Furstner synthesis

From ortho-Acyl-Anilides The Furstner Synthesis ... 

SCHEME 2 The first steps of Furstner synthesis of amphidinolide Tl, T3, T4, and T5. 

Acyl)anilides 78 can be cydized by intramolecular reductive coupling of the two carbonyl moieties mediated by low-valent titanium (abbreviated [Ti]), thus creating the C-2/C-3 bond of 2,3-disubstituted indoles 79 (Furstner synthesis) [166] ... 

This process is similar to the Mcmurry reaction [167] the reductive dimerization of aldehydes and ketones by [Ti] forming oleftnic C=C bonds. The mechanism of the Furstner synthesis presumably involves single-electron transfer to the carbonyl groups (78 -> 80) and intramolecular radical combination in 80 (supported by Ti-chelation) to... 

Scheme 53 Furstner s RCM-based synthesis of muscopyridine (264) with integrated selfclearance by proper choice of catalyst activity [122]...

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. 

Furstner A (1998) Ruthenium-Catalyzed Metathesis Reactions in Organic Synthesis. 1 37-72... 

TMS group and the Suzuki cross-coupling reaction is again repeated. This sequential process allows for the introduction of different aromatic groups at positions 3 and 4 of the pyrrole system. The synthesis of the Furstner intermediate (6) is completed by removal of the sulfonamide group. 

Furstner s group has also developed [58] a very practical strategy (Scheme 24) for the relay synthesis of permethyl storniamide A (120) via an important diester (126), which was the precursor to the Boger diacid (118) presented in Scheme 23. 

In this method, Furstner converts N-BOC protected pyrrole to the 2,5-dibromo compound (122) with NBS and this is followed by metalation and carbomethoxylation with t-butyl lithium in THF and subsequent trapping of the metalated species with methyl chloroformate to yield a pyrrole diester (123). Bromination of this diester at positions 3 and 4 with bromine in water followed by Suzuki cross-coupling with 3,4,5-trimethoxyphenyl boronic acid yields the symmetrical tetrasubstituted pyrrole (125). Base-mediated N-alkylation of this pyrrole with 4-methoxyphenethyl bromide produces the key Boger diester (126) and thereby constitutes a relay synthesis of permethyl storniamide A (120). 

Scheme 24 Furstner Group Synthesis of Storniamide Natural Products...

Scheme 28 Furstner Group Synthesis of the Halitulin Core...

As recently demonstrated by Furstner and Langemann, higher yields of the disubstituted olefin 83 can be obtained under high dilution conditions using la as the catalyst. Our experiments clearly illustrate that synthesis of trisubstituted macrocyclic alkenes is more complicated than that of their disubstituted analogues. See Furstner A, Langemann K (1996) J Org Chem 61 3942... 

Furstner, A. Konetzki, L, A practical synthesis of beta-D-mannopyranosides. 

Furstner succeeded in the synthesis of dactylol using ring-closing metathesis of 9d. Crimmins synthesized enantioselectively diene 9e, and RCM of 9e gave eight-membered ring compound lOe, which is an intermediate for the synthesis of laurencin [Eq. (6.12)] ... 

Furstner A, Radkowski K, Enantioselective total synthesis of the phytotoxic lactone herbarumin I. Chem Commun 7 671—672, 2001. 

Intramolecular McMurry olefmation was realized by Furstner et al., who achieved synthesis of indol derivatives with a catalytic amount of TiCls. They employed zinc metal as a reductant and Me3SiCl as a deoxygenating agent... 

Furstner and Leitner " have recently described the synthesis of (f )-(-t-)-muscopyridine. This elegant strategy is based on two regioselective iron-catalyzed heteroaryl-alkyl coupling reactions (Scheme 65). 

The iron-catalyzed addition of Grignard reagents to propargylic epoxides developed by Furstner and Mendez allows one to prepare a yw-allenol, which is an important intermediate for the synthesis of a precursor of the amphidinolide X (Scheme 67). 

The reaction of a ketone with an amide provides a unique entry into the indole skeleton (Furstner Indole Synthesis). 

FUrstner has employed the Trost pyrrole synthesis in the first total synthesis of roseophilin, wherein this N-benzylpyrrole-ring forming step occurred in 70% yield [23]. Backvall has found that primary amines react with dienes under the guidance of Pd(II) to form pyrroles 170 in variable yields [121]. The intermediate ir-allyl-palladium complexes are quite stable. 

Scheme 5.24 Synthesis of 2,3-allenol derivatives developed by Furstner and coworkers.

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