Origins of Regioselectivity in the Fischer Indole Synthesis of a Selective Androgen Receptor Modulator

Abstract

The selective androgen receptor modulator, (S)-(7-cyano-4-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid isopropyl ester, LY2452473, is a promising treatment of side effects of prostate cancer therapies. An acid-catalyzed Fischer indolization is a central step in its synthesis. The reaction leads to only one of the two possible indole regioisomers, along with minor decomposition products. Computations show that the formation of the observed indole is most favored energetically, while the potential pathway to the minor isomer leads instead to decomposition products. The disfavored [3,3]-sigmatropic rearrangement, which would produce the unobserved indole product, is destabilized by the electron-withdrawing phthalimide substituent. The most favored [3,3]-sigmatropic rearrangement transition state is bimodal, leading to two reaction intermediates from one transition state, which is confirmed by molecular dynamics simulations. Both intermediates can lead to the observed indole product, albeit through different mechanisms.

Low dimensional representations along intrinsic reaction coordinates and molecular dynamics trajectories using interatomic distance matrices

“…2 In addition to generating RDPESs, similar approaches (e.g., choosing specic bond distances, angles, and dihedrals along the course of trajectories as in ref. [3][4][5][6][7][8] are oen used to plot several MD trajectories, and to carry out free energy sampling [e.g., using methods like umbrella sampling, 9 metadynamics, 10 boxed molecular dynamics (BXD), 11,12 forward ux sampling, 13 milestoning, 14 all of which require a well-dened reduced dimensional space of collective variables from which to sample]. In general, these sorts of analyses tend to rely heavily on user input, i.e., the person making the surface uses their chemical intuition to pick geometric criteria that will make the analysis useful.…”

Cp*IrIII‐Catalyzed [3+2] Annulations of N‐Aryl‐2‐aminopyrimidines with Sulfoxonium Ylides to Access 2‐Alkyl Indoles Through C–H Bond Activation

“…2‐Alkyl indoles are important structural motifs because of their abundance in natural products and drugs,, such as Umifenovirl and Efipladib (Figure ), which have attractive pharmacological and biological activities Consequently, the synthesis of 2‐alkyl indole nucleus have been intensively investigated. The synthesis of indoles are well studied . However, due to the non‐commercial starting materials used in these previously developed reactions, the application of these methodologies are limited.…”

Bifurcating reactions: distribution of products from energy distribution in a shared reactive mode

“…As such, reactions 1-48 served as a training set for the model. Next, we proceed to evaluate its performance on a test set of 13 additional reactions, 49-61, 64,65,66,67,68,69,70 shown in Figure 5. is carried out according to the description in Scheme 2.…”