Diastereoselective radical cyclization reactions; the synthesis of O -methylcorytenchirine

Highly diastereoselective cyclization of radicals such as 4 provides a model for the synthesis of 8-substituted berbines. Thus the reaction of 6,7-dimethoxyisoquinoline 21 with the acid chloride 19 affords the key intermediate 22 , which undergoes free radical cyclization on treatment with tributylstannane to give (±)- 23 as the sole product. Reduction of 23 affords (±)- O - methylcorytenchirine 14 . The carbamate 24 does not undergo radical cyclization when treated with tributylstannane, but the acetyl pyridine 33 affords the cyclized products 37 and 38 in reasonable yield and with good diastereoselectivity.


Introduction
In an earlier communication 1 we briefly described the intramolecular addition reactions of radicals of the general type 1 (n = 1 or 2) and 2 and used molecular mechanics calculations to support the notion that non-bonded interactions between the amide carbonyl group and the substituent R in the transition structures account for the very high diastereoselectivity exhibited by such processes.For example, treatment of the bromide 3a with tributyl-stannane gave 6a in good yield (91%), while 6b was the sole product of the cyclization of 3b (Scheme 1).
Indolizidines such as 7 and 8 were similarly prepared in high yield by treatment of the appropriate bromides.The high diastereoselectivity of these reactions underpinned other work in the field, 2 while their synthetic utility was illustrated by the efficient syntheses of (±)-lasubine 9.These results indicate that the reaction mechanism involves intermediate radicals such as 4b that undergo ring closure exclusively trans to the phenyl substituent to give 5b.Hydrogen atom transfer from the stannane to 5b then affords 6b.An important feature of the earlier work 1 was that the dihydroquinoline 10 also undergoes highly diastereoselective radical cyclization to afford 11 (90%) as the only detectable product.This observation suggested that related aryl radicals such as 12 should undergo similarly diastereoselective ring closure to afford products e.g. 13 in which the substituent at C8 is cis to the proton at the ring junction.Since this stereochemistry is a unique feature of the dibenzoquinazoline alkaloids containing a substituent on C8 it seemed possible that radical cyclization might provide a useful method for their synthesis.We now demonstrate the validity of this hypothesis by the preparation of the alkaloid (±)-O-methylcorytenchirine 14.In addition, we examine the cyclization behaviour of some related radicals that may also find use in alkaloid synthesis.

Results and Discussion
(−)-Corytenchirine 15 was first isolated in 1975 by Kametani et al. 3,4 from a biennial herb, corydalis ochotensis.This was the first report of an 8-substituted berbine alkaloid although the isolation of many 13-methyl substituted alkaloids having the same basic heterocyclic frame work had previously been reported. 5More recently a number of new 8-substituted berbines have been described. 6Coralydine 16, a diastereomer of 14, has also been synthesized 7 but appears not to occur in nature.There are relatively few reported syntheses of corytenchirine (−)-15 and its O-methylated derivative.Immediately following the isolation of 15, Brossi 8 described the first preparation of (±)-O-methylcorytenchirine 14 and Kametani reported the first total synthesis of (±)corytenchirine 15 by two different routes. 9Other syntheses have more recently been reported. 7he sequence we eventually employed for the synthesis of (±)-O-methyl corytenchirine 14 is illustrated in Scheme 3. Initially we planned to obtain the key intermediate 22 by acid catalyzed cyclization of the amide 20.Condensation of 3,4-dimethoxybenzaldehyde with the amino acetal 17 under Dean-Stark conditions gave the imine 18 in good yield.However, when 18 was treated sequentially with the acid chloride 19 and methylmagnesium chloride as previously described 10 only starting material was recovered.Reverse addition of the two reagents i.e. the Grignard reagent followed by the acid chloride, was similarly unsuccessful (Scheme 2).In view of our failure to successfully prepare the proposed intermediate 20 we decided to investigate the formation of 22 directly from 6,7-dimethoxyisoquinoline 21 which was obtained in good yield (86%) by dropwise addition of 18 in trifluoroacetic anhydride to a solution of boron trifluoride acetic acid complex in trifluoroacetic anhydride following the published procedure. 11When 21 was treated with the acid chloride 19 in THF at -23 o C and stirred for 1h a precipitate was formed (presumably an isoquinolinium quaternary salt) which redissolved on the addition of methylmagnesium iodide.Chromatography of the crude product gave 22 in good yield (92%).
The spectral characteristics of the isolated product were found to be in full agreement with those expected for 22.Thus the mutually coupled AB system of doublets with a J value of 8 Hz in the 1 H NMR spectrum at δ 5.86 and 6.55 established the presence of the double bond essential for the radical ring closure step, while the presence of the methyl substituent and the adjacent benzylic proton was confirmed by the quartet at δ 5.81 coupled (J = 7 Hz) with a three proton doublet at δ 1.28 assigned to the C1 methyl protons.Treatment of the radical precursor 22 with tributylstannane and AIBN over 6 hours in benzene at reflux proceeded smoothly to give 23 as the single product in good yield (76%).Spectroscopic methods and elemental analysis confirmed the structure of 23.The absence of the mutually coupled doublets assigned to the C3-C4 vinylic protons of 22 in the 1 H NMR spectrum of the single product isolated from the radical reaction was indicative of ring closure.In addition an ABX system was observed.The two AB signals centred at δ 2.84 and 3.03 assigned to the C13 methylene protons have the characteristics of two geminal and diastereotopic protons, the former relationship evident from a large coupling constant (J = 16 Hz) and the latter revealed by the diminished intensity of the outer signals.As expected, the signal at δ 4.83 assigned to the C13a proton has a large (J = 12 Hz) coupling arising from an axial -axial interaction with one benzylic proton and a small (J = 3 Hz) arising from axial -equatorial interaction with the other.These observations conform to X-ray data for model compounds 12 which indicate that the equivalent proton in compounds related to 23 assumes a pseudo-axial conformation.
Confirmation of the stereochemical outcome of the above reaction was established by nOe difference spectroscopy.As expected upon irradiation of the signal assigned to the C13a proton there was a 16% enhancement of the methyl signal and 4% enhancement of the C8 proton.Saturation of the C8 proton resulted in a 11% enhancement of the methyl signal but only 2% of the C13a signal.Thus, these two experiments alone provide unequivocal evidence of the syn disposition of the C13a proton and the methyl group.Similar but less reliable confirmation was obtained by saturation of the methyl signal, which provided enhancements of 5 and 7% to C13a and C8 signals respectively.
Having in hand a precursor 23 with the required stereochemistry, we addressed the reduction of the C6 carbonyl function necessary to complete the preparation of 14. LiAlH 4 is often used for the reduction of amides to amines.However, there was no reaction when 23 in THF was stirred with LiAlH 4 for 24 hours at room temperature, while heating of the mixture led to decomposition resulting in highly polar baseline material.On the basis of previous work with similar compounds, 1 the amide 23 was treated with AlH 3 generated in situ by addition of a third of a molar equivalent of AlCl 3 to a suspension of LiAlH 4 .Reduction of the C6 carbonyl was rapid and efficient as observed on TLC.Purification of the crude residue by column chromatography over basified alumina afforded (±)-O-methylcorytenchirine 14 in 43% overall yield from 3,4-dimethoxybenzaldehyde and the amino acetal 17.
(±)-O-methylcorytenchirine 14 thus obtained had all the expected spectral and the analytical characteristics.The 1 H NMR spectrum agreed closely with the published data. 3The assignment of the signals is given in the experimental section.The 13 C APT NMR spectrum consisted of three methylene signals at δ 29.46, 35.63, and 47.16 that confirmed the complete reduction of the carbonyl function and were assigned to C5, C13 and C6 respectively with the aid of heteronuclear correlation spectroscopy.In addition the spectrum displayed one methyl signal (δ 17.97), two methine carbons (δ 50.35 and 59.22), two signals for the four methoxy carbons (δ 55.81, 55.93), signals for the four aromatic methine carbons (δ 109.08,109.75, 111.11, 111.39) and five quaternary carbon signals.The molecular ion at m/z 369 together with exact mass calculations as given in the experimental section confirmed the identity of (±)-O-methylcorytenchirine 14.
The successful preparation of (±)-O-methylcorytenchirine via diastereoselective radical cyclization encouraged us to examine the synthetic potential of similar processes.For example cyclization of 24 similar to that of its carbon analog 3b might be expected to give 25, hydrolysis of which would afford the trans 3,6-disubstituted product 26.The successful development of such a reaction series would allow simple access to a wide variety of alkaloids, e.g. the selenopsines, 13  The radical precursor 24 was readily prepared from 4-methoxypyridine by treatment with 2bromophenylacetyl chloroformate and phenylmagnesium bromide following standard procedures. 16However, syringe pump slow addition of tributylstannane to 24 in benzene or t-butylbenzene at 80°C or 110°C afforded only the directly reduced product 27.It is clear from these observations that the radical derived from 24 undergoes cyclization too slowly to compete effectively with hydrogen atom transfer from the stannane under the conditions employed to give 27.

Scheme 4
The two radicals chosen for model studies to test this hypothesis were 31 and 34.The precursors 30 and 33 were readily prepared from 3-acetylpyridine by N-acylation of the lithioenamide with the appropriate acid chlorides.Unfortunately treatment of 30 with tributylstannane gave solely the directly reduced product 32 (Scheme 5).Once again it appears that under our conditions cyclization of the radical 31 is too slow to compete with hydrogen atom transfer from stannane under the conditions employed.More encouraging results were obtained with the aryl radical precursor 33.Treatment of 33 with tributylstannane in benzene (Scheme 6) at 80 o C gave three products identified as the uncyclized compound 35 (35%), the indolizidine 37 (55%) and its diastereoisomer 38 (6%).The assignment of structure to 37 and 38 rests on spectral data.The key data were the signals attributable to the C10a protons.For the major isomer the doublet coupling of J = 10.5 Hz is indicative of axial -axial doublet coupling with the C10 proton, an orientation that is diagnostic of structure 37.The doublet coupling for the C10a proton of J = 4.5 Hz in the minor isomer 38 is diagnostic of the expected axial -equatorial coupling.Although the yield of the major cyclized product 37 is modest, the relatively high diastereoselectivity (9:1) of the atom transfer step 36 → 37 leading to its formation indicates that this type of reaction could be synthetically useful.Further theoretical studies designed to determine the factors controlling the conformations of the radicals involved in the reactions described above, and their relative rates of hydrogen atom transfer and cyclization are in hand and will be separately reported.

Experimental Section
General Procedures.All reactions were carried out under an atmosphere of dry nitrogen in predried glassware unless specified otherwise.The solvents used in the reactions were distilled and dried prior to use.Benzene for radical reactions was freshly distilled over sodium wire under nitrogen and degassed by purging with a stream of argon for 15 minutes.Merck Kieselgel 60 (230-400 mesh ASTM) was used for Flash chromatography.Preparative radial chromatography was conducted on a Chromatotron model 7924 with 1, 2 and 4 mm plates prepared from Merck Kieselgel 60 PF 254 (with gypsum).Preparative liquid chromatography was performed using glass backed precoated with Kieselgel with PF 254 indicator.TLC was conducted on glass backed Whatman MK6F precoated silica microscopic slide plates with 254 nm indicator.The solvents used for chromatography are specified in each experiment.Petroleum spirits refer to the fraction bp 60-80°C unless indicated otherwise. 1H NMR spectra (300, 500 MHz) and 13 C(75, 125 MHz) were measured in CDCl 3 with tetramethylsilane (TMS) and residual CHCl 3 as internal standards (in some cases signals for two rotamers were detected).Low resolution EIMS were recorded at 70 eV on either a VG7070F or a VGZAB-2SEQ spectrometer.All elemental analyses were carried out by the microanalytical unit at the Research School of Chemistry.The melting points are uncorrected and were determined on a Reichert microscopic Kofler hot-stage apparatus.

OH
We next turned to reactions of the radicals containing a carbonyl activating group exocylic to the ring.Diastereoselective cyclization of a suitably constituted radical such as 28 could provide a key step in a simple synthesis of polyhydroxylated indolizidine alkaloids such as swainsonine 29 (Scheme 4).