Sml2-mediated intramolecular

Procter employed a highly diastereoselective Sml2-mediated intramolecular 1,4-addition during studies on the synthesis of faurinone treatment of iodide 77 with Sml2 in THF-HMPA gave cis-hydrindane 78 in good yield (Scheme 5.51).84... 

In 1993, Molander found that in the presence of catalytic Fe(III) salts, Sml2 mediates intramolecular Barbier additions to esters to give cyclic ketones (or cyclic hemiketals, if they prove to be stable).135 Double addition to the ester is not observed, nor is reduction of the cyclic ketone product. This suggests that the tetrahedral intermediate, a samarium alkoxide of a cyclic hemiketal, is partially stable to the reaction conditions and the ketone group is not revealed until work-up. Molander found that both alkyl and allyl halides could be used in the additions (Scheme 5.83).135... 

The Sml2-mediated intramolecular Barbier addition to amides is less common Fadel reported the diastereoselective cyclisation of chloroimide 122,137 while Ha carried out an intramolecular Barbier addition to the carbonyl of cyclic imide 123 (Scheme 5.86).138... 

Scheme 39 An example of a Sml2-mediated intramolecular pinacol coupling...

The Sml2-mediated intramolecular pinacol coupling reactions of carbonyls 151 were found to afford heterocyclic diols 152 in diastereoselective... 

In contrast to other reported methods of 1,3-asymmetric induction, the Sml2-mediated intramolecular Reformatsky procedure permits strict control of stereochemistry even in diastereomeric pairs of substrates bearing a-substituents (equations 58 and 59). ° Although the diastereoselectivity is somewhat lower for the syn diastereomeric substrate, where the a-substituent would be axially disposed in the proposed transition structure leading to the product, 1,3-asymmetric induction is still predominant and overwhelms other effects to an impressive extent. 

Curiously, the relative stereochemistry between the carboxylate and the adjacent hydroxy group in the Sml2-mediated intramolecular pinacolic coupling reaction is opposite to that observed in the intramolecular Barbier reactions and ketone-alkene reductive coupling reactions discussed previously (compare... 

Seven-membered ring lactones can be accessed in excelloit yields by die Sml2 mediated intramolecular Reformateky reaction as well. Although several substitution patterns provide exceptional relative asymmetric induction in this process (equation 62), it is clear that high diastereoselectivity cannot be achieved for all substitution patterns in the formation of seven-membered ring lactones. ... 

A total synthesis of pseudolaric acid A was reported, featuring a Sml2-mediated intramolecular alkene-ketyl radical cyclization to generate the highly functionalized cyclopentane 141 (Scheme 25.67). ° When 140 was subjected to the annulation reaction in the presence of HMPA without... 

The intramolecular Sml2-mediated pinacol coupling has been well exploited as a key step in many natural product syntheses for the construction of different ring sizes. For example, in 1997, Pancrazi reported a formal total synthesis of... 

Intramolecular Sml2-mediated Barbier Reactions Involving Addition to Aldehydes and Ketones... 

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. 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

Molander has also studied the Sml2-mediated double Barbier additions of alkyl dihalides to ketoesters.22,23 These impressive anionic-anionic, inter-molecular-intramolecular sequences require the use of Nil2 as an additive and irradiation with visible light and allow access to a range of bicyclic and tricyclic systems. The reactions proceed by reduction of the more reactive alkyl halide, intermolecular Barbier addition to the ketone, lactonisation and a second Barbier addition to the lactone carbonyl (Scheme 6.18).22... 

In 2008, Wang and Li reported the synthesis of both the proposed and the revised structure of ( )-laurentristich-4-ol using an intramolecular Sml2-mediated ketyl radical addition to a benzofuran to construct the spirocyclic... 

Total synthesis of pyranicin by Takahashi et al. used a Sml2-mediated reductive free radical reaction to constmct the desired cw-THP ring 223 (Scheme 10-37). The stereochemistry of hydroxyl on the THP ring was reversed by an intramolecular Sn2 substitution, giving the lactone 224. A Wittig reaction between 225 and known aldehyde 110 furnished the skeleton of the target. 

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. ... 

L-C/tiVo-inositol. Chiara has reported a synthesis of L-c/nVo-inositol from D-sorbi-tol that employed a highly stereoselective intramolecular pinacol coupling reaction as the key step (Eq. 3.5) [21]. Thus, treatment of the illustrated dialdehyde with Sml2 afforded the desired diastereomer with 94 6 stereoselection (neither of the other two diastereomers was detected) in >78% yield. The major reaction product was the one expected based upon previous studies of Sml2-mediated pinacol cy-clizations [22]. 

Forskolin. Prange has described a formal total synthesis of forskolin, a diteipe-noid that serves as an activator of adenylate cyclase, in which an intramolecular Sml2-mediated pinacol coupling reaction was a pivotal transformation (Eq. 3.6) [23]. Only the desired diastereomer was produced in this process. 

Another cyclization method towards synthesis of myo- inositols and chiro-inositols resulted from a Sml2-promoted intramolecular pinacol reaction. Treatment of dienes 34 and 35 with ozone produced a dialdehyde after reduction of the ozonide with dimethyl sulfide. Subsequent Sml2-mediated pinacol coupling gave the corresponding protected inositols as a mixture of diastereomers [89]. 

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