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- - - - Rapport projet ete 95 superviseur de recherche:Dr. Claude Spino synthese chirale du (S)-(E)-undeca-6-en-l,lO-diyn-3-ol par Christian Beaulieu Universite de Sherbrooke ete 1995 -- - - - -------- --

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Page 1: Rapport superviseur de recherche:Dr. Claude Spino synthese ... · Rapport projet ete 95 superviseur de recherche:Dr. Claude Spino synthese chirale du (S)-(E)-undeca-6-en-l,lO-diyn-3-ol

- - - -

Rapport

projet ete 95

superviseur de recherche:Dr. Claude Spino

synthese chirale du (S)-(E)-undeca-6-en-l,lO-diyn-3-ol

parChristian Beaulieu

Universite de Sherbrooke

ete 1995

-- - - - -------- - -

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2

INTRODUCTION:

Les srerordessont des hormones responsables d'un grand nombre de

fonctions a I'interieur du corps humain. Le cholesrerolqui est synthetise par les

mammiferes est Ie precurseur de plusieurs autres importants sterordes1. Les hormones

sexuelles sont des sterordesproduits par les gonades (ovaires, testicules), ces hormones

sont responsables entre autre, du developpement des caracreristiques sexuelles

secondaires chez les mammiferes et ont de plus, des effets anabolisants1. L'androsrerone,

auquelle ce rapport s'interesse, est une hormone srerordemale, qui comme beaucoup

plusieurs autres hormones de ce type, peut-etre synthetisee a partir de precurseur tel Ie

Squalene ou a partir de molecules dont la stucture proche des sterordes permet la

construction de la molecule a quatre cycles caracteristique aux srerordes, cela a l' aide dereactions de Diels-Alder et d' annelation de Robinson.

On essait maintenant de synthetiser les sterordesa partir de molecules de

depart tres simple, afin de rendre leur synthese moins dispendieuse, plus facile et

permettant de mieux controler la stereochimie des divers centres chiraux caracteristiquesaux sterordes.

Ainsi, ce rapport traite d'une nouvelle fa~onde synthetiser l' androsrerone

a partir d'une molecule simple et plus particulierement de la synthese chirale d' un des

intermediaire de cette synthese, soit; Ie (S)--(E)-undeca-6-en-1,1O-diyn-3-01(schema 1).

En effet, les alcools secondaires optiquement actives sont d' importants materiaux de

depart pour la synthese chirale de molecules complexes tels les sterordes. La synthese

chrirale de ces alcools par la reduction de cetone prochirale avec des agents reducteurs

chiraux a connu de grands developpements depuis de recentes annees avec les travaux de

groupes comme celui de Noyori sur Ie BINAL-H3, de H.C. Brown2, 4 et de Mark M.

Midland5, 6 sur Ie B-3-pinanyl-9-borabicyclo[3.3.1](aussi appele Alpine-Borane)

(schema 3) . Dans notre cas, c'est avec l' Alpine-Boraneque fut effectue la reduction

chirale du (E)-undeca-6-en-1, 1O-diyn-3-oneen (S)-(E)-undeca-6-en-1,10-diyn-3-01 et

cela avec succes, ayant obtenu I'alcoolde stereochimie desiree avec un tres bon exces

enantiomerique de l' ordre de 93.2%.

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3

De plus, ce projet avait pour autre but de developper une autre sequence

(schema 2) permettant d'effectuer la synthese du (S)-(E)-undeca-6-en-l,1O-diyn-3-ol

avec deux etapes de moins que la sequence originale. Les travaux sur cete nouvelle voie

permettant d' obtenir cette alcool furent vain et et la sequence originale reste la plus

appropriee jusqu'a maintenant. De plus durant ce projet quelques etudes de modeles

furent effectees afin de determiner si certaines reactions peuvent s'appliquer a la synthese

de l'androsterone, il en sera plus longuement discute dans la section resultats etdiscussion.

schema 1:

~OH

1

DMSO,Et3N(COCI)2 .-

CH2CI2-6aoC ;rH

~MgBrEt20..

-7aoC~

OH3

CH3C(OEtbC2HsC02H.-

toluenereflux

DIBAL-H-.-

O~ Et20-7aoC

H

4 o 5

6 OH

Dess-Martin

periodin~CH2CI2

r.t

== MgBr.-THF -

aOc -r.t.

Alpine-Borane~ --

aOc~r.t.7 o 8 OH

- - -

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- - ----

schema 2:

.?'MgBr

Et20..-

-7aoe

~Br9b

recJudeur chirale~

schema 3:

- - - - -- - -

..

Base

:)'H

?..

o

8 OH

4

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5

RESULT ATS ET DISCUSSION:

1. synthese du (S)-(E)-undeca-6-en-1.lO-diyn-3-01

La premiere etape dans cette synthese consiste a oxider Ie 4-pentynol

commercial en 4-pentynal a l'aide d'une oxydation de Swern l'aldehyde obtenu n'etant pas

tres stable celui-ci est utilise sans etre purifie dans la reaction suivante, dft a sa rapide

decomposition sous forme concentre a la temperature de la piece. L'oxydation du 4-

pentynol a l'aide du Dess-Martin periodinane a ete essayee et s'est avere moins efficace

que l'oxydation de Swern, apres cinq heures aucun aldehyde n'ayant ete forme. Dans

l'etape suivante, on obtient l'hept-l-en-6-yn-3-01par la reduction, a l'aide d'une reaction

de Grignard, du 4-pentynal en utilisant pour reactif Ie vinyl magnesium bromide. Cette

reaction simple, permet d'obtenir l'alcool desire avec un rendement de 73% apres deux

etapes .L'ethyl (E)- non-4-en-8-ynoateest obtenu apres une condensation de Claisen sur

l'hept-l-en-2-yn-3-01, l'ester est obtenu avec un rendement de 81% et peut etre aussi bien

purifie par colonne chromatographique que par distillation sous pression reduite, Ie

produit obtenu est de plus tres stable. L'ester forme est ensuite transforme en (E)-non-4-

en-8-ynal en utilisant Ie DIBAL-H comme reactif. L'aldehyde est obtenu avec unrendement de 92% et celui-ci est

relativement stable.On obtient ensuite Ie (E)-undeca-6-en-l,1O-diyn-3-01par un Grignard

utilisant l'ethynylmagnesium bromide comme reactif et cela avec un rendement 87%.

L'alcool racemique est ensuite oxyde en une cetone ( (E)-undeca-6-en-l,1O-diyn-3-one)

en se servant du Dess-Martin periodinane comme agent oxydant avec un rendement de

87%. La cetone produite permet ensuite d'effectuer une reduction chirale pour obtenir Ie

(S)-(E)-undeca-6-en-l,1O-diyn-3-01.La reduction chirale de cette cetone s'est fait en

utilisant l'Alpine-Borane comme agent reducteur chirale 5,6,7,8. Cette reduction a

comme avantage sa simplicite, car on ne fait qu'ajouter la solution commerciale O.5M

d'Alpil,1e-Boraneala cetone qui est ensuite agitee pour 14heures et plus. Le rendement

---- -- --

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6pour cette reaction est de 70% mais cela apres seulement un essai. De plus, apres avoir

purifie Ie residu obtenu par-chromatographiesur colonne une certaine quantite de la

cetone de depart a ete recouvert, ceci laisse croire que Ie rendement pour cette reaction

pourrait etre ameliore en augmentant Ie temps de reaction ou la quantite de reactif. Pour

ce qui est des resultats obtenus au niveau de la srereochimieun exces enantiomerique de

93.2% a ere obtenu, cela determine par l'analyse du RMN 19p du melangediasrereoisomerique de l'ester de Mosher derive a partir (S)-(-)-a-methoxy-a-

(trifluoromethyl)phenyl acetic acid. De plus la srereochimiedesiree pour l'alcool est

confmnee en utilisant la methode d'analyse du RMN 19p con~upar Mosher et Dale9,1O.

En effet sur RMN 19p , les signaux pour les derives du MTPA avec la configuration

absolue (R,R)- ou (S,S)- apparaissent generalement a plus bas champs que les derivees

correspondantes du MTPA ayant comme configuration absolue (R,S)- ou (S,R)-. Ainsi

des deux resonnance observees sur Ie RMN 19p c'est celle qui se trouve a plus bas

champs (-73.11 ppm ) qui possede la plus grande integration ce qui confmne que c'est

Ie diastereoisomere avec la configuration absolue (S,S) qui a ere obtenu majoritairement

ce qui implique que c'est reellement bien Ie (S)-(E)-undeca-6-en-l,1O-diyn-3-oiqui a ere

obtenu en exces avec un ratio (S):(R) de 96.6:2.4.

On a tout d'abord tenre de faire cette reduction chirale avec Ie BINAL-H, car celui -ci est

reconnu pour donner de tres bon exces enantiomerique (ee>90%) avec les alcools

propargylique3,11,12,13 comme la notre. Tous les essais avec ce reactiffurent non

concluant, car it fut impossible de preparer une solution de LiAIH4 d'environ 1M qui

n'etait que tres legerement trouble, co~e Ie recommande"lalitteratureI2,14. Les essais

furent donc fait avec une solution de LiAIH4 trouble, et apres 12 heures de reaction

aucune reduction n'avait eu lieu par TLC. n serait interessant d'essayer cette reduction

avec la solution 1M commerciale de LiAIH4vendu par Aldrich co. , qui elle, est claire,

afin de comparer les exces enantiomerique obtenus avec Ie BINAL-H et l'Alpine-Borane

pour l'alcool 8.

En vue d'ecourter de deux etapes la synthese de l'alcool 8 (voir schema 2) il

fut tente d'obtenir un bromure allylique terminale «E)-I-bromo-hept-2-en-6-yne) a partirde l'alcool 3. Pour ce faire on fit reagir l'alcool avec du CBr4 et PPh3 dans Ie

dichloromethane pour obtenir Ie bromure desire par mecanisme SN2', mais ce fut plutot

Ie mecanisme SN2 qui intervena donnant ainsi un bromure interne Ie 3-bromo-hept-l-en-

6-yne avec un rendement de 70%. n fut tenred'obtenir ce bromure allylique en faisant

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-- ~- -- -. -------

7

reagir Ie meme alcool aye du OMS et du NBS dans Ie dichloromethane en agitant a

temperature de la piece pendant 24 heures.Pour cette reaction Ie 3-bromo-hept-l-en-6-

yne est obtenu majoritairement avec un rendement de 17%et Ie bromure desire «E)-l-

bromo-hept-2-en-6-yne) minoritairement avec un rendement de,7%. L'etape suivant laformation du bromure allylique etait une alkylationutilisant Ie 2-butyn-3-one, et Ie LOA

comme base pour obtenir Ie (E)-undeca-6-en-l,1O-diyn-3-one.Mais it fut impossible de

faire cette alkylation, la cetone se decomposantdes l'ajout de la premiere goutte de LOA

Ie proton qui devait etre arrache ayant un pKa trop pres du proton de la triple liaison.

Plusieurs essais furent fait a diverses temperature (25, 0, -60 et -780C) et eurent les

memes resultats. Oevant ce probleme l'idee de cette nouvelle voie pour obtenir l'alcool 8fut abandonnee.

-- -----

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8

Experimental section

All reaction in this experimental section were run under nitrogen atmosphere. All

solvents used were of reagent grade and anhydrous solvents were dried prior to usel5.Infrared spectra were recorded in CHCl3 on a Perkin Elmer PARAGON 1000Infrared

spectrophotometer and are reported in reciprocal centimeters. 1H NMR were run inCDCl3 and were recorded on a AC-300 (300 MHz) spectrophotometer and the splitting

patters were designated as a s=singlet, d=doudlet, t=triplet, q=quartet, qui=quintet and

m=multiplet Be were run in CDCl3 on Broker AMX 360 (90MHz) spectrophotometer.

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9

1. synthese du (S)-(E)-undeca-6-en-1.10-diyn-3-one

4 -pentynal

~H21

To a -600C solution of dimethyl sulfoxide (1.56 mL , 22 mmol) in dichloromethane (110

mL) was added oxalyl chloride (1.92 mL , 22 mmol ) . The resulting mixture was stirred

for 15 minutes, then commercial 4- pentynol (1.85 mL, 20 mmol) was added over a 2

minutes period. The resulting mixture was then stirred for a further 20 minutes, at wich

point triethylamine (8.35 mL, 60 mmol) was added. The reaction mixture was then

allowed to warm to room temperature, and was stirred for 45 minutes. The mixture was

then filtered to remove the triethylamine salt and then the resulting clear solution was

quenched with IN HCI (60 mL). The layers were then separated and the aqueous layer

was washed twice with dichloromethane.Thecombined organic layers were then dried

over anhydrous magnesium sulphate, filtered, concentrated by rotary evaporation, and

used in the next reaction without further purification. The product was obtened as a

yellow oil.

-- ----

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- - - -- - - - - - - - --

10

hept-l-en-6-yn-3-o1

~H2 3

To a -780 solution of 4-pentynal (20 mmol, 1.642 g) in diethyl ether (150 mL) was added

vinylmagnesium bromide (1.0 M solution in TIIF, 30 mmol, 30 mL). After stirring for

two hours, the reaction was quenched with IN HCI (50 mL). The organic and aqueous

layers were then separated, and the aqueous layer was washed twice with diethyl ether.

The combined organic layers were then dried over magnesium sUlfate,fIltered, and

concentrated by rotary evaporation. After chromatrography of the residue over silica gel

using a 3:1 mixture of hexane:ethyl acetate, the product was obtained a a pale yellow oil

in a yield of73% (1.61g, yield measured from the commercial pe~tynol).

1H NMR (300 MHz, CDCI3) 0 5.81(ddd, J=17.2, 10.4,6.1, Hz, 1H) ,5.22 (dt, J=17.2,

1.4 Hz, 1H), 5.08(dt, J=IO.4, 1.3 Hz, 1H),4.22(qt, J=6.5, 1.2 Hz, 1H), 2.25(qd, J=7.5, 2.6

Hz, 2H), 2.16(s,lH), 1.94(t, J=2,7 Hz, 1H), 1.69(q,J=6.6 Hz, 2H)

13C NMR (90 MHz, CDCI3) 0 140.2(d), 115(t), 83.8(d), 71.6(d), 68.7(s), 35.1(t), 14.5(t)

IR(CHCl3) 3606, 3298, 3018, 2932, 2403, 1427, 1215cm-1

MS (CI;m/e, relative intensity) 109 (M-H, 20), 95(32)Exact mass (CI) m/e calculated for C7H100 (M-H) : 109.0653, found:109.0657

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11

ethyl (E)-non-4-en-8-ynoate

~OH

3

CH3C(OEtbC2HsC02H..

toluenereflux

0...............IIo

4

To toluene (250 mL) was added: hept-1-en-6-yn-3-01 (4.18 g, 38 mmol), triethyl

orthoacetate (35 mL, 190 mmol) and propionic acid (0.58 mL, 7.6mmol). The mixture

was then heated to reflux and stirred for 16hours. Following removal of the solvents by

rotary evaporation, the residue was chromatogrphed over silica gel using a 3:1 mixture of

hexane:ethyl acetate as an eluent. The product was isolated as a pale yellow oil in a yield

of 81% (5.51g). The residue can be also purified by distillation under reduce pressure.

1HNMR(300MHz,CDCI3)()5.45(q,J=1.7Hz,2H),4.07(q,J=7.1Hz,2H),2.31-2.28(m, 4H), 2.17-2.16(m,4H), 1.90(t,J=2.5Hz, 1H), 1.2(1,J=7.1 Hz; 3H)

13C NMR (90 MHz, CDCI3) () 173(s), 129.6(d), 129.2(d), 83.8(d), 69(s), 60.1(t), 34(t),

31.3(t),27.7(t), 18.6(t), 14.1(q)IR(CHCI3) 3307, 3028,2990,2932,2855, 1725, 1224, 1210,970 cm-1

MS (CI;m/e,relative intensity) 198(M+18,22), 181(M+H,100), 135(132)

Exact mass (CI) m/e calculated for C11 H1602 (M+l) 181.1228, found:181.1231

--

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- - - - - - -- - - - - - --

(E)-non-4-en-S-ynal

4 5

o

- - -

12

H

To a -7S0C solution of ethyl (E)-non-4-en-8-ynoate(920 mg, 5.1 mmol) in diethyl ether

(50 mL) was added 0.97 M diisopropylaluminumhydride in hexane (6.3mL, 6.1 mmol).

After the mixture was then stirred for 90 minutes, the reaction was quenched with IN

HCI at -780C. The mixture was then allowed to warm to room temperature. Following

separation of the organic and aqueous layers, the aqueous layer was washed twice with

diethyl ether. The combined organic fractions were then dried over anhydrous

magnesium sulfate, f1lteredand the solvent was removed by rotary evaporation. The

residue was then chromatographed over silica gel using a 3:1 hexane:ethyl acetate as an

eluent The product was obtained as a colourless oil in a yield of 92% (640mg).IH NMR (300 MHz, CDCI3) B 9.75(s,IH), 5.44(m, 2H), 2.44(t, 1=7.2 Hz, 2H), 2.3-

2.26(m, 2H), 2.16-2.12(m, 4H), 1.90(t,1=2.5Hz, IH)

13C NMR (90 MHz, CDCI3) B202(d), 129.4(d), 129.3(d),83.7(d), 68.5(s), 43.2(t),

31.3(t),24.9(t), 18.6(t)

IR(CH03) 3307, 3026, 2917, 2852, 2097, 1682, 1442, 1404,969 cm-l

MS (CI;m/e, abundance), 135(M-H,40000), 107(160000)

Exact mass (CI) m/e calculated for C9H120 (M-H): 135.0810, found: 135,0809

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13

(E)-undec-6-en-l.lO-diyn-3-ol

H == MgBr_.-THF -aOc--r.t.o

5 6

To a OOCsolution of (E)-non-4-en-8-ynal (1.04g,7.6mmol) in THF (75 mL) was added

0.5M ethynylmagnesium bromide in THF (16mL, 8.0mmol). The mixture was then

allowed to warm to room temperature and was stirred for 2 hours. The reaction was then

quenched with IN HCl. After separati<;>nof the organic ~d aqueous layers, the aqueous

layer was washed twice with diethyl ether. The organic layers were then combined,

dried over anhydrous magnesium sulfate and fIltered. Following removal of the solvent

by rotary evaporation, the residue was chromatographedover silica gel using a 3:1

mixture of hexane:ethyl acetate as an eluent to afford the product as a colourless oil in a

yield of 87% (1.07g)

IH NMR (300 MHz, CDCI3) 0 5.55-5.43(m, 2H), 4.37(td, J=6.5, 2.1 Hz, IH), 2.45(d,

J=2.2 Hz, IH), 2.23-2.14(m, 6H), 1.94(t, J=2.4 Hz,IH), 1.83-1.73(m,3H)

BC NMR (300MHz, CDCl3) 0 130.4(d), 129.2(d), 84.7(d), 84(d), 73(s), 68.6(s), 61.5(d),

37(t), 31.4(t), 27.9(t), 18.7(t)IR(CHCI3) 3606, 3307, 3030, 2931, 2852, 2117, 1433, 1248,970 cm-1

MS (CI;m/e, relative intensity), 161(M-H, 1), 105(72),91(78)Exact mass (CI) m/e calculated for C11H140 (M-H):161.0966, found:161.0964

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-- - -- -- - - - - - -- --

14

(E)-undeca-6-en-l.l O-diyn-3-one

~ De~s-~artinpenodln~_

OH CH2CI2r.t. o

6 7

To a solution of ,(E)-undeca-6-en-l 1O-diyn-3-01(94 mg, 058 mmol) in dichloromethane

(5mL) was added Dess-Martin periodinane (271 mg, 0.64 mmol). After stirring for 60

minutes, the reaction was quenched with a solution of 5% sodium bicarbonate and 5%

sodium bisulfite in water. The mixture was then stirred vigorously for 30 minutes, or

until the aqueous and organic layers were clear. The organic and aqueous layers were

then separated, and the aqueous layer was washed twice with dichloromethane. The

combined organic fractions were dried over anhydrous magnesium sulfate, f1lteredand

concentrated by rotary evaporation. The residue was then chromatographed over silica gel

using a 5:1 mixture of hexane:ethyl acetate as an eluent to afford the product as a pale

yellow oil in a yield of 78% (72mg).

INMR (300 MHz, CDCI3) 0 5.55-5.45(m, 2H), 3.20(s,IH), 2.63(t, J=7.4 Hz, 2H), 2.37-

2.30(m, 2H), 2.2-2.17(m,4H), 1.92(t, J=2.5 Hz, IH)13C NMR (90 MHz, CDCI3) 0 186.6(s), 129.8(d), 83.8(d), 81.3(d), 78.6(s), 68.6(s),

45(t), 31.4(t), 26.5(t), 18.6(t)IR(CHCI3) 3301,3026,2917,2852,2097, 1692, 1442, 1403,969 cm-l

MS (CI;m/e, relative intensity) 178(M+18, 100), 161(M+H,5), 159(M-H, 10)

Exact mass (CI) m/e calculated for CI1H120 (M-H):159.081O,found:159.0813

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15

(S)-(E)-undeca-6-en-1.1O-diyn-3-o1

Alpine-Borane~

aOe'-r.t.o

7 8

To a OOCsolution of Alpine borane 0.5 M in TIiF (5.24mL, 2.62 mmol) was added (E)-

undeca-6-en-l,1O-diyn-3-one (300mg, 1.87mmol). Then the solution was allowed to

warm to room temperature and was stirred for 14hours. Then, was added

propianaldehyde (0.14mL)and the mixture was stirred for 1 hour. The pinene was then

removed under vacuum at 400C (2 hours). To the residue was added THF (1.3mL),NaOH 3M (0.98mL), H202 30 % (0.98 mL) and the mixture was stirred for 3 hours at

40 0C. After the separation of the organic and aqueous layers, the aqueous layer was

washed twice with diethyl ether. The organic layers were then combined, dried over

anhydrous magnesium sulphate and filterd. Following removal of the solvent by rotary

evaporation, the residue was chromatographedover silica gel using a 15:1 mixture of

hexane:ethylacetateas an eluentto affordtheproductas a paleyellowoil in a yieldof .

70% (200mg). An enantiomeric excess of 93.2% was determined by 19F NMR analysis

of the diastereomeric mixture of Mosher's ester and these analysis revealed that the ratioof (S) -alcool to (R) - alcool was 96.6:3.4.

IH NMR (300 MHz, CDCI3) 0 5.55-5.43(m, 2H), 4.37(td, J=6.5, 2.1 Hz, IH), 2.45(d,

J=2.2 Hz, IH), 2.23-2.14(m, 6H), 1.94(t,J=2.4 Hz,IH), 1.83-1.73(m,3H)

13C NMR (300MHz, CDCI3) 0 130.4(d), 129.2(d), 84.7(d), 84(d), 73(s), 68.6(s), 61.5(d),

37(t), 31.4(t), 27.9(t), 18.7(t)

IR(CHCI3) 3606, 3:107,3030, 2931, 2852, 2117, 1433, 1248,970 cm-1

MS (CI;m/e, relative intensity),.161(M-H, 1), 105(72),91(78)Exact mass (CI) m/e calculated for CUH140 (M-H):161.0966, found:161.0964

..

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- - - - - -

16

Prl S .-

(E)-undeca-6-en-1.10-diyn-3-01

* .~DMAP, DCC

CH2CI2OOC--r.t.

8 16

*=(S)-( -)-a-methoxy-a-(trifluoromethyl)phenyl acetic acid

To a OOCsolution of (S)-(E)-undeca-6-en-l,1O-diyn-3-01(150mg, 0.93 mmol) in

dichloromethane were added (S)-(-)-a-methoxy-a-( trifluoromethyl)phenyl acetic acid

(218mg, 0.93 mmol) andDMAP (11.66mg,0.095 mmol). The resulting mixture was

stirred for 30 minutes, then DCC (192mg, 0.93 mmol) was addedand the mixture was

allowed to warm to room temperatureand stirred for 2 hours. Then the mixture was

fIltered and the solution was concentratedby rotary evaporation.Then the residue was

dissolved in the smallest amount of dic~loromethaneand ~ltered again. The solvant was

removed by rotary evaporation and theproduct waschromatographedover silica gel

using a 3:1 mixture of hexane:ethylacetate,the product was isolated asa colourless oil in

a yield of 71%(269mg).Analysis of 1Hand 19p NMR revealed that the ratio of (S, S) to

(R,S) ester was 96.6:3.4;thus the starting (S)-alcool had an enantiomeric excess of 93.2%.

1H NMR (300 MHz, CDCI3) ()7.57-7.51(m, 2H), 7.43-7.38(m, 3H), 5.56-5.51(m, 1H),

5.45-5.40(m, 2H), 3.60(s, 3H), 2.55(d, J=2.2Hz), 2.25-2.17(m,6H), 1.97(t,J=2.4 Hz, 1H),

1.95-1.83(m,3H)

19p NMR (CD03) () -73.11 (s, integration=17.393, CP3 of (S,S)-isomer), -73.41 (s,

integration=O.61, CP3 of (R, S)-isomer)

IR(CHCI3) 3307, 3037, 3008, 2941, 2855, 2114,1756,1446,1239,1171,1118,1012,

760, 753, 638 cm-1

MS (CI;m/e, relative intensity), 396(M=18, 40), 189(100)

Exact mass (CI) m/e calculated for C21H2103P3 (M+18):396.1786, found: 396.1780

OH

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17

2. reactions diverses: bromure allylique et modeles

3-bromo-hept-l-en-6-yne

~OH

3

Ph3P,CBr4

CH2Ci2 ·-7SoC- r.t.

-~Br

9a

To a -780C solution ofhept-l-en-6-yn-3-o1 (250mg,2.33 mmol) in dichloromethane (15

mL) was added triphenyl phosphine (730mg, 3.03 mmol) and carbon tetrabromide

(lg,3.03 mmol).The mixture was then allowed to wann to room temperature and was

stirred for 1 hour. Then the solvent was removed by rotary evaporation and the residuewas dissolved in the minimal amount of dichloromethane and filtered over a silica

pad.The solvent was removed by rotary evaporation and the same procedure was repeated

again. The final residue was chromatographedover silica gel using as an eluent a mixture

of hexane:ethyl acetate 15:1. The product was isolated as a pale yellow oil in a yield of

70% (300mg).

IHNMR (300 MHz, CDCI3) B6.0 (m, IH), 5.28(d, J=18 Hz~IH), 5.1(d, J=8.9 Hz, IH),

4.63(q, J=7.2 Hz, IH), 2.43-2.33(m, 2H), 2.2-2.1(m, 2H), 2.0(t, J=2.4 Hz, IH)IR(CHCI3) 3307, 3009,2933,2117, 1427, 1218,984,926 cm-1

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- - - - - - -- -- - - - -

18

3-bromo-hept-l-en-6-yne and (E)-I-bromo-hept-2-en-6-yne

~OH

3

~Sr

9a

To a OOCsolution of NBS (455mg, 2.56 mmol) in dichloromethane (3 mL) was added by

dropwise a solution of DMS (173.96, 2.80 mmol) in dichloromethane (2 mL) the mixture

was stirred for 10 minutes and then a solution of hept-l-en-6-yn-3-o1 (250mg, 2.33

mmol) in dichloromethane (2 mL) was added by dropwise. The mixture was then allowed

to warm to room temperature and was stirred for 24 hours.Then the solution was diluted

in diethyl ether and was pored into a mixture of brine and ice.The organic and aqueous

layers were then separated, and the aqueous layer was washed twice with diethyl ether.

The combined organic layers were then dried over anhydrous magnesium sulfate, fIltered,

and concentrated by rotary evaporation. The residue was then chromatographed over

silica gel using 3:1 mixture of hexane:ethyl acetate as an eluent. The product was

isolated as a colourless oil in a yield of 17%(70mg)of the internal bromide and

7%(30mg) of the terminal bromide.Internal bromide: IH NMR (300 MHz, CDCI3) 06.0 (m, IH), 5.28(d, J=18 Hz, IH),

5.1(d, J=8.9 Hz, IH), 4.63(q, J=7.2 Hz, IH), 2.43-2.33(m, 2H), 2.2-2.1(m, 2H), 2.0(t,

J=2.4 Hz, IH)

IR(CHCI3) 3307, 3009, 2933, 2117, 1427, 1218,984,926 cm-1

Terminal bromide:1H NMR (300 MHz, CDCI3)0 6.32(m, 2H), 3.95(d, J=5.7 Hz, 2H),

2.33-2.27(m, 4H), 1.98(t, J=2.5 Hz, IH)

IR(CHCI3) 3307, 2999, 2952, 2913, 2855, 2117, 1460, 1205,960 cm-1

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19

hept-l-en-6-yn-3-ethanoate

~OH

3

AC20, Et3N ...

DMAPCH2CI2 0°

~OAe

10

To a OOCsolution of hept-l-en-6-yn-ol (250 mg, 2.27 mmol) in dichloromethane (5 mL)

was added acetic anhydride (463 mg, 4.54 mmol), triethylamine (575 mg, 5.68 mmol)

and DMAP (58 mg, 0.454 mmol). The mixture was then allowed to warm to room

temperature "andstir 16hours. Then the mixture was quenched with IN HCI .Folowingseparation of the organic and aqueous layers, the aqueous layer was washed twice with

dichloromethane. The combined organic layers were washed with a solution of sodium

bicarbonate in water and then were dried over anhydrousmagnesium sulphate, filtered,

and the solvent was removed by rotary evaporation.The residue was then

chromatographed over silica gel using a 5:1 mixture of hexane:ethyl acetate as an eluent.

The product was obtained as a colourless oil in a yield of 60% .IH NMR (300 MHz, CDCI3) B5.78(ddd, J=17.1, 10.4,6.2 Hz, IH), 5.38-5.18(m, 38),

5.23(td, J=6.0, 2.5 Hz, 2H), 2.17(s,3H), 1.98(t,J=2.5 Hz, IH), 1.85(m, 28)IR(CHCI3) 3308, 3026, 2959, 2930, 2119,1733, 1432, 1373, 1248, 1212, 1030 em-1

MS (CI;m/e, abundance), 151(M-H, 1000), 137(M-CH3,60000),109(110000)

Exact mass (CI) m/e calculated for C9H1202 (M-H): 151.0759, found: 151.0763

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- - -- - - - ------- ------

20

l-indanone

oH Dess-Martin 0~ periodinane ~VLJ CH2CI2. VLJ

r.t11 12

To a solution of l-indanol (lg, 7.45 mmol) in dichloromethane (60mL) was added Dess-

Martin periodinane (3.47g, 8.195mmol).After stirring for 5 hours, the reaction was

quenched with asolution of 5% sodium bicarbonate and 5% sodium bisulfite in water.

The mixture was then stirred vigorously for 30 minutes, or until the aqueous and

organic layers were clear. The organic and aqueous layers were then separated, and the

aqueous layer was washed twice with dichloromethane.The combined organic fractions

were dried over anhydrous magnesium sulfate, filtered and concentrated by rotary

evaporation. The residue was then chromatographedover silica gel using a 3:1 mixture of

hexane:ethyl acetate as an eluent to afford the product as a colourless oil in a yield of83% (80g).

IH NMR (300 MHz, CDC13)0 7.76(d, 1=7.2 Hz, IH), 7.58(t, 1=7Hz, IH), 7.47(d, 1=7.2

Hz, IH), 7.36(t, 1=7.1 Hz, IH), 3.15(t, 1=6.0 Hz, 2H), 2.6(t, 6.1 Hz,2H)IR(CHCI3) 3019,2922,2865, 1710, 1605, 1436, 1205cm-1

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21

I-tributylstannyl-pent-l-en-5-o1

~OHreflux

BU3S~OH

131

To a solution of 4-pentynol (336mg, 4 mmol) in benzene (25 mL) were added Tribut)'ltin

hydride (1.28g, 4.4 mmol) and AIBN (131.2 mg, 0.8 mmol). The mixture was then heated

to reflux and stirred for 2 hours. Then to the mixture were added water and diethyl

ether. The organic and aqueous layers were then separated and the aqueous layer was

washed twice with diethyl ether. The combined organic layers were then dried over

anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation. After

chromatography of the residue over silica gel, using a 3:1 mixture of hexane:ethyl acetate

as an eluent, the product was obtained as a colourless oil in a yield of 90% (1.15g) ;67%

of cis product and 33% of the trans product (finded by NMR).

cis product: IH NMR (300 MHz, CDCI3) B6.6-6.47(m, IH), 5.83(d, J=IO.1 Hz, IH),

3,67(t, J=6.5 Hz, 2H), 2.l1(q, J=7.6 Hz, 2H), 1.67(qui, J=6.8 Hz, 2H), 1.52-1.44(m, 6H),1.33-1.26(m, 7H), 0.93-0.83(m, 15H)

trans product: IH NMR (300 MHz, CDCI3) B5.95(m, 2H), 3.63(t, J=6.5 Hz, 2H),

2.22(m, 2H), 1.67(qui, J=6.8 Hz, 2H), 1.52-1.44(m,6H), 1.33-1.26(m, 7H), 0.93-0.83(m,15H)

IR(CHCI3) 3625, 3461, 3009, 2960, 2836, 1600, 1460, 1070-990cm-1

MS (CI; m/e, relative intensity) 319(M+-C4H9, 100), 318(M-C4H9,35), 263(35) .

Exact mass (CI) m/e calculated for C13H270Sn (M-C4H9):318.1084, found:318.1081

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--------- - - - - -- -

22

7-(t-butyldimethylsiloxy )-hept- 3-yn- 2-01

o

EtMgBr/ ~H

~OTBDMS TUI:: .HO~TBDMSr.t

14 15

To a solution of 3-(t-butyldimethylsiloxy)-(E)-undeca-6-en-l,IO-diyne(198mg, 1

mmol) in THF was added ethyl magnesium bromide 2.8 M (0.46 mL, 1.3 mmol). Themixture was then heated to reflux and stirred for 2 hours. Then the mixture was cooled to

OOCand acetaldehyde was added. The mixture was then allowed to warm to room

temperature and stirred for 2 hours. Then to the mixture were added NH4Cl and diethyl

ether. The organic and aqueous layers were then separated and the aqueous layer was

washed twice with diethyl ether. The combined organic layers were then dried over

magnesium sulfate, filtered, and concentrated by rotary evaporation. The residue was

chromatographed over silica gel using a 10:1 mixture of hexane:ethyl acetate, the

product was isolated as a pale yellow oil in a yield of70%(169mg)IH NMR (300 MHz, CDCI3) (54.5(m, IH), 3.68(t, J=6.1 Hz, 2H), 2.28(td, J=7.1, 2.0 Hz

IH), 1.70(qui, J=6.3 Hz, 2H), 1.43(d,J=6.6 Hz, 3H), 1.4(s, 9H), 0.05(s, 6H)

IR(CHCI3) 3605, 3500-3400, 2955, 2858, 2341, 2243, 1471, 1104, 1075 cm-1

MS(CI; m/e, relative intensity), 243(M+H, 5), 260(M+18, 5), 225(100)Exact mass (CI) m/e calculated for C13H2602Si (M-H): 241.1624, found: 241.1617

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23

REFERENCES

1) Pine, Stanley H., Organic chemistry, 5e edition, McGraw Hill, New-York, 1987

2)Brown, H.C.;Ramachandran, P.V.;Chandrasekharan,J., J.Org.Chem., 1985,50,5446

3)Noyori, R.;'Tomino, Y;Nishizawa, M., J. Am.chem.Soc., 1984, 106,6709.

4)Brown, H.C.;Ramachandran, P.V.;Chandrasekharan,J., J.Org.Chem, 1986,51,3396.

5)Midland, M.M.;Kazubski, A., J.Org.Chem., 1982,47,2816.

6)Midland, M.M.;McLoughlin, J.I., J.Org.Chem., 1984,49, 1317.

7)Midland, M.M., et aI.,J.Am.Chem.Soc., 1979,2352.

8)Midland, M.M., et aI.,Tetrahedron, 1984,40, 1371.

9)DaIe, J.A.;DulI, D.L.;Mosher, H.S., J.Org.Chem., 1969,34,2543.

IO)DaIe,J.A.;Mosher, H.S., J.Am.Chem.Soc., 1973,95,512.

ll)Brown, H.C.; et aI.,J.Org.Chem., 1987,52,5406.

12)Noyori, J.;et aI., J.Am.Chem.Soc., 1984, 106,6717.

13)Nyori, J.;et aI., Tetrahedron Letters, 1981,22,247.

14)Chong, J.M.;Chan, P.C.-M., J.Org.Chem., 1980,53, 5586.

15)Perrin, D.D.;Armarego, W.L.F., Purification of Laboratory Chemicals. 3rd edition,Pergamon Pless, Great Britain, 1989.

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