ABSTRACT
An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl(3)·2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed.
Subject(s)
Alkenes/chemistry , Phenols/chemical synthesis , Catalysis , Hydrogenation , Molecular Structure , Phenols/chemistry , StereoisomerismABSTRACT
The enantioselective conjugate addition of alkynyl nucleophiles has been a long-standing challenge in synthetic chemistry. This paper describes a highly practical asymmetric conjugate alkynylation of Meldrum's acid-derived acceptors using cinchonidine (<$100/kg) as the chiral mediator. The process provides practical access to chiral beta-alkynyl acids. Noteworthy attributes of the method are its broad scope, high functional-group compatibility, and ease of scalability.
Subject(s)
Alkynes/chemical synthesis , Carboxylic Acids/chemical synthesis , Dioxanes/chemistry , Alkynes/chemistry , Carboxylic Acids/chemistry , Molecular Structure , StereoisomerismABSTRACT
A variety of 4-oxobutenamides 1 were subjected to rhodium-catalyzed conjugate addition with arylboronic acids providing high regio- and enantioselectivity (97:3 to >99:1, >96% ee) and moderate to excellent yields (54-99%). The key to high selectivity is the use of sterically demanding P-chiral diphosphines, such as Tangphos or Duanphos. The product oxobutanamides 2 may be converted to alternate targets by selective derivatization of either the amide or ketone functional group. A stereochemical model predicting the absolute sense of induction was developed based on single-crystal X-ray structures of product and precatalyst.
ABSTRACT
Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric hydroxylated derivatives, the 1,22-dihydroxynitianes. Key stereodefining steps in the construction of the A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction, a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps. The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural products, nitiol and variculanol, was completed.
Subject(s)
Terpenes/chemical synthesis , Gentianella/chemistry , Molecular StructureABSTRACT
The conversion of sterically hindered carboxylic acids to N-methoxy-N-methyl amides can be efficiently carried out with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine. Yields for this process range from 59% to 88%. The major byproduct in these reactions, N-methoxy-N-methylmethanesulfonamide, can be removed by placing the product mixture under vacuum for 14-24 h.
Subject(s)
Amides/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/chemical synthesis , Molecular ConformationABSTRACT
[reaction: see text] X = CH2, C[double bond]O, R2 = H, alkyl. A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.