General Cyclopropane Assembly by Enantioselective Transfer of a Redox-Active Carbene to Aliphatic Olefins

Article abstract of DOI:10.1002/anie.201814123

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. The redox-active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect allowed the asymmetric cyclopropanation of various olefins, including unfunctionalized aliphatic alkenes, that enables the three-step total synthesis of (?)-dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally differentiated diazocompounds are viable and advantageous equivalents of single-carbon chirons.

Full text of DOI:10.1002/anie.201814123

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Accepted Article
Title: General Cyclopropane Assembly via Enantioselective Transfer of
a Redox-Active Carbene to Aliphatic Olefins
Authors: Marc Montesinos-Magraner, Matteo Costantini, Rodrigo
Ramírez-Contreras, Michael E. Muratore, Magnus J.
Johansson, and Abraham Mendoza
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814123
Angew. Chem. 10.1002/ange.201814123
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10.1002/anie.201814123
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General Cyclopropane Assembly via Enantioselective
Transfer of a Redox-Active Carbene to Aliphatic Olefins
Marc Montesinos-Magraner,[a]‡ Matteo Costantini,[a]‡ Rodrigo Ramírez-Contreras,[a] Michael E.
Muratore,[b] Magnus J. Johansson[b] and Abraham Mendoza*[a]
10]
Abstract: Asymmetric cyclopropane synthesis currently requires
bespoke strategies, methods, substrates and reagents, even when
targeting similar compounds. This slows down discovery and limits
its available chemical space. Here we introduce a practical and
versatile diazocompound, and we demonstrate its performance in
the first unified asymmetric synthesis of functionalized
cyclopropanes. We found that the redox-active leaving group in this
reagent enhances the reactivity and selectivity of geminal carbene
transfer. This effect allowed for the asymmetric cyclopropanation of
various olefins including unfunctionalized aliphatic alkenes, that
enables the 3-step total synthesis of (–)-dictyopterene A. This unified
synthetic approach delivers high enantioselectivities that are
independent of the stereoelectronic properties of the functional
groups transferred. Our results demonstrate that orthogonally-
differentiated diazocompounds are viable and advantageous
equivalents of single-carbon chirons.
interactions of their alkyl substituent.[7b-i,
Importantly, many
̈
interesting functionalized carbenes 6-12 (FG-C-H), such as
alkyl-,[11a,
hydroxy-,[11c] amino-,[11d] boryl-,[11e] selenyl-,[11f]
11b]
heteroaryl-,[11g] or alkenyl-methylidenes[11h] are too unstable to
engage in cyclopropanation reactions. As a result, the derived
cyclopropanes still require long and specific syntheses.[5, 6d, 6e, 11e,
12]
Cyclopropanes have attracted the attention of chemists for
decades. The high strain and unique bonding of these
carbocycles display enhanced conformational control and
oxidative resistance that have been exploited in organic
synthesis,[1a] asymmetric catalysis[1b] and medicinal chemistry.[1c]
Cyclopropanes are common in advanced total syntheses both
as structural elements in challenging natural products,[1d] and as
enabling instruments to drive creative disconnections.[1e]
Different asymmetric syntheses of functionalized cyclopropanes
1 have thus been developed (Scheme 1a).[2],[3] However, similar
targets with different peripheral functionality still require discrete
strategies based on specific reagents, catalysts, and substrates
that are elaborated over several steps from raw sources. The
key enantioselective step on these routes are often based on
allylic alcohols 2,[4] 1,1-disubstituted cyclopropenes 3,[5] or
electron-deficient alkenes 4.[6] The asymmetric cyclopropanation
of unfunctionalized olefins (5; i.e. electron-rich and styrenes)
with diazoesters, has been extensively developed with metal-,[7]
and bio-catalysts.[8] However, common aliphatic alkenes[9] are,
despite elegant approaches,[7b, 7c, 8c, 8d] still problematic due to
their low nucleophilicity, and the flexibility and weak dispersive
Scheme 1. State-of-the-art, concept and challenges towards the unified
assembly of diverse chiral cyclopropanes. hetAr = heteroaryl, FG = functional
group.
We conceived a unified strategy[13] to comprehensively
address the formal asymmetric transfer of carbenes 6-12 to
alkene feedstocks 5 through a two-stage process (Scheme 1b):
[1] enantioselective cyclopropanation of 5 with a diazocompound
featuring a leaving group (13); and [2] late-stage diversification
of the resulting intermediates 14. This approach would produce
chiral products with identical enantioselectivity regardless of
their specific functionality, while simplifying the optimization of
the enantioselective cyclopropanation by using a single carbene
[a]
Dr. M. Montesinos-Magraner,‡ M. Costantini,‡ Dr. R. Ramírez-
Contreras, Dr. A. Mendoza
Dept. of Organic Chemistry, Stockholm University
Arrhenius Laboratory 106 91 Stockholm (Sweden)
E-mail: abraham.mendoza@su.se
Dr. M. E. Muratore, Dr. M. J. Johansson
Cardiovascular, Renal and Metabolism IMED Biotech Unit
AstraZeneca Gothenburg
Pepparedsleden 1, 431 83 Mölndal (Sweden)
These authors contributed equally
[b]
[‡]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201814123
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COMMUNICATION
precursor. However, leaving group-functionalized carbenes [M]-
13 (Scheme 1c) are known to be poorly reactive, non-
enantioselective, and their precursors tend to undergo
substitution prior to the carbene transfer.[14] We envisioned that
redox-active carbenes [M]-13a (Scheme 1c) – containing an N-
hydroxyphthalimide (NHPI) ester leaving group – could become
equivalent to all the distinct carbenes 6-12, due to the dual
capacity of NHPI esters to act as acyl electrophile[15] and radical
precursors. Their vividly expanding C-C,[16] C-N,[17] C-O[18] or C-
B[19] bond forming reactions, are well beyond the reach of
current divergent strategies towards chiral cyclopropanes.[20, 21a]
Despite their versatility, the orthogonality of NHPI esters to
metal-carbenes was unknown, and a logical concern when
considering their facile irreversible fragmentation upon activation
with various transition metals and/or visible light.[16-19]
After extensive experimentation, we found that the designed
N-hydroxyphthalimidoyl diazoacetate reagent (NHPI-DA, 13a;
Scheme 2a)[22] can be isolated in gram-amounts as a crystalline
solid that is bench-stable for months. NHPI-DA (13a) does not
require solution storage, and thus allows for easier handling. It
also displays higher stability than the benchmark ethyl
diazoacetate, as evidenced by DSC (EDA, 15a; Scheme 2b).
Initial evaluation of NHPI-DA (13a) in cyclopropanation reactions
using common rhodium, copper and palladium catalysts[2]
displayed low efficiency and selectivity (Table S3), as
anticipated for this challenging transformation (vide supra).
Fortunately, we discovered that NHPI-DA (13a) is effective in
combination with the electron-rich metallacyclic ruthenium
Scheme 2. Properties and performance of NHPI-DA (13a). Conditions: 5 (0.1
mmol), RuL1 (1 mol%), 13,15 (0.1 mmol; 1 s addition time), CH2Cl2, 0 °C;
DSC = differential scanning calorimetry, EDA = ethyl diazoacetate, Bn =
benzyl, ArO = 2,6-di-(tert-butyl)-4-methylphenoxy, TFE = 2,2,2-trifluoroethoxy,
TCE = 2,2,2-trichloroethoxy.
catalyst RuL1[21] (Scheme 2c), displaying
a
remarkable
cyclopropanation selectivity over the competing dimerization
pathway (16-18/19). We compared this intrinsic selectivity
against various conventional diazo reagents with different steric
and electronic properties (15a-f). For this study, we used
equimolar conditions, fast addition of 13a,15a-f, and model
olefins 5a-c with distinct nucleophilicities (N;[23] Scheme 2d), to
minimize substrate-specific bias. It was found that NHPI-DA
(13a) outperforms diazocompounds 15a-f using styrene (5a, N=
+1.70), and this trend is importantly accentuated with more
Although RuL1 is a competent catalyst in asymmetric
cyclopropanation,[21] we have found that NHPI-DA (13a)
expands its scope into an unprecedentedly wide selection of
alkenes with surprisingly high enantioselectivities (Scheme 3).[2]
Functionalized styrenes with various substitution patterns lead,
without slow addition, to redox-active cyclopropanes 16,20-28 in
excellent
yields,
and
with
high
diastereo-
and
challenging
olefins,
such
as
1-hexene
(5b,
enantioselectivities. Different nucleophilic enol ethers smoothly
produce push-pull products 29,30, even in the presence of a
primary alcohol (no O–H insertion observed). Various types of
enamines (31-33) or an allylic silane (34), are also efficiently
cyclopropanated. Importantly, weakly nucleophilic aliphatic
olefins with flexible alkyl substituents,[7, 10] furnish cyclopropanes
17,35 with high diastereo- and enantioselectivity under standard
conditions. We explored the functional group tolerance of this
method in these series using substrates equipped with a
pendant arene (36), ketone (37), chloride (38), Weinreb amide
(39), alcohol derivative (40) and alkyne (41), observing high
enantioselectivity in all cases. Likewise, methylenecycloalkanes
produce the interesting spiro-cyclopropane building blocks
42,43, and protected amines (44) were also tolerated. As far as
we are aware, the NHPI-DA / RuL1 combination is the simplest
homogeneous system to achieve highly enantioselective
N= –2.77) and vinyltrimethylsilane (5c, N < –1.46). This effect
can be rationalized by the stronger electron-withdrawing effect of
the ester moiety in 13a, which allows less reactive olefins to
effectively compete for the electrophilic carbene Int-A (Scheme
2c).
8, 10]
cyclopropanation on a wide range of aliphatic alkenes.[7,
Natural aliphatic olefin feedstocks offer an opportunity to explore
its performance in complex settings. Complete discrimination
between olefins of different nucleophilicity (including enones and
1,3-dienes)
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COMMUNICATION
Scheme 3. Scope of the enantioselective cyclopropanation with NHPI-DA (13a). Conditions: 5 (1.0 equiv), 13a (1.2 equiv, 40 min addition time), (S)-RuL1 (1
mol%), CH2Cl2, 0 °C. [a] 13a (1 s addition time). [b] 13a (6 h addition time), cat. (2 mol%). [c] 13a (3 equiv, 16 h addition time), cat. (3 mol%), rt. [d] 13a (3 equiv, 24 h
addition time), cat. (5 mol%), rt. [e] Cat. (R)-RuL1. [f] Absolute configuration confirmed. See SI for experimental details.[32] Bz = benzoyl, TIPS = triisopropylsilyl, Boc
= tert-butyloxycarbonyl, Ac = acetyl.
enables the selective modification of carvone, nopadiene, and
gibberellic acid (45-47). Hindered olefins in the pinane (48) and
We explored the synthetic potential of enantioenriched
redox-active cyclopropane scaffolds derived from the
representative olefins 5d,e (Scheme 4a). Upon decarboxylation,
these are versatile precursors of catecholboronates[19b] that can
be readily converted into pinacolboronates 56-57 or oxidized to
cyclopropanols 58-59. Radical decarboxylative alkylation (60,61)
and selenation (62,63)[24] yield enantioenriched alkyl- and
selenylcyclopropane products. To the best of our knowledge,
this represents the first enantioselective synthesis of selenyl
cyclopropanes. Basic and electron-rich heteroaromatics can be
installed through telescoped cross-coupling with the
corresponding bromides or lithiated heterocycles[25] (see 64-66).
Taking advantage of the capacity of NHPI esters as acyl
donors,[15] we added Grignard nucleophiles to produce the
corresponding alkyl- and arylketones 67-69. We also developed
steroid
(49-50)
frameworks
also
undergo
smooth
cyclopropanations. In the latter, either enantiomer of the catalyst
RuL1 can be used to access alternative diastereomers 49 and
50 with complete facial discrimination. This system is also
primed for late-stage functionalization of macromolecular natural
glycosides and pharmaceuticals that would be problematic with
existing biocatalysts,[8] like rebaudioside A obtained from a
Stevia extract (51) and the cholesterol-regulating drug
simvastatin (Zocor®) (52). Electron-poor olefins produce the
differentiated bis-carboxylate 53 and the cyclopropyl amino acid
derivative 54. Silylcyclopropanes 18,55 are also obtained with
high diastereo- and enantioselectivity from vinylsilanes, despite
their high steric bulk.
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10.1002/anie.201814123
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Scheme 4. Synthesis of unrelated enantioenriched functionalized cyclopropanes via redox-active intermediates. See SI for experimental details.[32] [a]C-3 acetate
cleaved. [b] Absolute configuration confirmed. [c] Yield of the cyclopropanation step. Yields are calculated on the isolated product. Bpin = boronic acid pinacol ester,
3-Quin = quinolin-3-yl; 3-Py = pyridin-3-yl, 2-Thiop = thiophen-2-yl, Cbz = benzyloxycarbonyl, Teoc = (2-(trimethylsilyl)ethoxycarbonyl), Alloc = allyloxycarbonyl,
Fmoc = 9-fluorenylmethyloxycarbonyl.
a direct Curtius amination protocol towards cyclopropylamines
70-75, including the ticagrelor® fragments 70-74.[26] It is
important to highlight that the synthesis of products 56-75 did
not require neither an individual synthesis of suitable carbene
precursors, nor custom catalysts to accommodate their diverse
functionalities. These results illustrate the unique versatility of
enantioenriched redox-active cyclopropane carboxylates, now
accesible in one-step from feedstock alkenes using NHPI-DA
(13a).
feedstock materials, utilizing
a
single strategy, carbene
precursor (13a) and catalyst (RuL1). If step count is used to
illustrate the tactical value of this new scheme, previous
strategies for the asymmetric synthesis of products 70-
74,76,78,80,83 required at least twice as many, and up to 15
steps (see Scheme 4) using custom methods, materials, and
reagents. The 2-step enantioselective formal transfer of
carbenes 6-12 is unprecedented to the best of our knowledge.
The current momentum of redox-active ester chemistry and the
rich reactivity of carbene transfer suggest future synthetic
upgrades of this technology, some of which are underway in our
laboratories.
With these results in hand, we explored the valorization of
simple feedstocks in the synthesis of relevant chiral
cyclopropanes (Scheme 4b-d). As such, 5-bromopentene (5f)
can be transformed in
a
three-step process into the
In summary, NHPI-DA (13a) is a practical, safe, and
crystalline methine precursor that provides a comprehensive
solution to the enantioselective formal transfer of various
functionalized methylidenes. This reagent (i) renders the
synthesis of custom and unstable carbene reagents
unnecessary, (ii) simplifies the optimization of the asymmetric
carbene transfer step, and (iii) enables the synthesis of targets
with distinct functionalities with the same enantioselectivity and
conceptual approach. The unexpected synergistic effect
between the geminal redox-active ester and carbene functions
enables the general asymmetric cyclopropanation of challenging
aliphatic alkenes. Moreover, the NHPI ester function has the
unique capacity to promote both acyl-transfer and radical
derivatization reactions that enhance the synthetic utility of the
resulting enantioenriched cyclopropane intermediates. NHPI-DA
(13a) provides the foundation for further asymmetric assembly of
enantioenriched cyclopropanol fragment 76 of the drug
grazoprevir®.[27] L-allylglycine (5g) can be utilized to produce
(via 77) the cyclopropylamine fragment 78 of the bioactive
natural product (+)-belactosin A (Scheme 4c).[28] Moreover,
propene gas (5h), the simplest pro-chiral aliphatic olefin, leads
efficiently on a gram-scale to 79 en-route to the enantiopure
cyclopropylboronate building block 80, used in the total
synthesis of (–)-spongidepsin (Scheme 4d).[29] After olefination
of the inexpensive 2-heptenal (81; Scheme 4e), the resulting
1,3-diene, is cyclopropanated to yield 82 and further vinylated
30]
using
a
telescoped Zweifel process[25b,
into the
divinylcyclopropane natural product (–)-dictyopterene A (83).[31]
To put these results in perspective, it is important to highlight
that the synthesis of the diverse cyclopropane fragments in
commercial drugs (70-74,76), natural products (78,80), and the
shortest total synthesis of 83 invariably required 2-3 steps from
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10.1002/anie.201814123
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COMMUNICATION
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Acknowledgements
The authors are grateful to Dr E. Martínez de Castro for valuable
technical developments and Prof. H. Waldmann, Prof. P. S.
Baran and Prof. F. Rodríguez for fruitful discussions. We 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. M.M.-M. thanks the Generalitat Valenciana and
the European Social Fund for a postdoctoral contract. M.E.M. is
a fellow of the AstraZeneca postdoc programme.
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A priority patent application has been filed (1850940-6), where
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Keywords: Cyclopropane • Enantioselective catalysis • Redox-
active • Diazocompound • Aliphatic Alkene
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Marc Montesinos-Magraner,[a]‡ Matteo
Costantini,[a]‡ Rodrigo Ramírez-
Contreras,[a] Michael E. Muratore,[b]
Magnus J. Johansson[b] and Abraham
Mendoza*[a]
Page No. – Page No.
Text for Table of Contents
General Cyclopropane Assembly via
Enantioselective Transfer of a Redox-
Active Carbene to Aliphatic Olefins
The asymmetric synthesis of cyclopropanes is currently designed using specific strategies that depend on the
materials available and the final functionality of each target. In this communication, we present a comprehensive
approach that engages simple feedstocks, including aliphatic olefins, with a single redox-active carbene
precursor (NHPI-DA) that acts as a universal source of a chiral C–H unit.
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