From Acyclic Precursors

The Diels-Alder is an excellent example of forming rings via reaction of two acyclic precursors. Other cyclization reactions generate rings and will be discussed in this section. 

A particularly good route to four-membered rings is via a (2-i-2]-cycloaddition. With a suitably functionalized precursor, this is a good method for preparing amino-cyclobutane amino acids. Reaction of enamine 7319 (derived from isobutyraldehyde) 

Cyclopropane derivatives can be prepared by several methods. Michael addition of the enolate of ethyl chloroacetate to ethyl acrylate generated the cyclopropane ring in 7.223 via addition to form a carbanion and internal expulsion of the chlorine moietyl Manipulation of functional groups allowed selective reduction to 7.224 and conversion to 7.225 (as a mixture of cis- and trans-isomers). Rearrangement and hydrolysis led to c/s-2-(2-amino-l-cyclopropyl)ethanoic acid, 7,226. The analogous cyclobutane derivatives were also prepared by a similar route. 

A different route involved rhodium catalyzed addition of the carbene derived from methyl a-diazoacetate to 7.227 to give 7.228 (as a 34 66 cis trans mixture). 

Reaction with HCl gave the amine and separation of diastereomers on Lewatit S-100 gave rrans-methyl-2-aminomethyl-l-cyclopropanecarboxylate, 7.229. 

---

These consider ring syntheses from non-heterocyclic compounds first, followed by transformation of other heterocyclics. Syntheses in which no new heterocyclic ring is formed are dealt with primarily in the appropriate reactivity section, but with cross-referencing when necessary. Ring syntheses from acyclic precursors are dealt with as logically as possible according to the number and nature of the new ring bonds formed in the process. 

Stereocontrolled synthesis of thiosugars from acyclic precursors and preparation of pseudonucleosides with thiosugar moiety 97YGK186. 

Nitro and 3-amino sugars have been prepared via stepv/ise constnicdon from acyclic precursors by the nitro-aldol strategy as shovm in Scheme 3 8... 

Malacria, M. (1996) Selective Preparation of Complex Polycyclic Molecules from Acyclic Precursors via Radical Mediated or Transition Metal-Catalyzed Cascade Reactions. Chemical Reviews, 96, 289-306. 

If the attacking radical contains an adequately placed radical acceptor functionality, the possibility of a radical cycloaddition is provided, offering a procedure to construct cyclic products from acyclic precursors. For this type of ring-forming process, in which two molecular fragments are united with the formation of two new bonds, the term annulation has been adopted (Scheme 3.3). 

Another method that yields quinolizidine derivatives by creation of two ct-bonds from acyclic precursors is based on a domino process involving a sequence of a double N-deprotection and a double intramolecular Michael addition sequence of reactions, as summarized in Scheme 75 <2002TL6505>. 

Formation of Three New Bonds from Acyclic Precursors... 

In connection with a study of potential serotonin receptor antagonists, some decahydrocyclazin-6-ones and -6-ols have been synthesized from acyclic precursors <1992SC3115> (Scheme 115), but those esters derived from the latter (both epimers) which have been tested to date as potential 5-HT3 receptor antagonists have shown little biological activity <1993EJM869>. 

It can form a six-membered ring with as many as four new stereocenters created in a single stereospecific step from acyclic precursors. 

In the model studies toward the total synthesis of dimethyl sulfomycinamate, Kelly et al. successfully carried out the Stille couplings of oxazolyl triflate 18 with an array of organostannanes [19, 20]. Thus, 2-aryl-4-oxalone 17 was transformed into the corresponding triflate 18, which was then coupled with 2-trimethylstannylpyridine under the agency of Pd(Ph3P)4 and LiCl to provide adduct 19. The couplings of triflate 18 with phenyl-, vinyl- and phenylethynyl trimethyltin all proceeded in excellent yields. Unfortunately, application to the more delicate system in the natural product failed and the oxazole moiety was installed from acyclic precursors. 

ArmentroutPB (1999) Gas-Phase Organometallic Chemistry. 4 1-45 Astruc D, Daniel M-C, Ruiz J (2006) Metallodendritic Exo-Receptors for the Redox Recognition of Oxo-Anions and Halides. 20 121-148 Aubert C, Fensterbank L, Gandon V, MalacriaM (2006) Complex Polycyclic Molecules from Acyclic Precursors via Transition Metal-Catalyzed Cascade Reactions. 19 259-294... 

In the area of stereoselective processes, it is worth mentioning Reaction (7.18) starting from acyclic precursor 13, where the origin of stereoselectivity could be found on the transiency of radicals and their ability of reacting before racemi-zation or conformational changes. This principle is based on the knowledge of lifetime and reactivity of radicals and is called stereoselection at the steady state [29]. 

The stereoselective synthesis of carbohydrates from acyclic precursors is a research topic that has attracted considerable attention over the past decadeT Efforts in this area are easily justified and have maximum impact particularly when directed toward rare sugars or other polyhydroxylated molecules that are not conveniently accessed via classical "chiron" approaches.2 An underlying theme of such efforts, of course, is the development of practical synthetic methodology that will find broad application in the enantio- and diastereoselective synthesis of natural products, their analogues, and other compounds of biological interest. 

This manuscript is based on a lecture presented in the "Stereoselective Synthesis of Carbohydrates from Acyclic Precursors" Symposium at the 194th American Chemical Society National Meeting, New Orleans, September 2,1987. This research is also discussed in Roush, W. R., "Strategies and Tactics in Organic Synthesis," Vol. 2. Lindberg, T., ed. Academic Press New York, 1988. 

Several enzymatic procedures have been developed for the synthesis of carbohydrates from acyclic precursors. Aldolases appear to be useful catalysts for the construction of sugars through asymmeteric C-C bond formation. 2-deoxy-KDO, 2-deoxy-2-fluoro-KDO, 9-0-acetyl sialic acid and several unusual sugars were prepared by a combined chemical and enzymatic approach. Alcohol dehydrogenases and lipases have been used in the preparation of chiral furans, hydroxyaldehydes, and glycerol acetonide which are useful as building blocks in carbohydrate synthesis. 

A chemical transformation in which a ring structure is fused to a molecular entity by way of two newly formed bonds. Some investigators distinguish annulation (the formation of a ring from acyclic precursors) from annela-tion (the fusion of an additional ring to a ring already in existence). 

---