A highly diastereoselective vinylogous Mannich condensation and 1,4-conjugate addition of (Z)-propenyl cuprate in the synthesis of an influenza neuraminidase inhibitor

Intermolecular Addition Reactions of N-Acyliminium Ions (Part II)¹

“…This substituent was proposed to adopt a pseudo-axial orientation to minimise A 1,2 strain with the N-Boc group. 91 The 2,3-O-isopropylidene-protected pyrrolidine 340 reacted with allyltrimethylsilane in the presence of boron trifluoride-diethyl ether complex to give the 2-allylated pyrrolidine 341 in 52% yield and with complete 2,3-trans selectivity (trans/cis = 100:0) (Scheme 136). Magnesium bromide, tin(IV) chloride, dichlorodiisopropoxytitanium(IV), and ytterbium(III) triflate were found to be ineffective in this reaction.…”

Aminomethylated Pyrroles: Casting a Spotlight

“…The versatile synthon (10) could be exploited in vinylogous Mannich-type addition to aldimines to gain easy access to biologically relevant chiral nitrogen-containing compounds through nucleophilic Lewis acid-assisted reactions at C-5 [36]. A pertinent example of this successful strategy is the preparation of the influenza neuraminidase inhibitor (13) [37] which comprises the stereoselective condensation of imine (12) and N-Boc-2-(tertbutyldimethylsilyloxy)pyrrole (10) as a pivotal step of the synthetic sequence (Scheme 6). Other pyrrole substrates similar to silyloxypyrrole (10) were involved in reactions with preformed aldimines [38], or, in an even more classical approach, with aldehydes and amines [39] to give rise to the corresponding 5-aminoalkyl pyrrolidones.…”

“…N The limitations of the classical Mannich reaction have led to a search for more convenient synthetic methodologies. Aldimines (27) represent a category of such preformed aminoalkylation reagents which have been used in the aminoalkylation of pyrrole substrates [37,38,42,47] often undergo with a high stereoselectivity. 1) has often overcome these limitations, providing in the same time easy access to aminoalkylation reactions otherwise difficult to achieve [58].…”

“…For example, several derivatives of primary pyrrole Mannich bases exhibited a significant degree of central nervous system depressant activity [96], and the Mannich reaction of ethyl 4-(1-pyrrolyl)benzoate proved to be a valuable modification that allowed the scaling-up of the preparation of the angiotensin II receptor antagonist FR143187 [107]. It is worth mentioning that a highly diastereoselective vinylogous aminomethylation of N-Boc-2-tert-butyldimethylsilyloxypyrrole was the key step in the large scale asymmetric synthesis of the influenza neuraminidase inhibitor A-315675 [37]. Aminomethylated pyrroles have been involved as well in the preparation of Ketorolac analogues useful as antiinflammatory, analgesic and fibrinolytic agents, platelet aggregation inhibitors, and smooth muscle relaxants [76].…”

N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions

“…6c In addition to the aforementioned N-Ar group products contain an easily removable Boc-amide (Boc = t -butoxycarbonyl). The importance of the present type of EVM processes is underscored by a recent total synthesis of influenza neuroaminidase inhibitor A-315675 (Scheme 1b); 10 preparation of this biologically active compound and its analogues would likely be facilitated substantially due to the availability of the catalytic protocols that are outlined below. We also report on the first examples of diastereo- and enantioselective phosphine–Ag-catalyzed additions with 5-substituted siloxyfurans, leading to the formation of O-substituted quaternary carbon stereogenic centers that are adjacent to a tertiary N-substituted stereogenic center (Scheme 1b).…”