Cinchona Alkaloids in Asymmetric Catalysis

16 Pages·2005·1.13 MB·English

Cinchona Alkaloids in Asymmetric Catalysis
Rob Moncure
MacMillan Group Meeting
August 13, 2003
Introduction
Cinchona Alkaloids in Phase Transfer Catalysis
Cinchona Alkaloids as Nucleophiles/Bases
Sharpless Asymmetric Dihydroxylation
Useful Reviews
Kacprzak, K. et al. Synthesis, 2001, 7, 961-988.
Kwan, B.; MacMillan, D.W.C.; New Strategies for Organocatalysis: Enantioselective Amine Catalysis. 2003, unpublished.
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
H
Introduction to Cinchona Alkaloids H
HOH N
MeO
! Quinine isolated by Pelletier in 1820.
N
! First used for a resolution of a racemate in 1853 by Pasteur.
Quinine
! Quinine and derivatives were quickly recognized as antimalarial agents.
R2 H R2 H
H
HOH N pseudoenantiomers HHO N
H
R1 R1
N N
R1 = OMe R1 = OMe
Quinine R2 = vinyl Quinine R2 = vinyl
Dihydroquinine R2 = Et Dihydroquinine R2 = Et
R1= H R1= H
Cinchonidine R2 = vinyl Cinchonidine R2 = vinyl
Dihydrocinchonidine R2 = Et Dihydrocinchonidine R2 = Et
1
H
The First Total Synthesis H
HOH N
! Quinine was first synthesized by R.B. Woodward in 1944. MeO
N
Quinine
Me
N OH H2SO4 N OH N OH
EtO
OEt
Me Me
H2, Pt HN OH 1. Ac2O, MeOH AcN OH 1. H2CrO4, AcOH
HOAc 2. H2, EtOH, Raney Ni + trans 2. EtOH/NaOEt, EtONO
CO2Et CO2H
Me
1. H2, AcOH Quinine
N
OH 2. MeI, EtOH, K2CO3
N 3. 60 % NaOH
Ac NAc WWooooddwwaarrdd,, RR.. BB.. eett aall. J J.. AAmm.. CChheemm.. SSoocc.. 11994454,, 6676,, 886409..
Cinchona Alkaloids Are Versatile Catalysts
! These are just a few of the reactions that can be performed asymmetrically.
C-C Bond Forming C-O Bond Forming C-X Bond Forming
Alkylation Epoxidation of Enones Aziridination
Aldol Epoxidation of cis-Olefins Azirination
Darzens Asymmetric Dihydroxylation Formation of !-Hydroxyphosphonate Esters
Michael Addition Asymmetric Aminohydroxylation Addition of Thiols to Cyclic Enones
Diels-Alder !-Hydroxylation of Ketones
Claisen Rearrangement
Miscellaneous Reactions
Hydrogenation
Desymmetrization
Decarboxylation
! Cinchona Alkaloids have been explored in asymmetric synthesis for the last 35 years.
H
Li
H
H3Al OH N OH
O MeO
Me
Me N
Ether 48% ee
Cervinka, O.; Belovsky, O. Coll. Czech. Chem. Commun., 1967, 30, 2487.
2
Br H
Cinchona Alkaloids as Phase Transfer Catalysts H
HOH N
! Alkylation of Substituted Indanones MeO Ph
N
Cl O Cl O PTC
Cl MeCl Cl Ph
Ph
MeO Tolu1e0n-e5, 0a mq. oNl%aO PHT,C 20°C MeO Me
95% yield, 92% ee
! Ion pairing between indanone anion and PTC proposed as reason for selectivity
H
Cl Cl O HOH H N !-face bloc"k#efda cine rtiog imd ecothnyfloartmioantion, opens
MeO
MeO
N
Dolling, U. -H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
O'Donnell: Pioneer in PTC with Cinchona Alkaloids Cl H
H
HOH N
! Efforts to synthesize chiral !"amino acids
MeO Ph
O Ph 10 mol % PTC O Ph N
N R-Br N
t-BuO Ph 50% aq. NaROTH / CH2Cl2 t-BuO R Ph PTC
R Time % Yield % ee
Allyl 5 75 66
Bn 9 75 66
Me 24 60 42
n-Bu 14 61 52
C6H4Cl-4 12 81 66
CH2-2-naph 18 82 54
! Recrystallization procedures were developed to obtain enantiopure compounds, but low
yields indicated a need for improvement.
O'Donnell, et al. J. Am. Chem. Soc. 1989, 111, 2353.
3
Cl H
Mechanism for Phase-Transfer Alkylation
H
HOH N
MeO Ph
! Proposed Mechanism for O'Donnell's PTC Alkylation
N
O Ph (R4N)*
N O Ph R2-X
Organic Phase R1O Ph R1O N
Ph
O Ph
N
R1O
Base R2 Ph
Base-H
Aqueous Phase
X
O Ph (R4N)* X
N
R1O
Ph
Corey Modifications to O'Donnell's Work Br H
H
N
! By using 9-(chloromethyl)anthracene to quaternize the PTC,
approach from the front and right side of the catalyst is blocked. N O
! Corey chose to block ion-pairing from the
bottom face of the catalyst by O-allylation.
! Therefore, the top left quadrant is now the only region open to the substrate.
PTC
O Ph 10 mol % PTC O Ph
N R-Br N
t-BuO Ph S-6o0li°dC C osrO -7H8,° HC2O / CH2Cl2 t-BuO R Ph
R Time / % Yield / % ee / %
Me 28 71 97
Et 30 82 98
n-Hexyl 32 79 > 99
CH2c-C3H5 36 75 99
Allyl 22 89 97
Methallyl 20 91 92
CH2CCTBS 18 68 95
Bn 22 73 > 99
! Enantioselectivity greatly enhanced by Corey's rational approach to catalyst design.
Corey arrived at these results while trying to understand the origin of enantioselectivity in the Sharpless
Asymmetric Dihydroxylation. For relavent references, see the Kwan review.
4
An Interesting Sterics Versus Electronics Argument
! Corey then tried a different experiment using diphenylalkylidene as a substrate, under the same
conditions.
R R
Br H
H
N
CO2t-Bu Br 10 mol % PTC CO2t-Bu
CsOH H2O N O
CH2Cl2 : Et2O (1 : 1)
-65 °C
R R
PTC
R !p ee / %
Ph 0.00 67
t-Bu -0.15 81
OMe -0.28 91
NMe2 -0.63 96
! He found that the more electron-donating the subsituent on the phenyl ring, the more
enantioselective the reaction.
! He then theorized that the more electron donating, the more negatively the ester oxygen is charged,
and therefore the more tightly it can bind to the catalyst, thereby enhancing the selectivity.
Corey, E. J. et al. J. Am. Chem. Soc. 1998, 120, 13000.
Corey's Catalyst Applied to Epoxidation of Enones
Br H
! Corey's catalyst modifications proved successful in the
H
epoxidation of certain enones. N
O O
R 10 mol % PTC R O N O
KOCl, Toluene, -40°C
X 12 h X
R X Yield / % ee / % PTC
C6H5 H 96 93
C6H5 F 93 98
C6H5 Br 92 93
C6H4NO2-4 H 90 94
C6H4NO2-4 F 97 95
n-C5H11 F 90 91
c-C6H11 H 85 94
c-C6H11 F 87 95
C6H5 OC6H5 89 93
2-naphthyl H 97 93
! Exocyclic enones were epoxidized, though with extensive erosion in enantioselectivity.
Corey, E. J.; Zhang, F. -Y. Org. Lett. 1999, 1, 1287.
5
Aldol Reaction with Cinchona Derivatives
! Shibasaki was the first to report an aldol reaction using a Cl
Cinchona-derived catalyst. OMe H
H
O CHO O NO2 N
10 mol % PTC OH
CH3NO2 15 mol % KF N OH
Toluene, -20 °C, 19 h
41 % yield,
PTC
23 % ee
! At the same time, Shibasaki was developing a lanthanum BINOL catalyst and was achieving better
results, so he did not pursue the matter further.
! Corey used a derivative of the epoxidation catalyst to develop this methodology for ester enolate
equivalents.
OTMS Ph O 10 mol % PTC-2 O OH
t-BuO N Ph R H 3 : 1 / C -H728C °lC2 : Hexanes t-BuO R
NH2
R Yield / % syn : anti syn ee / % F H
i-Pr 70 6 : 1 83 H
c-C6H11 81 13 : 1 46 N
n-C6H13 79 3 : 1 91
(CH2)3Cl 48 1 : 1 86 N O
(CH2)2Ph 64 1 : 1 86
i-Bu 61 3 : 1 70
Ph
Corey, E. J. ... Angew. Chem. Int. Ed. 1999, 38, 1931.
Corey, E. J. ... Tetrahedron Lett. 1999, 40, 3843.
Shibasaki, M. et al. Tetrahedron Lett. 1993, 34, 855. PTC-2
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PTC with Cinchona Alkaloids in Total Synthesis
! Corey extended this methodology to develop a diastereoselective Henry reaction starting with chiral
aldehydes in order to synthesize Amprenavir, an HIV-protease inhibitor.
F H
H
N
O N O OH
10 mol %
Bn2N H CH3NO2 Ph Bn2N NO2
12.5 equiv KF
Ph Ph
THF, -10 °C, 6 h 86 % yield
17 : 1 dr
OH
! The key step of Corey's Amprenavir
O NH N SO2 synthesis, the Henry reaction of nitroethane
O and the chiral aldehyde, proceeded in good
Ph yield with excellent selectivity.
Amprenavir NH2
! The same model for selectivity as in the
PTC-alkylation can be proposed here. The !-
stacking between the aromatic aldehyde and
the aromatic rings on the catalyst leave only
one face of the aldehyde open to nucleophilic
Corey, E. J. et al. Angew. Chem. Int. Ed. 1999, 38, 1931. attack.
Cinchona Alkaloids as Nucleophilic Catalysts
! In 1989, Kagan reported the first asymmetric cycloaddition OMe
with chiral amines acting as basic catalysts.
O O OH H
10 mol % Amine
N Me N Me N N
CHCl3, -50 °C O H
15 min
O O HO
Amine
97 % yield
61 % ee (endo)
O
O
! Mechanism 1: Me
H *NR2 N Me N
O
O
O O
O
O
H N Me
O ! Mechanism dismissed. Subjection of the conjugate adduct to
reaction conditions failed to produce the cycloaddition product.
HO
! Mechanism 2: ! In this mechanism, the deprotonated anthrone
N forms an ion-contact pair with the quaternized
nitrogen of the catalyst. Meanwhile, the
OMe
H dienophile is hydrogen-bonded through the
O HN O H MeN O hydroxyl group of the catalyst.
O
Kagan, H. B.; Riant, O. Tetrahedron Lett. 1989, 52, 7403.
H
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Catalytic Asymmetric Synthesis of !"Lactones
! In 1982, Wynberg published one of the first truly remarkable OMe
results in asymmetric catalysis.
O OH H
O O 2.5 mol % Amine O
H H Cl3C H Toluene, -50 °C, 1 h Cl3C N H N
95 % yield Amine
98 % ee
! Based on this result, he attempted to expand substrate scope to include ketones.
O
O O 2.5 mol % Amine O
H H R1 R2 Toluene, -50 °C, 1 h R1 R2
R1 R2 Yield / % ee / %
CCl3 H 89 98
CHCl2 H 67 45
CCl2Me H 95 91
CCl2Et H 87 89
CCl2Ph H 89 90
CCl3 Me 72 94
CCl3 Et 1 n.d.
CCl3 Ph 0 n.d.
CCl3 C6H4Cl-4 68 90
CCl3 C6H4NO2-4 95 89
Wynberg, H. ... J. Am. Chem. Soc. 1982, 104, 166.
Wynberg, H. ... J. Org. Chem. 1985, 50, 1977.
Model for Stereoselectivity in Asymmetric Lactone Synthesis
! Wynberg proposed this model to account for the observed stereoselectivity. He used 1,2-
dimethylpyrrolidine as a simple model of the Cinchona catalyst.
O Me
H
MeCH2
O H
O CCl3 O O
N Me
H H Me CCl3 Cl3C
H O
HC Me
MeO H
! Wynberg did not propose that either of these states is more likely than the other, because both lead
to the observed stereochemistry in the product.
! In the top form, the ketene oxygen faces the methylene of the catalyst ring. When chloral
approaches the catalyst, it forms a complex with the trichloromethyl group facing away from the methyl
group of the catalyst to avoid steric strain.
! In the bottom form, the ring is the dominant form of stereocontrol, and the CCl3 orients itself away
from the ring methylene protons.
Wynberg, H. et al. J. Am. Chem. Soc. 1982, 104, 166.
8
Dimerization of in-situ Generated Ketenes with a Synthetic Application
! Calter and coworkers published a ketene dimerization process in which the ketene was generated in
situ and used as a solution in THF.
OMe
OH H
MeBrOBr Zn dust, THF MeO 1 mol % N H N Me O MOe LTiHAFlH, 4-78 °C Me OMe OH
! This methodology was applied to a convergent, stereospecific synthesis of a fragment of Pamamycin
621A.
SiMe3
O ii)i) LTiNMMSeC(lOMe) Me O ONOMe Pd(OAc)2 O ONOMe
O Me Me Me Me
+
Me Me HcaNt.M pey(rOidMonee) Me O ONOMe KBEt3H Me OH ONOMe
Me Me Me Me
O OH
MeO Me McCarney, C. C.; Ward, R. S. J. Chem. Soc. Perkin Trans. 1 1975, 1600.
N O Calter, M. A.; J. Org. Chem. 1996, 61, 8006.
Me H H Calter, M. A. et al. Org. Lett. 2000, 2, 1529.
Me Me
Asymmetric Synthesis of Bicyclic Lactones
! Romo reported a catalytic asymmetric synthesis of bicyclic lactones using a cinchona catalyst via
intramolecular activation of ketene equivalents. The reaction involves both an alkaloid as well as a more
simple tertiary amine base.
R CO2H 10 mol % Amine O OMe
R CHO 3 equiv RR O OAc H
N Cl
Me N
4 equiv i-Pr2NEt N H
MeCN, RT
Amine
R Yield / % ee / %
H 54 92
OCH2CH2O 37 92
Me 45 90
! It was observed that blocking the hydroxyl groups with different carbonyl derivatives did not affect
enantioselectivity very much, and thus the following stereochemical rationale was proposed.
! Once the acylammonium enolate is formed, the aldehyde
OMe approaches the enolate from the si face, away from the
H
methyoxyquinoline moiety.
H ! Per Corey's procedure of converting gem-trichloromethyl alcohols
AcO N H tgoe anmeriantoe a!-csidusb,s tthitiust ereda acmtioinno c aocuildds b.e used to enantioselectively
N
Romo, D. et al. J. Am. Chem. Soc. 2001, 123, 7945.
O O RCoomreoy,, DE.. Je.t eatl .a lS. y Jn.t hAems.i sC. h 2e0m0.1 S, 1o7c.3 11.992, 114, 1906.
9
Asymmetric Michael Addition of Thiols to Cyclic Enones
! Recently, Li Deng developed a highly enantioselective 1,4-addition reaction of thiols to cyclic
enones. O
O Et Et
1 mol % (DHQD)2PYR N Ph N
Toluene, RT H O O H
SH * H
ArS MeO N N H OMe
Enone Yield / % ee / %
Ph
n = 0 55 41 N N
O nn == 12 7876 9947 (DHQD)2PYR
n = 3 82 > 99
(O )n n = 4 91 97 !hy Odrrodxinyaprryo lcininec dheornivaa ctiavteasly wstesr ea ste wsteelld a, sa nd alteration
of the hydroxy group was deleterious to
enantioselectivity. Therefore, a bifunctional catalytic
71 92 mechanism was presumed.
Me ! It was believed that the cyclic enone and the thiol
Me
were simultaneously activated by the hydroxy and
O
amino groups, respectively.
! However, this cannot be the case for (DHQD)2PYR,
88 95 because it lacks a hydrogen donor. Also,
Me Me (DHQD)2PYR gave the R isomer as the major product,
while quinidine gave the S isomer.
! Therefore, the mechanism for the natural cinchona derivatives must differ significantly from
that of the modified systems.
Deng, L., et al. Angew. Chem. Int. Ed. 2002, 41, 338.
Catalytic Asymmetric Cyanation of Ketones with Cinchona Alkaloid Catalysts
! Deng has also recently described the asymmetric cyanation of ketones, catalyzed by cinchona
Alkaloids acting as chiral Lewis bases. He used slightly modified cinchona catalysts.
O
O O 10-35 mol % catalyst OMe
O OEt
R1 R2 NC OEt CH0C.5l3 -, 7-1 d2a tyos -24 °C NCR1 R2 OMe H
Substrate Catalyst Yield / % ee / % N N
H
O 2 66 97
Me DHQD
Me
DQHD
O
Me 2 52 87
O 2 55 88 Catalyst 1
Me DHQD-PHN
Me Me
Me O O DHQD
EtO 1 78 96
EtO
O 1 65 90 O DHQD
Me Catalyst 2
EtEOtO Me Deng, L. et al. J. Am. Chem. Soc. 2001, 123, 7475. (DHQD)2-AQN
10