Stereoselective intramolecular cyclopropanation through catalytic olefin activation

Article abstract of DOI:10.1039/c2sc21914j

A novel stereoselective and convergent catalytic method for the cyclopropanation of electron-neutral and -rich olefins by sulfonium ylides is reported which unusually proceeds through olefin activation rather than by metal carbene formation.

Full text of DOI:10.1039/c2sc21914j

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Stereoselective intramolecular cyclopropanation
through catalytic olefin activation†
Cite this: DOI: 10.1039/c2sc21914j
a
a
b
a
*
´
Xueliang Huang, Sebastian Klimczyk, Luıs F. Veiros and Nuno Maulide
Received 5th November 2012
Accepted 3rd December 2012
A novel stereoselective and convergent catalytic method for the cyclopropanation of electron-neutral and
-rich olefins by sulfonium ylides is reported which unusually proceeds through olefin activation rather than
by metal carbene formation.
DOI: 10.1039/c2sc21914j
www.rsc.org/chemicalscience
The direct cyclopropanation of olens is an important and with the aliphatic alkyne 2. Much to our surprise, spectroscopic
valuable transformation in organic synthesis from a laboratory characterisation showed this side product to be the bicyclo
scale up to industrial production, as cyclopropanes are common [3.1.0]hexane 4a (Scheme 2).8 Furthermore, compound 4a
structural features of both naturally occurring and non-natural became the sole product of reaction when the alkyne reagent
bioactive substances.1 Olen cyclopropanation is dominated by was omitted. Herein, we report on the development of this
the chemistry of diazo compounds, which can be decomposed initial observation into a mechanistically unusual approach to
by specic transition metals (commonly rhodium, ruthenium, stereoselective, convergent cyclopropanation.9,10
palladium, iridium or copper) to produce metallocarbene
As depicted in Scheme 3, a variety of different ester and
complexes in situ.2 These metallocarbenes are mild and selec- ketone moieties are compatible with the reaction conditions
tive cyclopropanating agents and perform best with electron- (100 ꢀC in 1,2-dichloroethane), leading to the corresponding
rich or -neutral olenic partners (Scheme 1a).
bicyclic lactones in high yields.11 Interestingly, the ylides
In contrast, the cyclopropanation of electron-poor alkenes is derived from b-ketoesters required longer reaction times to
the province of sulfonium and sulfoxonium ylide chemistries,3 reach full conversion than those derived from malonate scaf-
and the classic Corey–Chaykovsky reaction4 is still the synthetic folds (cf. 4e–p vs. 4a–d). This may be connected to a lower
benchmark when electronically decient olens are considered nucleophilicity (due to better formal negative charge delocali-
(Scheme 1b).
sation) of the former compounds. Diverse aryl-substituted
During our recent studies on the gold-catalysed rearrange- ketones ranging from electron-poor to electron-rich (cf. 4f–n),
ment of sulfonium ylides bearing an allyloxycarbonyl moiety,5,6 including naphthoyl- and heteroaryl-substrates (cf. 4o–p) were
we noticed the formation of signicant amounts of an tolerated. It should be noted that sulfonium ylides derived from
unidentied by-product in the reaction of sulfonium ylide 17 arylketones bearing ortho-aromatic substituents led to much
slower conversions, indicating that this system is sensitive to
steric effects (cf. 4i). Nevertheless, a solvent change was suffi-
cient to produce cyclopropane 4i in very good yield. Moreover, a
bicyclo[4.1.0]heptane 4q,12 resulting from six-membered ring
formation, could be obtained in good yield. Importantly, the
catalyst loading can be lowered down to 1 mol% without any
impact on the yield (cf. 4f), a potentially valuable observation for
larger-scale transformations.
In addition (Scheme 4), substitution of the olen is broadly
Scheme 1 General approaches for the synthesis of cyclopropanes.
tolerated allowing the generation of two quaternary centers
a
¨
¨
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 145470, Mulheim an
der Ruhr, Germany. E-mail: maulide@mpi-muelheim.mpg.de; Fax: +49-208-3062999;
Tel: +49-206-3062450
b
´
´
Centro de Quımica Estrutural, Complexo I, Instituto Superior Tecnico, Universidade
´
Tecnica de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal
† Electronic supplementary information (ESI) available. CCDC 885364. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2sc21914j
Scheme 2 The reaction of ylide 1 with aliphatic alkyne 2 and the discovery of a
gold-catalysed cyclopropanation of sulfonium ylides.
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Scheme 5 Gold-catalyzed cyclopropanation of carbon- and nitrogen-based
tethers.a
positions of the allylic system leads to densely functionalised
bicyclolactones bearing up to three congested stereocenters in
high yield and diastereoselectivity (cf. 4w).
We then sought to extend this transformation to other types
of rings and probed fully carbon-based systems or amide-con-
taining tethers, as shown in Scheme 5. In the event, a range of
cyclopentane and g-lactam derivatives could be obtained in
good to very good yields. The importance of these products is
documented by the reported transformation of 6c into a
powerful analogue of Atipamezole, a synthetic a2-adrenergic
antagonist.13,14 It is interesting to note that when 6c was
Scheme 3 Substrate scope for the gold-catalyzed cyclopropanation towards
bicyclic lactones.a
(cf. 4r–s). Particularly interesting is the very high stereoselectivity
observed when a (1-alkyl)allylic ester is employed, as the products
are formed in a larger than 12 : 1 ratio of diastereoisomers. The
relative stereochemical conguration was elucidated by X-ray
crystallography (cf. 4t, 4u–v). Simultaneous substitution at two
prepared by
a diazo-mediated, rhodium-catalysed cyclo-
propanation, a slightly lower yield of 76% for the product as well
as a ca. 10% of a formal C–H insertion adduct were obtained.13
In the present reaction, the cyclopropanated 6c was the only
detected product, an observation with mechanistic conse-
quences (vide infra). It is of note that all transformations
depicted in Scheme 5 proceed to completion in short reaction
times (<5 h).
Scheme 6 Unexpected regio- and stereoconvergence upon gold-catalysed
Scheme 4 Cyclopropanation of sulfonium ylides with substituted double bonds.
cyclopropanation of sulfonium ylides with terminal double-bond substituents.
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Scheme
7
Control experiments for gold- and rhodium-catalysed
cyclopropanation.
Scheme 8 Calculated cyclopropanation mechanism for the formation of bicyclic
lactone 4e.
During our study of the cyclopropanation of substituted
allylic tethers, we observed that the gold-catalysed trans-
formation of “linear” allylic ester 8a led to a single bicyclo-
lactone product. Surprisingly, this was not the anticipated
cyclopropane 4t0 but rather its isomer 4t, the same product that
we had already obtained through cyclopropanation of the
“branched” isomer of 8a (Scheme 6a; cf. Scheme 4).
This intriguing observation prompted us to examine the
cyclopropanation of both the (E)- and (Z)-isomers of the linear
ester 8b. As depicted, regardless of the double-bond geometry of
the starting material, the same bicyclo[3.1.0]lactone product is
obtained, in similarly high 17 : 1 diastereomeric ratio (Scheme
6b). The cyclopropanation protocol described herein is there-
fore an unusual regio- and stereoconvergent transformation.15
Control experiments aimed at probing the intermediacy of a
gold carbene complex are depicted in Scheme 7. The decom-
position of diazo reagent 9a by Rh2(OAc)4 under standard
conditions led to the endo-cyclopropane 10 in a stereospecic
manner,16 as is well-established for rhodium carbene chemistry.
In contrast, the treatment of 9a by the catalyst employed in our
studies, which can be expected to mediate formation of a
transient gold carbene,17 led to complete degradation of the
starting material and no products of cyclopropanation (neither
10 nor isomers thereof) were observed.
The decisive piece of evidence comes from examination of a
prior report on oxidative cyclopropanation8n that proceeds
through gold carbene intermediates. As shown in Scheme 7c, in
that work it was conclusively shown that the conformational
properties of an a-allyloxycarbonyl gold carbene10d such as 11
render it virtually ineffective towards the tethered alkene
moiety. In the event, intermediate 11 prefers to undergo inter-
molecular insertion into the O–H bond of MsOH to generate
linear product 12. This strongly suggests that the >20 different
successful cyclopropanations depicted in Schemes 3 and 4 do
not result from a gold carbene intermediate, pointing towards
an entirely different mechanism of action of the gold catalyst in
the chemistry reported herein.18 Indeed, it is apparent that
this cyclopropanation rather proceeds via olen activation by
the metal catalyst followed by internal attack by the sulfonium
cyclopropanation, unveiling a type of reactivity that could lead
to interesting ramications.
The catalytic cycle was further investigated by DFT compu-
tational methods.19,20 Formation of lactone 4e was used for the
computational studies and in the catalyst model the ligand is
L ¼ PPh3. The calculated path is depicted in Scheme 8 in a
simplied way, and the complete energy prole is presented as
ESI (Fig. S1†).
As depicted, the reaction starts with the activation of the allylic
moiety by the cationic Au(I),21,22 through coordination of the C]C
double bond to the metal, in intermediate A. Nucleophilic attack
of the ylidic C-atom on the internal carbon of the coordinated
olen leads to formation of the lactone ring concomitantly with
generation of a Au(I)–alkyl complex (cf. intermediate B). In the
second part of the mechanism, a nucleophilic attack of the
coordinated C-atom onto the carbon bearing the SPh2 substit-
uent takes place, resulting in the closure of the cyclopropane ring
and loss of diphenyl sulde (cf. conversion of B to C). In C, the
product, 4e, is weakly bonded to the metal through a C–C s bond
23
˚
(dAu–C ¼ 2.55 and 2.59 A ). As a consequence of coordination,
that particular C–C bond is signicantly longer in C (dC–C ¼ 1.59
˚
˚
A) than in free lactone 4e (dC–C ¼ 1.52 A). The catalytic cycle is
closed by a ligand exchange reaction, with release of the product,
4e, and addition of a new substrate molecule, 1e.
Scheme 9 Complementary gold-catalysed approaches to cyclopropanation of
ylide moiety. This is a conceptually novel approach to olen enynes requiring an external oxidant.
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All steps of the calculated mechanism are thermodynami-
cally favorable, and the rate limiting step corresponds to lactone
ring formation (from A to B) with a barrier 4.2 kcal molꢁ1 higher
than the one calculated for cyclopropanation and SPh2 loss.
It is instructive to compare the procedure reported herein
with other approaches to similar structures that employ enynes
as starting materials (Scheme 9). In those latter cases, palla-
dium(II)8f–i or gold(I)8m,n catalysis (Scheme 9a and b) trigger an
oxidative cycloisomerisation which typically requires an excess
of external oxidant. In the process that we have developed, the
ylide moiety acts as a formal internal oxidant and no additional
reagents are needed.
In addition, the starting ylides are generally very easily
handled, indenitely stable crystalline compounds which are
clearly safer to process and store than the classically used, toxic
and hazardous diazo derivatives. Although the use of sulfonium
ylides is less atom-economical in a strict sense,24 the easily
separable by-product diphenyl sulde in these cyclo-
propanations is actually the starting material for the prepara-
tion of the ylide transfer reagent Martin's sulfurane.25 This has
obvious implications if one considers large-scale applications.
Importantly, the advent of direct ylide transfer methodologies
as alternatives to the well-known diazo-transfer means that the
step count on both sequences is identical.
In summary, we have developed a gold-catalysed cyclo-
propanation of electron neutral olens by sulfonium ylides.
This process allows direct access to functionalised bicyclic
products and employs stable, readily available and easily
handled ylidic substrates, thus providing an interesting
alternative to the hazardous and potentially explosive diazo
derivatives. The cyclopropane products obtained are formed
with high diastereoselectivity and the transformation displays
remarkably high regio- and stereoconvergent behaviour. Most
importantly, mechanistic studies supported by DFT calcula-
tions demonstrate that this novel cyclopropanation proceeds
by an unusual olen activation, followed by two consecutive
intramolecular C–C bond formations. The notion that cyclo-
propanation can be triggered by addition of a suitable
nucleophile to a gold-activated olen is most intriguing and
further studies aimed at the development of this concept are
underway.
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Planck-Institut fur Kohlenforschung for generous funding of
our research programs. This work has been supported by the
Deutsche Forschungsgemeinscha (Grant MA-4861/4-1), and
~
ˆ
the Fundaçao para a Ciencia e Tecnologia (PEst-OE/QUI/
UI0100/2011 and PTDC/QUI-QUI/099389/2008).
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.
ˇ´
´
´
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~
(g) A. Iglesias and K. Muniz, Chem.–Eur. J., 2009, 15, 10563;
(h) R. L. LaLonde, Jr, W. E. Brenzovich, D. Benitez, 23 These values may be compared with the distances of the
E. Tkatchouk, K. Kelley, W. A. Goddard III and F. D. Toste,
Chem. Sci., 2010, 1, 226; (i) H. Li, F. Song and
R. A. Widenhoefer, Adv. Synth. Catal., 2011, 353, 955; (j)
olen C-atoms coordinated to the metal in A (dAu–C ¼ 2.28
˚
and 2.35 A) and with the Au–C bond length in the alkyl
˚
complex B (2.09 A).
Y.-P. Xiao, X.-Y. Liu and C.-M. Che, Angew. Chem., Int. Ed., 24 B. M. Trost, Science, 1991, 254, 1471.
2011, 50, 4937; (k) O. Kanno, W. Kuriyama, Z. J. Wang and 25 J. C. Martin, R. J. Arhart, J. A. Franz, E. F. Perozzi and
F. D. Toste, Angew. Chem., Int. Ed., 2011, 50, 9919.
L. J. Kaplan, Org. Synth., 1977, 57, 22.
Chem. Sci.
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