Diastereoselective Fluorocyclopropanation of Chiral Allylic Alcohols Using an α-Fluoroiodomethylzinc Carbenoid

Article abstract of DOI:10.1021/acs.orglett.5b02097

Chiral fluorocyclopropyl carbinols were synthesized in high diastereoselectivities via a zinc mediated cyclopropanation reaction, using sec-allylic alcohols as simple building blocks. An enantioselective version of this transformation was achieved through

Full text of DOI:10.1021/acs.orglett.5b02097

Letter
pubs.acs.org/OrgLett
Diastereoselective Fluorocyclopropanation of Chiral Allylic Alcohols
Using an α‑Fluoroiodomethylzinc Carbenoid
Chandrasekhar Navuluri and Andre B. Charette*
́
Center in Green Chemistry and Catalysis, Faculty of Arts and Sciences, Department of Chemistry, Universite
6128, Station Downtown, Montreal, Quebec Canada, H3C 3J7
́
de Montreal, P.O. Box
S
* Supporting Information
ABSTRACT: Chiral fluorocyclopropyl carbinols were synthesized
in high diastereoselectivities via a zinc mediated cyclopropanation
reaction, using sec-allylic alcohols as simple building blocks. An
enantioselective version of this transformation was achieved
through in situ formation of chiral allylic zinc sec-alkoxides from
the requisite aldehydes using Walsh’s protocol.
luorocyclopropanes bring together the biologically benefi-
cial properties of the fluorine atom1 to the medicinally
Scheme 1. 1,2,3-Substituted Halocyclopropane Synthesis by
Diastereoselective Carbenoid Transfer
F
important cyclopropane scaffold.2 The traditional methodologies
to access monofluorocyclopropanes3 involve (1) a Michael
induced ring closure (MIRC) strategy using α-fluoro carban-
ions;4 (2) the cyclopropanation of vinyl fluorides;5 or (3) the use
of fluorocarbenoids.6 In comparison to other halocyclo-
propanations,7 the stereoselective synthesis of fluorocyclo-
propanes from fluoro-substituted carbenoids is relatively under-
studied, mainly in part due to the lack of suitable methods for the
efficient generation of the reagent. The diastereoselective
transfer of carbenoids using chiral secondary allylic alcohols8 is
an efficient strategy to synthesize 1,2,3-substituted halocyclo-
propanes,9,10 containing up to four stereocenters (Scheme 1).
We reasoned that this strategy could be applied toward the
stereoselective formation of fluoro-substituted cyclopropanes.
The diastereoselective transfer of iodo-, bromo-, and chloro-
methyl carbenoids using chiral secondary allylic alcohols has
previously been studied;10b however, to our knowledge, no
examples are known for the transfer of fluoro-substituted
carbenoids in such a system.
Our group recently described an efficient enantioselective
synthesis of monofluorocyclopropanes from primary allylic
alcohols using a chiral dioxaborolane ligand.11 This methodology
hinges on the formation of the active monofluoromethylene
carbenoid 1 (Scheme 1) via a halogen scrambling of its
difluoromethylene precursor, difluoroiodomethane, used in
place of the customary diiodofluoromethane, an expensive and
difficult to prepare reagent.
In this letter, we report the diastereoselective fluorocyclo-
propanation of chiral secondary allyl alcohols using a fluoro-
substituted zinc carbenoid prepared from difluoroiodomethane.
We began our study by exposing the ethylzinc alkoxide of
( )-cyclohexyl-3-phenylpropenol 2 (Table 1, entry 1) to 2 equiv
of the fluorocarbenoid 1 in dichloromethane at −40 °C.
Encouragingly, this afforded the desired fluorocyclopropane 3
in 30% yield, with an 8:1 dr. We were pleased to find that, by
simply adding a larger excess of the carbenoid,8b both the yield
and the diastereoselectivity of 3 were improved (Table 1, entries
2−5). Ultimately, the use of 5 equiv of the carbenoid proved
optimal, giving complete consumption of the starting material
and affording 3 in 69% yield and a 15:1 dr. The use of more than
5 equiv of carbenoid led to an unclean reaction and the formation
of nonpolar byproducts.
Received: July 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of the Fluorocyclopropanation Conditions
Table 2. Scope of the Fluorocyclopropanation Using
Optimized Conditions
b
c
c
entry
R1
x
dr
yield 3 (%)
recovered 2 (%)
1
2
3
4
5
6
ZnEt
ZnEt
ZnEt
ZnEt
ZnEt
H
2
3
4
5
6
5
5
8:1
10:1
13:1
15:1
13:1
6:1
30
56
62
69
61
71
63
57
20
8
0
0
0
d
7
ZnEt
9:1
13
a
Carbenoid prepared by mixing 1 M CH2Cl2 solution of EtZnI·Et2O
b
with a 1 M CH2Cl2 solution of CHF2I at −78 °C. Determined by 19
NMR of the crude reaction mixture. Isolated yields. Reaction run in
the presence of 15 equiv of PhMe.
F
c
d
In related halocyclopropanation reactions of sec-allylic
alcohols, the use of the dihalomethyl zinc trifluoroethoxide is
necessary in order to achieve high yields and diastereoselectivi-
ties.10b In view of this, the high yield and diastereoselectivity
observed with carbenoid 1 is particularly noteworthy. Submitting
2 to 5 equiv of the carbenoid 1 without preforming the ethylzinc
alkoxide yielded 3 in 71% yield but with a reduced 6:1 dr (entry
5). This exemplified the importance of the preformation of the
allylic zinc alkoxide on the diastereoselectivity of the fluorocyclo-
propanation. Furthermore, derivatization of 3 as its 3,5-
dinitrobenzoate allowed isolation of a crystalline compound of
suitable quality for X-ray crystallography. The obtained X-ray
crystal structure confirmed the overall configuration of 3 to have
a trans relationship between the fluorine and carbinol
substituents (see Supporting Information).12 Also, the presence
of 15 equiv of toluene in this reaction led to a decreased 9:1 dr,
suggesting π type interactions between toluene and the
fluorocarbenoid 1 (vide infra).
With the optimized conditions in hand, the scope of the
reaction with a range of sec-allylic alcohols was examined.
Gratifyingly, excellent diastereoselectivities (15:1) were obtained
when R3 was sterically demanding (Table 2, entries 1−2). The
level of diastereoselection remained high for 2,3-trisubstituted
allylic alcohol 4c (entry 3).
A loss in dr to 2:1 was observed when the steric demand of R3
was reduced (entry 4). The diastereoselectivity was regained
when substrate 4e, bearing a larger n-butyl chain, was used (entry
5). We next explored the effect of the electronic properties of R1
on the outcome of the developed reaction. Interestingly, the
presence of electron-deficient (entries 6 and 7) and electron-
donating aryl groups in the R3 position (entry 8) did not have any
marked influence on the diastereoselectivity (which remained
uniform at 7:1) and yield of the reaction. The presence of the
bulkier mesityl group (entry 9) was also well tolerated, affording
5i in 65% yield, with a 7:1 dr. In the case of the cis allylic alcohol
(entry 10), the developed methodology afforded a diminished
diastereoselectivity (1.5:1).
a
b
Isolated yield of the diastereomerically pure compound. Determined
by 19F NMR of the crude reaction mixture.
Figure 1. Transition state model for trans diastereoselective fluoro-
cyclopropanation.
Keeping in view the improved diastereoselectivity with the
increase in the equivalents of the fluorocarbenoid and the known
precedents of Zn(II) interactions with π systems,13 we propose
that Figure 1 likely best depicts the transition state model for this
trans diastereoselective fluorocyclopropanation.
With the successful diastereoselective formation of
fluorocyclopropanes starting from racemic allylic alcohols in
B
DOI: 10.1021/acs.orglett.5b02097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hand, we sought to further explore the possibilities for the
development of a diastereoselective cyclopropanation of chiral
allylic ethers. In such context, we decided to evaluate the
stereochemical outcome of the fluorocyclopropanation of trans-
styryldioxolane 6 derived from D-glyceraldehyde acetonide. We
were delighted to find that the reaction of 6 with 5 equiv of the
carbenoid 1 afforded the fluorocyclopropane 7 in 73% yield, in
15:1 dr and 99% ee, with the fluorine substituent being oriented
trans to the dioxolane (Scheme 2). In the case of the cis isomer 8,
Table 3. One-Pot Enantioselective Fluorocyclopropanation
Using MIB Catalysis
Scheme 2. Diastereoselective Fluorocyclopropanation Using
a b
,
Styryl Dioxolanes
a
Dialkylzinc reagents in entries 1, 2, and 3 were ethereal solutions.
b
c
Isolated yield of the diastereomerically pure compound. Determined
d
by 19F NMR of the crude reaction mixture. Determined by SFC on a
chiral stationary phase.
in the diastereoselective fluorocyclopropanation, two other
dialkylzinc reagents16 were evaluated within this one-pot
fluorocyclopropanation protocol. The reaction using dibutylzinc
delivered 14b in 63% yield, with a 7:1 dr and in 90% ee (Table 3,
entry 2). Some loss in yield in this reaction was attributed to the
formation of a minor byproduct, arising from reduction of
cinnamaldehyde during the addition reaction of dibutyl zinc.
While the diastereoselectivity with the more hindered
dicyclohexyl zinc was high (Table 3, entry 3), the enantiose-
lectivity dropped to 70%. The fluorocyclopropyl carbinols
synthesized could be further functionalized to prepare various
biologically important fluorocyclopropanes. Stereodefined
fluorocyclopropylcarboxylic acid 16 was accessed from 5b by a
simple oxidation protocol involving a sequential Dess-Martin
oxidation, Baeyer−Villiger reaction, and saponification (Scheme
3). A Curtius rearrangement of 16 in a reaction with diphenyl
phosphorylazide gave access to the corresponding amino
cyclopropane 17 in 73% yield.
a
b
Determined by 19F NMR of the crude reaction mixture. Determined
1
by H NMR of the crude reaction mixture.
the reaction proceeded with a 3:1 dr. The major isomer, isolated
in 62% yield and 99% ee, was found to be the all-cis
fluorocyclopropane 9, the structure of which was confirmed by
X-ray crystallography (see Supporting Information).14
A
sequence of acid catalyzed acetonide deprotection, periodate
mediated cleavage, and sodium borohydride reduction of the
resulting aldehyde then allowed access to the all-cis fluorocyclo-
propyl carbinol 10 in 78% yield over three steps.
Walsh et al. recently reported an excellent methodology for the
one-pot synthesis of halocyclopropyl carbinols with high
enanatio- and diastereocontrol (Scheme 1, eq 2).10b The
methodology relies on the enantioselective addition of dialkyl
zinc reagents to unsaturated aldehydes using chiral aminoalcohol
MIB.15 To the formed enantioenriched sec-allylic zinc alkoxide
intermediates are then added halomethyl carbenoids furnishing
enantioenriched iodo-, bromo-, and chlorocyclopropanes. In
order to circumvent the preparation of enantiopure sec-allylic
alcohols and seeking to further build on the success of the
diastereoselective transfer of fluorocarbenoid 1, we envisioned
achieving the one-pot fluorocyclopropanation protocol under
Walsh’s protocol.
In summary, we have successfully developed a new method-
ology for the fluorocyclopropanation of a range of racemic sec-
Scheme 3. Synthesis of Fluorocyclopropane Carboxylic Acid
and Fluoroaminocyclopropane
In our initial attempt, cinnamaldehyde was reacted with
diethylzinc under MIB catalysis conditions in toluene at 0 °C to
form the ethylzinc adduct. After removal of the volatiles under
vacuum, dichloromethane and 5 equiv of the fluorocarbenoid 1
were added. We were pleased to find that the desired
fluorocyclopropane 14a (Table 3, entry 1) was isolated in 68%
yield as a 8:1 diastereomeric mixture in 90% ee. Since electronic
and steric effects on the aromatic ring did not seem to play a role
C
DOI: 10.1021/acs.orglett.5b02097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi,
S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893.
allylic alcohols and ethers in high yields and diastereoselectivities.
The use of glyceraldehyde derived allyl ethers allows synthesis of
the corresponding fluorocyclopropanes in excellent yields and
enantioselectivities. The methodology could also be extended in
a one-pot fluorocyclopropanation protocol using in situ
generated enantioenriched allylic alkoxides to give access to
chiral, nonracemic fluorocyclopropanes.
(6) (a) Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.;
Nakatani, K.; Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S.
Tetrahedron 1994, 50, 3889. (b) Akiba, T.; Tamura, O.; Hashimoto, M.;
Kobayashi, Y.; Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.;
Terashima, S. Tetrahedron 1994, 50, 3905.
(7) For reviews, see: (a) Charette, A. B.; Beauchemin, A. Org. React. (N.
Y.) 2001, 58, 1. (b) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A.
B. Chem. Rev. 2003, 103, 977. (c) Roy, M.-N.; Lindsay, V. N. G.;
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Double Bonds (Science of Synthesis Series); de Vries, J. G., Vol. Ed.;
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(8) For earlier work on the diastereoselective cyclopropanation of
acyclic allylic alcohols and ethers using zinc carbenoids, see: (a) Ratier,
M.; Castaing, M.; Godet, J. Y.; Pereyre, M. J. Chem. Res. (M) 1978, 2309.
(b) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966. (c) Charette,
A. B.; Lacasse, M. C. Org. Lett. 2002, 4, 3351.
(9) (a) Fournier, J. F.; Mathieu, S.; Charette, A. B. J. Am. Chem. Soc.
2005, 127, 13140. (b) Charette, A. B.; Mathieu, S.; Fournier, J. F. Synlett
2005, 1779.
(10) (a) Kim, H. Y.; Lurain, A. E.; Garcia-Garcia, P.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138. (b) Kim, H. Y.; Salvi, L.;
Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 954. (c) Infante,
R.; Nieto, J.; Andres, C. Org. Biomol. Chem. 2014, 12, 345.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02097.
Experimental procedures, NMR spectra, and compound
characterization data (PDF)
Crystallographic data for 9 (CIF)
Crystallographic data for 18 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andre.charette@umontreal.ca.
Notes
The authors declare no competing financial interest.
(12) In the dinitrobenzoate derivative of 3, as observed in the case of
the related iodocyclopropanes, the cis disposed cyclopropane ring
hydrogen atom relative to the fluoromethine hydrogen atom exhibits a
ACKNOWLEDGMENTS
■
3
This work was supported by the Natural Science and Engineering
Research Council of Canada (NSERC), the Canada Research
Chair Program, the Canada Foundation for Innovation, the
FRQNT Centre in Green Chemistry and Catalysis, and
higher JFCH‑Hcis proton coupling constant of 6.7 Hz, while the trans
disposed hydrogen atom exhibits a lower 3JFCH‑Hcis coupling constant of
2.4 Hz. Also, the fluorine atom displays a strong 3JF‑Hcis coupling constant
of 20.3 Hz and a smaller 3JF‑Htrans coupling constant of 6.9 Hz. These 1H
and 19F coupling constants have been used to assign the stereochemistry
of the fluorocyclopropane carbinols synthesized (see Supporting
Information). For use of coupling constants in assignment of
stereochemistry of halocyclopropanes, see: (a) Miyano, S.;
Hashimoto, H. Bull. Chem. Soc. Jpn. 1974, 47, 1500. (b) Miyano, S.;
Matsumoto, Y.; Hashimoto, H. J. Chem. Soc., Chem. Commun. 1975, 364.
(c) Seyferth, D.; Yamazaki, H.; Alleston, D. L. J. Org. Chem. 1963, 28,
703. (d) Miyano, S.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1973, 46, 892.
(e) Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009,
131, 954.
Universite
́ ́
de Montreal.
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3
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