Triclorosilane-mediated stereoselective synthesis of β-amino esters and their conversion to highly enantiomerically enriched β-lactams

Article abstract of DOI:10.1039/c0ob00570c

A highly stereoselective trichlorosilane-mediated reduction of N-benzyl enamines was developed; the combination of a low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed to perform the reaction on substrates with different structural features often with total control of the stereoselectivity. By easy deprotection through hydrogenolysis followed by conversion of β-aminoester to 2-azetidinones, the synthesis of enantiomerically pure β-lactams (>98% e.e.) was successfully accomplished.

Full text of DOI:10.1039/c0ob00570c

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PAPER
Triclorosilane-mediated stereoselective synthesis of b-amino esters and their
conversion to highly enantiomerically enriched b-lactams†
Stefania Guizzetti,* Maurizio Benaglia,* Martina Bonsignore and Laura Raimondi
Received 12th August 2010, Accepted 5th October 2010
DOI: 10.1039/c0ob00570c
A highly stereoselective trichlorosilane-mediated reduction of N-benzyl enamines was developed; the
combination of a low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed
to perform the reaction on substrates with different structural features often with total control of the
stereoselectivity. By easy deprotection through hydrogenolysis followed by conversion of b-aminoester
to 2-azetidinones, the synthesis of enantiomerically pure b-lactams (>98% e.e.) was successfully
accomplished.
classes of chiral Lewis bases has led to the development of some
efficient catalysts able to control the stereochemical outcome of
the reaction.8,9
Introduction
The tremendous growth of the interest in what is currently referred
to as the “organocatalytic” approach toward enantioselective
synthesis, is strongly indicative of the general direction toward
which modern stereoselective synthesis is moving. After scattered
reports on this methodology in the 1970s, organic catalysis
represents now an established possibility of using an organic
molecule of relatively low molecular weight, simple structure, and
low cost to promote a given transformation in substoichiometric
quantity, in the absence of any metal, and under non-stringent
reaction conditions that are typical of organometallic catalysis.1
These considerations may hold true also for the enantioselective
reduction of carbon–nitrogen double bond. Hydrosilylation of
imines2 or enantioselective hydrogenation3 have been widely
studied in these years, leading to the development of a few
efficient chiral catalytic organometallic systems currently available
for C N bond reduction.4 Although recently a few excellent
results have been obtained with Rh, Ru, and specially Ir catalysts,5
the research of alternative metal-free procedures is still very
active. Basically two organocatalytic methodologies have been
recently developed for the stereoselective reduction of ketimines:
binaphthol-derived phosphoric acids were successfully employed
in a process that involves the use of a dihydropyridine-based
compound as the reducing agent.6 Alternatively the reduction
was performed in the presence of trichlorosilane, that needs to be
activated by co-ordination with Lewis bases;7 the use of different
Trichlorosilane-based methodologies have allowed to efficiently
perform the reduction of not only N-aryl, N-benzyl and N-
alkyl ketoimines, but also of imines derived from a-ketoesters,
leading to the synthesis of natural and unnatural a-aminoacids.10
Very recently this metal-free procedure has been employed in the
reduction of b-enamino esters, as valid alternative to the metal-
catalyzed hydrogenations.11 Malkov and Kocovsky, taking advan-
tage of the fast equilibration between enamine and imine form,
have successfully accomplished the synthesis of b-aminoacids by
trichlorosilane mediated enamine reduction catalyzed by the (S)-
valine-derived formamide A.12 Analogously Zhang developed an
efficient methodology where the catalyst of choice was found to
be the chiral picolinamide B of Fig. 1.13 Even if high enantioselec-
tivities were reached, it must be noted that both methods rely on
the use of N-aryl enamines, whose conversion to N-deprotected
aminoacids require an oxidative deprotection protocol, with CAN
(cerium ammonium nitrate) or TCCA (trichloroisocyanuric acid).
Dipartimento di Chimica Organica e Industriale - Universita’ degli Studi di
Milano, Via Golgi 19, I-20133 Milano, Italy and Giuseppe Celentano Dipar-
timento di Scienze Molecolari Applicate ai Biosistemi - Universita` degli Studi
di Milano, Via Golgi 19, I-20133, Milano, Italy. E-mail: maurizio.benaglia@
unimi.it; Fax: ++390250314159
† Electronic supplementary information (ESI) available: Experimental
details for enamines synthesis, reduction, hydrogenolysis procedures and
b-lactams synthesis. Characterization details for reaction products. 1H-
NMR spectra and HPLC chromatograms on chiral stationary phase of
chiral amines and b-lactams. See DOI: 10.1039/c0ob00570c
Fig. 1 Organocatalytic reduction of N-aryl enamines.
Following our interest in the development of trichlorosilane-
mediated reactions14 we wish to report here a highly stereoselective
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Table 2 Stereoselective reduction of N-benzyl enamines 3–17 promoted
by catalyst 1 at 0 ◦Ca
reduction of N-benzyl enamines, to afford the corresponding
b-aminoesters which can be conveniently deprotected by hy-
drogenolysis and finally converted to b-lactams. By performing
the stereo determining crucial reductive step in the best conditions
almost enantiomerically pure b-lactams were obtained (98% e.e.).
Based on our previous experiences we decided to investigate
the behaviour of the ephedrine-derived 4-chloropicolinamide 19a,9d
and bis-picolinamide derivative of 1,1-binaphthyl-2,2¢-diamine
Entry
Enamine
Yield (%)b
e.e. (%)c
1
2
3
4
5
6
7
8
9
3
73
70
97
75
80
71
75
85
80e
67
5
99d
78
7
9
11
13
15
17
5
99d
70
99d
68
2
9b,9c in the trichlorosilane-promoted reduction of N-benzyl enam-
ine (Scheme 1)
99d
99d
a Typical experimental conditions: 0.1 mol equiv of catalyst 1, 3 mol equiv
of trichlorosilane, 18 h reaction time in DCM at 0 ◦C. b Yields of isolated
products. c As determined by HPLC on a chiral stationary phase; yields
and ee are average of duplicate experiments. d Diastereoisomeric ratio
determined by 1H-NMR and by HPLC. e Reaction time: 36 h.
In the attempt of improving the selectivity of the process,
we decided to take advantage of the presence of a removable
chiral auxiliary at the imine nitrogen;9d therefore trichlorosilane
mediated reduction of enamine 5 derived from (R)-1-phenyl-ethyl
amine was studied.17 By running the reaction at 0 ◦C the chiral
b-amino ester 6a was obtained after 12 h in 70% yield with a total
control of the stereoselectivity (Table 1, entry 6).18
Also binaphthyl-derived bis-picolinamide 2 catalyzed efficiently
the reduction of chiral enamines 5, although with a lower
selectivity (81% d.r., entry 7, Table 1). In this case the matching
pair was represented by (S)-binaphthyl diamine derivative 2 and
enamine prepared from (R) methyl benzyl amine.18
Having proofed the potentiality of the synthetic approach, the
methodology was extended to the synthesis of other enantiomer-
ically pure b-aryl-b-amino esters (Table 2). N-a-methyl benzyl
enamines of different electronic properties were effectively reduced
always maintaining an absolute control of the stereoselectivity of
the process (Scheme 1). While the reduction of N-benzyl enamine
7 derived from 3-oxo-3-(4-trifluoromethyl-phenyl)-propionic acid
methyl ester afforded chiral amine 8a with 78% e.e. (entry 3,
Table 2), the trichlorosilane addition to enamine 9 led to the
corresponding amino ester 10a with a diastereoisomeric ratio
higher than 99/1 (entry 4).
Analogous results were obtained with electron rich aryl-
substituted substrates. In both cases, starting from chiral enamines
13 and 17 the reduction was successfully accomplished in 71% and
85% yield, respectively and always with complete stereocontrol
(entries 6 and 8). Noteworthy the chiral Lewis base amount could
be decreased and the reaction was successfully performed in the
presence of only 1% of catalyst 1. The reduction of 5 afforded
amine 6 with 65% yield, although with a lower selectivity (91 : 9
d.r.).
Obviously the present methodology becomes synthetically
appealing only if the benzyl group removal may be successful
realized, thus demonstrating the feasibility of the approach
for the preparation of enantiomerically pure primary amino
esters. Therefore hydrogenolysis of different chiral b-amino esters
was attempted (Scheme 2).19 When 3-N-benzylamine-3-phenyl
propionic acid methyl ester 4a was reacted with hydrogen in the
presence of catalytic amount of Pd/C in methanol at 1 atm at
25 ◦C, chiral amino ester 19 was isolated in quantitative yield after
16 h. Starting from an enantiomerically enriched compound (81%
Scheme 1 Stereoselective reduction of N-benzyl enamines.
The reduction of N-benzyl enamine 3 of 3-oxo-3-phenyl-
propionic acid methyl ester,15 by employing 10% of chiral Lewis
base at 0 ◦C in dichloromethane afforded the product in 73% and
71% yield with catalyst 1 and 2 respectively, and comparable level
of stereoselectivity (67% and 61% e.e., see Table 1)16 Lower reaction
temperatures allowed only to slightly increase the enantioselection
up to 81% e.e.
Table 1 Reduction of N-benzyl enamines 3 and 5 of 3-oxo-3-phenyl-
methyl propionatea
Entry
Catalyst
T/◦C
Enamine
Yield (%)b
e.e. (%)c
1
2
3
4
5d
6
7
1
2
1
2
1
1
2
0
0
3
3
3
3
3
5
5
73
71
70
43
98
70
75
67
61
81
73
71
99f
81f
-20e
-20e
-20e
0
0
a Typical experimental conditions: 0.1 mol equiv of catalyst, 3 mol equiv of
trichlorosilane, 18 h reaction time in DCM. b Yields of isolated products.
c As determined by HPLC on a chiral stationary phase; yields and ee are
average of duplicate experiments. d Reaction solvent was CHCl3. e Reaction
time 30 h. f Diastereoisomeric ratio determined by 1H-NMR and by
HPLC.
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Table 3 Stereoselective reduction of N-benzyl enamines 23–37 promoted
by catalyst 1a
Entry
T/◦C
Enamine
Yield (%)b
e.e. (%)c
1
2
3
4
5d
6
7
0
0
0
0
-20
0
0
23
25
27
29
29
31
33
63
51
45
55
31
65
98
21
53
71
51
71
75
76
a Typical experimental conditions: 0.1 mol equiv of catalyst, 3 mol equiv of
trichlorosilane, 18 h reaction time in DCM. b Yields of isolated products.
c As determined by HPLC on a chiral stationary phase; yields and e.e. are
average of duplicate experiments. d Reaction run in CHCl3.
When the reduction of enamine 29 (R¢ = isopropyl) was
attempted the product was isolated in 55% yield and 51% e.e.
The stereoselection of the process could be improved by running
the reaction at lower temperatures (71% e.e. at -20 ◦C), although
in modest yield (entries 3–5). In that case even the use of the
chiral auxiliary did not allow to obtain a diastereoisomerically
pure compound and by reduction of 31 the chiral amino ester 32a
was produced in 75% e.e.
In order to further increase the selectivity and obtain a total
stereocontrol also for that substrate the role of the ester group
was briefly investigated. N-benzyl enamine of 3-oxo-3-phenyl-
propionic acid t-butyl ester 33 was synthesized and reacted with
trichlorosilane in the presence of catalyst 1. The product was
Scheme 2 Chiral auxiliary removal by hydrogenolysis.
e.e.), the corresponding product 19 was obtained in 79% e.e., with
basically no loss of stereochemical information.
◦
The deprotection of N-a-methyl benzyl amine 6 required
more drastic conditions and it was successfully performed by
hydrogenating the starting material for 16 h in methanol with
Pd/C at 15 atm.20 Noteworthy the reaction occurred without
any appreciable loss of stereochemical integrity.21 Similarly it was
demonstrated that -a-methyl benzyl-removal was possible also
for substrates bearing electron rich-substituted aromatic rings.
Chiral amines 18a gave the corresponding primary amine ester
21 basically in quantitative yield and as single stereoisomer.
Then the trichlorosilane mediated reduction was applied
to enamines of b-alkyl-b-keto esters (Scheme 3). While the
reduction of 23 (alkyl = R¢ = ethyl) afforded the product in low
enantioselectivity, some more interesting results were obtained
with enamine 27 (R¢ = benzyl). In this case the product was
isolated in 71% d.r. at 0 ◦C.
obtained at 0 C in 71% yield and higher enantioselectivity than
the corresponding methyl ester (75% e.e. vs. 67% e.e., entry 7
Table 3 vs. entry 1 Table 2). However any attempt to perform
the reduction on the analogous t-butyl ester derivative of enamine
31 was unsuccessful.
Having demonstrated the generality of the approach, a few sub-
strates were finally converted to b-lactams. Starting from a sample
of N-benzyl aminoester 4a with 80% e.e. hydrogenolysis followed
by reaction with LDA in THF afforded the chiral 4-(R)-phenyl
azetidin-2-one 35 in 77% e.e. in 82% overall yield (Scheme 4).
Similarly when b-amino ester 10a was reduced by hydrogenation
and converted to the corresponding chiral 4-(4-trifluoromethyl
phenyl)-substituted b-lactam, the product 36 was isolated in 80%
yield after chromatographic purification andas single stereoisomer
(Scheme 4) Finally, by following the same synthetic procedure
4-methyl-2-amino-methyl pentanoate 22, known precursor of 4-
isopropyl azetidin-2-one, 37, was obtained in 90% yield through
hydrogenolysis of 32a.
In conclusion, the organocatalytic reduction of N-benzyl
enamines with trichlorosilane was succesfully accomplished; the
combination of low cost, easy to make metal-free catalyst and
an inexpensive chiral auxiliary allowed to obtain chiral b-amino
esters often with total control of the stereoselectivity. Finally hy-
drogenolysis of N-benzyl aminoesters followed by LDA-promoted
ring closure afforded enantiomerically pure 4-aryl or 4-alkyl
substituted b-lactams.
Experimental Section
General. All reactions were carried out in oven-dried glass-
Scheme 3 Stereoselective reduction of N-benzyl b-enamino esters.
ware with magnetic stirring under nitrogen atmosphere, unless
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Scheme 4 Synthesis of highly enantiomerically enriched b-lactams.
otherwise stated. All commercially available reagents including dry
solvents were used as received. Organic extracts were dried over
sodium sulfate, filtered, and concentrated under vacuum using a
rotatory evaporator. Nonvolatile materials were dried under high
vacuum. Reactions were monitored by thin-layer chromatography
on pre-coated Merck silica gel 60 F254 plates and visualized either
by UV or by staining with a solution of cerium sulfate (1 g) and
ammonium heptamolybdate tetrahydrate (27 g) in water (469 mL)
and concentrated sulfuric acid (31 mL). Flash chromatography
was performed on Fluka silica gel 60. Proton NMR spectra were
recorded on spectrometers operating at 200, 300 or 500 MHz
respectively. Proton chemical shifts are reported in ppm (d) with
the solvent reference relative to tetramethylsilane (TMS) employed
as the internal standard (CDCl3 d = 7.26 ppm). Carbon chemical
shifts are reported in ppm (d) relative to TMS with the respective
solvent resonance as the internal standard (CDCl3, d = 77.0 ppm).
Optical rotations were obtained on a polarimeter at 589 nm using
a 5 mL cell with a length of 1 dm. HPLC for e.e. determination
was performed under the conditions reported below. Mass spectra
(MS) were performed on a hybrid quadrupole time of flight
mass spectrometer equipped with an ESI ion source. Microwave-
accelerated reactions were performed in CEM Discover class S
instrument.
The mixture was then cooled to the chosen temperature and
trichlorosilane (3.5 mmol/eq) was added drop wise by means of
a syringe. After stirring at the proper temperature, the reaction
was quenched by the addition of a saturated aqueous solution
of NaHCO3 (1 mL). The mixture was allowed to warm up to
room temperature and water (2 mL) and dichloromethane (5 mL)
were added. The organic phase was separated and the combined
organic phases were dried over Na2SO4, filtered, and concentrated
under vacuum at room temperature to afford the crude product.
If necessary, the amine was purified by flash chromatography. For
the characterization of the reaction products see ESI†.
Hydrogenolysis
Typical experimental procedure for N-benzyl amines. A sus-
pension of (R)-methyl 3-(benzylamino)-3-phenylpropanoate (4a)
(0.58 mmol) and Pd/C (10%, 36 mg) in methanol (3.5 mL) were
stirred in under hydrogen atmosphere at room temperature for
16 h. The catalyst was removed by filtration through a pad of
celite, and the filtrate was concentrated and purified by column
chromatography (5 : 5 hexane–ethyl acetate 100 mL, 4 : 6 hexane–
ethyl acetate 100 mL, 3 : 7 hexane–ethyl acetate 100 mL mixture
as eluent).
1
Yield = 98%; H-NMR (300 MHz, CDCl3): d 2.31 (br, 2H); d
2.67 (d, 2H); d 3.66 (s, 3H); d 4.42 (t, 1H); d 7.21–7.38 (m, 5H). The
enantiomeric excess was determined by HPLC on a Chiralcel OD–
H (98 : 2 hexane–isopropanol; flow rate: 0.8 mL min-1; l = 210 nm):
tR = 26.04 min, tS = 32.44 min. [a]2D5 = + 10.5 (c = 0.258 g/100 mL,
DCM, l = 589 nm).
Reduction reaction
General procedure. To a stirred solution of catalyst (0.1–
0.01% mol/eq mmol) in the chosen solvent (2 mL), the enamine
(1 mmol/eq) was added (for the synthesis of enamines see ESI†).
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Typical experimental procedure for N-a-methylbenzyl amines.
The deprotection of N-a-methyl benzyl amine 10a required
more drastic conditions and it was successfully performed by
hydrogenating the starting material for 16 h in methanol with
Pd/C at 15 atm.
J. Zhou, S. Hoffmann and B. List, Angew. Chem., Int. Ed., 2010, 49,
4612 and references cited there.
7 Reviews: (a) M. Benaglia, S. Guizzetti and L. Pignataro, Coord. Chem.
Rev., 2008, 252, 492; (b) S. E. Denmark and G. L. Beutner, Angew.
Chem., Int. Ed., 2008, 47, 1560; (c) Y. Orito and M. Nakajima,
Synthesis, 2006, 9, 1391.
8 Selected references: for chiral N-formyl derivatives see (a) F. Iwasaki,
O. Onomura, K. Mishima, T. Kanematsu, T. Maki and Y. Matsumura,
Tetrahedron Lett., 2001, 42, 2525; (b) A. V. Malkov, A. Mariani, K.
N. MacDougal and P. Kocˇovsky´, Org. Lett., 2004, 6, 2253; (c) A. V.
Malkov, S. Stoncˇius and P. Kocˇovsky´, Angew. Chem., Int. Ed., 2007,
46, 3722; (d) A. V. Malkov, M. Figlus, S. Stoncˇius and P. Kocˇovsky´,
J. Org. Chem., 2009, 74, 5839; (e) A. V. Malkov, K. Vrankova´, R. C.
Sigerson, S. Stoncˇius and P. Kocˇovsky´, Tetrahedron, 2009, 65, 9481;
(f) Y. Matsumura, K. Ogura, Y. Kouchi, F. Iwasaki and O. Onomura,
Org. Lett., 2006, 17, 3789; (g) Z. Wang, X. Ye, S. Wei, P. Wu, A.
Zhang and J. Sun, Org. Lett., 2006, 5, 999; (h) C. Baudequin, D.
Chaturvedi and S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 2623–2629;
(i) For chiral picolinamides see: O. Onomura, Y. Kouchi, F. Iwasaki
and Y. Matsumura, Tetrahedron Lett., 2006, 47, 3751; (j) H. Zheng, J.
Deng, W. Lin and X. Zhang, Tetrahedron Lett., 2007, 48, 7934; (k) see
reference 9; (l) For other chiral Lewis bases see: A. V. Malkov, A. J. P.
S. Liddon, P. Ram´ırez-Lo´pez, L. Bendova´, D. Haigh and P. Kocˇovsky´,
Angew. Chem., Int. Ed., 2006, 45, 1432; (m) D. Pei, Z. Wang, S. Wei,
Y. Zhang and J. Sun, Org. Lett., 2006, 25, 5913; (n) D. Pei, Y. Zhang,
S. Wei, M. Wang and J. Sun, Adv. Synth. Catal., 2008, 350, 619; (o) C.
Wang, X. Wu, L. Zhou and J. Sun, Chem.–Eur. J., 2008, 14, 8789;
(p) F.-M. Gautier, S. Jones and S. J. Martin, Org. Biomol. Chem., 2009,
7, 229.
1
Yield = 98%; H-NMR (200 MHz, CDCl3): d 2.43 (br, 2H); d
2.72 (d, 2H); d 3.68 (s, 3H); d 4.52 (t, 1H); d 7.51 (d, 2H); d 7.60
(d, 2H). The enantiomeric excess was determined by HPLC on a
Chiralpak AD (9 : 1 hexane–isopropanol; flow rate: 0.8 mL min-1;
l = 210 nm): tS = 9.7 min, tR = 10.5 min. For other products see
ESI†.
Synthesis of b-lactams
Typical procedure: Synthesis of (R)-4-phenylazetidin-2-one (35).
To a solution of LDA (0.676 mmol) in THF (3 mL) at -78 ◦C
was added a THF (1 mL) solution of (R)-methyl 3-amino-3-
phenylpropanoate (19). After stirring at -78 ◦C for 16 h the
reaction was quenched with NaHCO3 aq., and then extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated. The residue was purified by
column chromatography (7 : 3 hexane–ethyl acetate 100 mL, 5 : 5
hexane–ethyl acetate 100 mL mixture as eluent).
9 For our contribution in the field see: (a) S. Guizzetti, M. Benaglia, R.
Annunziata and F. Cozzi, Tetrahedron, 2009, 65, 6354; (b) S. Guizzetti,
M. Benaglia, F. Cozzi, S. Rossi and G. Celentano, Chirality, 2009, 21,
233; (c) S. Guizzetti, M. Benaglia and G. Celentano, Eur. J. Org. Chem.,
2009, 3683; (d) S. Guizzetti, M. Benaglia and S. Rossi, Org. Lett., 2009,
11, 2928; (e) S. Guizzetti, C. Biaggi, M. Benaglia and G. Celentano,
Synlett, 2010, 134.
Yield = 84%; [a]2D5 = + 106 (c = 0.02 g/100 mL, EtOH, l =
1
589 nm). H-NMR (300 MHz, CDCl3): d 2.87 (dd, 1H); d 3.44
(dd, 1H); d 4.71 (dd, 1H); d 6.30 (br, 1H); d 7.30–7.43 (m, 5H).
GC on chiral stationary phase (Agilent HP-chiral): tR = 66.0 min,
tS = 74.0 min. For other products see ESI†.
10 See ref. 9d and Z.-Y. Xue, Y. Jiang, W.-C. Yuan and X.-M. Zhang, Eur.
J. Org. Chem., 2010, 616 See also; C. Wang, X. Wu, L. Zhou and J. Sun,
Chem.–Eur. J., 2008, 14, 8789.
11 For a very recent review on the importance of b-amino acids see: B.
Weiner, W. Szymansky, D. B. Janssen, A. J. Minaard and B. L. Feringa,
Chem. Soc. Rev., 2010, 39, 1656.
Acknowledgements
This work was supported by MIUR (Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali).
12 A. V. Malkov, S. Stoncˇius, K. Vrankova´, M. Arndt and P. Kocˇovsky´,
Chem.–Eur. J., 2008, 14, 8082.
13 H.-J. Zheng, W.-B. Chen, Z.-J. Wu, J.-G. Deng, W.-Q. Lin, W.-C. Yuan
and X.-M. Zhang, Chem.–Eur. J., 2008, 14, 9864.
14 (a) S. Guizzetti, M. Benaglia, European Patent Application November
30 2007; PCT/EP/2008/010079, Nov. 27, 2008. WO2009068284 (A2),
2009-06-04; (b) S. Guizzetti, M. Benaglia, European Patent Appl.
n.EP07023240.0, September 22, 2008.
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15 For the preparation of enamines see details in ESI.
16 The reduction of N-phenyl enamine in the same experimental condi-
tions led to the correspondingb-amino ester in better yields (88%) and
moderately higher enantioselectivities (80% e.e.).
2 X. Verdaguer, U. E. W. Lange and S. L. Buchwald, Angew. Chem., Int.
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17 For the use ofa-phenyl ethylamine as chiral auxiliary see references
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18 The favourably match or mismatch combinations of chiral amine
auxiliary and catalysts have been already clarified in ref. 9d. The
reduction of chiral enamine 5 with achiral Lewis base, such as
DMF, at 0 ◦C in our hands afforded the reduction product in 53%
diastereoisomeric ratio.
19 For selective debenzylation reactions see: M. Kanai, M. Yasumoto, Y.
Kuriyama, K. Inomiya, Y. Katsuhara, K. Higashiyama and A. Ishii,
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20 The quality and the age of Pd/C are critical elements influencing the
reaction efficiency; the experimental conditions are very dependent on
the activity of the catalyst (5-15 atm, Pd/C, EtOH, 4-12 h, RT). See
also ref. 9e.
3 For a special issue on hydrogenation and transfer hydrogenation see:
M. J. Krische and Y. Sun, Acc. Chem. Res., 2007, 40(12), 1237Ed., all
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21 See ESI for HPLC traces and spectroscopic details.
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The Royal Society of Chemistry 2011
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