4. RESULTS AND DISCUSSION
4.2. Part B: Total synthesis of FIS via direct ArLi addition/oxidative cyclisation
4.2.7. Asymmetric conjugate addition of 157 to malonates
A series of protected ylidenemalonates were prepared by the Knoevenagel condensation of vanillin with the respective malonic ester, followed by protection with the 2-(trimethylsilyl)ethyl group (scheme 53). The condensation leading to methyl ester 170a, ethyl ester 170b and ispopropyl ester 170c afforded high (86-99%) yields of benzylidene malonates after simple precipitation. The subsequent Mitsunobu reaction with 2-(trimethylsilyl)ethanol in toluene afforded protected malonates 171a-d in 78-88% yields.
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Scheme 53. Preparation of protected malonates 170a-d.
The direct conjugate addition of stilbene 157 to malonates was optimized using malonate 171b first (table 8). The baseline reactivity was again established in an experiment in the absence of any ligand (entry 1), which gave only 22% of the Michael adduct rac-172b. The original conditions using catalytic CuBr·DMS in THF similarly afforded 21% of 172b (entry 2). The achiral form of Tomioka’s ligand meso-L1 this time failed to increase the yield significantly (entry 3). In contrast to that, the C2-symmetric (S,S)-L1 proved to be a very efficient promoter, affording 80% of (S)-172b in 51% ee. The configuration of the product was assigned based on Tomioka’s model (chapter 4.2.1, scheme 46).
All modified Tomioka-type ligands were less effective both in terms of yield and ee, with L4 and L7 giving moderate yields of 172b and rather low ee of 37-43% (entries 5, 9) and ligands L5, L6 and L8 failing to promote the reaction altogether (entries 6-8). Cyclohexane diol-derived L13 performed almost equally well as (S,S)-L1 giving 80% yield and 49% ee (entry 10). Pinane diol- derived L14 was moderately competent in directing the 1,4-addition but failed to exert any asymmetric induction (entry 11). Binol-derived diether L12 did not seem to affect the course of the reaction compared to the reaction in pure solvent at all (entry 12) giving 23% of racemic 172b. Dianhydro- sugar derived ligands L9, L10 and L11 were all highly capable of promoting the 1,4-addition in very high yields, however the asymmetric induction was moderate, with L11 giving the highest ee of 40%
(entries 13-15).
Bisoxazoline ligand (S,S)-L16 afforded 71% yield of close-to-racemic 172b (entry 16).
Cinchonine-derived aminoether L17 on the other hand practically prevented conjugate addition, presumably due to its instability towards strong bases (entry 17). Diamine (S,S)-L3 afforded a moderate yield of 172b, but essentially no asymmetric induction, while reaction in the presence of bispidine (R,R)-L15 was unchanged compared to the baseline reaction in pure toluene (entries 18, 19).
In contrast to the other (di)amine ligands, pachycarpine (+)-L2 proved very efficient, affording 76%
yield of (S)-172b in 49% ee.
63 Table 8. Screening of ligands in direct conjugate addition of stilbene 157 to malonate 171b.
Entry Ligand 172b (%) ee (%)
1 - 22 -
2 - 21 a) -
3 meso-L1 27 -
4 (S,S)-L1 80 51 (S)
5 (R)-L4 59 37 (R)
6 (S)-L5 10 -
7 (R,R)-L6 24 5 (R)
8 (S,S)-L8 32 3 (S)
9 (R,R)-L7 56 43 (R)
10 (S,S)-L13 80 49 (S)
11 (−)-L14 66 8 (R)
12 (R)-L12 23 -
13 D-L9 81 26 (R)
14 (+)-L1 95 36 (R)
15 (+)-L11 100 40 (R)
16 (S,S)-L16 71 19 (S)
17 (9S)-L17 10 -
18 (S,S)-L3 52 13 (S)
19 (R,R)-L15 21 0
20 (+)-L2 76 49 (S)
a) THF used as solvent instead of toluene, CuBr·DMS (0.2 equiv.) and LiBr (2.0 equiv.) used as additives.
Out of the three best-performing ligands, Tomioka’s diether (L1) and sparteine (L2) were selected for further optimization due to their good availability. Increasing the loading of (R,R)-L1 from 1.5 equiv. to 4 equiv. did not significantly increase the ee (table 9, entries 1-3). Previously, we observed that the L2-mediated conjugate addition was faster than the reaction mediated by other ligands, that is essentially instant at –78 °C. We therefore decided to test the lower temperature limit of the conjugate addition with (+)-L2. The melting point of toluene (–95 °C) and its increasing viscosity near the melting point necessitated the use of eutectic solvent mixture composed of toluene/ethylbenzene, to which n-pentane of isohexane can be added to further decrease viscosity.
Addition at –90 °C using 4 equiv. of (+)-L2 proceeded fast and afforded 68% of (S)-172b in increased 61% ee (entry 4). Decreasing the temperature further to –115 °C led to further improvement to 70%
ee (entry 5). At –140 °C the ligand-organolithium complex precipitated, leading to a slight decrease
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in ee to 65% (entry 6). In contrast to (+)-L2, decreasing the temperature when using diether ligand (R,R)-L1 led to drop in both yield and ee (entry 7) due to issues with solubility of the lithium complex.
Table 9. Optimization of conjugate addition of 157 to 171b focused on ligands (R,R)-L1 and (+)- L2.
Entry Ligand (equiv.) Solvent T1 °C Yield (%) ee (%)
1 (R,R)-L1 (1.5) Tol –78 78 a) 53 (R)
2 (R,R)-L1 (1.5) Tol –78 71 47 (R)
3 (R,R)-L1 (4.0) Tol –78 73 53 (R)
4 (+)-L2 (4.0) Tol/PhEt (1:1) −90 68 61 (S)
5 (+)-L2 (4.0) Tol/PhEt/n-pentane (1:1:1) −115 79 70 (S) 6 (+)-L2 (4.0) Tol/PhEt/isopentane (1:2:2) –140 b) 77 65 (S) 7 (R,R)-L1 (4.0) Tol/PhEt/n-pentane (1:1:1) −115 c) 35 48 (R)
a) TMSCl added prior addition of 171b. b) Lithiated 157-sparteine complex precipitated prior addition of 171b, the precipitate fully dissolved again at –90 °C. c) Lithiated 157-(R,R)-L1 complex precipitated prior addition of 171b.
To conclude the results presented in tables 8 and 9, ligands (R,R)-L1 and (+)-L2 performed roughly equally –78 °C both in terms of yield (70-80%) and ee (around 50%). Unlike the aromatic Tomioka’s diether L1, the aliphatic diamine ligand (+)-L2 performed better under the deep cryogenic conditions, presumably due to better solubility of its complexes, and/or stronger ligand- acceleration effect.
Next our attention turned to the last component of the direct conjugate addition, that is the Michael acceptor. Ylidenemalonates 171a,c,d, differing in the size of the ester alkyl group were compared at –78 °C using ligands (R,R)-L1 and (+)-L2. Dimethylmalonate 171a behaved similarly to 171b, affording very good yields of 172a with similar ee (table 10, entries 1, 2). Assuming Tomioka’s model, (R,R)-L1 gave (R)-171a, therefore (+)-L2 gave the opposite enantiomer. Diisopropyl malonate 171c afforded 80% yield of (S)-172c in 52% ee using (+)-L2, but reactivity and selectivity was completely lost using (R,R)-L1 (entries 3, 6). Decreasing the temperature in the reaction with (+)-L1 to –93 °C led to improved asymmetric induction, the effect however levelled off at –115 °C giving (S)-172c in 85% yield and 65% ee (entries 4, 5). The most hindered di-(tert-butyl) malonate 171d was significantly less reactive than the other acceptors and underwent addition with inferior asymmetric induction (entries 7-9). Based on these results, conjugate addition of 157 to ethyl ester 171b or isopropyl ester 171c using (+)-SP at –115 °C or lower was selected as the optimal method to carry into the one-pot in situ oxidative cyclisation protocol.
65 Table 10. Comparison of malonates 171a,c,d as acceptors in asymmetric conjugate addition.
Entry Malonate Ligand Solvent T1 °C 172 (%) ee (%) 1 171a (+)-L2 Tol –78 172a (82) 50 (S) 2 171a (R,R)-L1 Tol –78 172a (71) 54 (R) 3 171c (+)-L2 Tol –78 172c (80) 52 (S) 4 171c (+)-L2 Tol/PhEt/pentane –93 172c (72) 62 (S) 5 171c (+)-L2 Tol/PhEt/cumene –115 172c (85) 65 (S) 6 171c (R,R)-L1 Tol –78 172c (7) 29 (R) 7 171d (+)-L2 Tol –78 172d (61) 44 (S) 8 171d (R,R)-L1 Tol –78 172d (<12) a) - 9 171d (R,R)-L1 Tol –78 b) 172d (30) 36 (R)
a) Crude yield by 1H NMR spectroscopy. b) Warmed to –20 °C before quenching.