Versatile building blocks with ability to participate in a diverse array of reactions

The past couple of decades have witnessed a surge in the popularity of allenes as viable building blocks for a wide variety of synthetic applications.1 Their versatility allows them to participate in nucleophilic and electrophilic additions, cycloadditions and cyclizations, as well as various palladium- and gold-catalyzed reactions. In addition, the allene is present in many bioactive natural compounds and pharmaceutical reagents.

Bolte and Gagosz have recently accomplished the hydroalkylation of allenyl ethers to generate various fused and spiro tetrahydrofurans and tetrahydropyrans when catalyzed by a gold(I) phosphite complex or Brønsted acid (Scheme 1). The Brønsted acid catalyzed reaction proceeds under mild conditions and in a stereoselective manner, forming two adjacent asymmetric centers. Interestingly, when the gold(I) catalyst is employed, the product selectivity is reversed and the fused product dominates.2

Hydroalkylation of allenyl-containing ethers

Scheme 1.Hydroalkylation of allenyl-containing ethers

A recent report from Poonoth and Krause described the cycloisomerization of allenic hydroxyl ketones to form 3(2H)-furanones by aqueous NaOH at room temperature (Scheme 2).3 The reaction proceeds smoothly without any heating or cooling, nor does it require any metal catalysts.

Cycloisomerization of allenes to form 3(2H)-furanones

Scheme 2.Cycloisomerization of allenes to form 3(2H)-furanones

The Krische group at the University of Texas at Austin has reported the ruthenium-catalyzed hydrohydroxyalkylation of 1,1-disubstituted allenes under various conditions to form quaternary centers with excellent levels of anti-diastereoselectivity (Scheme 3).4 Similarly, Lu and coworkers have devised an enantioselective [3+2] cycloaddition of allenes to acrylates to form cyclic scaffolds containing quaternary stereogenic centers (Scheme 4).5 Various amino acid based phosphines were found to catalyze the reaction with the O-TBDPS-D-Thr-L-tert-Leu-derived variant outperforming the others.

Hydrohydroxyalkylation of 1,1-disubstituted allenes

Scheme 3.Hydrohydroxyalkylation of 1,1-disubstituted allenes

Enantioselective [3+2] cycloaddition of allenes to acrylates

Scheme 4.Enantioselective [3+2] cycloaddition of allenes to acrylates

Ryu and coworkers have reported a regioselective radical bromoallylation of allenes that generates 2-bromo-1,5-dienes when AIBN is used as the initiator (Scheme 5)6. Under similar conditions, Kwon and coworkers have demonstrated the triphenylphosphine-catalyzed b’-umpolung addition of nucleophiles to activated a-alkyl allenoates to produce functionalized alkenes with high levels of E/Z selectivity (Scheme 6).7

Generation of 2-bromo-1,5-dienes via radical bromoallylation

Scheme 5.Generation of 2-bromo-1,5-dienes via radical bromoallylation

b’-Umpolung addition of nucleophiles to activated allenes

Scheme 6.b’-Umpolung addition of nucleophiles to activated allenes

Fujii, Ohno, and coworkers have recently disclosed the enantioselective total synthesis of (+)-lysergic acid and related indole alkaloids wherein a key feature of the synthesis is a Pd(0)-catalyzed domino cyclization of an allene that contains amino and bromoindolyl moieties (Scheme 7).8 This cyclization forms the C and D rings of the alkaloid skeleton and proceeds with good diastereoselectivity (dr = 92:8).

Pd(0)-catalyzed domino cyclization of allene in the synthesis of (+)-lysergic acid

Scheme 7.Pd(0)-catalyzed domino cyclization of allene in the synthesis of (+)-lysergic acid


Selected recent reviews: (a) Ma, S. Aldrichimica Acta 2007, 40, 91. (b) Brummond, K. M.; Chen, H. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, pp 1041-1089. (c) Aubert, C. et al. Chem. Rev. 2011, 111, 1954. (d) Zimmer, R. et al. Chem. Rev. 2000, 100, 3067. (e) Sydnes, L. Chem. Rev. 2003, 103, 1133. (f) Ma, S. Chem. Rev. 2005, 105, 2829. (g) Alcaide, B. et al. Chem. Soc. Rev. 2010, 39, 783. (h) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994..
Bolte B, Gagosz F. 2011. Gold and Brønsted Acid Catalyzed Hydride Shift onto Allenes: Divergence in Product Selectivity. J. Am. Chem. Soc.. 133(20):7696-7699.
Poonoth M, Krause N. 2011. Cycloisomerization of Bifunctionalized Allenes: Synthesis of 3(2H)-Furanones in Water. J. Org. Chem.. 76(6):1934-1936.
Zbieg JR, McInturff EL, Leung JC, Krische MJ. 2011. Amplification of Anti-Diastereoselectivity via Curtin?Hammett Effects in Ruthenium-Catalyzed Hydrohydroxyalkylation of 1,1-Disubstituted Allenes: Diastereoselective Formation of All-Carbon Quaternary Centers. J. Am. Chem. Soc.. 133(4):1141-1144.
Han X, Wang Y, Zhong F, Lu Y. 2011. Enantioselective [3 + 2] Cycloaddition of Allenes to Acrylates Catalyzed by Dipeptide-Derived Phosphines: Facile Creation of Functionalized Cyclopentenes Containing Quaternary Stereogenic Centers. J. Am. Chem. Soc.. 133(6):1726-1729.
Kippo T, Fukuyama T, Ryu I. 2011. Regioselective Radical Bromoallylation of Allenes Leading to 2-Bromo-Substituted 1,5-Dienes. Org. Lett.. 13(15):3864-3867.
Martin TJ, Vakhshori VG, Tran YS, Kwon O. 2011. Phosphine-Catalyzed ??-Umpolung Addition of Nucleophiles to Activated ?-Alkyl Allenes. Org. Lett.. 13(10):2586-2589.
Inuki S, Iwata A, Oishi S, Fujii N, Ohno H. 2011. Enantioselective Total Synthesis of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol by Palladium-Catalyzed Domino Cyclization of Allenes Bearing Amino and Bromoindolyl Groups. J. Org. Chem.. 76(7):2072-2083.