of compound 18.
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[α]D = +7.4 (c 1.0, CHCl3); IR (neat) νmax 3394, 2939, 2862, 1461, 1373, 1254, 1135, 1059, 764
cm−1; H NMR (500 MHz, CDCl3) δ 5.84 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.07– 4.94 (m, 2H), 3.88
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(m, 1H), 3.58 (m, 1H), 2.25–2.08 (m, 2H), 1.61–1.49 (m, 6H), 1.15 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H),
0.07 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 138.7, 114.6, 71.5, 68.7, 36.6, 35.8, 33.2, 30.1,
25.9, 23.2, 18.1, −4.5, −4.8 ppm; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H33O2Si: 273.2250,
Found: 273.2255.
Determination of absolute stereochemistry of hydroxyl group in compound (18a):
(S)-((5R,8S)-8-(tert-Butyldimethylsilyloxy)non-1-en-5-yl)3,3,3-trifluoro-2-methoxy-2-phenylpro
panoate (18a′): (S)-MTPA ester 18a′ was prepared as a colorless liquid from 18a following the
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similar protocol utilized for the synthesis of 18′. H NMR (400 MHz, CDCl3) δ 7.42 – 7.35 (m, 5H),
5.78 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.09 (m, 1H), 5.04 – 4.96 (m, 2H), 3.69 (dd, J = 11.9, 6.0 Hz,
1H), 3.56 (d, J = 1.2 Hz, 3H), 2.12 – 2.03 (m, 2H), 1.83 – 1.67 (m, 3H), 1.52 (m, 1H), 1.32 – 1.25 (m,
2H), 1.04 (d, J = 6.1 Hz, 3H), 0.86 (s, 9H), 0.01 (d, J = 6.2 Hz, 3H) ppm.
(R)-((5R,8S)-8-(tert-Butyldimethylsilyloxy)non-1-en-5-yl)3,3,3-trifluoro-2-methoxy-2-phenylpro
panoate (18a″): (R)-MTPA ester 18a″ was prepared as a colorless liquid from 18a following the
similar protocol utilized for the synthesis of 18′. 1H NMR (500 MHz, CDCl3) δ 7.42–7.35 (m, 5H),
5.72 (ddt, J = 16.3, 9.6, 6.6 Hz, 1H), 5.09 (m, 1H), 4.98–4.92 (m, 2H), 3.76 (dd, J = 11.9, 6.0 Hz, 1H),
3.55 (d, J = 1.0 Hz, 3H), 2.02–1.89 (m, 2H), 1.80 (m, 1H), 1.73–1.59 (m, 3H), 1.45–1.39 (m, 2H), 1.11
(d, J = 6.1 Hz, 3H), 0.87 (s, 9H), 0.03 (d, J = 6.9 Hz, 3H) ppm.
(5R,8S)-5-(But-3-enyl)-8,10,10,11,11-pentamethyl-2,4,9-trioxa-10-siladodecane (19a): Compound
19a (1.5 g, 98%) was prepared from 18a by following the similar procedure described for the
synthesis of compound 19. [α]D20 = +11.5 (c 1.9, CHCl3); IR (neat) νmax 2943, 1459, 1373, 1216,1158,
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