Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
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 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 ]
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 ]
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 ]
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.
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.
Unsubstituted Pyrroles as Dienes in (4+3) Cycloadditions
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.
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 = CO2 Me) via a chiral oxyallylic cation.[20b ] The yield was moderate, but the diastereoselectivity was high (Equation 1).
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 (Et3 N/CF3 CH2 OH) 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 ]
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.
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 ]
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 ]
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 Et2 Zn.[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 ]
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 ]
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 ]
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.
Scheme 11 (4+3) Cycloadditions of pyrroles with heteroatom-stabilized siloxyallylic alcohols[51 ]
[52 ]
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 .
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.
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.
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 ]
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 ]).
Scheme 15 Asymmetric formal (4+3) cycloadditions of pyrroles by a chiral auxiliary approach[55 ]
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 ]
C-Substituted Pyrroles as Dienes in (4+3) Cycloadditions
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 Et2 Zn 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 Et2 Zn mediated the (4+3) cycloaddition of unsubstituted pyrroles effectively, only Et2 Zn 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 .
Scheme 17 (4+3) Cycloadditions of substituted pyrroles with α,α′-dibromo ketones[29 ]
[41 ]
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 Tf2 NH 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.
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 ]).
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.
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.
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 ]
Scheme 22 Asymmetric formal (4+3) cycloadditions of substituted pyrroles[61 ]
Intramolecular Pyrrole (4+3) Cycloadditions
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 .
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 ]
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.
Scheme 25 Intramolecular (4+3) cycloaddition of pyrroles and tethered epoxy enolsilanes[70 ]
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.
