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3 1 a C CF b c 4 5 Me Me S Jacobsen's catalyst Scheme 1. eagents and conditions: (a) C (1.5 equiv), Jacobsen's catalyst (0.05 equiv), toluene, 0 C, 40 h, then trifluoroacetic anhydride (4.0 equiv), 60 C, h, 86%, 95% ee; (b) S 4 / (1/1, v/v), rt, 40 h; (c) S 4 / (1/5, v/v), reflux, 4 h, % ( steps). a 5 6 b c ()-( )-calycotomine 8 Scheme. eagents and conditions: (a) (Boc) ( equiv), C, rt, 0 min, 99%; (b) LiAl 4 (1equiv),TF,rt,h,99%;(c)TMSTf( equiv), C, rt, 0 min, 81%.

4 a Ts 9 b c Me Me (S)-( )-salsolidine 11 d Me Me (S)-( )-carnegine 1 Scheme. eagents and conditions: (a) Ts (1.5 equiv), pyridine, rt, h, 81%; (b) LiAl 4 (4 equiv), TF, 60 C, 5 h, 56%; (c) TMSTf ( equiv), C, rt, 0 min, 86%; (d) Caq. (5 equiv), ab C (1.6 equiv), C C, rt, h, 8%. 6 Boc a 1 Boc b Boc 14 c Boc d e 16 ( )-trolline (1) 15 f g ( )-crispine A (18) Boc h Boc i 19 Boc Boc 0 ( )-crispine E (1) Scheme 4. eagents and conditions: (a) DIBAL- (.0 equiv) C, 8 C, 0 min, 9%; (b) trimethyl phosphonoacetate (5 equiv), a (ca. 4 equiv), benzene, rt, 1 h, 95%; (c),%pd/c,,rt,1h,9%; (d) TMSTf ( equiv), C, rt, 0 min, then Et (4equiv),rt,h,99%;(e)BBr (5 equiv), C, 0 C, 4 h, 9%; (f) LiAl 4 (5 equiv), TF, reflux, h, 9%; (g) LiAl 4 (5 equiv), TF, rt, 1 h, 9%; (h) PPh (5 equiv), DEAD (5 equiv), 1,-bis(tert-butoxycarbonyl)guanidine ( equiv), toluene, rt, 8 h, 95%; (i) TMSTf (5 equiv), C, rt, 1 h, 86%.

6 Table 1. Thiourea catalyzed asymmetric acyl-strecker reaction of isoquinolines a S CF CF 1 1 catalyst additive Me C toluene C 5-40 o C, h 1,, 4 6,, 8 Me entry substrate 1 additive (mol%) product yield (%) b ee (%) c 1 1 Me Me none Me Me TFA () none TFA () Me Me none Me Me TFA () a The reaction was carried out with isoquinoline (0.5 mmol), 5 (0.5 mmol), and catalyst (0.05 mmol) in toluene (0.5 ml) at 40 C for h. b Yield of isolated product. c Determined by PLC analysis with a chiral column. Table. Chiral sulfonamide 9 catalyzed asymmetric hetero-diels Alder reaction CF Me TMS 0 S CF 9 TFA Et Et Et rt temp, 4 h 1 h 1 entry a 0 (equiv) 1 (equiv) 9 (mol%) MS 4A temp ( C) yield (%) b ee (%) c a The reaction was carried out with Danishefsky s diene 0 and ethyl glyoxylate 1 in the presence of catalyst 9 for 4 h. b Yield of isolated product. c Determined by PLC analysis with a chiral column.

7 Table. Asymmetric alkylations of tert-butyl methyl malonate 4 with various alkylation reagents C 4 -X ( mol%) toluene 50% K 0 C, time * C 5-40 entry -X product time (h) yield (%) a ee (%) b 1 I Br 5 86 Br c C -I c C C -I I Bn Br a Isolated yields. b Determined by chiral PLC. c 4.0 equiv of alkylating agent was used. C TFA, C rt quant. C C DPPA, Et, toluene, reflux Li, then ac, TF,, reflux reflux 41 8% 4 8% ()-4 94% ee 5 94% ee Li, reflux quant. 44 DPPA, Et, toluene, reflux TFA then ac, TF,, reflux C rt % 84% 45 (S)-4 94% ee Scheme 5. Synthesis of ()- and (S)- -allylphenylalanine

9 Table 4. L-t-Leucine 46 catalyzed asymmetric aldol reaction. 4 48a-k 46 (0 mol%) DMS, rt, d 49a-k entry [a] product yield dr (%) [b] (syn/anti) [c] ee of anti (%) [d] 1 [e] C C C CC 6 4,5-(CF ) C 6 4-C CF C 6 4 C 6 5 -naphthyl 4-pyridinyl -qunolinyl 49a 49b 49c 49d 49e 49f 49g 49h 49i 49j 49k /1 1/8.1 1/1 1/. 1/5. 1/6. 1/5. 1/9.0 1/9.0 1/6.1 1/ [a] Unless otherwise stated, the reaction was performed with p- nitrobenzaldehyde (1 equiv), cyclohexanone (1.5 equiv), and L-t-leucine (0. equiv) in DMS in the presence of (50 equiv) for d. [b] The combined isolated yield of the diastereomers. [c] Determined by 1 - M. [d] Determined by PLC. [e] The reaction was performed in the presence of 0.1 equiv. of L-t-leucine. Table 5. L-t-Leucine 46 catalyzed asymmetric aldol reaction of cycloheptanone and cyclooctanone n 50 or neat rt n 5 or 5 entry [a] n catalyst (mol%) time (days) product yield (%) [b] dr (syn/anti) [c] ee of syn (%) [d] 1 4- C 6 4 5a / C b 84 6./1 1 4-CC d 89 5./1 6 4,5-(CF ) C 6 0 5e / pyridinyl 0 5j 89 6./1 50 6,4-( ) C 6 0 5l 8 4.0/ C a 68 / CC d 51 /1 51 9,5-(CF ) C 6 0 5e 9 1/1 1 4-pyridinyl 0 5j 1 /1 5 [a] The reaction was performed with aldehyde (1 equiv), cyclic ketone ( equiv). [b] The combined isolated yield of the diastereomers. [c] Determined by 1 -M. [d] Determined by PLC.

10 s-trans-enamine anti-aldol syn-aldol s-cis-enamine Scheme 6. Proposed transition states of anti- and syn-aldol reactions.

11 L-alanine L-valine L-leucine C L-t-leucine unstable Scheme. eactions between amino acids and aryl aldehyde Table 6. L-t-Leucine 46 catalyzed asymmetric aldol reaction of chloroacetone (54) 46 (0 mol%) neat rt, d 54 48a-i 55a-i 56a-i 5a-i entry a product (syn) yield (%) b (5556)/5 c 55/56 c ee of 55 (%) d C C C CC C MeC 6 4 -BrC 6 4 -CF C 6 4 C naphthyl 55a 55b 55c 55d 55e 55f 55g 55h 55i >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 94/6 >99/1 /1 6/1 8/1 5/1 /1 /1 /1 5/1 16/ a The reaction was performed with arylaldehyde 48 (1 equiv), chloroacetone 54 ( equiv), and L-t-leucine (0. equiv) at rt for d. b Thecombinedisolatedyieldofthediastereomers. c Determined by 1 -M. d Determined by PLC.

12 a) proline catalyst b) primary amino acid catalyst < (Z)-enamine (E)-enamine < (E)-enamine (Z)-enamine 56 anti 55 syn Scheme 8. A proposed mechanism for the organocatalyzed asymmetric aldol reaction of chloroacetone (54)

16 Abstract

Precisely Designed Catalysts News Letter Vol. 5 May, 2016

Precisely Designed Catalysts News Letter Vol. 5 May, 2016 recisely Designed Catalysts ews Letter Vol. 5 May, 2016 E-mail: sawamura@sci.hokudai.ac.jp Silica-SMA Silica-TI S-T Figure 1 Si 3 Si Si Si Si 2 Silica-SMA Si 3 Si Si Si Si 2 Silica-TI t Bu S S S-T t Bu