Highly enantioselective simmons-smith fluorocyclopropanation of allylic alcohols via the halogen scrambling strategy of zinc carbenoids

Article abstract of DOI:10.1021/ja402393w

Highly enantio- and diastereoenriched monofluorocyclopropanes were accessed via the Simmons-Smith fluorocyclopropanation of allylic alcohols using difluoroiodomethane and ethylzinc iodide as the substituted carbenoid precursors. The scrambling of halogens

Full text of DOI:10.1021/ja402393w

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Communication
Highly Enantioselective Simmons-Smith Fluorocyclopropanation of
Allylic Alcohols via the Halogen Scrambling Strategy of Zinc Carbenoids
Louis-Philippe B. Beaulieu, Jakob F. Schneider, and André B. Charette
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402393w • Publication Date (Web): 09 May 2013
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Highly Enantioselective Simmons-Smith Fluorocyclopropa-
nation of Allylic Alcohols via the Halogen Scrambling
Strategy of Zinc Carbenoids
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Louis-Philippe B. Beaulieu, Jakob F. Schneider and André B. Charette*
Centre in Green Chemistry and Catalysis, Department of Chemistry, Université de Montréal, P.O. Box 6128, Station
Downtown, Montréal, Québec, Canada H3C 3J7.
Supporting Information Placeholder
ABSTRACT: Highly enantio- and diastereoenriched monofluorocy-
clopropanes were accessed via the Simmons-Smith fluorocyclopropa-
(a) Previous work from Hu
cis
nation of allylic alcohols using difluoroiodomethane and ethylzinc
Li
O
NHTs
F
iodide as the substituted carbenoid precursors. The scrambling of hal-
ogens at the zinc carbenoid led to the formation of the fluorocyclopro-
panating agent (fluoroiodomethyl)zinc(II) fluoride. This strategy
circumvented the ongoing limitation in Simmons-Smith fluorocyclo-
propanations relying on the use of the relatively inaccessible and ex-
pensive carbenoid precursor fluorodiiodomethane.
S
F
Ph
OMe
N
O
1
O
R1
Me
R1
N
O
(b) This work
ICHF2
F
ZnI
IZnEt
-EtI
F
I
halogen
scrambling
*
O
F
ZnF
F
B
O
O
Organofluorine compounds elicit significant interest in medicinal
and agrochemistry as they display enhanced metabolic stability, lipo-
philicity and have distinctive physicochemical properties when com-
pared to their isosteric dehalogenated analogues. There is also a grow-
ing body of evidence pointing towards a marked increase in binding
efficacy and selectivity in pharmaceuticals comprising fluorine atoms.1
As a testament to the promise of organofluorine chemistry, nearly 20%
of all pharmaceuticals and 40% of agrochemicals under development
contain fluorine.2 It is therefore increasingly necessary to develop syn-
thetic routes for the incorporation of fluorine atoms into organic scaf-
folds in order to study the effect of hydrogen to fluorine substitutions.
R3
trans
i) Et2Zn
Bu
R3
ZnEt
R2
R3
R1
R2
OH
ii)
R1
CONMe2
CONMe2
R1
OH
O
R2
B
O
Bu
2
Scheme 1. Highly enantioselective monofluorocyclopropana-
tion reactions
Our group has lately been interested in the enantioselective Sim-
mons-Smith monohalocyclopropanation of allylic alcohols using a
dioxaborolane chiral ligand (2), leading to the cyclopropane products
in which the halogen atom has a trans relationship to the proximal basic
alcohol group. Highly stereoselective iodo- and chlorocyclopropana-
tion reactions have thus been achieved with substituted zinc carbe-
noids derived from diethylzinc and the corresponding haloform (CHI3
Monofluorocyclopropanes have become prime synthetic targets as
they combine the advantages of organofluorine compounds with the
added structural rigidity and metabolic stability of cyclopropanes,
which act as alkene3 and peptide bond4 bioisosteres. In spite of the
considerable efforts to develop methodologies for the preparation of
monofluorocyclopropanes, limited progress has been accomplished for
their asymmetric synthesis, which relies in most cases on the cyclopro-
8
9
and ClCHI2, respectively,).
6
panation of alkenyl fluorides.5, Hu and collaborators have recently
While numerous Simmons-Smith monoiodo-, bromo- and chloro-
10
cyclopropanation reactions have been reported, there is a dearth of
monofluorocyclopropanation reactions in the literature. This is as-
cribed to the difficult preparation of the carbenoid precursor FCHI2
reported the first enantioselective monofluorocyclopropanation reac-
tion through a Michael-induced ring closure (MIRC) reaction involv-
ing the chiral carbanion (1) generated by fluorinating (NFSI) a sul-
foximine auxiliary and α,β-unsaturated Weinreb amides (Scheme
1(a)).7 While this major contribution enables the enantioselective
formation of monofluorocyclopropanes where the fluorine atom and
the amide group have a cis relationship, developing a methodology to
access the trans diastereomer as well would result in a significant ad-
vance in the field. Herein we disclose the first highly stereoselective
Simmons-Smith monofluorocyclopropanation, which takes advantage
of the scrambling of halogens at the zinc carbenoid and leads to the
trans diastereomer (Scheme 1(b)).
11
from CHI3, involving stoichiometric amounts of highly toxic HgF2, or
12 13
,
expensive AgF.
One notable application of this reaction is the fluo-
rocyclopropanation reported by Terashima that leads to a mixture of
four diastereomers en route to the antibiotic sitafloxacin (Scheme 2).
14
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Ph
O
Ph
changes in stereoselectivity. However, the preformation of the zinc
alkoxide derived from Et2Zn and cinnamyl alcohol followed by its
complexation with the dioxaborolane ligand 2 and reaction with the
fluoromethylzinc carbenoid led to excellent ee and dr (entry 7). These
conditions were used to elaborate the scope of the reaction (Table 2).
Ph
Ph
1
2
3
4
5
6
7
8
O
N
F
N
F
Ph
O
O
O
FCHI2 (3.0 equiv)
Et2Zn (3.0 equiv)
Ph
25
65
Ph
N
Ph
O
Ph
O
DME (3.0 equiv)
88%
Ph
O
Table 1. Optimization of the enantioselective monofluorocy-
clopropanation reaction
N
5
F
N
5
F
O
O
i) I2 (3.0 equiv), cosolvent (x equiv)
ii) Et2Zn (3.0 equiv)
9
iii) ICHF2 (3.0 equiv)
iv) 8a (1.0 equiv), 2 (1.1 equiv)
Scheme 2. Diastereoselective Simmons-Smith fluorocyclopro-
panation reaction
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F
OH
Ph
OH
CH2Cl2, −78 to −40 °C, 15 h
Ph
Conversely, since difluoroiodomethane (ICHF2) is readily ac-
cessed in one step from inexpensive chlorodifluoroacetic acid
8a
9a
15
(ClCF2COOH), CuI and KI, we envisioned that it would constitute
x
yield
(%)a
recov.
(%)a
ee
entry
cosolv.
drb
an optimal fluorocarbenoid precursor. Our investigation began by
treating cinnamyl alcohol with preformed fluoromethylzinc carbenoid
3 or 4 (Scheme 3), obtained from diethylzinc and difluoroidomethane,
and dioxaborolane ligand 2. Unfortunately, although the reagent was
(equiv)
(%)c
1d
2
Et2O
none
Et2O
DME
THF
Et2O
Et2O
3
-
0
25
100
58
0
-
-
-
≥20:1
≥20:1
-
1
formed in solution (as observed by H NMR), quantitative recovery of
3
6
3
6
3
3
76
82
-
cinnamyl alcohol was observed thus indicating that neither reagent 3 or
4 is a suitable cyclopropanating reagent (Table 1, entry 1). In our stud-
ies of Simmons-Smith monohalocyclopropanation reactions, we have
observed scrambling of halogen atoms in dihalomethylzinc halide spe-
cies.9 We then sought to capitalize on this interesting observation to
generate the iodofluoromethylzinc carbenoid 6 in situ from iodoethyl-
zinc iodide and ICHF2. To confirm that the halogen exchange was
indeed taking place, IZnCHF2 was prepared using the optimal condi-
tions (Table 2, entry 7) and then quenched with Br2 (Scheme 3).
Bromofluoroiodomethane (7) formation was observed by GC/MS and
4
0
100
100
0
5
0
-
-
6
7e
79
83
96
≥20:1
≥20:1
75(71)
≤5
1H NMR yield using 1,3,5-trimethoxybenzene as the internal
a
standard, isolated yield in brackets. b Determined by 1H NMR from the
c
d
crude mixture. Determined by SFC on a chiral stationary phase.
16
1H NMR, indicating that the halogen scrambling was operative.
Reagent formation was conducted with Et2Zn (3.0 equiv)/ICHF2 (3.0
e
equiv) instead of EtZnI/ ICHF2 (3.0 equiv). Reaction conducted by
ICHF2
ICHF2
I2
F
Zn
F
ZnEt
F
ZnI
Et2Zn
preforming the zinc alkoxide derived from 8a and Et2Zn, followed by
complexation with 2 and reaction with the fluoromethylzinc carbenoid.
Et2Zn
IZnEt
or
-EtI
F
F
4
-EtI
-EtI
F
5
2
3
Gratifyingly, the reaction displayed high diastereo- and enantiose-
lectivities for various cinnamyl alcohol derivatives bearing electron-
withdrawing groups (Table 2, entries 2-5) and electron-donating
groups (entries, 6-8). While the fluorocyclopropanation of 4-methoxy
derivative 8f led to decreased enantioselectivity at −40 °C (85% ee,
entry 6), its stereoselectivity could be increased by performing the
reaction at −63 °C (94% ee), albeit at the expense of reaction conver-
sion.16 The reaction was also compatible with allylic alcohols substitut-
ed with primary or secondary alkyl groups (entries 9-10 and 11, respec-
tively). Unsurprisingly, 2,3-trisubstituted allylic alcohol 8l gave de-
creased enantioselectivity due to destabilizing 1,3-allylic strain interac-
tions in both reactive conformations of the allylic alkoxide leading to
ineffective
cyclopropanating reagents
(formation confirmed by NMR)
F
ZnF
F
Br
Br2
I
I
6
7
Identified by GC-MS
Scheme 3. Flurohalomethylzinc Reagents
This reagent procedure was then used in the enantioselective cy-
clopropanation of cinnamyl alcohol in the presence of the dioxaboro-
lane ligand 2 (Table 1, entries 2-7). The first set of conditions using
this reagent led to conversion to fluorocyclopropane 7a with very high
17
diastereoselectivity but low yield (Table 1, entry 2). The reaction
22
either enantiomers (entry 12). Interestingly, (Z)-cinnamyl alcohol
mixture was heterogeneous throughout the reaction period. We then
surmised that the incorporation of a cosolvent might provide a homo-
geneous reaction mixture and thus increase the rate of the halogen
8m displayed increased diastereoselectivity favoring the trans diastere-
omer 9m (4:1 dr) when compared to the homologous chlorocyclopro-
panation (1:1 dr) and iodocyclopropanation (1:3 dr) reactions.9b
18
scrambling and/or the cyclopropanation event. The addition of two
equivalents of Et2O relative to diethylzinc led to complete consump-
tion of the allylic alcohol and an encouraging enantiomeric ratio (entry
3). The use of DME or THF completely suppressed reactivity, presum-
ably because of their higher Lewis basicity when compared to Et2O
Table 2. Scope of the enantioselective monofluorocyclopropa-
nation reaction
19
i) Et2Zn (0.9 equiv),
ii) 2 (1.1 equiv)
iii) EtZnI•Et2O (2.1 equiv)
ICHF2 (2.1 equiv)
(entries 4 and 5). The complexation of such stronger Lewis bases to
the zinc atom would decrease the electrophilicity and hence the reac-
F
20
tivity of the zinc carbenoid towards the allylic alkoxide. In an effort to
increase the enantioselectivity of the reaction, the amount of Et2O
relative to Et2Zn was lowered from 2 to 1 equivalent, as the cosolvent
may compete with the chiral ligand for complexation with the zinc
OH
R1
OH
CH2Cl2, −78 to −40 °C, 15 h
R1
8a-m
9a-m
21
carbenoid (entry 6). Unfortunately, this did not result in significant
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Experimental procedures, compound characterization data, and NMR
spectra for new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
yield
(%)a
ee
entry
1
product
drb
(%)c
1
2
3
4
5
6
7
8
F
9a
9b
9c
71
60
66
96
95
≥20:1
OH
AUTHOR INFORMATION
Corresponding Author
Ph
F
2
3
≥20:1
≥20:1
≥20:1
OH
andre.charette@umontreal.ca
4-FC6H4
F
98d
9
Notes
OH
The authors declare no competing financial interests.
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4-ClC6H4
F
ACKNOWLEDGMENT
4
5
6
7
9d
9e
9f
75
69
49
74
97
98
85
96
OH
OH
OH
4-BrC6H4
4-CF3C6H4
4-MeOC6H4
This work was supported by the Natural Science and Engineering Re-
search Council of Canada (NSERC), the Canada Foundation for In-
novation, the Canada Research Chair Program, the Centre in Green
Chemistry and Catalysis (CGCC) and Université de Montréal.
L.P.B.B. is grateful to NSERC (PGS D) and Université de Montréal for
postgraduate fellowships. We wish to thank Francine Bélanger for the
X-ray analysis. We thank Genentech for partial support.
F
≥20:1
≥20:1
≥20:1
F
F
9g
OH
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F
8
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62
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6
F
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9m
4:1
OH
Ph
a Isolated yield of the diastereomerically pure material. b Determined
by H NMR from the crude mixture. Determined by SFC on a chiral
The absolute configuration of its O-3,5-
dinitrobenzoyl derivative was determined by X-ray crystallography.
1
c
d
stationary phase.
In summary, we have reported the first highly enantioselective
monofluorocyclopropanation reaction of allylic alcohols. The reaction
features a broad scope and gives access to biologically relevant mono-
fluorocyclopropane units from readily available precursors. Quenching
experiments have confirmed the halogen scrambling at the zinc carbe-
noid, which precedes the cyclopropanation event. This contribution
has overcome the ongoing limitation in Simmons-Smith monofluoro-
cyclopropanations involving the use of FCHI2 as carbenoid precursor.
Further applications of this strategy are ongoing and will be reported in
due course.
7 Shen, X.; Zhang, W.; Zhang, L.; Luo, T.; Wan, X.; Gu, Y.; Hu, J. Angew. Chem.,
Int. Ed. 2012, 51, 6966.
8
For other cyclopropanation methodologies relying on the use of the dioxabo-
rolane ligand, see: (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116,
2651. (b) Charette, A. B.; Lemay, J. Angew. Chem., Int. Ed. 1997, 36, 1090. (c)
Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120,
11943. (d) Goudreau, S. R.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15633.
(e) Zimmer, L. E.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15624.
9
(a) Beaulieu, L.-P. B.; Zimmer, L. E.; Charette, A. B. Chem. Eur. J. 2009, 15,
ASSOCIATED CONTENT
11829. (b) Beaulieu, L.-P. B.; Zimmer, L. E.; Gagnon, A.; Charette, A. B. Chem.
Eur. J. 2012, 18, 14784.
Supporting Information
10 Charette, A. B.; Beauchemin, A. Org. React. (NY) 2001, 58, 1.
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13
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Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 131, 954.
14
Akiba, T.; Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani,
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15 Cao, P.; Duan, J.-X.; Chen, Q.-Y. J. Chem. Soc., Chem. Commun. 1994, 6, 737.
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16 See Supporting Information
17 See Supporting Information for complete details relative to reaction optimiza-
tion.
18
The use of Lewis-basic cosolvents such as Et2O or THF was required for the
solubilisation of organozinc species such as EtZnI, IZnCH2I and Zn(CH2I)2 in
dichloromethane: (a) Charette, A. B.; Marcoux, J.-F. J. Am. Chem. Soc. 1996,
118, 4539. (b) See ref. 8e.
19
Laurence, C.; Gal, J.-F. Lewis Basicity and Affinity Scales Data and Measure-
ment; 1st edition; John Wiley & Sons, New York, 2010, p. 143.
20
The Simmons-Smith monofluorocyclopropanation using FCHI2 as the car-
benoid precursor also leads to no conversion when THF is used as the solvent:
Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada,
M.; Hayakawa, I.; Akiba, T.; Terashima, S. Tetrahedron 1994, 50, 3889.
21
Lower enantioselectivities were observed in the Simmons-Smith cyclopropa-
nations with the dioxaborolane chiral ligand in Lewis basic solvents such as Et2O
or t-BuOMe: see Ref. 8c.
22
(a) Wang, T.; Liang, Y.; Yu, Z.-X. J. Am. Chem. Soc. 2011, 133, 9343. (b) See
Ref. 8c.
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