General diastereoselective synthetic approach toward isospongian diterpenes. Synthesis of (-)-marginatafuran, (-)-marginatone, and (-)-20-acetoxymarginatone

Article

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General Diastereoselective Synthetic Approach toward Isospongian

Diterpenes. Synthesis of (−)-Marginatafuran, (−)-Marginatone, and

(−)-20-Acetoxymarginatone

Antonio Gris,^†Nuria Cabedo,^‡Ismael Navarro,^†Ignacio de Alfonso,^†Consuelo Agullo,^†

́

and Antonio Abad-Somovilla*^,†

^†Departamento de Química Organ

́

ica, Facultad de Química, Universidad de Valencia, Dr Moliner 50, 46100 Burjassot, Valencia, Spain

nica de Valencia, Campus de Vera, Ediﬁcio 6C, 46022 Valencia, Spain

^‡Centro de Ecología Química Agrícola, Universidad Politec

́

S

* Supporting Information

ABSTRACT: This work describes a synthetic approach to the

carbocyclic skeleton of isospongian diterpenes that uses the

commercially available monoterpene (S)-carvone as a C-ring

synthon, which is incorporated into the tetracyclic isospongian

framework via a C→ABC→ABCD ring annulation strategy using

intramolecular Diels−Alder and ring-closing metathesis reac-

tions. This approach has been successfully used to prepare both

the title natural isospongians and several nonnatural oxygenated

analogues. A preliminary evaluation of the inhibitory activity of

the small collection of synthesized isospongians on the mammalian mitochondrial respiratory chain revealed that most were able

to inhibit the integrated electron transfer chain (NADH oxidase activity) in the micromolar range.

INTRODUCTION

■

A remarkable collection of terpenoid compounds has been

isolated from diﬀerent marine organisms, primarily sponges and

nudibranchs, over the last three decades.^1,2Among them is a

small group of diterpenic compounds that share the tetracyclic

isospongian carbon skeleton 1,³which has a 2,3-fused

tetrahydrofuran ring instead of the 3,4-fused tetrahydrofuran

ring normally found in the more common spongian diterpenes

(2) (Figure 1).⁴⁻⁶

Figure 2.

isolated from the sponge Aplysilla polyrhaphis,¹⁰marginatone

(5), which was isolated from the sponge Aplysilla glacialis,¹¹and

its derivative 20-acetoxymarginatone (6), which was isolated

from skin extracts of the nudibranch Cadlina luteomarginata.⁹

Isospongian diterpenes are not the only terpene-type

compounds of marine origin with an octahydronaphtho[1,2-

b]furan or octahydronaphtho[1,2-b]furan-2-one system form-

ing part of their structure, as a large number of sesquiterpenes

and sesterterpenes with these structural characteristics are also

Figure 1.

Marginatafuran (3) (Figure 2), the ﬁrst example of an

isospongian-type diterpenoid, was isolated in 1985 from skin

extracts of the northwestern Paciﬁc common dorid nudibranch

Cadlina luteomarginata.^7,8This is a delicate, shell-less mollusk

that primarily feeds on a variety of sponges to obtain selected

metabolites that are stored in its dorsal glands and skin as a

defense against predator attacks. In fact, this compound was

later found in the extract of a sponge belonging to the genus

Aplysilla, a normal part of this nudibranch’s diet.⁹Other

examples of these diterpenes are polyrhaphin D (4), which was

Received: April 23, 2012

Published: June 7, 2012

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known, many of which possess diverse biological activities.^1,12,13

Representative examples of these compounds are furanosesqui-

terpene pallescensin A¹⁴(7) and furanosesterterpene furo-

scalarol (8).¹⁵

Scheme 1. C→ABC→ABCD Approach Used To Prepare

Isospongian-Type Diterpenes

The synthesis of isospongians has been the objective of

various research groups, and several syntheses of the

isospongian framework have been described. Indeed, the

isospongian skeleton was synthesized before the ﬁrst isolation

of a naturally occurring example by Sharma during his studies

on the biomimetic cyclization of ambliofuran.¹⁶Nishizawa¹⁷

and, more recently, Loh¹⁸have also prepared the furanoiso-

spongian skeleton via biomimetic-like oleﬁn and epoxide-

initiated cyclizations, respectively. In the early 1990s, Zoretic

used the Mn(III)-mediated oxidative free-radical cyclization of

a polyene to prepare a tricyclic system that transformed into an

nonnatural isospongian compound after subsequent elaboration

of the furan ring.¹⁹Finally, Ragoussis and co-workers have

recently described the ﬁrst and only synthesis of a natural

isospongian, (−)-marginatone (5), using the labdane-type

diterpene (+)-coronarin E as the starting material and a

stereocontrolled, intramolecular electrophilic cyclization as the

key synthetic step.²⁰

In this paper, we describe a general approach for the

synthesis of isospongian diterpenes as a continuation of our

previous work on synthesizing spongian diterpenes.²¹The

purpose of our work was not only to synthesize the most

representative of these natural diterpenes but also to prepare

the related nonnatural analogues and create a small collection

of isospongian-like compounds with diverse functionalities for

biological activity screening. As far as we know, despite the

diverse biological activities of the structurally related

furanosesquiterpenes and furanosesterterpenes as well as

regioisomeric spongian diterpenes,²²the biological activities

of compounds of this type have not yet been investigated.

angular methyl group, speciﬁcally, marginatone (5), and several

novel nonnatural analogs. The synthesis of these compounds

started with the preparation of the required hydrophenan-

threnone derivative, 18, from (S)-(+)-carvone (Scheme 2).

Therefore, the known dialkylated epoxy carvone 14, which was

obtained from (S)-carvone at an overall yield of 68% after two

consecutive alkylation reactions using MeI and 3-iodopropa-

naldehyde diethyl acetal followed by the subsequent stereo-

selective epoxidation of the enone moiety with alkaline

hydrogen peroxide,²⁶was transformed into dicarbonyl com-

pound 15 via the acid hydrolysis of the diethyl acetal with

pyridinium p-toluenesulfonate (PPTS) in aqueous acetone. The

chemoselective Horner−Wadsworth−Emmons oleﬁnation re-

action of the aldehyde group in 15 with the sodium salt of 2-

(diethoxyphosphoryl)-3-oxobutane (generated in situ from the

reaction of the corresponding diethylphosphonate and sodium

hydride) in THF at room temperature (rt) stereoselectively

produced the (E)-enone 16,²⁷which aﬀorded dienol silyl ether

17 via the subsequent TBDMS triﬂate and Et₃N treatment

under standard kinetic conditions with nearly 61% overall yield

over the ﬁnal three steps. Dienol silyl ether 17 underwent a

stereoselective intramolecular Diels−Alder (IMDA) reaction at

190−200 °C in toluene over 7 days in the presence of

propylene oxide as an acid scavenger to yield Diels−Alder

adduct 18 in very high yield after chromatographic puriﬁcation.

After completing the ABC ring system of the isospongian

framework and before preparing the D ring, enol silyl ether 18

was subjected to Simmons−Smith cyclopropanation reaction

conditions to cyclopropanate the A-ring double bond, a

transformation that was required to form the geminal dimethyl

group at C-4 in the target compounds.

RESULTS AND DISCUSSION

■

As the retrosynthetic analysis in Scheme 1 illustrates, we

considered compounds such as 9 as good intermediates for the

synthesis of these compounds. This key synthetic intermediate

possesses adequate functionalities for completing the diterpe-

noid isospongian framework and introducing a variety of

oxygenated groups at various positions, such as those

characteristic of natural isospongians. Therefore, the 2,5-

dihydrofuran ring can be used to prepare the D-ring of furano-

and lactone-isospongians via the dehydrogenation of either the

dihydrofuran ring or allylic oxidation, respectively. The

oxygenated function at C-12 (diterpene numbering) and the

tert-butyldimethylsilyloxy cyclopropane ring are convenient for

managing not only the functionalization of the C and A rings

but also the C-17 position of the isospongian system.²³The

2,5-dihydrofuran moiety in 9 could be prepared via ring-closing

metathesis (RCM) using dioleﬁn 10, which would be derived

from an appropriately substituted trans-anti-trans-hydrophenan-

threnone system, such as 11, that could conceivably be

prepared in an enantiomerically pure form from (S)-

(+)-carvone (12) using well-established methodology.^24,25It

must be noted that the synthesis of isospongian systems

functionalized at the C-20 position, e.g., 3 and 6, requires that

this position is functionalized at the beginning of the synthesis,

which could, in principle, be accomplished via the allylic

oxidation of the isopropylene group in carvone.

We began our work by using this synthetic strategy to

prepare isospongians that were not functionalized at the C-10

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With compound 19 in hand, we focused on preparing the D

ring of the isospongian skeleton. After exploring several

possibilities, all of which were based on ﬁrst opening the

methyloxirane moiety in 19 to form an allylic alcohol, we

discovered that a good means for achieving this task was via the

RCM of a bis-allyl ether such as 22. First, ketone 19 was

stereoselectively reduced under Luche conditions to the

equatorial alcohol 20,³⁰which was then allylated using allyl

bromide and sodium hydride with a catalytic amount of

tetrabutylammonium iodide (TBAI) to yield allyl ether 21.

Subsequent treatment of this compound with N,N-diethylalu-

minum tetramethylpiperidide (Et₂AlTMP) in benzene at 0 °C

promoted the desired eliminative ring-opening of the epoxide

moiety to aﬀord the allylic alcohol 22 in 83% overall yield from

ketoepoxide 19. The ﬁrst attempt to perform this RCM

reaction using Grubbs’ second-generation catalyst [(1,3-

dimesityl-2-imidazolylidene)(PCy₃)Cl₂RuCHPh] in reﬂux-

ing CH₂Cl₂resulted in a modest (55−60%) yield of the

cyclized product. The low yield was caused partly by

competitive homodimerization; however, the primary cause

was the isomerization of the allyloxy moiety to an E/Z mixture

of vinyl ethers.³¹These side reactions could be almost entirely

suppressed by diluting the reaction mixture (0.02 M in

CH₂Cl₂) and adding 20% of 1,4-benzoquinone.³²Under such

conditions, the RCM took less than 1 h under reﬂux to

complete, resulting in a 90% yield of 2,5-dihydrofuran

derivative 23 after the chromatographic puriﬁcation of the

crude product.³³

Scheme 2. Synthesis of the Tricyclic ABC System 18

The dehydrogenation of the dihydrofuran ring in 23 was

accomplished using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DDQ) in anhydrous benzene at rt. The oxidative aromatiza-

tion of 23 using DDQ provided the desired furan 24 in 87%

yield.³⁴The hydroxyl group in 24 was oxidized to the

corresponding carbonyl group using tetrapropylammonium

perruthenate (TPAP) and 4-methylmorpholine N-oxide

(NMO) in the presence of powdered 4 Å molecular sieves

before opening the cyclopropane ring to complete the geminal

dimethyl group at C-4. Attempts to open the tert-

butyldimethylsilyloxy cyclopropane moiety in 25 using PTSA

in reﬂuxing CHCl₃under the conditions used to previously

open a related system³⁵formed a complex mixture of products.

This result was attributed to the furan ring being incompatible

This reaction was more troublesome than initially expected,

and a good yield for the cyclopropanated product was only

achieved when a large excess of the Furukawa reagent

(EtZnCH₂I),²⁸which was prepared using a 1:1 stoichiometry

of Et₂Zn to CH₂I₂,²⁹was used in toluene at 0 °C (Scheme 3).

The reaction was stereoselective for the less hindered α-side of

the double bond under these conditions and aﬀorded

cyclopropanated derivative 19 with an excellent yield of 95%.

Scheme 3. Synthesis of the Isospongian Skeleton

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with these conditions. Therefore, an alternative, two-step

procedure involving milder conditions was used to achieve

this transformation. First, compound 25 was treated with an

HF−pyridine complex in acetonitrile at 0 °C to remove the

TBDMS protecting group, and the resulting cyclopropanol was

subjected to a ring-opening reaction using two equivalents of

NaOH in a 4:1 mixture of dioxane−H₂O under reﬂux in a

strictly oxygen-free atmosphere.³⁶Under these conditions, the

transformation of compound 25 into isospongian-3,12-dione

(26) was achieved with an excellent overall yield of 91%.

Having completed the isospongian framework, we were

ready to make the necessary functional group modiﬁcations to

form marginatone (5) (Scheme 4). This was successfully

corresponding tricyclic systems started with the allylic

chlorination of the isopropenyl group in compound 14 using

sodium hypochlorite in the presence of cerium trichloride

heptahydrate as the Lewis acid catalyst in a CH₂Cl₂and water

biphasic system.³⁷The reaction proceeded rapidly at 0 °C

without any noticeable hydrolysis of the labile diethyl ketal

group to form chloride derivative 29 in high yield (Scheme

5).³⁸

Scheme 5. Synthesis of the Tricyclic ABC System

Functionalized at the Angular Position

Scheme 4. Synthesis of the Isospongian Diterpene

(−)-Marginatone (5)

accomplished by taking advantage of the diﬀerent electronic

natures at the C-3 and C-12 positions. First, both of the

carbonyl groups in 26 were stereoselectively reduced under

Luche conditions to give isospongian-3β,12β-diol (27). The

hydroxyl group at the C-12 position was then chemoselectively

oxidized to form a keto group using activated manganese

dioxide in CHCl₃at rt. Both transformations occurred

eﬀectively to provide 3β-hydroxyisospongian-12-one (28) in

90% yield. Finally, the reduction of the hydroxyl moiety in the

C-3 position, which completes the synthesis of the target

natural isospongian, was accomplished via a radical deoxyge-

nation of the corresponding thionocarbonate derivative.

Therefore, 28 was treated with pentaﬂuorophenyl chlorothio-

formate in CH₂Cl₂in the presence of DMAP to yield the O-

(perﬂuorophenoxy)carbonothioyl derivative that, when reacted

with tributyltin hydride−azoisobutyronitrile in boiling benzene,

produced 5, which had physical and spectroscopic properties

consistent with those reported for (−)-marginatone, with a

79% overall yield.^9,11

Having successfully synthesized marginatone, we attempted

to use the same synthetic strategy to prepare isospongian

systems functionalized at the angular C-20 position by focusing

on the natural isospongians marginatafuran (3) and 20-

acetoxymarginatone (6) as the primary synthetic targets.

The ﬁrst step to achieving this goal was to prepare a tricyclic

system, such as 11 (see Scheme 1), that possessed an adequate

functionality in the angular R¹group to prepare the required C-

20 functionalization in the target isospongians.

This allylic chloride was oxidized to the corresponding α,β-

unsaturated aldehyde by treating with N-ethylmorpholine N-

oxide (NEMO)³⁹and a catalytic amount of LiI in DMF at 55

°C.⁴⁰This procedure worked more eﬃciently than those based

on Kornblum oxidation⁴¹(DMSO and NaHCO₃at 90 °C;

DMSO−MeNO₂and AgBF₄at rt) and aﬀorded aldehyde 30 in

74% yield along with the corresponding alcohol, 30a (9%), and

formate, 30b (7%), derivatives,⁴²which were further trans-

formed into the aldehyde via either oxidation (TPAP, NMO, 5

Å MS, CH₂Cl₂, rt, 80%) or hydrolysis−oxidation (Na₂CO₃,

MeOH, rt, 98% then TPAP, NMO, 5 Å MS, CH₂Cl₂, rt, 78%)

reactions, respectively. Next, aldehyde 30 was oxidized to

carboxylic acid 31 via the reaction with sodium chlorite in a

A carboxylate group was chosen as the most appropriate of

the various options available. The preparation of the

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Scheme 6. Synthesis of the Isospongian Diterpene (−)-Marginatafuran (3)

NaH₂PO₄-buﬀered solution in the presence of 2-methyl-2-

butene as a chlorine scavenger and methylated with diazo-

methane to produce methyl ester 32 in a 95% overall yield for

the last two steps.

the irradiation of both the AB-ring fusion proton H-4a (δ 2.97

ppm) and the axial methyl group at C-6a (δ 0.841 ppm) caused

a weak (less than 1%) but signiﬁcant increase in the intensity of

the methyl ester group (δ 3.27 ppm).⁴⁶

The remaining steps to form the 1,3,9-decatriene, which was

required for the IMDA reaction, from methyl ester 32 involved

the hydrolysis of the diethyl ketal moiety to the aldehyde

followed by Wittig oleﬁnation to generate the methyl trans-

enone and ﬁnally, the formation of the kinetic dienol silyl ether

function. Except for the oleﬁnation reaction, which was

performed using 3-(triphenylphosphoranylidene)butan-2-one

as the Wittig reagent,^43,44the remaining steps were performed

under basically identical conditions to those used to transform

13 into 17. All of the reactions proceeded satisfactorily to

produce dienol silyl ether 35 in 86% overall yield for all three

steps.

As expected, the IMDA reaction of the α,β-unsaturated ester

35 proceeded under milder conditions and was more rapid than

that of 17; in this case, the IMDA reaction was completed upon

heating a solution of 35 in toluene to 140 °C for 4 days. This

reaction occurred with a very high yield; however, unlike the

results obtained for the related reaction of 17, it led to an 87:13

mixture of the trans-anti-trans and cis-anti-trans fused adducts

36 and 37, respectively.⁴⁵Although the diastereomeric adducts

could not be easily separated via conventional column

chromatography, the desired major adduct 36 was obtained

nearly pure via crystallization from hexanes in a yield of

approximately 60%. The minor diastereomeric adduct 37 was

obtained for analytical purposes via preparative reversed-phase

HPLC of the residue from the crystallized mother liquor, which

was an approximately 1:1 mixture of both adducts. The

structure and stereochemistry of the two adducts were

established via conventional NMR; the trans-anti-trans adduct

36 showed the same ¹H and ¹³C NMR signal patterns as those

of 18 except for the expected modiﬁcations associated with the

diﬀerent functionalization of the angular position. The cis-anti-

trans stereochemistry of the minor adduct 37 was inferred from

its ¹³C NMR data and later conﬁrmed via NOE experiments

that showed, as expected for the proposed stereochemistry, that

Having completed the preparation of the isospongian ABC

core system, i.e., compound 36, we then proceeded to build the

furan ring and elaborate the geminal dimethyl group in the A

ring. As summarized in Scheme 6, the reaction sequence used

to eﬀect these transformations was identical to that previously

used for the noncarboxylated tricyclic system 18, with a few

minor modiﬁcations. The most noteworthy modiﬁcation was

the change to the reagent used during the TBDMS

deprotection step; in this case, we used aqueous hexaﬂuor-

osilicic acid in MeCN at 4 °C, which not only led to a very

smooth hydrolysis of the silyl ether moiety in 43 but also to a

nearly quantitative yield for the corresponding cyclopropanol

intermediate. Having optimized the reaction conditions for

each step, the transformation of Diels−Alder adduct 36 into the

C-20-functionalized isospongian 45 was accomplished via this

eight-step sequence, which resulted in a 60% overall yield.

The remaining transformations required to complete the

synthesis of the target natural isospongians only required an

apparently simple manipulation of the functional groups in 45.

Initially, we examined the transformation of this intermediate

into marginatafuran (3), which required reducing the C-3 and

C-12 carbonyl groups to the corresponding methylenes. After

evaluating several methods that use relatively mild reaction

conditions to produce this reduction,⁴⁷we found that treating

45 with the rather harsh classical Wolﬀ−Kishner reaction

conditions (hydrazine and diethylene glycol at 120 °C then

potassium hydroxide at 185 °C for 8 h) not only reduced both

carbonyl groups to the methylene but also hydrolyzed the ester

group at C-20 to produce 3 with a moderate yield of 61%. This

synthesized 3 possessed nearly identical physical and spectral

properties to those reported for the natural (−)-marginatafuran

product.⁷

The synthesis of the last natural isospongian target,

compound 6, from 45 proved to be somewhat more elaborate.

As in the synthesis of marginatone (5) above, the selective

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Scheme 7. Synthesis of the Isospongian Diterpene (−-)-20-Acetoxymarginatone (6)

reduction of the C-3 carbonyl group to a methylene was

indirectly accomplished through a four-step process (Scheme

7) involving the stereoselective reduction of both carbonyl

groups to the corresponding equatorial alcohols, the chemo-

selective oxidation of the benzylic hydroxyl group to a keto

group, and ﬁnally, the free-radical reductive deoxygenation of

the remaining C-3 hydroxyl after its derivatization to the

corresponding thionocarbonate. This four-step reduction of the

C-3 carbonyl group to methylene produced keto ester 48 with

an overall yield of approximately 83% from the key

intermediate, 45.

In addition to the synthetic work, most of the prepared

isospongians were assayed for inhibition of the bovine heart

mitochondrial respiratory chain as a ﬁrst evaluation of the

potential biological activity of these compounds.⁵¹Many of the

tested compounds were able to inhibit the integrated electron

transfer chain, which includes respiratory complexes I, III, and

IV (NADH oxidase activity), in the micromolar range with IC₅₀

values ranging from 1.04 μM for both marginatone (5) and 48

to 9.5 μM for 47 (Table 1). These compounds showed a

Table 1. IC₅₀Values of Some Isospongian Diterpenes

a

against Their NADH Oxidase Activity

The necessary reduction of the hindered C-20 methox-

ycarbonyl group to a hydroxymethylene group was not easy,

and it was necessary to evaluate various reaction conditions to

ﬁnd an appropriate one. The treatment of keto ester 48 with a

LiAlH₄·2THF complex in THF at low temperature followed by

reﬂuxing exclusively reduced the C-12 keto group even after

reﬂuxing overnight. Unexpectedly, changing the solvent to

bis(2-methoxyethyl) ether (diglyme) and heating to 120 °C for

5 h only led to the reduction of the carbonyl group and the

hydrolysis of the methyl ester moiety to produce hydroxy acid

49 (12-hydroxymarginatafuran) in 69% yield as the only

identiﬁed product after chromatographic puriﬁcation of the

crude product.⁴⁸Finally, we found that changing the solvent

from diglyme to toluene and heating at 120 °C for 8 h reduced

both the keto and carboxylate groups to give diol 50 in high

yield. A byproduct identiﬁed as compound 51 was also isolated

in small, variable amounts in some of the runs of this

reaction.^49,50It was found after some experimentation that

performing the reduction of 48 with an excess of LiAH₄·2THF

under the reaction conditions speciﬁed above but in the

presence of 3−4 equiv of 6,7-dihydrobenzofuran-4(5H)-one

(see the Experimental Section) resulted in no observable

formation of compound 51.

compd

IC₅₀(μM)

3

5

6

2.5 0.4

1.04 0.09

4.4 1.1

1.8 0.8

b

25a

26

>10

27

>10

28

45

46

47

9.5 1.1

48

1.04 0.13

3.7 1.1

1.2 0.3

2.49 0.15

1.4 0.9

5.4 1. 8

49

50

51

c

51 acetate

52

a

Data are the means

the SD for three determinations of each

b

compound. Cyclopropanol intermediate derived from the HF-Py

c

treatment of 25 (i.e., 25 with R¹= H and R²= O). Prepared by

treating 51 with Ac₂O, DMAP, and Et₃N in CH₂Cl₂.

Having successfully prepared 50, the synthesis of (−)-20-

acetoxymarginatone (6) was then accomplished using two ﬁnal,

conventional operations. First, the oxidation of the secondary

alcohol in 50 with activated MnO₂to produce hydroxy ketone

52 followed by the acetylation of the primary hydroxyl group to

aﬀord 6, which was spectroscopically identical to that isolated

from natural sources.

midrange potency relative to the most potent respiratory chain

inhibitors, for example, Annonaceous acetogenins such as

bullatacin (IC₅₀of 0.8 nM)⁵²and the classic inhibitor rotenone

(IC₅₀of 5.1 nM),⁵³which are considered to be potent

antitumor agents. Analysis of the data presented in Table 1

indicates that a lack of oxygenated substituents at the C-3

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10.8, 5.0 Hz, H-4), 2.282 (3H, s, Me-C_5′), 2.27 (1H, m, H-2′), 2.26

(1H, ddd, J = 15.2, 4.9, 2.7 Hz, H-5α), 2.16 (1H, ddd, J = 15.2, 10.8,

1.6 Hz, H-5β), 2.04 (1H, m, H′-2′), 1.84 (1H, ddd, J = 13.6, 12.1, 4.5

Hz, H-1′), 1.764 (3H, s, Me-C_2′′), 1.746 (3H, s, Me-C_4′), 1.60 (1H,

ddd, J = 13.6, 11.8, 5.1 Hz, H′-1′), 1.420 (3H, s, Me-C₁), 0.999 (3H, s,

Me-C₃); ¹³C NMR (CDCl₃, 75 MHz) δ 212.8 (C_5′), 209.6 (C₂), 144.0

(C_2′′), 143.0 (C_3′), 137.7 (C_4′), 115.5 (C_1′′), 60.9 (C₆), 58.5 (C₁), 49.6

(C₃), 40.5 (C₄), 35.5 (C_1′), 26.4 (C₅), 25.4 (Me-C_5′), 24.4 (C_2′), 23.3

(Me-C_2′′), 21.0 (Me-C₃), 16.3 (Me-C₁), 11.1 (Me-C_4′); MS (EI) m/z

290 (M⁺, 1.7), 218 (11), 180 (58), 165 (51), 164 (30), 163 (52), 137

(74), 112 (83), 111 (100); HRMS m/z calcd for C₁₈H₂₆O₃290.1882,

found 290.1862.

position improved the activity against NADH oxidase as a

general trend, while the various oxygenated functional groups at

C-12 and C-20 did not drastically change the activity even

though they may contribute to its modulation.

EXPERIMENTAL SECTION

■

General Features. See the Supporting Information.

Biological Assay Procedures. Stock solutions (30 mM in

absolute EtOH) of the tested compounds were prepared and stored

in the dark at −20 °C. Inverted submitochondrial particles (SMP)

from beef heart were obtained via Fato’s method 52,⁵⁴which involved

the ultrasonic disruption of frozen−thawed mitochondria to produce

open membrane fragments that lost the permeability barriers to the

substrates and stored at −70 °C at 28 mg/mL (protein measured by

the Biuret method). The beef heart SMP were transferred to glass test

tubes, diluted to 0.5 mg/mL with 250 mM sucrose and 10 mM Tris-

HCl buﬀer, pH 7.4, and treated with 300 μM NADH to activate

complex I before starting experiments. Aliquots of the stocks solutions

(1 μL) were successively added to 500 μL of the SMP preparations

followed by 5 min incubation on ice (ethanol never exceeded 2% of

the total volume). After each incubation, an aliquot of the SMP (25

μL) was diluted to 6 μg/mL in 50 mM potassium phosphate buﬀer

(pH 7.4) and 1 mM EDTA in a cuvette at 22 °C in the presence of 75

μM NADH. Immediately, NADH oxidase activity was measured as the

aerobic oxidation of NADH. Reaction rates were calculated for each

inhibitor (at increasing concentrations) by spectrophotometrically

measuring the linear decrease in NADH concentration (λ 340 nm, ε

6.22 mM⁻¹cm⁻¹). The inhibitory concentration (IC₅₀) was taken as

the concentration in the assayed cuvette that yielded 50% inhibition of

the NADH oxidase activity. Data from individual titrations were used

to assess the mean and standard deviation over three assays for each

compound.

(1S,3R,4R,6S)-3-((E)-5-((tert-Butyldimethylsilyl)oxy)-4-meth-

ylhexa-3,5-dien-1-yl)-1,3-dimethyl-4-(prop-1-en-2-yl)-7-

oxabicyclo[4.1.0]heptan-2-one (17). A solution of enone 16 (520

mg, 1.79 mmol) in CH₂Cl₂(18 mL) was cooled to −78 °C and

sequentially treated with Et₃N (0.75 mL, 5.37 mmol) and

TBDMSOTf (0.53 mL, 2.32 mmol). After 1 h at −78 °C, the

reaction mixture was quenched with 5% NaHCO₃solution, poured

into water, and extracted with CH₂Cl₂. The combined extracts were

washed with brine, dried, and concentrated. Puriﬁcation of the

obtained residue by column chromatography (9:1 hexanes−Et₂O with

0.2% of Et₃N) aﬀorded silyl enol ether 17 (653 mg, 91%) as a colorless

oil: [α]²⁰+35 (c 0.75, CHCl₃); IR ν_max/cm⁻¹(NaCl) 1701s, 1633w,

D

1

1590 m; H NMR (C₆D₆), 300 MHz) δ 6.30 (1H, br dd, J = 7.4, 7.4

Hz, H-3′), 4.81 and 4.60 (1H each, each br s, 2 × H-1′′), 4.48 and 4.37

(1H each, each s, 2 × H-6′), 2.90 (1H, dd, J = 11.1, 4.6 Hz, H-4), 2.78

(1H, dd, J = 2.5, 1.6 Hz, H-6), 2.26 (1H, m, H-2′), 1.97 (1H, ddd, J =

15.7, 13.4, 5.1 Hz, H′-2′), 1.83 (1H, m, H-5), 1.775 (3H, s, Me-C_4′),

1.65 (1H, ddd, J = 13.5, 11.1, 5.5 Hz, H-1′), 1.55 (1H, ddd, J = 12.7,

11.2, 2.3 Hz, H′-5), 1.504 (3H, s, Me-C_2′′), 1.48 (1H, m, H′-1′), 1.340

(3H, s, Me-C₁), 1.022 (9H, s, Me₃CSi), 0.820 (3H, s, Me-C₃), 0.173

(6H, s, 2 × MeSi); ¹³C NMR (C₆D₆, 75 MHz) δ 209.1 (C₂), 158.0

(C_5′), 144.7 (C_2′′), 131.8 (C_4′), 131.8 (C_3′), 115.1 (C_1′′), 91.3 (C_6′),

60.7 (C₆), 58.6 (C₁), 49.7 (C₃), 41.0 (C₄), 37.2 (C_1′), 26.5 (C₅), 26.1

(Me₃CSi), 23.9 (C_2′), 23.4 (Me-C_2′′), 21.2 (Me-C₃), 18.5 (Me₃CSi),

16.5 (Me-C₁), 13.4 (Me-C_4′), −4.5 (2 × MeSi); MS (EI) m/z 404

(M⁺,20), 389 (4), 347 (2), 250 (4), 226 (19), 225 (100), 223 (15),

197 (16), 168 (52); HRMS m/z calcd for C₂₄H₄₀O₃Si 404.2747, found

404.2757.

3-((1S,3R,4R,6S)-1,3-Dimethyl-2-oxo-4-(prop-1-en-2-yl)-7-

oxabicyclo[4.1.0]heptan-3-yl)propanal (15). A solution of ketal

14²⁶(1.64 g, 5.3 mmol) and PPTS (1.33 g, 5.3 mmol) in 4% aqueous

acetone (80 mL) was heated at 45 °C for 1.5 h. The mixture was

cooled to rt, poured into water, and extracted with EtOAc. The usual

workup left a residue that was puriﬁed by column chromatography

(8:2 hexanes−EtOAc) to aﬀord aldehyde 15 (1.121 g, 89%) as a

colorless oil: [α]²⁰_D+80 (c 1.2, CHCl₃); IR ν_max/cm⁻¹(NaCl) 1727s,

1701s, 1639w; ¹H NMR (CDCl₃, 300 MHz) δ 9.72 (1H, d, J = 1.5 Hz,

H-1), 4.94 (1H, br s, H-1′′), 4.74 (1H, br s, H′-1′′), 3.41 (1H, br s H-

6′), 2.77 (1H, dd, J = 10.7, 5.3 Hz, H-4′), 2.45 (1H, dddd, J = 17.6,

11.0, 5.2, 1.5 Hz, H-2), 2.37 (1H, dddd, J = 17.6, 11.0, 5.0, 1.5 Hz, H′-

2), 2.20 (2H, m, H-5′), 2.02 (1H, ddd, J = 14.0, 11.0, 5.0 Hz, H-3),

1.80 (1H, ddd, J = 14.0, 11.0, 5.2 Hz, H′-3), 1.734 (3H, s, Me-C_2′′),

1.408 (3H, s, Me-C_1′), 1.006 (3H, s, Me-C_3′); ¹³C NMR (CDCl₃, 75

MHz) δ 209.1 (C_2′), 201.7 (C₁), 143.7 (C_2′′), 115.7 (C_1′′), 60.8 (C_6′),

58.2 (C_1′), 48.9 (C_3′), 40.5 (C_4′), 39.3 (C₂), 28.2 (C₃), 26.3 (C_5′), 23.3

(Me -C_2′′), 20.5 (Me-C_3′), 16.2 (Me-C_1′); MS (EI) m/z 236 (M⁺, 4),

221 (13), 208 (15), 207 (13), 193 (26), 179 (31), 137 (62), 123 (54),

109 (53), 107 (53), 85 (63), 81 (100), 67 (60); HRMS m/z calcd for

C₁₄H₂₀O₃236.1412, found 236.1369.

(4aR,6aR,7aS,8aS,9aR,9bS)-3-((tert-Butyldimethylsilyl)oxy)-

4,6a,7a,9b-tetramethyl-1,4a,5,6,6a,7a,8a,9,9a,9b-

decahydrophenanthro[2,3-b]oxiren-7(2H)-one (18). A small

crystal of BHT was added to a solution of triene 17 (470.5 mg,

1.16 mmol) in toluene (13 mL) that had been placed in a previously

silylated and dried ampule. After rigorously degassing using the

freeze−thaw method, the mixture was cooled under N₂before adding

a drop of propylene oxide and sealing the ampule under vacuum. After

the mixture was heated to 195 °C for 7 days, the solvent was

eliminated on a rotary evaporator, and the crude product was puriﬁed

by column chromatography (95:5 hexanes−EtOAc) to yield Diels−

Alder adduct 18 as a white solid (444.5 mg, 94%): mp 165−168 °C

(from hexanes); [α]²⁰−28 (c 0.5 CHCl₃); IR ν_max/cm⁻¹(KBr)

D

1

1711s, 1675 m; H NMR (C₆D₆, 300 MHz) δ 2.86 (1H, br t, J = 2.0

Hz, H-8a), 2.05−1.86 (4H, m, 2 × H-2, H-6, H-9), 1.60−1.50 (3H, m,

H′-6, H-5, H-4a), 1.581 (3H, s, Me-C₄), 1.50−1.30 (3H, m, H-9a, H′-

9, H-1), 1.385 (3H, s, Me-C_7a), 1.033 (9H, s, Me₃CSi), 0.98 (1H, m,

H′-5), 0.83 (1H, ddd, J = 11.7, 11.7, 7.5 Hz, H′-1), 0.757 (3H, s, Me-

C_6a), 0.651 (3H, s, Me-C_9b), 0.130 (6H, s, 2 × MeSi); ¹³C NMR

(C₆D₆, 75 MHz) δ 207.2 (C₇), 142.3 (C₃), 112.3 (C₄), 59.3 (C_8a),

56.4 (C_7a), 47.9 (C_4a), 45.9 (C_6a), 40.4 (C_9a), 35.7 (C_9b), 35.3 (C₁),

33.9 (C₆), 27.8 (C₂), 26.1 (Me₃CSi), 21.7 (C₉), 20.5 (C₅), 18.4

(Me₃CSi), 18.1 (Me-C_6a), 17.0 (Me-C_7a), 13.6 (Me-C_9b), 12.9 (Me-

C₄), −3.4 and −3.6 (2 × MeSi); MS (EI) m/z 404 (M⁺, 100), 389

(43), 347 (10), 237 (7), 211 (6), 185 (6), 173 (7), 171 (8), 159 (9);

HRMS m/z calcd for C₂₄H₄₀O₃Si 404.2747, found 404.2744.

(1S,3R,4R,6S)-1,3-Dimethyl-3-((E)-4-methyl-5-oxohex-3-en-

1-yl)-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptan-2-one (16).

Diethyl 2-oxobutane-3-phosphonate (1.30 g, 1.15 mL, 6.3 mmol)

was added to a stirred slurry of prewashed NaH (60% dispersion oil;

199 mg, 5.0 mmol) in THF (21 mL) at 0 °C dropwise using a syringe.

After hydrogen evolution had ceased, the mixture was warmed to rt

and stirred for 10 min. The resulting mixture was cooled to 0 °C, and a

solution of aldehyde 15 (1.12 g, 4.7 mmol) in THF (27 mL) was

added. After being stirred at rt for 30 min, the mixture was quenched

with saturated aqueous NH₄Cl and poured into water. Extraction with

CH₂Cl₂followed by the usual workup aﬀorded an oil, which was

puriﬁed by column chromatography (9:1 hexanes−Et₂O) to yield (E)-

oleﬁn 16 (1.03 g, 75%): [α]²⁵−51 (c 1.0, CHCl₃), IR ν_max/cm⁻¹

( 1 a S , 1 b R , 3 a R , 4 a S , 5 a S , 6 a R , 6 b S , 8 a R ) - 8 a - ( ( t e r t -

Butyldimethylsilyl)oxy)-1a,3a,4a,6b-tetramethyldodecahydro-

1H-cyclopropa[7,8]phenanthro[2,3-b]oxiren-4(1aH)-one (19).

CH₂I₂(408 μL, 5.1 mmol) was added dropwise to a stirred solution

D

1

(NaCl) 1670s, 1667s, 1643s; H NMR (CDCl₃, 300 MHz) δ 6.53

(1H, ddd, J = 7.2, 7.2, 1.1 Hz, H-3′), 4.96 (1H, t, J = 1.4 Hz, H-1′′),

4.78 (1H, br s, H′-1′′), 3.42 (1H, t, J = 2.0 Hz, H-6), 2.90 (1H, dd, J =

5670

dx.doi.org/10.1021/jo3008034 | J. Org. Chem. 2012, 77, 5664−5680

The Journal of Organic Chemistry

Article

of diethylzinc in hexane (0.85 M, 6 mL, 5.1 mmol) at 0 °C under N₂.

After 5 min, a solution of tert-butyldimethyl silyl enol ether 18 (258

mg, 0.638 mmol) in dry toluene (3.9 mL) was added via cannula at 0

°C, and the mixture was stirred for 2 h. The mixture was diluted with

Et₂O (2−3 mL), quenched by the addition of a saturated NH₄Cl

solution, and extracted with Et₂O. The organic extracts were

successively washed with 10% Na₂S₂O₃solution, water, and brine

before drying and concentrating to yield a solid. Chromatography

(10:0 → 9:1 hexanes−EtOAc) aﬀorded the cyclopropanated

compound 19 (248 mg, 95%) as a white solid: mp 168−169 °C

hydride was quenched with water. After being stirred for a few

minutes, the mixture was extracted with CH₂Cl₂and worked up.

Chromatographic puriﬁcation of the residue after evaporating the

solvent (9:1 hexanes−EtOAc) yielded allyl epoxide 21 (137 mg, 96%)

as a white solid: mp 133−134 °C (from MeOH−pentane); [α]²⁵_D+20

(c 0.9, CHCl₃); IR ν_max/cm⁻¹(KBr) 3048w, 2930s, 2858s,, 835s, 774s;

¹H NMR (CDCl₃, 300 MHz) δ 5.92 (1H, dddd, J = 17.2, 10.4, 5.5, 5.5

Hz, H-2′), 5.28 (1H, dq, J = 12.7, 1.6 Hz, H-3′), 5.15 (1H, dq, J = 10.4,

1.3 Hz, H′-3′), 4.20 (1H, dddd, J = 12.7, 5.3, 1.4, 1.4 Hz, H-1′), 3.98

(1H, dddd, J = 12.7, 5.7, 1.3, 1.3 Hz, H′-1′), 3.05 (1H, br s, H-5a), 2.80

(1H, s, H-4), 2.06 (1H, ddd, J = 13.7, 6.3, 1.5 Hz, H-8α), 2.03−1.91

(2H, m, H-7, H-3β), 1.87 (1H, ddd, J = 13.7, 13.3, 7.0 Hz, H-8β),

1.70−1.57 (3H, m, H′-7, H-6, H-2α), 1.35 (1H, ddd, J = 13.1, 13.1, 2.9

Hz, H-2β), 1.305 (3H, s, Me-C_4a), 1.024 (3H, s, Me-C_1a), 0.91 (1H, m,

H-3α), 0.883 (3H, s, Me-C_6b), 0.851 (9H, s, Me₃−C-Si), 0.833 (3H, s,

Me-C_3a), 0.77 (1H, dd, J = 13.1, 3.0 Hz, H-1b), 0.70 (1H, dd, J = 12.8,

4.8 Hz, H-6a), 0.51 (1H, ddd, J = 13.3, 13.3, 6.1 Hz, H′-6), 0.48 (1H,

dd, J = 5.1, 1.0 Hz, H-1β), 0.21 (1H, d, J = 5.1 Hz, H-1α), 0.097 and

0.041 (3H each, each s, 2 × Me-Si); ¹³C NMR (CDCl₃, 75 MHz) δ

134.8 (C_2′), 116.5 (C_3′), 89.0 (C₄), 74.5 (C_1′), 61.2 (C_5a), 60.1 (C_4a),

58.5 (C_8a), 54.3 (C_1b), 43.9 (C_6a), 38.5 (C₃), 37.5 (C_3a), 35.2 (C₇),

34.9 (C_6b), 29.0 (C₈), 28.7 (C₁), 25.8 (Me₃CSi), 22.3 (C₂), 22.1 (C_1a),

21.8 (C₆), 19.9 (Me-C_4a), 17.9 (Me₃CSi), 15.6 (Me-C_1a), 13.6 (Me-

C_6b), 13.0 (Me-C_3a), −3.0 and −3.8 (2 × MeSi); MS (EI) m/z 460

(M⁺, 26), 445 (7), 419 (7), 403 (54), 211 (100); HRMS m/z calcd for

C₂₈H₄₈O₃Si 460.3373, found 460.3374.

(from MeOH−hexanes); [α]²⁵−9 (c 1.0, CHCl₃), IR ν_max/cm⁻¹

D

1

(KBr) 1706s, 1660w; H NMR (CDCl₃, 300 MHz) δ 3.34 (1H, br s,

H-5a), 2.24 (1H, ddd, J = 15.3, 3.0, 3.0 Hz, H-6α), 2.09 (1H, ddd, J =

13.7, 6.2, 1.5 Hz, H-8α), 1.97−1.73 (4H, m, H-8β, H-6β, H-3, H-2),

1.66 (1H, ddd, J = 13.3, 7.1, 1.5 Hz, H-7β), 1.50−1.33 (2H, m, H′-3,

H′-2), 1.403 (3H, s, Me-C_4a), 1.26 (1H, dd, J = 12.7, 3.7 Hz, H-6a),

1.064 (3H, s, Me-C_3a), 1.029 (3H, s, Me-C_1a), 0.893 (3H, s, Me-C_6b),

0.852 (9H, s, Me₃CSi), 0.78 (1H, dd, J = 12.5, 2.7 Hz, H-1b), 0.57

(1H, ddd, J = 13.3, 13.3, 6.2 Hz, H-7α), 0.51 (1H, dd, J = 5.3, 1.0 Hz,

H-1β), 0.22 (1H, d, J = 5.3 Hz, H-1α), 0.101 and 0.041 (3H each, each

s, 2 × MeSi); ¹³C NMR (CDCl₃, 75 MHz) δ 208.1 (C₄), 59.6 (C_5a),

58.2 (C_8a), 56.3 (C_4a), 53.6 (C_1b), 45.8 (C_3a), 39.5 (C_6a), 35.4 (C_6b),

35.2 (C₇), 33.2 (C₃), 28.9 (C₈), 28.8 (C₁), 25.8 (Me₃CSi), 21.9 (C_1a),

21.5 (C₆), 21.4 (C₂), 17.9 (Me₃CSi), 17.7 (Me-C_3a), 16.7 (Me-C_4a),

15.5 (Me-C_1a), 13.4 (Me-C_6b), −3.8 and −3.1 (2 × MeSi); MS (EI)

m/z 418 (M⁺, 82), 403 (34), 389 (9), 361 (100), 345 (13), 333 (9),

211 (58); HRMS m/z calcd for C₂₅H₄₂O₃Si 418.2903, found

418.2860.

(1aS,1bR,3aR,4S,6S,7aR,7bR,9aR)-4-(Allyloxy)-9a-((tert-

butyldimethylsilyl)oxy)-1a,3a,7b-trimethyl-5-methylenetetra-

decahydro-1H-cyclopropa[a]phenanthren-6-ol (22). BuLi (1.39

M in hexane, 0.92 mL, 1.27 mmol) was added to a stirred solution of

2,2,6,6-tetramethylpiperidine (0.247 mL, 1.46 mmol) in dry benzene

(1.4 mL) at 0 °C. After 10 min, the reaction mixture was treated with

Et₂AlCl (1.8 M in toluene, 0.76 mL, 1.27 mmol) and stirred for an

additional 30 min at the same temperature. Then, a solution of

epoxide 21 (147 mg, 0.32 mmol) in benzene (0.5 mL) was added to

the mixture and stirred at 0 °C for 30 min before being quenched with

5% NaHCO₃and extracted with EtO₂. The combined organic phases

were worked up as usual, and the residue obtained after evaporation of

the solvent was puriﬁed by column chromatography (9:1 → 8:2

hexanes−EtOAc) to aﬀord allyl alcohol 22 (138 mg, 94%) as an

(1aS,1bR,3aR,4S,4aR,5aS,6aR,6bR,8aR)-8a-((tert-

Butyldimethylsilyl)oxy)-1a,3a,4a,6b-tetramethyltetradecahy-

dro-1H-cyclopropa[7,8]phenanthro[2,3-b]oxiren-4-ol (20).

CeC1₃·7H₂O (146 mg, 0.0.39 mmol) was added to a solution of

epoxy ketone 19 (164 mg, 0.39 mmol) in MeOH (9.4 mL) and

CH₂Cl₂(2.8 mL). This mixture was stirred at rt until the cerium salt

completely dissolved and then cooled to −30 °C. NaBH₄(29.5 mg,

0.78 mmol) was then added slowly in small portions while the reaction

was monitored by TLC (8:2 hexanes−EtOAc). Upon the completion

(ca. 30 min), the reaction was quenched with acetone (0.4 mL),

diluted with water, and extracted with CH₂Cl₂. The usual workup

followed by chromatographic puriﬁcation (8:2 hexanes−EtOAc)

aﬀorded epoxy alcohol 20 (152 mg, 92%) as a white solid: mp

amorphous solid: [α]²⁰+32 (c 0.62, CHCl₃); IR ν_max/cm⁻¹(KBr)

D

1

205−206 °C (from benzene−hexanes); [α]²⁵+35 (c 0.96, CHCl₃),

3360 m, 1654w, 1588w, 835s; H NMR (CDCl₃, 300 MHz) δ 5.91

D

IR ν_max/cm⁻¹(KBr) 3256 m, 3054w, 1253s, 1055s, 998s, 832s, 780s;

(1H, dddd, J = 17.2, 10.6, 5.8, 5.3 Hz, H-2′), 5.26 (1H, dq, J = 17.2, 1.6

Hz, H-3′), 5.13 (1H, dq, J = 10.6, 1.3 Hz, H′-3′), 4.97 (2H, m, 2 × H-

1′′), 4.46 (1H, m, H-4), 4.07 (1H, dddd, J = 12.8, 5.3, 1.5, 1.5 Hz, H-

1′), 3.87 (1H, dddd, J = 12.8, 5.8, 1.3, 1.3 Hz, H′-1′), 3.63 (1H, br s, H-

6), 2.08 (1H, ddd, J = 13.6, 7.5, 1.4 Hz, H-9α), 1.99 (1H, ddd, J = 13.0,

3.2, 3.2 Hz, H-3β), 1.92 (1H, m, H-9β), 1.75−1.63 (2H, m, H-2α, H-

8β), 1.74 (1H, dddd, J = 19.5, 14.0, 2.5, 2.5 Hz, H-7β), 1.57−1.42

(2H, m, H-7α, H-2β), 1.33 (1H, dd, J = 14.0, 2.5 Hz, H-7a), 1.13 (1H,

ddd, J = 13.0, 13.0, 3.2 Hz, H-3α), 1.031 (3H, s, Me-C_1a), 0.88 (1H,

dd, J = 13.0, 3.5 Hz, H-1b), 0.854 (9H, s, Me₃CSi), 0.790 and 0.785

(3H each, each s, Me-C_7band Me-C_3a), 0.62 (1H, ddd, J = 13.1, 13.1,

6.4 Hz, H-8α), 0.51 (1H, dd, J = 5.1, 1.2 Hz, H-1β), 0.23 (1H, d, J =

5.1 Hz, H-1α), 0.102 and 0.046 (3H each, each s, 2 × MeSi); ¹³C

NMR (CDCl₃, 75 MHz) δ 147.5 (C₅), 135.9 (C_2′), 116.3 (C_3′), 109.2

(C_1′′), 86.0 (C₆), 73.0 (C₄), 71.8 (C_1′), 58.4 (C_9a), 54.6 (C_1b), 46.4

(C_7a), 41.3 (C_3a), 38.2 (C₃), 35.7 (C₈), 35.1 (C_7b), 29.5 (C₇), 29.2

(C₉), 29.0 (C₁), 25.8 (Me₃CSi), 22.4 (C₂), 22.2 (C_1a), 17.9 (Me₃CSi),

15.5 (Me-C_1a), 13.3 (Me-C_3a), 12.4 (Me-C_7b), −3.0 and −3.8 (2 ×

MeSi); MS (EI) m/z 460 (M⁺, 14), 445 (4), 442 (4), 419 (6), 403

(23), 385 (6), 253 (6), 211 (87), 73 (100); HRMS m/z calcd for

C₂₈H₄₈O₃Si 460.3373, found 460.3373.

¹H NMR (CDCl₃, 300 MHz) δ 3.20 (1H, d, J = 5.1 Hz, H-4), 3.08

(1H, br s, H-5a), 2.10−1.97 (2H, m, H-8, H-6), 1.93−1.81 (2H, m, H′-

8, H-3), 1.73−1.58 (3H, m, H-7β, H′-6, H-2α), 1.40 (1H, ddd, J =

13.1, 13.1, 3.1 Hz, H-2β), 1.312 (3H, s, Me-C_4a), 1.027 (3H, s, Me-

C_1a), 0.96 (1H, m, H-3α), 0.880 (3H, s, Me-C_6b), 0.851 (9H, s,

Me₃CSi), 0.851 (3H, s, Me-C_3a), 0.77 (1H, dd, J = 13.0, 3.7 Hz, H-1b),

0.73 (1H, dd, J = 12.5, 4.5 Hz, H-6a), 0.53 (1H, ddd, J = 13.2, 13.2, 6.1

Hz, H-7α), 0.49 (1H, dd, J = 5.2, 1.0 Hz, H-1β), 0.22 (1H d, J = 5.2

Hz, H-1α), 0.097 and 0.040 (3H each, each s, 2 × MeSi); ¹³C NMR

(CDCl₃, 75 MHz) δ 81.1 (C₄), 61.1 (C_5a), 59.7 (C_4a), 58.4 (C_8a), 54.1

(C_1b), 43.3 (C_6a), 38.5 (C₃), 36.9 (C_3a), 35.2 (C₇), 34.8 (C_6b), 29.0

(C₈), 28.7 (C₁), 25.8 (Me₃CSi), 22.3 (C₆), 22.0 (C_1a), 21.8 (C₂), 19.7

(Me-C_4a), 17.9 (Me₃CSi), 15.6 (Me-C_1a), 13.0 (Me-C_6b), 12.9 (Me-

C_3a), −3.0 and −3.8 (2 × MeSi); MS (EI) m/z 420 (M⁺, 8), 405 (4),

402 (3), 363 (23), 345 (7), 253 (4), 211 (100); HRMS m/z calcd for

C₂₅H₄₄O₃Si 420.3060, found 420.3023.

(1aS,1bR,3aR,4S,4aS,5aS,6aR,6bR,8aR)-4-(Allyloxy)-

1a,3a,4a,6b-tetramethyltetradecahydro-1H-cyclopropa[7,8]-

phenanthro[2,3-b]oxiren-8a-yl)oxy)(tert-butyl)dimethylsilane

(21). A solution of epoxy alcohol 20 (130 mg, 0.30 mmol) and TBAI

(22.5 mg, 0.07 mmol) in dry THF (5.3 mL) was slowly added to a

stirred suspension of sodium hydride (184 mg of 60% dispersion in oil,

4.6 mmol, prewashed with pentane) in THF (5 mL) at 0 °C. The

reaction mixture was allowed to warm to rt and stirred for 30 min

before addition of allyl bromide (282 mg, 203 μL 2.32 mmol) and

heating to 50 °C. After being stirred for 24 h at this temperature, the

reaction mixture was cooled in an ice bath, and the excess sodium

3β-((tert-Butyldimethylsilyl)oxy)-3α,18-cyclo-isospongia-

13(15)-en-12α-ol (23). A solution of 1,4-benzoquinone (4 mg, 0.038

mmol) in CH₂Cl₂(1 mL) was added over 30 min via a syringe pump

to a stirred solution of Grubbs second-generation catalyst [(1,3-

dimesityl-2-imidazolylidene)(PCy₃) Cl₂RuCHPh] (19.4 mg, 0.022

mmol) and diene 22 (71 mg, 0.154 mmol) in reﬂuxing CH₂Cl₂(8

mL). The reaction was reﬂuxed for an additional 20 min period,

5671

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The Journal of Organic Chemistry

Article

cooled, concentrated under vacuum to 25% of its original volume,

charged onto a silica gel chromatography column, and eluted with 97:3

CHCl₃−EtOAc to yield dihydrofuran 23 (60 mg, 90%) as a solid.

1.87 (1H, dddd, J = 14.0, 3.7, 3.2, 3.3 Hz, H-6α), 1.72 (1H, m, H-6β),

1.72 (1H, m, H-1β), 1.69 (1H, dd, J = 13.0, 3.5 Hz, H-9), 1.55 (1H,

ddd, J = 13.1, 13.1, 3.7 Hz, H-7α), 1.325 (3H, s, Me-C₈), 1.075 (3H, s,

Me-C₄), 0.949 (3H, s, Me-C₁₀), 0.91 (1H, dd, J = 12.9, 3.7 Hz, H-5)

0.866 (9H, s, Me₃CSi), 0.61 (1H, ddd, J = 13.1, 13.1, 6.6 Hz, H-1α),

0.55 (1H, dd, J = 5.3, 1.2 Hz, H-18β), 0.25 (1H, d, J = 5.3 Hz, H-18α),

0.120 and 0.053 (3H each, each s, 2 × MeSi); ¹³C NMR (CDCl₃, 75

MHz) δ 194.8 (C₁₂), 175.9 (C₁₄), 142.2 (C₁₆), 118.4 (C₁₃), 106.3

(C₁₅), 58.0 (C₃), 54.3 (C₅), 52.6 (C₉), 37.00 (C₈), 35.8 (C₁₁), 35.5

(C₁), 35.4 (C₁₀), 34.6 (C₇), 29.1 (C₁₈), 28.9 (C₂), 25.8 (Me₃CSi), 22.0

(C₄), 21.7 (C₆), 20.2 (Me-C₈), 17.9 (Me₃CSi), 15.3 (Me-C₄), 12.0

(Me-C₁₀), −3.0 and −3.8 (2 × MeSi); MS (EI) m/z 428 (M⁺, 19),

413 (11), 372 (30), 371 (100), 235 (10), 211 (63); HRMS m/z calcd

for C₂₆H₄₀O₃Si 428.2747, found 428.2753.

Isospongia-13,15-diene-3,12-dione (26). A solution of tert-

butyldimethylsilyl ether 25 (60 mg, 0.14 mmol) in anhydrous MeCN

(5 mL) was cooled to 0 °C and treated with 10 drops of 70% w/w HF

in pyridine before being stirred at rt under N₂for 24 h. The reaction

mixture was quenched by the slow addition of a saturated Na₂CO₃

solution and then poured into a 5% NaHCO₃solution and extracted

with EtOAc. The combined organic layers were washed with a

saturated CuSO₄solution and brine before drying. Chromatography

(9:1 CHCl−EtOAc) of the residue remaining after solvent evaporation

aﬀorded the corresponding cyclopropanol (40 mg) as an amorphous

white solid: ¹H NMR (C₆D₆, 300 MHz) δ 6.75 (1H, d), 6.22 (1H, d),

2.42 (1H, dd), 2.17 (1H, dd), 2.05 (1H, ddd), 1.95 (1H, ddd), 1.64

(1H, m), 1.47 (1H, dddd), 1.32 (1H, m), 1.23 (1H, dd), 1.22 (2H, m),

1.073 (3H, s), 0.931 (3H, s), 0.575 (3H, s), 0.51 (1H), 0.46 (1H, dd),

0.12 (1H, ddd), 0.086 (1H, d).

1

Although pure by H NMR analysis, the compound obtained in this

way was slightly colored, presumably due to the presence of trace

amounts of the Grubbs catalyst. This compound was used in the next

step without further puriﬁcation. An analytical sample was obtained by

crystallization from hexanes−Et₂O: mp 184−185 °C (from hexanes−

Et₂O); [α]²⁰+61 (c 0.46, CHCl₃); IR ν_max/cm⁻¹(KBr) 3396s, 1644

D

m, 830s, 758s; ¹H NMR (CDCl₃, 300 MHz) δ 5.66 (1H, d, J = 1.8 Hz,

H-15), 4.67 (1H, br s, H-12), 4.65 (1H, ddd, J = 11.4, 3.9, 1.2 Hz, H-

16β), 4.57 (1H, ddd, J = 11.4, 6.0, 1.5 Hz, H-16α), 4.43 (1H, m, H-

14), 2.09 (1H, ddd, J = 13.8, 6.3, 1.5 Hz, H-2α), 1.97−1.84 (2H, m, H-

2β, H-7β), 1.79−1.67 (3H, m, H-1β, H-6α, H-11α), 1.56−1.38 (2H,

m, H-6β, H-11β), 1.22 (1H, dd, J = 12.9, 1.8 Hz, H-9), 1.19 (1H, ddd,

H-7α), 1.034 (3H, s, Me-C₄), 0.89 (1H, dd, J = 12.9, 3.3 Hz, H-5),

0.855 (9H, s, Me₃CSi), 0.813 (3H, s, Me-C₁₀), 0.802 (3H, s, Me-C₈),

0.65 (1H, ddd, J = 12.9, 12.9, 6.3 Hz, H-1α), 0.51 (1H, dd, J = 5.1, 0.9

Hz, H-18β), 0.25 (1H, d, J = 5.1 Hz, H-18α), 0.105 and 0.047 (3H

each, each s, 2 × MeSi); ¹³C NMR (CDCl₃, 75 MHz) δ 140.3 (C₁₃),

120.5 (C₁₅), 93.5 (C₁₄), 75.9 (C₁₆), 65.4 (C₁₂), 58.4 (C₃), 54.5 (C₅),

44.1 (C₉), 41.6 (C₈), 38.9 (C₇), 35.8 (C₁), 35.0 (C₁₀), 29.3 (C₁₁), 29.3

(C₂), 28.9 (C₁₈), 25.8 (Me₃CSi), 22.2 (C₄), 22.0 (C₆), 17.9 (Me₃CSi),

15.5 (Me-C₄), 12.6* (Me-C₁₀), 12.5* (Me-C₈), −3.0 and −3.8 (2 ×

MeSi); MS (EI) m/z 432 (M⁺, 12), 417 (4), 414 (28), 399 (15), 375

(12), 357 (35), 282 (12), 211 (66), 73 (100); HRMS m/z calcd for

C₂₆H₄₄O₃Si 432.3060, found 432.3068.

3β-((tert-Butyldimethylsilyl)oxy)-3α,18-cycloisospongia-

13,15-dien-12α-ol (24). A solution of dihydrofuran 23 (112 mg,

0.258 mmol) and DDQ (39.4 mg, 0.335 mmol) in dry benzene (10

mL) was stirred at rt for 36 h under N₂. The reaction mixture was

quenched with 5% NaHCO₃solution, poured into water, and

extracted with EtOAc. Workup and chromatography of the residue

left after evaporation of the solvent on silica gel (8:2 hexanes−EtOAc)

gave furan 24 (89 mg, 87% based on the starting material consumed)

Both the product obtained above and NaOH (10.2 mg, 0.255

mmol) were dissolved under N₂in a 4:1 mixture of dioxane−water (5

mL) previously degasiﬁed in an ultrasonic bath under a N₂ﬂow. The

reaction mixture was heated to 90 °C for 6 h, cooled to 0 °C, acidiﬁed

by the addition of 0.1 M hydrochloric acid, and extracted with EtOAc.

The organic phase was washed with both a 5% NaHCO₃solution and

brine, dried and evaporated to aﬀord a solid residue that was puriﬁed

by column chromatography on silica gel (95:5 CHCl₃−EtOAc) to

aﬀord the 3-oxomarginatone (26, 40 mg, 91%): mp 167−169 °C

as an oil: [α]²⁴−14 (c 0.28, CHCl₃); IR ν_max/cm⁻¹(NaCl) 3328w,

D

1

1618w, 1257s, 831s; H NMR (CDCl₃, 300 MHz) δ 7.20 (1H, d, J =

1.9 Hz, H-16), 6.30 (1H, d, J = 1.9 Hz, H-15), 4.70 (1H, br s, H-12),

2.20 (1H, ddd, J = 12.9, 3.1, 3.1 Hz, H-7β), 2.13 (1H, ddd, J = 13.9,

6.6, 1.6 Hz, H-2α), 1.98 (1H, m, H-2β), 1.90−1.60 (5H, m, 2 × H-11,

2 × H-6, H-1β), 1.44 (1H, dd, J = 12.5, 1.9 Hz, H-9α), 1.43 (1H, ddd,

J = 12.9, 12.9, 3.5 Hz, H-7α), 1.173 (3H, s, Me-C₈), 1.065 (3H, s, Me-

C₄), 0.91 (1H, dd, H-5α), 0.887 (3H, s, Me-C₁₀), 0.867 (9H, s,

Me₃CSi), 0.64 (1H, ddd, J = 13.0, 12.9, 6.6 Hz, H-1α), 0.53 (1H, dd, J

= 5.2, 1.0 Hz, H-18β), 0.25 (1H, d, J = 5.2 Hz, H-18α), 0.120 and

0.055 (3H each, each s, 2 × MeSi); ¹³C NMR (CDCl₃, 75 MHz) δ

162.0 (C₁₄), 140.8 (C₁₆), 116.3 (C₁₃), 109.1 (C₁₅), 63.1 (C₁₂), 58.3

(C₃), 54.7 (C₅), 47.3 (C₉), 36.5 (C₈), 35.9 (C₁), 35.5 (C₇), 34.9 (C₁₀),

29.2 (C₁₈), 29.1 (C₂), 28.9 (C₁₁), 25.8 (Me₃CSi), 22.2 (C₄), 22.0 (C₆),

20.7 (Me-C₈), 17.9 (Me₃CSi), 15.4 (Me-C₄), 12.2 (Me-C₁₀), −3.0 and

−3.8 (2 × MeSi); MS (EI) m/z 430 (M⁺, 17), 415 (7), 412 (8), 397

(24), 373 (38), 355 (9), 281 (14), 265 (11), 211 (100); HRMS m/z

calcd for C₂₆H₄₂O₃Si 430.2903, found 430.2900.

(from hexanes−Et₂O); [α]²⁰−9 (c 0.65, CHCl₃), IR ν_max/cm⁻¹

D

1

(KBr) 3109w, 1711s, 1661s, 1459 m, 1268 m, 1142 m, 771w; H

NMR (CDCl₃, 400 MHz) δ 7.28 (1H, d, J = 2.0 Hz, H-16), 6.60 (1H,

d, J = 2.0 Hz, H-15), 2.63−2.52 (3H, m, H-2α, 2 × H-11), 2.47 (1H,

ddd, J = 15.9, 7.7, 4.24 Hz, H-2β), 2.35 (1H, br ddd, J = 5.6 3.3, 3.3,

Hz, H-7β), 1.99−1.89 (2H, m, H-1β, H-9), 1.79−1.59 (3H, m, 2 × H-

6, H-7α), 1.57−1.44 (2H, H-1β, H-5), 1.330 (3H, s, Me-C₈), 1.115

(3H, s, Meα-C₄), 1.090 (6H, s, Meβ-C₄and Me-C₁₀); ¹³C NMR

(CDCl₃, 75 MHz) δ 216.4 (C₃), 194.1 (C₁₂), 175.1 (C₁₄), 142.5 (C₁₆),

118.4 (C₁₃), 106.3 (C₁₅), 55.1 (C₉), 54.7 (C₅), 47.3 (C₄), 38.3 (C₁),

37.2 (C₈), 36.6 (C₁₀), 35.6 (C₁₁), 34.7 (C₇), 33.6 (C₂), 26.5 (Meα-

C₄), 20.9 (Meβ-C₄), 19.9 (Me-C₈), 18.9 (C₆), 15.7 (Me-C₁₀); MS

(EI) m/z 314 (M⁺, 43), 299 (16), 272 (15), 189 (21), 178 (57), 161

(100), 147 (39), 135 (45); HRMS m/z calcd for C₂₀H₂₆O₃314.1882,

found 314.1880.

Isospongia-13,15-diene-3β,12β-diol (27). CeC1₃·7H₂O (68.4

mg, 0.182 mmol) was added to a solution of dienone 26 (38 mg, 0.122

mmol) in MeOH (2.4 mL). The mixture was stirred at rt until the

cerium salt had completely dissolved. After addition of CH₂Cl₂(1.2

mL), the mixture was cooled to −65 °C, and NaBH₄was slowly added

in small portions while the reaction was montiored by TLC (7:3

hexanes−EtOAc). Upon completion of the reduction (ca. 30 min), the

reaction was quenched with acetone (0.4 mL), stirred for a few

minutes, diluted with water, and extracted with EtOAc. The combined

organic phases were washed with brine and dried. The solvent was

removed and the residue was puriﬁed by column chromatography (7:3

hexanes−EtOAc) to aﬀord isospongiadiol 27 (36.5 mg, 96%) as a

Further elution using the same eluent aﬀorded the unreacted

starting material 23 (10.5 mg, 9%).

3β-((tert-Butyldimethylsilyl)oxy)-3α,18-cycloisospongia-

13,15-dien-12-one (25). NMO (48 mg, 0.408 mmol), 5 Å molecular

sieves (114 mg), and TPAP (5 mg, 0.014 mmol) were added to a

solution of furan alcohol 24 (100 mg, 0.232 mmol) in anhydrous

CH₂Cl₂(3.6 mL) at 0 °C under N₂. The reaction was stirred at rt until

complete by TLC (approximately 25 min). The reaction mixture was

directly transferred to the top of a silica gel chromatographic column,

which was eluted with 9:1 hexanes−EtOAc to yield keto furan 25 (86

mg, 86%) as a white solid: mp 137−140 °C (from hexanes); [α]²⁴

D

−86 (c 0.42, CHCl₃); IR ν_max/cm⁻¹(KBr) 1667s, 1585w, 1432 m,

1246 m, 1000 m, 831 m, 771 m; ¹H NMR (CDCl₃, 300 MHz) δ 7.25

(1H, d, J = 2.0 Hz, H-16), 6.59 (1H, d, J = 2.0 Hz, H-15), 2.54 (1H,

dd, J = 17.4, 3.5 Hz, H-11α), 2.44 (1H, dd, J = 17.4 13.0, Hz, H-11β),

2.29 (1H, ddd, J = 13.1, 3.2, 3.2, Hz, H-7β), 2.14 (1H, ddd, J = 14.1,

6.6, 1.6 Hz, H-2α), 1.96 (1H, dddd, J = 14.1, 12.7, 7.3, 1.2 Hz, H-2β),

white solid: mp 203−206 °C (from EtOAc); [α]²⁵−22 (c 0.45,

D

CHCl₃), IR ν_max/cm⁻¹(KBr) 3399s, 1448w, 1388w, 1142w, 1039s,

1

899w 711w; H NMR (CDCl₃, 300 MHz) δ 7.21 (1H, d, J = 1.9 Hz,

H-16), 6.34 (1H, d, J = 1.9 Hz, H-15), 4.64 (1H, dd, J = 9.4, 6.5 Hz,

H-12), 3.20 (1H, dd, J = 11.1, 5.2 Hz, H-3), 2.28−2.12 (2H, m, H-7β,

5672

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Article

H-11α), 1.79 (1H, ddd, J = 12.8, 3.6, 3.6 Hz, H-1β), 1.76−1.35 (6H,

m, 2 × H-2, 2 × H-6, H-7α, H-11β), 1.28 (1H, m, H-9), 1.247 (3H, s,

Me-C₈), 1.03 (1H, dd, J = 12.6, 4.7 Hz, H-1α), 0.977 (3H, s, Meα-C₄),

0.924 (3H, s, Meβ-C₄), 0.85 (1H, dd, J = 11.6, 2.5 Hz, H-5), 0.804

(3H, s, Me-C₁₀); ¹³C NMR (CDCl₃, 75 MHz) δ 160.6 (C₁₄), 141.1

(C₁₆), 118.0 (C₁₃), 108.1 (C₁₅), 78.7 (C₃), 67.2 (C₁₂), 55.5 (C₉), 55.1

(C₅), 38.9 (C₄), 38.1 (C₁), 36.8 (C₇), 36.8 (C₁₀), 36.7 (C₈), 30.2

(C₁₁), 27.9 (Meα-C₄), 27.1 (C₂), 22.3 (Me-C₈), 17.9 (C₆), 16.5 (Meβ-

C₄), 15.1 (Me-C₁₀); MS (EI) m/z 318 (M⁺, 15), 303 (18), 300 (13),

267 (18), 171 (23), 145 (29), 133 (42), 131 (100); HRMS m/z calcd

for C₂₀H₃₀O₃318.2195, found 318.2203.

1.15 (1H, ddd, J = 13.5, 13.3, 4.0 Hz, H-3α), 0.982 (3H, s, Me-C₁₀),

0.94 (1H, m, H-5), 0.882 (4H, s overlapped with m, Meα-C₄and H-

1α), 0.856 (3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 75 MHz) δ 195.3

(C₁₂), 176.1 (C₁₄), 142.3 (C₁₆), 118.2 (C₁₃), 106.2 (C₁₅), 56.5 (C₅),

56.0 (C₉), 41.8 (C₃), 39.3 (C₁), 37.4 (C₈), 37.3 (C₁₀), 35.5 (C₇), 35.3

(C₁₁), 33.2 (C₄), 21.3 (Meα-C₄), 20.5 (Me-C₈), 18.2* (C₂), 17.9*

(C₆), 16.0 (Meβ-C₄), 13.6 (Me-C₁₀); MS (EI) m/z 300 (M⁺, 100),

285 (42), 258 (32), 242 (18), 203 (14), 189 (13), 176 (14), 161 (81);

HRMS m/z calcd for C₂₀H₂₈O₂300.2089, found 300.2080.

(1S,3R,4S,6S)-4-(3-Chloroprop-1-en-2-yl)-3-(3,3-diethoxy-

propyl)-1,3-dimethyl-7-oxabicyclo[4.1.0]heptan-2-one (29). A

solution of CeCl₃·7H₂O (3.666 g, 9.84 mmol, 1.5 equiv) in water (34

mL) was added to a well-stirred solution of 14 (2.025 g, 6.52 mmol) in

CH₂Cl₂(34 mL) at 0 °C. The resulting emulsion was treated dropwise

with an aqueous solution of NaOCl (8% available chlorine, 10.5 mL, 4

equiv), and the mixture was vigorously stirred at 0 °C until TLC

analysis (8:2 hexanes−EtOAc) indicated the conversion was nearly

complete (ca. 1 h). A saturated Na₂S₂O₃solution was added, and the

mixture was extracted with CH₂Cl₂. The combined organic layers were

washed with brine and dried. Evaporation of the solvent followed by

chromatographic puriﬁcation (9:1 hexanes−EtOAc) aﬀorded chloride

3β-Hydroxyisospongia-13,15-dien-12-one (28). A solution of

diol 27 (36 mg, 0.112 mmol) in CHCl₃(6 mL) was treated with active

manganese dioxide (5 μm, activated 85%, 240 mg, 2.8 mmol) and

stirred for 3 days at rt. The reaction mixture was diluted with EtOAc

(6 mL) and centrifuged. The supernatant was decanted and the

precipitate was washed/centrifuged with EtOAc. Evaporation of the

solvent aﬀorded a solid residue that was puriﬁed by column

chromatography (9:1 CHCl₃−EtOAc) to yield 3β-hydroxymargina-

tone 28 (30.5 mg, 94% based on the starting material consumed) as a

white solid: mp 163−164 °C (from hexanes−Et₂O); [α]²⁶−65 (c

D

0.40, CHCl₃); IR ν_max/cm⁻¹(KBr) 3439 m, 1671s, 1586w, 1440 m,

1133 m, 1052 m, 754 m; ¹H NMR (CDCl₃, 300 MHz) δ 7.26 (1H, d, J

= 2.0 Hz, H-16), 6.58 (1H, d, J = 2.0 Hz, H-15), 3.21 (1H, dd, J =

11.4, 4.7 Hz, H-3), 2.51 (1H, dd, J = 17.2, 3.8 Hz, H-11α), 2.49 (1H,

dd, J = 17.2, 16.5 Hz, H-11β), 2.30 (1H, ddd, J = 20.7, 13.0, 3.2 Hz, H-

7β), 1.86 (1H, dd, J = 16.5, 3.8, Hz, H-9), 1.77 (1H, ddd, J = 11.9, 5.7,

2.2 Hz, H-6α), 1.74−1.53 (5H, m, H-1β, 2 × H-2, H-6β, H-7α,), 1.284

(3H, s, Me-C₈), 1.06 (1H, dd, J = 13.0, 4.4 Hz, H-1α), 1.002 (3H, s,

Meα-C₄), 0.984 (3H, s, Meβ-C₄), 0.91 (1H, dd, J = 2.4, 11.5 Hz, H-5),

0.823 (3H, s, Me-C₁₀); ¹³C NMR (CDCl₃, 75 MHz) δ 194.7 (C₁₂),

175.7 (C₁₄), 142.3 (C₁₆), 118.2 (C₁₃), 106.2 (C₁₅), 78.4 (C₃), 55.8

(C₉), 55.3 (C₅), 38.9 (C₄), 37.7 (C₁), 37.2 (C₈), 37.0 (C₁₀), 35.5 (C₇),

35.3 (C₁₁), 27.9 (Meα-C₄), 26.9 (C₂), 20.4 (Me-C₈), 17.7 (C₆), 16.1

(Meβ-C₄), 15.2 (Me-C₁₀); MS (EI) m/z 316 (M⁺, 100), 301 (9), 298

(9), 283 (36), 274 (20), 187 (21), 178 (89), 161 (76), 147 (52);

HRMS m/z calcd for C₂₀H₂₈O₃316.2038, found 316.2035.

29 (2.027 g, 90%) as a colorless oil: [α]²¹−32 (c 1.8, CHCl₃); IR

D

1

ν_max/cm⁻¹(NaCl) 1705s, 1443 m, 1372 m, 1121s, 1061s; H NMR

(C₆D₆, 300 MHz) δ 5.13 (1H, br s, H-1′′), 4.66 (1H br s, H′-1′′), 4.31

(1H, dd, J = 6.0, 4.0 Hz, H-3′), 4.05 (1H, dd, J = 12.3, 1.1 Hz, H-3′′),

3.81 (1H, dd, J = 12.3, 0.6 Hz, H′-3′′), 3.47 and 3.26 (2H each, each m,

2 × MeCH₂O), 3.19 (1H, dd, J = 12.2, 4.4 Hz, H-4), 2.75 (1H, d, J =

1.9 Hz, H-6), 2.04 (1H, ddd, J = 12.8, 12.8, 4.8 Hz, H-1′), 1.91−1.77

(2H, m, H-2′, H-5), 1.70 (1H, dddd, J = 12.5, 12.5, 4.3, 4.3 Hz, H′-2′),

1.54 (1H, ddd, J = 15.0, 12.0, 1.0 Hz, H′-5), 1.39 (1H, dd, J = 12.6, 3.6

Hz, H′-1′), 1.299 (3H, s, Me-C₁), 1.055 (6H, t, J = 7.0 Hz, 2 ×

MeCH₂O), 0.727 (3H, s, Me-C₃); ¹³C NMR (C₆D₆, 75 MHz) δ 208.8

(C₂), 145.1 (C_2′′), 118.5 (C_1′′), 103.1 (C_3′), 62.2 (MeCH₂O), 60.6

(MeCH₂O), 60.1 (C₆), 58.1 (C₁), 49.9 (C_3′′), 49.3 (C₃), 34.9 (C₄),

31.9 (C_1′), 29.0 (C_2′), 27.4 (C₅), 21.1 (Me-C₃), 16.4 (Me-C₁), 15.6

and 15.4 (2 × MeCH₂O); HRMS (ESI) m/z calcd for C₁₈H₂₉NaO₄Cl

[M + Na]⁺367.1652, found 367.1656.

Further elution with the same eluent aﬀorded the unreacted starting

diol (4 mg, 11%).

2-((1S,3R,4R,6S)-4-(3,3-Diethoxypropyl)-4,6-dimethyl-5-oxo-

7-oxabicyclo[4.1.0]heptan-3-yl)acrylaldehyde (30).). A solution

of chloride 29 (467 mg, 1.36 mmol), LiI (353 mg, 2.63 mmol), and

NEMO (2.12 mL of a 25% (m/v) solution in DMF, 4.04 mmol) in dry

DMF (6 mL) was heated to 55 °C for 30 h. The reaction mixture was

cooled to rt, diluted with water, and extracted with EtOAc. The

organic extracts were successively washed with both 10% Na₂SO₃and

1.5% LiCl solutions as well as brine, dried, and concentrated to

dryness. Column chromatography of the residue (8:2 → 7:3 hexanes−

EtOAc) gave, in order of elution, unreacted 29 (93 mg, 20%), formate

30b (28 mg, 7% based on recovered starting material), and aldehyde

30 (261 mg, 74% based on recovered starting material).

Isospongia-13,15-dien-12-one (Marginatone, 5). Pentaﬂuor-

ophenyl chlorothionoformate (20 μL, 0.12 mmol) was added to a

solution of alcohol 28 (18 mg, 0.06 mmol) and DMAP (21.9 mg, 0.18

mmol) in anhydrous CH₂Cl₂(405 μL) at 0 °C under N₂. The mixture

was stirred for 6 h at rt and then diluted with EtOAc. The mixture was

transferred to a separatory funnel, washed with water and brine, dried,

and concentrated. The obtained residue was puriﬁed by column

chromatography (10:0 → 9:1 hexanes−EtOAc) to yield the

pentaﬂuorophenyl thionocarbonate intermediate (28.5 mg): ¹H

NMR (CDCl₃, 300 MHz) δ 7.27 (1H, d, J = 2.0 Hz, H-16), 6.60

(1H, d, J = 2.0 Hz, H-15), 4.93 (1H, dd, J = 11.6, 4.7 Hz, H-3), 2.53

(1H, br s, H-11α), 2.50 (1H, d, J = 2.0, 16.5 Hz, H-11β), 1.310 (3H, s,

Me-C₈), 1.065 (3H, s, Meα-C₄), 1.018 (3H, s, Meβ-C₄), 1.008 (3H, s,

Me-C₁₀).

A solution of this compound and AIBN (2.5 mg) in anhydrous

benzene (5 mL) was rigorously degassed using the freeze−thaw cycle,

treated with Bu₃SnH (48 μL, 0.12 mmol), and reﬂuxed for 6 h. The

reaction mixture was cooled to rt, poured into a 5% NaHCO₃solution,

and extracted with EtOAc. The combined organic layers were washed

three times with a 1 M aqueous solution of KF followed by water and

brine before drying. Chromatography of the residue (9:1 hexanes−

EtOAc) aﬀorded (−)-marginatone (5, 13.5 mg, 79%) as a white solid:

mp 174−175 °C (from hexanes) [lit.²⁰mp 167−168 °C]; [α]²⁵_D−22

(c 0.45, CHCl₃) [lit.²⁰−26 (c 0.36, CHCl₃), lit.¹¹−16 (c 0.4,

CHCl₃)]; IR ν_max/cm⁻¹(KBr) 1671s, 1268w, 1132 m, 1050w, 771w,

722w; ¹H NMR (CDCl₃, 400 MHz) δ 7.26 (1H, d, J = 2.0 Hz, H-16),

6.59 (1H, d, J = 2.0 Hz, H-15), 2.55 (1H, dd, J = 17.2, 3.7 Hz, H-11α),

2.46 (1H, dd, J = 17.2, 12.9 Hz, H-11β), 2.28 (1H, ddd, J = 12.2, 2.6,

2.6 Hz, H-7β), 1.90 (1H, dd, J = 12.9, 3.7 Hz, H-9), 1.75 (1H, m, H-

2), 1.70−1.52 (4H, m, H-1β, H′-2, H-6 and H-7α), 1.48 (1H, ddd, J =

10.1, 6.9, 3.1 Hz, H′-6), 1.40 (1H, m, H-3β), 1.289 (3H, s, Me-C₈),

Data for aldehyde 30: oil; [α]²⁸−48 (c 0.375, CHCl₃); IR ν_max

/

D

cm⁻¹(NaCl) 1738 m, 1694s, 1132 m, 1061 m; H NMR (C₆D₆, 300

MHz) δ 9.07 (1H, s, H-1), 5.54 (1H, s, H-3), 5.32 (1H, s, H′-3), 4.49

(1H, dd, J = 5.5, 5.5 Hz, H-3′′), 3.65 (1H, dd, J = 12.1, 4.3 Hz, H-3′),

3.57 and 3.39 (2H each, each m, 2 × MeCH₂O), 2.74 (1H, d, J = 2.2

Hz, H-1′), 2.16 (1H, m, H-1′′), 2.01 (1H, ddd, J = 12.5, 13.2, 3.9 Hz,

H-2′′), 1.81−1.61 (2H, m, H′-1′′, H-2′), 1.52 (1H, ddd, J = 14.6, 3.9,

3.5 Hz, H′-2′), 1.24 (1H, dd, J = 13.2, 12.5, 3.9 Hz, H′-2′′), 1.312 (3H,

s, Me-C_6′), 1.116 (6H, t J = 7.0 Hz, 2xMeCH₂O), 0.721 (3H, s, Me-

C_4′); ¹³C NMR (C₆D₆, 75 MHz) δ 208.9 (C_5′), 193.3 (C₁), 149.5 (C₂),

137.2 (C₃), 103.2 (C_3′′), 61,2 (MeCH₂O), 60.3, (C_1′), 60.1

(MeCH₂O), 58.7 (C_6′), 49.1 (C_4′), 32.7 (C_2′′), 31.9 (C_3′), 28.7 (C_1′′),

25.9 (C_2′), 21.4 (Me-C_4′), 16.4 (Me-C_6′), 15.6 (2xMeCH₂O); MS (EI)

m/z 295 (M⁺-CHO, 1), 279 (M⁺-EtO, 1), 233 (2), 205 (1), 187 (3),

149 (2), 129 (2), 103 (100); HRMS m/z calcd for C₁₆H₂₃O₄[M −

EtO]⁺279.1591, found 279.1592.

1

Further elution with 7:3 hexanes−EtOAc aﬀorded alcohol 30a (32

mg, 9% based on recovered starting material) as an oil.

Methyl 2-((1S,3S,4R,6S)-4-(3,3-Diethoxypropyl)-4,6-dimeth-

yl-5-oxo-7-oxabicyclo[4.1.0]heptan-3-yl)acrylate (32). A solu-

tion of NaClO₂(1.334 g, 11.7 mmol) and NaH₂PO₄·H₂O (1.113 g,

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Article

10.2 mmol) in water (7.5 mL) and 2-methyl-2-butene (1.6 mL 15.3

mmol) were consecutively added to a solution of aldehyde 30 (1.654

mg, 5.1 mmol) in t-BuOH (18 mL) cooled to 0 °C. The reaction ﬂask

was tightly closed, and the mixture was stirred for 3 h before pouring

into a saturated NH₄Cl solution, extracting with EtOAc and working

up as usual to aﬀord acid 31 (1.66 g) as a semisolid. This compound

was esteriﬁed by treating with freshly distilled diazomethane at 0 °C to

yield methyl ester 32 (1.71 g, 95%) after concentrating to dryness

under vacuum as a suﬃciently pure oil to use in the next step without

further puriﬁcation: [α]²⁰_D−50 (c 1.35, CHCl₃); IR ν_max/cm⁻¹(NaCl)

1722s, 1694s, 1618w, 1252s, 1142s, 1061s, ¹H NMR(C₆D₆, 300 MHz)

δ 6.14 (1H, d, J = 0.8 Hz, H-3), 5.05 (1H, sa, H′-3), 4.44 (1H, dd, J =

5.4, 5.4 Hz, H-3′′), 3.81 (1H, dd, J = 9.6, 6.9 Hz, H-3′), 3.54 and 3.35

(2H each, each m 2 × MeCH₂O), 3.394 (3H, s, MeO), 2.75 (1H, dd, J

= 2.0, 1.0 Hz, H-1′), 2.15 (1H, dddd, J = 12.6, 12.6, 5.6, 3.9 Hz, H-2′′),

2.05 (1H, ddd, J = 12.6, 12.6, 3.1 Hz, H-1′′), 1.80−1.65 (3H, m, H′-2′′,

2 × H-2′), 1.41 (1H, ddd, J = 12.6, 12.6, 3.1 Hz, H′-1′′), 1.311 (3H, s,

Me-C_6′), 1.089 and 1.078 (3H each, each t, J = 7.1 Hz, 2xMeCH₂O),

0.783 (3H, s, Me-C_4′); ¹³C NMR (C₆D₆, 75 MHz) δ 209.0 (C_5′), 168.0

(C₁), 141.0 (C₂), 126.9 (C₃), 103.3 (C_3′′), 61.2 (MeCH₂O), 60.3 (C_1′),

60.0 (MeCH₂O), 58.6 (C_6′), 51.74 (MeO), 49.5 (C_4′), 34.4 (C_3′), 33.0

(C_2′′), 28.8 (C_1′′), 26.7 (C_2′), 20.9 (Me-C_4′), 16.4 (Me-C_6′), 15.6 and

15.5 (2xMeCH₂O); MS (EI) m/z 309 (M⁺-EtO, 10), 263 (1), 231 (1),

203 (2), 175 (1), 163 (1), 147 (2), 103 (100); HRMS m/z calcd for

C₁₇H₂₅O₅[M − EtO]⁺309.1697, found 309.1704.

Methyl 2-((1S,3S,4R,6S)-4-((E)-5-((tert-Butyldimethylsilyl)-

oxy)-4-methylhexa-3,5-dien-1-yl)-4,6-dimethyl-5-oxo-7-

oxabicyclo[4.1.0]heptan-3-yl)acrylate (35). Compound 34 (259

mg, 0.78 mmol) was reacted according to the procedure described

above for 17 using CH₂Cl₂(8.6 mL), Et₃N (248 μL, 1.76 mmol) and

TBDMOTf (231 μL, 1.01 mmol). Puriﬁcation of the crude product by

column chromatography (9:1 hexanes−Et₂O with 0.2% of Et₃N)

yielded dienol silyl ether 35 (339 mg, 97%) as a colorless oil: [α]²¹

D

−7° (c 0.55, CHCl₃); IR ν_max/cm⁻¹(NaCl) 1727s, 1700s, 1596w,

1

1263 m, 1148 m, 1011 m, 837s; H NMR (C₆D₆, 300 MHz) δ 6.24

(1H, ddd, J = 7.6, 7.6, 0.8 Hz, H-3′′), 6.12 and 5.03 (1H each, each br

s, 2 × H-3), 4.46 and 4.34 (1H each, each s, 2 × H-6′′), 3.87 (1H, dd, J

= 10.9, 5.7 Hz, H-3′), 3.376 (3H, s, MeO), 2.76 (1H, dd, J = 2.6, 1.4

Hz, H-1′), 2.59 and 2.21 (1H each, each m, 2 × H-2′′), 1.98 (1H, ddd,

J = 13.6, 13.4, 4.8 Hz, H-1′′), 1.807 (3H, d, J = 0.5 Hz, Me-C_4′′), 1.79−

1.67 (2H, m, 2 × H-2′), 1.33 (1H, m, H′-1′′), 1.329 (3H, s, Me-C_6′),

1.007 (9H, s, Me₃CSi), 0.740 (3H, s, Me-C_4′), 0.159 (6H, s, 2 ×

MeSi); ¹³C NMR (C₆D₆, 75 MHz) δ 208.8 (C_5′), 167.9 (COOMe)

158.1 (C_5′′), 141.0 (C₂), 131.8 (C_4′′), 128.5 (C_3′′), 126.8 (C₃) 91.2

(C_6′′), 60.3 (C_1′), 58.7 (C_6′), 51.7 (COOMe), 49.8 (C_4′), 37.9 (C_1′′),

34.2 (C_3′), 26.7 (C_2′), 26.1 (Me₃CSi), 23.9 (C_2′′), 20.9 (Me-C_4′), 18.5

(Me₃CSi), 16.4 (Me-C_6′), 13.4 (Me-C_4′′), −4.5 (2 × MeSi); MS (EI)

m/z 448 (M⁺,14), 433 (3), 417 (3), 225 (100), 223 (10), 197 (13),

168 (30); HRMS m/z calcd for C₂₅H₄₀O₅Si 448.2645, found

448.2651.

( 4 a S , 6 a R , 7 a S , 8 a S , 9 a S , 9 b R ) - M e t h y l 3 - ( ( t e r t -

Butyldimethylsilyl)oxy)-4,6a,7a-trimethyl-7-oxo-

1,2,4a,5,6,6a,7,7a,8a,9,9a,9b-dodecahydrophenanthro[2,3-b]-

oxirene-9b-carboxylate (36). Heating a solution of 35 (490 mg,

1.09 mmol) in toluene (14.4 mL) to 140 °C for 4 days as described

above for 18 followed by chromatographic puriﬁcation (8:2 hexanes−

Methyl 2-((1S,3S,4R,6S)-4,6-Dimethyl-5-oxo-4-(3-oxoprop-

yl)-7-oxabicyclo[4.1.0]heptan-3-yl)acrylate (33). Aldehyde 33

was prepared from ketal 32 (1.77 g, 4.99 mmol) as described above

for 15 using PPTS (1.26 g, 5.00 mmol) in 4% aqueous acetone (78

mL). The crude material was puriﬁed by column chromatography (6:4

hexanes−EtOAc) to yield the desired product (1.27 g, 91%) as a

colorless oil: [α]²¹_D−85 (c 0.75, CHCl₃); IR ν_max/cm⁻¹(NaCl) 1716s,

1

EtOAc) aﬀorded a white solid (481 mg, 98%) that was shown by H

1

NMR to be an 83:17 mixture of Diels−Alder adducts 36 and 37.

Crystallization of this mixture from hexanes yielded two essentially

pure crops of the single diastereomeric adduct 36 (288 mg, 60%): mp

1694s, 1618w, 1257 m, 1153 m, 1082w, 995w; H NMR (C₆D₆, 300

MHz) δ 9.29 (1H, br s, H-3′′), 6.10 (1H, d, J = 0.6 Hz, H-3), 4.96 (1H,

br s, H′-3), 3.68 (1H, dd, J = 11.9, 4.9 Hz, H-3′), 3.30 (3H, s, MeO),

2.71 (1H, dd, J = 2.9, 1.0 Hz, H-1′), 2.58 (1H, dddd, J = 18.0, 11.0, 2.9,

1.0 Hz, H-2′′), 2.13 (1H, dddd, J = 18.0, 10.9, 5.3, 0.8 Hz, H′-2′′), 2.00

(1H, ddd, J = 14.4, 11.3, 5.3 Hz, H-1′′), 1.61 (1H, ddd, J = 15.2, 5.0,

3.3 Hz, H-2′), 1.53 (1H, ddd, J = 15.2, 11.9, 1.2 Hz, H′-2′), 1.43 (1H,

ddd, J = 14.6, 11.1, 3.6 Hz, H′-1′′), 1.306 (3H, s, Me-C_6′), 0.602 (3H, s,

Me-C_4′); ¹³C NMR (C₆D₆, 75 MHz) δ 208.1 (C_5′), 200.1 (C_3′′), 167.7

(C₁), 140.2 (C₂), 126.7 (C₃), 60.0 (C_1′), 58.1 (C_6′), 51.9 (MeO), 48.7

(C_4′), 39.6 (C_2′′), 32.8 (C_3′), 28.8 (C_1′′), 26.3 (C_2′), 20.2 (Me-C_4′), 16.3

(Me-C_6′); MS (EI) m/z 280 (M⁺, 0.3), 233 (2), 187 (4), 149 (2), 123

(3), 103 (100); HRMS m/z calcd for C₁₅H₂₀O₅280.1311, found

280.1306.

153−154 °C (from hexanes); [α]²⁰−36 (c 0.225 CHCl₃); IR ν_max

/

D

1

cm⁻¹(KBr) 1732s, 1700s, 1678 m, 1219 m, 1192s, 1159s, 837s; H

RNMR (C₆D₆, 300 MHz) δ 3.243 (3H, s, MeO), 2.89 (1H, br d, J =

2.0 Hz, H-8a), 2.29 (1H, ddd, J = 13.5, 2.0, 2.0 Hz, H-9), 2.25−2.15

(2H, m, H-1, H-6), 2.10 (1H, ddd, J = 13.0, 13.0, 3.5 Hz, H-5), 1.97

(2H, m, 2 × H-2), 1.91 (1H, J = 13.5, 13.0, 1,0 Hz, H′-9), 1.84 (1H,

dd, J = 13.0, 1.5 Hz, H-9a), 1.71 (1H, br dd, J = 13.0, 1.3 Hz, H-4a),

1.647 (3H, dd, J = 3.2, 1.5 Hz, Me-C₄), 1.59 (1H, m, H′-5), 1.434 (1H,

dd, J = 13.6, 4.5 Hz, H′-6), 1.360 (3H, s, Me-C_7a), 0.998 (9H, s, Me₃-

C-Si), 0.94 (1H, ddd, J = 11.7, 11.7, 6.9 Hz, H′-1), 0.727 (3H, s, Me-

C_6a), 0.105 and 0.083 (3H each, each s, 2 × Me-Si); ¹³C NMR (C₆D₆,

75 MHz) δ 207.4 (C₇), 175.0 (COO), 141.1 (C₃), 114.3 (C₄), 59.6

(C_8a), 56.4 (C_7a), 50.8 (MeO), 48.0 (C_9b), 46.5 (C_4a), 46.0 (C_6a), 40.9

(C_9a), 34.1 (C₆), 33.9 (C₁), 28.5 (C₂), 26.1 (Me₃-C-Si), 22.6 (C₉),

21.5 (C₅), 18.4 (Me₃-C-Si), 16.8 (Me-C_7a), 16.2 (Me-C_6a), 12.8 (Me-

C₄), −3.5 and −4.0 (2 × Me-Si); MS (EI) m/z 448 (M⁺, 100), 433

(18), 391 (24), 211 (11), 171 (11), 159 (8), 141 (16); HRMS m/z

calcd for C₂₅H₄₀O₅Si 448.2645, found 448.2646.

Methyl 2-((1S,3S,4R,6S)-4,6-Dimethyl-4-((E)-4-methyl-5-oxo-

hex-3-en-1-yl)-5-oxo-7-oxabicyclo[4.1.0]heptan-3-yl)acrylate

(34). A solution of aldehyde 33 (290 mg, 1.0 mmol) and 3-

(triphenylphosphoranylidene)butan-2-one (450 mg, 1.4 mmol) en

CH₂Cl₂(10 mL) was stirred at 28 °C under N₂for 36 h, after which

the reaction mixture was concentrated to half its original volume by

rotary evaporation and transferred to the head of a silica gel column.

Elution with 8:2 hexanes−EtOAc aﬀorded the methyl ketone 34 (327

mg, 94%) as an oil: [α]²¹_D−23 (c 1.5, CHCl₃); IR ν_max/cm⁻¹(NaCl)

Analytically pure 37 was obtained by preparative reversed-phase

HPLC of a small amount of the residue obtained from the crystallized

mother liquor, which was an approximately 1:1 mixture of both

adducts. HPLC separation was performed on a semipreparative C18

prepacked Spherisorb ODS2 (250 × 10 mm, 5 μm) column

(Teknokroma) using a 65:15 CH₃CN−water mixture (by volume)

as eluent and a ﬂow rate of 1.5 mL/min. Retention times were 16.7

min for 36 and 18.8 min for 37.

1

1716s, 1694s, 1667s, 1629w, 1263 m, 1148s; H NMR (C₆D₆, 300

MHz) δ 6.24 (1H, ddq, J = 7.3, 7.3, 1.2 Hz, H-3′′), 6.12 (1H, d, J = 0.5

Hz, H-3), 5.03 (1H, br s, H′-3), 3.82 (1H, dd, J = 11.5, 5.2 Hz, H-3′),

3.281 (3H, s, MeO), 2.76 (1H, dd, J = 2.8, 1.2 Hz, H-1′), 2.55 (1H, m,

H-2′′), 2.09 (1H, m, H′-2′′), 1.962 (3H, s, Me-C_5′′), 1.884 (3H, br d, J =

1.2 Hz, Me-C_4′′), 1.86 (1H, ddd, J = 13.6, 11.7, 4.9 Hz, H-1′′), 1.77−

1.57 (2H, m, 2 × H-2′), 1.329 (3H, s, Me-C_6′), 1.16 (1H, ddd, J = 13.6,

11.6, 4.8 Hz, H′-1′′), 0.729 (3H, s, Me-C_4′); ¹³C NMR (C₆D₆, 75

MHz) δ 208.8 (C_5′), 198.0 (C_5′′), 167.9 (C₁), 142.1 (C_3′′), 140.7 (C₂),

138.1 (C_4′′), 127.1 (C₃), 60.2 (C_1′), 58.6 (C_6′), 51.8 (MeO), 49.6 (C_4′),

36.6 (C_1′′), 33.8 (C_3′), 26.7 (C_2′), 25.1 (Me-C_5′′), 24.6 (C_2′′), 20.9 (Me-

C_4′), 16.4 (Me-C_6′), 11.3 (Me-C_4′′); MS (EI) m/z 334 (M⁺, 2), 319

(2), 303 (2), 277 (10), 224 (91), 206 (36), 192 (39), 174 (30), 147

(47), 139 (28), 111 (100); HRMS m/z calcd for C₁₉H₂₆O₅334.1780,

found 334.1793.

Adduct 37 was obtained as a white solid: mp 123−125 °C (by slow

evaporation of a hexane solution); [α]²⁰−40 (c 0.25 CHCl₃); IR

D

ν_max/cm⁻¹(KBr) 1727s, 1705s, 1645 m, 1175s, 1104s; ¹H NMR

(C₆D₆, 400 MHz) δ 3.274 (3H, s, MeO), 2.97 (1H, br s, H-4a), 2.87

(1H, d, J = 2.5 Hz, H-8a), 2.51 (1H, dd, J = 13.3, 3.3 Hz, H-9a), 2.37

(1H, br dd, J = 14.7, 13.3 Hz, H-9), 2.16−1.82 (5H, m, H-1, H-2, H-5,

H-6, H-9), 1.71 (1H, ddd, J = 15.0, 7.0, 3.5 Hz, H′-1), 1.562 (3H, d, J

= 1.2 Hz, Me-C₄), 1.51 (1H, ddd, J = 12.6, 12.6, 6.3 Hz, H′-6), 1.43

(1H, ddd, J = 14.2, 14.2, 3.5 Hz, H′-5), 1.316 (3H, s, Me-C_7a), 0.99

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(1H, m, H′-2), 0.987 (9H, s, Me₃-C-Si), 0.823 (3H, s, Me-C_6a), 0.173

and 0.107 (3H each, each s, 2 × Me-Si); ¹³C NMR (C₆D₆, 100 MHz)

δ 208.1 (C₇), 177.3 (COO), 143.7 (C₃), 112.0 (C₄), 59.7 (C_8a), 56.8

(C_7a), 51.2 (MeO), 46.2 (C_9b), 45. Nine (C_6a), 40.8 (C_4a), 31.2 (C₆),

30.4 (C_9a), 29.5 (C₅), 27.0 (C₂), 26.1 (Me₃-C-Si), 23.0 (C₉), 21.0

(C₁), 18.3 (Me₃-C-Si), 17.0 (Me-C_6a), 16.8 (Me-C_7a), 13.5 (Me-C₄),

−3.5 and −4.1 (2 × Me-Si); HRMS m/z calcd for C₂₅H₄₁O₅Si [M +

H]⁺449.2723, found 449.2717.

evaporating the solvent aﬀorded a residue that was chromatographed

(9:1 → 8:2 hexanes−EtOAc) to yield the allyl ether 40 (130 mg, 94%)

as a white solid: mp 116−117 °C (from hexanes); [α]²⁰−6 (c 1.8,

D

CHCl₃); IR ν_max/cm⁻¹(KBr) 1716s, 1252 m, 1203s, 1170 m, 1082s,

1055s, 831s; ¹H NMR (CDCl₃, 300 MHz) δ 5.91 (1H, dddd, J = 16.7,

10.7, 5.5, 5.5 Hz, H-2′), 5.27 (1H, ddd, J = 16.7, 3.2, 1.5 Hz, H-3′),

5.15 (1H, br dd, J = 10.4, 1.4 Hz, H′-3′), 4.22 (1H, dddd, J = 12.5, 5.2,

1.2, 1.2 Hz, H-1′), 3.98 (1H, dddd, J = 12.5, 5.7, 1.2, 1.2 Hz, H′-1′),

3.673 (3H, s, MeO), 3.07 (1H, br s, H-5a), 2.82 (1H, s, H-4), 2.23−

1.93 (6H, m, 2 × H-6, H-2, H-8, H-7, H-3), 1.75−1.53 (2H, m, H′-2,

H′-8), 1.300 (3H, s, Me-C_4a), 1.109 (3H, s, Me-C_1a), 1.10−0.93 (3H,

m, H-1b, H-3, H-6a), 0.821 (9H, s, Me₃-C-Si), 0.70 (1H, m, H′-7),

0.658 (3H, s, Me-C_3a), 0.52 (1H, dd, J = 5.2, 1.0 Hz, H-1β), 0.22 (1H,

d, J = 5.2 Hz, H-1α), 0.053 and 0.003 (3H each, each s, 2 × Me-Si);

¹³C NMR (CDCl₃, 75 MHz) δ 175.4 (COOMe), 134.6 (C_2′), 116.6

(1aS,1bS,3aR,4aS,5aS,6aS,6bR,8aR)-Methyl 8a-((tert-

Butyldimethylsilyl)oxy)-1a,3a,4a-trimethyl-4-oxotetradecahy-

dro-1H-cyclopropa[7,8]phenanthro[2,3-b]oxirene-6b-carboxy-

late (38). Compound 36 (261 mg, 0.58 mmol) was treated as

described above for 19 by stirring with CH₂I₂(377 μL, 4.71 mmol),

diethylzinc in hexane (1 M, 4.71 mL, 4.71 mmol), and toluene (15

mL) at 0 °C for 4 h. Workup and chromatography (9:1 hexanes−

EtOAc) aﬀorded cyclopropane 38 (258 mg, 96%) as a solid: mp 150−

(C_3′), 88.5 (C₄), 74.7 (C_1′), 61.2 (C_5a), 59.4* (C_4a), 59.3* (C_8a), 53.0

(C_1b), 50.8 (COOMe), 47.1 (C_6b), 44.2 (C_6a), 38.9 (C₃), 37.5 (C_3a),

33.6 (C₇), 29.8 (C₈), 29.5 (C₁), 25.7 (Me₃CSi), 23.6 (C_1a), 22.6 (C₂),

22.5 (C₆), 19.8 (Me-C_4a), 17.8 (Me₃CSi), 15.5 (Me-C_1a), 11.7 (Me-

C_3a), −3.6 and −3.8 (2 × MeSi); MS EI) m/z 504 (M⁺, 8), 475 (8),

447 (21), 317 (12), 211 (52), 172 (21), 141 (9), 116 (100); HRMS

m/z calcd for C₂₉H₄₈O₅Si 504.3271, found 504.3255.

151 °C (from hexanes); [α]²⁰−68 (c 0.8, CHCl₃); IR ν_max/cm⁻¹

D

1

(KBr) 1722s, 1700s, 1252 m, 1192 m, 826s; H NMR (CDCl₃, 300

MHz) δ 3.689 (3H, s, MeO), 3.39 (1H, d, J = 1.9 Hz, H-5a), 2.50 (1H,

ddd, J = 15.8, 3.3, 3.3 Hz, H-6α), 2.31 (1H, ddd, J = 15.6, 12.8, 1.0 Hz,

H-6β), 2.20−1.90 (4H, m, H-2β, H-3, H-7, H-8α), 1.84 (1H, dddd, J =

10.4, 6.8, 3.7, 1.3 Hz, H-2α), 1.70 (1H, dd, J = 12.6, 3.9 Hz, H-6a),

1.61 (1H, dddd, J = 14.0, 14.0, 5.8, 1.2 Hz, H-8β), 1.382 (3H, s, Me-

C_4a), 1.29 (1H, dd, J = 14.3, 4.3 Hz, H′-3), 1.129 (3H, s, Me-C_1a),

1.043 (1H, dd, J = 12.9, 3.8 Hz, H-1b), 0.828 (9H, s, Me₃CSi), 0.814

(3H, s, Me-C_3a), 0.73 (1H, dd, J = 13.8, 5.0 Hz, H′-7), 0.54 (1H, dd, J

= 5.4, 1.2 Hz, H-1β), 0.24 (1H, d, J = 5.4 Hz, H-1α), 0.060 and 0.011

(3H each, each s, 2 × MeSi); ¹³C NMR (CDCl₃, 75 MHz) δ 208.3

(C₄), 175.6 (COOMe), 60.0 (C_5a), 59.2 (C_8a), 56.4 (C_4a), 52.6 (C_1b),

51.0 (COOMe), 46. 9* (C_6b), 45.7* (C_3a), 41.0 (C_6a), 33.9 (C₃), 33.5

(C₇), 29.7 (C₈), 29.4 (C₁), 25.7 (Me₃CSi), 23.4 (C_1a), 22.4 (C₂), 21.8

(C₆), 17.9 (Me₃CSi), 16.5 (Me-C_3a), 16.4 (Me-C_4a), 15.4 (Me-C_1a),

−3.8 and −3.3 (2 × MeSi); MS (EI) m/z 462 (M⁺, 27), 447 (10), 433

(10), 405 (48), 211 (96), 185 (7), 73 (100); HRMS m/z calcd for

C₂₆H₄₂O₅Si 462.2802, found 462.2812.

(1aS,1bS,3aR,4S,6S,7aS,7bS,9aR)-Methyl 4-(Allyloxy)-9a-

((tert-butyldimethylsilyl)oxy)-6-hydroxy-1a,3a-dimethyl-5-

methylenetetradecahydro-1H-cyclopropa[a]phenanthrene-

7b-carboxylate (41). BuLi (1.54 M in hexanes, 0.886 mL, 1.36

mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiper-

idine (238 μL, 1.42 mmol) in anhydrous toluene (1.6 mL) at 0 °C.

After 10 min, the reaction mixture was treated with a 1 M solution of

Et₂AlCl in hexane (1.32 mL, 1.32 mmol) and stirred for an additional

30 min at the same temperature. A solution of epoxide 40 (176 mg,

0.34 mmol) in toluene (8.8 mL) was added dropwise and the mixture

stirred at 0 °C for 40 min. The reaction mixture was treated with 5%

NaHCO₃solution, poured into a 10% aqueous solution of sodium

citrate, and extracted with Et₂O. The usual workup and subsequent

silica gel chromatography (9:1 → 8:2 hexanes−EtOAc) produced

allylic alcohol 41 (167 mg, 95%) as an amorphous solid: [α]²⁰_D−12 (c

0.65, CHCl₃); IR ν_max/cm⁻¹(KBr) 3431 m, 1727s, 1257 m, 1203 m,

(1aS,1bS,3aR,4S,4aR,5aS,6aS,6bS,8aR)-Methyl 8a-((tert-

Butyldimethylsilyl)oxy)-4-hydroxy-1a,3a,4a-trimethyltetrade-

cahydro-1H-cyclopropa[7,8]phenanthro[2,3-b]oxirene-6b-car-

boxylate (39). Compound 39 was prepared from 38 (145 mg, 0.33

mmol) as described above for 20 using CeCl₃·7H₂O (123 mg, 0.33

mmol), NaBH₄(23 mg, 0.58 mmol), MeOH (9.3 mL), and CH₂Cl₂

(4.7 mL). Chromatographic puriﬁcation (8:2 → 7:3 hexanes−EtOAc)

yielded epoxy alcohol 39 (141 mg, 97%) as a white solid: mp 181−184

1

1142 m, 1082 m, 837s; H NMR (CDCl₃, 300 MHz) δ 5.90 (1H,

dddd, J = 17.2, 10.7, 5.5, 5.5 Hz, H-2′), 5.26 (1H, ddd, J = 17.2, 1.6, 1.4

Hz, H-3′), 5.14 (1H, dd, J = 10.4, 1.4 Hz, H′-3′), 4.95 (2H, m, 2 × H-

1′′), 4.48 (1H, dd, J = 2.7, 2.7 Hz, H-4), 4.07 (1H, dddd, J = 12.5, 5.3,

1.2, 1.2 Hz, H-1′), 3.87 (1H, dddd, J = 12.8, 5.8, 1.2, 1.2 Hz, H′-1′),

3.67 (1H, br s, H-6), 3.653 (3H, s, MeO), 2.2−2.0 (5H, m, H-3, H-8,

H-7, H-9, H-2), 1.9−1.7 (2H, m, H′-7, H′-2), 1.65 (1H, dd, J = 13.1,

2.8 Hz, H-7a), 1.59 (1H, m, H′-9), 1.2−1.1 (2H, m, H-1b, H′-3), 1.156

(3H, s, Me-C_1a), 0.837 (9H, s, Me₃CSi), 0.75 (1H, m, H′-8), 0.575

(3H, s, Me-C_3a), 0.53 (1H, dd, J = 5.2, 0.8 Hz, H-1β), 0.25 (1H, d, J =

5.2 Hz, H-1α), 0.066 and 0.023 (3H each, each s, 2 × MeSi); ¹³C

NMR (CDCl₃, 75 MHz) δ 175.5 (COOMe), 146.8 (C₅), 135.2 (C_2′),

116.4 (C_3′), 108.8 (C_1′′), 85.0 (C₆), 72.8 (C₄), 71.8 (C_1′), 59.4 (C_9a),

53.3 (C_1b), 50.7 (COOMe), 47.0 (C_7a), 46.4 (C_7b), 41.5 (C_3a) 38.5

(C₃), 33.6 (C₈), 30.7 (C₇), 29.8 (C₉), 29.4 (C₁), 25.7 (Me₃CSi), 23.6

(C_1a), 23.1 (C₂), 17.8 (Me₃CSi), 15.5 (Me-C_1a), 10.7 (Me-C_3a), −3.2

and −3.8 (2 × MeSi); MS (EI) m/z 504 (M⁺, 4), 486 (7), 447 (5),

429 (15), 237 (18), 211 (35), 187 (8), 173 (7), 155 (12), 73 (100);

HRMS m/z calcd for C₂₉H₄₈O₅Si 504.3271, found 504.3282.

°C (from benzene−hexanes); [α]²⁰+2 (c 0.85, CHCl₃); IR ν_max

/

D

cm⁻¹(KBr) 3453 m, 1738s, 1257 m, 1208 m, 1121 m, 1050 m, 842s;

¹H NMR (CDCl₃, 300 MHz) δ 3.688 (3H, s, MeO), 3.25 (1H, d, J =

5.7 Hz, H-4), 3.11 (1H, br s, H-5a), 2.30−1.93 (6H, m, H-7, H-3, H-8,

2 × H-6, H-2), 1.75 (1H, ddd, J = 15.8, 7.8, 4.9 Hz, H′-2), 1.65 (1H,

dddd, J = 14.0, 14.0, 6.4, 1.2 Hz, H′-8), 1.311 (3H, s, Me-C_4a), 1.13−

0.93 (3H, m, H′-3, H-6a, H-1b), 1.117 (3H, s, Me-C_1a), 0.826 (9H, s,

Me₃CSi), 0.716 (1H, dd, J = 13.3, 5.1 Hz, H′-7), 0.661 (3H, s, Me-

C_3a), 0.54 (1H, dd, J = 5.2, 1.2 Hz, H-1β), 0.24 (1H d, J = 5.2 Hz, H-

1α), 0.058 and 0.007 (3H each, each s, 2 × MeSi); ¹³C NMR (CDCl₃,

75 MHz) δ 175.5 (COOMe), 80.6 (C₄), 61.1 (C_5a), 59.3* (C_8a), 59.0*

(C_4a), 53.0 (C_1b), 50.9 (COOMe), 47.1 (C_6b), 43.6 (C_6a), 39.1 (C₃),

36.9 (C_3a), 33.6 (C₇), 29.8 (C₈), 29.6 (C₁), 25.7 (Me₃CSi), 23.6 (C_1a),

22.7 (C₂), 22.6 (C₆), 19.6 (Me-C_4a), 17.9 (Me₃CSi), 15.5 (Me-C_1a),

11.1 (Me-C_3a), −3.2 and −3.7 (2 × MeSi); MS (EI) m/z 464 (M⁺,

63), 450 (17), 449 (16), 446 (6), 435 (33), 407 (89) 389 (14), 255

(13), 211 (100); HRMS m/z calcd for C₂₆H₄₄O₅Si 464.2958, found

464.2954.

(1aS,1bS,3aR,4S,4aS,5aS,6aS,6bS,8aR)-Methyl 4-(Allyloxy)-

8a-((tert-butyldimethylsilyl)oxy)-1a,3a,4a-trimethyltetradeca-

hydro-1H-cyclopropa[7,8]phenanthro[2,3-b]oxirene-6b-car-

boxylate (40). A solution of epoxy alcohol 39 (127 mg, 0.27 mmol)

and allyl iodide (74 μL, 0.81 mmol) in dry DMF (4 mL) was added

dropwise to a stirred suspension of NaH (27 mg of 60% dispersion in

oil, 0.68 mmol, prewashed with pentane) at 0 °C. After being stirred at

this temperature for 12 h, the mixture was quenched with a saturated

NH₄Cl solution and diluted with water. Extracting with EtOAc,

washing the extracts with a 1.5% LiCl solution and brine, drying, and

Methyl 3β-((tert-Butyldimethylsilyl)oxy)-12α-hydroxy-3α,18-

cycloisospongia-13(15)-en-20-oate (42). A solution of 1,4-

benzoquinone (8 mg, 0.074 mmol), [(1,3-dimesityl-2-

imidazolylidene)(PCy₃)Cl₂RuCHPh] (40 mg, 0.0046 mmol), and

diene 41 (160 mg, 0.32 mmol) in dry CH₂Cl₂(20 mL) was reﬂuxed

for 1 h. Evaporation of the solvent under vacuum followed by

chromatography (9:1 → 7:3 CHCl₃−EtOAc) aﬀorded the dihydrofur-

an 42 (132 mg, 88%). Although obtained as a slightly colored solid,

the product was pure according to ¹H NMR analysis. A colorless

sample could be obtained by crystallization from hexanes−Et₂O: mp

178−180 °C; [α]²⁵+20 (c 0.8, CHCl₃); IR ν_max/cm⁻¹(KBr) 3431s,

D

1716s, 1634w, 1208s, 1061s, 1039s, 837s; ¹H NMR (CDCl₃, 300

MHz) δ 5.64 (1H, br d, J = 1.6 Hz, H-15), 4.68 (1H, br d, H-12), 4.64

5675

dx.doi.org/10.1021/jo3008034 | J. Org. Chem. 2012, 77, 5664−5680

The Journal of Organic Chemistry

Article

1

(1H, ddd, J = 12.5, 3.5, 1.2 Hz, H-16β), 4.54 (1H, ddd, J = 12.5, 6.1,

1.2 Hz, H-16α), 4.47 (1H, ddd, J = 5.8, 3.4, 2.0 Hz, H-14), 3.657 (3H,

s, MeO), 2.20−2.00 (2H, m, H-6, H-11), 2.18 (1H, ddd, J = 7.3, 5.8,

2.0 Hz, H-1), 1.95 (1H, ddd, J = 13.0, 3.3, 2.9 Hz, H-7), 1.90−1.70

(2H, m, H′-6, H′-11), 1.65−1.50 (2H, m, H-2, H-9), 1.30−1.20 (2H,

m, H′-2, H′-7), 1.16 (1H, dd, J = 12.0, 3.4 Hz, H-5), 1.142 (3H, s, Me-

C₄), 0.828 (9H, s, Me₃CSi), 0.76 (1H, m, H′-1), 0.583 (3H, s, Me-C₈),

0.53 (1H, dd, J = 5.2, 1.0 Hz, H-18β), 0.26 (1H, d, J = 5.2 Hz, H-18α),

0.058 and 0.013 (3H each, each s, 2 × MeSi); ¹³C NMR (CDCl₃, 75

MHz) δ 175.5 (COOMe), 139.8 (C₁₃), 119.9 (C₁₅), 92.8 (C₁₄), 76.0

(C₁₆), 65.2 (C₁₂), 59.4 (C₃), 53.2 (C₅), 50.8 (COOMe), 47.0 (C₁₀),

44.3 (C₉), 41.8 (C₈), 39.4 (C₇), 33.9 (C₁), 30.5 (C₁₁), 29.9 (C₂), 29.4

(C₁₈), 25.7 (Me₃CSi), 23.6 (C₄), 22.8 (C₆), 17.9 (Me₃CSi), 15.6 (Me-

C₄), 10.3 (Me-C₈), −3.2 and −3.7 (2 × MeSi); MS (EI) m/z 476 (M⁺,

1), 458 (6), 419 (3), 401 (15), 267 (22), 211 (67), 192 (17), 73

(100); HRMS m/z calcd for C₂₇H₄₄O₅Si 476.2958, found 476.2944.

Methyl 3β-((tert-Butyldimethylsilyl)oxy)-12α-hydroxy-3α,18-

cycloisospongia-13,15-dien-20-oate (43). Dihydrofuran 42 (93

mg, 0.21 mmol) was oxidized with DDQ (58 mg, 0.0.50 mmol) in

benzene (7.5 mL) as described for the preparation of 24. Column

chromatography (8:2 hexanes−EtOAc) of the crude product obtained

aﬀorded unreacted dihydrofuran 42 (7.5 mg, 8%) followed by the

furan 43 (79.5 mg, 93% based on recovered starting material) as a

colorless oil: [α]²⁴_D−87 (c 0.25, CHCl₃); IR ν_max/cm⁻¹(NaCl) 3431

hexanes−Et₂O); H NMR (CDCl₃, 400 MHz) δ 7.27 (1H, d), 6.60

(1H, d), 3.720 (3H, s), 2.88 (1H, dd), 2.79 (1H, dd), 2.40−2.25 (2H,

m), 2.25−2.15 (2H, m), 2.00−1.90 (2H, m), 1.60−1.50 (2H, m),

1.312 (3H, s), 1.21 (1H, dd), 1.128 (3H, s), 0.88 (1H), 0.65 (1H, dd),

0.33 (1H, d)].

The cyclopropanol obtained above (59 mg, 0.164 mmol) and

NaOH (13.1 mg, 0.33 mmol) were dissolved in a 4:1 mixture of

dioxane−water (6 mL), previously degasiﬁed by passage of a N₂

stream and sonication. The mixture was heated at 90 °C for 6 h, then

cooled to 0 °C, acidiﬁed with 0.1 M hydrochloric acid, and extracted

with EtOAc. The extracts were washed with 5% NaHCO₃solution and

brine and dried. Column chromatography (8:2 hexanes−EtOAc) of

the residue left after evaporation of the solvent aﬀorded the diketone

45 (57.9 mg, 96%) as a white solid: mp 140−141 °C (from hexane−

Et₂O); [α]²⁷_D−125 (c 0.8, CHCl₃); IR ν_max/cm⁻¹(KBr) 1705s, 1672s,

1459 m, 1268 m, 1164 m, 1137s,; ¹H NMR (CDCl₃, 300 MHz) δ 7.29

(1H, d, J = 2.0 Hz, H-16), 6.61 (1H, d, J = 2.0 Hz, H-15), 3.724 (3H,

s, MeO), 2.89−2.71 (2H, m, part AB of ABX system, 2 × H-11), 2.65

(1H, ddd, J = 13.1, 5.9, 2.9 Hz, H-1), 2.50−2.25 (4H, m, 2 × H-2, H-6,

H-7), 2.16 (1H, dd, part X of ABX system, J = 11.4, 5.4 Hz, H-9),

1.80−1.60 (2H, m, H′-6, H′-7), 1.59 (1H, dd, J = 9.7, 2.4 Hz, H-5),

1.50 (1H, ddd, J = 13.1, 13.1, 5.5 Hz, H′-1), 1.199 (3H, s, Me-C₈),

1.182 (3H, s, Meβ-C₄), 1.159 (3H, s, Meα-C₄); ¹³C NMR (CDCl₃, 75

MHz) δ 213.9 (C₃), 193.5 (C₁₂), 174.4* (COOMe), 174.1* (C₁₄),

142.8 (C₁₆), 118.6 (C₁₃), 106.2 (C₁₅), 56.1 (C₅), 53.2 (C₉), 51.6

(COOMe), 48.0^#(C₁₀), 47.9^#(C₄), 37.3 (C₁₁), 37.2 (C₈), 35.3 (C₇),

35.0 (C₂), 34.8 (C₁), 27.5 (Meα-C₄), 22.1 (C₆), 19.6 (Meβ-C₄), 17.6

(Me-C₈); MS (EI) m/z 358 (M⁺, 100), 326 (15), 299 (16), 289 (32),

276 (41), 248 (26), 229 (16) 204 (20), 176 (25), 161 (67), 148 (90);

HRMS m/z calcd for C₂₁H₂₆O₅358.1780, found 358.1797.

1

m, 1722s, 1623w, 1252 m, 1213s, 1044 m, 842s; H NMR (CDCl₃,

300 MHz) δ 7.21 (1H, d, J = 1.9 Hz, H-16), 6.30 (1H, d, J = 1.9 Hz,

H-15), 4.72 (1H, dd, J = 3.7, 1.7 Hz, H-12), 3.680 (3H, s, MeO),

2.30−2.10 (5H, m, H-1, H-2, H-6, H-7, H-11), 2.10−1.80 (2H, m, H′-

6, H′-11), 1.76 (1H, dd, J = 12.6, 1.3 Hz, H-9), 1.62 (1H, m, H′-2),

1.43 (1H, ddd, J = 13.2, 13.1, 4.2 Hz, H′-7), 1.19 (1H, m, H-5), 1.195

(3H, s, Me-C₄), 0.958 (3H, s, Me-C₈), 0.85 (1H, m, H′-1), 0.845 (9H,

s, Me₃CSi), 0.55 (1H, dd, J = 5.3, 1.0 Hz, H-18β), 0.27 (1H, d, J = 5.3

Hz, H-18α), 0.077 and 0.029 (3H each, each s, 2 × MeSi); ¹³C NMR

(CDCl₃, 75 MHz) δ 175.5 (COOMe), 160.9 (C₁₄), 141.2 (C₁₆), 116.5

(C₁₃), 109.1 (C₁₅), 62.8 (C₁₂), 59.5 (C₃), 53.6 (C₅), 50.9 (COOMe),

46.8 (C₉), 46.6 (C₁₀), 36.6 (C₈), 36.0 (C₇), 33.6 (C₁), 30.3 (C₁₁), 29.7

(C₂), 29.5 (C₁₈), 25.7 (Me₃CSi), 23.5 (C₄), 22.8 (C₆), 17.9 (Me-C₈),

17.9 (Me₃CSi), 15.4 (Me-C₄), −3.2 and −3.7 (2 × MeSi); HRMS

(ESI) m/z calcd for C₂₇H₄₂NaO₅Si [M + Na]⁺497.2699, found

497.2705.

Isospongia-13,15-dien-20-oic Acid (Marginatafuran, 3). A

solution of diketone 45 (30 mg, 0.084 mmol) and hydrazine hydrate

(0.4 mL) in diethylene glycol (2.6 mL) was heated to 120 °C for 1.5 h

under N₂The temperature was raised to 170 °C to remove any excess

hydrazine, KOH (106 mg, 1.9 mmol) was added, and the reaction

mixture was further heated to 185 °C for 8 h before being cooled to rt,

poured into 1 M hydrochloric acid, and extracted with CH₂Cl₂. The

extracts were washed with a 5% NaHCO₃solution and brine before

drying. Evaporating the solvent and purifying the residue by column

chromatography (7:3 hexanes−EtOAc) yielded marginatafuran 3 (16

mg, 61%) as a white solid: mp 202−205 °C (from hexanes; crystals

begin to change appearance at 180 °C) (lit.⁷mp 208 °C); [α]²²_D−91

(c 0.37, CHCl₃) (lit.⁷[α]_D−102); IR ν_max/cm⁻¹(KBr) 3437s, 1700s,

Methyl 3β-((tert-Butyldimethylsilyl)oxy)-12-oxo-3α,18-cyclo-

isospongia-13,15-dien-20-oate (44). Alcohol 43 (86 mg, 0.18

mmol) was oxidized in anhydrous CH₂Cl₂(4 mL) using NMO (42

mg, 0.36 mmol), TPAP (3.8 mg, 0.01 mmol), and 5 Å molecular sieves

(86 mg) as described for 26 to yield ketone 44 (82.5 mg, 96%) as a

1

1454 m, 1388w, 1268w, 1230 m, 1181w, 1142w, 1039w, 940w; H

NMR (CDCl₃, 500 MHz) δ 10.58 (1H, br s, COOH), 7.17 (1H, d, J =

1.8 Hz, H-16), 6.09 (1H, d, J = 1.8 Hz, H-15), 2.62 (1H, br d, J = 12.8

Hz, H-1), 2.47 (1H, dd, J = 15.0, 5.0 Hz, H-11), 2.35−2.20 (3H, m, H-

6, H-7, H′-11), 2.14 (1H, dd, J = 12.5, 5.5 Hz, H-12), 1.75−1.35 (7H,

2 × H-2, H-3, H′-6, H′-7, H-9, H′-12), 1.19 (1H, ddd, J = 14.0, 13.7,

3.6 Hz, H′-3), 1.129 (3H, s, Me-C₈), 1.11 (1H, dd, J = 12.5, 2.5 Hz, H-

5), 1.00 (1H, ddd, J = 12.8, 3.2, 3.2 Hz, H′-1), 0.927 (3H, s, Meα-C₄),

0.918 (3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 125 MHz) δ 180.4

(COOH), 159.3 (C₁₄), 140.3 (C₁₆), 113.6 (C₁₃), 109.9 (C₁₅), 56.8

(C₅), 56.0 (C₉), 48.3 (C₁₀), 42.4 (C₃), 38.7 (C₁), 37.2 (C₇), 37.1 (C₈),

33.8 (C₄), 33.7 (Meα-C₄), 23.0 (C₁₁), 22.7 (Meβ-C₄), 20.4 (C₁₂), 20.2

(C₂), 19.7 (Me-C₈), 18.8 (C₆); MS (EI) m/z 316 (M⁺, 46), 301 (100),

299 (1), 270 (10), 256 (67), 199 (2), 147 (4), 109 (9); HRMS m/z

calcd for C₂₀H₂₈O₃316.2038, found 316.2025.

Methyl 3β,12β-Dihydroxyisospongia-13,15-dien-20-oate

(46). CeCl₃·7H₂O (104 mg, 0.28 mmol) was added to a solution of

diketone 45 (50 mg, 0.14 mmol) in MeOH (2.8 mL), which was

stirred at rt until a homogeneous solution formed. CH₂Cl₂(2.8 mL)

was then added, and the reaction was cooled to −78° followed by the

addition of NaBH₄(23 mg, 0.58 mmol) in small portions over a 50

min period. After completion of the reduction reaction was conﬁrmed

by TLC (5:5 hexanes−EtOAc), the excess NaBH₄was quenched by

the addition of acetone (1 mL) and the reaction mixture diluted with a

10% aqueous solution of sodium citrate. The usual workup using

EtOAc as the extractant yielded a solid residue, which was puriﬁed by

chromatography (6:4 hexanes−EtOAc) to yield diol 46 (47.9 mg,

white solid: mp 121−123 °C (from hexanes); [α]²⁵−76 (c 1.5,

D

CHCl₃); IR ν_max/cm⁻¹(KBr) 1727s, 1683s, 1246 m, 1213 m, 1142 m,

837s,; ¹H NMR (CDCl₃, 300 MHz) δ 7.27 (1H, d, J = 2.0 Hz, H-16),

6.59 (1H, d, J = 2.0 Hz, H-15), 3.713 (3H, s, MeO), 2.92 (1H, dd, J =

17.6, 13.0 Hz, H-11β), 2.81 (1H, dd, J = 17.6, 3.8 Hz, H-11α), 2.40−

2.10 (4H, m, H-1, H-2, H-6, H-7), 1.95 (1H, m, H′-6), 1.93 (1H, dd, J

= 13.0, 3.8 Hz, H-9), 1.56 (1H, m, H′-7), 1.199 (3H, s, Me-C₄), 1.16

(1H, m, H-5), 1.124 (3H, s, Me-C₈), 0.844 (9H, s, Me₃CSi), 0.80 (1H,

m, H′-1), 0.57 (1H, dd, J = 5.4, 1.1 Hz, H-18β), 0.27 (1H, d, J = 5.4

Hz, H-18α), 0.076 and 0.027 (3H each, each s, 2 × MeSi); ¹³C NMR

(CDCl₃, 75 MHz) δ 194.4 (C₁₂), 174.8* (COOMe), 174.4* (C₁₄),

142.6 (C₁₆), 118.6 (C₁₃), 106.2 (C₁₅), 59.2 (C₃), 53.3 (C₅), 51.4

(COOMe), 51.2 (C₉), 46.8 (C₁₀), 37.1 (C₁₁), 36.9 (C₈), 35.1 (C₇),

33.1 (C₁), 29.5 (C₂), 29.4 (C₁₈), 25.7 (Me₃CSi), 23.3 (C₄), 22.4 (C₆),

17.9 (Me₃CSi), 17.5 (Me-C₈), 15.4 (Me-C₄), −3.2 and −3.7 (2 ×

MeSi); HRMS (ESI) m/z calcd for C₂₇H₄₀NaO₅Si [M + Na]⁺

495.2543, found 495.2543.

Methyl 3,12-Dioxoisospongia-13,15-dien-20-oate (45). A

solution of tert-butyldimethylsily ether 44 (80 mg, 0.169 mmol) in

anhydrous MeCN (2 mL) was cooled to 0 °C and treated with 10

drops of a 70% aqueous solution of H₂SiF₆. The mixture was stirred at

4 °C for 18 h, quenched by the addition of a saturated NaHCO₃

solution, and worked up using EtOAc as the extractant. Chromato-

graphic puriﬁcation (6:4 hexanes−EtOAc) yielded the intermediate

cyclopropanol (59 mg) as a white solid: mp 171−173 °C (from

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95%) as a white solid: mp 155−158 °C (CDCl₃); [α]²⁵_D−73 (c 0.24,

CHCl₃); IR ν_max/cm⁻¹(KBr) 3420s, 1738 m, 1711 m, 1175 m, 1137

m, 1033s; ¹H NMR (CDCl₃, 300 MHz) δ 7.21 (1H, d, J = 1.9 Hz, H-

16), 6.34 (1H, d, J = 1.9 Hz, H-15), 4.61 (1H, m, H-12), 3.64 (3H, s,

MeO), 3.22 (1H, dd, J = 11.6, 4.1 Hz, H-3), 2.61 (1H, ddd, J = 13.0,

3.3, 3.3 Hz, H-1), 2.49 (1H, br dd, J = 11.2, 6.4, H-11), 2.34 (1H,

dddd, J = 16.0, 16.0, 13.3, 3.0 Hz, H-6), 2.27 (1H, ddd, J = 13.3, 3.0,

3.0 Hz, H-7), 1.78−1.65 (2H, m, H-2, H′-6), 1.55−1.35 (3H, m, H′-7,

H-9, H′-11), 1.32 (1H, br dd, J = 13.8, 3.0 Hz, H′-2), 1.14−0.98 (2H,

m, H′-1, H-5), 1.093 (3H, s, Me-C₈), 1.033 (3H, s, Meα-C₄), 0.843

(3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 75 MHz) δ 174.8 (COOMe),

160.0 (C₁₄), 141.3 (C₁₆), 118.1 (C₁₃), 108.0 (C₁₅), 78.7 (C₃), 66.8

(C₁₂), 55.7 (C₅), 53.8 (C₉), 51.0 (COOMe), 47.7 (C₁₀), 39.4 (C₄),

36.9 (C₇), 36.6 (C₈), 36.2 (C₁), 31.7 (C₁₁), 28.5 (C₂), 28.4 (Meα-C₄),

19.4 (Me-C₈), 18.4 (C₆), 16.0 (Meβ-C₄); MS (EI) m/z 362 (M⁺, 6),

344 (24), 311 (11), 251 (100), 215 (12), 197 (11); HRMS m/z calcd

for C₂₁H₃₀O₅362.2093, found 362.2096.

cooled to −20 °C, carefully treated with acetone (0.2 mL), poured

into a 5% hydrochloric acid solution containing 10% (w/v) sodium

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

washed with 5% NaHCO₃and brine, dried, and concentrated to

dryness. Puriﬁcation of the residue after solvent evaporation (7:3

hexanes−EtOAc) yielded hydroxy acid 49 (8 mg, 69%) as a solid: mp

134−135 °C (from hexanes−Et₂O); [α]²²−40 (c 0.1, CHCl₃); IR

D

ν_max/cm⁻¹(KBr) 3426s, 1710s, 1705s, 1656 m, 1612 m, 1142 m, 1039

1

m; H NMR (CDCl₃, 300 MHz) δ 7.21 (1H, d, J = 1.9 Hz, H-16),

6.35 (1H, d, J = 1.9 Hz, H-15), 4.63 (1H, ddd, J = 9.1, 6.2, 1.2 Hz, H-

12), 2.61 (1H, m, H-1), 2.54 (1H, dd, J = 11.6, 6.5 Hz, H-11), 2.36−

2.18 (2H, m, H-6, H-7), 1.70 (1H, m, H′-6), 1.65−1.50 (3H, m, H-2,

H-9, H′-11), 1.50−1.37 (3H, m, H′-2, H-3, H′-7), 1.181 (3H, s, Me-

C₈), 1.18 (1H, m, H′-3), 1.08 (1H, dd, J = 12.6, 2.8 Hz, H-5), 1.00

(1H, ddd, J = 12.9, 12.9, 3.4 Hz, H′-1), 0.924 (3H, s, Meα-C₄), 0.918

(3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 100 MHz) δ 179.4 (COOH),

160.2 (C₁₄), 141.2 (C₁₆), 118.1 (C₁₃), 108.1 (C₁₅), 66.9 (C₁₂), 56.7

(C₅), 53.8 (C₉), 47.9 (C₁₀), 42.3 (C₃), 38.6 (C₁), 37.1 (C₈), 37.0 (C₇),

33.8 (C₄), 33.7 (Meα-C₄), 31.8 (C₁₁), 22.7 (C₂), 20.1 (Meβ-C₄), 19.5

(Me-C₈), 18.7 (C₆); HRMS (ESI) m/z calcd for C₂₀H₂₇O₄[M − H]⁺

331.1909, found 331.1913.

Isospongia-13,15-diene-12β,20-diol (50) and Isospongia-

13,15-dien-20-ol (51). A solution of LiAlH₄·2THF (1 M in toluene,

0.6 mL, 0.60 mmol) was added dropwise to a solution of keto ester 48

(18 mg, 0.051 mmol) and 6,7-dihydrobenzofuran-4(5H)-one (18 μL,

0.15 mmol) in toluene (8 mL) at −78 °C under N₂. After being stirred

for 10 min at the same temperature, the mixture was allowed to warm

to rt before reﬂuxing for 8 h. The workup described for the

transformation of 48 into 49 was followed by chromatographic

puriﬁcation (8:2 → 6:4 hexanes−EtOAc) to aﬀord spongiadiol 50 (15

mg, 90%) as a white solid: mp 153−154 °C (from hexanes−Et₂O);

[α]¹⁹_D−30 (c 0.13, CHCl₃); IR ν_max/cm⁻¹(KBr) 3382s, 1650w, 1137

m, 1055s, 1028s, 984 m; ¹H NMR (CDCl₃, 400 MHz) δ 7.22 (1H, d, J

= 1.9 Hz, H-16), 6.35 (1H, d, J = 1.9 Hz, H-15), 4.48 (1H, dd, J = 9.8,

6.1 Hz, H-12), 4.07 (1H, d, J = 11.8 Hz, CHHOH), 3.98 (1H, dd, J =

11.8, 1.7 Hz, CHH′OH), 2.43 (1H, dd, J = 12.9, 6.0 Hz, H-11), 2.29−

2.21 (2H, m, H-1, H-7), 1.76 (1H, ddd, J = 12.7, 12.7, 9.8 Hz, H′-11),

1.70−1.44 (5H, m, 2 × H-2, 2 × H-6, H′-7), 1.42 (1H, m, H-3), 1.419

(3H, s, Me-C₈), 1.38 (1H, d, J = 12.7 Hz, H-9), 1.17 (1H, ddd, J =

13.6, 13.6, 4.4 Hz, H′-3), 1.03 (1H, dd, J = 11.8, 2.5 Hz, H-5), 0.864

(3H, s, Meα-C₄), 0.793 (1H, dddd, J = 13.1, 13.1, 4.2, 1.7 Hz, H′-1),

0.778 (3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 100 MHz) δ 160.6 (C₁₄),

141.0 (C₁₆), 118.4 (C₁₃), 108.1 (C₁₅), 67.9 (C₁₂), 62.9 (CH₂OH),

57.3 (C₅), 55.2 (C₉), 42.3 (C₁₀), 41.8 (C₃), 37.5 (C₇), 37.0 (C₈), 34.5

(C₁), 33.74 (C₄), 33.72 (Meα-C₄), 33.1 (C₁₁), 21.7 (Meβ-C₄), 21.3

(Me-C₈), 18.4* (C₂), 18.0* (C₆); HRMS (ESI) m/z calcd for

C₂₀H₂₉O₂[M − OH]⁺301.2162, found 301.2168.

Methyl 3β-Hydroxy-12-oxo-isospongia-13,15-dien-20-oate

(47). Oxidation of diol 46 (44 mg, 0.122 mmol) with activated

MnO₂(352 mg, 4.2 mmol) in CHCl₃(8 mL), as described for the

oxidation of 27, yielded the hydroxy ketone 47 (42 mg, 97%) as a

white solid after chromatography with 8:2 CHCl₃−EtOAc: mp 164−

167 °C (from hexanes−Et₂O); [α]²⁸−69 (c 0.7, CHCl₃); IR ν_max

/

D

1

cm⁻¹(KBr) 3344 m, 1732s, 1678s, 1585w; H NMR (CDCl₃, 300

MHz) δ 7.26 (1H, d, J = 2.0 Hz, H-16), 6.58 (1H, d, J = 2.0 Hz, H-

15), 3.674 (3H, s, MeO), 3.23 (1H, ddd, J = 11.5, 6.5, 4.7 Hz, H-3),

2.78 (1H, dd, J = 17.5, 3.2 Hz, H-11α), 2.60−2.38 (2H, m, H-1, H-6),

2.55 (1H, dd, J = 17.5, 13.5 Hz, H-11β), 2.38 (1H, ddd, J = 13.5, 3.2,

3.2 Hz, H-7), 2.06 (1H, dd, J = 13.5, 3.2, Hz, H-9), 1.85−1.55 (3H, m,

H-2, H′-6, H′-7), 1.33 (1H, m, H′-2), 1.20−1.00 (2H, m, H′-1, H-5),

1.165 (3H, s, Me-C₈), 1.057 (3H, s, Meα-C₄), 0.831 (3H, s, Meβ-C₄);

¹³C NMR (CDCl₃, 75 MHz) δ 193.9 (C₁₂), 175.3* (COOMe), 174.3*

(C₁₄), 142.5 (C₁₆), 118.4 (C₁₃), 106.2 (C₁₅), 78.4 (C₃), 55.4 (C₅),

53.9 (C₉), 51.2 (COOMe), 47.8 (C₁₀), 39.5 (C₄), 37.2 (C₈), 37.0

(C₁₁), 35.8 (C₁), 35.5 (C₇), 28.5 (C₂), 28.2 (Meα-C₄), 18.2 (C₆), 17.7

(Me-C₈), 16.0 (Meβ-C₄); HRMS (ESI) m/z calcd for C₂₁H₂₈NaO₅

[M + Na]⁺383.1834, found 383.1847.

Methyl 12-Oxoisospongia-13,15-dien-20-oate (48). Reaction

of alcohol 47 (33 mg, 0.091 mmol) with pentaﬂuorophenyl

chlorothioformate (30 μL, 0.18 mmol) and DMAP (33 mg, 0.27

mmol) in CH₂Cl₂(1.8 mL), as described for 28, gave the

corresponding thionocarbonate derivative (51.7 mg) after chromato-

graphic puriﬁcation (9:1 CH₂Cl₂−EtOAc): ¹H NMR (CDCl₃, 300

MHz) δ 7.28 (1H, d), 6.60 (1H, d), 4.93 (1H, dd), 2.79 (1H, dd), 2.68

(1H, ddd), 2.57 (1H, dd), 2.42 (1H, ddd), 2.11 (1H, dd), 1.84 (1H,

ddd), 1.190 (3H, s), 1.072 (3H, s), 1.002 (3H, s). Following the same

procedure described for the deoxygenation of 28, this compound was

treated with AIBN (4 mg) and Bu₃SnH (53 μL, 0.195 mmol) in

toluene (2.5 mL) to yield keto ester 48 (28.5 mg, 90%) as a white

solid after chromatography with 9:1 CH₂Cl₂-EtOAc: mp 131−133 °C

Small, variable amounts of a secondary, less polar compound also

formed in the reduction of keto ester 48 with LiAH₄·2THF in toluene

when the above reaction was carried out in the absence of

dihydrobenzofuranone. This compound, obtained as an amorphous

(from hexanes); [α]²⁶−105 (c 0.4, CHCl₃); IR ν_max/cm⁻¹(KBr)

D

solid, was identiﬁed as isospongiadienol 51: [α]²⁰−20 (c 0.1,

1

1732s, 1678s, 1514 m, 1454 m, 1437 m, 1137s, 1044 m; H NMR

D

1

CHCl₃); IR ν_max/cm⁻¹(KBr) 3437s, 1700w, 1148 m, 1033 m; H

(CDCl₃, 300 MHz) δ 7.26 (1H, d, J = 2.0 Hz, H-16), 6.59 (1H, d, J =

2.0 Hz, H-15), 3.665 (3H, s, MeO), 2.81 (1H, dd, J = 17.6, 3.2 Hz, H-

11α), 2.58 (1H, dd, J = 17.6, 13.5 Hz, H-11β), 2.53 (1H, m, H-1),

2.50−2.30 (2H, m, H-6, H-7), 2.11 (1H, dd, J = 13.5, 3.2 Hz, H-9),

1.78 (1H, m, H′-6), 1.64 (1H, m, H′-7), 1.53 (1H, m, H-2), 1.44 (1H,

m, H-3), 1.35−1.20 (2H, m, H′-2, H′-3), 1.20−1.11 (1H, m, H-5),

1.161 (3H, s, Me-C₈), 1.05−0.90 (1H, m, H′-1), 0.943 (3H, s, Meα-

C₄), 0.881 (3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 75 MHz) δ 194.6

(C₁₂), 175.7* (COOMe), 174.9* (C₁₄), 142.5 (C₁₆), 118.3 (C₁₃),

106.2 (C₁₅), 56.5 (C₅), 54.1 (C₉), 51.0 (COOMe), 48.3 (C₁₀), 42.2

(C₃), 38.2 (C₁), 37.4 (C₈), 37.0 (C₁₁), 35.6 (C₇), 33.8 (C₄), 33.5

(Meα-C₄), 22.5 (Meβ-C₄), 20.0 (C₂), 18.5 (C₆), 17.6 (Me-C₈);

HRMS (ESI) calcd for C₂₁H₂₉O₄[M + H]⁺345.2066, found 345.2066.

12β-Hydroxyisospongia-13,15-dien-20-oic Acid (49).

LiAlH₄·2THF (1 M in toluene, 140 μL, 0.14 mmol) was added to a

solution of 48 (12 mg, 0.034 mmol) in diglyme (4 mL) at −78 °C

under N₂. This mixture was allowed to warm slowly to rt before being

heated to 120 °C for 5 h. After this time, the reaction mixture was

NMR (CDCl₃, 300 MHz) δ 7.19 (1H, d, J = 1.8 Hz, H-16), 6.10 (1H,

d, J = 1.8 Hz, H-15), 4.07 (1H, d, J = 11.8 Hz, CHHOH), 4.00 (1H,

dd, J = 11.8, 1.5 Hz, CHH′OH), 2.42 (1H, ddd, J = 15.7, 5.4, 1.4 Hz,

H-11), 2.37−2.11 (3H, m, H-1, H-7, H′-11), 2.07 (1H, br dd, J = 13.4,

5.6 Hz, H-12), 1.78 (1H, ddd, J = 13.4, 5.5, 1.2 Hz, H′-12), 1.74−1.39

(7H, m, 2 × H-2, H-3, 2 × H-6, H′-7, H-9), 1.375 (3H, s, Me-C₈), 1.18

(1H, ddd, J = 13.6, 13.2, 4.0 Hz, H′-3), 1.06 (1H, dd, J = 12.0, 2.8 Hz,

H-5), 0.872 (3H, s, Meα-C₄), 0.83 (1H, m, H′-1), 0.794 (3H, s, Meβ-

C₄); ¹³C NMR (CDCl₃, 100 MHz) δ 159.6 (C₁₄), 140.1 (C₁₆), 113.8

(C₁₃), 110.0 (C₁₅), 63.2 (CH₂OH), 57.5 (C₉), 57.4 (C₅), 42.7 (C₁₀),

41.9 (C₃), 37.7 (C₇), 37.0 (C₈), 34.5 (C₁), 33.9 (C₄), 33.1 (Meα-C₄),

24.2 (C₁₁), 22.2 (C₁₂), 21.7 (Meβ-C₄), 21.6 (Me-C₈), 18.5 (C₂), 18.1

(C₆); HRMS (ESI) m/z calcd for C₂₀H₃₁O₂[M + H]⁺303.2324,

found 303.2325.

20-Hydroxyisospongia-13,15-dien-12-one (52). The selective

oxidation of diol 50 (12 mg, 0.0378 mmol) with activated MnO₂(192

mg, 1.87 mmol) in CHCl₃(4.5 mL) using the same procedure as

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described for 27, aﬀorded 20-hydroxymarginatone 52 (11.3 mg, 94%)

as a white solid after chromatographic puriﬁcation (8:2 CHCl₃−

EtOAc): mp 176−177 °C (from hexanes−Et₂O); [α]²³_D−17 (c 0.12,

CHCl₃); IR ν_max/cm⁻¹(KBr) 3426s, 1661s, 1563w, 1366 m, 1050 m,

Data for Diels−Alder adduct 37a [4aR,6aR,7aS,8aS,9aR,9bR)-

3-((tert-butyldimethylsilyl)oxy)-4,6a,7a-trimethyl-7-oxo-

1,2,4a,5,6,6a,7,7a,8a,9,9a,9b-dodecahydrophenanthro[2,3-b]-

oxirene-9b-carbaldehyde]: white solid; mp 134−136 °C (from

hexanes); [α]²²−46 (c 0.65, CHCl₃); IR ν_max/cm⁻¹(KBr) 2710s,

1

D

1028 m; H NMR (CDCl₃, 400 MHz) δ 7.26 (1H, d, J = 2.0 Hz, H-

1711 m, 1672 m, 1175s, 842s; ¹H NMR (C₆D₆, 300 MHz) δ 9.42 (1H,

s, CHO), 2.76 (1H, br d, J = 1.0 Hz, H-8a), 2.49 (1H, s, H-4a), 2.26

(1H, dd, J = 13.0, 4.2 Hz, H-9a), 1.92 (1H, dd, J = 15.0, 1.3 Hz, H-5),

1.87 (1H, ddd, J = 13.0, 4.2, 1.3 Hz, H-9), 1.84−1.72 (3H, m, H-2, H-

6, H′-9), 1.60 (1H, m, H-1), 1.509 (3H, s, Me-C4), 1.50−1.29 (3H,

H′-1, H′-5, H′-6), 1.268 (3H, s, Me-C7a), 0.96 (1H, m, H′-2

overlapped with Me₃CSi signal), 0.959 (9H, s, Me₃CSi), 0.659 (3H, s,

Me-C6a), 0.106 and 0.053 (3H each, each s, 2 × MeSi); ¹³C NMR

(C₆D₆, 75 MHz) δ 206.9 (C7), 204.8 (CHO), 144.0 (C3), 111.4

(C4), 58.9 (C8a), 56.5 (C7a), 48.8 (C9b), 45.4 (C6a), 38.7 (C4a),

30.0 (C9a), 28.3 (C6), 26.7 (C5), 26.5 (C2), 26.0 (Me₃CSi), 20.9

(C9), 20.4 (C1), 18.3 (Me₃CSi), 17.6 (Me-C6a), 16.7 (Me-C7a), 13.2

(Me-C4), −3.6 and −4.0 (2 × MeSi); MS (EI) m/z 418 (M + , 6),

390 (3), 387 (2), 372 (6), 361 (3), 333 (2), 316 (3), 275 (3), 235 (5),

73 (100); HRMS m/z calcd for C₂₄H₃₈O₄Si 418.2539, found

418.2529.

16), 6.59 (1H, d, J = 2.0 Hz, H-15), 4.14 (1H, d, J = 11.2 Hz,

CHHOH), 4.03 (1H, dd, J = 11.4, 2.0 Hz, CHH′OH), 3.11 (1H, dd, J

= 17.6, 13.7 Hz, Hβ-11), 2.72 (1H, dd, J = 17.6, 2.7 Hz, Hα-11), 2.35

(1H, br dd, J = 10.0, 2.9 Hz, H-7), 2.20 (1H, br dd, J = 13.1, 0.8 Hz,

H-1), 1.94 (1H, dd, J = 13.7, 2.2 Hz, H-9), 1.76−1.51 (5H, m, 2 × H-

2, 2 × H-6, H′-7), 1.45 (1H, m, H-3), 1.468 (3H, s, Me-C₈), 1.18 (1H,

ddd, J = 13.5, 13.5, 4.4 Hz, H′-3), 1.08 (1H, dd, J = 12.0, 2.1 Hz, H-5),

0.887 (3H, s, Meα-C₄), 0.85 (1H, ddd, J = 13.1, 4.0, 1.4 Hz, H′-1),

0.797 (3H, s, Meβ-C₄); ¹³C NMR (CDCl₃, 100 MHz) δ 195.9 (C₁₂),

175.9 (C₁₄), 142.1 (C₁₆), 118.2 (C₁₃), 106.1 (C₁₅), 62.7 (CH₂OH),

56.9 (C₅), 56.0 (C₉), 42.2 (C₁₀), 41.6 (C₃), 38.7 (C₁₁), 37.5 (C₈), 36.2

(C₇), 34.1 (C₁), 33.8 (Meα-C₄), 33.1 (C₄), 21.7 (Meβ-C₄), 19.5 (Me-

C₈), 18.3 (C₂), 17.8 (C₆); HRMS (ESI) m/z calcd for C₂₀H₂₉O₃[M +

H]⁺317.2117, found 317.2117.

12-Oxoisospongia-13,15-dien-20-yl Acetate (20-Acetoxy-

marginatone, 6). Et₃N (112 μL, 1.08 mmol), Ac₂O (108 μL, 1.04

mmol) and a small crystal of DMAP were added to a solution of

hydroxy ketone 52 (8 mg, 0.025 mmol) in anhydrous CH₂Cl₂(2 mL).

The mixture was stirred at rt for 1 h before diluting with water and

extracting with EtOAc. The organic extracts were washed successively

with 5% hydrochloric acid, 5% NaHCO₃and brine. Evaporation of the

dried solution produced a residue, which was puriﬁed by

chromatography (9:1 hexanes−EtOAc) to yield 20-acetoxymargina-

tone 6 (8 mg, 88%) as a white solid: mp 60−64 °C (from cold

ASSOCIATED CONTENT

■

S

* Supporting Information

Schemes SI-1 and SI-2, which were cited in refs 42 and 46,

1

respectively, general experimental details, and copies of the H

and ¹³C NMR spectra of all new compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

hexanes) (lit.⁹clear colorless oil); [α]²⁰−30 (c 0.07, CHCl₃) ([α]_D

D

AUTHOR INFORMATION

has been not reported for this compound in the literature); IR ν_max

/

■

cm⁻¹(KBr) 1732s, 1683s, 1558 m, 1386w, 1235w, 1050w, 1030w; ¹H

NMR (C₆D₆, 400 MHz) δ 6.79 (1H, d, J = 2.0 Hz, H-16), 6.66 (1H, d,

J = 2.0 Hz, H-15), 4.66 (1H, br d, J = 12.3 Hz, CHHO), 4.03 (1H, dd,

J = 12.3, 1.2 Hz, CHH′O), 2.82−2.72 (2H, m, 2 × H-11), 2.07 (1H, m,

H-7), 1.77 (1H, br dd, J = 13.1, 1.5 Hz, H-1), 1.532 (3H, s, MeCOO),

1.51 (1H, m, H-9), 1.38−1.18 (6H, m, 2 × H-2, H-3, 2 × H-6, H′-7),

1.090 (3H, s, Me-C₈), 0.92 (1H, ddd, J = 13.8, 13.2, 4.5 Hz, H′-3),

0.688 (3H, s, Meα-C₄), 0.655 (3H, s, Meβ-C₄), 0.57 (1H, dd, J = 12.5,

1.9 Hz, H-5), 0.36 (1H, dddd, J = 13.6, 13.6, 4.0, 2.1 Hz, H′-1); ¹³C

NMR (C₆D₆, 100 MHz) δ 193.4 (C₁₂), 174.7 (C₁₄), 170.0 (MeCOO),

142.3 (C₁₆), 119.1 (C₁₃), 106.8 (C₁₅), 64.2 (CH₂O), 56.4 (C₅), 55.2

(C₉), 41.5 (C₃), 40.6 (C₁₀), 38.5 (C₁₁), 37.5 (C₈), 36.1 (C₇), 34.2

(C₁), 33.6 (Meα-C₄), 32.9 (C₄), 21.6 (Meβ-C₄), 20.3 (MeCOO), 19.3

(Me-C₈), 18.3 (C₂), 17.9 (C₆); HRMS (ESI) m/z calcd for C₂₂H₃₁O₄

[M + H]⁺359.2222, found 359.2228.

Corresponding Author

*E-mail: antonio.abad@uv.es.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Spanish Ministerio de Ciencia e Innovacion

́

(MICINN) and the company EPA S.L. (Carlet, Spain) for their

continuous support of our work (Projects BQU2002-00272 and

AGL2009-12940-C02-02). We also thank the S.C.S.I.E. of the

University of Valencia for providing access to their NMR

facilities and E. Estornell and V. Romero for biological assay

support.

Physical and Spectroscopic Data for Diels−alder Adducts

36a and 37a. See ref 46 and Scheme SI-2, Supporting Information.

Data for Diels−Alder adduct 36a [(4aS,6aR,7aS,8a-

S,9aR,9bR)-3-((tert-butyldimethylsilyl)oxy)-4,6a,7a-trimethyl-

7-oxo-1,2,4a,5,6,6a,7,7a,8a,9,9a,9b-dodecahydrophenanthro-

[2,3-b]oxirene-9b-carbaldehyde]: white solid; mp 156−158 °C

REFERENCES

■

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General diastereoselective synthetic approach toward isospongian diterpenes. Synthesis of (-)-marginatafuran, (-)-marginatone, and (-)-20-acetoxymarginatone

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