Bridgehead Enolates:  Substitution and Asymmetric Desymmetrization of Small Bridged Carbonyl Compounds by Lithium Amide Bases

Abstract

[reaction: see text] Contrary to expectations, a number of bridged carbonyl compounds undergo facile bridgehead metalation with lithium amide bases. Diketone, lactone, lactam, and imide functions are all demonstrated to participate in this type of "bridgehead enolate" chemistry, leading to a range of substituted products. Meso compounds can also be desymmetrized in very high ee by asymmetric bridgehead metalation.

Synthesis of (+/−)-Clusianone: High-Yielding Bridgehead and Diketone Substitutions by Regioselective Lithiation of Enol Ether Derivatives of Bicyclo[3.3.1]nonane-2,4,9-triones

“…On the basis of our successful bridgehead lithiation−substitution results on related [3.3.1] systems, we anticipated adopting this method for appending appropriate substituents onto a core structure 5 at either (or both) bridgehead substituent. Direct substitution at the vinylic position (C-3) by metalation also appeared viable .…”

Synthesis of (±)-Aphanorphine Using Rh-Catalyzed Cyclohydrocarbonylation

“…R f = 0.43; EtOAc/n-Hex = 1:1. 1 H NMR (400 MHz, 25 °C, CDCl 3 , δ): 2.00–2.10 (m, 1H, H-10), 2.26 (dddd, J = 1.6, 3.6, 6.8, and 13.2 Hz, 1H, H-10), 2.67 (dd, J = 8.4 and 15.6 Hz, 1H, H-5), 2.94 (dd, J = 4.8 and 15.6 Hz, 1H, H-5), 3.62 (s, 3H, −NHCO 2 C H 3 ), 3.72 (s, 3H, −CO 2 C H 3 ), 3.73 (s, 3H, −OC H 3 at C-8), 3.90–4.02 (m, 2H, H-1 and H-4), 5.54 (brs, 1H, −N H ), 6.69 (d, J = 2.4 Hz, 1H, H-9), 6.73 (dd, J = 2.8 and 8.4 Hz, 1H, H-7), 6.97 (d, J = 8.4 Hz, 1H, H-6). 13 C NMR (100 MHz, 25 °C, CDCl 3 , δ): 31.8 (t, C-10), 34.9 (t, C-5), 44.2 (d, C-1), 45.5 (d, C-4), 51.8 (q, −NHCO 2 C H 3 ), 52.3 (q, −CO 2 C H 3 ), 55.2 (q, −O C H 3 at C-8), 113.1 (d, C-9), 113.3 (d, C-7), 126.4 (s, C-5a), 130.6 (d, C-6), 132.8 (s, C-9a), 156.3 (s, −NH C O 2 CH 3 ), 158.0 (s, C-8), 175.0 (s, C-2).…”

“…These conditions generally brought formation of either decomposed residue or starting material recovery. Although the Simpkins’ protocol , using LDA/LiCl or LTMP/LiCl complex followed by alkylating reagents was known as a practical route to alkylate the bridge methine in a bicyclo system, the conditions only afforded an undesired N -methyl lactam 10 . Formation of N -methylated product 10 could be attributed to the fact that the strong base reacted first with the N-carbamate group to yield the resulting anion, rather than abstracted a proton from the methine position.…”

Adventures in bridgehead substitution chemistry: synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs)

“…11 Examples of reactions described in our 2003 communication are shown in Scheme 1. 12 The conversion of [3.3.1]dione 5 into the silylated derivative 6, albeit in modest yield, was a first indication that bridgehead substitution in a parent system closely related to those present in PPAPs could be realized. This particular example is atypical, in that the 1,3-diketone is surely enolized first, thus implicating either a dianion or perhaps a labile enol silane as intermediate.…”