Carbapenem Precursors From Allyl and (Allenylmethyl)silanes

Monteith, Michael J (1991) Carbapenem Precursors From Allyl and (Allenylmethyl)silanes. PhD thesis, University of Glasgow.

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Most successful syntheses of beta-lactam antibiotics involve the early generation of a monocyclic 6-lactam ring. The addition of CSI to functionalised alkenes has proven to be of great synthetic utility in this step. Generally the addition is performed on enol acetate type alkenes, the product 4-acetoxyazetidinones finding widespread use since the 4-acetoxy substituent can be replaced by a variety of nucleophiles in an elimination/addition sequence. Unfortunately none of the additions of CSI to functionalised alkenes is generally applicable to the formation of 4-carbon substituted azetidinones, which could then serve as carbapenem precursors. Earlier reports by Dunogues(1) and Fleming(2) intrigued us since the addition of CSI to allylsilanes produced N-chlorosulphonyl-O-silyl imidates via the corresponding N-chlorosulphonyl beta-lactams arising from formal [2+2] cycloaddition between the allylsilane and CSI. These intermediate beta-lactams possessed a 4-carbon substituent as found in the carbapenem series and we have been able to repeat the work of Dunogues and intercept the intermediate beta-lactams with Na2SO3 to furnish the corresponding N-protio beta-lactams(3) in yields generally superior to those of other CSI/alkene addition/reduction sequences. (4) The regiochemistry of cycloaddition is controlled by the beta-effect of silicon, i. e. , silicon's ability to stabilise the development of partial positive charge beta to itself. This is well demonstrated by the regiochemistry of addition of CSI to l-trimethylsilyl-4-methylpenta-2,3-diene, which will be described, when contrasted with the addition of CSI to 2-methylpenta-2,3-diene, which has previously been described by Moriconi. (5) Generally, yields in the addition of CSI to (allenylmethyl)silanes were low, but the 3-alkylidene-4-(silylmethyl)azetidinones produced are advanced carbapenem precursors difficult to access by other methodologies. Initial studies by Dunogues, Fleming and ourselves made use of trimethyl substituted silyl moieties which served to demonstrate the scope and utility of the method, but rendered the product azetidinones of little utility. Extending the cycloaddition to oxidatively cleavable silyl residues, namely phenyldimethyl substituted silicon moieties, furnished high yields in the cycloaddition, although a slightly lower allylsilane reactivity was observed as the trimethylsilyl substituent was replaced by a phenyldimethylsilyl moiety. Unfortunately the fluoroborane(6) and KBr/AcOOH(7) mediated procedures developed by Fleming to accomplish oxidative cleavage of the phenyldimethylsilyl species did not furnish any of the target 4-(hydroxymethyl)-azetidinone but the mercuridesilylation/oxidative rearrangement protocol, also developed by Fleming(7), accomplished the required transformation, albeit in low yield. Further synthetic manipulations were then carried out on this oxidatively cleaved 3-unsubstituted-azetidinone, namely Peterson olefination, which was found to be impossible with the corresponding 4-(phenyldimethylsilylmethyl)azetidinone, and conversion into a thienamycin precursor possessing the correct relative configuration at all three chiral centres.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1991
Depositing User: Enlighten Team
Unique ID: glathesis:1991-78347
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:32
Last Modified: 30 Jan 2020 15:32

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