On the inherent instability of alpha-amino alpha'-fluoro ketones. Evidence for their transformation to reactive oxyvinyliminium ion intermediates.

Article abstract of DOI:10.1021/ol006931x

[figure: see text] alpha-Amino alpha'-fluoro ketones are shown to be inherently unstable intermediates. Evidence is presented that they undergo enolization toward the amino group followed by expulsion of fluoride ion, forming a proposed oxyvinyliminium io

Full text of DOI:10.1021/ol006931x

ORGANIC
LETTERS
2001
Vol. 3, No. 3
425-428
On the Inherent Instability of r-Amino
r′-Fluoro Ketones. Evidence for Their
Transformation to Reactive
Oxyvinyliminium Ion Intermediates
Andrew G. Myers* and Joseph K. Barbay
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
myers@chemistry.harVard.edu
Received November 28, 2000
ABSTRACT
r-Amino r′-fluoro ketones are shown to be inherently unstable intermediates. Evidence is presented that they undergo enolization toward the
amino group followed by expulsion of fluoride ion, forming a proposed oxyvinyliminium ion (amino-substituted oxyallyl cation). In protic,
nucleophilic media the proposed intermediate is trapped by solvent. In the presence of a reactive diene, [4 + 3] cycloadducts have been
isolated. Prior observations concerning fluorinated amino ketones are discussed in light of these findings.
R-Fluorinated ketones have been investigated extensively as
inhibitors of proteolytic enzymes.1 They are proposed to react
by the addition of an active-site nucleophile to the electro-
philic carbonyl group, generating a stable and tightly enzyme-
bound mimic of a tetrahedral species along the pathway for
peptide hydrolysis. Fluoro ketone protease inhibitors contain-
ing stereogenic fluorinated carbon atoms have been little
studied, presumably due to their synthetic inaccessibility.2
In the context of research directed toward the development
of methodology for the asymmetric synthesis of chiral
organofluorine compounds, we targeted ketone anti-1 and
its diastereomer syn-1, analogues of Merck’s HIV-protease
inhibitor indinavir3 (Crixivan, 2), containing a monofluoro
(1) (a) Brodbeck, U.; Schweikert, K.; Gentinetta, R.; Rottenberg, M.
Biochim. Biophys. Acta 1979, 567, 357-369. (b) Gelb, M. H.; Svaren, J.
P.; Abeles, R. H. Biochemistry 1985, 24, 1813-1817. (c) Imperiali, B.;
Abeles, R. H. Biochemistry 1986, 25, 3760-3767. (d) Mehdi, S. Bioorg.
Chem. 1993, 21, 249-259, and references therein. (e) Sham, H. L. In
Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J. R.,
Welch, J. T., Eds.; American Chemical Society: Washington DC, 1996;
pp 184-195, and references therein.
(2) (a) Garrett, G. S.; Emge, T. J.; Lee, S. C.; Fischer, E. M.; Dyehouse,
K.; McIver, J. M. J. Org. Chem. 1991, 56, 4823-4826. (b) Hoffman, R.
V.; Saenz, J. E. Tetrahedron Lett. 1997, 38, 8469-8472. (c) Hoffman, R.
V.; Tao, J. Tetrahedron Lett. 1998, 39, 4195-4198. (d) Hoffman, R. V.;
Tao, J. J. Org. Chem. 1999, 64, 126-132.
ketomethylene dipeptide isostere. These were considered
targets of obvious interest in light of the synthetic challenge
they presented, the importance of indinavir in current HIV
therapy, and the fundamental questions they raised concern-
ing enzyme inhibitory activity and its relation to the
stereochemistry of the fluorinated center. In the course of
studies directed toward the preparation of these compounds,
we have learned that R-amino R′-fluoro ketones are inher-
(3) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J.
P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J.
C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.; Axel,
M. G.; Ostovic, D.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1994, 37,
3443-3451.
10.1021/ol006931x CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

ently unstable structures. They undergo an interesting and
unanticipated series of reactions, leading to the formation
of a proposed oxyvinyliminium ion, as detailed herein.
The diastereomeric fluoro ketones anti-1 and syn-1 were
envisioned to arise by oxidation of fluorohydrin precursors
(3), followed by acetonide deprotection. The fluorohydrin
precursors were prepared as part of another study that led to
the development of enantioselective and stereocontrolled
synthetic routes to protease inhibitors containing the four
stereoisomeric monofluoro hydroxyethylene dipeptide isos-
teres.4 Swern oxidation5 of fluorohydrin anti,anti-3 ef-
ficiently formed the ketone anti-4 (Scheme 1). Similarly,
Scheme 2. Proposed Mechanism of Hydrolytic Fragmentation
Scheme 1
zine 7 and the aldehyde 8,7 as observed by 1H NMR
spectroscopy (Scheme 2). The rate of fragmentation was
observed to be concentration dependent; at higher initial
concentrations of substrate, the fragmentation reaction was
faster. This is believed to reflect catalysis of the decomposi-
tion reaction by the tertiary amine. Even dilute solutions of
the ketones decomposed quickly. For example, anti-4 was
consumed completely within 19 h at 23 °C in a solution
initially 16 mM in substrate. The rates of fragmentation of
the two diastereomeric ketones anti-4 and syn-4 were
qualitatively comparable (5 mM initial concentrations: anti-
4, 42% conversion at 50 h, 23 °C; syn-4, 38% conversion
at 57 h, 23 °C).
We propose that the decompositions occur by the mech-
anism shown in Scheme 2 (for anti-4). In this mechanism,
enolization of the fluoro ketone forms the γ-fluorinated
enamine 5.8 Expulsion of fluoride is then proposed to form
the oxyvinyliminium ion 6. Reaction of this intermediate with
water leads to the observed products, 7 and 8. In contrast,
incubation of anti-4 or syn-4 in methanol-d4 containing
triethylamine (2 equiv) at 23 °C cleanly produced the
nonfluorinated methanol adducts 9 (Scheme 3), supporting
Swern oxidation of fluorohydrin anti,syn-3 (structure not
shown) led to the ketone syn-4. Surprisingly, both ketones
were observed to fragment when they were subjected to
chromatography on silica gel; the piperazine 76 and the
aldehyde 8 were identified as the primary products of the
fragmentation. Decomposition of ketones 4 also occurred
upon attempted acidic hydrolysis of the acetonide groups.
The instability of these compounds was clearly associated
with the presence of the fluorine atom, for the corresponding
nonfluorinated ketone4 was found to be quite stable and
withstood deprotection under acidic conditions (48% yield,
unoptimized).
(4) Myers, A. G.; Barbay, J. K.; Zhong, B. To be submitted for
publication.
(5) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(6) The structure of this compound was confirmed by independent
synthesis; see the Supporting Information for details.
(7) The aldehyde 8 was slowly converted to the corresponding keto
aldehyde hydrate under these conditions.
(8) Fluoro ketones 4 do not epimerize under the conditions of fragmenta-
tion, nor is deuterium incorporated at the fluorinated position, suggesting
that enolization is regiospecific (away from fluorine). We have previously
noted that tertiary amides of pseudoephedrine with an “epimerizable”
R-fluorinated center can be hydrolyzed under basic conditions without
isomerization (Myers, A. G.; McKinstry, L.; Barbay, J. K.; Gleason, J. L.
Tetrahedron Lett. 1998, 39, 1335-1338). This apparent kinetic barrier to
enolization likely reflects a preference for fluorine to form a bond to carbon
with maximal p-character (sp3 versus sp2), and perhaps also repulsion
between the base and fluorine atom in the disfavored enolization reaction.
The fragmentation reaction was monitored spectroscopi-
cally. Pure samples of the labile ketones anti-4 and syn-4
were obtained by gel filtration chromatography (Sephadex
LH-20). Incubation of each in D2O-p-dioxane-d8 (1:1, v/v)
at 23 °C led to smooth fragmentation, affording the pipera-
426
Org. Lett., Vol. 3, No. 3, 2001

single diastereomer; this product is believed to arise by
cycloaddition of the proposed intermediate (in the illustrated
s-trans conformation) through a compact (endo-like) transi-
tion state.14 Oxyallyl cations related to the proposed oxyvi-
nyliminium intermediate, including oxygen-, sulfur-, and
amido-substituted variants, are an important class of sub-
strates in [4 + 3] cycloaddition reactions; however, cycload-
ditions involving amino-substituted oxyallylic cations have
not been previously reported.15
Scheme 3
The generality of the oxyvinyliminium ion formation
outlined above was further investigated with the chiral
substrate 15, with a view toward corroborating the proposed
cycloaddition model, here in the context of the well-defined
imidazolidinone iminium ion system of MacMillan and co-
workers.16 The cycloaddition substrate 15 was prepared by
ytterbium triflate-catalyzed opening of epifluorohydrin with
amine 1316a followed by Swern oxidation of the resultant
diastereomeric mixture of alcohols 14 (1:1, Scheme 5). In
the assertion that fluoride loss occurs prior to scission of
the carbon-nitrogen bond. Both ketones anti-4 and syn-4
produced the same ratio of diastereomeric N,O-acetals 9 (2:1
mixture, >75% yield, isolation by chromatography on
Sephadex LH-20). The acetal proton (C16H) in each product
was clearly resolved in the 1H NMR spectrum of the
methanolysis reactions, allowing assessment of deuterium
incorporation at this position. No deuterium incorporation
was detected, suggesting that enolization of ketones 4 is not
rapid and reversible and may be the rate-limiting step.9
To investigate the generality of our observations and to
further probe the chemistry of R-amino R′-fluoro ketones, a
simpler system was studied (Scheme 4). Whereas Swern
Scheme 5a
Scheme 4
a (a) Epifluorohydrin, Yb(OTf)3, CH2Cl2, 23 °C, 70%; (b) DMSO,
(COCl)2, Et3N, -78 f 0 °C, 81%.
oxidation of 1-fluoro-3-piperidin-1-yl-propan-2-ol (10)10
resulted in nonspecific decomposition (with complete loss
of fluoride, as determined by 19F NMR), under less basic
oxidation conditions (DCC, DMSO-d6, PhH-d6, TFA, pyr,
1
4 Å MS)11 the labile ketone 11 was observed by H NMR
marked contrast to the R-fluoro R′-amino ketones described
thus far, 15 was found to be stable to chromatography on
silica gel. Although cycloaddition between ketone 15 and
spectroscopy. When the oxidation was conducted in the
presence of cyclopentadiene (5 equiv), it was possible to trap
the proposed oxyvinyliminium ion by cycloaddition (∼35%
yield).12,13 The endo cycloadduct (12) was produced as a
(13) Attempts to trap the proposed oxyvinyliminium ion 6 with cyclo-
pentadiene were unsuccessful, presumably due to steric factors.
(14) The stereochemistry of cycloadduct 12 was confirmed by a NOESY
experiment.
(9) Rate-limiting proton abstraction followed by rapid halide expulsion
has been observed in the Favorskii rearrangement of certain R-bromo and
R-chloro ketones, see: Bordwell, F. G.; Frame, R. R.; Scamehorn, R. G.;
Strong, J. G.; Meyerson, S. J. Am. Chem. Soc. 1967, 89, 6704-6711, and
references therein.
(10) Rozen, S.; Shahak, I.; Bergmann, E. D. Synthesis 1971, 646-647.
(11) (a) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87, 5661-
5670. (b) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87, 5670-
5679.
(12) Isolation of cycloadduct 12 is complicated by its instability to silica
gel chromatography. Two-dimensional TLC suggests that this compound
undergoes a reversible reaction upon exposure to silica gel; the product is
tentatively assigned as the hydrate.
(15) For reviews of cycloaddition reactions involving oxyallyl cations,
see: (a) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351-478. (b)
Hosomi, A.; Tominga, Y. In ComprehensiVe Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 5.1, pp 593-
615. (c) Mann, J. Tetrahedron 1986, 42, 4611-4659. (d) Hoffman, H. M.
R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1-88. For the specific case of
amido-substituted oxyallyl cations, see: (e) Walters, M. A.; Arcand, H. R.
J. Org. Chem. 1996, 61, 1478-1486. (f) Walters, M. A.; Arcand, H. R.;
Lawrie, D. J. Tetrahedron Lett. 1995, 36, 23-26.
(16) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243-4244. (b) Jen, W. S.; Wiener, J. J. M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-9875.
Org. Lett., Vol. 3, No. 3, 2001
427

cyclopentadiene proceeded poorly or not at all in CH3CN,
DMSO, CH2Cl2, THF, 2-propanol, or neat cyclopentadiene
as solvent (each containing 2 equiv of Et3N), use of 2,2,2-
trifluoroethanol (TFE) as solvent led to the formation of a
mixture of cycloadducts and solvolysis products, the latter
predominating (2.9:1 mixture).17 Use of the polar, nonnu-
cleophilic solvent hexafluoro-2-propanol, by contrast, af-
forded a mixture of four diastereomeric cycloaddition
products in 94% combined yield (endo:exo products ) 7.1:
1; endo diastereomers ) 6.8:1).18 The major cycloadduct (16)
was isolated as a single stereoisomer in 65% yield by column
chromatography. The stereochemistry of this product was
confirmed by X-ray structure determination (see Supporting
Information) and is consistent with preferred cycloaddition
of the proposed oxyvinyliminium ion from the less hindered
Re-face, in accord with the MacMillan model,16 in a compact
(endo-like) transition state.
of R-hydroxy ketones 20 and 21 was observed (Figure 1b).20
These results can be rationalized by a simple tautomeriza-
tion-hydrolysis mechanism. In these cases, neither expulsion
of fluoride ion nor elimination of HF occurs, likely a result
of the energetic cost associated with conversion of a
trifluoromethyl group to a divinyl fluoride.21 An important
counterpoint and prior example of the preparation of R-amino
R′-monofluoro ketones is the synthesis of the series of
N-(triphenylmethyl)amines 22 (Figure 1c) by Hoffman and
co-workers. These compounds evidently did not display
unexpected reactivity and could be purified by chromatog-
raphy on silica gel without decomposition, factors which may
be attributable to the bulky amino group.2d,22 Finally, it should
be noted that N-acyl R-amino R′-fluoro ketones and am-
monium salts of R-amino R′-fluoro ketones23 have been
frequently employed as inhibitors of proteolytic enzymes and
as synthetic intermediates, suggesting that the availability
of the nitrogen lone pair is central to the instability of
R-amino R′-fluoro ketones.
In conclusion, we have described unexpected reactivity
associated with R′-monofluorinated R-amino ketones. The
development of an improved understanding of the properties
of R-amino R′-fluorinated ketones is of particular significance
in light of their role as inhibitors of proteolytic enzymes. It
is conceivable, for example, that a new class of “suicide”
inhibitors could be derived from such intermediates if they
could be delivered to or formed at an enzyme active site.
The instability of R-amino R′-fluoro ketones is proposed to
result from the formation of an oxyvinyliminium ion
intermediate. This intermediate undergoes solvolysis in
protic, nucleophilic media and [4 + 3] cycloaddition reac-
tions when generated in the presence of a reactive diene.
It is interesting to compare the reactivity of the fluorinated
ketones described herein with literature reports regarding
other R-amino R′-fluoro ketones. There are at least two
reports of the hydrolytic fragmentation of R-amino R′-(tri)-
fluoro ketones. In 1990, Peet and co-workers reported that
attempted acidic hydrolysis (concentrated hydrochloric acid,
reflux) of R-amido R′-trifluoromethyl ketones 17 led to the
formation of R-hydroxy ketones 18 rather than the anticipated
products of amide hydrolysis (Figure 1a).19 Subsequently, a
Acknowledgment. Financial support from the National
Institutes of Health is gratefully acknowledged. We thank
Andrew Haidle for obtaining crystallographic data for
cycloadduct 16.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 4, 7-10,
and 12-16 and X-ray crystal data for 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL006931X
(18) The four diastereomeric cycloadducts were separable by silica gel
chromatography. The relative stereochemistry of the centers within the
bicyclo[3.2.1]octenone ring system in each product was assigned on the
basis of observed NOESY cross-peaks.
Figure 1. Reported properties of R-amino R′-fluoro ketones. (a)
R-Amido R′-trifluoromethyl ketones 17 fragmented under acidic
conditions.19 (b) Ketones 19 fragmented upon purification on SiO2.20
(c) R-Amino R′-monofluoro ketones stable to SiO2 chromatography.2d
(19) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi,
S.; Bey, P.; Kolb, M. K.; Neises, B.; Schirlin, D. J. Med. Chem. 1990, 33,
394-407.
(20) Be´gue´, J.-P.; Bonnet-Delpon, D.; Sdassi, H. Tetrahedron Lett. 1992,
33, 1879-1882.
(21) Smart, B. E. In Molecular Structure and Energetics; Liebman, J.
F., Greenberg, A., Eds.; VCH: Deerfield Beach, FL, 1986; Vol. 3, pp 141-
190.
series of R-dialkylamino R′-trifluoromethyl ketones (see
structure 19) were reported to be unstable toward chromato-
graphic purification on silica gel; fragmentation to a mixture
(22) For another example of a stable R-amino R′-monofluoro ketone,
see: Blanco, M.-J.; Sardina, F. J. J. Org. Chem. 1996, 61, 4748-4755.
(23) See, for example: (a) Angelastro, M. R.; Burkhart, J. P.; Bey, P.;
Peet, N. P. Tetrahedron Lett. 1992, 33, 3265-3268. (b) Dancer, J. E.; Ford,
M. J.; Hamilton, K.; Kilkelly, M.; Lindell, S. D.; O′Mahony, M. J.; Saville-
Stones, E. A. Bioorg. Med. Chem. Lett. 1996, 6, 2131-2136.
(17) The CF3CH2OH/Et3N system has been previously employed in
cycloadditions of oxyallylic cations: Fo¨hlisch, B.; Gehrlach, E.; Herter, R.
Angew. Chem., Int. Ed. Engl. 1982, 2, 137.
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