Diastereoselective synthesis of antiquorin and related polyoxygenated atisene-type diterpenes

Tetrahedron 63 (2007) 1664–1679

Diastereoselective synthesis of antiquorin and related

polyoxygenated atisene-type diterpenes

*

Antonio Abad, Consuelo Agullo, Ana C. Cunat, Ignacio de Alfonso Marzal, Antonio Gris,

ꢀ

Ismael Navarro and Carmen Ramırez de Arellano

˜

y

ꢀ

Departamento de Quꢀımica Orgaꢀnica, Universitat de Valencia, C. Dr. Moliner 50, 46100 Burjassot (Valencia), Spain

Received 7 November 2006; revised 30 November 2006; accepted 30 November 2006

Available online 26 December 2006

Abstract—A diastereoselective approach to polyoxygenated atisene-type diterpenes starting from (S)-(+)-carvone is described. The key steps

used in the preparation of the atisene framework are an intramolecular Diels–Alder reaction, an intramolecular diazoketone cyclopropanation,

an endocyclic cyclopropane ring cleavage and the regioselective reduction of an allylic bromide by a low-valent chromium species. The syn-

thesis of natural atisanes antiquorin (1), atis-16-ene-3,14-dione (3), atis-16-ene-2,3,14-trione (8) and 3b-hydroxy-atis-16-ene-2,14-dione (9)

following this approach is presented. Also described is the synthesis of 18-hydroxy-atis-16-ene-3,14-dione (5), the structure erroneously as-

signed to an atisene isolated from the Fijian plant Euphorbia ﬁdjiana. This work shows that the natural atisene isolated from this plant is, in

fact, the epimer at C-4 of this compound.

1. Introduction

Antiquorin (1) is a relevant member of a subclass of poly-

oxygenated tetracyclic atisane diterpenes, structurally based

on the atisene skeleton (2) (Scheme 1), which is also com-

mon to the related atisine-diterpene alkaloids.¹Initially iso-

lated from Euphorbia antiquorum,^2,3antiquorin has also

been obtained from Euphorbia ﬁdjiana,^4–6Euphorbia sie-

boldiana,^7,8Euphorbia neriifolia,⁹Euphorbia quinquecos-

tata¹⁰and more recently Euphorbia ebracteolata.¹¹The

initial structure proposed for antiquorin²was later revised

as 1 by X-ray diffraction analysis.^12,13Other atisene diter-

penes related to antiquorin, e.g., 3,^4,5,144,^5,7,9,115–7,⁵and

8,¹⁴have been obtained from other species of the

Euphorbia genus, but others have been isolated from differ-

ent sources. For example, compound 9 has been found in

extracts from the Samoan tree Homalanthus acuminatus,¹⁵

while 10 and 11 have been isolated from the New Zealand

liverwort Lepidolaena clavigera.¹⁶In spite of the promising

wide spectrum of biological activities exhibited by other

atisane-type diterpenes,¹⁷only some of these compounds

have been evaluated for their biological activity. Antiquorin

(1)⁵and compounds 3⁵and 10¹⁶have shown cytotoxic activ-

ity, while compound 9 has shown AIDS antiviral activity.¹⁵

Scheme 1. Some polyoxygenated atisenes.

Keywords: Diterpene; Atisane; Carvone; Cyclopropane; Radical cleavage;

Diels–Alder reaction.

The absolute stereochemistry for antiquorin and the rest of

natural atisenes described here has not been rigorously

established. It has been assumed that these atisenes belong

to the ent-enantiomeric series on the basis of biogenetic con-

siderations and their co-occurrence with other ent-atisanes

* Corresponding author. Tel.: +34 6 3864509; fax: +34 6 3864328; e-mail:

antonio.abad@uv.es

Corresponding author for X-ray crystal structure. Departamento de

y

ꢀ

Quımica Organica, Facultad de Farmacia, Universitad de Valencia, Av.

Vicente Andres s/n, 46100-Valencia, Spain.

ꢀ

doi:10.1016/j.tet.2006.11.083

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1665

isolated from the same plants (see for example, Refs. 5 and

14). Some confusion also exists in the literature over the ap-

propriate use of the R/S nomenclature to deﬁne the conﬁgu-

ration at C-13 (see for example, Refs. 5 and 7). As conﬁrmed

by the data presented in this work, antiquorin belongs to the

ent-enantiomeric series and has the following absolute con-

ﬁguration 5S,8S,9S,10R,12S,13R (i.e., ent-1).

based on the preparation from carvone (15) of the penta-

cyclic intermediate 12, which already contains the basic

atisane skeleton. This compound has a functionalization at

different positions of the atisane framework adequate for

further elaboration of the required functionalization around

the A, C and D rings of the target compounds. The bicy-

clo[2.2.2]octane moiety of the atisane skeleton is originated

by regioselective cleavage of the C13–C16 cyclopropane

bond of the key trachylobane-type intermediate 13, which

in turn is easily accessible from carvone, via the tricyclic

intermediate 14, using an IMDA reaction and an intramolec-

ular diazoketone cyclopropanation of the unsaturated ketone

moiety as key steps.

A relatively important amount of effort has been dedicated to

the synthetic preparation of atisane-type diterpenes. A large

part of this work has been based on the transformation of

the carbon skeleton of other polycyclic diterpenes into the

atisane framework, generally via skeletal rearrangements,

which are promoted either chemically or microbiologi-

cally.¹⁸On the other hand, and after the pioneering work of

Ireland on the synthesis of atiserene (2),¹⁹most of the syn-

thetic work aimed at the total synthesis of atisanes has been

undertaken by Fukumoto et al., who have developed two con-

ceptually and tactically different synthetic approaches for the

elaboration of the bicyclo[2.2.0]octane moiety characteristic

of the atisane framework based on an intramolecular double

Michael reaction²⁰and a homoallyl–homoallyl radical rear-

rangement reaction, respectively.²¹By using these strategies,

they have completed the synthesis of several atisanes, e.g.,

atiserene,²²methyl atis-16-ene-19-oate,²³methyl gummifer-

olate,²⁴and, more recently, serofendic acids A and B.²⁵

2.2. Preparation of key trachylobane-type

intermediate 13

The synthesis of the key intermediate 13 is summarised in

Scheme 3. The synthesis commences from the known alde-

hyde 16, obtained stereoselectively from carvone by reaction

of its kinetic enolate with pyruvonitrile, followed by C-alkyl-

ation of the resulting b-diketone with 3-iodopropanaldehyde

diethyl acetal and then acid hydrolysis with PPTS, giving an

overall yield of 80% for the three steps.²⁶Elaboration of the

oxygenated diene moiety required for the construction of the

AB rings via an intramolecular Diels–Alder (IMDA) reaction

was effected in two steps. First, Horner–Wadsworth–Em-

mons oleﬁnation reaction of the tricarbonyl compound 16

with the a-phosphonate carbanion derived from the reaction

of 2-oxabutane-3-phosphonate and sodium hydride in THF at

ꢀ40 ^ꢁC.²⁸Under these conditions, the reaction was com-

pletely chemo- and stereoselective, affording the (E)-enone

17in83%yield.Theuseofhighertemperaturesledtoasignif-

icant lowering in the yield of 17. In the second step, the enone

17 was treated with tert-butyldimethylsilyl triﬂuoromethane-

sulfonate (TBDMSOTf) and triethylamine (Et₃N) at low tem-

perature. Under the kinetic conditions used, only the dienol

silyl ether 18 was obtained in about 90% yield, without sig-

niﬁcant amounts of other possible enol ethers being observed.

We have recently described a general synthetic approach to

the polycyclic carbon skeleton of biogenetically related be-

yerane, kaurane and atisane diterpenes from carvone.²⁶This

approach is based on the initial preparation of a pentacyclic

hydrocarbonated system containing the tricyclo[3.2.1.0^2,7]-

octane moiety, characteristic of the trachylobane-type diter-

penes, which is regioselectively cleaved to obtain the

bicyclo[3.2.1]- and bicyclo[2.2.2]octane moieties, character-

istic of beyeranes/kauranes and atisanes, respectively. As

a continuation of this work, we wish to report here the appli-

cation of this strategy for the preparation of polyoxygenated

atisane-type compounds such as antiquorin and the other

related natural atisenes mentioned above. These following

results show that this approach represents a complement to

the existing strategies for the preparation of this type of

terpenes, being particularly useful for the preparation of the

highly functionalized atisane framework. A preliminary

account of part of this work has previously been published.²⁷

The dienol silyl ether 18 underwent a stereoselective IMDA

reaction when it was heated at 190–200 ^ꢁC in a toluene

solution containing a small amount of propylene oxide, for

7 days, to afford the adduct 14 in 95% yield after the chro-

matographic puriﬁcation. The use of previously silylated

ampoules and propylene oxide as acid scavenger in this

reaction was essential to avoid partial hydrolysis of the

dienol silyl ether moiety of 18, which otherwise resulted in

a marked lowering in the yield of the Diels–Alder adduct

formed. Although expected from the results previously

obtained in the IMDA reaction of 1,3,9-decatrienes,^26,29

the stereochemistry of compound 14 was ﬁrmly established

by a detailed spectroscopic study that conﬁrmed the trans–

anti–trans ring conﬁguration of the tricyclic framework.

2. Results and discussion

2.1. Retrosynthetic route to polyoxygenated atisanes

from carvone

The retrosynthetic route to antiquorin and related atisenes is

depicted in Scheme 2. The synthesis of these compounds is

Scheme 2. Retrosynthetic route to atisene-type diterpenes from carvone.

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A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

Scheme 3. Preparation of the key trachylobane-type intermediate 13.

Prior to the elaboration of the tricyclo[3.2.1.0^2,7]octane moi-

ety of the trachylobane-type intermediate 13, the tricyclic

enol silyl ether 14 was submitted to Simmons–Smith cyclo-

propanation conditions to stereoselectively cyclopropanate

the ring A double bond, necessary for the introduction of

the geminal dimethyl group at C-4 in the natural compounds.

This reaction takes place stereoselectively from the less

hindered a-side of the double bond, affording the tert-

butyldimethylsilyloxy cyclopropane 19 in 91% yield.

21 with respect to diketone 13 (Dd¼12 ppm). Subjection of

the hydroxyketone 21 to conventional mesylation conditions

gave the mesylate 22, which was then transformed into the

iodide 23 by treatment with sodium iodide in acetone at

40 ^ꢁC, in an overall yield for the two steps of 93%. The inver-

sion of the conﬁguration at C-15 in this substitution reaction

was evident from the analysis of the NMR data of 23, partic-

ularly through the strong deshielding experienced by C-9 in

the ¹³C NMR spectra with respect to the same carbon atom of

the alcohol 21 (Dd¼7.6 ppm), resulting from the disappear-

ance of the g-interaction that exists in the latter between this

position and the hydroxylic oxygen atom. Finally, treatment

of iodide 23 with samarium iodide in THF–MeOH produced

the corresponding C15-centred cyclopropyl carbinyl radical,

which then underwent cleavage of the endocyclic C13–C16

cyclopropane bond to give the atisene-type compound 12

in 95% yield. The transformation of iodide 23 into compound

12 was also effected, although in slightly lower yield, using

the stronger lithium–liquid ammonia reductive system.^z

The synthesis of compound 13 was completed via the

a-diazoketone 20, which was prepared from methyl-ketone

19 in high yield using a diazo-transfer reaction.³⁰First, the

methyl-ketone 19 was transformed into the corresponding

triﬂuoromethyl b-diketone by reaction of its lithium enolate

with 2,2,2-triﬂuoroethyltriﬂuoroacetate, followed by diazo-

transfer reaction and subsequent in situ retro-Claisen reac-

tion on treatment with p-acetamidobenzenesulfonyl azide

(p-ABSA) and Et₃N in MeCN in the presence of a 1.5 equiv

of water. Intramolecular addition of the a-diazoketone

moiety to the enone double bond took place smoothly and

efﬁciently when 20 was treated with a catalytic amount of

bis(N-tert-butylsalicylaldiminate)copper(II) in reﬂuxing tol-

uene, affording the hexacyclic compound 13 in 90% yield.

2.4. Functionalization of the atisane skeleton. Synthesis

of antiquorin (1) and atis-16-ene-3,14-dione (3)

Our attention was now directed to the modiﬁcation of the

functionalization of the atisane-type compound 12 necessary

for the preparation of the polyoxygenated target atisanes.

Our ﬁrst synthetic objective was antiquorin (1). The transfor-

mation of 12 into 1 requires (i) stereoselective introduction

of the hydroxyl group at C-13, (ii) acid-catalysed opening

of the siloxycyclopropane moiety that completes the

2.3. Trachylobane-to-atisane skeleton transformation.

Synthesis of the pivotal atisane-type intermediate 12

With the trachylobane-type compound 13 readily at hand,

we then focused on the transformation of the tricy-

clo[3.2.1.0^2,7]octane moiety into the bicyclo[2.2.2]octane

system characteristic of the atisane framework. This trans-

formation was effected by regioselective reductive cleavage

of the C13–C16 cyclopropane bond. First, the carbonyl

group at C-15 of 13 was chemo- and stereoselectively re-

duced by hydrogenation at ambient temperature in AcOEt

with 10% Pt on carbon as the catalyst to give the hydroxy-

ketone 21 in 95% yield (Scheme 4). The same reduction

was also effected in similar yield by NaBH₄reduction in

MeOH–CH₂Cl₂at 0 ^ꢁC. The a-disposition for the hydroxyl

group at C-15 was supported, in addition to other spectro-

scopic data, by the strong shielding experienced by C-9 in

z

The regioselective reductive cleavage of the C13–C16 cyclopropane

bond, thus completing the tricyclo[3.2.1.0^2,7]octane moiety to bicy-

clo[2.2.2]octane moiety transformation, was also effected directly from

cyclopropyl diketone 13 by treatment with Li in liquid NH₃or SmI₂in

THF–MeOH (see scheme below and Section 4). However, the functional-

ization around the bicyclo[2.2.2]octane moiety of the atisane-type com-

pound obtained, i.e., I–II, in this transformation is less suitable for the

preparation of the target atisanes.

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

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Scheme 4. Trachylobane-to-atisane skeleton transformation. Failed attempted transformation of 12 into antiquorin (1).

installation of the geminal dimethyl group at C-4 and the car-

bonyl group at C-3 and (iii) isomerisation of the endocyclic

C15–C16 double bond to the exocyclic C16–C17 position.

enol ether 24a underwent stereoselective epoxidation from

the less hindered face of the C13–C14 double bond on treat-

ment with m-chloroperbenzoic acid (m-CPBA), providing

the corresponding epoxide that was not puriﬁed, but directly

hydrolysed to the a-hydroxyketone 25 by smooth acid treat-

ment with oxalic acid in MeOH at rt, in an overall yield of

79% from 12. The stereochemistryat theC-13 carbinoliccen-

tre of 25 was consistent with the absence of NOE enhance-

ment at the methyl group at C-16 upon irradiation of H-13

and the small but signiﬁcant deshielding observed in the

¹³C NMR spectra for this methyl group relative to that of

the precursor 12 (Dd¼1.2 ppm), which is due to the syn ori-

entation of the OH group with respect to this methyl group

(d-effect).³⁴

Attempted direct introduction of the hydroxyl group at C-13

via reaction of the lithium enolate (generated at this position

by treatment of 12 with LDA at low temperature) with the

Vedejs reagent [oxidodiperoxymolybdenum(pyridine)(hexa-

methylphosphoric triamide), MoOPH]³¹was unsuccessful.

However, an alternative procedure, based on the epoxidation

of a silyl enol ether, worked quitewell (Scheme 4).³²Thus, 12

was converted into the mildly acidic labile trimethylsilyl enol

ether 24a by treatment with trimethylsilyl triﬂuoromethane-

sulfonate (TMSOTf) and Et₃N at rt. It must be noted that

the formation of 24a does not take place at a lower tempera-

ture, which suggests the existence of a relatively high steric

hindrance around the oxygen atom of the C-14 carbonyl moi-

etyof 12. Infact, 12did notreactatall withthemore sterically

demanding TBDMSOTf to give the tert-butyldimethylsilyl

enol ether 24b under the same reaction conditions.^xThe silyl

The functionalization of the A ring as in antiquorin (1)

was readily achieved by treatment of 25 with 1 equiv of p-

toluenesulfonic acid (PTSA) in reﬂuxing chloroform, which

promoted concomitant hydrolysis of the tert-butyldimethyl-

silyl protecting group and cyclopropane ring cleavage to

give the hydroxy-atisenedione 26 in 86% yield. The use of

alternative reaction conditions for the opening of the cyclo-

propane ring, such as TBAF in THF or 1 M HCl in MeOH,

led to a much lower yield of 26.

x

Even the reaction of the sodium enolate of 12, generated by treatment of 12

with sodium hexamethyldisilazide, with TBDMSOTf in THF failed to pro-

duce the silyl enol ether 24b, and instead the compound III (see below),

originated by an unusual nucleophilic enolate opening of THF catalysed

by TBDMSOTf, was obtained (see Ref. 33 for a related precedent for

this reaction and Section 4 for details of the preparation of compound III).

Finally, isomerisation of the C15–C16 double bond to the

C16–C17 position, which is required to complete the synthe-

sis of antiquorin (1), was attempted through a two-step

procedure based on the reduction of an allylic bromide by

a low-valent chromium species in the presence of a proton

source.^35,36In the ﬁrst step, allylic bromination of 26 with

N-bromosuccinimide (NBS) in a mixture of CH₂Cl₂and

MeOH afforded ca. 2:1 mixture of regioisomeric allylic bro-

mides 27a and 27b, which could not be easily separated.

Therefore the mixture of both was used directly in the next

step. In principle, this should be irrelevant from the synthetic

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A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

point of view since both bromides should afford the same

allylic radical intermediate in the subsequent reductive

step. Contrary to expectation, however, reduction of the mix-

ture of allylic bromides 27a and 27b with chromous chloride

(CrCl₂), previously generated from the reaction of CrCl₃

with LiAlH₄in THF, in the presence of isopropanol as proton

source, did not afford the anticipated product antiquorin (1),

but instead gave the starting atisene 26 in a 91% overall yield

for the two steps. A tentative mechanism for the unexpected

formation of the more substituted alkene in the above reduc-

tive process is given in Scheme 5.

approach to antiquorin (1) from 12 commences with the

acid-catalysed cyclopropane ring opening that leads to

atisenedione 28 (Scheme 6). The reaction was effected, as

described above for 25, by treatment of 12 with 1 equiv of

PTSA in reﬂuxing chloroform, affording the compound 28

in 94% yield. Allylic bromination of this compound in the

conditions previously mentioned, and the subsequent treat-

ment of the mixture of allyl bromides obtained, i.e.,

29a/29b, with the CrCl₂/iso-PrOH reductive system, led to

atisene 3, with a global yield for the two steps of 91%. As

already mentioned in Section 1, this atisene has been isolated

from the same Euphorbia species as antiquorin, which

suggests that 3 is most probably the biogenetic precursor

of antiquorin.

In order to introduce the required hydroxyl group adjacent to

the C-14 carbonyl group that would complete the synthesis

of antiquorin, it was previously necessary to block the

more reactive C-2 methylenic moiety contiguous to the other

carbonyl group of diketone 3. This was effected by forma-

tion of the corresponding tert-butyldimethylsilyl enol ether

by treatment of 3 with TBDMSOTf and Et₃N at low temper-

ature. Under these conditions, only the enol silyl ether of the

C-3 carbonyl group was formed, cleanly affording the tert-

butyldimethylsilyl enol ether 30 in nearly quantitative yield.

A ﬁrst attempt to hydroxylate C-13 was carried out using the

same procedure used previously to obtain 25 from 12 (see

Scheme 4). Although the formation of the trimethylsilyl

enol ether 31 could be performed in very high yield under

similar reaction conditions as those described above for

24a, the subsequent reaction with m-CPBA under a variety

of reaction conditions was not selective, always affording,

after the hydrolytic treatment with methanolic oxalic acid,

mixtures of hydroxylated products at C-2 and/or C-13. How-

ever, reaction of the lithium or potassium enolate of 30,

formed by reaction with lithium or potassium hexamethyl-

disilazide, respectively, with the Vedejs reagent (MoOPH)

in THF at low temperature afforded stereoselectively the

a-hydroxy carbonyl compound 32, which was directly

Scheme 5. Tentative mechanistic proposal for the formation of 26 from

27a–b.

In accordance with this proposed mechanism, the reaction

presumably involves the transference of the halogen atom

from carbon to chromium to produce the allyl radical in-

termediate i, which is followed by formation of the allyl-

chromium species ii. Probably, the formation of this

regioisomeric s-allyl metal intermediate is favoured by the

stabilisation provided by the C-13 hydroxyl group, which

also makes possible a rapid intramolecular transference of

a proton to C-17, through a six-membered cyclic transition

state, to afford the oleﬁn 26.

On the basis of the above mechanistic interpretation, it was

hoped that the required less substituted double bond could be

obtained by simply interchanging the order of the hydroxy-

lation and double bond isomerisation steps. This modiﬁed

Scheme 6. Successful transformation of 12 into atisene 3 and antiquorin (1).

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1669

Scheme 7. Transformation of 3 into atisenes 8 and 9.

hydrolysed with methanolic oxalic acid to give antiquorin

(1) in 90% overall yield for the last two steps.

The physical and spectroscopic properties of the synthetic

atisenes prepared from (S)-(+)-carvone, i.e., 1, 3, 8 and 9,

were in good agreement with those reported in the literature

for the corresponding natural products. The sole discrepancy

in all cases was found in the sign of the optical rotation,

which showed that we had synthesised the enantiomers of

the natural atisenes. This evidence deﬁnitively conﬁrms

the absolute stereochemistry of the natural atisenes as that

of the ent-atisane framework, i.e., ent-1, ent-3, ent-8 and

ent-9 (Scheme 8).

Compound 3 was also a suitable intermediate for the prepa-

ration of other polyoxygenated natural atisenes, such as 8

and 9. This transformation only required the adequation of

the functionalization of the A ring of 3 to that of these natural

compounds, which was done by taking advantage of the

higher reactivity of the C-2 methylene group. Thus, as in

the synthesis of 1, the compound 3 was ﬁrst transformed

into the tert-butyldimethylsilyl enol ether 30 (Scheme 7),

which after stereoselective epoxidation from the less a-

hindered face by treatment with m-CPBA in the presence

of NaHCO₃in CH₂Cl₂at 0 ^ꢁC, followed by oxalic acid cat-

alysed hydrolysis of the resulting tert-butyldimethylsilyloxy

epoxide, furnished the a-hydroxy carbonyl compound 33 in

88% overall yield from 30. The a-orientation, equatorial dis-

position, of the hydroxyl group in 33 was established by the

analysis of the coupling constants of H-2, which appears in

the ¹H NMR spectrum at 4.48 ppm as double double doublet

with coupling constants of 13.6, 6.4 and 2.2 Hz, the two for-

mer being characteristic for axial–axial and axial–equatorial

interaction with H-1a and H-1b, respectively.

Scheme 8.

In the last part of this paper, we describe the synthesis of

atisene 5, which, as already mentioned, was isolated in

1990 from the heart-wood of E. ﬁdjiana, an endemic plant

from the Fidji Islands traditionally used in folk medicine.

The differential functional characteristic of this atisene with

respect to those previously synthesised is the hydroxylation

of theC-18 position. As shown below, the synthesisofthis ati-

sene can also be completed from theintermediate 12, which is

therefore a common intermediate for all the polyoxygenated

atisenes whose synthesis is described in this paper.

All attempts to directly isomerise the acyloin moiety of 33 to

obtain the regioisomeric atisene 9 were unsuccessful, and

therefore we used an indirect procedure, based on one devel-

oped by Mori for a related acyloin isomerisation,³⁷to

achieve this objective. The ﬁrst step involves the oxidation

of the hydroxyl group of 33 to the corresponding carbonyl

group. This was accomplished using standard Swern oxida-

tion conditions and afforded the atisene-trione 8 in 93%

yield. This compound is one of the most recent polyoxygen-

ated atisenes to be isolated from natural sources,¹⁴and

exists, at least in CDCl₃solution, in the enolic tautomeric

form depicted in Scheme 7.

This transformation was initiated by the treatment of 12 with

NBS under the allylic bromination conditions described

above. This treatment not only produces the bromination

of the allylic position to the double bond, but also the elec-

trophilic opening of the cyclopropane ring to give 36 as

a mixture of regioisomeric allyl bromides (Scheme 9).³⁸

Chemoselective reduction of the allyl bromide moieties of

36 to the less substituted exocyclic double bond by CrCl₂

in the presence of isopropanol in DMF at rt afforded the

compound 37 in an overall yield of 91% for the two chemical

steps from 12. The structure and stereochemistry of this

compound were conﬁrmed by means of a detailed spectro-

scopic analysis and X-ray crystal structure determination.

The X-ray structure of compound 37 (Fig. 1) shows ring

C5–C6–C7–C8–C9–C10 in the expected chair conforma-

tion, with the methyl group at C-10 oriented axially, while

The enolized a-hydroxyketone group of 8 was then pro-

tected as the corresponding tert-butyldimethylsilyl enol

ether under conventional silylation conditions, and the C-3

carbonyl group was chemo- and stereoselectively reduced

with LiAlH₄in THF at low temperature to give, after acidic

work-up of the reaction mixture, ca. 4:1 mixture of readily

separable epimeric a-hydroxyketones 9 and 35. These latter

transformations were effected without puriﬁcation of the

intermediate enol silyl ether 34, giving the atisene 9 in

70% yield after chromatographic puriﬁcation.

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A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

rings C1–C2–C3–C4–C5–C10 and C8–C9–C11–C12–C13–

˚

C14 are in half-chair (C10 is ca. 0.7 A out of the plane) and

˚

boat conformations (atoms C8 and C12 at ca. 0.7 A out of the

main plane), respectively.

Figure 1. Thermal ellipsoids plot of 37 (50% probability levels) with the

usual diterpene labelling scheme. Hydrogen atoms have been omitted for

clarity.

Scheme 9. Transformation of 12 into atisene 5.

The ﬁnal substitution of bromine at C-18 by the hydroxyl

group that completes the synthesis of atisene 5 was some-

what problematic due to the neopentylic nature of the

C-18 position. Several well-established procedures available

for this purpose failed to afford the desired alcohol 5. For

example, direct substitution of bromine by H₂O in HMPT

at high temperature³⁹afforded a complex mixture of prod-

ucts, while the indirect substitution, via the initial formation

of the corresponding formate ester by treatment of bromide

37 with triethylammonium formate in acetonitrile or HMPT

at temperatures of up to 100 ^ꢁC,⁴⁰or the tributyltin oxide

intermediate by reaction with bis(tributyltin)oxide and silver

tetraﬂuoroborate in DMF at 95 ^ꢁC,⁴¹led essentially to the

recovery of the starting bromide. However, we observed

the formation of a small amount (ca. 2–3%) of the formate

39 in the last reaction (see Scheme 9), obviously originated

by the nucleophilic substitution of bromine by DMF. This

observation prompted us to explore whether this type of

formyloxylation reaction with DMF could be used to accom-

plish the desired transformation in synthetically useful yield.

After some investigation, it was found that the treatment of

bromide 37 with silver tetraﬂuoroborate in a mixture of

MeNO₂–DMF at 60 ^ꢁC afforded the formate 39 in an excel-

lent 88% yield. The same compound was also obtained in

higher yield, under still milder reaction conditions, from

iodide 38, prepared from bromide 37 in 93% yield by using

the Finkelstein reaction (NaI–acetone). In any case, hydroly-

sis of the formate ester with methanolic HCl at rt took place

smoothly and efﬁciently to give the desired b-hydroxy-

ketone 5 in 95% yield.⁴²It must be noted that the overall

yield of transformation of bromide 37 into 5 did not decrease

when the two steps were performed successively without

puriﬁcation of the formate ester intermediate.

of the original structure. In particular, comparison of the ¹³C

NMR data of the natural atisene with those of synthetic 5 re-

veals signiﬁcant differences only in the chemical shift of the

signals corresponding to the C-5 carbon atom (Dd¼7.3 ppm)

and, to a lesser extent, to the methyl group at C-4

(Dd¼4.7 ppm), thus suggesting that both compounds are

most probably epimers at C-4. The large shielding of C-5

in the synthetic atisene 5 is in good agreement with the

equatorial disposition of the hydroxymethylene group at

C-4 in this compound, which introduces the g-interaction

between the oxygen atom and C-5 responsible for this

shielding effect. On the other hand, this g-effect does not

exist in the natural atisene, which is consistent with an

axial orientation of the hydroxymethylene group at C-4.

The epimeric relationship at C-4 in both compounds is

also coherent with the different ¹³C chemical shifts observed

for the methyl group at C-4.⁴³On the basis of this result, it is

therefore necessary to modify the structure initially assigned

to the atisene isolated from E. ﬁdjiana, whose stereochem-

istry at C-4 should be reassigned as it appears in structure

4-epi-ent-5 (see Scheme 8). The ent-stereochemistry is

assumed for this compound in coherence with the absolute

stereochemistry determined here for the other related natural

atisenes.

3. Conclusions

In conclusion, we have developed a convenient diastereo-

selective approach for the construction of the complete car-

bon framework of atisene-type diterpenes. This approach

involves the initial preparation of the pivotal atisane-type

intermediate 12 from carvone, using an intramolecular

Diels–Alder reaction, an intramolecular diazoketone cyclo-

propanation of an unsaturated ketone and a regioselective

endocyclic cleavage of a cyclopropyl carbinyl radical as

key synthetic steps. This approach has been successfully

Our synthetic sample of atisene 5 showed somewhat differ-

ent physical and spectroscopic properties from those

reported in the literature for the natural compound isolated

from E. ﬁdjiana, suggesting a possible incorrect assignment

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1671

applied to the efﬁcient preparation of several naturally

4.2. Preparation of the trachylobane-type

intermediate 13

occurring highly polyoxygenated atisenes, e.g., antiquorin

(1) and related atisenes 3, 8 and 9. In particular, the synthe-

sis of antiquorin (1), the more representative member of

this class of polyoxygenated atisenes, involves 16 synthetic

transformations with an overall yield of approximately

25%. These syntheses have further served to unambigu-

ously establish the hitherto unknown absolute conﬁguration

of the natural atisenes as ent-1, ent-3, ent-8 and ent-9.

Additionally, the synthesis of 18-hydroxy-16-atisene-3,14-

dione (5), the structure originally proposed for the natural

atisene isolated from the heart-wood of E. ﬁdjiana, has

also been completed and it has been shown that this

initial structure assignment was erroneous and needs to

be revised to 4-epi-ent-5. The strategy herein described is

general and suitable for the synthesis of other natural and

non-natural highly functionalised atisanes in both enantio-

meric forms, since both antipodes of carvone are commer-

cially available.

4.2.1. (5R,6R)-6-Acetyl-2-methyl-6-((E)-4-methyl-5-

oxohex-3-enyl)-5-(prop-1-en-2-yl)cyclohex-2-enone (17).

To a stirred slurry of pre-washed NaH (60% dispersion oil;

360 mg, 9.4 mmol) in THF (60 mL) at 0 ^ꢁC was added,

dropwise via syringe, diethyl 2-oxobutane-3-phosphonate

(2.05 g, 2.22 mL, 9.84 mmol) over 45 min. After hydrogen

evolution had ceased, the mixture was warmed to rt and

stirred for 15–20 min. The resulting mixture was cooled

down to ꢀ50 ^ꢁC and a solution of the aldehyde 16²⁶

(2.22 g, 8.95 mmol) in THF (40 mL) was added dropwise.

After being stirred at the same temperature for 30 min, the

mixture was treated with saturated aq NH₄Cl solution,

then poured into water and worked up using hexane to

extract it. Puriﬁcation by chromatography (hexane–AcOEt

8:2) gave the enone 17 (2.21 g, 83%) as an oil. [a]²_D⁴+49.7

(c 1.9, CHCl₃); IR v_max/cm^ꢀ1(NaCl) 2924s, 2819m,

1

1702s, 1664s, 1438m, 1364m, 1281w, 1186w; H NMR

(300 MHz) d 6.75 (1H, br s, H-3), 6.52 (1H, ddd, J¼7.16,

7.16, 1.51 Hz, H-3⁰), 4.88 (1H, t, J¼1.5 Hz, H-2⁰⁰), 4.75

(1H, br s, H-2⁰⁰), 2.92 (1H, d, J¼6.4, 6.4 Hz, H-5), 2.69

(1H, br d, J¼19.4 Hz, H-2⁰), 2.52 (1H, br d, J¼19.4 Hz,

H⁰-2⁰), 2.37 (1H, ddd, J¼12.8, 11.3, 5.0 Hz, H-4), 2.2–1.9

4. Experimental

4.1. General information

Reagents were obtained from commercial sources and were

used without puriﬁcation. Solvents were dried by distillation

from the appropriate drying agents immediately prior to

use. THF and Et₂O were distilled from sodium and benzo-

phenone under an argon atmosphere. MeCN, CH₂Cl₂,

Et₃N and diisopropylamine were distilled from calcium

hydride under argon. Moisture- and air-sensitive reactions

were carried out under an atmosphere of nitrogen or argon.

The reactions were monitored with the aid of thin-layer

chromatography (TLC) using 0.25 mm precoated silica gel

plates. Visualization was carried out with UV light and

aq ceric ammonium molybdate solution or 50% (v/v) concd

H₂SO₄in water. Flash column chromatography was per-

formed with the indicated solvents on silica gel 60 (particle

size 0.040–0.063 mm). All melting points were determined

using a Koﬂer hot-stage apparatus and are uncorrected.

Optical rotations were determined using a 5 cm path length

cell. [a]_Dvalues are given in units of 10^ꢀ1deg cm²g^ꢀ1. ¹H

(2H, m, H₂-1⁰), 2.27 (3H, s, MeCO-C₁), 2.16 (3H, s, Me-

0

C₆), 1.82 (3H, s, Me-C₂), 1.81 (1H, m, H -4), 1.71 (3H, br

00

s, Me-C₄), 1.68 (3H, br s, Me-C₁); ¹³C NMR (75 MHz)

00

0

d 207.86 (C₁), 200.02 (C₅), 197.80 (COMe), 144.45 (C₃),

00

144.40 (C₁), 142.17 (C₃), 138.06 (C₄), 134.68 (C₂),

0

00

115.76 (C₂), 65.37 (C₆), 48.92 (C₅), 32.10 (C₆), 30.37

0

(MeCO), 28.99 (C₄), 25.45 (C₂), 24.23 (C₁), 22.27

0

+

00

(Me-C₁), 16.38 (Me-C₂); MS (EI) m/z (%) 302 (M , 2.3),

274 (27), 192 (100), 177 (36), 163 (43), 151 (47), 121

(27), 82 (20); HRMS m/z calcd for C₁₉H₂₆O₃302.1881,

found 302.1871.

4.2.2. (5R,6R)-6-Acetyl-6-((E)-5-(tert-butyldimethylsilyl-

oxy)-4-methylhexa-3,5-dienyl)-2-methyl-5-(prop-1-en-

2-yl)cyclohex-2-enone (18). Enone 17 (3.09 g, 10.2 mmol)

in dry CH₂Cl₂(98 mL) was cooled to ꢀ78 ^ꢁC and treated

sequentially with Et₃N (4.4 mL, 31 mmol) and TBDMSOTf

(3.36 mL, 15 mmol). After 1 h at ꢀ78 ^ꢁC, the reaction mix-

ture was quenched with 5% aq NaHCO₃solution, poured

into water and extracted with hexane. Work-up as usual

and puriﬁcation by column chromatography (hexane–

AcOEt 8:2, containing a 0.1% of Et₃N) as eluent, afforded

dienol silyl ether 18 (3.8 g, 90%) as a colourless oil. [a]_D²⁴

+43.3 (c 1.0, CHCl₃); IR v_max/cm^ꢀ1(KBr) 2929s, 2858m,

1702s, 1595m, 1445m, 1354m, 1229m, 1016m, 834s,

spectra were referenced to residual CHCl₃(d 7.26) and ¹³

C

spectra to the central component of the CDCl₃triplet at

d 77.0. Carbon substitution degrees were established by

DEPT pulse sequences. A combination of COSY, HSQC

and NOE experiments was utilised when necessary for the

assignment of H and ¹³C chemical shifts. IR spectra were

1

measured using KBr pellets or liquid ﬁlms; peak intensities

are speciﬁed as strong (s), medium (m) or weak (w).

Elemental analyses were performed by servicio de semi-

1

780m; H NMR (400 MHz, C₆D₆) d 6.00 (1H, br s, H-3),

6.27 (1H, dd, J¼7.53, 7.53 Hz, H-3⁰), 4.68 (1H, br s,

H-2⁰⁰), 4.67 (1H, br s, H-2⁰⁰), 4.45 (1H, s, H-6⁰), 4.33 (1H,

s, H-6⁰), 2.62 (1H, dd, J¼6.6, 6.6 Hz, H-5), 2.44 (1H, ddd,

J¼13.5, 10.5, 6.0 Hz, H-4), 2.38 (1H, br d, J¼19.2 Hz,

H-2⁰), 2.16–2.03 (1H, m), 1.98 (3H, s, MeCO-C₁), 1.97–

ꢀ

microanalisis of S.C.S.I.E. (Valencia); ﬁnal puriﬁcation of

all products for microanalysis was done by preparative

HPLC on a m-Porasil column, 7.8ꢂ300 mm (semi-prep)

column. Mass spectra were obtained by electron impact

(EI) at 70 eV. Crystallographic data (excluding structure fac-

tors) for the structures in this paper have been deposited with

the Cambridge Crystallographic Data Centre as supplemen-

tary publication number CCDC 626412. Copies of the data

can be obtained, free of charge, on application to CCDC,

12 Union Road, Cambridge CB2 1EZ, UK (fax: +44

(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).

00

1.84 (1H, m), 1.76 (3H, br s, Me-C₄), 1.71 (3H, s, Me-

00

C₂), 1.52 (3H, br s, Me-C₁), 0.99 (9H, s, Me₃CSi), 0.15

(6H, s, Me₂Si); ¹³C NMR (75 MHz, C₆D₆) d 206.88

0

(COMe), 197.39 (C₁), 157.82 (C₅), 145.32 (C₃), 143.67

00

(C₁), 134.58 (C₂), 132.30 (C₄), 128.29 (C₃), 115.24

0

00

(C₂), 91.41 (C₆), 65.79 (C₆), 49.68 (C₅), 33.43 (C₂),

0

29.91 (MeCO), 29.18 (C₄), 26.05 (Me₃CSi), 23.82 (C₁),

1672

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

00

22.45 (Me-C₁), 18.3 (Me₃CSi), 16.60 (Me-C₂), 13.30 (Me-

Me-C₅), 0.99 (3H, s, Me-C_1a), 0.84 (9H, s, Me₃CSi), 0.80

(3H, s, Me-C_7a), 0.59 (1H, ddd, J¼13.1, 13.1, 6.2 Hz,

H⁰-8), 0.51 (1H, d, J¼5.3 Hz, H-1), 0.21 (1H, d, J¼5.3 Hz,

H⁰-1), 0.09 (3H, s, MeSi), 0.03 (3H, s, MeSi); ¹³C NMR

(75 MHz) d 207.49 (C₄), 198.03 (COMe), 148.11 (C₆),

131.32 (C₅), 64.05 (C_3a), 58.11 (C_9a), 53.83 (C_1b), 52.09

(C_7a), 36.33 (C_7b), 34.01 (C₈), 32.43 (C₃), 28.90 (C₁),

28.81 (C₉), 28.06 (COMe), 25.75 (Me₃CSi), 25.53 (C₇),

23.30 (C₂), 21.64 (C_1a), 17.88 (Me₃CSi), 16.56 (Me-C₅),

15.39 (Me-C_1a), 13.22 (Me-C_7b), ꢀ3.06 and ꢀ3.84 (Me₂Si);

MS (EI) m/z (%) 431 (M⁺+1, 5), 430 (M⁺, 18), 387 (79), 373

(100), 255 (11), 211 (30), 177 (27), 121 (22), 73 (65); HRMS

m/z calcd for C₂₆H₄₂O₃Si 430.2916, found 430.2903. Anal.

Calcd for C₂₆H₄₂O₃Si: C, 72.51; H, 9.83. Found: C, 72.58;

H, 9.90.

+

0

C₄), ꢀ4.48 (Me₂Si); MS (EI) m/z (%) 416 (M , 3.3), 359 (3),

291 (4), 250 (9), 249 (44), 225 (47), 224 (44), 168 (100), 75

(40); HRMS m/z calcd for C₂₅H₄₀O₃Si 416.2748, found

416.2730.

4.2.3. (4aR,4bS,8aR,10aR)-10a-Acetyl-7-(tert-butyldime-

thylsilyloxy)-2,4b,8-trimethyl-4,4a,5,6,8a,9,10,10a-octa-

hydrophenanthren-1(4bH)-one (14). A solution of dienol

silyl ether 18 (350 mg, 0.84 mmol) in toluene (5 mL) was

transferred to a previously silylated ampoule and rigorously

degassed by the freeze–thaw cycle. The ampoule was cooled

down under argon, a drop of propylene oxide was added and

it was then sealed under vacuum. After heating at 195–

200 ^ꢁC for 5 days, the solvent was eliminated under vacuum

and the residue was chromatographed, using 8:2 hexane–

AcOEt (containing 0.1% of Et₃N) as eluent, to give the

Diels–Alder adduct 14 as a solid (332 mg, 95%). Mp

110 ^ꢁC (with decomposition); [a]_D¹⁸+60 (c 0.4, CHCl₃); IR

v_max/cm^ꢀ1(KBr) 2929s, 2857m, 1704s, 1663s, 1462m,

4.2.5. (1aS,1bR,3aS,7aR,7bS,9aR)-9a-(tert-Butyldi-

methylsilyloxy)-3a-(2-diazo acetyl)-1a,5,7b-trimethyl-

1b,2,3,3a,7,7a,7b,8,9,9a-decahydro-1H-cyclopropa[a]-

phenanthren-4(1aH)-one (20). A solution of methyl-

ketone 19 (330 mg, 0.76 mmol) in THF (2 mL) was added

dropwise over a period of 30 min to a THF solution of lith-

ium hexamethyldisilazide (LiHMDS) [prepared from 1.6 M

BuLi in hexanes (0.51 mL, 0.82 mmol), hexamethyldisil-

azane (0.175 mL, 0.83 mmol) and THF (3 mL)] at ꢀ78 ^ꢁC.

The solution was stirred for an additional 30 min at

ꢀ78 ^ꢁC and then treated with 2,2,2-triﬂuoroethyltriﬂuoro-

acetate (0.13 mL, 0.95 mmol). The reaction mixture was

stirred for 10 min, then poured into cool 5% aq HCl solution

and extracted with ether. The organic layer was washed

sequentially with 5% aq NaHCO₃solution, water and brine,

then dried over MgSO₄and concentrated under vacuum to

give the crude triﬂuoroketone derivative of diketone 19.

1

1355m, 1256m, 1178m, 837s, 778m; H NMR (300 MHz)

d 6.87 (1H, br s, H-3), 3.06 (1H, ddd, J¼19.2, 11.7, 2.5,

2.5 Hz, H-4), 2.85 (1H, ddd, J¼14.7, 3.3, 3.3 Hz, H-10),

2.33 (1H, ddd, J¼19.2, 4.5 Hz, H⁰-4), 2.18 (3H, s, MeCO-

C_10a), 2.12–1.86 (3H, m, H-9, H₂-6), 1.86–1.71 (2H, m,

H-4a, H-5), 1.72 (3H, s, Me-C₂), 1.55 (1H, m, H⁰-10), 1.54

(3H, s, Me-C₈), 1.48 (1H, dd, J¼14.7, 3.8 Hz, H-8a),

1.39–1.15 (2H, m, H⁰-9, H⁰-5), 0.71 (3H, s, Me-C_4b), 0.93

(9H, s, Me₃CSi), 0.10 (3H, s, MeSi), 0.09 (3H, s, MeSi);

¹³C NMR (75 MHz) d 207.83 (C₁), 197.90 (COMe),

148.52 (C₃), 142.13 (C₇), 131.17 (C₂), 111.91 (C₈), 63.81

(C_10a), 52.94 (C_4a), 48.14 (C_8a), 36.63 (C_4b), 33.92 (C₅),

32.38 (C₁₀), 28.50 (COMe), 27.51 (C₆), 25.80 (C₄), 25.67

(Me₃CSi), 22.49 (C₉), 18.14 (Me₃CSi), 16.38 (Me-C₂),

14.02 (Me-C₈), 12.36 (Me-C_4b), ꢀ3.96 and ꢀ3.57

(Me₂Si); MS (EI) m/z (%) 417 (M⁺+1, 35), 416 (M⁺, 100),

401 (33), 373 (53), 358 (25), 255 (80), 195 (12), 121 (13),

73 (30); HRMS m/z calcd for C₂₅H₄₀O₃Si 416.2753, found

416.2747.

A mixture of the residue obtained above, Et₃N (0.32 mL,

2.28 mmol), H₂O (20 mL, 1.14 mmol) and p-acetamidobenz-

enesulfonyl azide (p-ABSA) (730 g, 3.0 mmol) in MeCN

(20 mL) was stirred at 35 ^ꢁC for 7 h. The reaction mixture

was diluted with ether and washed with 10% aq NaOH solu-

tion, then brine and dried over Na₂SO₄. The residue left after

evaporation of the solvent was chromatographed (hexane–

Et₂Ot 8:2) to afford a-diazoketone 20 (300 mg, 87% from

19) as a white foam. [a]²_D⁵ꢀ60 (c 0.1, CHCl₃); IR v_max/cm^ꢀ1

(KBr) 2927s, 2851m, 2100s, 1665m, 1627m, 1335s, 1259m,

4.2.4. (1aS,1bR,3aR,7aR,7bS,9aR)-3a-Acetyl-9a-(tert-

butyldimethylsilyloxy)-1a,5,7b-trimethyl-1b,2,3,3a,7,7a,

7b,8,9,9a-decahydro-1H-cyclopropa[a]phenanthren-4-

(1aH)-one (19). Diethyl zinc (1.0 M solution in hexane,

23.1 mL, 17.3 mmol) and diiodomethane (3.57 mL,

34.5 mmol) were added to a solution of 14 (1.20 g,

2.88 mmol) in anhydrous toluene (50 mL) at 0 ^ꢁC. The reac-

tion mixture was allowed to slowly warm to rt (ca. 1 h) and

then stirred at this temperature for 2 h. The mixture was

quenched by the addition of saturated aq NH₄Cl solution

and extracted with hexane. The organic extracts were washed

successively with 10% aq solution of Na₂S₂O₃, water and

brine, then dried over MgSO₄and concentrated to give a

solid. Chromatography (hexane–AcOEt 9:1) yielded the di-

ketone 19 (1.114 g, 91%) as a white solid. Mp 107–109 ^ꢁC

(from cold hexane); [a]¹_D⁸+104 (c 4.4, CHCl₃); IR v_max/cm^ꢀ1

(KBr) 2953s, 2857m, 1700s, 1678s, 1435m, 1355m, 1256s,

1202m, 832s, 774m; ¹H NMR (300 MHz) d 6.83 (1H, br s,

H-6), 3.00 (1H, ddd, J¼19.2, 11.5, 2.3, 2.3 Hz, H-7), 2.77

(1H, ddd, J¼14.7, 3.5, 3.5 Hz, H-3), 2.24 (1H, ddd,

J¼19.2, 4.0, 4.0 Hz, H⁰-7), 2.14 (3H, s, MeCO-C_3a),

2.12–1.83 (4H, m), 1.70 (1H, m, H-8), 1.55 (1H, dd,

J¼11.5, 5.1 Hz, H-7a), 1.46–1.35 (2H, m), 1.69 (3H, s,

1

915m, 833s, 771m; H NMR (300 MHz) d 6.88 (1H, br s,

H-6), 5.56 (1H, s, CHN₂), 3.05 (1H, ddd, J¼19.2, 11.5,

2.3, 2.3 Hz, H-7), 2.45 (1H, ddd, J¼14.0, 3.2, 3.2 Hz,

H-3), 2.28 (1H, ddd, J¼19.2, 3.8, 3.8 Hz, H⁰-7), 2.12 (1H,

dd, J¼13.9, 6.4 Hz, H-7a), 2.12–1.4 (5H, m, H₂-2, H-8,

H₂-9), 1.74 (3H, s, Me-C₅), 1.02 (3H, s, Me-C_1a), 0.91

(3H, s, Me-C_7a), 0.84 (10H, s, Me₃CSi, H-1b), 0.62 (1H,

ddd, J¼13.2, 13.2, 5.9 Hz, H⁰-8), 0.52 (1H, d, J¼5.3 Hz,

H-1), 0.23 (1H, d, J¼5.3 Hz, H⁰-1), 0.11 (3H, s, MeSi),

0.04 (3H, s, MeSi); ¹³C NMR (75 MHz) d 198.33 (C₄),

193.06 (COCHN₂), 148.44 (C₆), 131.92 (C₅), 60.84 (C_3a),

58.11 (C_9a), 54.79 (C_7a), 54.00 (CHN₂), 52.48 (C_1b), 36.47

(C_7b), 34.14 (C₈), 32.42 (C₃), 28.91 (C₁), 28.84 (C₉), 25.52

(Me₃CSi), 25.51 (C₇), 22.93 (C₂), 21.70 (C_1a), 17.91

(Me₃CSi), 16.66 (Me-C₅), 15.84 (Me-C_1a), 13.03 (Me-

C_7b), ꢀ3.03 and ꢀ3.82 (Me₂Si); MS (EI) m/z (%) 456

(M⁺, 5), 428 (29), 399 (22), 371 (100), 211 (84), 75 (40),

73 (89); HRMS m/z calcd for C₂₆H₄₀N₂O₃Si 456.2827,

found 456.2808.

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1673

4.2.6. 3(R)-3-(tert-Butyldimethylsilyloxy)-3a,18-cyclo-

trachylobane-14,15-dione (13). degassed solution

d 210.31 (C₁₄), 209.22 (C₁₅), 65.76 (C₈), 58.87 (C₃), 51.72

(C₅), 46.16 (C₉), 46.13 (C₁₆), 46.00 (C₁₃), 37.59 (C₁₀),

34.14 (C₁), 32.09 (C₁₂), 28.50 (C₂), 28.32 (C₁₈), 26.18

(Me₃CSi), 22.65 (C₁₁), 22.56 (C₇), 21.72 (C₄and C₆),

21.56 (Me-C₁₆), 17.89 (Me₃CSi), 15.60 (Me-C₄), 11.25

(Me-C₁₀), ꢀ3.07 and ꢀ3.84 (Me₂Si); MS (EI) m/z (%) 431

(M⁺+1, 5), 430 (M⁺, 19), 387 (65), 373 (100), 211 (50), 73

(72); HRMS m/z calcd for C₂₆H₄₂O₃Si 430.2903, found

430.2902.

A

of bis(N-tert-butylsalicylaldiminato)copper(II) (20 mg,

0.043 mmol) in anhydrous toluene (90 mL) was stirred and

heated at reﬂux. Then, the a-diazoketone 20 (422 mg,

0.93 mmol) was added dropwise during 4 h using a syringe

pump and the reaction mixture was stirred at the same tem-

perature for 15 min. After this time, the reaction was allowed

to cool down to rt. The solvent was evaporated under vacuum

and the residue was puriﬁed by chromatography (hexane–

AcOEt 8:2) to give compound 13 (357 mg, 90%) as a white

solid. Mp 186–188 ^ꢁC (from MeOH); [a]²_D⁵+40 (c 2.1,

CHCl₃); IR v_max/cm^ꢀ1(KBr) 2955s, 2842m, 1762s, 1705s,

1460m, 1260m, 1075m, 802s, 774s, 671m; ¹H NMR

(300 MHz) d 2.58 (1H, d, J¼7.9 Hz, H-13), 2.46 (1H, ddd,

J¼7.7, 2.3, 2.3 Hz, H-12), 2.12 (1H, ddd, J¼13.2, 10.0,

3.1 Hz, H-11), 2.01 (1H, ddd, J¼13.6, 5.7, 2.5 Hz, H-7),

1.88 (1H, ddd, J¼13.2, 7.9, 2.1 Hz, H⁰-11), 1.85–1.40 (6H,

m), 1.38 (3H, s, Me-C₁₆), 1.33 (1H, ddd, J¼13.6, 6.4,

6.4 Hz, H-1), 1.02 (3H, s, Me-C₄), 0.80 (1H, m, H-5), 0.75

(3H, s, Me-C₁₀), 0.84 (9H, s, Me₃CSi), 0.54 (1H, ddd,

J¼13.6, 13.6, 5.8 Hz, H⁰-1), 0.48 (1H, d, J¼5.3 Hz, H-18),

0.21 (1H, d, J¼5.3 Hz, H⁰-18), 0.07 (3H, s, MeSi), 0.02

(3H, s, MeSi); ¹³C NMR (75 MHz) d 207.26 (C₁₄), 206.62

(C₁₅), 58.56 (C₃), 57.27 (C₉), 55.29 (C₈), 52.01 (C₅), 49.54

(C₁₆), 47.11 (C₁₃), 43.09 (C₁₂), 36.95 (C₁₀), 34.53 (C₁),

28.24 (C₂), 28.24 (C₁₈), 25.73 (Me₃CSi), 21.87 (C₆), 21.53

(C₄), 21.43 (C₇), 19.71 (C₁₁), 17.89 (Me₃CSi), 15.60 (Me-

C₄), 12.82 (Me-C₁₆), 11.02 (Me-C₁₀), ꢀ2.14 and ꢀ3.01

(Me₂Si); MS (EI) m/z (%) 429 (M⁺+1, 5), 428 (M⁺, 25),

372 (29), 371 (100), 343 (11), 265 (11), 211 (51), 75 (16),

73 (39); HRMS m/z calcd for C₂₆H₄₀O₃Si 428.2741, found

428.2747. Anal. Calcd for C₂₆H₄₀O₃Si: C, 72.85; H, 9.41.

Found: C, 72.77; H, 9.48.

Data for the minor epimer II: an amorphous solid; IR

v_max/cm^ꢀ1(KBr) 2958s, 2845m, 1735s, 1703s, 1473m,

1197m, 1094m, 920m, 844s, 777m; H NMR (300 MHz)

1

d 2.56 (1H, ddd, J¼19.9, 3.0, 3.0 Hz, H-13), 2.42–2.21

(4H, m), 2.06 (1H, ddd, J¼13.8, 5.6, 1.7 Hz, H-7), 1.96

(1H, m), 1.87 (1H, ddd, J¼13.9, 6.4, 1.1 Hz), 1.83–1.70

(2H, m), 1.56–1.31 (3H, m), 1.09 (3H, d, J¼7.1 Hz, Me-

C₁₆), 1.00 (3H, s, Me-C₄), 0.95–0.75 (2H, m), 0.84 (9H,

s, Me₃CSi), 0.71 (3H, s, Me-C₁₀), 0.59 (1H, ddd, J¼13.6,

13.6, 5.6 Hz, H-1), 0.51 (1H, dd, J¼5.0, 1.0 Hz, H-18),

0.22 (1H, d, J¼5.0 Hz, H⁰-18), 0.09 (3H, s, MeSi), 0.04

(3H, s, MeSi); ¹³C NMR (75 MHz) d 210.79 (C₁₄),

208.95 (C₁₅), 65.85 (C₈), 58.95 (C₃), 52.75 (C₅), 45.26

(C₉), 31.69 (C₁₂), 45.20 (C₁₆), 40.15 (C₁₃), 37.50 (C₁₀),

34.02 (C₁), 29.69 (C₁₁), 28.49 (C₂), 28.33 (C₁₈), 26.18

(Me₃CSi), 23.06 (C₇), 21.75 (C₄), 21.62 (C₆), 17.89

(Me₃CSi), 15.65 (Me-C₄), 14.91 (Me-C₁₆), 11.32 (Me-

C₁₀), ꢀ3.07 and ꢀ3.84 (Me₂Si); HRMS m/z calcd for

C₂₆H₄₂O₃Si 430.2903, found 430.2899.

4.3.2. 3(R),15(S)-3-(tert-Butyldimethylsilyloxy)-15-

hydroxy-3a,18-cyclo-trachyloban-14-one (21). A solution

of diketone 13 (226 mg, 0.53 mmol) in AcOEt (4 mL) was

hydrogenated over 10% Pt/C (65 mg) at 66 psi (4.5 atm)

for 24 h. The mixture was ﬁltered through Celite and the

ﬁltrate concentrated under vacuum. Flash chromatography

on silica gel, eluting with a 7:3 mixture of hexane–EtOAc,

provided 21 (216 mg, 95%) as a white solid. Mp 175–

176 ^ꢁC (from MeOH); [a]_D²⁵+55 (c 0.65, CHCl₃); IR

v_max/cm^ꢀ1(KBr) 2955s, 2847m, 1686s, 1460m, 1260s,

1075m, 1004m, 973m, 835s, 758s, 666m; ¹H NMR

(300 MHz) d 3.58 (1H, s, H-15), 2.18–1.93 (2H, ddd,

J¼12.8, 10.0, 2.6 Hz, H-11), 1.93–1.6 (9H, m, H-13, H-

12, H⁰-11, H-9, H-7, H₂-6, H₂-2), 1.45–1.1 (2H, m, H⁰-7,

H-1), 1.33 (3H, s, Me-C₁₆), 0.99 (3H, s, Me-C₄), 0.89–

0.75 (1H, m, H-5), 0.84 (9H, s, Me₃CSi), 0.69 (3H, s,

Me-C₁₀), 0.57 (1H, ddd, J¼13.8, 13.8, 5.9 Hz, H⁰-1),

0.46 (1H, d, J¼5.0 Hz, H-18), 0.21 (1H, d, J¼5.0 Hz, H⁰-

18), 0.07 (3H, s, MeSi), 0.03 (3H, s, MeSi); ¹³C NMR

(75 MHz) d 212.49 (C₁₄), 77.02 (C₁₅), 59.06 (C₃), 52.80

(C₅), 49.52 (C₈), 45.25 (C₉), 40.12 (C₁₃), 37.78 (C₁₆),

35.62 (C₁₀), 34.75 (C₁₂), 34.46 (C₁), 28.47 (C₂), 28.37

(C₁₈), 27.96 (C₇), 25.77 (Me₃CSi), 22.48 (C₆), 21.76

(C₄), 19.32 (C₁₁), 17.95 (Me-C₁₆), 17.91 (Me₃CSi), 15.58

(Me-C₄), 11.03 (Me-C₁₀), ꢀ3.84 and ꢀ3.02 (Me₂Si); MS

(IE) m/z (%) 431 (M⁺+1, 15), 430 (M⁺, 49), 415 (12),

374 (29), 373 (100), 281 (17), 212 (24), 211 (98), 75

(37), 73 (76); HRMS m/z calcd for C₂₆H₄₂O₃Si

430.2903, found 430.2909.

4.3. Trachylobane-to-atisane skeleton transformation.

Preparation of the atisane-type intermediate 12

4.3.1. 3(R),16(S)-3-(tert-Butyldimethylsilyloxy)-3a,18-

cyclo-atisane-14,15-dione (compounds I and II). A 0.1 M

solution of SmI₂in THF was added dropwise to a solution of

cyclopropyl diketone 13 (20 mg, 0.046 mmol) in a 3:1 mix-

ture of THF–MeOH (1.5 mL) until persistence of the blue

colour. The reaction mixture was stirred at rt for 1 h, then

treated with a saturated aq NH₄Cl solution and extracted

with ether. The organic layer was washed with water, 5%

aq Na₂S₂O₄solution and brine, and dried over Na₂SO₄.

The residue obtained after evaporation of the solvent was

chromatographed (hexane–AcOEt 95:5) to give atisane-

dione I (13 mg, 65%) followed by the 16a-H epimer II

(5.5 mg, 27%).

Data for the major epimer I: a white solid, mp 220–222 ^ꢁC

(from MeOH); [a]_D²⁹+13.3 (c 0.45, CHCl₃); IR v_max/cm^ꢀ1

(KBr) 2955s, 2842m, 1731s, 1700s, 1470m, 1225m,

1

1193m, 1091m, 917m, 840s, 773m; H NMR (300 MHz)

d 2.56 (1H, dd, J¼19.8, 3.6 Hz, H-13), 2.40–2.00 (5H, m,

H-16, H⁰-13, H-12, H₂-11), 1.92–1.30 (8H, m), 0.89–0.70

(1H, m, H-5), 1.23 (3H, d, J¼7.1 Hz, Me-C₁₆), 1.01 (3H,

s, Me-C₄), 0.84 (9H, s, Me₃CSi), 0.71 (3H, s, Me-C₁₀),

0.56 (1H, dd, J¼12.4, 12.4, 4.7 Hz, H-1), 0.49 (1H, d,

J¼5.0 Hz, H-18), 0.22 (1H, d, J¼5.0 Hz, H⁰-18), 0.085

(3H, s, MeSi), 0.03 (3H, s, MeSi); ¹³C NMR (75 MHz)

4.3.3. 3(R),15(R)-3-(tert-Butyldimethylsilyloxy)-15-iodo-

3a,18-cyclo-trachyloban-14-one (23). Et₃N (0.34 mL,

2.16 mmol) was added to a solution of alcohol 21

1674

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

(200 mg, 0.48 mmol) in CH₂Cl₂(5 mL) at 0 ^ꢁC, followed by

MsCl (0.15 mL, 1.58 mmol) over a period of 5 min. The

mixture was stirred at 0 ^ꢁC for an additional 2 h and

diluted with water. Work-up as usual afforded a yellowish

residue of crude mesylate 22 (215 mg) that was used in the

next step without further puriﬁcation.

(C₂), 25.77 (Me₃CSi), 22.62 (C₆), 21.94 (C₄), 20.05 (Me-

C₁₆), 17.92 (Me₃CSi), 15.61 (Me-C₄), 10.99 (Me-C₁₀),

ꢀ3.03 and ꢀ3.82 (Me₂Si); MS (EI) m/z (%) 415 (M⁺+1,

15), 414 (M⁺, 33), 358 (29), 357 (100), 211 (62), 105 (32),

75 (37), 73 (83); HRMS m/z calcd for C₂₆H₄₂O₂Si

414.2954, found 414.2953.

A mixture of the above-obtained mesylate in a 10% solution

of NaI in dry acetone (4 mL) was stirred and heated at 40 ^ꢁC

for 2 h. The reaction mixture was cooled down to rt, diluted

with water and worked up. Puriﬁcation by chromatography

(hexane–AcOEt 9:1) afforded iodo-ketone 23 (240 mg,

93% from alcohol 21) as a white solid. Mp 189–191 ^ꢁC

(with decomposition) (from cold ethyl ether); [a]²_D⁵+61

(c 1.7, CHCl₃); IR v_max/cm^ꢀ1(KBr) 2924s, 2842s, 1726s,

4.3.5. 3(R)-(tert-Butyldimethylsilyloxy)-13(S)-(4-(tert-

butyldimethylsilyloxy)butyl)-3a,18-cyclo-atis-15-en-14-

one (compound III). A solution of ketone 12 (15 mg,

0.036 mmol) in THF (0.2 mL) was added dropwise to a

1 M solution of NaHMDS in THF (47 mL, 0.047 mmol) at

ꢀ78 ^ꢁC. After 30 min, TBDMSOTf (11 mL, 0.047 mmol)

was added all at once and the mixture was stirred at the

same temperature for 3 h, then poured into water and ex-

tracted with ether. The combined organic layers were

washed with 5% aq HCl solution, 5% aq NaHCO₃and brine

and dried over MgSO₄. Chromatography (hexane–AcOEt

9:1) of the residue left after removal of the solvent afforded

the compound III (15.5 mg, 70%) as a viscous oil. ¹H NMR

(400 MHz) d 5.25 (1H, s, H-15), 3.61 (2H, dd, J¼6.0,

6.0 Hz, H-4⁰), 2.61 (1H, m, H-12), 2.41 (1H, ddd, J¼13.0,

3.0, 3.0 Hz, H-7), 2.02 (1H, ddd, J¼13.5, 5.8, 1.7 Hz,

H-2), 1.88–1.60 (4H, m, H-13, H-11, H-6, H⁰-2), 1.77 (3H,

d, J¼1.0 Hz, Me-C₁₆), 1.60–1.05 (11H, m, H⁰-11, H-9,

H⁰-7, H⁰-6, H-1, H₂-1⁰, H₂-2⁰, H₂-3⁰), 0.99 (3H, s, Me-C₄),

0.89 and 0.84 (9H each, each s, 2ꢂMe₃CSi), 0.88 (1H, m,

H-5), 0.63 (3H, s, Me-C₁₀), 0.64 (1H, m, H⁰-1), 0.49 (1H,

dd, J¼5.0, 1.0 Hz, H-18), 0.24 (1H, d, J¼5.0 Hz, H⁰-18),

0.09, 0.07, 0.04 and 0.03 (3H each, each s, 2ꢂMe₂Si); ¹³C

NMR (75 MHz) d 215.77 (C₁₄), 145.23 (C₁₆), 127.35

1

1460m, 1250m, 830s, 768m; H NMR (400 MHz) d 4.32

(1H, s, H-15), 2.12 (1H, m, H-11), 2.11 (1H, d, J¼7.3 Hz,

H-13), 2.02 (1H, m, H-2), 1.98–1.62 (6H, m, H-12, H⁰-11,

H-9, H₂-6, H-2), 1.40 (1H, m, H-1), 1.32 (3H, s, Me-C₁₆),

1.23 (1H, m, H-7), 1.12 (1H, m, H⁰-7), 1.00 (3H, s, Me-

C₄), 0.91 (1H, m, H-5), 0.84 (9H, s, Me₃CSi), 0.69 (3H, s,

Me-C₁₀), 0.60 (1H, m, H⁰-1), 0.46 (1H, d, J¼5.0 Hz, H-

18), 0.27 (1H, d, J¼5.0 Hz, H⁰-18), 0.09 (3H, s, MeSi),

0.035 (3H, s, MeSi); ¹³C NMR (75 MHz) d 207.14 (C₁₄),

58.90 (C₃), 52.90 (C₉), 52.79 (C₅), 52.42 (C₁₅), 49.49 (C₈),

43.23 (C₁₂), 38.53 (C₁₀), 38.05 (C₁₂), 36.26 (C₁₆), 34.52

(C₁), 28.53 (C₇), 28.47 (C₂and C₁₈), 25.77 (Me₃CSi),

22.09 (C₆), 21.73 (C₄), 21.07 (Me-C₁₆), 17.91 (C₁₁and

Me₃CSi), 15.49 (Me-C₄), 10.41 (Me-C₁₀), ꢀ3.03 and

ꢀ3.82 (Me₂Si); MS (EI) m/z (%) 541 (M⁺+1, 15), 540

(M⁺, 24), 483 (56), 413 (66), 391 (45), 281 (30), 211

(100), 75 (28), 73 (71); HRMS m/z calcd for C₂₆H₄₁IO₂Si

540.1921, found 540.1916.

0

(C₁₅), 62.94 (C₄), 59.02 (C₃), 53.75 (C₅), 51.95 (C₈),

51.71 (C₁₃), 51.33 (C₉), 40.42 (C₁₂), 35.69 (C₁₀), 35.04

0

(C₁), 32.77 (C₃), 30.58 (C₁), 29.70 (C₂), 28.63 (C₁₈),

4.3.4. 3(R)-(tert-Butyldimethylsilyloxy)-3a,18-cyclo-atis-

15-en-14-one (12). A solution of iodo cyclopropyl-ketone

23 (240 mg, 0.44 mmol) in a 3:1 mixture of THF and

MeOH (5.6 mL) was treated dropwise with a 0.1 M stock

solution of SmI₂in THF at rt until persistence of the blue

colour. After being stirred at the same temperature for 1 h,

saturated aq NH₄Cl solution was added and the mixture

was poured into water and extracted with ether. The com-

bined organic layers were washed with 10% aq Na₂S₂O₃

and then brine, dried over MgSO₄and evaporated. Chroma-

tography (hexane–AcOEt 9:1) gave the compound 12

(178 mg, 95%) as a white solid. Mp 213–215 ^ꢁC (from

MeOH); [a]²_D⁰ꢀ51 (c 1.3, CHCl₃); IR v_max/cm^ꢀ1(KBr)

2924s, 2858m, 1705s, 1470m, 1250m, 1091m, 973m,

28.51 (C₇), 27.55 (C₁₁), 26.77 and 25.96 (2ꢂMe₃CSi),

0

24.18 (C₂), 22.66 (C₆), 21.41 (Me-C₁₆), 21.94 (C₄), 18.33,

17.92 (2ꢂMe₃CSi), 15.60 (Me-C₄), 11.35 (Me-C₁₀),

ꢀ3.03, ꢀ3.82, ꢀ5.26 and ꢀ5.26 (4ꢂMeSi); MS (EI) m/z

(%) 601 (M⁺+1, 5), 600 (M⁺, 12), 543 (100), 487 (9), 211

(16), 75 (17), 73 (36); HRMS m/z calcd for C₃₆H₆₄O₃Si₂

600.4394, found 600.4383.

4.4. Synthesis of atisene 3

4.4.1. 3(R),13(S)-3-(tert-Butyldimethylsilyloxy)-13-

hydroxy-3a,18-cyclo-atis-15-en-14-one (25). Ketone 12

(35.7 mg, 0.086 mmol) and Et₃N (29.5 mL, 0.21 mmol)

were dissolved in 0.7 mL of CH₂Cl₂and cooled to 0 ^ꢁC.

TMSOTf (23 mL, 0.13 mmol) was added and the reaction

mixture was allowed to warm slowly to rt and then stirred

for 30 min. The reaction mixture was poured into a mixture

of hexane and 5% aq NaHCO₃. The layers were separated

and the organic phase was washed with water and then

brine. The solution was dried over Na₂SO₄, ﬁltered and then

evaporated under vacuum to yield a yellowish oil (38.3 mg)

as the crude product (compound 24a). This trimethylsilyl

enol ether was quite labile, being readily hydrolysed to the

starting ketone when chromatographed on silica gel, so it

was used in the next step without further puriﬁcation.

1

917m, 840s, 773s; H NMR (400 MHz) d 5.25 (1H, s, H-

15), 2.58 (1H, m, H-12), 2.44 (1H, ddd, J¼13.0, 3.4,

3.4 Hz, H-7), 2.14 (1H, ddd, J¼18.0, 3.0, 3.0 Hz, H-13),

2.05 (1H, m, H-2), 1.99 (1H, dd, J¼18.0, 3.0 Hz, H⁰-13),

1.88 (1H, ddd, J¼13.6, 6.0, 1.1 Hz, H⁰-2), 1.83–1.35 (5H,

m, H₂-11, H₂-6, H-1), 1.78 (3H, d, J¼1.0 Hz, Me-C₁₆),

1.30 (1H, dd, J¼11.2, 6.0 Hz, H-9), 1.15 (1H, m, H⁰-7),

1.01 (3H, s, Me-C₄), 0.92 (1H, dd, J¼12.8, 3.8 Hz, H-5),

0.84 (9H, s, Me₃CSi), 0.66 (3H, s, Me-C₁₀), 0.64 (1H, ddd,

J¼13.4, 13.4, 6.0 Hz, H⁰-1), 0.49 (1H, dd, J¼5.0, 1.1 Hz,

H-18), 0.24 (1H, d, J¼5.0 Hz, H⁰-18), 0.09 (3H, s, MeSi),

0.04 (3H, s, MeSi); ¹³C NMR (75 MHz) d 214.36 (C₁₄),

146.17 (C₁₆), 128.06 (C₁₅), 58.99 (C₃), 53.70 (C₉), 52.17

(C₈), 51.39 (C₅), 41.84 (C₁₃), 37.13 (C₁₂), 35.70 (C₁₀),

35.06 (C₁), 29.52 (C₇), 28.66 (C₁₁), 28.51 (C₁₈), 27.42

The crude product obtained above was dissolved in CH₂Cl₂

(0.7 mL), NaHCO₃was added (8.4 mg) and the resulting

suspension was cooled to 0 ^ꢁC. A solution of m-CPBA

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1675

(40 mg, 0.23 mmol) in CH₂Cl₂(1 mL) was slowly added and

the mixture was stirred at 0 ^ꢁC for 1 h. The reaction mixture

was quenched by the addition of saturated aq NH₄Cl solution

and worked up using hexane to extract it. The residue left

after evaporation of the solvent was dissolved in MeOH

(1 mL) and treated with (COOH)₂(8 mg). A white precipi-

tate immediately appeared and the mixture was stirred at rt

for 15 min. The reaction mixture was poured into a 1:1 mix-

ture of hexane–ethyl ether, which was successively washed

with 5% aq NaHCO₃, water and brine, then dried over

MgSO₄and concentrated to give a solid. Chromatography

(hexane–AcOEt 8:2) gave the hydroxyketone 25 (28.3 mg,

79% from 12) as a white solid. Mp 178–180 ^ꢁC (from

Et₂O); [a]²_D²ꢀ85 (c 1.2, CHCl₃); IR v_max/cm^ꢀ1(KBr)

3534s, 2929s, 2852m, 1710s, 1455m, 1255m, 1193m,

4.4.3. Atis-15-ene-3,14-dione (28). In the same manner

as described above for 25, a solution of 12 (209 mg,

0.50 mmol) and PTSA (125 mg, 0.63 mmol) in CHCl₃

(18 mL) was heated at reﬂux for 1.5 h. Work-up, followed

by puriﬁcation by chromatography (hexane–AcOEt 8:2),

afforded the atisene diketone 28 (142 mg, 94%) as a solid.

Mp 156–158 ^ꢁC (from MeOH); [a]_D²⁰ꢀ98 (c 0.6, CHCl₃);

IR v_max/cm^ꢀ1(KBr) 2939s, 2873m, 1700s, 1459m, 1413m,

1

1372m, 1075m, 793w, 691w, 578w; H NMR (300 MHz)

d 5.37 (1H, br s, H-15), 2.65 (1H, m, H-12), 2.56 (1H,

ddd, J¼15.6, 13.0, 6.6 Hz, H-2), 2.53 (1H, ddd, J¼11.7,

2.8, 2.8 Hz, H-7), 2.31 (1H, ddd, J¼15.6, 5.7, 3.1 Hz,

H⁰-2), 2.18 (1H, ddd, J¼18.1, 2.8, 2.8 Hz, H-13), 2.06

(1H, dd, J¼18.1, 2.1 Hz, H⁰-13), 1.86–1.75 (1H, m, H-1),

1.80 (3H, d, J¼1.7 Hz, Me-C₁₆), 1.68 (1H, ddd, J¼12.9,

12.3, 3.4 Hz, H-11), 1.61–1.47 (3H, m, H⁰-11, H₂-6), 1.45–

1.32 (3H, m, H-9, H-5, H⁰-1), 1.24 (1H, ddd, J¼13.2, 12.9,

4.5 Hz, H⁰-7), 1.09 (3H, s, Mea-C₄), 1.01 (3H, s, Meb-C₄),

0.89 (3H, s, Me-C₁₀); ¹³C NMR (75 MHz) d 216.58 (C₃),

213.94 (C₁₄), 146.28 (C₁₆), 128.21 (C₁₅), 55.38 (C₅), 53.93

(C₉), 52.34 (C₈), 47.64 (C₄), 41.63 (C₁₃), 38.11 (C₁), 37.04

(C₁₀and C₁₂), 34.26 (C₂), 29.40 (C₇), 26.68 (C₁₁), 25.94

(Mea-C₄), 21.72 (Me-C₁₆), 20.03 (C₆), 19.91 (Meb-C₄),

12.69 (Me-C₁₀); MS (EI) m/z (%) 300 (M⁺, 14), 259 (100),

258 (100), 240 (14), 139 (15), 135 (27), 105 (38); HRMS

m/z calcd for C₂₀H₂₈O₂300.2089, found 300.2082. Anal.

Calcd for C₂₀H₂₈O₂: C, 79.96; H, 9.39. Found: C, 79.86;

H, 9.46.

1

1040m, 835s, 763s; H NMR (400 MHz) d 5.30 (1H, br s,

H-15), 3.69 (1H, d, J¼2.4 Hz, H-13), 2.78 (1H, br s, OH),

2.72 (1H, m, H-12), 2.49 (1H, ddd, J¼13.3, 3.1, 3.1 Hz,

H-7), 2.06 (1H, ddd, J¼13.4, 5.8, 1.7 Hz, H-2), 1.92–1.66

(3H, m, H₂-6, H⁰-2), 1.59–1.38 (3H, m, H₂-11, H-1), 1.32

(1H, dd, J¼12.3, 6.2 Hz, H-9), 1.80 (1H, ddd, J¼13.3,

13.3, 4.3 Hz, H⁰-7), 1.83 (3H, d, J¼1.0 Hz, Me-C₁₆), 0.90

(1H, dd, J¼12.9, 3.3 Hz, H-5), 0.99 (3H, s, Me-C4), 0.84

(9H, s, Me₃CSi), 0.64 (1H, ddd, J¼13.4, 13.4, 5.7 Hz, H⁰-

1), 0.61 (3H, s, Me-C₁₀), 0.50 (1H, dd, J¼5.0, 1.0 Hz, H-

18), 0.25 (1H, d, J¼5.0 Hz, H⁰-18), 0.09 and 0.04 (3H

each, each s, Me₂Si); ¹³C NMR (75 MHz) d 216.12 (C₁₄),

145.82 (C₁₆), 126.13 (C₁₅), 73.55 (C₁₃), 58.94 (C₃), 53.56

(C₄), 51.61 (C₉), 49.98 (C₈), 43.21 (C₁₂), 35.65 (C₁₀),

34.65 (C₁), 28.78 (C₂), 28.66 (C₁₈), 28.46 (C₇), 26.18

(Me₃CSi), 24.89 (C₁₁), 21.85 (C₄), 21.56 (C₆), 21.27

(Me-C₁₆), 17.89 (Me₃CSi), 15.62 (Me-C₄), 12.12

(Me-C₁₀), ꢀ3.04 and ꢀ3.82 (Me₂Si); MS (EI) m/z (%) 430

(M⁺, 29), 374 (30), 373 (100), 211 (79), 75 (32), 73 (81);

HRMS m/z calcd for C₂₆H₄₂O₃Si 430.2903, found 430.2893.

4.4.4. Atis-16-ene-3,14-dione (3). MeOH (4.8 mL) was

dropwise added to a light-protected, stirred solution of

recrystallised NBS (96 mg, 0.54 mmol) and atisene 28

(110 mg, 0.36 mmol) in CH₂Cl₂(14.5 mL) at 0 ^ꢁC. After

45 min of stirring at this temperature, the reaction mixture

was poured into hexane and worked up to afford a mixture

of allyl bromides 29a and 29b (150 mg) in the proportion

1

4.4.2. 13(S)-Hydroxy-atis-15-ene-3,14-dione (26). A solu-

tion of compound 25 (24 mg, 0.056 mmol) and PTSA

(14 mg, 0.070 mmol) in CHCl₃(4 mL) was heated at reﬂux

for 1.5 h. The reaction mixture was treated with a 5% aq

NaHCO₃solution, poured into water, and then worked up

using ether to extract it. After evaporation of the solvent,

the crude product was puriﬁed by chromatography (hexane–

AcOEt 8:2) to give the diketone 26 (14.8 mg, 86%) as a solid.

Mp 145–147 ^ꢁC (from MeOH); [a]_D²⁵ꢀ168 (c 0.5, CHCl₃);

IR v_max/cm^ꢀ1(KBr) 3528m, 2931s, 2850s, 1712s, 1694s,

of about 3:1, as inferred from the analysis of the H NMR

of the crude mixture, which was used without further puriﬁ-

cation in the next step.

¹H NMR data for the major regioisomeric bromide was de-

duced from the spectrum of the mixture: d 5.72 (1H, br s, H-

15), 4.11 (2H, s, H₂-17), 2.98 (1H, m, H-12), 2.64–2.52 (2H,

m, H-2 and H-7), 2.31 (1H, ddd, J¼16.0, 5.6, 3.2 Hz, H⁰-2),

2.22 (1H, ddd, J¼18.0, 2.8, 2.8 Hz, H-13), 2.15 (1H, dd,

J¼18.0, 2.8 Hz, H⁰-13), 1.69 (1H, ddd, J¼13.2, 13.2,

4.0 Hz, H-11), 1.09 (3H, s, Mea-C₄), 1.01 (3H, s, Meb-

C₄), 0.92 (3H, s, Me-C₁₀).

1

1460m; H NMR (300 MHz) d 5.37 (1H, br s, H-15), 3.75

(1H, d, J¼2.0 Hz, H-13), 2.77 (1H, m, H-12), 2.58 (1H,

ddd, J¼13.2, 3.3, 3.3 Hz, H-7), 2.56 (1H, ddd, J¼15.6,

12.9, 6.3 Hz, H-2), 2.34 (1H, ddd, J¼15.6, 5.4, 3.3 Hz, H⁰-

2), 1.90–1.73 (2H, m, H-11, H-1), 1.86 (3H, d, J¼2.1 Hz,

Me-C₁₆), 1.62–1.49 (3H, m, H⁰-11, H₂-6), 1.48–1.18 (4H,

m, H-9, H⁰-7, H-5, H⁰-1), 1.09 (3H, s, Mea-C₄), 1.01 (3H,

s, Meb-C₄), 0.84 (3H, s, Me-C₁₀); ¹³C NMR (75 MHz)

d 216.12 (C₃), 213.50 (C₁₄), 146.24 (C₁₆), 125.74 (C₁₅),

73.34 (C₁₃), 55.23 (C₅), 52.44 (C₉), 51.81 (C₈), 47.54 (C₄),

37.70 (C₁), 43.06 (C₁₂), 37.02 (C₁₀), 34.21 (C₂), 28.71

(C₇), 24.25 (C₁₁), 26.13 (Mea-C₄), 21.29 (Me-C₁₆), 19.91

(C₆), 21.18 (Meb-C₄), 13.73 (Me-C₁₀); MS (EI) m/z (%)

316 (M⁺, 10), 290 (20), 288 (100), 118 (40), 105 (32), 91

(18); HRMS m/z calcd for C₂₀H₂₈O₃316.2039, found

316.2043. Anal. Calcd for C₂₀H₂₈O₃: C, 75.91; H, 8.92.

Found: C, 75.84; H, 8.90.

A mixture of CrCl₃(785 mg, 5 mmol) and LiAlH₄(95 mg,

2.5 mmol) was dissolved in THF (5 mL) and stirred at rt un-

til the hydrogen evolution ceased. Then, DMF (10 mL) and

iso-PrOH (0.68 mL) were added, and the mixture was stirred

at rt for 20 min. A solution of the above-obtained allyl

bromides 29a–b (150 mg) in DMF (5 mL) was added, and

the resulting mixture was stirred at rt overnight. After this

time, the reaction mixture was poured into a 1:1 mixture

of hexane–Et₂O, the organic layer was washed sequentially

with diluted hydrochloric acid, 5% aq NaHCO₃and brine,

and then dried over MgSO₄. Evaporation of the solvent

and chromatography (hexane–AcOEt 8:2) provided com-

pound 3 (100 mg, 91% for the two steps) as a white solid.

Mp 153–155 ^ꢁC (from MeOH); [a]_D²²ꢀ5.5 (c 0.7, CHCl₃)

1676

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

{lit.^3,4mp 160–164 ^ꢁC; [a]_D²⁵+5.5}; IR v_max/cm^ꢀ1(KBr)

2922s, 2855m, 1757s, 1710s, 1467m, 1265m, 1187w,

1156w, 1078w, 1011w, 835s, 767m; H NMR (300 MHz)

washed sequentially with 5% aq NaHCO₃and brine, and

then dried over MgSO₄. Chromatography (hexane–AcOEt

7:3) of the residue left after removal of the solvent, afforded

antiquorin (1) (21.3 mg, 90% from 30) as a white solid. Mp

174–176 ^ꢁC (from MeOH); [a]_D²⁷ꢀ42 (c 0.4, CHCl₃) {lit.^3,4

mp 175–177 ^ꢁC; [a]²_D⁵+44}, {lit.⁶mp 162–163 ^ꢁC; [a]²_D⁵

+42}; IR v_max/cm^ꢀ1(KBr) 3534m, 2929s, 2852s, 1712s,

1

d 4.89 (1H, br s, H-17), 4.68 (1H, br s, H⁰-17), 2.73 (1H,

m, H-12), 2.56 (1H, ddd, J¼19.8, 13.4, 6.4 Hz, H-2),

2.40–2.15 (6H, m, H₂-15, H₂-13, H-7, H⁰-2), 2.0–1.76 (2H,

m, H-11, H-1), 1.75–1.44 (4H, m, H⁰-11, H-9, H₂-6), 1.35

(1H, ddd, J¼13.2, 13.2, 5.3 Hz, H⁰-1), 1.27 (1H, dd,

J¼12.4, 2.5 Hz, H-5), 0.91 (1H, ddd, J¼13.2, 13.2, 4.7 Hz,

H⁰-7), 1.08 (3H, s, Mea-C₄), 1.01 (3H, s, Meb-C₄), 0.87

(3H, s, Me-C₁₀); ¹³C NMR (75 MHz) d 216.42 (C₃),

216.14 (C₁₄), 147.07 (C₁₆), 42.61 (C₁₅), 55.33 (C₅), 51.84

(C₉), 47.59 (C₈), 47.68 (C₄), 44.56 (C₁₃), 37.18 (C₁), 38.30

(C₁₂), 37.18 (C₁₀), 34.09 (C₂), 31.17 (C₇), 27.86 (C₁₁),

25.95 (Mea-C₄), 107.15 (C₁₇), 20.02 (C₆), 21.83 (Meb-

C₄), 12.77 (Me-C₁₀); HRMS m/z calcd for C₂₀H₂₈O₂

300.2089, found 300.2085.

1

1694s, 1454m, 1190m, 1040m, 836s; H NMR (400 MHz)

d 5.02 (1H, br s, H-17), 4.86 (1H, br s, H⁰-17), 3.96 (1H, s,

OH), 3.88 (1H, d, J¼3.2 Hz, H-13), 2.82 (1H, ddd, J¼3.0,

3.0, 3.0 Hz, H-12), 2.55 (1H, ddd, J¼15.8, 13.0, 6.3 Hz,

H-2), 2.41 (1H, ddd, J¼13.2, 3.8, 3.8 Hz, H-7), 2.34 (1H,

ddd, J¼15.8, 5.6, 3.2 Hz, H⁰-2), 2.32 (1H, m, H-15), 2.03

(1H, ddd, J¼15.4, 11.6, 3.9 Hz, H-11), 1.86 (1H, ddd,

J¼13.3, 6.3, 3.3 Hz, H-1), 1.76 (1H, ddd, J¼13.9, 6.3,

2.6 Hz, H⁰-11), 1.66 (1H, dd, J¼11.6, 6.3 Hz, H-9), 1.56–

1.47 (2H, m, H₂-6), 1.39 (1H, ddd, J¼13.3, 13.0, 5.6 Hz,

H⁰-1), 1.34–1.26 (2H, m, H-5, H⁰-1), 0.95 (1H, m, H⁰-7),

1.09 (3H, s, Me-C_4a), 1.01 (3H, s, Me-C_4b), 0.84 (3H, s,

Me-C₁₀); ¹³C NMR (75 MHz) d 217.96 (C₁₄), 216.06 (C₃),

142.3 (C₁₆), 111.13 (C₁₇), 75.16 (C₁₃), 55.21 (C₅), 51.16

(C₉), 43.77 (C₁₅), 47.50 (C₈), 47.35 (C₄), 44.86 (C₁₂),

37.58 (C₁₀), 36.73 (C₁), 34.04 (C₂), 30.42 (C₇), 26.21

(Me-C_4a), 25.39 (C₁₁), 21.85 (Me-C_4b), 19.98 (C₆), 13.72

(Me-C₁₀); HRMS m/z calcd for C₂₀H₂₈O₃316.2038, found

316.2041.

4.5. Synthesis of antiquorin (1)

4.5.1. 3-(tert-Butyldimethylsilyloxy)-atis-2,16-diene-14-

one (30). A solution of diketone 3 (25 mg, 0.083 mmol) in

CH₂Cl₂(0.5 mL) was cooled to ꢀ78 ^ꢁC and treated sequen-

tially with Et₃N (14 mL, 0.097 mmol) and TBDMSOTf

(21 mL, 0.091 mmol). After 30 min at ꢀ78 ^ꢁC, the reaction

mixture was diluted with hexane and worked up as usual

to give silyl enol ether 30 (34 mg, 98%) as an oil, which

1

was proven to be nearly pure by H NMR analysis and

was used in the next step without further puriﬁcation.

4.6. Synthesis of atisenes 8 and 9

4.6.1. 2(R)-2-Hydroxy-atis-16-ene-3,14-dione (33). Solid

NaHCO₃(5 mg, 0.06 mmol) and a solution of m-CPBA

(40 mg, 0.23 mmol) in CH₂Cl₂(2 mL) were successively

added to a solution of enolsilyl ether 30 (36 mg,

0.087 mmol) in CH₂Cl₂(1.5 mL) at 0 ^ꢁC. After 15 min,

the reaction mixture was quenched by the addition of 5%

aq NaHCO₃solution and extracted with CH₂Cl₂. The com-

bined organic layers were washed sequentially with 5% aq

NaHSO₃solution, 5% aq NaHCO₃solution and brine, then

dried with Na₂SO₄, ﬁltered and concentrated under vacuum

to leave a solid. This crude material was dissolved in MeOH

(2 mL), then solid (COOH)₂(20 mg, 0.22 mmol) was added

and the mixture was stirred at rt for 3 h. The mixture was di-

luted with a 1:1 mixture of hexane–Et₂O, washed sequen-

tially with 5% aq NaHCO₃solution, water and brine, and

then dried over MgSO₄. Chromatography (hexane–AcOEt

8:2) of the residue left after removal of the solvent afforded

the hydroxyketone 33 (22.7 mg, 88%) as a white solid. Mp

155–157 ^ꢁC (from MeOH); [a]_D²⁷ꢀ8 (c 1.7, CHCl₃); IR

v_max/cm^ꢀ1(KBr) 3487m, 3421w, 2940m, 2899m, 1710s,

1449w, 1388m, 1260w, 1250m, 988w, 881m; ¹H NMR

(400 MHz) d 4.90 (1H, br s, H-17), 4.68 (1H, br s, H⁰-17),

4.48 (1H, ddd, J¼13.6, 6.4, 2.2 Hz, H-2), 3.63 (1H, d,

J¼2.2 Hz, OH), 2.74 (1H, quint, J¼2.7 Hz, H-12), 2.40–

2.15 (6H, m, H₂-15, H₂-13, H-7, H-1), 1.95 (1H, dddd,

J¼10.9, 10.9, 5.8, 2.2 Hz, H-11), 1.74–1.55 (4H, m, H⁰-11,

H-9, H-6, H⁰-1), 1.50 (1H, dddd, J¼13.8, 4.9, 4.7. 2.8 Hz,

H-6), 1.22 (1H, dd, J¼12.4, 2.2 Hz, H-5), 0.91 (1H, ddd,

J¼13.2, 13.2, 4.9 Hz, H⁰-7), 1.16 (3H, s, Me-C₁₀), 1.09

(3H, s, Mea-C₄), 1.01 (3H, s, Meb-C₄); ¹³C NMR

(75 MHz) d 215.87 (C₃), 216.42 (C₁₄), 146.66 (C₁₆),

107.42 (C₁₇), 68.87 (C₂), 56.92 (C₅), 52.08 (C₉), 47.60

(C₈), 47.47 (C₄), 47.18 (C₁), 44.52 (C₁₃), 42.55 (C₁₅),

38.21 (C₁₀), 38.14 (C₁₂), 31.04 (C₇), 28.00 (C₁₁), 24.92

Spectroscopic data for 30: ¹H NMR (300 MHz, C₆D₆) d 4.75

(1H, dd, J¼4.0, 2.4 Hz, H-17), 4.61 (1H, dd, J¼6.6, 2.2 Hz,

H-2), 4.53 (1H, dd, J¼4.0, 2.2 Hz, H⁰-17), 2.27 (1H, quint,

J¼2.9 Hz, H-12), 2.37 (1H, ddd, J¼13.2, 3.9, 2.9 Hz, H-

7), 2.13–1.98 (2H, m, H-15, H-13), 1.91–1.72 (2H, m, H⁰-

15, H⁰-13), 1.60 (1H, ddd, J¼15.9, 6.6 Hz, H-1), 1.56–1.25

(5H, m, H-11, H-9, H₂-6, H⁰-1), 1.20 (1H, m, H⁰-11), 1.11

(3H, s, Me-C_4b), 1.04 (1H, dd, J¼12.7, 2.7 Hz, H-5), 0.97

(3H, s, Me-C_4a), 0.96 (9H, s, Me₃CSi), 0.69 (3H, s, Me-

C₁₀), 0.6 (1H, ddd, J¼13.2, 13.2, 4.6 Hz, H⁰-7), 0.15 and

0.12 (3H each, each s, Me₂Si); ¹³C NMR (75 MHz, C₆D₆)

d 213.71 (C₁₄), 156.39 (C₃), 148.23 (C₂), 148.23 (C₁₆),

106.35 (C₁₇), 52.47 (C₅), 50.91 (C₉), 47.34 (C₈), 45.74

(C₄), 44.57 (C₁₃), 42.59 (C₁₅), 37.64 (C₁), 38.91 (C₁₂),

38.16 (C₁₀), 31.43 (C₇), 28.74 (Me-C_4a), 27.25 (C₁₁),

25.98 (Me₃CSi), 20.40 (Me-C_4b), 20.04 (C₆), 18.37

(Me₃CSi), 12.96 (Me-C₁₀), ꢀ4.15 and ꢀ4.55 (Me₂Si).

4.5.2. 13(S)-13-Hydroxy-atis-16-ene-3,14-dione (anti-

quorin, 1). A solution of the above-obtained compound 30

(30 mg, 0.074 mmol) in THF (0.45 mL) was added dropwise

over a period of 15 min to a 0.5 M solution of LiHMDS in

THF (195 mL, 0.097 mmol) at ꢀ78 ^ꢁC. The reaction mixture

was allowed to warm to ꢀ30 ^ꢁC, and then solid MoOPH⁴⁴

(48 mg, 0.112 mmol) was added all at once, while the head-

space in the reaction ﬂask was ﬂushed with argon. After

30 min, the reaction mixture was poured into hexane and

washed successively with 5% aq HCl solution, 5% aq

NaHCO₃and brine, then dried over MgSO₄. The residue ob-

tained after evaporation of the solvent was dissolved in a so-

lution of (COOH)₂(3 mg) in MeOH (0.75 mL). The mixture

was stirred at rt for 15 min, and then the resulting white sus-

pension was diluted with a 1:1 mixture of hexane–Et₂O, and

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1677

(Mea-C₄), 21.70 (Meb-C₄), 19.75 (C₆), 13.96 (Me-C₁₀); MS

(EI) m/z (%) 317 (M⁺+1, 3), 316 (M⁺, 15), 260 (48), 124

(35), 109 (36), 85 (46), 71 (64), 69 (61), 57 (100), 55 (68);

HRMS m/z calcd for C₂₀H₂₈O₃316.2038, found 316.2039.

H-12), 2.01 (1H, d, J¼12.3 Hz, H-1), 2.02–1.8 (2H, m,

H-13, H-15), 1.85 (1H, dd, J¼18.8, 2.7 Hz, H⁰-13), 1.79

(1H, dt, J¼18.1, 2.3 Hz, H⁰-15), 1.54 (1H, m, H-6), 1.39–

1.31 (2H, m, H⁰-6, H⁰-1), 1.21 (1H, dddd, J¼14.1, 11.2,

3.3, 3.3 Hz, H-11), 0.96–0.86 (2H, m, H⁰-11, H-5), 0.52

(1H, ddd, J¼13.4, 13.4, 5.1 Hz, H⁰-7), 1.09 (1H, dd,

J¼10.8, 6.4 Hz, H-9), 1.08 (3H, s, Mea-C₄), 0.61 (3H, s,

Meb-C₄), 0.47 (3H, s, Me-C₁₀); ¹³C NMR (75 MHz,

C₆D₆) d 213.25 (C₁₄), 209.43 (C₂), 147.65 (C₁₆), 106.74

(C₁₇), 82.62 (C₃), 53.42 (C₅), 51.69 (C₉), 50.62 (C₁), 47.61

(C₈), 45.36 (C₄), 44.29 (C₁₃), 43.88 (C₁₀), 42.44 (C₁₅),

38.55 (C₁₂), 31.28 (C₇), 27.27 (C₁₁), 29.31 (Mea-C₄),

19.19 (C₆), 16.51 (Meb-C₄), 13.88 (Me-C₁₀); HRMS m/z

calcd for C₂₀H₂₈O₃316.2038, found 316.2029.

4.6.2. 2-Hydroxy-atis-1,16-diene-3,14-dione (8). A solu-

tion of DMSO (58 mL, 0.76 mmol) in CH₂Cl₂(0.2 mL)

was added dropwise to a solution of oxalyl chloride

(37.5 mL, 0.40 mmol) in CH₂Cl₂(0.3 mL) at ꢀ60 ^ꢁC. After

stirring for 5 min, a solution of the hydroxyketone 33

(22 mg, 0.070 mmol) in CH₂Cl₂(0.25 mL) was added drop-

wise and the mixture was stirred at the same temperature for

15 min. Et₃N (277 mL, 1.96 mmol) was added, and the reac-

tion was slowly warmed to 0 ^ꢁC, at which it was stirred for

30 min. The reaction was quenched with water at 0 ^ꢁC and

worked up as usual. Concentration and ﬁltration through a

short plug of silica gel gave compound 8 (20.5 mg, 93%)

as a white solid. Mp 159–162 ^ꢁC (from hexane–Et₂O);

[a]²_D¹+17 (c 0.3, CHCl₃) {lit.¹⁴mp 161 ^ꢁC; [a]²_D⁵ꢀ20};

IR v_max/cm^ꢀ1(KBr) 3365m, 1714s, 1670s, 1654m, 1402m,

Further elution with the same eluent afforded the C-3 epi-

mericalcohol35(3.7 mg, 17%from 8) asanamorphoussolid.

4.7. Synthesis of atisene 5

1

1385m, 1055m, 914s; H NMR (300 MHz) d 6.09 (1H, s,

4.7.1. 18-Bromo-atis-16-ene-3,14-dione (37). A solution of

NBS (48 mg, 0.27 mmol) in MeOH (2.4 mL) was added

dropwise to a light-protected, stirred solution of compound

12 (55 mg, 0.18 mmol) in CH₂Cl₂(7.2 mL) at 0 ^ꢁC. After

50 min of stirring at this temperature, the reaction mixture

was poured into hexane and worked up. Evaporation of

the solvent afforded a mixture of the allyl bromides 36

that was dissolved in DMF (2.5 mL) and added to a solution

of CrCl₂[generated from CrCl₃(392 mg, 2.5 mmol) and

LiAlH₄(47 mg, 1.25 mmol) in THF (2.5 mL)] in DMF

(5 mL) and iso-PrOH (0.34 mL) at rt. The mixture was

stirred at the same temperature overnight and then worked

up in the same manner as described above for the preparation

of 3. Puriﬁcation by column chromatography (hexane–

AcOEt 8:2) afforded bromide 37 (50 mg, 91%) as a white

solid. Mp 159–161 ^ꢁC (from MeOH); IR v_max/cm^ꢀ1(KBr)

2941s, 2930s, 2872m, 1710s, 1450m, 1074w, 652w; ¹H

NMR (300 MHz) d 4.90 (1H, br s, H-17), 4.69 (1H, br s,

H⁰-17), 3.80 (1H, d, J¼10.0 Hz, H-18), 3.17 (1H, d,

J¼10.0 Hz, H⁰-18), 2.76 (1H, quint, J¼2.8 Hz, H-12),

2.54–2.26 (7H, m, H₂-15, H₂-13, H-7, H₂-2), 2.08 (1H, dd,

J¼12.7, 2.6 Hz, H-5), 1.95 (1H, m, H-11), 1.85–1.52 (3H,

m, H⁰-11, H-6, H-1), 1.41 (1H, ddd, J¼13.2, 13.2, 6.4 Hz,

H⁰-1), 1.31 (1H, J¼13.2, 4.9, 2.6, 2.6 Hz, H⁰-6), 1.04 (1H,

ddd, J¼13.4, 13.4, 4.9 Hz, H⁰-7), 1.65 (1H, dd, J¼12.8,

3.4 Hz, H-9), 1.09 (3H, s, Meb-C₄), 0.87 (3H, s, Me-C₁₀);

¹³C NMR (75 MHz) d 216.64 (C₁₄), 212.45 (C₃), 146.84

(C₁₆), 107.26 (C₁₇), 51.35 (C₄), 51.17 (C₉), 48.32 (C₅),

47.56 (C₈), 44.52 (C₁₃), 42.38 (C₁₅), 39.31 (C₁), 38.28

(C₁₂), 37.00 (C₁₀), 34.71 (Mea-C₄), 34.46 (C₂), 30.84

(C₇), 27.83 (C₁₁), 21.52 (Meb-C₄), 19.83 (C₆), 12.38 (Me-

C₁₀). MS (EI) m/z (%) 381 (M⁺+1 for ^8lBr, 3), 380 (M⁺for

⁸¹Br, 13), 379 (M⁺+1 for ⁷⁹Br, 4), 378 (M⁺for ⁷⁹Br, 11),

300 (20), 299 (100), 187 (19), 105 (20), 91 (22); HRMS

m/z calcd for C₂₀H₂₇⁸¹BrO₂380.1174, found 380.1180;

calcd for C₂₀H₂₇⁷⁹BrO₂378.1194, found 378.1200.

H-1), 6.02 (1H, br s, OH), 4.92 (1H, br s, H-17), 4.69

(1H, br s, H⁰-17), 2.78 (1H, quint, J¼3.0 Hz, H-12), 2.4–

2.21 (5H, m, H₂-15, H₂-13, H-7), 2.07 (1H, m, H-11), 1.90

(1H, dd, J¼10.7, 6.4 Hz, H-9), 1.80 (1H, ddd, J¼12.8, 7.4,

2.6 Hz, H⁰-11), 1.70–1.60 (2H, m, H-6, H-5), 1.55 (1H,

m, H⁰-6), 1.21 (3H, s, Me-C₁₀), 1.08 (3H, s, Mea-C₄),

0.98 (3H, s, Meb-C₄), 0.92 (1H, m, H⁰-7); ¹³C NMR

(75 MHz) d 216.35 (C₁₄), 200.67 (C₃), 146.50 (C₁₆),

144.16 (C₂), 124.89 (C₁), 107.57 (C₁₇), 53.19 (C₅), 48.82

(C₉), 47.98 (C₈), 44.51 (C₁₃), 43.84 (C₄), 42.57 (C₁₅),

39.08 (C₁₀), 38.07 (C₁₂), 31.01 (C₇), 28.04 (C₁₁), 26.89

(Mea-C₄), 21.89 (Meb-C₄), 19.13 (C₆), 17.17 (Me-C₁₀);

HRMS m/z calcd for C₂₀H₂₆O₃314.1882, found 314.1893.

4.6.3. 3(R)-3-Hydroxy-atis-16-ene-2,14-dione (9). Et₃N

(28 mL, 0.20 mmol) and TBDMSOTf (28 mL, 0.122 mmol)

were added to a solution of compound 8 (21.6 mg,

0.069 mmol) in CH₂Cl₂(0.6 mL) at 0 ^ꢁC. The reaction mix-

ture was allowed to warm slowly to rt and stirred for 30 min.

The mixture was diluted with hexane and washed sequen-

tially with 5% aq NaHCO₃solution and brine, then dried

over K₂CO₃, ﬁltered and concentrated under vacuum to

give crude enolsilyl ether 34 (29 mg). A solution of this com-

pound in THF (0.6 mL) was cooled to ꢀ78 ^ꢁC and then

LiAlH₄(16 mg, 0.42 mmol) was added all at once while

the headspace in the reaction ﬂask was ﬂushed with argon.

The grey suspension was stirred at ꢀ78 ^ꢁC for 1.5 h and

then carefully treated with a few drops of water to destroy

the excess of hydride and allowed to slowly warm to rt. A

few drops of 1 M aq HCl solution were added and the stirring

was continued for 15 min. The reaction mixture was poured

into water and worked up using hexane to extract it. The resi-

due left after evaporation of the solvent was puriﬁed by

chromatography (hexane–EtOAc 8:2) to give pure atisene

9 (15.3 mg, 70% from 8) as a white solid. Mp 164–165 ^ꢁC

(from MeOH); [a]_D²⁶+14 (c 1.0, CHCl₃) {lit.¹⁵mp 155 ^ꢁC;

[a]_Dꢀ15.7}; IR v_max/cm^ꢀ1(KBr) 3489m, 2971m, 2890m,

1711s, 1448w, 1375m, 1252w, 1094m, 986w; ¹H NMR

(400 MHz, C₆D₆) d 4.76 (1H, dd, J¼4.0, 2.4 Hz, H-17),

4.55 (1H, dd, J¼4.0, 2.0 Hz, H⁰-17), 3.62 (1H, dd, J¼5.2,

1.6 Hz, H-3), 3.60 (1H, d, J¼5.2 Hz, OH), 2.32 (1H, ddd,

J¼13.2, 3.7, 2.4 Hz, H-7), 2.17 (1H, quint, J¼2.9 Hz,

X-ray data for compound 37: colourless prism grown by

cooling a diethyl ether solution, 0.47ꢂ0.40ꢂ0.33 mm size,

orthorhombic, P2₁2₁2₁, a¼7.7732(16), b¼9.0255(18),

3

˚

c¼25.320(5) A,

V¼1776.4(6) A ,

Z¼4,

r_calcd

¼

1.418 g cm^ꢀ3, q_max¼24.97, Mo Ka, l¼0.71073 A, u-scan,

˚

diffractometer Nonius CAD4, T¼293(2) K, 3559 reﬂections

1678

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

2. Zhi-Da, M.; Mizuno, M.; Tanaka, T.; Iinuma, M.; Guang-Yi,

X.; Qing, H. Phytochemistry 1989, 28, 553–555.

collected of which 3111 were independent (R_int¼0.026),

direct primary solution and reﬁnement on F²(SHELXS-97

3. Shu, S.; Hai-Ming, S.; Liang, J.; Xue-Ting, L.; Zhi-Da, M.

Zhongguo Tianran Yaowu 2005, 3, 31–33.

4. Lal, A. R.; Cambie, R. C.; Rutledge, P. S.; Woodgate, P. D.;

Rickard, C. E. F.; Clark, G. R. Tetrahedron Lett. 1989, 30,

3205–3208.

5. Lal, A. R.; Cambie, R. C.; Rutledge, P. S.; Woodgate, P. D.

Phytochemistry 1990, 29, 1925–1935.

6. Prasad, R.; Aalbersberg, B. ACGC Chem. Res. Commun. 1994,

2, 7–10.

€

and SHELXL-97, G. M. Sheldrick, University of Gottingen,

1997), 210 reﬁned parameters, methyl group hydrogen

atoms reﬁned as rigid, others riding, the absolute structure

was established by anomalous dispersion effects (Flack

parameter 0.010(15), Flack, H. D. Acta Crystallogr. 1983,

A39, 876) and conﬁrmed by reference to an unchanging chi-

ral centre in the synthetic procedure, R₁[I>2s(I)]¼0.0503,

wR₂(all data)¼0.1009.

7. Jia, Z.; Ding, Y.; Wang, Q.; Liu, Y. Phytochemistry 1990, 29,

2343–2345.

8. Ding, Y.; Jia, Z.; Wang, Q.; Chen, J.; Liu, Y. Chin. J. Chem.

1991, 9, 131–135.

9. Ng, A. S. Phytochemistry 1990, 29, 662–664.

10. Mbwambo, Z. H.; Lee, S. K.; Mshiu, E. N.; Pezzuto, J. M.;

Kinghorn, A. D. J. Nat. Prod. 1996, 59, 1051–1055.

11. Shi, H.-M.; Williams, I. D.; Sung, H. H.-Y.; Zhu, H.-X.; Ip,

N. Y.; Min, Z.-D. Planta Med. 2005, 71, 349–354.

12. Zhi-Da, M.; Bing, W.; Qi-Tai, Z.; Mizuno, M.; Iinuma, M.;

Tanaka, T. Phytochemistry 1990, 29, 3952–3953.

13. Cambie, R. C.; Clark, G. R.; Lal, A. R.; Rickard, C. E. F.;

Rutledge, P. S.; Woodgate, P. D. Acta Crystallogr. 1990, C46,

2387–2389.

14. Appendino, G.; Belloro, E.; Tron, G. C.; Jakupovic, J.; Ballero,

M. Fitoterapia 2000, 71, 134–142.

15. Gustafson, K. R.; Munro, M. H. G.; Blunt, J. W.; Cardellina,

J. H., II; McMahon, J. B.; Gulakowski, R. J.; Cragg, G. M.;

Cox, P. A.; Brinen, L. S.; Clardy, J.; Boyd, M. R.

Tetrahedron 1991, 47, 4547–4554.

4.7.2. 18-Hydroxy-atis-16-ene-3,14-dione (5). A solution

of bromide 37 (26.4 mg, 0.070 mmol) in DMF (0.3 mL,

3.5 mmol) was added to a light-protected, stirred solution

of AgBF₄(70 mg, 0.35 mmol) in MeNO₂(3.2 mL). The

reaction mixture was stirred at 60 ^ꢁC for 15 h, and then

ﬁltered through a short pad of Celite, which was washed

with ethyl ether. The ﬁltrate was washed successively

with water and brine, and then dried over MgSO₄. The sol-

vent was removed and the resulting residue (which was

shown to be nearly pure formate ester 39 by ¹H NMR anal-

ysis) was dissolved in MeOH (1 mL) containing a 1% of

concd HCl. The mixture was stirred at rt for 5 h, then

diluted with a 1:1 mixture of hexane–Et₂O and washed

sequentially with 5% aq NaHCO₃solution, water and brine,

then dried over MgSO₄, and concentrated. Puriﬁcation by

chromatography (hexane–AcOEt 78:3) afforded atisene 5

(18.1 mg, 82%) as a white solid. Mp 150–152 ^ꢁC (from

hexane); [a]²_D³ꢀ10 (c 0.3, CHCl₃); IR v_max/cm^ꢀ1(KBr)

1

3520m, 2950s, 1711m, 1706m, 1410m, 1039s, 804w; H

NMR (400 MHz) d 4.90 (1H, br s, H-17), 4.69 (1H, br s,

H⁰-17), 3.69 (1H, d, J¼10.8 Hz, H-18), 3.35 (1H, d,

J¼10.8 Hz, H⁰-18⁰), 2.73 (1H, quint, J¼2.8 Hz, H-12),

2.61 (1H, ddd, J¼15.1, 13.0, 6.5 Hz, H-2), 2.40–2.15 (6H,

m, H₂-15, H₂-13, H-7, H⁰-2), 1.98–1.55 (6H, m, H₂-11,

H-9, H-6, H-5, H-1), 1.49–1.15 (2H, m, H⁰-1, H⁰-6), 0.98

(1H, ddd, J¼12.4, 12.4, 5.6 Hz, H⁰-7), 0.96 (3H, s, Meb-

C₄), 0.94 (3H, s, Me-C₁₀); ¹³C NMR (75 MHz) d 217.91

(C₃), 216.49 (C₁₄), 146.99 (C₁₆), 107.26 (C₁₇), 66.52

(C₁₈), 51.68 (C₉), 51.63 (C₄), 48.51 (C₅), 47.75 (C₈),

44.62 (C₁₃), 42.61 (C₁₅), 38.36 (C₁₂), 37.39 (C₁₀), 36.98

(C₁), 34.97 (C₂), 30.89 (C₇), 28.03 (C₁₁), 19.63 (C₆),

17.06 (Meb-C₄), 13.26 (Me-C₁₀). MS (EI) m/z (%) 316

(M⁺, 7), 286 (100), 274 (25), 244 (29), 187 (17), 105

(40), 91 (36); HRMS m/z calcd for C₂₀H₂₈O₃316.2038,

found 316.2048.

16. Perry, N. P.; Burgess, E. J.; Baek, S.-H.; Weavers, R. T. Org.

Lett. 2001, 3, 4243–4245.

17. For recent examples of relevant biologically active atisanes,

see: (a) Inden, M.; Kitamura, Y.; Kondo, J.; Hayashi, K.;

Yanagida, T.; Takata, K.; Tsuchiya, D.; Yanagisawa, D.;

Nishimura, K.; Taniguchi, T.; Shimohama, S.; Sugimoto, H.;

Akaike, A. J. Neurochem. 2005, 95, 950–961; (b) Ono, T.;

Akaike, A.; Kenji, K.; Sugimoto, H. (Eisai Ltd., Japan). Jpn.

Kokai Tokkyo Koho JP 2005289863, 20 October 2005. (c)

Osakada, F.; Kawato, Y.; Kume, T.; Katsuki, H.; Sugimoto,

H.; Akaike, A. J. Pharmacol. Exp. Ther. 2004, 311, 51–59;

(d) Akaike, A.; Sugimoto, H.; Nishizawa, Y.; Yonaga, M.;

Asakawa, N.; Asai, N.; Mano, N.; Terauchi, T.; Doko, T.

PCT Int. Appl. WO 2002088061, 7 November 2002.

18. For preparation of atisanes from other polycyclic terpenes, see:

(a) Terauchi, T.; Asai, N.; Yonaga, M.; Kume, T.; Akaike, A.;

Sugimoto, H. Tetrahedron Lett. 2002, 43, 3625–3628; (b)

Berettoni, M.; De Chiara, G.; Iacoangeli, T.; Lo Surdo, P.;

Marini, B. R.; Montagnini di Mirabello, L.; Nicolini, L.;

Scarpelli, R. Helv. Chim. Acta 1996, 79, 2035–2041; (c)

Garcia-Granados, A.; Duen˜as, J.; Guerrero, A.; Martinez, A.;

Parra, A. J. Nat. Prod. 1996, 59, 124–130; (d) Fraga, B. M.;

Guillermo, R.; Hanson, J. Phytochemistry 1992, 31, 503–

506; (e) Fraga, B. M.; Guillermo, R.; Hanson, J. R. J. Chem.

Res., Synop. 1990, 4, 99–101; (f) Campbell, H. M.; Gunn,

P. A.; McAlees, A. J.; McCrindle, R. Can. J. Chem. 1975, 53,

20–25; (g) Rodriguez, B.; Valverde, S. Chem. Ind. (London)

1974, 1010–1011; (h) Campbell, H. M.; Gunn, P. A.;

McAlees, A. J.; McCrindle, R. Can. J. Chem. 1973, 51,

4167–4174; (i) Baker, K. M.; Briggs, L. H.; Buchanan,

J. G. St. C.; Cambie, R. C.; Davis, B. R.; Hayward, R. C.;

Long, G. A. S.; Rutledge, P. S. J. Chem. Soc., Perkin Trans. 1

Acknowledgements

ꢀ

Financial support from the Direccion General de Ensen˜anza

ꢀ

Superior e Investigacion Cientıﬁca (Grant BQU2002-00272)

is gratefully acknowledged. We are grateful to the Conselle-

ꢀ

0

ꢀ

ria d Educacio i Ciencia de la Generalitat Valenciana and the

Ministerio de Educacion y Ciencia for providing research

ꢁ

ꢀ

fellowships to I.N. and I.A.M., respectively.

References and notes

1. Connolly, J. D.; Hill, R. A.; Dictionary of Terpenoids, 1st ed.;

Chapman and Hall: London, 1991; Vol. 2, pp 963–968.

A. Abad et al. / Tetrahedron 63 (2007) 1664–1679

1679

1972, 190–194; (j) Coates, R. M.; Bertram, E. F. J. Org. Chem.

1971, 36, 2625–2631; (k) Coates, R. M.; Bertram, E. F.

J. Chem. Soc., Chem. Commun. 1969, 797–798; (l) Appleton,

R. A.; Gunn, P. A.; McCrindle, R. A. J. Chem. Soc.,

Chem. Commun. 1968, 1131–1132; (m) Zalkow, L. H.;

Oehlschlager, A. C. J. Org. Chem. 1967, 32, 808–810; (n)

Hugel, G.; Lods, L.; Mellor, J. M.; Ourisson, G. Bull. Soc.

Chim. Fr. 1965, 10, 2894–2902.

Greenwich, CT, 1990; Vol. 2, pp 91–146; (c) Takao, K.;

Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807.

30. (a) Regitz, M. Synthesis 1972, 351–373; (b) Danheiser, R. L.;

Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990,

55, 1959–1964.

31. Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1990,

55, 3715–3717.

32. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R.

Tetrahedron Lett. 1974, 4319–4322.

33. Saito, S.; Yamazaki, S.; Shiozawa, M.; Yamamoto, H. Synlett

1999, 581–583.

34. Wehrli, F. W.; Marchand, A. P.; Wehrli, S. Interpretation of

Carbon-13 NMR Spectra; Wiley: New York, NY, 1988; p 54.

35. Omoto, M.; Kato, N.; Sogon, T.; Moei, A. Tetrahedron Lett.

2001, 42, 939–941.

36. The isomerisation of the C15–C16 double bond was ﬁrst

attempted photochemically without success, see: Kropp, P. J.;

Reardon, E. J.; Gaibel, Z. L. F.; Williard, K. F.; Hattaway,

J. H. J. Am. Chem. Soc. 1973, 95, 7058–7067.

37. Yajima, A.; Mori, K. Eur. J. Org. Chem. 2000, 4079–4091.

38. For related opening of silyl cyclopropyl ethers to give b-bromo

ketones, see: (a) Murai, S.; Seki, Y.; Sonoda, N. J. Chem. Soc.,

Chem. Commun. 1974, 1032–1033; (b) Gibson, D. H.; Charles,

H. D. Chem. Rev. 1974, 74, 605–623.

19. (a) Bell, R. A.; Ireland, R. E.; Partyka, R. A. J. Org. Chem.

1966, 31, 2530–2561; (b) Goldsmith, D. The Total Synthesis

of Tri- and Tetracyclic Diterpenes; ApSimon, J., Ed.; The

Total Synthesis of Natural Products; Wiley: New York, NY,

1992; Vol. 8, pp 115–118.

20. (a) Ihara, M.; Toyota, M.; Fukumoto, K.; Kametani, T.

Tetrahedron Lett. 1985, 26, 1537–1540; (b) Ihara, M.;

Toyota, M.; Fukumoto, K.; Kametani, T. Tetrahedron Lett.

1984, 25, 2167–2170; (c) Ihara, M.; Toyota, M.; Fukumoto,

K.; Kametani, T. Tetrahedron Lett. 1984, 25, 3235–3238.

21. Toyota, M.; Yokota, M.; Ihara, M. Tetrahedron Lett. 1999, 40,

1551–1554.

22. Ihara, M.; Toyota, M.; Fukumoto, K.; Kametani, T. J. Chem.

Soc., Perkin Trans. 1 1986, 2151–2161.

23. (a) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65,

4565–4570; (b) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara,

M. J. Am. Chem. Soc. 1998, 120, 4916–4925.

39. Hutchins, R. O.;Taffer, I.M. J. Org. Chem. 1983, 48, 1360–1362.

40. Alexander, J.; Renyer, M. L.; Veerapanane, H. Synth. Commun.

1995, 25, 3875–3881.

41. Chan, T. H.; Gingras, M. Tetrahedron Lett. 1989, 30, 279–282.

42. We have found that this procedure is very efﬁcient for the

preparation of different types of alcohols from halides under

24. (a) Toyota, M.; Yokota, M.; Ihara, M. J. Am. Chem. Soc. 2001,

123, 1856–1861; (b) Toyota, M.; Yokota, M.; Ihara, M. Org.

Lett. 1999, 1, 1627–1629.

25. Toyota, M.; Asano, T.; Ihara, M. Org. Lett. 2005, 7, 3929–3932.

ꢀ

26. Abad, A.; Agullo, C.; Cunat, A. C.; de Alfonso Marzal, I.;

Navarro, I.; Gris, A. Tetrahedron 2006, 62, 3266–3283.

˜

ꢀ

very mild conditions, see: Abad, A.; Agullo, C.; Cun˜at, A. C.;

ꢀ

27. Abad, A.; Agullo, C.; Cun˜at, A. C.; Navarro, I. Tetrahedron

Lett. 2001, 42, 8965–8968.

Navarro, I. Synthesis 2005, 3355–3361.

43. See, for example: (a) Takaishi, Y.; Miyagi, K.; Kawazoe, K.;

Nakano, K.; Li, K.; Duan, H. Phytochemistry 1997, 45, 975–

28. Corbel, B.; Medinger, L.; Haelters, J. P.; Sturtz, G. Synthesis

1985, 1048–1051.

29. (a) Craig, D. Chem. Soc. Rev. 1987, 16, 187–238; (b) Roush,

W. R. Advances in Cycloaddition; Curran, D. P., Ed.; JAI:

ꢀ

978; (b) Nun˜ez, M. J.; Reyes, C. P.; Jimenez, I. A.; Moujir,

L.; Bazzocchi, I. L. J. Nat. Prod. 2005, 68, 1018–1021.

44. Vedejs, E.; Larsen, S. Org. Synth. Coll. 1990, 7, 277–282.

Article Doi

Diastereoselective synthesis of antiquorin and related polyoxygenated atisene-type diterpenes

DOI: 10.1016/j.tet.2006.11.083

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