Catalytic enantioselective cyclization and c3-fluorination of polyenes

Article abstract of DOI:10.1021/ja3116795

(Xylyl-phanephos)Pt²⁺ in combination with XeF₂ mediates the consecutive diastereoselective cation-olefin cyclization/ fluorination of polyene substrates. Isolated yields were typically in the 60-69% range while enantioselectivities reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P₂Pt-alkyl cation intermediate.

Full text of DOI:10.1021/ja3116795

Communication
pubs.acs.org/JACS
Catalytic Enantioselective Cyclization and C3-Fluorination of
Polyenes
Nikki A. Cochrane, Ha Nguyen, and Michel R. Gagne*
Department of Chemistry, University of North Carolina at Chapel Hill, CB # 3290, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: (Xylyl-phanephos)Pt2+ in combination with
XeF2 mediates the consecutive diastereoselective cation-
olefin cyclization/fluorination of polyene substrates.
Isolated yields were typically in the 60−69% range while
enantioselectivities reached as high as 87%. The data are
consistent with a stereoretentive fluorination of a P2Pt-
Table 1. Selected Optimizing Conditions
alkyl cation intermediate.
he fluorination of pharmaceutical drug candidates is an
1
Timportant strategy for masking metabolic hot spots.
Despite recent progress with electrophilic fluorinating
reagents,2 the synthesis of such compounds is still challenging
and many deficiencies remain, especially in the asymmetric
fluorination of nonenolate-based carbon nucleophiles.3−5
Fluorinated steroids (Scheme 1), in particular, are important
bioactive compounds with a deficiency of methods for their
synthesis.6−8
De novo syntheses of carbocycles with the flexibility for F-
incorporation are rare, though such methods would consid-
erably expand the accessibility of such privileged structures.1
Transition metal catalyzed cyclizations, if suitably coupled to
M−C fluorination reactions,4 could provide a route to complex
fluorinated carbo- and heterocycles with control of absolute and
relative stereochemistry.
a
b
Uncorrected GC percentages. Determined by chiral GC.
Electrophilic Pt(II) complexes are effective initiators of C−C
bond forming cation-olefin cascades.9−11 The fate of the
organometallic intermediate of these cascades can be controlled
through ligand choice, and when the supporting ligand is a
diphosphine, this intermediate is susceptible to β-H elimination
and leads to net dehydrogenated products. If this complex
could instead be intercepted by a Pt−C fluorination reaction, a
catalytic cyclization/fluorination protocol would result with
concomitant access to C3-fluorinated compounds.6d The
rapidity and stereospecificity with which [(triphos)Pt−
R][BF4] reacts with XeF2 to yield C−F products (eq 1)
suggested that the desired interception might be capable of
competing with β-H elimination.12
In the diphosphine catalyst series that we have examined,
(S)-xylyl-phanephos ((S)-(−)-4,12-bis[di(3,5-xylyl)-
phosphine]-[2,2]-paracyclophane) has consistently provided
the highest enantioselectivity for various cyclization chemistries.
As a starting point for our catalytic cyclization/fluorination
goal, we adapted conditions previously optimized for
cyclization/β-H elimination reactions.10b The modified con-
ditions included use of AgBF4 and NCC6F5 to generate the
“active” [(S)-(xylyl-phanephos)Pt(NCC6F5)2][(BF4)2] catalyst.
Subsequent addition of a base (to facilitate cyclization),
substrate, and an electrophilic fluorine source generated the
desired product (1) as a single (stereoretentive) isomer, along
with variable quantities of β-H eliminated product (3) and the
Brønsted product (5) (Table 1); several additional phosphines
are included for comparison.
Scheme 1. Common Fluorinated Steroids
Received: November 29, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3116795 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Proposed Catalytic Cycle for Electrophilic
Fluorination
Table 2. Catalytic Electrophilic Fluorination
In screening a variety of electrophilic fluorine sources, it was
discovered that only XeF2 effectively competed with β-H
elimination. Other less reactive F+ sources showed a
predominance to exclusive β-H elimination to 3.13 In addition
to the desired 1, over-fluorination to 4 was also observed. Since
controls showed that 1 does not react with XeF2 and acid is
known to enhance the F+ potential of XeF2,14 we surmised that
the HF byproduct of cyclization was activating the XeF2. This
problem was easily solved by the addition of TMSOMe as an
HF sponge, which additionally obviates the need for a base.15
Optimization studies included testing multiple bisphos-
phines, solvents, and other TMS-X derivatives.15 Once again
(S)-xylyl-phanephos was uniquely enantioselective (∼75%) for
controlling the % ee of the cation-olefin cascades. Of the tested
HF scavengers, TMSOMe was the most effective inhibitor of
double fluorination, and like previous ionic cascades, nitro-
methane was the optimum solvent. A catalyst formulation
comprised of 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol %
AgBF4, 30 mol % NCC6F5, and stoichiometric quantities of
XeF2 and TMSOMe at 0 °C provided 1 in 67% yield and with a
75% enantiomeric excess.16
These optimized conditions were subsequently applied to a
variety of alcohol and phenol terminated dienes and trienes
(Table 2). In most cases, a high conversion of substrate
occurred within 3 h; however, the reactions were allowed to
proceed for 24 h at 0 °C to ensure complete consumption of
the XeF2. For the substrate classes in Table 2, no Brønsted acid
derived products such as 5 were observed, and a single
diastereomer consistent with stereoretentive fluorination of the
intermediate P2Pt-alkyl cation was observed.
As shown in Table 2, variants on the phenol termini were
well tolerated, except for α-naphthol (entry 3), wherein
competitive fluorination of the aryl ether product occurs even
with TMSOMe. In situ monitoring indicated that aryl
fluorination occurred after cyclization/Pt−C fluorination. In
this case, extra XeF2 was used to compensate for the
difluorination stoichiometry. Unexpectedly, para-substituents
improved the ee’s (entries 4−7).
a
Conditions: 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol % AgBF4,
30 mol % NCC6F5, 1.1 equiv of TMS-OMe, 1.1 equiv of XeF2, 0.4 mL
of CD3NO2, 0 °C, 24 h. Starting material is mass balance of reaction.
b
c
d
Isolated yield, % ee determined by chiral GC. GC yield. Reaction
e
run using 1.6 equiv of XeF2. Percentage is fluorinated elimination
species only. Reaction with 20 mol % polystyrene-bound piperidine
base run with no TMS-OMe; see SI for details. Due to the volatility
of this compound, a GC yield is reported. Contains 23% unidentified
species; mass balance is unreacted starting materisl. Cannot separate
the unidentified species from the product; therefore GC yield is
reported.
f
g
h
alcohol in entry 10 performed better under the standard
conditions. These base effects are not yet understood.
In situ monitoring of a cyclization/fluorination of 2 indicated
that the alkyl cation (as the nitrile adduct, 6) serves as the
catalyst resting state (31P NMR). These data support our
current view of the mechanism (Scheme 2) that has 6
competitively undergoing β-H elimination or F+ attack to
generate a [Pt]IVR(F) dication, which undergoes a stereo-
retentive reductive elimination to 1. Neither the [Pt]IV nor the
Dienyl and trienyl alcohols and phenols were also viable
substrates though they behaved peculiarly. In the case of entries
8 and 9, the yields were poor under standard conditions but
could be recovered by exchanging TMSOMe for a polystyrene-
bound piperidine base (see Table 1). In contrast, the triene
B
dx.doi.org/10.1021/ja3116795 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50,
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[Pt]−H species are observable by NMR; however, literature
precedence suggests that both routes are viable.5d,f,i,k,17
In summary, we illustrate that P2Pt-dicationic catalysts can
mediate the enantioselective cation-olefin cyclization/fluorina-
tion reactions of polyenes to yield C3-fluorinated carbocycles.
The key feature of the putative catalytic cycle is the selective
reaction of XeF2 with P2Pt-alkyl cations over P2Pt-dications,
which enables the sequential cyclization/fluorination.
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data for all new compounds and synthetic
procedures are included in the Supporting Information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(6) For steroid fluorination see for example: (a) Poss, A. J.; Shia, G.
A. Tet. Lett. 1995, 36, 4721. (b) Rozen, S.; Ben-Shushan, G. J. Org.
Chem. 1986, 51, 3522. (c) Bowers, A.; Ringold, H. J. Tetrahedron
1958, 3, 14. (d) For C3 fluorinated steroids: Liu, W.; Huang, X.;
Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A.; Groves, J. T. Science
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AUTHOR INFORMATION
Corresponding Author
mgagne@unc.edu
Notes
■
(7) For a recent enantioselective I+ initiated cascade to yield C3-
halopolyprenoids, see: (a) Chen, G.; Ma, S. Angew. Chem., Int. Ed.
2010, 49, 8306. (b) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007,
445, 900. (c) Sakakura, A.; Ishihara, K. ChimicaOggi-Chemistry Today
2007, 25, 9.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. M. S. Brookhart for insightful comments and
the National Institute of General Medical Sciences for generous
support (Grant GM-60578). H. N. also thanks the VEF for
their support.
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(15) NMR data and a comprehensive list of tested silyl ethers are
available in the Supporting Information.
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