Zafar Qureshi

Total Synthesis of (+)‐Linoxepin by Utilizing the Catellani Reaction

Lignans are a diverse class of plant-derived natural products belonging to the phytooestrogen family. They have long been used as herbal remedies for pain, rheumatoid arthritis, and warts.1 However, more recently, lignans exhibiting immunosuppressive activity, tumor growth inhibition, and anti-fungal properties have been used in disease therapy, such as the anticancer agent etoposide.2

Rhodium-Catalyzed Asymmetric Arylation of Diarylmethylamines

Significance: Triarylmethanes are an important class of compounds that are useful in medicinal chemistry and materials science. Reports on their asymmetric synthesis include cross-coupling (B. L. H. Taylor et al. Angew. Chem. Int. Ed. 2013, 51, 7790), selective oxidation (B. F. Shi et al. Angew. Chem. Int. Ed. 2008, 47, 4882) and Friedel– Crafts reaction (M.-H. Zhuo et al. Org. Lett. 2014, 16, 1096). The authors report a rhodium-catalyzed 1,4-addition strategy of an o-quinone methide generated in situ for the synthesis of chiral triarylmethanes. Comment: A variety of triarylmethanes were generated using this strategy. Substitution of all three aryl groups were tolerated well, giving good to excellent enantioselectivities. One limitation was noted: the enantioselectivity was reduced for substrates with ortho-substitution on Ar1. The final products could also be deoxygenated through triflation followed by palladium-catalyzed hydrogenolysis. Selected examples: Ar1 N OH

Enantioselective Michael Addition Using a Nickel/Rotaxane Catalyst

Significance: In contrast to traditional ligands, rotaxanes can provide a more well-defined binding pocket leading to enhanced enantioenduction. The authors report the synthesis of the above [2]rotaxane along with its application as a ligand for a nickel-catalyzed Michael addition. Comment: Although the reaction with rotaxane was considerably slower than with a traditional diamine (27 vs. 2 days) the enantioenduction for the rotaxane was much higher in the nickel-catalyzed process. One drawback of this methodology is the high molecular weight of the ligand (1896 g/mol). On 0.2 mmol scale, 30 mg of nitro olefin requires 38 mg of ligand. NiBr2 (4.5–10 mol%) rotaxane (10 mol%)

Enantioselective Rhodium-Catalyzed Allylation of 2-Pyridones

Significance: Enantioenriched N-substituted 2pyridones are an important class of biologically active molecules. Their synthesis has been described starting from chiral electrophiles (Y.-Q. Fang et al. J. Am. Chem. Soc. 2010, 132, 15525) and chiral amines (Y. Yu et al. J. Nat. Prod. 2013, 76, 2226). The authors report a chiral allylation strategy beginning from 2-pyridones and allenes. Comment: Almost all substrates preferred N-allylation over O-allylation, except the 5-iodopyridone substrate. A 1:1 mixture of N/O-allylated products was observed in this case. Substitution on the allene component was also tolerated, including a tertiary alcohol. A decrease in N/O selectivity was observed for the substrate with a phthalamido group. [{Rh(cod)Cl}2] (5 mol%) ligand (10 mol%) phosphoric acid (5 mol%)

Enantioselective Zr-Catalyzed Carboalumination Plus Cu-Catalyzed Cross-Coupling

Significance: Deuterium-labeled chiral compounds can be excellent tools for probing reaction mechanisms. Commonly used strategies for their synthesis include the use of chiral auxiliaries in stoichiometric quantities (J. Haesler et al. Nature 2007, 446, 526). The authors present an asymmetric zirconium-catalyzed carboalumination. Following ee upgrades by lipase treatment, deuterium was incorporated to generate cryptochiral molecules (G. Zhang et al. J. Am. Chem. Soc. 2006, 128, 6026). Comment: The products of the zirconium-catalyzed reaction were produced in modest ee’s (80– 88%), which were then upgraded to >99% ee by lipase treatment. Introduction of deuterium was accomplished by treatment with LiAlD4 or via copper-catalyzed cross-coupling. The enantiomeric ratios were determined via Mosher’s method (see recent Review below).

Enantioselective Palladium-Catalyzed Allylic Dearomatization

Significance: Chiral α-acyloxy-1-arylethanols are an important class of useful structural motifs (R. S. Bhondwea et al. Bioorg. Med. Chem. Lett. 2012, 22, 3656). The authors report a palladium catalyzed enantioselective reduction of α-acyloxy-1arylethanones to access α-acyloxy-1-arylethanols in high enantioselectivities. Comment: The first synthesis of α-acyloxy-1arylethanols was achieved using a chiral diamine ligand and SnCl2 (T. Mukaiyama, K. Tomimori, T. Oriyama Chem. Lett. 1985, 1359). Then, the use of enzymatic methods for their synthesis with excellent enantioselectivities but moderate regioselectivity was reported (A. Manzocchi, A. Fiecchi, E. Santaniello J. Org. Chem. 1988, 53, 4405; T. Ema, Y. Sugiyama, M. Fukumoto, H. Moriya, J.-N. Cui, T. Sakai, M. Utaka J. Org. Chem. 1988, 63, 4996; R. Hayakawa, M. Shimizu, T. Fujisawa Tetrahedron Asymmetry 1997, 8, 3201). With a palladium catalyst and a bisphosphine ligand, the authors were able to show excellent selectivities for a variety of substrates. In addition, catalyst loadings could be lowered to 0.2 mol% without affecting enantioselectivity. EtOH–TFE (4:1, 0.1 M) 0 °C, 24 h

Rhodium-Catalyzed Asymmetric Transfer Hydrogenation

58 M . K . L E M K E , P . S C H W A B , P . F I SC H E R , S . TI SC H E R , M . WI T T , L . N O E H R I N G E R , V . R O G A C H E V , A . J Ä G E R , O . K A T A E V A, R . F R ÖH L I C H, P . M E T Z * ( TE C H NI SC H E U N I V E R S I T Ä T D R E S DE N U N D WE S T F ÄL I SC H E WI L H E L M S U N I V E R SI T Ä T M ÜN S T E R, G E R M A NY ; TO M S K P O L Y T E C H N I C U N I V E R SI T Y, R U S S I A ) A Practical Access to Highly Enantiomerically Pure Flavanones by Catalytic Asymmetric Transfer Hydrogenation Angew. Chem. Int. Ed. 2013, 52, 11651–11655.