Enantioselective dirhodium(II)-catalyzed cyclopropanations with trimethylsilylethyl and trichloroethyl aryldiazoacetates

Article abstract of DOI:10.1016/j.tet.2015.05.045

Abstract Highly functionalized cyclopropanecarboxylates were readily prepared by rhodium-catalyzed cyclopropanation of alkenes with aryldiazoacetates and styryldiazoaceates, in which the ester functionality is either trimethylsilylethyl (TMSE) or trichlor

Full text of DOI:10.1016/j.tet.2015.05.045

Tetrahedron xxx (2015) 1e6
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Tetrahedron
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Enantioselective dirhodium(II)-catalyzed cyclopropanations with
trimethylsilylethyl and trichloroethyl aryldiazoacetates
*
Solymar Negretti, Carolyn M. Cohen, Jane J. Chang, David M. Guptill, Huw M.L. Davies
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly functionalized cyclopropanecarboxylates were readily prepared by rhodium-catalyzed cyclo-
propanation of alkenes with aryldiazoacetates and styryldiazoaceates, in which the ester functionality is
either trimethylsilylethyl (TMSE) or trichloroethyl (TCE). By having labile protecting groups on the ester,
chiral triarylcyclopropane carboxylate ligands were conveniently prepared. The asymmetric induction
during cyclopropanation is dependent on the nature of the ester group and the chiral dirhodium tet-
racarboxylate catalyst. The prolinate catalyst Rh2(S-DOSP)4 was the optimum catalyst for asymmetric
intermolecular cyclopropanation of TMSE diazoesters with styrene, while Rh2(R-BPCP)4 was the opti-
mum catalyst for TCE diazoesters.
Received 14 March 2015
Received in revised form 1 May 2015
Accepted 13 May 2015
Available online xxx
This paper is dedicated to the memory of
Professor Alan R. Katritzky, an inspirational
leader in the field of heterocyclic chemistry
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric cyclopropanation
Cyclopropanes
Donor/acceptor carbenoids
Dirhodium catalysis
1. Introduction
Rh2(DOSP)4. The former provided high levels of enantioinduction
when the acceptor of the aryldiazoacetate precursor was varied.
Cyclopropanes are a common motif in natural products and
medicinal targets, and are useful building blocks in complex mol-
ecule synthesis.1e4 Therefore, the development of methods for their
enantioselective synthesis has been of general interest.5e11 Cyclo-
propanation between metal carbenes and alkenes is recognized as
a classic reaction for the synthesis of cyclopropanes.12 We have
previously shown that the cyclopropanation reaction of aryldia-
zoacetates proceeds with high diastereoselectivity even under
thermal conditions.13 When cyclopropanation with donor/acceptor
carbenoids is catalyzed by chiral dirhodium(II) tetracarboxylates,
the reaction can proceed with high levels of enantioselectivity.14e18
The reaction is even effective for electron deficient alkanes with the
appropriate catalyst.18 Mechanistic studies have suggested that
these rhodium-catalyzed cyclopropanation reactions proceed by
means of a concerted-asynchronous process.19
Whereas Rh2(R-BNP)4 was well suited for catalyzing highly enan-
tioselective cyclopropanation of alkoxy-substituted methyl aryl-
diazoacetates. A drawback of Rh2(DOSP)4, however, is that high
levels of enantioselectivity are typically achieved only when the
In a comparative study of different catalysts, Rh2(DOSP)4 was
found to be the optimal catalyst for a broad range of methyl aryl-
diazoacetates (Fig. 1).20 In addition, the two other chiral dirhodiu-
m(II) catalysts studied, Rh2(S-PTAD)4 and Rh2(R-BNP)4, were shown
to have enantioselectivity profiles complementary to that of
* Corresponding author. Tel.: þ1 404 727 6839; e-mail address: hmdavie@emory.
edu (H.M.L. Davies).
Fig. 1. Dirhodium(II) catalysts.
http://dx.doi.org/10.1016/j.tet.2015.05.045
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2
S. Negretti et al. / Tetrahedron xxx (2015) 1e6
acceptor group is a methyl ester as opposed to larger alkyl esters.14
Additionally a model was developed to predict the stereochemistry
of the Rh2(S-DOSP)4-catalyzed cyclopropanation.21
entry 1). Rh2(S-BTPCP)4 afforded the desired cyclopropane in
moderate yield but low enantioselectivity, 67% yield and 43% ee,
respectively (Table 1 entry 2). Both the phthalimido dirhodium(II)
catalysts Rh2(S-PTAD)4 and Rh2(S-NTTL)4 provided low yields and
enantioselectivity in the reaction.
A new generation of chiral D2-symmetric dirhodium(II) catalysts
has emerged from the Davies group that employs chiral triar-
ylcyclopropane carboxylates as ligands.22 These ligands are derived
from Rh2(R-DOSP)4 catalyzed cyclopropanation of 1,1-disubstituted
olefins with aryldiazoacetates, followed by ester hydrolysis. The
first member of this class was Rh2(R-BTPCP)4, which was found to
catalyze classic reactions of donor/acceptor carbenoids such as
cyclopropanation, tandem cyclopropanation/Cope rearrangement
and combined CeH functionalization/Cope rearrangement/retro-
Cope rearrangement. Furthermore, it was employed in the enan-
tioselective synthesis of 2-arylbicyclo[1.1.0]butane carboxylates.23
These catalysts also show promise in controlling the reactivity of
rhodium-stabilized carbenoids derived from vinyldiazoacetates,
which traditionally react at the carbene site with the benchmark
catalysts, Rh2(R-DOSP)4 and Rh2(S-PTAD)4. A related analogue,
Rh2(R-TPCP)4 was employed for the generation of [3þ2] cycload-
dition products derived from initial attack at the vinylogous posi-
tion of the rhodium vinylcarbene.24 Most recently, the biphenyl
derivative Rh2(R-BPCP)4 has shown promise for site selective CeH
functionalization. It was applied to the selective functionalization
of activated primary CeH bonds, such as allylic and benzylic sites.25
Furthermore, in combination with the more sterically hindered
2,2,2-trichloroethyl aryldiazoacetates, site selective and enantio-
selective CeH functionalization of methyl ethers was achieved.26
Given the important role that different ester groups play in the
reactivity and selectivity of carbenoid CeH functionalization re-
actions, we undertook a study to uncover the role of 2-(trime-
thylsilyl)ethyl (TMSE) and 2,2,2-trichloroethyl (TCE) esters in
cyclopropanation reactions. Previously, we had shown that the TMSE
esters are prone to intramolecular reactions,27 but we anticipated
that this ester functionality would be compatible with in-
termolecular reactions of reactive alkenes. The TCE group appears to
be very robust for rhodium carbene reactions, and so we expected
donor/acceptor carbenes bearing TCE ester acceptor group would be
very effective in intermolecular cyclopropanations. Both ester groups
would be more easily removed than the corresponding methyl ester,
which would expand the range of useful carbene transformations for
the preparation of novel chiral carboxylate ligands. Herein we report
the results of our efforts to develop asymmetric cyclopropanation
reactions of TMSE aryldiazoacetates and TCE aryldiazoacetates.
On the basis of the initial evaluation, Rh2(S-DOSP)4 was used to
study the scope of the cyclopropanation with a series of TMSE
aryldiazoacetates and styrene derivatives. The results are summa-
rized in Table 2. The enantioselectivity of 3a was slightly higher in
pentane, therefore it was used in the scope study (see Table 1, entry
1
and Table 2, entry 1). The Rh2(S-DOSP)4-catalyzed cyclo-
propanation of TMSE aryldiazoacetates was fairly general with re-
spect to the donor group on the diazoacetates, as cyclopropanes
3ae3c were formed in high yields and high levels of enantiose-
lectivity when the reactions were conducted at room temperature.
Both 4-bromophenyl and styryl substituted TMSE diazoacetates
yielded the cyclopropanes 3b and 3c with fairly high levels of
enantioinduction (88% and 85% ee, respectively, entries 2 and 3).
Both electron-withdrawing and electron-donating substituents
were well tolerated on the styrene derivative as well (entries 4e7).
Both the 4-methoxy and 4-trifluoromethyl substituted styrenes
afforded the cyclopropanes in 72% yield. The 4-acetoxy and 4-
Table 2
Substrate scope of the cyclopropanation of TMSE aryldiazoacetates and styrenes
Entry
1
Product
rt (% yield, % ee)
ꢀ40 ꢁC(% yield, % ee)
86% yield
88% ee
69% yield
96% ee
2
3
4
5
6
7
73% yield
89% ee
63% yield
96% ee
64% yield
85% ee
71% yield
87% ee
2. Results and discussion
The study began with the reaction of TMSE phenyldiazoacetate
1a and styrene 2a to determine the optimal chiral dirhodium(II)
catalyst for the formation of cyclopropane 3a as a single di-
astereomer with high levels of enantioselectivity. Of the catalysts
screened, Rh2(S-DOSP)4 provided the highest yield and level of
enantioinduction, producing 3a in 87% yield and 87% ee (Table 1,
61% yield
88% ee
65% yield
96% ee
72% yield
81% ee
76% yield
91% ee
Table 1
Chiral dirhodium(II)-catalyzed cyclopropanation of TMSE phenyldiazoacetate and
styrene
72% yield
84% ee
50% yield
96% ee
Entry
Catalyst
Yield (%)
ee (%)
1
2
3
4
Rh2(S-DOSP)4
Rh2(S-BTPCP)4
Rh2(S-PTAD)4
Rh2(S-NTTL)4
87
67
46
35
87
43
74% yield
86% ee
67% yield
96% ee
ꢀ35
ꢀ51
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S. Negretti et al. / Tetrahedron xxx (2015) 1e6
3
bromo substituted styrenes afforded the cyclopropanes 3d and 3f
in good yields and similar enantioselectivity (88% ee and 86% ee,
respectively, entries 4 and 7). Good yields and moderately high
levels of enantioselectivity were observed in all cases (81e88% ee).
The asymmetric induction could be further improved by lowering
the reaction temperature to ꢀ40 ꢁC. In nearly all cases, the products
were formed with >90% ee. The absolute configuration of the
products was assigned based on the previously proposed model.21
For confirmation, 3a was hydrolyzed to the acid, and converted the
corresponding methyl ester, whose absolute configuration is re-
ported in the literature (see Supplementary data).22
The reaction was then applied to the enhanced synthesis of the
Rh2(S-BTPCP)4 ligand. The cyclopropanation of 2g with 1b afforded
cyclopropane 4 in 73% yield and 88% ee (Scheme 1, Eq. 1). The TMSE
ester was then cleaved under mild conditions using tetrabuty-
lammonium fluoride (TBAF) in DMF to yield the ligand 5 in 81%
complete racemization of the chiral center (Scheme 1, Eq. 2). Syn-
thesis of ligand 8 in an enantiomerically enriched form was suc-
cessfully achieved employing TMSE diazo compound 9 together
with Rh2(S-PTTL)4 as the chiral catalyst in the cyclopropanation to
form 10 in 91% ee, which was with TBAF (Scheme 1, Eq. 3) to give 8
without loss of enantioenrichment.
Next, we explored the use of TCE aryldiazoacetates in cyclo-
propanation reactions. A catalyst screen was performed to find the
optimal conditions for this transformation (Table 3). Rh2(S-DOSP)4
afforded the desired cyclopropane 12a in good yield and moder-
ately high enantioselectivity, 88% yield and ꢀ83% ee, while the yield
and enantioinduction decreased with Rh2(S-PTAD)4 to 64% yield
and 62% ee (entries 1e2). The use of dirhodium(II) triar-
ylcyclopropanecarboxylate catalysts greatly enantioselectivity of
the reaction (entries 3e9). In pentane, Rh2(S-BTPCP)4 and Rh2(R-
BPCP)4 provided 12a in ꢀ90% ee and 70% ee, respectively. The po-
larity of the solvent had substantial effects on the enantioselectivity
with these catalysts, particularly with Rh2(R-BPCP)4, which in DCM
resulted in the formation of 12a n 69% yield and 96% ee (entry 5).
Similar results were observed with DCE as solvent, but the enan-
tioselectivities were slightly lower than in DCM (entries 7e9). The
absolute configuration of the product was assigned by hydrolysis of
the TCE ester and subsequent conversion into the corresponding
methyl ester, which is known in the literature.28
The scope of the reaction was examined using the optimized
conditions of 0.5 mol % of Rh2(R-BPCP)4 in DCM at room temper-
ature and the results are summarized in Table 4. In the Rh2(R-
BPCP)4 catalyzed cyclopropanation of styrene with TCE diazo-
acetates, both electron-donating groups and electron-withdrawing
groups were tolerated (Table 4). The t-butyl-substituted cyclopro-
pane 12b was obtained in good yields and excellent enantiose-
lectivity (74% yield, 98% ee), whereas the electron-withdrawing 4-
fluoro TCE diazoacetate yielded the desired cyclopropane 12c in
58% yield and 93% ee (entries 1e2). Additionally, heterocycles such
as pyridines and isoxazoles are tolerated as the aryl group of the
TCE diazoacetates. Cyclopropanes 12d and 12e were obtained in
moderate yields, 61% and 63% respectively, and excellent levels of
enantioselectivity, 93% ee and 85% ee respectively (entries 3e4).
TCE styryldiazoacetate was also well tolerated and cyclopropane
12f was formed with high yield and enantioinduction (90% yield
and 93% ee, entry 5), whereas with the TMSE stryldiazoacetate 1c
the highest level of enantioselectivity observed was 87% ee. Upon
modification of the styrene unit, cyclopropane 12h, the TCE pre-
cursor for the Rh2(R-BTPCP)4 ligand, was obtained in good yields
and moderately high enantioselectivity (77%, 86% ee, entry 6). The
electronics of the styrene had little effect on the enantioselectivity
of the reaction, as both cyclopropanes 12i and 12j, with 4-methoxy
Scheme 1. Synthesis of triarylcyclopropane carboxylate ligands through TMSE ar-
yldiazoacetate cyclopropanation. (a) Rh2(S-DOSP)4, pentane rt (b) TBAF, DMF, 81%, 88%
ee (c) Rh2(S-DOSP)4, pentane, PhCF3, 82%, 96% ee (d) KOtBu, DMSO (e) Rh2(S-PTTL)4,
pentanes, PhCF3, e78 ꢁC, 87%, 91% ee (f) TBAF, DMF, 77%, 91% ee.
yield. Most importantly the enantioselectivity remained un-
changed after the hydrolysis. Additionally, this material was
recrystallized from pentane/diethyl ether and enriched to high
optical purity (>99.5% ee). An excellent example of the utility of the
TMSE esters can be seen from the synthesis of 8 (Scheme 1, Eqs. 2
and 3). Though cyclopropanation of methyl 2-diazo-2-(4-
nitrophenyl)acetate 6 and 2g afforded cyclopropane 7 in 82%
yield and 96% ee, the vigorous hydrolysis conditions resulted in
Table 3
Chiral dirhodium (II)-catalyzed cyclopropanation of TCE 4-bromophenyldiazoacetate and styrene
Entry
Catalyst
Catalyst loading (mol %)
Solvent
Temp (ꢁC)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Rh2(S-DOSP)4
Rh2(S-PTAD)4
Rh2(S-BTPCP)4
Rh2(R-BPCP)4
Rh2(R-BPCP)4
Rh2(S-BTPCP)4
Rh2(R-BPCP)4
Rh2(S-BTPCP)4
Rh2(R-BPCP)4
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
pentane
pentane
pentane
pentane
DCM
DCM
DCE
DCE
DCE
rt
rt
rt
rt
rt
rt
rt
rt
0
88
64
81
80
69
73
71
68
70
ꢀ83
62
ꢀ90
70
96
ꢀ95
92
ꢀ90
95
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4
S. Negretti et al. / Tetrahedron xxx (2015) 1e6
Table 4
withdrawing nature of the TCE ester group protects against for-
mation of
-lactones from intramolecular CeH insertion.31e33 The
Substrate scope of the cyclopropanation of TCE aryldiazoacetates and styrenes
b
TCE aryldiazoacetates have been reported recently as robust re-
agents and were successfully applied to the selective asymmetric
CeH functionalization of methyl ethers by the Davies group.26
Furthermore, the TCE group can be used with hetero-
aryldiazoacetates generating heteroaryl-substituted cyclopro-
panes, further expanding the scope of the reaction. Like TMSE, the
TCE ester can be cleaved under mild conditions with Zn/AcOH (see
Supplementary data). Finally, the TCE diazoacetates afford cyclo-
propanes with high levels of enantioinduction in Rh2(R-BPCP)4 in
DCM, a complementary catalyst/solvent system to Rh2(S-DOSP)4
in pentane.
Entry
1
Product
Yield (%)
74
ee (%)
98
3. Conclusion
2
3
4
5
58
61
63
90
93
93
88
93
This study describes intermolecular asymmetric cyclo-
propanations of aryldiazoacetates containing different ester groups
and styrene derivatives catalyzed bychiral dirhodium (II) complexes
Rh2(S-DOSP)4 and Rh2(R-BPCP)4. The TMSE aryldiazoacetates afford
cyclopropanes in high yields and good enantioselectivity (61e86%
yield, 81e88% ee) with Rh2(S-DOSP)4 as the chiral catalyst in pen-
tane. The enantioinduction can be further improved by lowering the
reaction temperature to ꢀ40 ꢁC (87e96% ee). The reaction was tol-
erant of different functionality on the styrene as well as in the aryl
group of the TMSE diazoacetates. The TCE aryldiazoacetates afford
the cyclopropanes in high yields and good enantioselectivity
(61e90% yield, 85e98% ee) with Rh2(R-BPCP)4 as the chiral catalyst
in DCM, even at room temperature. This study hallmarks the im-
portance and effect of the ester group in chiral dirhodium-(II) cat-
alyzed cyclopropanations of aryldiazoacetates. Finally, this study
serves as the cornerstone for our ongoing program to develop tri-
arylcyclopropane carboxylates as ligands for the synthesis of novel
chiral dirhodium (II) catalysts.
4. Experimental section
4.1. General
6
77
86
All reactions were conducted under anhydrous conditions in
oven-dried glassware under an inert atmosphere of dry argon,
unless otherwise stated. Hexanes, pentane, and toluene were dried
by a solvent purification system (passed through activated alumina
columns). All solvents were degassed by bubbling argon through
the solvent for a minimum of 10 min prior to use. All dirhodium(II)
catalysts were lyophilized for 48 h from benzene prior to use with
a VirTis Benchtop K lyophilizer. Unless otherwise noted, all other
reagents were obtained from commercial sources and used as re-
ceived. 1H Nuclear Magnetic Resonance (NMR) spectra were
recorded at 400 MHz or 600 MHz. Data presented as follows:
7
8
90
64
94
95
chemical shift (in ppm on the
d scale relative to dH 7.26 for the
residual protons in CDCl3), coupling constant (J/Hz), integration.
Coupling constants were taken directly from the spectra and are
uncorrected. 13C NMR spectra were recorded at 100 MHz and all
chemical shift values are reported in ppm on the
d scale, with an
and 4-chloro substituents respectively, were obtained in greater
than 94% ee, albeit in a lower yield for 12j (90% and 64% yield
respectively).
internal reference of dC 77.00 for CDCl3. Mass spectral de-
terminations were carried out by using APCI or NSI as ionization
source. Melting points are uncorrected. Infrared spectral data are
reported in units of cmꢀ1. Analytical TLC was performed on silica
gel plates using UV light. Flash column chromatography was per-
These novel TCE and TMSE esters offer several advantages over
the methyl ester. The TMSE group provides the advantage of very
mild hydrolysis conditions as well as providing high levels of
enantioinduction with the benchmark catalyst Rh2(S-DOSP)4 in
non-polar solvents. The additional steric bulk provided by TCE
and TMSE aryldiazoacetates diminish dimerization of the diazo
compound, which is often encountered as a side product, partic-
ularly in CeH insertions.29,30 Additionally the electron-
ꢀ
formed on silica gel 60 A (230e400 mesh). Optical rotations were
measured on Jasco polarimeters. Enantioselectivity was de-
termined using chiral HPLC on a Varian Prostar instrument, with
isopropanol/hexanes as the eluent. Chiral HPLC conditions were
determined analysis of racemic material, obtained by cyclo-
propanation with Rh2(R/S-DOSP)4 and Rh2(OOct)4.
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S. Negretti et al. / Tetrahedron xxx (2015) 1e6
5
4.2. General procedures for the synthesis of diazo compounds
in pentane (3 mL). The flask was cooled down to ꢀ40 ꢁC by means
of an acetonitrile/dry ice bath. Once cooled, a solution of diazo
(0.5 mmol, 1.0 equiv) in pentane (3 mL) was added to the reaction
mixture dropwise over 1 h via syringe pump. The reaction was
allowed to stir at ꢀ40 ꢁC for at least 1 h after the addition was
complete. The volatiles were removed by rotary evaporation, and
the crude residue was purified by silica gel column chromatography
(Hexanes:EtOAc or pentane:ether).
4.2.1. General procedure for the preparation of TMSE
aryldiazoacetates. A solution of the corresponding carboxylic acid
(1.0 equiv), DMAP (0.1 equiv), and 2-(trimethylsilyl)ethanol
(1.2 equiv) in DCM (0.6 M in acid) was cooled to 0 ꢁC. Then a solu-
tion of N,N0-dicyclohexylcarbodiimide (DCC) (1.1 equiv) in DCM
(2.6 M) was quickly poured into the cold reaction mixture. The
solution was stirred overnight, after, which time it had warmed to
room temperature. The precipitate was removed by filtration,
washing several times with Et2O. The filtrate was concentrated and
the crude material purified by column chromatography (EtOAc in
hexanes) to give the TMSE ester intermediate as a colorless oil.
The TMSE arylacetate (1 equiv) and p-ABSA (1.3 equiv) were
dissolved in acetonitrile and cooled to 0 ꢁC using an ice bath under
an argon atmosphere. 1,8-Diazabicycloundec-7-ene (DBU,
2.0 equiv) was then added dropwise to the stirring mixture over the
course of 1 min. The reaction mixture was allowed to stir for 24 h at
while warming to room temperature. The resulting orange solution
was quenched with saturated aqueous NH4Cl and the aqueous layer
was extracted with diethyl ether (3x). The organic layer was then
washed with deionized H2O to remove any residual salts. The
combined organic layers were dried over MgSO4 and filtered. The
organic layer was then concentrated under reduced pressure. The
residue was purified via flash chromatography on silica gel.
4.4. General procedure for the Rh2(R-BPCP)4 catalyzed
cyclopropanation
In a 25-mL round bottom flask equipped with a magnetic stir
bar, Rh2(R-BPCP)4 (4.4 mg, 0.5 mol %) and styrene (0.12 mL,
1.0 mmol, 2.0 equiv) were dissolved 2 mL DCM at room tempera-
ture. A solution of the diazo (0.5 mmol, 1.0 equiv) in 5 mL DCM was
added dropwise to the reaction mixture via syringe pump over
30 min. The reaction was allowed to stir at rt for at least 1 h after the
addition was complete. The solvent was removed, and the crude
residue was purified by silica gel column chromatography (diethyl
ether:pentanes) to give the desired product.
Acknowledgements
Changming Qin is acknowledged for preliminary data on the
synthesis of 8 from the methyl ester 7 and the observation that the
hydrolysis of the methyl ester in 7 results in racemization of the
product. This work was supported by the National Science Foun-
dation under the CCI Center for Selective CeH Functionalization,
CHE-1205646, the National Institutes of Health (GM099142) and
unrestricted support from Novartis.
4.2.2. General
procedure
for
the
preparation
of
TCE
aryldiazoacetates. A solution of the corresponding carboxylic acid
(1.0 equiv), DMAP (0.1 equiv), and 2,2,2-trichloroethanol (1.2 equiv)
in DCM (0.6 M in acid) was cooled to 0 ꢁC. Then a solution of DCC
(1.1 equiv) in DCM (2.6 M) was quickly poured into the cold reaction
mixture. The solution was stirred overnight, after which time it had
warmed to room temperature. The precipitate was removed by
filtration, washing several times with Et2O. The filtrate was con-
centrated and the crude material purified by column chromatog-
raphy (EtOAc in hexanes) to give the TCE ester intermediate as
a colorless oil.
The TCE arylacetate (1 equiv) and o-NBSA (1.3 equiv) were dis-
solved in acetonitrile and cooled to 0 ꢁC using an ice bath under an
argon atmosphere. 1,8-Diazabicycloundec-7-ene (DBU, 2.0 equiv)
was then added dropwise to the stirring mixture. After the addition
of the DBU, the reaction mixture continued to stir at 0 ꢁC for 2 h. The
resulting orange solution was quenched with saturated NH4Cl and
the aqueous layer was extracted with diethyl ether (3x). The or-
ganic layer was then washed with deionized H2O to remove any
residual salts. The combined organic layers were dried over MgSO4
and filtered. The organic layer was then concentrated under re-
duced pressure. The residue was purified via flash chromatography
on silica gel (EtOAc in hexanes).
Supplementary data
Supplementary data (Detailed experimental for the compounds,
HPLC traces for all chiral compounds, 1H NMR and 13C NMR spectra
for all new compounds are described in Supplementary data.
Supplementary data associated with this article can be found in the
online version.) related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.045.
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4.3. General procedures for Rh2(S-DOSP)4 catalyzed
cyclopropanation
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4.3.1. Room temperature reaction. In a 25-mL round bottom flask
equipped with
a magnetic stir bar, Rh2(S-DOSP)4 (9.28 mg,
0.005 mmol, 1 mol %) and styrene (0.29 mL, 2.5 mmol, 5.0 equiv)
were dissolved in pentane (3 mL). To this was added a solution of
diazo (0.5 mmol, 1.0 equiv) in pentane (3 mL) dropwise over 1 h via
syringe pump. The reaction was allowed to stir at rt for at least 1 h
after the addition was complete. The volatiles were removed by
rotary evaporation, and the crude residue was purified by silica gel
column chromatography (Hexanes:EtOAc or pentane:ether).
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4.3.2. ꢀ40 ꢁC reaction. In a 25-mL round bottom flask equipped
with a magnetic stir bar, Rh2(S-DOSP)4 (9.28 mg, 0.005 mmol,
1 mol %) and styrene (0.29 mL, 2.5 mmol, 5.0 equiv) were dissolved
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M. L. J. Am. Chem. Soc. 2011, 133, 19198.
Please cite this article in press as: Negretti, S.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.045

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S. Negretti et al. / Tetrahedron xxx (2015) 1e6
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Please cite this article in press as: Negretti, S.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.045