CC BY-ND-NC 4.0 · Synthesis 2019; 51(05): 1073-1086
DOI: 10.1055/s-0037-1611660
short review
Copyright with the author

Pyrroles as Dienes in (4+3) Cycloadditions

Fan Hu
,
Jerome P. L. Ng
,
State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China   Email: pchiu@hku.hk
› Author Affiliations
Funding support from the State Key Laboratory of Synthetic Chemistry, and the University of Hong Kong are gratefully acknowledged.
Further Information

Publication History

Received: 24 December 2018

Accepted: 30 December 2018

Publication Date:
06 February 2019 (online)

 


Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

This short review summarizes the examples to date of successful (4+3) cycloadditions, including formal (4+3) cycloadditions, where pyrrole derivatives reacted as the diene component, to provide aza-bridged bicyclic and polycyclic adducts.

1 Introduction

2 Unsubstituted Pyrroles as Dienes in (4+3) Cycloadditions

3 C-Substituted Pyrroles as Dienes in (4+3) Cycloadditions

4 Intramolecular Pyrrole (4+3) Cycloadditions

5 Conclusions


# 1

Introduction

Natural products have played a vital role in the history and discovery of drugs.[1] Alkaloids that can be obtained by isolation using acid-base extractions are among the earliest classes of compounds to be studied and identified from natural sources.[2]

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Pauline Chiu studied at the University of Toronto, Canada. She ­obtained her M.Sc. degree working on silene chemistry with the late Professor Adrian G. Brook, and her Ph.D. on reactions of oxabicyclic compounds with Professor Mark Lautens. Subsequent to her postdoctoral studies on the total synthesis of gelsemine with Professor Samuel J. Danishefsky at Columbia University, she started her independent ­career at the Department of Chemistry at The University of Hong Kong, where she has been Full Professor since 2011. Efforts in the Chiu group are directed to research on novel synthetic reactions, and total synthesis of natural products. Her co-authors on this paper are Fan Hu and Jerome P. L. Ng, first- and final-year graduate students in the Chiu group.

One class of these ‘true alkaloids’[2] are the tropanes, characterized by N-methyl-8-azabicyclo[3.2.1]octane frameworks (Figure 1), which are among the world’s oldest plant medicines.[3] The tropanes were first identified from two plant sources; from the Erythroxylaceae family, to which the coca plant belongs, was isolated the infamous cocaine.[4] The pervilleines are toxic alkaloids isolated from the extracts of the roots of Erythroxylum pervillei that shows multi­drug resistance reversal ability against MDR cancer cell lines.[5] From the Solanaceae family was isolated many bioactive alkaloids that are powerful anticholinergics. Scopolamine (Figure [1]), also known as hyoscine, was isolated from Hyoscyamus niger and is a sedative and treats nausea and vomiting.[6] Atropine isolated from Atropa belladonna, is a stimulant and pupil dilator, and is a treatment for bradycardia (i.e., slow heart rate) and poisoning.[7] Both of these are on the WHO’s Model List of Essential Medicines.

Homatropine methylbromide, and tiotropium bromide are synthetic drugs modelled on the atropine skeleton (Figure 1). The latter was marketed as Spiriva by Boehringer Ingelheim for the management of chronic obstructive pulmonary ­disease.[8] There are more than 20 medicines currently in the market with the tropane framework,[9] and therefore it is a highly desirable scaffold from a pharmacological perspective. Tropane alkaloids frameworks are also embedded in various natural products, such as himandrine and stemo­foline (Figure 1).[10]

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Figure 1 Representative tropane alkaloids and natural products with embedded nortropane frameworks

To secure the tropane, or more generally the nortropane (desmethyltropane) nucleus by laboratory synthesis,[11] a retrosynthetic analysis would suggest a (4+3) cycloaddition with a pyrrole as the diene component, as a convergent and step-economical assembly of the 8-azabicyclo[3.2.1]octane framework. Moreover, stereochemically defined, amine-substituted arrays can also be generated from the cleavage of 8-azabicyclo[3.2.1]octene products of pyrrole (4+3) cyclo­additions, to exploit the anticipated stereoselectivity generally available from cycloaddition reactions.

However, effective (4+3) cycloadditions of pyrrole derivatives are considerably more challenging to accomplish, and there are far fewer examples in the literature compared to the analogous reactions of furans.[12] Pyrroles are more aromatic, and the tendency toward aromaticity competes with cycloaddition reactions, which are necessarily dearomatizing.[13] Moreover, pyrroles are rather reactive towards acids, electrophiles, oxidants, and polymerization, which consume the pyrroles from the intended cycloadditions. Finally, the pyrrole cycloadducts themselves are also comparatively less stable and tend to degrade to rearomatized pyrroles as decomposition products.

Yet, due to the high value of the tropane skeleton, studies on the (4+3) cycloaddition of pyrroles with various three-atom dienophiles have continued. Despite the general incompetence of pyrroles as dienes, there are successful reports in the literature. This short review aims to summarize the range of aza-bridged bicyclic or tricyclic cyclo­adducts that have been obtained from engaging pyrrole derivatives as dienes successfully for (4+3) cycloadditions, through various strategies. Efforts and strategies to render these (4+3) cycloadditions enantioselective in order to procure enantiomerically enriched nortropane frameworks are also highlighted.

1.1

Classical (4+3) Cycloadditions of Allylic Cations and Related Electrophiles

Classical (4+3) cycloadditions generally involve the reaction of a diene 1 with an allylic cation (typically 2-oxy­allylic cation 2), although related electrophilic species also react (Scheme [1]).[12]

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Scheme 1 Allylic cations in classical (4+3) cycloadditions of pyrroles

Since pyrroles are more electron-rich compared with furans, they have a characteristically high reactivity for electrophiles. The reactions tend to proceed as substitution reactions rather than additions, to restore aromaticity. When the bond formations are concerted, cycloadditions are more favored.[14] Via a stepwise mechanism, the 2H-­pyrrolium cationic intermediate 4 stabilized by the nitrogen atom is formed, and its aromatization is a major side reaction that produces a Friedel–Crafts substitution product 5 rather than cycloadduct 3.[15]

Allylic cations, oxyallyl cations, and their related electro­philic derivatives are reactive intermediates that have been generated in situ from a variety of precursors, and many react promiscuously with furans as dienes.[12] However, the requirements for reactions with pyrroles are more austere, and the properties of these dienophiles need to be tuned and matched to undergo (4+3) cycloaddition successfully with pyrrole derivatives. The pyrrole electron density can also be tuned and decreased by using N-protecting groups that are more electron-withdrawing.[16]

As in typical (4+3) cycloadditions, pyrrole cycloadditions proceed via endo- and exo-transition states resulting in diastereomeric cycloadducts. Stepwise cycloadditions could generate additional diastereomers, as would the subsequent epimerizations of certain cycloadducts. Cycloadditions of unsymmetrical dienes and dienophiles would encounter issues of regioselectivity. These selectivities could vary depending on the exact reaction conditions.[17] This summary will have remarks on some of these, but due to the brevity of this review, the emphasis will be on reactivity issues, and readers are directed to the primary literature to seek out the details of each reaction of interest.


# 1.2

Formal (4+3) Cycloadditions via Domino Cyclopropanation/Cope Rearrangement Reactions

A very versatile method with wide scope for accomplishing an overall, formal (4+3) cycloaddition is via a domino cyclopropanation/Cope rearrangement involving a vinyl carbene, the most selective and commonly used being a metal carbene, as the dienophile.[18] In this reaction, catalytically generated metal carbenes 6 first cyclopropanate the diene 1, and the resultant cis-1,2-divinylcyclopropane 7 then undergoes a Cope rearrangement to provide a cycloheptadiene 8 via a boat transition state (Scheme [2]). This is a powerful synthetic strategy because of its possibility for ­enantioselection through using chiral auxiliaries or chiral catalysis, and its applicability to a wide range of dienes, including pyrroles. This reaction was developed largely due to the efforts of the Davies group and constitutes one of the most successful methods to access nortropane frameworks.

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Scheme 2 Formal (4+3) cycloadditions of pyrroles via cyclopropanation/Cope rearrangement

This reaction is favored by employing donor-acceptor carbenes generated from rhodium catalysts with comparatively electron-rich ligands. It is also favored by nonpolar reaction media and higher reaction temperatures that prevent bis-cyclopropanation of the pyrrole, to promote the Cope rearrangement instead to complete the cascade reaction.


#
# 2

Unsubstituted Pyrroles as Dienes in (4+3) Cycloadditions

2.1

α-Halo Ketones and α-Haloureas

Monohalogenated ketones engaged in the first reported (4+3) cycloaddition with furan in 1962.[19] α-Halogenated ­ketones generate oxyallylic cations for cycloaddition under basic and/or ionizing conditions, via deprotonation and enolate formation, then dehalogenation. Alternatively, ­enolate-type species like enamines have also been employed as intermediates.

There have only been a few examples of pyrrole derivatives that engaged in (4+3) cycloaddition with α-halo ­ketones. Mann’s early studies showed that α-bromo ketone 9 underwent cycloaddition only with N-ethoxycarbonyl-protected pyrrole to provide a moderate yield of cyclo­adduct 10a (Scheme [3]).[20a] The same reaction with N-methylpyrrole generated the Friedel–Crafts product in 67% yield.

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Scheme 3 (4+3) Cycloaddition of pyrrole with the oxyallyl cation ­derived from 1-bromo-1-phenylpropan-2-one[20a]

In 2006, MaGee and co-workers demonstrated a similar reaction involving bromo ketone 11 bearing a chiral oxa­zolidone auxiliary that underwent (4+3) cycloaddition with N-methoxycarbonyl-protected pyrrole 1a (R1 = CO2Me) via a chiral oxyallylic cation.[20b] The yield was moderate, but the diastereoselectivity was high (Equation 1).

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Equation 1 (4+3) Cycloaddition of methyl 1H-pyrrole-1-carboxylate and a chiral oxyallyl cation derivative[20b]

The Cha group studied the (4+3) cycloaddition of a ­cyclic, allylic cation with N-Boc-protected pyrrole 1b.[21] The reaction of 2-chlorocyclohexanone under basic conditions (Et3N/CF3CH2OH) with 1b resulted in low cycloaddition yields. However, pre-forming the corresponding enamine 13a, and dehalogenating with silver tetrafluoroborate in the presence of 1b generated aza-bridged tricyclic adduct 14a in 52% yield as a single diastereomer (Scheme [4]). Carpenter and co-workers reported another example of this reaction between enamine 13b and N-tosylated pyrrole 1c. The cyclo­adduct 14b thus obtained was converted into 15, a ­recyclable amine capable of mediating the photochemical reduction of CO2.[22]

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Scheme 4 (4+3) Cycloadditions of pyrroles and cyclic oxyallyl ­cations[21] [22]

Kende and Huang generated chiral imine 16 from optically pure (–)-phenethylamine and 3-chloro-3-methyl­butan-2-one; the chiral imine 16 underwent asymmetric (4+3) cycloadditions with N-Cbz-protected pyrrole 1d via chiral 2-aminoallyl cation 17 (Scheme [5]).[23] After hydrolysis, 8-azabicyclo[3.2.1]octanone derivative 18 was obtained with 41% ee, but in a low yield. This reaction was sensitive to the electronic properties of the pyrrole, and attempts to engage N-methylpyrrole 1e resulted only in Friedel–Crafts products in 50–70% yields.

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Scheme 5 (4+3) Cycloadditions of N-Cbz-pyrrole and a chiral α-choro imine[23]

Under similar basic and ionizing conditions, chlorourea 19 is dehydrohalogenated to afford a diaza-oxyallic cation 20 that underwent (4+3) cycloadditions with various dienes, including pyrroles, to generate diazacycloadducts 21 and 22 in high yields (Scheme [6]).[24]

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Scheme 6 (4+3) Cycloadditions of pyrroles with a diaza-oxyallylic cation[24]

# 2.2

α,α′-Polyhalo Ketones

Polybromo and polyiodo ketones under reducing conditions generate oxyallylic cations that undergo (4+3) cyclo­additions.[25] [26] [27] [28] Different reductants afford oxyallylic cations with different counterions, which influence the electronic properties of the resultant cations and their subsequent ­cycloadditions. This is a consequential issue for pyrrole cyclo­additions where the success is quite dependent on electronic factors.

For electron-rich pyrroles such as N-methylpyrrole 1e (Scheme [7]), only the reduction of α,α′-dibromo ketones with NaI/Cu resulted in sodium oxyallylic cations, which are comparatively less electrophilic, that underwent (4+3) cycloaddition to any extent.[29] Other reductive methods that produce iron or zinc oxyallylic cations reacted with 1e to give only Friedel–Crafts products.[30] [31] [32]

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Scheme 7 (4+3) Cycloadditions of N-(electron-rich group)-substituted pyrroles[29] [30] [31]

Pyrroles bearing electron-withdrawing R1 groups on ­nitrogen are less nucleophilic, and (4+3) cycloadditions can proceed with more electrophilic oxyallyl cations generated under a wider range of reducing conditions, including Fe2(CO)9, [25] [33] [34] Zn/Cu,[17,27,28,36] Zn/B(OEt)3,[37] [38] and Et2Zn.[39] [40] The resulting cycloadducts having electron-withdrawing groups on the aza-bridge are also more stable under acidic conditions.[35]

Scheme [8] shows the results of cycloadditions with pyrroles bearing electron-deficient R1 groups.[27] [28] [33] [34] [36] [39] [41] [42] The ranges in yields shown are due to different results ­obtained by different reducing methods. In some cases, the yields varied even by using the same reductive methods, because the reaction conditions were further optimized. For example, Grée and co-workers obtained 30 in only 12% yield following the procedure of Mann and de Almeida ­Barbosa,[39] but they found that the use of excess 29 improved the yield of 30 to 88%.[41]

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Scheme 8 (4+3) Cycloadditions of N-(electron-deficient group)-substituted pyrroles[27] [28] [33] [34] [36] [39] [41] [42]

As the unsubstituted oxyallyl cation without any alkyl groups is too unstable to form, 1,1,3,3-tetrabromoacetone is used as a surrogate to generate the brominated oxyallyl cation 40 for (4+3) cycloadditions (Scheme [9]).[35] [36] Pyrroles bearing different electron-withdrawing N-protecting groups have also proceeded to (4+3) cycloadditions under these conditions. Cycloadduct 41 thus obtained is reductively debrominated to afford desired 8-azabicyclo[3.2.1]octenone 42, a valuable meso intermediate for the synthesis of tropinoids and other natural products.[35] [36] [39] , [43] [44] [45] [46] [47] [48] [49] [50]

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Scheme 9 (4+3) Cycloadditions of pyrroles with 1,1,3,3-tetrabromoacetone[35] [36] [39] , [43] [44] [45] [46] [47] [48] [49] [50]

Starting from meso 42, Mann and de Almeida Barbosa reported a synthetic route to (±)-scopoline (Scheme [10]).[39] The Noyori group converted 42 into (–)-hyoscyamine in 3–4 steps.[35] In 2008, the Perlmutter group enantioselectively desymmetrized 42 in an asymmetric synthesis of the cancer MDR reversal agent, (+)-pervilleine C,[45] and in 2010 Hodgson and co-workers reported a synthesis of (±)-peduncularine from 42.[43]

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Scheme 10 Natural products from a nortropinone precursor[35] [39] [43] [45]

# 2.3

Siloxyallylic Alcohol Derivatives

Namba, Tanino and co-workers designed sulfur- and ­oxygen-substituted siloxyallylic alcohol derivatives 47a and 47b, respectively, to generate heteroatom-stabilized siloxyallylic cations upon acid-induced dehydration (Scheme [11]).[51] [52] N-Acetyl-, N-benzyl-, and N-Cbz-protected, and unprotected pyrroles all failed to undergo cycloaddition; only N-sulfonylated pyrroles reacted, of which the most electron-deficient nosyl-protected 1f reacted with the highest cycloaddition yields. These results suggested that electron-withdrawing effect of the pyrrole protecting group, rather than its steric bulkiness, exerted a greater impact to facilitate the (4+3) cycloaddition.

Siloxyallylic alcohol 55a also underwent a similar (4+3) cycloaddition, showing that sufficient alkyl substitution also stabilized the siloxyallylic cation and promoted its formation.[51] The reaction in dichloromethane proceeded in 54% yield, but increased to generate a 67% yield of the gem-dimethylated 57 in the ionizing solvent hexafluoroisopropanol (HFIP) (Equation 2). However, the monomethylated alcohol 55b failed to undergo cycloaddition under any conditions. These results indicated that a gem-dimethyl group is approximately as effective as a thiomethyl group in stabilizing the 2-siloxyallylic cation 56 for reaction with pyrroles, whereas a single methyl group is not sufficient.

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Scheme 11 (4+3) Cycloadditions of pyrroles with heteroatom-­stabilized siloxyallylic alcohols[51] [52]
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Equation 2 (4+3) Cycloaddition of N-nosylpyrrole with a siloxyallylic alcohol[51]

# 2.4

Siloxyacrolein

2-Siloxyacrolein under acid activation possesses siloxyallylic cation character, and undergoes (4+3) cycloaddition with electron-deficient N-nosylpyrrole 1f (Scheme [12]).[52] The TIPS-derivative 58a reacted with N-nosylpyrrole 1f to afford cycloadduct 59 in excellent yield under protic acid catalysis at room temperature. The more reactive TBS-­siloxyacrolein 58b reacted at lower temperature with 1f with a cycloaddition yield of 94%, consisting of silylated 60a and desilylated cycloadduct 60b.

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Scheme 12 (4+3) Cycloadditions of N-nosylpyrrole and activated ­siloxyacroleins[52]

# 2.5

Allenamides via Epoxidation

The epoxidation of chiral allenamides, and ring opening to generate iminium-stabilized oxyallylic cations for (4+3) cycloaddition has been explored by Hsung and co-workers for the asymmetric synthesis of azabicyclic adducts (Scheme [13]).[53] Again, the use of pyrroles with electron-withdrawing N-protecting groups, such as 1b, was key to a successful cycloaddition, in this case to prevent competitive oxidation of the pyrrole, which was still problematic unless the dimethyldioxirane (DMDO) was added via a syringe pump. The oxyallylic cations thus formed were overall relatively neutral and underwent concerted (4+3) cycloadditions that were endo diastereoselective. A range of chiral auxiliaries on the allenamide were examined. It was found that, while many auxiliaries promoted highly diastereoselective furan (4+3) cycloadditions, only allenamide 61 and that bearing Seebach’s auxiliary reacted to afford cycloadducts 64, 65, and 66 in high diastereoselectivities when a pyrrole was the diene.

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Scheme 13 (4+3) Cycloadditions of pyrroles with iminium-stabilized oxyallyl cations derived from epoxidation of chiral allenamides[53]

Hsung and co-workers also investigated the reaction for allenamide 68 derived from an arylamine (Equation 3).[54] Epoxidation resulted in a nitrogen-stabilized oxyallylic cation 70 that underwent (4+3) cycloaddition with protected pyrrole 1b in moderate yield.

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Equation 3 (4+3) Cycloaddition of N-Boc-pyrrole with an oxyallyl ­cation derived from the epoxidation of an allenamide[54]

# 2.6

Vinylcarbenes as Dienophiles

Davies and co-workers reported the formal (4+3) cyclo­addition of pyrroles to afford nortropanes, through a rhodium vinylcarbene cyclopropanation/Cope rearrangement cascade reaction. The cyclopropanation did not require high temperatures, but nevertheless the reaction was carried out at 50 °C to prevent the bis-cyclopropanation of the pyrrole and encourage the Cope rearrangement to proceed.[55] [56] [57] Both diazo esters and diazo ketones reacted effectively in this formal cycloaddition.

Davies and other groups studied the scope of this reaction for pyrroles (Scheme [14]).[56] [57] [58] [59] [60] Cyclopropanation still failed for electron-rich N-methylpyrrole 1e, but for pyrroles bearing electron-withdrawing protecting groups, such as N-(methoxycarbonyl)pyrrole 1a, rhodium(II) acetate catalyzed decomposition of vinyldiazoester 72 induced the domino reaction and directly provided azabicyclohepta­diene 73. Compound 82 was applied to a racemic synthesis of (±)-scopolamine.[58]

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Scheme 14 Formal (4+3) cycloaddition of pyrroles by a domino cyclopropanation/Cope rearrangement reaction[56] [57] [58] [59] [60]

An asymmetric version of this formal (4+3) cycloaddition by a chiral auxiliary approach was developed by Davies and co-workers.[55] Vinyldiazoesters derived from hydroxy esters (R)-pantolactone or ethyl (S)-lactate as auxiliaries underwent moderately diastereoselective cycloadditions to provide optically enriched azabicyclic products (Scheme [15]). Compound 87a was used in an asymmetric synthesis of (–)-anhydroecgonine methyl ester and (–)-ferruginine.[55]

A catalytic asymmetric formal (4+3) cycloaddition initiated by an asymmetric pyrrole cyclopropanation was also realized by Davies and co-workers using chiral rhodium catalysts.[61] While the degree of enantioselectivity depended on the interaction of between the vinyldiazo precursors and the catalysts, the most successful rhodium catalysts were found to be sterically demanding catalysts such as ­chiral Rh2(PTAD)4 or Rh2(PTTL)4 bearing adamantyl (Ad) and tert-butyl groups respectively, which were found to facilitate high enantiomeric excesses in the cycloadducts (Scheme [16]).

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Scheme 15 Asymmetric formal (4+3) cycloadditions of pyrroles by a chiral auxiliary approach[55]
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Scheme 16 Formal (4+3) cycloadditions of pyrroles mediated by chiral rhodium catalysts[61] [62] [63]

In the landmark total synthesis of the pyrrolidine alkaloid, (+)-batzelladine B, Herzon and co-workers exploited the matched effects of the chiral auxiliary [Xc = (S)-pantolactonyl] and a chiral rhodium catalyst [Rh2(S-PTTL)4] to generate cycloadduct 97 in excellent yield and high ee.[62] The formal cycloaddition was employed as an efficient strategy to set up, in correct absolute configuration, two stereocenters of the pyrrolidine moiety, which was revealed by cleaving the three carbon bridge of 97. Cycloadduct ent-96 obtained from catalysis by Rh2(R-PTTL)4 was similarly used in the follow-up total syntheses of (–)-dehydrobatzelladine C, and (+)-batzelladine K.[63]


#
# 3

C-Substituted Pyrroles as Dienes in (4+3) Cycloadditions

Pyrrole derivatives having C2 to C5 substituents can be considerably more challenging dienes for effective cyclo­additions than the unsubstituted pyrroles. Firstly, the substituents inevitably increase the steric demands of the cyclo­addition transition state. Moreover, substituents also impact on the electron density of the pyrrole, wherein pyrrole (4+3) cycloadditions are particularly sensitive to electronic factors. However, (4+3) cycloadditions which can ­accommodate substituted pyrroles are highly desirable as more complex aza-bridged cycloadducts could be secured.

3.1

α,α′-Polyhalo Ketones

Pyrroles with substituents on the ring were examined for their (4+3) cycloadditions with α,α′-dibromo ketones (Scheme [17]). There are fewer reports of cycloadditions with substituted pyrroles, but under the same conditions, these generally proceeded in lower yields compared with those of the unsubstituted pyrroles (cf. Scheme [7]).[29] For unsymmetrical 2-substituted pyrroles reacting with unsymmetrical oxyallylic cations, the regioselectivity of the cycloaddition varied from 2–4:1. The acetal group was demonstrated to be stable under Et2Zn reducing conditions, and cyclo­adducts such as 103 should offer new opportunities and synthetic applications.[41]

(4+3) Cycloadditions of substituted pyrroles and 1,1,3,3-tetrabromoacetone were also studied.[40] The changes in the electronics of the pyrrole derivatives due to the substituents necessitated more specific reducing conditions and electrophilic requirements of the resultant metal oxyallylic cation. Whereas both Fe2(CO)9 and Et2Zn mediated the (4+3) cycloaddition of unsubstituted pyrroles effectively, only Et2Zn reduction led to acceptable yields of cycloaddition for 2- and 3-substituted pyrroles (Scheme [18]).[40] For comparison, the yields for 107 and 114 were only 15% and 13%, respectively, when mediated by Fe2(CO)9.

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Scheme 17 (4+3) Cycloadditions of substituted pyrroles with α,α′-dibromo ketones[29] [41]
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Scheme 18 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with 1,1,3,3,-tetrabromoacetone[40]

# 3.2

Siloxyallylic Alcohol Derivatives

Sulfur-stabilized siloxyallylic cations generated from ­siloxyallylic alcohols underwent (4+3) cycloadditions with unsubstituted pyrroles in the presence Tf2NH in up to 85% yield.[51] Unfortunately, the scope could not be extended to 2-substituted pyrroles, which reacted to give a 64% yield of the Friedel–Crafts product. However, 3-substituted pyrroles underwent cycloaddition effectively (Scheme [19]), including a 3-bromopyrrole, with the lower yield attributed to the instability of cycloadduct 118 bearing the vinyl bromide functional group.

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Scheme 19 (4+3) Cycloadditions of substituted pyrroles with a sulfur-substituted siloxyallylic alcohol[51]

In contrast, the geminally dialkyl-substituted siloxyallylic cation derived from alcohol 55a underwent cycloaddition successfully with 2-methylpyrrole 119 as a single regio­isomer, albeit in a moderate yield.[51] However, cycloaddition with 3-methylpyrrole 115 was not regioselective, in contrast with the exclusive regioselectivity observed in the cycloaddition that afforded cycloadduct 116 (Scheme [20]).

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Scheme 20 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with dimethyl-substituted siloxyallylic cation[51]

# 3.3

Siloxyacrolein

2-Siloxyacrolein can be activated by a catalytic amount of either Cu(OTf)2 or Sc(OTf)3 to undergo (4+3) cycloadditions with various 2-substituted pyrroles (Scheme [21]).[52] The regioselectivity is typically high and indicative of a stepwise cycloaddition mechanism initiated by bond formation at the less-substituted carbons on both the pyrrole and the activated acrolein, as a concerted cycloaddition would probably favor the minor regioisomer to avoid steric clash between the two incoming substituents. Interestingly, a 2-bromopyrrole also underwent cycloaddition effectively to yield 128 as the sole regioisomer. However the 2-formylpyrrole derivative did not undergo cycloaddition, probably due to it being too electron-deficient.

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Scheme 21 (4+3) Cycloadditions of 2-substituted pyrroles and 2-­siloxyacrolein[52]

# 3.4

Vinylcarbenes as Dienophiles

The formal (4+3) cycloaddition through cyclopropanation/Cope rearrangement as developed by Davies and co-workers has been tremendously successful as applied to pyrroles as dienes.[61] For 2-substituted pyrroles as dienes, the scope remains broad, and the regioselectivities are high, inferring that the cyclopropanation of the unsymmetrically substituted pyrroles was regioselective. Kende and co-workers engaged 2,3-disubstituted pyrrole 130 in a formal (4+3) cycloaddition to secure aza-bridged cycloadduct 131 in excellent yield and as the only regioisomer (Equation 4).[64] This cycloadduct contributed the nortropane framework that eventually culminated in the first total synthesis of (±)-isostemofoline.

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Equation 4 (4+3) Cycloaddition of a 2,3-disubstituted pyrrole leading to a total synthesis of (±)-isostemofoline[64]

Davies and co-workers further demonstrated that the formal (4+3) cycloadditions of 2-, 2,3-, and 2,5-substituted pyrroles provided azabicyclic adducts regioselectively and with excellent enantioselectivities by using chiral rhodium catalyst Rh2(PTAD)4 (Scheme [22]).[61] Quite remarkable is that even a diene as electron-poor as a pyrrole-2-carboxylate also reacted smoothly under these conditions, to provide cycloadduct 136. Clearly, the rhodium-catalyzed cyclopropanation is more lenient on the electron density requirement of the pyrrole as compared to the classical (4+3) cyclo­addition, and this has greatly increased the scope and applications of the intermolecular formal (4+3) cycloaddition. This asymmetric reaction was also applied to pyrrole 130 to provide tropinoid 137 with good ee, intercepting the route of Kende and co-workers to constitute an asymmetric synthesis of isostemofoline.[61]

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Scheme 22 Asymmetric formal (4+3) cycloadditions of substituted pyrroles[61]

#
# 4

Intramolecular Pyrrole (4+3) Cyclo­additions

The intramolecular (4+3) cycloaddition of pyrroles is an ideal strategy to construct tropane-embedded frameworks efficiently. However, there have been only a few reports of intramolecular pyrrole cycloadditions in the literature. Synthetic efforts in this area may be deterred possibly due to the challenges presented by pyrrole (4+3) cycloadditions, and the need to prepare more complex substrates that tether the dienophile precursor to the pyrrole, which necessitates additional synthetic work. As intramolecular cyclo­addition substrates are by nature substituted pyrroles, the tethers would exert both steric and electronic effects. In this connection, studies that have been done have uncovered some surprising results.

The formal (4+3) cycloaddition of pyrroles tethered to a diazo ester was examined by Davies and co-workers.[65] [66] Based on the highly versatile and successful intermolecular reactions, the intramolecular version could be expected to be possibly even more efficient, but this was not the case (Scheme [23]).[65,66] Some diazoesters formed carbenes that then reacted to generate little or none of the expected (4+3) cycloadduct. It was postulated that the tether disfavored ­cyclopropanation and prevented the usual formal (4+3) ­cycloaddition pathway, giving way to the formation of zwitterions instead. However, donor-acceptor carbenes still reacted effectively to afford (4+3) cycloadducts via zwitter­ionic intermediates, to afford 139 as a major product, and quite remarkably, even the anti-Bredt tricyclic adduct 144.

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Scheme 23 Intramolecular formal (4+3) cycloadditions of pyrroles[66]

In 2011, Jeffrey and co-workers described aza-oxyallylic cation formation from the dehydrohalogenation of α-halobenzylhydroxylamines.[67] These dienophiles underwent intermolecular cycloadditions with furans, but this report did not examine the corresponding reaction with pyrroles. In 2013, Jeffrey and co-workers reported an intramolecular version of this cycloaddition that proceeded with a N-substituted pyrrole tethered by the aminoxy bond (Scheme [24]).[68]

Zoom Image
Scheme 24 Intramolecular aza-(4+3) cycloaddition of tethered ­pyrroles[68]

Chiu and co-workers reported that epoxy enolsilanes activated by silyl triflates engaged in (4+3) cycloadditions with dienes, and computations suggested that the activated epoxide, rather than the typical oxyallylic cation, was the dienophile.[69] Consequently, the stereochemistry of the enantiomerically enriched epoxide directed the cycloaddition to afford cycloadducts with retained ee.

While (4+3) cycloaddition did not proceed intermolecularly with pyrroles, the intramolecular reaction generated bicyclic alkaloids with embedded nortropane frameworks efficiently (Scheme [25]).[70] Interestingly, pyrroles bearing a wide range of N-protecting groups, from very electron-­donating to highly electron-withdrawing, all underwent ­effective and diastereoselective cycloadditions. This reaction reliably provided optically enriched aza-polycyclic products from enantiomerically pure epoxy enolsilanes and is superior to a chiral auxiliary approach since the functional groups in the cycloadducts can be readily manipulated or incorporated into syntheses. For example, cycloadduct (–)-160 thus obtained was converted into the pentacyclic substructure of the Type II galbulimima alkaloids.

Namba and co-workers described a clever and concise assembly of an intramolecular (4+3) cycloaddition precursor and its cycloaddition in one-pot cascade that provided a wide variety of polycyclic tropinones (Scheme [26]).[71] Acidic conditions promoted both the in situ intermolecular condensation of a pyrrole derivative bearing a nucleophilic residue with a 2-siloxyacrolein, and its subsequent siloxyallylic cation formation and intramolecular (4+3) cycloaddition, to generate azatricyclic adducts.

Zoom Image
Scheme 25 Intramolecular (4+3) cycloaddition of pyrroles and ­tethered epoxy enolsilanes[70]
Zoom Image
Scheme 26 Condensation and intramolecular (4+3) cycloaddition cascade reactions of N-nosylpyrrole derivatives[71]

Both pyrrolyl alcohols and thiols were effective nucleophiles for the condensation, but pyrrolyl amines failed to react. The ensuing intramolecular (4+3) cycloaddition was remarkably efficient, able to form five-, six-, seven-, and even eight-membered intervening rings. Employing structurally diverse pyrrolyl alcohols produced tricyclic and tetra­cyclic adducts in high yields and as single diastereomers. The cycloaddition was diastereoselective and the use of an optically enriched pyrrolyl alcohol of 85% ee also generated cycloadduct 169 with retained ee and without racemization under the acidic reaction conditions. The nosyl protecting group of the pyrroles appeared to play a vital role, as all other N-protecting groups failed to facilitate this intramolecular (4+3) cycloaddition. Interestingly, allylic ­alcohols, such as 163, were also accommodated, resulting in an excellent yield of cycloadduct 164 bearing a dihydro­pyran moiety.


# 5

Conclusions

This review has summarized all examples reported to date of pyrrole derivatives that reacted as dienes in classical and formal (4+3) cycloadditions to afford nortropane frameworks to show what has been possible for this challenging, but desirable, reaction. The (4+3) cycloadducts have already been applied in a number of natural product synthesis efforts, particularly those of the tropane family.

The examples show that the pyrrole (4+3) cycloaddition posed reactivity problems. Friedel–Crafts products are often the side products arising from either a stepwise cyclo­addition terminated by deprotonation, or the decomposition of the cycloadduct particularly under acidic conditions. The high aromaticity of the pyrrole and also its reactivity as a nucleophile and proneness to oxidation further complicate the design of successful (4+3) cycloadditions. The substituents on the nitrogen and carbon atoms of the pyrrole that impacted the cycloaddition sterically and electronically, limit scope of the reaction.

However, those pyrrole (4+3) cycloadditions that proceeded were generally diastereoselective, and regioselectivity has been observed in many cases of unsymmetrical ­dienophiles undergoing cycloaddition with unsymmetrically substituted pyrroles.

Optically pure nortropane derivatives still remain challenging to secure. Some strategies to overcome this limitation include the subsequent enantioselective desymmetrization of meso aza-bridged cycloadducts. There are only a limited number of (4+3) cycloaddition strategies to directly generate these compounds with high enantioselectivity, which will allow them to be applied to the asymmetric syntheses of alkaloids or drugs. The method that offers the most elegant solution and wide versatility is the chiral ­rhodium-catalyzed formal (4+3) cycloaddition of pyrroles. For the intramolecular reaction, diastereoselective pyrrole (4+3) cycloadditions with enantiomerically enriched epoxy enolsilanes as dienophiles, or optically pure pyrrolyl alcohols as dienes hold promise. Additional strategies to construct aza-polycyclic frameworks by asymmetric (4+3) cyclo­additions of pyrroles is an area that needs further ­efforts and research in the future.


#
#

Acknowledgment

The authors thank Dr. Zengsheng Yin and Mr. Yun He for their suggestions on the preparation of the review.

  • References

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    • 4a Gaedcke F. Arch. Pharm. (Weinheim, Ger.) 1855; 132: 141
    • 4b Pomara C, Cassano T, D’Errico S, Bello S, Romano AD, Riezzo I, Serviddio G. Curr. Med. Chem. 2012; 19: 5647
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  • 17 Rawson DI, Carpenter BK, Hoffmann HM. R. J. Am. Chem. Soc. 1979; 101: 1786

    • For reviews on the cyclopropanation/Cope rearrangement cascade reaction, see ref. 12a and:
    • 18a Cheng Q.-Q, Deng Y, Lankelma M, Doyle MP. Chem. Soc. Rev. 2017; 46: 5425
    • 18b Thumar NJ, Wei QH, Hu WH. Adv. Organomet. Chem. 2016; 66: 33
    • 18c Davies HM. L, Denton JR. Chem. Soc. Rev. 2009; 38: 3061
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  • 22 Richardson RD, Holland EJ, Carpenter BK. Nat. Chem. 2011; 3: 301
  • 23 Kende AS, Huang H. Tetrahedron Lett. 1997; 38: 3353
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    • 25a Cookson RC, Nye MJ, Subrahmanyam G. J. Chem. Soc. C 1967; 473
    • 25b Noyori R, Makino S, Takaya H. J. Am. Chem. Soc. 1971; 93: 1272
  • 26 Hoffmann HM. R, Clemens KE, Smithers RH. J. Am. Chem. Soc. 1972; 94: 3940
  • 27 Montaña AM, Grima PM. Tetrahedron Lett. 2001; 42: 7809
  • 28 Montaña AM, Grima PM. Synth. Commun. 2003; 33: 265
  • 29 Fierz G, Chidgey R, Hoffmann HM. R. Angew. Chem., Int. Ed. Engl. 1974; 13: 410
  • 30 Cowling AP, Mann J. J. Chem. Soc., Perkin Trans. 1 1978; 1564
  • 31 Sarhan AE.-W. A. O. Monatsh. Chem. 1999; 130: 563
  • 32 Only one other successful example for engaging 1a in a (4+3) cycloaddition was with a cyclopropanone, although the yield was not reported: Turro NJ, Edelson SS, Williams JR, Darling TR, Hammond WB. J. Am. Chem. Soc. 1969; 91: 2283
  • 33 Takaya H, Makino S, Hayakawa Y, Noyori R. J. Am. Chem. Soc. 1978; 100: 1765
  • 34 Noyori R, Makino S, Baba Y, Hayakawa Y. Tetrahedron Lett. 1974; 15: 1049
    • 35a Noyori R, Baba Y, Hayakawa Y. J. Am. Chem. Soc. 1974; 96: 3336
    • 35b Hayakawa Y, Baba Y, Makino S, Noyori R. J. Am. Chem. Soc. 1978; 100: 1786
    • 36a Mihovilovic MD, Grötzl B, Kandioller W, Snajdrova R, Muskotál A, Bianchi DA, Stanetty P. Adv. Synth. Catal. 2006; 348: 463
    • 36b Xia Y, Chackalamannil S, Greenlee WJ, Jayne C, Neustadt B, Stamford A, Vaccaro H, Xu X, Baker H, O’Neill K, Woods M, Hawes B, Kowalski T. Bioorg. Med. Chem. Lett. 2011; 21: 3290
  • 37 Reinecke J, Hoffmann HM. R. Chem. Eur. J. 1995; 1: 368
  • 38 Hoffmann HM. R, Iqbal MN. Tetrahedron Lett. 1975; 16: 4487
  • 39 Mann J, de Almeida Barbosa L.-C. J. Chem. Soc., Perkin Trans. 1 1992; 787
  • 40 Kim KD, Park YH. J. Korean Chem. Soc. 1996; 40: 590
  • 41 Paparin J.-L, Crévisy C, Toupet L, Grée R. Eur. J. Org. Chem. 2000; 3909
  • 42 Paparin J.-L, Crévisy C, Grée R. Tetrahedron Lett. 2000; 41: 2343
  • 43 Hodgson DM, Shelton RE, Moss TA, Dekhane M. Org. Lett. 2010; 12: 2834
  • 44 Cramer N, Laschat S, Baro A, Frey W. Synlett 2003; 2175
  • 45 Kulkarni K, Zhao AY, Purcell AW, Perlmutter P. Synlett 2008; 2209
  • 46 Vlahovic S, Schädel N, Tussetschläger S, Laschat S. Eur. J. Org. Chem. 2013; 1580
  • 47 Smits R, Fischer S, Hiller A, Deuther-Conrad W, Wenzel B, Patt M, Cumming P, Steinbach J, Sabri O, Brust P, Hoepping A. Bioorg. Med. Chem. 2014; 22: 804
  • 48 Niethe A, Blechert S. Heterocycles 2007; 74: 803
  • 49 Hodgson DM, Paruch E. Tetrahedron 2004; 60: 5185
  • 50 Affolter O, Baro A, Laschat S, Fischer P. Z. Naturforsch. B 2007; 62: 82
  • 51 Fuchigami R, Namba K, Tanino K. Tetrahedron Lett. 2012; 53: 5725
  • 52 Shibata M, Fuchigami R, Kotaka R, Namba K, Tanino K. Tetrahedron 2015; 71: 4495
  • 53 Antoline JE, Hsung RP, Huang J, Song Z, Li G. Org. Lett. 2007; 9: 1275
  • 54 He S, Hsung RP, Presser WR, Ma Z.-X, Haugen BJ. Org. Lett. 2014; 16: 2180
    • 55a Davies HM. L, Huby NJ. S. Tetrahedron Lett. 1992; 33: 6935
    • 55b Davies HM. L, Matasi JJ, Hodges LM, Huby NJ. S, Thornley C, Kong N, Houser JH. J. Org. Chem. 1997; 62: 1095
  • 56 Davies HM. L, Young WB, Smith HD. Tetrahedron Lett. 1989; 30: 4653
  • 57 Davies HM. L, Saikali E, Young WB. J. Org. Chem. 1991; 56: 5696
  • 58 Nocquet P.-A, Opatz T. Eur. J. Org. Chem. 2016; 1156
  • 59 Riché F, Masri F, Lopez M. Tetrahedron Lett. 2007; 48: 1609
  • 60 Davies HM. L, Saikali E, Huby NJ. S, Gilliatt VJ, Matasi JJ, Sexton T, Childers SR. J. Med. Chem. 1994; 37: 1262
  • 61 Reddy RP, Davies HM. L. J. Am. Chem. Soc. 2007; 129: 10312
  • 62 Parr BT, Economou C, Herzon SB. Nature (London) 2015; 525: 507
  • 63 Economou C, Romaire JP, Scott TZ, Parr BT, Herzon SB. Tetrahedron 2018; 74: 3188
  • 64 Kende AS, Smalley TL, Huang H. J. Am. Chem. Soc. 1999; 121: 7431
  • 65 Davies HM. L, Matasi JJ. Tetrahedron Lett. 1994; 35: 5209
  • 66 Davies HM. L, Matasi JJ, Ahmed G. J. Org. Chem. 1996; 61: 2305
  • 67 Jeffrey CS, Barnes KL, Eickhoff JA, Carson CR. J. Am. Chem. Soc. 2011; 133: 7688
  • 68 Acharya A, Eickhoff JA, Jeffrey CS. Synthesis 2013; 45: 1825
    • 69a Lo B, Lam S, Wong WT, Chiu P. Angew. Chem. Int. Ed. 2012; 51: 12120
    • 69b Krenske EH, Lam S, Ng JP. L, Lo B, Lam SK, Chiu P, Houk KN. Angew. Chem. Int. Ed. 2015; 54: 7422
  • 70 He J, Chen Z, Li W, Low K.-H, Chiu P. Angew. Chem. Int. Ed. 2018; 57: 5253
  • 71 Okamoto T, Shibata M, Karanjit S, Nakayama A, Yoshida M, Namba K. Chem. Eur. J. 2018; 24: 9508

  • References

    • 1a Dias DA, Urban S, Roessner U. Metabolites 2012; 2: 303
    • 1b Shen B. Cell 2015; 163: 1297
    • 1c Bernardini S, Tiezzi A, Laghezza Masci V, Ovidi E. Nat. Prod. Res. 2018; 32: 1926
  • 2 Hesse M. Alkaloids. Nature’s Curse or Blessing? . Wiley-VCH; Weinheim: 2002
    • 4a Gaedcke F. Arch. Pharm. (Weinheim, Ger.) 1855; 132: 141
    • 4b Pomara C, Cassano T, D’Errico S, Bello S, Romano AD, Riezzo I, Serviddio G. Curr. Med. Chem. 2012; 19: 5647
    • 5a Silva GL, Cui B, Cha’vez D, You M, Chai H.-B, Rasoanaivo P, Lynn SM, O’Neill MJ, Lewis JA, Besterman JM. J. Nat. Prod. 2001; 64: 1514
    • 5b Mi Q, Cui B, Lantvit D, Reyes-Lim E, Chai H, Pezzuto JM, Kinghorn AD, Swanson SM. Anticancer Res. 2003; 23: 3607
    • 5c Mi Q, Cui B, Silva GL, Lantvit D, Lim E, Chai H, You M, Hollingshead MG, Mayo JG, Kinghorn AD. Cancer Res. 2001; 61: 4030
    • 6a Ladenburg A. Justus Liebigs Ann. Chem. 1881; 206: 274
    • 6b Ullrich SF, Hagels H, Kayser O. Phytochem. Rev. 2017; 16: 333
    • 7a Mein HF. G. Ann. Pharm. (Lemgo, Ger.) 1833; 6: 67
    • 7b Geiger PL, Hesse H. Ann. Pharm. (Lemgo, Ger.) 1833; 5: 4
  • 8 Corey EJ, Czako B, Kürti L. Molecules and Medicine . John Wiley & Sons; Hoboken: 2007
  • 9 Grynkiewicz G, Gadzikowska M. Pharmacol. Rep. 2008; 60: 439
    • 10a Ritchie E, Taylor WC. In The Alkaloids: Chemistry and Physiology, Vol. 9. Manske RH. F. Academic Press; New York: 1967: 529
    • 10b Irie H, Masaki N, Ohno K, Osaki K, Taga T, Uyeo S. J. Chem. Soc. D 1970; 1066
    • 10c Sakata K, Aoki K, Chang C.-F, Sakurai A, Tamura S, Murakoshi S. Agric. Biol. Chem. 1978; 42: 457
    • 10d Ke C, He ZS, Yang YP, Ye Y. Chin. Chem. Lett. 2003; 14: 173
    • 10e Pilli RA, Ferreira de Oliveira MC. Nat. Prod. Rep. 2000; 17: 117
    • 10f Pilli RA, Rosso GB, Ferreira de Oliveira MC. Nat. Prod. Rep. 2010; 27: 1908
  • 11 For a review on a range of synthetic strategies toward the tropanes, see: Pollini GP, Benetti S, De Risi C, Zanirato V. Chem. Rev. 2006; 106: 2434
  • 13 Lubell W, Saint-Cyr D, Dufour-Gallant J, Hopewell R, Boutard N, Kassem T, Dorr A, Zelli R. In Science of Synthesis Updates . Thieme; Stuttgart: 2013: 157
  • 14 Cramer CJ, Barrows SE. J. Phys. Org. Chem. 2000; 13: 176
  • 15 Cramer CJ, Barrows SE. J. Org. Chem. 1998; 63: 5523
  • 16 Jolicoeur B, Chapman EE, Thompson A, Lubell WD. Tetrahedron 2006; 62: 11531
  • 17 Rawson DI, Carpenter BK, Hoffmann HM. R. J. Am. Chem. Soc. 1979; 101: 1786

    • For reviews on the cyclopropanation/Cope rearrangement cascade reaction, see ref. 12a and:
    • 18a Cheng Q.-Q, Deng Y, Lankelma M, Doyle MP. Chem. Soc. Rev. 2017; 46: 5425
    • 18b Thumar NJ, Wei QH, Hu WH. Adv. Organomet. Chem. 2016; 66: 33
    • 18c Davies HM. L, Denton JR. Chem. Soc. Rev. 2009; 38: 3061
    • 18d Davies HM. L. Tetrahedron 1993; 49: 5203
  • 19 Fort AW. J. Am. Chem. Soc. 1962; 84: 4979
    • 20a Cowling AP, Mann J, Usmani AA. J. Chem. Soc., Perkin Trans. 1 1981; 2116
    • 20b MaGee DI, Godineau E, Thornton PD, Walters MA, Sponholtz DJ. Eur. J. Org. Chem. 2006; 3667
  • 21 Jin S.-j, Choi J.-R, Oh J, Lee D, Cha JK. J. Am. Chem. Soc. 1995; 117: 10914
  • 22 Richardson RD, Holland EJ, Carpenter BK. Nat. Chem. 2011; 3: 301
  • 23 Kende AS, Huang H. Tetrahedron Lett. 1997; 38: 3353
  • 24 Jeffrey CS, Anumandla D, Carson CR. Org. Lett. 2012; 14: 5764
    • 25a Cookson RC, Nye MJ, Subrahmanyam G. J. Chem. Soc. C 1967; 473
    • 25b Noyori R, Makino S, Takaya H. J. Am. Chem. Soc. 1971; 93: 1272
  • 26 Hoffmann HM. R, Clemens KE, Smithers RH. J. Am. Chem. Soc. 1972; 94: 3940
  • 27 Montaña AM, Grima PM. Tetrahedron Lett. 2001; 42: 7809
  • 28 Montaña AM, Grima PM. Synth. Commun. 2003; 33: 265
  • 29 Fierz G, Chidgey R, Hoffmann HM. R. Angew. Chem., Int. Ed. Engl. 1974; 13: 410
  • 30 Cowling AP, Mann J. J. Chem. Soc., Perkin Trans. 1 1978; 1564
  • 31 Sarhan AE.-W. A. O. Monatsh. Chem. 1999; 130: 563
  • 32 Only one other successful example for engaging 1a in a (4+3) cycloaddition was with a cyclopropanone, although the yield was not reported: Turro NJ, Edelson SS, Williams JR, Darling TR, Hammond WB. J. Am. Chem. Soc. 1969; 91: 2283
  • 33 Takaya H, Makino S, Hayakawa Y, Noyori R. J. Am. Chem. Soc. 1978; 100: 1765
  • 34 Noyori R, Makino S, Baba Y, Hayakawa Y. Tetrahedron Lett. 1974; 15: 1049
    • 35a Noyori R, Baba Y, Hayakawa Y. J. Am. Chem. Soc. 1974; 96: 3336
    • 35b Hayakawa Y, Baba Y, Makino S, Noyori R. J. Am. Chem. Soc. 1978; 100: 1786
    • 36a Mihovilovic MD, Grötzl B, Kandioller W, Snajdrova R, Muskotál A, Bianchi DA, Stanetty P. Adv. Synth. Catal. 2006; 348: 463
    • 36b Xia Y, Chackalamannil S, Greenlee WJ, Jayne C, Neustadt B, Stamford A, Vaccaro H, Xu X, Baker H, O’Neill K, Woods M, Hawes B, Kowalski T. Bioorg. Med. Chem. Lett. 2011; 21: 3290
  • 37 Reinecke J, Hoffmann HM. R. Chem. Eur. J. 1995; 1: 368
  • 38 Hoffmann HM. R, Iqbal MN. Tetrahedron Lett. 1975; 16: 4487
  • 39 Mann J, de Almeida Barbosa L.-C. J. Chem. Soc., Perkin Trans. 1 1992; 787
  • 40 Kim KD, Park YH. J. Korean Chem. Soc. 1996; 40: 590
  • 41 Paparin J.-L, Crévisy C, Toupet L, Grée R. Eur. J. Org. Chem. 2000; 3909
  • 42 Paparin J.-L, Crévisy C, Grée R. Tetrahedron Lett. 2000; 41: 2343
  • 43 Hodgson DM, Shelton RE, Moss TA, Dekhane M. Org. Lett. 2010; 12: 2834
  • 44 Cramer N, Laschat S, Baro A, Frey W. Synlett 2003; 2175
  • 45 Kulkarni K, Zhao AY, Purcell AW, Perlmutter P. Synlett 2008; 2209
  • 46 Vlahovic S, Schädel N, Tussetschläger S, Laschat S. Eur. J. Org. Chem. 2013; 1580
  • 47 Smits R, Fischer S, Hiller A, Deuther-Conrad W, Wenzel B, Patt M, Cumming P, Steinbach J, Sabri O, Brust P, Hoepping A. Bioorg. Med. Chem. 2014; 22: 804
  • 48 Niethe A, Blechert S. Heterocycles 2007; 74: 803
  • 49 Hodgson DM, Paruch E. Tetrahedron 2004; 60: 5185
  • 50 Affolter O, Baro A, Laschat S, Fischer P. Z. Naturforsch. B 2007; 62: 82
  • 51 Fuchigami R, Namba K, Tanino K. Tetrahedron Lett. 2012; 53: 5725
  • 52 Shibata M, Fuchigami R, Kotaka R, Namba K, Tanino K. Tetrahedron 2015; 71: 4495
  • 53 Antoline JE, Hsung RP, Huang J, Song Z, Li G. Org. Lett. 2007; 9: 1275
  • 54 He S, Hsung RP, Presser WR, Ma Z.-X, Haugen BJ. Org. Lett. 2014; 16: 2180
    • 55a Davies HM. L, Huby NJ. S. Tetrahedron Lett. 1992; 33: 6935
    • 55b Davies HM. L, Matasi JJ, Hodges LM, Huby NJ. S, Thornley C, Kong N, Houser JH. J. Org. Chem. 1997; 62: 1095
  • 56 Davies HM. L, Young WB, Smith HD. Tetrahedron Lett. 1989; 30: 4653
  • 57 Davies HM. L, Saikali E, Young WB. J. Org. Chem. 1991; 56: 5696
  • 58 Nocquet P.-A, Opatz T. Eur. J. Org. Chem. 2016; 1156
  • 59 Riché F, Masri F, Lopez M. Tetrahedron Lett. 2007; 48: 1609
  • 60 Davies HM. L, Saikali E, Huby NJ. S, Gilliatt VJ, Matasi JJ, Sexton T, Childers SR. J. Med. Chem. 1994; 37: 1262
  • 61 Reddy RP, Davies HM. L. J. Am. Chem. Soc. 2007; 129: 10312
  • 62 Parr BT, Economou C, Herzon SB. Nature (London) 2015; 525: 507
  • 63 Economou C, Romaire JP, Scott TZ, Parr BT, Herzon SB. Tetrahedron 2018; 74: 3188
  • 64 Kende AS, Smalley TL, Huang H. J. Am. Chem. Soc. 1999; 121: 7431
  • 65 Davies HM. L, Matasi JJ. Tetrahedron Lett. 1994; 35: 5209
  • 66 Davies HM. L, Matasi JJ, Ahmed G. J. Org. Chem. 1996; 61: 2305
  • 67 Jeffrey CS, Barnes KL, Eickhoff JA, Carson CR. J. Am. Chem. Soc. 2011; 133: 7688
  • 68 Acharya A, Eickhoff JA, Jeffrey CS. Synthesis 2013; 45: 1825
    • 69a Lo B, Lam S, Wong WT, Chiu P. Angew. Chem. Int. Ed. 2012; 51: 12120
    • 69b Krenske EH, Lam S, Ng JP. L, Lo B, Lam SK, Chiu P, Houk KN. Angew. Chem. Int. Ed. 2015; 54: 7422
  • 70 He J, Chen Z, Li W, Low K.-H, Chiu P. Angew. Chem. Int. Ed. 2018; 57: 5253
  • 71 Okamoto T, Shibata M, Karanjit S, Nakayama A, Yoshida M, Namba K. Chem. Eur. J. 2018; 24: 9508

Zoom Image
Pauline Chiu studied at the University of Toronto, Canada. She ­obtained her M.Sc. degree working on silene chemistry with the late Professor Adrian G. Brook, and her Ph.D. on reactions of oxabicyclic compounds with Professor Mark Lautens. Subsequent to her postdoctoral studies on the total synthesis of gelsemine with Professor Samuel J. Danishefsky at Columbia University, she started her independent ­career at the Department of Chemistry at The University of Hong Kong, where she has been Full Professor since 2011. Efforts in the Chiu group are directed to research on novel synthetic reactions, and total synthesis of natural products. Her co-authors on this paper are Fan Hu and Jerome P. L. Ng, first- and final-year graduate students in the Chiu group.
Zoom Image
Figure 1 Representative tropane alkaloids and natural products with embedded nortropane frameworks
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Scheme 1 Allylic cations in classical (4+3) cycloadditions of pyrroles
Zoom Image
Scheme 2 Formal (4+3) cycloadditions of pyrroles via cyclopropanation/Cope rearrangement
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Scheme 3 (4+3) Cycloaddition of pyrrole with the oxyallyl cation ­derived from 1-bromo-1-phenylpropan-2-one[20a]
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Equation 1 (4+3) Cycloaddition of methyl 1H-pyrrole-1-carboxylate and a chiral oxyallyl cation derivative[20b]
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Scheme 4 (4+3) Cycloadditions of pyrroles and cyclic oxyallyl ­cations[21] [22]
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Scheme 5 (4+3) Cycloadditions of N-Cbz-pyrrole and a chiral α-choro imine[23]
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Scheme 6 (4+3) Cycloadditions of pyrroles with a diaza-oxyallylic cation[24]
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Scheme 7 (4+3) Cycloadditions of N-(electron-rich group)-substituted pyrroles[29] [30] [31]
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Scheme 8 (4+3) Cycloadditions of N-(electron-deficient group)-substituted pyrroles[27] [28] [33] [34] [36] [39] [41] [42]
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Scheme 9 (4+3) Cycloadditions of pyrroles with 1,1,3,3-tetrabromoacetone[35] [36] [39] , [43] [44] [45] [46] [47] [48] [49] [50]
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Scheme 10 Natural products from a nortropinone precursor[35] [39] [43] [45]
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Scheme 11 (4+3) Cycloadditions of pyrroles with heteroatom-­stabilized siloxyallylic alcohols[51] [52]
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Equation 2 (4+3) Cycloaddition of N-nosylpyrrole with a siloxyallylic alcohol[51]
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Scheme 12 (4+3) Cycloadditions of N-nosylpyrrole and activated ­siloxyacroleins[52]
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Scheme 13 (4+3) Cycloadditions of pyrroles with iminium-stabilized oxyallyl cations derived from epoxidation of chiral allenamides[53]
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Equation 3 (4+3) Cycloaddition of N-Boc-pyrrole with an oxyallyl ­cation derived from the epoxidation of an allenamide[54]
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Scheme 14 Formal (4+3) cycloaddition of pyrroles by a domino cyclopropanation/Cope rearrangement reaction[56] [57] [58] [59] [60]
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Scheme 15 Asymmetric formal (4+3) cycloadditions of pyrroles by a chiral auxiliary approach[55]
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Scheme 16 Formal (4+3) cycloadditions of pyrroles mediated by chiral rhodium catalysts[61] [62] [63]
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Scheme 17 (4+3) Cycloadditions of substituted pyrroles with α,α′-dibromo ketones[29] [41]
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Scheme 18 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with 1,1,3,3,-tetrabromoacetone[40]
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Scheme 19 (4+3) Cycloadditions of substituted pyrroles with a sulfur-substituted siloxyallylic alcohol[51]
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Scheme 20 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with dimethyl-substituted siloxyallylic cation[51]
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Scheme 21 (4+3) Cycloadditions of 2-substituted pyrroles and 2-­siloxyacrolein[52]
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Equation 4 (4+3) Cycloaddition of a 2,3-disubstituted pyrrole leading to a total synthesis of (±)-isostemofoline[64]
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Scheme 22 Asymmetric formal (4+3) cycloadditions of substituted pyrroles[61]
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Scheme 23 Intramolecular formal (4+3) cycloadditions of pyrroles[66]
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Scheme 24 Intramolecular aza-(4+3) cycloaddition of tethered ­pyrroles[68]
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Scheme 25 Intramolecular (4+3) cycloaddition of pyrroles and ­tethered epoxy enolsilanes[70]
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Scheme 26 Condensation and intramolecular (4+3) cycloaddition cascade reactions of N-nosylpyrrole derivatives[71]