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Volume 86, Issue 7

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Efficient asymmetric syntheses of alkaloids and medicinally relevant molecules based on heterocyclic chiral building blocks

Ai-E Wang
  • Department of Chemistry and Fujian Provincial Key Laboratory for Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
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/ Pei-Qiang Huang
  • Corresponding author
  • Department of Chemistry and Fujian Provincial Key Laboratory for Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
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Published Online: 2014-04-04 | DOI: https://doi.org/10.1515/pac-2013-1210

Abstract

In this report, we present recent progress in synthetic methodologies based on three heterocyclic chiral building blocks developed from our laboratories. The potential of these chiral building block-based methods in the concise asymmetric synthesis of alkaloids and medicinally interesting molecules has been demonstrated by the total syntheses of 8-aza-prostaglandin E1, 11-hydroxylated analogues of the lead compounds CP-734432 and PF-04475270, (+)-castanospermine, (+)-1-epi-castanospermine, 7-deoxy-6-epi-castanospermine as well as 9-epi-sessilifoliamide J.

Keywords: alkaloids; asymmetric synthesis; chiral building blocks; ICHC-24; synthetic methodology; total synthesis

Article note: A collection of invited papers based on presentations at the 24th International Congress on Heterocyclic Chemistry (ICHC-24), Shanghai, China, 8–13 September 2013.

Dedicated to Prof. Dr. Li-Xin Dai on occasion of his 90th birthday.

Introduction

Nature affords us a great variety of secondary metabolites, namely, natural products. As the results of millions of years of co-evolution, these molecules play a major role in drug discovery. Indeed, more than half of the drugs currently in clinical use are originated or derived from natural products [1]. Although the use of natural products for drug discovery has declined in the era of combinatorial chemistry, there has been a renaissance of natural products as drug candidates recently [1, 2]. In biosynthetic routes to secondary metabolites, nature usually uses a limited number of simple building blocks normally from primary metabolism (such as amino acids for nonribosomal peptides, acyl-CoA thioesters for polyketides, isoprenyl diphosphates for terpenes). So the building block approach can be regarded as the basic strategy for nature to synthesize natural products. Recently, with the emergence of chemomics as a interdiscipline of chemoinformatics, bioinformatics and synthetic chemistry for drug innovation [3], a new era of building block strategy [4] is expected to come not only in the total synthesis of natural products but also in the fields of drug innovation.

In recent years, we have been engaged in the development of synthetic methodologies based on heterocyclic building blocks for the total synthesis of bioactive alkaloids [5]. We shall present herein our recent synthetic methodologies based on building blocks 1–3 (Fig. 1) and their applications in the syntheses of natural products and medicinally relevant molecules.

Three versatile heterocyclic chiral building blocks.
Fig. 1

Three versatile heterocyclic chiral building blocks.

Building block 1: enantioselective syntheses of 8-aza- prostaglandin E1 (8-aza-pge1) and its analogues

Prostaglandins (PGs) are a group of naturally occurring lipid compounds found in trace amount in animals and in humans, which display strong and diverse physiological activities [6]. The total synthesis of prostaglandins has attracted tremendous attention since the late 1960s [7]. Up to 1984, over 5000 prostaglandin analogues have been synthesized and tested biologically [8]. Those efforts have resulted in the discovery of several drugs currently in clinical use [7a], four of which have entered the list of top 200 brand-name drugs by total US prescriptions in 2010 [9]. In recent years, some medicinally interesting γ-lactam analogues have been discovered, such as CP-734432 (4 in Fig. 2), a highly selective EP4 receptor agonist, and PF-04475270 (5), a novel ocular hypotensive compound. In order to develop medicinally relevant analogues, we embarked on the enantioselective synthesis of 8-aza-PGE1 (7) and the 11-hydroxylated analogues (8 and 9) of the leads CP-734432 (4) and PF-04475270 (5) in light of the structure, medical usage [10] and side effects [11] of PGE1 (alprostadil, 6).

PGE1, 8-aza-PGE1 and their analogues.
Fig. 2

PGE1, 8-aza-PGE1 and their analogues.

The enantioselective synthesis of 8-aza-PGE1 (7)

Taking advantages of the chemistry of malimide 1 (10 in Scheme 2), a modular strategy has been developed for the first enantioselective synthesis of 8-aza-PGE1 (7) (Scheme 1) [12].

Synthetic plan for the modular enantioselective synthesis of 8-aza-PGE1 (7).
Scheme 1

Synthetic plan for the modular enantioselective synthesis of 8-aza-PGE1 (7).

Malimide 10 was first prepared by condensation of (R)-malic acid with the commercially available α,ω-amino ester hydrochloride salt [13] followed by O-benzylation. It was then converted to 5-vinyl-γ-lactam 13 in four steps via Ley’s sulfone-based α-amidoalkylation protocol [14] (dr = 6.8: 1) and O-debenzylation (Scheme 2). On the other hand, (S)-allylic alcohol 14 was synthesized from (E)-2-octenol in 99 % ee via Sharpless asymmetric epoxidation (SAE) [15] followed by Yadav’s titanocene-mediated epoxide opening (Cp2TiCl2, Zn, and ZnCl2 in THF at rt) [16]. Finally, the cross olefin metathesis reaction (CM) [17] was used to connect the 5-vinyl-γ-lactam subunit 12 with the chiral pro-ω-chain 14.

Enantioselective synthesis of 8-aza-PGE1 (7).
Scheme 2

Enantioselective synthesis of 8-aza-PGE1 (7).

This modular approach is very concise and efficient [with the longest linear sequence of eight steps from (R)-malic acid in 17 % overall yield], which provides a versatile strategy for the synthesis of analogues of 8-aza-PGE1 (7), as well as PGs, prostacyclins and analogues in general.

The enantioselective synthesis of 11-hydroxylated analogues of CP-734432 and PF-04475270

For the asymmetric synthesis of the novel 11-hydroxylated analogues (8 and 9) of the lead compounds CP-734432 (4) and PF-04475270 (5), a novel convergent strategy has been developed (Scheme 3) [18]. The key element of this approach resides in the intermolecular radical addition based on synthon A to build the pro-ω-chain. Although β-hydroxylated lactam N-α-alkyl radical-based C–C bond forming methodology, pioneered by Hart and co-workers [19], allows for intramolecular reactions, the corresponding intermolecular version was unprecedented and challenging.

Synthetic plan for the convergent synthesis of the 11-hydroxylated analogues (8 and 9) of the leads CP-734432 (4) and PF-04475270 (5).
Scheme 3

Synthetic plan for the convergent synthesis of the 11-hydroxylated analogues (8 and 9) of the leads CP-734432 (4) and PF-04475270 (5).

An exploration of the intermolecular radical addition with activated alkenes based on synthon A was first undertaken. The combination of the chemistry of SmI2 [20], invented by Kagan and co-workers, with the lactam 2-pyridyl sulfone 18 (Scheme 4), inspired from the work of Beau [21], turned out to be fruitful for the desired intermolecular radical addition.

Asymmetric synthesis of 11-hydroxylated analogues (8 and 9) of the leads CP-734432 (4) and PF-04475270 (5).
Scheme 4

Asymmetric synthesis of 11-hydroxylated analogues (8 and 9) of the leads CP-734432 (4) and PF-04475270 (5).

The synthesis started from the known malimide [22] 17, which was converted to the γ-lactam 2-pyridyl sulfone 18 in three steps. The key SmI2-mediated cross coupling of sulfone 18 with methyl acrylate underwent smoothly in the presence of t-BuOH at –60 °C to produce the desired product 19 as a single diastereomer in 90 % yield. Ester 19 was converted into ketone 20 via the corresponding Weinreb amide [23]. The CBS reduction [24] yielded alcohol (8R/8S)-21 (dr =3: 1) in 95 % yield. The major diastereomer was successively subjected to O-benzylation, N-deprotection, N-alkylation with iodide 15, and bis-O-debenzylation to produce 11-hydroxy-PF-04475270 (9). Saponification of compound 9 afforded 11-hydroxy-CP-734432 (8).

Building block 3: the asymmetric syntheses of (+)-castanospermine (22), (+)-1-epi-castanospermine (33), and 7-deoxy-6-epi-castanospermine (23)

Azasugars (also called iminosugars) constitute a class of sugar mimetics. Due to their remarkable and widespread bioactivities, these compounds have attracted considerable attention from organic, biological and medicinal chemists [25, 26]. Several pharmaceuticals have thus been developed and some are currently under clinical uses [26]. Among azasugars, castanospermine (22 in Fig. 3) is the one that attracts the most attention because of its remarkable bioactivity and challenging structural feature (bearing five contiguous chiral centers). Castanospermine (22), and its congener 7-deoxy-6-epi-castanospermine (23) were isolated [27] from the seeds of Castanospermum australe and the dried pod of Alexa leiopetala. Possessing powerful and selective inhibitory activities towards α- and β-glucosidases [28], castanospermine (22) and analogues have potential uses as anticancer, antiviral, anti-HIV, and antidiabetic agents. For example, castanospermine (22) has once entered phase II clinical trials as an anticancer agent, and 6-O-butanoyl castanospermine (MBI-3253, celgosivir) (24) is currently under Phase II clinical trials for the treatment of patients with chronic HCV [29].

Castanospermine and its analogues.
Fig. 3

Castanospermine and its analogues.

A very attractive convergent retrosynthetic analysis of castanospermine (22) and analogues is outlined in Scheme 5 [30]. The synthon B/ C-based methodologies (approach A) is challenging, however, due to β-elimination [31] of carbanions B/ C, quick proton exchange of carbanion C [32], low stereoselectivity in C–C bond formation and difficult access to the enantiomeric pure forms of carbanion B/C [30]. So we opted to develop methodologies based on the tetramic acid derivative 3 as a versatile chiral building block (approach B) [33]. We have previously developed C-5-alkylation reaction with alkyl halides using chiral building block 3 as a synthetic equivalent of the heterocyclic synthons G and H [33]. For the synthesis of castanospermine (22) and analogues, the vinylogous aldol reaction of 3 was investigated.

Retrosynthetic analysis of castanospermine and analogues.
Scheme 5

Retrosynthetic analysis of castanospermine and analogues.

Thanks to the extensive studies of Casiraghi and co-workers, the vinylogous aldol reaction of heterocyclic silyloxy dienes has become a powerful methodology for the synthesis of heterocycles [34]. In our studies, we found that the silyloxy diene 27, in situ generated from the tetramic acid derivative 3, could react with aldehydes in the presence of SnCl4 at –78 °C to provide the corresponding aldol products in excellent diastereoselectivity [35]. The vinylogous aldol reaction with 4-O-(4-methoxybenzyl)-2,3-bis-(O-benzyl)-L-threose (28) produced the vinylogous aldol product 29 as the sole product in 60 % yield (Scheme 6). Hydrolysis of compound 29 under acidic conditions gave tetramic acid derivative 30, which was reduced with NaBH4 in methanol to yield hydroxy-lactams 31 and its C-4 diastereomer in a ratio of 7: 1. Compound 31 was converted into (+)-castanospermine (22) in six steps. When tetramic acid 30 was reduced with NaBH4 in the presence of AcOH, the diastereomer 32 was produced as the single diastereomer, which was converted into 1-epi-castanospermine (33) in seven steps.

Nine-step total synthesis of (+)-castanospermine (22) and ten-step total synthesis of (+)-1-epi-castanospermine (33) from building block 3.
Scheme 6

Nine-step total synthesis of (+)-castanospermine (22) and ten-step total synthesis of (+)-1-epi-castanospermine (33) from building block 3.

Further studies on the coupling of the vinylogous silyl enol ether 27 with achiral aldehydes showed that only one diastereomer (34) of four possible ones was obtained in each case (de≥ 95 %) (Scheme 7). The result indicates that the stereoselection of the vinylogous Mukaiyama type reaction is governed by the chiral auxiliary (via the favored transition state TS1) rather than the chiral aldehyde 28.

Diastereoselective reaction of vinylogous silyl enol ether derived from 3 with achiral aldehydes and possible transition states.
Scheme 7

Diastereoselective reaction of vinylogous silyl enol ether derived from 3 with achiral aldehydes and possible transition states.

Starting from the reaction of vinylogous silyl enol ether 27 with aldehyde 35, the synthesis of alkaloid 7-deoxy-6-epi-castanospermine (23) was accomplished accordingly in ten steps with an overall yield of 7.8 % (Scheme 8).

Ten-step total synthesis of 7-deoxy-6-epi-castanospermine (23) from building block 3.
Scheme 8

Ten-step total synthesis of 7-deoxy-6-epi-castanospermine (23) from building block 3.

Building block 2: the asymmetric syntheses of 9-epi-sessilifoliamide J (38)

3-Hydroxypiperidine is a structural motif found in many alkaloids and pharmaceutically relevant compounds [36]. The building block-based strategy has achieved great success in the symmetric synthesis of piperidine ring-containing heterocycles [37]. In recent years, we have been engaged in the development of synthetic methodologies based on protected 3-hydroxyglutarimide 2 [5, 38]. The value of this chiral building block is being demonstrated by other research groups [39]. A recent application of this methodology has led to the asymmetric synthesis of 9-epi-sessilifoliamide J (38) [40].

(3S,9S,9aS,11R,14S,16S)-Sessilifoliamide J (37) (Scheme 9) is a stemona alkaloid isolated in 2008 from the roots of Stemona sessilifolia (Miq.) Miq. (Stemonaceae) [41]. The six-membered piperidin-2-one ring present in sessilifoliamide J is unique among the known Stemona alkaloids. The basic strategy of our approach is to use the building block (R)-2 as the template for the core piperidin-2-one ring, which, after regio- and diastereoselective reductive alkylation and suitable functional group transformations, would enable the installation of two lactone moieties by vinylogous Mannich reaction [42] and SmI2-mediated lactonization [20, 43].

Plan for the total synthesis of sessilifoliamide J (37).
Scheme 9

Plan for the total synthesis of sessilifoliamide J (37).

Stepwise reductive alkylation [5] of the building block (R)-2 [38b] with Grignard reagent 39 gave the concomitantly O-desilylated hydroxylactam 40 (dr = 96: 4) in 56 % yield over two steps, along with its regioisomer (yield: 12 %, Scheme 10). N-de-allylation of 40 produced the desired lactam 41 in 81 % yield, which was subjected to oxidation (IBX, DMSO) and acetylation (Ac2O, NEt3, CH2Cl2) to give acetate 42 in 85 % yield. The vinylogous Mannich reaction between N,O-acetal 42 and 2-methylsilyloxyfuran 43 (TMSOTf, CH2Cl2, –78 °C; rt, 1 h) produced compound 44 as a 78: 22 diastereomeric mixture. The observed threo-diastereoselection is in agreement with most vinylogous Mannich reactions involving cyclic iminium ion intermediates [42]. A plausible Diels-Alder transition state has been suggested to account for the threo-diastereoselection [42f]. Reduction of the butenolide (NaBH4/NiCl2, MeOH) [44] followed by de-benzylation afforded compound 45. Finally, Ley oxidation [45] and SmI2-mediated reductive coupling of the resulting piperidinedione with methyl methacrylate yielded predominantly 9-epi-sessilifoliamide J (38), along with three minor diastereomers including sessilifoliamide J (37).

Ten-step asymmetric synthesis of 9-epi-sessilifoliamide J (38) based on building block (R)-2.
Scheme 10

Ten-step asymmetric synthesis of 9-epi-sessilifoliamide J (38) based on building block (R)-2.

Conclusion

In summary, we have demonstrated that optically active chiral heterocyclic building blocks 13 are versatile molecular platforms for the concise asymmetric syntheses of bioactive alkaloids and N-containing medicinally relevant molecules. There’s still a great potential to develop in terms of asymmetric synthesis of more structurally complex bioactive N-containing compounds. Development of building block-based synthetic strategies will at the same time promote the innovation of synthetic technology.

Acknowledgments

The authors are grateful for financial support from the National Basic Research Program (973 Program) of China (Grant No. 2010CB833200), the NSF of China (21332007, 21072160), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education, China.

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About the article

Corresponding author: Pei-Qiang Huang, Department of Chemistry and Fujian Provincial Key Laboratory for Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China, e-mail:


Published Online: 2014-04-04

Published in Print: 2014-07-22


Citation Information: Pure and Applied Chemistry, Volume 86, Issue 7, Pages 1227–1235, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2013-1210.

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