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Enantioselective Synthesis of -Methylserines.

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Table 1. NMR data (6, rel. to TMS) of compounds (5). (6). (8). and (9)
Enantioselective Synthesis of cY-Methylserines'**l
"C-NMR ( p = primary, q=quaternary)
(CDEI?, RT): 4.05 (lH),
1.59 (9H). 1.47 (18H). 1.14
(CDCI,, RT): 2.57 (IH),
1.56 (OH). 1.24 (9H), 1.20
(9H). 1.04 (W.0.98 (YH)
(CD2C12, -60°C):
(18H), 1.22 (18H)
(CDK12, RT): 1.32 (18H).
1.14 (18H)
(CDzC12, -60°C): 159.42 (C-2). 156.00
(C-I, C-3), 78.48 (C-4; not dewupled
d), 37.74 (4). 36.63 (4). 35.90 (q), 30.33
(p. 1 tBu), 29.80 (p, 3 tBu)
(CDCI,, RT): 151.58 (olefinic), 151.06
(olefinic), 84.85 (C-0), 60.42 (allylic,
ring), 38.46 (4). 33.63 (q), 32.80 (q),
32.55 (q), 31.06 (p), 30.76 (p), 30.33 (p),
27.81 (p)
(CD2C12, -60°C): 161.44 (olefinic),
108.73 (C-0). 34.48 (q), 34.04 (q), 31.77
(P). 28-93 (P)
(CD2C12, RT): 218.12 (C-0),
(olefinic), 45.15 (9). 35.43 (q), 33.13 (p).
28.53 (p)
R T = room temperature.
dranec2],it nevertheless remains to be examined whether this
kind of stabilization [transition from the more energetic D4h
to DZd(or D2) instead of Dzh symmetry[']] might also be significant in other cases too, possibly even in the unsubstituted
parent compound.
Received July 11, 1979;
revised: November 2, 1979 [Z 404 b IE]
German version: Angew. Chem. 92, 214 (1980)
Room temperature, M O Kradiation,
Siemens AED, graphite monochromator, sin WAs0.664 k'.
2267 independent reflections (of which 662 were
unobserved); crystallographic data: a = 17.749(4), b=9.271(2), c= 11.870(2)
p = 106.90(2)"; monoclinic space group C2/c, 2=4;eC.,. =0.98 g c n r 3 .
G. Maier, S. Pfiem, (1. Schoyer, R. Matusch, Angew. Chem. YO, 552 (1978);
Angew. Chem. Int. Ed. Engl. 17, 520 (1978).
a) H. hgariinger, H. Rodewald, Angew. Chem. 84. 783 (1974); Angew.
Chem. Int. Ed. Engl. 13, 740 (1974); b) A. Krebs, J. Pocklington, H. Schmalstieg, H. Irngortinger, N. Riegler, Israel J. Chem., in press; c) L. T. J. Delbaere, M. N. G. James, N. Nakamura, S. Masamune, J. Am. Chem. SOC.97,
1973 (1975).
Review: 7: 7'. Tidwefl,Tetrahedron 34, 1855 (1978).
Review: D. Seebach in Houben/ Weyl: Methoden der organischen Chemie.
Thieme, Stuttgart 1971, Vol. IV/4, p. 11, Table 4.
a) G. Maier, W. Sauer, Angew. Chem. 87, 675 (1975); 89, 49 (1977); Angew.
Chem. Int. Ed. Engl. 14. 648 (1975); 16, 51 (1977); b) this phenomenon does
not occur in cyclosilane: K . D. Malsch, K. A. Schneider, G. Maier, H . - 0 . Kalinowski, unpublished.
In the latest calculations too [8] only planar arrangements are considered. It
should also be mentioned that the same number (7) of active vibrations is to
be expected in the IR spectrum 191 of unsubstituted cyclobutadiene whether
in a folded (D2.,) or rectangular geometry.
H.. Kollmar, V. Staemmler, J. Am. Chem. Soc.YY, 3583 (1977); W. 7'. Borden,
E. R. Davidson, P. Hart, ibrd. too, 388 (1978); J. A. Jafri, M . D. Newton, ibid.
too, 5012 (1978).
By Ulrich Schollkopf; Wolfgang Hartwig, and Ulrich
Dedicated to Professor Matthias Seefelder on the occassion
of his 60th birthday
Optically active synthetic amino acids are gaining increasing importance in research and practice, e. g. as enzyme inhibitors or as pharmaceuticals.
We recently reported on the enantioselective synthesis of
a-methylamino acids by base-induced alkylation of (3S,6S)( + )-2,5-dimethoxy-3,6-dimethyl-3,6-dihydropyrazine ( I ) ,
which is obtainable by reaction of cyclo(L-Ala-L-Ala) with
trimethyloxonium tetrafluoroboratel']. We have now found
that lithiated lactim ethers (2) also react with carbonyl compounds (3) -in tetrahydrofuran (THF) or (better) dimethoxyethane- with, in some cases very high, induction at C3 (cf. Table 1). With aldehydes or unsymmetric ketones, a
chirality center is also established at C-7 of the product (4).
The induction is somewhat lower in this case, being 41-78%
(cf. Table 1).
The configuration and degree of induction at C-3 of (4)
can-if R' or R2is ary- be determined 'H-NMR spectroscopically from the signal of the C-6 methyl protons. This appears at relatively high field in the case of the isomer formed
in lower yield because the methyl group is situated in the
shielding anisotropic region of the aryl group, which might
lie n-complex-like over the heterocyclefz1.Accordingly, the
carbonyl compound adds to (2) preferably in the trans-position to the C-6 methyl group, so that an R-configuration is
induced at C-3 of (4). This also applies in the case of formaldehyde, since @)-( -)-~-methylserine[~lis obtained on hydrolysis of (4a). Acid hydrolysis of the adduct (4) leads to Qmethylserine esters (5). Their enantiomeric purity at the Qcarbon atom corresponds to the asymmetric induction, when
optically pure ( I ) is used as starting
Table 1. Adducts (4) synthesized from the metalated lactim ethers (2) and carbonyl compounds (3).
M.p. ["C]
B.p. ["C/torr]
at C-3
50-55; 60/0.1
95-1 05/15
115-1 20/0.1
85-90 [a, c]
80 [a, d] 85 [b]
>95 [a]
86 [a] >95 [b]
76 [a] 82 [b]
73 [a] 85 [b]
at C-7
41 [a1
21 [a] 52 [b]
48 [a] 74 [b]
[a] In THF. [b] In dimetboxyethane. [c] Determined with Eu(tfc), on (4a). [d] Determined with Eu(tfc), on (Sb)
191 Experiment: S. Masamune, E A. Souto-Bachiller, 7'. Machiguchi, J. E. Bertie,
J. Am. Chem. Soc. 100,4889 (1978); theory: H . Kollmar, V. Staemmler, ibid.
100, 4304 (1978); L. J. Schaad, B. A. Hess, C. S. Ewig, ibid. 101, 2281
0 Verlag Chemie. GmbH, 6940 Weinheim, 1980
U. Groth
Organisch-chemisches Institut der Universitat
Tammannstrasse 2, D-3400 Gottingen (Germany)
I*] Prof. Dr. U. Schollkopf, Dr. W.Hartwig, Dip].-Chem.
Asymmetric syntheses via Heterocyclic Intermediates, Part 3. -Part
$ 02.SO/O
2: [l].
Angew. Chem. In(. Ed. Engl. 19 (1980) No. 3
A retroaldol reaction can occur during the hydrolysis.
Thus, (4c) readily decomposes to benzophenone and ( I ) ,
whereas the hydrolysis of (4a) or (4b) is straightforward. The
diastereomers of (4e) (separated by HPLC) primarily afford
methyl esters, which decompose uia retroaldol reaction on distillation[51,while the
(ZR,3S)-diastereomer is t h e r m ~ s t a b l e ~ ~ ~ .
Lactim ethers of type ( I ) , which are differently substituted
on C-3 and C-6, also react with carbonyl compounds with
high asymmetric induction; e. g., in the reaction of (3s)-6-
lithio-2.5-dimethoxy-3-(3,4-dimethoxybe~yl)-3-methyl-3,6dihydropyrazine with acetone it is z 93%161.
(1)+(4): Butyllithium (11 mmol, 7 ml of a 1.55 N solution
in hexane) is added to a solution of (I)['] (1.7 g, 10 mmol) in
ca. 20 ml of THF or (better) dimethoxyethane at - 70 "C. A
solution of the carbonyl compound (3) (10 mmol) in ca. 20
ml THF or dimethoxyethane, precooled to - 70 "C, is then
added dropwise to the mixture. In the case of formaldehyde
a suspension of 20 mmol of paraformaldehyde in 20 ml of
THF is added. After stirring for 6-10 h (20 h in the case of
(4a)) at - 70 "C the mixture is treated with 0.66 g of glacial
acetic acid in ca. 5 ml of THF and the temperature allowed
to come to room temperature. After removal of solvent in uacuo the residue is shaken with 30 ml of ether and 50 ml of
phosphate buffer solution (pH = 7); the aqueous solution is
then extracted twice more with 20 ml ether and the combined ether extracts are dried over sodium sulfate. After removal of ether, (4) is distilled in a bulb-to-bulb apparatus.
(4b)-+(5b):A mixture of (4b) (0.23 g, 1 mmol) and 0.13 N
HCI (16 ml) is stirred for 15 min at room temperature. After
removal of solvent in a vacuum (bath temp. 40°C) the remaining mixture is covered with a layer of ether ( 5 ml). The
vigorously stirred mixture is then treated with dilute ammonia solution until the pH = 8. The ether phase is saturated with
sodium chloride and extracted a further five times with ether.
The combined ether extracts are dried over sodium sulfate
and, after removal of ether, distilled (slight decomposition);
yield 0.11 g (72%) (R)-(-)-a,P,@-trimethylserine methyl ester, b. p. 1oO-11O0C/O.1 torr, enantiomeric purity 71% (determined with Eu(hfc),), corresponding to an asymmetric induction in the case of (46) of ca. 80%.-'H-NMR (CDCI,):
6 = 1.26 and 1.40 (s, CH39H), 1.49 (s, NH22H), 3.75 (s,
OCHj, 3H); 8.3 (br., OH); [a]g= -64.1" ( c = l . l in ethanol).
Received: January 2, 1980 [Z 403 IE]
German version: Angew. Chem. 92, 205 (1980)
CAS Registry numbers:
(I), 72953-31-2; (2). 72953-32-3; (3a). 50-00-0; (3b). 67-64-1; (34, 119-61-9; (3d),
98-86-2. (3e). 100-52-7; (33. 123-11-5; (4a). 72953-33-4; (4b), 72968-03-7; (4c),
71785-63-2; (4d). 72953-34-5; (4e).72953-35-6; (4&, 72953-36-7; (Sa), 72953-37-8;
(Sb),72953-38-9 ( 5 ~ )71785-69-8;
(Sd), 72953-39-0; (5e), 73035-89-9; (Sn,7295340-3
111 U. Scho/lkopJ W. Harrwig, U.Goth, Angew. Chem. 91, 922 (1979); Angew.
Chem Int. Ed. Engl. 18, 863 (1979).
[2] Such preferred conformations (folded conformations) have been demonstrated on a number of occasions with benzyl-substituted heterocycles; cf. A.
K. Bose, M. S. Manhas. R. V. Tavates, J. M. van der Veen, H . Fujiwara, Heterocycles 7, 1227 (1977).
131 N Takamura. S. Terashima, K. Achiwa, S. Yamado, Chem. Pharm. BuII. IS.
1776 (1967).
[4] The compound ( I ) described in [ I ] is 93-95% optically pure. -Triethyloxonium tetrafluoroborate reacts more rapidly than trimethyloxonium tetrafluoroborate with cyc/o-(L-Ala-L-Ala), In the case of the ethyl lactim ethersOEt instead of OMe in (I) -the asymmetric inductions are just as high as in
the case of (/), but the 'H-NMR spectra are less informative.
[5] Cf. U. Grorh, Diplomarbeit, Universitit Gottingen 1979.
161 Cf. H. Kehne. Dissertation, Universitat Gottingen 1980.
171 Synthesized as in [I]; b. p. 75OC/8-10 torr, [a]&"= +82.6" (c=l.O, ethanol)
Angew. Chem. Int. Ed. Engl. 19 (1980) No. 3
a Building Block for the Synthesis of
By Rotf Appel and Gerhard Haubrichr"
Dedicated to Professor Matthias Seefelder on the occasion
of his 60th birthday
Previous studies have shown that the deprotonation of methylene-bridged bisphosphonium salts (1) always takes place
at the central C-atom. Either carbodiphosphoranes (2) or
double ylides (3) containing a conjugated P-C- -P bond
system are obtainedf2].The formation of isomeric bis(methylenephosphoranes) of type (7) containing two terminal ylide
functions, which are of interest as potential chelating agents,
has hitherto not been observed[21.
We have now found that the salt (5), i.e. the title compound, which is obtainable from [bis(trimethylsilyl)methylldiphenylphosphane (4) and n-butyllithium, permits the
synthesis of the novel double ylides (7a)-(7c). From the
smooth reaction of (5) with diiodomethane (6a), 1,2-dibromoethane (6b) and dichloro(pheny1)phosphane(6c) it can be
concluded that the species originally deprotonated at the aC-atom reacts ambivalently as "Li-phosphoranide" with the
difunctional halogen compounds.
x 2/+ Y X = ( ~ )
- 2 LIX
C (Si Me,),
(6), ( 7 j ; ( a ) , X
= I, Y = CH,; ( b ) X = B r ,
Y = (CH,),; (c) X = C1, Y = P P h
Only the reaction with diiodomethane yields (7a);dichloromethane is dehydrochlorinated by (S), while reaction with
dibromomethane leads to (4) together with three further still
unidentified products.
The structure and composition of the double ylides are
confirmed by elemental analysis, characteristic fragmentation pattern in the mass spectrum[3],and above all by the po-
NMR spectroscopic data of the bis(methy1enephosphoranes)(41
(7a): "P/'H:-NMR: 6=18.7 (s); 'H-NMR: 6=0.05 (s, SICHI), 0.31 (s, SiCH,),
1.20 (1, 'J(PCH)= 12.0 Hz, CH2). 7.45 (m. C,H,); "C 'Hj -NMR: 6=3.0 (d.
'J(PCSiC)= 1.4 Hz, Sic), 7.1 (pseudo-1, 3J(PCSiC)+5J(PCPCSiC)=3.6 Hz,
Sic), 13.8 (1, J(PC)=53.6 Hz, CH2), 128.6 (d, 'J(PC-3)=23.8 Hz, C-3). 131.6 (s.
C-4). 133.8 (pseudo-dd, 'J(PC-2)+ 4J(PCPC-2)= 10.2 Hz, C-2). 139.8 (pseudodd, J(PC-1)+ ]J(PCPC-1)=87.4 Hz,C-1).
(76): "P('H:-NMR: 6=16.1 (s); 'H-NMR: 6=0.22 (s, SiCH,), 2.80 (m. CH2),
7.35 (m, CaHS); "C('HI-NMR: 6=6.5 (s, SIC), 27.5 (pseudo-t,
J(PC) + 'J(PCC)= 50.6 Hz, CH2), 128.6 (pseudo-1, 'J(PC-3) + 'J(PCCPC3)= 10.4 Hz, C-3), 131.1 (s. C-4). 132.5 (pseudo-t, 2J(PC-2)+ 'J(PCCPC2)=11.2 Hz, C-2), 136.4 (dd, J(PC-1)=39.5 Hz, 4J(PCCPC-l)=1.2 Hz, C-1).
(7c): "P:'H:-NMR: 6=35.2 (Ph2P), 8.1 (PhP, A2B system mit J(AB)=441.2
Hz); 'H-NMR: 6=0.20 (s, SiCH,), 7.25 (m. C6H,); "C('H;-NMR- 6=5.9 (d,
'J(PCSiC)=l.l Hz, Sic), the complex aromatic region could not be assigned
r]Prof. Dr. R. Appel, Dip1.-Chem. G. Haubrich
Anorganisch-chemisches Institut der Universilat
Gerhard-Domagk-Strasse 1, D-5300 Bonn 1 (Germany)
@ Verlag Chemre, GmbH, 6940 Weinheim, 1980
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synthesis, enantioselectivity, methylserines
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