Diastereo- and enantioselective preparation of cyclopropanol derivatives

Article abstract of DOI:10.3762/bjoc.15.71

The diastereoselective carbocupration reaction of alkoxy-functionalized cyclopropene derivatives, followed by a subsequent trapping of the resulting cyclopropylmetal species with an electrophilic source of oxygen (oxenoid) afforded various tetrasubstituted cyclopropanol derivatives in high diastereo- and enantiomeric ratios. Similarly, the enantioselective copper-catalyzed carbomagnesiation/oxidation (or amination) sequence on achiral nonfunctionalized cyclopropenes provided the desired cyclopropanol (and cyclopropylamine) derivatives in excellent diastereo- and enantiomeric excesses.

Full text of DOI:10.3762/bjoc.15.71

Diastereo- and enantioselective preparation of
cyclopropanol derivatives
Marwan Simaan and Ilan Marek*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 752–760.
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty
of Chemistry, Technion-Israel Institute of Technology, Haifa, 32000,
Israel
doi:10.3762/bjoc.15.71
Received: 01 January 2019
Accepted: 11 March 2019
Published: 21 March 2019
Email:
Ilan Marek* - chilanm@technion.ac.il
This article is part of the thematic issue "Cyclopropanes and
cyclopropenes: synthesis and applications".
* Corresponding author
Keywords:
Guest Editor: M. Tortosa
carbocupration; cyclopropanol; cyclopropene; regioselectivity;
stereoselectivity
© 2019 Simaan and Marek; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The diastereoselective carbocupration reaction of alkoxy-functionalized cyclopropene derivatives, followed by a subsequent trap-
ping of the resulting cyclopropylmetal species with an electrophilic source of oxygen (oxenoid) afforded various tetrasubstituted
cyclopropanol derivatives in high diastereo- and enantiomeric ratios. Similarly, the enantioselective copper-catalyzed carbomagne-
siation/oxidation (or amination) sequence on achiral nonfunctionalized cyclopropenes provided the desired cyclopropanol (and
cyclopropylamine) derivatives in excellent diastereo- and enantiomeric excesses.
Introduction
The highly strained structure and bonding properties of cyclo- proaches have been described for their preparation [3]. Among
propyl rings have constantly fascinated successive generations all possible three-membered ring subunits that have been re-
of chemists. These small carbocycles are known to have high ported, cyclopropanols have recently attracted renewed atten-
ring strain (27.5 kcal/mol) and limited degrees of freedom, tion as they are not only contained in many natural products but
making them very attractive substrates for various chemical they are also important precursors in the synthesis of various
transformations [1]. The cyclopropane subunit is also present in biologically active molecules and pharmaceuticals such as anti-
many biologically important compounds such as pheromones, depressants, antiviral and antibacterial drugs [4]. Cyclopro-
fatty acid metabolites, unusual amino acids and possess interest- panols and their derivatives are considered to be carbocyclic
ing herbicidal, insecticidal, antibiotic, antibacterial, antifungal, homologues of enols presenting similar chemical properties
antiviral and antitumor activities [2]. For these reasons, cyclo- which are caused by the unsaturated character of the cyclo-
propanes have been extensively studied and numerous ap- propyl ring. Although cyclopropanols are usually less reactive
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Beilstein J. Org. Chem. 2019, 15, 752–760.
than enols and enolates, their chemical properties are somehow tion of nucleophiles to carbonyl groups [19-25], elimination
more diverse as they undergo useful transformations either with [26,27], oxidation [28] or on the Kulinkovich reaction [29-41]
preservation or rupture of the cyclic structure [5]. Several reli- as summarized in Scheme 1. However, and despite the increas-
able approaches to produce cyclopropanols have been reported ing and justified popularity of all of these methods, the short
in the literature (Scheme 1) [6] but a number of challenges still summary described in Scheme 1 emphasizes an intrinsic prob-
exist particularly for the stereoselective preparation of cyclopro- lem: a different strategy is required for every cyclopropanol and
panols of high structural complexity and substitution pattern. cyclopropylamine that one needs to prepare, limiting the rapid
Since the first synthesis of cyclopropanol by Cottle [7], the structural diversification which is usually essential for biologi-
most popular methods for the preparation of cyclopropanols cal studies. From this rapid tour d’horizon, it is clear that if one
rely on the transformation of enolates [8,9], silyl enol ether [10- could design a stereoselective synthetic pathway to afford poly-
12], vinyl borane [13-17], Fischer carbene addition [18], addi- substituted cyclopropanols (or cyclopropylamines) potentially
Scheme 1: Various strategies leading to the formation of cyclopropanols.
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bearing several diastereo- and enantiomerically enriched adja- selectivity when R1 is different to H and enantioselectivity
cent stereogenic centers, including quaternary carbon stereo- when R1 is equal to H (left or right) and (ii) diastereotopic face
centers, as single diastereo- and enantiomer from a simple pre- selection (top or bottom) as described in Scheme 2. Since the
cursor, it would certainly provide an additional and useful entry pioneering addition of a carbon–metal bond (carbometalation)
to the synthesis of these heterosubstituted three-membered across the double bond of cyclopropenes [42], a very large
rings.
number of groups have reported the addition of organometallic
species demonstrating the generality of this approach for the
preparation of cyclopropanes [43-63]. To achieve good dia-
Results and Discussion
To reach these goals, we are describing herein the diastereo- stereoselectivity during the carbometalation reaction, few
and enantioselective carbometalation reaction of cyclopropenes conditions needed to be fulfilled in the design of the starting
to provide cyclopropylmetal species. By subsequent stereose- cyclopropenyl ring (Figure 1):
lective reactions of the cyclopropylmetal species with an elec-
trophilic source of oxygen (or nitrogen), cyclopropanols (and
cyclopropylamines) should be easily accessible (Scheme 2).
1. The presence of a coordinating group (such as an
oxygen) at the C3 position is crucial for the selective
facial addition of the incoming organometallic species.
2. The presence of a bulky substituent (alkyl or aryl) at the
opposite face at the C3 position might equally be impor-
tant as it might induce an additional steric parameter
leading to a potentially more selective carbometalation
reaction.
3. The substitution pattern on the double bond needs to be
addressed carefully as it plays an important role in the
control of the regioselectivity of the reaction pathway.
An alkyl group on the C1 position of the cyclopropene
should control the regioselectivity of the addition of the
organometallic species to give the more stable second-
ary cyclopropylmetal species (metal at C2).
We therefore decided to start our research with cyclopropanes
bearing an electron-rich methoxy group on one side of the ring
and a phenyl or methyl substituent on the opposite side, respec-
tively. Following reported methods from the literature [64-67],
cyclopropenes 3 were easily prepared through the well-known
RhII-catalyzed decomposition of diazo esters in the presence of
alkynes to give cyclopropenyl esters 1. Reduction of 1 using
DIBAL-H afforded cyclopropenyl alcohols 2 and subsequent
protection of the primary alcohols gave 3 in good yields
(Scheme 3).
Scheme 2: General approach to the preparation of cyclopropanol and
cyclopropylamine derivatives.
First, we checked that the carbometalation reaction was regio-
In order to assemble both cyclopropanols and cyclopropyl- and diastereoselective by addition of lower order cyanocuprate,
amines from a single and unique precursor in a single-pot reac- easily obtained from the corresponding organolithium and a
tion double facial selection by the catalyst is required: (i) regio- stoichiometric amount of CuCN (Scheme 4) [68-70].
Figure 1: Prerequisite for a regio- and diastereoselective carbometalation.
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Scheme 3: Preparation of cyclopropenyl methyl ethers 3a–d.
Scheme 4: Regio- and diastereoselective carbocupration of cyclopropenyl methyl ethers 3a,c.
The addition reaction proceeds similarly for the addition of several studies have been reported on the reactivity of oxenoids
alkyl- or arylcuprate (4a,b and 4c) as well as for the addition on [74-77], indicating that the reaction of a nucleophile with
cyclopropene possessing either a primary or secondary alkyl oxenoid proceeds through an SN2 process [74]. Following the
group at the vinylic carbon center (4a–c and 4d,e). Having in carbocupration of cyclopropene 3 into cyclopropylcopper
hand diastereoisomerically pure and configurationally stable species, the subsequent oxidation with the amphiphilic lithiated
cyclopropylcopper species 3Cu, we next turned our attention to hydroperoxide t-BuOOLi (oxenoid), simply generated by de-
their stereoselective oxidation reaction (Scheme 5). Consid- protonation of t-BuOOH with n-BuLi, led to the copper alk-
ering electrophilic oxidation processes of organometallic oxide, as anticipated, without the formation of free radical inter-
species, molecular oxygen seems to be the most obvious choice mediates. As already reported [78], the expected 2,2,3,3-tetra-
due to its abundancy and low cost. Nevertheless, the reaction of substituted cyclopropanols 5 were obtained as single diastereo-
molecular oxygen with a organocopper species usually proceeds isomers (Scheme 5).
through single-electron transfer to dioxygen, leading to either a
loss of stereoselectivity, degradation of the organocopper or to The reaction proceeded for all R1 and R2 groups tested and de-
the formation of dimer as major products [71]. Therefore, it was termination of the stereochemistry confirmed that the oxidation
clear that a different approach for the oxidation process was reaction proceeds with pure retention of configuration at the
needed. Oxenoid, possessing the general structure M–O–LG, metalated center (intramolecular SN2 reaction or 1,2-metalate
with a metal and a leaving group connected to an oxygen atom, rearrangement) [78-80]. It should be noted that when the same
have been shown to be an excellent electrophilic oxygen source sequence of diastereoselective carbometalation/oxidation was
for nucleophilic organometallic species [72]. Since the original performed on cyclopropenyl ester 1, the in situ-formed
discovery of Müller and Töpel of lithiated peroxides [73], donor–acceptor cyclopropanol undergoes a selective ring-
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Beilstein J. Org. Chem. 2019, 15, 752–760.
Scheme 5: Diastereoselective formation of cyclopropanols.
opening to provide the acyclic product possessing a quaternary of the cyclopropylcopper species proceeded equally well and
carbon stereocenter [57]. As the enantioselective synthesis of gave the corresponding cyclopropanols possessing two adja-
the cyclopropenylmethyl ether 3 was easily achieved in high cent quaternary carbon stereocenters (7i–r) in good yields and
enantiomeric ratio (er 93:7, Scheme 5 [78,81,82]), the subse- excellent diastereomeric ratios. Here again, the methyl, the alkyl
quent combined diastereoselective carbometalation reaction and group from the organometallic and the alcohol in the resulting
oxidation gave the enantiomerically enriched cyclopropanols 5 cyclopropanols are syn-oriented as previously observed. As re-
as unique diastereoisomer with the same enantiomeric ratio as ported in a different context, the nature of the two substituents
the starting material (Scheme 5, dr 98:2:0:0, er 93:7). Having on the cyclopropene rings could be changed without drastically
established the optimized reaction conditions for the prepara- altering the selectivity of the reaction [83,91].
tion of diastereomerically pure 2,2,3,3-tetrasubstituted cyclo-
propanol derivatives 5, we were interested to expand the scope We were also interested to develop the access to non-racemic
of this transformation and include different types of cyclo- unfunctionalized cyclopropanols. Based on the pioneering work
propene precursors. We concentrated our efforts on the reaction of Lautens [62], Nakamura [60], Fox [61], Gevorgyan [51] and
of diversely substituted 3-methyl-3-arylcyclopropenes 6. In this Tortosa [84], we anticipated that an enantioselective copper-cat-
case, as there is no coordinating functionality to dictate the alyzed carbometalation reaction [83,85] would be an ideal solu-
facial selectivity, the control of the diastereoselectivity may be tion to access the desired polysubstituted enantioenriched cyclo-
more challenging. Performing the same carbocupration/oxida- propanols. As reported, the copper-catalyzed diastereo- and en-
tion sequence on 3-methyl-3-phenylcyclopropene 6a,b antioselective carbomagnesiation reaction of cyclopropenes 6
(R1 = H), we were pleased to observe that trisubstituted cyclo- was easily achieved in the presence of (R,S)-Josiphos
propanols 7a–h were obtained in good yields with excellent dia- (2.2 mol %, Scheme 7). Having in hand, diastereoisomerically
stereoselectivities (Scheme 6).
pure and enantiomerically enriched cyclopropylmagnesium
species 6MgBr, the selective oxidation reaction of the copper
The addition of primary, secondary and tertiary alkylcuprates or species, resulting from a transmetalation reaction, was similarly
arylcuprates proceeded smoothly to give the desired cyclopro- achieved by reaction with oxenoid [71,79,80,86-89]. In all
panols (7a–h) after hydrolysis. In all cases, the easily prepared cases, cyclopropanols 7 were obtained as single diastereoiso-
cyclopropanol derivatives were obtained with the methyl, the mer (dr 98:2:0:0) with excellent enantiomeric ratios (er up to
incoming organometallic and the alcohol in the syn-orientation 99:1, Scheme 7). Following the same concept of copper-cata-
which was determined through comparison of the hydrolyzed lyzed diastereo- and enantioselective carbomagnesiation reac-
carbometalated products with compounds already described in tion of cyclopropenes 6 followed now by a selective electrophil-
the literature [83]. To further increase the structural complexity ic amination reaction, a powerful entry to cyclopropylamines as
of the final cyclopropanols, we also tested the reaction on single diastereoisomer and in excellent enantiomeric ratios
nonfunctionalized trisubstituted cyclopropenes (6c–g). Addi- could also be achieved (Scheme 7) [89]. However, the enantio-
tion of primary alkyl- or arylcuprates followed by the oxidation selective and catalytic copper-catalyzed carbomagnesiation
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Beilstein J. Org. Chem. 2019, 15, 752–760.
Scheme 6: Diastereoselective carbometalation/oxidation of nonfunctionalized cyclopropenes 6.
reaction gave poor enantiomeric ratios for the addition of vinyl, Conclusion
aryl and allyl groups and alternative strategies have been In conclusion, we have successfully merged the regio- and dia-
recently developed in our research group [90-92].
stereoselective carbocupration reaction of alkoxy-functionali-
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Beilstein J. Org. Chem. 2019, 15, 752–760.
Scheme 7: Preparation of diastereoisomerically pure and enantioenriched cyclopropanols and cyclopropylamines.
General procedure for the combined
zed cyclopropenes with electrophilic oxidation of the resulting
cyclopropylcopper species to afford 2,2,3,3-polysubstituted carbocupration/oxidation sequence
cyclopropanol derivatives bearing two adjacent quaternary The reaction was performed on a 1 mmol scale. To a suspen-
stereogenic centers in a single pot operation. The simple prepa- sion of CuCN (2 equiv) in 8 mL of Et2O was added alkyl-
ration of enantiomerically enriched cyclopropene afforded the lithium dropwise at −35 °C (2 equiv/2 mmol). The resulting
corresponding cyclopropanols in high enantiomeric excess. This mixture (pale yellow in case of MeLi and PhLi and dark brown
transformation was then applied to unfunctionalized diversely in case of n-BuLi and n-HexLi) was allowed to stir for 30 min.
substituted cyclopropenes. Using the catalytic and enantioselec- Cyclopropene 6a–g (1 equiv/1 mmol in 2 mL of Et2O) was
tive carbometalation reaction of unfunctionalized cyclo- added at that temperature and the reaction mixture was stirred
propenes followed by an electrophilic oxidation reaction, poly- until TLC shows complete consumption of the starting material
substituted cyclopropanols were obtained as single diastereoiso- (eluent hexane/EtOAc 9:1, ca. 30 min). The oxenoid was pre-
mer with high enantiomeric ratios. In all cases, the configura- pared in a different flask by slowly adding n-BuLi (1.2 equiv)
tionally stable cyclopropylmetal species reacted with retention to a solution of tert-butyl hydroperoxide (2 equiv) in THF
of configuration with those electrophiles opening a new ap- (5 mL/2 mmol) at −80 °C. After 30 min at −80 °C, the resulting
proach to O-heterosubstituted cyclopropyl rings.
t-BuOOLi was transferred to the organocopper dropwise at
−78 °C via a cannula. The mixture (orange to brown) was
stirred at this temperature until disappearance of the cyclo-
propylcopper species (followed by TLC, eluent hexane/EtOAc
9:1, ca. 30 min). The reaction was then quenched with an
aqueous solution of NH4Cl/NH4OH (2:1). The aqueous layer
was extracted twice with Et2O and the combined organic phases
were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. Crude mixtures were then
purified by flash chromatography using pentane/diethyl ether as
eluent.
Experimental
General procedure for the carbocupration
reaction of 3a,c with RCuCNLi
To a suspension of CuCN (1.5 equiv) in 8 mL of Et2O was
added alkyllithium dropwise at −35 °C (2 equiv). The resulting
mixture (pale yellow in case of MeLi and PhLi and dark brown
in case of n-BuLi and n-HexLi) was allowed to stir for 30 min.
Cyclopropene 3a,c (1 equiv in 2 mL/mmol of Et2O) was added
at that temperature and the reaction mixture was stirred until
TLC shows complete consumption of the starting material
(eluent hexane/EtOAc 9:1, ca. 30 min). The reaction was then
quenched with an aqueous solution of NH4Cl/NH4OH (2:1).
The aqueous layer was extracted twice with EtOAc and the
combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude mixtures were then purified by flash chromatography
using pentane/diethyl ether as eluent.
Supporting Information
Supporting Information File 1
Experimental part.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-71-S1.pdf]
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Acknowledgements
This project has received funding from the European Union’s
Horizon 2020 research and innovation program under grant
agreement No 786976. I. M. is holder of the Sir Michael and
Lady Sobell Academic Chair.
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ORCID® iDs
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