pyrroles as dienes in (4+3) cycloadditions · where pyrrole derivatives reacted as the diene...

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F. Hu et al. Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2019, 51, 1073–1086short reviewen

Pyrroles as Dienes in (4+3) CycloadditionsFan Hu Jerome P. L. Ng Pauline Chiu* 0000-0001-5081-4756

State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of [email protected]

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

R3Y

R1N

R2

R2

N

R6

R1

R5

Formal

Classical

BocN

OHOH

NsN

O

N

RO2CTBSO

NBoc

NHBoc

N

O CO2Me

O

O

BocN

OTBS

O

O

O

H

H OMe

R3Y

N

R1

R2

R6

M

R5

(4+3) cycloadditions

Received: 24.12.2018
Accepted: 30.12.2018Published online: 06.02.2019DOI: 10.1055/s-0037-1611660; Art ID: ss-2018-z0864-sr
License terms:

Abstract This short review summarizes the examples to date of suc-cessful (4+3) cycloadditions, including formal (4+3) cycloadditions,where pyrrole derivatives reacted as the diene component, to provideaza-bridged bicyclic and polycyclic adducts.1 Introduction2 Unsubstituted Pyrroles as Dienes in (4+3) Cycloadditions3 C-Substituted Pyrroles as Dienes in (4+3) Cycloadditions4 Intramolecular Pyrrole (4+3) Cycloadditions5 Conclusions

Key words (4+3) cycloadditions, pyrroles, oxyallylic cations, tropanes,alkaloids, aza-bridge, cyclopropanation, Cope rearrangement

1 Introduction

Natural products have played a vital role in the historyand discovery of drugs.1 Alkaloids that can be obtained byisolation using acid-base extractions are among the earliestclasses of compounds to be studied and identified from nat-ural sources.2

One class of these ‘true alkaloids’2 are the tropanes,characterized by N-methyl-8-azabicyclo[3.2.1]octaneframeworks (Figure 1), which are among the world’s oldestplant medicines.3 The tropanes were first identified fromtwo plant sources; from the Erythroxylaceae family, towhich the coca plant belongs, was isolated the infamous co-caine.4 The pervilleines are toxic alkaloids isolated from theextracts of the roots of Erythroxylum pervillei that showsmultidrug resistance reversal ability against MDR cancercell lines.5 From the Solanaceae family was isolated manybioactive alkaloids that are powerful anticholinergics. Sco-polamine (Figure 1), also known as hyoscine, was isolatedfrom Hyoscyamus niger and is a sedative and treats nauseaand vomiting.6 Atropine isolated from Atropa belladonna, is

a stimulant and pupil dilator, and is a treatment for brady-cardia (i.e., slow heart rate) and poisoning.7 Both of theseare on the WHO’s Model List of Essential Medicines.

Homatropine methylbromide, and tiotropium bromideare synthetic drugs modelled on the atropine skeleton (Fig-ure 1). The latter was marketed as Spiriva by BoehringerIngelheim for the management of chronic obstructive pul-monary disease.8 There are more than 20 medicines cur-rently in the market with the tropane framework,9 andtherefore it is a highly desirable scaffold from a pharmaco-logical perspective. Tropane alkaloids frameworks are alsoembedded in various natural products, such as himandrineand stemofoline (Figure 1).10

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 postdoc-toral 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 synthe-sis of natural products. Her co-authors on this paper are Fan Hu and Je-rome P. L. Ng, first- and final-year graduate students in the Chiu group.

Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, 1073–1086

http://orcid.org/0000-0001-5081-4756

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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 aretrosynthetic analysis would suggest a (4+3) cycloadditionwith a pyrrole as the diene component, as a convergent andstep-economical assembly of the 8-azabicyclo[3.2.1]octaneframework. Moreover, stereochemically defined, amine-substituted arrays can also be generated from the cleavageof 8-azabicyclo[3.2.1]octene products of pyrrole (4+3)cycloadditions, to exploit the anticipated stereoselectivitygenerally available from cycloaddition reactions.

However, effective (4+3) cycloadditions of pyrrole deriv-atives are considerably more challenging to accomplish, andthere are far fewer examples in the literature compared tothe analogous reactions of furans.12 Pyrroles are more aro-matic, and the tendency toward aromaticity competes withcycloaddition reactions, which are necessarily dearomatiz-ing.13 Moreover, pyrroles are rather reactive towards acids,electrophiles, oxidants, and polymerization, which con-sume the pyrroles from the intended cycloadditions. Final-ly, the pyrrole cycloadducts themselves are also compara-tively less stable and tend to degrade to rearomatized pyr-roles as decomposition products.

Yet, due to the high value of the tropane skeleton, stud-ies on the (4+3) cycloaddition of pyrroles with variousthree-atom dienophiles have continued. Despite the gener-

al incompetence of pyrroles as dienes, there are successfulreports in the literature. This short review aims to summa-rize the range of aza-bridged bicyclic or tricyclic cyclo-adducts that have been obtained from engaging pyrrole de-rivatives as dienes successfully for (4+3) cycloadditions,through various strategies. Efforts and strategies to renderthese (4+3) cycloadditions enantioselective in order to pro-cure enantiomerically enriched nortropane frameworks arealso highlighted.

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

Classical (4+3) cycloadditions generally involve the re-action of a diene 1 with an allylic cation (typically 2-oxy-allylic cation 2), although related electrophilic species alsoreact (Scheme 1).12

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

Since pyrroles are more electron-rich compared withfurans, they have a characteristically high reactivity forelectrophiles. The reactions tend to proceed as substitutionreactions rather than additions, to restore aromaticity.When the bond formations are concerted, cycloadditionsare more favored.14 Via a stepwise mechanism, the 2H-pyrrolium cationic intermediate 4 stabilized by the nitro-gen atom is formed, and its aromatization is a major sidereaction that produces a Friedel–Crafts substitution product5 rather than cycloadduct 3.15

Allylic cations, oxyallyl cations, and their relatedelectrophilic derivatives are reactive intermediates thathave 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 aremore austere, and the properties of these dienophiles needto be tuned and matched to undergo (4+3) cycloadditionsuccessfully with pyrrole derivatives. The pyrrole electrondensity can also be tuned and decreased by using N-pro-tecting groups that are more electron-withdrawing.16

MeN

O

O(−)-scopolamine

O

Ph

OH MeN

O

O

PhMeO2C

(−)-cocaine

N

OH CO2MeOBz

H OMe

H

(−)-himandrine

NO

O

H

OO

MeO

stemofoline

MeN

O

O

O

O

OMe

OMe

OMe(+)-pervilleine C

OMe

OMe

OMe

MeN

O

O

Ph

atropine

Me2N

O

O

Ph

OH

methylhomatropine

Br

Me2N

O

O O

OHS S

tiotropium bromide

OH

Br

N

R2

2

1

N

R1

R2

3

R1

R3

R3

12

3

2

N

R2

4

R3

concertedcycloaddition

stepwisecycloaddition

N

R2

R1

R3

5

O

O

N

R1

R2

R32

O

O

O


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As in typical (4+3) cycloadditions, pyrrole cycloaddi-tions proceed via endo- and exo-transition states resultingin diastereomeric cycloadducts. Stepwise cycloadditionscould generate additional diastereomers, as would the sub-sequent epimerizations of certain cycloadducts. Cycloaddi-tions of unsymmetrical dienes and dienophiles would en-counter issues of regioselectivity. These selectivities couldvary depending on the exact reaction conditions.17 Thissummary will have remarks on some of these, but due tothe brevity of this review, the emphasis will be on reactivi-ty issues, and readers are directed to the primary literatureto seek out the details of each reaction of interest.

1.2 Formal (4+3) Cycloadditions via Domino Cyclo-propanation/Cope Rearrangement Reactions

A very versatile method with wide scope for accom-plishing an overall, formal (4+3) cycloaddition is via a dom-ino cyclopropanation/Cope rearrangement involving a vinylcarbene, the most selective and commonly used being ametal carbene, as the dienophile.18 In this reaction, catalyti-cally generated metal carbenes 6 first cyclopropanate thediene 1, and the resultant cis-1,2-divinylcyclopropane 7then undergoes a Cope rearrangement to provide a cyclo-heptadiene 8 via a boat transition state (Scheme 2). This is apowerful synthetic strategy because of its possibility forenantioselection through using chiral auxiliaries or chiralcatalysis, and its applicability to a wide range of dienes, in-cluding pyrroles. This reaction was developed largely due tothe efforts of the Davies group and constitutes one of themost successful methods to access nortropane frameworks.

Scheme 2 Formal (4+3) cycloadditions of pyrroles via cyclopropana-tion/Cope rearrangement

This reaction is favored by employing donor-acceptorcarbenes generated from rhodium catalysts with compara-tively electron-rich ligands. It is also favored by nonpolar re-action media and higher reaction temperatures that pre-vent bis-cyclopropanation of the pyrrole, to promote theCope rearrangement instead to complete the cascade reac-tion.

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

2.1 -Halo Ketones and -Haloureas

Monohalogenated ketones engaged in the first reported(4+3) cycloaddition with furan in 1962.19 -Halogenatedketones generate oxyallylic cations for cycloaddition underbasic and/or ionizing conditions, via deprotonation andenolate formation, then dehalogenation. Alternatively,enolate-type species like enamines have also been em-ployed as intermediates.

There have only been a few examples of pyrrole deriva-tives that engaged in (4+3) cycloaddition with -haloketones. Mann’s early studies showed that -bromo ketone9 underwent cycloaddition only with N-ethoxycarbonyl-protected pyrrole to provide a moderate yield of cyclo-adduct 10a (Scheme 3).20a The same reaction with N-meth-ylpyrrole generated the Friedel–Crafts product in 67% yield.

Scheme 3 (4+3) Cycloaddition of pyrrole with the oxyallyl cation derived from 1-bromo-1-phenylpropan-2-one20a

In 2006, MaGee and co-workers demonstrated a similarreaction involving bromo ketone 11 bearing a chiral oxa-zolidone auxiliary that underwent (4+3) cycloaddition withN-methoxycarbonyl-protected pyrrole 1a (R1 = CO2Me) viaa chiral oxyallylic cation.20b The yield was moderate, but thediastereoselectivity was high (Equation 1).

Equation 1 (4+3) Cycloaddition of methyl 1H-pyrrole-1-carboxylate and a chiral oxyallyl cation derivative20b

The Cha group studied the (4+3) cycloaddition of acyclic, allylic cation with N-Boc-protected pyrrole 1b.21 Thereaction of 2-chlorocyclohexanone under basic conditions

R2N

R5

M

R4 N

R5

R1

R4

R1

R2+

cyclopropanation

Cope rearrangementN

R1R5

R4

R2

1 6

7

8

910a (34%)

N

CO2Et

Ph

O

N

CO2EtO

Ph

Et3N, MeCNAgBF4

Br

10b, R = Me (45%)

N

EtO2CO

R

10c, R = CH2CH2CH3 (39%)

Ph

O

OTBDPS

O

NO

11

1a

12 (35%, dr > 11:1)

N

CO2Me

Xc

O

Br N

CO2MeO

Xc

Xc =

*

Et3NCF3CH2OH


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(Et3N/CF3CH2OH) with 1b resulted in low cycloadditionyields. However, pre-forming the corresponding enamine13a, and dehalogenating with silver tetrafluoroborate in thepresence of 1b generated aza-bridged tricyclic adduct 14ain 52% yield as a single diastereomer (Scheme 4). Carpenterand co-workers reported another example of this reactionbetween enamine 13b and N-tosylated pyrrole 1c. Thecycloadduct 14b thus obtained was converted into 15, arecyclable amine capable of mediating the photochemicalreduction of CO2.22

Scheme 4 (4+3) Cycloadditions of pyrroles and cyclic oxyallyl cations21,22

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

Under similar basic and ionizing conditions, chlorourea19 is dehydrohalogenated to afford a diaza-oxyallic cation20 that underwent (4+3) cycloadditions with variousdienes, including pyrroles, to generate diazacycloadducts21 and 22 in high yields (Scheme 6).24

2.2 ,′-Polyhalo Ketones

Polybromo and polyiodo ketones under reducing condi-tions generate oxyallylic cations that undergo (4+3) cyclo-additions.25–28 Different reductants afford oxyallylic cationswith different counterions, which influence the electronicproperties of the resultant cations and their subsequentcycloadditions. This is a consequential issue for pyrrolecycloadditions where the success is quite dependent onelectronic factors.

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

Pyrroles bearing electron-withdrawing R1 groups onnitrogen are less nucleophilic, and (4+3) cycloadditions canproceed with more electrophilic oxyallyl cations generatedunder a wider range of reducing conditions, includingFe2(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-withdrawinggroups on the aza-bridge are also more stable under acidicconditions.35

Scheme 8 shows the results of cycloadditions with pyr-roles bearing electron-deficient R1 groups.27,28,33,34,36,39,41,42

The ranges in yields shown are due to different resultsobtained by different reducing methods. In some cases, theyields varied even by using the same reductive methods,because the reaction conditions were further optimized.

N

14a (52%)21

ClCl

ON

Boc

NBoc

O

1b

13a

AgBF4then

NaOH/H2O

N

Cl

OTIPS14b (54%)22

NTs

O

N

Ts

1c

AgBF4

OTIPS

NMe

OMe

13b15

O

Cl

OTIPSthen

NaOH/H2O

Scheme 5 (4+3) Cycloadditions of N-Cbz-pyrrole and a chiral -choro imine23

AgBF4CH2Cl2, rt

NH

16 17

H3O

18(23%, 41% ee)

N

Cbz

N

NH

PhBF4

N

O

CbzCbz

1d

Ph

Cl

N

Ph

Scheme 6 (4+3) Cycloadditions of pyrroles with a diaza-oxyallylic cation24

1921, R1= Boc (82%)22, R1= CO2Me (90%)

N

N N

O

OBnBn

NH

NCl

OBn

O

R1

Bn N NN

R1

OBnO

Bn

20

NaOCH2CF2CHF2

CF2HCF2CH2OHMeCN


1077


For example, Grée and co-workers obtained 30 in only 12%yield following the procedure of Mann and de AlmeidaBarbosa,39 but they found that the use of excess 29 im-proved the yield of 30 to 88%.41

As the unsubstituted oxyallyl cation without any alkylgroups is too unstable to form, 1,1,3,3-tetrabromoacetoneis used as a surrogate to generate the brominated oxyallylcation 40 for (4+3) cycloadditions (Scheme 9).35,36 Pyrrolesbearing different electron-withdrawing N-protectinggroups have also proceeded to (4+3) cycloadditions underthese conditions. Cycloadduct 41 thus obtained is reduc-

tively debrominated to afford desired 8-azabicyclo[3.2.1]oc-tenone 42, a valuable meso intermediate for the synthesis oftropinoids and other natural products.35,36,39,43–50

Starting from meso 42, Mann and de Almeida Barbosareported 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 enantioselectivelydesymmetrized 42 in an asymmetric synthesis of the can-cer MDR reversal agent, (+)-pervilleine C,45 and in 2010Hodgson and co-workers reported a synthesis of (±)-pedun-cularine from 42.43

Scheme 7 (4+3) Cycloadditions of N-(electron-rich group)-substituted pyrroles29–31

Br

O

Br

25 (70%)29

N

MeO

N

MeO

N

R1O

27, R1 = H (65%, dr = 6:1)29

28, R1 = Me (52–89%)29,30

N

Me

23 24 (57%)30

1e

NaI, Cu0

MeCN

O−Na+

N

OOAc

26 (76%)31

Scheme 8 (4+3) Cycloadditions of N-(electron-deficient group)-substituted pyrroles27,28,33,34,36,39,41,42

Br

O

Br

39 (68%)33,3434 (84%, dr >30:1)4133 (12–58%)41

N

CO2MeO

N

AcO

N

R1O

31, R1 = CO2Me (42–88%)27,28,33,36,39,41

32, R1 = Boc (63–69%)41,42

N

R1O

Ph

35, R1 = Boc (76%)41

36, R1 = CO2Me (74%)41

N

R1O

Ph

37, R1 = Boc (51–63%)41,42 38, R1 = CO2Me (77%)41

N

BocO

PhPh

N

CO2Me

29 30 (88%, de = 85%)41

1a

Et2Zn, PhMe

Ph Ph

O

N

Boc

OZnX

Scheme 9 (4+3) Cycloadditions of pyrroles with 1,1,3,3-tetrabromoacetone35,36,39,43–50

O

Br

Br

Br

Br

N

CO2Me

N

CO2MeO

1a

42 (59%)39

Et2Zn, PhH

Zn-Cu

NH4ClMeOH

N

R1O

45, R1 = Ts, (60%)4444, R1 = Boc (24%)49

42, R1 = CO2Me, (25–60%)35–36,40,43–45

43, R1 = Cbz (24–57%)44, 46–48

46, R1 = O

OiPr

(40%)50

N

CO2MeO

Br BrOZnX

Br Br

40 41


1078


Scheme 10 Natural products from a nortropinone precursor35,39,43,45

2.3 Siloxyallylic Alcohol Derivatives

Namba, Tanino and co-workers designed sulfur- andoxygen-substituted siloxyallylic alcohol derivatives 47a and47b, respectively, to generate heteroatom-stabilized siloxy-allylic cations upon acid-induced dehydration (Scheme11).51,52 N-Acetyl-, N-benzyl-, and N-Cbz-protected, and un-protected pyrroles all failed to undergo cycloaddition; onlyN-sulfonylated pyrroles reacted, of which the most elec-tron-deficient nosyl-protected 1f reacted with the highestcycloaddition yields. These results suggested that electron-withdrawing effect of the pyrrole protecting group, ratherthan its steric bulkiness, exerted a greater impact to facili-tate the (4+3) cycloaddition.

Siloxyallylic alcohol 55a also underwent a similar (4+3)cycloaddition, showing that sufficient alkyl substitutionalso stabilized the siloxyallylic cation and promoted its for-mation.51 The reaction in dichloromethane proceeded in54% yield, but increased to generate a 67% yield of the gem-dimethylated 57 in the ionizing solvent hexafluoroisopro-panol (HFIP) (Equation 2). However, the monomethylatedalcohol 55b failed to undergo cycloaddition under any con-ditions. These results indicated that a gem-dimethyl groupis approximately as effective as a thiomethyl group in stabi-lizing the 2-siloxyallylic cation 56 for reaction with pyr-roles, whereas a single methyl group is not sufficient.

Equation 2 (4+3) Cycloaddition of N-nosylpyrrole with a siloxyallylic alcohol51

2.4 Siloxyacrolein

2-Siloxyacrolein under acid activation possesses siloxy-allylic cation character, and undergoes (4+3) cycloadditionwith electron-deficient N-nosylpyrrole 1f (Scheme 12).52

The TIPS-derivative 58a reacted with N-nosylpyrrole 1f toafford cycloadduct 59 in excellent yield under protic acidcatalysis at room temperature. The more reactive TBS-siloxyacrolein 58b reacted at lower temperature with 1fwith a cycloaddition yield of 94%, consisting of silylated 60aand desilylated cycloadduct 60b.

Scheme 12 (4+3) Cycloadditions of N-nosylpyrrole and activated siloxyacroleins52

2.5 Allenamides via Epoxidation

The epoxidation of chiral allenamides, and ring openingto generate iminium-stabilized oxyallylic cations for (4+3)cycloaddition has been explored by Hsung and co-workersfor the asymmetric synthesis of azabicyclic adducts(Scheme 13).53 Again, the use of pyrroles with electron-

(±)-scopoline39

(±)-peduncularine43

N

MeO2CO

N

Me

O

HO

MeN

O

O

O

O

OMe

OMe

OMe(+)-pervilleine C45

OMe

OMe

OMe

MeN

O

O

Ph

OH

(–)-hyoscyamine35

42

NiPr

HN

OTIPS

R OH

NsN

NsN

O

1f

57 (67%)

600 mol%Tf2NHHFIP0 °C

OTIPS

5655a, R = R' = Me55b, R = Me, R' = H

R'

Scheme 11 (4+3) Cycloadditions of pyrroles with heteroatom-stabilized siloxyallylic alcohols51,52

OTIPS

X OH

NsN

NsN

O

1f

49 (58%)51

600 mol%Tf2NHCH2Cl2–78 °C

N

R1O

OTIPS

MeS

48

MeS

50, R1 = Ms (33%)51

51, R1 = Ts (46%)51

47a, X = SMe47b, X = OMe

MeSNsN

OMeS

52 (55%)51

NsN

OMeS

53 (25%)51

NsN

O

54 (76%)52

MeO

O

OTIPS

59 (89%)

60a, R = TBS (78%)60b, R = H (16%)

N

Ns

NsN

O

NsN

O

TIPSO

RO

58a

1f

HO

OTIPS

20 mol%Tf2NH

CH2Cl2, rt

TIPSO

OTIPS

O

OTBS

58b

1f HO

OTBS

10 mol%Tf2NHCH2Cl2

0 °CTBSO

OTBS


1079


withdrawing N-protecting groups, such as 1b, was key to asuccessful cycloaddition, in this case to prevent competitiveoxidation of the pyrrole, which was still problematic unlessthe dimethyldioxirane (DMDO) was added via a syringepump. The oxyallylic cations thus formed were overall rela-tively neutral and underwent concerted (4+3) cycloaddi-tions that were endo diastereoselective. A range of chiralauxiliaries on the allenamide were examined. It was foundthat, while many auxiliaries promoted highly diastereose-lective furan (4+3) cycloadditions, only allenamide 61 andthat bearing Seebach’s auxiliary reacted to afford cycload-ducts 64, 65, and 66 in high diastereoselectivities when apyrrole was the diene.

Hsung and co-workers also investigated the reaction forallenamide 68 derived from an arylamine (Equation 3).54

Epoxidation resulted in a nitrogen-stabilized oxyallylic cat-ion 70 that underwent (4+3) cycloaddition with protectedpyrrole 1b in moderate yield.

Equation 3 (4+3) Cycloaddition of N-Boc-pyrrole with an oxyallyl cation derived from the epoxidation of an allenamide54

2.6 Vinylcarbenes as Dienophiles

Davies and co-workers reported the formal (4+3) cyclo-addition of pyrroles to afford nortropanes, through a rhodi-um vinylcarbene cyclopropanation/Cope rearrangementcascade reaction. The cyclopropanation did not requirehigh temperatures, but nevertheless the reaction was car-

ried out at 50 °C to prevent the bis-cyclopropanation of thepyrrole and encourage the Cope rearrangement to pro-ceed.55–57 Both diazo esters and diazo ketones reacted effec-tively in this formal cycloaddition.

Davies and other groups studied the scope of this reac-tion for pyrroles (Scheme 14).56–60 Cyclopropanation stillfailed for electron-rich N-methylpyrrole 1e, but for pyrrolesbearing electron-withdrawing protecting groups, such asN-(methoxycarbonyl)pyrrole 1a, rhodium(II) acetate cata-lyzed decomposition of vinyldiazoester 72 induced thedomino reaction and directly provided azabicyclohepta-diene 73. Compound 82 was applied to a racemic synthesisof (±)-scopolamine.58

An asymmetric version of this formal (4+3) cycloaddi-tion by a chiral auxiliary approach was developed by Daviesand co-workers.55 Vinyldiazoesters derived from hydroxyesters (R)-pantolactone or ethyl (S)-lactate as auxiliariesunderwent moderately diastereoselective cycloadditions toprovide optically enriched azabicyclic products (Scheme15). Compound 87a was used in an asymmetric synthesis of(–)-anhydroecgonine methyl ester and (–)-ferruginine.55

A catalytic asymmetric formal (4+3) cycloaddition initi-ated by an asymmetric pyrrole cyclopropanation was alsorealized by Davies and co-workers using chiral rhodiumcatalysts.61 While the degree of enantioselectivity depend-ed on the interaction of between the vinyldiazo precursorsand the catalysts, the most successful rhodium catalystswere found to be sterically demanding catalysts such aschiral Rh2(PTAD)4 or Rh2(PTTL)4 bearing adamantyl (Ad) andtert-butyl groups respectively, which were found to facili-tate high enantiomeric excesses in the cycloadducts(Scheme 16).

In the landmark total synthesis of the pyrrolidine alka-loid, (+)-batzelladine B, Herzon and co-workers exploitedthe matched effects of the chiral auxiliary [Xc = (S)-panto-lactonyl] and a chiral rhodium catalyst [Rh2(S-PTTL)4] togenerate cycloadduct 97 in excellent yield and high ee.62

The formal cycloaddition was employed as an efficientstrategy to set up, in correct absolute configuration, two

Scheme 13 (4+3) Cycloadditions of pyrroles with iminium-stabilized oxyallyl cations derived from epoxidation of chiral allenamides53

62 63

1b

64 (93%, dr = 95:5)

67 (86%, dr = 83:17)65 (81%, dr = 95:5) 66 (61%, dr = 95:5)

O N

O

Ph

O

O N

O

Ph

N

Boc

N

OO

N

O

Ph

N

OO

N

O

Ph

Bz

BocNO

O

Ph

DMDO viasyringepump

O

61Ph Ph Ph

Ph

N

OO

N

i-Pr

Boc

OPh

Ph

N

OO

N

i-Pr

CO2Me

OPh

Ph

ZnCl2

DMDOZnCl2

68

1b

71 (50%)

N

Boc

N

OTsN

I

Boc

69 70

NO

N

O

N

Ts

I

Ts Ts


1080


stereocenters of the pyrrolidine moiety, which was revealedby cleaving the three carbon bridge of 97. Cycloadduct ent-96 obtained from catalysis by Rh2(R-PTTL)4 was similarlyused in the follow-up total syntheses of (–)-dehydrobatzel-ladine C, and (+)-batzelladine K.63

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

Pyrrole derivatives having C2 to C5 substituents can beconsiderably more challenging dienes for effective cyclo-additions than the unsubstituted pyrroles. Firstly, the sub-stituents inevitably increase the steric demands of thecycloaddition transition state. Moreover, substituents alsoimpact on the electron density of the pyrrole, wherein pyr-role (4+3) cycloadditions are particularly sensitive to elec-

tronic factors. However, (4+3) cycloadditions which canaccommodate substituted pyrroles are highly desirable asmore complex aza-bridged cycloadducts could be secured.

Scheme 14 Formal (4+3) cycloaddition of pyrroles by a domino cyclopropanation/Cope rearrangement reaction56–60

N2

CO2Etcat. Rh2(OAc)4

1a

7273 (62%)56

78 (54%)56 79, R = CO2Et (71%)56

80, R = H (62%)5774, R = Ph (53%)56

75, R = SO2Ph (61%)56

76, R = H (75%)57

77 (18%)56

N

CO2Me

N

RCO2CH2CH2TMS

N

CO2MeEtO2CEtO2C

N

CO2MeREtO2C

N

CO2EtCO2EtEtO2C

N

CO2MeEtO2C CO2Et

EtO2C

N

CO2Me

EtO2C CO2Et

Ph

85 (73%)57

N

CO2CH2CH2TMSO

83, R = Me (56%)60

84, R = Et (33%)60

N

BocR

O

N

R1MeO2C

OTBS

81, R1 = Boc (77%)59

82, R1 = CO2Me (60%)58

Scheme 15 Asymmetric formal (4+3) cycloadditions of pyrroles by a chiral auxiliary approach55

N2 cat.1b

8687b, Y= OTBS (64%, de = 66%)

N

Boc

N

Boc

N

CO2Me

COXc1

YO

Xc1

Y

Y

87a, Y= H (82%, de = 66%)

88b, Y= OTBS (66%, de = 68%)

N

Boc

88a, Y= H (64%, de = 69%)

Rh2(OOct)4

Xc1=

O (S)(S) CO2Et

Me Xc2=

O(R)(R)

O

O Y

Xc1

O

Xc2

O

Scheme 16 Formal (4+3) cycloadditions of pyrroles mediated by chiral rhodium catalysts61–63

OTBS

CO2Me

N2

1% mol Cat

89

1b

91 (64%, 97% ee)61 92 (68%, 94% ee)61

N

Boc

N

MeO2C BocOTBS

N

MeO2C TolTBSO

N

MeO2C PhOTBS

90 (cat. A: 86%, 92% ee)612,2-dimethylbutane

50 °C

ON

O

Rh

Rh

O

O

R4

cat A= Rh2(S-PTAD)4: R= Ad

(cat. B: 86%, 88% ee)61

cat B= Rh2(S-PTTL)4: R= t-Bu

95, X= OMe (91%, 72% ee)62

N

XOCTBSO

NBoc

NHBoc

96, X= Ot-Bu (71%, 76% ee)62

97, X= Xc (93%, >90% ee)62

93, R= Me (93%, 80% ee)62

N

RO2CTIPSO

NBoc

NHBoc

94, R= Et (45%, 86% ee)62

98, X= ent-Xc (81%, 52% ee)62

ent-96, X= Ot-Bu (88%, 76% ee)63

Xc= O(S)(S)

O

O


1081


3.1 ,′-Polyhalo Ketones

Pyrroles with substituents on the ring were examinedfor their (4+3) cycloadditions with ,′-dibromo ketones(Scheme 17). There are fewer reports of cycloadditions withsubstituted pyrroles, but under the same conditions, thesegenerally proceeded in lower yields compared with those ofthe unsubstituted pyrroles (cf. Scheme 7).29 For unsymmet-rical 2-substituted pyrroles reacting with unsymmetricaloxyallylic cations, the regioselectivity of the cycloadditionvaried from 2–4:1. The acetal group was demonstrated tobe stable under Et2Zn reducing conditions, and cyclo-adducts such as 103 should offer new opportunities andsynthetic applications.41

(4+3) Cycloadditions of substituted pyrroles and 1,1,3,3-tetrabromoacetone were also studied.40 The changes in theelectronics of the pyrrole derivatives due to the substitu-ents necessitated more specific reducing conditions andelectrophilic requirements of the resultant metal oxyallyliccation. Whereas both Fe2(CO)9 and Et2Zn mediated the(4+3) cycloaddition of unsubstituted pyrroles effectively,only Et2Zn reduction led to acceptable yields of cycloaddi-tion for 2- and 3-substituted pyrroles (Scheme 18).40 Forcomparison, the yields for 107 and 114 were only 15% and13%, respectively, when mediated by Fe2(CO)9.

Scheme 17 (4+3) Cycloadditions of substituted pyrroles with ,′-di-bromo ketones29,41

3.2 Siloxyallylic Alcohol Derivatives

Sulfur-stabilized siloxyallylic cations generated fromsiloxyallylic alcohols underwent (4+3) cycloadditions withunsubstituted pyrroles in the presence Tf2NH in up to 85%

yield.51 Unfortunately, the scope could not be extended to2-substituted pyrroles, which reacted to give a 64% yield ofthe Friedel–Crafts product. However, 3-substituted pyrrolesunderwent cycloaddition effectively (Scheme 19), includinga 3-bromopyrrole, with the lower yield attributed to the in-stability of cycloadduct 118 bearing the vinyl bromidefunctional group.

Scheme 19 (4+3) Cycloadditions of substituted pyrroles with a sulfur-substituted siloxyallylic alcohol51

In contrast, the geminally dialkyl-substituted siloxyal-lylic cation derived from alcohol 55a underwent cycloaddi-tion successfully with 2-methylpyrrole 119 as a singleregioisomer, albeit in a moderate yield.51 However, cycload-dition with 3-methylpyrrole 115 was not regioselective, incontrast with the exclusive regioselectivity observed in thecycloaddition that afforded cycloadduct 116 (Scheme 20).

104 (50%, rr = 4:1)41 105 (50%, rr = 2:1)41103 (81%, dr = 93:7)41

NaI, Cu

100 (74%)29

101 (66%)29 102 (50%)29

MeN

Br

O

Br

MeN

O

HN

O

HN

O

N

O

N

OPh

CO2Me MeO2C

N

O

MeO2C

29

O

O

O

O

O

OPh

MeCN

99

Scheme 18 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with 1,1,3,3,-tetrabromoacetone40

Br

Br

O

Br

Br

1. Et2Zn

2. Zn/Cu couple

108, R = TBS (58%)

107 (74%)

114 (69%)

N

CO2Me

N

O

N

O

106 CO2Me

CO2Me

OR

109, R = CO2Et (62%)110, R = COEt (65%)

111, R = TBS (63%)112, R = CO2Et (53%)113, R = COEt (61%)

N

OCO2Me

OR N

O

CO2Me

MeS

OTIPS

OH

47a 116 (71%)

118 (30%)

N

Ns

NsN

OMeS

NsN

O

Br

MeS

Tf2NH, CH2Cl2, –60 °C

NsN

OMeS

117 (0 %)

115


1082


Scheme 20 (4+3) Cycloadditions of 2- and 3-substituted pyrroles with dimethyl-substituted siloxyallylic cation51

3.3 Siloxyacrolein

2-Siloxyacrolein can be activated by a catalytic amountof either Cu(OTf)2 or Sc(OTf)3 to undergo (4+3) cycloaddi-tions with various 2-substituted pyrroles (Scheme 21).52

The regioselectivity is typically high and indicative of astepwise cycloaddition mechanism initiated by bond for-mation at the less-substituted carbons on both the pyrroleand the activated acrolein, as a concerted cycloadditionwould probably favor the minor regioisomer to avoid stericclash between the two incoming substituents. Interestingly,a 2-bromopyrrole also underwent cycloaddition effectivelyto yield 128 as the sole regioisomer. However the 2-formylpyrrole derivative did not undergo cycloaddition,probably due to it being too electron-deficient.

Scheme 21 (4+3) Cycloadditions of 2-substituted pyrroles and 2-siloxyacrolein52

3.4 Vinylcarbenes as Dienophiles

The formal (4+3) cycloaddition through cyclopropana-tion/Cope rearrangement as developed by Davies and co-workers has been tremendously successful as applied topyrroles as dienes.61 For 2-substituted pyrroles as dienes,the scope remains broad, and the regioselectivities are high,inferring that the cyclopropanation of the unsymmetricallysubstituted pyrroles was regioselective. Kende and co-workers engaged 2,3-disubstituted pyrrole 130 in a formal(4+3) cycloaddition to secure aza-bridged cycloadduct 131in excellent yield and as the only regioisomer (Equation4).64 This cycloadduct contributed the nortropane frame-work that eventually culminated in the first total synthesisof (±)-isostemofoline.

Equation 4 (4+3) Cycloaddition of a 2,3-disubstituted pyrrole leading to a total synthesis of (±)-isostemofoline64

Davies and co-workers further demonstrated that theformal (4+3) cycloadditions of 2-, 2,3-, and 2,5-substitutedpyrroles provided azabicyclic adducts regioselectively andwith excellent enantioselectivities by using chiral rhodiumcatalyst Rh2(PTAD)4 (Scheme 22).61 Quite remarkable is thateven a diene as electron-poor as a pyrrole-2-carboxylatealso reacted smoothly under these conditions, to providecycloadduct 136. Clearly, the rhodium-catalyzed cyclopro-panation is more lenient on the electron density require-ment of the pyrrole as compared to the classical (4+3)cycloaddition, and this has greatly increased the scope andapplications of the intermolecular formal (4+3) cycloaddi-tion. This asymmetric reaction was also applied to pyrrole130 to provide tropinoid 137 with good ee, intercepting theroute of Kende and co-workers to constitute an asymmetricsynthesis of isostemofoline.61

TIPSO

OH

(CF3)2CHOH, 0 °C

TIPSO

55a 56

122 (65%, rr = 1:1)

120 (48%)

N

Ns

NsN

O

NsN

O

119

121 (33%)

Tf2NH

NsN

O

I

O

OTBS

124 (84%, rr = 13:1) 125 (59%, rr > 19:1) 126 (93%, rr > 19:1)

127 (38%, rr = 1:0) 128 (88%, rr = 1:0)

N

Ns

NsN

O

TBSO

NsN

O

HOMeO

NsN

O

TBSO

Br

58b

119

NsN

OTBSO

123 (91%, rr = 15:1)

10 mol% Cu(OTf)2

MeNO2, 0 °CO

TBSO

XCu

AcO

NsN

O

TBSO

EtO2C NsN

O

TBSO

I

TBSCl

pyridineDMF

129 (0%)

NsN

O

TBSO

OHC

cat. Rh2(OOct)4

O

O

OMe Nn-Bu

OH

O

(±)-isostemofoline

N

Boc

n-Bu

OMOM

N

Boc CO2Me

OTBS

n-Bu

MOMO

OTBS

N2

CO2Me

89

130

131 (90%)

pentanereflux


1083


Scheme 22 Asymmetric formal (4+3) cycloadditions of substituted pyrroles61

4 Intramolecular Pyrrole (4+3) Cyclo-additions

The intramolecular (4+3) cycloaddition of pyrroles is anideal strategy to construct tropane-embedded frameworksefficiently. However, there have been only a few reports ofintramolecular pyrrole cycloadditions in the literature. Syn-thetic efforts in this area may be deterred possibly due tothe challenges presented by pyrrole (4+3) cycloadditions,and the need to prepare more complex substrates that teth-er the dienophile precursor to the pyrrole, which necessi-tates additional synthetic work. As intramolecular cyclo-addition substrates are by nature substituted pyrroles, thetethers would exert both steric and electronic effects. Inthis connection, studies that have been done have uncov-ered some surprising results.

The formal (4+3) cycloaddition of pyrroles tethered to adiazo ester was examined by Davies and co-workers.65,66

Based on the highly versatile and successful intermolecularreactions, the intramolecular version could be expected tobe possibly even more efficient, but this was not the case(Scheme 23).65,66 Some diazoesters formed carbenes thatthen reacted to generate little or none of the expected (4+3)cycloadduct. It was postulated that the tether disfavoredcyclopropanation and prevented the usual formal (4+3)cycloaddition pathway, giving way to the formation of zwit-terions instead. However, donor-acceptor carbenes still re-acted effectively to afford (4+3) cycloadducts via zwitter-ionic intermediates, to afford 139 as a major product, andquite remarkably, even the anti-Bredt tricyclic adduct 144.

Scheme 23 Intramolecular formal (4+3) cycloadditions of pyrroles66

In 2011, Jeffrey and co-workers described aza-oxyallyliccation formation from the dehydrohalogenation of -halo-benzylhydroxylamines.67 These dienophiles underwent in-termolecular cycloadditions with furans, but this report didnot examine the corresponding reaction with pyrroles. In2013, Jeffrey and co-workers reported an intramolecularversion of this cycloaddition that proceeded with a N-sub-stituted pyrrole tethered by the aminoxy bond (Scheme24).68

Scheme 24 Intramolecular aza-(4+3) cycloaddition of tethered pyrroles68

Chiu and co-workers reported that epoxy enolsilanesactivated by silyl triflates engaged in (4+3) cycloadditionswith dienes, and computations suggested that the activatedepoxide, rather than the typical oxyallylic cation, was thedienophile.69 Consequently, the stereochemistry of the en-antiomerically enriched epoxide directed the cycloadditionto afford cycloadducts with retained ee.

While (4+3) cycloaddition did not proceed intermolecu-larly with pyrroles, the intramolecular reaction generatedbicyclic alkaloids with embedded nortropane frameworksefficiently (Scheme 25).70 Interestingly, pyrroles bearing awide range of N-protecting groups, from very electron-donating to highly electron-withdrawing, all underwenteffective and diastereoselective cycloadditions. This reac-tion reliably provided optically enriched aza-polycyclicproducts from enantiomerically pure epoxy enolsilanes and

133 (69%, 96% ee)

134 (72%, 98% ee) 135 (76%, 91% ee)

N

MeO2C BocTBSO

N

MeO2C BocTBSO

N

MeO2C BocTBSO

OTBS

CO2Me

N2 1 mol% Rh2(S-PTAD)4

2,2-dimethylbutane, 50 °C89

132

N

Boc

N

MeO2C BocTBSO

CO2Me

136 (71%, 89% ee)

N

Boc CO2Me

OTBS

n-Bu

MOMO

137 (79%, 84% ee)

139 (63%)

140 (56%) 141 (32%) 144 (53%)

N

TBSO

O

O

N

BocOTBS

O

O

N

BocOTBS

O

O

N

BocOTBS

O

O

138

BocN

O

O OTBS

N2

Boc

N

BocPhO

O

142, n = 1 (24%)

( )n

143, n = 0 (0%)

Rh2(OOct)4

NN

BocO

O

145 146

147 (85%)

148 (66%, dr = 4:1) 149 (57%, dr = 3:1)

NN

BocO

OCl

NN

BocO

OEt

O

HN

O

Br

BocN

O

N

O

Et3N

(CF3)2CHOHBocN


1084


is superior to a chiral auxiliary approach since the function-al groups in the cycloadducts can be readily manipulated orincorporated into syntheses. For example, cycloadduct (–)-160 thus obtained was converted into the pentacyclic sub-structure of the Type II galbulimima alkaloids.

Namba and co-workers described a clever and conciseassembly of an intramolecular (4+3) cycloaddition precur-sor and its cycloaddition in one-pot cascade that provided awide variety of polycyclic tropinones (Scheme 26).71 Acidicconditions promoted both the in situ intermolecular con-densation of a pyrrole derivative bearing a nucleophilic res-idue with a 2-siloxyacrolein, and its subsequent siloxyallyl-ic cation formation and intramolecular (4+3) cycloaddition,to generate azatricyclic adducts.

Both pyrrolyl alcohols and thiols were effective nucleo-philes for the condensation, but pyrrolyl amines failed toreact. The ensuing intramolecular (4+3) cycloaddition wasremarkably efficient, able to form five-, six-, seven-, andeven eight-membered intervening rings. Employing struc-turally diverse pyrrolyl alcohols produced tricyclic andtetracyclic adducts in high yields and as single diastereo-mers. The cycloaddition was diastereoselective and the useof an optically enriched pyrrolyl alcohol of 85% ee also gen-erated cycloadduct 169 with retained ee and without race-mization under the acidic reaction conditions. The nosylprotecting group of the pyrroles appeared to play a vitalrole, as all other N-protecting groups failed to facilitate thisintramolecular (4+3) cycloaddition. Interestingly, allylicalcohols, such as 163, were also accommodated, resulting inan excellent yield of cycloadduct 164 bearing a dihydro-pyran moiety.

5 Conclusions

This review has summarized all examples reported todate of pyrrole derivatives that reacted as dienes in classicaland formal (4+3) cycloadditions to afford nortropaneframeworks to show what has been possible for this chal-lenging, but desirable, reaction. The (4+3) cycloadductshave already been applied in a number of natural productsynthesis efforts, particularly those of the tropane family.

Scheme 26 Condensation and intramolecular (4+3) cycloaddition cascade reactions of N-nosylpyrrole derivatives71

OTBS

O

58b

163N

OH

164 (quant)

OH

ONs

N

OH ONs

H

H

173 (73%)

N

OH ONs

H

H

174 (88%)

N

OH ONs

H

H

175 (67%)

N

OH ONs

H

H

OMe

176 (91%)

N

OHNs O

165 (51%)

N

OHNs O

167 (76%)

N

OHNs O

168 (44%)

N

OH ONs Ph

169 (50%, 85% ee)

N

OH SNs

172 (93%)

NsN

OTBSO

NsN

OTBS

O

NsN

OH2

10 mol% Tf2NH(CF3)2CHOH

– H2O

N

OH ONs

166 (88%)

N

OH ONs

N

OH ONs

170 (94%) 171 (90%)

Scheme 25 Intramolecular (4+3) cycloaddition of pyrroles and tethered epoxy enolsilanes70

Boc

1. 10 mol% TESOTf, –78 °C

150 (94% ee)151

(77%, dr = 11:1, 94% ee)

154, R1 = trisyl (85%, dr > 25:1)

158 (41%, dr > 25:1)

162 (75%, dr > 25:1)161 (87%, dr = 4:1)

BocN N

BocO

HOH

N

BocOHO

N

BocO

HOH

N

BocO

HOH

N

OHO

H

N

R1OHO

H

OOTES

2. Et3N-3HF

152, R1 = Ns (75%, dr = 19:1)

155, R1 = Cbz (85%, dr = 8:1)

153, R1 = Ts (76%, dr > 25:1)

156, R1 = Bn (60%, dr > 25:1)157, R1 = Me (82%, dr > 25:1)

N

BocO

HOH

TBDPSO

(–)-160 (51%, dr = 5:1, 97% ee)

BocN

OOTESTES

159 (74%, dr > 25:1)


1085


The examples show that the pyrrole (4+3) cycloadditionposed reactivity problems. Friedel–Crafts products are of-ten the side products arising from either a stepwise cyclo-addition terminated by deprotonation, or the decomposi-tion of the cycloadduct particularly under acidic conditions.The high aromaticity of the pyrrole and also its reactivity asa nucleophile and proneness to oxidation further compli-cate the design of successful (4+3) cycloadditions. The sub-stituents on the nitrogen and carbon atoms of the pyrrolethat impacted the cycloaddition sterically and electronical-ly, limit scope of the reaction.

However, those pyrrole (4+3) cycloadditions that pro-ceeded were generally diastereoselective, and regioselectiv-ity has been observed in many cases of unsymmetricaldienophiles undergoing cycloaddition with unsymmetri-cally substituted pyrroles.

Optically pure nortropane derivatives still remain chal-lenging to secure. Some strategies to overcome this limita-tion include the subsequent enantioselective desymmetri-zation of meso aza-bridged cycloadducts. There are only alimited number of (4+3) cycloaddition strategies to directlygenerate these compounds with high enantioselectivity,which will allow them to be applied to the asymmetric syn-theses of alkaloids or drugs. The method that offers themost elegant solution and wide versatility is the chiralrhodium-catalyzed formal (4+3) cycloaddition of pyrroles.For the intramolecular reaction, diastereoselective pyrrole(4+3) cycloadditions with enantiomerically enriched epoxyenolsilanes as dienophiles, or optically pure pyrrolyl alco-hols as dienes hold promise. Additional strategies to con-struct aza-polycyclic frameworks by asymmetric (4+3)cycloadditions of pyrroles is an area that needs furtherefforts and research in the future.

Funding Information

Funding support from the State Key Laboratory of Synthetic Chemis-try, and the University of Hong Kong are gratefully acknowledged.

Acknowledgment

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

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pyrroles as dienes in (4+3) cycloadditions · where pyrrole derivatives reacted as the diene...

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