LETTER 773

Synlett 2001 No. 6, 773–776 ISSN 0936-5214 © Thieme Stuttgart · New York

Unusual Fused Tricyclic 2-Azetidinones: Stereocontrolled Synthesis of Rigid Dipeptide Surrogates from b-Lactam-Tethered Imines via Sequential Cycloaddition/Ring-Closing MetathesisBenito Alcaide,* Pedro Almendros, Jose M. Alonso, Moustafa F. Aly,† María C. RedondoDepartamento de Química Orgánica I. Facultad de Química. Universidad Complutense 28040-Madrid, SpainFax +34 91 39 44 103; E-mail: alcaide@eucmax.sim.ucm.esReceived 22 March 2001

Abstract: The combination of [3+2] and [2+2] cycloaddition reac-tions of 2-azetidinone-tethered imines with ring-closing methatesisoffers an asymmetric entry to a variety of unusual fused tricyclic2-azetidinones bearing a bridgehead nitrogen atom, related to con-formationally restricted peptidomimetics.

Key words: b-lactams, polycyclic amides, metathesis, peptidomi-metics, asymmetric synthesis

Ring-closing metathesis (RCM) has recently emerged asa powerful tool for the formation of a variety of ring sys-tems.1 Although many investigations have been made inthis field using various types of dienes, nothing wasknown about the use of b-lactam building blocks for met-athesis until Barrett merged into this field, both in theracemic2a and the optically pure forms.2c

On the other hand, fused nitrogen heterocyclic systemsbearing bridgehead nitrogen atoms have attracted wide-spread attention in the field of medicinal and synthetic or-ganic chemistry due to the incorporation of thesecompounds in peptidomimetics.3 In connection with ourprevious work,4,5 we wish to report here the combinationof cycloaddition reactions of 2-azetidinone-tethered imi-nes with ring-closing metathesis as an asymmetric route tounusual fused tricyclic 2-azetidinones bearing two bridge-head nitrogen atoms, which can be considered as rigiddipeptide surrogates.

Cycloaddition precursors, alkenyl-4-oxoazetidine-2-car-baldehydes 1a-d, were prepared in optically pure formusing standard methodology.4 Treatment of aldehydes 1with various a-amino esters in the presence of 4 Å molec-ular sieves provided the corresponding aliphatic aldi-mines 2. These were obtained in quantitative yields and

NO

X

NO R2

N

R4

CO2MeH

NO R2

HN

CO2Me

R4H

R3MeO2C

R1O

R1O

R1O

MeO2C

CO2MeR3

H

H

R2

H

R3

1, X = O

2, X = NCH(R4)CO2Me

AgOAc/Et3N

3

4

+

H2NCH(R4)CO2Me,

4Å molecular sieves

Table 1 Synthesis of cyclization precursors, pyrrolidinyl-b-lactams 3 and 4

a The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude re-action mixtures before purification. PMP = 4-MeOC6H4.

b Yield of pure, isolated product with correct ana-lytical and spectral data.

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Synlett 2001, No. 6, 773–776 ISSN 0936-5214 © Thieme Stuttgart · New York

used in next step without further purification. 1,3-Dipolarcycloaddition of 2-azetidinone-tethered azomethineylides 2 was achieved via metal ion catalysis to affordmixtures of cycloadducts 3 and 4, having an alkene tetherat C3 or N1 positions of the 2-azetidinone ring, as we pre-viously reported for alanine (glycine) derived iminoestersbearing a N-(4-methoxyphenyl) unit at the b-lactam ring(Table 1).5a,b

The diolefinic cyclization precursors 5 can be easily ob-tained via N-acylation of the pyrrolidinyl nitrogen atomon cycloadducts 3a-e. We examined then the ring-closingmetathesis of our novel pyrrolidinyl-b-lactam diene sub-strates 5a-e for the obtention of less common fused tricy-clic 2-azetidinones bearing bridgehead nitrogen atoms,related to conformationally restricted peptidomimetics.This approach has not been hitherto applied for the syn-thesis of tricyclic b-lactams. Treating dienes 5 undersmooth ring-closing metathesis conditions (GrubbsCl2(Cy3P)2Ru=CHPh carbene, CH2Cl2, 25 °C), as previ-ously reported for bicyclic b-lactams,2 did not give the de-sired tricycles. Next, we examined other solvents andconditions. Thus, using toluene at reflux gave the bestyields (35-67%) of tricyclic pyrrolidinyl-b-lactams 6a-efused to eight-, nine- and ten-membered rings (Table 2).

In order to expand the scope of this approach we thoughtof the [2+2] cycloaddition of alkenyl-imine b-lactamsbearing an extra alkene tether at the b-lactam ring as a re-lated and direct access to structurally different diolefinicprecursors. The starting C4,C4'-bis-b-lactam (+)-7 wasprepared from aldehyde (+)-1a following our previouslyreported two-step route.5c Thus, treatment of (+)-1a withallylamine followed by ketene-imine cyclization directlyprovided the diene bis-b-lactam (+)-7 (81%) as a singlediastereoisomer. The fused azatricycle (+)-8 was cleanlyachieved in good yield (69%) via Grubbs carbene mediat-ed ring-closing metathesis in boiling toluene (Scheme).

Scheme

NO

MeOH

N

OPhO

HN

O

HMeO N

H

OPhO

(+)-7 (+)-8 (69%)

Grubbs carbene

NO

O

PMP

N

O

H H

H

MeCO2Me

CO2Me

NO

HN

R4

CO2MeH

MeO2C

R1O

R2

Cl

O

O

R3

NO

HMeO N

OH

R4

CO2Me

R3

MeO2C

6e

Et3N

5

Grubbscarbene

6a–d

( )n

3

a Yield of pure, isolated product with correct analytical and spectral data. PMP = 4-MeOC6H4. b The ratio was de-

termined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before pu-rification.

Table 2 Synthesis of fused tricyclic pyrrolidinyl-b-lactams 6

LETTER Unusual Fused Tricyclic 2-Azetidinones 775

Synlett 2001, No. 6, 773–776 ISSN 0936-5214 © Thieme Stuttgart · New York

It is believed that high temperature is favorable for rota-tion about the single bond connecting the two rings, and a"cis"-like conformation is probably necessary for cy-clization. Not unexpectedly, only the cis-olefin wasformed for eight- and nine-membered rings (compounds6a-c, 6e and 8), while for the ten-membered diazocinone6d only the trans-olefin was obtained.6 Importantly, thestereochemical integrity of the stereogenic centers at thefour- and five-membered rings remained unaltered duringthe transformation of diolefinic compounds 5 and 7 intotricyclic products 6 and 8.7

In conclusion, we have shown that the combination of[2+2] or [3+2] cycloaddition and ring-closing metathesisis a useful synthetic tool for the asymmetric synthesis ofunusual tricyclic 2-azetidinones bearing a fused medium-sized ring and two bridgehead nitrogen atoms, related toconformationally restricted peptidomimetics. This meth-odology is very versatile with the possibility of obtaininga variety of conveniently functionalized tricyclic b-lac-tams just by changing the substituents in readily available4-oxoazetidine-2-carbaldehydes, dipolarophiles, aminesand acid chlorides. In addition to the novelty of this se-quential strategy, the method proved to be general andhighly diastereoselective for the preparation of up to ten-membered fused-rings, offering the possibility of a futureapplication to different chiral building blocks other than2-azetidinones. The scope and limitations of this chemis-try are currently under investigation in our laboratory.

Acknowledgement

Support for this work by the DGI-MCYT (Project BQU2000-0645)is gratefully acknowledged. J. M. A. thanks the UCM for a predoc-toral grant, and M. C. R. thanks the MEC for a studentship.

References and Notes

† Permanent adress: Department of Chemistry, Faculty of Science at Qena, South Valley University, Qena, Egypt.

(1) For some recent reviews on olefin metathesis, see: (a) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012. (b) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073. (c) Fürstner, A. Synlett 1999, 1523. (d) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (f) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (g) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (h) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.

(2) For racemic synthesis, see: (a) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack, K.; Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White, A. J. P.; Williams D. J. J. Org. Chem. 1998, 63, 7893. (b) Tarling, C. A.; Holmes, A. B.; Markwell, R. E.; Pearson, N. D. J. Chem. Soc., Perkin Trans. 1 1999, 1695. For asymmetric synthesis, see: (c) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.; Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams D. J. J. Org. Chem. 2000, 65, 3716. (d) Duboc, R.; Hénaut, C.; Savignac, M.; Genet, J.-P.; Bhatnagar, N. Tetrahedron Lett. 2001, 42, 2461.

(3) (a) Qiu, W.; Gu, X.; Soloshonok, V. A.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 145. (b) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65, 2484. (c) Gosselin, F.; Lubell, W. D. J. Org. Chem. 2000, 65, 2163. (d) Li, W.; Hanau, C. E.; d'Avignon, A.; Moeller, K. D. J. Org. Chem. 1995, 60, 8155.

(4) See, for instance: (a) Alcaide, B.; Almendros, P.; Salgado, N. R. J. Org. Chem. 2000, 65, 3310. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2000, 2, 1411. (c) Alcaide, B.; Aly, M. F.; Rodríguez, C.; Rodríguez-Vicente, A. J. Org. Chem. 2000, 65, 3453. (d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 2000, 757. (e) Alcaide, B.; Sáez, E. Tetrahedron Lett. 2000, 41, 1647.

(5) (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem. Commun. 2000, 485. (b) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. J. Org. Chem. 2001, 66, 1351. (c) Alcaide, B.; Martín-Cantalejo, Y.; Pérez-Castells, J.; Sierra, M. A.; Monge, A. J. Org. Chem. 1996, 61, 9156.

(6) It is well known that the J value for trans-olefins is approximately 12-18 Hz while for cis-olefins its is approximately 7-11 Hz. In addition, NOE experiments were performed confirming this assignment.

(7) 1H NMR analysis of the reaction mixtures showed a single diastereoisomer for compounds 6, and 8 in all cases. The stereochemistry of fused tricyclic 2-azetidinones 6, and 8 was deduced by qualitative homonuclear NOE difference spectra. The stereochemistry for cyclization precursors 3 and 7 was assigned on the basis of our previous results: see reference 11.All new compounds were fully characterized by spectroscopic methods and microanalysis and/or HRMS. General Procedure for the RCM Reaction. To a solution protected from the sunlight of the corresponding dienes 5 or 7 (0.20 mmol) in anhydrous toluene (6 mL), was added in portions Cl2(Cy3P)2Ru=CHPh (0.02 mmol) under argon. The resulting mixture was heated at reflux until complete disappearance of the starting material (TLC), and was concentrated under reduced pressure. Chromatography of the residue eluting with ethyl acetate/hexanes mixtures gave analytically pure compounds 6 or 8. Selected data: Tricyclic 2-Azetidinone (+)-6a. From 71 mg (0.178 mmol) of diene (+)-5a, 44.5 mg (67%) of compound (+)-6a was obtained as a pale brown oil. [a]D = +196.9 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3): d 1.72 (s, 3H), 2.13 (dd, 1H, J = 12.6, 5.7 Hz), 2.69 (t, 1H, J = 13.2 Hz), 3.35 (m, 1H), 3.49 (m, 4H), 3.78 (s, 3H), 3.81 (s, 3H), 4.11 (dd, 1H, J = 15.6, 8.1 Hz), 4.27 (dd, 1H, J = 10.5, 4.5 Hz), 4.33 (d, 1H, J = 4.5 Hz), 4.59 (dd, 1H, J = 10.8, 4.2 Hz), 6.11 (d, 1H, J = 9.6 Hz), 6.25 (m, 1H). 13C NMR (300 MHz, CDCl3): d 173.5, 170.8, 166.9, 166.2, 130.1, 129.1, 83.5, 65.8, 61.6, 59.3, 58.6, 56.5, 52.9, 52.1, 44.8, 40.8, 40.6, 36.7, 21.8. IR (CHCl3, cm-1): n 1740, 1659. MS (CI), m/z : 367 (M+ +1, 100), 366 (M+, 17). (Anal. Calcd. for C17H22N2O7: C, 55.73; H, 6.05; N, 7.65. Found: C, 55.80; H, 6.08; N, 7.61). Tricyclic 2-Azetidinone (+)-6e. From 45 mg (0.093 mmol) of diene (+)-5e, 15 mg (35%) of compound (+)-6e was obtained as a pale yellow oil. [a]D = +214.1 (c 0.8, CHCl3).

1H NMR (300 MHz, CDCl3): d 1.48 (s, 3H), 2.09 (dd, 1H, J = 12.5, 4.6 Hz), 2.71 (dd, 1H, J = 13.2, 12.9 Hz), 3.48 (m, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.09 (m, 1H), 4.38 (m, 1H), 4.54 (d, 1H, J = 4.1 Hz), 4.91 (m, 2H), 5.67 (d, 1H, J = 16.7 Hz), 6.31 (dd, 1H, J = 16.4, 10.1 Hz). 13C NMR (300 MHz, CDCl3): d 174.6, 173.0, 166.8, 165.1, 157.0, 132.7, 128.1, 127.0, 120.1, 114.2, 82.3, 77.4, 67.0, 60.9, 58.8, 55.8, 53.2, 52.6, 45.5, 41.8, 22.2. IR (CHCl3, cm-1): n 1744, 1660. MS (CI), m/z : 459 (M+ +1, 100), 458 (M+, 11). (Anal. Calcd. for C23H26N2O8: C, 60.26; H, 5.72; N, 6.11. Found: C, 60.34; H, 5.70; N, 6.14). Tricyclic 2-Azetidinone (+)-8. From 60 mg

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Synlett 2001, No. 6, 773–776 ISSN 0936-5214 © Thieme Stuttgart · New York

(0.175 mmol) of diene (+)-7, 38 mg (69%) of compound(+)-8 was obtained as a pale yellow oil. [a]D = +304.8 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3): d 3.36 (s, 3H), 3.99 (m, 6H), 4.46 (dd, 1H, J = 2.7, 1.7 Hz), 5.30 (dd, 1H, J = 2.7, 1.9 Hz), 6.06 (m, 2H), 6.94 (m, 2H), 7.04 (m, 3H), 7.20 (m, 2H).

13C NMR (300 MHz, CDCl3): d 166.2, 164.7, 157.5, 129.7, 129.6, 129.2, 122.6, 115.9, 83.2, 80.0, 59.7, 58.6, 58.3, 36.3, 36.1. IR (CHCl3, cm-1): n 1763, 1752. MS (CI), m/z : 343 (M+

+1, 100), 342 (M+, 11). (Anal. Calcd. for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.90; H, 5.73; N, 8.95).

Article Identifier:1437-2096,E;2001,0,06,0773,0776,ftx,en;G05901ST.pdf