Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven‐Membered Lactones: Neutron Diffraction Study of the Stereoselective Deuteration of a Chiral Organosamarium Intermediate

Abstract Seven‐membered lactones undergo selective SmI2–H2O‐promoted radical cyclization to form substituted cyclooctanols. The products arise from an exo‐mode of cyclization rather than the usual endo‐attack employed in the few radical syntheses of cyclooctanes. The process is terminated by the quenching of a chiral benzylic samarium. A labeling experiment and neutron diffraction study have been used for the first time to probe the configuration and highly diastereoselective deuteration of a chiral organosamarium intermediate.

Mappingnew routes to challenging molecular architectures is am ajor driving force in the development of synthetic chemistry. [1] Cyclooctanes are found in important natural products and pharmaceuticals and present af ascinating synthetic challenge due to their high ring strain and transannular interactions. [2,3] Ther ace towards the total synthesis of paclitaxel (Taxol) [4] spurred particular interest in the motif and the construction of cyclooctanes has become afertile field (Scheme 1). [5][6][7][8][9][10][11] Among these methods,r adical cyclization approaches are scarce and have relied mainly on radicals generated from halides, [12] ketones [13,14] and aldehydes [15] and 8-endo cyclization modes (Scheme 2A). [16] Samarium diiodide (Kagansr eagent, SmI 2 ) [17,18] is perhaps the most versatile reductive electron transfer (ET) reagent and has been used extensively for carbon-carbon bond forming reactions. [19] We recently expanded the scope of SmI 2 -mediated reactions by introducing activation modes involving the reduction of carboxylic acid derivatives using SmI 2 -H 2 O. [20] Theacyl-type radicals now accessible have been exploited in new functional group transformations and highly selective radical cyclizations involving carbon-carbon bond formation. [20][21][22][23][24] In the case of lactones,E Tf rom Sm II to the carbonyl gives rise to radical anions (cf. I in Scheme 2) that are stabilized by hyperconjugation with the adjacent oxygens and by H 2 O. [20, 21a-e] Very recently,wedemonstrated that ET to all lactones using SmI 2 -H 2 Oi sr eversible and this back ET typically impedes productive reductive transformations. [21d] However,new opportunities for carbon-carbon bond formation arise if the transient radical anions can be trapped by asuitably placed radical acceptor.
Here we describe as ynthesis of substituted cyclooctanes that exploits the first radical cyclizationsofseven-membered lactones,w hich can be easily accessed by Baeyer-Villiger oxidation of cyclohexanones.T he process involves ET to the lactone 1,a nd generation of radical anion I,f ollowed by trapping of the radical by the tethered alkene.C rucially, potential issues involving back ET to Sm III ,r adical fragmentation, and radical reduction are overcome.I ns itu reduction of the hemiketal intermediate 3 delivers 1,4-cyclooctandiols 2 (Scheme 2B). The5 -exo-trig radical cyclization of lactones stands in sharp contrast to most radical approaches to cyclooctanes that involve 8-endo attack (Scheme 2B). [3b] Furthermore,w er eport the use of al abeling experiment and aneutron diffraction study to probe for the first time the configuration and highly diastereoselective quenching of ac hiral organosamarium.
Thef easibility of the transformation was first assessed using lactone 1a (R 1 = Me;R 2 = Ph;R 3 = H) ( Table 1). As expected, no reaction was observed when 1a was treated with SmI 2 in THF (2-fold excess) and only upon addition of H 2 O was conversion observed. After optimization of the amount of H 2 Oa dditive employed, 1,4-cyclooctandiol 2a was obtained in good isolated yield. Oxidation of the crude diol 2a with Dess-Martin periodinane facilitated assessment of the diastereoselectivity and stereochemical course of the radical cyclization by simplifying the diastereoisomeric mixture and providing crystalline product 3a in 74 %o verall, isolated yield. 7-Methyl substituted lactones 1b-h (R 1 = Me), bearing aryl-substituted alkene tethers with various groups in all positions of the aromatic moiety,underwent efficient cyclization to give the corresponding hemiketals 3b-h in good to excellent yields (62-93 %, 2s teps) and with good diastereoselectivities (75:25 to 89:11 d.r.). Va riation of the substituent in position 7o ft he lactone proved possible.F or example, benzyl substituted hemiketals 3l,m (R 1 = Bn) were obtained in good to excellent isolated yield and with good diastereocontrol. Halogen substituents were compatible with the cyclization conditions (formation of 3b, 3c, 3d, 3e, 3m, 2o) and serve as handles for further functionalization of the products.The trifluoromethyl group also proved stable to the reducing conditions and cyclooctane 3c was obtained in excellent overall isolated yield. X-ray crystallographic analysis of 3a-d revealed the syn selectivity of the cyclization. [25] Te rminal alkenes could also be employed to intercept the radical anion intermediate,however, in the absence of an aryl substituent on the alkene,radical cyclization was less efficient and cyclooctanes 3i and 3kwere obtained in low overall yield and with lower diastereoselectivity.T he cyclization proved surprisingly tolerant of steric hindrance:l actone 1j,b earing gem-disubstitution a to the lactone carbonyl, underwent efficient radical cyclization upon treatment with SmI 2 -H 2 O. In this particular case,t he product obtained in good overall yield after oxidation was the hydroxyketone 3j rather than the corresponding hemiketal.
Lactones 1n and 1o lacking an alkyl substituent at the 7 position of the ring (R 1 = H) also underwent cyclization to give 1,4-cyclooctandiols 2n and 2o in moderate yield. This observation likely results from the lower relative stability of the required reactive conformation in which the alkene tether adopts apseudo-axial conformation (Scheme 3). Theabsence of an alkyl substituent in position 7ofthe lactone ring favors [a] Conditions:S mI 2 (8 equiv,2-fold excess), THF, H 2 O( 800 equiv), room temperature. Isolated yields for 2steps. Diastereoselectivities were determined from 1 HNMR spectra of crude product mixtures. ap seudo-equatorial conformation of the tether, disfavoring its interaction with the radical anion.
Ther elative configuration of the products is consistent with an anti attack of the radical anion intermediate on the tethered alkene (conformation IIb)i nvolving ap roduct-like transition state,f ollowed by as econd ET and subsequent protonation (or deuteration, see below) (Scheme 4). The observed selectivity likely results from minimization of electrostatic interactions and steric clashes between the alkene and the radical anion intermediate,t hus favoring IIb over IIa. [26] Subsequent ET to III and protonation of IV gives rise to hemiketal 3a,w hich is then reduced further.
Interestingly,carrying out the cyclization of 1awith SmI 2 -D 2 Og ave d-3 a with high diastereoselectivity at the benzylic position (> 90:10 d.r.). To gain further insight into the mechanism of the radical cyclization and the nature of the organosamarium intermediate IV, [27] formed upon reduction of radical III,wedetermined the relative configuration of the deuterated product d-3 a using neutron diffraction (Scheme 5). [28] Based on the analysis of ac rystalline sample of d-3 a,w ep ropose that ac helated, chiral organosamarium intermediate IV is formed [29] and the more stable anti-IV diastereomer is quenched selectively with retention of configuration at carbon to generate samarium alkoxide V.Finally, deuteration of samarium(III) alkoxide V delivers d-3 a. [30] To our knowledge this is the first time that the configuration of adiastereoselectively deuterated product has been confirmed using neutron diffraction. [31] In conclusion, radical exo-cyclization of unsaturated seven-membered lactones,t riggered by single ET to the carbonyl group by SmI 2 -H 2 O, generates cyclooctanes typically in good yield and high diastereoselectivity.N eutron diffraction has been used to probe,f or the first time,t he stereochemical course of the selective deuteration of achiral organosamarium intermediate.