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Current Organic Chemistry, 2009, 13, 683-719 683

1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Synthesis of Pheromones: Highlights from 2005-2007

J. Bergmann1, J.A.F.P. Villar

2, M.F. Flores

1 and P.H.G. Zarbin

3,*

1Instituto de Química, Pontificia Universidad Católica de Valparaíso, Avenida Brasil 2950, Valparaíso, Chile

2Campus Centro-Oeste Dona Lindu, Universidade Federal de São João Del Rei, 35501-296, Divinópolis- MG, Brazil

3Departamento de Química, Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil

Abstract: The synthesis of insect pheromones published in the period 2005-2007 is reviewed. A total of 66 compounds

from different insect orders and belonging to different structural classes were included.

1. INTRODUCTION

Pheromones are naturally occurring chemicals which are produced and released by an organism in order to transmit information to another individual of the same specie. So far, the use of pheromones has been documented for many spe-cies belonging to different taxa, with the insects clearly standing out in terms of number of species studied. This is probably due to several factors, including the relatively sim-ple behavior of insects (facilitating the design of bioassays), their occurrence in great numbers (easy access to material), and their importance as pests in agriculture.

The study of insect pheromones is a fascinating research field. The prospect of unraveling the molecular basis of chemical communication as well as the possibility of devel-oping environmentally benign methods of pest control is driving many research activities. In this context, pheromones need to be synthesized for two reasons. First, to provide authentic reference material needed for unambiguous identi-fication of the natural compound by comparing their analyti-cal data. Second, to provide the material necessary for the evaluation of their effect on insect behavior in laboratory bioassays or under natural conditions in the field. In many cases, insect pheromones were found to occur as pure or as defined mixtures of stereoisomers, so synthetic routes have to be developed, which lead with high selectivity to the de-sired geometric and/or absolute configuration. The synthesis of insect pheromones has been reviewed in a number of arti-cles. Mori provided comprehensive overviews in 1981 and 1992 [1, 2] with a partial update in 2004 [3] and also pub-lished articles relating pheromone synthesis to specific topics [4-6]. The application of biocatalysis to pheromone synthesis

has also been reviewed recently [7].

The present article is a follow-up of our summary of pheromone syntheses published from 2002-2004 [8]. Here, we review the most recent advances in the synthesis of

pheromones published in the triennium 2005-2007.

*Address correspondence to this author at the Departamento de Química, Universidade Federal do Paraná, CP 19081, 81531-990, Curitiba-PR, Brazil; Fax: +55 41 3361 3186; E-mail: [email protected]

2. SYNTHESIS OF ALKANES AS PHEROMONES

2.1. meso-7,11-Dimethylheptadecane (1)

The branched alkanes meso-7,11-dimethylheptadecane

(1) and (S)-7-methylheptadecane constitute the female sex

pheromones of the spring hemlock looper Lambdina

athasaria and of the pitch pine looper L. pellucidaria [9, 10].

Nagano et al. [11] presented a stereoselective synthesis

of 1. Starting from ethyl bromomethacrylate (A), they pre-

pared diethyl 4-benzyloxy-2,6-dimethyleneheptanedioate

(B), which was used in a diastereoselective chelation-

controlled radical reaction with pentyl iodide in the key step

(Scheme 1). Use of 6 equivalents of the Lewis acid

MgBr2·OEt2 and low temperatures turned out to be crucial

for the high diastereoselectivity of the reaction.

2.2. 5,9-Dimethylpentadecane (2) and 5,9-dimethylhexa-

decane (3)

5,9-Dimethylpentadecane (2) and 5,9-dimethylhexa-

decane (3) are components of the sex pheromone of the cof-

fee leaf miner Leucoptera coffeella [12].

Racemic mixtures of both compounds were synthesized

starting from citronellol by Doan et al. [13], using a se-

quence of ultrasound-assisted tosylation and alkylation reac-

tions (Scheme 2). The overall yield was above 50 % over six

steps in both cases, and the use of ultrasound shortened con-

siderably the reaction times as compared to conventional

procedures.

3. SYNTHESIS OF ALKENES AS PHEROMONES

3.1. (Z,Z)-5,25-Hentriacontadiene (4) and (Z,Z)-5,27-

tritriacontadiene (5)

(Z,Z)-5,25-Hentriacontadiene (4) and (Z,Z)-5,27-tritria-

contadiene (5), have been identified as the major sex phero-

mone components from female cuticular extracts of Droso-

phila ananassae and D. pallidosa, respectively. The authors

indicate that the major sex pheromone compounds are key

factors in male recognition between D. ananassae and D.

pallidosa, and that morphological differences are less impor-

tant [14, 15].

684 Current Organic Chemistry, 2009, Vol. 13, No. 7 Bergmann et al.

Scheme 1.

Scheme 2.

Scheme 3.

Morita et al. [16] described a synthesis of these two

compounds employing Wittig olefination followed by a sul-

fone coupling (Scheme 3).

3.2. 9-Methylgermacrene-B (6)

The structure of the sex pheromone produced by the

males of the sandfly Lutzomyia longipalpis, from the Lap-

OHHO OH

OBn

CO2EtEtO2C

OBn

CO2EtEtO2C

OHEtO2C

BrEtO2C

1

5( )

5( )

1) MsCl, Py, CH2Cl2, 96%

2) LiAlH4, Et2O, 88%

4( )

4( )

.

n-C5H11I, n-Bu3SnH, Et3B,

6 equiv. MgBr2 OEt2,

CH2Cl2, -60 oC, 59%

1) DIBAL-H, CH2Cl2, 96%

2) H2, Pd/C, EtOH, 100%

1) A, Zn, aq NH4Cl, 54%

2) BnOC(=NH)CCl3, TfOH

cyclohexane/CH2Cl2 (2:1), 70%

1) H2C=O, H2O/EtOH (1:1), 79%

2) PCC, AcONa, CH2Cl2

B

A

O

TsOH

n = 4, (2)

n = 5, (3)

3( ) n

n( )n

( )

n = 4 or 5

n( )

2-hexylMgBr, Li2CuCl4,

THF, -78 oC, ultrasound

1) NaBH4, MeOH,

2) TsCl, Py, CHCl3,

ultrasound

1) perphthalic acid

2) HIO4, THF

R = n - C4H9

R = n - C5H11

RMgBr, Li2CuCl4,

THF, -78 oC, ultrasound

TsCl, Py, CHCl3,

ultrasound, 80 - 92%

O

( )

OH OTs

n = 4 or 5 n = 4 or 5

n = 18 (4)n = 20 (5)

BrOH

n = 8n = 10

PhO2S

n = 8n = 10

H

O

PhO2S

n = 8n = 10

OHBr

Br2, Ph3P, Py,

CH2Cl2, 96%103103

4n3

1) n-BuLi, A, THF/HMPA

(n = 8, 70%; n = 10, 88%)

2) SmI2, THF/HMPA

(n = 18, 74%; n = 20, 76%)

[CH3(CH2)5PPh3]+Br-, KHMDS,

THF/HMPA (n = 8, 92%; n = 10, 99%)

4n

1) PhSO2Me, n-BuLi,

THF/HMPA

(n = 8, 97%; n = 10, 88%)

2) DMSO, (COCl)2, Et3N,

CH2Cl2 (n = 8, quant; n = 10, 99%)

nn

A

( )

( ) ( ) ( )( )( )

( ) ( ) ( ) ( )

( )

Synthesis of Pheromones Current Organic Chemistry, 2009, Vol. 13, No. 7 685

inha Cave (Minas Gerais State) region of Brazil, has been

proposed as the novel homosesquiterpene 9-methylger-

macrene-B [17]. The structure and absolute configuration

was defined as (S) by comparing analytical data and biologi-

cal activity of the synthetic enantiomers with the natural

product [18].

Hooper et al. [19] described a synthesis of 6 starting from

germacrone, which is the main component of the essential oil

of the cranesbill Geranium macrorrhizum (Zdravets oil) and

was obtained in pure form by recrystallization. Subsequent

methylation and deoxygenation afforded the racemic phero-

mone over 4 steps (Scheme 4).

3.3. (3Z,6Z,9Z)-3,6,9-Nonadecatriene (7)

(3Z,6Z,9Z)-3,6,9-Nonadecatriene is the pheromone of a number of geometrid and noctuid moths, for example it has been identified in the autumn gum moth Mnesampela privata [20].

The use of butylated hydroxytoluene as an antioxidant to prevent loss of product was the key factor in the short syn-thesis presented by Davies et al. [21]. Methyl linoleate (ei-ther enriched from linseed oil or pure) was reduced to the alcohol, which was converted to the tosylate. Reaction with lithium dimethyl cuprate afforded 7 without C19 contami-

nants in 65 % (starting from enriched methyl linoleate) and 85 % (starting from pure methyl linoleate) yield, respectively (Scheme 5). All steps were carried out in the presence of 1 % the antioxidant, which was carried through the synthesis and

assured an improved yield as compared to previous methods.

4. SYNTHESIS OF EPOXY PHEROMONES

4.1. (3Z,6Z,9S,10R)-9,10-Epoxy-1,3,6-heneicosatriene (8)

and (3Z,6Z,9S,10R)-9,10-epoxy-3,6-heneicosadiene (9)

(3Z,6Z)-9,10-Epoxy-1,3,6-heneicosatriene (8) and (3Z, 6Z)-9,10-epoxy-3,6-heneicosadiene (9) were identified in the sex pheromone gland of the arctiid moth, Hyphantria cunea. Of the synthesized enantiomers, the (9S,10R) alkenes were biologically active, while the (9R,10S) forms were inactive

[22].

Diacrisia obliqua is a polyphagous insect attacking many crops, particularly oil seed crops in India and Bangladesh [23]. Persoons et al. showed that the pheromone of D. obli-qua is a five component blend consisting of 8, 9, (9Z,12Z)-octadecadienal, (9Z,12Z,15Z)-octadecatrienal and (3Z,6Z,

9Z)-heneicosatriene [24].

Che and Zhang [25] described an enantioselective syn-thesis of 8 utilizing a coupling reaction between a 1,4-diyne

and the chiral epoxy tosylate A (Scheme 6).

Scheme 4.

Scheme 5.

CS2Me

O

OH OAcO

O

6

Bu3SnH, BEt3, O2,

35% on 1g scale

over 2 steps

n-BuLi, CS2, MeI Li, HNEt2, -10 oC,

10% on 1g scale

Ac2O, DMAP,

Py, 93% (2 steps)

LDA, MeI, HMPA

-78 oC, 54%

recrystallisation

from EtOHGeranium macrorrhizum

essential oil

(Zdravets oil)

LiAlH4

OTs

OHO

OCH3

7

8( )

8( )

Me2CuLi,

THF, 0 oC

TsCl, Py,

CH2Cl2, 0 oC

LiAlH4, THF,

0 oC to rt.


Nakanishi and Mori [26] described a new and more prac-tical synthesis of 8 and 9 to furnish these compounds in a suitable quantity (Scheme 7). The synthesis of both phero-mones was performed employing the chiral epoxide A ob-tained in 84-87% e.e. from lipase-catalyzed asymmetric ace-tylation of the racemic epoxide in the key step. (2S,3R)-A was converted to the triflate and alkylated with diynes D (synthesis of 8) and E (synthesis of 9), respectively. The resulting epoxy diynes were further transformed to 8 and 9, respectively, including Lindlar semihydrogenation and a final alkylation step.

4.2. (7R,8S)-(+)-7,8-Epoxy-2-methyloctadecane (10) (dis-parlure)

Disparlure (2-methyl-7,8-epoxyoctadecane, 10) is the single sex attractant pheromone emitted by the female gypsy moth, Lymantria (Porthetria) dispar [27]. Iwaki et al. [28] established the configuration of natural 10 to be (7R,8S) by synthesis, and also observed that this isomer is attractive

while the enantiomer results in an inhibitory response.

Koumbis and Chronopoulos [29] described a short route to obtain both enantiomers of disparlure, starting from iso-propylidene D- and L-erythrose (both available in multigram quantities from D- and L-arabinose), respectively, which

were subjected to two Wittig olefinations. The saturated ace-tonide obtained after hydrogenation with Raney-Ni was

transformed to the epoxide via the diol (Scheme 8).

An enantiodivergent route to both enantiomers of dispar-lure was developed by Prasad and Anbarasan [30]. The com-mon precursor for both enantiomers was the homoallylic alcohol A, obtained in 5 steps from the bis-Weinreb amide of L-tartaric acid. The hydroxy group of A was either protected as tosylate (synthesis of (-)-10) or as tert-butyldimethylsilyl ether (synthesis of (+)-10). Building up of the carbon skele-ton by cross metathesis reactions and subsequent partial de-protection and cyclization furnished the enantiomers in a high overall yield (Scheme 9).

4.3. (6Z,9Z,11S,12S)-trans-11,12-Epoxy-6,9-heneicosa-diene (11) (posticlure)

Posticlure [(6Z,9Z,11S,12S)-trans-11,12-epoxy-6,9-heneicosadiene (11)] is the pheromone of the tussock moth Orgyia postica, a pest of mango and litchi trees in Japan [31]. A multigram synthesis of the trans-epoxide phero-mone, starting from diethyl L-tartrate was carried out by Fernandes [32], employing Wittig olefinations and the stereoselective conversion of an intermediate diol to the ep-oxide (Scheme 10).

Scheme 6.

OO

OH

OTHPHO

TsO

OTHP

O

HO

O

TsO

O

HOHOHO

10( )

10( )

10( )10

( )

8

1) H2, Pd-CaCO3, quinoline, CH3OH, rt.

2) (i) MsCl, Et3N, CH2Cl2, 0 oC to rt. , 1 h

(ii) LiBr, NaHCO3, THF, 8 h.

3) K2CO3, CH3OH, rt., 48 h.

1) PTSA, CH3OH, rt., 5 h

2) K2CO3, CH3OH, rt., 30 min

1) n-BuLi, -78 oC, 20 min

2) BF3 Et2O, -78 oC, 10 min

3) (2S,3S)-A, -78 oC, 3h

3) (i) TsCl, powered KOH, Et2O,

-5 oC to 0 oC, 3 h

(ii) flash chromatography employed

to separate diastereoisomer(2S,3S)-A

1) AcOH, PPh3, DIAD, THF, rt., 24 h

2) K2CO3, CH3OH, 0oC, 1 h. D-(-)-DCHT,

dicyclohexyl D-(-)-tartrate; TBHP, tert-butyl

hydroperoxide; DIAD, diisopropyl

azodicarboxylate.

1) m-CPBA, CH2Cl2, rt., 24 h

2) (i) TsCl, powdered KOH, Et2O,

-5 oC to 0 oC, 3 h

(ii) flash chromatography employed

to separate diastereoisomer

+

4Å MS, D-(-)-DCHT, Ti(O-i-Pr)4,

TBHP, CH2Cl2, -20 oC

10( )10

( )10( )

.


5. SYNTHESIS OF NON-ISOPRENOIDAL PHERO-

MONE ALCOHOLS AND THEIR ESTERS

5.1. (2S,3S,7S)-3,7-Dimethylpentadecan-2-ol (12) and

(2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (13)

Since the pioneering work of Coppel, Jewett and co-workers [33, 34], it is known that the sex pheromones of

several species of pine sawflies are esters that share a com-mon alcohol moiety, namely 3,7-dimethylpentadecan-2-ol (12). Neodiprion lecontei and N. sertifer produce the acetate 13 as the major component of their pheromones, whereas Diprion similis uses the propionate [33]. Later studies re-vealed that the (2S,3S,7S) stereoisomers showed the highest activity for all Neodiprion species [35, 36].

Scheme 7.

OHO

O

Br

OTBSO

OH

OTBS

O

1) EtMgBr, Cu2Cl2

CCH2Br, THF, 55%CH

OTMSOH

O

OHO

OTBS

O

O

OHTBSO

EtMgBr, Cu2Cl2

CCH2Br, THF, 55%CH

O

OAcTBSO

O

OHTBSO

O

OHTBSOOHHO

8

9

1) TsCl, Py

2) (n-C10H21)2CuLi,

Et2O (65%, 2 steps)

1) t-BuOK, 18-crown-6,

hexane, 77%

2) TBAF, THF, 90%

1) H2, Lindlar Pd-CaCO3-Pb2+,

cyclohexane, cyclohexene, 83%

2) CBr4, PPh3, CH2Cl2, 96%

1) n-BuLi, Tf2O, THF/HMPA, -78 oC

2) n-BuLi, D, THF, -78 oC

3) K2CO3, MeOH

[3 steps, 73% (average 60%)]

2) TMSCl, Et3N, DMAP,

CH2Cl2, 93%

1) TsCl, Py

2) (n-C10H21)2CuLi,

Et2O (62%, 2 steps)

1) H2, Lindlar Pd-CaCO3-Pb2+,

cyclohexane, 77%

2) TBAF, THF, 96%

E

1) n-BuLi, Tf2O, THF/HMPA, -78 oC

2) n-BuLi, E, THF, -78 oC (67%, 2 steps)

(2S,3R)-A

(2S,3R)-B

49%, 84-87% e.e.

(2R,3S)-A

47%, 81% e.e.

1) K2CO3, MeOH, quant.

Lipase PS-C,

CH2=CHOAc, Et2O, 3 h

+

1) NaH, TBSCl, THF

2) m-CPBA, CH2Cl2, 81% (2 steps)

D

(2R,3S)-A

(2R,3S)-A


Bekish et al. [37] reported a stereoselective synthesis of alcohol 12 and acetate 13 based on the creation of methyl branches in the carbon chain using the transformation of carboxylic esters into 2-substituted allyl halides via sul-

fonates of tertiary cyclopropanols (Scheme 11).

5.2. 7-Methyloctyl 5-methylhexanoate (14), 7-methyloctyl

octanoate (15), 7-methyloctyl 7-methyloctanoate (16), and

7-methyloctyl (Z)-4-decenoate (17)

7-Methyloctyl 5-methylhexanoate (14), 7-methyloctyl

octanoate (15), 7-methyloctyl 7-methyloctanoate (16), 7-

Scheme 8.

Scheme 9.

O

OH

O O

O

O

HO

HO

O O

O O

OH

O O

O

(-)-10

(+)-10

Similarly

1) H2, Raney-Ni, MeOH, rt., 98%

2) 37% HCl, THF/H2O (2:1), rt., 98%2

1) (COCl)2, DMSO,

CH2Cl2 then Et3N, -55 oC to rt.

2) [(CH3)2CH(CH2)3Ph3P+]Br-,

n-BuLi, THF, 0 oC to rt., 91% (2 steps)

1) CH3C(OEt)3, PPTS, toluene, 110 oC

2) TMSCl, CH2Cl2, rt.

3) 1 N KOH in MeOH,

THF, 0 oC to rt., 90%

7

[CH3(CH2)8Ph3P]+Br-, n-BuLi,

THF, 0 oC to rt., 95%

( )

( )7( )

HO

O

O

( )( )

OBn

OTs

OTs

OTBDMS

OH

OTBDMS

OBn

OTBDMSOTBDMS

OBnOBn

OH

OH

OTs

OBn

OTs

OBn

OH

(-)-10

(+)-10

9( )

9( )

9( )99

9( )

9( )9( )9( )

TBAF, THF, rt.,

10 h, 89%

TsCl, DMAP, CH2Cl2

rt., 8 h, 90%

H2, Pd/C, MeOH,

rt., 3 h, 81%

4-methyl-1-pentene,

Grubbs 2nd gen. catalyst (5 mol%),

CH2Cl2, reflux 8 h

TBDMSOTf, Py,

CH2Cl2, 0 oC, 1 h, 98%

K2CO3, MeOH,

rt., 1 h, 89%

H2, Pd/C, MeOH,

rt., 3 h, 90%

4-methyl-1-pentene,

Grubbs 2nd gen. catalyst (5 mol%),CH2Cl2, reflux 6 h, 92%

TsCl, DMAP,

CH2Cl2, rt., 5 h, 87%

A

A


Scheme 10.

Scheme 11.

7( )

7( )

7( )

OCOCH3OH

OTHPO

N

OH

OOOO

Br

OTHP

OH

OTHPOTHP

CO2Et

1312

CH3COCl, Et3N, Et2O1) N2H4, KOH, triethylene

glycol, 180 - 210 oC

2) MeOH, PPTS, reflux

1) DHP, PPTS, CH2Cl2

2) (2R)-2-methyldecyllithium,

Et2O/THF, -78 oCcis/trans = 99:1

1) morpholine, 100 oC, 24 h

2) recrystallization

cis/trans = 10:1

NaBH4, NiCl2,

B(OH)3, H2O, 98%

1) Zn, CuCl, 1,2-dibromoethane,

ClCO2Et, reflux

2) MeOH, THF, HCl, reflux3) Et3N, reflux. (74%, 3 steps)

1) MsCl, Et3N, Et2O

2) MgBr2, Et2O/CHCl3, reflux

(57%, 4 steps)

1) DHP, PPTS, CH2Cl2, reflux

2) EtMgBr, Ti(O-i-Pr)4, Et2O/THF

A

O O

O

H

H

HO

HO

O

H

H

HO

HO

OBn

OHO

H

H

OBn

OH

O

O

CO2Et

CO2Et

O

O

O

O

OBnO

H

H

OHO

O

OBnO

O

HO

HO

CO2Et

CO2Et

(-)-11

4

( )

6( )

(-)-11

8( )8

( )

4( )4

( )

8( )

4( )

6( )

6( )

6( )6

( )

6( )

Pd(OH)2/C (20%),

H2 (80 psi),

MeOH/EtOAc, rt.,

12 h, 95%

4 N HCl, MeOH,

rt., 8 h, 92%

1) CH3C(OCH3)3, PTSA, CH2Cl2,

rt., 20 min

2) CH3COBr, CH2Cl2, rt., 1.5 h

3) K2CO3, MeOH, rt., 2.5 h, 89%

1) (COCl)2, DMSO, -78 oC, "20 min, B", 45 min,

Et3N, -78 oC, 30 min, rt., 1 h

2) [(Z)-n-C5H11CH=CHCH2CH2PPh3]+I-, n-BuLi,

r.t., 30 min, -80 oC, aldehyde "from D", 1 h, rt.

overnight, 79%

1) PCC, NaHCO3, CH2Cl2, 0 oC, 4 h

2) [(Z)-n-C5H11CH=CHCH2CH2PPh3]+I-,

n-BuLi, rt., 30 min, -80 oC,

aldehyde "from C" , 1 h, rt., overnight, 77%

Pd(OH)2/C 20%, H2 (80 psi)

MeOH/EtOAc (1:5), rt.,

12 h, 94%

1) CH3C(OCH3)3, PTSA, CH2Cl2, rt., 30 min

2) CH3COBr, CH2Cl2, rt., 1.5 h

3) K2CO3, MeOH, rt., 2.5 h, 90% overall

4N HCl, MeOH

rt., 8 h, 93%

1) (COCl)2, DMSO, -78 oC, 30 min, rt., 1h

2) [n-C7H15CH2PPh3]+Br-, n-BuLi, rt., 30 min

-80 oC, aldehyde "from A", 2 h, rt.,

overnight, 80%

1) LiAlH4, THF, reflux, 4 h.

2) NaH, DMF, -15 oC, 30 min,

BnBr, 1 h, rt., 82%

(CH3)2C(OCH3)2, PTSA,

benzene, reflux, 8 h, quant.

B

B

D

C

A


Scheme 12. methyloctyl (Z)-4-decenoate (17) were identified by Tolasch

et al. as components of the sex pheromone produced by fe-

males of the click beetle Elater ferrugineus [38]. The same

authors described a simple synthesis to obtain all four com-

pounds. The alcohol moiety A common to all esters was ob-

tained in four steps from 1,5-pentanediol, involving mono-

protection, partial oxidation, Wittig olefination and hydro-

genation reactions. The acid moieties were either commer-

cially available or synthesized from the corresponding alco-

hols by Jones oxidation (Scheme 12).

5.3. (2S,10S)-2,10-Diacetoxyundecane (18)

(2S,10S)-2,10-Diacetoxyundecane (18) constitutes, to-

gether with (2S,9S)-2,9-diacetoxyundecane and (S)-2-

acetoxyundecane, the sex pheromone of the swede midge

Contarinia nasturtii [39].

A novel approach for a remote asymmetric induction to

obtain 1,9-anti diols was presented by Cahill et al. [40]. The

diastereoselective synthesis of the furanyl spiroacetal A al-

lowed the preparation of spiroacetal fluit fly pheromones B

and C, which were used in the synthesis of the diastereo-

merically pure mixture of (R,R) and (S,S) isomers of 1,9-anti

diol D by transacetalisation. Kinetic resolution of (±)-D us-

ing Candida antarctica lipase B afforded the (R,R)-diacetate

and the (S,S)-diol, which was converted to 18 with acetic

anhydride (Scheme 13).

5.4. (2S,7S)-2,7-Dibutyroxynonane (19)

The orange wheat blossom midge Sitodiplosis mosellana

is a worldwide pest of wheat crops. The sex pheromone has

been identified as (2S,7S)-2,7-dibutyroxynonane (19) [41],

and a mixture of isomers is effective in monitoring the pest.

The stereoselective synthesis of (2S,7S)-19 was achieved by Hooper et al. [42] using a diastereoselective ring closure metathesis reaction of the mixed silaketal A in the key step (Scheme 14). The other stereogenic center had been defined

by the use of (S)-5-hexen-2-ol during preparation of A.

5.5. (4E,7Z)-4,7-Tridecadienyl acetate (20)

(4E,7Z)-4,7-Tridecadienyl acetate (20) is a component of the pheromone of the potato moth Phthorimaea opercucella

[43].

Starting from acrolein, Vakhidov and Musina [44] ob-tained the allylic alcohol A by Grignard reation. The key step was a stereoselective Claisen rearrangement of A with triethylorthoacetate in the presence of propanoic acid. Oxida-tion of the resulting hydroxy ester and stereoselective Wittig reaction completed the carbon chain and was followed by reduction and acetylation to obtain 20 in high purity

(Scheme 15).

5.6. (4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol (21)

(4E,6Z,10Z)-4,6,10-Hexadecatrien-1-ol (21) is the one of five components of the pheromone bouquet of the cocoa pod

borer Conopomorpha cramerella [45].

Pereira and Cabezas [46] described a new method of preparation of 1,5-diynes, by reaction of 1,3-dilithiopropyne and propargylic chlorides. Two methodologies were used for the synthesis of endiyne C. In the first, the authors coupled the lithiated 1,5-dialkyne A with the vinylic iodide obtained from alkyne B by hydroboration and reaction with iodine. Alternatively, the vinylic bromide obtained from B by hidrozirconation and reaction with NBS, was coupled to A using Sonogashira’s palladium cross coupling reaction

(Scheme 16).

O

OOH

O

O

O

OHOH

O

O

O

O

O

HO

HOBnO

H

OBnOOHBnO

Jones

acetone

14

15

16

17

[(CH3)2CHCH2PPh3]+Br-

BuLi/THF

Jones, acetone,

(COCl)2/CH2Cl2, A/py

(COCl)2/CH2Cl2,

A/Py

Jones

acetone

(COCl)2/CH2Cl2, A/Py

Py /Et2O, H3C(CH2)6COClH2, Pd/C

(COCl)2/DMSO/Et3N

CH2Cl2

A

A


Scheme 13.

Scheme 14.

O O

Si

O

O

O

O

O O

Si

19

1) 10 equiv TBAF, 4 Å mol sieves, reflux 18 h, 78%

2) H2, PtO2, MeOH, 83%3) butyric anhydride, Py, 85%

Grubbs' catalyst, CH2Cl2

40 oC, 70 %

THF, Py, DMAP,

0 oC, cool to -78 oC,

(S)-5-hexen-2-ol, warm to rt.,

1,4-pentadien-3-ol

A

TfO OTf

Si

S S

OTs

OHOH

OAcOAc

OMeO

O

O

OHO

O

O

O

O

O

OTMS

O

OAc OAc

OHOH

OHOHS S

OHOH

S SOHOH

OH

(R,R)-19

(S,S)-D

+

(S,S)-19

NaBH4, t-BuOH,

MeOH, reflux

MeI, K2CO3,

DMF, 70 oC

RuCl3, NaIO4,

H2O-MeCN-CH2Cl2

1) n-BuLi, THF, -78 oC to 0 oC

2) H2, Pd/C, EtOAc, rt.

3) TBAF, CH2Cl2, rt.

4) PTSA, H2O, CH2Cl2, rt.

+

Ac2O, DMAP,

CH2Cl2, rt., quant.

polyacrylamide-bound Novozym 435

10 equiv vinyl acetate, toluene,

rt., 18 h, 50%

(+/-)

Raney-Ni, EtOH,

reflux, 90%

NaBH4, DMSO,

80 oC, 87%

ethanedithiol, BF3 Et2O

CH2Cl2, rt., 71%

TsCl, Et3N, CH2Cl2,

0 oC, 89%

ethanedithiol, BF3 Et2O

CH2Cl2, rt., 94%

D

C (obtained from B in two steps)

C

B

A

O

O

O

O

HO

O

O

.

.


Scheme 15.

Scheme 16.

6. SYNTHESIS OF NON-ISOPRENOIDAL ALDE-

HYDES, KETONES, ACIDS, AND ESTERS AS

PHEROMONES

6.1. 4,8-Dimethyldecanal (22)

The aggregation pheromone of the stored foodstuffs pests Tribolium castaneum and T. confusum was isolated and iden-tified by Suzuki as 4,8-dimethyldecanal (22) [47, 48]. Mori and co-workers [49] developed the first total synthesis of all of the four possible isomers of 22, establishing the absolute configuration of the natural pheromone as (4R,8R)-22. Later, bioassays showed that a 8:2 mixture of the isomers (4R,8R)

and (4R,8S) was about 10 times more active than (4R,8R)

alone [50].

Zarbin et al. [51] described a synthesis of (4R,8R)- and (4S,8R)-22, coupling the Grignard reagent obtained from (R)-2-methyl-1-bromobutane A and the tosylate of (R)- and (S)-citronellol, respectively (Scheme 17), followed by ozo-nolysis of the double bond of the resulting alkene. The key intermediate A was obtained optically pure in five steps from

methyl (S)-3-hydroxy-2-methylpropionate [52, 53].

Another methodology was described by Kameda and Na-

gano [54]. Starting from (R)-2,3-O-isopropylideneglycer-

aldehyde, they obtained 22 in 11 steps and 7% overall yield

MgBrTHPO

OAc

COOEt

H

COOEtO

COOEtHO

OH

THPO

O

20

81%

[hexyl-PPh3]+Br-,

t-BuOK, 64%

pyridinium chromate,

CHCl3 , 62%

1) triethylorthoacetate,

propionic acid, 138 oC

2) PTSA, rt., 56%A

H

Li

BrTBDMSO

Cl

Li

Li

Br

TBDMSOHO

21

1) Sia2BH, HOAc, 60%

2) Bu4NF, 99%

Sia2BH, I2,

NaOH/H2O2, 86%

Pd(PPh3)4, A,

Et2NH, CuI, 94%

Cp2Zr(H)Cl,

NBS, 79%

81%

n-BuLi, TMEDA

99%

C

B

n-BuLi

A

A

n-BuLi

TBDMSCl

H

H

H

H

TBDMSO

HO


(Scheme 18). The key step in the synthesis was the highly

diastereoselective chelation-controlled radical reaction of

ethyl (4S,5R)-4-benzyloxy-5,6-(isopropylidenedioxy)-2-me-

thylenehexanoate with ethyl (R)-5-iodo-3-methylpentanoate

performed in the presence of 7 equivalents of MgBr2 OEt2.

6.2. (E)-4-Oxo-2-hexenal (23), (E)-4-oxo-2-octenal (24), and (E)-4-oxo-2-decenal (25)

Defensive secretions of stink bugs (Heteroptera: Penta-tomidae) are characterized by the presence of (E)-4-oxo-2-alkenals with chain lenghts of 6, 8, and 10 carbon atoms [55, 56]. More recently, these compounds also have been identi-fied as pheromone components of nymphal [57] and adult

bugs [56, 58].

Moreira and Millar [59] described a simple one step syn-theses of (E)-4-oxo-2-hexenal (23) and (E)-4-oxo-2-octenal

(24) from commercially available 2-ethyl- and 2-butylfurans respectively, and a two step synthesis of (E)-4-oxo-2-decenal

(25) (Scheme 19).

6.3. 3,11-Dimethylnonacosan-2-one (26)

In 1974, Nishida et al. [60] isolated and identified 3,11-

dimethyl-2-nonacosanone (26) as the major component of

the female-produced contact sex pheromone of the German

cockroach, Blattella germanica.

Ahn et al. [61] described a simple synthesis of 26, start-

ing from 1,8-octanediol. The key steps are the alkylation of

the methyl ketone A (obtained from methylation of 8-

bromooctanoic acid) to yield bromoalcohol B, and coupling

of B with the anion of the commercially available ethyl 2-

methylacetoacetate. The final decarboxylation step yielded

26 (Scheme 20).

Scheme 17.

Scheme 18.

OTsOH

O

OMeHOTHPO

Br

O

TsCl, Py, 0 oC

CHCl3, 86%

*

(R)-citronellol; 97% e.e.

(S)-citronellol; 67% e.e.

[53]PPh3, Br2,

CH2Cl2, 75%

(R)-A, Mg, THF,

Li2CuCl4, 82%

*

O3, CH2Cl2,

DMS, 83%

*

(4R,8R)-22 (58% overall yield; 96% e.e.)

(4S,8R)-22 (66% e.e.)

(R)-A

O

H

O

O

OBn

O

O

CO2EtOBn

O

O CO2Et

CO2EtI

OBn

O

O CO2Et

OBn

O

O CO2Et

OBn

O

O CO2EtCO2EtBr

O

O H

O

.

1) H2, Pd/C, EtOH

2) PhOC(=S)Cl, Py, CH2Cl23) n-Bu3SnH, AIBN,

toluene, 85 oC

1) LiAlH4, Et2O

2) TsCl, Py, CH2Cl23) LiAlH4, Et2O

n-Bu3SnH, Et3B,

MgBr2 OEt2, CH2Cl2

Recrystallisation,

26% from A

2.8:1

+

1) Zn, THF, aq NH4Cl

2) BnBr, Ag2O, toluene

1) HCl, THF/H2O (1:1);

2) NaIO4, aq. CH3CN.

+

A

(4R,8R)-22


6.4. (Z)-6-Heneicosen-11-one (27)

(Z)-6-Heneicosen-11-one (27) was first reported in 1975 as the pheromone of the Douglas-fir tussock moth Orgyia pseudotsugata [62]. It has also been found that a 60:40 (E/Z) mixture of 27 was considerably more active than pure (Z)-27

[63].

Shin et al. [64] developed a selective method for the transformation of 6,8-dioxabicyclo[3.2.1]octanes to , -enones by Lewis acid-induced C–O bond cleavage. The use of AcCl–NaI was crucial for the selectivity of the reaction.

The method was applied to the synthesis of 27, employing 5-decyl-7-pentyl-6,8-dioxabicyclo[3.2.1]octane, which was prepared by the reaction of the dimer of acrolein with n-pentylmagnesium bromide, with subsequent alkylation and cyclization steps (Scheme 21).

6.5. (4S,6S,7S)-7-Hydroxy-4,6-dimethyl-3-nonanone (28) (serricornin)

Serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethyl-3-nona-none, (4S,6S,7S)-28] is the sex pheromone produced by fe-

males of the cigarette beetle, Lasioderma serricorne [65-69].

Scheme 19.

Scheme 20.

Scheme 21.

H

H

O

O

H

OO

4-oxo-(E)-2-octenal (24)

4-oxo-(E)-2-hexenal (25)

4-oxo-(E)-2-decenal (23)

2

Commercially

available

2

4

NBS, Py

THF/acetone/H2O, 48%

4

n-BuLi, THF,

1-iodohexane, 89,8%

( )

( )

( )

( )

O

O

O

O

O

O

O

OO

OH

O

H O

O

8( )

4( )

4( )

4( )

9( )

27 (E:Z 7:3)

(endo:exo 7:3)

AcCl, NaI, AcOH

1) t-BuLi

2) 1-iododecane

3) H+

n-C5H11MgBr

O

O

CO2Et

Br

HOLiOH

BrBr

O

HOOHHO

26

16

1) Et3SiH, BF3 Et2O/CH2Cl2,

0 oC, 2 h, 95%

2) ethyl-2-methyl acetoacetate,

K2CO3, KI/acetone, reflux, 20 h, 93%

716

616Et2O, 0 oC, 3h, 60%16

1) PBr3/Et2O, reflux, 2 h, 95%

2) Li/Et2O, rt., 30 min16

5

CH3Li, THF,

-78 oC to 0 oC, 1 h, 64%

15% NaOH, (n-Bu)4NOH

THF, rt., 2 h, 73%

5

1) HBr (48% aq)/benzene,

reflux, 18 h, 72%

2) Jones reagent, acetone,

0 oC to rt., 1 h, 80%

6

B

B

A

A

( ) ( ) ( )

O

( ) ( )( )

( )

( )

( )

( )

.


Ward et al. [70] described a synthesis of serricornin in 7 steps and 31% overall yield, employing an enantioselective direct aldol reaction with a chiral tetrazole catalyst derived from L-proline in the key step. The keto group of the aldol adduct was stereoselectively reduced using Li(sec-Bu)3BH, and the resulting diol A was monosilylated and submitted to Barton-McCombie deoxygenation followed by desulfuriza-tion and deprotection to afford 28, which was isolated and

characterized as the acetate 29 (Scheme 22).

6.6. 5-Hydroxy-4-methyl-3-heptanone (30) (sitophilure)

Sitophilure (5-hydroxy-4-methyl-3-heptanone, 30) was identified in 1984 by Phillips et al. [71, 72] as the male-produced aggregation pheromone of the rice weevil, Sitophi-lus oryzae and of the maize weevil, Sitophilus zeamais. The synthesis of the four possible stereoisomers of 30 followed by indoor bioassays, revealed the (4S,5R) isomer to be the

active form of the pheromone [73, 74].

Kalaitzakis et al. [75] described a chemoenzymatic syn-thesis of sitophilure in two steps and an overall yield of 81%, starting from commercially available 3,5-heptanedione (Scheme 23). The key step of this synthesis relies on the stereoselective reduction of the chemically synthesized pre-cursor of (+)-sitophilure, 4-methyl-3,5-heptanedione, by iso-lated NADPH-dependent ketoreductases (KRED) (Table 1).

The absolute stereochemistry of products 30 B and 30 D was

determined by the use of chiral derivatizing agents.

6.7. 1-Ethylpropyl 3-hydroxy-2-methylpentanoate (31) (sitophilate)

Sitophilate (1-ethylpropyl 2-methyl-3-hydroxypenta-noate, 31) was identified by Phillips et al. [76] as the male-produced aggregation pheromone of the granary weevil Sito-philus granarius. Bioassays employing all of the synthetic isomers revealed (2S,3R)-31 to be the natural pheromone

[77].

Kalaitzakis et al. [78] worked out a chemoenzymatic syn-thesis using a ketoreductase (KRED) for the selective reduc-tion of -ketoester A. Of over 100 enzymes tested, the KRED-A1B gave the best selectivity towards the desired (2S,3R) configuration. The diastereomeric purity of sitophi-late was improved either by chromatographic separation after transesterification (Scheme 24, pathway 1) or by use of an enzymatic hydrolysis of the resulting -hydroxyester B (pathway 2) and subsequent esterification with 3-bromo-

pentane.

Gil et al. [79] described a two-step synthesis of 31 em-ploying the condensation of the dianion of propanoic acid and propanal, and subsequent esterification with 3-pentanol

(Scheme 25). Different bases, reaction conditions and chiral

Scheme 22.

Scheme 23.

OOH OOAc

OSiEt3

S S

OOOHOH

S S

OO

OHO

S S

OO

H H

H

N

NN

NN

O

H

S

OOO

S

29

AcCl, DMAP,

CH2Cl2 (72% 2 Steps)

28

1) Raney-Ni, EtOH, reflux, 82%

2) HOAc, CH2Cl2

1) Et3SiOTf, 2,6-lutidine,

CH2Cl2, 0 oC, 97%

2) NaH, CS2, MeI, 93%

3) Bu3SnH, AIBN, PhMe,

110 oC, 91-97%

75% (> 98% e.e.)

LisBu3BH, THF,

-78 oC, 83%

wet

DMSO

+

OH

OHOH

OHO

(4S,5R)-30 B

(4S,5S)-30 D

K2CO3, MeI

Acetone, 95%

30 C

30 A

O O O

OO

Table 1O O


Table 1.

Diastereomeric Ratio % (30) Substrate KRED

A B C D

Conversion

(time) U/mg Product

101 3 - 6 91 100% (6h) 0.042

114 8 4 - 88 90% (24h) 0.042

115 4 - 4 92 100% (6h) 0.016

118 4 - - 96 93% (24h) 0.069

119 <1 - - >99 100% (12h) 0.204

123 20 - - 80 100% (6h) 0.032

128 3 - 1 96 100% (3h) 0.180

130 6 - - 94 100% (16h) 0.046

A1A <2 - - >98 20% (24h) 0.058

A1B - 97 3 - 100% (40min) 0.184

A1C - 98 2 - 100% (1h) 0.168

O O

A1D - 97 3 - 100% (1h) 0.131

OH O

Scheme 24.

Scheme 25.

OH

OHOH O

O

OH O

O

OH

O

O

O

O

O

KOH, 3-bromopentane, DMF

50 oC, 80%, 99% d.e., >99% e.e.

31

82% d.e., >99% e.e.

90% d.e., >99% e.e.

98% d.e., >99%e.e.

KRED-EXP-A1B,

NADPH, pH 8.0,

0 oC (12 h),

25 oC (12 h), 90%

1) NaOH, MeOH/H2O, (1:1)

2) 3-bromopentane, DMF, 50 oC,

chromatography, 65%

98% d.e. >99% e.e.

ICR-112, 25 oC, 83%

KRED-EXP-A1B,

NADPH, pH 6.9

25 oC, 95%

K2CO3, MeI,

acetone, reflux, 99%

pathway 2:

pathway 1:

A

A

B

A

O O

O

O

H+

OH

OH

O

OH

O

O OH

O

O

OH

OH

OO

HOLi

OLi

OH

O

31

+

+Base

OH


Scheme 26.

Scheme 27. amines as bases were tested, but only a modest diastereose-lectivity and a modest degree of asymmetric induction was obtained.

6.8. 4-Methyloctanoic acid (32)

4-Methyloctanoic acid (32) and its ethyl ester (33) are aggregation pheromones of Oryctes rhinoceros beetles, pests of coconut and date palm crops in Southeast Asia and North

Africa [80-82].

A five-step synthesis with high overall yield was devel-oped by Ragoussis et al. [83]. The key step is a Claisen or-thoester rearrangement of the intermediate formed by reac-tion of 2-methylene-1-hexanol and triethylorthoacetate, re-sulting in chain elongation and completion of the carbon

skeleton (Scheme 26).

7. SYNTHESIS OF LACTONES AS PHEROMONES

7.1. (5R,6S)-6-Acetoxyhexadecan-5-olide (34)

The major component of the oviposition attractant pheromone of the mosquito Culex pipiens fatigans was iden-tified by Laurence and Pickett [84] in 1982 as erythro-6-acetoxy-5-hexadecanolide (34). The absolute configuration was established as (-)-(5R,6S) by comparative chromatogra-phy of the 6-trifluoroacetoxy derivatives of the natural pheromone and of the synthetic (–)-(5R,6S) and (+)-(5S,6R)

enantiomers [85].

Sun et al. [86] described a synthesis of (5R,6S)-34 em-ploying a L-proline-catalyzed asymmetric aldol reaction in the key step, giving diastereomeric intermediates A and B in a 85:15 ratio. A was obtained in 96% e.e., but it was not stated if or how the diastereomers were separated. Transfor-mation of A by Baeyer-Villiger oxidation followed by acety-

lation (or the inverse sequence) yielded 34 (Scheme 27).

In a similar approach, Ikishima et al. [87] obtained the

aldol adducts B and C (75:25) by L-proline-catalyzed aldol

condensation between 1,3-dithiane A and cyclopentanone.

Adduct B was obtained in 83% e.e. and separated from C by

chromatography. Desulfurization of B followed by Baeyer-

Villiger oxidation and acetylation yielded 34 (Scheme 28).

Dhotare et al. [88] reported the synthesis of (5R,6S)-34

by a stereoselective addition of n-decyllithium to (R)-2,3-

cyclohexylideneglyceraldehyde A in the key step. The ad-

duct was straightforwardly converted to 34 in 8 steps (Scheme 29).

The stereoselective synthesis developed by Prasad and

Anbarasan [89] started from the bis-Weinreb amide of L-

tartaric acid which was converted to the benzyloxy aldehyde

A. Allylation of A and acetalisation of the resulting homoal-

lylic alcohol with acrolein diethyl acetal afforded key inter-

mediate B, which was subjected to a ring closure metathesis

reaction. Mitsunobu inversion and a final lactol oxidation are

further key steps in this synthesis (Scheme 30).

COOHCOOEt

COOEtOH

HH

3233

KOH/EtOH/H2O

reflux 2.5 h, 95%

H2, 10% Pd/C,

EtOH, 3 h, 92%

CH3C(OC2H5)3, propanoic acid,

138 oC, 5 h, 76%

NaBH4, 5% NaHCO3

MeOH, 5 oC, 1 h, 90%

(CH3)2NH HCl, 37% formaldehyde,

70 oC, 24 h, 88%

O O

OO

OAc

OO

OH

OAc O

OHOH

H

(-)-(5R,6S)-34

9

m-CPBA, CH2Cl2,

NaHCO3, rt., 82-85%

Ac2O, Py, DMAP,

rt., 100%9

m-CPBA, CH2Cl2,

NaHCO3, rt., 82-85%

Ac2O, Py, DMAP,

rt., 100%

9

85:15. 96% e.e. syn

+ 99

L-proline (30 mol %),

CHCl3, 24 h, 80%+

A

A

BA

O O O O

( ) ( )

( )

( )

( )


7.2. (4R,9Z)-Octadec-9-en-4-olide (35)

In 2001 Cossé et al. [90] isolated and identified (Z)-

octadec-9-en-4-olide (35) as a female-specific and antennally

active compound from the female currant stem girdler, Janus

integer, a pest of red currant in North America. The absolute

configuration has been established as (R) by synthesis [91]

and bioassays [92].

Mori [93] described a synthesis of 35 in a gram quantities

using a Sharpless asymmetric dihydroxylation obtaining the

chiral diol A, which was converted to epoxide B presenting

87% e.e. Jacobsen hydrolytic kinetic resolution improved the

optical purity to 96% e.e. Meyer’s oxazoline alkylation

method [94, 95] was adopted to convert (R)-B to (R)-

octadec-9-yn-4-olide, which was partially hydrogenated to

yield 35 (Scheme 31).

A stereoselective synthesis of 35 was presented by Sabitha et al. [96]. Base-induced ring opening of the chiral epoxy chloride A and subsequent treatment with butyl bro-mide, gave the acetylenic diol B, which was subjected to a zipper isomerization by treatment with 1,3-diaminopropane and sodium amide in the key step (Scheme 32). The resulting terminal alkyne was chain elongated and transformed to 35

in 4 further steps.

Another sequence, using similiar intermediates, was pre-sented by the same author [97] (Scheme 33). The chiral ep-oxy chloride A was prepared in several steps, including a Sharpless asymmetric epoxidation. The resulting alkynol B was methoxycarbonylated at the triple bond after protection of the hydroxyl group, while the other extreme was subjected to deprotection, oxidation, and stereoselective Wittig reac-tion resulting in chain-elongation; followed by the final de-

protection and cyclization steps.

Scheme 28.

Scheme 29.

HO O

OAcH

O O

OTBDPS

O

OTBDPS

HO

OTBDPS

OH

OH

OO

OH

OO

H

O

OO

34

99 1) TBAF, THF, rt., 69%

2) Ac2O, Py, 0 to -10 oC, 79%.

91) TsCl, Py, 0 oC

2) K2CO3, MeOH, rt.,

89% (2 steps)

9

1) TBDPSCl, imidazole, rt.

2) CF3CO2H, H2O,

0 oC, 91% (2 steps)

+99

A) n-decyllithium, hexane,

- 40 oC to rt., 75%

or B) n-decyllithium, Et2O,

- 40 to 0 oC, 78%

Method A: syn/anti 7:93

Method B: syn/anti 5:95

1) 3-butenyl-MgBr, CuBr,

- 40 oC to rt., 77%

2) O3, MeOH, NaOH,

-15 oC, 77%

A

( )

( ) ( )

( )

( ) ( )

O O

OAcOHO

OHO SSOHO SSSS

H

O

COOEt

O

COOEt

O

34

7

1) m-CPBA, NaHCO3,

CH2Cl2, rt., 9 h, 90%

2) Ac2O, DMAP, Py,

rt. 4 h, 100%

7

Raney Ni (W-4),

AcOEt, rt., 1 h, 62%

C (90% e.e.)B (83% e.e.)

+

7730 mol % L-proline

13 oC, 20 h, 85% B/C 75:257

1) HS(CH2)3SH, BF3 OEt2,

AcOH, rt. 3 h, 98%

2) DIBAL-H, CH2Cl2,

-78 oC, 30 min, 99%7

LDA (2 eq.) THF, -78 oC

C7H15Br, 0 oC, 1 h, 60%

A

B ( )( )

( ) ( )( )

( )

O


7.3. (S)-5-Hexadecanolide (36)

(S)-5-Hexadecanolide (36) was isolated from mandibular glands of the queens of the oriental hornet, Vespa orientalis [98] where it functions as a pheromone to stimulate the workers to construct queen cells.

Sabitha et al. [99, 100] described two similar approaches to the synthesis of this pheromone. In both syntheses the key step was the base-induced opening of a chiral epoxide by lithium amide in liquid ammonia at -78 °C, and subsequent

treatment with 1-bromononane to give the chiral alkynols A

and B, which finally were converted to 36 (Scheme 34).

7.4. (R)-4-Dodecanolide (37)

(R)-4-Dodecanolide (37) is a defensive secretion isolated from the pygidial glands of rove beetles, Bledius mandibu-

laris and Bledius spectabilis [101].

The synthesis of Sabitha et al. [99] started with the chiral propargylic alcohol A [102], which was methoxycarbony-

Scheme 30.

Scheme 31.

SnBu3

OBn

O

H

O

OAc

O

OAc

EtO O

OH

EtO O

OH

EtO OOBn

EtO O

OBn

EtO O

OEt

OEt

OBn

HO

9( )

9( )

9( )9

( )

9( )

9

( )9( )

9( )

34

1) DIAD, PNBA, PPh3, THF

0 oC, rt., 6 h

2) K2CO3, MeOH, rt., 2 h

86% (two steps)

1) 3M HCl-THF, rt., 3.5 h

2) PCC, NaOAc, Celite

CH2Cl2, rt., 2.5 h

72% for two steps

Ac2O, Et3N

DMAP, CH2Cl2rt., 2.5 h, 94%

H2, 10% Pd/C,

MeOH, 3 h, 99%

Grubbs 1st gen, cat. (5 mol%)

toluene, 60 oC, 8 h, 86%PPTS, benzene

reflux, 3 h, 62%

A B

O

O

O

O

OO

OMeO

O OAc

BrOH

OH

IOH

35

7

7

1) 2,4,4-trimethyl-2-oxazoline,

n-BuLi, THF, -78 oC to rt.

2) dil. HCl, THF, 60 oC,

30 min (58%, 2 steps)

H2, Lindlar Pd-CaCO3-Pb2+,

hexane, -5 to 0 oC, 94 %

(R)-B (87% e.e.)

7

(R)-B (96% e.e.)

Jacobsen's (R,R)-salen

cobalt catalyst, 0.4 equiv.

H2O, THF, 72%7

K2CO3, MeOH,

87% (3 steps)

AcBr,

CH2Cl2

7

MeC(OMe)3,

PPTS, CH2Cl2

* Used in the next step

7

recrystallization from hexane

[1x(84%) for (R)-A of 75% e.e;

2x(60%) for (R)-A of 87% e.e.*;

5x(20%) for (R)-A of 98% e.e.]

7

1) n-C8H17C CH, n-BuLi, THF, 71 %

2) AD-mix , t-BuOH, H2O, 0-5 oC, 6 h,

then rt. overnight

1) TsCl, Py

2) NaI, DMF, 92% (2 steps)

(R)-A( )

( ) ( )

( )

( )


lated after protection. Hydrogenation and deprotection gave

directly 37 (Scheme 35).

7.5. (4R,5Z)-5-Tetradecen-4-olide (38) (japonilure)

(R)-Japonilure [(4R,5Z)-5-tetradecen-4-olide, (38)] is the

female-produced pheromone of the Japanese beetle Popillia

japonica [103].

The synthesis of 38 presented by Sabitha et al. [97] in-

volved the preparation of the chiral epoxy chloride A (by

stereoselective reduction of a triple bond and asymmetric

Sharpless epoxidation), which was subjected to a base-

induced ring opening followed by treatment with 1-

bromooctane in a one-pot reaction to give alkynol B with the

carbon skeleton already established. B was further trans-

formed to 38 in five steps (Scheme 36).

Scheme 32.

Scheme 33.

OH

OMOM

O

OMOM

HO

C8H17

O O

OMOM

THPO

OH

THPO

O

ClTHPO

35

7( )

1) IBX, DMSO,CH2Cl2,

rt., 2 h, 80%

2) NaClO2, NaH2PO4 2H2O,

aq. DMSO, rt., 1 h, 74%7( )

1) PTSA, MeOH, 12 h, 80%

2) H2, Lindlar catalyst,

quinoline, EtOAc, 2 h, 90%

1) n-BuLi, n-C8H17Br

THF, -78 oC, 2 h, 70%

2) PPTS, MeOH, 12 h, rt., 72%

1) NaNH2, 1,3-diaminopropane

60 oC, 6 h, 60%

2) MOMCl, Hunigís base, CH2Cl2,

0oC to rt., 2 h, 85%

1) Li/Liq NH3, Fe(NO3)3, -78 oC, THF, 2 h

2) n-C4H9Br, THF, 4 h, 70%B

A

H

O

COOMe

OMOM

O

O

COOMe

OMOM

THPO

OH

THPO

O

ClTHPO

O

OHTHPO

OHTHPO

OHTHPO

OHBrTHPO

35

7( )

1) [C9H19PPh3]+Br-, THF-HMPA,

n-BuLi, -78 oC to rt., 75%

2) PTSA, MeOH, 12 h, 80%

1) Pd/C, H2, MeOH, 6 h, 70%

2) IBX, DMSO, CH2Cl2,rt., 2 h, 75%

1) MOMCl, Hunig's base,

0 oC to rt., 2 h, 90%

2) n-BuLi, methylchloroformate,

THF, -78 oC, 30 min, 73%

Li/liq. NH3, Fe(NO3)3,

THF, 6 h, 70%

PPh3, NaHCO3, CCl4,

reflux, 4 h, 80%

(-)-DET, Ti(O-i-Pr)4, cumenehydroperoxide,

MS 4 Å, CH2Cl2, -24 oC, 6 h, 83

+

LiAlH4, THF,

0 oC to rt., 3 h, 90%

Li/liq. NH3, Fe(NO3)3,

THF, 6 h, 70%

B

A


Scheme 34.

Scheme 35.

Scheme 36.

OO

OMe

O

OMOMOH

37

1) MOMCl, i-Pr2NEt, CH2Cl2,

0 oC to r.t., 2 h, 90%

2) n-BuLi in hexane, ClCO2Me,

THF, -78 oC, 30 min, 90%

1) H2, Pd/C, EtOAc, 4 h, 90%

2) PTSA, MeOH, rt., 12 h, 80%

A

O

OO

O

OTBDMS

COOH

OTBDMS

OH

OH

OTHPO

ClOTHP

O

HOOTHPOTHP

HO

38

7( )7

( )

7( )

Lindlar catalyst, H2, quinoline,

EtOAc, 2 h, 85%

PTSA, MeOH, rt.,3 h, 85%1) Dess-Martin periodinane,

CH2Cl2, 0 oC to rt., 2 h, 85%

2) NaClO2, NaH2PO4 H2O,

DMSO, 0 oC to rt., 80%

1) TBDMSCl, imidazole,

CH2Cl2, 0 oC to rt., 83%

2) recrystallized PPTS, MeOH,

rt., 2 h, 63%

1) Li/Liq NH3, Fe(NO3)3,

-78 oC, THF, 2 h

2) n-C8H17Br, THF, 70%

PPh3, NaHCO3, CCl4,

reflux, 4 h, 79%

(-)-DET, Ti(O-i-Pr)4,

cumenehydroperoxide,

MS 4 Å, CH2Cl2, -24 oC, 4 h, 77%

BA

OO

OMOM

OH

OH

OTHP

O

OHTHPO

OOCO2Et

OBn

OH

OTHP

O

ClTHPO

36

36

910

1) MOMCl, i-Pr2NEt,

0 oC to rt., 2 h, 98%

2) H2, 10% Pd/C, EtOH,

rt., 6 h, 80%

8

1) Ph3P, NaHCO3, CCl4,

reflux, 4 h, 80%

2) Li/liq NH3, Fe(NO3)3 (cat.),

THF, C9H19Br, 8 h, 60%

1) IBX, DMSO, CH2Cl2,

rt., 2 h, 77%

2) NaClO2, NaH2PO4, aq DMSO,

rt., 1 h, 71%;

3) PTSA, MeOH, rt., 12 h, 80%.

9

8

1) NaH, BnBr, THF,

0 oC to rt., 98%

2) PPTS, MeOH, rt., 96%

3) (COCl)2, DMSO, Et3N,

Ph3P=CHCO2Et, CH2Cl2,

-78 oC, 70%

8

Li/liq NH3, Fe(NO3)3 (cat.),

Me(CH2)8Br, dry THF, 70%

H2, 10% Pd/C (cat.),

EtOH, 12 h, 70%.

B

A

( )

( )

( )

( )

( )( )


Scheme 37.

Scheme 38.

7.6. (3S,4R)-3,7-Dimethyl-6-octen-4-olide (39) (elda-nolide)

Eldanolide [(3S,4R)-3,7-dimethyl-6-octen-4-olide, (39)] is a male-produced monoterpenoid sex attractant for the Af-

rican sugarcane stem borer Eldana sacharina [104].

The synthesis of 39 presented by Kong et al. [105] in-volved the preparation of the chiral epoxy alcohol A (93.4% e.e.) in 4 steps from propargyl alcohol, including a Sharpless epoxidation (Scheme 37). Methylation of the epoxide pro-vided a mixture of a 1,2- and a 1,3-diol B, which was re-solved by cleavage of the 1,2-diol by reaction with NaIO4

and subsequent chromatography, providing pure B. Chain elongation by reaction with cyanide, hydrolysis and lactoni-

zation finally provided 39 in 22 % overall yield.

8. SYNTHESIS OF ISOPRENOIDS AS PHEROMONES

8.1. Synthesis of Isoprenoidal Pheromone Alcohols and

their Esters as Pheromones

8.1.1. Maconelliyl 2-methylbutanoate (40) and lavandulyl

2-methylbutanoate (41)

Maconelliyl 2-methylbutanoate (40) and lavandulyl 2-methylbutanoate (41) have been identified as constituents of

OH

OH

OOOH

CN

OH

OH

O

OH

OH

OH

OH

39

elimination of 1,2-diol,

by reaction with NaIO4

1) TsCl, Et3N, DMAP

2) NaCN, NaI, 75%

1) NaOH

2) H2SO4, 86%

+Me2CuLi, 84%(-)-DIPT, Ti(O-i-Pr)4, TBHP,

MS 4 Å, 75%

LiAlH4, 89%1) EtMgBr, CuI

2) Prenyl-Br, 93%

B

BA

O

O

O

OHO

O

O

O

OHO

O

O

O

O

O

O

O

O

HOHO

O

OH

HO

O

HO

O

O

(R)-B

(R,S)-41(S,S)-41

(R,R)-41(R,S)-41

(S,R)-40(S,S)-40(R,R)-40(R,S)-40

(S)-(+) or

(R)-(-)-2-methylbutyric acid

(COCl)2, DMF/benzene

rt., 1.5 h, 79%

(S)-A (70% e.e.)

Similarly

(R)-A (78% e.e.)

(S)-(+)-pinononic acid

from (S)-(-)-verbenone

LiAlH4, Et2O, rt.,

overnight, 88%

1) POCl3, Py, rt., 24 h, 75%

2) PTSA, benzene, reflux,

24 h, 78%

1) MeLi/ether, 1.0 e.q.,

THF, -20 oC, 15 min

2) MeMgCl/THF, 1.6 e.q.,

-10 oC, 30 min, rt., 1 h, 89%(R)-(-)-Pinononic acid

from (R)-(+)- -pinene

(S)-B


the female-produced pheromone of the pink hibiscus mealy-bug, Maconellicoccus hirsutus, which is an exotic insect pest

in Southern California and Florida [106].

Zhang and Nie [107] described an enantioselective syn-thesis of all stereoisomers of these two compounds, starting from (R)- and (S)-pinononic acids, which are easily prepared from (R)- -pinene and (S)-verbenone, respectively. Methyla-tion, elimination of water, and reduction of the carboxyl group afforded (R)- and (S)-maconelliol (A), respectively. Esterification of A was carried out with commercially avail-able (S)-2-methylbutyric acid and previously prepared (R)-2-methylbutyric acid [108] to afford all four stereoisomers of 40. For the synthesis of all isomers of 41, (R)- and (S)-lavandulol (B), prepared according to the method described by Cardillo et al. [108], were esterified with (S)- and (R)-2-

methylbutyric acids (Scheme 38).

8.1.2. 3,7-Dimethyl-2-oxo-6-octene-1,3-diol (42)

Dickens et al. [109] identified 3,7-dimethyl-2-oxo-6-octene-1,3-diol (42) as the male-produced aggregation pheromone from the Colorado potato beetle (Leptinotarsa decemlineata). The absolute configuration of natural 42 was determined by Oliver et al. [110] to be (S) by synthesis of the racemate and both enantiomers from geraniol and (R)-

and (S)-linalool, respectively.

Tashiro and Mori [111] described the synthesis of pure enantiomers of 42 employing the lipase-catalysed enantiose-lective acetylation of (±)-2,3-epoxynerol in the key step, yielding acetate (2S,3R)-A (98.8% e.e.) and alcohol (2R,3S)-B (98.6% e.e.). Ring opening under inversion of the configu-ration at carbon 3 of A by treatment with HClO4 in DMF at 0 °C and subsequent protection of the primary hydroxyl group was followed by selective oxidation and deprotection to give (S)-42. The enantiomer was obtained similarly starting with

alcohol B (Scheme 39).

8.1.3. (1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol (43)

(1S,4R)-4-Isopropyl-1-methyl-2-cyclohexen-1-ol (43) is the aggregation pheromone of the ambrosia beetle Platypus quercivorus, and the absolute configuration of the phero-mone was established as (1S,4R) [112, 113].

Mori [114] described a synthesis of the (1S,4R), (1R,4R), and (1S,4S) isomers and of a racemic mixture of 43. In this paper Mori mentioned that (1R*,4R*)-4-isopropyl-1-methyl-2-cyclohexen-1-ol was detected as a minor component of the frass volatiles of P. quercivorus. Synthesis of (1S,4R)-43 was performed by addition of methyl lithium to (R)-cryptone (91.5–93% e.e.) obtained in six steps from (S)-perillyl alco-hol. The racemic pheromone was also prepared by methyla-tion of (±)-cryptone, prepared from (+)-nopinone. Both (1R,4R)- and (1S,4S)-isomers (98% e.e.) of the pheromone were synthesized from the enantiomers of dihydrolimonene

oxide (Scheme 40).

8.1.4. cis-2-(2-Isopropenyl-1-methylcyclobutyl)ethanol (44) (grandisol)

Grandisol [cis-2-(2-isopropenyl-1-methylcyclobutyl) ethanol, 44] has first been identified as a male-produced pheromone from the boll weevil Anthonomus grandis [115], and has since been found in other insect species [116-118].

Racemic grandisol, contaminated with 10% of the trans diastereomer fragranol (45) was prepared by Bernard et al. [119] via an efficient route starting from 2-(1-methyl-2-phenylthioethyl)cyclobutanone (A), involving the 1,4-addition of lithium dimethylcuprate to the cyclobutylidene

aldehyde B in the key step (Scheme 41).

Pure (1R,2S)-(-)-grandisol was prepared following a similar sequence (Scheme 42). A more bulky substituent at position 2 of the enantiopure cyclobutylidene aldehyde B improved the diastereoselectivity of the copper-catalyzed

Scheme 39.

OH

OH

OAc

O

OH

O

O

OH

OH

OTBDPS

OH

OH

OH

O

OAc

O

OH

O

Similarly

(R)-42

(S)-42

1) SO3 Py, DMSO, Et3N,

CH2Cl2, 0 oC to rt., 24 h, 78-91%

2) TBAF, THF, 0 oC, 5 min, 65%-quant.

1) 60% HClO4, DMF, 0 oC to rt., 12 h

then K2CO3, MeOH, rt., 20 h, 77-92%

2) TBDPSCl, Et3N, DMAP,

CH2Cl2, rt., 24 h, 93-97%

+

10 - 16%, 98.8% e.e. (2S,3R)-A 11 - 22%, 98.6% e.e. (2R,3S)-B

Lipase PS (Amano),

CH2=CHOAc, Et2O, 0 oC, 4 h

Ac2O, DMAP, Py,

30 min, 86-92%

A

O


methylation key step. B (obtained from A by reduction and partial oxidation) was used as the substrate, because direct

methylation of TBDMSOTf-activated A with Me2CuLi re-

sulted in lower diastereoselectivity.

Scheme 40.

OHO

OH

H

SePhOH

OH

H

SePh

SePh

H

OH

O

O

OO

OHOHOH

OO

OHO

O

OTBS

O

OTBSOH

10%44%

Similarly

(1S,4S)-43 (97.8 - 98.2% e.e.)

44% after chromatography

(1R,4R)-43 (98.3 - 98.7% e.e.) 25% overall yield

30% H2O2, THF, Py,

rt. 1 h, 61%.

From B

++

Ph2Se2, NaBH4,

EtOH, reflux, 2 h

+

H2, PtO2,

MeOH, 92%

++

(±)-(R*,R*)-43(±)-(S*,R*)-43

10 - 15%

AlCl3, CH2Cl2,

0 - 5 oC, 70 min, 89%

MeLi, LiBr, Et2O/ THF,

-40 oC to rt,

+

(S)-Perillyl alcohol

(R)-cryptone (91.5-93% e.e.) (1S,4R)-43 (93.3% e.e.)

MeLi, LiBr,

Et2O, THF, 44%.

H2, PtO2, hexane,

EtOAc (1:1), quant.

1) t-BuOOH, VO(acac)2,

toluene, rt., 2.5 h, quant.

2) TBSCl, imidazole,

DMF, quant.

1) Ph2Se2, NaH, THF,

HMPA, reflux, 3 h

2) TBAF, THF, rt.

3) NaIO4, THF, H2O, rt,

1.5 h, 28% (three steps)

BA

O


8.1.5. 1-Acetoxymethyl-2,3,4,4-tetramethylcyclopentane

(46)

(1R*,2R*,3S*)-1-Acetoxymethyl-2,3,4,4-tetramethyl-cyclopentane (46) is the female-produced sex pheromone of

the obscure mealybug Pseudococcus viburni [123].

The synthesis developped by Millar and Midland [124] started with a polyphosphoric acid-catalyzed cyclization of isobutyl methacrylate to obtain the , -unsaturated cy-clopentenone A. 1,4-Addition of lithium dimethylcuprate to

A usually affords the trans isomer, but careful selection of the reaction conditions (reaction at -40 ºC and quenching with ethyl salicylate at -78 ºC) resulted in a 72:28 cis:trans mixture of intermediate B. Conversion of the carbonyl group to a methylene group and subsequent hydroboration yielded alcohol C as a mixture of isomers, from which (1S*,2R*, 3S*)-C was isolated by column chromatography and Kugelrohr distillation. Inversion of the stereogenic center at carbon 1 and acetylation gave (1R*,2R*,3S*)-46, showing

90% isomeric purity (Scheme 43).

Scheme 41.

Scheme 42.

OH

H

OH

H

HO

SPh

H

HO

SPh

H

H

O

SPh

SPh

COOMe

SPhSPh

O

(±)-45(±)-44

+

+

(cis/trans) = (90:10)

Three steps, 75%

[120, 121]

Me2CuLi

Et2O, - 78 oC, 98%

PCC, CH2Cl2

0 oC, 90%

DIBAL-H

THF -78 oC, 90%

TMPA/NaH,

THF, reflux, 88%

B

A

OH

OH

OH

H

O

OBz

H

HO

O

O

H

OH

H

OBz

OH

OH

H

OBz

O

O

H

OH

O

O

H

HO

O

O

H

OH

O

O

H

COOMe

O

O

H

(-)-44(1S,2S,2'S)-(cis)

[122]DIBAL-H

THF, -78 oC, 94%

DIAD/PPh3

benzene, 91%

TFA, MeOH/H2O

rt., 91%

BzCl/DMAP

Et3N/CH2Cl2, 94%

NaBH4, MeOH/THF 1:1

0 oC, 94%

Me2CuLi

Et2O, -78 oC, 97%

PCC, CH2Cl2

0 oC, 88%

DIBAL-H

THF, -78 oC, 88%

A B


8.1.6. 2-Isopropyl-5-methyl-2,4-hexadienyl acetate (47)

Ho et al. identified 2-isopropyl-5-methyl-2,4-hexadienyl acetate (47) as the sex pheromone produced by females of the passionvine mealybug Planococcus minor, and presented

a non-stereoselective synthesis of the compound [125].

Wittig reaction between ethyl 3-methyl-2-oxobutanoate and the ylide of 3-methyl-but-2-enyltriphenylphosphonium bromide yielded a mixture of the esters (E)- and (Z)-A, which was transformed to a mixture of (E)- and (Z)-47 by reduction and acetylation (Scheme 44). The stereoisomers were separated by HPLC for assignment of the geometry of

the natural product, which turned out to be (E).

8.1.7. 2-Methyl-6-(4’-methylenebicyclo[3.1.0]hexyl)hept-2-

en-1-ol (48)

The aggregation pheromone of the stink bug Erysarcoris lewisi has been proposed to be (E)-2-methyl-6-(4’-

methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (48) [126].

Mori synthesized the (2E,6R)-, (2E,6S)-, (2Z,6R)-, and (2Z,6S)-isomers of 48, starting from citronellal [127]. The

absolute configuration at carbon 6 was defined by the use of (R)- or (S)-citronellal, respectively, while the geometry of the double bond was established by stereoselective olefina-tion reactions. Citronellal was converted to diazoketone A in 7 steps, including methylenation and a Claisen orthoester rearrangement as the key steps of this part of the synthesis (Scheme 45). The -ketocarbene generated from A added intramolacularly to the exo methylene double bond, estab-lishing the bicyclic structure in intermediate B. This reaction cannot be controlled stereochemically and a mixture of two diastereomers of B was obtained in each case. The double bond of B was cleaved oxidatively to give aldehyde C, which was converted to (E)-48 in 3 further steps with the (E)-selective olefination of the formyl group with (carbe-thoxymethylidene)triphenylphosphorane as the key step. To obtain (Z)-48, the olefination of aldehyde C was carried out employing Ando’s reagent ethyl 2-(di-o-tolylphosphono) propanoate, which in turn was prepared in three steps from triethyl orthophosphite and ethyl 2-bromopropanoate (Scheme 45). Bioassays with the synthetic isomers suggested

the natural pheromone to show (2Z,6R) configuration.

Scheme 43.

Scheme 44.

OHOO

O

O

PPh3Br

O

O

O

(E)-47(Z)-47

Ac2O, Et3N

DMAP, CH2Cl2

DIBAL-H

CH2Cl2, -78 oC

n-BuLi

THF, reflux

+

+

A

O O

O

O

OAcOHO H

O HOH

OO

(1S*, 2R*, 3S*)-46

mainly (1S*, 2R*, 3S*)-C

B

(cis:trans 72:28)

AcCl, Py

CH2Cl2, 81%

NaBH4, EtOH

93%

NaOMe, MeOH

PDC, CH2Cl2

81%

BH3 DMS, THF, 0 oC

aq. NaOH, H2O2, 75%

Me2CuLi, ethyl salicylate

quench, -78 oC, 89%polyphosphoric acid

100 oC, 34%

A

Zn-CH2Br2-TiCl4


8.2 Synthesis of Isoprenoidal Aldehydes, Ketones and

Acids as Pheromones

8.2.1. (R)-1,1,5,8-Tetramethyl-1,2,3,4,5-pentahydrobenzo

[a][7]annulene (49) [(R)-ar-himachalene]

In 2001 Bartelt et al. [128] isolated and identified the male-produced pheromone of the flea beetle Aphthona flava as (S)-ar-himachalene (49). Mori [129] proposed the oppo-

site absolute configuration for the natural compound.

Mori [130, 131] described a synthesis of (R)-turmerone A from (4-methylphenyl)acetic acid employing Evans’ asym-metric alkylation in the key step. (R)-Turmerone was con-verted to (R)-ar-himachalene according to Pandey and Dev’s

procedure [132] (Scheme 46). Interestingly, (R)-49 was dex-

trorotatory in hexane, while levorotatory in chloroform.

8.2.2. (2E,4S)-2,4-Dimethylhex-2-enoic acid (50), 4,6-dimethylnon-4-en-3-one [(S)-manicone, 51], 3,5-dimethyl-

oct-3-en-2-one [(S)-normanicone], 52, (1S)-1-methylbutyl-

(2E)-2-methylpent-2-enoate (dominicalure-I, 53) and (1S)-

1-methylbutyl (2E)-2,4-dimethylpent-2-enoate (domini-

calure-II, 54)

(2E,4S)-2,4-Dimethylhex-2-enoic acid (50) is a caste-specific substance present in the mandibular glands of the male carpenter ants in the genus Camponotus [133]. (S)-Manicone (4,6-dimethylnon-4-en-3-one, 51) and (S)-

Scheme 45.

Me

CHCO2Et

O

PO

Me

(EtO)2PCHCO2EtMeCHCO2Et

OH

OH

CHO

OH

CO2Et

H

O

O

O

COCHN2

COClCO2H

OHCHOCHO

o-cresol, Et3N, CH2Cl2,

0 oC - 5 oC, 30 min, rt., 1 h, 60%

2

PCl5, 75-80 oC

14 h, 67%

160 oC, 2 h

60%

(EtO)3P +

or

(2Z,6S)-48(2E,6S)-48

Similarly

1) [CH3PPh3]+Br-, n-BuLi, THF, 96%

2) DIBAL-H, toluene, 22%

(2Z,6R)-48

(o-MeC6H4O)2P(O)CHMeCO2Et,

NaH, THF, -78 oC to 5 oC, quant.

OsO4, NaIO4, t-BuOH,

THF, H2O, quant

Cu, CuSO4,

cyclohexane,

reflux, 1 h, 58%

CH2N2, Et2O

quant.

1) NaOEt, EtOH

2) (COCl)2, Py, hexane,

quant. (2 steps)

1) MeC(OEt)3, propanoic acid,

140 oC, 1 h, 95%

2) KOH, EtOH, H2O, reflux, 2 h, 83%

LiAlH4, Et2O,

91%

37% CH2O, propanoic acid,

pyrrolidine, i-PrOH,

45 oC, 4 h, 90%

C

BA

Br Me

O

Cl2PCHCO2Et

Me

O

O

C

OH

CO2Et

(2E,6R)-48

DIBAL-H, toluene

55%

1) Ph3P=C(Me)CO2Et,

THF, CH2Cl2, 57%

2) [CH3PPh3]+Br-,

n-BuLi, THF, 96%


normanicone (3,5-dimethyl-oct-3-en-2-one, 52) are the man-dibular-gland alarm pheromone components of the ants in the genus Manica [134, 135]. Dominicalure-I [(1S)-1-Methylbutyl (2E)-2-methylpent-2-enoate, 53] and domini-calure-II [(1S)-1-methylbutyl (2E)-2,4-dimethylpent-2-enoate, 54] are the aggregation pheromones of the lesser

grain borer Rhyzopertha dominica [136].

Das et al. [137] described a synthesis of these pheromone compounds employing Baylis–Hillman adducts. Compounds

50, 51 and 52 were obtained from Baylis-Hillman adduct A, which was treated with sodium borohydride in the presence of CuCl2·2H2O in MeOH to give the corresponding (E)-2-methyl-2-alkenoate, which was hydrolyzed yielding acid 50. Transformation of 50 to the acid chloride and alkylation with lithium diethylcuprate and lithium dimethylcuprate yielded 51 and 52, respectively. For the synthesis of 53 and 54, the Baylis-Hillman adducts B and B’ were subjected to a similar

reaction sequence (Scheme 47).

Scheme 46.

Scheme 47.

O

O

O

O

OHROMe

OH

RO

O

O

HR

OClOH

OMe

OH

O

O

CHO

54

53

52

51

50

or1) SOCl2

2) (+)-(2S)-pentan-2-ol

R = Et

R = iPr

1) NaBH4, CuCl2 2H2O

MeOH, rt.

2) NaOH, MeOH/H2O

R = Et (B)

R = iPr (B')

R = Et

R = iPr

DABCO+

Et2CuLi,

Et2O, -78oC

Me2CuLi,

Et2O, -78oC

SOCl2, Benzene

1) NaBH4, CuCl2 2H2O

MeOH, rt.

2) NaOH, MeOH/H2O

DABCO, dioxane,

0 oC, 20 h

+

A

O

O

O

O

O

O

O

OH

CNOH

O

Bn

ON

O

CO2H

[ ]D23 = +3.8o (hexane)

[ ]D23 = -2.4o (CHCl3)

(R)-ar-himachalene (49)

AlCl3, CS2, -40 to -20 oC, 1 h,

then reflux , 46 oC, 4 h, 40%

N2H4 H2O, KOH, diethylene glycol,

200 - 210 oC, 3 h, 42%.

(R)-turmerone (A)

KOH, HO(CH2)2OH, H2O,

100 oC, 3 h, 91%

1) TsCl, DMAP, Py,

0-5 oC, 2 h, 95%

2) NaCN, NaI, DMSO,

110 oC, 30 min, 78%

1) NaHMDS, MeI, THF,

-78 oC, 3 h, then rt., 97%

2) LiAlH4, THF,

0 oC to rt., 69%

1) SOCl2, C6H6, reflux, quant.

2) (S)-4-benzyl-2-oxazolidinone, n-BuLi,

THF, -78 oC, 30 min, then rt., 79%

1) MeNHOMe HCl, EDC, DMAP,

(i-Pr)2NEt, CH2Cl2, 0 oC, 4 d, 84%

2) Me2C=CHMgBr, THF,

-20 oC to rt., 2 h, 88%.

O


8.2.3. (3Z,7E)-9-Isopropyl-2,6-dimethylene-3,7-cyclodeca-

dien-1-one (periplanone C, 55)

Periplanone C [(3Z,7E)-9-isopropyl-2,6-dimethylene-3,7-cyclodecadien-1-one, 55] is one of at least four biologically active components of the sex pheromone of the American

cockroach, Periplaneta americana [138-143].

The key steps of the synthesis of racemic 55 presented by

Matovic et al. [144] are a ring closure metathesis (RCM)

reaction, assuring the Z configuration of the newly formed

double bond in the bicyclic intermediate D, and subsequent

rupture of the central bond yielding E. The monocyclic pre-

cursor B was obtained from the anisol derivative A and sub-

mitted to RCM using Grubbs first generation catalyst (C) to

yield the bicyclic intermediate D. The rupture of the central

bond was achieved by Grob fragmentation under ionic con-

ditions and yielded the (Z,Z)-cyclodecadienone E, which

could be isomerized photochemically under radical condi-

tions to the (Z,E)-cyclodecadienone F. The lithium enolate of

F was aminomethylated with Eschenmoser’s reagent and 55

was obtained after spontaneous elimination of dimethyl-

amine (Scheme 48).

8.2.4. (E)- and (Z)-3-Methyl-4-heptenoic acid (56), and 3-methyleneheptanoic acid (57)

The volatile sex pheromone released by females of the cowpea weevil Callosobruchus maculatus has been identi-

fied to be a mixture of (E)- and (Z)-3-methyl-2-heptenoic acid, (E)- and (Z)-3-methyl-4-heptenoic acid (56), and 3-

methyleneheptanoic acid (57) [145].

The three latter compounds have been synthesized by Yajima et al. [146]. 57 was prepared using Chong’s proce-dure of alkylation of the dianion of 3-methyl-3-buten-1-ol, followed by sequential Dess-Martin and Pinnick oxidations to give the target molecule in a moderate yield but without isomerization of the somewhat sensitive 3-exo methylene double bond. For the synthesis of 56, the (E) and (Z) isomers of the vinylic iodide 4-iodo-3-methyl-3-buten-1-ol were pre-pared from 3-butyn-1-ol, respectively, and further trans-formed via alkylation and oxidation to the desired products

(Scheme 49) [147, 148].

9. SYNTHESIS OF ACETALS AS PHEROMONES

9.1. (1S,3R,5R,7S)-1-Ethyl-3,5,7-trimethyl-2,8-dioxabi-

cyclo[3.2.1]octane [(+)-sordidin, 58] and (1S,3R,5R,7R)-1-

ethyl-3,5,7-trimethyl-2,8-dioxabicyclo[3.2.1]octane [(–)-7-

epi-sordidin, 59]

The banana weevil Cosmopolites sordidus is the most devastating insect pest on banana plants worldwide [149]. The major compound of the male-produced aggregation pheromone has been identified as (1S,3R,5R,7S)-1-ethyl-3,5,7-trimethyl-2,8-dioxabicyclo[3.2.1]octane (58), which was given the common name sordidin [150-152]. A minor component of the volatile bouquet released by the weevil is

Scheme 48.

OO

O

OMs

HO

OH

CO2CH3

CO2CH3

HO

CO2CH3

O

CO2CH3

OCH3

OCH3

Periplanone C (55)

1) LDA, THF, -78 oC

2) Me2N=CH2I, THF,

HMPA, -78 oC to rt.

3) MeI, rt., 2 h

4) NaOAc, H2O, Et2O, rt.,

1 h, 53% from FE 58% + F 38%

E

PhSSPh (2 mol%), hn (vis.),

benzene, 15 oC, 10 min

KOH, 18-crown-6, benzene,

rt. 1.5 h, 74% (2 steps)

1) LiAlH4, THF, rt. 20 h, 96%

2) MsCl, Et3N, CH2Cl2,

-15 oC, 5 min

C (3 mol%), CH2Cl2,

rt., 23 h, 81%

C =

Zn, allyl bromide,

DMF, rt. 20 h, 89%

1) K, THF, NH3, t-BuOH, -68 oC

2) LiBr (2.2 eq), allyl bromide, -68 oC to rt.

3) HCl (cat.), acetone, 4 oC, 5 min,

46% (3 steps)

1) n-BuLi, cyclohexane, , 15h

2) CO2, Et2O, -78 oC to rt.

3) MeOH, toluene, PTSA (cat.)

, 8h, 45% (3 steps)

B D

A

F

Cl2Ru

Ph(Cy3)P

(Cy3)P


(1S,3R,5R,7R)-7-epi-sordidin (59) [153]. Interestingly, the

enantiomer of the latter has been found in caddisflies [154].

An asymmetric synthesis of (1S,3R,5R,7S)-58 and (1S,3R,5R,7R)-59 was performed by Enders et al. [155]. The first two stereogenic centers were formed by three -alkylations of the RAMP-hydrazone of 2,2-dimethyl-1,3-dioxan-5-one A. The third stereogenic center was formed by diastereoselective epoxide opening employing the aza-enolate of 3-pentanone SAEP-hydrazone in the key step (Scheme 50). The mixture of the diastereomers was sepa-rated by preparative gas chromatography, furnishing the pure

enantiomers with e.e. > 98%.

9.2. 1,5-Dimethyl-6,8-dioxabicyclo[3.2.1]octane (60) (frontalin)

Frontalin (1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane, 60) was first isolated and identified as a component of the aggregation pheromones of the southern pine beetle (Den-droctonus frontalis) and of the western pine beetle (Den-droctonus brevicomis) by Kinzer et al. [158]. By means of bioassays with pure synthetic enantiomers, Mori [159, 160] showed the absolute configuration of natural 60 to be

(1S,5R) in both species.

Prasad et al. [161] described an enantioselective formal synthesis of frontalin employing the addition of Grignard reagents to the bis-Weinreb amide A derived from L-(+)-

tartaric acid and to B as the key steps (Scheme 51).

Schuster et al. [163] described a stereoselective synthesis of 60 by addition of an organo zinc reagent to an -keto ester

coupled to a chiral auxiliary. The synthesis was performed either in solution (98 % e.e. for (+)-60) or with the -keto ester-chiral auxiliary complex immobilized (86 % e.e.)

(Scheme 52).

9.3. exo-Brevicomin (61), 1’-hydroxy-exo-brevicomin (62) and 2-hydroxy-exo-brevicomin (63)

exo-Brevicomin (61) and endo-brevicomin (exo- and endo-7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane) are common components of the aggregation pheromone system of several bark beetle species of the genera Dendroctonus and Dryocoetes [160, 164-166]. Francke et al. [167] have identified 1’-hydroxy-exo-brevicomin (62) and 2-hydroxy-exo-brevicomin (63) from the pine beetle Dendroctonus

ponderosae.

Prasad et al. [168-170] described a synthesis of 61, 62, and 63 employing addition of Grignard reagents to the bis-Weinreb amide A derived from L-(+)-tartaric acid and sub-sequent stereoselective reduction of the keto function with L-selectride or K-selectride as common steps (Schemes 53 – 55). 61 was synthesized from diol B by oxidative cleavage with lead tetraacetate in benzene and subsequent stereoselec-tive alkylation of the resulting aldehyde to yield the corre-sponding threo alcohol C as a single diastereomer. Wacker oxidation of terminal olefin and simultaneous debenzylation and intramolecular acetalization with Pd/C in MeOH and a trace of 3 M HCl gave the compound 61 (Scheme 53). For the synthesis of 62, TBDMS protected amide D was reduced with sodium borohydride, tosylated, and reduced with super

hydride to obtain acetonide E. Wacker oxidation and cycliza-

Scheme 49.

OH

COOH

OHOTBS

I

COOH

OHOTBS

IOH

COOH

OHOH

(Z)-56

(E)-56

57

1) Dess-Martin periodinane, CH2Cl2

2) NaClO2, NaH2PO4, 2-methyl-2-butene

THF, t-BuOH, H2O, 0 oC, 49%

1) n-C3H7MgBr, PdCl2(dppf), Et2O

2) TBAF, THF, 84%

1) Dess-Martin periodinane, CH2Cl2



1) n-C3H7MgBr, PdCl2(dppf), Et2O

2) TBAF, THF, 73%

1) Ref. 14, 60%,

2) TBSCl, Et3N, DMAP

CH2Cl2, quant.

1) [147], 80%

2) TBSCl, Et3N, DMAPCH2Cl2, 92%

1) Dess-Martin periodinane,

CH2Cl2, rt.



n-BuLi, TMEDA, n-C3H7Br

Et2O, -78 oC to 0 oC, 46%


Scheme 50.

Scheme 51.

O

O

O

O

TBSO HO

OCH3

N

OCH3

NN

OOTBS

OTs

OO

OBn

OO

OBn

OH

OO

OBn

OCH3

NN

OO

OCH3

NN

OO

OCH3

NN

OO

(1S,3R,5R,7R)-7-epi-(-)-sordidin (59)(1S,3R,5R,7S)-(+)-sordidin (58)

d.r.

+

1.5 : 1.0

>>d.e. 97% e.e. 98%>>d.e. 99% e.e. 98%

1) LiCl, LDA, THF, -78 oC,

1 h, then 0 oC, 10 min,

2) B, -78 oC to rt.,15 h

3 N HCl, H2O/pentane,

rt., 6 d, 84%

>d.e, e.e. 96%

1) Ca/NH3, 97%

2) ) Et3N, DMAP,

CH2Cl2, TsCl, rt. quant.

1) i. NaH, THF, 0 oC

ii. CS2, MeI, 98%

2) n-Bu3SnH, AIBN,

toluene, reflux, 98%

1) O3, CH2Cl2, -78 oC, 79%

2) NaBH4, MeOH, 0 oC, quant.

>d.e, e.e. 96%

1) t-BuLi, THF, - 78 oC

2) BOMCl, -100 oC to rt. 92%

1) 3N HCl, H2O/MeOH,

rt. 87%

2) 2,6-lutidine, CH2Cl2,

TBSOTf, 0 oC, quant.

3) NaH, THF, 0 oC, 99%

>d.e, e.e. 96%

[156, 157]

79% (2 steps)

A

B

O

O

BnO

OHOBn

BnO

HO

HO

OH

HO

O

O

O

O

O

OMgBr

OMeMe

OMeMeN

O

N

O

O

O

60

[162]

3

3

3

1) Pb(OAc)4, benzene,

rt. 1.5 h

2) NaBH4/MeOH,

0 oC, 1 h, 90% (2 steps)

1) NaH, DMF, BnCl,

rt., 4h,

2) FeCl3 6H2O, CH2Cl2,

rt. 4 h, 40% (2 steps)

3

3

MeMgBr, MgBr2, Et2O

CH2Cl2, -78 oC, 3.5 h, 74%

3

3THF, 0 oC, 1 h, 94%

3

BA

( ) ( )

( )

( )

( )

( )

( )( )

.


Scheme 52.

Scheme 53.

tion yielded 62 (Scheme 54). For the synthesis of 63, TBDMS protected amide F was reduced with DIBAL-H and treated with phosphorus ylide to give the , -unsaturated ketone G. Hydrogenation over Pd/C and simultaneous deprotection of the silyl ether and acetonide afford triol H, which instantly ketalized to 63 (Scheme 55).

9.4. (±)-1,7-Dioxaspiro[5.5]undecane (64) and (2R*,6S*)-2-methyl-1,7-dioxaspiro[5.5]undecane (65)

1,7-Dioxaspiro[5.5]undecane (64) has been identified as the major component of the sex pheromone released by fe-males of the olive fruit fly Dacus oleae [171]. In bioassays, (R)-64 was shown to be active against the males, whereas (S)-64 was active against females [172]. 2-Methyl-1,7-

dioxaspiro[5.5]undecane (65) was identified as volatile com-ponent of the cleptoparasite bee Epeolus cruciger [173]. Conway et al. [174] described a synthesis of these two spi-roketal compounds employing stereospecific Stille coupling reactions of 2-metallo-dihydropyrans with suitable (Z)-1-

iodoalkenols and subsequent cyclisation (Scheme 56).

10. SYNTHESIS OF ALLENES AS PHEROMONES

10.1. Methyl (R,E)-tetradeca-2,4,5-trienoate (66)

Methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (66) has been of synthetic interest since Horler determined it to be a sex attractant produced by the male bean weevil, Acan-thoscelides obtectus [175].

O

OOH

OH

OH

R

O

OOO

ZnCl

R

O

O

OOO

R = Me or Wang resin

60

O3, CH2Cl2

-78 oC

solution phase 99:1 (98% e.e.)

solid phase 93:7 (86% e.e.).

Solution Phase Synthesis 81% and 92% d.e.

Solution Phase Synthesis 80%

Solid Phase Synthesis 50% 2 steps 86% e.e.

LiAlH4, THF

R = Me or Wang resin

O

O

OOBn

OH

OBn

OH

OBn

O

H

HO

HO

OBn

OBn

OH

OH

O

O

O

O

O

OMgBr

OMeMe

OMeMeN

O

N

O

O

O

61

H2, 10% Pd/C, MeOH

3N HCl, rt., 2.5 h, 72%

PdCl2, CuCl, O2, DMF/H2O,

rt., 2.5 h, 85%

EtMgBr, MgBr2, CH2Cl2,

-78 oC, 4.5 h, 78%

Pb(OAc)4, benzene,

rt., 1.5 h, 98%3

3

1) NaH, DMF, BnBr,

0 oC to rt., 2 h, 97%

2) FeCl3 6H2O, CH2Cl2,

rt. 2 h, 89%

3

3

L-selectride (4 eq.)

THF, -78 oC, 2.5 h, 94%

(4 eq.) 3

3THF, 0 oC, 1h, 96%

3

B

C

A

( )( )

( )

( )

( )

( )

( ).


Ogasawara et al. [176] described an enantioselective syn-thesis of this chiral allene using a palladium-catalyzed reac-tion for the synthesis of the allene moiety in the key step. Allene intermediate A was prepared by reaction of 3-bromo-1,3-dodecadiene and dimethyl malonate. The use of Pd(dba)2/(R)-segphos catalyst and 5 equivalents of malonate

were the best conditions in terms of both yield and asymmet-ric induction (71% yield, 77% e.e.). Methanolic hydrolysis, acidic decarboxylation and treatment with diazomethane resulted in decarboxylation of A nearly without racemiza-tion. A final desaturation step gave 66 in 76% e.e. (Scheme

57).

Scheme 54.

Scheme 55.

OH

O

O

OTBDMS

O

O

OTs

OTBDMS

O

O

MgBr

Me OMe

O

N

OTBDMS

O

O

Me OMe

O

N

O

O

O

OMeMe

OMeMeN

O

N

O

O

O

E

62

PdCl2, CuCl, O2,

DMF/H2O, rt., 6 h, 74%

3

super hydride, THF,

rt. 2 h, 94%3

1) NaBH4, MeOH,

0 oC to rt., 3 h, 95%

2) TsCl, DMAP, CH2Cl2,

rt., 5 h, 92%

33(1.5 eq)

THF, -15 oC, 30 min, 92%

3

1) L-selectride

THF, -78 oC, 2.5 h, 98%

2) TBDMSOTf, Py,

CH2Cl2, 0 oC to rt., 1 h, 98%

D

( )

( )( )

( )

OH

O

O

OH OH

OH

O

OTBDMS

O

O

O

OTBDMS

O

O

O

PPh3

Me OMe

O

N

OTBDMS

O

O

Me OMe

O

N

O

O

O

OMeMe

OMeMeN

O

N

O

O

O

G

63

2

FeCl3 6H2O, CH2Cl2,

rt. 1.5 h, 87%

H2, 10% Pd/C,

rt. 1.5 h, quant.

1) DIBAL-H, THF, -78oC, 2h

2)

benzene, reflux, 4 h,

74% (2 steps)

1) K-selectride

THF, -78 oC, 25 min

2) TBDMSCl, imidazole,

DMAP, DMF, 80 oC, 1.5 h,

68% (2 steps)

EtMgBr, THF,

-15 oC, 30 min, 88%

F

H

O

( )


Scheme 56.

Scheme 57.

O

O

OH

HO

ZnClOHO

I H

H

TBDMSO

OH

TBDMSO

H

TBDMSO

OEt

OOH

OEt

O

O

OH

HO

MO

IH

OHH

OTBDMSHO

65

64

1) CSA, CH2Cl2, 20 oC, 66%

2) H2, 5%, Pd/C, EtOAc, 6 h, 74%

(Z : E = 6.4 : 1)

, Pd(PPh3)4 (5 mol%),

THF, 5 oC, 1 h, 48-76%

1) Ph3P=CHI, 73%

2) CSA, MeOH, 20 oC, 85%

(COCl)2, DMSO, -78 oC

1) DIBAL-H (1.6 equiv),

toluene, -78 oC,

2) citric acid, -78 oC, 88%

TBDMSCl, DBU,

CH2Cl2, 20 oC, 99%

(Z : E = 6.4 : 1)

(Z : E = 6.4 : 1)

1) CSA, CH2Cl2, 20 oC, 82%

2) H2, 5% Pd/C, EtOAc, 6 h, 93%

(Z : E = 6 : 1)

a) M = SnBu3; (o-Tol)3P (10 mol%), Pd(OAc)2 (5 mol%),

Et3N, CH3CN, 80 oC, 1.5 h, 33%, or

b) M = ZnCl; '(Ph3P)2Pd' (5 mol%), THF, 0 oC, 1 h, 71%, or

c) M = ZnCl; Pd(Ph3P)4 (5 mol%), THF, 0 oC, 1 h, 72%

1) (COCl)2, DMSO,

CH2Cl2, -78 oC, 92%

2) Ph3P=CHI, THF, -78 oC, 78%

3) CSA, MeOH, 20 oC, 15 h, 78%

A

A

O O

DIBAL-H,

toluene, -78 -20 oC

COOMe

H

COOMe

COOMe

H

H

PPh2

PPh2

O

O

O

O

Br

66 76% e.e.

1) LDA, THF, -78 oC

2) PhSeBr

3) NaIO4, THF/H2O76% e.e.

1) KOH, H2O/MeOH

2) dil. H2SO4, 100oC

3) CH2N2 in Et2O

A 77% e.e.

(R)-segphos

Pd(dba)2/(R)-segphos(10 mol%),

CsOt-Bu (1.0 eq), 71%+

CH2(COOMe)2 (5.0 eq)

7( )

( )7

H

( )7

COOMe

H

H

( )7


ABBREVIATIONS

Ac = acetyl

AIBN = azobisisobutyronitrile

BnBr = benzyl bromide

BOMCl = benzyloxymethyl chloride

m-CPBA = m-chloroperbenzoic acid

CSA = camphorsulfonic acid

DABCO = 1,4-diazabicyclo[2.2.2]octane

DBU = diazabicyclo[5.4.0]undecene

DCHT = dicyclohexyl tartrate

DET = diethyl tartrate

DHP = 3,4-dihydro-2H-pyran

DIAD = diisopropyl azodicarboxylate

DIBAL-H = diisobutylaluminium hydride

DIPT = diisopropyl tartrate

DMAP = 4-dimethylaminopyridine

DMF = N,N-dimethylformamide

DMS = dimethylsulfide

DMSO = dimethylsulfoxide

EDC = 1-ethyl-3-(3-dimethyl aminopro-

pyl)carbodiimide

HMPA = hexamethylphosphoramide

IBX = 2-iodoxybenzoic acid

KHMDS = potassium hexamethyldisilazide

LDA = lithium diisopropylamide

MOMCl = methoxymethyl chloride

MsCl = methanesulfonyl chloride (mesyl

chloride)

NaHMDS = sodium hexamethyldisilazide

PCC = pyridinium chlorochromate

PDC = pyridinium dichromate

PNBA = p-nitrobenzoic acid

PPh3 = triphenyl phosphine

PPTS = pyridinium p-toluenesulfonate

PTSA = p-toluenesulfonic acid

Py = pyridine

TBAF = tetra-n-butylammonium fluoride

TBDMSCl = tert-butyldimethylsilyl chloride

TBDPSCl = tert-butyldiphenylchlorosilane

TBHP = tert-butyl hydroperoxide

TBSCl = tert-butyldimethylsilyl chloride

TBSOTf = tert-butyldimethylsilyl triflate

TFA = trifluoroacetic acid

THF = tetrahydrofurane

THP = tetrahydropyranyl

TMEDA = tetramethylethylenediamine

TMSCl = trimethylsilyl chloride

TsCl = p-toluenesulfonyl chloride (tosyl

chloride)

ACKNOWLEDGEMENTS

PHGZ thanks CNPq, CAPES and Fundação Araucária/PR for financial support. JAFPV thanks CAPES

for a doctoral fellowship. JB thanks DII-PUCV and Fonde-cyt (Chile) for financial support. MFF thanks Conicyt

(Chile) for a doctoral fellowship.

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