[dufour, castets,..] lu. longipalpis

8/11/2019 [Dufour, Castets,..] Lu. Longipalpis

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A diastereoselective synthesis of (1SR,3SR,7RS)-3-methyl-a-himachalene, the sex

pheromone of the sandy, Lutzomyia longipalpis (Diptera: Psychodidae)

Samuel Dufour, Pascalie Castets, John A. Pickett, Antony M. Hooper *

Biological Chemistry Department, Centre for Sustainable Pest and Disease Management, Rothamsted Research, Harpenden, Hertfordshire AL5 2JQ, UK

a r t i c l e i n f o

Article history:

Received 14 November 2011

Received in revised form 20 March 2012

Accepted 10 April 2012

Available online 19 April 2012

Keywords:

3-Methyl-a-himachalene

a-Himachalene

Lutzomyia longipalpis

Sex pheromone

Diastereoselective synthesis

a b s t r a c t

The sand

y,Lutzomyia longipalpis, vectors the causative agent of visceral leishmaniasis in the New World.The male-produced pheromone, (1S,3S,7R)-3-methyl-a-himachalene provides an opportunity for pest

managing this pest problem by inuencing the behaviour of the biting female. Previous syntheses of the

pheromone have all focused on a late stage DielseAlder cyclisation to generate the bicyclic cis-hi-

machalene skeleton. By adopting a new retrosynthetic analysis that depends on an early stage

DielseAlder cyclisation, the number of steps has been reduced to ten, of which ve are catalytic and so

provides access to quantities suitable for eld-scale experiments.

2012 Elsevier Ltd. All rights reserved.

1. Introduction

The sandy,Lutzomyia longipalpis(Diptera: Psychodidae) is the

vector of the protozoan parasite Leishmania chagasi (Kinetoplas-

tida: Trypanosomatidae), the causative agent of visceral leish-

maniasis in the New World.1 The parasite is transmitted by biting

females seeking a blood meal, to aid egg development, after

mating in leks formed by males, which attract females through the

release of a pheromone.2 Amongst the Brazilian population, the

sex pheromone structure is different among biochemical pheno-

types (chemotypes). The pheromone structures elucidated so far

include the Lapinha chemotype, (S)-9-methylgermacrene B,3 and

the Jacobina chemotype, (1S,3S,7R)-3-methyl-a-himachalene (1).4

A facile synthesis, suitable for scale-up, would allow production of

the sex pheromone for lures to attract the biting females and

therefore provides the potential to reduce infection rates inhumans. The structure of the Lapinha chemotype pheromone, (S)-

9-methylgermacrene B, has been veried through total synthesis

both racemically5 and enantiospecically.6 In this case, the large

number of transformations were unsuitable for large-scale syn-

thesis, however, we subsequently developed a route from ger-

macrone, isolated from the essential oil of the renewable resource,

Geranium macrrorhizum, that is suitable for scale-up.7 The struc-

ture of the Jacobina pheromone was also veried by total

synthesis both racemically8 and enantioselectively.9,10 Behav-

ioural and electrophysiological work demonstrated that of theeight isomers of 3-methyl-a-himachalene, only one was natural

and biologically active while the other isomers would not

interfere with the biological activity, as they themselves were not

active.11 These and other syntheses of 3-methyl-a-himachalene all

required a late-stage DielseAlder reaction to generate the hima-

chalene ring-system (Fig. 1),12 and the only enantioselective syn-

thesis ofa-himachalene also used an enantioselective late-stage

DielseAlder reaction.13 In the work reported here, we discon-

nected the himachalene skeleton to generate an early, monocyclic

DielseAlder intermediate (Fig. 1). Although this appears less ele-

gant initially, the stereoselectivity of the DielseAlder reaction was

expected to be higher than the tethered late-stage reaction, while

the predominantly catalytic reactions used for the rest of the

synthesis would make it shorter (ten steps) and more efcient forscale-up.

The disconnection approach shown (Fig. 1) reveals a synthetic

route with an early stage DielseAlder reaction to construct the six-

membered ring with the seven-membered ring generated later by

a RCM reaction. Ring junction diastereoselectivity is predicted to be

cis through a concerted DielseAlder mechanism. The 3-methyl

group would then be introduced either by a diastereoselective

methylation reaction (R]H) of the reduced norhimachalene ketone

or by methylation of the enol intermediate generated by 1,4 re-

duction of the unsaturated ketone. A third option is diaster-

eselective protonation after 1,4 reduction of the methylated

unsaturated ketone (R]Me).* Corresponding author. Tel.: 44 1582 763133; fax: 44 1582 762595; e-mail

addresses: [email protected], [email protected](A.M. Hooper).

Contents lists available atSciVerse ScienceDirect

Tetrahedron

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m/ l o c a t e / t e t

0040-4020/$ esee front matter 2012 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2012.04.037

Tetrahedron 68 (2012) 5102e5108
mailto:[email protected]:[email protected]://www.sciencedirect.com/science/journal/00404020http://www.elsevier.com/locate/tethttp://dx.doi.org/10.1016/j.tet.2012.04.037http://dx.doi.org/10.1016/j.tet.2012.04.037http://dx.doi.org/10.1016/j.tet.2012.04.037http://dx.doi.org/10.1016/j.tet.2012.04.037http://dx.doi.org/10.1016/j.tet.2012.04.037http://dx.doi.org/10.1016/j.tet.2012.04.037http://www.elsevier.com/locate/tethttp://www.sciencedirect.com/science/journal/00404020mailto:[email protected]:[email protected]


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2. Results and discussion

Following the disconnection approach proposed in Fig. 1, the

synthesis was undertaken as shown in Scheme 1. Synthesis of the

triene 3 was achieved from a commercially available mixture of

ethyl chrysanthemate ester isomers. LiAlH4reduction was followed

by catalytic TPAP oxidation, which could be completed using 2%

catalyst, to yield 2. Acid catalysed rearrangement with p-TsOH

generated an aldehyde with the artemesyl carbon skeleton,14 which

underwent Wittig chemistry to give triene 3 in 41% yield over 4

steps (Scheme 1).

The DielseAlder cyclisation could be catalysed by a range of

Lewis acids (20% SnCl4.5H2O, ZnCl2 or ZnBr2), which all gave only

one detectable regioisomer and high diastereoselectivity. The cat-

alyst of choice was ZnCl2(Scheme 1). This gave a endo:exoratio of

16:1, which demonstrated an improvement on the diaster-

eoselectivity compared to late-stage DielseAlder selectivity of

4.6:1.8 In the rst instance, intermediate 4-endowas transformed

into a-himachalene by reaction with vinylmagnesium bromide,

ring-closing metathesis (RCM) using Grubbs rst generation cat-

alyst, followed by TPAP oxidation of the alcohol to give enone 7ain

75% yield over 4 steps. RCM was performed at the allylic alcohol

H

H

OH

H

OHH

H

OH

H

R

O

OEt

1. Reduce2. TPAP3. p-TsOH4. Wittig

Early-stageDiels-Alder

1. Grignard2. RCM

TPAP

1. Reduce(methylate)2. Methylenate

(1SR,3SR,7RS)-1 R = H, Me

O Late-stageDiels-Alder reaction

O

Fig. 1. Retrosynthetic analysis for the disconnection of 3-methyl-a-himachalenevia an early stage DielseAlder reaction.

H

O

H

H

H

OH

H

H

O

4-endo 4-exo

H

H

H

H

H

H

O

OEt

O

iii)p-TsOH,

benzene,

iv) P(Ph)3CH2

v) Acrolein,Lewis acid cat., 20%

CH2Cl2 +

SnCl4.5H2O 95% endo:exo10:1ZnBr2 84% endo:exo10:1ZnCl2 95% endo:exo16:1

5a, R = H; 95%5b, R = Me; 95%

viii) TPAP, NMO

R

R R

7a, R = H; 98%7b, R = Me; 91%

i) LiAlH4ii) TPAP, NMO

vi)

OHvii) Grubbs' firstgeneration catalyst,

benzene

6a, R = H; 85%6b, R = Me; 76%

OH

2 394% 2 steps 43% 2 steps

MgBrR

Scheme 1. Synthesis of the norhimachalene and normethylhimachalene carbon skeletons.

S. Dufour et al. / Tetrahedron 68 (2012) 5102e5108 5103


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stage (5a) rather than after oxidation of the alcohol as the reaction

proceeded more smoothly. The synthesis ofa-himachalene could

be completed by reduction of the double bond with L-Selectride

and methylenation with Tebbe reagent,4 which occurred smoothly

with yields of 76% and 50%, respectively (Scheme 2). The overall

yield ofa-himachalene was 12% from ethyl chrysanthemate.

In order to adapt this synthesis to produce the desired phero-

mone with the extra stereogenic centre at the 3-methyl position,

we proposed that the cis-ring fusion would direct methylation of

the intermediate formed by L-Selectride onto the top face of 7a.This approach, however, was unsuccessful with the intermediate

resistant to methylation even at 0 C and when forced, the only

isolated product was the incorrect diastereoisomer (1SR,3RS,7RS)-

8b. As a result of this we attempted to alkylate a lithium enolate of

8a, analogous to the intermediate generated in the L-Selectride

approach. Again, the substrate was resistant to alkylation at low

temperatures and at 0 C the only isolable product was again the

incorrect diastereoisomer (1SR,3RS,7RS)-8b.

As late-stage methylation proved problematic and only gener-

ated methylation on the back face of the molecule, we synthesised

the unsaturated ketone 7b, in which the methyl group is already

present. Surprisingly, Grignard addition to 4-endo with iso-

propenylmagnesium bromide produced only one detectable di-

astereoisomer, which was acetylated and the product characterisedas (1SR,2SR,7RS)-10by 1D selective GOESY NMR spectroscopy. The

H-1 proton of10 could be relaxed by irradiating one of the 6-Me

groups and so is on the same face, while the other 6-Me group

relaxed the acetate moiety (Fig. 2) and so is on the opposite face.

As quenching the L-Selectride intermediate of7a produced back

face methylation we proposed by analogy back face protonation

would occur with 7b under the same conditions to yield the desired

isomer (1SR,3SR,7RS)-8b. After a normal quench the product was

a 3:1 mixture of8b isomers but again, the major product was the

incorrect isomer after protonation on the top face. The best results

were obtained by a reverse quench of the reaction after it was held

at

78

C for 4 h. Under such conditions only 1,4-reduction oc-curred and ketone reduction was prevented. This produced the two

diastereoisomers in a 1.4 (1SR,3RS,7RS)-8b:1 (1SR,3SR,7RS)-8bratio

(Scheme 3). Although unfavourable, previous diastereoselective

synthetic routes are even less favourable giving the ratio of 8b

isomers as 1.75:1 when generated through DielseAlder chemistry.8

The desired isomer (1SR,3SR,7RS)-8b was unstable in solution

and in time produced an insoluble white solid unlike its di-

astereoisomer (1SR,3RS,7RS)-8b. After the two diastereoisomers

were separated by ash column chromatography, methylenation

was attempted with Tebbe reagent as described by the literature

procedures and analogous to our synthesis of a-himachalene(above).8,9 However, in our hands we were only able to isolate

(1SR,3RS,7RS)-1, the product from methylenation of the undesired

isomer, while the desired product (1SR,3SR,7RS)-1 was obtained

only very slowly and in poor yield. Adding an excess of reagent,

warming the reagent and preparing fresh Tebbe reagent were all

unsuccessful. Freshly prepared Lombardos reagent was successful

on a small scale but could not be applied on larger synthetic scales.

Finally, TiCH2MgCl2$THF complex was freshly prepared and used to

methylenate (1SR,3SR,7RS)-8b to (1SR,3SR,7RS)-1, which could be

carried outon a gram scale. The stereochemistry of the product was

veried by 1D GOESY NMR spectroscopy. Irradiation of the H-1

proton relaxed H-7, verifying the cis ring junction, and the 6-Me

group on the same face. The other 6-Me group, when irradiated,

relaxed H-3 demonstrating H-3 to be on the opposite face to H-1and H-7 (Fig. 2). The structure and purity of the product was also

veried by comparison with literature data for the natural product

and by gas chromatographic analysis.

3. Conclusion

This synthesis produces the L. longipalpis pheromone

(1SR,3SR,7RS)-1 in 10 steps. It is amenable to large scale prepa-

rations due to its diastereoselectivity and use of catalysis to reduce

the number of steps, reagents and purications. The sequence

could be adapted to an enantioselective synthesis to double the

active component if the DielseAlder reaction could be performed

enantioselectively. We have previously shown that small amounts

of diasteroisomeric impurities do not interfere with biologicalactivity induced by the pheromone.11 Therefore, this work de-

scribes a route, by which quantities suitable for studying eld

monitoring or eld trapping of the disease vector can be obtained.

4. Experimental

4.1. General

Nuclear magnetic resonance was performed using a Bruker

Avance 500 MHz instrument and deuteriochloroform as solvent.

Mass spectra were recorded on a Mat95 XP magnetic sector mass

spectrometer (Thermo Finnigan). Ionisation was by electron impact

at 70eV in positive ion mode with a source temperature of 220 C.

Infra-red spectra were recorded on a Perkine

Elmer Spectrum 100FTIR spectrometer. Column chromatography was performed on

H

H

OH

H

ix) L-Selectride

7a 9

H

H

O

x) Tebbe reagent

8a

76% 69 %

Scheme 2. Synthesis of a-himachalene.

O H

H

H

O

10

H

H

H

(1SR,3SR,7RS)-1

Fig. 2. Key NOE correlations dening the relative stereochemistry of the acetate (10),

and pheromone (1SR,3SR,7RS)-1.

S. Dufour et al. / Tetrahedron 68 (2012) 5102e51085104


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silica gel (220e400 mesh, Fluka) and silica gel Merck 60 F254plates

were used for TLC. Solvents were dried by distillation over CaH2(benzene, dichloromethane) or sodium wire (tetrahydrofuran).

Chiral GC was performed using a b-cyclodextrin column

(30 m0.25 mm id25mm lm thickness) operated from 40 C to

180 C at 3 C/min and held at 180 C for a further 30 min.

4.1.1. Chrysanthemyl aldehyde (2). To a suspension of LiAlH4(3.87 g, 2.0 equiv, 0.10 mol) in THF (170 mL) under nitrogen at 0 C

was added dropwise a solution of ethyl chrysanthemate (mixture of

isomers, 10.0 g, 0.051 mol) in THF (50 mL). The reaction mixture

was stirred at room temperature overnight then quenched by

careful addition of water (4 mL), NaOH (15%, 4 mL) and water

(12 mL). The aluminium salts formed were removed by ltration

through Celite and the solution was dried over MgSO4. The solvent

was evaporated to give a quantitative yield of crude chrysanthemylalcohol (mixture of isomers, 7.85 g) as a clear, colourless oil, Rf0.47

(ethyl acetate/hexane 2:3);

IR (neat) nmax3324, 1448, 1376, 1019, 845 cm1; dH (500 MHz,

CDCl3) major isomer 4.87 (1H, d,J8.1, ]CH), 3.77 (1H, dd,J6.6, 11.4,

CHHOH), 3.55 (1H, dd,J8.5,11.4, CHHOH),1.70 (3H, s, CH3), 1.67 (3H,

s, CH3), 1.15 (3H, s, CH3), 1.11 (1H, dd, J5.3, 8.1, cyclopropaneeCH),

1.06 (3H, s, CH3), 0.83 (1H, ddd, J8.5, 6.6, 5.3, cyclopropaneeCH);

minor isomer 4.96 (1H, d, J 8.2, ]CH), 3.67 (1H, dd, J 7.6, 11.6,

CHHOH), 3.61 (1H, dd,J8.0,11.6, CHHOH), 1.73 (3H, s, CH3), 1.70 (3H,

s, CH3), 1.38 (1H, dd, J 8.2, cyclopropaneeCH), 1.12 (3H, s, CH3),

1.07e1.04 (1H, m, cyclopropaneeCH), 1.04 (3H, s, CH3); dC(125 MHz, CDCl3) major isomer 133.0, 123.5, 63.5, 35.1, 28.6, 25.6,

22.7, 21.3, 18.3,15.5; minor isomer 135.0, 119.1, 60.4, 31.0, 28.8, 26.2,

25.8, 22.3, 20.8,18.4; EIMS (rel intensity) m/z154 (M

, 8),123 (100),111 (10), 93 (18), 81 (59), 69 (14), 67 (14), 55 (18); EI-HRMS m/z

calcd for C10H18O [M] 154.1358, found 154.1359.

Without further purication, a solution of the alcohol (7.12 g,

46.2 mmol) in CH2Cl2(20 mL) was added dropwise to a mixture of

TPAP (324 mg, 0.92 mmol), NMO (10.90 g, 92 mmol) and 4 A mo-

lecular sieves in CH2Cl2 (150 mL). The mixture was stirred over-

night at room temperature and was then ltered through a pad of

silica. The solvent was removed. The crude residue was puried by

column chromatography on silica gel, eluting with petroleEtOAc

(95:5), to give the corresponding aldehyde 2 (6.58 g, 94%) as a clear,

colourless oil; Rf 0.67 (ethyl acetate/hexane 1:4); IR (neat) nmax1696,1450, 1378, 1111, 845 cm1; dH (500 MHz, CDCl3) major isomer

9.37 (1H, d,J5.5, CHO), 4.89 (1H, dm,J7.9, ]CH), 2.30 (1H, dd,J5.1,

7.9, cyclopropanee

CH), 1.69 (3H, s, CH3), 1.67 (3H, s, CH3), 1.59 (1H,dd, J 5.1, 5.5, CHCHO), 1.30 (3H, s, CH3), 1.14 (3H, s, CH3); minor

isomer 9.30 (1H, d,J6.7, CHO), 5.34 (1H, dm,J7.5, ]CH), 2.06 (1H, t,

J 7.5, cyclopropaneeCH), 1.71 (3H, s, CH3), 1.73e1.70 (1H, m,CHCHO), 1.66 (3H, s, CH3), 1.35 (3H, s, CH3), 1.18 (3H, s, CH3); dC(125 MHz, CDCl3) major isomer 200.9, 136.0, 120.2, 45.1, 34.6, 31.5,

25.6, 22.1, 21.6, 18.4; minor isomer 202.3, 137.2, 117.1, 40.9, 35.4,

29.6, 28.6, 25.6, 18.4, 15.9; EIMS (rel intensity)m/z152 (M, 3), 123

(100), 111 (16), 109 (16), 107 (31), 95 (26), 81 (55), 69 (22), 67 (26),

55 (26); EI-HRMS m/z calcd for C10H16O [M] 152.1201, found

152.1199.

4.1.2. (5E)-4,4,7-Trimethylocta-1,5,7-triene (3).14 To a solution of

aldehyde 2 (5.20 g, 34.2 mmol) in dry benzene (200 mL), under

nitrogen, was added dried 4 A molecular sieves (1.00 g) and a cat-

alytic amountof driedp-TsOH (60 mg, 0.32 mmol). The mixture was

heated at 70 C for 3 h. Once the reaction cooled, water (100 mL)

was added and the aqueous layer was extracted with Et2O(2100 mL). The combined organic layers were dried over MgSO 4and ltered before the solvents were removed under reduced

pressure to give the crude intermediate compound (4.99 g, 96%) as

a light brown oil;Rf0.65 (ethyl acetate/hexane 1:4); IR (neat) nmax1721, 1608, 1479, 1366, 970, 676 cm1; dH (500 MHz, CDCl3) 9.69

(1H, t, J3.1, CHO), 6.12 (1H, d, J16.1, trans-CH), 5.71 (1H, d, J16.1,

trans-CH), 4.94 (2H, s, ]CH2), 2.37 (2H, d, J3.1, CH2), 1.76 (3H, s,

CH3), 1.17 (6H, s, 2CH3); dc (125 MHz, CDCl3) 203.2, 141.5, 137.7,

129.9, 115.9, 55.2, 35.2, 27.8 (2C), 18.6; EIMS (rel intensity)m/z152

(M, 6),135(15),123 (73),109 (81), 96 (77), 95 (81), 81 (80), 67 (92),

55 (56); EI-HRMS m/z calcd for C10H16O [M] 152.1201, found

152.1197.

To a suspension of methyltriphenylphosphonium bromide

(23.4 g, 65.5 mmol) in THF (100 mL) was added dropwise n-butyllithium (2.5 M, 27.6 mL, 69.0 mmol) at 10 C. The mixture

was warmed toroomtemperature and after 30 min it was cooled to

10 C. A solution of the rearranged aldehyde (4.99 g, 32.8 mmol)

in THF (50 mL) was then added dropwise via canula and the mix-

ture stirred for 3 h at room temperature. Water (100 mL) was added

and the aqueous layer was extracted with Et2O (2100 mL). The

combined organic layers were dried over MgSO4, ltered and the

solvent removed under reduced pressure. The crude residue was

puried by column chromatography, eluting with petroleum ether,

to give3 (2.20 g, 45%) as a colourless oil;Rf0.71 (petroleum ether);

IR (neat) nmax 1682, 1640, 1609, 1467, 1437, 1383, 1363, 969, 912,

882 cm1; dH(500 MHz, CDCl3) 6.11 (1H, d, J16.1, trans-CH), 5.80

(1H, ddt, J 10.2, 17.2, 7.5, H-2), 5.69 (1H, d, J 16.1, trans-CH),

5.07e

5.02 (1H, m, H-1a), 5.05e

5.01 (1H, m, H-1b), 4.95 (1H, br s, H-8a), 4.94 (1H, br s, H-8b), 2.12 (2H, d, J7.5, H-3), 1.88 (3H, s, 7-Me),

H

HH

H

O

H

H

O

H

H

O

7b

H

H

ix) L-Selectride (1SR,3SR,7RS)-8b

(1SR,3RS,7RS)-8b

Tebbe reagent

Ti=CH2MgCl2.THF,

(1SR,3SR,7RS)-1

(1SR,3RS,7RS)-1

Ratio 1 (1SR,3SR,7RS)-8b: 1.4 (1SR,3RS,7RS)-8b

81%

51%

84%

Scheme 3. Completion of the synthesis of the sex pheromone ofLutzomyia longipalpis (1SR,3SR,7RS)-1 and its diastereoisomer.



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1.08 (6H, s, 2(4-Me)); dc(125 MHz, CDCl3) 142.2, 140.1, 135.5,128.8,

116.8, 114.6, 47.5, 35.9, 27.0 (2C), 18.7; EIMS (rel intensity) m/z150

(M, 7), 137 (11), 123 (28), 111 (100), 97 (29), 95 (34), 85 (44), 83

(52), 71 (58), 55 (72); EI-HRMS m/zcalcd for C11H18[M] 150.1409,

found 150.1401.

4.1.3. (1SR,2RS)-1-Carboxaldehyde-2-(10,10-dimethylbut-30-enyl)-4-

methylcyclohex-3-ene (4). To a solution of ZnCl2(0.2 equiv, 1.00 g,

7.34 mmol) in CH2Cl2 (250 mL) was added acrolein (4.0 equiv,

10.3 mL, 147 mmol), then triene 3(5.49 g, 36.6 mmol). The reaction

was stirred overnight, then preabsorbed onto silica. Purication by

quick ltration through silica gel, eluting with petroleEtOAc (95:5)

gave4 (7.17 g, 95%) as a clear, colourless oil. Analysis of the minor

product aldehyde signal d 9.57 (1H, d,J2.0, CHO) and integration by

NMR showed the ratio of isomers to be 94:6, a diastereomeric ex-

cess of 88%; Rf0.34 (diethyl ether/petroleum ether 1:19); IR (neat)

nmax1712, 1638, 1446, 1390, 1368, 912 cm1; dH(500 MHz, CDCl3)

9.90 (1H, d,J5.8, CHO), 5.78 (1H, ddt,J10.4,16.8, 7.5, H-30),5.50 (1H,

d,J1.2, H-3), 5.04e5.02 (1H, m, H-40a), 5.03e5,00 (1H, m, H-40b),

2.67 (1H, br qu,J3.9, H-1), 2.34e2.29 (1H, br m, H-2), 2.11e1.86 (6H,

m, H2-5, H2-6, H2-20), 1.73 (3H, s, 4-Me), 0.87 (3H, s, Me-10a), 0.84

(3H, s, Me-10b);dc(125 MHz, CDCl3) 208.3, 135.2, 134.9, 121.2, 117.6,

47.5, 46.9, 45.4, 36.0, 27.4, 27.0, 25.6, 25.0, 23.8; EIMS (rel intensity)m/z206 (M, 4), 191 (2), 177 (2),165 (13), 147 (8),137 (24), 124 (65),

109 (21), 95 (46), 93 (90), 83 (76), 67 (20), 55 (100); EI-HRMS m/z


4.1.4. (1SR,2RS,10SR)-1-(10-Hydroxyprop-20-enyl)-2-(100,100-dime-

thylbut-300-enyl)-4-methylcyclohex-3-ene (5a). To a solution of al-

dehyde4(1.30 g, 6.31 mmol) in THF (100 mL) at 78 C was added

dropwise vinylmagnesium bromide (9.40 mmol, 9.40 mL). The re-

action mixture was warmed to room temperature and stirred for

2 h. Water (70 mL) was added and the aqueous layer was extracted

with Et2O (250 mL). The combined organic layers were dried over

MgSO4 and ltered before the solvents were removed under re-

duced pressure. The crude residue was puried by column chro-

matography on silica gel, eluting with petroleum ethereEtOAc(9:1), to give compound5a (1.40 g, 95%) as a clear, colourless oil;Rf0.37 (diethyl ether/petroleum ether 1:9); IR (neat) nmax3565, 1638,

1449, 1370, 993, 912 cm1; dH(500 MHz, CDCl3) 5.92e5.81 (2H, m,

H-20, H-30), 5.59 (1H, br s, H-3), 5.34 (1H, dt, J17.2, 1.7. H-3a0), 5.16

(1H, dt,J10.7, 1.7, H-3b0), 5.07 (1H,d,J10.1, H-4a0), 5.06 (1H, d,J16.9,

H-4b0), 4.76 (1H, br s, H-10), 2.77 (1H, br s, OH), 2.35 (1H, br s, H-2),

2.29e2.27 (1H, m, H-5a), 2.18 (2H, d,J7.5, H-20), 2.10 (1H, ddd,J2.4,

6.6, 13.7, H-6a), 2.01 (1H, br s, H-1), 1.91 (1H, dd, J7.1, 17.9, H-5b),

1.71 (3H, s, 4-Me),1.60 (1H, m, H-6b),1.06 (3H, s, 20-Me), 1.05 (3H, s,

20-Me); dc(125 MHz, CDCl3) 139.5, 138.2, 135.3, 122.5, 117.4, 113.5,

74.1, 46.3, 45.6, 37.1, 35.6, 28.8, 25.5, 24.7, 24.5, 23.9; EIMS (rel in-

tensity)m/z234 (M, 1), 216 (3), 201 (3),177 (10),175 (10),133 (18),

119 (10),109 (32), 95 (100), 81 (23); EI-HRMSm/zcalcd for C16H26O

[M]

234.1984, found 234.1987.

4.1.5. (1SR,2SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undeca-3,8-dien-2-

ol (6a). To a solution of rst generation Grubbs rst generation

catalyst (28.0 mg, 0.03 mmol) in degassed benzene (80 mL) under

N2 was added a solution of alcohol 5a (160 mg, 0.68 mmol) in

benzene (10 mL) at room temperature. The reaction mixture was

stirred for 3 h until disappearance of the starting material was

observed by TLC analysis. The solution was passed through a pad of

silica under vacuum and was rinsed with petroleum ether: EtOAc

(85:15) to give compound 6a as a clear, colourless oil (120 mg, 85%);

Rf0.25 (diethyl ether/petroleum ether 1:4); IR (neat) nmax 3379,

1659,1447,1364, 907, 729 cm1;dH(500 MHz, CDCl3) 5.66 (1H, dt,J

11.3, 2.3, H-3), 5.54e5.49 (1H, m, H-4), 5.43 (1H,s, H-8), 4.40 (1H,br

d, J 10.1, H-2), 2.24 (1H, br s, H-7), 2.19e

2.16 (1H, m, H-11a),2.17e2.14 (1H, m, H-1), 2.10 (1H, dd, J5.7, 15.2, H-5a), 2.07e2.00

(1H, m, H-10a), 1.93 (1H, br s, OH), 1.87 (1H, dd, J5.9, 17.9, H-10b),

1.77 (1H, dd,J7.5, 15.2, H-5b), 1.70 (3H, s, 9-Me), 1.58e1.52 (1H, m,

H-11b), 0.99 (3H, s, 6-Me), 0.94 (3H, s, 6-Me); dc(125 MHz, CDCl3)

137.6, 135.4, 126.8, 121.4, 68.4, 49.5, 38.1, 36.8, 34.5, 29.1, 28.2, 27.0,

26.2, 23.8; EIMS (rel intensity)m/z206 (M, 25), 191 (24), 188 (60),

173 (43), 163 (21), 145 (100), 119 (52), 93 (64), 91 (73), 79 (58); EI-

HRMS m/zcalcd for C14H22O [M] 206.1671, found 206.1669.

4.1.6. (1SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undeca-3,8-dien-2-one

(7a). To solution of alcohol 6a (800 mg, 3.86 mmol) in CH2Cl2(100 mL) were added NMO (905 mg, 7.73 mmol), 4 A molecular

sieves (1.00 g) and TPAP (136 mg, 0.38 mmol). The mixture was

stirred for 2 h at room temperature and was then ltered through

a pad of silica eluting with petroleum ether/EtOAc (95:5). The

solvent was removed to give the corresponding ketone7a(780 mg,

98%) as a white, waxy solid; Rf0.33 (diethyl ether/petroleum ether

1:9); IR (neat) nmax1661, 164, 1447, 1366, 7484 cm1; dH(500 MHz,

CDCl3) 6.17 (1H, ddd,J3.8, 5.9, 12.7, H-4), 5.96 (1H, br d,J12.7, H-3),

5.45 (1H, s, H-8), 2.83 (1H, q, J4.3, H-1), 2.45 (1H, dt, J19.7, 3.8, H-

5a), 2.40e2.35 (1H, m, H-11a), 2.31 (1H, br s, H-7), 2.13(1H, dd,J5.9,

19.7, H-5b), 2.04e1.98 (1H, m, H-10a), 1.78 (1H, dd, J5.9, 18.1, H-

10b), 1.65 (1H, ddd, J3.9, 5.8, 12.6, H-11b), 1.64 (3H, s, 9-Me), 1.06

(3H, s, 6-Me), 1.05 (3H, s, 6-Me); dc(125 MHz, CDCl3) 206.1, 142.8,136.3, 132.4, 120.2, 47.2, 45.8, 42.1, 35.8, 29.9, 27.7, 27.1, 26.2, 23.9;

EIMS (rel intensity) m/z204 (M, 73), 189 (43), 161 (25), 148 (20),

133 (20),121 (52), 97 (100), 79 (47); EI-HRMSm/zcalcd for C14H20O

[M] 204.1514, found 204.1517.

4.1.7. (1SR,7RS)-6,6,9-Trimethylbicyclo[5.4.0]undec-8-en -2-one

(8a). To a solution of ketone 7a (300 mg, 1.47 mmol) in dry THF

(10 mL) at 78 C was added a 1 M solution of L-Selectride in THF

dropwise (1.3 equiv, 1.90 mL, 1.90 mmol). The solution was stirred

for 4 h at 78 C, water (20 mL) was added and the aqueous layer

was extracted with Et2O (220 mL). The combined organic layers

were dried over MgSO4 and ltered before the solvents were re-

moved under reduced pressure. The crude residue was puried by

column chromatography on silica gel, eluting with petroleumether/Et2O (95:5), to give8a(230 mg, 76%) as a clear, colourless oil;

Rf0.32 (diethyl ether/petroleum ether 1:9); IR (neat) nmax 1693,

1646, 1450, 1367, 753 cm1; dH(500 MHz, CDCl3) 5.55 (1H, s, H-8),

2.71 (1H, q,J4.1, H-1), 2.52 (1H, ddd,J2.8,11.3,13.8, H-3a), 2.35 (1H,

dd,J6.8, 11.3, H-3b), 2.20 (1H, br s, H-7), 2.11e2.07 (1H, m, H-10a),

1.88e1.80 (3H, m, H-10b, H2-11), 1.71 (1H, dd, J3.9, 13.5, H-5a), 1.71

(3H, s, 9-Me), 1.70e1.62 (1H, m, H-4a), 1.46 (1H, ddq,J1.6, 2.8, 12.9,

H-4b), 1.30 (1H, dt,J3.7, 13.5, H-5b), 1.06 (3H, s, 6-Me), 0.88 (3H, s,

6-Me); dc (125 MHz, CDCl3) 218.3, 134.4, 122.3, 48.0, 45.2, 44.6, 38.0,

36.5, 31.2, 28.9, 27.1, 25.2, 24.0, 21.7; EIMS (rel intensity) m/z206

(M, 100), 191 (21), 161 (21), 159 (24), 147 (42), 134 (37), 123 (50),

121 (42), 105 (41), 94 (71), 79 (60); EI-HRMSm/zcalcd for C14H22O

[M] 206.1671, found 206.1677.

4.1.8. a-Himachalene (9). To a solution of ketone 8a (160 mg,

0.78 mmol) in THF (5 mL) at78 C was added dropwise a solution

of Tebbe reagent in toluene(0.5 M, 3.10 ml,1.55 mmol). The solution

was stirred overnight, warming to room temperature, after which

15% aqueous NaOH (5 mL) was added very slowly. The crude resi-

due was puried by a ltration through a pad of silica gel, eluting

with petroleum ether/ether (9:1), to give 9(110 mg, 69%) as a clear,

colourless oil. Rf 0.85 (diethyl ether/petroleum ether 1:19); IR

(neat) nmax 1629, 1447, 1389, 1377, 1363, 884, 867 cm1

dH

(500 MHz, CDCl3) 5.54 (1H, s, H-8), 4.83 (1H, s, methyleneeH), 4.78

(1H, s, methyleneeH), 2.88 (1H, br s, H-1), 2.52 (1H, br dd, J4.2, 6.5,

12,1, H-3a), 2.19 (1H, br s, H-7), 2.10 (1H, t, J12.1, H-3b), 1.96e1.89

(2H, m, H-10a, H-11a), 1.84e1.80 (2H, m, H-10b, H-11b), 1.73 (3H, s,

9-Me), 1.74e

1.68 (1H, m, H-4a), 1.65 (1H, dd, J 4.1, 13.5, H-5a),1.42e1.32 (1H, m, H-4b),1.23e1.18 (1H, m, H-5b),1.06 (3H, s, 6-Me),



6/7

1.02 (3H, s, 6-Me); dc (125 MHz, CDCl3) 159.9, 133.9, 123.7, 111.2,

47.8, 39.9, 38.3, 36.6, 36.6, 34.8, 32.1, 28.3, 26.6, 25.1, 24.2; EIMS (rel

intensity)m/z204 (M, 65), 189 (60), 161 (49), 133 (47), 119 (80),

105 (66), 93 (100), 79 (55); EI-HRMS m/zcalcd for C15H24 [M]

204.1878, found 204.1869.

4.1.9. (1SR,2RS,10SR)-1-(10-Hydroxy-2 0-methylprop-20-enyl)-2-(100,100-

dimethylbut-300-enyl)-4-methylcyclohex-3-ene (5b). To a solution of

aldehyde 4 (3.50 g,17.0mmol) inTHF (300 mL) at30 C was added

isopropenylmagnesium bromide (1 M in THF, 25.5 mL 25.5 mmol)

dropwise. The reaction mixture was warmed to room temperature

and stirred for 4 h. The reaction was quenched with aqueous am-

monium chloride (70 mL) and the aqueous layer wasextracted with

Et2O (350 mL). The combined organic layers were dried over

MgSO4 ltered and the solvent removed under reduced pressure.

The crude residue was puried by column chromatography, eluting

with petroleum ether/EtOAc (9:1), to give 5b (3.70 g, 88%) as a clear,

colourless oil;Rf0.74 (diethyl ether/petroleum ether 1:4); IR (neat)

nmax3560, 1638, 1448, 1371, 994, 900 cm1; dH (500 MHz, CDCl3)

5.88 (1H, ddt,J10.3, 17.0, 7.4, H-300), 5.62 (1H, s, H-3), 5.22 (1H, s, H-

30a), 5.09e5.06 (1H, m, H-400a), 5.07e5.04 (1H, m, H-400b), 4.96 (1H,

s, H-30b), 4.60 (1H, s, H-1), 2.97 (1H, s, OH), 2.39 (1H, br s, H-2),

2.33e2.21(1H,m, H-5a), 2.21 (2H, d,J7.4, H-200), 2.15 (1H, br s, H-1),1.95 (1H, ddd, J2.9, 7.0, 13.7, H-5b), 1.89 (1H, dd, J 7.0, 18.3, H-6a),

1.73 (6H, s,2 0-Me, 4-Me),1.55 (1H, m, H-6b), 1.08 (3H, s,100-Me), 1.07

(3H, s, 100-Me);dc(125 MHz, CDCl3) 145.0, 138.5, 135.4, 122.6, 117.4,

109.7, 76.4, 45.9, 45.6, 35.6, 33.6, 28.7, 25.6, 24.4, 24.3, 24.0, 20.1;

EIMS (rel intensity) m/z248 (M,1), 230 (3), 215 (5),189 (8),177 (9),

147 (18),137 (21),121 (15),109 (45), 95 (100), 81 (28); EI-HRMS m/z


4.1.10. (1SR,2SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undeca-3,8-

dien-2-ol (6b). To a solution of Grubbs rst generation catalyst

(300 mg, 0.36 mmol) in degassed benzene (450 mL) under N2 at

50 C was added a solution of5b (3.70 g, 14.9 mmol) in benzene

(50 mL). The reaction mixture was stirred overnight. The solution

was ltered through a pad of silica under vacuum, eluting withpetroleum ether/EtOAc (95:5), to give the cyclised alkene 6b

(2.49 g, 76%) as a clear, colourless oil;Rf0.35 (diethyl ether/petro-

leum ether 1:4); IR (neat) nmax1668, 1446, 1385, 1377, 1362, 1036,

1011, 759 cm1; dH(500 MHz, CDCl3) 5.49e5.46 (2H, m, H-4, H-8),

4.41 (1H, dd,J5.8, 8.4, H-2), 2.19 (1H, br s, H-7), 2.10e2.03 (1H, m,

H-10a), 2.02e1.90 (5H, m, H-10b, H-11, H2-5, H-1), 1.81 (3H, s, 3-

Me), 1.72 (3H, s, 9-Me), 1.67 (1H, d, J5.8, OH), 1.65e1.61 (1H, m,

H-11b), 0.95 (3H, s, 6-Me), 0.91 (3H, s, 6-Me); dc(125 MHz, CDCl3)

140.9,135.3, 122.4, 122.3, 72.6, 47.3, 39.4, 38.1, 34.9, 29.9, 28.8, 27.8,

25.1, 23.8, 20.2; EIMS (rel intensity)m/z220 (M, 33), 218 (47), 203

(30), 177 (14), 161 (40), 135 (100), 125 (36), 119 (69), 107 (37), 93

(45), 79 (33); EI-HRMSm/zcalcd for C15H24O [M] 220.1827, found

220.1821.

4.1.11. (1SR,2SR,7RS)-2-Acetoxy-3,6,6,9-tetramethylbicyclo[5.4.0]un-

deca-3,8-diene (10). Alcohol6b (20 mg, 0.091 mmol) was added to

a solution of pyridine (0.5 mL) and acetyl chloride (0.25 ml) in Et 2O

(10 mL) and reuxed overnight. The reaction was diluted with Et2O

(30 mL), extracted with water (50 mL), washed with aqueous HCl

(1 M, 20 mL), and brine (20 mL) and the ethereal solution dried

(MgSO4), ltered and the solvent removed in vacuo to yield 10

(20 mg, 84%) as a clear, colourless oil; Rf 0.32 (diethyl ether/pe-

troleum ether 1:9); IR (neat) nmax 1736, 1669, 1436, 1370, 1237,

1029 cm1; dH (500 MHz, C6D6) 5.61 (1H,br d,J7.4,H-2), 5.57 (1H, s,

H-8), 5.52, (1H, t,J7.2, H-4), 2.27 (1H, br s, H-7), 2.22 (1H, br s, H-1),

2.10 (1H, dd, J7.2, 14.2, H-5a), 2.00e1.94 (1H, m, H-5b), 1.90 (3H,

obscured m, H2-10, H-11a), 1.89 (3H, s, MeCO2), 1.76 (3H, s, 3-Me),

1.73 (3H, s, 9-Me),1.52e

1.48 (1H, m, H-11b), 0.99 (3H, s, 6-Me), 0.96(3H, s, 6-Me); dc(125 MHz, CDCl3) 170.6, 137.5, 135.3, 124.1, 122.2,

75.4, 47.4, 37.9, 36.5, 35.0, 29.8, 28.5, 27.7, 24.8, 23.7, 20.8, 20.5;

EIMS (rel intensity) m/z262 (M, 1), 220 (61), 202 (72),187 (44), 159

(100), 146 (46), 125 (62), 107 (29), 94 (47), 79 (34); EI-HRMS m/z

calcd for C17H26O2[M] 262.1933, found 262.1932.

4.1.12. (1SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undeca-3, 8-dien-

2-one (7b). To a mixture of TPAP (200 mg, 0.57 mmol), NMO

(2.55 g, 21.8 mmol) and 4 A molecular sieves (1.50 g) in CH2Cl2(150 mL), was added dropwise a solution of alcohol 6b (2.40 g,

10.9 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 3 h at

room temperature and was then ltered through a pad of silica,

eluting with petroleum ether/EtOAc (95:5), to yield the corre-

sponding ketone 7b (1.99 g, 84%) as a clear, colourless oil; Rf0.42

(diethyl ether/petroleum ether 1:19); IR (neat) nmax 1665, 1654,

1448. 1366, 1084, 872, 798 cm1; dH(500 MHz, CDCl3) 6.20 (1H, t,J

5.2, H-4), 5.31 (1H, s, H-8), 2.90 (1H, dt, J6.6, 3.5, H-1), 2.40e2.35

(2H, m, H-7, H-10), 2.30e2.26 (2H, m, H-5). 2.13e2.09 (1H, m, H-11),

1.80 (3H, s, 9-Me), 1.79e1.76 (1H, m, H-10), 1.65 (3H, s, 3-Me),

1.64e1.56 (1H, m, H-11), 1.04 (3H, s, 6-Me), 0.75 (3H, s, 6-Me); dc(125 MHz, CDCl3) 206.8, 138.9, 138.2, 135.6, 119.6, 47.4, 47.1, 42.3,

36.7, 28.4, 27.5, 26.5, 25.7, 23.9, 19.9; EIMS (rel intensity) m/z218

(M, 100), 203 (30), 175 (22), 162 (15), 147 (22), 135 (17), 121 (60),

109 (41), 93 (24), 79 (24); EI-HRMS m/zcalcd for C15H22O [M]

218.1671, found 218.1663.

4.1.13. (1SR,3SR,7RS)-3,6,6,9-Tetramethylbicyclo[5.4.0]undec-8-en-2-

one (8b).8 To a solution of ketone 7b (100 mg, 0.46 mmol) in THF

(4 mL) at 78 C was added dropwise a solution of L-Selectride

(1.0 M in THF, 0.60 mL, 0.60 mmol). The solution was stirred while

warming to room temperature over 3 h and then cooled to 78 C.

The reaction was reverse quenched by transferring it cold through

a canula into water (20 mL) and the aqueous layer then extracted

with Et2O (220 mL). The combined organic layers were dried over

MgSO4 and ltered before the solvents were removed under re-

duced pressure. The crude residue was passed through a silica gel

plug, eluting with petrol-Et2O (95:5), to give the8b(93 mg, 92%) as

a 1 (1SR,3SR,7RS)-8b : 1.4 (1SR,3RS,7RS)-8b mixture of di-astereoisomers as analysed by 1H NMR spectroscopy and chiral GC.

Separation of the diastereoisomers was performed by ash column

chromatography using 2% diethyl ether in petroleum ether to yield

clear, colourless oils.

(1SR,3RS,7RS)-8b. Chiral GC; 44.88 min; Rf0.45 (diethyl ether/

petroleum ether 1:19); IR (neat) nmax1701, 1452, 1389, 1376, 1365,

755 cm1; dH(500 MHz, CDCl3) 5.47 (1H, br s, H-8), 2.90e2.84 (1H,

m, H-3), 2.68 (1H, br s, H-7), 2.42 (1H, ddd, J3.0, 6.2, 11.9, H-1), 2.18

(1H, ddd, J2.8, 6.2, 13.9, H-11a), 2.02 (1H, dd, J 5.9, 17.6, H-10a),

1.93e1.86 (1H, m, H-10b),1.70 (3H, s, 9-Me), 1.67 (1H, dq,J13.9, 4.8,

H-4a), 1.58e1.44 (3H, m, H-5, H-11b), 1.36e1.28 (1H, m, H-4b), 1.05

(3H, d, J 6.6, 3-Me), 1.00 (3H, s, 6-Me), 0.69 (3H, s, 6-Me); dC(125 MHz, CDCl3) 216.2, 135.3, 122.0, 51.4, 44.3, 43.8, 42.1, 37.9, 31.7,

31.0, 29.7, 24.0, 23.0, 20.2, 17.0; EIMS (rel intensity) m/z220 (M

,79), 205 (12), 163 (6), 151 (19), 123 (100), 107 (13), 94 (53), 79 (32),

69 (12), 56 (26); EI-HRMS m/zcalcd for C15H24O [M] 220.1827,

found 220.1827.

(1SR,3SR,7RS)-8b. Chiral GC; 42.01, 42.25 min; Rf0.42 (diethyl

ether/petroleum ether 1:19); IR (neat) nmax1702, 1451, 1389, 1375,

1365, 1187, 865 cm1; dH (500 MHz, CDCl3) 5.59 (1H, br s, H-8),

2.80e2.78 (1H, m, H-1), 2.70 (1H, d sextet, J2.5, 6.6, H-3), 2.19 (1H,

br s, H-7), 2.09 (1H, ddd,J1.7, 5.4, 10.0, H-11a), 1.90e1.86 (1H, m, H-

10a), 1.83 (1H, t,J10.0, H-11b), 1.81e1.77 (1H, m, H-5a), 1.74 (3H, s,

9-Me), 1.75e1.70 (1H, m, H-10b), 1.45 (1H, dq, J 14.5, 3.8, H-4a),

1.36e1.30 (1H, m, H-4b),1.27 (1H, dt,J14.5, 3.5, H-5b), 1.10 (3H, s, 6-

Me), 0.98 (3H, d, J 6.6, 3-Me), 0.87 (3H, s, 6-Me); dC (125 MHz,

CDCl3) 219.4, 134.4, 122.4, 48.1, 46.4, 45.3, 37.3, 36.1, 31.6, 30.9, 29.7,

27.0, 24.8, 24.0, 17.1; EIMS (rel intensity)m/z220 (M

, 80), 205 (18),177 (10), 163 (6), 151 (23), 123 (100), 107 (18), 94 (63), 79 (37), 55



7/7

(18); EI-HRMS m/z calcd for C15H24O [M] 220.1827, found

220.1823.

4.1.14. (1SR,3RS,7RS)-1. 3-Methyl-a-himachalene.8 To a solution of

ketone (1SR,3RS,7RS)-8b (80 mg, 0.36 mmol) in THF (2 mL) at

78 C was added dropwise a solution of Tebbe reagent (0.5 M in

toluene, 1.45 mL, 0.73 mmol). The solution was stirred overnight,

warming to room temperature, and quenched by adding 15%

aqueous NaOH (2 mL) very slowly. The crude residue was puried

by a ltration through a pad of Celite and then silica, eluting with

5% diethyl ether in petrol, to give (1SR,3RS,7RS)-1 (66 mg, 84%) as

a colourless oil.

Chiral GC; 39.74 min; Rf0.80 (petroleum ether); IR (neat) nmax1634, 1386, 1363, 885 cm1; dH(500 MHz, CDCl3) 5.52 (1H, br s, H-

8), 4.89 (1H, s, methyleneeH), 4.85 (1H, s, methyleneeH),

2.48e2.38 (1H, m, H-3), 2.39e2.35 (2H, m, H-1, H-7), 2.09e1.99 (3H,

m, H-10, H-11a), 1.84e1.78 (1H, m, H-4a), 1.73 (3H, s, 9-Me),

1.73e1.65 (1H, m, H-11b), 1.54 (1H, ddd, J3.4, 8.2, 13.9, H-5a), 1.36

(1H, ddd,J3.3, 9.7, 13.9, H-5b),1.28 (1H, dt,J3.3, 9.7, H-4b), 1.13 (3H,

d,J6.9, 3-Me), 0.97 (3H, s, 6-Me), 0.83 (3H, s, 6-Me); dc(125 MHz,

CDCl3) 158.9, 133.9, 123.6, 105.4, 44.1 (2C), 42.5, 38.0, 37.4, 34.1,

32.0, 30.3, 25.1, 24.0, 23.8, 21.8. EIMS (rel intensity) m/z218 (M,

19), 203 (30), 175 (19), 162 (18), 148 (26), 133, (17), 121 (48), 107(34), 94 (100), 79 (49); EI-HRMS m/z calcd for C16H26 [M]

218.2035, found 218.2028.

4.1.15. (1SR,3SR,7RS)-1. 3-Methyl-a-himachalene.8 Dry CH2Cl2(2 mL)

was added to Mg turnings (70 mg, 2.88 mmol) in a ame-dried ask.

TiCl4 (1M inC H2Cl2, 0.73 mL, 0.73 mmol)was added, followed by dry

THF (1 mL) dropwise. After 20 min, a solution of ketone

(1SR,3SR,7RS)-8b (80 mg, 0.36 mmol) in CH2Cl2 (1 mL) was added

dropwise and the solution stirred for 48 h. The reaction was

quenched by adding saturated aqueous K2CO3 (1 mL) slowly. The

crude residue was washed through a pad of Celite with diethyl ether

and then puried on ash silica, eluting with 5% diethyl ether in

petrol, to give (1SR,3SR,7RS)-1(40 mg, 51%) as a clear, colourless oil.

Chiral GC; 36.16, 36.45 min; Rf0.78 (petroleum ether); IR (neat)nmax 1627, 1447, 1389, 1377, 1363, 885, 864 cm

1; dH (500 MHz,

CDCl3) 5.54 (1H, br s, H-8), 4.84 (1H, s, methyleneeH), 4.79 (1H, s,

methyleneeH), 2.88e2.85 (1H, m, H-1), 2.30 (1H, dq, J10.6, 6.9, H-

3), 2.16 (1H, br s, H-7), 1.92e1.86 (1H, m, H-11a), 1.83e1.78 (2H, m,

H-10), 1.78e1.74 (1H, m, H-11b), 1.70 (3H, s, 9-Me),1.65 (1H, dt,J4.1,

13.2, H-5a), 1.52 (1H, dm, J13.6, H-4a), 1.25e1.18 (1H, m, H-4b),

1.17e1.11 (1H, m, H-5b), 1.04 (3H, d,J6.9, 3-Me), 1.02 (3H, s, 6-Me),

0.99 (3H, s, 6-Me); dc (125 MHz, CDCl3) 162.2, 134.1, 124.0, 107.1,

47.6, 41.5, 37.9, 36.8, 36.5, 36.4, 35.2, 32.0, 26.7, 25.1, 24.2, 21.6; EIMS

(rel intensity) m/z218 (M, 29), 203 (44), 175 (60), 161 (23), 147

(26),133 (31),121 (56),107 (51), 94 (100), 79 (40), 69 (32); EI-HRMS

m/zcalcd for C16H26[M] 218.2035, found 218.2037.

Acknowledgements

Rothamsted Research receives grant-aided support from the

Biotechnology and Biological Sciences Research Council of the UK

(BBSRC).

References and notes

1. http://www.who.int.topics/leishmaniasis/en/ Lainson, R.; Shaw, J. J. Nature1978, 273, 595e600.

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4. Hamilton, J. G. C.; Hooper, A. M.; Mori, K.; Pickett, J. A.; Sano, S.Chem. Commun.1999, 355e356.

5. Muto, S.-E.; Nishimura, Y.; Mori, K. Eur. J. Org. Chem.1999, 2159e2165.6. Kurosawa, S.; Mori, K.Eur. J. Org. Chem. 2000, 955e962.7. Hooper, A. M.; Farcet, J.-B.; Mullholland, N. P.; Pickett, J. A.Green. Chem.2006,8,

513e515.8. Sano, S.; Mori, K. Eur. J. Org. Chem.1999, 1679e1686.9. Mori, K.; Tashiro, T.; Sano, S.Tetrahedron Lett. 2000, 41, 5243e5247.

10. Tashiro, T.; Bando, M.; Mori, K.Synthesis 2000,13, 1852e1862.11. Spiegel, C. N.; Jeanbourquin, P.; Guerin, P. M.; Hooper, A. M.; Claude, S.; Ta-

bacchi, R.; Sano, S.; Mori, K. J. Insect Physiol. 2005, 51, 1366e1375.12. Wenkert, E.; Naemura, K.Synth. Commun.1973, 31, 45e48.13. Evans, D. A.; Ripin, D. H. B.; Johnson, J. S.; Shaughnessy, E. A.Angew. Chem., Int.

Ed.1997, 36, 2119e2121.14. Crombie, L.; Houghton, R. P.; Woods, D. K.Tetrahedron Lett. 1967,8, 4553e4557.

http://www.who.int.topics/leishmaniasis/en/http://www.who.int.topics/leishmaniasis/en/

[dufour, castets,..] lu. longipalpis

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