Samarium diiodide mediated reactions in total synthesis

Abstract

Introduced by Henri Kagan more than three decades ago, samarium diiodide (SmI(2)) has found increasing application in chemical synthesis. This single-electron reducing agent has been particularly useful in C-C bond formations, including those found in total synthesis endeavors. This Review highlights selected applications of SmI(2) in total synthesis, with special emphasis on novel transformations and mechanistic considerations. The examples discussed are both illustrative of the power of this reagent in the construction of complex molecules and inspirational for the design of synthetic strategies toward such targets, both natural and designed.

Scheme 1

Common mechanisms of SmI₂-mediated activation of a) alkyl halides and b) carbonyl compounds.

Scheme 2

Some representative SmI₂-mediated transformations: a) Barbier, b) radical–alkene/alkyne, c) Reformatsky, d) carbonyl–alkene/alkyne, e) pinacol, f) fragmentation, and g) elimination reactions.

Scheme 3

Formation of the 8-membered ring of vinigrol model 8 by a Barbier cyclization (Matsuda et al., 1997).[11]

Scheme 4

Construction of phorbol system 11 by a Barbier cyclization (Carroll and Little, 2000).[12]

Scheme 5

Synthesis of variecolin model 16 through halide-selective Barbier reactions (Molander et al., 2001).[14]

Scheme 6

Barbier macrocyclization in a total synthesis of kendomycin (20) (Lowe and Panek, 2008).[16]

Scheme 7

Application of a radical–alkyne cyclization in the synthesis of methyl-α-C-isomaltoside (23) and its peracetate (24) (Beau, Skrydstrup et al., 1994).[18]

Scheme 8

Two possible mechanisms of Sm^III enolate formation.

Scheme 9

a) An unexpected intermolecular Reformatsky reaction/dimerization and b) an intermolecular Reformatsky reaction used in the total synthesis of acutiphycin (38) (Moslin and Jamison, 2006).[23]

Scheme 10

An intramolecular Reformatsky reaction to form B ring system 40 during the total synthesis of Taxol^® (41) (Mukaiyama et al., 1997).[26]

Scheme 11

Formation of the A ring of Taxol^® ABC model system 44 through an aldol-type reaction (Arseniyadis et al., 2005).[27]

Scheme 12

Carbonyl–alkene cyclizations in the a) first- and b) second-generation total syntheses of patchoulenone (49) (Banwell et al., 1998).[32]

Scheme 13

A carbonyl–alkene cyclization to complete the total synthesis of isoschizandrin (53) (Molander et al., 2003).[33]

Scheme 14

A double carbonyl–alkene cyclization in the total synthesis of brevetoxin B (57) (Nakata et al., 2004).[37]

Scheme 15

Carbonyl–alkene cyclizations in a) racemic and b) enantioselective total syntheses of platensimycin (61) (Nicolaou et al., 2006, 2007).[39,40]

Scheme 16

Application of a carbonyl–alkene cyclization to a total synthesis and structural revision of laurentristich-4-ol (67) (Li et al., 2008).[41]

Scheme 17

Synthesis of both enantiomers of 14-O-methyl pestalotiopsin (71) through a carbonyl–alkene cyclization (Procter et al., 2001, 2008).[42]

Scheme 18

a) Carbonyl–alkene fragment coupling in the synthesis of phorbol system 11 and b) a stereochemically distinct coupling result (Carroll and Little, 2000).[12]

Scheme 19

SmI₂-mediated nitrone–acrylate reductive coupling in the total synthesis of hyacinthacine A₂ (82) (Py et al., 2005).[44]

Scheme 20

SmI₂-mediated thioester–acrylate reductive coupling in the total synthesis of aliskiren (86) (Lindsay and Skrydstrup, 2006).[45]

Scheme 21

Formation of welwitindolinone A isonitrile model 89 through SmI₂-mediated isocyanate–alkene coupling (Wood et al., 2004, 2008).[47, 50]

Scheme 22

Mechanism of the SmI₂-mediated pinacol reaction.

Scheme 23

Synthesis of rocaglamide diastereomer 97 through an intramolecular keto–nitrile pinacol reaction (Kraus and Sy, 1989).[58]

Scheme 24

An aldehyde–oxime pinacol macrocyclization in the second total synthesis of diazonamide A (103) (Nicolaou et al., 2001, 2003).[61]

Scheme 25

Cyclopropane fragmentation in the total synthesis of Taxol^® (41) (Kuwajima et al., 1998).[64]

Scheme 26

Synthesis of cyclocitrinol system 108 through a cyclopropane fragmentation/ring expansion (Schmalz et al., 2007).[65]

Scheme 27

A cyclobutane fragmentation/ring expansion in the total synthesis of guanacastepenes A (111) and E (112) (Shipe and Sorensen, 2002).[66]

Scheme 28

SmI₂-promoted isoxazole ring cleavage in the total synthesis of epothilones A (117) and B (118) (Bode and Carreira, 2001).[67]

Scheme 29

Synthesis of actinopyrone A (120) through an ε-elimination of a methoxy group (Tatsuta et al., 2006).[70]

Scheme 30

Epoxide elimination in the total synthesis of Taxol^® (41) (Danishefsky et al., 1995).[72]

Scheme 31

Synthesis of dibromophakellstatin (126) through SmI₂-mediated double deprotection (Lindel et al., 2005).[73]

Scheme 32

a) A SmI₂-mediated isomerization in the synthesis of monolomaiviticin aglycon (131) and b) application to the total synthesis of kinamycin C (134) (Nicolaou et al., 2009).[74, 75]

Scheme 33

Synthesis of the BCD ring system (139) of penitrem D through a radical–alkene cyclization/Barbier-type reaction cascade (Curran et al., 2004).[76]

Scheme 34

A reductive double enolate alkylation in the total synthesis of meso-chimonanthine (144) and meso-calycanthine (145) (Link and Overman, 1996).[77]

Scheme 35

Synthesis of the C ring of a 19-hydroxy taxoid (149) through an epoxide fragmentation/aldol cyclization cascade (Mukaiyama et al., 2004, 2005).[79]

Scheme 36

An elimination/Barbier cyclization cascade in the total synthesis of upial (155) (Yamada et al., 1993).[80]

Scheme 37

A SmI₂-promoted cyclization cascade in the total synthesis of martinellic acid (160) (Naito et al., 2008).[82]

Scheme 38

SmI₂-mediated ring closure in the total synthesis of the a) originally proposed (166) and b) corrected (169) structures of vannusal B (Nicolaou et al., 2008, 2009).[84, 85]

Scheme 39

SmI₂-mediated ring expansion in the total synthesis of sarcodonin G (174) (Piers et al., 2000).[86]

Scheme 40

A palladium- and samarium-mediated cascade sequence in the synthesis of vitamin D₃ analogs 179 and 180 (Aurrecoechea et al., 1989).[91]

Scheme 41

Synthesis of lactarane system 184 through a cyclobutane/cyclopropane fragmentation cascade (Lange and Corelli, 2007).[93]

Scheme 42

An unexpected cascade sequence during a guanacastepene model study (Shipe and Sorensen, 2006).[66]

Scheme 43

A SmI₂-promoted fragmentation/elimination/bromination cascade in the total synthesis of cortistatin A (196) (Baran et al., 2008).[95]

Scheme 44

A SmI₂-promoted radical cascade in the total synthesis of hypnophilin (203) and formal synthesis of coriolin (204) (Curran et al., 1988).[97]

Scheme 45

a) A SmI₂-mediated cascade in the synthesis of paeonilactone B (210) and b) clarification of the source of stereoinduction (Kilburn et al., 1998).[98]

Scheme 46

Synthesis of PGG₂ methyl ester (219) and 12-epi-PGG₂ methyl ester (220) through a SmI₂-catalyzed oxidative cascade (Corey and Wang, 1994).[101]