General Synthesis of Cyclopropanols via Organometallic Addition to 1-Sulfonylcyclopropanols as Cyclopropanone Precursors

Article abstract of DOI:10.1021/acs.orglett.0c02303

The addition of organometallic reagents to ketones constitutes one of the most straightforward synthetic approaches to tertiary alcohols. However, due to the absence of a well-behaved class of cyclopropanone surrogates accessible in enantioenriched form, such a trivial synthetic disconnection has received very little attention in the literature for the formation of tertiary cyclopropanols. In this work, we report a simple and high-yielding synthesis of 1-substituted cyclopropanols via the addition of diverse organometallic reagents to 1-phenylsulfonylcyclopropanols, acting here as in situ precursors of the corresponding cyclopropanones. The transformation is shown to be amenable to sp-, sp2-, or sp3-hybridized organometallic C-nucleophiles under mild conditions, and the use of enantioenriched substrates led to highly diastereoselective additions and the formation of optically active cyclopropanols.

Full text of DOI:10.1021/acs.orglett.0c02303

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Letter
General Synthesis of Cyclopropanols via Organometallic Addition to
‑Sulfonylcyclopropanols as Cyclopropanone Precursors
1
Roger Machín Rivera, Yujin Jang, Christopher M. Poteat, and Vincent N. G. Lindsay*
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ABSTRACT: The addition of organometallic reagents to ketones constitutes one of the most straightforward synthetic approaches
to tertiary alcohols. However, due to the absence of a well-behaved class of cyclopropanone surrogates accessible in enantioenriched
form, such a trivial synthetic disconnection has received very little attention in the literature for the formation of tertiary
cyclopropanols. In this work, we report a simple and high-yielding synthesis of 1-substituted cyclopropanols via the addition of
diverse organometallic reagents to 1-phenylsulfonylcyclopropanols, acting here as in situ precursors of the corresponding
2
3
cyclopropanones. The transformation is shown to be amenable to sp-, sp -, or sp -hybridized organometallic C-nucleophiles under
mild conditions, and the use of enantioenriched substrates led to highly diastereoselective additions and the formation of optically
active cyclopropanols.
yclopropanols constitute versatile building blocks for the
elaboration of complex natural products and pharma-
Scheme 1. Common Approaches to Tertiary
Cyclopropanols
C
1
,2
ceuticals.
In particular, extensive chemistry has been
developed over the last decades by using the intrinsic
propensity of cyclopropanols to act as homoenolate equiv-
alents in the presence of a variety of transition metals and
3
(
pseudo)electrophiles. For example, the pluripotential of
cyclopropanols was recently demonstrated via late-stage
functionalization, affording different derivatives of chlamydo-
4
cin, a histone deacetylase inhibitor. Despite the obvious
relevance of cyclopropanols in the construction of biologically
relevant molecules, the development of novel and general
methods for the formation of enantioenriched tertiary
5
,6
derivatives, leading to β-nucleophilic ketone equivalents,
7
,8
has remained scarce. The most conventional approaches to
tertiary cyclopropanols include the cyclopropanation of enols
3
e,9,10
using carbenoid species (Scheme 1a)
or the Kulinkovich
11−13
cyclopropanation of esters (Scheme 1b),
both of which
competitively equilibrate to β-nucleophilic esters in basic
are rarely amenable to the formation of enantioenriched
products and possess considerable limitations in terms of
3,18
conditions,
overall reducing the yield of desired cyclo-
14
propanol. On the other hand, the direct organometallic
addition to the parent cyclopropanone itself is very rarely a
viable approach, mainly due to the extreme kinetic instability
practicality and sustainability. A distinct approach, which
consists of introducing the C(1)-substituent last via
nucleophilic addition to a cyclopropanone surrogate, is not
general mainly due to the absence of suitable precursors readily
accessible in enantioenriched form (Scheme 1c). Indeed, as
19
and difficulty of preparation of such highly strained ketones,
typically using ketenes and explosive diazomethane.
20,21
15,16
initially reported by Wasserman,
cyclopropanone hemi-
Received: July 10, 2020
ketals can be used as substrates to afford tertiary cyclo-
propanols via equilibration to cyclopropanones and reaction
with Grignard reagents, though these typically require harsh
conditions to react and are not generally accessible in optically
1
7
active form, precluding their general use for this purpose.
Moreover, these same hemiketal reagents are also known to
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02303
A
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Letter
In 2008, Chen reported a new crystalline, bench-stable, and
particularly well-behaved precursor of unsubstituted cyclo-
tertiary alkoxide 2′ initially produced to residual cyclo-
propanone species present in solution. As such an addition is
reversible, warming the reaction to room temperature for a
longer period of time eventually eliminated these undesired
oligomers and offered reasonable yields of 2a (entry 4). A
survey of various ethereal solvents revealed that THF and t-
22
propanone, 1-phenylsulfonylcyclopropanol. In our group, we
recently reported a general enantioselective method allowing
access to different substituted cyclopropanone precursors of
this type in two simple steps starting from readily available
2
3
24
substrates. With general access to this new type of highly
reactive cyclopropanone precursor now established, we
envisioned that we could use them to access a wide variety
of tertiary cyclopropanols. Herein, we report a simple and
general high-yielding synthesis of 1-substituted cyclopropanols
via the addition of diverse organometallic reagents to 1-
phenylsulfonylcyclopropanol derivatives, acting here as in situ
precursors of the corresponding cyclopropanones (Scheme
BuOMe both provided good yields of product (entries 4−6).
Lowering the concentration (entry 7) or using a slight excess
of nucleophile (entry 8) both improved the reaction efficiency,
and combining this information led to an excellent isolated
yield of 91% (entry 9). While our reaction represents a distinct
synthetic disconnection, it is interesting to note that
25
26
Kulinkovich (75%) and enol cyclopropanation (39%)
approaches typically afford significantly lower yields for the
formation of 2a.
1
d). To avoid the use of excess nucleophile, a variant using
MeMgBr as a base to trigger the initial equilibration to
cyclopropanone is also included, and the use of enantioen-
riched substituted derivatives is shown to afford optically active
tertiary cyclopropanols in high yields and complete diaster-
eoselectivity for the cis product.
Using cyclopropanone precursor 1a and p-methoxyphenyl-
magnesium bromide as model substrates, we first investigated
various conditions to access tertiary cyclopropanol 2a (Table
In an effort to avoid the use of excess Grignard reagent used
in the reaction, we sought to evaluate external bases that would
play the role of triggering equilibration to cyclopropanone.
Indeed, especially for the construction of natural products or
other complex molecules, the nucleophile could be valuable
and should not be wasted in a simple deprotonation step. To
do so, we evaluated different bases and initial temperatures that
would promote such deprotonation while avoiding equilibra-
tion to unstable cyclopropanone until addition of the desired
nucleophile (Table 2). While strong lithium and sodium bases
1
). In such a situation, an excess of Grignard reagent (>2
Table 1. Method A Optimization: Grignard As Sacrificial
Base
Table 2. Method B Optimization: Grignard Economy via
the Use of an External Base
a
entry equiv
solvent
temp (°C) conc (M) time (h) yield (%)
a
b
,
c
,
d
entry
base
LDA
LDA
NaH
equiv
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2.2
2.2
THF
THF
THF
THF
0
−78
1.0
1.0
1.0
1.0
1.0
1.0
0.10
1.0
5
5
2
5
5
5
5
5
5
71
,
cd
ND
bc
,
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
0.95
0.95
0
−78
0
0
0
10
15
7
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
0 to rt
62
75
78
63
86
89
t-BuOMe
Et N
3
7
Et O
MeMgBr
MeMgBr
MeMgBr
60
79
2
THF
THF
THF
−78
−78
−78
1
b
86 (86)
0.10
91
b
(n-Bu) Mg
2
92
a
a
Isolated yield on 0.25 mmol scale unless otherwise noted. Yield
Yield on 0.25 mmol scale determined by H NMR using 1,3,5-
trimethoxybenzene as standard. Isolated yield in parentheses.
1
b
determined by H NMR using 1,3,5-trimethoxybenzene as standard.
a could not be isolated due to the presence of unseparable dimeric
c
2
d
product 3. Reaction was quenched at low temperature.
led to extensive decomposition and polymerization likely due
to the formation of free cyclopropanone in solution (entries
equiv) is required since 1 equiv is initially consumed to
deprotonate the hydroxyl group in 1a and trigger its
equilibration to cyclopropanone. Surprisingly, while running
the reaction at 0 or −78 °C (entries 1 and 2) or using a short
reaction time (entry 3) afforded complete consumption of 1a,
only small amounts of desired 2a could be isolated in pure
form. Further analysis of the crude mixture revealed the
presence of unseparable oligomers such as 3 as the main side
products (Scheme 2), resulting from the addition of the
1−3), weaker bases such as Et N only afforded poor
3
conversion (entry 4). In contrast, the use of a cheaper
Grignard reagent (MeMgBr) as initial base led to a magnesium
alkoxide intermediate more stable than its lithium or sodium
analogues and could be sustained at low temperature for longer
periods of time, affording an optimal yield of 2a when added in
substoichiometric amount at −78 °C and warmed to room
temperature after the addition of the nucleophile (entries 5−
7). Although (n-Bu) Mg afforded a slightly higher yield (entry
2
8), MeMgBr was selected as ideal base for the method due to
Scheme 2. Formation of Undesired Dimeric Products 3
its lower price and increased functional group compatibility.
In preliminary scope studies with these methods, we noticed
that alkyl Grignard reagents afforded only poor yields of the
desired addition products and significant decomposition, likely
due to their increased basicity (Table 3, entry 1). To address
this, we imagined that the use of softer organometallic reagents
B
https://dx.doi.org/10.1021/acs.orglett.0c02303
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Table 3. Method C Optimization: Access to 1-Alkyl-
Substituted Cyclopropanols via Transmetalation
Scheme 3. Scope of Accessible 1-Substituted
a
Cyclopropanols
a
entry
MXn
temp (°C)
yield (%)
b
1
2
3
4
5
6
7
8
none
CeCl3
CuCN
FeCl2
rt
0
<20
30
20
27
61
10
47
0 to rt
rt
0
−78 to rt
0 to rt
0 to rt
c
Et Zn
2
c
Et Zn
2
d
Bn Zn
2
e
f
(TMSCH ) Zn
76
2
2
a
1
Yield determined by H NMR using 1,3,5-trimethoxybenzene as
b
1
c
standard. Significant decomposition observed by H NMR. Slow
addition of Grignard reagent via syringe pump. Prepared in situ from
Zn(OMe) (2.2 equiv) and BnMgCl (2.2 equiv).
d
32a e
Prepared in situ
2
from ZnCl (1.2 equiv), TMSCH MgCl (2.4 equiv), and LiCl (6
2
2
f
equiv) and reaction run for 12 h. Isolated yield.
accessible through in situ transmetalation could potentially
help solve this issue. For instance, organometallic reagents
2
7
28
29
30
31
32
based on Ce, Fe, Cu, Ce, La, and Zn are known to
smoothly add to enolizable ketones in appropriate conditions.
We thus started evaluating different transition metals using
benzylmagnesium chloride as reagent, leading to adduct 2p
a
All yields correspond to yields of isolated product on 0.25 mmol
(
entries 2−8). While the use of cerium-, copper-, or iron-based
b
scale of 1a unless otherwise noted. Isolated yield on 2.5 mmol scale
reagents afforded the product in only low yields (entries 2−4),
zinc salts, and particularly mixed Si-stabilized zincates formed
c
of 1a in parentheses. Reaction was stirred at rt for 16 h instead of 5 h.
d
32c
Using (phenylethynyl)lithium (2.2 equiv), at −78 °C to rt.
using Ishihara’s method, led to a good isolated yield of 2p
(
entry 8).
Scheme 4. Synthesis of Enantioenriched 1,2-Disubstituted
Cyclopropanols
With these methods in hand and using 1a as substrate,
,
a b
evaluation of various organometallic nucleophiles revealed an
impressive generality for the formation of achiral tertiary
cyclopropanols (Scheme 3). Both electron-rich (2a−2c) and
electron-poor (2d−2h) para- or meta-substituted arylmagne-
sium bromides generally afforded good isolated yields of 1-aryl-
substituted cyclopropanols. More hindered ortho-substituted
reagents were also found to be compatible in the trans-
formation (2i−2l), as well as phenyl (2m), heteroaryl- (2n),
and alkynyl-substituted (2o) nucleophiles. Notably, as the
difference between methods A and B is simply the nature of
the Grignard reagent effecting the initial deprotonation and no
major change in the reaction mechanism is expected, both
approaches generally lead to similar efficiency for a given
nucleophile. Moreover, method C proved to be useful for the
formation of 1-alkylcyclopropanols 2p and 2q in moderate to
good yields.
a
All yields correspond to yields of isolated product on 0.25 mmol
b
scale of 1b or 1c. Enantiomeric excesses were determined by HPLC
analysis using a chiral stationary phase (ee of starting material 1b or
1
Our group recently reported a simple approach to optically
active substituted 1-sulfonylcyclopropanols, which constitutes
c in parentheses).
23
the first general enantioselective route to cyclopropanones.
Using this method, enantioenriched substrates 1b and 1c were
prepared and evaluated in our addition reaction (Scheme 4).
Gratifyingly, highly enantioenriched aryl- and vinyl-substituted
tertiary cyclopropanols 2r−2t were thus obtained in good to
excellent yields using modified method A, affording complete
diastereoselectivity for the cis isomer, as evidenced by X-ray
analysis of 2s (Scheme 4a). Employing our modified method C
instead, 1-benzyl-substituted product 2u could also be
obtained in highly enantioenriched form and as a single
diastereomer, albeit with some erosion of enantiomeric excess
(Scheme 4b). This partial loss of optical activity is likely a
consequence of the use of a zincate as effective nucleophile,
where the zinc alkoxide initially formed can equilibrate to its
zinc-homoenolate form prior to protonation at the end of the
3
,33,34
reaction.
To the best of our knowledge, these examples
constitute the first enantioselective syntheses of cyclopropanols
via the addition of nucleophiles to cyclopropanone equivalents.
The tertiary cyclopropanols obtained through these methods
are known substrates used for further functionalization through
3
35
homoenolate chemistry, including sulfonylation, alkynyla-
C
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Letter
3
6
37
38
tion, halogenation, cross-coupling, C−H functionaliza-
Authors
3
9
40
tion, and formal cycloadditions reactions, all of which
typically occur via the corresponding metal alkoxide.
Cognizant of this, we envisioned that such β-functionalized
ketones could potentially be obtained in a one-pot, sequential
fashion starting from a cyclopropanone surrogate (Scheme 5).
Roger Machín Rivera − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695,
United States
Yujin Jang − Department of Chemistry, North Carolina State
University, Raleigh, North Carolina 27695, United States
Christopher M. Poteat − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695,
United States
Scheme 5. One-Pot Sequential Addition and Homoenolate
β-Functionalization: Cyclopropanone as a Three-Carbon
Linchpin
a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02303
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by North Carolina State University
startup funds. All X-ray, NMR, and HRMS measurements were
performed by the Molecular Education, Technology, and
Research Innovation Center (METRIC) at NC State
University, which is supported by the State of North Carolina.
We are grateful to Dr. Roger D. Sommer for X-ray analysis of
compound 2s. R.M.R. is grateful to NC State University for
Diversity Graduate Assistance grants. Y.J. is grateful to NC
State University for a Burroughs Wellcome Fellowship in
Organic Chemistry. C.M.P. is grateful to NC State University
for a Percy Lavon Julian Award in Organic Chemistry.
a
All yields correspond to yields of isolated product directly from 1a
(
0.25 mmol scale).
As such and using method A, γ-ketosulfone 4 and β,γ-
alkynylketone 5 could thus be obtained directly from substrate
1
a using known copper-mediated conditions, following
addition of p-methoxyphenylmagnesium bromide as nucleo-
phile.
In summary, we report a general high-yielding synthesis of
3
5,36
2
3
tertiary cyclopropanols via the addition of sp-, sp -, or sp -
hybridized organometallic C-nucleophiles to 1-phenylsulfonyl-
cyclopropanol derivatives, acting here as in situ precursors of
the corresponding cyclopropanones. A Grignard economy
variant using MeMgBr as external base to initiate the
equilibrium to cyclopropanone is also included, and the use
of enantioenriched substituted derivatives is shown to afford
optically active tertiary cyclopropanols in high yields and
complete diastereoselectivity. The addition of other nucleo-
philes to 1-sulfonylcyclopropanols as cyclopropanone surro-
gates and subsequent rearrangements are currently ongoing in
our laboratories and will be reported in due course.
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