Enantioselective, Catalytic Fluorolactonization Reactions with a Nucleophilic Fluoride Source

Article abstract of DOI:10.1021/jacs.6b09499

The enantioselective synthesis of 4-fluoroisochromanones via chiral aryl iodide-catalyzed fluorolactonization is reported. This methodology uses HF-pyridine as a nucleophilic fluoride source with a peracid stoichiometric oxidant and provides access to lactones containing fluorine-bearing stereogenic centers in high enantio- and diastereoselectivity. The regioselectivity observed in these lactonization reactions is complementary to that obtained with established asymmetric electrophilic fluorination protocols.

Full text of DOI:10.1021/jacs.6b09499

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Communication
Enantioselective, Catalytic Fluorolactonization
Reactions with a Nucleophilic Fluoride Source
Eric Woerly, Steven M. Banik, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09499 • Publication Date (Web): 06 Oct 2016
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Enantioselective, Catalytic Fluorolactonization Reactions with a Nu-
cleophilic Fluoride Source
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Eric M. Woerly, Steven M. Banik, Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
4-fluoroisochromanones in high enantio- and diastereoselec-
tivity.
ABSTRACT: The enantioselective synthesis of 4-
fluoroisochromanones via chiral aryl iodide-catalyzed fluoro-
lactonization is reported. This methodology uses
HF•pyridine as a nucleophilic fluoride source with a peracid
stoichiometric oxidant, and provides access to lactones con-
taining fluorine-bearing stereogenic centers in high enantio-
and diastereoselectivity. The regioselectivity observed in
these lactonization reactions is complementary to that ob-
tained with established asymmetric electrophilic fluorination
protocols.
Scheme 1. Enantioselective fluorolactonizations with elec-
trophilic and nucleophilic fluorinating agents
The stereocontrolled construction of C–F bonds repre-
sents a frontier endeavor in synthetic chemistry, motivated in
large part by the important ways that fluorine incorporation
is known to modulate the physical and biological properties
of organic molecules.1 Electrophilic fluorine sources (“F+”)
such as Selectfluor, N-fluoropyridinium salts, and N-
fluorobenzenesulfonimide (NFSI) have been used extensive-
ly in the enantiocontrolled generation of fluorine-bearing
stereogenic centers,2 most often via the intermediacy of eno-
late equivalents to produce -fluorocarbonyl compounds.2a,3
Fluorofunctionalization of alkenes using F+ sources is anoth-
er powerful approach to the enantioselective synthesis of
fluorine-containing chiral compounds that allows for the
synthesis of highly functionalized products from simple ole-
fin-containing starting materials.4,5 In reported efforts di-
rected toward enantioselective fluorolactonization reactions,
electrophilic fluorinating reagents have been shown to afford
-butyrolactone products with exocyclic fluoromethyl sub-
stituents in moderate-to-high enantioselectivity (Scheme 1,
top).6 We hypothesized that a hypervalent iodine catalysis of
a nucleophilic fluorination pathway (“F–”) could provide a
complementary approach to regioisomeric fluorolactone
products containing a C–F stereogenic center (Scheme 1,
bottom), in a manner analogous to that observed in recently
described enantioselective acetoxylactonization reactions.7
Herein, we report the development of an enantioselective,
catalytic fluorolactonization reaction for the preparation of
Scheme 2. Anchimeric assistance in 1,2-difluorination of
styrenes with ArI-catalysts and an analogous fluorolactoniza-
tion pathway
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We reported recently a protocol for the aryl iodide- tions. Variation of the ester group of the catalyst had very
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catalyzed diastereoselective 1,2-difluorination of both termi-
nal and internal alkenes8,9 using HF-pyridine (pyr9HF) as a
nucleophilic fluorine source and meta-chloroperbenzoic acid
(mCPBA) as a stoichiometric oxidant. These conditions
were first developed by Shibata and coworkers in the context
of catalytic aminofluorination reactions.10 Alkenes bearing
proximal weakly Lewis basic groups were shown to undergo
net anti-difluorination, while substrates lacking such func-
tionality afforded syn-difluoride products. We proposed that
properly positioned weakly nucleophilic groups (e.g. the o-
NO2 group in Scheme 2) can displace the aryl iodide from
intermediate I to form an unstable bridged intermediate II.
Invertive displacement of the neighboring group by fluoride
led to the anti-diastereomeric outcome. The propensity for
such anchimeric assistance in these reactions suggested that
styrenes containing other nucleophilic neighboring groups
such as an ortho-carboxylic acid or ester might undergo
fluorolactonization reactions.11 As outlined in the proposed
catalytic pathway in Scheme 2, nucleophilic displacement of
the aryliodo group in intermediate I with a carboxylate
equivalent would lead to formation of 4-
fluoroisochromanone products. This approach would pro-
duce a fluorine-bearing stereogenic center with a syn rela-
tionship between the two newly formed bonds,12 a stereo-
chemical outcome distinct from prototypical bromo- and
iodolactonizations.13 Furthermore, as members of the
polyketide-derived 4-oxyisochromanone class of natural
products are known to possess interesting biological activi-
ty,14 we were motivated by the possibility that an efficient,
stereocontrolled route to 4-fluoro analogs may be of interest
for biological or pharmacological applications.
little effect on the enantioselectivity of the fluorolactoniza-
tion reaction, but measurably improved yields were obtained
with benzyl ester catalysts 2a and 2d relative to their methyl
ester counterparts. On the basis of these results, 2d was se-
lected as the optimal catalyst for further study.
Table 1. Optimization of the fluorolactonization reaction
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Variation of the carboxylate equivalent (1a–c) or use of
the free carboxylic acid 1d resulted in formation of fluorolac-
tonization product 3, albeit with discernible changes in ee
and yield (entries 4-7) and with methyl ester 1a affording the
best results.
Methyl benzoate derivative 1a was evaluated as a model
substrate for the proposed fluorolactonization reaction. Var-
ious classes of chiral aryl iodides were examined as potential
catalysts, including chiral resorcinol derivatives such as 2a-
2d,7,15 which have found application previously in a variety of
enantioselective alkene oxidation reactions.16 In the presence
of catalysts 2a–d, mCPBA as oxidant, and pyr9HF as the
fluorine source and acid promoter, 1a was observed to un-
dergo cyclization to fluoroisochromanone 3 as a single ob-
servable diastereomer (Table 1).17 The syn relative configu-
ration was determined via X-ray crystallographic analysis,
consistent with the reaction pathway outlined in Scheme 2.18
Table 2. Fluorolactonization of aryl-substituted substrates
Catalysts 2c and 2d were found to impart significantly
higher enantioselectivities than the corresponding benzyl-
substituted analogs 2a–b (entries 1-4). This observation
stands in contrast to results obtained in the migratory gemi-
nal difluorination of -substituted styrenes reported recently
by our group,19 where that trend was reversed and the polar-
izable benzylic groups in para-substituted analogs of 2a–b
were shown to play a critical role in enhancing ee. It is evi-
dent that subtle yet fundamentally different factors are re-
sponsible for enantioinduction in these closely related reac-
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The effect of arene substitution in the enantioselective
fluorolactonization reaction catalyzed by 2d is illustrated in
Table 2. Alkyl, halide, or trifluoromethoxy substitution at the
6, 5, and 4-positions of 1 is generally well tolerated, with the
fluorolactone products obtained in 80-96% ee (entries 1-3,
5-10). However, substrates bearing more electron-deficient
trifluoromethyl or carbomethoxy groups underwent reaction
in reduced yields and enantioselectivities (entries 12-15). In
all cases, the fluorolactone product was obtained as a single
diastereomer.20
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The new fluorolactonization reaction was also extended
successfully to a variety of -substituted styrene derivatives
(Table 3). In general, substituents of varying size and func-
tionality have little impact on reaction enantioselectivity.
The Lewis basic ether and cyano substituents in 7f and 7g are
observed not to alter the relative stereochemical outcome of
the fluorolactonization reaction, despite the propensity to-
ward anchimeric assistance pathways in these reactions as
noted above. Catalyst control over stereoselectivity of the
reaction was observed with 7h and 7i, with complementary
diastereoselectivity obtained using 2d or ent-2d.
Table 3. Fluorolactonization of substituted alkene substrates
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2d (10 mol%)
O
O
mCPBA (1.2 equiv)
pyr 9HF (2.8 equiv)
As illustrated in Scheme 3, the regioselectivity observed in
the fluorolactonization reactions with a nucleophilic fluoride
source is opposite to that obtained with electrophilic rea-
gents.21 Furthermore, as demonstrated with 1d, electrophilic
fluorolactonizations of disubstituted styrenes are observed to
be poorly diastereoselective. The successful introduction of
C-F stereocenters in a highly stereocontrolled manner is thus
a significant feature of the new catalytic protocol.
OMe
R
O
0.4 M CH2Cl2
–50 C, 24 h
R
6a h
7a i
F
O
O
O
O
O
O
Cl
Me
F
F
F
7a, 49% yield
87% ee
7b, 62% yield
7c,a 60% yield
Scheme 3. Comparison of the reactivity of electrophilic and
nucleophilic fluorinating reagents
95% ee
95% ee
O
O
O
O
Ph
F
F
7d
7e
, 58% yield
92% ee
, 55% yield
90% ee
O
O
O
O
OMe
CN
F
F
7f,a 57% yield
7g, 41% yield
90% ee
91% ee
O
O
F
O
H
O
H
Me
Me
Me
Me
In conclusion, the enantio- and diastereoselective, catalytic
synthesis of 4-fluoroisochromanones can be accomplished
with HF-pyridine as a nucleophilic fluoride source. Readily
accessible chiral aryl iodides catalyze fluorolactonization
with generation of C–F stereogenic centers from simple sty-
rene precursors. Ongoing efforts are directed toward explor-
ing the scope of fluorofunctionalization reactions induced by
F
Me
Me
7h, 6:1 d.r. 7h:7i
7i, 6:1 d.r. 7i:7h
(w/ ent-2d)
49% yield
57% yield
Conditions: substrate (1 mmol), catalyst (10 mol%), mCPBA (1.2
mmol), pyr 9HF (25 mmol HF) in CH2Cl2 (2.5 mL) cooled to –50 C, 24
h. Enantioselectivities were determined by HPLC or GC analysis with
commercial chiral columns. Isolated yields are reported. aAbsolute
configuration was determined by X-ray crystallographic analysis; all
other products are assigned by analogy.
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(6) (a) Parmar, D.; Maji, M.S.; Rueping, M. Chem. Eur. J. 2014, 20,
hypervalent iodine(III) catalysis, as well as elucidating the
basis of the subtle catalyst structural properties that control
the enantioselectivity in these reactions.
83. (b) Egami, H.; Asada, J.; Sato, K.; Hashizume, D.; Kawato, Y.;
Hamashima, Y. J. Am. Chem. Soc. 2015, 137, 10132.
(7) (a) Fujita, M.; Yoshida, Y.; `Miyata, K.; Wakisaka, A.; Sugimura,
T. Angew. Chem. Int. Ed. 2010, 49, 7068. (b) Shimogaki, M.; Fu-
jita, M.; Sugimura, T. Eur. J. Org. Chem. 2013, 7128.
(8) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. J. Am. Chem. Soc.
2016, 138, 5000.
(9) Gilmour and coworkers independently reported a similar protocol
for the 1,2-difluorination of terminal alkenes: Molnár, I.G.; Gil-
mour, R. J. Am. Chem. Soc. 2016, 138, 5004.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and charac-
terization data for new compounds are available free of charge
via the internet at http://pubs.acs.org.
9
(10) (a) Suzuki, S.; Kamo, T.; Fukushi, K.; Hiramatsu, T.; Tokunaga,
E.; Dohi, T.; Kita, Y.; Shibata, N. Chem. Sci. 2014, 5, 2754. For an
additional report utilizing HF-pyridine and mCPBA in catalytic
fluorination reactions, see: (b) Kitamura, T.; Muta, K.; Oyamada,
J. J. Org. Chem. 2015, 80, 10431.
(11) For an example of an enantioselective fluorinative intramolecular
cyclization reaction of alkenes with stoichiometric, chiral io-
dine(III) reagents, see: Kong, W.; Feige, P.; de Haro, T.; Nevado,
C. Angew. Chem. Int. Ed. 2013, 52, 2469.
(12) Alternatively, cyclization prior to nucleophilic fluorination would
also provide 4-fluoroisochromanone products with syn-
configurations. Such a mechanism cannot be ruled out based on
the data presented here. For reactions where cyclization is pro-
posed to precede fluorination, see Sawaguchi, M.; Hara, S.; Fuku-
hara, T.; Yoneda, N. J. Fluorine Chem. 2000, 104, 277.
(13) Chen, J.; Zhou, L.; Tan, C.K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77,
999.
AUTHOR INFORMATION
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Corresponding Author
jacobsen@chemistry.harvard.edu
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
This work was supported by the NIH (GM043214), by an
NSF pre-doctoral fellowship to S.M.B., and by a Suzanne and
Bob Wright postdoctoral fellowship to E.M.W. from the Damon
Runyon Cancer Research Foundation (DRG-2180-14). We
thank Dr. Shao-Liang Zheng for crystal structure determination
and Jennifer Wang for mass spectrometry analysis.
(14) (a) Aldridge, D.C.; Galt, S.; Giles, D.; Turner, W.B. J. Chem. Soc.
C 1971, 1623. (b) Zhang, W.; Krohn, K.; Draegar, S.; Schultz, B. J.
Nat. Prod. 2008, 71, 1078.
(15) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010,
49, 2175.
REFERENCES
(1) (a) Gillis, E.P.; Eastman, K.J.; Hill, M.D.; Donnelly, D.J.; Mean-
well, N.A. J. Med. Chem. 2015, 58, 8315. (b) Wang, J.; Sanchez-
Rosello, M.; Acena, J.L.; del Pozo, C.; Sorochinsky, A.E.; Fustero,
S.; Soloshonok, V.A.; Liu, H. Chem. Rev. 2014, 114, 2432. (c)
Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (d) Hagmann, W.K. J. Med. Chem. 2008, 51,
4359.
(2) For reviews on this topic, see: (a) Yang, X.; Tao, W.; Phipps, R.J.;
Toste, F.D. Chem. Rev. 2015, 115, 826. (b) Champagne, P.A.;
Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.F. Chem.
Rev. 2015, 115, 9073.
(3) For seminal examples utilizing organocatalysts, see: (a) Shibata,
N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728.
(b) Cahard, D.; Audouard, C.; Plaquevent, J.-C.; Roques, N. Org.
Lett. 2000, 2, 3699. (c) Kim, D.Y.; Park, E.J. Org. Lett. 2002, 4,
545. (d) Enders, D.; Hüttl, M.R. Synlett 2005, 6, 991. (e) Marigo,
M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2005, 44, 3703. (f) Steiner, D.D.; Mase, N.;
Barbas, C.F. III. Angew. Chem. Int. Ed. 2005, 44, 3706. (g)
Beeson, T.D.; MacMillan, D.W.C. J. Am. Chem. Soc. 2005, 127,
8826.
(4) For reviews on this topic, see: (a) Wolstenhulme, J.R.; Gouver-
neur, V. Acc. Chem. Res. 2014, 47, 3560. (b) Denmark, S.E.;
Kuester, W. E.; Burk, M.T. Angew. Chem. Int. Ed. 2012, 51,
10938. (c) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke,
X. Chem. Soc. Rev. 2010, 39, 558.
(16) For reviews on this topic, see: (a) Yoshimura, A; Zhdankin, V.V.
Chem. Rev. 2016, 116, 3328. (b) Romero, R.M.; Woste, T.H.;
Muniz, K. Chem. Asian J. 2014, 9, 972. (c) Parra, A.; Reboredo, S.
Chem. Eur. J. 2013, 19, 17244.
(17) Reducing the number of equivalents of pyr9HF resulted in lower
yields of 3, albeit with consistent enantioselectivities (1.1 equiv.
pyr9HF: 93% ee and 28% yield; 5.6 equiv. pyr9HF: 93% ee and
83% yield). Reactions conducted at –20 oC led to the generation of
3 in 86% ee and 71% yield (yields determined by GC analysis).
(18) For examples of syn 1,2 additions to alkenes promoted by hyperva-
lent iodine reagents, see references 7, 8, and Hara, S.; Nakahigashi,
J.; Ishi-I, K.; Sawaguchi, M.; Sakai, H.; Fukuhara, T.; Yoneda, N. Syn-
lett 1998, 495.
(19) Banik, S.M.; Medley, J.W.; Jacobsen, E.N. Science 2016, 353, 51.
(20) The remainder of the mass balance in these reactions can be at-
tributed to unreacted starting material and to the formation of sev-
eral uncharacterized, but readily separable, byproducts. For a dis-
cussion of background reactions in closely related catalytic oxylac-
tonization reactions, see reference 7b
(21) For an additional example of a racemic, regioselective fluorocy-
clization reaction with hypervalent iodine reagents, see: Geary,
G.C.; Hope, E.G.; Stuart, A.M. Angew. Chem. Int. Ed. 2015, 54,
14911.
(5) For specific examples, see: (a) Greedy, B.; Paris, J.-M.; Vidal, T.;
Gouverneur, V. Angew. Chem. Int. Ed. 2003, 42, 3291. (b) Wil-
kinson, S.C.; Lozano, O.; Schuler, M.; Pacheco, M.; Salmon, R.;
Gouverneur, V. Angew. Chem. Int. Ed. 2009, 48, 7083. (c)
Rauniyar, V.; Lackner, A.D.; Hamilton, G.L.; Toste, F.D. Science
2011, 334, 1681. (d) Wolstenhulme, J.R.; Rosenqvist, J.; Lozano,
O.; Ilupeju, J.; Wurz, N.; Engle, K.M.; Pidgeon, G.W.; Moore,
P.R.; Sandford, G.; Gouverneur, V. Angew. Chem. Int. Ed. 2013,
52, 9796.
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