Unusual rearrangements and cyclizations involving polycyclic indolic systems

During the course of experiments to explore and develop cyclization reactions of indolic systems, a number of unusual rearrangement reactions were discovered


Introduction
There are an enormous number of important indolic natural products, containing a plethora of fused ring systems, as exemplified below (Figure 1).Our interest has been in using tryptophan as the chiral starting material for the synthesis of such compounds, 2 and in developing synthetic methods for accessing the polycyclic structures.We describe herein some of our cyclization studies, which have led to unusual and unexpected rearrangements.The first of these is a Sommelet-Hauser rearrangement, observed during the attempted ring-closure to the [6.5.5] fused system found in brevianamide E (2) and okaramine A (4); the second is a cyclopropanone forming reaction, observed whilst attempting the preparation of the spiro-system found in ajmaline (3).

Section A. Methylsulfanylmethylation via Sommelet-Hauser rearrangements
A key reaction in the synthesis of brevianamide E (2) and okaramine A (4) would be a difficult oxidative cyclization, in which the indolic 2-position becomes bonded to nitrogen. 4We decided to explore this process using the model cyclization of brevianamide F (6) (Scheme 1, a), for which we were able to confirm that the use of t-butyl hypochlorite proceeds in only about 30% yield.4d We had reasoned that treatment with Swern reagents 5 ought to achieve the desired cyclization, and we explored the same model cyclization (Scheme 1, b). 6 To our surprise, although the desired polycyclic skeleton was generated in 33% yield using trifluoroacetic anhydride as the Swern electrophile, 7 a methylsulfanylmethyl group was concurrently attached to the indole 4-position.Although unwanted for our work towards the brevianamides, accessing 4substituted tryptophans is difficult, and such compounds are of importance for QSAR studies of tryptophyl peptides, or for the synthesis of natural products such as lysergic acid (1); we therefore sought to explore the scope and limitations of this chemistry, as well as an understanding of the mechanism of the reaction.Our first set of indole analogues were simple acyl derivatives of tryptamine 8 and tryptophan methyl ester 9. We found that both of these reactions also proceeded with both cyclization and rearrangement, giving the 4-substituted products 10 and 11 in moderate yield, although the yield of the latter reaction was dramatically improved (to 95%) when the reaction was carried out in acetonitrile.

Scheme 2
The tryptophan derivative might be especially useful; for example, reduction with Raney nickel should generate the 4-methyltryptophan derivative, whilst other 4-substituted derivatives should be accessible using sulfide/sulfoxide chemistry, for incorporation into peptides.We were therefore pleased that reductive ring-opening of the tryptamine derivative 10 took place essentially quantitatively, thereby confirming that the ring-opening/unmasking can be easily achieved.
We next explored the range of indolic substrates suitable for the Sommelet-Hauser rearangement (Figure 2).Our choice was significantly guided by our proposed mechanism (see Scheme 3 below, and associated discussion), and we were therefore disappointed that only the three derivatives shown in Schemes 1 and 2 underwent the reaction.
Substrates that failed to undergo the rearrangement.
Next we turned to the mechanism for this reaction, for which our proposal is shown in Scheme 3, in which a sulfonium intermediate is in equilibrium with an ylide, which can then undergo the Sommelet-Hauser rearrangement.When the reaction was carried out entirely at low temperature, then the expected cyclization took place without introduction of the MeSCH 2 group; similarly, using only one equivalent of the Swern reagent, but allowing the reaction to warm up, also led to the simple cyclization product; finally, replacing trifluoroacetic anhydride with oxalyl chloride 9 also led to cyclization without rearrangement.
These results indicate that the [6.5.5] system must be pre-formed before the Sommelet-Hauser rearrangement can occur (in these systems, at least).Crucially, the Sommelet-Hauser rearrangement requires de-aromatization of the 'pyrrolic' indole ring before the [2,3] sigmatropic shift can occur, and it is noteworthy that the sulfonium salt (Figure 2, final entry) failed to undergo any reaction with triethylamine under our 'Swern' conditions.We had hoped that other heteroatoms tethered to the indole 3-position would be able to stabilise the key intermediates required for the Sommelet-Hauser rearrangement, but this turned out not to be the case.Although Swern et al have reported ortho-CH 2 SMe insertion in the oxidation of an aniline derivative, 7b our Swern-induced Sommelet-Hauser rearrangement for indolic systems has not been previously reported.

Section B. Cyclopropanone formation from a diazomethyl ketone
In work towards the [6.5.5.6] spiro system in ajmaline (3), we hoped to use a carbene insertion reaction, as outlined in Scheme 4.
We prepared the model diazoketone as shown in Scheme 5. Thus, allyl ester 14 10 was benzylated, after which the trans specific Pictet-Spengler reaction 11 gave the tetrahydro-βcarboline 15.After N in -methylation, and palladium catalyzed deprotection of the ester, the diazoketone 19 was prepared via the mixed anhydride 18. Intriguingly, reaction with rhodium II acetate generated the cyclopropanone 22 instead of the desired spiro system, as a single diastereoisomer, for which the IR stretch at 1805 cm -1 and 13 C peak at 205 ppm were indicative of the strained ketone.If the mechanism propose in Scheme 5 is correct, then the trans product shown would be expected, via pseudo-axial attack on the iminium intermediate in which the phenyl group is axial.3b As in the case of the Sommelet-Hauser rearrangement, the fine interplay of steric and electronic factors are probably prerequisites for the rearrangement/cyclization, involving hydride shift and subsequent ring closure.We are exploring the generality of this unusual reaction, and the possible synthetic utility of the resulting cyclopropanones.

Section B L-Tryptophan allyl ester (14)
To L-tryptophan (15 g, 61 mmol) dissolved in allyl alcohol (150 ml), acetyl chloride was then added, and the resulting purple solution was maintained at reflux for 18 hr.It was then cooled to RT, and 10 % ammonia solution (250 ml) and CH 2 Cl 2 (150 ml) were added.The phases were separated and the aqueous extracted with CH 2 Cl 2 (2 x 250 ml).The combined organics were dried over MgSO 4 , filtered and solvent removed in vacuo.The product was purified by column chromatography using 50:50 CHC1 3 : diethyl ether, giving 6.02 g (26 %) of the white solid 14, which exhibited spectra in accordance with those already reported. 10