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First synthesis of an indole glucosinolate
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FIRST SYNTHESIS OF AN INDOLE GLUCOSINOLATE1
M.C.Viiud Laboratoire
de Chimie Bioorganique
& P.Rollin*
et Analytique,UniversitB France
Summary: The synthesis of glucobrassicin, desulfo-analogue is described.
d’O&ans,
the parent structure
B.P.6759,45067 Orl6ans Cedex 2,
of the indole glucosinolate
family, and its
Optimal utilization of the high nutritive value of rapeseed meal requires maximum lowering and control of its glucosinolate content. Glucosinolates _I constitute a structurally homogeneous grou anomeric thiohydroximoyl derivatives of 1-thio-B-D-glucopyranose which differ only in the aglycon A.
R- H, OUe, OSO, HO R'- H, 4-OH, 4-We
A
1
-
It
Among the ten major glucosinolates of oil-seed rape, tryptophan-derived indole structures 2 seem to induce a strong physiological activity (goitrogenicity, nitrite-trapping, alteration of chemically-induced carcinogenesis...) in animals bred on rapeseed meal diets3A better knowledge of their behaviour requires efficient synthetic routes to the glucobrassicins 2. Thus, 3-formyl-indole was converted in a 56% ‘eld to 3-(2’~nitroethyl)-indole s4 through a Knoevenageltype condensation (MeNO AcGNH4, 1WC) s followed by chemoselective hydrogenation (NaBH4, Si02 230-400 mesh, CHCl3, &OH )6 of the intermediate 3-(2’~nitrovinyi)-indole.
a)
HaNO,
! AcORH,
NO,
3-formyl-indole
\
b) NaBH,
)
w
3 -
8’7”
RloR&s RlO
d I’
4
1 c)
HeONa
d) SOCl,, DUE Cl
p-thiol, NEt, \
NH
5
R,- AC
B2- H
-6
R,- R,- H
7
R,- AC
R,-
SO,K
8
R,- H
R,-
SO,K
The sodium nitronate derived Born 3 (MeONa, MeOH, Et20) was transformed (SOClz, DMB, -7VC) into (indol-3’-yl)acethydroxamoyi chloride 2 which was used directly in the next step : in situ generation &O, Et3N) of the correspondii (indoW-yl)acetonitrile oxide in the presence of 23,4,a_tetra-0-acctyI_l-thio-8D-glucopyranose led stereospeciBcapy to the (2)~thiohydroximate 5 (50% overall yield from a7*81417
1418
DeacetyIation of 5 (MeOH H20, Et3N) yielded (92%) destdfoghtcobrassicin @. On the other hand, selective 0-stdfation of 2 (pyr.So3, CH2Cla RT, then aq.KHCO3) furnished proghtcobrassicin 2 in 85% yield10 and fmaI deacetyktion (I&OH, H20, Et3N) gave a 96% yield of ghrcobrassicin 8”. Synthetic accesses to other biologicapy significaut substituted ghrcobrassicins ,2 are now beimg studied in our laboratory. Acknowkdgments The authors wish to thank ProtGuiUaumet for multiform support and A.Quinsac for HPLC anaIysis. References and notes 1) Taken from the forthcoming doctorate thesis of M.C.Viiud, Universitd d’Orl&rts, this work was presented at EUROCARB V, 21-25/08/1989, Prague. 2) More than 100 molecuks have now been characterized mainly in plants of the family Cruciferae; for a recentreview,see G.R.FenwicIc, RKHeaney & WJ.MuIIen, CRC Crit.Rev.Fd.Sci.Nutr.&, 123 (1983). 3) R.McDa.neII, A.E.M.McI.ean, A.B.Haniey, R.K.Heaney & G.R.Fenwick, Fd.Chem.Toxic., &59 (1988). 4) D.Ranganathan, C.Bhushan Rao, S.Ranganathan, AkMehrotra (1980). 5) LCan~ira, J.GouzaIo.Rodrig.uez, J.B.Subiiats, JAEscario, EurJ.Med.Chem., & 39 (1989). 6) A.K.Siibabu
& RJyengar, J.Org.Chem., a
I Jimenez
1185
& A.R.Martinez-Fernandez,
& R.T.Borchardt, Tetrahedron Lett., a227 (1983).
7) Anterior use of the nitronate-pathway : seeAJ.McLeod & J.T.Rossiter, J.Chem.Soc. Perkin Trans. I, 717 (1983) and references cited therein. 8) Fury satisfactory spectroscopic (IR, UV and 300 MHz lH NMR) and analytical data were obtained for ah new cOmp0Unds.d: SITUP,[a]~ +4” (C 0.70, CHCl3), NMR (CDCI3), &pm) 7.61 (d, lH, J4i i 7.8 Hz, H-4i), 7.40 (d, II& J7i6i 7.9 Hz, H-7i), 7.24 (ft, lH, H-6& 7.15 (ft, lH, H-5i), 7.10 (d, lH, 52 NH ZT0 Hz, H2i), 4.90-5.05 (m, 4H, H-l, H-2, H-3, H-4), 4.10 & 4.02 (26, 2H, Jgem 16.4 Hz, H-8 & H-8’), 4.07 (dd, ,jI-I, J63 5.5 Hz, Jgem 12.5 Hz, H-6), 3.94 (dd, lH, J6*,5 2.2 Hz, H-6’), 3.27 (m, lH, H-5). Hi refers throughout to the indole moiety. 9) 6 :SyUp, [a]D +2" (C 0.70,MeOH), NMR (D20), &(ppm) 7.72 (d, lH, J4i5i 7.8 Hz, H4i), 7.57 (d, lH, JTb6i 8.1 w H-7i), 7.32 (s,U-I,H-2i), 7.30(ft, lH, Hdi), 7.22 (ft, lH, H-5i), 4.85 (d, lH, J12 9.5 Hz, H-l), 4.21& 4.11(2d, 2H, Jgem 16.2 Hz, H-8 & H-8’), 3.62 (d, 2H, J6 5 3.0 Hz, H-6 & H-6’), 338 (dd, lI-& J4,5 9.7 Hz, H-4), 3.33 (dd, lH, Ju 9.5 Hz, H-2), 3.25 (dd, lH, J3,4 9.5 Hz, H-3), 3.01 (ddd, lH, H-5). 10) 2 : amorphous solid, [a]D 4” (C 2.40, MeOH), NMR (DMSO-d6), G(ppm) 7.67 (d, lH, J4i 5i 7.8 Hz, H4i), 7.37 (d lH, J2iNH 2.5.H~, H-ti), 7.35 (d, lH, J7 6i 8.0 Hz, H-7i), 7.07 (ft, lH, Hai), 6.96 (ft, lH, H5i), 5.41 (d, E-I, J12 10.0 Hz, H-l), 5.24 (dd, lH, 53 4 $.OHz, H-3), 4.89 (dd, lH J 9.0 Hz, H-4). 4.80 (dd, 1I-k J 3 8.8 Hz, H)-2),4.06 (dd, lH, J6,5 5.2 Hz, Jg;m 12.3 Hz, H-6), 4.05 (s, 2H,‘g&H-8’),3,95(m,lH, H-5), “382 (dd, lH, J&s 1.5 Hq H-6’). 11) 8 : amorphous solid, [a]D -95” (c 2.0, H20) 12, NMR (D20), i(ppm) 7.79 (d, lH, J4i,5i 7.8 Hz, H-4i), 7.56 (d, lH, J7i6i 8.1 Hg H-7i), 7.37 (s, lH, H-2$7.31 (ft, lH, Hdi), 7.23 (ft, lH, Hdi), 4.83 (d, lH, Jl2 9.6 Hz, H-l), 4.31& 4.21 (2d, W, Jgem 16.3 Hz, H-8 & H-8’), 3.59 (d, 2H, J6 5 3.3 Hz, H-6 & H-6’), 3.& (dd, lH, J4,5 9.8 Hz, H-4), 3.31 (dd, lH, Jq3 9.6 Hz, H-2). 3.21 (dd, lH, J3,4 9.6 H+ H-3), 2.% (ddd, lH, H-5). 12) R.GmeIim 8c A.I.Virtanen, AnnAcad.Sci.Fenn.(A), lez, 1 (l%l); [a]D -X3.3’(c 3.0, H20) reported for the tetramethylammonium salt. (Received in France 29 November 1989)
FIRST SYNTHESIS OF AN INDOLE GLUCOSINOLATE1
M.C.Viiud Laboratoire
de Chimie Bioorganique
& P.Rollin*
et Analytique,UniversitB France
Summary: The synthesis of glucobrassicin, desulfo-analogue is described.
d’O&ans,
the parent structure
B.P.6759,45067 Orl6ans Cedex 2,
of the indole glucosinolate
family, and its
Optimal utilization of the high nutritive value of rapeseed meal requires maximum lowering and control of its glucosinolate content. Glucosinolates _I constitute a structurally homogeneous grou anomeric thiohydroximoyl derivatives of 1-thio-B-D-glucopyranose which differ only in the aglycon A.
R- H, OUe, OSO, HO R'- H, 4-OH, 4-We
A
1
-
It
Among the ten major glucosinolates of oil-seed rape, tryptophan-derived indole structures 2 seem to induce a strong physiological activity (goitrogenicity, nitrite-trapping, alteration of chemically-induced carcinogenesis...) in animals bred on rapeseed meal diets3A better knowledge of their behaviour requires efficient synthetic routes to the glucobrassicins 2. Thus, 3-formyl-indole was converted in a 56% ‘eld to 3-(2’~nitroethyl)-indole s4 through a Knoevenageltype condensation (MeNO AcGNH4, 1WC) s followed by chemoselective hydrogenation (NaBH4, Si02 230-400 mesh, CHCl3, &OH )6 of the intermediate 3-(2’~nitrovinyi)-indole.
a)
HaNO,
! AcORH,
NO,
3-formyl-indole
\
b) NaBH,
)
w
3 -
8’7”
RloR&s RlO
d I’
4
1 c)
HeONa
d) SOCl,, DUE Cl
p-thiol, NEt, \
NH
5
R,- AC
B2- H
-6
R,- R,- H
7
R,- AC
R,-
SO,K
8
R,- H
R,-
SO,K
The sodium nitronate derived Born 3 (MeONa, MeOH, Et20) was transformed (SOClz, DMB, -7VC) into (indol-3’-yl)acethydroxamoyi chloride 2 which was used directly in the next step : in situ generation &O, Et3N) of the correspondii (indoW-yl)acetonitrile oxide in the presence of 23,4,a_tetra-0-acctyI_l-thio-8D-glucopyranose led stereospeciBcapy to the (2)~thiohydroximate 5 (50% overall yield from a7*81417
1418
DeacetyIation of 5 (MeOH H20, Et3N) yielded (92%) destdfoghtcobrassicin @. On the other hand, selective 0-stdfation of 2 (pyr.So3, CH2Cla RT, then aq.KHCO3) furnished proghtcobrassicin 2 in 85% yield10 and fmaI deacetyktion (I&OH, H20, Et3N) gave a 96% yield of ghrcobrassicin 8”. Synthetic accesses to other biologicapy significaut substituted ghrcobrassicins ,2 are now beimg studied in our laboratory. Acknowkdgments The authors wish to thank ProtGuiUaumet for multiform support and A.Quinsac for HPLC anaIysis. References and notes 1) Taken from the forthcoming doctorate thesis of M.C.Viiud, Universitd d’Orl&rts, this work was presented at EUROCARB V, 21-25/08/1989, Prague. 2) More than 100 molecuks have now been characterized mainly in plants of the family Cruciferae; for a recentreview,see G.R.FenwicIc, RKHeaney & WJ.MuIIen, CRC Crit.Rev.Fd.Sci.Nutr.&, 123 (1983). 3) R.McDa.neII, A.E.M.McI.ean, A.B.Haniey, R.K.Heaney & G.R.Fenwick, Fd.Chem.Toxic., &59 (1988). 4) D.Ranganathan, C.Bhushan Rao, S.Ranganathan, AkMehrotra (1980). 5) LCan~ira, J.GouzaIo.Rodrig.uez, J.B.Subiiats, JAEscario, EurJ.Med.Chem., & 39 (1989). 6) A.K.Siibabu
& RJyengar, J.Org.Chem., a
I Jimenez
1185
& A.R.Martinez-Fernandez,
& R.T.Borchardt, Tetrahedron Lett., a227 (1983).
7) Anterior use of the nitronate-pathway : seeAJ.McLeod & J.T.Rossiter, J.Chem.Soc. Perkin Trans. I, 717 (1983) and references cited therein. 8) Fury satisfactory spectroscopic (IR, UV and 300 MHz lH NMR) and analytical data were obtained for ah new cOmp0Unds.d: SITUP,[a]~ +4” (C 0.70, CHCl3), NMR (CDCI3), &pm) 7.61 (d, lH, J4i i 7.8 Hz, H-4i), 7.40 (d, II& J7i6i 7.9 Hz, H-7i), 7.24 (ft, lH, H-6& 7.15 (ft, lH, H-5i), 7.10 (d, lH, 52 NH ZT0 Hz, H2i), 4.90-5.05 (m, 4H, H-l, H-2, H-3, H-4), 4.10 & 4.02 (26, 2H, Jgem 16.4 Hz, H-8 & H-8’), 4.07 (dd, ,jI-I, J63 5.5 Hz, Jgem 12.5 Hz, H-6), 3.94 (dd, lH, J6*,5 2.2 Hz, H-6’), 3.27 (m, lH, H-5). Hi refers throughout to the indole moiety. 9) 6 :SyUp, [a]D +2" (C 0.70,MeOH), NMR (D20), &(ppm) 7.72 (d, lH, J4i5i 7.8 Hz, H4i), 7.57 (d, lH, JTb6i 8.1 w H-7i), 7.32 (s,U-I,H-2i), 7.30(ft, lH, Hdi), 7.22 (ft, lH, H-5i), 4.85 (d, lH, J12 9.5 Hz, H-l), 4.21& 4.11(2d, 2H, Jgem 16.2 Hz, H-8 & H-8’), 3.62 (d, 2H, J6 5 3.0 Hz, H-6 & H-6’), 338 (dd, lI-& J4,5 9.7 Hz, H-4), 3.33 (dd, lH, Ju 9.5 Hz, H-2), 3.25 (dd, lH, J3,4 9.5 Hz, H-3), 3.01 (ddd, lH, H-5). 10) 2 : amorphous solid, [a]D 4” (C 2.40, MeOH), NMR (DMSO-d6), G(ppm) 7.67 (d, lH, J4i 5i 7.8 Hz, H4i), 7.37 (d lH, J2iNH 2.5.H~, H-ti), 7.35 (d, lH, J7 6i 8.0 Hz, H-7i), 7.07 (ft, lH, Hai), 6.96 (ft, lH, H5i), 5.41 (d, E-I, J12 10.0 Hz, H-l), 5.24 (dd, lH, 53 4 $.OHz, H-3), 4.89 (dd, lH J 9.0 Hz, H-4). 4.80 (dd, 1I-k J 3 8.8 Hz, H)-2),4.06 (dd, lH, J6,5 5.2 Hz, Jg;m 12.3 Hz, H-6), 4.05 (s, 2H,‘g&H-8’),3,95(m,lH, H-5), “382 (dd, lH, J&s 1.5 Hq H-6’). 11) 8 : amorphous solid, [a]D -95” (c 2.0, H20) 12, NMR (D20), i(ppm) 7.79 (d, lH, J4i,5i 7.8 Hz, H-4i), 7.56 (d, lH, J7i6i 8.1 Hg H-7i), 7.37 (s, lH, H-2$7.31 (ft, lH, Hdi), 7.23 (ft, lH, Hdi), 4.83 (d, lH, Jl2 9.6 Hz, H-l), 4.31& 4.21 (2d, W, Jgem 16.3 Hz, H-8 & H-8’), 3.59 (d, 2H, J6 5 3.3 Hz, H-6 & H-6’), 3.& (dd, lH, J4,5 9.8 Hz, H-4), 3.31 (dd, lH, Jq3 9.6 Hz, H-2). 3.21 (dd, lH, J3,4 9.6 H+ H-3), 2.% (ddd, lH, H-5). 12) R.GmeIim 8c A.I.Virtanen, AnnAcad.Sci.Fenn.(A), lez, 1 (l%l); [a]D -X3.3’(c 3.0, H20) reported for the tetramethylammonium salt. (Received in France 29 November 1989)