High‐Yielding Synthesis of the Anti‐Influenza Neuramidase Inhibitor (−)‐Oseltamivir by Three “One‐Pot” Operations

Abstract

A great deal of attention has been paid both in the scientific literature and the general media to the high potential risk of a worldwide spread of avian H5N1 influenza virus, the death rate of which is over 50 %.[1] Indeed, should this virus acquire the ability to become capable of spreading easily and directly from human to human it could very possibly cause a disastrous pandemic. (À)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza, [2] is one of the most promising therapeutics, and many nations have plans to stock a significant amount of this compound in case of a possible influenza outbreak. Moreover, the recent emergence of Tamiflu-resistant virus strains has prompted the chemical community to develop medicines effective against the mutated virus.[3] To meet these demands, intensive efforts have been devoted to the development of efficient preparations of this life-saving drug [1,2,4] and of its derivatives. For our synthesis of Tamiflu, we set the following objectives, because meeting these requirements would allow a large amount to be prepared in a short time and at low cost: 1) The number of synthetic reactions should be not more than ten, and the number of separate operations should be as few as possible.2) The overall yield should be over 50 %. 3) Only inexpensive reagents should be employed. Preparing a molecule of this complexity, possessing three contiguous chiral centers, in no more than ten synthetic reactions in over 50 % overall yield is a very challenging goal. Even if each individual reaction of a sequence proceeds in 90 % yield-an excellent yield in organic synthesis-the overall yield falls to 35 % after ten reactions (0.9 10 = 0.35). The best yield yet achieved for the total synthesis of Tamiflu is approximately 35 %. [4b, d] Moreover, in order to supply Tamiflu to developing countries where influenza might spread, production costs should be kept low. This requires that only inexpensive reagents be used. Although several syntheses of Tamiflu have been reported, previous methods do not meet all these requirements, and developing a method which does so remains a great challenge for the chemical community.One-pot operations are effective for carrying out several transformations and forming several bonds in a single pot, while at the same time cutting out several purification steps, minimizing chemical waste generation, and saving time. To simplify the synthesis we investigated the preparation of Tamiflu by a small number of one-pot operations. Our strategy was to construct a key, fully functionalized ethyl cyclohexenecarboxylate intermediate in a single-pot operation as the first step; after this, the remainder of the synthesis consists simply of functional group manipulations, also carried out in one-pot operations.The first key reaction relied on organocatalysis, a relatively new, rapidly developing technology in synthetic organic chemistry.[5] Diphenylprolinol silyl ether 4, [6] which was developed independently by ou...

Multicatalytic, asymmetric Michael/Stetter reaction of salicylaldehydes and activated alkynes

“…Especially powerful in its application to total synthesis, asymmetric tandem catalysis has enabled rapid access to enantioenriched products with high levels of selectivity (1, 4-8, 10, 11). Although most examples exploit a single catalyst to promote multiple, sequential transformations (12)(13)(14)(15)(16)(17)(18)(19), systems relying on two or more catalysts have been reported (2,3,11,20). Inherent in any multiple catalyst system is the challenge of compatibility.…”

Organocatalytic Conjugate Addition in Stereoselective Synthesis

“…56,57 This synthesis is impressive in terms of both practicability and chemical efficiency. It takes advantage of the addition of aldehyde 92 to the vinyl nitroester 93.…”

Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

“…Incorporation of organocatalytic functionalizations in complex one-pot reactions has recently emerged as an efficient strategy for the formation of many important optically active compounds, otherwise difficult to obtain (19)(20)(21)(22)(23)(24)(25). The present work shows the development of an organocatalytic synthetic process, making use of a single amino-catalyst (26)(27)(28)(29)(30)(31) in combination with cheap and readily available starting materials, for the formation of allylic alcohols and amines in moderate to good yields and excellent enantioselectivities (Scheme 2).…”