A detailed account is given describing the approaches used toward the total synthesis of aliskiren. In particular, ring-closing metathesis with the Hoveyda-Grubbs catalyst accelerates the formation of a 9-membered lactone from an (R)-ester. The diastereomeric (S)-ester leads to the formation of dimeric dilactones, which were characterized by X-ray analysis and chemical conversions.

The effects of isopropyl substituents and molar concentration of diastereomeric esters toward the formation of nine-membered unsaturated lactones, in the context of the synthesis of the intermediates of the antihypertensive drug aliskiren, have been studied.The now-venerable Grubbs olefin metathesis reaction 1 and its many recent variants 2 is an exceedingly useful and versatile method to construct internally unsaturated compounds of varying ring sizes. 3 Among these, the synthesis of nine-membered unsaturated lactones 4 and ethers 5 is of particular interest because of their limited occurrence in nature and their interesting biological activity. 6 In a recent paper 7 on the total synthesis of the marketed antihypertensive drug aliskiren (Tekturna TM ) 8 we utilized a ring-closing metathesis reaction with the ester 1a using Grubbs' 1st generation catalyst (G1) 9 to obtain a critical nine-membered unsaturated lactone intermediate 2a that harbored two isopropyl groups in strategically pre-defined positions on an 8-aryloctanoic acid core unit (Scheme 1). The lactone 2a was further elaborated to provide aliskiren in seven steps and 7% overall yield from readily available starting materials. 7 Compared to recent syntheses, 10 and a plethora of published patents, 11 our synthesis proved to be the shortest to date.During the ring-closing metathesis reaction of a mixture of esters 1a and diastereomeric 3a with G1 catalyst in refluxing toluene at a concentration of 10 mM, we observed that only the (S,R,S)-ester 1a was converted into the lactone 2a. The same observation was made with the (S,R,S)-ester of the corresponding p-methoxyphenyl analogue 1b. The diastereomeric ester 3b did not give the expected lactone 4b and remained unchanged. Further studies with Grubbs second-generation (G2) 12 and Hoveyda-Grubbs secondgeneration (H-G2) 2b catalysts with a 4:1 diastereomeric mixture of p-methoxyphenyl analogue 1b led to the lactone 2b in excellent yield and in much shorter time. Under these conditions, the diastereomeric (S,S,S)-ester 3b, obtained independently from a stereoselective reduction of the correScheme 1 Synthetic route to aliskiren via a nine-membered lactone G1 (5 mol%) toluene (10 mM) r.t. O O MeO MeO O O 7 steps MeO OH H 2 N O H N NH 2 O R 1a, R = O(CH 2 ) 3 OMe 1b, R = H R 2a, R = O(CH 2 ) 3 OMe 2b, R = H aliskiren (Tekturna TM ) R = O(CH 2 ) 3 OMe G1 (5 mol%) O O MeO MeO O O R 3a, R = O(CH 2 ) 3 OMe 3b, R = H R 4a, R = O(CH 2 ) 3 OMe 4b, R = H R S S S S S R toluene (10 mM) r.t.

A series of alkyl and alkenyl p-methoxy arenes containing α,β-disubstituted diamino and amino alcohol groups were synthesized from β-nitro and β-azido benzylic alcohols in the presence of AuCl3 as catalyst. The formation of predominantly syn-disubstituted products were rationalized on the basis of mechanistic considerations and transition state models relying on A1,3-allylic strain. The products could have utility in the design of medicinally relevant compounds and as chiral ligands for asymmetric catalysis. A new synthesis of (+)-sertraline (Zoloft) was achieved.

A series of electron-rich arenes were reacted with 1-alkyl or 1-aryl 1′-allyl benzylic alcohols to give the corresponding 1,1′-diarylalkanes, in the presence of Lewis and Brønsted acids as catalysts. In the presence of HBF4, 1,1′-diarylalkanes containing an allylic chain were shown to form tetrahydronaphthalenes through a rearrangement involving spirocyclic intermediates. The mechanism of the cyclization is discussed.