Enantioselective Assembly of Congested Cyclopropanes using Redox-Active Aryldiazoacetates

Article abstract of DOI:10.1021/acscatal.9b02615

The enantioselective assembly of quaternary stereocenters through sequential functionalization of versatile carbon-atom precursors has the potential to systematize the synthesis of these ubiquitous stereogenic elements. Herein, we report two catalytic processes that allow the realization of this concept in the enantioselective synthesis of cyclopropanes. We demonstrate that C-H functionalization, carbene-transfer, and decarboxylative cross-coupling can sequentially take place in the same carbon atom to obtain highly enantioenriched cyclopropane products. The reactions reported herein give access to redox-active analogues of privileged aryldiazoacetates and demonstrate their enantioselective carbene transfer with a simple and practical rhodium catalyst.

Full text of DOI:10.1021/acscatal.9b02615

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Letter
Enantioselective Assembly of Congested
Cyclopropanes using Redox-Active Aryldiazoacetates
Zhunzhun Yu, and Abraham Mendoza
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02615 • Publication Date (Web): 26 Jul 2019
Downloaded from pubs.acs.org on July 26, 2019
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Enantioselective Assembly of Congested Cyclopropanes using
Redox-Active Aryldiazoacetates
Zhunzhun Yua and Abraham Mendozaa,*
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Dept. of Organic Chemistry, Stockholm University, Arrhenius laboratory 106 91 Stockholm (Sweden)
ABSTRACT: The enantioselective assembly of quaternary stereocenters through sequential functionalization of versatile carbon-
atom precursors has the potential to systematize the synthesis of these ubiquitous stereogenic elements. Herein, we report two catalytic
processes that allow the realization of this concept in the enantioselective synthesis of cyclopropanes. We demonstrate that C–H
functionalization, carbene-transfer and decarboxylative cross-coupling can sequentially take place in the same carbon atom to obtain
highly enantioenriched cyclopropane products. The reactions reported herein give access to redox-active analogs of privileged
aryldiazoacetates and demonstrate their enantioselective carbene transfer with a simple and practical rhodium catalyst.
KEYWORDS: Asymmetric catalysis, C–H arylation, Cyclopropanes, Quaternary centers, Carbenes.
Chemoselective methods that evade protecting group
manipulations1 have significantly simplified synthesis,2 and
enabled relevant applications in bio-orthogonal coupling and
ester moiety, which can undergo oxidative addition and/or
single electron transfer with palladium intermediates through
its activated N–O bond.9 Even after successful arylation, the
3
chemical biology.1, While chemoselective manipulations in
electron-rich
redox-active
diazocompounds
3
are
poly-functional molecules have been extensively developed,1-3
the orthogonal functionalization of a single carbon atom has
proven more challenging due to the easier mutual interference
stereoelectronically distinct from 1h, and would require specific
developments to achieve high turnover and enantioselectivity in
cyclopropanation reactions. Evaluation of current arylation and
4
of reactive handles upon co-localization.3c, To address this
challenge, functionalized carbene and carbyne equivalents 1a-c
have been explored (Scheme 1A), but taming their extreme
reactivity still requires static substituents (EWG, R, R') that
remain in the resulting products.3c, 4a-h,s,t Other carbon precursors
such as haloforms and their derivatives (1d,e) are yet unsuitable
for enantioselective catalysis,4i-l and those with organozinc and
organoboron manifolds are yet confined to the asymmetric
synthesis of tertiary stereocenters (1f,g).4m-r
Recently, our group has reported on the orthogonality of
redox-active esters towards carbene-transfer, using the
diazoacetate
reagent
NHPI-DA
(1h;
NHPI,
N-
hydroxyphtalimide).5 Despite the versatility demonstrated in
the asymmetric synthesis of cyclopropanes, the carbene transfer
of 1h was limited to products with tertiary stereocenters.5
Overcoming this limitation would enable a systematic and
enantioselective assembly of congested cyclopropanes,6 using
their quaternary carbon6f-i, 7 as the key connective unit (Scheme
1B). If the functionalization of the C–H bond in 1h could be
orthogonal to the existing diazo and redox-active ester groups,
it could enable a rapid entry into more complex redox-active
diazocompounds (i.e. 3). In principle, enantioselective
cyclopropanation with these reagents would deliver enantiopure
cyclopropane intermediates 5, direct precursors of a wide range
of densely-functionalized products 6. In particular, the C–H
arylation of 1h is an attractive entry into redox-active analogs
of privileged aryldiazoesters (3).4b-h However, the arylation of
diazocompounds is an inherently challenging transformation
due to the competitive formation of metal carbenes.8 In this
case, the reaction is further complicated by the redox-active
Scheme 1. Background, approach and initial evaluation. EWG =
CO(2)R, PO(OR)2, SO3R, CF3; NHPI, N-hydroxyphtalimide.
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cyclopropanation methods showcased their unsuitability for this
purpose (Scheme 1C). The redox-active diazocompound 1h
extensively decomposes under the arylation conditions that are
efficient with conventional diazoesters.10 Also, the resulting
aryldiazocompound 3a was found to be much less reactive than
1h in cyclopropanation reactions, even towards activated
styrene substrates such as 4a.5
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reaction can be utilized in the late-stage modification of
biomolecules and their conjugates. For example, we could
obtain the redox-active diazocompound derived from
iodophenylalanine (3ab) in high enantiomeric purity.
Moreover, peptide and steroid conjugates (3ac,ad) could also
be functionalized with the potent redox-active diazoacetate
moiety to enable further coupling reactions. This adds to the
value of these compounds in medicinal chemistry particularly
to construct fluorinated scaffolds (3d,i,s,t).
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Table 1. Optimization of the C–H arylation of NHPI-DA (1h).
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ano Et3N; brapid decomposition of 3a detected by TLC at low
conversion; cno Ag2CO3.
Exploration of palladium catalysts for the arylation of NHPI-
DA (1h) revealed that [Pd(PPh3)4], the only catalyst known for
the arylation of conventional diazocompounds,11 proved
unsuitable in this case (Table 1, entries 1,2). We found that
other Pd(0) pre-catalysts based on phosphines and NHCs as
ligands also lead to extensive decomposition of 1h (see Table
S1).10-11 We observed that its degradation is slower in ethyl
acetate (entry 3), and hypothesized that Pd(0) pre-catalysts were
incompatible with the redox-active diazocompound.10-11
Although most ligands were unsuitable using Pd(II)-sources
(entries 4-9, see Table S2 for details), we discovered that the
simple tris-(2-furyl)phosphine – P(2-Fu)3 – is singular at
promoting this coupling in high yield (entry 10). This is likely
the result of its strong binding to Pd(0) and weak coordination
to Pd(II).12 The Et3N additive, which is common in previous
arylations of diazocompounds,10 prevents the rapid
decomposition of 3a (entry 11), and Ag2CO3 is required as
iodide scavenger (entry 12).
Scheme 2. Scope of the C–H arylation of NHPI-DA (1h).
Unfortunately, the cyclopropanation of styrene 4a with
diazocompound 3b using privileged cyclopropanation catalysts
based on ruthenium and rhodium lead to only low yields and/or
enantioselectivities (Table 2, entries 1-4).13 Moderate activity
and enantioselectivity was observed using Davies' rhodium
catalyst with the cyclopropane carboxylate ligand L5 (entry
5).13c It was discovered that the enantioselectivity is
significantly higher in ethyl acetate (entries 4,5, see Table S4
for details). This result is remarkable in the context of carbene
transfer reactions, in which solvents of lower polarity such as
CH2Cl2 or pentane are commonplace.13-14 However, more
evolved catalysts in the same ligand series (L6-L10)4c-h
displayed variable efficiencies and lower enantioselectivities
(entries 7-11). We reasoned that a catalyst with a more open and
flexible environment could be more suited to accommodate the
bulkier redox-active carbene derived from 3b. To our delight,
the simplest catalyst in this series 1,2,2-triphenylcyclopropane
carboxylate (L11),15 provided quantitative yield and the highest
enantioselectivity (entry 12), even with as low as 0.5 mol%
loading and without inert atmosphere (entry 13). Remarkably,
L11 has never been reported to be effective in asymmetric
cyclopropanation,13a, 13b and is known to produce less efficient
and stereoselective catalysts than L5-L10 in other reactions.16
The C–H arylation conditions for the redox-active
diazoacetate 1h can be applied in a wide range of arenes and
heteroarenes (Scheme 2). In the aryl iodide, neutral substituents
(3b,c) and the complete halogen series (3d-g) were included
with total chemoselectivity, including the monoarylation of 1,4-
diiodobenzene (3g). Various electron-poor substituents (3h-l)
with particular emphasis on distinct carbonyl derivatives (3j-l)
could be seamlessly installed. The alkyne in 3m allows for
further diversification and click reactions. Unfortunately,
diazocompounds with electron-rich functions in the 4-position
proved to be unstable. However, strong electron-donors are
suitable in the 3-position (3n-r), as well as fluorinated groups
(3s,t), and functionalized aliphatics (3u-x) containing alcohol
(3v), nitrile (3w), and aldehyde derivatives (3x). Interestingly,
activated alkene (3y), phenol (3n) and aniline (3q) functions
prove to be orthogonal to the redox-active diazocompound.
Also, unprotected -deficient (3z), and even -excessive (3aa)
heterocycles engaged in the cross-coupling. Importantly, this
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Table 2. Optimization of the enantioselective cyclopropanation with redox-active aryl-diazocompounds 3.
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aopposite enantioselectivity; byield, diastereo- and enantioselectivity was identical under an inert atmosphere of Ar.
A telescoped arylation-cyclopropanation protocol poses an
additional challenge for the rhodium catalyst to maintain its
turnover efficiency and enantioselectivity. Previous systems
required the isolation of the aryldiazoacetate before the carbene
transfer step,10 and slow addition or inert atmosphere during the
cyclopropanation reaction.10c To our delight, the simple Rh2(S-
L11)4 allowed for cyclopropanation with the same
enantioselectivity and without slow addition, after filtration of
the cross-coupling mixture (Scheme 3). Without this filtration
the cyclopropanation reaction does not occur. On the aryl iodide
(2), the cyclopropanation can engage electron-rich (5c,h,i) and
electron-poor (5d-g,j) aryl sources in good yields and high
enantioselectivities. This includes medicinally-relevant
fluorinated moieties (5d,j) and interesting handles that enable
further manipulation of the products (5e-g), which can be
incorporated in various positions in the aromatic ring. However,
ortho-functionalized diazocompounds have proven to be
particularly unstable.17 The absolute configuration of
compound 5g was confirmed by X-ray diffraction.18
Scheme 3. Scope of the telescoped assembly of cyclopropanes from aryl iodides (2), olefins (4) and NHPI-DA (1h). In parenthesis,
yield obtained using isolated 3 (identical e.r. was obtained). Diastereoselectivities have been determined by 1H-NMR analysis of the
reaction crude.
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The chemoselectivity and functional group tolerance of both
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direct Curtius protocol5 can be used to obtain the congested
cyclopropylamine 6c, precursor of histone demethylase
inhibitors.20 The chiral cyclopropylether 6d can be obtained21
avoiding routes involving unstable 1-arylcyclopropanol
intermediates. Likewise, a versatile selenyl unit can be
introduced (6e) to drive downstream radical and polar reactions.
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arylation and cyclopropanation enable the incorporation of
biomolecules with complete stereocontrol. This way, steroids
with a phenylacetate linker (5k), and the more polar dipeptide
(5l) can be selectively arylated and cyclopropanated. On the
olefin component (4), this process accommodates styrenes with
electron-rich (5a,m-o,t,u,w-y) and electron-poor (5p-s,v) m- or
p-substituents. High enantioselectivities are observed with the
o-functionalized styrenes (5x,y). Moreover, interesting
organometallic (5z), heterocyclic (5aa,ab), and stereoidal
frameworks (5ac) of importance in non-linear optics and
medicinal chemistry can engage in this process. The 1,1- and
1,2-disubstituted styrenes produce the corresponding
enantioenriched cyclopropanes (5ad,ae), albeit with slightly
lower enantioselectivity in the latter class. Aliphatic olefins are
To summarize, two catalytic systems have been developed
for the synthesis and asymmetric cyclopropanation of redox-
active aryldiazoesters. It has been found that these reactions can
be combined in the telescoped assembly of arylcyclopropanes
from abundant iodoarenes and olefins of relevance in
biomolecules, heterocycles, and organometallics. The
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enantioselective
carbene
transfer
of
redox-active
aryldiazoesters requires only a simple catalyst, and opens the
door for further developments with push-pull redox-active
diazocompounds. Late-stage decarboxylative coupling
reactions deliver distinct chiral products with identical
enantiomeric excess. These results demonstrate the viability of
unified synthetic strategies towards ubiquitous carbon
traditionally more challenging substrates in the context of
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asymmetric cyclopropanation reactions.5,
However, we
observe surprisingly high enantioselectivities using unactivated
mono- (5af-ai) and disubstituted olefins (5aj), which can
include halide (5ah,ai) and masked alcohol functions (5ag).
The high enantioselectivities obtained without isolation nor
slow addition of the aryldiazoacetates (3) are remarkable, and
seem to originate in the particular topology of the redox-active
carbene intermediate.5
stereocenters
using
orthogonal
and
stereoselective
manipulations of programmable carbon-atom precursors.
AUTHOR INFORMATION
Corresponding Author
* E-mail: abraham.mendoza@su.se
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and characterization data (PDF)
Crystallographic information files (CIF)
Scheme 4. Two-step enantioselective assembly of diverse
cyclopropanes
from
a
carbon-atom
precursor.
Raw data for this article can be downloaded from Zenodo DOI:
10.5281/zenodo.3350527
1
Diasteroselectivities determined by H-NMR analysis of the
reaction crude; aRelative stereochemistry could not be
confirmed. Conditions (see SI for details): [B] B2cat2, blue
LEDs, then pinacol, Et3N, r.t.; [C] Methyl vinyl ketone, Et3N,
Eosin Y cat., blue LEDs, r.t.; [N] NaN3, HCl, r.t., then 90 °C,
then BnOH, 90 °C; [O] 2-Methoxyphenol, Ir(III) cat., Cu(I)
cat., Et3N, blue LEDs, r.t.; [Se] (PhSe)2, Hantzsch ester, Et3N,
Ru cat., blue LEDs, r.t.; Cbz, benzyloxycarbonyl; Ar, 2-
methoxyphenyl.
ACKNOWLEDGMENT
The authors are indebted to the personnel of AstraZeneca
Gothenburg and Stockholm University for unrestricted support.
Funds from the Knut and Alice Wallenberg Foundation
(KAW2016.0153), and the European Research Council (714737)
are gratefully acknowledged.
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17. We have detected the formation of ortho-functionalized
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reasons that are unclear at this point.
18. CCDC 1909222 (5g), and 1909223 (6b) contain the
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obtained free of charge from The Cambridge Crystallographic Data
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