Total synthesis of zaragozic acid C by an aldol-based strategy

Tetrahedron 61 (2005) 11078–11106

*

Seiichi Nakamura, Hiroki Sato, Yuuki Hirata, Nobuhide Watanabe and Shunichi Hashimoto

Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

Received 10 August 2005; revised 9 September 2005; accepted 12 September 2005

Available online 7 October 2005

Abstract—A total synthesis of zaragozic acid C by a convergent strategy is described in which the key features include (1) the simultaneous

creation of the C4 and C5 quaternary stereogenic centers by a Sn(OTf)₂-promoted aldol coupling reaction between an a-keto ester and a silyl

ketene thioacetal derived from ^L- and D-tartaric acids, respectively, (2) the direct introduction of lithium acetylide as the C1 side chain

equivalent onto the fully functionalized aldehyde, and (3) construction of the bicyclic core structure by acid-catalyzed internal ketalization

under kinetically controlled conditions.

1. Introduction

zaragozic acid C (1) and zaragozic acid A, respectively, in

1994. Since then the Evans¹⁰and Armstrong¹¹groups

reported the total syntheses of 1, while the efforts of the

Heathcock,¹²and Tomooka and Nakai¹³groups culminated

in the total syntheses of zaragozic acid A. In addition to the

six total syntheses, a total synthesis of 6,7-dideoxysquale-

statin H5, a less oxygenated congener of the zaragozic acids,

has also been reported by Martin and co-workers.¹⁴All of

these approaches involve internal ketalization to construct

the core structure; only Heathcock adopted a stepwise

approach, wherein the full C1 alkyl side chain was installed

after the ketalization event. Our own efforts in this area have

led to two total syntheses of zaragozic acid C (1) through

entirely distinct routes based on an aldol approach¹⁵and a

carbonyl ylide cycloaddition approach,¹⁶respectively. In

this article, we describe the details of the total synthesis of 1

by the aldol-based strategy.

The zaragozic acids and squalestatins, fungal metabolites

isolated and characterized independently by researchers at

Merck,¹Glaxo,²and Tokyo Noko University/Mitsubishi

Kasei Corporation³in 1992, have been shown to be

picomolar competitive inhibitors of the enzyme squalene

synthase. Consequently, they are considered to be promising

lead compounds for the development of new serum

cholesterol-lowering drugs.⁴Some members of this family

have also been found to display farnesyl-protein transferase

inhibitory activity,^1e,5which has implications in the

development of antitumor agents. Structurally, these

molecules share a 4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]-

octane-3,4,5-tricarboxylic acid core with an array of six

stereogenic centers including contiguous quaternary ones,

and represent considerable variations in the C1 alkyl and C6

acyl side chains. The gross structural similarity between

presqualene pyrophosphate (PSPP) and zaragozic acids, that

is, a highly acidic central core with two long lipophilic side

chains, has led to the speculation that zaragozic acids inhibit

squalene synthase by effectively mimicking the binding of

PSPP to the enzyme.^1c,3Due to the biological activity of

these compounds and their novel structural aspects,

zaragozic acids (squalestatins) have elicited considerable

attention from numerous synthetic chemists.^6,7Of a variety

of approaches to preparing the densely oxygenated 2,8-

dioxabicyclo[3.2.1]octane ring system by innovative

strategies and tactics, the two research groups of Carreira⁸

and Nicolaou⁹accomplished the ﬁrst total syntheses of

2. Results and discussion

2.1. Synthetic plan

Keywords: Zaragozic acids; Aldol reaction; a-Keto ester; Silyl ketene

thioacetal; Internal ketalization.

The main problem in zaragozic acid synthesis is the

construction of the highly oxygenated bicyclic core bearing

an array of six stereogenic centers, including contiguous

*

Corresponding author. Tel.: C81 11 706 3236; fax: C81 11 706 4981;

e-mail: hsmt@pharm.hokudai.ac.jp

doi:10.1016/j.tet.2005.09.030

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11079

quaternary ones. Our retrosynthetic analysis of zaragozic

acid C (1) originated from the identiﬁcation of ^L- and

D-tartaric acids in the core structure (Scheme 1).¹⁷While

some concern arose over the formation of the isomeric

bicycloketal 4, we expected that the natural 2,8-

dioxabicyclo[3.2.1]octane core structure 3 would be

thermodynamically more stable than 4. We envisioned

that the addition of the metalated C1 alkyl side chain

equivalent 7 to aldehyde 6, followed by oxidation, would

provide the ketalization precursor 5. The aldol moiety in 6

allowed the indicated disconnection, deﬁning the tartrate-

derived a-keto ester 8 and enolate 9 as potential

intermediates. This approach has the advantage of mini-

mizing the use of protecting groups and oxidation state

manipulation.

yield.¹⁸Provided that the nucleophilic addition of enolate 9

to a-keto ester 8 occurs in accord with the Felkin-Anh

model, the formation of the desired stereoisomer 10 with the

correct stereochemistry would be expected (Eq. 1).¹⁹

(1)

2.2. Preparation of substrates for the aldol coupling

At the outset of our studies, a number of enolate precursors

and a-keto esters were prepared to investigate the key aldol

reaction. The enolate precursors 13 and 14 were readily

available via short synthetic routes depicted in Scheme 2.

The known ^D-tartaric acid-derived aldehyde 11²⁰was

subjected to a Pinnick oxidation²¹to give carboxylic acid

(C)-12 in 95% yield. Treatment of (C)-12 with CH₂N₂in

Et₂O afforded methyl ester 13 in 78% yield, whereas the

corresponding thioester 14 could be obtained through the

intermediacy of the acid chloride in 77% yield in two steps.

Scheme 2. Reagents and conditions: (a) NaClO₂, NaH₂PO₄, 2-methyl-2-

butene, ^tBuOH–H₂O, 18 h; (b) CH₂N₂, Et₂O, 0 8C, 30 min, then rt, 30 min;

(c) (COCl)₂, cat. DMF, CH₂Cl₂, 1.5 h; (d) 20% aqueous MeSNa, Bu₄NI,

CH₂Cl₂, 0 8C, 10 min.

On the other hand, a-keto ester 17 could be prepared from

the ^L-tartaric acid-derived carboxylic acid (K)-12 in four

steps via the a-keto vinyl ether intermediate 16

(Scheme 3).²²The reaction of (K)-12 with (COCl)₂,

Scheme 1. Retrosynthetic analysis of zaragozic acid C (1).

With regard to the aldol reactions associated with our

scenario, Seebach and co-workers reported that the

acetonide derivative of dimethyl ^L-tartrate could be

deprotonated without b-elimination by LDA at K78 8C to

provide the corresponding lithium enolate, the reaction of

which with acetone took place preferentially from the less

hindered face to give a 4:1 mixture of adducts in 60%

Scheme 3. Reagents and conditions: (a) (COCl)₂, cat. DMF, CH₂Cl₂,

30 min; (b) MeONHMe$HCl, pyridine, CH₂Cl₂, 0 8C, 1 h; (c) ethyl vinyl

ether (EVE), BuLi, THF, K78 8C, 3 h; (d) O₃, CH₂Cl₂, K78 8C, 10 min,

t

then Me₂S, K78 8C to rt, 1 h.

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S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

followed by condensation with N,O-dimethylhydroxyl-

amine hydrochloride, afforded the Weinreb amide 15 in

92% yield, which upon treatment with lithiated ethyl vinyl

ether gave the a-keto vinyl ether 16 in 85% yield.

Ozonolysis of 16 furnished the desired a-keto ester 17 in

96% yield. The synthetic schemes described above proved

to be effective for a variety of thioesters and a-keto esters.

Since the tartrate-derived a-keto esters were prone to

hydration, they were azeotropically dried with benzene prior

to use.

2.3. Aldol reaction

(2)

With the enolate precursors and a-keto esters in hand, we

then proceeded to investigate the key aldol coupling

reaction. Since the simultaneous creation of the consecutive

quaternary stereogenic centers by an aldol reaction of

a-keto esters is unprecedented in the literature,^23,24we felt it

was prudent to test the viability of the reaction using a

simple a-keto ester. The known compound 18²⁵was then

chosen as a model substrate for the reaction. We initially

explored the reaction of the lithium enolate derived from

ester 13 with a-keto ester 18 (Eq. 2). Treatment of ester 13

with LDA at K78 8C followed by the addition of a-keto

ester 18 led to an inseparable mixture of four aldol adducts

19 in 84% combined yield, the ratio of which was

The enolate precursors 13 and 14 could be converted to the

corresponding silyl ketene acetals by treatment with

LiHMDS at K78 8C followed by the addition of TMSCl

(Scheme 4). Although the hydrolysis-prone silyl ketene

acetal derived from ester 13 could not be obtained in

synthetically useful levels of purity in our hands, silyl

ketene thioacetal 20 (Z/EZ99:1), derived from thioester 14

in 95% yield, was more stable than the corresponding ester

derivative,²⁶and could be puriﬁed on Florisil. The

1

stereochemistry of the major isomer was veriﬁed by H

NOE correlation (0.3%) between Si(CH₃)₃and the methine

proton in 20. At the inception of this project, several

literature reports appeared documenting the effectiveness of

TiCl₄and Sn(OTf)₂as promoters in the Mukaiyama aldol

addition to a-keto esters.^23b–gWhile TiCl₄had no effect on

the reaction of a-keto ester 18 with silyl ketene thioacetal

20, the use of Sn(OTf)₂in EtCN, a combination developed

for aldol reactions of pyruvates by Kobayashi and

co-workers,^23e,g,27resulted in a quantitative reaction,

whereby a 1:2.6 mixture of two adducts 21a and 21b with

1

determined to be 61:15:15:9 by 270 MHz H NMR. The

stereochemical assignment of the two isomers 19a and 19b

will be presented later (vide infra). A similar result (84%

yield, drZ60:17:16:7) was obtained when HMPA was used

as a co-solvent. However, under these conditions the

reaction with 17 did not proceed beyond a 50% conversion.

As a result, we were prompted to investigate the Lewis acid-

promoted aldol reaction.

Scheme 4. Reagents and conditions: (a) LiHMDS, THF, K78 8C, 30 min, then TMSCl, K78 8C, 1 h, and rt, 15 min; (b) a-keto ester 18, Sn(OTf)₂, EtCN,

K78 8C, 30 min; (c) Hg(OCOCF₃)₂, MeCN; (d) K₂CO₃, MeOH; (e) H₂, 10% Pd/C, EtOH, 2 h; (f) DMAP, CH₂Cl₂, 1 h.

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11081

the correct stereochemistry at C4 out of the four possible

diastereomers was obtained. The absolute stereochemical

relationship of each of the easily separable diastereomers

was determined based on the C3 stereocenter, the

conﬁguration of which was secure. The treatment of each

diastereomer with Hg(OCOCF₃)₂in MeCN resulted in the

formation of b-lactone,²⁸thus affording 22a and 22b,

survey of reaction solvents (EtCN, CH₂Cl₂, toluene, THF,

Et₂O) revealed that EtCN was the only solvent that

permitted the present coupling to proceed. Of the Lewis

acids screened, Sc(OTf)₃, TiF₄, and (ⁱPrO)₂TiCl₂also

promoted the formation of aldol adducts (entries 2–4).

Although the diastereoselectivity could be improved by

employing (ⁱPrO)₂TiCl₂as a promoter, a much reduced

yield (55%) was obtained, even when 5 equiv of 20 were

used (entry 5). Kobayashi and co-workers demonstrated that

the syn:anti stereoselectivity is controlled by the geometry

of silyl ketene thioacetals in Sn(OTf)₂-promoted aldol

additions to pyruvate esters.^23e,g,27After considerable

experimentation, it was found that the dropwise addition

of KHMDS to the thioester 14 over a period of 2 h at

K78 8C (inverse addition) followed by treatment with

TMSCl furnished silyl ketene thioacetal 25 in 87% yield

with virtually complete E-selectivity (Z/EZ1:99,

Scheme 5). Since the preferential formation of (Z)-silyl

ketene thioacetal (Z/EZ72:28) was observed with KHMDS

at K78 8C by the internal quench method,²⁹this outcome

would be a consequence of thermodynamic control.

Disappointingly, however, (E)-silyl ketene thioacetal 25

was found to be a less reactive nucleophile compared to the

corresponding (Z)-isomer 20, and the Sn(OTf)₂-promoted

aldol reaction of 25 (Z/EZ1:99) with a-keto ester 17

proceeded slowly at K55 8C to afford adducts in 36% yield

with 1:10 stereoselectivity favoring the undesired dia-

stereomer 24b. These results deﬁnitely revealed the

advantages of the (Z)-silyl ketene thioacetal over its (E)

counterpart in terms of both yield and ratio of the desired

product.

1

respectively, in high yields. The H NOE (4%) between

C3–H and C6–H conﬁrmed the relative stereochemical

relationship between the quaternary stereocenters in 22b,

whereas the absence of an NOE between C3–H and C6–H in

22a indicated an opposite relationship to that in 22b.

Methanolysis of b-lactones 22a and 22b afforded methyl

esters 19a and 19b, respectively. Debenzylation of 19a and

19b followed by treatment with DMAP effected the

g-lactone formation, insuring the relative stereochemical

relationship between C3 and C4. This sequence of

experiments established the stereochemistry of 21a/19a

and 21b/19b as 4S,5R and 4S,5S, respectively. Despite the

lack of carbonyl diastereofacial selectivity, it appeared

attractive for the present coupling that the Sn(OTf)₂-

promoted reaction occurred exclusively from the less

hindered si-face of silyl ketene thioacetal 20 due to the

steric demands of the benzyloxymethyl group, thus creating

the proper conﬁguration at C4. Following these results, this

reaction was applied to the more functionalized substrate

17.

Under the foregoing conditions, the aldol reaction between

a-keto ester 17 and silyl ketene thioacetal 20 (Z/EZ99:1)

proceeded to completion within 1.5 h to give a 1:2.2 mixture

of aldol adducts 24a and 24b in 90% combined yield

(Table 1, entry 1). In an effort to reverse the stereochemical

outcome of the aldol reaction to give the desired

stereoisomer, alternate conditions were investigated. A

Table 1. Lewis acid-promoted aldol reaction of a-keto ester 17 with

(Z)-silyl ketene thioacetal 20

Scheme 5. Reagents and conditions: (a) KHMDS (inverse addition), THF,

K78 8C, 2.5 h, then TMSCl, K78 8C, 30 min, and rt, 15 min; (b) a-keto

ester 17, Sn(OTf)₂, EtCN, K55 8C, 1 h.

These results suggest that Sn(OTf)₂was the optimal Lewis

acid and (Z)-silyl ketene thioacetal 20 was identiﬁed as a

suitable coupling partner for this reaction. During the course

of these studies, we found that when Sn(OTf)₂was used as a

promoter, the product ratio (24a:24b) changed as the

reaction proceeded (Table 2). Although undesired isomer

24b was exclusively formed during the initial 5-min period

of the reaction (entry 1), a 1:2.2 mixture of adducts was

obtained on completion of the reaction. Since the

isomerization of 24b to 24a did not occur under these

conditions, these observations suggest that multiple reaction

pathways are involved in this coupling.

Entry

Lewis acid

Temperature Time

(h)

Yield

(%)

24a:24b^a

(8C)

1

2

3

Sn(OTf)₂

Sc(OTf)₃

TiF₄

K70

K45

K60

1.5

0.5

2

90

31

70

30

55

1:2.2

1:5.3

1:5

1:1.5

4

(ⁱPrO)₂TiCl₂rt

12

5^b

^aThe ratio was determined by 270 MHz ¹H NMR analysis of the crude

mixture.

^bThe reaction was performed using 5 equiv of silyl ketene thioacetal 20.

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S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

Table 2. Sn(OTf)₂-promoted aldol coupling between a-keto ester 17 and

silyl ketene thioacetal 20

desired product to the undesired C5 epimer increased

slightly when the pentylidene acetal 27 was used (entries 3

vs 1, 2, and 4). With regard to acetal protection in silyl

ketene thioacetals, an exceptionally high order of selectivity

for the undesired C5 epimer was obtained in the case of

methylene acetal 33, with little variation being observed

between isopropylidene and pentylidene acetals 20 and 34

(entries 5 vs 3 and 6). Switching protection of the primary

alcohol in 20 or 27 from a benzyl ether to a tert-

butyldiphenylsilyl ether led to the predominant formation

of the undesired isomers 41b and 42b (entries 3 vs 7 and 8),

suggesting that the chelating ability of the oxygen atoms

might be responsible for the desired p-facial selectivity. Of

the substituted methyl ethers surveyed for R²(entries 9–11),

MEM ether proved to be the protecting group of choice for

the primary alcohol at C1, providing a mixture of aldol

adducts 45a and 45b in a ratio of 1.6:1 (entry 11).

Entry

Time (min)

Yield (%)

24a:24b^a

The stereochemical outcome of each reaction was inferred

on the basis of the chemical transformations and NOE data

analogous to that illustrated in Scheme 4. For example,

isomers 37a and 37b were converted to b-lactones 46a and

46b, respectively, and the NOE experiments indicated

unequivocally relative stereochemical relationships

between the quaternary stereocenters for both isomers

(Scheme 6). The fact that the methanolysis of b-lactones

46a and 46b followed by debenzylation and treatment with

DMAP gave g-lactones 47a and 47b, respectively,

conﬁrmed a 4S conﬁguration. As the work progressed and

we acquired a library of spectral data, we also noticed that

1

2

3

5

15

90

28

75

90

0:1

1:3.2

1:2.2

^aThe ratio was determined by 270 MHz ¹H NMR analysis of the crude

mixture.

We next anticipated that the carbonyl p-facial selectivity

might be reversed by the judicious choice of protecting

groups imparted to each reaction partner. A number of

thioesters and a-keto esters were prepared by routes

analogous to that illustrated for 14 (Scheme 2) and 17

(Scheme 3), and evaluated as substrates for the Sn(OTf)₂-

promoted aldol reaction. The results of the aldol reactions

are shown in Table 3.

1

these isomers were readily distinguishable by the H NMR

signals for the S-methyl protons, which were always 0.04–

0.1 ppm downﬁeld in the desired product relative to its C5

epimer. It is also noteworthy that the cyclization of

undesired isomer 37b proceeded to completion within

10 h, while extended reaction times (200 h) were required

While the acetal moiety in the a-keto esters had a little

inﬂuence on the carbonyl facial selectivity, the ratio of the

Table 3. Sn(OTf)₂-promoted aldol coupling between an a-keto ester and a silyl ketene thioacetal

Entry

a-Keto ester

R¹

Silyl ketene thioacetal

Aldol adducts

Yield (%)

R²

R³

R⁴

Desired:

undesired^a

1

2

3

4

5

6

7

8

17

26

27

28

27

29

30

31

32

Me

H

Bn

TBDPS

MOM

BOM

MEM

20

33

34

35

20

Me

H

Bn

TBDPS

Bn

24

36

37

38

39

40

41

42

43

44

45

90

49

79

82

67

65

45

79

90

83

1:2.2

1:2.6

1:1.1

1:1.6

1:O20

1:1.9

1:O20

1:5

Et

ⁿPr

Et

Me

9

10

11

1.1:1

1:1.6

1.6:1

Bn

1

^aThe ratio was determined by 270 MHz H NMR analysis of the crude mixture.

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11083

by the retro-aldol reaction of 45b, and that the desired

isomer 45a is thermodynamically more stable than 45b.³²

The low yield can be attributed to the lability of 32 to base.

Despite the low yields of the products, this equilibration/

recycling process permitted the undesired isomer 45b to be

productively utilized and therefore enhanced the overall

synthetic efﬁciency.

(3)

2.4. Synthesis of internal ketalization precursor

Having accomplished the simultaneous creation of the

consecutive quaternary stereogenic centers by a Sn(OTf)₂-

promoted aldol coupling between an a-keto ester and a silyl

ketene thioacetal, we then proceeded to the elaboration of

the internal ketalization precursor. The aldol coupling of

a-keto ester 32³³with 1.7 equiv of silyl ketene thioacetal 20

on a multigram scale proceeded in 81% yield, albeit with a

slightly diminished selectivity (45a:45bZ1.3:1, Scheme 7).

After separation of the C5 epimer 45b, thioester 45a was

converted to methyl ester 49 in 87% yield by treatment with

Hg(OCOCF₃)₂in reﬂuxing MeOH.²⁸Although the hydro-

genolysis of 49 over 10% Pd/C in MeOH gave the

corresponding alcohol 50, we found these conditions to be

capricious due to the formation of g-lactone 51 as a

byproduct. This side reaction could be minimized by the use

of 20% Pd(OH)₂/C in AcOEt. The lactonization-prone

alcohol 50 was then converted into a carboxylic acid by two

successive oxidations (Dess-Martin periodinane;³⁵

NaClO₂), which was subjected to CH₂N₂to provide triester

52 in 84% overall yield without intervening puriﬁcation. It

should be noted that the application of the standard Swern

protocol³⁶in place of the Dess-Martin procedure resulted in

the signiﬁcant epimerization at C3. The selective removal of

the MEM ether was effected with TMSCl/NaI in MeCN at

K23 8C,³⁷affording diol 53 in 94% yield. At this juncture,

the C5 tertiary alcohol was protected as its TMS ether via a

two-step bissilylation–monodesilylation sequence^9b,dto

give alcohol 54 in 87% yield, which, upon treatment with

Dess-Martin periodinane, furnished aldehyde 55 in 91%

yield.

Scheme 6. Reagents and conditions: (a) Hg(OCOCF₃)₂, MeCN, 200 h (for

37a) or 10 h (for 37b); (b) K₂CO₃, MeOH, 1.5 h; (c) H₂, 10% Pd/C, MeOH,

1 h; (d) DMAP, MeCN, 1.5 h.

for the complete conversion of 37a to 46a under the same

reaction conditions.

Ironically, the undesired diastereomers 39b and 41b were

exclusively formed by the proper choice of the protecting

groups for each reaction partner; however, it was quite

difﬁcult to obtain the desired isomer predominantly by this

aldol coupling.³⁰Our attention was then directed to

recycling the undesired isomer back to the starting a-keto

ester and thioester. After considerable experimentation, we

found that the treatment of 45b with KHMDS in THF at

temperatures above K23 8C effected a retro-aldol reaction.

Surprisingly, when the reaction was performed at substrate

concentrations of more than 0.08 M, the undesired isomer

45b was completely consumed within 2 h and the desired

isomer 45a was formed in 23% yield, along with 20% of

thioester 14 (Eq. 3). It is clear that the observed

isomerization of 45b to 45a is the result of an aldol reaction

between a-keto ester 32 and potassium enolate 48, produced

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S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

Scheme 8. Reagents and conditions: (a) alkyne 56, BuLi, THF, K78 8C,

45 min, then aldehyde 55, 30 min; (b) Dess–Martin periodinane, CH₂Cl₂,

11 h; (c) H₂, 10% Pd/C, AcOEt, 10 min.

groups and concomitant ketalization, affording bicycloketal

59 in 68% yield (Scheme 9). While the formation of the 6,8-

dioxabicyclo[3.2.1]octane isomer 61 was not observed, a

minor byproduct 60 arising from dehydration of the C6

hydroxyl group was isolated.³⁹When the reaction was

quenched after a 10-min period, alcohol 62 and hemiketal

63 were obtained as intermediates in 53 and 29% yields,

respectively. Monitoring the internal ketalization by TLC

analysis showed that desilylation occurred immediately,

forming hydroxyketone 62, from which the pentylidene

ketal was subsequently removed to give the ﬁve-membered

hemiketal 63 through closure of the C5 hydroxyl group onto

the C1 carbonyl. The steric congestion around the acetonide

required 15 h for its hydrolytic removal to reach completion,

and then the desired bicycloketal 59 was formed as a single

stereoisomer. These observations suggest that the selectivity

in the internal ketalization process is mainly due to the

differential rates of hydrolysis of the protecting groups.

Independent of our study, a similar conclusion was reached

by Armstrong and co-workers in their total synthesis of

zaragozic acid C.¹¹The ratio of TFA/H₂O in this reaction is

not arbitrary: extended reaction times (48 h) were required

for complete conversion with 80% aqueous TFA, lowering

the product yield due to the formation of a debenzylated

byproduct.

Scheme 7. Reagents and conditions: (a) Sn(OTf)₂, EtCN, K70 8C, 1.5 h;

(b) Hg(OCOCF₃)₂, MeOH, reﬂux, 10 h; (c) H₂, 20% Pd(OH)₂/C, AcOEt,

10 h; (d) Dess–Martin periodinane, CH₂Cl₂, 8 h; (e) NaClO₂, NaH₂PO₄,

2-methyl-2-butene, ^tBuOH–H₂O (10/3), 2.5 h; (f) CH₂N₂, Et₂O, 0 8C,

10 min; (g) TMSCl, NaI, MeCN, K23 8C, 2 h; (h) MeN(TMS)COCF₃,

90 8C, 3 h; (i) 10% aqueous HCl, Et₂O, 1.5 h; (j) Dess–Martin periodinane,

CH₂Cl₂, 3.5 h.

To install the C1 alkyl side chain, initial attempts to employ

Grignard reagent 7 (MZMgBr) resulted in a low yield. We

then elected to use alkyne 56³⁸as a C1 alkyl side chain

equivalent (Scheme 8). As anticipated, the installation of the

C1 alkyl side chain was uneventfully achieved by the

addition of the lithium acetylide, generated from alkyne 56,

to aldehyde 55, providing a diastereomeric mixture of

coupling products, which, upon treatment with Dess-Martin

periodinane, furnished ynone 57 in 79% yield in two steps.

Finally, catalytic hydrogenation of the triple bond gave the

internal ketalization precursor 58 in 93% yield.

2.6. Completion of the total synthesis

To avoid concomitant hydrolytic cleavage of the C6 acyl

side chain at the end of the synthesis, the triesters present in

59 should be hydrolyzed and converted to the corresponding

tri(tert-butyl) ester at this stage. Although the C4 methyl

ester proved to be extremely resistant to hydrolysis, the

reaction of 59 with 1 N aqueous KOH in dioxane at 100 8C

furnished the triacid which, upon treatment with N,N⁰-

diisopropyl-O-tert-butylisourea,⁴⁰gave tri(tert-butyl ester)

64 in 40% yield in two steps (Scheme 10). Hydrogenolysis

of the C4⁰benzyl ether provided tetraol 65 in 90% yield,

which was acetylated to give triacetate 66 in quantitative

yield. The route to 66 constitutes a formal synthesis of

zaragozic acid C (1) since it intersects the same intermediate

employed by Carreira and Du Bois.⁸However, the speciﬁc

2.5. Internal ketalization

With a viable route to ketone 58 secured, the stage was now

set for the crucial internal ketalization. Exposure of 58 to

90% aqueous TFA resulted in the removal of protecting

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11085

Scheme 9. Internal ketalization.

Scheme 10. Reagents and conditions: (a) 1 N aqueous KOH, dioxane, 100 8C, 24 h; (b) ⁱPrN]C(O^tBu)NHⁱPr, CH₂Cl₂, 24 h; (c) H₂, 10% Pd/C, MeOH, 17 h;

(d) Ac₂O, DMAP, CH₂Cl₂, 0 8C, 30 min; (e) 0.2% K₂CO₃in MeOH, 1 h; (f) (Boc)₂O, 4-pyrrolidinopyridine, Et₃N, CH₂Cl₂, 0 8C, 12 h; (g) carboxylic acid 2,

DCC, DMAP, CH₂Cl₂, 48 h; (h) TFA, CH₂Cl₂, 16 h.

rotation of compound 66 [[a]²_D¹C17.6 (c 0.91, CH₂Cl₂)]

was not in agreement with the reported value [[a]_DC69.9

(c 0.29, CH₂Cl₂)].^8bFollowing the procedure developed by

Carreira,^8bselective removal of the C6 and C7 acetyl groups

by treatment with 0.2% K₂CO₃in MeOH, selective

protection of the C7 hydroxyl group by (Boc)₂O,

esteriﬁcation with acid 2,^1fand global deprotection with

TFA gave zaragozic acid C (1) in 60% overall yield. The

synthetic material 1, [a]²_D³C9.4 (c 0.30, EtOH) [lit.,^1b[a]²_D⁰

C9.6 (c 0.29, EtOH)], was obtained as a white ﬁlm and

relevant spectroscopic data were identical with those

stereocenters at C4 and C5 could be formed simultaneously

in a single operation by a Sn(OTf)₂-promoted aldol reaction

between an a-keto ester and a silyl ketene thioacetal. We

also demonstrate that the selectivity in the internal

ketalization process was mainly due to the differential

rates of hydrolysis of the protecting groups.

4. Experimental

4.1. General

1

reported for natural zaragozic acid C (IR, H NMR, ¹³C

NMR, HRMS).

Melting points were determined on a Bu¨chi 535 digital

melting point apparatus and were uncorrected. Optical

rotations were recorded on JASCO DIP-370 or P-1030

digital polarimeters. Infrared (IR) spectra were recorded on

a JASCO FT/IR-5300 spectrophotometer and absorbance

bands are reported in wavenumber (cm^K1). Proton nuclear

magnetic resonance (¹H NMR) spectra were recorded on

JEOL EX-270 (270 MHz), JEOL EX-400 (400 MHz) or

Bruker ARX500 (500 MHz) spectrometers with tetra-

methylsilane (d_H0.00) as an internal standard. Coupling

3. Conclusion

The total synthesis of zaragozic acid C was completed in 30

steps for the longest linear sequence from diethyl ^L-tartrate

and 1.4% overall yield. Although our synthesis incurs a

stereochemical problem at C5 in the key fragment assembly

aldol process, we found that the contiguous quaternary

11086

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

constants (J) are reported in hertz (Hz). Abbreviations of

multiplicity are as follows: s, singlet; d, doublet; t, triplet; q,

quartet; m, multiplet; br, broad. Data are presented as

follows: chemical shift, multiplicity, coupling constants,

integration, and assignment. Zaragozic acid numbering is

used for proton assignments of all intermediates. Carbon

nuclear magnetic resonance (¹³C NMR) spectra were

recorded on JEOL EX-270 (67.8 MHz), JEOL EX-400

(100.6 MHz) or Bruker ARX500 (125.8 MHz) spec-

trometers with CDCl₃(d_C77.0) as an internal standard.

Fast atom bombardment (FAB) mass spectra were recorded

on a JEOL JMS-HX110 spectrometer.

1H, C3–H), 4.36 (d, JZ7.7 Hz, 1H, C4–H), 4.54 (d, JZ

12.0 Hz, 1H, OCHPh), 4.57 (d, JZ12.0 Hz, 1H, OCHPh),

7.17–7.30 (m, 5H, ArH), 9.51 (br s, 1H, CO₂H); ¹³C NMR

(125.8 MHz, CDCl₃) d 25.6 (CH₃), 26.8 (CH₃), 69.6 (CH₂),

73.7 (CH₂), 75.3 (CH), 78.2 (CH), 111.9 (C), 127.7 (CH),

127.8 (CH), 128.4 (CH), 137.6 (C), 174.9 (C]O); FAB-

HRMS m/z calcd for C₁₄H₁₉O₅(MCH)^C267.1233, found

267.1240.

4.2.2. Methyl (2S,3R)-4-benzyloxy-2,3-(dimethylmethyl-

enedioxy)butyrate (13). A solution of diazomethane in

Et₂O was added to a solution of carboxylic acid (C)-12

(4.32 g, 16.2 mmol) in Et₂O (30 mL) at 0 8C until a yellow

color persisted. After stirring at 0 8C for 30 min and then

room temperature for 30 min, the reaction was quenched

with AcOH. The resulting mixture was washed successively

with water (10 mL), saturated aqueous NaHCO₃(10 mL)

and brine (10 mL), and dried over anhydrous Na₂SO₄.

Filtration and evaporation in vacuo followed by column

chromatography (silica gel 100 g, 6:1 n-hexane/AcOEt)

afforded methyl ester 13 (3.55 g, 78%) as a pale yellow oil:

[a]²_D¹C19.0 (c 1.30, CHCl₃); IR (ﬁlm) 2992, 2938, 1761,

Column chromatography was carried out on Merck

Kieselgel 60 (63–200 mm or 40–63 mm), Fuji Davison silica

gel BW-200 (40–50 mm) or Wakogel C-200 (75–150 mm).

Analytical thin-layer chromatography (TLC) was carried

out on Merck Kieselgel 60 F₂₅₄plates. Visualization was

accomplished with ultraviolet light and anisaldehyde or

phosphomolybdic acid stain, followed by heating.

Reagents and solvents were puriﬁed by standard means or

used as received unless otherwise noted. Tetrahydrofuran

(THF) and diethyl ether (Et₂O) were distilled from sodium

metal/benzophenone ketyl prior to use. Dichloromethane

(CH₂Cl₂), propionitrile (EtCN), acetonitrile (MeCN), and

diisopropylamine (ⁱPr₂NH) were distilled from calcium

hydride prior to use. Dimethyl sulfoxide (DMSO) was

distilled under reduced pressure from calcium hydride.

1

1454, 1381, 1208, 1107, 1024, 853, 740, 700 cm^K1; H

NMR (500 MHz, CDCl₃) d 1.46 (s, 3H, acetonide CH₃),

1.49 (s, 3H, acetonide CH₃), 3.68 (dd, JZ5.3, 10.7 Hz, 1H,

CHOBn), 3.75 (dd, JZ3.2, 10.7 Hz, 1H, CHOBn), 3.76 (s,

3H, CO₂CH₃), 4.35 (ddd, JZ3.2, 5.3, 7.6 Hz, 1H, C3–H),

4.40 (d, JZ7.6 Hz, 1H, C4–H), 4.61 (d, JZ12.0 Hz, 1H,

OCHPh), 4.63 (d, JZ12.0 Hz, 1H, OCHPh), 7.25–7.37 (m,

5H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 25.7 (CH₃),

26.9 (CH₃), 52.3 (CH₃), 69.8 (CH₂), 73.6 (CH₂), 75.7 (CH),

78.4 (CH), 111.6 (C), 127.6 (CH), 127.7 (CH), 128.4 (CH),

137.9 (C), 171.0 (C]O); FAB-HRMS m/z calcd for

C₁₅H₂₁O₅(MCH)^C281.1389, found 281.1411.

All reactions were conducted under an argon atmosphere.

Ethyl 2-oxo-5-phenylpentanoate,²⁵diisopropoxytitanium(IV)

dichloride [(ⁱPrO)₂TiCl₂],⁴¹Dess-Martin periodinane⁴²

(4R,5R)-4-benzyloxy-5-methyl-6-phenyl-1-hexyne (56),³⁸

N,N⁰-diisopropyl-O-tert-butylisourea⁴⁰and (4E,6R)-6-

methyl-9-phenyl-4-nonenoic acid (2)^1fwere prepared accord-

ing to literature procedures.

4.2.3. S-methyl (2S,3R)-4-benzyloxy-2,3-(dimethyl-

methylenedioxy)butanethioate (14). Oxalyl chloride

(1.8 mL, 20.6 mmol) and DMF (0.1 mL, 1.3 mmol) were

added to a solution of carboxylic acid (C)-12 (4.75 g,

17.8 mmol) in CH₂Cl₂(50 mL). The mixture was stirred at

room temperature for 1.5 h and evaporated in vacuo. The

residual oil was dissolved in CH₂Cl₂(50 mL), and n-Bu₄NI

(76 mg, 0.2 mmol) and a 20% aqueous solution of MeSNa

(7.5 mL, 21.4 mmol) were added at 0 8C. After stirring

vigorously at 0 8C for 10 min, the mixture was partitioned

between CH₂Cl₂(50 mL) and water (50 mL). The organic

extract was washed successively with water (30 mL) and

brine (30 mL), and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo followed by column chromato-

graphy (silica gel 100 g, 20:1 n-hexane/AcOEt) afforded

thioester 14 (4.04 g, 77%) as a pale yellow oil: [a]²_D⁵K8.95

(c 1.2, CHCl₃); IR (ﬁlm) 2990, 2930, 1676 (C]O), 1454,

4.2. Preparation of substrates for the aldol coupling

4.2.1. (2S,3R)-4-benzyloxy-2,3-(dimethylmethylene-

dioxy)butyric acid [(C)-12]. A solution of NaH₂PO₄

(5.8 g, 48.0 mmol) in water (80 mL) was added to a solution

of (2S,3R)-4-benzyloxy-2,3-(dimethylmethylenedioxy)-

butanal (11)²⁰(12.0 g, 48.0 mmol) and 2-methyl-2-butene

(21 mL, 199 mmol) in tert-butyl alcohol (250 mL). NaClO₂

(14.8 g, 164 mmol) was added portionwise to the mixture.

After stirring at room temperature for 18 h, the mixture was

evaporated in vacuo. The residue was dissolved in saturated

aqueous NaHCO₃(50 mL) and water (100 mL) and the

whole was washed with n-hexane (3!30 mL). The aqueous

layer was acidiﬁed with 10% aqueous HCl (40 mL),

saturated with NaCl, and then extracted with AcOEt (3!

100 mL). The combined organic extracts were washed with

brine (50 mL) and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo followed by column chromato-

graphy (silica gel 100 g, AcOEt) afforded carboxylic acid

(C)-12 (12.1 g, 95%) as a pale yellow oil: [a]²_D⁴C13.7 (c

1.19, CHCl₃); IR (ﬁlm) 3700–2300, 2990, 1734, 1454, 1383,

1381, 1215, 1090, 852, 739, 698 cm^K1

;

¹H NMR

(500 MHz, CDCl₃) d 1.51 (s, 6H, 2!acetonide CH₃), 2.28

(s, 3H, SCH₃), 3.66 (dd, JZ5.7, 10.8 Hz, 1H, CHOBn), 3.81

(dd, JZ2.5, 10.8 Hz, 1H, CHOBn), 4.24 (ddd, JZ2.5, 5.7,

8.0 Hz, 1H, C3–H), 4.35 (d, JZ8.0 Hz, 1H, C4–H), 4.62 (s,

2H, OCH₂Ph), 7.25–7.38 (m, 5H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 10.8 (CH₃), 26.0 (CH₃), 27.1

(CH₃), 69.7 (CH₂), 73.6 (CH₂), 78.8 (CH), 81.6 (CH),

112.1 (C), 127.7 (CH), 128.4 (CH), 137.8 (CH), 201.4

(C]O); FAB-HRMS m/z calcd for C₁₅H₂₁O₄S (MCH)^C

1215, 1101, 852, 752, 698 cm^K^{1 1}H NMR (500 MHz,

;

CDCl₃) d 1.38 (s, 3H, acetonide CH₃), 1.42 (s, 3H, acetonide

CH₃), 3.63 (dd, JZ5.2, 10.7 Hz, 1H, CHOBn), 3.71 (dd, JZ

3.2, 10.7 Hz, 1H, CHOBn), 4.29 (ddd, JZ3.2, 5.2, 7.7 Hz,

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11087

297.1161, found 297.1152. Anal. Calcd for C₁₅H₂₁O₄S: C,

60.79; H, 6.80; S, 10.82. Found: C, 60.63; H, 6.78; S, 11.07.

4.2.6.

Ethyl

(3R,4S)-5-benzyloxy-3,4-(dimethyl-

methylenedioxy)-2-oxopentanoate (17). A stream of

ozone in oxygen was bubbled through a stirred solution of

enone 16 (386 mg, 1.21 mmol) in CH₂Cl₂(7 mL) at K78 8C

until the solution turned pale blue. After stirring at K78 8C

for 10 min, excess ozone was removed by bubbling a stream

of nitrogen, and Me₂S (1 mL) was added. After stirring at

room temperature for 1 h, the volatile elements were

removed in vacuo. The residue (548 mg) was puriﬁed by

column chromatography (silica gel 10 g, 4:1/5:2

n-hexane/AcOEt) to give a-keto ester 17 (371 mg, 96%)

as a colorless oil: [a]_D²²K5.39 (c 1.6, CHCl₃); IR (ﬁlm)

3449, 2990, 1730, 1454, 1373, 1254, 1217, 1094, 1042, 853,

741, 700 cm^K1; ¹H NMR (500 MHz, CDCl₃) d 1.34 (t, JZ

7.2 Hz, 3H, CO₂CH₂CH₃), 1.40 (s, 3H, acetonide CH₃),

1.50 (s, 3H, acetonide CH₃), 3.71 (dd, JZ5.3, 10.5 Hz, 1H,

CHOBn), 3.75 (dd, JZ4.2, 10.5 Hz, 1H, CHOBn), 4.23–

4.36 (m, 2H, CO₂CH₂CH₃), 4.43 (ddd, JZ4.2, 5.3, 7.0 Hz,

1H, C7–H), 4.61 (s, 2H, OCH₂Ph), 4.85 (d, JZ7.0 Hz, 1H,

C6–H), 7.25–7.38 (m, 5H, ArH); FAB-HRMS m/z calcd for

C₁₇H₂₃O₆(MCH)^C323.1495, found 323.1508.

4.2.4. (2R,3S)-4-benzyloxy-2,3-(dimethylmethylene-

dioxy)-N-methoxy-N-methylbutanamide (15). Oxalyl

chloride (6 mL, 69 mmol) and DMF (0.3 mL, 3.9 mmol)

were added to a solution of carboxylic acid (K)-12 (15.20 g,

57.1 mmol) in CH₂Cl₂(170 mL). The mixture was stirred at

room temperature for 30 min and evaporated in vacuo. The

residual oil was dissolved in CH₂Cl₂(170 mL), and N,O-

dimethylhydroxylamine hydrochloride (6.1 g, 62.5 mmol)

and pyridine (12 mL, 148 mmol) were added at 0 8C. After

stirring at 0 8C for 1 h, the reaction was quenched with 1 N

aqueous HCl (100 mL), and the layers were separated. The

organic layer was washed successively with 1 N aqueous

HCl (2!100 mL), saturated aqueous NaHCO₃(80 mL) and

brine (80 mL), and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo followed by column chromato-

graphy (silica gel 150 g, 3:1/2:1 n-hexane/AcOEt)

afforded amide 15 (16.28 g, 92%) as a colorless oil: [a]_D²⁵

C3.97 (c 2.03, CHCl₃); IR (ﬁlm) 2988, 2938, 1780, 1669,

1

1454, 1381, 1256, 1165, 1092, 997, 910, 855 cm^K1; H

Since the tartrate-derived a-keto esters were prone to

hydration, they were azeotropically dried with benzene prior

to use.

NMR (500 MHz, CDCl₃) d 1.48 (s, 3H, acetonide CH₃),

1.49 (s, 3H, acetonide CH₃), 3.20 (s, 3H, NCH₃), 3.63–3.71

(m, 2H, C1–H₂), 3.76 (s, 3H, OCH₃), 4.59 (m, 1H, C7–H),

4.60 (d, JZ12.0 Hz, 1H, OCHPh), 4.61 (d, JZ12.0 Hz, 1H,

OCHPh), 4.71 (br s, 1H, C6–H), 7.25–7.33 (m, 5H, ArH);

¹³C NMR (67.8 MHz, CDCl₃) d 26.1 (CH₃), 26.7 (CH₃),

32.3 (CH₃), 61.5 (CH₃), 69.8 (CH₂), 73.4 (CH₂), 74.1 (CH),

77.7 (CH), 111.2 (C), 127.6 (CH), 127.8 (CH), 138.0 (CH),

170.3 (C]O); FAB-HRMS m/z calcd for C₁₆H₂₃NO₅(M)^C

309.1576, found 309.1575.

4.3. Aldol reaction

4.3.1. Reaction of a-keto ester 18 with lithium enolate

generated from ester 13. Butyllithium in n-hexane

(1.60 M, 0.35 mL, 0.56 mmol) was added to a solution of

ⁱPr₂NH (0.08 mL, 0.61 mmol) in THF (1.5 mL) at K5 8C.

After stirring at K5 8C for 20 min, the solution was cooled

to K78 8C, and a solution of ester 13 (129 mg, 0.46 mmol)

in THF (0.6 mL) was added dropwise over 10 min. After

stirring at K78 8C for 1 h, a solution of a-keto ester 18

(51 mg, 0.23 mmol) in THF (0.3 mL) was added to the

mixture at K78 8C. After stirring at K78 8C for 10 min, the

mixture was quenched with saturated aqueous NH₄Cl

(3 mL), and the whole was extracted with AcOEt (15 mL).

The organic extract was washed with brine (2!5 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo furnished the crude product (168 mg), which was

puriﬁed by ﬂash column chromatography (silica gel 5 g,

10:1/3:1 n-hexane/AcOEt) to give an inseparable mixture

of aldol adducts 19 (96 mg, 84%) as a colorless oil. The ratio

of the adducts was determined to be 61:15:15:9 by 270 MHz

4.2.5. (4R,5S)-6-benzyloxy-4,5-(dimethylmethylene-

dioxy)-2-ethoxy-1-hexen-3-one (16). tert-Butyllithium in

pentane (2.13 M, 1.95 mL, 4.15 mmol) was added to a

stirred solution of ethyl vinyl ether (0.4 mL, 4.18 mmol) in

THF (4 mL) at K78 8C. After stirring at 0 8C for 30 min, the

mixture was cooled to K78 8C and a solution of amide 15

(437 mg, 1.41 mmol) in THF (1 mL) was added. After

stirring at K78 8C for 3 h, the reaction mixture was poured

into a well-stirred mixture of saturated aqueous NH₄Cl

(20 mL) and Et₂O (10 mL) at 0 8C. The layers were

separated, and the organic layer was washed with brine

(8 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo followed by column chromatography

(silica gel 10 g, 10:1/7:1 n-hexane/AcOEt) afforded

enone 16 (386 mg, 85%) as a colorless oil: [a]²_D⁵K49.9 (c

2.03, CHCl₃); IR (ﬁlm) 2986, 2936, 1723, 1610, 1454, 1379,

1

¹H NMR: H NMR (270 MHz, CDCl₃) d 1.10–1.60 (m,

10H, CO₂CH₂CH₃, 2!acetonide CH₃, one of CH₂), 1.70–

1.95 (m, 2H, CH₂), 1.95–2.15 (m, 1H, one of CH₂), 2.46–

2.71 (m, 2H, PhCH₂), 3.35–3.53 (m, 1H, BnOCH), 3.65 (s,

1.83H, OCH₃), 3.67 (s, 0.45H, OCH₃), 3.74 (s, 0.27H,

OCH₃), 3.75 (s, 0.45H, OCH₃), 3.82–4.32 (m, 4H, BnOCH,

CO₂CH₂CH₃, OH), 4.40–4.75 (m, 3H, C3–H, PhCH₂O),

7.25–7.38 (m, 10H, ArH).

1285, 1215, 1117, 1092, 976, 853 cm^K^{1 1}H NMR

;

(500 MHz, CDCl₃) d 1.18 (t, JZ7.0 Hz, 3H, OCH₂CH₃),

1.43 (s, 3H, acetonide CH₃), 1.51 (s, 3H, acetonide CH₃),

3.66 (dd, JZ6.0, 10.5 Hz, 1H, C1–H), 3.75 (dd, JZ3.1,

10.5 Hz, 1H, C1–H), 3.76 (q, JZ7.0 Hz, 2H, OCH₂CH₃),

4.40 (ddd, JZ3.1, 6.0, 6.5 Hz, 1H, C7–H), 4.53 (d, JZ

2.7 Hz, 1H, CH]C), 4.60 (d, JZ12.3 Hz, 1H, OCHPh),

4.64 (d, JZ12.3 Hz, 1H, OCHPh), 4.92 (d, JZ6.5 Hz, 1H,

C6–H), 5.31 (d, JZ2.7 Hz, 1H, CH]C), 7.26–7.34 (m, 5H,

ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 14.3 (CH₃), 26.7

(CH₃), 27.7 (CH₃), 64.1 (CH₃), 70.8 (CH₂), 73.8 (CH₂), 78.2

(CH), 79.1 (CH), 93.7 (CH), 112.1 (C), 127.9 (CH), 128.6

(CH), 138.2 (CH), 156.6 (CH₂), 194.2 (C]O); FAB-LRMS

m/z 309 (MKCH₂CH)^C, 277 (MKOEtCH)^C.

4.3.2. (R,Z)-4-(benzyloxy)methyl-5-[methylthio(tri-

methylsilyloxy)methylene]-2,2-dimethyl-1,3-dioxolane

(20). Butyllithium in n-hexane (1.61 M, 12.7 mL,

20.4 mmol) was added to a stirred solution of 1,1,1,3,3,3-

hexamethyldisilazane (4.5 mL, 21.3 mmol) in THF (80 mL)

at K5 8C. After stirring at K5 8C for 30 min, the solution

was cooled to K78 8C, and a solution of thioester 14

11088

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

(5.51 g, 18.6 mmol) in THF (15 mL) was added. After

stirring at K78 8C for 30 min, TMSCl (2.7 mL, 21.3 mmol)

was added, and the resulting mixture was stirred at K78 8C

for 1 h. The mixture was allowed to warm to room

temperature. After stirring at room temperature for

15 min, the volatile elements were removed in vacuo. The

residue was suspended in n-hexane and passed through a

short plug of Florisil (eluting with AcOEt) to give silyl

ketene thioacetal 20 (6.71 g, 95%, Z/EZ99:1) as a yellow

oil: [a]²_D⁶C148.7 (c 1.16, benzene); IR (ﬁlm) 2990, 2957,

2865, 1740, 1680, 1454, 1373, 1254, 1213, 1138, 1028, 883,

739, 700 cm^K1; ¹H NMR (500 MHz, CDCl₃) d 1.24 (t, JZ

7.1 Hz, 3H, CO₂CH₂CH₃), 1.25 (m, 1H, one of (CH₂)₂),

1.40 (s, 3H, acetonide CH₃), 1.74 (s, 3H, acetonide CH₃),

1.78–1.95 (m, 3H, three of (CH₂)₂), 2.14 (s, 3H, COSCH₃),

2.54 (ddd, JZ2.1, 6.7, 13.7 Hz, 1H, CHPh), 2.63 (ddd, JZ

3.0, 5.9, 13.7 Hz, 1H, CHPh), 3.39 (dd, JZ8.0, 11.1 Hz, 1H,

CHOBn), 3.54 (s, 1H, OH), 3.94 (dd, JZ1.8, 11.1 Hz, 1H,

CHOBn), 4.14 (dq, JZ10.9, 7.1 Hz, 1H, CO₂CHCH₃), 4.21

(dq, JZ10.9, 7.1 Hz, 1H, CO₂CHCH₃), 4.50 (d, JZ

12.1 Hz, 1H, OCHPh), 4.61 (d, JZ12.1 Hz, 1H, OCHPh),

4.67 (dd, JZ1.8, 8.0 Hz, 1H, C3–H), 7.12 (m, 2H, ArH),

7.16 (m, 1H, ArH), 7.22–7.30 (m, 3H, ArH), 7.30–7.37 (m,

4H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 11.8 (CH₃),

14.0 (CH₃), 25.2 (CH₂), 26.4 (CH₃), 27.3 (CH₃), 32.7 (CH₂),

35.8 (CH₂), 62.3 (CH₂), 70.2 (CH₂), 73.4 (CH₂), 79.4 (CH),

80.9 (C), 91.3 (C), 112.1 (C), 125.8 (CH), 127.6 (CH), 127.7

(CH), 128.3 (CH), 138.0 (C), 141.8 (C), 172.4 (C]O),

203.8 (C]O); FAB-HRMS calcd for C₂₈H₃₇O₇S (MCH)^C

517.2260, found 517.2267.

1

849, 737 cm^K1; H NMR (500 MHz, C₆D₆) d 0.23 (s, 9H,

Si(CH₃)₃), 1.33 (s, 3H, acetonide CH₃), 1.53 (s, 3H,

acetonide CH₃), 2.12 (s, 3H, SCH₃), 3.74 (dd, JZ6.2,

10.6 Hz, 1H, CHOBn), 4.04 (dd, JZ1.9, 10.6 Hz, 1H,

CHOBn), 4.52 (d, JZ12.2 Hz, 1H, OCHPh), 4.58 (d, JZ

12.2 Hz, 1H, OCHPh), 5.11 (dd, JZ1.9, 6.2 Hz, 1H, C3–H),

7.08–7.24 (m, 3H, ArH), 7.36 (m, 2H, ArH); ¹³C NMR

(67.8 MHz, C₆D₆) d 1.0 (CH₃), 16.6 (CH₃), 26.2 (CH₃), 27.1

(CH₃), 71.3 (CH₂), 73.9 (CH₂), 79.0 (CH), 112.1 (C), 123.9

(C), 128.2 (CH), 129.0 (CH), 139.6 (C), 144.7 (C); FAB-

LRMS m/z 369 (MCH)^C, 277 (MKBnCH)^C.

4.3.4. Ethyl (3R,4S,8R)-8-(benzyloxymethyl)-6,6-di-

methyl-1-oxo-3-(3-phenylpropyl)-2,5,7-trioxaspiro[3.4]

octane-3-carboxylate (22a). Hg(OCOCF₃)₂(139 mg,

0.325 mmol) was added to a stirred solution of thioester

21a (80 mg, 0.155 mmol) in MeCN (16 mL). After stirring

for 48 h, the reaction mixture was evaporated in vacuo. The

residue was suspended in Et₂O (5 mL) and passed through a

short plug of silica gel (eluting with Et₂O) to remove

insoluble Hg salt. Puriﬁcation of the crude product (87 mg)

by column chromatography (silica gel 10 g, 8:1 n-hexane/

AcOEt) afforded b-lactone 22a (63 mg, 87%) as a colorless

oil: [a]²_D⁶C50.3 (c 2.01, CHCl₃); IR (ﬁlm) 2931, 1844,

4.3.3. Ethyl (3S,4R)-5-benzyloxy-3,4-(dimethylmethyl-

enedioxy)-2-hydroxy-3-(methylthio)carbonyl-2-(3-

phenylpropyl)pentanoate (21). Sn(OTf)₂(566 mg,

1.36 mmol) was added to a stirred solution of a-keto ester

18 (149 mg, 0.68 mmol) and silyl ketene thioacetal 20

(500 mg, 1.36 mmol) in EtCN (14 mL) at K78 8C. After

stirring at K78 8C for 30 min, the reaction was quenched

with saturated aqueous NaHCO₃(10 mL). The mixture was

diluted with AcOEt (10 mL) and n-hexane (1 mL), and

ﬁltered through a Celite pad. The ﬁltrate was extracted with

AcOEt (10 mL), and the organic extract was washed with

brine (10 mL) and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo furnished the crude product

(850 mg), which was puriﬁed by ﬂash column chromato-

graphy (silica gel 20 g, 20:1/15:1 n-hexane/AcOEt) to

give aldol adducts 21a (98 mg, 28%) and 21b (252 mg,

72%) as pale yellow oils. Data for (2R,3S,4R)-isomer (21a).

[a]²_D⁴K33.5 (c 1.81, CHCl₃); IR (ﬁlm) 3499, 2980, 2930,

2866, 1734, 1682, 1454, 1381, 1256, 1113, 1022, 750,

1

1734, 1509, 1456, 1375, 1094 cm^K1; H NMR (500 MHz,

CDCl₃) d 1.14 (t, JZ7.3 Hz, 3H, CO₂CH₂CH₃), 1.39 (s, 3H,

acetonide CH₃), 1.54 (s, 3H, acetonide CH₃), 1.56 (m, 1H,

C7–H), 1.87 (m, 1H, C7–H), 2.05 (ddd, JZ4.8, 11.5,

14.7 Hz, 1H, C6–H), 2.14 (ddd, JZ5.0, 11.5, 14.7 Hz, 1H,

C6–H), 2.65 (ddd, JZ6.6, 8.8, 13.6 Hz, 1H, CHPh), 2.67

(ddd, JZ6.6, 8.8, 13.6 Hz, 1H, CHPh), 3.56 (dd, JZ7.3,

9.1 Hz, 1H, CHOBn), 3.75 (dd, JZ6.3, 9.1 Hz, 1H,

CHOBn), 3.97 (dq, JZ10.9, 7.3 Hz, 1H, CO₂CHCH₃),

4.21 (dq, JZ10.9, 7.3 Hz, 1H, CO₂CHCH₃), 4.44 (d, JZ

11.8 Hz, 1H, OCHPh), 4.50 (d, JZ11.8 Hz, 1H, OCHPh),

4.60 (dd, JZ6.3, 7.3 Hz, 1H, C3–H), 7.13–7.23 (m, 3H,

ArH), 7.23–-7.40 (m, 7H, ArH); ¹³C NMR (125.8 MHz,

CDCl₃) d 14.0 (CH₃), 24.9 (CH₂), 25.2 (CH₃), 26.5 (CH₃),

32.9 (CH₂), 35.5 (CH₂), 61.2 (CH₂), 68.7 (CH₂), 73.8 (CH₂),

76.7 (CH), 86.6 (C), 94.6 (C), 112.9 (C), 126.0 (CH), 127.8

(CH), 128.1 (CH), 128.31 (CH), 128.34 (CH), 128.4 (CH),

137.1 (C), 141.3 (C), 168.16 (C]O), 168.23 (C]O); FAB-

HRMS m/z calcd for C₂₇H₃₃O₇(MCH)^C469.2226, found

469.2243.

700 cm^K^{1 1}H NMR (500 MHz, CDCl₃) d 1.18 (t, JZ

;

7.2 Hz, 3H, CO₂CH₂CH₃), 1.25 (m, 1H, one of (CH₂)₂),

1.50 (s, 3H, acetonide CH₃), 1.68 (m, 1H, one of (CH₂)₂),

1.73 (s, 3H, acetonide CH₃), 1.81 (m, 1H, one of (CH₂)₂),

2.12 (m, 1H, one of (CH₂)₂), 2.15 (s, 3H, COSCH₃), 2.56

(dt, JZ10.3, 3.2 Hz, 2H, CH₂Ph), 3.33 (dd, JZ8.0, 10.9 Hz,

1H, CHOBn), 3.67 (s, 1H, OH), 3.86 (dd, JZ1.7, 10.9 Hz,

1H, CHOBn), 4.00 (dq, JZ10.8, 7.2 Hz, 1H, CO₂CHCH₃),

4.22 (dq, JZ10.8, 7.2 Hz, 1H, CO₂CHCH₃), 4.46 (d, JZ

12.2 Hz, 1H, OCHPh), 4.65 (d, JZ12.2 Hz, 1H, OCHPh),

4.66 (dd, JZ1.7, 8.0 Hz, 1H, C3–H), 7.11 (m, 2H, ArH),

7.16 (m, 1H, ArH), 7.22–7.31 (m, 3H, ArH), 7.31–7.38 (m,

4H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 11.9 (CH₃),

13.9 (CH₃), 25.2 (CH₂), 26.4 (CH₃), 27.0 (CH₃), 32.5 (CH₂),

35.8 (CH₂), 62.4 (CH₂), 70.2 (CH₂), 73.4 (CH₂), 79.0 (CH),

79.2 (C), 92.4 (C), 111.9 (C), 125.8 (CH), 127.6 (CH), 127.8

(CH), 138.0 (C), 141.8 (C), 172.4 (C]O), 203.0 (C]O);

FAB-HRMS calcd for C₂₈H₃₇O₇S (MCH)^C517.2260,

found 517.2252. Data for (2S,3S,4R)-isomer (21b). [a]_D²³

K23.2 (c 1.63, CHCl₃); IR (ﬁlm) 3518, 2980, 2932, 2866,

1738, 1678, 1454, 1381, 1254, 1219, 1182, 1089, 1022, 853,

4.3.5. Ethyl (2R,3S,4R)-5-benzyloxy-3,4-(dimethyl-

methylenedioxy)-2-hydroxy-3-methoxycarbonyl-2-(3-

phenylpropyl)pentanoate (19a). Potassium carbonate

(20 mg, 0.145 mmol) was added to a solution of b-lactone

22a (52 mg, 0.111 mmol) in MeOH (1 mL). After stirring

for 30 min, the mixture was evaporated in vacuo. The

residue (75 mg) was puriﬁed by column chromatography

(silica gel 10 g, 4:1 n-hexane/AcOEt) to give methyl ester

19a (46 mg, 83%) as a colorless oil: [a]²_D⁶K14.8 (c 1.07,

CHCl₃); IR (ﬁlm) 3501, 3027, 2988, 1732, 1497, 1454,

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11089

1373, 1250, 1181, 1105 cm^K1; ¹H NMR (500 MHz, CDCl₃)

d 1.19 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃), 1.25 (m, 1H, C7–

H), 1.44 (s, 3H, acetonide CH₃), 1.56 (s, 3H, acetonide

CH₃), 1.80 (ddd, JZ4.2, 12.1, 13.9 Hz, 1H, C6–H), 1.82 (m,

1H, C7–H), 2.06 (ddd, JZ4.2, 12.1, 13.9 Hz, 1H, C6–H),

2.58 (ddd, JZ6.5, 8.4, 14.3 Hz, 1H, CHPh), 2.59 (ddd, JZ

6.5, 8.4, 14.3 Hz, 1H, CHPh), 3.39 (dd, JZ7.2, 11.0 Hz, 1H,

CHOBn), 3.61 (s, 1H, OH), 3.64 (s, 3H, CO₂CH₃), 3.85 (dd,

JZ1.8, 11.0 Hz, 1H, CHOBn), 4.06 (dq, JZ10.8, 7.1 Hz,

1H, CO₂CHCH₃), 4.20 (dq, JZ10.8, 7.1 Hz, 1H, CO₂-

CHCH₃), 4.48 (d, JZ12.1 Hz, 1H, OCHPh), 4.62 (dd, JZ

1.8, 7.2 Hz, 1H, C3–H), 4.63 (d, JZ12.1 Hz, 1H, OCHPh),

7.11 (d, JZ7.3 Hz, 2H, ArH), 7.15 (t, JZ7.3 Hz, 1H, ArH),

7.23–7.32 (m, 3H, ArH), 7.34 (m, 4H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 14.2 (CH₃), 25.4 (CH₃), 26.8 (CH₃),

27.3 (CH₃), 33.1 (CH₂), 36.0 (CH₂), 52.3 (CH₂), 62.7 (CH₂),

70.4 (CH₂), 73.7 (CH₂), 79.2 (C), 79.6 (C), 89.2 (C), 111.3

(C), 126.1 (CH), 127.9 (CH), 128.1 (CH), 128.56 (CH),

128.59 (CH), 138.2 (CH), 142.0 (C), 171.1 (C]O), 172.8

(C]O); FAB-HRMS m/z calcd for C₂₈H₃₇O₈(MCH)^C

501.2488, found 501.2497.

0.489 mmol) was added to a stirred solution of thioester

21b (120 mg, 0.233 mmol) in MeCN (23 mL). After stirring

for 4 h, the reaction mixture was evaporated in vacuo. The

residue was suspended in Et₂O (5 mL) and passed through a

short plug of silica gel (eluting with Et₂O) to remove

insoluble Hg salt. Puriﬁcation of the crude product (130 mg)

by column chromatography (silica gel 10 g, 8:1 n-hexane/

AcOEt) afforded b-lactone 22b (92 mg, 84%) as a colorless

oil: [a]²_D⁶K18.1 (c 2.06, benzene); IR (ﬁlm) 2935, 1842,

1

1757, 1454, 1381, 1271, 1094 cm^K1; H NMR (500 MHz,

CDCl₃) d 1.29 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.31 (s, 3H,

acetonide CH₃), 1.49 (s, 3H, acetonide CH₃), 1.53 (m, 1H,

C7–H), 1.74 (m, 1H, C7–H), 2.04 (ddd, JZ6.8, 8.7,

13.9 Hz, 1H, C6–H), 2.15 (ddd, JZ6.4, 8.9, 13.9 Hz, 1H,

C6–H), 2.46 (ddd, JZ4.9, 11.3, 13.7 Hz, 1H, CHPh), 2.47

(ddd, JZ4.9, 11.3, 13.7 Hz, 1H, CHPh), 3.66 (dd, JZ8.7,

9.1 Hz, 1H, CHOBn), 3.85 (dd, JZ5.1, 8.7 Hz, 1H,

CHOBn), 4.24 (dq, JZ10.9, 7.2 Hz, 1H, CO₂CHCH₃),

4.32 (dq, JZ10.9, 7.2 Hz, 1H, CO₂CHCH₃), 4.40 (d, JZ

11.1 Hz, 1H, OCHPh), 4.50 (d, JZ11.1 Hz, 1H, OCHPh),

4.62 (dd, JZ5.1, 9.1 Hz, 1H, C3–H), 7.07 (d, JZ7.2 Hz,

2H, ArH), 7.16 (t, JZ7.3 Hz, 1H, ArH), 7.20–7.38 (m, 7H,

ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 14.1 (CH₃),

25.2 (CH₂), 25.4 (CH₃), 26.8 (CH₃), 31.1 (CH₂), 35.3

(CH₂), 62.1 (CH₂), 68.6 (CH₂), 73.8 (CH₂), 75.7 (CH),

87.7 (C), 95.5 (C), 113.1 (C), 125.9 (CH), 128.0 (CH),

128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 137.1

(C), 141.3 (C), 167.9 (C]O), 168.1 (C]O); FAB-HRMS

m/z calcd for C₂₇H₃₃O₇(MCH)^C469.2226, found

469.2257.

4.3.6. Ethyl [2R,2(3aS,6aR)]-2-hydroxy-5-phenyl-2-

(tetrahydro-2,2-dimethyl-4-oxofuro[3,4-d][1,3]dioxol-

3a-yl)pentanoate (23a). Palladium on carbon (10%, 7 mg)

was added to a solution of benzyl ether 19a (44 mg,

0.088 mmol) in EtOH (1 mL), and the mixture was

vigorously stirred under 1 atm of hydrogen for 2 h. The

catalyst was ﬁltered through a Celite pad, and the ﬁltrate

was evaporated in vacuo. The crude product (33 mg) thus

obtained was used without further puriﬁcation.

4.3.8. Ethyl (2S,3S,4R)-5-benzyloxy-3,4-(dimethyl-

methylenedioxy)-2-hydroxy-3-methoxycarbonyl-2-(3-

phenylpropyl)pentanoate (19b). Potassium carbonate

(24 mg, 0.175 mmol) was added to a solution of b-lactone

22b (63 mg, 0.134 mmol) in MeOH (1.3 mL). After stirring

for 1 h, the mixture was evaporated in vacuo. The residue

(68 mg) was puriﬁed by column chromatography (silica gel

10 g, 4:1 n-hexane/AcOEt) to give methyl ester 19b (60 mg,

89%) as a colorless oil: [a]²_D⁶C13.5 (c 2.03, CHCl₃); IR

(ﬁlm) 3513, 3029, 2986, 1732, 1497, 1454, 1373, 1240,

DMAP (43 mg, 0.352 mmol) was added to a solution of the

crude g-hydroxyester (33 mg) in CH₂Cl₂(1 mL). After

stirring for 1 h, the reaction was quenched with saturated

aqueous NH₄Cl (6 mL), and the whole was extracted with

AcOEt (10 mL). The organic extract was washed with brine

(6 mL), and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (33 mg),

which was puriﬁed by column chromatography (silica gel

10 g, 5:1 n-hexane/AcOEt) to give g-lactone 23a (33 mg,

98%) as a colorless oil: [a]²_D⁴K55.9 (c 1.02, CHCl₃); IR

(ﬁlm) 3486, 2990, 2940, 2866, 1790, 1728, 1456, 1377,

1

1101, 1024 cm^K1; H NMR (500 MHz, CDCl₃) d 1.22 (m,

1

1263, 1117, 1019, 972, 914 cm^K1; H NMR (500 MHz,

1H, C7–H), 1.29 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.35 (s,

3H, acetonide CH₃), 1.57 (s, 3H, acetonide CH₃), 1.82 (m,

1H, C7–H), 1.86 (ddd, JZ2.8, 8.2, 12.0 Hz, 1H, C6–H),

2.02 (ddd, JZ3.4, 8.9, 12.0 Hz, 1H, C6–H), 2.53 (ddd, JZ

6.3, 8.4, 13.6 Hz, 1H, CHPh), 2.61 (ddd, JZ4.9, 8.7,

13.6 Hz, 1H, CHPh), 3.47 (dd, JZ7.2, 11.1 Hz, 1H,

CHOBn), 3.66 (s, 3H, CO₂CH₃), 3.68 (s, 1H, OH), 3.93

(dd, JZ1.8, 11.1 Hz, 1H, CHOBn), 4.17 (dq, JZ10.8,

7.2 Hz, 1H, CO₂CHCH₃), 4.28 (dq, JZ10.8, 7.2 Hz, 1H,

CO₂CHCH₃), 4.52 (d, JZ12.2 Hz, 1H, OCHPh), 4.63 (d,

JZ12.2 Hz, 1H, OCHPh), 4.66 (dd, JZ1.8, 7.2 Hz, 1H,

C3–H), 7.07 (d, JZ7.2 Hz, 2H, ArH), 7.16 (t, JZ7.4 Hz,

1H, ArH), 7.23–7.35 (m, 7H, ArH); ¹³C NMR (125.8 MHz,

CDCl₃) d 14.3 (CH₃), 25.4 (CH₃), 26.7 (CH₃), 27.2 (CH₃),

33.3 (CH₂), 36.0 (CH₂), 52.4 (CH₂), 62.7 (CH₂), 70.3 (CH₂),

73.8 (CH₂), 79.3 (C), 81.2 (C), 88.3 (C), 111.6 (C), 126.1

(CH), 127.9 (CH), 128.0 (CH), 128.57 (CH), 128.60 (CH),

138.2 (CH), 142.1 (C), 171.1 (C]O), 172.9 (C]O); FAB-

HRMS m/z calcd for C₂₈H₃₇O₈(MCH)^C501.2488, found

501.2501.

CDCl₃) d 1.29 (m, 1H, C7–H), 1.32 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.38 (s, 3H, acetonide CH₃), 1.44 (s, 3H,

acetonide CH₃), 1.82 (m, 1H, C7–H), 2.12 (ddd, JZ4.6,

12.3, 13.8 Hz, 1H, C6–H), 2.20 (ddd, JZ4.6, 12.3, 13.8 Hz,

1H, C6–H), 2.60 (ddd, JZ6.0, 9.5, 14.0 Hz, 1H, CHPh),

2.66 (ddd, JZ6.0, 9.5, 14.0 Hz, 1H, CHPh), 3.76 (s, 1H,

OH), 4.23 (dq, JZ10.8, 7.1 Hz, 1H, CO₂CHCH₃), 4.32 (d,

JZ1.7 Hz, 2H, lactone CH₂), 4.36 (dq, JZ10.8, 7.1 Hz, 1H,

CO₂CHCH₃), 4.56 (t, JZ1.7 Hz, 1H, C3–H), 7.13–7.19 (m,

3H, ArH), 7.26–7.28 (m, 2H, ArH); ¹³C NMR (125.8 MHz,

CDCl₃) d 14.3 (CH₃), 25.3 (CH₃), 26.9 (CH₃), 27.4 (CH₂),

32.1 (CH₂), 36.0 (CH₂), 63.3 (CH₂), 71.0 (CH₂), 78.0 (CH),

79.1 (C), 86.4 (C), 114.3 (C), 126.1 (CH), 128.5 (CH), 128.6

(CH), 142.1 (C), 173.3 (C]O), 174.2 (C]O); FAB-HRMS

calcd for C₂₀H₂₇O₇(MCH)^C379.1757, found 379.1753.

4.3.7. Ethyl (3S,4S,8R)-8-(benzyloxymethyl)-6,6-di-

methyl-1-oxo-3-(3-phenylpropyl)-2,5,7-trioxaspiro[3.4]

octane-3-carboxylate (22b). Hg(OCOCF₃)₂(209 mg,

11090

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

4.3.9. Ethyl [2S,2(3aS,6aR)]-2-hydroxy-5-phenyl-2-

(tetrahydro-2,2-dimethyl-4-oxofuro[3,4-d][1,3]dioxol-

3a-yl)pentanoate (23b). Palladium on carbon (10%, 7 mg)

was added to a solution of benzyl ether 19b (41 mg,

0.082 mmol) in EtOH (1 mL), and the mixture was

vigorously stirred under 1 atm of hydrogen for 2 h. The

catalyst was ﬁltered through a Celite pad, and the ﬁltrate

was evaporated in vacuo. The crude product (32 mg) thus

obtained was used without further puriﬁcation.

1.36 (s, 6H, 2!acetonide CH₃), 1.62 (s, 3H, acetonide

CH₃), 1.82 (s, 3H, acetonide CH₃), 2.17 (s, 3H, COSCH₃),

3.25 (dd, JZ7.8, 10.4 Hz, 1H, CHOBn), 3.56 (dd, JZ6.4,

10.4 Hz, 1H, C1–H), 3.72 (dd, JZ3.4, 10.4 Hz, 1H, C1–H),

3.83 (dd, JZ1.7, 10.4 Hz, 1H, CHOBn), 3.98 (s, 1H, OH),

3.99 (ddd, JZ3.4, 6.4, 8.0 Hz, 1H, C7–H), 4.12 (dq, JZ

10.7, 7.2 Hz, 1H, CO₂CHCH₃), 4.23 (dq, JZ10.7, 7.2 Hz,

1H, CO₂CHCH₃), 4.41 (d, JZ8.0 Hz, 1H, C6–H), 4.48 (d,

JZ12.4 Hz, 1H, OCHPh), 4.57 (s, 2H, OCH₂Ph), 4.65 (d,

JZ12.4 Hz, 1H, OCHPh), 5.32 (dd, JZ1.7, 7.8 Hz, 1H,

C3–H), 7.21–7.39 (m, 10H, ArH); ¹³C NMR (125.8 MHz,

CDCl₃) d 12.1 (CH₃), 14.1 (CH₃), 26.2 (CH₃), 27.1 (CH₃),

27.3 (CH₃), 27.5 (CH₃), 63.3 (CH₂), 70.7 (CH₂), 72.1 (CH₂),

73.5 (CH₂), 73.6 (CH₂), 76.7 (CH), 77.5 (CH), 78.1 (CH),

79.1 (C), 93.9 (C), 110.9 (C), 112.2 (C), 127.8 (CH), 127.85

(CH), 127.91 (CH), 127.93 (CH), 128.5 (CH), 128.6 (CH),

138.1 (C), 138.5 (C), 170.2 (C]O), 204.3 (C]O); FAB-

HRMS m/z calcd for C₃₂H₄₃O₁₀S (MCH)^C619.2577,

found 619.2588. Data for [2S,2(1R,2S),3S,4R]-isomer

(24b). [a]²_D⁵K30.9 (c 0.74, CHCl₃); IR (ﬁlm) 3510, 2930,

1736, 1670, 1381, 1260, 1219, 1148, 1088, 860, 737,

DMAP (40 mg, 0.328 mmol) was added to a solution of the

crude g-hydroxyester (32 mg) in CH₂Cl₂(1 mL). After

stirring for 1 h, the reaction was quenched with saturated

aqueous NH₄Cl (6 mL), and the whole was extracted with

AcOEt (10 mL). The organic extract was washed with brine

(6 mL), and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (30 mg),

which was puriﬁed by column chromatography (silica gel

5 g, 5:1 n-hexane/AcOEt) to give g-lactone 23b (29 mg,

94%) as a colorless oil: [a]²_D⁶K24.0 (c 1.46, CHCl₃); IR

(ﬁlm) 3472, 2990, 2938, 1786, 1726, 1497, 1456, 1377,

1

1256, 1218, 1179, 1101, 1074 cm^K1; H NMR (500 MHz,

698 cm^K^{1 1}H NMR (270 MHz, CDCl₃) d 1.09 (t, JZ

;

CDCl₃) d 1.28 (m, 1H, C7–H), 1.32 (t, JZ7.2 Hz, 3H,

CO₂CH₂CH₃), 1.44 (s, 6H, 2!acetonide CH₃), 1.74 (ddd,

JZ4.4, 12.3, 16.0 Hz, 1H, C6–H), 1.82 (m, 1H, C7–H), 2.24

(ddd, JZ4.4, 12.3, 16.0 Hz, 1H, C6–H), 2.63 (ddd, JZ6.1,

8.6, 13.7 Hz, 1H, CHPh), 2.65 (ddd, JZ6.1, 8.6, 13.7 Hz,

1H, CHPh), 3.72 (s, 1H, OH), 4.26 (dd, JZ3.8, 10.5 Hz, 1H,

one of lactone CH₂), 4.31 (dd, JZ3.8, 10.5 Hz, 1H, one of

lactone CH₂), 4.34 (dq, JZ10.9, 7.2 Hz, 1H, CO₂CHCH₃),

4.35 (dq, JZ10.9, 7.2 Hz, 1H, CO₂CHCH₃), 4.82 (t, JZ

3.8 Hz, 1H, C3–H), 7.14–7.19 (m, 3H, ArH), 7.27 (m, 2H,

ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 15.1 (CH₃), 25.6

(CH₃), 27.8 (CH₃), 28.3 (CH₂), 33.9 (CH₂), 36.8 (CH₂), 64.4

(CH₂), 72.2 (CH₂), 78.4 (CH), 79.5 (C), 88.2 (C), 115.5 (C),

127.1 (CH), 129.4 (CH), 129.5 (CH), 142.7 (C), 174.1

(C]O), 175.8 (C]O); FAB-HRMS m/z calcd for

C₂₀H₂₇O₇(MCH)^C379.1757, found 379.1763.

7.1 Hz, 3H, CO₂CH₂CH₃), 1.42 (s, 3H, acetonide CH₃),

1.49 (s, 3H, acetonide CH₃), 1.68 (s, 3H, acetonide CH₃),

1.82 (s, 3H, acetonide CH₃), 2.08 (s, 3H, COSCH₃), 3.34 (d,

JZ4.5 Hz, 2H, C1–H₂), 3.35 (dd, JZ7.7, 10.8 Hz, 1H,

CHOBn), 3.69 (d, JZ0.8 Hz, 1H, OH), 3.75 (dq, JZ10.7,

7.1 Hz, 1H, CO₂CHCH₃), 3.86 (dd, JZ2.2, 10.8 Hz, 1H,

CHOBn), 3.90 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.23

(dt, JZ7.5, 4.5 Hz, 1H, C7–H), 4.49 (d, JZ12.5 Hz, 1H,

OCHPh), 4.51 (dd, JZ0.8, 7.5 Hz, 1H, C6–H), 4.52 (d, JZ

12.5 Hz, 1H, OCHPh), 4.61 (d, JZ12.5 Hz, 2H, 2!

OCHPh), 5.37 (dd, JZ2.2, 7.7 Hz, 1H, C3–H), 7.20–7.38

(m, 10H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 12.0

(CH₃), 13.9 (CH₃), 26.2 (CH₃), 26.7 (CH₃), 27.79 (CH₃),

27.83 (CH₃), 62.5 (CH₂), 70.4 (CH₂), 71.0 (CH₂), 73.3

(CH₂), 73.6 (CH₂), 76.7 (CH), 77.5 (CH), 79.2 (CH), 80.1

(C), 91.0 (C), 111.2 (C), 113.6 (C), 127.7 (CH), 127.8 (CH),

127.9 (CH), 128.0 (CH), 128.5 (CH), 128.6 (CH), 138.2 (C),

138.4 (C), 171.2 (C]O), 205.6 (C]O); FAB-HRMS m/z

calcd for C₃₂H₄₃O₁₀S (MCH)^C619.2577, found 619.2571.

4.3.10. Typical procedure for the aldol reaction of a-keto

esters with silyl ketene thioacetals: ethyl [2(1R,2S),3S,

4R]-5-benzyloxy-2-[3-benzyloxy-1,2-(dimethylmethyl-

enedioxy)propyl]-3,4-(dimethylmethylenedioxy)-2-

hydroxy-3-(methylthio)carbonylpentanoate (24).

Sn(OTf)₂(42 mg, 0.10 mmol) was added to a stirred

solution of a-keto ester 17 (16.5 mg, 0.051 mmol) and

silyl ketene thioacetal 20 (37 mg, 0.10 mmol) in EtCN

(1 mL) at K70 8C. After stirring at K70 8C for 1.5 h, the

reaction was quenched with saturated aqueous NaHCO₃

(1 mL). The mixture was diluted with 1:1 AcOEt/n-hexane

(10 mL) and ﬁltered through a Celite pad. The layers were

separated, and the organic layer was washed successively

with saturated aqueous NaHCO₃(3 mL) and brine (3 mL),

and dried over anhydrous Na₂SO₄. Filtration and evapor-

ation in vacuo furnished the crude product (45 mg), whose

¹H NMR revealed a 24a/24b ratio of 1:2.2. Puriﬁcation by

column chromatography (silica gel 5 g, 7:1/4:1 n-hexane/

AcOEt) afforded aldol adducts 24b (19.5 mg, 62%) and 24a

(8.9 mg, 28%) as colorless oils. Data for

[2R,2(1R,2S),3S,4R]-isomer (24a). [a]²_D⁴K12.1 (c 0.36,

CHCl₃); IR (ﬁlm) 3468, 2928, 1734, 1671, 1456, 1373,

4.3.11. (R,E)-4-(benzyloxy)methyl-5-[methylthio(tri-

methylsilyloxy)methylene]-2,2-dimethyl-1,3-dioxolane

(25). KHMDS in toluene (0.5 M, 5.0 mL, 2.5 mmol) was

added to a stirred solution of thioester 14 (697 mg,

2.35 mmol) in THF (10 mL) at K78 8C over a 2-h period.

After stirring at K78 8C for 30 min, TMSCl (0.33 mL,

21.3 mmol) was added, and the resulting mixture was stirred

at K78 8C for 30 min. The mixture was allowed to warm to

room temperature. After stirring at room temperature for

15 min, the mixture was evaporated in vacuo. The residue

was suspended in n-hexane and passed through a short plug

of Florisil (eluting with AcOEt) to give silyl ketene

thioacetal 25 (751 mg, 87%, Z/EZ1:99) as a yellow oil:

¹H NMR (500 MHz, C₆D₆) d 0.36 (s, 9H, Si(CH₃)₃), 1.33 (s,

3H, acetonide CH₃), 1.51 (s, 3H, acetonide CH₃), 1.98 (s,

3H, SCH₃), 3.84 (dd, JZ5.6, 10.6 Hz, 1H, CHOBn), 3.94

(dd, JZ2.0, 10.6 Hz, 1H, CHOBn), 4.51 (s, 2H, OCH₂Ph),

5.13 (dd, JZ2.0, 5.6 Hz, 1H, C3–H), 7.07–7.37 (m, 5H,

ArH); ¹³C NMR (67.8 MHz, C₆D₆) d 1.1 (CH₃), 16.3 (CH₃),

27.2 (CH₃), 27.5 (CH₃), 72.8 (CH₂), 73.9 (CH₂), 78.8 (CH),

1259, 1219, 1086, 866, 737, 698 cm^K1

;

¹H NMR

(270 MHz, CDCl₃) d 1.23 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃),

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11091

112.8 (C), 121.8 (C), 128.2 (CH), 128.9 (CH), 139.5 (C),

141.5 (C).

7.2 Hz, 3H, CO₂CH₂CH₃), 1.39–1.74 (m, 4H, 2!pentyl-

idene CH₂), 1.63 (s, 3H, acetonide CH₃), 1.82 (s, 3H,

acetonide CH₃), 2.17 (s, 3H, COSCH₃), 3.28 (dd, JZ7.8,

10.5 Hz, 1H, CHOBn), 3.57 (dd, JZ6.1, 10.4 Hz, 1H, C1–

H), 3.73 (dd, JZ3.5, 10.4 Hz, 1H, C1–H), 3.86 (dd, JZ1.8,

10.5 Hz, 1H, CHOBn), 4.00 (ddd, JZ3.5, 6.1, 8.5 Hz, 1H,

C7–H), 4.03 (s, 1H, OH), 4.13 (dq, JZ10.7, 7.2 Hz, 1H,

CO₂CHCH₃), 4.19 (dq, JZ10.7, 7.2 Hz, 1H, CO₂CHCH₃),

4.37 (d, JZ8.5 Hz, 1H, C6–H), 4.48 (d, JZ12.5 Hz, 1H,

OCHPh), 4.57 (s, 2H, OCH₂Ph), 4.66 (d, JZ12.5 Hz, 1H,

OCHPh), 5.35 (dd, JZ1.8, 7.8 Hz, 1H, C3–H), 7.22–7.38

(m, 10H, ArH); FAB-HRMS m/z calcd for C₃₄H₄₇O₁₀S

(MCH)^C647.2890, found 647.2911. Data for

[2S,2(1R,2S),3S,4R]-isomer (37b). [a]²_D⁴K27.7 (c 0.51,

CHCl₃); IR (ﬁlm) 3515, 2928, 1736, 1671, 1456, 1383,

4.3.12. Sn(OTf)₂-promoted aldol reaction between

a-keto ester 17 and (E)-silyl ketene thioacetal 25. The

aldol reaction was performed according to the typical

procedure (2 mL EtCN, K55 8C, 1 h) employing a-keto

ester 17 (30 mg, 0.093 mmol), (E)-silyl ketene thioacetal 25

(69 mg, 0.187 mmol), and Sn(OTf)₂(78 mg, 0.187 mmol).

A diastereomeric mixture of aldol adducts 24 (21 mg, 36%,

24a:24bZ1:10) was obtained as a colorless oil after ﬂash

column chromatography (silica gel 5 g, 8:1 n-hexane/

AcOEt).

4.3.13. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-benzyl-

oxy-1,2-(methylenedioxy)propyl]-3,4-(dimethylmethyl-

enedioxy)-2-hydroxy-3-(methylthio)carbonylpentanoate

(36). The aldol reaction was performed according to the

typical procedure (1.2 mL EtCN, K70 8C, 1.5 h) employing

a-keto ester 26 (19 mg, 0.063 mmol), silyl ketene thioacetal

20 (50 mg, 0.136 mmol), and Sn(OTf)₂(53 mg,

0.127 mmol). The diastereomeric ratio of the products was

1

1261, 1147, 1090, 737, 698 cm^K1; H NMR (270 MHz,

CDCl₃) d 0.87 (t, JZ7.3 Hz, 3H, pentylidene CH₃), 0.94 (t,

JZ7.5 Hz, 3H, pentylidene CH₃), 1.09 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.47–1.85 (m, 4H, 2!pentylidene CH₂),

1.69 (s, 3H, acetonide CH₃), 1.82 (s, 3H, acetonide CH₃),

2.09 (s, 3H, COSCH₃), 3.337 (d, JZ4.2 Hz, 2H, C1–H₂),

3.340 (dd, JZ7.9, 10.6 Hz, 1H, CHOBn), 3.66 (s, 1H, OH),

3.73 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 3.87 (dd, JZ

2.0, 10.6 Hz, 1H, CHOBn), 3.88 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 4.24 (dt, JZ8.2, 4.2 Hz, 1H, C7–H), 4.44 (d,

JZ8.2 Hz, 1H, C6–H), 4.48 (d, JZ12.4 Hz, 1H, OCHPh),

4.50 (d, JZ12.4 Hz, 1H, OCHPh), 4.61 (d, JZ12.4 Hz, 1H,

OCHPh), 4.62 (d, JZ12.4 Hz, 1H, OCHPh), 5.39 (dd, JZ

2.0, 7.9 Hz, 1H, C3–H), 7.21–7.37 (m, 10H, ArH); FAB-

HRMS m/z calcd for C₃₄H₄₇O₁₀S (MCH)^C647.2890,

found 647.2881.

1

determined to be 1:2.6 by H NMR of the crude product

(43 mg), from which an inseparable mixture of aldol

adducts 36 (18 mg, 49%, 36a:36bZ1:2.6) was obtained as

a colorless oil after ﬂash column chromatography (silica gel

8 g, 5:1/3:1 n-hexane/AcOEt): [a]²_D⁶K40.0 (c 0.81,

CHCl₃); IR (ﬁlm) 3504, 2869, 1734, 1671, 1456, 1383,

1

1261, 1221, 1094, 737, 698 cm^K1; H NMR (270 MHz,

CDCl₃) for 36b d 1.12 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃),

1.66 (s, 3H, acetonide CH₃), 1.81 (s, 3H, acetonide CH₃),

2.09 (s, 3H, COSCH₃), 3.38 (dd, JZ7.6, 10.8 Hz, 1H,

CHOBn), 3.41 (dd, JZ6.0, 10.6 Hz, 1H, C1–H), 3.49 (dd,

JZ3.1, 10.6 Hz, 1H, C1–H), 3.72 (d, JZ0.8 Hz, 1H, OH),

3.85 (dq, JZ10.8, 7.1 Hz, 1H, CO₂CHCH₃), 3.89 (dd, JZ

2.2, 10.8 Hz, 1H, CHOBn), 4.03 (dq, JZ10.8, 7.1 Hz, 1H,

CO₂CHCH₃), 4.15 (dt, JZ3.1, 6.0 Hz, 1H, C7–H), 4.52 (d,

JZ12.3 Hz, 1H, OCHPh), 4.53 (d, JZ12.3 Hz, 1H,

OCHPh), 4.55 (m, 1H, C6–H), 4.59 (d, JZ12.3 Hz, 2H,

2!OCHPh), 5.10 (s, 2H, OCH₂O), 5.40 (dd, JZ2.2,

7.6 Hz, 1H, C3–H), 7.22–7.38 (m, 10H, ArH). The minor

isomer (36a) had additional signals at 1.22 (t, JZ7.1 Hz,

3H, CO₂CH₂CH₃), 2.17 (s, 3H, COSCH₃), and 5.40 (dd, JZ

1.6, 7.7 Hz, 1H, C3–H); FAB-LRMS m/z 591 (MCH)^C.

4.3.15. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-benzyl-

oxy-1,2-(dipropylmethylenedioxy)propyl]-3,4-(dimethyl-

methylenedioxy)-2-hydroxy-3-(methylthio)carbonyl-

pentanoate (38). The aldol reaction was performed

according to the typical procedure (1.2 mL EtCN,

K70 8C, 1.5 h) employing a-keto ester 28 (21.0 mg,

0.055 mmol), silyl ketene thioacetal 20 (52.1 mg,

0.14 mmol), and Sn(OTf)₂(39.0 mg, 0.094 mmol). The

diastereomeric ratio of the products was determined to be

1:1.6 by ¹H NMR of the crude product (62 mg), from which

aldol adducts 38a (12.8 mg, 34%) and 38b (17.8 mg, 48%)

were obtained as colorless oils after ﬂash column

chromatography (silica gel 8 g, 10:1/8:1/5:1 n-hexane/

AcOEt). Data for [2R,2(1R,2S),3S,4R]-isomer (38a). [a]_D²⁵

K13.6 (c 0.52, CHCl₃); IR (ﬁlm) 3464, 2961, 1734, 1676,

4.3.14. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-benzyl-

oxy-1,2-(diethylmethylenedioxy)propyl]-3,4-(dimethyl-

methylenedioxy)-2-hydroxy-3-(methylthio)carbonyl-

pentanoate (37). The aldol reaction was performed

according to the typical procedure (4 mL EtCN, K70 8C,

1.5 h) employing a-keto ester 27 (111 mg, 0.32 mmol), silyl

ketene thioacetal 20 (204 mg, 0.055 mmol), and Sn(OTf)₂

(269 mg, 0.65 mmol). The diastereomeric ratio of the

1

1456, 1375, 1260, 1219, 1103, 735, 698 cm^K1; H NMR

(270 MHz, CDCl₃) d 0.82 (t, JZ7.3 Hz, 3H, heptylidene

CH₃), 0.92 (t, JZ7.3 Hz, 3H, heptylidene CH₃), 1.22 (t, JZ

7.1 Hz, 3H, CO₂CH₂CH₃), 1.20–1.72 (m, 8H, 4!heptyl-

idene CH₂), 1.62 (s, 3H, acetonide CH₃), 1.82 (s, 3H,

acetonide CH₃), 2.17 (s, 3H, COSCH₃), 3.27 (dd, JZ7.8,

10.4 Hz, 1H, CHOBn), 3.55 (dd, JZ6.0, 10.3 Hz, 1H, C1–

H), 3.72 (dd, JZ3.7, 10.3 Hz, 1H, C1–H), 3.85 (dd, JZ1.5,

10.4 Hz, 1H, CHOBn), 3.97 (m, 1H, C7–H), 4.03 (s, 1H,

OH), 4.14 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.19 (dq,

JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.38 (d, JZ8.3 Hz, 1H,

C6–H), 4.48 (d, JZ12.5 Hz, 1H, OCHPh), 4.56 (s, 2H,

OCH₂Ph), 4.66 (d, JZ12.5 Hz, 1H, OCHPh), 5.33 (dd, JZ

1.5, 7.8 Hz, 1H, C3–H), 7.20–7.40 (m, 10H, ArH); FAB-

LRMS m/z 675 (MCH)^C, 631 (MKC₃H₇)^C. Data for

[2S,2(1R,2S),3S,4R]-isomer (38b). [a]²_D⁶K25.3 (c 0.76,

1

products was determined to be 1:1.1 by H NMR of the

crude product (263 mg), from which aldol adducts 37a

(79 mg, 39%) and 37b (82 mg, 40%) were obtained as

colorless oils after ﬂash column chromatography (silica gel

13 g, 8:1/6:1 n-hexane/AcOEt). Data for

[2R,2(1R,2S),3S,4R]-isomer (37a). [a]²_D²K13.3 (c 0.45,

CHCl₃); IR (ﬁlm) 3461, 2930, 1725, 1673, 1455, 1377,

1257, 1221, 1174, 1097, 736, 698 cm^K^{1 1}H NMR

;

(270 MHz, CDCl₃) d 0.86 (t, JZ7.6 Hz, 3H, pentylidene

CH₃), 0.91 (t, JZ7.6 Hz, 3H, pentylidene CH₃), 1.22 (t, JZ

11092

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

1

CHCl₃); IR (ﬁlm) 3510, 2961, 1736, 1669, 1456, 1383,

1256, 936, 737, 698 cm^K1; H NMR (270 MHz, CDCl₃) d

1

1261, 1148, 1090, 736, 698 cm^K1; H NMR (270 MHz,

0.88 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 0.90 (t, JZ

7.4 Hz, 3H, pentylidene CH₃), 0.94 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 1.05 (t, JZ7.5 Hz, 3H, pentylidene CH₃),

1.25 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.47–1.75 (m, 4H,

2!pentylidene CH₂), 1.86–1.98 (m, 2H, pentylidene CH₂),

2.05–2.20 (m, 2H, pentylidene CH₂), 2.14 (s, 3H, COSCH₃),

3.29 (dd, JZ7.2, 10.6 Hz, 1H, CHOBn), 3.57 (dd, JZ6.0,

10.4 Hz, 1H, C1–H), 3.76 (dd, JZ3.1, 10.4 Hz, 1H, C1–H),

3.86 (dd, JZ1.7, 10.6 Hz, 1H, CHOBn), 3.93 (s, 1H, OH),

4.01 (ddd, JZ3.1, 6.0, 8.2 Hz, 1H, C7–H), 4.17 (dq, JZ

10.7, 7.2 Hz, 1H, CO₂CHCH₃), 4.23 (dq, JZ10.7, 7.2 Hz,

1H, CO₂CHCH₃), 4.39 (d, JZ8.2 Hz, 1H, C6–H), 4.49 (d,

JZ12.5 Hz, 1H, OCHPh), 4.57 (s, 2H, OCH₂Ph), 4.61 (d,

JZ12.5 Hz, 1H, OCHPh), 5.30 (dd, JZ1.7, 7.2 Hz, 1H,

C3–H), 7.22–7.37 (m, 10H, ArH); FAB-HRMS m/z calcd

for C₃₆H₅₁O₁₀S (MCH)^C675.3203, found 675.3234. Data

for [2S,2(1R,2S),3S,4R]-isomer (40b). [a]²_D⁷K27.0 (c 0.68,

CHCl₃); IR (ﬁlm) 3512, 2940, 1738, 1667, 1368, 1090, 930,

737, 698 cm^K1; ¹H NMR (270 MHz, CDCl₃) d 0.88 (t, JZ

7.4 Hz, 3H, pentylidene CH₃), 0.925 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 0.928 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 1.04 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 1.10 (t, JZ

7.1 Hz, 3H, CO₂CH₂CH₃), 1.55–1.82 (m, 4H, 2!pentyl-

idene CH₂), 1.92–2.18 (m, 4H, 2!pentylidene CH₂), 2.07

(s, 3H, COSCH₃), 3.33 (dd, JZ6.0, 11.2 Hz, 1H, C1–H),

3.37 (dd, JZ7.2, 11.2 Hz, 1H, CHOBn), 3.40 (dd, JZ2.4,

11.2 Hz, 1H, C1–H), 3.69 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 3.74 (s, 1H, OH), 3.88 (dq, JZ10.7, 7.1 Hz,

1H, CO₂CHCH₃), 3.89 (dd, JZ2.3, 11.2 Hz, 1H, CHOBn),

4.22 (ddd, JZ2.4, 6.0, 7.8 Hz, 1H, C7–H), 4.49 (d, JZ

7.8 Hz, 1H, C6–H), 4.51 (d, JZ12.5 Hz, 1H, OCHPh), 4.59

(d, JZ12.5 Hz, 1H, OCHPh), 4.60 (d, JZ12.5 Hz, 1H,

OCHPh), 4.60 (d, JZ12.5 Hz, 1H, OCHPh), 5.39 (dd, JZ

2.3, 7.2 Hz, 1H, C3–H), 7.20–7.40 (m, 10H, ArH); FAB-

HRMS m/z calcd for C₃₆H₅₁O₁₀S (MCH)^C675.3203,

found 675.3214.

CDCl₃) d 0.85 (t, JZ7.3 Hz, 3H, heptylidene CH₃), 0.92 (t,

JZ7.3 Hz, 3H, heptylidene CH₃), 1.09 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.18–1.80 (m, 8H, 4!heptylidene CH₂),

1.68 (s, 3H, acetonide CH₃), 1.82 (s, 3H, acetonide CH₃),

2.09 (s, 3H, COSCH₃), 3.33 (d, JZ4.5 Hz, 2H, C1–H₂),

3.34 (dd, JZ7.9, 10.7 Hz, 1H, CHOBn), 3.67 (d, JZ0.8 Hz,

1H, OH), 3.74 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 3.86

(dd, JZ2.1, 10.7 Hz, 1H, CHOBn), 3.88 (dq, JZ10.7,

7.1 Hz, 1H, CO₂CHCH₃), 4.23 (dt, JZ7.9, 4.5 Hz, 1H, C7–

H), 4.43 (dd, JZ0.8, 7.9 Hz, 1H, C6–H), 4.48 (d, JZ

12.5 Hz, 1H, OCHPh), 4.53 (d, JZ12.5 Hz, 1H, OCHPh),

4.59 (d, JZ12.5 Hz, 1H, OCHPh), 4.61 (d, JZ12.5 Hz, 1H,

OCHPh), 5.37 (dd, JZ2.1, 7.9 Hz, 1H, C3–H), 7.20–7.40

(m, 10H, ArH); FAB-LRMS m/z 675 (MCH)^C, 631 (MK

C₃H₇)^C.

4.3.16. Ethyl [2S,2(1R,2S),3S,4R]-5-benzyloxy-2-[3-

benzyloxy-1,2-(diethylmethylenedioxy)propyl]-2-

hydroxy-3,4-(methylenedioxy)-3-(methylthio)carbonyl-

pentanoate (39b). The aldol reaction was performed

according to the typical procedure (1.5 mL EtCN,

K70 8C, 1.5 h) employing a-keto ester 27 (27.3 mg,

0.078 mmol), silyl ketene thioacetal 33 (53.2 mg,

0.156 mmol), and Sn(OTf)₂(65.0 mg, 0.156 mmol). The

diastereomeric ratio of the products was determined to be

1

1:O20 by H NMR of the crude product (83.2 mg), from

which aldol adduct 39b (32.3 mg, 67%) was obtained as a

colorless oil after ﬂash column chromatography (silica gel

5 g, 8:1/5:1 n-hexane/AcOEt): [a]²_D⁴K3.0 (c 0.92,

CHCl₃); IR (ﬁlm) 3493, 2975, 1738, 1672, 1454, 1368,

1260, 1150, 1094, 980, 752, 698 cm^K1

;

¹H NMR

(270 MHz, CDCl₃) d 0.87 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 0.94 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 1.09 (t, JZ

7.2 Hz, 3H, CO₂CH₂CH₃), 1.60–1.83 (m, 4H, 2!pentyli-

dene CH₂), 2.11 (s, 3H, COSCH₃), 3.31 (d, JZ4.2 Hz, 2H,

C1–H₂), 3.36 (dd, JZ7.8, 10.7 Hz, 1H, CHOBn), 3.62 (s,

1H, OH), 3.74 (dq, JZ10.6, 7.2 Hz, 1H, CO₂CHCH₃), 3.78

(dd, JZ2.2, 10.7 Hz, 1H, CHOBn), 4.01 (dq, JZ10.6,

7.2 Hz, 1H, CO₂CHCH₃), 4.21 (dt, JZ8.0, 4.2 Hz, 1H, C7–

H), 4.44 (d, JZ8.0 Hz, 1H, C6–H), 4.47 (d, JZ12.3 Hz, 1H,

OCHPh), 4.52 (d, JZ12.3 Hz, 1H, OCHPh), 4.57 (d, JZ

12.3 Hz, 2H, 2!OCHPh), 5.16 (dd, JZ2.2, 7.8 Hz, 1H,

C3–H), 5.36 (s, 1H, OCHO), 5.50 (s, 1H, OCHO), 7.22–7.37

(m, 10H, ArH); FAB-LRMS m/z 619 (MCH)^C, 589 (MK

Et)^C.

4.3.18. Ethyl [2S,2(1R,2S),3S,4R]-2-[3-benzyloxy-1,2-

(diethylmethylenedioxy)propyl]-5-(tert-butyldiphenyl-

silyl)oxy-3,4-(dimethylmethylenedioxy)-2-hydroxy-3-

(methylthio)carbonylpentanoate (41b). The aldol reaction

was performed according to the typical procedure (5 mL

EtCN, K70 8C, 1.5 h) employing a-keto ester 27 (69.6 mg,

0.199 mmol), silyl ketene thioacetal 35 (209.1 mg,

0.405 mmol), and Sn(OTf)₂(170.6 mg, 0.409 mmol). The

diastereomeric ratio of the products was determined to be

1

1:O20 by H NMR of the crude product (284.2 mg), from

4.3.17. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-benzyl-

oxy-1,2-(diethylmethylenedioxy)propyl]-3,4-(diethyl-

methylenedioxy)-2-hydroxy-3-(methylthio)carbonyl-

pentanoate (40). The aldol reaction was performed

according to the typical procedure (3 mL EtCN, K70 8C,

1.5 h) employing a-keto ester 27 (62.2 mg, 0.178 mmol),

silyl ketene thioacetal 34 (137.3 mg, 0.346 mmol), and

Sn(OTf)₂(151.6 mg, 0.364 mmol). The diastereomeric ratio

which aldol adduct 41b (102.0 mg, 65%) was obtained as a

colorless oil after ﬂash column chromatography (silica gel

15 g, 15:1 n-hexane/AcOEt): [a]²_D³K10.6 (c 0.39, CHCl₃);

IR (ﬁlm) 3515, 2932, 2884, 2859, 1738, 1667, 1462, 1427,

1

1375, 1262, 1221, 1111, 1026, 912, 887 cm^K1; H NMR

(270 MHz, CDCl₃) d 0.88 (t, JZ7.4 Hz, 3H, pentylidene

CH₃), 0.92 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 1.03 (s, 9H,

SiC(CH₃)₃), 1.07 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃), 1.50–

1.79 (m, 4H, 2!pentylidene CH₂), 1.69 (s, 3H, acetonide

CH₃), 1.79 (s, 3H, acetonide CH₃), 2.01 (s, 3H, COSCH₃),

3.33 (d, JZ4.1 Hz, 2H, C1–H₂), 3.54 (dd, JZ7.2, 11.2 Hz,

1H, CHOTBDPS), 3.69 (s, 1H, OH), 3.71 (dq, JZ10.7,

7.1 Hz, 1H, CO₂CHCH₃), 3.85 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 4.01 (dd, JZ2.7, 11.2 Hz, 1H, CHOTBDPS),

4.26 (dt, JZ8.0, 4.1 Hz, 1H, C7–H), 4.41 (d, JZ8.0 Hz, 1H,

1

of the products was determined to be 1:1.9 by H NMR of

the crude product (161.6 mg), from which aldol adducts 40a

(31.3 mg, 26%) and 40b (49.2 mg, 41%) were obtained as

colorless oils after ﬂash column chromatography (silica gel

10 g, 15:1/10:1/8:1 n-hexane/AcOEt). Data for

[2R,2(1R,2S),3S,4R]-isomer (40a). [a]²_D⁹K5.4 (c 1.0,

CHCl₃); IR (ﬁlm) 3464, 2975, 1723, 1672, 1456, 1366,

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11093

C6–H), 4.47 (d, JZ12.5 Hz, 1H, OCHPh), 4.62 (d, JZ

12.5 Hz, 1H, OCHPh), 5.31 (dd, JZ2.7, 7.2 Hz, 1H, C3–H),

7.23–7.45 (m, 9H, ArH), 7.66–7.73 (m, 6H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 5.4 (CH₃), 6.5 (CH₃), 9.5 (CH₃),

11.4 (CH₃), 17.0 (CH₃), 23.8 (CH₃), 24.5 (CH₃), 25.3 (CH₃),

26.9 (CH₃), 27.9 (CH₂), 59.9 (CH₂), 62.1 (CH₂), 68.5 (CH₂),

71.0 (CH₂), 73.9 (CH₂), 76.9 (CH), 79.5 (C), 88.5 (C), 110.8

(C), 112.7 (C), 125.2 (CH), 125.3 (CH), 125.4 (CH), 125.6

(CH), 126.1 (CH), 127.2 (CH), 128.5 (CH), 133.5 (C), 133.6

(C), 168.9 (C]O), 203.5 (C]O); FAB-HRMS m/z calcd

for C₄₃H₅₉O₁₀SSi (MCH)^C795.3598, found 795.3590.

pentylidene CH₃), 0.92 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 1.22 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃), 1.43–1.70 (m,

4H, 2!pentylidene CH₂), 1.65 (s, 3H, acetonide CH₃), 1.83

(s, 3H, acetonide CH₃), 2.17 (s, 3H, COSCH₃), 3.29 (dd, JZ

7.8, 10.4 Hz, 1H, CHOBn), 3.35 (s, 3H, OCH₃), 3.65 (dd,

JZ6.6, 10.8 Hz, 1H, C1–H), 3.83 (dd, JZ3.0, 10.8 Hz, 1H,

C1–H), 3.83 (dd, JZ1.7, 10.4 Hz, 1H, CHOBn), 3.95 (s,

1H, OH), 3.99 (ddd, JZ3.0, 6.6, 8.3 Hz, 1H, C7–H), 4.13

(dq, JZ10.8, 7.1 Hz, 1H, CO₂CHCH₃), 4.19 (dq, JZ10.8,

7.1 Hz, 1H, CO₂CHCH₃), 4.39 (d, JZ8.3 Hz, 1H, C6–H),

4.48 (d, JZ12.5 Hz, 1H, OCHPh), 4.64 (s, 2H, OCH₂O),

4.67 (d, JZ12.5 Hz, 1H, OCHPh), 5.33 (dd, JZ1.7, 7.8 Hz,

1H, C3–H), 7.20–7.45 (m, 5H, ArH); FAB-LRMS m/z

601 (MCH)^C, 543 (MKC₄H₉)^C. Data for

[2S,2(1R,2S),3S,4R]-isomer (43b). [a]²_D⁷K33.3 (c 0.67,

CHCl₃); IR (ﬁlm) 3525, 2932, 1736, 1671, 1458, 1383,

1261, 1149, 1096, 1043 cm^K1; ¹H NMR (270 MHz, CDCl₃)

d 0.88 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 0.94 (t,

JZ7.4 Hz, 3H, pentylidene CH₃), 1.24 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.55–1.86 (m, 4H, 2!pentylidene CH₂),

1.71 (s, 3H, acetonide CH₃), 1.83 (s, 3H, acetonide CH₃),

2.11 (s, 3H, COSCH₃), 3.34 (s, 3H, OCH₃), 3.35 (dd, JZ

7.8, 10.8 Hz, 1H, CHOBn), 3.40 (dd, JZ6.4, 11.2 Hz, 1H,

C1–H), 3.50 (dd, JZ2.2, 11.2 Hz, 1H, C1–H), 3.69 (d, JZ

0.7 Hz, 1H, OH), 3.88 (dd, JZ2.2, 10.8 Hz, 1H, CHOBn),

4.10 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.19 (dq, JZ

10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.22 (ddd, JZ2.2, 6.4,

7.7 Hz, 1H, C7–H), 4.46 (dd, JZ0.7, 7.7 Hz, 1H, C6–H),

4.51 (d, JZ12.5 Hz, 1H, OCHPh), 4.61 (s, 2H, OCH₂O),

4.62 (d, JZ12.5 Hz, 1H, OCHPh), 5.41 (dd, JZ2.2, 7.8 Hz,

1H, C3–H), 7.20–7.40 (m, 5H, ArH); FAB-LRMS m/z 601

(MCH)^C.

4.3.19. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-(tert-

butyldiphenylsilyl)oxy-1,2-(diethylmethylenedioxy)pro-

pyl]-3,4-(dimethylmethylenedioxy)-2-hydroxy-3-

(methylthio)carbonylpentanoate (42). The aldol reaction

was performed according to the typical procedure (1.2 mL

EtCN, K70 8C, 1.5 h) employing a-keto ester 29 (28 mg,

0.056 mmol), silyl ketene thioacetal 20 (43 mg,

0.117 mmol), and Sn(OTf)₂(47 mg, 0.113 mmol). The

diastereomeric ratio of the products was determined to be

1

1:5 by H NMR of the crude product (57 mg), from which

an inseparable mixture of aldol adducts 42 (20 mg, 45%,

42a:42bZ1:5) was obtained as a colorless oil after ﬂash

column chromatography (silica gel 8 g, 7:1 n-hexane/

AcOEt): [a]²_D³K25.8 (c 0.97, CHCl₃); IR (ﬁlm) 3511,

2934, 1736, 1667, 1462, 1429, 1381, 1262, 1219, 1088, 741,

1

702 cm^K1; H NMR (270 MHz, CDCl₃) for 42b d 0.91 (t,

JZ7.5 Hz, 3H, pentylidene CH₃), 0.95 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 1.01 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃),

1.07 (s, 9H, SiC(CH₃)₃), 1.60–1.86 (m, 4H, 2!pentylidene

CH₂), 1.72 (s, 3H, acetonide CH₃), 1.83 (s, 3H, acetonide

CH₃), 2.09 (s, 3H, COSCH₃), 3.32 (dd, JZ4.3, 11.7 Hz, 1H,

C1–H), 3.36 (dd, JZ7.9, 10.6 Hz, 1H, CHOBn), 3.56 (dq,

JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 3.66 (d, JZ0.8 Hz, 1H,

OH), 3.76 (dd, JZ1.6, 11.7 Hz, 1H, C1–H), 3.87 (dd, JZ

2.1, 10.6 Hz, 1H, CHOBn), 3.92 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 4.14 (ddd, JZ1.6, 4.3, 7.8 Hz, 1H, C7–H),

4.51 (d, JZ12.4 Hz, 1H, OCHPh), 4.62 (d, JZ12.4 Hz, 1H,

OCHPh), 4.75 (dd, JZ0.8, 7.8 Hz, 1H, C6–H), 5.47 (dd, JZ

2.1, 7.9 Hz, 1H, C3–H), 7.21–7.46 (m, 11H, ArH), 7.64–

7.75 (m, 4H, ArH). The minor isomer (42a) had additional

signals at 1.05 (s, 9H, SiC(CH₃)₃), 2.16 (s, 3H, COSCH₃),

and 5.34 (dd, JZ1.6, 7.7 Hz, 1H, C3–H); FAB-LRMS m/z

795 (MCH)^C, 765 (MKEt)^C.

4.3.21. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[3-benzyl-

oxymethoxy-1,2-(diethylmethylenedioxy)propyl]-3,4-

(dimethylmethylenedioxy)-2-hydroxy-3-(methylthio)

carbonylpentanoate (44). The aldol reaction was per-

formed according to the typical procedure (1.2 mL EtCN,

K70 8C, 1.5 h) employing a-keto ester 31 (19.6 mg,

0.052 mmol), silyl ketene thioacetal 20 (51.0 mg,

0.138 mmol), and Sn(OTf)₂(60 mg, 0.144 mmol). The

diastereomeric ratio of the products was determined to be

1

1:1.6 by H NMR of the crude product, from which aldol

adducts 44a (12.4 mg, 36%) and 44b (18.9 mg, 54%) were

obtained as colorless oils after ﬂash column chromato-

graphy (silica gel 8 g, 6:1 n-hexane/AcOEt). Data for

[2R,2(1R,2S),3S,4R]-isomer (44a). [a]²_D⁷K11.6 (c 0.55,

CHCl₃); IR (ﬁlm) 3462, 2936, 1734, 1671, 1456, 1380,

4.3.20. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[1,2-

(diethylmethylenedioxy)-3-(methoxymethoxy)]propyl-3,

4-(dimethylmethylenedioxy)-2-hydroxy-3-(methylthio)

carbonylpentanoate (43). The aldol reaction was per-

formed according to the typical procedure (1.2 mL EtCN,

K70 8C, 1.5 h) employing a-keto ester 30 (18 mg,

0.059 mmol), silyl ketene thioacetal 20 (52 mg,

0.141 mmol), and Sn(OTf)₂(54 mg, 0.13 mmol). The

diastereomeric ratio of the products was determined to be

1.1:1 by ¹H NMR of the crude product (55 mg), from which

aldol adducts 43a (14.7 mg, 41%) and 43b (13.5 mg, 38%)

were obtained as colorless oils after ﬂash column

chromatography (silica gel 8 g, 10:1/6:1/4:1 n-hexane/

AcOEt). Data for [2R,2(1R,2S),3S,4R]-isomer (43a). [a]_D²⁷

K12.3 (c 0.66, CHCl₃); IR (ﬁlm) 3462, 2930, 1732, 1672,

1256, 1171, 1096, 1042, 737, 698 cm^K^{1 1}H NMR

;

(270 MHz, CDCl₃) d 0.89 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 0.92 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 1.21 (t, JZ

7.1 Hz, 3H, CO₂CH₂CH₃), 1.45–1.73 (m, 4H, 2!pentyl-

idene CH₂), 1.65 (s, 3H, acetonide CH₃), 1.82 (s, 3H,

acetonide CH₃), 2.17 (s, 3H, COSCH₃), 3.28 (dd, JZ7.8,

10.4 Hz, 1H, CHOBn), 3.72 (dd, JZ6.5, 10.8 Hz, 1H, C1–

H), 3.86 (dd, JZ1.7, 10.4 Hz, 1H, CHOBn), 3.90 (dd, JZ

3.0, 10.8 Hz, 1H, C1–H), 3.92 (s, 1H, OH), 4.01 (ddd, JZ

3.0, 6.5, 8.3 Hz, 1H, C7–H), 4.13 (dq, JZ10.8, 7.1 Hz, 1H,

CO₂CHCH₃), 4.16 (dq, JZ10.8, 7.1 Hz, 1H, CO₂CHCH₃),

4.43 (d, JZ8.3 Hz, 1H, C6–H), 4.48 (d, JZ12.6 Hz, 1H,

OCHPh), 4.61 (s, 2H, OCH₂O), 4.68 (d, JZ12.6 Hz, 1H,

OCHPh), 4.78 (s, 2H, OCH₂Ph), 5.34 (dd, JZ1.7, 7.8 Hz,

1H, C3–H), 7.22–7.39 (m, 10H, ArH); FAB-LRMS m/z 677

1

1458, 1383, 1256, 1219, 1098, 1042, 735, 698 cm^K1; H

NMR (270 MHz, CDCl₃) d 0.89 (t, JZ7.5 Hz, 3H,

11094

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

(MCH)^C, 647 (MKEt)^C. Data for [2S,2(1R,2S),3S,4R]-

isomer (44b). [a]²_D⁷K27.2 (c 0.86, CHCl₃); IR (ﬁlm) 3506,

2937, 1736, 1671, 1456, 1383, 1261, 1148, 1090, 1044, 735,

7.4 Hz, 3H, pentylidene CH₃), 0.94 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 1.24 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃),

1.58–1.87 (m, 4H, 2!pentylidene CH₂), 1.71 (s, 3H,

acetonide CH₃), 1.83 (s, 3H, acetonide CH₃), 2.11 (s, 3H,

COSCH₃), 3.35 (dd, JZ7.8, 10.5 Hz, 1H, CHOBn), 3.42

(dd, JZ6.6, 11.2 Hz, 1H, C1–H), 3.38 (s, 3H, OCH₃), 3.52

(dd, JZ2.0, 11.2 Hz, 1H, C1–H), 3.52–3.57 (m, 2H, OCH₂),

3.63–3.72 (m, 2H, OCH₂), 3.69 (s, 1H, OH), 3.88 (dd, JZ

2.0, 10.5 Hz, 1H, CHOBn), 4.09 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 4.19 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃),

4.22 (m, 1H, C7–H), 4.45 (d, JZ7.9 Hz, 1H, C6–H), 4.51

(d, JZ12.4 Hz, 1H, OCHPh), 4.61 (d, JZ12.4 Hz, 1H,

OCHPh), 4.69 (d, JZ6.8 Hz, 1H, OCHO), 4.71 (d, JZ

6.8 Hz, 1H, OCHO), 5.40 (dd, JZ2.0, 7.8 Hz, 1H, C3–H),

7.25 (m, 1H, ArH), 7.29–7.38 (m, 4H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 7.5 (CH₃), 8.5 (CH₃), 11.8 (CH₃),

13.7 (CH₃), 26.0 (CH₃), 27.4 (CH₃), 29.3 (CH₂), 30.0 (CH₂),

58.9 (CH₃), 62.5 (CH₂), 66.8 (CH₂), 68.1 (CH₂), 70.2 (CH₂),

71.6 (CH₂), 73.1 (CH₂), 76.0 (CH), 76.8 (CH), 79.0 (C),

79.9 (CH), 90.7 (C), 95.5 (CH₂), 113.2 (C), 114.9 (C), 127.4

(CH), 127.5 (CH), 128.2 (CH), 138.1 (C), 170.9 (C]O),

205.5 (C]O); FAB-HRMS m/z calcd for C₃₁H₄₉O₁₂S (MC

H)^C645.2945, found 645.2950.

698 cm^K^{1 1}H NMR (270 MHz, CDCl₃) d 0.89 (t, JZ

;

7.3 Hz, 3H, pentylidene CH₃), 0.95 (t, JZ7.3 Hz, 3H,

pentylidene CH₃), 1.14 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃),

1.55–1.87 (m, 4H, 2!pentylidene CH₂), 1.72 (s, 3H, aceto-

nideCH₃),1.84(s, 3H, acetonideCH₃),2.11(s, 3H, COSCH₃),

3.35 (dd, JZ8.1, 10.6 Hz, 1H, CHOBn), 3.44 (dd, JZ6.6,

11.2 Hz, 1H, C1–H), 3.58 (dd, JZ2.2, 11.2 Hz, 1H, C1–H),

3.68 (s, 1H, OH), 3.88 (dd, JZ2.2, 10.6 Hz, 1H, CHOBn),

3.97 (dq, JZ10.6, 7.2 Hz, 1H, CO₂CHCH₃), 4.11 (dq, JZ

10.6, 7.2 Hz, 1H, CO₂CHCH₃), 4.26 (m, 1H, C7–H), 4.48 (d,

JZ8.1 Hz, 1H, C6–H), 4.51 (d, JZ12.5 Hz, 1H, OCHPh),

4.59(s, 2H, OCH₂Ph), 4.63(d, JZ12.5 Hz, 1H, OCHPh), 4.74

(d, JZ6.8 Hz, 1H, OCHO), 4.77 (d, JZ6.8 Hz, 1H, OCHO),

5.41 (dd, JZ2.2, 8.1 Hz, 1H, C3–H), 7.20–7.40 (m, 10H,

ArH); FAB-LRMS m/z 677 (MCH)^C, 647 (MKEt)^C.

4.3.22. Ethyl [2(1R,2S),3S,4R]-5-benzyloxy-2-[1,2-

(diethylmethylenedioxy)-3-[(2-methoxyethoxy)methoxy]

propyl]-3,4-(dimethylmethylenedioxy)-2-hydroxy-3-

(methylthio)carbonylpentanoate (45). The aldol reaction

was performed according to the typical procedure (1.2 mL

EtCN, K70 8C, 1.5 h) employing a-keto ester 32 (24 mg,

0.069 mmol), silyl ketene thioacetal 20 (52 mg,

0.141 mmol), and Sn(OTf)₂(49 mg, 0.118 mmol). The

diastereomeric ratio of the products was determined to be

1.6:1 by ¹H NMR of the crude product (58 mg), from which

aldol adducts 45a (22.6 mg, 51%) and 45b (14.2 mg, 32%)

were obtained as colorless oils after ﬂash column

chromatography (silica gel 8 g, 4:1/7:2 n-hexane/

AcOEt). Data for [2R,2(1R,2S),3S,4R]-isomer (45a). [a]_D²⁵

K13.1 (c 1.0, CHCl₃); IR (ﬁlm) 3459, 2938, 1732, 1672,

4.3.23. Ethyl [3R,3(1R,2S),4S,8R]-3-[3-benzyloxy-1,2-

(diethylmethylenedioxy)propyl]-8-(benzyloxymethyl)-6,

6-dimethyl-1-oxo-2,5,7-trioxaspiro[3.4]octane-3-car-

boxylate (46a). Hg(OCOCF₃)₂(133 mg, 0.31 mmol) was

added to a stirred solution of thioester 37a (98 mg,

0.15 mmol) in MeCN (16 mL). After stirring for 200 h,

the reaction mixture was evaporated in vacuo. The residue

was suspended in Et₂O and passed through a short plug of

silica gel (eluting with Et₂O) to remove insoluble Hg salt.

Puriﬁcation of the residue (97 mg) by column chromato-

graphy (silica gel 5 g, 11:1 n-hexane/AcOEt) afforded

b-lactone 46a (52 mg, 58%) as a colorless oil: [a]²_D⁹C18.6

(c 1.15, CHCl₃); IR (ﬁlm) 2978, 1848, 1730, 1456, 1379,

1

1462, 1377, 1254, 1175, 1046, 858, 793, 698 cm^K1; H

NMR (500 MHz, CDCl₃) d 0.88 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 0.91 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 1.22 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.55–1.70 (m,

4H, 2!pentylidene CH₂), 1.65 (s, 3H, acetonide CH₃), 1.83

(s, 3H, acetonide CH₃), 2.17 (s, 3H, COSCH₃), 3.29 (dd, JZ

7.8, 10.4 Hz, 1H, CHOBn), 3.37 (s, 3H, OCH₃), 3.52–3.57

(m, 2H, OCH₂), 3.67 (dd, JZ6.4, 10.7 Hz, 1H, C1–H),

3.67–3.72 (m, 2H, OCH₂), 3.87 (dd, JZ1.4, 10.4 Hz, 1H,

CHOBn), 3.88 (dd, JZ2.8, 10.7 Hz, 1H, C1–H), 3.98 (ddd,

JZ2.8, 6.4, 8.4 Hz, 1H, C7–H), 3.99 (s, 1H, OH), 4.13 (dq,

JZ10.7, 7.2 Hz, 1H, CO₂CHCH₃), 4.19 (dq, JZ10.7,

7.2 Hz, 1H, CO₂CHCH₃), 4.39 (d, JZ8.4 Hz, 1H, C6–H),

4.48 (d, JZ12.5 Hz, 1H, OCHPh), 4.67 (d, JZ12.5 Hz, 1H,

OCHPh), 4.72 (s, 2H, OCH₂O), 5.33 (dd, JZ1.4, 7.8 Hz,

1H, C3–H), 7.27 (m, 1H, ArH), 7.29–7.37 (m, 4H, ArH);

¹³C NMR (125.8 MHz, CDCl₃) d 8.1 (CH₃), 8.3 (CH₃), 11.8

(CH₃), 13.7 (CH₃), 26.2 (CH₃), 27.2 (CH₃), 29.1 (CH₂), 29.8

(CH₂), 58.9 (CH₃), 63.1 (CH₂), 66.7 (CH₂), 69.3 (CH₂), 70.3

(CH₂), 71.2 (CH₂), 73.1 (CH₂), 76.4 (CH), 77.9 (CH), 78.9

(CH), 79.1 (C), 93.6 (C), 95.4 (CH₂), 111.8 (C), 114.8 (C),

127.5 (CH), 127.6 (CH), 128.2 (CH), 138.3 (C), 170.6

(C]O), 193.7 (C]O); FAB-HRMS m/z calcd for

C₃₁H₄₉O₁₂S (MCH)^C645.2945, found 645.2916. Anal.

Calcd for C₃₁H₄₈O₁₂S: C, 57.75; H, 7.50; S, 4.97. Found: C,

57.47; H, 7.43; S, 4.84. Data for [2S,2(1R,2S),3S,4R]-

isomer (45b). [a]²_D⁵K33.5 (c 1.5, CHCl₃); IR (ﬁlm) 3459,

2938, 1732, 1672, 1462, 1377, 1254, 1175, 1046, 858, 793,

1

1219, 1103, 1094 cm^K1; H NMR (270 MHz, CDCl₃) d

0.85 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 0.89 (t, JZ

7.5 Hz, 3H, pentylidene CH₃), 1.17 (t, JZ7.0 Hz, 3H,

CO₂CH₂CH₃), 1.35 (s, 3H, acetonide CH₃), 1.41 (s, 3H,

acetonide CH₃), 1.59–1.72 (m, 4H, 2!pentylidene CH₂),

3.50 (dd, JZ7.9, 8.2 Hz, 1H, CHOBn), 3.64 (dd, JZ5.5,

10.6 Hz, 1H, C1–H), 3.76 (dd, JZ6.0, 8.2 Hz, 1H,

CHOBn), 3.78 (dd, JZ5.5, 10.6 Hz, 1H, C1–H), 3.96 (dq,

JZ10.6, 7.0 Hz, 1H, CO₂CHCH₃), 4.27 (dq, JZ10.6,

7.0 Hz, 1H, CO₂CHCH₃), 4.37 (m, 1H, C7–H), 4.39 (d,

JZ11.9 Hz, 1H, OCHPh), 4.51 (d, JZ11.9 Hz, 1H,

OCHPh), 4.60 (s, 2H, OCH₂Ph), 4.63 (d, JZ6.5 Hz, 1H,

C6–H), 4.81 (dd, JZ6.0, 7.9 Hz, 1H, C3–H), 7.25–7.37 (m,

10H, ArH); ¹³C NMR (67.8 MHz, CDCl₃) d 8.0 (CH₃), 8.1

(CH₃), 8.2 (CH₃), 13.9 (CH₃), 24.9 (CH₃), 26.4 (CH₂), 26.5

(CH₂), 29.7 (CH₂), 29.8 (CH₂), 62.1 (CH₂), 68.1 (CH₂), 70.1

(CH₂), 73.4 (CH), 73.8 (CH), 76.4 (CH), 85.6 (C), 94.2 (C),

113.3 (C), 114.6 (C), 127.6 (CH), 127.7 (CH), 127.9 (CH),

128.2 (CH), 128.3 (CH), 128.9 (CH), 136.9 (C), 138.1 (C),

166.1 (C]O), 167.5 (C]O); FAB-HRMS m/z calcd for

C₃₃H₄₃O₁₀(MCH)^C599.2856, found 599.2826.

4.3.24. Ethyl [2R,2(1R,2S),3S,4R]-5-benzyloxy-2-[3-ben-

zyloxy-1,2-(diethylmethylenedioxy)propyl]-3,4-(dimethyl-

methylenedioxy)-2-hydroxy-3-(methoxycarbonyl)pen-

tanoate. Potassium carbonate (15.6 mg, 0.113 mmol) was

698 cm^K^{1 1}H NMR (500 MHz, CDCl₃) d 0.87 (t, JZ

;

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11095

added to a solution of b-lactone 46a (51.6 mg, 0.086 mmol)

in MeOH (1.5 mL). After stirring for 1.5 h, the mixture was

partitioned between AcOEt (10 mL) and brine (7 mL). The

organic extract was washed successively with saturated

aqueous NH₄Cl (7 mL) and brine (7 mL), and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (57.3 mg), which was puriﬁed

by column chromatography (silica gel 8 g, 7:2 n-hexane/

AcOEt) to give methyl ester (46.5 mg, 86%) as a colorless

oil: [a]²_D⁸K5.20 (c 1.0, CHCl₃); IR (ﬁlm) 3464, 2976, 2940,

of lactone CH₂), 4.00 (dd, JZ9.5, 10.4 Hz, 1H, one of

lactone CH₂), 4.23 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃),

4.35 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.36 (dd, JZ

3.7, 11.2 Hz, 1H, C1–H), 4.38 (dd, JZ7.9, 11.2 Hz, 1H,

C1–H), 4.39 (s, 1H, OH), 4.48 (ddd, JZ3.7, 4.4, 7.9 Hz, 1H,

C7–H), 4.61 (dd, JZ4.7, 10.4 Hz, 1H, C3–H), 5.05 (d, JZ

4.4 Hz, 1H, C6–H); ¹³C NMR (125.8 MHz, CDCl₃) d 8.1

(CH₃), 8.2 (CH₃), 14.2 (CH₃), 27.1 (CH₃), 27.2 (CH₃), 30.0

(CH₂), 30.2 (CH₂), 63.15 (CH₂), 63.21 (CH₂), 73.1 (CH₂),

76.8 (CH), 77.8 (CH), 79.0 (CH), 79.1 (C), 85.1 (C), 113.4

(C), 114.2 (C), 171.5 (C]O), 176.1 (C]O); FAB-HRMS m/z

calcd for C₁₉H₃₁O₁₀(MCH)^C419.1917, found 419.1890.

1

1732, 1497, 1454, 1372, 1258, 1090, 936 cm^K1; H NMR

(500 MHz, CDCl₃) d 0.87 (t, JZ7.4 Hz, 3H, pentylidene

CH₃), 0.90 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 1.24 (t, JZ

7.2 Hz, 3H, CO₂CH₂CH₃), 1.53 (q, JZ7.4 Hz, 2H,

pentylidene CH₂), 1.55 (s, 3H, acetonide CH₃), 1.62 (q,

JZ7.5 Hz, 2H, pentylidene CH₂), 1.64 (s, 3H, acetonide

CH₃), 3.40 (dd, JZ6.3, 10.6 Hz, 1H, CHOBn), 3.60 (dd, JZ

5.8, 10.3 Hz, 1H, C1–H), 3.61 (s, 3H, CO₂CH₃), 3.70 (dd,

JZ3.9, 10.3 Hz, 1H, C1–H), 3.90 (dd, JZ1.3, 10.6 Hz, 1H,

CHOBn), 4.00 (ddd, JZ3.9, 5.8, 8.6 Hz, 1H, C7–H), 4.14

(dq, JZ10.8, 7.2 Hz, 1H, CO₂CHCH₃), 4.20 (s, 1H, OH),

4.24 (dq, JZ10.8, 7.2 Hz, 1H, CO₂CHCH₃), 4.41 (d, JZ

8.6 Hz, 1H, C6–H), 4.51 (d, JZ12.4 Hz, 1H, OCHPh), 4.57

(s, 2H, OCH₂Ph), 4.62 (d, JZ12.4 Hz, 1H, OCHPh), 5.34

(dd, JZ1.3, 6.3 Hz, 1H, C3–H), 7.26–7.33 (m, 10H, ArH);

¹³C NMR (125.8 MHz, CDCl₃) d 8.1 (CH₃), 8.2 (CH₃), 13.8

(CH₃), 26.7 (CH₃), 27.2 (CH₃), 29.3 (CH₂), 29.9 (CH₂), 52.2

(CH₃), 62.8 (CH₂), 70.1 (CH₂), 71.5 (CH₂), 73.3 (CH₂), 73.4

(CH₂), 77.6 (CH), 78.8 (CH), 79.2 (C), 89.6 (C), 111.2 (C),

114.4 (C), 127.5 (CH), 127.6 (CH), 127.7 (CH), 128.2 (CH),

128.3 (CH), 137.7 (C), 138.3 (C), 170.5 (C]O), 171.3

(C]O); FAB-HRMS m/z calcd for C₃₄H₄₇O₁₁(MCH)^C

631.3118, found 631.3139.

4.3.26. Ethyl [3S,3(1R,2S),4S,8R]-3-[3-benzyloxy-1,2-

(diethylmethylenedioxy)propyl]-8-(benzyloxymethyl)-6,

6-dimethyl-1-oxo-2,5,7-trioxaspiro[3.4]octane-3-car-

boxylate (46b). Hg(OCOCF₃)₂(155 mg, 0.36 mmol) was

added to a stirred solution of thioester 37b (112 mg,

0.17 mmol) in MeCN (18 mL). After stirring for 10 h, the

reaction mixture was evaporated in vacuo. The residue was

suspended in Et₂O and passed through a short plug of silica

gel (eluting with Et₂O) to remove insoluble Hg salt.

Puriﬁcation of the residue by column chromatography

(silica gel 5 g, 8:1 n-hexane/AcOEt) afforded b-lactone 46b

(74.5 mg, 72%) as a colorless oil: [a]²_D⁹C6.52 (c 1.09,

CHCl₃); IR (ﬁlm) 2980, 2939, 2882, 1852, 1762, 1738,

1497, 1454, 1375, 1273, 1204, 1171, 1098, 1026,

937 cm^K^{1 1}H NMR (270 MHz, CDCl₃) d 0.76 (t, JZ

;

7.5 Hz, 3H, pentylidene CH₃), 0.86 (t, JZ7.4 Hz, 3H,

pentylidene CH₃), 1.21 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃),

1.38 (s, 3H, acetonide CH₃), 1.42–1.67 (m, 4H, 2!

pentylidene CH₂), 1.53 (s, 3H, acetonide CH₃), 3.46 (dd,

JZ6.6, 11.0 Hz, 1H, C1–H), 3.58 (dd, JZ3.2, 11.0 Hz, 1H,

C1–H), 3.72 (dd, JZ8.7, 9.7 Hz, 1H, CHOBn), 3.87 (dd,

JZ2.0, 9.7 Hz, 1H, CHOBn), 4.09 (ddd, JZ3.2, 6.6,

8.1 Hz, 1H, C7–H), 4.10 (q, JZ7.2 Hz, 2H, CO₂CH₂CH₃),

4.49 (d, JZ12.0 Hz, 1H, OCHPh), 4.52 (d, JZ12.5 Hz, 1H,

OCHPh), 4.56 (d, JZ12.5 Hz, 1H, OCHPh), 4.61 (d, JZ

8.1 Hz, 1H, C6–H), 4.68 (d, JZ12.0 Hz, 1H, OCHPh), 4.94

(dd, JZ2.0, 8.7 Hz, 1H, C3–H), 7.26–7.38 (m, 10H, ArH);

¹³C NMR (125.8 MHz, CDCl₃) d 7.8 (CH₃), 7.9 (CH₃), 13.9

(CH₃), 25.8 (CH₃), 27.2 (CH₃), 29.6 (CH₂), 29.9 (CH₂), 62.5

(CH₂), 69.2 (CH₂), 70.6 (CH₂), 73.6 (CH₂), 73.7 (CH₂), 75.2

(CH), 76.2 (CH), 79.0 (CH), 85.7 (CH), 96.4 (C), 113.7 (C),

114.5 (C), 127.65 (C), 127.70 (CH), 127.74 (CH), 128.0

(CH), 128.35 (CH), 128.37 (CH), 137.70 (C), 137.73 (C),

165.3 (C]O), 166.6 (C]O); FAB-HRMS m/z calcd for

C₃₃H₄₃O₁₀(MCH)^C599.2856, found 599.2830.

4.3.25. Ethyl [2R,2(3aS,6aR),3R,4S]-3,4-(diethylmethyl-

enedioxy)-2,5-dihydroxy-2-(tetrahydro-2,2-dimethyl-4-

oxofuro[3,4-d][1,3]dioxol-3a-yl)pentanoate

(47a).

Palladium on carbon (10%, 10.8 mg) was added to a

solution of benzyl ether (46.2 mg, 0.073 mmol) in MeOH

(2 mL), and the mixture was vigorously stirred under 1 atm

of hydrogen for 1 h. The catalyst was ﬁltered through a

Celite pad, and the ﬁltrate was evaporated in vacuo. The

crude product (32.9 mg) thus obtained was used without

further puriﬁcation.

DMAP (38.6 mg, 0.316 mmol) was added to a solution of

the crude g-hydroxyester (32.9 mg) in MeCN (1.5 mL).

After stirring for 1.5 h, the reaction was quenched with

saturated aqueous NH₄Cl (6 mL), and the whole was

extracted with AcOEt (15 mL). The organic extract was

washed with brine (6 mL), and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (36.5 mg), which was puriﬁed by column

chromatography (silica gel 5 g, 2:1 n-hexane/AcOEt) to

give g-lactone 47a (30.0 mg, 98%) as a colorless oil: [a]_D²⁸

K77.5 (c 1.01, CHCl₃); IR (ﬁlm) 3480, 2978, 2942, 1790,

4.3.27. Ethyl [2S,2(1R,2S),3S,4R]-5-benzyloxy-2-[3-

benzyloxy-1,2-[1,2-(diethylmethylenedioxy)propyl]-3,4-

(dimethylmethylenedioxy)-2-hydroxy-3-(methoxycar-

bonyl)pentanoate. Potassium carbonate (22.0 mg,

0.159 mmol) was added to a solution of b-lactone 46b

(74.5 mg, 0.124 mmol) in MeOH (1.5 mL). After stirring

for 1.5 h, the mixture was partitioned between AcOEt

(10 mL) and brine (7 mL). The organic extract was washed

successively with saturated aqueous NH₄Cl (7 mL) and

brine (7 mL), and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo furnished the crude product

(85.3 mg), which was puriﬁed by column chromatography

(silica gel 8 g, 5:1 n-hexane/AcOEt) to give methyl ester

(78.3 mg, quant.) as a colorless oil: [a]³_D⁰C6.76 (c 1.0,

1

1730, 1464, 1377, 1256, 1171, 1090, 976 cm^K1; H NMR

(500 MHz, CDCl₃) d 0.84 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 0.89 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 1.35 (t, JZ

7.1 Hz, 3H, CO₂CH₂CH₃), 1.46 (s, 3H, acetonide CH₃),

1.50 (s, 3H, acetonide CH₃), 1.58 (q, JZ7.4 Hz, 2H,

pentylidene CH₂), 1.64 (q, JZ7.5 Hz, 2H, pentylidene

CH₂), 2.23 (br s, 1H, OH), 3.92 (dd, JZ4.7, 9.5 Hz, 1H, one

11096

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

CHCl₃); IR (ﬁlm) 3513, 2978, 2942, 1738, 1496, 1454,

(CH), 78.5 (C), 85.9 (C), 114.0 (C), 114.3 (C), 170.8

(C]O), 175.5 (C]O); FAB-HRMS m/z calcd for

C₁₉H₃₁O₁₀(MCH)^C419.1917, found 419.1925.

1

1372, 1262, 1221, 1093, 932 cm^K1; H NMR (270 MHz,

CDCl₃) d 0.88 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 0.94 (t,

JZ7.5 Hz, 3H, pentylidene CH₃), 1.09 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.61 (s, 3H, acetonide CH₃), 1.66 (s, 3H,

acetonide CH₃), 1.73 (m, 2H, pentylidene CH₂), 1.77 (m,

2H, pentylidene CH₂), 3.26 (dd, JZ2.5, 10.7 Hz, 1H, C1–

H), 3.35 (dd, JZ6.4, 10.7 Hz, 1H, C1–H), 3.42 (dd, JZ6.8,

11.0 Hz, 1H, CHOBn), 3.56 (s, 3H, CO₂CH₃), 3.63 (s, 1H,

OH), 3.74 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 3.84 (dd,

JZ2.3, 11.0 Hz, 1H, CHOBn), 3.93 (dq, JZ10.7, 7.1 Hz,

1H, CO₂CHCH₃), 4.29 (ddd, JZ2.5, 6.4, 8.1 Hz, 1H, C7–

H), 4.40 (d, JZ8.1 Hz, 1H, C6–H), 4.47 (d, JZ12.6 Hz, 1H,

OCHPh), 4.55 (d, JZ12.2 Hz, 1H, OCHPh), 4.59 (d, JZ

12.2 Hz, 1H, OCHPh), 4.62 (d, JZ12.6 Hz, 1H, OCHPh),

5.30 (dd, JZ2.3, 6.8 Hz, 1H, C3–H), 7.22–7.36 (m, 10H,

ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 8.7 (CH₃), 9.7

(CH₃), 14.9 (CH₃), 27.6 (CH₃), 28.4 (CH₃), 30.5 (CH₂), 31.4

(CH₂), 53.1 (CH₃), 63.3 (CH₂), 71.0 (CH₂), 71.9 (CH₂), 74.4

(CH₂), 74.5 (CH₂), 77.0 (CH), 78.4 (CH), 78.7 (CH), 79.8

(CH), 80.8 (C), 87.7 (C), 113.9 (C), 115.8 (C), 128.6 (CH),

128.75 (CH), 128.79 (CH), 129.0 (CH), 129.1 (CH), 129.2

(CH), 129.4 (CH), 129.5 (CH), 139.1 (C), 139.2 (C), 173.1

(C]O), 173.8 (C]O); FAB-HRMS m/z calcd for

C₃₄H₄₇O₁₁(MCH)^C631.3118, found 631.3152.

4.3.29. Isomerization of 45b to 45a. KHMDS in toluene

(0.5 M, 1.54 mL, 0.77 mmol) was added to a solution of

undesired isomer 45b (332 mg, 0.51 mmol) in THF (5 mL)

at K78 8C under an argon atmosphere, and the resulting

mixture was stirred at K23 8C for 2 h. The reaction was

quenched with saturated aqueous NH₄Cl (5 mL), and the

whole was extracted with AcOEt (20 mL). The organic

extract was washed with brine (2!5 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (308 mg), which was puriﬁed

by ﬂash column chromatography (silica gel 10 g, 15:1/3:1

n-hexane/AcOEt) to give desired isomer 45a (77 mg, 23%)

as a colorless oil, along with thioester 14 (30 mg, 20%) as a

pale yellow oil.

4.3.30. Aldol reaction of a-keto ester 32 with potassium

enolate 48 generated from thioester 14. A solution of

thioester 14 (34 mg, 0.115 mmol) in THF (0.2 mL) was

added to a 0.6 M solution of KHMDS in toluene (0.23 mL,

0.137 mmol) at K78 8C. After stirring at K78 8C for

30 min, a solution of a-keto ester 32 (20 mg, 0.057 mmol)

in THF (0.2 mL) was added. After stirring at K23 8C for

1 h, the reaction was quenched with saturated aqueous

NH₄Cl (5 mL), and the whole was extracted with AcOEt

(15 mL). The organic extract was washed with brine (8 mL)

and dried over anhydrous Na₂SO₄. Filtration and evapor-

ation in vacuo furnished the crude product (62 mg), whose

¹H NMR revealed a 45a/45b ratio of 2:1. Puriﬁcation by

column chromatography (silica gel 8 g, 4:1/7:2 n-hexane/

AcOEt) afforded aldol adducts 45a (8.9 mg, 23%) and 45b

(4.4 mg, 12%) as colorless oils.

4.3.28. Ethyl [2S,2(3aS,6aR),3R,4S]-3,4-(diethylmethyl-

enedioxy)-2,5-dihydroxy-2-(tetrahydro-2,2-dimethyl-4-

oxofuro[3,4-d][1,3]dioxol-3a-yl)pentanoate

(47b).

Palladium on carbon (10%, 11.7 mg) was added to a

solution of benzyl ether (78.3 mg, 0.124 mmol) in MeOH

(2 mL), and the mixture was vigorously stirred under 1 atm

of hydrogen for 1 h. The catalyst was ﬁltered through a

Celite pad, and the ﬁltrate was evaporated in vacuo. The

crude product (64.3 mg) thus obtained was used without

further puriﬁcation.

4.4. Synthesis of internal ketalization precursor

DMAP (76.4 mg, 0.625 mmol) was added to a solution of

the crude g-hydroxyester (64.3 mg) in MeCN (1 mL). After

stirring for 1.5 h, the reaction was quenched with saturated

aqueous NH₄Cl (6 mL), and the whole was extracted with

AcOEt (10 mL). The organic extract was washed with brine

(6 mL), and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (68 mg),

which was puriﬁed by column chromatography (silica gel

5 g, 2:1 n-hexane/AcOEt) to give g-lactone 47b (46.2 mg,

89%) as a colorless oil: [a]²_D⁸K49.9 (c 1.5, CHCl₃); IR

(ﬁlm) 3459, 2978, 2942, 2883, 1782, 1730, 1462, 1377,

1206, 1022, 928, 907 cm^K1; ¹H NMR (500 MHz, CDCl₃) d

0.89 (t, JZ7.5 Hz, 3H, pentylidene CH₃), 0.91 (t, JZ

7.5 Hz, 3H, pentylidene CH₃), 1.40 (t, JZ7.1 Hz, 3H,

CO₂CH₂CH₃), 1.43 (s, 3H, acetonide CH₃), 1.48 (s, 3H,

acetonide CH₃), 1.67 (q, JZ7.5 Hz, 2H, pentylidene CH₂),

1.71 (q, JZ7.5 Hz, 2H, pentylidene CH₂), 1.97 (br s, 1H,

OH), 3.38 (dd, JZ3.3, 12.2 Hz, 1H, one of lactone CH₂),

3.72 (dd, JZ1.6, 12.2 Hz, 1H, one of lactone CH₂), 4.11 (m,

2H, C1–H₂), 4.32 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃),

4.35 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.37 (s, 1H,

OH), 4.40 (ddd, JZ3.6, 3.9, 8.1 Hz, 1H, C7–H), 4.49 (d, JZ

8.1 Hz, 1H, C6–H), 5.51 (dd, JZ1.6, 3.3 Hz, 1H, C3–H);

¹³C NMR (125.8 MHz, CDCl₃) d 7.8 (CH₃), 8.2 (CH₃), 13.9

(CH₃), 26.5 (CH₃), 27.4 (CH₃), 29.6 (CH₂), 29.9 (CH₂), 61.9

(CH₂), 63.6 (CH₂), 71.5 (CH₂), 76.1 (CH), 76.5 (CH), 77.1

4.4.1. Diethyl (4R,5R)-2,2-diethyl-1,3-dioxolane-4,5-di-

carboxylate. p-Toluenesulfonic acid (202 mg, 1.6 mmol)

was added to a stirred solution of diethyl ^L-(C)-tartrate

(26.2 g, 0.127 mol) and 3,3-dimethoxypentane (25.1 g,

0.190 mol) in benzene (200 mL). The ﬂask was ﬁtted with

a Soxhlet extractor and reﬂux condenser, and a thimble

˚

containing freshly activated 4 A molecular sieves (11 g)

was placed in the Soxhlet extractor. The whole was reﬂuxed

for 3 h, during which time the thimble was recharged with

fresh sieves every 1 h. The reaction mixture was cooled to

room temperature, and anhydrous K₂CO₃(400 mg) was

added. After stirring at room temperature for 10 min, the

mixture was ﬁltered, and the ﬁltrate was evaporated in

vacuo. The residue was partitioned between AcOEt

(150 mL) and water (50 mL). The organic extract was

washed successively with water (50 mL), saturated aqueous

NaHCO₃(50 mL) and brine (50 mL), and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

followed by distillation under reduced pressure afforded the

title compound (19.59 g, 96%) as a pale yellow oil: bp 124–

125 8C (0.1 mmHg); [a]_D²²K20.2 (c 1.3, CHCl₃); IR (ﬁlm)

2980, 2943, 1757, 1466, 1200, 1113 cm^K^{1 1}H NMR

;

(270 MHz, CDCl₃) d 0.95 (t, JZ7.5 Hz, 6H, 2!pentylidene

CH₃), 1.32 (t, JZ7.1 Hz, 6H, 2!CO₂CH₂CH₃), 1.74 (q,

JZ7.5 Hz, 4H, 2!pentylidene CH₂), 4.28 (q, JZ7.1 Hz,

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11097

4H, 2!CO₂CH₂CH₃), 4.71 (s, 2H, 2!CHCO₂Et); ¹³C

NMR (100.6 MHz, CDCl₃) d 7.8 (CH₃), 14.1 (CH₂), 29.6

(CH₂), 61.8 (CH₂), 77.4 (CH), 117.8 (C), 169.5 (C]O);

FAB-HRMS m/z calcd for C₁₃H₂₃O₆(MCH)^C275.1495,

found 275.1506. Anal. Calcd for C₁₃H₂₂O₆: C, 56.92; H,

8.08. Found: C, 56.72; H, 8.01.

and the mixture was stirred for 15 min. Et₃N (15 mL,

110 mmol) was added, and the resulting mixture was stirred

at K40 8C for 15 min. The reaction mixture was poured into

pH 7 phosphate buffer (100 mL), and the whole was

extracted with Et₂O (50 mL). The aqueous layer was

saturated with NaCl and extracted with Et₂O (3!30 mL).

The combined organic extracts were washed with brine

(30 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (2.77 g),

which was used without further puriﬁcation for the next

reaction.

4.4.2. (2S,3S)-2,3-(diethylmethylenedioxy)butane-1,4-

diol. A solution of the diester (30.2 g, 0.11 mol) in THF

(50 mL) was added dropwise over a 50-min period to a

stirred suspension of LiAlH₄(8.3 g, 0.22 mol) in THF

(200 mL) at 0 8C. After stirring at 0 8C for 40 min, the

reaction was quenched by dropwise addition of water

(8 mL) followed by 15% aqueous NaOH (8 mL) and water

(24 mL). The mixture was stirred vigorously for 10 min, and

then anhydrous MgSO₄was added. After stirring at room

temperature for additional 1 h, the suspension was ﬁltered

through a Celite pad, and the ﬁltrate was evaporated in

vacuo. Puriﬁcation of the residue by column chromato-

graphy (silica gel 60 g, 2:1/1:2 n-hexane/AcOEt) afforded

the title compound (19.0 g, 91%) as a white solid: mp 39.5–

41.5 8C; [a]²_D²C5.05 (c 5.00, CHCl₃); IR (ﬁlm) 3410 (br),

A solution of NaH₂PO₄(1.30 g, 10.8 mmol) in water

(12 mL) was added to a solution of the crude aldehyde

(2.77 g) and 2-methyl-2-butene (7 mL, 66 mmol) in

tert-butyl alcohol (50 mL). NaClO₂(4.70 g, 40.5 mmol)

was added portionwise to the mixture. After stirring at room

temperature for 8 h, the mixture was evaporated in vacuo.

The residue was dissolved in 10% aqueous NaOH (5 mL)

and water (30 mL), and the whole was washed with 1:1

n-hexane/Et₂O (3!20 mL). The aqueous layer was

acidiﬁed with 10% aqueous HCl (8 mL), saturated with

NaCl, and extracted with AcOEt (3!50 mL). The

combined organic extracts were washed with brine (3!

50 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo followed by column chromatography

(silica gel 25 g, 10:1 CHCl₃/MeOH) afforded the title

compound (2.26 g, 79%) as a colorless oil: [a]²_D³K8.26 (c

2.0, CHCl₃); IR (ﬁlm) 3700–3300 (br), 2940, 1736, 1462,

1

2934, 1464, 1201, 1172, 1053 cm^K1; H NMR (270 MHz,

CDCl₃) d 0.92 (t, JZ7.5 Hz, 6H, 2!pentylidene CH₃), 1.67

(q, JZ7.5 Hz, 4H, 2!pentylidene CH₂), 2.44 (br s, 2H,

OH), 3.67–3.85 (m, 4H, 2!CH₂OH), 3.97 (m, 2H, 2!

OCH); ¹³C NMR (100.6 MHz, CDCl₃) d 8.0 (CH₃), 30.4

(CH₂), 61.2 (CH₂), 78.4 (CH), 113.0 (C); FAB-HRMS m/z

calcd for C₉H₁₉O₄(MCH)^C191.1285, found 191.1290.

1175, 1107, 1044, 982, 928, 849 cm^K1

;

¹H NMR

(500 MHz, CDCl₃) d 0.92 (t, JZ7.4 Hz, 3H, pentylidene

CH₃), 0.95 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 1.71 (q, JZ

7.4 Hz, 4H, 2!pentylidene CH₂), 3.40 (s, 3H, OCH₃),

3.56–3.61 (m, 2H, OCH₂), 3.70–3.75 (m, 2H, OCH₂), 3.77

(dd, JZ5.3, 11.1 Hz, 1H, C1–H), 3.93 (dd, JZ2.9, 11.1 Hz,

1H, C1–H), 4.31 (ddd, JZ2.9, 5.3, 8.4 Hz, 1H, C7–H), 4.40

(d, JZ8.4 Hz, 1H, C6–H), 4.78 (d, JZ6.8 Hz, 1H, OCHO),

4.80 (d, JZ6.8 Hz, 1H, OCHO), 8.5 (br s, 1H, COOH); ¹³C

NMR (125.8 MHz, CDCl₃) d 7.5 (CH₃), 8.2 (CH₃), 29.7

(CH₂), 29.8 (CH₂), 58.9 (CH₃), 66.9 (CH₂), 67.1 (CH₂), 71.7

(CH₂), 75.5 (CH), 78.4 (CH), 95.8 (CH₂), 115.9 (C), 173.7

(C]O); FAB-HRMS m/z calcd for C₁₃H₂₅O₇(MCH)^C

293.1600, found 293.1619.

4.4.3. (2S,3S)-2,3-Diethylmethylenedioxy-4-[(2-methoxy-

ethoxy)methoxy]-1-butanol. A solution of the diol (2.00 g,

10.5 mmol) in THF (6 mL) was added dropwise to a

suspension of NaH (60% in oil, 430 mg, 10.8 mmol) in THF

(40 mL). After stirring at room temperature for 1 h, the

mixture was cooled to 0 8C, and MEMCl (1.82 mL,

10.5 mmol) was added. After stirring at 0 8C for 1.5 h, the

mixture was poured into brine (100 mL), and the whole was

extracted with AcOEt (2!50 mL). The combined organic

extracts were washed with brine (30 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

followed by column chromatography (silica gel 50 g, 1:1

n-hexane/AcOEt) afforded the title compound (2.72 g, 93%)

as a colorless oil: [a]²_D⁵K7.16 (c 1.0, EtOH); IR (ﬁlm) 3472

(br), 2973, 2938, 2882, 1464, 1202, 1175, 1092, 1046, 982,

934, 849 cm^K1; ¹H NMR (500 MHz, CDCl₃) d 0.91 (t, JZ

7.5 Hz, 3H, pentylidene CH₃), 0.92 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 1.60–1.73 (m, 4H, 2!pentylidene CH₂),

2.25 (br s, 1H, OH), 3.39 (s, 3H, OCH₃), 3.53–3.60 (m, 2H,

OCH₂), 3.65–3.83 (m, 6H, 3!OCH₂), 3.91 (dt, JZ8.5,

4.2 Hz, 1H, OCH), 4.03 (dt, JZ8.5, 5.2 Hz, 1H, OCH), 4.75

(s, 2H, OCH₂O); ¹³C NMR (125.8 MHz, CDCl₃) d 8.0

(CH₃), 30.36 (CH₂), 30.41 (CH₂), 59.0 (CH₃), 62.6 (CH₂),

67.0 (CH₂), 68.1 (CH₂), 71.7 (CH₂), 76.8 (CH), 79.6 (CH),

97.5 (CH₂), 113.2 (C); FAB-HRMS m/z calcd for C₁₃H₂₇O₆

(MCH)^C279.1808, found 279.1795.

4.4.5. (2R,3S)-2,3-(diethylmethylenedioxy)-N-methoxy-

4-[(2-methoxyethoxy)methoxy]-N-methylbutanamide.

To a solution of the carboxylic acid (199 mg, 0.682 mmol)

in DMF (5 mL) at 0 8C was added N,O-dimethylhydroxyl-

amine hydrochloride (110 mg, 1.13 mmol), followed by

addition of diethyl cyanophosphonate (DEPC, 0.12 mL,

0.791 mmol) and Et₃N (0.26 mL, 1.87 mmol). After stirring

at room temperature for 1.5 h, the reaction was quenched

with 1 N aqueous HCl (5 mL), and the whole was extracted

with AcOEt (2!15 mL). The combined organic extracts

were washed successively with brine (8 mL), saturated

aqueous NaHCO₃(10 mL) and brine (8 mL), and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (267 mg), which was puriﬁed

by column chromatography (silica gel 10 g, 3:2 n-hexane/

AcOEt) to give the title compound (203 mg, 89%) as a

colorless oil: [a]²_D⁴K17.1 (c 2.0, benzene); IR (ﬁlm) 2940,

4.4.4. (2R,3S)-2,3-(diethylmethylenedioxy)-4-[(2-meth-

oxyethoxy)methoxy]butyric acid. A solution of DMSO

(1.1 mL, 15.5 mmol) in CH₂Cl₂(3 mL) was added to a

stirred solution of oxalyl chloride (1.1 mL, 12.6 mmol) in

CH₂Cl₂(40 mL) at K78 8C. After 15 min, a solution of the

alcohol (2.00 g, 10.5 mmol) in CH₂Cl₂(7 mL) was added,

1

1672, 1464, 1175, 1098, 1046, 993, 932, 846 cm^K1; H

NMR (270 MHz, CDCl₃) d 0.926 (t, JZ7.5 Hz, 3H,

11098

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

pentylidene CH₃), 0.931 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 1.65–1.79 (m, 4H, 2!pentylidene CH₂), 3.24 (s, 3H,

NCH₃), 3.39 (s, 3H, OCH₃), 3.53–3.59 (m, 2H, OCH₂),

3.65–3.74 (m, 3H, OCH₂, C1–H), 3.75 (s, 3H, NOCH₃),

3.82 (dd, JZ3.2, 10.8 Hz, 1H, C1–H), 4.48–4.68 (m, 2H,

C6–H, C7–H), 4.76 (d, JZ6.8 Hz, 1H, OCHO), 4.78 (d, JZ

6.8 Hz, 1H, OCHO); ¹³C NMR (125.8 MHz, CDCl₃) d 7.6

(CH₃), 8.2 (CH₃), 29.5 (CH₂), 29.9 (CH₂), 32.2 (CH₃), 58.8

(CH₃), 61.6 (CH₃), 66.8 (CH₂), 67.2 (CH₂), 71.6 (CH₂), 74.1

(CH), 77.5 (CH), 95.7 (CH₂), 114.9 (C), 169.9 (C]O);

FAB-HRMS m/z calcd for C₁₅H₃₀NO₇(MCH)^C336.2022,

found 336.2016.

1.57–1.76 (m, 4H, 2!pentylidene CH₂), 3.40 (s, 3H,

OCH₃), 3.52–3.60 (m, 2H, OCH₂), 3.67–3.76 (m, 2H,

OCH₂), 3.78 (dd, JZ5.4, 10.8 Hz, 1H, C1–H), 3.88 (dd, JZ

5.4, 10.8 Hz, 1H, C1–H), 4.36 (q, JZ7.2 Hz, 2H, CO₂CH₂-

CH₃), 4.42 (m, 1H, C7–H), 4.73–4.81 (m, 3H, C6–H,

OCH₂O); ¹³C NMR (125.8 MHz, CDCl₃) d 7.5 (CH₃), 8.2

(CH₃), 13.9 (CH₃), 29.3 (CH₂), 29.8 (CH₂), 58.9 (CH₃), 62.5

(CH₂), 66.9 (CH₂), 67.2 (CH₂), 71.6 (CH₂), 77.3 (CH), 80.0

(CH), 95.7 (CH₂), 116.0 (C), 162.0 (C), 193.0 (C]O);

FAB-HRMS m/z calcd for C₁₆H₂₉O₈(MCH)^C349.1863,

found 349.1850.

4.4.8. Ethyl [2R,2(1R,2S),3S,4R]-5-benzyloxy-2-{1,2-

(diethylmethylenedioxy)-3-[(2-methoxyethoxy)methoxy]

propyl}-3,4-(dimethylmethylenedioxy)-2-hydroxy-3-

(methylthio)carbonylpentanoate (45a). A solution of

a-keto ester 32 (3.62 g, 10.4 mmol) and silyl ketene

thioacetal 20 (6.71 g, 17.7 mmol) in EtCN (15 mL) was

added to a solution of Sn(OTf)₂(7.08 g, 17.0 mmol) in

EtCN (60 mL) at K70 8C. After stirring at K70 8C for

1.5 h, the reaction was quenched with saturated aqueous

NaHCO₃(50 mL). The mixture was diluted with AcOEt

(300 mL) and n-hexane (30 mL), and ﬁltered through a

Celite pad. The layers were separated and the organic layer

was washed successively with saturated aqueous NaHCO₃

(100 mL) and brine (2!100 mL), and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (9.98 g), which was puriﬁed by ﬂash column

chromatography (silica gel 360 g, 4:1/7:2 n-hexane/

AcOEt) to give aldol adducts 45a (3.09 g, 46%) and 45b

(2.37 g, 35%) as colorless oils.

4.4.6. (4R,5S)-4,5-(diethylmethylenedioxy)-2-ethoxy-6-

[(2-methoxyethoxy)methoxy]-1-hexen-3-one. tert-Butyl-

lithium in pentane (2.13 M, 6.0 mL, 12.8 mmol) was

added to a stirred solution of ethyl vinyl ether (1.4 mL,

14.7 mmol) in THF (18 mL) at K78 8C. After stirring at

0 8C for 30 min, the mixture was added to a stirred solution

of the amide (1.38 g, 4.12 mmol) in THF (30 mL) at

K78 8C via cannula over a 20-min period. After stirring at

K78 8C for 30 min, the reaction was quenched with

saturated aqueous NH₄Cl (50 mL), and the whole was

partitioned between AcOEt (100 mL) and water (30 mL).

The organic extract was washed with brine (30 mL) and

dried over anhydrous Na₂SO₄. Filtration and evaporation in

vacuo followed by column chromatography (silica gel 15 g,

4:1 n-hexane/AcOEt) afforded the title compound (1.29 g,

90%) as a colorless oil: [a]²_D³K35.1 (c 1.0, CHCl₃); IR

(ﬁlm) 2976, 2940, 1732, 1611, 1462, 1366, 1287, 1175,

1098, 1046, 978, 851 cm^K1; ¹H NMR (270 MHz, CDCl₃) d

0.93 (t, JZ7.4 Hz, 6H, 2!pentylidene CH₃), 1.40 (t, JZ

7.0 Hz, 3H, OCH₂CH₃), 1.66 (q, JZ7.4 Hz, 2H, pentyl-

idene CH₂), 1.73 (q, JZ7.4 Hz, 2H, pentylidene CH₂), 3.39

(s, 3H, OCH₃), 3.52–3.60 (m, 2H, OCH₂), 3.68–3.77 (m,

3H, OCH₂, C1–H), 3.85 (q, JZ7.0 Hz, 2H, OCH₂CH₃),

3.92 (dd, JZ3.0, 10.9 Hz, 1H, C1–H), 4.35 (ddd, JZ3.0,

6.4, 7.3 Hz, 1H, C7–H), 4.60 (d, JZ2.8 Hz, 1H, C]CH),

4.77 (d, JZ6.8 Hz, 1H, OCHO), 4.79 (d, JZ6.8 Hz, 1H,

OCHO), 4.84 (d, JZ7.3 Hz, 1H, C6–H), 5.35 (d, JZ2.8 Hz,

1H, C]CH); ¹³C NMR (100.6 MHz, CDCl₃) d 7.7 (CH₃),

8.3 (CH₃), 14.2 (CH₃), 29.6 (CH₂), 30.1 (CH₂), 59.0 (CH₃),

63.9 (CH₂), 66.9 (CH₂), 68.1 (CH₂), 71.7 (CH₂), 77.7 (CH),

78.7 (CH), 93.8 (CH₂), 95.8 (CH₂), 115.5 (C), 156.5 (CH₂),

193.7 (C]O); FAB-HRMS m/z calcd for C₁₇H₃₁O₇(MC

H)^C347.2070, found 347.2044.

4.4.9. Ethyl [2R,2(1R,2S),3S,4R]-5-benzyloxy-2-[1,2-

(diethylmethylenedioxy)-3-[(2-methoxyethoxy)methoxy]

propyl]-3,4-(dimethylmethylenedioxy)-2-hydroxy-3-

(methoxycarbonyl)pentanoate (49). Hg(OCOCF₃)₂

(4.06 g, 9.52 mmol) was added to a stirred solution of

thioester 45a (3.06 g, 4.75 mmol) in MeOH (120 mL). The

mixture was reﬂuxed for 10 h and evaporated in vacuo. The

residue was suspended in Et₂O (30 mL) and passed through

a short plug of silica gel (eluting with Et₂O) to remove

insoluble Hg salt. Puriﬁcation by column chromatography

(silica gel 150 g, 2:1/3:2 n-hexane/AcOEt) afforded

methyl ester 49 (2.59 g, 87%) as a colorless oil: [a]_D²³

C5.58 (c 3.4, benzene); IR (ﬁlm) 3461 (br), 2942, 1730,

1456, 1372, 1252, 1175, 1096, 935, 864, 739, 698 cm^K1; ¹H

NMR (500 MHz, CDCl₃) d 0.89 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 0.90 (t, JZ7.5 Hz, 3H, pentylidene

CH₃), 1.24 (t, JZ7.3 Hz, 3H, CO₂CH₂CH₃), 1.57 (s, 3H,

acetonide CH₃), 1.65 (s, 3H, acetonide CH₃), 1.48–1.65 (m,

4H, 2!pentylidene CH₂), 3.37 (s, 3H, OCH₃), 3.40 (dd, JZ

6.3, 10.6 Hz, 1H, CHOBn), 3.54 (m, 2H, OCH₂), 3.62 (s,

3H, CO₂CH₃), 3.68 (m, 2H, OCH₂), 3.69 (dd, JZ6.2,

10.6 Hz, 1H, C1–H), 3.86 (dd, JZ3.1, 10.6 Hz, 1H, C1–H),

3.89 (dd, JZ1.9, 10.6 Hz, 1H, CHOBn), 3.99 (ddd, JZ3.1,

6.2, 8.4 Hz, 1H, C7–H), 4.12 (br s, 1H, OH), 4.15 (dq, JZ

10.9, 7.3 Hz, 1H, CO₂CHCH₃), 4.23 (dq, JZ10.9, 7.3 Hz,

1H, CO₂CHCH₃), 4.42 (d, JZ8.4 Hz, 1H, C6–H), 4.51 (d,

JZ12.3 Hz, 1H, OCHPh), 4.63 (d, JZ12.3 Hz, 1H,

OCHPh), 4.73 (s, 2H, OCH₂O), 5.32 (dd, JZ1.9, 6.3 Hz,

1H, C3–H), 7.25–7.35 (m, 5H, ArH); ¹³C NMR (67.8 MHz,

CDCl₃) d 8.1 (CH₃), 8.2 (CH₃), 13.8 (CH₃), 26.7 (CH₃),

27.2 (CH₃), 29.3 (CH₂), 29.9 (CH₂), 52.2 (CH₃), 58.9 (CH₃),

4.4.7. Ethyl (3R,4S)-3,4-(diethylmethylenedioxy)-5-[(2-

methoxyethoxy)methoxy]-2-oxopentanoate (32).

A

stream of ozone in oxygen was bubbled through a stirred

solution of the enone (1.27 g, 3.67 mmol) in CH₂Cl₂

(15 mL) at K78 8C until the solution turned pale blue.

After stirring at K78 8C for 10 min, excess ozone was

removed by bubbling a stream of nitrogen, and Me₂S (3 mL)

was added. After stirring at room temperature for 1 h, the

volatile elements were removed in vacuo. The residue was

puriﬁed by column chromatography (silica gel 20 g, 4:1

n-hexane/AcOEt) to give a-keto ester 32 (1.10 g, 86%) as a

colorless oil: [a]²_D⁴C7.71 (c 2.0, CHCl₃); IR (ﬁlm) 2976,

2940, 1732, 1611, 1462, 1366, 1287, 1175, 1098, 1046, 978,

851 cm^K^{1 1}H NMR (500 MHz, CDCl₃) d 0.91 (t, JZ

;

7.5 Hz, 3H, pentylidene CH₃), 0.92 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 1.38 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃),

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11099

63.0 (CH₃), 66.8 (CH₂), 69.2 (CH₂), 70.0 (CH₂), 71.7 (CH₂),

73.3 (CH₂), 77.0 (CH), 77.7 (CH), 78.8 (CH), 79.2 (C), 89.7

(C), 95.5 (CH₂), 111.3 (C), 114.5 (C), 127.5 (CH), 127.6

(CH), 128.2 (CH), 138.3 (C), 170.6 (C]O), 171.3 (C]O);

FAB-HRMS m/z calcd for C₃₁H₄₉O₁₃(MCH)^C629.3173,

found 629.3203. Anal. Calcd for C₃₁H₄₈O₁₃: C, 59.22; H,

7.70. Found: C, 59.04; H, 7.65.

6.1, 8.5 Hz, 1H, C7–H), 4.28 (dq, JZ10.7, 7.1 Hz, 1H,

CO₂CHCH₃), 4.35 (dq, JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃),

4.38 (d, JZ8.5 Hz, 1H, C6–H), 4.75 (s, 2H, OCH₂O), 5.73

(s, 1H, C3–H); ¹³C NMR (67.8 MHz, CDCl₃) d 8.0 (CH₃),

8.1 (CH₃), 13.6 (CH₃), 26.7 (CH₃), 26.9 (CH₃), 29.5 (CH₂),

30.0 (CH₂), 52.4 (CH₃), 52.6 (CH₃), 58.9 (CH₃), 63.0 (CH₃),

66.8 (CH₂), 69.0 (CH₂), 71.7 (CH₂), 76.5 (CH), 77.6 (CH),

79.1 (C), 79.3 (CH), 91.2 (C), 95.5 (CH₂), 114.2 (C), 114.4

(C), 169.4 (C]O), 170.5 (C]O), 170.8 (C]O); FAB-

HRMS m/z calcd for C₂₅H₄₃O₁₄(MCH)^C567.2653, found

567.2664. Anal. Calcd for C₂₅H₄₂O₁₄: C, 53.00; H, 7.47.

Found: C, 53.24; H, 7.48.

4.4.10. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5S)-4,5-

(diethylmethylenedioxy)-1,2-(dimethylmethylenedioxy)-

3-hydroxy-6-[(2-methoxyethoxy)methoxy]hexane-1,2,3-

tricarboxylate (52). Palladium hydroxide on carbon (20%,

240 mg) was added to a solution of benzyl ether 49 (2.39 g,

3.81 mmol) in AcOEt (20 mL), and the mixture was

vigorously stirred under 1 atm of hydrogen for 10 h. The

catalyst was ﬁltered through a Celite pad, and the ﬁltrate

was evaporated in vacuo to furnish the crude product

(2.47 g) as a colorless oil.

Data for ethyl [2R,2(3aS,6aR),3R,4S]-3,4-(diethylmethyl-

enedioxy)-2-hydroxy-5-[(2-methoxyethoxy)methoxy]-2-

(tetrahydro-2,2-dimethyl-4-oxofuro[3,4-d][1,3]dioxol-3a-

yl)pentanoate (51). [a]²_D⁵K59.2 (c 2.2, CHCl₃); IR (ﬁlm)

3478 (br), 2976, 2942, 2883, 1790, 1761, 1730, 1462, 1375,

1248, 1173, 1096, 1046 cm^K1; ¹H NMR (500 MHz, CDCl₃)

d 0.83 (t, JZ7.4 Hz, 3H, pentylidene CH₃), 0.87 (t, JZ

7.4 Hz, 3H, pentylidene CH₃), 1.33 (t, JZ7.2 Hz, 3H,

CO₂CH₂CH₃), 1.46 (s, 3H, acetonide CH₃), 1.50 (s, 3H,

acetonide CH₃), 1.54–1.66 (m, 4H, 2!pentylidene CH₂),

3.39 (s, 3H, OCH₃), 3.57 (t, JZ4.5 Hz, 2H, OCH₂), 3.75

(dd, JZ4.9, 10.3 Hz, 1H, one of lactone CH₂), 3.76 (t, JZ

4.5 Hz, 2H, OCH₂), 4.05 (dd, JZ2.1, 10.5 Hz, 1H, C1–H),

4.22 (dq, JZ10.9, 7.2 Hz, 1H, CO₂CHCH₃), 4.31 (s, 1H,

OH), 4.32 (dd, JZ8.3, 10.5 Hz, 1H, C1–H), 4.33 (dq, JZ

10.9, 7.2 Hz, 1H, CO₂CHCH₃), 4.38 (dd, JZ10.3, 10.5 Hz,

1H, one of lactone CH₂), 4.60 (ddd, JZ2.1, 4.7, 8.3 Hz, 1H,

C7–H), 4.65 (dd, JZ4.9, 10.5 Hz, 1H, C3–H), 4.79 (d, JZ

8.9 Hz, 1H, OCHO), 4.81 (d, JZ8.9 Hz, 1H, OCHO), 5.15

(d, JZ4.7 Hz, 1H, C6–H); ¹³C NMR (125.8 MHz, CDCl₃) d

8.08 (CH₃), 8.13 (CH₃), 14.2 (CH₃), 27.0 (CH₃), 27.3 (CH₃),

30.0 (CH₃), 30.3 (CH₂), 59.2 (CH₂), 63.0 (CH₂), 66.9 (CH₂),

68.8 (CH₂), 72.0 (CH₂), 73.5 (CH₂), 75.9 (CH₂), 77.5 (CH),

78.8 (CH), 79.3 (CH), 85.0 (C), 96.0 (C), 113.8 (C), 114.0

(C), 171.5 (C]O), 176.2 (C]O); FAB-HRMS m/z calcd

for C₂₃H₃₉O₁₂(MCH)^C507.2442, found 507.2453.

Dess-Martin periodinane (4.36 g, 10.3 mmol) was added to

a solution of the crude alcohol 50 (2.47 g) in CH₂Cl₂

(30 mL). After stirring at room temperature for 8 h, the

mixture was diluted with Et₂O (40 mL) and poured into an

ice-cooled saturated aqueous NaHCO₃(100 mL) containing

Na₂S₂O₃$5H₂O (15 g). The layers were separated, and the

organic layer was washed successively with saturated

aqueous NaHCO₃(2!50 mL), water (40 mL) and brine

(50 mL), and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo gave the crude product (2.14 g), which

was used without further puriﬁcation.

A solution of NaH₂PO₄(915 mg, 7.62 mmol) in water

(10 mL) was added to a solution of the crude aldehyde

(2.14 g) and 2-methyl-2-butene (10 mL, 95 mmol) in tert-

butyl alcohol (50 mL), followed by addition of a solution of

NaClO₂(1.10 g, 9.52 mmol) in water (5 mL). After stirring

at room temperature for 2.5 h, the mixture was evaporated in

vacuo, and the residue was partitioned between AcOEt

(120 mL) and 1 N HCl (60 mL). The aqueous layer was

saturated with NaCl and extracted with AcOEt (2!40 mL).

The combined organic extracts were washed with brine

(40 mL) and dried over anhydrous Na₂SO₄. Filtration and

evaporation in vacuo furnished the crude product (2.31 g),

which was used without further puriﬁcation.

4.4.11. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5S)-4,5-

(diethylmethylenedioxy)-1,2-(dimethylmethylenedioxy)-

3,6-dihydroxyhexane-1,2,3-tricarboxylate (53). To a

solution of MEM ether 52 (1.23 g, 2.18 mmol) in MeCN

(25 mL) was added sodium iodide (3.27 g, 21.8 mmol)

followed by addition of chlorotrimethylsilane (2.35 g,

21.7 mmol) at K23 8C. After stirring at K23 8C for 2 h,

the mixture was poured into brine (30 mL), and the whole

was partitioned between AcOEt (30 mL) and water

(10 mL). The organic layer was washed successively with

saturated aqueous Na₂S₂O₃(3!20 mL) and brine (15 mL),

and dried over anhydrous Na₂SO₄. Filtration and evapor-

ation in vacuo furnished the crude product (1.16 g), which

was puriﬁed by column chromatography (silica gel 30 g, 1:1

n-hexane/AcOEt) to give diol 53 (978 mg, 94%) as a

colorless oil: [a]²_D⁴C4.19 (c 3.1, CHCl₃); IR (ﬁlm) 3468

(br), 2978, 2946, 2884, 1748, 1462, 1441, 1381, 1256, 1221,

1177, 1092, 935 cm^K1; ¹H NMR (270 MHz, CDCl₃) d 0.88

(t, JZ7.4 Hz, 3H, pentylidene CH₃), 0.90 (t, JZ7.4 Hz, 3H,

pentylidene CH₃), 1.34 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃),

1.58 (s, 3H, acetonide CH₃), 1.67 (s, 3H, acetonide CH₃),

1.50–1.70 (m, 4H, 2!pentylidene CH₂), 2.07 (t, JZ6.1 Hz,

1H, C1-OH), 3.76 (s, 6H, 2!CO₂CH₃), 3.77 (ddd, JZ5.0,

A solution of diazomethane in Et₂O was added to a solution

of the crude carboxylic acid (2.31 g) in Et₂O (20 mL) at 0 8C

until a yellow color persisted. The mixture was evaporated

in vacuo to furnish the crude product (2.28 g), which was

puriﬁed by column chromatography (silica gel 50 g, 2:1/

1:1 n-hexane/AcOEt) to give methyl ester 52 (1.81 g, 84%

for four steps) as a colorless oil: [a]²_D⁶K9.39 (c 2.1,

benzene); IR (ﬁlm) 3463 (br), 2978, 2944, 2884, 1738,

1462, 1441, 1383, 1254, 1209, 1177, 1117, 982, 937,

756 cm^K^{1 1}H NMR (270 MHz, CDCl₃) d 0.89 (t, JZ

;

7.4 Hz, 3H, pentylidene CH₃), 0.90 (t, JZ7.4 Hz, 3H,

pentylidene CH₃), 1.34 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃),

1.58 (s, 3H, acetonide CH₃), 1.68 (s, 3H, acetonide CH₃),

1.45–1.71 (m, 4H, 2!pentylidene CH₂), 3.38 (s, 3H,

OCH₃), 3.52–3.59 (m, 2H, OCH₂), 3.69 (dd, JZ6.1,

10.8 Hz, 1H, C1–H), 3.65–3.74 (m, 2H, OCH₂), 3.75 (s,

3H, CO₂CH₃), 3.76 (s, 3H, CO₂CH₃), 3.89 (dd, JZ3.0,

10.8 Hz, 1H, C1–H), 4.09 (s, 1H, OH), 4.12 (ddd, JZ3.0,

11100

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

6.1, 11.7 Hz, 1H, C1–H), 3.88 (ddd, JZ3.7, 6.1, 11.7 Hz,

1H, C1–H), 4.02 (s, 1H, C5–OH), 4.07 (ddd, JZ3.7, 5.0,

8.4 Hz, 1H, C7–H), 4.30 (dq, JZ10.7, 7.2 Hz, 1H, CO₂-

CHCH₃), 4.35 (dq, JZ10.7, 7.2 Hz, 1H, CO₂CHCH₃), 4.44

(d, JZ8.4 Hz, 1H, C6–H), 5.67 (s, 1H, C3–H); ¹³C NMR

(67.8 MHz, CDCl₃) d 8.0 (CH₃), 8.1 (CH₃), 13.6 (CH₃),

26.7 (CH₃), 26.9 (CH₃), 29.6 (CH₂), 30.0 (CH₂), 52.4 (CH₃),

52.7 (CH₃), 58.9 (CH₃), 63.2 (CH₂), 63.7 (CH₂), 76.4 (CH),

78.5 (CH), 79.1 (C), 79.2 (CH), 91.1 (C), 114.1 (C), 114.3

(C), 169.3 (C]O), 170.6 (C]O), 170.9 (C]O); FAB-

HRMS m/z calcd for C₂₁H₃₅O₁₂(MCH)^C479.2129, found

479.2144.

saturated aqueous NaHCO₃(60 mL) containing Na₂S₂-

O₃$5H₂O (10 g). The layers were separated, and the organic

layer was washed successively with saturated aqueous

NaHCO₃(2!20 mL) and brine (10 mL), and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (436 mg), which was puriﬁed

by column chromatography (silica gel 8 g, 4:1 n-hexane/

AcOEt) to give aldehyde 55 (387 mg, 91%) as a white solid:

mp 104.5–105.5 8C (colorless prisms from n-hexane); [a]_D²⁵

K12.5 (c 2.0, CHCl₃); IR (nujol) 2978, 2953, 1740, 1462,

1

1439, 1375, 1252, 1175, 1132, 849, 758 cm^K1; H NMR

(270 MHz, CDCl₃) d 0.14 (s, 9H, Si(CH₃)₃), 0.89 (t, JZ

7.6 Hz, 3H, pentylidene CH₃), 0.90 (t, JZ7.4 Hz, 3H,

pentylidene CH₃), 1.32 (t, JZ7.3 Hz, 3H, CO₂CH₂CH₃),

1.51 (s, 3H, acetonide CH₃), 1.63 (s, 3H, acetonide CH₃),

1.48–1.72 (m, 4H, 2!pentylidene CH₂), 3.74 (s, 3H,

CO₂CH₃), 3.76 (s, 3H, CO₂CH₃), 4.21 (dq, JZ10.9, 7.3 Hz,

1H, CO₂CHCH₃), 4.30 (dq, JZ10.9, 7.3 Hz, 1H, CO₂-

CHCH₃), 4.63 (dd, JZ1.0, 6.9 Hz, 1H, C7–H), 4.76 (d, JZ

6.9 Hz, 1H, C6–H), 5.49 (s, 1H, C3–H), 9.72 (d, JZ1.0 Hz,

1H, CHO); ¹³C NMR (125.8 MHz, CDCl₃) d 2.6 (CH₃), 8.0

(CH₃), 8.2 (CH₃), 13.8 (CH₃), 26.7 (CH₃), 27.0 (CH₃), 28.5

(CH₂), 29.0 (CH₂), 52.4 (CH₃), 62.1 (CH₃), 77.7 (CH), 79.4

(CH), 80.9 (CH), 82.8 (C), 90.8 (C), 113.5 (C), 116.2 (C),

169.0 (C]O), 169.2 (C]O), 169.8 (C]O), 198.6 (C]O);

FAB-HRMS m/z calcd for C₂₄H₄₁O₁₂Si (MCH)^C

549.2368, found 549.2350. Anal. Calcd for C₂₄H₄₀O₁₂Si:

C, 52.54; H, 7.35. Found: C, 52.44; H, 7.28.

4.4.12. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5S)-4,5-

(diethylmethylenedioxy)-1,2-(dimethylmethylenedioxy)-

6-hydroxy-3-(trimethylsilyloxy)hexane-1,2,3-tricar-

boxylate (54). A mixture of diol 53 (978 mg, 2.04 mmol)

and N-methyl-N-(trimethylsilyl)triﬂuoroacetamide (3.0 mL,

16.2 mmol) was heated at 90 8C for 3 h. After cooling to

room temperature, the mixture was evaporated in vacuo to

provide a crude product (1.42 g), which was used without

further puriﬁcation.

To a solution of the crude bis(trimethylsilyl) ether in Et₂O

(15 mL) was added 10% aqueous HCl (2 mL), and the

biphasic mixture was stirred vigorously at room temperature

for 1.5 h. The reaction was quenched by addition of solid

NaHCO₃at 0 8C, and the layers were separated. The organic

layer was washed with brine (5 mL) and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

furnished the crude product (1.16 g), which was puriﬁed by

column chromatography (silica gel 30 g, 4:1 n-hexane/

AcOEt) to give alcohol 54 (975 mg, 87%) as a white solid:

mp 105–106 8C (colorless prisms from n-hexane); [a]_D²⁴

K12.6 (c 1.1, CHCl₃); IR (nujol) 3526 (br), 2978, 1738,

4.4.14. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5R,10R,11R)-

10-benzyloxy-4,5-(diethylmethylenedioxy)-1,2-(dimethyl-

methylenedioxy)-11-methyl-6-oxo-12-phenyl-3-(tri-

methylsilyloxy)-7-dodecyne-1,2,3-tricarboxylate (57).

Butyllithium in n-hexane (1.54 M, 0.91 mL, 1.40 mmol)

was added to a solution of alkyne 56 (440 mg, 1.58 mmol)

in THF (5 mL) at K78 8C. After stirring at K78 8C for

45 min, a solution of aldehyde 55 (387 mg, 0.705 mmol) in

THF (2 mL) was added. After stirring at K78 8C for 30 min,

the reaction was quenched with saturated aqueous NH₄Cl

(10 mL), and the whole was extracted with AcOEt (2!

15 mL). The combined organic extracts were washed with

brine (15 mL) and dried over anhydrous Na₂SO₄. Filtration

and evaporation in vacuo furnished the crude product

(888 mg), which was puriﬁed by column chromatography

(silica gel 8 g, 20:1/6:1 n-hexane/AcOEt) to give a

diastereomeric mixture of coupling products (565 mg,

97%) as a colorless viscous oil, along with recovered

alkyne 56 (261 mg) as a colorless oil.

1

1437, 1375, 1252, 846, 758 cm^K1; H NMR (270 MHz,

CDCl₃) d 0.15 (s, 9H, Si(CH₃)₃), 0.85 (t, JZ7.5 Hz, 3H,

pentylidene CH₃), 0.89 (t, JZ7.5 Hz, 3H, pentylidene CH₃),

1.30 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃), 1.54 (s, 3H, acetonide

CH₃), 1.64 (s, 3H, acetonide CH₃), 1.44–1.67 (m, 4H, 2!

pentylidene CH₂), 2.01 (t, JZ6.5 Hz, 1H, OH), 3.70 (ddd,

JZ4.8, 6.5, 11.8 Hz, 1H, C1–H), 3.73 (s, 3H, CO₂CH₃),

3.76 (s, 3H, CO₂CH₃), 3.90 (ddd, JZ2.8, 6.5, 11.8 Hz, 1H,

C1–H), 4.22 (ddd, JZ2.8, 4.8, 8.5 Hz, 1H, C7–H), 4.17 (dq,

JZ10.7, 7.1 Hz, 1H, CO₂CHCH₃), 4.29 (dq, JZ10.7,

7.1 Hz, 1H, CO₂CHCH₃), 4.42 (d, JZ8.5 Hz, 1H, C6–H),

5.49 (s, 1H, C3–H); ¹³C NMR (125.8 MHz, CDCl₃) d 2.7

(CH₃), 8.0 (CH₃), 8.1 (CH₃), 13.8 (CH₃), 26.7 (CH₃), 27.2

(CH₃), 29.7 (CH₂), 30.2 (CH₂), 52.3 (CH₃), 52.4 (CH₃), 61.9

(CH₃), 63.8 (CH₂), 76.2 (CH), 78.4 (CH), 79.6 (CH), 89.3

(C), 91.3 (C), 113.7 (C), 169.4 (C]O), 169.7 (C]O), 169.9

(C]O); FAB-HRMS m/z calcd for C₂₄H₄₃O₁₂Si (MCH)^C

551.2524, found 551.2549. Anal. Calcd for C₂₄H₄₂O₁₂Si: C,

52.35; H, 7.69. Found: C, 52.30; H, 7.53.

A solution of the coupling product (565 mg) in CH₂Cl₂

(2 mL) was added to a suspension of Dess-Martin

periodinane (727 mg, 1.71 mmol) in CH₂Cl₂(5 mL). After

stirring at room temperature for 11 h, the mixture was

diluted with Et₂O (20 mL) and poured into an ice-cooled

saturated aqueous NaHCO₃(20 mL) containing Na₂S₂-

O₃$5H₂O (1 g). The layers were separated, and the organic

layer was washed successively with saturated aqueous

NaHCO₃(2!5 mL) and brine (5 mL), and dried over

anhydrous Na₂SO₄. Filtration and evaporation in vacuo

followed by column chromatography (silica gel 23 g, 8:1

n-hexane/AcOEt) afforded ynone 57 (461 mg, 82%) as a

colorless oil: [a]²_D⁵K8.31 (c 1.2, CHCl₃); IR (ﬁlm) 2976,

4.4.13. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5R)-4,5-

(diethylmethylenedioxy)-1,2-(dimethylmethylenedioxy)-

5-formyl-3-(trimethylsilyloxy)pentane-1,2,3-tricarboxy-

late (55). A solution of alcohol 54 (425 mg, 0.771 mmol) in

CH₂Cl₂(1.5 mL) was added to a suspension of Dess-Martin

periodinane (890 mg, 2.10 mmol) in CH₂Cl₂(4 mL). After

stirring at room temperature for 3.5 h, the mixture was

diluted with Et₂O (10 mL) and poured into an ice-cooled

2211, 1748, 1682, 1456, 1373, 1250, 1098, 849, 700 cm^K1

;

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11101

¹H NMR (500 MHz, CDCl₃) d 0.12 (s, 9H, Si(CH₃)₃), 0.87

(t, JZ7.5 Hz, 3H, pentylidene CH₃), 0.91 (t, JZ7.4 Hz, 3H,

pentylidene CH₃), 0.96 (d, JZ6.8 Hz, 3H, C5⁰–CH₃), 1.33

(t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.56 (s, 3H, acetonide

CH₃), 1.67 (s, 3H, acetonide CH₃), 1.45–1.77 (m, 4H, 2!

pentylidene CH₂), 2.19 (m, 1H, C5⁰–H), 2.51 (dd, JZ8.8,

13.5 Hz, 1H, C6⁰–H), 2.66 (dd, JZ6.6, 17.4 Hz, 1H, C3⁰–

H), 2.79 (dd, JZ6.2, 17.4 Hz, 1H, C3⁰–H), 2.84 (dd, JZ6.2,

13.5 Hz, 1H, C6⁰–H), 3.63 (m, 1H, C4⁰–H), 3.75 (s, 3H,

CO₂CH₃), 3.77 (s, 3H, CO₂CH₃), 4.22 (dq, JZ10.8, 7.2 Hz,

1H, CO₂CHCH₃), 4.31 (dq, JZ10.8, 7.2 Hz, 1H, CO₂-

CHCH₃), 4.54 (d, JZ11.6 Hz, 1H, OCHPh), 4.65 (d, JZ

5.7 Hz, 1H, C6–H), 4.73 (d, JZ11.6 Hz, 1H, OCHPh), 5.09

(d, JZ5.7 Hz, 1H, C7–H), 5.67 (s, 1H, C3–H), 7.15 (m, 2H,

ArH), 7.20 (m, 1H, ArH), 7.26–7.35 (m, 3H, ArH), 7.37–

7.42 (m, 4H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 2.5

(CH₃), 8.0 (CH₃), 8.5 (CH₃), 13.6 (CH₃), 13.8 (CH₃), 22.6

(CH₂), 26.7 (CH₃), 26.9 (CH₃), 28.1 (CH₂), 28.7 (CH₂), 38.7

(CH), 39.6 (CH₂), 52.3 (CH₃), 62.0 (CH₃), 72.3 (CH₂), 77.5

(CH), 79.4 (CH), 81.4 (C), 81.8 (CH), 82.8 (C), 90.9 (C),

95.1 (C), 113.7 (C), 116.4 (C), 125.9 (CH), 127.6 (CH),

127.7 (CH), 128.3 (CH), 128.4 (CH), 129.1 (CH), 138.3 (C),

140.6 (C), 169.3 (C]O), 169.5 (C]O), 170.0 (C]O),

184.8 (C]O); FAB-HRMS m/z calcd for C₄₄H₆₁O₁₃Si

(MCH)^C825.3882, found 825.3849.

Calcd for C₄₄H₆₄O₁₃Si: C, 63.74; H, 7.78. Found: C, 63.59;

H, 7.79.

4.5. Internal ketalization

4.5.1. 5-Ethyl 3,4-dimethyl [1S,1(4R,5R),3S,4S,5R,6R,

7R]-1-(4-benzyloxy-5-methyl-6-phenylhexyl)-4,6,7-tri-

hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxy-

late (59). A solution of ketone 58 (95 mg, 0.115 mmol) in

90% aqueous triﬂuoroacetic acid (10 mL) was stirred at

room temperature for 15 h. The reaction mixture was

evaporated in vacuo, and the crude product was concen-

trated from toluene (2!20 mL) to remove residual

triﬂuoroacetic acid. Puriﬁcation of the residue by column

chromatography (silica gel 10 g, 1:1/1:2 n-hexane/

AcOEt) afforded bicyclic compound 59 (49.5 mg, 68%) as

a colorless oil, along with ketone 60 (4.9 mg, 7%) as a

colorless oil: [a]²_D⁴C3.30 (c 3.0, acetone); IR (ﬁlm) 3493,

2975, 2870, 1748, 1495, 1441, 1373, 1279, 1117, 958, 833,

747 cm^K^{1 1}H NMR (500 MHz, CDCl₃) d 0.84 (d, JZ

;

6.9 Hz, 3H, C5⁰-CH₃), 1.27 (t, JZ7.1 Hz, 3H, CO₂CH₂-

CH₃), 1.52–1.75 (m, 4H, C2⁰–H₂, C3⁰–H₂), 1.90–2.00 (m,

2H, C1⁰–H₂), 2.07 (m, 1H, C5⁰–H), 2.31 (dd, JZ10.0,

13.2 Hz, 1H, C6⁰–H), 2.90 (dd, JZ4.4, 13.2 Hz, 1H, ₀C6⁰–

H), 3.15 (br s, 1H, OH), 3.26–3.40 (m, 2H, OH, C4 –H),

3.72 (s, 3H, CO₂CH₃), 3.83 (s, 1H, C4–OH), 3.89 (s, 3H,

CO₂CH₃), 4.13 (m, 1H, C7–H), 4.25 (q, JZ7.1 Hz, 2H,

CO₂CH₂CH₃), 4.55 (d, JZ11.7 Hz, 1H, OCHPh), 4.58 (d,

JZ11.7 Hz, 1H, OCHPh), 5.06 (m, 1H, C6–H), 5.18 (s, 1H,

C3–H), 7.11 (m, 2H, ArH), 7.17 (m, 1H, ArH), 7.22–7.31

(m, 3H, ArH), 7.31–7.41 (m, 4H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 14.0 (CH₃), 14.7 (CH₃), 19.6

(CH₂), 29.7 (CH₂), 35.2 (CH₂), 37.7 (CH), 38.3 (CH₂),

52.6 (CH₃), 53.5 (CH₃), 62.5 (CH₂), 71.6 (CH₂), 74.8 (C),

75.5 (CH), 78.4 (CH), 82.2 (CH), 82.5 (CH), 91.1 (C), 106.4

(C), 125.7 (CH), 127.6 (CH), 127.9 (CH), 128.2 (CH), 128.4

(CH), 129.1 (CH), 138.9 (C), 141.6 (C), 166.4 (C]O),

167.2 (C]O), 169.9 (C]O); FAB-HRMS m/z calcd for

C₃₃H₄₃O₁₂(MCH)^C631.2754, found 631.2758.

4.4.15. 3-Ethyl 1,2-dimethyl (1S,2S,3R,4R,5R,10R,11R)-

10-benzyloxy-4,5-(diethylmethylenedioxy)-1,2-(dimethyl-

methylenedioxy)-11-methyl-6-oxo-12-phenyl-3-(tri-

methylsilyloxy)dodecane-1,2,3-tricarboxylate (58).

Palladium on carbon (10%, 240 mg) was added to a solution

of alkyne 57 (461 mg, 0.559 mmol) in AcOEt (15 mL), and

the mixture was vigorously stirred under 1 atm of hydrogen

for 10 min. The catalyst was ﬁltered through a Celite pad,

and the ﬁltrate was evaporated in vacuo. Puriﬁcation of the

residue by column chromatography (silica gel 20 g, 7:1

n-hexane/AcOEt) afforded ketone 58 (432 mg, 93%) as a

colorless oil: [a]²_D⁷K2.97 (c 3.2, EtOH); IR (ﬁlm) 2951,

1740, 1456, 1375, 1252, 1209, 1111, 910, 847, 735 cm^K1

;

¹H NMR (500 MHz, CDCl₃) d 0.08 (s, 9H, Si(CH₃)₃), 0.81

(t, JZ7.5 Hz, 3H, pentylidene CH₃), 0.87 (d, JZ6.8 Hz,

3H, C5⁰-CH₃), 0.89 (t, JZ7.5 Hz, 3H, pentylidene CH₃),

1.31 (t, JZ7.1 Hz, 3H, CO₂CH₂CH₃), 1.54 (s, 3H, acetonide

CH₃), 1.63 (s, 3H, acetonide CH₃), 1.37–1.81 (m, 8H, 2!

pentylidene CH₂, C2⁰–H₂, C3⁰–H₂), 2.05 (m, 1H, C5⁰–H),

2.34 (dd, JZ9.8, 13.3 Hz, 1H, C6⁰–H), 2.62 (m, 1H, C1⁰–

H), 2.77 (m, 1H, C1⁰–H), 2.90 (dd, JZ4.9, 13.3 Hz, 1H,

C6⁰–H), 3.32 (m, 1H, C4⁰–H), 3.72 (s, 3H, CO₂CH₃), 3.74

(s, 3H, CO₂CH₃), 4.19 (dq, JZ10.8, 7.1 Hz, 1H, CO₂-

CHCH₃), 4.28 (dq, JZ10.8, 7.1 Hz, 1H, CO₂CHCH₃), 4.56

(s, 2H, OCH₂Ph), 4.58 (d, JZ5.7 Hz, 1H, C6–H), 5.03 (d,

JZ5.7 Hz, 1H, C7–H), 5.61 (s, 1H, C3–H), 7.11 (m, 2H,

ArH), 7.17 (m, 1H, ArH), 7.22–7.30 (m, 3H, ArH), 7.31–

7.41 (m, 4H, ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 2.4

(CH₃), 8.1 (CH₃), 8.5 (CH₃), 13.8 (CH₃), 14.4 (CH₃), 19.9

(CH₂), 26.7 (CH₃), 26.8 (CH₃), 27.8 (CH₂), 28.6 (CH₂), 30.1

(CH₂), 37.9 (CH), 38.7 (CH₂), 40.3 (CH₂), 52.3 (CH₃), 61.9

(CH₃), 71.7 (CH₂), 77.2 (CH), 79.4 (CH), 80.6 (CH), 82.4

(CH), 82.9 (CH), 90.9 (C), 113.7 (C), 115.7 (C), 125.7 (CH),

127.4 (CH), 127.6 (CH), 128.2 (CH), 128.3 (CH), 129.1

(CH), 139.1 (C), 141.6 (C), 169.4 (C]O), 169.5 (C]O),

170.0 (C]O), 207.6 (C]O); FAB-HRMS m/z calcd for

C₄₄H₆₅O₁₃Si (MCH)^C829.4195, found 829.4153. Anal.

Data for 5-ethyl 3,4-dimethyl [1S,1(4R,5R),3S,4S,5R]-1-(4-

benzyloxy-5-methyl-6-phenylhexyl)-4-hydroxy-7-oxo-2,8-

dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (60). IR

1

(CHCl₃) 3543, 1772, 1741, 1263, 1228, 1150 cm^K1; H

NMR (500 MHz, CDCl₃) d 0.85 (d, JZ6.9 Hz, 3H, C5⁰-

CH₃), 1.30 (t, JZ7.2 Hz, 3H, CO₂CH₂CH₃), 1.40–1.69 (m,

4H, C2⁰–H₂, C3⁰–H₂), 1.93 (m, 1H, C1⁰–H), 1.97–2.07 (m,

2H, C1⁰–H, C5⁰–H), 2.34 (dd, JZ9.7, 13.3 Hz, 1H, C6⁰–H),

2.68 (d, JZ18.8 Hz, 1H, C6–H), 2.88 (dd, JZ4.4, 13.3 Hz,

1H, C6⁰–H), 3.31 (m, 1H, C4⁰–H), 3.55 (d, JZ18.8 Hz, 1H,

C6–H), 3.75 (s, 3H, CO₂CH₃), 3.90 (s, 1H, C4OH), 3.91 (s,

3H, CO₂CH₃), 4.28 (dq, JZ10.7, 7.2 Hz, 1H, CO₂CHCH₃),

4.30 (dq, JZ10.7, 7.2 Hz, 1H, CO₂CHCH₃), 4.54 (s, 2H,

OCH₂Ph), 4.88 (s, 1H, C3–H), 7.10–7.40 (m, 10H, ArH);

¹³C NMR (125.8 MHz, CDCl₃) d 13.9 (CH₃), 14.5 (CH₃),

18.9 (CH₂), 30.3 (CH₂), 31.3 (CH₂), 37.8 (CH), 38.7 (CH₂),

41.7 (CH₃), 52.9 (CH₃), 53.7 (CH₃), 62.8 (CH₂), 71.6 (CH₂),

74.9 (C), 75.8 (CH), 82.2 (CH), 83.8 (C), 101.9 (C), 125.7

(CH), 127.4 (CH), 127.7 (CH), 128.2 (CH), 128.3 (CH),

128.4 (CH), 129.1 (CH), 139.2 (C), 141.6 (C), 166.3

(C]O), 166.8 (C]O), 169.4 (C]O), 205.4 (C]O); FAB-

HRMS m/z calcd for C₃₃H₄₁O₁₁(MCH)^C613.2649, found

613.2653.

11102

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

4.5.2. Isolation of the cyclization intermediates 62 and

63. Aqueous triﬂuoroacetic acid (90%, 5 mL) was added to

ketone 58 (113 mg, 0.136 mmol) at 0 8C. After stirring at

room temperature for 10 min, the reaction mixture was

diluted with toluene (10 mL) and evaporated in vacuo. The

residue was azeotropically dried with toluene (2!10 mL)

and puriﬁed by ﬂash column chromatography (silica gel

7.5 g, 4:1/2:1/1:1/1:2 n-hexane/AcOEt) to give

hydroxyketone 62 (55 mg, 53%) and hemiketal 63 (28 mg,

29%) as white foams.

(C), 114.1 (C), 125.7 (CH), 127.6 (CH), 127.8 (CH), 128.2

(CH), 128.4 (CH), 129.0 (CH), 138.7 (C), 141.5 (C), 169.3

(C]O), 169.5 (C]O), 173.7 (C]O); FAB-HRMS m/z

calcd for C₃₆H₄₉O₁₃(MCH)^C689.3173, found 689.3198.

4.6. Completion of the total synthesis

4.6.1. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,7R]-1-(4-

benzyloxy-5-methyl-6-phenylhexyl)-4,6,7-trihydroxy-2,

8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (64). A

1 N aqueous KOH (1.5 mL, 1.5 mmol) was added to a

solution of triester 59 (49 mg, 0.078 mmol) in 1,4-dioxane

(3 mL), and the whole was heated at 100 8C for 24 h. After

cooling, 1 N aqueous HCl (2 mL) was added, and the

mixture was evaporated in vacuo. The crude mixture thus

obtained was suspended in CH₂Cl₂(5 mL), and N,N⁰-

diisopropyl-O-tert-butylisourea (505 mg, 2.53 mmol) was

added. After stirring at room temperature for 24 h, the

mixture was ﬁltered through a Celite pad, and the ﬁltrate

was evaporated in vacuo. Puriﬁcation of the residue by

column chromatography (silica gel 8 g, 3:2/1:1 n-hexane/

AcOEt) afforded tri(tert-butyl) ester 64 (23 mg, 40%) as a

colorless oil: [a]²_D³K2.90 (c 1.5, EtOH); IR (ﬁlm) 3486 (br),

Data for 3-ethyl 1,2-dimethyl (1S,2S,3R,4R,5R,10R,11R)-

10-benzyloxy-4,5-(diethylmethylenedioxy)-1,2-(dimethyl-

methylenedioxy)-3-hydroxy-11-methyl-6-oxo-12-phenyl-

dodecane-1,2,3-tricarboxylate (62). [a]²_D⁶K5.27 (c 1.1,

CHCl₃); IR (ﬁlm) 3472, 2942, 1732, 1454, 1375, 1254,

1

1096, 932, 741 cm^K1; H NMR (270 MHz, CDCl₃) d 0.85

(d, JZ6.6 Hz, 3H, C5⁰-CH₃), 0.88 (t, JZ7.3 Hz, 6H, 2!

pentylidene CH₃), 1.33 (t, JZ7.3 Hz, 3H, CO₂CH₂CH₃),

1.53 (s, 3H, acetonide CH₃), 1.65 (s, 3H, acetonide CH₃),

1.50–1.80 (m, 8H, 2!pentylidene CH₂, C2⁰–H₂, C3⁰–H₂),

2.04 (m, 1H, C5⁰–H), 2.33 (dd, JZ9.9, 13.2 Hz, 1H, C6⁰–

H), 2.68 (t, JZ6.6 Hz, 2H, C1⁰–H₂), 2.89 (dd, JZ5.3,

13.2 Hz, 1H, C6⁰–H), 3.30 (m, 1H, C4⁰–H), 3.736 (s, 3H,

CO₂CH₃), 3.743 (s, 3H, CO₂CH₃), 4.13 (s, 1H, OH), 4.26–

4.37 (m, 2H, CO₂CH₂CH₃), 4.49 (d, JZ6.6 Hz, 1H, C6–H),

4.55 (s, 2H, OCH₂Ph), 4.83 (d, JZ6.6 Hz, 1H, C7–H), 5.58

(s, 1H, C3–H), 7.11 (m, 2H, ArH), 7.18 (m, 1H, ArH), 7.22–

7.33 (m, 3H, ArH), 7.34–7.40 (m, 4H, ArH); ¹³C NMR

(67.8 MHz, CDCl₃) d 7.9 (CH₃), 8.4 (CH₃), 13.7 (CH₃),

14.4 (CH₃), 19.7 (CH₂), 26.6 (CH₃), 26.8 (CH₃), 29.09

(CH₂), 29.15 (CH₂), 29.9 (CH₂), 37.8 (CH), 38.7 (CH₂),

39.7 (CH₂), 52.4 (CH₃), 52.6 (CH₃), 62.9 (CH₂), 71.6 (CH₂),

76.7 (CH), 79.0 (CH), 79.2 (C), 81.0 (CH), 82.3 (CH), 90.7

(C), 114.0 (C), 116.0 (C), 125.6 (CH), 127.4 (CH), 127.6

(CH), 128.2 (CH), 128.3 (CH), 129.1 (CH), 139.1 (C), 141.5

(C), 169.1 (C]O), 170.0 (C]O), 170.1 (C]O), 208.5

(C]O); FAB-HRMS m/z calcd for C₄₁H₅₇O₁₃(MCH)^C

757.3799, found 757.3790.

1

2932, 1732, 1456, 1370, 1157, 843, 739, 700 cm^K1; H

NMR (500 MHz, CDCl₃) d 0.85 (d, JZ6.8 Hz, 3H, C5⁰-

CH₃), 1.44 (s, 9H, CO₂C(CH₃)₃), 1.48 (s, 9H, CO₂C(CH₃)₃),

1.52–1.73 (m, 4H, C2⁰–H₂, C3⁰–H₂), 1.59 (s, 9H,

CO₂C(CH₃)₃), 1.86–1.99 (m, 2H, C1⁰–H₂), 2.05 (m, 1H,

C5⁰–H), 2.35 (dd, JZ9.7, 13.3 Hz, 1H, C6⁰–H), 2.50 (br s,

2H, 2!OH), 2.88 (dd, JZ4.8, 13.3 Hz, 1H, C6⁰–H), 3.32

(m, 1H, C4⁰–H), 3.90 (s, 1H, C4–OH), 4.07 (br s, 1H, C7–

H), 4.55 (d, JZ11.8 Hz, 1H, OCHPh), 4.56 (d, JZ11.8 Hz,

1H, OCHPh), 4.92 (s, 1H, C3–H), 5.02 (br s, 1H, C6–H),

7.11 (d, JZ7.3 Hz, 2H, ArH), 7.17 (t, JZ7.3 Hz, 1H, ArH),

7.23–7.31 (m, 3H, ArH), 7.32–7.41 (m, 4H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 14.5 (CH₃), 19.6 (CH₂), 28.0 (CH₃),

28.1 (CH₃), 28.2 (CH₃), 29.9 (CH₂), 35.4 (CH₂), 37.7 (CH),

38.7 (CH₂), 71.6 (CH₂), 74.3 (C), 75.1 (CH), 78.8 (CH),

82.1 (CH), 82.4 (CH), 83.1 (C), 84.2 (C), 85.0 (C), 91.2 (C),

105.2 (C), 125.6 (CH), 127.5 (CH), 127.9 (CH), 128.2 (CH),

128.3 (CH), 129.1 (CH), 139.1 (C), 141.7 (C), 165.9

(C]O), 166.5 (C]O), 168.5 (C]O); FAB-HRMS m/z

calcd for C₄₁H₅₉O₁₂(MCH)^C743.4007, found 743.3984.

Data for dimethyl {4S,4[2R,3R,4R,5(4R,5R)],5S}-4-[5-(4-

benzyloxy-5-methyl-6-phenylhexyl)-2-ethoxycarbonyl-3,4,

5-trihydroxytetrahydrofuran-2-yl]-2,2-dimethyl-1,3-dioxo-

lane-4,5-dicarboxylate (63). [a]²_D⁴C16.5 (c 1.0, CHCl₃); IR

(CHCl₃) 3543, 3028, 2955, 1738, 1439, 1373, 1260, 1109,

4.6.2. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,7R]-4,6,7-

trihydroxy-1-(4-hydroxy-5-methyl-6-phenylhexyl)-2,8-

dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (65).

Palladium on carbon (10%, 28.6 mg) was added to a

solution of benzyl ether 64 (57.7 mg, 0.077 mmol) in MeOH

(2 mL), and the mixture was vigorously stirred under 1 atm

of hydrogen for 17 h. The catalyst was ﬁltered through a

Celite pad, and the ﬁltrate was evaporated in vacuo.

Puriﬁcation of the residue (55.1 mg) by column chroma-

tography (silica gel 8 g, 1:1/1:2 n-hexane/AcOEt)

afforded tetraol 65 (46 mg, 90%) as a white foam: [a]_D²³

C4.69 (c 1.3, EtOH); IR (ﬁlm) 3481 (br), 2980, 2932, 1732,

1

1055 cm^K1; H NMR (500 MHz, CDCl₃) d 0.87 (d, JZ

6.9 Hz, 3H, C5⁰-CH₃), 1.26 (t, JZ7.1 Hz, 3H, CO₂CH₂-

CH₃), 1.45 (s, 3H, acetonide CH₃), 1.51–1.76 (m, 4H, C2⁰–

H₂, C3⁰–H₂), 1.66 (s, 3H, acetonide CH₃), 1.88–2.03 (m,

2H, C1⁰–H₂), 2.10 (m, 1H, C5⁰–H), 2.30 (dd, JZ9.9,

13.2 Hz, 1H, C6⁰–H), 2.52 (d, JZ8.2 Hz, 1H, C7–OH), 2.92

(dd, JZ4.5, 13.2 Hz, 1H, C6⁰–H), 3.38 (m, 1H, C4⁰–H),

3.68 (d, JZ2.6 Hz, 1H, C6–OH), 3.77 (s, 3H, CO₂CH₃),

3.83 (s, 3H, CO₂CH₃), 4.09 (s, 1H, C1–OH), 4.11–4.19 (m,

2H, C7–H, CO₂CHCH₃), 4.25 (dq, JZ10.9, 7.1 Hz, 1H,

CO₂CHCH₃), 4.52 (d, JZ11.7 Hz, 1H, OCHPh), 4.62 (d,

JZ11.7 Hz, 1H, OCHPh), 4.73 (dd, JZ2.6, 8.7 Hz, 1H,

C6–H), 5.37 (s, 1H, C3–H), 7.12 (m, 2H, ArH), 7.19 (m, 1H,

ArH), 7.22–7.40 (m, 7H, ArH); ¹³C NMR (67.8 MHz,

CDCl₃) d 14.0 (CH₃), 14.7 (CH₃), 19.8 (CH₂), 26.5 (CH₃),

26.9 (CH₃), 30.0 (CH₂), 37.8 (CH), 38.1 (CH₂), 38.3 (CH₂),

52.8 (CH₃), 53.2 (CH₃), 61.9 (CH₂), 71.7 (CH₂), 77.1 (CH),

78.2 (CH), 79.0 (CH), 82.9 (CH), 87.7 (C), 89.0 (C), 102.2

1

1370, 1262, 1155, 739, 702 cm^K1; H NMR (500 MHz,

CDCl₃) d 0.84 (d, JZ6.8 Hz, 3H, C5⁰-CH₃), 1.44 (s, 9H,

CO₂C(CH₃)₃), 1.48 (s, 9H, CO₂C(CH₃)₃), 1.50–1.85 (m,

4H, C2⁰–H₂, C3⁰–H₂), 1.59 (s, 9H, CO₂C(CH₃)₃), 1.86–2.03

(m, 3H, C1⁰–H₂, C5⁰–H), 2.41 (dd, JZ9.0, 13.3 Hz, 1H,

C6⁰–H), 2.80 (dd, JZ5.9, 13.3 Hz, 1H, C6⁰–H), 3.10 (br s,

1H, OH), 3.50–3.60 (m, 2H, C4⁰–H, OH), 3.99 (s, 1H,

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11103

C4–OH), 4.14 (br s, 1H, C7–H), 4.97 (s, 1H, C3–H), 5.01 (br

s, 1H, C6–H), 7.13–7.20 (m, 3H, ArH), 7.23–7.29 (m, 2H,

ArH); ¹³C NMR (125.8 MHz, CDCl₃) d 11.4 (CH₃), 19.7

(CH₂), 28.0 (CH₃), 28.1 (CH₃), 28.2 (CH₃), 33.9 (CH₂), 35.1

(CH₂), 39.8 (CH₂), 40.6 (CH), 74.2 (CH), 74.3 (C), 75.1

(CH), 78.8 (CH), 82.5 (CH), 83.4 (C), 84.2 (C), 85.0 (C),

91.3 (C), 105.3 (C), 125.7 (CH), 128.2 (CH), 129.2 (CH),

141.2 (C), 166.2 (C]O), 166.4 (C]O), 168.7 (C]O);

FAB-HRMS m/z calcd for C₃₄H₅₃O₁₂(MCH)^C653.3537,

found 653.3527.

C3⁰–H₂), 1.79–1.93 (m, 2H, C1⁰–H₂), 2.05 (m, 1H, C5⁰–H),

2.06 (s, 3H, COCH₃), 2.36 (dd, JZ9.1, 13.4 Hz, 1H, C6⁰–

H), 2.74 (dd, JZ5.6, 13.4 Hz, 1H, C6⁰–H), 4.00 (d, JZ

1.8 Hz, 1H, C7–H), 4.87 (m, 1H, C4⁰–H), 4.96 (d, JZ

1.8 Hz, 1H, C6–H), 4.97 (s, 1H, C3–H), 7.12–7.18 (m, 3H,

ArH), 7.21–7.27 (m, 2H, ArH); ¹³C NMR (125.8 MHz,

CD₃OD) d 14.2, 20.1, 21.1, 28.4, 28.5, 28.7, 32.5, 36.6,

39.5, 40.6, 76.0, 76.8, 78.3, 79.9, 84.2, 84.3, 84.5, 93.2,

106.4, 126.9, 129.3, 130.2, 142.0, 167.4, 168.3, 169.8,

173.0; FAB-HRMS m/z calcd for C₃₆H₅₅O₁₃(MCH)^C

695.3643, found 695.3670.

4.6.3. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,7R]-6,7-

diacetoxy-1-(4-acetoxy-5-methyl-6-phenylhexyl)-4-

hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxyl-

ate (66). To a solution of tetraol 65 (45.7 mg, 0.070 mmol) in

CH₂Cl₂(5 mL) at 0 8C was added 4-N,N-dimethylamino-

pyridine (86 mg, 0.705 mmol) followed by addition of

acetic anhydride (0.035 mL, 0.37 mmol). After stirring at

0 8C for 30 min, the reaction was quenched with 1 N

aqueous KH₂PO₄(5 mL) and the mixture was extracted

with 10:1 Et₂O/n-hexane (11 mL). The organic extract was

washed with brine (2!4 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo furnished the

crude product (59.8 mg), which was puriﬁed by column

chromatography (silica gel 5 g, 7:3 n-hexane/AcOEt) to

give triacetate 66 (54 mg, quant.) as a white foam: [a]_D²¹

C17.6 (c 0.91, CH₂Cl₂) [lit.^8b[a]_DC69.9 (c 0.29,

CH₂Cl₂)]; IR (ﬁlm) 3453 (br), 2978, 2934, 1759, 1732,

4.6.5. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,7R]-1-(4-

acetoxy-5-methyl-6-phenylhexyl)-7-(tert-butoxycarbonyl)

oxy-4,6-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-

tricarboxylate (67). A 0.1 M solution of di-tert-butyl

dicarbonate in CH₂Cl₂(0.84 mL, 0.084 mmol) was added

to a solution of triol 3 (14.5 mg, 0.0209 mmol), 4-pyrroli-

dinopyridine (4.9 mg, 0.033 mmol) and Et₃N (12 mL,

0.086 mmol) in CH₂Cl₂(2.5 mL) at 0 8C. After stirring at

0 8C for 12 h, the mixture was diluted with 1:1 n-hexane/

Et₂O (12 mL) and quenched with 1 M aqueous K₂HPO₄

(3 mL). The layers were separated, and the organic layer

was washed with brine (3 mL) and dried over anhydrous

Na₂SO₄. Filtration and evaporation in vacuo followed by

column chromatography (silica gel 8 g, 3:1 n-hexane/

AcOEt) afforded tert-butyl carbonate 67 (11.8 mg, 71%)

as a colorless foam: [a]_D²¹C23.8 (c 0.59, EtOH) [lit. [a]_D

C43.3 (c 0.25, CH₂Cl₂),^8b[a]_D²⁷C25.8 (c 0.47,

CH₂Cl₂)^11b]; IR (ﬁlm) 3459 (br), 2980, 2933, 1733, 1456,

1

1477, 1456, 1372, 1236, 1154, 1119, 1040, 702 cm^K1; H

NMR (500 MHz, CDCl₃) d 0.84 (d, JZ6.8 Hz, 3H, C5⁰-

CH₃), 1.460 (s, 9H, CO₂C(CH₃)₃), 1.464 (s, 9H,

CO₂C(CH₃)₃), 1.51–1.71 (m, 4H, C2⁰–H₂, C3⁰–H₂), 1.62

(s, 9H, CO₂C(CH₃)₃), 1.88–2.12 (m, 3H, C1⁰–H₂, C5⁰–H),

2.05 (s, 3H, COCH₃), 2.07 (s, 3H, COCH₃), 2.15 (s, 3H,

COCH₃), 2.30 (dd, JZ9.7, 13.4 Hz, 1H, C6⁰–H), 2.76 (dd,

JZ4.9,₀13.4 Hz, 1H, C6⁰–H), 4.07 (s, 1H, C4–OH), 4.88 (m,

1H, C4 –H), 4.88 (s, 1H, C3–H), 5.09 (d, JZ1.8 Hz, 1H,

C7–H), 6.34 (d, JZ1.8 Hz, 1H, C6–H), 7.13 (m, 2H, ArH),

7.17 (m, 1H, ArH), 7.23–7.31 (m, 2H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 14.3, 20.1, 20.5, 20.7, 21.1, 28.4,

28.5, 32.3, 36.5, 39.7, 40.6, 75.6, 76.9, 77.9, 81.6, 85.0,

85.4, 86.4, 91.2, 105.6, 127.0, 129.3, 130.2, 142.0, 165.6,

167.4, 168.8, 170.2, 171.1, 173.0; FAB-HRMS m/z calcd for

C₄₀H₅₉O₁₅(MCH)^C779.3853, found 779.3823.

1395, 1371, 1278, 1257, 1159, 1121, 967, 845, 743 cm^K1

;

¹H NMR (500 MHz, CDCl₃) d 0.84 (d, JZ6.9 Hz, 3H, C5⁰–

CH₃), 1.45 (s, 9H, CO₂C(CH₃)₃), 1.49 (s, 9H, CO₂C(CH₃)₃),

1.50 (s, 9H, CO₂C(CH₃)₃), 1.58 (s, 9H, CO₂C(CH₃)₃), 1.54–

1.73 (m, 4H, C2⁰–H₂, C3⁰–H₂), 1.87–2.12 (m, 3H, C1⁰–H₂,

C5⁰–H), 2.06 (s, 3H, COCH₃), 2.31 (dd, JZ9.6, 13.4 Hz,

1H, C6⁰–H), 2.75 (dd, JZ4.9, 13.4 Hz, 1H, C6⁰–H), 2.85 (d,

JZ3.5 Hz, 1H, C6–OH), 3.94 (s, 1H, C4–OH), 4.64 (d, JZ

1.8 Hz, 1H, C7–H), 4.72 (s, 1H, C3–H), 4.88 (s, 1H, C4⁰–H),

5.11 (brs, 1H, C6–H), 7.13 (m, 2H, ArH), 7.17 (m, 1H,

ArH), 7.23–7.29 (m, 2H, ArH); ¹³C NMR (125.8 MHz,

CDCl₃) d 13.8, 18.9, 21.2, 27.7, 27.79, 28.04, 28.1, 30.9,

35.5, 37.9, 39.4, 74.0, 75.3, 76.9, 77.0, 83.2, 83.8, 84.0,

85.0, 85.5, 90.7, 103.8, 125.8, 128.2, 129.1, 140.7, 153.7,

165.2, 165.8, 168.5, 170.9; FAB-HRMS m/z calcd for

C₄₁H₆₂O₁₅Na (MCNa)^C817.3986, found 817.3989.

4.6.4. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,7R]-1-(4-

acetoxy-5-methyl-6-phenylhexyl)-4,6,7-trihydroxy-2,8-

dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (3). A

0.2% solution of potassium carbonate in MeOH (1.5 mL)

was added to triacetate 66 (50.7 mg, 0.065 mmol) at 0 8C.

After stirring at room temperature for 1 h, the reaction was

quenched with 0.3 N aqueous KH₂PO₄(1 mL), and the

whole was partitioned between AcOEt (10 mL) and brine

(4 mL). The organic layer was washed with brine (4 mL)

and dried over anhydrous Na₂SO₄. Filtration and evapor-

ation in vacuo followed by column chromatography (silica

gel 5 g, 3:2 n-hexane/AcOEt) afforded triol 3 (42.5 mg,

94%) as a white foam: [a]²_D³C7.58 (c 1.0, CH₂Cl₂); IR

(ﬁlm) 3482, 2980, 2932, 1733, 1456, 1393, 1372, 1258,

1156, 965, 845, 701 cm^K1; ¹H NMR (500 MHz, CD₃OD) d

0.87 (d, JZ6.9 Hz, 3H, C5⁰-CH₃), 1.45 (s, 9H,

CO₂C(CH₃)₃), 1.46 (s, 9H, CO₂C(CH₃)₃), 1.52–1.65 (m,

2H, C2⁰–H₂), 1.60 (s, 9H, CO₂C(CH₃)₃), 1.66–1.75 (m, 2H,

4.6.6. Tri(tert-butyl) [1S,1(4R,5R),3S,4S,5R,6R,6(4E,6R),

7R]-1-(4-acetoxy-5-methyl-6-phenylhexyl)-7-(tert-

butoxycarbonyloxy)-4-hydroxy-6-(6-methyl-9-phenyl-4-

nonenoyl)oxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricar-

boxylate (68). DCC (31 mg, 0.150 mmol) was added to a

solution of carboxylic acid 2 (37 mg, 0.150 mmol) in

CH₂Cl₂(1.5 mL), and the mixture was stirred at room

temperature for 15 min. The solution of DCC–carboxylic

acid 2 in CH₂Cl₂(0.5 mL) was added to a solution of diol 67

(11.8 mg, 0.0149 mmol) and DMAP (14.5 mg, 0.119 mmol)

in CH₂Cl₂(2 mL). After stirring at room temperature for

48 h, the reaction was quenched with saturated aqueous

NaHCO₃(6 mL), and the whole was extracted with 3:1

Et₂O/n-hexane (8 mL). The organic extract was washed

successively with saturated aqueous NaHCO₃(3 mL) and

brine (3 mL), and dried over anhydrous Na₂SO₄. Filtration

11104

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

and evaporation in vacuo followed by column chromato-

graphy (silica gel 8 g, 5:1 n-hexane/AcOEt) afforded ester

68 (13.7 mg, 90%) as a colorless oil: [a]²_D³C8.4 (c 0.38,

CH₂Cl₂) [lit. [a]_DC8.5 (c 0.27, CH₂Cl₂),^8b[a]_D²³C9.0 (c

0.27, CH₂Cl₂)^11b]; IR (ﬁlm) 3452 (br), 2978, 2932, 1748,

Center for Instrumental Analysis, Hokkaido University, for

technical assistance in MS and elemental analysis.

1

1456, 1395, 1372, 1281, 1256, 1159, 1119, 700 cm^K1; H

NMR (500 MHz, CDCl₃) d 0.83 (d, JZ6.8 Hz, 3H, C5⁰–

CH₃), 0.93 (d, JZ6.7 Hz, 3H, C6⁰⁰–CH₃), 1.29 (q, JZ

7.7 Hz, 2H, C7⁰⁰–H₂), 1.44 (s, 9H, CO₂C(CH₃)₃), 1.45 (s,

9H, CO₂C(CH₃)₃), 1.47 (s, 9H, CO₂C(CH₃)₃), 1.61 (s, 9H,

CO₂C(CH₃)₃), 1.50–1.72 (m, 6H, C2⁰–H₂, C3⁰–H₂, C8⁰⁰–

H₂), 1.89–2.13 (m, 4H, C1⁰–H₂, C5⁰–H, C6⁰⁰–H), 2.04 (s,

3H, COCH₃), 2.24–2.43 (m, 5H, C6⁰–H, C2⁰⁰–H₂, C3⁰⁰–H₂),

2.57 (t, JZ7.7 Hz, 2H, C9⁰⁰–H₂), 2.76 (dd, JZ4.7, 13.4 Hz,

1H, C6⁰–H), 4.06 (s, 1H, C4–OH), 4.86 (d, JZ1.7 Hz, 1H,

C7–H), 4.87 (m, 1H,₀₀C4⁰–H), 4.91 (s, 1H, C3–H), 5.28–5.40

(m, 2H, C4⁰⁰–H, C5 –H), 6.40 (d, JZ1.7 Hz, 1H, C6–H),

7.10–7.20 (m, 6H, ArH), 7.23–7.30 (m, 4H, ArH); ¹³C NMR

(125.8 MHz, CDCl₃) d 13.9, 18.9, 20.6, 21.2, 27.68, 27.71,

27.9, 28.0, 28.1, 29.2, 30.9, 34.1, 35.8, 36.1, 36.5, 36.6,

38.0, 39.4, 74.0, 75.3, 76.2, 77.0, 83.1, 83.3, 83.4, 83.9,

86.1, 89.8, 103.8, 125.6, 125.8, 126.1, 128.20, 128.23,

128.4, 129.1, 137.6, 140.8, 142.8, 152.4, 164.0, 165.6,

168.6, 170.7, 170.8; FAB-HRMS m/z calcd for

C₅₇H₈₂O₁₆Na (MCNa)^C1045.5500, found 1045.5450.

References and notes

1. (a) Wilson, K. E.; Burk, R. M.; Biftu, T.; Ball, R. G.;

Hoogsteen, K. J. Org. Chem. 1992, 57, 7151–7158. (b)

Dufresne, C.; Wilson, K. E.; Zink, D.; Smith, J.; Bergstrom,

J. D.; Kurtz, M.; Rew, D.; Nallin, M.; Jenkins, R.; Bartizal, K.;

Trainor, C.; Bills, G.; Meinz, M.; Huang, L.; Onishi, J.;

Milligan, J.; Mojena, M.; Pelaez, F. Tetrahedron 1992, 48,

10221–10226. (c) Bergstrom, J. D.; Kurtz, M. M.; Rew, D. J.;

Amend, A. M.; Karkas, J. D.; Bostedor, R. G.; Bansal, V. S.;

Dufresne, C.; VanMiddlesworth, F. L.; Hensens, O. D.; Liesch,

J. M.; Zink, D. L.; Wilson, K. E.; Onishi, J.; Milligan, J. A.;

Bills, G.; Kaplan, L.; Nallin Omstead, M.; Jenkins, R. G.;

Huang, L.; Meinz, M. S.; Quinn, L.; Burg, R. W.; Kong, Y. L.;

Mochales, S.; Mojena, M.; Martin, I.; Pelaez, F.; Diez, M. T.;

Alberts, A. W. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 80–84.

(d) Hensens, O. D.; Dufresne, C.; Liesch, J. M.; Zink, D. L.;

Reamer, R. A.; VanMiddlesworth, F. Tetrahedron Lett. 1993,

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Zink, D. L.; Bergstrom, J. D.; Rew, D.; Polishook, J. D.;

Meinz, M.; Huang, L.; Silverman, K. C.; Lingham, R. B.;

4.6.7. Zaragozic acid C (1). Triﬂuoroacetic acid (2.2 mL)

was added to a solution of compound 68 (13.5 mg,

0.0132 mmol) in CH₂Cl₂(6.5 mL). After stirring at room

temperature for 16 h, the mixture was evaporated in vacuo,

and the crude product was concentrated from toluene

(10 mL) to remove residual triﬂuoroacetic acid. Trituration

of the residue with petroleum ether provided zaragozic acid

C (1) (10.1 mg, quant.) as a white ﬁlm: [a]²_D³C9.4 (c 0.30,

EtOH) [lit. [a]²_D⁰C9.6 (c 0.29, EtOH),^1b[a]_DC9.0 (c 0.23,

EtOH),^8b[a]_D²⁴C9.6 (c 1.0, EtOH)^11b]; IR (ﬁlm) 3453 (br),

2928, 1732, 1495, 1454, 1375, 1250, 1148, 1026, 970, 745,

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Mojena, M.; Cascales, C.; Pelaez, F.; Gibbs, J. B. J. Nat. Prod.

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1

700 cm^K1; H NMR (500 MHz, CD₃OD) d 0.86 (d, JZ

6.8 Hz, 3H, C5⁰-CH₃), 0.93 (d, JZ6.7 Hz, 3H, C6⁰⁰-CH₃),

1.19–1.37 (m, 2H, C7⁰⁰–H₂), 1.50–1.64 (m, 4H, C2⁰–H₂,

C8⁰⁰–H₂), 1.64–1.73 (m, 2H, C3⁰–H₂), 1.82–1.94 (m, 2H,

C1⁰–H₂), 1.97–2.12 (m, 2H, C5⁰–H, C6⁰⁰–H), 2.05 (s, 3H,

COCH₃), 2.22–2.30 (m, 2H, C3⁰⁰–H₂), 2.30–2.39 (m, 3H,

C6⁰–H, C2⁰⁰–H₂), 2.50–2.61 (m, 2H, C9⁰⁰–H₂), 2.73 (dd, JZ

5.6, 13.3 Hz, 1H, C6⁰–H), 4.00 (d, JZ1.6 Hz, 1H, C7–H),

4.90 (m, 1H, C4⁰–H), 5.22 (s, 1H, C3–H), 5.31 (dd, JZ7.6,

15.₀3₀Hz, 1H, C5⁰⁰–H), 5.37 (dt, JZ15.3, 6.2 Hz, 1H,

C4 –H), 6.23 (br s, 1H, C6–H), 7.09–7.17 (m, 6H, ArH),

7.19–7.27 (m, 4H, ArH); ¹³C NMR (125.8 MHz, CD₃OD) d

14.3, 20.2, 21.1, 21.3, 28.8, 30.5, 32.5, 35.4, 36.3, 36.9,

37.6, 37.8, 39.7, 40.5, 75.7, 76.7, 78.2, 81.3, 82.3, 91.1,

107.2, 126.6, 126.9, 127.6, 129.26, 129.28, 129.4, 130.2,

138.8, 142.0, 143.9, 168.7, 170.3, 172.6, 173.1, 173.2; FAB-

HRMS m/z calcd for C₄₀H₅₀O₁₄Na (MCNa)^C777.3098,

found 777.3049.

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Acknowledgements

This research was supported in part by a Grant-in-Aid for

Scientiﬁc Research from the Ministry of Education, Culture,

Sports, Science and Technology, Japan. We thank Ms. H.

Matsumoto, A. Maeda, K. Nakaoka, and S. Oka of the

S. Nakamura et al. / Tetrahedron 61 (2005) 11078–11106

11105

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93%; (4) (COCl)₂, DMSO, CH₂Cl₂, K78 8C, 15 min, then

Et₃N, K40 8C, 15 min; (5) NaClO₂, NaH₂PO₄, 2-methyl-2-

butene, ^tBuOH–H₂O (4:1), 8 h, 79% (two steps); (6)

MeONHMe$HCl, DEPC, Et₃N, DMF, 1.5 h, 89%; (7) EVE,

^tBuLi, THF, K78 8C, 50 min, 90%; (8) O₃, CH₂Cl₂, K78 8C,

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Only milligram quantities of 60 were isolated at the time that

our preliminary account was published, and the incorrect

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Article Doi

Total synthesis of zaragozic acid C by an aldol-based strategy

DOI: 10.1016/j.tet.2005.09.030

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Article abstract of DOI:10.1016/j.tet.2005.09.030

Full text of DOI:10.1016/j.tet.2005.09.030

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