Qinghua Bian

Highly Enantioselective Zinc/Amino Alcohol-Catalyzed Alkynylation of Aldehydes

Meeting the challenge: The zinc/amino alcohol catalyzed enantioselective addition of terminal alkynes to aldehydes is effective with both phenylacetylene and methyl propiolate, leading to chiral secondary propargyl alcohols with very high enantioselectivity (see scheme).

Highly Enantioselective Addition of Trimethylsilylacetylene to Aldehydes Catalyzed by a Zinc–Amino-Alcohol Complex

The enantioselective alkynylation of aldehydes is one of the most useful carbon–carbon bond-forming reactions for the preparation of chiral propargylic alcohols, which are versatile building blocks for fine chemicals, pharmaceuticals, and natural products. Accordingly, much progress has been made in the asymmetric addition of terminal alkynes to aldehydes, which has been established as a reliable platform for the efficient synthesis of a wide array of chiral propargylic alcohols. Various alkyne derivatives such as arylacetylene, alkylacetylene, ethynylcyclohexene, acetalacetylene, methyl propiolate, 1,3-diyne, and trimethylsilylacetylene have been used as the alkyne nucleophiles. Among these nucleophiles, trimethylsilylacetylene is highly attractive due to the potential application of the corresponding trimethylsilyl alkynol product. The product can be easily desilylated to give the corresponding terminal alkynol, which can further be used as the precursor to carry out the alkylation or the Sonogashira coupling for the synthesis of some natural products and useful chemicals. A variety of effective catalytic systems including amino-alcohol–Zn, iminoalcohol–Zn, hydroxyl-carboxyamide–Zn, proline-derived dinuclear Zn, bisoxazolidine–Zn, 1,1’-bi-2-naphthol (BINOL)–Ti, bisphosphine–Cu, sulfonamide-alcohol– Ti, and bis(oxazolinyl)phenyl–Ru have been developed for the addition of trimethylsilylacetylene to aldehydes. In particular, by using catalytic systems such as Trost s prolinederived dinuclear Zn, Wolf s bisoxazolidine–Zn, Pu s BINOL–Ti, Wang s sulfonamide alcohol–Ti, and Nishiyama s bis(oxazolinyl)-phenyl–Ru, excellent enantioselectivity (>90 % enantiomeric excess (ee)) can be achieved in the addition of trimethylsilylacetylene to aldehydes. Among the catalytic systems reported so far for the alkynylation of aldehydes, the amino-alcohol–Zn system is particularly noteworthy in terms of its operational simplicity and mild reaction conditions. The amino-alcohol–Zn catalytic system has attracted much attention since the pioneering contribution from Carreira and co-workers, who demonstrated that by using a combination of ZnACHTUNGTRENNUNG(OTf)2 and Nmethylephedrine, the addition of terminal acetylenes to aldehydes afforded the desired products in high yields and enantioselectivities. 12] However, to the best of our knowledge, no impressive amino-alcohol–Zn system (except for Trost s dinuclear Zn catalyst) for the alkynylation of aldehydes with trimethylsilylacetylene has been reported so far, therefore a new, generally applicable procedure using amino-alcohol–Zn would still be highly desirable. In this context, we conceived the possibility of introducing a new type of 1, 4-amino alcohol, based on the chiral cyclopropane backbone (1–3), which might serve as an excellent chiral ligand in the alkynylation of aldehydes with trimethylsilylacetylene. Herein, we report the highly enantioselective addition of trimethylsilylacetylene to a wide range of aldehydes catalyzed by the zinc complexes of chiral 1,4-amino alcohols. Recently we reported a series of chiral amino alcohols based on the cyclopropane backbone, which exhibited an advantageous combination of structural rigidity, low molecular weight on a well-defined and highly variable platform, and unusual bond angles. By using these amino alcohols in combination with dialkylzinc, the addition of dialkylzinc or some alkyne derivatives to aldehydes could be carried out with high enantioselectivity. 13] As a continuing effort to develop highly enantioselective alkynylation catalysts, we speculated that modification of the ligand structure, by introducing another chiral center on the side chain of the chiral cyclopropane backbone, might provide extra steric discriminations that may enhance the enantioselectivity. With this in mind, new chiral ligands 1, 2, and 3 were designed and synthesized by introduction of the (R)and (S)prolinols into the side chain of a chiral cyclopropane backbone by using a four-step reaction (Scheme 1). To increase the steric effect, the hydroxyl group in prolinol was protected with tert-butyldimethylsilyl (TBDMS) or tert-butyldiphenylsilyl (TBDPS). With the amino alcohols 1, 2, and 3 in hand, our initial attempts at amino-alcohol–Zn-catalyzed asymmetric addition of trimethylsilylacetylene to aldehydes commenced with the reactions of benzaldehyde and trimethylsilylacetylene. Table 1 presents the results of the model reaction between benzaldehyde and trimethylsilylacetylene, in which we established appropriate reaction conditions by screening [a] Z.-Y. Li, Dr. M. Wang, Dr. Q.-H. Bian, B. Zheng, J.-Y. Mao, S.-N. Li, Dr. S.-Z. Liu, Dr. M.-A. Wang, Dr. J.-C. Zhong, Dr. H.-C. Guo Department of Applied Chemistry, China Agricultural University 2 Yuanmingyuan West Road, Beijing 100193 (P.R. China) Fax: (+86) 10-62820325 E-mail : dr_zhongjiangchun@yahoo.com.cn hchguo@gmail.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100535.

Cobalt–Bisoxazoline-Catalyzed Asymmetric Kumada Cross-Coupling of Racemic α-Bromo Esters with Aryl Grignard Reagents

The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.

Highly enantioselective addition of 1,3-diynes to aldehydes catalyzed by a zinc-amino alcohol complex.

Asymmetric catalysis: A highly enantioselective and efficient procedure for the amino alcohol-zinc-catalyzed addition of 1,3-diynes to various aromatic, α,β-unsaturated, and aliphatic aldehydes has been developed. The present catalytic system was successfully applied in the concise synthesis of natural products such as (S)-strongylodiols A and B (see scheme).

Total Syntheses of (R)-Strongylodiols C and D

The first total syntheses of two marine natural products, (R)-strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy include the zipper reaction of an alkyne, the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed with Trosts ProPhenol ligand, and the Cadiot-Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a bromoalkyne.

Synthesis of Chrysogeside B from Halotolerant Fungus Penicillium and Its Antimicrobial Activities Evaluation

Chrysogeside B, a natural cerebroside, was efficiently synthesized from commercial feedstocks. The bioassays showed that compounds 4, 5 and 6 exhibited enhanced biological activities compared Chrysogeside B. Further studies revealed that free hydroxyl groups and glycosidic bond have significant impact on the antimicrobial activities. The synthesis of Chrysogeside B and analogues designed to allow identification of the features of this glycolipid required for recognition by tested bacteria and Hela cells is described.

Cobalt‐Catalyzed Enantioselective Negishi Cross‐Coupling of Racemic α‐Bromo Esters with Arylzincs

The first cobalt-catalyzed enantioselective Negishi cross-coupling reaction, and the first arylation of α-halo esters with arylzinc halides, are disclosed. Employing a cobalt-bisoxazoline catalyst, various α-arylalkanoic esters were synthesized in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield). A diverse range of functional groups, including ether, halide, thioether, silyl, amine, ester, acetal, amide, olefin and heteroaromatics is tolerated by this method. This method was suitable for gram-scale reactions, enabling the synthesis of (R)-xanthorrhizol with high enantiopurity. Radical clock experiments support the intermediacy of radicals.

Highly Enantioselective Addition of Phenylethynylzinc to Aldehydes Catalyzed by Chiral Cyclopropane-Based Amino Alcohols

The enantioselective addition of phenylethynylzinc to aldehydes catalyzed by a series of cyclopropane-based amino alcohol ligands 7 was investigated. The reactions afforded chiral propargylic alcohols in high yields (up to 96%) and with excellent enantioselectivities (up to 98% ee) under mild conditions. Furthermore, studies on the structural relationship show that the matching of the chiral center configuration is crucial to obtain the high enantioselectivity.