Asymmetric syntheses of functionalized pyrrolizidin-3-ones

The syntheses of 1-and 7-hydroxypyrrolizidin-3-ones are described via asymmetric catalytic hydrogenation or diastereoselective reduction of ketones as key steps. 2,7-Disubstituted pyrrolizidin-3-ones are also prepared. The second chiral center is created using stereoselective electrophilic amination or hydroxylation reactions.


Introduction
Functionalized bicyclic lactams with the nitrogen atom at the bridgehead position are interesting structures well studied in the literature.One commonly encountered function of this skeleton is in the formation of rigid dipeptide mimics. 1 Moreover, these bicyclic systems are known to be effective intermediates in the preparation of alkaloids such as the polyhydroxylated pyrrolizidines or indolizidines, [2][3][4] and of more complex structures like lepadiformine 5 or furopyrrolizidinone. 6 The synthesis of pyrrolizidin-3-ones mono-or disubstituted at positions 1 or 7 was reviewed in 2000. 7e have been interested in the preparation of such systems, in particular the (1R,7aS)-and (1S,7aS)-1-hydroxypyrrolizidin-3-ones (1 and 2) on one hand, and in a second line of study the O-protected (7S,7aS)-and (7R,7aS)-7-hydroxypyrrolizidin-3-ones (3 and 4) (Figure 1).][10][11][12][13][14][15][16][17] Most of the reported syntheses started from the amino acid proline or its derivatives, as these substrates have the advantage of introducing directly the stereocenter at C-7a of the ring system.The center at C-1 was controlled by asymmetric synthesis, by formation of a -hydroxyester or amide and subsequent cyclisation under basic conditions, by aldol condensation or by reduction of pyrrolizidine-1,3-dione leading to 1 as a major product (90% d.e.).Other methods for the preparation of 2 have been described, such as the catalytic hydrogenation of 1,2-dihydro-1-hydroxypyrrolizin-3-one or pyrrolizine-1,3-dione.From all these preparations, the overall yields are quite often low due to multistep syntheses, with d.e. from 60 to 99% for 1, and up to 99% for 2.
Concerning the 7-hydroxypyrrolizidinones 3 and 4, few examples of synthesis are reported in the literature. 4,18,19In particular, the lactam 3 is described as an intermediate in the preparation of (-)-supidine, 18 whereas its 7a-epimer led to 1-hydroxypyrrolizidine. 4 We present in this manuscript a new route to the bicyclic compounds 1 and 2 from L-proline and of 3 and 4 from L-pyroglutamic acid (PGA) based on diastereoselective reduction or catalytic hydrogenation.
Then we extended the pool to 2,7-difunctionalized pyrrolizidin-3-ones (Figure 2).In the literature, one example of the preparation of the protected dihydroxylated compound is reported, by tandem cycloaddition of nitroalkene.19b In our approach, the chiral center at C-2 is created by electrophilic hydroxylation or amination reactions.

Results and Discussion
We prepared the methyl -ketoester 6 by the method of Masamune 20 from the commercial N-Boc L-proline 5, in good yield (88%) without epimerization at chiral center (Scheme 1).The deprotection of the carbamate using trifluoroacetic acid (TFA) gave 7, which was purified and reduced using sodium borohydride (NaBH4).This reaction led to two separable diastereoisomers whose NMR spectra are in accord with the hydroxypyrrolizidinone structures 1 and 2, with predominance of the first.After 2 hours at 25 °C, with 1.2 mol% of NaBH4, the compounds 1 and 2 were obtained in a 54/46 ratio and 81% yield.By decreasing the temperature to -10 °C and with a slow addition of 0.6 mol% of NaBH 4 , we managed to upgrade the diastereoisomeric ratio to 85/15, although in lower yield (67%).The 1-hydroxypyrrolizidin-3-one 1 was isolated in 57% yield from 7 after separation by chromatography over silica gel.The formation of the bicyclic compounds could proceed by reduction of the ketone and subsequent cyclisation.The formation of 1 would then be in agreement with a chelated transition state for the reduction step.Scheme 1. Formation of the (1R,7aS)-1-hydroxypyrrolizidin-3-one 1.
The bicyclic compound 2 was obtained from the -ketoester 6 following a similar way to that described by Genêt 10 for the preparation of ent-2 from D-proline.We first performed a classical reduction of 6 with NaBH4 to give the -hydroxy-esters 8 and 9 in a 56/44 ratio and in 81% yield (Table 1, scheme 2).Physical separation of the two epimers by silica gel chromatography led to the two references for HPLC analysis.The hydrogenation of 6 run in the presence of [(R)-BinapRu]Br2 as catalyst at 50 °C led to 8 in yields of up to 97% and d.e. of 96% depending on the pressure and reaction time.The use of [(S)-BinapRu]Br2 as catalyst for the hydrogenation of 6 was not very efficient, the best ratio 8/9 being 16/84.After treatment of 8 with TFA, the intermediate pyrrolidine was treated with potassium carbonate to give the expected (1S)-hydroxypyrrolizidin-3-one 2 (94% for the 2 steps) (Scheme 2).
We reported few years ago the catalytic hydrogenation of -ketoesters bearing a -lactam moiety. 21The full syntheses of 3 and 4 from commercial pyroglutamic acid 10 are detailed next.They began with the formation of the N-Boc protected 11 in three steps as described in the literature 22 (Scheme 3).The homologation using Masamune′s method led to the expected ketoester 12 in 67% yield after 4 days of reaction.In the earlier communication we reported the catalytic hydrogenation of 12 and showed that the best conditions for obtaining the hydroxyester 13 or its diastereoisomer 14 selectively was to use the catalyst under atmospheric pressure at 55 °C for 40 hours.We observed the removal of the tert-butoxycarbamate protecting group concomitantly with the hydrogenation reaction under these conditions.The -hydroxyester with the 3S configuration (13) can be obtained in 94% diastereomeric excess and in nearly quantitative yield by using the [(R)-BinapRu]Br2 complex.The use of the (S)-catalyst led to the epimer 3R 14 as the sole isomer, also in good yield (89%).Scheme 3. Formation of the -hydroxyesters 13 and 14.
The transformation of 13 and 14, respectively, into the epimeric pyrrolizidinones 3 and 4 was effected through the sequences described below (Scheme 4).After protection of the hydroxy functions as tert-butyldimethylsilyl ethers (15: 75%, 17: 88%), a first assay of the selective reduction of the methyl ester group with calcium borohydride formed in situ led to 16 and 18 in yields of 81 and 69% respectively.The yields were improved by reaction of 15 and 17 with a large excess of sodium borohydride (15 equiv.) in methanol, giving the same products 16 or 18 in yields of 94 and 77%.Their cyclisation was previously performed in a short sequence: mesylation of the primary alcohol function, and cyclisation in the presence of potassium carbonate, leading to the pyrrolizidinones 3 and 4 in yields of around 60%. 21 The yields have now been increased by the use of sodium hydride in tetrahydrofuran, becoming 84 and 85% respectively for the two-step sequence.Scheme 4. Formation of the protected 7-hydroxypyrrolizidin-3-ones 3 and 4.
We have shown access to the monohydroxylated pyrrolizidin-3-ones 1-4 in d.e. of up to 99%.For the two pyrrolizidinones 1 and 2 prepared in three and four steps respectively from 5, the diastereoselectivity is analogous to previously reported values, and is particularly remarkable for 2 (d.e.96%, overall yield 80%) via a catalytic hydrogenation.Nevertheless, the very short synthesis described for compound 1 (d.e.70%) via low temperature reduction made this a particularly interesting and inexpensive scheme despite the moderate overall yield (50%).Finally, the (7S,7aS)-7-(tert-butyldimethylsilyloxy)pyrrolizidin-3-one (3) and its epimer (7R,7aS)-4 were reached in nine steps from PGA (10) in overall yields of 30% and 27% respectively and excellent diastereoselectivities.
In a second project our aims were the 2,7-disubstituted derivatives 2,7-dihydroxypyrrolizidin-3-one and 2-amino-7-hydroxypyrrolizidin-3-one.The new functionality at position 2 was introduced at the beginning of the synthesis.We tested firstly the amination and hydroxylation reactions of PGA (10).
Beside the preparations of 3-amino -lactam described in the literature, [23][24][25] there are very few instances of the direct amination  to the carbonyl of PGA.These last syntheses were based mainly on the reaction of the corresponding enolate with diphenylphosphoryl azide, 24 or the hydrogenation of the oxime formed by the action of Bredereck′s reagent followed by nitrous acid treatment. 25In these two cases the relative configuration of the amino-PGA in the major product was always cis.We have developed a way of direct amination of protected PGA leading to the trans configuration in the product.The Boc-protected methyl pyroglutamate 19 26 was treated with 1.1 equivalents of LiHMDS at -78 °C for 1 hour, followed by addition of 2.0 equivalents of dibenzyl azodiformate (DBAD) in tetrahydrofuran at -60 °C (scheme 5).After purification, the expected hydrazino derivative 20 was obtained in 66% yield, as only one diastereomer (d.e.>95%, measured by NMR).The stereochemistry of the newly formed center of 20 was elucidated by conversion into the corresponding amine by a three-step sequence, namely, classical hydrogenation using Pd/C followed by the addition of Raney nickel in the reaction mixture, then by cleavage of the tert-butoxycarbonyl protecting group with TFA, leading to 21.The NMR spectral data of the product were in concordance with the structure of 21, and the trans configuration was proved by NOESY correlation studies.In particular, we found a strong effect between the protons H-4 and H-3b, and also between H-2, H-3a and NH2.There is clearly no effect between H-2 and H-4.All these results are in agreement with the (R) configuration of the newly formed aminated stereocenter, showing that the enolate was attacked by the azodicarboxylate at its less hindered side only, leading to the one diastereoisomer.This result was particularly interesting in being the first example of direct amination of a protected PGA leading to the corresponding derivative with the trans configuration.Scheme 5. Electrophilic amination and hydroxylation of protected PGA.
The electrophilic hydroxylation of the enolate of 22 22 by 3-phenyl-N-p-toluenesulfonyloxaziridine (TPO) has been first described by Nozoe 27 and completed by Young 28 .The reaction led to the hydroxylated 23 with a d.e.>99% but in low yield (30%).We increased this yield to 55% by the action of TPO at -78 °C over 45 minutes followed by hydrolysis in the presence of camphorsulfonic acid (CSA) (Scheme 5).The d.e. was as good as those of the earlier authors, as only the trans isomer was obtained (d.e.>95%, measured by NMR studies).The newly-formed hydroxyl function was protected as a tert-butyldimethylsilyl ether under classical conditions to give 24 (92%).
Thus, the 3-amino-and 3-hydroxy-APG have been prepared with excellent d.e. and in short preparative sequences.The fully-protected hydroxy compound 24 was used in the synthesis of 2,7-dihydroxypyrrolizidin-3-ones (Scheme 6).
To perform the synthesis of 2,7-dihydroxypyrrolizidin-3-ones, the carboxylic acid was first restored by hydrogenolysis of the benzyl ester of 24 and the subsequent homologation led to the -ketoester 25 (75% in two steps).The best results for the catalytic hydrogenation of the ketoester were obtained with the N-and O-free compound 27, from successive treatment of 25 with tetrabutylammonium fluoride giving 26, then trifluoroacetic acid.The hydrogenation of 27 was performed at 55 °C and atmospheric pressure in the presence of 2% mol of [(R)-BinapRu]Br2 or [(S)-BinapRu]Br2 catalyst.It gave the -hydroxyesters 28 and 29 respectively with comparable diastereoselectivities and yields of 98% and 82%.Scheme 6. Formation of the -hydroxyesters 28 and 29.
The diol 28 was transformed into the corresponding bicyclic system 31 in four steps (Scheme 7).Regioselective silylation of 28 using triisopropylsilyl chloride in a mixture DMF/imidazole led to the intermediate 3′-triisopropylsilyloxy compound.The methyl ester was then reduced by the action of an excess of NaBH4, leading to 30.The primary alcohol was selectively tosylated and a cyclisation under basic conditions gave the pyrrolizidinone 31 with a yield of 43% for the 2 steps.The same sequence applied to 29 led to the compound 33 with a yield of 18% for the 4 steps.
A similar synthetic way is actually under progress for the obtaining of 2-amino-7hydroxypyrrolizidin-3-one.
Finally, we tested the functionalization in  of the carbonyl of the pyrrolizidinones 1, 2, 3 and 4 in the way to increase our pool of disubstituted pyrrolizidin-3-ones.The functionalization of the derivatives 1, 2 and 3 by electrophilic amination or hydroxylation failed.Only 4 led to the hydrazine 34 (Scheme 8) with the yield of 63% using strong conditions: 5.0 equivalents of LDA, then the addition of a solution containing 4.0 equivalents of DTBAD at -60 °C.In term of diastereoselectivity for 34, NOESY correlation studies showed that the irradiation of the proton H-2 induced an effect at the proton H-7a, which is in favour of a cis relation.When the proton H-7 was irradiated, no effect with the H-2 was observed that confirmed a 2S absolute configuration of the new asymmetric aminated center.

Conclusions
In conclusion, we report the synthesis of seven mono-and di-substituted pyrrolizidin-3-ones from L-proline or L-pyroglutamic acid.Starting from L-proline, a very short synthetic sequence was developed to reach 1. Treatment of the -ketoester derived from L-proline with sodium borohydride resulted in a one pot reduction/cyclisation.The hydroxypyrrolizidin-3-ones 2, 3 and 4 were obtained using asymmetric catalytic hydrogenation as the key step.2,7-Disubstituted pyrrolizidin-3-ones were synthesized from L-pyroglutamic acid.The chiral centers were created at C-2 by electrophilic amination or hydroxylation and at C-7 by catalytic hydrogenation as before.The two stereomeric 2,7-dihydroxypyrrolizidin-3-ones 31 and 33 were prepared by this way.The N,O-diprotected 2-hydrazino-7-hydroxypyrrolizidin-3-one 34 was obtained by direct electrophilic amination of the corresponding 7-hydroxypyrrolizidin-3-one 4. Electrophilic amination of N-Boc PGA methyl ester was also performed, leading exclusively to the 3-amino-PGA methyl ester 21 with a trans relative configuration, which should be an attractive building block for organic synthesis.

Methyl (2S,4R)-4-Amino-5-oxopyrrolidine-2-carboxylate, trifluoroacetate salt (21).
To the derivative 20 (1.7 g, 3.1 mmol) dissolved in MeOH (40 mL), was added Pd/C (88 mg).The overall was stirred vigorously under an atmospheric pressure of dihydrogen for 2 hours.Then Raney nickel was added, and the overall was stirred until the disappearance of the intermediate hydrazine (12 hours).The reaction mixture was passed through celite and washed with MeOH for give crude (518 mg) as yellow-green crystals.Purification under flash chromatography (EtOAc) gave two products, corresponding to the 1N-Boc and the 3N-Boc derivatives of 20 (64%).Each one was treated as follows, to give the same final derivative 21: they were retaken into TFA (0.85 mL for 80 mg of substrate), and after stirring 10 min the mixture was concentrated to give yellow and very hygroscopic crystals of 21 (86%; 55% from 20); []