Diastereoselective Alkyl Grignard 1,4‐Additions to para‐Substituted (2R)‐N‐Cinnamoylbornane‐10,2‐sultam Derivatives: Influence of N‐Atom Pyramidalization

Abstract

Dedicated to Dr. Charles Fehr, on the occasion of his 65th birthday Several typical 13 C-NMR displacements (of C¼O, C(a), C(b), and C ipso ), as well as conformational or energy properties (SÀNÀC¼O dihedral angle, DE syn/anti; HOMO/LUMO) could be correlated with the electronic parameters of p-substituted N-cinnamoylbornane-10,2-sultams 2. Even under nonchelating conditions, the pyramidalization of the sultam N-atom decreases for electron-attracting psubstituents, inducing a modification of the sultam-ring puckering. Detailed comparison of the X-ray structure analyses of 2b, 2d, and 2m showed that the orientation of the sterically directing pseudo-axial S¼O(2) and HÀC(2) is modified and precludes any conclusion about the p-facial stereoelectronic influence of the N lone pair on the alkyl Grignard 1,4-addition. We also showed that the aggregating alkyl Grignard reagent may be used in equimolar fashion, demonstrating that the sultam moiety is chelated with a Lewis acid such as MgBr 2 . The Schlenk equilibrium may also be used to generate the appropriate conditions of effective 1,4-diastereoselectivity. Although the anti-s-cis/syn-s-cis difference of conformational energies for N-cinnamoyl derivatives 2 is higher than for the simple N-crotonoyl analogue, an Xray structure analysis of the SO 2 /C¼O syn derivative 10 confirms the predictive validity of our conformational calculations for DE 1.8 kcal/mol. 3 ) Thus, for example, the conjugate addition of an organozirconocene proceeds with only 9% d.e. on the N-crotonoylbornane-10,2-sultam [3a], while, in absence of electronic conjugation with the carbonyl group, syn-dihydroxylation involving the C(b) atom proceeds with only 0 -20% d.e., even in the cooperative presence of two conformationally rigidifying and directing prosthetic groups [4]. In this latter case, it is noteworthy that the weak purely steric influence of the sultam moiety on C(b) directs the approach on the same face as for a C(a) steric attack.Helvetica Chimica Acta -Vol. 94 (2011) 2142 4 ) Indeed, whereas chemical reactions involving either the C(a) or both C(a) and C(b) atoms are legion (> 300 reports), specific reactions at the C(b) atom are limited, e.g., to either MeNOor electrochemical CO 2 [7], or RS À [8] Michael additions, as well as the 1,4additions of simple Grignard reagents [9], Mg-cuprates [10], Li-cuprates [11], t BuHgCl-or InÀCu Igenerated alkyl radical [12], Rh I or Cu I /zirconocenes [3], EtAlCl 2 or Cu I /zincates [13], TiCl 4 / allylSiMe 3 [14], TiCl 4 /Cl 3 CLi [15], or Li-enolates [16]. Method [6] apparently does not involve any chelate and gave ca. 50% d.e. in favor of the same face as for a C(a) steric attack, anti to the N lp, in case of the more reactive SO 2 ÀC¼O syn s-cis conformer. The same p-facial selectivity was also obtained in almost all the other examples of chelation [3b] [8 -16] (see the discussion for exceptions). The absolute configuration of the 1,4-adducts was not determined in [3a] [7] [11f] [12] [13b] [14]. We are indebted to Prof. M. J. Wu for providing confir...

Grignard 1,4‐Additions to para‐Substituted (2R)‐N‐Cinnamoylbornane‐10,2‐sultam Derivatives: Revised Configuration for the N,OAc‐Keteneacetal Formation in the Presence of Cu(I)

“…= −0.466 σ para + 0.82, n = 13, R 2 = 0.91, SD = 0.059). It is noteworthy that the usual picture in the 500 MHz 1 H‐NMR shows two major singlet s for the gem ‐dimethyl groups, accompanied by two minor signals for the minor ( S )‐diastereoisomer . Based on the 13 examples earlier studied, it appears that the worse separation between the major Me(8) and the minor Me(9) of the ( S )‐diastereoisomer is observed for 2a and 2b , thus slightly corrupting the measured ratio between major and minor Me(8) signals by integration, although we still remain within the deviation of the standard error ( ca .…”

“…We concentrated our attention on both anomalous results considered in the introduction, in addition to their p ‐CF 3 analog 2c (measured 62%, calculated 59% de) . The initial analytical method was based on the integration of the Me(8) singlet in the 1 H‐NMR analysis of the crude reaction products, as earlier reported in a similar case .…”

“…4%) with respect to the initial results. After correcting the error, the Michael additions under different conditions as summarized in the Table were studied, more specifically either in different solvents, or in the presence of both a Lewis acid and a single equivalent of EtMgX, in analogy to the Schlenk equilibrium . The diastereoselectivity is slightly higher in toluene as compared to THF ( Entries 4 , 10 vs. 6 , 12 ), while the reaction is eventually sluggish in CH 2 Cl 2 ( Entry 10 vs. 11 ), although the π ‐facial selectivity is not drastically influenced ( Entries 4 , 10 vs. 5 , 11 ).…”

“…They invoked a s‐ trans conformation, rather than a s‐ cis conformation of the C α =C β bond to rationalize their results. Our substrates are energetically less prone to such a s‐ trans conformation, as compared to either their N ‐crotonoyl or C α ‐substituted Michael acceptors . Due to the lower reactivity of 1a ( Entry 26 ), the conversion was again carried out at 4 °C ( Entry 27 ).…”

“…Four years ago, we presented a series of alkyl 1,4‐additions to electronically modified para ‐substituted (2 R )‐ N ‐cinnamoylbornane‐10,2‐sultam derivatives 1 …”