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Chemistry of cis-Trioxatris--homobenzene. A Simple Total Synthesis of Streptamine

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step (1)-+(3) with methylmagnesium halide [R3=CH3 in
(2)] are unsatisfactory, presumably because this relatively
small reagent preferably adds to the ester carbonyl group.
Experimental:
All operations are carried out under nitrogen. A solution
of
(20 mmol) in light petroleum (20 ml) and ether (20 ml)
is added dropwise over 30min to a stirred (magnetic stirrer)
solution of (2) (40mmol, prepared in situ from alkyl bromide
and magnesium)in ether (50ml) (but not in tetrahydrof~ran"~)
at -5°C. The addition product precipitates as a brown "tar"
and should not be dissolved by addition of more solvent since
otherwise (3) cannot be isolated.
Stirring is continued for 30min at -5°C and the mixture
is cooled with ice-water prior to addition of glacial acetic
acid (40mmol) in water (50ml), whereupon the precipitate
dissolves. The ethereal phase is separated off, the aqueous
phase extracted twice with ether (2 x 50ml), and the ether
extracts dried over sodium sulfate. The solvent is drawn off
and the residue distilled. - An effective precision glass stirrer
should be used for quantities exceeding 0.1 mol, and the excess
of (2) should not be greater than 20%.
[ 2 ] U . Schollkopf and F. Gerhart, Angew. Chem. 82, 842 (1968); Angew.
Chem. internat. Edit. 7, 805 (I%@.
[3] Cf. [I]; U . Schollkopfand K . Hantke, Liebigs Ann. Chem. 1973, 1571;
D. Hoppe and U . Schiilfkopf, ibid. 763, I (1972); U . SchBllkopf, F. Gerhart,
R. Schroder, and D. Hoppe, ibid. 766, 116 (1972); M . Suzuki, Z Iwasaki,
K . Matsumoto, and K . Okumura, Chem. Ind. (London) 1972, 687; 1973,
228; W Vaalburg,J . Strating, M. G. Woldring,and H . Wynberg,Synth. Commun.
2, 423 (1972).
[4] Cf. U . SchBllkopf, D. Hoppe, and R. Jentsch, Angew. Chem. 83, 357
(1971); Angew. Chem. internat. Edit. JO, 331 (1971).
[5] Cf. H.-J. Prdtorius, Diplomarbeit, Universitat Braunschweig 1973.
[6] U . SchoIlkopJ R . Harms, and D. Hoppe, Liebigs Ann. Chem. 1973. 61 1 ;
route B was preferred.
[7] With Grignard reagents available only in tetrahydrofuran the reaction
gives only poor yields.
Chemistry of cis-Trioxatris-o-homobenzene. A Simple
Total Synthesis of Streptarnine[**]
By Reinhard Schwesinger and Horst Prinzbach"]
Preparative studies with cis-trioxatris-o-homobenzene(cis"benzene trioxide") (5)[11 have so far met with difficulties
because radical bromination of the epoxide (I) afforded at
best only 20% yields of the em-cisdibromide (2), along
with about 26% truns-(3) and very small amounts of the
endo-cis products ( 4 ) . The findingr2]that dibromides ( 2 ) - ( 4 )
equilibrate and that the individual equilibrium partners can
be isolated in pure form-thus making it possible to isolate
( 5 ) in increased yields of ca. 26 % [w.r.t. ( I )]-has
opened
'1. We
up a number of Dreparatively interesting pos~ibilities[~*
Table I . z-tert-Alkyl-substituted ethyl a-isocyanoacetates (3) [a] and a-tert-alkyl-substituted N-formylglycines ( 4 )
[b] prepared.
R'
[a]
[b]
[c]
[d]
[el
R2
R3
NMR
["/I
(3)
B. p.
[ C/torr]
62
72
76
79
73
87
71
73
58-61/0.3
107-1 l0/0.05
82-8610.4
121--128/0.1
103- l06/0.05
[el
92-96/0.1
133--134/0.1
4.06
4.36
4.20
4.37
4.48
4.48
4.3 1
4.20
Yield
180-182
179-180
171-172
209-212
167-168
178-181
179-180
222-225
4.24
4.68
4.65
5.05
5.06
5.68
4.48
4.48
IR bands at ca. 2140 (NC) and 1745cm-' (CO).
IR bands (KBr) at ca. 3320 (NH), 1620 (CH=O), and 1710cm-' (C02H).
'H-NMR (CDCIa), signal of the CH proton, T values.
Yield of conversion (3)-(4) almost quantitative.
Not distillable.
For the conversion ( 3 ) + ( 4 ) , compound (3) (10mmol) is
refluxed with KOH (0.6g) in 90% ethanol (20ml) for 30
min. The solvent is drawn off in a water pump vacuum,
the solvent is dissolved in water (15ml) (if necessary with
slight warming), and the solution acidified with 1 ml of conc.
hydrochloric acid (to pH 1-2). The N-formyl amino acids
( 4 ) , which often precipitate as oils, can be induced to crystallize
in an ice bath. They are filtered off under suction, dissolved
in a small volume of ethanol, and water is added dropwise
to the hot solution until it remains turbid. The compounds
( 4 ) precipitate on cooling. Correct elemental analyses were
obtained in all cases.
Received: December 3.1973 [ Z 965 IE]
German version: Angew. Chem. 86, 624 (1974)
Publication delayed at authors' request
[l] Syntheses with a-Metalated Isocyanides, Part 26.- Part 25: U . Schollkopf
and P.-H. Porsch, Chem. Ber. 106,3382 (1973).
630
CCI
report here on a simple and productive synthesis of streptamine (1Oa) from (5)c51.
Brief reaction of ( 5 ) with a 5 % aqueous solution of hydrazine
(molar ratio cu. 3: 1, 50°C, 35min) leads to formation of
the previously postulated[61 intermediary epoxyhydrazine
adduct (6a) [colorless crystals, m.p. ca. 235°C (decomp.);
tetracetate (6 b), m. p. 179-1 81 "C] in 97 % yield (30% conversion) together with traces of ( I I) (colorless crystals, > ca.
220°C decomp. ; tetraacetate ( I l b ) , m.p. 5747°C). (6a)
reacts with phthalic anhydride under mild conditions (water,
10min at 20"C, 1 min at 60°C) to give the sparingly soluble
['I
Prof. Dr. H. Prinzbach and DipL-Chem. R. Schwesinger
Lehrstuhl fur Organische Chemie der Universitat
78 Freiburg, Albertstrasse 21 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
Angew. Chem. internat. Edit. 1 Vol. 14 ( 1 975) j No. 9
dione (7) (colorless crystals, m.p. ca. 285°C (decomp.)). On
heating with 20mol-% phthalic acid in water under pressure
(170°C), ( 7 ) is hydrolyzed quantitatively to the scyllo-tetrol
(8) (m.p. ca. 297°C (decomp.)). Treatment of (8) with 5~
acid at lOO"C, ( 1 2 ) is converted into the tetrol ( 1 3 ) (94 %,
m. p.ca. 252°C (decomp.)),which can be hydrogenated (RaneyNi, 20°C, 1 at) to ( 1 4 ) (m.p. 218°C) and then cleaved with
aqueous hydrazine to give (9). This route, however, has its
disadvantages compared to the reaction sequence (5) --t. ( 1 0 )
in than it is necessary to isolate the intermediates ( 6 ) , (12),
and (13).
Br
Br
NaOH (molar ratio 1 :6, 90min, iW"C) yields the readily
soluble hydrazine compound (9)[7]; hydrogenolysis of ( 9 )
over Raney nickel affords streptamine ( I O U ) . (IOa) was
precipitated as the sulfate and identified as the hexaacetate
(lob) by comparison with an authentic sample (melting point,
IR, 'H-NMR)['I. The yield of this preparatively simple
synthesis-no intermediate needs to be isolated-amounts
to 7 6 7 5 % referred to (5).
f
OR
1
OH
fOj
( a j , R = R' = H
( b ) , R = R' = COCHz
The pressure reaction necessary for the hydrolysis (7) 4(8)
can be circumvented by resorting to a slightly different route
in which the pyridazinedione ( 1 2 ) (faint yellow crystals, m.p.
ca. 246°C (decomp.)),obtained by reaction of ( 6 a ) with maleic
anhydride (anhydrous methanol, 0"C, 10min) followed by
treatment with very dilute sulfuric acid (I min, 50"C, 97%),
is used in place of (7). On heating for 5 h in 5 % sulfuric
Angew. Chem. internat. Edit. / Vol. 14 fl97.5) / NO. 9
The obvious direct hydrolysis (6) 4(9) is not attainable;
both in alkaline as well as in acid solution, competing reactions
are clearly favored.
The structures of the compounds (6)-(14) are confirmed
by elemental analysis and spectral data; the stereochemical
details follow, primarily, from the results of 'H-NMR decoupling experiments at 270 and 360 MHztgl.
Received: November 13. 1974 [Z 125 IE]
German version: Angew. Chem. 87. 625 ( 1 975)
Publication delayed at authors' request
CAS Registry numbers:
IS). 39078-11-0; / 6 a ) , 53993-34-3; 16b). 53993-35-4; (71, 53993-36-5:
(8).53993-37-6; ( 9 ) . 51607-70-6; ( I O a ) , 488-52-8; ( / O h ) , 7380-63-4;
( I l ) > 54020-23-6; ( I Z ) , 53993-38-7; 1131, 53993-39-8; (14). 53993-40-1
[t] R. Schwesinger and H . Prinzbach, Angew. Chem. 84, 990 (1972); Angew.
Chem. internat. Edit. J I , 942 (1972); E. Vogel, H . 4 . Altenbach, and C. D.
Sommerfeld, Angew. Chem. 84, 986 (1972); Angew. Chem. internat. Edit.
J I, 939 ( t 972).
[2] R. Schwesinger, Dissertation. Universitat Freiburg 1975.
[3] R. Schwesinger, H . Fritz. and H . Prinzbach, Angew. Chem. 85, 1 I10
(1973); Angew. Chem. internat. Edit. 12, 993 (1973); R. Schwesinyer, H. Fritz.
and H . Prinzbach, Angew. Chem. 85, 1107 11973): Angcw. Chem. internat.
Edit. 12.989 (1973);S.Kagabu and H . Prinzbach,Angew. Chem. 87.248 (1975);
Angew. Chem. internat. Edit. 14, 252 (1975); H. Prinzbach, C. Kaiser. and
H. Fritz, Angew. Chem. 87,249 (1975); Angew. Chem. internat. Edit. 14. 253
(1975); H. Prinzbach, H.-W Schneider, and R . Schwesinger, unpublished;
t.Knorhe and H . Prinzbach. Tetrahedron Lett., in press.
[4] For the use of ( 4 ) in the synthesis, inter alia, of trans-"benzene trioxide"
and of ris-"benzenediimine" see R. Keller, Diplomarbeit, Universitat Freiburg
1974; 8. G a ~ ~ e n k a mPart
p , of a dissertation, in preparation, Universitlt Freiburg.
[5] Earlier syntheses: M. L. Wol/rom, S. M . Ohn, and W J . Polglase, J.
Amer. Chem. SOC. 72, 1724 (1950); K . Heyns and H. Paulsen, Chem. Ber.
89, 1152 (1956): 7: Suami and S. Ogawa, Bull. Chem. SOC. Jap. 38, 2026
(1965); N . Kurihara, 7: Kurokawa, and M . Nakajima, Agr. Biol. Chem. 31,
1166 (1967): S. Ogawa, 7: Abe, H . Sano, K . Kotera, and 7: Suami, Bull.
Chem. SOC.Jap. 40,2405 (1967); F. W Lichtenthaler, H . Leinerl, and 7:Suami,
Chem. Ber. 100,2383 (1967); 7: Suumi, S. Ogawa. H . Urhino,and M. Uchida,
Bull. Chem. SOC.Jap. 46, 3840 (1973).
[ 6 ] R . Schwrsinger, H . Fritz, and H . Prinzbach, Angew. Chem, 85. 1 I 1 1
(1973); Angew. Chem. internat. Edit. 12, 994 (1973).
[7] T Suami. S. Ogawa, H . Uchino, and M . Uchida, Bull. Chem. SOC.Jap.
46, 3840 (1973).
[XI We thank Prof. F. W Lichrenthaler for asample ofstreptamine hexaacetate
(IOh).
191 We thank Prof. H. Arhenbach for the MS measurements, Dr. H. Fritz
for recording the high-field 'H-NMR and I3C-NMR spectra, and Dr. H. K6n$
for valuable suggestions.
631
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simple, chemistry, trioxatris, synthesis, streptamine, tota, homobenzene, cis
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