Stereoselective, Directed Aldol Reaction

24 Pages·2013·1.16 MB·English

by  Fan Liu

Myers Stereoselective, Directed Aldol Reaction Chem 115
Reviews:
• Note: the enantiomeric transition states (not shown) are, by definition, of equal energies. The
Heathcock, C. H. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
pericyclic transition state determines syn/anti selectivity. To differentiate two syn or two anti
Press: New York, 1991, Vol. 2, pp. 133-238.
transition states, a chiral element must be introduced (e.g., R , R , or L), thereby creating
1 2
diastereomeric transition states which, by definition, are of different energies.
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.
(E)-enolates R L
1
H O OH
M
O OH O O L
2 H3C O R1 R2
H3C H H3C H OML2 R2 CH3
H
R anti
1 FAVORED
CH
3
• The aldol reaction was discovered by Aleksandr Porfir'evich Borodin in 1872 where he first + R L
1
observed the formation of "aldol", 3-hydroxybutanal, from acetaldehyde under the influence of R2 O OH
R CHO M
catalysts such as hydrochloric acid or zinc chloride. 2 O L
H3C O R1 R2
H CH3
H
syn
DISFAVORED
Diastereofacial Selectivity in the Aldol Addition Reaction-
Zimmerman-Traxler Chair-Like Transition States
• Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a
(Z)-enolates R1 L chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent.
H O OH
M Only a few metals, such as boron, reliably follow the indicated pathways.
O L
H O R1 R2
R2 CH3 • (Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing
OML2 CH3 1,3-diaxial interactions between R1 and R2 in each chair-like TS‡.
syn
R CH3 FAVORED
1
+ R L
1
R2CHO R2 M O OH
O L
H R R Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-1923.
O 1 2
H CH
3
CH3 Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225-1228.
anti
DISFAVORED
Heathcock, C. H.; Buse, C. T.; Kleschnick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J.
Org. Chem. 1980, 45, 1066-1081.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Preparation of (Z)- and (E)-Boron Enolates (Z)-Selective Preparation of Boron Enolates from Evans' Acyl Oxazolidinones (Imides)
n-Bu n-Bu
Et O CH3 iP(nr-BNuE)2t,B EOtTOf Et OB(n-CBHu)32 P–h7C8 HºCO Et O OHPh Bn O O BO –OTf
2 2 (n-Bu) BOTf
–78 ºC, 30 min 77% CH3 N CH3 2 O N CH3
CH Cl
>97% (Z) syn >99% O 2 2
O Bn
O (c-Hex)2BCl OB(c-Hex)2 PhCHO O OH
CH n-Bu n-Bu
Et 3 Et3N, Et2O Et –78 ºC Et Ph H H
n-Bu n-Bu
–78 ºC, 10 min CH CH B O B O
3 75% 3
O O
O N O N
>99% (E) anti >97%
H3C H H H CH3 H
Bn Bn
FAVORED DISFAVORED
• Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the amine i-Pr NEt i-Pr NEt
2 2
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. n-Bu n-Bu n-Bu n-Bu
B B
• The combination of (c-Hex) BCl and Et N provides the (E)-boron enolate preferentially. O O O O
2 3
CH
O N 3 O N
CH
3
Bn Bn
Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120-6123.
• Observed selectivity > 100:1 Z : E.
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.; 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. Chem. 1981, 53, 1109-1127.
1989, 111, 3441-3442.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
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.
Open coordination site
required for pericyclic aldol rxn
• Dipole-dipole interactions within the imide are minimized in the reactive conformation (see:
n-Bu n-Bu
Noe, E. A.; Raban, M J. Am. Chem. Soc. 1975, 97, 5811-5820).
Li
B
O O Bn OB(n-Bu)2 O O
O N CH3 N CH3 O N CH3
O H3C CH3 H3C CH3
Bn O Bn O 1. n-Bu2BOTf, i-Pr2NEt O OH
UNREACTIVE cf. reactive enolate in N CH3 CH2Cl2, 0 °C N R
Evans' asymmetric
RCHO O A 2. RCHO O CH
alkylation O –78 " 23 °C O 3
CH3 O 1. n-Bu2BOTf, i-Pr2NEt CH3 O OH
O Bn H O Ph N CH3 CH2Cl2, 0 °C Ph N R
N H n-Bu n-BuBn N O O B 2 . –R7C8H "O 23 °C O O CH3
O H vs. H O
O B n-Bu n-Bu B O
H O O H
R R diastereomerica
CH3 CH3 imide aldehyde ratio yield (%)
FAVORED DISFAVORED A (CH3)2CHCHO 497:1 78
B (CH3)2CHCHO <1:500 91

A n-C4H9CHO 141:1 75
n-Bu n-Bu n-Bu n-Bu B n-C4H9CHO <1:500 95
B B A C6H5CHO >500:1 88
Bn O O Bn O O B C6H5CHO <1:500 89
N R N R aRatio of major syn product to minor syn product.
O CH O CH
3 3
O O
• A variety of chiral imides can be used for highly selective aldol reactions.
• Anti products are typically formed in less than 1% yield.
Bn O OH Bn O OH
N R N R • Often, a single crystallization affords diastereomerically pure product.
O CH O CH
3 3
O O
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.
Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J. Bartroli, J. Pure & Appl.
Chem. 1981, 53, 1109-1127.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Carboximide Hydrolysis with Lithium Hydroperoxide Other Methods for Removal of the Chiral Auxiliary
• Reductive cleavage:
O O
LiOOH O O O
O N R LioOrH HO R + OH NH R O N Br LiAlH4, THF HO Br
O A B Bn CH CH3 CH2 –78 ! 0 °C CH3 CH2
3
90%
substrate reagent yield of A (%)a yield of B (%)a
• Esterification:
Bn O H CH
3
H LiOOH 76 16
H C
N 3
O H LiOH 0 100 H C O CH3
3 OBOMOBn
O CH O
3 H C
CH3 O OH LiOOH 98 <1 O 3N OH O H CH3 CH3 CH3
Ph O
N Ph
O LiOH 43 30 CH3
CH Ph BnOLi
O 3
THF, 0 °C
aYield of diastereomerically pure (>99:1) product. 77%
H C
3
CH
• LiOOH displays the greatest regioselectivity for attack of the exocyclic carbonyl group. H C O 3
3 OBOMOBn
O
H C
• This selectivity is most pronounced with sterically congested acyl imides. 3 O CH
H H 3
BnO O CH3 CH3
• This is a general solution for the hydrolysis of all classes of oxazolidinone-derived
carboximides and allows for efficient recovery of the chiral auxiliary.
• Transamination:
O Bn O O O OH
O OH
Al(CH )
CH 33
N OH O N 3 CH3O N CH3
H3CO N3 O O LiOOH H3CO N3 Bn CH3OBn CH3 CHC3HO2NCHl2C, H0 3°•CHCl CH3 OBn CH3
O THF, H O; O
NHBoc Na SO2 NHBoc 92%
OBn 02 °C 3 OBn
O 96% O • A free "-hydroxyl group is required.
• The selective hydrolysis of carboximides can be achieved in the presence of unactivated • Weinreb amides can be readily converted into ketones or aldehydes (see: Nahm, S.;
esters using LiOOH. Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818).
Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526.
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.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
H C
Cytovaricin: 3 CH3 O O
H3C O H + H3C O NCHO3 Ph Ph OCHN3 O CH3 +PMBH =O p-MethoOxPybMeBnzyl TBSO H3C O N OO+ DEOIPSOHH HHO CH3 Ph O NO CH3 + H OBn
O O H O 1. n-Bu2BOTf, Et3N
n - BCuH2B2COl2T,f ,0 E °tC3N; n - BCuH2B2COl2T,f ,0 E °tC3N; H3C Ph H CH3OCH2OCH2CCl3 2 . A C ClH(CHOH2C3N)lH23,, CT–H7H8F• °HCCl
RCHO, –78; RCHO 1. n-Bu2BOTf, Et3N 3 3
H2O2, 0 °C –78 ! 23 °C; CH2Cl2, –78 °C; 83%
H2O2, 0 °C RCHO O OH
92% 2. Al(CH ) , THF
87% CH O3NH3CH •HCl H3CO N OBn
3 3
OH O CH3 CH3 O OH CH3 CH3
H3C N Ph Ph N OPMB H3C 92%
CH O O CH
3 3 DEIPSO
O O H
1. Al(CH3)3 OH HH O CH3 t-Bu t-Bu
CH3ONHCH3•HCl H
THF, 0 °C TBSO O Si
2. TESCl, Im. DMF H O O
H3C O N CH3CH OCH2OCH2CCl3 OBn
H3C CH3 CH3 91% OCH 3
O O N N CH OTESO 3 CH3 CH3
3
H3C CH3 + CH3O N OPMB
CH3 LDA, Et O, CH3 CH3
2 CH
THF, 0 °C; 3 TESO CH
–45, 90 % H3C H O OCH OCH CCl HO 3OSi t-tB-Buu
2 2 3
H3C HO3C COH3H3C CNHN3 H OTESO TBSDOEIHPS3CO CHHHO HO CH3 + O TEHS3OC OO HOOCH3COHT3ES
OPMB CH
CH3 CH3 OPMB PhSO2 OTES3
CH
3
HF, H O, CH CN
2 3 H
25 °C H3C O O
H3C 92% H3C HHO HH O O OCHH
HO DEIPSO H3C O H CH3CH3 OH3
H H HO
HH O CH3 O HH HO CH3 Cytovaricin OH OHOOHOOCH3COHH3
PMBO H O H H O CH3
O OCH OCH CCl
CH3 CH3 2 2 3 Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
DEIPS = diethylisopropylsilyl 7001-7031. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Diastereoselective Syn-Aldol Reaction of !-Ketoimides Diastereoselective Anti-Aldol Reaction of !-Ketoimides
Xp O O O 1. (c-Hex)2BCl O O O OH O O O OH
EtS3Nn,( OCTHf2)2Cl2 SnL HH3HC O O O N O O OHR O N CH CH3 E0 t°NC(,C 1H h3)2, Et2O O N CH CH R + O N CH CH R
O 3 2. RCHO 3 3 3 3
RCHO, –20 °C L O H CH3 CH3 Bn –78 °C, 3h Bn Bn
R Bn anti-anti syn-anti
O O O CH3 anti-syn
O N CH3 ratio
aldehyde yield %a anti-anti : syn-anti
CH3 Xp
Bn i-Pr NTEitC, lC4H Cl HH3C O Cl O O O OH (CH3)2CHCHO 78 84:16
2 2 2 H
O TI Cl O N R CH2=C(CH3)CHO 72 92:8
–7R8 C"H 0O °C H R O Cl Bn CH3 CH3 CH3CH2CHO 70b 80:20
CH3 syn-syn PhCH CH CHO 84b 88:12
2 2
CHO
enolization ratio Ph 84 97:3
conditions RCHOa yield %b anti-syn : syn-syn CH
3
aIsolated yield of major diastereomer. bYield of
A H3C CHO 83 95:5 purified mixture of diastereomers.
B CH 86 <1:99
3
• Enolization of the less hindered side of the ketone under Brown's conditions affords the
A H3C CHO 77c 95:5 (E)-boron enolate.

B CH 64c 2:98
2
• The C2 stereocenter is the dominant control element in these aldol reactions; "matched" vs.
A 71 79:21 "mismatched" effects of the remote auxiliary are negligible.
H C CHO
3
O OH
B 86 <1:99
RCHO R
Si face L R
A CHO 85 89:11
CH CH
3 3
B 81 4:96 O M syn-anti, predicted
O H
A: Sn(OTf)2, Et3N; B: TiCl4, i-Pr2NEt. a1.0-1.1 equiv bIsolated yield of RL H3C CH +
major diastereomer (>99% purity). c3-5 equiv of RCHO was used. CH3 CH3 RL H 3 O OH
• Both enolization methods provide (Z)-enolates and (diastereomeric) syn aldol products. Re face RCHO RL R
CH CH
3 3
• The stereochemical outcome of both reactions is dominated by the C methyl-bearing
2
anti-anti, observed
stereocenter, as shown in the proposed transition states above.
• The sense of asymmetric induction observed in these reactions was unexpected
• The chirality of the oxazolidinone has little influence on the diastereoselectivity of these and opposite to a prediction based on a reactant-like transition state model minimizing
reactions. A strain.
(1,3)
Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. Evans, D. A.; Ng, H. P.; Clark, J. S.; Reiger, D. L. Tetrahedron 1992, 48, 2127-2142.
1990, 112, 866-868. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Directed Reduction of !-Hydroxy Ketones
O O O
O O
Internal hydride delivery:
CH
O N 3 BnO CH3 BzO CH3
• In addition to B!n-ketCoHim3ides, the two chiral ethyCl kHe3tones above are known CtoH u3ndergo aldol R1 HOO+HHOBA–OcAc R1 OH OHR2
reactions at the unexpected Re face of the enolate, deilvering anti-anti aldol products. OH O R2 1,3-anti-diol
(CH ) NBH(OAc) FAVORED
34 3
Paterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121-7124. R1 R2
Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-652.
H OAc OH OH
R2 –
R1 O B OAc R1 R2
Syn-Anti-Selective Aldol Reactions of Chiral Ethyl Ketones H
+
H O 1,3-syn-diol
1. (c-Hex) BCl DISFAVORED
2
TBSO O Et3N, Et2O TBSO O OH
H3C CH3 0 °C H3C CH3 • 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.
CH3 CH3 2. i-PrCHO CH3 CH3 CH3 CH3
–78 °C
90%, 88% de
External hydride delivery:
1. (c-Hex) BCl
2
TBSO O E0 t°3CN, Et2O TBSO O OH OH O HBH4– L OH OH
H3C CH3 H3C CH3 Zn(BH4)2
CH CH 2. i-PrCHO CH CH CH CH R1 R2 R1 O Zn L R1 R2
3 3 3 3 3 3 O
–78 °C 75%, 92% de R2 1,3-syn-diol
• The C2 stereocenter is believed to be the dominant control element for both substrates.
• Chelated transition state, axial attack provides 1,3-syn-diol.
CH(i-Pr)OTBS
H
TBSO OB(c-Hex)2 CH3 c-Hex TBSO O OH • These directed reductions are applicable to #-hydroxy-!-ketoimides:
H C H H C
3 B 3 R
O c-Hex
CH3 CH3 CH3 H3C O CH3 CH3 CH3 CH3 O O OH CH3 O OH OH
R Ph N CH3 NaBH(OAc)3 Ph N CH3
AcOH, CH CN
• Minimization of A(1,3) interactions in the enolate biases the approach of the aldehyde to the O O CH3 CH3 25 °C, 30 3min O O CH3 CH3
methyl-bearing "-face of the enolate, while the (E)-enolate geometry affords anti-aldol products.
99%, >96% de
Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757-6761.
Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560-3578.
Jaron Mercer, M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Premonensin Anti-Aldols with Magnesium Enolates
O O O O O O 1. MgCl (10-20 mol%), O O OH
O 2
O N CH3 + H CH3 O N CH3 + Et3N, TMSCl O N R
H R
CH CH CH EtOAc, 23 ºC CH
3 3 3 3
Bn Sn(OTf) Bn 2. TFA; CH OH Bn
2 3
N-ethylpiperidine
CH2Cl2, –78 °C aldehyde dr yield (%)
94%, 94% de
CHO X = CH3 24:1 -
O O O OH
X = OCH 32:1 91
CH 3
O N 3 X
CH CH CH CH X = NO2 7:1 71
3 3 3 3
Bn
NaBH(OAc)
3
AcOH Y X = Ph, Y = H 21:1 92
91%, >94 de X CHO X = Ph, Y = CH3 28:1 92
O O OH OH X = H, Y = CH3 16:1 77
CH
O N 3
CH CH CH CH "-napthaldehyde 14:1 91
3 3 3 3
Bn
furfural 6:1 80
H C CH
3 3 • Silylation of the magnesium alkoxide in the aldol product turns over the magnesium.
NO2 O O O O O H3CO OCH3
• The aldehyde component is limited to non-enolizable aromatic and ",#-unsaturated aldehydes.
O H + H3C CH3
CH3 CH3 CH3 CH3 H C CH3 CH3 CH3 Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392-393.
2, LDA, THF 3
1 –78 °C; 1 2
57% (+19% undesired diastereomer) • Use of the analogous N-acylthiazolidinethione chiral auxiliary affords products of the opposite
H C CH
3 3
anti-stereochemistry in comparable yields and with high selectivities.
NO2 O O O OH O H3CO OCH3
O CH
3 S O 1. MgBr •Et O, (10 mol%), S O OH
CH3 CH3 CH3 CH3 H3C CH3 CH3 CH3 S N CH3 + O Et3N, 2TMS2Cl, S N R
h!, THF, 0 °C; H R
EtOAc, 23 ºC CH
H O, HCl, 25 °C 3
2 Bn 2. 5:1 THF/1 N HCl Bn
58%
O OH OH OH O O
• Both reactions are proposed to proceed through boat transition states. See: Evans, D. A.;
HO CH
3 Downey, W. C.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127-1130.
CH CH CH CH CH CH CH
3 3 3 3 H C 3 3 3
3
Premonensin
Evans, D. A.; DiMare, M. J. Am. Chem. Soc. 1986, 108, 2476-2478.
M. Movassaghi Chris Coletta, Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Open Transition State Aldol Reactions Synthesis of Oxazolidinethione and Thiazolidinethione Chiral Auxiliaries
• Heathcock and coworkers reported that complexation of the aldehyde with an added Lewis
S
acid allows access to non-Evans syn and anti aldol products via open transition states.
Cl CS, Et N
2 3 O NH
Bu Bu CH2Cl2
B O 95% Bn
O O N O CH3 Bu2BOCTHf2, Ci-lP2;r2NEt, O O N O H CH3LA O O N O OHR HO BnNH2 NaTBHHF4, I2 HO BnNH2
Lewis acid, RCHO R H O CH3 95% S
t-Bu t-Bu t-Bu CS , KOH
2 S NH
1, favored for small non-Evans syn
Lewis acids H2O
80% Bn
aldehyde Lewis acid anti:syn* yield (%)*
Crimmins, M. T; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894-902.
SnCl 10:90 66
H C CHO 4
3
TiCl 12:88 72
4 Asymmetric Aldol Reactions with Titanium Enolates of N-Acylthiazolidinethiones
Ph CHO TiCl4 8:92 65 S O 1. TiCl4 (1.1 equiv) S O OH S O OH
(–)-sparteine
S N CH3 CH2Cl2, 0 °C S N R + S N R
BuBBu Bn 2. RCHO, 0 °C Bn CH3 Bn CH3
O O Bu BOTf, i-Pr NEt, O O O O OH A B
2 2 R
O N CH3 CH2Cl2; O N CH3 O N R
Lewis acid, RCHO H H O CH RCHO (–)-sparteine (equiv) yield (%) A : B
3
i-Pr i-Pr LA i-Pr
CH =CHCHO 1.0 49 >99:1
2, favored for large anti 2
Lewis acids
i-PrCHO 1.0 60 98:2
aldehyde Lewis acid anti:syn* yield (%)* CH =CHCHO 2.0 77 <1:99
2
H3C CHO Et2AlCl 88:12 81 i-PrCHO 2.0 75 3:97
• Selectivities are generally >95:5 for syn:anti products.
PhCHO Et AlCl 74:26 62
2
• Both the yield and diastereoselectivities are high and synthetically useful, although they are
*Determined by 1H NMR. Yield given is the total yield of diastereomeric aldol mixture.
typically lower than the corresponding oxazolidine aldol reactions.
• Gauche interactions around the forming C-C bond dictate which face of the aldehyde reacts. For • An advantage of this method is that a single acyloxazolidinethione can provide either syn
small Lewis acids, transition state 1 is favored. For large Lewis acids, transition state 2 is aldol product by changing the amount of sparteine in the reaction mixture.
favored.
Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750.
Jaron Mercer, M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
• Proposed transition states provide a rationale for the selectivity dependence on amine equivalents: Anti-Selective Aldol Reactions with Titanium Enolates of N-Glycolyloxazolidinethiones
S O
S N CH3 S O 1. TiCl , (–)-sparteine S O OH S O OH
4
TiCl4 TiCl O N OR O N R' + O N R'
(–)-sparteine (1 equiv) Bn (–)-sparteine4 (2 equiv) 2. TiCl4, R'CHO OR OR
RCHO RCHO Bn Bn Bn
A B
S Bn
S R aldehyde A : B : syn yield (%)
H S H
HBn N TIClCl S NH allyl H3CCHO 94 : 6 : 0 84
O TiL
HR O x
O Cl H O allyl Ph CHO 65 : 24 : 11 56
CH R
3
CH3 allyl CHO 94 : 6 : 0 74
CH
3
allyl CHO 95 : 5 : 0 58
S O OH S O OH
Bn CHO 88 : 12 : 0 64
S N R S N R CH3
CH3 CH3 Bn CHO 74 : 26 : 0 48
Bn Bn
CH CHO 84 : 11 : 5 63
• The thiazolidinethione auxiliary is easily removed under mild conditions: 3 CH3
OH O OH CH3 CHO 88 : 12 : 0 59
i-Pr
HO Ph BnHN
CH NaBH PhCH NH CH
3 4 2 2 3 • Complexation of the aldehyde with excess titanium occurs in situ to give anti products with high
83% 79%
selectivity.
i-Bu O OH
• The proposed transition state is analogous to that of the anti-selective Heathcock aldol.
N R
S CH CH3ONHCH3•HCl
DI6B9A%L-H S 3 imidazole L
77% 4
O OH imCiHda3OzoHle O OH STi OR' R
H i-Pr 79% CH3O N i-Pr O N O TiL4
CH3 O OH CH3 CH3 H H O
t-Bu
i-Pr
CH O
3
CH
3
• The thiazolidinethione auxiliary is recovered by basic extraction (1 M NaOH) of the product Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591-594.
mixture.
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.
M. Movassaghi, Jaron Mercer