Heterocyclic Chemistry 1. New Synthetic Methodology for Piperidines and Pyrrolidines
Cyclic Sulfamidates as Enantiomerically Pure Building Blocks for Heterocyclic Synthesis  

NEWS: John Bower has applied cyclic sulfamidate methodology to the successful synthesis of (i) (-)- Paroxetine (ii) (+)-laccarin and most recently (iii) Levofloxacin (Org. Lett.; 2007, 9, 3283-3286).

This is the first synthesis of laccarin and has allowed us to assign the absolute stereochemistry of this natural product. This work is was published in Chem Commun in 2007.

John has also recently completed the synthesis of (-)-aphanorphine in a very direct and efficient manner, key features of which are illustrated below.

Background: Asymmetric Piperidine Synthesis via 1,3-Cyclic Sulfates

The advent of the Sharpless asymmetric dihydroxylation was rapidly followed by the development of chemistry associated with the corresponding 1,2-cyclic sulfates. These reactive C2 units are synthetically equivalent to epoxides since the two adjacent carbon centres each carry a (potential) leaving group. In the case of the cyclic sulfate, initial nucleophilic attack (and ring cleavage) produces an intermediate – a sulfate –OSO3- that is already activated towards a second nucleophilic displacement.

 

The synthesis of sedridine relied on constructing a 1,3-cyclic sulfate capable of undergoing ONE alkylation step as a means of generating a piperidine ring.

The synthesis of coniine, the famous hemlock alkaloid- see right and Socarates (below) whose fate was sealed by hemlock - and much-used vehicle for the exemplification of new asymmetric methodology, takes this chemistry that step further.

Here we have used a C,N-dianion (based on an N-sulfonyl a-sulfonyl acetamide) as one component and the enantiomerically pure (>95% e.e.) 1,3-cyclic sulfate as the other half of the new piperidine ring.


CURRENT WORK - The Chemistry of Cyclic Sulfamidates

We are now focussed on developing this methodology in a number of directions. Of particular importance, given our interest in heterocyclic chemistry, is the synthetic chemistry of 1,2- and 1,3-cyclic sulfamidates. Both 1,2- and 1,3-cyclic sulfamidates are readily prepared from 1,2- and 1,3-amino alcohols (often from the corresponding amino acids) and function as synthetic equivalents of aziridines and azetidines.

These systems also offer advantages over cyclic sulfates for heterocyclic synthesis. Constructing nitrogen heterocycles via a cyclic sulfate requires generating a new C-N - look at the coniine example above – and this nucleophilic displacement can be “problematic” in terms of the levels of enantiospecificity observed – complete stereochemical integrity is difficult to achieve. With a cyclic sulfamidate, then the key C-N bond is already there and the regioselectivity of nucleophilic attack – at the O vs the N centre - is clear cut: The C-O bond is cleaved preferentially.

Using a range of cyclic sulfamidates, we have employed a number of nucleophiles based on a-heteroatom substituted esters or more recently functionalised enolates. These systems serve to (i) ring open the cyclic sulfamidate and (ii) a subsequent cyclisation hen generates the N-heterocycle (as a lactam).

Work in this area is now focussed on defining the scope of this chemistry – the range of nucleophiles that can be used and the downstream chemistry that is then available. Using heteroatoms as nucleophiles, we have defined routes of various heterocycles (piperazines and thiomorpholines) and the chemistry is very tolerant of potentially sensitive stereocentres.


We have also used carbon based nucleophiles - stabilised enolates - to incorporate a broad range of functionality within a substituted pyrrolidine or piperidine framework. Current work is focussed on the application of cyclic sulfamidates to interesting and challenging natural product targets, such as (-)-aphanorphine (see NEWS above) and saxitoxin.