Tetrahedron Letters 54 (2013) 5227–5231

Contents lists available at SciVerse ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

Combining a-amidoalkylation reactions of N-acyliminium ionswith ring-closing metathesis: access to versatile novel isoindolonesspirocyclic compounds

0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.07.077

⇑ Corresponding author.E-mail address: mohamed.othman@univ-lehavre.fr (M. Othman).

N

ON

N

O

NHO

O

NH

OHO

N

H H

O

Rhynchophylline: 4

Cl

NO

Zoplicone (anxiolytic): 1 Aldose reductase inhibitor: 2

B

DE

AN

N

RO

O

O

R

Spiroimide: 5

R NH

O

N

H H

Petropodine: 6

B

DE

A

N

OOO

Lennoxamin: 3

OO

Figure 1. Representative isoindole and spirooxindole alkaloids.

Anthony Pesquet, Mohamed Othman ⇑a URCOM, EA 3221, INC3M, FR-CNRS 3038, Université du Havre, BP: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France

a r t i c l e i n f o

Article history:Received 30 April 2013Revised 9 July 2013Accepted 12 July 2013Available online 20 July 2013

Keywords:MetathesisSpiroisoindolesN-Acyliminium ionTandem reactionAlkaloids

a b s t r a c t

A novel approach to diversely spirocyclic isoindoles has been developed by using N-acyliminium/ring-closing metathesis strategy. Spirocyclization precursors, diolefinic, and enyne spiro-fused-isoindolederivatives have been obtained by a regioselective reduction of the spiro-imide compounds, followedby the allylation of the N-acyliminium intermediates (generated from the acetoxylactam compounds).Ruthenium catalyzed ring-closing metathesis of the above unsaturated derivatives provided novelspiroisoindoles.

� 2013 Elsevier Ltd. All rights reserved.

O

O

OO

Isoindolinone and C3 isoindolinone-derived heterocycles1 areprevalent structural motifs in numerous synthetic and naturalproducts, which exhibit important biological activities. Many ofthem have been prepared and examined as antihypertensive,2 anti-psychotic,3 antiinflammatory,4 anesthetic,5 antiulcer,6 and vasodi-latory7 agents. Antiviral,8 antileukemic,9 and aldose reductaseinhibitory10 properties have also been observed in this class ofstructures.

On the other hand, indoles and oxindoles derivatized at C3 asspirocarbocycles, spirolactones, and spiroheterocycles are eleganttargets in organic synthesis because of their significant biologicalactivities.11 For example, rhynchophylline (4),12 a natural alkaloidisolated from the traditional Chinese medicinal herb Uncariarhynchophylla, has been identified as a neuroprotective and anti-cancer agent. The spiroimides (5), another example of the spiroox-indole derivatives, are unnatural spirooxindole compounds, beingwell known as aldose reductase inhibitors, antihyperglycemicagents,13 and also efficient for the treatment of allergic inflamma-tory diseases.14 Finally, petropodine (6) and its stereoisomers, an-other alkaloids from the spirooxindole family, are produced byUncaria tomentosa, and have been shown to modulate the functionof muscarin serotonin receptors (Fig. 1).15

Inspired by the interesting biological activities of the spiro-oxindole alkaloids, and in connection with our current research

interest in the development of synthetic methodologies towardoriginal aza-heterocyclic systems embodying the 3-isoindolinonemoiety with promising pharmaceutical properties,16 we describeherein the synthesis of novel spiro-fused-isoindole products oftypes II and III (Fig. 2). For this purpose a combination of N-acyli-minium ion chemistry17 and ring-closing metathesis reactions(RMC) is explored.18–20

Our retrosynthetic analysis of spiroisoindolinones II and III isshown in Scheme 1. These compounds could be assembled fromthe 3-allylic spirosuccinimide A via ring-closing metathesis(RCM) protocol. Access to A would then be achieved by a selective

O

N

O

NR2

O

R1

N

O

NR2

O

N R1

O

N

O

III

N

O

NR2

O

R1

N

O

NR2

O

R1

ON

O

R1

CO2Et

2) L A

RMC

RMCII

D

A

C

BN-acyliminium ions

1) [H]

Scheme 1. Retrosynthetic analysis of the target of types II and III.

N R1

O

CO2Et

N R1

O

CO2Et

N R1

O

NO

O

R2OHN R2

R2 NH

OBr

7a-c 9a-d 10a-d

8a-c

N R1

O

NO R2

11a-d

N R1

O

NO R2

12a-d

OHOAc

i

ii

iii

(±) (±)

(±)(±)

Scheme 2. Reaction conditions: (i) K2CO3, bromoacetamide 8, CH3CN, reflux, 12 h,53–83%; (ii) NaBH4, EtOH, 0 �C (1.5–3 h); (iii) Ac2O, Et3N, 4-DMAP, CH2Cl2, rt, 3 h,73–93%.

Table 1Results of the two-step (reduction and acetylation) synthesis of the acetoxylactams(±)-12a–d

Entry R1 R2 Product Yielda (%) drb

1 PMB Allyl (±)-12a 93 82:182 Bn Propargyl (±)-12b 73 70:303 Allyl Bn (±)-12c 93 78:224 Propargyl Bn (±)-12d 91 80:20

a Isolated yields.b Determined by 1H NMR (200 MHz) integration of the hydrogen attached to the

a-nitrogen carbon on the crude reaction mixture.

H

(±)-10a-d

NR1

O

N OO

R2

NR1

O

N OHO

R2

(±)-11a-d (A: Maj)

NR1

O

N OHO

R2

(±)-11a-d (B: Min)

H

(±)-10a-d

NR1

O

N OO

R21

2

3

5

Scheme 3. Concept of the regioselective reduction of imide (±)-10a–d intohydroxy-lactams (±)-11a–d.

N

N

O

R N

N

O

R

(II) (III)

OO

3-Spiroindolizine oxindole

N

N

A B

DE

O

R(I)

A AB B

E ED

(±)3-Spiroisoindole- (±)3-Spiroisoindole-

Figure 2.

Table 2Optimization of the a-amidoalkylation reaction of acetoxylactam (±)-12c

N

O

NO

N

NO

OAc

O

Ph PhN

OPh

HNCO2H

OAcand/or

Nu (2 equiv)acid

solvent, t,rt

Si(Me)3 Sn(Bu)3,=Nu (Nu-1) (Nu-2)

12c 14c 17c(±) (±) (±)

Entry Acid (equiv) Nu Solvent Product Yield (%)

1 TFA (excess) Nu-1 — — NRa

2 BF3�Et2O (2) Nu-1 CH2Cl2 — NRb,c

3 TiCl4 Nu-1 CH2Cl2 — NRb,c

4 Bi(OTf)3 (0.1) Nu-1 CH2Cl2 — NRb,c

5 TIPSOTf (0.1) Nu-1 CH2Cl2 — NRb

6 TIPSOTf (0.1) Nu-1 CH3CN (±)-17c 437 TMSOTf (0.1) Nu-1 CH2Cl2 — NRb

8 TMSOTf (0.1) Nu-1 CH3CN (±)-17c 37d

9 TIPSOTf (1) Nu-2 CH3CN (±)-14c 5410 TMSOTf (1) Nu-2 CH3CN (±)-14c 7411 TMSOTf (0.5) Nu-2 CH3CN (±)-14c 33e

a Hydroxylactam (±)-11c was partially recovered.b Starting material (±)-12c was partially recovered.c Similar results were obtained when CH2Cl2 was replaced by CH3CN.d 5% of (±)-14c was observed in the reaction mixture.e Besides (±)-14c, derivative (±)-17c and the recovered staring material (±)-12c

were obtained in 12% and 28% yields respectively.

N

O

N

O

Ph

N

O

N

Ph

O

AcO

N

O

N

Ph

OOAc

HN

N

Ph

OOAc

CO2H

N

O

N

O

Ph

OAcTMSOTf

(±) 12c 13c (±) 15c

(±) 16c(±) 17c

Scheme 4. Plausible mechanism for the formation of (±)-17c.

5228 A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231

reduction of the spirosuccinimide C, followed by the allylation ofthe N-acyliminium intermediate B. The latter spirocycle C is readilyaccessible in a tandem process from the well-known phthalimidineD.

As a starting point of our study, the requisite spirosuccinimides(±)-10 were synthesized according to the procedure shown inScheme 2.21 Treatment of phthalimidines 7 with K2CO3 to effectenolate formation followed by reaction with various N-substituteda-bromoacetamides of type 8 furnishes spiroimides (±)-10 in one

step and in satisfactory yields. This straightforward approach is areal improvement of the existing methods for the synthesis of spi-roisoindoles bearing an imide function. 22

The next step was the synthesis of the required a-acetoxy- lac-tams (±)-12. Regioselective reduction of imides (±)-10a–d was per-formed with a large excess of NaBH4 in dry ethanol at 0 �C undercarefully controlled conditions23 for 1.5–3 h and afforded a-hydroxylactams (±)-11a–d as diastereoisomeric mixtures, whichwere used in the next step without further purification. After acyl-ation of the hydroxylactams (±)-11a–d with acetic anhydride, thedesired N-acyliminium ion precursors (±)-12a–d were isolated invery good yields (73–93%) and in good levels of diastereoselectionafter the two stages (Table 1).

Table 3Yields and diastereomeric ratios for compounds (±)-14a–d

Entry Substrate Product Yielda (%) drb

1 (±)-11a N

N

O

O

OMe14a(±)

76 100:0

2 (±)-11bN

N

O

O

14b(±)

97 100:0

3 (±)-11cN

N

O

O

14c(±)

74 100:0

4 (±)-11dN

N

O

O

14d(±)

72 75:25

a Isolated yields.b Determined by 1H NMR (200 MHz) integration of the hydrogen attached to the

a-nitrogen carbon on the crude reaction mixture.

(±) 14a-d (Maj)Possibletransition state

NONO

R1 R2

NR1

O

N O

R2

AcO

Nu (AllylSn(Bu)3)

LA NR1

O

N O

R2

(±) 12a-d

Scheme 5. Plausible mechanism for the formation of (±)-14a–d.

A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231 5229

It is noteworthy that our recently reported one-pot reduction–acetylation protocol could be used as a shortened procedure.24

However, on a large scale of 2 g of 10a, the yield dropped down(78% instead of 93%), and so the two-step procedure was preferred.Importantly, in all cases, the reaction seems to be highly regiose-lective because during the reduction process (NaBH4 or LiEt3BH)only regioisomers (±)-11a–d were obtained.

The regiospecificity of the reduction can be explained based onthe concept pioneered by Speckamp’s group in this area.25 In fact,as a result of the Bürghi–Dunitz (107�) angle there are two possibletrajectories for the hydride to approach the carbonyl function ofthe spiro-imide (±)-10a–d. In this context, the reduction of the car-bonyl at position 2 is favored leading to (±)-11a–d as major regioi-somers (see Scheme 3).

Afterward, the intermolecular allylation reaction was investi-gated. For this purpose, a model reaction between acetoxylactam(±)-12c and allyltrimethylsilane (Nu-1) (or allyltributylstanate(Nu-2)) was examined under a wide range of conditions. The ob-tained results are summarized in Table 2.

A careful screening of acids revealed that conventional Brønstedor Lewis acids did not promote any transformation, irrespective ofthe solvent and the amount of acid, and the starting material (±)-12c or its parent hydroxylactam (±)-11c was partially recovered

even after a prolonged reaction time (entries 1–3). Similarly, a cat-alytic amount (10 mol %) of Lewis acids such as Bi(OTf)3,26 TIP-SOTf,17h and TMSOTf,27 which are traditionally recognized ashighly efficient for this kind of a-amidoalkylation reactions, failedto catalyze this allylation when the reaction was performed in CH2-

Cl2 (Table 2, entries 4, 5, and 7). In contrast, the analogous reac-tions in CH3CN resulted in the formation of compound (±)-17c(Table 2, entries 6 and 8).

The reaction mechanism for this cascade sequence is proposedalong Scheme 4. The reaction is initiated by the generation of N-acyliminium ion 13c. Indeed of the intermolecular allylation of13c, intramolecular a-amidoalkylation reaction takes place to formspiroindolizidine (±)-16c. The formed tetracyclic intermediate (±)-16c is not stable and opens to form the ultimate derivative (±)-17c,probably because of the high ring strain involved within the forma-tion of the six-membered ring within the spiro-fused-isoindoleproduct (±)-17c. Further studies exploring and exploiting this dif-ference of reactivity are ongoing and will be reported in a forth-coming full letter.

The reaction outcomes suggested that allyltrimethylsilane wasnot sufficiently reactive to undergo reaction with the N-acylimini-um ion 13c. Consequently, we turned our attention to replacing thetrimethylsilyl group (Si(Me)3) with a more reactive functionalitysuch as (Sn(Bu)3).

To our delight, treatment of (±)-12c with (Nu-2) in the presenceof 1 equiv of TIPSOTf at rt in CH3CN for 6 h resulted in the forma-tion of the desired adduct (±)-14c as a single diastereoisomer in54% yield. Besides (±)-14c, derivative (±)-17c and the recoveredstarting material (±)-12c were obtained in 5% and 14% yieldsrespectively (Table 2, entry 9). The chemical yield of (±)-14c wasimproved significantly by using 1 equiv of TMSOTf in CH3CN for4 h, and (±)-14c was obtained in 74% yield (Table 2, entry 10). Adramatic decrease in the yield (33%) of (±)-14c was observed whenthe amount of TMSOTf was reduced from 1 equiv to 50 mol % (Ta-ble 2, entry 11). Similar conditions (1 equiv of TMSOTf, CH3CN at rtfor 4 h) appeared successful for the other N-acyliminium precur-sors (±)-12a,b,d to provide the other expected RCM precursors(±)-14a,b,d in high yields and with excellent diastereoselectivityas shown in Table 3.

Because of a-hydroxy-lactams (±)-11a–d and correspondinga-acetoxy-lactams (±)-12a–d were used in a-amidoalkylationreaction via the racemate acyliminium species, no attempts werededicated to the isolation of (±)-11a–d and (±)-12a–d, respectively.Elsewhere, all attempts to isolate allyl compounds (±)-14a–d, as ofthe acidic stable products, in crystalline form for the X-ray struc-ture determinations were aborted.

However, the formation of exclusive isomers (±)-14a–c or bothisomers (±)-14d can be explained by the p-allyl attack of the cationintermediate being formed in acidic media. Presumably the nucle-ophile approaches the iminium intermediate from the least hin-dered side, which is opposite to the bulky NR1 group. This fact isprobably at the origin of the high diastereoselectivity we observed(see Scheme 5). After successful formation of a range of RCM pre-cursors, the ring-closing metathesis reaction of diene (±)-14a andenyne (±)-14b was first investigated.

The diolefinic spirosuccinimide (±)-14a was subjected to firstgeneration Grubbs’ catalyst G1 (3 mol %, CH2Cl2 at reflux for 8 h),resulting in the formation of the six-membred ring indolizidineproduct (±)-18a in 74% yield after silica gel column chromatogra-phy. Similarly, the same reaction conditions when applied to enyne(±)-14b afforded spiroindolizidine (±)-18b in 85% yield. Similarly(±)-14c gave (±)-18c in low yield of 34% along with starting mate-rial (±)-14c in 40% yield. Similar results were obtained when CH2-

Cl2 was replaced by C2H4Cl2 (30%) or toluene (28%). For successfultotal closure of compound (±)-14c, the second generation Grubbs’catalyst G2 (2 � 5 mol %) was required, giving the seven-mem-

Table 4Optimal RCM conditions for the synthesis of spirocycles (±)-18a–da

N

O

NR2

O

R1

N

O

NR2

O

N R1

O

N

O

G1

14a-d18c,d

Path 1

Path 2G2

18a,b

iii

(±) (±) (±)

N

N

O

O

OMe18a 74%(±)

RuPhPCy3

ClCl

GrubbsI = G1

PCy3

N

N

O

O

18b 85%(±)

N

N

O

O

18c 64%(±)

N N

RuPhPCy3

ClCl

Mes Mes

Grubbs II = G2N

N

O

O

18d _(±)a Reaction conditions: (i) G1, 3 mol %, CH2Cl2, reflux, 8 h, (±)-18a, 74%, (±)-18b,

85%. (ii) G2, (2 � 5 mol %), toluene, reflux, 24 h, (±)-18c, 64%.

5230 A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231

bered ring product (±)-18c in 64% yield. Treatment of enyne (±)-14d with first or second generation Grubbs’ catalysts did not pro-vide the desired spirocycle (±)-18d even under harsher reactionconditions. Even if the reasons of the cyclization reaction werenot yet defined exactly, we speculate nevertheless that the lackof reactivity of substrate (±)-14d is due to the ring strain inherentto the spirocyclic product and probably to the perpendicular posi-tioning of the alkene function toward the alkyne one and vice versa(Table 4).

To the best of our knowledge, this represents the first report ofthe synthesis of 3-spiroisoindole derivatives from the readily avail-able phthalimidines 7.

In this Letter, we successfully introduced a new and expedientsynthetic entry to spiroisoindolones (±)-18, which have till datenot been described. A central step in this synthesis is the ring-clos-ing metathesis of alkene (alkyne) substituted nitrogen-containingprecursors, which delivers an aza-tetracyclic compound containingnovel spiroisoindole rings. We believe that the chemistry describedherein will open the way to the design and synthesis of wide vari-ety of novel spiroisoindole compounds with promising pharmaco-logical profiles. For full exploitation of the N-acyliminium-RMCstrategy, further work is currently underway to enlarge the scopeof this application by accessing a wider variety of these structures.

Acknowledgement

The authors are grateful to Pr. Adam Daïch (URCOM) for manyfruitful discussions throughout the course of this work.

Supplementary data

Supplementary data associated with this article can be found,in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.077.

References and notes

1. For an excellent recent papers dealing with the construction of isoindolones,see: (a) Zhu, C.; Falck, J. R. S. Tetrahedron 2012, 68, 9192–9199; (b) Hacklady-McAtee, D. M.; Dasgupta, S.; Watson, M. P. Org. Lett. 2011, 13, 3490–3493. andreferences therein; (c) Chiurato, M.; Routier, S.; Troin, Y.; Guillaumet, G.Tetrahedron 2010, 66, 4647–4653; (d) Worlikar, S. A.; Larock, R. C. J. Org. Chem.2008, 73, 7175–7180; (e) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10,5281–5284; (f) Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361–7364; (g) Yao, T.;Larock, R. C. J. Org. Chem. 2005, 70, 1432–1437; (h) Alsarabi, A.; Canet, J.-L.;Troin, Y. Tetrahedron Lett. 2004, 45, 9003–9006. and references cited therein.

2. Ferland, J.-M.; Demerson, C. A.; Humber, L. G. Can. J. Chem. 1985, 63, 361–365.3. (a) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med. Chem. 1998, 41, 157–

166; (b) Linden, M.; Hadler, D.; Hofmann, S. Hum. Psychopharmacol. 1997, 12,445–452; (c) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39,149–157.

4. Li, S.; Wang, X.; Guo, H.; Chen, L. Yiyano Gongye 1985, 16, 543. Chem. Abstr.1986, 105, 6378n.

5. Laboratori Baldacci, S. P. A. Japanese Patent 5,946,268, 1984; Chem. Abstr. 1984,101, 54922.

6. Lippmann, W. U.S. Patent 4,267,189, 1981; Chem. Abstr. 1981, 95, 61988m.7. Achinami, K.; Ashizawa, N.; Kobayasui, F. Japanese Patent 03,133,955, 1991;

Chem. Abstr. 1991, 115, 255977j.8. (a) De Clercq, E. J. Med. Chem. 1995, 38, 2491–2517; (b) Pendrak, I.; Barney, S.;

Wittrock, R.; Lambert, D. M.; Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623–2625.

9. (a) Taylor, E. C.; Zhou, P.; Jenning, L. D.; Mao, Z.; Hu, B.; Jun, J.-G. TetrahedronLett. 1997, 38, 521–524; (b) Fuska, J.; Fuskova, A.; Proksa, B. Zb. Pr.Chemickotechn. Fak, SVST, 1979–1981 (pub. 1986), 285–291; Chem. Abstr.1987, 106, 95582k.

10. Wrobel, J.; Dietrich, A.; Woolson, S. A.; Millen, J.; McCaleb, M.; Harrison, M. C.;Hohman, T. C.; Sredy, J.; Sullivan, D. J. Med. Chem. 1992, 35, 4613–46227.

11. (a) Lesma, G.; Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron 2010, 66, 4474–4478; (b) Sasaki, Y.; Kato, D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 13533–13544; (c) Kato, D.; Sasaki, Y.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3685–3687; (d) Ishikawa, H.; Boger, D. L. Hetereocycles 2007, 72, 95–102; (e)Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc.2006, 128, 10596–10612; (f) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y.; Boger,D. L. Angew. Chem., Int. Ed. 2006, 45, 620–623; (g) Choi, Y.; Ishikawa, H.;Velcicky, J.; Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539–4542; (h) Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361–7364; (i)Ibrahim-Ouali, M.; Sinibaldi, M.-E.; Troin, Y.; Guillaume, D.; Germain, J.-C.Tetrahedron 1997, 47, 16083–16096.

12. (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155; (b) Chou, C.-H.;Gong, C.-L.; Chao, C.-C.; Lin, C.-H.; Kwan, C.-Y.; Hsieh, C.-L.; Leung, Y.-M. J. Nat.Prod. 2009, 72, 830–834.

13. (a) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya,M.; Suzuki, K.; Matsumoto, J. J. Med. Chem. 1998, 41, 4118–4129; (b) Ref. 10.

14. Crosignani, S.; Page, P.; Missotten, M.; Colovray, V.; Cleva, C.; Arrighi, J. F.;Atherall, J.; Macritchie, J.; Martin, T.; Humbert, Y.; Gaudet, M.; Pupowicz, D.;Maio, M.; Pittet, P. A.; Golzio, L.; Giachetti, C.; Rocha, C.; Bernardinelli, G.;Filinchuk, Y.; Scheer, A.; Schwarz, M. K.; Chollet, A. J. Med. Chem. 2008, 51,2227–2243.

15. Kang, T. H.; Matsumoto, K.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.;Watanabe, H. Eur. J. Pharmacol. 2002, 444, 39–45.

16. (a) Ben Othman, R.; Othman, M.; Ciamala, K.; Knorr, M.; Strohmann, C.;Decroix, B. Tetrahedron 2009, 65, 4846–4854; (b) Rammah, M. M.; Othman, M.;Ciamala, K.; Strohmann, C.; Rammah, M. B. Tetrahedron 2008, 64, 3505–3516;(c) Ben Othman, R.; Othman, M.; Decroix, B. Tetrahedron 2008, 64, 559–567; (d)Rammah, M. M.; Othman, M.; Rammah, M. B. Heterocycles 2008, 75, 1971–1981.

17. (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856; (b)Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.Rev. 2004, 104, 1431–1628; (c) Royer, J.; Micouin, L.; Bonin, M. Chem. Rev. 2004,104, 2311–2352; (d) Yazici, A.; Pyne, S. G. Synthesis 2009, 3, 339–368; (e)Yazici, A.; Pyne, S. G. Synthesis 2009, 4, 513–541; (f) Boiaryna, L.; El Mkaddem,M. K.; Taillier, C.; Othman, M.; Dalla, V. Chem. Eur. J. 2012, 18, 14192–14200; (g)Tranchant, M. J.; Moine, C.; Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla, V.Tetrahedron Lett. 2006, 47, 4477–4480; (h) Ben Othman, R.; Fousse, A.;Bousquet, T.; Othman, M.; Dalla, V. Org. Lett. 2005, 7, 2825–2828; (i) BenOthman, R.; Bousquet, T.; Othman, M.; Dalla, V. Org. Lett. 2005, 7, 5335–5337.

18. For recent reviews on metathesis reactions, see: (a) Donohoe, T. J.; Bower, J. F.;Chan, L. K. M. Org. Biomol. Chem. 2012, 10, 1322–1328; (b) Vougioukalakis, G.C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746–1787; (c) Lozano-Vila, A. M.;Monsaert, S.; Bajek, A.; Verpoort, F. Chem. Rev. 2010, 110, 4865–4909; (d)Nolan, S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305–3316; (e) Monfette, S.;Fogg, D. E. Chem. Rev. 2009, 109, 3783–3805; (f) Samojłowicz, C.; Bieniek, M.;Grela, K. Chem. Rev. 2009, 109, 3708–3742; (g) Bieniek, M.; Michrowska, A.;Usanov, D. L.; Grela, K. Chem. Eur. J. 2008, 14, 806–818.

19. For some representative examples of synthesis of indolizidines using N-acyliminium-RMC strategy, see (a) Martin, S. F.; Chen, H. J.; Kourtnney, A. K.;Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251–7264; (b) Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605–5608; (c)Lenmartz, M.; Steckhan, E. Tetrahedron 2001, 57, 675–680; (d) Lenmartz, M.;

A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231 5231

Steckhan, E. Synlett 2000, 319–322; (e) Chevallier, F.; Le Grognec, E.; Beaudet,I.; Fliegel, F.; Evain, M.; Quintard, J. P. Org. Biomol. Chem. 2004, 2, 3128–3133.

20. For some representative examples of synthesis of perhydroazaazulenes usingN-acyliminium-RMC strategy, see (a) Alibés, R.; Bayon, P.; March, P. D.;Figueredo, M.; Font, J.; Garcia, E. G.; Galvez, D. Org. Lett. 2005, 7, 5107–5109;(b) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem. 2003, 68, 7219–7233; (c) Beal, L. M.; Moeller, K. D. Tetrahedron Lett. 1998, 39, 4639–4642; (d)Beal, L. M.; Liu, B.; Chu, W.; Moeller, K. D. Tetrahedron 2000, 56, 10113–10125.

21. (a) Allous, I.; Comesse, S.; Sanselme, M.; Daïch, A. Eur. J. Org. Chem. 2011, 5303–5310; (b) Allous, I.; Comesse, S.; Berkeš, D.; Alkyat, A.; Daïch, A. TetrahedronLett. 2009, 50, 4411–4415.

22. See Ref. 10.

23. See Ref. 19a.24. Szemes, F.; Fousse, A.; Bousquet, T.; Ben Othman, R.; Othman, M.; Dalla, V.

Synthesis 2006, 875–879.25. For representative reviews on N-acyliminium ion chemistry relating these

problematics, see: Refs, 17a,b.26. Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, S.; Daïch, A. J. Org. Chem. 2007, 72,

1181–1191.27. (a) Yamada, S.; Takahashi, Y. Tetrahedron Lett. 2009, 50, 5395–5398; (b)

Sugiura, M.; Kobayashi, S. Org. Lett. 2001, 3, 477–480; (c) D’ Oca, M. G. H.; Pilli,R. A.; Vencato, I. Tetrahedron Lett. 2000, 41, 9709–9712; (d) Louwrier, S.;Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1996, 52,2603–2628.