Final Report Summary - ACAD (Asymmetric Chlorofunctionalization of Activated carbon-carbon Double bonds)
Summary Description of Project Objectives:
The development of a novel, asymmetric, Lewis base-activated, Lewis acid-catalyzed chlorofunctionalization of a,b-unsaturated electrophiles was proposed. This methodology would allow for the diastereo- and enantioselective synthesis of a wide range of 1,2-difunctionalized motifs that are suitable for small molecule and complex natural product synthesis. The ultimate objective of this proposal being the development of an asymmetric 1,2-dichlorination protocol for the large-scale synthesis of building blocks crucial to the synthesis of the chlorosulfolipids; a family of natural products of significant current interest (Figure 1).
Results – Outgoing Phase:
During the planning stages of this work the proposed methodology was considered as two parts: (i) the Michael addition of A- (e.g. Cl- ), after heterolysis of an achiral Lewis acid, using a chiral Lewis base, to an a,b-unsaturated electrophile and, (ii) the trapping of the resulting silyl enol ether, using a trapping agent “B+”, as illustrated in Figure 1. With the preceding steps already reported in the lierature, and to simplify the investigation, it was decided to first trial potential trapping agents. To this end, the a-functionalization of silyl enol ethers was adopted as a model system. The outgoing phase of this Fellowship successfully addressed this, highly challenging, and highly novel, trapping step; demonstrating the a-sulfenylation of trimethyl silyl enol ethers and evaluating it with a view to combining it with the chloride Michael-addition process (JACS, 2014, 136, 13016-13028). Moreover, this system could be rendered asymmetric to give a catalytic enantioselective method for the synthesis of a-keto sulfides; this was demonstrated to be successful for substrates of varying steric bulk and nucleophilicity and to tolerate weakly Lewis basic functional groups (Figure 2). Excellent isolated yields and good to excellent enantiomeric ratios were obtained. This work constitutes the first direct method for the catalytic enantioselective sulfenylation of enol ethers and is therefore expected to be of interest to both academia and industry.
Results – Incoming Phase:
The lessons learned during the outgoing phase, with respect to reactivity trends, operational details, etc, were then applied to the development of a 1,2-difunctionalization reaction. The 1,2- dichlorination procedure was prioritized, specifically due to its potentially significant impact in the synthesis of chlorosulfolipids. Systematic investigation of achiral Lewis acids, Lewis bases, electrophiles and trapping agents identified conditions for the straightforward and rapid racemic dichlorination of a,b-unsaturated esters, ketones and aldehydes (Figure 3). Unfortunately, despite the evaluation of a wide range of chiral Lewis bases, this process could not be rendered enantioselective and racemic products were obtained in each instance. In this case, it is postulated that dichlorination occurs via the in situ production of molecular chlorine as opposed to the mechanism proposed in Figure 1.
The final aim of this research programme was the application of the developed methodology to an efficient large scale synthesis of a chlorosulfolipid natural product. Whilst this became unfeasible, due to the inability to render the methodology enantioselective, the large scale synthesis of polyhalogenated hydrocarbons could still be carried out to assist with efforts toward the synthesis and structural reassignment of undecachlorosulfolipid A (Figure 4). Lessons learned during the outgoing phase and the dichlorination investigation, specifically with respect to the Lewis base-activation of SiCl4, inspired the development of improved reaction conditions for 2 distinct transformations. (Manuscript in preparation).
Final results and their potential impact and use:
The methodologies developed throughout the Fellowship are expected to be of great interest to both academia and industry where the need for streamlined chemical syntheses of novel molecular architectures is ongoing. Furthermore, work carried out toward the total synthesis and structural reassignment of undecachlorosulfolipid A, the most complex chlorosulfolipid isolated to date, will also generate significant interest from the scientific community not only for synthetic endeavour but also as another stepping stone towards understanding the biosynthesis of mechanism of such unique natural products. Carried out under the auspices of the European Union and the Marie Curie Actions, the significant science conducted throughout the fellowship unquestionably raises the profile of European research both at home and abroad.
Dissemination/Outreach Activities:
Research conducted/concepts learned during the outgoing phase were disseminated to European researchers during several events via oral & poster presentations. Outreach activities were conducted in the UK for a full week including the teaching and promoting of science to students aged 8-18 years.
The development of a novel, asymmetric, Lewis base-activated, Lewis acid-catalyzed chlorofunctionalization of a,b-unsaturated electrophiles was proposed. This methodology would allow for the diastereo- and enantioselective synthesis of a wide range of 1,2-difunctionalized motifs that are suitable for small molecule and complex natural product synthesis. The ultimate objective of this proposal being the development of an asymmetric 1,2-dichlorination protocol for the large-scale synthesis of building blocks crucial to the synthesis of the chlorosulfolipids; a family of natural products of significant current interest (Figure 1).
Results – Outgoing Phase:
During the planning stages of this work the proposed methodology was considered as two parts: (i) the Michael addition of A- (e.g. Cl- ), after heterolysis of an achiral Lewis acid, using a chiral Lewis base, to an a,b-unsaturated electrophile and, (ii) the trapping of the resulting silyl enol ether, using a trapping agent “B+”, as illustrated in Figure 1. With the preceding steps already reported in the lierature, and to simplify the investigation, it was decided to first trial potential trapping agents. To this end, the a-functionalization of silyl enol ethers was adopted as a model system. The outgoing phase of this Fellowship successfully addressed this, highly challenging, and highly novel, trapping step; demonstrating the a-sulfenylation of trimethyl silyl enol ethers and evaluating it with a view to combining it with the chloride Michael-addition process (JACS, 2014, 136, 13016-13028). Moreover, this system could be rendered asymmetric to give a catalytic enantioselective method for the synthesis of a-keto sulfides; this was demonstrated to be successful for substrates of varying steric bulk and nucleophilicity and to tolerate weakly Lewis basic functional groups (Figure 2). Excellent isolated yields and good to excellent enantiomeric ratios were obtained. This work constitutes the first direct method for the catalytic enantioselective sulfenylation of enol ethers and is therefore expected to be of interest to both academia and industry.
Results – Incoming Phase:
The lessons learned during the outgoing phase, with respect to reactivity trends, operational details, etc, were then applied to the development of a 1,2-difunctionalization reaction. The 1,2- dichlorination procedure was prioritized, specifically due to its potentially significant impact in the synthesis of chlorosulfolipids. Systematic investigation of achiral Lewis acids, Lewis bases, electrophiles and trapping agents identified conditions for the straightforward and rapid racemic dichlorination of a,b-unsaturated esters, ketones and aldehydes (Figure 3). Unfortunately, despite the evaluation of a wide range of chiral Lewis bases, this process could not be rendered enantioselective and racemic products were obtained in each instance. In this case, it is postulated that dichlorination occurs via the in situ production of molecular chlorine as opposed to the mechanism proposed in Figure 1.
The final aim of this research programme was the application of the developed methodology to an efficient large scale synthesis of a chlorosulfolipid natural product. Whilst this became unfeasible, due to the inability to render the methodology enantioselective, the large scale synthesis of polyhalogenated hydrocarbons could still be carried out to assist with efforts toward the synthesis and structural reassignment of undecachlorosulfolipid A (Figure 4). Lessons learned during the outgoing phase and the dichlorination investigation, specifically with respect to the Lewis base-activation of SiCl4, inspired the development of improved reaction conditions for 2 distinct transformations. (Manuscript in preparation).
Final results and their potential impact and use:
The methodologies developed throughout the Fellowship are expected to be of great interest to both academia and industry where the need for streamlined chemical syntheses of novel molecular architectures is ongoing. Furthermore, work carried out toward the total synthesis and structural reassignment of undecachlorosulfolipid A, the most complex chlorosulfolipid isolated to date, will also generate significant interest from the scientific community not only for synthetic endeavour but also as another stepping stone towards understanding the biosynthesis of mechanism of such unique natural products. Carried out under the auspices of the European Union and the Marie Curie Actions, the significant science conducted throughout the fellowship unquestionably raises the profile of European research both at home and abroad.
Dissemination/Outreach Activities:
Research conducted/concepts learned during the outgoing phase were disseminated to European researchers during several events via oral & poster presentations. Outreach activities were conducted in the UK for a full week including the teaching and promoting of science to students aged 8-18 years.