- - - -
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
-- - - - -------- - -
- -- -- - --- -----
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%.
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
- - -
- - ----
schema 2:
.?'MgBr
Et20..-
-7aoe
~Br9b
recJudeur chirale~
schema 3:
- - - - -- - -
..
Base
:)'H
?..
o
8 OH
4
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
---- -- --
----- --- - - --
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
-- ~- -- -. -------
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.
-- -----
- -- --- - --
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.
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.
-- ----
- - - -- - - - - - - - --
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
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
--
- - - - - - -- - - - - - --
(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
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
-- - -- -- - - - - - -- --
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
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
..
- - - - - -
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
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
- - - - - - -- -- - - - -
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
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
- - -- - - - ------- ------
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
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
--------- - - - - -- -
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
23
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