A convergent synthesis of the right-hand fragment of ciguatoxin CTX3C

Tetrahedron 68 (2012) 2245e2260

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Tetrahedron

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A convergent synthesis of the right-hand fragment of ciguatoxin CTX3C

*

Hiroyoshi Takamura , Takashi Abe, Naoki Nishiuma, Rie Fujiwara, Takahiko Tsukeshiba, Isao Kadota

Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

A convergent synthesis of the right-hand fragment of ciguatoxin CTX3C was investigated. The ﬁrst and

second generation stereocontrolled syntheses of the LM ring fragment were achieved via spiroacetali-

zation as a key step, respectively. The polyether framework of the HIJKLM ring fragment was constructed

in a convergent manner by using intramolecular allylation, ring-closing metathesis, and stereoselective

hydrogenation to form the 36-methyl substituent as the key transformations.

Received 17 November 2011

Received in revised form 23 January 2012

Accepted 24 January 2012

Available online 31 January 2012

Keywords:

Polyether marine natural product

Ciguatoxin CTX3C

Convergent synthesis

Intramolecular allylation

1. Introduction

chemists as the target molecule.^6,7Previously, we synthesized the

left-hand ABCDE ring fragment of 1, stereoselectively.⁸In this full

Various biologically and physiologically active secondary me-

tabolites have been isolated from marine origin.¹In particular, pol-

yether and polyol marine natural products with a large molecular

weight, such as brevetoxins, maitotoxin, and palytoxins are some of

the most attractive molecules for natural product chemists, syn-

thetic chemists, biochemists, and pharmacological scientists due to

their extraordinary structures and signiﬁcant biological activities.²

Ciguatera is a food poisoning caused by eating toxic specimens

of normally edible ﬁshes in tropical and subtropical areas.³Cigua-

tera poisoning has affected a large and diverse population in pre-

viously non-endemic regions due to the increase of tourism and

international trade in seafood from tropical region. The research

report in 2010 shows that the global number of poisonings is es-

timated to be 50,000e500,000 cases annually.⁴

account, we report the development of the convergent synthetic

route to the right-hand HIJKLM ring fragment of 1, the useful syn-

thetic intermediate toward the total synthesis of 1.⁹

2. Results and discussion

2.1. Retrosynthetic analysis

Our retrosynthetic analysis of 1 is illustrated in Scheme 1. Pre-

viously, we reported a convergent method for the construction of

the polycyclic ether frameworks via intramolecular allylation and

subsequent ring-closing metathesis.¹⁰On the basis of this method,

the polycyclic framework of 1 was broken down into the left-hand

ABCDE ring fragment 2 and the right-hand HIJKLM ring fragment 3.

The IJ ring moiety of 3 could be constructed by applying the same

procedure to allylic stannane 4. The cyclization precursor 4 could be

synthesized by esteriﬁcation of alcohol 5 and carboxylic acid 6. The

KLM ring system 6 could be synthesized from the LM ring system 7,

of which the carbon framework could be constructed via stereo-

selective spiroacetalization and installation of the methyl sub-

stituent at the C48 position of ketone 8.¹¹

Ciguatoxin CTX3C (1, Scheme 1) was isolated from cultured di-

noﬂagellate Gambierdiscus toxicus by Yasumoto’s group and was

found to be one of the causative toxins of ciguatera poisoning.⁵This

molecule exhibits potent neurotoxicity [LD₅₀(mouse, ip): 1.3 mg/kg]

by binding to the voltage-sensitive sodium channels. The chemical

structure of 1, which possesses ladder-shaped 13 ether rings and 30

stereogenic centers, was elucidated on the basis of the COSY, TOCSY,

and NOESY spectra by using 0.7 mg specimen obtained from 1100 L

of the culture. Its structural complexity and biologically important

activities⁴have attracted much attention from the synthetic

2.2. Synthesis of the H ring system

First, we investigated the stereoselective synthesis of the H ring

system (Scheme 2). Benzyl protection of known alcohol 9¹²fol-

lowed by ozonolysis and two-carbon elongation with a Wittig re-

* Corresponding authors. Tel.: þ81 86 251 7839; fax: þ81 86 251 7836 (H.T.); tel./

fax: þ81 86 251 7836 (I.K.); e-mail addresses: takamura@cc.okayama-u.ac.jp (H.

Takamura), kadota-i@cc.okayama-u.ac.jp (I. Kadota).

agent gave a,b-unsaturated ester 10. After the ester 10 was reduced

doi:10.1016/j.tet.2012.01.071

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H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

Scheme 1. Structure and retrosynthetic analysis of ciguatoxin CTX3C (1).

Scheme 2. Synthesis of the H ring system 5.

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2247

to allylic alcohol 11 with DIBAL-H, Sharpless asymmetric epoxida-

tion¹³of 11 by using (þ)-diethyl tartrate (DET) provided the desired

epoxy alcohol as the sole product. Treatment of the resulting epoxy

alcohol with Red-Al afforded 1,3-diol 12.^14,15The diol 12 was pro-

tected with BnBr and the benzylidene acetal moiety was removed

to yield diol 13. After the diol 13 was transformed to alcohol 14 by

bis-silylation and selective desilylation, treatment of 14 with I₂/

PPh₃/imidazole and subsequent cyanation of the corresponding

iodide gave nitrile 15 in 87% yield from 14. The nitrile 15 was

converted to alkene 17 by the following four-step sequence: (1)

DIBAL-H reduction, (2) reaction of the resulting aldehyde with

MeMgBr, (3) TPAP oxidation¹⁶of alcohol 16 (1:1 diastereomixture),

and (4) Wittig methylenation of the corresponding ketone. The TBS

ether 17 was reacted with TBAF to produce the H ring system 5.

provide spiroacetal 25 in 95% yield.²²Next, we investigated the

stereoselective introduction of the methyl substituent at the C48

position. Thus, after the primary hydroxy group of 25 was selec-

tively protected as a TBS ether, TPAP oxidation¹⁶and subsequent

23

methylenation of the resulting ketone with Cp₂TiMe₂afforded

alkene 26. When the alkene 26 was hydrogenated with Pd/C in

EtOAc, unfortunately, we obtained alkane 27, which has the un-

desired stereochemistry at the C48 position, as the sole stereoiso-

mer in 77% yield. Other reaction conditions, hydrogenation with

Pd/C in THF or diimide reduction, also produced 27.

Although the detailed conformational analysis of 26 was not

carried out, H-46 seems to prevent the reagent approaching from

the a-face of the oleﬁn (Fig. 1). Therefore, we had to change the

synthetic pathway for the stereoselective installation of the 48-

methyl group. We planned that the 48-methyl substituent could

be stereoselectively introduced by utilizing the isomerization of the

aldehyde and subsequent reduction because the methyl group at

the C48 position of the LM ring system 7 would be oriented in the

equatorial conformation.

2.3. First generation synthesis of the LM ring system

Next, the stereoselective synthesis of the LM ring system was

examined (Scheme 3). The aldol reaction of known aldehyde 18,

prepared from L-ascorbic acid in ﬁve steps by the known pro-

cedure,¹⁷with propionyl oxazolidinethione 19 was performed in

the presence of TiCl₄(2.0 equiv)/(ꢀ)-sparteine (1.1 equiv)¹⁸to give

the syn aldol adduct 20 as a single stereoisomer in 89% yield. The

stereochemistry at the C46 position was determined by the modi-

ﬁed Mosher method.¹⁹The structural elucidation at the C47 posi-

tion was carried out at a later stage. Reductive removal of the

oxazolidinethione chiral auxiliary with NaBH₄and protection of the

resulting diol provided benzylidene acetal 21. Regioselective acetal

cleavage of 21 with DIBAL-H and subsequent Swern oxidation²⁰

afforded aldehyde 22. The aldehyde 22 was coupled with dithiane

23²¹to yield alcohol 24 as a 4:1 diastereomixture. The dithioacetal

moiety of 24 was deprotected with I₂/NaHCO₃in aqueous CH₃CN to

give ketone 8. Removal of the butane-2,3-diacetal and TBS pro-

tective groups and spiroacetalization were performed with TfOH to

Fig. 1. Plausible rationale for the outcome of hydrogenation of 26.

Hydroboration of 26 with BH₃$SMe₂followed by oxidative

workup gave the corresponding alcohol as a 2:1 diastereomixture

(Scheme 4). TPAP oxidation¹⁶of the resulting alcohol afforded al-

dehyde 28 (

a

/

b

¼2:1). After the detailed examination on the isom-

erization at the C48 position of 28, it was found that treatment of 28

Scheme 3. Synthesis of alkene 26.

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H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

Scheme 4. First generation synthesis of the LM ring system 7.

with DBU in CH₂Cl₂at 30 ^ꢁC provided the desired aldehyde 29, in

which the 48-formyl group was in the equatorial position, in 93%

yield. The aldehyde 29 was transformed to alkane 30 by the three-

step sequence: (1) reduction with NaBH₄, (2) iodination of the

resulting alcohol, and (3) lithiumehalogen exchange followed by

protonation. The TBS group of 30 was deprotected with TBAF to

give the LM ring system 7. The conﬁgurational determination of 7

was veriﬁed by NOE experiments. Thus, the observed NOEs of H-45/

H-47 and H-46/H-48 conﬁrmed that the 47- and 48-methyl sub-

stituents had the equatorial orientations, respectively. Further-

more, the correlation of H-45/H₂-52 by NOE experiment elucidated

that they were in a syn relationship to each other.

DIBAL-H to yield the LM ring system 7. The overall yield in the

second generation synthesis of 7 was 30% from -ascorbic acid,

which was a 7-fold increase in comparison with that in the ﬁrst

generation synthesis and enabled us to supply 7 in the gram-scale.

L

2.5. Construction of the K ring

Next, we carried out the stereoselective construction of the K

ring (Scheme 6). The alcohol 7 was oxidized to the corresponding

aldehyde and the aldehyde was treated with propionyl oxazolidi-

nethione 19/TiCl₄(2.0 equiv)/(ꢀ)-sparteine (5.0 equiv)¹⁸to give the

syn aldol product 41 as a single stereoisomer in 92% yield in two

steps. The absolute conﬁguration at the C44 position was de-

termined by the modiﬁed Mosher method.¹⁹The stereochemical

assignment at the C43 position was carried out after the con-

struction of the K ring. The chiral auxiliary of 41 was removed with

NaBH₄, and the primary and secondary hydroxy groups were pro-

tected with TBSCl and MOMCl, respectively, to provide MOM ether

42. Deprotection of the benzyl moiety of 42 by hydrogenolysis and

subsequent treatment of the resulting alcohol with ethyl propiolate

2.4. Second generation synthesis of the LM ring system

Although we synthesized the targeted LM ring system 7 ster-

eoselectively, the transformation for the introduction of the 48-

methyl group was lengthy, which resulted in lowering the overall

yield (4.4% from L-ascorbic acid). Therefore, we examined the more

efﬁcient synthesis of 7, wherein the 48-methyl substituent could be

stereoselectively installed before spiroacetalization (Scheme 5). We

planned that the vicinal two methyl groups at the C47 and C48

positions could be stereoselectively introduced by the sequential

1,2-chiral induction utilizing the C46 chiral center, according to

in the presence of NMM afforded the corresponding

a,b-un-

saturated ester. The TBS protective group was removed with CSA in

MeOH to yield alcohol 43 in 96% yield in three steps. After the al-

cohol 43 was oxidized to the aldehyde with SO₃$pyr/Et₃N/DMSO,²⁶

the resulting aldehyde was subjected to the SmI₂-induced reductive

cyclization²⁸to produce lactone 44 and hydroxy ester 45 in 85%

combined yield in two steps. The hydroxy ester 45 was transformed

to the lactone 44 with CSA. The observed NOEs of H-41/H-46 and H-

42/Me-43 in 44 elucidated that they had syn relationships to each

other. The large magnitude of J_41,42(8.5 Hz) conﬁrmed that they

were in axial and axial orientations. Deprotection of the MOM

group of 44 with ZnBr₂/EtSH²⁹followed by TBS protection of the

resulting secondary alcohol provided the TBS ether. Reduction of

the lactone part with LiAlH₄and selective protection of the primary

hydroxy group with PivCl afforded pivalate 46. The alcohol 46 was

Hanessian’s protocol.²⁴Thus, treatment of

synthesized from

a,

b

-unsaturated ester 31,

L

-ascorbic acid in six steps,²⁵with MeLi$LiBr/CuI/

TMSCl provided ﬁrst-methylated ester 32. Generation of the po-

tassium enolate from 32 with KHMDS followed by trapping the

resulting enolate with MeI gave second-methylated ester 33, pos-

sessing the desired contiguous stereochemistry, as a single ste-

reoisomer in 96% yield in two steps. Reduction of 33 with DIBAL-H

and subsequent ParikheDoering oxidation²⁶of the resulting alco-

hol afforded the corresponding aldehyde. The aldehyde was reacted

with the lithium acetylide, derived from alkyne 34 and n-BuLi, to

yield propargyl alcohol 35 as a 1:1 diastereomixture. Oxidation of

the alcohol 35 followed by hydrogenation of the alkyne moiety gave

ketone 36. Treatment of 36 with CSA in MeOH at 40 ^ꢁC provided

spiroacetal 37 as the sole product. Next, we carried out the con-

ﬁgurational inversion at the C46 position. Thus, acetylation of the

alcohol 37 and subsequent removal of the benzyl protective group

gave the corresponding secondary alcohol. TPAP oxidation¹⁶of the

alcohol followed by deacetylation yielded hydroxy ketone 38.

reacted with g-methoxyallylstannane 47 in the presence of CSA to

produce mixed acetal 48 as a 1:1 diastereomixture.³⁰Reductive

removal of the pivaloyl moiety of 48 with DIBAL-H followed by

31

stepwise oxidation with TPAP¹⁶and NaClO₂gave the KLM ring

system coupling precursor 6.

2.6. Synthesis of the HIJKLM ring system

27

Diastereoselective reduction of 38 with NaBH(OAc)₃proceeded

smoothly to provide diol 39 as a single stereoisomer. Protection of

the diol 39 with PhCH(OMe)₂afforded benzylidene acetal 40. The

benzylidene acetal moiety of 40 was regioselectively cleaved with

With the H and KLM ring systems in hand, we next examined

the coupling of these two fragments and construction of the IJ ring

system (Scheme 7). The connection of the H ring system alcohol 5

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2249

Scheme 5. Second generation synthesis of the LM ring system 7.

Scheme 6. Construction of the K ring.

and KLM ring system carboxylic acid 6 was performed by Yama-

guchi esteriﬁcation³²to produce ester 49 in 82% yield in three steps.

Treatment of the mixed acetal 49 with TMSI/HMDS³⁰provided al-

lylic stannane 50 as a 4:1 Z/E diastereomixture in 73% yield. After

the detailed investigation on the transformation of the ester 50 to

a

-chloroacetoxy ether 4, it was found that reduction of 50 with

DIBAL-H in toluene at ꢀ95 ^ꢁC and subsequent capture of the

resulting aluminum hemiacetal with (ClCH₂CO)₂O/pyridine^33,34at

2250

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

Scheme 7. Synthesis of the HIJKLM ring system 54.

ꢀ95 ^ꢁC to ꢀ10 ^ꢁC afforded 4.³⁵Treatment of 4 with MgBr₂$OEt₂/MS

which enabled us to synthesize 7 in the gram-scale. The K ring was

constructed via the SmI₂-induced reductive cyclization, stereo-

selectively. The H and KLM ring fragments, 5 and 6, were connected

by esteriﬁcation, and the IJ ring system were constructed by

intramolecular allylation, ring-closing metathesis, and stereo-

selective hydrogenation to yield the HIJKLM ring system 54. Further

studies toward the total synthesis of ciguatoxin CTX3C are currently

underway in our laboratory.

4 A in CH₃CN at 40 ^ꢁC gave the desired intramolecular allylated

ꢀ

product 51 and its 39-epimer 52 in 43% and 40% yields in two steps,

respectively. The observed NOEs of H-38/H-42 in 51 and 52 eluci-

dated that they were in syn relationships to each other. Further-

more, J_38,39(51: 8.9 Hz, 52: 0 Hz) conﬁrmed that the correlations of

H-38/H-39 were trans in 51 and cis in 52, respectively. The diene 51

was subjected to ring-closing metathesis with the Hoveydae-

Grubbs second generation catalyst³⁶to provide alkene 53 in 82%

yield. Hydrogenation of 53 with Crabtree catalyst³⁷proceeded

stereoselectively to produce the HIJKLM ring system 54 as a single

stereoisomer in 88% yield.^7e,38The NOE correlations between H-36

and H-38 in 54, which were observed by 600 MHz NMR spectros-

copy in CDCl₃, determined the absolute conﬁguration of the 36-

4. Experimental section

4.1. General

Reagents were used as received from commercial suppliers

unless otherwise indicated. All reactions were carried out under an

atmosphere of argon. Reaction solvents were purchased as dehy-

methyl substituent to be a.

ꢀ

3. Conclusion

drated solvents and stored with active molecular sieves 4 A under

argon prior to use for reactions. All solvents for workup procedure

were used as received. Analytical thin-layer chromatography (TLC)

was performed with aluminum TLC plates (Merck TLC silica gel

60F₂₅₄). Column chromatography was performed with Fuji Silysia

silica gel BW-300 or Kanto Chemical silica gel 60N. Optical rotations

were recorded on a JASCO DIP-1000. IR spectra were recorded on

a JASCO FT/IR-460 plus. ¹H and ¹³C NMR spectra were recorded on

JEOL JNM-AL400 or Varian 600 MHz spectrometer. Chemical shifts

are reported in parts per million with reference to the internal re-

sidual solvent (¹H NMR, CHCl₃: 7.24 ppm, C₆HD₅: 7.15 ppm; ¹³C

NMR, CDCl₃: 77.0 ppm, C₆D₆: 128.0 ppm). The following abbrevi-

ations are used to designate the multiplicities: s¼singlet,

First, we synthesized the H ring coupling precursor 5 in 17 steps

from the known alcohol 9. In the ﬁrst generation synthesis of the

LM ring system 7, the key transformations were spiroacetalization

and isomerizationereduction sequence of the aldehyde 28 for the

stereoselective introduction of the 48-methyl group. The overall

yield and total steps from L-ascorbic acid were 4.4% and 23 steps,

respectively. The second generation synthesis of 7 has featured

sequential conjugate addition/alkylation for the stereoselective

installation of the contiguous 47,48-methyl groups and spiroace-

talization. The overall yield and total steps (30% and 21 steps from

L-

ascorbic acid) were improved over those of the ﬁrst synthesis,

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2251

d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. Coupling

constants (J) are in hertz. High resolution mass spectra were

recorded on a Micromass LCT (ESI-TOF-MS) spectrometer.

(250 mg, 0.630 mmol) in CH₂Cl₂(3.0 mLþ1.0 mLþ1.0 mL) at the

same temperature. After the mixture was stirred for 1 h at the same

temperature, to the mixture was added TBHP (ca. 5.0 M in 2,2,4-

trimethylpentane, 0.19 mL, 0.945 mmol) at the same temperature.

After the mixture was stirred for 2 h at 0 ^ꢁC, the mixture was

allowed to warm up to room temperature. After the mixture was

stirred for 8 h at room temperature, the reaction was quenched

with saturated aqueous Na₂SO₄(3.0 mL). Subsequently, to the re-

action mixture was added a Celite. The insoluble material was ﬁl-

4.1.1.

a,b-Unsaturated ester 10. To a suspension of NaH (60% dis-

persion in oil, 330 mg, 8.25 mmol, washed with hexane in advance)

in THF (20 mL) were added alcohol 9 (1.50 g, 5.43 mmol) in DMF

(10 mLþ5.0 mLþ5.0 mL) and BnBr (0.77 mL, 6.51 mmol) at 0 ^ꢁC.

After the mixture was stirred for 4 h at room temperature, the re-

action was quenched with MeOH (10 mL). The mixture was diluted

with EtOAc (50 mL), washed with H₂O (20 mL) and brine (20 mL),

and then dried over Na₂SO₄. Concentration and column chroma-

tography (hexane/EtOAc¼7:1) gave the corresponding benzyl ether

(2.18 g), which was used for the next step without further

puriﬁcation.

Ozone was passed through a solution of the alkene obtained

above (2.18 g) in MeOH (30 mL) and CH₂Cl₂(15 mL) at ꢀ78 ^ꢁC until

the solution turned blue. After removal of excess ozone with an

oxygen stream, the mixture was treated with Me₂S (0.66 mL,

8.93 mmol) and allowed to warm up to room temperature with

stirring. Concentration gave the corresponding aldehyde (2.82 g),

which was used for the next step without further puriﬁcation.

To a solution of the aldehyde obtained above (2.82 g) in benzene

(20 mL) was added Ph₃P]CHCO₂Me (2.98 g, 8.93 mmol) at room

temperature. After the mixture was stirred for 3 h at reﬂux, to the

mixture was added Ph₃P]CHCO₂Me (973 mg, 2.98 mmol) at room

temperature. The mixture was stirred for 2 h at reﬂux. Concentra-

tered through

a

Celite pad. Concentration and column

chromatography (hexane/EtOAc¼2:1) gave the corresponding ep-

oxy alcohol (246 mg), which was used for the next step without

further puriﬁcation.

To a solution of the epoxy alcohol obtained above (246 mg) in

THF (6.0 mL) was added Red-Al (65% in toluene, 1.6 mL, 5.19 mmol)

at ꢀ40 ^ꢁC. After the mixture was stirred at room temperature for

6 h, the reaction was quenched with saturated aqueous sodium

potassium tartrate (3.0 mL). Subsequently, to the reaction were

added a Celite and silica gel. The insoluble material was ﬁltered

through a Celite pad. Concentration and column chromatography

(hexane/EtOAc¼1:1) gave diol 12 (226 mg, 87% in two steps): col-

a ²²

orless oil; R_f¼0.10 (hexane/EtOAc¼1:1); ½ ꢂ_Dꢀ30.9 (c 1.12, CHCl₃);

IR (neat) 3444, 2878 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

; d 7.47e7.28

(m, 10H), 5.49 (s, 1H), 4.63 (d, J¼11.7 Hz, 1H), 4.49 (d, J¼11.7 Hz, 1H),

4.23e4.17 (m, 1H), 3.94 (dd, J¼11.5, 4.4 Hz, 1H), 3.83e3.78 (m, 3H),

3.64e3.60 (m, 2H), 3.44e3.42 (m, 1H), 2.47e2.34 (m, 2H), 1.84e1.71

(m, 3H), 1.26 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 137.9, 137.3, 129.1,

tion and column chromatography (hexane/EtOAc¼20:1) gave

a

,

b

-

128.4, 128.3, 127.8, 127.6, 126.1, 101.7, 79.2, 77.2, 74.7, 74.1, 71.2, 69.8,

66.4, 61.7, 32.6, 30.3, 14.2; HRMS (ESI-TOF) calcd for C₂₄H₃₀O₆Na

(MþNa)^þ437.1940, found 437.2024.

unsaturated ester 10 (2.06 g, 89% in three steps): colorless oil;

R_f¼0.34 (hexane/EtOAc¼4:1); ½a _D²¹

ꢂ

ꢀ23.6 (c 0.34, CHCl₃); IR (neat)

2949, 1723, 1661 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.48e7.46 (m,

2H), 7.38e7.25 (m, 8H), 7.10 (d, J¼15.9 Hz, 1H), 6.04 (d, J¼15.9 Hz,

1H), 5.50 (s, 1H), 4.60 (d, J¼11.7 Hz, 1H), 4.46 (d, J¼11.7 Hz, 1H),

4.29e4.22 (m, 1H), 3.74 (s, 3H), 3.69e3.63 (m, 2H), 3.44e3.38 (m,

2H), 2.45e2.40 (m, 1H), 1.85e1.76 (m, 1H), 1.41 (s, 3H); ¹³C NMR

4.1.4. Diol 13. To a suspension of NaH (60% dispersion in oil,

996 mg, 24.9 mmol, washed with hexane in advance) in THF

(10 mL) was added diol 12 (1.03 g, 2.49 mmol) in DMF

(5.0 mLþ4.0 mLþ3.0 mL) at 0 ^ꢁC. To the mixture were added BnBr

(3.0 mL, 24.9 mmol) and TBAI (1.84 g, 4.98 mmol) in THF (2.0 mL) at

the same temperature. After the mixture was stirred for 19 h at

60 ^ꢁC, the reaction was quenched with MeOH (10 mL). The mixture

was diluted with EtOAc (60 mL), washed with H₂O (20 mL) and

brine (20 mL), and then dried over Na₂SO₄. Concentration and

column chromatography (hexane/EtOAc¼4:1) gave the corre-

sponding tris-benzyl ether (1.32 g), which was used for the next

step without further puriﬁcation.

(100 MHz, CDCl₃) d 167.1,151.1,137.6,137.3,129.0,128.4,128.3,127.8,

127.6, 126.1, 118.9, 101.7, 78.1, 77.2, 77.1, 71.5, 69.9, 66.5, 51.6, 30.6,

16.2; HRMS (ESI-TOF) calcd for C₂₅H₂₈O₆Na (MþNa)^þ447.1783,

found 447.1817.

4.1.2. Allylic alcohol 11. To a solution of ester 10 (2.06 g, 4.85 mmol)

in CH₂Cl₂(50 mL) was added DIBAL-H (1.02 M in hexane, 11 mL,

10.7 mmol) at ꢀ78 ^ꢁC. After the mixture was stirred for 20 min, the

reaction was quenched with a solution of MeOH/H₂O (20 mL).

Subsequently, to the reaction mixture were added a Celite and silica

gel at the same temperature, and the mixture was allowed to warm

up to room temperature. After the mixture was stirred for 30 min at

room temperature, the insoluble material was ﬁltered through

a Celite pad. Concentration and column chromatography (hexane/

EtOAc¼2:1) gave allylic alcohol 11 (1.64 g, 85%): colorless oil;

To a solution of the benzylidene acetal obtained above (1.32 g)

in MeOH (22 mL) was added CSA (154 mg, 0.660 mmol) at room

temperature. After the mixture was stirred for 24 h at the same

temperature, the reaction was quenched with Et₃N (2.0 mL).

Concentration and column chromatography (hexane/EtOAc¼1:1)

gave diol 13 (1.06 g, 84% in two steps): light yellow oil; R_f¼0.54

(EtOAc); ½a ²_D⁴

ꢂ

ꢀ2.3 (c 0.81, CHCl₃); IR (neat) 3399, 2923 cm^ꢀ1

;

¹H

R_f¼0.29 (hexane/EtOAc¼2:1); ½a _D²⁹

ꢂ

ꢀ42.3 (c 1.37, CHCl₃); IR (neat)

7.48e7.46 (m,

NMR (400 MHz, CDCl₃)

d

7.31e7.20 (m, 15H), 4.58 (d, J¼11.7 Hz,

3253, 2888, 1638 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

1H), 4.49e4.47 (m, 4H), 4.30 (d, J¼11.7 Hz, 1H), 3.86 (dd, J¼11.7,

4.6 Hz, 1H), 3.75e3.71 (m, 3H), 3.63e3.55 (m, 3H), 3.40e3.35 (m,

1H), 2.43 (dt, J¼11.9, 4.6 Hz, 1H), 2.07e1.99 (m, 1H), 1.93e1.85 (m,

1H), 1.63e1.57 (m, 1H), 1.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

2H), 7.38e7.26 (m, 8H), 5.90 (dt, J¼15.6, 5.1 Hz, 1H), 5.82 (d,

J¼15.6 Hz, 1H), 5.50 (s, 1H), 4.62 (d, J¼11.9 Hz, 1H), 4.44 (d,

J¼11.9 Hz, 1H), 4.28e4.22 (m, 1H), 4.11 (t, J¼5.1 Hz, 2H), 3.69e3.62

(m, 2H), 3.49e3.43 (m, 1H), 3.39 (dd, J¼11.5, 4.4 Hz, 1H), 2.43 (dt,

J¼11.8, 4.1 Hz, 1H), 1.79 (q, J¼11.8 Hz, 1H), 1.38 (s, 3H); ¹³C NMR

d

138.6, 138.4, 128.3, 128.3, 127.7, 127.6, 127.5, 127.4, 127.1, 79.7,

79.2, 74.2, 74.1, 73.8, 72.9, 70.1, 67.3, 66.7, 63.4, 33.4, 29.9, 14.4;

HRMS (ESI-TOF) calcd for C₃₁H₃₈O₆Na (MþNa)^þ529.2566, found

529.2552.

(100 MHz, CDCl₃)

d 137.9, 137.3, 135.5, 128.9, 128.2, 128.1, 128.1,

127.6, 126.0, 101.6, 78.9, 77.3, 76.8, 71.4, 69.9, 66.3, 63.0, 30.8, 16.2;

HRMS (ESI-TOF) calcd for C₂₄H₂₈O₅Na (MþNa)^þ419.1834, found

419.1814.

4.1.5. Alcohol 14. To a solution of diol 13 (197 mg, 0.390 mmol) in

DMF (2.0 mL) were added imidazole (133 mg, 1.95 mmol) and TBSCl

(176 mg, 1.17 mmol) at room temperature. After the mixture was

stirred for 2 h at 60 ^ꢁC, the reaction was quenched with MeOH

(2.0 mL). The mixture was diluted with EtOAc (30 mL), washed with

H₂O (10 mL) and brine (10 mL), and then dried over Na₂SO₄.

ꢀ

4.1.3. Diol 12. To a suspension of MS 4 A (250 mg) in CH₂Cl₂

(5.0 mL) were added (þ)-DET (21

(28 L, 95.0

mol) at 0 ^ꢁC. After the mixture was stirred for 1 h at

the same temperature, to the mixture was added allylic alcohol 11

mL, 0.126 mmol) and Ti(Oi-Pr)₄

m

2252

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

Concentration and column chromatography (hexane/EtOAc¼1:0,

5:1) gave the corresponding bis-silyl ether, which was used for the

next step without further puriﬁcation.

alcohol 16 (5.03 g, 76% in two steps) as a 1:1 diastereomixture:

colorless oil; R_f¼0.38 (hexane/EtOAc¼4:1); IR (neat) 3512,

2857 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

; d 7.29e7.20 (m, 15H),

To a solution of the bis-silyl ether obtained above in MeOH

(4.0 mL) was added CSA (9.1 mg, 39.0

4.56e4.26 (m, 5H), 4.07e3.94 (m, 1H), 3.88e3.80 (m, 1H),

3.77e3.71 (m, 1H), 3.59e3.43 (m, 4H), 3.27e3.19 (m, 1H), 2.22 (dt,

J¼12.2, 4.6 Hz, 1H), 2.07e2.00 (m, 1H), 1.93e1.87 (m, 1H), 1.84e1.76

(m, 1H), 1.70 (t, J¼4.9 Hz, 1H), 1.58e1.51 (m, 1H), 1.45e1.37 (m, 1H),

1.23e1.14 (m, 6H), 0.85e0.84 (m, 9H), 0.03e0.02 (m, 6H); ¹³C NMR

m

mol) at 0 ^ꢁC. After the

mixture was stirred for 1 h at the same temperature, the reaction

was quenched with Et₃N (2.0 mL). The mixture was diluted with

EtOAc (30 mL), washed with H₂O (10 mL) and brine (10 mL), and

then dried over Na₂SO₄. Concentration and column chromatogra-

phy (hexane/EtOAc¼10:1, 4:1) gave alcohol 14 (204 mg, 84% in two

(100 MHz, CDCl₃)

d 138.9, 138.6, 138.5, 128.2, 128.2, 127.7, 127.6,

127.5, 127.4, 127.3, 127.1, 79.6, 79.4, 79.1, 75.9, 73.9, 73.4, 73.3, 73.2,

72.9, 72.8, 70.6, 70.2, 68.7, 68.0, 67.3, 64.4, 40.4, 38.8, 34.5, 34.4,

30.2, 29.9, 25.8, 23.5, 23.4, 18.0, 14.8, 14.3, ꢀ3.9, ꢀ4.5, ꢀ4.6; HRMS

(ESI-TOF) calcd for C₃₉H₅₆O₆SiNa (MþNa)^þ671.3744, found

671.3793.

steps): colorless oil; R_f¼0.10 (hexane/EtOAc¼7:1); ½a _D²⁵

þ21.0 (c

ꢂ

0.44, CHCl₃); IR (neat) 3458, 2951 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.31e7.25 (m,15H), 4.56e4.37 (m, 5H), 4.33 (d, J¼11.5 Hz,1H), 3.81

(dd, J¼11.8, 4.7 Hz, 1H), 3.74e3.68 (m, 2H), 3.58e3.45 (m, 4H),

3.38e3.34 (m, 1H), 2.25 (dt, J¼12.0, 4.8 Hz, 1H), 2.08e2.00 (m, 1H),

1.94e1.87 (m, 1H), 1.62e1.53 (m, 2H), 1.21 (s, 3H), 0.85 (s, 9H), 0.04

4.1.8. Alkene 17. To a solution of alcohol 16 (4.00 g, 6.17 mmol) and

(s, 3H), 0.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d

138.8, 138.6, 138.5,

MS 4 A (4.4 g) in CH₂Cl₂(60 mL) were added TPAP (110 mg,

ꢀ

128.3, 128.3, 127.7, 127.5, 127.5, 127.4, 127.2, 79.9, 79.1, 74.7, 74.2,

73.7, 72.9, 70.2, 67.3, 66.7, 62.8, 34.2, 29.9, 25.8, 18.0, 14.5, ꢀ4.1,

ꢀ4.8; HRMS (ESI-TOF) calcd for C₃₇H₅₂O₆SiNa (MþNa)^þ643.3431,

found 643.3419.

0.31 mmol) and NMO (870 mg, 7.40 mmol) at 0 ^ꢁC. The mixture was

stirred for 1 h at room temperature. Short column chromatography

(hexane/EtOAc¼4:1) gave the corresponding ketone (3.86 g), which

was used for the next step without further puriﬁcation.

To a suspension of Ph₃P^þCH₃Br^ꢀ(2.90 g, 8.00 mmol) in THF

(40 mL) was added NaHMDS (1.0 M in THF, 8.0 mL, 8.00 mmol) at

4.1.6. Nitrile 15. To a solution of alcohol 14 (203 mg, 0.328 mmol)

in benzene (1.6 mL) and Et₂O (1.6 mL) were added imidazole

(60.0 mg, 0.890 mmol), PPh₃(140 mg, 0.660 mmol), and I₂(120 mg,

0.490 mmol) at room temperature. After the mixture was stirred for

1 h at 40 ^ꢁC, the reaction was quenched with saturated aqueous

Na₂S₂O₃(2.0 mL). The mixture was diluted with EtOAc (30 mL),

washed with H₂O (10 mL) and brine (10 mL), and then dried over

Na₂SO₄. Concentration gave the corresponding iodide, which was

used for the next step without further puriﬁcation.

0

^ꢁC. After the mixture was stirred for 15 min at the same tem-

perature, to the reaction mixture was added the ketone obtained

above (3.86 g) in THF (8.0 mLþ2.0 mL) at 0 ^ꢁC. After the mixture was

stirred for 2 h at room temperature, the reaction was quenched

with brine (10 mL). The mixture was diluted with EtOAc (100 mL),

washed with H₂O (30 mL) and brine (30 mL), and dried over

Na₂SO₄. Concentration, short column chromatography (hexane/

EtOAc¼2:1), and column chromatography (hexane/EtOAc¼20:1,

10:1) gave alkene 17 (2.68 g, 67% in two steps): colorless oil;

To a solution of the iodide obtained above in DMSO (3.2 mL) was

added NaCN (19.0 mg, 0.390 mmol) at room temperature. After the

mixture was stirred for 3 h at 70 ^ꢁC, the reaction was quenched with

H₂O (2.0 mL). The mixture was diluted with EtOAc (30 mL), washed

with H₂O (10 mL) and brine (10 mL), and then dried over Na₂SO₄.

Concentration and column chromatography (hexane/EtOAc¼10:1)

gave nitrile 15 (181 mg, 87% in two steps): light yellow oil; R_f¼0.51

R_f¼0.54 (hexane/EtOAc¼4:1); ½a _D²⁸

ꢂ

þ33.0 (c 0.89, CHCl₃); IR (neat)

2952 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

; d 7.30e7.21 (m, 15H),

4.71e4.70 (m, 2H), 4.61 (d, J¼11.7 Hz, 1H), 4.54 (d, J¼11.7 Hz, 1H),

4.48 (d, J¼11.7 Hz, 1H), 4.44e4.36 (m, 2H), 4.34 (d, J¼11.7 Hz, 1H),

3.79 (dd, J¼11.6, 4.8 Hz, 1H), 3.67 (dd, J¼8.7, 2.8 Hz, 1H), 3.57e3.48

(m, 2H), 3.44e3.39 (m,1H), 3.26e3.20 (m,1H), 2.46 (br d, J¼14.4 Hz,

1H), 2.23 (dt, J¼12.2, 4.4 Hz, 1H), 2.03e1.88 (m, 3H), 1.72 (s, 3H),

1.26e1.25 (m, 1H), 1.19 (s, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H);

(hexane/EtOAc¼4:1); ½a _D²⁴

ꢂ

þ25.1 (c 0.10, CHCl₃); IR (neat) 2925,

2350 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

; d 7.31e7.25 (m, 15H),

4.61e4.35 (m, 6H), 3.81 (dd, J¼11.7, 4.9 Hz, 1H), 3.75 (dd, J¼9.0,

2.9 Hz, 1H), 3.61e3.58 (m, 2H), 3.53e3.48 (m, 1H), 3.36e3.30 (m,

1H), 2.64 (dd, J¼16.6, 3.2 Hz, 1H), 2.46 (dd, J¼16.6, 7.1 Hz, 1H), 2.21

(dt, J¼12.2, 4.6 Hz, 1H), 2.11e2.04 (m, 1H), 2.01e1.90 (m, 1H),

1.58e1.49 (m, 1H), 1.24 (s, 3H), 0.85 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H);

¹³C NMR (100 MHz, CDCl₃)

d 139.2, 138.7, 128.2, 128.2, 128.1, 127.8,

127.6, 127.3, 127.3, 127.2, 127.1, 111.7, 80.4, 79.2, 74.6, 73.3, 73.1, 72.8,

70.6, 70.2, 67.6, 40.3, 34.9, 29.7, 25.9, 22.8, 13.9, ꢀ3.8, ꢀ4.5; HRMS

(ESI-TOF) calcd for C₄₀H₅₆O₅SiNa (MþNa)^þ667.3795, found

667.3802.

¹³C NMR (100 MHz, CDCl₃)

d 139.1, 138.6, 138.4, 128.3, 128.2, 127.7,

127.6, 127.5, 127.4, 127.2, 117.5, 80.3, 80.0, 74.2, 73.1, 72.9, 71.1, 70.6,

69.6, 67.3, 34.5, 29.8, 25.7, 21.5, 17.9, 13.9, ꢀ3.9, ꢀ4.7; HRMS (ESI-

TOF) calcd for C₃₈H₅₁NO₅SiNa (MþNa)^þ652.3434, found 652.3446.

4.1.9. Alcohol 5. To a solution of silyl ether 17 (640 mg,

0.990 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 2.0 mL,

2.00 mmol) at room temperature. The mixture was stirred for 2 h at

45 ^ꢁC. The mixture was diluted with EtOAc (40 mL), washed with

H₂O (10 mL) and brine (10 mL), and then dried over Na₂SO₄. Con-

centration and column chromatography (hexane/EtOAc¼4:1) gave

4.1.7. Alcohol 16. To a solution of nitrile 15 (6.40 g, 10.2 mmol) in

CH₂Cl₂(100 mL) was added DIBAL-H (1.02 M in hexane, 15 mL,

15.0 mmol) at ꢀ78 ^ꢁC. After the mixture was stirred for 2 h at the

same temperature, the reaction was quenched with MeOH (10 mL).

Subsequently, to the reaction mixture were added a Celite and silica

gel. The insoluble material was ﬁltered through a Celite pad. Con-

centration and short column chromatography (hexane/EtOAc¼6:1)

gave the corresponding aldehyde (5.04 g), which was used for the

next step without further puriﬁcation.

To a solution of the aldehyde obtained above (5.04 g) in THF

(80 mL) was added MeMgBr (3.0 M in THF, 4.0 mL, 12.0 mmol) at

0 ^ꢁC. After the mixture was stirred for 3 h at the same temperature,

the reaction was quenched with saturated aqueous NH₄Cl (10 mL).

The mixture was diluted with EtOAc (100 mL), washed with H₂O

(30 mL) and brine (30 mL), and then dried over Na₂SO₄. Concen-

tration and column chromatography (hexane/EtOAc¼5:1) gave

alcohol

5

(525 mg, quant): colorless oil; R_f¼0.31 (hexane/

EtOAc¼2:1); ½a ²_D¹

ꢂ

þ9.3 (c 0.24, CHCl₃); IR (neat) 3435, 2938,

1648 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.31e7.22 (m,15H), 4.79 (br

s,1H), 4.76 (br s,1H), 4.59e4.39 (m, 5H), 4.31 (d, J¼11.7 Hz,1H), 3.85

(dd, J¼11.6, 4.8 Hz, 1H), 3.69 (dd, J¼8.9, 3.1 Hz, 1H), 3.59e3.44 (m,

3H), 3.40e3.32 (m, 1H), 2.46e2.38 (m, 2H), 2.19 (dd, J¼14.1, 7.8 Hz,

1H), 2.05e1.89 (m, 2H), 1.77 (s, 3H), 1.74e1.71 (m, 1H), 1.62e1.51 (m,

1H), 1.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 128.2, 128.2, 128.1,

127.6, 127.4, 127.3, 127.2, 127.1, 112.4, 80.2, 79.3, 74.5, 73.3, 72.8, 72.7,

70.4, 70.1, 67.5, 41.2, 33.8, 29.8, 23.0, 13.9; HRMS (ESI-TOF) calcd for

C₃₄H₄₂O₅Na (MþNa)^þ553.2930, found 553.2936.

4.1.10. Alcohol 20. To a solution of oxazolidinethione 19 (2.52 g,

10.1 mmol) in CH₂Cl₂(36 mL) was added TiCl₄(2.2 mL, 20.2 mmol)

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2253

in CH₂Cl₂(4.0 mL) at 0 ^ꢁC. After the mixture was stirred for 10 min

at the same temperature, to the mixture was added (ꢀ)-sparteine

(2.60 mL, 11.1 mmol) at 0 ^ꢁC. After the mixture was stirred for

30 min at the same temperature, the reaction mixture was cooled

down to ꢀ78 ^ꢁC. To the mixture was added aldehyde 18 (2.26 g,

11.1 mmol) in CH₂Cl₂(7.0þ2.0þ1.0 mL) at ꢀ78 ^ꢁC. After the mixture

was stirred for 40 min at the same temperature, the mixture was

allowed to warm up to 0 ^ꢁC for 80 min gradually. After the mixture

was stirred for 1 h at 0 ^ꢁC, the reaction was quenched with satu-

rated aqueous NH₄Cl (10 mL). The mixture was diluted with EtOAc

(100 mL), washed with H₂O (30 mL) and brine (30 mL), and then

dried over Na₂SO₄. Concentration and column chromatography

(hexane/EtOAc¼4:1, 2:1) gave alcohol 20 (4.08 g, 89%): yellow oil;

EtOAc¼2:1); ½a ²_D¹

ꢂ

þ117 (c 0.39, CHCl₃); IR (neat) 3478, 2948 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

7.31e7.24 (m, 5H), 4.61 (d, J¼11.3 Hz,

1H), 4.56 (d, J¼11.3 Hz,1H), 4.04 (ddd, J¼11.0, 7.1, 3.7 Hz,1H), 3.74 (t,

J¼11.0 Hz, 1H), 3.67 (dd, J¼11.0, 3.7 Hz, 1H), 3.61 (dd, J¼7.1, 3.1 Hz,

1H), 3.58e3.56 (m, 2H), 3.27 (s, 3H), 3.25 (s, 3H), 2.15e2.07 (m, 1H),

1.65 (br s, 1H), 1.27 (s, 3H), 1.27 (s, 3H), 0.96 (d, J¼7.1 Hz, 1H); ¹³C

NMR (100 MHz, CDCl₃)

d 138.3, 128.3, 127.8, 127.6, 99.2, 98.0, 80.3,

74.2, 67.6, 66.0, 61.6, 48.3, 48.0, 37.1, 18.0, 17.7, 11.3; HRMS (ESI-TOF)

calcd for C₁₉H₃₀O₆Na (MþNa)^þ377.1940, found 377.1925.

To a solution of DMSO (2.8 mL, 40.0 mmol) in CH₂Cl₂(40 mL)

was added (COCl)₂(2.1 mL, 24.0 mmol) at ꢀ78 ^ꢁC. After the mixture

was stirred for 15 min at ꢀ78 ^ꢁC, to the resulting mixture was added

the alcohol obtained above (5.70 g, 16.0 mmol). After the mixture

was stirred for 30 min at ꢀ78 ^ꢁC, to the mixture was added Et₃N

(11 mL, 80.0 mmol), and the mixture was allowed to warm up to

room temperature. The mixture was diluted with EtOAc (100 mL),

washed with H₂O (30 mL) and brine (30 mL), and then dried over

Na₂SO₄. Concentration and column chromatography (hexane/

EtOAc¼6:1) gave aldehyde 22 (5.59 g, 98%): colorless oil; R_f¼0.48

R_f¼0.24 (hexane/EtOAc¼2:1); ½a _D²²

ꢂ

þ139 (c 0.61, CHCl₃); IR (neat)

7.35e7.20 (m,

3503, 2989, 1690 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

5H), 5.17 (qd, J¼7.1, 1.9 Hz, 1H), 4.89e4.83 (m, 1H), 4.30e4.20 (m,

2H), 4.06 (dt, J¼9.9, 1.9 Hz, 1H), 3.91 (td, J¼9.9, 3.4 Hz, 1H), 3.80 (dd,

J¼11.5, 3.4 Hz,1H), 3.72 (t, J¼11.5 Hz,1H), 3.31 (s, 3H), 3.31e3.27 (m,

1H), 3.27 (s, 3H), 2.99 (br d, J¼1.9 Hz, 1H), 2.66 (dd, J¼13.2, 10.7 Hz,

1H), 1.31 (s, 3H), 1.29 (s, 3H), 1.28 (d, J¼7.1 Hz, 3H); ¹³C NMR

(hexane/EtOAc¼2:1); ½a _D²³

ꢂ

þ74.1 (c 0.62, CHCl₃); IR (neat) 2946,

(100 MHz, CDCl₃)

d

184.5, 179.0, 135.2, 129.3, 129.0, 127.4, 99.1, 98.1,

1724 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d 9.73 (s, 1H), 7.32e7.22 (m,

71.7, 69.9, 65.6, 62.0, 60.1, 48.3, 48.1, 38.0, 37.7,18.0,17.6,10.5; HRMS

(ESI-TOF) calcd for C₂₂H₃₁NO₇SNa (MþNa)^þ476.1719, found

476.1718.

5H), 4.46 (d, J¼11.2 Hz, 1H), 4.34 (d, J¼11.2 Hz, 1H), 3.97e3.92 (m,

2H), 3.77e3.74 (m, 1H), 3.68e3.60 (m, 1H), 3.25 (s, 3H), 3.24 (s, 3H),

2.83 (qd, J¼7.1, 1.6 Hz, 1H), 1.27 (s, 3H), 1.26 (s, 3H), 1.18 (d, J¼7.1 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃)

d 203.4, 137.4, 128.4, 127.8, 127.7,

4.1.11. Benzylidene acetal 21. To a solution of oxazolidinethione 20

(22.5 g, 49.6 mmol) in CH₂Cl₂(20 mL) and MeOH (80 mL) was

added NaBH₄(2.06 g, 54.6 mmol) at 0 ^ꢁC. After the mixture was

stirred for 10 min at the same temperature, the reaction was

quenched with acetone (10 mL). The solvent was removed under

the reduced pressure and the residue was diluted with EtOAc

(100 mL), washed with H₂O (30 mL) and brine (30 mL), and then

dried over Na₂SO₄. Concentration gave the corresponding diol

99.5, 98.0, 77.5, 73.1, 66.7, 62.0, 48.3, 48.1, 17.8, 17.6, 7.6; HRMS (ESI-

TOF) calcd for C₁₉H₂₈O₆Na (MþNa)^þ375.1783, found 375.1790.

4.1.13. Alcohol 24. To a solution of dithiane 23 (791 mg, 2.71 mmol)

in THF (6.0 mL) was added n-BuLi (1.59 M in hexane, 1.7 mL,

2.71 mmol) at ꢀ15 ^ꢁC. After the mixture was stirred for 20 min at

the same temperature, the mixture was cooled down to ꢀ78 ^ꢁC. To

the mixture was added aldehyde 22 (318 mg, 0.902 mmol) in THF

(1.8 mLþ0.6 mLþ0.6 mL) at ꢀ78 ^ꢁC. After the resulting mixture was

allowed to warm up to ꢀ20 ^ꢁC for 35 min, the reaction was

quenched with saturated aqueous NH₄Cl (5.0 mL). The mixture was

diluted with EtOAc (50 mL), washed with H₂O (20 mL) and brine

(20 mL), and then dried over Na₂SO₄. Concentration and column

chromatography (hexane/EtOAc¼20:1, 10:1) gave alcohol 24

(542 mg, 93%) as a 4:1 diastereomixture: colorless oil; R_f¼0.24

(11.1 g, 84%): light yellow oil; R_f¼0.10 (hexane/EtOAc¼1:1); ½a _D²²

ꢂ

þ134 (c 1.65, CHCl₃); IR (neat) 3436, 2949 cm^ꢀ1; ¹H NMR (400 MHz,

CDCl₃)

d

3.88 (dd, J¼8.8, 5.1 Hz,1H), 3.81 (dd, J¼8.4, 2.4 Hz,1H), 3.79

(dd, J¼10.5, 3.9 Hz, 1H), 3.72e3.68 (m, 3H), 3.27 (s, 3H), 3.25 (s, 3H),

2.19 (br s, 2H), 2.05e2.01 (m, 1H), 1.27 (s, 3H), 1.26 (s, 3H), 1.01 (d,

J¼7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 99.1, 97.9, 74.7, 67.9, 67.0,

61.7, 48.2, 48.0, 34.8, 17.9, 17.7, 10.0; HRMS (ESI-TOF) calcd for

C₁₂H₂₄O₆Na (MþNa)^þ287.1471, found 287.1458.

(hexane/EtOAc¼4:1); ¹H NMR (400 MHz, CDCl₃)

d 7.31e7.21 (m,

To a solution of the diol obtained above (9.30 g, 35.1 mmol) in

CH₂Cl₂(85 mL) were added PhCH(OMe)₂(5.8 mL, 38.6 mmol) and

CSA (815 mg, 3.51 mmol) at room temperature. After the mixture

was stirred for 5 h at same temperature, the reaction was quenched

with Et₃N (3.0 mL). Concentration and column chromatography

(hexane/EtOAc¼40:1) gave benzylidene acetal 21 (10.2 g, 82%):

5H), 4.75e4.53 (m, 2H), 4.28e4.25 (m, 1H), 4.11e4.03 (m, 1H),

3.81e3.68 (m, 2H), 3.59e3.56 (m, 2H), 3.49e3.44 (m, 4H),

3.32e3.22 (m, 8H), 2.85e2.69 (m, 2H), 2.57e2.52 (m, 1H),

2.23e2.19 (m, 1H), 1.93e1.65 (m, 3H), 1.28e1.24 (m, 6H), 1.08 (d,

J¼7.3 Hz, 3H), 0.88 (s, 9H), 0.04e0.03 (m, 6H); ¹³C NMR (100 MHz,

CDCl₃)

d 138.6, 128.1, 127.9, 127.4, 99.2, 97.9, 84.8, 72.7, 69.8, 68.0,

colorless oil; R_f¼0.47 (hexane/EtOAc¼4:1); ½a _D²¹

ꢂ

þ96.8 (c 0.54,

63.2, 61.3, 60.5, 48.5, 48.0, 35.2, 34.3, 31.4, 28.2, 26.0, 25.8, 25.3,

24.4, 18.0, 17.7, 14.3, 11.2, ꢀ5.2; HRMS (ESI-TOF) calcd for

C₃₂H₅₆O₇S₂SiNa (MþNa)^þ667.3135, found 667.3137.

CHCl₃); IR (neat) 2925 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.42e7.27

(m, 5H), 5.45 (s, 1H), 4.10e3.99 (m, 3H), 3.91 (dd, J¼9.3, 2.2 Hz, 1H),

3.73 (dd, J¼11.5, 3.4 Hz, 1H), 3.65 (t, J¼11.5 Hz, 1H), 3.34 (s, 3H), 3.27

(s, 3H), 1.97e1.92 (m, 1H), 1.30 (s, 3H), 1.28 (s, 3H), 1.25 (d, J¼6.8 Hz,

4.1.14. Ketone 8. To a solution of dithiane 24 (61.0 mg, 93.0 mmol) in

3H); ¹³C NMR (100 MHz, CDCl₃)

d

138.4, 128.7, 128.1, 125.9, 101.7,

CH₃CN (1.5 mL) and saturated aqueous NaHCO₃(0.5 mL) was added

I₂(94.4 mg, 0.372 mmol) at 0 ^ꢁC. After the mixture was stirred for

10 min at the same temperature, the mixture was diluted with Et₂O

(10 mL), and then quenched with saturated aqueous Na₂S₂O₃and

NaHCO₃(3.0 mL). The mixture was diluted with EtOAc (30 mL),

washed with brine (10 mL), and dried over Na₂SO₄. Concentration

and column chromatography (hexane/EtOAc¼4:1) gave ketone 8

(50.2 mg, 97%) as a diastereomixture: yellow oil; R_f¼0.31 (hexane/

98.9, 98.2, 80.4, 73.8, 65.0, 62.4, 48.7, 48.1, 28.5, 18.0, 17.8, 11.6;

HRMS (ESI-TOF) calcd for C₁₉H₂₈O₆Na (MþNa)^þ375.1783, found

375.1768.

4.1.12. Aldehyde 22. To a solution of benzylidene acetal 21 (7.68 g,

21.7 mmol) in CH₂Cl₂(54 mL) was added DIBAL-H (1.02 M in hex-

ane, 43 mL, 43.4 mmol) at 0 ^ꢁC. After the mixture was stirred for

28 h at room temperature, the reaction was quenched with MeOH

(20 mL). Subsequently, to the mixture was added a Celite. After the

mixture was stirred for 30 min at room temperature, the insoluble

material was ﬁltered off through a Celite pad. Concentration and

column chromatography (hexane/EtOAc¼4:1, 1:1) gave the corre-

sponding alcohol (7.49 g, 97%): colorless oil; R_f¼0.29 (hexane/

EtOAc¼4:1); ¹H NMR (400 MHz, CDCl₃)

d 7.36e7.23 (m, 5H),

4.72e4.55 (m, 2H), 4.38 (br s, 1H), 4.19e4.14 (m, 1H), 4.04e3.85 (m,

1H), 3.68e3.51 (m, 5H), 3.28e3.21 (m, 6H), 2.58e2.41 (m, 2H),

2.36e2.28 (m, 1H), 1.83e1.74 (m, 2H), 1.29e1.27 (m, 6H), 0.86e0.82

(m, 12H), 0.02e0.00 (m, 6H); ¹³C NMR (100 MHz, CDCl₃)

d

211.6,

138.4, 128.3, 128.1, 127.7, 127.6, 99.3, 98.0, 81.2, 77.9, 73.9, 73.9, 68.6,

2254

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

62.0, 60.6, 48.1, 48.0, 37.9, 34.7, 27.0, 26.8, 26.0, 18.0, 17.6, 9.4, ꢀ5.3;

HRMS (ESI-TOF) calcd for C₂₉H₅₀O₈SiNa (MþNa)^þ577.3173, found

577.3146.

gave alkene 26 (838 mg, 57%): light yellow oil; R_f¼0.48 (hexane/

EtOAc¼7:1); ½a ²_D⁴

ꢂ

ꢀ29.4 (c 0.20, CHCl₃); IR (neat) 2930, 1653 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

7.33e7.30 (m, 5H), 5.06 (d, J¼1.5 Hz,

1H), 4.83 (d, J¼2.0 Hz, 1H), 4.64 (d, J¼11.1 Hz, 1H), 4.57 (d, J¼11.1 Hz,

1H), 3.92e3.75 (m, 5H), 3.10 (t, J¼9.4 Hz, 1H), 2.79e2.75 (m, 1H),

2.17e1.90 (m, 4H), 1.16 (d, J¼6.6 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H),

4.1.15. Spiroacetal 25. To a solution of ketone 8 (3.80 g, 6.84 mmol)

in CH₂Cl₂(230 mL) and H₂O (1.2 mL) was added TfOH (1.2 mL,

13.7 mmol) in CH₂Cl₂(5.0 mL) at ꢀ15 ^ꢁC. The resulting mixture was

allowed to warm up to 0 ^ꢁC for 25 min. After the mixture was

stirred for 80 min at 0 ^ꢁC, the reaction was quenched with Et₃N

(5.0 mL). The solvent was removed under the reduced pressure. The

residue was diluted with EtOAc (100 mL), washed with H₂O (30 mL)

and brine (30 mL), and then dried over Na₂SO₄. Concentration and

column chromatography (hexane/EtOAc¼3:1, 1:1) gave spiroacetal

25 (2.00 g, 95%) as a diastereomixture: yellow oil; R_f¼0.25 (hexane/

0.03 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 147.8, 138.9, 128.6, 128.1,

127.8, 107.1, 106.6, 81.3, 74.4, 74.1, 67.2, 63.4, 40.0, 34.1, 26.3, 23.9,

18.8, 14.7, ꢀ4.5, ꢀ4.9; HRMS (ESI-TOF) calcd for C₂₄H₃₈O₄SiNa

(MþNa)^þ441.2437, found 441.2460.

4.1.17. Alkane 27. A mixture of alkene 26 (13.6 mg, 33.6 mmol) and

5% Pd/C (5.0 mg) in EtOAc (2.0 mL) was stirred for 3 h under H₂

atmosphere at room temperature. The catalyst was ﬁltered off.

Concentration and column chromatography (hexane/EtOAc¼60:1)

gave alkane 27 (10.8 mg, 77%): colorless oil; R_f¼0.37 (hexane/

EtOAc¼1:1); ¹H NMR (400 MHz, CDCl₃)

d 7.33e7.27 (m, 5H),

4.61e4.59 (m, 2H), 3.95e3.91 (m, 2H), 3.81e3.68 (m, 3H), 3.20e3.13

(m, 2H), 2.44e2.17 (m, 1H), 1.90e1.75 (m, 4H), 1.54 (br s, 2H),

EtOAc¼10:1); ½a _D²³

ꢂ

ꢀ55.9 (c 0.16, CHCl₃); IR (neat) 2928 cm^ꢀ1

;

¹H

1.20e1.14 (m, 3H); ¹³C NMR (100 MHz, CDCl₃)

d

138.0, 128.4, 127.8,

NMR (400 MHz, CDCl₃)

d

7.33e7.29 (m, 5H), 4.61 (d, J¼11.0 Hz, 1H),

127.8, 127.7, 107.4, 106.9, 78.3, 75.7, 75.3, 74.4, 74.2, 73.7, 73.4, 73.0,

68.6, 68.3, 62.5, 62.4, 41.7, 37.7, 35.0, 33.7, 24.3, 23.8, 14.6, 14.0;

HRMS (ESI-TOF) calcd for C₁₇H₂₄O₅Na (MþNa)^þ331.1521, found

331.1520.

4.54 (d, J¼11.0 Hz, 1H), 3.89e3.81 (m, 3H), 3.72 (dd, J¼11.5, 1.7 Hz,

1H), 3.59e3.55 (m, 1H), 3.38 (t, J¼9.8 Hz, 1H), 2.37e2.32 (m, 1H),

2.03e1.69 (m, 4H), 1.62e1.53 (m, 1H), 0.99 (d, J¼6.8 Hz, 3H), 0.93 (d,

J¼7.1 Hz, 3H), 0.90 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃)

d 138.9, 128.2, 127.8, 127.4, 108.6, 75.5, 74.1, 74.0,

4.1.16. Alkene 26. To a solution of diol 25 (1.89 g, 6.03 mmol) in

CH₂Cl₂(21 mL) were added imidazole (738 mg, 10.9 mmol) and

TBSCl (1.18 g, 7.84 mmol) at 0 ^ꢁC. After the resulting mixture was

stirred for 15 min at the same temperature, the reaction was

quenched with MeOH (5.0 mL). The mixture was diluted with

EtOAc (50 mL), washed with H₂O (20 mL) and brine (20 mL), and

then dried over Na₂SO₄. Concentration and column chromatogra-

phy (hexane/EtOAc¼20:1, 8:1) gave the corresponding silyl ether

(1.72 g, 67%) as a diastereomixture: yellow oil; R_f¼0.52 (hexane/

66.7, 63.0, 42.0, 35.6, 35.3, 26.0, 23.4, 18.4, 15.6, 10.4, ꢀ4.9, ꢀ5.2;

HRMS (ESI-TOF) calcd for C₂₄H₄₀O₄SiNa (MþNa)^þ443.2594, found

443.2581.

4.1.18. Aldehyde 28. To a solution of alkene 26 (1.85 g, 4.41 mmol)

in THF (22 mL) was added BH₃$SMe₂(0.84 mL, 8.82 mmol) at 0 ^ꢁC.

After the mixture was stirred for 1 h at room temperature, to the

mixture were added 3 M aqueous NaOH (7.0 mL) and 30% aqueous

H₂O₂(3.5 mL) at 0 ^ꢁC. After the resulting mixture was stirred for

35 min at room temperature, the reaction was quenched with

saturated aqueous Na₂SO₃(10 mL). The mixture was diluted with

EtOAc (40 mL), washed with H₂O (10 mL) and brine (10 mL), and

then dried over Na₂SO₄. Concentration and column chromatogra-

phy (hexane/EtOAc¼10:1, 5:1) gave the corresponding alcohol

(1.66 g, 86%) as a 2:1 diastereomixture: colorless oil; R_f¼0.26

EtOAc¼2:1); ¹H NMR (400 MHz, CDCl₃)

d 7.33e7.23 (m, 5H),

4.69e4.54 (m, 2H), 3.93e3.56 (m, 5H), 3.45e3.10 (m, 2H), 2.19e1.76

(m, 5H), 1.25e1.12 (m, 4H), 0.90e0.85 (m, 9H), 0.06e0.02 (m, 6H);

¹³C NMR (100 MHz, CDCl₃)

d 138.5, 128.3, 127.9, 127.8, 127.6, 106.7,

78.1, 75.7, 75.1, 74.3, 74.1, 73.8, 73.7, 68.4, 68.1, 62.7, 41.8, 37.6, 35.0,

33.6, 29.8, 26.0, 24.3, 23.8, 18.5, 14.7, 14.1, ꢀ4.8, ꢀ4.9, ꢀ5.1; HRMS

(ESI-TOF) calcd for C₂₃H₃₈O₅SiNa (MþNa)^þ445.2386, found

445.2386.

(hexane/EtOAc¼4:1); ¹H NMR (400 MHz, CDCl₃)

d 7.34e7.25 (m,

5H), 4.72e4.58 (m, 2H), 3.93e3.82 (m, 5H), 3.77e3.20 (m, 3H),

2.96e2.62 (m, 1H), 2.51e2.22 (m, 1H), 2.13e1.76 (m, 4H), 1.63e1.47

(m, 1H), 1.16e1.09 (m, 3H), 0.90e0.90 (m, 9H), 0.05e0.05 (m, 6H);

To

0.248 mmol) and MS 4 A (50.0 mg) in CH₂Cl₂(2.0 mL) were added

TPAP (4.2 mg, 12.0

mol) and NMO (34.9 mg, 0.298 mmol) at 0 ^ꢁC.

a solution of the alcohol obtained above (105 mg,

ꢀ

m

¹³C NMR (100 MHz, CDCl₃)

d 132.5, 132.4, 128.3, 127.6, 127.5, 102.9,

The mixture was stirred for 2 h at room temperature. Short column

chromatography (hexane/EtOAc¼1:1) and puriﬁcation by column

chromatography (hexane/EtOAc¼50:1) gave the corresponding

ketone (88.0 mg, 84%): colorless oil; R_f¼0.66 (hexane/EtOAc¼4:1);

74.6, 74.5, 73.6, 66.8, 66.7, 62.7, 61.4, 59.3, 47.7, 35.4, 35.2, 29.8, 26.0,

23.3, 18.0, 15.6, ꢀ5.1, ꢀ5.3; HRMS (ESI-TOF) calcd for C₂₄H₄₀O₅SiNa

(MþNa)^þ459.2543, found 459.2552.

To a solution of the alcohol obtained above (1.87 g, 4.28 mmol)

½

a ²_D³

ꢂ

ꢀ21.4 (c 0.25, CHCl₃); IR (neat) 2930, 1733 cm^ꢀ1

;

¹H NMR

and MS 4 A (1.00 g) in CH₂Cl₂(30 mL) were added TPAP (30.0 mg,

ꢀ

(400 MHz, CDCl₃)

d

7.34e7.26 (m, 5H), 4.71 (d, J¼11.0 Hz, 1H), 4.59

86.0 m

mol) and NMO (602 mg, 5.14 mmol) at 0 ^ꢁC. The mixture was

(d, J¼11.0 Hz, 1H), 4.03e3.87 (m, 5H), 3.45 (t, J¼10.8 Hz, 1H), 2.99

(dq, J¼10.8, 6.6 Hz, 1H), 2.50 (dt, J¼13.2, 8.7 Hz, 1H), 2.08e1.97 (m,

1H), 1.95e1.85 (m, 1H), 1.77 (ddd, J¼13.2, 8.1, 4.8 Hz, 1H), 1.17 (d,

J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); ¹³C NMR

stirred for 2 h at room temperature. Short column chromatography

(hexane/EtOAc¼4:1) and puriﬁcation by column chromatography

(hexane/EtOAc¼40:1, 1:1) gave aldehyde 28 (1.52 g, 81%) as a dia-

stereomixture: colorless oil; R_f¼0.35 (hexane/EtOAc¼7:1); ¹H NMR

(100 MHz, CDCl₃)

d

200.9, 138.0, 128.4, 127.9, 127.8, 106.4, 80.4, 74.4,

(400 MHz, CDCl₃) d 9.77e9.38 (m, 1H), 7.33e7.26 (m, 5H),

74.2, 69.3, 62.3, 47.7, 31.3, 26.0, 24.5, 18.5, 10.5, ꢀ4.9, ꢀ5.2; HRMS

(ESI-TOF) calcd for C₂₃H₃₆O₅SiNa (MþNa)^þ443.2230, found

443.2263.

4.73e4.56 (m, 2H), 3.94e3.20 (m, 6H), 2.52e2.24 (m, 2H), 2.11e1.59

(m, 4H), 1.04e0.95 (m, 3H), 0.90e0.90 (m, 9H), 0.05e0.04 (m, 6H);

¹³C NMR (100 MHz, CDCl₃)

d 203.2, 202.8, 138.4, 135.2, 128.3, 127.8,

To a solution of the ketone obtained above (1.46 g, 3.49 mmol) in

toluene (28 mL) was added Cp₂TiMe₂(1.56 M in THF freshly pre-

pared, 6.7 mL, 10.5 mmol) at room temperature. Subsequently, the

resulting mixture was allowed to warm up to 90 ^ꢁC. After the

mixture was stirred for 20 h at the same temperature, the mixture

was diluted with hexane (50 mL). The insoluble material was ﬁl-

tered off through a Celite pad. Concentration and short column

chromatography (hexane/EtOAc¼5:1) gave the crude alkene. Puri-

ﬁcation by column chromatography (hexane/EtOAc¼100:1, 50:1)

127.7, 127.6, 104.9, 104.4, 78.0, 75.7, 74.5, 74.4, 73.7, 67.6, 66.7, 62.7,

62.6, 61.7, 60.5, 35.5, 33.6, 29.8, 26.0, 23.9, 23.5, 18.5, 18.4, 16.5, 15.6,

ꢀ4.8, ꢀ5.1, ꢀ5.2, ꢀ5.5; HRMS (ESI-TOF) calcd for C₂₄H₃₈O₅SiNa

(MþNa)^þ457.2386, found 457.2379.

4.1.19. Aldehyde 29. To

0.544 mmol,

1.09 mmol) at room temperature. The mixture was stirred for 24 h

a solution of aldehyde 28 (236 mg,

¼2:1) in CH₂Cl₂(5.0 mL) was added DBU (0.16 mL,

a

/b

at 30 ^ꢁC. Short column chromatography (hexane/EtOAc¼60:1) and

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2255

puriﬁcation by column chromatography (hexane/EtOAc¼40:1)

gave aldehyde 29 (186 mg, 79%) and aldehyde 28 (35.2 mg, 15%

temperature for 20 min, and cooled to ꢀ78 ^ꢁC. To the mixture were

added TMSCl (9.4 mL, 74.5 mmol) and

a,b-unsaturated ester 31

recovery,

To a solution of the recovered aldehyde 28 (35.2 mg, 81.0

L, 0.160 mmol) at

a

/b

¼1:1).

(1.99 g, 6.21 mmol) in THF (9.0 mLþ4.0 mLþ2.0 mL) at ꢀ78 ^ꢁC. The

reaction mixture was stirred for 11 h at ꢀ78 ^ꢁC, and the reaction

was quenched with a 1:1 solution of 25% NH₄OH/saturated aqueous

NH₄Cl (20 mL). The mixture was diluted with Et₂O (100 mL) and

warmed to room temperature. The mixture was washed with sat-

urated aqueous NH₄Cl (30 mL) and brine (30 mL), and dried over

Na₂SO₄. Concentration and column chromatography (hexane/

EtOAc¼10:1, 4:1) gave ester 32 (2.07 g), which was used for the

next step without further puriﬁcation.

mmol,

a

/

b

¼1:1) in CH₂Cl₂(1.0 mL) was added DBU (24

m

room temperature. The mixture was stirred for 24 h at 30 ^ꢁC. Short

column chromatography (hexane/EtOAc¼5:1) and puriﬁcation by

column chromatography (hexane/EtOAc¼40:1) gave aldehyde 29

(32.3 mg, 92%, total: 219 mg, 93%): colorless oil; R_f¼0.53 (hexane/

EtOAc¼4:1); ½a ²_D⁵

ꢂ

ꢀ64.1 (c 0.36, CHCl₃); IR (neat) 2929, 1724 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

9.38 (d, J¼4.9 Hz, 1H), 7.33e7.27 (m,

5H), 4.71 (d, J¼11.0 Hz, 1H), 4.58 (d, J¼11.0 Hz, 1H), 3.91e3.70 (m,

5H), 3.20 (t, J¼9.9 Hz, 1H), 2.52e2.42 (m, 1H), 2.23 (dd, J¼11.8,

4.9 Hz, 1H), 2.04e1.73 (m, 4H), 0.96 (d, J¼6.6 Hz, 3H), 0.90 (s, 9H),

To a solution of ester 32 obtained above (2.07 g) in THF (40 mL)

at ꢀ78 ^ꢁC was added KHMDS (0.5 M in toluene, 25 mL, 12.4 mmol).

After the mixture was stirred at ꢀ78 ^ꢁC for 35 min, to the mixture

was added MeI (1.9 mL, 31.1 mmol). After the mixture was stirred

for 3 h at ꢀ78 ^ꢁC, the reaction was quenched with a solution of

saturated aqueous NH₄Cl/MeOH (20 mL). The mixture was diluted

with EtOAc (100 mL), washed with H₂O (30 mL) and brine (30 mL),

and then dried over Na₂SO₄. Concentration and column chroma-

tography (hexane/EtOAc¼10:1) gave ester 33 (2.08 g, 96% in two

0.05 (s, 3H), 0.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 202.8, 138.4,

128.3, 127.8, 127.6, 104.9, 78.0, 74.4, 73.7, 67.6 62.7, 60.5, 35.5, 33.6,

26.0, 23.5, 18.5, 16.5, ꢀ4.8, ꢀ5.1; HRMS (ESI-TOF) calcd for

C₂₄H₃₈O₅SiNa (MþNa)^þ457.2386, found 457.2391.

4.1.20. Alcohol 7 transformed from 29. To a solution of aldehyde 29

(1.15 g, 2.63 mmol) in MeOH (20 mL) was added NaBH₄(99.0 mg,

2.63 mmol) at 0 ^ꢁC. After the mixture was stirred for 15 min at the

same temperature, the reaction was quenched with acetone

(5.0 mL). The solvent was removed under the reduced pressure. The

residue was diluted with EtOAc (100 mL), washed with H₂O (20 mL)

and brine (20 mL), and then dried over Na₂SO₄. Concentration gave

the crude alcohol, which was used for the next step without further

puriﬁcation.

To a solution of the alcohol obtained above in benzene (25 mL)

were added imidazole (716 mg, 10.5 mmol), PPh₃(2.07 g,

7.89 mmol), and I₂(1.34 g, 5.26 mmol) at room temperature. After

the resulting mixture was stirred for 2 h at 35 ^ꢁC, the reaction was

quenched with saturated aqueous Na₂S₂O₃(10 mL). The mixture

was diluted with EtOAc (100 mL), washed with H₂O (30 mL) and

brine (30 mL), and then dried over Na₂SO₄. The solvent was re-

moved under the reduced pressure. The residue was diluted with

hexane/Et₂O (5:1). The insoluble material was ﬁltered off. Con-

centration gave the crude iodide, which was used for the next step

without further puriﬁcation.

steps): light yellow oil; R_f¼0.50 (hexane/EtOAc¼4:1); ½a _D²⁴

ꢀ8.4 (c

ꢂ

0.70, CHCl₃); IR (neat) 2983, 1730 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

7.35e7.22 (m, 5H), 4.74 (d, J¼11.5 Hz, 1H), 4.58 (d, J¼11.5 Hz, 1H),

4.23 (dt, J¼7.6, 6.2 Hz, 1H), 4.09e3.99 (m, 3H), 3.75 (t, J¼7.6 Hz, 1H),

3.27 (t, J¼5.8 Hz, 1H), 2.73e2.64 (m, 1H), 2.32e2.19 (m, 1H), 1.43 (s,

3H), 1.35 (s, 3H), 1.20 (t, J¼6.6 Hz, 3H), 1.08 (d, J¼7.1 Hz, 3H), 0.92 (d,

J¼6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 176.3, 138.5, 128.2, 127.7,

127.4, 108.9, 81.9, 77.6, 73.5, 66.2, 60.3, 40.0, 36.8, 26.6, 25.6, 14.3,

13.2, 12.6; HRMS (ESI-TOF) calcd for C₂₀H₃₀O₅Na (MþNa)^þ

373.1991, found 373.1994.

4.1.22. Alcohol 35. To a solution of ester 33 (4.48 g, 12.8 mmol) in

CH₂Cl₂(40 mL) was added DIBAL-H (1.02 M in hexane, 28 mL,

28.2 mmol) at ꢀ78 ^ꢁC. After the resulting solution was stirred for

2 h at ꢀ20 ^ꢁC, the reaction was quenched with MeOH (20 mL).

Subsequently, to the resulting mixture was added a Celite, and the

mixture was allowed to warm up to room temperature. The in-

soluble material was ﬁltered through a Celite pad. Concentration

gave the corresponding alcohol, which was used for the next step

without further puriﬁcation.

To a solution of the alcohol obtained above and Et₃N (5.4 mL,

38.4 mmol) in CH₂Cl₂(30 mL) and DMSO (10 mL) was added

SO₃$pyr (3.87 g, 25.6 mmol) at 0 ^ꢁC. After the mixture was stirred

for 14 h at room temperature, the reaction mixture was diluted

with Et₂O (100 mL). The mixture was washed with H₂O (30 mL) and

brine (30 mL), and dried over Na₂SO₄. Concentration gave the

corresponding aldehyde, which was used for the next step without

further puriﬁcation.

To a solution of the iodide obtained above in Et₂O (25 mL) was

added t-BuLi (1.58 M in pentane, 5.0 mL, 7.89 mmol) at ꢀ78 ^ꢁC.

After the resulting mixture was stirred for 10 min at the same

temperature, the reaction was quenched with MeOH (10 mL). The

mixture was diluted with EtOAc (100 mL), washed with H₂O

(20 mL) and brine (20 mL), and then dried over Na₂SO₄. Concen-

tration gave alkane 30, which was used for the next step without

further puriﬁcation.

To a solution of silyl ether 30 obtained above in THF (20 mL) was

added TBAF (1.0 M in THF, 4.0 mL, 4.00 mmol) at room temperature.

The reaction mixture was stirred for 4 h at 45 ^ꢁC. The mixture was

diluted with EtOAc (80 mL), washed with H₂O (20 mL) and brine

(20 mL), and then dried over Na₂SO₄. Concentration and column

chromatography (hexane/EtOAc¼7:1, 3:1) gave alcohol 7 (757 mg,

To a solution of alkyne 34 (10.3 g, 35.0 mmol) in THF (30 mL) was

added n-BuLi (1.65 M in hexane, 20 mL, 33.3 mmol) at 0 ^ꢁC. The

resulting mixture was stirred for 20 min at the same temperature,

and then cooled down to ꢀ78 ^ꢁC. To the reaction mixture was

added the aldehyde obtained above in THF (8.0 mLþ1.0 mLþ1.0 mL)

at ꢀ78 ^ꢁC. After the mixture was stirred for 3 h at the same tem-

perature, the reaction was quenched with a 1:1 solution of satu-

rated aqueous NH₄Cl/MeOH (20 mL). The mixture was diluted with

EtOAc (100 mL), washed with H₂O (30 mL) and brine (30 mL), and

dried over Na₂SO₄. Concentration and column chromatography

(hexane/EtOAc¼20:1, 8:1, 4:1) gave alcohol 35 (6.68 g, 87% in three

steps) as a 1:1 diastereomixture: colorless oil; R_f¼0.29 (hexane/

94% in four steps): colorless oil; R_f¼0.20 (hexane/EtOAc¼4:1); ½a _D²⁶

ꢂ

ꢀ67.4 (c 0.36, CHCl₃); IR (neat) 3473, 2971 cm^ꢀ1

;

¹H NMR

(400 MHz, C₆D₆)

d

7.32e7.09 (m, 5H), 4.65 (d, J¼11.5 Hz,1H), 4.51 (d,

J¼11.5 Hz, 1H), 3.91 (dt, J¼9.8, 3.4 Hz, 1H), 3.79 (br s, 2H), 3.68e3.62

(m, 2H), 3.10 (t, J¼9.8 Hz, 1H), 2.01e1.91 (m, 1H), 1.71e1.65 (m, 4H),

1.46e1.31 (m, 2H), 0.99 (d, J¼6.3 Hz, 3H), 0.84 (d, J¼6.6 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃) d 138.4, 128.3, 127.7, 127.6, 108.3, 79.5, 73.8,

72.6, 67.6, 62.9, 42.4, 39.3, 35.0, 24.5, 15.7, 13.5; HRMS (ESI-TOF)

EtOAc¼4:1); IR (neat) 3436, 2931 cm^ꢀ1

;

¹H NMR (400 MHz, C₆D₆)

d 7.80e7.77 (m, 4H), 7.40e7.38 (m, 2H), 7.23e7.06 (m, 9H),

calcd for C₁₈H₂₆O₄Na (MþNa)^þ329.1729, found 329.1730.

4.94e4.89 (m, 1H), 4.58e4.54 (m, 1H), 4.39e4.27 (m, 3H),

4.07e3.98 (m, 2H), 3.63e3.57 (m, 1H), 3.25e3.16 (m, 1H), 2.16e1.93

(m, 2H), 1.45 (s, 1.5H), 1.44 (s, 1.5H), 1.36 (s, 3H), 1.15 (s, 9H), 1.10 (d,

J¼6.8 Hz, 3H), 0.98 (d, J¼7.1 Hz, 1.5H), 0.86 (t, J¼7.1 Hz, 1.5H); ¹³C

4.1.21. Ester 33. To a suspension of CuI (3.49 g, 18.6 mmol) in THF

(25 mL) at ꢀ15 ^ꢁC was added MeLi$LiBr (1.5 M in Et₂O, 25 mL,

37.3 mmol). The resulting solution was stirred at the same

2256

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

NMR (100 MHz, C₆D₆)

d

136.0, 130.1, 128.4, 109.2, 86.5, 85.1, 84.7,

Concentration gave hydroxy ketone 38 (2.00 g), which was used for

the next step without further puriﬁcation.

84.2, 79.3, 74.5, 66.8, 66.7, 66.6, 53.0, 44.8, 39.7, 39.5, 35.8, 34.3, 27.1,

26.2, 19.5, 14.0, 12.5; HRMS (ESI-TOF) calcd for C₃₇H₄₈O₅SiNa

(MþNa)^þ623.3169, found 623.3174.

To a solution of hydroxy ketone 38 obtained above (2.00 g) in

CH₃CN (35 mL) and AcOH (35 mL) was added NaBH(OAc)₃(6.08 g,

28.7 mmol) at ꢀ15 ^ꢁC. After the mixture was stirred for 1 h at the

same temperature, the reaction was quenched with acetone

(20 mL). The mixture was diluted with EtOAc (200 mL), washed

with saturated aqueous NaHCO₃(50 mL), H₂O (50 mL), and brine

(50 mL), and then dried over Na₂SO₄. Concentration and column

chromatography (hexane/EtOAc¼1:1) gave diol 39 (1.53 g, 74% in

ﬁve steps): white needle; mp 114e117 ^ꢁC (hexane); R_f¼0.11 (hex-

4.1.23. Spiroacetal 37. To

a solution of alcohol 35 (8.23 g,

13.7 mmol) and Et₃N (5.7 mL, 41.1 mmol) in CH₂Cl₂(40 mL) and

DMSO (10 mL) was added SO₃$pyr (4.14 g, 27.4 mmol) at 0 ^ꢁC, and

the mixture was stirred for 1 h at room temperature. To the mixture

were added Et₃N (2.9 mL, 20.5 mmol) and SO₃$pyr (2.07 g,

13.7 mmol) at 0 ^ꢁC. After the mixture was further stirred for 1 h at

room temperature, the reaction mixture was diluted with EtOAc

(300 mL). The solution was washed with H₂O (100 mL) and brine

(100 mL), and dried over Na₂SO₄. Concentration and column

chromatography (hexane/EtOAc¼15:1) gave the corresponding

ynone (7.17 g), which was used for the next step without further

puriﬁcation.

A mixture of the ynone obtained above (7.17 g) and 5% Pd/C

(720 mg) in EtOAc (120 mL) was stirred for 2 h under H₂atmo-

sphere at room temperature. The catalyst was ﬁltered off. Con-

centration gave ketone 36, which was used for the next step

without further puriﬁcation.

ane/EtOAc¼1:1); ½a _D²²

ꢂ

ꢀ60.2 (c 1.29, CHCl₃); IR (neat) 3401,

3.91e3.81 (m, 2H), 3.74 (d,

2975 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

J¼4.4 Hz, 2H), 3.60 (dt, J¼9.6, 4.4 Hz, 1H), 3.15 (t, J¼9.6 Hz, 1H),

2.30e2.25 (br s, 2H), 2.10e1.90 (m, 2H), 1.83e1.74 (m, 2H),

1.58e1.47 (m, 2H), 1.03 (d, J¼5.9 Hz, 3H), 0.89 (d, J¼6.3 Hz, 3H); ¹³C

NMR (100 MHz, CDCl₃) d 108.3, 73.0, 72.6, 67.7, 63.6, 42.0, 40.4, 35.0,

24.5, 15.4, 13.4; HRMS (ESI-TOF) calcd for C₁₁H₂₀O₄Na (MþNa)^þ

239.1259, found 239.1258.

4.1.25. Benzylidene acetal 40. To a solution of diol 39 (2.88 g,

13.3 mmol) in CH₂Cl₂(134 mL) were added PhCH(OMe)₂(2.4 mL,

16.8 mmol) and CSA (622 mg, 2.68 mmol) at room temperature.

After the mixture was stirred for 2 h at the same temperature, the

reaction was quenched with Et₃N (3.0 mL). Concentration and

column chromatography (hexane/EtOAc¼50:1, 30:1) gave benzy-

lidene acetal 40 (4.11 g, quant): colorless amorphous solid; R_f¼0.24

To a solution of ketone 36 obtained above in MeOH (40 mL) was

added CSA (829 mg, 3.57 mmol) at room temperature. After the

mixture was stirred for 3 h at 40 ^ꢁC, the reaction was quenched with

Et₃N (3.0 mL). Concentration and column chromatography (hex-

ane/EtOAc¼7:1, 5:1) gave spiroacetal 37 (3.17 g, 76% in three steps):

colorless oil; R_f¼0.30 (hexane/EtOAc¼2:1); ½a _D²⁵

ꢂ

ꢀ73.0 (c 1.25,

(hexane/EtOAc¼20:1);

½

a ²_D⁴

ꢂ

ꢀ39.9 (c 0.45, CHCl₃); IR (neat)

CHCl₃); IR (neat) 3445, 2971 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

2970 cm^ꢀ^{1 1}H NMR (400 MHz, CDCl₃)

;

d

7.50e7.46 (m, 2H),

d

7.36e7.24 (m, 5H), 4.59 (d, J¼11.5 Hz, 1H), 4.54 (d, J¼11.5 Hz, 1H),

7.36e7.29 (m, 3H), 5.50 (s, 1H), 4.16 (dd, J¼12.9, 8.1 Hz, 1H),

3.94e3.81 (m, 3H), 3.62 (t, J¼10.0 Hz, 1H), 3.14 (t, J¼10.0 Hz, 1H),

2.03e1.95 (m, 2H), 1.86e1.76 (m, 3H), 1.67e1.59 (m, 1H), 1.03 (d,

J¼6.3 Hz, 3H), 0.94 (d, J¼6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

3.91e3.79 (m, 3H), 3.73 (t, J¼9.1 Hz,1H), 3.54e3.50 (m, 1H), 3.34 (br

s, 1H), 2.02e1.72 (m, 7H), 1.02 (d, J¼6.8 Hz, 3H), 0.85 (d, J¼6.8 Hz,

3H); ¹³C NMR (100 MHz, CDCl₃)

d 138.3, 128.2, 128.1, 127.7, 108.8,

77.8, 75.1, 73.1, 67.5, 63.2, 37.9, 36.9, 35.0, 24.7, 16.3, 13.0; HRMS

d 138.0, 128.7, 128.1, 126.1, 108.8, 101.6, 83.2, 69.7, 67.9, 65.2, 43.0,

(ESI-TOF) calcd for C₁₈H₂₆O₄Na (MþNa)^þ329.1729, found 329.1730.

37.5, 35.2, 24.4, 14.6, 13.3; HRMS (ESI-TOF) calcd for C₁₈H₂₄O₄Na

(MþNa)^þ327.1572, found 327.1570.

4.1.24. Diol 39. To a solution of alcohol 37 (2.93 g, 9.56 mmol) in

CH₂Cl₂(48 mL) were added pyridine (2.3 mL, 28.7 mmol), Ac₂O

(1.8 mL, 19.1 mmol), and DMAP (350 mg, 2.87 mmol) at room

temperature. After the mixture was stirred for 30 min at the same

temperature, the reaction was quenched with saturated aqueous

NH₄Cl (10 mL). The mixture was diluted with EtOAc (100 mL),

washed with saturated aqueous CuSO₄(30 mL, two times), satu-

rated aqueous NaHCO₃(30 mL), H₂O (30 mL), and brine (30 mL),

and then dried over Na₂SO₄. Concentration gave the corresponding

acetate (3.30 g), which was used for the next step without further

puriﬁcation.

4.1.26. Alcohol 7 transformed from 40. To a solution of benzylidene

acetal 40 (2.13 g, 7.00 mmol) in toluene (40 mL) was added DIBAL-H

(1.02 M in hexane, 21 mL, 21.0 mmol) at 0 ^ꢁC, and the mixture was

stirred for 4 h at the same temperature. To the mixture was added

DIBAL-H (1.02 M in hexane, 14 mL, 14.0 mmol) at 0 ^ꢁC. After the

mixture was stirred for 7 h at the same temperature, the reaction

was quenched with MeOH (20 mL). Subsequently, to the mixture

was added a Celite. After the mixture was stirred for 30 min at room

temperature, the insoluble material was ﬁltered through a Celite

pad. Concentration and column chromatography (hexane/

EtOAc¼4:1) gave alcohol 7 (2.04 g, 95%).

A mixture of the benzyl ether obtained above (3.30 g) and 5%

Pd(OH)₂/C (333 mg) in EtOH (100 mL) was stirred for 30 min under

H₂atmosphere at room temperature. The catalyst was ﬁltered off.

Concentration and short column chromatography (hexane/

EtOAc¼4:1) gave the corresponding alcohol (2.27 g), which was

used for the next step without further puriﬁcation.

4.1.27. Alcohol 41. To a solution of alcohol 7 (233 mg, 0.763 mmol)

and Et₃N (0.43 mL, 3.05 mmol) in CH₂Cl₂(4.0 mL) and DMSO

(1.0 mL) was added SO₃$pyr (346 mg, 2.29 mmol) at 0 ^ꢁC. After the

mixture was stirred for 2 h at room temperature, the reaction

mixture was diluted with EtOAc (50 mL). The mixture was washed

with saturated aqueous NH₄Cl (20 mL), H₂O (20 mL), and brine

(20 mL), and then dried over Na₂SO₄. Concentration gave the cor-

responding aldehyde, which was used for the next step without

further puriﬁcation.

To a solution of oxazolidinethione 19 (228 mg, 0.916 mmol) in

CH₂Cl₂(3.0 mL) was added TiCl₄(0.17 mL, 1.53 mmol) in CH₂Cl₂

(1.0 mL) at 0 ^ꢁC. After the resulting mixture was stirred for 10 min at

the same temperature, to the mixture was added (ꢀ)-sparteine

(0.88 mL, 3.82 mmol) at 0 ^ꢁC. After the mixture was stirred for

20 min at the same temperature, to the mixture was added the

aldehyde obtained above in CH₂Cl₂(1.5 mLþ1.0 mLþ0.5 mL) at 0 ^ꢁC.

After the resulting mixture was stirred for 40 min at the same

ꢀ

To a solution of the alcohol obtained above (2.27 g) and MS 4 A

(400 mg) in CH₂Cl₂(50 mL) were added TPAP (168 mg, 0.478 mmol)

and NMO (1.37 g, 11.5 mmol) at 0 ^ꢁC. The mixture was stirred for 2 h

at room temperature. Short column chromatography (hexane/

EtOAc¼4:1) gave the corresponding ketone (2.36 g), which was

used for the next step without further puriﬁcation.

To a solution of the ketone obtained above (2.36 g) in MeOH

(150 mL) was added K₂CO₃(1.45 g, 10.5 mmol) in H₂O (20 mL) at

0 ^ꢁC. After the mixture was stirred for 1 h at room temperature, the

reaction was quenched with 3 M HCl. The mixture was extracted

with EtOAc (200 mL), and then washed with H₂O (50 mL) and brine

(50 mL). The aqueous phase was extracted with EtOAc (80 mL, four

times). The combined organic phase was dried over Na₂SO₄.

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2257

temperature, the reaction was quenched with saturated aqueous

NH₄Cl (5.0 mL). The mixture was diluted with EtOAc (80 mL),

washed with H₂O (20 mL) and brine (20 mL), and then dried over

Na₂SO₄. Concentration and column chromatography (hexane/

EtOAc¼10:1, 5:1) gave alcohol 41 (387 mg, 92% in two steps): col-

the resulting mixture was allowed to warm up to reﬂux. When the

reaction stopped, to the mixture were added ethyl propiolate

(0.34 mL, 3.05 mmol) and N-methylmorpholine (0.34

mL,

3.05 mmol) at room temperature. This operation was performed

three times until the starting material was consumed. Short column

chromatography (hexane/EtOAc¼11:1) and column chromatogra-

orless oil; R_f¼0.47 (hexane/EtOAc¼2:1); ½a _D²⁴

ꢀ12.1 (c 0.31, CHCl₃);

ꢂ

IR (neat) 3501, 2973, 1700 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

phy (hexane/EtOAc¼20:1, 7:1) gave the corresponding

a,b-un-

d

7.35e7.19 (m, 10H), 4.95e4.84 (m, 2H), 4.71 (d, J¼10.7 Hz, 1H),

saturated ester, which was used for the next step without further

puriﬁcation.

4.65 (d, J¼10.7 Hz, 1H), 4.27 (dd, J¼9.3, 2.0 Hz, 1H), 4.25e4.22 (m,

1H), 4.18e4.13 (m, 1H), 3.95e3.86 (m, 2H), 3.70 (dd, J¼9.4, 7.9 Hz,

1H), 3.39 (d, J¼1.5 Hz, 1H), 3.28 (dd, J¼13.3, 3.2 Hz, 1H), 3.21 (t,

J¼9.9 Hz, 1H), 2.72 (dd, J¼13.3, 10.1 Hz, 1H), 2.02e1.65 (m, 5H),

1.60e1.52 (m, 1H), 1.31 (d, J¼6.8 Hz, 3H), 1.07 (d, J¼6.6 Hz, 3H), 0.88

To a solution of the silyl ether obtained above in MeOH (15 mL)

was added CSA (244 mg, 1.05 mmol) at 0 ^ꢁC. After the mixture was

stirred for 4 h at the same temperature, the reaction was quenched

with Et₃N (3.0 mL). Concentration and column chromatography

(hexane/EtOAc¼7:1, 2:1) gave alcohol 43 (422 mg, 96% in three

(d, J¼6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 184.6, 176.7, 137.4,

135.3, 129.4, 128.9, 128.4, 127.8, 127.7, 127.3, 108.3, 85.0, 77.2, 74.5,

72.6, 71.2, 69.9, 68.3, 60.4, 42.4, 39.8, 39.3, 37.6, 35.2, 24.5, 15.4, 13.4,

11.4; HRMS (ESI-TOF) calcd for C₃₁H₃₉NO₆SNa (MþNa)^þ576.2396,

found 576.2313.

steps): yellow oil; R_f¼0.21 (hexane/EtOAc¼4:1); ½a _D²⁶

ꢀ84.0 (c 0.18,

ꢂ

CHCl₃); IR (neat) 3439, 2977, 1705, 1638 cm^ꢀ1; ¹H NMR (400 MHz,

CDCl₃)

d

7.49 (d, J¼12.1 Hz, 1H), 5.27 (d, J¼12.1 Hz, 1H), 4.72 (d,

J¼6.6 Hz, 1H), 4.59 (d, J¼6.6 Hz, 1H), 4.13 (q, J¼7.1 Hz, 2H), 4.03 (dd,

J¼9.8, 2.9 Hz, 1H), 3.91e3.80 (m, 2H), 3.69 (dd, J¼4.9, 2.9 Hz, 1H),

3.57e3.51 (m, 3H), 3.39 (s, 3H), 2.11e1.74 (m, 8H), 1.25 (t, J¼7.1 Hz,

3H), 0.96 (d, J¼6.6 Hz, 3H), 0.94 (d, J¼7.0 Hz, 3H), 0.89 (d, J¼6.6 Hz,

4.1.28. MOM ether 42. To a solution of oxazolidinethione 41

(387 mg, 0.699 mmol) in MeOH (7.0 mL) was added NaBH₄

(52.9 mg, 1.40 mmol) at 0 ^ꢁC. After the mixture was stirred for

15 min at the same temperature, the reaction was quenched with

acetone (3.0 mL). The mixture was diluted with EtOAc (50 mL),

washed with H₂O (20 mL) and brine (20 mL), and then dried over

Na₂SO₄. Concentration gave the corresponding diol, which was

used for the next step without further puriﬁcation.

To a solution of the diol obtained above in CH₂Cl₂(7.0 mL) were

added imidazole (71.4 mg, 1.05 mmol) and TBSCl (126 mg,

0.839 mmol) at 0 ^ꢁC. After the resulting mixture was stirred for 2 h

at room temperature, the reaction was quenched with saturated

aqueous NH₄Cl (5.0 mL). The mixture was diluted with EtOAc

(50 mL), washed with H₂O (10 mL) and brine (10 mL), and then

dried over Na₂SO₄. Concentration gave the corresponding silyl

ether, which was used for the next step without further

puriﬁcation.

3H); ¹³C NMR (100 MHz, CDCl₃)

d 168.0. 163.4, 107.9, 97.5, 97.4, 85.6,

79.5, 71.9, 68.0, 65.4, 59.7, 56.1, 42.0, 39.3, 37.2, 35.0, 24.4, 15.4, 14.4,

13.3, 12.6; HRMS (ESI-TOF) calcd for C₂₁H₃₆O₈Na (MþNa)^þ

439.2308, found 439.2320.

4.1.30. Lactone 44. To a solution of alcohol 43 (422 mg, 1.01 mmol)

and Et₃N (0.56 mL, 4.04 mmol) in CH₂Cl₂(8.0 mL) and DMSO

(4.0 mL) was added SO₃$pyr (458 mg, 3.03 mmol) at 0 ^ꢁC. After the

mixture was stirred for 1 h at room temperature, the reaction

mixture was diluted with EtOAc (50 mL). The mixture was washed

with H₂O (20 mL) and brine (20 mL), and dried over Na₂SO₄.

Concentration and short column chromatography (hexane/

EtOAc¼4:1) gave the corresponding aldehyde (400 mg), which was

used for the next step without further puriﬁcation.

To a solution of the aldehyde obtained above (400 mg) and

MeOH (0.13 mL, 3.23 mmol) in THF (10 mL) was added SmI₂(0.1 M

in THF, 30 mL, 3.03 mmol) at ꢀ15 ^ꢁC. After the resulting mixture

was stirred for 1 h at the same temperature, the reaction was

quenched with saturated aqueous Na₂S₂O₃(15 mL). The solvent

was removed under reduced pressure. The mixture was diluted

with EtOAc (100 mL), washed with H₂O (30 mL) and brine (30 mL),

and then dried over Na₂SO₄. Concentration and column chroma-

tography (hexane/EtOAc¼6:1, 2:1) gave lactone 44 (90.5 mg, 55%)

and hydroxy ester 45 (40.0 mg, 30%). Lactone 44: colorless needle;

To a solution of the alcohol obtained above in CH₂Cl₂(7.0 mL)

were added (i-Pr)₂NEt (2.4 mL, 14.0 mmol) and MOMCl (0.53 mL,

6.99 mmol) at room temperature. After the mixture was stirred for

4 h at reﬂux, to the mixture were added (i-Pr)₂NEt (1.2 mL,

7.00 mmol) and MOMCl (0.265 mL, 3.50 mmol) at room tempera-

ture. After the mixture was stirred for 50 min at reﬂux, the reaction

was quenched with MeOH (3.0 mL). The mixture was diluted with

EtOAc (50 mL), washed with H₂O (20 mL) and brine (20 mL), and

then dried over Na₂SO₄. Concentration and column chromatogra-

phy (hexane/EtOAc¼20:1) gave MOM ether 42 (300 mg, 82% in

mp 110ꢀ112 ^ꢁC (hexane); R_f¼0.40 (hexane/EtOAc¼2:1); ½a ²_D⁵

ꢀ13.2

ꢂ

three steps): colorless oil; R_f¼0.31 (hexane/EtOAc¼7:1); ½a _D²⁶

ꢂ

ꢀ69.7

(c 0.19, CHCl₃); IR (neat) 2921, 1782 cm^ꢀ^{1 1}H NMR (400 MHz,

;

(c 0.36, CHCl₃); IR (neat) 2928 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

CDCl₃)

d

4.69 (d, J¼6.6 Hz, 1H), 4.66 (d, J¼6.6 Hz, 1H), 4.52 (dt,

d

7.32e7.21 (m, 5H), 4.79e4.75 (m, 2H), 4.64 (d, J¼6.3 Hz, 1H), 4.49

J¼10.2, 8.3 Hz, 1H), 3.91e3.74 (m, 3H), 3.64e3.62 (m, 2H), 3.46 (t,

J¼9.4 Hz, 1H), 3.36 (s, 3H), 2.77 (dd, J¼17.2, 8.3 Hz, 1H), 2.58 (dd,

J¼17.2, 10.2 Hz,1H), 2.08e1.45 (m, 7H),1.19 (d, J¼7.1 Hz, 3H),1.02 (d,

J¼6.3 Hz, 3H), 0.87 (d, J¼6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

(d, J¼11.0 Hz, 1H), 4.03 (dd, J¼10.0, 1.5 Hz, 1H), 3.86e3.83 (m, 3H),

3.53e3.52 (m, 2H), 3.40 (s, 3H), 3.07 (t, J¼10.0 Hz, 1H), 2.10e1.75

(m, 6H), 1.55e1.48 (m, 1H), 1.02 (d, J¼6.6 Hz, 3H), 1.01 (d, J¼6.6 Hz,

3H), 0.88 (d, J¼6.6 Hz, 3H), 0.84 (s, 9H), ꢀ0.02 (s, 3H), ꢀ0.03 (s, 3H);

d

173.4, 108.1, 96.0, 89.6, 82.3, 77.2, 74.3, 71.5, 67.7, 55.6, 41.6, 40.2,

¹³C NMR (100 MHz, CDCl₃)

d

138.7, 128.1, 127.5, 127.2, 107.7, 96.9,

38.5, 36.3, 35.0, 24.4, 19.1, 16.1, 13.4; HRMS (ESI-TOF) calcd for

80.1, 80.0, 77.2, 74.0, 72.6, 67.6, 66.4, 55.8, 42.2, 39.7, 37.1, 35.2, 26.1,

24.5, 18.5, 15.7, 13.5, 13.4, ꢀ5.3; HRMS (ESI-TOF) calcd for

C₂₉H₅₀O₆SiNa (MþNa)^þ543.3275, found 543.3279.

C₁₉H₃₀O₇Na (MþNa)^þ393.1889, found 393.1888. Hydroxy ester 45:

colorless oil; R_f¼0.20 (hexane/EtOAc¼2:1); ½a _D²⁵

ꢀ83.3 (c 0.19,

ꢂ

CHCl₃); IR (neat) 3468, 2972, 1737 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃)

d

4.85 (d, J¼6.3 Hz, 1H), 4.70 (d, J¼6.3 Hz, 1H), 4.16e4.05 (m, 3H),

4.1.29. Alcohol 43. A mixture of benzyl ether 42 (551 mg,

1.05 mmol) and 5% Pd(OH)₂/C (55.0 mg) in THF (18 mL) was stirred

for 30 min under H₂atmosphere at room temperature. The catalyst

was ﬁltered off. Concentration gave the corresponding alcohol,

which was used for the next step without further puriﬁcation.

To a solution of the alcohol obtained above in CH₂Cl₂(1.0 mL)

were added ethyl propiolate (0.59 mL, 5.25 mmol) and N-methyl-

morpholine (0.58 mL, 5.25 mmol) at room temperature, and then

3.96 (d, J¼5.9 Hz, 1H), 3.88e3.73 (m, 3H), 3.40 (s, 3H), 3.30 (d,

J¼8.3 Hz, 1H), 3.23 (t, J¼9.8 Hz, 1H), 2.75 (dd, J¼15.1, 2.9 Hz, 1H),

2.50e2.41 (m, 2H), 1.99e1.86 (m, 2H), 1.80e1.71 (m, 2H), 1.59e1.44

(m, 2H), 1.27e1.23 (m, 4H), 1.07 (d, J¼7.6 Hz, 3H), 0.92 (d, J¼6.1 Hz,

3H), 0.86 (d, J¼6.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 171.9,108.6,

97.2, 83.5, 82.3, 81.9, 79.1, 71.3, 67.6, 60.5, 55.9, 42.6, 42.3, 41.2, 39.3,

35.3, 24.4, 18.0, 15.2, 14.3, 13.5; HRMS (ESI-TOF) calcd for

C₂₁H₃₆O₈Na (MþNa)^þ439.2308, found 439.2303.

2258

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

To a solution of hydroxy ester 45 (68.0 mg, 0.163 mmol) in

CH₂Cl₂(2.0 mL) was added CSA (11.3 mg, 49.0 mol) at room

a 1:1 diastereomixture: colorless oil; R_f¼0.33 (hexane/EtOAc¼7:1);

IR (neat) 2926, 1730 cm^ꢀ^{1 1}H NMR (400 MHz, C₆D₆)

4.58e4.40

m

;

d

temperature. After the mixture was stirred for 1 h at the same

temperature, the reaction was quenched with Et₃N (2.5 mL). Con-

centration and column chromatography (hexane/EtOAc¼5:1, 4:1)

gave lactone 44 (54.4 mg, 89%).

(m, 2.5H), 4.30e4.20 (m, 1.5H), 4.07e4.02 (m, 1H), 3.98e3.93 (m,

1H), 3.78e3.62 (m, 2H), 3.52 (d, J¼9.5 Hz, 0.5H), 3.41 (td, J¼9.9,

3.6 Hz, 1H), 3.23 (d, J¼9.5 Hz, 0.5H), 3.19 (s, 1.5H), 3.18 (s, 1.5H),

2.69e2.66 (m, 0.5H), 2.56e2.49 (m, 0.5H), 2.38e2.34 (m, 0.5H),

2.26e2.20 (m, 0.5H), 1.99e1.85 (m, 5H), 1.83e1.68 (m, 6H),

1.65e1.55 (m, 6H), 1.46e1.37 (m, 6H), 1.29 (s, 4.5H) 1.26 (s, 4.5H),

1.21 (d, J¼6.6 Hz, 3H), 1.17 (s, 4.5H), 1.16 (s, 4.5H), 1.12 (d, J¼2.9 Hz,

1.5H), 1.09 (d, J¼7.8 Hz, 1.5H), 1.01e0.95 (m, 15H), 0.85 (d, J¼6.6 Hz,

1.5H), 0.84 (d, J¼6.6 Hz, 1.5H), 0.29e0.27 (m, 6H); ¹³C NMR

4.1.31. Pivalate 46. To a solution of ZnBr₂(61.0 mg, 0.271 mmol) in

CH₂Cl₂(2.5 mL) were added lactone 44 (50.2 mg, 0.136 mmol) and

EtSH (40

m

L, 0.542 mmol) in CH₂Cl₂(1.5 mLþ0.5 mLþ0.5 mL) at

0 ^ꢁC. After the mixture was stirred for 2 h at room temperature, the

reaction was quenched with saturated aqueous NaHCO₃(2.0 mL).

The mixture was diluted with EtOAc (30 mL), washed with H₂O

(10 mL) and brine (10 mL), and then dried over Na₂SO₄. Concen-

tration and column chromatography (hexane/EtOAc¼10:1) gave

the corresponding alcohol, which was used for the next step

without further puriﬁcation.

(100 MHz, C₆D₆)

d 109.7, 108.8, 108.8, 104.3, 87.5, 83.0, 82.1, 81.9,

80.0, 79.6, 78.4, 78.3, 72.0, 67.3, 61.7, 61.5, 52.7, 52.6, 44.4, 42.9, 42.4,

40.1, 39.0, 35.3, 35.1, 31.2, 31.1, 30.3, 29.8, 28.0, 27.8, 27.7, 26.5, 24.7,

20.7, 19.2, 18.9, 16.2, 14.1, 13.8, 9.3, 9.2, 3.5, 3.0, ꢀ3.6, ꢀ3.7, ꢀ4.6,

ꢀ4.7; HRMS (ESI-TOF) calcd for C₄₄H₈₆O₈SiSnNa (MþNa)^þ

913.5022, found 913.5026.

To a solution of the alcohol obtained above in DMF (0.5 mL)

were added imidazole (18.5 mg, 0.272 mmol), DMAP (33.2 mg,

0.272 mmol), and TBSCl (30.7 mg, 0.204 mmol) at room tempera-

ture. After the mixture was stirred for 14 h at 120 ^ꢁC, the reaction

was quenched with saturated aqueous NH₄Cl (2.0 mL). The mixture

was diluted with EtOAc (30 mL), washed with H₂O (10 mL) and

brine (10 mL), and then dried over Na₂SO₄. Concentration and

column chromatography (hexane/EtOAc¼200:1, 4:1) gave the cor-

responding silyl ether, which was used for the next step without

further puriﬁcation.

4.1.33. Ester 49. To a solution of pivalate 48 (115 mg, 0.129 mmol)

in CH₂Cl₂(1.3 mL) was added DIBAL-H (1.02 M in hexane, 0.38 mL,

0.387 mmol) at ꢀ78 ^ꢁC. After the mixture was stirred for 10 min at

the same temperature, the reaction was quenched with MeOH

(2.0 mL). Subsequently, to the resulting mixture was added a Celite,

and then the mixture was allowed to warm up to room tempera-

ture. The insoluble material was ﬁltered through a Celite pad.

Concentration and column chromatography (hexane/EtOAc¼15:1,

4:1, including 1% Et₃N) gave the corresponding alcohol (95.1 mg,

To a solution of the lactone obtained above in THF (2.5 mL) was

added LiAlH₄(5.7 mg, 0.150 mmol) at 0 ^ꢁC. After the mixture was

stirred for 20 min at the same temperature, the reaction was

quenched with H₂O (2.0 mL). The resulting mixture was diluted

with Et₂O (30 mL), and then to the mixture was added a Celite. The

insoluble material was ﬁltered through a Celite pad. Concentration

and column chromatography (hexane/EtOAc¼10:1, 0:1) gave the

corresponding diol, which was used for the next step without fur-

ther puriﬁcation.

91%) as

a

diastereomixture: colorless oil; R_f¼0.16 (hexane/

EtOAc¼7:1); IR (neat) 3478, 2925 cm^ꢀ1

;

¹H NMR (400 MHz, C₆D₆)

d

4.47 (dd, J¼6.1, 4.1 Hz, 0.5H), 4.41e4.29 (m, 2H), 4.04 (ddd, J¼7.3,

5.9, 1.0 Hz, 1H), 3.99e3.64 (m, 1.5H), 3.77e3.65 (m, 3H), 3.46e3.38

(m, 2H), 3.18 (s, 1.5H), 3.17 (s, 1.5H), 2.70e2.59 (m, 0.5H), 2.41e2.28

(m, 1H), 2.22e2.11 (m, 0.5H), 2.03e1.82 (m, 5H), 1.81e1.66 (m, 6H),

1.65e1.55 (m, 6H), 1.46e1.34 (m, 6H), 1.19e1.15 (m, 13.5H), 1.10 (d,

J¼7.8 Hz, 1.5H), 1.00e0.92 (m, 15H), 0.87 (d, J¼6.6 Hz, 1.5H), 0.86 (d,

J¼6.6 Hz, 1.5H), 0.28e0.25 (m, 6H); ¹³C NMR (100 MHz, C₆D₆)

To a solution of the diol obtained above in pyridine (1.4 mL) was

d 108.8, 104.3, 104.0, 86.3, 82.0, 81.9, 81.1, 78.4, 71.9, 67.7, 60.1, 53.0,

added PivCl (34

m

L, 0.272 mmol) at 0 ^ꢁC. After the mixture was

43.4, 42.9, 42.4, 39.8, 39.6, 37.9, 35.3, 31.3, 31.0, 30.3, 30.2, 29.8, 28.0,

26.5, 24.7, 20.7, 18.9, 16.1, 14.1, 13.8, 9.3, 3.1, ꢀ3.6, ꢀ4.5; HRMS (ESI-

TOF) calcd for C₃₉H₇₈O₇SiSnNa (MþNa)^þ829.4445, found 829.4477.

stirred for 30 min, the reaction was quenched with saturated

aqueous NH₄Cl (3.0 mL). The mixture was diluted with EtOAc

(30 mL), washed with H₂O (10 mL) and brine (10 mL), and then

dried over Na₂SO₄. Concentration and column chromatography

(hexane/EtOAc¼10:1, 7:1) gave pivalate 46 (58.9 mg, 82% in four

steps): colorless amorphous solid; R_f¼0.60 (hexane/EtOAc¼4:1);

To a solution of the alcohol obtained above (40.6 mg, 50.4 mmol)

ꢀ

and MS 4 A (20.0 mg) in CH₂Cl₂(1.0 mL) were added TPAP (3.5 mg,

10.1

m

mol) and NMO (17.7 mg, 0.151 mmol) at 0 ^ꢁC. The mixture was

stirred for 1 h at room temperature. Short column chromatography

(hexane/EtOAc¼5:1, including 1% Et₃N) gave the corresponding

aldehyde (38.4 mg) as a diastereomixture, which was used for the

next step without further puriﬁcation.

To a solution of the aldehyde obtained above (38.4 mg) in t-

BuOH (0.4 mL) and 2-methyl-2-butene (0.4 mL) were added 5%

aqueous NaH₂PO₄(0.4 mL) and NaClO₂(13.7 mg, 0.151 mmol) at

0 ^ꢁC. The mixture was stirred for 2 h at the same temperature. The

mixture was diluted with EtOAc (50 mL), washed with H₂O (10 mL)

and brine (10 mL), and then dried over Na₂SO₄. Concentration gave

carboxylic acid 6 as a diastereomixture, which was used for the

next step without further puriﬁcation.

½

a ²_D⁴

ꢂ

ꢀ44.7 (c 1.83, CHCl₃); IR (neat) 3544, 2964, 1732 cm^ꢀ1

;

¹H

NMR (400 MHz, CDCl₃)

d

4.27e4.16 (m, 2H), 4.05 (dd, J¼6.3, 1.7 Hz,

1H), 3.89e3.77 (m, 2H), 3.70e3.63 (m, 2H), 3.31 (br s, 1H), 3.10 (t,

J¼10.0 Hz,1H), 2.93 (br s,1H), 2.42e2.33 (m,1H), 2.15e2.06 (m,1H),

2.01e1.85 (m, 2H), 1.82e1.69 (m, 3H), 1.65e1.54 (m, 1H), 1.48e1.40

(m, 1H), 1.18 (s, 9H), 1.03 (d, J¼6.3 Hz, 3H), 1.01 (d, J¼4.9 Hz, 3H),

0.89 (s, 9H), 0.88 (d, J¼6.6 Hz, 3H), 0.11 (s, 3H), 0.11 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃)

d 178.2, 108.4, 84.3, 81.9, 80.2, 78.6, 71.0, 67.6,

61.2, 43.5, 42.2, 39.5, 35.6, 34.7, 27.3, 27.1, 26.1, 24.3, 18.3, 17.2, 15.7,

13.5, ꢀ4.0, ꢀ4.9; HRMS (ESI-TOF) calcd for C₂₈H₅₂O₇SiNa (MþNa)^þ

551.3380, found 551.3381.

To a solution of carboxylic acid 6 obtained above in THF (1.0 mL)

4.1.32. Mixed acetal 48. To a solution of alcohol 46 (117 mg,

were added Et₃N (11 L, 75.6

m

mmol) and 2,4,6-trichlorobenzoyl

0.221 mmol) in CH₂Cl₂(1.5 mL) were added

g-methoxyallyl-

chloride (10 L, 65.5 mmol) at room temperature. The mixture was

m

stannane 47 (0.14 mL, 0.440 mmol) and CSA (25.5 mg, 0.110 mmol)

at room temperature. After the mixture was stirred for 30 min at

the same temperature, the reaction was quenched with Et₃N

(1.0 mL). Concentration and column chromatography (hexane/

EtOAc¼20:1, 15:1, 4:1, including 1% Et₃N) gave mixed acetal 48

(55.6 mg, 28%) and alcohol 46 (82.8 mg, 71% recovery). The same

operation was repeated eight times using the recovered alcohol.

Finally, these operations gave mixed acetal 48 (114.7 mg, 58%) as

stirred for 3 h at the same temperature. After THF was removed

under reduced pressure, toluene (0.8 mL) was added. To the

resulting mixture was added a solution of alcohol 5 (29.4 mg,

55.4

mmol) and DMAP (12.3 mg, 0.101 mmol) in toluene

(0.8 mLþ0.5 mLþ0.5 mL) at room temperature. After the mixture

was stirred for 1 h at the same temperature, the insoluble material

was ﬁltered through a Celite pad. Concentration, short column

chromatography (hexane/EtOAc¼7:1, 1:1, including 1% Et₃N), and

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

2259

column chromatography (hexane/EtOAc¼20:1, including 1% Et₃N)

gave ester 49 (54.8 mg, 82% in three steps) as a diastereomixture:

colorless oil; R_f¼0.49 (hexane/EtOAc¼4:1); IR (neat) 2925, 1742,

chloroacetoxy ether 4 as a diastereomixture, which was used for

the next step without further puriﬁcation.

To a solution of 4 obtained above in CH₃CN (1.0 mL) was added

1650 cm^ꢀ1; ¹H NMR (400 MHz, C₆D₆)

d

7.38e7.33 (m, 2H), 7.31e7.24

a suspension of MgBr₂$OEt₂(38.9 mg, 0.151 mmol) and MS 4 A

ꢀ

(m, 4H), 7.22e7.04 (m, 9H), 5.00e4.74 (m, 5H), 4.64 (d, J¼3.2 Hz,

0.6H), 4.61 (d, J¼3.2 Hz, 0.4H), 4.44 (t, J¼4.8 Hz, 0.4H), 4.39e4.25

(m, 3.6H), 4.14 (d, J¼5.4 Hz, 0.6H), 4.11 (d, J¼5.1 Hz, 0.4H),

4.08e4.05 (m, 1H), 3.99 (d, J¼2.4 Hz, 0.4H), 3.97 (d, J¼2.4 Hz, 0.6H),

3.91e3.60 (m, 5H), 3.54e3.48 (m, 1.4H), 3.45 (dd, J¼9.5, 2.6 Hz,

0.6H), 3.23 (dd, J¼15.6, 1.7 Hz, 0.6H), 3.21 (s, 1.8H), 3.15 (s, 1.2H),

2.94 (dd, J¼14.8, 2.6 Hz, 0.4H), 2.86e2.78 (m, 1H), 2.75e2.57 (m,

1.6H), 2.51 (d, J¼14.1 Hz, 0.4H), 2.44e2.36 (m, 1H), 2.28 (dd, J¼14.6,

9.3 Hz, 0.4H), 2.22e2.12 (m, 1.6H), 2.10e1.86 (m, 4H), 1.82e1.50 (m,

18H), 1.44e1.34 (m, 6H), 1.31e1.11 (m, 16H), 1.05e0.91 (m, 18H),

0.89 (d, J¼6.6 Hz, 3H), 0.32 (s, 1.2H), 0.31 (s, 1.8H), 0.27 (s, 3H); ¹³C

(14.1 mg) in CH₃CN (0.5 mL) at 40 ^ꢁC. After the mixture was stirred for

2 h at the same temperature, the reaction was quenched with Et₃N

(1.0 mL). The insoluble material was ﬁltered through a Celite pad.

Concentration and column chromatography (hexane/EtOAc¼10:1,

7:1) gave diene 51 (3.2 mg, 43% in two steps) and diene 52 (3.0 mg,

40% in two steps). Diene 51: colorless oil; R_f¼0.66 (hexane/

EtOAc¼4:1); ½a ²_D³

ꢂ

ꢀ8.8 (c 0.16, CHCl₃); IR (neat) 2930, 1657 cm^ꢀ1; ¹H

NMR (400 MHz, CDCl₃)

d

7.31e7.21 (m, 15H), 5.89 (ddd, J¼17.4, 10.6,

6.0 Hz, 1H), 5.34 (d, J¼17.4 Hz, 1H), 5.18 (d, J¼10.6 Hz, 1H), 4.70 (br s,

2H), 4.58 (d, J¼11.7 Hz,1H), 4.56 (d, J¼11.7 Hz,1H), 4.48 (d, J¼11.7 Hz,

1H), 4.43 (d, J¼12.0 Hz,1H), 4.38 (d, J¼12.0 Hz,1H), 4.35 (d, J¼11.7 Hz,

1H), 3.88e3.74 (m, 4H), 3.66 (dd, J¼8.8, 3.2 Hz, 2H), 3.58e3.49 (m,

3H), 3.46e3.39 (m, 2H), 3.27 (t, J¼9.6 Hz,1H), 3.01 (td, J¼10.0, 3.6 Hz,

2H), 2.93 (dd, J¼9.3, 3.9 Hz,1H), 2.51 (d, J¼13.9 Hz, 1H), 2.36e2.24 (m,

3H), 2.05e1.84 (m, 7H),1.70 (s, 3H),1.62e1.47 (m, 4H),1.17 (s, 3H),1.09

(d, J¼7.8 Hz, 3H),1.05 (d, J¼6.3 Hz, 3H), 0.90 (s, 9H), 0.87 (d, J¼4.6 Hz,

NMR (100 MHz, C₆D₆) d 142.6, 139.5, 139.2, 129.5, 128.8, 127.3, 127.0,

112.7, 112.6, 109.0, 108.9, 82.1, 81.3, 80.1, 79.7, 78.5, 76.8, 75.0, 74.1,

73.0, 72.1, 71.8, 70.5, 70.4, 70.3, 70.2, 67.8, 53.3, 52.7, 44.6, 43.9, 43.0,

40.9, 39.8, 35.3, 31.2, 30.9, 30.3, 29.8, 28.0, 27.9, 26.5, 24.7, 24.4,

23.3, 23.1, 19.4, 18.9, 16.3, 14.1, 13.8, 13.3, 9.3, 3.3, ꢀ3.7, ꢀ3.8, ꢀ4.6,

ꢀ5.3; HRMS (ESI-TOF) calcd for C₇₃H₁₁₆O₁₂SiSnNa (MþNa)^þ

1355.7175, found 1355.7211.

3H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 143.3,

139.3, 138.7, 136.3, 136.1, 128.2, 128.2, 128.1, 127.7, 127.6, 127.3, 127.3,

127.1,117.0,111.8,108.2, 86.9, 80.7, 80.2, 79.0, 78.7, 78.3, 77.5, 76.4, 74.4,

74.2, 72.9, 72.8, 72.0, 71.5, 70.2, 67.6, 67.4, 43.7, 42.1, 40.0, 39.7, 38.5,

34.8, 32.8, 29.8, 26.0, 24.3, 22.9, 19.9, 18.3, 16.1, 13.8, 13.5, ꢀ4.2, ꢀ5.1;

HRMS (ESI-TOF) calcd for C₆₀H₈₆O₁₀SiNa (MþNa)^þ1017.5888, found

4.1.34. Allylic stannane 50. To a solution of mixed acetal 49

(7.0 mg, 5.2

0.104 mmol) and TMSI (7.4

m

mol) in CH₂Cl₂(0.5 mL) were added HMDS (23

mL,

mL, 52.0

m

mol) at 0 ^ꢁC. After the mixture

was stirred for 40 min, the reaction was quenched with saturated

aqueous NaHCO₃(1.0 mL). The mixture was diluted with EtOAc

(30 mL), washed with H₂O (10 mL) and brine (10 mL), and then

dried over Na₂SO₄. Concentration and column chromatography

(hexane/EtOAc¼60:1, including 1% Et₃N) gave allylic stannane 50

(5.0 mg, 73%) as a 4:1 Z/E diastereomixture: colorless oil; R_f¼0.56

1017.5889. Diene 52: colorless oil; R_f¼0.49 (hexane/EtOAc¼4:1); ½a _D²⁷

ꢂ

þ6.7 (c 0.55, CHCl₃); IR (neat) 2926, 1650 cm^ꢀ1; ¹H NMR (400 MHz,

CDCl₃)

d

7.30e7.21 (m,15H), 5.86(ddd, J¼17.6,11.5, 6.4 Hz,1H), 5.21 (d,

J¼17.6 Hz, 1H), 5.09 (d, J¼11.5 Hz, 1H), 4.74 (br s, 1H), 4.73 (br s, 1H),

4.60e4.37 (m, 6H), 4.30 (d, J¼11.5 Hz,1H), 4.06 (td, J¼11.0, 4.2 Hz,1H),

3.88e3.83 (m, 1H), 3.81e3.65 (m, 5H), 3.57e3.51 (m, 4H), 3.44 (br s,

1H), 3.25 (t, J¼9.8 Hz,1H), 2.99e2.90 (m, 2H), 2.54 (d, J¼14.4 Hz, 1H),

2.35e2.30 (m, 1H), 2.21 (dt, J¼12.9, 3.2 Hz, 1H), 2.12e1.85 (m, 6H),

1.80e1.70 (m, 4H), 1.56e1.49 (m, 1H), 1.45e1.35 (m, 3H), 1.24 (s, 3H),

1.19 (s, 3H), 1.08 (d, J¼7.8 Hz, 3H), 1.01 (d, J¼6.1 Hz, 3H), 0.88 (s, 9H),

(hexane/EtOAc¼4:1); IR (neat) 2925, 1743, 1650 cm^ꢀ1

;

¹H NMR

(400 MHz, C₆D₆)

d 7.38e7.34 (m, 2H), 7.31e7.25 (m, 4H), 7.21e7.05

(m, 9H), 6.01 (d, J¼12.0 Hz, 0.2H), 5.76 (d, J¼6.1 Hz, 0.8H), 5.27 (dt,

J¼12.0, 8.6 Hz, 0.2H), 5.06 (td, J¼9.8, 2.0 Hz, 0.8H), 4.98e4.75 (m,

4.2H), 4.65e4.57 (m, 1.8H), 4.40e4.25 (m, 3H), 4.13 (d, J¼11.5 Hz,

0.2H), 4.11 (d, J¼11.7 Hz, 0.8H), 4.03 (d, J¼5.1 Hz, 0.2H), 3.96e3.81

(m, 3.8H), 3.77e3.60 (m, 3.2H), 3.51 (ddd, J¼10.2, 4.4, 4.1 Hz, 0.8H),

3.45 (dd, J¼9.6, 1.8 Hz, 0.2H), 3.35 (dd, J¼9.5, 3.7 Hz, 0.8H), 3.04

(dd, J¼15.6, 2.2 Hz, 0.8H), 2.93 (dd, J¼15.5, 2.6 Hz, 0.2H), 2.88e2.79

(m, 1H), 2.66e2.57 (m, 1H), 2.55e2.35 (m, 2H), 2.27 (dd, J¼14.5,

9.1 Hz, 0.8H), 2.23e2.12 (m, 1H), 2.09e1.89 (m, 2.2H), 1.89e1.49 (m,

17H), 1.47e1.35 (m, 8H), 1.30 (s, 3H), 1.26e1.21 (m, 3H), 1.18 (s,

1.8H), 1.17 (s, 7.2H), 1.10e0.87 (m, 21H), 0.29 (s, 0.6H), 0.28 (s,

2.4H), 0.26 (s, 0.6H), 0.24 (s, 2.4H); ¹³C NMR (100 MHz, C₆D₆)

0.04 (s, 3H), 0.01 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 142.7, 139.3,

138.8, 136.8, 128.2, 128.2, 128.1, 127.7, 127.6, 127.3, 127.3, 127.1, 127.0,

115.9,111.8,108.2, 87.6, 80.8, 80.4, 79.2, 79.1, 78.3, 76.0, 75.5, 74.9, 73.1,

72.8, 72.5, 71.6, 70.9, 70.1, 67.6, 67.4, 44.1, 42.0, 39.9, 38.5, 36.5, 34.8,

31.0, 29.7, 26.0, 24.3, 23.1, 20.0,18.4,15.9,13.6,13.5, ꢀ4.2, ꢀ5.1; HRMS

(ESI-TOF) calcd for C₆₀H₈₆O₁₀SiNa (MþNa)^þ1017.5888, found

1017.5878.

4.1.36. Alkene 53. To a solution of diene 51 (3.0 mg, 3.01

toluene (0.5 mL) was added HoveydaeGrubbs second generation

catalyst (0.4 mg, 0.638 mol) at room temperature. The mixture

mmol) in

d

170.8, 142.6, 140.2, 139.5, 139.2, 128.5, 128.4, 128.4, 127.6, 127.5,

m

127.5, 127.3, 114.7, 112.8, 108.8, 106.3, 89.2, 83.5, 81.4, 80.1, 79.8,

78.6, 77.6, 75.0, 74.1, 73.0, 72.2, 72.0, 70.5, 70.3, 67.7, 44.3, 42.8,

41.9, 40.9, 39.8, 39.6, 35.2, 32.4, 31.2, 30.9, 30.6, 30.3, 29.9, 29.8,

28.0, 26.5, 24.7, 23.2, 20.0, 18.8, 16.4, 14.5, 14.1, 13.8, 13.3, 9.9, ꢀ3.8,

ꢀ4.5; HRMS (ESI-TOF) calcd for C₇₂H₁₁₂O₁₁SiSnNa (MþNa)^þ

1323.6913, found 1323.6946.

was stirred for 6 days at 100 ^ꢁC. The reaction was quenched with

Et₃N (0.5 mL) and the mixture was ﬁltered through a short column

chromatography (hexane/EtOAc¼4:1). Concentration and column

chromatography (hexane/EtOAc¼12:1, 10:1) gave alkene 53

(2.4 mg, 82%): colorless oil; R_f¼0.52 (hexane/EtOAc¼4:1); ½a _D²⁵

ꢂ

ꢀ62.5 (c 0.17, CHCl₃); IR (neat) 2926 cm^ꢀ1

;

¹H NMR (400 MHz,

7.31e7.21 (m, 15H), 5.32 (d, J¼4.6 Hz, 1H), 4.55 (d,

CDCl₃)

d

4.1.35. Diene 51. To a solution of ester 50 (9.8 mg, 7.53

mmol) in

J¼11.7 Hz, 1H), 4.50 (br s, 2H), 4.46 (d, J¼12.0 Hz, 1H), 4.41 (d,

J¼12.0 Hz, 1H), 4.28 (d, J¼11.7 Hz, 1H), 3.90e3.81 (m, 2H), 3.76 (q,

J¼7.4 Hz, 1H), 3.70e3.52 (m, 7H), 3.28 (ddd, J¼12.0, 9.4, 4.1 Hz, 1H),

3.21 (t, J¼9.8 Hz, 1H), 3.08 (ddd, J¼11.1, 9.0, 4.3 Hz, 1H), 2.86 (dd,

J¼9.4, 3.4 Hz, 1H), 2.73 (dd, J¼13.7, 4.6 Hz, 1H), 2.36e2.24 (m, 2H),

2.07e1.84 (m, 6H), 1.79 (s, 3H), 1.76e1.65 (m, 2H), 1.64e1.47 (m,

2H), 1.45e1.31 (m, 3H), 1.16 (s, 3H), 1.08 (d, J¼7.6 Hz, 3H), 0.98 (d,

J¼6.1 Hz, 3H), 0.91 (s, 9H), 0.86 (d, J¼6.6 Hz, 3H), 0.05 (s, 3H), 0.03

toluene (0.5 mL) was added DIBAL-H (1.02 M in hexane, 15

m

L,

15.1

m

mol) at ꢀ95 ^ꢁC. After the mixture was stirred for 20 s at the

same temperature, to the resulting mixture were added pyridine

(0.30 mL) and (ClCH₂CO)₂O (12.9 mg, 75.3 mmol) in toluene (0.3 mL)

at ꢀ95 ^ꢁC. After the mixture was allowed to warm up to ꢀ10 ^ꢁC

gradually for 50 min, the reaction was quenched with saturated

aqueous sodium potassium tartrate (1.0 mL). The mixture was di-

luted with Et₂O (30 mL), washed with saturated aqueous sodium

potassium tartrate (10 mL), H₂O (10 mL), and brine (10 mL), and

then dried over Na₂SO₄. Concentration and short column chroma-

(s, 3H); ¹³C NMR (100 MHz, CDCl₃)

d 139.5, 138.7, 138.6, 135.4, 128.2,

128.2, 128.1, 127.6, 127.5, 127.4, 127.3, 127.1, 127.0, 126.8, 108.2, 86.8,

80.3, 80.0, 79.4, 78.8, 78.3, 77.8, 77.5, 75.2, 74.7, 74.4, 74.1, 73.0, 72.9,

71.5, 70.1, 67.5, 67.4, 43.7, 42.1, 39.5, 38.4, 35.2, 34.8, 32.3, 29.8, 26.0,

tography (hexane/EtOAc¼5:1, including 1% Et₃N) gave

a-

2260

H. Takamura et al. / Tetrahedron 68 (2012) 2245e2260

K.; Takakura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795; (c) Fujiwara, K.;

Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T.

Tetrahedron Lett. 2004, 45, 7011; (d) Domon, D.; Fujiwara, K.; Ohtaniuchi, Y.;

Takezawa, A.; Takeda, S.; Kawasaki, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetra-

hedron Lett. 2005, 46, 8279; (e) Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.;

Suzuki, T. Tetrahedron Lett. 2005, 46, 8285; (f) Takizawa, A.; Fujiwara, K.; Doi, E.;

Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2006, 62, 7408; (g) Clark, J. S.;

Conroy, J.; Blake, A. J. Org. Lett. 2007, 9, 2091; (h) Goto, A.; Fujiwara, K.; Kawai,

A.; Kawai, H.; Suzuki, T. Org. Lett. 2007, 9, 5373.

25.9, 24.3, 19.9, 18.3, 15.7, 14.0, 13.5, ꢀ4.2, ꢀ5.1; HRMS (ESI-TOF)

calcd for C₅₈H₈₂O₁₀SiNa (MþNa)^þ989.5575, found 989.5576.

4.1.37. Alkane 54. To a solution of alkene 53 (2.4 mg, 2.48

CH₂Cl₂(1.5 mL) was added [(cod)(pyr)(Cy₃P)Ir]PF₆(0.2 mg,

0.248

mol) at 0 ^ꢁC. After the mixture was stirred under H₂atmo-

sphere for 2 h at the same temperature, additional [(cod)(pyr)(Cy₃P)

Ir]PF₆(0.2 mg, 0.248 mol) was added. After the mixture was stirred

for 2 h at the same temperature, additional [(cod)(pyr)(Cy₃P)Ir]PF₆

(0.2 mg, 0.248 mol) was added. The mixture was stirred for further

mmol) in

m

8. Kadota, I.; Abe, T.; Uni, M.; Takamura, H.; Yamamoto, Y. Tetrahedron 2009, 65,

7784.

m

9. For our communication, see: Takamura, H.; Nishiuma, N.; Abe, T.; Kadota, I. Org.

Lett. 2011, 13, 4704.

10. (a) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123,

6702; (b) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,

124, 3562.

11. The carbon numbering corresponds to that of the natural product.

12. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron 1990,

46, 4517.

m

2 h at the same temperature. Concentration and column chroma-

tography (hexane/EtOAc¼15:1, 12:1) gave alkane 54 (2.1 mg, 88%):

colorless oil; R_f¼0.52 (hexane/EtOAc¼4:1); ½a _D²³

ꢀ0.27 (c 0.11,

ꢂ

CHCl₃); IR (neat) 2925 cm^ꢀ1; ¹H NMR (600 MHz, CDCl₃)

d 7.30e7.21

(m, 15H), 4.60 (d, J¼11.4 Hz, 1H), 4.53 (d, J¼11.4 Hz, 1H), 4.48 (d,

J¼11.4 Hz, 1H), 4.43 (d, J¼12.0 Hz,1H), 4.40 (d, J¼12.0 Hz, 1H), 4.24 (d,

J¼11.4 Hz, 1H), 3.86e3.74 (m, 4H), 3.67e3.63 (m, 2H), 3.57e3.50 (m,

3H), 3.31 (td, J¼10.2, 3.0 Hz, 1H), 3.21 (t, J¼10.2 Hz, 1H), 3.15e3.11 (m,

1H), 3.08e3.03 (m, 1H), 2.96 (td, J¼10.2, 3.0 Hz, 1H), 2.82 (dd, J¼9.3,

3.9 Hz, 1H), 2.40 (dt, J¼12.0, 4.8 Hz, 1H), 2.26 (dt, J¼12.0, 4.8 Hz, 1H),

2.02e1.85 (m, 5H), 1.83e1.82 (m, 1H), 1.81e1.80 (m, 1H), 1.77e1.70

(m, 3H), 1.64e1.58 (m, 2H), 1.46e1.35 (m, 4H), 1.15 (s, 3H), 1.07

13. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.

14. Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719.

15. Derivatization for the stereochemical conﬁrmation at the C29 position of 12

was carried out as described below. Selective protection of the primary hydroxy

group of 12 gave pivalate 55. Removal of the benzyl and benzylidene acetal

protecting groups by hydrogenolysis and subsequent treatment of the resulting

tetraol with PhCH(OMe)₂/CSA provided bis-benzylidene acetal 56. The ob-

served NOE of H-29/Me-30 in 56 conﬁrmed the stereochemistry at the C29

position.

16. For a review of TPAP oxidation, see: Ley, S. V.; Norman, J.; Grifﬁth, W. P.;

Marsden, S. P. Synthesis 1994, 639.

17. Michel, P.; Ley, S. V. Angew. Chem., Int. Ed. 2002, 41, 3898.

18. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883; (b)

Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,

894.

19. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,

4092.

20. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.

(d, J¼7.8 Hz, 3H), 1.01 (d, J¼6.0 Hz, 3H), 1.00 (d, J¼6.6 Hz, 3H), 0.88 (s,

9H), 0.86 (d, J¼6.6 Hz, 3H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR

(100 MHz, CDCl₃) d 139.0, 138.7, 138.6, 128.2, 128.2, 128.1, 127.8, 127.6,

127.6, 127.4, 127.2, 127.0, 108.2, 86.8, 83.5, 80.8, 80.0, 78.7, 78.6, 78.3,

77.6, 74.7, 74.6, 73.6, 73.5, 72.8, 71.6, 69.8, 67.6, 67.4, 43.9, 42.0, 40.8,

38.4, 34.8, 33.8, 32.0, 29.8, 27.6, 26.0, 24.3, 22.8, 19.9, 18.3, 15.9, 14.3,

14.2, 13.5, ꢀ4.2, ꢀ5.2; HRMS (ESI-TOF) calcd for C₅₈H₈₄O₁₀SiNa

(MþNa)^þ991.5731, found 991.5735.

21. Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am.

Chem. Soc. 2005, 127, 16028.

22. For selected reviews of spiroacetals, see: (a) Perron, F.; Albizati, K. F. Chem.

Rev. 1989, 89, 1617; (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005,

105, 4406.

Acknowledgements

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24. (a) Hanessian, S.; Sumi, K. Synthesis 1991, 1083; (b) Hanessian, S.; Gai, Y.; Wang,

W. Tetrahedron Lett. 1996, 37, 7473.

This research was supported by Grant-in-Aid for Scientiﬁc Re-

search from Japan Society for the Promotion of Science (JSPS). We

appreciate Kato Memorial Bioscience Foundation, Mitsubishi

Chemical Corporation Fund, and the Asahi Glass Foundation for

their ﬁnancial supports. A research fellowship for T.A. from JSPS is

thankfully acknowledged.

25. Ermolenko, L.; Sasaki, N. A. J. Org. Chem. 2006, 71, 693.

26. Parikh, J. R.; Doering, W. v. E J. Am. Chem. Soc. 1967, 89, 5505.

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28. (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999, 40,

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Article Doi

A convergent synthesis of the right-hand fragment of ciguatoxin CTX3C

DOI: 10.1016/j.tet.2012.01.071

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