AFM, SPM
N- PROTECTED (S)-AMINO ACYL CHLORIDES
EFFECT OF N-PROTECTION
Postovsky Institute of Organic Synthesis of the Russian Academy of Sciences (Ural Division), Ekaterinburg, Russia
D.A. Gruzdev G.L. Levit
V.P. Krasnov gruzdev-da@ios.uran.ru
Acylative kinetic resolution of racemic amines is under active investigation for the last years. Previously we showed that acylation of heterocyclic amines 1a,b with N-phthaloyl-(S)-alanyl and N-phthaloyl-(S)-phenylalanyl chlorides1,2 (2a,b) leads to the predominant formation of (S,S)- amides (de up to 74%).
O NH
Me NH
Me
O NH
Me F
F
1b 1c
1a
In the present work we demonstrated that the change in N-protection from phthaloyl to 1,8- naphthtaloyl leads to the inversion of stereoselectivity. Acylation of racemic amines 1a-c with acyl chlorides 2c,d resulted in (R,S)-amides as the major diastereoisomers (de up to 68%).
N O
O Cl
O N
O
O Cl
Me
O H
N Cl
O
Ts N
Cl O O
O
N Cl
Me O O
O
N Cl
O Ts
Me
(S)-selectivity
2a 2b 2e 2c 2d 2f
(R)-selectivity
Kinetic resolution of amine 1b with acyl chlorides 2b and 2d in CH2Cl2 at +20 °C led to amides (S,S)-3 (de 60%) and (R,S)-4 (de 63%), respectively. We carried out the parallel kinetic resolution of 1b using the equimolar mixture of chlorides 2b and 2d with of the same (S)- configuration. In this case the formation of amides (S,S)-3 and (R,S)-4 (de 71 and 74%, respectively) was observed (Scheme 1).
O NH
Me
+ N
O
O Cl
O
(RS)-1b (S,S)-3
+
de71%
CH2Cl2, +20 oC, 6h
N Cl
O O
O
N N
O O
O O
Me N
N O
O Me O
+ O
(R,S)-4
2b 2d de 74%
0.5 equiv. 0.5 equiv.
PhNEt2
Scheme 1.
It was also shown that N-tosyl-(S)-phenylalanyl (2e) and N-methyl-N-tosyl-(S)-phenylalanyl (2f) chlorides exhibit the opposite stereoselectivity in acylation of amine 1c. Thus, the kinetic resolution of 1c using 2e in toluene resulted in (S,S)-amide (de 24%), while acylation of 1c with N- methylated compound 2f under the same conditions led to (R,S)-amide (de 73%).
Thus, it was shown that the minor changes in the structure of chiral acylating agent is accompanied by significant change in the stereochemical result of kinetic resolution of heterocyclic amines up to the total inversion of stereoselectivity.
References:
1. Krasnov V.P., Levit G.L., Kodess M.I. et al. // Tetrahedron: Asymmetry, 2004, 15, 859-862.
2. Gruzdev D.A., Levit G.L. Krasnov V.P. et al. // Tetrahedron: Asymmetry, 2010, 21, 936-942.
The work was financially supported by RFBR (grant 10-03-00084), the State Program for Supporting of Leading Scientific Schools of the RF (grant NSh 65261.2010.3), the State Contract 02.522.12.2011 and by the Ural Division of RAS (grants 09-P-3-2001, 09-I-3-2004, 10-3-NP-322).
2. “Chiral” Organic Chemistry: Poster presentation P-255 CHIRAL BLOCKS FROM [2+2]-CYCLOADDUCT OF
DICHLOROKETENE AND DIMETHYLFULVENE Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, Russia
N.A. Ivanova N.P. Akhmetdinova
Z.R. Valiullina V.A. Akhmetyanova
M.S. Miftakhov ivanova_NA@anrb.ru
Obtaining chiral block - synthons from available raw materials is an important
"component" of an enantiospecific synthesis of physiologically active compounds. Using as a «source of chirality» (+)-α-methylbenzylamine from [2+2]-cycloadducts dimetylfulfene and dichloroketene were developed hemorational syntheses of optically active exo- isopropylidenecyclopentenes 5a,5b и 7a,7b.
O N
H Ph CHCl2
O N
О
OH Ph
O
O О
+
Сl Cl
O
NH Ph CHCl2
O
NH Cl
Cl Ph
OHO
NH Cl
Cl Ph
OHO
O O
O O O
O
+ N
О
OH Ph
a
a,b
b,c
Reagents:
a. (+)-α-PhMeCHNH2; b. SiO2; c. NaHCO3.
Cl Cl
Cl Cl C O
(±)-2
(±)-1 3a 3b
5a 4a 4b 5b
6a
6b
7a
7b
This work was supported by the state contract the Ministry of Education and Science
№ 4.740.11.0367 (with BashSU).
2. “Chiral” Organic Chemistry: Poster presentation P-256 NEW POLYHYDROXYAMINOCYCLOHEPTANES AS
A PERSPECTIVE GLYCOSIDASE INHIBITORS Moscow State University, Chemistry Department, Moscow, Russia D.A. Khlevin
S.E. Sosonyuk M.V. Proskurnina
N.S. Zefirov hlevin@mail.ru
Stereoselective approach to polyhydroxyaminocycloheptanes as potential glycosidase inhibitors from available diketone (1) [1] was proposed. Introduction of amino function in 8-oxabicyclo[3.2.1]octane framework was intriguing as the route to calystegine analogs – potential glucosidase inhibitiors [2]. Reduction of diketone (1) by DIBAL-H followed by dechlorination led to a separable mixture of ketoalcohol stereoisomers (3a) and (3b).
CH3 Cl O
OH
2 O
Zn, AcOH 50oC, 30 min
O OH
O CH3
3a
O OH
O CH3
3b 74 %
5:2 CH3
Cl O
O
O
1
DIBAL-H (1.5 eq) THF, rt, 1h
72 %
The major isomer (3a) was involved in a reductive amination process. Amine (5) was separated from the reaction mixture as individual isomer. We assume it could be transformed to a potential glycosidase inhibitor by double bond bishydroxylation.
3a O
OH
NOH CH3
4.87%
O OH
NH2 CH3
5,68%
major isomer NH2OH-HCl
Py, MeOH 50oC, 5 h
Zn, HCOOH 60oC, 2 h
O OH
NH2 CH3 HO
HO
Expanding our strategy we have developed a route to monocyclic cycloheptane derivatives. Benzyl protected diol (6) was synthesized from compound (1), then using DIBAL-H mediated reductive ring opening in the presence of nickel complexes unsaturated compound (7) was obtained. We consider this alcohol as a precursor for aminoderivatives with the structure close to some known glycosidase inhibitors [3].
CH3 O
OBn
6 OBn
1) DIBAL-H Ni(acac)2, toluene-hexane, rt
2) DIBAL-Cl reflux, 3h 68% (2 steps)
HO OBn
OBn CH3
7
R OH
OH CH3
1
1) Zn, AcOH 50oC, 30 min 2) NaBH4,MeOH 3) BnBr, NaH, THF
rt, 24 h 36 % (3 steps)
R
R R=OH or NH2
Configuration of products was determined by X-ray and NMR experiments.
Proposed strategy is flexible and allows to obtain a wide range of mono- and bicyclic aminopolyols with different given regio- and stereochemistry.
References:
1. Tafeenko, V. A., Aslanov, L. A., Proskurnina, M. V., Sosonyuk, S. E., Khlevin, D. A. Acta Cryst. 2009.
E65, 1580
2. Asano, N., Nash, R. J., Molyneux, R. J., Fleet, G. W. J. Tetrahedron: Asymmetry. 2000, 11, 1645–1680 3. Gravier-Pelletier, C., Maton, W., Dintinger, T., Tellier, C., Le Merrer, Y. Tetrahedron. 2003. 59, 8705-8720.
2. “Chiral” Organic Chemistry: Poster presentation P-257 SYNTHESIS AND MEMBRANE TRANSPORT
PROPERTIES OF OPTICALLY ACTIVE α-AMINOPHOSPHINE OXIDES
Kazan Federal University, A.M. Butlerov Institute of Chemistry, Kazan, Russia
S.A. Koskin A.R. Garifzyanov
R.A. Cherkasov scioris@yandex.ru
In recent years the increased interest to aminophosphine oxides due to their ability to form the different structure complexes that allowing use them in the processes of liquid and membrane extraction of inorganic and organic substrates. Besides presence of optically active centers and centers of specific interaction in molecules enables apply α-aminophosphine oxides for concentration and separation of optical isomers of organic compounds.
Therefore we have developed a method of synthesis the functionalized α-aminophosphine oxides based on a three-component Kabachnick-Fields reaction with formaldehyde, phosphinic acid, amines or amino acid. The introduction of chiral centers in the α-aminophosphine oxides carried out by involving to Kabachnik-Fields reaction of reagents with chiral carbon and phosphorus atoms – (R)-, (S)-methylbenzylamines, (S)-alanine, (S)-valine, (S)-leucine, (S)-glutamic acid and mixtures of enantiomers decylphenylphosphinic acid. The synthesis conditions were chosen to achieve maximum yield (85-95%). Enantiomers of compounds derived from racemic decylphenylphosphinic acid were separated by crystallization of tartrates. The structure of the obtained compounds was conformed by 1H NMR, IR-spectroscopy.
For obtained (R)- and (S)-didecyl-(N-1-phenylethanamino)methylphosphine oxides have been studied the membrane transport of the tartaric and aspartic acid stereoisomers (Table) and stereoselectivity of the transfer found.
Flow*106 mol*min/m2
Tartaric acid Aspartic acid Carrier
D-form L-form D-form L-form
(R) 17.4 13.6 1.75 4.70
C10H21 P C10H21
O CH2
NH CH Ph
CH3 (S) 6.43 10.27 6.33 3.66
2. “Chiral” Organic Chemistry: Poster presentation P-258 PHENYLETHANOL, PHENYLETHYL AMINES AND AMINOSILANES CONTAINING CHIRAL CENTRES
IN THIOPHOSPHORILATION REACTIONS 1 - Kazan (Volga region) Federal University, Kazan, Russia
2 - A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan, Russia
Ye.M. Martianov1 L.A. Almetkina1
I.S. Nizamov1 R.A. Cherkasov1 D.B. Krivolapov2
I.A. Litvinov2 isnizamov@mail.ru
Tetracoordinated phosphorus organic thioacids, their ammonium salts and esters containing chiral centres are interest from the point of fundamental organic chemistry and the development of facile methods of obtaining new products with biological activity. The interest in chiral tetracoordinated phosphorus organic thioacids and their derivatives is due to their potential metabolic regulation activity. We have obtained racemic dithiophosphoric and aryldithiophosphonic acids by the reactions of tetraphosphorus decasulfide and 2,4-diaryl 1,3,2,4-dithiadiphosphetane- 2,4-disulfides with R,S-α-phenylethanol. These thioacids were transformed into the corresponding ammonium salts by the treatment of ammonia and (S)-(-)-(α -phenylethyl) amine.
S S S
S
S S H Ar
S Ar Ar-P P-Ar + 2
Ar = HO
NH3 * Ph
Me HO
H4NS
O ,
P-O * Ph Me
P-O * Ph Me
Aminosilanes obtained on the basis of enantiomeric pure (S)-(-)-(α-phenylethyl) amine, (R)- (+)-(α-phenylethyl) amine and racemic α-phenylethyl amine were also involved in the reactions with 2,4-diaryl 1,3,2,4-dithiadiphosphetane-2,4-disulfides to form S-trimethylsilyl esters of amino- dithiophosphonic acids.
S S S
S
Me3SiS S C Ar
Ph
H
C Ph
H Ar-P P-Ar + 2
Ar = O , HO
Me3SiNH * P- Me S-(-)
NH * Me S-(-) 2
*
The reaction of O,O-diethyl dithiophosphoric acid with (R,S)-α-phenylethylamine serve as a method for obtaining dithiophosphates bearing a chiral centre in the alkylamine fragment.
EtO S
EtO S
H C
Ph
H H
* Ph
Me H2N
EtO
P-SH EtO
P-S_
R,S- N *
Me H +
Its structure was established by X-ray single crystal diffraction.
2. “Chiral” Organic Chemistry: Poster presentation P-259 HIGH PERFORMANCE NMR ANALYSIS OF
ENANTIOMERIC PURITY AND ABSOLUTE CONFIGURATION OF CHIRAL ALCOHOLS AND
AMINES ON A MICROGRAM SCALE Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, NMR Laboratory, Moscow, Russia