Direct Catalytic Asymmetric Doubly Vinylogous Michael Addition of α,β-Unsaturated γ-Butyrolactams to Dienones**

An asymmetric doubly vinylogous Michael addition (DVMA) of α,β-unsaturated γ-butyrolactams to sterically congested β-substituted cyclic dienones with high site-, diastereo-, and enantioselectivity has been achieved. An unprecedented DVMA/vinylogous Michael addition/isomerization cascade reaction affords chiral fused tricyclic γ-lactams with four newly formed stereocenters.

In most studies as ingle vinylogous substrate,e ither the electrophilic or nucleophilic partner,w as used. [1,[3][4][5][6][7] In 2013 Jørgensen and co-workers reported the first organocatalytic doubly vinylogous Michael-type reaction, namely the 1,6addition of alkylidene lactones to 2,4-dienals with the formation of an ew stereocenter (Scheme 1a). [8] It is significantly difficult to simultaneously activate the two vinylogous partners at their remote reactive sites whilst achieving high regio-, diastereo-, and enantiocontrol. Indeed, to the best of our knowledge there are no precedents for the catalytic, asymmetric doubly vinylogous Michael addition (DVMA) to 2,4-dienones,the much less reactive analogues of 2,4-dienals. Ther ealization of such ar eaction would prove the broad applicability of the organocatalytic vinylogous activation patterns,t hus representing as ignificant advance in the field. Moreover,asymmetric doubly vinylogous reactions naturally leave two unsaturated CÀCbonds in the product and provide Scheme 1. a) First asymmetric organocatalytic doubly vinylogous Michael addition. b) Use of a,b-unsaturated g-butyrolactams in vinylogous Michael additions. c) This work:unprecedentedasymmetric organocatalyticDVMA and arelated cascade between a,b-unsaturated g-butyrolactamsa nd dienones.B oc = tertbutoxycarbonyl. apotential opportunity for additional transformations for the construction of complex chiral molecules.
Herein we report the first doubly vinylogous Michael addition to 2,4-dienones by using adiamine derived from tertleucine as an organocatalyst (Scheme 1c). [9] Thechallenging g to d 1,6-addition reaction of N-protected a,b-unsaturated gbutyrolactams [10] to sterically congested b-substituted cyclic dienones proceeds with high regio-and stereoselectivity wherein strong hydrogen-bonding interactions between the N-protected, deprotonated butyrolactam and the catalyst are believed to be responsible for the observed control. In addition we report that by using 3-alkenyl cyclopent-2enones as substrates,t he initial DVMA is followed by av inylogous Michael addition/isomerization cascade,t hus affording tricyclic g-lactams with four new stereocenters.
Our investigations began with as creen of as et of chiral diamines (3a-d)inthe DVMA of the dienone 1a and the Nprotected a,b-unsaturated g-butyrolactam 2a as shown in Table 1. The l-tert-leucine derivative 3d afforded the desired product 4a with encouraging conversion and good stereoselectivity (entry 4). This catalyst performed well in most solvents,b ut provided the best ee values in chlorinated solvents (89-91 % ee,e ntries 4-6), compared to the 85 % ee obtained with ethers and the less than 80 % ee obtained with polar solvents (see Table S1 in the Supporting Information). An extensive screening of acidic additives (see Table S2 in the Supporting Information) allowed identification of p-anisic acid as ideal. By using 20 mol %ofp-anisic acid in CH 2 Cl 2 at 4 8 8C, the product was obtained with 19:1 d.r. and 91 % ee (Table 1, entry 13;s ee Tables S3-S6 in the Supporting Information for full optimization studies). Finally,byincreasing the amount of p-anisic acid to 40 mol %a nd adjusting the dienone/butyrolactam ratio to 2:1, the d.r.a nd ee values were slightly increased (entry 14). When the reaction was run under these optimized reaction conditions for 60 hours,t he desired product was obtained with 95 %yield upon isolation, in greater than 19:1 d.r. and 91 % ee (see Table 2).
Next, the scope of the asymmetric DVMA with respect to dienone reaction partners was explored. By using the N-Bocprotected g-butyrolactam 2a as the reacting partner, an extensive range of 3-alkenyl cyclohex-2-enones were transformed into the desired products 4 with good to excellent stereoselectivity ( Table 2). Aryl-substituted dienones with electron-donating substituents in the para-and meta-positions of the aromatic ring gave excellent enantioselectivities and diastereoselectivities (4b,c,f), whilst substrates with substituents in the ortho-position resulted in as lightly diminished ee value (4d,e). Thee nantioselectivity remained excellent when the aryl ring bore electron-withdrawing and halogen substituents (4g-j), although in the presence of the nitro group the d.r. value was reduced. Also,less reactive aliphatic substituted dienones (4k,l)a nd bulky substrates with gemdimethyl groups on the cyclohexenone (4m,n)w ere welltolerated. Thea bsolute configuration of 4p was determined by X-ray crystallographic analysis. [11] Ther eaction was scaled up to obtain 1.06 grams of 4a (Scheme 2). By lowering the catalyst loading to 10 mol %, raising the temperature to 25 8 8C, and prolonging the reaction time to 72 hours the yield of the isolated product (93 %) and enantioselectivity (90 % ee)w ere comparable to those obtained on smaller scale. N-Ts-and N-Cbz-protected a,b-unsaturated g-butyrolactams were also compatible with the reaction conditions ( Table 3, 4q-4v). Compared to N-Boc-protected substrates, the enantioselectivity remained good (83-91 % ee). However the yields (45-72 %) and diastereoselectivities (7:1 to 10:1 d.r.)w ere slightly diminished.
Interestingly,when switching from six-to five-membered cyclic dienones,adoubly vinylogous Michael addition/vinylogous Michael addition/isomerization cascade resulted (Table 4). Thec ascade reaction proceeded with excellent enantioselectivity (92-99 % ee), but poor to moderate diaste- . . reoselectivity (d.r. from 1:1t o5 :1). In our proposed mechanism for the cascade reaction (Scheme 3), the initial DVMA is followed by av inylogous Michael addition from the gposition of the cyclopentenone to the b-position of the butyrolactam. Migration of the CÀCdouble bond to the other side of the carbonyl group may be ascribed to an isomerization via the dienamine of cyclopentenone, [12] presumably driven by the thermodynamic stability of the product 6. This mechanism is supported by the outcomes of the intermolecular vinylogous additions of 3-phenylcyclopent-2enone (7a)a nd 3-phenylcyclohex-2-enone (7b)t ot he a,bunsaturated g-butyrolactam 2a (Scheme 4). Av inylogous Michael addition between 7a and 2a,w hich mimics the second step of the reaction cascade,took place with 30 mol % catalyst at 40 8 8Ci n4 3% yield. On the contrary,n or eaction was observed using 7b.
Therelative stereochemical configuration of the products of the cascade reaction (Table 4) was determined by singlecrystal X-ray analysis of the compound 6d.T he absolute [a] Reactionsperformed using 1.0 equiv of 2 (0.2 mmol, 0.5 m), 2.0 equiv of 1,0.2 equiv of 3d,and 0.4 equiv of p-anisicacid in CH 2 Cl 2 at 4 8 8C.
Yields of isolatedproducts are given. The d.r.values were determined by 1 HNMR analysis of the crude reaction mixture. The ee values were determined by HPLC analysis using achiral stationary phase. Table 3: Scope of the DVMA with respect to the N-protected a,bunsaturated g-butyrolactams. [a] [a] Reactionsperformed using 1.0 equiv of 2 (0.2 mmol, 0.5 m), 2.0 equiv of 1,0.2 equiv of 3d,and 0.2 equiv p-anisic acid in CH 2 Cl 2 at 4 8 8C, unless otherwise stated. Yields of isolated products are given. The d.r.values were determined by 1 HNMR analysis of the crude reaction mixture. The ee values were determined by HPLC analysis using achiral stationary phase. [b] Reaction performed at RT.Cbz = carboxybenzyl, Ts = 4-toluenesulfonyl. Table 4: Scope of the cascade reaction between 3-alkenyl cyclopent-2enones and N-protected a,b-unsaturated g-butyrolactams. [a] [a] Reactionsperformed using 1.0 equiv of 2 (0.2 mmol, 0.5 m), 2.0 equiv of 5,0.3 equiv of 3d,and 0.3 equiv p-anisic acid in CH 2 Cl 2 at 4 8 8Cfor 4 days. Yields of the isolated products are given. The d.r.values were determined by 1 HNMR analysis of the crude reaction mixture. The ee values were determined by HPLC analysis using achiral stationary phase.

Angewandte
Chemie configuration was assigned by analogy with that determined for the six-membered ring analogues,u nder the assumption that 3-alkenyl cyclopent-2-enones undergo the DVMA with the same enantiofacial selectivity.
In conclusion, we have developed an ovel asymmetric direct doubly vinylogous Michael addition between a,bunsaturated g-butyrolactams and sterically congested b-substituted cyclic dienones,a ffording products with significant levels of diastereo-and enantioselectivity.R emote transmission of the stereochemical information was successfully realized through the two conjugated p systems by taking advantage of abifunctional diamine catalyst. In addition, this method has provided access to chiral tricyclic g-lactams with up to four newly formed stereocenters,g enerated from 3alkenyl cyclopentenones substrates by an unprecedented vinylogous Michael addition/vinylogous Michael addition/ isomerization cascade.