Regioselective preparation of tetrasubstituted alkenes from ketones using Krief's methodology as a key step for a straightforward synthesis of dienynes

Dienynes 2a-c bearing a silylated substituent (Si t BuMe 2 , SiMe 2 Ph, Si( i Pr) 3 ) at the terminal position of the 1,3-butadiene moiety are highly valuable compounds as they constitute the north part of polyunsaturated precursors to the taxane framework that we have reached through [2+2+2]/[4+2] cyclization strategies. They have been efficiently prepared over ten steps from the corresponding trialkylsilylchlorosilanes, the crucial step of these syntheses being the olefination of a ketone that was eventually successful via selenoacetals.


Introduction
In the past ten years, taxane diterpenoids have been one of the most challenging synthetic targets due to the unique tetracyclic structure which includes an eight-membered ring and a bridgehead double bond.They also display a high therapeutic potential. 1As a consequence, an impressive range of synthetic designs was proposed toward syntheses of taxol and its analogues; to date, six total syntheses have been reported. 2n this context and as part of our ongoing research program directed toward metal-catalyzed reactions and cascades for the elaboration of basic skeletons of natural products, 3 we have recently described an approach to the taxane framework. 4Indeed, a combination of a cobalt(I)mediated [2+2+2] cyclization and a [4+2] cycloaddition allows the formation of the tetracyclic skeleton of taxoids starting from highly functionalized polyunsaturated partners as depicted in Scheme 1.The link between the two unsaturated moieties 2 and 3 can be either an alkylated (-(CH 2 ) 4 -) or a silylated tether (-O-Si(iPr) 2 -O-) which ensures the chemo-and the regioselectivity of the [2+2+2] cyclizations between the three alkyne units.The success of these cycloaddition reactions was related to the presence of a sterically demanding substituent such as trialkylsilyl group at the terminal position of the 1,3-butadiene moiety which prevents some competitive cyclizations.If the preparation of dienyne moiety 2 with R = SitBuMe 2 of the precursor 1 is now quite efficient through the use of selenoacetals described by Krief, 5 it requires to adapt the reported procedures to the requisite substrates.In this paper, we report in details our efforts toward the preparation of a series of dienynes 2.

Results and Discussion
In order to evaluate the influence of the sterical demand of the silylated substituent at the terminal position of the 1,3 butadiene moiety on the course of the cyclizations, we envisioned to prepare the dienynes 2a-c with R = SitBuMe 2 , SiMe 2 Ph, Si(iPr) 3 starting from the corresponding E-3-trialkylsilyl-2-methyl-2-propen-1-ol 6a-c.Those were prepared following a procedure reported by our laboratory 6 which consists in the sequence -generation of the silyl allyl carbanion 7 from 2-methyl-3-trialkylsilyl-prop-1-ene 5a-c prepared quantitatively from 3-chloro-2-methylprop-1-ene and trialkylchlorosilane under Barbier's conditions, alkylation with dimethylchlorosilane and then chemoselective Tamao oxidation.Consecutive Swern oxidation 8 furnished the aldehydes 7a-c in high overall yield.The high steric hindrance brought by Si(iPr) 3 did not allow a regioselective deprotonation of 5c with Schlosser's base and two inseparable allylic alcohols 6c and 6c' were obtained as a 60:40 mixture in 50% yield (Scheme 2).In a first set of experiments carried out with aldehyde 7a, we envisioned to introduce in a straightforward manner the triple bond and the double bond according to Scheme 3. Indeed, the alkylation of 7a with copper(I) reagent 9 derived from (4-chlorobut-1ynyl)trimethylsilane prepared from the corresponding zinc derivative 10 furnished in presence of Et 2 O•BF 3 , alcohol 8a in 54% yield; it is worthy of note that this reaction is not reproducible.Subsequent oxidation led to enone 9a in 90% yield which was alkylated with isopropylmagnesium chloride in presence of 2 equivalents of HMPA to give tertiary alcohol 10a in 50% yield beside starting material.In the absence of HMPA, the reduction of the enone occured and the secondary alcohol was obtained admixed with 10a in a 1:1 mixture.Several attempts aiming at the elimination of tertiary alcohol 10a were unsuccessful and whatever the conditions we used, we were unable to get the desired diene.Two transformations were only observed in acidic media.Indeed, in presence of PTSA in refluxing benzene or Et 2 O•BF 3 in refluxing ether, 10a underwent a protodesilylation affording compound 11a.On the contrary, phosphorous pentoxide allowed dehydration of 10a leading to diene 12a.

Issue in
Considering the above results, two issues had to be addressed : (i) the introduction of the homopropargylic chain, (ii) the olefination of the ketone.To answer to the first item, we envisaged to alkylate the aldehydes 7a-c with an alkyl chain bearing a silylated ether which could be further transformed in a simple manner into an alkyne.Thus, addition of the aldehydes 7a-b to the lithio derivative of 3-(tert-butyldimethylsilyloxy)-1-iodo propane furnished the corresponding alcohols 13a-b in 90% and 70% respectively (Scheme 4).Swern oxidation led to the enones 14a-b in very high yields.The sequence -Swern oxidation, alkylation, Swern oxidation-from the 60:40 mixture of alcohols 6c and 6c' led to the corresponding enones 14c and 14c' in 75% overall yield with the same ratio.In order to produce efficiently the tetrasubstituted double bond, we next turned our attention to 2,2-bis(methylseleno)propane. 5,11Indeed, Krief et al. has reported that such reagents can be quantitatively reduced with n-BuLi to the α-selenoalkylithiums.Those are highly reactive toward aldehydes and ketones, leading to the hydroxyselenides which can be eliminated to highly substituted olefins.The use of such a reagent or its homologue 2,2bis(phenylseleno)propane has been already described by Williams 12 and Jenkins 13 in their approach to taxane model system.However, as far as we were aware, they had never been employed for the generation of a 1,3-butadiene moiety bearing a silylated group at the terminal position.Depending on the nature of the substituent on selenium, methyl versus phenyl, two procedures for the elimination of the hydroxyselenides are available.They consist in employing PI 3 14 or thionyl chloride respectively in presence of triethylamine in dichloromethane.
At the time we started this study, 2,2-bis(methylseleno)propane was commercially available but unfortunately its marketing disappeared and in spite of a generous gift from Krief's laboratory we were unable to run the whole study.Therefore, we decided to employ 2,2bis(phenylseleno)propane which was prepared according to the work of Krief with phenylselenol and acetone in presence of a Lewis acid. 5 However, we slightly modified the procedure by using Et 2 O•BF 3 in chloroform instead of TiCl 4 or ZnCl 2 .In that case, treatment with aqueous NaOH and evaporation of the solvent furnished 2,2-bis(phenylseleno)propane in 81% yield.
Whatever the reagent that we used, the olefination of the enones 14a-c were very successful and after subsequent deprotection of the silylated ethers, the dienols 15a-c were obtained in 63% to 87% yield over three steps according to Scheme 5.It is noteworthy that the mixture of enones 14c and 14c' was converted only into the most stable dienol 15c.

Conclusions
In summary, we have developed an efficient preparation of dienynes 2a-c.They were obtained in ten steps from the corresponding commercially available chorosilanes in 27% overall yield (2b).This required the optimization of each step especially the olefination of the ketone which was particularly successful through the use of selenoacetals and Krief' methodology.The dienynes 2a-c are highly valuable compounds as they constitute the north part of functionalized polyunsaturated precursors to the taxane framework that we have reached through the [2+2+2]/[4+2] cyclizations strategy.

Experimental Section
General Procedures.Reactions were carried out under argon in flame-dried glassware, with magnetic stirring and degassed anhydrous solvents.All commercially available reagents were used without further purification unless otherwise noted.All solvents were reagent grade and distilled under positive pressure of dry nitrogen before use.THF was distilled from sodium/benzophenone. Solid reagents were dried in vacuo (0.5 to 0.1 mmHg).Thin layer chromatography (TLC) was performed on Merck 60 F 254 silica gel.Merck Geduran SI 60 Å silica gel (35-70 µm) was used for column chromatography according to Still's method. 17

3-(Dimethylphenylsilyl)-2-methyl-propenal (7a) 1. 3-(dimethylphenylsilyl)-2-methyl-prop-2-en-1-ol (6a).
To a cooled (0°C) suspension of 9.19 g of t-BuOK (81.9 mmol, 1.1 equiv) in 85 mL of hexane were added dropwise 39 mL of n-BuLi (solution 2.1 M in hexane, 81.9 mmol, 1.1 equiv).The solution was stirred for 10 min at this temperature and then cooled to -78 °C.After dilution of the reaction mixture with 57 mL of Et 2 O, a solution of 14.2 g of 5a (74.5 mmol, 1.0 equiv) in 57 mL of Et 2 O was added.Then, the mixture was warmed to room temperature and stirred for 4h.After being cooled to -78 °C, 9.1 mL of the chlorodimethyl-silane (81.9 mmol, 1.1 equiv) were added.After 1h, the solution was diluted with Et 2 O and washed successively with a saturated solution of NH 4 Cl and brine, dried over MgSO 4 , filtered and concentrated in vacuo.The resulting compound was used directly in the oxidation procedure without further purification.
To a solution of the preceding compound (74.5 mmol, 1.0 equiv) in 310 mL of THF and 310 mL of MeOH were added 22.4 g of KHCO 3 (223.5 mmol, 3.0 equiv) and 22.