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Asymmetric Hydrogenation of -(Acetylamino)cinnamic Acid with a Novel Rhodium Complex; the Design of an Optimal Ligand.

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[I] F. A. Cotton, G. E. Lewis, G. N. Mott, Inorg. Chem. 21 (1982) 3127.
[2] B. N. Figgis, G. B. Robertson, Nature (London) 205 (1965) 694; S. C.
Chang, G. A. Jeffrey, Acfa Crysfallogr..Sect. 8 26 (1970) 673.
[3] L. W. Hessel, C. Romers, Recl. Trav. Chim. Pays-Bas 88 (1969) 545; T.
Lis, B. Jezowska-Trzebiatowska, Acta Crysfallogr. 8 3 3 (1977) 2112.
[4] E. M. Holt, S. L. Holt, W. F. Tucker, R. 0. Asplund, K. J. Watson, J.
Am. Chem. SOC.96 (1974) 2621; W. F. Tucker, R. 0. Asplund, S. L. Holt,
Arch. Biochem. Biophys. 166 (1975) 433.
[5] F. A. Cotton, J. G. Norman, Jr., Inorg. Chim. Acfa 6 (1972) 41 1.
[6] F. A. Cotton, W. Wang, Inorg. Chem. 21 (1982) 2675.
[7] A. R. E. Baikie, M. B. Hursthouse, D. B. New, P. Thornton, J. Chem.
SOC.Chem. Commun. 1978, 62.
[Sl A. C. Skapski, M. L. Smart, Chem. Commun. 1970, 658.
[9] A. Birnbaum, F. A. Cotton, 2. Dori, D. 0. Marler, G. M. Reisner, W.
Schwotzer, M. Shaia, Inorg. Chem. 22 (1983) 2723.
[lo] A. Bino, F. A. Cotton, 2. Dori, S. Koch, H. Kiippers, M. Millar, J. C. Sekutowski, Inorg. Chem. 17 (1978) 3245.
the conditions used for the catalysis. It does not contain
any P-0 or P-N bonds, which undergo solvolysis on prolonged reaction12],and it imposes a markedly rigid conformation (A-conformation) on the five-membered metallacycie[31.
Variation of the substituents on the nitrogen atom of 1
has no marked influence on the catalytic activity and the
selectivity of the resulting rhodium complex. Only in the
case of 2 ( R = H ) is the catalytic hydrogenation slower,
which could be due to an oxidative addition of N-H to
Rh'. Even substituents on the phenyl group of 4 have little
influence on the optical yield; thus, e.g., the 4-hydroxy-, 4methoxy-, 4-hydroxy-3-methoxy-, or 3,4-methylenedioxyderivatives all give over 95% ee.
Asymmetric Hydrogenation of
a-(Acety1amino)cinnamic Acid
with a Novel Rhodium Complex;
the Design of an Optimal Ligand**
By Ulrich Nagel*
Rhodium complexes of optically active bisphosphanes
facilitate the asymmetric hydrogenation of prochiral olefins, in some cases in high optical yields"]. The new 1,2bisphosphane 1 (benzoylpyrphos) is presented here as a ligand especially suited for the hydrogenation of a-(acylamino)acrylic acids to (S)-N-acylamino acids.
I lo'"'
1, R
2, K = 1-1
Ph, P,,,
P h 2 PC N - g - P h
The novel rhodium complex ((R,R)-P,P'-[N-benzoylpyrrolidine-3,4-diyl]bis(diphenylphosphane))1,5-cyclooctadienerhodium tetrafluoroborate 3 catalyzes the hydrogenation of a-(acety1amino)cinnamic acid 4 to (S)-N-acetylphenylalanine 5 with 99% ee. In contrast to hydrogenations with other enantioselective catalysts, this hydrogenation can be carried out under pressure without loss of selectivity. The reaction rate increases linearly with the hydrogen pressure (0.8 min-' at 1 bar, 40 min-' at 50 bar).
Even high substrate to catalyst ratios (10000: 1) can be
used without lowering the selectivity and, at 50 bar hydrogen pressure, such conversions are achievable in only
10 h.
All structural units known to increase the optical yield in
the hydrogenation of acryl acid derivatives were incorporated in the ligand 1. The ligand is chemically stable under
[*I Dr. U. Nagel
lnstitut fur Anorganische Chemie der Universitat
Meiserstrasse 1, D-8000 Miinchen 2 (FRG)
This work was supported by Degussa AG, Hanau (FRG).
Angew. Chem. h i . Ed. Engl. 23 (1984) No. 6
BOC= -CO-O-C(CH3)3;
M ~ =s -S0,-CH3
Scheme I.
1 was obtained in eight steps from natural ( R , R ) - ( + ) tartaric acid 6 (overall yield 36%) (Scheme 1). Attempts to
prepare (S,S)-3,4-dihydroxypyrrolidine9 via the tartrimide met without success ; N-benzyltartrimide was therefore
used. The Boc-moiety in 11, which was obtained via the
sequence 7+8 +9 -+ 10 -+ 11, must be removed since reaction of 11 with sodium diphenyl phosphide leads to elimination products. The reaction of 12 is critical and only affords satisfactory yields when carried out in dimethylformamide (DMF)[51.-So far the only optically active 3,4-dihydroxypyrrolidine described in the literature since we
completed our studies has been the N-phenyl derivative[*].
A particular advantage of the new ligand is that the Nsubstituent can be varied, i.e. the ligand itself can be tailored according to its intended use. Two polymer-bound
chiral bisphosphanes (DIOP and PPM) are
Preliminary experiments with 2 bonded to Merrifield
resin or silica gel furnished heterogeneous catalysts which
hydrogenate 4 in methanol with 95% ee-an enantioselectivity which has so far never been achieved in heterogene-
0 Verlag Chemie GmbH. 0-6940 Weinheim, 1984
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ous catalysis. The hydrogenation with the silica-bound catalyst is only slightly slower than in solution; after filtration, the catalyst could even be used again without reducing the selectivity.
Received: May 10, 1982;
revised: March 27, 1984 [Z 36 IE]
German version: Angew. Chem. 96 (1984) 425
Publication delayed at author's request
V. taplar, G. Comisso, V. Sunjib, Synthesis 1981, 85.
J. Bourson, L. Oliveros, J . Organornet. Chem. 229 (1982) 77.
M. D. Fryzuk, B. Bosnich, J. A m . Chem. Soc. 99 (1977) 6262.
G. L. Baker, S . J . Fritschel, J. R. Stille, J. K. Stille, J. Org. Chem. 46
(1981) 2954.
[5] Procedure: A solution of NaPPh2'2dioxane (10.5 g, 27.5 mmol) in DMF
(60 mL) is treated at -35°C with 2.6 g (7.6 mmol) 12 and the mixture
stirred for ca. 12 h at - 12°C. After removal of the solvent, dissolution of
the residue in water, and extraction of the aqueous solution with ether,
2 N HCI is added to the ether extract to precipitate 2 as the hydrochloride. Treatment of 2 with benzoyl chloride affords 1 [colorless, m.p.
180-182°C; [a]?
153 (c=2.84, toluene), reprecipitation from toluene/
hexane]. 1 reacts with [Rh(cod),]BF, to give 3 [yellow, readily soluble in
methanol, reprecipitation with ether]. Typical experiment: A solution of
4 (2.05 g, 10mmol) in methanol (30mL) was treated with 1 mg
(0.0012 mmol) 3 and the mixture stirred in a 50 mL steel autoclave under
an average pressure of 40 bar H2 (ca. 12 h at RT). After addition of 1 m L
0.1 N HCI, the solution was evaporated to dryness, the residue taken up
in NaOH, and the catalyst removed by extraction with dichlorornethane.
The aqueous solution was acidified and extracted with ethyl acetate.
After removal of the ethyl acetate, pure 5 was obtained in quantitative
yield. According to polarimetric measurements the optical purity was
99%; the rotation of a recrystallized sample agreed to within 0.1 with the
value quoted in the literature [6] [a12 f47.4 (c=1.95%, ethanol), and
was taken as reference.
[6] B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, D. J.
Weinkauff, J. Am. Chem. SOC.99 (1977) 5948.
The Allyloxycarbonyl (Aloc) MoietyConversion of an Unsuitable into a Valuable Amino
Protecting Group for Peptide Synthesis**
By Horst Kunz* and Carlo Unverzagt
For the synthesis of sensitive peptides and glycopeptides, we have used the allyl moiety to block carboxy
groups reversibly~'*21.
This protecting group can be rapidly
removed under mild, practically neutral conditions either
via rhodium(1)-catalyzed isomeri~ation[~]
or by palladium(o)-catalyzed allyl transfer[']. In attempting to use
these advantageous properties also for the protection of
the N-terminal group, we became aware of the allyloxycarbony1 (Aloc) protecting group, which Stevens and Watanube['] investigated with D,L-amino acids. These authors
established that hydrogenolytic cleavage of the Aloc
moiety leads to marked hydrogenation, forming noncleavable propoxycarbonyl groups. Also, reduction with sodium
in liquid ammonia (yield 65-85%) and cleavage with
phosphonium iodide in glacial acetic acid (yield 70-75%)
affords only incomplete deblocking. The Aloc moiety
therefore appeared to be less than suitable for peptide synthesisL6'.
We have now found, however, that the combination of
the Aloc amino-protecting group with a novel cleavage
method is highly propitious.
Although the Aloc moiety can be introduced using the
allyl chloroformate 1 under Schotten-Baumann condi[*I Prof. Dr. H. Kunz, C. Unverzagt
Institut fur Organische Chemie der Universitat
Johann-Joachim-Becher-Weg 18-20, D-6500 Maim (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
by the Fonds der Chemischen Industrie.
0 Verlag Chemie GmbH. 0-6940 Weinheim. 1984
-1 1
+ A
2 a , AS = Phe, 8470;
Zc, AS = S e r , 790/0,
Zb, A S = M e t , 80%,
2d, AS = A l a , 7 7 %
tionsr5I,it is more advantageous to use the pH-stat method
at pH 10-11. The Aloc-amino acids 2 (2c forms a crystalline hydrate, m.p. = 52"C), which are generally oily, were
identified by elemental analysis and by 'H-NMR spectroscopy[']. The advantage of the small Aloc protecting group
is demonstrated by the condensation reactions. In the presence of ethyl-2-ethoxy- 1,2-dihydroquinoline- 1-carboxylate
(EEDQ)[", Aloc-amino acids 2 react with tert-butyl amino
acid esters to afford the Aloc-dipeptide tert-butyl esters 3
in high yield.
+ H-AS-OfHu
3a, AS-AS'= Met-Phe, 92%
3b, AS-AS'= Phe-Ser(tBu), 95%
312, AS-AS'= Ala-Ser(tBu), 94%
The tert-butyl esters 3 can be smoothly and selectively decomposed with trifluoroacetic acid, without the Aloc
group being attacked. The latter group survives even the
considerably lengthened reaction times required for the
complete cleavage of the tert-butyl ether of serine.
4a, 84%
-'' $0,""
4b, 83%
For the cleavage of the Aloc moiety from the esters 3,
we chose catalytic allyl transfer with tetrakis(tripheny1phosphane)palladium(o)[zt.However, as allyl acceptor, we
used 5,5-dimethyl-1,3-cyclohexanedione (dimedone) instead of morpholine.
The CH-acid dimedone @Ka= 5.2) can readily be separated from liberated amine. C-ally1 substituted dimedone is
an acid which can also be readily separated. Dimedone, especially if it is used in a 7- to 8-fold excess, protonates the
free amino function (pK, = 8) to such an extent that the latter can neither function as an allyl acceptor nor is able to
form an enamine with dimedone within the reaction
By means of this method['01,the Aloc protecting group
can be completely removed from the dipeptide esters 3 in
30 min in tetrahydrofuran (THF) at room temperature using 5-10 mol-% of catalyst.
5a, 88%
5b, 95%
The thioether function of methionine influences neither
the activity of the palladium catalyst nor is itself alkylated.
The very mild and highly selective deblocking method is
therefore widely applicable.
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Angew. Chem. h i . Ed. Engl. 23 (1984) No. 6
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acid, asymmetric, complex, design, acetylamino, rhodium, cinnamic, hydrogenation, optima, novem, ligand
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