Transcript The Hetero-Ene Reaction: Development and Synthetic Utility
The Hetero-Ene Reaction: Development and Synthetic Utility
October 13, 2005 Laura Wysocki Burke Group 1
Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion 2
Discovery: Alder’s “Substituting Addition” O O O O O O O O O O O O Alder, K.; Pascher, F.; Schmitz, A.
Ber. Dtsch. Chem. Ges.
1943
,
76
, 27 Nobel Lectures. Chemistry. 1942-1962. Elsevier: Amsterdam.
1964
, 253 3
Discovery: Tandem Substituting Addition and Diene Synthesis "substituting addition" 2 O O O O O O O O O O "diene synthesis" O O Alder, K.; Münz, F.
Ann. Chem.
1949
,
565
, 126 Nobel Lectures. Chemistry. 1942-1962. Elsevier: Amsterdam.
1964
pp. 253 4
Ene and Diels-Alder X Y : R
Diels-Alder:
diene X Y dienophile
Ene:
R H ene X Y enophile C C C C C N O O R R C O N O X Y X Y H C S N N • “Enophile” rather than “Dienophile” • Good dienophile usually good enophile • Ene often side reaction of Diels-Alder • Some catalysts are effective for both reactions 5
Ene and Diels-Alder • Endo and exo transition states can be described, like Diels-Alder 2 s • Slight endo preference is sensitive to steric effects 2 s H H CO 2 CH 3 O 2 s • Ene has higher activation energy than Diels-Alder, leading to the necessity of higher temperatures • Ene favored by electron withdrawing groups on enophile, strain in ene, and geometric alignment endo H HOMO H O CO 2 CH 3
Ene
exo
Enophile
LUMO 6
Mechanism: Concerted or Stepwise?
• Continuum of possible reaction mechanisms • Placement of reaction on continuum depends on system and conditions: • Thermal, all carbon, low strain - asynchronous concerted • Strained systems unable to achieve geometry - biradical • Lewis acid catalyzed - close to zwitterionic X Y H concerted X Y H biradical X Y H zwitterionic 7
Intramolecular Ene Reaction • Intramolecular lower activation energy than intermolecular because of entropic advantage • Useful regio- and stereoselectivity • Classified into three major types X Y H Type I X YH X Y Type II H X YH Y X H Type III HY X 8 Oppolzer, W.; Snieckus, V.
Angew. Chem., Int. Ed. Engl.
1978
,
17
, 476
Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion 9
Carbonyl-Ene H H O CO 2 CH 3 H O CO 2 CH 3 10
Carbonyl-Ene: Thermal vs. Lewis Acid MeO 2 C CO 2 Me OH CO 2 Me CO 2 Me O HO CO 2 Me CO 2 Me 180°C 48h 92 8 2.5
97.5
SnCl 4 (0.2 eq) 0°C, 5 min •
Thermal Ene:
Steric accessibility of double bond and allylic hydrogen are primary concern •
Lewis Acid-Promoted Ene:
component so trisubstituted alkene more reactive than monosubstituted Positive charge develops at the ene 11 Mikami, K.; Shimizu, M.
Chem. Rev.
1992
,
92
, 1021
Carbonyl-Ene: Thermal vs. Lewis Acid H O CCl 3 130°C AlCl 3 16 OH CCl 3 85 84 OH CCl 3 15
syn/anti
selectivity is
reversed
with the use of a Lewis Acid 12 Mikami, K.; Shimizu, M.
Chem. Rev.
1992
,
92
, 1021
Transition State Geometry H H O AlL 3 H Thermal Reaction “Envelope” Early Transition State Lewis Acid Catalyzed “Chair-like” Late Transition State Loncharich, R. J.; Houk, K. N.
J. Am. Chem. Soc.
Mikami, K.; Loh, T.-P.; Nakai, T.
Tetrahedron Lett.
1987
,
109
, 6947
1988
,
29
, 6305 13
Thermal Transition State H O CCl 3 OH CCl 3 OH CCl 3 CH 3 CH 3 H H H Cl 3 C CH 3 O H CH 3 O H Cl 3 C H
syn anti
14 Benner, J. P.; Gill, G. B.; Parrott, S. J.; Wallace, B.; Begley, M. J.
J. Chem. Soc. Perkin Trans. I
1984
, 315
Lewis Acid Transition State H O CCl 3 OH CCl 3 Cl 3 C H CH 3 O Al H H Cl 3 C CH 3 O CH 3
syn
CH 3
anti
Al Mikami, K.; Shimizu, M.
Chem. Rev.
1992
,
92
, 1021 H OH CCl 3 15
Carbonyl-Ene: Asymmetric Reaction Ph O O H O SnCl 4 , 1 eq -78°C, 94%
>99% de
Ph O O OH SnL 4 Ph O O H O
si
face addition Whitesell, J. K.
Acc. Chem. Res.
1985
,
18
, 280 16
PhS Carbonyl-Ene: Asymmetric Reaction H O F F F F F SiPh 3 O O Al Me SiPh 3 (20 mol%) 4Å MS -78°C
88%
PhS OH F F F 88% ee F F Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H.
Tetrahedron Lett.
1988
,
29
, 3967 17
Ph Carbonyl-Ene: Asymmetric Reaction O O X Ti X X = Cl, Br, OTf O (
i
PrO) 2 TiCl 2 / (
R
)-BINOL (1 mol%) H O CO 2 CH 3 MS 4Å, CH 2 Cl 2 (
i
PrO) 2 TiBr 2 / (
R
)-BINOL (5 mol%) H CO 2 CH 3 MS 4Å, CH 2 Cl 2 With BINOL 33% ee, product in 91.4% yield and
92% ee
Ph OH CO 2 CH 3
97% yield, 97% ee
OH CO 2 CH 3
89% yield, 98% ee
H O (
i
PrO) 2 TiBr 2 / (
R
)-BINOL (5 mol%) OH OH CO 2 CH 3 MS 4Å, CH 2 Cl 2
73% yield overall
CO 2 CH 3 91 (
98% ee
) Mikami, K.; Terada, M.; Nakai, T.
J. Am. Chem. Soc.
1990
,
112
, 3949 9 (
>90% ee
) CO 2 CH 3 18
Carbonyl-Ene: Positive Non Linear Effect Mikami, K.; Shimizu, M.
Chem. Rev.
1992
,
92
, 1021 19
Carbonyl-Ene: Proposed Transition State OTDS H O (
R
)-BINOL-TiCl 2 (10 mol%) CO 2 CH 3 MS 4Å CH 2 Cl 2 , 0°C 53% OH OTDS
>99%
syn
>99% ee
CO 2 CH 3 Mikami, K.; Narisawa, S.; Shimizu,M.; Terada, M.
J. Am. Chem. Soc.
1992
,
114
, 6566 Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N.
Tetrahedron Lett.
1997
,
38
, 6513 20
Carbonyl-Ene: Asymmetric Reaction CH C 2 O O Me 3 C N H 2 O Cu N OH 2 CMe 3 2 SbF 6
1
R O H CO 2 Et
R = cat. (mol%) Yield
Me
1
(1)
2
(10) 83% 92% Ph
1
(1)
2
(10) 97% 99% 5 2 OBn H 11
1 2 2 1
(10) (2) (1) (10) 62% 88% 89% 81% 2 O O Ph N Cu N Ph
2
2 OTf R OH CO 2 Et
% ee Regioselection
96 ( 92 (
S R
93 (
S
) 89 (
R
) ) ) - - - - 98 (
S
) 92 (
R
) 96 (
S
) 91 (
R
) 100:0 100:0 74:26 90:10 Johnson, J. S.; Evans, D. A.
Acc. Chem. Res.
2000
,
33
, 325 21
Carbonyl-Ene: Reversal of Stereochemistry 2 2 O O Me 3 C N H 2 O N Cu OH 2 CMe 3 2 SbF 6
1
O O Ph N H 2 O Cu N OH 2
2
Ph 2 SbF 6 O 1 -Cu-N 1 -C 1 dihedral < +30.2° O 2 -Cu-N 2 -C 2 dihedral < +35.9° O 1 -Cu-N 1 -C 1 dihedral < -11.3° O 2 -Cu-N 2 -C 2 dihedral < -7.2° X-Ray crystal structures Geometry distortion from planarity 22 Evans, D. A.; Johnson, J. S.; Burgey, C. S.; Campos, K. R.
Tetrahedron Lett.
1999
,
40
, 2879
Carbonyl-Ene: Transition State 2 Me 3 C O N O N Cu O O CMe 3 Square planar Cu(II) Nucleophilic attack from
si
face H OEt Nu 2
endo
transition state anti selective H O O OEt O O Me 3 C N H 2 O N Cu OH 2 CMe 3 2 SbF 6 (1 mol %) CH 2 Cl 2 , 25°C 86% yield O OEt OH 98% ee
endo:exo
78:22
Johnson, J. S.; Evans, D. A.
Acc. Chem. Res.
2000
,
33
, 325 Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.
J. Am. Chem. Soc.
23
2000
,
122
, 7936
Carbonyl-Ene: Asymmetric Reaction Ph O N N TfO Sc N OTf OTf
3
O Ph H O O H N Ph 5 mol %
3
CH 2 Cl 2 , 4 A MS, rt 78% yield OH H N O 94% ee
syn/anti 13:1
Ph
exo
transition state syn selectivity Evans, D.A.; Wu, J.
J. Am. Chem. Soc.
2005
,
127
, 8006 24
Carbonyl-Ene: Desymmetrization H H Ph O O O H 1.5 eq SnCl 4 , CH 2 Cl 2 -78°C 30°C
81%
H HO H H O H O O O H OEt HO O O H OEt Specionin Spruce bud worm antifeedant Whitesell, J. K., Allen, D. E.
J. Org. Chem.
Whitesell, J. K.; Allen, D. E.
J. Am. Chem. Soc.
1985
,
50
, 3025
1988
,
110
, 3585 25
Carbonyl-Ene in Synthesis 4 steps O ZnBr 2 benzene 5-10°C OH H 2 OH -pinene (
R
)-citronellal
l
-isopulegol 94:6 dr Takagaso Process for production of menthol (-)-menthol H O ZnL n Nakatani, Y.; Kawashima, K.
Synthesis
1978
, 147 26
Carbonyl-Ene in Synthesis O O N O Ph 11 steps TBSO H O H O H OEt O (
S
)-BINOL-TiBr 2 CH 2 Cl 2 , toluene 74% TBSO EtO 2 C OH H O H 11 steps O H OH O O O OH H O H >95% ds Shortened synthesis of this piece by 13 steps laulimalide Potential anti-tumor agent stabilizes microtubuli Pitts, M. R.; Mulzer, J.
Tetrahedron Lett.
2002
,
43
, 8471 27
Oxonium-Ene in Synthesis Me 3 Si Br 8 steps Me 3 Si EtO O Cl OTs 1) SnCl 4 (2 eq) 0°C, CH 2 Cl 2 , 1.5 h 2) TBAF-THF TBDPSO Me 3 Si O Cl OTs HO
37% only isomer
Cl 10 steps O Laurenyne 28 Overman, L. E.; Thompson, A. S.
J. Am. Chem. Soc.
1988
,
110
, 2248
Oxonium-Ene in Synthesis R O R 3 R 1 O R 2
H
Lewis Acid R 3 O Stepwise Prins Intramolecular Reaction R R 2 Concerted Ene Reaction R 3 O H R 2
H
R R R 3 O R 2
k
H /
k
D = 1.65
R R 3 O R 2 Blumenkopf, T. A.; Look, G. C.; Overman, L. E.
J. Am. Chem. Soc.
1990
,
112
, 4399 29
S H X Thio-Ene H H S X X H S 30
Thio-Ene: Regioselectivity R S R 1 S R R 1 R R 1 SH R CF 3 CH 3 S CO 2 Et CO 2 Et CO 2 Me
Ph
R 1 CF 3 CN CO 2 Et H H
H
% sulfide Only 83 Only 78 75
19
% thiol -- -- -- 21 <2
38
Bachrach, S. M.; Jiang, S.
J. Org. Chem.
1997
,
62
, 8319 31
Thio-Ene: Regioselectivity To alcohol E a = 31.12
E rxn = -7.97
To thiol E a = 20.15
E rxn = -18.75
To ether E a = 44.73
E rxn = -1.04
To sulfide E a = 21.44
E rxn = -19.70
All numbers in kcal/mol Bachrach, S. M.; Jiang, S.
J. Org. Chem.
1997
,
62
, 8319 32
R 1 N R 2 H H R 3 Imino-Ene concerted R 4 pericyclic ene NHR 2 R 1 R 3 R 4 R 1 N R 2 R 3 R 1 N R 2 R 3 Mannich (stepwise) R 1 N R 2 R 3 Borzilleri, R. M.; Weinreb, S. M.
Synthesis
1995
, 347 33
Imino-Ene: Asymmetric Reaction Ar Ar P P CuClO 4 Ar Ar Ar = 4-MeC 6 H 4 alkene R 1 R 2 EtO O N Ts H catalyst (5 mol %) PhCF 3 , rt product NHTs OEt O R R 2 1 95% yield 99% ee NHTs OEt O O O NHTs OEt O NHTs OEt 85% yield 92% yield 95% ee 90%ee O Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J. III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. L.
J. Am. Chem. Soc.
2002
,
124
, 67 34
Imino-Ene: Synthesis CO 2 Me H O H H 2 N(CH 2 ) 3 NH 2 PhMe/ /16h 70% CO 2 Me H H SiMe 2 Ph H N H N H H H SiMe 2 Ph H H H SiMe 2 Ph H H H N H H PhMe 2 Si H N H H H SiMe 2 Ph H H H H N H N H H H H H (-)-Papuamine anti-fungal activity H Borzilleri, R. M.; Weinreb, S. M.; Parvez, M.
J. Am. Chem. Soc.
1995
,
117
, 10905 35
Br Imino-Ene: Synthesis tol tol P CuClO 4 P tol tol 3 steps O Br H EtO NH 2 Br N Ts NTs PhCF 3 , rt 76% yield 94% ee OMe Br H NHTs CO 2 Et N Ts TBDPSO N H O H N N H O H NHTs OH O F D Cl O 2 C H N N O H N N H O H N N H N H O OH Cl O O O O E Cl Cl Cl Cl OH OH OH Complestatin anti-apoptotic activity Elder, A. M.; Rich, D. H.
Org. Lett.
1999
,
1
, 1443 36
Oxo-Ene (Schenck Reaction) O 2 visible light dyes OOH Schenck, G. O.; Schulte-Elte, K.
Liebigs Ann. Chem.
1958
,
618
, 185 37
Schenck Reaction: Transition State 1 O 2 perepoxide O O HOO biradical concerted CASSCF/6-31G* O O UB3LYP/6-31G* HOO HOO Houk used potential energy surfaces to conclude a highly asynchronous concerted mechanism takes place RB3LYP/6-31 38 Leach, A. G.; Houk, K. N.
Chem. Commun.
2002
, 1243
Schenck Reaction: Regioselectivity 10% 48% 52% 22% 68% 4% 43% 53% 22% ‘
cis
effect’: the more substituted side of the double bond is the most reactive - also seen with allylic alcohols, styrene-type molecules, and trisubstituted enol ethers 78% O O H vs.
H O O H H O Hydrogen next to bulky group is usually more reactive L S L H O S Stratakis, M.; Orfanopoulos, M.
Tetrahedron
2000
,
56
, 1595 OOH L S major product 39
Schenck Reaction: Synthesis C 16 H 33 O N OMe 3 steps DTBN
t
-BuOOH 65% 1:1.2 ratio C 16 H 33 OH C 16 H 33 OH OTIPS TPP, O 2 h 62% OH C 16 H 33 OOH 98:2
syn
/
anti
OTIPS 7 steps OTIPS OOH C 16 H 33 MeO
en
O O H -Chondrillin CO 2 Me (anti-tumor activity) MeO O O 3:1 ratio C 16 H 33 H Plakorin ATPase activator CO 2 Me DTBN = N O 40 Dussault, P. H.; Woller, K. R.
J. Am. Chem. Soc.
1997
,
119
, 3824
Aza-Ene N CO 2 C 2 H 5 C 2 H 5 O 2 C N 80°C H N CO 2 C 2 H 5 N CO 2 C 2 H 5 Hoffman, H. M. R.
Angew. Chem., Int. Ed. Engl.
1969
,
8
, 556 41
O H N N N O Aza-Ene: Transition State O H N O N N O H N O N NH O H N O N N Stepwise Ene reactions proceed through diradical intermediates, which have high rotational barriers about the single bonds.
42 Leach, A. G.; Houk, K. N.
Chem. Commun.
2002
, 1243
Aza-Ene: Indole Protection Using Methyl Triazolinedione (MTAD) N H O N N N O CH 2 Cl 2 , 0°C, 1 min quantitative 120°C, 1 min quantitative N O HN N O N N H CO 2 Me NH O N N N O CH 2 Cl 2 , 0°C, 80% 250°C in vacuo 65% N O HN N O N CO 2 Me N H 43 Baran, P. S.; Guerrero, C. A.; Corey, E. J.
Org. Lett.
2003
,
5
, 1999
N H CO 2 Me NHBoc Aza-Ene: Synthesis N O H H N N H O O N N N O CH 2 Cl 2 , -5°C; O 2 , h , 7.5 h MeOH, methylene blue, -28°C; Me 2 S N H O N N N H H N O O H N N OH H O 110°C, 10 min N O H H N N OH H O N N H okaramine N insecticide Baran, P. S.; Guerrero, C. A.; Corey, E. J.
J. Am. Chem. Soc.
2003
,
125
, 5628 44
Retro-Ene ene reaction H ene X Y enophile retro-ene reaction X Y H ene adduct • Higher temperatures required for retro-ene (Flash Vacuum Thermolysis) • Like Ene reaction, the mechanism of Retro-ene can be anywhere from concerted to stepwise radical or polar, depending on the ene-adduct • Hetero-retro-ene reactions are widespread with heteroatoms in any of the 5 centers involved • Retro-ene can be used to generate reactive species O H O Ph Ph 560-640°C 0.1 mbar - Ph 2 CO 65% O 510-560°C 0.05 mbar CO 2 H O O H O H O H CN 800-1000°C 10 -5 mbar - propene H O 450-800°C 10 -2 mbar CN - allylbenzene Ph H O H CN 45 Ripoll, J.-L.; Vallée, Y.
Synthesis
1993
, 659
Retro-Ene: Synthesis O B O N N Bn TMS O S N Ph O O H 2 steps CHCl 3 , reflux 14 h Et H OH N N Bn O H N TMS Et H OH H O S N N N H Bn O TMS Ph 5 steps Ph Et H NaOH 0°C to rt; aq. HCl, 0°C; NaHCO 3 N O OMe OH (-)-methyl palustramate H O S O Et H OH N N Bn O H N TMS Ph 46 Touré, B. B.; Hall, D. G.
J. Org. Chem.
2004
,
69
, 8429
Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion 47
All-Carbon Ene • Carbon-carbon bond forming with atom economy • Can proceed with high levels of selectivity • Thermal reaction still suffers from high temperatures • Alkyne enophiles proceed more easily than alkene enophiles • Recent advances in transition metal catalyzed all-carbon ene reactions have greatly improved their synthetic utility - Trost’s Ru catalyst for alkene-alkyne coupling 48
All-Carbon Ene: Stereoselectivity MeO 2 C O O 5 steps heptane 235°C 2 days sealed tube quantitative H CO 2 Me O H O 3 steps H H H CO 2 Me 4 steps isodihydronepetalactone O O H H isoiridomyrmecin Mikami, K.; Takahashi, K.; Nakai, T.
Synlett
1989
, 45 49
All-Carbon Ene: Ru Catalyst Ru(N CCH 3 ) 3 PF 6 7 CO 2 CH 3 7 CO 2 CH 3 N C N C 10 mol % catalyst 30 mol % CSA acetone 50°C 78% yield 10 mol % catalyst DMF N N C N C C 7 CO 2 CH 3 7 CO 2 CH 3 Branched 1:1.1
Linear 7 CO 2 CH 3 82% yield 8.9:1 OH 10 mol % catalyst DMF OH 59% yield 17.4:1 OH OH 7 CO 2 CH 3 HO 10 mol % catalyst DMF HO 7 CO 2 CH 3 91% yield 1:32 Trost, B. M.; Toste, F. D.
Tetrahedron Lett.
1999
,
40
, 7739 Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M.
J. Am. Chem. Soc.
50
2001
,
123
, 12504
R All-Carbon Ene: Ru Catalyst Mechanism R 1 R 1 R 1 R R Ru R Ru H R 1 R Ru H R 1 R Ru R 1 Ru R R 1 R Ru Ru R 1 R 1 R 51 Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M.
J. Am. Chem. Soc.
2001
,
123
, 12504
R All-Carbon Ene: Ru Catalyst Mechanism R 1 R 1 R 1 R R Ru R Ru H R 1 R Ru H R 1 R Ru R 1 Ru R R 1 R Ru Ru R 1 R 1 R 52 Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M.
J. Am. Chem. Soc.
2001
,
123
, 12504
R All-Carbon Ene: Ru Catalyst Mechanism R 1 R 1 R R R 1 Ru R Ru R 1 R Ru H R 1 H Ru R R 1 R Ru H R 1 Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc.
2002
,
124
, 5025 53
R All-Carbon Ene: Ru Catalyst Mechanism R 1 R 1 R R R 1 Ru R Ru R 1 R Ru H R 1 H Ru R R 1 R Ru H R 1 Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc.
2002
,
124
, 5025 54
O B O All-Carbon Ene: Ru Catalyst Application OAc RuCp(CH 3 CN) 3 PF 6 acetone, 25°C 70% O EtO I Pd(PPh 3 ) 4 , TiOEt OR O EtO Pd(OAc) 2 , O 2 O OEt AcO
Z
isomer is major product Hansen, E. C.; Lee, D.
J. Am. Chem. Soc.
2005
,
127
, 3252 O B O AcO 55
Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion 56
H O S Tandem Reactions Et 2 AlCl, CH 2 Cl 2 -78°C to 0°C, 2 h S O H HO S Kraus, G. A.; Kim, J.
Org. Lett.
2004
,
6
, 3115 57
H O O O OTMS CO 2 CH 3 O Tandem Reactions O 4 steps O OTMS O CO 2 CH 3 mesitylene 155°C, 9 h 63% OH 1) NaBH 4 , MeOH OTMS CO 2 CH 3 2) CrO 3 •2pyr, CH 2 Cl 2 O OH O OTMS OTMS CH 3 O 2 C O O 470°C 89% OTMS O O O H H O O HO (±)-verrucarol cytotoxicity OH 58 Trost, B. M.; McDougal, P. G.
J. Am. Chem. Soc.
1982
,
104
, 6110
HO HO O Ph Tandem Reactions O Ph (COCl) 2 , DMSO Et 3 N, CH 2 Cl 2 OHC OHC 1) NH 3 , CH 2 Cl 2 2)HOAc (77% from diol) N OCH 2 Ph O Ph CO 2 Me OCH 2 Ph N HN HN (±)-Methyl Homosecodaphalphyllate 59 Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H.
J. Am. Chem. Soc.
1988
,
110
, 8734
Conclusions • While the mechanism may not be well-defined, high levels of stereoselectivity can be achieved through organized transition states.
• Lewis acid promoted ene reactions can proceed quickly at moderate temperatures.
• The development of chiral Lewis acid catalysts has led to synthetically useful enantioselectivity of the ene reaction. • The ene reaction is a powerful, versatile transformation in synthesis.
60
Acknowledgements • Prof. Steven D. Burke • Greg Hanson • Brian Lucas • Andy Hawk • Chris Marvin • Andrew Dilger • Matt Dodge • Chris Paradise • Vicki Wilde • Dan Paluchowski • Matt Bowman • Matthew Christianson • Kris Kolonko • Luke Lavis • Alex Clemens • Susie Lucas 61