Tandem diastereo- and enantioselective preparation of aryl and alkyl cyclopropyl carbinols with three adjacent stereocenters using perhydrobenzoxazines and diethylzinc

Article abstract of DOI:10.1039/c3ob41797b

The enantio- and diastereoselective one-pot ethylation/cyclopropanation is efficiently promoted by a chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di- and trisubstituted α,β-unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading to intermediates lacking allylic strain or with either A^1,2 or A^1,3 strain afford the corresponding syn hydroxycyclopropanes very selectively. While α-methyl enals are successfully ethylated/ cyclopropanated, the presence of bulky substituents at the alpha position of the enal constitutes a limitation to the substrate scope. The use of 1,1-diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbinol, which bears carbon-substituents at all three positions of the ring, with good enantiocontrol, although moderate diastereoselectivity. A procedure for the asymmetric one-pot arylation/cyclopropanation of enals is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.

Full text of DOI:10.1039/c3ob41797b

Organic &
Biomolecular Chemistry
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PAPER
Tandem diastereo- and enantioselective
preparation of aryl and alkyl cyclopropyl carbinols
with three adjacent stereocenters using
perhydrobenzoxazines and diethylzinc†
Cite this: Org. Biomol. Chem., 2014,
12, 345
Rebeca Infante, Javier Nieto* and Celia Andrés*
The enantio- and diastereoselective one-pot ethylation/cyclopropanation is efficiently promoted by a
chiral perhydrobenzoxazine. The catalytic system tolerates a wide range of di- and trisubstituted
α,β-unsaturated aldehydes and has been found to be highly diastereo- and enantioselective. Enals leading
to intermediates lacking allylic strain or with either A1,2 or A1,3 strain afford the corresponding syn hydroxy-
cyclopropanes very selectively. While α-methyl enals are successfully ethylated/cyclopropanated, the pres-
ence of bulky substituents at the alpha position of the enal constitutes a limitation to the substrate scope.
The use of 1,1-diiodoethane allows the obtention of the corresponding enantioenriched cyclopropylcarbi-
nol, which bears carbon-substituents at all three positions of the ring, with good enantiocontrol, although
moderate diastereoselectivity. A procedure for the asymmetric one-pot arylation/cyclopropanation of enals
is proposed, which involves the use of triarylboroxin, diethylzinc and diiodomethane.
Received 3rd September 2013,
Accepted 4th November 2013
DOI: 10.1039/c3ob41797b
www.rsc.org/obc
diazocompounds and chiral auxiliaries as well as chiral cata-
lysts.1,6 More recently, a promising strategy has emerged from
Introduction
Enantioenriched cyclopropanes constitute one of the most the organocatalysis, which allowed the synthesis of enantio-
attractive subunits in organic chemistry, probably due to the enriched cyclopropanes, usually via a Michael-initiated ring
diverse biological properties, such as enzyme inhibition, insec- closure.1,7 Another approach to the stereoselective synthesis of
ticidal, antifungal, herbicidal, antimicrobial, antibiotic, anti- cyclopropanes concerns the halomethylmetal-mediated cyclo-
bacterial, antitumor and antiviral activities, that simple propanation reactions, which are commonly known as
cyclopropanes or those with more complex functionalities Simmons–Smith reaction.1,8 Although the first report by
present.1 This structure is an important scaffold to elaborate Emschwiller dates from 1929,9 in which diiodomethane was
more complex molecules, and it can be found in more than reacted with zinc to give iodomethylzinc species, more than 30
4000 natural compounds and approximately 120 therapeutic years were necessary for the introduction of the cyclopropana-
agents.1,2 Additionally, due to the three-membered ring strain, tion of alkenes with diiodomethane in the presence of acti-
these compounds can undergo an assortment of synthetically vated zinc by Simmons and Smith.10 Since then, different
useful ring-opening reactions.3,4 For these reasons, novel and alternative procedures for the preparation of a variety of metal
more efficient methodologies for the preparation of enantio- carbenoid species have been developed, and one of the most
pure cyclopropanes are continuously emerging.1–3,5 To date, popular methods is the alkyl exchange of diethylzinc with
the different synthetic strategies can be generally classified diiodomethane.1f
into three main groups.1j In first place, the transition metal-
The foremost advantages that have contributed to the
catalyzed decomposition of diazoalkanes has been probably attractiveness of Simmons–Smith reagents are associated to a
one of the most studied approaches for the cyclopropanation broad substrate generality, a wide tolerance of functional
of olefins, and very important advances in terms of stereo- groups and the chemoselectivity with respect to alkene geome-
selectivity have been achieved in this area employing try. In addition, proximal oxygen atoms have been found to
enhance the syn-directing effect and a superior reactivity has
been demonstrated when an allylic alcohol was employed as a
substrate instead of unfunctionalized alkenes.1f,j The stereo-
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid, Paseo de Belén, 7, 47011 Valladolid, Spain.
chemistry of this transformation has been explained through a
E-mail: javiernr@qo.uva.es
†Electronic supplementary information (ESI) available: Copies of NMR spectra
‘butterfly-type’ transition state.1a,11,12 The first stereoselective
cyclopropanation of acyclic allylic alcohols by means of
and HPLC chromatograms. See DOI: 10.1039/c3ob41797b
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Simmons–Smith reagent was performed by Pereyre in 1978,13
who attained high syn selectivities for (Z)-disubstituted olefins
Results and discussion
but very poor for the (E)-isomers. In this context, Charette The asymmetric ethylation/cyclopropanation of β-phenylcinnam-
demonstrated that the nature of the carbenoid was very impor- aldehyde to yield the corresponding (cyclopropyl)propan-1-ol,
tant in order to obtain similar stereocontrol for both (E)- and in the presence of
4 mol% of perhydrobenzoxazine 1
(Z)-disubstituted allylic alcohols.1f,14 However, the highly (Scheme 1),19 was chosen as a model reaction to examine the
stereoselective cyclopropanation of acyclic trisubstituted allylic reaction conditions. As we commented before, the reaction
alcohols has proven to be more challenging, because the takes place in two steps, but in a one-pot way. While the first
allylic strains in the transition-state and the different protec- step involves the enantioselective ethylation of the aldehyde by
tive groups of the alcohol, as well as the reagent, play an Et2Zn addition promoted by the chiral inductor 1, the second
important role.1f
Despite these magnificent features, the enantiocontrol of alkoxide
step concerns the cyclopropanation of the intermediate allylic
employing the highly reactive reagent
Simmons–Smith-type cyclopropanations of olefins and allylic CF3CH2OZnCH2I,16a generated in situ from Et2Zn, CF3CH2OH
alcohols has been found to be more difficult in contrast to the and CH2I2. For the ethylation step, we considered the best
two other approaches (organocatalysis and decomposition of reaction conditions established in a reported study,18a which
diazocompounds), which lead to enantioenriched cyclopro- involved the use of 2 equivalents of diethylzinc in toluene at
panes with high selectivity. Nevertheless, some exceptions are room temperature. Concerning the cyclopropanation step
gradually arising,15,16 one of which is constituted by the work several reaction parameters, such as temperature, solvent and
developed by Walsh et al., who have described the first highly reaction time, were investigated.
stereoselective one-pot synthesis of a large family of cyclopro-
Surprisingly, we found that the efficiency of the catalytic
panes from achiral precursors with up to four contiguous system in terms of stereocontrol was maintained very high
stereocenters.16 The intermediate allylic alkoxides were pre- independent of the solvent employed (toluene, hexane or a
pared by enantioselective alkyl and vinylzinc additions to car- mixture of both) and the reaction temperature (−20 °C, 0 °C or
bonyls promoted by (−)-MIB as a chiral catalyst.
25 °C). The target syn hydroxy cyclopropane was obtained in all
In spite of these numerous high-quality contributions, cur- cases with excellent diastereoselection and 93% ee, and the
iously no related examples of the stereoselective preparation of chemical yields were higher when toluene was employed as a
cyclopropyl(phenyl)methanols through one-pot phenylation/ solvent at room temperature. Finally, the reaction time was fixed
cyclopropanation of α,β-unsaturated aldehydes were studied.
to 24 h in order to obtain an almost quantitative yield (92%).
Once the optimized conditions for the one-pot ethylation/
In previous work we have reported the utility of chiral per-
hydro-1,3-benzoxazines in different diastereoselective cycliza- cyclopropanation were confirmed, the substrate scope was
tion processes17 and recently we have shown that explored and a variety of acyclic di- and trisubstituted enals
conformationally restricted perhydro-1,3-benzoxazines behave were considered. The results for the known (entries 1, 5) and
as excellent ligands for the enantioselective addition of novel hydroxy cyclopropanes (entries 2–4, 6–8) are summarized
organozinc reagents to carbonyl compounds.18 Encouraged by in Table 1.
the excellent results obtained in the asymmetric alkylation and
It is noteworthy that the transformations afforded only a
arylation of aldehydes promoted by our perhydrobenzoxazine single diastereoisomer in each case, which was determined by
1 (Scheme 1),19 we decided to tackle the challenging prepa- 1H-NMR, independently of the allylic strains exhibited by the
ration of cyclopropyl(phenyl)methanols in a tandem way intermediate alkoxide: A1,2 strain (entries 1, 2), A1,3 strain
employing the in situ generated EtZnPh. Previously, we (entries 3, 4), or neither A1,2 nor A1,3 strain (entries 5–8). To
planned to study more extensively the scope and limitations of our delight, all reactions carried out on trisubstituted α,β-un-
ethylation/cyclopropanation of a variety of acyclic di- and tri- saturated aldehydes allowed the obtention of the corres-
substituted α,β-unsaturated aldehydes using the methodology ponding syn hydroxy cyclopropanes in excellent yields and total
developed by Walsh, and also to verify whether our ligand diastereoselection with high enantioselectivities for different
behaves similarly to (−)-MIB.
substitution patterns (entries 1–4). Nevertheless, an exception to
this behavior was the transformation of aldehyde 2b (entry 2),
which leads to an intermediate allylic alkoxide with A1,2 strain.
The corresponding hydroxy cyclopropane 3b was obtained in
absolute diastereoselectivity but in low yield and with moder-
ate optical purity, while the main product detected by 1H-NMR
in the crude reaction mixture was the corresponding allylic
alcohol. Probably, as a result of steric hindrance and the elec-
tronic effect. The Br is very deactivating, slowing the cyclopro-
panation while the carbenoid decomposes. In contrast, when
the reaction was carried out on α-methyl-trans-cinnamaldehyde
2a (R3 = Me, entry 1), the hydroxy cyclopropane 3a was pro-
vided quantitatively in 91% ee.
Scheme 1 Model reaction to establish the optimal conditions using the
perhydrobenzoxazine 1.
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Table 1 One-pot catalytic asymmetric ethylation/cyclopropanation of several trisubstituted and disubstituted α,β-unsaturated aldehydes in the
presence of 1
Entrya
2
R1
R2
R3
3
Yieldb (%)
drc (syn : anti)
eed (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
H
H
Me
Ph
H
H
H
H
Ph
Ph
Ph
Ph
Me
Br
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
97
37
94
92
90
93
82
85
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
91e
78
90
93
90e
84
80
90
Ph
o-MeOC6H4
p-MeOC6H4
2-Furyl
2g
2h
3g
3h
a 1–ZnEt2–aldehyde–ZnEt2–CF3CH2OH–CH2I2 = 0.04/2/1/2/2/2. b Yield of isolated product after purification by flash chromatography. c Only a
single diastereomer was detected in the crude 1H-NMR spectra in each case. d Determined by HPLC employing chiral columns (AS-H, OD, AD
and AD-H). e Configuration was assigned by comparing 1H-NMR spectra and the sign of specific rotation with reported values (see supporting
information for further details).
Good to high enantioselectivities were reached when no
allylic strains were present on the acyclic disubstituted allylic
alkoxides derived from aldehydes 2e–h (R1 = R3 = H, R2 ≠ H,
entries 5–8). An alkoxy group in ortho- and para-positions of
the phenyl ring in R2 resulted in a decrease of ee (entries 6, 7),
but interestingly the chemical yield of 3f was high, which
might be attributed to additional interactions with the Scheme 3 One-pot method for the synthesis of 1,2,3-substituted
cyclopropanes from enals.
o-methoxy substituent in the transition-state. Moreover,
2-furylacrylaldehyde 2h (entry 8) was as well tolerated as trans-
cinnamaldehyde 2e (entry 5) under our optimal conditions,
affording selectively the syn hydroxy cyclopropane with good
yield and 90% ee.
In order to increase the substrate generality and bearing in
mind that 1,2,3-substituted cyclopropanes belong to a large
family of pharmacologically active and natural compounds, we
tested the one-pot ethylation/cyclopropanation reaction
employing
results are shown in Scheme 3.
Considering the poor yield obtained with 2b (entry 2), we
were interested in studying the influence exerted by a phenyl
group at the alpha position of the enal, so aldehydes 2i–k were
subjected to the alkylation/cyclopropanation protocol
(Scheme 2). The results indicated a very low yield of the
hydroxy cyclopropane in 24 h, less than 10%, independently of
the nature of the R2 substituent (alkyl or aryl). In all cases the
main products isolated were the corresponding enantio-
enriched allylic alcohol, and total absence of the starting alde-
hydes 2i–k was observed. An increase of the cyclopropanation
reaction time to 50 h resulted in similar conversions. So
summing up, while a methyl substituent is well tolerated at
the alpha position of the enal, the presence of either a phenyl
or a voluminous group at this position constitutes one limit-
ation for these one-pot reactions.
a
different diiodide (1,1-diiodoethane).20 The
Although in this way the creation of an additional stereo-
center might complicate the diastereocontrol a priori, only two
epimeric diastereoisomers were formed with good diastereo-
meric ratio. Furthermore the enantioselectivity of the reaction
was maintained high, while the yield was moderate. Concern-
ing the stereochemical assignment, the value of the H–H coup-
ling constant between the two hydrogens attached to the
cyclopropane ring (CHMe–R′CHR, J = 5.7 Hz) and a NOESY
experiment suggested a trans disposition between each other
for the major diastereomer 4d.16b
Taking into account the excellent precedents in arylation of
aldehydes promoted by our ligand, a new protocol for the
synthesis of cyclopropyl(phenyl)methanols through tandem
phenylation/cyclopropanation of acyclic di- and trisubstituted
α,β-unsaturated aldehydes using the ligand 1 as a chirality source
and EtZnPh species generated in situ from triphenylboroxin and
diethylzinc was developed. The results are collected in Table 2.
Initially, the phenyl(ethyl)zinc species was generated in situ
through transmetallation between triphenylboroxin and
diethylzinc in toluene at 60 °C for 30 min,21 and subsequently
Scheme 2 Ethylation/cyclopropanation of α-phenyl enals.
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Table 2 One-pot catalytic asymmetric phenylation/cyclopropanation
of several α,β-unsaturated aldehydes in the presence of 1 and triphenyl-
boroxin as an aryl source
Scheme 4 Transformation of hydroxycyclopropane 6e to 8e.
values in terms of optical purity of the products, albeit moder-
ate diastereoselection was achieved.
Finally, the transformation of the purified enantioenriched
hydroxy cyclopropane 6e into the known α-ketocyclopropane
8e with PCC in DCM at rt allowed the confirmation of the
cyclopropane ring stereochemistry by comparison of the sign
of the specific rotation with reported data (Scheme 4).22
Yieldb
(%)
Entrya
2
R1 R2
Ph
R3
drc (syn : anti)
4 : 1 (6a : 7a)
>20 : 1 (6d : 7d) 51
4 : 1 (6e : 7e)
eed (%)
86 (85)
1
2
3
4
2a
H
Me 91
2d Ph Ph
2e
2h
H
H
H
76e
87
H
H
Ph
2-Furyl
80g (79)
57 f
2 : 1 (6h : 7h) 80 (81)
Conclusions
a 1–(PhBO)3–Et2Zn–aldehyde–Et2Zn–CF3CH2OH–CH2I2 = 0.1/0.6/2.4/1/
2.2/2.2/2.2. b Yield of isolated product after purification by flash
To sum up, a set of some new and known (cyclopropyl)propan-
chromatography. c Determined by 1H-NMR of the crude reaction. 1-ols could be prepared in very good yields with total diastereo-
d Determined by HPLC employing chiral columns (ee for anti
selectivity and high enantiocontrol independently of the sub-
stitution pattern of the α,β-unsaturated aldehydes by
diastereoisomers in parenthesis). e 17% of allylic alcohol was recovered
after column chromatography purification configuration. f 23% of
allylic alcohol were recovered after column chromatography ethylation/cyclopropanation employing the ligand 1 as the
purification. g In order to determine the configuration, the
chiral source. An extended study was carried out to elucidate
hydroxycyclopropane was subjected to oxidation to the corresponding
the reach and limitations of this reaction, which not only
ketone. The configuration was assigned by comparing the sign of
specific rotation of the derived α-ketocyclopropane with reported permits the use of aldehydes possessing A1,2 and A1,3 strain
values.
but also tolerates well strain-lacking substrates. Besides, we
verified experimentally that a bulky substituent at the alpha
position of the enal still constitutes an unresolved aspect of
this reaction. In order to confirm the generality of the method,
the addition of the aldehyde to the reaction mixture in the pre-
viously reported optimal conditions18b was carried out. Next,
a hydroxy cyclopropane with carbon-substituents at all posi-
instead of quenching the zinc alkoxide, the cyclopropanation
tions of the ring was isolated for the first time in a one-pot way
of the double bond was performed at room temperature in
in a reasonable yield with high stereoselection. Finally, a novel
light exclusion without the need of removing the boron
protocol for the preparation of enantioenriched cyclopropyl-
species. The quantities of the reagents for the cyclopropana-
tion step were adequate in order to obtain the best yields. As
can be regarded in Table 2, although variable diastereoselectiv-
ities were found in the tandem phenylation/cyclopropanation,
(phenyl)methanols through tandem arylation/cyclopropana-
tion of α,β-unsaturated aldehydes was successfully developed.
This procedure involved the in situ generated PhZnEt, from tri-
phenylboroxin and diethylzinc, and it avoids the need for
the desired products were afforded in moderate to good yields
removing the boron byproducts.
for the four essayed substrates. Complete diastereoinduction
was perceived when the reaction was run over the trisubsti-
tuted aldehyde 2d (entry 2), which leads to A1,3 strain in the
Experimental section
transition-state; nevertheless, the ee reached with such sub-
strate was poor. High enantioselectivities were obtained for the
two diastereoisomers isolated in the reaction carried out over a
different trisubstituted aldehyde (2a, entry 1), whose corres-
ponding allylic alkoxide presents A1,2 strain. However, the
diastereoselectivity was not as high as the corresponding ethy-
lated hydroxycyclopropane counterpart (see entry 1, Table 1 vs.
Table 2). Unfortunately, diastereoselectivity was not improved by
adding cosolvents such as hexane or dichloromethane, and a
decrease in reaction temperature at 0 °C only results in a signifi-
cant decrease in chemical yield. Screening other zinc carbenoids,
such as CF3CO2ZnCH2I or EtZnCH2I was also unsuccessful.
The disubstituted α,β-unsaturated aldehydes 2e and 2h (aro-
matic and heterocyclic respectively, entries 3, 4) were also well
tolerated by our protocol and resulted in great competitive
All reactions were carried out in anhydrous solvents under an
argon atmosphere in flame-dried glassware by means of
Schlenk techniques. 1H-NMR (300 MHz or 400 MHz) and
13C-NMR (75 MHz or 100 MHz) spectra were recorded in
CDCl3. Chemical shifts for protons are reported in ppm from
tetramethylsilane with the residual CHCl3 resonance as an
internal reference. Chemical shifts for carbons are reported in
ppm from tetramethylsilane and are referenced to the carbon
resonance of the solvent. Data are reported as follows: chemi-
cal shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, sp = septet, m = multiplet, br = broad), coupling con-
stants in hertz, and integration. Specific rotations were
measured using a 5 mL cell with a 1 dm path length, and a
sodium lamp, and concentration is given in g per 100 mL.
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Flash chromatography was carried out using silica gel (c 1.2, CHCl3). 1H-NMR (300 MHz, CDCl3) δ 0.81 (s, 3H),
(230–240 mesh). Chemical yields refer to pure isolated sub- 0.85–0.99 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H), 1.53–1.88 (m, 3H),
stances. TLC analysis was performed on glass-backed plates 2.03 (dd, J1 = 8.7 Hz, J2 = 6.0 Hz, 1H), 2.95 (dd, J1 = 7.9 Hz, J2 =
coated with silica gel 60 and an F254 indicator, and visualized 5.5 Hz, 1H), 7.17–7.26 (m, 3H), 7.27–7.37 (m, 2H). 13C-NMR
by either UV irradiation or by staining with I2 or phospho- (75 MHz, CDCl3) δ 11.0 (CH3), 12.3 (CH3), 16.2 (CH2), 27.0
molybdic acid solution. Chiral HPLC analysis was performed (CH2), 27.0 (CH), 27.7 (C), 81.8 (CH), 125.8 (CH), 127.9 (2CH),
using a Daicel Chiralcel OD Column, Chiralpak AD-H or Chir- 128.9 (2CH), 138.6 (C). IR (neat) νmax 3370, 3060, 3030, 2960,
alpak AS-H. UV detection was monitored at 220 nm or at 2935, 2875, 1605, 1500, 1450, 1080, 1015, 955, 775, 740, 700,
254 nm. High resolution mass spectrometry analysis (HRMS) 600 cm−1. HPLC (Chiralcel OD, hexane–isopropanol = 99 : 01,
was performed by a quadrupole spectrometer with a TOF 1 mL min−1, λ = 220 nm) tR = 16.3 min for enantiomer (S)-
analyzer.
1-(1S,2R), tR = 17.3 min for enantiomer (R)-1-(1R,2S). Configur-
Unless otherwise indicated, all compounds were purchased ation was assigned by comparing the 1H- and 13C-NMR spectra
from commercial sources and used as received. Aldehydes 2c and sign of optical rotation with literature data.16a
and 2i were synthesized from commercially available ethyl
(R)-1-((1S,2S)-1-Bromo-2-phenylcyclopropyl)propan-1-ol (3b).
trans-β-methylcinnamate and (Z)-2,3-diphenyl-2-propenoic acid This compound was obtained from (Z)-α-bromocinnamalde-
respectively by reduction with LiAlH4 followed by Swern oxi- hyde (105 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and puri-
dation of the corresponding alcohol.23 Racemic hydroxycyclo- fied by flash chromatography (ethyl acetate–hexane = 1/20).
propanes were synthesized according to the general procedure Colorless oil. [α]2D0 −12.6 (c 0.7, CHCl3). 1H-NMR (300 MHz,
employing racemic 3-hydroxy-N-methylpyrrolidine as a ligand. CDCl3) δ 1.09 (t, J = 7.5 Hz, 3H), 1.51–1.68 (m, 2H), 1.71–1.87
1,1-Diiodoethane was prepared according to the literature pro- (m, 2H), 1.94 (d, J = 7.7 Hz, 1H), 2.21 (dd, J1 = 9.9 Hz, J2 = 7.5 Hz,
cedure.20 Triphenylboroxin was freshly prepared by heating the 1H), 2.96 (dt, J1 = 7.7 Hz, J2 = 5.5 Hz, 1H), 7.18–7.41 (m, 5H).
corresponding phenylboronic acid for 8 h at 110 °C in a con- 13C-NMR (75 MHz, CDCl3) δ 10.4 (CH3), 19.6 (CH2), 27.9 (CH),
ventional oven and used without further purification.24 Ligand 29.0 (CH2), 50.1 (C), 80.8 (CH), 126.9 (CH), 128.0 (2CH), 128.9
1 was prepared according to reported procedures.19
Compounds 5d and 6h could not be obtained pure after 1605, 1500, 1455, 1095, 1040, 1030, 980, 770, 740, 695, 605,
(2CH), 136.9 (C). IR (neat) νmax 3370, 3030, 2965, 2935, 2880,
flash chromatography.
530 cm−1. HRMS calcd for C12H15BrO + Na+, 277.0198; found,
277.0217. HPLC (Chiralcel OD, hexane–isopropanol = 98 : 02,
1 mL min−1, λ = 220 nm) tR = 20.6 min for enantiomer (S)-
1-(1R,2R), tR = 24.8 min for enantiomer (R)-1-(1S,2S).
General procedure for the enantioselective one-pot synthesis
of (cyclopropyl)propan-1-ols from α,β-unsaturated aldehydes
and diethylzinc
(R)-1-((1R,2R)-2-Methyl-2-phenylcyclopropyl)propan-1-ol (3c).
To a flame-dried, argon-purged flask containing the ligand This compound was obtained from (E)-3-phenylbut-2-enal
(7.1 mg, 0.02 mmol, 4 mol%) and dry toluene (1 mL) was (73 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and purified by
added a 1 M solution of diethylzinc in hexane (1 mL, 1 mmol) flash chromatography (ethyl acetate–hexane = 1/20). Colorless
at room temperature. After stirring for 10 min, a solution of oil. [α]2D0 −34.5 (c 1.4, CHCl3). 1H-NMR (300 MHz, CDCl3) δ
the corresponding α,β-unsaturated aldehyde (0.5 mmol) in dry 0.73 (m, 1H), 1.09 (t, J = 7.5 Hz, 3H), 1.16–1.24 (m, 2H), 1.44 (s,
toluene (0.5 mL) was added and allowed to react at room temp- 3H), 1.71–1.84 (m, 3H), 3.31–3.48 (m, 1H), 7.16–7.23 (m, 1H),
erature (TLC, 30–45 min). Next, the reaction mixture was 7.25–7.36 (m, 4H). 13C-NMR (75 MHz, CDCl3) δ 9.9 (CH3), 18.5
cooled to 0 °C with light exclusion and Et2Zn (1 mL, 1 mmol) (CH2), 21.4 (CH3), 25.3 (C), 30.9 (CH2), 32.2 (CH), 74.0 (CH),
was added. Dropwise addition of CF3CH2OH (73 μL, 1 mmol) 125.8 (CH), 127.0 (2CH), 128.3 (2CH), 147.5 (C). IR (neat) νmax
was performed over 20 min. After stirring at 0 °C for 20 min, 3355, 3060, 3025, 2965, 2930, 2875, 1605, 1495, 1445, 1045,
CH2I2 (80 μL, 1 mmol) or CH3CHI2 (282 mg, 1 mmol) was 1025, 960, 760, 700, 590, 540 cm−1 HRMS calcd for C13H18O +
added and the reaction mixture was stirred at room tempera- Na+, 213.1250; found, 213.1250. HPLC (Chiralpak AD-H,
ture for 24 h. Finally, the reaction mixture was quenched by hexane–isopropanol = 90 : 10, 1 mL min−1, λ = 220 nm) tR
=
dropwise addition of an aqueous ammonium chloride solu- 5.4 min for enantiomer (R)-1-(1R,2R), tR = 6.2 min for enantio-
tion. The organic layer was separated and the aqueous phase mer (S)-1-(1S,2S).
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
(R)-1-((R)-2,2-Diphenylcyclopropyl)propan-1-ol
(3d). This
layers were washed with brine and dried over anhydrous compound was obtained from β-phenylcinnamaldehyde
MgSO4. The solvents were removed under reduced pressure (104 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and purified
and the residue was purified by column chromatography on by flash chromatography (ethyl acetate–hexane = 1/15). Color-
1
silica gel using mixtures of hexane–EtOAc as an eluent. The ee less oil. [α]2D0 −103.1 (c 2.2, CHCl3). H-NMR (300 MHz, CDCl3)
values were determined by HPLC on a chiral stationary phase.
δ 0.98 (t, J = 7.4 Hz, 3H), 1.27 (dd, J1 = 8.9 Hz, J2 = 4.8 Hz, 1H),
(R)-1-((1R,2S)-1-Methyl-2-phenylcyclopropyl)propan-1-ol (3a). 1.58 (s, 1H), 1.63–1.74 (m, 2H), 1.74–1.86 (m, 1H), 1.91 (dt, J1 =
This compound was obtained from (E)-α-methylcinnamalde- 8.5 Hz, J2 = 6.0 Hz, 1H), 2.96 (td, J1 = 8.1 Hz, J2 = 3.5 Hz, 1H),
hyde (71 μL, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and puri- 7.16–7.29 (m, 2H), 7.29–7.43 (m, 8H). 13C-NMR (75 MHz,
fied by flash chromatography (ethyl acetate–hexane = 1/20). CDCl3) δ 9.9 (CH3), 17.0 (CH2), 29.8 (CH2), 31.6 (CH), 35.7 (C),
Colorless oil. [α]D20 −20.0 (c 1.0, CHCl3), (lit.16a [α]2D0 +10.5 72.8 (CH), 125.9 (CH), 126.4 (CH), 128.1 (2CH), 128.2 (2CH),
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128.3 (2CH), 129.8 (2CH), 141.0 (C), 146.4 (C). IR (neat) νmax Na+, 229.1199; found, 229.1193. HPLC (Chiralpak AS-H,
3345, 3060, 3025, 2960, 2925, 2875, 1600, 1495, 1445, 1040, hexane–isopropanol = 90 : 10, 1 mL min−1, λ = 220 nm) tR
=
1025, 955, 770, 755, 695, 630, 615, 545 cm−1. HRMS calcd for 7.0 min for enantiomer (R)-1-(1R,2R), tR = 8.1 min for enantio-
C18H20O + Na+, 275.1406; found, 275.1401. HPLC (Chiralcel mer (S)-1-(1S,2S).
OD, hexane–isopropanol = 99 : 01, 1 mL min−1, λ = 220 nm)
(R)-1-((1R,2R)-2-(2-Furyl)cyclopropyl)propan-1-ol (3h). This
tR = 23.2 min for enantiomer (R)-1-(R), tR = 26.1 min for enan- compound was obtained from (E)-3-(2-furyl)acrylaldehyde
tiomer (R)-1-(R). (63.0 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and purified
(R)-1-((1R,2R)-2-Phenylcyclopropyl)propan-1-ol (3e). This by flash chromatography (ethyl acetate–hexane = 1/10). Color-
compound was obtained from (E)-cinnamaldehyde (63 μL, less oil. [α]2D0 −79.5 (c 1.0, CHCl3). 1H-NMR (300 MHz, CDCl3) δ
0.5 mmol) and CH2I2 (80 μL, 1 mmol), and purified by flash 0.87–1.05 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H), 1.31 (m, 1H),
chromatography (ethyl acetate–hexane = 1/15). Colorless oil. 1.59–1.73 (m, 3H), 1.83 (dt, J1 = 9.2 Hz, J2 = 4.9 Hz, 1H), 3.09
[α]2D0 −66.2 (c 0.6, CHCl3). 1H-NMR (300 MHz, CDCl3) δ (q, J = 6.8 Hz, 1H), 5.95 (d J = 3.2 Hz, 1H), 6.26 (dd, J1 = 3.2 Hz,
0.84–1.08 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H), 1.25 (m, 1H), J2 = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H). 13C-NMR (75 MHz,
1.63–1.75 (m, 2H), 1.84 (dt, J1 = 8.7 Hz, J2 = 4.9 Hz, 1H), 3.11 CDCl3) δ 9.9 (CH3), 10.7 (CH2), 14.3 (CH), 26.5 (CH), 30.2
(dt, J1 = 8.1 Hz, J2 = 6.3 Hz, 1H), 7.04–7.10 (m, 2H), 7.19 (m, (CH2), 76.1 (CH), 103.6 (CH), 110.2 (CH), 140.5 (CH), 156.0 (C).
1H), 7.23–7.32 (m, 2H). 13C-NMR (75 MHz, CDCl3) δ 10.1 IR (neat) νmax 3360, 3010, 2965, 2925, 2880, 1600, 1510, 1175,
(CH3), 13.1 (CH2), 21.2 (CH), 29.3 (CH), 30.2 (CH2), 77.1 (CH), 1150, 1010, 965, 915, 790, 725, 595 cm−1. HRMS calcd for
125.6 (CH2), 125.8 (2CH), 128.3 (2CH), 142.4 (C). IR (neat) νmax C10H14O + Na+, 189.0886; found, 189.0894. HPLC (Chiralpak
3365, 3065, 3025, 2965, 2925, 2875, 1605, 1500, 1465, 1095, AD-H, hexane–isopropanol = 98 : 02, 1 mL min−1, λ = 220 nm)
1030, 970, 750, 695, 545 cm−1 HPLC (Chiralcel OD, hexane– tR = 16.3 min for enantiomer (R)-1-(1R,2R), tR = 18.7 min for
isopropanol = 90 : 10, 1 mL min−1, λ = 220 nm) tR = 6.5 min for enantiomer (S)-1-(1S,2S).
enantiomer (S)-1-(1S,2S), tR = 17.3 min for enantiomer (R)-
(R)-1-((1R,3R)-3-Methyl-2,2-diphenylcyclopropyl)propan-1-ol
1-(1R,2R). Configuration was assigned by comparing the 1H- (4d). This compound was obtained from β-phenylcinnamalde-
and 13C-NMR spectra with literature data14,16a and the known hyde (104 mg, 0.5 mmol) and CH3CHIZnOCH2CF3 (1.1 mmol,
absolute configuration of the corresponding allylic alcohol.18a
from Et2Zn (1.1 mL, 1.1 mmol), CF3CH2OH (80 μL, 1.1 mmol)
(R)-1-((1R,2R)-2-(2-Methoxyphenyl)cyclopropyl)propan-1-ol and CH3CHI2 (310 mg, 1.1 mmol)), and purified by flash
(3f). This compound was obtained from (E)-2-methoxycinna- chromatography (Et2O–CH2Cl2–hexane = 1/3/16). Colorless oil.
1
maldehyde (84 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and [α]2D0 −231 (c 0.4, CHCl3). H-NMR (400 MHz, CDCl3) δ 0.91 (t,
purified by flash chromatography (ethyl acetate–hexane = J = 7.4 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H), 1.21 (br s, 1H), 1.51
1/10). Colorless oil. [α]2D0 −23.4 (c 1.6, CHCl3). 1H-NMR (dd, J1 = 8.3 Hz, J2 = 5.7 Hz, 1H), 1.60 (m, 1H), 1.73 (m, 1H),
(300 MHz, CDCl3) δ 0.91–0.97 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H), 1.90 (dq, J2 = 5.7 Hz, J2 = 6.2 Hz, 1H), 2.89 (td, J1 = 8.0 Hz, J2 =
1.20 (m, 1H), 1.52–1.78 (m, 2H), 1.83 (s, 1H), 2.10 (m, 1H), 3.18 3.6 Hz, 1H), 7.11–7.19 (m, 2H), 7.20–7.29 (m, 8H). 13C-NMR
(td, J1 = 7.6 Hz, J2 = 5.0 Hz, 1H), 3.86 (s, 3H), 6.80–6.92 (m, (100 MHz, CDCl3) δ 9.9 (CH3), 15.5 (CH3), 19.9 (CH), 29.9
3H), 7.18 (m, 1H). 13C-NMR (75 MHz, CDCl3) δ 10.0 (CH3), 11.5 (CH2), 37.0 (CH), 40.8 (C), 73.2 (CH), 126.1 (CH), 126.1 (CH),
(CH2), 15.1 (CH), 27.7 (CH), 29.4 (CH2), 55.3 (CH3), 76.9 (CH), 128.2 (2CH), 128.2 (2CH), 129.6 (2CH), 130.1 (2CH), 142.8 (C),
110.0 (CH), 120.4 (CH), 125.6 (CH), 126.6 (CH), 130.4 (C), 158.0 142.9 (C). IR (neat) νmax 3342, 3060, 3025, 2960, 2925, 2855,
(C). IR (neat) νmax 3370, 3070, 2995, 2960, 2935, 2875, 2835, 1600, 1495, 1445, 960, 770, 750, 700, 650 cm−1. HRMS calcd
1600, 1585, 1495, 1460, 1435, 1240, 1115, 1030, 750 cm−1 for C19H22O + Na+, 2 891 563; found, 2 891 550. HPLC (Chiral-
HRMS calcd for C13H18O2 + Na+, 229.1199; found, 229.1191. pak OD, hexane–isopropanol = 98 : 02, 1 mL min−1, λ =
HPLC (Chiralpak AS-H, hexane–isopropanol = 99 : 01, 1 mL 220 nm) tR = 10.0 min for enantiomer (R)-1-(1R,3R), tR
min−1, λ = 220 nm) tR = 17.2 min for enantiomer (S)-1-(1S,2S), 12.2 min for enantiomer (S)-1-(1S,3S).
tR = 19.1 min for enantiomer (R)-1-(1R,2R).
=
Typical procedure for enantioselective one-pot synthesis of
(R)-1-((1R,2R)-2-(4-Methoxyphenyl)cyclopropyl)propan-1-ol (3g).
This compound was obtained from (E)-4-methoxycinnamalde-
(cyclopropyl)(phenyl)methanols from α,β-unsaturated
aldehydes, diethylzinc and triphenylboroxin
hyde (83 mg, 0.5 mmol) and CH2I2 (80 μL, 1 mmol), and puri-
fied by flash chromatography (ethyl acetate–hexane = 1/10– To a suspension of triphenylboroxin (106.3 mg, 0.3 mmol) in
1/4). Colorless oil. [α]2D0 −52.5 (c 0.6, CHCl3). 1H-NMR anhydrous toluene (0.5 mL) under an argon atmosphere was
(300 MHz, CDCl3) δ 0.82–0.96 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H), added dropwise a 1.1 M solution of Et2Zn in toluene (1.1 mL,
1.17 (m, 1H), 1.60–1.74 (m, 3H), 1.78 (dt, J1 = 9.1 Hz, J2 = 5.0 1.2 mmol). The resulting mixture was heated at 60 °C in a pre-
Hz, 1H), 3.06 (dt, J1 = 8.1 Hz, J2 = 6.3 Hz, 1H), 3.78 (s, 3H), 6.82 heated bath for 30 min to give a clear solution. Once this solu-
(d, J1 = 8.8 Hz, 2H), 7.00 (d, J1 = 8.6 Hz, 2H). 13C-NMR tion was cooled to room temperature, a solution of the ligand
(75 MHz, CDCl3) δ 10.1 (CH3), 12.6 (CH2), 20.4 (CH), 28.8 (CH), 1 (18 mg, 0.05 mmol) in toluene (0.5 mL) was added. The
30.2 (CH2), 55.3 (CH3), 77.2 (CH), 113.8 (2CH), 126.9 (2CH), resulting mixture was then cooled to 0 °C in an ice bath and
134.3 (C), 157.7 (C). IR (neat) νmax 3380, 3070, 3000, 2960, after 15 min of stirring at that temperature, the aldehyde
2930, 2875, 2835, 1615, 1580, 1515, 1460, 1295, 1245, 1180, (0.5 mmol) was added. After 60 min, Et2Zn (1 mL, 1.1 mmol)
1035, 970, 825, 805, 550 cm−1. HRMS calcd for C13H18O2
+
was added to the reaction mixture at 0 °C. Next, dropwise
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addition of CF3CH2OH (80 μL, 1.1 mmol) was performed over 143.2 (C), 146.1 (C). IR (neat) νmax 3335, 3060, 3025, 2920,
20 min and after another 20 min, CH2I2 (88 μL, 1.1 mmol) was 2855, 1600, 1495, 1445, 1150, 1035, 1020, 760, 750, 695, 640,
added. Then, the reaction mixture was stirred at room temp- 625, 585, 550, 535 cm−1. HRMS calcd for C22H20O + Na+,
erature with light exclusion for 24 h. Finally, the reaction 323.1406; found, 323.1389. HPLC (Chiralcel OD, hexane–
mixture was quenched with saturated aqueous NH4Cl, isopropanol = 98 : 02, 1 mL min−1, λ = 220 nm) tR = 21.2 min
extracted with CH2Cl2 (3 × 15 mL), dried over MgSO4, filtered for enantiomer (R)-(S), tR = 24.0 min for enantiomer (S)-(R).
off, and the solvents were evaporated. Purification by silica gel
(S)-Phenyl((1R,2R)-2-phenylcyclopropyl)methanol (6e). This
column chromatography with different mixtures of ethyl compound was obtained from (E)-cinnamaldehyde (63 μL,
acetate–hexane gave the pure alcohols. Enantiomeric excesses 0.5 mmol) and purified by flash chromatography (ethyl
were determined by chiral HPLC.
acetate–hexane = 1/15). White solid. Mp 57–58 °C. [α]2D0 −61.2
1
(S)-((1R,2S)-1-Methyl-2-phenylcyclopropyl)(phenyl)methanol (c 0.6, CHCl3). H-NMR (400 MHz, CDCl3) δ 1.07 (dt, J1 = 8.4
(6a). This compound was obtained from (E)-α-methylcinna- Hz, J2 = 5.2 Hz, 1H), 1.20 (dt, J1 = 8.9 Hz, J2 = 5.3 Hz, 1H),
maldehyde (71 μL, 0.5 mmol) and purified by flash chromato- 1.51–1.60 (m, 1H), 1.86–2.14 (m, 2H), 4.38 (d, J = 7.4 Hz, 1H),
graphy (ethyl acetate–hexane = 1/30). Colorless oil. [α]D20 −26.6 6.98–7.07 (m, 2H), 7.10–7.18 (m, 1H), 7.20–7.26 (m, 2H),
1
(c 0.3, CHCl3). H-NMR (400 MHz, CDCl3) δ 0.66 (s, 3H), 0.96 7.27–7.33 (m, 1H), 7.33–7.40 (m, 2H), 7.41–7.50 (m, 2H).
(dd, J1 = 5.9 Hz, J2 = 5.0 Hz, 1H), 1.18 (dd, J1 = 8.9 Hz, J2 = 4.9 13C-NMR (100 MHz, CDCl3) δ 13.6 (CH2), 21.0 (CH), 30.0 (CH),
Hz, 1H), 1.94 (br s, 1H, OH), 2.38 (dd, J1 = 8.9 Hz, J2 = 6.0 Hz, 76.8 (CH), 125.7 (CH), 126.0 (2CH), 126.0 (2CH), 127.7 (CH),
1H), 4.38 (s, 1H), 7.02–7.11 (m, 2H), 7.11–7.18 (m, 1H), 128.3 (2CH), 128.5 (2CH), 142.0 (C), 143.5 (C).1 IR (neat) νmax
7.19–7.25 (m, 2H), 7.28–7.34 (m, 1H), 7.36–7.43 (m, 2H), 3230, 3025, 1600, 1500, 1455, 1090, 1055, 1030, 1020, 765, 755,
7.45–7.53 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 13.8 (CH3), 695, 635, 550, 535 cm−1. HRMS calcd for C16H16O + Na+,
15.9 (CH2), 26.4 (CH), 28.7 (C), 80.7 (CH), 125.9 (CH), 126.3 247.1093; found, 247.1075. HPLC (Chiralpak AS-H, hexane–
(2CH), 127.4 (CH), 127.9 (2CH), 128.1 (2CH), 129.1 (2CH), isopropanol = 99 : 01, 1 mL min−1, λ = 220 nm) tR = 26.1 min
138.5 (C), 142.4 (C). IR (neat) νmax 3390, 3060, 3030, 2960, for enantiomer (R)-(1S,2S), tR = 27.6 min for enantiomer (S)-
2920, 2850, 1605, 1495, 1450, 1025, 775, 740, 725, 695, (1R,2R). Configuration was assigned by comparing the sign of
580 cm−1. HRMS calcd for C17H18O + Na+, 261.1250; found, optical rotation of the derived ketocyclopropane (see prepa-
261.1254. HPLC (Chiralcel OD, hexane–isopropanol = 90 : 10, ration of 8e from 6e below).
1 mL min−1, λ = 220 nm) tR = 9.7 min for enantiomer
(S)-(1R,2S), tR = 11.7 min for enantiomer (R)-(1S,2R).
(S)-Phenyl((1S,2S)-2-phenylcyclopropyl)methanol (7e). This
compound was obtained from (E)-cinnamaldehyde (63 μL,
(S)-((1S,2R)-1-Methyl-2-phenylcyclopropyl)(phenyl)methanol 0.5 mmol) and purified by flash chromatography (ethyl
(7a). This compound was obtained from (E)-α-methylcinna- acetate–hexane = 1/15). Colorless oil. [α]2D0 −13.1 (c 0.3, CHCl3).
maldehyde (71 μL, 0.5 mmol) and purified by flash chromato- 1H-NMR (400 MHz, CDCl3) δ 0.99 (dt, J1 = 8.7 Hz, J2 = 5.2 Hz,
graphy (ethyl acetate–hexane = 1/30). Colorless oil. [α]2D0 +6.6 (c 1H), 1.09 (dt, J1 = 8.9 Hz, J2 = 5.4 Hz, 1H), 1.52–1.62 (m, 1H),
0.3, Et2O). 1H-NMR (400 MHz, CDCl3) δ 0.67 (s, 3H), 0.89 (t, J = 2.00 (br s, 1H, OH), 2.10 (dt, J1 = 9.4 Hz, J2 = 4.7 Hz, 1H), 4.32
5.6 Hz, 1H), 1.25 (dd, J1 = 8.8 Hz, J2 = 5.1 Hz, 1H), 1.91 (d, J = (d, J = 7.8 Hz, 1H), 7.04–7.13 (m, 2H), 7.13–7.21 (m, 1H),
3.2 Hz, 1H, OH), 2.35 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 1H), 4.42 (d, 7.23–7.34 (m, 3H), 7.35–7.41 (m, 2H), 7.43–7.48 (m, 2H).
J = 2.9 Hz, 1H), 7.15–7.22 (m, 3H), 7.24–7.34 (m, 3H), 7.35–7.41 13C-NMR (100 MHz, CDCl3) δ 13.5 (CH2), 21.9 (CH), 30.7 (CH),
(m, 2H), 7.42–7.47 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 14.1 77.5 (CH), 125.7 (CH), 125.9 (2CH), 126.1 (2CH), 127.7 (CH),
(CH3), 15.2 (CH2), 27.0 (CH), 28.6 (C), 80.1 (CH), 125.9 (CH), 128.4 (2CH), 128.5 (2CH), 142.3 (C), 143.4 (C). IR (neat) νmax
126.4 (2CH), 127.5 (CH), 128.0 (2CH), 128.2 (2CH), 129.1 3355, 3060, 2920, 2850, 1605, 1460, 1455, 1020, 760, 740, 700,
(2CH), 139.0 (C), 142.5 (C). IR (neat) νmax 3410, 3060, 3030, 550 cm−1. HRMS calcd for C16H16O + Na+, 247.1093; found,
2920, 2850, 1605, 1495, 1450, 1025, 775, 740, 725, 700 cm−1
.
247.1098. HPLC (Chiralpak AS-H, hexane–isopropanol =
HRMS calcd for C17H18O + Na+, 261.1250; found, 261.1265. 99 : 01, 1 mL min−1, λ = 220 nm) tR = 23.8 min for enantiomer
HPLC (Chiralpak AS-H, hexane–isopropanol = 98 : 02, 1 mL (R)-(1R,2R), tR = 26.1 min for enantiomer (S)-(1S,2S).
min−1, λ = 220 nm) tR = 9.7 min for enantiomer (R)-(1R,2S),
tR = 11.2 min for enantiomer (S)-(1S,2R).
(S)-((1R,2R)-2-(2-Furyl)cyclopropyl)(phenyl)methanol (6h).
This compound was obtained from (E)-3-(2-furyl)acrylaldehyde
(S)-(R)-2,2-Diphenylcyclopropyl)(phenyl)methanol (6d). This (63.0 mg, 0.5 mmol) and purified by flash chromatography
compound was obtained from β-phenylcinnamaldehyde (ethyl acetate–hexane = 1/15). The product was obtained as an
(104 mg, 0.5 mmol) and purified by flash chromatography inseparable mixture of diastereoisomers 6h and 7h (enriched
1
(ethyl acetate–hexane = 1/20). White solid. Mp 104–106 °C. in 6h). Yellow oil. H-NMR (400 MHz, CDCl3) δ 1.02–1.28 (m,
[α]2D0 −34.4 (c 1.2, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 1.42 2H), 1.58–1.72 (m, 1H), 1.94 (br s, 1H, OH), 1.91–2.05 (m, 2H),
(dd, J1 = 8.8 Hz, J2 = 5.0 Hz, 1H), 1.85 (t, J = 5.5 Hz, 1H), 1.92 4.42 (d, J = 7.0 Hz, 1H), 5.92 (dt, J1 = 3.2 Hz, J2 = 0.8 Hz, 1H),
(br s, 1H, OH), 2.28 (td, J1 = 8.8 Hz, J2 = 5.9 Hz, 1H), 3.97 (d, J = 6.24 (dd, J1 = 3.2 Hz, J2 = 1.9 Hz, 1H), 7.21 (dd, J1 = 1.9 Hz, J2 =
8.8 Hz, 1H), 7.10–7.31 (m, 12H), 7.31–7.42 (m, 3H). 13C-NMR 0.9 Hz, 1H), 7.27–7.33 (m, 1H), 7.34–7.40 (m, 2H), 7.41–7.49
(100 MHz, CDCl3) δ 17.9 (CH2), 32.5 (CH), 35.9 (C), 74.7 (CH), (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 11.3 (CH2), 14.1 (CH),
126.0 (CH), 126.6 (CH), 126.8 (2CH), 127.8 (CH), 128.0 (2CH), 27.3 (CH), 75.7 (CH), 103.8 (CH), 110.2 (CH), 126.0 (2CH),
128.1 (2CH), 128.2 (2CH), 128.4 (2CH), 130.2 (2CH), 140.5 (C), 127.7 (CH), 128.5 (2CH), 140.6 (CH), 143.2 (C), 155.6 (C). IR
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(neat) νmax 3375, 3030, 2925, 2855, 1600, 1510, 1455, 1080,
1010, 730, 700, 600 cm−1. HRMS calcd for C14H14O2 + Na+,
237.0886; found, 237.0881. HPLC (Chiralcel OD, hexane–
isopropanol = 99 : 01, 1 mL min−1, λ = 220 nm) tR = 57.1 min
for enantiomer (S)-(1R,2R), tR = 60.7 min for enantiomer
(R)-(1S,2S).
Notes and references
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(S)-((1R,2R)-2-(2-Furyl)cyclopropyl)(phenyl)methanol (minor
diaster) (7h). This compound was obtained from (E)-3-(2-furyl)-
acrylaldehyde (63.0 mg, 0.5 mmol) and purified by flash
chromatography (ethyl acetate–hexane = 1/15). An analytical
amount of 7h could be obtained for characterisation purposes.
Yellow oil. [α]2D0 −19.3 (c 0.1, CHCl3). 1H-NMR (400 MHz,
CDCl3) δ 0.94–1.11 (m, 2H), 1.60–1.71 (m, 1H), 1.98 (br s, 1H,
OH), 2.10 (dt, J1 = 8.9 Hz, J2 = 5.0 Hz, 1H), 4.29 (d, J = 7.7 Hz,
1H), 5.98 (dt, J1 = 3.2 Hz, J2 = 0.8 Hz, 1H), 6.27 (dd, J1 = 3.2 Hz,
J2 = 1.9 Hz, 1H), 7.24 (dd, J1 = 1.9 Hz, J2 = 0.9 Hz, 1H),
7.28–7.33 (m, 1H), 7.34–7.40 (m, 2H), 7.42–7.46 (m, 2H).
13C-NMR (100 MHz, CDCl3) δ 11.1 (CH2), 15.0 (CH), 28.0 (CH),
76.8 (CH), 103.8 (CH), 110.3 (CH), 126.1 (2CH), 127.8 (CH),
128.5 (2CH), 140.6 (CH), 143.1 (C), 155.7 (C). IR (neat) νmax
3395, 2925, 2855, 1600, 1455, 1265, 1080, 1010, 735, 700,
600 cm−1. HRMS calcd for C14H14O2 + Na+, 237.0886; found,
237.0884. HPLC (Chiralcel OD, hexane–isopropanol = 99 : 01,
1 mL min−1, λ = 220 nm) tR = 63.3 min for enantiomer (S)-
(1S,2S), tR = 90.2 min for enantiomer (R)-(1R,2R).
Configuration assignment of cyclopropane 6e: Synthesis of
phenyl((1R,2R)-2-phenylcyclopropyl)methanone
8e
from
6e. To a solution of 6e (56 mg, 0.25 mmol) in CH2Cl2 (5 mL)
at room temperature was added carefully PCC (83 mg,
0.38 mmol, 1.5 eq.). After 60 min stirring (TLC monitored), a
1.0 M solution of NaOH (3 mL) was added and the resulting
mixture was extracted with CH2Cl2 (5 × 15 mL), dried over
MgSO4, filtered off, and the solvents were evaporated. Purifi-
cation by silica gel column chromatography with ethyl acetate–
hexane = 1/75 gave the pure ketone 8e. White solid. Mp
46–48 °C. [α]2D0 −288 (c 0.2, acetone), [lit.22 [α]2D9 +351, (c 0.549,
acetone) for (1S,2S)]. 1H-NMR (400 MHz, CDCl3) δ 1.56 (ddd,
J1 = 8.0 Hz, J2 = 6.6 Hz, J3 = 4.1 Hz, 1H), 1.93 (ddd, J1 = 9.2 Hz,
J2 = 5.3 Hz, J3 = 4.1 Hz, 1H), 2.71 (ddd, J1 = 9.0 Hz, J2 = 6.6 Hz,
J3 = 4.0 Hz, 1H), 2.91 (ddd, J1 = 8.1 Hz, J2 = 5.3 Hz, J3 = 4.0 Hz,
1H), 7.15–7.21 (m, 2H), 7.21–7.25 (m, 1H), 7.28–7.34 (m, 2H),
7.41–7.49 (m, 2H), 7.52–7.60 (m, 1H), 7.96–8.02 (m, 2H).
13C-NMR (100 MHz, CDCl3) δ 19.2, 29.3, 30.0, 126.2 (2), 126.6,
128.1 (2), 128.6 (4), 132.9, 137.7, 140.5, 198.5. IR (neat) νmax
3060, 3025, 2920, 2875, 1680, 1665, 1595, 1580, 1450, 1400,
1205, 980, 750, 730, 695, 685, 565, 525, 500 cm−1. Absolute
configuration was assigned by comparing the sign of optical
rotation with literature data.22
Acknowledgements
We acknowledge the financial support by the Spanish DGICYT
(Project CTQ2011-28487). R. I. also thanks Junta de Castilla y
León for a predoctoral fellowship
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