Synthesis studies directed toward gelsemine. A new synthesis of highly functionalized cis-hydroisoquinolines

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 ...

399KB Sizes 7 Downloads 78 Views

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