Enantioselective Desymmetrization of Prochiral Cyclohexanones by Organocatalytic Intramolecular Michael Additions to α,β-Unsaturated Esters

A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an α,β-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83–99 % ee) and in good yields (60–90 %). Calculations revealed that stepwise C–C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst.

develop an ew catalytic asymmetric method to access the morphan motif with high efficiencya nd selectivity.R etrosynthetic analysis revealed that ad irect approach could exploit ad esymmetrization [3] of prochiral ketone I by an intramolecular Michael addition reaction to an a,b-unsaturated ester under enamine catalysis. [4] Although aldol variants of this type are known, [5] such acatalytic asymmetric Michael reaction has not been reported to date,despite its potential to directly provide morphan skeleton II,w hich possesses three stereocenters and at wo carbon appendage useful for subsequent synthetic manipulation (Scheme 1). [6] Accordingly, we viewed this proposed desymmetrization reaction as agood opportunity to unveil new reactivity in organocatalysis whilst accessing key bicyclic building blocks that are useful for the synthesis of morphan-like natural product libraries.
Initially,substrate 2a was chosen as amodel system to test our concept;i ts precursor 1 was accessible on scale, [7] the spirocyclic pyrrolidinone backbone would place reactive functionality in close proximity, [8] and its synthesis by cross metathesis would provide ap oint of diversity if the desymmetrization proved successful.
Proof of concept was established quickly and unexpectedly;t he attempted purification of 2a from ruthenium residues that had remained from the cross metathesis reaction with QuadraSil AP,ap ropylamine-functionalized silica gel scavenger, facilitated the formation of cyclized product (AE)-3a in quantitative yield and excellent diastereoselectivity (Scheme 2). Control experiments using propylamine in CH 2 Cl 2 at room temperature,w ith and without additional benzoic acid as ac o-catalyst, afforded the same product in high yields as as ingle diastereomer,a nd the primary amine functionality was thus identified as ac atalytically competent species.
Consequently,ar ange of commonly used chiral singleenantiomer primary [9] and secondary [10] amine organocatalysts 4a-4e were screened at 20 mol %l oading against the model system in the presence of benzoic acid as ac ocatalyst [11] (Table 1). In terms of reactivity and enantioselectivity,( 1 R,2R)-cyclohexanediamine (4e)w as the most promising lead, and accordingly,d erivatives were sought with the aim to boost enantioselectivity.C ommercially available (1R,2R)-trans-N-Boc-1,2-cyclohexanediamine (4j)g ave similar results to 4e.However,J acobsens thiourea catalyst 4k, [4d] with its increased hydrogen-bond-donor ability arising from the thiourea moiety, [12] resulted in as ignificant increase in enantioselectivity whilst maintaining as hort reaction time and high diastereoselectivity;t he major diastereomeric product 3a was obtained in 90 % ee and > 98:2 d.r.T he loading of the primary amine catalyst could be reduced to 5mol %w ith an ominal increase in enantioselectivity albeit with al onger reaction time,w hich was subsequently overcome by elevating the reaction temperature to 45 8 8C.
increase the benzoic acid co-catalyst loading to 2.5 mol %t o maintain good reaction rates (entries [5][6][7][8]. Pleasingly an onspirocyclic substrate possessing N-ethyl and 4-methyl substituents underwent cyclization with equally high diastereoand enantiocontrol (96 % ee)b ut at am arginally diminished reaction rate (entry 9). Related secondary amine substrates 2j and 2kpossessing larger C4 substituents also reacted to afford the N-unprotected morphan products 3j and 3k as single diastereomers with 84 and 83 % ee,r espectively (entries 10 and 11). Substrates with ah ydrogen atom at the C4 position would be the most relevant to natural product synthesis (Scheme 1), and accordingly,this scaffold type was assessed in the desymmetrization reaction. As eries of ester substrates, 2l-2q,e ach possessing an N-benzyl protecting group,w ere then examined. Pleasingly,t hese were found to give the highest enantioselectivities (96-99 % ee)ofall of the scaffolds tested, albeit with diminished reaction rates (entries 12-17). Furthermore,arange of differentially N-protected substrates 2r-2vgave the desired cyclized products 3r-3vwith excellent enantioselectivities (95-98 % ee;e ntries 18-22). In total, 22 unactivated a,b-unsaturated esters substrates with three points of diversity successfully cyclized under the action of catalyst 4k to give the bicyclicp roducts with the morphan skeleton in high diastereo-and enantioselectivity.The relative stereochemical configuration of 3p and the absolute stereochemical configuration of asulfonamide derivative of 3rwere established by single-crystal X-ray analysis (see the Supporting Information). Interestingly,w hen Z-configured Michael acceptor (Z)-2b was subjected to the optimized reaction conditions,i t afforded the same morphan product (AE)-3b as the racemate indicating that geometrically pure trans-configured starting materials were crucial to achieving the high enantioselectivities observed. Taken together,t hese results clearly demonstrate that diastereoselectivity is aresult of inherent substrate control and not ac onsequence of the chiral catalyst employed, which governs enantioselectivity.T ou nderstand the mechanism and origins of the high stereocontrol, quantum-chemical calculations were performed for the racemic and enantioselective series of our reaction. [13] Stationary points were optimized at the M06-2X/6-311 + G(d,p) level of theory; [14] implicit solvation [15] by CH 2 Cl 2 was included using ac onductor-like polarizable continuum model (CPCM). These results were corroborated by other computational methods (see the Supporting Information for details). [16] In the interest of tractability,calculations were performed on Nmethyl substrate 2v with am ethylamine catalyst as am odel for propylamine.T he s-cis enamine conformation is more stable than the s-trans conformation by 2.9 kcal mol À1 ;h owever,wefound that only the latter is able to undergo Michael addition as the enamine NÀHm ust be oriented towards the ester:P roton transfer to the oxygen atom occurs along the (intrinsic) reaction coordinate,w hich is not possible for the s-cis conformer.Aconcerted ene reaction can be dismissed, as this step has an unfeasibly high activation barrier of 33.4 kcal mol À1 .F rom the s-trans enamine,f ormation of the Michael endo diastereomer was computed to occur via chair-shaped TS-A,with astaggered conformation about the incipient CÀC bond (Figure 1). In this transition state,proton transfer occurs asynchronously with CÀCbond formation, giving enol adduct E.T he keto tautomer results from a1 ,3-prototropic shift in TS-C,a ssisted by the imine Natom to form endo adduct F. Formation of the alternative exo diastereomer is possible via TS-B.Int his transition state,the forming six-membered ring adopts aboat conformation with greater eclipsing interactions about the incipient CÀCb ond than in endo-TS-A.T he exo pathway is kinetically disfavored by 1.7 kcal mol À1 ,b ut more importantly,i ntramolecular proton transfer to the ester acarbon atom is geometrically impossible for this diastereomer. We thus predict that exo enol G will revert back to the more stable starting enamine and not proceed to the keto tautomer.T he exclusive endo selectivity results from an irreversible,k inetically favored pathway.T ransition states corresponding to the formation of cyclobutane [17] and cyclic enol ether intermediates [18] were also located. Only cyclobutane I was computed to be more stable than the starting enamine,h owever, its formation is disfavored (TS-D)w ith respect to proton transfer to TS-C and is thus unlikely to constitute as ignificant resting state in the catalytic cycle.
We then considered the asymmetric induction arising from thiourea catalyst 4k.O ur computations considered an enamine derived from substrate 2v with as implified, truncated thiourea catalyst 4l.L ow-energy conformations for each stationary point along the potential energy surface were located with Monte Carlo conformational searches [19] employing semi-empirical PM6-DH2 calculations [20] and subsequent refinement with M06-2X/6-311 + G(d) optimizations ( Figure 2). Ther eactive enamine geometry differs between the two pathways,w ith the s-cis enamine yielding the major enantiomer and the s-trans enamine yielding the minor enantiomer,a st hese conformations enable both pathways to benefit from stabilizing hydrogen bonding interactions between ester and thiourea. Energetic discrimination between Michael transition states TS-J and TS-K results

Angewandte
Chemie from differing cyclohexylthiourea conformations:R otation about the C(cyclohexyl) À N(thiourea) bond reveals a4kcal mol À1 conformational preference for the thiourea CÀNb ond to be syn-coplanar with the cyclohexyl CÀHb ond (f CNCH = 308 8)o ver the antiperiplanar conformation (f CNCH = 1808 8). In the favored transition state TS-J,t he catalyst adopts this preferred conformation (f CNCH = 318 8)w hereas in disfavored TS-K,t he less stable form is adopted (f CNCH = 1788 8). The thiourea catalyst stabilizes ester enolate formation such that CÀCb ond formation and proton transfer now occur in two separate steps (see the Supporting Information for af ull energy profile). Thecalculated enantioselectivity imparted by catalyst 4l amounts to 96 % ee based on a DDG°value of 2.4 kcal mol À1 between the selectivity-determining transition states along the two pathways,which agrees with the absolute sense and magnitude (96 % ee)o btained with 4k.O ur computational studies predicted that thiourea catalyst 4l would thus be as competent as 4k despite being greatly simplified. Thecomputed transition state TS-J suggests alack of any significant contribution from the tert-leucine fragment in catalyst 4k,asitwould be oriented away from the substrate into space.Accordingly, 4l was then synthesized and tested in the cyclization of 2v to validate the computational prediction of enantioselectivity (Scheme 3). Pleasingly,p roduct 3v was obtained in 83 %y ield and 97 % ee as as ingle diastereomer, showing excellent agreement between experiment and theory.
In summary,wehave developed ahighly enantioselective primary amine catalyzed Michael addition of ak etone to unactivated a,b-unsaturated esters.T he reaction benefits from three points of diversity-the C4 substituent, the nitrogen group,a nd the ester moiety-and provides access to the morphan scaffold in high enantio-and diastereoselectivity (up to 99 % ee and > 98:2 d.r.). Computational studies to probe the origins of the high enantiocontrol have been performed, and the results of the calculations identified anew low-molecular-weight catalyst that can impart the same level of enantioselectivity.T he application of this new enantioselective desymmetrization method to complex natural product synthesis is ongoing in our group,a nd the findings will be reported in due course.