First highly stereocontrolled synthesis of tetrahydro trans -β-carboline derivatives by exploiting the influence of a cyclic amide

Stereocontrolled synthesis of trans -β-carboline derivatives by employing amidation strategy is presented.

The Pictet-Spengler reaction 4 that involves the cyclization of relatively electron-rich aromatic framework by involving imine or iminium moieties is method of choice for constructing carbolines. 5This strategy has been employed in the total synthesis of numerous natural products including azatoxin, 1a 6 and alstophylline 1b. 7,8Additionally, tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline piperazinedione scaffolds were also identified to have anti-cancer 9 and anti-HIV activities. 10We were interested to work on tadlafil and its isomers and the literature search revealed that the first synthesis of tadalafil 1c was described by two groups Martin et al. 11 and Daugan et al. 12 Both the approaches involve cyclization of D-tryptophan methyl ester 3 with piperonal 2 using trifluoroacetic acid (TFA) in dichloromethane that afforded (1R,3R)-cis-pyrido-indole derivative 4 via isomerization (cis/trans: from 60/40 to 97/03).Thereafter, acylation of 4 with chloroacetyl chloride 5 yielded the chloroacetyl derivative 8, which was finally subjected to cyclization with methylamine in methanol to yield 1c as shown in Scheme 1.Moreover, direct activation of tryptophan 6 with DCC/HOBt followed by reaction with 9 afforded tadalafil 1c.
Considering the presence of two chiral centres, most of the synthesis of 1c employed the commercially available D-tryptophan derivative that has predisposed systemic chirality, and the second chiral center was generated through substrate controlled Pictet-Spengler type cyclization followed by acid mediated transformation of the trans isomer to the desired cis isomer predominantly as shown in Figure 2. 13 Unlike to amino ester, β-carboline trans-4, isomerization of trans-tadalafil 12 to tadalafil 1c was unsuccessfully attempted (Figure 2).
An alternative synthesis of 1c was reported 14 starting from L-tryptophan in seven steps.Another approach employed sarcosine ester 9 through double amidation 15 based two-step synthesis of 1c.Recently, Shi.et al. 16 has published the synthesis of 1c using an improved acid catalyzed stereoselective Pictet-Spengler reaction.So far, to the best of our knowledge, apart from substrate controlled stereocontrolled synthesis disclosed by Cook et al., 17 there is no methodology reported that describes the synthesis of exclusively trans-β-carboline derivatives by manipulating amide functionalty.Herein, we disclose a methodology that enabled us to synthesize trans-β-carboline derivative in a stereocontrolled manner using the diketopiperazine moiety present in the substrate.Scheme 1. Precedented approaches for tadalafil synthesis.In our endeavors, we attempted the synthesis of 1c and its isomer via new intermediates starting from the commercially available N-Boc-D-tryptophan 10.In this approach, mixed anhydride methodology was adopted for amidation using sarcosine moiety.Considering the thermodynamic stability of trans-β-carboline over its cis isomer as reported, 9,[16][17][18][19] we first explored the possibility of a stereocontrolled synthesis of the S,R diastereomer of trans tadalafil 12.
As shown in Scheme 2, substrate 10 was treated with ethyl chloroformate (ECF) to generate its mixed anhydride in situ followed by reaction with 9 to yield an intermediate 11.Thereafter, at higher temperature, we were able to construct piperazine ring in a trans (S,R) fashion yielding 12 while at lower temperature R,R isomer, tadalafil 1c was observed.Predominant formation of 1c, at low temperature, is due to the fact that the slow reaction rate of piperazine ring construction led to an epimerization of the trans isomer to cis isomer 13 13,16,20 followed by intramolecular amidation.
Scheme 2. New synthetic approach for tadalafil 1c and its trans isomer 12.
Secondly, we examined the transformation switch strategy where the piperazine ring was constructed first either starting from intermediate 11 or 3 to access 15.Thereafter, reaction of 15 with aldehyde 2 afforded stereocontrolled trans isomer 12 in excellent yield as shown in Scheme 3.

Scheme 3. Transformation switch strategy for trans tadalafil 12.
Encouraged by the outcome of Scheme 3, we intended to establish a generality of this approach by diversifying the intermediate 15 to synthesize few derivatives of trans tadalafil 12.Such an approach led to a new methodology (Schemes 3 and 4) for modified stereocontrolled Pictet-Spengler reaction to synthesize β-carboline derivatives starting from 1,4-diketopiperazine scaffold.This type of diketopiperazine derivatives e.g. S isomer of 15 are recently disclosed in different context by using the Ugi reaction strategy. 21Hitherto known procedures for modified Pictet-Spengler reaction were found to utilize amines, substituted amines 1,3,12,14,15,22 or carbamates 23 for β-carboline synthesis.However, in our approach, we utilized amide 15 to yield β-carboline derivatives 17a-c and 12 as shown in Scheme 4.

Scheme 4. Synthesis of congeners of trans tadalafil 12.
Isomerisation of β-carbolines 9,19 are well documented and the literature findings reveal that the use of bulky moieties e.g.] Considering the low reactivity than amines and structural attributes of amide, it is quite apparent that the intermediate 15 can offer conformationally locked six membered sterically constrained amide ring system which is amenable to afford trans products 17a-c including 12 plausibly due the iminium transition state where the carboline ring might form from top of the plane as depicted in the Figure 3.We also observed the influence of acid and solvent in the condensation to obtain in situ iminium species followed by carboline ring formation.Aq.HCl in 1,4-dioxane was found to be suitable to affect the carboline ring formation at 100 °C in 95% conversion as shown in Table 1 (entry 2).

Conclusions
In summary, we have successfully demonstrated an unprecedented stereocontrolled synthesis of trans isomer of tadalafil 12 and β-carboline derivatives 17a-c.The method disclosed here is the first of its kind for the synthesis of β-carbolines that employs the less reactive amide rather than the amine.

Experimental Section
General.All starting materials were commercial substances.LR grade solvents and commercial reagents were used without further purification.The FT IR spectra were recorded as KBr pallet and only diagnostic and/or intense peaks are reported.Mass spectra (70 eV) were recorded on LC-MS spectrometer.The melting points were determined by using the capillary method and are uncorrected. 1HNMR spectra were recorded in CDCl3 and DMSO-d6 using a 400 MHz instrument. 13C NMR spectra were recorded in CDCl3 and DMSO-d6 using a 400 MHz instrument.Signals due to the solvent ( 13 C NMR) or residual protonated solvent ( 1 H NMR) served as the internal standard.The 1 H NMR chemical shifts and coupling constants were determined assuming first-order behavior.Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad); the list of coupling constants (J) corresponds to the order of multiplicity assignment.TLC analyses were performed on silica gel precoated-plates (250 μm layers).We note that our stereo chemical assignments are supported by comparisons with the literature.HPLC analysis was performed with Waters Symmetry shield RP18 (250X4.6 mm, 5µ) column by using gradient elution and monitored at 220 nm.

(R)-Ethyl 2-(2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)-N-methyl propanamido) acetate (11).
A mixture of N-Boc-D-tryptophan (5 g, 16.4 mmol) and THF (25 mL) was cooled to -20 °C under nitrogen atmosphere.To the mixture charged N-methyl morpholine (1.83 g, 18 mmol) and stirred for 20 min.Thereafter, a solution of ethyl chloroformate (1.95 g, 18 mmol) in THF (2 mL) was slowly added and stirred the reaction mass for 30 min.Subsequently, a solution of sarcosine ethyl ester in THF (5 mL) was prepared by treating sarcosine ethyl ester hydrochloride (2.76 g, 18 mmol) with N-methyl morpholine (2 g).This solution was added to the solution of mixed anhydride in THF drop wise at -20 °C.The reaction mass was allowed to attain ambient temperature and maintained for 1 h.After completion of the reaction, solvent was removed by distillation (CAUTION: THF forms peroxides while distillation and hence PPE should be wear during concentration of THF) and to the obtained residue water and DCM were charged.After stirring, organic layer was separated and 2N HCl washings (2 x 10 mL) were given followed by bicarbonate washing (1 x 10 mL).The organic layer was evaporated to give compound 11 in 5. ) and stirred at ambient temperature for 5 h.Thereafter, reaction mass was concentrated under reduced pressure.Charged DCM and washed with saturated sodium bicarbonate solution (15 mL).Then, solvent was evaporated under reduced pressure to get the desired compound 15 in 0.9 g, 70% yield.Method b.A suspension of HCl salt of compound 3 (1.17g, 4.58 mmol) in chloroform (10 mL), to that added aqueous ammonia solution (2 mL) and water (10 mL) and stirred at ambient temperature for 10 min.Organic layer was separated and solvent was evaporated under reduced pressure.The obtained residue was diluted with chloroform (10 mL) then added triethyl amine (0.394 g, 3.894 mmol) and cooled to 0 °C.Compound 5 (0.66 g, 5.84 mmol) was added and the reaction mass was stirred for 1 h.Thereafter, water (10 mL) was added to the mass below 10 °C, and organic layer was separated and washed with saturated sodium bicarbonate solution followed by water.Finally, organic layer was distilled under vacuum.To the obtained compound, methylamine (0.42 g, 13.548 mmol) in methanol (10 mL) was added and stirred for 6 h at 55 °C for completion of the reaction.Subsequently, the reaction mass was cooled to ambient temperature and separated solids were filtered.After stirring for 1 h, reaction mass was concentrated under reduced pressure and DCM was charged and washed with saturated sodium bicarbonate solution (30 mL).Theraafter, solvent was evaporated under reduced pressure to get crude compound 17 followed by its purification through column chromatography using petroleum ethers: ethylacetate

Figure 1 .
Figure 1.Core structure of carbolines and medicinally relevant entities.

Figure 3 .
Figure 3. Transition state disposed for affording trans product.

Table 1 .
Acid screening for β-carboline synthesis *reaction did not proceed to completion.
(0.36 g, 12.65 mmol) were stirred for 10 min.Trifluoroacetic acid was added slowly and the reaction mass was heated to 45-50 °C, maintained at the same temperature for 15 h and concentrated under vacuum.To the obtained residue, charged water (5 mL) and dichloromethane (5 mL) and the mixture was neutralized with saturated sodium bicarbonate solution.Organic layer was separated and concentrated below 35 °C under vacuum.