Total synthesis of (+)-methynolide using a Ti-mediated aldol reaction of a lactyl-bearing oxazolidin-2-one, and a vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1016/j.tet.2017.03.093

A highly convergent total synthesis of (+)-methynolide, based on two types of stereoselective aldol reaction, was achieved. The C1-C8 and C9-C11 fragments of (+)-methynolide were prepared by a vinylogous Mukaiyama aldol reaction using a vinyl ketene silyl

Full text of DOI:10.1016/j.tet.2017.03.093

Accepted Manuscript
Total synthesis of (+)-methynolide using a Ti-mediated aldol reaction of a lactyl-
bearing oxazolidin-2-one, and a vinylogous Mukaiyama aldol reaction
Takahiro Suzuki, Masataka Fujimura, Kazuhiro Fujita, Susumu Kobayashi
PII:
S0040-4020(17)30361-7
10.1016/j.tet.2017.03.093
TET 28599
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 January 2017
Revised Date: 25 March 2017
Accepted Date: 31 March 2017
Please cite this article as: Suzuki T, Fujimura M, Fujita K, Kobayashi S, Total synthesis of (+)-
methynolide using a Ti-mediated aldol reaction of a lactyl-bearing oxazolidin-2-one, and a vinylogous
Mukaiyama aldol reaction, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.093.
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Total synthesis of (+)-methynolide using a
Ti-mediated aldol reaction of a lactyl-
bearing oxazolidin-2-one, and a vinylogous
Mukaiyama aldol reaction
Leave this area blank for abstract info.
Takahiro Suzuki, Masataka Fujimura, Kazuhiro Fujita, and Susumu Kobayashi

1
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Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of (+)-methynolide using a Ti-mediated aldol reaction of a lactyl-
bearing oxazolidin-2-one, and a vinylogous Mukaiyama aldol reaction
Takahiro Suzukia,b, , Masataka Fujimurab, Kazuhiro Fujitab, and Susumu Kobayashib,*
a
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly convergent total synthesis of (+)-methynolide, based on two types of stereoselective
aldol reaction, was achieved. The C1-C8 and C9-C11 fragments of (+)-methynolide were
prepared by a vinylogous Mukaiyama aldol reaction using a vinyl ketene silyl N,O-acetal, and a
Ti-mediated aldol reaction of a lactyl-bearing chiral oxazolidin-2-one, respectively. Yamaguchi
esterification of both fragments and ring-closing metathesis afforded (+)-methynolide.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Aldol reaction
Convergent synthesis
Natural Product
Oxazolidin-2-one
Total synthesis
1. Introduction
Asymmetric aldol reactions using chiral oxazolidin-2-one auxiliaries are efficient and robust methods for
natural product syntheses.1 In this context, we have developed two highly stereoselective aldol reactions
(Scheme 1): a Ti-mediated aldol reaction of a lactyl-bearing chiral oxazolidin-2-one,2 and a vinylogous
Mukaiyama aldol reaction (VMAR)3 that enabled 1,7-remote asymmetric induction through the use of a
vinyl ketene silyl N,O-acetal. In the former reaction, the protecting group of the secondary alcohol in the
lactyl moiety controls the stereochemistry of lithium enolate, resulting in the stereoselective formation of
an anti- or syn-1,2-diol derivative through chelation-controlled Zimmerman-Traxler type transition states.
The latter reaction directly affords the anti-δ-hydroxy-α,γ-dimethyl α,β-unsaturated carbonyl unit, which is
present in many naturally occurring compounds. Both types of aldol reaction have been successfully used
in natural product syntheses by many research groups, including our own.4-6
To further demonstrate the synthetic utility of these methods, we chose (+)-methynolide (1) as a target
molecule. (+)-Methynolide is an aglycon of the 12-membered macrolidic antibiotic methymycin6 and has
———
Corresponding authors. Tel.: +81-11-706-2703; fax: +81-11-706-4920 (T. S.); e-mail: takahiro-suzuki@sci.hokudai.ac.jp (T. Suzuki),
kobayash@rs.noda.tus.ac.jp (S. Kobayashi)

2
Tetrahedron
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been a key target molecule over the past four decades (Figure 1). Since the first total synthesis of (±)-1 by
Masamune and colleagues,7 seven total syntheses8-14 and two formal total syntheses15,16 have been reported.
Structurally, an anti-vicinal, secondary-tertiary diol and a δ-hydroxy-α,γ-dimethyl ketone constitute the
seco-acid of 1. Herein, we report a highly convergent total synthesis of (+)-methynolide that demonstrate
the utility of our synthetic methodologies.
Scheme 1. Two types of aldol reaction developed by us.
Figure 1. (+)-Methynolide and its seco-acid.
2. Results and Discussion
Our strategy involved the construction of the macrocyclic ring in 1 using a Yamaguchi esterification17
and a ring-closing metathesis18 (RCM) between the C9-C11 fragment 2, and the C1-C8 fragment 3
(Scheme 2). The stereochemistry of anti-1,2-diol 2 could be constructed by the Ti-mediated aldol reaction
of chiral oxazolidin-2-one 5, which possesses a benzyl-protected lactyl group. C1-C8 fragment 3 could be
derived from chiral aldehyde 715b by the anti-selective VMAR of N,O-acetal 8, followed by the
stereoselective 1,4-reduction of the resulting imide 6.

3
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Scheme 2. Retrosynthetic analysis of (+)-1.
Preparation of the C9-C11 fragment was commenced with the Ti-mediated aldol reaction of the lactyl-
bearing chiral oxazolidin-2-one 5 (Scheme 3). Deprotonation of imide 5 with LDA at −78 °C afforded the
lithium (E)-enolate, which underwent a Li/Ti exchange by exposure to excess TiCl(Oi-Pr)3 at −40 °C. Next,
the stereoselective aldol reaction with propanal proceeded through a chelation-controlled Zimmerman-
Traxler type transition state,19 to give the aldol product 4 as a single isomer (>20:1) in 91% yield.
Reductive cleavage of the oxazolidin-2-one moiety with LiBH4 in the presence of MeOH and the TEMPO-
mediated selective oxidation of the resulting primary alcohol gave aldehyde 10. Wittig olefination of
aldehyde 10 with Ph3PCH3Br and BuLi provided terminal olefin 11 in moderate yield. Deprotection of the
tertiary alcohol was best carried out under Birch condition to accomplish the synthesis of the C9-C11
fragment 2 in five steps. The spectral data of 2 are identical to those reported by Kang et al.14
Scheme 3. Preparation of the C9-C11 fragment.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1. Vinylogous Mukaiyama aldol reactions.
entry
1
aldehyde
7a
equiv.
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
2.0
solvent
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
time (h)
36
yield of 6 (%) dra
recovered 8 (%)
imide 12 (%)
-
-
77
65
20
43
ND
15
4
16
11
40
29
25
18
16
20
19
6
2
7a
36
21 (for 6d)
>20:1
2:1
3
7b
36
10
14
48
64
77
70
77
90
4
7b
36
4:1
5
7c
36
1.3:1
>20:1
>20:1
>20:1
>20:1
>20:1
6
7c
36
7
7c
120
36
8
7c
8
9b
10b
7c
36
4
7c
108
3
a Diastereomeric ratio (dr) was determined by 1H-NMR analysis. b H2O (0.1 equiv) was added.
Synthesis of the C1-C8 fragment began with an anti-selective VMAR between chiral aldehydes 7a-c and
the vinyl ketene silyl N,O-acetal 8 (Table 1). Recent examples5e,5f reveal the difficulty of using VMARs
with β-oxyaldehydes, probably due to the β-elimination of an oxygen functional group, and/or chelation
that results in the deactivation of the Lewis acid. Indeed, our VMAR using aldehydes 7a (R = TBS) or 7b
(R = TIPS) failed (entries 1−4). In entry 2, aldol product 6d was obtained in 21% yield probably due to
desilylation of 6a or 7a. When using aldehyde 7b (entries 2 and 3), the desired aldol 6b was obtained in
low yield, along with recovered 8 and imide 12, derived by hydrolysis of 8. The VMAR with aldehyde 7c
(R = TBDPS, entry 5) gave a mixture of aldol products (dr 1.3:1) in moderate yield, under standard
conditions. In contrast, the use of toluene as the solvent (entry 6) resulted in increased yield and selectivity
(dr > 20:1), although measurable amounts of 8 and 12 remained. After extensive experiments, we found
that the desired anti-aldol product 6c could be obtained in 90% yield on a gram scale using 2.0 equiv of
aldehyde 7c in the presence of catalytic amounts of H2O (entry 10). The rate enhancement effect of H2O in
the VMAR was demonstrated in our previous studies.3c

5
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Scheme 4. Preparation of the C1-C8 fragment.
Next, we investigated the construction of the remaining, C6, stereocenter (Scheme 4). At first, we
attempted the epimerization of lactone 13c, which was prepared by the alkaline methanolysis of 6c using
NaOMe, followed by Pd-catalyzed hydrogenation involving concomitant lactonization. Although the
treatment of the diastereomeric mixture of 13c (dr 1:1) with DBU15 increased the dr to 3:1, this route
proved to be ineffective for the concise total synthesis. Recently, Hosokawa and colleagues reported the
stereoselective 1,4-reduction of an anti-δ-hydroxy-α,γ-dimethyl α,β-unsaturated imide, and accomplished
the total synthesis of septoriamycin A.5d When alcohol 6a, prepared from 6c by protecting group exchange,
was subjected to Birch reaction according to Hosokawa’s protocol (Na, liq. NH3/THF, −78 °C), the desired
lactone 13a was obtained in 78% yield as a single diastereomer. The stereochemistry of 13a was confirmed
by comparison of its spectra with the spectral data reported by Cossy et al.15 It is noteworthy that this
methodology provides an efficient route to the Prelog-Djerassi lactone.20 Weinreb amide formation using
Me3Al and protection of the resulting secondary alcohol with a TBS group using TBSCl and AgNO3
provided amide 14. Addition of vinyl magnesium bromide and selective deprotection of the primary
alcohol using TBAF in the presence of AcOH afforded alcohol 15. Two-step oxidation (Dess-Martin
oxidation and Pinnick oxidation) of alcohol 15 afforded the C1-C8 fragment 16 in 10 steps from N,O-acetal
8.
With both fragments 2 and 16 in hand, we proceeded to the final stage of the total synthesis of
methynolide (Scheme 5). Yamaguchi esterification of 16 and 2 afforded ester 17 in 78% yield.

6
Tetrahedron
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Macrocyclization of 17 by RCM, using Grubbs 2nd generation catalyst, gave the corresponding
macrolactone in 98% yield. Finally, desilylation with TBAF completed the total synthesis of (+)-1 in 25%
overall yield and in 13 steps from the N,O-acetal 8 (total of 18 steps). The spectroscopic data of our
synthetic (+)-1 are identical to those reported by Kang et al.14
Scheme 5. Completion of the total synthesis of (+)-1
In conclusion, we have accomplished the highly convergent total synthesis of (+)-methynolide based on
two types of stereoselective aldol reactions: a Ti-mediated aldol reaction of the lactyl-bearing chiral
oxazolidin-2-one 5, and a vinylogous Mukaiyama aldol reaction of the vinyl ketene silyl N,O-acetal 8,
developed in our laboratory.
3. Experimental section
3.1. General methods
All non-aqueous reactions were performed under an atmosphere of dry argon in flame-dried glassware unless otherwise
indicated. Solvents were distilled under an atmosphere of argon before use and transferred via an oven-dried syringe or
cannula. CH2Cl2, DMF, DMSO, Et3N, i-Pr2NH, toluene were distilled from CaH2. EtOH was distilled from Mg(OEt)2.
MeOH was distilled from Mg(OMe)2. TiCl4 was distilled from granular copper and stored in ampoules. Dry THF (209-
13967) and Et2O (047-25497) were purchased from Kanto Pure Chemical Industries Ltd, in anhydrous Grade. Flash
chromatography was performed with PSQ-100B (Fuji Silysia Co. Ltd. Japan). Solvents for chromatography are listed as
volume/volume ratios. Analytical thin layer chromatography was performed using commercial silica gel plates (E. Merck,
1
Silica Gel 60 F254). H and 13C NMR spectra were recorded on a JEOL JNM-LD400 (400MHz) and ECA-500 (400MHz)
1
spectrometer in CDCl3 as a solvent. Tetramethylsilane (TMS) served as internal standard (δ 0.0) for H NMR. CDCl3 (δ
77.0) were used as internal references for 13C NMR. Multiplicities are indicated as: br (broadened), s (singlet), d (doublet),
t (triplet), q (quartet), or m (multiplet). Coupling constants (JH) are reported in Hertz (Hz). Diastereomeric ratio was
determined by 1H NMR analysis. Infrared spectra (FT-IR) were recorded on a PerkinElmer Spectrum spectrometer and a
JASCO FT-IR-4100. Absorbance frequencies are recorded in reciprocal centimeters (cm−1). High resolution mass spectra
(HRMS) were obtained from Applied Biosystems mass spectrometer (API QSTAR pulsar i) and Thermo Scientific
Exactive for electrospray ionization (ESI). Optical rotations were determined using a JASCO P-1030 and P-2200 digital
polarimeter in 100-mm cells and the sodium D line (589 nm) at room temperature in the solvent and concentration
indicated.

7
3.1.1. (R)-3-((2R,3R)-2-(benzyloxyA)-3C-ChyEdProTxEyD-2-MmeAthNyUlpSenCtRanIoPyTl)-5,5-dimethyl-4-
phenyloxazolidin-2-one (4)
To a solution of LDA (prepared from DIPA (1.3 ml, 9.05 mmol) and n-BuLi (2.66 M in hexane, 3.2 ml, 8.49 mmol) at
−78°C for 30 min) in THF (24.0 ml), was added a solution of 5 (2.0 g, 5.66 mmol) in THF (16.0 ml) at −78°C. After
stirring for 30 min at −78°C, Ti(O-iPr)3Cl (1.0 M in THF, 22.6 ml, 22.6 mmol) was added to the resulting mixture and
stirred for 90 min at −40°C. After cooling to −78°C, a solution of propanal (493 mg, 8.49 mmol) in THF (16.0 ml) was
added via cannula and stirred for 3 h at −40°C. The reaction mixture was quenched with a saturated aqueous NH4Cl
solution and a saturated aqueous potassium sodium tartrate solution. After vigorous stirring for 3 h at room temperature,
the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 4/1) to
25
1
afford 4 (2.1 g, 91%, dr >20:1) as a colorless oil. Rf 0.48 (Hexane/EtOAc = 2/1); [α]D −33.8 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.40-7.20 (m, 8H), 7.19-7.16 (m, 2H), 5.16 (s, 1H), 4.48 (s, 2H), 4.33-4.20 (m, 1H), 2.95 (d, J = 6.8
Hz, 1H), 1.74 (s, 3H), 1.48-1.34 (m, 2H), 0.99 (dd, J = 7.3, 7.3 Hz, 3H), 0.97 (s, 6H); 13C NMR (100 MHz, CDCl3; DEPT)
δ 174.2 (C), 151.8 (C), 138.1 (C), 136.2 (C), 128.7 (CH, 2C), 128.5 (CH, 2C), 128.2 (CH, 2C), 127.3 (CH, 2C), 127.2 (CH,
2C), 86.0 (C), 82.1 (C), 75.4 (CH), 69.0 (CH), 66.4 (CH2), 28.5 (CH3), 24.9 (CH2), 23.5 (CH3), 17.0 (CH3), 10.7 (CH3); IR
(ATR) νmax 3529, 2976, 1780, 1698, 1366, 1320, 1269, 1150, 1104 cm-1; HRMS (ESI) calcd for C24H29NO5Na [M+Na]+
434.1937; found 434.1947.
3.1.2. (2S,3R)-2-(benzyloxy)-2-methylpentane-1,3-diol (9)
To a solution of 4 (278 mg, 676 ꢀmol) and MeOH (0.055 mL, 1.35 mmol) in THF (6.8 mL), was added a solution of
LiBH4 in THF (2.0 M 0.68 mL, 1.35 mmol) dropwise at 0°C. After stirring for 1.5 h, the reaction was quenched with
saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in EtOAc, diluted with
hexane, and filtered to remove recrystallized SuperQuats. The residue was purified by flash column chromatography
25
(hexane/EtOAc = 4/1) to afford 9 (130 mg, 86%) as a colorless oil. Rf 0.13 (Hexane/EtOAc = 2/1); [α]D +14.0 (c 0.9,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 4.57 (d, J = 11.0 Hz, 1H), 4.47 (d, J = 11.0 Hz, 1H), 3.80 (dd, J
= 12.0, 5.7 Hz, 1H), 3.71 (dd, J = 12.0, 5.1 Hz, 1H), 3.69-3.64 (m, 1H), 2.77 (brs, 1H), 2.72 (dd, J = 5.7, 5.1 Hz, 1H), 1.68-
1.58 (m, 1H), 1.52-1.41 (m, 1H), 1.16 (s, 3H), 1.08 (dd, J = 7.3, 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 138.7
(C), 128.4 (CH, 2C), 127.62 (CH, 2 C), 127.59 (CH), 79.1 (C), 77.8 (CH), 64.9 (CH2), 63.9 (CH2), 24.2 (CH2), 16.6 (CH3),
11.5 (CH3); IR (ATR) νmax 3412, 2967, 2933, 2876, 1454, 1106, 1049, 1027, 975, 732, 695 cm-1; HRMS (ESI) calcd for
C13H20O3Na [M+Na]+ 247.1304; found 247.1306.
3.1.3. (2R,3R)-2-(benzyloxy)-3-hydroxy-2-methylpentanal (10)
To a solution of 9 (25.5 mg, 110 ꢀmol) and TEMPO (1.7 mg, 11 ꢀmol) in CH2Cl2 (1.1 ml), PIDA (40.3 mg, 125 ꢀmol)
was added at room temperature After stirring for 18 h at room temperature, the reaction was diluted with CH2Cl2 and
quenched with a saturated aqueous Na2S2O3 solution. The aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc = 8/1) to afford 10 (20.4 mg, 88%) as colorless oil. Rf 0.60 (Hexane/EtOAc
1
= 2/1); [α]D25 +49.5 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.40-7.29 (m, 5H), 4.57 (d, J = 11.2 Hz,
1H), 4.47 (d, J = 11.2 Hz, 1H), 3.71-3.67 (m, 1H), 2.51 (d, J = 3.2 Hz, 1H), 1.64-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.36 (s,
3H), 1.03 (dd, J = 7.4, 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 205.1 (CH), 137.9 (C), 128.5 (CH, 2C), 128.0

8
Tetrahedron
ACCEPTED MANUSCRIPT
(CH), 127.5 (CH, 2C), 84.8 (C), 77.2 (CH), 66.7 (CH2), 24.0 (CH2), 14.2 (CH3), 10.9 (CH3); IR (ATR) νmax 3455, 2968,
2936, 2877, 1730, 1454, 1385, 1134, 1111, 1052, 1026, 976, 736, 697 cm-1; HRMS (ESI) calcd for C13H18O3Na [M+Na]+
245.1148; found 245.1153.
3.1.4. (3R,4S)-4-(benzyloxy)-4-methylhex-5-en-3-ol (11)
To a solution of methyltriphenylphosphonium bromide (136 mg, 380 ꢀmol) in THF (1.1 ml), a solution of n-BuLi in
hexane (1.62 M, 0.205 mL, 332 ꢀmol) was slowly added at 0°C. After stirring for 1 h at 0°C, a solution of 10 (21.1 mg, 95
ꢀmol) in THF (0.8 ml) was added and the resulting mixture was stirred for 3 h at 0°C, the reaction mixture was quenched
with ice-cold H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography
25
(hexane/EtOAc = 10/1) to afford 11 (11.7 mg, 56%) as a colorless oil. Rf 0.76 (Hexane/EtOAc = 2/1); [α]D −3.6 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.37-7.20 (m, 5 H), 5.97 (dd, J = 17.7, 11.0 Hz, 1H), 5.98 (dd, J = 11.0, 1.2 Hz,
1H), 5.28 (dd, J = 17.7, 1.2 Hz, 1H), 4.41 (s, 2H), 3.45 (ddd, J = 10.5, 5.3, 3.1 Hz, 1H), 2.61 (d, J = 3.1 Hz, 1H), 1.56-1.49
(m, 1H), 1.37-1.20 (m, 1H), 1.34 (s, 3H), 1.02 (dd, J = 7.6, 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 139.2 (C),
138.9 (CH), 128.3 (CH), 127.28 (CH, 2C), 127.24 (CH, 2C), 117.8 (CH2), 80.9 (C), 79.2 (CH), 64.6 (CH2), 24.0 (CH2),
17.4 (CH3), 11.2 (CH3); IR (ATR) νmax 3571, 2978, 2932, 2975, 1454, 1414, 1114, 1089, 1047, 1027, 977, 926, 733, 696
cm-1; HRMS (ESI) calcd for C14H20O2Na [M+Na]+ 243.1355; found 243.1357.
3.1.5. (3S,4R)-3-methylhex-1-ene-3,4-diol (2)
To a solution of 11 (14.4 mg, 65 ꢀmol) and t-BuOH (1.6 mL) in liquid NH3/THF (1/3, 4.4 mL) at −78 °C was added Na
(7.51 mg, 327 ꢀmol). After stirring for 13 h at −78 °C, the reaction was quenched with solid NH4Cl. The mixture was
stirred for 6 h at room temperature, and then extracted with CH2Cl2. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography
25
(petroleum ether/Et2O = 3/2 to 1/1) to afford 2 (4.0 mg, 47%) as a colorless oil. Rf 0.47 (Hexane/EtOAc = 2/1); [α]D
+16.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.93 (dd, J = 17.3, 10.7 Hz, 1H), 5.33 (dd, J = 17.3, 1.2 Hz, 1H), 5.21
(dd, J = 10.7, 1.2 Hz, 1H), 3.33 (d, J = 10.2 Hz, 1H), 2.29 (s, 1H), 1.87 (br, 1H), 1.65-1.56 (m, 2H), 1.30 (s, 3H), 1.02 (dd,
J = 7.3, 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 140.6 (CH), 114.5 (CH2), 79.9 (CH), 75.5 (C), 24.9 (CH2),
24.4 (CH3), 11.1 (CH3); IR (ATR) νmax 3401, 2931, 1458, 1413, 1096, 976, 922, 689 cm-1; HRMS (ESI) calcd for
C7H14O2Na [M+Na]+ 153.0891; found 153.0886.
3.1.6. (S)-3-((4S,5S,6S,E)-7-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-2,4,6-trimethylhept-2-enoyl)-
4-isopropyloxazolidin-2-one (6c)
To a solution of aldehyde 7c (3.8 g, 11.6 mmol) and H2O (10.4 mg, 0.58 mmol) in toluene (20 mL) were slowly added a
solution of TiCl4 in toluene (1.0 M, 5.8 mL, 5.8 mmol), followed by N,O-acetal 8 (2.0 g, 5.8 mmol) for one portion at
−78 °C. After stirring for 108 h at −40 °C, the reaction was poured into a 1:1 mixture of saturated aqueous NaHCO3
solution and saturated aqueous Rochelle’s salt solution. The mixture was diluted with Et2O and stirred vigorously at room
temperature until the white slurry was completely dissolved. The aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc = 10/1) to afford 6c (2.9 g, 90%, dr >50:1) as a colorless oil. Rf 0.57
(Hexane/EtOAc = 2/1); [α]D25 +11.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 4H), 7.43-7.35 (m, 6H),
5.78 (dq, J = 10.2, 1.5 Hz, 1H), 4.56 (ddd, J = 9.0, 5.6, 4.5 Hz, 1H), 4.33 (dd, J = 9.0, 8.8 Hz, 1H), 4.18 (dd, J = 9.0, 5.6

9
ACCEPTED MANUSCRIPT
Hz, 1H), 3.76 (dd, J = 9.8, 6.8 Hz, 1H), 3.64 (dd, J = 9.9, 6.5 Hz, 1H), 3.54 (d, J = 9.0 Hz, 1H), 3.11 (s, 1H), 2.75-2.60 (m,
1H), 2.39-2.31 (m, 1H), 1.96-1.84 (m, 1H), 1.96 (d, J = 1.5 Hz, 3H), 1.06 (s, 9H), 0.99-0.86 (m, 12H); 13C NMR (100
MHz, CDCl3; DEPT) δ 171.6 (C), 154.3 (C), 142.2 (CH), 135.58 (CH, 2C), 135.56 (CH, 2C), 133.99 (C), 133.97 (C),
131.2 (C), 129.46 (CH), 129.44 (CH), 127.56 (CH, 2C), 127.53 (CH, 2C), 74.4 (CH), 67.3 (CH2), 63.4 (CH2), 58.0 (CH),
37.0 (CH, 2C), 28.4 (CH), 26.9 (CH3, 3C), 19.2 (C), 17.8 (CH3), 15.6 (CH3), 15.1 (CH3), 13.9 (CH3), 9.1 (CH3);IR (ATR)
νmax 3525, 2963, 2931, 2858, 1770, 1687, 1210, 1111, 702 cm-1; HRMS (ESI) calcd for C32H45NO5SiNa [M+Na]+
574.2959; found 574.2974.
3.1.7. (S)-3-((4S,5S,6S,E)-5,7-dihydroxy-2,4,6-trimethylhept-2-enoyl)-4-isopropyloxazolidin-2-one
(6d)
To a solution of 6c (480 mg, 0.87 mmol) in CH3CN (8.7 mL), 46% HF aqueous solution (1.2 mL) was slowly added at
0 °C. After stirring for 12 h at 0 °C, the reaction mixture was quenched with an aqueous 20% KOH solution (KOH: 2.8 g,
H2O: 10 ml). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography
25
(hexane/EtOAc = 1/1) to afford 6d (269 mg, 99%) as a colorless oil. Rf 0.10 (Hexane/EtOAc = 2/1); [α]D +13.5 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.73 (dq, J = 10.3, 1.3 Hz, 1H), 4.59 (ddd, J = 8.9, 5.7, 4.4 Hz, 1H), 4.36 (dd, J =
9.1, 8.9 Hz, 1H), 4.21 (dd, J = 9.1, 5.7 Hz, 1H), 3.80 (dd, J = 10.6, 5.8 Hz, 1H), 3.70 (dd, J = 10.6, 5.4 Hz, 1H), 3.58 (dd,
J = 9.4, 2.3 Hz, 1H), 2.81-2.70 (m, 1H), 2.39-2.30 (m, 1H), 1.96-1.80 (m, 3H), 1.95 (d, J = 1.3 Hz, 3H), 1.05 (d, J = 7.1 Hz,
3H), 0.92-0.90 (m, 9H); 13C NMR (100 MHz, CDCl3; DEPT) δ 171.4 (C), 154.7 (C), 141.4 (CH), 131,7 (C), 77.5 (CH),
67.9 (CH2), 63.5 (CH2), 58.0 (CH), 37.3 (CH), 35.2 (CH), 28.4 (CH), 17.8 (CH3), 15.3 (CH3), 15.1 (CH3), 13.9 (CH3), 8.7
(CH3); IR (ATR) νmax 3516, 2964, 2932, 1765, 1683, 1389, 1365, 1300, 1280, 1205, 1019, 983 cm-1; HRMS (ESI) calcd
for C16H27NO5Na [M+Na]+ 336.1781; found 336.1774.
3.1.8. (S)-3-((4S,5S,6S,E)-7-((tert-butyldimethylsilyl)oxy)-5-hydroxy-2,4,6-trimethylhept-2-enoyl)-
4-isopropyloxazolidin-2-one (6a)
To a solution of 6d (128 mg, 400 ꢀmol) in CH2Cl2 (6.8 ml) were added Et3N (0.23 ml, 1.63 mmol), tert-
butyldimethylsilyl chloride (246 mg, 1.63 mmol), followed by DMAP (9.9 mg, 82.0 ꢀmol) at room temperature. After
stirring for 12 h at room temperature, the reaction mixture was quenched with a saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 5/1) to
25
1
afford 6a (169 mg, 97%) as a colorless oil. Rf 0.69 (Hexane/EtOAc = 2/1); [α]D +16.0 (c 1.0, CHCl3); H NMR (400
MHz, CDCl3) δ 5.80 (dq, J = 10.2, 1.4 Hz, 1H), 4.57 (ddd, J = 8.9, 6.2, 5.1 Hz, 1H), 4.34 (dd, J = 9.0, 8.9 Hz, 1H), 4.19
(dd, J = 9.0, 6.2 Hz, 1H), 3.69 (dd, J = 9.8, 6.7 Hz, 1H), 3.58 (dd, J = 9.8, 6.6 Hz, 1H), 3.48 (ddd, J = 9.3, 4.6, 2.2 Hz, 1H),
3.19 (d, J = 2.2 Hz, 1H), 2.78-2.60 (m, 1H), 2.40-2.33 (m, 1H), 1.95 (d, J = 1.4 Hz, 3H), 1.93-1.85 (m, 1H), 0.94-0.80 (m,
21H), 0.06 (s, 6H); 13C NMR (100 MHz, CDCl3; DEPT) δ 171.6 (C), 154.3 (C), 142.3 (CH), 131.2 (C), 74.7 (CH), 67.0
(CH2), 63.0 (CH2), 58.1 (CH), 37.1 (CH), 37.0 (CH), 28.4 (CH), 26.0 (CH3, 3C), 18.3 (C), 17.8 (CH3), 15.6 (CH3), 15.1
(CH3), 14.0 (CH3), 9.0 (CH3), −5.4 (CH3, 2C); IR (ATR) νmax 3528, 2959, 2929, 1770, 1686, 1207, 1090, 1057, 834, 774
cm-1; HRMS (ESI) calcd for C22H41NO5SiNa [M+Na]+ 450.2646; found 450.2633.
3.1.9. (3R,5S,6S)-6-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3,5-dimethyltetrahydro-2H-
pyran-2-one (13a)

10
Tetrahedron
ACCEPTED MANUSCRIPT
To a solution of 6a (550 mg, 1.29 mmol) in liquid NH3/THF (5/1, 77 mL) was added Na (88.8 mg, 3.86 mmol) at
−78 °C. After stirring for 5 min at −78 °C, the reaction was quenched with solid NH4Cl. The mixture was stirred for 6 h at
room temperature, and then extracted with CH2Cl2. The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/Et2O =
25
8/1) to afford lactone 13a (293 mg, 78%) as a colorless oil. Rf 0.33 (Hexane/Et2O = 7/3); [α]D +48.3 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 4.19 (dd, J = 10.5, 1.2 Hz, 1H), 3.67 (dd, J = 9.7, 8.8 Hz, 1H), 3.49 (dd, J = 9.7, 6.1 Hz, 1H),
2.53-2.40 (m, 1H), 1.96-1.80 (m, 3H), 1.38 (ddd, J = 12.3, 12.3, 12.3 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H), 0.96 (d, J = 6.4 Hz,
3H), 0.89 (s, 9H), 0.84 (d, J = 7.1 Hz, 3H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3; DEPT) δ 174.6 (C), 85.5 (CH), 64.7
(CH2), 37.7 (CH2), 37.5 (CH), 36.3 (CH), 30.6 (CH), 25.9 (CH3, 3C), 18.3 (C), 17.4 (CH3), 17.1 (CH3), 8.9 (CH3), −5.4
(CH3, 2C); IR (ATR) νmax 2956, 2930, 1731, 1087, 833, 774 cm-1; HRMS (ESI) calcd for C16H32O3SiNa [M+Na]+
323.2012; found 323.2021.
3.1.10. (2R,4S,5S,6S)-5,7-bis((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2,4,6-
tetramethylheptanamide (14)
To a suspension of N,O-dimethylhydroxylamine hydrochloride (127 mg, 1.30 mmol) in CH2Cl2 (2.3 mL) was added a
solution of Me3Al in hexane (1.05M, 1.24 ml, 1.30 mmol) very slowly at −78 °C. The mixture was allowed to warm up to
room temperature and the clear colorless resulting solution was stirred for 2 h. After cooling the solution to 0 °C, a solution
of 13 (130 mg, 0.43 mmol) in CH2Cl2 (2.0 mL) was added via cannula. The reaction mixture was stirred for 12 h at room
temperature. The mixture was diluted with CH2Cl2 and cooled to 0 °C. To the mixture, a saturated aqueous Rochelle’s salt
solution was added very slowly and stirred for 1.5 h at room temperature. The aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/Et2O = 2/1) to afford the Weinreb amide (134 mg, 86%) as a
colorless oil. Rf 0.14 (Hexane/Et2O = 1/1); [α]D25 −12.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 3.71-
3.65 (m, 2H), 3.44 (dd, J = 8.3, 1.7 Hz, 1H), 3.19 (s, 3H), 3.08 (brs, 1H), 2.85 (brs, 1 H), 2.21-2.15 (m, 1H), 1.78-1.73 (m,
1H), 1.43-1.40 (m, 1H), 1.15-1.08 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (d, J = 3.2 Hz, 3H), 0.84 (d, J = 6.8
Hz, 3H), 0.06 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 178.2, 78.1, 68.4, 61.5, 37.7, 36.6, 34.8, 33.3, 25.9, 18.8, 18.3, 16.8,
9.5, -5.51; IR (ATR) νmax 3465, 2957, 2928, 2857, 1646, 1462, 1089, 835, 775 cm-1; HRMS (ESI) calcd for
C18H39NO4SiNa [M+Na]+ 384.2540; found 384.2549.
To a solution of the Weinreb amide (62 mg, 172 ꢀmol) and AgNO3 (58 mg, 344 ꢀmol) in DMF (2.0 mL) was added
tert-butyldimethylsilyl chloride (52 mg, 344ꢀmol) at 0 °C, then a white precipitate appeared immediately. After stirring for
1 h at 0 °C, the reaction mixture was diluted with Et2O and quenched with an ice-cold aqueous NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/Et2O = 8/1) to
25
1
afford Weinreb amide 14 (77 mg, 94%) as a colorless oil. Rf 0.60 (Hexane/Et2O = 1/1); [α]D −2.3 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.58 (dd, J = 4.4, 3.0 Hz, 1H), 3.43 (dd, J = 9.8, 6.8 Hz, 1H), 3.36 (dd, J = 9.8, 6.8
Hz, 1H), 3.17 (s, 3H), 2.99 (brs, 1H), 1.89-1.82 (m, 1H), 1.78-1.72 (m, 1H), 1.58-1.51 (m, 1H), 1.13-1.04 (m, 1H), 1.12 (d,
J = 7.1 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.85 (d, J = 6.8 Hz, 3H), 0.03 (s, 12H); 13C NMR (125
MHz, CDCl3) δ177.9, 75.3, 66.7, 61.4, 38.0, 37.3, 36.6, 32.9, 32.2, 26.1, 25.9, 18.7, 18.4, 18.3, 16.1, 12.2, -3.9, -4.4, -5.4;
IR (ATR) νmax 2956, 2929, 2857, 1669, 1462, 1251, 1093, 833, 772 cm-1; HRMS (ESI) calcd for C24H53NO4Si2Na
[M+Na]+ 498.3405; found 498.3411.

11
3.1.11. (4R,6S,7S,8S)-7-((tert-butyAldCimCeEthPyTlsEilDyl)MoxAy)N-9U-hSyCdrRoIxPyT-4,6,8-trimethylnon-1-en-3-one
(15)
To a solution of 14 (270 mg, 568 ꢀmol) in THF (12.8 mL) was added a solution of vinylmagnesium bromide in THF
(0.37M, 4.6 ml, 1.70 mmol) at 0 °C. After stirring for 1.5 h the reaction mixture was diluted with Et2O and quenched with
a saturated aqueous NH4Cl solution. The organic layer was separated, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane/Et2O = 25/1) to afford the enone (223 mg, 89%) as a colorless oil. Rf
25
1
0.83 (Hexane/Et2O = 2/1); [α]D +4.3 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 6.45 (dd, J = 17.4, 10.5 Hz, 1H),
6.28 (dd, J = 17.4, 1.3 Hz, 1H), 5.75 (dd, J = 10.5, 1.3 Hz, 1H), 3.67 (dd, J = 4.6, 2.4 Hz, 1H), 3.41 (dd, J = 9.5, 7.8 Hz,
1H), 3.34 (dd, J = 9.5, 6.1 Hz, 1H), 2.98-2.89 (m, 1H), 1.88-1.81 (m, 1H), 1.77-1.71 (m, 1H), 1.60-1.53 (m, 1H), 1.16-1.08
(m, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.90-0.88 (m, 21H), 0.82 (d, J = 6.8 Hz, 3H), 0.03 (s, 6H), 0.02 (s, 6H); 13C NMR (100
MHz, CDCl3; DEPT) δ 204.0 (C), 134.9 (CH), 127.9 (CH2), 74.3 (CH), 66.4 (CH2), 41.4 (CH), 37.7 (CH), 36.7 (CH2),
36.3 (CH), 26.1 (CH3, 3C), 26.0 (CH3, 3C), 18.3 (C), 18.2 (C), 17.5 (CH3), 16.1 (CH3), 11.8 (CH3), -3.9 (CH3), -4.4 (CH3),
-5.4 (CH3, 2C); IR (ATR) νmax 2956, 2929, 2885, 2857, 1700, 1681, 1472, 1251, 1092, 1047, 834, 772 cm-1; HRMS (ESI)
calcd for C24H50O3Si2Na [M+Na]+ 465.3190; found 465.3200.
To a solution of the enone (203 mg, 460 ꢀmol) in THF (5.6 mL) was added an equimolar mixture of AcOH/TBAF in
THF (ca 1.0 M, 15 eq., 6.9 mL) portionwise over 1.5 days at room temperature. A saturated aqueous NaHCO3 solution was
added and the organic layer was separated. The aqueous layer extracted with Et2O. The combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/Et2O = 8/1) to afford alcohol 15 (127 mg, 85%) as a colorless oil. Rf 0.16 (Hexane/EtOAc = 5/1);
27
1
[α]D +3.2 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3) δ 6.45 (dd, J = 17.3, 10.5 Hz, 1H), 6.29 (dd, J = 17.3, 1.4 Hz,
1H), 5.78 (dd, J = 10.5, 1.4 Hz, 1H), 3.62-3.55 (m, 2H), 3.47 (dd, J = 10.5, 5.9 Hz, 1H), 2.99-2.90 (m, 1H), 1.95-1.83 (m,
2H), 1.77 (brs, 1H), 1.62-1.56 (m, 1H), 1.18-1.06 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 0.93-0.90 (m, 12H), 0.86 (d, J = 6.8
Hz, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 204.2 (C), 135.1 (CH), 128.1 (CH2), 76.4 (CH),
66.5 (CH2), 41.3 (CH), 38.4 (CH), 36.2 (CH2), 35.5 (CH), 26.0 (CH3, 3C), 18.2 (C), 18.1 (CH3), 16.8 (CH3), 12.4 (CH3),
−4.0 (CH3), −4.4 (CH3). IR (ATR) νmax 3448, 2957, 2928, 2883, 2856, 1697, 1677, 1460, 1403, 1251, 1096, 1042, 835,
771 cm-1; HRMS (ESI) calcd for C18H36O3SiNa [M+Na]+ 351.2326; found 351.2325.
3.1.12. (2R,3S,4S,6R)-3-((tert-butyldimethylsilyl)oxy)-2,4,6-trimethyl-7-oxonon-8-enoic acid (16)
To a solution of 15 (7 mg, 0.021 mmol) in CH2Cl2 (2.0 ml), Dess-Martin periodinane (22.6 mg, 53 ꢀmol) was added at
room temperature After stirring for 2 h at room temperature, the reaction mixture was quenched with a saturated aqueous
Na2S2O3 solution and a saturated aqueous NaHCO3 solution. The aqueous layer was extracted with hexane. The combined
organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane/EtOAc = 12/1) to afford the aldehyde (6.6 mg, 95%) as a colorless oil. Rf 0.50
(Hexane/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 0.8 Hz, 1H), 6.43 (dd, J = 17.4, 10.5 Hz, 1H), 6.28 (dd,
J = 17.4, 1.5 Hz, 1H), 5.79 (dd, J = 10.5, 1.5 Hz, 1H), 3.96 (dd, J = 8.5, 4.2 Hz, 1H), 2.95-2.88 (m, 1H), 2.53-2.47 (m, 1H),
1.89-1.82 (m, 1H), 1.61-1.55 (m, 1H), 1.21-1.07 (m, 1H), 1.12 (d, J = 7.3 Hz, 3H), 1.10 (d, J = 7.3 Hz, 3H), 0.92 (d, J =
6.8 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 205.0 (CH), 203.7 (C), 135.0
(CH), 128.3 (CH2), 74.9 (CH), 49.8 (CH), 41.3 (CH), 36.2 (CH2), 25.7 (CH), 25.9 (CH3, 3C), 18.3 (C), 18.2 (CH3), 16.2
(CH3), 9.4 (CH3), −4.2 (CH3), −4.3 (CH3).

12
Tetrahedron
ACCEPTED MANUSCRIPT
To a solution of the aldehyde (6.0 mg, 18ꢀmol) and 2-methyl-2-butene (9.7ꢀl, 92ꢀmol) in t-BuOH (1.7 ml) were added
NaH2PO4ꢁ2H2O (22 mg, 144 ꢀmol) and a solution of NaClO2 (13 mg, 140 ꢀmol ) in water (1.0 ml) at room temperature.
The mixture was allowed to stir for 3 h at room temperature, and then extracted with AcOEt. The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane/EtOAc = 12/1) to afford carboxylic acid 16 (5.0 mg, 87%) as a colorless oil. Rf 0.10
(Hexane/EtOAc = 5/1); [α]D22 +1.8 (c 0.23, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.45 (dd, J = 17.3, 10.3 Hz, 1H), 6.28
(dd, J = 17.3, 1.3 Hz, 1H), 5.77 (dd, J = 10.3, 1.3 Hz, 1H), 3.88 (dd, J = 9.3, 4.1 Hz, 1H), 2.95-2.86 (m, 1H), 2.67-2.61 (m,
1H), 1.95-1.88 (m, 1H), 1.61-1.55 (m, 1H), 1.34-1.25 (m, 1H), 1.18-1.11 (m, 1H), 1.17 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 7.1
Hz, 3H), 0.93-0.88 (m, 12H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3; DEPT) δ 203.8 (C), 179.3 (C), 134.8
(CH), 128.3 (CH2), 76.9 (CH), 42.3 (CH), 41.4 (CH), 36.1 (CH2), 35.3 (CH), 25.9 (CH3, 3C), 18.2 (C), 18.0 (CH3), 16.1
(CH3), 12.6 (CH3), −4.3 (CH3), −4.4 (CH3); IR (ATR) νmax 2956, 2929, 2857, 1715, 1461, 1383, 1254, 1058, 836, cm-1;
HRMS (ESI) calcd for C18H33O4Si [M−H]− 341.2154; found 341.2153.
3.1.13. (3R,4S)-4-hydroxy-4-methylhex-5-en-3-yl (2R,3S,4S,6R)-3-((tert-butyldimethylsilyl)oxy)-
2,4,6-trimethyl-7-oxonon-8-enoate (17)
To a solution of carboxylic acid 16 (41 mg, 120 ꢀmol) in THF (1.8 mL) at room temperature were added triethylamine
(22 ꢀl, 156 ꢀmol) and 2,4,6-trichlorobenzoyl chloride (35 mg, 144 ꢀmol). The mixture was stirred for 3 h at room
temperature and the solids were filtered off and washed with hexane (3.6 ml). The combined solution was concentrated
under reduced pressure. The residue was dissolved in benzene (1.2 ml). To the resulting solution, a solution of diol 2 (25
mg, 192 ꢀmol) and DMAP (21 mg, 168 ꢀmol) in benzene (2.4 ml) was added. After stirring for 3 h, the reaction mixture
was diluted with Et2O, and washed with the saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 12/1) to afford ester 17 (42 mg, 78%)
as a colorless oil. Rf 0.74 (Hexane/EtOAc = 2/1); [α]D23 +18.1 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.41 (dd, J =
17.5, 10.2 Hz, 1H), 6.29 (dd, J = 17.5, 1.4 Hz, 1H), 5.97 (dd, J = 17.3, 10.8 Hz, 1H), 5.82 (dd, J = 10.2, 1.4 Hz, 1H), 5.37
(dd, J = 17.3, 1.2 Hz, 1H), 5.17 (dd, J = 10.8, 1.2 Hz, 1H), 4.79 (dd, J = 9.8, 3.2 Hz, 1H), 3.83 (dd, J = 8.6, 1.7 Hz, 1H),
3.40 (s, 1H), 2.97-2.84 (m, 2H), 2.01-1.94 (m, 1H), 1.71-1.55 (m, 3H), 1.40-1.34 (m, 1H), 1.21 (d, J = 7.5 Hz, 3H), 1.13 (d,
J = 7.5 Hz, 3H), 0.97-0.85 (m, 9H), 0.91 (s, 9H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 205.2, 176.4, 140.8, 135.5,
129.0, 113.9, 80.9, 76.8, 74.5, 43.4, 40.7, 36.5, 33.9, 26.1, 25.2 (3C), 23.1, 18.9, 18.5, 17.9, 16.1, 10.7, −3.71, −3.74; IR
(ATR) νmax 3500, 2960, 2933, 2882, 2858, 1729, 1613, 1460, 1407, 1375, 1255, 1175, 1091, 1051, 836, 773 cm-1; HRMS
(ESI) calcd for C25H46O5SiNa [M+Na]+ 477.3007; found 477.3001.
3.1.14. Methynolide (1)
To a solution of ester 17 (12 mg, 26.4 ꢀmol) in CH2Cl2 (5.3 mL) was added Grubbs catalyst 2nd Generation (3.4 mg,
4.0 ꢀmol) at room temperature. The mixture was stirred for 3 h at room temperature and then concentrated in vacuo to give
dark brown oil. The residue was purified by flash column chromatography (hexane/EtOAc = 6/1) to afford the
macrolactone (11 mg, 98%) as a colorless oil. Rf 0.62 (Hexane/EtOAc = 2/1); [α]D23 +68.6 (c 0.12, CHCl3); 1H NMR (400
MHz, CDCl3) δ 6.59 (d, J = 16.0 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 4.76 (dd, J = 11.0, 2.2 Hz, 1H), 3.64 (d, J = 10.2 Hz,
1H), 2.68-2.51 (m, 2H), 1.96-1.89 (m, 1H), 1.68-1.48 (m, 2H), 1.37 (s, 3H), 1.30-1.20 (m, 9H), 0.95-0.88 (m, 15H), 0.08 (s,
3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 204.2, 175.4, 148.7, 125.7, 79.1, 76.2, 74.5, 45.1, 44.4, 34.5, 33.5, 26.2
(3 C), 21.3, 19.5, 18.6, 18.5, 17.7, 17.4, 10.7, −3.1, −3.3; IR (ATR) νmax 3462, 2959, 2927, 2856, 1731, 1691, 1629, 1460,

13
ACCEPTED MANUSCRIPT
1373, 1256, 1168, 1138, 1089, 1056, 1024, 977, 836, 755 cm-1; HRMS (ESI) calcd for C23H42O5SiNa [M+Na]+ 449.2694;
found 449.2688.
To a solution of the macrolactone (7.2 mg, 17 ꢀmol) in THF (3.2 mL) at room temperature was added a solution of
TBAF in THF (1.0 M, 0.169 ml, 0.169 mmol) and stirred for 14 h. The reaction mixture was quenched with the saturated
NH4Cl solution and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered and concentrated
in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 3/1) to afford methynolide 1 (5.1
mg, 96%) as a white amorphous solid. Rf 0.45 (Hexane/EtOAc = 1/1); [α]D +72.8 (c 0.11, CHCl3); 1H NMR (500 MHz,
22
CDCl3) δ 6.59 (1H, d, J = 16.0 Hz), 6.34 (1H, d, J = 16.0 Hz), 4.78 (1H, dd, J = 10.9, 2.3 Hz), 3.58 (1H, d, J = 10.3 Hz),
2.64-2.53 (2H, m), 1.97-1.90 (2H, m), 1.63 (1H, t, J = 12.3 Hz), 1.53-1.51 (3H, m), 1.38 (3H, s), 1.34 (3H, d, J = 7.4 Hz),
1.33-1.27 (1H, m), 1.21 (3H, d, J = 7.4 Hz), 1.02 (3H, d, J = 5.7 Hz), 0.91 (3H, t, J = 7.2 Hz); 13C NMR (125 MHz,
CDCl3) δ 204.1, 174.8, 148.8, 125.5, 77.9, 76.4, 74.5, 45.2, 43.5, 33.4, 33.1, 21.2, 19.4, 17.6, 17.4, 16.6, 10.7; IR (ATR)
νmax 3432, 2970, 2936, 2878, 1723, 1688, 1628, 1457, 1374, 1279, 1169, 1152, 1081, 992, 951 cm-1; HRMS (ESI) calcd
for C17H28O5Na [M+Na]+ 335.1829; found 335.1828.
Acknowledgments
This research was supported in part by a Grant-in-Aid for a Scientific Research (B, KAKENHI No. 22390004) from the
Japan Society for the Promotion Science.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
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