Tetrahedron Letters 55 (2014) 777–783

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Digest papers

Recent advances in metal carbenoid mediated nitrogen-containingzwitterionic intermediate trapping process

0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.12.026

⇑ Corresponding author.E-mail address: whu@chem.ecnu.edu.cn (W. Hu).

Dong Xing, Wenhao Hu ⇑Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663, North Zhongshan Road, Shanghai 200062, China

a r t i c l e i n f o

Article history:Received 13 September 2013Revised 2 December 2013Accepted 8 December 2013Available online 12 December 2013

Keywords:CarbenoidDiazo compoundZwitterionic intermediateTrapping processEnamine

a b s t r a c t

Zwitterionic intermediates generated from metal carbenoids and compounds containing enamine unitsbelong to a class of highly active synthetic intermediates that undergo different types of transformations.They can undergo rapid proton transfer to afford C–H functionalization products, or undergo intramolec-ular trapping process to give [3+2] annulation products. Recently, by taking advantage of its unique elec-tronic feature, novel transformations have been developed by applying suitable electrophiles to trap suchtype of zwitterionic intermediates. The successful trapping process offers a powerful strategy for theeffective construction of diversified nitrogen-containing molecules.

� 2013 Elsevier Ltd. All rights reserved.

Metal carbenoids generated from transition metal-catalyzeddecomposition of diazo compounds belong to the most activeand useful intermediates in organic chemistry.1 Among differenttypes of metal carbenoid-mediated transformations includingcyclopropanations,2 X–H (X = C, N, O, Si, P, S) insertions,3 and ylideformations,4 it is a well-established process that compounds con-taining enamine units (i.e., nitrogen-containing aromatic heterocy-cles) react with metal carbenoids to generate active nitrogen-containing zwitterionic intermediates (Scheme 1).5 This pathwayis favored because the electrophilic center of the intermediate isstabilized by the nitrogen lone pair while the nucleophilic centeris stabilized by the carbenoid component. The active zwitterionicintermediates undergo different types of further transformations,including rapid proton transfer to afford C–H functionalizationproducts (Scheme 1, pathway a), intramolecular trapping processto afford [3+2] annulation products (Scheme 1, pathway b), or, asillustrated most recently by our research group, undergo electro-philic trapping process with suitable electrophiles such as iminesor active carbonyl compounds to give zwitterionic intermediatetrapping products (Scheme 1, pathway c). The establishment ofthese transformations opens a door for the efficient constructionof diversified nitrogen-containing molecules.

In the present digest, we will focus on recent advances in differ-ent types of trapping process of the active zwitterionic intermedi-ates that generated from metal carbenoids and compoundspossessing enamine units. Specially, since the synthesis of

complicated chiral molecules has become a central theme in mod-ern organic chemistry, we will put particular emphasis on thedevelopment of enantioselective catalytic systems for thosetransformations.

Proton transfer

Metal carbenoid-mediated C–H functionalization is among themost effective approaches for the direct replacement of C–H bondswith new bonds.6 Among different types of these transformations,Doyle and co-workers discovered that oxindole 2 was producedfrom N-aryl diazoacetamide 1 in the presence of Rh2(OAc)4 cata-lyst.7 The C–N bond and its adjacent aromatic C–C bond in sub-strate 1 could be considered as an enamine unit. The authorsproposed that a zwitterionic intermediate was formed during theintramolecular insertion of the carbenoid into the aromatic ring.This zwitterionic intermediate undergoes rapid proton transfer togive the C–H functionalized product (Scheme 2).

Nitrogen-containing aromatic heterocycles, such as pyrrolesand indoles, are also good substrates to react with metal carbe-noids to afford C–H functionalized products via zwitterionic inter-mediate formation/proton transfer process. For example, N-alkylpyrroles reacted with ethyl diazoacetate 3 in the presence ofCu(acac)2 catalyst to form C–H alkylation products in low tomoderate yields.8 The efficiency and regioselectivity of the reactionis highly dependent on the alkyl substitution on nitrogen atom.Carbenoid predominantly attacks at 2-position with N-methylsubstitutent to form 2-alkylation product 5a, while substrate bear-ing more bulky tert-butyl substituent at nitrogen atom gave

R1

MLn

CO2R2

+

proton transfer

[3+2] annulation

electrophilictrapping

NR3

NR3

R1

CO2R2[M]

NR3

R1

CO2R2[M]

zwitterionic intermediate

NR3

X R

X = C, N

NR3

R1

CO2R2E

NR3

R1

CO2R2

pathway a

pathway b

pathway c

Scheme 1.

N

OR2

N2

N NO

R2 [Rh] R2

O[Rh]1,2 protontransfer

NO

R2

1 2

zwitterionic intermediate

Rh2(OAc)4

67-98% yield

R1

R1 R1

R1

Scheme 2.

778 D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783

3-alkylation product 4b exclusively (Scheme 3). On the other hand,cyclopropanation instead of alkylation occurs when N-acyl pyrroleis employed as the substrate due to its less electron-rich feature re-sulted from the conjugation effect of the nitrogen lone pair on pyr-role ring with the carbonyl group.9

Indoles also undergo effective C–H functionalization with metalcarbenoids. Since indoles behave more like isolated enamines, theytypically react with electrophilic carbenoids at 3-position to afford3-alkylation products. For example, N-methyl indole 6 reacts withethyl diazoacetate 3 to generate 3-alkylation product 7 in low tomoderated yields (Scheme 4).10 The possible pathway for thistransformation also involves the formation of a zwitterionic inter-mediate and following a 1,2-proton transfer process. When di-methyl diazomalonate 8 is employed, the 3-alkylation product of6a is achieved in much higher yield than that from ethyl diazoace-

N

R

N

R

CO2Et[Cu]

N

R

N

R

CO2Et[Cu]

CO2Et

[Cu]N

RCO

[

+ N2 CO2Et

3

Cu(acac)2

zwitterionic intermediate

zwitterionic intermediate

N

R4

prtra

R = Me

R = t-Bu

Scheme

tate 3 (Eq. 1).11 This is presumably owing to the fact that the accep-tor–acceptor carbenoid derived from 8 is more electrophilic andtherefore favors the formation of zwitterionic intermediates.

N+

6a

N2 CO2Me

8

N

CO2Me

9 96% yield

CO2Me Rh2(OAc)4

MeO2C

ð1Þ

Owing to the wide existence of indole structures in naturalproducts and biologically active molecules, great efforts have beenmade toward the development of enantioselective carbenoid-med-iated C–H functionalization of indoles. In 2009, Davies and co-workers used chiral dirhodium(II) complexes to catalyze the reac-tion of methyl phenyldiazoacetate 10 with 1,2-dimethyl indole 6b.In the presence of Rh2(S-DOSP)4 catalyst, the desired transforma-tion is very efficient, yielding the 3-alkylation product 11 in 95%yield, however, with negligible asymmetric induction (<5% ee)(Scheme 5).12 As the authors proposed, the lack of asymmetricinduction may be resulted from an achiral enol B, which is gener-ated from the zwitterionic intermediate A via a rapid protontransfer.

In 2011, a highly enantioselective C–H functionalization ofindoles by carbenoids derived from a-alkyl-a-diazoesters wasreported by Fox and co-workers.13 In the presence of chiral dirho-dium(II) catalyst Rh2(S-NTTL)4, which is proposed to adopt chiral‘crown conformation’ for asymmetric induction, 1,2-dimethyl-indole 6b reacts with ethyl 2-diazohexanoate 12 to generate

2Et

Cu]proton

transfer

CO2Et

N

R

CO2Et

5

a: R = Me53% yield, 4a:5a = 6:94

b: R = t-Bu34% yield, 4b:5b > 98:2

+

otonnsfer

3.

N+

N

[Cu]CO2Et

N

CO2Et

zwitterionic intermediate

6a R = H6b R = Me

N2 CO2Et

3

Cu bronzeR

NR

CO2Et

7a R = H, 27% yield7b R = Me, 51% yield

[Cu]

R R

Scheme 4.

N

6bn-Bu

N2

CO2Et12

+

N

CO2Et

13

n-Bu

95% yield95% ee

toluene, -78 oC

O

O

Rh

Rh4

Rh2(S-NTTL)4

Rh2(S-NTTL)4(0.5 mol%)

t-BuO

ON

O

OEtn-Bu

[Rh]H

C

Scheme 6.

N

6bPh

N2

CO2Me10

+

N

CO2Me

11

Ph

95% yield5% ee

Rh2(S-DOSP)4toluene, -45 oC

N

PhCO2Me

[Rh]

N

Ph OH

OMe

A B

N

O

O

Rh

Rh

H

SO2Ar 4Rh2(S-DOSP)4

Ar = C6H4(C12H25)

Scheme 5.

D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783 779

3-alkylation product 13 in 95% yield with 95% ee (Scheme 6). FromDFT calculations, the authors proposed a mechanism that involvesa zwitterionic intermediate C with oxocarbenium character.

N

Ph CO2Me

N2

Rh2(S-DOSP)4( 2 mol %)

toluene, -45 oC

+R2

R1

16

6b

6d

R1 R2

H Me

Me H

17

17 only

18 only

6

Scheme

Zhou and co-workers reported an iron-catalyzed C–H function-alization of indoles with aryldiazoacetates by employing chiralspirobisoxazoline ligands.14 In the presence of chiral Fe(II) complexgenerated from Fe(ClO4)2 and spirobisoxazoline 14, N-substitutedindole 6 reacts with methyl phenyldiazoacetate 10 to afford 3-alkylation product 15 (Eq. 2). The use of N-TBS (tert-butyldimeth-ylsilyl) substituted indole 6c as the substrate gave better enanti-oselectivity than that of N-methyl indole 6a. The authorsproposed a plausible mechanism that involves a zwitterionic inter-mediate generated from iron carbenoid, followed by a 1,2-protontransfer process to give the product.

NR

6a R = Me6c R = TBS

Ph

N2

CO2Me10

+

NR

CO2Me

15a R = Me90% yield, 60% ee

PhFe(ClO4)2 (5 mol%)

14 (6 mol%)NaBArF (6 mol%)

CHCl3, 40 oC

15b R = TBS92% yield, 73% eeN

O

O

N Ph

Ph

14

ð2Þ

[3+2] Annulation

In 2009, Davies and co-workers developed a novel enantioselec-tive [3+2] annulation of indoles with rhodium-stabilized vinylcarb-enoids that proceed via zwitterionic intermediates. The initialpurpose to use a vinyldiazoester as the carbenoid was to avoid un-wanted formation of achiral intermediates from arylcarbenoid(Scheme 5).12 However, this chemistry eventually led to a highlyenantioselective method for the synthesis of fusedcyclopenta[b]indoles.

When N-methyl indole 6a reacted with methyl styryldiazoace-tate 16 in the presence of Rh2(R-DOSP)4, two regioisomeric fusedindoline derivatives were generated in an about 4:1 ratio, bothwith high asymmetric induction. By extending the substrate toeither 1,2-disubstituted indole 6b or 1,3-disubstituted indole 6d,the reaction proceeded regiospecifically to afford the correspond-ing single regioisomer 17 or 18 in high yields with excellentenantioselectivities (Scheme 7). Based on the fact that the twotypes of indoline products give opposite absolute configuration atthe ring-fusion stereocenters, a plausible mechanism that involvesthe formation of zwitterionic intermediates was proposed(Scheme 8).

Most recently, by utilizing 4-aryl-1-sulfonyl-1,2,3-triazoles as acarbenoid precursor, Davies and co-workers reported a Rh(II)-catalyzed asymmetric formal [3+2] annulation of indoles for thesynthesis of pyrroloindolines.15 In the presence of rhodium (II)-

N

R1

R2 Ph N

PhR1

R2CO2Me

MeO2C

17 18

+

18

(68% yield, 97% ee)

(74% yield, 99% ee)

7.

Rh

MeO2C

PhN

+

Rh

MeO2C+

N

Rh

MeO2C

PhN

H

17

Ph

Rh

MeO2C

N

PhH

18

s-trans

s-cis

TSI

TS2

Scheme 8.

780 D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783

tetracarboxylate catalyst Rh2(S-PTAD)4, 4-phenyl-1-(methanesulfo-nyl)-1,2,3-tria-zole 19 reacted with 1,3-dimethyl indole 6d to affordpyrroloindoline 20 in 84% yield with 94% ee (Scheme 9). Consideringthe electron-rich feature of N-alkyl indoles in favoring a zwitter-ionic-type pathway, the authors proposed a mechanism throughzwitterionic intermediate 21 (Scheme 9, path a). Due to the abnor-mal regioselectivity and strong solvent effect observed in this trans-formation, a mechanism involving an initial cyclopropanation of theC2–C3 bond of indole followed by ring-opening to a metal free zwit-terionic intermediate 23 is also possible (Scheme 9, path b).

Trapping of active zwitterionic intermediates with differenttypes of electrophiles

In recent years, our research group has been devoted to thedevelopment of novel multi-component reactions (MCRs) via trap-

N

Rh2(S-PTAD)4( 1 mol %)

cyclohexane65 oC

+

6d

NMsN

NPh

19

Ph

[Rh]NMs

6d N

RPh

[Rh]

NMs

N

RNMs

PhH

21

22

patha

pathb

Scheme

N

OR

N2

1a (R = H)1b (R = Me)

+ Rh2(OAc)4 (2 mol%)

THF, 25 oCN

O

N

O

O

BnR

NHOO

B

2526a (R = H)66% yield, 92:26b (R = Me)50% yield, 50:

ping of active onium ylide intermediates generated from metalcarbenoids with a number of electrophiles.16 Inspired by these re-search progresses, we envisioned that similar electrophilic trap-ping process could also be applied to zwitterionic intermediatesthat derived from metal carbenoids and compounds possessing en-amine units, therefore providing new and valuable transformationsfor synthesizing polyfunctional nitrogen-containing molecules.

We began our initial exploration with N-aryl diazoacetamidesubstrates, which had been used as unique substrates for intra-molecular C–H functionalization through the formation of pro-posed zwitterionic intermediates (Scheme 10, path a).7 Thepresence of a suitable electrophile may inhibit the 1,2-protontransfer process by an efficient trapping of the zwitterionic inter-mediate followed with a ‘delayed proton transfer’ (Scheme 10,path b).

Highly electrophilic isatins were employed as the trapping re-agent. In the presence of Rh2(OAc)4 catalyst, N-benzyl isatin 25 re-acted with N-methyl-N-phenyl diazoacetamide 1a and the desired3-hydroxy-3,30-bioxindole product 26 was afforded in good yield(Eq. 3).17 A brief condition optimization indicated that solventshad a significant effect on diastereoselectivity. When THF was cho-sen as the solvent, the reaction was finished in 92:8 dr while onlymoderate diastereoselectivities were observed when halogenatedsolvents or toluene were used. A variety of substitutions on bothisatin and the aromatic ring of diazo compound were tolerated inthis reaction, affording desired products in good yields with highdiastereoselectivities, but 4-substituted isatin gave lower yield,indicating a strong steric effect during the trapping process ofthe zwitterionic intermediate. However, when a-methyl substi-tuted diazo compound 1b was used as the substrate, the desiredproduct was only afforded in moderate yield with poor diastere-oselectivity (50:50).

NNMs

Ph

20H84% yield94% ee

O

O

Rh

Rh4

N

R H

O

O

R = adamantylRh2(S-PTAD)4

N

RPh

NMs

23

9.

n

8 dr

50 dr

ð3Þ

N Ph

N2

CO2Me+

N

PhCO2Me

[Rh]

N

Ph O

OMe

[Rh]

zwitterionic intermediate

106a

NPh

Ph

30

Rh2(OAc)4 (1 mol%)28 (5 mol%)

toluene, 4 A MS N

MeO2CPh

31

Ph

NHPh

94% yield>20:1 dr97% ee

+

Rh 1,2 protontransfer

N

PhCO2Me

path a32

×

Scheme 11.

N

OR

N2

[Rh]

N NO

R [Rh] R

O[Rh]

1,2 protontransfer

NO

path a

12

suitableelectrophile

NO

R E

path b

zwitterionic intermediatedelayedproton

transfer

R H

NO

R EH

24

Scheme 10.

D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783 781

In order to develop highly enantioselective transformations forzwitterionic trapping chemistry, the choice of suitable catalyticsystem is crucial. Recently, we identified rhodium and chiral phos-phoric acid (PPA) co-catalytic system for the trapping of ammo-nium ylides or oxonium ylides with imine substrates to achievehighly enantioselective three-component transformations.18 Theuse of chiral PPA co-catalyst not only activated the imine substratetoward desired trapping process and suppressed unwanted side

N

O

N21b

N

Cl27

+ Rh2(OAc)4 (2 mol%)

28 (10 mol%)CH2Cl2, -20 oC

NO

29

NH

Cl

75% yield97:3 dr91% eeO

OP

O

OH

SiPh3

SiPh328

ð4Þ

reactions, but also provided an efficient chiral environment forenantioselective control. With these successes, we chose chiralPPA-activated imines as appropriate electrophiles to trap theabove-mentioned zwitterionic intermediate for the effective syn-thesis of chiral oxindole derivatives.

By applying the rhodium/chiral PPA co-catalytic system, N-methyl-N-phenyl diazopropanamide 1b reacted with imine 27smoothly to afford the desired zwitterionic intermediate trappingproduct 29. The screening of various chiral PPAs revealed that

there was no conspicuous electronic effect and PPA 28 bearing abulky triphenyl silyl substitution was the most optimal. Eventually,product 29 was afforded in 75% yield with 97:3 dr and 91% ee (Eq.4).19 Other aromatic imines were applied, yielding the desiredproducts in good yields with high to excellent dr and ee. Differentalkyl substitutions at the nitrogen atom and different substitutionson the aromatic ring of the diazo compounds were well tolerated inthis reaction and gave good results.

With the successful development of this highly enantioselectiveprocess with imines as the electrophile by a rhodium/chiral PPAco-catalytic system, we turn our attention to the reaction of metalcarbenoid with electron-rich N-alkyl indole, which also generates azwitterionic intermediate through a similar iminium fragment(Scheme 11). By applying the same trapping strategy with imineas the electrophile, a novel enantioselective three-component reac-tion that leads to densely functionalized indole derivative was also

782 D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783

developed. After thorough condition optimizations, the reaction ofmethyl phenyldiazoacetate 10 with N-methyl indole 6a and imine30 afforded the desired zwitterionic intermediate trapping product31 in 94% yield with >20/1 dr and 97% ee (Scheme 11).19 Thisthree-component transformation also showed a very broad sub-strate scope. A broad range of aryl imines, aryldiazoacetates andsubstituted indoles could be used to afford functionalized indolederivatives in good yields with high stereoselectivities. It is note-worthy that methyl styryldiazoacetate 16, which has been re-ported to react with N-alkyl indole through [3+2] annulation toafford fused indolines,12 were also adapted to this co-catalytic sys-tem, resulting the desired three-component product 33 in moder-ate yield with 97% ee (Eq. 5).

N

N2

CO2Me

16

+ + NPh

Ph6a 30

Rh2(OAc)4 (1 mol%)28 (5 mol%)

toluene, 4 A MS N

MeOOC

33

Ph

NHPh

50% yield>20:1 dr97% ee

Ph

Ph

ð5Þ

O

OP

O

OH

R

R

28 (R = SiPh3)

C2RR

OOP

O O

N

LnRhO Ph

H

NPh

HH

TSI

Figure 1.

N

N

[Rh]

O

R1

R2

N

N

O[Rh]

R1

R2

zwitterionic intermediate

NO

Bn

NBnN2

+N

N OH

CO2EtO

Bn

Bn

CO2Et

O

Rh2(OAc)4 (1 mol %)CH2Cl2

yield: 88%dr: 98:2

6e37

38

39

38

To rationalize the observed stereochemistry of the zwitterionictrapping process with imines, an interaction model proposed bySimón and Goodman20 is applied to explain the Rh2(OAc)4/chiralPPA co-catalyzed reaction of N-methyl-N-phenyl diazopropana-mide 1b and imine 27. Transition state I (TSI) is proposed to afford29 with the observed stereochemistry (Fig. 1). The imine substrateinitially interacts with PPA catalyst, with the direction of the N-phenyl group on the E-imine toward the empty pocket of the cat-alyst. The imine is protonated by the PPA catalyst while the iminemaintained its E configuration. We proposed that a weak hydrogenbond between the Lewis basic phosphoryl oxygen atom and theacidic C–H proton in the zwitterionic intermediate may be respon-sible for the stereochemical outcome of this reaction while protontransfer occurs through PPA to form the product. As a result ofthese interactions, efficient chiral induction is achieved.

To gain more insight into the proposed proton transfer pathwayof the zwitterionic intermediate, a deuterium isotope experimentfor the Rh2(OAc)4/chiral PPA co-catalyzed C–D insertion of d5-1bwas first conducted. When the reaction was finished, only 26% ofdeuterium transferred product was observed. The dramatic de-crease in the deuterium content of the product indicated an ’indi-rect proton transfer’ from the corresponding zwitterionicintermediate (Eq. 6). On the other hand, the Rh2(OAc)4-catalyzedreaction of N-methyl indole 6a with methyl phenyldiazoacetate10 in the presence of 1 equiv. D2O resulted in 27% deuteriumsubstituted product 35 (Eq. 7). This result indicated that traceamount of water in the reaction system may act as a ‘proton-trans-fer shuttle’ for the proton transfer process instead of a direct 1,2-proton transfer.21

N

O

N2

d5-1d

Rh2(OAc)4 (2 mol%)

28 (10 mol%)CH2Cl2 N

O

D (26%)

quantitative yield30% ee

DD

DD

DD

D

DD

34

ð6Þ

NPh

N2

CO2Me10

+

6a

Rh2(OAc)4D2O (1 equiv)

toluene N

Ph

35

CO2Me

H/D(27% D)

quantitative yield

ð7Þ

With these observations, we successfully developed a highlyenantioselective C–H functionalization of indoles with phenyl dia-zoesters by applying chiral PPA as the chiral ‘proton transfer shut-tle’. In the presence of Rh2(OAc)4 and chiral PPA 36, N-methylindole 6a reacted with methyl phenyldiazoacetate 10 to affordthe 3-alkylation product 15a in 96% yield with 92% ee (Eq. 8).22 A

number of indoles including N-alkyl, aryl, silyl, and a number ofa-aryl-a-diazoesters were well tolerated, affording the desiredproducts in good results.

Scheme 12.

N

N OH

COOEtO

TBSOTf2,6-Lutidine

39

Bn

BnN

N OTBS

COOEtO

40

Bn

BnN

N OTBS

O

41

N

N OTBS

O

O

CH2Cl20 oC

DIBAL-HCH2Cl2

78 oCOH

DMPPyridineCH2Cl2

rt

Bn

Bn

Bn

Bn

NH

NN

HN O

OH

Me

gliocladin C

O

42

60% 69%

98%

(+)

Scheme 13.

D. Xing, W. Hu / Tetrahedron Letters 55 (2014) 777–783 783

NPh

N2

CO2Me10

+

6a

Rh2(OAc)4 (1 mol%)36 (5 mol%)

toluene, 0 oCN

Ph

15a

CO2Me

96% yield92% eeO

OP

O

OH

R

R36

R = 2,4,6-(i-Pr)3C6H2

ð8Þ

We further applied this zwitterionic trapping chemistry to thesynthesis of more complicated structural motifs. By applying ethylglyoxylate 38 as the trapping reagent, mixed 3,30-bisindole 39,which is the key structural skeleton for a number of indole alka-loids, were effectively synthesized from 3-diazooxindole 37 andN-benzyl indole 6e in good yield and high diastereoselectivity(Scheme 12).23 A series of substituted 3-diazooxindoles and in-doles were used as the substrates, affording the correspondingthree-component products in good yields with high diastereoselec-tivities, but 4-substituted indole resulted in poor yield of the three-component product, indicating a strong steric effect. On the otherhand, the use of other aldehydes, such as benzaldehyde or cinna-maldehyde as the substrate resulted in no desired product forma-tion under the optimized reaction conditions, indicating the highelectrophilicity of ethyl glyoxylate was essential for the zwitter-ionic trapping process.

The mixed 3,30-bisindole structural motif could be applied tothe synthesis of related natural indole alkaloids. For example, thehydroxyl group of 39 was firstly protected with TBS group to afford40 in good yield. Reduction of the ester group of 40 with DIBAL-Hfurnished the corresponding primary alcohol 41 in 69% yield. Then,under Dess–Martin condition, primary alcohol 41 was oxidizedinto aldehyde 42, which could be used as a key intermediate forthe total synthesis of (±)-gliocladin C (Scheme 13).

By taking advantage of the unique electronic feature of thezwitterionic intermediate generated from metal carbenoid andcompound possessing enamine unit, we successfully developed aseries of novel transformations by introducing suitable electro-philes to trap the zwitterionic intermediates. A number of structur-ally diversified nitrogen-containing molecules are generated withthese transformations. As an infant research area in carbenoidchemistry, they will receive more attention from the synthetic

community. Further research efforts in this area may involve theintroduction of other types of zwitterionic intermediate precur-sors, such as pyrroles, simple enamines, etc.; the introduction ofdifferent types of electrophilic trapping reagents, which wouldlead to complicated and synthetically useful products; and thedevelopment of effective catalytic systems that could give highlystereoselective controls.

References and notes

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