A Two-Directional Synthesis of (+)-β-Isosparteine

Abstract

ABSTRACT:A two-directional synthesis of (+)-β-isosparteine is described in 5 steps from glutaric acid, where the entire carbon and nitrogen backbone of the alkaloid, possessing the requisite relative and absolute stereochemistry at its four stereogenic centers, is assembled using a double imino-aldol reaction.Sparteine alkaloids represent a sub-set of a larger group of quinolizidine-containing alkaloids known as lupinus or lupin alkaloids due to their widespread occurrence as secondary metabolites in lupins.1 Both enantiomeric forms of sparteine ((-)-1 and (+)-1) are present in nature, 2 as are the less abundant C 2 symmetrical diastereoisomers (-)-α-and (-)-β-isosparteine (2 and 3, respectively, Figure 1). 3 The enantiomers of sparteine are valued by organic chemists for a diversity of applications as chiral diamines in asymmetric synthesis, 4 although supply issues have stimulated interest in the development of surrogates. 4e,5 Reported bioactivity is also dominated by the more available stereoisomer, 1d and (-)-sparteine even found clinical applications, for example as an oxytocic agent, 6,7 although its FDA approved drug status was withdrawn due to safety concerns. Comparatively less is known about the more scarce C 2 symmetrical isomers either in terms of pharmacology, 8 or synthetic applications as ligands.4f,9There have been racemic total synthesis of α-and β-isosparteine, and enantiomerically enriched α-and β- We have shown that simple quinolizidine alkaloids, such as epilupinine 3, possessing a "syn" relationship are conveniently accessible using syn-selective imino-aldol reactions wherein control of absolute stereochemistry is enabled through use of tert-butanesulfinyl auxiliaries. [13][14][15] Stereochemically, the possible diastereoisomeric sparteine alkaloids 1-3 may also be considered to posses "syn" or "anti" relationships between adjacent stereogenic centers based upon their synthetic origin from amino-aldols (Figures 1 and 2). For example, C6/C7 and C9/C11 have "syn" and "anti" relationships in sparteine, while the relative relationships are both "syn" in (+)-β-isosparteine ((+)-2). Here we show how a two-directional, syn-selective, double imino-aldol reaction can be applied to achieve a short synthesis of (+)-β-isosparteine. Figure 2. Two-directional synthesis approach to (+)-β-isosparteinePrevious studies from our laboratory involving imino-aldol reactions of tert-butanesulfinimines showed that lithium enolates of phenyl esters underwent addition to alkyl-and alkenyl-substituted tert-butanesulfinimines with good to excellent diastereoselectivity.13 Furthermore, these imino-aldol reactions tolerated a reasonable variety of functionalization in both ester and sulfinimine substrates. Our starting point for the current work was to explore whether this methodology could be used in a two-directional approach to the C 2 -symmetrical tetracyclic lupin alkaloid (+)-β-isosparteine. Deprotonation of Page 1 of 3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 ...

Synthesis of Natural Compounds Based on the [3,7]‐Diazabicyclo[3.3.1]nonane (Bispidine) Core

“…The synthesis of (+)‐ β ‐isosparteine, a natural isomer of sparteine, has been recently described by Brown and co‐workers [29] . This compound is particularly interesting for its oxytocic and anti‐arrhythmic properties.…”

Strategies for the Diversity-Oriented Synthesis of Macrocycles

“…Two-directional strategies have found several applications in the generation of complex molecules − and as a versatile synthetic strategy in total synthesis of natural products. − This was recognized by O’Connell et al, who applied a two-directional strategy in their effort to synthesize macrocycles, see Figure . Bis-enyne amides ( 33 - 1 ) generated in the “build” and “couple” phases were paired with bis-azides ( 33 - 3 ) using CuAAC conditions to afford the corresponding bis-triazole compounds (example 33 - 5 ).…”

Visible-Light-Mediated Efficient Metal-Free Catalyst for α-Oxygenation of Tertiary Amines to Amides

“…In order to prove the synthetic practicability of the present metal-free α-oxygenation protocol, the oxidation of drug molecules was performed. As shown in Scheme , oxidation of meclizine and donepezil was performed smoothly in our system with a good yield of the corresponding amide (Scheme , compounds 30–31b ). , Finally, we also investigated the applicability of our protocol for the direct synthesis of natural products including ( S )-(−)-8-oxoxylopinine and 17-oxosparteine (Scheme , compounds 32b – 33b ). , In fact, both of these natural products can be synthesized directly in a single step, using this metal-free pathway.…”

“…62,63 Finally, we also investigated the applicability of our protocol for the direct synthesis of natural products including (S)-(−)-8-oxoxylopinine and 17-oxosparteine (Scheme 5, compounds 32b−33b). 64,65 In fact, both of these natural products can be synthesized directly in a single step, using this metal-free pathway.…”