Total synthesis of 10-isocyano-4-cadinene and its stereoisomers and evaluations of antifouling activities

ARTICLE

pubs.acs.org/joc

Total Synthesis of 10-Isocyano-4-cadinene and Its Stereoisomers

and Evaluations of Antifouling Activities

Keisuke Nishikawa,^†Hiroshi Nakahara,^†Yousuke Shirokura,^†Yasuyuki Nogata,^‡Erina Yoshimura,^§

Taiki Umezawa,^†Tatsufumi Okino,^†and Fuyuhiko Matsuda*^,†

^†Division of Environmental Materials Science, Graduate School of Environmental Science, Hokkaido University,

Sapporo 060-0810, Japan

^‡Environmental Science Research Laboratory, Central Research Institute of Electric Power Industry, 1646 Abiko, Abiko,

Chiba 270-1194, Japan

^§CERES, Inc., 1-6-1 Ogawa-cho, Kanda, Chiyoda-ku, Tokyo 101-0052, Japan

S Supporting Information

b

ABSTRACT: The ﬁrst enantioselective total synthesis of 10-

isocyano-4-cadinene, a marine sesquiterpene isolated from

nudibranchs of the family Phyllidiidae, and determination of

its absolute stereochemistry were achieved. 10-Isocyano-4-

cadinene is expected to be a novel nontoxic antifouling agent.

In the synthesis, intermolecular DielsÀAlder reaction and

samarium diiodide induced Barbier-type cyclization were employed as key steps. The absolute conﬁguration of 10-isocyano-4-

cadinene was determined as (1S,6S,7R,10S) by comparison of the optical rotations between natural and synthetic samples. In

addition, the authors successfully synthesized 10-epi- and di-1,6-epi-10-isocyano-4-cadinene through the same synthetic pathway.

Antifouling activities against Balanus amphitrite with the cadinenes were also evaluated.

’ INTRODUCTION

10-Isocyano-4-cadinene (1), a marine sesquiterpene isolated

by Okino et al.¹from nudibranchs of the family Phyllidiidae along

with other sesquiterpenes such as 10-isocyano-4-amorphene (2),

2-isocyanotrachyopsane (3), 1,7-epidioxy-5-cadinene (4), and

axisonitrile-3 (5), exhibits potent antifouling activity²against the

larvae of the barnacle Balanus amphitrite (EC₅₀= 0.14 μg/mL)

(Figure 1). It was revealed that the isonitrile group at the

quaternary carbon center is especially important for the antifoul-

ing activity.³Cadinene 1 is expected to be a novel lead compound

for nontoxic antifouling agents. As a fouling inhibitor, tributyltin

(TBT)⁴has been widely used in ships’ hulls and ﬁshing nets since

Figure 1. Sesquiterpenes from nudibranchs of the Family Phyllidiidae.

the early 1960s. Unfortunately, due to the toxicity of TBT, the

marine environment has been seriously compromised. For

example, TBT-exposed oysters have abnormal shell develop-

ment, brittle shells, poor weight gain, and imposex.⁵To prevent

pollution of the ocean environment, the marine environment

protection committee of the International Maritime Organiza-

tion (IMO) has prohibited the use of organotin compounds since

2008. Since the use of TBT was restricted in 1992 in Japan,

Japanese ships have been commonly coated with cuprous oxide

paints to prevent the settlement of fouling organisms. However,

the use of cuprous oxide and other copper compounds has also

been reported to cause environmental contamination.⁶

conﬁguration has not been determined. We have achieved the

ﬁrst enantioselective total synthesis of 1. In a previous letter, we

reported the determination of the absolute conﬁguration of 1

through the total synthesis of (+)-1 and (À)-1.⁷In the synthesis,

an intermolecular DielsÀAlder reaction and a samarium diiodide

(SmI₂)-induced Barbier-type reaction were employed as key

steps. The absolute conﬁguration of 1 was unambiguously

determined to be (1S,6S,7R,10S) on the basis of the total

synthesis. Antifouling activities against Balanus amphitrite with

both enantiomers of 1 were also evaluated. Moreover, we

successfully synthesized 10-epi- and di-1,6-epi-10-isocyano-4-

cadinene to examine the structureÀactivity relationship of the

As structural features, 1 has four continuous stereocenters,

including a quaternary carbon center with an isonitrile group.

Although the relative stereochemistry of 1 was assigned as shown

in Figure 1 using 1D and 2D NMR experiments, the absolute

Received: April 26, 2011

Published: July 14, 2011

r

2011 American Chemical Society

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Scheme 1. Intramolecular DielsÀAlder Reaction of

(()-Trienone 6

Scheme 3. Synthesis of Diene 18

Scheme 2. Retrosynthetic Analysis of 10-Isocyano-

4-cadinene (1)

Table 1. Optimization for Installation of E-Oleﬁn 18

entry

X

yield (%)^a

E:Z

1

2

3

PPh₃CI (17a)

POPh₂(17b)

PO(OEt)₂(17c)

46

45

84

80:20

100:0

^aIsolated yield in 2 steps from the alcohol 15.

functional groups at C10 of 1 would be installed with the ketone

9 at a later stage of the synthesis. To construct the cyclohexane

ring of 9, Barbier-type cyclization induced by SmI₂would

be applied to the aldehyde 10, which was derived from the

carboxylic acid 11. As mentioned above, the trans relationship at

C1 and C6 in 11 would be constructed by an intermolecular

DielsÀAlder reaction with the diene 12 and methyl acrylate,

followed by isomerization. The diene 12 would be synthesized

from the known imide 13.

Syntheses of the Intermolecular DielsÀAlder Reaction

Precursors 12. The total synthesis commenced with the known

imide 13,¹⁰prepared via Evans alkylation with allyl bromide

(Scheme 3). After OsO₄oxidation of the olefin moiety followed

by spontaneous lactonization of the resultant diol, acetylation of

the primary alcohol gave the acetate 14, and the chiral auxiliary

was recovered.^10bThe acetate 14 was converted into the alcohol

15 through LiBH₄reduction¹¹and subsequent selective aceto-

nide protection of the 1,2-diol moiety, which was then subjected

to Swern oxidation to provide the aldehyde 16. For the inter-

molecular DielsÀAlder reaction, the installation of the E-diene

moiety was required because a preliminary study indicated

that only the E-olefin reacted with the dienophile to afford the

DielsÀAlder adducts. The optimization for the E-selective olefina-

tion is shown in Table 1. Attempted olefination of 16 with

(2-methyl-2-propenyl)triphenylphosphonium chloride (17a)^12b,c

led to a 46% yield (based on the alcohol 15) of the diene (E)-18

and minor amounts of (Z)-18 in a ratio of 80:20 (E:Z) (entry 1).

When the reaction of 16 was carried out using (2-methyl-2-

propenyl)-diphenylphosphine oxide (17b),^12a,eonly the E-diene

cadinenes. In this article, we describe the full details of the total

synthesis of 1 and its isomers and evaluation of their antifouling

activities.

’ RESULTS AND DISCUSSION

Retrosynthetic Analysis of 10-Isocyano-4-cadinene (1).

We envisioned the construction of the trans relationship between

C1 and C6 by intermolecular DielsÀAlder reaction⁸followed by

equilibrium of the resultant mixture under basic conditions

because it is known that cis-decalin frameworks are selectively

formed through the corresponding intramolecular DielsÀAlder

reaction.⁹For a typical example, the intramolecular DielsÀAlder

reaction of the (()-trienone 6 afforded a mixture of the (()-cis-

decalins 7 and 8 in a ratio of 90:10 (7:8) (Scheme 1).^9bThe

mixture of 7 and 8 was isomerized by NaOMe in MeOH, form-

ing an inseparable mixture of 7, 8, and the (()-trans-decalin 9 in

a ratio of 43:47:10 (9:7:8). With this strategy in mind, retro-

synthetic analysis of 1 shown in Scheme 2 was planned. The

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Scheme 4. Synthesis of Intermolecular DielsÀAlder

Scheme 6. Intermolecular Aqueous DielsÀAlder Reactions

of Carboxylic Acid 12a, Successive Epimerization, and

Selective Hydrolysis

Reaction Precursor 12

Scheme 5. Synthesis of Esters 12e and 12f

1

(Scheme 5). The H NMR spectrum of 12e was not identical

to that of 12f, indicating that epimerization did not occur

under the strong basic conditions required in the HornerÀ

WadsworthÀEmmons reaction.

Intermolecular DielsÀAlder Reaction of Diene 12. We first

investigated the intermolecular DielsÀAlder reaction in water

between the carboxylic acid 12a and methyl acrylate. Aqueous

DielsÀAlder reactions were reported previously by Grieco

et al.¹⁶during the total synthesis of vernolepin.^16aThe reaction

of 12a under basic conditions at 80 °C for 96 h afforded the

adduct 19a in 86% yield as a mixture of four diastereomers

(Scheme 6). After the selective reduction of the carboxylic acid of

19a, the resultant mixture 19b was equilibrated with NaOMe

(25 equiv to 19b) in MeOH (0.08 M of substrate) to a mixture of

the two trans-esters 20 and 21. The desired ester 21 was

hydrolyzed with complete selectivity by the slow addition of 1

M HCl to the MeOH solution at 0 °C to provide the easily

separable mixture of the desired carboxylic acid 11 and the

unhydrolyzed ester 20 (11:20 = 1:2). Separation of the

diastereomers was essential for the total synthesis. After

extensive studies, we found the best procedure described

above. For example, treatment of 19b (four diastereomers)

with NaOMe (25 equiv to 19b) in dilute MeOH solution (0.02

M of substrate) and neutralization with 1 M HCl afforded a

mixture of 20 and 21 without hydrolysis of the methyl ester.

Attempted separation of 20 and 21 by silica gel chromatogra-

phy failed. Moreover, when the treatment of 19b with NaOMe

(25 equiv to 19b), followed by neutralization with 1 M HCl,

was conducted in concentrated MeOH solution (0.16 M of

substrate), both 20 and 21 were hydrolyzed.

was selectively obtained in 45% yield in 2 steps (entry 2). HornerÀ

WadsworthÀEmmons reaction of 16 with diethyl 2-methyl-2-

propenyl phosphonate (17c), according to the protocol reported

by Wang et al.,^9m,12d,12fcleanly proceeded to afford only (E)-18 in

good yield (84% based on 15) (entry 3).

As illustrated in Scheme 4, the intermolecular DielsÀAlder

reaction precursors 12aÀ12d were synthesized from 18. The

(E)-diene 18 was converted into the aldehyde by one-pot

deprotection of the acetonide group and oxidative treatment

with NaIO₄.¹³The carboxylic acid 12a was prepared by PDC

oxidation of the resultant aldehyde.¹⁴The alcohol 12b was

synthesized by NaBH₄reduction of the aldehyde. Subsequent

esteriﬁcation of 12b with acetic anhydride or diphenylacetic acid

aﬀorded the esters 12c or 12d, respectively.

In order to conﬁrm the optical purity of 12b, esteriﬁcation of

12b with (S)- or (R)-O-methylmandelic acid¹⁵was carried out to

give the esters 12e or 12f, respectively, as sole products

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Table 3. Examination of Intermolecular DielsÀAlder

Reactions Using Lewis Acids

Figure 2. Structures of hydroxyesters 20 and 21 and siloxyesters

22 and 23.

Table 2. Examination of Intermolecular Aqueous

DielsÀAlder Reactions

entry

diene

Lewis acid

solvent

yield(%)^a

ratio of 11:20

1

12c

12b

12d

12e

12f

BF₃OEt₂

toluene

CH₂Cl₂

benzene

xylene

0^b

0^c

3

2

ZnCI₂

3

Me₃AI

4

Me₂AICI

Et₂AICI

MeAICI₂

5

6

51

11

52

70

0^c

2:1

7

8

9

10

11

12

13

xylene

entry

diene

yield (%)^a

ratio of 11:20

xylene

36

0^c

1:1.5

1

2^b

12b

12c

12d

12e

12f

78

11

32

45

44

40

22

1:2

1:1

xylene

^aIsolated yield. ^bNo reaction. ^cComplex mixture.

3

4^b

5

Intermolecular aqueous DielsÀAlder reactions between the

various dienes 12bÀ12f and methyl acrylate were investigated.

In Table 2, isolated yields of DielsÀAlder adducts 19bÀ19f and

the ratios between desired 11 and unhydrolyzed 20 obtained

after the equilibration and the following selective hydrolysis are

shown. DielsÀAlder reaction of the alcohol 12b aﬀorded the

corresponding adducts 19b in 78% isolated yield, and desired

11 was obtained as the minor product in a ratio of 1:2 (11:20)

(entry 1). When Yb(OTf)₃was added as the Lewis acid, the

adduct 19a was obtained in 11% yield (entry 2). The acetate 12c

is less eﬀective for aqueous DielsÀAlder reaction, and a low yield

(32%) of 19c and a stereoselectivity ratio of 1:2 (11:20) were

observed (entry 3). By the addition of Yb(OTf)₃, the intermo-

lecular reaction of 12c resulted in 45% isolated yield of 19c and a

selectivity of 1:2 (11:20) (entry 4). Although intermolecular

reactions with 12dÀ12f aﬀorded 11 and 20 in a ratio of 1:1,

isolated yields of these adducts 19dÀ19f were low (22À44%)

(entries 5À7).

6

7

^aisolated yield. ^bYb(OTf)₃was added as Lewis acid.

We also examined the inﬂuence of the OH group in the

stereoselective hydrolysis and found that intramolecular

H-bonding plays an important role. As expected, when 1 M

HCl was added to a MeOH solution (0.08 M of substrate) of the

hydroxyester 21¹⁷and NaOMe (25 equiv to 21) at 0 °C,

hydrolysis of the methyl ester group smoothly occurred to aﬀord

the carboxylic acid 11 in almost quantitative yield (Figure 2). In

stark contrast, when the neutralization was carried out using the

siloxyester 23¹⁷under the exact same conditions, 23 was

quantitatively recovered without any hydrolysis of the methyl

ester moiety. Furthermore, the same treatment of the 1:1 mixture

of the siloxyesters 22¹⁷and 23 resulted in complete recovery of

the starting materials 22 and 23 without any cleavage of the

methyl ester group.¹⁸Apparently, the OH group of 21 enhances

the reactivity of 21 toward hydrolysis of its ester group. On the

other hand, IR spectra of 20 and 21 were measured in dilute

CCl₄solutions (0.01 M, 0.005, and 0.0025 M, Supporting

Information). Although the intramolecular H-bonding OH

absorption peak is appreciably weaker than the free OH absorp-

tion peak in the IR spectrum of 20, it is stronger than the free OH

absorption peak in the IR spectrum of 21. Therefore, it seems

feasible that intramolecular H-bonding between the OH and

CdO groups of 21 eﬀectively accelerates the hydrolysis of the

methyl ester moiety.

Next, we investigated the intermolecular DielsÀAlder reaction

of the dienes 12bÀ12f with methyl acrylate in organic solvent in

the presence of Lewis acids¹⁹(Table 3). Among various Lewis

acids (BF₃OEt₂, ZnCl₂, Me₃Al, Me₂AlCl, Et₂AlCl, and

3

MeAlCl₂) examined in toluene with 12c, only MeAlCl₂provided

the DielsÀAlder adducts 19c in 51% yield (entries 1À6). Similar

to the aqueous DielsÀAlder reactions, the mixture of the adducts

(4 diastereomers) was equilibrated with NaOMe in MeOH to

two trans-diastereomers 20 and 21. The desired product 11 was

obtained as the major product in a 2:1 (11:20) ratio after

diastereoselective hydrolysis of the methyl ester group of 21 by

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Scheme 7. Construction of trans-Decalin Skeleton via SmI₂-

Scheme 8. Synthesis of 10-epi-10-Isocyano-4-cadinene (30)

Mediated Cyclization

adding 1 M HCl to the MeOH solution (entry 6). Screening of

solvents in the presence of MeAlCl₂revealed that xylene was the

best for yield (70%), although the selectivity was only 2:1

(11:20) (entries 7À9). Therefore, the optimized conditions

for the DielsÀAlder reaction were found to be those in entry 9.

Intermolecular DielsÀAlder reactions with other dienes 12b and

12dÀ12f were examined under the optimized conditions and

resulted in low yields of the adducts or formation of complex

mixtures (entries 10À13).

stereochemistry at C10 could not be assigned. The conversion of

27 into 1 allowed the stereochemistry to be assigned. Thus,

Pinnick oxidation²⁴of 27 led to the carboxylic acid 28, which was

subjected to Curtius rearrangement using DPPA^9l,25to afford the

isocyanate. The isocyanato group was transformed to the iso-

nitrile group in 2 steps: NaBH₄reduction of the isocyanate to the

As mentioned so far, we found that the intermolecular

DielsÀAlder reaction using MeAlCl₂in xylene gave the desired

carboxylic acid 11 as the major product. Natural 1 was synthe-

sized from 11. Since the intermolecular aqueous DielsÀAlder

reaction aﬀorded the unhydrolyzed ester 20 as the major

product, 20 was used toward the synthesis of di-1,6-epi-10-

isocyano-4-cadinene to explore the structureÀactivity relation-

ships of the diastereomers. As described in this section, the

observed stereocomplementarity is highly advantageous because

it enhances the possibilities for application to divergent syntheses

of products with complementary stereochemistry.

1

formamide 29 and dehydration. Unfortunately, the H NMR

spectrum of synthetic 30 was not identical to that of natural 1.

From the NOESY spectrum, 30 was found to be the 10-epimer of

1.²⁶Therefore, an alternative procedure for the construction of

C10 stereochemistry was required.

Synthesis of 10-Isocyano-4-cadinene (1). The R-alkylation

of aldehyde 26 with MeI proceeded from the equatorial

orientation.²³Thus, we planned to construct an axial methyl

group in C10 by the following sequence: (1) introduction of an

equatorial hydroxyl methyl group with protecting group by the

alkylation of 26, (2) reduction of the aldehyde to the axial methyl

group, and (3) deprotection followed by oxidation. As expected,

the alkylation of 26 with p-methoxybenzyl chloromethyl ether

31²⁷successfully afforded the PMB ether 32, which was reduced

under WolffÀKishner conditions²⁸to afford the PMB ether 33 as

a single diastereomer (Scheme 9). The PMB ether 33 was

converted into the aldehyde by removal of the PMB group with

DDQ,²⁹followed by DessÀMartin oxidation. The aldehyde

group was converted into an isonitrile group by a 4-step reaction

sequence identical to that shown in the synthesis of 30: (1)

Pinnick oxidation, (2) Curtius rearrangement of the carboxylic

acid 34 with DPPA, (3) NaBH₄reduction of the isocyanate, and

(4) dehydration of 10-formamide-4-cadinene (35)³⁰with POCl₃

Synthesis of 10-epi-10-Isocyano-4-cadinene (30). We

turned our attention to the construction of the right cyclohexane

ring and the quaternary carbon center at C10 (Scheme 7). The

carboxylic acid 11 was transformed to the cyclization precursor

10 in a 4-step reaction sequence: (1) esterification with CH₂N₂,

(2) iodination of the primary alcohol, (3) DIBALH reduction of

the ester to the alcohol, and (4) oxidation with DessÀMartin

periodinane.²⁰The treatment of 10 with SmI₂in the presence of

HMPA afforded the alcohol 24 in 94% isolated yield,²¹which was

then oxidized with DessÀMartin periodinane. To install the

quaternary carbon center, the ketone 9 was first converted into

the nitrile 25 with p-toluenesulfonylmethyl isocyanide

(TosMIC).^9l,22The nitrile 25 was next reduced to the aldehyde

26, which was successfully methylated with MeI in the presence

of KOt-Bu to afford 27 as a single diasteromer (Scheme 8).²³In

contrast, direct methylation of 25 under various conditions

resulted in a low yield or complex mixture.^9lAt this stage, the

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Scheme 9. Synthesis of (+)-10-Isocyano-4-cadinene (1)

induced Barbier-type cyclization reaction of the aldehyde 36,

prepared from ester 20 in 3 steps, afforded the alcohol 37 in 91%

yield. The alcohol 37 was converted into the aldehyde in 3 steps.

The methyl group at C10 was introduced using MeI and t-BuOK.

The stereochemistry of 40 was unambiguously confirmed by a

NOESY spectrum of the alcohol 44 synthesized from 40 by

NaBH₄reduction (Scheme 12).³¹Pinnick oxidation of 40

afforded the carboxylic acid 41. The carboxylic acid 41 was

converted to (+)-di-1,6-epi-10-isocyano-4-cadinene (43) in a

3-step sequence.

We then synthesized the enantiomers, (+)-10-epi-10-isocya-

no-4-cadinene (ent-30) and (À)-di-1,6-epi-10-isocyano-4-cadi-

nene (ent-43), from (+)-imide ent-13 by the use of the same

synthetic procedure (Scheme 13).

Antifouling Activities with the Cadinenes. With 10-isocya-

no-4-cadinene (1) and its two diastereomers 30 and 43 in hand,

we evaluated their biological activities along with the synthetic

intermediates, 24, 9, and 25, and the enantiomers of 1, 30, and

43, prepared from ent-(+)-13 via the same synthetic scheme. The

activities were evaluated as EC₅₀(50% effective concentration)

values against cyprid larvae of the barnacle Balanus amphitrite

exposed to each compound for 48 h. The results are shown in

Table 4. Interestingly, (+)-1 and (À)-1 exhibited slightly differ-

ent EC₅₀values, which both corresponded closely to that of the

natural sample. Furthermore, both 30 and 43 exhibited potent

activities without regard to stereochemistry, although they were

less active than 1. In addition, 1 showed 100% inhibition at 1.0

μg/mL, whereas 30 and 43 inhibited 54À88% of larval meta-

morphosis. These results suggested that configurational differ-

ences in 1, 30, and 43 affected the antifouling activity against the

barnacle Balanus amphitrite. Among the synthetic intermediates

tested, 24-ax, 24-eq, and 9 showed activities similar to that of

CuSO₄(EC₅₀0.19 μg/mL), which is used as a fouling inhibitor.

However, most larvae exposed to 24-ax, 24-eq, and 9 floated on

the surface of the test seawater. The high rate of floating larvae

resulted in a low EC₅₀value. The effects of these intermediates

should be considered to be different from the antifouling

activities of the isocyano compounds. The nitriles 25-ax and

25-eq were revealed to be much less potent.

Scheme 10. Synthesis of (À)-10-Isocyano-4-cadinene (ent-1)

’ CONCLUSION

In summary, the total synthesis of 10-isocyano-4-cadinene was

achieved by intermolecular DielsÀAlder reaction and SmI₂-

induced Barbier-type reaction as the key steps. The absolute

conﬁguration of natural 10-isocyano-4-cadinene was determined

as (1S,6S,7R,10S). In the course of the synthesis, we successfully

synthesized10-epi- and di-1,6-epi-10-isocyano-4-cadinene in a

diastereoselective manner. With (+)- and (À)-10-isocyano-4-

cadinenes, their diastereomers, and intermediates, we evaluated

the antifouling activities against cyprid larvae of the barnacle

Balanus amphitrite and revealed that both enantiomers of

10-isocyano-4-cadinene exhibited potent activity. These results

indicate that the absolute conﬁguration of the cadinenes had little

eﬀect on the antifouling activity against the barnacle Balanus

amphitrite and lead us to investigate the structureÀactivity

relationship in more detail.

to achieve the total synthesis of 10-isocyano-4-cadinene (1). All

data (¹H and ¹³C NMR, MS, and IR) of the synthetic 1 were

completely identical with those of the natural sample. The optical

rotation of synthetic (+)-1, [R]²³+59.8 (c 0.65, CHCl₃), is

D

similar to that of the natural product, [R]²³+63.6 (c 0.60,

D

CHCl₃).¹Additionally, we synthesized the enantiomer, (À)-10-

isocyano-4-cadinene (ent-1), from (+)-imide ent-13 via (À)-

carboxylic acid ent-11 by the use of the same synthetic procedure

(Scheme 10). The optical rotation of (À)-ent-1, [R]²³_DÀ58.2 (c

0.68, CHCl₃), is opposite in sign to that of the natural product.

Therefore, the absolute configuration of (+)-1 is unambiguously

established as (1S,6S,7R,10S).

Syntheses of Stereoisomers. We performed the enantiose-

lective synthesis of di-1,6-epi-10-isocyano-4-cadinene (43) in a

similar manner in order to explore the structureÀactivity rela-

tionships of the cadinene diastereomers (Scheme 11). The SmI₂-

’ EXPERIMENTAL SECTION

General Methods. The optical rotations were determined with a

polarimeter. The melting points were determined using melting point

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Scheme 11. Synthesis of Di-1,6-epi-10-isocyano-4-cadinene (43)

Scheme 12. Conﬁrmation of Stereochemistry of Alcohol 44

Scheme 13. Synthesis of (+)-10-epi-10-Isocyano-4-cadinene

(ent-30) and (À)-Di-1,6-epi-10-isocyano-4-cadinene (ent-43)

apparatus. The IR spectra were recorded using IR spectrometer using a

NaCl cell or KBr disk. Nuclear magnetic resonance spectra were

recorded on 400 MHz spectrometer (¹H and ¹³C). Chemical shifts

were reported in ppm downfield from the peak of Me₄Si (TMS) used as

the internal standard. Splitting patterns are designed as “s, d, t, q, and m”,

indicating “singlet, doublet, triplet, quartet, and multiplet” respectively.

Tetrahydrofuran (THF) and ether were distilled from Na metal/

benzophenone ketyl. Dichloromethane (CH₂Cl₂), triethylamine (Et₃N),

iodomethane (MeI), and hexamethylphosphoramide (HMPA) were distilled

from CaH₂. All commercially obtained reagents were used as received.

Analytical and preparative TLC was carried out using precoated, glass-backed

silica gel plates. The column chromatography was performed using 230À400

mesh silica.

3022, 2958, 2914, 2866, 1776, 1694, 1639, 1603, 1495, 1452, 1383, 1347,

1289, 1232, 1207, 1124, 1099, 1074, 1050, 1000, 916, 839, 762, 746,

702 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (6H, d, J = 6.8 Hz), 2.01

(1H, octet, J = 6.8 Hz), 2.34À2.54 (2H, m), 2.64 (1H, dd, J = 10.2, 13.4

Hz), 3.31 (1H, dd, J = 3.2, 13.4 Hz), 3.86 (1H, m), 4.10À4.17 (2H, m),

4.69 (1H, m), 5.02 (1H, d, J = 10.2 Hz), 5.10 (1H, dd, J = 1.4, 17.1 Hz),

5.82 (1H, m), 7.20À7.37 (5H, m); ¹³C NMR (CDCl₃, 100 MHz)

δ 19.3, 20.9, 30.3, 33.7, 38.1, 48.2, 55.7, 65.7, 116.8, 127.2, 128.8, 129.3,

135.44, 135.50, 153.1, 175.6; EI-MS m/z 301 (M⁺); HR EI-MS m/z

301.1677 (M⁺, calcd for C₁₈H₂₃NO₃301.1678).

Acetate (14)^10b. To a solution of 13 (19.8 g, 65.8 mmol) in CH₃CN

(165 mL) were added NMO (50.0% in H₂O, 30.8 mL, 132 mmol) and

OsO₄(0.020 M in H₂O, 32.9 mL, 0.658 mmol) at room temperature

under Ar atmosphere. The mixture was stirred for 15 h, quenched with

saturated aqueous Na₂SO₃, and extracted with EtOAc. The combined

organic layers were washed with brine, dried over Na₂SO₄, filtered, and

Imide (13)¹⁰. Evans alkylation of (R)-3-(3-methylbutanoyl)-4-ben-

zyloxazolidin-2-one was performed using the previously described

procedure¹to afford 13 as a colorless oil: [R]²³= À65.4 (c 0.67,

D

CHCl₃), enantiomer [R]²³_D= +66.3 (c 0.71, CHCl₃); IR (neat) 3064,

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Table 4. Biological Activities of Synthetic (+)- and (À)-10-

Isocyano-4-cadinene, its Stereoisomers and the Synthetic

Intermediates

extracted with EtOAc. The combined organic layers were washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. Silica gel

column chromatography (EtOAc/hexane, 10:90) provided 15 (4.54 g,

22.4 mmol, 84% in 2 steps) as a colorless oil in a 3:2 mixture of two

diastereomers: IR (neat) 3426, 2950, 2866, 1464, 1368, 1247, 1216,

1159, 1058, 923, 863, 791 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.88,

0.90, 0.94 (total 6H, d, J = 6.8 Hz), 1.36, 1.37, 1.43 (total 6H, each s),

1.44À1.61 (1.6H, m), 1.61À1.88 (2.4H, m), 2.28 (0.6H, t, J = 5.8 Hz),

3.03 (0.4H, dd, J = 5.0, 7.9 Hz), 3.47À3.72 (3H, m), 4.02À4.20

(1.4H, m), 4.25 (0.6H, quintet, J = 6.4 Hz); ¹³C NMR (CDCl₃, 100

MHz) δ 19.1, 19.6, 19.9, 20.1, 25.7, 25.9, 26.89, 26.91, 28.2, 30.3, 32.5,

33.8, 43.4, 45.7, 63.9, 64.8, 69.7, 70.0, 74.0, 76.2, 108.8, 109.2; FAB-MS

m/z 203 (M⁺+ H); HR FAB-MS m/z 203.1654 (M⁺+ H, calcd for

C₁₁H₂₃O₃203.1647).

compound

EC₅₀(μg/mL)^a

compound

EC₅₀(μg/mL)^a

natural (+)-1^b

synthetic (+)-1

ent-(À)-1

(À)-30

0.14

0.06

0.08

0.21

0.40

0.16

0.20

24-ax

24-eq

9

0.31

0.38

0.26

4.36

1.48

0.27

25-ax

25-eq

ent-(+)-30

(+)-43

b

CuSO₄

ent-(À)-43

^aEC₅₀(μg/mL): Antifouling Activities against Balanus amphitrite.

Phosphonate (17c)^12d,f. A mixture of triethyl phosphite (19.3 g,

31.6 mmol) and 3-chloro-2-methylpropene (31.6 g, 348 mmol) was

heated at reflux for 9 days at 130 °C. Evaporation of the remaining

3-chloro-2-methylpropene afforded 17c (6.07 g, 31.6 mmol) as a

colorless oil, which was directly employed in the next reaction: IR

(neat) 3470, 3072, 2978, 2904, 1645, 1475, 1443, 1389, 1283, 1250,

^bReference.¹

1161, 1096, 1055, 1027, 963, 893, 859, 837, 795, 769, 736, 679 cm^À1

;

¹H NMR (CDCl₃, 400 MHz) δ 1.32 (6H, t, J = 7.2 Hz), 1.88 (3H, s),

2.56 (1H, s), 2.61 (1H, s), 4.05À4.18 (4H, m), 4.88 (1H, d, J = 5.1 Hz),

4.94 (1H, d, J = 3.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 16.39, 16.45,

23.62, 23.64, 34.7, 36.1, 61.78, 61.85, 115.2, 115.3, 136.0, 136.1; EI-MS

m/z 192 (M⁺); HR EI-MS m/z 192.0910 (M⁺, calcd for C₈H₁₇O₃P

192.0915).

Diene (18). DMSO (5.68 mL, 80.0 mmol) was added at À78 °C

under Ar atmosphere to a solution of oxalyl chloride (3.49 mL, 40.0

mmol) in CH₂Cl₂(95 mL). After 15 min of stirring, a solution of 15

(2.89 g, 14.3 mmol) in CH₂Cl₂(29 mL) was added dropwise. After

stirring for 50 min, the white suspension was treated with Et₃N

(14.9 mL, 107 mmol). The reaction was allowed to warm to room

temperature and stirred for 1 h. Saturated aqueous NH₄Cl was added to

the solution, and the mixture was extracted with EtOAc. The combined

organic layers were washed with brine, dried over Na₂SO₄, and filtered.

After the solvent was removed in vacuo, the resulting crude aldehyde was

used directly in the next reaction.

To a solution of 17c (8.24 g, 42.9 mmol) in THF (65 mL) was added

n-BuLi (2.64 M in hexane, 16.2 mL, 42.9 mmol) dropwise at À78 °C

under Ar atmosphere. After 30 min of stirring, HMPA (14.9 mL, 85.7

mmol) was added dropwise. A solution of the aldehyde in THF (20 mL)

was next added dropwise. The mixture was gradually warmed to room

temperature over 3 h, stirred for 12 h, quenched with saturated aqueous

NH₄Cl, and extracted with EtOAc. The combined organic layers were

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated in

vacuo. Silica gel column chromatography (EtOAc/hexane, 3:97) pro-

vided 18 (2.86 g, 12.0 mmol, 84% in 2 steps) as a colorless oil in a 3:2

ratio of two diastereomers: IR (neat) 3076, 2952, 2866, 1606, 1452,

1367, 1242, 1217, 1159, 1109, 1062, 969, 882, 826, 790 cm^À1; ¹H NMR

(CDCl₃, 400 MHz) δ 0.84, 0.88 (each 1.2H, d, J = 6.8 Hz), 0.85, 0.89

(each 1.8H, d, J = 6.8 Hz), 1.33, 1.40 (each 1.8H, brs), 1.33, 1.40 (each

1.2H, brs), 1.40À1.70 (2H, m), 1.70À1.89 (1.4H, m), 1.83 (3H, brs),

2.08 (0.6H, m), 3.40À3.53 (1H, m), 3.93À4.09 (2H, m), 4.88 (2H, brs),

5.36 (0.6H, dd, J = 10.0, 15.6 Hz), 5.43 (0.4H, dd, J = 9.2, 15.6 Hz), 6.05

(0.4H, d, J = 15.6 Hz), 6.13 (0.6H, d, J = 15.6 Hz); ¹³C NMR (CDCl₃,

100 MHz) δ 18.8, 18.9, 19.0, 20.5, 20.6, 25.8, 27.0, 27.1, 32.4, 32.6, 36.4,

37.0, 46.35, 46.44, 69.4, 70.0, 74.6, 75.0, 108.1, 108.3, 114.7, 114.8,

131.47, 131.52, 134.0, 134.4, 141.6; EI-MS m/z 238 (M⁺), 223 (M⁺À

CH₃); HR EI-MS m/z 238.1937 (M⁺, calcd for C₁₅H₂₆O₂238.1933).

Carboxylic Acid (12a). To a solution of 18 (2.17 g, 9.10 mmol) in

80% AcOH aqueous (446 mL) was slowly added NaIO₄(4.87 g, 22.8

mmol) at 0 °C under Ar atmosphere. The mixture was stirred for 4 h at

room temperature, diluted with H₂O, extracted with EtOAc, washed

concentrated under reduced pressure. The crude lactone was used

immediately for the next step.

The lactone was dissolved in pyridine (18 mL) and cooled to 0 °C.

Ac₂O (31.0 mL, 329 mmol) and DMAP (80.3 mg, 0.658 mmol) were

added to the solution under Ar atmosphere. The mixture was stirred for

2 h at 0 °C, quenched with MeOH (26 mL) at 0 °C, diluted with EtOAc,

and washed with saturated aqueous CuSO₄, H₂O, and saturated aqueous

NaHCO₃. The combined organic layers were dried over Na₂SO₄,

ﬁltered, and concentrated in vacuo. The crude product was puriﬁed by

silica gel column chromatography (EtOAc/hexane, 10:90) to give 14

(12.9 g, 64.5 mmol, 98% in 2 steps) as a colorless oil in a 1:1 ratio of two

diastereomers: IR (neat) 2956, 2870, 1770, 1740, 1643, 1466, 1369,

1339, 1234, 1166, 1120, 1075, 1043, 972, 843, 796, 746, 699 cm^À1; ¹H

NMR (CDCl₃, 400 MHz) δ 0.94, 1.05 (each 1.5H, d, J = 7.1 Hz), 0.95,

1.04 (each 1.5H, d, J = 6.8 Hz), 1.79 (0.5H, dt, J = 10.2, 12.2 Hz),

2.01À2.32 (2.5H, m), 2.10 (3H, s), 2.64 (1H, m), 4.11 (0.5H, d, J = 12.2

Hz), 4.13 (0.5H, dd, J = 1.7, 12.2 Hz), 4.26 (0.5H, dd, J = 3.6, 12.2 Hz),

4.34 (0.5H, dd, J = 2.9, 12.2 Hz), 4.57 (0.5H, m), 4.67 (0.5H, m); ¹³C

NMR (CDCl₃, 100 MHz) δ 18.1, 18.3, 20.3, 20.5, 20.66, 20.73, 25.86,

25.93, 27.6, 28.8, 45.1, 46.2, 64.9, 65.6, 74.9, 75.2, 170.3, 170.4,

177.0, 177.8; FAB-MS m/z 201 (M⁺+ H); HR FAB-MS m/z

201.1140 (M⁺+ H, calcd for C₁₀H₁₇O₄201.1127).

Alcohol (15). Compound 14 (5.32 g, 26.6 mmol) was dissolved in

THF (53 mL) under Ar atmosphere and cooled to 0 °C. LiBH₄(2.90 g,

133 mmol) was added to the solution. The mixture was stirred for 15

min, warmed to room temperature, and stirred for 12 h. The reaction

was slowly quenched with 1 N HCl (140 mL) at 0 °C, filtered through a

Celite pad, washed with THF, and concentrated under reduced pressure

to obtain the crude triol, which was directly reacted in the following

reaction.

To a solution of the triol in DMF (24 mL) were added 2,2-

dimethoxypropane (11.1 mL, 90.4 mmol) and p-TsOH H₂O (2.53 g,

3

13.3 mmol) at room temperature under Ar atmosphere. The mixture

was stirred for 15 h, quenched with saturated aqueous NaHCO₃, and

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with 15% NaOH aqueous solution and brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. The crude aldehyde was employed

directly in the next reaction.

(141 mg, 1.15 mmol), and DCC (297 mg, 1.44 mmol) at room

temperature under Ar atmosphere. The mixture was stirred for 2 h,

diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. The residue was purified by silica gel

column chromatography (EtOAc/hexane, 5:95) to give 12d (203 mg,

0.560 mmol, 97%) as a colorless oil: [R]²³_D= +18.3 (c 2.00, CHCl₃),

To a solution of the crude aldehyde in DMF (13 mL) was added PDC

(6.85 g, 18.2 mmol) at room temperature under Ar atmosphere. The

mixture was stirred for 15 h at room temperature, quenched with H₂O,

ﬁltered with a Celite pad, washed with Et₂O, extracted with Et₂O,

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. The residue

was puriﬁed by silica gel column chromatography (EtOAc/hexane/

CH₃CO₂H, 10:89:1) to give 12a (1.29 g, 7.10 mmol, 78% in 2 steps) as a

colorless oil: [R]²³_D= À9.9 (c 2.00, CHCl₃), enantiomer [R]²³_D= +9.8

(c 2.22, CHCl₃); IR (neat) 3076, 2954, 2868, 1707, 1607, 1436, 1409,

1384, 1368, 1294, 1260, 1165, 1100, 1033, 967, 884, 804 cm^À1; ¹H NMR

(CDCl₃, 400 MHz) δ 0.87, 0.90 (each 3H, d, J = 6.8 Hz), 1.70 (1H, m),

1.82 (3H, s), 2.33 (1H, dd, J = 8.5, 13.9 Hz), 2.44 (1H, m), 2.51 (1H, dd,

J = 5.1, 13.9 Hz), 4.89 (2H, s), 5.47 (1H, dd, J = 8.5, 15.6 Hz), 6.15 (1H,

d, J = 15.6 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 18.7, 18.9, 20.5, 31.8,

37.7, 45.4, 115.2, 129.9, 134.4, 141.7, 179.3; EI-MS m/z 182 (M⁺); HR

EI-MS m/z 182.13054 (M⁺, calcd for C₁₁H₁₈O₂182.13068).

Alcohol (12b). To a solution of 18 (32.6 g, 137 mmol) in 80%

aqueous AcOH (685 mL) was added NaIO₄(73.3 g, 343 mmol) at 0 °C

under Ar atmosphere. The mixture was stirred for 4 h at room temper-

ature, diluted with H₂O, and extracted with EtOAc. The combined

organic layers were washed with 15% NaOH aqueous solution and brine,

dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude

aldehyde was used directly in the next reaction.

enantiomer [R]²³= À17.6 (c 4.48, CHCl₃); IR (neat) 3058, 3022,

D

2952, 2864, 1733, 1602, 1494, 1451, 1383, 1365, 1347, 1304, 1271, 1226,

1

1185, 1148, 1080, 1029, 1007, 971, 883, 742, 700 cm^À1; H NMR

(CDCl₃, 400 MHz) δ 0.80, 0.83 (each 3H, d, J = 6.8 Hz), 1.46À1.62

(2H, m), 1.75À1.89 (2H, m), 1.80 (3H, s), 4.03, 4.17 (each 1H, m),

4.82, 4.86 (each 1H, s), 5.01 (1H, s), 5.33 (1H, dd, J = 9.5, 15.6 Hz), 5.95

(1H, d, J = 15.6 Hz), 7.20À7.38 (10H, m); ¹³C NMR (CDCl₃, 100

MHz) δ 18.8, 19.1, 20.6, 31.1, 32.2, 46.0, 57.3, 64.0, 114.8, 127.1, 128.48,

128.54, 128.6, 131.1, 134.6, 138.67, 138.70, 141.7, 172.3; EI-MS m/z

362 (M⁺); HR EI-MS m/z 362.2237 (M⁺, calcd for C₂₅H₃₀O₂

362.2246).

Ester (12e). To a solution of 12b (22.9 mg, 0.136 mmol) in CH₂Cl₂

(2.7 mL) were added (S)-(+)-methoxyphenyl acetic acid (33.9 mg,

0.204 mmol), DMAP (33.2 mg, 0.272 mmol), and DCC (70.2 mg, 0.340

mmol) at room temperature under Ar atmosphere. The mixture was

stirred for 2 h, diluted with EtOAc, washed with saturated aqueous

CuSO₄, saturated aqueous NaHCO₃, H₂O, and brine, dried over

Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified

by silica gel column chromatography (EtOAc/hexane, 3:97) to afford

12e (42.7 mg, 0.135 mmol, 99%) as a colorless oil; [R]²³= +88.6

D

(c 1.63, CHCl₃), enantiomer [R]²³_D= À83.2 (c 1.03, CHCl₃); IR (neat)

A solution of the aldehyde in MeOH (274 mL) was cooled to 0 °C

under Ar atmosphere. After NaBH₄(2.59 g, 68.5 mmol) was added to

this solution, the mixture was stirred for 30 min, quenched with

saturated aqueous NH₄Cl, and concentrated in vacuo. The aqueous

solution was extracted with EtOAc. The combined organic layers were

washed with brine, dried over Na₂SO₄, ﬁltered, and concentrated in

vacuo. The residue was puriﬁed by silica gel column chromatography

(EtOAc/hexane, 5:95) to aﬀord 12b (19.8 g, 118 mmol, 86% in 2 steps)

3072, 3025, 2952, 2918, 2866, 2820, 1747, 1603, 1492, 1452, 1383, 1367,

1256, 1197, 1172, 1116, 1074, 1028, 1010, 969, 883, 802, 730, 696 cm^À1

;

¹H NMR (CDCl₃, 400 MHz) δ 0.78, 0.82 (each 3H, d, J = 6.8 Hz),

1.43À1.60 (2H, m), 1.72À1.83 (2H, m), 1.78 (3H, s), 3.41 (3H, s), 4.00

(1H, m), 4.13 (1H, m), 4.75 (1H, s), 4.77 (1H, s), 4.84 (1H, s), 5.28

(1H, dd, J = 9.5, 15.6 Hz), 5.80 (1H, d, J = 15.6 Hz), 7.30À7.40 (3H, m),

7.41À7.47 (2H, m); ¹³C NMR (CDCl₃, 100 MHz) δ 18.8, 19.0, 20.6,

31.1, 32.1, 45.9, 57.3, 63.9, 82.6, 114.8, 127.1, 128.5, 128.6, 130.8, 134.6,

136.4, 141.6, 170.5; EI-MS m/z 316 (M⁺); HR FAB-MS m/z 339.1952

(M⁺+ Na, calcd for C₂₀H₂₈O₃Na 339.1936).

as a colorless oil: [R]²³_D= +15.5 (c 2.03, MeOH), enantiomer [R]²³

=

D

À15.3 (c 2.11, MeOH); IR (neat) 3350, 3074, 2950, 2866, 1606, 1464,

1452, 1383, 1366, 1257, 1165, 1047, 969, 883 cm^À1; ¹H NMR (CDCl₃,

400 MHz) δ 0.85, 0.90 (each 3H, d, J = 6.8 Hz), 1.40À1.70 (3H, m),

1.76 (1H, m), 1.84 (3H, s), 1.99 (1H, m), 3.52À3.71 (2H, m), 4.88

(2H, s), 5.44 (1H, dd, J = 9.5, 15.6 Hz), 6.13 (1H, d, J = 15.6 Hz);

¹H NMR (C₆D₆, 400 MHz) δ 0.83, 0.89 (each 3H, d, J = 6.6 Hz),

1.36À1.62 (2H, m), 1.70 (1H, m), 1.76 (3H, s), 2.01 (1H, m), 3.40À3.67

(2H, m), 4.88, 4.92 (each 1H, s), 5.39 (1H, dd, J = 9.5, 15.6 Hz), 6.16 (1H,

d, J = 15.6 Hz); ¹³C NMR (C₆D₆, 100 MHz) δ 19.7, 20.0, 21.7, 33.4,

36.6, 47.1, 61.9, 115.6, 133.1, 135.3, 142.7; EI-MS m/z 168 (M⁺), 153

(M⁺À CH₃); HR EI-MS m/z 168.1520 (M⁺, calcd for C₁₁H₂₀O 168.1514).

Acetate (12c). To a solution of 12b (6.06 g, 36.0 mmol) in CH₂Cl₂

(120 mL) were added Et₃N (20.0 mL, 144 mmol), Ac₂O (6.80 mL, 72.0

mmol), and DMAP (220 mg, 1.80 mmol) at 0 °C under Ar atmosphere.

The mixture was stirred for 30 min at 0 °C, diluted with CH₂Cl₂, washed

with brine and saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered,

and concentrated in vacuo. Purification over silica gel column chroma-

tography (EtOAc/hexane, 5:95) afforded 12c (7.50 g, 35.6 mmol, 99%)

Ester (12f). To a solution of 12b (68.9 mg, 0.409 mmol) in CH₂Cl₂

(8.2 mL) were added (R)-(À)-methoxyphenyl acetic acid (102 mg,

0.614 mmol), DMAP (99.9 mg, 0.818 mmol), and DCC (211 mg, 1.02

mmol) at room temperature under Ar atmosphere. The mixture was

stirred for 12 h, diluted with EtOAc, washed with H₂O and brine, dried

over Na₂SO₄, filtered, and concentrated in vacuo. The residue was

purified by silica gel column chromatography (EtOAc/hexane, 5:95) to

yield 12f (93.2 mg, 0.294 mmol, 72%) as a colorless oil; [R]²³_D= À19.4

(c 1.92, CHCl₃), enantiomer [R]²³_D= +18.8 (c 2.50, CHCl₃); IR (neat)

3070, 3024, 2952, 2868, 2820, 1746, 1641, 1605, 1492, 1452, 1383, 1366,

1347, 1256, 1197, 1174, 1113, 1073, 1027, 1006, 970, 884, 799, 729,

697 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.77, 0.79 (each 3H, d, J = 7.2

Hz), 1.42À1.53 (2H, m), 1.70À1.79 (2H, m), 1.80 (3H, s), 3.41 (3H, s),

4.01 (1H, m), 4.16 (1H, m), 4.74 (1H, s), 4.83 (1H, s), 4.86 (1H, s), 5.31

(1H, dd, J = 9.1, 15.6 Hz), 5.96 (1H, d, J = 15.6 Hz), 7.30À7.40 (3H, m),

7.41À7.46 (2H, m); ¹³C NMR (CDCl₃, 100 MHz) δ 18.7, 18.9, 20.5,

31.1, 32.0, 45.7, 57.3, 63.9, 82.6, 114.8, 127.1, 128.5, 128.6, 130.9, 134.6,

136.3, 141.6, 170.4; EI-MS m/z 316 (M⁺); HR EI-MS m/z 316.2045

(M⁺, calcd for C₂₀H₂₈O₃316.2039).

as a colorless oil: [R]²³_D= +7.7 (c 4.74, CHCl₃), enantiomer [R]²³

=

D

À7.9 (c 4.74, CHCl₃); IR (neat) 3076, 2952, 2866, 1739, 1606, 1464,

1

1384, 1365, 1235, 1037, 969, 884, 807 cm^À1; H NMR (CDCl₃, 400

MHz) δ 0.85, 0.89 (each 3H, d, J = 6.8 Hz), 1.49À1.69 (2H, m), 1.81

(1H, m), 1.83 (3H, s), 1.96 (1H, m), 2.03 (3H, s), 3.97 (1H, m), 4.08

(1H, m), 4.88 (2H, s), 5.39 (1H, dd, J = 9.2, 15.6 Hz), 6.08 (1H, d, J =

15.6 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 18.7, 19.0, 20.5, 20.9, 31.2,

32.2, 46.2, 63.3, 114.7, 131.1, 134.3, 141.6, 170.8; EI-MS m/z 210 (M⁺);

HR EI-MS m/z 210.1617 (M⁺, calcd for C₁₃H₂₂O₂210.1620).

Carboxylic Acid (11) and Ester (20). To a solution of 12a (181

mg, 0.995 mmol) in H₂O (1.00 mL) was NaHCO₃(100 mg, 1.19 mmol)

at room temperature. After the mixture was stirred for 30 min, methyl

acrylate (0.718 mL, 7.96 mmol) was added. The mixture was warmed to

80 °C and stirred for 96 h. The mixture was diluted with 1 N HCl at

room temperature, extracted with EtOAc, washed with brine, dried over

Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified

by silica gel column chromatography (EtOAc/hexane, 10:90) to yield

Ester (12d). To a solution of 12b (96.9 mg, 0.576 mmol) in CH₂Cl₂

(12 mL) were added diphenylacetic acid (183 mg, 0.864 mmol), DMAP

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colorless oil 19a (230 mg, 0.859 mmol, 86%) as a mixture of four

diastereomers: H NMR (CDCl₃, 400 MHz) δ 0.80, 0.85, 0.89, 0.92,

2 μmol, 99% in 2 steps) as a colorless oil: [R]²³= +26.5 (c 0.66,

D

CHCl₃), enantiomer [R]²³_D= À24.4 (c 0.85, CHCl₃); IR (neat) 2948,

2924, 2852, 1734, 1461, 1433, 1384, 1360, 1306, 1255, 1221, 1188, 1158,

1095, 1022, 932, 835, 808, 775, 662 cm^À1; ¹H NMR (CDCl₃, 400 MHz)

δ 0.05 (6H, s), 0.82, 0.87 (each 3H, d, J = 6.8 Hz), 0.89 (9H, s), 1.19, 1.48

(eacn 1H, m), 1.54À1.65 (2H, m), 1.69À1.99 (4H, m), 1.65 (3H, s),

2.50À2.58 (2H, m), 3.50À3.65 (2H, m), 3.66 (3H, s), 5.33 (1H, brs);

¹³C NMR (CDCl₃, 100 MHz) δ À5.2, 18.7, 23.1, 23.8, 25.8, 26.0, 26.1,

28.0, 28.9, 31.1, 40.3, 42.7, 43.3, 51.4, 62.9, 122.4, 133.3, 176.6; EI-MS

m/z 368 (M⁺); HR EI-MS m/z 368.2746 (M⁺, calcd for C₂₁H₄₀O₃Si

368.2747).

1

0.97 (total 6H, each d, J = 6.8 Hz), 1.68À2.37 (8H, m), 2.38À2.48,

2.49À2.58, 2.60À2.72, 2.72À2.84 (total 2H, each m), 3.64, 3.66, 3.69,

3.71 (total 3H, each s), 5.18, 5.26, 5.31, 5.41 (total 1H, each s).

To a solution of 19a (746 mg, 2.78 mmol) in THF (28 mL) was

added dropwise Et₃N (0.504 mL, 3.61 mmol) at À10 °C under Ar

atmosphere. Ethyl chloroformate (0.345 mL, 3.61 mmol) was added.

After 10 min of stirring, NaBH₄(841 mg, 22.2 mmol) was added. After

MeOH (18.5 mL) was slowly added, the mixture was warmed to room

temperature and stirred for 30 min. The mixture was adjusted with 1 N

HCl to pH 7, extracted with EtOAc, washed with brine, dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo. The residue was puriﬁed

by silica gel column chromatography (EtOAc/hexane, 10:90) to give

colorless oil 19b (683 mg, 2.68 mmol, 97%) as a mixture of four

diastereomers: ¹H NMR (CDCl₃, 400 MHz) δ 0.78, 0.83, 0.866, 0.874,

0.878, 0.883, 0.92, 0.93 (total 6H, d, J = 6.8 Hz), 1.27 (1H, m),

1.37À2.10 (6H, m), 1.66, 1.68 (total 3H, each s), 2.37, 2.47À2.58,

2.62À2.82 (total 2H, each m), 3.50À3.67 (2H, m), 3.66, 3.68, 3.69

(total 3H, each s), 5.22, 5.33, 5.47 (total 1H, each s).

Ester (23). To a solution of 20 (72.6 mg, 0.285 mmol) in CH₂Cl₂

(0.57 mL) were added Et₃N (47.7 μL, 0.342 mmol), DMAP (2.09 mg,

17.1 μmol), and TBSCl (47.3 mg, 0.314 mmol) under Ar atmosphere.

The mixture was stirred for 24 h, quenched with saturated aqueous

NaHCO₃and saturated aqueous NH₄Cl, extracted with EtOAc, dried

over Na₂SO₄, filtered, and concentrated under reduced pressure. The

residue was purified by silica gel column chromatography (EtOAc/

hexane, 5:95) to afford 23 (0.104 g, 0.282 mmol, 99%) as a colorless oil:

[R]²³_D= À40.3 (c 1.49, CHCl₃), enantiomer [R]²³_D= +39.9 (c 1.58,

CHCl₃); IR (neat) 2948, 2924, 2852, 1734, 1467, 1432, 1383, 1367,

1307, 1254, 1218, 1189, 1159, 1094, 1042, 1028, 1008, 937, 915, 833,

Na (1.62 g, 70.4 mmol) was slowly dissolved in MeOH (28 mL) at

room temperature under Ar atmosphere. To the mixture was added

dropwise a solution of 19b (358 mg, 1.41 mmol) in MeOH (7.1 mL).

The mixture was stirred for 24 h, slowly quenched with 1 N HCl to pH 1

at 0 °C, extracted with EtOAc, washed with brine, dried over Na₂SO₄,

ﬁltered, and concentrated in vacuo. The residue was puriﬁed by silica gel

column chromatography (EtOAc/hexane, 20:80) to aﬀord 11 (113 mg,

0.471 mmol, 33%) and 20 (240 mg, 0.994 mmol, 67%) as colorless oils:

11: [R]²³_D= +20.2 (c 0.53, CHCl₃), enantiomer [R]²³_D= À21.4 (c 0.70,

CHCl₃); IR (neat) 3010, 2950, 2868, 1700, 1449, 1432, 1409, 1384,

1

812, 775 cm^À1; H NMR (CDCl₃, 400 MHz) δ 0.04 (6H, s), 0.89

(9H, s), 0.90, 0.91 (each 3H, d, J = 7.0 Hz), 1.32À1.51 (2H, m),

1.58À1.84 (3H, m), 1.65 (3H, s), 1.84À2.05 (3H, m), 2.33 (1H, dt, J =

2.7, 9.7 Hz), 2.68 (1H, m), 3.54 (2H, t, J = 7.3 Hz), 3.66 (3H, s), 5.22

(1H, brs); ¹³C NMR (CDCl₃, 100 MHz) δ À5.1, 18.6, 20.4, 21.3, 23.9,

26.1, 26.9, 29.5, 30.8, 32.3, 38.6, 43.0, 44.8, 51.5, 63.4, 121.7, 134.1,

176.5; EI-MS m/z 368 (M⁺); HR EI-MS m/z 368.2742 (M⁺, calcd for

C₂₁H₄₀O₃Si 368.2747).

1365, 1293, 1259, 1239, 1191, 1045, 1009, 893, 875, 811, 771, 701 cm^À1

;

¹H NMR (CDCl₃, 400 MHz) δ 0.83, 0.89 (each 3H, d, J = 6.8 Hz), 1.35

(1H, m), 1.48 (1H, m), 1.63À1.82 (4H, m), 1.67 (3H, s), 1.88À2.11

(3H, m), 2.55 (1H, dt, J = 2.2, 10.1 Hz), 2.62 (1H, m), 3.63À3.80 (2H,

m), 5.33 (1H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 19.0, 23.4, 23.7, 26.4,

27.7, 29.1, 30.2, 39.2, 42.2, 43.3, 61.4, 121.3, 133.3, 181.0; FAB-MS m/z

239 (M⁺À H); HR FAB-MS m/z 239.1642 (M⁺À H, calcd for

C₁₄H₂₃O₃239.1647). 20: [R]²³_D= À34.2 (c 5.56, CHCl₃), enantiomer

1432, 1370, 1261, 1239, 1191, 1160, 1045, 1011, 936, 872, 811 cm^À1; ¹H

NMR (CDCl₃, 400 MHz) δ 0.91, 0.92 (each 3H, d, J = 6.8 Hz),

1.37À1.58 (2H, m), 1.62À1.85 (3H, m), 1.66 (3H, s), 1.85À2.10 (3H,

m), 2.37 (1H, dt, J = 2.7, 10.2 Hz), 2.68 (1H, d, J = 10.2 Hz), 2.78 (1H,

brs), 3.48À3.69 (2H, m), 3.68 (3H, s), 5.22 (1H, s); ¹³C NMR (CDCl₃,

100 MHz) δ 20.4, 21.2, 23.7, 26.5, 29.3, 30.9, 32.2, 38.9, 43.3, 44.8, 51.5,

63.0, 121.2, 134.6, 176.7; EI-MS m/z 254 (M⁺), 236 (M⁺À H₂O); HR

EI-MS m/z 254.1881 (M⁺, calcd for C₁₅H₂₆O₃254.1882).

Preparation of diazomethane. To a solution of KOH (6.08 g)

in Et₂O (76 mL) and H₂O (15 mL) was slowly added 1-methyl-3-nitro-

1-nitrosoguanidine (MNNG) (1.24 g, 5.16 mmol) at 0 °C. After 30 min

of stirring, the organic layers were directly employed as a solution of

CH₂N₂in Et₂O in the following reaction.

Ester (22). To a solution of 11 (12.7 mg, 52.7 μmol) in MeOH

(11 μL) was added CH₂N₂in Et₂O (0.78 mL) at room temperature

under Ar atmosphere. The mixture was stirred for 2 h at room

temperature and concentrated under reduced pressure. The crude ester

21 was directly employed in the next reaction.

Carboxylic Acid (11) and Ester (20). To a solution of methyl

acrylate (5.85 mL, 64.8 mmol) in xylene (54.2 mL) was added MeAlCl₂

(1.0 M in hexane, 23.8 mL, 23.8 mmol) dropwise at 0 °C under Ar

atmosphere. A solution of 12c (2.28 g, 10.8 mmol) in xylene (54 mL)

was next added dropwise. The mixture was stirred for 3 h at 0 °C and

gradually warmed to room temperature over 5 h. The mixture was

quenched with saturated aqueous NH₄Cl. After the two layers were

separated, the aqueous solution was extracted with EtOAc. The com-

bined organic layers were washed with brine, dried over Na₂SO₄, and

filtered. After the solvent was removed in vacuo, the residue was purified

by silica gel column chromatography (EtOAc/hexane, 5:95) to give the

DielsÀAlder adduct 19c (2.24 g, 7.56 mmol, 70%) as a colorless oil,

[R]²³= +34.4 (c 5.02, CHCl₃); IR (neat) 3428, 2948, 2866, 1733,

D

1

which was a mixture of four diastereomers: H NMR (CDCl₃, 400

MHz) δ 0.77, 0.78, 0.83, 0.85, 0.87, 0.88, 0.93, 0.94 (total 6H, d, J = 6.8

Hz), 1.18À2.12 (10H, m), 1.66, 1.68 (total 3H, each s), 2.03, 2.038,

2.042, 2.05 (total 3H, each s), 2.15À2.42, 2.42À2.89 (total 2H, each m),

3.65, 3.66, 3.67, 3.68 (total 3H, each s), 3.91À4.14 (2H, m), 5.21, 5.31,

5.34, 5.40 (total 1H, each s).

NaOMe solution was prepared by adding Na metal (9.32 g, 405

mmol) in small pieces to MeOH (160 mL) at room temperature. The

mixture was stirred until the metal was completely consumed. To the

mixture was added a solution of 19c (4.80 g, 16.2 mmol) in MeOH

(41 mL). The mixture was stirred for 24 h, slowly quenched with 1 N

HCl to pH 1 at 0 °C, and extracted with EtOAc. The combined organic

layers were washed with brine, dried over Na₂SO₄, and ﬁltered. After the

solvent was removed in vacuo, the residue was puriﬁed by silica gel

column chromatography (EtOAc/hexane, 20:80) to give 11 (2.60 g,

10.8 mmol, 67%) and 20 (1.37 g, 5.40 mmol, 33%) as colorless oils.

Ester (45). To a solution of 11 (764 mg, 3.18 mmol) in MeOH

(0.10 mL) was added CH₂N₂in Et₂O (47 mL) at room temperature

under Ar atmosphere. The mixture was stirred for 2 h at room

temperature and concentrated under reduced pressure. The crude ester

21 was directly employed in the next reaction.

To a solution of 21 in CH₂Cl₂(0.11 mL) were added Et₃N (8.81 μL,

63.2 μmol), DMAP (0.40 mg, 3.16 μmol), and TBSCl (8.70 mg, 58.0

μmol) under Ar atmosphere. The mixture was stirred for 24 h, quenched

with saturated aqueous NaHCO₃and saturated aqueous NH₄Cl,

extracted with EtOAc, dried over Na₂SO₄, ﬁltered, and concentrated

under reduced pressure. The residue was puriﬁed by silica gel column

chromatography (EtOAc/hexane, 5:95) to aﬀord 22 (19.2 mg, 52.

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ARTICLE

A solution of 21 in benzene (18 mL) was cooled to 0 °C under Ar

atmosphere. Then imidazole (325 mg, 4.78 mmol), triphenylphosphine

(1.25 g, 4.78 mmol), and I₂(2.26 g, 8.90 mmol) were added to the

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

quenched with saturated aqueous Na₂SO₃. After the two layers were

separated, the aqueous solution was extracted with EtOAc. The com-

bined organic layers were washed with brine, dried over Na₂SO₄, and

ﬁltered. After the solvent was removed in vacuo, the residue was puriﬁed

by silica gel column chromatography (EtOAc/hexane, 3:97) to give 45

(1.10 g, 3.02 mmol, 95% in 2 steps) as a colorless oil: [R]²³_D= +43.8

(c 1.81, CHCl₃), enantiomer [R]²³_D= À43.9 (c 2.11, CHCl₃); IR (neat)

2948, 2918, 2864, 1731, 1684, 1432, 1381, 1364, 1308, 1258, 1189, 1160,

1103, 1055, 1030, 843, 802, 725 cm^À1; ¹H NMR (CDCl₃, 400 MHz)

δ 0.82, 0.90 (each 3H, d, J = 6.8 Hz), 1.24 (1H, m), 1.67 (3H, s),

1.68À2.05 (7H, m), 2.50 (1H, t, J = 11.5 Hz), 2.59 (1H, brs), 3.12 (1H,

q, J = 8.6 Hz), 3.29 (1H, dt, J = 5.1, 9.3 Hz), 3.70 (3H, s), 5.29 (1H, s);

¹³C NMR (CDCl₃, 100 MHz) δ 6.5, 19.2, 23.2, 23.8, 26.4, 27.7, 29.1,

32.6, 39.6, 43.4, 47.6, 51.7, 121.5, 133.9, 176.4; EI-MS m/z 364 (M⁺),

237 (M⁺ÀI); HR EI-MS m/z 364.0901 (M⁺, calcd for C₁₅H₂₅IO₂

364.0900).

1283, 1238, 1226, 1187, 1157, 1138, 1112, 1091, 1054, 1028, 1012, 989,

1

978, 955, 906, 884, 855, 835, 805, 793 cm^À1; H NMR (CDCl₃, 400

MHz) δ 0.74, 0.91 (each 3H, d, J = 6.8 Hz), 0.98À1.34 (5H, m),

1.56À1.72 (3H, m), 1.66 (3H, s), 1.92À2.08 (3H, m), 2.10À2.24

(2H, m), 3.24 (1H, dt, J = 4.4, 10.3 Hz), 5.50 (1H, s); ¹³C NMR (CDCl₃,

100 MHz) δ 15.1, 21.6, 22.7, 24.0, 25.4, 26.1, 30.2, 35.6, 41.2, 45.8, 47.5,

74.2, 121.5, 134.9; EI-MS m/z 208 (M⁺), 190 (M⁺À H₂O); HR EI-MS

m/z 208.1824 (M⁺, calcd for C₁₄H₂₄O 208.1827). 24-ax: [R]²³_D= À9.3

(c 4.73, CHCl₃), enantiomer [R]²³_D= +9.3 (c 4.93, CHCl₃); IR (neat)

3364, 3044, 3000, 2950, 2952, 2862, 1684, 1462, 1447, 1388, 1368, 1333,

1297, 1212, 1188, 1138, 1118, 1094, 1074, 1054, 979, 951, 927, 886, 860,

792, 758, 727 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.79, 0.91 (each

3H, d, J = 6.8 Hz), 1.02 (1H, m), 1.18À1.67 (7H, m), 1.66 (3H, s),

1.83À2.25 (5H, m), 3.85 (1H, d, J = 2.0 Hz), 5.56 (1H, s); ¹³C NMR

(CDCl₃, 100 MHz) δ 15.3, 18.5, 21.5, 23.9, 26.2, 27.0, 30.8, 33.4, 35.8,

44.2, 46.8, 70.6, 122.5, 134.3; EI-MS m/z 208 (M⁺) 190 (M⁺À H₂O);

HR EI-MS m/z 208.1823 (M⁺, calcd for C₁₄H₂₄O 208.1827).

Ketone (9). DMP (1.08 g, 2.55 mmol) was added to a solution of 24

(213 mg, 1.02 mmol) in CH₂Cl₂(10 mL) at room temperature under Ar

atmosphere. The mixture was stirred for 1 h, quenched with saturated

aqueous Na₂S₂O₃and saturated aqueous NaHCO₃, and extracted with

CH₂Cl₂. The combined organic layers were washed with brine, dried

over Na₂SO₄, filtered, and concentrated in vacuo. The residue was

purified by silica gel column chromatography (EtOAc/hexane, 3:97) to

give 9 (198 mg, 0.959 mmol, 94%) as white crystals: mp 28À31 °C;

[R]²³_D= À84.1 (c 4.48, CHCl₃), enantiomer [R]²³_D= +87.3 (c 4.90,

CHCl₃); IR (KBr) 3040, 3004, 2952, 2922, 2864, 2826, 2720, 1712,

1451, 1429, 1367, 1313, 1291, 1259, 1234, 1204, 1185, 1143, 1065, 1030,

Alcohol (46). A solution of 45 (880 mg, 2.42 mmol) in CH₂Cl₂

(8.1 mL) was cooled to 0 °C under Ar atmosphere. DIBALH (1.01 M in

toluene, 4.78 mL, 4.83 mmol) was added dropwise to the solution. The

mixture was stirred for 1 h, quenched with MeOH (0.97 mL) and trace

of H₂O at 0 °C, filtered through a Celite pad, washed with CH₂Cl₂, and

concentrated in vacuo. Purification over silica gel column chromatogra-

phy (EtOAc/hexane, 10:90) yielded 46 (807 mg, 2.40 mmol, 99%) as

a colorless oil: [R]²³_D= +37.7 (c 3.84, CHCl₃), enantiomer [R]²³

=

D

À37.9 (c 3.89, CHCl₃); IR (neat) 3334, 3035, 2950, 2918, 2866, 2724,

1722, 1669, 1463, 1446, 1432, 1384, 1365, 1264, 1238, 1167, 1048, 1021,

974, 937, 877, 848, 806 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.82, 0.90

(each 3H, d, J = 6.8 Hz), 1.38 (1H, m), 1.49À2.04 (10H, m), 1.65

(3H, s), 3.15 (1H, q, J = 9.3 Hz), 3.27 (1H, dt, J = 5.4, 9.3 Hz), 3.54 (1H,

dd, J = 7.0, 10.6 Hz), 3.63 (1H, dd, J = 5.0, 10.6 Hz), 5.27 (1H, brs); ¹³C

NMR (CDCl₃, 100 MHz) δ 7.5, 18.3, 22.9, 23.91, 23.94, 27.8, 28.0, 32.3,

37.3, 38.1, 47.3, 65.4, 121.9, 134.1; EI-MS m/z 336 (M⁺); HR EI-MS

m/z 336.0950 (M⁺, calcd for C₁₄H₂₅IO 336.0951).

Preparation of THF Solution of SmI₂-HMPA. To a slurry of Sm

metal powder (1.50 g, 9.98 mmol) in THF (50 mL) was added CH₂I₂

(0.450 mL, 5.60 mmol) at room temperature under Ar atmosphere, and

the mixture was stirred overnight. HMPA (3.89 mL, 22.4 mmol) was

added, and the initially blue solution turned deep purple. The resulting

solution was directly used to effect the following reductive cyclization.

Alcohol (24-ax and 24-eq). To a solution of 46 (623 mg, 1.85

mmol) in CH₂Cl₂(19 mL) was added DessÀMartin periodinane

(DMP) (1.95 g, 4.63 mmol) at room temperature under Ar atmosphere.

The mixture was stirred for 1 h, quenched with saturated aqueous

Na₂S₂O₃and saturated aqueous NaHCO₃, and extracted with EtOAc.

The combined organic layers were washed with brine, dried over

Na₂SO₄, filtered, and concentrated under reduced pressure. The crude

aldehyde 9 was directly used in the next step.

1

1015, 971, 954, 941, 902, 874, 847, 830, 803, 784 cm^À1; H NMR

(CDCl₃, 400 MHz) δ 0.78, 0.99 (each 3H, d, J = 6.8 Hz), 1.36À1.60

(4H, m), 1.69 (3H, s), 1.90À2.47 (8H, m), 5.55 (1H, s); ¹³C NMR

(CDCl₃, 100 MHz) δ 15.0, 21.6, 21.9, 23.8, 25.4, 26.4, 29.7, 41.1, 44.3,

46.0, 51.1, 121.3, 135.7, 212.7; EI-MS m/z 206 (M⁺); HR EI-MS m/z

206.1679 (M⁺, calcd for C₁₄H₂₂O 206.1671).

Nitrile (25-eq and 25-ax). To a solution of 9 (195 mg, 0.943

mmol) in DME (4.7 mL) were added EtOH (0.155 mL, 2.64 mmol) and

p-toluenesulfonylmethyl isocyanide (TosMIC) (331 mg, 1.70 mmol).

After t-BuOK (359 mg, 3.21 mmol) was slowly added at 5À10 °C to the

solution, the mixture was warmed to room temperature and stirred for

1 h. The mixture was quenched with H₂O, neutralized with 1 N HCl to

pH 7, and extracted with EtOAc. The combined organic layers were

washed with brine, dried over Na₂SO₄, and filtered. After the solvent was

removed in vacuo, the residue was purified by silica gel column

chromatography (EtOAc/hexane, 3:97) to afford 25 (170 mg, 0.784

mmol, 83%) as a colorless oil in a 1:1 mixture of two diastereomers. A

part of the mixture was further separated by HPLC (Mightysil Si-60,

4.6 Â 250 mm, EtOAc/hexane, 2:98, flow rate 1.0 mL/min). 25-eq:

[R]²³_D= +44.0 (c 0.71, CHCl₃), enantiomer [R]²³_D= À43.5 (c 0.71,

CHCl₃); IR (neat) 3048, 3006, 2952, 2920, 2860, 2824, 2230, 1729,

1664, 1443, 1383, 1365, 1325, 1289, 1259, 1185, 1167, 1100, 1045, 987,

962, 902, 878, 852, 805, 759 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.74,

0.91 (each 3H, d, J = 7.0 Hz), 0.98À1.13 (2H, m), 1.29À1.44 (2H, m),

1.51À1.82 (3H, m), 1.67 (3H, s), 1.89À2.30 (6H, m), 5.49 (1H, s); ¹³C

NMR (CDCl₃, 100 MHz) δ 15.0, 21.3, 23.7, 23.8, 26.0, 28.4, 30.1, 30.3,

35.0, 42.5, 42.7, 45.5, 120.7, 122.1, 135.3; EI-MS m/z 217 (M⁺); HR EI-

After a solution of 9 in THF (19 mL) was degassed by freeze

treatment, a 0.100 M THF-HMPA solution of SmI₂(55.5 mL, 5.55

mmol) was added at room temperature under Ar atmosphere. The

mixture was stirred for 30 min and quenched with saturated aqueous

NaHCO₃. After the two layers were separated, the aqueous solution was

extracted with EtOAc. The combined organic layers were washed with

brine, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. The

product was puriﬁed by silica gel column chromatography (EtOAc/

hexane, 5:95) to give 24-eq (254 mg, 1.22 mmol, 66% in 2 steps) as

white crystals and 24-ax (109 mg, 0.522 mmol, 28% in 2 steps) as a

colorless oil. 24-eq: mp 99À102 °C; [R]²³_D= +37.3 (c 2.80, CHCl₃),

MS m/z 217.1830 (M⁺, calcd for C₁₅H₂₃N 217.1831). 25-ax: [R]²³

=

D

À52.4 (c 0.80, CHCl₃), enantiomer [R]²³_D= +56.7 (c 0.61, CHCl₃); IR

(neat) 3048, 3006, 2952, 2922, 2864, 2228, 1734, 1661, 1447, 1383,

1368, 1285, 1256, 1187, 1139, 1102, 1047, 951, 875, 799 cm^À1; ¹H NMR

(CDCl₃, 400 MHz) δ0.82, 0.92 (each 3H, d, J = 7.1 Hz), 1.03 (1H, dt, J =

2.9, 11.4 Hz), 1.32À1.50 (2H, m), 1.52À1.83 (4H, m), 1.67 (3H, s),

1.90À2.27 (5H, m), 2.83 (1H, brs), 5.53 (1H, s); ¹³C NMR (CDCl₃,

100 MHz) δ 15.3, 21.1, 21.5, 23.9, 26.2, 28.58, 28.64, 29.1, 30.2, 34.0,

enantiomer [R]²³= À37.9 (c 2.84, CHCl₃); IR (KBr) 3414, 3048,

D

3006, 2948, 2912, 2852, 1701, 1664, 1453, 1384, 1366, 1353, 1335, 1314,

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The Journal of Organic Chemistry

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39.1, 41.0, 46.4, 120.6, 121.1, 134.6; EI-MS m/z 217 (M⁺); HR EI-MS

m/z 217.1833 (M⁺, calcd for C₁₅H₂₃N 217.1831).

Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by

silica gel column chromatography (EtOAc/hexane, 1:99) to yield 30

(18.1 mg, 78.3 μmol, 93%) as a colorless oil: [R]²³_D= À22.3 (c 0.56,

Carboxylic Acid (28). To a solution of 25 (80.0 mg, 0.368 mmol)

in Et₂O (1.5 mL) was slowly added DIBALH (0.743 mL, 0.736 mmol)

at 0 °C under Ar atmosphere. The mixture was stirred for 15 min,

quenched with 1 N HCl, and stirred for 30 min. The mixture was diluted

with EtOAc, washed with brine, dried over Na₂SO₄, filtered, and concen-

trated in vacuo. The crude aldehyde 26 was employed directly in the next

reaction.

CHCl₃), enantiomer [R]²³= +23.7 (c 0.63, CHCl₃); IR (neat) 724,

D

794, 871, 886, 941, 1010, 1046, 1069, 1100, 1127, 1150, 1191, 1210,

1251, 1270, 1300, 1367, 1382, 1448, 1461, 1663, 2122, 2866, 2950,

3070 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.82, 0.92 (each 3H, d, J =

6.8 Hz), 0.96À1.14 (2H, m), 1.33À1.83 (5H, m), 1.41 (3H, s), 1.62

(3H, s), 1.88À2.10 (4H, m), 2.18 (1H, m), 5.51 (1H, s); ¹³C NMR

(CDCl₃, 100 MHz) δ 15.3, 20.1, 21.5, 23.2, 23.8, 26.2, 27.8, 30.5, 38.0,

39.8, 46.2, 47.3, 60.5 (as a triplet), 121.6, 134.3, 154.2 (as a triplet); EI-

MS m/z 231 (M⁺), 216 (M⁺À CH₃); HR EI-MS m/z 231.1972 (M⁺,

calcd for C₁₆H₂₅N 231.1987).

To a solution of 26 in toluene (5.3 mL) and CH₂Cl₂(5.3 mL) was

added t-BuOK (288 mg, 2.57 mmol) at 0 °C under Ar atmosphere. The

mixture was warmed to room temperature and stirred for 10 min. After

the mixture was cooled to 0 °C, MeI (0.688 mL, 11.0 mmol) was slowly

added. The mixture was warmed to room temperature and stirred for

15 h. The mixture was diluted with H₂O, extracted with EtOAc, washed

with brine, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. The

crude aldehyde 27 was employed directly in the next reaction.

To a solution of 27 in t-BuOH (4.9 mL) and H₂O (2.6 mL) were

added NaH₂PO₄(221 mg, 1.84 mmol) and 2-methyl-2-butene

(0.526 mL, 4.97 mmol). After 30 min, NaClO₂(208 mg, 1.84 mmol)

was slowly added. The mixture was stirred for 1 h at room temperature,

diluted with saturated aqueous NaCl, extracted with EtOAc, dried over

Na₂SO₄, ﬁltered, and concentrated in vacuo. The residue was puriﬁed by

silica gel column chromatography (EtOAc/hexane, 10:90) to aﬀord 28

(74.6 mg, 0.298 mmol, 81% in 3 steps) as white crystals: mp 66À69 °C;

[R]²³_D= À15.0 (c 0.77, CHCl₃), enantiomer [R]²³_D= +15.7 (c 0.95,

CHCl₃); IR (KBr) 2950, 2928, 2910, 2864, 1695, 1464, 1454, 1405,

Sulfide (47)²⁷. After a solution of NaI (3.61 g, 24.1 mmol) and NaH

(55%, 2.10 g, 48.2 mmol) in THF (27 mL) was cooled to 0 °C under Ar

atmosphere, (4-methoxyphenyl)methanol (3.00 mL, 24.1 mmol) was

added dropwise to the solution. The mixture was warmed to room

temperature and stirred for 1 h. Chloromethyl methyl sulfide (1.99 mL,

24.1 mmol) was added at 0 °C. The mixture was stirred for 12 h at room

temperature, quenched with H₂O, and extracted with EtOAc. The

combined organic layers were washed with brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. Silica gel column chromatography

(EtOAc/hexane, 5:95) provided 47 (4.54 g, 22.9 mmol, 95%) as a

colorless oil: IR (neat) 2990, 2950, 2914, 2830, 1610, 1582, 1510, 1461,

1439, 1379, 1299, 1246, 1172, 1108, 1059, 1035, 957, 909, 818, 760, 729,

680 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 2.18 (3H, s), 3.80 (3H, s),

4.55 (2H, s), 4.66 (2H, s), 6.88, 7.28 (each 2H, d, J = 8.5 Hz); ¹³C NMR

(CDCl₃, 100 MHz) δ 13.9, 55.3, 69.0, 74.0, 113.8, 129.4, 129.7, 159.2;

EI-MS m/z 198 (M⁺); HR EI-MS m/z 198.0713 (M⁺, calcd for

C₁₀H₁₄O₂S 198.0715).

1

1384, 1317, 1266, 1229, 1190, 1145, 1044, 934, 799 cm^À1; H NMR

(CDCl₃, 400 MHz) δ 0.77, 0.90 (each 3H, d, J = 6.8 Hz), 0.92À1.77

(7H, m), 1.26 (3H, s), 1.67 (3H, s), 1.83À2.07 (3H, m), 2.07À2.22

(2H, m), 5.51 (1H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 15.4, 21.4, 24.0,

24.2, 26.2, 26.3, 31.5, 38.3, 38.6, 45.3, 47.2, 49.0, 122.8, 134.4, 182.7; EI-

MS m/z 250 (M⁺); HR EI-MS m/z 250.1927 (M⁺, calcd for C₁₆H₂₆O₂

250.1933).

Chloride²⁷. To a solution of 47 (4.64 g, 23.4 mmol) in CH₂Cl₂

(59 mL) was dropwise added SO₂Cl₂(2.41 mL, 25.7 mmol) at À78 °C

under Ar atomosphere. The resulting solution of crude 31 was directly

used to the following step.

Formamide (29). To a solution of 28 (32.3 mg, 0.129 mmol)

in toluene (1.8 mL) were added diphenylphosphorylazide (DPPA)

(33.3 μL, 0.154 mmol) and Et₃N (21.6 μL, 0.154 mmol) at room

temperature under Ar atmosphere. After 30 min, the mixture was

warmed to 100 °C, stirred for 1 h, and concentrated in vacuo. The

crude isocyanate was employed directly in the next reaction.

PMB Ether (33). DIBALH (0.99 M in toluene, 0.901 mL, 0.892

mmol) was added to a solution of 25 (96.9 mg, 0.446 mol) in Et₂O

(1.5 mL) at 0 °C under Ar atmosphere. The mixture was stirred for

15 min, quenched with 1 N HCl, stirred for another 30 min, and

extracted with EtOAc. The combined organic layers were washed with

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude

aldehyde 26 was immediately employed in the next reaction.

A solution of 26 in toluene (6.4 mL) and CH₂Cl₂(6.4 mL) was cooled

to 0 °C under Ar atmosphere. After t-BuOK(350mg,3.12mmol) was added

to the solution, the mixture was stirred for 10 min at room temperature.

A solution of 31 (1.00 g, 5.35 mmol) in toluene (6.4 mL) and CH₂Cl₂

(6.4 mL) was added dropwise at 0 °C. The mixture was gradually

warmed to room temperature over 2 h, quenched with H₂O, and

extracted with EtOAc. The combined organic layers were washed with

brine, dried over Na₂SO₄, and ﬁltered. After the solvent was removed in

vacuo, the resulting residue was puriﬁed by silica gel column chroma-

tography (EtOAc/hexane, 3:97) to give the PMB ether 32.

To a solution of the isocyanate in EtOH (2.6 mL) was added NaBH₄

(29.3 mg, 0.774 mmol) at 0 °C under Ar atmosphere. The mixture was

warmed to room temperature, stirred for 3 h, diluted with H₂O,

extracted with EtOAc, washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo. The residue was puriﬁed by silica gel column

chromatography (EtOAc/hexane, 30:70) to give 29 (27.4 mg, 0.110

mmol, 85% in 2 steps) as white crystals: mp 99À102 °C; [R]²³_D= À47.5

(c 0.60, CHCl₃), enantiomer [R]²³_D= +48.3 (c 0.77, CHCl₃); IR (KBr)

3326, 3266, 2942, 2928, 2856, 2743, 1670, 1652, 1525, 1506, 1445, 1386,

1

1364, 1304, 1245, 1228, 1152, 1045, 883, 805, 670 cm^À1; H NMR

(CDCl₃, 400 MHz) δ 0.78, 0.92 (each 3H, d, J = 6.6 Hz), 1.05 (1H, m),

1.11À1.32 (2H, m), 1.40, 1.49 (total 3H, each s), 1.53 (1H, m), 1.67

(3H, s), 1.73À2.08 (6H, m), 2.18 (1H, m), 2.74 (1H, dd, J = 2.9, 10.4

Hz), 5.50, 5.52 (total 1H, each s), 5.11, 5.77 (total 1H, each s), 8.14, 8.23

(total 1H, each d, J = 1.7, 12.4 Hz); ¹³C NMR (CDCl₃, 100 MHz)

δ 15.3, 19.4, 19.8, 21.4, 21.5, 22.9, 23.0, 23.8, 25.6, 26.2, 27.9, 29.8, 30.8,

31.1, 36.0, 37.7, 37.9, 40.4, 46.6, 46.7, 48.6, 49.1, 53.7, 55.5, 121.6, 122.0,

134.5, 134.6, 160.5, 163.1; FAB-MS m/z 250 (M⁺+ H); HR FAB-MS

m/z 250.2168 (M⁺+ H, calcd for C₁₆H₂₈NO 250.2171).

Isonitrile (30). To a solution of 29 (21.0 mg, 84.2 μmol) in CH₂Cl₂

(8.4 mL) were added dropwise POCl₃(23.1 μL, 0.253 mmol) and Et₃N

(0.106 mL, 0.758 mmol) at 0 °C under Ar atmosphere. After 30 min, the

mixture was warmed to room temperature, stirred for 1 h, quenched with

cooled water, extracted with EtOAc, washed with brine, dried over

To a solution of the PMB ether 32 in diethylene glycol (18 mL) were

added KOH (450 mg, 8.03 mmol) and NH₂NH₂H₂O (0.546 mL, 11.2

3

mmol) at room temperature under Ar atmosphere. The mixture was

heated at 180 °C for 2 h, diluted with EtOAc, washed with saturated

aqueous NH₄Cl, dried over Na₂SO₄, ﬁltered, and concentrated in vacuo.

Silica gel column chromatography (EtOAc/hexane, 1:99) provided 33

(67.0 mg, 0.187 mmol, 42% in 3 steps) as a colorless oil: [R]²³_D= +7.9

(c 1.24, CHCl₃), enantiomer [R]²³_D= À7.9 (c 1.27, CHCl₃); IR (neat)

3060, 2950, 2924, 2850, 2720, 1728, 1611, 1582, 1510, 1461, 1453, 1364,

1299, 1245, 1206, 1170, 1091, 1038, 884, 875, 821, 752 cm^À1; ¹H NMR

(CDCl₃, 400 MHz) δ 0.75 (3H, s), 0.78, 0.90 (each 3H, d, J = 6.8 Hz),

0.97 (1H, m), 1.07À1.70 (6H, m), 1.65 (3H, s), 1.78À2.00 (4H, m),

2.14 (1H, m), 3.07, 3.26 (each 1H, d, J = 8.8 Hz), 3.81 (3H, s), 4.38, 4.46

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ARTICLE

(each 1H, d, J = 12.0 Hz), 5.53 (1H, s), 6.87, 7.24 (each 2H, d, J = 8.7

Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 15.4, 16.2, 19.8, 21.6, 23.7, 24.0,

26.3, 31.3, 36.1, 37.0, 37.5, 43.2, 46.9, 55.3, 72.8, 78.5, 113.5, 123.1,

128.7, 131.1, 134.2, 158.7; EI-MS m/z 356 (M⁺); HR EI-MS m/z

356.2717 (M⁺, calcd for C₂₄H₃₆O₂356.2715).

Carboxylic Acid (34). To a solution of 33 (7.10 mg, 19.9 μmol) in

CH₂Cl₂(2.0 mL) were added H₂O (0.10 mL) and DDQ (6.80 mg, 29.9

μmol) at room temperature under Ar atmosphere. The mixture was

stirred for 1 h, quenched with saturated aqueous Na₂S₂O₃and saturated

aqueous NaHCO₃, and extracted with CH₂Cl₂. The combined organic

layers were washed with brine, dried over Na₂SO₄, filtered, and concen-

trated in vacuo. The crude alcohol was immediately employed in the

next step.

DMP (21.0 mg, 49.8 μmol) was added to a solution of the alcohol in

CH₂Cl₂(2.0 mL) at room temperature under Ar atmosphere. The

mixture was stirred for 1 h and quenched with saturated aqueous

Na₂S₂O₃and saturated aqueous NaHCO₃. After the two layers were

separated, and the aqueous solution was extracted with EtOAc. The

combined organic layers were washed with brine, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The crude aldehyde

was directly used in the following reaction.

Isonitrile (10-Isocyano-4-cadinene) (1). After 35 (6.30 mg,

25.3 μmol) was dissolved in CH₂Cl₂(2.5 mL) and cooled to 0 °C under

Ar atmosphere, POCl₃(6.90 μL, 75.8 μmol) and Et₃N (31.7 μL, 0.228

mmol) were added to the solution, and the mixture was stirred for 30

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

with cooled H₂O, and extracted with EtOAc. The combined organic

layers were washed with brine, dried over Na₂SO₄, filtered, and concen-

trated in vacuo. Purification over silica gel column chromatography

(EtOAc/hexane, 1:99) gave 1 (5.50 mg, 23.8 μmol, 94%) as a colorless

oil: [R]²³_D= +59.8 (c 0.65, CHCl₃), enantiomer [R]²³_D= À58.2 (c 0.68,

CHCl₃); IR (neat) 3052, 2922, 2864, 2729, 2122, 1733, 1464, 1452,

1381, 1259, 1210, 1170, 1152, 1127, 1080, 1043, 1012, 955, 908, 884,

871, 809 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.76, 0.91 (each 3H, d,

J = 6.8 Hz), 1.01À1.19 (2H, m), 1.19À1.41 (2H, m), 1.30 (3H, s),

1.54À1.78 (2H, m), 1.68 (3H, s), 1.83 (1H, m), 1.95À2.22 (5H, m),

5.46 (1H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 15.2, 20.2, 20.4, 21.5, 23.8,

23.9, 26.0, 30.8, 38.0, 40.7, 46.3, 48.1, 60.8 (as a triplet), 121.1, 135.2,

151.8 (as a triplet); EI-MS m/z 231 (M⁺), 216 (M⁺ÀCH₃); HR EI-MS

m/z 231.1975 (M⁺, calcd for C₁₆H₂₅N 231.1987).

Ester (48). To a solution of 20 (1.20 g, 4.72 mmol) in benzene

(19 mL) were added imidazole (482 mg, 7.08 mmol), triphenylphosphin

(1.86 g, 7.08 mmol), and I₂(3.35 g, 13.2 mmol) at 0 °C under Ar

atmosphere. The mixture was warmed to room temperature, stirred for 1

h, quenched with saturated aqueous Na₂SO₃, extracted with EtOAc,

washed with brine, dried over Na₂SO₄, filtered, and concentrated in

vacuo. The residue was purified by silica gel column chromatography

(EtOAc/hexane, 3:97) to afford 48 (1.63 g, 4.48 mmol, 95%) as a

To a solution of the aldehyde in t-BuOH (0.27 mL) and H₂O

(0.13 mL) were added NaH₂PO₄(11.9 mg, 99.5 μmol) and 2-methyl-2-

butene (28.5 μL, 0.269 mmol) at room temperature. After 30 min of

stirring, NaClO₂(11.2 mg, 99.5 μmol) was slowly added for 30 min. The

mixture was diluted with saturated aqueous NaCl, extracted with EtOAc,

washed with brine, dried over Na₂SO₄, and ﬁltered. After the solvent was

removed in vacuo, the residue was puriﬁed by silica gel column chro-

matography (EtOAc/hexane, 10:90) to aﬀord 34 (4.00 mg, 16.0 μmol,

colorless oil: [R]²³= À65.2 (c 2.77, CHCl₃), enantiomer [R]²³

=

D

+66.3 (c 2.90, CHCl₃); IR (neat) 3034, 2950, 2868, 2824, 1732, 1461,

1432, 1368, 1209, 1259, 1235, 1189, 1160, 1093, 1056, 1032, 942, 906,

880, 809 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.91, 0.93 (each 3H, d,

J = 6.8 Hz), 1.66 (3H, s), 1.66À1.84 (5H, m), 1.87À2.08 (3H, m), 2.32

(1H, dt, J = 2.9, 10.0 Hz), 2.68 (1H, m), 3.15 (2H, m), 3.68 (3H, s), 5.18

(1H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 6.8, 20.3, 21.2, 23.8, 26.7, 29.3,

30.1, 34.1, 38.4, 44.8, 48.6, 51.6, 121.2, 134.9, 176.3; EI-MS m/z 364

(M⁺), 237 (M⁺ÀI); HR EI-MS m/z 364.0898 (M⁺, calcd for C₁₅H₂₅IO₂

364.0899).

81% in 3 steps) as a colorless oil: [R]²³= +36.2 (c 0.92, CHCl₃),

D

enantiomer [R]²³= À39.4 (c 0.91, CHCl₃); IR (neat) 2950, 2924,

D

2910, 2864, 1695, 1463, 1451, 1404, 1383, 1286, 1257, 1239, 1202, 1190,

1

1120, 1070, 1045, 949, 906, 871, 816 cm^À1; H NMR (CDCl₃, 400

MHz) δ 0.79, 0.92 (each 3H, d, J = 6.8 Hz), 1.04À1.44 (4H, m), 1.12

(3H, s), 1.47À2.11 (7H, m), 1.66 (3H, s), 2.18 (1H, m), 5.52 (1H, s);

¹³C NMR (CDCl₃, 100 MHz) δ 14.6, 15.3, 19.6, 21.5, 24.0, 26.0, 26.2,

31.1, 36.8, 37.1, 44.1, 46.4, 46.6, 122.1, 134.6, 184.0; EI-MS m/z 250

(M⁺); HR EI-MS m/z 250.1935 (M⁺, calcd for C₁₆H₂₆O₂250.1933).

Formamide (10-Formamido-4-cadinene) (35). To a solution

of 34 (8.70 mg, 34.8 μmol) in toluene (0.99 mL) were added

diphenylphosphoryl azide (DPPA) (9.00 μL, 41.7 μmol) and Et₃N

(5.80 μL, 41.7 μmol) at room temperature under Ar atmosphere. The

mixture was stirred for 30 min, heated to 100 °C, stirred for 1 h, filtered,

and concentrated in vacuo. The crude isocyanate was used immediately

in the next reaction.

Alcohol (49). To a solution of 48 (1.46 g, 4.01 mmol) in CH₂Cl₂

(13 mL) was added dropwise DIBALH (0.99 M in toluene) (8.10 mL,

8.02 mmol) at 0 °C under Ar atmosphere. After 1 h of stirring, MeOH

(1.60 mL) and a trace of H₂O were added dropwise at 0 °C. The mixture

was filtered with a Celite pad, washed with CH₂Cl₂, and concentrated in

vacuo. The residue was purified by silica gel column chromatography

(EtOAc/hexane, 3:97) to afford 49 (1.33 g, 3.97 mmol, 99%) as a

colorless oil; [R]²³= À38.8 (c 3.00, CHCl₃), enantiomer [R]²³

=

D

After a solution of the isocyanate in EtOH (0.70 mL) under Ar

atmosphere was cooled to 0 °C, NaBH₄(3.90 mg, 0.104 mmol) was

added to the solution. The reaction was stirred for 3 h at room

temperature, diluted with H₂O, and extracted with EtOAc. The com-

bined organic layers were washed with brine, dried over Na₂SO₄, ﬁltered,

and concentrated in vacuo. The residue was puriﬁed by silica gel column

chromatography (EtOAc/hexane, 30:70) to aﬀord 35 (7.60 mg, 30.4 μmol,

+38.2 (c 3.20, CHCl₃); IR (neat) 3338, 3024, 2950, 2918, 2866, 2697,

1463, 1440, 1432, 1383, 1365, 1232, 1171, 1051, 1026, 935, 846,

809 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.91, 0.92 (each 3H, d, J =

6.8 Hz), 1.21À1.35 (2H, m), 1.35À1.65 (3H, m), 1.66 (3H, s),

1.69À2.01 (5H, m), 2.07 (1H, m), 3.10À3.26 (2H, m), 3.48 (1H,

ddd, J = 1.2, 6.6, 10.5 Hz), 3.71 (1H, dd, J = 3.7, 10.5 Hz), 5.19 (1H, s);

¹³C NMR (CDCl₃, 100 MHz) δ 8.1, 20.4, 20.6, 24.0, 25.0, 28.7, 30.1,

33.9, 37.1, 39.3, 47.7, 65.7, 121.9, 134.2; EI-MS m/z 336 (M⁺); HR EI-

MS m/z 336.0950 (M⁺, calcd for C₁₄H₂₅IO 336.0950).

88% in 2 steps) as a colorless oil: [R]²³= +28.4 (c 0.66, CHCl₃),

D

enantiomer [R]²³= À22.3 (c 0.71, CHCl₃); IR (neat) 3278, 3050,

D

2950, 2918, 2848, 1675, 1664, 1535, 1463, 1451, 1384, 1313, 1259, 1192,

1152, 1127, 1071, 1046, 876 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.77,

0.78, 0.91, 0.92 (total 6H, each d, J = 6.8 Hz), 0.99À1.38 (3H, m), 1.22,

1.26 (total 3H, each s), 1.49À1.67 (2H, m), 1.67 (3H, s), 1.76À2.26

(7H, m), 5.16, 5.74 (total 1H, each brs), 5.49 (1H, s), 8.07, 8.28 (total

1H, each d, J = 12.5 and 2.2 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ 15.2,

18.9, 19.1, 20.8, 21.6, 23.1, 23.5, 23.8, 26.07, 26.11, 30.96, 31.05, 37.5,

38.6, 38.8, 41.9, 45.8, 46.3, 46.4, 49.1, 55.8, 57.4, 121.8, 122.2, 134.5,

134.8, 160.2, 162.6; FAB-MS m/z 250 (M⁺+ H); HR FAB-MS m/z

250.2166 (M⁺+ H, calcd for C₁₆H₂₈NO 250.2171).

Alcohol (37-eq and 37-ax). To a solution of 49 (930 mg, 2.77

mmol) in CH₂Cl₂(28 mL) was added DMP (2.34 g, 5.54 mmol) at

room temperature under Ar atmosphere. The mixture was stirred for 1 h,

quenched with saturated aqueous Na₂S₂O₃and saturated aqueous

NaHCO₃, extracted with EtOAc, washed with brine, dried over Na₂SO₄,

filtered, and concentrated in vacuo. The crude aldehyde 36 was employed

directly in the next reaction.

A solution of 36 in THF (28 mL) was degassed by freeze treatment,

and a 0.100 M THF-HMPA solution of SmI₂(83.1 mL, 8.31 mmol) was

added at room temperature under Ar atmosphere. The mixture was

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stirred for 30 min, quenched with saturated aqueous NaHCO₃, extracted

with EtOAc, washed with brine, dried over Na₂SO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by silica gel column

chromatography (EtOAc/hexane, 5:95) to aﬀord 37-eq (368 mg, 1.76

mmol, 64% in 2 steps) and 37-ax (158 mg, 0.756 mmol, 27% in 2 steps)

HCl, and stirred for 30 min. The mixture was diluted with EtOAc,

washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.

The crude aldehyde was employed directly in the next reaction.

To a solution of aldehyde in toluene (22 mL) and CH₂Cl₂(22 mL)

was added t-BuOK (1.22 g, 10.9 mmol) at 0 °C under Ar atmosphere.

The mixture was warmed to room temperature and stirred for 10 min.

After the reaction was cooled to 0 °C, MeI (2.91 mL, 46.8 mmol) was

slowly added. The mixture was warmed to room temperature, stirred for

15 h, diluted with H₂O, extracted with EtOAc, washed with brine, dried

over Na₂SO₄, ﬁltered, and concentrated in vacuo. The crude mixture of

the crude aldehyde 40 was employed directly in the next reaction.

To a solution of 40 in t-BuOH (21 mL) and H₂O (10 mL) were

added NaH₂PO₄(0.936 mg, 7.80 mmol) and 2-methyl-2-butene

(2.23 mL, 21.7 mmol). After 30 min of stirring, NaClO₂(0.882 mg,

7.80 mmol) was slowly added. The mixture was stirred for 1 h, diluted

with saturated aqueous NaCl, extracted with EtOAc, washed with brine,

dried over Na₂SO₄, ﬁltered, and concentrated in vacuo. Silica gel column

chromatography (EtOAc/hexane, 10:90) yielded 41 (316 mg, 1.26

as colorless oils: 37-eq: [R]²³= +24.8 (c 2.85, CHCl₃), enantiomer

D

[R]²³= À23.4 (c 2.77, CHCl₃); IR (neat) 3328, 2946, 2922, 2864,

D

2714, 1705, 1451, 1383, 1361, 1293, 1238, 1179, 1153, 1110, 1055, 1031,

1

992, 978, 919, 892, 866, 839, 816, 732 cm^À1; H NMR (CDCl₃, 400

MHz) δ 0.90, 0.93 (each 3H, d, J = 6.6 Hz), 1.16 (1H, m), 1.23À1.55

(5H, m), 1.63 (3H, s), 1.75À2.10 (6H, m), 2.21 (1H, dd, J = 2.7, 10.0

Hz), 3.27 (1H, dt, J = 4.9, 10.0 Hz), 5.27 (1H, s); ¹³C NMR (CDCl₃, 100

MHz) δ 22.7, 23.3, 23.5, 26.1, 26.5, 27.9, 29.8, 31.1, 40.9, 44.28, 44.33,

75.4, 126.9, 130.7; EI-MS m/z 208 (M⁺), 190 (M⁺À H₂O); HR EI-MS

m/z 208.1827 (M⁺, calcd for C₁₄H₂₄O 208.1827). 37-ax: [R]²³

=

D

+47.8 (c 1.54, CHCl₃), enantiomer [R]²³_D= À47.3 (c 1.60, CHCl₃); IR

(neat) 3408, 2948, 2912, 2864, 2714, 1711, 1662, 1452, 1383, 1365,

1305, 1259, 1234, 1179, 1132, 1100, 1053, 1000, 979, 960, 924, 890, 848,

814, 766, 715 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.89, 0.92 (each

3H, d, J = 6.6 Hz), 0.99À1.77 (8H, m), 1.61 (3H, s), 1.77À1.96 (3H, m),

2.02 (1H, m), 2.55 (1H, m), 3.86 (1H, s), 5.27 (1H, s); ¹³C NMR

(CDCl₃, 100 MHz) δ 22.9, 23.6, 23.7, 24.0, 25.8, 26.7, 29.3, 30.3, 37.7,

38.4, 44.9, 70.5, 128.1, 130.3; EI-MS m/z 208 (M⁺) 190 (M⁺À H₂O);

HR EI-MS m/z 208.1825 (M⁺, calcd for C₁₄H₂₄O 208.1827).

mmol, 86% in 3 steps) as white crystals: mp 104À107 °C; [R]²³

=

D

+79.0 (c 1.11, CHCl₃), enantiomer [R]²³_D= À76.3 (c 1.00, CHCl₃); IR

(KBr) 3500, 2963, 2930, 2910, 2864, 2820, 1696, 1488, 1464, 1446,

1404, 1375, 1320, 1288, 1270, 1212, 1150, 1067, 945, 903, 889, 823, 786,

670, 650 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.88, 0.92 (each 3H, d,

J = 6.6 Hz), 0.92À1.66 (5H, m), 1.25 (3H, s), 1.61 (3H, s), 1.66À2.02

(6H, m), 2.66 (1H, m), 5.22 (1H, s); ¹³C NMR (CDCl₃, 100 MHz)

δ 22.7, 23.6, 23.8, 24.5, 26.0, 26.2, 26.3, 31.0, 33.6, 41.2, 42.2, 44.5, 45.6,

127.7, 130.7, 182.9; EI-MS m/z 250 (M⁺); HR EI-MS m/z 250.1937

(M⁺, calcd for C₁₆H₂₆O₂250.1933).

Ketone (38). To a solution of 37 (520 mg, 2.50 mmol) in CH₂Cl₂

(25 mL) was added DMP (2.63 g, 6.24 mmol) at room temper-

ature under Ar atmosphere. The mixture was stirred for 1 h, quenched

with saturated aqueous Na₂S₂O₃and saturated aqueous NaHCO₃,

extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,

and concentrated in vacuo. Silica gel column chromatography (EtOAc/

hexane, 3:97) provided 38 (450 mg, 2.18 mmol, 87%) as a colorless oil:

[R]²³= +155 (c 2.03, CHCl₃), enantiomer [R]²³= À158 (c 2.00,

Formamide (42). To a solution of 41 (230 mg, 0.919 mmol) in

toluene (26 mL) were added diphenylphosphorylazide (0.237 mL, 1.10

mmol) and Et₃N (0.154 mL, 1.10 mmol) at room temperature under Ar

atmosphere. After stirring for 30 min, the mixture was warmed to

100 °C, stirred for 1 h, filtered, and concentrated in vacuo. The crude

isocyanate was employed directly in the next reaction.

D

CHCl₃); IR (neat) 3012, 2950, 2918, 2864, 2826, 2716, 1709, 1451,

1431, 1384, 1360, 1335, 1318, 1291, 1232, 1213, 1152, 1174, 1110, 1037,

1

1012, 935, 881, 854, 830, 802 cm^À1; H NMR (CDCl₃, 400 MHz)

To a solution of isocyanate in EtOH (18 mL) was added NaBH₄(313

mg, 8.27 mmol) at 0 °C under Ar atmosphere. The mixture was warmed

to room temperature and stirred for 3 h. The mixture was diluted with

H₂O, extracted with EtOAc, washed with brine, dried over Na₂SO₄, and

ﬁltered. After the solvent was removed in vacuo, the residue was puriﬁed

by silica gel column chromatography (EtOAc/hexane, 30:70) to aﬀord

δ 1.00, 1.02 (each 3H, d, J = 6.8 Hz), 1.42 (1H, m), 1.61 (1H, m), 1.64

(3H, s), 1.72 (1H, m), 1.88À2.18 (5H, m), 2.29 (1H, m), 2.36À2.51

(3H, m), 5.34 (1H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 22.2, 22.4, 23.2,

23.5, 26.3, 28.8, 29.4, 37.9, 43.8, 45.9, 46.4, 125.8, 132.0, 212.4; EI-MS

m/z 206 (M⁺); HR EI-MS m/z 206.1668 (M⁺, calcd for C₁₄H₂₂O

206.1671).

42 (195 mg, 0.781 mmol, 85% in 2 steps) as a colorless oil: [R]²³

=

D

+98.0 (c 0.97, CHCl₃), enantiomer [R]²³_D= À99.9 (c 0.99, CHCl₃); IR

(neat) 3306, 3044, 2940, 2926, 2864, 2756, 1666, 1528, 1444, 1386,

1300, 1258, 1226, 1191, 1161, 1101, 1065, 1033, 955, 931, 911, 858, 814,

755 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.90, 0.927, 0.933 (total 6H,

each d, J = 6.6 Hz), 1.21 (1H, m), 1.31À2.07 (9H, m), 1.40, 1.50 (total

3H, each s), 1.62 (3H, s), 2.30 (1H, dt, J = 2.5, 11.6 Hz), 2.47 (1H, td, J =

3.3, 14.1 Hz), 5.22, 5.24 (total 1H, each s), 5.23, 5.88 (total 1H, each

brs), 8.13, 8.23 (total 1H, each d, J = 1.7, 12.4 Hz); ¹³C NMR (CDCl₃,

100 MHz) δ 22.69, 22.73, 22.8, 23.3, 23.4, 23.6, 23.7, 24.7, 25.3, 25.5,

26.0, 27.8, 29.7, 30.2, 30.4, 31.4, 36.0, 40.5, 40.7, 42.2, 42.9, 44.3, 44.6,

54.2, 56.0, 127.1, 127.4, 130.8, 130.9, 160.7, 163.3; FAB-MS m/z

272 (M⁺+ Na); HR FAB-MS m/z 272.1986 (M⁺+ Na, calcd for

C₁₆H₂₇NONa 272.1990).

Nitrile (39). To a solution of 38 (195 mg, 0.943 mmol) in DME

(4.7 mL) were added EtOH (0.155 mL, 2.64 mmol) and p-toluenesul-

fonylmethyl isocyanide (TosMIC) (331 mg, 1.70 mmol). After the

mixture was cooled to 5À10 °C, t-BuOK (359 mg, 3.21 mmol) was

slowly added. The mixture was warmed to room temperature and stirred

for 1 h. The mixture was diluted with H₂O, neutralized with 1 N HCl to

pH 7, extracted with EtOAc, washed with brine, dried over Na₂SO₄, and

filtered. After the solvent was removed in vacuo, the residue was purified

by silica gel column chromatography (EtOAc/hexane, 3:97) to give 39

(166 mg, 0.764 mmol, 81%) as a colorless oil in a 1:1 mixture of two

diastereomers: IR (neat) 2956, 2928, 2864, 2832, 2724, 2230, 1706,

1451, 1384, 1363, 1321, 1302, 1263, 1180, 1161, 1122, 1101, 1046, 1015,

1

987, 919, 891, 815 cm^À1; H NMR (CDCl₃, 400 MHz) δ 0.89, 0.90,

Isonitrile (43). To a solution of 42 (21.0 mg, 84.2 μmol) in CH₂Cl₂

(8.4 mL) were added dropwise POCl₃(23.1 μL, 0.253 mmol) and Et₃N

(0.106 mL, 0.758 mmol) at 0 °C under Ar atmosphere. After stirring for

30 min, the mixture was warmed to room temperature, stirred for 1 h,

quenched with cooled water, extracted with EtOAc, washed with

brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Silica gel

column chromatography (EtOAc/hexane, 1:99) provided 43 (18.1 mg,

0.927, 0.931 (each 1.5H, d, J = 6.6 Hz), 1.04 (0.5H, m), 1.14À2.26

(11.5H, m), 1.63 (3H, s), 2.48, 2.88 (each 0.5H, m), 5.22, 5.25 (each

0.5H, s); ¹³C NMR (CDCl₃, 100 MHz) δ 22.6, 22.7, 23.3, 23.4, 23.51,

23.54, 24.8, 25.7, 26.2, 26.3, 28.6, 28.8, 28.9, 29.7, 34.2, 34.3, 35.6, 36.1,

42.1, 44.0, 44.1, 45.9, 120.9, 122.1, 126.3, 126.6, 130.9, 131.3; EI-MS

m/z 217 (M⁺); HR EI-MS m/z 217.1834 (M⁺, calcd for C₁₅H₂₃N

217.1831).

Carboxylic Acid (41). To a solution of 39 (340 mg, 1.56 mmol) in

Et₂O (5.2 mL) was added DIBALH (3.16 mL, 3.13 mmol) at 0 °C under

Ar atmosphere. The mixture was stirred for 15 min, quenched with 1 N

78.3 μmol, 93%) as a colorless oil: [R]²³= +108 (c 0.80, CHCl₃),

D

enantiomer [R]²³= À107 (c 0.92, CHCl₃); IR (neat) 3050, 2940,

D

2866, 2828, 2721, 2122, 1640, 1452, 1381, 1363, 1302, 1273, 1250, 1232,

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The Journal of Organic Chemistry

ARTICLE

1191, 1152, 1127, 1105, 1067, 1005, 956, 930, 893, 864, 841, 815,

721 cm^À1; ¹H NMR (CDCl₃, 400 MHz) δ 0.89, 0.94 (each 3H, d, J = 6.8

Hz), 1.41À1.63 (4H, m), 1.43 (3H, s), 1.68À1.84 (4H, m), 1.63 (3H, s),

1.88À2.09 (3H, m), 2.50 (1H, m), 5.24 (1H, s); ¹³C NMR (CDCl₃, 100

MHz) δ 22.8, 23.2, 23.4, 23.6, 25.4, 26.3, 27.7, 30.0, 35.8, 40.7, 41.0, 44.2,

61.5 (as a triplet), 126.9, 130.3, 153.8 (as a triplet); EI-MS m/z 231

(M⁺), 216 (M⁺À CH₃); HR EI-MS m/z 231.1987 (M⁺, calcd for

C₁₆H₂₅N 231.1987).

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D

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2922, 2862, 2727, 1708, 1467, 1452, 1383, 1314, 1292, 1188, 1157, 1123,

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’ ASSOCIATED CONTENT

1

Supporting Information. Copies of H NMR and ¹³C

S

b

NMR spectra. This material is available free of charge via the

Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: fmatsuda@ees.hokudai.ac.jp.

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’ ACKNOWLEDGMENT

We are grateful for the 21 Century COE Research Assistant-

ship for doctoral candidates and Global COE Research Assistant-

ship for doctoral candidates (to K.N.) and the Global COE

Research grant for young scientists (to T.U. and K.N.).

(17) The carboxylic acid 11 was converted into 23 via 21 by the

following sequence of reactions: (1) esteriﬁcation of 11 with CH₂N₂,

(2) protection of the OH group of 21 with t-BuMe₂SiCl, (3) protection

of the hydroxyester 20 with t-BuMe₂SiCl to produce 22.

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ARTICLE

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(26) Natural (+)-10-isocyano-4-cadinene (1) was synthesized from

the carboxylic acid 11. Obviously, the absolute conﬁgurations in

isonitrile 30, prepared from 11, are identical to those of 1 at C1, C6,

and C7. In the 2D-NOESY spectrum of 30, an NOE correlation was

observed between C1-H and C10-Me. Therefore, the stereochemistry of

30 at C10 was opposite to that of 1.

(27) p-Methoxybenzyl chloromethyl ether 31 was prepared from

p-anisylalcohol. (a) Benneche, T.; Strande, P.; Undheim, K. Synthesis

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(30) 10-Formamide-4-cadinene (35), a natural product isolated

from the sponge Acanthella cavernosa, exhibits antifouling activity against

the larvae of the barnacle Balanus amphirite (EC₅₀0.50 μg/mL). All data

(¹H and ¹³C NMR, MS) of the synthetic 35 were completely identical

with those in the literature. Nogata, Y.; Yoshimura, E.; Shinshima, K.;

Kitano, Y.; Sakaguchi, I. Biofouling 2003, 19, 193–196.

(31) On the basis of the ¹H NMR spectra of the ester 20 and

carboxylic acid 11, it was found that 20 has a trans relationship at C1 and

C6, opposite to that of 11. Since 11 led to natural (+)-1, the absolute

stereochemistry of alcohol 44, synthesized from 20, was determined at

6573

dx.doi.org/10.1021/jo2008109 |J. Org. Chem. 2011, 76, 6558–6573

Article Doi

Total synthesis of 10-isocyano-4-cadinene and its stereoisomers and evaluations of antifouling activities

DOI: 10.1021/jo2008109

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Article abstract of DOI:10.1021/jo2008109

Full text of DOI:10.1021/jo2008109

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