BUDAPEST UNIVERSITY OF TECHNOLOGY AND ECONOMICS FACULTY OF CHEMICAL AND BIOENGINEERING
GEORGE OLAH PHD SCHOOL
Synthesis of optically active 3-, 4- and 5- membered N- and O- heterocycles using stereoselective organometallic reactions
Theses
Written by: Ferenc Farkas
Supervisor: Prof. Dr. Ferenc Faigl Consultant: Dr. AngelikaThurner
Department of Organic Chemistry and Technology
2010
1. Introduction
Synthesis and stereoselective rearrangements of 2,3-disubstituted oxiranes (1) have been investigated in the research group of the Department of Organic Chemistry and Technology since 1996. Experimental results have shown that functionalized oxiranyl ethers 1 can be converted into hydroxy oxetanes (2) and cis-but-2-ene-1,4-diol derivatives (3) by treatment of 1 with organometallic bases. The rearrangement reactions are completely diastereo- and enantioselective. Consequently, the products (2 and 3) could be prepared in optically active form if the starting material 1 would be available in optically active form.
O
OH R
OH H OH
R O
R O
BuLi / DIA / tBuOK 1:1:1
4 BuLi
BuLi / DIA / tBuOK 3:1:1 25°C
25oC -75°C
1a-d 2a-d
3a-d
R a: piperidino b: diethylamino c: dibenzylamino d: triphenylmethoxy
Furthermore, compounds 2 and 3 could serve as valuable intermediates in the synthesis of optically active five membered heterocycles (e.g. pyrrolidines and tetrahydrofuranes).
The primary aim of this thesis is to elaborate efficient methods for the synthesis of new optically active oxiranes like 1, and to use them in the above mentioned organometallic base promoted rearrangements. These studies can
confirm the preliminary observed high stereoselectivities of the reactions, can show the scope and limitation of the methods. In addition, numerous new optically active oxetane and cis-but-2-ene-1,4-diol derivatives can be prepared. The secondary motivation of my work is to investigate chemical transformations of the optically active products 2 and 3 into optically active di- or trisubstituted heterocycles. These latter compounds could be used as chiral tools in the synthesis of pesticides and API-s (active pharmaceutical ingredients).
2. Experimental methods
Conventional methods of preparative organic chemistry were used in synthesis. Schlenk technique (continous dry nitrogen or argon flow) was applied in case of organometallic reactions. Crystallization and/or column chromatography were applied in order to purify the crude products.
The new compounds were indentified by conventional spectroscopic methods (IR, 1H and 13C NMR, MS, HRMS). In addition two-dimensional NMR technique and elemental analysis were applied in some cases.
3. New scientific results
Major new results of my research work are as follows:
3.1. Crystallization time dependent efficiency of optical resolution of dialkyl- aminooxiranes (1a-b)
Starting from the previous findings of our research group, optical resolutions of racemic 1a and 1b aminooxiranes were accomplished with O,O’- dibenzoyl-(R,R)-tartaric acid monohydrate in ethyl acetate.
O
N O
O
N O
1a 1b
During optimization experiments a rare kinetic effect in resolution process was discovered: ee values of the bases 1a an 1b, found in the crystallized diastereoisomeric salts, depended on the duration of crystallization.
Based on that observation, optimal crystallization times were determined (48-72 hours) and the efficiencies of the resolution processes were improved.
3.2. Enzymatic resolutions
New, enzyme catalyzed kinetic resolution of 4 was developed (ee = 97
%). Optical isomers of 4 were used as starting materials in the synthesis of enantiomerically pure 1-benzyloxy-4-substituted-2,3-epoxybutanes.
O
OH OBn
O O R
O
O
OBn R
O
H H
O
OH OBn
H H
O
OBn OH
H H
resolution
R = Me, Et, Pr
+ 4
(+)-(2R, 3S)-4 (-)-(2S, 3R)-5
R = Me (5a) R = Et (5b) R = Pr (5c)
(-)-(2S, 3R)-4
In order to find the optimum reaction conditions, the influence of solvent and acylating reagent was investigated. The reaction was the fastest in a
1 to 1 mixture of hexane and tetrahydrofuran and vinyl butyrate was the best reagent for PPL (porcine pancrease lipase) catalyzed reactions. The (-)-4 enantiomer (ee > 99) was also prepared via PPL catalyzed alcoholysis of (-)- 5a.
Enantioselective rearrangement of a tritylated oxirane derivative 6 was also investigated, therefore the enzyme-catalyzed kinetic resolution of rac-6 have been carried out in my research work.
O
OCPh3OH O
O
O
OCPh3O O H H
O
OCPh3OH H H
O
OCPh3OH H H
6
THF, enzyme
+
(+)-(2R,3S)-6
Amano Lipase PS
(-)-(2S,3R)-6 (-)-(2S,3R)-7
H2O, phosphate buffer
On the basis of the test reactions two enzymes (Lipozyme TL IM, Amano Lipase PS) showed appropriate enantioselectivities in the esterification with vinyl acetate (ee > 99 %). Pure (-)-6 (ee > 99 %) was obtained via Amano Lipase PS catalyzed hydrolysis of (-)-7 in acetonitril / water mixture.
2-Methylbut-3-yne-1,2-diol (8) can be used as building block in the synthesis of biologically active compounds. On the basis of my experience in the enzymatic resolutions of compounds 4 and 6, lipase catalyzed esterification and/or hydrolysis seemed to be the best way to prepare optically active 8. Racemic 8 was synthesized from 2-methylbut-1-en-3-yne via epoxidation followed by acid catalyzed hydrolysis. Then a new method was developed for enantiomer separation by double enzymatic resolutions.
OH OH
OH O
O
OH OH
8
THF, vinyl butyrate
(-)-(R*)-9
Candida Cylindracea lipase Amano Lipase A phosphate buffer H2O
(S*)-8
In the first step rac-8 was acylated in presence of Candida cylindracea lipase (ee = 33 %), then the enantiomeric excess of (-)-9 was increased by Amano Lipase A catalyzed hydrolysis of (-)-9. Practically pure product ((S*)-8, ee = 95 %) was obtained by a base catalyzed hydrolysis of the unreacted (-)-9.
3.3. Rearrangement reactions
The prepared new optically active oxiranes (4, 6) were transformed into novel optically active oxetane (2c-e) and diol (3e) derivatives by the before mentioned organometallic base catalyzed enantioselective rearrangement reactions.
O R
H H
OH O
R
H H
OBn
H OH R H OH BuLi / DIA / tBuOK 1:1:1
4 BuLi 25oC -75 °C
(2R,3R,1'R)-2c-e ee: 100 %
(R)-3d (2S,3R)-1c, e ee: 100 %
1 2 1' 3 2'
R c: dibenzylamino d: triphenylmethoxy e: N-benzyl-N-methylamino (2R,3S)-1d
3.4. Enantioselective synthesis of heterocycles
According to my aims, the optically active oxetane (2c-d) and diol (3e) derivatives were applied as starting materials in the novel synthesis of several optically active heterocycles.
Dihydropyrrole 11 was obtained from 3e in two steps. First the hydroxyl groups of 3e were activated with mesyl chloride, then 10 was treated with benzylamine.
NH2 OMes
Ph3CO Ph
OMes
N OCPh3 Ph
O OCPh3 K2CO3 / acetonitrile Ph
10 11
Bn
+
12
Surprisingly, formation of significant amount of dihydrofuran (12) was observed beside the product 11.
In order to study the diastereoselectivity of acetal formation reactions, triol 13 was prepared by deprotection of 3e. Then compound 13 was treated with benzaldehyde.
CHO
O O
OH Ph
H Ph
O O Ph OH
H Ph
O
OH Ph
O Ph H OH
OH Ph
OH
DCM, TsOH
+ +
molecular sieve
14 15 16
13
I wanted to indentify the structure of the main product of acetal formation therefore synthesis of 17a-b diastereoisomers was also performed.
O O
Ph H
Ph
OBz O O
Ph H
Ph
OBz
17a 17b
Comparison of the NOESY spectra of dioxolanes 17a, 17b and 14 let me concluded that cis-14 acetal was formed diastereoselectively.
An interesting solvent effect was observed in course of hydrogenation of benzoylated trityl-oxetane (18). Compound 18 was prepared by benzoylation of 2d. Catalytic hydrogenation of 18 provided 20 in good yield when the reaction was carried out in a methanol / dichloromethane mixture. Experimental results showed, that acid catalyzed hydrolytic decomposition of the trityloxy group from 19 resulted in the formation of 3,4-disubstituted tetrahydrofuran (22). Rational explanation of the crucial role of dichloromethane could be given when I have taken into account that there are traces of hydochloric acid in the solution which could be formed by reductive dehalogenation of the solvent.
O H
OBz OH Ph3CO Ph
OBz OH Ph Ph
O Ph3CO Ph
H H OBz
H2/Pd/C, 10bar, 25°C
(-)-(2S,3R)-19
+
(+)-(2S,3R)-20
1 2 1' 3 2'
(+)-(2R,3R,1'R)-18
3
4 2
1 1
3 2 4
Synthesis of a new optically active pyrrolidine derivative (21) was accomplished starting from (+)-20 in two steps. Hydroxyl groups of 20 were changed to better leaving groups with thionyl chloride, afterwards ring closure was performed by tosylamide. The optically active tetrahydrofuran derivative (22) was synthesized by Mitsunobu reaction.
OH
OBz O Ph H N
Ph OH
SO2 NH2
O
Ph OBz
(+)-(2S,3R)-20 1. SOCl2
THF/TEA
Ts
2.
(+)-(3R,4S)-21
Ph3P, DEAD THF
(+)-(3S,4R)-22
3 4
Optically active oxetane (2c) was also useful intermediate of the enantioselective synthesis of pyrrolidine derivatives. In the first step, the secondary hydroxyl group was protected by benzoylation (23), then an amino alcohol (24) was prepared by catalytic hydroganation. The 3,4-disubstituted pyrrolidine (25) was obtained by Mitsunobu reaction. The pyrrolidine can be used as building block in the synthesis of Balanol analogs (anticancer agents).
N H2
O H
OH Ph Ph
O Ph
H N H
Ph
Ph OBz
N H Ph OBz H2/Pd/C
13 bar, 8 h MeOH
(-)-(2S,3R,1'S)-23 (2S,3R)-24
1 3 2 2'1'
3 2
Ph3P, DEAD THF
(-)-(3S,4R)-25
3 4
5. Theses
1. I have found that the enantiomeric excesses of cis-2-dialkylaminomethyl-3- benzyloximethyl-oxiranes in their O,O’-dibenzoil-(R,R’)-tartaric acid salts depended on the duration of crystallization. On the basis of this finding, new efficient resolution methods were developed to prepare pure cis-2- dialkylaminomethyl-3-benzyloximethyl-oxirane enantiomers [1].
2. I elaborated a new optical resolution process for the separation of the enantiomers of cis-2-benzyloxymethyl-3-hydroxymethyl-oxirane. Due to that enzyme catalyzed kinetic resolution I could prepare numerous new, optically active oxirane derivatives [2, 5].
I have also accomplished the very first optical resolution of cis-2- hydroxymethyl-3-trityloxymethyl-oxirane. The pure enantiomers were used as starting materials in the synthesis of cis-2-benzyloxymethyl-3-trityloxymethyl- oxirane enantiomers. Furthermore, these chiral compounds can be used in the synthesis of other new oxirane derivatives by modification of the hydroxymethyl group [3, 5].
In addition, I have developed a new enzyme catalyzed kinetic resolution process for the separation of the optical isomers of 2-methylbut-3-ine-1,2-diol.
3. My experiments confirmed that the prepared optically active oxirane derivatives undergo enantioselective rearrangements in the presence of organometallic bases. That synthetic method was used in the preparation of several new, optically active oxetane and cis-but-2-ene-1,4-diol derivatives [2, 3, 5].
4. I recognized a tetrahydrofurane forming side reaction which occured during the chemical transformation of (Z)-2-phenyl-5-trityloxypent-2-ene-1,4-diol into a dihydropyrrole derivative. Starting from that finding I accomplished the synthesis of the above mentioned tetrahydrofurane derivative, too [6].
5. I prepared a new dioxolane derivative via diastereoselective acetal forming reaction. The structures of the diastereoisomers of 2-phenyl-4-(2-phenyl-3- benzoyloxyprop-1-enyl)dioxolane were confirmed by their NOESY spectra [7].
6. I have found that chemoselectivity of the catalytic hydrogenation of 3-(2- trityloxy-1-benzoyloxyethyl)-2-phenyloxetane depends on the quality of solvent. I have shown experimental evidences of hydrolytic detritylation in the presence of trace amount of acids. Crucial role of dichloromethane in that hydrogenation could be explained by reductive dehalogenation of the solvent which provides catalytic amount of hydrochloric acid for fast detritylation of the model compound [4].
7. I developed two new enantioselective routes for the transformation of optically active oxetanes into 3-benzyl-4-benzoyloxypyrrolidines and tetrahydrofuran derivatives [6].
6. Applicability of the results
The developed new resolution methods and enantioselective reactions have been applied in laboratory scale, until now. These experiments provided novel routes to several intermediates of biologically active compounds, too. For example, optically active 3-benzoyloxy-4-benzylpyrrolidine can be used as a building block in the synthesis of Balanol analogs (known as an anti-cancer agents). Optically active 2-methylbut-3-yne-1,2-diol – after methylation of its primary hydroxyl group – could be applied in the synthesis of a pharmaceutically important compound. Several among the prepared new heterocycles could be used as chiral ligands, too.
My findings, such as the time dependent efficiencies of diastereoisomeric salt forming resolutions or the new enzymes catalyzed consecutive kinetic resolution method may help to solve similar problems in this research field. The new, highly
selective organometallic reactions and the selective detritylation method can be used as tools in realization of similar chemical processes.
7. Articles and presentations
7.1. Publications written in English
1. F. Faigl, A. Thurner, F. Farkas, Á. Proszenyák, M. Valacchi, A. Mordini:
Time dependent efficiency of optical resolution of aminooxiranes with O,O’-dibenzoyl-(R,R)-tartaric acid
Arkivoc, (vii), 53-59 (2004) (IF: 1,377)
2. F. Faigl, A. Thurner, M. Battancs, F. Farkas, L. Poppe, V. Bódai, I. Kmecz, B. Simándi:
Efficient, scalable kinetic resolution of cis-4-benzyloxy-2,3-epoxybutanol Tetrahedron: Asymmetry, 16, 3841-3847 (2005) (IF: 2,796)
3. F. Faigl, A. Thurner, F. Farkas, M. Battancs, L. Poppe:
Synthesis and enantioselective rearrangement of (Z)-4-triphenylmethoxy-2,3- epoxybutan-1-ol enantiomers
Chirality, 19, 197-202 (2007) (IF: 2,212)
4. F. Farkas, A. Thurner, E. Kovács, F. Faigl, L. Hegedűs:
Hydrogenolysis of O-protected hydroxyoxetanes over palladium: An efficient method for a one-step ring opening and detrytilation reaction Catalysis communications, 10, 635-639 (2009) (IF: 2,791)
7.2. Publications written in Hungarian
5. F. Farkas, M. Battancs, A. Thurner, B. Simándi, L. Poppe, F. Faigl:
Racém (Z)-2,3-epoxibutanol-származékok enzimkatalizált kinetikus rezolválása (Enzyme catalyzed kinetic resolution of racemic (Z)-2,3- epoxybutanol derivatives).
Műszaki szemle, 39-40, 13-16 (2007)
6. F. Faigl, F. Farkas, E. Kovács, A. Thurner, L. Hegedűs, A. Mordini:
Racém 2,3-epoxibutanol-származékok rezolválása és enantioszelektív
átrendeződési reakciói (Optical resolution and enantioselective rearrangements of racemic 2,3-epoxybutanol derivatives).
Magy. Kém. Folyóirat, 114, 114-119 (2008)
7. E. Kovács, F. Farkas, L. Hegedűs, Á. Szöllősy, A. Thurner, F. Faigl:
Új, királis, nitrogén- és oxigéntartalmú heterociklusos vegyületek
enantioszelektív szintézise (Enantioselective synthesis of new, chiral nitrogen- and oxygen-containing heterocycles).
Műszaki szemle, 38, 270-275 (2008)
7.3. Conference presentations
1. A. Thurner, F. Farkas, M. Battancs and F. Faigl:
Organometallic Approach to the Synthesis of New Optically Active Oxetane a and Pyrrolidine Derivatives.
XVI. FECHEM Conference on Organometallic Chemistry, Budapest, September 2005. Poster presentation.
2. F. Faigl, A. Thurner, B. Feldhofferné Vas, F. Farkas:
Új királis pirrol- és pirrolidin-származékok szintézise (Synthesis of new chiral pyrrole- and pyrrolidine derivatives).
MTA Terpenoidkémiai és Elemorganikus Munkabizottság Ülése, Budapest, 2005 szept. Oral presentation.
3. F. Farkas, M. Battancs, A. Thurner, B. Simándi, L. Poppe, F. Faigl:
Racém (Z)-2,3-epoxibutanol-származékok enzimkatalizált kinetikus rezolválása (Kinetic resolution of racemic (Z)-2,3-epoxybutanol derivatives).
12th International Conference of Chemistry, Hung. Technical Scientific Society of Transylvania, Cluj, 2006. Poster presentation.
4. F. Farkas, A. Thurner, E. Kovács, F. Faigl:
Enantioselective synthesis of new, chiral, four- and fivemembered O- and N- Heterocycles.
12th International Conference of Chemistry, Hung. Technical Scientific Society of Transylvania, Cluj, 2006. Poster presentation.
5. F. Faigl, F. Farkas, A. Thurner, G. Tárkányi, A. Mordini:
Novel Methods for the Synthesis of Optically Active Oxirane, Oxetane and Pyrrolidine Derivatives.
7th Korea-Hungary Symposium on Organic Chemistry, Budapest, 2007. Oral presentation
6. F. Farkas, A. Thurner, E. Kovács, L. Hegedűs, Á. Szöllősy, F. Faigl:
Új, királis, négy-, és öttagú heterociklusok enantioszelektív szintézise (Enantioselective synthesis of new four- and five-membered heterocycles).
MKE Centenáriumi Vegyészkonferencia, Sopron, 2007. Poster presentation.
7. F. Farkas, A. Thurner, E. Kovács, L. Hegedűs, F. Faigl:
Optikailag aktív heterociklusok előállítása (Synthesis of optically active heterocycles).
Műszaki Kámiai Napok `08, Veszprém, 2008. Oral presentation.
8. F. Farkas, A. Thurner, E. Kovács, L. Hegedűs, Á. Szöllősy, F. Faigl:
Új, királis oxigén- és nitrogéntartalmú heterociklusos vegyületek enantioszelektív szintézise (Enantioselective synthesis of novel O- and N- heterocyclic compounds).
14th International Conference of Chemistry, Hung. Technical Scientific Society of Transylvania, Cluj. 2008. Poster presentation.
