Concise synthesis of the C15-C38 fragment of okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A

Tetrahedron xxx (2015) 1e15

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Tetrahedron

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Concise synthesis of the C15eC38 fragment of okadaic acid,

a speciﬁc inhibitor of protein phosphatases 1 and 2A

*

Haruhiko Fuwa , Keita Sakamoto, Takashi Muto, Makoto Sasaki

Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

A marine polyether natural product okadaic acid is known to be a potent and speciﬁc inhibitor of protein

phosphatases 1 and 2A. Herein, concise synthesis of the C15eC38 fragment of okadaic acid is reported.

We investigated two different strategies for the construction of two spiroacetal substructures found in

the target compound. The ﬁrst strategy involved SuzukieMiyaura coupling for the synthesis of endo-

cyclic enol ethers and subsequent spiroacetalization. The second strategy exploited SuzukieMiyaura

coupling for the synthesis of exo-oleﬁns as the precursor of spiroacetals. An alkynylaluminumeanomeric

sulfone coupling effectively assembled the key spiroacetal substructures and completed the target

compound.

Received 25 February 2015

Received in revised form 31 March 2015

Accepted 1 April 2015

Available online xxx

This paper is dedicated to Professor Jiro Tsuji

on the occasion of his receiving the 2014

Tetrahedron Prize for Creativity in Organic

Chemistry

Keywords:

Marine toxins

Polyethers

Spiroacetals

SuzukieMiyaura coupling

Anomeric sulfones

1. Introduction

Okadaic acid (1, Fig. 1) was ﬁrst isolated from the marine

sponges Halichondria okadai and Halichondria melanodocia,¹and

subsequently discovered from the marine dinoﬂagellates Pro-

rocentrum lima and Dinophysis fortii as a toxic constituent.²The

complex structure of okadaic acid was established on the basis of an

X-ray crystallographic analysis of the corresponding o-bromoben-

zyl ester.¹A number of natural congeners of okadaic acid, including

dinophysistoxin-1 (2)³and -2 (3),⁴and acanthifolicin (4),⁵have

been identiﬁed so far. It is now considered that okadaic acid would

be the secondary metabolite of symbiotic microorganisms.⁶It is

known that okadaic acid and its congeners accumulate in shellﬁsh

and are responsible for diarrhetic shellﬁsh poisoning.⁷Okadaic acid

exhibits a wide range of biological activities, including tumor-

promoting activity,⁸apoptosis-inducing activity,⁹and most nota-

bly, highly potent and speciﬁc inhibitory activity against protein

phosphatases 1 and 2A (PP1 and PP2A, respectively).¹⁰PP1 and

PP2A are known to dephosphorylate serine and threonine residues

of proteins and play signiﬁcant roles in controlling the phosphor-

ylation level and activity of many proteins.¹¹Thus, okadaic acid has

Fig. 1. Structures of okadaic acid (1), dinophysistoxin-1 (2), dinophysistoxin-2 (3),

acanthifolicin (4), and the C15eC38 fragment 5 of okadaic acid.

* Corresponding author. E-mail address: hfuwa@m.tohoku.ac.jp (H. Fuwa).

http://dx.doi.org/10.1016/j.tet.2015.04.001

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

been widely utilized in cell biology as a potent and speciﬁc PP1/

PP2A inhibitor, and its cellular effect has been investigated in sev-

eral cell models.¹²James and co-workers have reported the crys-

tallographic structure of okadaic acid bound to PP1 at a resolution

of 1.9 A.¹³Subsequently, Shi and colleagues have disclosed the X-ray

ꢀ

crystallographic analysis of a co-crystal of okadaic acid and PP2A at

2.6 A resolution.¹⁴These studies have established the binding mode

ꢀ

of okadaic acid to PP1 and PP2A at the atomic level. Recent studies

by Konoki et al. have identiﬁed new speciﬁc targets, okadaic acid-

binding proteins (OABPs), from H. okadai, although their exact

physiological role awaits elucidation.¹⁵Quite recently, a synthetic

derivative of okadaic acid has been shown to display selective cy-

totoxicity against undifferentiated human pluripotent stem cells,

where the different expression pattern of ATP-binding cassette

(ABC) transporters between differentiated cells and pluripotent

stem cells is responsible for the selectivity.¹⁶

Scheme 2. Synthesis of oleﬁn 8.

2.2. Synthesis of oleﬁn 8

The structureeactivity relationship (SAR) of okadaic acid with

respect to PP1/PP2A inhibitory activity has been investigated mainly

by evaluating natural congeners and their derivatives.¹⁷The Isobe,¹⁸

Forsyth,¹⁹and Ley²⁰groups have independently achieved the total

synthesis of okadaic acid, enabling the assessment of the PP1/PP2A

inhibitory activity of selected synthetic compounds.²¹In contrast,

neither the structural elements required for binding to OABPs nor

those crucial for ABC transporter selectivity have not been in-

vestigated in detail. To help elucidate the SAR of okadaic acid, we

embarked on the development of a concise synthetic entry to oka-

daic acid and its analogs. Herein, we report in detail our synthetic

studies on the C15eC38 fragment 5 (Fig. 1) of okadaic acid.²²

The synthesis of the oleﬁn 8 commenced with silylation of the

alcohol 12,²⁷leading to the silyl ether 13 (Scheme 2). Regioselective

reductive opening of the p-methoxybenzylidene acetal with

DIBALH²⁸delivered the alcohol 14, which was oxidized²⁹and then

methylenated to afford the oleﬁn 8.

2.3. Synthesis of enol phosphates 9 and 16

Next, we prepared the enol phosphate 9 from the lactone 15³⁰

(Scheme 3). Treatment of 15 with LHMDS and (PhO)₂P(O)Cl³¹de-

livered the enol phosphate 9. However, it was found that this

compound readily underwent hydrolysis to give the lactone 15

under alkaline conditions and could not be used as an electrophile

in SuzukieMiyaura coupling.²⁵This disappointing outcome

prompted us to use the acyclic counterpart 16.^23aExposure of the

acetate 17³²to LHMDS in the presence of (PhO)₂P(O)Cl³¹delivered

the enol phosphate 16.

2. Results and discussion

2.1. Initial synthesis plan

The C15eC38 fragment 5, the target compound of this study,

would be derived from the sulfone 6 and the alkyne 7²⁰by

considering an alkynylaluminumeanomeric sulfone coupling

(Scheme 1). This strategy originally developed by the Ley group²⁰

should allow for a convergent and ﬂexible access to the target

compound 5 and its analogs. On the basis of our previous expe-

rience on spiroacetal synthesis,²³we initially envisioned that 6

could be synthesized from the oleﬁn 8 and the enol phosphate 9

(or its acyclic equivalent)²⁴via a SuzukieMiyaura coupling²⁵and

a spiroacetalization.²⁶Likewise, 7 would be obtainable from the

oleﬁn 10 and the enol phosphate 11.

Scheme 3. Synthesis of enol phosphates 9 and 16.

2.4. Synthesis of sulfone 6

The oleﬁn 8 was reacted with 9-BBN-H to generate the alkyl-

borane 18, which was coupled with the enol phosphate 16 (pre-

pared from 1.8 equiv of the acetate 17, Scheme 3) under the

inﬂuence of Pd(PPh₃)₄and aqueous Cs₂CO₃in DMF at room tem-

perature to afford the diene 19 (Scheme 4). This was exposed to the

second-generation Grubbs catalyst (G-II)³³in toluene at 70 ^ꢀC to

provide the endocyclic enol ether 20. Since 20 was quite sensitive to

silica gel and too unstable to be isolated, it has to be immediately

used in the next step without any puriﬁcation. Finally, removal of

the MPM group with DDQ and spontaneous spiroacetalization

furnished the spiroacetal 21 (35% overall yield from 8), along with

its C19 diastereomer 22 (12% overall yield from 8). Isomerization

of 22 under mild acidic conditions provided additional 21. The

Scheme 1. Initial synthesis plan toward 5.

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Scheme 4. Synthesis of sulfone 6.

Fig. 2. Stereochemical analysis on 21 and 22.

stereostructures of 21 and 22 were determined on the basis of NOE

experiments, as shown in Fig. 2. Finally, oxidation of 21 with m-

CPBA afforded the sulfone 6 in 91% yield.

2.5. Synthesis of alkyne 7 via spiroacetalization of endocyclic

enol ether 25

The synthesis of alkyne 7 started from the diol 23,^19awhich was

prepared in four steps from (S)-Roche ester (Scheme 5). Silylation of

23 with TBSOTf/2,6-lutidine gave the bis-silyl ether 10 quantita-

tively. Hydroboration of 10 with 9-BBN-H followed by coupling of

the derived alkylborane 24 with the enol phosphate 11³⁴(5 equiv)

in the presence of Pd(PPh₃)₄and aqueous K₃PO₄in DMF at 50 ^ꢀC

afforded the endocyclic enol ether 25 in 82% yield. Excess molar

amounts of 11 were indispensable for achieving the optimal

product yield. Exposure of 25 to acidic MeOH at room temperature

resulted in desilylation and concomitant spiroacetalization to de-

liver the alcohol 26^19aquantitatively as a single stereoisomer (dr

>20:1). Oxidation of 26 with o-iodoxybenzoic acid (IBX)³⁵and

subsequent alkynylation using OhiraeBestmann reagent³⁶(K₂CO₃,

MeOH, 0 ^ꢀC to room temperature) furnished the alkyne 7 in 71%

yield (two steps).

Scheme 5. Synthesis of alkyne 7 via spiroacetalization of endocyclic enol ether 25.

the sulfone 6 at room temperature. However, the coupling reaction

did not take place at all and only returned the sulfone 6 (84%) and

the alkyne 7 (63%) (Scheme 6A). The coupling of simpler sulfone 28,

prepared from 8, with the alkyne 7 under the same conditions was

also completely unsuccessful (Scheme 6B). In contrast, when we

reacted the sulfone 6 with the alkynylaluminum prepared from

ethynylbenzene under the same conditions, we found that the re-

action proceeded smoothly to provide the coupling product 30 in

81% yield as a single stereoisomer (dr >20:1) (Scheme 6C). Simi-

larly, coupling of 28 with ethynylbenzene was successful, giving the

internal alkyne 31 in 93% yield (dr 9:1) (Scheme 6D). The conﬁg-

uration of the newly generated stereogenic center of 30 and 31 was

2.6. Investigating alkynylaluminumeanomeric sulfone

coupling

3

Next, we investigated the coupling of the sulfone 6 and the al-

kyne 7, according to the procedure described by Ley et al.²⁰

(Scheme 6). Thus, deprotonation of the alkyne 7 (1.5 equiv) with

n-BuLi (1.5 equiv, toluene, 0 ^ꢀC) followed by addition of Me₂AlCl

(1.5 equiv, diluted with CH₂Cl₂, 0 ^ꢀC to room temperature) gener-

ated the corresponding alkynylaluminum, which was reacted with

determined on the basis of J_H,Hvalues, as shown in Fig. 3.

Here, we considered that the nucleophilicity of the alkynylalu-

minum species prepared from the alkyne 7 should be lower than

that of dimethyl(2-phenylethynyl)aluminum because 7 has two

Lewis basic oxygen atoms. The poor reactivity of alkynylaluminum

reagents having an ether oxygen atom has been described in the

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

Scheme 6. Alkynylaluminumeanomeric sulfone coupling.

Fig. 3. (A) Stereochemical analysis on 30. (B) Stereochemical analysis on 31.

literature.³⁷Ley et al. have overcome this problem by introducing

an ortho-methoxy group to the sulfone benzene ring of the

anomeric sulfone, thereby enhancing the coordinating ability of the

sulfonyl group to incoming alkynylaluminum reagent.³⁸

2.7. Revised synthesis plan

In our initial synthetic approach toward the C15eC38 fragment

5, the two spiroacetal substructures were synthesized via Suzu-

kieMiyaura coupling²⁵of the enol phosphates 11 and 16. However,

the low stability of 11 and 16 under alkaline conditions was rather

problematic and necessitated their use in excess molar amounts.

The endocyclic enol ether 20 was also found to be quite unstable

and could not be isolated. The stability problem of these in-

termediates has turned out to be a serious drawback especially

with regard to material throughput. In addition, the alkynylalu-

minumeanomeric sulfone coupling of 6 and 7 was completely in-

effective presumably because of the low reactivity of 7 having Lewis

basic oxygen atoms.

Scheme 7. Revised synthesis plan.

should be easily obtainable from the respective exo-oleﬁns 33 and

34 via an oxidative cleavage of the double bond followed by a spi-

roacetalization. The exo-oleﬁn 33 could be synthesized via a Suzu-

kieMiyaura coupling²⁵of the oleﬁn 35 and the enol triﬂate 36. The

exo-oleﬁn 34 could be prepared from the oleﬁn 10 and the enol

triﬂate 37 in the same manner.

With these problems in mind, we revised our synthetic ap-

proach toward 5, as depicted in Scheme 7. To improve the reactivity

toward the alkynylaluminum species derived from 7, we consid-

ered the o-methoxyphenyl counterpart of 6 as the C15eC26 sulfone

(i.e., 32). We envisioned a uniﬁed strategy for the synthesis of 32

and 7. Given that the spiroacetal substructures are both thermo-

dynamically favored by the virtue of anomeric effect, 32 and 7

2.8. Synthesis of sulfone 32

At ﬁrst, the oleﬁn 35 was synthesized from D-mannose pentaa-

cetate (38) (Scheme 8). Thioglycosylation of 38 with o-MeOC₆H₄SH

in the presence of BF₃$OEt₂provided the thioglycoside 39 quanti-

tatively (dr >20:1). After removal of the acetyl groups, the resultant

tetraol was selectively protected as its p-methoxybenzylidene

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Scheme 8. Synthesis of sulfone 32.

acetal derivative to give the diol 40. Selective benzylation of the

axially oriented hydroxy group under phase-transfer conditions,³⁹

followed by silylation of the remaining alcohol, delivered the silyl

ether 41. This was elaborated to the oleﬁn 35 in the same manner as

that described for 8 (Scheme 2). Meanwhile, the enol triﬂate 36 was

readily prepared from the alcohol 43⁴⁰in three steps. Protection of

43 as its MPM ether followed by Wacker oxidation⁴¹gave a methyl

ketone, which was treated with KHMDS/PhNTf₂to provide the enol

triﬂate 36.

SuzukieMiyaura coupling²⁵of the alkylborane 44, derived

from 35, with the enol triﬂate 36 proceeded uneventfully under

the inﬂuence of PdCl₂(dppf)$CH₂Cl₂/Ph₃As and aqueous Cs₂CO₃in

DMF at room temperature⁴²to afford the exo-oleﬁn 33 in 90%

yield. Oxidative cleavage of the double bond of 33 with con-

comitant oxidation of the sulﬁde led to the ketone 45. Depro-

tection of the MPM groups with DDQ resulted in spontaneous

spiroacetalization to furnish the sulfone 32 as a single stereoiso-

mer (dr >20:1). The conﬁguration of the C19 stereogenic center

was determined on the basis of an ROE experiment, as shown.

Thus, we were able to construct the spiroacetal substructure of 32

in just three steps from 35 and 36 in a highly stereocontrolled

manner.

Scheme 9. Synthesis of alkyne 7 via spiroacetalization of ketone 47.

2.9. Synthesis of alkyne 7 via spiroacetalization of ketone 47

2.10. Completion of the synthesis of the C15eC38 fragment 5

Hydroboration of the oleﬁn 10 with 9-BBN-H followed by

coupling of the resultant alkylborane 24 with the enol triﬂate 37

(PdCl₂(dppf)$CH₂Cl₂/Ph₃As, aqueous Cs₂CO₃, DMF, room temper-

ature)⁴²provided the exo-oleﬁn 34 (Scheme 9). The enol triﬂate

37 was prepared from the methyl ketone 46⁴³under standard

conditions (LDA, PhNTf₂, THF, ꢁ78 to 0 ^ꢀC). The double bond of 34

was cleaved to give the ketone 47. Exposure of 47 to acidic

methanol resulted in removal of the silyl groups and simultaneous

spiroacetalization to afford the alcohol 26^19aas a single stereo-

isomer (dr >20:1). This was converted to the alkyne 7 as described

above.

Coupling of the sulfone 32 with the alkynylaluminum species

prepared from the alkyne 7 afforded the coupling product 48 in

60e63% yield as a single stereoisomer (dr >20:1) (Scheme 10). It

was found that more than 2 equiv of 7 was required for complete

consumption of 32. However, the excess 7 could be recovered after

aqueous workup and puriﬁcation by ﬂash column chromatography

using silica gel. Hydroboration of 48 with 9-BBN-H in reﬂuxing THF

followed by alkaline oxidative workup provided the ketone 49

(68%, 94% based on recovered starting material (BORSM)). The

regioselectivity of the hydroboration could be ascribed to the

electronic effect induced by the C26 ether oxygen atom.⁴⁴Here, the

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

Scheme 10. Synthesis of the C15eC38 fragment 5.

conﬁguration of the C26 stereogenic center was established by

a conformational analysis on the basis of NOE experiments and ³J_H,H

values (Fig. 4A). Treatment of 49 with NaBH₄(EtOH, ꢁ20 to 0 ^ꢀC)

gave the alcohol 50 in 86% yield as a single stereoisomer (dr >20:1).

The newly generated C27 stereogenic center was assigned on the

basis of a modiﬁed Mosher analysis (Fig. 4B).⁴⁵The stereoselectivity

could be rationalized by considering a polar FelkineAnh mod-

el.^18d,46Silylation of 50 with TIPSOTf/2,6-lutidine and cleavage of

the benzyl ethers by hydrogenolysis gave the diol 51. Selective

silylation of the C15 alcohol led to the alcohol 52. Oxidation of 52

with DesseMartin periodinane (DMP)⁴⁷followed by methylenation

of the derived ketone by using Tebbe reagent⁴⁸furnished the

C15eC38 fragment 5.

and 34 were efﬁciently converted to the sulfone 32 and the alkyne

7, respectively. An alkynylaluminumeanomeric sulfone coupling of

32 and 7 and subsequent functional group manipulations com-

pleted the synthesis of the C15eC38 fragment 5. The present syn-

thesis proceeded in only 19 linear steps from commercially

available D-mannose pentaacetate, demonstrating the efﬁciency of

our synthetic strategy. Work toward the synthesis and evaluation of

okadaic acid analogs will be reported in due course.

4. Experimental section

4.1. General remark

All reactions sensitive to moisture and/or air were carried out

under an atmosphere of argon in dry, freshly distilled solvents

under anhydrous conditions using oven-dried glassware unless

otherwise noted. Anhydrous dichloromethane (CH₂Cl₂) was pur-

chased from Kanto Chemical Co. Inc. and used directly without

further drying unless otherwise noted. Anhydrous tetrahydrofuran

(THF), diethyl ether (Et₂O), and toluene were purchased from Wako

Pure Chemical Industries, Ltd. and further puriﬁed by a Glass

Contour solvent puriﬁcation system under an atmosphere of argon

immediately prior to use. 1,2-Dichloroethane (DCE), diisopropyl-

amine, diisopropylethylamine, 2,6-lutidine, methanol (MeOH),

pyridine, and triethylamine (Et₃N) were distilled from calcium

hydride under an atmosphere of argon. N,N-Dimethylformamide

(DMF) and dimethyl sulfoxide (DMSO) were distilled from mag-

nesium sulfate under reduced pressure. Hexamethylphosphor-

amide (HMPA) was distilled from calcium hydride under reduced

pressure. All other chemicals were purchased at highest commer-

cial grade and used directly. Analytical thin-layer chromatography

(TLC) was performed using E. Merck silica gel 60 F₂₅₄plates (0.25-

mm thickness). Flash column chromatography was carried out

using Kanto Chemical silica gel 60N (40e100 mesh, spherical,

neutral) or Fuji Silysia silica gel BW-300 (200e400 mesh). Optical

rotations were recorded on a JASCO P-1020 digital polarimeter. IR

spectra were recorded on a JASCO FT/IR-4100 spectrometer. ¹H and

¹³C NMR spectra were recorded on a JEOL JNM ECA-600 spec-

Fig. 4. (A) Stereochemical analysis on 49. (B) Determination of the absolute conﬁgu-

ration of the C27 stereogenic center of 50.

3. Conclusions

In this paper, we described a concise synthesis of the C15eC38

fragment 5 of okadaic acid. Two different approaches were in-

vestigated for the construction of the spiroacetal substructures of 5.

Our initial approach involved SuzukieMiyaura coupling of enol

phosphates and subsequent spiroacetalization of the resultant

endocyclic enol ethers for the synthesis of the sulfone 6 and the

alkyne 7. However, sufﬁcient quantities of these important in-

termediates could not be obtained because of the low material

throughput that could be at least partly ascribed to the instability of

the intermediary enol phosphates (i.e., 11 and 16). Furthermore, the

reactivity of the sulfone 6 toward the alkynylaluminum prepared

from 7 proved to be insufﬁcient. Accordingly, we devised a more

robust approach that featured the synthesis of the exo-oleﬁns 33

and 34 via SuzukieMiyaura coupling. The derived exo-oleﬁns 33

trometer, and chemical shift values are reported in ppm (d)

downﬁeld from tetramethylsilane with reference to internal re-

sidual solvent [¹H NMR, CHCl₃(7.24), C₆HD₅(7.15), CHD₂OD (3.31),

CHD₂COCD₃(2.05); ¹³C NMR, CDCl₃(77.0), C₆D₆(128.0), CD₃OD

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

7

(49.8), (CD₃)₂CO (29.8)]. Coupling constants (J) are reported in

Hertz (Hz). The following abbreviations were used to designate the

multiplicities: s¼singlet; d¼doublet; t¼triplet; q¼quartet;

m¼multiplet; br¼broad. ESI-TOF mass spectra were measured on

a Bruker microTOFfocus spectrometer. Diastereomer ratio (dr) and

E/Z isomer ratio were estimated by ¹H NMR spectroscopic analysis

(600 MHz), unless otherwise noted.

was dried (MgSO₄), ﬁltered, and concentrated under reduced

pressure. The residual aldehyde was passed through a short pad of

silica gel and used in the next reaction without further puriﬁcation.

To a suspension of Ph₃P^þCH₃Br^ꢁ(84 mg, 0.24 mmol) in THF

(0.40 mL) at 0 ^ꢀC was added n-BuLi (2.69 M solution in n-hexane,

0.080 mL, 0.22 mmol), and the resultant mixture was stirred at 0 ^ꢀC

for 30 min. To this mixture was added a solution of the above al-

dehyde in THF (0.4 mL), and the resultant mixture was stirred at

0 ^ꢀC for 35 min. The reaction was quenched with saturated aqueous

NH₄Cl solution. The resultant mixture was extracted with EtOAc,

and the organic layer was washed with H₂O and brine. The organic

layer was dried (Na₂SO₄), ﬁltered, and concentrated under reduced

pressure. Puriﬁcation of the residue by ﬂash column chromatog-

4.2. Silyl ether 13

To a solution of alcohol 12 (178 mg, 0.370 mmol) in CH₂Cl₂

(3.7 mL) at 0 ^ꢀC were added 2,6-lutidine (0.130 mL, 1.11 mmol) and

TIPSOTf (0.150 mL, 0.555 mmol), and the resultant solution was

stirred at room temperature for 1 h. The reaction was quenched

with saturated aqueous NH₄Cl solution at 0 ^ꢀC. The resultant mix-

ture was extracted with EtOAc. The organic layer was washed with

H₂O and brine, dried (Na₂SO₄), ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 5% EtOAc/hexanes) gave silyl ether 13

raphy (silica gel, 5% EtOAc/hexanes) gave oleﬁn 8 (42 mg, 84% for

21

the two steps) as a colorless oil: [

a]

þ124.3 (c 1.00, CHCl₃); IR

D

(ﬁlm) 2943, 1727, 1514, 1464, 1248, 1080 cm^ꢁ1; ¹H NMR (600 MHz,

CDCl₃) 7.42e7.41 (m, 2H), 7.38e7.37 (m, 2H), 7.36e7.33 (m, 2H),

d

7.27e7.22 (m, 6H), 6.85e6.82 (m, 2H), 5.96 (ddd, J¼16.9, 10.1,

6.9 Hz, 1H), 5.54 (d, J¼1.9 Hz, 1H), 5.41 (d, J¼16.9 Hz, 1H), 5.22 (d,

J¼10.1 Hz, 1H), 4.72 (d, J¼11.0 Hz, 1H), 4.69 (d, J¼11.9 Hz, 1H), 4.65

(d, J¼11.9 Hz, 1H), 4.54 (d, J¼11.0 Hz, 1H), 4.48 (dd, J¼9.2, 6.9 Hz,

1H), 4.22 (dd, J¼9.2, 2.8 Hz, 1H), 3.98 (dd, J¼2.8, 1.9 Hz, 1H), 3.79 (s,

3H), 3.70 (dd, J¼9.2, 9.2 Hz, 1H), 1.12e1.08 (m, 21H); ¹³C NMR

(253 mg, quant) as a colorless oil: [

NMR (600 MHz, C₆D₆)

a

]

²⁴þ116.4 (c 1.00, benzene); ¹H

D

d

7.53e7.52 (m, 2H), 7.45e7.41 (m, 4H),

7.20e7.17 (m, 2H), 7.08 (m, 1H), 7.01e6.94 (m, 3H), 6.83e6.80 (m,

2H), 5.76 (d, J¼1.4 Hz, 1H), 5.26 (s, 1H), 4.65 (d, J¼11.0 Hz, 1H), 4.61

(dd, J¼10.1, 3.3 Hz, 1H), 4.57 (ddd, J¼10.1, 10.1, 5.0 Hz, 1H), 4.45 (d,

J¼11.0 Hz, 1H), 4.35 (dd, J¼9.7, 9.7 Hz, 1H), 4.16 (dd, J¼3.2, 1.4 Hz,

1H), 4.13 (dd, J¼10.1, 5.1 Hz, 1H), 3.66 (dd, J¼10.1, 10.1 Hz, 1H), 3.23

(150 MHz, CDCl₃) d 159.0, 138.3, 135.3, 134.8, 131.8, 131.5 (2C), 130.8,

129.2 (2C), 129.0 (2C), 128.2 (2C), 127.5 (2C), 127.3 (2C), 118.3, 113.5,

85.7, 79.7, 77.2, 76.8, 74.4, 73.3, 72.2, 55.3,18.2 (6C),12.9 (3C); HRMS

(ESI) calcd for C₃₇H₅₀O₅SiSNa [(MþNa)^þ] 657.3040, found 657.3037.

(s, 3H), 1.18e1.15 (m, 21H); ¹³C NMR (150 MHz, C₆D₆)

d 159.3, 138.5,

131.7 (2C), 129.4 (2C), 128.34 (2C), 128.29 (4C), 128.0 (2C), 127.9,

127.6, 113.5 (2C), 102.7, 87.6, 82.5, 79.7, 73.7, 71.6, 68.6, 66.4, 54.6,

18.4 (6C), 12.9 (3C); HRMS (ESI) calcd for C₃₆H₄₉O₆SSi [(MþH)^þ]

637.3014, found 637.3021.

4.5. Enol phosphate 16

To a solution of acetate 17 (354 mg, 1.51 mmol) in THF (15 mL) at

ꢁ78 ^ꢀC were added HMPA (0.80 mL, 4.6 mmol), (PhO)₂P(O)Cl

(0.45 mL, 2.2 mmol), and LHMDS (1.0 M solution in THF, 2.0 mL,

2.0 mmol), and the resultant solution was stirred at ꢁ78 ^ꢀC for 1 h.

The reaction was quenched with 3% NH₄OH solution. The resultant

mixture was stirred vigorously at room temperature for 30 min and

then extracted with Et₂O. The organic layer was washed with brine,

dried (Na₂SO₄), ﬁltered, and concentrated under reduced pressure.

The residual enol phosphate 16 was immediately used in the next

reaction without further puriﬁcation.

4.3. Alcohol 14

To a solution of silyl ether 13 (0.955 g, 1.50 mmol) in CH₂Cl₂

(15 mL) at ꢁ78 ^ꢀC was added DIBALH (1.02 M solution in n-hexane,

5.90 mL, 6.00 mmol), and the resultant solution was allowed to

warm to 0 ^ꢀC over a period of 3 h. The reaction was quenched with

MeOH at 0 ^ꢀC. The resultant mixture was diluted with EtOAc and

saturated aqueous potassium sodium tartrate solution, and stirred

vigorously at room temperature until the layers became clear. The

organic layer was separated and washed with H₂O and brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

4.6. Spiroacetals 21 and 22

20% EtOAc/hexanes) gave alcohol 14 (0.936 g, 98%) as a colorless oil:

To a solution of oleﬁn 8 (292 mg, 0.460 mmol) in THF (2 mL) was

added a solution of 9-BBN-H dimer (151 mg, 0.604 mmol) in THF

(1.6 mLþ1.0 mL rinse), and the resultant solution was stirred at

room temperature for 3 h. To this solution was added 3 M aqueous

Cs₂CO₃solution (0.50 mL, 1.5 mmol), and the resultant mixture was

stirred at room temperature for 20 min. To this mixture was added

a solution of the above enol phosphate 16 in DMF (2.6 mLþ2.0 mL

rinse) and Pd(PPh₃)₄(55 mg, 0.048 mmol), and the resultant mix-

ture was stirred at room temperature overnight. The reaction

mixture was diluted with Et₂O and washed with H₂O and brine. The

organic layer was dried (Na₂SO₄), ﬁltered, and concentrated under

reduced pressure. The residual enol ether 19 was rapidly passed

through a short pad of silica gel to remove baseline impurities and

used immediately in the next reaction without further puriﬁcation.

To a solution of the above enol ether 19 in toluene (70 mL) was

added a solution of the second-generation Grubbs catalyst (G-II)

(39 mg, 0.061 mmol) in toluene (22 mL), and the resultant solution

was stirred at 70 ^ꢀC for 1 h. The reaction mixture was cooled to

room temperature, stirred at room temperature under air for 2 h,

and then concentrated under reduced pressure. The residual

endocyclic enol ether 20 was used in the next reaction without any

puriﬁcation.

23

[

a]

þ116.2 (c 1.00, benzene); IR (ﬁlm) 3503, 2943, 2866, 1514,

D

1248, 1086 cm^ꢁ^{1 1}H NMR (600 MHz, C₆D₆)

; d 7.51e7.50 (m, 2H),

7.39e7.38 (m, 2H), 7.26e7.25 (m, 2H), 7.18e7.17 (m, 2H), 7.07e7.01

(m, 3H), 6.96 (m, 1H), 6.79e6.77 (m, 2H), 5.71 (d, J¼1.9 Hz, 1H), 4.90

(d, J¼11.0 Hz, 1H), 4.61 (d, J¼11.5 Hz, 1H), 4.56 (dd, J¼9.6, 2.8 Hz,

1H), 4.47 (d, J¼11.5 Hz, 1H), 4.41 (d, J¼11.5 Hz, 1H), 4.30 (ddd, J¼9.6,

3.7, 3.7 Hz, 1H), 4.25 (dd, J¼9.6, 9.6 Hz, 1H), 4.11 (dd, J¼2.8, 1.9 Hz,

1H), 3.80e3.77 (m, 2H), 3.27 (s, 3H), 1.25e1.18 (m, 21H); ¹³C NMR

(150 MHz, C₆D₆)

d 159.6, 138.7, 135.2, 132.0, 131.2 (2C), 129.3 (2C),

129.2 (2C), 128.5 (2C), 128.3 (2C), 127.8 (2C), 127.7, 114.0, 86.3, 81.9,

76.3, 75.0, 74.6, 74.3, 72.3, 62.4, 54.7,18.5 (6C),13.3 (3C); HRMS (ESI)

calcd for C₃₆H₅₀O₆SSiNa [(MþNa)^þ] 661.2990, found 661.2990.

4.4. Oleﬁn 8

To a solution of alcohol 14 (49 mg, 0.077 mmol) in CH₂Cl₂/DMSO

(1:1, v/v, 0.78 mL) at 0 ^ꢀC were added Et₃N (0.045 mL, 0.32 mmol)

and SO₃$pyridine (38 mg, 0.24 mmol), and the resultant mixture

was stirred at 0 ^ꢀC for 45 min. The reaction mixture was diluted

with Et₂O, washed successively with 1 M aqueous HCl solution,

saturated aqueous NaHCO₃solution, and brine. The organic layer

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8

H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

To a solution of the above endocyclic enol ether 20 in CH₂Cl₂/pH

128.31 (2C), 128.29 (2C), 127.8 (2C), 127.7, 127.6 (2C), 127.4, 106.2,

92.9, 77.5, 76.0, 74.3, 73.8, 73.1, 72.3, 71.3, 70.5, 36.7, 33.1, 26.3, 26.2,

18.2 (3C), 18.1 (3C), 12.6 (3C); HRMS (ESI) calcd for C₄₁H₅₆O₈SSiNa

[(MþNa)^þ] 759.3357, found 759.3353.

7 buffer (10:1, v/v, 4.6 mL) at 0 ^ꢀC was added DDQ (104 mg,

0.458 mmol), and the resultant mixture was stirred at room tem-

perature for 1 h. The reaction was quenched with saturated aque-

ous NaHCO₃solution. The resultant mixture was extracted with

EtOAc, and the organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

ﬁrst-round: 2e8% EtOAc/hexanes; second-round: benzene) gave

spiroacetal 21 (113 mg, 35% for the three steps) as a colorless oil,

along with its diastereomer 22 (39 mg, 12% for the three steps) as

a colorless oil.

4.8. Bis-silyl ether 10

To a solution of diol 23 (166 mg, 1.15 mmol) in CH₂Cl₂(12 mL) at

0

^ꢀC were added 2,6-lutidine (0.40 mL, 3.5 mmol) and TBSOTf

(0.58 mL, 2.5 mmol), and the resultant solution was stirred at 0 ^ꢀC

for 20 min. The reaction was quenched with saturated aqueous

NH₄Cl solution at 0 ^ꢀC. The resultant mixture was extracted with

EtOAc, and the organic layer was washed with H₂O and brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

To a solution of spiroacetal 22 (39 mg, 0.055 mmol) in (CH₂Cl)₂

(0.55 mL) was added PPTS (4.5 mg, 0.018 mmol), and the resultant

solution was stirred at room temperature overnight. The reaction

mixture was neutralized with Et₃N and concentrated under re-

duced pressure. Puriﬁcation of the residue by ﬂash column chro-

matography (silica gel, 4e8% EtOAc/hexanes) gave additional

hexanes) gave bis-silyl ether 10 (430.3 mg, quant) as a colorless oil:

24

[a

]

þ21.2 (c 1.00, CHCl₃); IR (ﬁlm) 2956, 2929, 2858, 1472, 1254,

D

1105, 1052, 856, 774 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

; d 5.79 (ddd,

spiroacetal 21 (28 mg, 71%) as a colorless oil.

J¼17.9, 10.3, 7.6 Hz, 1H), 4.98e4.91 (m, 2H), 3.66 (dd, J¼6.8, 2.4 Hz,

1H), 3.42 (dd, J¼9.7, 7.9 Hz, 1H), 3.33 (dd, J¼9.7, 6.5 Hz, 1H), 2.33

(ddd, J¼7.6, 6.8, 6.8 Hz, 1H), 1.75 (m, 1H), 0.98 (d, J¼6.8 Hz, 3H), 0.89

(s, 9H), 0.87 (s, 9H), 0.77 (d, J¼6.8 Hz, 3H), 0.04 (s, 6H), 0.01 (s, 6H);

24

21: [a

]

þ63.9 (c 1.0, CHCl₃); IR (ﬁlm) 3734, 2942, 2864, 2361,

D

2324, 1456, 1146, 1028, 736 cm^ꢁ^{1 1}H NMR (600 MHz, CD₃OD)

;

d

7.44e7.21 (m, 15H), 5.49 (d, J¼1.9 Hz, 1H), 4.71 (d, J¼11.9 Hz, 1H),

4.68 (d, J¼11.9 Hz, 1H), 4.57 (s, 2H), 4.37 (m, 1H), 4.17 (dd, J¼10.1,

3.2 Hz,1H), 4.08 (dd, J¼10.1, 10.1 Hz,1H), 3.99 (dd, J¼3.2, 1.9 Hz,1H),

3.91 (ddd, J¼10.1, 10.1, 4.1 Hz, 1H), 3.55 (dd, J¼10.5, 4.1 Hz, 1H), 3.51

(dd, J¼10.1, 5.5 Hz, 1H), 2.10 (m, 1H), 2.02e1.89 (m, 3H), 1.87e1.79

(m, 2H), 1.76 (m, 1H), 1.70 (m, 1H), 1.50 (s, 21H); ¹³C NMR (150 MHz,

¹³C NMR (150 MHz, CDCl₃)

d 142.2, 113.3, 74.9, 66.0, 42.8, 38.8, 26.2,

25.9, 18.5, 18.2, 16.9 (3C), 10.6 (3C), ꢁ3.7, ꢁ4.1, ꢁ5.27, ꢁ5.32; HRMS

(ESI) calcd for C₂₀H₄₄O₂Si₂Na [(MþNa)^þ] 395.2772, found 395.2766.

4.9. Endocyclic enol ether 25

CD₃OD) d 139.7, 139.6, 135.7, 132.7 (2C), 130.2 (2C), 129.3 (3C), 129.0

(2C), 128.8 (2C),128.7, 128.6 (2C), 128.5, 107.9, 88.1, 83.0, 78.9, 74.2,

74.1, 73.5, 73.3, 72.6, 71.3, 37.6, 34.3, 27.2, 26.8, 18.8 (6C), 13.9 (3C);

HRMS (ESI) calcd for C₄₁H₅₆O₆SSiNa ([MþNa]^þ) 727.3459, found

727.3466.

To a solution of bis-silyl ether 10 (45.0 mg, 1.21 mmol) in THF

(1.2 mL) was added 9-BBN-H dimer (40.6 mg, 1.66 mmol), and the

resultant solution was stirred at room temperature for 2.5 h. To this

solution was added 3 M aqueous K₃PO₄solution (0.14 mL,

0.42 mmol), and the resultant mixture was stirred at room tem-

perature for 20 min. To this mixture was added a solution of enol

22: [

a]

²⁴þ92.2 (c 0.5, CHCl₃); IR (ﬁlm) 3649, 2942, 2865, 2361,

D

2311, 1457, 1151, 1038, 737 cm^ꢁ1

;

¹H NMR (600 MHz, C₆D₆)

d

7.53e7.52 (m, 2H), 7.37e7.35 (m, 4H), 7.21e6.94 (m, 9H), 5.80 (d,

phosphate 11 (prepared from d-valerolactone (0.55 mL, 0.61 mmol)

J¼1.4 Hz, 1H), 4.60 (d, J¼11.9 Hz, 1H), 4.90e4.54 (m, 3H), 4.43 (d,

J¼11.5 Hz, 1H), 4.26e4.19 (m, 2H) 4.12 (dd, J¼3.2, 1.4 Hz, 1H), 3.96

(dd, J¼9.7, 9.7 Hz, 1H), 3.80 (dd, J¼9.7, 6.4 Hz, 1H), 3.59 (dd, J¼9.7,

5.5 Hz, 1H), 2.02 (ddd, J¼11.9, 7.3, 1.8 Hz, 1H), 1.95 (ddd, J¼13.3, 13.3,

4.6 Hz, 1H), 1.81e1.73 (m, 2H), 1.64e1.56 (m, 2H), 1.44 (ddd, J¼13.3,

immediately prior to use) in DMF (2.4 mL), Et₃N (0.040 mL,

0.26 mmol), and Pd(PPh₃)₄(10.0 mg, 0.00865 mmol), and the re-

sultant mixture was stirred at 50 ^ꢀC for 20 h. The reaction mixture

was cooled to room temperature, diluted with Et₂O, washed with

H₂O and brine, dried (Na₂SO₄), ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 1% Et₃N/hexanes) gave endocyclic enol

4.1, 4.1 Hz, 1H), 1.26 (m, 21H), 1.03 (ddd, J¼11.9, 11.9, 7.8 Hz, 1H); ¹³

C

NMR (150 MHz, C₆D₆)

d 139.1, 138.5, 130.9 (2C), 130.7, 129.1 (2C),

128.2 (2C), 128.0 (2C), 127.7 (2C), 127.5, 127.5 (2C), 127.3, 127.0,

108.5, 86.6, 82.2, 79.3, 75.7, 74.4, 73.3, 72.8, 71.9, 70.1, 34.4, 32.4,

28.0, 27.2, 18.4 (6C), 12.9 (3C); HRMS (ESI) calcd for C₄₁H₅₆O₆SSiNa

[(MþNa)^þ] 727.3459, found 727.3466.

ether 25 (45.3 mg, 82%) as a colorless oil: [

a

]

²⁴þ13.8 (c 1.00, ben-

D

zene); IR (ﬁlm) 1716, 1472, 1388, 1361, 1006 cm^ꢁ1

;

¹H NMR

(600 MHz, C₆D₆)

d

4.53 (dd, J¼3.8, 3.8 Hz, 1H), 3.81e3.76 (m, 3H),

3.56 (dd, J¼9.6, 7.6 Hz, 1H), 3.43 (dd, J¼9.6, 6.2 Hz,1H), 2.26 (m, 1H),

2.11 (m, 1H), 1.98e1.82 (m, 4H), 1.74 (m, 1H), 1.51e1.40 (m, 3H),

1.03e0.98 (m, 24H), 0.15 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.07 (s,

4.7. Sulfone 6

3H); ¹³C NMR (150 MHz, C₆D₆)

d

155.2, 95.1, 75.5, 66.3, 66.0, 39.4,

To a solution of spiroacetal 21 (50.0 mg, 0.0709 mmol) in CH₂Cl₂

(1.0 mL) at 0 ^ꢀC were added NaHCO₃(36.3 mg, 0.465 mmol) and m-

CPBA (43.0 mg, 0.254 mmol), and the resultant mixture was stirred

at room temperature for 1 h. The reaction was quenched with a 1:1

mixture of saturated aqueous NaHCO₃solution and saturated

aqueous Na₂SO₃solution. The resultant mixture was extracted with

EtOAc, and the organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

37.7, 33.0, 31.4, 26.4 (3C), 26.1 (3C), 22.8, 20.6, 18.7, 18.4, 16.1, 12.3,

ꢁ3.6, ꢁ3.9, ꢁ5.2 (2C); HRMS (ESI) calcd for

[(MþNa)^þ] 479.3347, found 479.3370.

C₂₅H₅₂O₃Si₂Na

4.10. Alcohol 26 (from 25)

To a solution of endocyclic enol ether 25 (256 mg, 0.560 mmol)

in MeOH (6.0 mL) at 0 ^ꢀC was added p-TsOH$H₂O (32 mg,

0.17 mmol), and the resultant solution was stirred at room tem-

perature for 20.5 h. The reaction mixture was neutralized with Et₃N

and concentrated under reduced pressure. Puriﬁcation of the resi-

due by ﬂash column chromatography (silica gel, 5e15% EtOAc/

3% Et₂O/benzene) gave sulfone 6 (49.5 mg, 91%) as a colorless oil:

23

[

a]

þ23.4 (c 1.0, CHCl₃); IR (ﬁlm) 2943, 2865, 2360, 1490, 1456,

D

1308, 1159, 1123, 1078, 1026 cm^ꢁ1

;

¹H NMR (600 MHz, CDCl₃)

d

7.69e7.68 (m, 2H), 7.53 (m, 1H), 7.44e7.41 (m, 2H), 7.21e7.12 (m,

hexanes) gave alcohol 26 (128 mg, quant, dr >20:1) as a colorless

24

10H), 4.75 (d, J¼11.9 Hz, 1H), 4.58 (s, 1H), 4.48e4.40 (m, 5H), 4.23

(m, 1H), 4.06 (m, 1H), 3.98 (dd, J¼5.0, 5.0 Hz, 1H), 3.39e3.37 (m,

2H), 1.99 (m, 1H), 1.84e1.58 (m, 7H), 1.09e1.02 (m, 21H); ¹³C NMR

oil: [

a

]

þ92.2 (c 1.00, CHCl₃); IR (ﬁlm) 3397, 2937, 2874, 1452,

D

1384, 1234, 1044, 998, 976 cm^ꢁ1

3.67e3.63 (m, 2H), 3.56e3.52 (m, 2H), 3.47 (m, 1H), 2.01 (m, 1H),

1.88e1.74 (m, 3H), 1.62 (ddd, J¼13.3, 1.9, 1.9 Hz, 1H), 1.59e1.47 (m,

;

¹H NMR (600 MHz, CDCl₃)

d

(150 MHz, CDCl₃)

d 138.5, 137.9, 137.2, 134.0, 129.1 (2C), 128.7 (2C),

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

9

4H), 1.43 (dd, J¼13.3, 4.1 Hz, 1H), 1.39e1.33 (m, 2H), 1.11 (d,

J¼6.9 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H), one proton missing due to H/D

n-hexane, 0.10 mL, 0.10 mmol) and CH₂Cl₂(0.20 mL), and the re-

sultant solution was stirred at room temperature for 30 min. To this

solution was added a solution of sulfone 6 (24.1 mg, 0.0327 mmol)

in CH₂Cl₂(0.2 mLþ0.2 mL rinse), and the resultant solution was

stirred at room temperature for 1.5 h. The reaction was quenched

with saturated aqueous NH₄Cl solution at 0 ^ꢀC. The resultant mix-

ture was extracted with EtOAc, and the organic layer was washed

with brine, dried (Na₂SO₄), ﬁltered, and concentrated under re-

duced pressure. Puriﬁcation of the residue by ﬂash column chro-

matography (silica gel, 5% EtOAc/hexanes) gave alkyne 30 (18.7 mg,

exchange; ¹³C NMR (150 MHz, CDCl₃)

d 95.7, 72.6, 64.9, 60.4, 37.5,

35.8, 30.3, 28.0, 26.5, 25.4, 18.7, 14.4, 11.3; HRMS (ESI) calcd for

C

₁₃H₂₄O₃Na [(MþNa)^þ] 251.1618, found 251.1600.

4.11. Alkyne 7

To a solution of alcohol 26 (143.3 mg, 0.6280 mmol) in DMSO

(6.3 mL) was added 2-iodoxybenzoic acid (IBX, 352 mg, 1.26 mmol),

and the resultant solution was stirred at room temperature for 3 h.

The reaction mixture was diluted with Et₂O and washed succes-

sively with a 1:1 mixture of saturated aqueous NaHCO₃solution

and saturated aqueous Na₂SO₃solution, H₂O, and brine. The or-

ganic layer was dried (MgSO₄), ﬁltered, and concentrated under

reduced pressure to give crude aldehyde, which was used in the

next reaction without further puriﬁcation.

81%, dr >20:1) as a colorless oil: [

a]

²⁵þ54.6 (c 1.0, CHCl₃); IR (ﬁlm)

D

3030, 2942, 2864, 2360, 1490, 1456, 1362, 1249, 1122, 1101, 1028,

882 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d 7.41e7.39 (m, 4H), 7.33e7.29

(m, 9H), 7.26e7.23 (m, 2H), 4.92 (d, J¼2.3 Hz, 1H), 4.82 (d,

J¼12.4 Hz, 1H), 4.71 (d, J¼12.4 Hz, 1H), 4.59 (d, J¼12.4 Hz, 1H), 4.56

(d, J¼12.4 Hz 1H), 4.38 (dd, J¼9.6, 2.8 Hz 1H), 4.33 (m, 1H), 4.05 (dd,

J¼9.7, 9.6 Hz 1H), 3.87 (dd, J¼2.8, 2.3 Hz, 1H), 3.65 (ddd, J¼11.5, 9.6,

4.1 Hz, 1H), 3.54e3.49 (m, 2H), 2.10e1.98 (m, 2H), 1.92e1.81 (m,

4H), 1.77e1.68 (m, 2H), 1.14e1.08 (m, 21H); ¹³C NMR (150 MHz,

To a solution of the above aldehyde in MeOH (6.3 mL) at 0 ^ꢀC

were added OhiraeBestmann reagent (180 mg, 0.938 mmol) and

K₂CO₃(218 mg, 1.58 mmol), and the resultant mixture was allowed

to warm to room temperature over a period of 3 h. The reaction

mixture was partitioned between EtOAc and H₂O. The organic layer

was separated and washed with brine. The organic layer was dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

CDCl₃)

d 138.61, 138.58, 131.7 (2C), 128.7, 128.33 (2C), 128.29 (2C),

128.2 (2C), 127.6 (2C), 127.5 (2C), 127.4 (2C), 122.2, 106.2, 88.3, 84.6,

81.9, 77.4, 73.13, 73.08, 72.3, 72.1, 71.9, 71.6, 67.8, 36.8, 33.4, 26.3,

26.2, 18.23 (3C), 18.16 (3C), 12.7 (3C); HRMS (ESI) calcd for

C

₄₃H₅₆O₆SiNa [(MþNa)^þ] 719.3738, found 719.3761.

1% Et₂O/hexanes) gave alkyne 7 (99.0 mg, 71% for the two steps) as

4.14. Alkyne 31

24

a colorless oil: [

a]

þ94.2 (c 1.00, CHCl₃); IR (ﬁlm) 3310, 2938,

D

2874, 2359, 2324, 1062, 997, 983 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

To a solution of ethynylbenzene (0.010 mL, 0.091 mmol) in tol-

uene (0.3 mL) at 0 ^ꢀC was added n-BuLi (1.63 M solution in n-

hexane, 0.056 mL, 0.091 mmol), and the resultant solution was

stirred at 0 ^ꢀC for 30 min. To this solution were added Me₂AlCl

(1.0 M solution in n-hexane, 0.091 mL, 0.091 mmol) and CH₂Cl₂

(0.3 mL), and the resultant solution was stirred at room tempera-

ture for 30 min. To this solution was added a solution of sulfone 28

(47.7 mg, 0.0715 mmol) in CH₂Cl₂(0.3 mLþ0.3 mL rinse), and the

resultant solution was stirred at room temperature for 1.5 h. The

reaction was quenched with saturated aqueous NH₄Cl solution at

d

3.62 (dd, J¼11.0, 2.7 Hz, 1H), 3.56 (m, 1H), 3.52 (dd, J¼10.6, 2.3 Hz,

1H), 2.48, (m, 1H), 2.12 (m, 1H), 2.04 (m, 1H), 2.01 (d, J¼2.8 Hz, 1H),

1.81 (m, 1H), 1.59e1.46 (m, 5H), 1.43 (dd, J¼13.3, 4.1 Hz, 1H),

1.41e1.36 (m, 2H), 1.31 (d, J¼6.4 Hz, 3H), 0.93 (d, J¼6.9 Hz, 3H); ¹³

C

NMR (150 MHz, CDCl₃)

d 95.8, 85.9, 74.1, 69.4, 60.4, 35.7, 30.1, 28.9,

28.3, 26.1, 25.3, 18.7, 18.4, 10.9; HRMS (ESI) calcd for C₁₄H₂₃O₂

[(MþH)^þ] 223.1693, found 223.1701.

4.12. Sulfone 28

0

^ꢀC. The resultant mixture was extracted with EtOAc, and the or-

To a solution of oleﬁn 8 (115 mg, 0.180 mmol) in CH₂Cl₂(1.8 mL)

at 0 ^ꢀC were added NaHCO₃(76.0 mg, 0.974 mmol) and m-CPBA

(95.2 mg, 0.562 mmol), and the resultant mixture was stirred at

room temperature for 2.5 h. The reaction was quenched with a 1:1

mixture of saturated aqueous NaHCO₃solution and saturated

aqueous Na₂SO₃solution. The resultant mixture was extracted with

EtOAc, and the organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

ganic layer was washed with brine, dried (Na₂SO₄), ﬁltered, and

concentrated under reduced pressure. Puriﬁcation of the residue by

ﬂash column chromatography (silica gel, 5e20% EtOAc/hexanes)

gave alkyne 31 (41.8 mg, 93%, dr 9:1) as a colorless oil: [

a]

²⁶þ27.4 (c

D

1.0, CHCl₃); IR (ﬁlm) 3734, 2942, 2865, 2361, 1514, 1457, 1248, 1247,

1089, 1037, 756 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

; d 7.42e7.41 (m,

2H), 7.38e7.28 (m, 8H), 7.23e7.21 (m, 2H), 6.83e6.81 (m, 2H), 5.98

(ddd, J¼17.5, 10.6, 6.9 Hz, 1H), 5.44 (d, J¼17.5 Hz, 1H), 5.24 (d,

J¼10.6 Hz,1H), 5.00 (d, J¼2.3 Hz,1H), 4.74 (s, 2H), 4.71 (d, J¼10.5 Hz,

1H), 4.53 (d, J¼10.5 Hz, 1H), 4.52 (dd, J¼9.2, 2.8 Hz, 1H), 4.27 (dd,

J¼7.8, 7.8 Hz, 1H), 3.91 (dd, J¼2.8, 2.3 Hz, 1H), 3.78 (s, 3H), 3.64 (dd,

J¼9.2, 7.8 Hz, 1H), 1.10e1.09 (m, 21H); ¹³C NMR (150 MHz, CDCl₃)

riﬁcation of the residue by ﬂash column chromatography (silica gel,

23

benzene) gave sulfone 28 (96.9 mg, 81%) as a colorless oil: [a]

D

þ62.5 (c 1.0, CHCl₃); IR (ﬁlm) 2942, 2866, 1514, 1457, 1249, 1152,

1126, 1079, 1036 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

7.84e7.82 (m,

;

d

2H), 7.62 (m, 1H), 7.52e7.50 (m, 2H), 7.37e7.36 (m, 2H), 7.33e7.30

(m, 2H), 7.27 (m, 1H), 7.20e7.18 (m, 2H), 6.84e6.83 (m, 2H), 5.75

(ddd, J¼16.9, 10.5, 6.4 Hz, 1H), 5.22 (d, J¼16.9 Hz, 1H), 5.12 (d,

J¼10.5 Hz, 1H), 4.78e4.75 (m, 2H), 4.68e4.54 (m, 5H), 4.50 (d,

J¼11.0 Hz, 1H), 3.79 (s, 3H), 3.62 (m, 1H), 1.29e1.07 (m, 21H); ¹³C

d 159.0, 138.4, 135.6, 131.7 (2C), 130.7, 129.4 (2C), 128.7, 128.3 (2C),

128.2 (2C),127.50 (2C),127.46 (2C),122.0,118.1,113.5 (2C), 79.7 (2C),

76.3 (2C), 74.5, 73.3, 72.3, 55.2 (2C), 18.24 (3C), 18.20 (3C),13.0 (3C);

HRMS (ESI) calcd for C₃₉H₅₀O₅SiNa [(MþNa)^þ] 649.3320, found

649.3345.

NMR (150 MHz, CDCl₃)

d 159.0, 137.7, 137.2, 135.1, 133.9, 129.1 (4C),

129.0 (4C), 128.9 (2C), 128.3 (4C), 127.9, 127.8, 113.5 (2C), 73.34 (2C),

55.3 (3C), 18.2 (6C),13.0 (3C); HRMS (ESI) calcd for C₃₇H₅₀O₇SSiNa

[(MþNa)^þ] 689.2939, found 689.2945.

4.15. Thioglycoside 39

To

a

solution of

D

-mannose pentaacetate (38) (1.20 g,

3.07 mmol) and o-MeOC₆H₄SH (0.49 mL, 4.0 mmol) in CH₂Cl₂

(30 mL) at 0 ^ꢀC was added BF₃$OEt₂(1.90 mL, 15.4 mmol), and the

resultant solution was stirred at 0 ^ꢀC for 30 min and then at room

temperature for 12 h. The reaction was quenched with saturated

aqueous NaHCO₃solution at 0 ^ꢀC. The resultant mixture was di-

luted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄),

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

4.13. Alkyne 30

To a solution of ethynylbenzene (0.011 mL, 0.10 mmol) in tolu-

ene (0.2 mL) at 0 ^ꢀC was added n-BuLi (1.64 M solution in n-hexane,

0.061 mL, 0.10 mmol), and the resultant solution was stirred at 0 ^ꢀC

for 30 min. To this solution were added Me₂AlCl (1.0 M solution in

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10

H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

the residue by ﬂash column chromatography (silica gel, 10e40%

EtOAc/hexanes) gave thioglycoside 39 (1.49 g, quant, dr >20:1) as

concentrated under reduced pressure. The residue was roughly

puriﬁed by ﬂash column chromatography (silica gel, 20% EtOAc/

hexanes) and then by recrystallization from EtOAc/hexanes to give

a benzyl ether (1.05 g, 41%) as colorless crystals. The mother liquor

was concentrated under reduced pressure, and the residue was

puriﬁed by ﬂash column chromatography (silica gel, 20% EtOAc/

hexanes) and then by recrystallization from EtOAc/hexanes to give

additional benzyl ether (0.21 g, 8%) as colorless crystals (total yield:

a yellow oil: [

a

]

²⁴þ122.8 (c 1.00, CHCl₃); IR (ﬁlm) 2942, 1749, 1370,

D

1245, 1227, 1063 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d

7.45 (dd, J¼7.8,

1.8 Hz, 1H), 7.26 (m, 1H), 6.90e6.86 (m, 2H), 5.61 (d, J¼1.4 Hz, 1H),

5.49 (dd, J¼3.7, 1.8 Hz, 1H), 5.41 (dd, J¼9.7, 3.2 Hz, 1H), 5.30 (dd,

J¼10.1, 10.1 Hz, 1H), 4.48 (ddd, J¼10.1, 5.5, 2.3 Hz, 1H), 4.25 (dd,

J¼12.4, 5.5 Hz, 1H), 3.96 (dd, J¼12.4, 2.3 Hz, 1H), 3.86 (s, 3H), 2.13

(s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H); ¹³C NMR (150 MHz,

1.26 g, 49%): mp 150e151 ^ꢀC (recrystallized from EtOAc/hexanes);

24

CDCl₃)

d

170.6, 169.9, 169.8 (2C), 158.7, 134.0, 129.9, 121.1, 119.4,

[

a

]

þ165.2 (c 1.00, C₆H₆); IR (KBr) 3476, 2901, 1248, 1093,

D

111.0, 83.1, 70.8, 69.5, 69.4, 66.3, 62.3, 55.8, 20.9, 20.70, 20.66,

20.63; HRMS (ESI) calcd for C₂₁H₂₆O₁₀SNa [(MþNa)^þ] 493.1139,

found 493.1143.

751 cm^ꢁ1; ¹H NMR (600 MHz, acetone-d₆)

d

7.50 (dd, J¼7.8, 1.8 Hz,

1H), 7.47e7.42 (m, 4H), 7.37e7.28 (m, 4H), 7.03 (dd, J¼8.3, 0.9 Hz,

1H), 6.96e6.91 (m, 3H), 5.77 (s, 1H), 5.58 (s, 1H), 4.80 (s, 2H), 4.32

(d, J¼6.4 Hz, 1H), 4.18 (ddd, J¼10.1, 5.0, 5.0 Hz, 1H), 4.11e4.06 (m,

2H), 4.02e3.90 (m, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.74 (dd, J¼10.1,

4.16. Diol 40

10.1 Hz, 1H); ¹³C NMR (150 MHz, acetone-d₆)

d 160.9, 159.6, 139.5,

To a solution of thioglycoside 39 (1.39 g, 3.07 mmol) in MeOH

(10 mL) was added NaOMe (324 mg, 6.00 mmol), and the resultant

solution was stirred at room temperature for 16 h. The reaction

mixture was neutralized with Amberlyst^Ò15 ion-exchange resin,

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

the residue by ﬂash column chromatography (silica gel, CHCl₃to

20% MeOH/CHCl₃) gave a tetraol (0.88 g, 95%) as a pale yellow foam:

134.1, 131.6, 130.1, 129.0 (2C), 128.7 (2C), 128.6 (2C), 128.3, 123.0,

121.9, 114.0 (2C), 112.1, 102.5, 85.4, 81.6, 80.3, 73.7, 70.1, 68.9, 66.3,

56.2, 55.5; HRMS (ESI) calcd for C₂₈H₃₀O₇SNa [(MþNa)^þ] 533.1604,

found 533.1581.

To a solution of the above benzyl ether (1.04 g, 2.04 mmol) in

CH₂Cl₂(20 mL) at 0 ^ꢀC were added 2,6-lutidine (0.650 mL,

5.61 mmol) and TIPSOTf (0.700 mL, 2.60 mmol), and the resultant

solution was stirred at room temperature for 5 h. The reaction was

quenched with saturated aqueous NaHCO₃solution at 0 ^ꢀC. The

resultant mixture was diluted with EtOAc, washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

[

a]

²⁴þ190.2 (c 1.00, CHCl₃); IR (ﬁlm) 3365, 2934, 1580, 1477, 1246,

D

1065, 796 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d

7.40 (dd, J¼8.0, 1.6 Hz,

1H), 7.16 (m, 1H), 6.82e6.76 (m, 2H), 5.58 (s, 1H), 5.34e5.11 (m, 3H),

4.41 (s, 1H), 4.18 (s, 1H), 4.10e3.90 (m, 2H), 3.93e3.90 (m, 2H), 3.75

(s, 3H), 3.60 (d, J¼11.9 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃)

d 158.2,

133.2, 129.0, 121.2, 121.1, 110.8, 86.0, 73.4, 72.5, 72.1, 66.4, 60.9, 55.7;

HRMS (ESI) calcd for C₁₃H₁₈O₆SNa [(MþNa)^þ] 325.0716, found

325.0724.

10% EtOAc/hexanes) gave silyl ether 41 (1.25 g, 92%) as a pale yellow

23

oil: [

a

]

D

þ129.1 (c 1.00, CHCl₃); IR (ﬁlm) 2941, 2865, 1519, 1477,

1463, 1248, 1096 cm^ꢁ^{1 1}H NMR (600 MHz, acetone-d₆)

; d 7.51

To a solution of the above tetraol (8.39 g, 27.8 mmol) in CH₃CN

(270 mL) at 0 ^ꢀC were added p-methoxybenzaldehyde dimethyl

acetal (7.10 mL, 41.7 mmol) and PPTS (1.40 g, 5.57 mmol), and the

resultant solution was stirred at 0 ^ꢀC for 70 min. The reaction was

quenched with saturated aqueous NaHCO₃solution at 0 ^ꢀC. The

resultant mixture was extracted with CH₂Cl₂, and the organic

layer was washed with brine, dried (Na₂SO₄), ﬁltered, and con-

centrated under reduced pressure. The residue was recrystallized

from CH₂Cl₂/hexanes to give diol 40 (6.11 g, 52%) as colorless

crystals. The mother liquor was concentrated under reduced

pressure, and the residue was puriﬁed by ﬂash column chroma-

tography (silica gel, 50% EtOAc/hexanes then 10% MeOH/CHCl₃) to

give additional diol 40 (2.71 g, 23%) as colorless crystals. Total

yield: 8.82 g, 75%. Data for 40: mp 122e123 ^ꢀC (recrystallized from

(dd, J¼7.8, 1.8 Hz, 1H), 7.45e7.42 (m, 4H), 7.37e7.28 (m, 4H), 7.04

(dd, J¼8.2, 1.4 Hz, 1H), 6.96e6.90 (m, 3H), 5.78 (d, J¼1.4 Hz, 1H),

5.59 (s, 1H), 4.82 (d, J¼11.5 Hz, 1H), 4.79 (d, J¼11.5 Hz, 1H), 4.40

(dd, J¼9.6, 3.2 Hz, 1H), 4.21 (ddd, J¼9.6, 4.6, 4.6 Hz, 1H), 4.10e4.00

(m, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.76 (dd, J¼10.2, 10.1 Hz, 1H),

1.07e1.05 (m, 21H); ¹³C NMR (150 MHz, acetone-d₆)

d 161.0, 159.6,

139.6, 134.3 (2C), 132.2, 130.2, 129.0 (2C), 128.7 (2C), 128.5 (2C),

128.3, 121.9, 121.8, 113.9, 112.1, 102.9, 85.6, 82.5, 80.2, 73.8, 71.8,

68.9, 66.8, 56.2, 55.5, 18.5 (6C), 13.2 (3C); HRMS (ESI) calcd for

C

₃₇H₅₀O₇SSiNa [(MþNa)^þ] 689.2939, found 689.2947.

4.18. Alcohol 42

To a solution of silyl ether 41 (1.25 g, 1.87 mmol) in CH₂Cl₂

(20 mL) at ꢁ78 ^ꢀC was added DIBALH (1.02 M solution in n-hexane,

7.40 mL, 7.55 mmol), and the resultant solution was allowed to

warm to 0 ^ꢀC over a period of 4 h. The reaction was quenched with

MeOH at 0 ^ꢀC. The resultant solution was diluted with EtOAc and

saturated aqueous potassium sodium tartrate solution. The re-

sultant biphasic mixture was stirred vigorously at room tempera-

ture until the layers became clear and then separated. The organic

layer was washed with brine, dried (Na₂SO₄), ﬁltered, and con-

centrated under reduced pressure. Puriﬁcation of the residue by

CH₂Cl₂/hexanes); [

a

]

²⁴þ269.5 (c 1.00, CHCl₃); IR (KBr) 3418, 1518,

D

1477, 1248, 1092, 1068, 1026 cm^ꢁ1; ¹H NMR (600 MHz, acetone-d₆)

d

7.52 (dd, J¼7.8, 1.9 Hz, 1H), 7.42e7.40 (m, 2H), 7.31 (m, 1H), 7.03

(dd, J¼8.2, 1.4 Hz, 1H), 6.97e6.90 (m, 3H), 5.64 (s, 1H), 5.55 (s, 1H),

4.47 (d, J¼5.5 Hz, 1H), 4.45 (d, J¼3.2 Hz, 1H), 4.21e4.17 (m, 2H),

4.02 (ddd, J¼9.6, 5.5, 3.7 Hz, 1H), 3.99e3.95 (m, 2H), 3.90 (s, 3H),

3.80 (s, 3H) 3.72 (dd, J¼10.5, 10.1 Hz, 1H); ¹³C NMR (150 MHz,

acetone-d₆)

d 161.0, 159.7, 134.2, 131.6, 130.0, 128.5 (2C), 122.1,

121.9, 114.0 (2C), 112.0, 102.5, 87.6, 80.0, 73.6, 69.7, 69.0, 65.9, 56.2,

55.5; HRMS (ESI) calcd for C₂₁H₂₄O₇SNa [(MþNa)^þ] 443.1135,

found 443.1121.

ﬂash column chromatography (silica gel, 20% EtOAc/hexanes) gave

24

alcohol 42 (1.23 g, 98%) as a colorless oil: [

a]

þ134.7 (c 1.00,

D

CHCl₃); IR (ﬁlm) 3485, 2942, 2866, 1514, 1247, 1092 cm^ꢁ1; ¹H NMR

(600 MHz, CDCl₃)

4.17. Silyl ether 41

d

7.43 (dd, J¼7.3, 1.9 Hz, 1H), 7.38e7.31 (m, 4H),

7.27e7.23 (m, 4H), 6.90e6.84 (m, 4H), 5.68 (d, J¼1.4 Hz,1H), 4.84 (d,

J¼11.5 Hz, 1H), 4.70 (d, J¼12.0 Hz, 1H), 4.66 (d, J¼12.0 Hz, 1H), 4.54

(d, J¼11.5 Hz, 1H), 4.36 (dd, J¼8.7, 2.8 Hz, 1H), 4.05 (ddd, J¼9.6, 4.6,

3.2 Hz, 1H), 4.00 (dd, J¼1.8, 1.4 Hz, 1H), 3.90 (dd, J¼9.2, 9.2 Hz, 1H),

3.84 (s, 3H), 3.78 (s, 3H), 3.68e3.60 (m, 2H), 1.65 (m, 1H), 1.15e1.10

To a solution of diol 40 (2.08 g, 4.95 mmol) in CH₂Cl₂(50 mL)

were added Bu₄NHSO₄(337.7 mg, 0.9946 mmol), BnBr (0.70 mL,

5.9 mmol), and 3 M aqueous NaOH solution (4.0 mL, 12 mmol), and

the resultant biphasic mixture was heated to reﬂux for 10 h. The

resultant mixture was cooled to room temperature, diluted with

EtOAc, and washed with saturated aqueous NaHCO₃solution and

brine. The organic layer was dried (Na₂SO₄), ﬁltered, and

(m, 21H); ¹³C NMR (150 MHz, CDCl₃)

d 159.1,158.6,138.4,134.2 (2C),

130.6, 129.5, 129.3 (2C), 128.3 (2C), 127.5, 127.4 (2C), 121.2, 121.1,

113.7 (2C), 111.0, 83.3, 81.2, 74.7, 73.7, 73.6, 72.2, 62.3, 55.8, 55.3,

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

11

18.22 (3C),18.17 (3C),12.9 (3C); HRMS (ESI) calcd for C₃₇H₅₂O₇SSiNa

To a solution of the above MPM ether (740 mg, 2.26 mmol) in

N,N-dimethylacetamide (DMA)/H₂O (7:1, v/v, 24 mL) were added

Cu(OAc)₂(861 mg, 4.74 mmol) and PdCl₂(80 mg, 0.45 mmol), and

the resultant mixture was stirred at room temperature under an

atmosphere of O₂(balloon) for 9 h 20 min. The resultant mixture

was cooled to 0 ^ꢀC, diluted with H₂O, stirred at room temperature

for 15 min, and then ﬁltered through a pad of Celite to remove

insoluble materials. The ﬁltrate was diluted with t-BuOMe and

washed with H₂O and brine. The organic layer was dried (MgSO₄),

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

the residue by ﬂash column chromatography (silica gel, ﬁrst round:

10e30% EtOAc/hexanes; second round: 30% t-BuOMe/hexanes)

[(MþNa)^þ] 691.3095, found 691.3118.

4.19. Oleﬁn 35

To a solution of alcohol 42 (3.98 g, 5.95 mmol) and Et₃N

(3.40 mL, 24.4 mmol) in CH₂Cl₂/DMSO (1:1, v/v, 58 mL) at 0 ^ꢀC was

added SO₃$pyridine (2.86 g, 18.0 mmol), and the resultant solution

was stirred at 0 ^ꢀC for 40 min. The reaction mixture was diluted

with Et₂O and washed successively with 1 M aqueous HCl solution,

saturated aqueous NaHCO₃solution, and brine. The organic layer

was dried (MgSO₄), ﬁltered, and concentrated under reduced

pressure to give crude aldehyde, which was used in the next re-

action without further puriﬁcation.

gave a methyl ketone (672 mg, 87%) as a pale yellow oil: [

a]

²⁴þ27.9

D

(c 1.00, CHCl₃); IR (ﬁlm) 2858, 1714, 1513, 1246, 1030 cm^ꢁ1; ¹H NMR

(600 MHz, CDCl₃)

d 7.35e7.32 (m, 4H), 7.29e7.22 (m, 3H), 6.85 (d,

To a suspension of Ph₃P^þCH₃Br^ꢁ(6.38 g, 17.9 mmol) in THF

(58 mL) at 0 ^ꢀC was added n-BuLi (2.65 M solution in n-hexane,

6.40 mL, 17.0 mmol), and the resultant suspension was stirred at

J¼8.3 Hz, 2H), 4.59 (d, J¼11.5 Hz,1H), 4.53 (s, 2H), 4.43 (d, J¼11.5 Hz,

1H), 3.78 (s, 3H), 3.57 (m, 1H), 3.53 (dd, J¼10.1, 5.5 Hz, 1H), 3.48 (dd,

J¼10.1, 4.6, 1H), 2.52e2.40 (m, 2H), 2.05 (s, 3H), 1.87 (m, 1H), 1.75

0

^ꢀC for 30 min. To this suspension was added a solution of the

(m, 1H); ¹³C NMR (150 MHz, CDCl₃)

d 208.6, 159.1, 138.2,130.7, 129.4

above aldehyde in THF (5 mLþ5 mL rinse), and the resultant mix-

ture was allowed to warm to room temperature over a period of

2 h. The reaction was quenched with saturated aqueous NH₄Cl

solution at 0 ^ꢀC. The resultant mixture was extracted with t-

BuOMe, and the organic layer was washed with brine, dried

(MgSO₄), ﬁltered, and concentrated under reduced pressure. Puri-

ﬁcation of the residue by ﬂash column chromatography (silica gel,

5% EtOAc/hexanes) gave oleﬁn 35 (3.30 g, 83% for the two steps) as

(2C), 128.3 (2C), 127.55 (2C), 127.53, 113.7 (2C), 76.4, 73.3, 72.5, 71.5,

55.2, 39.3, 29.8, 25.9; HRMS (ESI) calcd for C₂₁H₂₆O₄Na [(MþNa)^þ]

365.1723, found 365.1712.

To a solution of the above methyl ketone (383.4 mg, 1.120 mmol)

in THF (11 mL) at ꢁ78 ^ꢀC was added KHMDS (0.5 M solution in

toluene, 2.7 mL, 1.4 mmol), and the resultant solution was stirred at

ꢁ78 ^ꢀC for 20 min. To this solution was added a solution of PhNTf₂

(480.3 mg, 1.344 mmol) in THF (1 mL), and the resultant solution

was stirred at ꢁ78 ^ꢀC for 50 min. The reaction was quenched with

saturated aqueous NaHCO₃solution at ꢁ78 ^ꢀC. The resultant mix-

ture was allowed to warm to room temperature and then extracted

with t-BuOMe. The organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

5e10% Et₂O/hexanes) gave enol triﬂate 36 (338.4 mg, 64%) as

a colorless oil, which was contaminated with a small amount of

unidentiﬁed impurities. This material was immediately used in the

next reaction without further puriﬁcation. Data for 36: ¹H NMR

a pale yellow oil: [

a

]

²⁴þ110.4 (c 1.00, CHCl₃); IR (ﬁlm) 2942, 2865,

D

1514, 1463, 1247, 1087, 1068 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d

7.49

(dd, J¼7.3, 1.8 Hz, 1H), 7.43e7.41 (m, 2H), 7.36e7.34 (m, 2H),

7.30e7.24 (m, 4H), 6.90 (dd, J¼7.3, 1.4 Hz, 1H), 6.92e6.85 (m, 3H),

5.95 (ddd, J¼17.5, 10.6, 6.9 Hz, 1H), 5.73 (s, 1H), 5.37 (d, J¼17.5 Hz,

1H), 5.19 (d, J¼10.6 Hz, 1H), 4.75 (d, J¼11.0 Hz, 1H), 4.74e4.70 (m,

2H), 4.57 (d, J¼10.6 Hz, 1H), 4.51 (dd, J¼9.1, 6.8 Hz, 1H), 4.36 (dd,

J¼8.7, 3.2 Hz, 1H), 4.05 (s, 1H), 3.85 (s, 3H) 3.80 (s, 3H), 3.72 (dd,

J¼9.2, 9.2 Hz, 1H), 1.16e1.14 (m, 21H); ¹³C NMR (150 MHz, CDCl₃)

d

158.9, 158.3, 138.5, 135.4, 133.5, 130.8, 129.1 (2C), 128.9, 128.2 (2C),

127.4 (2C), 121.8, 121.1, 118.1, 113.4 (2C), 110.8, 83.3, 81.3, 79.7, 77.2,

74.5, 74.4, 73.2, 72.0, 55.8, 55.2, 18.23 (3C), 18.19 (3C), 12.8 (3C);

HRMS (ESI) calcd for C₃₈H₅₂O₆SSiNa [(MþNa)^þ] 687.3146, found

687.3133.

(600 MHz, C₆D₆)

d 7.27e7.25 (m, 2H), 7.21e7.17 (m, 4H), 7.10 (m,

1H), 6.80e6.78 (m, 2H), 4.69 (d, J¼3.7 Hz, 1H), 4.51 (d, J¼11.5 Hz,

1H), 4.30e4.28 (m, 3H), 4.25 (d, J¼3.7 Hz, 1H), 3.41e3.33 (m, 1H),

3.30 (s, 3H), 3.21 (dd, J¼9.6, 5.0 Hz, 1H), 2.29 (ddd, J¼15.5, 7.8,

7.8 Hz, 1H), 2.13 (ddd, J¼15.5, 8.3, 7.8 Hz, 1H), 1.60e1.55 (m, 3H);

HRMS (ESI) calcd for C₂₂H₂₅F₃O₆SNa [(MþNa)^þ] 497.1216, found

497.1216.

4.20. Enol triﬂate 36

To a solution of (R)-1-benzyloxyhex-5-en-2-ol (43) (496 mg,

2.40 mmol) in DMF (8 mL) at 0 ^ꢀC was added NaH (60% dispersion

in mineral oil, 192 mg, 4.80 mmol), and the resultant mixture was

stirred at room temperature for 15 min. To this mixture at 0 ^ꢀC were

added MPMCl (0.400 mL, 2.96 mmol) and Bu₄NI (89.0 mg,

0.241 mmol), and the resultant mixture was stirred at room tem-

perature overnight. The reaction was quenched with saturated

aqueous NH₄Cl solution at 0 ^ꢀC. The resultant mixture was diluted

with EtOAc and washed with H₂O and brine. The organic layer was

dried (Na₂SO₄), ﬁltered, and concentrated under reduced pressure.

Puriﬁcation of the residue by ﬂash column chromatography (silica

4.21. exo-Oleﬁn 33

To a solution of oleﬁn 35 (308.4 mg, 0.4638 mmol) in THF (3 mL)

was added a solution of 9-BBN-H dimer (184.2 mg, 0.7548 mmol) in

THF (2 mLþ1 mL rinse), and the resultant solution was stirred at

room temperature for 3 h. To this solution was added 3 M aqueous

Cs₂CO₃solution (0.460 mL, 1.38 mmol), and the resultant mixture

was stirred at room temperature for 20 min. To this mixture were

added a solution of enol triﬂate 36 (338.4 mg, 0.7131 mmol) in DMF

(2.5 mL), PdCl₂(dppf)$CH₂Cl₂(38.9 mg, 0.0476 mmol), and Ph₃As

(58.0 mg, 0.189 mmol), and the resultant mixture was stirred at

room temperature for 14 h. The reaction mixture was diluted with

t-BuOMe and H₂O and stirred at room temperature for a while. The

organic layer was separated, washed with brine, dried (MgSO₄),

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

the residue by ﬂash column chromatography (silica gel, ﬁrst round:

gel, ﬁrst round: 10% t-BuOMe/hexanes; second round: 5% t-BuOMe/

24

hexanes) gave an MPM ether (761 mg, 97%) as a colorless oil: [a]

þ17.0 (c 1.00, CHCl₃); IR (ﬁlm) 2912, 2857,1612,1513,1268 cm^ꢁ1; ¹^DH

NMR (600 MHz, CDCl₃) d 7.37e7.36 (m, 4H), 7.32e7.29 (m, 3H), 6.88

(d, J¼8.7 Hz, 2H), 5.81 (ddt, J¼17.4, 10.1, 6.4 Hz, 1H), 5.02 (dd, J¼17.4,

1.4 Hz, 1H), 4.96 (d, J¼10.1 Hz, 1H), 4.64 (d, J¼11.5 Hz, 1H), 4.57

(s, 2H), 4.51 (d, J¼11.5 Hz, 1H), 3.80 (s, 3H), 3.64e3.52 (m, 3H) 2.20

(m, 1H), 2.12 (m, 1H) 1.71e1.64 (m, 2H); ¹³C NMR (150 MHz, CDCl₃)

5e10% EtOAc/hexanes; second round: 1% EtOAc/benzene) gave exo-

24

oleﬁn 33 (413.0 mg, 90%) as a colorless oil: [

a

]

þ93.4 (c 1.00,

D

d

159.0, 138.4, 138.3, 130.9, 129.3 (2C), 128.3 (2C), 127.50 (2C),

CHCl₃); IR (ﬁlm) 2942, 2865, 1513, 1247, 1090 cm^ꢁ1

(600 MHz, CDCl₃)

7.44 (dd, J¼7.8, 1.8 Hz, 1H), 7.39e7.38 (m, 2H),

7.33e7.30 (m, 6H), 7.27e7.20 (m, 6H), 7.16 (m, 1H), 6.86e6.79 (m,

;

¹H NMR

127.46, 114.6, 113.6 (2C), 77.0, 73.2, 72.7, 71.6, 55.2, 31.2, 29.6; HRMS

d

(ESI) calcd for C₂₁H₂₆O₃Na [(MþNa)^þ] 349.1774, found 349.1746.

Please cite this article in press as: Fuwa, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.001

12

H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

6H), 5.75 (d, J¼1.4 Hz, 1H), 4.83 (d, J¼11.0 Hz,1H), 4.70 (d, J¼11.5 Hz,

1H), 4.66 (d, J¼11.5 Hz, 1H), 4.59e4.50 (m, 6H), 4.43 (d, J¼11.5 Hz,

1H), 4.32 (dd, J¼9.2, 2.8 Hz, 1H), 3.97 (s, 1H), 3.87 (ddd, J¼9.2, 9.1,

1.4 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 3.61 (dd, J¼9.2,

9.2 Hz, 1H), 3.51e3.43 (m, 3H), 2.00 (m, 1H), 1.92e1.82 (m, 3H), 1.70

(m, 1H), 1.57e1.53 (m, 3H), 1.43 (m, 1H), 1.11 (s, 21H); ¹³C NMR

73.76, 73.0, 72.3, 71.3, 70.7, 56.2, 36.6, 33.0, 26.2, 18.2 (3C), 18.1 (3C),

12.6 (3C); HRMS (ESI) calcd for

789.3463, found 789.3439.

C

₄₂H₅₈O₉SSiNa [(MþNa)^þ]

4.24. Enol triﬂate 37

(150 MHz, CDCl₃)

d

159.0, 158.1, 149.2, 138.50, 138.45, 133.3, 131.1,

To a solution of i-Pr₂NH (0.640 mL, 4.57 mmol) in THF (19 mL) at

0

^ꢀC was added n-BuLi (2.65 M solution in n-hexane, 1.70 mL,

130.8, 129.35 (2C), 129.31 (2C), 128.8, 128.3 (2C), 128.2 (2C), 127.57

(2C), 127.51, 127.4 (4C), 121.8, 121.1, 113.68 (2C), 113.64 (2C), 110.7,

108.5, 82.4, 81.3, 79.8, 77.4, 74.9, 73.9, 73.3, 72.98, 72.92, 72.1, 71.6,

55.7, 55.25, 55.22, 32.2, 31.6, 30.0, 29.5, 18.29 (3C), 18.24 (3C), 13.0

(3C); HRMS (ESI) calcd for C₅₉H₇₈O₉SSiNa [(MþNa)^þ] 1013.5028,

found 1013.5035.

4.51 mmol), and the resultant solution was stirred at 0 ^ꢀC for

20 min. To this solution at ꢁ78 ^ꢀC was added a solution of 6-tert-

butyldimethylsilyloxyhexan-2-one (46) (821.2 mg, 3.564 mmol)

and PhNTf₂(1.63 g, 4.56 mmol) in THF (3 mLþ1 mL rinse), and the

resultant solution was stirred at ꢁ78 ^ꢀC for 1 h and then allowed to

warm to 0 ^ꢀC over a period of 1 h. The reaction was quenched with

saturated aqueous NaHCO₃solution at 0 ^ꢀC. The resultant mixture

was extracted with t-BuOMe, and the organic layer was washed

with brine, dried (MgSO₄), ﬁltered, and concentrated under re-

duced pressure. Puriﬁcation of the residue by ﬂash column chro-

matography (silica gel, 2% Et₂O/hexanes) gave enol triﬂate 37

(1.057 g, 82%) as a pale yellow oil: IR (ﬁlm) 2955, 2931, 2859, 1671,

4.22. Ketone 45

To a solution of exo-oleﬁn 33 (402.0 mg, 0.4059 mmol) in THF/

acetone/H₂O (5:5:1, v/v, 11 mL) were added NMO (4.8 M solution in

H₂O, 0.72 mL, 3.5 mmol) and OsO₄(10 mg/mL solution in t-BuOH,

1.0 mL, 0.039 mmol), and the resultant solution was stirred at room

temperature for 14 h. To this solution was added NaIO₄(436.1 mg,

2.039 mmol), and the resultant mixture was stirred at room tem-

perature for 6 h. The reaction was quenched with saturated aque-

ous Na₂SO₃solution at 0 ^ꢀC. The resultant mixture was extracted

with EtOAc, and the organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica gel,

1419, 1252, 1211 cm^ꢁ1; ¹H NMR (600 MHz, C₆D₆)

d

4.71 (d, J¼3.2 Hz,

1H), 4.29 (ddd, J¼3.7, 1.4, 0.9 Hz, 1H), 3.34 (t, J¼5.9 Hz, 2H), 1.93 (m,

2H), 1.33e1.28 (m, 2H), 1.25e1.20 (m, 2H), 0.96 (s, 9H), 0.02 (s, 6H);

¹³C NMR (150 MHz, C₆D₆)

d

157.1,121.0 (q, J¼246 Hz,1C),104.0, 62.4,

33.5, 31.7, 26.0 (3C), 22.6, 18.4, ꢁ5.3 (2C); HRMS (ESI) calcd for

C

₁₃H₂₅F₃O₄SSiNa [(MþNa)^þ] 385.1087 found 385.1086.

20e40% EtOAc/hexanes) gave ketone 45 (361.6 mg, 87%) as a pale

4.25. exo-Oleﬁn 34

23

yellow oil: [

a

]

þ71.0 (c 1.00, CHCl₃); IR (ﬁlm) 2941, 2865, 1713,

D

1612, 1513, 1248 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d

7.90 (dd, J¼7.8,

To a solution of bis-silyl ether 10 (897.0 mg, 2.407 mmol) in THF

(12 mL) was added a solution of 9-BBN-H dimer (648.0 mg,

2.655 mmol) in THF (8 mLþ4 mL rinse), and the resultant solution

was stirred at room temperature for 1 h. To this solution was added

3 M aqueous Cs₂CO₃solution (2.40 mL, 7.20 mmol), and the re-

sultant mixture was stirred at room temperature for 20 min. To this

mixture were added a solution of enol triﬂate 37 (1.057 g,

2.916 mmol) in DMF (12 mLþ12 mL rinse), PdCl₂(dppf)$CH₂Cl₂

(193.8 mg, 0.2373 mmol), and Ph₃As (294.6 mg, 0.9202 mmol), and

the resultant mixture was stirred at room temperature overnight.

The reaction mixture was diluted with t-BuOMe and washed with

H₂O and brine. The organic layer was dried (MgSO₄), ﬁltered, and

concentrated under reduced pressure. Puriﬁcation of the residue by

ﬂash column chromatography (silica gel, 2% Et₂O/hexanes) gave

1.4 Hz, 1H), 7.45 (m, 1H), 7.35e7.19 (m, 14H), 7.00 (dd, J¼7.8, 7.8 Hz,

1H), 6.90, (d, J¼8.2 Hz, 1H), 6.84e6.82 (m, 4H), 5.36 (d, J¼4.1 Hz,

1H), 4.71 (m, 1H), 4.66 (d, J¼11.5 Hz, 2H), 4.56 (d, J¼11.5 Hz, 2H),

4.51 (s, 2H), 4.47 (m, 2H), 4.39 (d, J¼11.5 Hz, 2H), 3.82 (s, 3H), 3.76 (s,

3H), 3.75 (s, 3H), 3.52e3.43 (m, 4H), 2.28e2.09 (m, 2H), 1.85e1.83

(m, 2H), 1.77e1.62 (m, 3H), 1.42 (m, 1H), 1.07 (m, 21H); ¹³C NMR

(150 MHz, CDCl₃) d 209.7, 159.2 (2C), 157.5, 138.2, 137.8, 135.7, 131.0,

130.7, 130.2, 129.36 (2C), 129.32 (2C), 128.38 (2C), 128.31, 128.2 (2C),

127.8 (2C), 127.63 (3C), 127.59 (2C), 120.5, 113.72 (2C), 113.70 (2C),

112.1, 89.4, 76.5, 73.4, 73.0, 72.5, 71.5, 60.3, 56.2, 55.2 (2C), 38.2*

(2C), 29.3* (1C), 25.8* (2C), 21.0, 18.2 (6C), 14.2, 12.8 (3C), signals

with asterisk were assigned on the basis of HMQC spectrum; HRMS

(ESI) calcd for

1047.4719.

C

₅₈H₇₆O₁₂SSiNa [(MþNa)^þ] 1047.4719, found

exo-oleﬁn 34 (1.384 g, 98%) as a pale yellow oil: [

a]

²⁴þ8.7 (c 1.00,

D

CHCl₃); IR (ﬁlm) 2954, 2929, 2894, 2858, 1472, 1463, 1254, 1100,

4.23. Sulfone 32

836, 773 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d 4.67 (s, 2H), 3.63e3.56

(m, 3H), 3.43 (dd, J¼9.6, 6.8 Hz, 1H), 3.33 (dd, J¼9.6, 6.8 Hz, 1H),

2.06e1.98 (m, 3H), 1.89 (m, 1H), 1.73 (ddd, J¼13.7, 6.8, 3.2 Hz, 1H),

1.63e1.41 (m, 6H), 1.16 (m, 1H), 0.88e0.86 (m, 27H), 0.84 (d,

J¼6.8 Hz, 3H), 0.81 (d, J¼6.9 Hz, 3H), 0.03 (s, 9H), 0.02 (s, 3H), 0.01

To a solution of ketone 45 (330.9 mg, 0.3227 mmol) in CH₂Cl₂/

H₂O (10:1, v/v, 3.3 mL) at 0 ^ꢀC was added DDQ (186.4 mg,

0.8211 mmol), and the resultant mixture was stirred at room

temperature for 1.5 h. The reaction was quenched with saturated

aqueous NaHCO₃solution at 0 ^ꢀC. The resultant mixture was

extracted with EtOAc, and the organic layer was washed with H₂O

and brine, dried (Na₂SO₄), ﬁltered, and concentrated under reduced

pressure. Puriﬁcation of the residue by ﬂash column chromatog-

(s, 6H); ¹³C NMR (150 MHz, CDCl₃)

d 150.2, 108.6, 75.3, 66.2, 63.1,

38.9, 37.9, 35.9, 34.2, 32.6, 31.8, 26.1 (3C), 26.0 (3C), 25.9 (3C), 24.0,

18.44, 18.36, 18.22, 15.6, 12.1, ꢁ3.8, ꢁ4.1, ꢁ5.27 (2C), ꢁ5.33, ꢁ5.36;

HRMS (ESI) calcd for C₃₂H₇₀O₃Si₃Na [(MþNa)^þ] 609.4525, found

609.4524.

raphy (silica gel, 10% EtOAc/hexanes) gave sulfone 32 (211.2 mg,

24

85%, dr >20:1) as a pale yellow oil: [

a

]

þ34.3 (c 1.00, CHCl₃); IR

4.26. Ketone 47

D

(ﬁlm) 2943, 2865, 2360, 2341, 1155, 1117 cm^ꢁ1; ¹H NMR (600 MHz,

CDCl₃)

d

7.86 (dd, J¼7.8, 1.9 Hz, 1H), 7.51 (m, 1H), 7.29e7.16 (m, 10H),

To a solution of exo-oleﬁn 34 (1.384 g, 2.349 mmol) in THF/H₂O

(2:1, v/v, 24 mL) were added NMO (4.8 M solution in H₂O, 1.5 mL,

7.2 mmol) and OsO₄(37.3 mg, 0.147 mmol), and the resultant

mixture was stirred at room temperature for 10 h. To this mixture

was added NaIO₄(2.01 g, 9.40 mmol), and the resultant mixture

was stirred at room temperature for 1.5 h. The reaction was

quenched with saturated aqueous Na₂SO₃solution at 0 ^ꢀC. The

resultant mixture was extracted with t-BuOMe, and the organic

7.01 (m, 1H), 6.91 (d, J¼8.2 Hz, 1H), 5.28 (s, 1H), 4.80 (d, J¼11.9 Hz,

1H), 4.57 (d, J¼11.9 Hz, 1H), 4.52e4.46 (m, 3H), 4.40 (d, J¼3.7 Hz,

1H), 4.27 (m, 1H), 4.01 (dd, J¼10.1, 9.6 Hz, 1H), 3.92 (m, 1H), 3.76 (s,

3H), 3.44e3.41 (m, 2H), 2.01 (m, 1H), 1.85 (m, 1H), 1.76e1.60 (m,

5H), 1.48 (m, 1H), 1.06 (s, 21H); ¹³C NMR (150 MHz, CDCl₃)

d 157.5

(2C), 138.5, 138.2, 135.9, 131.2, 128.24 (2C), 128.22 (2C), 127.50 (2C),

127.46 (3C), 127.4, 125.1, 120.7, 112.3, 106.2, 91.2, 77.4, 76.2, 73.83,

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H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

13

layer was washed with brine, dried (MgSO₄), ﬁltered, and concen-

trated under reduced pressure. Puriﬁcation of the residue by ﬂash

column chromatography (silica gel, 3% Et₂O/hexanes) gave ketone

solution was heated to reﬂux for 14 h. The resultant solution was

cooled to 0 ^ꢀC and treated sequentially with H₂O (10

L), saturated

aqueous NaHCO₃solution (100 L), and 30% aqueous H₂O₂solution

(50 L). The resultant mixture was diluted with THF (320 L) and

m

47 (1.188 g, 86%) as a pale yellow oil: [

a]

²⁴þ12.4 (c 1.00, CHCl₃); IR

m

D

(ﬁlm) 2955, 2929, 2886, 2857, 1717, 1472, 1254, 1098, 1048, 836,

stirred at 0 ^ꢀC for 1 h and then at room temperature for 2.5 h. The

resultant mixture was diluted with H₂O and extracted with EtOAc.

The organic layer was washed with saturated aqueous Na₂SO₃so-

lution and brine, dried (Na₂SO₄), ﬁltered, and concentrated under

reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 10% EtOAc/hexanes) gave ketone 49

(9.5 mg, 68%, 94% based on recovered starting material) as a color-

774 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d

3.60 (dd, J¼5.0, 3.2 Hz, 1H),

3.59 (d, J¼6.4 Hz, 1H), 3.58 (d, J¼6.4 Hz, 1H), 3.41 (dd, J¼9.6, 7.4 Hz,

1H), 3.33 (dd, J¼9.6, 6.4 Hz, 1H), 2.43e2.37 (m, 3H), 2.32 (ddd,

J¼16.0, 10.1, 5.9 Hz, 1H), 1.77e1.70 (m, 2H), 1.62e1.57 (m, 2H),

1.55e1.51 (m, 2H), 1.50e1.45 (m, 2H), 1.32 (m, 1H), 0.873 (s, 9H),

0.866 (s, 9H), 0.865 (s, 9H), 0.83 (d, J¼6.9 Hz, 3H), 0.81 (d, J¼6.8 Hz,

3H), 0.02 (s, 9H), 0.010 (s, 3H), 0.008 (s, 3H), 0.006 (s, 3H); ¹³C NMR

less oil, along with recovered 48 (3.7 mg, 27%) as a colorless oil. 49:

24

(150 MHz, CDCl₃)

d

211.3, 75.0, 66.0, 62.8, 42.5, 41.2, 38.8, 37.7, 32.3,

[a

]

þ4.65 (c 1.00, CHCl₃); IR (ﬁlm) 2940, 2865, 1714, 1454, 1131,

D

27.6, 26.1 (3C), 26.0 (3C), 25.9 (3C), 20.3, 18.4, 18.3, 18.2, 15.7, 11.9,

ꢁ3.8, ꢁ4.1, ꢁ5.3 (3C), ꢁ5.4; HRMS (ESI) calcd for C₃₁H₆₈O₄Si₃Na

[(MþNa)^þ] 611.4318, found 611.4321.

1099, 1066, 999 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

; d 7.37e7.36 (m,

2H), 7.32e7.22 (m, 8H), 4.87 (d, J¼11.9 Hz, 1H), 4.61, (d, J¼11.9 Hz,

1H), 4.57 (d, J¼12.4 Hz, 1H), 4.55 (d, J¼12.4 Hz, 1H), 4.32 (m, 1H),

4.25 (dd, J¼3.2, 1.9 Hz, 1H), 4.17 (d, J¼1.9 Hz, 1H), 4.03 (dd, J¼9.7,

9.6 Hz, 1H), 3.77 (dd, J¼9.7, 3.2 Hz, 1H), 3.62 (ddd, J¼11.9, 11.0,

2.3 Hz, 1H) 3.54 (m, 1H), 3.50e3.49 (m, 2H), 3.35 (dd, J¼10.1, 2.3 Hz,

1H), 2.94 (m, 1H), 2.42 (dd, J¼16.5, 10.1 Hz, 1H) 2.33 (dd, J¼16.5,

3.2 Hz, 1H), 2.12e1.96 (m, 4H),1.89e1.76 (m, 5H), 1.75e1.59 (m, 4H),

1.57e1.45 (m, 4H), 1.42 (dd, J¼13.3, 4.1 Hz, 1H), 1.40e1.35 (m, 2H),

4.27. Alcohol 26 (from ketone 47)

To a solution of ketone 47 (1.188 g, 2.016 mmol) in MeOH

(20 mL) was added TsOH$H₂O (116.2 mg, 0.6109 mmol), and the

resultant solution was stirred at room temperature for 18 h. The

reaction mixture was neutralized with Et₃N and concentrated un-

der reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 20% EtOAc/hexanes) gave spiroacetal 26

(440.5 mg, 96%, dr >20:1) as a colorless oil.

1.10e1.09 (m, 21H), 0.97 (d, J¼6.8 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H); ¹³

C

NMR (150 MHz, CDCl₃)

d 210.8, 138.8, 138.6, 128.3 (2C), 128.2 (2C),

127.61 (2C), 127.55 (2C), 127.4, 106.1, 95.6, 83.6, 77.9, 77.5, 74.6, 74.0,

73.7, 73.1, 72.3, 71.9, 71.4, 60.4, 40.7, 36.7, 35.8, 34.7, 33.3, 31.5, 30.1,

27.7, 26.41, 26.36, 26.2, 25.4, 22.6, 18.7, 18.2 (3C), 18.1 (3C), 12.6 (3C),

11.0; HRMS (ESI) calcd for C₄₉H₇₄O₉SiNa [(MþNa)^þ] 857.4994,

found 857.5004.

4.28. Alkyne 48

To a solution of alkyne 7 (132.0 mg, 0.5937 mmol) in toluene

(0.25 mL) at 0 ^ꢀC was added n-BuLi (2.65 M solution in n-hexane,

0.230 mL, 0.610 mmol), and the resultant solution was stirred at

0 ^ꢀC for 30 min. To this solution were added CH₂Cl₂(0.20 mL) and

Me₂AlCl (1.0 M solution in n-hexane, 0.59 mL, 0.59 mmol), and the

resultant solution was stirred at room temperature for 30 min. To

this solution was added a solution of sulfone 32 (197.4 mg,

0.2573 mmol) in CH₂Cl₂(0.2 mLþ0.4 mL rinse), and the resultant

solution was stirred at room temperature for 4.5 h. The reaction was

quenched with saturated aqueous NH₄Cl solution at 0 ^ꢀC. The re-

sultant mixture was diluted with EtOAc and ﬁltered through a pad

of Celite. The ﬁltrate was washed with brine, dried (Na₂SO₄), ﬁl-

tered, and concentrated under reduced pressure. Puriﬁcation of the

residue by ﬂash column chromatography (silica gel, ﬁrst round:

5e10% EtOAc/hexanes; second round: 2% Et₂O/benzene) gave al-

4.30. Alcohol 50

To a solution of ketone 49 (41.8 mg, 0.0500 mmol) in EtOH

(0.5 mL) at ꢁ20 ^ꢀC was added NaBH₄(37.7 mg, 0.997 mmol), and

the resultant solution was stirred at ꢁ20 ^ꢀC for 15 min and then at

0

^ꢀC for 14 h. The reaction was quenched with saturated aqueous

NH₄Cl solution at 0 ^ꢀC. The resultant mixture was extracted with

EtOAc, and the organic layer was washed with brine, dried

(Na₂SO₄), ﬁltered, and concentrated under reduced pressure. Pu-

riﬁcation of the residue by ﬂash column chromatography (silica

gel, 10e20% EtOAc/hexanes) gave alcohol 50 (36.2 mg, 86%, dr

>20:1) as a colorless oil: [

a

]

²⁴þ9.9 (c 1.00, CHCl₃); IR (ﬁlm) 3443,

D

2941, 2865, 1454, 1384, 1065, 999, 879 cm^ꢁ1

;

¹H NMR (600 MHz,

CDCl₃)

d 7.37e7.35 (m, 2H), 7.32e7.27 (m, 6H), 7.26e7.21 (m, 2H),

kyne 48 (132.7 mg, 63%, dr >20:1) as a pale yellow oil: [

a

]

D

²⁴þ55.0

4.82 (d, J¼11.9 Hz, 1H), 4.61 (d, J¼11.9 Hz, 1H), 4.58 (d, J¼12.4 Hz,

1H), 4.55 (d, J¼12.4 Hz, 1H), 4.32 (m, 1H), 4.08 (dd, J¼9.6, 9.6 Hz,

1H), 3.93e3.90 (m, 2H), 3.67e3.63 (m, 2H), 3.57e3.49 (m, 4H),

3.28 (m, 1H), 3.20 (dd, J¼10.1, 2.3 Hz, 1H), 2.51 (s, 1H), 2.09e1.96

(m, 3H), 1.95e1.68 (m, 9H), 1.64e1.48 (m, 5H), 1.44 (dd, J¼13.3,

4.1 Hz, 1H), 1.41e1.37 (m, 2H), 1.09e1.08 (m, 21H), 1.02 (d,

J¼6.4 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H), 0.68 (dd, J¼12.4, 10.9 Hz, 1H),

one proton missing due to H/D exchange; ¹³C NMR (150 MHz,

(c 1.00, CHCl₃); IR (ﬁlm) 2939, 2865, 2229, 1454, 1383, 1092, 996,

879 cm^ꢁ1; ¹H NMR (600 MHz, CDCl₃)

d 7.37e7.36 (m, 2H), 7.33e7.27

(m, 6H), 7.26e7.21 (m, 2H), 4.79 (d, J¼11.9 Hz, 1H), 4.69 (dd, J¼1.9,

1.8 Hz, 1H), 4.67 (d, J¼11.9 Hz, 1H), 4.58 (d, J¼12.4 Hz, 1H), 4.55 (d,

J¼12.4 Hz, 1H), 4.32 (m, 1H), 4.25 (dd, J¼9.7, 2.8 Hz, 1H), 3.99 (dd,

J¼9.7, 9.6 Hz,1H), 3.72 (dd, J¼2.8, 2.3 Hz,1H), 3.62 (ddd, J¼11.9, 11.0,

2.8 Hz, 1H), 3.57 (m, 1H), 3.54e3.48 (m, 4H), 2.52 (dqd, J¼10.6, 6.4,

1.8 Hz, 1H), 2.10e1.95 (m, 4H), 1.90 (m, 1H), 1.85e1.77 (m, 4H),

1.76e1.67 (m, 2H), 1.62e1.48 (m, 5H), 1.44 (dd, J¼13.3, 4.1 Hz, 1H),

1.41e1.36 (m, 2H),1.30 (d, J¼6.4 Hz, 3H),1.10e1.09 (m, 21H), 0.92 (d,

CDCl₃)

d 138.55, 138.51, 128.3 (2C), 128.2 (2C), 128.0 (2C), 127.6

(2C), 127.5, 127.4, 106.2, 95.6, 81.9, 77.7, 77.5, 75.1, 73.5, 73.2, 72.3,

71.9, 71.6, 71.1, 63.4, 60.3, 36.7, 36.4, 35.9, 33.4, 30.9, 30.3, 27.4,

26.4, 26.3 (2C), 25.4, 18.7, 18.3 (3C), 18.2 (3C), 16.3, 12.8 (3C), 10.6;

HRMS (ESI) calcd for C₄₉H₇₆O₉SiNa [(MþNa)^þ] 859.5151, found

859.5122.

J¼6.9 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)

d 138.7, 138.6, 128.3 (2C),

128.2 (2C), 127.6 (2C), 127.44 (2C), 127.40, 127.3, 106.2, 95.8, 90.3,

82.1, 77.3, 74.0, 73.1, 73.0, 72.3, 71.9, 71.8, 71.5, 67.6, 60.4, 36.8, 35.6,

33.5, 30.1, 29.2, 28.7, 27.0, 26.3, 26.12, 26.08, 25.3, 18.7, 18.4, 18.2

(3C), 18.1 (3C), 12.6 (3C), 11.0; HRMS (ESI) calcd for C₄₉H₇₂O₈SiNa

[(MþNa)^þ] 839.4889, found 839.4910.

4.31. Diol 51

To a solution of alcohol 50 (17.5 mg, 0.0209 mmol) in (CH₂Cl)₂

(0.3 mL) at 0 ^ꢀC were added 2,6-lutidine (0.015 mL, 0.13 mmol) and

TIPSOTf (0.015 mL, 0.056 mmol), and the resultant solution was

stirred at 60 ^ꢀC for 3 h. The reaction mixture was cooled to 0 ^ꢀC and

treated with additional portions of 2,6-lutidine (0.010 mL,

4.29. Ketone 49

Alkyne 48 (13.6 mg, 0.0166 mmol) was mixed with 9-BBN-H

(0.5 M solution in THF, 0.160 mL, 0.0800 mmol), and the resultant

Please cite this article in press as: Fuwa, H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.001

14

H. Fuwa et al. / Tetrahedron xxx (2015) 1e15

0.086 mmol) and TIPSOTf (0.010 mL, 0.037 mmol), and the resultant

solution was stirred at 60 ^ꢀC for 1 h. The reaction was quenched

with saturated aqueous NaHCO₃solution at 0 ^ꢀC. The resultant

mixture was extracted with EtOAc, and the organic layer was

washed with brine, dried (Na₂SO₄), ﬁltered, and concentrated un-

der reduced pressure. Puriﬁcation of the residue by ﬂash column

chromatography (silica gel, 10% Et₂O/hexanes) gave a silyl ether

(33.2 mg), which was contaminated with TIPSOH. This material was

used in the next reaction without further puriﬁcation.

The resultant mixture was diluted with EtOAc and stirred at room

temperature for 10 min. The organic layer was separated, washed

with brine, dried (Na₂SO₄), ﬁltered, and concentrated under re-

duced pressure. Puriﬁcation of the residue by ﬂash column chro-

matography (silica gel, 5% Et₂O/hexanes) gave a ketone (16.8 mg,

24

94%) as a colorless oil: [

a

]

D

þ28.5 (c 1.00, CHCl₃); IR (ﬁlm) 2943,

2893, 2866, 1732, 1464, 1148, 1113, 1087, 998, 881 cm^ꢁ1

;

¹H NMR

(600 MHz, CDCl₃) 7.71e7.66 (m, 4H), 7.41e7.34 (m, 6H), 4.32 (m,

d

1H), 4.25e4.19 (m, 2H), 4.10 (ddd, J¼10.1, 10.1, 5.0 Hz, 1H), 4.05 (d,

J¼4.1 Hz, 1H), 3.83 (dd, J¼10.1, 9.6 Hz, 1H), 3.69 (dd, J¼10.5, 4.1 Hz,

1H), 3.64e3.60 (m, 2H), 3.52 (m, 1H), 3.28 (dd, J¼9.6, 2.3 Hz, 1H),

2.10 (m, 1H), 2.01e1.77 (m, 10H), 1.66 (m, 1H), 1.62e1.57 (m, 2H),

1.56e1.46 (m, 3H), 1.42 (dd, J¼13.3, 4.1 Hz, 1H), 1.39e1.29 (m, 3H),

1.09e1.03 (m, 45H), 1.02 (s, 9H), 0.87 (d, J¼7.3 Hz, 3H); ¹³C NMR

To a solution of the above silyl ether in THF/MeOH (1:1, v/v,

0.5 mL) was added 20% Pd(OH)₂/C (1.5 mg), and the resultant

mixture was stirred at room temperature under an atmosphere of

H₂(balloon) for 15 h. The reaction mixture was ﬁltered through

a pad of Celite, and the ﬁltrate was concentrated under reduced

pressure. Puriﬁcation of the residue by ﬂash column chromatog-

raphy (silica gel, 10% Et₂O/hexanes) gave diol 51 (16.9 mg, 99% for

(150 MHz, CDCl₃)

d 207.5, 135.64 (2C), 135.60 (2C), 133.72, 133.65,

129.58, 129.53, 127.61 (2C), 127.58 (2C), 105.9, 95.7, 85.7, 79.14,

79.12, 77.2, 76.1, 75.0, 71.6, 66.1, 60.3, 36.8, 36.1, 35.8, 32.6, 31.9, 30.3,

27.8, 26.8 (3C), 26.6, 26.5, 25.7, 25.4,19.3, 18.7, 18.32 (3C), 18.28 (3C),

18.0 (6C), 17.3, 13.6 (3C), 12.7 (3C), 11.4; HRMS (ESI) calcd for

the two steps) as a colorless oil: [

a

]

²⁴þ6.9 (c 1.00, CHCl₃); IR (ﬁlm)

D

3443, 2942, 2892, 2867, 1464, 1384, 1096, 1065, 999, 880 cm^ꢁ1; ¹H

NMR (600 MHz, CDCl₃)

d

4.20e4.12 (m, 2H), 4.05 (d, J¼3.7 Hz, 1H),

3.98 (dd, J¼9.7, 4.1 Hz, 1H), 3.96 (d, J¼4.6 Hz, 1H), 3.84 (dd, J¼9.7,

9.6 Hz, 1H), 3.70e3.62 (m, 3H), 3.54 (m, 1H), 3.46 (m, 1H), 3.30 (dd,

J¼9.1, 1.8 Hz, 1H), 3.05 (s, 1H), 2.02e1.96 (m, 2H), 1.91 (dd, J¼12.4,

3.2 Hz, 1H), 1.89e1.65 (m, 10H), 1.61 (m, 1H), 1.59e1.47 (m, 5H), 1.42

(dd, J¼13.3, 4.1 Hz, 1H), 1.39e1.35 (m, 2H), 1.28 (ddd, J¼15.1, 9.1,

5.9 Hz, 1H), 1.08e1.05 (m, 45H), 0.88 (d, J¼6.9 Hz, 3H); ¹³C NMR

C

₆₀H₁₀₀O₉Si₃Na [(MþNa)^þ] 1071.6567, found 1071.6576.

To a solution of the above ketone (15.8 mg, 0.0151 mmol) in THF

(0.5 mL) at 0 ^ꢀC was added Tebbe reagent (0.5 M solution in toluene,

0.15 mL, 0.08 mmol), and the resultant solution was stirred at 0 ^ꢀC

for 40 min. The reaction was quenched with 1 M aqueous NaOH

solution at 0 ^ꢀC. The resultant mixture was diluted with t-BuOMe

and stirred at room temperature for 30 min. Insoluble material was

ﬁltered off, and the ﬁltrate was washed with brine, dried (MgSO₄),

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

the residue by ﬂash column chromatography (silica gel, 5% Et₂O/

(150 MHz, CDCl₃) d 106.3, 95.7, 80.7, 78.5, 75.2, 73.1, 72.2, 71.8, 71.5,

71.2, 64.9, 60.4, 37.5, 37.1, 35.9, 33.1, 31.8, 30.3, 27.8, 26.66, 26.63,

25.4, 25.3,18.7,18.4 (6C),18.0 (3C),17.9 (3C),17.1,13.7 (3C),12.4 (3C),

11.3; HRMS (ESI) calcd for C₄₄H₈₄O₉Si₂Na [(MþNa)^þ] 835.5546,

found 835.5533.

hexanes) gave C15eC38 fragment 5 (15.7 mg, 99%) as a colorless oil:

24

[a

]

ꢁ4.6 (c 1.00, CHCl₃); IR (ﬁlm) 2942, 2865, 1463, 1145, 1112,

D

4.32. Alcohol 52

1081, 999, 881 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

; d 7.70e7.65 (m,

4H), 7.41e7.34 (m, 6H), 5.35 (s, 1H), 5.02 (s, 1H), 4.40 (dd, J¼9.1,

8.3 Hz, 1H), 4.21 (m, 1H), 4.13e4.09 (m, 2H), 3.69 (dd, J¼11.0, 4.1 Hz,

1H), 3.65e3.60 (m, 2H), 3.53e3.47 (m, 2H), 3.42 (dd, J¼9.6, 9.2 Hz,

1H), 3.17 (dd, J¼10.1, 2.3 Hz, 1H), 2.06 (m, 1H), 1.99e1.74 (m, 9H),

1.63 (d, J¼13.3 Hz, 1H), 1.57e1.47 (m, 4H) 1.42 (dd, J¼13.3, 4.1 Hz,

1H), 1.39e1.28 (m, 3H), 1.27e1.23 (m, 2H), 1.10e1.06 (m, 42H), 1.03

(d, J¼6.4 Hz, 3H), 1.02 (s, 9H), 0.87 (d, J¼6.8 Hz, 3H), 0.80 (m, 1H);

To a solution of diol 51 (21.6 mg, 0.0266 mmol) in DMF (0.3 mL)

were added imidazole (39.0 mg, 0.573 mmol) and TBDPSCl

(0.070 mL, 0.27 mmol), and the resultant solution was stirred at

50 ^ꢀC for 9 h. The reaction was quenched with saturated aqueous

NH₄Cl solution at 0 ^ꢀC. The resultant mixture was extracted with t-

BuOMe, and the organic layer was washed with brine, dried

(MgSO₄), ﬁltered, and concentrated under reduced pressure. Puri-

ﬁcation of the residue by ﬂash column chromatography (silica gel,

¹³C NMR (150 MHz, CDCl₃)

d 146.3, 135.64 (2C), 135.59 (2C), 133.8,

133.7,129.55,129.50,127.6 (4C),112.8,106.2, 95.6, 87.3, 78.92, 77.88,

75.6, 72.7, 71.4, 67.2, 66.0, 60.1, 37.8, 36.9, 35.9, 33.3, 30.8, 30.4, 29.7,

27.4, 26.7 (3C), 26.5, 25.7, 25.5, 19.3, 18.8, 18.6 (6C), 18.3 (3C), 18.1

(3C), 16.1, 13.8 (3C), 12.8 (3C), 10.8; HRMS (ESI) calcd for

10% Et₂O/hexanes) gave alcohol 52 (25.0 mg, 89%) as a colorless oil:

24

[

a]

þ5.7 (c 1.00, CHCl₃); IR (ﬁlm) 3443, 2942, 2893, 2866, 1463,

D

1112, 1100, 998, 880 cm^ꢁ^{1 1}H NMR (600 MHz, CDCl₃)

; d 7.70e7.66

(m, 4H), 7.41e7.34 (m, 6H), 4.21e4.16 (m, 2H), 4.05 (d, J¼3.7 Hz,1H),

4.00e3.96 (m, 2H), 3.87 (dd, J¼9.7, 9.6 Hz, 1H), 3.69 (dd, J¼10.5,

4.1 Hz, 1H), 3.65 (m, 1H), 3.62 (dd, J¼10.6, 4.1 Hz, 1H), 3.54 (m, 1H),

3.31 (dd, J¼9.6,1.8 Hz,1H), 3.04 (s,1H), 2.10e1.89 (m, 3H),1.88e1.73

(m, 9H),1.64e1.47 (m, 6H),1.42 (dd, J¼13.3, 4.1 Hz,1H),1.38 (m, 2H),

1.29 (ddd, J¼12.8, 9.2, 5.9 Hz, 1H), 1.09e1.06 (m, 45H), 1.02 (s, 9H),

C

₆₁H₁₀₂O₈Si₃Na [(MþNa)^þ] 1069.6775, found 1069.6777.

Acknowledgements

We thank Professor Keiichi Konoki (Tohoku University) for

helpful discussions. This work was supported by a Grant-in-Aid for

Scientiﬁc Research on Innovative Areas ‘Chemical Biology of

Natural Products’ (No. 26102708) from the Ministry of Education,

Culture, Sports, Science and Technology (MEXT), Japan.⁴⁹

0.88 (d, J¼7.3 Hz, 3H), one proton missing due to H/D exchange; ¹³

C

NMR (150 MHz, CDCl₃)

d 135.63 (2C), 135.59 (2C), 133.7, 133.6,

129.56, 129.51, 127.6 (4C), 106.4, 95.7, 80.7, 79.0, 77.2, 75.3, 72.9,

72.2, 71.9, 71.7, 71.1, 66.0, 60.4, 37.6, 37.0, 35.9, 33.2, 31.8, 30.3, 27.8,

26.8 (3C), 26.7, 25.8, 25.5, 19.2, 18.7, 18.4 (6C), 18.0 (3C), 17.9 (3C),

17.1, 13.7 (3C), 12.4 (3C), 11.3; HRMS (ESI) calcd for C₆₀H₁₀₂O₉Si₃Na

[(MþNa)^þ] 1073.6724, found 1073.6746.

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Concise synthesis of the C15-C38 fragment of okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A

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