Intramolecular reactions steroid skeletons

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers111 in the intramolecular Diels-Alder reaction of the a, jS-unsaturated sulfone moiety of 165 (equation 117). Thus, when the sulfone 165 is heated in 1,2-dichlorobenzene for 6h, the steroidal compound 166 can be obtained in 62% yield. The compound 166 produces estrone (167) by elimination of benzenesulfinic acid and subsequent hydrogenation of the formed double bond. The stereoselectivity of the addition reflects a transition state in which the p-tosyl group occupies the exo position to minimize the steric repulsion between methyl and t-butoxy groups and the o-quinodimethane group as shown in equation 117. 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers in the intramolecular Diels-Alder reaction of the ot, jS-unsaturated sulfone... 

Entry 9 uses the oxaborazolidine catalysts discussed on p. 505 with 2-bromopropenal as the dienophile. The aldehyde adopts the exo position in each case, which is consistent with the proposed TS model. Entry 10 illustrates the use of a cationic oxaborazolidine catalyst. The chirality is derived from trans-1,2-diaminocyclohcxanc. Entry 12 shows the use of a TADDOL catalyst in the construction of the steroid skeleton. Entry 13 is an intramolecular D-A reaction catalyzed by a Cu-Ws-oxazoline. Entries 14 and 15 show the use of the oxazaborolidinone catalyst with more complex dienes. 

The presence of a 5-hexenyl substituent in 28i allowed the o-quinodimethane 229b to be captured in an intramolecular Diels-Alder reaction, producing 230, having a tetracyclic steroidal skeleton, in a single operation (Scheme 20.47) [33, 34], The fused tetracyclic 5,6,6,5-ring system was likewise produced from 34f and 34g. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Steroids are naturally occurring terpenoids that are based on a system consisting of four fused rings. In 2006, Chung and co-workers published the synthesis of the basic steroidal skeleton (54->56) and employed an intramolecular PK reaction as the key step (55 —> 56 - Scheme 21).69... 

The synthesis of the female sex hormone progesterone by W. S. Johnson and co-workers at Stanford University is considered one of the classics in total synthesis. The last six-membered ring needed in the steroid skeleton was prepared by a two-step sequence using an intramolecular aldol reaction, as shown in Figure 24.5. 

TMG (1), as well as benzyltrimethylammonium hydroxide (Triton B) in pyridine and sodium ethoxide in ethanol, was found to work as base catalyst in the cyclopropanation of steroid skeletons controlled by intramolecular Sn2 reaction [70]. Thus, 6-oxo-3a,5-cyclo-5ot-steroids were given in high yields for the reaction of 3p-tosyloxy (or -chloro)-6-oxo derivatives (Table 4.8). 

By starting from the enyne-allene 27, the o-quinodimethane 28 was captured in an intramolecular Diels-Alder reaction to give 29 having the tetracyclic steroidal skeleton (Scheme 6) (19,20). It is worth noting that this cascade reaction could involve an energy loss of more than 100 kcal/mol with conversion of four n bonds in 27 to four o bonds in 29 along with the formation of a benzene ring. 

In the first synthesis to be discussed [14] an intramolecular Diels/Alder reaction is the key reaction to construct the steroid skeleton, according to the constitutional pattern A+D -> AD ->ABCD. 

Intramolecular Cycloadditions.—Application of certain intramolecular reactions allows the synthetic chemist to generate complex carbon skeletons more readily than by using intermolecular processes, and to exercise considerable control over regio- and stereo-specificity. It is not surprising, therefore, that this area of endeavour has become increasingly popular in recent years. Dominant among the reactions under study has been the intramolecular [4 + 2] cycloaddition (i.e. the intramolecular variant of the Diels-Alder reaction), some examples of which have already been noted in earlier sections. The reaction has also been applied in total syntheses of steroids, ( )-cedrol, eudesmane sesquiterpenes, and norpatchoulenol. The intramolecular [3 + 2] cycloaddition, a related process, has been used by Confalone et al. in a synthesis of ( )-biotin. The key steps are... 

In the presence of an excess of small alkynes the typical [3+2+1 jbenzannulation has to compete with a [2+2+1+lj (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels-Alder reaction of the more electron-deficient bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky s diene a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30%... 

One of the key features in Scheme 27 is the intramolecular cycloaddition of an o-quinodimethane intermediate, and this reaction has featured in several other new approaches to steroidal and related polycyclic carbon skeletons (Scheme 28). The last example in Scheme 28 also illustrates a new route to the cyclization precursor (119) via a nucleophilic induced elimination-addition of an a-halogeno-... 

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