Sml2-mediated Reformatsky reaction

The Sml2-mediated Reformatsky reaction provides a useful alternative to traditional versions of the reaction as it proceeds under mild, homogeneous conditions, with high chemo- and diastereoselectivity. Although a-halo esters are the most common substrates for the reaction, in principle any a-halo carbonyl compound can be employed in the reaction. The reactions are most often carried out by the addition of Sml2 to a 1 1 mixture of the a-halocarbonyl compound and the coupling partner. These are often referred to as Barbier conditions (see Section 5.4). 

In 1980, Kagan reported the first example of a Sml2-mediated Reformatsky reaction.98 Kagan s study involved the coupling of ethyl a-bromopropionate with cyclohexanone (Scheme 5.88). 

A Sml2-mediated Reformatsky reaction involving formaldehyde as the electrophile has been exploited by Otaka in a synthesis of a dipeptide isostere treatment of y,y-difluoro-ot,p-enoate 130 with Sml2 in the presence of in situ-generated formaldehyde gave adduct 131 in good yield (Scheme 5.92).145... 

It is in the intramolecular sense that the Sml2-mediated Reformatsky reaction has been used to greatest effect. Rather surprisingly, there are several examples of intramolecular Sml2 Reformatsky reactions that employ protic cosolvents. In some cases, the alcohol cosolvent is essential for efficient Reformatsky cyclisation. 

The bicyclic core of the targets was constructed using a Sml2-mediated Reformatsky reaction (Scheme 7.26). Shiina found that the use of HMPA in the Reformatsky reaction had a dramatic effect on its outcome. When a-bromo ester 58 was treated with Sml2 in the absence of HMPA, alcohol 60 (containing the incorrect stereochemistry required for the natural products) was obtained... 

In 1998, Tachibana used a Sml2-mediated Reformatsky reaction to form the nine-membered oxonone F ring of ciguatoxin.70 Treatment of bromide 72 with... 

Sml2-mediated Reformatsky and Aldol-type Reactions... 

In 1993, Corey reported the first synthesis of paeoniflorin.56 The core of paeoniflorin was constructed using a Sml2-mediated Reformatsky-type reaction (Scheme 7.16). Treatment of a-chloronitrile 31 with Sml2 gave cyclobutanol 32 in excellent yield. The sensitivity of cyclobutanol 32 to base precluded the use of more conventional aldol-type cyclisations.56... 

Reductive cyclizadons of 3-bromoacetoxy aldehydes and ketones promoted by Sml2 afford 3-hydroxyvalerolactones with unprecedented degrees of 1,3-asymmetric induction (equation 57). Numerous attempts at utilizing zinc-mediated intramolecular Reformatsky reactions to access these lactones have failed. The successful development of the Smh-based methodology therefore provides perhaps the most convenient entry to this important class of molecules. ... 

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