Homopropargylic alcohols synthesis

Seeking to expand the scope of the transformation, Danheiser investigated the use of an a,/ -unsaturated ketone as the electrophilic component in the homopropargylic alcohol synthesis. The first reaction attempted was that of cyclohexenone (17) with silylallene 18 using TiCU as a Lewis acid catalyst. After treatment of the initial isolated product 19 with fluoride, a,y0-unsaturated ketone 20 was isolated as the major product. After verification of the structure of a,yff-unsaturated ketone 20, the course of the reaction could be deduced. 

These mesylates, in turn, can be converted to enantioenriched allenyltin, zinc, and indium reagents which add to aldehydes with excellent diastereo-and enantioselectivity to afford either syn- or anti-homopropargylic alcohols or allenylcarbinols (eq 2, 3, and 4).3 4 Adducts of this type serve as useful intermediates for the synthesis of polyketide and hydrofuran natural products.5... 

As an extension of this work, the same authors explored such methodology for the synthesis of 2,6-disubstituted dihydropyrans using secondary homopropargylic alcohols (Scheme 10, route E). Surprisingly, the treatment of pent-4-yn-2-ol and 3-methylbutanal in the presence of FeCls led to unsaturated ( )-(3-hydroxyketone and ( )-a,p-unsaturated ketone in 2.5 1 ratio and 65% yield, without any trace of the expected Prins-type cyclic product (Scheme 22) [36]. To test the anion influence in this coupling, FeCE and FeBrs were used in a comparative study for the reaction of pent-4-yn-2-ol (R = R" = H, = Me) and several aldehydes. A range of aldehydes except for benzaldehyde was transformed into unsaturated (3-hydroxy-ketones in moderate to good yields. 

Synthetic transformations of the products of the intramolecular bis-silylation have been examined. The five-membered ring products derived from homopropargylic alcohols were hydrogenated in a stereoselective manner (Scheme ll).90 Oxidation of the products under the Tamao oxidation conditions (H202/F /base)96 leads to the stereoselective synthesis of 1,2,4-triols. This method can be complementary to the one involving intramolecular bis-silylation of homoallylic alcohols (vide infra). 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

In 1993, Hayashi and co-workers reported a catalytic asymmetric synthesis of alle-nylboranes 256 by palladium-catalyzed hydroboration of conjugated enynes 253 (Scheme 4.66) [105]. Reaction of but-l-en-3-ynes 253 with catecholborane 254 in the presence of a catalyst, prepared from Pd2(dba)3 CHC13 (1 mol%) and a chiral mono-dentate phosphine ligand (S)-MeO-MOP 255 (1 mol%), gave an allenylborane 256. The ee of 256 was determined by the reaction with benzaldehyde affording the corresponding optically active homopropargyl alcohols 257 with up to 61% ee (syn anti= 1 1—3 1). 

Table 9.16 Synthesis of homopropargylic alcohols from B-allenyl-9-BBN.

An early synthesis of allenylzinc reagents employed a two-step procedure in which monosubstituted allenes were subjected to lithiation in THF with tBuLi at -90 °C and the resulting allenyllithium intermediates were treated with ZnCl2. The allenylzinc reagents thus generated react in situ with aldehydes to afford mainly anti homopropargyl alcohols (Table 9.46) [98],... 

The addition of allenyl metal reagents to aldehydes affords homopropargylic alcohols with contiguous OH- and Me-substituted stereocenters, which serves as a complementary approach to the aldol condensation for polyketide synthesis. Marshall has developed this method extensively and this work is the subject of a more detailed review (cf. Chapter 9) [50]. The applications of this method to the synthesis of naturally occurring compounds have also been wide-ranging and a few are highlighted below. 

Synthesis of homopropargylic alcohols To a solution of telluroallene (1.0 mmol) in THF (12 mL) under N2 at -78°C, n-BuLi (1.1 mmol) was added at once, followed by the immediate addition of benzaldehyde (1.0 mmol). The reaction was stirred for 1.5 h (monitored by TLC using hexane/AcOEt - 8 2). A saturated solution of NH4CI (3 mL) was added still at -78°C and then the reaction mixture was allowed to reach room temperature. After normal work-up the product was purified by flash chromatography using a mixture of hexane/ethyl acetate (8 2) as eluent. 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

Enantio- and diastereomerically pure homopropargyl alcohols 38 constitute an interesting class of compounds, which have frequently served as building blocks in natural product synthesis (Scheme 1.3.17) [25]. 

Scheme 1.3.17 Asymmetric synthesis of homopropargyl alcohols via a-elimination of alkylidene aminosulfoxonium ylides.

A range of electrophiles has been applied successfully, including I2, NCS, TMSC1, acid chlorides and aldehydes. The use of the latter allows the stereoselective synthesis of homopropargylic alcohols 34 (equation 14). 

Lin, M.-J. Loh, T.-P. Indium-mediated reaction of trialkylsilyl propargyl bromide with aldehydes highly regioselective synthesis of allenic and homopropargylic alcohols. /. Am. Chem. Soc. 2003, 325,13042-13043. 

An intramolecular Heck-carbonylation/cyclization of the vinyl iodide 881 provides the 5,6-dihydropyran-2-one 882 during a total synthesis of manoalide (Equation 354) <1997CC1139>. The reaction of but-3-yn-l-ol with diaryl sulfides and carbon monoxide in the presence of a palladium(O) catalyst leads to a novel thiolactonization and hence arylthiosubstituted 5,6-dihydropyran-2-one 883 (Equation 355). Similar results are obtained with diaryl diselenides (Equation 355) <1997JOC8361>. Hydrozirconation of O-protected homopropargylic alcohols followed by carbonyla-tion and quenching with iodine provides a simple route to 5,6-dihydropyran-2-ones <1998TA949>. 

Homopropargylic alcohols are readily available substrates that can be used for the synthesis of 7-lactones. Cul-catalyzed selenation with PhSeBr at the alkyne terminus affords alkynyl aryl selenides. These react with an excess of /i-toluenesulfonic acid monohydrate, in dichloromethane at 60°C, to form a selenium-stabilized vinyl cation intermediate. The cation is then intramolecularly trapped by the tethered hydroxyl group to afford a cyclic selenoketene acetal, which readily adds a molecule of water to give the 7-lactone products (Scheme 55) <2006SL587>. 

The asymmetric approaches include the preparation of the configurationally stable chiral aUenyltin starting from enantio-enriched propargyUc precursors. When submitted to transmetaUation with Sn, Bi or In Lewis acids before addition to the aldehyde, the homopropargyl alcohol is obtained in a 95 5 anti/syn ratio and in a 90% ee . On the other hand, the use of a chiral aUenyltin reagent, without prior transmetaUation, gives the syn adduct selectively (95 5) (equation 12) . However, the use of chiral aUenyltin and chiral aldehydes may lead to the same match/mismatch effect that was observed with allyltins . Both approaches were applied to the synthesis of macrolides subunits ° i . 

The ate complexes prepared from 4-tosyloxy-l-butyne and trialkylboranes also provides a selective synthesis of cyclopropyl ketones and homopropargylic alcohols simply by changing the reaction temperature (Eq. 53)... 

Homopropargylic alcohols ot-allenic alcohols. The synthesis of alkylallenes (5, 397) by the reaction of trialkylboranes and lithium chioropropargylide, ClCH2C=CLi (1), has been extended to these two systems. Thus addition of acrolein to the organoborane a can lead to either 2 or 3, depending on the temperature at which a is kept before reaction with the aldehyde (equation I). If the aldehyde is... 

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