1 The Selective Aldol Reaction

22 Pages·2005·1.47 MB·English

The Selective Aldol Reaction
O O OH O
R3
R1 R2 R4 X R1R2 R3 R4 X
Alan B. Northrup
MacMillan Group Meeting
September 18, 2002
A Brief Recent General Review:
Palomo, C.; Oiarbide, M.; García, J. M. "The Aldol Addition Reaction: An Old Transformation at Constant Rebirth" Chem.
Eur. J. 2002, 8, 36.
Review Focusing on Enzymatic and other Catalytic Aldols:
Machajewski, T. D.; Wong, C.- H. "The Catalytic Asymmetric Aldol Reaction" Angew. Chem. Int. Ed. 2000, 39, 1352.
Classic Reviews
Evans, D. A.; Nelson, J. V.; Taber, T. R. "Stereoselective Aldol Condensations," in Topics in Stereochemistry,
New York, 1982; Vol. 13, p. 2.
Mukaiyama, T. "The Directed Aldol Reaction," in Organic Reactions, New York, 1982; Vol. 28, p 203.
Heathcock, C. H. Asymmetric Synthesis; Morrion, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, part B, p 111.
Aldol Reaction Time-Line
OTMS O OH
2 O NaOH OH O TiCl4 H Ph OTMS 20 mol% cat O OH
Me H rt Me H PhCHO EtS RCHO EtS R
50% yield Me Me
82%, 3:1 syn:anti ! 93:7 dr
Aldol Reaction ! 91% ee
Discovered Independently Mukaiyama Publishes Mukaiyama Describes
By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective
and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction
1957 1981 1997
1864 1973 1990
Zimmerman Proposed Evans Oxazolidone Shibasaki Claims
Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic
Led to Zimmerman-Traxler Models Described Enantioselective
X Catalytic Direct Aldol
H M OH O OBR2
O
O R X N O LLB O OH
R(Z'R)-Enolate syn -R A'ldol O O Ph Me RCHO Ph R
X PhCHO up to 94% ee
H OH O
M
O
R' O R X O OH
R R'
(E)-Enolate anti - Aldol N Ph
O Me
O
88%, > 500 : 1
1
Racemic Aldol Technology
OTMS O OH
2 O NaOH OH O TiCl4 H Ph OTMS 20 mol% cat O OH
Me H rt Me H PhCHO EtS RCHO EtS R
50% yield Me Me
82%, 3:1 syn:anti ! 93:7 dr
Aldol Reaction ! 91% ee
Discovered Independently Mukaiyama Publishes Mukaiyama Describes
By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective
and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction
1957 1981 1997
1864 1973 1990
Zimmerman Proposed Evans Oxazolidone Kobayashi Claims
Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic
Led to Zimmerman-Traxler Models Described Enantioselective
X Catalytic Direct Aldol
H M OH O OBR2
O
O R X N O LLB O OH
R(Z'R)-Enolate syn -R A'ldol O O Ph Me RCHO Ph R
X PhCHO up to 94% ee
H OH O
M
O
R' O R X O OH
R R'
(E)-Enolate anti - Aldol N Ph
O Me
O
88%, > 500 : 1
Enolate Geometry Correlates with Product Diastereoselectivity Under Kinetic Control
! The anti - Aldol Stereochemistry is Thermodynamically Favored:
OLi PhCHO OH O OH O Subsequent cross-over experiments
Ph OLi 25 ºC, 3d Ph OH Ph OH irmatphleicra tthea anl deopli-mreetrroiz-aatlidoonl equilibration
Ph Ph
8% 92% Mulzer, et al. Tet. Lett., 1977, 4651.
! Zimmerman Proposed a Chair Transition State for Kinetic Selectivity of the Ivanov Reaction:
OMgBr PhCHO OMHgBr OMHgBr OH O
Ph OMgBr - 78 ºC Ph OOMgBr OOMgBr Ph OH
Ph Ph Ph
diequatorial favored Ph 3:1 anti:syn
should lead to anti-aldol Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
! Model Holds for a Variety of Enolates Both E and Z
X
OM PhCHO OH O HO M OH O
X Me R' X O R X
Me R'R R'
M X Z:E anti:syn (Z)-Enolate syn - Aldol
BLLii Miie--PPsirrtyl >>599:899::521 >9890:79::1230 R' XHOOM R OH O X
B St-Bu 5:95 5:95 R R'
Mg t-Bu >99:1 >97:3 (E)-Enolate anti - Aldol
2
Selective Enolization Can Be Achieved
! Kinteic vs. Thermodynamic Acidity:
OLi OLi O OLi OLi
Me Me LDA Me Ph3CLi Me Me
– 78 ºC !
99% 1% 10% 90%
For other examples, see Evans 206 Kinetic Acidity
! Structure of Carbonyl Compound Can Influence Ratio of Enolates Formed under Kinetic Control:
These result can be rationalized with the Ireland model:
O LDA OLi OLi R
R Me THF R R Me HO Me
(E)-enolMatee (Z)-enolate O R NLiH (E)
R R
R E : Z R Me MeO H
Li (Z)
OR, SR 95 : 5 R N H
Et 77: 23
R
t-Bu 0 : 100
NR2 0 : 100 Ireland et al. J. Am. Chem. Soc., 1976, 98, 2868
Ireland, J. Org. Chem. 1991, 56, 650
! Solvent Can Impact Enolate Ratios:
R Solvent E : Z
OMe THF 95 : 5 Difference due to Enolate Equilibration
OMe THF/HMPA 16 : 84
The Mukaiyama Aldol Reaction
! Mukaiyama's Report of a New Aldol-Type Process:
O OTMS O OH
LDA, TMSCl 1.02 eq TiCl4 H Ph ••• BR50rao-n9ag3de% R o ayf niAegllddee ohfy Kdeet o+n Kee Ntouncele Eolpehcitlreosphiles
1.0 eq PhCHO • 1:1 to 3:1 syn:anti
1.0 eq – 78 ºC, CH2Cl2 •• OUspee no fT SraKnAs iotior nth Siot-aSteKA can increase the dr
aq. TsOH workup
Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011
Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503
! Reaction is syn-Selective Regardless of Enolsilane Geometry
OTMS TiCl4 O OH OTMS TiCl4 O OH
Me PhCHO PhCHO
EtO – 78 ºC EtO Ph EtO – 78 ºC EtO Ph
Me Me Me
3:1 syn:anti 2:1 syn:anti
! Attractive Prospects for Catalysis...More on this Later
R3Si O OMLn silyl transfer O OSiR3
MLn X R catalyst turnover R + MLn
OSiR3 O Path A X
R
X H
PathM BLn OMLn R3Si O R LnM O OSiR3R
X H X
metal readily
transmetalation dissociates from product
3
Chiral Auxiliary Technology
OTMS O OH
2 O NaOH OH O TiCl4 H Ph OTMS 20 mol% cat O OH
Me H rt Me H PhCHO EtS RCHO EtS R
50% yield Me Me
82%, 3:1 syn:anti ! 93:7 dr
Aldol Reaction ! 91% ee
Discovered Independently Mukaiyama Publishes Mukaiyama Describes
By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective
and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction
1957 1981 1997
1864 1973 1990
Zimmerman Proposed Evans Oxazolidone Kobayashi Claims
Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic
Led to Zimmerman-Traxler Models Described Enantioselective
X Catalytic Direct Aldol
H M OH O OBR2
O
O R X N O LLB O OH
R(Z'R)-Enolate syn -R A'ldol O O Ph Me RCHO Ph R
X PhCHO up to 94% ee
H OH O
M
O
R' O R X O OH
R R'
(E)-Enolate anti - Aldol N Ph
O Me
O
88%, > 500 : 1
The Evans Aldol Reaction
! Chelate Organization Allowed for Highly Diastereoselective Alkylations of Imide Enolates
Li
O O O O O O
LDA R'–Br
O N Me O N Me Re-face O N R' Rre'a–cBtriv me,u Rst' b"e i- Pr
Me
R R R
! 99 : 1 dr all cases
Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737
! Chelate Organization Precluded in Aldol Process
Bu Bu H
B O O OH
O O O R Re-face
Me O N R
Bu Bu O N Me
B R
O O RCHO R free rotation
Me
O N
Bu Bu H
R R O B O R Si-face R O OH
N R
Me
N O Me
O O
O
! Will this Reaction be Selective Given Lack of Chelate Control?
4
The Evans Aldol Reaction
! Surprisingly, This Reaction is Highly Enolate Face-Selective:
Bu Bu Bu Bu
O B O RCHO i-Pr O OH O B O RCHO Me O OH
O N Me N R O N Me Ph N R
O Me O Me
i-Pr O Ph Me O
Evans, D. A.; Bartroli, J.; Shih, T. L.
! Reaction is Highly Diastereoselective in all propionate cases (141 : 1 to > 500 : 1) J. Am. Chem. Soc. 1981, 103, 2127
! Reaction is Tolerant of a Broad Range of Aldehydes; R = Alkyl, Aryl, hindered, unhindered
! Acetyl-done provides poor selectivity—1 : 1 for the two diastereomers; Acetate aldol product via desulfurization
! One of the most reliable and predictable reactions in organic synthesis; industrially useful
! Possible Model for Asymmetric Induction:
O
O O BR2 H OR O O OH
Si-face i-Pr N disfavored
O N Me R O B R O N R
dipole maximized O Me
i-Pr Me i-Pr
O
i-PrN O BR2Me dipolRe em-fiancimeized O NHOiO-PrRB R favored i-PrN O OHR
O R O Me
O Me O
! Model does not account for the impact of the acyl-done !-substituent on diastereoselectivity. Perhaps a boat TS
should be considered for smaller acyl donors as a competitive pathway
Heathcock's Modification to the Evans Aldol
! Chelated S-imides give Re-face attack and Non-Chelated Imides give Si-Face Attack
Li Bu Bu H
O O N O Me RRe'-–faBcre O O N O MeR' R N O B OMe R' Si-face R N O OHR'
R R O O Me
! 99 : 1 dr all cases O O
"Evans" syn
! Based on that Observation, Heathcock Developed a "non-Evans" syn or anti Aldol: J. Org. Chem. 1991, 56, 5747
O O OH Bu Bu Bu Bu O O OH
B B
O O O O
O N R' H R' O N R'
Me Me
Me O NR' O LA O N H O Me
R H H R
LA
"non-Evans" syn R R "non-Evans" anti
Method R R' Lewis Acid equiv. syn: anti "non-Evans" : "Evans"
A or C t-Bu i-Pr TiCl4 2.0 94 : 6 100 : 0
B t-Bu i-Pr SnCl4 2.0 93 : 7 100 : 0
C i-Pr i-Pr Et2AlCl 3.0 5 : 95 100 : 0
Method A: Lewis acid added to enolate at – 78ºC followed by slow addition of isobutyraldehyde
Method B: Aldehyde added to enolate at – 78ºC followed by slow addition of Lewis acid
Method C: Precomplexed aldehyde and Lewis acid cannulated into solution of enolate at – 78ºC
! "Size" of Lewis acid affects selectivity; propionaldehyde, isovaleraldehyde work well, benzaldehyde syn-only
5
Crimmins's Modification of the Evans Aldol
! Crimmins's Hypothesis for Observed Lower Selectivies with Titanium Imide Enolates (88-96% de):
O
O NHOBCnlTi CCll "Evans" syn BnN O OHR Ti has a hiTgihLner affinity for S TthiLann O e.g.:
R O Cl O Me O S
Me O
+ Cl- – Cl- S O
O Fowles, et al. J. Chem. Soc. 1971, 1920.
O O OH
BnR HNO XTi CCll "non-Evans" syn O N R If X = S, then Ti chelate prefered
O Cl Me
Me Bn
! Evans vs non-Evans Path Dictated by Auxiliary and Stoichiometry of Amine Base: J. Org. Chem. 2001, 66, 894.
X O Rc O OH X O OH
Me 1. 1-2 eq TiCl4, Base
Y N N R Y N R + anti isomers
2. 1-1.1 eq RCHO Y Me Me
Rc X A: "Evans" Rc B: "Non-Evans"
X, Y = O; Rc = Bn X, Y = S; Rc = i-Bu (X = S, Y = O, Rc = Bn gave similar)
T (ºC) R yield A : B : anti Base equiv. R yield A : B : anti
DIEA 2.5 i-Pr 86 86 : 14 : 0.3
0 Et 84 99 : 1 : 0 DIEA 1.1 i-Pr 75 5 : 95 : n.a.
0 MeCH=CH 89 97 : 3 : 0 TMEDA 2.5 i-Pr 57 96 : 4 : n.a.
0 i-Pr 89 98 : 2 : 0 TMEDA 1.1 i-Pr 50 <1 : >99 : n.a.
0 t-Bu 87 97 : 3 : 0 Sparteine 2.5 i-Pr 84 95 : 5 : 0
– 78 i-Pr 98 98 : 2 : 0 Sparteine 1.1 i-Pr 63 5 : 95 : n.a.
Summary of Aldols with Imide Auxiliaries
! Syn Aldols:
R O OH i-Bu O OH
O O N O MeBuE2tB3ON,T fRCHEOvans,O J. Am.NO Chem. MSoec. !!19 998R891,%: 11 0sd3ye,n 2s:1ay2nn7ti S S N O Me Ti2.C5l 4e qR CSHpaOrteine S NS !! M9909e%:1 sdyeRn s:aynnti
R 2. T1i.C Bl4u•2RBCOHTOf, Et3N O O N O OHR i-Bu 1.1 eTqi CSlp4a RrtCeiHneO S S N O OHR
Me! 98% de syn Me
R ! 87:13 syn:anti i-Bu! 90% de syn
! 99:1 syn:anti
Heathcock J. Org. Chem. 1991, 56, 5747 Crimmins J. Org. Chem. 2001, 66, 894.
! Anti Aldols:
O O BuB Bu O O OH
O N Me 1. Bu2BOTf, NEt3 O O R'Me O N R'
R 2. Et2AlCl•RCHO O NR H H OAlEt2 "noRn-EvaMnes" a!!n t98i86%:14 d aen atin:stiyn
Heathcock J. Org. Chem. 1991, 56, 5747
! Auxiliary can be converted to the corresponding alcohols, aldehydes, acids, esters, thioesters, Weinreb amides
6
Other Useful Chiral Auxiliaries
! Oppolzer's Sultam: Both Propionate and Acetate Aldols Possible
Me Me Me Me
O OH
SO2 N O Me RE2Bt3ONTf SO2 N OBR2Me boRtatCottHmaOc fkace Xc Me R ! 95% de
Oppolzer, J. Am. Chem. Soc. 1990, 112, 2767
Me Me Me Me
O LDA TBS O OH
SO2 N TBS-Cl SO2 N HOLnTiO Xc R 90 to 95% de
R Oppolzer, Tet. Lett. 1992, 33, 2442
! Abiko and Masamune's Norephedrine-Derived Auxiliary Gives anti Aldols
Me PhO O Me (c-HeExt3)2NBOTf Me PhO BR2 cloRsCeHd OTS XcO O OHR !! 9908%:2 adnet ia:snytin
BnN SO2Mes BnN SO2Mes Me Me
E - enolate AJ.b Aikmo,. AC.h; eLmiu,. JS.o- cF.. ;1 M99a7s,a 1m1u9n, e2,5 S8.6
! Masamune/Reetz Chiral Boron Enolates Give anti Aldols
t-BuS O R 9125.. %MRe 'CeeHOBOTf MDeIEA RR' HSROMeOB Me R RS'RHOOB Me t-BuS O R OHR'
R = Me, H Me R = Me, 93-96% ee
disfavored favored R = H, 87-94% ee
Masamune, J. Am. Chem. Soc. 1986, 108, 8279
Reetz, Tet. Lett. 1986, 4721
Chiral Ethyl Ketone Aldol Reactions (Z)-Enolates
! Even Simple !-Chiral (Z)-Ethyl Ketone Enolates Give High dr's:
R dr
O O OH O OP Ph 97 : 3
Bu2BOTf, Et3N Et 98 : 2
RCHO R HO R BnOCi-PHr2CH2 >9969 :: 4<1
OTBS TBSO Me Me
Masamune J. Am. Che. Soc. 1981, 103, 1566
! A "-Stereocenter Usually has Little Impact:
OTBSO OTBSO OH
Me Me TiCl4, Et3N Me Me
i-PrCHO
Me Me Me Me Me Me
both 95:5 dr
OTBSO OTBSO OH
Me Me TiCl4, Et3N Me Me
i-PrCHO
Me Me Me Me Me Me
Evans J. Am. Chem. Soc. 1991, 113, 1047
! Stereochemical Model: Me
R
O O OH
RL OM Me RCHO LFaMLvorOeHdH RRLMH RL RM maMjoer R
RM MeR O OH
H OO L RL R
M
RRLM DHisHfavorLed RM mMineor
7
Chiral Ethyl Ketone Aldol Reactions (E)-Enolates
! Simple !-Chiral (E)-Ethyl Ketone Enolates also Give High dr's:
OTBSO OTBSO OH
(c-Hex)2BCl, Et3N
Me Me Me Me
i-PrCHO 94:6 dr
Me Me Me Me Me Me
OTBSO OTBSO OH
Me Me (c-Hex)2BCl, Et3N Me Me
96:4 dr
i-PrCHO
Me Me Me Me Me Me
! Stereochemical Model:
H H
OM O R R O O OH
RL RCHO L M O Me Me O M L RL R
RM Me DiLsfavRoLreHd RHM avoid A1,3 RHL HFRaMvorLed RMmaMjoer
Evans, J. Am. Chem. Soc. 1991, 113, 1047
! However, not all (E)-enolates are well-behaved
O O OH
(c-Hex)2BCl, Et3N Me
BnO i-PrCHO BnO
Me Me Me Me
95:5 dr
Patterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121
Chiral Ethyl Ketone Aldol Reactions—!-Keto Imides
! Diastereomer Depends on Enolate Geometry and Lewis Acid
Xp
Me
O Cl O O O OH
TiCl4 H HO Ti Cl O N R
DIEA R O Cl Me Me
Z-EnoMlaete Chelation Control Bn 96:4 to 99:1 dr
Xp
Me O O O OH
L O
Sn(OTf)2 Sn OHH O N R
Et3N L O Me Me
O O O RMe Bn 89:11 to 95:5 dr
Z-Enolate Dipole Minimized
O N Xp
Me Me O O O OH
Bn (c-EHtNexM)2eB2Cl L BL OHH MOe O N Me Me R
O
RH Bn 84:16 to 97:3 dr
E-Enolate Dipole Minimized
Xp O O O OH
Me
? O
MeH HO MLn O N Me Me R
R O Bn unknown
H
ABN: E-Enolate Chelation Control? Evans, J. Am. Chem. Soc. 1990, 112, 866
Open TS (Z)-enolate in anaolgy to Heathcock? Evans, Tetrahedron, 1992, 48, 2127
8
Chiral Ketone Aldol Reactions–1,5 Induction
! Evans and Patterson Independently Observed this Phenomenon:
OR OM RCHO OR O OH
Evans J. Org. Chem. 1997, 62, 788
R R R Patterson Tet. Lett. 1996, 8585
1,5 anti
! Levels of Induction Strongly Dependent on Metal, Protecting Group and Solvent:
anti:syn
PMBO OM Ph CHO PMBO O OH TBSO OBBu2
Bn Solvent – 78 ºC Bn Bn Bn 40:60
M solvent yield anti:syn Ph
Li THF 79 40:60
TMS/BF3•Et2O CH2Cl2 85 50:50 O O OBBu2 >95:5
Cy2B CH2Cl2 85 82:18 TrO
Bu2B CH2Cl2 80 87:13
Bu2B Et2O 85 98:02
! Chiral Ethyl Ketones Exhibit 1,5-Syn Induction:
t-Bu t-Bu t-Bu t-Bu
Si Si
O O OBPhCl i-PrCHO O O O OH
Me Me Me >99:1 syn:anti
CH2Cl2, – 78 ºC i-Pr
Me 72% yield Me Me
1,5 syn
! No Good Models have been Presented to Account for the Observed Selectivities
Chiral Methyl Ketone Aldol Reactions–1,5 Induction in Synthesis
Long-Range Transmission of Stereochemical Information: 10
O OH
No proposed model to account for the sense of diastereocontrol
O HO
For a detailed investigation, see Evans J. Org. Chem. 1997, 62, 788 29 15
25 21
Patterson Roxaticin Synthesis: C-10 to C-29 Fragment OH OH OH OH OH
(+) Roxaticin
OTBS 1,5 anti
29 25H 21 OTBS (c-Hex)2BCl 29 OTBS
O O OPMB Et3N86, %Et2O 2O5H O 2O1PMB OTBS
95 : 5 dr
OTBS
29
25 21 O
10
O O OPMB I OTIPS
(c-Hex)2BCl OTBS PMBO
29 15
Et3N, Et2O 25 21
10 75%
15 O O OPMBOH O 1,5 anti
I
O OPMBOTIPS 75 : 25 dr
Paterson, I.; Collett, L. A.; Tet. Lett., 2001, 42, 1187
! The analogous ethyl ketone enolates give 1,5-syn selectivity
9
Chiral Aldehyde Aldol Reactions–!-Chiral Aldeyhdes
! (E) Enolates Give the Felkin Product
Me
H O OH
Favored LnMOROLH HMe R Me MeRL
R
Felkin
OMLn O Felkin Attack
R H RL syn-pentane
Me Me H
H
O OH
Disfavored MeMe RHROLOMLn R Me MeRL
Anti-Felkin Attack Anti-Felkin
Evans Topics in Stereochemistry, 1982, 13, 1-115
Roush J. Org. Chem. 1991, 56, 4151
! A Complex Case: Woodward's Erythromycin Synthesis
Me Me Me Me Me Me Me Me
OLi O O OAc O OMOM O OH O OAc O OMOM
O O 85% yield O O
Me Me
t-BuS H one isomer t-BuS
Me Me Me Me Me Me Me Me Me Me Me Me
Felkin anti-aldol product
Woodward, et al. J. Am. Chem. Soc., 1981, 103, 3210
Chiral Aldehyde Aldol Reactions–!-Chiral Aldeyhdes
! (Z) Enolates Give the Anti-Felkin Product:
Li
OLi O OBn O OH OBn
Me Me Me
H
Me Me Me Me Me
Initially rationalized via a Cram-Chelate Model... Anti-Felkin 98:2 dr Masamune J. Am. Chem. Soc. 1982, 104, 5526
However...
O OH OTBS
TMSO OLi O OTBS TMSO Me
Me Me
Me H MeMe Me Me Me
Me Me Me
Anti-Felkin 73:27 dr Brooks Tet. Lett. 1982, 23, 4991
! Stereochemical Model:
syn-pentane
Me O OH
ORL MHe R RL
OMLn DiOsfavored LnM OHR H MFeelkinMe
R Me H RL Felkin Attack
Me H
Me
O OH
Favored HMe RHROLOMLn R Me MeRL
Anti-Felkin Attack Anti-Felkin
10