C-10b Functionalized 5,6-dihydropyrrolo[2,1-a ]isoquinolines as intermediates in the synthesis of erythrinane systems. Intra-vs. intermolecular conjugate addition based strategies

C - 10b Functionalized 5,6-dihydropyrrolo[2,1-a ]isoquinolines have been prepared via Parham cyclization and α -amidoalkylation reactions, using functionalized organolithium reagents. Their utility as intermediates in the synthesis of erythrinanes via intra or intermolecular conjugate addition reactions has been studied. Thus, a protocol for preparing the erythrinane skeleton through a Parham cyclization − intermolecular α -amidoalkylation − intermolecular conjugate addition − ring-closing metathesis process has been described


Introduction
The erythrinanes represent a significant class of alkaloids of broad pharmacological activity.Besides the curare-like and hypnotic action, they are known to display sedative, hypotensive, neuromuscular blocking, and CNS activity.This activity is attributed to antagonistic action of the nicotinic acetylcholine receptors in the brain. 1 Because of their unique spiro amine structure and physiological activities, these alkaloids have been a target of synthesis for a long time. 2 Over the last years we have developed 3 new procedures for the synthesis of tetrahydro-and dihydropyrroloisoquinolones based on organolithium 4 and N-acyliminium chemistry. 5These approaches proved to be an effective and expeditious method for the synthesis of these heterocycles in enantiomerically pure form. 6A notable characteristic of these processes is that products are armed with a readily functionalized substituent at C-10b, and that they posses the α,β-unsaturated lactam unit, which is suitable for conjugate addition reactions.This feature offered a potentially facile route for erythrinane skeleton assembly, by closing ring A in the final step.We describe the reduction of this plan to practice. 7The retrosynthetic analysis for our first approach to erythrinanes of general structure 1 is described in Scheme 1.

Scheme 1
We anticipated that the spiroamine unit could be assembled through an intramolecular conjugate addition reaction of a dihydropyrroloisoquinoline 2, which incorporates a functionalized four-carbon atom substituent in C-10b.Compared with some other classes of conjugate acceptors, α,β−unsaturated amides and lactams are usually less reactive. 8Thus, success of the conjugate addition reaction might require the presence of an activating group attached to the unsaturated system.Therefore, two types of 5,6-dihydropyrroloisoquinolones 2a (R = H) and 2b (R = CO 2 Bn) would be compared for efficiency.These key intermediates 2 would be derived from pyrroloisoquinolines 3 or 4, which would be obtained by addition of a functionalized organolithium reagent 6 to known imides 5, followed by intramolecular αamidoalkylation reaction.

Results and Discussion
Synthesis of precursors 2a,b is depicted in Schemes 2 and 3.The first task was the choice of the organolithium 6, which would behave as a 1,4-dianion equivalent.In this context, we had previously reported that 2-(3-lithiopropyl)-2-trimethylsilyl-1,3-dithiane 6c (Figure 1) may be used in this addition-α-amidoalkylation sequence for the synthesis of functionalized dihydropyrroloisoquinolines of general structure 2a.3d However, desilylation was problematic, and subsequent attempts of intramolecular conjugate addition were unsuccessful. 9Therefore, we decided to test other possible 1,4-dianion equivalents, and selected protected βcarbonylorganolithiums, as 2-(2-lithioethyl)-2-methyl- [1,3]dioxolane 6a and 2-(2-lithioethyl)-2methyl- [1,3] dithiane 6b (Figure 1).Thus, organolithium 6a was generated in situ from phenylsulfanyl derivative 7a by reductive lithiation 10 with Li/DBB (4,4'-di-tert-butylbiphenyl), and reacted with imide 5a to afford hydroxylactam 8. Cyclization and simultaneous hydrolysis of the acetal were accomplished upon treatment with TFA.The α-amidoalkylation reaction proceeded stereoselectively, affording isoindoloisoquinoline 4a as a single diastereomer.Finally, thermal retro Diels-Alder reaction gave functionalized 5,6-dihydroisoquinoline 2a in high overall yield (Scheme 2).An analogous addition-α-amidoalkylation sequence was applied for the synthesis of 2b.In this case, organolithium 6b was generated from phenylsulfanyl derivative 7b, and reacted with imide 5b.Without purification, the crude reaction mixture was treated with TFA in refluxing CH 2 Cl 2 to afford 10b substituted tetrahydropyrroloisoquinoline 3 in high overall yield.Unsaturation was then introduced by a two step procedure. 11Thus, LDA deprotonation and sequential treatment with ClCO 2 Bn and PhSeBr afforded pyrroloisoquinoline 9. Oxidative βelimination of phenylselenyl group and hydrolysis of dithiane was accomplished in a single step using PIFA [Bis(trifluoroacetoxy)iodobenzene]. 12Once the dihydropyrroloisoquinolines 2a,b had been prepared, we studied the intramolecular conjugate addition reaction.Thus, the kinetic control enolate was generated by treatment of 2a,b with LDA at -78 °C, but no cyclization was observed under any of the experimental conditions tested.The use of other bases (LiHMDS) or additives (HMPA) did not improve the results.In all cases, no reaction was observed with 2a, recovering starting material, while 2b led to a mixture of products.To check that the enolate was being efficiently formed, we carried out the deprotonation with LDA at -78 °C, and quenched the reaction with TMSCl, obtaining the corresponding enol ethers that could be characterized by 1 H NMR. Without purification, these enol ethers were treated with SnCl 4 or TiCl 4 under Michael-Mukaiyama conditions.However, no cyclization product was obtained under the conditions tested, recovering the corresponding pyrroloisoquinolines 2a,b.Therefore, although functionalized dihydropyrroloisoquinolines 2a,b have been prepared through organolithium addition-αamidoalkylation sequences, the α,β-unsaturated lactam unit is unreactive towards the intramolecular conjugate addition of enolates or enol ethers, under the conditions tested.
In view of these results, we thought of an alternate route that would involve an intermolecular conjugate addition.Thus, ring A of the erythrinane system could be assembled through the ring-closing metathesis (RCM) reaction of pyrroloisoquinolones 10.The allyl group on C-1 could be introduced by conjugate addition on the dihydro derivatives 2c,d.These key intermediates 2 would be derived from the known imides 5, via N-acyliminium or Parham cyclizations. 13(Scheme 4).
The first goal of our synthetic sequence was to elaborate the dihydropyrroloisoquinolones that would install the allyl group at the C-10b position.As depicted on Scheme 5, unactivated pyrroloisoquinoline 2c was obtained from maleimide 5c by allylmagnesium chloride addition and N-acyliminium cyclization (36% overall yield).It then remained to introduce the allyl group by conjugate addition.First, we studied the addition of Gilman's allylcuprate to lactam 2c.The cuprate could be efficiently prepared by addition of two equivalents of allylmagnesium chloride to a suspension of CuI in THF at -78°C.Several reaction conditions were tested, but no reaction was observed if the lactam 2c was added at this temperature, and the reaction mixture was allowed to warm up to temperatures ranging from -40 °C to 20 °C.The use of other solvents or additives such as TMSCl did not improve these results.Therefore, we decided to test the Sakurai reaction using allyltrimethylsilane and TBAF in DMF. 14 When the reaction was carried out at room temperature, starting material was recovered and operating under reflux lead to an intractable mixture of products.
Therefore, we focussed our attention on the conjugate addition to α,β−unsaturated lactam 2d with an activating benzyloxycarbonyl group at the α position of the lactam carbonyl group.Thus, as depicted on Scheme 6, succinimide 5d was cyclized under Parham reaction conditions to afford an α-hydroxylactam, which, without purification, was subjected to intermolecular αamidoalkylation with allyltrimethylsilane in the presence of TiCl 4 providing 11. 15 Subsequent sequential treatment with LDA, benzyl chloroformate, and phenylselenyl bromide, followed by β-elimination with H 2 O 2 provided the dihydropyrroloisoquinoline 2d (Scheme 6).After extensive screening of conditions, it was found that conducting the reaction with Gilman's allylcuprate (prepared as described above) with TMSCl as additive provided diastereoselectively the trans isomer 13 in high yield (96%), 16 thereby setting the stage for the key RCM reaction.The stereochemical outcome of the conjugate addition might be explained as a result of the attack of the nucleophile from the opposite side of the allyl group in C-10b, which would be in a pseudo-axial conformation.Protonation of the resulting enolate would lead to the more stable trans isomer.To test the RCM protocol 17 for the construction of the erythrinane framework, we chose the first generation Grubbs catalyst 13.Thus, RCM was carried out on the tetrahydropyrroloisoquinolone 12, which cyclized smoothly to give 1b as a single diastereomer in quantitative yield.rt.(e) (allyl) 2 CuMgI, TMSCl, THF, -78°C to 0 °C.(f) Grubbs catalyst 13 (20% mol), CH 2 Cl 2 , reflux.