Diastereofacial Selectivity in the Aldol Addition Reaction- zimmerman-Traxler Chair-Like Transition States
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- 1,3-anti-diol 1,3-syn-diol FAVORED DISFAVORED 1,3-syn-diol
- Premonensin
- Open Transition State Aldol Reactions
- Synthesis of Oxazolidinethione and Thiazolidinethione Chiral Auxiliaries
- Asymmetric Aldol Reactions with Titanium Enolates of N -Acylthiazolidinethiones
- Asymmetric Synthesis of Syn - !-Hydroxy- "-Amino Acids
- Asymmetric Synthesis of Anti - !-Hydroxy- "-Amino Acids
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Directed Reduction of !-Hydroxy Ketones TBSO
CH 3 O H 3 C CH 3 TBSO CH 3 O CH 3 H 3 C CH 3 TBSO
CH 3 O CH 3 H 3 C CH 3 TBSO
CH 3 O H 3 C CH 3 CH 3 CH 3 OH CH 3 CH 3 OH 1. (c-Hex) 2 BCl Et 3 N , Et 2 O 0 °C 2. i-PrCHO –78 °C 1. (c-Hex) 2 BCl Et 3 N , Et 2 O 0 °C 2. i-PrCHO –78 °C 90%, 88% de 75%, 92% de • The C2 stereocenter is believed to be the dominant control element for both substrates. TBSO
CH 3 OB(c-Hex) 2 CH 3 H 3 C CH 3 TBSO CH 3 O CH 3 H 3 C CH 3 R OH O B O H 3 C c-Hex c-Hex H CH(i-Pr)OTBS CH 3 R H • Minimization of A (1,3) interactions in the enolate biases the approach of the aldehyde to the methyl-bearing "-face of the enolate, while the (E)-enolate geometry affords anti-aldol products. CH 3 CH 3 H B O H R 1 R 2 O OAc OAc H B O H R 1 O OAc OAc R 2 H H R 1 R 2 O OH R 1 R 2 OH OH R 1 R 2 OH OH R 1 R 2 O OH O Zn O H R 1 L L R 2 R 1 R 2 OH OH O N CH 3 O O O CH 3 Ph CH 3 OH CH 3 O N CH 3 O O OH CH 3 Ph CH 3 OH CH 3 + + – – 1,3-anti-diol 1,3-syn-diol FAVORED DISFAVORED 1,3-syn-diol Internal hydride delivery: External hydride delivery: • The reactivity of the reagent is attenuated such that the reduction of ketones proceeds at convenient rates only intramolecularly, favoring formation of 1,3-anti-diols. • Chelated transition state, axial attack provides 1,3-syn-diol. • These directed reductions are applicable to #-hydroxy-!-ketoimides: NaBH(OAc) 3 AcOH, CH
3 CN 25 °C, 30 min 99%, >96% de (CH
3 ) 4 NBH(OAc) 3 Zn(BH 4 ) 2 BH 4 – Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560-3578. O N Bn O O CH 3 O CH 3 BnO CH 3 O CH 3 BzO CH 3 O CH 3 • In addition to !-ketoimides, the two chiral ethyl ketones above are known to undergo aldol reactions at the unexpected Re face of the enolate, deilvering anti-anti aldol products. Paterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121-7124. Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-652.
Chem 115 Stereoselective, Directed Aldol Reaction Myers Chris Coletta, Jaron Mercer Premonensin Evans, D. A.; DiMare, M. J. Am. Chem. Soc. 1986, 108, 2476-2478. Anti-Aldols with Magnesium Enolates O N Bn O O CH 3 O CH 3 O N Bn O O CH 3 O OH CH 3 CH 3 CH 3 CH 3 H O CH 3 CH 3 CH 3 O N Bn O O CH 3 OH OH
CH 3 CH 3 CH 3 CH 3 O O CH 3 O O CH 3 H CH 3 O NO 2 H 3 C O CH 3 CH 3 CH 3 CH 3 CH 3 OCH 3 H 3 CO H 3 C O O CH 3 O O CH 3 CH 3 OH NO 2 O CH 3 CH 3 CH 3 CH 3 CH 3 OCH 3 H 3 CO H 3 C HO O CH 3 OH OH CH 3 CH 3 OH O CH 3 CH 3 CH 3 CH 3 CH 3 H 3 C O + Sn(OTf) 2
CH 2
2 , –78 °C
94%, 94% de NaBH(OAc) 3 AcOH
91%, >94 de +
2 2, LDA, THF –78 °C; 1 h ! , THF, 0 °C; H 2 O, HCl, 25 °C 58% Premonensin CH 3 H 3 C CH 3 H 3 C O N Bn O CH 3 O H R O + O N Bn O O R OH CH 3 1. MgCl
2 (10-20 mol%), Et 3
EtOAc, 23 ºC aldehyde
yield (%) dr 24:1 32:1 7:1
21:1 28:1
16:1 14:1
6:1 - 91 71 92 92 77 91 80 CHO X X = CH 3 X = OCH
3 X = NO
2 X CHO Y X = Ph, Y = H X = Ph, Y = CH 3 X = H, Y = CH 3 "-napthaldehyde furfural • Silylation of the magnesium alkoxide in the aldol product turns over the magnesium. • The aldehyde component is limited to non-enolizable aromatic and ",#-unsaturated aldehydes. Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392-393. • Use of the analogous N-acylthiazolidinethione chiral auxiliary affords products of the opposite
S N Bn S CH 3 O H R O + S N Bn S O R OH CH 3 1. MgBr 2 •Et 2 O, (10 mol%), Et 3
EtOAc, 23 ºC 2. 5:1 THF/1 N HCl • Both reactions are proposed to proceed through boat transition states. See: Evans, D. A.; Downey, W. C.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127-1130. M. Movassaghi 57% (+19% undesired diastereomer) 2. TFA; CH 3 OH Chem 115 Stereoselective, Directed Aldol Reaction Myers Open Transition State Aldol Reactions O N t-Bu O CH 3 O aldehyde Lewis acid SnCl
4 TiCl
4 TiCl
4 • Heathcock and coworkers reported that complexation of the aldehyde with an added Lewis acid allows access to non-Evans syn and anti aldol products via open transition states.
• Gauche interactions around the forming C-C bond dictate which face of the aldehyde reacts. For small Lewis acids, transition state 1 is favored. For large Lewis acids, transition state 2 is favored. Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750. O N t-Bu O O CH 3 OH R Bu 2 BOTf, i-Pr 2 NEt, CH 2 Cl 2 ; Lewis acid, RCHO O N
O CH
O B Bu H O H R non-Evans syn CHO H
C anti:syn* 10:90
12:88 8:92
yield (%)* 66 72 65 O N i-Pr O CH 3 O O N i-Pr O O CH 3 OH R Bu 2 BOTf, i-Pr 2 NEt, CH 2 Cl 2 ; Lewis acid, RCHO O N
O CH
O B Bu H O R H anti LA LA 1, favored for small Lewis acids 2, favored for large Lewis acids aldehyde Lewis acid Et 2
Et 2 AlCl *Determined by 1 H NMR. Yield given is the total yield of diastereomeric aldol mixture. CHO H 3 C anti:syn* 88:12
74:26 yield (%)* 81 62
2 HO Bn S NH S Bn CS 2 , KOH H 2 O 80%
O NH S Bn Cl 2 CS, Et 3 N CH 2 Cl 2 95%
S N S Bn CH 3 O RCHO
CH 2 =CHCHO i-PrCHO CH 2 =CHCHO i-PrCHO S N S Bn O R OH CH 3 A S N S Bn O R OH CH 3 B 1. TiCl
4 (1.1 equiv) (–)-sparteine CH
2 Cl 2 , 0 °C 2. RCHO, 0 °C + (–)-sparteine (equiv) yield (%) A : B 1.0
1.0 2.0
2.0 49 60 77 75 >99:1 98:2 <1:99
3:97 • Selectivities are generally >95:5 for syn:anti products. • Both the yield and diastereoselectivities are high and synthetically useful, although they are typically lower than the corresponding oxazolidine aldol reactions. • An advantage of this method is that a single acyloxazolidinethione can provide either syn aldol product by changing the amount of sparteine in the reaction mixture. Ph CHO PhCHO
Jaron Mercer, M. Movassaghi Asymmetric Aldol Reactions with Titanium Enolates of N-Acylthiazolidinethiones Crimmins, M. T; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894-902. NH 2
Bn O NaBH 4 , I
2 THF
95% Bu Bu Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi, Jaron Mercer H CH
O TI O Cl Cl Cl N S S Bn H R H H
OH CH
O HO Ph OH CH 3 S N S Bn O R OH CH 3 S N S Bn CH 3 O S N i-Bu S O R OH CH 3 CH 3 O OH CH 3 O
S N
Bn O R OH CH 3 O TiL
x O CH 3 R N H H S S H Bn BnHN OH CH 3 O
N OH
3 O
CH 3
CH 3 NaBH 4 83%
DIBAL-H 69%
• The thiazolidinethione auxiliary is easily removed under mild conditions: • The thiazolidinethione auxiliary is recovered by basic extraction (1 M NaOH) of the product mixture. PhCH
2 NH 2 79% CH 3 ONHCH 3 •HCl imidazole 77%
CH 3 OH imidazole 79%
TiCl 4 (–)-sparteine (2 equiv) RCHO TiCl
4 (–)-sparteine (1 equiv) RCHO Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883-7884. Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-777. • Proposed transition states provide a rationale for the selectivity dependence on amine equivalents: O N
Bn O O N S Bn O R' OH OR A O N S Bn O R' OH OR B 1. TiCl
4 , (–)-sparteine 2. TiCl 4 , R'CHO + Anti-Selective Aldol Reactions with Titanium Enolates of N-Glycolyloxazolidinethiones aldehyde
yield (%) A : B : syn OR H 3 CCHO
CH 3 CHO CHO Ph CHO
CH 3 CHO CHO CH 3 CHO CHO
R 84 56 74 58 64 48 63 59 allyl allyl
allyl allyl
Bn Bn CH 3 CH 3 94 : 6 : 0 65 : 24 : 11 94 : 6 : 0 95 : 5 : 0 88 : 12 : 0 74 : 26 : 0 84 : 11 : 5 88 : 12 : 0 O N
S O O Ti H O R' H TiL 4 • Complexation of the aldehyde with excess titanium occurs in situ to give anti products with high selectivity. • The proposed transition state is analogous to that of the anti-selective Heathcock aldol. L 4
Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591-594. Chem 115 Stereoselective, Directed Aldol Reaction Myers Jaron Mercer Asymmetric Synthesis of Syn-!-Hydroxy-"-Amino Acids Sn(OTf)
2 ,
RCHO O
Bn O NCS O O N Bn O O R O N Bn O O aldehyde yield (%) ratio* H
CCHO PhCHO
91:9 99:1
99:1 94:6
97:3 75 91 92 73 71 CH 3 CHO CHO H 3 C CH 3 CH 3 CH 3 CHO
*Ratio of desired (illustrated) stereoisomer to the sum of all other stereoisomers. CH 3 N C S HN O S R • The isothiocyanate below serves as a chiral glycine equivalent. Stannous triflate-mediated aldol reactions give cyclized aldol adducts in high yield and diastereoselectivity. HO R NHCH 3 OH O 1. KOH
2. H 3 O + (H 3 C) 3 OBF 4 Mg(OCH
3 ) 2 HOCH 3 H 3 CO O N O R SCH 3 H 3 C H 2 O H 3 CO O N O R O H 3 C Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757-6761. • The N-methyl amino acid can be reached in 4 steps. O N Bn O O HN O S CH 3 H 3 C O HN O S R H 3 CO • 2-Chloro- and 2-Bromoacetyl imides undergo aldol addition with high diastereoselectivity. Asymmetric Synthesis of Anti-!-Hydroxy-"-Amino Acids O N O Br O O N O Cl O Bu 2 BOTf, Et
3 N,
Et 2 O; RCHO O N O O Cl R OH Bu 2 BOTf, Et
3 N,
Et 2 O; RCHO O N O O Br R OH aldehyde yield (%) ratio*
H 3 CCHO PhCHO 95:5
97:3 96:4
98:2 94:6
67 79 75 63 63 *Ratio of desired (illustrated) stereoisomer to the sum of all other stereoisomers. imide 1 2 1 1 1 2 2 H 3 C CHO
CHO H 3 C CH 3 Ph CH 3 Ph CH 3 Bn Bn CH 3 O CH 3 OH HO 1. NaN 3 2. LiOH/H 2 O Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39-42. • Halide displacement with NaN 3 occurs with inversion of stereochemistry. Hydrolytic removal of the auxiliary followed by hydrogenation of the azide delivers the amino acid. O N O O Cl CH 3 OH 3. H 2 , Pd/C, TFA 76%, ≥99% de Ph CH 3 NH 2 OSnL Chem 115 Stereoselective, Directed Aldol Reaction Myers Jaron Mercer O N
O O O N Bn O Br O NO 2 F Bu 2 BOTf, Et
3 N; OHC NO 2 F 76%, 95:5 dr
O N 3 NO 2 F HO O N Bn O NCS O Cl F NO 2 OHC Cl F O 2 N HO 2 C 1. TMGA, CH 2 Cl 2 2. LiOOH Sn(OTf)
2 , N-ethylpiperidine; 95:5 dr 1. Boc
2 O, DMAP; HCO 2
2 O 2 2. LiOOH Download 0.58 Mb. Do'stlaringiz bilan baham: 
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