Asymmetric synthetic study of macrolactin analogues

Tetrahedron 61 (2005) 2607–2622

Yusuke Kobayashi,^aAkihiro Fukuda,^aTetsutaro Kimachi,^bMotoharu Ju-ichi^b

and Yoshiji Takemoto^a,

*

^aGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan

^bFaculty of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan

Received 21 December 2004; revised 18 January 2005; accepted 18 January 2005

Abstract—We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and

metabolical stability. As a result of retrosynthetic analysis of these compounds 1a–b, two synthetic strategies have been examined. The ﬁrst

strategy includes the enantioselective addition of nonadienyl anion, derived from 3, to aldehyde 4 as a key step. The second one includes

epimerization of ynone 7 to (E,E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31. Although the former

route furnished no desired target, the latter one was revealed to work well for the synthesis of 1. Unfortunately, the aimed (2Z,4E)-analogue

1a could not be synthesized due to an epimerization of the (2Z)-oleﬁn into the (2E)-oleﬁn. However, these methods could be applied to the

total asymmetric synthesis of the (2E,4E)-analogue 1b. Overall, control of all of the four stereocenters was achieved by means of asymmetric

and diastereoselective reactions without using any chiral natural sources.

1. Introduction

(8E,10Z)-dienic moiety should adopt a s-cis or s-trans form

as a major conﬁguration, we designed 1,3-disubstituted

benzenes 1a–b and 1,7-disubstituted naphthalenes 2a–b,

Macrolactins A–M, which were isolated in 1989¹and 2001²

are a family of 24-membered polyene macrolides produced

by a deep sea marine bacterium. Though structurally quite

diverse, these macrolactins are distinguished by biological

activities against various viruses and cancer cell lines.

Among them, macrolactin A exhibits a broad spectrum of

activity with signiﬁcant antiviral and cancer cell cytotoxic

properties including inhibition of B16–F10 murine mela-

noma cell replication.^1,2In addition, this compound features

three sets of conjugated dienes and four stereogenic centers

in the molecule. Because of its unreliable supply from cell

culture as well as its structural characteristics and broad

therapeutic potential, macrolactin A has been an attractive

target for asymmetric synthesis. Thus far, three total

synthesis³and novel synthetic studies⁴have been

developed, but there are still problems to be solved for

therapeutic applications. With an aim of increasing the

metabolical stability and identifying requisite substructure

of macrolactin A to exhibit biological activity, we planed to

replace the (2Z,4E)- and (8E,10Z)-dienic moieties by the

(2E,4E)-dienoate and more stable aromatic ring,

respectively (Scheme 1). From the point of view that the

Keywords: Macrolactin A; Antibiotics; Antivirus; Asymmetric synthesis;

Ynone; Isomerization; (E,E)-Conjugated dienone.

* Corresponding author. Tel.: C81 75 753 4528; fax: C81 75 753 4569;

e-mail: takemoto@pharm.kyoto-u.ac.jp

Scheme 1. Macrolactin A analogues.

doi:10.1016/j.tet.2005.01.062

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Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

respectively. We ﬁrst targeted the benzene analogues 1a and

1b. While, in both analogues 1a and 1b, a rigid phenyl group

was introduced instead of the (8E,10Z)-dienic moiety, only

1b was replaced the (2Z,4E)-dienic moiety to the (2E,4E)-

dienic moiety.⁵We have already reported the synthetic

studies on macrolactin A and its analogues.⁶Then we

describe here the details of an asymmetric total synthesis of

a macrolactin analogue 1b by means of enantioselective and

diastereoselective reactions without using any chiral natural

sources.

investigate the key reaction, we examined two synthetic

routes; (1) the asymmetric addition of alkenylzirconocene

derived from 3 to aldehyde 4 and (2) the addition of alkynyl

anion of 8 to Winreb amide 9 and subsequent epimerization

and hydride-reduction of the resulting dienone 7.

Fortunately, these starting materials could be prepared

from the same compounds 10, 11, and 12.

2.1. Investigation of the route A using asymmetric

addition of alkenylzirconocene to aldehyde 4

The asymmetric synthesis of 3 and 4, which were required

to examine the enantioselective addition, was conducted as

follows. We have already reported the asymmetric synthesis

of nonracemic alcohol 13,^6awhich was obtained in 99%

yield with 95%ee according to the Seebach’s procedure⁷

(Scheme 3). The benzoylation and deprotection of the PMB-

group of 13 gave rise to alcohol 14 in 86% yield. The

subjection of 14 to oxidation with IBX⁸(2-iodoxybenzoic

acid) and subsequent Wittig oleﬁnation⁹afforded enyne 15,

which was converted to the desired product 3 by removal of

the TMS group. The E-conﬁguration of enynes 3 was

determined by the coupling constant (JZ14.4 Hz) between

oleﬁnic protons of 3.

2. Results and discussion

Retrosynthetic analysis. Our retrosynthetic analysis of the

macrolactin analogues 1a and 1b was described in

Scheme 2. This strategy relies on several asymmetric

reactions to construct three chiral carbon centers (C7, C13,

and C23). In addition, the key step of the strategy is a

introduction of the (16E,18E)-dienyl segment with con-

current formation of the C15 stereogenic center. To

Scheme 3. (a) BzCl, Et₃N, DMAP, CH₂Cl₂, 0 8C, quant; (b) DDQ, CH₂Cl₂–

,

H₂O, 86%; (c) IBX, DMSO–THF, 93%; (d) Ph₃P^CCH₂CCTMSBr^K

n-BuLi, THF, K25 8C, 91%; (e) TBAF, THF, 86%.

Having the requisite enyne 3 with high enantioselectivity,

our attention was directed to the asymmetric synthesis of

aldehyde 4. The synthesis of 4 commenced from the

diastereoselective aldol reaction of (S)-3-acetyl-4-isopro-

pyl-1,3-thiazolidine-2-thione 11¹⁰with dialdehyde 10. The

representative results were shown in Table 1. Although we

examined several reaction conditions, the aldol adducts 16

were obtained with moderate diastereoselectivity (53–68%

de). The two diastereomers 16 could be separated by

column chromatography, but we did not determine the

stereochemistry of these adducts. In addition, the side-

products 17 were produced as an inseparable mixture of four

diastereomers via double aldol reaction together with 16.

Then, we next investigated the aldol reaction of mono-

aldehyde 18, which was prepared in two steps from 10

(Scheme 4). The TiCl₄-mediated aldol reaction of 11 with

18 in the presence of i-Pr₂NEt proceeded with good

diastereoselectivity (88% de) to provide 19 in 80% yield.

The relative conﬁguration of 19 was determined to be R

based on the literature results¹⁰and the modiﬁed MTPA-

method.¹¹After protection of the hydroxy group of 19,

subjection of the resulting TBS-ether to methanolysis and

oxidation gave rise to aldehyde 20, which was converted to

TBS ether 21 stereoselectively by the diastereoselective

Scheme 2. Retrosynthetic analysis of macrolactin analogue 1a.

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

Table 1. Diastereoselective aldol reaction of 10 with 11

2609

Entry

Reaction conditions

Yield (%)

de of 16 (%)

16

17

1

2

3

4

Yb(OTf)₃, (i-Pr)₂NEt

Sn(OTf)₂, N-ethylpiperazine

TiCl₄, (i-Pr)₂NEt

0

—

53

68

64

23

39

42

35

19

22

TiCl₄, N-ethylpiperazine

propargylation with allenylboronic acid 12 according to the

Yamamoto’s protocol¹²and TBS protection of the resultant

alcohol. The propargylation proceeded with good stereo-

selectivity (R:SZ10:90) by using (C)-diisopropyl tartrate

as a chiral source. After transformation of 21 into TES ether

5 by the reduction and protection, (Z,E)-dienoester 22 was

derived from 5 in moderate yield by the standard three-step

sequence: bromination, hydrostanylation,¹³and Stille cross-

coupling.¹⁴The reaction of TES ether 22 with IBX directly

gave rise to the desired product 4 in 66% yield.¹⁵

amino alcohol A as a promoter. Then, we next investigated

the CrCl₂/NiCl₂-mediated cross-coupling¹⁷of 4 with the

alkadienyl iodide, which was easily prepared from 3 via the

corresponding alkenylzirconocene. Whereas the cross-

coupling reaction successfully occurred, the desired product

23a was obtained in 28% yield together with the

diastereomer 23b (23a:23bZ1:1). Since we could not

improve the stereoselectivity, we turned our attention to the

second strategy.

2.2. Investigation of the route B using the addition of

alkyne 8 to Winreb amide 9

We examined the ﬁnal coupling reaction of aldehyde 4 and

enyne 3 using the Wipf’s protocol¹⁶(Scheme 5). Although

the hydrozirconation of 3 with Cp₂Zr(H)Cl proceeded

cleanly, no desired product 23 was obtained by the

Me₂Zn-mediated nucleophilic addition of the corresponding

alkenylzirconocene with 4, even in the presence of chiral

The strategy involves assembly of three fragments 6, 8, and

9 as shown in Scheme 2. Alkyne 8 bearing a stereogenic

center (C23), plays a central role in our strategy, serving not

only as an ideal nucleophile for joining with the amide 9, but

also as a latent functional group of the (16E,18E)-

conjugated dienone moiety of 1.

We anticipated that these compounds 8 and 9 could be

prepared from 24 and 18 by the same reactions such as

asymmetric methylation, asymmetric propargylation of 12,⁶

and diastereoselective aldol condensation of 11.⁷We

commenced from an efﬁcient enantioselective preparation

of alkyne 8 (Scheme 6). Synthesis of 8 began with PMB

aldehyde 24 derived from 1,7-heptanediol in two steps. This

aldehyde 24 was ﬁrst subjected to the reported asymmetric

methylation using Me₂Zn and Ti(O-i-Pr)₄in the presence of

(C)-TADDOL⁷(20 mol%) to give the desired secondary

alcohol 25 in 90% yield with high enantioselectivity

(95%ee). The enantioselectivity and absolute conﬁguration

were determined by a modiﬁed method of the Mosher

Scheme 4. (a) NaBH₄, MeOH, 0 8C, 64%; (b) BzCl, Et₃N, CH₂Cl₂, 0 8C,

quant; (c) N-acetyl-(S)-4-IPTT 11, TiCl₄, i-Pr₂NEt, CH₂Cl₂, K78 8C, 80%,

88%de; (d) TBSOTf, 2,6-lutidine, CH₂Cl₂, 84%; (e) K₂CO₃, MeOH;

(f) IBX, DMSO–THF, 84% (2 steps); (g) CH₂]C]CHB(OH)₂12, (C)-

diisopropyl tartrate, MS 4A, toluene, K78 8C, 88%, 80%de; (h) TBSCl,

imidazole, DMF, quant; (i) DIBAL, CH₂Cl₂, K78 8C then NaBH₄, MeOH,

0 8C 86%; (j) TESCI, imidazole, DMF, quant; (k) BrCN, n-BuLi, THF,

K78 to K40 8C, 93%; (l) PdCl₂(PPh₃)₂, Bu₃SnH, benzene; (m) Pd₂(dba)₂,

ethyl (Z)-3-iodopropenoate 6, i-Pr₂NEt, DMF, 33% (2 steps); (n) IBX,

DMSO–H₂O, 66%.

Scheme 5. (a) Cp₂Zr(H)Cl, CH₂Cl₂; (b) Me₂Zn, chiral ligand A, 4, toluene,

25 8C–rt; (c) Cp₂Zr(H)Cl, CH₂Cl₂then NIS, 0 8C, 77%; (d) CrCl₂, NiCl₂, 4,

DMSO, 56%.

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Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

(80%ee) from a mixture of AcOEt and hexane. The

enantioselectivity and absolute conﬁguration were deter-

mined by a modiﬁed method of the Mosher protocol.¹¹After

protection of the alcohol 28, hydrolysis of the benzoate

afforded the primary alcohol (K₂CO₃, MeOH), which was

oxidized with IBX⁸to provide the desired aldehyde 29.

Condensation of 29 with 11 in the presence of TiCl₄

(1.1 equiv) and i-Pr₂NEt (1.1 equiv) afforded aldol product

30¹⁰along with a small amount of its diastereomer (80%

yield, 92% de). These products were separated by column

chromatography, and major product 30 was treated with

N-methoxymethylamine, followed by TESCl to yield

Weinreb amide 9 in good yield. With the two chiral

building blocks now accessible, we investigated the key

steps of this strategy, that is, their coupling reaction and

stereoselective construction of the (E,E)-conjugated die-

none unit. The coupling reaction of 8 and 9 proceeded

smoothly using ethylmagnesium bromide as a base¹⁹to

afforded the desired ynone 7 in good yield. Although the

triphenylphosphine-catalyzed isomerization of an ynone to

a conjugated dienone has been reported,²⁰the desired

product could not be obtained in reasonable yield under the

standard conditions (Table 2, entry 1). After many

experiments as shown in Table 2, use of bis(diphenylpho-

sphino)butane (dppb) in a mixture of toluene and THF (1:1)

at room temperature led to the best result to give 31 in 49%

yield (entry 5).

Scheme 6. (a) PMBCI, NAH, THF, 0 8C; (b) IBX, DMSO, THF, 48%

(2 steps); (c) Me₂Zn, (C)-TADDOL, Ti(O-i-Pr)₄, toluene, K25 8C, 90%,

95%ee; (d) BzCl, Et₃N, DMAP, CH₂Cl₂, 0 8C, quant; (e) DDQ, CH₂Cl₂,

H₂O, 80%; (f) IBX, DMSO, THF, 95%; (g) (MeO)₂P(O)CHN₂, t-BuOK,

THF, K78 8C/rt, 85%; (h) 3 N KOH/MeOH (1:1), 87%; (i) TBSCl,

imidazole, DMF, quant.

protocol.¹¹The resulting alcohol 25 was protected as a

benzoate before removal of the terminal PMB ether to

furnish primary alcohol 26. Oxidation of 26 to an aldehyde,

followed by exposure to the Seyferth–Gilbert reagent,¹⁸

produced alkyne 27 which ﬁnally replaced the protecting

group from benzoate to tert-butyldimethysilyl (TBS) ether

to give the desired product 8.

Having established the synthesis of the C16–C24 fragment

8, we next sought the construction of 9 from aldehyde 18.

Propargylation of 18 with allenylboronic acid 12 under the

same conditions¹²as that of 20 gave chiral alcohol 28 as the

single product with moderate enantioselectivity (85% yield,

80%ee) (Scheme 7). Fortunately, the optically pure alcohol

28 (O95%ee) was easily obtained by recrystallization of 28

Table 2. Phosphine-catalyzed epimerization of ynone 7 to dienone 31

Entry

Reaction conditions

Yield (%)

1

2

3

4

5

PPh₃, toluene, 110 8C

n-Bu₃P, toluene, rt

n-Bu₃P, toluene/THF, rt

dppb, toluene, rt

31

20

28

30

49

dppb, toluene/THF, rt

After removal of the TES protecting group, subsequent

construction of the fourth stereogenic center was carried out

by hydroxyl-directed reduction.²¹Reduction of the resulting

alcohol derived from 31 with Me₄NBH(OAc)₃provided the

corresponding 1,3-anti-diol in 89% yield and 93:7 dia-

stereoselectivity. This 1,3-anti-diol was protected as

acetonide under the standard conditions to afford 32 as a

single isomer. The relative conﬁguration of 32 was

determined by the inspection of the ¹³C chemical shifts of

the acetonide methyl groups of 32,^1bthat is, both signals of

two methyl groups appeared at 25 ppm (d: 25.1 and 25.5).

This phenomena strongly indicates that acetonide 32

possesses the 1,3-anti conﬁguration.

We ﬁnally examined the cross-coupling reaction of

acetonide 32 and iodide 6 (Scheme 8 and Table 3). At

ﬁrst, the Pd-mediated cross-coupling was examined in the

same manner^13,14as that of 5, but the desired product 33 was

obtained only in a miserable yield (entry 1). Therefore, we

undertook the exploration of other cross-coupling reactions.

Whereas the desired product 33 was obtained under neither

Negishi²²nor Denmark²³reaction conditions, the Cu-

catalyzed reaction of 32a (MXZBu₃Sn) with 6 proceeded

smoothly to give 33 in 58% yield from 32 (entries 2–4).²⁴

Although the reaction of 33 under acidic conditions gave a

mixture of mono-TBS adducts, the C7 TBS group of 33

Scheme 7. (a) CH₂]C]CHB(OH)₂12, (C)-diisopropyl tartrate, MS 4A,

toluene, K78 8C, 85%, 80%ee; (b) TBSCl, imidazole, DMF, quant;

(c) K₂CO₃, MeOH, 95%; (d) IBX, DMSO, THF, 90%; (e) 11, TiCl₄,

i-Pr₂NEt, CH₂Cl₂, K78 8C, 80%, 92%de; (f) MeONHMe$HCl, Et₃N,

CH₂Cl₂91%; (g) TESCI, pyridine, quant; (h) EtMgBr, 8, THF, 70%;

(i) dppb, toluene, THF; (j) AcOH/THF/H₂O (8:8:1), 40% (2 steps);

(k) Me₄NBH(OAc)₃, AcOH, MeCN, 89%; (l) 2,2-dimethoxypropane,

PPTS, CH₂Cl₂, 83%.

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2611

Scheme 8. (a) Conditions A; (b) conditions B; (c) TBAF, THF, 0 8C, 92%; (d) CH₂]CMe(OMe), PPTS, CH₂Cl₂, K40 8C, 82%; (e) TBAF, AcOH (1:1), THF,

89%; (f) 3 N KOH, THF, EtOH, 60 8C; (g) 2,4,6-trichlorobenzoyl chloride, Et₃N, THF, then DMAP, toluene, 40% (3 steps); (h) PPTS; MeOH, 61%.

Table 3. Transition metal-catalyzed cross-coupling reaction of 32 and 6a,b

Entry

Conditions A

Conditions B

Yield (%)

1

2

3

4

BrCN, BuLi; Bu₃SnH, PdCl₂(PPh)₃

Cp₂Zr(H)Cl; ZnCl₂

(HMe₂Si)₂O, t-Bu₃P-Pt(DVDS)

BrCN, BuLi; Bu₃SnH, PdCl₂(PPh)₃

6, Pd(dba)₂

32

0

58

6, PdCl₂(PPh₃)₂, DIBAL

6, TBAF, Pd(dba)₂

6, CuTC

could be removed regioselectively with TBAF, which was

followed by protection/deprotection manipulation to furnish

the desired alcohol 34 as the single isomer. After hydrolysis

of 34, lactonization of the resulting (2Z,4E)-carboxylic acid

(J_Ha–HbZ11.3 Hz) by a modiﬁed Yamaguchi’s method²⁵

did not provide the desired (2Z,4E)-lactone 35 at all, and

gave unexpected (2E,4E)-lactone 36 as the single isomer

(J_Ha–HbZ15.3 Hz).²⁶From the fact that McClure et al.^3c

succeeded in a total synthesis of macrolactin A by the same

procedure, the replacement of the (8E,10Z)-dienic moiety to

the aromatic ring seems to prohibit the macrocyclization

into the (2Z,4E)-lactone. Finally, global deprotection of the

methoxyisopropylidene acetal and acetonide of 36 afforded

the macrolactin A analogue 1b in 61% yield.

coupling reaction to construct the (Z,E)-conjugated

dienoate. The biological activities of the synthetic inter-

mediates and 1b, prepared in this study, are now

investigated in order to establish structure–activity relation-

ship of macrolactin A. These results will be reported in the

future.

4. Experimental

4.1. General information

Melting points are uncorrected. IR spectra were obtained

using a JASCO FTIR-410 spectrometer. ¹H NMR

(500 MHz) and ¹³C NMR (125.7 MHz) spectra were

obtained using a JEOL JNM-LA-500 spectrometer using

TMS as an internal standard. Optical rotations were

measured with a JASCO DIP-360 polarimeter. Nominal

(MS) and high resolution mass spectra (HRMS) were

measured with a JEOL JMS-01SG-2 or JMS-HX/HX 110A

mass spectrometer. Column chromatography was carried

out using Merck Kieselgel 60. Dry solvents purchased from

Kanto Chemicals were used in all reactions.

3. Conclusion

The synthesis of 1b was thus completed in 23 steps in the

longest linear sequence, while another aimed compound 1a

could not be synthesized. This strategy features the

following reactions: (1) three asymmetric reactions to

generate the chiral centers, (2) isomerization of ynone to

(E,E)-conjugated dienone, (3) the Cu-catalyzed cross-

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Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

4.1.1. (2R)-6-Hydroxyhexan-2-yl Benzoate (14). To a

solution of (2R)-6-(4-methoxybenzyloxy)-2-hexanol 13^6a

(2.80 g, 11.7 mmol), triethylamine (3.28 mL, 23.5 mmol),

and DMAP (72.0 mg, 0.580 mmol) in CH₂Cl₂(40 mL) was

added benzoyl chloride (1.78 mL, 15.3 mmol) at 0 8C. The

whole mixture was stirred at ambient temperature for 1 h,

before quenching with a saturated sodium bicarbonate

solution. The organic layer was extracted with ether three

times. The combined extracts were washed with water and

brine, dried over magnesium sulfate, and then concentrated

under reduced pressure. The crude mixture was puriﬁed on

silica gel (elution: 5:1 hexane/ethyl acetate) to give the

benzoate (3.52 g, 85%) as a colorless oil. To a mixture of the

benzoate (3.52 g, 10.5 mmol), CH₂Cl₂(36 mL), and H₂O

(2 mL) was added DDQ (3.04 g, 13.4 mmol) at 0 8C and the

resulting mixture was stirred at room temperature for 2 h,

before quenching with a saturated sodium bicarbonate

solution. The mixture was diluted with ether and then

ﬁltered through a pad of Celite. The combined ﬁltrates were

condensed and puriﬁed by column chromatography on silica

gel (elution: 2:1 hexane/ethyl acetate) to furnish 14 (1.90 g,

2H, JZ7.9, 7.9 Hz), 6.00 (dt, 1H, JZ15.9, 7.0 Hz), 5.34 (d,

1H, JZ15.9 Hz), 4.98 (m, 1H), 1.96 (m, 2H), 1.58–1.29 (m,

4H), 1.15 (d, 3H, JZ6.1 Hz), 0.00 (s, 9H); ¹³C NMR (JZ

126 Hz, CDCl₃) d: 166.1, 145.3, 132.8, 130.8, 129.5, 128.3,

110.2, 103.9, 92.9, 71.3, 35.5, 32.8, 24.5, 20.1, 0.0; IR

(CHCl₃): 2957, 2139, 1710 cm^K1; MS (CI) m/z (relative

intensity) 314 (M^C, 6), 242 (56), 91 (100); HRMS (CI^C)

calcd for C₁₉H₂₆O₂Si (M^C) 314.1702, found 314.1706.

4.1.3. (2R,6E)-Nona-6-en-8-yn-2-yl benzoate (3). To a

solution of 15 (504 mg, 1.60 mmol) in THF (12 mL) was

added a 1.0 M solution of tetra-n-butylammonium ﬂuoride

(3.20 mL, 3.20 mmol) in THF at 0 8C. The reaction mixture

was stirred at 0 8C for 1 h, before being diluted with diethyl

ether. The reaction mixture was quenched with a saturated

ammonium chloride solution and then the whole was poured

into a saturated sodium bicarbonate solution. The organic

layer was separated and the aqueous layer was extracted

with diethyl ether. The combined organic extracts were

washed with brine, dried, concentrated in vacuo. The crude

product was puriﬁed by SiO₂column chromatography

(elution: 10:1 hexane/ethyl acetate) to give 3 as a colorless

oil (321 mg, 64%) [a]_D²⁴Z24.3 (cZ1.47, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d: 7.90 (d, 1H, JZ7.6 Hz), 7.41 (dd, 1H,

JZ7.6, 7.6 Hz), 7.30 (dd, 2H, JZ7.9, 7.9 Hz), 6.09 (dt, 1H,

JZ15.3, 7.0 Hz), 5.34 (d, 1H, JZ15.3 Hz), 5.03 (m, 1H),

2.66 (s, 1H), 2.01 (m, 2H), 1.64–1.30 (m, 4H), 1.20 (d, 3H,

JZ6.4 Hz); ¹³C NMR (JZ126 Hz, CDCl₃) d: 166.0, 145.9,

132.7, 130.7, 129.4, 128.2, 109.0, 82.3, 75.9, 71.2, 35.3,

32.6, 24.3, 20.0; IR (CHCl₃): 3021, 1709, 1279 cm^K1; MS

(CI) m/z (relative intensity) 242 (M^C, 36), 91 (100); HRMS

(CI^C) calcd for C₁₆H₁₈O₂(M^C) 242.1307, found 242.1309.

81%) as a colorless oil. [a]²_D⁶Z28.1 (cZ1.25, CHCl₃); H

1

NMR (500 MHz, CDCl₃) d: 8.04 (d, 2H, JZ7.6 Hz), 7.54

(dd, 1H, JZ7.6, 7.6 Hz), 7.43 (dd, 2H, JZ7.6, 7.6 Hz), 5.17

(m, 1H), 3.63 (m, 2H), 1.77 (m, 1H), 1.63 (m, 4H), 1.47 (m,

2H), 1.34 (d, 3H, JZ6.4 Hz); ¹³C NMR (JZ126 Hz,

CDCl₃) d: 166.3, 132.7, 130.7, 129.5, 128.3, 71.5, 62.5,

35.7, 32.4, 21.6, 19.9; IR (CHCl₃): 3515, 3020, 1708,

1280 cm^K1; MS (EI) m/z (relative intensity) 222 (M^C, 82),

91 (100); HRMS (EI^C) calcd for C₁₃H₁₈O₃(M^C) 222.1256,

found 222.1252.

4.1.2. (2R,6E)-9-(Trimethylsilyl)non-6-en-8-yn-2-yl

benzoate (15). To a solution of 14 (1.00 g, 4.50 mmol) in

a 2:1 mixture of DMSO and THF (45 mL) was added IBX

(1.89 g, 6.75 mmol), and the mixture was stirred at room

temperature for 30 min. After being quenched with a

saturated sodium bicarbonate solution, the aqueous layer

was extracted with diethyl ether and the combined organic

extracts were washed with brine, dried, and then concen-

trated in vacuo. The crude product was puriﬁed by SiO₂

column chromatography (elution: 5:1 hexane/ethyl acetate)

to give the aldehyde (893 mg, 90%) as a colorless oil. A

magnetically stirred slurry of (3-(trimethylsilyl)prop-2-

ynyl)triphenylphosphinium bromide (2.07 g, 4.55 mmol)

in dry THF (10 mL) was cooled to K78 8C under an argon

atmosphere. A 1.58 M solution of n-butyllithium (3.10 mL,

4.55 mmol) in n-hexane was added dropwise over a 1 min

period, and this mixture was stirred at K78 8C for 5 min.

During this time, the color of the reaction mixture changed

from pale yellow to brown. Subsequently, a solution of the

prepared aldehyde (836 mg, 3.80 mmol) in THF (10 mL)

was added to the mixture over a 1 min period. The resulting

mixture was stirred at K78 8C for 12 h and then allowed to

warm to ambient temperature. Stirring was continued for an

additional 2 h, and then the reaction mixture was quenched

with water. Extraction of the mixture with dichloromethane,

washing of the combined extracts with brine, drying, and

removal of solvents afforded the crude product, which was

puriﬁed by SiO₂column chromatography (elution: 15:1

hexane/ethyl acetate) to furnish 15 (532 mg, 44%). [a]²_D³Z

22.1 (cZ1.04, CHCl₃); ¹H NMR (500 MHz, CDCl₃) d: 7.85

(d, 2H, JZ7.9 Hz), 7.36 (dd, 1H, JZ7.9, 7.9 Hz), 7.25 (dd,

4.1.4. 3-[1-Hydroxy-3-((4S)-4-isopropyl-2-thioxothiazo-

lidin-3-yl)-3-oxopropyl]benzaldehyde (16). (Table 1,

entry 2): To a ﬂeshly dried tin(II) triﬂate (451 mg,

1.08 mmol) were successively added a solution of 11

(200 mg, 0.983 mmol) in CH₂Cl₂(2.5 mL) and N-ethyl-

piperazine (0.148 mL, 1.08 mmol) at K40 8C under an

argon atmosphere. After the mixture was stirred for 4 h, a

solution of 10 (132 mg, 0.938 mmol) in CH₂Cl₂(2.5 mL)

was added to the mixture at K78 8C, and the whole was

stirred for 2 h. The mixture was poured into a mixture of a

phosphate buffer solution (pH 7.0, 200 mL) and ethyl

acetate with vigorous stirring. The organic layer was

washed with brine, dried, concentrated in vacuo. The

crude products were puriﬁed by SiO₂column chromato-

graphy (elution: 2:1 hexane/ethyl acetate) to give two

diastereomers of 16 (60.0 mg, 18% and 18.0 mg, 5.4%) and

17 (190 mg, 35%). (Entry 3): To a solution of 11 (275 mg,

1.34 mmol) in CH₂Cl₂(7 mL) were successively added

titanium(IV) chloride (0.162 mL, 1.48 mmol) and diiso-

propylethylamine (0.256 mL, 1.48 mmol) at K40 8C under

an argon atmosphere. After the mixture was stirred at this

temperature for 2 h, a solution of 10 (181 mg, 1.34 mmol) in

dry CH₂Cl₂(7 mL) was added to the mixture at K78 8C,

and the mixture was stirred at K78 8C for 30 min. The

mixture was poured into a mixture of aqueous phosphate

buffer solution (pH 7.0, 200 mL) and ethyl acetate with

vigorous stirring. The organic layer was washed with brine,

dried, concentrated in vacuo. The crude products were

puriﬁed by SiO₂column chromatography (elution: 2:1

hexane/ethyl acetate) to give two diastereomers of 16

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2613

(139 mg, 33% and 26.0 mg, 6.2%) and 17 (136 mg, 19%).

(Entry 4): To a solution of 11 (100 mg, 0.492 mmol) in

CH₂Cl₂(2.5 mL) were successively added titanium(IV)

chloride (0.059 mL, 0.54 mmol) and N-ethylpiperazine

(0.074 mL, 0.54 mmol) at K40 8C under an argon

atmosphere. The same procedure described above gave

two diastereomers of 16 (57.1 mg, 34% and 12.5 mg, 7.5%)

and 17 (58.4 mg, 22%). Less polar isomer of 16; [a]²_D³Z

4.1.6. 3-((1R)-1-Hydroxy-3-((4S)-isopropyl-2-thioxothia-

zolidin-3-yl)-3-oxopropyl)benzyl benzoate (19). To a

solution of 11 (100 mg, 0.492 mmol) in CH₂Cl₂(2.5 mL)

were successively added titanium(IV) chloride (0.059 mL,

0.54 mmol) and diisopropylethylamine (0.092 mL,

0.54 mmol) at K40 8C under an argon atmosphere. After

the mixture was stirred at K40 8C for 2 h, a solution of 18

(107 mg, 0.447 mmol) in CH₂Cl₂(2.5 mL) was added to

this mixture at K78 8C, and the whole was stirred for

30 min. The same work-up procedure described for 16 gave

the desired product 19 (150 mg, 76%) along with the minor

diastereomer (9.0 mg, 4.5%). 19: [a]²_D³ZC210 (cZ1.20,

1

C315 (cZ1.09, CHCl₃); H NMR (500 MHz, CDCl₃) d:

10.6 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H, JZ7.6 Hz), 7.69 (d,

1H, JZ7.6 Hz), 7.54 (dd, 1H, JZ7.6, 7.6 Hz), 5.35 (d, 1H,

JZ8.9 Hz), 5.16 (t, 1H, JZ7.1 Hz), 3.90 (dd, 1H, JZ17.4,

2.7 Hz), 3.55–3.49 (m, 2H), 3.38 (br, 1H), 3.05 (d, 1H, JZ

11.6 Hz), 2.38 (m, 1H), 1.07 (d, 3H, JZ6.7 Hz), 1.00 (d,

3H, JZ6.7 Hz); ¹³C NMR (JZ126 Hz, CDCl₃) d: 203.0,

192.2, 172.2, 143.6, 136.6, 131.8, 129.2, 128.9, 127.1, 71.4,

69.5, 46.9, 30.8, 30.7, 19.0, 17.8; IR (CHCl₃): 3575, 1698,

1604, 1361, 1311 cm^K1; MS (FAB) m/z (relative intensity)

338 (MH^C, 30), 162 (88), 154 (100), 136 (77); HRMS

(FAB^C) calcd for C₁₆H₂₀NO₃S₂(MH^C) 338.0885, found

338.0894. Polar isomer of 16; [a]²_D⁴ZC208 (cZ1.93,

1

CHCl₃); H NMR (500 MHz, CDCl₃) d: 8.07 (d, 2H, JZ

7.6 Hz), 7.55 (t, 1H, JZ7.3 Hz), 7.48 (s, 1H), 7.43 (t, 2H,

JZ7.6 Hz), 7.37 (m, 3H), 5.36 (s, 2H), 5.29 (d, 1H, JZ

8.6 Hz), 5.11 (t, 1H, JZ7.0 Hz), 3.80 (dd, 1H, JZ17.4,

2.44 Hz), 3.60 (dd, 1H, JZ17.6, 9.3 Hz), 3.45 (dd, 1H, JZ

11.3, 7.9 Hz), 3.34 (s, 1H), 2.99 (d, 1H, JZ11.6 Hz), 2.35

(m, 1H), 1.04 (d, 3H, JZ6.7 Hz), 0.97 (d, 3H, JZ6.7 Hz);

¹³C NMR (JZ126 Hz, CDCl₃) d: 203.1, 172.4, 166.4,

142.9, 136.3, 133.0, 130.0, 129.7, 128.8, 128.4, 127.4,

125.7, 125.5, 71.4, 69.9, 66.5, 46.7, 30.7, 30.6, 18.9, 17.6;

IR (CHCl₃): 1713, 1274 cm^K1; MS (EI) m/z (relative

intensity) 443 (M^C, 0.3), 105 (100); HRMS (EI^C) calcd for

C₂₃H₂₅NO₄S₂(M^C) 443.1225, found 443.1222.

1

CHCl₃); H NMR (500 MHz, CDCl₃) d: 10.0 (s, 1H), 7.92

(s, 1H), 7.82 (d, 1H, JZ7.6 Hz), 7.69 (d, 1H, JZ7.6 Hz),

7.54 (dd, 1H, JZ7.6, 7.6 Hz), 5.22 (m, 2H), 3.84 (m, 2H),

3.57 (m, 2H), 3.07 (d, 1H, JZ11.6 Hz), 2.38 (m, 1H), 1.08

(d, 3H, JZ6.7 Hz), 1.00 (d, 3H, JZ6.7 Hz); ¹³C NMR

(JZ126 Hz, CDCl₃) d: 203.2, 192.3, 172.8, 143.7,

136.7, 132.0, 129.3, 129.1, 127.3, 71.3, 70.0, 46.7,

4.1.7. Methyl (3R)-3-(3-formylphenyl)-3-(tert-butyl-

dimethylsillyloxy)propanoate (20). To a solution of 19

(57.0 mg, 0.128 mmol) in CH₂Cl₂(1.3 mL) were added 2,6-

lutidine (0.045 mL, 0.39 mmol) and TBSOTf (0.044 mL,

0.19 mmol) at 0 8C, and the whole mixture was stirred at

room temperature for 30 min. After being quenched with a

saturated sodium bicarbonate solution, the mixture was

extracted with ether. The combined extracts were washed

with brine, dried, and then concentrated in vacuo. The crude

product was puriﬁed by SiO₂column chromatography

(elution: 5:1 hexane/ethyl acetate) to give TBS ether as a

colorless oil (60.0 mg, 84%). To a solution of the obtained

TBS ether (60.0 mg, 0.107 mmol) in methanol (4.3 mL) was

added K₂CO₃(32.6 mg, 0.236 mmol) at room temperature,

and the whole was stirred at room temperature for 2 h. After

the solvent was removed, ethyl acetate and water were

added to the residue, and the separated organic extract was

concentrated in vacuo. To a solution of the obtained residue

in a 2/1 mixture of DMSO and THF (1.2 mL) was added

IBX (58.0 mg, 0.207 mmol), and the whole was stirred at

room temperature for 30 min. After being quenched with a

saturated sodium bicarbonate solution, the aqueous layer

was extracted with diethyl ether. The combined organic

extracts were washed with brine, dried, and then concen-

trated in vacuo. The crude product was puriﬁed by SiO₂

column chromatography (elution: 5:1 hexane/ethyl acetate)

to give aldehyde (28.0 mg, 84% in 2 steps) as a colorless oil.

[a]²_D³ZC61.6 (cZ1.09, CHCl₃); ¹H NMR (500 MHz,

CDCl₃) d:10.0 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H, JZ

7.6 Hz), 7.64 (d, 1H, JZ7.6 Hz), 7.51 (dd, 1H, JZ7.6,

7.6 Hz), 5.24 (dd, 1H, JZ4.2, 9.2 Hz), 3.67 (s, 3H), 2.75

(dd, 1H, JZ14.7, 9.2 Hz), 2.58 (dd, 1H, JZ14.7, 4.2 Hz),

0.85 (s, 9H), 0.04 (sm, 3H), K0.16 (s, 3H); ¹³C NMR (JZ

126 Hz, CDCl₃) d: 192.2, 171.1, 145.3, 136.6, 131.9, 129.1,

129.0, 127.0, 71.6, 51.7, 46.0, 25.6, 18.0, K4.7, K5.3; IR

(CHCl₃): 2254, 1734, 1700 cm^K1; MS (FAB) m/z (relative

30.7, 30.6, 19.0, 17.8; IR (CHCl₃): 3549, 1699 cm^K1

;

MS (FAB) m/z (relative intensity) 338 (MH^C, 17), 162

(100); HRMS (FAB^C) calcd for C₁₆H₂₀NO₃S₂(MH^C)

338.0885, found 338.0888.

4.1.5. 3-Formylbenzyl benzoate (18). To a solution of 10

(19.0 g, 0.142 mol) in ethanol (420 mL) was added sodium

borohydride (1.33 g, 35.4 mmol) at 0 8C and the mixture

was stirred at room temperature for 1 h. After the solvent

was removed, ethyl acetate and water were added to the

residue. The combined extracts were washed with brine,

dried, and then concentrated in vacuo. The crude product

was puriﬁed by SiO₂column chromatography (elution: 1:1

hexane/ethyl acetate) to furnish the desired aldehyde

(12.1 g, 63%) as a colorless oil along with diol (5.97 g,

30%). To a solution of the aldehyde (1.00 g, 7.34 mmol) in

CH₂Cl₂(25 mL) were successively added triethylamine

(2.04 mL, 14.7 mmol) and benzoyl chloride (1.11 mL,

9.55 mmol) at 0 8C. After being stirred at ambient

temperature for 1 h, the mixture was quenched with a

saturated sodium bicarbonate solution, and the resultant

mixture was extracted with ether. The combined extracts

were washed with water and brine, dried, concentrated in

vacuo. The crude product was puriﬁed by SiO₂column

chromatography (elution: 5:1 hexane/ethyl acetate) to

give 18 (1.54 g, 87%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) d:9.97 (s, 1H), 8.04 (d, 2H, JZ

7.0 Hz), 7.92 (s, 1H), 7.79 (d, 1H, JZ7.6 Hz), 7.66 (d,

1H, JZ7.6 Hz), 7.49 (m, 1H), 7.37 (t, 2H, JZ7.8 Hz), 5.37

(s, 2H); ¹³C NMR (JZ126 Hz, CDCl₃) d: 192.0, 166.2,

137.4, 136.7, 133.9, 133.3, 129.8, 129.7, 129.5, 129.4,

129.0, 128.5, 65.7; IR (CHCl₃): 1693, 1605, 1451,

1372 cm^K1; MS (EI) m/z (relative intensity) 240 (M^C, 1),

105 (100); HRMS (EI^C) calcd for C₁₅H₁₂O₃(M^C)

240.0786, found 240.0788.

2614

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

intensity) 323 (MH^C, 15), 265 (100); HRMS (FAB^C) calcd

for C₁₇H₂₇O₄Si (MH^C) 323.1679, found 323.1659.

dried, and then concentrated in vacuo. The crude product

was puriﬁed by SiO₂column chromatography (elution: 5:1

hexane/ethyl acetate) to give alcohol (1.03 g, 86%).

[a]²_D⁷ZC26.2 (cZ1.09, CHCl₃); ¹H NMR (500 MHz,

CDCl₃) d: 7.43–7.25 (m, 4H), 5.03 (m, 1H), 4.88 (m, 1H),

3.78 (m, 2H), 2.70–2.51 (m, 3H), 2.01 (m, 3H), 0.96 (s, 9H),

0.95 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H), 0.00 (s, 3H), K0.08

(s, 3H); ¹³C NMR (JZ126 Hz, CDCl₃) d: 144.2, 143.9,

128.0, 125.0, 124.8, 123.5, 81.5, 74.6, 73.8, 69.9, 60.3, 42.0,

30.9, 25.8, 25.7, 18.2, 18.1, K4.6, K4.7, K4.9, K5.2; IR

(CHCl₃): 3308, 2955, 2932 cm^K1; MS (FAB) m/z (relative

intensity) 449 (MH^C, 2), 317 (25), 73 (100); HRMS

(FAB^C) calcd for C₂₅H₄₅O₃Si₂(MH^C) 449.2907, found

449.2858. To a solution of the obtained alcohol (200 mg,

0.446 mmol) in DMF (4.5 mL) were added imidazole

(91.0 mg, 1.33 mmol) and TESCl (0.150 mL, 0.891 mmol)

at room temperature, and the mixture was stirred at room

temperature for 5 h. After being quenched with a saturated

sodium bicarbonate solution, the mixture was extracted with

ether. The extract was washed with water and brine, dried,

and then concentrated in vacuo. The crude product was

puriﬁed by SiO₂column chromatography (elution: 15:1

hexane/ethyl acetate) to give 5 (250 mg, quantitative yield)

as a colorless oil. [a]²_D⁷ZC9.7 (cZ0.97, CHCl₃); ¹H NMR

(500 MHz, CDCl₃) d: 7.43–7.25 (m, 4H), 4.75 (m, 2H), 3.63

(m, 1H), 3.52 (m, 1H), 2.50 (m, 1H), 2.40 (m, 1H), 1.85 (m,

2H), 1.73 (m, 1H), 0.90 (t, 9H, JZ7.9 Hz), 0.81 (s, 9H),

0.80 (s, 9H), 0.51 (q, 6H, JZ7.9 Hz), K0.03 (s, 3H), K0.05

(s, 3H), K0.16 (s, 3H), K0.24 (s, 3H); ¹³C NMR (JZ

126 Hz, CDCl₃) d: 145.4, 143.8, 127.9, 125.1, 124.5, 123.6,

81.7, 73.9, 71.9, 69.8, 59.4, 44.0, 30.9, 25.9, 25.8, 18.3,

18.2, 6.8, 4.5, K4.6, K4.7, K5.0, K5.1; IR (CHCl₃): 2955,

2879 cm^K1; MS (EI) m/z (relative intensity) 562 (M^C, 1.5),

505 (70), 477 (78), 75 (100); HRMS (EI^C) calcd for

C₃₁H₅₈O₃Si₃(M^C) 562.3694, found 562.3687.

4.1.8. Methyl (3R)-3-(tert-butyldimethylsillyloxy)-3-[3-

((1S)-1-(tert-butyldimethylsillyloxy)-3-butynyl)phenyl]-

propanoate (21). To a solution of the chiral boron reagent,

prepared from 12 (0.148 mmol) according to the literature

procedure,¹²was added 20 (24.0 mg, 0.0744 mmol) at

K78 8C, and the mixture was allowed to stand at K78 8C

for 20 h. After being quenched with a 1.0 M hydrochloric

acid solution, the mixture was extracted with ether two

times. The combined extracts were washed with water and

brine, dried, and then concentrated in vacuo. The crude

product was puriﬁed by SiO₂column chromatography

(elution: 3:1 hexane/ether) to give alcohol (23.3 mg, 88%,

80% de) as a colorless oil. [a]²_D⁸ZC32.7 (cZ1.09, CHCl₃);

¹H NMR (500 MHz, CDCl₃) d: 7.38–7.25 (m, 4H), 5.14 (dd,

1H, JZ3.4, 9.5 Hz), 4.86 (m, 1H), 3.67 (s, 3H), 2.71 (dd,

1H, JZ14.7, 9.5 Hz), 2.62 (m, 1H), 2.54 (dd, 1H, JZ14.7,

3.4 Hz), 2.42 (m, 1H), 2.04 (s, 1H), 0.83 (s, 9H), 0.00 (s,

3H), K0.21 (s, 3H); ¹³C NMR (JZ126 Hz, CDCl₃) d:

171.5, 144.3, 142.6, 128.5, 125.4, 124.9, 123.2, 80.5, 72.3,

72.2, 71.0, 51.6, 46.2, 29.5, 25.6, 18.0, K4.7, K5.3; IR

(CHCl₃): 3307, 1733 cm^K1; MS (FAB) m/z (relative

intensity) 363 (MH^C, 9), 305 (100); HRMS (FAB^C)

calcd for C₂₀H₃₁O₄Si (MH^C) 363.1992, found 363.1976.

To a solution of the obtained alcohol (1.04 g, 2.88 mmol) in

DMF (28 mL) were added imidazole (587 mg, 8.63 mmol)

and TBSCl (867 mg, 5.75 mmol) at room temperature, and

the whole was stirred at room temperature for 4 h. After

being quenched with a saturated sodium bicarbonate

solution, the mixture was extracted with ether. The extract

was washed with water and brine, dried, and then

concentrated in vacuo. The crude product was puriﬁed by

SiO₂column chromatography (elution: 10:1 hexane/ethyl

acetate) to give 21 (1.28 g, quantitative yield) as a colorless

1

oil. [a]²_D⁸ZC23.0 (cZ1.09, CHCl₃); H NMR (500 MHz,

4.1.10. Ethyl (7S,2Z,4E)-7-(tert-butyldimethylsillyloxy)-

7-[3-((1R)-1-(tert-butyldimethylsillyloxy)-3-triethylsillyl-

oxypropyl)phenyl]hepta-2,4-dienoate (22). To a solution

of 5 (882 mg, 1.57 mmol) in THF (15.6 mL) was added a

1.58 M solution of n-butyllithium (1.49 mL, 2.35 mmol) in

n-hexane. After the solution was stirred at K78 8C for 1 h, a

1 M solution of cyanogen bromide (3.10 mL, 3.10 mmol) in

THF was added to the mixture. The reaction mixture was

stirred at K78 8C for an additional hour, before warming to

K40 8C. The mixture was then poured into a 1 M solution of

sodium hydroxide and the mixture was extracted with

diethyl ether. The combined organic extracts were ﬁltered

through a pad of Celite. The ﬁltrate was concentrated in

vacuo and the crude product was puriﬁed by SiO₂column

chromatography (elution: 40:1 hexane/ethyl acetate) to give

bromoalkyne (939 mg, 93%) as a colorless oil. To a benzene

solution (14.6 mL) of the obtained bromoalkyne (939 mg,

1.46 mmol) was added bis(triphenylphosphine)palladium(II)-

chloride (51.3 mg, 0.5 mol%), which was followed by the

slow addition of tri-n-butyltinhydride (0.620 mL,

3.21 mmol) over a 5 min period. The resulting mixture

was stirred at room temperature for 30 min. After the

solvent was removed, the crude vinyl stannane was

dissolved in DMF (11 mL) and to the solution were

successively added (Z)-3-iodopropenoate (372 mg,

1.64 mmol), Pd₂(dba)₂(626 mg, 0.109 mmol), and diiso-

propylethylamine (0.284 mL, 1.65 mmol). The whole was

CDCl₃) d: 7.27–7.20 (m, 4H), 5.12 (m, 1H), 4.78 (m, 1H),

3.66 (s, 3H), 2.71 (m, 1H), 2.59–2.43 (m, 3H), 1.90 (s, 1H),

0.86 (s, 9H), 0.82 (s, 9H), 0.05 (s, 3H), 0.00 (s, 3H), K0.10

(s, 3H), K0.20 (s, 3H); ¹³C NMR (JZ126 Hz, CDCl₃) d:

171.5, 144.1, 143.9, 128.1, 125.1, 123.6, 123.4, 81.5, 73.8,

72.2, 69.9, 51.5, 46.2, 30.9, 25.7, 25.6, 18.2, 18.0, K4.6,

K4.7, K4.9, K5.3; IR (CHCl₃): 2955, 2857, 1734 cm^K1

;

MS (EI) m/z (relative intensity) 476 (M^C, 0.3), 419 (100);

HRMS (EI^C) calcd for C₂₆H₄₄O₄Si₂(M^C) 476.2778, found

476.2780.

4.1.9. 1-((1S)-1-(tert-Butyldimethylsillyloxy)-3-butynyl)-

3-[(1R)-1-(tert-butyldimethylsillyloxy)-3-(triethylsillyl-

oxy)propyl]benzene (5). To a stirred solution of 21 (1.28 g,

2.68 mmol) in CH₂Cl₂(15 mL) was added a 0.93 M

solution of DIBAL (11.5 mL, 10.7 mmol) in n-hexane at

K78 8C under an argon atmosphere, and this mixture was

stirred for 1 h. After being quenched with water, the mixture

was extracted with three portions of dichloromethane. The

combined extracts were washed with brine, drying, and

concentrated in vacuo. The crude product was then

dissolved in methanol (27 mL), and sodium borohydride

(405 mg, 107 mmol) was added to the mixture. After the

whole was stirred at ambient temperature for 1 h, the solvent

was removed and ethyl acetate and water were added to the

residue. The organic layer was washed with water and brine,

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2615

stirred at room temperature for 1 h before being quenched

with a saturated sodium bicarbonate solution. The mixture

was extracted with ether, and the extract was washed with

water and brine, dried, and then concentrated in vacuo. The

crude product was puriﬁed by SiO₂column chromatography

(elution: 10:1 hexane/ethyl acetate) to give the desired

product 22 (315 mg, 33% in 2 steps) as a colorless oil.

[a]³_D⁴ZC14 (cZ0.97, CHCl₃); ¹H NMR (500 MHz,

CDCl₃) d:7.34 (dd, 1H, JZ11.3, 14.7 Hz), 7.28–7.11 (m,

4H), 6.48 (dd, 1H, JZ11.3, 11.3 Hz), 5.98 (dt, 1H, JZ14.7,

7.9 Hz), 5.55 (d, 1H, JZ11.3 Hz), 4.78 (dd, 1H, JZ7.9,

4.3 Hz), 4.68 (m, 1H), 4.16 (q, 2H, JZ7.0 Hz), 3.70 (m,

1H), 3.56 (m, 1H), 2.57 (m, 1H), 2.50 (m, 1H), 1.89 (m, 1H),

1.78 (m, 1H), 1.27 (t, 3H, JZ7.0 Hz), 0.90 (t, 9H, JZ

7.9 Hz), 0.81 (s, 9H), 0.80 (s, 9H), 0.51 (q, 6H, JZ7.9 Hz),

K0.03 (s, 3H), K0.05 (s, 3H), K0.16 (s, 3H), K0.19 (s,

3H); ¹³C NMR (JZ126 Hz, CDCl₃) d: 166.3, 145.5, 144.9,

144.5, 141.4, 128.9, 127.9, 124.9, 124.5, 123.5, 116.0, 74.9,

71.8, 59.7, 59.3, 44.4, 44.0, 25.8, 25.7, 18.2, 18.1, 14.2, 6.8,

4.5, K4.6, K4.7, K5.0, K5.1; IR (CHCl₃): 2955,

2360 cm^K1; MS (CI) m/z (relative intensity) 663 (MH^C,

4), 605 (10), 399 (72), 133 (100); HRMS (CI^C) calcd for

C₃₆H₆₇O₅Si₃(MH^C) 663.4296, found 663.4283.

a colorless oil; ¹H NMR (CDCl₃) d: 7.26 (d, 2H, JZ8.2 Hz),

6.87 (d, 2H, JZ8.2 Hz), 4.43 (s, 2H), 3.80 (s, 3H), 3.63 (m,

2H), 3.43 (t, 2H, JZ6.4 Hz), 1.63–1.53 (m, 4H), 1.40–1.30

(m, 6H), 1.20 (br, 1H); ¹³C NMR (CDCl₃) d: 159.0, 130.6,

129.1, 113.6, 72.4, 70.0, 62.8, 55.1, 32.6, 29.6, 29.1, 26.1,

25.6; IR (CHCl₃): 3623, 3443, 3008, 2963, 2860, 1612,

1513, 1462, 1248, 1090, 1035, 777 cm^K1; MS (EI) m/z

(relative intensity) 252 (M^C,10), 137 (97), 121 (100), 107

(16), 91 (14); HRMS (EI^C) calcd for C₁₅H₂₄O₃(M^C)

252.1725, found 252.1719. To a solution of oxalyl chloride

(4.05 mL, 46.4 mmol) in CH₂Cl₂(40 mL) were success-

ively added a solution of DMSO (3.8 mL, 54 mmol) in

CH₂Cl₂(50 mL) at K50 8C and a solution of the obtained

alcohol (9.00 g, 35.6 mmol) in CH₂Cl₂(30 mL) at K78 8C.

After being stirred for 1.5 h, the mixture was quenched with

triethylamine (15 mL) at K78 8C, and the whole mixture

was allowed to warm to 0 8C. The mixture was then

quenched with water at 0 8C, and the mixture was extracted

with ethyl acetate. The extract was washed with water and

brine, dried, and then concentrated in vacuo. The residue

was puriﬁed by SiO₂column chromatography (elution: 5:1

hexane/ethyl acetate) to give 24 (8.32 g, 93%) as a colorless

1

oil; H NMR (CDCl₃) d: 9.76 (s, 1H), 7.25 (d, 2H, JZ

8.5 Hz), 6.88 (d, 2H, JZ8.5 Hz), 4.43 (s, 2H), 3.80 (s, 3H),

3.43 (t, 2H, JZ6.6 Hz), 2.42 (t, 2H, JZ7.4 Hz), 1.67–1.56

(m, 4H), 1.43–1.29 (m, 4H); C NMR (CDCl₃) d: 202.6,

158.9, 130.6, 129.1, 113.6, 72.4, 69.8, 55.1, 43.7, 29.4, 28.8,

25.9, 21.9; IR (CHCl₃): 3007, 2938, 2860, 1722, 1612,

1247, 1224, 1091, 1035 cm^K1; MS (EI) m/z (relative

intensity) 250 (M^C,3.2), 137 (30), 121 (100), 91 (10);

HRMS (EI^C) calcd for C₁₅H₂₂O₃(M^C) 250.1569, found

250.1564.

4.1.11. Ethyl (7S,2Z,4E)-7-tert-Butyldimethylsillyloxy-7-

[3-((1R)-1-tert-butyldimethylsillyloxy-2-formylethyl)-

phenyl]hepta-2,4-dienoate (4). To a solution of 22

(250 mg, 0.377 mmol) in a mixture of DMSO, THF, and

H₂O (2.6/1.3/0.02 mL) was added IBX (232 mg,

0.829 mmol), and the mixture was stirred at room

temperature for 1 h before being quenched with a saturated

sodium bicarbonate solution. The mixture was extracted

with diethyl ether, and the combined extracts were washed

with brine, dried, and concentrated in vacuo. The crude

product was puriﬁed by SiO₂column chromatography

(elution: 5:1 hexane/ethyl acetate) to give 4 as a colorless oil

13

4.1.13. (2R)-8-(4-Methoxyphenylmethoxy)octan-2-ol

(25). (C)-TADDOL (1.01 g, 2.16 mmol) was placed in a

dry Schlenk tube under an argon atmosphere. To this, Ti(O-

i-Pr)₄(0.764 mL, 2.59 mmol) and toluene (16 mL) were

successively added, and the mixture was stirred at room

temperature for 5 h. After toluene and 2-propanol were

removed in vacuo, toluene (32 mL) and Ti(O-i-Pr)₄

(5.57 mL, 21.6 mmol) were added to the yellow residue at

room temperature. After being cooled to K25 8C, to the

resulting mixture were added a solution of 24 (2.40 g,

10.8 mmol) in toluene (24 mL) and then a 1.0 M solution of

Me₂Zn (21.6 mL, 21.6 mmol) in n-hexane, and the mixture

was stirred at the same temperature for 12 h. After being

quenched with an ammonium chloride solution, the mixture

was ﬁltrated through a pad of Celite. The ﬁltrate was washed

with brine, dried, and then concentrated in vacuo. The

residue was puriﬁed by SiO₂column chromatography

(elution: 2:1 hexane/ethyl acetate) to furnish 25 (2.58 g,

90%, 95%ee) as a colorless oil; [a]²_D²Z3.60 (cZ1.05,

CHCl₃); ¹H NMR (CDCl₃) d: 7.26 (d, 2H, JZ8.2 Hz), 6.88

(d, 2H, JZ8.2 Hz), 4.43 (s, 2H), 3.81 (s, 3H), 3.78 (m, 1H),

3.43 (t, 2H, JZ6.7 Hz), 1.64–1.55 (m, 2H), 1.50–1.25 (m,

8H), 1.18 (d, 3H, JZ6.1 Hz); ¹³C NMR (CDCl₃) d: 159.0,

130.7, 129.2, 113.7, 72.5, 70.1, 68.0, 52.2, 39.2, 29.6, 29.4,

26.1, 25.7, 23.4; IR (CHCl₃): 3454, 3009, 2934, 2860, 1513,

1462, 1248, 1232, 1093 cm^K1; MS (EI) m/z (relative

intensity) 266 (M^C,3.0), 137 (45), 121 (100), 91 (10);

HRMS (EI^C) calcd for C₁₆H₂₆O₃(M^C) 266.1882, found

266.1892. The enantiomeric excess of 25 was determined by

HPLC analysis. Chiral column; eluent; ﬂow rate; retention

1

(136 mg, 66%). [a]_D²⁸ZC26 (cZ0.97, CHCl₃); H NMR

(500 MHz, CDCl₃) d:9.77 (s, 1H), 7.36 (dd, 1H, JZ11.3,

14.5 Hz), 7.30–7.17 (m, 4H), 6.50 (dd, 1H, JZ11.3,

11.3 Hz), 5.99 (m, 1H), 5.56 (d, 1H, JZ11.3 Hz), 5.20

(m, 1H), 4.73 (m, 1H), 4.17 (q, 2H, JZ6.7 Hz), 2.85 (m,

1H), 2.62–2.41 (m, 3H), 1.28 (t, 3H, JZ6.7 Hz), 0.86 (s,

18H), 0.04 (s, 3H), 0.01 (s, 3H), K0.26 (s, 3H), K0.27 (s,

3H); ¹³C NMR (JZ126 Hz, CDCl₃) d: 201.1, 166.3, 144.9,

144.7, 143.5, 140.9, 129.1, 128.4, 125.1, 124.6, 123.2,

116.1, 74.6, 70.8, 59.8, 53.8, 44.3, 25.7, 25.6, 18.1, 18.0,

14.2, K4.6, K4.7, K5.0, K5.2; IR (CHCl₃): 2955, 2931,

2857, 1717, 1638 cm^K1; MS (CI) m/z (relative intensity)

547 (MH^C, 12), 489 (20), 283 (100); HRMS (CI^C) calcd for

C₃₀H₅₁O₅Si₂(MH^C) 547.3275, found 547.3284.

4.1.12. 7-(4-Methoxyphenylmethoxy)heptanal (24). To a

suspension of sodium hydride (1.80 g, 75.6 mmol) in DMF

(200 mL) was added 1,7-heptanediol (10.0 g, 75.6 mmol) at

0 8C under an argon atmosphere, and the mixture was stirred

at room temperature for 30 min. To the resulting solution

was slowly added 4-methoxybenzyl chloride (10.3 mL,

75.6 mmol) at K20 8C, and the whole was stirred overnight

at 0 8C. After being quenched with water, the mixture was

extracted with ether. The extract was washed with brine,

dried, and then concentrated in vacuo. The crude residue

was puriﬁed by SiO₂column chromatography (elution: 2:1

hexane/ethyl acetate) to give PMB alcohol (9.37 g, 50%) as

2616

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

times for each compounds are as follows: Daicel Chiralcel

OD, 3% 2-propanol in hexane, 1.2 mL/min, (R) (major)

20.5 min, (S) (minor) 21.7 min.

26 (4.70 g, 18.8 mmol) in a 2/1 mixture of DMSO and THF

(180 mL) was added IBX (7.90 g, 28.1 mmol), and the

mixture was stirred at room temperature for 30 min. After

being poured into a saturated sodium bicarbonate solution,

the whole was extracted with ether. The combined extracts

were washed, dried, and then concentrated in vacuo. The

residue was puriﬁed by SiO₂column chromatography

(elution: 5:1 hexane/ethyl acetate) to give aldehyde

(4.40 g, 95%) as a colorless oil; [a]¹_D⁸Z29.6 (cZ0.960,

CHCl₃); ¹H NMR (CDCl₃) d: 9.73 (s, 1H), 8.04 (d, 2H, JZ

7.4 Hz), 7.55 (dd, 1H, JZ7.4, 7.4 Hz), 7.43 (dd, 2H, JZ7.4,

7.4 Hz), 5.15 (m, 1H), 2.40 (m, 2H), 1.80–1.70 (m, 1H),

1.66–1.58 (m, 3H), 1.45–1.35 (m, 4H), 1.33 (d, 3H, JZ

6.4 Hz); ¹³C NMR (CDCl₃) d: 202.3, 165.9, 132.5, 130.6,

129.2, 128.0, 71.2, 43.5, 35.6, 28.7, 25.0, 21.7, 19.8; IR

4.1.14. Determination of the absolute conﬁguration of 25.

The absolute conﬁguration of 25 was determined by H

1

NMR methods previously described by Kusumi et al.¹¹The

¹H NMR chemical shifts of (C) and (K)-MTPA esters of

25 are as follows: (C)-MTPA ester; H NMR (CDCl₃) d:

1

7.53 (m, 2H), 7.37 (m, 3H), 7.23 (d, 2H, JZ8.5 Hz), 6.87 (d,

2H, JZ8.5 Hz), 5.14 (m, 1H), 4.40 (s, 2H), 3.80 (s, 3H),

3.56 (s, 3H), 3.35 (t, 2H, JZ6.4 Hz), 1.67–1.48 (m, 10H),

1.32 (d, 3H, JZ6.1 Hz), (K)-MTPA ester; ¹H NMR

(CDCl₃) d: 7.53 (m, 2H), 7.37 (m, 3H), 7.23 (d, 2H, JZ

8.5 Hz), 6.87 (d, 2H, JZ8.5 Hz), 5.14 (m, 1H), 4.41 (s, 2H),

3.80 (s, 3H), 3.42 (t, 2H, JZ6.4 Hz), 1.48–1.33 (m, 10H),

1.24 (d, 3H, JZ6.1 Hz).

(CHCl₃): 3028, 2939, 2863, 1715, 1453, 1281, 1116 cm^K1

;

MS (CI) m/z (relative intensity) 249 (MH^C, 100), 127 (45),

123 (40), 109 (27); HRMS (EI^C) calcd for C₁₅H₂₁O₃

(MH^C) 249.1491, found 249.1497. A magnetically stirred

slurry of potassium tert-butoxide (3.97 g, 35.4 mmol) in

THF (40 mL) was cooled to K78 8C under an argon

atmosphere. To this mixture was added a solution of

dimethyl (diazomethyl)phosphonate (6.31 g, 35.4 mmol) in

THF (50 mL) dropwise over a 1 min period, and the

resulting mixture was stirred for 5 min. During this time,

the color of the reaction mixture changed from pale yellow

to brown. Subsequently, to the mixture was added a solution

of the obtained aldehyde (4.40 g, 17.7 mmol) in THF

(40 mL) over a 1 min period. The resulting solution was

stirred at K78 8C for 24 h and then allowed to warm to

ambient temperature. Stirring was continued for an

additional 4 h, and then the reaction mixture was quenched

with water. The mixture was extracted with three portions of

dichloromethane, and the combined extracts were washing

with brine, drying, and then concentrated in vacuo. The

residue was puriﬁed by SiO₂column chromatography

(elution: 10:1 hexane/ethyl acetate) to furnish 27 (3.70 g,

4.1.15. (7R)-7-Benzoyloxyoctanol (26). To a solution of 25

(3.29 g, 12.2 mmol) in CH₂Cl₂(20 mL) were successively

added triethylamine (3.67 mL, 24.4 mmol), DMAP

(74.5 mg, 0.610 mmol), and benzoyl chloride at 0 8C. The

whole mixture was stirred at ambient temperature for 20 h.

After being quenched with a saturated sodium bicarbonate

solution, the mixture was extracted with ether. The organic

layer was washed with water and brine, dried, and then

concentrated in vacuo. The residue was puriﬁed by SiO₂

column chromatography (elution: 10:1 hexane/ethyl

acetate) to give benzoate (3.98 g, quantitative yield) as a

1

pale yellow oil; [a]_D²²Z19.0 (cZ1.01, CHCl₃); H NMR

(CDCl₃) d: 8.04 (d, 2H, JZ7.4 Hz), 7.55 (dd, 1H, JZ7.4,

7.4 Hz), 7.43 (dd, 2H, JZ7.4, 7.4 Hz), 7.25 (d, 2H, JZ

8.2 Hz), 6.87 (d, 2H, JZ8.2 Hz), 5.15 (m, 1H), 4.41 (s, 2H),

3.80 (s, 3H), 3.42 (t, 2H, JZ6.7 Hz), 1.74–1.70 (m, 1H),

1.65–1.55 (m, 3H), 1.40–1.30 (m, 6H), 1.33 (d, 3H, JZ

6.1 Hz); ¹³C NMR (CDCl₃) d: 166.1, 158.9, 132.6, 130.8,

129.4, 129.1, 128.2, 113.6, 72.4, 71.5, 69.9, 55.1, 35.9, 29.6,

29.2, 26.0, 25.3, 19.9; IR (CHCl₃): 3007, 2937, 2860, 1708,

1512, 1280, 1248, 1108 cm^K1; MS (CI) m/z (relative

intensity) 371 (MH^C,5.0), 241 (11), 121 (100); HRMS

(CI^C) calcd for C₂₃H₃₁O₄(MH^C) 371.2222, found

371.2210. To a solution of the obtained benzoate (1.24 g,

3.35 mmol) in a mixture of CH₂Cl₂and H₂O (34 mL and

2 mL) was added DDQ (850 mg, 3.74 mmol) at 0 8C and the

mixture was stirred at room temperature for 1 h. After being

quenched with a saturated sodium bicarbonate solution, the

reaction mixture was diluted with ether and ﬁltered through

a pad of Celite. The combined ﬁltrates were concentrated in

vacuo. The residue was puriﬁed by SiO₂column chroma-

tography (elution: 5:1 hexane/ethyl acetate) to furnish 26

(790 mg, 80%) as a colorless oil; [a]²_D²Z26.4 (cZ0.97,

CHCl₃); ¹H NMR (CDCl₃) d: 8.04 (d, 2H, JZ7.4 Hz), 7.55

(dd, 1H, JZ7.4, 7.4 Hz), 7.43 (dd, 2H, JZ7.4, 7.4 Hz), 5.15

(dt, 1H, JZ6.4, 8.9 Hz), 3.62 (t, 2H, JZ6.4 Hz), 1.80–1.70

(m, 1H), 1.65–1.60 (m, 1H), 1.60–1.53 (m, 2H), 1.45–1.35

(m, 6H), 1.33 (d, 3H, JZ6.4 Hz); ¹³C NMR (CDCl₃) d:

166.2, 132.6, 130.7, 129.3, 128.2, 71.5, 62.6, 35.8, 32.5,

29.1, 25.5, 25.3, 19.9; IR (CHCl₃): 3481, 2936, 2861, 1708,

1281, 1117 cm^K1; MS (CI) m/z (relative intensity) 251

(MH^C,75), 123 (4.0); HRMS (CI^C) calcd for C₁₅H₂₃O₃

(MH^C) 251.1647, found 251.1658.

85%). [a]²_D³Z34.4 (cZ1.17, CHCl₃); H NMR (CDCl₃) d:

1

8.03 (d, 2H, JZ7.4 Hz), 7.55 (dd, 1H, JZ7.4, 7.4 Hz), 7.44

(dd, 2H, JZ7.4, 7.4 Hz), 5.15 (m, 1H), 2.18 (m, 2H), 1.93

(s, 1H), 1.80–1.70 (m, 1H), 1.66–1.58 (m, 1H), 1.58–1.49

(m, 2H), 1.50–1.35 (m, 4H), 1.34 (d, 3H, JZ6.4 Hz); ¹³C

NMR (CDCl₃) d: 166.2, 132.7, 130.8, 129.5, 128.3, 84.5,

71.5, 68.2, 35.9, 28.5, 28.3, 24.9, 20.1, 18.3; IR (CDCl₃):

3307, 2940, 2963, 1709, 1453, 1281, 1120 cm^K1; MS (CI)

m/z (relative intensity) 245 (MH^C, 100), 227 (16), 123 (73),

105 (67); HRMS (EI^C) calcd for C₁₆H₂₁O₂(MH^C)

245.1542, found 245.1535.

4.1.17. (8R)-8-(tert-Butyldimethylsilyloxy)-1-nonyne (8).

To a solution of 27 (3.00 g, 12.3 mmol) in methanol

(80 mL) was added a 3 N potassium hydroxide solution

(80 mL) and the whole was stirred at room temperature for

3 h. After being concentrated in vacuo, the mixture was

extracted with ether. The extracts were washed with water

and brine, drying, and then concentrated in vacuo. The

residue was puriﬁed by SiO₂column chromatography

(elution: 2:1 hexane/ether) to give alcohol (1.43 g, 87%)

1

as a colorless oil; [a]¹_D⁹Z7.9 (cZ0.96, CHCl₃); H NMR

(CDCl₃) d: 3.80 (m, 1H), 2.20 (m, 2H), 1.97 (s, 1H), 1.66

(br, 1H), 1.60–1.50 (m, 2H), 1.50–1.38 (m, 5H), 1.38–1.28

(m, 1H), 1.19 (d, 3H, JZ6.4 Hz); ¹³C NMR (CDCl₃) d:

84.5, 68.2, 67.9, 39.1, 28.7, 28.4, 25.2, 23.5, 18.3; IR

4.1.16. (8R)-8-Benzoyloxy-1-nonyne (27). To a solution of

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2617

(CHCl₃): 3610, 3306, 3008, 2936, 2861 cm^K1; MS (EI) m/z

(relative intensity) 140 (M^C, 100), 96 (17); HRMS (EI^C)

calcd for C₉H₁₇O (M^C) 140.1201, found 140.1212. To a

solution of the obtained alcohol (700 mg, 4.99 mmol) in

DMF (50 mL) were added imidazole (1.02 g, 14.9 mmol)

and TBSCl (1.50 g, 9.98 mmol) at room temperature. The

whole was stirred at room temperature for 2 h. After being

quenched with a saturated sodium bicarbonate solution, the

mixture was extracted with ether. The combined extracts

were washed with water and brine, dried, and then

concentrated in vacuo. The residue was puriﬁed by SiO₂

column chromatography (elution: 20:1 hexane/ethyl

acetate) to give the desired product 8 (1.26 g, quantitative

was puriﬁed by SiO₂column chromatography (elution: 20:1

hexane/ethyl acetate) to give TBS ether (6.07 g, quantitative

yield) as a colorless oil; [a]²_D⁶Z17.0 (cZ1.48, CHCl₃); H

1

NMR (CDCl₃) d:8.08 (d, 2H, JZ7.3 Hz), 7.56 (dd, 1H, JZ

7.3, 7.3 Hz), 7.47–7.41 (m, 3H), 7.37–7.30 (m, 3H), 5.37

(m, 2H), 4.84 (t, 1H, JZ6.4 Hz), 2.59 (ddd, 1H, JZ16.5,

6.4, 2.3 Hz), 2.49 (ddd, 1H, JZ16.5, 6.4, 2.3 Hz), 1.94 (t,

1H, JZ2.3 Hz), 0.87 (s, 9H), 0.08 (s, 3H), K0.08 (s, 3H);

¹³C NMR (CDCl₃) d: 166.5, 144.5, 135.9, 133.1, 130.2,

129.8, 128.4, 128.3, 127.2, 125.8, 125.6, 81.4, 73.5, 70.1,

66.6, 30.9, 25.7, 18.2, K4.9, K5.0; IR (CHCl₃); 3308,

2931, 2857, 1715, 1603, 1455, 1274, 1199, 1110 cm^K1; MS

(FAB) m/z (relative intensity) 395 (MH^C, 14), 231 (35), 73

(100); HRMS (FAB^C) calcd for C₂₄H₃₁O₃Si (MH^C)

395.2042, found 395.2049. To a solution of the obtained

TBS ether (6.07 g, 15.3 mmol) in methanol (150 mL) was

added potassium carbonate (20.0 g, 153 mmol) at room

temperature, and the mixture was stirred for 1 h. After

evaporation and washing with water of the reaction mixture,

the obtained product was dissolved in a 2/1 mixture of

DMSO and THF (120 mL) and to this mixture was added

IBX (4.40 g, 15.7 mmol). The crude product obtained by the

usual workup was puriﬁed by SiO₂column chromatography

(elution: 5:1 hexane/ethyl acetate) to give aldehyde 29

(3.44 g, 86% in two steps) as a colorless oil; [a]²_D⁰Z33.5

(cZ1.08, CHCl₃); ¹H NMR (CDCl₃) d: 10.0 (s, 1H), 7.87 (s,

1H), 7.77 (d, 1H, JZ7.6 Hz), 7.65 (d, 1H, JZ7.6 Hz), 7.50

(dd, 1H, JZ7.6, 7.6 Hz), 4.89 (t, 1H, JZ6.4 Hz), 2.59 (ddd,

1H, JZ16.5, 6.4, 2.3 Hz), 2.49 (ddd, 1H, JZ16.5, 6.4,

2.3 Hz), 1.95 (t, 1H, JZ2.3 Hz), 0.88 (s, 9H), 0.08 (s, 3H),

K0.08 (s, 3H); ¹³C NMR (CDCl₃) d: 192.1, 144.9, 136.3,

131.9, 128.9, 128.8, 127.1, 80.7, 73.0, 70.5, 30.7, 25.7, 18.1,

K4.9, K5.0; IR (CHCl₃):3307, 2955, 2932, 2889, 2858,

1698, 1215, 1103 cm^K1; MS (FAB) m/z (relative intensity)

289 (MH^C, 12), 249 (55), 231 (45), 97 (32), 73 (100);

HRMS (FAB^C) calcd for C₁₇H₂₅O₂Si (MH^C) 289.1624,

found 289.1622.

1

yield) as a colorless oil; [a]¹_D⁹Z11.2 (cZ1.04, CHCl₃); H

NMR (CDCl₃) d: 3.73 (m, 1H), 2.13 (m, 2H), 1.88 (s, 1H),

1.54–1.44 (m, 2H), 1.44–1.28 (m, 5H), 1.28–1.18 (m, 1H),

1.07 (d, 3H, JZ6.4 Hz), 0.84 (s, 9H), 0.01 (s, 3H), 0.00 (s,

3H); ¹³C NMR (CDCl₃) d: 84.6, 77.2, 76.9, 76.7, 68.5, 68.1,

39.5, 28.8, 28.5, 25.9, 25.2, 23.8, 18.3, 18.1, K4.4, K4.7;

IR (CHCl₃):3306, 2933, 2858 cm^K1; MS (CI) m/z (relative

intensity) 255 (MH^C, 100), 140 (11), 96 (17); HRMS (CI^C)

calcd for C₁₅H₃₁OSi (MH^C) 255.2144, found 255.2149.

4.1.18. (1S)-1-(3-Benzoyloxymethylphenyl)-3-butyn-1-ol

(28). By using the same procedure described for 21, the

aldehyde 18 (7.00 g, 29.1 mmol) was transformed into the

crude product 28, which was puriﬁed by SiO₂column

chromatography (elution: 3:1 hexane/ether) to give a

recovered starting material (2.10 g, 29%) and 28 (4.75 g,

56%, 80%ee) as colorless crystals. The enantiomeric excess

of the product was improved from 80 to 99%ee by

recrystallization from hexane/ethyl acetate. The ee was

1

determined by H NMR analysis of (C)- and (K)-MTPA

esters of 28; mp 70–72 8C; [a]²_D³Z30.9 (cZ1.11, CHCl₃);

¹H NMR (CDCl₃) d:8.05 (d, 2H, JZ7.3 Hz), 7.54 (dd, 1H,

JZ7.3, 7.3 Hz), 7.49–7.32 (m, 6H), 5.33 (s, 2H), 4.87 (m,

1H), 2.79 (m, 1H), 2.63 (m, 2H), 2.04 (s, 1H); ¹³C NMR

(CDCl₃) d: 166.4, 143.0, 136.2, 133.0, 129.9, 129.6, 128.7,

128.3, 127.6, 125.7, 125.5, 80.5, 72.0, 71.0, 66.5, 29.3; IR

(CHCl₃): 3595, 3306, 3023, 2360, 1715, 1603, 1452, 1376,

1274 cm^K1; MS (EI) m/z (relative intensity) 280 (M^C, 37),

231 (35), 129 (20), 73 (100); Anal. calcd for C₁₅H₂₁O₃: C,

77.12; H, 5.75. found: C, 77.36; H, 5.90.

4.1.21. (4S)-N-[(3R)-3-[3-((1S)-1-tert-Butyldimethylsilyl-

oxy-3-butynyl)phenyl]-3-hydroxypropanoyl]-4-iso-

propyl-1,3-thiazolidine-2-thione (30). According to the

procedure described for 16, the same reaction of aldehyde

29 (2.68 g, 9.33 mmol), 11 (2.09 g, 10.3 mmol), titanium(IV)

chloride (1.23 mL, 11.2 mmol), and diisopropylethylamine

(1.93 mL, 11.2 mmol) provided the desired product 30

(3.45 g, 74%) along with the minor diastereomer (142 mg,

3.1%) after puriﬁcation by SiO₂column chromatography

(elution: 3:1 hexane/ethyl acetate); 30: [a]¹_D⁷ZC213 (cZ

4.1.19. Determination of the absolute conﬁguration of 28.

The absolute conﬁguration was determined by H NMR

analysis of (C)- and (K)-MTPA esters of 28: (C)-MTPA

1

ester; H NMR (CDCl₃) d: 8.06 (d, 2H, JZ7.6 Hz), 7.58

(dd, 1H, JZ7.3 Hz), 7.46–7.20 (m, 11H), 6.09 (dd, 1H, JZ

8.1, 5.0 Hz), 5.28 (m, 1H), 3.62 (s, 3H), 2.85 (ddd, 1H, JZ

16.9, 8.2, 2.4 Hz), 2.74 (ddd, 1H, JZ17.2, 5.0, 2.6 Hz), 2.02

1

1.09, CHCl₃); H NMR (CDCl₃) d:7.31 (m, 4H), 5.27 (m,

1H), 5.14 (t, 1H, JZ7.0 Hz), 4.82 (t, 1H, JZ6.4 Hz), 3.80

(m, 1H), 3.52 (m, 2H), 3.14–3.00 (m, 1H), 2.58 (ddd, 1H,

JZ16.6, 6.4, 2.6 Hz), 2.48 (ddd, 1H, JZ16.6, 6.4, 2.6 Hz),

2.38 (m, 1H), 1.96 (t, 1H, JZ2.6 Hz), 1.07 (d, 1H, JZ

6.7 Hz), 1.00 (d, 1H, JZ7.0 Hz), 0.88 (s, 9H), 0.07 (s, 3H),

K0.07 (s, 3H); ¹³C NMR (CDCl₃) d: 203.0, 172.6, 144.3,

142.3, 128.4, 125.3, 124.8, 123.5, 81.6, 73.6, 71.4, 70.1,

47.0, 30.9, 30.8, 30.7, 25.8, 19.0, 18.2, 17.8, K4.8, K5.0;

IR (CHCl₃): 3570, 3307, 2959, 2857, 1681, 1468, 1362,

1311, 1256, 1167, 1093 cm^K1; MS (FAB) m/z (relative

intensity) 492 (MH^C, 1.2), 162 (83), 73 (100); HRMS

(FAB^C) calcd for C₂₅H₃₈O₃NSiS₂(MH^C) 492.2062, found

492.2047.

1

(t, 1H, JZ2.4 Hz), (K)-MTPA ester; H NMR (CDCl₃) d:

8.06 (d, 2H, JZ7.3 Hz), 7.57 (dd, 1H, JZ7.3 Hz), 7.47–

7.30 (m, 11H), 6.14 (t, 1H, JZ6.6 Hz), 5.36 (m, 1H), 3.46

(s, 3H), 2.82 (ddd, 1H, JZ17.2, 7.3, 2.3 Hz), 2.73 (ddd, 1H,

JZ16.9, 6.0, 2.8 Hz), 1.90 (t, 1H, JZ2.4 Hz).

4.1.20. 3-[(1S)-1-(tert-Butyldimethylsilyloxy)but-3-ynyl]-

benzaldehyde (29). To a solution of 28 (4.80 g, 17.0 mmol)

in DMF (170 mL) were added imidazole (2.30 mg,

34.0 mmol) and TBSCl (3.80 g, 25.0 mmol) at room

temperature, and the whole was stirred at room temperature

for 2 h. After the usual workup, the obtained crude product

2618

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

4.1.22. Determination of the absolute conﬁguration of 30.

The absolute conﬁguration of 30 was determined by H

4.1.24. (1R,11R)-11-(tert-Butyldimethylsilyloxy)-1-[3-

[(1S)-1-(tert-butyldimethylsilyloxy)-3-butynyl]phenyl]-

1-triethylsilyloxy-4-dodecyn-3-one (7). To a solution of

alkyne 8 (172 mg, 0.676 mmol) in THF (1.5 mL) was added

a 1.0 M solution of ethylmagnesium bromide (0.66 mL,

0.66 mmol) in THF at 0 8C and the mixture was stirred at

room temperature for 30 min. To this mixture was added a

solution of 17 (260 mg, 0.442 mmol) in THF (2.0 mL) over

a 5 min period, and the whole mixture was stirred at room

temperature for 2 h. After being quenched with water, the

mixture was extracted with ethyl acetate. The combined

extracts were washed with brine, dried, and then concen-

trated in vacuo. The residue was puriﬁed by SiO₂column

chromatography (elution: 20:1–5:1 hexane/ethyl acetate) to

furnish 7 (240 mg, 70%) as a colorless oil; [a]²_D²ZC3.10

(cZ1.08, CHCl₃); ¹H NMR (CDCl₃) d: 7.34–7.23 (m, 4H),

5.27 (dd, 1H, JZ8.9, 4.3 Hz), 4.80 (t, 1H, JZ6.4 Hz), 3.77

(m, 1H), 3.02 (dd, 1H, JZ8.9, 14.9 Hz), 2.70 (dd, JZ4.3,

14.9 Hz), 2.57 (ddd, 1H, JZ16.6, 6.4, 2.4 Hz), 2.47 (ddd,

1H, JZ16.6, 6.4, 2.4 Hz), 2.36 (t, 2H, JZ7.0 Hz), 1.94 (t,

1H, JZ2.4 Hz), 1.45–1.33 (m, 5H), 1.34–1.22 (m, 3H), 1.12

(d, 3H, JZ6.1 Hz), 0.88 (s, 9H), 0.88 (s, 9H), 0.83 (t, 9H,

JZ7.9 Hz), 0.51 (q, 6H, JZ7.9 Hz), 0.07 (s, 3H), 0.05 (s,

3H), 0.04 (s, 3H), K0.08 (s, 3H); ¹³C NMR (CDCl₃) d:

185.5, 144.1, 144.0, 128.2, 125.1, 125.0, 123.5, 94.7, 81.4,

81.3, 73.7, 71.3, 69.9, 68.4, 56.4, 39.4, 30.8, 28.9, 27.6,

25.8, 25.7, 25.1, 23.7, 18.9, 18.1, 18.0, 6.6, 4.6, K4.5, K4.8,

K4.9, K5.1; IR (CHCl₃): 3308, 2955, 2933, 2881, 2858,

2213, 1668, 1466, 1255, 1217, 1100, 1080, 837 cm^K1; MS

(FAB) m/z (relative intensity) 697 (MH^K, 20), 565 (32), 153

(64), 131 (100); HRMS (FAB^K) calcd for C₄₀H₆₉O₄Si₃

(MH^K) 697.4504, found 697.4517.

1

NMR analysis of (C)- and (K)-MTPA esters derived from

30 in 4 steps: (C)-MTPA ester; ¹H NMR (CDCl₃) d: 7.39–

7.28 (m, 9H), 6.18 (dd, 1H, JZ8.9, 4.9 Hz), 4.80 (t, 1H, JZ

6.3 Hz), 3.51 (m, 2H), 3.42 (s, 3H), 2.57 (ddd, 1H, JZ16.5,

7.0, 2.8 Hz), 2.46 (ddd, 1H, JZ16.6, 5.9, 2.6 Hz), 2.19 (m,

1H), 1.96 (m, 1H), 1.92 (t, 1H, JZ2.6 Hz), 0.89 (s, 9H),

0.86 (s, 9H), 0.06 (s, 3H), 0.01 (s, 6H), K0.11 (s, 3H), (K)-

MTPA ester; ¹H NMR (CDCl₃) d: 7.37–7.12 (m, 9H), 6.11

(dd, 1H, JZ8.7, 5.3 Hz), 4.77 (dd, 1H, JZ7.0, 5.8 Hz), 3.68

(m, 1H), 3.58 (m, 1H), 3.50 (s, 3H), 2.55 (ddd, 1H, JZ16.5,

7.0, 2.8 Hz), 2.43 (ddd, 1H, JZ16.6, 5.9, 2.6 Hz), 2.21 (m,

1H), 2.00 (m, 1H), 1.93 (t, 1H, JZ2.6 Hz), 0.90 (s, 9H),

0.87 (s, 9H), 0.06 (s, 3H), 0.03 (s, 6H), K0.11 (s, 3H).

4.1.23. (3R)-3-[3-[(1S)-1-(tert-Butyldimethylsilyloxy)-3-

butynyl]phenyl]-N-methoxy-N-methyl-3-triethylsilyloxy-

propionamide (9). A mixture of N,O-dimethylhydroxyl-

amine hydrochloride (7.01 g, 72.7 mmol) and triethylamine

(9.69 mL, 72.7 mmol) in CH₂Cl₂(70 mL) was stirred at

room temperature for 1 h. The reaction mixture was added

to a solution of 30 in CH₂Cl₂(18 mL) at room temperature

and the whole mixture was stirred for 21 h. After being

poured into a 5% hydrochloric acid solution at 0 8C, the

mixture was extracted with ethyl acetate. The extracts were

washed with brine, dried, and then concentrated in vacuo.

The residue was puriﬁed by SiO₂column chromatography

(elution: 1:1 to 1:2 hexane/ethyl acetate) to furnish Weinreb

amide (2.30 g, 91%) as a colorless oil; [a]¹_D⁷ZC22 (cZ

0.95, CHCl₃); ¹H NMR (CDCl₃) d: 7.42–7.24 (m, 4H), 5.15

(m, 1H), 4.83 (t, 1H, JZ6.4 Hz), 4.30 (br, 1H), 3.61 (s, 3H),

3.20 (s, 3H), 2.90–2.70 (m, 2H), 2.58 (ddd, 1H, JZ16.6, 6.4,

2.6 Hz), 2.48 (ddd, 1H, JZ16.6, 6.4, 2.6 Hz), 1.95 (t, 1H,

JZ2.6 Hz), 0.89 (s, 9H), 0.08 (s, 3H), K0.08 (s, 3H); ¹³C

NMR (CDCl₃) d: 173.1, 144.0, 142.9, 128.1, 124.9, 124.6,

123.2, 81.6, 73.6, 70.1, 70.0, 69.9, 61.1, 40.3, 31.8, 30.9,

25.7, 18.1, K4.8, K5.0; IR (CHCl₃): 3480, 3307, 3008,

4.1.25. (1R,4E,6E,11R)-11-(tert-Butyldimethylsilyloxy)-

1-[3-[(1S)-1-(tert-butyldimethylsilyloxy)-3-butynyl]-

phenyl]-1-triethylsilyloxy-4,6-dodecadien-3-one (31).

(Entry 1): To a solution of ynone 7 (46.0 mg,

0.658 mmol) in toluene (0.3 mL) was added triphenyl-

phosphine (17.2 mg, 0.0658 mmol) and the mixture was

stirred at 100 8C for 6 h. After removal of solvent under

reduced pressure, puriﬁcation on silica gel (elution: 30:1

hexane/ethyl acetate) furnished 31 as a colorless oil

(14.5 mg, 31%). (Entry 2): To a solution of ynone 7

(50.0 mg, 0.0715 mmol) in toluene (0.35 mL) was added tri-

n-butylphosphine (0.018 mL, 0.072 mmol) and the mixture

was stirred at room temperature for 1 h. The same work-up

described above furnished 31 as a colorless oil (10.0 mg,

20%). (Entry 3): To a solution of ynone 7 (80.0 mg,

0.114 mmol) in THF–toluene (0.25–0.25 mL) was added

tri-n-butylphosphine (0.0030 mL, 0.011 mmol) and the

mixture was stirred at room temperature for 5 h. The same

work-up described above furnished 31 as a colorless oil

(22.6 mg, 28%). (Entry 4): To a solution of ynone 7

(34.0 mg, 0.0486 mmol) in toluene (0.24 mL) was added

1,4-bis(diphenylphosphino)butane (41.5 mg, 0.097 mmol)

and the mixture was stirred at room temperature for 1 h. The

same work-up described above furnished 31 as a colorless

oil (10.5 mg, 30%). (Entry 5): To a solution of ynone 7

(570 mg, 0.815 mmol) in a 1/1 mixture of THF and toluene

(4 mL) was added 1,4-bis(diphenylphosphino)butane

(69.5 mg, 0.163 mmol), and the mixture was stirred at

room temperature for 6 h. The same work-up described

above furnished 31 as a colorless oil (280 mg, 49%) along

2933, 2889, 2858, 1640, 1468, 1422, 1390, 1255, 1105 cm^K1

;

MS (FAB) m/z (relative intensity) 392 (MH^C, 18), 374

(100), 332 (33), 73 (68); HRMS (FAB^C) calcd for

C₂₁H₃₄O₄NSi (MH^C) 392.2257, found 392.2264. To a

solution of the Weinreb amide in pyridine (20 mL) was

added triethylsilylchloride (1.08 mL, 6.46 mmol) at 0 8C,

and the mixture was stirred at room temperature for 2 h. The

reaction mixture was diluted with toluene (20 mL) and then

concentrated in vacuo. The residue was puriﬁed by SiO₂

column chromatography (elution: 10:1 hexane/ethyl

acetate) to give 9 (2.90 g, quantitative yield) as a colorless

oil; [a]¹_D⁸ZC25.8 (cZ1.02, CHCl₃); H NMR (CDCl₃) d:

1

7.42–7.24 (m, 4H), 5.26 (dd, 1H, JZ8.6, 4.6 Hz), 4.81 (t,

1H, JZ6.3 Hz), 3.61 (s, 3H), 3.16 (s, 3H), 3.04 (m, 1H),

2.61–2.43 (m, 3H), 1.93 (t, 1H, JZ2.1 Hz), 0.88 (s, 9H),

0.84 (t, 9H, JZ8.1 Hz), 0.52 (q, 6H, JZ8.1 Hz), 0.08 (s,

3H), K0.07 (s, 3H); ¹³C NMR (CDCl₃) d: 171.6, 144.7,

143.9, 128.0, 125.0, 124.8, 123.4, 81.4, 73.7, 71.7, 69.8,

61.1, 43.0, 31.7, 30.7, 25.6, 18.1, 6.5, 4.5, K4.9, K5.2; IR

(CHCl₃): 3308, 3003, 2956, 2879, 2360, 1649, 1466, 1388,

1254, 1079 cm^K1; MS (FAB) m/z (relative intensity) 506

(MH^C, 6.5), 476 (58), 374 (73), 115 (42), 73 (100); HRMS

(FAB^C) calcd for C₂₇H₄₈O₄NSi₂(MH^C) 506.3122, found

506.3107.

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2619

1

with the recovered starting material 7 (170 mg, 30%).

[a]²_D²ZC35.5 (cZ1.09, CHCl₃); ¹H NMR (CDCl₃) d:

7.44–7.18 (m, 4H), 7.11 (dd, 1H, JZ15.6, 9.8 Hz), 6.16 (m,

2H), 6.06 (d, 1H, JZ15.6 Hz), 5.21 (dd, 1H, JZ8.4,

4.1 Hz), 4.80 (t, 1H, JZ6.3 Hz), 3.78 (m, 1H), 3.10 (dd, 1H,

JZ8.4, 14.7 Hz), 2.70 (dd, JZ4.1, 14.7 Hz), 2.57 (ddd, 1H,

JZ16.7, 6.3, 2.6 Hz), 2.47 (ddd, 1H, JZ16.7, 6.4, 2.6 Hz),

2.18 (m, 2H), 1.93 (t, 1H, JZ2.6 Hz), 1.62–1.46 (m, 1H),

1.47–1.35 (m, 3H), 1.12 (d, 3H, JZ6.1 Hz), 0.89 (s, 9H),

0.88 (s, 9H), 0.81 (t, 9H, JZ7.9 Hz), 0.48 (q, 6H, JZ

7.9 Hz), 0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), K0.08 (s,

3H); ¹³C NMR (CDCl₃) d: 198.8, 145.7, 144.8, 144.0, 143.8,

129.1, 128.1, 125.0, 124.9, 123.5, 81.6, 73.8, 71.2, 69.8,

68.3, 51.2, 39.0, 33.1, 30.8, 25.8, 25.7, 24.8, 23.8, 18.2,

18.0, 6.6, 4.6, K4.5, K4.8, K5.1; IR (CHCl₃): 3307, 2956,

2932, 2880, 2858, 1633, 1592, 1467, 1364, 1255, 1101,

1004, 939, 909, 837 cm^K1; MS (FAB) m/z (relative

intensity) 697 (MH^K, 6.5), 565 (13), 153 (100), 131 (93);

HRMS (FAB^K) calcd for C₄₀H₆₉O₄Si₃(MH^K) 697.4504,

found 697.4512.

85%); [a]²_D²Z22.1 (cZ1.00, CHCl₃); H NMR (CDCl₃) d:

7.43–7.19 (m, 4H), 6.19 (dd, 1H, JZ15.3, 10.4 Hz), 6.03

(dd, 1H, JZ14.8, 10.4 Hz), 5.66 (m, 2H), 5.03 (m, 1H), 4.82

(t, 1H, JZ6.1 Hz), 4.37 (m, 1H), 3.78 (m, 1H), 3.14 (br,

1H), 2.62 (br, 1H), 2.58 (ddd, 1H, JZ16.6, 6.1, 2.6 Hz),

2.47 (ddd, 1H, JZ16.6, 6.1, 2.6 Hz), 2.07 (m, 2H), 2.00–

1.90 (m, 2H), 1.94 (t, 1H, JZ2.6 Hz), 1.52–1.32 (m, 4H),

1.11 (d, 3H, JZ6.1 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.07 (s,

3H), 0.05 (s, 3H), 0.04 (s, 3H), K0.08 (s, 3H); ¹³C NMR

(CDCl₃) d: 144.2, 144.1, 135.6, 132.6, 130.9, 129.4, 128.3,

124.9, 124.7, 123.2, 81.6, 73.7, 71.7, 70.1, 70.0, 68.4, 44.5,

39.1, 32.6, 30.9, 25.8, 25.7, 25.3, 23.7, 18.2, 18.1, K4.5,

K4.8, K4.9, K5.0; IR (CHCl₃): 3601, 3503, 3307, 2931,

2858, 1467, 1378, 1255, 1105, 992, 909, 837 cm^K1; MS

(FAB) m/z (relative intensity) 609 (MCNa^C, 18), 249 (8),

73 (100); HRMS (FAB^C) calcd for C₃₄H₅₈NaO₄Si₂(MC

Na^C) 609.3771, found 609.3766. To a solution of the

obtained diol (370 mg, 0.640 mmol) in dichloromethane

(6.0 mL) were successively added 2,2-dimethoxypropane

(0.784 mL, 6.40 mmol) and a catalytic amount of pyri-

dinium p-toluenesulfonate at 0 8C and the reaction mixture

was stirred for 1 h. After being poured into a saturated

sodium bicarbonate solution, the aqueous layer was

extracted with diethyl ether. The combined extracts were

washed with brine, dried, and then concentrated in vacuo.

The residue was puriﬁed by SiO₂column chromatography

(elution: 20:1 hexane/ethyl acetate) to furnish a major

diastereomer 32 (288 mg, 74%) as a colorless oil along with

a minor diastereomer (21.4 mg, 5.6%). 32; [a]²_D¹Z3.0 (cZ

0.70, CHCl₃); ¹H NMR (CDCl₃) d: 7.43–7.19 (m, 4H), 6.22

(dd, 1H, JZ15.3, 10.4 Hz), 6.04 (dd, 1H, JZ14.8, 10.4 Hz),

5.68 (m, 2H), 4.93 (m, 1H), 4.83 (t, 1H, JZ6.1 Hz), 4.52 (m,

1H), 3.77 (m, 1H), 2.57 (ddd, 1H, JZ16.6, 6.1, 2.6 Hz),

2.47 (ddd, 1H, JZ16.6, 6.1, 2.6 Hz), 2.10–2.00 (m, 4H),

1.96 (t, 1H, JZ2.6 Hz), 1.52–1.32 (m, 4H), 1.47 (s, 3H),

1.46 (s, 3H), 1.11 (d, 3H, JZ6.1 Hz), 0.89 (s, 9H), 0.88 (s,

9H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), K0.07 (s, 3H);

¹³C NMR (CDCl₃) d: 144.1, 142.4, 135.6, 131.4, 130.7,

129.6, 128.1, 124.9, 124.8, 123.4, 100.7, 81.8, 73.6, 69.9,

68.4, 68.3, 67.7, 39.3, 39.2, 32.6, 31.0, 25.9, 25.8, 25.6,

25.4, 25.1, 23.9, 18.2, 18.1, K4.3, K4.7, K4.8, K4.9; IR

(CHCl₃): 3307, 2931, 2858, 1467, 1378, 1255, 1105, 992,

909, 837 cm^K1; MS (FAB) m/z (relative intensity) 649

(MCNa^C, 3.0), 587 (4.0), 176 (8.2), 73 (100); HRMS

(FAB^C) calcd for C₃₇H₆₂NaO₄Si₂(MCNa^C) 649.4084,

found 649.4077.

4.1.26. (4R,6R)-4-[3-[(1S)-1-(tert-Butyldimethylsilyloxy)-

3-butynyl]phenyl]-6-[(1E,3E,8R)-8-(tert-butyldimethyl-

silyloxy)nona-1,3-dienyl]-2,2-dimethyl-1,3-dioxane (32).

Dienone 31 (630 mg, 0.901 mmol) was dissolved in a

mixture of AcOH/THF/H₂O (8:8:1, 10 mL), and the

solution was stirred at room temperature for 24 h. After

being quenched with a saturated sodium bicarbonate

solution, the mixture was extracted with ethyl acetate. The

combined extracts were washed with brine, dried, and then

concentrated in vacuo. The residue was puriﬁed by SiO₂

column chromatography (elution: 3:1 hexane/ethyl acetate)

to give alcohol (440 mg, 83%) as a colorless oil; [a]²_D⁰Z

C12 (cZ0.96, CHCl₃); ¹H NMR (CDCl₃) d: 7.34–7.19 (m,

4H), 7.11 (dd, 1H, JZ15.6, 9.8 Hz), 6.15 (m, 2H), 6.03 (d,

1H, JZ15.6 Hz), 5.16 (m, 1H), 4.79 (t, 1H, JZ6.4 Hz), 3.73

(m, 1H), 2.90 (m, 2H), 2.53 (ddd, 1H, JZ16.7, 6.3, 2.6 Hz),

2.43 (ddd, 1H, JZ16.7, 6.4, 2.6 Hz), 2.15 (m, 2H), 1.91 (t,

1H, JZ2.6 Hz), 1.62–1.46 (m, 1H), 1.47–1.35 (m, 3H), 1.08

(d, 3H, JZ6.1 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H),

0.05 (s, 3H), 0.04 (s, 3H), K0.08 (s, 3H); ¹³C NMR (CDCl₃)

d: 200.6, 146.7, 144.5, 144.2, 142.9, 128.8, 128.3, 127.9,

125.0, 124.7, 123.2, 81.6, 73.6, 70.0, 69.9, 68.2, 48.4, 39.0,

33.1, 30.9, 25.8, 25.7, 24.7, 23.7, 18.1, 18.0, K4.5, K4.9,

K5.0; IR (CHCl₃): 3672, 3510, 3307, 2955, 2932, 2858,

1633, 1593, 1467, 1362, 1255, 1105, 1002, 937, 909, 837

cm^K1; MS (FAB) m/z (relative intensity) 607 (MCNa^C,

28), 73 (100); HRMS (FAB^C) calcd for C₃₄H₅₆NaO₄Si₂

(MCNa^C) 607.3615, found 607.3621. To a solution of

tetramethylammonium triacetoxyborohydride (1.42 g,

6.01 mmol) in acetonitrile (3 mL) was added acetic acid

(3 mL), and the mixture was stirred at room temperature for

30 min. To the cooled mixture at K40 8C was added a

solution of the obtained alcohol (440 mg, 0.752 mmol) in

acetonitrile (2.2 mL) via cannula. After being stirred at

K40 8C for 18 h, the mixture was quenched with a 0.5 N

sodium potassium tartrate solution and then diluted with

chloroform. The aqueous layer was extracted with chloro-

form and the combined extracts were washed with a

saturated sodium bicarbonate solution and brine, dried,

and then concentrated in vacuo. The residue was puriﬁed by

SiO₂column chromatography (elution: 2:1 hexane/ethyl

acetate) to give alcohols as a diastereomixture (374 mg,

4.1.27. (2Z,4E,7S)-7-tert-Butyldimethylsilyloxy-7-[3-

[(4R,6R)-6-[(1E,3E,8R)-8-(tert-butyldimethylsilyloxy)-

nona-1,3-dienyl]-2,2-dimethyl-1,3-dioxan-4-yl]]phenyl-

hepta-2,4-dienoic acid ethyl ester (33). (Entry 1): To a

cooled solution of alkyne 32 (100 mg, 0.159 mmol) in THF

(1.9 mL) was added a 1.58 M solution n-butyllithium in

n-hexane (0.190 mmol, 0.120 mL). The solution was stirred

at K78 8C for 1 h, before being quenched with a solution of

cyanogen bromide in THF (0.190 mmol, 0.190 mL). The

reaction mixture was stirred at K78 8C for an additional

hour and then allowed to warm to K40 8C. The reaction

mixture was then poured into a sodium hydroxide solution

(1 M) and extracted with diethyl ether. The combined

organic layers were dried and ﬁltered through a pad of

Celite. After concentration in vacuo, the crude bromoalkyne

(87.0 mg, 0.123 mmol) was dissolved in benzene (1.4 mL).

2620

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

The addition of bis(triphenylphosphine)palladium(II)-

chloride (5.4 mg, 0.5 mol%) to the solution was followed

by a slow addition of tri-n-butyltinhydride (0.066 mL,

0.34 mmol) over 5 min. The solution was stirred at room

temperature for 30 min before removal of the solvent under

reduced pressure. The crude vinyl stannane was dissolved in

DMF (0.43 mL) and to the solution were added (Z)-3-

iodopropenoate (15.0 mg, 0.0664 mmol), Pd₂(dba)₂

(3.1 mg, 0.0039 mmol), and diisopropylethylamine

(0.011 mL, 0.064 mmol). The whole was stirred at room

temperature for 1 h before being quenched with a saturated

sodium bicarbonate solution. The organic layer was

extracted with ether. The extract was washed with water

and brine, dried, condensed in vacuo. The residue was

puriﬁed by SiO₂column chromatography (elution: 10:1

hexane/ethyl acetate) to give 33 as a colorless oil (15.6 mg,

32% in 3 steps). (Entry 4): To a cooled solution of alkyne 32

(110 mg, 0.159 mmol) in THF (1.7 mL) was added a 1.58 M

solution of n-butyllithium (0.190 mmol, 0.120 mL) in

n-hexane, and the mixture was stirred at K78 8C for 1 h.

After a 1 M solution of cyanogen bromide (0.190 mmol,

0.190 mL) in THF was added to the mixture, the reaction

mixture was stirred at K78 8C for 1 h and then allowed to

warm to K40 8C over a 10 min period. The mixture was

poured into a 1 M sodium hydroxide solution and the

resulting mixture was extracted with diethyl ether. The

combined extracts were washed with brine, dried, and

ﬁltered through a pad of Celite. The solvent was removed

under reduced pressure to provide a crude product, which

was dissolved in benzene (1.4 mL). To the mixture was

Na^C, 5.0), 587 (10), 247 (9.2), 73 (100); HRMS (FAB^C)

calcd for C₄₂H₇₀NaO₆Si₂(MCNa^C) 749.4609, found

749.4615.

4.1.28.

(2Z,4E,7S)-7-[3-[(4R,6R)-6-[(1E,3E,8R)-8-

Hydroxynona-1,3-dienyl]-2,2-dimethyl-1,3-dioxan-4-yl]]-

phenyl-7-(1-methoxy-1-methylethoxy)hepta-2,4-dienoic

acid ethyl ester (34). To a solution of 33 (76.0 mg,

105 mmol) in THF (1.0 mL) was added a 1 M solution of

tetra-n-butylammonium ﬂuoride (0.21 mL, 0.21 mmol) in

THF at 0 8C, and the reaction mixture was stirred for 1 h.

The reaction mixture was quenched with a mixture of ether

and a saturated ammonium chloride solution and then the

resulting mixture was poured into a saturated sodium

bicarbonate solution. The mixture was extracted with

diethyl ether several times. The combined extracts were

washed with brine, dried, and then concentrated in vacuo.

The residue was puriﬁed by SiO₂column chromatography

(elution: 4:1 hexane/ethyl acetate) to give alcohol (58.9 mg,

92%) as a colorless oil; [a]²_D⁶ZC8.60 (cZ1.01, CHCl₃); ¹H

NMR (CDCl₃) d:7.48 (dd, 1H, JZ11.3, 11.3 Hz), 7.41–7.21

(m, 4H), 6.54 (dd, 1H, JZ11.3, 11.3 Hz), 6.22 (dd, 1H, JZ

15.3, 10.4 Hz), 6.05 (m, 2H), 5.69 (m, 2H), 5.60 (d, 1H, JZ

11.3 Hz), 4.93 (m, 1H), 4.79 (m, 1H), 4.53 (m, 1H), 4.17 (q,

2H, JZ7.3 Hz), 3.78 (m, 1H), 2.65 (m, 2H), 2.14 (br, 1H),

2.06 (m, 4H), 1.48 (s, 6H), 1.45–1.32 (m, 4H), 1.29 (t, 3H,

JZ7.3 Hz), 1.11 (d, 3H, JZ5.8 Hz), 0.88 (s, 9H), 0.04 (s,

6H); ¹³C NMR (CDCl₃) d: 166.5, 144.5, 144.1, 142.9, 140.3,

135.7, 131.5, 130.6, 129.6, 129.5, 128.7, 125.5, 124.9,

123.4, 116.7, 100.8, 73.6, 68.4, 68.3, 67.8, 59.9, 42.6, 39.4,

39.1, 32.6, 25.8, 25.5, 25.3, 25.0, 23.8, 18.0, 14.2, K4.5,

K4.8; IR (CHCl₃): 3686, 3026, 2993, 2932, 2858, 1705,

1603, 1466, 1377, 1193, 994 cm^K1; MS (FAB) m/z (relative

intensity) 635 (MCNa^C, 64), 211 (11), 176 (12), 91 (12),

73 (100); HRMS (FAB^C) calcd for C₃₆H₅₆NaO₆Si (MC

Na^C) 635.3744, found 635.3738. To a cooled solution of the

obtained alcohol (58.9 mg, 96.2 mmol) in dichloromethane

(1.0 mL) were added 2-methoxypropene (18.4 mL,

193 mmol) and a catalytic amount of pyridinium p-toluene-

sulfonate at 0 8C and the mixture was stirred for 1 h. After

being poured into a saturated sodium bicarbonate solution,

the mixture was extracted with diethyl ether. The combined

extracts were washed with brine, dried, and then concen-

trated in vacuo. The residue was puriﬁed by SiO₂column

chromatography (elution: 85:15:0.5 hexane/ethyl acetate/

triethylamine) to furnish ether (53.2 mg, 82%) as a colorless

oil; [a]³_D¹ZC7.3 (cZ0.74, CHCl₃); ¹H NMR (CDCl₃)

d:7.36 (dd, 1H, JZ11.3, 11.3 Hz), 7.30–7.11 (m, 4H), 6.48

(dd, 1H, JZ11.3, 11.3 Hz), 6.22 (dd, 1H, JZ15.1, 10.5 Hz),

6.04 (dd, 1H, JZ15.0, 10.5 Hz), 5.94 (m, 1H), 5.69 (m, 2H),

5.56 (d, 1H, JZ11.3 Hz), 4.92 (m, 1H), 4.76 (t, 1H, JZ

6.6 Hz), 4.52 (m, 1H), 4.17 (q, 2H, JZ7.2 Hz), 3.78 (m,

1H), 3.08 (s, 3H), 2.66 (ddd, 1H, JZ14.2, 7.3, 7.2 Hz), 2.55

(ddd, 1H, JZ14.2, 6.9, 6.6 Hz), 2.04 (m, 4H), 1.48 (s, 3H),

1.47 (s, 3H), 1.44–1.31 (m, 4H), 1.38 (s, 3H), 1.28 (t, 3H,

JZ7.2 Hz), 1.12 (s, 3H), 1.11 (d, 3H, JZ6.1 Hz), 0.88 (s,

9H), 0.04 (s, 6H); ¹³C NMR (CDCl₃) d: 166.5, 144.8, 144.5,

142.6, 141.1, 135.7, 131.4, 130.7, 129.6, 129.0, 128.4,

125.3, 124.6, 124.0, 116.2, 101.1, 100.7, 72.8, 68.4, 68.3,

67.7, 59.8, 49.3, 42.6, 39.4, 39.1, 32.6, 26.0, 25.8, 25.5,

25.3, 25.1, 25.0, 23.8, 18.1, 14.2, K4.5, K4.8; IR (CHCl₃):

2994, 2933, 2850, 1707, 1634, 1603, 1459, 1378, 1233,

1217, 1199, 1073, 1014, 995 cm^K1; MS (FAB) m/z (relative

added

bis(triphenylphosphine)palladium(II)chloride

(6.1 mg, 0.5 mol%), which was followed by a slow addition

of tri-n-butyltinhydride (0.060 mL, 0.31 mmol) over a

5 min period. After the mixture was stirred at room

temperature for 30 min and concentrated in vacuo, the

obtained vinylstannane was dissolved in NMP (1.4 mL). To

the mixture were successively added (Z)-3-iodopropenoate

(38.4 mg, 0.170 mmol) and copper (I) 2-thiophenecar-

boxylate (40.5 mg, 0.212 mmol) at 0 8C. The reaction

mixture was then diluted with ether and ﬁltered through a

plug of alumina to remove copper salts and tri-n-butyltin

thiophene-2-carboxylate. The combined ﬁltrates were

washed with brine, dried, and the concentrated in vacuo.

Several drops of triethylamine were added to the residue

before puriﬁcation by SiO₂column chromatography

(elution: 100:1:0.5 to 100:20:0.5 hexane/ethyl acetate/

triethylamine) to give 33 as a colorless oil (72.6 mg,

58%). [a]²_D³Z1.50 (cZ1.75, CHCl₃); H NMR (CDCl₃) d:

1

7.38 (dd, 1H, JZ11.3, 11.3 Hz), 7.33–7.10 (m, 4H), 6.51

(dd, 1H, JZ11.3, 11.3 Hz), 6.21 (dd, 1H, JZ15.1, 10.5 Hz),

6.03 (m, 2H), 5.68 (m, 2H), 5.57 (d, 1H, JZ11.3 Hz), 4.91

(m, 1H), 4.72 (m, 1H), 4.52 (m, 1H), 4.17 (q, 2H, JZ

7.0 Hz), 3.76 (m, 1H), 2.53 (m, 2H), 2.03 (m, 4H), 1.48 (s,

3H), 1.46 (s, 3H), 1.44–1.31 (m, 4H), 1.28 (t, 3H, JZ

7.0 Hz), 1.10 (d, 3H, JZ6.1 Hz), 0.87 (s, 9H), 0.86 (s, 9H),

0.04 (s, 3H), 0.03 (s, 3H), K0.01 (s, 3H), K0.15 (s, 3H); ¹³C

NMR (CDCl₃) d: 166.5, 145.1, 145.0, 142.6, 141.7, 135.7,

131.4, 130.8, 129.7, 129.0, 128.3, 124.7, 124.6, 123.4,

116.1, 100.7, 74.7, 68.4, 68.3, 67.8, 59.8, 44.5, 39.4, 39.2,

32.6, 25.9, 25.7, 25.6, 25.4, 25.1, 23.8, 18.1, 18.0, 14.2,

K4.5, K4.7, K4.8, K5.0; IR (CHCl₃): 2955, 2931, 2857,

1706, 1638, 1602, 1467, 1378, 1255, 1231, 1074, 996, 904,

836 cm^K1; MS (FAB) m/z (relative intensity) 749 (MC

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

2621

intensity) 707 (MCNa^C, 28), 176 (13), 173 (8.0), 73 (100);

HRMS (FAB^C) calcd for C₄₀H₆₄NaO₇Si (MCNa^C)

707.4319, found 707.4311. To a solution of the obtained

ether (53.2 mg, 78.6 mmol) in THF (0.8 mL) was added a

1/1 mixture of tetra-n-butylammonium ﬂuoride and acetic

acid (1.2 mL) at room temperature. After being stirred for

24 h and poured into a saturated sodium bicarbonate

solution, the mixture was extracted with diethyl ether. The

combined extracts were washed with brine, dried, and then

concentrated in vacuo. The residue was puriﬁed by SiO₂

column chromatography (elution: 80:20:0.5 hexane/ethyl

acetate/triethylamine) to give 34 (40.0 mg, 89%) as a

colorless oil; [a]_D³¹ZC11 (cZ0.74, CHCl₃); ¹H NMR

(CDCl₃) d:7.35 (dd, 1H, JZ11.3, 11.3 Hz), 7.30–7.11 (m,

4H), 6.48 (dd, 1H, JZ11.3, 11.3 Hz), 6.22 (dd, 1H, JZ15.3,

10.4 Hz), 6.05 (dd, 1H, JZ15.3, 10.4 Hz), 5.94 (m, 1H),

5.69 (m, 2H), 5.56 (d, 1H, JZ11.3 Hz), 4.92 (m, 1H), 4.76

(t, 1H, JZ6.4 Hz), 4.52 (m, 1H), 4.17 (q, 2H, JZ7.2 Hz),

3.79 (m, 1H), 3.08 (s, 3H), 2.66 (ddd, 1H, JZ14.1, 7.1,

7.1 Hz), 2.55 (ddd, 1H, JZ14.1, 6.9, 6.7 Hz), 2.06 (m, 4H),

1.49 (s, 3H), 1.49 (s, 3H), 1.44–1.31 (m, 4H), 1.40 (s, 3H),

1.28 (t, 3H, JZ7.2 Hz), 1.19 (d, 3H, JZ6.1 Hz), 1.12 (s,

3H); ¹³C NMR (CDCl₃) d: 166.5, 144.8, 144.5, 142.6, 141.1,

135.3, 131.3, 130.9, 129.9, 129.0, 128.4, 125.3, 124.6,

124.0, 116.2, 101.2, 100.7, 72.8, 68.3, 68.0, 67.7, 59.8, 49.3,

42.6, 39.4, 38.7, 32.5, 26.0, 25.5, 25.3, 25.1, 25.0, 23.5,

14.2; IR (CHCl₃): 3700, 2995, 2935, 2354, 1708, 1641,

1603, 1378, 1187, 1066, 1034, 994, 908 cm^K1; MS (FAB)

m/z (relative intensity) 593 (MCNa^C, 33), 176 (14), 173

(6.2), 73 (100); HRMS (FAB^C) calcd for C₃₄H₅₀NaO₇

(MCNa^C) 593.3454, found 593.3449.

124.4, 124.3, 124.0, 120.5, 101.2, 100.5, 73.0, 70.4, 67.9,

67.8, 49.2, 41.9, 39.5, 34.1, 31.3, 26.4, 26.1, 25.7, 24.9,

23.5, 19.6; IR (CHCl₃): 3002, 2935, 2870, 2366, 2340,

1701, 1640, 1615, 1445, 1379, 1249, 1201, 1151, 1111,

1074, 1034, 996, 908, 739 cm^K1; MS (FAB) m/z (relative

intensity) 547 (MCNa^C, 38), 176 (10), 73 (100); HRMS

(FAB^C) calcd for C₃₂H₄₄NaO₆(MCNa^C) 547.3036, found

547.3032.

4.1.30. (2R,4R,5E,7E,12R,15E,17E,20S)-2,4,20-Tri-

hydroxy-13-oxabicyclo[19.3.1]pentacosa-1(25),5,7,15,17,

21,23-heptaen-14-one (1b). The lactone 36 (9.0 mg,

17 mmol) was dissolved in wet methanol (0.3 mL) and the

mixture was treated with a catalytic amount of PPTS. After

being stirred at room temperature for 1 h, the mixture was

concentrated in vacuo and the resulting residue was puriﬁed

by SiO₂column chromatography (elution: 1:2 hexane/ethyl

acetate) to give 1b (4.3 mg, 61%) as a white amorphous;

1

[a]²_D³Z93 (cZ0.40, CHCl₃); H NMR (CDCl₃) d: 7.45–

7.30 (m, 2H), 7.19 (m, 2H), 7.08 (dd, 1H, JZ15.3, 11.0 Hz),

6.15 (m, 2H), 6.02 (m, 1H), 5.93 (m, 1H), 5.72 (d, 1H, JZ

15.3 Hz), 5.61 (m, 2H), 5.03 (m, 1H), 4.97 (m, 1H), 4.92

(dd, 1H, JZ6.7, 2.4 Hz), 4.41 (m, 1H), 3.56 (br, 1H), 2.79

(m, 1H), 2.69 (br, 1H), 2.62 (m, 1H), 2.21 (br, 1H), 2.09 (m,

2H), 1.98 (m, 2H), 1.55–1.37 (m, 4H), 1.22 (d, 3H, JZ

6.4 Hz); ¹³C NMR (CDCl₃) d: 166.7, 143.9, 137.7, 134.6,

132.6, 131.7, 130.7, 130.3, 129.2, 129.0, 128.4, 124.9,

124.8, 123.7, 121.1, 73.4, 71.7, 70.5, 70.4, 44.1, 41.8, 34.4,

31.5, 24.1, 19.9; IR (CHCl₃): 3559, 3156, 2254, 1794, 1697,

1642, 1466, 1381, 1096, 991 cm^K1; MS (FAB) m/z (relative

intensity) 435 (MCNa^C, 10), 281 (10), 207 (10), 176 (19),

147 (32), 73 (93), 55 (100); HRMS (FAB^C) calcd for

C₂₅H₃₂NaO₅(MCNa^C) 435.2147, found 435.2154.

4.1.29. (2R,4R,5E,7E,12R,15E,17E,20S)-2,4-Dihydroxy-

20-(1-methoxy-1-methylethoxy)-13-oxabicyclo[19.3.1]-

pentacosa-1(25),5,7,15,17,21,23-heptaen-14-one di-

methylacetal (36). A solution of ester 34 (35.0 mg,

61.3 mmol) in a 1/1/1 mixture of THF, ethanol, and 3 N

KOH (0.6 mL) was heated to 60 8C for 2 h. After the solvent

was evaporated under reduced pressure, diethyl ether and a

saturated ammonium chloride solution were added to the

residue. The resulting mixture was extracted with diethyl

ether. The combined extracts were dried and ﬁltered through

a pad of Celite. Triethylamine was added to the ﬁltrates

before evaporation of the solvents. To a solution of the

triethylamine salt in THF (0.6 mL) was added 2,4,6-

trichlorobenzoyl chloride (30.0 mg, 122 mmol) at 0 8C,

and the reaction mixture was stirred at room temperature

for 4 h. After removal of the solvents, DMAP (45.0 mg,

368 mmol) was added to a solution of the obtained residue in

toluene (6.0 mL) at room temperature. The mixture was

stirred for 1 h. After the solvent was removed under reduced

pressure, the residue was puriﬁed by SiO₂column

chromatography (elution: 85:15:0.5 hexane/ethyl acetate/

triethylamine) to give 36 (14.0 mg, 44% in 3 steps);

Acknowledgements

This research was supported by grants from 21st Century

COE Program ‘Knowledge Information Infrastructure for

Genome Science’.

References and notes

1. (a) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc.

1989, 111, 7519. (b) Rychonovsky, S. D.; Skalitzky, D. J.;

Pathirana, C.; Jensen, P. R.; Fenical, W. J. Am. Chem. Soc.

1992, 114, 671.

2. Nagao, T.; Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H.

J. Antibiot. 2001, 54, 333.

3. (a) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118,

13095. (b) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew.

Chem., Int. Ed. 1998, 37, 1261. (c) Marino, J. P.; McClure,

M. S.; Holub, D. P.; Comasseto, J. V.; Tucc, F. C. J. Am.

Chem. Soc. 2002, 124, 1664.

1

[a]³_D¹ZC63 (cZ0.90, CHCl₃); H NMR (CDCl₃) d: 7.44–

7.28 (m, 3H), 7.05 (dd, 1H, JZ11.1, 11.1 Hz), 6.84 (s, 1H),

6.22–5.91 (m, 3H), 5.74 (d, 1H, JZ15.9 Hz), 5.70 (m, 1H),

5.70 (m, 1H), 5.60 (m, 1H), 5.51 (m, 1H), 4.90 (m, 2H), 4.66

(dd, 1H, JZ9.8, 4.0 Hz), 4.53 (m, 1H), 3.15 (s, 3H), 2.55

(m, 2H), 2.11 (m, 2H), 1.93 (t, 2H, JZ7.2 Hz), 1.48 (s, 6H),

1.44–1.31 (m, 4H), 1.40 (s, 3H), 1.20 (d, 3H, JZ6.4 Hz),

1.12 (s, 3H); ¹³C NMR (CDCl₃) d: 166.5, 144.1, 143.4,

142.2, 139.5, 134.6, 131.3, 131.2, 130.7, 130.0, 129.2,

4. (a) Boyce, R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37,

3501. (b) Donaldson, W. A.; Bell, P. T.; Wang, Z.; Bennett,

D. W. Tetrahedron Lett. 1994, 35, 5829. (c) Prahlad, V.;

Dnaldson, W. A. Tetrahedron Lett. 1996, 37, 9169. (d)

Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama, M. Synth.

´

Commun. 1996, 26, 559. (e) Benvegnu, T. J.; Gree, R. L.

2622

Y. Kobayashi et al. / Tetrahedron 61 (2005) 2607–2622

´

Tetrahedron 1996, 52, 11821. (f) Gonzalez, A.; Aiguade, J.;

´

Urpı, F.; Vilarrasa, J. Tetrahedron Lett. 1996, 37, 8949. (g)

´

Trans. 1 1996, 2417. Zhang, H. X.; Guibue, F.; Balavoine, G.

J. Org. Chem. 1990, 55, 1857.

¨

Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.;

Donaldson, W. A. Tetrahedron 2000, 56, 2283. (h) Li, S.; Xu,

R.; Bai, D. Tetrahedron Lett. 2000, 41, 3463. (i) Bonini, C.;

14. Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1990, 1643.

Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.

15. Wu, Y.; Huang, J.; Shen, X.; Hu, Q.; Tang, C.; Li, L. Org. Lett.

2002, 4, 2141.

´

Chiummiento, L.; Pullez, M.; Solladie, G.; Colobert, F. J. Org.

Chem. 2004, 69, 5015.

5. (a) Hachem, A.; Floc’h, Y. L.; Gree, R.; Rolland, Y.; Simonet,

S.; Verbeuren, T. Tetrahedron Lett. 2002, 43, 5217. (b)

16. Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1779. Wipf, P.;

Ribe, E. J. Org. Chem. 1998, 63, 6454.

´

17. (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.

Tetrahedron Lett. 1983, 24, 5281. (b) Fu¨rstner, A. Chem. Rev.

1999, 99, 991.

´

Benvegnu, T. J.; Gree, R. Tetrahedron 1996, 52, 11821.

6. (a) Fukuda, A.; Kobayashi, Y.; Kimachi, T.; Takemoto, Y.

Tetrahedron 2003, 59, 9305. (b) Kobayashi, Y.; Fukuda, A.;

Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron Lett.

2004, 45, 677.

18. Hartman, C.; Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org.

Chem. 1971, 36, 1379. Brown, D. G.; Velthuisen, E. J.;

Commerford, J. R.; Brisbois, R. G.; Hoye, T. R. J. Org. Chem.

1996, 61, 2540.

7. Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,

30, 99.

19. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

20. Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.

Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921.

21. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.

Soc. 1998, 110, 3560.

8. First preparation of IBX: Hartman, C.; Meyer, V. Chem. Ber.

1893, 26, 1727. For a superior route to IBX, see: Frigerio, M.;

Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.

9. (a) Corey, E. J.; Fleet, G. W. J.; Kato, M. Tetrahedron Lett.

1973, 14, 3963. (b) Ahmed, M.; Barley, G. C.; Hearn,

M. T. W.; Jones, E. R. H.; Thaller, V.; Yates, J. A. J. Chem.

Soc., Perkin Trans. 1 1974, 1981.

22. Zeng, F.; Negishi, E. Org. Lett. 2002, 4, 703.

23. Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073.

24. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,

2748.

10. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.;

Hashimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.

11. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,

34, 2543. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,

H. J. Am. Chem. Soc. 1991, 113, 4092.

25. Hioka, M.; Tone, H.; Horita, K.; Yonemitsu, O. Tetrahedron

1990, 46, 4613. Inagawa, J.; Hirata, K.; Saeki, H.; Katsuki, T.;

Yamagutchi, M. Bull. Chem. Soc. Jpn. 1989, 1979, 52.

26. Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66,

8973. Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49,

4332.

12. Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986,

108, 483.

13. Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin

Article Doi

Asymmetric synthetic study of macrolactin analogues

DOI: 10.1016/j.tet.2005.01.062

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Full text of DOI:10.1016/j.tet.2005.01.062

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