Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols Martine Bonin, Laurent Micouin, Ariane Chauveau

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Martine Bonin, Laurent Micouin, Ariane Chauveau. Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols. SYNLETT, Georg Thieme Verlag, 2006, 2006 (15), pp.2349-2363. 10.1055/s-2006-949626. hal-02185347

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Asymmetric 1,3-Dipolar Cycloadditions of Cyclic Stabilized Ylides Derived from Chiral 1,2-Amino Alcohols AsymmetricMartine 1, 3-Dipolar Cycloadditions Bonin,* Ariane Chauveau, L. Micouin* Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS, Université René Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 av de l’Observatoire, 75270 Paris cedex 06, France Fax +33(1)43291403; E-mail: [email protected]; E-mail: [email protected] Received 2 March 2006

tionalized heterocycles in a very convergent manner with Abstract: The use of structurally similar chiral non-racemic 2 azomethine ylides, nitrones and azomethine imines derived from limited side reactions. 1,2-aminol alcohols in asymmetric dipolar cycloadditions is re- One more advantage of the 1,3-dipolar cycloaddition re- viewed. This general survey underlines the great synthetic potential action is its high stereospecificity, leading to the creation of dipolar cycloadditions, especially in a diversity-oriented ap- of up to four stereocenters in a single operation. Further- proach and enables a direct comparison of the reactivity of appar- ently closely related reactive systems. more, an appropriate set of reaction conditions and reagents enables, in principle, the tuning of relative 1 Introduction configuration of the final cycloadduct by controlling the 2 Azomethine Ylides reactive configuration of the reaction partners.3 This ste- 2.1 Reactions Involving Ylides Derived from Formaldehyde reochemical diversity is a key element if one wishes to use 2.2 Reactions Involving Ylides Derived from Aliphatic or Aro- asymmetric multicomponent reactions in diversity-orient- matic Aldehydes ed syntheses.4 2.3 Reactions Involving Ylides Derived from Alkyl Glyoxy- lates or Ketones Several parameters are responsible for the stereochemical 2.4 Synthetic Applications outcome of a 1,3-dipolar cycloaddition (Scheme 1). The 3 Nitrones configuration of stereocenters a and c will be determined 3.1 Reactions with Alkenes by the configuration of the reactive dipole [with syn (anti) 3.2 Synthetic Applications 1 2 syn anti 4 Azomethine Imines dipoles leading to R ,R ( ) stereoisomers, respec- 4.1 Ylide Generation tively) as well as the facial selectivity of the reaction. The 4.2 Reactions Involving Ylides Derived from Aliphatic or Aro- relative configuration between stereocenters d and e is de- matic Aldehydes termined by the configuration of the double bond in its re- 4.3 Reactions Involving Ylides Derived from Alkyl Glyoxy- active form, the relative a,d or c,e configurations being lates determined by the facial as well as the endo-exo selectiv- 4.4 Synthetic Applications ities. All these rules, of course, only apply provided that 5 Conclusion the condensation occurs in a concerted manner, delivering Key words: cycloadditions, ylides, stereoselective synthesis, het- a non-epimerizable final cycloadduct. erocycles, multicomponent reactions

1 2 R b – R E,E (syn) ac+ 1 Introduction

2 b – R The power of multicomponent reactions (MCRs) as diver- Z,E (anti ) ac+ R4 R1 b R2 R1 de a c sity-generating processes for the convergent preparation 3 * * of combinatorial libraries of compounds having interest- R de 1 or 3 ** 4 E,Z (anti ) R b 3 4 R R ing chemical, physical, or biological properties is nowa- ac+ – R R 1 1 days widely recognized. In this context, [3+2] R2 de cycloadditions are particularly appealing, for numerous b reasons: they generally combine three widely available – Z,Z (syn) ac+ classes of compounds (i.e. aldehydes, amines and alk- 1 2 enes), with a good functional group tolerance, under ex- R R perimentally simple reaction conditions (generally Scheme 1 General five-membered-ring synthesis by a dipolar [3+2] thermal, aerobic conditions) leading to cyclic rigid func- cycloaddition process.

As depicted in Scheme 1, a mixture of stereoisomers can be expected from a cycloaddition based on configuration- SYNLETT 2006, No. 15, pp 2349–2363 18.09.2006 ally labile dipoles, unless an efficient dynamic resolution Advanced online publication: 08.09.2006 can occur. The incorporation of the a–b or b–c bond of the DOI: 10.1055/s-2006-949626; Art ID: A41606ST © Georg Thieme Verlag Stuttgart · New York 2350 M. Bonin et al. ACCOUNT ylide into a cyclic, rigid element has therefore been pro- use of chiral 1,2-amino alcohols, and more particularly posed in order to increase rotational barriers in these reac- phenylglycinol, as a chiral element in three closely-related tive species. Furthermore, the use of a chiral tether in such cyclic ylides will be discussed. a strategy should enable the control of the facial selectivity, leading to the control of the relative and absolute configuration of centers a and c of 1. 2 Azomethine Ylides In a general research project on the use of cyclic hydra- zines for the synthesis of polyfunctional amines,5 we were Although the use of chiral non-racemic morpholinones in asymmetric transformations had been described since the particularly interested by works reporting stereoselective 8 dipolar cycloadditions of azomethine ylides6 and nitrones7 late sixties, the first examples of stereoselective cycload- using similar cyclic templates derived from a common ditions of templated azomethine ylides derived from morpholinones were reported by the groups of L. M. morpholinone (Figure 1). The apparent excellent facial 9a 10 selectivities prompted us to investigate such cyclic pre- Harwood and R. M. Williams in the early 1990s. cursors in the azomethine imine series. In this account the 2.1 Reactions Involving Ylides Derived from O O X O O O O Formaldehyde N – – Ph N+ 2.1.1 Ylide Generation Ph N+ Ph N + O – R1 R1 Ylides are typically generated by condensation of the morpholinones 5–7 with an excess of paraformaldehyde Figure 1 Cyclic amino alcohol derived azomethine ylide, nitrones under thermal activation in the presence of molecular and azomethine imines.

Biographical Sketches

Martine Bonin was born in son’s group (1983), she on the development of new 1957. She trained as a phar- began collaboration with diastereoselective routes macist in the University of Dr. J.-C. Quirion on amino- giving access to polyfunc- Bordeaux (1979), and ob- nitrile and oxazolidine syn- tional nitrogen derivatives tained her PhD in Chemistry thons and followed that with for medicinal or pharmaco- from the University of Par- a one-year postdoc in Orsay logical applications. She is-Sud (Orsay) in 1986 on (Drs. G. Balavoine and F. then took a project manager the total synthesis of piperi- Guibe, organometallic and position at the INTAS orga- dine alkaloids. Enlisted as radical chemistry, 1992). nization in Brussels in 2004. researcher in CNRS in Pro- From 1998, she worked fessor Henri-Philippe Hus- with Dr. Laurent Micouin Ariane Chauveau was born tionale Supérieure de Chi- 1999. She obtained her PhD in 1977. She was trained as mie de Paris and received on azomethine imine cyclo- a chemist at the Ecole Na- her engineer diploma in additions reactions in 2003.

Laurent Micouin was born fessor J.-C. Quirion in 1995. Directeur de Recherche. His in Clermont Ferrand in After a postdoctoral stay in scientific interests include 1968. He studied at the Marburg (Germany) as a the development of new Ecole Nationale Supérieure Humboldt Fellow under the methods in the field of de Chimie de Paris, where direction of Professor Paul asymmetric synthesis of ni- he obtained an engineer di- Knochel, he got a perma- trogen compounds, organo- ploma in 1990. He obtained nent position in CNRS in aluminum chemistry, as his PhD in the laboratory of 1996 and returned to Paris well as the development of Professor Henri-Philippe (Faculty of Pharmacy, Paris new tools in the field of Husson (University Paris V) V) as Chargé de Recherche, fragment-based approach under the guidance of Pro- and, since October 2005, as for the discovery of bioac- tive compounds.

Synlett 2006, No. 15, 2349–2363 © Thieme Stuttgart · New York ACCOUNT Asymmetric 1,3-Dipolar Cycloadditions 2351 sieves,9a,b or in the presence of a catalytic amount of p-tol- In all the cases, complete facial selectivity has been ob- uenesulfonic acid at room temperature over extended pe- served, and the endo cycloadduct was isolated as a major riods.10a Due to their high reactivity, these species are diastereomer under thermal activation. When conducted trapped in situ by the dipolarophiles, generally used in ex- in the presence of MgBr2·OEt2, the cycloaddition led to cess. Another procedure involves the use of stable precur- the exo adduct as either the major product (entries 4 and sors, such as alkoxy amines 2–4,10a hemi-aminal 811 or 11) or almost exclusively (entries 5 and 8). All the reac- aminobenzotriazole 9 derivatives,12 which can regenerate tions performed on acyclic dipolarophiles were fully ste- the ylide under acidic or thermal conditions (Scheme 2). reospecific (entries 4 and 5). Although the one-pot methodology is a simple process, X O O X O O the generation of the reactive ylide from a stable precursor generally provides a way to obtain cycloadducts in supe- Ph N Ph N 10a,12 H rior yields (Scheme 4), and avoids the sometimes 5, X = H 2, X = H OMe troublesome use of a large excess of paraformaldehyde. In 3, X = Ph 6, X = Ph 7, X = i-Pr 4, X = i-Pr (CH2O)n all cases, the stereochemical issue is similar to the one-pot ∆ , PTSA X O O ∆ or PTSA procedure, showing that the same reactive intermediate is generated. – ∆ , PTSA O O O O Ph N+ TFA Ph O O ∆ Ph N , PTSA, benzene H Ph N O 6 Ph N CO2Me t N N O Bu MeO2C CO2Me ent-13 H N CO Me 89N O 2 79% H Scheme 2 Ylide generation from morpholinones. NR

Ph N H+ HH O 2.1.2 Reactions with Alkynes ent-9 O O ent-18 35% (exo = 33%) Alkynes are mechanistically useful dipolarophiles since endo ent-19 50% (exo = 26%) H+ they can lead to only two possible diastereomers with H+ CO2Me formaldehyde-derived dipoles. The stereochemical issue CO2Me of the cycloaddition is therefore directly related to the fa- Ph N CO Me Ph N CO Me 2 cial selectivity, and provides a way to evaluate the chiral- 2 H ity transfer from the morpholinone. H O O O O Thus, use of a symmetrical electron-deficient alkyne re- endo sulted in a single cycloadduct 10, and only one regioiso- ent-15 50% ent-12 20% (exo = 9%) mer could be obtained stereoselectively from methylpropynoate (Scheme 3).9a,13 A better yield (56%) Scheme 4 Cycloadditions from stable ylides precursors. of compound 11 could be obtained when conducting the reaction under Lewis acid assistance (1.1 equiv of dipo- Singly activated alkenes are much less reactive dipolaro- larophile, excess of freshly prepared MgBr2·OEt2, reflux- philes, as depicted in Scheme 5.16 All the cyclic dipolaro- 14 ing THF). These results clearly indicate that the facial philes led to the predominant formation of exo-addition ‘steric’ selectivity is perfectly controlled with phenylgly- products with almost complete regioselectivity; whereas cinol as a chiral tether in azomethine ylide cycloadditions. the use of acyclic dipolarophiles had been reported to result in failure to isolate cycloadducts under thermal condi- R tions, except with phenylsulfone when the major isomer H was found to be the endo-cycloadduct 27 with only traces Ph N Ph N CO2Me (HCHO)n benzene of the exo-diastereomer being detected. However, methyl H R CO2Me acrylate and acrylonitrile have been reported to react with O O O O (5–7 equiv) the ylide under Lewis acid activation, leading to comple- ent-5 ∆ 10, R = CO2Me 29% mentary regiocontrol, in a low diastereoselectivity. ‘Un- 11, R = H 30% activated alkenes’ are generally considered to be poorly Scheme 3 Cycloadditions with activated alkynes. reactive in intermolecular 1,3-dipolar cycloadditions involving stabilized azomethine ylides. Thus, the reaction with cis- or trans-stilbene gave particularly low yields of 2.1.3 Reactions with Alkenes the corresponding adducts 23 and 24. Doubly activated alkenes react generally well with azomethine ylides, delivering cycloadducts in good chemical yields (Table 1).9a,b,10a,15

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Table 1 Reaction of Azomethine Ylides with Doubly Activated Alkenesa

H X X H H Y Z Ph N Ph N Z Ph N Y (HCHO) n H + H dipolarophile R O O R O O R O O endo exo

Entry R Dipolarophile Method Adduct endo exo Compd (isolated yield, %)(isolated yield, %) XYZ

1H A CO2Me CO2Me H 20 6 12 MeO2CCO2Me b 2Ph B CO2Me CO2Me H 39 13 MeO2CCO2Me c 3 i-Pr C CO2Me CO2Me H 34 14 MeO2CCO2Me

4H D CO2Me CO2Me H 40 20 12 MeO2CCO2Me

5HMeO2C D CO2Me H CO2Me 0 52 15

CO2Me 6 HH A CON(H)CO 54 – 16 O N O

7 HMe A CON(Me)CO 41 19 17 O N O

8HMe D CON(Me)CO <1 80 17 O N O

9 i-PrMe C CON(Me)CO 58 d 18 O N O

10 HPh A CON(Ph)CO 45 13 19 O N O

11 HPh D CON(Ph)CO 9 54 19 O N O

12 H A COOCO 49 – 20 O O O

a Method A: excess (HCHO)n, 3–7 equiv dipolarophile, benzene, 3 Å MS, reflux. Method B: excess (HCHO)n, 3 equiv dipolarophile, PTSA, benzene, r.t. Method C: excess (HCHO)n, 5 equiv dipolarophile, toluene, 80 °C. Method D: 5 equiv (HCHO)n, 1.1 equiv dipolarophile, excess MgBr2·OEt2, THF, reflux. b The amount of the exo stereoisomer was not reported. c The endo/exo ratio in the crude reaction mixture was 85:8. d The endo/exo ratio in the crude reaction mixture was 55:25.

2.2 Reactions Involving Ylides Derived from In fact, four of the eight possible cycloadducts were Aliphatic or Aromatic Aldehydes obtained in the reaction involving benzaldehyde and N-methyl maleimide (Scheme 6).13 A similar observation 2.2.1 Reactions with Alkenes was made in the diphenylmorpholinone series The use of higher aldehydes in cycloadditions can lead to (Table 2).10a a more complex situation. The additional substituent on Despite total endo selectivity, most of the aldehydes led to the ylide will not only introduce a new stereogenic ele- an almost equimolar ratio of C-7 epimers. Interestingly, ment, but can also tune the general reactivity of the ylides, the use of isobutyraldehyde led to the stereoselective for- as well as the FMO-related stereocontrol. mation of 34 as a single adduct. This excellent stereo-

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O Table 2 Reaction of Branched Azomethine Ylides with Dimethyl- maleate O O O R CO2Me O Ph N O H H Ph N RCHO, benzene ∆ Ph N CO2Me Ph N O O Ph N H H 21 H Ph O O 6 MeO2C CO2Me Ph O O O O O O 28 27%a 22 a 53% Entry Aldehyde Yield (%) dr Compd Ph PhO2S H 28%a 5 1 Propionaldehyde 32 1.33:1 33 c Ph N Ph Ph N b 3.6%a H 2 Isobutyraldehyde 52 1:0 34 H b a 3% O O 3 Benzaldedhyde 70 1.7:1 35 O O 23 27 Ph 4 p-Anisaldehyde 71 1:1 36 H Ph N Ph N Ph X 5 p-Nitrobenzaldehyde 71 1:1 37 H H

O O O O 6 2-Furaldehyde 61 1:1 38 24 25, X = CN, 70% a Reaction conditions : Aldehyde (1.4 equiv), dipolarophile (3.5 26, X = CO2Me, 62% equiv), PTSA (0.4 equiv), benzene, reflux. Scheme 5 Cycloadditions with mono- or non-activated alkenes. b The all-syn stereoisomer was obtained. Reagents and conditions: (a) (CHO)n (10 equiv), dipolarophile (7 equiv), benzene, reflux, MS 3 Å; (b) (CHO)n (5 equiv), dipolarophile (1.1 equiv), MgBr Et O (excess), THF, reflux, MS 3 Å; 0% de for 2. 2 Table 3 Stereoselective Formation of Spirocyclic Indolinones X = CN, 35% de for X = CO2Me; (c) thermal conditions, yield not given. EtO2C Ph O O O O H H O Ph Ph Ph N NMe NMe H N H ent-6 39 Ph N Ph N ∆ H O H O RCHO, toluene, H H Ph Ph Ph O O O O Ph Ph Ph H PhCHO, 30, 38% O O O Ph N 29, 13% benzene H N N N O O R O R O R O ∆ O H O H H O H O O Ph Ph NMe ent-5 NMe CO2Et EtO2C CO2Et HN NH HN Ph N Ph N H O H O H H a c O O O O b 31, 9% 32, 11% Entry R Temp Yield Yield Yield dr Scheme 6 Reaction of ylide derived from benzaldehyde and doubly (% a) (% b) (% c) activated dipolarophiles. 1 H Reflux 28 11 0 – selectivity with branched aldehydes has led recently to a 2BzOCH Reflux 44 14 0 >20:1 very powerful method for the synthesis of spirooxindole 2 17 derivatives (Table 3). This highly exo-selective reaction 3BzOCH2 60 °C 54 8 0 >20:1 that can establish in a single operation four contiguous 4 i-Pr Reflux 43 11 5 8.6:1 stereogenic centers, including the quaternary center, has found several applications in the total synthesis of natural 5 i-Pr 60 °C 74 6 Trace >20:1 products (see part 2.4). 6 i-Bu Reflux 84 1 0 >20:1

i 2.2.2 Reactions with Aldehydes or Imines 7 -Bu 60 °C 86 0 0 >20:1 A typical side product that can be obtained in the one-pot 8(Me)2(OMe)CCH2 Reflux 29 0 0 >20:1 procedure is the reaction of the ylide with a second mole- 9(Me)2(OMe)CCH2 60 °C 82 1 0 >20:1 cule of aldehyde. This reaction has been exploited for the synthesis of b-hydroxy-a-amino acids (Table 4).18 10 p-MeOC6H4 Reflux 60 0 0 >20:1 In all cases, cycloadducts were isolated in good to excellent yields as single diastereoisomers. Aliphatic aldehydes

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a CO Et Table 4 Reaction of Azomethine Ylides with Aldehydes EtO2C 2 R O Ph N CO2Et H H Ph N RCHO, solvent Ph N R CO Et EtO C ∆ H EtO2C 2 O O 2 53 O O O O Ph N CO2Et 5 Ph N CO2Et H 44%a H 65%b Entry R Solvent Yield (%) Compd O O O O 54 57 37%a 21%a 1 Ph Toluene 69 40 b 5 44% 40%b

2 p-FC6H4 Toluene 61 41 a 28% 25%a O O 32%b 23%b 3 p-NO2C6H4 Toluene 45 42 EtO2C EtO2C NMe NPh 4 p-MeOC6H4 Toluene 50 43 Ph N Ph N O O H 5 2-Furyl Toluene 51 44 H O O O O 55 6 Pr Benzene 86 45 56

7 Bu Benzene 80 46 Scheme 7 Reagents and conditions: (a) ethyl glyoxalate trimer, dipolarophile, toluene, MS, reflux; (b) ethyl glyoxalate trimer, di- 8 Cyclohexyl Toluene 80 47 polarophile, MgBr2·OEt2, THF, r.t. a Reaction conditions: aldehyde (3 equiv), toluene, 3 Å MS, reflux. The reaction can be conducted under thermal or Lewis are particularly reactive in this transformation (entries 6– acidic conditions. In the latter case, both chemical yields 8).19 It is interesting to note that the yilde generated from and, where appropriate, exo-isomer proportion, were in- benzaldehyde (entry 1) led to a single adduct, whereas the creased.21 N same reactive intermediate reacted with -methylmaleim- Ketones are not usually ylide precursors, probably be- ide in a non-stereoselective manner (Scheme 6). cause of their reduced electrophilicity and the allylic A similar approach has been conducted with imines, lead- strain created during the formation of the dipole. The for- ing to the stereoselective construction of threo-2,3-diami- mation of cycloadducts bearing a quaternary center a to no acids (Table 5). The use of acidic conditions proved to the nitrogen atom could, however, be achieved from a be essential for ylide generation via a trans-imination transient tetrahedral precursor (Table 6).22 20 step. In all the cases the major diastereomer was the endo Table 5 Reaction of Azomethine Ylides with Iminesa adduct, although the selectivity was relatively poor with symmetrical Z alkenes (entries 1–3). Monoactivated Ar NR H ArCH=NR, solvent a Ph N Ph N Ar Table 6 Cycloadditions with Ketone-Derived Azomethine Ylides PPTS, ∆ H Z OMe Z Y Y O O OMe 5 O O MgBr ⋅Et O Ph N X 5 2 2 Ph N X Entry Ar R Yield (%) Compd H H Z 1 Ph Me 69 48 O O O O YX endo exo 2 Ph Bn 61 49 Entry X Y Z endo (%) exo (%) Compd 3 p-MeOC6H4 Bn 45 50 1 (CO)NPh(CO) H 43 30 58 4 p-NO2C6H4 Bn 50 51 2 (CO)NMe(CO) H 33 26 59 5 p-FC6H4 Bn 51 52 3 CO Me CO Me H 23 16 60 a Reaction conditions: imine (3 equiv), PPTS, 3 Å MS, reflux. 2 2

4 CO2Me CO2Me 70 0 61

2.3 Reactions Involving Ylides Derived from 5 HCO2Me H 14 0 62 Alkyl Glyoxylates or Ketones 6 H CN H 40 0 63

Interesting substituted proline precursors can be obtained a Reaction conditions: 2,2-dimethoxypropane (2 equiv), MgBr2·OEt2, when using ethyl glyoxylate as the aldehydic partner in di- dipolarophile (2 equiv), THF, reflux. polar cycloadditions (Scheme 7).

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Table 7 Cycloadditions with Benzophenone-Derived Azomethine Table 8 Chiral Appendage Cleavage Ylidesa 1 Y R1 Y R Y OMe Ph Z 2 Z Ph OMe R2 X R X H2, Pd(OH)2 Z Ph N H HN H H MgBr2⋅Et2O Ph N H 5 X TFA, MeOH H Z O O HO O O O 1 2 XY anti-endo Entry R R X Y Z Yield (%) 1 Entry X Y Z endo (%) Compd Me Me (CO)NPh(CO) H 72 2 Me Me (CO)NMe(CO) H 71 3 CO2Me CO2Me H 8 64

3 Me Me CO2Me CO2Me H 65 4 HCO2Me H 43 65 5 HCNH2066 4 Me Me CO2Me H CO2Me Quant.

5 Me Me H CO2Me H 78 6 HCO2Me H 38 67 6 HCOEt (CO)NMe(CO) H 85 a Reaction conditions: acetophenone dimethylacetal (2 equiv), 2 MgBr ·OEt , dipolarophile (3 equiv), THF, reflux. 2 2 7 HCO2Et CO2Me CO2Me H 90

8 HCO2Et CO2Me H CO2Me 75 alkenes reacted in a regio- and stereoselective manner (entries 5, 6). R CO2Me R CO2Me The use of unsymmetrical ketones can theoretically lead to a complex stereochemical issue. However, except with Ph N CO Me HN CO Me 2 H , PdCl (0.5 equiv) 2 maleimide dipolarophiles, only the anti-endo cyclo- H 2 2 EtOH, THF adducts could be isolated from the reaction mixture Ph O O HO O 23 (Table 7). 69, R = H 98% 70, R = Pr 93% Interestingly, the use of electron-deficient aldehyde as 71, R = i-Bu 99% dipolarophile led chemoselectively to the mixed endo cycloadducts 68, useful precursors of b-hydroxy-a-amino Scheme 9 Access to polysubstituted prolines by hydrogenolysis. acids (Scheme 8). morpholinone is cleaved under ‘neutral’ conditions NO 10a Ph 2 (Scheme 9). O Despite a milder procedure, sensitive heterocycles such as Ph N H furans have been reported to be reduced during this step.24 42% H OMe Ph OMe Furthermore, the regioselective catalytic hydrogenolysis O O of adducts bearing two C–N benzylic bonds failed. A two- MgBr ⋅Et O 5 2 2 68 anti-exo step alternative pathway, involving an oxidative cleavage p-NO2PhCHO NO2 procedure, has been proposed to overcome these side re- Ph O actions (Scheme 10). In some cases, epimerization of the 18% Ph N H amino ester intermediate can occur. H

O O R CO2Me R CO2Me 68 syn-exo Ph N CO2Me 6.5 N HCl Ph N CO2Me Scheme 8 Cycloadditions with electron-deficient aldehyde. H MeOH CO2Me Ph O O Ph OH

2.4 Synthetic Applications Pb(OAc)4 CH2Cl2 The cycloadducts can be converted to polysubstituted prolines in a straightforward manner. The chiral appendage is R CO2Me classically removed in a single-pot operation by hydro- 72, R = Ph 57% 73, R = p-MeOC6H4 66% genolysis with concomitant cleavage of the lactone HN CO2Me 74, R = p-NO C H 56% (Table 8).21,22 2 6 4 Acidic conditions are generally required with phenylgly- HO O cinol-derived morpholinones, whereas the diphenyl- Scheme 10 Access to polysubstituted prolines by oxidative cleavage.

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Ar O O HO H , Pd(OH) Boc Ph N Ar 2 2 H2N Ar H O Ph O O TFA, aq MeOH Boc N H O H N A O O HO O Ph N Ar ent-6 O D 75 Ph 65% O O N CO Me 76 p-FC6H4 75% 2 a O O E 77 p-NH2C6H4 84% O 78 p-MeOC6H4 76% N 86 Boc 85, 35% Ar NBn H2N Scheme 13 Synthesis of nakadomarin A precursor. H , Pd(OH) Ph N Ar 2 2 H2N Ar TFA, aq MeOH H

O O HO O Ar 3 Nitrones 79 Ph 83% 80 p-FC6H4 64% a The 1,3-dipolar cycloaddition of nitrones with alkenes can 81 p-NH2C6H4 66% 82 p-MeOC6H4 81% be considered as a useful three-component reaction, since a From the corresponding nitro-precursor the nitrone itself is easily generated from a hydroxylamine Scheme 11 Synthesis of amino acid derivatives. and an aldehyde. However, the stereospecificity of this condensation can be hampered by the known configura- tional lability of the nitrones. This problem can be avoided Cycloadducts resulting from the use of aldehydes or imi- by incorporationg the nitrone into a cyclic structure. Al- nes can also be hydrogenolyzed. This procedure provides though less general, the resulting two-component reaction an efficient entry to b-hydroxy- or -amino acids can, however, deliver very useful synthetic intermediates (Scheme 11).18,19 in a straightforward manner. Several total syntheses of spirocyclic natural products Morpholinone-derived nitrones were first reported in the based on azomethine ylide 1,3-dipolar cycloadditions late nineties by the groups of Tamura, Sakamoto,28 and have recently been reported (Scheme 12).25 Baldwin.29 They can be prepared either by the condensation of an hydroxylamine and glyoxylic acid or by the di-

MeO2C Ph rect oxidation of morpholinone 5. Ph O MeO O N O N N MeO MeO N O O O O H H

Me HN CO2Et HN O OMe Ph NH2 Ph N Ph N OHC p-MeOC6H4CHO MCPBA Me toluene, reflux OH OH 83, 82% spirotrypostatin B OH 87 88 ent-6 Ph Ph MeO O NH2OH·HCl 93% O N from 87 Me N OMe N OHC O O O OH Me H O O H Ph N Ph N Ph NH H2NCONH2·H2O2 OHCCO2H HN HN TsOH MeReO3 (cat) O O O O OH O 70–80% 5 90 89 MeO N H OMe OMe Scheme 14 Synthesis of nitrone 90. 84, 44% spirotrypostatin A

Scheme 12 Synthesis of spirotrypostatin A and B. In the latter case, the methyltrioxorhenium/urea–hydro- gen peroxide system30 appeared to be the best oxidant for the preparation of nitrone 90 in a reproducible manner on The same strategy has also been used for the elaboration a multigram scale (Scheme 14).31 Both methods deliver of the AD-spirocyclic system of nakadomarin A the nitrone without racemization. (Scheme 13).26 This rapid and stereoselective construction of polyfunc- 3.1 Reactions with Alkenes tionnal spirocycles has been recently exploited in the sol- id-phase-supported diversity-oriented synthesis of Nitrone 90 (or its enantiomer ent-90) reacts at its less-hin- libraries of compounds for a chemical genetic program.27 dered face with linear alkenes in good yields, leading to a

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Table 9 Cycloaddition of Nitrone with Alkenes Table 10 Cycloaddition of Nitrone with Substituted Styrenes

O O O O O O O O alkene H H benzene H 1–5 equiv H Ph N Ph N ∆ H Ph N+ Ph N+ CHCl3, 10 equiv O O O– O– X H X H Ar

Entry Alkene Conditions Yield (%, ratio) Compd Entry Alkene exo/endo Combined yield (%)Compd

1 r.t., 16 h 87 (83:8:9) 91 1 10:1 73 101 OEt 2 60 °C, 8 h 89 (75:5:11:9) 92 C4H9 2 10:1 71 102 3a r.t., 13–20 h >90 (single isomer) 93 C6H13 4OTBDMS 60 °C, 12 h 89 (75:5:11:9) 94 Me 3 7:1 85 103 5 r.t. to 50 °C 83 (87:13) 95 19 h t-Bu O 6b 60 °C, 25 h 95 (single isomer) 96 4 Me >20:1 49 104

7 r.t. to 50 °C, 87 (single isomer) 97 Me 32 h 5 Me 5:1 55 105

8 r.t., 9 h 92 (single isomer) 98 Me 6 5:1 84 106

9 r.t., 30 h 90 (single isomer) 99 OAc 7 10:1 70 107 10 r.t., 30 h 76c (80:16:4) 100

a Reaction performed in CHCl3. HO b Only 3 equiv of dipolarophile were used. c Isolated yield of the major isomer. O O O O O O mixture of diastereoisomers with the exo adduct being the N 32 H Ph N major compound (Table 9, entries 1–4). Ph N Ph N CH Cl O A better stereoselectivity has been observed with 2 2 O – branched or cyclic alkenes (entries 6–9), delivering a sin- O HO gle adduct, with the exception of dihydrofuran (entry 5) N HO H NH and cyclopentadiene (entry 10). A comparative study with 108 a wide range of substituted styrenes has been performed, showing that a remote substituent on the aromatic ring can conditions: Yield (%) exert a strong influence on the exo/endo ratio (Table 10).33 MgBr2⋅Et2O 100:0 98 The cycloaddition with allylic alcohols can also be con- r.t., 3 d trolled by the presence of MgBr2·OEt2. Thus, cycloadduct r.t., 15 d 1:6.2 97 108 was obtained as the sole product in 98% yield under Lewis acidic conditions, whereas standard conditions pro- Scheme 15 Lewis acid vs. thermal activation of nitrone cycloadditions. vided the alternative diastereomer as the major compound (Scheme 15).34 procedure enables the removal of the morpholinone in substrates bearing unsaturation (Scheme 17).32 3.2 Synthetic Applications As expected, cycloadducts can be cleaved under reductive 4 Azomethine Imines conditions. A short synthesis of (–)-monatin 111 has been reported in this manner (Scheme 16).33 Although less studied than azometine ylides or nitrones, The chiral appendage can also be removed under non-re- azomethine imine ylides have been known since the late ductive conditions using molybdenum hexacarbonyl. This 1960s to be excellent reagents in 1,3-dipolar cycloaddi-

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O O NHBoc NH2 Ph Ph Ph OH OH OH O ab 1) H2, Pd(OH)2, HO2C NH N N Ph N MeOH NO NH2 O HO O Ph Ph 2) Boc2O Ph BocN CO2H 92% CO H 3) PDC 2 114 115 116 HO 69% c NBoc NH Ph Ph O O d 109 110 111 HN N N O N O H H Scheme 16 Stereoselective synthesis of monatin. Ph 118 117

OH Scheme 18 Reagents and conditions: a) NaNO2, H2O–HCl, 70 °C, NHBoc O O Mo(CO)6, 92%; b) LiAlH4, Et2O, –78 °C to –10 °C, 84%; c) Im2CO, CH2Cl2, Ph O H H MeCN, H2O N Boc2O r.t., 74%; d) H2, Pd(OH)2, 10 bar, MeOH, 97%. H H Ph N ∆ O 68% O O OMe O H O O H O O O O H – R OMe RCHO N 100 112 113 Ph N + NH ∆, PTSA NH Ph N ∆ Ph N H Scheme 17 Non-reductive cleavage of chiral appendage. R H 118 118 tions.35 Furthermore, very exciting results had been reported in stereoselective cycloadditions of five-membered O O 36 racemic azomethine imines by the group of Stanovnik. N We started to investigate the use of cyclic carbazate 118 Ph N R in similar reactions in 1998. O R Although the synthesis of a closely related compound in Scheme 19 Azomethine imine ylides generation. the ephedrine series had been reported by Trepanier,37 we redesigned this original route slightly in order to obtain the ylide precursor in an improved and reproducible yield membered series, and were not isolated prior to the cy- (Scheme 18). The reduction step of the nitrosoamine cloaddition step. 11538 proved to be particularly difficult to optimize. We finally found that when conducted with an internal 4.2 Reactions Involving Ylides Derived from Al- temperature maintained between –10 °C and 0 °C, the iphatic or Aromatic Aldehydes strongly exothermic LAH reduction could lead to the corresponding crystallized hydrazine in a reproducible 4.2.1 Reactions with Alkynes 84% yield on medium scale (10–15 g). The same experi- As in the azomethine series, only one cycloadduct could mental procedure was conducted twice at a 100-g-scale, be obtained with diethylacetylene dicarboxylate.42 The re- 39 leading to the same product in 69% yield. The two final action had to be performed in a stepwise manner, using steps have also been performed on a relatively large scale the acid-catalyzed transacetalization process to avoid the (20 g), although some reduction problems can occur if competitive formation of the Michael-type direct addition traces of imidazole are not carefully removed after the of the carbazate onto the dipolarophile. The cycloadduct cyclization step. Compound 118 is a stable, crystalline is air-stable when properly recrystallized, whereas its oily compound that can be obtained in five steps from (R)-(–)- form rapidly oxidized to pyrazoline 120 (Scheme 20). phenylglycinol on a multigram scale, without any 40 chromatographic purification. Ph Ph O OH N PhCH(OMe) Ph N Ph 2 N O air N 4. 1 Ylide Generation 118 EtO2C CO2Et Attempts to generate the ylide from formaldehyde led to EtO2C CO2Et EtO2C CO2Et 41 35% very inconsistent results. On the contrary, numerous 119 120 ylides could be prepared from various aldehydes, either in a direct manner by condensation under dehydrating con- Scheme 20 Cycloadditions with activated alkynes. ditions or from the corresponding acetal under acid catal- ysis, or indirectly by a cycloreversion process (Scheme 19). The ylides proved to be much less stable 4.2.2 Reactions with Alkenes than the crystalline compounds described in the five- Carbazate-derived ylides reacted with a wide range of dipolarophiles (Table 11).43 In all the cases, the facial ‘ster-

Synlett 2006, No. 15, 2349–2363 © Thieme Stuttgart · New York ACCOUNT Asymmetric 1,3-Dipolar Cycloadditions 2359

Table 11 Cycloaddition of Azomethine Imines

R Y R W W Y H X Z Ph N Ph N Z Ph N X RCHO N N NH + dipolarophile O O O O O O endo exo

Entrya R Dipolarophile Adduct endo/exo Yield (%) Compd WX YZ

1 Ph CO2Me CO2Me H H >99:1 63 121 MeO2CCO2Me

2 PhMeO2C CO2Me H H CO2Me 73:27 82 122

CO2Me

3 Ph CO2Me H H H >99:1 74 123 CO2Me

4 PhPh CO2Me H H Ph 96:4 40 124

CO2Me 5 PhPh HPhHH14:8648125

6 PhC6H13 H C6H13 HH<1:9950126

7 3-Pyr CO2Me CO2Me H H >99:1 69 127 MeO2CCO2Me

83-PyrMeO2C CO2Me H H CO2Me 85:15 80 128

CO2Me 93-PyrPh HPhHH15:8578129

103-Pyr CO2Me H H H >99:1 78 130 CO2Me

11Pr CO2Me CO2Me H H >98:2 27 131 MeO2CCO2Me

12Pr CO2Me H H H 65:35 62 132 CO2Me 13 PrPh H Ph H H 65:35 11 133 a Reagents and conditions: RCHO (1.2–5 equiv), dipolarophile (2–4 equiv) refluxing CHCl3 or DCE. ic’ selectivity was fully controlled. The cycloaddition was O O generally endo-selective with dipolarophiles bearing elec- N tron-withdrawing groups, and fully stereospecific (entries N Ph 1, 2, 4, 7, 8). Singly activated dipolarophiles also reacted Ph + N Ph N N – N in a totally regioselective manner (entries 3, 4 and 10). In- 118 terestingly, styrene and the even less activated octene re- O O O O acted with the ylide, in an exo-mode and in a 134 regioselective manner. Although the general behavior of the azomethine imine ylide was quite similar to the reac- O O O O tivity of the corresponding azomethine ylide, no reaction N N + could be observed with maleimide derivatives. N Ph N Ph N With butyraldehyde-derived ylides, the endo/exo ratio Ph Ph N NH N – was also generally lower than in the aromatic series. Fur- thermore, cycloadducts were obtained in lower yields, as O O O O 135 a result of a formal head-to-tail dimerization of the transient ylide, followed by a non-concerted ring-opening and Scheme 21 Competitive degradation pathway of alkyl-based azo- intramolecular prototropy (Scheme 21). methine imines.

Synlett 2006, No. 15, 2349–2363 © Thieme Stuttgart · New York 2360 M. Bonin et al. ACCOUNT

Table 12 Tandem Cycloreversion–Cycloaddition Process

R Y R W R R W Y O H X Z Ph N ∆ Ph N dipolarophile Ph N Z Ph N X RCHO Ph N R – NH N N N + N

O O O O O O O O O O endo exo 118 136

Entry R 136 (%, dr) Dipolarophile Adduct endo/exo Yield (%) Compd WXYZ

1 Pr 97, >98:2 CO2Me CO2Me H H >98:2 71 131 MeO2CCO2Me

2 Pr 97, >98:2MeO2C CO2Me H H CO2Me 95:5 54 137

CO2Me

3 Pr 97, >98:2Me CO2Me H H Me 88:12 40 138

CO2Me

4 Pr 97, >98:2 CO2Me H H H 65:35 38 132 CO2Me

5 Ph(CH2)2 80, 70:20:10 CO2Me CO2Me H H >98:2 89 139 MeO2CCO2Me

6 Ph(CH2)2 80, 70:20:10MeO2C CO2Me H H CO2Me 89:11 85 140

CO2Me

7 Ph(CH2)2 80, 70:20:10Me CO2Me H H Me 84:16 73 141

CO2Me

This troublesome side reaction can be avoided by playing Ph O with the cycloaddition–cycloreversion equilibrium 44 EtO2C N (Table 12). Although this equilibrium is strongly shifted EtO2CCHO EtO2CCHO N O degradation 128 toward the oxadiazolidine 136 (which is the only species toluene, MgBr2⋅Et2O O 70 °C THF, 65 °C, 7 h CO2Et detectable by NMR in solution), it should be displaced by 142 the irreversible reaction of the ylide with a dipolarophile. 71% dr = 46:38:16 This process, delivering only a very small amount of dipole in solution, should lower the above-mentioned Scheme 22 Oxadiazolidine synthesis. dimerization side reaction. A general yield improvement could be observed using this procedure, except with me- in generally good chemical yields (Table 13).46 As in the thylacrylate.45 The stereochemical outcome of the tandem azomethine ylide series, the exo proportion of adducts in- cycloreversion–cycloaddition pathway was similar to the creased (entries 1–4), and was almost exclusive with direct one-pot procedure, showing that the reactive inter- ‘non-activated’ alkenes (entries 5–7). For the first time in mediates were identical. this series, a cycloadduct could be obtained with N-phe- nylmaleimide as a dipolarophile. 4.3 Reactions Involving Ylides Derived from Alkyl Glyoxylates 4.4 Synthetic Applications All attempts to use alkylglyoxalates in a direct cycloaddi- As in the azomethine ylide series, cleavage of the chiral tion from carbazate 118 were unsuccessful. The cyclore- appendage can be performed under hydrogenolytic condi- version route was therefore investigated, but the tions. This step was particularly difficult to optimize. The formation of oxadiazolidine 142 was problematic. While nature of the acidic co-catalyst proved to be crucial, since thermal or acidic activation failed, we were pleased to see the use of 6 N aqueous hydrochloric acid instead of con- that a diastereomeric mixture of 142 could be obtained in centrated sulfuric acid led to compound 143 in a non-re- a good yield when the condensation was performed in the producible low yield, and no reaction could be obtained presence of magnesium bromide etherate (Scheme 22). with trifluoroacetic acid (Scheme 23). Only starting mate- This diastereomeric mixture reacted with a wide range of rial was recovered when performing the hydrogenolysis dipolarophiles, leading to the corresponding cycloadducts without any acidic co-catalyst or substoichiometric quan- tities of sulfuric acid. The change of palladium hydroxide

Table 13 Tandem Cycloreversion–Cycloaddition Process O O O O O O

N N N Ph N CO2Et Ph N W Ph N Y Y O W EtO C EtO C EtO C 2 2 Z X 2 X Z 142 endo exo

Entry W X Y Z endo/exo Yield (%)

1 CO2Et CO2Et H H 85:15 84

2 CO2Et H H CO2Et 66:36 71 3 (CO)NPh(CO) H H 75:25 73

4 HCO2Me Me H 59:41 71 5 Ph H H H 5:95 48

6 p-MeOC6H4 HHH 3:9751

7 p-MeO2CC6H4 HHH 7:9365

COPh COPh for platinum as a catalyst led to the reduction product COPh without hydrogenolysis or N–N bond cleavage. Finally, Ph(CH ) N Ph(CH ) N 2 2 NCOPh Pr N 2 2 NCOPh best results were obtained when the hydrogenolysis was NCOPh performed with Pearlman’s catalyst in methanol in the CO2Me Me MeO2C CO2Me MeO2C presence of three equivalents of concentrated sulfuric ac- MeO2C 147, 79% 149, 67% 148, 60% id. The resulting pyrrazolidines had to be protected as bis- dr > 98:2 dr = 95:5 dr > 98:2 benzamides, in order to avoid a rapid oxidation to the COPh PhOC corresponding hydrazones. COPh Pr N Pr N NCOPh Ph(CH ) N NCOPh 2 2 NCOPh Ph Ph O Me CO2Me MeO2C CO2Me MeO2C MeO2C O N 150, 40% 152, 62% H N 151, 85% 2 O dr = 85:15 dr = 91:9 Pr N dr = 89:7:4 N O CO2Me MeO2C Figure 2 Synthesis of protected functionalized pyrrazolidines. Ph MeO C CO2Me a O c 145 2 143 R(CH ) N tive cleavage of the N–N bond. Although several 2 2 N O d COPh procedures have been described for this transformation, H N they proved to be unsuitable on our densely functionalized Ph(CH ) N b CO2Me Ph(CH2)2 COPh 2 2 N MeO2C N substrates. The use of Raney nickel, for instance, enabled R = Me 126 the one-pot reduction of the hydrazine bond and the re- CO2Me R = Ph 134 MeO C CO2Me MeO2C 2 moval of the chiral appendage, but led to the formation of 144 146 amino pyrrolidinone 153 as the result of the lactamization of the transient amino ester (Scheme 24). Scheme 23 Reagents and conditions: (a) (R = Me) H2, Pd(OH)2, MeOH, 6 N aq HCl, 25%; (b) (R = Ph) (i) H2, Pd(OH)2, MeOH, 1) H2, Pd(OH)2 H2SO4 (3 equiv); (ii) silica gel, 29%; (c) (R = Ph) H2, Pt black, Ph H SO , MeOH 2 4 H MeOH, H2SO4 (1 equiv), 19%; d) (R = Ph) (i) H2, Pd(OH)2, MeOH, O 2) H2, Raney Ni, Ph(CH ) N O H SO (2 equiv); (ii) PhCOCl (5.5 equiv), DBU (3 equiv), CH Cl , N 2 2 2 4 2 2 Ph(CH2)2 H2SO4, MeOH 79%, dr >98:2. N O 3) PhCOCl, Et3N MeO2C NHCO2Bn MeO C CO2Me CH2Cl2 This procedure enabled the preparation of a range of pro- 2 139 153, 35% tected pyrrazolidines without any racemization (Figure 2). Scheme 24 Synthesis of fucntionnalized pyrrolidinones. Despite extensive investigations, all hydrogenolyses performed on cycloadducts bearing two benzylic positions We finally found that pyrrazolidinones 154–159 could be led exclusively to the cleavage of the five-membered ring. cleanly reduced electrochemically, leading to the desired Not only pyrrazolidines, but also diamines can be ob- final diamides with very little epimerization of sensitive tained from azomethine imine cycloadditions after reduc- centers, provided that the reduction was conducted under carefully buffered neutral pH (Table 14).47

Table 14 Electrochemical N–N Bond Cleavage

PhOC COPh 2e–, AcOH 0.01 M, PhCONH NHCOPh N N AcOLi 0.3 M in MeOH, X R X R Y Y pH 7–8 CO2Me CO2Me

Entry R X Y dr Yield (%) Compd

1 Ph(CH2)2 CO2Me H 96:4 65 154

2 Ph(CH2)2 HCO2Me >98:2 73 155

3 Ph(CH2)2 H Me 97:3 71 156

4 Pr CO2Me H 97:3 90 157

5 Pr H CO2Me 95:5 80 158 6 Pr H Me 97:3 69 159

5 Conclusion R R O Ph N Ph N Ph N This general survey clearly highlights the great synthetic N potential of cyclic ylides derived from chiral amino alcohols. They can lead, by simple experimental manipula- O O O O O O tion, to a wide range of interesting structures with a great functional, regio- and stereodiversity, in a predictable dipoledipolarophile dipoledipolarophile dipole dipolarophile manner. Despite their apparent structural similarities, LUMO LUMO LUMO LUMO LUMO leading to an identical ‘steric’ control of the cycloaddition LUMO process, the three classes of ylides exhibited different reactivity patterns. Azomethine ylides generally react under thermal activation with electron-deficient alkenes (prefer- HOMO HOMO HOMO HOMO HOMO ably doubly activated) mainly in an endo manner, and HOMO poorly with dipolarophiles bearing neutral or electron-do- Type 1 Type 2 Type 3 nating groups. On the contrary, nitrones give excellent re- Figure 3 sults with electron-rich alkenes, leading mainly to exo adducts. Azomethine imine ylides exhibit an intermediate reactivity, leading to endo adducts with electron-deficient References and Notes dipolarophiles and exo derivatives with non-activated alkenes. These different reactivities, with structurally very (1) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Ulaczyk-Lesanko, A.; similar systems, clearly outline the importance of elec- Hall, D. G. Curr. Opin. Chem. Biol. 2005, 9, 2666. (c) Zhu, tronic effects and orbital control in dipolar cycloadditions. J. Eur. J. Org. Chem. 2003, 1133. (d) Bienaymé, H.; Thus, according to the Sustmann classification Hulme, C.; Odon, G.; Schmidt, P. Chemistry 2000, 6, 3321. (Figure 3),48 azomethine ylides behave as type 1 dipoles, (2) (a) Karlsson, S.; Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 105. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. leading to reactions with a predominant HOMOdipole– LUMO control, whereas nitrones react as type 3 Rev. 1998, 98, 863. dipolarophile (3) For a general review on asymmetric multicomponent dipoles by a LUMOdipole–HOMOdipolarophile pathway. reactions, see: Ramón, D. J.; Yus, M. Angew. Chem. Int. Ed. The reactivity of azomethine imines is more typical for a 2005, 44, 1602. type 2 dipole, with the cycloaddition being mainly gov- (4) Schreiber, S. L. Science 2000, 287, 1964. erned by the level of the dipolarophile’s FMOs. It can (5) (a) Bournaud, C.; Robic, D.; Bonin, M.; Micouin, L. J. Org. therefore be expected that such ylide, able to react with al- Chem. 2005, 70, 3316. (b) Pérez Luna, A.; Cesario, M.; Bonin, M.; Micouin, L. Org. Lett. 2003, 5, 4771. (c) Pérez most all kinds of dipolarophiles in a predictable manner, Luna, A.; Bonin, M.; Micouin, L.; Husson, H.-P. J. Am. will be an excellent tool for a rapid generation of function- Chem. Soc. 2002, 124, 12098. (d) Pérez Luna, A.; Ceschi, ally and stereochemically diverse molecules. M.-A.; Bonin, M.; Micouin, L.; Husson, H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522. Acknowledgment (6) For an excellent recent review on azomethine ylides, see: Curr. Org. Chem. 2003 7 Prof. H.-P. Husson is acknowledged for his interest in this work. We Nájera, C.; Sansano, J. M. , , 1105. thank Prof. L. M. Harwood for a critical reading of this manuscript. (7) For a general review on cycloadditions with nitrones, see: Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.

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