Asymmetric synthesis of multiple quaternary stereocentre-containing cyclopentyls by oxazolidinone-promoted Nazarov cyclizations

Ox-activated divinyl ketones undergo torquoselective Nazarov cyclization to give cyclopentanoids containing up to three new contiguous quaternary (4°) stereocentres.


Introduction
The enantioselective synthesis of quaternary (4 ) stereocentres is a major challenge in organic synthesis, hindering access to sp 3 -rich scaffolds in drug discovery and natural products synthesis. 1,2 Particularly problematic is the enantioselective formation of multiple 4 -stereocentres, which requires control over both relative and absolute stereochemistry.
The Nazarov cyclization offers inherent control over relative stereochemistry through conservation of orbital symmetry and constitutes an attractive route to multistereocentre-containing cyclopentanoids. 3 However, the potential of the Nazarov cyclization for 4 -stereocentre formation has not yet been fully realized due to two signicant challenges: (i) stereoselective access to highly substituted divinyl (and aryl vinyl) ketone substrates 4 and (ii) torquoselective 5 ring closure. In a landmark study, Tius and co-workers 6 reported chiral Brønsted acid-catalyzed Nazarov cyclizations of divinyl ketones 1 (Scheme 1a) leading to cyclopentenols 3 containing two new vicinal 4 -stereocentres (R 1-3 s H) with high enantioselectivities (oen er > 97 : 3). Careful design of the divinyl ketone 1 with dual-activating electron donor (OCHPh 2 ) and acceptor (CO 2 R) elements was key to attaining efficient cyclization. 6 Electrofugal release of Ph 2 HC + from the intermediate oxyallyl cation 2 further promoted the cyclization and suppressed competing Wagner-Meerwein rearrangements ([1,2]-sigmatropic shis of R 1-3 within 2). Herein, we report that highly substituted aryl vinyl and divinyl ketones 5 can be readily accessed through carbometalations of oxazolidinone (Ox)-substituted ynamides 4 (Scheme 1b). 7 The Ox-group proves to be remarkably effective as a single chiral activating group for the Nazarov cyclizations of these highly substituted and sterically congested substrates 5, giving exo-methylene cyclopentanones 7 under remarkably mild conditions, with excellent and predictable enantiocontrol. Furthermore, since no electrofugal release is required for Scheme 1 Nazarov substrate activation modes for the enantioselective synthesis of 4 -stereocentres.
substrate activation or suppression of Wagner-Meerwein rearrangements, the oxyallyl cation 6 can be exploited in nucleophilic trapping 7,8 to afford multistereocentre-centre-containing products 8 with up to three all-carbon 4 -stereocentres. The rapid assembly of such levels of complexity from a prochiral starting material highlights the powerful activating and stereocontrolling inuence of the Ox group. Using theoretical calculations, we show that the exceptional activating properties of Ox originate from a combination of covalent and non-covalent transition-state stabilizing effects.
Nazarov cyclizations of divinyl and aryl vinyl ketones 5a-j were performed using either BF 3 $THF or TfOH as catalyst in CH 2 Cl 2 , giving cyclopentanoids 7a-i (5f and 5j did not cyclize) containing one new 4 -stereocentre (Table 1). Broadly speaking, these Nazarov cyclizations performed very well, particularly where the "inner" substituent (R 2 ) in 5 was Me, Et or Ph (BF 3 $THF or TfOH). Use of TfOH as catalyst allowed the Nazarov cyclization to be conducted at temperatures as low as À78 C, but generally the reactions were performed at 0 C to rt or in reuxing CH 2 Cl 2 (40 C) using either TfOH or BF 3 -$THF. ‡ The torquoselectivities were very high (dr > 20 : 1 for C1 relative to Ox), with the sole exception of 7d (dr ¼ 2 : 1 (S) : (R)-C1, entry 6). X-ray crystal structure and density functional theory (DFT) studies have shown that Ox auxiliaries of this conguration consistently favor anticlockwise conrotation leading to R 1 -b stereochemistry (see below); 7b we have therefore assigned this stereochemistry to each product in Table 1. Most likely, the cyclization of 5d, which required heating to 40 C due to the sterically encumbering isopropyl group (R 2 ¼ iPr), gave lower selectivity due to partial Z/Eisomerization of the oxazolidinyl-alkene prior to cyclization, rather than because of poor stereoinduction by the auxiliary (see also below).
The presence of two aliphatic substituents on the tetrasubstituted alkene terminus, as in 5e, led to slower cyclization, but the stereoinduction remained high (entry 7). Diaryl-substituted alkene 5f underwent undesired side reactions to give multiple minor products along with return of starting material (entry 8). In a number of cases, the presence of epimers at C2 (the carbon bearing Ox) was apparent, but both epimers lead to the same product once the auxiliary is removed by reductive cleavage (see below). Cyclizations of electron-rich aryl vinyl ketones were successful (entries 9-11), even for the very hindered substrate 5h where R 2 ¼ iPr. For the less activated aryl vinyl ketone 5j, alkene isomerization to form b,g-unsaturated ketone 11 became the dominant pathway and no Nazarov cyclization was observed.
As has been demonstrated in our previous study utilizing a diverse array of less substituted Nazarov products 7 (R 2 ¼ R 3 ¼ H), the oxazolidinone can be removed by reductive-cleavage using lithium naphthalenide (LiNph). 7c Two examples are given as part of this work (eqn (1)): reductive cleavage of the Ox group in 7c and 7i gave 12 (79%) and 13 (55%), respectively, both in high enantiomeric purity (er > 98 : 2).
(1) Also, as per our previous work, additional stereochemical complexity can be built up by nucleophilic trapping of the intermediate oxyallyl cations 6. 7c Accordingly, the highly substituted divinyl ketone 5c was converted into the indoletrapped product 14 (75%) (eqn (2)). Notably, this tandem sequence generates four new contiguous stereocentres, including two 4 -centres, with excellent control over both relative and absolute stereochemistry: only a single isomer was observed. (2) Having achieved stereoselective Nazarov cyclizations leading to products with adjacent 3 and 4 -stereocentres, we next addressed the formation of vicinal 4 -stereocentres. To prepare the fully substituted Nazarov substrate 17 we developed a convergent carbometalation approach starting from two alkynes: ynamide 4a and 3-hexyne (Scheme 2a). Cucatalyzed addition of MeMgBr to 4a, followed by in situ formylation with ethylformate, afforded 15 (52%) stereoselectively. Carboalumination of 3-hexyne to give 16, 11 followed by 1,2-addition of 16 to 15 and oxidation with DMP, gave divinyl ketone 17 (71%). The C2-C3 double bond retained its Z stereochemistry while the C5-C6 double bond was formed as a 3 : 1 E : Z mixture. 12 § Separation of these isomers proved challenging; however, a pure sample of (2Z,5E)-17 was isolated in 24% yield (from 15). We also prepared the fully substituted ketone 20 (Scheme 2b) bearing a tethered nucleophile (electron-rich aryl group). Access to 20 commenced with formation of vinyl bromide 19 from bromoalcohol 18. 13 Lithiation of 19, followed by addition to a solution of 15 and AlMe 3 (Lewis acid) and DMP oxidation of  14 The stereochemistry of these products was conrmed by X-ray crystallography of (3S)-23. ‡ We believe that the origin of this epimeric mixture is partial double-bond isomerization of (2Z,5E)-17 to (2E,5E)-17 under the acidic conditions prior to Nazarov cyclization. While this isomerization was undesired, the rapid (<2 h) cyclisation of both isomers of 17 at À78 C demonstrates the remarkable ability of the Ox group to activate the Nazarov reaction. Upon further experimentation with reaction conditions (acids and solvents) to avoid double-bond isomerization of (2Z,5E)-17 to (2E,5E)-17, we found that treatment of (2Z,5E)-17 with MeSO 3 H in 1,4-dioxane with mild heating gave cyclopentanone 24 stereoselectively in 52% isolated yield (eqn (3)). The stereochemistry of (E)-and (Z)-24 were conrmed by X-ray crystallography and 2D NMR, respectively. ‡ Replacing CH 2 Cl 2 with 1,4-dioxane as solvent appears to exert different effects on the rates of the various competing reactions involved in the formation of 21, 23 and 24 (Scheme 3 and eqn (3)). Solvation of MeSO 3 H by 1,4-dioxane likely reduces the rates of all of these reactions, however, its strongest effects appear to be the suppression of C2-C3 double-bond isomerization in 17 and Wagner-Meerwein rearrangement in 22, leading to the observed stereo-and chemoselective formation of 24. 15 Cyclization of 20 (eqn (4)) under these conditions was also successful, yielding the intramolecularly trapped product 25 as the only product discernable by 1 H-NMR (53% isolated yield). Conversion of 20 to 25 forms two new rings and three contiguous 4 -stereocentres, underscoring the effectiveness of the Ox-controlled Nazarov reaction for synthesis of structurally complex, 4 -stereocentre-containing scaffolds. The asymmetric formation of three contiguous 4 -stereocentres entirely from prochiral carbons is a rare transformation; a Diels-Alder reaction reported by Nicolaou et al. is the only other example known to us. 16 (3) These Ox-promoted Nazarov cyclizations are remarkably facile, allowing efficient generation of sterically congested products at temperatures as low as À78 C. This points to a powerful activating inuence of the Ox auxiliary. In order to determine the origins of this activation, we performed DFT calculations (Fig. 1). ‡ Calculations with M06-2X show that in the absence of an oxazolidinone, the activation energies (DG ‡ ) for Nazarov cyclizations of 26-28 leading to zero, one, or Scheme 3 Nazarov cyclization of 17 in CH 2 Cl 2 . two 4 -centres are 16.8, 22.5, and 28.9 kcal mol À1 , respectively. Each new 4 -stereocentre raises the barrier by 6 kcal mol À1 . ‡ An achiral oxazolidinone devoid of Ph substituents (OxH 2 , see 29-31) lowers the cyclization barrier by 7-13 kcal mol À1 (DG ‡ ¼ 9.7-15.6 kcal mol À1 ) relative to the oxazolidinone-free substrates, while the diphenyloxazolidinone (Ox, see 32-34) provides further activation still, leading to cyclization barriers of only 8.5-10.9 kcal mol À1 . These very low barriers are consistent with the facile ring closures observed for 5, 17, and 20.
The transition states (TSs) for OxH 2 -and Ox-promoted cyclizations benet from several stabilizing effects. Firstly, the nitrogen lone pair affords resonance stabilization of the incipient oxyallyl cation. Secondly, the oxazolidinone-containing TSs feature a longer forming C-C bond than the corresponding oxazolidinone-free TSs, leading to reduced steric repulsion between the Me groups about the forming C-C bond (see Fig. 1b). A third activating inuence of Ox is evident from a comparison of the cyclizations of 33 and 34 (containing Ox) with those of 30 and 31 (containing OxH 2 ). The two Oxsubstituted TSs have DG ‡ values about 6 kcal mol À1 lower than those of the corresponding OxH 2 derivatives. The additional activation by Ox can be traced to a CH-p interaction in the TS between the "inner" substituent on C2 (R 2 , rotating downwards) and the nearby Ph substituent on Ox (see red arrow in Fig. 1). Together, these three TS-stabilizing inuences of Ox make it an exceptionally powerful activating group, capable of reducing the barrier for vicinal 4 -centre formation by almost 18 kcal mol À1 (28 vs. 34). Indeed, computations predict that when the R 1 substituent is an aryl group, like in many of our substrates (5, 17, and 20) (with R 2 ¼ alkyl) the barrier for cyclization is even lower still. ‡

Conclusions
To conclude, carbometalation of Ox-ynamides affords direct access to highly substituted Ox-divinyl and -aryl vinyl ketones, which undergo exceptionally facile Nazarov cyclizations leading to 4 -stereocentre-containing cyclopentanoids. In addition to the powerful activating and stereodirecting inuence of Ox in the Nazarov cyclization, the Ox auxiliary helps suppress undesired Wagner-Meerwein rearrangements in the intermediate oxyallyl cations, and facilitates nucleophilic trapping of these intermediates enabling rapid assembly of multiple stereocentres (including vicinal 4 -stereocentres) with excellent stereochemical control. Theoretical studies allowed us to discover the electronic origin of the strong activating effect of the Ox, which is traced to a combination of covalent (lone pair donation to the incipient oxyallyl cation and reduced steric crowding about the newly forming bond) and non-covalent (CH-p interaction) effects which are generally applicable across most of the divinyl (or aryl vinyl) ketones reported here.

Conflicts of interest
There are no conicts to declare.