Ketyl radical cyclization using tris(trimethylsilyl)silane
SyntheticPage 751
DOI:
Submitted: July 10, 2014, published: August 11, 2014
Authors
Chris Donner (cdonner@unimelb.edu.au)
A contribution from
Chemicals
Aldehyde (Prepared in-house)
Tris(trimethylsilyl)silane [(TMS)3SiH] (Sigma-Aldrich)
Azobis(isobutyronitrile) (AIBN)
Benzene (Distilled from sodium-benzophenone ketyl)
Procedure
To a solution of the aldehyde (80 mg, 0.25 mmol, 1 equiv.) in benzene (4 mL) were added (TMS)3SiH (117 μL, 0.38 mmol, 1.5 equiv.) and AIBN (4 mg, 0.02 mmol, 0.08 equiv.). The solution was sparged by bubbling argon through the solution for 30 minutes after which the solution was maintained under an atmosphere of argon and heated at reflux for 4 hours. After cooling and removal of the solvent in vacuo the remaining residue was purified by flash column chromatography (silica gel, EtOAc-hexane, 1:20) to yield the cyclopentane (134 mg, 94%) as a mixture of four diastereoisomers. Integration of the methyl ether (OMe) signals between 3.2-3.4 ppm in the 1H NMR spectrum established the diastereoisomeric ratio to be 35:25:20:20.
Author Comments
The radical reducing agent (TMS)3SiH has been used as a less toxic substitute for Bu3SnH and in many situations shows similar reactivity to the more commonly used tin-based reagent (see Other References 1). In this example (TMS)3SiH is able to replace Bu3SnH in a ketyl radical cyclization (Page 735), however, the stronger silicon-oxygen bond that is formed results in the protection of the new secondary alcohol as a silyl ether. Overall, the reaction produces a new 5-membered ring, two contiguous asymmetric centres (secondary alcohol and protected tertiary alcohol) with in situ protection of the secondary alcohol.
Note 1. The (TMS)3Si (sisyl) group has been shown to be a photolabile protecting group, being cleaved by exposure to UV light (254 nm), and also hydrolytically labile as is the case for other silyl ethers (see Other References 2). This provides an orthogonal protection strategy even in the presence of a TBS ether.
Note 1. The (TMS)3Si (sisyl) group has been shown to be a photolabile protecting group, being cleaved by exposure to UV light (254 nm), and also hydrolytically labile as is the case for other silyl ethers (see Other References 2). This provides an orthogonal protection strategy even in the presence of a TBS ether.
Data
GC-MS: tR = 38.65, 38.88 (2 diastereoisomers), 39.01 min
HRMS (ESI): calcd for C24H56O5Si5Na [M + Na+] 587.2866, found 587.2881
Lead Reference
Hong, L. P. T.; Chak, C.; Donner, C. D. Org. Biomol. Chem., 2013, 11, 6186-6194.
Other References
1. Chatgilialoglu, C. Acc. Chem. Res., 1992, 25, 188-194; Chatgilialoglu, C. Chem. Eur. J., 2008, 14, 2310-2320.
2. Brook, M. A.; Balduzzi, S.; Mohamed, M.; Gottardo, C. Tetrahedron, 1999, 55, 10027-10040.
Keywords
AIBN, cyclopentane, ketyl radical cyclization, secondary alcohol protecting group, sisyl ether, Tris(trimethylsilyl)silane, TTMSS