Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons**

Abstract

The stereoselectivity and stereospecificity of the triflate-mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine,t he structural skeleton of several important families of alkaloids such as the Stemona alkaloids,h as been examined. The reaction involves an initial intramolecular S N 2r eaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N 2 -elimination followed by hydride-mediated iminium salt reduction. Remarkably,c hiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process,leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1Hpyrrolo[1,2-a]azepine.T he origin of the stereoselectivity is rationalized based on theoretical calculations.T he concise synthesis of (À)-(cis)-3-propylindolizidine and (À)-(cis)-3butyllehmizidine,two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster,isreported.

Stereoselective and Stereospecific Triflate‐Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons**

“…-13 were attributed based on reported stereochemical outcome of similar reactions.F or compound 10,single crystal X-ray analysis of the 4-bromo-3-nitrobenzoate ester 10 bnb [16] confirmed its (S)-absolute configuration in accordance with expectations. [25] Theintramolecular Schmidt reaction involving 10-13 was investigated next (Table 2).…”

“…This conformation was also found to be prevalent in the solid-state structure of 6im determined by single crystal X-ray analysis (Figure 1). [16] In the lowest energy conformer of iminium salt 6im,t he face syn to the phenyl group is blocked by triflate anion, thus favouring the formation of the cis product through anti addition of the hydride (Model F). Calculation of transition state energies were performed to get ab etter understanding of the factors governing the stereochemistry of the reduction of 6im + with DIBAL.…”

“…Thec onfiguration of the starting material 7 was assigned by single crystal X-ray analysis of the 3,5-dinitrobenzoate ester 7dnb. [16] During the Schmidt reaction, as econd chiral center at C( 7) is created during the 1,2-migration process and at hird one at C(9a) is introduced during the final hydride addition step.D esilylation during workup eventually leads to aminoalcohol 8.W hent he reaction was run with DIBAL, am ixture of 2d iastereomers (out of the four possible) in a8 5:15 ratio was observed. By running the final iminium reduction step with NaBH 4 ,asingle diastereomer was obtained (Scheme 3).…”

“…The3 ,5-dinitrobenzoate ester 8dnb was prepared from the major isomer of 8 by acylation with 3,5-dinitrobenzoyl chloride.I ts relative (1RS,7SR,9aSR)c onfiguration could be determined unambiguously by single crystal X-ray analysis (Scheme 3). [16] Based on the relative configuration of the starting azide 7 (azido group trans to the phenyl substituent, see X-ray structure of 7dnb in Scheme 3) and the relative configuration of the final product 8 (see X-ray structure of 8dnb in Scheme 3), one can conclude that the CÀCb ond anti to the OTBS group is migrating (Figure 2, G)a nd that the final hydride addition to the iminium ion 7im + is taking place anti to the phenyl group (1,4-induction) and syn to the adjacent OTBS group.…”

“…Under the standard reaction conditions,a ll four alcohols gave the desired bicyclic amides 15-18 in 32-85 %yield as asingle diastereomer.Interestingly, the enantiomeric ratio of the starting material was fully preserved for 15 and 16 and only slight loss of optical purity was observed for 17 and even more remarkably for 18 derived from the benzylic alcohol 13.The absolute configuration of 15 could be established using single crystal X-ray analysis of its (R)-mandelic acid salt (Figure 3). [16] Thea bsolute configurations (S)-10 and (3R)-15 demonstrate that the intramolecular Schmidt reaction proceeds with inversion of configuration at the alcohol stereocenter.T his indicates that an S N 2-type mechanism is involved in the formation of the intermediate spirocyclic aminodiazonium salt 10 ad + (Figure 4, I). Even the benzylic alcohol 13 reacts mainly via an S N 2pathway since only limited racemization is observed.…”