Fully Substituted Carbon Centers by Diastereoselective Spirocyclization: Stereoselective Synthesis of (+)-Lepadiformine C

Abstract

Reductive lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A 1,3 -strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.Stereoselective construction of fully-substituted carbon atoms is a challenge that is often at the heart of a successful complex natural product synthesis. Several years ago we reported a synthesis of spirocycles that was based on stereoselective generation of alkyllithium reagents arising from anomeric stabilization of radical intermediates.1 , 2 Herein we describe studies on the generation of α-hetero alkyllithium reagents where classic anomeric stabilization is not relevant, but that still show highly stereoselective transformations. This new stereoselective strategy leads to fully substituted carbon atoms and is illustrated with a concise synthesis of lepadiformine C.3Reduction of N-protected α-amino nitriles with Freeman's reagent (LiDBB)4 is an effective strategy to generate tertiary α-amino alkyllithium reagents.5 An N-alkyl 2-cyano piperidine generally leads to the alkyllithium with high selectivity, but when the nitrogen atom is protected as a Boc carbamate the alkyllithium is produced as a 1.5:1 mixture of isomers.6 The reductive lithiation of N-Boc piperidine 1 in Scheme 1 was instigated to probe the reactivity of the Boc-protected α-amino alkyllithium reagent. Although the lithiation is not stereoselective, both alkyllithium isomers cyclize effectively at −78 °C to produce the bicycle 2 in excellent yield. These tertiary N-Boc α-amino alkyllithium reagents are expected to be conformationally stable at −78 °C, with inversion barriers ca. 20 kcal/mol.7 This experiment demonstrated that tertiary N-Boc alkyllithium reagents may cyclize with retention (SE ret ) or inversion (SE inv ), and the suitably constrained systems can produce single isomers in high yields.8 , 9* srychnov@uci.edu .Supporting Information Available: Experimental procedures for all compounds, X-ray analysis of compound 21 and configuration assignments for compound 26 and 31 are included. The spirocyclizations of nitriles 3 and 5 were highly stereoselective. Both cyclizations proceed with overall retention at the fully substituted center,10 and the heteroatom ends up in the equatorial position. The rationale...

Marine natural products

“…837 Two syntheses of the tricyclic alkaloid lepadiformine C (Clavelina moluccensis) 838 have been reported, one featuring a tandem Prins addition/intramolecular Schmidt rearrangement 839 while the second route made use of diastereoselective spirocyclisation methodology. 840 A straightforward synthesis of the mildly cytotoxic b-carboline alkaloid eudistalbin A 921 (Eudistoma album) 841 established a (10S) configuration. 842 Structural analogues of the cytotoxic alkaloid ascididemin were moderately anti-tuberculosis with negligible cytotoxicity.…”

Direct Access to Cumbersome Aminated Quaternary Centers by Hyperbaric Aza‐Michael Additions

“…In most cases, no general solution is available and the fine‐tuning of particular reaction conditions is necessary to achieve the target in acceptable yields and selectivities 1. Aminated quaternary carbon centers are no exception to this rule, even if they are found in many natural products such as important alkaloids, including, FR9014832 and (+)‐lepadiformine C,3 and the proteosome inhibitors salinosporamide A, omuralide, and lactacystin 4. The design of efficient routes to these compounds is far from trivial, and significant difficulties lie in the assembling of the aminated quaternary center.…”

Studies toward the Synthesis of Lepadiformine A

“…The combined organic layers were washed with brine (20 mL), filtered, and concentrated to afford 3.71 g (94%) of 7chloro-4-methoxyquinoline: 1 H NMR (CDCl 3 , 400 MHz) δ 8.75− 8.73 (d, 1H, J = 5.6 Hz), 8.13−8.11 (d, 1H, J = 8.8 Hz), 8.02−8.01 (d, 1H, J = 2.4 Hz), 7.45−7.42 (dd, 1H, J = 9.2, 2.0 Hz). 6.73−6.72 (d, 1H, J = 5.2 Hz), 4.04 (s, 3H); 13 C NMR (CDCl 3 , 100 MHz) δ 162.5, 125.7, 149.9, 135.9, 128.1, 126.7, 123.6, 120.0, 100.5, 56.0.…”

“…The solvent was removed via rotary evaporation. The oil was purified by column chromatography (silica gel, 5% MeOH/CH 2 Cl 2 ) to afford 10.2 g (60%) of compound 8: IR (neat) 2935, 1578, 1475, 1439, 1336, 1289, 1160, 1109, 1089, 1057, 997, 879, 808 cm −1 ; 1 H NMR (CDCl 3 , 400 MHz) δ 8.25, (d, 1H, J = 5.6 Hz), 6.57, (d, 1H, J = 5.6 Hz), 3.84 (s, 3H), 2.87 (t, 2H, J = 6.0 Hz), 2.62 (t, 2H, J = 6.4 Hz), 1.80 (m, 4H); 13 rac-Phenyl 2-n-Hexyl-4-oxo-3,4,5,6,7,8-hexahydroquinoline-1(2H)-carboxylate (11a). To a solution of 4-methoxy-5,6,7,8tetrahydroquinoline 8 (638 mg, 3.91 mmol) in 10 mL of anhydrous THF was added dropwise phenyl chloroformate (0.54 mL, 4.32 mmol) at −42 °C.…”