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Highly Enantioselective Synthesis of a 2 3-Dihydroindole Mediated by N-Methylephedrine.

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spectrum, however, is the unexpectedly intense signals associated with the half-field transition (AMs = k 2). According to theory, the intensity of the half-field transition is determined by the strength of the dipolar interaction. Recently Eaton and Eaton["] calculated that the relative intensity defined by the ratio (intensity of AMs = It 2)/(total
intensity of AMs = f 1) should be approximately 20/r6,
where r is the interspin distance in Assuming there is no
gross distortion of the porphyrin rings, their equation estimates the su. . .Cu distance in the dicopper complex of 7
to be < 2 A, a highly unlikely situation. This issue will
have to be resolved by an X-ray structure determination.
20 mT
Highly Enantioselective Synthesis of a
2,3-Dihydroindole Mediated by N-Methylephedrine
By Robert Jan Vijn, W. Nico Speckamp*, Bart S. de Jong,
and Henk Hiemstra
The single-step synthesis of enantiomerically pure compounds from prochiral educts via the intermediary of a
chiral catalyst is the pinnacle of asymmetric synthesis['].
Reactions that approach such enzymatic processes are still
scarce[']. Here, we wish to communicate the discovery of
such a reaction in the course of our investigations of the
synthesis of dihydroindole~[~],
valuable intermediates in
the total synthesis of mitomycins and indole a l k a I o i d ~ [ ~ * ~ ~ .
Cyclization of azomethines 1 to afford the 2,3-dihydroindoles 2 and 3 proceeds with lithium alkoxide or sodium alkoxide in the presence of the corresponding alcohol in tetrahydrofuran (THF) at 0-20°C. If a bulky secondary or tertiary alcohol is used, the predominant product is the cis-2,3-dihydroindole 2, with less than 10% of the
trans-isomer 3 being formed"].
We recently reported"] that low asymmetric induction
(ee 17-31%) results if a chiral alcohol, i.e. (-)-menthol or
(-)-borneol, is used in this reactionL5].The degree of enantioselectivity showed little dependence on the structure of
chiral alcohol or azomethine, the nature of the cation (Li
or Na), or on temperature.
Fig. I. X-band EPR spectrum of Cu(rQ-Cu(ii) complex of diporphyrin 7 in
toluene at - 15OoC, c = 1 mmol/L. Modulation amplitude= 1 mT;
v=9.2 GHz. D is half the distance between the centers of the parallel absorptions. g,,=2.18, g 1 =2.05.
The dicobalt complex of 7 has been synthesized, and
preliminary study indicates that a pyrolytic graphite- surface coated by this cobalt diporphyrin is indeed able to reduce O2 almost exclusively via the 4e path in 0.5 M aqueous trifluoroacetic acid"'].
Received: October 26, 1983 [Z 604 IE]
German version: Angew. Chem. 96 (1984) 154
[I] J. P. Collman, P. Denisevich, Y. Konai, M. Marrocco, C. Koval, F. C.
Anson, J. Am. Chem. SOC.102 (1980) 6027; H. Y. Liu, M. Weaver, C. B.
Wang, C. K. Chang, J. Electroanal. Chem. 145 (1983) 439.
[2] T. L. Netzel, M. A. Bergkamp, C. K. Chang, J. Am. Chem. SOC.104
(1982) 1952.
[3] C. K. Chang, J. Heterocycl. Chem. 14 (1977) 1285; C . K. Chang, J. Chem.
SOC.Chem. Commun. 1977, 800.
(41 a) C. F. Wilcox, Jr., J. P. Uetrecht, K. G. Grohmann, J. A m . Chem. SOC.
94 (1972) 2532; b) C. D. Campbell, C. W. Rees, J. Chem. SOC.C 1969,
742; F. M. Logullo, A. H. Seitz, L. Friedman, Org. Synth. 48 (1968)
[5] C. F. Wilcox, Jr., G. D. Grantham, Tetrahedron 31 (1975) 2889.
[6] J. L. Abchibald, D. M. Walker, K. B. Shaw, A. Markovac, S. F. MacDonald, Can. J. Chem. 44 (1966) 345.
[7] 1: 'H-NMR (CDCI,): 6= 1.45 (12H, t, Et), 1.75 (12H, t, Et), 3.00 (12H,
s, Me), 3.25 (12H, s, Me), 3.80 (SH, q, Et), 3.50 and 4.15 (SH, 2q, Et),
6.90 (2H, d, H-4,5-biph.), 7.00 (2H, t, H-3,6-biph.), 7.25 (2H, d, H-2,7biph.), 8.45 (4H, s, meso-H), 8.95 (2H, s, meso-H), -7.45 (2H, s, NH),
-7.80 (ZH, s, NH); MS: m/z 1104 (M+), 552 (M2'); UV-VISh,.,(&M)
630 nm (2800), 578 (7500), 542 (7700), 508 (13200), 378 (189500).
[8] C. K. Chang, I. Abdalmuhdi, J. Org. Chem., in press.
[9] H. P. Figeys, J. Chem. SOC.Chem. Commun. 1967, 495.
[lo] T. D. Smith, J. R. Pilbrow, Coord. Chem. Rev. 13 (1974) 173; M. Chikira,
H. Kon, R. A. Hawley, K. M. Smith, J. Chem. Soc. Dalton Trans. 1979,
[ll] S. S. Eaton, G. R. Eaton, J. A m . Chem. SOC.104 (1982) 5002.
[12] C. K. Chang, H. Y. Liu, 1. Abdalmuhdi, unpublished.
Angew. Chem. Int. Ed. Engl. 23 (1984) NO. 2
a, R = CsH5 ; b, R = n-C3H, ; c, R = t-C&
; 'd, R = CH?-C-CH,
We report here the use of chiral fl-amino alcohols, which
have already been successfully employed as bifunctional
catalysts in chiral base catalysis[61.Although quinine and
(S)-N-methylprolinol gave very low chemical and/or enantiomeric yields, the results with derivatives of ephedrine
were good (Table 1). Treatment of the azomethine l b with
the reagent derived from 1 equiv. of nBuLi and 2.5 equiv.
of (+)-(lS,2R)-N-methylephedrine 4b in THF afforded
(-)-2,3-dihydroindole 2b in 50% yield and in more than
95% eel7](Table 1; entry 4); we were unable to detect the
other enantiomer in the 'H-NMR spectrum of the crude
Likewise, ( - )-(lR, 2S)-N-methylephedrine 5b
yielded the enantiomerically pure (+ )-enantiomer of 2b
(entry 5).
An unfortunate feature of this asymmetric synthesis is its
extreme sensitivity to small structural variations in substrate and catalyst system. Replacing Li@with Na' leads
to a drastic reduction in ee (entry 6). Ephedrine 4a (entries
2, 3) and N-benzoylephedrine 4f (entry 10) are useless as
chiral catalysts, whereas substitution of the N-methyl
group of 4b with larger groups is also detrimental (entries
7-9). Finally, the nature of R in the azomethine 1 appears
to be very important (entries I , 4, 11, and 12).
[*I Prof. Dr. W. N. Speckamp, R. J. Vijn, B. S. de Jong, Dr. H. Hiemstra
Laboratory of Organic Chemistry, University of Amsterdam
Nieuwe Achtergracht 129, NL-1018 WS Amsterdam (The Netherlands)
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0202-0165 $ 02.50/0
Table 1. Enantioselective synthesis of dihydroindoles 2 from azomethines 1
[a]. Cation: Li”.
3 [el
6 [el
Catalyst [b]
4b L=CH1
48 L = H
4b L=CHs
5b L=CH3
4~ L=C2Hs
46 L=CHzCH20CH,
4e L=CH2Ph
4f L = COPh
4b L=CH,
4b L=CH3
Sign of
[a] Experimental procedure: [7]. [b] 4a and 50 are commercially available;
4b-f and 5b were synthesized from 4a and 5a by either reductive methylation (4b, 5b) [9] or by acylation (4f), followed by LiAlH4 reduction (4c-e).
[c] Isolated yields except for entry 7, for which the ‘H-NMR yield is given.
[dl Determined by ’H-NMR spectroscopy using Eu(hfc), [5, 7). [el Cation:
Mechanistically, this ring-closure reaction must be
viewed as a disrotatory 1,5-electrocyclization[3~’01.
To account for the formation of the cis product we assume that
ring closure occurs from the Z-azomethine geometry and
that the imide enolate has the enolate oxygen directed toward the azomethine, both moieties being arranged in a
helix-type conformation. The favorable influence of the
hydroxy group is most probably the result of hydrogen
bonding with the azomethine nitrogen (0-H . . .N) in the
transition state. Furthermore, in the highly structured transition state the tertiary amine function of the chiral auxiliary is bound via Li’ to the enolate oxygen as shown in 6.
This model accounts for the failure of Na’ (entry 6 ) and of
the N-benzoyl group (entry 10) to induce high ee values.
Due to the weak Lewis acidity of Na’ and the weak Lewis
basicity of an amide nitrogen the interaction between enolate and catalyst is loosened in both cases.
Since the conversion of rac-2d into rac-vindorosine has
previously been reported[’], the present result can be formally regarded as an enantioselective synthesis of this alkaloid.
Received: September 26, 1983;
revised: November 7, 1983 [Z 572 IE]
German version: Angew. Chem. 96 (1984) 165
[I] J. W. ApSimon, R. P. Seguin, Tetrahedron 35 (1979) 2797; H. Wijnberg,
CHEMTECH 1982, 116.
[2] For an early and a recent example see: Z. G. Hajos, D. R. Parrish, J.
Org. Chem. 39 (1974) 1615; T. Katsuki, K. B. Sharpless, J. Am. Chem.
SOC.102 (1980) 5976.
[3] W. N. Speckamp, S. J. Veenstra, J. Dijkink, R. Fortgens, J. Am. Chem.
SOC.103 (1981) 4643. Review on 1,5-electrocyclizations:R. Huisgen, Angew. Chem. 92 (1980) 979; Angew. Chem. Inl. Ed. Engl. 19 (1980) 947.
[4] S. J. Veenstra, W. N. Speckamp, J . Am. Chem. SOC.103 (1981) 4645; J.
Dijkink, J. N. Zonjee, B. S. de Jong, W. N. Speckamp, Heterocycles 20
(1983) 1255.
[5] S. J. Veenstra, W. N. Speckamp, J. Chem. SOC.Chem. Commun. 1982,
[6] H. Hiemstra, H. Wynberg, J . Am. Chem. Soe. 103 (1981) 417.
[7] Procedure: To a well stirred solution of (IS,2R)-N-methylephedrine4b
(270 mg, 1.63 mmol) ([a]!&= +25 (c=6, EtOH)) in 5 mL THF under
nitrogen at 0°C was added 0.40 mL of a 1 . 6 ~
solution of nBuLi (0.64
mmol) in hexane. Two minutes later a solution of azomethine l b (210
mg, 0.63 mmol) in 1 mL of toluene was added. The resultant blue mixture slowly turned red and was stirred for 45 min at 0°C.5 mL of 2~
HCI was then added and the mixture extracted with ether (3 x 10 mL).
The ether solution thus obtained was dried (Na2S04)and evaporated to
leave a light yellow oil (110 mg). Purification via column chromatography [SO2 (70-150 mesh), EtOAc, hexane 1 :2] afforded 104 mg (0.31
mmol, 50%) of Zb as light yellow crystals, m.p. 118-119°C (EtOAc/
hexane); m.p. (rac-2b) 125--126°C [3, 81. [a]?$,-71 (c=5.25, CHCI3);
IR(KBr): 3320 (NH), 1760 and 1685 (C=O), 1600,1385,1340,1165,935,
695 cm-I. ’H-NMR (250 MHz, CDCI,): 6=7.45-6.65 (m, 9H), 4.70 (d,
1 H, J = 14 Hz, CH.H,Ph), 4.61 (d, 1 H, J = 14 Hz, CH,H,Ph), 3.85-3.70
(m, 2H, NH and >CH-nPr), 3.17 (d, 1 H, J = 19 Hz, -CH.H,CONa,
1.7-1.1 (m, 4H, CHICHI),
2.70 (d, l H , J = 1 9 Hz, -CH,H,CON=),
0.79 (t. 3H, CH,). Addition of Eu(hfc), did not change the ‘H-NMR
spectrum (in the case of the racemic compound the signal originally at
S=3.17 was split into two doublets of equal intensity).
[8] S. J. Veenstra, Dissertation, University of Amsterdam 1982.
[9] H. T. Clark, H. B. Gillespie, S. Z. Weisshaus, J. Am. Chem. SOC.55
(1933) 4571.
[lo] D. N. Reinhoudt, G. W. Visser, W. Verboom, P. H. Benders, M. L. M.
Pennings, J . Am. Chem. SOC.10s (1983) 4775.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
1,2-Dioxetane: Synthesis, Characterization, Stability,
and Chemiluminescence**
By Waldemar Adam* and Wilhelm J. Baader
To the best of our knowledge“’, the parent 1,2-dioxetane
1 has been observed only as a transient species in the gas
phase via the formaldehyde fluorescence arising from the
cycloaddition of singlet oxygen to ethenel’l. The statement
... “isolation and characterization of 1,2-dioxetane still remain a challenge” ...131 encouraged us to try to prepare the
parent 1,2-dioxetane. Here, we report its synthesis, characterization, stability, and chemilurninescen~e~~~”.
- CHzO
--+ hu
Synthesis: After photosensitized singlet-oxygenation of
ethene in trichlorofluoromethane at - 40°C and in the gas
phase both failed to produce even traces (monitored by
chemiluminescence) of dioxetane 1, we returned to the
now classical Kopecky methodL5).A solution of 2.82g
(20.0 mmol) I-bromo-2-hydroperoxyethane (2)161in 20 mL
dichloromethane and a solution of 8.00 g (143 mmol) KOH
in 20 mL water was vigorously mechanically stirred for ca.
15 min: the mixture was then warmed up from 0°C to
20°C. The organic phase was washed with 10 mL cold water, dried over MgS04, and the 1,2-dioxetane 1 distilled as
a CHzClz solution at O”C/lOO torr to 2OoC/10 torr. Thin
[*I Prof. Dr. W. Adam, Dr. W. J. Baader
Institut fur Organische Chemie der UniversitPt
Wtirzburg (FRG)
[**I We thank the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Stiftung Volkswagenwerk for generous financial support.
0570-0833/84/0202-0166 $02.50/0
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 2
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methylephedrinium, synthesis, enantioselectivity, dihydroindole, highly, mediated
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