Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

Tetrahedron 67 (20 1 1 ) 6730e6745

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Tetrahedron

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Total syntheses of (þ)-spiculoic acid A and (þ)-zyggomphic acid, new marine

natural products of polyketide origin

Daisuke Matsumura, Toshimasa Takarabe, Takumi Toda, Takashi Hayamizu, Kiyoto Sawamura,

*

Ken-ichi Takao, Kin-ichi Tadano

Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

The total syntheses of both natural (þ)-spiculoic acid A and (þ)-zyggomphic acid, new cytotoxic marine

natural products of polyketide origin, have been accomplished for the ﬁrst time. These syntheses were

achieved by the highly stereoselective and high-yielding intramolecular DielseAlder reaction of a func-

tionalized (E,E,E)-2,7,9-dodecanal derivative to construct the core tetrahydroindan-2-one skeleton.

A stereocongener of (þ)-spiculoic acid A, i.e., the (2R,5S,6R)-isomer, was also synthesized. The details of

these total syntheses are described.

Received 17 March 2011

Received in revised form 1 April 2011

Accepted 5 April 2011

Available online 12 April 2011

Keywords:

(þ)-Spiculoic acid A

(þ)-Zyggomphic acid

Marine natural product

Cytotoxicity

Intramolecular reaction DielseAlder

reaction

1. Introduction

these marine natural products was (þ)-zyggomphic acid (6), a pol-

yketide possessing an (E,E)-conjugated diene unit in the side chain.

Marine organisms produce a number of structurally unique and

synthetically formidable natural products.¹Many marine natural

products exhibit a useful level of biological activities, including an-

tibacterial, antifungal, and cytotoxic activities against tumor cells. In

2004, Andersen et al. reported the isolation, structural de-

termination, and biological assay of two polyketides, (þ)-spiculoic

acid A (1) and (ꢀ)-spiculoic acid B (2) (Fig. 1), as secondary metab-

olites produced by the Caribbean marine sponge Plakortis angulo-

spiculatus (Carter).²The relative stereochemistries of 1 and 2 were

determined by the Andersen group based on NMR spectroscopic

analysis. Although the natural product 1 showed in vitro cytotoxicity

against human breast cancer MCF-7 cells, compound 2 showed no

cytotoxicity against the same cancer cells. To date, a number of

closely related spiculane-type natural products have been isolated

from the Plakortis species.³The Amade group has been involved in

the isolation of new spiculoic acid congeners from the Plakortis

species. In 2005, their group reported three spiculoic acid conge-

ners: (þ)-isospiculoic acid A (3), (þ)-nor-spiculoic acid A (4), and

(þ)-dinor-spiculoic acid A (5) isolated from Plakortis zyggompha.⁴

Later, the Amade group reported the isolation and characterization

of additional spiculoic acid congeners from the same sponge.⁵One of

All of these natural products 3e6 showed marginal cytotoxicity

against several tumor cells. The structures of 1e6 are characterized

by their multiply substituted trans-fused tetrahydroindan-2-one

core structure carrying six stereogenic carbons, including two con-

tiguous all-carbon quaternary centers, a trisubstituted Z-oleﬁn, and

a styryl side chain. The Andersen group has proposed that the bi-

cyclic structure of 1 might be constructed in its biosynthetic path-

way through an enzyme-catalyzed intramolecular DielseAlder

(IMDA) reaction of a linear (E,E,E)-2,7,9-triene carboxylic acid, which

is equipped with all of the alkyl and styryl groups.²Since their iso-

lation, synthetic studies on these spiculane-polyketides have been

conducted by several groups.^6e9In 2006, Baldwin et al. reported the

ﬁrst total synthesis of (ꢀ)-spiculoic acid A, thereby establishing the

absolute stereochemistry of the natural product 1 as depicted in

Fig.1.^7a,10The Baldwin/Lee group has achieved the total synthesis of

(ꢀ)-spiculoic acid A by using the IMDA reaction of a linear conju-

gated diene (4p) installing a terminal unsaturated ester (2p) for the

stereoselective construction of the bicyclic core structure. In 2009,

we reported the ﬁrst total synthesis of natural (þ)-spiculoic acid

A (1).¹¹Furthermore, we have recently completed the total synthesis

of natural (þ)-zyggomphic acid (6) using a modiﬁed synthetic ap-

proach to1. In this paper, we describe the details of our total syn-

theses of 1 and 6 and the establishment of the undetermined

absolute stereochemistry of 6.

* Corresponding author. Tel.: þ81 45 566 1516; e-mail address: tadano@

applc.keio.ac.jp (K.-i. Tadano).

doi:10.1016/j.tet.2011.04.006

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6731

1or methyl for 6). These two vinylboronates 9 in turn would

be synthesized straightforwardly from known enantiomerically

homogeneous branched ﬁve-carbon diol 10. The conventional

synthesis of the differentially protected chiral diol 10, i.e., (2S)-

2-[(tert-butyldimethylsilyloxy)methyl]butan-1-ol, was developed

by Fukumoto et al. using Evans’ asymmetric aldol strategy with

(S)-phenylalanine-derived chiral oxazolin-2-one.¹³

Me

H

5R

6S

2S

O

1

Me

HO₂C

H

Me

H

Me

HO₂C

Me

2

Me

1

R¹

R²

H

Me

2.2. Total synthesis of (D)-spiculoic acid A (1)

H

O

Me

HO₂C

3: R¹=Et, R²=Et

4: R¹=Et, R²=Me

5: R¹=Me, R²=Me

O

The synthesis and IMDA reaction of substrate 26 for the total

synthesis of 1 is depicted in Scheme 2. Swern oxidation of the

starting chiral pool 10 provided aldehyde 11, which was subjected

to Wittig oleﬁnation with Ph₃P]C(Et)CO₂Et in reﬂuxing toluene to

provide the (E)-unsaturated ester 12 stereoselectively (E/Z >20:1

based on ¹H NMR analysis). Hydride reduction of 12 followed by

protection of the resulting allylic alcohol 13 as (4-methoxyphenyl)

methyl (MPM) ether provided 14. Deprotection of the TBS ether

with aqueous acetic acid produced 15. Swern oxidation of 15 pro-

duced aldehyde 16, which was subjected to anti-selective methyl-

homoallylic alcohol formation. We eventually found that

crotylboration using Brown chiral borane,¹⁴produced in situ by

treating trans-2-butene with a mixed base (t-BuOK and n-BuLi) and

then adding (ꢀ)-methoxydiisopinocampheylborane in the pres-

ence of BF₃$Et₂O, was the best choice of reagent in terms of ster-

eoselectivity. After oxidative treatment of the reaction mixture

H

Me

HO₂C

Me

H

Me

6

Fig. 1. (þ)-Spiculoic acid A and related natural products.

2. Results and discussion

2.1. Uniﬁed retrosynthetic analyses of (D)-spiculoic acid A (1)

and (D)-zyggomphic acid (6)

In Scheme 1, our common synthetic approach to 1 and 6 is sum-

marized. The central feature of the total syntheses of 1 and 6 is the

construction of the core tetrahydroindan-2-one structure using the

stereoselective (endo/exo and p

-facial) IMDA reaction¹²of a common

with alkaline aqueous H₂O₂, anti-

was obtained as the major product of an inseparable diastereomeric

b-methylhomoallylic alcohol 17

triene, such as two types of (E,E,E)-2,7,9-decatrienal derivatives7. The

substituents (OP¹and R²) in the resulting cycloadducts would

be further functionalized for completion of the total syntheses of

1 and 6. We considered that the attempted IMDA reactions would be

accelerated in the presence of the terminal unsaturated aldehyde

moiety as a dienophile in place of the corresponding unsaturated

ester used in Baldwin and Lee’s total synthesis. Moreover, the pres-

ence ofa bulkysilyl ether, such as (tert-butyldimethylsilyloxy)methyl

(TBSOCH₂) as R²would be beneﬁcial for the outcome of stereo-

selectivity in the IMDA reactions. The Baldwin/Lee group in-

corporated a styryl group as R²for their IMDA reaction, which may

have deactivated to some extent in the diene part.

R

TBSO

R

Me

OTBS

Me

a

b-d

e, f

10

OHC

MPMO

12 R=CO₂Et E:Z >20:1

11

15 R=CH₂OH

16 R=CHO

13 R=CH₂OH

14 R=CH₂OMPM

Me

OMOM

Me

OP

Me

OMOM

g, h

j

i

OHC

HO

Me

OH

Me

IMDA then

R¹

MPMO

17 P=H

18 P=MOM

MPMO

R¹

functionaization

Me

H

20

19

of the substituents

R²

Me

HO₂C

R²

O

OP¹

Me

Br

Me

OMOM

I

H

O

Me

OHC

B

O

k

l, m

Me

+

Me

1: R¹=Et, R²= (E)-CH=CHPh

6: R¹=Me,

Me

TBSO

Me

IMDA substrates 7

R¹=Et or Me

PO

MPMO

22 P=MPM

23 P=H

24

21 E:Z >20:1

R²= (E,E)-CH=C(Et)CH=CHPh

R²=CH₂OP³or

(E)-CH=C(Et)CH₂OP³

Me

H

OMOM

Me

n, o

TBSO

p

Suzuki-Miyaura

OMOM

Me

cross coupling

Me

H

TBSO

Me

R

OHC

Me

27

R¹

Me

25 R=CH₂OH

26 R=CHO

RO

OP¹

Me

I

B

OTBS

Me

+

OR

R²

Scheme 2. Synthesis of the IMDA substrate 26 and the IMDA reaction. Reagents and

conditions: (a) DMSO, (COCl)₂, CH₂Cl₂, ꢀ78 ^ꢁC then Et₃N, rt; (b) Ph₃P]C(Et)CO₂Et,

toluene, reﬂux, 85% over two steps; (c) DIBAL-H, CH₂Cl₂, ꢀ78 ^ꢁC, 95%; (d) MPMCl, NaH,

Bu₄NI, DMF, rt, 94%; (e) AcOH/THF/H₂O¼3:2:1, rt, 87%; (f) DMSO, (COCl)₂, CH₂Cl₂,

ꢀ78 ^ꢁC then Et₃N, rt, 95%; (g) t-BuOK, n-BuLi, THF, trans-2-butene, ꢀ100 ^ꢁC to ꢀ50 ^ꢁC

Me

P²O

OH

(E)-vinyl iodides 8

known 10

(E)-vinylboronates 9

then (ꢀ)-B-methoxydiisopinocampheylborane, BF₃$Et₂O, 16, ꢀ78 ^ꢁC then

3 M aq

Scheme 1. Retrosynthetic analysis.

NaOH, 35% H₂O₂, reﬂux; (h) MOMCl, i-Pr₂NEt, CH₂Cl₂, reﬂux, 65% over two steps: (i)

OsO₄in t-BuOH, NMO, acetone/H₂O¼6:1, rt, 92%; (j) NaIO₄, acetone/H₂O¼4:1, rt; (k)

1,1-(dibromopropyl)triphenylphosphonium bromide, n-BuLi, Et₂O, ꢀ78 ^ꢁC, 77% over

two steps; (l) bis(pinacolato)diboron, PdCl₂(PPh₃)₂, PPh₃, PhOK, toluene, 50 ^ꢁC, 78%;

(m) DDQ, CH₂Cl₂, aq phosphate buffer, rt, 79%; (n) PdCl₂(dppf) (cat.), 3 M aq NaOH,

degassed THF, rt, 71%; (o) MnO₂, CH₂Cl₂, rt, 97%; (p) degassed toluene, BHT (cat.), 70 ^ꢁC,

5 days, 97%.

The IMDA substrates 7 would be obtained via stereoselective

SuzukieMiyaura coupling between (E)-vinyl iodides 8 (two types

of R²) and highly functionalized (E)-vinylboronates 9 (R¹is ethyl for

6732

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

mixture. The diastereomeric ratio of the crotylboration was ap-

proximately 3 to 1 based on ¹H NMR analysis, and the minor isomer

was cleanly separated by chromatography on silica gel after sub-

sequent protection of the allylic alcohol. Protection of the mixture

as the methoxymethyl (MOM) ethers provided the anti-isomer 18

in 65% yield over the two steps. The structure of the desired 18 was

conﬁrmed by examination of the ¹H NMR analysis of some ad-

vanced intermediates. Oxidative two-step carbonecarbon bond

cleavage via diol 19 produced aldehyde 20, which was subjected to

Wittig oleﬁnation using the ylide produced by the treatment of

1,1-(dibromopropyl)triphenylphosphonium bromide with n-BuLi

at ꢀ78 ^ꢁC,¹⁵which in turn provided (E)-trisubstituted vinyl bromide

21 (E/Z >20:1 based on ¹H NMR analysis). Treatment of 21 with

bis(pinacolate)diboron in the presence of PdCl₂(PPh₃)₂, PPh₃, and

PhOK in toluene at 50 ^ꢁC¹⁶provided vinylboronate 22 (9: R¹¼Et,

P¹¼MOM, P²¼MPM) in a good yield of 78%. Deprotection of the

MPM group in 22 with DDQ in aqueous phosphate buffer provided

allylic alcohol 23. SuzukieMiyaura coupling between (E)-vinyl-

boronate 23 and (E)-vinyl iodide 24 (8: R²¼CH₂OTBS) was per-

formed under the Pd-catalyzed standard conditions to construct

the (E,E)-diene moiety, producing 25 efﬁciently in 71% yield. The

vinyl iodide 24 was conventionally synthesized from diethyl eth-

ylmalonate by the procedure analogous to Baker’s precedent,

which was adapted to diethyl methylmalonate.¹⁷Oxidation of the

allylic alcohol moiety in 25 with MnO₂provided the IMDA substrate

26 (7: R¹¼Et, R²¼CH₂OTBS, P¹¼MOM). To our satisfaction, pro-

longed (5 days) heating 26 in toluene at 70 ^ꢁC produced the desired

endo-adduct 27 as a sole product in an excellent yield of 97%.The

IMDA reaction of 26 proceeded rather slowly but cleanly at 70 ^ꢁC.

After heating was performed at 70 ^ꢁC for 1 or 2 days, a substantial

amount of the substrate 26 remained intact.

The completion of the total synthesis of 1 from the IMDA adduct

27 is shown in Scheme 3. NaBH₄reduction of 27 produced 29. On

the other hand, we observed a one-step formation of the IMDA

substrate 26 in the SuzukieMiyaura coupling between 23 and 24

when the cross-coupling was executed with an excess amount of

the Pd-catalyst in DMF in the presence of Cs₂CO₃at 70 ^ꢁC for

a prolonged reaction time (more than 3 days). Under these condi-

tions, the formation of 26¹⁸and a spontaneous IMDA reaction

occurred. NaBH₄reduction of the crude mixture and puriﬁcation on

silica gel provided 29 in a less effective yield of 33% from 23. Pro-

tection of the resulting primary alcohol 29 as the MOM ether

produced 30. Deprotection of the TBS group in 30 and successive

Swern oxidation of the resulting 31 provided aldehyde 32. Hor-

nereWadswortheEmmons (HWE) oleﬁnation of 32 with the anion

generated from diethyl benzylphosphonate using n-BuLi as base

introduced a styryl moiety to produce 33 in a good yield of 88%.

Deprotection of both MOM groups in 33 and DesseMartin oxida-

tion¹⁹of the resulting diol 34 provided aldehydeeketo in-

termediate 35. KrausePinnick oxidation²⁰of 35 eventually

provided (þ)-spiculoic acid A (1). The spectral data of the synthetic

1 were identical to those reported for the natural product. Fur-

25

thermore, [

a

]

of the synthetic 1 [[

a]

þ102 (c 0.38, CH₂Cl₂)]

D

established the absolute stereochemistry of the natural product

[[a

]

D

þ110 (c 0.1, CH₂Cl₂) for natural 1²] as depicted.

Me

TBSO

Me

H

a, b

c,d

R

Me

OMOM

Me

OMOM

Me

27

Me

RO

MOMO

Me

31 R=CH₂OH

32 R=CHO

29 R=H

30 R=MOM

As depicted in Fig. 2, the observed exclusive endo- and p-facial

selectivity in the IMDA reaction of 26 was reasonably explained

using two transition states, endo TS leading to 27 and exo TS leading

to undesired cis-fused exo-adduct 28 (not obtained). It is obvious

that the C-8 substituent (an ethyl group) cooperated in realizing the

high stereoselectivity. In the transition states depicted in Fig. 2,

Me

H

Me

O

H

g

e, f

h

OR

1

Me

RO

Me

OHC

H

Me

both

opposite

p

-facial selectivities were the same. On the other hand, the

-facial attack in endo TS was signiﬁcantly unfavorable

33 R=MOM

34 R=H

35

p

owing to a severe allylic interaction (A^1,3strain) generated between

the ethyl group at C-8 and the ethyl group in the dienophile part.

Regarding the two transition states depicted in Fig. 2, exo TS was

signiﬁcantly disfavored as a result of a severe A^(1,3)strain occurring

between the ethyl substituent at C-4 and the methyl group at C-6.

In the case of endo TS, this interaction could be avoided; thus the

IMDA reaction proceeded via endo TS exclusively to produce 27 as

the sole product.

Scheme 3. Completion of the total synthesis of (þ)-spiculoic acid A (1). Reagent and

conditions: (a) NaBH₄, MeOH/THF¼1:1, rt, 91%; (b) MOMCl, i-Pr₂NEt, CH₂Cl₂, reﬂux; (c)

n-Bu₄NF, THF, 50 ^ꢁC, 99% over two steps; (d) DMSO, (COCl)₂, CH₂Cl₂, ꢀ78 ^ꢁC then Et₃N,

rt, 90%; (e) diethyl benzylphoshonate, n-BuLi, THF, ꢀ78 ^ꢁC then 32, 0 ^ꢁC, 88%; (f) CSA,

MeOH, 40 ^ꢁC, 6 days; (g) DesseMartin periodinane, CH₂Cl₂, rt, 85% over two steps; (h)

NaClO₂, 2-methyl-2-butene, phosphate buffer, t-BuOH/H₂O¼5:1, rt, 82%.

In another approach, we obtained the following unsuccessful

results.NaClO₂oxidation of the aldehyde functionality in an endo-

adduct similar to 27, which possessed a (4-methoxyphenyl)methyl

(MPM) group in place of TBS group in 27, provided the corre-

sponding carboxylic acid. After methyl esteriﬁcation and the re-

moval of the MPM group of the resulting ester, the

product was obtained as a sole product. It was thus obvious that the

facile -lactone formation occurred spontaneously owing to the

Me

CHO

Me

H

8

27

g-lactonization

MOMO

Me

H

OTBS

H

Me

endo TS

g

vicinal cis-relationship of the carboxylic acid and the primary hy-

droxy group. We could not ﬁnd efﬁcient conditions to open this

26

g-lactone for further functionalization. We concluded that the

synthetic route involving direct oxidation of the aldehyde 27 to the

corresponding carboxylic acid could not evade the above-

mentioned synthetic dead end.

CHO

Me

OTBS

H

Me

MOMO

Me

TBSO

Me

H

4

6

OMOM

Me

2.3. Synthesis of (2R,5S,6R)-isomer of (D)-spiculoic acid A (46)

H

OHC

Me

A^(1,3)strain

To obtain greater insight into the stereoselectivity of the IMDA

reaction to construct the core bicyclic structure and to synthesize

the stereoisomers of (þ)-spiculoic acid A (1), we next investigated

exo TS

28

Fig. 2. The endo- and exo-transition states for the IMDA reaction of 26.

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6733

the synthesis of another diastereomeric substrate for the IMDA

reaction. The synthesis of the substrate 41, its IMDA reaction, and

transformation of the IMDA adduct into the (2R,5S,6R)-isomer

(46)²¹of (þ)-spiculoic acid A are summarized in Scheme 4.

the unsaturated aldehyde 41 directly. The IMDA reaction of 41

started at 110 ^ꢁC (toluene, reﬂux) slowly. After 16 h, 76% of 41 was

recovered. Although the IMDA reaction completed by heating 41 at

160 ^ꢁC (toluene in a sealed tube) for 16 h, a signiﬁcant amount of an

inseparable unidentiﬁed product was produced along with the de-

sired IMDA adduct 42 (approximately 1:1 ratio). The thermal IMDA

reaction of 41 accelerated in the presence of silica gel (Wako gel

C-300) at 80 ^ꢁC. After 2 days of heating, an IMDA adduct 42 was

obtained as a predominant product in a high yield of 82%. Although

we have no rational explanation for the role of the silica gel, some

examples of the silica-gel-promoted IMDA reaction are known.²³

The adduct 42 contained a small amount of another product as an

inseparable byproduct in a ratio of >11:1 (based on ¹H NMR analy-

sis). Although this minor product was removed in the next step, we

could not determine its precise structure. The structure and ste-

reochemistry of the predominant IMDA adduct 42 were determined

to be a cis-fused hexahydroindane derivative byNOE experiments on

42 and the ﬁnal product 46 (Fig. 3). NaBH₄reduction of the aldehyde

group in 42 and protection of the resulting primary hydroxyl group

as the MOM ether provided 43. By deprotection of the MPM group

with DDQ, followed by DesseMartin oxidation, the fully protected

bicyclic compound 43 was converted into aldehyde 44. By using the

analogous four steps employed for the conversion of 32 into 1

(Scheme 3), the (2R,5S,6R)-isomer 46 of (þ)-spiculoic acid A was

efﬁciently obtained from 44 via 45. The structure of 46 was de-

termined precisely by examination of its NOE experiment as

depicted in Fig. 3. The formation of the exo-adduct 42 is rationalized

by the transition state argument using an exo-mode transition state

Me

OMOM

Me

OMOM

Me

OHC

e

a, b

c,d

16

Me

MPMO

Me

36

37

Me

Br

Me

OMOM

Me

I

Me

O

B

f,g

Me

+

Me

O

Me

MPMO

Me

HO

MPMO

h

39

40

38 E:Z >20:1

Me

H

OMOM

Me

MPMO

Me

i

OMOM

Me

MPMO

Me

OHC

Me

42

Me

41

Me

OMOM

Me

MPMO

H

Me

H

OHC

j,k

l,m

q

OMOM

Me

H

Me

MOMO

H

Me

MOMO

(exo TS) as depicted in Fig. 4. In this TS, the p-facial selectivity is the

Me

44

43

same as that in the case of the exo TS in Fig. 2. Consequently, the

conﬁguration of carbon bearing the methyl substituent(C-6) is a sole

stereocontrolling factor for the IMDA reaction of substrate 26 or 41.

In the case of 41, a severe A^(1,3)strain interaction was most likely in

the case of the endo-transition state. As a result, the IMDA reaction

proceeded favorably through the exo TS.

Me

H

5

H

n - p

6

O

2

Me

H

Me

OHC

45

HO₂C

Me

46

Scheme 4. Synthesis of the (2R,5S,6R)-isomer (46) of spiculoic acid A. Reagents and

conditions: (a) t-BuOK, n-BuLi, THF, cis-2-butene, ꢀ78 ^ꢁC to ꢀ50 ^ꢁC then (2⁰Z,4S,5S)-2-

1.3%

Me

ꢀ

Me

(but-2-enyl)-4,5-di(isopropyloxycarbonyl)-1,3,2-dioxaborolane, toluene, 16, MS 4 A,

H

Me

ꢀ78 ^ꢁC then 3 M aq NaOH, rt, 83%; (b) MOMCl, i-Pr₂NEt, CH₂Cl₂, reﬂux, 94%; (c) OsO₄in

t-BuOH, NMO, acetone/H₂O¼6:1, rt, 96%; (d) NaIO₄, acetone/H₂O¼4:1, rt; (e) 1,1-(di-

bromopropyl)triphenylphosphonium bromide, n-BuLi, Et₂O, ꢀ78 ^ꢁC, 50% over two

steps; (f) bis(pinacolato)diboron, PdCl₂(PPh₃)₂, PPh₃, PhOK, toluene, 50 ^ꢁC, 74%; (g)

DDQ, CH₂Cl₂, aq phosphate buffer, rt, 88%; (h) Pd(PPh₃)₄(excess), Cs₂CO₃, degassed

DMF, 70 ^ꢁC, 74%; (i) toluene, BHT (cat.), Wako Gel C-300, 80 ^ꢁC, 2 days, 82% (>11:1

mixture); (j) NaBH₄, MeOH, rt, 77%; (k) MOMCl, i-Pr₂NEt, CH₂Cl₂, reﬂux, 88%; (l) DDQ,

CH₂Cl₂, aq phosphate buffer, rt, 99%; (m) DesseMartin periodinane, CH₂Cl₂, rt, 82%; (n)

diethyl benzylphoshonate, n-BuLi, THF, ꢀ78 ^ꢁC then 44, 0 ^ꢁC, 96%; (o) 6 M aq HCl/

THF¼1:1, rt, 84%; (p) DesseMartin periodinane, NaHCO₃, CH₂Cl₂, rt, 81%; (q) NaClO₂,

2-methyl-2-butene, phosphate buffer, t-BuOH/H₂O¼5:1, rt, 91%.

H

MPMO

Me

OMOM

Me

1.9%

Me

O

6.3%

Me

H

O C

HO₂C

Me

1.5%

H

46

42

Fig. 3. NOE experiments for 42 and 46.

CHO

Me

OMPM

H

Me

The aforementioned aldehyde 16 was subjected to the crotylbo-

ration conditions developed by Roush et al. using (S,S)-diisopropyl

tartrate-modiﬁed chiral crotylboronate prepared from cis-2-bu-

Me

MOMO

Me

4

H

42

41

6

H

tene.²²As a result, syn-

b-methyl-homoallylic alcohol, with a conﬁg-

Me

exo TS

uration at the methyl-bearing carbon opposite to that in 17, was

obtained as the sole product in a high yield of 83%. Thus obtained

Fig. 4. exo-Transition state for the IMDA reaction of 41.

syn-b-methyl-homoallylic alcohol was protected as the MOM ether

to provide 36. The reaction sequence from 36 to 46 was mostly

analogous to that used for the synthesis of 1. OsO₄-mediated diol

formation of 36, with oxidative cleavage of the resulting diol pro-

vided 37, which was subjected to Wittig oleﬁnation to produce the

expected (E)-bromooleﬁn 38 almost exclusively (E/Z >20:1). The

Miyaura vinylboronation of 38 and deprotection provided 39 with-

out event. The SuzukieMiyaura coupling between 39 and vinyl

iodide 40, which was prepared analogously as TBS ether 24, efﬁ-

ciently provided the desired (E,E)-diene 41. By using an excess

amount of the palladium catalyst, the coupling reaction furnished

2.4. Total synthesis of (D)-zyggomphic acid (6)

The proposed planar structure of (þ)-zyggomphic acid (6) dif-

fers from that of (þ)-spiculoic acid A (1) in the C-4 substituent of

the trisubstituted oleﬁn moiety (an ethyl for 1 and a methyl for 6)

and in one of the C-2 substituents [an (E)-styryl for 1 and an (E,E)-2-

ethyl-4-phenyl-1,3-butadienyl for 6]. As the relative stereo-

chemistries of 1 and 6 for all stereogenic carbons are same, the

total synthesis of 6 would be expected to be realized using the

6734

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

synthetic approach analogous to that employed for 1. The total

synthesis of 6 was started from diol 19, which was subjected to

oxidative cleavage to produce aldehyde 20 (Scheme 5). The Wittig

oleﬁnation of 20 with 1,1-(dibromoethyl)triphenylphosphonium

bromide¹⁵using n-BuLi as a base provided (E)-vinyl bromide 47

stereoselectively. The vinylboronate formation by the Pd-catalyzed

coupling between 47and bis(pinacolate)diboron and deprotection

of the MPM group in the resulting boronate produced (E)-vinyl

boronate 48 in moderate overall yield. The SuzukieMiyaura cou-

pling between 48 and (E,E)-4-iodo-1,3-diethyl-1-(tert-butyldime-

thylsilyloxy)methyl-1,3-butadiene (49) proceeded smoothly under

the same conditions used for the coupling of 23 and 24. The vinyl

iodide 49 was synthesized from diethyl ethylmalonate.²⁴

DesseMartin oxidation of the resulting coupling product pro-

vided unsaturated aldehyde 50. The IMDA reaction of the conjugate

triene enal-type substrate 50 proceeded regio- and stereo-

selectively at 70 ^ꢁC in the presence of Wako gel C-300 to produce

the desired endo-adduct 51 in 74% yield and a separable minor

product. Although this minor product could not be fully charac-

terized, it may be a hetero-DielseAlder adduct. The IMDA adduct 51

was transformed to (þ)-zyggomphic acid (6) in eight further con-

ventional steps without event. Thus, reduction of the aldehyde

group in 51, protection as the MOM ether, and deprotection of the

TBS group provided allylic alcohol 52. DesseMartin oxidation of 52,

the HWE oleﬁnation of the resulting unsaturated aldehyde with

diethyl benzylphosphonate, followed by deprotection of the MOM

groups by acid hydrolysis produced 53. The ﬁnal two-step oxidation

of 53 eventually provided (þ)-zyggomphic acid (6). The spectral

comparison (¹H and ¹³C NMR) of the synthetic 6 with the reported

data for the natural product revealed that they are identical. Fur-

21.5

thermore, speciﬁc rotation of the synthetic 6 [[

a

]

þ82.0 (c

D

24

0.140, CH₂Cl₂)] well matched with that of natural sample [[a]

D

þ85.9 (c 0.05, CHCl₃)].⁵Thus we established the relative and ab-

solute stereo-chemistries of natural (þ)-zyggomphic acid as shown.

3. Conclusion

We have achieved the total synthesis of (þ)-spiculoic acid A (1)

for the ﬁrst time. The total synthesis featured the highly endo- and

p-facial selective IMDA reaction of a multisubstituted trienal de-

rivative 26 for an expeditious construction of the core bicyclic

skeleton with correct stereochemistry. The synthesis of the IMDA

substrate should be speciﬁed by the SuzukieMiyaura coupling

between the (E)-vinylboronate 23 and the (E)-vinyl iodide 24 for

the construction of the 1,1,3,4-tetra-substituted (E,E)-1,3-butadiene

moiety. The highly stereoselective outcome of the IMDA reaction

can be rationalized by the conﬁguration at the C-6 methyl group in

26, which directs the endo-transition states. Relying on this tran-

sition state argument, we also synthesized the (2R,5S,6R)-isomer

46 of (þ)-spiculoic acid A through the exo-selective IMDA reaction

using a C-6 diastereomeric trienal 41. Finally, we have completed

the ﬁrst total synthesis of natural (þ)-zyggomphic acid (6), which

relied on the endo- and p-facial selective IMDA reaction of a more

functionalized tetraenal 50. Our approaches to the syntheses of

1 and 6 are promisingly applicable for the syntheses of other

spiculane-type natural products of polyketide origin.

4. Experimental section

4.1. General

Me

OMOM

Me

OMOM

Me

Speciﬁc rotations were measured in a 10 mm cell. ¹H NMR

spectra were recorded at 300 MHz with tetramethylsilane as an

internal standard with a Varian 300 or a JEOL JNM LA-300 spec-

trometer. ¹³C NMR spectra were recorded at 68 MHz or at 75 MHz

with the same spectrometer. High-resolution mass spectra (HRMS)

were measured with a JEOL GC-Mate mass spectrometer by the EI

method (70 eV). Thin-layer chromatography (TLC) was performed

on Merck Kieselgel 60 F₂₅₄plates. The crude reaction mixtures and

extractive materials were puriﬁed by chromatography on Silica gel

60 (Merck) or Wako gel C-300 (Wako). Combined organic extracts

were dried over anhydrous Na₂SO₄. Solvents were removed from

the reaction mixture or combined organic extracts by concentration

under reduced pressure using an evaporator with bath at 35e45 ^ꢁC.

Me

O

B

Br

c,d

a,b

Me

19

O

Me

MPMO

I

HO

47

48

Me

OMOM

e,f

g

+

48

Me

TBSO

49

OHC

Me

TBSO

50

TBSO

Me

HO

Me

H

Me

H

h-j

OMOM

Me

OMOM

Me

4.2. Total synthesis of (D)-spiculoic acid A (1)

Me

H

MOMO

OHC

Me

51

4.2.1. Ethyl (2E,4S)-4-(tert-butyldimethylsilyloxy)methyl-2-ethyl-hex-

2-enoate (12). The following reaction was carried out under argon.

To a cooled (ꢀ78 ^ꢁC), stirred solution of oxalyl chloride (1.9 mL,

22 mmol) in CH₂Cl₂(50 mL) was added dropwise DMSO (3.1 mL,

43 mmol). The mixture was stirred at ꢀ78 ^ꢁC for 30 min and then

a solution of 10 (3.05 g, 14.0 mmol) in CH₂Cl₂(3.4 mL) was added.

The mixture was stirred at ꢀ78 ^ꢁC for 1 h and then Et₃N (12 mL,

86 mmol) was added. The mixture was warmed gradually to room

temperature and then stirred for 1 h. The mixture was diluted with

H₂O (120 mL) at 0 ^ꢁC and extracted with CH₂Cl₂(60 mLꢂ2). The

combined organic layers were washed with saturated aqueous

NaHCO₃(40 mL) and H₂O (40 mLꢂ2), dried, and concentrated under

reduced pressure to give crude 11, which was used in the next step

without further puriﬁcation.

52

Me

H

k-m

n,o

6

OH

Me

HO

H

Me

53

Scheme 5. Total synthesis of (þ)-zyggomphic acid (6). Reagents and conditions: (a)

NaIO₄, acetone/H₂O¼4:1, rt; (b) 1,1-(dibromoethyl)triphenylphosphonium bromide,

n-BuLi, THF, ꢀ78 ^ꢁC, 41% over two steps; (c) bis(pinacolato)diboron, PdCl₂(PPh₃)₂, PPh₃,

PhOK, toluene, 50 ^ꢁC, 50%; (d) DDQ, CH₂Cl₂, aq phosphate buffer, rt, 60%; (e)

PdCl₂(dppf) (cat), 3 M aq NaOH, degassed THF, rt, 72%; (f) DesseMartin periodinane,

CH₂Cl₂, rt, 88%; (g) degassed toluene, BHT (cat.), Wako Gel C-300, rt, 21 h, 74%; (h)

NaBH₄, MeOH/THF¼1:1, rt, 81%; (i) MOMCl, i-Pr₂NEt, CH₂Cl₂, reﬂux, 89%; (j) n-Bu₄NF,

THF, rt, 93%; (k) DesseMartin periodinane, CH₂Cl₂, rt; (l) diethyl benzylphoshonate,

n-BuLi, THF, ꢀ78 ^ꢁC then aldehyde, 0 ^ꢁC, 78% over two steps; (m) CSA, MeOH, 40 ^ꢁC, 5

days; (n) DesseMartin periodinane, NaHCO₃, CH₂Cl₂, rt, 86% over two steps; (o)

NaClO₂, 2-methyl-2-butene, phosphate buffer, t-BuOH/H₂O¼5:1, rt, 68%.

The following reaction was carried out under argon. To a stirred

solution of the crude 11 obtained above in toluene (30 mL)

was added 1-[(ethoxycarbonyl)propylidene]triphenylphosphorane

(13.5 g, 35.8 mmol). The mixture was reﬂuxed for 40 h. After being

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6735

cooled to room temperature, the mixture was concentrated under

reduced pressure. The residue was puriﬁed by column chromatog-

raphy on silica gel (EtOAc/hexane, 1:200) to provide 3.74 g (85% for

two steps) of 12 (E/Z¼>20:1,¹H NMR) as a pale yellowoil: TLC R_f0.46

1H), 1.39e1.56 (m, 1H), 1.67 (br s, 1H), 2.07e2.25 (m, 2H), 2.43e2.55

(m, 1H), 3.38 (dd, J¼8.3, 10.4 Hz, 1H), 3.56 (dd, J¼5.6, 10.4 Hz, 1H),

3.81 (s, 3H), 3.96 (s, 2H), 4.41 (s, 2H), 5.11 (d, J¼10.2 Hz, 1H),

6.86e6.91 (m, 2H), 7.24e7.29 (m, 2H); ¹³C NMR (68 MHz, CDCl₃)

(EtOAc/hexane,1:5); [

a

]

²⁶þ16.4 (c 1.53, CHCl₃); ¹H NMR (300 MHz,

d 11.7, 13.3, 21.5, 24.4, 42.3, 55.2, 66.3, 71.3, 73.4, 113.7 (2C), 128.9,

D

CDCl₃)

d

0.02 (s, 3H), 0.03 (s, 3H), 0.87 (t, J¼7.5 Hz, 3H), 0.88 (s, 9H),

129.3 (2C),130.4, 141.5,159.1; IR (neat) 3270, 2960, 2890,1615,1515,

1455 cm^ꢀ1; HRMS calcd for C₁₇H₂₆O₃[M]^þ278.1882, found

278.1870.

1.02 (t, J¼7.5 Hz, 3H), 1.30 (t, J¼7.2 Hz, 3H), 1.57e1.69 (m, 2H),

2.27e2.40 (m, 2H), 2.43e2.57 (m,1H), 3.48e3.59 (m, 2H), 4.12e4.27

(m, 2H), 6.47 (d, J¼10.8 Hz, 1H); ¹³C NMR (68 MHz, CDCl₃)

d

ꢀ5.5,

ꢀ5.4, 11.8 (2C), 14.3 (2C), 20.4, 24.0, 25.9 (3C), 43.3, 60.2, 65.9, 135.2,

4.2.5. (2S,3E)-2-Ethyl-4-(4-methoxybenzyloxy)methylhex-3-enal

(16). The following reaction was carried out under argon. To

a cooled (ꢀ78 ^ꢁC), stirred solution of oxalyl chloride (0.72 mL,

8.4 mmol) in CH₂Cl₂(20 mL) was added dropwise DMSO (1.2 mL,

17 mmol). The mixture was stirred at ꢀ78 ^ꢁC for 40 min and a so-

lution of 15 (1.33 g, 4.78 mmol) in CH₂Cl₂(2.8 mL) was added. The

mixture was stirred at ꢀ78 ^ꢁC for 1 h and Et₃N (4.7 mL, 34 mmol)

was added. The mixture was warmed gradually to room tempera-

ture and stirred for 1 h. The mixture was diluted with H₂O (30 mL)

at 0 ^ꢁC and extracted with CH₂Cl₂(15 mLꢂ3). The combined organic

layers were washed with saturated aqueous NaHCO₃(10 mL) and

brine (10 mL), dried, and concentrated under reduced pressure. The

residue was puriﬁed by column chromatography on silica gel

143.5, 167.8; IR (neat) 2980, 2935, 2860, 1715, 1650, 1460 cm^ꢀ1

;

HRMS calcd for C₁₃H₂₅O₃Si [Mꢀt-Bu]^þ257.1573, found 257.1573.

4.2.2. (2E,4S)-4-(tert-Butyldimethylsilyloxy)methyl-2-ethylhex-2-en-

1-ol (13). The following reaction was carried out under argon. To

a cooled (ꢀ78 ^ꢁC), stirred solution of 12 (3.74 g, 11.9 mmol) in

CH₂Cl₂(75 mL) was added DIBAL-H (36 mL of 0.99 M solution in

toluene, 36 mmol). The mixture was stirred at ꢀ78 ^ꢁC for 40 min

and quenched with H₂O (5 mL) at ꢀ78 ^ꢁC. This was diluted with

aqueous solution (150 mL) of potassium sodium (þ)-tartrate tet-

rahydrate (50.4 g) and warmed to room temperature. The mixture

was stirred vigorously for 3.5 h, diluted with H₂O (75 mL), and

extracted with CH₂Cl₂(60 mLꢂ2). The combined organic layers

were dried and concentrated under reduced pressure. The residue

was puriﬁed by column chromatography on silica gel (EtOAc/hex-

(EtOAc/hexane, 1:35) to provide 1.26 g (95%) of 16 as a colorless oil:

24.5

TLC R_f0.50 (EtOAc/hexane, 1:3); [

NMR (300 MHz, CDCl₃)

a

]

þ43.9 (c 1.18, CHCl₃); ¹H

D

d

0.93 (t, J¼7.5 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H),

ane, 1:40 to 1:5) to provide 3.08 g (95%) of 13 as a colorless oil: TLC

1.45e1.59 (m, 1H), 1.75e1.89 (m, 1H), 2.15 (q, J¼7.5 Hz, 2H),

3.12e3.21 (m, 1H), 3.81 (s, 3H), 3.98 (s, 2H), 4.41 (s, 2H), 5.25 (d,

J¼9.9 Hz, 1H), 6.86e6.91 (m, 2H), 7.24e7.28 (m, 2H), 9.50 (d,

R_f0.72 (EtOAc/hexane, 1:5); [

(300 MHz, CDCl₃)

a]

þ28.4 (c 1.89, CHCl₃); ¹H NMR

25

D

d

0.03 (s, 6H), 0.85 (t, J¼7.4 Hz, 3H), 0.88 (s, 9H),

1.01 (t, J¼7.6 Hz, 3H), 1.09e1.18 (m, 1H), 1.29 (br s,1H), 1.58e1.66 (m,

1H), 2.13 (dq, J¼2.4, 7.6 Hz, 2H), 2.34e2.44 (m, 1H), 3.46 (d,

J¼6.6 Hz, 2H), 4.07 (s, 2H), 5.10 (d, J¼10.0 Hz, 1H); ¹³C NMR

J¼2.7 Hz, 1H); ¹³C NMR (68 MHz, CDCl₃)

d 11.5, 13.1, 21.8, 22.6, 53.3,

55.3, 71.5, 72.8, 113.8 (2C), 121.4, 129.3 (2C), 130.3, 143.8, 159.2,

201.3; IR (neat) 2960, 2940, 2880, 1725, 1615, 1515, 1460 cm^ꢀ1

HRMS calcd for C₁₇H₂₄O₃[M]^þ276.1726, found 276.1722.

;

(68 MHz, CDCl₃)

d

ꢀ5.4 (2C), 11.7 (2C), 13.6, 21.4, 24.4, 25.9 (3C),

42.0, 66.7 (2C), 127.7, 142.3; IR (neat) 3340, 2880, 2860, 1460 cm^ꢀ1

;

HRMS calcd for C₁₁H₂₃O₂Si [Mꢀt-Bu]^þ257.1467, found 257.1468.

4.2.6. (3S,4S,5S,6E)-5-Ethyl-7-(4-methoxybenzyloxy)methyl-4-me-

thoxymethoxy-3-methylnona-1,6-diene (18). The following reaction

wascarried out under argon. To a cooled (ꢀ100 ^ꢁC), stirred suspension

of t-BuOK (2.04 g, 18.2 mmol) and trans-2-butene (excess) in THF

(15 mL) was added dropwise n-BuLi (5.7 mL of 2.73 M solution in

hexane, 15 mmol). The mixture was stirred at ꢀ50 ^ꢁC for 15 min.

The resulting solution was cooled to ꢀ100 ^ꢁC, and a solution of

(ꢀ)-B-methoxydiisopinocampheylborane (4.89 g, 15.5 mmol) in THF

(15 mL) was added. The mixture was stirred at ꢀ78 ^ꢁC for 30 min, and

BF₃$OEt₂(2.7mL, 21mmol)was addeddropwise. Thenasolutionof 16

(1.26g, 4.55 mmol) in THF (3.5 mL) was added dropwise. After being

stirred at ꢀ78 ^ꢁC for 20 h, to the mixture were added 3 M aqueous

NaOH (50 mL) and 35% H₂O₂(25 mL), and the resulting mixture was

reﬂuxed for 1 h. After being cooled to room temperature, the mixture

was extracted with EtOAc (30 mLꢂ3). The combined organic layers

were washed with H₂O (20 mL) and brine (20 mL), dried, and con-

centrated under reduced pressure. The residue was puriﬁed by col-

umn chromatography on silica gel (acetone/hexane, 1:30) to provide

5.45 g of an inseparable mixture of 17, one diastereomer (dr¼ca. 3:1),

and IpcOH. By further column chromatographic puriﬁcation, 5.17 g of

an inseparable mixture of 17 and (ꢀ)-IpcOH was obtained as a color-

less oil, which was used in the next step.

4.2.3. (3E,5S)-5-(tert-Butyldimethylsilyloxy)methyl-3-(4-methox-

ybenzyloxy)methylhept-3-ene (14). To a cooled (0 ^ꢁC), stirred solu-

tion of 13 (3.08 g, 11.3 mmol) in DMF (62 mL) was added NaH (60%

in oil, 839 mg, 20.8 mmol). The mixture was stirred at 0 ^ꢁC for

10 min and MPMCl (3.8 mL, 28 mmol) and n-Bu₄NI (10.5 g,

28.3 mmol) were added at 0 ^ꢁC. The mixture was stirred at room

temperature for 21 h, diluted with saturated aqueous NaHCO₃

(120 mL), and extracted with Et₂O (120 mLꢂ3). The combined or-

ganic layers were washed with H₂O (60 mLꢂ3), dried, and con-

centrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:150) to

provide 4.16 g (94%) of 14 as a colorless oil: TLC R_f0.58 (EtOAc/

23.5

hexane, 1:6); [

CDCl₃)

a]

þ19.2 (c 1.44, CHCl₃); ¹H NMR (300 MHz,

D

d

0.03 (s, 6H), 0.87 (t, J¼7.5 Hz, 3H), 0.88 (s, 9H), 1.00 (t,

J¼7.5 Hz, 3H), 1.05e1.17 (m, 1H), 1.57e1.70 (m, 1H), 2.14 (q, J¼7.5 Hz,

2H), 2.35e2.48 (m, 1H), 3.44 (dd, J¼6.4, 9.8 Hz, 1H), 3.49 (dd, J¼6.4,

9.8 Hz, 1H), 3.80 (s, 3H), 3.96 (s, 2H), 4.38 (s, 2H), 5.10 (d, J¼10.0 Hz,

1H), 6.85e6.90 (m, 2H), 7.24e7.29 (m, 2H); ¹³C NMR (68 MHz,

CDCl₃)

d

ꢀ5.3 (2C), 11.8 (2C), 13.3, 21.4, 24.5, 25.9 (3C), 42.2, 55.2,

66.7, 70.8, 73.7, 113.7 (2C), 129.3 (3C), 130.0, 139.2, 159.0; IR (neat)

2940, 2860, 1615, 1515, 1460 cm^ꢀ1; HRMS calcd for C₁₉H₃₁O₃Si

[Mꢀt-Bu]^þ335.2043, found 335.2042.

To a stirred solution of the mixture obtained above in CH₂Cl₂

(100 mL) were added i-Pr₂NEt (27 mL, 0.16 mol) and MOMCl

(5.9 mL, 78 mmol). The mixture was reﬂuxed for 14 h, diluted with

saturated aqueous NH₄Cl (200 mL), and extracted with CH₂Cl₂

(100 mLꢂ3). The combined organic layers were dried and con-

centrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:50 to 1:20)

4.2.4. (2S,3E)-2-Ethyl-4-(4-methoxybenzyloxy)methylhex-3-en-1-ol

(15). A solution of 14 (4.16 g, 10.6 mmol) in AcOH/THF/H₂O (3:2:1,

84 mL) was stirred at room temperature for 21.5 h and concentrated

under reduced pressure with the aid of EtOH and toluene. The

residue was chromatographed on silica gel (EtOAc/hexane, 1:40 to

1:8) to provide 2.55 g (87%) of 15 as a colorless oil: TLC R_f0.25

to provide 1.11 g (65% for two steps) of 18 as a colorless oil: TLC R_f

23

0.50 (EtOAc/hexane, 1:4);

NMR(300 MHz, CDCl₃)

[

a

]

D

þ7.5 (c 2.23, CHCl₃); ¹H

(EtOAc/hexane, 1:3); [

a

]

²²þ9.8 (c 1.62, CHCl₃); ¹H NMR (300 MHz,

d

0.83 (t, J¼7.4 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H),

D

CDCl₃)

d

0.89 (t, J¼7.5 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 1.12e1.27 (m,

1.07 (d, J¼7.2 Hz, 3H), 1.12e1.28 (m, 1H), 1.69e1.81 (m, 1H),

6736

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

2.03e2.23 (m, 2H), 2.41e2.51 (m, 2H), 3.22 (dd, J¼3.3, 7 5 Hz, 1H),

3.41 (s, 3H), 3.81 (s, 3H), 3.96 (s, 2H), 4.38 (s, 2H), 4.65 (d, J¼6.9 Hz

1H), 4.68 (d, J¼6.9 Hz, 1H), 4.96e5.04 (m, 2H), 5.12 (d, J¼10.5 Hz,

1H), 5.88 (ddd, J¼7.2, 9.9,17.7 Hz,1H), 6.88 (d, J¼8.4 Hz, 2H), 7.26 (d,

d

0.84 (t, J¼7.5 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.03 (d, J¼7.2 Hz, 3H),

1.07 (t, J¼7.5 Hz, 3H), 1.19e1.34 (m, 1H), 1.62e1.79 (m, 1H),

1.98e2.32 (m, 3H), 2.35e2.55 (m,2H), 2.57e2.70 (m, 1H), 3.22 (dd,

J¼3.9, 6.9 Hz, 1H), 3.40 (s, 3H), 3.81 (s, 3H), 3.95 (s,2H), 4.40 (s, 2H),

4.64 (d, J¼7.1 Hz, 1H), 4.67 (d, J¼7.1 Hz, 1H), 5.13 (d, J¼10.2 Hz, 1H),

5.89 (d, J¼9.6 Hz, 1H), 6.86e6.89 (m, 2H), 7.24e7.27 (m, 2H); ¹³C

J¼8.4 Hz, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 11.9, 12.6, 18.2, 21.6, 23.6,

40.8, 42.8, 55.2, 56.1, 71.0, 73.4, 87.0, 98.5, 113.7 (2C), 114.8, 129.2

(2C), 129.4, 130.7, 138.9, 140.4, 159.1; IR (neat) 2960, 2930,

1615,1515 cm^ꢀ1; HRMS calcd for C₂₃H₃₆O₄[M]^þ376.2614, found

376.2617.

NMR (68 MHz, CDCl₃)

d 11.9, 12.7, 13.4, 18.6, 21.5, 23.6, 29.3, 37.5,

42.6, 55.3, 56.2, 71.2, 73.5, 86.2, 98.3, 113.7 (2C), 127.9, 128.7 (2C),

129.2 (2C), 133.6, 139.2, 159.1; IR (neat) 2960, 1615, 1515 cm^ꢀ1

HRMS calcd for C₂₅H₃₉O₄Br [M]^þ482.2032, found 482.2020.

;

4.2.7. (2RS,3S,4R,5S,6E)-5-Ethyl-7-(4-methoxybenzyloxy)methyl-4-

methoxymethoxy-3-methylnon-6-ene-1,2-diol (19 as a ca. 3:1 di-

astereomeric mixture). To a stirred solution of 18 (1.11 g, 2.95 mmol)

in acetone/H₂O (6:1, 35 mL) were added OsO₄(3.0 mL of 0.05 M

solution in t-BuOH, 0.15 mmol) and NMO (995 mg, 8.49 mmol). The

mixturewas stirred at room temperature for 6 h and additional OsO₄

(1.5 mL of 0.05 M solution in t-BuOH, 75 mmol) was added. The

mixture was stirred at room temperature for 2 h and additional

NMO (350 mg, 2.99 mmol) was added. The mixture was stirred at

room temperature for additional 1.5 h, quenched with 1 M aqueous

NaHSO₃(55 mL) at 0 ^ꢁC, ﬁltered through cotton, and washed with

EtOAc. The combined ﬁltrate and washings were extracted with

EtOAc (30 mLꢂ3), dried, and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography on silica gel

4.2.9. 2-[(3Z,5S,6S,7S,8E)-7-Ethyl-9-(4-methoxybenzyloxy)-methyl-

6-methoxymethoxy-5-methylundeca-3,8-dien-3-yl]-4,4,5,5-tetra-

methyl-1,3,2-dioxaborolane (22). The following reaction was

carried out under argon. To a stirred solution of 21 (1.01 g,

2.09 mmol) in toluene (40 mL) were added bis(pinacolato)diboron

(1.19 g, 4.69 mmol), PdCl₂(PPh₃)₂(117 mg, 0.170 mmol), PPh₃

(91.4 mg, 0.348 mmol), and KOPh (670 mg, 5.07 mmol). The mix-

ture was stirred at 50 ^ꢁC for 5 h and additional bis(pinacolato)

diboron (265 mg, 1.05 mmol) and KOPh (60 mg, 0.45 mmol) were

added. The mixture was stirred at 50 ^ꢁC for 2 h and then additional

bis(pinacolato)diboron (159 mg, 0.626 mmol) and KOPh (80 mg,

0.61 mmol) were added. The mixture was stirred at 50 ^ꢁC for 1 h.

After being cooled to room temperature, the mixture was diluted

with H₂O (50 mL) and extracted with EtOAc (50 mL). The organic

layer was washed with 2 M aqueous NaOH (30 mLꢂ2) and brine

(30 mL), dried, and concentrated under reduced pressure. The

residue was puriﬁed by column chromatography on silica gel

(EtOAc/hexane, 2:1 to 1:2) to provide 1.11 g (92%) of 19 as a pale

21

yellow oil: TLC R_f0.35 (EtOAc/hexane, 2:1); [

a]

ꢀ14.7 (c 0.98,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃) for major isomer

d

0.85

(t, J¼7.5 Hz, 3H), 0.92 (d, J¼6.9 Hz, 3H), 1.00 (t, J¼7.5 Hz, 3H),

1.11e1.28 (m, 1H), 1.64e1.84 (m, 1H), 1.89e2.02 (m, 1H), 2.09e2.22

(m, 2H), 2.51e2.61 (m, 1H), 3.31e3.53 (m, 2H), 3.42 (s, 3H),

3.64e3.73 (m, 2H), 3.81 (s, 3H), 3.96 (s, 2H), 4.39 (s, 2H), 4.69 (s, 2H),

5.19 (d, J¼10.2 Hz, 1H), 6.88 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼8.4 Hz, 2H);

(EtOAc/hexane, 1:50 to 1:20) to provide 862 mg (78%) of 22 as

18.5

a colorless oil: TLC R_f0.35 (EtOAc/hexane, 1:5); [

a

]

D

þ20.9 (c

1.55, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.84 (t, J¼7.5 Hz, 3H), 0.94

(t, J¼7.5 Hz, 3H), 0.98 (t, J¼7.5 Hz, 3H), 1.01 (d, J¼6.9 Hz, 3H),

1.19e1.32 (m, 1H), 1.23 (s, 6H), 1.24 (s, 6H), 1.66e1.76 (m, 1H),

1.99e2.21(m, 4H), 2.39e2.49 (m, 1H), 2.78e2.90 (m, 1H), 3.23 (t,

J¼5.7 Hz, 1H), 3.38 (s, 3H), 3.80(s, 3H), 3.91 (d, J¼12.0 Hz, 1H), 3.99

(d, J¼12.0 Hz, 1H), 4.35 (d, J¼11.4 Hz, 1H), 4.40(d, J¼11.4 Hz, 1H),

4.65 (s, 2H), 5.18 (d, J¼10.2 Hz, 1H), 6.28 (d, J¼9.3 Hz, 1H),6.86e6.90

¹³C NMR (68 MHz, CDCl₃) for major isomer

d 12.1, 12.7, 14.7, 21.6,

23.2, 38.4, 43.2, 55.3, 56.4, 64.8, 71.2, 73.3, 74.3, 87.2, 98.4,113.7 (2C),

129.3 (3C),130.5,139.5,159.1; IR (neat) 3500, 2960,1615,1515 cm^ꢀ1

;

HRMS calcd for C₂₃H₃₇O₆[MꢀH]^þ409.2590, found 409.2579.

4.2.8. (3E,5S,6S,7S,8E)-3-Bromo-7-ethyl-9-(4-methoxybenzyl-oxy)

methyl-6-methoxymethoxy-5-methylundeca-3,8-diene (21). To a co-

oled (0 ^ꢁC), stirred solution of the 3:1 diastereomeric mixture 19

(1.11 g, 2.70 mmol) in acetone/H₂O (4:1, 35 mL) was added NaIO₄

(1.56 g, 7.29 mmol). The mixture was stirred at room temperature

for 30 min and additional NaIO₄(288 mg, 1.35 mmol) was added at

(m, 2H), 7.24e7.27 (m, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 12.0, 12.7,

14.9, 18.1, 21.5, 22.1, 23.3, 24.5 (2C), 24.9 (2C), 35.8, 42.2, 55.2, 56.1,

70.8, 73.7, 82.8, 86.4 (2C), 98.0, 113.7 (2C), 129.2 (2C), 129.3, 129.8,

130.8, 138.4, 147.1, 159.0; IR (neat) 2960, 1615, 1515 cm^ꢀ1; HRMS

calcd for C₃₁H₅₁BO₆[M]^þ530.3779, found 530.3770.

0

^ꢁC. The mixture was stirred at room temperature for 20 min,

4.2.10. 2-[(3Z,5S,6S,7S,8E)-7-Ethyl-9-hydroxymethyl-6-methox-

ymethoxy-5-methylundeca-3,8-dien-3-yl]-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (23). To a cooled (0 ^ꢁC), stirred solution of 22

(862 mg, 1.62 mmol) in CH₂Cl₂(18 mL) were added aqueous

quenched with 1 M aqueous NaHSO₃(55 mL), and extracted with

EtOAc (30 mLꢂ3). The combined organic layers were washed with

saturated aqueous NaHCO₃(30 mL) and brine (30 mL), dried, and

concentrated under reduced pressure to provide 977 mg of crude

(2R,3R,4S,5E)-4-ethyl-6-(4-methoxybenzyloxy)methyl-3-methox-

ymethoxy-2-methyloct-5-enal (20), which was used in the next

step without further puriﬁcation.

phosphate buffer (0.5

M aqueous Na₂HPO₄/0.5 M aqueous

NaH₂PO₄, 2:1, 2.0 mL) and DDQ (1.10 g, 4.86 mmol). The mixture

was stirred at room temperature for 1 h, diluted with saturated

aqueous NaHCO₃(35 mL), and extracted with CH₂Cl₂(20 mLꢂ3).

The combined organic layers were dried and concentrated under

reduced pressure. The residue was puriﬁed by column chroma-

tography on silica gel (EtOAc/hexane, 1:30 to 1:10) to provide

525 mg (79%) of 23 as a colorless oil: TLC R_f0.30 (EtOAc/hexane,

The following reaction was carried out under argon. To a cooled

(ꢀ40 ^ꢁC), stirred suspension of (1,1-dibromopropyl)triphenyl-

phosphonium bromide (6.31 g, 11.6 mmol) in Et₂O (30 mL) was

added n-BuLi (4.0 mL of 2.73 M solution in hexane, 11 mmol). The

mixture was stirred at ꢀ40 ^ꢁC for 40 min and cooled to ꢀ78 ^ꢁC.

Then a solution of the crude 20 obtained above (977 mg) in Et₂O

(3.0 mL) was added dropwise. The mixture was stirred at ꢀ78 ^ꢁC for

1.5 h, quenched with H₂O (5 mL), diluted with saturated aqueous

NaHCO₃(40 mL) and H₂O (200 mL), and extracted with EtOAc

(80 mLꢂ3).The combined organic layers were washed with satu-

rated aqueous NaHCO₃(40 mL), dried, and concentrated under

reduced pressure. The residue was puriﬁed by column chroma-

tography on silica gel (EtOAc/hexane, 1:100 to 1:50) to provide

1.01 g (77% for two steps) of 21 as a colorless oil: TLC R_f0.47 (EtOAc/

1:4); [

a

]

^19.5þ81.6 (c 1.05, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.80

D

(t, J¼7.5 Hz, 3H), 0.98 (t, J¼7.5 Hz, 3H), 1.01 (d, J¼7.2 Hz, 3H), 1.02 (t,

J¼7.5 Hz, 3H), 1.06e1.19 (m, 1H), 1.26 (s, 6H), 1.27 (s, 6H), 1.69e1.82

(m, 1H), 2.05e2.29(m, 4H), 2.40e2.51 (m, 1H), 2.92e3.03 (m, 1H),

3.34 (dd, J¼3.3, 8.1 Hz, 1H), 3.42 (s, 3H),3.96 (d, J¼13.5 Hz, 1H), 4.10

(d, J¼13.5 Hz, 1H), 4.68 (d, J¼6.9 Hz, 1H), 4.74 (d, J¼6.9 Hz, 1H), 4.96

(d, J¼10.8 Hz, 1H), 6.08 (d, J¼8.7 Hz, 1H); ¹³C NMR (68 MHz, CDCl₃)

d

11.5, 12.6, 14.9, 15.1, 21.3, 22.0, 24.3 (2C), 24.6, 24.7 (2C), 35.9, 41.1,

55.9, 66.0,83.3, 85.5 (2C), 97.0, 127.0 (2C), 140.6, 148.7; IR (neat)

3500, 2970, 1630 cm^ꢀ1; HRMS calcdforC₂₃H₄₃BO₅[M]^þ410.3204,

found 410.3215.

hexane, 1:5); [

a

]

²¹þ5.4 (c 1.33, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

D

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6737

4.2.11. (2E,4S,5S,6S,7E,9E)-10-(tert-Butyldimethylsilyloxy)-methyl-

2,4,8-triethyl-5-methoxymethoxy-6-methyldodeca-2,7,9-trien-1-ol

(25). The following reaction was carried out under argon. To a stirred

4.2.14. (1R,2Z,4S,5R,6R,7S,8S,9S)-4-(tert-Butyldimethylsilyloxy)

methyl-2,4,5,7-tetraethyl-5-hydroxymethyl-8-methoxymethoxy-9-

methylbicyclo[4.3.0]non-2-ene (29). To a cooled (0 ^ꢁC), stirred solu-

tion of 27 (55.6 mg, 0.116 mmol) in MeOH/THF (1:1, 2.0 mL) was

addedNaBH₄(15.0mg, 0.397mmol). Themixturewasstirredatroom

temperature for 2.5 h and additional NaBH₄(13.2 mg, 0.348 mmol)

was added at 0 ^ꢁC. The mixture was stirred at room temperature for

1 h and additional NaBH₄(13.2 mg, 0.348 mmol) was added at 0 ^ꢁC.

The mixture was stirred at room temperature for 1 h and additional

NaBH₄(13.2 mg, 0.348 mmol) was added at 0 ^ꢁC. The mixture was

stirred at room temperature for additional 1.5 h, quenched with

saturated aqueous NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with EtOAc

(5 mLꢂ3). The combined organic layers were dried and concentrated

under reduced pressure. The residue was puriﬁed by column chro-

matography on silica gel (EtOAc/hexane, 1:60 to 1:50) to provide

51.0 mg (91%) of 29 as a colorless oil: TLC R_f0.50 (EtOAc/hexane,1:5);

solution of 23 (16.6 mg, 40.4

mmol) and 24 (34.6 mg, 0.106 mmol) in

degassed THF (4.2 mL) were added 3 M aqueous NaOH (80

mL,

0.24 mmol) and PdCl₂(dppf) (3.3 mg, 4.0 mmol). The mixture was

stirred at room temperature for 53.5 h, diluted with saturated aqueous

NH₄Cl (10 mL), and extracted with EtOAc (5 mLꢂ3). The combined

organic layers were dried and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography on silica gel

(EtOAc/hexane,1:150to1:15)toprovide13.8mg(71%from23)of25as

25

a colorless oil: TLC R_f0.17 (EtOAc/hexane, 1:5); [

a

]

þ57.6 (c 1.18,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.07 (s, 6H), 0.82 (t, J¼7.5 Hz, 3H),

0.92 (s, 9H), 0.93 (t, J¼7.5 Hz, 3H), 0.98 (t, J¼7.8 Hz, 3H),1.01 (t, J¼7.5 Hz,

3H), 1.04 (d, J¼6.6 Hz, 3H), 1.12e1.28 (m, 1H), 1.66e1.79 (m, 1H),

1.85e1.96 (m, 1H), 1.97e2.08 (m, 1H), 2.09e2.23 (m, 4H), 2.35e2.45

(m,1H), 2.65e2.76 (m,1H), 3.22(dd, J¼4.2, 6.6Hz,1H), 3.39(s, 3H), 4.06

(s, 2H), 4.12 (d, J¼1.5 Hz, 2H), 4.64 (d, J¼6.6 Hz, 1H), 4.66 (d, J¼6.6 Hz,

1H), 5.14 (d, J¼9.9 Hz, 1H), 5.28 (d, J¼9.6 Hz, 1H), 5.80 (br s, 1H); ¹³C

[a]

²²ꢀ25.1 (c 1.51, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.13 (s, 3H),

D

0.14 (s, 3H), 0.92 (t, J¼7.5 Hz, 3H), 0.94 (s, 9H), 0.95 (t, J¼7.5 Hz, 3H),

1.01 (t, J¼7.5 Hz, 3H), 1.02 (t, J¼7.5 Hz, 3H), 1.24 (d, J¼6.9 Hz, 3H),

1.30e1.38 (m, 2H), 1.41e1.53 (m, 2H), 1.56e1.69 (m, 2H), 1.80e1.91

(m, 2H),1.96e2.21 (m, 3H), 2.33 (t, J¼11.4 Hz,1H), 3.34 (d, J¼10.8 Hz,

1H), 3.37 (s, 3H), 3.54 (dd, J¼5.3, 9.2 Hz, 1H), 3.62 (d, J¼4.5 Hz, 1H),

3.64e3.73 (m, 2H), 3.79 (d, J¼10.8 Hz,1H), 4.53 (d, J¼6.9 Hz,1H), 4.69

NMR (68 MHz, CDCl₃)

d

ꢀ5.3 (2C), 11.9, 12.8, 13.3, 13.6, 18.4, 19.1, 21.4,

21.6, 23.4, 24.2, 25.9 (3C), 35.6, 42.4, 55.9, 66.3, 66.6, 87.5, 98.3, 126.2,

128.0,129.8,137.7,141.1, 141.2; IR (neat) 3430, 2960, 2930,1460 cm^ꢀ1

;

HRMS calcd for C₂₈H₅₄O₄Si [M]^þ482.3791, found 482.3792.

(d, J¼6.9 Hz, 1H), 4.94 (br s, 1H); ¹³C NMR (68 MHz, CDCl₃)

d

ꢀ5.9,

4.2.12. (2E,4S,5S,6S,7E,9E)-10-(tert-Butyldimethylsilyloxy)-methyl-

2,4,8-triethyl-5-methoxymethoxy-6-methyldodeca-2,7,9-trienal

ꢀ5.8, 8.8, 9.5,12.7,13.2,14.7,18.2, 21.9, 25.9 (4C), 28.4, 29.2, 40.7, 44.1,

44.6, 44.9, 49.4, 52.8, 55.4, 64.4, 65.2, 86.3, 93.8,123.9,144.8; IR (neat)

3520, 2960, 2880, 1470 cm^ꢀ1; HRMS calcd for C₂₈H₅₄O₄Si [M]^þ

482.3791, found 482.3777.

(26). To a stirred solution of 25 (13.3 mg, 27.5

mmol) in CH₂Cl₂

(1.0 mL) was added MnO₂(66.5 mg). The mixture was stirred at

room temperature for 30 min, ﬁltered through a pad of Celite, and

washed well with CH₂Cl₂. The combined ﬁltrate and washings were

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:40) to pro-

vide 12.8 mg (97%) of 26 as a colorless oil: TLC R_f0.45(EtOAc/hexane,

4.2.15. (1R,2Z,4S,5R,6R,7S,8S,9S)-4-(tert-Butyldimethylsilyloxy)

methyl-2,4,5,7-tetraethyl-8-methoxymethoxy-5-(methoxymethoxy)

methyl-9-methylbicyclo[4.3.0]non-2-ene (30). To a stirred solution

of 29 (48.7 mg, 0.10 mmol) in CH₂Cl₂(2.0 mL) were added i-Pr₂NEt

1:5); [

a

]

²⁶þ52.6(c 0.59, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.07 (s,

(40 mL, 0.50 mmol) and MOMCl (0.18 mL, 1.0 mmol). The mixture

D

6H), 0.85 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H), 0.92 (t, J¼7.5 Hz, 3H), 0.97 (t,

J¼7.5 Hz, 3H), 1.00 (t, J¼7.5 Hz, 3H), 1.06 (d, J¼6.9 Hz, 3H), 1.34e1.49

(m, 1H), 1.78e1.95 (m, 2H), 2.06e2.29 (m, 5H), 2.61e2.78 (m, 2H),

3.36 (dd, J¼2.1, 4.2 Hz,1H), 3.40 (s, 3H), 4.12 (d, J¼1.5 Hz, 2H), 4.65 (d,

J¼6.9 Hz,1H), 4.68 (d, J¼6.9 Hz,1H), 5.27 (d, J¼9.6 Hz,1H), 5.79 (br s,

1H), 6.26 (d, J¼10.5 Hz, 1H), 9.37 (s, 1H); ¹³C NMR (68 MHz, CDCl₃)

was reﬂuxed for 13 h, diluted with saturated aqueous NH₄Cl

(15 mL), and extracted with CH₂Cl₂(5 mLꢂ3). The combined organic

layers were dried and concentrated under reduced pressure. The

residue was puriﬁed by column chromatography on silica gel

(EtOAc/hexane, 1:100) to provide 52.7 mg (quantitative) of 30 as

a colorless oil: TLC R_f0.60 (EtOAc/hexane,1:6); [

a

]

^22.5þ10.4 (c 1.40,

D

d

ꢀ5.3 (2C), 12.0, 13.1, 13.3, 13.6, 17.9 (2C), 19.3, 21.7, 23.3, 24.3, 25.9

CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.01 (s, 3H), 0.02 (s, 3H), 0.89 (s,

(3C), 35.9, 44.2, 56.1, 66.2, 86.0, 98.2, 125.8, 128.7, 138.5, 141.4, 145.6,

155.9, 195.3; IR (neat) 2960, 2930, 1695, 1460 cm^ꢀ1; HRMS

calcd forC₂₈H₅₂O₄Si [M]^þ480.3635, found 480.3656.

9H), 0.90 (t, J¼7.5 Hz, 3H), 0.92e0.99 (m, 6H), 1.01 (t, J¼7.5 Hz, 3H),

1.23e1.33 (m, 1H), 1.24 (d, J¼6.9 Hz, 3H), 1.35e1.47 (m, 3H),

1.53e1.65 (m, 2H), 1.69e1.75 (m, 1H), 1.79e1.95 (m, 2H), 2.00e2.18

(m, 2H), 2.28 (t, J¼11.6 Hz, 1H), 3.38 (s, 6H), 3.41 (d, J¼10.7 Hz, 1H),

3.53 (d, J¼9.8 Hz, 1H), 3.57 (d, J¼9.8 Hz, 1H), 3.60 (d, J¼4.5 Hz, 1H),

3.83 (d, J¼10.7 Hz, 1H), 4.54 (d, J¼6.8 Hz, 1H), 4.55 (d, J¼6.5 Hz, 1H),

4.61 (d, J¼6.5 Hz,1H), 4.73 (d, J¼6.8 Hz,1H), 4.99 (br s,1H); ¹³C NMR

4.2.13. (1R,2Z,4S,5R,6R,7S,8S,9S)-4-(tert-Butyldimethylsilyloxy)

methyl-2,4,5,7-tetraethyl-5-formyl-8-methoxymethoxy-9-methyl-

bicyclo[4.3.0]non-2-ene (27). The following reaction was carried

out under argon. To a stirred solution of 26 (59.9 mg, 0.124 mmol)

in degassed toluene (12.4 mL) was added a crystal of BHT. The

mixture was stirred at 70 ^ꢁC for 5.5 days. After being cooled to room

temperature, the mixture was concentrated under reduced pres-

sure. The residue was puriﬁed by column chromatography on silica

gel (hexane, to EtOAc/hexane, 1:60) to provide 58.0 mg (97%) of

(68 MHz, CDCl₃)

d

ꢀ5.7, ꢀ5.6, 9.2,10.3,13.1,13.2,14.7,18.2, 22.5, 25.4,

25.9 (3C), 28.3, 29.1, 40.5, 43.4, 44.2, 45.4, 48.8, 54.3, 55.3, 55.6, 65.6,

70.9, 86.0, 93.6, 97.3, 124.8, 143.1; IR (neat)2960, 2880, 1470 cm^ꢀ1

HRMS calcd forC₃₀H₅₈O₅Si [M]^þ526.4054, found 526.4043.

;

4.2.16. (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-Tetraethyl-4-hydrox-

ymethyl-8-methoxymethoxy-5-(methoxymethoxy)methyl-9-methyl-

bicyclo[4.3.0]non-2-ene (31). To a cooled (0 ^ꢁC), stirred solution of

27as a colorless oil: TLC R_f0.61 (EtOAc/hexane, 1:5); [

a

]

^25.5þ13.0

D

(c 1.02, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.03 (s, 3H), 0.04 (s, 3H),

0.86 (t, J¼7.2 Hz, 3H), 0.88 (s, 9H), 0.93 (t, J¼7.5 Hz, 3H), 1.00 (t,

J¼7.5 Hz, 3H), 1.02 (t, J¼7.5 Hz, 3H), 1.06e1.19 (m, 1H), 1.24e1.35 (m,

3H), 1.25 (d, J¼6.6 Hz, 3H), 1.54e1.83 (m, 3H), 1.91e2.21 (m, 4H),

2.36 (t, J¼11.4 Hz, 1H), 3.36 (s, 3H), 3.36 (d, J¼10.8 Hz, 1H), 3.69 (d,

J¼5.1 Hz, 1H), 3.83 (d, J¼10.8 Hz, 1H), 4.53 (d, J¼6.8 Hz, 1H), 4.65 (d,

J¼6.8 Hz, 1H), 4.97 (br s, 1H), 9.71 (s, 1H); ¹³C NMR (68 MHz, CDCl₃)

30 (51.8 mg, 98.3 mmol) in THF (1.0 mL) was added n-Bu₄NF

(0.30 mL of 1.0 M solution in THF, 0.30 mmol). The mixture was

stirred at 50 ^ꢁC for 19.5 h, diluted with saturated aqueous NH₄Cl

(12 mL) at 0 ^ꢁC, and extracted with EtOAc (5 mLꢂ3). The combined

organic layers were dried and concentrated under reduced pres-

sure. The residue was puriﬁed by column chromatography on silica

gel (EtOAc/hexane, 1:30 to 1:10) to provide 40.3 mg (99%) of 31 as

d

ꢀ6.0, ꢀ5.8, 8.3,10.0,12.2,13.0,15.0,18.0, 20.9, 24.3, 25.6 (3C), 28.2,

28.3, 40.0, 45.5 (2C), 50.0, 51.3, 55.5, 56.3, 63.0, 85.4, 94.2, 122.2,

144.7, 204.5; IR (neat) 2960, 2920, 1715, 1470 cm^ꢀ1; HRMS calcd for

C₂₈H₅₂O₄Si [M]^þ480.3635, found 480.3650.

a colorless oil: TLC R_f0.19 (EtOAc/hexane, 1:6); [

a

]

²⁷ꢀ53.3 (c 0.94,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.98 (t, J¼7.5 Hz, 3H), 0.99 (t,

J¼7.5 Hz, 3H), 1.00 (t, J¼7.5 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 1.24 (d,

6738

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

J¼6.6 Hz, 3H), 1.31e1.55 (m, 4H), 1.59e1.80 (m, 3H), 1.81e1.87 (m,

1H),1.92e2.21 (m, 3H), 2.35 (t, J¼11.4 Hz,1H), 3.32 (br s,1H), 3.37 (s,

3H), 3.42 (s, 3H), 3.63 (dd, J¼4.2, 9.3 Hz, 1H), 3.70 (d, J¼10.2 Hz, 1H),

3.79 (d, J¼10.2 Hz, 1H), 3.83 (d, J¼10.2 Hz, 1H), 3.83 (d, J¼10.2 Hz,

1H), 4.53 (d, J¼6.9 Hz, 1H), 4.63 (d, J¼6.6 Hz, 1H), 4.67 (d, J¼6.6 Hz,

1H), 4.69 (d, J¼6.9 Hz, 1H), 5.02 (br s, 1H); ¹³C NMR (68 MHz, CDCl₃)

4.2.19. (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-Tetraethyl-8-hydroxy-5-hy-

droxymethyl-9-methyl-4-(1E)-styrylbicyclo-[4.3.0]non-2-ene

(34). To a stirred solution of 33 (32.9 mg, 67.9

(1.0 mL) was added CSA (79.0 mg, 0.340 mmol). The mixture was

stirred at 40 ^ꢁC for 60 h and additional CSA (8.0 mg, 34

mol) was

added. The mixture was stirred at 40 ^ꢁC for 25 h and additional CSA

(8.0 mg, 34

mol) was added. The mixture was stirred at 40 ^ꢁC for

mmol) in MeOH

m

d

9.0, 9.3, 12.6, 13.2, 14.7, 22.2, 25.5, 28.3, 29.1, 40.7, 43.2, 44.5, 45.0,

m

49.8, 52.6, 55.4, 56.1, 64.6, 70.6, 86.2, 93.8, 97.0, 124.5, 143.8; IR

(neat) 3500, 2960, 2880, 1470 cm^ꢀ1; HRMS calcd for C₂₄H₄₄O₅[M]^þ

412.3189, found 412.3189.

48 h, diluted with saturated aqueous NaHCO₃(10 mL), and

extracted with EtOAc (5 mLꢂ3). The combined organic layers were

dried and concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (EtOAc/hexane,

1:10 to 1:8) to provide 26.9 mg (quantitative) of 34 as a colorless

4.2.17. (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-Tetraethyl-4-formyl-8-me-

thoxymethoxy-5-(methoxymethoxy)methyl-9-methylbicyclo-[4.3.0]

non-2-ene (32). The following reaction was carried out under ar-

oil: TLC R_f0.09 (EtOAc/hexane, 1:4); [

NMR (300 MHz, CDCl₃)

a

]

²⁶þ3.9 (c 0.67, CHCl₃); ¹H

D

d

0.83 (t, J¼7.2 Hz, 3H), 0.86 (t, J¼7.2 Hz, 3H),

gon. To a cooled (ꢀ78 ^ꢁC), stirred solution of oxalyl chloride (40

m

L,

1.09 (t, J¼7.1 Hz, 3H), 1.11 (t, J¼7.1 Hz, 3H), 1.27 (d, J¼7.2 Hz, 3H),

1.44e1.64 (m, 6H), 1.70e1.90 (m, 2H), 2.10e2.25 (m, 3H), 2.34 (t,

J¼11.0 Hz, 1H), 3.69 (dd, J¼6.0, 10.2 Hz, 1H), 3.74 (d, J¼11.3 Hz, 1H),

3.81 (d, J¼11.3 Hz,1H), 5.13 (br s,1H), 6.21 (d, J¼16.1 Hz,1H), 6.31 (d,

J¼16.1 Hz, 1H), 7.19 (t, J¼7.5 Hz, 1H), 7.30 (t, J¼7.5 Hz, 2H), 7.37 (d,

0.41 mmol) in CH₂Cl₂(1.0 mL) was added dropwise DMSO (60

0.81 mmol). The mixture was stirred at ꢀ78 ^ꢁC for 40 min and then

a solution of 31 (16.7 mg, 40.5 mmol) in CH₂Cl₂(0.8 mL) was added.

The mixture was stirred at ꢀ78 ^ꢁC for 1 h and then Et₃N (0.23 mL,

1.6 mmol) was added. The mixture was warmed gradually to room

temperature and stirred for 40 min. The mixture was diluted with

H₂O (10 mL) at 0 ^ꢁC and extracted with CH₂Cl₂(5 mLꢂ3). The

combined organic layers were washed with saturated aqueous

NaHCO₃(5 mL) and brine (5 mL), dried, and concentrated under

reduced pressure. The residue was puriﬁed by column chroma-

tography on silica gel (EtOAc/hexane, 1:30) to provide 15.0 mg

J¼7.5 Hz, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 9.6, 10.3, 12.4, 13.5, 14.2,

21.3, 28.2, 28.5, 29.7, 41.2, 44.1, 45.3, 48.4, 50.6, 52.5, 65.3, 82.9,

124.3, 126.2 (2C), 126.7, 128.4 (2C), 131.9, 137.6, 138.0, 142.6; IR

(neat) 3360, 2960, 2880, 1470 cm^ꢀ1; HRMS calcd for C₂₇H₄₀O₂[M]^þ

396.3028, found 396.3027.

4.2.20. (1R,2Z,4S,5R,6R,7S,9S)-2,4,5,7-Tetraethyl-5-formyl-9-methyl-

4-(1E)-styrylbicyclo[4.3.0]non-2-en-8-one (35). To a cooled (0 ^ꢁC),

stirred solution of 34 (27.5 mg, 69.3 mmol) in CH₂Cl₂(1.0 mL) was

added DesseMartin periodinane (76.5 mg, 0.180 mmol). The mix-

ture was stirred at room temperature for 1.5 h, quenched saturated

aqueous NaHCO₃(5 mL) and 20% aqueous Na₂S₂O₃(5 mL), and

extracted with CH₂Cl₂(5 mLꢂ3). The combined organic layers were

dried and concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (EtOAc/hexane,

1:80) to provide 22.7 mg (85%) of35 as a colorless oil: TLC R_f0.63

(90%) of 32 as a colorless oil: TLC R_f0.57 (EtOAc/hexane, 1:6);

23.5

[

a]

þ75.5 (c 0.90, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.92 (t,

D

J¼7.5 Hz, 6H), 0.99 (t, J¼7.5 Hz, 3H), 1.04 (t, J¼7.5 Hz, 3H), 1.27 (d,

J¼6.6 Hz, 3H), 1.37e1.50 (m, 2H), 1.51e1.61 (m, 1H), 1.64e1.84 (m,

5H), 2.17e2.34 (m, 3H), 2.41 (t, J¼12.3 Hz, 1H), 3.37 (s, 3H), 3.38 (s,

3H), 3.54 (d, J¼10.2 Hz, 1H), 3.62 (d, J¼4.5 Hz, 1H), 3.70 (d,

J¼10.2 Hz, 1H), 4.54 (d, J¼6.6 Hz, 1H), 4.57 (d, J¼6.6 Hz, 1H), 4.60 (d,

J¼6.6 Hz, 1H), 4.69 (d, J¼6.6 Hz, 1H), 4.91 (br s, 1H), 9.68 (s, 1H); ¹³C

NMR (68 MHz, CDCl₃) d 9.2, 9.5, 12.5,13.0,14.7, 22.8, 23.9, 28.2, 28.4,

40.9, 44.5, 44.6, 45.2, 51.9, 55.4, 56.0, 61.0, 69.7, 86.0, 93.9, 97.1,

119.5, 146.8, 205.0; IR (neat) 2960, 2880, 1715, 1470 cm^ꢀ1; HRMS

calcd for C₂₄H₄₂O₅[M]^þ410.3032, found 410.3050.

(EtOAc/hexane,1:4); [

a

]

²⁵þ83.9 (c 0.47, CHCl₃); ¹H NMR (300 MHz,

D

CDCl₃)

d

0.67 (t, J¼7.4 Hz, 3H), 0.85 (t, J¼7.5 Hz, 3H), 0.96 (t, J¼7.4 Hz,

3H), 1.15 (t, J¼7.4 Hz, 3H), 1.21e1.40 (m, 1H), 1.38 (d, J¼6.9 Hz, 3H),

1.43e1.58 (m, 3H), 1.80e1.98 (m, 2H), 2.17e2.33 (m, 4H), 2.44 (ddd,

J¼3.6, 5.1, 12.5 Hz, 1H), 2.87 (t, J¼12.5 Hz, 1H), 5.20 (d, J¼1.2 Hz, 1H),

6.05 (d, J¼15.8 Hz, 1H), 6.42 (d, J¼15.8 Hz, 1H), 7.20e7.28 (m, 1H),

7.30e7.32 (m, 4H), 9.68 (d, J¼0.9 Hz, 1H); ¹³C NMR (68 MHz, CDCl₃)

4.2.18. (1R,2Z,4S,5R,6R,7S,8S,9S)-2,4,5,7-Tetraethyl-8-methox-

ymethoxy-5-(methoxymethoxy)methyl-9-methyl-4-(1E)-styr-

ylbicyclo[4.3.0]non-2-ene (33). The following reaction was carried

out under argon. To a cooled (ꢀ78 ^ꢁC), stirred solution of diethyl

benzylphosphonate (0.10 mL, 0.46 mmol) in THF (1.0 mL) was

added n-BuLi (0.15 mL of 2.63 M solution in hexane, 0.39 mmol).

The mixture was stirred at ꢀ78 ^ꢁC for 30 min and a solution of 32

d

9.0, 9.4, 11.4, 12.9, 16.0, 20.2, 20.7, 27.4, 28.2, 41.0, 44.5, 48.4, 51.6,

52.3, 57.8, 122.6, 126.2 (2C), 127.6, 128.6 (2C), 134.2, 134.4, 136.8,

141.8, 206.6, 219.5; IR (neat) 2960, 2880, 1730, 1715, 1455 cm^ꢀ1

HRMS calcd for C₂₇H₃₆O₂[M]^þ392.2715, found 392.2715.

;

(31.7 mg, 77.2

m

mol) in THF (1.0 mL) was added dropwise at ꢀ78 ^ꢁC.

The mixture was warmed to 0 ^ꢁC over 3 h, quenched with saturated

aqueous NH₄Cl (10 mL), and extracted with EtOAc (5 mLꢂ3). The

combined organic layers were dried and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatog-

4.2.21. (þ)-Spiculoic acid A (1). To a cooled (0 ^ꢁC), stirred solution

of 35 (22.7 mg, 57.8 mmol) in t-BuOH/H₂O (5:1, 1.0 mL) were added

2-methyl-2-butene (40

mL, 0.35 mmol), NaH₂PO₄(20.8 mg,

0.173 mmol), and NaClO₂(20.1 mg, 0.173 mmol). The mixture was

stirred at room temperature for 1.5 h and additional 2-methyl-2-

butene (0.20 mL, 1.7 mmol), NaH₂PO₄(104 mg, 0.865 mmol), and

NaClO₂(101 mg, 0.865 mmol) were added at 0 ^ꢁC. The mixture was

stirred at room temperature for 1.5 h and additional 2-methyl-2-

butene (0.14 mL, 1.2 mmol), NaH₂PO₄(69.3 mg, 0.577 mmol), and

NaClO₂(67.0 mg, 0.577 mmol) were added at 0 ^ꢁC. The mixture was

stirred at room temperature for 3 h, quenched saturated aqueous

NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with CH₂Cl₂(5 mLꢂ3). The

combined organic layers were dried and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatog-

raphy on silica gel (EtOAc/hexane, 1:60 to 1:15) to provide 19.4 mg

raphy on silica gel (EtOAc/hexane,1:100 to 1:60) to provide 32.9 mg

24

(88%) of 33 as a colorless oil: TLC R_f0.57 (EtOAc/hexane, 1:4); [a]

D

ꢀ2.6 (c 0.83, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.81 (t, J¼7.5 Hz,

6H), 1.03 (t, J¼7.5 Hz, 3H), 1.09 (t, J¼7.5 Hz, 3H), 1.28 (d, J¼6.6 Hz,

3H), 1.38e1.73 (m, 6H), 1.80e1.97 (m, 2H), 2.13e2.27 (m, 3H), 2.40

(t, J¼11.1 Hz, 1H), 3.37 (s, 3H), 3.46 (s, 3H), 3.56 (d, J¼10.5 Hz, 1H),

3.58 (d, J¼4.2 Hz, 1H), 3.59 (d, J¼10.5 Hz, 1H), 4.53 (d, J¼7.2 Hz, 1H),

4.64 (d, J¼7.2 Hz, 1H), 4.68 (d, J¼7.2 Hz, 1H), 4.68 (d, J¼7.2 Hz, 1H),

5.13 (br s,1H), 6.21 (d, J¼16.1 Hz,1H), 6.27 (d, J¼16.1 Hz,1H), 7.19 (tt,

J¼1.5, 7.1 Hz, 1H), 7.27e7.32 (m, 2H), 7.35 (dd, J¼1.5, 8.4 Hz, 2H); ¹³C

NMR (68 MHz, CDCl₃) d 9.5, 9.6, 12.3, 13.6, 14.7, 21.7, 28.1, 28.3, 28.9,

41.0, 44.5, 44.7, 44.9, 51.1, 52.6, 55.4, 55.7, 70.6, 86.3, 93.8, 97.1,

124.3, 126.1 (2C), 126.6, 128.4 (2C), 131.8, 137.9, 138.3, 142.7; IR

(neat) 2960, 2880, 1470 cm^ꢀ1; HRMS calcd for C₃₁H₄₈O₄[M]^þ

484.3553, found 484.3550.

(82%) of 1 as a colorless oil: TLC R_f0.22 (Et₂O/petroleum ether, 3:7);

25

[a

]

þ102 (c 0.38, CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃)

d 0.65 (t,

D

J¼7.4 Hz, 3H), 0.88 (t, J¼7.4 Hz, 3H), 1.08 (t, J¼7.4 Hz, 3H), 1.15 (t,

J¼7.4 Hz, 3H), 1.36 (d, J¼6.9 Hz, 3H), 1.52e1.63 (m, 1H), 1.64e1.73

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6739

(m, 2H), 1.77e1.86 (m, 2H),1.86e1.95 (m, 1H), 2.16 (t, J¼11.7 Hz,1H),

2.24e2.32 (m, 3H), 2.46 (ddd, J¼3.5, 5.3, 11.7 Hz, 1H), 2.66 (t,

J¼11.7 Hz, 1H), 5.26 (br s, 1H), 6.06 (d, J¼15.8 Hz, 1H), 6.27 (d,

J¼15.8 Hz, 1H), 7.17 (dd, J¼1.7, 7.1 Hz, 1H), 7.25 (t, J¼7.1 Hz, 2H), 7.31

column chromatography on silica gel (EtOAc/hexane, 1:2.5 to 1:2) to

provide 1.69 g (96%) of diol (ca. 2:1 diastereomeric mixture based

on ¹H NMR)as a colorless oil: TLC R_f0.29 (EtOAc/hexane, 2:1);

22

[a]

ꢀ5.2 (c1.52, CHCl₃); ¹H NMR (300 MHz, CDCl₃) for major

D

(dd, J¼1.7, 7.1 Hz, 2H); ¹³C NMR (68 MHz, CDCl₃)

d

9.1, 9.6, 12.3, 13.0,

isomer

d

0.84 (t, J¼6.9 Hz, 3H), 0.87 (d, J¼7.5 Hz, 3H), 1.00 (t,

15.5, 22.1, 22.8, 27.2, 28.2, 42.1, 46.0, 47.7, 51.1, 52.3, 54.0,123.1,126.2

(2C), 127.1, 128.5 (2C), 132.2, 136.5, 137.7, 140.9, 179.0, 220.3; IR

(neat) 3060, 2980, 2860, 1730, 1715, 1470 cm^ꢀ1; HRMS calcd for

C₂₇H₃₆O₃[M]^þ408.2665, found 408.2662.

J¼7.5 Hz, 3H), 1.06e1.15 (m, 1H), 1.62e1.78 (m, 2H), 2.16 (q, J¼7.5 Hz,

2H), 2.33 (br s, 1H), 2.46e2.58 (m, 1H), 3.35e3.46 (m, 1H), 3.45 (s,

3H), 3.49e3.54 (m, 1H), 3.69e3.76 (m, 2H), 3.80 (s, 3H), 3.94 (s, 2H),

4.05 (br s, 1H) 4.35 (s, 2H), 4.71 (d, J¼6.9 Hz, 1H), 4.76 (d, J¼6.9 Hz,

1H), 4.98 (d, J¼10.8 Hz, 1H) 6.85e6.90 (m, 2H), 7.22e7.27 (m, 2H);

4.3. Synthesis of (2R,5S,6R)-isomer (46) of (D)-spiculoic acid A

¹³C NMR (68 MHz, CDCl₃) for major isomer

d 10.2, 11.8, 12.4, 21.5,

24.6, 38.0, 42.8, 55.2, 56.3, 65.1, 70.9, 73.1, 73.6, 83.2, 99.3, 113.8 (2C),

128.3, 129.3 (2C), 130.5, 139.4, 159.1; IR (neat) 3460, 2960, 2930,

1615,1515 cm^ꢀ1; HRMS calcd for C₂₃H₃₇O₆[MꢀH]^þ409.2590, found

409.2571.

4.3.1. (3R,4S,5S,6E)-5-Ethyl-7-(4-methoxybenzyloxy)methyl-4-me-

thoxymethoxy-3-methylnona-1,6-diene (36). The following reaction

ꢀ

was carried out under argon. To a stirred suspension of MS 4 A

powder (380 mg) in toluene (19 mL) was added (2⁰Z,4S,5S)-2-(but-

2-enyl)-4,5-di(isopropyloxycarbonyl)-1,3,2-dioxaborolane (0.73 M

solution in toluene, 14 mL, 10 mmol), prepared from cis-2-bute-

ne.The mixture was cooled to ꢀ78 ^ꢁC and a solution of 16 (1.89 g,

6.84 mmol) in toluene (9.5 mL) was added. After being stirred at

ꢀ78 ^ꢁC for 1 h, the mixture was treated with 3 M aqueous NaOH

(20 mL), stirred at room temperature for 18 h, and extracted with

EtOAc (10 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (Et₂O/toluene, 1:50) to pro-

To a cooled (0 ^ꢁC), stirred solution of diol obtained above (1.56 g,

3.80 mmol) in acetone/H₂O (4:1, 50 mL) was added NaIO₄(2.19 g,

10.3 mmol). The mixture was stirred at room temperature for

30 min, quenched with 1 M aqueous NaHSO₃(50 mL) at 0 ^ꢁC, and

extracted with EtOAc (25 mLꢂ3). The combined organic layers were

washed with saturated aqueous NaHCO₃(20 mL) and brine (20 mL),

dried, and concentrated under reduced pressure to provide crude

(2S,3R,4S,5E)-4-ethyl-6-(4-methoxybenzyloxy)methyl-3-methox-

ymethoxy-2-methyloct-5-enal (37), which was used in the next

step without further puriﬁcation.

vide 1.88 g (83%) of the crotylation product as a colorless oil: TLC R_f

The following reaction was carried out under argon. To a cooled

(ꢀ40 ^ꢁC), stirred suspension of 1,1-dibromopropytriphenylphos-

phonium bromide (8.83 g, 16.3 mmol) in Et₂O (45 mL) was added

n-BuLi (2.77 M solution in hexane, 5.5 mL, 15 mmol). The mixture

was stirred at ꢀ40 ^ꢁC for 30 min and cooled to ꢀ78 ^ꢁC. Then a solu-

tion of the crude 37 obtained above in Et₂O (4.5 mL) was added

dropwise. The mixture was stirred at ꢀ78 ^ꢁC for 1 h, quenched with

H₂O (5 mL), diluted with saturated aqueous NaHCO₃(45 mL) and

H₂O (50 mL), and extracted with EtOAc (25 mLꢂ3). The combined

organic layers were washed with saturated aqueous NaHCO₃

(40 mL), dried, and concentrated under reduced pressure. The res-

idue was puriﬁed by column chromatography on silica gel (EtOAc/

hexane, 1:60 to 1:30) to provide 915 mg (50% for two steps) of 38 as

22

0.34 (EtOAc/hexane, 1:5); [

(300 MHz, CDCl₃)

a

]

ꢀ0.5 (c 1.48, CHCl₃); ¹H NMR

D

d

0.86 (t, J¼7.5 Hz, 3H), 0.98 (d, J¼6.9 Hz, 3H), 1.01

(t, J¼7.5 Hz, 3H),1.17e1.27 (m, 1H),1.54 (br s,1H), 1.78e1.88 (m, 1H),

2.17 (q, J¼7.5 Hz, 2H), 2.34e2.48 (m, 2H), 3.39 (dd, J¼6.6, 3.6 Hz,

1H), 3.80 (s, 3H), 3.97 (s, 2H), 4.38 (s, 2H), 5.05e5.11 (m, 2H), 5.15 (d,

J¼10.5 Hz, 1H), 5.79e5.90 (m, 1H), 6.87e6.90 (m, 2H), 7.24e7.27 (m,

2H); ¹³C NMR (68 MHz, CDCl₃)

d 11.7,12.2,12.7, 21.5, 23.5, 40.3, 42.4,

55.3, 71.0, 73.3, 77.3, 113.7 (2C), 114.7, 128.9 (2C), 129.3, 130.6, 139.2,

142.1, 159.1; IR (neat) 3460, 2960, 2930,1615, 1515 cm^ꢀ1; HRMS

calcd for C₂₁H₃₂O₃[M]^þ332.2352, found 332.2360.

To a stirred solution of the product obtained above (1.50 g,

4.51 mmol) in CH₂Cl₂(30 mL) were added i-Pr₂NEt (7.9 mL,

45 mmol) and MOMCl (1.7 mL, 23 mmol). The mixture was reﬂuxed

for 13 h, diluted with saturated aqueous NH₄Cl (130 mL), and

extracted with CH₂Cl₂(30 mLꢂ3). The combined organic layers

were dried and concentrated under reduced pressure. The residue

was puriﬁed by column chromatography on silica gel (EtOAc/hex-

ane, 1:30) to provide 1.60 g (94%) of 36 as a colorless oil: TLC R_f0.66

a colorless oil: TLC R_f0.46 (EtOAc/hexane, 1:5); [

a

]

^24.5þ9.9 (c1.43,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.84 (t, J¼7.5 Hz, 3H), 1.01 (d,

J¼6.6 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 1.08 (t, J¼7.5 Hz, 3H), 1.14e1.25

(m, 1H), 1.63e1.80 (m, 1H), 2.14 (q, J¼7.5 Hz, 2H), 2.33e2.49 (m, 1H),

2.39 (q, J¼7.5 Hz, 2H), 2.56e2.68 (m, 1H), 3.18 (t, J¼5.7 Hz, 1H), 3.41

(s, 3H), 3.81 (s, 3H), 3.96 (s, 2H), 4.38 (s, 2H), 4.65 (s, 2H), 5.16 (d,

J¼10.5 Hz,1H), 5.78 (d, J¼10.2 Hz,1H), 6.86e6.89 (m, 2H), 7.24e7.26

(EtOAc/hexane, 1:3); [

a

]

²³þ9.3 (c1.25, CHCl₃); ¹H NMR (300 MHz,

D

CDCl₃)

d

0.84 (t, J¼7.5 Hz, 3H), 1.00 (t, J¼7.5 Hz, 3H), 1.03 (d,

(m, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 12.1, 12.7, 13.3, 15.5, 21.5, 23.3,

J¼6.9 Hz, 3H),1.14e1.25 (m,1H),1.70e1.84 (m,1H), 2.14 (q, J¼7.5 Hz,

2H), 2.38e2.55 (m, 2H), 3.29 (dd, J¼6.6, 4.5 Hz, 1H), 3.39 (s, 3H),

3.81 (s, 3H), 3.96 (s, 2H), 4.38 (s, 2H), 4.61e4.68 (m, 2H), 4.98e5.05

(m, 2H), 5.16 (d, J¼10.5 Hz, 1H), 5.80e5.92 (m, 1H), 6.86e6.90 (m,

29.3, 37.3, 42.5, 55.3, 56.2, 71.1, 73.4, 86.1, 98.3,113.7 (2C),127.5,129.2

(2C), 129.3, 130.6. 135.3, 139.5, 159.1; IR (neat) 2980, 2930, 1615,

1515 cm^ꢀ1; HRMS calcd for C₂₅H₃₉BrO₄[M]^þ482.2032, found

482.2033.

2H), 7.23e7.28 (m, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 12.0, 12.7, 14.1,

21.4, 23.4, 40.5, 42.4, 55.3, 56.1, 70.9, 73.4, 85.9, 98.1, 113.7 (2C),

113.8, 129.2 (2C), 129.8, 130.6, 139.0, 142.7, 159.1; IR (neat) 2960,

2930, 1615, 1515 cm^ꢀ1; HRMS calcd for C₂₃H₃₆O₄[M]^þ376.2614,

found 376.2612.

4.3.3. 2-[(3Z,5R,6S,7S,8E)-7-Ethyl-9-hydroxymethyl-6-methox-

ymethoxy-5-methylundeca-3,8-dien-3-yl]-4,4,5,5-tetramethyl-1,3,2-

dioxaborolane (39). The following reaction was carried out under

argon. To a stirred solution of 38 (1.05 g, 2.17 mmol) in toluene

(40 mL) were added bis(pinacolato)diboron (993 mg, 3.91 mmol),

PdCl₂(PPh₃)₂(122 mg, 0.173 mmol), PPh₃(91.1 mg, 0.347 mmol),

and KOPh (517 mg, 3.91 mmol). The mixture was stirred at 50 ^ꢁC for

4 h and additional bis(pinacolato)diboron (276 mg, 1.08 mmol) and

KOPh (72.0 mg, 0.544 mmol) were added. The mixture was stirred

at 50 ^ꢁC for 2 h, diluted with H₂O (50 mL), and extracted with EtOAc

(50 mL). The organic layer was washed with 2 M aqueous NaOH

(20 mLꢂ2) and brine (20 mL), dried, and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatog-

4.3.2. (3E,5R,6S,7S,8E)-3-Bromo-7-ethyl-9-(4-methoxybenzyloxy)

methyl-6-methoxymethoxy-5-methylundeca-3,8-diene (38). To a stir-

red solution of 36 (1.60 g, 4.25 mmol) in acetone/H₂O (6:1, 35 mL)

were added OsO₄(0.05 M solution in t-BuOH, 4.3 mL, 0.22 mmol)

and NMO (1.24 g, 10.6 mmol). The mixture was stirred at room

temperature for 4.5 h and additional NMO (150 mg, 1.28 mmol) was

added. The mixture was stirred at room temperature for 2.5 h,

quenched with 1 M aqueous NaHSO₃(80 mL) at 0 ^ꢁC, and extracted

with EtOAc (40 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

raphy on silica gel (EtOAc/hexane, 1:30) to provide 855 mg (74%) of

23

boronate as a colorless oil: TLC R_f0.37 (EtOAc/hexane, 1:5); [a]

D

6740

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

þ8.4 (c 1.33, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.82 (t, J¼7.5 Hz,

puriﬁed by column chromatography on silica gel (EtOAc/hexane,

1:35) to provide 106 mg (82%) of an inseparable mixture of 42 and

3H), 0.94 (t, J¼7.5 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.01 (d, J¼6.6 Hz,

3H), 1.16e1.29 (m, 1H), 1.24 (s, 6H), 1.26 (s, 6H), 1.67e1.76 (m, 1H),

2.12 (q, J¼7.5 Hz, 2H), 2.39e2.48 (m, 1H), 2.78e2.90 (m, 1H), 3.23 (t,

J¼5.7 Hz,1H), 3.41 (s, 3H), 3.81 (s, 3H), 3.97 (s, 2H), 4.37 (s, 2H), 4.64

(d, J¼6.6 Hz, 1H), 4.67 (d, J¼6.6 Hz, 1H), 5.23 (d, J¼10.5 Hz, 1H), 6.18

(d, J¼9.9 Hz, 1H), 6.85e6.90 (m, 2H), 7.23e7.27 (m, 2H); ¹³C NMR

a small amount of a byproduct (>11:1 based on ¹H NMR analysis) as

22

a colorless oil: TLC R_f0.31 (EtOAc/hexane, 1:6); [

a

]

D

þ4.1 (c1.07,

CHCl₃); ¹H NMR for 42(300 MHz, CDCl₃)

d

0.70 (t, J¼7.5 Hz, 3H), 0.88

(t, J¼7.5 Hz, 3H), 0.97 (t, J¼7.5 Hz, 3H), 1.00 (t, J¼7.5 Hz, 3H), 1.24 (d,

J¼6.3 Hz, 3H), 1.21e1.45 (m, 2H), 1.60e1.81 (m, 4H), 1.84e1.94 (m,

2H), 2.01e2.11 (m, 2H), 2.17 (dd, J¼9.6, 7.8 Hz, 1H), 2.67 (dd, J¼9.6,

6.6 Hz, 1H), 3.36 (dd, J¼10.5, 4.8 Hz, 1H), 3.37 (d, J¼9.6 Hz, 1H), 3.38

(s, 3H), 3.44 (d, J¼9.6 Hz,1H), 3.80 (s, 3H), 4.37 (d, J¼11.7 Hz,1H), 4.48

(d, J¼11.7 Hz, 1H), 4.64 (d, J¼6.9 Hz, 1H), 4.68 (d, J¼6.9 Hz, 1H), 4.87

(br s,1H), 6.85e6.90 (m, 2H), 7.21e7.26 (m, 2H), 9.79 (s,1H); ¹³C NMR

(68 MHz, CDCl₃)

d 12.2, 12.8, 14.9, 15.8, 21.3, 22.1, 22.9, 24.4 (2C),

25.0 (2C), 35.6, 42.4, 55.2, 56.2, 70.8, 73.7, 83.0, 86.5 (2C), 98.3, 113.7

(2C), 129.2 (3C), 130.4, 130.7, 138.9, 148.2, 159.0; IR (neat)2960,

2930, 1615, 1515 cm^ꢀ1; HRMS calcd for C₃₁H₅₁BO₆[M]^þ530.3779,

found 530.3782.

To a cooled (0 ^ꢁC), stirred solution of boronate obtained above

(855 mg, 1.61 mmol) in CH₂Cl₂(16 mL) were added aqueous phos-

phate buffer (0.5 M aqueous Na₂HPO₄/0.5 M aqueous NaH₂PO₄, 2:1,

2.0 mL) and DDQ (1.06 g, 4.67 mmol). The mixture was stirred at

room temperature for 30 min, diluted with saturated aqueous

NaHCO₃(30 mL), and extracted with CH₂Cl₂(30 mLꢂ3). The com-

bined organic layers were dried and concentrated under reduced

pressure. The residue was puriﬁed by column chromatography on

silica gel (EtOAc/hexane,1:25 to1:8) to provide 579 mg(88%)of 39as

for 42 (68 MHz, CDCl₃) d 8.5, 9.7, 12.1, 12.7, 20.6, 23.1, 25.2, 25.3, 27.1,

27.6, 41.2, 44.9, 45.1, 46.6, 46.8, 55.2, 55.5, 71.0, 72.7, 89.8, 96.3, 113.7

(2C),122.6,129.0 (2C),130.3,141.2,159.1, 208.1; IR (neat) 2960, 2930,

1715, 1615, 1515 cm^ꢀ1; HRMS calcd for C₃₀H₄₆O₅[M]^þ486.3345,

found 486.3341.

4.3.6. (1S,2Z,4R,5R,6R,7S,8S,9R)-2,4,5,7-Tetraethyl-4-(4-methox-

ybenzyloxy)methyl-8-methoxymethoxy-5-[(methoxymethoxy)

methyl]-9-methylbicyclo[4.3.0]non-2-ene (43). To a cooled (0 ^ꢁC),

stirred solution of 42 containing a small amount of byproduct (ca.

11:1, 106 mg, 0.219 mmol) in MeOH (4.0 mL) was added NaBH₄

(25.0 mg, 0.661 mmol). The mixture was stirred at room tempera-

ture for 40 min and NaBH₄(13.0 mg, 0.343 mmol) was added. The

mixture was stirred at room temperature for 30 min and NaBH₄

(17.0 mg, 0.449 mmol) was added. The mixture was stirred at room

temperature for 30 min and then additional NaBH₄(15.0 mg,

0.397 mmol) was added. The mixture was stirred at room temper-

ature for additional 30 min, quenched with saturated aqueous

NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with EtOAc (5 mLꢂ3). The

combined organic layers were dried and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatogra-

phy on silica gel (EtOAc/hexane, 1:25 to 1:10) to provide 80.4 mg

a colorless oil: TLC R_f0.10 (EtOAc/hexane, 1:4); [

a

]

^22.5þ13.2 (c1.88,

D

CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.80 (t, J¼7.5 Hz, 3H), 0.96 (t,

J¼7.5 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.00 (d, J¼7.5 Hz, 3H), 1.11e1.35

(m, 1H), 1.24 (s, 6H), 1.26 (s, 6H), 1.60e1.75 (m, 1H), 2.10 (q, J¼7.5 Hz,

2H), 2.10 (q, J¼7.5 Hz, 2H), 2.31e2.43 (m,1H), 2.76e2.89 (m,1H), 3.20

(dd, J¼6.8, 4.8 Hz,1H), 3.42 (s, 3H), 4.06 (s, 2H), 4.63 (d, J¼6.6 Hz,1H),

4.68 (d, J¼6.6 Hz, 1H), 5.24 (d, J¼10.2 Hz, 1H), 6.14 (d, J¼9.9 Hz, 1H);

¹³C NMR (68 MHz, CDCl₃)

d 12.2,13.0, 14.9, 16.4, 21.3, 22.0, 22.7, 24.4

(2C), 24.9 (2C), 35.9, 42.3, 56.1, 66.6, 83.0, 87.1 (2C), 98.4, 128.6 (2C),

141.6, 148.0; IR (neat) 3280, 2960, 2930, 1630 cm^ꢀ1; HRMS calcd for

C₂₃H₄₃BO₅[M]^þ410.3204, found 410.3192.

4.3.4. (2E,4S,5S,6R,7E,9E)-2,4,8-Triethyl-10-(4-methoxybenzyloxy)

methyl-5-methoxymethoxy-6-methyldodeca-2,7,9-trienal (41). The

following reaction was carried out under argon. To a stirred solu-

tion of 39 (148 mg, 0.361 mmol) and 40(314 mg, 0.945 mmol) in

degassed DMF (38 mL) were added Cs₂CO₃(724 mg, 2.22 mmol)

(77%) of alcohol as a colorless oil: TLC R_f0.31 (EtOAc/hexane, 1:4);

26

[a

]

þ4.8 (c 0.515, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.75 (t,

D

J¼7.5 Hz, 3H), 0.91 (t, J¼7.5 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.08 (t,

J¼7.5 Hz, 3H),1.20 (d, J¼5.4 Hz, 3H),1.36e1.68 (m, 5H),1.80e2.12 (m,

7H), 3.21 (dd, J¼5.4, 7.2 Hz, 1H), 3.27 (d, J¼10.2 Hz, 1H), 3.38 (s, 3H),

3.44 (d, J¼10.2 Hz, 1H), 3.49 (d, J¼12.0 Hz, 1H), 3.61 (d, J¼12.0 Hz,

1H), 3.80 (s, 3H), 4.42 (d, J¼11.4 Hz, 1H),4.56 (d, J¼11.4 Hz, 1H), 4.65

(d, J¼6.9 Hz,1H), 4.72 (d, J¼6.9 Hz,1H), 4.80 (br s,1H), 6.87e6.90 (m,

and Pd(PPh₃)₄(42.0 mg, 36.3 mmol). The mixture was stirred at

70 ^ꢁC for 20 h, diluted with saturated aqueous NH₄Cl (80 mL), and

extracted with Et₂O (40 mLꢂ3). The combined organic layers were

dried and concentrated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (EtOAc/hexane,

1:40) to provide 129 mg (74%) of 41 as a colorless oil: TLC R_f0.33

2H), 7.25e7.28 (m, 2H); ¹³C NMR (68 MHz, CDCl₃)

d 8.3, 11.3, 11.4,

13.1, 19.8, 23.3, 25.0, 28.7, 29.2, 44.5, 45.4, 45.9 (2C), 46.0 (2C), 55.2,

55.4, 64.3, 71.4, 73.1, 92.9, 96.6, 113.9 (2C), 124.8, 128.8, 129.8 (2C),

140.5, 159.5; IR (neat) 3420, 2960, 2920 cm^ꢀ1; HRMS calcd for

C₃₀H₄₈O₅[M]^þ488.3502, found 488.3493.

(EtOAc/hexane, 1:4); [

CDCl₃)

a

]

²¹þ5.1 (c1.70, CHCl₃); ¹H NMR (300 MHz,

D

d

0.82 (t, J¼7.5 Hz, 3H), 0.94e1.06 (m, 12H), 1.38e1.51 (m,

1H), 1.77e1.85 (m, 1H), 2.03e2.17 (m, 2H), 2.21e2.33 (m,

4H),2.66e2.80 (m, 2H), 3.26 (dd, J¼7.3, 3.9 Hz,1H), 3.42 (s, 3H), 3.81

(s, 3H), 3.98 (s, 2H), 4.41 (s, 2H), 4.64 (d, J¼6.6 Hz, 1H), 4.67 (d,

J¼6.6 Hz, 1H), 5.11 (d, J¼10.0 Hz, 1H), 5.83 (s, 1H), 6.36 (d, J¼10.5 Hz,

1H), 6.87e6.91 (m, 2H), 7.26e7.28 (m, 2H), 9.41 (s, 1H); ¹³C NMR

To a stirred solution of alcohol (77.0 mg, 0.158 mmol) in CH₂Cl₂

(1.5 mL) were added i-Pr₂NEt (60

mL, 0.79 mmol) and MOMCl

(280 L,1.61 mmol). The mixture was reﬂuxed for 16 h, diluted with

m

saturated aqueous NH₄Cl (10 mL), and extracted with CH₂Cl₂

(5 mLꢂ3). The combined organic layers were dried and concen-

trated under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (EtOAc/hexane, 1:35 to 1:25) to pro-

(68 MHz, CDCl₃)

d 12.3, 13.2, 13.3 (2C), 17.5, 17.9, 21.9, 22.0, 24.3,

36.2, 43.9, 55.3, 56.2, 71.3, 73.3, 86.6, 98.6, 113.7 (2C), 129.2 (2C),

129.3, 130.2, 130.5, 138.0, 139.3, 145.7, 156.7, 159.1, 195.2; IR (neat)

2960, 2930, 1715, 1615, 1515 cm^ꢀ1; HRMS calcd for C₃₀H₄₆O₅[M]^þ

486.3345, found 486.3348.

vide 73.8 mg (88%) of 43 as a colorless oil: TLC R_f0.58 (EtOAc/

23.5

hexane, 1:4); [

CDCl₃)

a

]

D

þ2.7 (c 1.15, CHCl₃); ¹H NMR (300 MHz,

d

0.80 (t, J¼6.6 Hz, 3H), 0.93 (t, J¼7.2 Hz, 3H), 0.94 (t,

4.3.5. (1S,2Z,4R,5R,6R,7S,8S,9R)-2,4,5,7-Tetraethyl-5-formyl-4-(4-

methoxybenzyloxy)methyl-8-methoxymethoxy-9-methylbicyclo

[4.3.0]non-2-ene (42). The following reaction was carried out under

argon. To a stirred solution of 41 (129 mg, 0.265 mmol) in toluene

(27 mL) were added a crystal of BHT and Wako Gel C-300 (1.29 g).

The mixture was stirred at 80 ^ꢁC for 47 h and cooled to room tem-

perature. The silica gel was removed by ﬁltration through cotton

wool and washed with CH₂Cl₂. The combined ﬁltrate and washings

were concentrated under reduced pressure. The residue was

J¼7.2 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.17 (d, J¼4.8 Hz, 3H), 1.25e1.48

(m, 2H), 1.50e1.78 (m, 3H), 1.80e2.12 (m, 1H),1.89 (q, J¼6.6 Hz, 2H),

2.08 (q, J¼7.5 Hz, 2H), 2.16e2.20 (m,1H), 2.33 (dd, J¼5.7, 6.9 Hz,1H),

3.28e3.40 (m, 3H), 3.11 (s, 3H), 3.37 (s, 3H), 3.55 (br, 1H), 3.66 (br,

1H), 3.80 (s, 3H), 4.33 (d, J¼11.7 Hz, 1H),4.40 (d, J¼11.7 Hz, 1H), 4.53

(d, J¼6.6 Hz, 1H), 4.56 (d, J¼6.6 Hz, 1H), 4.65 (br, 1H), 4.94 (br, 1H),

6.85e6.89 (m, 2H), 7.25e7.27 (m, 2H); ¹³C NMR (68 MHz, CDCl₃)

d

8.6, 10.0, 11.5, 13.0, 21.1, 24.6, 26.3, 28.7 (2C), 43.2 (2C), 46.7 (2C),

46.8 (2C), 55.2, 55.3, 55.5, 71.9 (2C), 72.7, 95.7, 97.3 (2C), 113.5 (2C),

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6741

128.9 (3C), 131.0, 140.2, 158.9; IR (neat) 2960, 2920 cm^ꢀ1; HRMS

calcd for C₃₂H₅₂O₆[M]^þ532.3764, found 532.3755.

3H), 3.38 (s, 3H), 3.30e3.44 (m, 2H), 3.57 (d, J¼9.6 Hz, 1H),4.41 (br,

1H), 4.49 (d, J¼6.6 Hz, 1H), 4.58 (d, J¼6.9 Hz, 1H), 4.61 (d, J¼6.9 Hz,

1H), 5.40 (br s, 1H), 6.22 (d, J¼16.2 Hz, 1H), 6.34 (d, J¼16.2 Hz, 1H),

7.16 (t, J¼7.2 Hz, 1H), 7.24e7.34 (m, 4H); ¹³C NMR (68 MHz, CDCl₃)

4.3.7. (1S,2Z,4R,5R,6R,7S,8S,9R)-2,4,5,7-Tetraethyl-4-formyl-8-me-

thoxymethoxy-5-(methoxymethoxy)methyl-9-methylbicyclo[4.3.0]

non-2-ene (44). To a cooled (0 ^ꢁC), stirred solution of 43 (73.0 mg,

0.137 mmol) in CH₂Cl₂(1.5 mL) were added aqueous phosphate

buffer (0.5 M aqueous Na₂HPO₄/0.5 M aqueous NaH₂PO₄, 2:1,

0.15 mL) and DDQ (93.0 mg, 0.41 mmol). The mixture was stirred at

room temperature for 40 min, diluted with saturated aqueous

NaHCO₃(10 mL), and extracted with CH₂Cl₂(5 mLꢂ3). The com-

bined organic layers were dried and concentrated under reduced

pressure. The residue was puriﬁed by column chromatography on

silica gel (EtOAc/hexane, 1:30 to 1:10) to provide 55.7 mg (99%) of

de-MPM derivative as a colorless oil: TLC R_f0.25 (EtOAc/hexane,

d

8.5, 10.0, 12.6, 12.9, 20.1, 24.7 (2C), 28.3, 28.4, 29.1, 43.5, 46.2, 46.3,

46.4 (2C), 55.0, 55.7, 72.5, 94.4, 97.3 (2C), 123.0, 126.0 (2C), 126.4,

128.3 (2C), 130.6, 136.0, 138.6, 140.0; IR (neat) 2960, 2930 cm^ꢀ1

;

HRMS calcd for C₃₁H₄₈O₄[M]^þ484.3553, found 484.3552.

A solution of the styryl derivative (16.0 mg, 33.0 mmol) in 6 M

aqueous HCl/THF (1:1, 1.0 mL) was stirred at room temperature for

8 h. The mixture was quenched with saturated aqueous NaHCO₃

(10 mL) and extracted with EtOAc (5 mLꢂ3). The combined organic

layers were dried and concentrated under reduced pressure. The

residue was puriﬁed by column chromatography on silica gel

(EtOAc/hexane, 1:30 to 15:1) to provide 10.9 mg (84%) of de-MOM

25

1:4); [

a

]

²³þ24.0 (c 0.635, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.90

derivative as a colorless oil: TLC R_f0.27 (EtOAc/hexane, 1:4); [a]

D

(t, J¼7.5 Hz, 3H), 0.94 (t, J¼7.5 Hz, 3H), 1.02 (t, J¼7.5 Hz, 3H), 1.06 (t,

J¼7.8 Hz, 3H), 1.21 (d, J¼6.0 Hz, 3H), 1.25e1.54 (m, 3H), 1.62e1.85

(m, 3H), 1.88e2.18 (m, 6H), 3.29 (dd, J¼5.4, 6.6 Hz, 1H), 3.39 (s, 3H),

3.42 (s, 3H), 3.39e3.47 (m, 2H), 3.61e3.65 (m, 2H), 4.66 (d, J¼6.6 Hz,

1H),4.67 (s, 2H), 4.72 (d, J¼6.6 Hz, 1H), 4.87 (br s, 1H); ¹³C NMR

þ7.6 (c 0.55, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.79 (t, J¼7.2 Hz,

3H), 0.82 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz, 3H), 1.09 (t, J¼7.5 Hz,

3H),1.01e1.87 (m, 9H), 2.17e2.30 (m, 6H), 3.39 (br s, 1H), 3.61 (br,

1H), 3.77 (d, J¼11.1 Hz, 1H),5.54 (br s, 1H), 6.24 (d, J¼16.2 Hz, 1H),

6.31 (d, J¼16.2 Hz, 1H), 7.17e7.22 (m, 1H), 7.27e7.35 (m, 4H); ¹³C

(68 MHz, CDCl₃)

d

8.4, 11.4, 11.6, 13.1, 20.0, 23.9, 24.4, 24.5, 28.9, 29.1,

NMR (68 MHz, CDCl₃) d 8.5, 10.0, 12.7, 12.9, 19.5, 24.2 (2C), 28.0,

44.3, 46.4, 46.5, 46.9, 47.1, 55.4, 56.4, 64.3, 71.3, 92.5, 96.4, 97.0,

126.0, 140.0; IR (neat) 3440, 2960, 2920 cm^ꢀ1; HRMS calcd for

C₂₄H₄₄O₅[M]^þ412.3189, found 412.3190.

28.4, 29.0, 44.2, 45.9 (2C), 46.0 (2C), 67.1, 85.9, 126.0 (2C), 126.8,

128.5 (2C), 130.0 (2C), 138.0 (3C); IR (neat) 3440, 2960, 2930 cm^ꢀ1

HRMS calcd for C₂₇H₄₀O₂[M]^þ396.3028, found 396.3037.

;

To a cooled (0 ^ꢁC), stirred solution of the de-MPM derivative

(45.6 mg, 0.111 mmol) in CH₂Cl₂(1.0 mL) was added DesseMartin

periodinane (84.5 mg, 0.199 mmol). The mixture was stirred at

room temperature for 50 min and DesseMartin periodinane

To a cooled (0 ^ꢁC), stirred solution of the de-MOM derivative

(15.0 mg, 37.8 mmol) in CH₂Cl₂(1.0 mL) were added DesseMartin

periodinane (55.0 mg, 0.130 mmol) and NaHCO₃(23.0 mg,

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

quenched with saturated aqueous NaHCO₃(5 mL) and 20% aqueous

Na₂S₂O₃(5 mL) at 0 ^ꢁC, and extracted with CH₂Cl₂(5 mLꢂ3). The

combined organic layers were dried and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatog-

(26.1 mg, 61.5

room temperature for 50 min and additional DesseMartin peri-

odinane (25.3 mg, 59.7 mol) was added. The mixture was stirred at

m

mol) was added at 0 ^ꢁC. The mixture was stirred at

m

room temperature for 30 min, quenched with saturated aqueous

NaHCO₃(5 mL) and 20% aqueous Na₂S₂O₃(5 mL), and extracted

with CH₂Cl₂(5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:40 to 1:15)

to provide 37.4 mg (82%) of 44 as a colorless oil: TLC R_f0.50 (EtOAc/

raphy on silica gel (EtOAc/hexane, 1:100) to provide 12.0 mg (81%)

25.5

of 45 as a colorless oil: TLC R_f0.63 (EtOAc/hexane, 1:4); [a]

D

þ14.3 (c 0.60, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

0.83 (t, J¼7.2 Hz,

d

3H), 0.84 (t, J¼7.5 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H), 1.13 (t, J¼7.2 Hz,

3H), 1.30 (d, J¼7.2 Hz, 3H), 1.38e1.87 (m, 6H), 1.99e2.37 (m, 4H),

2.69 (t, J¼8.4 Hz, 1H), 2.96 (dd, J¼3.3, 8.4 Hz, 1H), 5.55 (d, J¼1.2 Hz,

1H), 6.23 (d, J¼16.2 Hz, 1H), 6.40 (d, J¼16.2 Hz, 1H), 7.22e7.28 (m,

hexane,1:4); [

a

]

þ6.9 (c 0.605, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

D²⁵

d

0.77 (t, J¼7.5 Hz, 3H), 0.93 (t, J¼7.5 Hz, 3H), 0.95 (t, J¼7.5 Hz, 3H),

1.06 (t, J¼7.5 Hz, 3H), 1.18 (d, J¼6.0 Hz, 3H), 1.34e1.71 (m, 4H), 1.67

(q, J¼7.5 Hz, 2H), 1.87 (br, 1H), 1.99e2.30 (m, 5H), 3.34e3.39 (m,

1H), 3.36 (s, 3H), 3.39 (s, 3H), 3.54 (d, J¼9.9 Hz, 1H),3.62 (d,

J¼9.9 Hz, 1H),4.62 (s, 2H), 4.63 (s, 2H), 5.54 (br s, 1H), 9.91 (s, 1H);

1H), 7.31e7.40 (m, 4H), 9.83 (s, 1H); ¹³C NMR (68 MHz, CDCl₃)

d 8.9,

11.0, 11.7, 12.7, 18.7, 23.6, 26.1, 28.8, 30.8, 39.7, 43.9, 47.8, 48.3, 53.1,

56.5, 123.5, 126.2 (2C), 127.5, 128.7 (2C), 131.5, 134.0, 137.1, 141.0,

207.2, 223.7; IR (neat) 2960, 2930, 1730, 1715 cm^ꢀ1; HRMS calcd for

C₂₇H₃₆O₂[M]^þ392.2715, found 392.2717.

¹³C NMR (68 MHz, CDCl₃)

d 8.9, 10.3, 11.7, 12.9, 20.2, 24.6, 24.7, 28.8,

28.9, 43.8, 44.7, 46.2, 46.3, 46.9 (2C), 55.3, 56.0, 71.2, 91.2, 95.8, 97.2,

120.2, 141.3, 207.8; IR (neat) 2960, 2930, 1715 cm^ꢀ1; HRMS calcd for

C₂₄H₄₂O₅[M]^þ410.3032, found 410.3029.

4.3.9. (1S,2Z,4R,5R,6R,7S,9R)-5-Carboxy-2,4,5,7-tetraethyl-9-methyl-

4-(1E)-styrylbicyclo[4.3.0]non-2-en-8-one (46). To a cooled (0 ^ꢁC),

stirred solution of 45 (12.0 mg, 30.6

mmol) in t-BuOH/H₂O (5:1,

4.3.8. (1S,2Z,4R,5R,6R,7S,9R)-2,4,5,7-Tetraethyl-5-formyl-9-methyl-

4-(1E)-styrylbicyclo[4.3.0]non-2-en-8-one (45). The following re-

action was carried out under argon. To a cooled (ꢀ78 ^ꢁC), stirred

solution of diethyl benzylphosphonate (0.72 mL, 3.5 mmol) in THF

(4.0 mL) was added n-BuLi (2.63 M solution in hexane, 1.0 mL,

2.6 mmol). The mixture was stirred at ꢀ78 ^ꢁC for 30 min and

1.0 mL) were added 2-methyl-2-butene (30

NaH₂PO₄(18.5 mg, 0.15 mmol), and NaClO₂(18.0 mg, 0.16 mmol).

The mixture was stirred at room temperature for 40 min and 2-

m

L, 0.28 mmol),

methyl-2-butene (100

mL, 0.94 mmol), NaH₂PO₄(54.9 mg,

0.46 mmol), and NaClO₂(53.1 mg, 0.46 mmol) were added at 0 ^ꢁC.

The mixture was stirred at room temperature for 30 min and ad-

a solution of 44 (35.0 mg, 85.2

mmol) in THF (2.2 mL) was added

ditional 2-methyl-2-butene (60 mL, 0.57 mmol), NaH₂PO₄(36.6 mg,

dropwise at ꢀ78 ^ꢁC. The mixture was warmed to 0 ^ꢁC over 2 h,

quenched with saturated aqueous NH₄Cl (10 mL), and extracted

with EtOAc (5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:100) to

0.305 mmol), and NaClO₂(35.4 mg, 0.305 mmol) were added. The

mixture was stirred at room temperature for 50 min, quenched

with saturated aqueous NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with

CH₂Cl₂(5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:100 to 1:10)

provide 39.6 mg (96%) of the styryl derivative as a colorless oil: TLC

23

R_f0.69 (EtOAc/hexane, 1:4); [

(300 MHz, CDCl₃)

a]

þ15.8 (c 0.80, CHCl₃); ¹H NMR

to provide 11.4 mg (91%) of 46 as a colorless oil: TLC R_f0.31 (EtOAc/

D

26

d

0.76 (t, J¼7.5 Hz, 3H), 0.79 (t, J¼7.8 Hz, 3H), 1.01

hexane, 1:4); [

a

]

þ13.4 (c 0.60, CHCl₃); ¹H NMR (300 MHz,

D

(t, J¼7.2 Hz, 3H), 1.06 (t, J¼7.5 Hz, 3H),1.03e1.07 (m, 3H), 1.26e1.42

(m, 1H), 1.52e1.87 (m, 5H), 2.16e2.30 (m, 5H), 2.46 (m, 1H), 3.23 (s,

CDCl₃)

d

0.78 (t, J¼7.5 Hz, 3H), 0.85 (t, J¼7.5 Hz, 3H),1.04 (t, J¼7.5 Hz,

3H), 1.16 (t, J¼7.5 Hz, 3H), 1.34 (d, J¼7.2 Hz, 3H),1.35e1.56 (m, 1H),

6742

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

1.61e1.96 (m, 4H), 2.00e2.39 (m, 4H), 2.46 (t, J¼7.2 Hz, 1H), 2.67

(dd, J¼8.1, 9.6 Hz, 1H), 3.10 (d, J¼8.1 Hz, 1H), 5.63 (br s, 1H), 6.36 (br

s, 2H), 7.23 (t, J¼7.5 Hz, 1H), 7.32 (t, J¼7.5 Hz, 2H), 7.42 (d, J¼7.5 Hz,

3H), 3.91 (d, J¼12.2 Hz, 1H), 3.99 (d, J¼12.2 Hz, 1H), 4.35 (d,

J¼11.6 Hz,1H), 4.40 (d, J¼11.6 Hz,1H), 4.66 (d, J¼6.0 Hz,1H), 4.68 (d,

J¼6.0 Hz, 1H), 5.14 (d, J¼10.5 Hz, 1H), 6.37 (dd, J¼1.5, 9.3 Hz, 1H),

6.86e6.89 (m, 2H), 7.24e7.26 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)

2H); ¹³C NMR (68 MHz, CDCl₃)

d 9.3, 11.9 (2C), 12.8, 18.7, 25.6, 27.3,

29.1, 32.3, 42.6, 44.7, 47.6, 48.8, 54.7, 55.6, 123.4, 126.2 (2C), 127.2,

128.6 (2C), 131.1, 135.5, 137.7, 139.4, 179.6, 224.4; IR (neat)

3450e3100, 2960, 2930, 1730, 1715 cm^ꢀ1; HRMS calcd for C₂₇H₃₆O₃

[M]^þ408.2665, found 408.2669.

d 11.9, 12.6, 13.9, 17.2, 21.4, 23.6, 24.7 (2C), 24.8 (2C), 36.1, 42.5, 55.2,

56.1, 70.9, 73.7, 83.0, 86.4 (2C), 98.1,113.7 (2C),129.1 (2C),129.5 (2C),

130.8, 138.6, 148.2, 159.1; IR (neat) 2960, 1615, 1515 cm^ꢀ1; HMRS

calcd for C₃₀H₄₉O₆B [M]^þ516.3643, found 516.3622.

To a cooled (0 ^ꢁC), stirred solution of the (E)-boronate obtained

4.4. Total synthesis of (D)-zyggomphic acid (6)

above (38.1 mg, 73.7

mmol) in CH₂Cl₂(1.0 mL) were added aqueous

phosphate buffer (0.5

M

aqueous Na₂HPO₄/0.5 aqueous

M

4.4.1. (2E,4S,5S,6S,7E)-2-Bromo-6-ethyl-8-(4-methoxybenzyloxy)

methyl-5-methoxymethoxy-4-methyldeca-2,7-diene (2:1 geometric

mixture) (47). To a cooled (0 ^ꢁC), stirred solution of 19 (133 mg,

0.324 mmol) in acetone/H₂O (4:1, 4.0 mL) was added NaIO₄

(187 mg, 0.875 mmol). The mixture was stirred at room tempera-

ture for 30 min, quenched with 1 M aqueous NaHSO₃(7 mL) at 0 ^ꢁC,

and extracted with EtOAc (5 mLꢂ3). The combined organic layers

were washed with saturated aqueous NaHCO₃(5 mL) and brine

(5 mL), dried, and concentrated under reduced pressure to provide

119 mg of crude aldehyde, which was used in the next step without

further puriﬁcation.

The following reaction was carried out under argon. To a cooled

(ꢀ40 ^ꢁC), stirred suspension of 1,1-(dibromoethyl)triphenylphos-

phonium bromide (741 mg,1.40 mmol) inTHF (4.0 mL) was added n-

BuLi (0.48 mL of 2.69 M solution in hexane, 1.2 mmol). The mixture

was stirred at ꢀ40 ^ꢁC for 30 min and cooled to ꢀ78 ^ꢁC. Then a solu-

tion of the crude aldehyde obtained above (119 mg) in THF (1.3 mL)

was added dropwise. The mixture was stirred at ꢀ78 ^ꢁC for 20 min,

quenched with H₂O (5 mL) at ꢀ78 ^ꢁC, diluted with saturated aqueous

NaHCO₃(10mL) andH₂O (5 mL), andextractedwith EtOAc(5 mLꢂ3).

The combined organic layers were washed with saturated aqueous

NaHCO₃(10 mL), dried, and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography on silica gel

NaH₂PO₄, 2:1, 0.1 mL) and DDQ (50.2 mg, 0.22 mmol). The mixture

was stirred at room temperature for 40 min, diluted with saturated

aqueous NaHCO₃(10 mL) at 0 ^ꢁC, and extracted with CH₂Cl₂

(5 mLꢂ3). The combined organic layers were dried and concen-

trated under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (EtOAc/hexane, 1:25 to 1:15) to pro-

vide 17.6 mg (60%) of 48 as a colorless oil: TLC R_f0.31 (EtOAc/

24.5

hexane, 1:3); [

CDCl₃)

a]

þ112 (c 0.62, CHCl₃); ¹H NMR (300 MHz,

D

d

0.80 (t, J¼7.4 Hz, 3H), 1.00 (d, J¼6.9 Hz, 3H), 1.02 (t,

J¼7.2 Hz, 3H), 1.07e1.15 (m, 1H), 1.26 (s, 6H), 1.27 (s, 6H), 1.66e1.83

(m, 1H), 1.70 (d, J¼1.5 Hz, 3H), 2.05e2.29 (m, 2H), 2.40e2.50 (m,

1H), 2.84 (br s, 1H), 2.90e3.01 (m, 1H), 3.35 (dd, J¼3.2, 8.6 Hz, 1H),

3.42 (s, 3H), 3.95 (d, J¼13.2 Hz, 1H), 4.10 (d, J¼13.2 Hz, 1H), 4.68 (d,

J¼6.8 Hz, 1H), 4.75 (d, J¼6.8 Hz, 1H), 4.92 (d, J¼10.8 Hz, 1H), 6.13

(dd, J¼1.5, 8.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)

d 11.6, 12.7, 13.8,

14.9 (2C), 21.4, 24.5, 24.6, 24.8 (2C), 36.3, 41.4, 56.0, 66.2, 83.5, 84.9

(2C), 97.1, 127.2 (2C), 140.7, 150.0; IR (neat) 3500, 2970, 1630 cm^ꢀ1

HRMS calcd for C₂₂H₄₁O₅B [M]^þ396.3052, found 396.3047.

;

4.4.3. (2E,4S,5S,6S,7E,9E,11E)-12-(tert-Butyldimethylsilyloxy)-

methyl-2,4,10-triethyl-5-methoxymethoxy-6,8-dimethyltetradeca-

2,7,9,11-tetraenal (50). The following reactionwas carried out under

argon. To a stirred solution of 48 (17.6 mg, 44.4

(43.9 mg, 115 mol) in degassed THF (4.4 mL) were added 3 M

aqueous NaOH (88 L, 0.27 mmol), PdCl₂(dppf)$CH₂Cl₂(3.6 mg,

4.4 mol), and a crystal of BHT. The mixture was stirred at room

mmol) and 49

(EtOAc/hexane, 1:50) to provide 62.9 mg (41% for two steps) of 47

m

24

(E/Z¼2:1) as a colorless oil: TLC R_f0.45 (EtOAc/hexane, 1:4); [

a

]

D

m

þ26.4 (c 1.00, CHCl₃); ¹H NMR (300 MHz, CDCl₃) for major isomer 47

m

d

0.84 (t, J¼7.5 Hz, 3H), 0.99 (t, J¼7.5 Hz, 3H), 1.02 (d, J¼7.2 Hz, 3H),

temperature for 20 h, diluted with saturated aqueous NH₄Cl (10 mL),

and extracted with EtOAc (5 mLꢂ3). The combined organic layers

were dried and concentrated under reduced pressure. The residue

was puriﬁed by column chromatography on silica gel (EtOAc/hex-

ane,1:15) to provide 16.8 mg (72%) of tetraene as a colorless oil: TLC

1.11e1.26 (m, 1H), 1.56e1.79 (m, 1H), 2.01e2.15 (m, 2H), 2.15

(d, J¼1.2 Hz, 3H), 2.31e2.44 (m, 1H), 2.53e2.65 (m, 1H), 3.22 (dd,

J¼3.6, 7.2 Hz, 1H), 3.41 (s, 3H), 3.81 (s, 3H), 3.95 (s, 2H), 4.40 (s, 2H),

4.66 (s, 2H), 5.10 (d, J¼10.5 Hz, 1H), 5.92 (dd, J¼1.2, 9.8 Hz, 1H),

6.86e6.89 (m, 2H), 7.24e7.27 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) for

R_f0.21 (EtOAc/hexane, 1:4); [

(300 MHz, CDCl₃)

a

]

^21.5þ82.0 (c 0.14, CH₂Cl₂); ¹H NMR

D

major isomer 47

d

11.9,12.7,17.4, 21.6, 23.8, 28.9, 37.8, 43.1, 55.3, 56.2,

d

0.08 (s, 6H), 0.82 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H),

71.4, 73.6, 86.3, 98.5, 113.8 (2C), 128.5 (2C), 129.3 (2C), 130.9, 134.2,

139.4, 159.2; IR (neat) 2960, 1615, 1515 cm^ꢀ1; HRMS calcd for

C₂₄H₃₇O₄Br [M]^þ468.1899, found 468.1875.

0.97 (t, J¼7.5 Hz, 3H), 0.98 (t, J¼7.5 Hz, 3H),1.02 (t, J¼7.5 Hz, 3H),1.03

(d, J¼7.5 Hz, 3H), 1.13e1.23 (m, 1H), 1.66e1.81 (m, 1H), 1.71 (d,

J¼0.6 Hz, 3H), 2.02 (dq, J¼7.5, 14.3Hz, 1H), 2.10e2.33 (m, 5H),

2.34e2.45 (m, 1H), 2.63e2.74 (m, 1H), 3.25 (dd, J¼3.9, 7.2 Hz, 1H),

3.41 (s, 3H), 4.07 (s, 2H), 4.14 (d, J¼1.2 Hz, 2H), 4.66 (d, J¼6.9 Hz,1H),

4.68 (d, J¼6.9 Hz, 1H), 5.13 (d, J¼10.2 Hz, 1H), 5.39 (d, J¼9.3 Hz, 1H),

4.4.2. 2-[(2Z,4S,5S,6S,7E)-6-Ethyl-8-hydroxymethyl-5-methox-

ymethoxy-4-methyldeca-2,7-dien-2-yl]-4,4,5,5-tetramethyl-1,3,2-di-

oxaborolane (48). The following reaction was carried out under

argon. To a stirred solution of 47 (69.1 mg, 0.147 mmol, E/Z¼2:1) in

toluene (2.8 mL) were added bis(pinacolato)diboron (101 mg,

5.70 (s, 1H), 5.86 (s, 1H); ¹³C NMR (75 MHz, CDCl₃)

d

ꢀ5.3 (2C), 11.9,

12.8, 13.6, 13.9, 17.1, 18.4, 21.4, 21.7, 23.7, 25.2, 26.0 (3C), 36.0, 42.6,

56.0, 66.3, 66.6, 87.4, 98.4,126.8,127.8,131.1,131.6,132.3,138.2,141.4,

141.6; IR (neat) 3420, 2960, 2880, 2860, 1460 m^ꢀ1; HRMS calcd for

C₃₁H₅₈O₄Si [M]^þ522.4103, found 522.4104.

0.397 mmol), PdCl₂(PPh₃)₂(10.3 mg, 14.7

mmol), PPh₃(7.7 mg,

29 mol), and KOPh (52.5 mg, 0.397 mmol). The mixture was stir-

m

red at 50 ^ꢁC for 4 h. After being cooled to room temperature, the

mixture was diluted with H₂O (20 mL) and extracted with EtOAc

(20 mL). The organic layer was washed with 2 M aqueous NaOH

(10 mLꢂ2) and brine (10 mL), dried, and concentrated under re-

duced pressure. The residue was puriﬁed by column chromatog-

raphy on silica gel (EtOAc/hexane, 1:40 to 1:20) to provide 38.1 mg

(50%) of (E)-boronate as a colorless oil: TLC R_f0.35 (EtOAc/hexane,

To a cooled (0 ^ꢁC), stirred solution of the tetraene obtained

above (16.8 mg, 32.1

mmol) in CH₂Cl₂(1.0 mL) were added

DesseMartin periodinane (21.8 mg, 51.4

mmol), NaHCO₃(8.7 mg,

0.10 mmol), and a crystal of BHT. The mixture was stirred at room

temperature for 15 min, quenched with saturated aqueous NaHCO₃

(5 mL) and 20% aqueous Na₂S₂O₃(5 mL) at 0 ^ꢁC, and extracted with

CH₂Cl₂(5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:80 to 1:60)

to provide 14.7 mg (88%) of 50as a colorless oil: TLC R_f0.58 (EtOAc/

1:5); [

a

]

²⁴þ37.5 (c0.56, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d 0.84

D

(t, J¼7.5 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H), 1.00 (d, J¼6.9 Hz, 3H), 1.24 (s,

12H), 1.68e1.79 (m, 1H), 1.97e2.18 (m, 3H), 2.38e2.48 (m, 1H),

2.78e2.90 (m, 1H), 3.31 (dd, J¼4.2, 6.3 Hz, 1H), 3.39 (s, 3H), 3.81 (s,

hexane, 1:4); ¹H NMR (300 MHz, CDCl₃)

d 0.08 (s, 6H), 0.85 (t,

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6743

J¼7.5 Hz, 3H), 0.88e0.96 (m, 3H), 0.94 (s, 9H), 0.97 (t, J¼7.5 Hz, 3H),

1.02 (t, J¼7.5 Hz, 3H), 1.06 (d, J¼7.2 Hz, 3H), 1.33e1.48 (m, 1H), 1.68

(s, 3H), 1.82e1.93 (m, 1H), 2.16e2.28 (m, 6H), 2.59e2.79 (m, 2H),

3.36e3.42 (m, 1H), 3.42 (s, 3H), 4.14 (d, J¼1.2 Hz, 2H), 4.68 (d,

J¼6.6 Hz, 1H), 4.71 (d, J¼6.6 Hz, 1H), 5.36 (d, J¼9.3 Hz, 1H), 5.67 (s,

1H), 5.85 (s, 1H), 6.23 (d, J¼10.8 Hz, 1H), 9.38 (s, 1H).

0.55, CHCl₃); ¹H NMR (300 MHz, CDCl₃)

d

0.04 (s, 6H), 0.79 (t,

J¼7.4 Hz, 3H), 0.88e0.93 (m, 3H), 0.89 (s, 9H), 0.90 (t, J¼7.2 Hz, 3H),

1.00 (t, J¼7.5 Hz, 3H), 1.23 (d, J¼6.9 Hz, 3H), 1.26e1.43 (m, 4H),

1.55e1.72 (m, 3H), 1.75e1.85 (m, 1H), 1.79 (s, 3H), 1.92e2.06 (m,

2H), 2.31 (t, J¼11.9 Hz, 1H), 2.44 (dq, J¼7.5, 13.4 Hz, 1H), 3.37 (s, 3H),

3.40 (s, 3H), 3.58 (d, J¼9.8 Hz, 1H), 3.60 (d, J¼3.3 Hz, 1H), 3.61 (d,

J¼9.8 Hz, 1H), 3.96 (d, J¼12.3 Hz, 1H), 4.05 (d, J¼12.3 Hz, 1H), 4.53

(d, J¼6.8 Hz, 1H), 4.58 (d, J¼6.5 Hz, 1H), 4.62 (d, J¼6.5 Hz, 1H),4.69

(d, J¼6.8 Hz, 1H), 5.21 (s, 1H), 5.36 (br s, 1H); ¹³C NMR (75 MHz,

4.4.4. (1R,2Z,4R,5R,6R,7S,8S,9S)-4-[[(1E)-2-(tert-Butyldimethylsily-

loxy)methyl]but-1-en-1-yl]]-4,5,7-triethyl-5-formyl-8-methox-

ymethoxy-2,9-dimethylbicyclo[4.3.0]non-2-ene (51). The following

reaction was carried out under argon. To a stirred solution of 50

CDCl₃)

d

ꢀ5.3 (2C), 9.4, 9.6, 12.3, 13.6, 14.6, 18.3, 19.8, 21.3, 22.6, 25.9

(2C), 28.8, 29.3, 40.5, 45.4, 45.6, 46.0, 51.9, 53.0, 55.4, 55.5, 68.2,

70.2, 86.2, 94.0, 97.0, 128.0, 129.5, 134.3141.7; IR (neat) 2960, 2930,

2880, 2860, 1460 cm^ꢀ1; HRMS calcd for C₃₃H₆₂O₅Si [M]^þ566.4385,

found 566.4367.

(14.7 mg, 28.2

mmol) in degassed toluene (2.8 mL) were added

Wako Gel C-300 (147 mg) and a crystal of BHT. The mixture was

stirred at room temperature for 21 h, ﬁltered through cotton, and

washed with EtOAc. The combined ﬁltrate and washings were

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (hexane to EtOAc/hexane,

1:200) to provide 10.8 mg (74%) of 51 and 3.3 mg of a byproduct.

To a cooled (0 ^ꢁC), stirred solution of the di-O-MOM derivative

obtained above (8.4 mg,15

mmol) inTHF (1.0 mL) was added n-Bu₄NF

(50 L of 1.0 M solution in THF, 50

m

mmol). The mixture was stirred at

room temperature for 2 h, diluted with saturated aqueous NH₄Cl

(12 mL) at 0 ^ꢁC, and extracted with EtOAc (5 mLꢂ3). The combined

organic layers were dried and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography on silica gel

Compound 51 was obtained as a colorless oil: TLC R_f0.60 (EtOAc/

24

hexane, 1:6); [

CDCl₃)

a

]

D

þ26.4 (c 0.50, CHCl₃); ¹H NMR (300 MHz,

d

0.03 (s, 6H), 0.79 (t, J¼7.4 Hz, 3H), 0.88 (s, 9H), 0.89 (t,

J¼7.2 Hz, 3H), 0.90 (t, J¼7.2 Hz, 3H), 0.94 (t, J¼7.4 Hz, 3H), 1.00e1.16

(m, 1H), 1.25 (d, J¼6.6 Hz, 3H), 1.30e1.38 (m, 2H), 1.50e1.60 (m, 2H),

1.77e1.88 (m, 1H), 1.82 (s, 3H), 1.90e2.12 (m, 3H), 2.30 (t, J¼11.4 Hz,

1H), 2.38e2.53 (m, 2H), 3.36 (s, 3H), 3.69 (dd, J¼1.5, 5.4 Hz, 1H),

3.94 (d, J¼13.1 Hz,1H), 4.01 (d, J¼13.1 Hz,1H), 4.54 (d, J¼6.8 Hz,1H),

4.65 (d, J¼6.8 Hz, 1H), 5.04 (s, 1H), 5.32 (br s, 1H), 9.76 (s, 1H); ¹³C

(EtOAc/hexane, 1:8) to provide 6.2 mg (93%) of 52 as a colorless oil:

25

TLC R_f0.33 (EtOAc/hexane, 1:2); [

NMR (300 MHz, CDCl₃)

a

]

D

þ42.7 (c 0.30, CHCl₃); ¹H

d

0.80 (t, J¼7.4 Hz, 3H), 0.93 (t, J¼7.5 Hz, 6H),

0.99 (t, J¼7.5 Hz, 3H), 1.24 (d, J¼6.9 Hz, 3H), 1.29e1.43 (m, 3H),

1.50e1.72 (m, 3H), 1.75e1.87 (m, 2H), 1.80 (s, 3H), 2.01 (dq, J¼7.5,

13.4 Hz, 1H), 2.11 (dq, J¼7.5, 13.6 Hz, 1H), 2.33 (t, J¼11.7 Hz, 1H), 2.47

(dq, J¼7.5, 13.6 Hz, 1H), 3.37 (s, 3H), 3.41 (s, 3H), 3.56 (d, J¼9.9 Hz,

1H), 3.61 (d, J¼3.0 Hz,1H), 3.62 (d, J¼9.9 Hz,1H), 4.03 (s, 2H), 4.53 (d,

J¼6.8 Hz, 1H), 4.59 (d, J¼6.5 Hz, 1H), 4.64 (d, J¼6.5 Hz, 1H), 4.69 (d,

J¼6.8 Hz, 1H), 5.28 (s, 1H), 5.36 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃)

NMR (75 Hz, CDCl₃)

d

ꢀ5.5, ꢀ5.4, 9.1, 10.2, 11.5, 13.5, 15.0, 18.2, 20.1,

20.6, 22.5, 25.8 (3C), 27.6, 29.1, 39.6, 46.1, 46.7, 48.7, 53.8, 55.5, 59.0,

67.3, 85.2, 94.6, 126.5, 127.5, 135.5, 143.5, 208.0; IR (neat) 2960,

2930, 2880, 2860, 1715, 1460 cm^ꢀ1; HRMS calcd for C₃₁H₅₆O₄Si

[M]^þ520.3961, found 520.3948.

d

9.4, 9.7, 12.3, 13.6, 14.7, 20.0, 21.3, 22.6, 28.9, 29.3, 40.6, 45.4, 45.5,

46.0, 52.0, 53.0, 55.4, 55.7, 68.8, 70.5, 86.1, 94.0, 97.2, 127.7, 131.5,

134.7, 142.3; IR (neat) 3440, 2960, 2930, 2880, 1460 cm^ꢀ1; HRMS

calcd for C₂₇H₄₈O₅[M]^þ452.3498, found 452.3502.

4.4.5. (1R,2Z,4R,5R,6R,7S,8S,9S)-4,5,7-Triethyl-4-[(1E)-2-hydrox-

ymethylbut-1-en-1-yl]-8-methoxymethoxy-5-(methoxymethoxy)

methyl-2,9-dimethylbicyclo[4.3.0]non-2-ene (52). To a cooled (0 ^ꢁC),

stirred solution of 51 (10.8 mg, 20.7

1.0 mL) was added NaBH₄(2.4 mg, 62

m

mol) in MeOH/THF (1:1,

4.4.6. (1R,2Z,4R,5R,6R,7S,8S,9S)-4,5,7-Triethyl-4-[(1E,3E)-2-ethyl-4-

phenylbuta-1,3-dien-1-yl]-8-hydroxy-5-hydroxymethyl-2,9-dime-

thylbicyclo[4.3.0]non-2-ene (53). To a cooled (0 ^ꢁC), stirred solution

mmol). The mixture was

stirred at room temperature for 30 min, quenched with saturated

aqueous NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with EtOAc (5 mLꢂ3).

The combined organic layers were dried and concentrated under

reduced pressure. The residue was puriﬁed by column chroma-

tography on silica gel (EtOAc/hexane, 1:100 to 1:30) to provide

of 52 (6.2 mg, 13

periodinane (9.3 mg, 22

m

mol) in CH₂Cl₂(1.0 mL) was added DesseMartin

mol). The mixture was stirred at room

m

temperature for 30 min, quenched with saturated aqueous NaHCO₃

(5 mL) and 20% aqueous Na₂S₂O₃(5 mL) at 0 ^ꢁC, and extracted with

CH₂Cl₂(5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:25) to pro-

vide 6.2 mg of unsaturated aldehyde as a colorless oil: TLC R_f0.60

8.7 mg (81%) of primary alcohol as a colorless oil: TLC R_f0.29

24.5

(EtOAc/hexane, 1:6); [

(300 MHz, CDCl₃)

a

]

D

ꢀ45.7 (c 0.16, CHCl₃); ¹H NMR

d

0.05 (s, 6H), 0.81 (t, J¼7.4 Hz, 3H), 0.88e0.93 (m,

3H), 0.90 (s, 9H), 0.90 (t, J¼7.2 Hz, 3H), 1.01 (t, J¼7.5 Hz, 3H), 1.23 (d,

J¼6.6 Hz, 3H), 1.25e1.44 (m, 4H), 1.57e1.72 (m, 3H), 1.75e1.92 (m,

2H), 1.79 (s, 3H), 2.01 (dq, J¼7.5, 13.4 Hz, 1H), 2.30 (t, J¼11.4 Hz, 1H),

2.44 (dq, J¼7.5, 13.4 Hz, 1H), 3.37 (s, 3H), 3.61 (d, J¼4.8 Hz, 1H), 3.76

(d, J¼11.4 Hz, 1H), 3.81 (d, J¼11.4 Hz, 1H), 3.98 (d, J¼12.5 Hz, 1H),

4.05 (d, J¼12.5 Hz, 1H), 4.54 (d, J¼6.9 Hz, 1H), 4.70 (d, J¼6.9 Hz, 1H),

(EtOAc/hexane, 1:2); ¹H NMR (300 MHz, CDCl₃)

d

0.81 (t, J¼7.5 Hz,

3H), 0.86e0.88 (m, 3H), 0.91 (t, J¼7.5 Hz, 3H), 1.02 (t, J¼7.5 Hz, 3H),

1.25 (d, J¼6.3 Hz, 3H), 1.35e1.50 (m, 4H), 1.57e1.72 (m, 2H),

1.83e1.95 (m, 2H), 1.83 (s, 3H), 2.22 (dq, J¼7.5, 13.5 Hz, 1H),

2.31e2.40 (m, 2H), 2.49 (dq, J¼7.5, 12.8 Hz, 1H), 3.37 (s, 3H), 3.43 (s,

3H), 3.55 (d, J¼10.4 Hz,1H), 3.60 (d, J¼4.8 Hz,1H), 3.65 (d, J¼10.4 Hz,

1H), 4.53 (d, J¼6.9 Hz, 1H), 4.62 (d, J¼6.5 Hz, 1H), 4.66 (d, J¼6.5 Hz,

1H), 4.67 (d, J¼6.9 Hz, 1H), 5.41 (br s, 1H), 6.40 (s, 1H), 9.36 (s, 1H).

The following reaction was carried out under argon. To a cooled

5.26 (s, 1H), 5.35 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃)

d

ꢀ5.4 (2C),

9.5, 9.7, 12.4, 13.6, 14.7, 18.3, 19.9, 21.1, 22.7, 25.9 (3C), 28.5, 29.8,

40.5, 45.5, 46.1, 46.2, 51.7, 52.8, 55.4, 64.7, 67.8, 86.3, 94.1, 127.8,

129.3, 134.5, 142.0; IR (neat) 3490, 2930, 2880, 2955, 1460 cm^ꢀ1

;

HRMS calcd for C₃₁H₅₈O₄Si [M]^þ522.4122, found 522.4104.

(ꢀ78 ^ꢁC), stirred solution of diethyl benzylphosphonate (40

mL,

To a stirred solution of the primary alcohol obtained above

(8.7 mg, 17 mol) in CH₂Cl₂(2.0 mL) were added i-Pr₂NEt (60 L,

0.34 mmol) and MOMCl (13 L, 0.17 mmol). The mixture was

0.19 mmol) in THF (1.0 mL) was added n-BuLi (50 mL of 2.69 M

m

solution in hexane, 0.13 mmol). The mixture was stirred at ꢀ78 ^ꢁC

m

for 30 min and then a solution of aldehyde obtained above (6.2 mg,

reﬂuxed for 10.5 h, diluted with saturated aqueous NH₄Cl (10 mL),

and extracted with CH₂Cl₂(5 mLꢂ3). The combined organic layers

were dried and concentrated under reduced pressure. The residue

was puriﬁed by column chromatography on silica gel (EtOAc/hex-

ane, 1:100 to 1:60) to provide 8.4 mg (89%) of di-O-MOM derivative

as a colorless oil: TLC R_f0.60 (EtOAc/hexane, 1:5); [

14

m

mol) in THF (0.7 mL) was added dropwise at ꢀ78 ^ꢁC. The

mixture was warmed to 0 ^ꢁC over 3 h, quenched with saturated

aqueous NH₄Cl (10 mL) at 0 ^ꢁC, and extracted with EtOAc (5 mLꢂ3).

The combined organic layers were dried and concentrated under

reduced pressure. The residue was puriﬁed by column chroma-

tography on silica gel (EtOAc/hexane, 1:70 to 1:50) to provide

21

a

]

ꢀ12.7 (c

D

6744

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

5.6 mg (78%) of styryl derivative as a colorless oil: TLC R_f0.58

room temperature for 2 h then additional 2-methyl-2-butene (20

0.19 mmol), NaH₂PO₄(11.1 mg, 92.5 mol), and NaClO₂(10.8 mg,

92.5

mol) were added at 0 ^ꢁC. The mixture was stirred at room

temperature for 1 h, quenched with saturated aqueous NH₄Cl

(10 mL) at 0 ^ꢁC, and extracted with CH₂Cl₂(5 mLꢂ3). The combined

organic layers were dried and concentrated under reduced pressure.

The residue was puriﬁed by column chromatography on silica gel

mL,

25.5

(EtOAc/hexane, 1:4); [

(300 MHz, CDCl₃)

a

]

ꢀ21.0 (c 0.21, CHCl₃); ¹H NMR

m

D

d

0.82 (t, J¼7.5 Hz, 3H), 0.85e0.92 (m, 3H), 1.01 (t,

m

J¼7.4 Hz, 3H), 1.02 (t, J¼7.4 Hz, 3H), 1.26 (d, J¼6.0 Hz, 3H), 1.30e1.43

(m, 4H), 1.53e1.59 (m, 2H), 1.62e1.72 (m,1H), 1.78e1.88 (m, 1H),

1.83 (s, 3H), 2.06 (dq, J¼7.4, 13.4 Hz, 1H), 2.31e2.41 (m, 1H), 2.35 (t,

J¼10.8 Hz,1H), 2.75 (dq, J¼7.4, 13.7 Hz,1H), 3.37 (s, 3H), 3.46 (s, 3H),

3.59 (d, J¼9.6 Hz, 1H), 3.60 (d, J¼3.6 Hz, 1H), 3.65 (d, J¼9.6 Hz, 1H),

4.53 (d, J¼6.8 Hz, 1H), 4.63 (d, J¼6.6 Hz, 1H), 4.67 (d, J¼6.6 Hz, 1H),

4.69 (d, J¼6.8 Hz, 1H), 5.43 (br s, 1H), 5.46 (s, 1H), 6.45 (d, J¼16.2 Hz,

1H), 6.68 (d, J¼16.2 Hz, 1H), 7.18 (t, J¼7.6 Hz, 1H), 7.30 (t, J¼7.6 Hz,

(EtOAc/hexane, 1:30 to 1:20) to provide 2.8 mg (68%) of 6 as a col-

21.5

orless oil: TLC R_f0.24 (EtOAc/hexane, 1:4); [

a]

þ82.0 (c 0.140,

D

CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃)

d

0.72 (t, J¼7.4 Hz, 3H), 0.88 (t,

J¼7.4 Hz, 3H), 0.99 (t, J¼7.4 Hz, 3H), 1.03 (t, J¼7.5 Hz, 3H), 1.33 (d,

J¼6.3 Hz, 3H),1.49 (dq, J¼7.4,13.4 Hz,1H),1.60e1.72 (m, 2H),1.84 (dq,

J¼7.4, 13.4 Hz, 1H), 1.89 (s, 3H), 1.93e2.03 (m, 2H), 2.08 (t, J¼11.4 Hz,

1H), 2.18e2.29 (m,1H), 2.38 (dq, J¼7.5,14.0 Hz,1H), 2.43 (ddd, J¼3.1,

5.8, 11.4 Hz, 1H), 2.63 (t, J¼11.4 Hz, 1H), 2.73 (dq, J¼7.5, 14.0 Hz, 1H),

5.21 (s,1H), 5.59 (br s,1H), 6.48 (d, J¼16.2 Hz,1H), 6.62 (d, J¼16.2 Hz,

1H), 7.18 (t, J¼7.2 Hz,1H), 7.29 (t, J¼7.2 Hz, 2H), 7.39 (d, J¼7.2 Hz, 2H);

2H), 7.41 (d, J¼7.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃)

d 9.5, 9.8, 12.4,

14.4, 14.7, 18.9, 21.5, 22.8, 29.0, 29.9, 40.7, 45.6 (2C), 46.2, 52.3, 54.4,

55.5, 55.8, 70.5, 86.2, 94.1, 97.2, 124.6, 126.2 (2C), 126.8, 127.5, 128.7

(2C), 135.0, 135.4 (2C), 139.8, 141.6; IR (neat) 2960, 2930, 2860,

1460 cm^ꢀ1; HRMS calcd for C₃₄H₅₂O₄[M]^þ524.3864, found

524.3866.

To a stirred solution of the styryl derivative obtained above

¹³C NMR (68 MHz, CDCl₃)

d 9.3, 9.9, 12.1, 14.2, 15.2, 19.1, 22.6, 22.9,

(5.6 mg, 11

m

mol) in MeOH (1.0 mL) was added CSA (12.4 mg,

23.2, 28.7, 43.3, 47.0, 47.2, 52.6, 52.7, 56.4, 125.8, 126.2 (2C), 126.3,

127.0, 128.5 (2C), 133.5, 134.6, 137.2, 137.8, 141.9, 176.8, 220.3; IR

(neat) 3300, 2960, 2930, 1730, 1700, 1460 cm^ꢀ1; HRMS calcd for

C₃₀H₄₀O₃[M]^þ448.2961, found 448.2978.

53.4

m

mol). The mixture was stirred at 40 ^ꢁC for 5 days, diluted with

saturated aqueous NaHCO₃(10 mL), and extracted with EtOAc

(5 mLꢂ3). The combined organic layers were dried and concen-

trated under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (EtOAc/hexane, 1:10) to provide

4.7 mg of 53 (quantitatively) as a colorless oil: TLC R_f0.36 (EtOAc/

Acknowledgements

25

hexane, 1:2); [

CDCl₃)

a]

ꢀ32.3 (c 0.13, CHCl₃); ¹H NMR (300 MHz,

D

ꢁ

d

0.85 (t, J¼7.5 Hz, 3H), 0.85e0.89 (m, 3H), 1.02 (t, J¼7.5 Hz,

This article is dedicated to Professor Satoshi Omura with

3H), 1.09 (t, J¼7.5 Hz, 3H), 1.24 (d, J¼6.9 Hz, 3H), 1.35e1.50 (m, 4H),

1.51e1.68 (m, 2H),1.73e1.80 (m,1H),1.83 (s, 3H), 2.00e2.10 (m,1H),

2.26e2.41 (m, 2H), 2.30 (t, J¼11.4 Hz, 1H), 2.76 (dq, J¼7.5, 13.7 Hz,

1H), 3.70 (d, J¼4.8 Hz,1H), 3.80 (d, J¼11.9 Hz,1H), 3.84 (d, J¼11.9 Hz,

1H), 5.44 (br s, 1H), 5.52 (s, 1H), 6.45 (d, J¼16.4 Hz, 1H), 6.74 (d,

J¼16.4 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.30 (t, J¼7.5 Hz, 2H), 7.42 (d,

admiration and respect on the occasion of his receipt of the 2010

Tetrahedron Prize for Creativity in Organic Chemistry. This work

was supported by Grants-in-Aid for Scientiﬁc Research on

Priority Areas (A) ‘Creation of Biologically Functional Molecules

(18032069)’ from the Ministry of Education, Culture, Sports,

Science, and Technology, Japan.

J¼7.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃)

d 9.4, 9.9, 12.2, 14.0, 14.1,

18.5, 20.7, 22.4, 28.3, 29.5, 40.5, 45.5, 46.8, 48.7, 51.6, 53.9, 64.9,

82.4, 122.4, 125.9 (2C), 126.5, 127.2 (2C), 128.3 (2C), 135.0, 137.9,

References and notes

139.3, 141.5; IR (neat) 3460, 2980, 2930, 2880, 2855, 1455 cm^ꢀ1

HRMS calcd for C₃₀H₄₄O₂[M]^þ436.3343, found 436.3341.

;

1. A recent review: Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,

P. T.; Prinsep, M. R. Nat. Prod. Rep. 2009, 26, 170e244.

2. Huang, X.-H.; van Soest, R.; Roberge, M.; Andersen, R. J. Org. Lett. 2004,

6, 75e78.

3. (a) Kobayashi, J.; Takeuchi, S.; Ishibashi, M.; Shigemori, H.; Sasaki, T. Tetrahedron

Lett. 1992, 33, 2579e2580; (b) Oureshi, A.; Stevenson, C. S.; Albert, C. L.; Jacobs,

R. S.; Faulkner, D. J. J. Nat. Prod. 1999, 62, 1205e1207.

4.4.7. (þ)-Zyggomphic acid (6). To a cooled (0 ^ꢁC), stirred solution

of 53 (4.7 mg, 11 mmol) in CH₂Cl₂(1.0 mL) was added DesseMartin

periodinane (11.9 mg, 28.1 mmol). The mixture was stirred at room

temperature for 30 min, quenched with saturated aqueous NaHCO₃

(5 mL) and 20% aqueous Na₂S₂O₃(5 mL) at 0 ^ꢁC, and extracted with

CH₂Cl₂(5 mLꢂ3). The combined organic layers were dried and

concentrated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (EtOAc/hexane, 1:100) to

provide 4.0 mg (86%) of keto aldehyde as a colorless oil: TLC R_f0.60

ꢂ

4. Berrue, F.; Thomas, O. P.; Fernandez, R.; Amade, P. J. Nat. Prod. 2005, 68,

547e549.

ꢂ

5. Berrue, F.; Thomas, O. P.; Laville, R.; Prado, S.; Golebiowski, J.; Fernandez, R.;

Amade, P. Tetrahedron 2007, 63, 2328e2334.

6. Mehta, G.; Kundu, U. K. Org. Lett. 2005, 7, 5569e5572.

7. (a) Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Chem. Commun. 2006, 2863e2865; (b)

Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Org. Lett. 2006, 8, 5537e5540 In this

article, the Baldwin group described the structural correction of the synthetic

intermediates described in the Mehta/Kundu’s publication (Ref. 6).

8. Crossman, J. S.; Perkins, M. V. Tetrahedron 2008, 64, 4852e4867.

(EtOAc/hexane, 1:4); ¹H NMR (300 MHz, CDCl₃)

d

0.74 (t, J¼7.5 Hz,

3H), 0.86 (t, J¼7.2 Hz, 3H), 0.92 (t, J¼7.5 Hz, 3H), 1.05 (t, J¼7.4 Hz,

3H), 1.26e1.49 (m, 2H), 1.37 (d, J¼6.6 Hz, 3H), 1.56e1.77 (m, 2H),

1.91 (s, 3H),1.93e2.05 (m, 2H), 2.12e2.25 (m,1H), 2.21 (t, J¼12.3 Hz,

1H), 2.30e2.42 (m, 1H), 2.46 (ddd, J¼3.8, 5.0, 12.3 Hz, 1H), 2.85 (dq,

J¼7.4,13.4 Hz,1H), 2.91 (t, J¼12.3 Hz,1H), 5.17 (s,1H), 5.53 (br s,1H),

6.50 (d, J¼16.2 Hz, 1H), 6.62 (d, J¼16.2 Hz, 1H), 7.21 (t, J¼7.5 Hz, 1H),

7.31 (t, J¼7.5 Hz, 2H), 7.40 (d, J¼7.5 Hz, 2H), 9.75 (d, J¼1.2 Hz, 1H).

To a cooled (0 ^ꢁC), stirred solution of the keto aldehyde obtained

€

9. Arzt, S.; Bourcet, E.; Muller, B.; Brase, S. Org. Biomol. Chem. 2010, 8, 3300e3306.

10. The absolute stereochemistries of 2e5 are yet unknown, and the structural

drawings in Fig. 1 are arbitrary.

11. (a) Matsumura, D.; Toda, T.; Hayamizu, T.; Sawamura, K.; Takao, K.; Tadano, K.

Tetrahedron Lett. 2009, 50, 3356e3358; (b) A microreview on the synthesis of 1:

Tadano, K. Eur. J. Org. Chem. 2009, 4381e4394.

12. Recent reviews on IMDA reaction: (a) Takao, K.; Munakata, R.; Tadano, K. Chem.

Rev. 2005, 105, 4779e4807; (b) Kelly, W. L. Org. Biomol. Chem. 2008,

6, 4482e4493; (c) Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983e2992.

13. Ihara, M. ,; Setsu, F.; Shoda, M.; Taniguchi, N.; Tokunaga, Y.; Fukumoto, K. J. Org.

Chem. 1994, 59, 5317e5323 The enantiomeric excess of 10 was reported to be

nearly 100%.

14. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919e5923.

15. Smithers, R. H. J. Org. Chem. 1978, 43, 2833e2838.

16. Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,

8001e8006.

17. Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47e65 Diethyl eth-

ylmalonate was converted to 24 by the following reaction sequence: (1) NaH,

Et₂O, reﬂux; then CHI₃, reﬂux, 24 h; (2) KOH, EtOH/H₂O¼3:1, reﬂux; (3)

LiAlH₄, THF, rt, 3 h, 30% over three steps; (4) TBSCl, DMAP, Et₃N, CH₂Cl₂, rt,

1 h, 83%.

above (4.0 mg, 9.3

2-methyl-2-butene (20

92.5 mol), andNaClO₂(10.8mg, 92.5

at room temperature for 1.5 h and then additional 2-methyl-2-bu-

tene (20 L, 0.19 mmol), NaH₂PO₄(11.1 mg, 92.5 mol), and NaClO₂

(10.8 mg, 92.5

mol) were added at 0 ^ꢁC. The mixture was stirred at

room temperature for 1.5 h then additional 2-methyl-2-butene

(20 L, 0.19 mmol), NaH₂PO₄(11.1 mg, 92.5 mol), and NaClO₂

(10.8 mg, 92.5

mol) were added at 0 ^ꢁC. The mixture was stirred at

m

mol) in t-BuOH/H₂O (5:1, 1.0 mL) were added

L, 0.19 mmol), NaH₂PO₄(11.1 mg,

mol). Themixturewas stirred

m

D. Matsumura et al. / Tetrahedron 67 (2011) 6730e6745

6745

18. For an example of the palladium-catalyzed oxidation of primary (allylic) alco-

hols, see: Tamaru, Y.; Yamada, Y.; Inoue, K.; Yamamoto, Y.; Yoshida, Z. J. Org.

Chem. 1983, 48, 1286e1292.

19. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc.1991,113, 7277e7287; (b) Ireland, R. E.;

Liu, L. J. Org. Chem. 1993, 58, 2899.

20. (a) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825e4830; (b) Bal, B. S.;

Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091e2096.

21. The numbering for the spiculane skeleton of 46 follows that used in the

Andersen’s paper, see Ref. 2.

22. Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am.

Chem. Soc. 1990, 112, 6339e6348.

23. (a) Veselovsky, V. V.; Gybin, A. S.; Lozanova, A. V.; Moiseenkov, A. M.;

Smit, W. A.; Caple, R. Tetrahedron Lett. 1988, 29, 175e178; (b) Herscovici,

J.; Delatre, S.; Boumalza, L.; Antonakis, K. J. Org. Chem. 1993, 58,

3928e3937.

24. The functionalized vinyl iodide 49 was synthesized as follows. Diethyl

ethylmalonate was ﬁrst converted to (E)-2-ethyl-iodo-2-propen-1-ol (A)

by the same procedure used for the preparation of 24, see Ref. 17.

Compound A was converted into 49 as follows: (1) DesseMartin period-

inane, CH₂Cl₂, rt; (2) EtC(CO₂Et)]PPh₃, toluene, 50 ^ꢁC, 20 h, 73% over two

steps: (3) DIBAL-H, CH₂Cl₂, ꢀ78 ^ꢁC, 91%: (4) TBSCl, DMAP, Et₃N, CH₂Cl₂, rt,

quant.

Article Doi

Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

DOI: 10.1016/j.tet.2011.04.006

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