Diastereofacial Selectivity in the Aldol Addition Reaction- zimmerman-Traxler Chair-Like Transition States
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- ( Z )-enolates ( E )-enolates
- Preparation of ( Z )- and ( E )-Boron Enolates ( Z )-Selective Preparation of Boron Enolates from Evans Acyl Oxazolidinones (Imides)
- Carboximide Hydrolysis with Lithium Hydroperoxide
- Cytovaricin
- Diastereoselective Syn -Aldol Reaction of !-Ketoimides
- Syn-Anti- Selective Aldol Reactions of Chiral Ethyl Ketones
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Chem 115 Stereoselective, Directed Aldol Reaction Myers Diastereofacial Selectivity in the Aldol Addition Reaction- Zimmerman-Traxler Chair-Like Transition States O M O CH 3 R 2 L R 1 H H L O M O CH 3 H L R 1 R 2 H L O M O H H L R 1 R 2 H 3 C L R 1 OML
2 CH 3 O M O H R 2 L R 1 H H 3 C L R 1 OML
2 CH 3 R 1 R 2 O CH 3 OH R 1 R 2 O CH 3 OH R 1 R 2 O CH 3 OH R 1 R 2 O CH 3 OH + + FAVORED DISFAVORED FAVORED DISFAVORED Reviews: • Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent. Only a few metals, such as boron, reliably follow the indicated pathways. • (Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing 1,3-diaxial interactions between R 1 and R
2 in each chair-like TS ‡ .
(E)-enolates Heathcock, C. H. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 133-238. Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 239-275. Paterson, I. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 301-319. H 3 C H O H 3 C OH H O 2 • The aldol reaction was discovered by Aleksandr Porfir'evich Borodin in 1872 where he first observed the formation of "aldol", 3-hydroxybutanal, from acetaldehyde under the influence of catalysts such as hydrochloric acid or zinc chloride. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-1923. Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225-1228. Heathcock, C. H.; Buse, C. T.; Kleschnick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J.
• Note: the enantiomeric transition states (not shown) are, by definition, of equal energies. The pericyclic transition state determines syn/anti selectivity. To differentiate two syn or two anti transition states, a chiral element must be introduced (e.g., R 1 , R
2 , or L), thereby creating diastereomeric transition states which, by definition, are of different energies.
M. Movassaghi R 2
R 2 CHO Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi Preparation of (Z)- and (E)-Boron Enolates (Z)-Selective Preparation of Boron Enolates from Evans' Acyl Oxazolidinones (Imides) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109-1127. Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120-6123. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure & Appl.
Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441-3442. Et CH 3 O Et CH 3 OB(n-Bu) 2 (n-Bu) 2 BOTf
>97% (Z) PhCHO
–78 ºC 77%
Et O Ph CH 3 OH syn >99% Et CH 3 O Et OB(c-Hex) 2 (c-Hex) 2 BCl
>99% (E) PhCHO
–78 ºC 75%
Et O Ph CH 3 OH anti >97% • Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the amine used or the steric requirements of the alkyl groups on the boron reagent. • In the case of dialkylboron chlorides the geometry of the product enolates is much more sensitive to variations in the amine and the alkyl groups on boron. • The combination of (c-Hex) 2 BCl and Et 3 N provides the (E)-boron enolate preferentially. O N
O CH 3 O (n-Bu) 2 BOTf
CH 2 Cl 2 O N Bn O CH 3 O B n-Bu n-Bu – OTf O N O O Bn H B n-Bu n-Bu H 3 C H H O N O O Bn H B n-Bu n-Bu H CH 3 H
DISFAVORED O N Bn O CH 3 O B n-Bu n-Bu O N Bn O O B n-Bu n-Bu CH 3 • Observed selectivity > 100:1 Z : E. i-Pr 2 NEt i-Pr 2 NEt iPr 2 NEt, Et 2 O –78 ºC, 30 min Et 3 N, Et 2 O –78 ºC, 10 min CH 3
Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J. Bartroli, J. Pure & Appl.
O N Bn O O R O CH 3 O N Bn O O R O CH 3 B B n-Bu n-Bu n-Bu n-Bu O N Bn O O R OH CH 3 O N Bn O O R OH CH 3 O N Bn O CH 3 OB(n-Bu) 2 O
O CH 3 R n-Bu N H n-Bu H O O H Bn O B O CH 3 R n-Bu N H n-Bu H O O Bn H vs. FAVORED DISFAVORED O N Bn CH 3 O O B n-Bu n-Bu UNREACTIVE O N Bn CH 3 O O Li cf. reactive enolate in Evans' asymmetric alkylation Open coordination site required for pericyclic aldol rxn RCHO
Syn-Selective Aldol Reactions of Imide-Derived Boron (Z)-Enolates • Chiral controller group biases enolate !-faces such that one of the two diastereomeric (syn) transition states is greatly favored. • Dipole-dipole interactions within the imide are minimized in the reactive conformation (see: Noe, E. A.; Raban, M J. Am. Chem. Soc. 1975, 97, 5811-5820). O N O CH 3 O H 3 C CH 3 O N CH 3 O CH 3 O Ph O N O O H 3 C CH 3 O N CH 3 O O Ph R R OH CH 3 OH CH 3 1. n-Bu 2 BOTf, i-Pr 2 NEt
CH 2 Cl 2 , 0 °C
2. RCHO –78 " 23 °C 1. n-Bu 2 BOTf, i-Pr 2 NEt
CH 2 Cl 2 , 0 °C
2. RCHO –78 " 23 °C aldehyde diastereomeric a ratio
a Ratio of major syn product to minor syn product. yield (%) 497:1
<1:500
141:1 <1:500
>500:1 <1:500 78 91 75 95 88 89 imide
• A variety of chiral imides can be used for highly selective aldol reactions. • Anti products are typically formed in less than 1% yield. • Often, a single crystallization affords diastereomerically pure product. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129. Evans, D. A.; Gage, J. R. Org. Syn. 1990, 68, 83.
(CH
3 ) 2 CHCHO (CH
3 ) 2 CHCHO n-C 4 H 9 CHO
n-C 4 H 9 CHO
C 6 H 5 CHO
C 6 H 5 CHO
A B A B A B Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi Carboximide Hydrolysis with Lithium Hydroperoxide Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141-6144. Gage, J. R.; Evans, D. A. Org. Syn. 1990, 68, 83-91. • Reductive cleavage: Other Methods for Removal of the Chiral Auxiliary O N O R O O N CH 3 O O OH HO R O N H R O OH O N Bn O O H CH 3 H CH 3 H CH 3 Ph Ph + LiOOH or LiOH
substrate reagent
76 0 16 100 98 43 <1 30 yield of A (%) a yield of B (%) a a
• LiOOH displays the greatest regioselectivity for attack of the exocyclic carbonyl group. • This selectivity is most pronounced with sterically congested acyl imides. • This is a general solution for the hydrolysis of all classes of oxazolidinone-derived carboximides and allows for efficient recovery of the chiral auxiliary. LiOOH LiOH
LiOOH LiOH
A B O H 3 CO N 3 N O NHBoc OBn
O O H 3 CO N 3 OH O NHBoc OBn
O O Bn O LiOOH
THF, H 2 O; Na 2 SO 3 0 °C
96% • The selective hydrolysis of carboximides can be achieved in the presence of unactivated esters using LiOOH. O OBOM CH 3 CH 3 OBn
CH 3 O O H 3 C CH 3 H 3 C H 3 C N O O O CH 3 Ph H H O OBOM
CH 3 CH 3 OBn
CH 3 O O H 3 C CH 3 H 3 C H 3 C O H H BnO O N CH 3 O O CH 3 Br Bn CH 2 CH 3 Br CH 2 HO O N CH 3 O O OBn
Bn OH CH 3 CH 3 N O OBn OH CH 3 CH 3 O CH 3 BnOLi THF, 0 °C 77%
LiAlH 4 , THF –78 ! 0 °C 90%
• Esterification: • Transamination: • A free "-hydroxyl group is required. • Weinreb amides can be readily converted into ketones or aldehydes (see: Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818). Al(CH
3 ) 3 CH 3 ONHCH 3 •HCl
CH 2 Cl 2 , 0 °C
92% CH 3 Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526. Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi Cytovaricin: Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001-7031. O N CH 3 O CH 3 O Ph O N CH 3 O O Ph OH CH 3 O H N O TESO CH 3 CH 3 O CH 3 O N CH 3 O H 3 C O Ph O H H 3 C O N CH 3 O O Ph OH CH 3 H 3 C H 3 C CH 3 N CH 3 N O O H 3 C CH 3 H 3 C N CH 3 H O O H 3 C CH
3 N H 3 C CH 3 CH 3 CH 3 O TESO CH 3 O O O CH 3 H CH 3 H H H 3 C HO H O O OCH
2 OCH
2 CCl
3 CH 3 O H CH 3 H H H 3 C H H H n-Bu 2 BOTf, Et 3 N CH 2 Cl 2 , 0 °C; RCHO
–78 ! 23 °C; H 2 O 2 , 0 °C PMB = p-Methoxybenzyl + 1. Al(CH 3 ) 3 CH 3 ONHCH 3 •HCl THF, 0 °C 2. TESCl, Im. DMF 91% n-Bu 2 BOTf, Et
3 N CH 2 Cl 2 , 0 °C; RCHO, –78; H 2
2 , 0 °C
+ LDA, Et
2 O, THF, 0 °C; –45, 90 % + HF, H 2 O, CH
3 CN 25 °C 92% DEIPS = diethylisopropylsilyl OPMB OPMB
OPMB OPMB
PMBO O O OCH 2 OCH 2 CCl
3 CH 3 O H CH 3 H H H 3 C DEIPSO H H H N O O H 3 C O H 3 C Ph O O OCH 2 OCH
2 CCl
3 CH 3 OH H CH 3 H H H 3 C DEIPSO H H H 3 C O N CH 3 OCH
3 TBSO
H 3 C CHO OPMB
O O H 3 C DEIPSO H CH 3 OCH 2 OCH 2 CCl
3 CH 3 H HH O Si O HO O PhSO
2 O O CH 3 OCH 3 OTES
t-Bu t-Bu H 3 C TESO CH
3 TESO
OTES CH 3 OH O O H 3 C HO H CH 3 O CH 3 H H H O H 3 C O OH CH 3 OH CH 3 HO CH 3 OH O O CH 3 OH OCH 3 H H O N CH 3 O CH 3 O Ph N O OH CH 3 OBn O OBn
H H 3 CO CH 3 O O CH 3 OBn
CH 3 Si t-Bu t-Bu + 1. n-Bu 2 BOTf, Et
3 N CH 2 Cl 2 , –78 °C; RCHO 2. Al(CH 3 ) 3 , THF
CH 3 ONHCH 3 •HCl
92% + +
2 BOTf, Et
3 N CH 2 Cl 2 , –78 °C 2. Al(CH 3 )
, THF CH
3 ONHCH
3 •HCl
83% Cytovaricin TBSO
TBSO OH DEIPSO 92% 87%
Chem 115 Stereoselective, Directed Aldol Reaction Myers M. Movassaghi Diastereoselective Syn-Aldol Reaction of !-Ketoimides Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866-868. Diastereoselective Anti-Aldol Reaction of !-Ketoimides H 3 C CHO
CH 2 H 3 C CHO CH 3 H 3 C CHO CHO 83 86 95:5 <1:99 77 c 64 c enolization conditions RCHO a
b ratio
anti-syn : syn-syn 71 86 85 81 95:5 2:98 79:21
<1:99 89:11
4:96 A: Sn(OTf) 2 , Et
3 N; B: TiCl 4 , i-Pr 2 NEt.
a 1.0-1.1 equiv b Isolated yield of major diastereomer (>99% purity). c 3-5 equiv of RCHO was used. O N Bn O O CH 3 O CH 3 O N Bn O O CH 3 O O N Bn O O CH 3 O R R OH CH 3 OH CH 3 O TI O H CH 3 R H H 3 C H O X p Cl Cl Cl Sn O O H R CH 3 H O X p H 3 C L L H Sn(OTf) 2 Et 3 N, CH
2 Cl 2 RCHO, –20 °C TiCl
4 i-Pr 2 NEt, CH 2 Cl 2 RCHO –78 " 0 °C anti-syn syn-syn • Both enolization methods provide (Z)-enolates and (diastereomeric) syn aldol products. • The stereochemical outcome of both reactions is dominated by the C 2 methyl-bearing stereocenter, as shown in the proposed transition states above. • The chirality of the oxazolidinone has little influence on the diastereoselectivity of these reactions. A B A B A B A B O N Bn O O CH 3 O O N Bn O O CH 3 O CH 3 O N Bn O O CH 3 O CH 3 R OH R OH 1. (c-Hex) 2 BCl
EtN(CH 3 ) 2, Et 2 O 0 °C, 1 h 2. RCHO –78 °C, 3h +
Ph CHO CH 3 aldehyde yield % a ratio anti-anti : syn-anti 78 72 70 b 84 b 84:16
92:8 80:20
88:12 a Isolated yield of major diastereomer. b Yield of purified mixture of diastereomers. • Enolization of the less hindered side of the ketone under Brown's conditions affords the (E)-boron enolate. • The C2 stereocenter is the dominant control element in these aldol reactions; "matched" vs. "mismatched" effects of the remote auxiliary are negligible. CH 3 O CH 3 CH 3 O CH 3 CH 3 O CH 3 R OH R OH R L R L R L O H CH 3 M H H 3 C R L +
syn-anti, predicted Si face Re face • The sense of asymmetric induction observed in these reactions was unexpected and opposite to a prediction based on a reactant-like transition state model minimizing A
(1,3) strain.
CH 3 84 97:3 (CH
3 ) 2 CHCHO CH 2 =C(CH 3 )CHO CH 3 CH 2 CHO
PhCH 2 CH 2 CHO
RCHO RCHO
Evans, D. A.; Ng, H. P.; Clark, J. S.; Reiger, D. L. Tetrahedron 1992, 48, 2127-2142. Chem 115 Stereoselective, Directed Aldol Reaction Myers Jaron Mercer, M. Movassaghi Syn-Anti-Selective Aldol Reactions of Chiral Ethyl Ketones Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757-6761. Download 0.58 Mb. Do'stlaringiz bilan baham: 
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