Chiral phosphoric acid catalyzed enantioselective synthesis of β-amino-α,α-difluoro carbonyl compounds

Article abstract of DOI:10.1021/ol200374m

A biphenol-based chiral phosphoric acid bearing a 9-anthryl group at each of the 3,3′-positions catalyzed the asymmetric Mannich-type reaction of N-Boc imine with difluoroenol silyl ethers in the presence of MS3A in THF to afford β-amino-α,α-difluoroketon

Full text of DOI:10.1021/ol200374m

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1860–1863
Chiral Phosphoric Acid Catalyzed
Enantioselective Synthesis of β-Amino-r,
r-difluoro Carbonyl Compounds
Wataru Kashikura, Keiji Mori, and Takahiko Akiyama*
Department of Chemistry, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-
8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received February 9, 2011
ABSTRACT
A biphenol-based chiral phosphoric acid bearing a 9-anthryl group at each of the 3,30-positions catalyzed the asymmetric Mannich-type reaction of
N-Boc imine with difluoroenol silyl ethers in the presence of MS3A in THF to afford β-amino-R,R-difluoroketones in good yields and with excellent
enantioselectivities. Optically pure 3,3-difluoroazetidin-2-one was readily synthesized from the Mannich-adduct.
The incorporation of fluorine atoms into a target or-
ganic molecule often dramatically changes the physical,
chemical, and biological properties of the molecule and
affects its application in various areas, including pharma-
ceutical, agrochemical, and material sciences.1 Among them,
β-amino-R,R-difluoro carbonyl compounds, which are valu-
able intermediates for and targets of drug design, have
attracted much attention due to their unique biological
properties.2 For example, some of the difluoro docetaxel
compounds2c showed activities that were comparable or
superior to that of docetaxel. A β-amino-R,R-difluoro carbo-
nyl unit containing a rhodopeptin derivative2d exhibited
improved physical and biological properties, such as acute
toxicity and solubility, while retaining its antifungal activity
(Figure 1). The gem-difluoromethylene group not only in-
creases the acidity of its neighboring group but also signifi-
cantly improves lipophilicity, because of its strong electron-
withdrawing effect.3 Furthermore, the gem-difluoromethy-
lene group also increases the electrophilicity of the neighbor-
ing carbonyl group. The R,R-difluoro carbonyl compounds
form stable hydrates or hemiketals that mimic tetrahedral
intermediates involved in the enzymatic cleavage of peptide
bonds, and inhibit the activity of a number of hydrolytic
enzymes.4 The development of a method for the preparation
of β-amino-R,R-difluoro carbonyl compounds in an opti-
cally pure form is extremely important from a synthetic
point of view. Three methods are available for the asym-
metric synthesis of β-amino-R,R-difluoro carbonyl com-
pounds: (1) deoxydifluorination of β-keto carbonyl compo-
und using diethylaminosulfur trifluoride (DAST),5 (2) the
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, U.
K., 2006. (b) Dolbier, W. R. J. Fluorine Chem. 2005, 126, 157–163. (c)
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Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886. (d)
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P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.
(f) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369. (g) Zhang, W.;
Cai, C. Chem. Commun. 2008, 5686–5694.
(2) For a review on gem-difluoromethylene compounds, see: (a)
Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683. For
examples on the utility of β-amino-R,R-difluoro carbonyl compounds,
also see:(b) Thaisrivongs, S.; Schostarez, H. J.; Pals, D. T.; Turner, S. R.
J. Med. Chem. 1987, 30, 1837–1842. (c) Uoto, K.; Ohsuki, S.; Take-
noshita, H.; Ishiyama, T.; Iimura, S.; Hirota, Y.; Mitsui, I.; Terasawa,
H.; Soga, T. Chem. Pharm. Bull. 1997, 45, 1793–1804. (d) Nakayama, K.;
Kawato, H. C.; Inagaki, H.; Nakajima, R.; Kitamura, A.; Someya, K.;
Ohta, T. Org. Lett. 2000, 2, 977–980.
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Viani, F. ChemBioChem 2004, 5, 590–613. (c) Bohm, H.-J.; Banner, D.;
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Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl,
M. ChemBioChem 2004, 5, 637–643.
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24, 1813–1817. (b) Gelb, M. H. J. Am. Chem. Soc. 1986, 108, 3146–3147.
(c) Damon, D. B.; Hoover, D. J. J. Am. Chem. Soc. 1990, 112, 6439–
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r
10.1021/ol200374m
Published on Web 03/10/2011
2011 American Chemical Society

Figure 2. Chiral phosphoric acids.
Figure 1. Examples of optically active β-amino-R,R-difluoro
carbonyl compounds.
type reaction of difluoroenol silyl ethers with aldimines
catalyzed bya chiralphosphoricacidfurnishedβ-amino-R,
R-difluoro carbonyl compounds with high to excellent
enantionselectivities.
Reformatsky reaction of R-bromo-R,R-difluoroacetate with
aldimines,6 and (3) the Mannich-type reaction of difluori-
nated silyl enol ether with aldimines.7 A highly diastereose-
lective Reformatsky reaction was reported and moderate
diastereoselectivity was observed in the Mannich-type reac-
tion. The catalytic enantioselective variant of these processes
leading to β-amino-R,R-difluoro carbonyl compounds, how-
ever, remains elusive.
As part of our ongoing work to develop chiral phos-
phoric acid (Figure 2)8,9 catalyzed reactions, we started a
program to study the chiral phosphoric acid catalyzed
Mannich-type reaction10 of aldimines with difluorinated
enol silyl ethers. This substrate is readily available from a
trifluoroacetophenone derivative.11 We wish to report
herein the first catalytic enantioselective synthesis of β-
amino-R,R-difluoro carbonyl compounds. The Mannich-
At the outset, the effect of the catalyst was investigated
on the reaction of N-tert-butoxycarbonyl (Boc) imines 4a
with difluoroenol silyl ethers 5a, and the results are sum-
marized in Table 1. On treatment of 4a and 5a with (R)-1a
(5 mol %) in toluene at room temperature for 23 h, the
corresponding β-amino-R,R-difluoroketone 6a was ob-
tained in 35% yield with 63% ee (entry 1, Table 1). Wher-
eas the use of catalysts (R)-1b and 1c bearing a bulky
substituent, such as 2,4,6-(iPr)3C6H2 and 9-anthryl groups,
slightly improved the enantioselectivity (entries 2 and 3),
whereas the use of 1d with SiPh3 groups resulted in low
enantioselectivity (entry 4). We found that the chiral
phosphoric acid scaffold affected both yield and ee, and
(6) (a) Vidal, A.; Nefzi, A.; Houghten, R. A. J. Org. Chem. 2001, 66,
8268–8272. (b) Soloshonok, V. A.; Ohkura, H.; Sorochinsky, A.;
Voloshin, N.; Markovsky, A.; Belik, M.; Yamazaki, T. Tetrahedron
Lett. 2002, 43, 5445–5448. (c) Niida, A.; Tomita, K.; Mizumoto, M.;
Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.; Inui, K.; Fujii, N. Org.
Lett. 2006, 8, 613–616. (d) Christianson, C. V.; Montavon, T. J.; Festin,
G. M.; Cooke, H. A.; Shen, B.; Bruner, S. D. J. Am. Chem. Soc. 2007,
129, 15744–15745. (e) Oishi, S.; Kamitani, H.; Kodera, Y.; Watanabe,
K.; Kobayashi, K.; Narumi, T.; Tomita, K.; Ohno, H.; Naito, T.;
Kodama, E.; Matsuoka, M.; Fujii, N. Org. Biomol. Chem. 2009, 7,
2872–2877.
Table 1. Effect of Catalyst and Solvent in the Mannich-type
Reaction of N-Boc Imine with Difluoroenol Silyl Ethera
(7) Jonet, S.; Cherouvrier, F.; Brigaud, T.; Portella, C. Eur. J. Org.
Chem. 2005, 4304–4312.
(8) For reviews, see:(a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth.
Catal. 2006, 348, 999–1010. (b) Akiyama, T. Chem. Rev. 2007, 107, 5744–
5758. (c) Terada, M. Chem. Commun. 2008, 4097–4112. (d) Terada, M.
Synthesis 2010, 1929–1982. (e) Zamfir, A.; Schenker, S.; Freund, M.;
Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8, 5262–5276.
(9) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566–1568. (b) Uraguchi, D.; Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356–5357.
(10) (a) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth.
Catal. 2005, 347, 1523–1526. (b) Yamanaka, M.; Itoh, J.; Fuchibe, K.;
Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756–6764. (c) Sickert, M.;
Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631–3634. (d) Akiyama,
T.; Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008, 350, 399–
402. (e) Giera, D. S.; Sickert, M.; Schneider, C. Org. Lett. 2008, 10, 4259–
4262. (f) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2008, 1319–1322.
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1666. (h) Giera, D. S.; Sickert, M.; Schneider, C. Synthesis 2009, 3797–
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Schneider, C. Chem.-Eur. J. 2010, 16, 2806–2818.
entry
catalyst
(R)-1a
solvent
yield (%)b
ee (%)c
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
35
9
63
89
2
(R)-1b
3
(R)-1c
36
11
38
16
24
44
58
60
89
84
4
(R)-1d
29
5
(R)-1e
64
6
(R)-2a
75
7
(R)-2b
93
8
(S)-3
92
9
(S)-3 (10 mol %)
(S)-3 (10 mol %)
(S)-3 (10 mol %)
93
10d
11d
93
94 (>99)e
a Reactions were performed with 4a (0.2 mmol, 1.0 equiv) and 5a (0.3
mmol, 1.5 equiv) in the presence of 5 mol % chiral phosphoric acid in 2
mL of toluene at rt (23 h). b Isolated yields. c Determined by chiral HPLC
analysis. d MS3A (100 wt %) was added. e Values in parentheses are the
ee values after one recrystallization from EtOH.
(11) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323–1324.
Org. Lett., Vol. 13, No. 7, 2011
1861

that (S)-3, derived from biphenol10g,12 bearing a 9-anthryl
group ateachof the 3,30-positions, was the optimalcatalyst
(entries 7 and 8). It was also found that the addition of
MS3A to the reaction system in THF significantly im-
proved the yield (entry 11).
An aldimine derived from aliphatic aldehyde did not give
the corresponding adduct 6o.
The absolute configuration of 6i was established to be S
by X-ray crystallographic analysis of 8 (Figure 3). 6i was
readily transformed into 8 in two steps: the removal of the Boc
group and the introduction of a benzoyl group. The absolute
stereochemistry of the other adducts was surmised by analogy.
Scheme 1. Results of the Mannich-type Reaction of N-Boc
Imine with Difluoroenol Silyl Ether Catalyzed by (S)-3a
Figure 3. X-ray crystal structure of 8.
To demonstrate the synthetic utility of the Mannich-
type reaction, we investigated a practical route for the
synthesis of enantiopure 3,3-difluoroazetidin-2-one, which
is a pharmaceutically important target as well as a useful
synthetic building block.2b,c,13 Treatment of 6a (>99% ee
after one recrystallization) with mCPBA in CH2Cl2/HFIP
in the presence of aqueous phosphate buffer (pH 7.6)14
furnished corresponding ester 9 without loss of enantios-
electivity. Ester 9 was converted into 3,3-difluoroazetidin-
2-one 10 in two steps via the removal of the Boc group and
the subsequent base-promoted cyclization (Scheme 2).
a Reactions were performed with 4 (0.2 mmol, 1.0 equiv) and 5 (0.3
mmol, 1.5 equiv) in the presence of 10 mol % (S)-3 and 100 wt % MS3A
in 2 mL of THF at rt (23 h). bResult was obtained after one recrystalliza-
tion from EtOH.
Scheme 2. Preparation of 3,3-Difluoroazetidin-2-one
Having established the optimal reaction conditions
(entry 11, Table 1), we studied the Mannich-type reaction
of a range of aldimines 4 with various difluoroenol silyl
ethers 5 and found that the reaction proceeded successfully
with excellent enantioselectivities and in good to high
yields (Scheme 1). A substrate bearing a bulky group, such
as 1-naphthyl, on R underwent the reaction smoothly to
giveaddition product6ein 81% isolatedyield with92% ee.
Both electron-withdrawing and electron-donating substi-
tuents on R or Ar were well tolerated in the reaction. A
heteroaromatic aldimine bearing a 2-furyl group also
afforded addition product 6n in good enantioselectivity.
Todisclosethe effectof a fluorine substituent, wetried to
perform the Mannich-type reaction of nonfluorinated enol
silyl ether 11 with 4a. We compared the reactivity of 5a and
its defluorinated analogue 11. Although we expected that
5a would be less reactive than 11 due to the -I effect and
(13) For a recent review, see: Tarui, A.; Sato, K.; Omote, M.;
Kumadaki, I. Adv. Synth. Catal. 2010, 352, 2733–2744.
(14) Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron
2003, 59, 1547–1552.
(12) Takai, M.; Urata, H.; Takahashi, T. Japan Patent JP
2004189696A, 2004.
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Org. Lett., Vol. 13, No. 7, 2011

the þIπ effect of fluorine,1a,15 competitive experiments
with 5a and 11 revealed that the reaction of 5a with 4a
was approximately twice as fast as that of 11 with 4a. The
ee of 6a was also higher than that of 12 (Scheme 3).16
Scheme 4. Enantioselective Synthesis of (R)- or (S)- β-Amino-R,
R-difluoroketone
Scheme 3. Comparison of Reactivity of Difluoroenol Silyl Ether
and Nonfluorinated Enol Silyl Ether
Although the reaction of N-p-methoxyphenyl (PMP)
imine 14 with 5a in the presence of (S)-3 yielded a product
with an extremely low ee in comparison with N-Boc imine
4a,17 the enantioselectivity was improved to 76% ee when
the reaction was carried out in the presence of (S)-13
instead of (S)-3 and in the absence of MS3A. Resulting
addition product 15 was obtained in an optically pure form
after recrystallization. Interestingly, these modified reac-
tion conditions exhibited opposite enantioselectivity for
the Mannich-type reaction of 4 to afford (R)-15. The
removal of PMP and Boc groups readily proceeded under
mild conditions to afford (R)-16 and (S)-16, respectively,
without racemization (Scheme 4).
a Values in parentheses are the ee values after recrystallization from
EtOH for 6a and hexane-CH2Cl2 for 15, respectively.
adduct could be readily transformed into versatile 3,3-
difluoroazetidin-2-one in three steps without loss of optical
purity. Furthermore, both enantiomers of β-amino-R,R-
difluoroketone could be prepared using the catalyst de-
rived from (S)-biphenol.
Acknowledgment. This work was partially supported
by a Grant-in-Aid for Scientific Research from Japan
Society forthe PromotionofScience. Wealsothank Kanto
Denka Kogyo Co., Ltd. for partial financial support and
Mitsubishi Chemical Group Science and Technology Re-
search Center, Inc. for the gift of (S)-3,30,5,50-tetra-tert-
butyl-6,60-dimethylbiphenyl-2,20 -diol.
In summary, we have developed catalytic enantioselec-
tive Mannich-type reactions of aldimine with difluoroenol
silyl ether by employing biphenol-derived chiral phospho-
ric acid. The reaction proceeded with good to excellent
enantioselectivities (up to 94% ee). The resulting Mannich
(15) (a) Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto,
S.; Kobayashi, Y. Tetrahedron 1997, 53, 10271–10280. (b) Kloetzing,
R. J.; Thaler, T.; Knochel, P. Org. Lett. 2006, 8, 1125–1128. (c) Guo, Y.;
Shreeve, J. M. Chem. Commun. 2007, 3583–3585. (d) Yue, X.; Zhang, X.;
Qing, F.-L. Org. Lett. 2009, 11, 73–76.
(16) The absolute stereochemistry of 12 was assigned by comparison
of optical rotation with literature data: Tillman, A. L.; Dixon, D. J. Org.
Biomol. Chem. 2007, 5, 606–609.
Supporting Information Available. Synthetic proce-
dures, CIF file of compound 8, together with character-
ization and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(17) 15 was obtained in 91% yield with 14% ee (S).
Org. Lett., Vol. 13, No. 7, 2011
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