raghavan b. sunoj - ircc.iitb.ac.in b. sunoj department of ... chem. int. ed., 2010, 49, 6373. n iit...
TRANSCRIPT
Transition States in Asymmetric Catalysis
RAGHAVAN B. SUNOJ Department of Chemistry
Indian Institute of Technology Bombay
2
Outline
1. Chirality
2. Transition States
3. Importance of Transition States in Asymmetric Catalysis
4. Examples of Asymmetric Catalysis
5. Computational Design of Asymmetric Catalysts
3
Chirality
The word ‘chiral’ is derived from Greek word ‘cheir = handed
Human hands have OBJECT and MIRRO IMAGE relationship and they are NON SUPERIMPOSABLE
Examples: Shoe, scissors, screw
4
Properties of Enantiomers
1. Enantiomers are chiral
2. Pure sample of a single enantiomer is optically active
3. Enantiomers have identical physical and chemical properties in an achiral environment
4. Different biological properties
Example CH3
C2H5 HCH2OH
CH3
C2H5H
CH2OH
(+) or dextro (-) or laevo
[α] +5.9 -5.9
BP 128.9 128.9
µ 1.4107 1.4107
6
NH
N
O O
O
O
*
HO
HONH2
COOH
*
Thalidomide
DOPA
• R against nausea • S cause fetal damage
• L treatment of Parkinson’s disease
• D biologically inactive !
Properties of Enantiomers differ in Chiral medium
Biological properties of enantiomers are different, as the receptor sites are chiral
E.g., 1
E.g., 2
E.g., 3
(+)-glucose is metabolized by animals but NOT (-) glucose!
DihydrOxyPhenylAlanine
7
Chiral Molecules-Optically Inactive
When there is equal composition (1:1) of enantiomers in the mixture, the resulting solution is optically inactive
External compensation OR cancellation due to opposite optical rotations: RACEMIC MIXTURE
CH3
C2H5 CNOH
CH3
C2H5 OHCN
+CH3
C2H5 O
HCN
(50%) (50%)1 1'
Achiral chiral chiral
Why Study Chiral Induction?
World drug market (several billion $): ~55% drugs are chiral
Depleting natural resources makes organic synthesis a major and viable alternative to generate chiral drugs
Produced using “Asymmetric Synthesis” [production of one enantiomer in excess of the other]
IIT Bom
bay
Why Study Catalytic Asymmetric Processes?
Majority of industrial production of drugs and fine chemicals involve catalytic processes
Homogeneous and Heterogeneous catalysis are widely used both in academia and industry
• Synthesis of chiral compounds demands the use of chiral environment, chiral catalyst, chiral auxiliary and so on
• How do we understand the process of stereoselectivity?
• What are the controlling factors?
• How can this knowledge be further utilized?
RH
O Nu-H
Nu-H
HO Nu
HR
OHNu
HR
Steric
RH
O Nu-H
Nu-H
HO Nu
HR
OHNu
HR
IIT Bom
bay Generation of Chiral Compounds
Reaction Coordinate
STEP-I
STEP-II
0.0
TS-I
TS-II
E
• Multi-step reactions would involve various intermediates and interconnecting transition states
Theoretical Methods can be effective employed to examine the electronic structure and energies of molecules
Reaction Mechanism IIT B
ombay
Experimental techniques are not fully adequate and not widely available Provides useful insights on stereoselectivity To understand the kinetic features of chemical reactions
HOW? Ab initio calculations* provide an useful alternative in studying potential energy surfaces and TSs Identify the geometry of TS using intuitive initial guess geometries * All electron computations involving solution of Schrodinger Equation
WHY? IIT Bom
bay Transition State
Climbing-up Algorithm Using Berny Algorithm
Geometry optimization methods
Towards Maximum
Towards Minimum
TS is a first order saddle point
Transition State on a Potential Energy Surface (PES)
Stereoselectivity depends on the energy difference between diastereomeric transition states
ΔΔG‡ = ΔG‡Si – ΔG‡
Re
Stereoselective Reactions – Energetics? IIT B
ombay
Proline-Catalyzed Organocatalytic Reactions IIT B
ombay
NH
COOHR1 R2
O ee = 94%ee = 76%
ee = 92%
NHO
R1
O
R2
ee = 97%
ee = 76%
NO2
R2
O
R1
Ph
O
R1
O
R1
HNPMP
CO2RN
R2
O
R1
HNCO2R
NPMP
Mannich (List)
Ph
NO2
Michael (Enders)
NO
Ph
α-aminoxylation (Zhong)
N
N
RO2C
CO2R
α-amination (Jørgensen)
aldol (List)
Ph
R1 = EtR2 = H
R1 = EtR2 = Me
OH
H
O
R1 = EtR2 = H
R1 =MeR2 =Me Ar(p-NO2)
Ar(p-NO2)
Ar(p-NO2)
Ar(p-NO2)
R1 =MeR2 =Me
Sunoj, R. B. Wiley Interdisciplinary Reviews: CMS, 2011
Enamine and Oxazolidinone Pathway
Akhilesh and Sunoj, Angew. Chem. Int. Ed., 2010, 49, 6373.
IIT Bom
bay
N
OO
N
O
O
N
OO
N
O
O
O
NH
OOH H2O
O
N
OOH
N
OO
OHO
H2O
OHO
Base
3
74
8
9
5
6
1
2
IIT Bom
bay GeneralTSModels:Synfaceaddi2on
Sunoj, R. B. Asymmetric Organocatalysis. (Dalko, P, Editor). Wiley-VCH, 2013.
N
O
O
O
R H
H
N
O
O
N
R H
HAr
N
O
O
N
O
H
N
O
O
N
NCO2R
HRO2CPh
N
O
O
Ar H
HNO2
1 2 3 4 5
Proline Analogues as Catalysts for Aldol Reaction
% ee Expt. = 76 DFT predicted = 75
Experimental % ee for Modified Proline
76
87
61 78
73
85
NH
COOH
NH
O
NH
S
O
MeO
NH
HN N
N
N
NH
COOH
HO
S
NH
COOH
S
NH
COOH
O
NO2
OH O
NO2
OH1) Catalysts
CHO
NO2
O
Major Minor
2) H2O++
Barbas, C. F.; III et. al. J. Am.Chem. Soc. (2001); Ley, S. V. et. al. Org. Biomol. Chem.(2005)
Bicyclic-bifunctional analogues of proline?
Catalyst Design: Putting Ideas Together
[2.2.1] or [2.1.1]
HN
COOH
nNH
COOH
n
NH
COOH
O
HN COOH
n S
HN COOH
n
O
OHN
OHO Hre
si
O OHO OH
MajorMinor
a-si a-re
*TS(a-re) *TS(a-si)
*TS(s-re) *TS(s-si)
Anti or Syn-Enamine
si or re face of electrophile
Representative Lower Energy TSs
ee = 87 %
ΔE = 0.00 kcal/mol ΔE = 1.60 kcal/mol
β
β
s-re
'
s-si
1.44
1.98
1.45
2.00
2.75
2.77
alkoxide...H-C interaction
Shinisha and Sunoj, Org. Biomol. Chem. 2007, 5, 1287-1294.
Stabilizing Weak Interactions in the TS
β β '
β β'
3.252.31
1.55
1.99
1.42
2.47 2.87
1.91
Improved enantioselectivity through modulating intramolecular interactions in the diastereomeric TSs
Heteroatom substitution of Cγ methylene: Increase C(β)-H acidity
s-re
s-re
[2.1.1] [2.2.1]
ee 91% ee 92%
Shinisha and Sunoj, Org. Biomol. Chem. 2007, 5, 1287-1294.
Catalysts and Calculated Enantiomeric Excess
Azabicyclic compounds proposed as catalysts for aldol reaction are found to be superior to proline
HN
COOHMe
HN
COOH
Me
HN
COOH
O
HN
COOH
O
HN
COOH
S
HN
COOH
S
HN
COOH
NH
COOH
NH
COOH
NH
COOH
87 85 82 91 92
90 84 95 75 80
Shinisha and Sunoj, Org. Biomol. Chem. 2007, 5, 1287-1294.
Selectivity is > 99% for ortho-substituted nitrobenzaldehyde
NH
COOH
92
97
HN
COOH
O
NO2
OH O
NO2
OH1) Catalysts
CHO
NO2
O
Major Minor
2) H2O++
2009, 74, 5041.
7-Azabicyclo[2.2.1]heptane-2-carboxylic acid 11 was prepared in enantiopure form, and its catalytic potential in the direct aldol reaction between acetone and 4-nitrobenzaldehyde was assessed. The bicyclic system was found to be more selective than its monocyclic analogue -proline 5b.
β-proline Example is now available
Aminocatalysis Hot PaperDOI: 10.1002/anie.201306037
The Catalytic Asymmetric a-Benzylation of Aldehydes**Benjamin List,* Ilija Coric, Oleksandr O. Grygorenko, Philip S. J. Kaib, Igor Komarov,Anna Lee, Markus Leutzsch, Subhas Chandra Pan, Andrey V. Tymtsunik, andManuel van Gemmeren
Dedicated to Professor Johann Mulzer
Abstract: The first aminocatalyzed a-alkylation of a-branchedaldehydes with benzyl bromides as alkylating agents has beendeveloped. Using a sterically demanding proline derivedcatalyst, racemic a-branched aldehydes are reacted withalkylating agents in a DYKAT process to give the correspond-ing a-alkylated aldehydes with quaternary stereogenic centersin good yields and high enantioselectivities.
Asymmetric SN2 a-alkylations of carbonyl compounds withalkyl halides are powerful transformations that commonlyinvolve chiral auxiliaries and phase-transfer catalysts.[1]
Recently, however, organocatalysis has significantly advancedthis area by providing new strategies for the direct catalyticasymmetric a-alkylation of aldehydes.[2] For example, ourgroup has described an intramolecular a-alkylation reactionof haloaldehydes using proline-based enamine catalysis.[3]
Subsequently, other groups have contributed additionalaminocatalytic methods for the asymmetric a-alkylation ofaldehydes, including strategies that combine enamine catal-ysis with radical or cationic (SN1) reaction pathways.[4–13]
Despite these unquestionable advancements though, theasymmetric intermolecular SN2 a-alkylation of aldehydeswith simple alkyl halides has remained a long-standingchallenge for enamine catalysis (Scheme 1).[2]
Here we report progress with the first catalytic enantio-selective a-benzylation of a-branched aldehydes. We have
developed a new bicyclic proline analogue that catalyzes thisreaction, delivering aldehydes with a quaternary center in a-position in high enantioselectivity.
A main difficulty in the aminocatalytic intermolecular a-alkylations of aldehydes with SN2-type alkylating agents is thetendency of inherently Lewis basic amine catalysts to undergoN-alkylation. This process is normally irreversible and resultsin the complete deactivation of the aminocatalyst, at leastunless SN1-reactive benzhydryl-type alkylating reagents areutilized. The unproductive catalyst-alkylation reaction isfurther enhanced by the stoichiometric base, which is addedto neutralize the strong acid formed in the a-alkylation, andwhich in principle can also be alkylated itself. The tendenciesof aldehydes to undergo self-aldolization and racemizationprovide for additional complications.
After exploring several different and yet more or lessunsuccessful strategies over the years, we hypothesized thata direct asymmetric aldehyde alkylation may be realizable, ifa-branched aldehydes are utilized, as the correspondingproducts are stable and do not undergo racemization and, ifan organic mixed acid/base “buffer” system is used instead ofa base alone. Such a reaction medium was expected 1) toaccelerate enamine formation through mild acid catalysis,2) to “neutralize” the acid by-product, and 3) to suppress thealkylation of base and/or catalyst. It has been shownpreviously that mixtures of acids and bases can be beneficialin related SN1 alkylations.[12]
Indeed, when we reacted hydratropaldehyde (1a) withbenzyl bromide (2a) in the presence of (S)-proline (3a,50 mol%) and a combination of both p-anisidic acid andH!nig"s base (diisopropylethylamine, iPr2NEt), the desiredproduct 4a could be detected for the first time (Table 1,entry 1). Essentially no product was obtained in the absenceof buffer and with acid or base alone. While both yield (12%)and enantioselectivity (51:49 e.r.) were poor and a significantamount of N-benzylated (S)-proline was still formed as a sideproduct, we were encouraged by this result. A broader screenof aminocatalysts towards improving the enantioselectivityand yield was therefore initiated. We investigated varioustypes of organocatalysts, of which selected examples aresummarized in Table 1. In contrast to what we foundpreviously in our intramolecular variant, the use of (S)-a-methylproline 3b as catalyst did not result in improved yieldor enantioselectivity (Table 1, entry 2). Imidazolidinone cata-lysts such as 3c[14] and prolinol ether catalyst 3d[15] proved tobe ineffective in catalyzing this reaction (Table 1, entries 3and 4). (S)-Proline derivative 3e and primary amino acids
Scheme 1. The catalytic asymmetric a-alkylation of aldehydes: A chal-lenge for enamine catalysis.
[*] Prof. Dr. B. List, Dr. I. Coric, P. S. J. Kaib, Dr. A. Lee, M. Leutzsch,Dr. S. Chandra Pan, M. van GemmerenMax-Planck-Institut f!r KohlenforschungKaiser Wilhelm-Platz 1, 45470 M!lheim an der Ruhr (Germany)E-mail: [email protected]
Dr. O. O. Grygorenko, Prof. Dr. I. Komarov, A. V. TymtsunikTaras Shevchenko National University of KyivVolodymyrska Street 60, Kyiv (Ukraine)
[**] Generous support from the Max-Planck-Society and the Fonds derChemischen Industrie is gratefully acknowledged. We also thank themembers of our HPLC and GC departments for their support.
Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/anie.201306037.
.AngewandteCommunications
282 ! 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53, 282 –285
3 f–h gave moderate yields but promising enantioselectivities(Table 1, entries 5–8). A cinchona-derived primary aminecatalyst (3 i) was found to be inactive in the reaction (Table 1,entry 9). This catalyst rapidly reacts with benzyl bromide andN-benzylated amines were detected by GC-MS analysis. In
a theoretical study, azabicyclic proline analogues werepredicted to give higher selectivities than simple proline inaldol reactions, due to better preorganization of the transitionstate and we reasoned that this might also be of help for our a-alkylation reaction.[16] Indeed, very interesting results wereobtained when we tested the sterically more demandingsecondary amino acid catalysts 3j–l (Table 1, entries 10–12).High enantioselectivity (93.5:6.5 e.r.) was observed in thepresence of catalyst 3 l even though the product was obtainedin modest yield (Table 1, entry 12). Amino acid 3 l wasdeveloped by the group of Komarov in 2006,[17] but had notpreviously been investigated in asymmetric catalysis.
With these intriguing results in hand, we were curiouswhether real turnover could be accomplished by optimizingthe reaction conditions. In earlier studies, we found that theadded base has a pronounced effect on both the reactivity andstereoselectivity in the a-alkylation of aldehydes. Therefore,different bases were investigated and selected examples aresummarized in Table 2.
Gratifyingly, after an extensive screening of various bases(see the Supporting Information for more details), we foundthe addition of guanidines to be beneficial (Table 2, entries 4–7). In particular, 1,1,3,3-tetramethylguanidine not only gavesome turnover but also did so with an even improved e.r.> 95:5 (Table 2, entry 6).
We also explored various acids as additives and found thatp-anisic acid consistently gave the best results (see theSupporting Information). It is noteworthy that a significantimprovement in yield and enantioselectivity was achievedwhen we used an excess of tetramethylguanidine, p-anisicacid, and benzyl bromide (5 equivalents each) under theoptimized reaction conditions.[18]
After identifying a suitable catalyst and establishingoptimized reaction conditions, we next investigated thescope of our catalytic asymmetric a-alkylation of a-branched
Table 1: Catalyst evaluation.[a]
Entry Catalyst Yield [%][b] e.r.[c]
1 12 51:49
2 10 51:49
3 n.r. –
4 n.r. –
5 65 80:20
6 52 60:40
7 46 79.5:20.5
8 55 86.5:13.5
9 n.r. –
10 20 62.5:37.5
11 22 90.5:9.5
12 25 93.5:6.5
[a] Unless otherwise noted, reactions were conducted with aldehyde 1a(0.1 mmol) and benzyl bromide 2a (0.3 mmol), catalyst 3 (0.05 mmol),iPr2NEt (0.3 mmol), p-anisic acid (0.3 mmol), 4 ! M.S. (80 mg) inchloroform (0.5 mL) at 50 8C for 120 h. [b] Determined by GC-MS usingn-dodecane as an internal standard. [c] Determined by GC analysis ona chiral stationary phase. n.r. : no reaction.
Table 2: Influence of the base.[a]
Entry Base Yield [%][b] e.r.[c]
1 DMAP 30 65:352 imidazole 33 61:393 DBU 20 79:214 1,3-diphenylguanidine 60 88:125 1,3-di-(o-tolyl)guanidine 63 90:106 1,1,3,3-tetramethylguanidine 80 95.5:4.57 2’,2’-(naphthalene-1,8-diyl)-
bis(1,1,3,3-tetramethylguanidine)80 53:47
[a] Reaction conditions: aldehyde 1a (0.1 mmol) and benzyl bromide 2a(0.5 mmol), catalyst 3 l (0.03 mmol), p-anisic acid (0.5 mmol), base(0.5 mmol), 4 ! M.S. (80 mg) in chloroform (0.5 mL) at 50 8C for 144 h.[b] Determined by GC-MS using n-dodecane as an internal standard.[c] Determined by GC analysis on a chiral stationary phase. DBU =1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP= 4-(dimethylamino)pyridine.
AngewandteChemie
283Angew. Chem. Int. Ed. 2014, 53, 282 –285 ! 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org
Asymmetric Induction
α-amina(on
• Differen2alweakinterac2onsholdsthekey
Summary
AccountsofChemicalResearch,2016(SpecialIssueonComputa(onalChemistryinOrganicSynthesis)
Computational Chemistry Group Department of Chemistry, IIT Bombay
AvtarChangotraMeghaAnandSoumiTribediVipinAbrahamSantanuMalakarSurya,K.Aswathi,R.Sukri(SinghSandipDas
ACKNOWLEDGEMENTS FUNDING
DST,CSIR,BRNSIITBombayYoung
Inves2gatorAwardScheme
IITComputerCenterforHPCfacili2es
IIT Bom
bay Dr. Shinisha, C. B. Dr. Akhilesh Sharma Dr. Garima Jindal Hemanta K. Kisan Dilna, S. Athira, C. Bhaskararao, B. Sreenithya, A. Yernaidu Reddi Monika Parek Anju Unnikrishnan