Total syntheses of multiple cladiellin natural products by use of a completely general strategy

Article

pubs.acs.org/joc

Total Syntheses of Multiple Cladiellin Natural Products by Use of a

Completely General Strategy

J. Stephen Clark,*^,†Raphaelle Berger,^†Stewart T. Hayes,^‡Hans Martin Senn,^†Louis J. Farrugia,^†

̈

Lynne H. Thomas,^†Angus J. Morrison,^§and Luca Gobbi^∥

^†WestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, United

Kingdom

^‡School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom

^§MSD Newhouse Research Site, Lanarkshire ML1 5SH, United Kingdom

^∥Discovery Chemistry (PRCB), F. Hoﬀmann-La Roche Ltd. Pharmaceuticals Division, CH-4070 Basel, Switzerland

S

* Supporting Information

ABSTRACT: The enantioselective total syntheses of 10

cladiellin natural products have been completed, starting

from the known allylic alcohol (+)-14, which can be prepared

in large quantities. The bridged tricyclic core of the cladiellins

has been constructed via three ring-forming reactions: (i) an

intramolecular reductive cyclization between an aldehyde and

an unsaturated ester, mediated by samarium(II) iodide, to

form a tetrahydropyranol; (ii) reaction of a metal carbenoid,

generated from a diazo ketone, with an ether to produce an

ylide-like intermediate that rearranges to produce E- or Z-

oxabicyclo[6.2.1]-5-undecen-9-one; and (iii) a Diels−Alder cycloaddition reaction to construct the third ring found in the core

structure of the cladiellins. The key ring-forming reaction, in which a diazo ketone is converted into a bridged bicyclic ether, can

be tuned to give either of the isomeric oxabicyclo[6.2.1]-5-undecen-9-ones as the major product by switching from a copper to a

rhodium catalyst and selecting the appropriate reaction conditions. The tricyclic products obtained from the three-step sequence

involving the Diels−Alder cycloaddition reaction can be employed as advanced intermediates to prepare a wide range of cladiellin

natural products.

sarcodictyins were isolated after Faulkner’s hypothesis but

conform to this general biosynthetic scheme.⁶

INTRODUCTION

■

In 1968, Kennard et al.¹reported the isolation of a novel

diterpene from samples of the gorgonian Eunicella stricta

collected in the Mediterranean near Banyuls-sur-Mer; the same

compound was later isolated from samples of Eunicella labiata

collected oﬀ the coast of southern Spain.²The compound was

named eunicellin and was identiﬁed as the ﬁrst member of what

transpired to be a large family of ether-bridged tricyclic

diterpenes (Figure 1).^3,4To date, more than 100 cladiellin (also

termed eunicellin) natural products have been isolated from

marine invertebrates found in diverse locations, and many of

them display signiﬁcant biological activities.^3,4

All cladiellins possess an oxatricyclo[6.6.1.0^2,7]pentadecane

ring system bearing one-carbon substituents at C-3, C-7, and C-

11 (cladiellin numbering) and an isopropyl group or oxidized

isopropyl group at C-14.^3,4In a few cases, an additional ether

bridge spans the nine-membered ring. The cladiellins also

possess varying levels of unsaturation and oxygenation;

unsaturation is usually located at C-6−C-7/C-7−C-16 and at

C-11−C-12/C-11−C-17, and oxygenation occurs at C-3 and

frequently at positions C-6, C-7, and C-11−C-13 (see examples

in Figure 1). Although the cladiellins share the same ether-

bridged skeleton, structural errors and stereochemical mis-

assignments have occurred in some cases where structure has

been deduced on the basis of NMR data alone. Friedrich and

Paquette⁷have attempted to correct errors associated with

polyhydroxylated cladiellins by reanalyzing the NMR data

reported for these compounds and comparing it to data

obtained from cladiellins whose structures have been conﬁrmed

by synthesis or by use of X-ray diﬀraction data. However, the

The cladiellins comprise the largest subset of a group of

diterpenes that includes the sarcodictyins, briarellins, and

asbestinins (Figure 2).³Faulkner and co-workers⁵proposed

that the cladiellins, briarellins, and asbestinins are connected

biosynthetically and are produced by transannular bond

formation between C-2 and C-11 and subsequent introduction

of the ether bridge. Formation of a seven-membered cyclic

ether or lactone by bond construction between the C-3

hydroxyl group and one of the methyl groups in the isopropyl

side chain leads to the briarellin skeleton, and subsequent

migration of a methyl group produces the asbestinins. The

Received: November 27, 2012

A

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Figure 1. Representative cladiellin natural products illustrating

structural diversity.

stuctures of many cladiellins have yet to be conﬁrmed by

synthesis, and it is likely that some errors remain.

The work presented in this article concerns the total

synthesis of the cladiellin natural products shown in Figure 3.

Over the past 15 years or so, the cladiellins have become

popular synthetic targets because of their challenging core

structures, the dense functionality found in many of them, and

the signiﬁcant challenges they present with regard to

stereocontrol.⁸

Figure 3. Cladiellin natural product targets.

that had been proposed to be sclerophytin A, thereby

demonstrating that the natural product did not have the

structure suggested originally (Figure 4).^9b,10In contempora-

The ﬁrst total synthesis of a cladiellin natural product was

reported by MacMillan and Overman in 1995.^9aThey

completed a total synthesis of (−)-6-acetoxycladiella-

7(16),11-dien-3-ol [also named (−)-deacetoxyalcyonin acetate]

in 19 steps, starting from (S)-dihydrocarvone. In this synthesis

a Prins-pinacol condensation−rearrangement sequence was

used to construct a reduced isobenzofuran system, and

formation of the medium ring was accomplished by an

intramolecular Nozaki−Hiyama−Kishi reaction. The same

combination of reactions was used to prepare the compound

Figure 4. Structure originally proposed for sclerophytin A.

neous studies, Paquette and co-workers¹¹prepared the

compound that had been proposed to be sclerophytin A,

Figure 2. Faulkner’s proposed biosynthesis of oxygen-bridged 2,11-cyclized diterpene natural products.

B

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using a ring-expanding Claisen rearrangement reaction to

construct the medium-sized ring. Subsequently, the Overman

and Paquette groups¹²assigned new structures to sclerophytins

A and B (compounds 7 and 8 in Figure 3) and completed total

syntheses of both natural products.

a subsequent radical cyclization reaction, and relied on RCM to

construct the third ring.

In published total syntheses where RCM has been used to

construct a medium-sized ring containing a trisubstituted Z-

alkene, yields of 40−50% have been obtained. The majority of

cladiellins possess a highly strained E-alkene or an anti 1,2-diol

that would result from syn dihydroxylation of an E-alkene,

rather than a Z-alkene, at C-6−C-7. However, with the

exception of that devised by Kim and co-workers,¹⁵published

strategies do not allow introduction of a strained E-alkene into

the nine-membered ring. Our objective was to develop a

completely general approach to the synthesis of cladiellins that

would not rely on RCM to construct the medium-sized ring

and that could be used to prepare compounds containing either

an E- or Z-alkene at C-6−C-7 and also the polyhydroxylated

sclerophytin-type natural products. We now report the

successful realization of this strategy and its application to the

total synthesis of 10 cladiellin natural products (Figure 3).²⁰

Following the pioneering work of the Overman and Paquette

groups, several other groups made signiﬁcant synthetic

contributions to this area. Molander et al.¹³synthesized

(−)-6-acetoxycladiella-7(16),11-dien-3-ol (Figure 1) in 18

steps, starting from the natural product (R)-(−)-α-phellan-

drene. In their synthetic route, sequential [4 + 3] cycloaddition

and Nozaki−Hiyama−Kishi reactions were used to construct a

tetracyclic intermediate that underwent ring scission to reveal

the medium-ring ether and deliver the tricyclic core. Crimmins

et al.¹⁴then developed a highly successful strategy for the

synthesis of many of the cladiellins in which ring-closing

metathesis (RCM) is used to construct the nine-membered

cyclic ether and the other rings are constructed stereoselectively

using an intramolecular Diels−Alder reaction. The Crimmins

group has used this strategy to prepare (−)-ophirin B,^14a,c

(−)-astrogorgin,^14c(+)-vigulariol (2),^14fand (−)-sclerophytin

A (7)^14fas well as 11-acetoxy-4-deoxyasbestinin,^14b,dasbestinin-

12,^14dand the compound originally purported to be briarellin

J.^14e

The vast majority of cladiellin natural products possess an E-

alkene at C-6 to C-7 or an anti 1,2-diol that would result from

syn dihydroxylation of this alkene. Most strategies used for the

construction of the cladiellins are not amenable to the

introduction of the strained E-alkene into the medium-sized

ring. However, in 2006, Kim and co-workers¹⁵reported that

intramolecular amide alkylation with an E allylic chloride as the

electrophile could be used to construct an E-oxonene that could

be elaborated to give the complete cladiellin system possessing

an E-alkene at C-6−C-7. This approach was used to complete

total syntheses of (−)-6-acetoxycladiella-7(16),11-dien-3-ol

(deacetoxyalcyonin acetate), (−)-cladiella-6,11-dien-3-ol (5),

(−)-cladiell-11-ene-3,6,7-triol (9), and (+)-polyanthellin A

(12) (Figures 1 and 3).¹⁵

RESULTS AND DISCUSSION

■

Total syntheses were based on the retrosynthetic analysis

shown in Scheme 1. In the case of (+)-cladiella-6Z,11(17)-dien-

3-ol (Z-1) and (+)-vigulariol (2), removal of the methylene

group at C-17 and the methyl substituent (C-15) at C-3 leads

to the ketone i-Z. For the E-conﬁgured natural products 3−6,

those containing an anti 1,2-diol at C-6 and C-7 (natural

products 7−10), and compounds containing a C-3−C7 ether

bridge (compounds 11 and 12), analogous disconnections of

Scheme 1. Retrosynthetic Analysis for Cladiellin Natural

Products

Over the past four years, several other research groups have

reported total syntheses of members of the cladiellin family of

natural products. Hoppe and co-workers¹⁶reported a concise

total synthesis of (+)-vigulariol from (R)-(−)-cryptone in

which their asymmetric homoaldol methodology was used to

generate a reduced isobenzofuran and RCM was employed to

construct the third ring. Although this synthesis is undoubtedly

the shortest reported for any cladiellin natural product, the

yield was modest for a route of such brevity, due to the

formation of mixtures of isomers and relatively low yields

during the homoaldol and RCM reactions. Nevertheless, this

synthesis is a testemony to the power of Hoppe’s asymmetric

homoaldol methodology.

In 2009, Campbell and Johnson¹⁷reported a concise total

synthesis of (+)-polyanthellin A from methallyl alcohol. In

common with the Overman and Hoppe strategies, a reduced

isobenzofuran was synthesized ﬁrst and RCM was then

employed to close the medium-sized ring. In this case,

however, a Lewis-acid-mediated [3 + 2] cycloaddition of a

cyclopropane to an aldehyde was used to construct the reduced

isobenzofuran system. The following year, Morken and co-

workers^18,19reported a synthesis of (−)-sclerophytin A from

geranial that also proceeded via a reduced isobenzofuran,

prepared by Oshima−Utimoto reaction of an allylic alcohol and

C

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one-carbon fragments from C-3 and C-15 give the isomeric

intermediate i-E. Conversion of the isopropyl group into a

methyl ketone and the C-11 carbonyl group into an enol ether

(C-11−C-10) in each case gives the tricylic systems ii-Z and ii-

E. Diels−Alder disconnection then reveals the isomeric bicyclic

dienes iii-Z and iii-E. The diene iii-Z is disconnected to give

the bicyclic ketone iv-Z, and the diene iii-E is disconnected to

give the bicyclic ketone iv-E. In principle, the isomeric ketones

iv-Z and iv-E could be prepared by rearrangement of an

oxonium ylide or ylide equivalent produced by reaction of the

ether with a metal carbenoid generated from the diazo ketone

v.²¹⁻²⁴The diazo ketone v can be disconnected further to give

the simple allylic alcohol vi as the starting material.

Scheme 3. Enantioselective Synthesis of Allylic Alcohol

(+)-14 on a Large Scale

The synthetic strategy implied by the analysis in Scheme 1

has several attractive features. First, the ketones iv-Z and iv-E

are isomers produced from a common intermediate (v)

relatively late in the synthesis. Second, the routes from ketones

iv-Z and iv-E to the late-stage tricyclic intermediates i-Z and i-E

run in parallel, with common methodology employed in both

series. Finally, the late-stage intermediates i-Z and i-E possess

the functionality required to access virtually any member of the

cladiellin family of natural products.

The ﬁrst objective was preparation of the cyclization

precursor corresponding to the diazo ketone v shown in

Scheme 1. The starting material selected for the synthesis is the

allylic alcohol (+)-14 and this compound was prepared with

high enantiomeric excess (ee) by two approaches (Schemes 2

the epoxyalcohol 20 in high yield and with high ee (conﬁrmed

by HPLC analysis of a later intermediate in the synthesis, vide

infra).²⁷The epoxy alcohol 20 was then converted into the

allylic alcohol (+)-14 in 97% yield by mesylation of the free

hydroxyl group and treatment of the resulting mesylate 21 with

sodium iodide and zinc powder in butanone at reﬂux.²⁶The

sequence provided the allylic alcohol (+)-14 with 94% ee and

in suﬃcient quantities (>30 g per batch) to complete the

syntheses of 10 cladiellin natural products.

Scheme 2. Enantioselective Synthesis of Alcohol (+)-14 by

Enantioselective Ketone Reduction

The synthesis of the key α-diazo ketone 26 was undertaken

as shown in Scheme 4. The allylic alcohol (+)-14 was converted

into the E-vinylogous carbonate (94% yield, 94% ee by chiral

HPLC analysis).²⁸Cleavage of the silyl ether provided the

Scheme 4. Synthesis of Diazo Ketone 26, the Key Cyclization

Precursor

and 3). In the ﬁrst approach (Scheme 2), addition of 2-

propenylmagnesium bromide to the aldehyde 13 or reaction of

the Grignard reagent 15 with methacrolein was used to prepare

the alcohol ( )-14. Oxidation and asymmetric reduction of the

resulting enone, by use of the oxazaborolidine 16 and following

the well-established CBS protocol, aﬀorded the alcohol (+)-14

in 83% yield and with 96% ee.²⁵

For large-scale work a more cost-eﬀective method for the

production of the allylic alcohol (+)-14 was required, and this

was accomplished via a route devised by Williams et al.²⁶

(Scheme 3). The synthesis commenced with Wittig oleﬁnation

of the aldehyde 13 with the stabilized ylide 17 to aﬀord the α,β-

unsaturated ester 18. Ester reduction aﬀorded the allylic alcohol

19, and subsequent Sharpless asymmetric epoxidation provided

D

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primary alcohol 22, and subsequent Swern oxidation delivered

the aldehyde 23. Stereoselective reductive cyclization was then

performed in high yield by use of SmI₂and employing a

procedure described by Nakata and co-workers.²⁹The resulting

tetrahydropyranol was then silylated to give the TBS ether 24

in 96% yield. The ethyl ester was then saponiﬁed to produce

the carboxylic acid 25, and the α-diazo ketone 26 was obtained

by formation of a reactive mixed anhydride and treatment of

this with a 10-fold excess of diazomethane.³⁰

It was anticipated that the key ring-forming reaction could be

performed by treatment of the diazo ketone 26 with a suitable

metal complex (ML_n) to produce an electrophilic metal

carbenoid 27 (Scheme 5). Reaction of the carbenoid with the

Table 1. Copper-Catalyzed Reactions of Diazo Ketone 26 to

Give Bridged Bicyclic Ethers Z-30 and E-30 (Scheme 5)

yield

b

30

ratio

Z:E 30

a

c

entry

catalyst

solvent

temp

time

3 h

(%)

1

Cu(acac)₂

CH₂Cl₂

reﬂux

rt

30

70

95

94

96

74

94

85

93

78

92

3.5:1

3.6:1

5.0:1

5.9:1

5.5:1

6.9:1

4.8:1

3.9:1

3.1:1

1.3:1

4.0:1

2

Cu(tfacac)₂

Cu(hfacac)₂

3 h

3

15 min

3 h

4

Cu(hfacac)₂CH₂Cl₂

Cu(hfacac)₂THF

5

0 °C

reﬂux

7 h

6

45 min

30 min

15 min

2 h

7

Cu(hfacac)₂

C₆H₆

DCE

8

9

Et₂O

Scheme 5. Metal-Mediated Formation of the 11-

Oxabicyclo[6.2.1]-5-undecen-9-one System

10

11

MeCN

hexane/

CH₂Cl₂

15 min

a

b

Commercially available complex (2 mol %) was used. Combined

c

isolated yield of Z and E isomers. Isomer ratios were determined by

¹H NMR analysis of products prior to puriﬁcation.

Previous work had shown that choice of solvent can have a

signiﬁcant inﬂuence on both the yield and level of

diastereocontrol obtained from reactions of metal carbenoids

with allylic ethers.^23,24In order to explore the eﬀect of solvent

on the yield and stereochemical outcome, the Cu(hfacac)₂-

catalyzed reaction was performed in a variety of solvents at

reﬂux (entries 6−11, Table 1). The reaction performed in

tetrahydrofuran (THF; entry 6, Table 1) resulted in highest

selectivity for the Z isomer (6.9:1 Z:E), albeit with a reduced

product yield. When the reaction was carried out in acetonitrile

at reﬂux (entry 10, Table 1), the proportion of the E isomer

increased substantially (1.3:1 Z:E). The use of benzene,

dichloroethane (DCE), diethyl ether, or a mixture of hexane

and dichloromethane aﬀorded the products 30 in excellent

yield but the Z:E isomer ratios were somewhat lower than those

obtained when the reactions were performed in dichloro-

methane or THF at reﬂux (entries 7−9 and 11, Table 1).

Interestingly, although the results presented in Table 1 show

that solvent has a signiﬁcant inﬂuence on the yield and isomer

ratio, a simple direct correlation to solvent polarity is not

evident.

Selective synthesis of the bicyclic ketone E-30 was required

in order to be able to synthesize the medium-ring core bearing

an E-alkene. Although it was possible to tune the copper-

catalyzed reaction by changing the solvent, it was not possible

to achieve complete reversal of stereoselectivity, and so

rhodium complexes were screened as catalysts. Copper

complexes are usually superior catalysts for the generation

and rearrangement of oxonium ylides or ylide-like intermedi-

ates from allylic ethers, but we have observed dramatic changes

in both the yield and stereochemical outcome when allylic

ethers react with rhodium carbenoids to give medium-ring

carbocycles.^23e,fThus, the use of rhodium complexes as

catalysts allowed both the steric and electronic properties of

the ligand(s) attached to the metal center to be varied in an

attempt to tune the reaction to give predominantly the bridged

bicyclic ether E-30.

ether and rearrangement of the resulting metal-bound ylide 28

or the free oxonium ylide 29 would then aﬀord the isomeric

ketones Z-30 and E-30 (Scheme 5).^20,23c,g,h

Results from studies concerning the rearrangement of

oxonium ylides or ylide-like intermediates generated from

metal carbenoids, performed by us and others,²¹⁻²⁴suggested

that copper acetylacetonate complexes would serve as eﬃcient

catalysts for carbenoid generation, and so the reactions

mediated by these complexes were investigated (Table 1).

Treatment of the diazo ketone 26 with Cu(acac)₂in

dichloromethane at reﬂux gave a low yield of the products Z-

30 and E-30 but with reasonable selectivity (3.5:1 Z:E) (entry

1, Table 1). A signiﬁcant increase in the overall yield was

obtained by use of the more electron-deﬁcient complex

Cu(tfacac)₂, but the Z:E isomer ratio altered little (entry 2,

Table 1). In contrast, a signiﬁcant improvement in both the

yield (95%) and level of stereocontrol (5.0:1 Z:E) was observed

when Cu(hfacac)₂was employed as the catalyst and the

reaction time was reduced substantially (entry 3, Table 1). A

brief study of the inﬂuence of reaction temperature on the

outcome of the Cu(hfacac)₂-mediated reaction was then

conducted (entries 3−5, Table 1). Reducing the temperature

to room temperature or 0 °C resulted in an increase in reaction

time but also gave a marginal increase in Z:E selectivity without

reducing the yield.

Preliminary results showed that reaction of the diazo ketone

26 with Rh₂(OAc)₄in dichloromethane delivered a mixture

(1.2:1 E:Z) of the bicyclic ethers 30 in 52% yield (entry 1,

Table 2). Five other rhodium(II) carboxylate complexes were

screened as catalysts in dichloromethane at reﬂux (entries 2−5

E

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diastereoselectivities did not arise because of product isomer-

ization, control reactions were performed in which each of the

bicyclic ketones 30 was heated at reﬂux in dichloromethane in

presence of either Cu(hfacac)₂or Rh₂(tpa)₄for 2 h. In both

cases, alkene isomerization was not observed, a ﬁnding which

means that the observed E:Z ratios reﬂect the kinetic ratios

produced by the rearrangement reaction. Given that the

rearrangement reaction is irreversible and there is no evidence

for alkene isomerization after rearrangement, the distribution of

isomers must arise either because rearrangement takes place

from diastereomeric ylides with diﬀering conﬁgurations at the

oxonium center or because C−C bond formation proceeds

directly from metal-bound intermediates that are not free

ylides.

With these experimental ﬁndings in mind, we embarked on a

computational study to explore the reactivities of the putative

diastereomeric free oxonium ylides (see Supporting Informa-

tion). The key question was whether rearrangement of the free

ylide 29 would be expected to give either the Z- or E-

conﬁgured product 30 preferentially. To shed light onto this

problem, we investigated the conformational landscape and the

[2,3]-sigmatropic rearrangement reaction of a slightly simpliﬁed

model ylide, an analogue of ylide 29 in Scheme 5, using density

functional theory (see Supporting Information). This computa-

tional study of the energetics of rearrangement of the free

oxonium ylide suggested that the reaction should proceed with

low E/Z selectivity. The fact that rearrangement in the presence

of the catalyst does proceed diastereoselectively, and that

selectivity can be controlled by choice of the catalyst and

reaction conditions, suggests that a free ylide is not involved in

the reaction.

Synthesis of (+)-Cladiella-6Z,11(17)-dien-3-ol (Z-1)

and (+)-Vigulariol (2). The ﬁrst natural product target

selected for total synthesis was (+)-vigulariol (2) (Figure

3).^20aThis compound was isolated from samples of the sea pen

Vigularia juncea collected near the Penghu Islands oﬀ the west

coast of Taiwan and was found to possess in vitro cytotoxic

activity against cultured A 549 (human lung adenocarcinoma)

cells with an IC₅₀of 18.33 μg/mL.³³Prior to its isolation from

natural sources, vigulariol had been obtained inadvertently by

Paquette and co-workers^12cduring their total synthesis of

sclerophytin A. However, full characterization had not been

reported prior to its isolation as a natural product.³³

We anticipated preparing (+)-vigulariol (2) from the alcohol

Z-1, which subsequently transpired to be a natural product in

its own right.³⁴To synthesize Z-1 from the bridged bicyclic

ether Z-30 following the general strategy outlined in Scheme 1,

the third ring would be constructed by a Diels−Alder reaction

(Scheme 6). The ketone Z-30 was ﬁrst converted into the enol

triﬂate Z-31 and then subjected to Stille coupling with

tributyl(1-ethoxyvinyl)tin to give the ethoxy diene Z-32

required for the subsequent cycloaddition reaction.³⁵The

Diels−Alder reaction of the diene Z-32 with methyl vinyl

ketone proceeded regioselectively and exhibited high diaster-

eofacial selectivity with respect to the diene Z-32. A mixture of

the isomeric tricyclic ketones Z-33 and Z-34 (2:1 ratio),

corresponding to the expected exo and endo adducts, was

obtained in 58% yield over three steps. The required isomer Z-

33 proved to be the more thermodynamically stable ketone,

and epimerization of the mixture of Diels−Alder adducts

aﬀorded the ketone Z-33 exclusively and in high yield (Scheme

6).

Table 2. Rhodium-Catalyzed Reactions of Diazo Ketone 26

to Give Bridged Bicyclic Ethers Z-30 and E-30 (Scheme 5)

yield

b

30

ratio Z:E

a

c

entry

catalyst

solvent

temp

time

1 h

(%)

30

1

Rh₂(OAc)₄

Rh₂(tfa)₄

CH₂Cl₂

THF

reﬂux

rt

52

90

63

d

1.2:1

1.7:1

1:1.2

d

2

25 min

15 min

30 min

15 min

30 min

15 min

1 h

3

Rh₂(tfacam)₄

Rh₂(cap)₄

Rh₂(pfb)₄

Rh₂(tpa)₄

4

5

71

36

74

19

66

63

49

45

32

56

1:2.7

1.5:1

1:1.7

1:1.1

1:1.4

1:4.3

1:1.8

1:2.7

1.4:1

1:6.3

6

7

reﬂux

rt

8

THF

9

DCE

reﬂux

rt

10

11

12

13

14

CH₂Cl₂

THF

reﬂux

rt

15 min

18 h

THF

DCE

reﬂux

15 min

a

b

2 mol % rhodium complex was used. Combined isolated yield of Z

c

and E isomers. Isomer ratios were determined by ¹H NMR analysis of

products prior to puriﬁcation. Neither of the desired bicyclic ketones

d

was produced and a complex mixture of other products was obtained.

and 10, Table 2).³¹The complex Rh₂(tfa)₄gave the bicyclic

ketones 30 in excellent yield (1.7:1 Z:E) (entry 2, Table 2),

31a

while Rh₂(tfacam)₄aﬀorded the bicyclic ketones 30 (1:1.2

Z:E) in 63% yield (entry 3, Table 2). When the reaction was

performed with Rh₂(cap)₄,^31bthe bicyclic ketones 30 were not

obtained (entry 4, Table 2). More promising results were

31c,d

31e

obtained when either Rh₂(pfb)₄

or Rh₂(tpa)₄

was

employed as the catalyst in dichloromethane at reﬂux (entries

5 and 10, Table 2). These catalysts delivered a reasonable yield

of the bridged bicyclic ethers 30 with a signiﬁcant preference

for the E isomer.

The promising initial results obtained when either Rh₂(pfb)₄

or Rh₂(tpa)₄was employed as the catalyst encouraged their

further investigation, and so reactions were performed in

dichloromethane, THF, or dichloroethane at room temperature

or at reﬂux (entries 5−14, Table 2). In the case of both

Rh₂(pfb)₄and Rh₂(tpa)₄, the yields and levels of E-selectivity

were generally lower when the reactions were performed at

room temperature. The best result was obtained when the

reaction was performed with Rh₂(tpa)₄in DCE at reﬂux. In this

case, the bridged bicyclic ethers 30 were obtained in 56% yield

with 1:6.3 preference for the required E isomer (entry 14, Table

2).

The isomeric products Z-30 and E-30 are separable by

column chromatography on silver nitrate-impregnated silica gel

and are crystalline solids. It was possible to conﬁrm their

structures by X-ray analysis (racemic material was used), and

the X-ray diﬀraction data for compound ( )-E-30 shows that

the alkene is twisted out of planarity by an angle of

approximately 20°, indicating that E-30 is signiﬁcantly higher

in energy than Z-30. This was conﬁrmed by exposure of ( )-E-

30 to a solution of 2,2′-azobis(isobutyronitrile) (AIBN) and

ethanethiol in benzene at reﬂux, which resulted in complete

isomerization to give the thermodynamically more stable

compound ( )-Z-30.³²

The fact that the changes in catalyst produce dramatic

variations in the stereochemical outcome suggests that the

reaction might proceed through a metal-bound ylide rather

than a free ylide. In order to prove that the observed

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Scheme 6. Conversion of Z-30 into the Tricyclic Cladiellin

Core by Diels−Alder Reaction

Scheme 8. Completion of the Total Synthesis of

(+)-Vigulariol (2)

workers.^12cIn addition, Paquette and co-workers reported that

they isolated the alcohol Z-1 as an oil, whereas the material

synthesized by us is a solid with melting point 91−93 °C.

Following the completion of our synthesis of (+)-cladiella-

6Z,11(17)-dien-3-ol (Z-1), the compound was isolated along

with several other cladiellin natural products from the soft coral

Cladiella pachyclados collected in the Red Sea.³⁴The NMR data

for the natural material and synthetic (+)-cladiella-6Z,11(17)-

dien-3-ol (Z-1) matched very well.³⁸Very recently, Crimmins

et al.^14edisclosed a total synthesis of this compound; the NMR

data, optical rotation {[α]²_D⁵+82.2 (c 0.27, CHCl₃)} and

melting point (91−92 °C) reported by them are in close

agreement with data for our sample of (+)-cladiella-6Z,11(17)-

dien-3-ol (Z-1).

Standard Wittig methylenation of the ketone and quenching

of the reaction with aqueous acid aﬀorded the hydroxyketone

Z-35, resulting from enol ether hydrolysis and concomitant loss

of the TBS group (Scheme 7). Selective hydrogenation of the

Scheme 7. Functionalization of the Tricyclic Core

The ﬁnal steps in the synthesis of (+)-vigulariol (2) involved

chemoselective and stereoselective alkene epoxidation, followed

by intramolecular nucleophilic epoxide opening by the tertiary

hydroxyl group to form the ether bridge. Initially, we expected

to perform this sequence of reactions in a stepwise manner, but

treatment of the diene Z-1 with m-chloroperoxybenzoic acid

(m-CPBA) in dichloromethane at 0 °C aﬀorded (+)-vigulariol

(2) directly.³⁹(+)-Vigulariol (2) was obtained instead of the

epoxide 38 even when a neutral oxidant such as dimethyldiox-

irane was used to epoxidize the diene Z-1. This observation

suggests that the epoxide is predisposed to undergo attack by

the C-3 hydroxyl group because conformational eﬀects place

this substituent in close proximity to C-6 and in a position that

favors nucleophilic opening of the epoxide via an S_N2 trajectory

(Scheme 8). This observation has been conﬁrmed by Hoppe

and co-workers¹⁶and by Crimmins et al.^14eduring their total

syntheses of (+)-vigulariol.

The total synthesis of (+)-cladiella-6Z,11(17)-dien-3-ol (Z-

1) from the known and readily available allylic alcohol (+)-14

was accomplished in 16 steps and 15.1% yield. The synthesis of

(+)-vigulariol (2) is one step longer and the natural product

was obtained in 13.8% overall yield from (+)-14.

Synthesis of (−)-Cladiella-6,11-dien-3-ol (5), (−)-3-

Acetoxycladiella-6,11-diene (6), (−)-Cladiell-11-ene-

3,6,7-triol (9), and (−)-3-Acetoxycladiell-11-ene-6,7-diol

(10). The vast majority of cladiellin natural products possess

either a highly strained 6E-alkene in the medium-sized ring or

an anti 1,2-diol at C-6 and C-7 that would result from syn

dihydroxylation of an E-alkene. However, researchers have

generally targeted cladiellins that contain a Z-alkene in the

medium ring or those that lack an alkene at this position. To

side-chain alkene of the diene Z-35 under carefully controlled

conditions delivered the ketone Z-36 in excellent yield.

Methylenation of the ketone Z-36 with a large excess of

methylene triphenylphosphonium ylide in benzene at reﬂux

then provided the alcohol Z-37 in excellent yield.³⁶

Introduction of a methyl substituent at the C-3 position was

required to complete the total syntheses of the natural products

1 and 2. Installation of the ﬁnal one-carbon fragment (C-15)

was accomplished by oxidation of the alcohol Z-37 by the use

of the Dess−Martin protocol³⁷and reaction of the resulting

ketone with methylmagnesium chloride in THF at 0 °C

(Scheme 8). This reaction provided the tertiary alcohol Z-1 in

excellent yield and with a very high degree of diastereocontrol.

The alcohol Z-1 had been synthesized by Paquette and co-

workers^12cduring studies concerning the total syntheses of

scelerophytins A and B, and the spectroscopic data for our

sample were found to be in close agreement with data reported

by them. However, the magnitude of the optical rotation

diﬀered: [α]²_D²+69.7 (c 0.60, CHCl₃) was recorded, compared

to [α]²_D²+95.3 (c 0.40, CHCl₃) reported by Paquette and co-

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date, only Kim and co-workers¹⁵have devised a general route

for the preparation of cladiellin natural products possessing the

common but more synthetically challenging 6E conﬁguration.

In most previous syntheses of natural products containing an

anti 1,2-diol at positions C-6 and C-7, this functionality has

been introduced by syn dihydroxylation of the 6Z-alkene,

followed by inversion of conﬁguration at the C-6 stereo-

center.¹²Thus, it is evident that any completely general strategy

for the synthesis of the cladiellin natural products must be

ﬂexible enough to allow construction of the strained 6E-alkene

as well as the 6Z-alkene. To test the generality of our strategy in

this regard, the natural products (−)-cladiella-6,11-dien-3-ol

(5),⁴⁰(−)-3-acetoxycladiella-6,11-diene (6),⁴¹(−)-cladiell-11-

ene-3,6,7-triol (9),⁴²and (−)-3-acetoxycladiell-11-ene-6,7-diol

(10)⁴²were selected as targets.

realistic proposition. The immediate synthetic objective was

construction of the complete tricyclic core found in the E-

conﬁgured cladiellins. A three-step sequence analogous to that

developed for the synthesis of the tricyclic core of (+)-vigulariol

(2) was utilized that delivered the tricyclic ketones E-33 and E-

34 (1.6:1 ratio) in 68% yield over three steps (Scheme 10);

Scheme 10. Conversion of E-30 into the Complete Tricyclic

Cladiellin Core via Diels−Alder Cycloaddition Reaction

The structure of (−)-cladiella-6,11-dien-3-ol (5) was ﬁrst

reported by Hochlowski and Faulkner in 1980⁴⁰following its

isolation from an unknown soft coral collected at Majuro Atoll

in the Marshall Islands. (−)-3-Acetoxycladiella-6,11-diene (6),

the acetate derivative of the alcohol 5, was later isolated by Shin

and co-workers⁴¹from a gorgonian of the genus Muricella that

had been collected near Jaeju Island, South Korea. Both the

alcohol 5 and the acetate 6 were found to be active in brine-

shrimp lethality assays, with the former compound having very

high activity (LD₅₀0.3 ppm). The acetate 6 also exhibited

moderate in vitro cytotoxicity against several human tumor cell

lines.

The natural products (−)-cladiell-11-ene-3,6,7-triol (9) and

(−)-3-acetoxycladiell-11-ene-6,7-diol (10) are dihydroxylated

(C-6, C-7) analogues of the cladiellins 5 and 6.^42,43The triol 9

and the diol 10 were isolated from a sample of a Cladiella

species of soft coral collected at Ishigaki Island, Okinawa.⁴²The

compounds were fully characterized by Uchio et al.,^42,43and the

structure of the crystalline triol 9 was conﬁrmed by X-ray

diﬀraction analysis.

At the outset of our synthetic studies, we recognized that the

cladiellin targets 6, 9, and 10 should be accessible from

(−)-cladiella-6,11-dien-3-ol (5) in just one or two additional

steps by acetylation and/or stereoselective dihydroxylation

(Scheme 9). Consequently, the stereoselective synthesis of

alcohol 5 was the primary objective.

The discovery that the bicyclic ketone E-30 could be

obtained as the major cyclization product from the rhodium-

catalyzed reaction of diazo ketone 26 meant that the total

synthesis of the cladiellin natural products possessing an E-

alkene (e.g., compounds 3−6, Figure 1) or an anti 1,2-diol in

the medium-sized ring (e.g., compounds 7−10, Figure 1) was a

subsequent epimerization of the mixture aﬀorded E-33 in 85%

yield. In order to obtain good yields from the Stille coupling

reaction, it was essential to use tributyl(1-ethoxyvinyl)tin that

had been freshly prepared and distilled immediately prior to

reaction with the enol triﬂate E-31.⁴⁴

The next objective was transformation of the methyl ketone

into the isopropyl group found in the majority of the cladiellins,

and it was expected that this could be achieved by sequential

ketone methylenation and selective hydrogenation by analogy

with the procedure used during the total synthesis of

(+)-vigulariol (2).^20aPreliminary studies were performed on

racemic material, and Wittig oleﬁnation of ketone ( )-E-33

delivered the triene ( )-39 (Scheme 11). Subsequent acid-

mediated hydrolysis of the enol ether in ( )-39 delivered the

Scheme 11. Attempted Installation of the Isopropyl Group

by Selective Hydrogenation

Scheme 9

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ketone ( )-40 as a crystalline solid, which was subjected to X-

ray crystallographic analysis. The X-ray data showed that

selective hydrogenation would be a challenging proposition

because the endocyclic E-alkene of the ketone ( )-40 is

twisted out of planarity by an angle of >20° and thus should be

highly reactive.

acid-mediated hydrolysis of the enol ether ( )-42 produced a

mixture of the required ketone ( )-43 and the bridged acetal

( )-44. An analogous reaction had been observed by

Crimmins et al.^14cduring their synthesis of ophirin B, and so

formation of the bridged acetal ( )-44 was unsurprising.

Consequently, the decision was made not to reveal the ketone

at C-11 until the extraneous oxygen substituent had been

excised from the side chain.

It was anticipated that deoxygenation of the tertiary alcohol

could be performed by use of the combination of a Lewis acid

and a trialkylsilane or by employing the Barton−McCombie

procedure.⁴⁷However, attempts to perform direct reduction of

the tertiary alcohol ( )-43 with boron triﬂuoride etherate and

triethylsilane led to isomerization and desilylation of the

starting material. Preparation of the xanthate derivative of the

tertiary alcohol, required to perform the Barton−McCombie

deoxygenation reaction, was also unsuccessful.⁴⁷

Selective hydrogenation of the diene Z-35 had been

accomplished by use of platinum oxide and hydrogen at

atmospheric pressure during the total synthesis of vigulariol

(Scheme 7),^20abut attempted hydrogenation of the diene

( )-40 employing these conditions failed to deliver the ketone

( )-E-41 and gave a complex mixture of products instead

(Scheme 11). When hydrogenation was performed at

atmospheric or higher pressure with catalysts such as

Wilkinson’s catalyst, titanocene dichloride,⁴⁵or Raney nickel,

mixtures of isomerized starting material, fully saturated

compounds, and decomposition products were obtained. A

possible complicating factor might have been the presence of

the sterically demanding TBS protecting group in ( )-40,

which could have been shielding the terminal alkene, thereby

hindering the approach of the catalyst. However, removal of the

TBS group to give the free alcohol ( )-E-35 and subsequent

hydrogenation failed to deliver the required compound ( )-E-

36.

It was clear that the isopropyl group could not be introduced

by selective alkene hydrogenation, and so alternative

approaches to the formation of this group were explored.

First, selective hydroboration of the terminal alkene of diene

( )-40 with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by

acidic treatment was explored.⁴⁶However, this reaction failed

to deliver the required product. Sequential reduction of the

ketone ( )-E-33, conversion of the resulting secondary alcohol

into a suitable leaving group (tosylate, mesylate, or triﬂate), and

displacement with various organometallic reagents also failed to

give the required product.

Kim and co-workers¹⁵had faced the challenge of converting

a tertiary alcohol into an isopropyl group in an analogous

compound during their total synthesis of cladiella-6,11-dien-3-

ol (5). They had solved the problem by converting the tertiary

alcohol into the corresponding acetate and subjecting it to

reduction conditions developed by Barton and co-workers,⁴⁸

and so this sequence was investigated. The alcohol 42 was

selected as the starting material in order to avoid generating the

side product 44 (Scheme 12). Acetylation of this alcohol under

standard conditions delivered the tertiary acetate 45 required

for the reduction reaction (Scheme 13). A solution of acetate

Scheme 13. Elaboration of the Tricyclic Core to Produce the

Key Advanced Intermediate E-41

A new approach to the construction of the isopropyl group

was required. Addition of methylmagnesium bromide to the

methyl ketone E-33 aﬀorded the tertiary alcohol 42, which we

hoped to deoxygenate (Scheme 12). In preliminary studies,

Scheme 12. Installation of Isopropyl Group by

Deoxygenative Removal of an Acetate Group

45 in THF was then added to the deep blue solution produced

by solvation of potassium metal by 18-crown-6 in a mixture of

t-butylamine and THF.^49,50After reappearance of the royal-blue

coloration, the remaining potassium was consumed by addition

of ethanol, and the alcohol 46 was then isolated in 65% yield

over two steps. Various workup procedures were explored in an

attempt to prevent loss of the TBS protecting group during the

reduction reaction, but the alcohol 46 was obtained as the

major or sole product in all cases.

Following the successful synthesis of alcohol 46 possessing

the requisite isopropyl substituent, the next objective was

formation of the trisubtituted alkene present in the six-

membered ring of cladiella-6,11-dien-3-ol (5). Hydrolysis of the

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enol ether 46 under acidic conditions aﬀorded the correspond-

ing ketone (Scheme 13). Reprotection of the secondary alcohol

as TBS ether was achieved to give the silyl ether E-41. Kinetic

deprotonation of the ketone and trapping of the enolate as the

triﬂate was performed by treatment of ketone 41 with sodium

bis(trimethylsilyl)amide (NaHMDS) in the presence of

PhNTf₂at −78 °C (Scheme 14). The resulting enol triﬂate

ylation was found to be highly diastereoselective, and the triol 9

was obtained as a single diastereomer in 66% yield by treatment

of the diene 5 with osmium tetroxide (2 mol %) in the presence

of N-methylmorpholine N-oxide (NMO) as stoichiometric

reoxidant (Scheme 15). The spectroscopic and other data for

Scheme 15. Synthesis of (−)-3-Acetoxycladiella-6,11-diene

(6), (−)-Cladiell-11-ene-3,6,7-triol (9), and (−)-3-

Acetoxycladiell-11-ene-6,7-diol (10) from (−)-Cladiella-

6,11-dien-3-ol (5)

Scheme 14. Completion of Synthesis of the (−)-Cladiella-

6,11-dien-3-ol (5)

synthetic (−)-cladiell-11-ene-3,6,7-triol (9) were identical to

those reported for the natural product.^42,52The triol 9 was

isolated as a colorless crystalline solid, allowing further

structural conﬁrmation by single-crystal X-ray crystallography.

Two further natural products (6 and 10) were prepared from

(−)-cladiella-6,11-dien-3-ol (5) (Scheme 15). (−)-Acetoxycla-

diella-6,11-diene (6) had not been synthesized previously, and

acetylation of the tertiary alcohol 5 to give this compound

proved to be surprisingly diﬃcult. After considerable

experimentation, the acetate 6 could be obtained by treatment

of the alcohol 5 with triethylamine and DMAP, with acetic

anhydride as solvent at 40 °C. Despite the modest yield,

suﬃcient material was prepared to show that spectroscopic and

other data matched those reported for the natural material.⁴¹

Interestingly, attempted acetylation of the alcohol 5 by

treatment with acetic anhydride and trimethylsilyl triﬂuorome-

thanesulfonate (TMSOTf) produced the tetracyclic compound

51 (Scheme 16).⁵³Hochlowski and Faulkner⁴⁰had reported

47 was subjected to a Kumada-type coupling reaction with

methylmagnesium chloride to aﬀord diene 48 possessing the

requisite trisubstituted alkene.⁵¹The diene 48 could not be

separated from phosphine impurities generated from the

palladium catalyst, and so the crude product was treated with

tetra-n-butylammonium ﬂuoride (TBAF) to give the secondary

alcohol 49, which could be puriﬁed more easily.

The alcohol 49 is the C-3 epimer of a compound prepared by

Kim and co-workers¹⁵as a late-stage intermediate during their

total synthesis of (−)-cladiella-6,11-dien-3-ol (5). The synthesis

of 5 was completed in two further steps: oxidation of the

secondary alcohol to give the ketone 50 and subsequent

nucleophilic addition to install the ﬁnal methyl group (Scheme

14). There were concerns regarding the stability of the ketone

50 and so this compound was subjected to the ﬁnal

nucleophilic addition reaction without puriﬁcation. Standard

Grignard addition of methylmagnesium chloride to the ketone

50 produced (−)-cladiella-6,11-dien-3-ol (5) in 58% over the

two steps, and the yield could be improved to 69% over two

steps by employing the protocol (reaction with methyllithium

in the presence of NaBF₄at −78 °C) developed by

Paquette.^11a,12c(−)-Cladiella-6,11-dien-3-ol (5) was obtained

with high diastereoselectivity, and the spectroscopic and other

data for this compound were identical to those reported for the

natural product.⁴⁰

Scheme 16

formation of this compound by treatment of the natural

product 5 with boron triﬂuoride etherate during their isolation

work. Kim and co-workers¹⁵had also observed this reaction

during their total synthesis of polyanthellin A. The diﬃculties

encountered when trying to acetylate the alcohol 5 and the

relative ease of cyclization to give the ether 51 suggest that the

alcohol 5 adopts a conformation in which the hydroxyl group is

positioned toward the interior of medium-sized ring and in

close proximity to the alkene.

Kim and co-workers¹⁵had reported that the natural product

(−)-cladiell-11-ene-3,6,7-triol (9) could be obtained by

dihydroxylation of (−)-cladiella-6,11-dien-3-ol (5). Dihydrox-

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The synthesis of 3-acetoxycladiellin-11-ene-6,7-diol (10), a

compound that had not been synthesized previously, was

undertaken with the small quantity of (−)-3-acetoxycladiella-

6,11-diene (6) that had been prepared (Scheme 15). Selective

dihydroxylation was performed by treatment of the acetate 6

with substoichiometric quantities of osmium tetroxide in the

presence of NMO at 0 °C to give 3-acetoxycladiellin-11-ene-

6,7-diol (10) in 36% yield. Due to the limited availability of the

starting material, the dihydroxylation reaction was not

optimized. This was the ﬁrst synthesis of 3-acetoxycladiellin-

11-ene-6,7-diol (10), and a suﬃcient amount of synthetic

material was obtained to demonstrate that the spectroscopic

and other data for synthetic material were identical to those

reported for the natural product.^42,54

Synthesis of (−)-Sclerophytin A (7), (−)-Sclerophytin B

(8), (+)-Deacetylpolyanthellin A (11), and (+)-Polyan-

thellin A (12). Following completion of the enantioselective

total syntheses of four members of the cladiellin family of

natural products featuring an endocyclic alkene in the six-

membered ring, attention turned to the synthesis of cladiellin

natural products possessing an exocyclic alkene (C-11−C-17)

in the six-membered ring (Scheme 17). The total syntheses of

a concentration of 0.001 μg·mL⁻¹. On the basis of extensive

NMR analysis, Sharma and Alam⁵⁷originally proposed

structures for sclerophytins A and B that had an additional

ether linkage bridging between C-3 and C-7. However, these

structures were subsequently shown to be incorrect following

pioneering synthetic studies performed by the groups of

Overman and Paquette;¹⁰⁻¹²these researchers later demon-

strated that sclerophytins A and B have the structures shown in

Figure 3 (7 and 8) by synthesizing both of them.

Polyanthellin A (12) was isolated from the gorgonian

Briareum polyanthes collected oﬀ the coast of Puerto Rico by

58

́

Rodriguez and co-workers, and its structure was reported in

́

2003. In the course of their characterization studies, Rodriguez

and co-workers⁵⁸prepared deacetylpolyanthellin A (11) by

deacetylation of polyanthellin A (12) using lithium aluminum

́

hydride. Following careful analysis of NMR data, Rodriguez

and co-workers⁵⁸concluded that compounds 11 and 12 were

spectroscopically identical (but with [α]_Dvalues that are

opposite, implying an antipodal relationship) to natural

products that had been isolated from samples of a Briareum

species by Bowden et al.⁵⁹However, these earlier workers had

misassigned the compounds as having tertiary hydroxyl groups

at C-3 and C-7 instead of the additional ether bridge spanning

58

these positions.⁵⁹Rodriguez and co-workers showed that

́

Scheme 17

deacetylpolyanthellin A (11) and polyanthellin A (12) have

activity against the malaria parasite Plasmodium falciparum with

IC₅₀values of 16 μg·mL⁻¹.

The synthesis of the new targets started from the alcohol 42,

a compound that features as a late-stage intermediate in our

syntheses of the cladiellin natural products 5, 6, 9, and 10

(Scheme 18). Acetylation of the tertiary alcohol followed by

Scheme 18. Elaboration of the Tricyclic Core

cladiellin (3) and litophytin A (4) have not been reported,

making them very attractive targets for synthesis. It seemed

likely that these compounds could be prepared from the alcohol

E-1 and that this late-stage intermediate could also serve as a

precursor to (−)-sclerophytin A (7), (−)-sclerophytin B (8),

(+)-deacetylpolyanthellin A (11), and (+)-polyanthellin A (12)

(Scheme 17).

Cladiellin (3) is a particularly signiﬁcant natural product

because it was the second oxygen-bridged 2,11-cyclized

diterpene to be isolated and it lends its name to the entire

family of marine natural products. Cladiellin (3) was ﬁrst

extracted from samples of a Cladiella species that had been

collected on the Great Barrier Reef and its structure was

reported by Wells and co-workers in 1977.⁵⁵Shin and co-

workers⁴¹later isolated it from samples of a Muricella species

that also contained the natural products 5 and 6.

acid-catalyzed enol ether hydrolysis aﬀorded the ketone 52, and

subsequent Wittig methylenation produced the diene 53 in

60% yield over the three-step sequence (Scheme 18).

Reductive removal of the acetate to give the isopropyl

substituent was performed by Barton’s procedure⁴⁸(Scheme

19). The TBS group was also removed during the reaction to

give the alcohol E-37 in 78% yield. At this stage, introduction of

the C-3 methyl substituent was required to give the tertiary

alcohol E-1. This transformation was achieved by oxidation of

secondary alcohol with Dess−Martin periodinane³⁷and

exposure of the resulting ketone to MeLi and NaBF₄in THF

at −78 °C.^11a,12c

Litophynin A (4) was isolated from a Litophyton species

collected in Sukumo Bay, Japan, and its structure was reported

in 1987.⁵⁶This natural product was reported to display

insecticidal activity against the silkworm Bombyx mori L. (ED₅₀

12 ppm).

In 1988, Sharma and Alam⁵⁷reported the isolation of

sclerophytins A and B (7 and 8) from samples of the soft coral

Sclerophytum capitalis collected in Micronesia. Sclerophytin A

was reported to possess cytotoxic activity against L1210 cells at

In principle, the alcohol E-1 could serve as an advanced

intermediate for the synthesis of many cladiellin natural

K

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previously reported by Paquette and co-workers,^12b,cselective

acetylation of the secondary alcohol was possible, and this

reaction delivered (−)-sclerophytin B (8) in 79% yield

(Scheme 20). Spectroscopic and other data for synthetic

(−)-sclerophytin A (7) and (−)-sclerophytin B (8) were

identical to those reported for the compounds isolated from

natural sources.⁵⁷

Scheme 19. Deoxygenative Removal of Acetate Group to

Give the Key Late-Stage Intermediate E-1

Although it was not possible to esterify the tertiary alcohol E-

1, an interesting transformation was encountered during

screening of potential acetylation conditions. Attempted acid-

catalyzed acetylation of tertiary alcohol E-1 with isopropenyl

acetate in the presence of p-toluenesulfonic acid (p-TSA)⁶⁰

aﬀorded the tetracyclic compound 54 instead of the acetate 3.

The tetracyclic compound 54 had been reported by Paquette

and co-workers^12cduring their synthesis of the compound that

had been proposed to be sclerophytin A (Figure 4), and our

spectroscopic data matched those reported for this compound.

Formation of the additional cyclic ether can be explained by the

fact that the hydroxyl group is located in close proximity to the

alkene, and upon treatment with a Brønsted acid, the oxygen

attacks the tertiary carbocation formed by protonation of the

strained E-alkene, resulting in relief of strain in the medium-

sized ring.

The formation of compound 54 presented an opportunity to

synthesize the cladiellin natural products (+)-deacetylpolyan-

thellin A (11) and (+)-polyanthellin A (12). These natural

products had been synthesized from the alkene 51, a

regioisomer of 54, by Kim and co-workers¹⁵using an

oxymercuration−demercuration sequence, and so these con-

ditions were applied to our system (Scheme 21). Treatment of

products. Esteriﬁcation of the tertiary alcohol E-1 to give the

natural products cladiellin (3) and litophynin A (4) was

explored ﬁrst (Scheme 19). Acetylation of (−)-cladiella-6,11-

dien-3-ol (5), a very similar compound to the alcohol E-1, had

been performed already, and so acetylation of the alcohol E-1

was expected to deliver cladiellin (3). However, reaction of the

alcohol E-1 with acetic anhydride in the presence of

triethylamine and DMAP at either room temperature or 40

°C produced a complex mixture of byproducts instead of the

required ester. Deprotonation of the tertiary alcohol prior to

addition of acetic anhydride, or the replacement of acetic

anhydride with acetyl chloride as the acetylating agent, also

failed to deliver cladiellin (3). The failure of these reactions

suggests that there are subtle conformational diﬀerences

between the medium-ring portions of the alcohols 5 and E-1,

with the tertiary hydroxyl group of the substrate E-1 being

shielded even more eﬀectively than that in the isomeric

compound 5.

Scheme 21. Completion of Syntheses of

(+)-Deacetylpolyanthellin A (11) and (+)-Polyanthellin A

(12)

The alcohol E-1 had been identiﬁed as a potential advanced

intermediate for the synthesis of sclerophytins A and B, and

work now focused on synthesizing these polyhydroxylated

natural products (Scheme 20). Chemoselective and diaster-

eoselective dihydroxylation of the trisubstituted E-alkene of

alcohol E-1 delivered (−)-sclerophytin A (7) in 59% yield. As

Scheme 20. Completion of the Syntheses of

(−)-Sclerophytin A (7) and (−)-Sclerophytin B (8)

the alkene 54 with mercury(II) acetate in aqueous THF

followed by demercuration⁶¹aﬀorded (+)-deacetylpolyanthellin

A (11) in 77% yield, as a 10:1 mixture of diastereomers,

favoring that shown; subsequent acetylation delivered (+)-poly-

anthellin A (12) in 55% yield (Scheme 21). Both enantiomers

of deacetylpolyanthellin A and polyanthellin A have been

isolated from natural sources and the present route provided

the dextrorotary compound consistent with reports of Kim and

co-workers,¹⁵Campbell and Johnson,¹⁷and Bowden et al.⁵⁹

Spectroscopic and other data for both synthetic (+)-deace-

L

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were combined and washed with brine (300 mL) and then dried

(MgSO₄) and concentrated in vacuo to aﬀord the crude aldehyde,

which was used for the next step without puriﬁcation.

tylpolyanthellin A (11) and (+)-polyanthellin A (12) were

identical to those reported for the natural products.

To a stirred solution of the unpuriﬁed aldehyde in anhydrous THF

(1.5 L) was added ethyl 2-(triphenylphosphoranylidene)propanoate

(82.5 g, 227 mmol) in one portion. The resulting solution was stirred

at rt for 48 h and the reaction was then quenched by addition of ethyl

acetate (500 mL) and water (500 mL). The aqueous phase was

separated and extracted with ethyl acetate (3 × 300 mL). The organic

extracts were combined, washed with brine (300 mL), dried (MgSO₄),

and concentrated in vacuo. Flash column chromatography of the

residue on silica gel (petroleum ether/ethyl acetate 20:1) aﬀorded the

alkene 18 (40.8 g, 95% over two steps) as a colorless oil. R_f= 0.77

(petroleum ether/ethyl acetate 2:1); ν_max(CHCl₃) 2955, 2930, 2887,

CONCLUSIONS

■

The enantioselective total syntheses of 10 cladiellin natural

products have been completed starting from the readily

available and known allylic alcohol (+)-14. Three important

ring-forming reactions have been used to construct the tricyclic

core of the cladiellins: (i) a SmI₂-mediated reductive cyclization

to form the tetrahydropyran 24; (ii) a metal-catalyzed reaction

of diazo ketone 26 to generate an ylide-like intermediate that

rearranges to produce the bridged bicyclic ethers Z-30 and E-

30; and (iii) a Diels−Alder cycloaddition reaction to construct

the third ring found in the core structure of the cladiellins. The

key ring-forming reaction, in which diazo ketone 26 is

converted into a bridged bicyclic ether, can be tuned to give

either of the isomeric ketones Z-30 or E-30 as the major

product by judicious choice of catalyst and reaction conditions.

A three-step sequence is then used to convert the ketones Z-30

and E-30 into the tricyclic ketones Z-33 or E-33, which can be

used as advanced intermediates to prepare virtually any

member of the cladiellin family of natural products.

1

2858, 1711, 833, 814 775, 745 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

6.77 (1H, tq, J = 7.5, 1.4 Hz), 4.18 (2H, q, J = 7.1 Hz), 3.62 (2H, t, J =

6.2 Hz), 2.26−2.21 (2H, m), 1.82 (3H, br d, J = 1.4 Hz), 1.65 (2H, tt,

J = 7.6, 6.2 Hz), 1.30 (3H, t, J = 7.1 Hz), 0.89 (9H, s), 0.04 (6H, s);

¹³C NMR (100 MHz, CDCl₃) δ 168.4, 142.0, 128.2, 62.5, 60.5, 31.8,

26.1, 25.2, 18.4, 14.4, 12.5, −5.2; high-resolution mass spectrometry

(HRMS) [chemical ionization (CI), isobutane] m/z calcd for

C₁₅H₃₁O₃Si [M + H]⁺287.2045, found 287.2041; low-resolution

mass spectrometry (LRMS) (CI, isobutane) m/z (% intensity) 287.3

(100), 241.3 (18), 229.3 (11). Anal. Calcd for C₁₅H₃₀O₃Si: C, 62.89;

H, 10.55. Found: C, 62.89; H, 10.48.

The versatility of our route has been demonstrated by

completion of the enantioselective syntheses of 10 natural

products from the alcohol (+)-14: (+)-cladiella-6Z,11(17)-

dien-3-ol (Z-1) in 16 steps, (+)-vigulariol (2) in 17 steps,

(−)-cladiella-6,11-dien-3-ol (5) in 20 steps, (−)-3-acetoxycla-

diella-6,11-diene (6) in 21 steps, (−)-sclerophytin A (7) in 18

steps, (−)-sclerophytin B (8) in 19 steps, (−)-cladiell-11-ene-

3,6,7-triol (9) in 21 steps, 3-acetoxycladiellin-11-ene-6,7-diol

(10) in 22 steps, (+)-deacetylpolyanthellin A (11) in 19 steps,

and (+)-polyanthellin A (12) in 20 steps.

(E)-6-(tert-Butyldimethylsilanyloxy)-2-methylhex-2-en-1-ol

(19).^26,27To a stirred solution of the ester 18 (39.8 g, 139 mmol) in

anhydrous dichloromethane (1.40 L) at −78 °C was added

diisobutylaluminium hydride (DIBAL-H; 350 mL of a 1.0 M solution

in hexane, 350 mmol) dropwise over 1.5 h. The resulting solution was

stirred for 30 min, then quenched with a saturated aqueous solution of

sodium potassium tartrate (500 mL) and allowed to warm to rt. The

reaction mixture was then diluted with ethyl acetate (800 mL) and

stirred vigorously until the appearance of two phases. The aqueous

phase was separated and extracted with ethyl acetate (3 × 500 mL).

The organic extracts were combined, washed with brine (500 mL),

dried (MgSO₄), and concentrated in vacuo to yield a colorless oil.

Flash column chromatography on silica gel (petroleum ether/ethyl

acetate 7:1) aﬀorded the allylic alcohol 19 (31.8 g, 94%) as a colorless

oil. R_f= 0.48 (petroleum ether/ethyl acetate, 2:1); ν_max(CHCl₃) 3339,

EXPERIMENTAL SECTION

■

General Experimental. Air- and moisture-sensitive reactions were

performed under an atmosphere of nitrogen or argon in oven or ﬂame-

dried apparatus. Organic solvents were dried by use of a Pure Solv

solvent puriﬁcation system or dried and distilled by standard methods:

tetrahydrofuran (THF) by distillation from sodium benzophenone

ketyl, dichloromethane by distillation from calcium hydride. Reagents

were obtained from commercial suppliers and used as supplied, unless

otherwise stated. Reactions were monitored by thin-layer chromatog-

raphy on plastic-backed 0.25 mm silica gel plates or Merck silica gel 60

covered alumina plates F254. Plates were viewed under UV light or

were visualized by use of either potassium permanganate solution or

acidic ethanolic anisaldehyde solution. Column chromatography was

performed under pressure on silica gel (Fluorochem LC60A, 35−70

μm, or Merck 7734 grade) with HPLC-grade solvents as eluent.

Petroleum ether used for column chromatography was the 40−60 °C

fraction. Unless stated otherwise, high-resolution mass spectra were

obtained on a mass spectrometer equipped with a double-focusing

magnetic sector mass analyzer.

1

2955, 2930, 2888, 2859, 1097, 1007, 835, 814, 775, 716 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 5.41 (1H, tq, J = 7.2, 1.2 Hz), 3.99 (2H, d,

J = 6.0 Hz), 3.61 (2H, t, J = 6.4 Hz), 2.09 (2H, q, J = 7.4 Hz), 1.66

(3H, s), 1.58 (2H, tt, J = 7.4, 6.4 Hz), 1.32−1.24 (1H, m), 0.89 (9H,

s), 0.05 (6H, s); ¹³C NMR (100 MHz, CDCl₃) δ 135.2, 126.1, 69.2,

62.7, 32.8, 26.1, 24.1, 18.5, 13.8, −5.1; HRMS (CI, isobutane) calcd

for C₁₃H₂₇OSi [M − OH]⁺227.1833, found 227.1832; LRMS (CI,

isobutane) m/z (% intensity); 245.5 (15), 227.5 (100), 95.2 (80).

Anal. Calcd for C₁₃H₂₈O₂Si: C, 63.88; H, 11.55. Found: C, 63.75; H,

11.64.

[(2R,3R)-3-[3-(tert-Butyldimethylsilanyloxy)propyl]-2-

methyloxiranyl]methanol (20).^26,27To a suspension of 4 Å

powdered molecular sieves (6 g) in anhydrous dichloromethane (1.0

L) at −20 °C were added freshly distilled titanium tetraisopropoxide

(1.74 g, 6.13 mmol), freshly distilled (−)-diethyl tartrate (1.89 g, 9.20

mmol), and tert-butylhydroperoxide (32.6 mL of a 5.62 M solution in

dichloromethane, 184 mmol). The reaction mixture was stirred for 20

min at −20 °C, and then a solution of the allylic alcohol 19 (30.0 g,

123 mmol) in anhydrous dichloromethane (200 mL) was added

slowly, with the temperature maintained at −20 °C. The mixture was

stirred for a further 1 h and the reaction was quenched by addition of

water (100 mL) and a solution of 30 wt % sodium hydroxide in brine

(100 mL). The reaction mixture was stirred for a further 30 min and

then allowed to warm to rt. The molecular sieves were removed by

ﬁltration, and the aqueous phase was separated and extracted with

dichloromethane (3 × 300 mL). The organic extracts were combined,

washed with brine (300 mL), dried (MgSO₄), and concentrated in

vacuo to yield a colorless oil. Flash column chromatography of the

residue on silica gel (petroleum ether/ethyl acetate, gradient elution

5:1 → 2:1) aﬀorded the epoxy alcohol 20 (30.3 g, 95%) as a colorless

(E)-6-(tert-Butyldimethylsilanyloxy)-2-methylhex-2-enoic

Acid Ethyl Ester (18).^26,27To a stirred solution of oxalyl chloride

(33.0 g, 373 mmol) in anhydrous dichloromethane (640 mL) cooled

at −78 °C was added slowly a solution of anhydrous dimethyl

sulfoxide (DMSO; 40.0 mL, 562 mmol) in anhydrous dichloro-

methane (200 mL), and the resulting solution was stirred for 30 min.

4-(tert-Butyldimethylsilyl)oxy-1-butanol (31.0 g, 152 mmol)⁶²in

anhydrous dichloromethane (460 mL) was then added dropwise.

The resulting solution was stirred at the same temperature for a further

2 h and then quenched with triethylamine (76.8 g, 760 mmol) at −78

°C. The reaction mixture was allowed to warm to room temperature

(rt), stirred for 30 min, and then diluted with dichloromethane (500

mL) and water (300 mL). The aqueous phase was separated and

extracted with dichloromethane (3 × 150 mL). The organic extracts

M

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oil. R_f= 0.40 (petroleum ether/ethyl acetate 1:1); [α]²_D³+14.9 (c 1.00,

CHCl₃) {lit.²⁷[α]_D²¹+10.7 (c 2.21, CHCl₃)}; ν_max(CHCl₃) 3433,

78%). R_f= 0.49 (petroleum ether/ethyl acetate 5:1); ν_max(CHCl₃)

2954, 2929, 2885, 2858, 1674, 1630, 1462, 1454, 1362, 1334, 1290,

1260, 1095, 1006, 965, 876, 839 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

5.95 (1H, br s), 5.73 (1H, br s), 3.61 (2H, t, J = 6.1 Hz), 2.75 (2H, t, J

= 7.3 Hz), 1.85 (3H, br s), 1.86−1.76 (2H, m), 0.86 (9H, s), 0.01 (6H,

s); ¹³C NMR (100 MHz, CDCl₃) δ 201.9, 144.6, 124.4, 62.2, 33.7,

27.5, 26.1, 18.3, 17.7, −5.3; HRMS (ESI) m/z calcd for C₁₃H₂₆O₂SiNa

[M + Na]⁺265.1594, found 265.1593.

(R)-6-tert-Butyldimethylsilyloxy-2-methyl-1-hexen-3-ol

[(+)-14] (Asymmetric Reduction).²⁶To a stirred solution of the

oxazaborolidine complex 16 (0.17 M solution in a 4:1 mixture of THF

and toluene, 19.7 mmol) at −78 °C was added a solution of the enone

(11.9 g, 49.3 mmol) in anhydrous THF (120 mL) over 2 h. The

reaction was stirred for 1 h and then quenched by dropwise addition of

methanol (20 mL) and warmed to rt. The mixture was diluted with

water (400 mL) and diethyl ether (400 mL) and the aqueous phase

was separated and extracted with diethyl ether (2 × 250 mL). The

organic extracts were combined, washed with brine (250 mL), dried

(MgSO₄), and concentrated in vacuo. Flash column chromatography

on silica gel (petroleum ether/diethyl ether, gradient elution 9:1 →

2:1) aﬀorded the alcohol (+)-14 as a colorless oil (10.0 g, 83%). [α]_D²¹

+9.11 (c = 1.25, CHCl₃). The enantiomeric excess was determined by

reverse-phase HPLC analysis (acetonitrile/water 55:45; 0.5 mL·min⁻¹)

of the corresponding benzoyl ester. The enantiomeric benzoates had

retention times of 48.05 min (1.84%) and 50.33 min (98.16%). A

racemic sample of the benzoates had components with retention times

of 48.05 min (49.52%) and 50.33 min (50.48%).

Ethyl (E)-3-[6-(tert-Butyldimethylsilyloxy)-2-methyl-1-

hexen-3-yl]oxypropenoate. To a stirred solution of alcohol

(+)-14 (668 mg, 2.73 mmol) in anhydrous dichloromethane (7 mL)

at rt were added ethyl propiolate (537 mg, 5.47 mmol) and N-

methylmorpholine (553 mg, 5.47 mmol). The resulting brown

solution was stirred for 18 h and then concentrated in vacuo to

yield a dark brown oil. Flash column chromatography on silica gel

(petroleum ether/ethyl acetate 30:1) aﬀorded the title compound as a

colorless oil (881 mg, 94%). The enantiomeric purity of this

compound was determined to be 94% by normal-phase chiral HPLC

analysis [AD-H column; temp 20 °C; 0.2% 2-propanol in hexane; ﬂow

rate 0.5 mL·min⁻¹). R_f= 0.71 (petroleum ether/ethyl acetate 2:1);

[α]²_D³−8.4 (c = 1.00, CHCl₃); ν_max(CHCl₃) 2955, 2929, 2897, 2859,

1713, 1643, 1624, 909, 835, 775 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

7.47 (1H, d, J = 12.4 Hz), 5.25 (1H, d, J = 12.4 Hz), 4.97 (1H, dd, J =

1.4, 1.4 Hz), 4.95 (1H, br s), 4.26 (1H, br t, J = 6.7 Hz), 4.13 (1H, q, J

= 7.1 Hz), 4.12 (1H, q, J = 7.1 Hz), 3.66−3.57 (2H, m), 1.81−1.67

(2H, m), 1.66 (3H, s), 1.61−1.47 (2H, m), 1.25 (3H, t, J = 7.1 Hz),

0.88 (9H, s), 0.04 (6H, s); ¹³C NMR (100 MHz, CDCl₃) δ 168.2,

161.6, 142.9, 114.7, 98.0, 86.6, 62.6, 59.8, 29.6, 28.6, 26.1, 18.4, 17.0,

14.5, −5.2; HRMS (CI, isobutane) m/z calcd for C₁₈H₃₅O₄Si [M +

H]⁺343.2305, found 343.2302; LRMS (CI, isobutane) m/z (%

intensity) 343.5 (7), 227.4 (18), 137.2 (100). Anal. Calcd for

C₁₈H₃₄O₄Si: C, 63.11; H, 10.00. Found: C, 63.14; H, 10.04.

(R)-Ethyl (E)-3-(6-Hydroxy-2-methyl-1-hexen-3-yl)-

oxypropenoate (22). To a stirred solution of the silyl ether (1.0 g,

2.9 mmol) in MeOH (30 mL) at rt was added camphorsulfonic acid

(CSA) (67 mg, 0.29 mmol). The resulting solution was stirred for 30

min at rt, and NaHCO₃was added to neutralize the CSA. The

remaining solid was ﬁltered and the solution was concentrated in

vacuo to yield a yellow oil. The crude product was puriﬁed by ﬂash

column chromatography on silica gel (petroleum ether/ethyl acetate,

gradient elution 5:1 → 2:1) to give the alcohol 22 as a colorless oil

(578 mg, 86%). R_f= 0.19 (petroleum ether/ethyl acetate 2:1); [α]_D²⁴

−8.3 (c 1.01, CHCl₃); ν_max(CHCl₃) 3436, 2979, 2949, 1707, 1640,

1622, 960, 911, 833 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (1H, d,

J = 12.4 Hz), 5.26 (1H, d, J = 12.4 Hz), 4.99 (1H, dd, J = 1.4, 1.4 Hz),

4.97 (1H, br s), 4.27 (1H, dd, J = 7.7, 5.5 Hz), 4.15 (1H, q, J = 7.1

Hz), 4.14 (1H, q, J = 7.1 Hz), 3.70−3.63 (2H, m), 1.87−1.51 (4H, m),

1.67 (3H, s), 1.35 (1H, br s), 1.26 (3H, t, J = 7.1 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 168.2, 161.5, 142.8, 114.9, 98.2, 86.5, 62.5, 59.9, 29.6,

28.7, 17.1, 14.5; HRMS (CI, isobutane) m/z calcd for C₁₂H₂₁O₄[M +

H]⁺229.1440, found 229.1441; LRMS (CI, isobutane) m/z (%

1

2955, 2929, 2886, 2858, 834, 813, 773 cm⁻¹; H NMR (400 MHz,

CDCl₃) δ 3.70−3.55 (4H, m), 3.07 (1H, dd, J = 6.0, 5.9 Hz), 1.74−

1.60 (5H, m), 1.28 (3H, s), 0.89 (9H, s), 0.05 (6H, s); ¹³C NMR (100

MHz, CDCl₃) δ 65.5, 62.7, 61.0, 60.1, 29.8, 26.1, 24.9, 18.4, 14.3,

−5.2; HRMS (CI, isobutane) calcd for C₁₃H₂₉O₃Si [M + H]⁺

261.1887, found 261.1888; LRMS (CI, isobutane) m/z (% intensity)

261.5 (30), 243.5 (42), 203.4 (100), 129.3 (90). Anal. Calcd for

C₁₃H₂₈O₃Si: C, 59.95; H, 10.84. Found: C, 59.98; H, 10.88.

6-tert-Butyldimethylsilyloxy-2-methyl-1-hexen-3-ol [( )-14].

To a stirred slurry of magnesium turnings (2.8 g, 86 mmol) and iodine

(trace) in anhydrous THF (12 mL) was added a solution of (3-

bromopropoxy)(tert-butyl)dimethylsilane (20 g, 78 mmol) in

anhydrous THF (130 mL) dropwise. After complete addition, the

resulting brown solution was stirred for a further 1 h before a solution

of freshly distilled methacrolein (2.7 g, 39 mmol) in anhydrous THF

(8 mL) was added dropwise over 30 min. The resulting mixture was

stirred for a further period of 1 h and then quenched by addition of a

saturated aqueous solution of NH₄Cl (160 mL) and diethyl ether (120

mL). The aqueous phase was separated and extracted with diethyl

ether (3 × 80 mL). The organic extracts were combined, washed with

brine (160 mL), dried (MgSO₄), and concentrated in vacuo to yield a

colorless oil. Flash column chromatography on silica gel (petroleum

ether/ethyl acetate 5:1) aﬀorded the alcohol ( )-14 as a colorless oil

(8.8 g, 93%).

(R)-6-tert-Butyldimethylsilyloxy-2-methyl-1-hexen-3-ol

[(+)-14] (Epoxide Opening).²⁶To a stirred solution of epoxy

alcohol 20 (30.3 g, 117 mmol) and triethylamine (17.7 g, 175 mmol)

in anhydrous dichloromethane (580 mL) at −10 °C was slowly added

methanesulfonyl chloride (16.0 g, 140 mmol). The solution was stirred

for 10 min, then quenched by addition of water (100 mL) and diluted

with dichloromethane (250 mL). The organic phase was washed with

brine (100 mL), dried (MgSO₄), ﬁltered, and concentrated in vacuo to

yield a colorless oil. The crude epoxy mesylate 21 was carried on to the

next step without further puriﬁcation.

To a stirred solution of the crude mesylate 21 in butan-2-one (580

mL) was added sodium iodide (87.4 g, 583 mmol), and the reaction

mixture was heated at reﬂux for 1 h, giving a brown slurry. Zinc

powder (11.4 g, 175 mmol) was then added and the reaction was

stirred at reﬂux for a further 1 h, giving a gray solution. The reaction

mixture was then allowed to cool to rt and diluted with ethyl acetate

(500 mL) and a saturated aqueous solution of NH₄Cl (300 mL). The

aqueous phase was separated and extracted with ethyl acetate (3 × 300

mL). The organic extracts were combined, washed with brine (300

mL), dried (MgSO₄), and concentrated in vacuo to yield a brown oil.

Flash column chromatography on silica gel (petroleum ether/diethyl

ether, gradient elution 30:1 → 20:1 → 15:1) aﬀorded the alcohol

(+)-14 as a colorless oil (27.6 g, 97% over two steps). R_f= 0.42

(petroleum ether/ethyl acetate 5:1); ν_max(CHCl₃) 3378, 2954, 2929,

2885, 2857, 898, 835, 774 cm⁻¹; [α]_D²³+8.7 (c 1.01, CHCl₃); ¹H NMR

(400 MHz, CDCl₃) δ 4.96 (1H, br s), 4.83 (1H, br s), 4.08−4.04 (1H,

m), 3.66 (2H, t, J = 5.7 Hz), 2.53 (1H, d, J = 3.8 Hz), 1.72 (3H, s),

1.71−1.56 (4H, m), 0.90 (9H, s), 0.06 (6H, s); ¹³C NMR (100 MHz,

CDCl₃) δ 147.7, 110.9, 75.6, 63.5, 32.5, 29.0, 26.1, 18.5, 18.0, −5.2;

HRMS (CI, isobutane) m/z calcd for C₁₃H₂₉O₂Si [M + H]⁺245.1937,

found 245.1932; LRMS (CI, isobutane) m/z (% intensity) 245.5 (80),

227.4 (100), 137.3 (60), 113.3 (80). Anal. Calcd for C₁₃H₂₈O₂Si: C,

63.88; H, 11.55. Found: C, 63.73; H, 11.65.

6-(tert-Butyldimethylsilanyloxy)-2-methylhex-1-en-3-one.

To a stirred solution of alcohol ( )-14 (9.7 g, 40 mmol) in anhydrous

dichloromethane (200 mL) at rt was added manganese dioxide (87 g,

1.0 mol) in ﬁve portions. The resulting solution was stirred for 1 h;

then additional manganese dioxide (17 g, 20 mmol) was added in one

portion and the reaction mixture was stirred for a further 1 h. The

mixture was ﬁltered through Celite, washed with dichloromethane

(400 mL) and boiling ethyl acetate (150 mL), and then concentrated

to give yield a yellow oil. Puriﬁcation of the residue by ﬂash column

chromatography on silica gel (petroleum ether/diethyl ether, gradient

elution 1:0 → 25:1) aﬀorded the enone as a colorless oil (7.54 g,

N

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The Journal of Organic Chemistry

Article

intensity) 229.4 (100), 221.4 (10), 183.3 (8), 137.3 (10), 117.2 (80);

113.2 (50). Anal. Calcd for C₁₂H₂₀O₄: C, 63.14; H, 8.83. Found: C,

62.86; H, 8.91.

(petroleum ether/ethyl acetate 2:1); [α]²_D⁴+59.0 (c 1.03, CHCl₃); ν_max

1

(CHCl₃) 2951, 2930, 2858, 1740, 898, 858, 835, 774 cm⁻¹; H NMR

(400 MHz, CDCl₃) δ 4.91 (1H, s), 4.78 (1H, s), 4.14 (2H, q, J = 7.1

Hz), 3.69 (1H, br d, J = 9.9 Hz), 3.65 (1H, ddd, J = 9.2, 9.1, 3.3 Hz),

3.40−3.32 (1H, m), 2.80 (1H, dd, J = 14.8, 3.3 Hz), 2.37 (1H, dd, J =

14.8, 9.2 Hz), 2.07−2.00 (1H, m), 1.84−1.77 (1H, m), 1.70 (3H, s),

1.56−1.48 (2H, m), 1.25 (3H, t, J = 7.1 Hz), 0.87 (9H, s), 0.06 (3H,

s), 0.05 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 172.0, 145.3, 110.3,

80.0, 79.6, 70.9, 60.4, 38.4, 33.5, 29.7, 25.9, 19.4, 18.1, 14.4, −3.9,

−4.6; HRMS (CI, isobutane) m/z calcd for C₁₈H₃₅O₄Si [M + H]⁺

343.2304, found 343.2307; LRMS (CI, isobutane) m/z (% intensity)

343.5 (100), 329.5 (11), 285.4 (15), 113 (44). Anal. Calcd for

C₁₈H₃₄O₄Si: C, 63.11; H, 10.00. Found: C, 62.95; H, 10.07.

(R)-Ethyl (E)-3-(5-Methyl-5-hexenal-4-yl)oxypropenoate

(23). To a stirred solution of oxalyl chloride (12.7 g, 158 mmol) in

dry dichloromethane (370 mL) at −78 °C was added anhydrous

DMSO (25.3 g, 324 mmol) in anhydrous dichloromethane (115 mL)

dropwise by cannula. The resulting solution was stirred for 30 min at

−78 °C, and then the alcohol 22 (20.0 g, 87.6 mmol) in anhydrous

dichloromethane (260 mL) was added dropwise by cannula. The

resulting solution was stirred for a further 3 h at −78 °C and then

quenched with Et₃N (44.3 g, 438 mmol). The reaction mixture was

allowed to warm to rt, stirred for 30 min, and then diluted with

dichloromethane (200 mL) and water (100 mL). The aqueous phase

was separated and extracted with dichloromethane (3 × 200 mL). The

organic extracts were combined, washed with brine (100 mL), dried

(MgSO₄), and concentrated in vacuo. Flash column chromatography

on silica gel (petroleum ether/ethyl acetate 5:1) aﬀorded the aldehyde

23 as a colorless oil (19.3 g, 97%). R_f= 0.41 (petroleum ether/ethyl

acetate 2:1); [α]_D²³−1.9 (c 1.00, CHCl₃); ν_max(CHCl₃) 2980, 2940,

1706, 1641, 1623, 957, 912, 834 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

9.78 (1H, s), 7.44 (1H, d, J = 12.4 Hz), 5.25 (1H, d, J = 12.4 Hz), 5.01

(1H, br s), 4.98 (1H, s), 4.29 (1H, dd, J = 7.9, 5.4 Hz), 4.15 (1H, q, J =

7.1 Hz), 4.14 (1H, q, J = 7.1 Hz), 2.56−2.52 (2H, m), 2.10−1.92 (2H,

m), 1.68 (3H, s), 1.26 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 201.2, 168.0, 161.0, 142.2, 115.2, 98.6, 85.1, 59.9, 39.8, 25.7,

17.2, 14.5; HRMS (CI, isobutane) m/z calcd for C₁₂H₁₉O₄[M + H]⁺

227.1283, found 227.1279; LRMS (CI, isobutane) m/z (% intensity)

227.4 (100), 209.4 (5), 111.2 (59). Anal. Calcd for C₁₂H₁₈O₄: C,

63.70; H, 8.02. Found: C, 63.27; H, 8.04.

(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-isopropenyltetra-

hydropyran-2-ylacetic Acid (25). To a stirred solution of ester 24

(10.2 g, 29.7 mmol) in ethanol (150 mL) and water (50 mL) was

added lithium hydroxide (3.74 g, 89.2 mmol) portionwise over 5 min.

The resulting solution was stirred at rt overnight and then acidiﬁed to

pH 2−3 with 1 M HCl. The reaction mixture was diluted with ethyl

acetate (300 mL) and water (200 mL), and the aqueous phase was

then separated and extracted with ethyl acetate (3 × 150 mL). The

organic extracts were combined, washed with brine (100 mL), dried

(MgSO₄), and concentrated in vacuo. Flash column chromatography

on silica gel (petroleum ether/ethyl acetate, gradient elution 20:1 →

4:1) aﬀorded the carboxylic acid 25 as a colorless gum (8.28 g, 89%).

R_f= 0.57 (petroleum ether/ethyl acetate 3:1); [α]²_D⁵+67.5 (c 1.00,

CHCl₃); ν_max(CHCl₃) 2951, 2930, 2887, 2859, 1715, 899, 837, 775

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 10.88 (1H, br s), 4.94 (1H, s),

4.82 (1H, s), 3.80 (1H, br d, J = 9.6 Hz), 3.62 (1H, ddd, J = 8.9, 8.9,

3.2 Hz), 3.40−3.32 (1H, m), 2.86 (1H, dd, J = 15.6, 3.2 Hz), 2.46 (1H,

dd, J = 15.6, 8.9 Hz), 2.08−2.02 (1H, m), 1.85−1.79 (1H, m), 1.72

(3H, s), 1.59−1.50 (2H, m), 0.87 (9H, s), 0.07 (6H, s); ¹³C NMR

(100 MHz, CDCl₃) δ 175.5, 144.7, 111.1, 80.6, 79.1, 70.8, 37.9, 33.4,

29.7, 25.9, 19.2, 18.0, −3.9, −4.6; HRMS (CI, isobutane) m/z calcd for

C₁₆H₃₁O₄Si [M + H]⁺315.1992, found 315.1995; LRMS (CI,

isobutane) m/z (% intensity) 315.4 (100), 297.4 (12), 257.4 (20),

183.8 (55).

Ethyl [(2R,3S,6R)-3-Hydroxy-6-isopropenyltetrahydropyran-

2-yl]acetate. To a stirred solution of the aldehyde 23 (244 mg, 1.08

mmol) and anhydrous MeOH (138 mg, 4.31 mmol) in anhydrous

THF (11 mL) at rt was added a freshly prepared solution of samarium

diiodide (0.1 M in THF) until the solution remained deep blue in

color (approximately 4 equiv added). The resulting solution was

stirred for 30 min and then quenched with ethyl acetate (5 mL) and a

saturated aqueous solution of sodium thiosulfate (12 mL). The

aqueous phase was separated and extracted with ethyl acetate (3 × 10

mL). The organic extracts were combined, washed with brine (15

mL), dried (MgSO₄), and concentrated in vacuo to yield a yellow oil.

Flash column chromatography on silica gel (petroleum ether/ethyl

acetate, gradient elution 4:1 → 1:1) aﬀorded the title tetrahydropyr-

anol (212 mg, 86%) as a yellow oil. R_f= 0.22 (petroleum ether/ethyl

acetate 2:1); [α]_D²⁵+42.6 (c 1.02, CHCl₃); ν_max(CHCl₃) 3456, 2979,

1-Diazo-3-[(2R,3S,6R)-3-(tert-butyldimethylsilyloxy)-6-iso-

propenyltetrahydropyran-2-yl]-propan-2-one (26). To a stirred

solution of carboxylic acid 25 (3.00 g, 9.55 mmol) and triethylamine

(1.32 g, 13.0 mmol) in anhydrous diethyl ether (120 mL) was added

isobutyl chloroformate (1.64 g, 12.0 mmol) dropwise, and the

resulting solution was stirred for 2.5 h (a white precipitate formed).

The solution of the anhydride was ﬁltered under suction; the residue

was washed with diethyl ether and then immediately added to a freshly

prepared ethereal solution of diazomethane (∼100 mmol) dropwise.

The solution was stirred for 2 days and quenched by addition of glacial

acetic acid (5 mL), then poured into a saturated aqueous solution of

NaHCO₃(200 mL) and stirred vigorously for 15 min. The aqueous

phase was separated and extracted with ethyl acetate (3 × 75 mL). The

combined organic extracts were washed with brine (75 mL), dried

(MgSO₄), and concentrated in vacuo to give a yellow oil. Flash column

chromatography on silica gel (petroleum ether/ethyl acetate 10:1)

aﬀorded diazo ketone 26 as a yellow oil (2.83 g, 88%). R_f= 0.51

(petroleum ether/ethyl acetate 2:1); [α]²_D³+95.7 (c 1.01, CHCl₃); ν_max

(CHCl₃) 2949, 2929, 2883, 2857, 2099, 1640, 897, 835, 774 cm⁻¹; ¹H

NMR (400 MHz, CDCl₃) δ 5.39 (1H, br s), 4.92 (1H, s), 4.80 (1H,

s), 3.72 (1H, d, J = 10.1 Hz), 3.58 (1H, ddd, J = 9.1, 9.1, 2.4 Hz),

3.37−3.29 (1H, m), 2.77 (1H, dd, J = 14.3, 2.4 Hz), 2.45−2.30 (1H,

m), 2.07−2.01 (1H, m), 1.83−1.77 (1H, m), 1.71 (3H, s), 1.60−1.43

(2H, m), 0.87 (9H, s), 0.06 (6H, s); ¹³C NMR (125 MHz, CDCl₃) δ

193.8, 145.3, 110.5, 80.2, 79.9, 70.8, 55.3, 44.3, 33.6, 29.8, 25.9, 19.4,

18.1, −3.9, −4.6; HRMS (FAB) m/z calcd for C₁₇H₃₁O₃N₂Si [M +

H]⁺339.2104, found 339.2105; LRMS (FAB) m/z (% intensity) 339.1

(100), 297.2 (18), 281.1 (99), 255.2 (25), 207.0 (37), 171.0 (62).

(1R,2S,5Z,8R)-2-(tert-Butyldimethylsilyloxy)-6-methyl-11-

oxabicyclo[6.2.1]-5-undecen-9-one (Z-30) and (1R,2S,5E,8R)-2-

(tert-Butyldimethylsilyloxy)-6-methyl-11-oxabicyclo[6.2.1]-5-

undecen-9-one (E-30). To a stirred solution of Rh₂(pfm)₂(360 mg,

0.34 mmol) in anhydrous dichloromethane (175 mL) at reﬂux was

1

2942, 2861, 1738, 1721, 901 cm⁻¹; H NMR (400 MHz, CDCl₃) δ

4.93 (1H, s), 4.81 (1H, s), 4.15 (2H, q, J = 7.1 Hz), 3.74 (1H, br d, J =

9.7 Hz), 3.60 (1H, ddd, J = 9.2, 7.0, 5.0 Hz), 3.44−3.34 (1H, m), 2.81

(1H, dd, J = 15.1, 5.0 Hz), 2.57 (1H, dd, J = 15.1, 7.0 Hz), 2.19−2.12

(1H, m), 2.02−1.96 (1H, m), 1.88−1.81 (1H, m), 1.72 (3H, s), 1.56−

1.48 (2H, m), 1.25 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ 172.4, 145.1, 110.7, 80.3, 79.0, 70.7, 60.8, 38.9, 33.2, 29.7, 19.3, 14.4;

HRMS (CI, isobutane) m/z calcd for C₁₂H₂₁O₄[M + H]⁺229.1439,

found 229.1438; LRMS (CI, isobutane) m/z (% intensity) 229.4

(100), 211.4 (5), 183.3 (10). Anal. Calcd for C₁₂H₂₀O₄: C, 63.14; H,

8.83. Found: C, 62.73; H, 8.95.

Ethyl [(2R,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-isoprope-

nyltetrahydropyran-2-yl]acetate (24). To a stirred solution of

tetrahydropyranol (7.44 g, 32.6 mmol) and imidazole (4.43 g, 65.2

mmol) in anhydrous N,N-dimethylformamide (DMF) (75 mL) was

added t-butyldimethylsilyl chloride (8.84 g, 58.7 mmol) portionwise

over 5 min. The resulting solution was stirred overnight at rt and then

quenched by addition of diethyl ether (300 mL) and water (600 mL).

The aqueous phase was separated and the organic phase was washed

with water (5 × 300 mL). The aqueous extracts were combined and

extracted with diethyl ether (300 mL). The organic extracts were

combined, washed with brine (200 mL), dried (MgSO₄), and

concentrated in vacuo to give a yellow oil. Flash column

chromatography on silica gel (petroleum ether/ethyl acetate 20:1)

aﬀorded the silyl ether 24 (10.7 g, 96%) as a colorless oil. R_f= 0.73

O

dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

added diazo ketone 26 (5.95 g, 17.5 mmol) in anhydrous

dichloromethane (880 mL) over 45 min, while vigorous reﬂux was

maintained. The resulting solution was stirred for a further 15 min,

allowed to cool, and concentrated in vacuo to give a brown solid.

Rapid column chromatography on deactivated alumina (petroleum

ether/ethyl acetate 15:1) allowed the removal of the catalyst. Flash

column chromatography on silver(II) nitrate (10%) impregnated silica

gel (petroleum ether/ethyl acetate, gradient elution 30:1 → 1:1)

aﬀorded ketone Z-30 (1.20 g, 22%) as a colorless crystalline solid and

ketone E-30 (2.26 g 41%) as a colorless crystalline solid.

Z-30: R_f= 0.56 (petroleum ether/diethyl ether 5:1); mp 88−90 °C;

[α]²_D⁸+31.8 (c 1.03, CHCl₃); ν_max(CHCl₃) 2954, 2927, 2856, 1754,

835, 775 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.41 (1H, dd, J = 11.6,

5.8 Hz), 4.23 (1H, t, J = 4.4 Hz), 4.17 (1H, t, J = 8.7 Hz), 3.42 (1H,

ddd, J = 10.8, 8.7, 2.7 Hz), 2.81−2.68 (3H, m), 2.29 (1H, d, J = 17.7

Hz), 2.21 (1H, dd, J = 14.6, 4.4 Hz), 2.02−1.93 (1H, m), 1.86 (1H,

dddd, J = 13.6, 10.8, 6.1, 2.7 Hz), 1.75 (3H, s), 1.69−1.58 (1H, m),

0.86 (9H, s), 0.05 (3H, s), 0.01 (3H, s); ¹³C NMR (100 MHz, CDCl₃)

δ 216.0, 132.5, 127.7, 80.4, 78.9, 75.5, 42.4, 33.5, 33.2, 26.9, 25.9, 18.0,

−3.7, −4.4; HRMS (CI, isobutane) m/z calcd for C₁₇H₃₁O₃Si [M +

H]⁺311.2042, found 311.2039; LRMS (CI, isobutane) m/z (%

intensity) 311.6 (100), 253.4 (18), 179.4 (18). Anal. Calcd for

C₁₇H₃₀O₃Si: C, 65.76; H, 9.74. Found: C, 65.78 H, 9.83.

E-30: R_f= 0.56 (petroleum ether/diethyl ether 5:1); mp 55−57 °C;

[α]²_D⁸−38.7 (c 0.99, CHCl₃); ν_max(CHCl₃) 2950, 2931, 2860, 1755,

837, 774 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.35 (1H, dd, J = 11.9,

4.3 Hz), 4.17−4.12 (2H, m), 3.02 (1H, dd, J = 8.9, 7.8 Hz), 2.78 (1H,

ddd, J = 18.0, 9.1, 1.4 Hz), 2.55−2.50 (2H, m), 2.28 (1H, br d, J = 18.0

Hz), 2.28−2.11 (2H, m), 1.96 (1H, dddd, J = 14.1, 11.8, 7.8, 3.9 Hz),

1.71 (1H, ddd, J = 14.1, 3.6, 3.6 Hz), 1.55 (3H, s), 0.86 (9H, s), 0.08

(3H, s), 0.03 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 217.4, 133.4,

124.8, 80.9, 78.5, 76.6, 42.1, 40.4, 35.9, 27.0, 25.9, 18.9, 18.0, −3.7,

−4.6; HRMS (CI, isobutane) m/z calcd for C₁₇H₃₁O₃Si [M + H]⁺

311.2042, found 311.2038; LRMS (CI, isobutane) m/z (% intensity)

311.6 (100), 253.4 (18), 179.4 (10). Anal. Calcd for C₁₇H₃₀O₃Si: C,

65.76; H, 9.74. Found: C, 65.78; H, 9.81.

1-{(1R,2R,3S,8R,10Z,14S)-14-(tert-Butyldimethylsilyloxy)-6-

ethoxy-10-methyl-15-oxatricyclo-[6.6.1.0^2,7]pentadeca-6,10-

dien-3-yl}ethan-1-one (Z-33). To a solution of bicyclic ketone Z-30

(1.06 g, 3.31 mmol) and PhN(Tf)₂(2.44 g, 6.82 mmol) in anhydrous

THF (70 mL) at −78 °C was added sodium bis(trimethylsilyl)amide

(NaHMDS; 8.53 mL of a 1.0 M solution in THF, 8.53 mmol)

dropwise over 10 min. The resulting solution was stirred at −78 °C for

2 h, then quenched with water (20 mL) at −78 °C and allowed to

warm to rt. The aqueous phase was separated and extracted with

diethyl ether (3 × 80 mL). The organic extracts were combined,

washed with brine (40 mL), dried (MgSO₄), and concentrated in

vacuo to give the crude enol triﬂate Z-31 as a yellow oil, which was

used in the subsequent Stille reaction without further puriﬁcation.

To a solution of the above crude enol triﬂate Z-31 and

CH₂C(OEt)SnBu₃(3.69 g, 10.2 mmol) in anhydrous THF (70 mL)

were added lithium chloride (434 mg, 10.2 mmol) and Pd(PPh₃)₄

(591 mg, 510 μmol), the solution was heated at reﬂux overnight. The

reaction mixture was cooled and diluted with ethyl acetate (30 mL).

The organic phase was washed with brine (20 mL), 5% aqueous

solution of NH₄OH (20 mL), and brine (20 mL). The organic extracts

were dried (Na₂SO₄) and concentrated in vacuo to give a yellow oil.

Rapid ﬂash column chromatography on silica gel (petroleum ether/

ethyl acetate 15:1 with 1% Et₃N) aﬀorded the highly unstable diene Z-

32 as a colorless oil, which was used immediately in the subsequent

Diels−Alder cycloaddition reaction.

(389 mg, 2.80 mmol), and the solution was stirred at rt overnight. The

reaction mixture was diluted with a saturated aqueous solution of

NH₄Cl (25 mL) and ethyl acetate (40 mL). The aqueous phase was

separated and extracted with ethyl acetate (2 × 40 mL). The organic

extracts were combined, washed with brine (20 mL), dried (MgSO₄),

and concentrated in vacuo to give a yellow oil. Flash column

chromatography on silica gel (petroleum ether/ethyl acetate 20:1 with

1% Et₃N) aﬀorded the ketone Z-33 as a colorless oil (929 mg, 91%).

R_f= 0.40 (petroleum ether/ethyl acetate 4:1); [α]²_D⁴+143 (c 0.99,

CHCl₃); ν_max(CHCl₃) 2951, 2928, 2855, 1714, 870, 833, 808, 772

cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.36 (1H, dd, J = 11.5, 5.6 Hz),

4.87−4.85 (1H, m), 3.78 (2H, q, J = 7.0 Hz), 3.70 (1H, dd, J = 9.3, 2.6

Hz), 3.59−3.57 (1H, m), 3.15−3.05 (1H, m), 2.96−2.87 (1H, m),

2.82 (1H, d, J = 14.0 Hz), 2.35−2.16 (3H, m), 2.15 (3H, s), 2.06−1.98

(1H, m), 1.92 (1H, dd, J = 14.0, 4.0 Hz), 1.88−1.72 (3H, m), 1.66

(3H, s), 1.65−1.54 (1H, m), 1.26 (3H, t, J = 7.0 Hz), 0.88 (9H, s),

0.04 (3H, s), 0.03 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 211.3,

143.8, 130.5, 130.2, 119.2, 88.2, 75.2, 72.0, 63.2, 52.3, 43.5, 37.5, 32.9,

29.8, 28.4, 27.2, 26.3, 24.6, 22.1, 18.7, 15.8, −4.3, −4.4; HRMS (CI,

isobutane) m/z calcd for C₂₅H₄₃O₄Si [M + H]⁺435.2933, found

435.2935; LRMS (CI, isobutane) m/z (% intensity); 435.5 (100),

377.4 (7).

(1R,2S,6S,7R,8R,9S,12Z)-6-(Propen-2-yl)-13-methyl-15-

oxatricyclo[6.6.1.0^2,7]-12-pentadecen-3-one-9-ol (Z-35). To a

stirred suspension of potassium t-butoxide (123 mg, 1.10 mmol) in

anhydrous THF (5 mL) was added methyltriphenylphosphonium

bromide (493 mg, 1.38 mmol) in one portion, and the solution was

stirred for 30 min. A solution of the ketone Z-33 (120 mg, 0.656

mmol) in anhydrous THF (2.5 mL) was then added dropwise to the

solution of phosphonium ylide. The ﬂask containing the ketone Z-33

was rinsed with further anhydrous THF (2 mL), and this was added

dropwise to the reaction mixture. The solution was heated to 50 °C

and stirred for 2 h, then allowed to cool and quenched with aqueous 2

M HCl solution (12 mL), and the mixture was stirred for a further 3 h.

The reaction mixture was diluted with ethyl acetate (20 mL). The

aqueous phase was separated and extracted with ethyl acetate (2 × 20

mL). The organic extracts were combined, washed with brine (25

mL), dried, and concentrated in vacuo to yield a white solid. Flash

column chromatography on silica gel (petroleum ether/ethyl acetate

4:1) aﬀorded the diene Z-35 (153 mg, 78%) as a colorless solid. R_f=

0.45 (hexane/ethyl acetate 2:1); mp 171−173 °C; [α]²_D⁵+2.0 (c 0.50,

CHCl₃); ν_max(CHCl₃) 3621, 2926, 1704, 1644, 1602, 1455, 1380,

1

1324, 1266, 1087, 1053, 1004, 948, 987 cm⁻¹; H NMR (500 MHz,

CDCl₃) δ 5.50 (1H, dd, J = 11.8, 5.7 Hz), 4.91 (1H, br s), 4.89 (1H,

dq, J = 1.5, 1.5 Hz), 4.35 (1H, ddd, J = 9.8, 3.3, 3.1 Hz), 3.66 (1H, d, J

= 9.3 Hz), 3.33−3.24 (1H, m), 2.84 (1H, br d, J = 14.9 Hz), 2.81−2.73

(2H, m), 2.57−2.49 (2H, m), 2.45 (1H, dddd, J = 16.0, 4.2, 2.6, 1.5

Hz), 2.36 (1H, ddd, J = 12.2, 12.2, 3.0 Hz), 2.02−1.93 (2H, m), 1.91

(3H, br t, J = 1.3 Hz), 1.84 (1H, dd, J = 14.9, 3.3 Hz), 1.81−1.70 (3H,

m), 1.72 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 210.3, 146.3, 132.8,

127.5, 113.3, 87.4, 80.8, 71.5, 52.1, 49.8, 44.6, 38.7, 35.0, 34.3, 30.5,

28.2, 26.1, 18.9; HRMS [positive electrospray ionization time-of-ﬂight

(+ESI-TOF)] m/z calcd for C₁₈H₂₆O₃Na [M + Na]⁺313.1774, found

313.1765.

(1R,2S,6R,7R,8R,9S,12Z)-6-Isopropyl-13-methyl-15-

oxatricyclo[6.6.1.0^2,7]-12-pentadecen-3-one-9-ol (Z-36). To a

stirred solution of the diene 35 (123 mg, 0.42 mmol) in ethyl acetate

(12 mL) was added platinum(IV) oxide (9.6 mg, 42 μmol). The

solution was placed under an atmosphere of hydrogen for 110 min,

and the reaction was monitored by ¹H NMR to ensure that

overreduction was avoided. The suspension was ﬁltered, washed

with ethyl acetate, and concentrated in vacuo to aﬀord the desired

product Z-36 (120 mg, 97%) as a colorless solid. R_f= 0.45 (hexane/

ethyl acetate 2:1); mp 162−165 °C; [α]²_D⁵+26.0 (c 0.50, CHCl₃); ν_max

(CHCl₃) 3623, 2927, 2874, 1704, 1455, 1380, 1370, 1349, 1323, 1263,

The above diene Z-32 and freshly distilled methyl vinyl ketone

(2.39 g, 34.1 mmol) were dissolved in anhydrous toluene (140 mL),

and the mixture was heated at reﬂux in a sealed tube overnight. The

volatiles were removed in vacuo to give a yellow oil. Flash column

chromatography on silica gel (petroleum ether/ethyl acetate 15:1 with

1% Et₃N) delivered a mixture (2:1) of the Diels−Alder cycloadducts

Z-33 and Z-34 (1.02 g, 69% over three steps) as a colorless oil.

To a solution of the mixture of cycloadducts Z-33 and Z-34 (1.02 g,

2.35 mmol) in methanol (25 mL) was added potassium carbonate

1

1172, 1084, 1046, 1022, 1007, 986, 970, 946, 909, 866, 841 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 5.49 (1H, dd, J = 11.7, 5.6 Hz), 4.32 (1H,

ddd, J = 9.8, 3.2, 3.0 Hz), 3.81 (1H, d, J = 9.2 Hz), 3.30 (1H, ddd, J =

9.2, 9.1, 5.6 Hz), 2.85−2.71 (3H, m), 2.50−2.34 (3H, m), 2.05−1.92

(3H, m), 1.90 (3H, s), 1.82 (1H, dd, J = 14.9, 3.2 Hz), 1.79−1.71 (2H,

P

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m), 1.57 (1H, ddd, J = 12.1, 11.9, 2.6 Hz), 1.47−1.37 (1H, m), 1.02

(3H, d, J = 6.9 Hz), 0.81 (3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz,

CDCl₃) δ 211.1, 132.9, 127.4, 87.2, 80.8, 71.8, 52.4, 50.8, 40.5, 38.6,

35.0, 34.4, 28.2, 28.1, 26.1, 24.1, 21.9, 15.4; HRMS (+ESI-TOF) m/z

calcd for C₁₈H₂₈O₃Na [M + Na]⁺315.1931, found 315.1930.

(1H, qd, J = 13.1, 3.2 Hz), 0.98 (3H, s), 0.97 (3H, d, J = 7.0 Hz), 0.78

(3H, d, J = 7.0 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 146.9, 136.6,

128.8, 110.7, 91.5, 80.4, 75.5, 48.2, 47.1, 42.5, 38.9, 34.5, 31.7, 29.2,

28.8, 28.6, 27.8, 25.4, 22.1, 15.4; HRMS (+ESI-TOF) m/z calcd for

C₂₀H₃₃O₂[M + H]⁺305.2475, found 305.2477.

(1R,2R,6R,7R,8R,9S,12Z)-6-Isopropyl-13-methyl-3-methyli-

dene-15-oxatricyclo[6.6.1.0^2,7]-12-pentadecene-9-ol (Z-37). To

a suspension of potassium t-butoxide (69 mg, 0.62 mmol) in

anhydrous benzene (1 mL) was added methyltriphenylphosphonium

bromide (221 mg, 0.619 mmol), and the yellow mixture was heated at

reﬂux for 1 h. To the reaction mixture was added a solution of ketone

36 (20 mg, 68 μmol) in anhydrous toluene (3 mL) dropwise, and the

resulting mixture was heated at reﬂux for 1 h. The reaction was then

quenched with water (10 mL) and diluted with ethyl acetate (10 mL).

The aqueous phase was separated and extracted with ethyl acetate (2

× 10 mL). The organic extracts were combined, dried (MgSO₄), and

concentrated in vacuo to yield a colorless solid. Flash column

chromatography on silica gel (hexane/ethyl acetate 5:1) aﬀorded diene

Z-37 (18 mg, 93%) as a colorless solid. R_f= 0.61 (hexane/ethyl acetate

2:1); mp 136−138 °C; [α]_D²²+47.4 (c 1.00, CHCl₃); ν_max(attenuated

total reﬂectance, ATR) 3432, 3074, 2956, 2939, 2915, 2871, 2852,

1648, 1466, 1439, 1427, 1367, 1343, 1315, 1261, 1182, 1110, 1082,

1045, 1026. 1014, 983, 945, 889, 861, 835, 791, 770, 741, 717, 661,

561 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.51 (1H, dd, J = 11.7, 5.9

Hz), 4.80 (1H, t, J = 1.9 Hz), 4.77 (1H, t, J = 1.7 Hz), 4.14 (1H, ddd, J

= 9.5, 3.1, 3.1 Hz), 3.66 (1H, d, J = 9.3 Hz), 3.44−3.36 (1H, m), 2.91−

2.81 (1H, m), 2.77 (1H, br d, J = 14.9 Hz), 2.72 (1H. dd, J = 9.5, 6.5

Hz), 2.28 (1H, ddd, J = 13.6, 3.2, 3.1 Hz,), 2.17−2.08 (1H, m), 2.00

(1H, dd, J = 11.8, 6.5 Hz), 2.03−1.83 (3H, m), 1.86 (3H, s), 1.81−

1.71 (3H, m), 1.39−1.30 (1H, m), 1.21 (1H, br s), 1.02 (1H, qd, J =

13.0, 3.2 Hz), 0.96 (3H, d, J = 7.0 Hz), 0.76 (3H, d, J = 6.9 Hz); ¹³C

NMR (125 MHz, CDCl₃) δ 147.0, 132.8, 127.6, 110.7, 87.5, 81.0, 71.6,

49.1, 46.5, 41.3, 34.6, 34.4, 31.6, 28.9, 28.5, 26.4, 25.5, 21.9, 15.6;

HRMS (+ESI-TOF) m/z calcd for C₁₉H₃₁O₂[M + H]⁺291.2319,

found 291.2312.

(+)-Vigulariol (2).^16,33To a stirred solution of the alcohol Z-1 (10

mg, 34 μmol) in anhydrous dichloromethane (1.5 mL) at 0 °C was

added a solution of m-chloroperoxybenzoic acid (m-CPBA; 0.05 M in

dichloromethane, 670 μL) dropwise. The mixture was stirred for 30

min at 0 °C and then quenched by addition of a saturated aqueous

solution of sodium thiosulfate (2 mL) and dichloromethane (3 mL).

The aqueous phase was separated and extracted with dichloromethane

(3 × 5 mL). The organic extracts were combined, washed with a

saturated aqueous solution of sodium hydrogen carbonate (3 mL) and

water (3 mL), dried (MgSO₄), and concentrated in vacuo to give a

yellow oil. Flash column chromatography on silica gel (hexane/diethyl

ether, gradient elution 5:1 → 2:1) aﬀorded (+)-vigulariol (2) (9.8 mg,

91%) as a colorless oil: R_f= 0.35; (petroleum ether/ethyl acetate 1:1);

ν_max(CHCl₃) 3601, 2961, 1715, 1601, 1458, 1376, 1064, 896 cm⁻¹; ¹H

NMR (500 MHz, CDCl₃) δ 4.72 (1H, dd, J = 2.1, 2.0 Hz), 4.71 (1H,

dd, J = 2.0, 1.7 Hz), 4.11−4.04 (2H, m), 3.69 (1H, t, J = 8.1 Hz), 3.65

(1H, s), 2.43 (1H, dddd, J = 11.8, 9.6, 9.3, 6.9 Hz), 2.28 (1H, dd, J =

15.1, 4.4 Hz), 2.26−2.22 (1H, m), 2.21−2.14 (2H, m), 2.10−1.96

(2H, m), 1.86 (1H, dd, J = 15.1, 2.9 Hz), 1.78 (1H, ddd, J = 12.5, 9.8,

9.6 Hz), 1.74−1.67 (2H, m), 1.53 (3H, s), 1.31−1.22 (1H, m), 1.18

(3H, s), 1.01 (1H, qd, J = 13.0, 2.9 Hz), 0.96 (3H, d, J = 6.9 Hz), 0.76

(3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 148.0, 110.0,

90.1, 87.2, 85.9, 80.7, 74.6, 47.6, 45.9, 43.1, 42.3, 38.5, 31.9, 31.4, 29.1,

28.0, 25.0, 24.0, 22.0, 15.5; HRMS (+ESI-TOF) m/z calcd for

C₂₀H₃₃O₃[M + H]⁺321.2424, found 321.2415.

1-{(1R,2R,8R,10E,14S)-14-(tert-Butyldimethylsilyloxy)-6-

ethoxy-10-methyl-15-oxatricyclo[6.6.1.0^2,7]pentadeca-6,10-

dien-3-yl}ethanone (E-33). To a solution of ketone E-30 (1.53 g,

4.93 mmol) and PhN(Tf)₂(3.52 g, 9.87 mmol) in anhydrous THF

(100 mL) at −78 °C was added NaHMDS (12.4 mL of a 1.0 M

solution in THF, 12.4 mmol) dropwise over 10 min. The resulting

solution was stirred at −78 °C for 2 h; the reaction was then quenched

with water (30 mL) at −78 °C and allowed to warm to rt. The

aqueous phase was separated and extracted with diethyl ether (3 × 80

mL). The organic extracts were combined and washed with brine (60

mL), then dried (MgSO₄) and concentrated in vacuo to give the crude

enol triﬂate E-31 as a yellow oil.

To a solution of enol triﬂate E-31 and CH₂C(OEt)SnBu₃(5.35 g,

14.8 mmol) in anhydrous THF (100 mL) were added LiCl (628 mg,

14.8 mmol) and Pd(PPh₃)₄(856 mg, 740 μmol), and the solution was

heated at reﬂux overnight. The reaction mixture was cooled and

diluted with ethyl acetate (50 mL). The organic phase was washed

with brine (30 mL), 5% aqueous solution of ammonium hydroxide (30

mL), and brine (30 mL). The organic phase was dried (Na₂SO₄) and

concentrated in vacuo to give a yellow oil. Rapid ﬂash column

chromatography on silica gel (petroleum ether/ethyl acetate 15:1 with

1% Et₃N) aﬀorded the highly unstable diene E-32 as a colorless oil,

which was used immediately.

Diene E-32 and freshly distilled methyl vinyl ketone (3.45 g, 49.3

mmol) were dissolved in anhydrous toluene (200 mL) and heated at

130 °C in a sealed tube overnight. The volatiles were removed in

vacuo to give a yellow oil. Flash column chromatography on silica gel

(petroleum ether/ethyl acetate 15:1 with 1% Et₃N) delivered a

mixture (1.6:1) of the Diels−Alder cycloadducts E-33 and E-34 (1.47

g, 68% over three steps) as a colorless oil.

To a stirred solution of the mixture of cycloadducts E-33 and E-34

(1.44 g, 3.31 mmol) in methanol (35 mL) was added potassium

carbonate (550 mg, 3.97 mmol), and the solution was stirred at rt

overnight. The reaction mixture was diluted with a saturated aqueous

solution of ammonium chloride (35 mL) and ethyl acetate (60 mL).

The aqueous phase was separated and extracted with ethyl acetate (2

× 50 mL). The organic extracts were combined, washed with brine (30

mL), dried (MgSO₄), and concentrated in vacuo to give a yellow oil.

Flash column chromatography on silica gel (petroleum ether/ethyl

acetate 20:1 with 1% Et₃N) aﬀorded the ketone E-33 as a colorless oil

(+)-Cladiella-6Z,11(17)-dien-3-ol (Z-1).^12c,14fTo a stirred

solution of alcohol Z-37 (58 mg, 0.20 mmol) and pyridine (81 μL,

1.00 mmol) in anhydrous dichloromethane (4 mL) was added Dess−

Martin periodinane (211 mg, 0.500 mmol) in one portion. The

mixture was stirred for 1 h, and the reaction was then quenched by

addition of a saturated aqueous solution of sodium thiosulfate/sodium

hydrogen carbonate (5:1, 5 mL). The mixture was diluted with

dichloromethane (5 mL) and water (2 mL), and the aqueous phase

was separated and extracted with dichloromethane (2 × 15 mL). The

organic extracts were combined, dried (MgSO₄), and concentrated in

vacuo to give the crude ketone as a yellow oil. The ketone was used

immediately in the next reaction without puriﬁcation.

To a stirred solution of MeMgCl (3.0 M in THF, 667 μL, 2.00

mmol) in anhydrous THF (4 mL) at 0 °C was added a solution of

ketone (58 mg, 0.20 mmol) in anhydrous THF (4 mL) dropwise. The

ﬂask containing the ketone was rinsed with further anhydrous THF (1

mL), and this was added dropwise to the reaction mixture. The

solution was stirred for 1.5 h and then quenched with a saturated

aqueous solution of ammonium chloride (7 mL). The reaction mixture

was then diluted with ethyl acetate (7 mL) and water (5 mL). The

aqueous phase was separated and extracted with ethyl acetate (2 × 25

mL). The organic extracts were combined, dried (MgSO₄), and

concentrated in vacuo to give a yellow oil. Flash column

chromatography on silica gel (hexane/diethyl ether, gradient elution

7:1 → 5:1) aﬀorded (+)-cladiella-6Z,11(17)-dien-3-ol (Z-1) (45 mg,

90%) as a colorless solid. R_f= 0.28; (petroleum ether/diethyl ether

5:1); mp 91−93 °C; [α]_D²²+69.7 (c 0.60, CHCl₃) {lit.^12c[α]²_D²+95.3 (c

0.40, CHCl₃); lit.^14f[α]_D²⁵+82.2 (c 0.27, CHCl₃)}; ν_max(CHCl₃) 3494,

2929, 1718, 1645, 1453, 1377, 1353, 1318, 1092, 1079, 1058, 979, 945,

896 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.88 (1H, dd, J = 11.1, 6.1

Hz), 4.77 (1H, t, J = 2.0 Hz), 4.71 (1H, br s), 4.13 (1H, ddd, J = 9.8,

3.1, 3.1 Hz), 3.91 (1H, s), 3.36−3.15 (1H, m), 2.90 (1H, br d, J = 4.4

Hz), 2.84 (1H, dd, J = 9.7, 6.9 Hz), 2.28 (1H, ddd, J = 13.5, 3.2, 3.0

Hz), 2.22 (1H, dd, J = 12.0, 6.9 Hz), 2.17−2.08 (1H, m), 2.05−1.87

(3H, m), 1.89 (3H, s), 1.84−1.70 (3H, m), 1.36−1.25 (2H, m), 1.04

Q

dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

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(1.22 g, 85%). R_f= 0.30 (petroleum ether/ethyl acetate 5:1); [α]_D²⁵

+119 (c 1.04, CHCl₃); ν_max(CHCl₃) 2951, 2927, 2856, 1713, 935,

896, 869, 836, 774 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.67 (1H, t, J

= 8.4 Hz), 4.84 (1H, d, J = 6.0 Hz), 3.91 (1H, dd, J = 8.3, 4.9 Hz), 3.80

(1H, q, J = 7.0 Hz), 3.79 (1H, q, J = 7.0 Hz), 3.66 (1H, dd, J = 6.3, 4.9

Hz), 2.68−2.62 (1H, m), 2.49 (1H, dd, J = 13.5, 6.0 Hz), 2.35−1.96

(8H, m), 2.15 (3H, s), 1.70−1.59 (2H, m), 1.65 (3H, s), 1.23 (3H, t, J

= 7.0 Hz), 0.92 (9H, s), 0.05 (3H, s), 0.04 (3H, s); ¹³C NMR (100

MHz, CDCl₃) δ 211.7, 143.3, 130.6, 125.5, 121.3, 88.0, 74.7, 74.0,

63.3, 52.9, 43.5, 42.8, 30.3, 28.9, 27.1, 26.1, 24.4, 21.6, 18.5, 18.3, 15.7,

−4.5, −4.6; HRMS (CI, isobutane) m/z calcd for C₂₅H₄₃O₄Si [M +

H]⁺435.2930, found 435.2922; LRMS (CI, isobutane) m/z (%

intensity) 435.7 (100), 303.6 (10), 113.3 (20). Anal. Calcd for

C₂₅H₄₂O₄Si: C, 69.08; H, 9.74. Found C, 68.93; H, 9.73.

(1R*,2S*,6S*,7R*,8R*,9S*,12E)-9-Hydroxy-13-methyl-6-

(propen-2-yl)-15-oxatricyclo[6.6.1.0^2,7]pentadec-12-en-3-one

[( )-E-35]. To a solution of silyl ether 40 (30 mg, 74 μmol) and 4 Å

molecular sieves in anhydrous THF (2 mL) was added tetra-n-

butylammonium ﬂuoride (TBAF; 148 μL of a 1 M solution in THF,

148 μmol). The reaction mixture was stirred at rt for 4 h and then

quenched with a saturated aqueous solution of NH₄Cl (1 mL). The

molecular sieves were ﬁltered oﬀ and rinsed with ethyl acetate. The

aqueous phase was separated and extracted with ethyl acetate (3 × 5

mL). The organic extracts were combined, washed with brine (5 mL),

dried (MgSO₄), and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography on silica gel (petroleum ether/ethyl

acetate, gradient elution 10:1 → 7:1 → 5:1) to deliver the alcohol

( )-E-35 (16 mg, 72%) as a colorless solid. R_f= 0.30 (petroleum

ether/ethyl acetate 2:1); mp 113−115 °C; ν_max(CHCl₃) 3440, 2925,

2864, 1705, 1645, 940, 898, 794 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ

5.30 (1H, br d, J = 12.4 Hz), 4.89 (1H, s), 4.87−4.84 (1H, m), 4.29

(1H, dd, J = 9.6, 5.8 Hz), 3.60 (1H, d, J = 9.4 Hz), 2.93−2.90 (1H, m),

2.78 (1H, dd, J = 9.6, 6.7 Hz), 2.58−2.48 (3H, m), 2.45−2.36 (2H,

m), 2.30 (1H, qd, J = 12.3, 4.3 Hz), 2.21−2.13 (1H, m), 2.10 (1H, d, J

= 13.8 Hz), 1.99−1.86 (2H, m), 1.85 (3H, s), 1.81−1.71 (2H, m),

1.69 (3H, s), 1.26−1.18 (1H, m); ¹³C NMR (100 MHz, CDCl₃) δ

210.4, 146.5, 133.8, 124.4, 113.5, 88.5, 80.5, 74.1, 53.6, 49.5, 44.8, 40.6,

38.5, 37.4, 30.5, 27.5, 20.8, 18.8; HRMS (CI, isobutane) m/z calcd for

C₁₈H₂₇O₃[M + H]⁺291.1960, found 291.1959; LRMS (CI,

isobutane) m/z (% intensity) 291.3 (17), 273.3 (7), 113.2 (13).

2-{(1R,2R,3R,8R,10E)-14-(tert-Butyldimethylsilyloxy)-6-

ethoxy-10-methyl-15-oxatricyclo[6.6.1.0^2,7]pentadeca-6,10-

dien-3-yl}propan-2-ol (42). To a solution of ketone E-33 (462 mg,

1.06 mmol) in anhydrous THF (50 mL) at 0 °C was added slowly

methylmagnesium bromide (2.12 mL of a 3 M solution in diethyl

ether, 6.36 mmol). The reaction mixture was allowed to warm to rt

and stirred for 3 h, then quenched with a saturated aqueous solution of

ammonium chloride (45 mL) and diethyl ether (15 mL). The aqueous

phase was separated and extracted with diethyl ether (3 × 30 mL).

The organic extracts were combined, washed with brine (20 mL),

dried (MgSO₄), and concentrated in vacuo to give the crude alcohol as

a yellow oil. Flash column chromatography on silica gel (petroleum

ether/diethyl ether, gradient elution 20:1 → 5:1 with 1% Et₃N)

aﬀorded the alcohol 42 as a colorless oil (373 mg, 78%). R_f= 0.39

(petroleum ether/ethyl acetate 4:1); [α]²_D³+79.3 (c 0.91, CHCl₃); ν_max

tert-Butyl({[(1R*,6S*,7R*,8R*,9S*,12E)-3-ethoxy-13-methyl-

6-(propen-2-yl)-15-oxatricyclo[6.6.1.0^2,7]pentadeca-2,12-dien-

9-yl]oxy})dimethylsilane [( )-39]. To a solution of methyltriphe-

nylphosphonium bromide (1.50 g, 4.19 mmol) in anhydrous THF (20

mL) at 0 °C was added dropwise NaHMDS (3.35 mL of a 1 M

solution in THF, 3.35 mmol). The resulting yellow reaction mixture

was stirred for 1 h at 0 °C. A solution of ketone ( )-E-33 (363 mg,

840 μmol) in anhydrous THF (10 mL) was then added dropwise to

the solution of the ylide. The mixture was stirred at rt for 1.5 h before

the reaction was quenched with a saturated aqueous solution of

ammonium chloride (50 mL) and diluted with diethyl ether (100 mL).

The aqueous phase was separated and extracted with diethyl ether (2

× 100 mL). The organic extracts were combined, dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (petroleum ether/ethyl acetate 25:1) to

aﬀord the alkene ( )-39 (289 mg, 80%) as a colorless solid. R_f= 0.56

(petroleum ether/ethyl acetate 4:1); mp 80−82 °C; ν_max(CHCl₃)

1

2949, 2926, 2854, 1709, 895, 862, 835, 773 cm⁻¹; H NMR (400

MHz, CDCl₃) δ 5.71−5.63 (1H, m), 4.85 (1H, d, J = 6.2 Hz), 4.75

(1H, br s), 4.73−4.68 (1H, m), 3.86 (1H, dd, J = 8.1, 4.6 Hz), 3.84−

3.74 (3H, m), 2.49 (1H, dd, J = 13.7, 6.2 Hz), 2.32−2.10 (5H, m),

2.06 (1H, d, J = 12.9 Hz), 1.93−1.69 (4H, m), 1.64 (3H, s), 1.63−1.54

(1H, m), 1.59 (3H, s), 1.23 (3H, t, J = 7.0 Hz), 0.92 (9H, s), 0.04 (3H,

s), 0.02 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 147.7, 144.0, 130.4,

126.0, 122.3, 112.2, 88.2, 75.1, 74.1, 63.3, 48.8, 43.9, 43.8, 29.3, 29.1,

26.4, 24.9, 21.9, 18.8, 18.6, 18.5, 15.9, −4.2, −4.6; HRMS (CI,

isobutane) m/z calcd for C₂₆H₄₅O₃Si [M + H]⁺433.3138, found

433.3137; LRMS (CI, isobutane) m/z (% intensity) 433.3 (100). Anal.

Calcd for C₂₆H₄₄O₃Si: C, 72.17; H, 10.25. Found: C, 72.14; H, 10.32.

(1R*,2S*,6S*,7R*,8R*,9S*,12E)-9-(tert-Butyldimethylsily-

loxy)-13-methyl-6-(propen-2-yl)-15-oxatricyclo[6.6.1.0^2,7]-

pentadec-12-en-3-one [( )-40]. To a stirred solution of enol ether

( )-39 (26 mg, 60 μmol) in THF (6 mL) was added a 1 M aqueous

solution of HCl (60 μL, 60 μmol). The solution was stirred at rt

overnight and then diluted with dichloromethane (15 mL) and water

(12 mL). The aqueous phase was separated and extracted with

dichloromethane (2 × 15 mL). The organic extracts were combined,

dried (MgSO₄), and concentrated in vacuo to give a colorless solid.

Flash column chromatography on silica gel (petroleum ether/ethyl

acetate 15:1) delivered the ketone ( )-40 (21 mg, 87%) as a colorless

solid. R_f= 0.46 (petroleum ether/ethyl acetate 4:1); mp 96−98 °C;

ν_max(CHCl₃) 2949, 2930, 2887, 2859, 1707, 949, 868, 837, 810, 773

1

(CHCl₃) 3458, 2953, 2926, 2855, 1708, 935, 899, 863, 774 cm⁻¹; H

NMR (400 MHz, CDCl₃) δ 5.71 (1H, br t, J = 8.9 Hz), 4.82 (1H, d, J

= 5.9 Hz), 4.64 (1H, dd, J = 7.2, 4.6 Hz), 4.34 (1H, dd, J = 7.8, 4.6

Hz), 3.79 (1H, q, J = 7.0 Hz), 3.78 (1H, q, J = 7.0 Hz), 2.45 (1H, dd, J

= 13.2, 5.9 Hz), 2.31−2.09 (6H, m), 1.94−1.82 (2H, m), 1.68−1.63

(1H, m), 1.63 (3H, s), 1.37−1.31 (2H, m), 1.28 (3H, s), 1.23 (3H, t, J

= 7.0 Hz), 1.03 (3H, s), 0.97 (1H, s), 0.93 (9H, s), 0.06 (3H, s), 0.05

(3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 143.6, 130.3, 125.9, 123.9,

88.0, 74.6, 73.7, 71.6, 62.9, 51.6, 43.6, 43.6, 32.1, 28.7, 27.5, 26.2, 25.1,

23.7, 21.9, 18.4, 18.2, 15.7, −4.2, −4.7; HRMS (CI, isobutane) m/z

calcd for C₂₆H₄₇O₄Si [M + H]⁺451.3243, found 451.3243; LRMS (CI,

isobutane) m/z (% intensity) 451.4 (100), 433.3 (13), 319.3 (8).

(1R*,2S*,6S*,7R*,8R*,9S*,12E)-9-(tert-Butyldimethylsily-

loxy)-6-(2-hydroxypropan-2-yl)-13-methyl-15-oxatricyclo-

[6.6.1.0^2,7]pentadec-12-en-3-one (43) and tert-Butyl-

{(1S*,2R*,3R*,4S*,7E,10R*,11S*,12R*)-12-ethoxy-8,14,14-tri-

methyl-13,17-dioxatetracyclo[10.2.2.1^3,10.0^2,11]heptadec-7-en-

4-yl}oxidimethylsilane (44). To a solution of enol ether ( )-42 (96

mg, 0.21 mmol) in THF (10 mL) was added a 1 M aqueous solution

of HCl (210 μL, 210 μmol). The solution was stirred at rt for 1 h and

then diluted with diethyl ether (30 mL) and water (20 mL). The

aqueous phase was separated and extracted with diethyl ether (3 × 20

mL). The organic extracts were combined, washed with brine (30

mL), dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography on silica gel (petroleum

ether/ethyl acetate 10:1) to deliver the ketone ( )-43 (39 mg, 43%)

as a colorless oil and the tetracycle ( )-44 (15 mg, 17%) as a colorless

oil.

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.30 (1H, br d, J = 12.3 Hz),

4.87 (1H, s), 4.86−4.84 (1H, m), 4.29 (1H, dd, J = 10.1, 5.9 Hz), 3.70

(1H, d, J = 9.2 Hz), 2.98 (1H, dd, J = 9.2, 7.6 Hz), 2.74 (1H, dd, J =

10.0, 4.9 Hz), 2.60−2.50 (2H, m), 2.45−2.42 (1H, m), 2.41−2.33

(2H, m), 2.25 (1H, qd, J = 12.3, 3.9 Hz), 2.18−2.12 (1H, m), 2.09

(1H, d, J = 13.8 Hz), 1.99−1.92 (1H, m), 1.88 (3H, s), 1.86−1.63

(3H, m), 1.67 (3H, s), 0.87 (9H, s), 0.09 (3H, s), 0.02 (3H, s); ¹³C

NMR (100 MHz, CDCl₃) δ 210.9, 146.1, 134.6, 124.4, 113.8, 88.4,

80.6, 73.9, 54.2, 49.0, 44.6, 40.5, 38.6, 37.6, 30.8, 27.5, 26.2, 21.1, 19.4,

18.2, −3.8, −4.0; HRMS (CI, isobutane) m/z calcd for C₂₄H₄₁O₃Si [M

+ H]⁺405.2825, found 405.2829; LRMS (CI, isobutane) m/z (%

intensity) 405.5 (100), 347.4 (20), 273.4 (56). Anal. Calcd for

C₂₄H₄₀O₃Si: C, 71.23; H, 9.96. Found: C, 71.22; H, 10.11.

(

)-43: R_f= 0.50 (petroleum ether/ethyl acetate 1:1); ν_max

(CHCl₃) 3456, 2954, 2929, 2887, 2859, 1710, 872, 837, 826, 807,

R

dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

779 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.32 (1H, br d, J = 12.3

(1R,2S,7R,8R,9S,12E)-9-Hydroxy-6-isopropyl-13-methyl-15-

oxatricyclo[6.6.1.0^2,7]pentadec-12-en-3-one (E-36). To a stirred

solution of enol ether 46 (33 mg, 0.10 mmol) in THF (5 mL) was

added a 1 M aqueous solution of HCl (100 μL, 100 μmol), and the

mixture was stirred at rt for 1 h and then diluted with diethyl ether (10

mL) and water (10 mL). The aqueous phase was separated and

extracted with diethyl ether (3 × 10 mL). The organic extracts were

combined, washed with brine (10 mL), dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (petroleum ether/ethyl acetate, gradient

elution 10:1 → 7:1 → 5:1) to deliver ketone E-36 (27 mg, 89%) as a

colorless solid. R_f= 0.23 (petroleum ether/ethyl acetate 3:1); mp

175−177 °C; [α]²_D⁴−19.5 (c 1.00, CHCl₃); ν_max(CHCl₃) 3531, 2954,

2926, 2855, 1694, 969, 937, 896, 856, 794 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃) δ 5.34−5.27 (1H, m), 4.26 (1H, dd, J = 9.8, 5.7 Hz), 3.76

(1H, d, J = 9.0 Hz), 2.96 (1H, dt, J = 9.0, 6.6 Hz), 2.75 (1H, dd, J =

9.8, 7.5 Hz), 2.52 (1H, dd, J = 13.6, 5.7 Hz), 2.49−2.37 (3H, m), 2.31

(1H, dddd, 12.3, 12.3, 12.3, 4.3 Hz), 2.23−2.14 (1H, m), 2.09 (1H, d,

J = 13.6 Hz), 2.02−1.87 (3H, m), 1.85 (3H, s), 1.75 (1H, ddd, J =

13.6, 3.6, 3.6 Hz), 1.64−1.58 (1H, m), 1.48−1.34 (1H, m), 1.21 (1H,

d, J = 6.6 Hz), 1.00 (3H, d, J = 6.9 Hz), 0.79 (3H, d, J = 6.9 Hz); ¹³C

NMR (100 MHz, CDCl₃) δ 211.3, 133.7, 124.5, 88.4, 80.5, 74.4, 53.9,

50.5, 40.7, 40.6, 38.4, 37.5, 28.1, 27.4, 24.1, 22.0, 20.8, 15.3; HRMS

(CI, isobutane) m/z calcd for C₁₈H₂₉O₃[M + H]⁺293.2116, found

293.2120; LRMS (CI, isobutane) m/z (% intensity) 293.5 (100),

275.5 (9), 222.4 (11). Anal. Calcd for C₁₈H₂₈O₃: C, 73.93; H, 9.65.

Found: C, 73.94; H, 9.63.

Hz), 4.56 (1H, d, J = 9.4 Hz), 4.27 (1H, dd, J = 9.8, 6.1 Hz), 3.04 (1H,

dd, J = 9.4, 7.8 Hz), 2.78−2.73 (1H, m), 2.62−2.42 (3H, m), 2.35−

2.27 (1H, m), 2.25 (1H, qd, J = 12.3, 4.0 Hz), 2.18−2.11 (1H, m),

2.08 (1H, d, J = 13.8 Hz), 2.02 (1H, dddd, J = 13.5, 4.2, 4.2, 4.2 Hz),

1.96−1.87 (1H, m), 1.86 (3H, s), 1.86−1.81 (1H, m), 1.71 (1H, ddd, J

= 14.2, 4.0, 2.8 Hz), 1.60 (1H, s), 1.55−1.42 (1H, m), 1.28 (3H, s),

1.17 (3H, s), 0.90 (9H, s), 0.15 (3H, s), 0.08 (3H, s); ¹³C NMR (100

MHz, CDCl₃) δ 210.9, 134.3, 124.1, 90.5, 81.2, 76.0, 74.1, 54.6, 48.3,

45.6, 40.6, 37.6, 37.0, 29.5, 28.6, 27.1, 26.2, 25.8, 20.9, 18.0, −3.6,

−4.1; HRMS (CI, isobutane) m/z calcd for C₂₄H₄₃O₄Si [M + H]⁺

423.2931, found 423.2936; LRMS (CI, isobutane) (% intensity) 423.3

(100), 405.3 (40), 365.5 (13), 291.3 (60). Anal. Calcd for C₂₄H₄₂O₄Si:

C, 68.20; H, 10.02. Found: C, 68.06; H, 10.06.

( )-44: R_f= 0.76 (petroleum ether/ethyl acetate 1:1); ν_max

(CHCl₃) 2956, 2928, 2856, 1730, 836, 772 cm⁻¹; ¹H NMR (400

MHz, CDCl₃) δ 5.24 (1H, br d, J = 8.6 Hz), 4.32−4.29 (1H, m),

3.63−3.52 (3H, m), 3.26 (1H, dd, J = 8.1, 8.1 Hz), 2.66−2.58 (2H,

m), 2.44 (1H, dd, J = 11.0, 3.6 Hz), 2.30−2.18 (1H, m), 2.17−2.09

(1H, m), 2.04 (1H, d, J = 13.3 Hz), 1.92−1.75 (5H, m), 1.78 (3H, s),

1.69−1.66 (1H, m), 1.42−1.36 (1H, m), 1.29 (3H, s), 1.26 (3H, s),

1.16 (3H, t, J = 7.0 Hz), 0.87 (9H, s), 0.11 (3H, s), 0.05 (3H, s); ¹³C

NMR (100 MHz, CDCl₃) δ 133.5, 125.8, 101.3, 89.8, 81.8, 78.7, 76.6,

56.8, 50.8, 46.6, 44.7, 37.6, 37.1, 29.0, 28.7, 27.5, 26.0, 24.0, 19.8, 17.9,

17.1, 15.7, −3.5, −4.6.

(1R,7R,6S,8R,9S,12E)-3-Ethoxy-6-isopropyl-13-methyl-15-

oxatricyclo[6.6.1.0^2,7]pentadeca-2,12-dien-9-ol (46). To a ﬂask

containing alcohol 42 (95 mg, 0.21 mmol), dimethylaminopyridine

(DMAP) (135 mg, 1.11 mmol), and distilled triethylamine (561 mg,

5.54 mmol) was added freshly distilled acetic anhydride (1.13 g, 11.1

mmol). The resulting solution was heated at 40 °C for 30 min, then

cooled at 0 °C and quenched with a saturated aqueous solution of

ammonium chloride (3 mL) and diethyl ether (5 mL). The aqueous

phase was separated and extracted with diethyl ether (3 × 5 mL). The

organic extracts were combined, washed with brine (5 mL), dried

(MgSO₄), and concentrated in vacuo. The residue was ﬁltered through

a pad of silica gel (petroleum ether/ethyl acetate 10:1 with 1% Et₃N)

to aﬀord the crude acetate 45 as a colorless oil. The crude acetate 45

was used in the following step without puriﬁcation.

A small freshly cut piece of potassium (∼100 mg) was added to a

solution of recrystallized 18-crown-6 (530 mg, 2.00 mmol) in freshly

distilled t-butylamine (20 mL) at rt. The mixture was sonicated and

then stirred at the same temperature until a dark blue color developed,

after which anhydrous THF (20 mL) was added. A solution of the

crude acetate 45 in anhydrous THF (4 mL) was added upon

reappearance of the blue color at such a rate that the color did not

disappear for a long time. After addition of the substrate and

reappearance of the blue color, excess potassium was destroyed by

addition of absolute ethanol and the resulting mixture was neutralized

by addition of a saturated aqueous solution of ammonium chloride.

The mixture was diluted with diethyl ether (20 mL), and the aqueous

phase was separated and extracted with diethyl ether (3 × 10 mL).

The organic extracts were combined, washed with brine (20 mL),

dried (Na₂SO₄), and concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography on silica gel (petroleum ether/ethyl

acetate, gradient elution 100:1 → 30:1 with 1% Et₃N) to aﬀord the

alcohol 46 as a colorless oil (44 mg, 65% over two steps). R_f= 0.30

(petroleum ether/ethyl acetate 3:1); [α]²_D⁵+106 (c 1.00, CHCl₃); ν_max

(CHCl₃) 3442, 2956, 2914, 2871, 1709, 966, 942, 895, 837, 803 cm⁻¹;

¹H NMR (400 MHz, CDCl₃) δ 5.45 (1H, tt, J = 8.8, 1.2 Hz), 4.86

(1R,2S,7R,8R,9S,12E)-9-(tert-Butyldimethylsilyloxy)-6-iso-

propyl-13-methyl-15-oxatricyclo[6.6.1.0^2,7]pentadec-12-en-3-

one (E-41). To a solution of alcohol E-36 (33 mg, 0.11 mmol) and

2,6-lutidine (35 mg, 0.33 mmol) in anhydrous dichloromethane (1

mL) at −78 °C was added tert-butyldimethylsilyl triﬂuoromethanesul-

fonate (TBSOTf; 45 mg, 0.17 mmol). The reaction mixture was stirred

at the same temperature for 1 h, then quenched by addition of a

saturated aqueous solution of sodium bicarbonate (2 mL) and diluted

with ethyl acetate (3 mL). The aqueous phase was separated and

extracted with ethyl acetate (3 × 3 mL). The organic extracts were

combined, washed with brine (5 mL), dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to

deliver the silyl ether 41 (36 mg, 78%) as a colorless solid. R_f= 0.58

(petroleum ether/ethyl acetate 4:1); mp 108−110 °C; [α]²_D⁷−44.5 (c

0.99, CHCl₃); ν_max(CHCl₃) 2956, 2930, 2859, 1707, 837, 824, 776

1

cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.34−5.27 (1H, m), 4.26 (1H,

dd, J = 10.0, 6.0 Hz), 3.78 (1H, d, J = 9.0 Hz), 2.96 (1H, dd, J = 9.0,

7.8 Hz), 2.69 (1H, dd, J = 10.0, 6.9 Hz), 2.51 (1H, dd, J = 13.7, 6.0

Hz), 2.50−2.43 (1H, m), 2.36 (1H, br d, J = 15.4 Hz), 2.31−2.19 (2H,

m), 2.18−2.11 (1H, m), 2.07 (1H, d, J = 13.7 Hz), 2.01−1.81 (3H,

m), 1.87 (3H, s), 1.70 (1H, ddd, J = 10.7, 3.3, 3.3 Hz), 1.59−1.53 (1H,

m), 1.36 (1H, dddd, J = 13.2, 13.2, 13.2, 3.6 Hz), 0.99 (3H, d, J = 6.9

Hz), 0.87 (9H, s), 0.75 (3H, d, J = 6.9 Hz), 0.10 (3H, s), 0.01 (3H, s);

¹³C NMR (100 MHz, CDCl₃) δ 211.5, 134.4, 124.2, 88.8, 80.7, 74.0,

54.4, 50.0, 40.8, 40.5, 38.2, 37.5, 27.8, 27.3, 26.0, 24.5, 22.2, 20.8, 17.9,

16.3, −4.1, −4.2; HRMS (CI, isobutane) m/z calc for C₂₄H₄₃O₃Si

407.2981 [M + H]⁺, found 407.2986; LRMS (CI, isobutane) m/z (%

intensity) 407.6 (18), 113.3 (18).

(1R,2R,6S,7R,8R,9S,12E)-6-Isopropyl-3,13-dimethyl-15-

oxatricyclo[6.6.1.0^2,7]pentadeca-3,12-dien-9-ol (49). To a stirred

solution of ketone 41 (44 mg, 0.11 mmol) and PhN(Tf)₂(78 mg, 0.22

mmol) in anhydrous THF (1.5 mL) at −78 °C was added dropwise a

solution of NaHMDS (270 μL of a 1.0 M solution in THF, 0.27

mmol). The resulting mixture was stirred at −78 °C for 2 h, and the

reaction was then quenched by addition of water (3 mL) at −78 °C.

The mixture was allowed to warm to rt and diluted with diethyl ether

(3 mL). The aqueous phase was separated and extracted with diethyl

ether (3 × 5 mL). The organic extracts were combined, washed with

brine (5 mL), dried (MgSO₄), and concentrated in vacuo. The residue

was ﬁltered through a pad of silica gel (petroleum ether/ethyl acetate

10:1) to aﬀord crude enol triﬂate 47, which was used for the next step

without further puriﬁcation.

(1H, d, J = 5.9 Hz), 4.05 (1H, dd, J = 8.2, 5.2 Hz), 3.95−3.88 (1H, m),

3.82 (1H, q, J = 7.0 Hz), 3.81 (1H, q, J = 7.0 Hz), 2.52 (1H, d, J = 9.5

Hz), 2.41 (1H, dd, J = 13.2, 5.9 Hz), 2.38−2.09 (6H, m), 1.91−1.85

(2H, m), 1.79 (1H, dd, J = 12.8, 6.5 Hz), 1.67 (3H, s), 1.66−1.60 (1H,

m), 1.23 (3H, t, J = 7.0 Hz), 1.22−1.12 (2H, m), 0.92 (3H, d, J = 6.9

Hz), 0.72 (3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 144.7,

128.8, 127.8, 122.1, 87.1, 75.2, 74.0, 62.9, 45.4, 44.0, 43.3, 28.7, 28.5,

24.9, 22.2, 21.8, 21.3, 18.3, 15.7, 15.7; HRMS (CI, isobutane) m/z

calcd for C₂₀H₃₃O₃[M + H]⁺321.2429, found 321.2433; LRMS (CI,

isobutane) m/z (% intensity); 321.5 (100).

S

dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

To a solution of the crude enol triﬂate 47, lithium chloride (23 mg,

0.54 mmol) and Pd(PPh₃)₄(12 mg, 11 μmol) in anhydrous THF (10

mL) was added dropwise a solution of methylmagnesium chloride

(180 μL of a 3 M solution in THF, 0.54 mmol). The mixture was

stirred at rt for 4 h, and the reaction was quenched at 0 °C by addition

of a saturated aqueous solution of ammonium chloride (5 mL). The

reaction mixture was allowed to warm to rt and diluted with diethyl

ether (5 mL). The aqueous phase was separated and extracted with

diethyl ether (3 × 5 mL). The organic extracts were combined, washed

with brine (5 mL), dried (MgSO₄), and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography on silica gel

(petroleum ether/ethyl acetate 100:1) to deliver the crude alkene 48

contaminated with traces of PPh₃. The crude alkene was used in the

next step without further puriﬁcation.

To a solution of the crude alkene 48 and 4 Å molecular sieves in

anhydrous THF (2 mL) was added TBAF (220 μL of a 1 M solution

in THF, 0.22 mmol). The reaction mixture was stirred at rt for 5 h and

then quenched by addition of a saturated aqueous solution of

ammonium chloride (1 mL). The molecular sieves were removed by

ﬁltration and rinsed with ethyl acetate. The aqueous phase was

separated and extracted with ethyl acetate (3 × 5 mL). The organic

extracts were combined, washed with brine (5 mL), dried (MgSO₄),

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (petroleum ether/ethyl acetate, gradient

elution 100:1 → 20:1 → 10:1) to deliver alcohol 49 (21 mg, 68% yield

over four steps) as a colorless oil. R_f= 0.26 (petroleum ether/ethyl

acetate 5:1); [α]_D²⁸+16.5 (c 1.00, CHCl₃); ν_max(CHCl₃) 3416, 2955,

2928, 2894, 2867, 943, 798 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.49

(1H, br d, J = 4.6 Hz), 5.37−5.30 (1H, m), 3.95 (1H, dd, J = 9.2, 5.8

Hz), 3.78 (1H, d, J = 9.1 Hz), 3.13−3.06 (1H, m), 2.60 (1H, dd, J =

13.6, 5.8 Hz), 2.42 (1H, dd, J = 9.2, 7.0 Hz), 2.32 (1H, dddd, J = 12.2,

12.2, 12.2, 4.3 Hz), 2.23 (1H, d, J = 13.6 Hz), 2.22−2.16 (1H, m),

2.10−1.89 (4H, m), 1.85 (3H, s), 1.82−1.68 (2H, m), 1.75 (3H, s),

1.53−1.44 (1H, m), 1.29 (1H, br d, J = 6.1 Hz), 0.93 (3H, d, J = 6.9

Hz), 0.78 (3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 133.5,

131.9, 124.8, 122.9, 86.0, 83.8, 74.9, 45.8, 44.8, 42.8, 37.7, 36.8, 27.5,

27.4, 23.6, 23.5, 21.6, 20.8, 14.9; HRMS (CI, isobutane) m/z calcd for

C₁₉H₃₁O₂[M + H]⁺291.2324, found 291.2328; LRMS (CI,

isobutane) m/z (% intensity) 291.5 (100), 273.4 (20).

CDCl₃) δ 5.56−5.48 (1H, m), 5.42−5.37 (1H, m), 4.10 (1H, dd, J =

5.7, 2.8 Hz), 3.82 (1H, d, J = 7.4 Hz), 2.50 (1H, dd, J = 13.8, 5.7 Hz),

2.47−2.34 (3H, m), 2.17−1.89 (5H, m), 1.82 (3H, s), 1.68 (3H, s),

1.62−1.50 (3H, m), 1.41 (3H, s), 1.06 (1H, br s), 0.96 (3H, d, J = 6.6

Hz), 0.84 (3H, d, J = 6.6 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 132.9,

129.4, 126.8, 121.5, 89.8, 81.0, 77.3, 47.0, 44.4, 40.3, 38.4, 36.8, 29.1,

27.5, 23.1, 22.9, 22.2, 21.7, 20.8, 19.0; HRMS (CI, isobutane) m/z

calcd for C₂₀H₃₃O₂[M + H]⁺305.2480, found 305.2477; LRMS (CI,

isobutane) m/z (% intensity) 305.5 (100), 287.5 (85).

(−)-3-Acetoxycladiella-6,11-diene (6).⁴¹To a ﬂask containing

(−)-cladiella-6,11-dien-3-ol (5) (7.2 mg, 23 μmol), DMAP (14 mg,

0.12 mmol), and distilled triethylamine (60 mg, 0.59 mmol) was added

freshly distilled acetic anhydride (128 mg, 1.18 mmol). The resulting

solution was heated at 40 °C for 30 min and then cooled at 0 °C, and

the reaction was quenched by addition of a saturated aqueous solution

of ammonium chloride (1 mL) and diethyl ether (2 mL). The aqueous

phase was separated and extracted with diethyl ether (3 × 2 mL). The

organic extracts were combined, washed with brine (2 mL), dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel (petroleum ether/ethyl

acetate 40:1) to aﬀord (−)-3-acetoxycladiella-6,11-diene (6) (2.0 mg,

25%) as a colorless oil. R_f= 0.50 (petroleum ether/diethyl ether 1:4);

[α]²_D⁶−28.5 (c 0.60, CHCl₃) {lit.⁴¹[α]²_D⁵−34.7 (c 0.5, CHCl₃)}; ν_max

(CHCl₃) 2959, 2929, 2870, 1732, 1450, 1370, 1246, 1069, 1022, 802

cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.47 (1H, dd, J = 11.3, 6.3 Hz),

5.41 (1H, br s), 4.07 (1H, dd, J = 5.5, 3.5 Hz), 4.05 (1H, d, J = 6.4

Hz), 2.52 (1H, dd, J = 13.7, 5.5 Hz), 2.44−2.33 (3H, m), 2.32−2.24

(1H, m), 2.18−2.08 (2H, m), 2.05 (1H, d, J = 13.7 Hz), 2.00 (1H,

ddd, J = 13.4, 11.0, 6.2 Hz), 1.93 (3H, s), 1.93−1.90 (1H, m), 1.81

(3H, d, J = 1.5 Hz), 1.74 (3H, s), 1.70 (3H, s), 1.65 (1H, heptet, J =

6.7 Hz), 1.43−1.41 (1H, m), 0.96 (3H, d, J = 6.7 Hz), 0.84 (3H, d, J =

6.7 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 132.7, 129.7, 126.6,

121.6, 89.5, 87.9, 81.1, 46.7, 43.9, 40.7, 38.4, 32.6, 28.7, 23.1, 23.1,

23.0, 22.4, 22.1, 21.9, 20.3, 19.4; HRMS (EI+) m/z calcd for C₂₂H₃₄O₃

[M]⁺346.2508, found 346.2506; LRMS (EI+) m/z (% intensity)

346.3 (18), 286.2 (62), 243.2 (32), 218.2 (54), 217.2 (45), 177.1 (20),

147.1 (56), 105.1 (76), 93.1 (100).

(−)-Cladiell-11-ene-3,6,7-triol (9).^9b,15,42To a solution of

(−)-cladiella-6,11-dien-3-ol (5) (5.0 mg, 16 μmol) in a mixture of

THF and water (1 mL of a 1:1 mixture) at 0 °C were added N-

methylmorpholine N-oxide (NMO; 19 μL of a 1.0 g/mL solution in

water, 0.16 mmol) and OsO₄(2 μL of a 4.0 wt % solution in water, 0.3

μmol). The mixture was stirred at 0 °C for 1 h and then allowed to

warm to rt and stirred at this temperature for 1 h. The reaction was

then quenched by addition of a saturated aqueous solution of sodium

thiosulfate (2 mL), and the mixture was stirred vigorously for 30 min

before being diluted with dichloromethane (2 mL). The aqueous

phase was separated and extracted with dichloromethane (3 × 3 mL).

The organic extracts were combined, washed with brine (3 mL), dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel (n-hexane/ethyl acetate,

gradient elution 2:1 → ethyl acetate 100%) to deliver (−)-cladiell-11-

ene-3,6,7-triol (9) (3.7 mg, 66%) as colorless crystals. R_f= 0.16

(petroleum ether/ethyl acetate 1:2); mp 195−198 °C {lit.¹⁵196.8−

198.4 °C, lit.^9b205−206 °C, lit.⁴²205.5−206.0 °C}; [α]²_D⁸−12.1 (c

0.70, CHCl₃) {lit.¹⁵[α]_D²⁵−11.9 (c 0.43, CHCl₃), lit.^9b[α]²_D⁵−12.3 (c

1.00, CHCl₃), lit.⁴²[α]_D−16.1 (c 0.75, CHCl₃)}; ν_max(CHCl₃) 3423,

(−)-Cladiella-6,11-dien-3-ol (5).^15,40,41To a solution of alcohol

49 (26 mg, 90 μmol) in anhydrous dichloromethane (4 mL) were

added pyridine (29 mg, 0.36 mmol) and Dess−Martin periodinane

(57 mg, 0.13 mmol). The mixture was stirred at rt for 30 min and then

the reaction was quenched by addition of a saturated aqueous solution

of sodium thiosulfate and sodium bicarbonate (5:1, 2 mL). The

mixture was diluted with diethyl ether (10 mL) and stirred vigorously

for 1 h. The aqueous phase was separated and extracted with diethyl

ether (3 × 5 mL). The organic extracts were combined, washed with

brine (5 mL), dried (MgSO₄), and concentrated in vacuo. The residue

was ﬁltered through a pad of silica gel (petroleum ether/ethyl acetate

10:1) to aﬀord crude ketone 50, which was used without further

puriﬁcation in the next step.

To a solution of crude ketone 50 in anhydrous THF (3 mL) was

added sodium tetraﬂuoroborate (100 mg, 900 μmol) at rt. The

mixture was stirred at rt for 10 min and then cooled at −78 °C. A

solution of methyllithium (170 μL of a 1.6 M solution in THF, 0.27

mmol) was added, and the mixture was stirred at −78 °C for 30 min.

The reaction was quenched by addition of a saturated aqueous

solution of sodium bicarbonate, diluted with diethyl ether (5 mL), and

allowed to warm to rt. The aqueous phase was separated and extracted

with diethyl ether (3 × 5 mL). The organic extracts were combined,

washed with brine (5 mL), dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography on silica gel

(n-hexane/ethyl acetate 15:1) to deliver (−)-cladiella-6,11-dien-3-ol

(5) (19 mg, 69% over two steps) as a colorless solid. R_f= 0.25

(petroleum ether/ethyl acetate 4:1); mp 51−53 °C {lit.⁴⁰48−52 °C;

lit.⁴¹56−57 °C; lit.¹⁵51−52 °C}; [α]_D²⁶−25.7 (c 0.30, CHCl₃)

{lit.⁴⁰[α]²_D⁵−22.7 (c 0.3, CHCl₃); lit.⁴¹[α]_D²⁵−18.1 (c 0.07, CHCl₃);

lit.¹⁵[α]²_D⁴−24.4 (c 0.25, CHCl₃)}; ν_max(CHCl₃) 3423, 2956, 2921,

2868, 1697, 1459, 1367, 1259, 1071 cm⁻¹; ¹H NMR (400 MHz,

1

2960, 2926, 1726, 1078, 1047, 1024, 929, 883, 798, cm⁻¹; H NMR

(500 MHz, CDCl₃) δ 5.44 (1H, br s), 4.56 (1H, br s), 4.34−4.28 (1H,

m), 3.73 (1H, d, J = 6.8 Hz), 2.61 (1H, ddd, J = 6.8, 6.5, 4.6 Hz), 2.28

(1H, br d, J = 6.5 Hz), 2.21−2.13 (1H, m), 2.11−1.94 (3H, m), 1.88−

1.78 (2H, m), 1.73−1.53 (6H, m), 1.66 (3H, s), 1.50−1.45 (1H, m),

1.36 (3H, s), 1.18 (3H, s), 0.97 (3H, d, J = 6.6 Hz), 0.87 (3H, d, J =

6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 132.5, 122.2, 87.0, 76.6, 76.1,

75.4, 75.1, 48.1, 46.6, 40.0, 39.6, 36.2, 30.6, 29.5, 28.9, 23.2, 22.9, 22.0,

21.5, 20.7; HRMS (CI, isobutane) m/z calcd for C₂₀H₃₃O₃[M −

OH]⁺321.2429, found 321.2434; LRMS (CI, isobutane) m/z (%

intensity) 321.4 (100), 305.4 (25), 303.4 (21), 287.4 (10).

3-Acetoxycladiellin-11-ene-6,7-diol (10).⁴³To a solution of

(−)-3-acetoxycladiella-6,11-diene (6) (3.1 mg, 8.9 μmol) in a mixture

T

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of THF and water (0.6 mL of a 1:1 mixture) at 0 °C were added NMO

(10 μL of a 1.0 g/mL solution in water, 89 μmol) and OsO₄(1.1 μL of

a 4.0 wt % solution in water, 0.17 μmol). The mixture was stirred at 0

°C for 1 h before being allowed to warm to rt and stirred at this

temperature for 1.5 h. The reaction was then quenched with a

saturated aqueous solution of sodium thiosulfate (2 mL) before being

stirred vigorously for 30 min and diluted with dichloromethane (2

mL). The aqueous phase was separated and extracted with

dichloromethane (3 × 3 mL). The organic extracts were combined,

washed with brine (3 mL), dried (MgSO₄), and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography on silica gel

(petroleum ether/ethyl acetate, gradient elution 2:1 → 1:1 → ethyl

acetate 100%) to deliver (−)-3-acetoxycladiellin-11-ene-6,7-diol (10)

(1.1 mg, 36%) as colorless crystals. R_f= 0.23 (petroleum ether/ethyl

acetate 1:2); [α]²_D⁸0 (c 0.30, CHCl₃) {lit.⁴³[α]_D−1.84 (c 2.17,

CHCl₃)}; ν_max(CHCl₃) 3446, 2963, 2959, 2934, 1734, 910, 731 cm⁻¹;

¹H NMR (500 MHz, CDCl₃) δ 5.45 (1H, br s), 4.55 (1H, br s), 4.30

(1H, dt, J = 11.8, 3.0 Hz), 3.89 (1H, d, J = 6.3 Hz), 2.60 (1H, ddd, J =

6.3, 6.3, 6.3 Hz), 2.32 (1H, br d, J = 6.3 Hz), 2.25−2.09 (3H, m), 1.99

(3H, s), 1.94−1.83 (3H, m), 1.73 (1H, dd, J = 15.0, 3.0 Hz), 1.67 (3H,

s), 1.64 (3H, s) 1.63−1.56 (4H, m), 1.39−1.35 (1H, m), 1.17 (3H, s),

0.96 (3H, d, J = 6.7 Hz), 0.86 (3H, d, J = 6.7 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 169.8, 132.2, 121.9, 86.6, 86.4, 77.6, 77.3, 75.9, 48.5,

46.8, 40.3, 39.4, 31.4, 30.5, 29.1, 23.4, 22.9, 22.9, 22.5, 22.0, 21.6, 20.2;

HRMS (EI) m/z calcd for C₂₂H₃₆O₅[M]⁺380.2565, found 380.2567;

LRMS (EI) m/z (% intensity) 380.3 (7), 362.3 (5), 320.3 (50), 302.3

(55), 93.1 (100).

were combined, washed with brine (30 mL), dried (MgSO₄), and

concentrated in vacuo. The residue was ﬁltered through a pad of silica

gel (petroleum ether/ethyl acetate 10:1) and the solvent was removed

in vacuo to deliver ketone 52, which was used without puriﬁcation in

to the susequent reaction.

To a solution of methyltriphenylphosphonium bromide (1.13 g,

3.16 mmol) in anhydrous THF (10 mL) at 0 °C was added dropwise a

solution of NaHMDS (0.34 mL of a 1 M solution in THF, 0.34

mmol). The resulting yellow solution was stirred for 1 h at rt. A

solution of crude ketone 52 in anhydrous THF (10 mL) was added

dropwise to the solution of ylide. The solution was stirred at reﬂux for

1 h and then cooled to rt before the reaction was quenched with a

saturated aqueous solution of ammonium chloride (10 mL). The

mixture was diluted with diethyl ether (20 mL), and the aqueous phase

was separated and extracted with diethyl ether (2 × 20 mL). The

organic extracts were combined, dried (MgSO₄), and concentrated in

vacuo. The residue was ﬁltered through a pad of silica gel (petroleum

ether/ethyl acetate 10:1) and the solvent was removed in vacuo to give

crude diene 53, which was used without further puriﬁcation in the next

step.

A small freshly cut piece of potassium (∼200 mg) was added to a

solution of recrystallized 18-crown-6 (780 mg, 2.95 mmol) in freshly

distilled t-butylamine (30 mL) at rt. The mixture was sonicated and

stirred at rt until a dark blue color developed, after which anhydrous

THF (30 mL) was added. A solution of crude diene 53 in anhydrous

THF (10 mL) was added upon reappearance of the blue color at such

a rate that the color did not disappear for a long time. After addition of

the substrate and reappearance of the blue color, excess potassium was

destroyed by addition of absolute ethanol, and the resulting mixture

was neutralized by addition of a saturated aqueous solution of

ammonium chloride. The mixture was diluted with diethyl ether (30

mL), and the aqueous phase was separated and extracted with diethyl

ether (3 × 20 mL). The organic extracts were combined, washed with

brine (20 mL), dried (Na₂SO₄), and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography on silica gel

(petroleum ether/ethyl acetate, gradient elution 100:1 → 10:1 with

1% Et₃N) to aﬀord alcohol E-37 as a colorless solid (81 mg, 47% for

four steps). R_f= 0.58 (petroleum ether/ethyl acetate 2:1); mp 149−

152 °C; [α]²_D⁶+5.95 (c 1.00, CHCl₃); ν_max(CHCl₃) 3426, 2932, 2870,

(1R,2R,6S,8R,9R,13R,14R)-2,6,10-Trimethyl-13-isopropyl-

15,16-dioxatetracyclo[6.6.1.1^2,6.0^9,14]hexadec-10-ene (51).¹⁵

To a solution of (−)-cladiella-6,11-dien-3-ol (5) (3.0 mg, 9.8 μmol)

in anhydrous dichloromethane (300 μL) at 0 °C was added freshly

distilled acetic anhydride (11 mg, 98 μmol) and a solution of

trimethylsilyl triﬂuoromethanesulfonate (10 μL of a 1 mg/mL solution

in anhydrous dichloromethane, 0.49 μmol). The reaction mixture was

stirred for 30 min at 0 °C and then quenched by addition of a

saturated aqueous solution of sodium bicarbonate (1 mL). The

aqueous phase was separated and extracted with dichloromethane (3 ×

3 mL). The organic extracts were combined, washed with brine (5

mL), dried (MgSO₄), and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography on silica gel (petroleum

ether/ethyl acetate 10:1) to deliver the tetracyclic ether 51 (2.2 mg,

81%) as a colorless oil. R_f= 0.65 (petroleum ether/ethyl acetate 6:1);

[α]²_D⁵+17.1 (c 0.73, CHCl₃) {lit.¹⁵[α]²_D³+19.0 (c 0.37, CHCl₃)}; ν_max

1

941, 895 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.37−5.30 (1H, m),

4.78 (1H, t, J = 1.9 Hz), 4.72 (1H, t, J = 1.9 Hz), 4.03 (1H, dd, J = 9.9,

5.9 Hz), 3.63 (1H, d, J = 9.2 Hz), 3.04 (1H, ddd, 9.2, 8.2, 6.5 Hz), 2.70

(1H, dd, J = 9.9, 6.5 Hz), 2.45 (1H, dd, J = 13.8, 5.9 Hz), 2.29 (1H, qd,

J = 12.3, 4.2 Hz), 2.26 (1H, ddd, J = 13.5, 3.2, 3.2 Hz), 2.24−2.16 (1H,

m), 2.16−2.10 (1H, m), 2.05 (1H, d, J = 13.8 Hz), 2.01 (1H, dd, J =

11.8, 6.5 Hz), 1.95−1.85 (2H, m), 1.85 (3H, s), 1.79−1.71 (2H, m),

1.41−1.32 (1H, m), 1.13 (1H, d, J = 6.5 Hz), 1.02−0.98 (1H, m), 0.95

(3H, d, J = 6.9 Hz), 0.74 (3H, d, J = 6.9 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 146.7, 133.5, 124.8, 110.5, 88.2, 80.6, 74.7, 48.7, 47.5, 41.1,

39.4, 37.5, 31.2, 28.3, 27.7, 25.3, 22.0, 21.1, 15.6; HRMS (EI) m/z

calcd for C₁₉H₃₀O₂[M]⁺290.2246, found 290.2245; LRMS (EI) m/z

(% intensity) 290.2 (62), 272.3 (15), 229.2 (12), 193.2 (21), 93.1

(71), 59.1 (100).

1

2959, 2923, 1761, 1734 cm⁻¹; H NMR (400 MHz, CDCl₃) δ 5.45

(1H, br d, J = 5.4 Hz), 4.01 (1H, td, J = 5.1, 1.0 Hz), 3.85 (1H, s),

2.95−2.90 (1H, m), 2.42−2.28 (2H, m), 2.21 (1H, dd, J = 14.4, 5.2

Hz), 1.93−1.81 (4H, m), 1.73−1.65 (1H, m), 1.66 (3H, s), 1.54−1.33

(5H, m), 1.31 (3H, s), 1.09 (3H, s), 0.93 (3H, d, J = 6.9 Hz), 0.77

(3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 133.7, 121.2,

91.7, 81.4, 75.9, 74.3, 48.3, 48.2, 42.1, 39.8, 38.9, 36.3, 35.8, 28.4, 28.2,

22.6, 22.3, 22.0, 18.4, 15.6.

(1R,2R,6R,7R,8R,9S,12E)-6-Isopropyl-13-methyl-3-methyli-

dene-15-oxatricyclo[6.6.1.0^2,7]pentadec-12-en-9-ol (E-37). To a

ﬂask containing alcohol 42 (265 mg, 590 μmol), DMAP (359 mg, 2.94

mmol), and distilled triethylamine (1.48 g, 14.7 mmol) was added

freshly distilled acetic anhydride (3.00 g, 29.4 mmol). The resulting

solution was heated at 40 °C for 30 min before being cooled at 0 °C,

and the reaction was quenched by addition of a saturated aqueous

solution of ammonium chloride (10 mL) and diethyl ether (20 mL).

The aqueous phase was separated and extracted with diethyl ether (3

× 20 mL). The organic extracts were combined, washed with brine (20

mL), dried (MgSO₄), and concentrated in vacuo. The residue was

ﬁltered through a pad of silica gel (petroleum ether/ethyl acetate 10:1

with 1% Et₃N) to aﬀord crude acetate 45 as a colorless oil, which was

used without puriﬁcation in the next reaction.

(1R,2R,6R,7R,8R,9R,12E)-6-Isopropyl-9,13-dimethyl-3-meth-

ylidene-15-oxatricyclo[6.6.1.0^2,7]pentadec-12-en-9-ol (E-1). To

a solution of alcohol E-37 (80 mg, 0.27 mmol) in anhydrous

dichloromethane (12 mL) were added pyridine (87 mg, 1.1 mmol)

and Dess−Martin periodinane (175 mg, 410 μmol) at rt. The reaction

mixture was stirred at this temperature for 30 min before being

quenched with a saturated aqueous solution of sodium thiosulfate and

sodium bicarbonate (5:1, 6 mL). The mixture was diluted with diethyl

ether (20 mL) and stirred vigorously for 1 h. The aqueous phase was

separated and extracted with diethyl ether (3 × 10 mL). The organic

extracts were combined, washed with brine (10 mL), dried (MgSO₄),

and concentrated in vacuo. The residue was ﬁltered through a pad of

silica gel (petroleum ether/ethyl acetate 15:1) to aﬀord crude ketone,

which was used in the next step without puriﬁcation.

To a solution of crude acetate 45 in THF (30 mL) was added a 1 M

aqueous solution of HCl (630 μL, 630 μmol), and the solution was

stirred at rt for 1 h. The mixture was diluted with diethyl ether (30

mL) and water (30 mL), and the aqueous phase was then separated

and extracted with diethyl ether (3 × 20 mL). The organic extracts

To a solution of the above crude ketone in THF (10 mL) was

added sodium tetraﬂuoroborate (301 mg, 2.75 mmol) at rt. The

mixture was stirred at rt for 10 min and then cooled at −78 °C. A

U

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solution of methyllithium (0.52 mL of a 1.6 M solution in THF, 0.83

mmol) was added, and the reaction mixture was stirred at −78 °C for

30 min. The reaction was quenched by addition of a saturated aqueous

solution of NaHCO₃(5 mL), and the mixture was diluted with diethyl

ether (10 mL) and then allowed to warm to rt. The aqueous phase was

separated and extracted with diethyl ether (3 × 10 mL). The organic

extracts were combined, washed with brine (10 mL), dried (MgSO₄),

and concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (n-hexane/ethyl acetate 20:1) to deliver

alcohol E-1 (65 mg, 78% over two steps) as a colorless solid. R_f= 0.64

(petroleum ether/diethyl ether 1:1); mp 139−140 °C; [α]²_D⁶−37.6 (c

1.00, CHCl₃); ν_max(CHCl₃) 3427, 2957, 2930, 2915, 2874, 1643,

1448, 890 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.58 (1H, br s), 4.77

(1H, t, J = 2.0 Hz), 4.70 (1H, s), 4.01 (1H, br s), 3.74 (1H, s), 2.69

(1H, br s), 2.45 (1H, dd, J = 13.8, 5.4 Hz), 2.44−2.36 (1H, m), 2.25

(1H, dt, J = 12.9, 3.4 Hz), 2.20−2.05 (3H, m), 2.02 (1H, d, J = 13.8

Hz), 1.87 (3H, s), 1.86−1.80 (1H, m), 1.72 (1H, dddd, 12.9, 3.5, 3.5,

3.4 Hz), 1.70−1.63 (2H, m), 1.35−1.25 (2H, m), 1.17 (3H, br s), 1.03

(1H, qd, J = 12.9, 3.5 Hz), 0.95 (3H, d, J = 6.9 Hz), 0.75 (3H, d, J =

6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 146.8, 132.9, 124.8, 110.4,

92.3, 80.4, 75.3, 48.1, 46.3, 42.7, 39.0, 38.7, 31.5, 29.8, 28.2, 25.4, 24.5,

22.1, 20.6, 15.5; HRMS (EI) m/z calcd for C₂₀H₃₂O₂[M]⁺304.2402,

found 304.2401; LRMS (EI) m/z (% intensity) 304.3 (25), 286.3

(10), 243.2 (9), 219.2 (19), 179.1 (91), 59.1 (100).

HRMS (CI, isobutane) m/z calcd for C₂₂H₃₅O₄[M − OH]⁺363.2535,

found 363.2536; LRMS (CI, isobutane) m/z (% intensity) 363.4 (40),

321.4 (100), 303.4 (60).

(1R,2R,6S,8R,9R,13R,14R)-2,6-Dimethyl-13-isopropyl-10-

methylidene-15,16-dioxatetracyclo[6.6.1.1^2,6.0^9,14]hexadecane

(54).^12cTo a ﬂask containing alcohol E-1 (5.0 mg, 16 μmol) and p-

toluenesulfonic acid monohydrate (12 mg, 65 μmol) was added freshly

distilled isopropenyl acetate (1 mL). The mixture was stirred at rt for 3

h, and the reaction then was quenched with a saturated aqueous

solution of sodium bicarbonate (1 mL). The mixture was diluted with

ethyl acetate (2 mL), and the aqueous phase was separated and

extracted with ethyl acetate (3 × 3 mL). The organic extracts were

combined, washed with brine (3 mL), dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (petroleum ether/diethyl ether 20:1) to

deliver tetracyclic ether 54 (4.5 mg, 90%) as colorless solid. R_f= 0.58

(petroleum ether/diethyl ether, 6:1); mp 101−103 °C; [α]²_D⁵−8.5 (c

1.00, CHCl₃) {lit.^12c[α]_D²⁰−8.5 (c 0.07, CHCl₃)}; ν_max(CHCl₃) 2962,

1

2929, 2871, 1654, 1458, 1370, 1108, 1062, 991, 957, 884 cm⁻¹; H

NMR (500 MHz, CDCl₃) δ 4.65−4.63 (2H, m), 3.92−3.88 (1H, m),

3.64 (1H, s), 3.42 (1H, dd, J = 6.8, 6.8 Hz), 2.36 (1H, qt, J = 13.1, 4.0

Hz), 2.27−2.21 (2H, m), 2.13 (1H, dd, J = 14.3, 5.1 Hz), 1.97 (1H, br

t, J = 13.3 Hz), 1.90 (1H, dd, J = 14.3, 1.0 Hz), 1.80 (1H, dddd, J =

13.5, 4.1, 2.8, 1.3 Hz), 1.72−1.65 (2H, m), 1.56−1.51 (1H, m), 1.48−

1.33 (3H, m), 1.32 (3H, s), 1.28−1.20 (1H, m), 1.06 (3H, s), 0.96

(1H, qd, J = 13.0, 2.8 Hz), 0.94 (3H, d, J = 6.9 Hz), 0.76 (3H, d, J =

6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 149.8, 108.6, 93.8, 81.9, 75.7,

74.5, 50.3, 46.3, 45.2, 43.9, 39.9, 36.4, 35.9, 31.5, 29.6, 27.9, 24.8, 22.1,

18.4, 15.9; HRMS (CI, isobutane) m/z calcd for C₂₀H₃₃O₂[M + H]⁺

305.2481, found 305.2487; LRMS (CI, isobutane) m/z (% intensity)

305.5 (11), 140.3 (10).

(−)-Sclerophytin A (7).^12c,18,57To a solution of alcohol E-1 (4.0

mg, 13 μmol) in a mixture of THF and water (0.8 mL of a 1:1

mixture) at 0 °C were added NMO (15 μL of a 1.0 g/mL solution in

water, 0.13 mmol) and OsO₄(1.7 μL of a 4.0 wt % solution in water,

0.26 μmol). The reaction mixture was stirred at 0 °C for 1 h and then

at rt for 1 h. The reaction was then quenched by addition of a

saturated aqueous solution of sodium thiosulfate (2 mL), and the

mixture was stirred vigorously for 30 min before being diluted with

dichloromethane (2 mL). The aqueous phase was separated and

extracted with dichloromethane (3 × 3 mL). The organic extracts were

combined, washed with brine (3 mL), dried (MgSO₄), and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography on silica gel (n-hexane/ethyl acetate 4:1) to deliver

(−)-sclerophytin A (7) (2.6 mg, 59%) as colorless crystals. R_f= 0.23

(ethyl acetate/petroleum ether 2:1); mp 186−188 °C {lit.⁵⁷mp 187

°C, lit.¹⁸mp 185−186 °C}; [α]_D²⁵−6.2 (c 1.00, CHCl₃) {lit.¹⁸[α]²_D⁰

−3.0 (c 1.00, CHCl₃), lit.^12a[α]_D²⁰−2.7 (c 0.11, CHCl₃)}; ν_max3415,

2962, 2927, 797, 668 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 4.66 (1H,

br s), 4.64 (1H, br s), 4.56 (1H, br d, J = 5.8 Hz), 4.11 (1H, ddd, J =

10.8, 6.6, 3.8 Hz), 3.62 (1H, s), 2.97 (1H, dd, J = 7.7, 6.6 Hz), 2.30−

2.21 (2H, m), 2.16 (1H, dd, J = 10.1, 7.7 Hz), 2.06−1.96 (2H, m),

1.90−1.75 (2H, m), 1.75−1.50 (6H, m), 1.30−1.24 (2H, m), 1.20

(3H, s), 1.15 (3H, s), 1.05 (1H, qd, J = 12.5, 3.0 Hz), 0.96 (3H, d, J =

6.9 Hz), 0.79 (3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ

148.0, 109.3, 90.6, 80.2, 78.2, 75.0, 53.1, 45.4, 45.3, 43.8, 40.1, 31.7,

30.4, 29.4, 29.2, 24.9, 23.1, 22.1, 16.1; HRMS (CI, isobutane) m/z

calcd for C₂₀H₃₃O₃[M − OH]⁺321.2430, found 321.2433; LRMS

(CI, isobutane) m/z (% intensity) 321.4 (18), 303.4 (15), 287.4 (10).

(−)-Sclerophytin B (8).^12c,57To a solution of (−)-sclerophytin A

(7) (3.5 mg, 10 μmol) in anhydrous dichloromethane (0.5 mL) at 0

°C were added DMAP (1.3 mg, 10 μmol), distilled triethylamine (3.1

mg, 31 μmol), and distilled acetic anhydride (1.7 mg, 15 μmol). The

resulting solution was stirred for 30 min before being concentrated in

vacuo. The residue was puriﬁed by ﬂash column chromatography on

silica gel (n-hexane/ethyl acetate 5:1) to aﬀord (−)-sclerophytin B (8)

(3.0 mg, 79%) as a colorless solid. R_f= 0.60 (ethyl acetate/petroleum

ether 2:1); mp 186−188 °C {lit.⁵⁷190−192 °C}; [α]²_D⁵−19.4 (c 1.00,

CHCl₃); ν_max3434, 2935, 2960, 1707, 990 cm⁻¹; ¹H NMR (500 MHz,

CDCl₃) δ 5.63 (1H, br d, J = 4.8 Hz), 4.65 (1H, t, J = 2.0 Hz), 4.61

(1H, br s), 4.13 (1H, ddd, J = 11.2, 7.2, 3.8 Hz), 3.68 (1H, s), 3.02

(1H, dd, J = 7.2, 7.2 Hz), 2.36−2.21 (3H, m), 2.15−2.00 (4H, m),

2.08 (3H, s), 1.78−1.67 (4H, m), 1.57 (1H, br s), 1.43−1.37 (1H, m),

1.34−1.24 (1H, m), 1.23 (3H, s), 1.14 (3H, s), 1.01−0.98 (1H, m),

0.96 (3H, d, J = 6.9 Hz), 0.78 (3H, d, J = 6.9 Hz); ¹³C NMR (125

MHz, CDCl₃) δ 172.0, 148.0, 109.5, 90.7, 85.2, 78.1, 76.1, 75.0, 53.4,

45.6, 45.5, 43.7, 40.0, 31.7, 30.4, 29.2, 28.2, 24.9, 23.9, 22.1, 21.7, 15.7;

(+)-Deacetylpolyanthellin A (11).^15,17,58,59To a solution of

tetracyclic alkene 54 (3.2 mg, 10 μmol) in a mixture of THF and water

(1 mL of a 1:1 mixture) was added mercury(II) acetate (6.7 mg, 21

μmol) at rt. The mixture was stirred for 30 min, and then additional

mercury(II) acetate (6.7 mg, 21 μmol) was added. The resulting

mixture was stirred for 1 h, diluted with THF (2 mL), and cooled to

−20 °C before successive addition of a solution of triethylborane (136

μL of a 1.0 M solution in THF, 136 μmol) and solid sodium

borohydride (6.7 mg, 0.18 mmol). The resulting mixture was stirred

overnight and then diluted with diethyl ether (3 mL). The aqueous

phase was separated and extracted with diethyl ether (3 × 3 mL). The

organic extracts were combined, washed with brine (3 mL), dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

ﬂash column chromatography on silica gel (petroleum ether/ethyl

acetate 2:1) to deliver (+)-deacetylpolyanthellin A (11) (2.6 mg, 77%)

as a colorless oil (10:1 mixture of diastereomers). R_f= 0.44 (petroleum

ether/ethyl acetate 2:1); [α]²_D⁵+14.6 (c 0.86, CHCl₃) {lit.¹⁵[α]²_D⁵

+18.1 (c 0.29, CHCl₃), lit.⁵⁹[α]_D²⁵+19.4 (c 0.57, CHCl₃), lit.⁵⁸[α]²_D⁵

−11.0 (c 0.6, CHCl₃)}; ν_max(CHCl₃) 3437, 2960, 2929, 2872, 955,

1

813 cm⁻¹; H NMR (500 MHz, CDCl₃) δ 3.87 (1H, dd, J = 5.3, 5.1

Hz), 3.58 (1H, s), 2.89−2.83 (1H, m), 2.42−2.29 (2H, m), 2.18 (1H,

dd, J = 14.2, 5.1 Hz), 1.85 (1H, d, J = 14.2 Hz), 1.81−1.74 (1H, m),

1.68 (1H, dqd, J = 6.8, 6.8, 2.2 Hz), 1.55−1.33 (9H, m), 1.29 (3H, s),

1.19 (3H, s), 1.18−1.12 (1H, m), 1.06 (3H, s), 0.93 (3H, d, J = 6.9

Hz), 0.82 (3H, d, J = 6.9 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 93.3,

78.6, 75.6, 74.4, 70.4, 53.9, 47.7, 42.4, 41.8, 39.8, 36.6, 36.0, 33.8, 29.8,

29.7, 27.6, 22.0, 18.4, 17.5, 16.0; HRMS (CI, isobutane) m/z calcd for

C₂₀H₃₅O₃[M + H]⁺323.2586, found 323.2583; LRMS (CI,

isobutane) m/z (% intensity) 323.3 (9), 305.5 (18), 113.3 (15).

(+)-Polyanthellin A (12).^{15,17,34,58,59}To a ﬂask containing

(+)-deacetylpolyanthellin A (11) (2.6 mg, 8.0 μmol), DMAP (5.0

mg, 40 μmol), and distilled triethylamine (41 mg, 0.40 mmol) was

added freshly distilled acetic anhydride (44 mg, 0.40 mmol). The

resulting solution was stirred at rt for 1 h, then cooled at 0 °C, and the

reaction was quenched by addition of a saturated aqueous solution of

sodium bicarbonate (1 mL) and diethyl ether (2 mL). The aqueous

phase was separated and extracted with diethyl ether (3 × 2 mL). The

organic extracts were combined, washed with brine (2 mL), dried

(MgSO₄), and concentrated in vacuo. The residue was puriﬁed by

V

dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

ﬂash column chromatography on silica gel (petroleum ether/ethyl

acetate 30:1) to aﬀord (+)-polyanthellin A (12) (1.6 mg, 55%) as a

colorless oil. R_f= 0.60 (petroleum ether/ethyl acetate 4:1); [α]²_D⁴+9.0

(c 0.40, CHCl₃) {lit.¹⁵[α]_D²⁰+10.5 (c 0.31, CHCl₃), lit.⁵⁹[α]²_D⁵+8.9 (c

0.22, CHCl₃), lit.⁵⁸[α]_D²⁵−9.9 (c 1.0, CHCl₃), lit.³⁴[α]²_D⁵+8.0 (c 0.75,

CHCl₃), lit.¹⁷[α]_D²⁵+9.9 (c 0.085, CHCl₃)}; ν_max(CHCl₃) 2952, 2927,

(9) (a) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,

117, 10391. (b) MacMillan, D. W. C.; Overman, L. E.; Pennington, L.

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L. A. Org. Lett. 2000, 2, 1879.

1

2896, 2875, 2363, 1731, 956 cm⁻¹; H NMR (500 MHz, CDCl₃) δ

3.91−3.89 (1H, m), 3.54 (1H, s), 3.23−3.19 (1H, m), 2.45−2.40 (1H,

m), 2.40−2.31 (1H, m), 2.30 (1H, dd, J = 10.4, 7.6 Hz), 2.19 (1H, dd,

J = 14.3, 5.0 Hz), 2.00 (3H, s), 1.86 (1H, d, J = 14.3 Hz), 1.79−1.76

(1H, m), 1.69−1.62 (1H, m), 1.55−1.47 (1H, m), 1.48 (3H, s), 1.47−

1.34 (4H, m), 1.33 (3H, s), 1.25−1.20 (1H, m), 1.19−1.15 (2H, m),

1.08 (3H, s), 0.92 (3H, d, J = 6.9 Hz), 0.80 (3H, d, J = 6.9 Hz); ¹³C

NMR (125 MHz, CDCl₃) δ 170.5, 93.9, 83.3, 77.6, 75.7, 74.5, 51.2,

47.7, 42.5, 41.8, 39.8, 36.4, 35.8, 29.9, 29.8, 27.7, 24.2, 22.7, 21.8, 18.3,

17.7, 15.7; HRMS (EI) m/z calcd for C₂₀H₃₂O₂[M − AcOH]⁺

304.2402, found 304.2398; LRMS (EI) m/z (% intensity) 304.3 (100),

261.2 (13), 243.2 (18), 219.2 (19), 179.1 (22).

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Org. Chem. 2006, 71, 1172.

́

B.; St. Jean, D. J., Jr. J.

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10264. (b) Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127,

17200. (c) Crimmins, M. T.; Brown, B. H.; Plake, H. R. J. Am. Chem.

Soc. 2006, 128, 1371. (d) Crimmins, M. T.; Ellis, J. M. J. Org. Chem.

2008, 73, 1649. (e) Crimmins, M. T.; Mans, M. C.; Rodríguez, A. D.

Org. Lett. 2010, 12, 5028. (f) Crimmins, M. T.; Stauffer, C. S.; Mans,

M. C. Org. Lett. 2011, 13, 4890.

ASSOCIATED CONTENT

* Supporting Information

Details of DFT calculations; X-ray crystallographic data for

■

S

1

compounds ( )-40, 9, and E-1; copies of H and ¹³C NMR

(15) Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.

spectra for compounds Z-1, E-1, 2−12, (+)-14−26, Z-30, E-

30, Z-33, E-33, Z-35−Z-37, ( )-E-35, E-36, E-37, ( )-39,

( )-40, E-41, 42, ( )-43, ( )-44, 49, 51, and 54. This

material is available free of charge via the Internet at http://

pubs.acs.org.

2006, 128, 15851.

(16) Becher, J.; Bergander, K.; Frohlich, R.; Hoppe, D. Angew. Chem.,

Int. Ed. 2008, 47, 1654.

̈

(17) (a) Campbell, M. J.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131,

10370. (b) Campbell, M. J.; Johnson, J. S. Synthesis 2010, 2841.

(18) Wang, B.; Ramirez, A. P.; Slade, J. J.; Morken, J. P. J. Am. Chem.

Soc. 2010, 132, 16380.

(19) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3367.

(20) For our preliminary results concerning the total synthesis of

cladiellin natural products, see (a) Clark, J. S.; Hayes, S. T.; Wilson,

C.; Gobbi, L. Angew. Chem., Int. Ed. 2007, 46, 437. (b) Clark, J. S.;

Berger, R.; Hayes, S. T.; Thomas, L. H.; Morrison, A. J.; Gobbi, L.

Angew. Chem., Int. Ed. 2010, 49, 9867.

AUTHOR INFORMATION

Corresponding Author

*E-mail stephen.clark@glasgow.ac.uk.

■

Notes

The authors declare no competing ﬁnancial interest.

(21) (a) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108,

6060. (b) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108,

6062.

ACKNOWLEDGMENTS

■

We thank Dr Marc Schmidtmann for providing X-ray crystal

data for compound ( )-40. We are grateful to EPSRC and F.

Hoﬀmann-La Roche Ltd. for funding to support a studentship

for S.T.H. We thank MSD, WestCHEM, and the University of

Glasgow for ﬁnancial support to fund a studentship for R.B. We

acknowledge funding from EPSRC for support of this project

(Grants GR/T21905/01 and/02). In addition, we thank

Novartis for the award of the European Young Investigator

Award to J.S.C., the funding from which partly supported this

work.

(22) For reviews concerning metal carbenoid reactions and covering

the generation of oxonium ylide-type species, see (a) Doyle, M. P.

Chem. Rev. 1986, 86, 919. (b) Adams, J.; Spero, D. M. Tetrahedron

1991, 47, 1765. (c) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48,

5385. (d) Doyle, M. P.; McKervey, M.; Ye, T. Modern Catalytic

Methods for Organic Synthesis with Diazo Compounds; Wiley: New

York, 1998. (e) Clark, J. S. Nitrogen, Oxygen and Sulfur Ylide Chemistry;

Oxford University Press: New York, 2002; Chapt. 1, pp 22−39.

(f) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027.

(23) (a) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. (b) Clark, J. S.;

Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385. (c) Clark,

J. S.; Dossetter, A. G.; Blake, A. J.; Li, W.-S.; Whittingham, W. G.

Chem. Commun. 1999, 749. (d) Clark, J. S.; Whitlock, G.; Jiang, S.;

Onyia, N. Chem. Commun. 2003, 2578. (e) Clark, J. S.; Walls, S. B.;

Wilson, C.; East, S. P.; Drysdale, M. J. Eur. J. Org. Chem. 2006, 323.

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dx.doi.org/10.1021/jo302542h | J. Org. Chem. XXXX, XXX, XXX−XXX

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Total syntheses of multiple cladiellin natural products by use of a completely general strategy

DOI: 10.1021/jo302542h

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