MacMillan total synthesis

Carpenter J, Northrup AB, Chung dM, Wiener JJM, Kim S-G, MacMillan DWC (2008) Total Synthesis and Structural Revision of Callipeltoside C. Angew Chem Int Ed 47 3568... 

An excellent synthetic example of the Prins reaction is found in MacMillan and Overman s total synthesis of (-)-7-deacetoxyalcyonin acetate (21), in which the core of the natural product is assembled via the Prins-pinacol reaction sequence.16 Treatment of diol 17 with aldehyde 18 in the presence of BF3 Et20 presumably gives oxonium ion 19, which then undergoes the Prins-pinacol reaction sequence to generate 20 in 79% yield, thereby establishing the entire core bicycle of 21 in one step. Intermediate 20 was then carried forward to complete the total synthesis of 7-deacetoxyalcyonin acetate (21).16... 

Iminium organocatalysis was key to the enantioselective total synthesis of (—)-flustramine B (157) from the marine bryozoan Flustra foliacea by MacMillan and co-workers (Scheme 31) [137], which is discussed here despite not incorporating the entire C5 unit in one step. On treatment of the Boc-protected... 

Scheme 21 Total synthesis of (+)-mmfiensme (99) by MacMillan and coworkers...

Jones SB, Simmons B, MacMillan DWC (2009) Nine-step enantioselective total synthesis of (+)-minfiensine. J Am Chem Soc 131 13606-13607... 

In 2009 the MacMillan group reported an enantioselective total synthesis of (-b)-minfiensine (109). The key step in this synthesis expands upon Levy s early work ° and takes advantage of an organocatalytic cascade sequence... 

In 2005, MacMillan reported an enantioselective organocatalytic intramolecular Diels-Alder reaction (IMDA) of a,p-unsaturated aldehyde and diene, as well as the application in the asymmetric synthesis of solanapyrone D (6), Scheme 3.1 [5]. Later, Danishefsky and Christmann individually reported the total synthesis of UCS1025A (9) by coupling reaction with MacMillan aldehyde (8) [6]. The malim-ide analogue 10 of the telomerase inhibitor UCS1025A (9) was also prepared by Christmann et al. by modified MacMillan s conditions (10 mol% catalyst loading in nitromethane, affording 74% yield and >99% ee after a sequence of recrystallization and oxidation). Scheme 3.2 [7]. 

Recently, MacMillan reported a nine-step enantioselective total synthesis of (+)-minflensine via the key step reaction of organocatalytic Diels-Alder-cascade cyclization. Scheme 3.43 [58],... 

Owing to their structural complexity, Strychnos alkaloids, especially strychnine itself, are a benchmark in synthetic organic chemistry and have been prepared numerous times ]92]. Another alkaloid of the Strychnos family that enjoys increasing popularity nowadays is (+)-minfiensine. It was isolated from Strychnos minfimsis and features a l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole motif, and hence is closely related to echitamine and vincorine [93]. A total synthesis of this beautiful structure was accomplished by MacMillan and coworkers [94]. Their key step was a highly efficient enantioselective domino Diels-Alder/isomerization/amine cycHzation reaction (Scheme 14.35). In this process, the chiral organocatalyst 226-TBA (TBA, tribromoacetic acid) was used, which reacted first with propargyl aldehyde 225 to form i minium ion 229 as intermediate, which underwent an endo-selective Diels-Alder reaction with 224... 

Soon afterward, MacMillan and co-workers [142, 143] also reported enantio-selective intramolecular a-arylation of aldehydes via organo-SOMO catalysis. [Fe(Phen)3l [PFsl 3, instead of CAN, as a single-electron oxidant together with designed imidazolidinone catalysts LXVIII and LXIX were found to be optimal for reaction efficiency and enantioselectivity (Scheme 8.35). Moreover, ortho selectivity, when 1,3-disubstituted aromatic systems were used, was observed. Methodologies presented by Nicolaou and MacMillan represent a useful tool for the total synthesis of various naturally occurring compounds, such as dimethyl calamenene, tashiromine, and so on. 

Many of these organocatalyzed domino reactions are initiated by an enantioselective Michael addition followed by an acetalization. The first example of such transformation was reported by Mangion and MacMillan [26] in 2005 as a key step for the total synthesis of brasoside and littoralisone (Scheme 16.12). Using (S)-proline, the dialdehyde underwent contra-thermodynamic diastereoselective Michael/acetalization for the formation of the desired lactol in good yield. 

In 2008, MacMillan and co-workers [13] reported the first total synthesis and structure revision of callipeltoside C (38), a cytotoxic marine macrolide, with amino acid proline as a suitable organocatalyst for the construction of three key intermediates. This elegant synthesis (18 steps, 12% overall yield) demonstrated the power of organocatalysis with unprecedented level of ease and efficiency, which involved a proline-catalyzed double diastereo-differentiating aldol reaction between propionaldehyde 18 and the Roche ester-derived aldehyde 28 to achieve 29 (12 1 dr, 99% ee), an organocatalytic a-oxyamination to afford 32 (99% ee), and proline-... 

MacMillan and co-workers [45] reported an organocatalytic Michael addition in their total synthesis of flustramine B (120) in 2004 (Scheme 17.20). Organocatalytic Michael addition of indole 116 to acrolein 118 using imidazolidinone catalyst 117... 

Recently, the MacMillan group reported the organocatalytic three-step total synthesis of (+)-Frondosin B (131), a marine sesquiterpene isolated from the marine... 

In 2005, MacMillan and co-workers [52] employed their second-generation imidazolidinone catalyst 117 for the organocatalytic total synthesis of solanapyrone D (139) as shown in Scheme 17.24. Diels-Alder cycloaddition of aldehyde 137 using catalyst 117 provided bicycle 138 in 71% yield (20 1 dr, 90% ee), which was transformed into solanapyrone D (139) in a straightforward manner. 

MacMillan and co-workers demonstrated the capabilities of collective total synthesis in combination with organocascade catalysis very recently [53], which provided them a new synthetic strategy to achieve large collections of complex molecular architectures from a common molecular scaffold [54]. The power of this... 

Consequently, the MacMillan group reported a novel SOMO a-arylation reaction to achieve the total synthesis of ( )-tashiromine (165), isolated from the Asian deciduous shmb, Maackia tashiroi [67]. Organocatalytic a-arylation reaction of the pyrrole amide 163 afforded the key intermediate-bicycle 164 (72% yield, 93% ee), which was converted into ( )-tashiromine (165) by LiAHt reduction and hydrogenation using catalytic RI1/AI2O3 in 37% yield for the three steps as shown in Scheme 17.28 [66b],... 

Maier and Varseev recently applied MacMillan s elegant one-pot three-step protocol 115) (1. a-hydroxylation, 2. Horner-Wadsworth-Emmons HWE) olefination, 3. N—O cleavage) for the conversion of the (5)-citronellol-derived aldehyde 132 to y-hydroxy-a,p-unsaturated ester 133 early in their 18-step first total synthesis of neosymbioimine (134) 116), a minor amphoteric metabolite of the symbiotic marine dinofiagellate Symbiodinium sp. 117) (Scheme 31). 

Another excellent example from the MacMillan laboratory using enamine-catalyzed key-transformations to accomplish a complex total synthesis was the first total synthesis and structural revision of the cytotoxic marine macrolide callipeltoside C (206) 184). Callipeltosides A-C were isolated and characterized in 1996 and 1997 by Minale et al. They were found to be cytotoxic against the human bronchopulmonary NSCLC-N6 cell line (/C50 values ranging from 11.3 to 30.0 pg/cm ) (185,186). MacMillan s synthesis of 206 takes advantage of three highly selective organocatalytic key transformations to obtain the target in 20 steps and a very... 

Very recently, MacMillan et al. applied an intermolecular combined Friedel-Crafts-type conjugate addition/cyclization procedure as a key step in the total synthesis of diazonamide A (297) (271). Diazonamides are secondary metabolites isolated from the marine ascidian Diazona sp. (272, 273). Diazonamide A (297) was found to be a potent antimitotic member of this structurally unique family, exhibiting low nanomolar G/50 values towards different human cancer cell lines (272, 274). The unique structure of two 12-membered macrocycles that are conjoined through a triaryl-substituted quaternary stereogenic center (C-10) that is embedded in a furanoindoline core makes this compound a very interesting and... 

Knowles RR, Carpenter J, Blakey SB, Kayano A, Mangion IK, Sinz CJ, MacMillan DWC (2011) Total Synthesis of Diazonamide A. Chem Sci 2 308... 

Reiter M, Torssell S, Lee S, MacMillan DWC (2010) The Organocatalytic Three-Step Total Synthesis of (-l-)-Frondosin B. Chem Sci 1 37... 

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