Natural product synthesis macrocyclic reactions

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

The nrild eonditions of the photo-Fries rearrangement in natural product synthesis were further demonstrated by Mulzer and eoUeagues with the total synthesis of the antibiotic kendomycin by a macrocyclization reaction using a combined photo-Fries rearrangement, ring-elosing metathesis approach (162 163) (Figure 18.10) [81]. 

As one of the earliest appUcatiOTis of RCM for macrocyclization in natural product synthesis, the Hoveyda group reported in 1995 that Schrock catalyst catalyzed Z-selective formation of the macrocycle in Fig. 24 as a single alkene stereoisomer, which is a late stage intermediate for the total synthesis of Fluvirucin B [54]. While the conformational control of the substrate was believed to be crucial for the selectivity, recent stodies showed that catalyst cmitrol also played a key role in the reaction outcome, as Ru-catalyzed RCM of a very similar substrate yielded a 1 1 mixture of Z E isomers [55]. 

The first examples of catalytic RCAM for the synthesis of functionalized macrocycles were reported by Ftirstner and Seidel [7]. Two catalyst systems were employed in this study the instant system prepared by reaction of catalytic amounts of Mo(CO)6 1 with stoichiometric quantities of phenols, and the well-defined tungsten-alkylidyne 2 first prepared by Schrock in 1981 [5, 8]. Subsequent applications of RCAM, particularly in natural product synthesis, have either utilized these two systems or a molybdenum system developed by Fiirstner that employs in situ reaction of trisamido molybdenum complex 3 [9] and CH2CI2 (Figure 7.1) [10]. 

An intriguing application of Zincke processes occurred in Marazano s synthesis of dimeric, tetrameric, and even octameric pyridinium macrocycles, including cyclostellettamine B, a sponge-derived natural product. The same strategy produced a synthesis of haliclamine A (121, Scheme 8.4.41), a cytotoxic sponge metabolite. Intermediate 119, itself produced via a Zincke route, underwent an intramolecular Zincke reaction, providing macrocycle 120, which was reduced to the natural product. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

In the area of allenic non-natural product chemistry, the synthesis of the [34]alle-nophane 14 (Scheme 2.4) is particularly noteworthy, with all four of its allenic bridges being formed through subsequent SN2 substitution reactions of propargylic acetates with a methyl magnesium cuprate [14] (see Section 2.5 for an alternative synthesis of macrocyclic allenes). 

The use of metals for prearranging reaction centers as neighboring groups has a special value in the production of macrocycles (template effect). Although these ligands can be sometimes prepared directly, the addition of metal ion during the synthesis will often increase the yield, modify the stereochemical nature of the product, or even be essential in the buildup of the macrocycle. There have been few mechanistic studies of these processes. The alkali and alkaline-earth metal ions can promote the formation of benzo[18]crown-6 in methanol ... 

Grasillas, A. Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products Reaction conditions and limitations. Angew. Chem. Int. Ed. 2006,45, 6086-6101. 

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