Indole-Diterpene Synthetic Studies.

Tetrahedron Letters,Vol.29,No.23,pp Printed in Great Britain

2787-2790,1988

0040-4039/88 $3.00 + .O0 Pergamon Press plc

Indole-Diterpene Synthetic S t u d i e s . 3. A Unified Synthetic Strategy For The Simple Indole Tremorgens Amos B. Smith, III.1 and Tamara L. Leenay Department of Chemistry, The Laboratory for Research on the Structure of Matter and The Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Summary. In this letter we record an efficient synthesis of tricyclic ketone 5, a common advanced intermediate for construction of the simple ind01e-diterpene tremorgenic alkaloids. in 1985, we announced completion of a first generation total synthesis of (-)-paspaline. 2,3

While

successful, considerable tactical difficulties were encountered with introduction of the quaternary vicinal centers at C(12b) and C(12c). Indeed, the strategy proved non-stereoselective and furthermore, appeared not to be readily amenable to other members of the indole-diterpene class of tremorgenic alkaloids. In this letter, we wish to record a second generation strategy, which is both stereocontrolled and which will, we believe, provide a unified synthetic approach to this class of novel natural products. Specifically, we have developed an economic

(he., short) synthesis of tricyclic ketone 5 (Scheme 1), a common advanced intermediate for construction of the Scheme 1

~ \

/

O

Paspalicine2

\~""

5

Common AdvancedIntermediate

/

\

structurally similar alkaloids: paspaline (1), a paspalicine (2),3 paspalinine (3) 4 and pa×illine (4). 5 From the retrosynthetic perspective, we envisioned tricyclic ketone 5 to arise from Wieland-Miescher ketone 6 as outlined in Scheme 2. Central to this scenario was the stereocontrolled introduction of the C(12b) quaternary methyl group trans to the vicinal quaternary center at C(12c).

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Analysis of this advanced

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intermediate (5) led us to consider tricyclic enone 6, wherein incorporation of the quaternary methyl group at C(12b), as well as formation of the requisite cyclopentanone ring, would derive via conjugate addition of an appropriate methyl nucleophile followed by ring contraction. Tricyclic enone 6 in turn was envisioned to arise via Robinson annulation7 of ketone 7.

Scheme 2

O 5

O @

7

Wieland-Miescher ketone

Preparation of cyclopentanone 5 began with known ketal 78 ([a]D 25 +23.9°; c = 1.49, CHCI3), available from Wieland-Miescher ketone 6 employing a modification of the Paquette ketalization protocol (Scheme 3). 8 An efficient, two step Robinson annulation7 procedure was then developed for the construction of tricyclic enone 6. Specifically, exposure of ketal 7 to a mixture of benzylamine (1.05 equiv.) in benzene with catalytic ptoluenesulfonic acid, followed by heating at reflux for 24 hours led to the corresponding imine, 9 which without purification was treated with excess methyl vinyl ketone in dry ethanol for several hours to afford an epimeric mixture of 1,5-diketones (87%) after aqueous workup. 10 Completion of the Robinson annulation protocol came upon exposure of the 1,5-diketones to excess sodium hydride in benzene at 65oc.

Importantly, this procedure

could be performed conveniently on large scale (ca. 0.15 mole) employing readily available, inexpensive reagents; the overall yield ranged from 70-75%. Having developed an efficient route to tricyclic enone 6,10 we next required introduction of the quaternary center at C(12b), trans to the methyl substituent at C(12c).

Initially, we explored a variety of cuprate

reagents. We were, of course, well aware that ~,~-substituted enones such as 6 often prove unreactive. 11 Indeed, the major product under these conditions was the 1,2-adduct. The poor chemoselectivity appeared to be due not only to the general unreactive nature of I~,l~-substituted enones, but also to the steric factors imposed by the adjacent quaternary methyl group at C(12c).

Fortunately, exposure of tricyclic enone 6 to the ZnMe2-

Ni(acac)2 reagent described by Luche eta/. 12 gave silyl enol ether 8 in near quantitative yield after quenching the reaction mixture with excess trimethylsilyl chloride and triethylamine. No trace of the 1,2-addition product could be detected by high field t H NMR. The high efficiency of this 1,4-addition process is presumed to be a direct result of the thermal stability of the organometallic reagent, allowing the reaction to proceed at room temperature 12

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With gram quantities of silyl enol ether 8 available, we turned next towards the ring contraction required for preparation of cyclopentanone 12. Silyl enol ether 8 was subjected to reductive ozonolysis to provide aldehyde 9 l ° a in 45% yield for two steps (6 to 9). ether, cat. p-TsOH, 0oc; (79%)].

This operation was followed by esterification [ethyl vinyl

Closure of the five membered ring was then effected with lithium

hexamethyldisilazide; the result was a 2:1 mixture of 13-hydroxy esters 11a,b. loa

Oxidation of 11a,b

employing the Swern trifluoroacetic anhydride-DMSO protocol, 13 and in turn hydrolysis and decarboxylation of the derived 13-keto acid (0.2N HCI in THF and mild heat) provided cyclopentanone 1210 ([(~]D25 -196 o; c = 0.95, CHCI3). The overall yield for the three step operation was 45%.

Finally, removal of the ketal unit

afforded crystalline enone 5.10 Single crystal X-ray analysis of the latter secured the overall structure, and in particular the trans relationship between the two vicinal quaternary methyl substitutents, a key architectural feature of this class of indole alkaloids.

Scheme 3 TsOH,A b) methylvinyl ketone, EtOH (82%) 2) Nail, benzene,&

Ni(acac)2 ether, RT L b) TMSCI,Et3N (90%) cat

(87%)

4) 0 3 ; D M S (50%)

R O O_C v A y I

5) ethylvinyle t h e r TsOH (79%)

O

A ~,, W[

6) UN(SiMe3~,

OHClV:=~,f -,~

EEO2C"~~

THF,-78°C -

9 R= H 10 R=EE

O

70% HClO4 CH2Cl2 0o (85%)

7) TFAA,DMSO; Et3N

8) 0.2NHCI; A-CO2H (45%3 steps)

~0 ~ 0 mp 128-130°C Common AdvancedInmrmediate

In summary, we have completed an efficient (i.e., 9 steps, 9.4% overall yield) preparation of tricyclic ketone 5. Exploitation of this common advanced intermediate in our second generation approach to (-)-paspaline (1) is presented in the following communication.

Progress towards the synthesis of other members of the

indole-diterpene family of tremorgenic alkaloids will be reported in due course.

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Acknowledgements. Support for this research was provided by the National Institutes of Health (Institute of Neurology, Communicative Disorders and Stroke) through Grant 18254. In addition, we thank Drs. G. Furst, J. Dykins and P. Carroll, Directors of the University of Pennsylvania Spectroscopic Facilities for aid in obtaining the high field NMR, high resolution mass spectral and X-ray crystallographic data. References and Notes. 1.

National Institutes of Health (National Cancer Institute) Career Development Awardee, 1980-1985; and J. S. Guggenheim Foundation Fellow, 1985-1986.

2.

(a) Fehr, Th.; Acklin, W. Helv. 1966, 49, 1907. (b) Gysi, R. R. Dissertation No. 4990, Eidgenossichen Technischen Hochschule, Zurich, Switzerland (1973). (c) Leutwiler, A Dissertation No. 5163, Eidgenossichen Technischen Hochschule, Zurich, Switzerland (1973). (d) Springer, J. P.; Clardy, J. Tetrahedron Lett. 1980, 231.

3.

Smith, A. B., III; Mewshaw, R. E. J. Am. Chem. Soc. 1985, 107, 1769.

4.

(a) Cole, R.J.; Dorner, J. W.; Lansden, J. A.; Cox, R. H.; Countney, P.; Cunfer, B.; Nicholson, S. S.; Bedell, D. M. J. Agric. Food Chem. 1977, 25, 1197 and references therein. (b) Cole, R. J.; Dorner, J. W.; Springer, J. P.; Cox, R. H. Ibid. 1961,29, 293. (c) Gallagher, R. T.; Finer, J.; Clardy, J.; Leutwiler, A.; Weibel, F.; Acklin, W.; Arigoni, D. Tetrahedron Lett. 1980, 235. (d) Weibel, F. Dissertation No. 6314, Eidgenossichen Technischen Hochschule, Zurich, Switzerland, (1979).

5.

(a) Cole, R.J.; Kirksey, J. W.; Wells, J. M. Can. J. MicrobioL 1974, 20, 1159. (b) Springer, J. P.; Clardy, J.; Wells, J. M.; Cole, R.J.; Kirksey, J.W. Tetrahedron Lett. 1975, 2531.

6.

(a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. 1971,83, 492.; Angew. Chem., Int. Ed. EngL 1971, 10, 496. (c) Gutzwiiler, J.; Buchschacher, P.; Furst, A. Synthesis 1977, 167. (d)Buchschacher, P.; Furst, A. Org. Synth. 1984, 63, 37.

7.

Jung, M. Tetrahedron 1976, 32, 3.

8.

Nitz, T.; Paquette, L.A.

9.

(a) Hickmott, P.W.; Rae, B. Tetrahedron Lett. 1985, 2577. (b) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc. 1985, 107, 273.

Tetrahedron Lett. 1984, 3047.

1 0. (a) The structure assigned to each new compound is in accord with its infrared and 250-MHz 1H NMR spectra, as well as appropriate parent ion identification by high resolution mass spectrometry. Purity (>97%) was accessed by either NMR or HPLC. (b) In addition, an analytical sample of this new compound, obtained by recrystallization or chromatography (LC or TLC), gave satisfactory C and H combustion analysis (ie. 0.4%). 11. Posner, G. H. Org. React. 1972, 19, 1. 12. (a) Greene, A. E.; Lansard, J. P.; Luche, J. L.; Petrier, C. J. Org. Chem. 1984, 49, 931 and references therein. (b) Luche, J. L.; Petrier, C.; Lansard, J. P.; Greene, A. E. J. Org. Chem. 1983, 48, 3837.; (c) For a review of activation methods for organozinc reagents, see Erdik, E. Tetrahedron 1967, 43, 2203. 13. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329. (Received in USA 26 February

1988)