Enantioselective catalytic fluorinative aza-semipinacol rearrangement

Article abstract of DOI:10.1021/ol5022355

An efficient and highly stereoselective fluorinative aza-semipinacol rearrangement is described. The catalytic reaction requires use of Selectfluor in combination with the chiral, enantiopure phosphate anion derived from acid L3. Under optimized condition

Full text of DOI:10.1021/ol5022355

Letter
pubs.acs.org/OrgLett
Enantioselective Catalytic Fluorinative Aza-semipinacol
Rearrangement
Fedor Romanov-Michailidis,† Marion Pupier,† Celine Besnard,‡ Thomas Burgi,*,§
́
̈
and Alexandre Alexakis*,†
‡
§
†Department of Organic Chemistry, Laboratory of Crystallography, and Department of Physical Chemistry, University of Geneva,
Quai Ernest Ansermet 30 CH-1211 Geneva 4, Switzerland
S
* Supporting Information
ABSTRACT: An efficient and highly stereoselective fluorinative aza-semipinacol rearrangement is described. The catalytic
reaction requires use of Selectfluor in combination with the chiral, enantiopure phosphate anion derived from acid L3. Under
optimized conditions, cyclopropylamines A were transformed into β-fluoro cyclobutylimines B in good yields and high levels of
diastereo- and enantiocontrol. Furthermore, the optically active cyclobutylimines were reduced diastereoselectively with L-
Selectride in the corresponding fluorinated amines C, compounds of significant interest in the pharmacological industry.
semipinacol reaction as a means to access the imine products (B)
directly.
To the best of our knowledge, the halogenation-initiated aza-
semipinacol rearrangement of allylic amines was not reported in
edicinally relevant molecules overwhelmingly bear nitro-
Mgen functionality, with 179 of the top 200 brand name
drugs containing at least one N-atom. Possible explanations for
the prevalence of nitrogen in pharmaceuticals are diverse and
include increased activity due to better interactions with the
biological target as well as improved bioavailability.1
Furthermore, nitrogenous compounds that incorporate at
least one fluorine atom are increasingly more valued as synthetic
targets. The importance of fluorine is underlined by the fact that,
despite its low abundance in biosynthetic routes, about 20−25%
of all modern pharmaceuticals and agrochemicals incorporate at
least one fluorine atom.2 Consequently, the ability to access
nitrogen- and fluorine-containing molecules bearing stereogenic
carbon atoms is important due to their omnipresence in
biologically active compounds.
Scheme 1. Motivation behind the Development of a Direct
Fluorinative Aza-semipinacol Reaction
Our group has recently applied the anionic phase-transfer
fluorination protocol of Toste et al.3 to perform the
enantioselective fluorination-initiated semipinacol rearrange-
ment of strained allylic alcohols.4 When studying synthetic
derivatizations of β-fluoro spiroketones (D) produced by our
reaction, it was quickly noted that the reactivity of the carbonyl
group in these molecules is significantly hampered, and synthetic
manipulations were limited to the smallest of nucleophiles (such
as the hydride anion for Red-Al reduction and the oxygen atom
for Baeyer−Villiger oxidation). All attempts to condense the
carbonyl function with a primary amine and carry out a reductive
amination reaction were unsuccessful (Scheme 1). This synthetic
limitation led us to consider the fluorination-initiated aza-
Received: July 30, 2014
Published: September 12, 2014
© 2014 American Chemical Society
4988
dx.doi.org/10.1021/ol5022355 | Org. Lett. 2014, 16, 4988−4991

Organic Letters
Letter
scientific literature. In our opinion, this is due to the lower
thermodynamic stability of the carbon−nitrogen double bond, as
opposed to the carbon−oxygen double bond that is formed in
the “normal” oxa-semipinacol transposition. Furthermore, if the
aza-semipinacol rearrangement were to be initiated by exposing a
strained allylic amine to an electrophilic halogen source, this last
reagent would tend to react at the nitrogen atom rather than the
carbon−carbon double bond. Nevertheless, we were motivated
to probe the reactivity of various N-protected dihydronaph-
thalene-based cyclopropylamines of the type A with Selectfluor,
under our previously established anionic phase-transfer con-
ditions (Scheme 1).4
Table 1. Optimization of the Reaction Conditions
Before tackling any optimization studies, a reliable synthetic
route to access compounds of the type A had to be established.
First, dihydronaphthalenyl nitriles of the type Y were prepared
from the commonly used α-tetralone scaffolds X (Scheme 2).
a
b
c
d
entry
Gx
Ly
L1
base
yield (%)
dr
er
Scheme 2. Preparation of the Substrate Allylic
Cyclopropylamines (A)
1
G1
G2
G3
G4
G5
G6
G1
G1
G1
G1
G1
G1
G1
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
none
67
48
73
0
>20:1
>20:1
>20:1
n.d.
91:9
88:12
89:11
n.d.
2
L1
3
L1
4
L1
e
5
L1
90
>20:1
n.d.
93:7
n.d.
6
L1
0
78
75
68
7
L2
>20:1
>20:1
>20:1
>20:1
n.d.
91:9
92:8
91:9
92:8
n.d.
8
L3
These compounds were then subjected to a Kulinkovich−
Szymoniak reaction with ethylmagnesium bromide and titanium-
(IV) isopropoxide.5 Protection of the free amines furnished the
desired allylic cyclopropylamines in moderate-to-good yields.7
Optimization studies were carried out next on the
dihydronaphthalene-based cyclopropylamines Ax with different
protecting groups at the nitrogen atom: PG = Ms (A1), Ps (A2),
Ts (A3), Tf (A4), Bz (A5), and Boc (A6). The initial trials were
made with (Ra)-TRIP phosphoric acid (L1), sodium phosphate
as base, at 0 °C, in the binary mixture PhF/n-Hex 1:1 (v/v) as
solvent (Table 1).
9
L4
f
10
11
12
13
L3
85
none
L1
trace
g
10
10:1
59:41
50:50
h
none
Na3PO4
93
4:1
a
b
Reaction conditions: see the Supporting Information. Isolated yield
c
after flash chromatography. Determined by 1H NMR analysis of
unpurified mixtures. Determined by chiral HPLC analysis of purified
compounds. Only the fluorocyclization product was isolated. The
d
e
f
reaction time was extended to 96 h, and the concentration was
g
h
increased to 0.08 M. 1H NMR conversion. The reaction was
performed in acetonitrile.
While no reaction took place with trifluoromethanesulfonyl-
and tert-butoxycarbonyl-protected amines (A4 and A6, respec-
tively), substrates A1 (PG = methanesulfonyl), A2 (PG =
phenylsulfonyl), A3 (PG = p-tolylsulfonyl), and A5 (PG =
benzoyl) reacted to various extents to furnish diastereomerically
Racemic material was prepared by treating A1 with Selectfluor
in acetonitrile, under homogeneous reaction conditions (entry
13). Interestingly, in contrast to the “normal” oxa-semipinacol
reaction for which the racemate was obtained as a ca. 1:1 mixture
of diastereomers, the title aza-semipinacol rearrangement was
moderately to-highly diastereoselective (depending on the
substrate) even under these homogeneous reaction conditions.
Finally, omitting the phosphoric acid catalyst altogether led to
no reaction in PhF/n-Hex (entry 11). Additionally, the addition
of base turned out to be detrimental for the success of the
fluorinative aza-semipinacol rearrangement, in terms of both the
yield and enantioselectivity. Thus, when employing phosphoric
acid L1 in the absence of the sodium phosphate additive (entry
12), a significant drop in conversion and enantiomeric excess was
noted. These observations support the assumption that the title
process operates through anionic phase-transfer catalysis, where
the chiral lipophilic phosphate anion is the catalytically active
species in solution.3,4
1
pure material (>20:1 dr, according to H NMR analysis of
unpurified compounds). To our great delight, the sulfonylated
products B1, B2, and B3 structurally corresponded to the
1
awaited β-fluoro cyclobutylimines (as evidenced from H, 13C,
and 19F NMR spectra) and were formed with decent levels of
asymmetric induction (91:9, 88:12 and 89:11 er, respectively).
On the other hand, the fluorinated product derived from the
benzoylated substrate A5 did not display a characteristic 13C
resonance at ca. 195 ppm (characteristic of an imine carbon),
whereas its overall spectral properties were more consistent with
a fluorocyclization-derived structure, similar to the ones reported
by Toste et al.3,7
Moving to the more lipophilic variants of (Ra)-TRIP, such as
phosphoric acids L2, L3, and L4, led to an observable increase in
yield of the β-fluoro cyclobutylimine product (B1). Moreover,
the TIPS (triisopropylsilyl)-substituted phosphoric acid L3 led
to a slight increase in enantiomeric excess as well (up to 92:8 er,
entry 8). Finally, the isolated yield of B1 could be further
improved by increasing the molar concentration to 0.08 M and
extending the reaction time to 96 h (up to 85% yield, entry 10).
Importantly, these changes did not affect the stereoselectivity of
the fluorination-initiated aza-semipinacol reaction.
Having established the optimal operational conditions, the
generality of the fluorination-initiated aza-semipinacol reaction
was probed next. To this end, methanesulfonyl- (x = 1−3, 5−7, 9,
10) and p-tolylsulfonyl- (x = 4, 8, 11) protected cyclopropyl-
amines Ax were stirred with Selectfluor, sodium phosphate, and
phosphoric acid L3, in PhF/n-Hex, at 0 °C, for 96 h (Scheme 3).
4989
dx.doi.org/10.1021/ol5022355 | Org. Lett. 2014, 16, 4988−4991

Organic Letters
Letter
contiguous stereogenic centers, compounds of significant
interest in the pharmacological industry.
Scheme 3. Substrate Scope of the Fluorinative Aza-
semipinacol Reaction
After a collection of different reducing agents were screened, it
was quickly established that L-Selectride in THF at −78 °C was
optimal. With these conditions in hand, a representative panel of
four β-fluoro cyclobutylimines Bx (x = 3, 8, 9 and 11) were
successfully reduced to their corresponding fluorinated cyclo-
butylamines Cx (x = 3, 8, 9 and 11) (Scheme 5).
Scheme 5. Diastereoselective Reduction of β-fluoro
Cyclobutylimines with L-Selectride
As can be seen from Scheme 5 above, the reduction took place
smoothly for all four β-fluoro cyclobutylimines, affording the
desired fluorinated amines in high isolated yields, high
diastereoselectivity, and with complete retention of the chiral
information.
Single crystals were grown from racemic β-fluoro cyclobutyl-
amine C8 for X-ray diffraction analysis.8 The structure of ent-C8
is given in Scheme 6 below. The high diastereoselectivity of L-
As can be seen from Scheme 3 above, the optimized aza-
semipinacol reaction seems to tolerate both electron-releasing
(MeO: products B9, B10, and B11) as well as electron-
withdrawing (F, Cl, and Br: products B5, B6, B7, and B8)
substituents at the C5 and C6 positions of the dihydronaph-
thalene ring. The enantiomer ratios of the product β-fluoro
cyclobutylimines were generally high (up to 95:5 er for product
B9). As already noted during optimization studies (vide supra),
methanesulfonyl-protected substrates invariably led to more
enantioselective reactions than their p-tolylsulfonyl-protected
counterparts (for example, compare products B7 and B8).
Initially, the relative configuration of the β-fluoro cyclo-
butylimine products in solution was tentatively assigned from
heteronuclear Overhauser enhancement spectroscopy (HOESY,
see Scheme 4).6,7 This attribution was later confirmed by X-ray
diffraction studies performed on the corresponding reduction
products (vide infra).
Scheme 6. X-ray Crystal Structure of ent-C8, Confirming the
Relative Configuration
Selectride reduction could be tentatively explained by the
hydride ion attacking the imine CN double bond from the face
anti to the bulky edge of the phenyl ring.
In accord with our previous assignment made from
heteronuclear Overhauser enhancement spectroscopy, the X-
ray crystal structure of racemic C8 confirmed the anti orientation
between the fluorine atom and the nitrogen-substituted terminus
of the cyclobutane ring. Such a relative configuration is consistent
with selective migration of the C−C bond that is syn to the
fluoronium bridge in the parent allylic cyclopropylamine A8.
This is rather unexpected because anti migration was observed
previously for halogenation/semipinacol reactions of the related
oxa substrates.4,9 The dichotomy between the diastereoselectiv-
ities of aza and oxa rearrangements can be tentatively explained
when considering the stronger electron-donating ability of
nitrogen versus oxygen atoms. Consequently, the aza-semi-
pinacol reaction presumably takes place via an open β-fluoro
carbocation, as opposed to the oxa-semipinacol reaction that
operates through a cyclic fluoronium bridge.
Scheme 4. Attribution of Relative Configuration of β-Fluoro
cyclobutylimines in solution from 1H−19F NOE
As a next step, we were interested whether β-fluoro
cyclobutylimines Bx, obtainable in high enantiomeric excesses
following the title fluorination/aza-semipinacol reaction, could
be reduced diastereselectively. If successful, the entire fluorina-
tion/aza-semipinacol/reduction sequence could provide a facile
access to optically active fluorinated amines with three
Alternatively, anchimeric assistance from the nitrogen
protecting group might be operating as well (Scheme 7). In
4990
dx.doi.org/10.1021/ol5022355 | Org. Lett. 2014, 16, 4988−4991

Organic Letters
Letter
strained allylic cyclopropylamines. The described reaction takes
place under heterogeneous anionic phase-transfer conditions,
and requires catalytic amounts of enantiopure phosphate anion
derived from acid L3 as the chirality inducer. The absolute
configuration of product β-fluoro cyclobutylimines was assigned
by VCD spectroscopy, while the relative configuration was
determined by X-ray crystallography. Unexpectedly, a relative
configuration consistent with syn-migration was observed. Most
importantly, the product β-fluoro cyclobutylimines were reduced
diastereoselectively into the corresponding chiral fluorinated
amines, compounds of significant interest in the pharmacological
industry.
Scheme 7. Tentative Stereochemical Model, Rationalizing the
Observed syn C−C Migration
both cases, the outcome of reaction (cyclization versus C−C
bond migration) becomes a function of the donor ability of the
nitrogen atom (which itself depends on the nature of the
protecting group).10
Depending on the chemical nature of the nitrogen protecting
group, it may contribute to different extents to the stabilization of
the intermediate β-fluoro carbocation. Thus, if fluorination
occurs anti with respect to the protecting group (anchimeric
assistance) and the subsequent C−C bond migration occurs anti
with respect to the cyclic oxonium ion then an overall syn
fluorination/C−C bond migration would result.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, NMR spectra, HPLC traces,
computational details, IR and VCD spectra, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
The absolute configuration of β-fluoro cyclobutylimine
products was unequivocally established from vibrational circular
dichroism (VCD) studies. To this end, calculations of several
conformers of ent-B4 were performed at the B3PW91/6-
31G(d,p) level of theory. VCD spectra were then constructed
for each conformer from the calculated rotational strengths.7 For
comparison with the experimental VCD spectra, a Boltzmann-
weighted average of the calculated spectra of the conformers was
used (Scheme 8).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: Thomas.Buergi@unige.ch
*E-mail: Alexandre.Alexakis@unige.ch
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
2010, 87, 1348. (b) Augner, D.; Gerbino, D. C.; Slavov, N.; Neudorfl, J.-
Scheme 8. Experimental VCD Spectra for Both Enantiomers
of B4 (Bottom), and Boltzmann-Weighted Average of
Calculated VCD Spectra of ent-B4 (Top)
̈
M.; Schmalz, H. G. Org. Lett. 2011, 13, 5374. (c) Nozawa, Y.;
Yamamoto, K.; Ito, M.; Sakai, N.; Mizoue, K.; Mizobe, F.; Hanada, K. J.
Antibiot. 1997, 50, 635. (d) Comins, D.; Schilling, S.; Zhang, Y. Org. Lett.
2005, 7, 95. (e) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T.;
Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org.
Process Res. Dev. 2003, 7, 851. (f) Belliotti, T. R.; Brink, W. A.; Kesten, S.
R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A.
E.; Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett.
1998, 8, 1499.
(2) (a) Gribble, G. W. In Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich, W., Tamm, C.,
Eds.; Springer: New York, 1996; Vol. 68, pp 1−498. (b) Gribble, G. W.
In Progress in the Chemistry of Organic Natural Products; Kinghord, A. D.,
Falk, H., Kobayashi, J., Eds.; Springer: New York, 2009; Vol. 91, pp 1−
613. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320−330. (d) O’Hagan, D.; Rzepa, H. S. Chem. Commun.
1997, 645−652.
(3) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science
2011, 334, 1681−1684.
(4) Romanov-Michailidis, F.; Guen
Int. Ed. 2013, 52, 9266−9270.
́ ́
ee, L.; Alexakis, A. Angew. Chem.,
(5) Bertus, P.; Szymoniak, J. Synlett 2007, 9, 1346−1356.
(6) (a) Rinaldi, P. L. J. Am. Chem. Soc. 1983, 105, 5167−5168. (b) Yu,
C.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533−6537.
(7) See the Supporting Information for details.
(8) The stereochemistry of rac-C8 was confirmed by X-ray diffraction
analysis. CCDC 1015431 contains all of the crystallographic data for this
paper. This data is available free of charge from the Cambridge
Crystallographic Data Centre under www.ccdc.cam.ac.uk/data_
request/cif.
A good match between experimental and theoretical data is
observed. By comparing the calculated spectrum for ent-B4 with
the experimental spectra for both enantiomers of B4, one can
conclude that the absolute configuration is S and R for the spiro
and the fluorinated carbons, respectively. This is consistent with
Re face fluorination of the C−C double bond in the prochiral
substrate.
(9) Romanov-Michailidis, F.; Guenee, L.; Alexakis, A. Org. Lett. 2013,
́
́
15, 5890−5893.
(10) As noted by one of the reviewers, depending on the chemical
nature of the nitrogen protecting group, it may contribute at different
extents to the stabilization of the intermediate β-fluoro carbocation.
In conclusion, we report here the first example of a highly
enantioselective fluorinative aza-semipinacol rearrangement of
4991
dx.doi.org/10.1021/ol5022355 | Org. Lett. 2014, 16, 4988−4991