Synthesis of Homopropargylic Alcohols

Homopropargylic alcohols are important intermediates, as these structural units are present in a variety of natural products and biologically active compounds [1]. Synthesis of these compounds is generally accomplished by reactions of their organometallic equivalents using an array of metals (Mg, Li, Ti, Zn, Al, Sn, Si) [2]. However, their utility is limited due to their ambident nucleophilic nature, which makes them to react with electrophiles unselectively to produce a mixture of products. 

Brown and coworkers [3,4] discovered that B-allenyl-9-BBN [3] readily prepared from B-chloro-9-BBN [5] and allenylmagnesium bromide [6] (Eq. 6.13) undergoes a facile condensation with aldehydes and ketones to yield exclusively the corresponding homopropargylic alcohols in excellent yields [3, 4]. B-Alle- 

Carbonyl compound Reaction time Product(s) Yield (%) 

Unlike trialkylboranes, B-allenyl-9-BBN reacts with a,(3-unsaturated carbonyl compounds in 1,2-fashion to give, exclusively, the olefinic homopropargylic alcohols (Table 6.14) [3]. 

Carboxylic acid esters exhibit no reactivity in presence of benzaldehyde at room temperature. The comparative reactive data are summarized in Table 6.15. 

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

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. 

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). 

Reactions of chiral allenes proceed with a preference for the formation of the syn diastereomer. The stereochemical outcome of these reactions can be rationalized by invoking an open transition state model for the addition reactions (Figure 12), which depicts an antiperiplanar orientation of the chiral allenylsi-lane to the aldehyde carbonyl. In this model, steric repulsion between the allenyl methyl and the aldehyde substituent is most likely responsible for the destabilization of transition state (B), which leads to the anti (minor) stereoisomer. This destabilizing interaction is minimized in transition state (A). Table 5 illustrates representative examples and summarizes the scope of the regiocontrolled synthesis of homopropargylic alcohols using allenylsilanes. 

Danheiser, R. L., Carini, D. J., Kwasigroch, C. A. Scope and stereochemical course of the addition of (trimethylsilyl)allenes to ketones and aldehydes. A regiocontrolled synthesis of homopropargylic alcohols. J. Org. Chem. 1986, 51, 3870-3878. 

Keck and Yu have reported the enantioselective synthesis of homopropargylic alcohols in the reactions of aldehydes with allenylstannane 456, promoted by the BINOL-Ti(IV) catalyst 451. The allenylstannane 456 provided enantiomerically... 

Allenyltitanium systems are formed from propargyl halides or carbonates and a low-valent diisopropoxo-772-propene Ti(n) species. They are excellent reagents for the synthesis of homopropargyl alcohols by reaction with carbonyl compounds, as examples of carbon-carbon bond-forming processes.36,37... 

In a protocol, similar to synthesis of homopropargylic alcohol, allenylborane derived from 3-(tert-butyldimethylsilyl)-l-(trimethylsilyl)-l-propyne affords, on condensation with conjugated acetylenic aldehydes (R = -BuC=C and Ph-C=C), the diynic alcohols with high diastereoselectivities. The SR/RS RR/SS ratio is >98 2 (Scheme 6.19) [1] with both aldehydes. 

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... 

Alkynic intermediates serve as important functional groups in organic synthesis. Many important reactions exploiting the unique and versatile chemistry of the carbon-carbon triple bond have been devised over the last few years. A general strategy for the synthesis of substituted alkynes involves substitution and addition reactions of propargylic anion equivalents this approach is particularly well suited for the preparation of homopropargylic alcohols (Scheme 28). 

Zhang XY, Qu YY, Wang YY, Fan XS. Synthesis of 1,2-aUenic ketones through oxidation of homopropargyl alcohols with Cr03(cat.)/TBHP under MWI. Chin Chem Lett. 2011 22 268-271. 

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). 

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). 

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. 

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. 

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