- Email: [email protected]
Synthesis studies directed toward gelsemine. A new synthesis of highly functionalized cis-hydroisoquinolines
Tetrahedron Letters,Vol.29,No.31,pp Printed in Great Britain
3781-3784,1988
0040-4039/88 $3.00 + .OO Pergamon Press plc
SYNTHESIS STUDIES DIRECTED TOWARD GELSEMINE. A NEW SYNTHESIS OF HIGHLY FUNCTIONALIZED CZS-HYDROISOQUINOLINES Wrlham G Earley, E Jon Jacobsen, G. Patnck Meier’, Taeboem Oh and Larry E. Overman* Depa0ment of Chemstry, Umversity of Cahforma Irvme, California 92717 Abstract:
Cis-Hydrowquinolmes can be prepared in good yields by treatment of [email protected] available endo-l(cyanomet~l)~-~~o~bydroxyblcyclo[222Jocr-5-en-l -ylanunes wth KH as summanzed m Scheme 3
Gelsermne (1). the mayor alkaknd of g&emu&a sernpervirens (Carolina or yellow psrmne) was first isolated m the 1870’~~ yet not fully charactenxed medrcmal hrstory4 and m VIVOphysrologrcal well as annhypertensive fornudable
synthens
thus far to total hydrorsoqumolmes
until
1959 2*3
Gelsennum
sempervrrens
has a long
studres reveal that gelsemme has strong CNS samulant
as
a8~tivity2~~ The unusual and compact hexacyclic skeleton of gelsemme presents a
challenge. synthesis.
Although
some progress has been munded,’
gelsenune
We report here a new method for preparmg
has not yrelded
hrghly functronahzcd
CIS-
whrch was developed durmg the early phase of our gelsemme total syntheses program
In the accompauymg commumcatron
we descnbe elaborauon
of one of these mtermedrates to assemble five
of the srx rmgs of gelsemme. Scheme 1
Gelaemlne (1) Our
basic
approach
azamcyclo[4 4 0.02g]decane precursor
(i.e.
3
+
2).
to gelsemme substructure We
is outhned
m Scheme
1 and
features
constructron
of gelsemine from a readrly avarlable brcyclot2 2 2loctenyl
envisaged
mmally
that
the cahomc
axi-Cope
of the amine
rearrangement-Manmch
cychzahon reactron outlmed m equatton 1 tmght accomphsh this cntrcal reorganixatron.
Our mvestrgatrons began wrth the stereoselective
synthesrs of several [email protected] 2.2$xX-S-en-l-y1
ammes by the strarghtforward Diels-A&r cyclo&ldmon7-Curdus rearrangement approach summanxed rn Scheme 2’ Most notable 111thrs sequence is the hrgh stereoselecttvity (end0 eu, = 8-10~1) of the AlC13 catalyzed Drels-Alder reaction of 1-aIkoxy-13cyclohexadrenes termmal vmyl subsntuent,
4a9 and 4bl” ovlth methyl acrylate. The destmed for the angular C-20 posmon of gelsemme, was readrly mtroduced by
Se02 oxrdatron of 5b followed by Wimg methylenanon of the resulmg enal to provide 9. 3781
3782
a b C
R=CHs
R-sP~$ A=H
huhally,m a model scnes, we explotzd rearrangement of the fomMimuuum eon denvcd from 7a. To our dwppomrment, 11 &d not undergo [3,3]-s~gmatroptcrearrangement but underwent sunple Maruuch cychzation at the pro& terrrrmus of the alkene double bond to affotxi ulumately the IO-methylene-d azamcyclo[4 3.1.03S7]decane128 (see equahon 2). As a result of the high electrophtbcq of the mum ion groupmg, bond formation may be far advanced wth respect to bond cleavage 111&urn ion [3,3]Thus, the greater straxn of the twstane tricyc1ode4xne skeleton 14 relative s1gmatrop1crearrangements l1 12 to 13 prowdes a rationakatum for the fa&re of 11 to undergo the desued aza-Cope rearrangement
7a
3783
One way to reheve constramts mrposed by the rigzd btcyclo[2.2.2]octenyl the electromc nature of the rearrangmg formanon
The rmpormnt studzes of Evans and Goddard13 on the orzgm of base acceleratzon14 m the oxy
Cope rearrangeznentl 16 +
suggested that the base-catalyzed
17) would have a “looser” trausmon
mrmmm
skeleton would be to alter
system m such a way to advance bond cleavage rehUzve to bond
ion.
The
deszred anionic
treatment of hydroxy cyanomethylamme
hydroxy-aza-Cope
[3,3]-sigmatropic
rearrangement
(see Scheme 3,
rearrangemenP
state than the rearrangement was
of the correspondmg successfully
alkoxy
accomphshed
K& wzth excess KH at room temperature 14*16
by
In the case of
15a, quenchmg thrs rearmzrgement after 2 5 h wrth an excess of HCN
provnied the crystallure (mp 128-
129’C) as-hydrorsoqmnohne
The smzcmral assignment for this
product was unambiguously 19 l7
Alternanvely,
18
m yzelds that ranged from 7694%
estabhshed by smglecrystal
x-ray drffractron analyszs of benzannde
derzvatzve
nnine enolate 17b was acylated at both heteroatoms by quenchmg wzth an excess of
methyl or ethyl chloroformate,
followed by selectzve cleavage of the resultmg encarbonate functronabty to
afford the bzcychc keto encarbamates 20* and 21* m excellent yzeld.
Scheme
3
17
16 d /
a, R=CH, b, R = CH=CH2
7694%
H CN N
0 ct?
b
7o.son
1 !
lR
W 16, W=H 1% Fr=coPh
20, IT=cy 21, R’=Et
* (CyO),, HCCKCN,THF2PC b ClCH&N, 2 mot%6u,NI. iPrzNEt,THF, 67% , Bu,NF, THF, 6% cexcess KH, THF, 23% d HCN-KCN, H# l CICQR’, py, -76&3%, KOH, [email protected],cp~
The
preparatton
of functtonahxed czs-hydrozsoqumolmes from madzly accessible e&-6hydroxybzcyclo[2.2 2]oct-5-en-l-y1 ammes consmutes a new and useful syntheses of thzs wzdely occumng rmg systeml*
The abihty to occasron am-Cope rearrangements m electron excesszve (nmne-alkoxrde) as well as electron deficzent (mnrnum ion-hydroxyl) systems conszderably broadens the scope of the am-Cope synthesis strategem. The converston of 2IJ to an advanced gelsemme mtermedzate IS descrzbed in the followmg commtmrcation
3784
Acknowledgment. Gur efforts m this area am supported by P.&S. Grant I-&25854 NMR, mass spectra, and x-ray expenments ualrxed msuuments whrch were purchased with the asststance of NSF Shared Instrumentation Grants We paracularly wish to acknowledge the asststance of Professor RJ Doedens with the x-ray study and the technical assistance of hi. Roof. References and Notes 1.
NIH Postdoctoral Fellow (GM OSlSS), 1981-1983.
2
(a) Saxton, JE. In The Afkalouk, Manske, R.&F., Ed.; Academrc Press, 1965, Vol. 8, pp 93-107. (b) Bmdra, J.S. &id., 1973; Vol. 14, pp 84-88.
3
(a) Conroy, H.; Chakrabarti, J.K. Tetrahedron Lat. 1959, No. 4, 1. W&on, A.J.C TetrahedronLett. 1959, No. 4,1
4.
Schun, Y.; Cordell, G.A J Nat Prod. 1985.48.969.
5
(a) Flemmg,
(b) Lavell, F.M ; Pepmsky, R ,
I. In New Trendr m Natural Products Cherrustry 1986; Atta-ur-Rahman, Le Quesne, (c) VrJn, RJ.; I-hemstra, I-L; Kok, J J ; Knot&r, M ;
P.W , Ed.; ElsevrerAmsterdam, 1986, 28, 1035 Speckamp, W.N. Tetrahedron 1987,43,5019.
6.
(a) Gvennan, LE; Kakuuoto, M.; Okazalo, M.E.; Merer, G.P. J. Am Chem Sot 1983, 105, 6622 (b) Overman, L E., Mendelson, L.T ; Jacobsen, E J. ibid., 1983, 6629 (c) Doedens, RJ , Merer, G P , Ovennan, L.E. J Org Chem 1988,53,685, and references cited thercm.
7
For an earher, less stereoselective preparation of Sa, see Alfaro, I ; Ashton, W.; McManus, LD.; Newstead, RC., Ra_hone, K.L.; Rogers, N.A.J ; Kermck, W. Tetrahedron 1970, 26, 20!. The endo and ~&somers sre mrsassrgned m thrs paper, see Jacobsen, E.J Ph.LI Thesis, Umversrty of Cahfornra,
8.
New compounds showed ‘H NMR, 13C NMR, IR, and mass spectra m accord wrth then assigned Elemental composmon was estabhshed by combusuon or hrgh resoluuon mass spectral structures. analysls.
9
Birch, A J ; Dastur, KP. J Chem Sot , Perkrn Tram Z 1973,165O.
10
Prepared m 78% yreld from 3-methyl-3-cyclohexen-l-one by successwe treatment wrth LDA and triisopropylsilyl chloride at -78’C, followmg the general procedure of Rubottom: Rubottom. GM, Gruber, J M. J Org Chem. 1977.42.1051.
11.
In the mechamsttc lmnt, thrs rearrangement Grob fragmentauon sequence
12.
Formaldimmmm ions derived from analogs of 11 wtth vmylic H or CGGMe substituents mstead of CH3 also undergo Manmch cyclrxatron rather than [3,3]-srgmatropic rearrangement.
13
Steigenvald, ML ; Goddard, W.A.; Evans, D A. J Am Chem Sot. 1979,101, 1994.
14.
Evans, D.A.; Golob, A.M J. Am Chem Sot. 1975.97,4765.
15.
This transformation has been developed in our laboratories, see. e.g. Okaxakr. ME. Ph.D Thesis, Universny of Cahforma, Irvine 1986 and also 111 collaborauon wrth Kakrmoto and Okawara, see Kakimoto, M , Okawara, M. Chem I.&t. 1979.1171
16.
For earlrer publicauons concermng the generation of formaldehyde munes m situ from cyanomethylammes, see Overman, L.E.; Burk, RM Tetrahedron L&t. 1984, 1635. Overman. L.E , O~awa, T. J Am Chem Sot 1985,107,1698.
17.
The final unwerghted and weighted R values were 0.062 and 0.072 subsequent full acount of thrs study
18
For key precedent and selected earlier uses of this general strategy for the synthesis of cis-decalins, Evans, D.A.; Scott, W.L., see Berson, J.A.; Jones, M. Jr. J Am. Chem. Sot. 1964. 86, 5017. Truesdale, L.K. Tetruhedron Len 1972, 137. Johnson, A.P., Rahman, M. rbuf 1974. 359. Adams, G., Gngg, R ; Grover, J.N. Ibid. 1974,363. (Received
in USA 5 May 1988)
could even occur by a stcpwrse Manmch cychxahon-
DetarIs wrll be published wrth a
3781-3784,1988
0040-4039/88 $3.00 + .OO Pergamon Press plc
SYNTHESIS STUDIES DIRECTED TOWARD GELSEMINE. A NEW SYNTHESIS OF HIGHLY FUNCTIONALIZED CZS-HYDROISOQUINOLINES Wrlham G Earley, E Jon Jacobsen, G. Patnck Meier’, Taeboem Oh and Larry E. Overman* Depa0ment of Chemstry, Umversity of Cahforma Irvme, California 92717 Abstract:
Cis-Hydrowquinolmes can be prepared in good yields by treatment of [email protected] available endo-l(cyanomet~l)~-~~o~bydroxyblcyclo[222Jocr-5-en-l -ylanunes wth KH as summanzed m Scheme 3
Gelsermne (1). the mayor alkaknd of g&emu&a sernpervirens (Carolina or yellow psrmne) was first isolated m the 1870’~~ yet not fully charactenxed medrcmal hrstory4 and m VIVOphysrologrcal well as annhypertensive fornudable
synthens
thus far to total hydrorsoqumolmes
until
1959 2*3
Gelsennum
sempervrrens
has a long
studres reveal that gelsemme has strong CNS samulant
as
a8~tivity2~~ The unusual and compact hexacyclic skeleton of gelsemme presents a
challenge. synthesis.
Although
some progress has been munded,’
gelsenune
We report here a new method for preparmg
has not yrelded
hrghly functronahzcd
CIS-
whrch was developed durmg the early phase of our gelsemme total syntheses program
In the accompauymg commumcatron
we descnbe elaborauon
of one of these mtermedrates to assemble five
of the srx rmgs of gelsemme. Scheme 1
Gelaemlne (1) Our
basic
approach
azamcyclo[4 4 0.02g]decane precursor
(i.e.
3
+
2).
to gelsemme substructure We
is outhned
m Scheme
1 and
features
constructron
of gelsemine from a readrly avarlable brcyclot2 2 2loctenyl
envisaged
mmally
that
the cahomc
axi-Cope
of the amine
rearrangement-Manmch
cychzahon reactron outlmed m equatton 1 tmght accomphsh this cntrcal reorganixatron.
Our mvestrgatrons began wrth the stereoselective
synthesrs of several [email protected] 2.2$xX-S-en-l-y1
ammes by the strarghtforward Diels-A&r cyclo&ldmon7-Curdus rearrangement approach summanxed rn Scheme 2’ Most notable 111thrs sequence is the hrgh stereoselecttvity (end0 eu, = 8-10~1) of the AlC13 catalyzed Drels-Alder reaction of 1-aIkoxy-13cyclohexadrenes termmal vmyl subsntuent,
4a9 and 4bl” ovlth methyl acrylate. The destmed for the angular C-20 posmon of gelsemme, was readrly mtroduced by
Se02 oxrdatron of 5b followed by Wimg methylenanon of the resulmg enal to provide 9. 3781
3782
a b C
R=CHs
R-sP~$ A=H
huhally,m a model scnes, we explotzd rearrangement of the fomMimuuum eon denvcd from 7a. To our dwppomrment, 11 &d not undergo [3,3]-s~gmatroptcrearrangement but underwent sunple Maruuch cychzation at the pro& terrrrmus of the alkene double bond to affotxi ulumately the IO-methylene-d azamcyclo[4 3.1.03S7]decane128 (see equahon 2). As a result of the high electrophtbcq of the mum ion groupmg, bond formation may be far advanced wth respect to bond cleavage 111&urn ion [3,3]Thus, the greater straxn of the twstane tricyc1ode4xne skeleton 14 relative s1gmatrop1crearrangements l1 12 to 13 prowdes a rationakatum for the fa&re of 11 to undergo the desued aza-Cope rearrangement
7a
3783
One way to reheve constramts mrposed by the rigzd btcyclo[2.2.2]octenyl the electromc nature of the rearrangmg formanon
The rmpormnt studzes of Evans and Goddard13 on the orzgm of base acceleratzon14 m the oxy
Cope rearrangeznentl 16 +
suggested that the base-catalyzed
17) would have a “looser” trausmon
mrmmm
skeleton would be to alter
system m such a way to advance bond cleavage rehUzve to bond
ion.
The
deszred anionic
treatment of hydroxy cyanomethylamme
hydroxy-aza-Cope
[3,3]-sigmatropic
rearrangement
(see Scheme 3,
rearrangemenP
state than the rearrangement was
of the correspondmg successfully
alkoxy
accomphshed
K& wzth excess KH at room temperature 14*16
by
In the case of
15a, quenchmg thrs rearmzrgement after 2 5 h wrth an excess of HCN
provnied the crystallure (mp 128-
129’C) as-hydrorsoqmnohne
The smzcmral assignment for this
product was unambiguously 19 l7
Alternanvely,
18
m yzelds that ranged from 7694%
estabhshed by smglecrystal
x-ray drffractron analyszs of benzannde
derzvatzve
nnine enolate 17b was acylated at both heteroatoms by quenchmg wzth an excess of
methyl or ethyl chloroformate,
followed by selectzve cleavage of the resultmg encarbonate functronabty to
afford the bzcychc keto encarbamates 20* and 21* m excellent yzeld.
Scheme
3
17
16 d /
a, R=CH, b, R = CH=CH2
7694%
H CN N
0 ct?
b
7o.son
1 !
lR
W 16, W=H 1% Fr=coPh
20, IT=cy 21, R’=Et
* (CyO),, HCCKCN,THF2PC b ClCH&N, 2 mot%6u,NI. iPrzNEt,THF, 67% , Bu,NF, THF, 6% cexcess KH, THF, 23% d HCN-KCN, H# l CICQR’, py, -76&3%, KOH, [email protected],cp~
The
preparatton
of functtonahxed czs-hydrozsoqumolmes from madzly accessible e&-6hydroxybzcyclo[2.2 2]oct-5-en-l-y1 ammes consmutes a new and useful syntheses of thzs wzdely occumng rmg systeml*
The abihty to occasron am-Cope rearrangements m electron excesszve (nmne-alkoxrde) as well as electron deficzent (mnrnum ion-hydroxyl) systems conszderably broadens the scope of the am-Cope synthesis strategem. The converston of 2IJ to an advanced gelsemme mtermedzate IS descrzbed in the followmg commtmrcation
3784
Acknowledgment. Gur efforts m this area am supported by P.&S. Grant I-&25854 NMR, mass spectra, and x-ray expenments ualrxed msuuments whrch were purchased with the asststance of NSF Shared Instrumentation Grants We paracularly wish to acknowledge the asststance of Professor RJ Doedens with the x-ray study and the technical assistance of hi. Roof. References and Notes 1.
NIH Postdoctoral Fellow (GM OSlSS), 1981-1983.
2
(a) Saxton, JE. In The Afkalouk, Manske, R.&F., Ed.; Academrc Press, 1965, Vol. 8, pp 93-107. (b) Bmdra, J.S. &id., 1973; Vol. 14, pp 84-88.
3
(a) Conroy, H.; Chakrabarti, J.K. Tetrahedron Lat. 1959, No. 4, 1. W&on, A.J.C TetrahedronLett. 1959, No. 4,1
4.
Schun, Y.; Cordell, G.A J Nat Prod. 1985.48.969.
5
(a) Flemmg,
(b) Lavell, F.M ; Pepmsky, R ,
I. In New Trendr m Natural Products Cherrustry 1986; Atta-ur-Rahman, Le Quesne, (c) VrJn, RJ.; I-hemstra, I-L; Kok, J J ; Knot&r, M ;
P.W , Ed.; ElsevrerAmsterdam, 1986, 28, 1035 Speckamp, W.N. Tetrahedron 1987,43,5019.
6.
(a) Gvennan, LE; Kakuuoto, M.; Okazalo, M.E.; Merer, G.P. J. Am Chem Sot 1983, 105, 6622 (b) Overman, L E., Mendelson, L.T ; Jacobsen, E J. ibid., 1983, 6629 (c) Doedens, RJ , Merer, G P , Ovennan, L.E. J Org Chem 1988,53,685, and references cited thercm.
7
For an earher, less stereoselective preparation of Sa, see Alfaro, I ; Ashton, W.; McManus, LD.; Newstead, RC., Ra_hone, K.L.; Rogers, N.A.J ; Kermck, W. Tetrahedron 1970, 26, 20!. The endo and ~&somers sre mrsassrgned m thrs paper, see Jacobsen, E.J Ph.LI Thesis, Umversrty of Cahfornra,
8.
New compounds showed ‘H NMR, 13C NMR, IR, and mass spectra m accord wrth then assigned Elemental composmon was estabhshed by combusuon or hrgh resoluuon mass spectral structures. analysls.
9
Birch, A J ; Dastur, KP. J Chem Sot , Perkrn Tram Z 1973,165O.
10
Prepared m 78% yreld from 3-methyl-3-cyclohexen-l-one by successwe treatment wrth LDA and triisopropylsilyl chloride at -78’C, followmg the general procedure of Rubottom: Rubottom. GM, Gruber, J M. J Org Chem. 1977.42.1051.
11.
In the mechamsttc lmnt, thrs rearrangement Grob fragmentauon sequence
12.
Formaldimmmm ions derived from analogs of 11 wtth vmylic H or CGGMe substituents mstead of CH3 also undergo Manmch cyclrxatron rather than [3,3]-srgmatropic rearrangement.
13
Steigenvald, ML ; Goddard, W.A.; Evans, D A. J Am Chem Sot. 1979,101, 1994.
14.
Evans, D.A.; Golob, A.M J. Am Chem Sot. 1975.97,4765.
15.
This transformation has been developed in our laboratories, see. e.g. Okaxakr. ME. Ph.D Thesis, Universny of Cahforma, Irvine 1986 and also 111 collaborauon wrth Kakrmoto and Okawara, see Kakimoto, M , Okawara, M. Chem I.&t. 1979.1171
16.
For earlrer publicauons concermng the generation of formaldehyde munes m situ from cyanomethylammes, see Overman, L.E.; Burk, RM Tetrahedron L&t. 1984, 1635. Overman. L.E , O~awa, T. J Am Chem Sot 1985,107,1698.
17.
The final unwerghted and weighted R values were 0.062 and 0.072 subsequent full acount of thrs study
18
For key precedent and selected earlier uses of this general strategy for the synthesis of cis-decalins, Evans, D.A.; Scott, W.L., see Berson, J.A.; Jones, M. Jr. J Am. Chem. Sot. 1964. 86, 5017. Truesdale, L.K. Tetruhedron Len 1972, 137. Johnson, A.P., Rahman, M. rbuf 1974. 359. Adams, G., Gngg, R ; Grover, J.N. Ibid. 1974,363. (Received
in USA 5 May 1988)
could even occur by a stcpwrse Manmch cychxahon-
DetarIs wrll be published wrth a