A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine

Abstract

The yohimbinoid alkaloids have received considerable attention from the synthetic community due to their interesting chemical structures and varied biological activity. Although there have been several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class have been hampered by a lack of complete control in setting the C(3) stereocenter at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on precedent from Stork, which addresses this long standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be effectively controlled in a Pictet-Spengler reaction. This approach has been applied to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.

Diastereoselective Pictet–Spengler Reactions of a Tethered 2-Aminoimidazole

“…We previously observed that the combination of Lewis acid and Brønsted base increased the rate of Pictet-Spengler cyclisation in the six-membered ring system. [11] Unfortunately, scandium, indium, and lanthanum did not significantly change the diastereomeric ratio (Table 2) but did increase the rate of the reaction (entries [3][4][5], with scandium triflate showing marginally better activity than the other two. Temperature can have a dramatic effect on stereoselectivity by favouring the kinetic product and temperature-dependent changes in the diastereoselectivity of the standard Pictet-Spengler reaction of tryptamine with enantiopure aldehydes is known.…”

“…d C (obtained from HMBC and HSQC) (100 MHz, [D6]DMSO) 148. 5,59.9,48.9,40.6,27.2,23.2,16.3. m/z (HRMS) …”

“…d C (100 MHz, CD 3 OD) 157. 5,148.3,129.9,128.2,80.0,61.0,47.8,30.0,28.7,25.7,17.1. m/z (HRMS) 318.1900 [M þ Na] þ ; C 14 H 25 N 5 O 2 Na requires 318.1900.…”

“…5, 148.3, 129.9, 128.2, 80.0, 61.0, 47.8, 30.0, 28.7, 25.7, 17.1. m/z (HRMS) 318.1906 [M þ Na] þ ; C 14 H 25 N 5 O 2 Na requires 318.1900. 4,5,6,7,8-hexahydroimidazo[4,5-c] 5,146.1,139.6,128.8,127.5,125.2,77.0,58.2,54.5,46.9,36.5,28.9,27.9,23.5. m/z (HRMS) 4,5,6,7,8-hexahydroimidazo[4,5-c] J 8.6, 4.3, 1H), 3.68 (d, J 8.6, 1H), 3.12-3.22 (m, 1H) 6,148.0,129.5,128.2,80.0,57.5,57.0,46.3,30.2,29.8,28.8,26.3,21.3,17.1.…”

“…1), [1] and has been found useful for the synthesis of tetrahydo-b-carbolines and tetrahydroisoquinolines and recently been proposed to be a common biosynthetic reaction for the construction of a range of alkaloids. [2] The reaction has been used to great avail in classic syntheses such as haemultine, [3] manzamine alkaloids, [4] yohimbinoid alkaloids, [5] and ecteinascidin 743. [6] Although the Pictet-Spengler reaction has been widely studied in indole and benzene chemistry, [7] less is known about the Pictet-Spengler cyclisation of other heterocycles such as imidazoles, an important component of many marine natural products.…”