Asymmetric synthesis of (αR)-polyfluoroalkylated prolinols based on the perfluoroalkyl-induced highly stereoselective reduction of perfluoroalkyl n-boc-pyrrolidyl ketones

Article abstract of DOI:10.1021/jo8004952

(Chemical Equation Presented) Reduction of the obtained chiral (S)-tert-butyl 2-(perfluoroalkanoyl)pyrrolidine-1-carboxylate with sodium borohydride or lithium aluminum hydride proceeded smoothly to give the corresponding (S)-tert-butyl 2-((R)-perfluoro-1

Full text of DOI:10.1021/jo8004952

reaction,17 and can also act as chiral ligands for the reduction
of ketones,18 and the alkylation19 and arylation20 of aldehydes.
Therefore, various approaches to optically pure prolinol deriva-
tives from commercially available L-proline have been devel-
oped over the past 30 years.21
Asymmetric Synthesis of (rR)-Polyfluoroalkylated
Prolinols Based on the Perfluoroalkyl-Induced
Highly Stereoselective Reduction of
Perfluoroalkyl N-Boc-pyrrolidyl Ketones
However, to the best of our knowledge, there has been no
report on the asymmetric synthesis or the use of R-fluoroalky-
lated optically pure prolinol derivatives,22–24 despite their
expected widespread applications, although some reports have
described the excellent properties of R-trifluoromethylated chiral
aminoalcohols,25–27which could be used as ligands, chiral
auxiliaries, or organocatalysts in the asymmetric addition of
diethyl zinc, the asymmetric Reformatsky reaction, the asym-
metric Simmons-Smith reaction, transesterification, and kinetic
resolutions.
Kazumasa Funabiki,*,† Akitsugu Shibata,† Hiroki Iwata,†
Keisuke Hatano,† Yasuhiro Kubota,† Kenichi Komura,†
Masahiro Ebihara,‡ and Masaki Matsui†
Department of Materials Science and Technology and
Department of Chemistry, Faculty of Engineering, Gifu
UniVersity, 1-1 Yanagido, Gifu 501-1193, Japan
funabiki@gifu-u.ac.jp
ReceiVed March 3, 2008
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Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
Reduction of the obtained chiral (S)-tert-butyl 2-(perfluoro-
alkanoyl)pyrrolidine-1-carboxylate with sodium borohydride
or lithium aluminum hydride proceeded smoothly to give
the corresponding (S)-tert-butyl 2-((R)-perfluoro-1-hydroxy-
alkyl)pyrrolidine-1-carboxylate in yields of 73-97% with
excellent diastereoselectivities (up to >98% de), compared
with the reduction of nonfluorinated (S)-tert-butyl 2-pen-
tanoylpyrrolidine-1-carboxylate.
(8) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 3703, and ref 7.
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Considerable attention has recently been addressed to optically
pure prolinol derivatives,1 since these compounds are some of
the most efficient organocatalysts2 in catalytic asymmetric
reactions, such as the Mannich reaction,3 Michael (conjugate)
addition,4 tandem reaction,5 R-oxidation,6 amination,7 R-halo-
genation,8 R-sulfenylation,9 R-seleneylation,10 R-arylation,11
epoxidation,12 aziridination,13 aldol reaction,14 ene reaction,15
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Int. Ed. 2006, 45, 6853.
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Tetrahedon Lett. 2007, 48, 6252.
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Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
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1987, 109, 7111. (c) Yang, X.; Shen, J.; Da, C.; Wang, R.; Choi, M. C. K.;
Yang, L.; Wong, K.-Y. Tetrahedron: Asymmetry 1999, 10, 133.
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(21) A recent example: Bejjani, J.; Chemla, F.; Audouin, M. J. Org. Chem.
2003, 68, 9747.
† Department of Materials Science and Technology, Faculty of Engineering,
Gifu University.
‡ Department of Chemistry, Faculty of Engineering, Gifu University.
(1) Reviews of the prolinol ethers: (a) Enders, D.; Klatt, M. Synthesis 1996,
1403. (b) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
(2) Recent reviews on organocatalysis: ref 1b and: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) List, B. Synlett 2001, 1675. (c)
List, B. Tetrahedron 2002, 58, 2481. (d) Dalko, P. I.; Moisan, L. Angew. Chem.,
Int. Ed. 2004, 43, 5138. (e) Special Issue, Acc. Chem. Res. 2004, 37, No. 8. (f)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
Germany, 2005. (g) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (h)
Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79. (i) List, B. Chem.
Commun. 2006, 819. (j) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
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Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (n) Akiyama, T.; Itoh, J.; Fuchibe,
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(22) R,R-Bis(4-perfluoroalkylphenyl)prolinol derivatives: (a) Chu, Q.; Yu,
M. S.; Curran, D. P. Org. Lett. 2008, 10, 749. (b) Zu, L.; Li, H.; Wang, J.; Yu,
X.; Wang, W. Tetahedron Lett. 2006, 47, 5131. (c) Dalicsek, Z.; Pollreisz, F.;
´
Go¨mo¨ry, A.; Soo´s, T. Org. Lett. 2005, 7, 3243. (d) Park, J. K.; Lee, H. G.;
Bolm, C.; Kim, B. M. Chem. Eur. J. 2005, 11, 945.
(23) R,R-Bis(perfluorohexylethyl)prolinol: Goushi, S.; Funabiki, K.; Ohta,
M.; Hatano, K.; Matsui, M. Tetrahderon 2007, 63, 4061.
(24) 2-Trifluoromethylprolinol: Chaume, G.; Severen, V. M.-C.; Marinkovic,
S.; Brigaud, T. Org. Lett. 2006, 8, 6123.
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Chem. Commun. 2002, 986. (b) Fujiwara, Y.; Katagiri, T.; Uneyama, K.
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4694 J. Org. Chem. 2008, 73, 4694–4697
10.1021/jo8004952 CCC: $40.75 2008 American Chemical Society
Published on Web 05/17/2008

SCHEME 1. Synthesis of Perfluoroalkylated
N-Boc-pyrrolidyl Ketones 1
On the other hand, the reduction of N-alkoxycarbonyl,28
N-alkoxycarbonyl-N-alkyl,29 or N,N-dialkyl R-amino ketones30
with various reducing agents has become one of the most
reliable and efficient methods for the stereoselective synthesis
of 1,2-aminoalcohols. There have been some systematic
studies28a,31 on the nature of the transition state, including the
relationship between the substituents on the nitrogen atom and
the stereoselectivity.
We describe here the first asymmetric synthesis of (RR)-
perfluoroalkylated prolinol derivatives based on the perfluoro-
alkyl-controlled highly stereoselective reduction of the corre-
sponding perfluoroalkyl N-tert-butoxycarbonyl (Boc)-pyrrolidyl
ketones, which is one of the most promising routes to access
(RR)-perfluoroalkyl prolinol derivatives.
Methyl (S)-N-Boc-pyrrolidine-2-carboxylate was reacted
with perfluoroalkyllithiums, prepared in situ from perfluo-
robutyl, perfluorohexyl, and perfluorooctyl iodides and
methyllithium-lithium bromide complex,32 to produce only
(S)-tert-butyl 2-(2,2,3,3,4,4,5,5,5-nonafluoropentanoyl)pyr-
rolidine-1-carboxylate (1a), (S)-tert-butyl 2-(2,2,3,3,4,4,5,-
5,6,6,7,7,7-tridecafluoroheptanoyl)pyrrolidine-1-carboxy-
late (1b), and (S)-tert-butyl 2-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-
heptadecafluorononanoyl)pyrrolidine-1-carboxylate (1c) in
respective yields of 78%, 60%, and 52%, via hydrolysis of
the stable lithium hemiketal intermediate (Scheme 1).
(S)-tert-Butyl 2-(2,2,2-trifluoroacetyl)pyrrolidine-1-carboxy-
late (1d) was obtained in 28% yield via the trifluoromethylation
of ester with trifluoromethyltrimethylsilane in the presence of
a catalytic amount (3 mol %) of tetrabutylammonium fluoride
(TBAF) in pentane, together with ketone 1d hydrate in 40%
yield (eq 1).33 Trifluoromethylation occurred predominantly at
the carbonyl carbon of the methoxycarbonyl group.
These ratios were 63:37 for perfluorobutylated ketone 1a and
58:42 for n-butylated 1e in CDCl3, respectively. The ratios of
the atropisomers of 1a,e were not significantly different. To
determine the enantiomeric purity of the perfluorobutyl N-Boc-
pyrrolidyl ketone 1a0, we performed GC and NMR analyses
of the crude reaction mixture of (+)-R-methoxy-R-(trifluorom-
ethyl)phenylacetic acid ((+)-MTPA) amide derivative 4, which
was obtained via a second perfluorobutylation of the perfluo-
robutyl N-Boc-pyrrolidyl ketone 1a giving bis(perfluorobutyl)
N-Boc-prolinol 3, cleavage of the Boc group by trifluoroacetic
acid (TFA), and condensation with (+)-R-methoxy-R-(trifluo-
romethyl)phenylacetyl chloride in the presence of sodium
hydroxide (see the Supporting Information). Consequently, the
enantiomeric purity of perfluorobutyl N-Boc-pyrrolidyl ketone
1a was found to be >99% ee.
Interestingly, when the resulting perfluorobutyl N-Boc-
pyrrolidyl ketone 1a was added to an ethanol solution of sodium
borohydride (NaBH4) at 0 °C and the mixture was stirred at
room temperature for 7 h, reduction of the ketone 1a proceeded
smoothly to produce the corresponding alcohol (RR)-5a in 78%
yield as a single diastereomer (Table 1, entry 1). Perfluorohexyl
and perfluorooctyl N-Boc-pyrrolidyl ketones 1b,c could also
participate in the reduction at room temperature to give the
corresponding (RR)-perfluorohexylated and (RR)-perfluorooc-
tylated N-Boc-prolinols (RR)-5b,c in respective yields of 77%
and 73% (entries 2 and 3). Use of a mixture of the trifluorom-
ethylated ketone 1d and its hydrate under the same reaction
conditions resulted in a decrease in diastereoselectivity (dr )
85:15) (entry 4).35 A lower reaction temperature was very
effective for increasing the diastereoselectivity of 5d in the
reduction of a mixture of the trifluoromethylated ketone 1d and
its hydrate to give R-trifluoromethylated N-Boc-prolinol (RR)-
5d in yields of 92-97% with excellent diastereoselectivities
(92-96% de) (entries 5 and 6). The hydrate of trifluorometh-
ylated ketone 1d is probably likely to be reduced via the in situ
generation of the ketone 1d to give the (RR)-trifluoromethylated
prolinol 5d with high diastereoselectivity. In contrast, the
reduction of fluorine-free (S)-tert-butyl 2-pentanoylpyrrolidine-
1-carboxylate (1e) gave the corresponding prolinol 5e with
extremely low to moderate diastereoselectivities (14-52% de),
even at a lower reaction temperature (-78 to 0 °C) (entries 7
The ester reacted with n-butyllithium (n-BuLi) to produce
(S)-tert-butyl 2-pentanoylpyrrolidine-1-carboxylate (1e) in 47%
yield, together with N-Boc-R,R-din-butylprolinol (2) in 41%
yield (eq 2).
1H and 13C NMR analyses revealed that atropisomers of the
N-Boc-pyrrolidyl ketones 1 arose from the carbamate moiety.34
(28) (a) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002,
67, 1045. (b) Harris, B. D.; Bhat, K. L.; Joullie, M. M. Tetrahedron Lett. 1987,
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Lee, J.-M. Tetrahedron: Asymmetry 1999, 10, 1441. Nishida, A.; Sorimachi,
H.; Iwaida, M.; Matsumizu, M.; Kawate, T.; Nakagawa, M. Synlett 1998, 389.
Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993, 34, 6765.
(30) Reetz, M. T.; Drewes, M. W.; Mattews, B. R.; Lennick, K. J. Chem.
Soc., Chem. Commun. 1989, 1474. Lagu, B. R.; Liotta, D. C. Tetrahedron Lett.
1994, 35, 547.
(35) Diastereoselective reduction of the R-protected amino trifluoromethylated
ketones: (a) Andre´s, J. M. Pedrosa, R. Pe´rez-Encabo, A. Eur. J. Org. Chem.
200471558. (b) Kawase, M.; Hirabayashi, M.; Kumakura, H.; Saito, S.;
Yamamoto, K. Chem. Pharm. Bull. 2000, 48, 114. (c) Peet, N. P. Burkhart, J. P.
Angelastro, M. R. Giroux, E. L. Mehdi, S. Bey, P. Kolb, M. Neises, B. Schirlin,
D. J. Med. Chem. 199033394. Non-stereoselective reduction of the R-protected
amino perfluoroalkylated ketones: (d) Omote, M.; Eto, Y.; Tarui, A.; Sato, K.;
Ando, A. Tetrahedron: Asymmetry 2007, 18, 2768.
(31) Ookawa, A.; Soai, K. J. Chem. Soc., Perkin Trans. 1987, 1, 1465.
(32) Uno, H.; Shiraishi, Y.; Simokawa, K.; Suzuki, H. Chem. Lett. 1987,
1153.
(33) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A.
Angew. Chem., Int. Ed. 1998, 37, 820.
(34) Tetrahedron Symposium-in-print on Axially Chiral Amides: Clayden,
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J. Org. Chem. Vol. 73, No. 12, 2008 4695

TABLE 1. Asymmetric Reduction of Perfluoroalkylated,
Trifluoromethylated, and n-Butylated N-Boc-pyrrolidyl Ketones 1
perfluorobutyl prolinol 5a could also be determined to be 2S,RR
by X-ray analysis, as shown in the Supporting Information.
Kawase et al. reported that the reduction of R-N-alkoxy-
carbonyl-N-alkylamino trifluoromethylated ketones with
NaBH4 in ethanol at room temperature gave the correspond-
ing syn-ꢀ-amino-R-trifluoromethyl alcohols in good to excel-
lent yields with excellent syn-selectivities.35b In the literature,
syn-selectivities have been explained by the Felkin-Anh
transition state model. This excellent syn-selectivity in the
reduction of R-dibenzylamino trifluoromethyl ketones with
NaBH4 in a mixture of solvent methanol and THF at -20
°C to give the corresponding ꢀ-dibenzylamino-R-trifluoro-
methyl alcohol has also been reported by Pedrosa et al.35a
On the basis of these reports as well as the results of the
X-ray analysis of 5a and the stereochemical assignment of
the oxazolidinones 6a,d, the reduction of perfluoroalkyl
N-Boc-pyrrolidyl ketones 1 proceeds via the Felkin-Anh
transition state TS-1, as shown in Figure 1.
Good to excellent diastereoselectivities were observed in the
reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones 1a-d even
at room temperature, since the steric repulsion between the
perfluoroalkyl group and the pyrrolidine ring should be much
greater than that with n-butylated ketone 1e. Thus, the diaste-
reoselectivities may depend on the bulkiness of the perfluoro-
alkyl or n-butyl groups, which are in the following order:
perfluorooctyl ) perfluorohexyl ) perfluorobutyl > trifluoro-
methyl (steric effect constant (Es) ) 1.16)36 . n-butyl (Es )
0.39).
entry
1
reducing agentsa
conditions
5, yield (%)b (RR:RS)
1
2
3
1a
1b
1c
1d
1d
1d
1e
1e
1a
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
LiAlH4
rt, 7 hc
rt, 7 hc
rt, 7 hc
rt, 7 hc
0 °C to rtf
5a 78% (>99: <1)
5b 77% (>99: <1)
5c 73% (>99: <1)
5d 83% (85: 15)
5d 92% (96: 4)
4d
5e
6e
7
-78 to 0 °Cg 5d 97% (98: 2)
rt, 7 hc
5e 96% (43: 57)
8
-78 to 0 °Cg 5e 88% (24: 76)
-78 to 0 °Cg 5a 77% (>99: <1)
9h
a Two equivalents was used. b Yields of isolated products. c An
ethanol solution of 1 was added at 0 °C. d A mixture of the ketone 1d
and the ketone hydrate (56:44) was used. e A mixture of the ketone 1d
and the ketone hydrate (40:60) was used. f The reaction mixture was
gradually warmed over 7 h. g The reaction mixture was gradually
warmed over 6 h. h THF was used as a solvent.
and 8). With regard to other reducing agents, when perfluo-
robutylated ketone 1a was added to a tetrahydrofuran (THF)
solution of lithium aluminum hydride (LAH) at -78 °C and
the resulting mixture was gradually warmed to 0 °C over 6 h,
reduction of the ketone 1a proceeded smoothly to give the
prolinol (RR)-5a in 77% yield with the same excellent diaste-
reoselectivity (entry 9).
As shown in eqs 3 and 4, the relative configurations of 5
could be determined by the vicinal coupling constants of the
oxazolidinones 6 in H NMR after prolinols 5 were converted
into oxazolidinones 6 (6e, 41%; 6e′, 34%) via cleavage of the
Boc group, reprotection by the ethoxycarbonyl group, and
cyclization in the presence of sodium hydride (NaH) as a base.
Direct conversion of the prolinols 5 to the oxazolidinones 6
was very sluggish, probably because of the steric hindrance of
the t-Bu group. n-Butylated oxazolidinone 6e, whose vicinal
protons at C-1 and C-7-a are situated in an anti arrangement,
has a smaller coupling constant (3JHa-Hb ) 4.1 Hz) than that of
6e′ (3JHa-Hb ) 8.3 Hz), according to the reported values.21,28
In conclusion, chiral perfluoroalkyl N-Boc-pyrrolidyl ke-
tones could be prepared by reacting methyl (S)-N-Boc-
pyrrolidine-2-carboxylate and perfluoroalkyllithium reagents
prepared from perfluoroalkyl iodides and methyllithium-
lithium bromide complex. Trifluoromethyl N-Boc-pyrrolidyl
ketone could also be obtained by reacting methyl (S)-N-Boc-
pyrrolidine-2-carboxylate and trifluoromethyltrimethylsilane
in the presence of a catalytic amount of tetrabutylammonium
fluoride, together with trifluoromethyl N-Boc-pyrrolidyl
ketone hydrate. We have achieved the perfluoroalkyl-induced
highly stereoselective reduction of the resulting perfluoroalkyl
N-Boc-pyrrolidyl ketones using common reducing agents,
such as NaBH4 and LAH. This method provides the first
efficient and asymmetric access to (RR)-perfluoroalkylated
prolinols. Further studies on the asymmetric synthesis of
R-perfluoroalkylated prolinols carrying a quaternary carbon
center at the R-position based on the carbon-carbon bond
formation of perfluoroalkyl N-Boc-pyrrolidyl ketones are now
in progress.
1
Experimental Section
Typical Procedure for the Reduction of Ketones. To a solution
of NaBH4 (0.076 g, 2 mmol) in EtOH (5 mL) was added an
EtOH solution (3 mL) of (S)-tert-butyl 2-(2,2,3,3,4,4,5,5,5-
nonafluoropentanoyl)pyrrolidine-1-carboxylate (1a) (0.417 g, 1
mmol) at 0 °C under argon. After the mixture was stirred at
room temperature for 7 h, the reaction was quenched with 10%
HCl aq solution (60 mL), and then subjected to extraction with
Et2O (3 × 30 mL). The organic layer was washed with brine
(70 mL), dried over Na2SO4, and concentrated by distillation
under reduced pressure. Purification of the residue by silica gel
Consequently, the structure of the obtained 1-perfluoroalky-
lated oxazolidinones 6a,d (6a, 28% from 5a; 6d, 32% from
5d) could also be assigned to be anti, since the vicinal coupling
3
constants (6a, Rf ) CF3(CF2)3, JHa-Hb ) 4.3 Hz; 6d; Rf )
CF3, 3JHa-Hb ) 3.3 Hz) are similar to those of n-butylated anti-
oxazolidinone 6e. The stereochemical assignment of N-Boc-R-
(36) Tafts, K. W., Jr. Steric Effects in Organic Chemistry; Newman, M. S.,
Ed.; John Wiley & Sons: New York, 1956; p 556.
4696 J. Org. Chem. Vol. 73, No. 12, 2008

FIGURE 1. Proposed transition state.
column chromatography (hexane-CH2Cl2 ) 1:2) gave (RR)-5a
(78%, 0.325 g).
Acknowledgment. We thank Professors T. Ishihara, T.
Konno, and H. Yamanaka of the Kyoto Institute of Technology
for the HRMS measurements.We are grateful to Daikin Inc.
for the gift of perfluoroalkyl iodides as well as Tosoh F-Tech,
Inc. for the gift of trifluoromethyltrimethylsilane. K.F. also
acknowledges the AJINOMOTO Award in Synthetic Organic
Chemistry, Japan.
(S)-tert-Butyl 2-((R)-2,2,3,3,4,4,5,5,5-Nonafluoro-1-hydroxy-
pentyl)pyrrolidine-1-carboxylate ((rR)-5a). Rf 0.33 (hexane-
CH2Cl2 ) 1:2); mp 74.6-75.3 °C; [R]25 -19.9 (c 1.00, CHCl3);
D
IR (KBr) 3250 (OH), 1682 (CdO) cm-1; HRMS (FAB) found m/z
420.1212, calcd for C14H19F9NO3 (M + H) 420.1221. Anal. Calcd
for C, 40.10; H, 4.33; N, 3.34. Found: C, 39.80; H, 4.18; N, 3.35.
1H NMR (400 MHz, CDCl3) δ 1.39 (9H, s), 1.78-1.86 (3H, m),
1.93-2.01 (1H, m), 3.25-3.40 (2H, m), 3.85 (1H, dt, J ) 19.9,
8.5 Hz), 4.26 (1H, t, J ) 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ
23.7 (s), 28.0 (s), 28.7 (s), 46.8 (s), 56.8 (s), 73.4-73.9 (m), 81.4
(s), 105.9-122.1 (4C, m), 158.8 (s); 19F NMR (372 MHz, CDCl3)
δ -52.48 to -51.66 (m, 2F), -49.96 to -47.71 (m, 2F), -46.36
to -41.03 (m, 2F), -5.73 (s, 3F).
Supporting Information Available: Detailed procedures and
1
characterization of all of the compounds, H and 13C NMR
spectra for 1a-d, 2, 3, 4, (RR)-5a-e, (RS)-5d,e, 6a,c,d, and
6c′, and crystallographic data for compound (RR)-5a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8004952
J. Org. Chem. Vol. 73, No. 12, 2008 4697