Asymmetric dihydroxylation Sharpless’ method

Previous syntheses of terminal alkynes from aldehydes employed Wittig methodology with phosphonium ylides and phosphonates. 6 7 The DuPont procedure circumvents the use of phosphorus compounds by using lithiated dichloromethane as the source of the terminal carbon. The intermediate lithioalkyne 4 can be quenched with water to provide the terminal alkyne or with various electrophiles, as in the present case, to yield propargylic alcohols, alkynylsilanes, or internal alkynes. Enantioenriched terminal alkynylcarbinols can also be prepared from allylic alcohols by Sharpless epoxidation and subsequent basic elimination of the derived chloro- or bromomethyl epoxide (eq 5). A related method entails Sharpless asymmetric dihydroxylation of an allylic chloride and base treatment of the acetonide derivative.8 In these approaches the product and starting material contain the same number of carbons. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Anti-tumor compound (205)-irinotecan (1) was prepared in 13 steps with an overall yield of 1.15 % for the longest linear synthesis. The short and selective preparation of aryl iodide 11 features two key steps - ortho metalation and Sharpless asymmetric dihydroxylation. In only one step 11 is transformed into the target molecule 1 by application of a radical domino annulation with isonitrile 15. This method gives access to the broad family of campthotecin derivatives because of the quite impressive generality of the substrates that can be employed. 

Sharpless et al.l20b have constructed chiral dendrimers by employing the doubleexponential synthetic method.[20c] Chirality was induced via the use of aryl acetonide monomers prepared by asymmetric dihydroxylation (AD) of the corresponding prochiral alkenes. Each monomeric unit possessed two asymmetric carbons. Examples described are C3-symmetric and contain up to 45 chiral building blocks with 24 acetonide termini. 

Unlike epoxides, these five-membered heterocyclics have received scant attention from organic chemists. But the recent catalytic asymmetric dihydroxylation of alkenes (14, 237-239), which is now widely applicable (this volume), and the ready access to optically active natural 1,2-diols has led to study of these compounds, including a convenient method for synthesis. They are now generally available by reaction of a 1,2-diol with thionyl chloride to form a cyclic sulfite of a 1,2-diol, which is then oxidized in the same flask by the Sharpless catalytic Ru04 system, as shown in equation I.1... 

Both resolution and Sharpless asymmetric dihydroxylation were successful in the synthesis of Crixivan but the best method is one v e shall keep till later. Only one stereogenic centre remains, and its stereoselective formation turns out to be the most remarkable reaction of the whole synthesis. The centre is the one created in the planned enolate alkylation step,... 

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

The Sharpless asymmetric dihydroxylation works best for tram disubstituted alkenes, while the Jacobsen epoxidation works best for cis disubstituted alkenes. Even in this small area, there is a need for better and more general methods. Organic chemistry has a long way to go. 

Stable and easily handled, protected forms of l- and D-glyceraldehyde were obtained by the Sharpless asymmetric dihydroxylation [56] of the benzene-1,2-dimethanol acetal of acrolein (Scheme 13.23). The method produces either diol (7 )-32 or (S)-32 with 97% ee after recrystallization from benzene. These diols can be converted into useful C-3 chiral building blocks such as epoxides (7 )-33 and (5)-33, respectively [28,57]. 

This procedure provides a good method for the construction of l,2-a ft-aldol moieties that are less accessible by the Sharpless asymmetric dihydroxylation (see Scheme 37,0 Scheme 58, O Scheme 92,0 Sect. 11) [138] because the corresponding Z-oleflns are difficult to obtain and show reduced enantioselectivity. The first demonstration of the use of the biologically significant substrate dihydroxyacetone as a donor in organocatalyzed aldol reaction was reported by Barbas 111 and co-workers [139]. The reactions of DHA with protected glyoxal and glycer-aldehydes, in aqueous media and in the presence of enantiomerically pure diamine 24, provide access to pentuloses and hexuloses, respectively (O Scheme 19). 

In summary, these studies demonstrated that in CTX the impaired synthesis of bile acids is due to a defect in the biosynthetic pathway involving the oxidation of the cholesterol side-chain. As a consequence of the inefficient side-chain oxidation, increased 23, 24 and 25-hydroxylation of bile acid precursors occurs with the consequent marked increase in bile alcohol glucuronides secretions in bile, urine, plasma and feces (free bile alcohols). These compounds were isolated, synthesized and fully characterized by various spectroscopic methods. In addition, their absolute stereochemistiy determined by Lanthanide-Induced Circular Dichroism (CD) and Sharpless Asymmetric Dihydroxylation studies. Further studies demonstrated that (CTX) patients transform cholesterol into bile acids predominantly via the 25-hydroxylation pathway. This pathway involves the 25-hydroxylation of 5P-cholestane-3a,7a, 12a-triol to give 5P-cholestane-5P-cholestane-3a,7a,12a,25- tetrol followed by stereospecific 24S-hydroxylation to yield 5P-cholestane-3a,7a,12a,24S,25-pentol which in turn was converted to cholic acid. 

Another way to improve the yield of such transformations is to combine a chemical asymmetric oxidation and a biocatalytic approach. This has been illustrated on 2-methyl-epoxyheptane as shown in Fig. 22. Thus, a 33% overall yield of the corresponding (S)-epoxide was obtained with an ee of 97% [149]. It is to be emphasized that, in this particular case the best corresponding chemical method for obtaining this epoxide, i. e. the Sharpless asymmetric dihydroxylation, only led to an ee of 71 %. 

These furfliryl alcohols can be produced in either enantiomeric form via asymmetric catalysis. Our preferred method for the asymmetric synthesis of these fiiran alcohols 4.2 is by the highly enantioselective Noyori reduction of achiral acylfurans 4.1 (Scheme 4). Alternatively fiirfurly alcohols like 4.4 can be prepared by the Sharpless asymmetric dihydroxylation of vinylfuran 4.3. Key to this later approach was the recognition that vinylfuran 4.3 could be made by a Petersen olefination reaction. 

We dedicate a large part of this chapter to two very important, and extraordinarily useful, enantioselective methods - catalytic asymmetric epoxidation (AE) and catalytic asymmetric dihydroxylation (AD). Impressively, both these methods were developed by Professor Barry Sharpless s research group and are therefore often referred to as the Sharpless epoxidation and the Sharpless dihydroxylation. Both are examples of ligand-accelerated catalysis. 

We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the chapter. Interestingly, Sharpless other famous asymmetric method - dihydroxylation - has not found widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic, too wilful. In other words, it is not sensitive to the chirality of the substrate and charges ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution with dihydroxylation,19 but they are more rare. However, the dihydroxylation is even more useful and much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric dihydroxylation is in the Double Methods section. 

From the standpoint of general applicability, and scope the osmium-catalyzed asymmetric dihydroxylation of alkenes (Sharpless dihydroxylation) has reached a level of effectiveness which is unique among asymmetric catalytic methods . In the presence of an optimized catalyst ligand system nearly every class of olefin can be dihydroxylated with high enantioselectivities. 

Although the use of yeasts as biocatalysts was quite effective in preparing extremely pure enantiomers of JHs, their synthetic routes were lengthy. Indeed, in the case of (+)-JH I (61), its overall yield was only 0.34% (21 steps) by the biocatalytic method.28 We therefore examined the application of Sharpless asymmetric dihydroxylation for the synthesis of (+)-JH I and (+)-JH II. 

Syntheses of relatively simple chiral drugs on an industrial scale are the domain of catalytic or enzymatic methods. In the case of the calcium antagonist diltiazem [113] Sharpless asymmetric dihydroxylation (AD-reaction) is employed which works particularly efficiently for cinnamic acid derivatives such as 48-1. In fact diol 48-2 is obtained with good optical enrichment and is then converted into the target compound via 6 routine steps. Alternatively diltiazem is prepared via classical optical resolution or via enzymatic kinetic resolution of suitable intermediates [113]. 

---