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Formation of Cyclic Structures

Abstract Rings in a target structure are to be made from acyclic precursors by intramolecular one-bond formation (ring closure reaction) or by two-bond formation in a cycloaddition reaction. Bicyclic and polycyclic target structures are approached in the same way, whereby two-bond disconnections or multi-bond disconnections in reaction cascades are preferred. Multi-bond disconnections may be advantageous, even when a surplus extra bond is generated in the forward synthesis.

A ring in a target structure can be formed by a ring closure reaction from open-chain precursors forming one ring bond. Two ring bonds may be formed in one stroke, when the ring is formed by a cycloaddition reaction [1]. Hence, when addressing the formation of rings in retrosynthesis, both one-bond disconnections and two-bond disconnections have to be evaluated. Regarding cyclopropanes, both alternatives appear to be well precedented. This is also true for cyclobutanes, for which both photo-[2 + 2]- and ketene[2 + 2]-cycloadditions are well established. For the formation of carbocyclic cyclopentanes or cycloheptanes, cycloadditions claim only a minor role, because [3 + 2]- and [4 + 3]-cycloaddition reactions [2] are not yet fully developed. Thus, for cyclopentanes and cycloheptanes ring closing reactions, such as intramolecular enolate alkylation and Dieckmann cyclizations, dominate. For an overview of ring forming reactions, see Scheme 6.1. For one-bond disconnections of a ring (planning ring closure reactions), one selects the cut according to the functional group presence or the presence of substituents (= branches). For two-bond disconnections one could envision stepwise formation of these bonds. This leads one to look back at the bivalent conjunctive reagents presented in Chap. 2.2.5 and 5 (cf. Schemes 5.7, 2.62, and 2.63). These reagents are well-suited for the formation of cyclic structures and are frequently used in this context. The available methodology for generating six-membered rings is quite varied and thus provides several options during the planning of a synthesis.

R.W. Hoffmann, Elements of Synthesis Planning, c Springer-Verlag Berlin Heidelberg 2009 DOI 10.1007/978-3-540-79220-8 6, 

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6 Formation of Cyclic Structures

Cyclic compounds by ring closure X

Cyclic compounds by cycloaddition X-CH2-Y Y

Scheme 6.1 Bond-sets for the construction of cyclic compounds

Principal possibilities [3] for the synthesis of cyclohexane 40 are illustrated in Scheme 6.2. COOR

COOR

(1) 40 COOR X (2) COOR ROOC

(3)

COOR (4)

Scheme 6.2 Retrosynthesis of cyclohexane 40

When a cyclohexane ring is present in the target, one should always determine whether or not a corresponding aromatic compound exists that

6 Formation of Cyclic Structures

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could be reduced to the desired cyclohexane by either hydrogenation or by Birch reduction followed by hydrogenation (Scheme 6.2, case (1)). One should also consider the classical ring-forming reactions (Scheme 6.2, cases (2) and (3)). It is most attractive to for