Desulfonylation reactions: Recent developments

Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.

Reductive Amination in the Synthesis of Pharmaceuticals.

A comprehensive program for the synthesis of natural (or unnatural) products is analogous to the construction of a pyramid. Careful planning followed by installation of numerous levels of support are required to complete the edifice. Specific “cornerstone” strategies are typically major motivations for undertaking the program. Finally, the venture reflects the desire of the research team to construct a lasting monument to their creativity and hard work (Figure 1). * Corresponding author. E-mail: pfuchs@purdue.edu. Chem. Rev. 2009, 109, 2315–2349 2315

Evolving organic synthesis fostered by the pluripotent phenylsulfone moiety.

The Pd- or Ni-catalyzed cross-coupling reactions of organometals containing Zn, Al, Zr, and B as well as related reactions of Mg and several other metals collectively represent the most widely appl...

Transition Metal-Catalyzed Organometallic Reactions that Have Revolutionized Organic Synthesis

A method for the selective reduction of carbohydrate 4,6-O-benzylidene acetals

A highly convergent total synthesis of the anthelmintic macrolide avermectin B1a 1 is described. The key features of this synthesis include the introduction of the C(11)–C(15) portion by selective ring opening of a symmetrical 1,4-bis-epoxide 4 followed by reaction with the anion derived from the 3-methyl-2-(1-methylpropyl)-6-phenylsulphonylpyran 3 to afford the ‘northern’ C(11)–C(25) fragment 39. Coupling of the derived C(11)–C(25) aldehyde unit 42 with a C(1)–C(10)‘southern’ fragment 2 was achieved via a novel deconjugative vinyl sulphone anion sequence. Macrolactonisation and subsequent introduction of the 3,4-double bond gave the aglycone portion 51. The oleandrosyloleandrose disaccharide was introduced by a novel silver-mediated coupling between the 5-acetylated aglycone 70 and the thiocarbonylimidazolide 69. Final deacetylation was accomplished using Super-Hydride to give the natural product 1.

Total synthesis of the anthelmintic macrolide avermectin B1a

Dispiroketals in synthesis (part 2): A new group for the selective protection of diequatorial vicinal diols in carbohydrates.

Stereospecific synthesis of the anaesthetic levobupivacaine

Patients susceptible to or suffering from central nervous system are treated by administering an effective amount of an aryl substituted olefinic amine compound, such as (E)-metanicotine. (E)-metanicotine is provided from nicotine. Nicotine is reacted with ethyl chloroformate to produce ethyl N-methyl-N-[4-chloro-4-(3-pyridyl)butyl]carbamate, which then is reacted in the presence of potassium tert-butoxide, tetrahydrofuran and dimethylformamide to produce (E)-metanicotine N-ethyl carbamate, which then is subjected to hydrolysis using hydrochloric acid to produce a reaction mixture containing (E)-metanicotine. The reaction mixture containing (E)-metanicotine is adjusted to a slightly basic pH, and then contacted with dichloromethane. The resulting water immiscible phase then is separated from the aqueous phase. The aqueous phase, then is adjusted to a very basic pH, and then contacted with methyl tert-butyl ether. (E)-metanicotine is taken up by the methyl tert-butyl ether, and after separation of the methyl tert-butyl ether from the aqueous phase, the desired product is separated from the methyl tert-butyl ether.

Method for preparation of aryl substituted alefinic secondary amino compounds

A preparation of the novel dispiroketal of D-glyceraldehyde is described. The diastereoselective addition of various organometallic reagents proceeds with anti selectivity due to the large steric bulk of the dispiroketal

Dispiroketals in Synthesis: Preparation of a Stable, Sterically Demanding Glyceraldehyde Ketal and Diastereoselective Reactions with Simple Organometallic Reagents

Martin Woods

Papers

Total synthesis of the anthelmintic macrolide avermectin B1a

Dispiroketals in synthesis (part 2): A new group for the selective protection of diequatorial vicinal diols in carbohydrates.

Stereospecific synthesis of the anaesthetic levobupivacaine

Method for preparation of aryl substituted alefinic secondary amino compounds

Dispiroketals in Synthesis: Preparation of a Stable, Sterically Demanding Glyceraldehyde Ketal and Diastereoselective Reactions with Simple Organometallic Reagents