Natural products rearrangements

Pelletier, S. W., Studies in the chemistry of natural products Rearrangement reactions of diterpenoid and norditerpenoid alkaloids, J. Nat. Prod., 55, 1-24 (1992). 

The principal steps in the mechanism of polyisoprene formation in plants are known and should help to improve the natural production of hydrocarbons. Mevalonic acid, a key intermediate derived from plant carbohydrate via acetylcoen2yme A, is transformed into isopentenyl pyrophosphate (IPP) via phosphorylation, dehydration, and decarboxylation (see Alkaloids). IPP then rearranges to dimethylaHyl pyrophosphate (DMAPP). DMAPP and... 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

The stereochemical outcome of the reaction is determined by the geometry of the transition state for the Claisen rearrangement a chairlike conformation is preferred,and it proceeds strictly by an intramolecular pathway. It is therefore possible to predict the stereochemical course of the reaction, and thus the configuration of the stereogenic centers to be generated. This potential can be used for the planning of stereoselective syntheses e.g the synthesis of natural products. 

The Neber rearrangement has for example found application in natural product synthesis. 

In this beautiful synthesis of periplanone B, Still demonstrated a classical aspect and use of total synthesis - the unambiguous establishment of the structure of a natural product. More impressively, he demonstrated the usefulness of the anionic oxy-Cope rearrangement in the construction of ten-membered rings and the feasibility of exploiting conformational preferences of these medium-sized rings to direct the stereochemical course of chemical reactions on such templates. 

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

Since its discovery two decades ago, the reversible interconversion of allylic sulfenates to sulfoxides has become one of the best known [2,3]-sigmatropic rearrangements. Certainly this is not only because of the considerable mechanistic and stereochemical interest involved, but also because of its remarkable synthetic utility as a key reaction in the stereospecific total synthesis of a variety of natural products such as steroids, prostaglandins, leukotrienes, etc. 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators110-113 have employed the allylic sulfenate-to-sulfoxide equilibrium in combination with the syn elimination of the latter as a method for the synthesis of conjugated dienes. For example, Reich and coworkers110,111 have reported a detailed study on the conversion of allylic alcohols to 1,3-dienes by sequential sulfenate sulfoxide rearrangement and syn elimination of the sulfoxide. This method of mild and efficient 1,4-dehydration of allylic alcohols has also been shown to proceed with overall cis stereochemistry in cyclic systems, as illustrated by equation 25. The reaction of trans-46 proceeds almost instantaneously at room temperature, while that of the cis-alcohol is much slower. This method has been subsequently applied for the synthesis of several natural products, such as the stereoselective transformation of the allylic alcohol 48 into the sex pheromone of the Red Bollworm Moth (49)112 and the conversion of isocodeine (50) into 6-demethoxythebaine (51)113. 

Further examples of the utility of the allylic sulfoxide-sulfenate interconversion in the construction of various biologically active natural products include intermediates such as the /Miydroxy-a-methylene-y-butyrolactones (e.g. 63)128 and tetrahydrochromanone derivative 64129. Interestingly, the facility and efficiency of this rearrangement has also attracted attention beyond the conventional boundaries of organic chemistry. Thus, a study on mechanism-based enzyme inactivation using an allyl sulfoxide-sulfenate rearrangement has also been published130 131. 

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

Two illustrations that show the power of this reaction for the preparation of strained cycloalkenes are the contractions of 102 to the propellane 103 , an application that has been reviewed , and of 104 to the bicyclo[2.1.1]hexene 105 . The utility of the Ramberg-Backlund rearrangement in the preparation of various natural products such as steroids , terpenoids and pheromones has been demonstrated. In addition to the synthetic applications mentioned in the previous subsection, several selected examples taken from the recent literature are given in equations 66-69. These examples further demonstrate the potential of this method for alkene synthesis in general. 

In addition to the synthetic applications related to the stereoselective or stereospecific syntheses of various systems, especially natural products, described in the previous subsection, a number of general synthetic uses of the reversible [2,3]-sigmatropic rearrangement of allylic sulfoxides are presented below. Several investigators 3 jj... 

Entry 2 illustrates the reversibility of the Cope rearrangement. In this case, the equilibrium is closely balanced with the reactant benefiting from a more-substituted double bond, whereas the product is stabilized by conjugation. The reaction in Entry 3 involves a cz s-divinylcyclopropane and proceeds at much lower temperature that the previous examples. The reaction was used in the preparation of an intermediate for the synthesis of pseudoguiane-type natural products. 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

Phospholipids or similar water-insoluble amphiphilic natural substances aggregate in water to form bilayer liquid crystals which rearrange when exposed to ultrasonic waves to give spherical vesicles. Natural product vesicles are also called liposomes. Liposomes, as well as synthetic bilayer vesicles, can entrap substances in the inner aqueous phase, retain them for extended periods, and release them by physical process. 

The possible occurrence of such major rearrangement of a compound s carbon skeleton, during the course of apparently unequivocal reactions, is clearly of the utmost significance in interpreting the results of experiments aimed at structure elucidation particularly when the actual product is isomeric with the expected one. Some rearrangements of this type are highly complex, e.g. in the field of natural products such as terpenes, and have often made the unambiguous elucidation of reaction pathways extremely difficult. The structure of reaction products should never be assumed but always confirmed as a routine measure lH and 13C n.m.r. spectroscopy have proved of enormous value in this respect. 

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