Tetrahedron Letters,Vol.27,No.l9,pp 2075-2078,1986 0040-4039/86 $3.00 + .OO Printed in Great Britain 81986 Pergamon Journals Ltd.

FORMATION OF REACTIVE TRICYCLIC INTERMEDIATES VIA THE INTRAMOLECULAR CYCLOPROPANATION OF DIHYDROPYRANS. SYNTHESIS OF EUCALYPTOL

Julian Adams* and Hlchel Belley Merck Frosst Canada Inc.

P.O. Box 1005, Polnte Claire-Dorval. Quebec, Canada, H9R 4PB

Summary: Trlcycllc compound 3 was syntheslzed via a cyclopropanatlon reaction promoted by [Rh(‘JAc)zl2. Thls highly strained compound was found to undergo selective chemical transformations to glve [2.2.2] oxa-bjcycllc ketones. This methodology was applled tn a total synthesis of the monoterpene, eucalyptol.

The reaction of a-dlazo carbonyl compounds wlth oleflns. medlated by transition metal

catalysts, provides a useful route to cyclopropanes.' Mechanlstlcally, the reactlon involves

the addltlon of the keto-carbene to a carbon-carbon double bond. The Intermolecular reactlon of

keto-carbenes and oleflns requires a hlgh concentration of the olefln (usually as the solvent)

since dlmerlzatlon of the carbene is usually a faster reaction than cyclopropanatlon. 2

Due to

this llmltatlon many researchers have chosen to explolt this reactlon In an Intramolecular sense,

thus obviating the carbene dlmerlzatlon problem. Upon surveying the llterature we noted that the

vast majority of the Intramolecular cyclopropanatlons studies to date have been systems which

produce bl- or trlcycllc carbocycles.3 This paper describes our efforts to produce novel oxygen

heterocycles by the Intramolecular cyclopropanatlon of cyclic enol ethers. Furthermore, the

reactlvlty of the stralned oxa-trlcycllc system was explored under a variety of reactlon

conditions, to produce reglospeclflc fragmentation of the cyclopropane ring to unveil novel

[2.2.2] oxablcyclooctanones.

Beglnnlng with the comerclally avallable 3,4-dlhydro-2H-pyran-2-carboxyllc acid, sodlum salt

1. we were able to produce the corresponding o-dlazo ketone 2 by a two-step procedure

outllned In Scheme I. Addition of a catalytic amount (2 weight X) of [Rh(OAc)2]2 In

CH2C12 at room temperature produced an efflux of nitrogen gas and provided the des\red

trlcycllc cyclopropyl ketone 3.4

SCHEME I

1. CICO2 isoBu

THFIRT [Rh(OAc)2]2

C4Na 2. CH2N2/Et20, CH2CI2. R-r

ooc 1 0

N2

3 2

53%

OVERALL

2075

2076

The ease of cyclopropanatlon underscores the mlldness of the rhodium II catalyst. Attempts

with tradltlonal copper catalysts provlded only decomposltlon products. Another factor promotlng

the reactlon Is that the double bond Is electron rich (due to the a-oxygen) and the keto-carbene

Is electronically deflclent (due to the carbonyl).

Catalytic hydrogenation of 3 cleanly reduced the cyclopropane rlng to glve the blcycllc ketone

4 as the major product along wlth a mlxture of eplmerlc alcohols 5a.b resultlng from a

subsequent reduction of 4. Blcycllc compound 4 has been described only once before In an

B-step synthesls.5 SCHEMEII

4 52% 6a,b, R=OMe 7b 50% + 7a,b, R=SPh “O% 0

d?

OH

d/

b Sa,b 30% C

a

13a,b 56% 11 40% 9 R=Me

10 R=tBU 70-80%

a) Hp /lO%Pd*C, EtOAc, 5Opsi; b) MeOHlcat pTs0l-l or

PhSWTHF cat pTsOH; c) PhSNalTHF. 1 10°C 4h; cl) MeLi,tBuLi

or MeMgCI/Et20, -7B’C lOInin; e) MesCuLi/EtsO, 0°C 2h;

f) Me2CuLi/BF3Et20/Et20 -78’C Bmin--,O’C 30min.

Dlssolutlon of oxa-tricycle 3 In acldlc (catalytic pTsOH) HeOH cleanly produced a mixture of

eplmerlc cyclic methyl acetals 6a and 6b In a ratio of 3:l. The corresponding reactlon was

seen to occur uslng thlophenol (catalytic pTSOH/THF), to glve a 5:l mlxture of thlo-acetals 7a

and 7b. We reasoned that thls mechanism occurs vla an acid catalyzed unlmolecular fragmentatlon

of 3 to form the oxonlum enol 8 which reacts wlth the nucleophlle preferentlally on the 1eSS

hindered slde (the enol).' However, when thlolate anlon was used (thlophenol, NaH/THF, 110°C.

sealed tube) nucleophlllc openlng via an SN2 mechanism produced only 7b, wlth the thlophenyl

group on the slde opposlte the carbonyl.

2077

Attempts to achieve nucleophlllc openlng reactlons uslng carbon nucleophlles In homo-conjugate

fashlon resulted only In I.2 addltlon to the carbonyl.7 Organometalllc reagents MeLi, Mef4gBr

and tBuL1 reacted on the less hlndered face of the carbonyl (exe) glvlng carblnols 9 and 10, whlle

He2CuLl dellvered a methyl group on the more hlndered concave part of the molecule affording

exclusively carblnol 11.' A ratlonallzatlon for the opposlte stereoselectlon of the cuprate

reaction ljes In the belief that the ring ether oxygen serves to complex the copper catlon masking

the convex face of the molecule and the nucleophlle Is dellvered from the opposlte slde.

Homo-conjugate openlng of the cyclopropane rlng with He2CuLl was flnally achieved In the

presence of BF .Et20.' 30a

Thls reactlon probably proceeds via an oxonlum-boron enolate

zwltterlon 12. which Is alkylated to glve a 1:l mlxture of eplmers 13a.b.

SCHEMEIII

3-

R=OMe Ba

SPh 7a

Thls reactlon allowed us to deslgn a short synthesl;,of the monoterpene, eucalyptol 10

(Scheme IV). Beglnnlng with the known dlhydropyran 14. the dlazoketone 15 was prepared

using the modlfled procedure of Harmon et al. l2 Cycllzatlon, medlated by [Rh(OAc)2]2

proceeded very smoothly to produce oxa-trlcyclanone 16. Homo-conjugate addltlon of

f4e2CuLl/BF3.Et 0 afforded blcycllc ketone 17, Itself an oxldatlve metabollte of

eucalyptol. 13.4

Thls constitutes a formal synthesls of eucalyptol since the Clenensen

reduction of 17 has been reported. 14

SCHEME=: SYNTHESIS OF EUCALYPTOL

1. EtONa/(C02Et),/EtOH 24h

'2.TsN3, 12h N2

0 0

14 ref 11 15 71%

[Rh(OAcb]2 O-c-0 Me2CuLi/BF,*Et20 9

CH,CI,,RT WW -7WC 45min 0

5min --) O’C 3Omin -&- 16 92%

17 45%

EUCALYPTOL

2078

In conclusion, the foroIat.ton of stralned trlcycllc heterocycles such as 3 or 16 provides a

useful entry Into oxa-blcycllc compounds by relylng on the regloselectlve fragmentation of the

cyclopropane rlng. We are also tnterested ln expanding this approach to different ring sizes, and

~111 soon report syntheses of substltuted 7- and I-membered rings.

References:

1. a) V. Dave and E.W. Warnhoff, Drganlc Reactions, Vol. 18, Chapter 3, pp 217-401. John Wiley C

Sons Inc., 1970, b) S.D. Burke and P.A. Grleco. Organic Reactions, Vol. 26, Chapter 2, pp.

361-475 (1979). John Wiley & Sons and references therein.

2. a) A.J. Anclaux, A.J. Hubert, A.F. Noels, N. Petlnlot and P. Teyssie, J. Org. Chem.. 45, 695

(1980). b) M.P. Doyle, D. Van Lensen, and W.H. Tamblyn, Synthesis, l0, 787 (1981). c) M.P.

Doyle, R.L. Dorow, W.H. Tamblyn and W.E. Buhro, Tetrahedron Lett.. 3, 2261 (1982), d) M.P.

Doyle, J.H. Grlffln, V. Bugherl and R.L. Dorow, Organometallics. 3, 53 (1984.

3. For example: a) T. Hudllcky, F.F. Koszyk, T.M, Kutchan and J.P. Sheth, J. Org. Chem., j&

5020 (198D), b) D. Becker and H.J.E. Loewenthal, Isr. J. Chem,, l0, 375 (1972), c) C.J.V.

Scanlo and D.L. Llckel, Tetrahedron Lett.. 1Q. 1363 (1972).

4. Satisfactory spectral data were obtained, including: 250 MHz ‘H NMR IR and hlgh

resolution mass spectra. For key compounds 3, 16 and 17, “C-NMR spectra were also

recorded.

5. Joan K. Glascock. Ph.D. dlssertatlon 1980, Duke University..

6. The stereochemlcal assignments were made by comparing the ‘H NMR chemical shifts of the

p-proton adjacent to the ketones, 6a and 6b. In 6a but not 6b the proton In questlon

experiences a profound downfield chemical shift due to the electronegative methoxy

substltuent. A similar but less pronounced effect is observed for 7a and 7b.

7. Homoconjugate addltlons with carbon nucleophlles usually requlre 2 activating groups. for

example see a) E.J. Corey and P.L. Fuchs, J. Am. Chem. Sot., 94, 4014 (1972), b) 6.M. Trost,

D.F. Taber and J.B. Alper, Tetrahedron Lett., lB, 3857 (1976).

8. Stereochemlcal asslgnments between 9 and 11 were made by ‘H NMR analysis of their

chemical shifts of the cyclopropyl methlne adjacent to the 3’y alcohol. The methlne proton in

11 appears at 1.53 ppm. deshlelded by the electronegative oxygen atom relatlve to the same

proton In 9 which appears at 1.40 ppm.

9. For experimental conditions see: A.B. Smith III and J. Jerrls, J. Am. Chem. Sot., l&3, 194

(1981).

10. Eucalyptol is also referred to as 1,8-cineole. Recent syntheses Include: a) J.P. BBgu@. H.

Charpantler-Morlze, D. Bonnet-Delpon and J. Sansoulet, J. Org. Chem. 45, 3357 (1980), b) C.H.

Link, O.K. Jansen and C.N. Sukenlk, J. Am. Chem. Sot., 102, 7798 (1980). c) R.M. Scarborough

Jr., A,B. Smith III, W.E. Barnette and K.C. Nlcolaou, J. Org. Chem., 44, 1742 (1979). d) J.H.

Coxan, M.P. Hartshorn, J.W. Mitchell and K.E. Roberts, Chem. and Ind., 652 (1968).

11. P. Chaquln, 8. Furth and J. Kossanyl, Rec. Trav. Chlm. Pays-Bas, 98. 346 (1979).

12. R.E. Harmon, V.K. Sood and S.K. Gupta. Synthesls, 577 (1974).

13. J.C. WacRae, V. Alberts, R.M. Carman and I.R. Shaw, Aust. J. Chem., 32. 917 (1979).

14. C.W. Wilson III and P.E. Shau, Aust. J. Chem.. 28. 2529 (1975).

(Received in USA 22 January 1986)