Enantioselective synthesis of (+)-Sedridine, (-)-Allosedridine and their N-Methyl analogs via Maruoka-Keck allylation and CBS reduction

Abstract A simple synthetic approach has been developed for the enantioselective total synthesis of (+)-Sedridine, (-)-Allosedridine and their analogs such as (+)-N- Methyl Sedridine and (-)-N-Methylallosedridine. The synthesis was achieved by using commercially available starting materials via Maruoka-Keck allylation, Wacker oxidation, and CBS reduction. The synthetic root provides a good diastereomeric ratio and high yields. Graphical Abstract


Introduction
Alkaloids are the most existing nitrogenous organic compounds in the natural product after terpenoids (Jones and Blum 1983;Hesse 2002;Buckingham et al. 2010). About 20,000 alkaloids are known and mostly isolated from various sources of the plant, animal, and fungus (Pinder 1992;Plunkett 1994;Angle and Breitenbucher 1995;Schneider and Pelletier 1996) and shows an enormous range of biological activities which includes antibacterial, antimicrobial, antifungal, anti-inflammatory, anticancer, analgesic, antitumor, etc (Srinivasan 2007;Singh et al. 2011;Marella et al. 2013;Cushnie et al. 2014;Cretton et al. 2016;Yadav et al. 2020). As a result, various alkaloid-containing drugs are present in the market (Amirkia and Heinrich 2014;Vitaku et al. 2014). Due to these broad applications in the medicinal and agrochemical industry, alkaloids are the primary target for a synthetic organic chemist (Bailey et al. 1998;Takahata et al. 1999;Lisnyak et al. 2018.). The six-membered piperidine and five-membered pyrrolidine containing functionalities are commonly present in various biologically active drug molecules and natural products. (Cossy 2005, Buffat 2004Bhat and Tilve 2013), and some representative examples are shown in Figure 1. The Allosedridine (1) , Sedridine (2) , shows Alzheimer activity (Meth-Cohn et al. 2000), Ritalin (methylphenidate) (3) used to treat attention deficit hyperactivity disorder (ADHD), Coniine (4) toxic alkaloids, Mefloquine (Lariam) (5) is an antimalarial drug and Perhexiline (6) act as an antifungal agent. Due to this structural assortment with different physiological effects and the challenge to construct the asymmetric variant, chemists have to pay attention to its synthesis. Also, these six-member alkaloid cores are the primary intermediate for the synthesis of complex natural products (O'Hagan 1997;Goel et al. 2018).
In 1965 (-) -sedridine isolation and its absolute configuration were determined by Beyerman's and Schopf's groups from Sedum acre, a perennial plant in Europe (Franck 1958;Beyerman et al. 2010). The other enantiomers of (-)-allosedridine and (þ)-allosedridine (memory-enhancing properties, Alzheimer's disease) were isolated from Sedum nudum. Few synthetic reports of sedridine, allosedridine and its N-methyl analog were reported in the literature (Uyehara et al. 1991;Littler et al. 1997;Louis and Hootel e 1997;Davis et al. 2003;Bisai and Singh 2007;Nuguri et al. 2013) . Most of these syntheses were started from chiral starting materials and involved multistep synthesis with selective enantiomer of sedridine or allosedridine. (Wulff and Ren 2013).

Result and discussion
The common piperidine intermediate 13 was synthesised from readily available starting material and the result is depicted in Scheme 1. The synthesis started with the benzyl protection of pentane diol using benzyl bromide to afford a benzyloxy ester 8 in 91% yield. The free hydroxyl group of alcohol 8 was oxidised to give corresponding aldehyde 9 in 92% yield. The aldehyde 9 was then subjected to catalytic asymmetric Maruoka-Keck allylation using [(S) -BINOL, Ti(O-iPr) 4 , (5 mol%) , allyl tributyltin, and dichloromethane (CH 2 Cl 2 ), À20 C] which furnishes homoallylic alcohol 10 in 90% yield and 98% ee. (Figure S2 in supplementary data). [a] D 25 ¼ þ4.1 (c 1, CHCl 3 ). The mesylation of the free hydroxy group of 10 was performed in dichloromethane (CH 2 Cl 2 ) , and catalytic amount DMAP and TEA as a base offered mesylate derivative. Further, this derivative was subjected to S N 2 displacement using sodium azide (NaN 3 ) in DMF gave respective azide 11. Benzyl deprotection of compound 11 in the presence of DDQ afforded corresponding alcohol 12. This alcohol readily converted into its mesylate derivative, which on intramolecular cyclisation under Staudinger reaction condition obtained piperidine core unit. After cyclisation, free cyclic amine was protected using Cbz-chloride to furnish carbamate derivative as common intermediate 13.

Experimental
Solvents were purified and dried by standard procedures before use. Dichloromethane were freshly distilled over calcium hydride under argon atmosphere, when the experiments were carried out. Optical rotations were measured using a sodium D line on a JASCO-181 digital polarimeter. Melting points are uncorrected. 1 H NMR and 13 C NMR spectra were recorded on Brucker AV-400 (100 MHz) and AV-500 (125 MHz) NMR spectrometer using residue solvent signals as an internal standard. Purification was done using column chromatography (60-120 and 100-200 mesh) . The enantiomeric excess and diastereomeric ratio were determined by HPLC analysis on a Daicel Chiralcel OD-H column (250 Â 4.6 mm). UV detector: Prominence I-Series LC2030C 3 D plus. Column: OD-H (250 Â 4.6 mm) . Flow rate: 1.0 mL/min.(k ¼ 254 nm) . The HRMS data were recorded on (electrospray ionisation (ESI) ) were obtained on Orbitrap (Quadrupole plus ion trap) and TOF mass spectrometer.

Conclusions
In conclusion, we have developed an efficient and straightforward enantioselective synthesis of (þ) -sedridine (1) and (-) -allosedridine (2) and its N-methyl analog by using asymmetric Keck allylation of aldehyde, nucleophilic substitution of azide, and diastereoselective CBS reduction of methyl ketone to introduce chirality from easily available starting material. The strategy described here has significant potential for the synthesis of biologically important pyrrolidine as well as piperidine alkaloids.