Angewandte
Chemie
20
point = 243–2458C. Optical rotation: ½aꢀD ¼ꢁ12.2 (c = 0.5; EtOH,
20
> 99% de). Literature value for the opposite enantiomer:[15d] ½aꢀD ¼
+ 12.4 (c = 0.1; EtOH, > 99% de).
For further experimental details, analytical data, and full
characterization of all products, see the Supporting Information.
Received: March 26, 2012
Published online: May 22, 2012
Keywords: alkaloids · asymmetric reductive amination ·
chiral piperidines · regioselectivity · w-transaminases
Scheme 3. Optically pure 2,6-disubstituted piperidines synthesized.
Reagents and conditions: a) 1b–d (0.5 mmol), w-TA from C. violaceum,
PLP (1 mm), NAD+ (1 mm), l-alanine (10 equiv), ammonium formate
(150 mm), 11 U FDH, 12 U AlaDH; 26 h, 308C, 120 rpm. b) Pd/C, H2,
4-15 h, RT; c) 1e (0.5 mmol), (R)-w-TA from Arthrobacter sp., PLP
(1 mm), NAD+ (1 mm), d-alanine (10 equiv), ammonium formate
(150 mm), 11 U FDH, 12 U AlaDH; 26 h, 308C, 120 rpm.
.
[1] For selected recent reviews on regioselective metalation, see:
a) B. Haag, M. Mosrin, H. Ila, V. Malakhov, P. Knochel, Angew.
9794 – 9824; for synthesis of pyrazoles, see: b) S. Fustero, M.
Sabꢃn, R. Morꢁn-Ramallal, F. Rebolledo, Chem. Soc. Rev. 2011,
40, 5321 – 5335; for enzymatic redox reactions, see: d) D. Monti,
4140; e) E. Fossati, S. Riva in Biocatalysis in the Pharmaceutical
and Biotechnology Industries (Ed.: R. N. Patel), CRC, Boca
Raton, 2007, pp. 591 – 604; for ring opening of aziridines, see:
of alkenes and alkynes, see: g) M. Beller, J. Seayad, A. Tillack,
regioselective hydroxylation, see: h) S. Kille, F. E. Zilly, J. P.
6a,b,d,e were obtained in good yields and respectable optical
purity (Scheme 3).[17]
In summary, the first regio- and stereoselective asymmet-
ric monoamination of diketones was reported. Various 1,5-
diketones were selectively transformed into optically pure
amino ketones through the use of w-transaminases. In the
current study, the intermediate amino ketones obtained
underwent a spontaneous ring-closure, to give D1-piperi-
deines. Diastereoselective reduction of these products estab-
lished a second chiral center, providing an efficient method
for the preparation of chiral 2,6-disubstituted piperidines.
Using this method, the shortest synthesis to date of the
alkaloid (+)-dihydropinidine 6a, and related piperidines, was
achieved. This methodology expands the toolbox for regio-
and stereoselective aminations, and is a step towards cleaner
and more selective organic transformations.[18]
[2] a) W. T. Green, P. G. Wuts, Protective Groups in Organic Syn-
thesis, 4th ed., Wiley, Hoboken, 2007; b) P. J. Kocienski, Protect-
ing Groups, 3rd ed., Thieme, New York, 2005.
[4] For selected examples, see: a) V. Hickmann, A. Kondoh, B.
Experimental Section
Representative preparative example for the regio- and stereoselec-
tive biocatalytic amination and subsequent diastereoselective reduc-
tion:
[5] M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi,
(2S)-2-methyl-6-propyl-2,3,4,5-tetrahydropyridine
((2S)-4a):
Lyophilized cells of E. coli containing overexpressed w-TA from C.
violaceum (225 mg) were rehydrated in a phosphate buffer (10 mL,
pH 7.0, 100 mm) containing PLP (1 mm), NAD+ (1 mm), ammonium
formate (150 mm), FDH (11 U, 5 mg), AlaDH (12 U, 150 mL) and l-
alanine (500 mm) at 228C for 30 min. Substrate 1a (78 mg, 0.5 mmol)
was added and the reaction was shaken at 308C for 26 h. Saturated
aqueous Na2CO3 solution was added (1.00 mL) and the mixture
extracted with small portions of EtOAc (4 ꢀ 5 mL). Combined
organic layers were dried (Na2SO4), filtered, and employed in the
next step without further purification. The product was obtained with
> 99% conversion in optically pure form (> 99% ee) as judged by
achiral and chiral GC.
[8] a) W. Zhu, M. Mena, E. Jnoff, N. Sun, P. Pasau, L. Ghosez,
Haroutounian, Curr. Org. Chem. 2008, 12, 1454 – 1467.
[9] For selected reviews on w-transaminases, see: a) P. Tufvesson, J.
Lima-Ramos, J. S. Jensen, N. Al-Haque, W. Neto, J. M. Woodley,
332; c) J. Ward, R. Wohlgemuth, Curr. Org. Chem. 2010, 14,
1431; e) M. Hçhne, S. Kꢄhl, K. Robins, U. T. Bornscheuer,
ChemCatChem 2008, 9, 363 – 365; f) S. Buchholz, H. Grçger in
Biocatalysis in the Pharmaceutical and Biotechnology Industries
(Ed.: R. N. Patel), CRC, Boca Raton, 2007, pp. 829 – 847; g) M.-
J. Kim, Y. Ahn, J. Park in Biocatalysis in the Pharmaceutical and
Biotechnology Industries (Ed.: R. N. Patel), CRC, Boca Raton,
(2S,6R)-2-Methyl-6-propyldihydropiperidine·HCl
((2S,6R)-
6a·HCl): The crude solution containing (2S)-4a was treated with
10% palladium on activated charcoal (10 mg) at room temperature
before a stream of hydrogen was bubbled through the solution for 4 h.
After completion of the reaction, the solution was filtered through
a pad of celite 545 and cooled to 08C. The product was crystallized by
the addition of a solution of HCl in Et2O. The HCl salt of the natural
product dihydropinidine ((2S,6R)-6a·HCl) was obtained as a colorless
1
solid in 94% yield (82 mg, 0.47 mmol, > 99% de). H and 13C NMR
data are in agreement with those previously reported.[15a] Melting
Angew. Chem. Int. Ed. 2012, 51, 6713 –6716
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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