Three different approaches to C-H bond functionalization in the synthesis of antitumor alkaloids rhazinilam, rhazinal and rhazinicine

In the past decade, metal catalyzed or promoted C-H bond activation appears as an attractive alternative to classical cross-coupling reaction. Although the studies of this methodology have grown considerably, applications in total synthesis of natural products remain rare. This short review will focus on the use of the metal catalyzed or promoted C-H bond functionalization for the total synthesis of rhazinilam and congeners and demonstrate the usefulness and the efficiency of this approach.


Table of contents
1. Introduction 2. Selective platinum-mediated sp 3 C-H insertion / -H elimination; the total synthesis of (-)-rhazinilam 3. Direct cross-coupling reaction; the total synthesis of (±)-rhazinilam and (±)-rhazinal 4. Metal-catalyzed C-H borylation / Suzuki coupling reaction and oxidative cyclization; the total synthesis of (±)-rhazinicine 5. Conclusions 6. References Introduction (-)-Rhazinilam 1, an axially chiral phenylpyrrole compound isolated first from Melodinus australis and latter from other species, has been shown to interact with tubuline and to mimic the effects of both vinblastine and taxol.Its structure has been established and presents a tetracyclic system comprising a phenyl A-ring, a 9-membered lactam B-ring, a pyrrole Cring and a piperidine D-ring (Figure 1).Although this alkaloid is now considered to be an artefact of isolation procedure, the unusual anti-mitotic properties and the original structure of 1 inspired several research groups to develop a number of approaches for its total synthesis.More recently, other compounds with closely related structure and similar biological activities were isolated such as (-)-rhazinal 2 and (-)-rhazinicine 3.  Transition-metal catalyzed or promoted reactions have totally transformed the organic synthesis.Over the past decades the palladium cross-coupling reactions have emerged as an essential tool for the construction of elaborated molecular structures.Today, it appears that the total synthesis has benefited significantly from these strategies and their uses have become common for the preparation of natural compounds. 2n recent years, the development of transition-metal mediated reactions involving C-H bond cleavage/C-C bond formation have emerged as one of the most powerful straightforward methods for synthesis of complex molecules. 3In the case of arene C-H bond functionalization, this synthetic strategy provides novel approaches as alternative to the Friedel-Crafts reactions or classical electrophilic aromatic substitution.The process of activating the C-H bond replaces also the usual reaction between the transition-metal and an active functional group and allows overcoming of the classic step of transmetallation in the catalytic cycle.This leads to an improvement of the atom economy and reduces the amount of waste in accordance with the principles of green chemistry. 4On the other hand, the formation of C-C bond from unactivated sp 3 C-H bond is more rare and often the reaction is successful when the substrate has an auxiliary-director group. 5The reaction is then initiated by chelation-directed cyclometallation before the C-H bond activation (Scheme 1).
Transition-metal mediated functionalization of C-H bonds.
To illustrate these class of reactions, this Account will focus on the synthesis of (-)rhazinilam 1, (dl)-rhazinal 2 and (dl)-rhazinicine 3 (Fig. 1), three antimitotic compounds belonging to the same family whose the strategy of synthesis is based around one or two steps of C-H bond activation.

Selective platinium-mediated sp 3 C-H insertion / β-H elimination; the total synthesis of (-)-rhazinilam
Among the various syntheses reported of (-)-rhazinilam 1, Sames and co-workers proposed an elegant demonstration of the efficiency of the concept of C-H bond functionalization and its applicability in stereoselective process. 6This key step involved a selective dehydrogenation of the enantiotopic ethyl groups corresponding to a metal-mediated C-H insertion / -hydride elimination process (Scheme 2).
Because the sp 3 C-H bond activation reactions require harsh reaction conditions, to carry out the C-H bond functionalization Sames and co-workers introduced an auxiliary group containing a pyridine moiety and a Shiff base within the rhazinilam precursor for binding the metal.Reaction of the pyrrole derivative 4 in the presence of the dimethyl platinium reagent [PtMe2(-SMe)2]2 in toluene furnished after chromatography on neutral alumina the isolated platinium complex 5 which after treatment with TfOH formed the cationic complex 6 with concomitant loss of methane.Upon addition of 2,2,2-trifluoroethanol and heating, the complex 6 underwent C-H insertion and subsequent -H elimination with a second loss of methane to form the cationic hydride platinium complex 7 as a single compound.It is noteworthy that the further transformations of complex 6 led to decomposition under these reaction conditions with R = H; the presence of a bulky substituent such as Ph appeared necessary for the success of this sequence.This was followed by the removal of the platinium metal via treatment with aqueous potassium cyanide and then hydrolysis of the Schiff base with hydroxylamine.The aniline 8 was obtained in 60% yield from 5 and the racemic rhazinilam 1 was isolated after two additional steps (Scheme 3).Having demonstrated the efficiency of this strategy to prepare the racemic rhazinilam 1, Sames and co-workers described a chiral auxiliary-directed diastereoselective C-H functionalization to synthesize (-)-1 (Scheme 4).For this several oxazoline Schiff base pyrrole compounds were prepared, placed in the presence of [PtMe2(-SMe)2]2 and submitted to the reaction conditions to induce the dehydrogenation.The best compromise diastereoselectivity / conversion (yield) was obtained when the reaction was carried out with the cyclohexyl oxazoline derivative 9 at 70 °C (Scheme 4).The decomplexation of the platinium metal afforded a mixture of diastereomers 11 with a good ratio in favor of the reaction of the pro-R ethyl group as expected (Table 1, entry 9).Using the bulkiest tert-butyl oxazoline (entry 10) a better selectivity was observed (dr > 20:1) but with a lowest conversion due to a very low yield of the platinium complexation step (< 10%).The authors showed that the selectivity of the dehydrogenation is also dependent of the temperature.At 60 °C whatever the substituent of the oxazoline, the selectivity is high but at the expense of low conversion.After separation of each stereoisomer with preparative HPLC and transamination in the presence of hydroxylamine, the aniline (-)-8 was isolated in high enantiomeric excess.Direct macrolactam formation via palladium-catalyzed carbonylation reaction followed by deprotection of the methyl ester group gave the (-)-rhazinilam 1 in 8% overall yield.

Direct cross-coupling reaction; the total synthesis of (±)-rhazinilam and (±)-rhazinal
Relying on their previous work on the direct palladium-catalyzed cross-coupling reaction to obtain the frondosin B a biaryl natural product, 7 Trauner and co-workers reported in 2005 a concise total synthesis of racemic rhazinilam 1 through an aromatic C-H functionalization followed recently by the extension of this approach to prepare (dl)-rhazinal 2. 8 The retrosynthetic plan of this work consists to form the tetrahydroindolizine intermediate by an oxidative Heck coupling reaction and to construct the lactam ring by the use of the palladium-catalyzed direct cross coupling reaction (Scheme 5).The total synthesis of the racemic rhazinilam 1 proposed by Trauner and co-workers began with the preparation of the iodoaryl 12 in few classical steps.The reaction of 12 in the presence of 10 mol% of palladium acetate, the monophosphine DavePhos and potassium carbonate as base furnished the lactam 15 in moderate yield (47%).The authors suggested the following mechanism.A nucleophilic attack of the pyrrole moiety on the palladium (II) in 13 gives the palladium intermediate 14 which after aromatization of the pyrrolium (loss of proton) undergoes a reductive elimination to afford the 9-membered cycle 15.The intramolecular C-H arylation occurred when the amide function was protected with a methoxymethyl group.In the absence of this protecting group the deiodination compound was formed.The presence of the MOM prevents probably the protonation of the palladium complex 13.The final steps of the synthesis of (dl)-1 were then achieved after carefully removal of the MOM protecting group, saponification of the ester and decarboxylation.This approach to the formation of the biaryl system by a C-H bond functionalization having shown to be efficient was then employed to prepare the racemic rhazinal 2 (Scheme 7).The tetrahydroindolizine moiety 19 was first prepared by using of an oxidative Heck cyclization from the pyrrole 16.This palladium (II) oxidation process was carried out in the presence of palladium diacetate and tert-butylhydroperoxide as oxidant to give 19 in 69% yield.This method which consists to functionalize a pyrrole catalyzed with palladium (II) under oxidative atmosphere was initially described by Gaunt and co-workers and used for the total synthesis of racemic rhazinicine 3 (see below). 9 with loss of acetic acid and a Heck-type reaction yields the tetrahydroindolizine 19.In parallel to this approach, Trauner and co-workers studied also the preparation of 25 from a classical Heck reaction.The iodopyrrole 24 obtained in few steps from the azafulvene 23 was submitted to modified Jeffery conditions to form 25 with good yield ready to be converted into 20.After few steps of conversion of 19 to the iodoaryl cylization's precursor 21, the intramolecular C-H arylation was then engaged to produce the biaryl derivative 22 under the previously established reaction conditions.The racemic rhazinal 2 was obtained after cleavage of the MOM protecting group with 10 equivalents of BCl3 at low temperature.

Metal-catalyzed C-H borylation / Suzuki coupling reaction and oxidative cyclization; the total synthesis of (±)-rhazinicine
Gaunt and co-workers reported recently the first total synthesis of the rhazinicine 3 a structurally very close compound of rhazinilam 1. 9 The synthetic plan was based on two key steps using a regioselective intermolecular C-H arylation of pyrrole and an oxidative Heck cyclization.To complete the synthesis a third important step consisted in the formation of the 9-membered lactam (Scheme 8).In previous works, they developed an efficient catalytic system to control the regioselectivity of the alkenylation of indoles 10 and pyrroles. 9It was shown that the regioselectivity of the functionalization depends strongly on the solvent system and on the N-pyrrole protecting group respectively.In accordance with these observations, the authors focused on the use of their palladium (II)-catalyzed C-H bond activation of pyrroles reaction conditions to form the biaryl system.Despite numerous attempts no satisfactory results were obtained.Therefore they decided to study the Ircatalyzed C-H borylation 11 followed by a Pd-catalyzed Suzuki coupling reaction.During this work, Gaunt and co-workers have shown that the Ir/Pd-catalytic process works well and the reaction is selective whatever the protecting group (N-Boc and N-TIPS) yielding only the coupling product at the C3 position of the pyrrole ring.Scheme 8. Gaunt's approach of (dl)-rhazinicine 3.
The strategy to functionalize the pyrrole ring has been established, the total synthesis of racemic rhazinicine was engaged as follows.The need to substitute the pyrrole moiety at the position C2 and C3 and to prevent the possible formation of byproducts as noticed by the authors, the installation of a trimethylsilyl group as blocking group at C5 was considered before the Ir-catalyzed C-H bond borylation.Therefore the 2-trimethylsilyl pyrrole N-Boc protected 26 was used as starting material and submitted to the sequential one-pot Ir/Pdcatalytic reaction to furnish in good yield the expected cross-coupling product 29 as single isomer.This reaction probably takes place as follows.The aromatic C-H bond cleavage occurs either through an oxidative addition or sigma bond metathesis 12 to form the iridium hydride complex 27 followed by a reductive elimination to form the pyrrol boronic acid 28.After removal of the Boc group, the pyrrole 30 was converted into the compound 32 ready to be submitted to the reaction conditions to perform the intramolecular oxidative Heck cyclization.Treatment of 32 with 10 mol% Pd(TFA)2 and tert-BuOOBz as oxidant give 33 with a similar mechanism described in Scheme 7. The last steps to obtain the target compound (±)-3 consist first to reduce the C-C double bond into ethyl group and the NO2 into aniline under H2 followed by a cleavage of the TMS and 2-trimethylsilylethyl protecting groups in the presence of AlCl3 and then a macrolactamization using the Mukaiyama's reagent.Scheme 9. Gaunt's synthesis of (dl)-rhazinicine 3.

Conclusions
The development of transition-metal mediated reactions involving C-H bond functionalization is among the topical areas of catalytic processes.Although this reaction is now widely studied, few examples have been reported showing its use in total synthesis of natural products.The three applications presented here to synthesize rhazinilam and related derivatives demonstrate the effectiveness of this methodology despite of remaining moderate yields.
We believe that continuous effort should be devoted to improve the field of use of this methodology, in particulary in respect to the diversity of organic functions in order to extend the C-H bond functionalization for the preparation of elaborated compounds.

Special
A plausible mechanism was proposed.A palladation at C2 occurs via the intermediate 17 followed by the rearomatization to 18