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The Control of Stereochemistry by the Pentafluorosulfanyl Group Organic & Biomolecular Chemistry View Article Online PAPER View Journal | View Issue The control of stereochemistry by the pentafluorosulfanyl group† Cite this: Org. Biomol. Chem., 2018, 16, 3151 Paul R. Savoie, Cortney N. von Hahmann, Alexander Penger, Zheng Wei and John T. Welch * The influence of pentafluorosulfanylation on biological activity has been revealed in numerous compara- tive studies of biologically active compounds, but considerably less is known about the influence of pen- tafluorosulfanylation on reactivity. Among the distinctive properties of the pentafluorosulfanyl group is the profound dipole moment that results from introduction of this substituent. It has been shown that dipolar Received 20th December 2017, effects coupled with the steric demand of the SF5 group may be employed to influence the stereo- Accepted 3rd April 2018 chemistry of reactions, especially those processes with significant charge separation in the transition DOI: 10.1039/c7ob03146g state. The Staudinger ketene-imine cycloaddition reaction is an ideal platform for investigation of dipolar rsc.li/obc control of diastereoselectivity by the pentafluorosulfanyl group. Introduction ation into a hydrocarbon chain, the restricted rotation about the carbon–sulfur bond that results from interactions with Numerous pentafluorosulfanyl(SF5)-containing organic nearby methylene groups, can lead to localized conformational – compounds1 10 have been prepared that have potential utility rigidity of the alkyl chain.21,22 in drug discovery, agrochemical synthesis and materials Pentafluorosulfanyl substituents adjacent to hydroxyl groups science. The surge of interest in this area is a consequence of also influence conformation. The constraint of the S–C–C–OH di- 22 the increasing availability of building blocks, or reagents, that hedral angle to ±85° by the SF5 group cannot be rationalized by were previously very difficult to access.7 Much of what is the stereoelectronic influences23 showntoconstrainthedihedral known about the effect of pentafluorosulfanylation is derived C(CF3)–C–C–OH angle in the analogous trifluoromethylated mole- from comparative studies of biologically active trifluoromethyl- cules. Stereoelectronic control of conformation by the SF5 group ff ated compounds, where the trifluoromethyl (CF3) group was involves very di erent orbital interactions, a consequence of the 11–17 22 replaced by an SF5 group. Reports of the physical chemical hypervalentsulfuroftheSF5 group. Published on 07 April 2018. Downloaded by State University of New York at Albany 11/28/2020 1:56:02 AM. influences of pentafluorosulfanylation on aliphatic systems are especially fragmented and tentative. Electronic effects ff The magnitude of the electron withdrawing e ects of SF5 Conformational control 24 24 (electronegativity, 3.65) and CF3 (electronegativity, 3.36) are “ ” 25,26 σ The SF5 group has been variously described as a super CF3 similar. When Hammett p values are compared, the value 18 19 27 group or a tert-butyl isostere. The volume of the SF5 group of SF5 (0.68) is greater than that of CF3 (0.54). The greater 3 3 1,20 (55.4 Å ) is less than that of a tert-butyl group (76.9 Å ), but σI value of SF5 (0.55) relative to the value for CF3 (0.39) is indica- 3 greater than that of a CF3 group (34.6 Å ). The octahedral geo- tive of a greater bond polarization, and is consistent with the metry around sulfur results in a dramatic reduction of the electronic effects observed in the estimation of electro- 25,26 σ 27 barrier to rotation of a carbon–SF5 bond relative to carbon– negativity. In contrast, R values of 0.11 for SF5 and 0.12 28,29 carbon bonds. The longer carbon–sulfur and sulfur–fluorine for CF3 indicate comparable resonance contributions from σ bonds have other surprising conformational effects as a conse- both functional groups to the respective p values. quence of the octahedral geometry around sulfur. On incorpor- Dipolar effects of the SF5 group on Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave., Albany, NY 12222, USA. E-mail: [email protected] reactivity †Electronic supplementary information (ESI) available. CCDC 1552163. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ The profound dipole of the hydrolytically and chemically 7,30–33 c7ob03146g stable SF5 group may be used to influence the stereo- This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem.,2018,16,3151–3159 | 3151 View Article Online Paper Organic & Biomolecular Chemistry selectivity of reactions, especially those processes where there is ority of carbon of the benzyloxy group relative to boron of the significant charge separation in the transition state. The compu- enolate). Selective enolization apparently is a result of simple tationally determined dipole moment of pentafluorosulfanyl- steric interactions. methane (2.78 D) (B3LYP/6-31G**) is significantly greater than that of 1,1,1-trifluoroethane (2.06 D) (B3LYP/6-31G**) and nearly as large as that of nitromethane (3.48 D) (B3LYP/6-31G**). Stereoselectivity in pericyclic reactions Steric demand, torsional strain, and electronic effects are [3,3]-Sigmatropic rearrangements well known to influence stereoselectivity.34,35 The staggered – transition state of the Felkin–Anh model36 38 for carbonyl The SF5 group may control the stereochemistry of sigmatropic ff additions (Fig. 1, structures A and B) can be supplanted by a rearrangements by electronic or steric e ects. Analogously, 47 modified Cornforth rationale (Fig. 1, structures C and D),39 7:1ul to lk diastereoselectivity was found in a [3,3]-sigmatro- – 48 when a significant dipole is induced by a substituent.40 42 The pic rearrangement of an allylic trifluoromethyl ester. In that Cornforth model is characterized by the antiperiplanar confor- stereoelectronically driven example, cyclization occurred oppo- mational preference of the dipole-inducing functional group site to the more electron-rich face of the double bond as would 49 (Fig. 1). be predicted by Cieplak analysis. Enol silyl ketene acetals α α TS B and C both are consistent with formation of the ul prepared from the cinnamyl -CF3- and -SF5-acetates failed to 50 – product, with C having the most accessibility to the Re face of demonstrate diastereoselectivity in the Ireland Claisen ff the aldehyde. The Cornforth model hence affords a rationale rearrangement as a consequence of SF5-induced steric e ects. for the very diastereoselective addition of even non-sterically However, [3,3]-sigmatropic rearrangement of SF5-acetates of demanding nucleophiles to SF -containing aldehydes as aliphatic allylic esters proceed diastereoselectively due to the 5 ff shown in Fig. 2.43 di erential reactivity of the intermediate (E/Z) silyl ketene acetals.51 The potential diastereoselectivity of the rearrange- Enolate selectivity ment was degraded by the steric-induced accessibility of both Benzyl,44,45 methyl46 and octyl44 esters of pentafluorosulfanyl chair- and boat-like transition states. acetic acid have been employed in directed aldol conden- [2 + 2]-Cycloaddition reactions sations. The selective addition of boryl enolates of the benzyl and octyl esters to carbonyl groups formed anti-aldol pro- The highly diastereoselective formation of SF5-containing β 52 ducts.44,45 The specificity was the consequence of (Z)-enolate -lactams has been previously reported. ASF5 group at a formation (n.b., the stereochemistry of the enolate is a result stereogenic center of the aldimine induced formation of the β rac of the pentafluorosulfanyl group being (Z) to the higher pri- u,l- -lactam -1 very selectively by lk,lk-1,2 (Si,Si-S or Re,Re-R) cyclization, albeit in only modest yield (Fig. 3).52 A more thorough investigation of the effect of pentafluorosulfanylation is necessary to assess the generality of dipolar stereocontrol by pentafluorosulfanylation. To that end a mechanistic study of the ketene-pentafluorosulfanylaldimine cycloaddition reaction was required. Published on 07 April 2018. Downloaded by State University of New York at Albany 11/28/2020 1:56:02 AM. Results and discussion The influence of the N-alkyl substituent on pentafluorosulfanyl aldimine reactivity The pronounced electron withdrawing effect of pentafluorosul- fanylation on the acidity of an adjacent proton may adversely affect pentafluorosulfanyl aldimine formation. Even though fl Fig. 1 Predicted in uence of SF5 group on additions to an aldehyde the ketene-imine cycloaddition process is very well – lk – according to the Felkin Anh TS (top row; A,( -attack) favored); or the studied,53 62 systematic comparative studies of the influence of Cornforth TS (bottom row; C,(ul-attack) favored). Fig. 2 The diastereoselectivity of Grignard addition to an α-SF5-alded- Fig. 3 Stereogenic SF5-substituted carbon directed u,l-β-lactam rac-1 hyde is consistent with the Cornforth TS model (ref. 45). by lk,lk-1,2 cyclization (ref. 52). 3152 | Org. Biomol. Chem.,2018,16,3151–3159 This journal is © The Royal Society of Chemistry 2018 View Article Online Organic & Biomolecular Chemistry Paper simple N-protection are far less abundant.62 Our hypothesis was that the 4-methoxybenzyl (PMB) group of pentafluorosulfa- 1 nyl aldimine rac-4 (R = 4-MeOC6H5 in Scheme 1) could render the imine nitrogen of rac-4 more basic, stabilizing the inter- mediate iminium ion of A. However, the amine should not be so basic as to promote formation of enamine 5 or acyl enamine 8. Precedence for the formation of pentafluorosulfa- nyl enamine 5 can be found in comparison with the published reactivity of the trifluoromethylated aldimine, N-ethyl 3,3,3-tri- fluoro-propanaldimine.63 Replacement of the para-methoxyphenyl (PMP) protecting group52 previously employed in the synthesis of rac-1 by the Fig. 4 The 3,4-lk stereochemistry of rac-7a as determined by single PMB group resulted in a modest reduction in the already crystal X-ray diffraction. Thermal ellipsoids are set at 50% probability. limited β-lactam yield. Whereas introduction of an allyl moiety had a very modest effect on increasing the overall yield of rac-7 from the published values for PMP protected imines.52 By 19F NMR, there was no detectable reduction in the 3,4-diastereo- selectivity (see Fig.
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