Joseph E. Lynch

Synthesis of an HMG-COA reductase inhibitor; A diastereoselective aldol approach

Abstract The synthesis of the β-hydroxy-δ-lactone moiety of an HMG-CoA reductase inhibitor in its correct absolute configuration (94% ee) has been accomplished via a diastereoselective aldol reaction between aldehyde 4 and the magnesium enolate of S(+)1,2,2-triphenylethylacetate, Claisen condensation, and hydroxyl directed reduction of the resulting δ-hydroxy-β-keto ester.

Synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677

Abstract The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.

An efficient synthesis of 4-benzoyloxyazetidinone: an important carbapenem intermediate

Abstract A short, stereoselective synthesis of the key carbapenem intermediate (3R,4R)-3-[(1R)-1-hydroxyethyl]-4-benzoyloxyazetidin-2-one is described.

A practical synthesis of the 5-chloromethyl-furo[2,3-b]pyridine pharmacophore

Synthesis of the furopyridine 2 was accomplished in 52% overall yield from 6-hydroxynicotinic acid (3). The synthesis is highighted by a Heck coupling of 5 with ethylene followed by an NCS mediated oxidative cyclization and elimination sequence.

A chemical synthesis of nicotinamide adenine dinucleotide (NAD

A practical synthesis of nicotinamide mononucleotide (β-NMN) and a high yield coupling with AMP-morpholidate that also provides NAD+ in an efficient manner are reported.

Towards the synthesis of HIV-protease inhibitors. Synthesis optically pure 3-carboxyl-decahydroisoquinolines.

Abstract The synthesis of optically pure decahydroisoquinoline 1 , a component of HIV-protease inhibitors, was accomplished in 30–33% overall yield from the readily available optically pure monoacid 4 .

Regioselective nucleophilic substitutions of fluorobenzene derivatives

Abstract Regioselective nucleophilic substitutions of tri- and di-substituted fluorobenzoates, fluorobenzonitriles, and fluoronitrobenzenes were accomplished by sequential addition of various nucleophiles, such as, potassium N-Boc-4-piperidinyl oxide, potassium methoxide, and piperidine.

A stereoselective synthesis of a key 1β-methylcarbapenem intermediate via a diastereoselective decarboxylation

(3S,4S)-3[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone 7a was prepared from (3R,4R)-4-acetoxy-3-[(R)-1-t-butyldimethylsilyloxy)ethyl]-2-azetidinone 3 via a sequence involving coupling with 2,2,5-trimethyl-1,3-dioxan-4,6-dione 4, N-silylation, solvolysis of the methylmeldrums acid moiety and a stereoselective acid catalyzed decarboxylation.

Practical synthesis of α-amino acids using cis-aminoindanol derived hippuric acid amide as a glycine enolate equivalent

Abstract The use of cis -aminoindanol as a chiral auxiliary for asymmetric synthesis of α-amino acids is described. Alkylation of the chirally modified glycine enolate 2 with a number of alkyl halides in the presence of lithium chloride gave the corresponding alkylated product in 90 ∼ 99% diastereoselectivity.

Crystallization-induced asymmetric transformation: Stereospecific synthesis of L-768,673

Abstract A highly convergent, asymmetric synthesis of L-768,673, an I ks Class III antiarrythmic drug candidate, is described. Synthesis of the recemic 1-trifluoroethyl-3-amino-5-phenyl benzodiazepinone [(±)-amine] was achieved by Ru-catalyzed hydrogenation of the corresponding oxime that was derived from commercially available 1-trifluoroethyl-5-phenyl benzodiazepine in 76% overall yield. An efficient one-pot resolution-racemization of (±)-amine provided the desired (±)-amine as its mandelate salt in 92% yield and 99.4% ee. Regioselective ortho-lithiation of 1,3-bis(trifluoromethyl)benzene with n-BuLi in the presence of a catalytic amount of 2,2′,6,6′-tetramethylpiperidine afforded its aryl lithium. Subsequent transmetalation and alkylation with allyl bromide produced the corresponding olefin. Ru-catalyzed oxidative cleavage of the terminated double bond of the olefin provided the desired 2,4-bis(trifluoromethyl)phenylacetic acid in 35% overall yield. A modified Schotten-Baumman procedure was developed for coupling of (+)-amine and the acid to produce L-768,673 in 92% yield without racemization.