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Regioselective anthranoylation of demethylated aconitine: Novel analogues of aconitine inuline and methyllycaconitine
Telmhedmn Letters, Vol. 35, No. 20. pp. 3371-3314, 1994 Elsevier ScienceLtd Printed in Great Britain 0040-4039~94 S6.00+0.00
0040-4039(94)EO520-8
of Deme4hylated Aconitine:
Regioselective Anthranoylation Novel Anahgues
of Aconitine,Inuline and Methyllycaconitine
David J. Hardick, Ian S. Blagbrougb*, Sumn Waunaa&t~ and Barry V. L. I%tter
&I.--t
of&dicbml
c-y,
mool
and E’tmrmocology,
%bool ufl’barmq
and
of Biology and Biochemistrg,
University of Bath, Clavertom Down, Batb BA2 7AY, U.K.
Manyxlmlrauyoccurring ‘~d~alkaloiidisplayimpartantbiologicalactivitiesdsemiThere is an urgent requirement to
synthesis has been used to prepare several analogues of these basesPS5
identify selective phazmaml ogicalrespomestosuchalkaloidsinordertodelineatcstructurc-activity relationships (SAR) and to clisseq wherever possible, toxic from bemficial activities. Thus, aconitine (1) is a potent ne tlmoxin6, acting by modulating voltage-sensitive alkaloid methyllycaumitine
sodium channels, but the related nordi~Oid
(MIA) (2) is the most potent, non-pm&acam,
neumnal niminic
acetylcholine.
receptor antagonkt yet found’ using qklsclecti~ly
demcthylated (1)8, we have prepand nowl aIuuogucs ofinuline (3) and then of
MLA (2). In this Lcner, we present an efficknt entry to these amlogues by regioselefzivc (12) with isatoic anhydride (13). and conversion of the comsponding
homochiral S-mcthylsuuSmide
mhmnoylatim
aniline in antbmn&te
(20). l’lds pr~oool will also have applicatba
of
(14) into the
in the prcpamion
of
analoguesoftheimineanhweidelpbinineaadaftkacetatenudicauline?3 16,18-Di-0 -&smethylaconitine anthranoyl ester after column cdgraphy
(4>8 was matted with (W). in DMF at 70°C. to sfkd (Siq,
5% MeOHCH&).
(45%) a mono-
However, detailed inspection of
the’HNMRsptceum(270MHz)trtvcalcdthatthc~~wasthtcsmQofthc~alcoholat C-3 and not of the desired C-l 8 neopmtyl alcohoL In particular, there was a chamcmistic
doublet of doublets
for H-3 at low field (5.10 ppm, 12.5 and 5.1 Hz) whilst H-18 was assigned to a multiplet at 3.11-3.25 ppm which also contained the methoxy signals (at 3.21 and 3.24 ppm) of C-l and C-6. 3371
3372
w&y,
the pmtons assigned to the AB pattan of the C-18 methylene group in (14). when it is
anthraIloylate&resoMte
at lower field (4.26-4.48 ppm) vidt
irlfra Thehigh reactivity of the C-3 secondary
alcohol has pnwiously been reported with respect to facile acetate ester formation5, but we cannot entirely discountC-18h~~aoetylationfallowedby1.3acylgFoupnri~~viassix~ transfers have pmcedent ia su&
chemisuy and as l&acyl
In order to prepare the corresponding MLA/aconitjne
ring. Such acyl aan&rs
in inositollochrmistry.
hybrid aaalogues of (2) and (3). the C-3 hydmxyl
ofaconitine(1)necdedtobetaqxmilypMectedaevenmmoved. demethylation using IvIe@& ill dichl me
Formation of (6) and subsequent
at 25% 8ave 0,
The C-3 acetate pmvented the desired Gdemethylation
(8) and (9) in a ratio 1:3:3 respectively.
at C- 18 which had previously been so facile8 with a
hydmxyl functianal gtwp at C-3. We the&ore dcckied to teamve completely the secondary alcohol from C-3 in (1). This reduction can be ef&iently pmceduret 1, and 3-deoxyaconitine
accomplished using a Barton radical (tin hydride) deoxygenation
(10) was pmpared by this w
and his co-workers.12 Thus, the imi&&e
thim
following the procedure of Pelletier
(II), pepad in1,2dichloroethane,
4 h at 80°C,
(85%). was treated with nBu$M-I, in toluene at 8O”C, to give (10) (76%).12 Regioselective demethylation of
(10) wasachieved smoothly with Me@, 10 h at 25oC. to reveal the
desired substituted neopentyl alcuhol in (12) (48%). Reaction with (W), 17 h at 75T, gave the anthranilate (14) xegios&ctively
(45%). a novel inuline (3) analogue. with no loss of acetate or benzoate.
The ‘H NNIR
spectroscopic evidence (270 MHz) for this regioselective ester formation includes the H-l 8 methylene signals of (14) resonating at low field (4.26 ppm, d, 10.4 Hz) and (4.44-4.48. m, H- 18 and H-15), whilst the comparable signals of aconitine (1) resonate at 3.50 and 3.63 ppn~ The 13C NMR spectmm was particularly useful in de&rmining the site of demthylation,
as then? was a significant upfield shift of the carbon attached to
the O-methyl ether. Thus, in 3-deoxyaconitine
(10) C-18 resonates at 80.2 ppm in the O-methyl ether,
whilstinthe~spondingprimaryatoobal(12)this~~hasmwedupfieldto71.2ppm. this primay alcohol, ester&&on
Withrespectto
at C- 18 pmduced no apprdablc change in chemical shift at C- 18 as (14)
also shows a chemical shift of 71.2 ppm which we assign to C- 18. This consistency in the chemical shift of C-l 8 on esterification is comparable with the similar values of the methylene signals found in ethanol (58.2 ppm) and in ethyl acetate (60.3 ppm). Erom the initial demethylation of (lo), some (l5) (19%) was also recovd
which was reacted with an
equivalent of (13) in the usual manner. From an inspection of the lH NMR qecuum, had also occm
some dianthmnoylation
to give (16). The low field signal at 5.38 ppm (d, 5.7 Hz), which resonated near to the
other methine ester pmton si8nal of H-14 (5.06 ppm, d, 4.9 Ha), was attributed to H-16 aud not to H-15. The H-15 proton still resonated at 4.70 ppm (ad, 5.7 and 3.1 Hz) coupling thmugh oxypn (d, 4.32 pprn, 3.1 Hz) and was similar to that seen in (1).‘3 Furthm, of (4), using two equivalents of acetic anhydrkie in dichlommethane
to the C-IJ-OH
from our studies of the acctylation
and catalysed by 4dimethylamino-
pyzidine, we know that the major product from this reaction is the C-16,18diacctate.
3373
(0
R’=OH
R2=McR3=Me
(4)
R’=OH
R2=H
R’=H R2=H
(2)
R=
(3)
RI
R’=H
NtEL (6)
R’=M&OO
(10)
R’=H
R’=Me
R’=Me
R2=Me
R’=Me
OH
Rz=Me
(11) R’ = 0.CS.N AN
R’s&
\3
(12)R’=H
R2=iI
(14)R’=H
R2=
Rt=Me o
R’=Me %
b (15) R’=H
R2=H
(16) R’=H
R2=’
R3=H o &-“=& 0
(18)R’=H
(19)
R’=H
(20)R1=H
R*=
R* =
R2=
&
v)
R’=Mc
R2=Mc
(8)
R’=Me
R2=H
(9)
R’=H
R2=H
H N 0
qHR3=Me
CqH
R’=Me
R’=Me
113)H
(17)
3374
Reactionof (14) with hcnnnchiml S-(-)-methylsuccinicanhydride(17) (3.4 equiv.). in dichlm at 25°C. affcsded the mixed half-acidamides (Is) and (I.9) which were not isolated,but wue bothconverted directlyintotheaneapardinghomochiml~(20)
on tnabnart withcarbonyldiimirlamlc(2.8
equiv.) at 25°C. Putifi&on on SiO, (5% MeG~2Cl2)
gave pute (20) (51%) aa a abdosr,
anxxphous
solid (satisfactory1H. ‘3c NMR and mass spectra). These novel semi-syntheticnolxli@qenoid qelolds (14) aod(2o)shouldbeusefulin~~respectiverole(s)of~~~~aadthc~~moieties for elicitingbinding(haptophores)resultingin the selectivebiochemicalphannacokqyofaIccld~(l)and MLA(2)atPRxeinreceptors.
sllchsARstudiesareinpmgmssinourlabomu+es.
AcknowIedgemenIx We acknowledgethe financialsupportof The Wellanne TNSt (Pmject Grant 036214). We wisk to expressour gratitudeto Dr MG Rowan and Ms PA &ates (Universityof Bath) and to Dr T Lewis (Zeneca Agrochemicals)for theirhelpfulcommalts,adviceandenco umgaualttbroughoutthese studies. BVLP is a Lista InstituteResearchPtofessor.
REFERENCES
1.
Pellet& S. W.; Mody, N. V.; Joshi, B. S.; Schramm, L. C. In AZkaZoiifs:CiremicaZandSioZogical
Perspectives; Pelleticr, S. W. Ed.; J. Wiley and Sons: New York, lw14.2, pp. 205-462; Pelletier. S. W.; Joshi. B. S. In A&a&i&: Springer-Verlag: New York,
Chemical and Biological Perspectives; Pdetier, S. W. Ed.;
1991,7, pp. 297-564.
2.
Yunusov, M. S. Natural Product
Reports 1991,8,499-526.
3.
Yunusov, M. S. NaturaZProduct Reports 1993, IO,411-485.
4.
Ross, S. A.; Pellet& S. W.
Heterocycles 1990.31, 67 l-675.
5.
Pelletier.S. W.; Ross, S. A.
Heterocycles 1991.32, 1307- 13 15.
6.
Benn, M. I-I.; Jacyno,J. M. In AZkuZoids:Chemicaland Biological Perspectives; RUetier, SW. Ed.; J. Wiley and Sons: New York,
1983.I.pp.153-210.
7.
Wo~acott, S.; Albuquerque,E. X.; Bertrand,D.
8.
Blagbrough, I. S.; Hatdick, D. J.; Wonnacott, S.; Potter,B. V. L.
Methods in NeruosciencesX993,12,263-275. Tetrahedron Len. 1994.35,
preeding titter. 9.
Chaplin, D.; Grout, D. I-I. G.; Bornemann,S.; Hutchinson,D. W. J. Chem. Sot.
Perkin I,
1992, 235-237. 10. Meek, J. L.; Davidson, F.; Hobbs, J. J. Amer. Chem. Sot. 1988, ZZO, 2317-2318. 11. Barton, D. H. R.; McCombie, S. W. J. Chem. Sm. Perkin I 1975,1574-1585. 12. Kulanthaivel,P.; Pelletier,S. W. Tetrahedron 1988,44,4313-4320. 13. Joshi, B. S.; Wunderlich. J. K.; Pelletier, S. W. Can. J. Chem. 1987.65,99-103. (Received in UK 31 January 1994; revised 4 March 1994, accepted
10 March 1994)
0040-4039(94)EO520-8
of Deme4hylated Aconitine:
Regioselective Anthranoylation Novel Anahgues
of Aconitine,Inuline and Methyllycaconitine
David J. Hardick, Ian S. Blagbrougb*, Sumn Waunaa&t~ and Barry V. L. I%tter
&I.--t
of&dicbml
c-y,
mool
and E’tmrmocology,
%bool ufl’barmq
and
of Biology and Biochemistrg,
University of Bath, Clavertom Down, Batb BA2 7AY, U.K.
Manyxlmlrauyoccurring ‘~d~alkaloiidisplayimpartantbiologicalactivitiesdsemiThere is an urgent requirement to
synthesis has been used to prepare several analogues of these basesPS5
identify selective phazmaml ogicalrespomestosuchalkaloidsinordertodelineatcstructurc-activity relationships (SAR) and to clisseq wherever possible, toxic from bemficial activities. Thus, aconitine (1) is a potent ne tlmoxin6, acting by modulating voltage-sensitive alkaloid methyllycaumitine
sodium channels, but the related nordi~Oid
(MIA) (2) is the most potent, non-pm&acam,
neumnal niminic
acetylcholine.
receptor antagonkt yet found’ using qklsclecti~ly
demcthylated (1)8, we have prepand nowl aIuuogucs ofinuline (3) and then of
MLA (2). In this Lcner, we present an efficknt entry to these amlogues by regioselefzivc (12) with isatoic anhydride (13). and conversion of the comsponding
homochiral S-mcthylsuuSmide
mhmnoylatim
aniline in antbmn&te
(20). l’lds pr~oool will also have applicatba
of
(14) into the
in the prcpamion
of
analoguesoftheimineanhweidelpbinineaadaftkacetatenudicauline?3 16,18-Di-0 -&smethylaconitine anthranoyl ester after column cdgraphy
(4>8 was matted with (W). in DMF at 70°C. to sfkd (Siq,
5% MeOHCH&).
(45%) a mono-
However, detailed inspection of
the’HNMRsptceum(270MHz)trtvcalcdthatthc~~wasthtcsmQofthc~alcoholat C-3 and not of the desired C-l 8 neopmtyl alcohoL In particular, there was a chamcmistic
doublet of doublets
for H-3 at low field (5.10 ppm, 12.5 and 5.1 Hz) whilst H-18 was assigned to a multiplet at 3.11-3.25 ppm which also contained the methoxy signals (at 3.21 and 3.24 ppm) of C-l and C-6. 3371
3372
w&y,
the pmtons assigned to the AB pattan of the C-18 methylene group in (14). when it is
anthraIloylate&resoMte
at lower field (4.26-4.48 ppm) vidt
irlfra Thehigh reactivity of the C-3 secondary
alcohol has pnwiously been reported with respect to facile acetate ester formation5, but we cannot entirely discountC-18h~~aoetylationfallowedby1.3acylgFoupnri~~viassix~ transfers have pmcedent ia su&
chemisuy and as l&acyl
In order to prepare the corresponding MLA/aconitjne
ring. Such acyl aan&rs
in inositollochrmistry.
hybrid aaalogues of (2) and (3). the C-3 hydmxyl
ofaconitine(1)necdedtobetaqxmilypMectedaevenmmoved. demethylation using IvIe@& ill dichl me
Formation of (6) and subsequent
at 25% 8ave 0,
The C-3 acetate pmvented the desired Gdemethylation
(8) and (9) in a ratio 1:3:3 respectively.
at C- 18 which had previously been so facile8 with a
hydmxyl functianal gtwp at C-3. We the&ore dcckied to teamve completely the secondary alcohol from C-3 in (1). This reduction can be ef&iently pmceduret 1, and 3-deoxyaconitine
accomplished using a Barton radical (tin hydride) deoxygenation
(10) was pmpared by this w
and his co-workers.12 Thus, the imi&&e
thim
following the procedure of Pelletier
(II), pepad in1,2dichloroethane,
4 h at 80°C,
(85%). was treated with nBu$M-I, in toluene at 8O”C, to give (10) (76%).12 Regioselective demethylation of
(10) wasachieved smoothly with Me@, 10 h at 25oC. to reveal the
desired substituted neopentyl alcuhol in (12) (48%). Reaction with (W), 17 h at 75T, gave the anthranilate (14) xegios&ctively
(45%). a novel inuline (3) analogue. with no loss of acetate or benzoate.
The ‘H NNIR
spectroscopic evidence (270 MHz) for this regioselective ester formation includes the H-l 8 methylene signals of (14) resonating at low field (4.26 ppm, d, 10.4 Hz) and (4.44-4.48. m, H- 18 and H-15), whilst the comparable signals of aconitine (1) resonate at 3.50 and 3.63 ppn~ The 13C NMR spectmm was particularly useful in de&rmining the site of demthylation,
as then? was a significant upfield shift of the carbon attached to
the O-methyl ether. Thus, in 3-deoxyaconitine
(10) C-18 resonates at 80.2 ppm in the O-methyl ether,
whilstinthe~spondingprimaryatoobal(12)this~~hasmwedupfieldto71.2ppm. this primay alcohol, ester&&on
Withrespectto
at C- 18 pmduced no apprdablc change in chemical shift at C- 18 as (14)
also shows a chemical shift of 71.2 ppm which we assign to C- 18. This consistency in the chemical shift of C-l 8 on esterification is comparable with the similar values of the methylene signals found in ethanol (58.2 ppm) and in ethyl acetate (60.3 ppm). Erom the initial demethylation of (lo), some (l5) (19%) was also recovd
which was reacted with an
equivalent of (13) in the usual manner. From an inspection of the lH NMR qecuum, had also occm
some dianthmnoylation
to give (16). The low field signal at 5.38 ppm (d, 5.7 Hz), which resonated near to the
other methine ester pmton si8nal of H-14 (5.06 ppm, d, 4.9 Ha), was attributed to H-16 aud not to H-15. The H-15 proton still resonated at 4.70 ppm (ad, 5.7 and 3.1 Hz) coupling thmugh oxypn (d, 4.32 pprn, 3.1 Hz) and was similar to that seen in (1).‘3 Furthm, of (4), using two equivalents of acetic anhydrkie in dichlommethane
to the C-IJ-OH
from our studies of the acctylation
and catalysed by 4dimethylamino-
pyzidine, we know that the major product from this reaction is the C-16,18diacctate.
3373
(0
R’=OH
R2=McR3=Me
(4)
R’=OH
R2=H
R’=H R2=H
(2)
R=
(3)
RI
R’=H
NtEL (6)
R’=M&OO
(10)
R’=H
R’=Me
R’=Me
R2=Me
R’=Me
OH
Rz=Me
(11) R’ = 0.CS.N AN
R’s&
\3
(12)R’=H
R2=iI
(14)R’=H
R2=
Rt=Me o
R’=Me %
b (15) R’=H
R2=H
(16) R’=H
R2=’
R3=H o &-“=& 0
(18)R’=H
(19)
R’=H
(20)R1=H
R*=
R* =
R2=
&
v)
R’=Mc
R2=Mc
(8)
R’=Me
R2=H
(9)
R’=H
R2=H
H N 0
qHR3=Me
CqH
R’=Me
R’=Me
113)H
(17)
3374
Reactionof (14) with hcnnnchiml S-(-)-methylsuccinicanhydride(17) (3.4 equiv.). in dichlm at 25°C. affcsded the mixed half-acidamides (Is) and (I.9) which were not isolated,but wue bothconverted directlyintotheaneapardinghomochiml~(20)
on tnabnart withcarbonyldiimirlamlc(2.8
equiv.) at 25°C. Putifi&on on SiO, (5% MeG~2Cl2)
gave pute (20) (51%) aa a abdosr,
anxxphous
solid (satisfactory1H. ‘3c NMR and mass spectra). These novel semi-syntheticnolxli@qenoid qelolds (14) aod(2o)shouldbeusefulin~~respectiverole(s)of~~~~aadthc~~moieties for elicitingbinding(haptophores)resultingin the selectivebiochemicalphannacokqyofaIccld~(l)and MLA(2)atPRxeinreceptors.
sllchsARstudiesareinpmgmssinourlabomu+es.
AcknowIedgemenIx We acknowledgethe financialsupportof The Wellanne TNSt (Pmject Grant 036214). We wisk to expressour gratitudeto Dr MG Rowan and Ms PA &ates (Universityof Bath) and to Dr T Lewis (Zeneca Agrochemicals)for theirhelpfulcommalts,adviceandenco umgaualttbroughoutthese studies. BVLP is a Lista InstituteResearchPtofessor.
REFERENCES
1.
Pellet& S. W.; Mody, N. V.; Joshi, B. S.; Schramm, L. C. In AZkaZoiifs:CiremicaZandSioZogical
Perspectives; Pelleticr, S. W. Ed.; J. Wiley and Sons: New York, lw14.2, pp. 205-462; Pelletier. S. W.; Joshi. B. S. In A&a&i&: Springer-Verlag: New York,
Chemical and Biological Perspectives; Pdetier, S. W. Ed.;
1991,7, pp. 297-564.
2.
Yunusov, M. S. Natural Product
Reports 1991,8,499-526.
3.
Yunusov, M. S. NaturaZProduct Reports 1993, IO,411-485.
4.
Ross, S. A.; Pellet& S. W.
Heterocycles 1990.31, 67 l-675.
5.
Pelletier.S. W.; Ross, S. A.
Heterocycles 1991.32, 1307- 13 15.
6.
Benn, M. I-I.; Jacyno,J. M. In AZkuZoids:Chemicaland Biological Perspectives; RUetier, SW. Ed.; J. Wiley and Sons: New York,
1983.I.pp.153-210.
7.
Wo~acott, S.; Albuquerque,E. X.; Bertrand,D.
8.
Blagbrough, I. S.; Hatdick, D. J.; Wonnacott, S.; Potter,B. V. L.
Methods in NeruosciencesX993,12,263-275. Tetrahedron Len. 1994.35,
preeding titter. 9.
Chaplin, D.; Grout, D. I-I. G.; Bornemann,S.; Hutchinson,D. W. J. Chem. Sot.
Perkin I,
1992, 235-237. 10. Meek, J. L.; Davidson, F.; Hobbs, J. J. Amer. Chem. Sot. 1988, ZZO, 2317-2318. 11. Barton, D. H. R.; McCombie, S. W. J. Chem. Sm. Perkin I 1975,1574-1585. 12. Kulanthaivel,P.; Pelletier,S. W. Tetrahedron 1988,44,4313-4320. 13. Joshi, B. S.; Wunderlich. J. K.; Pelletier, S. W. Can. J. Chem. 1987.65,99-103. (Received in UK 31 January 1994; revised 4 March 1994, accepted
10 March 1994)