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pyridine system diastereoselective synthesis of β-amino-α-hydroxyesters
Tetrahedron Letters, Vol. 36, No. 33, pp. 5955-5958, 1995 Elsevier Science Ltd Pnnted in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)0115 I-X
A Tricomponent Reaction Promoted by a Titanium Trichloride/Pyridine System Diastereoselective Synthesis of lS-Amino-~-hydroxyesters
Angelo Clerici, Laura Clerici and Ombretta Porta* Dipartimento di Chimica del Politecnico, Via Mancinelli 7, 20131
lvIilano, Italy
Methylphenylglyoxylale,aniline and aromaticaldehydes,on treatmentwith TiCl3/pyridinein anhydrous THF at room temperature, undergo rapid condensation to produce syn-13-amino-cthydroxyesters.The mechanismof the reactionis rationalized.
Abstract:
13-Amino~-hydroxyacids are of considerable importance because they are incorporated into many biologically active peptides, such as bestatin, l, 2 amastatin,2 norstatine3 and taxol. 4 Consequently, in recent years much attention has been devoted to the synthesis of these molecules, as potential useful intermediates, for the construction of new enzyme inhibitors.5 We report herein our preliminary model studies regarding the syn-diastereo-controlled synthesis of the title compounds 4 by a "one pot" condensation of three components (methyl phenylglyoxylate 1, aniline 2 and aromatic aldehydes 3) promoted by the TiCl3/PYr system in anhydrous TIlT at room temperature (Eq. 1).
-J~ MeO
Ph
+
PhNI'I2 +
H~
Ar
O 1
2
3
Ti(III)'THF Pyr, r.t. P-
0 Ph NHPh MeO Ar HO
(I)
syn-4 (53-67%)
This reaction, in which the aldehydic oxygen atom is directly replaced by an amino and an ct-subtituted benzyl group is closely related to the classical tricomponent Mannich reaction.6 After optimization, the following proved to be the best experimental conditions: a 1M TiCI3-THF/CH2CI2 (2:1) solution7 (5 mmol) was added, in one portion, with a syringe to a solution containing equimolar amounts of 1, 2 and 3 (2.5 mmol) in anhydrous TI-IF (10 mL) and pyridine (3 mmol) under nitrogen, at room temperature, with stirring. The blue colour of Ti(III) instantly discharged with the formation of a yellow precipitate.8 Half an hour later, upon quenching the reaction mixture with H20, the yellow precipitate dissolved. The aqueous layer was extracted with EtOAc, the combined extracts were washed with 1-120, dried over Na2SO 4 and evaporated i n v a c u o . By dissolving the thick-liquid residue in the appropriate solvent, the 13-amino-tx-hydroxyester 4 crystallized out as white crystals, on standing. Yields of isolated product, melting points and solvents of crystallization of 4a-e are shown in the Table. 5955
5956
An X-ray diffraction analysis9 of 4c showed that the structure corresponds to a simple syndiastereoselectivity. By analogy with 4c and by assuming an analogous topology in the transition state, compounds 4a, 4b, 4d, and 4e should have syn relative configuration also. Neither TLC nor 1H NMR analysis of the crude reaction mixture revealed the presence of the anti isomer, the only by-products being methyl mandelate 5 (12-14%) and dimethyl diphenyltartrate 6 (5%). Table Yields (%) of syn-l~-Amino-ct-hydroxyesters4a under Different Conditions Entry
Substrates
Isolated Yieldb (%)
Yield
(%)
mp (°C) (Solvent)
(ref to conv.)c a
1 + 2 + C6HsCHO
53
76
a'
1 + C6H5CH=N-Ph
40
54
b
1 + 2 +p-CH3C6H4CHO
67
75
b'
1 + 2 +p-CH3C6H4CHOd
38
55
c
1 + 2 +p-Br-C6H4CHO
61
76
c'
1 + p-Br-C6H4CH=N-Ph
48
60
d
1 + 2 +p-CN-C6H4CHO
63
82
d'
1 + p-CN-C6H4CH=N-Ph
54
72
e
1 + 2 + o-CH30-C6H4CHO
64
80
4a 188-9 (CHCI3)
4b 172 (Et20)
4c 144-6 (hexane/ Et20)
4d 150-2 (MeOH)
4e 125-6 (p. ether)
aAll products 4 have spectralcharacteristics(IH NMR, IR and MS) in agreementwith the structures proposed, blsolatedyield is based on the starting 1. Cyield is referredto the converted1. dpyridinewas not used as an additive. Pyridine was essential to achieve good yields of 4: in its absence, the yields of 4 strongly decreased in favour of the formation of 5 (entry b' and comparable results obtained with other aldehydes). 10 Mechanistically, the first step of the reaction involves the dimefization of 1 to A, via single electron transfer process (SET). A sequential Ti(IV)-catalyzed intramolecular heterolytic cleavage of A 11 regenerates 1, which is reduced back to A by the excess of Ti(III) and forms the stabilized Ti(IV)-ene diolate B, that is assumed to be the reactive intermediate in the formation of 4 (Scheme). Ti(IV)-ene diolate B, which may be formed either by Ti(IV)-catalyzed cleavage of dimethyl diphenyltanrates 611 or by Ti(III)-reductive dimerization of 1, followed by Ti(IV)catalyzed intramolecular cleavage of A in tandem, 12 undergoes diastereoselective aldol reaction with aromatic and aliphatic
5957
aldehydes I 1,12 and ketones, 13 provided that Pyr is present, 10 affording syn-et, l~-dihydroxyesters 7 (50*4 yield, starting from 6 and TiCI4; 60-94% yield, starting from 1 and TiCi3). Scheme
O 2 MeO~'~Ph + 2 T i ( l l l ) ~ O "-~1i(1V) MeOu
m,,v, O\"O
l OH J --~'~(IV)'THF~Pyr PIt I
e,n OMe
H20
OH I Ph
CO2Me CO2Me
A
6
iv Ph
Ph--~--H CO2Me
~ OMe
OH
2+3
CO2Me 7
I
syn-4 Nevertheless, when aniline was added to the reaction mixture, in equimolar amount with the aldehyde, formation of 7 was completely suppressed, 4 being formed instead (40% yield, starting from 6 and TiCI414; 53-67% yield, starting from I and TiCI3, Table). Very likely, aniline possesses a higher nucleophilic power than the enolate B, so that the aldehyde does not take part in an aldol reaction with B, but rather condenses with aniline itself affording the reactive counterpart of B in the formation of 4 (Eq. 2).
PhNH2 + 2
o--ri(IV)
Ar
3
~
~
PhNH
L
"fi(IV) ~
ArH C
~ PhN::~
II[
B]
8
"I](IV)(OH2)
/
(2)
syn-4 It must be highlighted that Ti(III) is a highly specific catalyst for these tricomponent reactions because, almost uniquely, it can perform three functions: a) as a reducing agent it promotes the one-electron dimerization of 1, b) having done this, in its higher oxidation state, Ti(IV), catalyzes the heterolytic cleavage of A, and c) by coordinating the aldehydic oxygen atom, it would prepare the carbonyl group for the attack by an amine. 15 Surprisingly, 16 the reaction with preformed arylimine 8 afforded lower yields of 4 than the tricomponent condensation (entries a', c', and d'). The high yields of dimer 6 (17-34 %) obtained in this two-step variant of the reaction would suggest that the imine, when present at higher concentration than that generated under
5958
equilibrium conditions (Eq. 2), may irreversibly complex with Ti(IV) 17 hampering further formation o f the chelate complex A, a pre-requisite for the heterolytic cleavage to occur. A n o t h e r possibility is that the tricomponent reaction would rather occur by an SN2 mechanism, in which the enolate B directly displaces the T i ( I V ) O H group from the intermediate titanated N,O-hemiacetal C. lg Efforts to extend the scope and utility o f this reaction further are presently being made in our laboratory. Acknowledgements
Financial support
o f this work
from Progetto
Strategico
"Tecnologie
Chimiche
Innovative", Centro Nazionale delle Ricercbe is gratefully acknowledged.
REFERENCES AND NOTES
1. Kabayashi, S.; Isob¢, T.; Ohno, M. Tetrahedron Lett., 1984, 25, 5079. 2.
Herranz, R.; Castro-Flchel, J.; Vinuesa, S.; Garcia Lopez, T. J. Org. Chem. 1990, 55, 2232.
3.
Dagger, R~ W.; Ralbowsky, J. L.; BryanL D.; Commander, J.; Masset, S. S.; Sage, N.; S¢lvidio, J. R. Tetrahedron Lett. 1992, 45, 6763.
4.
Jefford, C. W.; Wang, J. B.; Hin Lu, Z. Tetrahedron Lett. 1993, 47, 7557 and references cited therein.
5.
Palomo, C.; Aizpurna, J.; Cuevas, C. J. Chem. Soc. Chem. Comm. 1994, 1957 and references therein cited.
6.
For a review on Mannich reaction see: Tramontini, M. Synthesis, 1973, 703; Tramontini, M.; Angiolini., L. Tetrahedron
7.
Solutions ofTiCl 3 in THF/CH2CI 2 (1:2) are stable for long periods provided air and moisture are excluded, and, now,
1990, 46, 1791. commercially available. 8.
The yellow precipitate is an adduct of Ti(IV). Its IH NMR (DMSO) spectrum evidences the presence of THF and Pyr in the ratio 1:4. It is very sensitive to moisture and is completely destroyed by quenching the reaction with H20.
9.
Malpezzi, U Acta Cryst., sect. C, submitted for publication.
10. We believe that Pyr, a strong donor ligand, by saturating the coordinative valences of Ti(IV) in B would increase the electron density at titanium and, hence, the nucleophilic reactivity of the ene-diolate. 11. Cierici, A.; Cierici, L.; Porta, O. J. Org. Chem. 1995, 60, 480. 12. Clerici, A.; Clerici, L.; Porta, O. Tetrahedron, submitted for publication. 13. Unpublished results of this laboratory. 14. Equimolar amounts of 6, 2, and benzldehyde (0.6 mmol) were treated with a 1M TiCI4-CH2C! 2 solution (1.4 retool) in anhydrous THF (6 mL) and Pyr (1,7 retool) under N 2 at r.t. Workup as nsnal afforded 4a, 5, and I in 40, 10, 50 % yield, respectively. 15. Ti(IV) has been shown to facilitate the formation of enamines and imines in anhydrous solvents. White, W. A.; Weingarten, H.; d. Org. Chem. 1967, 32, 213; Weingarten, H.; Chupp, J. P.; White, W. A. 1bid. 1967, 32, 3246; Desai, M. C.; Thadeio P. F. TetrahedronLett. 1989, 30, 5223; Carlson, R.; Larson, U.; Hansson, L. Acta Chem. Scand. 1992, 46, 1211.
16. Enolate-imine condensations have been widespread investigated becanse of their application to [~-Iactam syntheses. For a review see: Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1; Trost, B.; Fleming, J. Comprehensive Organic Synthesis, Pergamon Press: Oxford, 1991; Vol. 2, pp. 893-951.
17. When the preformed arylamines were used as subtrates, a completely different colour change was observed during the reaction: from blue to green, and the yellow precipitate, obtained in the tricomponent condensation, was not formed. 18. Seebach, D.; Betschart, C.; Sehiess, M. Helv. Chim. Acta 1984, 67, 1593; Betschart, C.; Seebach, D. Ibid. 1987, 70, 2215.
(Received in U K 6 April 1995; revised 21 June 1995; accepted 23 June 1995)
Pergamon 0040-4039(95)0115 I-X
A Tricomponent Reaction Promoted by a Titanium Trichloride/Pyridine System Diastereoselective Synthesis of lS-Amino-~-hydroxyesters
Angelo Clerici, Laura Clerici and Ombretta Porta* Dipartimento di Chimica del Politecnico, Via Mancinelli 7, 20131
lvIilano, Italy
Methylphenylglyoxylale,aniline and aromaticaldehydes,on treatmentwith TiCl3/pyridinein anhydrous THF at room temperature, undergo rapid condensation to produce syn-13-amino-cthydroxyesters.The mechanismof the reactionis rationalized.
Abstract:
13-Amino~-hydroxyacids are of considerable importance because they are incorporated into many biologically active peptides, such as bestatin, l, 2 amastatin,2 norstatine3 and taxol. 4 Consequently, in recent years much attention has been devoted to the synthesis of these molecules, as potential useful intermediates, for the construction of new enzyme inhibitors.5 We report herein our preliminary model studies regarding the syn-diastereo-controlled synthesis of the title compounds 4 by a "one pot" condensation of three components (methyl phenylglyoxylate 1, aniline 2 and aromatic aldehydes 3) promoted by the TiCl3/PYr system in anhydrous TIlT at room temperature (Eq. 1).
-J~ MeO
Ph
+
PhNI'I2 +
H~
Ar
O 1
2
3
Ti(III)'THF Pyr, r.t. P-
0 Ph NHPh MeO Ar HO
(I)
syn-4 (53-67%)
This reaction, in which the aldehydic oxygen atom is directly replaced by an amino and an ct-subtituted benzyl group is closely related to the classical tricomponent Mannich reaction.6 After optimization, the following proved to be the best experimental conditions: a 1M TiCI3-THF/CH2CI2 (2:1) solution7 (5 mmol) was added, in one portion, with a syringe to a solution containing equimolar amounts of 1, 2 and 3 (2.5 mmol) in anhydrous TI-IF (10 mL) and pyridine (3 mmol) under nitrogen, at room temperature, with stirring. The blue colour of Ti(III) instantly discharged with the formation of a yellow precipitate.8 Half an hour later, upon quenching the reaction mixture with H20, the yellow precipitate dissolved. The aqueous layer was extracted with EtOAc, the combined extracts were washed with 1-120, dried over Na2SO 4 and evaporated i n v a c u o . By dissolving the thick-liquid residue in the appropriate solvent, the 13-amino-tx-hydroxyester 4 crystallized out as white crystals, on standing. Yields of isolated product, melting points and solvents of crystallization of 4a-e are shown in the Table. 5955
5956
An X-ray diffraction analysis9 of 4c showed that the structure corresponds to a simple syndiastereoselectivity. By analogy with 4c and by assuming an analogous topology in the transition state, compounds 4a, 4b, 4d, and 4e should have syn relative configuration also. Neither TLC nor 1H NMR analysis of the crude reaction mixture revealed the presence of the anti isomer, the only by-products being methyl mandelate 5 (12-14%) and dimethyl diphenyltartrate 6 (5%). Table Yields (%) of syn-l~-Amino-ct-hydroxyesters4a under Different Conditions Entry
Substrates
Isolated Yieldb (%)
Yield
(%)
mp (°C) (Solvent)
(ref to conv.)c a
1 + 2 + C6HsCHO
53
76
a'
1 + C6H5CH=N-Ph
40
54
b
1 + 2 +p-CH3C6H4CHO
67
75
b'
1 + 2 +p-CH3C6H4CHOd
38
55
c
1 + 2 +p-Br-C6H4CHO
61
76
c'
1 + p-Br-C6H4CH=N-Ph
48
60
d
1 + 2 +p-CN-C6H4CHO
63
82
d'
1 + p-CN-C6H4CH=N-Ph
54
72
e
1 + 2 + o-CH30-C6H4CHO
64
80
4a 188-9 (CHCI3)
4b 172 (Et20)
4c 144-6 (hexane/ Et20)
4d 150-2 (MeOH)
4e 125-6 (p. ether)
aAll products 4 have spectralcharacteristics(IH NMR, IR and MS) in agreementwith the structures proposed, blsolatedyield is based on the starting 1. Cyield is referredto the converted1. dpyridinewas not used as an additive. Pyridine was essential to achieve good yields of 4: in its absence, the yields of 4 strongly decreased in favour of the formation of 5 (entry b' and comparable results obtained with other aldehydes). 10 Mechanistically, the first step of the reaction involves the dimefization of 1 to A, via single electron transfer process (SET). A sequential Ti(IV)-catalyzed intramolecular heterolytic cleavage of A 11 regenerates 1, which is reduced back to A by the excess of Ti(III) and forms the stabilized Ti(IV)-ene diolate B, that is assumed to be the reactive intermediate in the formation of 4 (Scheme). Ti(IV)-ene diolate B, which may be formed either by Ti(IV)-catalyzed cleavage of dimethyl diphenyltanrates 611 or by Ti(III)-reductive dimerization of 1, followed by Ti(IV)catalyzed intramolecular cleavage of A in tandem, 12 undergoes diastereoselective aldol reaction with aromatic and aliphatic
5957
aldehydes I 1,12 and ketones, 13 provided that Pyr is present, 10 affording syn-et, l~-dihydroxyesters 7 (50*4 yield, starting from 6 and TiCI4; 60-94% yield, starting from 1 and TiCi3). Scheme
O 2 MeO~'~Ph + 2 T i ( l l l ) ~ O "-~1i(1V) MeOu
m,,v, O\"O
l OH J --~'~(IV)'THF~Pyr PIt I
e,n OMe
H20
OH I Ph
CO2Me CO2Me
A
6
iv Ph
Ph--~--H CO2Me
~ OMe
OH
2+3
CO2Me 7
I
syn-4 Nevertheless, when aniline was added to the reaction mixture, in equimolar amount with the aldehyde, formation of 7 was completely suppressed, 4 being formed instead (40% yield, starting from 6 and TiCI414; 53-67% yield, starting from I and TiCI3, Table). Very likely, aniline possesses a higher nucleophilic power than the enolate B, so that the aldehyde does not take part in an aldol reaction with B, but rather condenses with aniline itself affording the reactive counterpart of B in the formation of 4 (Eq. 2).
PhNH2 + 2
o--ri(IV)
Ar
3
~
~
PhNH
L
"fi(IV) ~
ArH C
~ PhN::~
II[
B]
8
"I](IV)(OH2)
/
(2)
syn-4 It must be highlighted that Ti(III) is a highly specific catalyst for these tricomponent reactions because, almost uniquely, it can perform three functions: a) as a reducing agent it promotes the one-electron dimerization of 1, b) having done this, in its higher oxidation state, Ti(IV), catalyzes the heterolytic cleavage of A, and c) by coordinating the aldehydic oxygen atom, it would prepare the carbonyl group for the attack by an amine. 15 Surprisingly, 16 the reaction with preformed arylimine 8 afforded lower yields of 4 than the tricomponent condensation (entries a', c', and d'). The high yields of dimer 6 (17-34 %) obtained in this two-step variant of the reaction would suggest that the imine, when present at higher concentration than that generated under
5958
equilibrium conditions (Eq. 2), may irreversibly complex with Ti(IV) 17 hampering further formation o f the chelate complex A, a pre-requisite for the heterolytic cleavage to occur. A n o t h e r possibility is that the tricomponent reaction would rather occur by an SN2 mechanism, in which the enolate B directly displaces the T i ( I V ) O H group from the intermediate titanated N,O-hemiacetal C. lg Efforts to extend the scope and utility o f this reaction further are presently being made in our laboratory. Acknowledgements
Financial support
o f this work
from Progetto
Strategico
"Tecnologie
Chimiche
Innovative", Centro Nazionale delle Ricercbe is gratefully acknowledged.
REFERENCES AND NOTES
1. Kabayashi, S.; Isob¢, T.; Ohno, M. Tetrahedron Lett., 1984, 25, 5079. 2.
Herranz, R.; Castro-Flchel, J.; Vinuesa, S.; Garcia Lopez, T. J. Org. Chem. 1990, 55, 2232.
3.
Dagger, R~ W.; Ralbowsky, J. L.; BryanL D.; Commander, J.; Masset, S. S.; Sage, N.; S¢lvidio, J. R. Tetrahedron Lett. 1992, 45, 6763.
4.
Jefford, C. W.; Wang, J. B.; Hin Lu, Z. Tetrahedron Lett. 1993, 47, 7557 and references cited therein.
5.
Palomo, C.; Aizpurna, J.; Cuevas, C. J. Chem. Soc. Chem. Comm. 1994, 1957 and references therein cited.
6.
For a review on Mannich reaction see: Tramontini, M. Synthesis, 1973, 703; Tramontini, M.; Angiolini., L. Tetrahedron
7.
Solutions ofTiCl 3 in THF/CH2CI 2 (1:2) are stable for long periods provided air and moisture are excluded, and, now,
1990, 46, 1791. commercially available. 8.
The yellow precipitate is an adduct of Ti(IV). Its IH NMR (DMSO) spectrum evidences the presence of THF and Pyr in the ratio 1:4. It is very sensitive to moisture and is completely destroyed by quenching the reaction with H20.
9.
Malpezzi, U Acta Cryst., sect. C, submitted for publication.
10. We believe that Pyr, a strong donor ligand, by saturating the coordinative valences of Ti(IV) in B would increase the electron density at titanium and, hence, the nucleophilic reactivity of the ene-diolate. 11. Cierici, A.; Cierici, L.; Porta, O. J. Org. Chem. 1995, 60, 480. 12. Clerici, A.; Clerici, L.; Porta, O. Tetrahedron, submitted for publication. 13. Unpublished results of this laboratory. 14. Equimolar amounts of 6, 2, and benzldehyde (0.6 mmol) were treated with a 1M TiCI4-CH2C! 2 solution (1.4 retool) in anhydrous THF (6 mL) and Pyr (1,7 retool) under N 2 at r.t. Workup as nsnal afforded 4a, 5, and I in 40, 10, 50 % yield, respectively. 15. Ti(IV) has been shown to facilitate the formation of enamines and imines in anhydrous solvents. White, W. A.; Weingarten, H.; d. Org. Chem. 1967, 32, 213; Weingarten, H.; Chupp, J. P.; White, W. A. 1bid. 1967, 32, 3246; Desai, M. C.; Thadeio P. F. TetrahedronLett. 1989, 30, 5223; Carlson, R.; Larson, U.; Hansson, L. Acta Chem. Scand. 1992, 46, 1211.
16. Enolate-imine condensations have been widespread investigated becanse of their application to [~-Iactam syntheses. For a review see: Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1; Trost, B.; Fleming, J. Comprehensive Organic Synthesis, Pergamon Press: Oxford, 1991; Vol. 2, pp. 893-951.
17. When the preformed arylamines were used as subtrates, a completely different colour change was observed during the reaction: from blue to green, and the yellow precipitate, obtained in the tricomponent condensation, was not formed. 18. Seebach, D.; Betschart, C.; Sehiess, M. Helv. Chim. Acta 1984, 67, 1593; Betschart, C.; Seebach, D. Ibid. 1987, 70, 2215.
(Received in U K 6 April 1995; revised 21 June 1995; accepted 23 June 1995)