Iron-catalyzed hydrogenation for the in situ regeneration of an NAD(P)H model: Biomimetic reduction of α-Keto-/α-iminoesters

Article abstract of DOI:10.1002/anie.201301972

Two irons for a smoother finish: An NAD(P)H model was regenerated readily in situ by iron-catalyzed reduction with molecular hydrogen. The subsequent biomimetic reduction of α-keto-/ α-iminoesters proceeded smoothly in the presence of an iron-based Lewis acid (LA) to provide α-hydroxyesters and amino acid esters in good to excellent yields (see scheme; NAD(P) ⁺=nicotinamide adenine dinucleotide (phosphate), TM=transition metal). Copyright

Full text of DOI:10.1002/anie.201301972

.
Angewandte
Communications
DOI: 10.1002/anie.201301972
Iron Catalysis
Iron-Catalyzed Hydrogenation for the In Situ Regeneration of an
NAD(P)H Model: Biomimetic Reduction of a-Keto-/a-Iminoesters**
Liang-Qiu Lu, Yuehui Li, Kathrin Junge, and Matthias Beller*
Over millions of years, nature has evolved processes that can
inspire chemists to improve the efficiency and sustainability
of organic synthesis today.[1] In particular, redox reactions
constitute fundamental transformations in biology, and many
kinds of redox enzymes catalyze these processes. Among
them, enzymes with NAD(P)H and their oxidized form
nicotinamide adenine dinucleotide (phosphate) [NAD(P)+]
as the cofactors have attracted much interest from the
viewpoints of both biomimetic catalysis and large-scale
industrial synthesis.[2] For such bioinspired reductions, a key
issue is the regeneration of the cofactor NAD(P)H or a model
of this cofactor in an efficient and economical way.[2,3] In
terms of availability, cost, and the removal of by-products,[4]
an in situ regeneration of the cofactor is preferred. When
reductive transformations are performed with living cells or
Scheme 1. In situ regeneration of NAD(P)H and its models with
organometallic complexes. Bn=benzyl.
isolated enzymes, the cofactor is commonly regenerated in
the presence of dehydrogenases, such as formate dehydrogen-
ase, glucose dehydrogenase, or alcohol dehydrogenase, by the
use of formic acid, glucose, or alcohols as the hydride source,
respectively.[2] However, in comparison with enzymatic meth-
ods, the chemical catalytic in situ regeneration of cofactor
NAD(P)H and its analogues is still in its infancy
(Scheme 1).[3,5] Notably, as early as 1982, Whitesides and
Abril[5a] reported a rhodium-complex-catalyzed in situ regen-
eration of NAD(P)H with hydrogen gas as the most benign
hydride source. Since then, interesting developments were
disclosed by the research groups of Steckhan,[5b] Bhaduri,[5c]
Fish,[5d] Wagenknecht,[5e] and others,[5f,g] who applied other
catalyst complexes based on precious metals, such as Rh, Ru,
Pt, and Ir. Recently, Zhou and co-workers showed that
[{Ru(p-cymene)I2}2] can be used as a highly efficient catalyst
for the in situ regeneration of two kinds of NAD(P)H models:
the Hantzsch ester (HEH) and dihydrophenanthridine
(DHPD) models. This system was applied to the asymmetric
biomimetic reduction of a series of azoheterocycles.[5h,i]
Nevertheless, in spite of the advances made in recent years,
so far all known catalysts are based on noble metals.
In the past decade, iron catalysis has provoked more and
more research interest in homogeneous catalysis, from the
development of novel energy technology to green organic
synthesis.[6] Owing to the ubiquity of iron in enzymes and its
good biotolerance, iron catalysts have also been widely
applied in biomimetic oxidation reactions.[7,8] For example,
in 2011, Grçger and co-workers[8f] reported the use of
a synthetic iron porphyrin for the biomimetic oxidation of
alcohols; oxygen was used as the terminal oxidant to
regenerate NAD(P)+ with the formation of water as the
only by-product (Scheme 2, left). Following our previous
studies on biologically inspired iron-catalyzed oxidation
reactions,[9] we present herein a reverse biomimetic reduction
[*] Dr. L.-Q. Lu, Dr. Y. Li, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: Matthias.Beller@catalysis.de
Dr. L.-Q. Lu
College of Chemistry, Central China Normal University
152 Luoyu Road, 430079 Wuhan (P.R. China)
[**] This research was supported by the State of Mecklenburg-Vor-
pommern and the BMBF. We also thank the Alexander von
Humboldt Foundation, the National Science Foundation for Young
Scientists of China (No. 21202053), and Shanghai Institute of
Organic Chemistry (SIOC)–Zhejiang Medicine (joint fellowship) for
financial support. NAD(P)H is the reduced form of nicotinamide
adenine dinucleotide (phosphate).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301972.
Scheme 2. Concept of biomimetic redox reactions under iron catalysis
for the in situ regeneration of an NAD(P)+/NAD(P)H model.
8382
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8382 –8386

Angewandte
Chemie
through dual iron catalysis. These iron catalysts are not only
responsible for the in situ regeneration of NAD(P)H models
with molecular hydrogen (transition-metal (TM) catalysis),
but also act as Lewis acids to promote the transfer hydro-
genation of carbonyl and imine groups (LA catalysis;
Scheme 2, right).
To probe the feasibility of the above proposal, we chose a-
ketoesters as substrates because of the significance of the a-
hydroxyester products and the reactivity of the substrates. For
these reasons, a-ketoesters are used frequently in biomimetic
reductions of NAD(P)H and its models.[10] We first tested
a series of representative NAD(P)+ models, such as diethyl
2,6-dimethylpyridine-3,5-dicarboxylate (3a), phenanthridine
(3b), acridine (3c), 2-phenylbenzo[d]thiazole (3d), and N-
methylphenanthridinium iodide (3e), with ethyl 2-oxo-2-
phenylacetate (1a) as the model substrate. Only phen-
anthridine (3b) showed minor catalytic activity in toluene
under H2 (50 bar) at 658C in the presence of [Fe3(CO)12]
(3.33 mol%; Table 1, entries 1–5). Although many different
iron–carbonyl complexes are known to catalyze the reduction
of carbonyl compounds,[11] only [Fe3(CO)12] promoted the
desired reaction of 1a in the presence of 3b (Table 1, entries 2
=
and 6–8), in agreement with its specific reduction of C N
groups.[11d]
Next, we conducted stoichiometric reactions of NAD(P)+
model 3b and its reduced form H2-3b with [Fe3(CO)12] as the
catalyst under H2 (50 bar) or Ar (50 bar), respectively. The
results in Equation (1) imply that NAD(P)H model H2–3b is
readily regenerated from its oxidized form 3b through iron-
catalyzed hydrogenation, although the reverse process occurs
with the same catalyst in the absence of H2. We therefore
considered that the low yield of the desired a-hydroxyester 2a
might be the result of the low Lewis acidity of the iron–
carbonyl complexes. When different higher-valent iron salts
were added to the reaction mixture as Lewis acids (Table 1,
entries 9–12), the product yield improved slightly, especially
with Fe(OTf)2 (Table 1, entry 12, 15% yield). Moreover,
ligand 4a also had a positive effect on the reactivity in toluene
(Table 1, entry 13, 28% yield). To further improve the
reaction efficiency, we tested different solvents and found
1,4-dioxane to be the most suitable (Table 1, entry 15, 30%
yield). However, in contrast to its effect in toluene, ligand 4a
had an adverse influence on the reaction in 1,4-dioxane
(Table 1, entry 14, 10% yield). Finally, the yield was funda-
mentally improved simply by increasing the catalyst loading
(Table 1, entry 16).[12] To verify our concept, we performed
several control experiments (Table 1, entries 17–21). We
could conclude that: 1) [Fe3(CO)12] is able to catalytically
hydrogenate the NAD(P)+ model 3b and also possesses some
Lewis acidity to promote the transfer hydrogenation of a-
ketoester 1a (Table 1, entry 17). On the other hand,
[Fe3(CO)12] failed to directly hydrogenate substrate 1a
(Table 1, entry 18). 2) NAD(P)+ model 3b is indispensable
for this biomimetic reduction process (Table 1, entry 21).
3) The higher-valent iron salt Fe(OTf)2 is unable to catalyze
the hydrogenation of NAD(P)+ model 3b and a-ketoester 1a
(Table 1, entries 19 and 20).
Having optimized the reaction conditions, we examined
the scope of the reaction and found that a variety of a-
ketoesters are suitable substrates for this biomimetic trans-
formation under dual iron catalysis (Table 2). Comparison of
the results with various aryl glyoxylic acid esters showed the
electronic effects of different substituents (Table 2, entries 1–
12). In general, better yields were observed when electron-
deficient substrates were used. In particular, in the case of the
highly electron rich substrate 1l, a prolonged reaction time
was needed for good conversion (81% yield of the isolated
product; Table 2, entry 12). Nevertheless, all aromatic sub-
strates tested were reduced to the corresponding a-hydroxy-
esters in good to excellent yields. Notably, this double iron-
Table 1: Iron-catalyzed biomimetic reduction of ethyl phenylglyoxylate in
the presence of different NAD(P)+ models.[a]
Entry
Fe carbonyl
Fe salt
NAD(P)+
model
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe2(CO)9]
[Fe(CO)5]
[NEt3H][HFe3(CO)11]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
[Fe3(CO)12]
–
–
–
–
–
–
–
–
–
3a
3b
3c
3d
3e
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
–
–
5
–
–
–
–
–
–
4
7
4
15
28
10
FeCl3
FeCl2
Fe(OTf)3
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
–
13[c]
14[c,d]
15[d]
16[d,e]
17[d,e]
18[d,e]
19[d,e]
20[d,e]
21[d,e]
30
93(89)[f]
28
–
–
–
–
–
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
3b
–
–
–
[Fe3(CO)12]
[a] Reaction conditions: 1a (0.25 mmol), iron carbonyl (10 mol%, based
on iron), iron salt (3.6 mol%), NAD(P)+ model 3 (10 mol%), toluene
(0.5 mL). [b] The yield was determined by GC. [c] Diamine 4a
(3.6 mol%) was added as a ligand. [d] 1,4-Dioxane was used as the
solvent. [e] [Fe3(CO)12] (6.67 mol%), Fe(OTf)2 (7.2 mol%), and 3b
(20 mol%) were used. [f] The yield of the isolated product is given in
parentheses.
Angew. Chem. Int. Ed. 2013, 52, 8382 –8386
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8383

.
Angewandte
Communications
Table 2: Scope of the iron-catalyzed biomimetic reduction.[a]
Entry
Substrate (R)
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a (Ph)
2a
2b
2c
2d
2e
2 f
2g
2h
2i
93 (89)
87 (86)
91 (89)
99 (95)
93 (92)
>99 (99)
86 (84)
>99 (96)
92 (87)
83 (81)
90 (85)
1b (p-MeO-C6H4)
1c (p-Me-C6H4)
1d (p-F-C6H4)
1e (p-Cl-C6H4)
1 f (p-CF3-C6H4)
1g (p-tBu-C6H4
1h (m-Cl-C6H4)
1i (3,5-F2-C6H3)
1j (3,4-Cl2-C6H3)
1k (3,4-Me2-C6H3)
Scheme 3. Mechanism for the biomimetic reduction of a-keto-/
a-iminoesters through dual iron catalysis (L: ligand or solvent).
10
11
2j
2k
5a and the cyclic a-iminoester 5b provided the desired a-
amino acid esters in excellent yield (Table 2, entries 18 and
19; 6a: 98%, 6b: 94%). Direct hydrogenation of the same
substrates gave the desired products in lower yields of 43 and
26%, respectively.
12[c]
1l
2l
82 (81)
92 (88)
13
1m
2m
The proposed mechanism of this biomimetic reduction is
shown in Scheme 3. In a similar process to the enzymatic
regeneration of cofactor NAD(P)H from its oxidized form
NAD(P)+, the NAD(P)H model H2-3b is generated from 3b
in the presence of a catalytic amount of [Fe3(CO)12] and
benign hydrogen. H2-3b then acts as a direct hydride source to
14
15
16
1n (nBu)
1o (iPr)
1p (cyclohexyl)
2n
2o
2p
96
98
98
17
1q:
2q
98 (91)
=
=
selectively reduce the a-keto C O or a-imino C N bond of
substrates 1 and 5.
18
19
5a:
5b:
6a
6b
98 (43)[d]
94 (26)[d]
For the left-hand part of the catalytic cycle, the regener-
ation of the NAD(P)H model with hydrogen, an inexpensive
and readily available iron–carbonyl complex is responsible;
the right-hand part of the catalytic cycle, the transfer hydro-
genation, is promoted by a Lewis acid catalyst, which
decreases the LUMO energy of substrates 1 and 5. According
to our control experiments, we believe that both [Fe3(CO)12]
or derived species and the dissolved Fe salt may act as Lewis
acids.[16]
[a] See the Experimental Section for the experimental details. [b] The
yield was determined by GC. The yield of the isolated product is given in
parentheses. [c] Reaction time: 48 h. [d] The yield determined by GC for
the direct hydrogenation of the a-iminoester in the absence of 3b and
Fe(OTf)2 is given in parentheses. PMP=p-methoxyphenyl.
If the proposed biomimetic reaction sequence is to be
used for stereoselective reduction, the inherent Lewis acidity
of [Fe3(CO)12] has to be inhibited. In this respect, we found
that the addition of nitrogen-containing ligands had a pro-
nounced effect on the iron catalysts when toluene was used as
the solvent. For example, the addition of diamine 4a as
a ligand had a positive effect on the Lewis acid catalyzed
transfer-hydrogenation process and inhibited the catalytic
activity of [Fe3(CO)12].[17] As a result, a reduced catalyst
loading provided the desired a-hydroxyester 2r in excellent
yield when Fe(OTf)3 was used as a Lewis acid in combination
with 4a in toluene. Encouraged by this positive result, we
conducted iron-catalyzed biomimetic reductions in the pres-
ence of chiral nitrogen-containing ligands. Indeed, when the
chiral bisoxazoline ligand 7a and diphenylamine-tethered
bisoxazoline 7b were used, this asymmetric biomimetic
reduction provided the desired chiral a-hydroxyacid esters
with moderate enantioselectivity in excellent yield
(Scheme 4).
catalyst system tolerates well carbon–chloride bonds (Table 2,
entries 5, 8, and 10) and heteroaryl substrates. For example,
when the 2-thiophenyl-substituted substrate 1m was used, the
biomimetic reduction also proceeded smoothly in 88% yield,
and was not hampered by the sulfur atom (Table 2, entry 13).
Alkyl-substituted a-ketoesters were also tested, and diverse
a-hydroxyesters were accessed readily in excellent yield, no
matter what acyclic or cyclic substituent was present (Table 2,
entries 14–16).[13] Moreover, this biomimetic reduction was
also successful in the case of cyclic substrate 1q, which
contains a sterically demanding quaternary carbon center
adjacent to the reaction center (Table 2, entry 17, 91%
yield).[14]
=
Selective reduction of the C N group of a-iminoesters is
one of the most important methods for the preparation of
natural and non-natural a-amino acid esters.[15] Although
[Fe3(CO)12] itself holds the potential to catalyze the direct
hydrogenation of a-iminoesters, the reaction efficiency was
improved remarkably when the biomimetic system was
applied. Biomimetic reduction of the acyclic a-iminoester
In conclusion, we have demonstrated that an iron-
catalyzed hydrogenation can readily be applied to the in
situ regeneration of the artificial NAD(P)H cofactor DHPD.
8384
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8382 –8386

Angewandte
Chemie
[3] For a recent review on chemical catalytic in situ regeneration of
the cofactor NAD(P)H and its models, see: W. Du, Z. Yu, Synlett
2012, 1300 – 1304.
[4] For recent reviews on the stoichiometric use of NAD(P)H
models, see: a) M. Rueping, J. Dufour, F. R. Schoepke, Green
Chem. 2011, 13, 1084 – 1105; b) C. Zheng, S.-L. You, Chem. Soc.
Rev. 2012, 41, 2498 – 2518.
[5] For previous examples of the use of noble metals as catalysts for
the in situ regeneration of cofactor NAD(P)H and its models,
see: a) O. Abril, G. M. Whitesides, J. Am. Chem. Soc. 1982, 104,
1552 – 1554; b) D. Westerhausen, S. Herrmann, W. Hummel, E.
Steckhan, Angew. Chem. 1992, 104, 1496 – 1498; Angew. Chem.
Int. Ed. Engl. 1992, 31, 1529 – 1531; c) S. Bhaduri, P. Mathur, P.
Payra, K. Sharma, J. Am. Chem. Soc. 1998, 120, 12127 – 12128;
d) H. C. Lo, R. H. Fish, Angew. Chem. 2002, 114, 496 – 499;
Angew. Chem. Int. Ed. 2002, 41, 478 – 481; e) P. S. Wagenknecht,
J. M. Penney, R. T. Hembre, Organometallics 2003, 22, 1180 –
1182; f) Hollmann, F. Kleeb, A. Otto, K. A. Schmid, Tetrahe-
dron: Asymmetry 2005, 16, 3512 – 3519; g) J. Canivet, G. Sꢀss-
Scheme 4. Demonstration of an asymmetric version of the biomimetic
reduction (yields and enantiomeric ratios were determined by GC and
GC on a chiral phase).
Thus, a biomimetic reduction of a-ketoesters and related a-
iminoesters was developed which makes use of dual iron
catalysis. This process provides the desired a-hydroxyesters
and amino acid esters in good to excellent yield with benign
hydrogen as the reductant and inexpensive iron complexes.
Further studies on the scope and optimization of this iron-
catalyzed biomimetic reduction are under way.
ˇ
˘
˘
Fink, P. Stepnieka, Eur. J. Inorg. Chem. 2007, 4736 – 4742; h) Q.-
A. Chen, D.-S. Wang, Y.-G. Zhou, Y. Duan, H.-J. Fan, Y. Yang, Z.
Zhang, J. Am. Chem. Soc. 2011, 133, 6126 – 6129; i) Q.-A. Chen,
M.-W. Chen, C.-B. Yu, L. Shi, D.-S. Wang, Y. Yang, Y.-G. Zhou, J.
Am. Chem. Soc. 2011, 133, 16432 – 16435.
[6] For selected reviews and books about iron catalysis, see: a) C.
Bolm, J. Legros, J. L. Paih, L. Zani, Chem. Rev. 2004, 104, 6217 –
6254; b) S. Enthaler, K. Junge, M. Beller, Angew. Chem. 2008,
120, 3363 – 3367; Angew. Chem. Int. Ed. 2008, 47, 3317 – 3321;
c) Iron Catalysis in Organic Chemistry (Eds.: B. Plietker), Wiley-
VCH, Weinheim, 2008; d) “Iron Catalysis”: Topics in Organo-
metallic Chemistry, Vol. 33 (Eds.: B. Plietker), Springer, Heidel-
berg, 2011; e) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Rev. 2011, 111,
1293 – 1314; f) M. Darwish, M. Wills, Catal. Sci. Technol. 2012, 2,
243 – 255.
[7] For selected reviews about iron-catalyzed biomimetic oxidation,
see: a) M. Costas, M. P. Mehn, M. P. Jensen, L. Que, Jr., Chem.
Rev. 2004, 104, 939 – 986; b) P. C. A. Bruijnincx, G. van Koten,
R. J. M. K. Gebbink, Chem. Soc. Rev. 2008, 37, 2716 – 2744.
[8] For studies on iron-catalyzed biomimetic oxidation, see: a) J.
Bautz, P. Comba, C. L. de Laorden, M. Menzel, G. Rajaraman,
Angew. Chem. 2007, 119, 8213 – 8216; Angew. Chem. Int. Ed.
2007, 46, 8067 – 8070; b) R. Mas-Ballestꢁ, L. Que, Jr., J. Am.
Chem. Soc. 2007, 129, 15964 – 15972; c) K. Suzuki, P. D. Old-
enburg, L. Que, Jr., Angew. Chem. 2008, 120, 1913 – 1915;
Angew. Chem. Int. Ed. 2008, 47, 1887 – 1889; d) A. Mukherjee,
M. Martinho, E. L. Bominaar, E. Mꢀnck, L. Que, Jr., Angew.
Chem. 2009, 121, 1812 – 1815; Angew. Chem. Int. Ed. 2009, 48,
1780 – 1783; e) D. Wang, E. R. Farquhar, A. Stubna, E. Mꢀnck,
L. Que, Jr., Nat. Chem. 2009, 1, 145 – 150; f) H. Maid, P. Bçhm,
S. M. Huber, W. Bauer, W. Hummel, N. Jux, H. Grçger, Angew.
Chem. 2011, 123, 2445 – 2448; Angew. Chem. Int. Ed. 2011, 50,
2397 – 2400; g) M. A. Bigi, S. A. Reed, M. C. White, Nat. Chem.
2011, 3, 216 – 220; h) P. Halder, S. Paria, T. K. Paine, Chem. Eur.
J. 2012, 18, 11778 – 11787.
Experimental Section
General procedure: Under an atmosphere of Ar, an a-ketoester
1 (0.5 mmol) or a-iminoester 5 (0.5 mmol), phenanthridine (3b;
18.0 mg, 0.1 mmol), Fe(OTf)2 (15.0 mg, 0.036 mmol, 85% purity),
[Fe3(CO)12] (16.8 mg, 0.0333 mmol), 1,4-dioxane (1.0 mL), and a mag-
netic stirrer were placed in a reaction vial, which was then capped
with a septum equipped with a syringe needle. The vial was then
placed together with an alloy plate in a predried autoclave. Once
sealed, the autoclave was purged three times with H2, then
pressurized to 50 bar and heated at 658C for 24 h. The autoclave
was then cooled to room temperature and depressurized. The
reaction mixture was analyzed by GC to determine the yield of the
product. Finally, the reaction mixture was concentrated, and the
residue was purified by column chromatography on silica gel (eluant:
n-pentane/ethyl acetate 12:1–8:1) to give the corresponding
a-hydroxyacid ester 2 or a-amino acid ester 6.
Received: March 8, 2013
Revised: May 31, 2013
Published online: June 26, 2013
Keywords: biomimetic reduction · hydrogenation · iminoesters ·
.
iron catalysis · a-ketoesters
[9] For our previous studies on iron-catalyzed biomimetic oxidation
reactions, see: a) F. G. Gelalcha, G. Anilkumar, M. K. Tse, M.
Beller, Chem. Eur. J. 2008, 14, 7687 – 7698; b) K. Schrçder, S.
Enthaler, B. Bitterlich, T. Schulz, A. Spannenberg, M. K. Tse, K.
Junge, M. Beller, Chem. Eur. J. 2009, 15, 5471 – 5481; c) K.
Schrçder, K. Junge, A. Spannenberg, M. Beller, Catal. Today
2010, 157, 364 – 370; d) K. Schrçder, B. Join, A. J. Amali, K.
Junge, X. Ribas, M. Costas, M. Beller, Angew. Chem. 2011, 123,
1461 – 1465; Angew. Chem. Int. Ed. 2011, 50, 1425 – 1429.
[10] For a review on the significance and synthesis of a-hydroxyest-
ers, see: a) a-Hydroxy Acids in Enantioselective Synthesis (Eds.:
G. M. Coppola, H. F. Schuster), Wiley-VCH, Weinheim, 1997;
for selected examples of the synthesis of a-hydroxyesters
[1] For selected books and reviews about biomimetic chemistry, see:
a) Artificial Enzymes (Ed.: R. Breslow), Wiley-VCH, Wein-
heim, 2005; b) P. A. Frey, A. D. Hegeman, Enzymatic Reaction
Mechanisms, Oxford University Press, New York, 2007; for
a recent special issue about biocatalysis and biomimetic catalysis,
see: c) ACS Catalysis, Vol. 1 (Ed.: H. Zhao), American Chemical
Society, New York, 2011, pp. 989 – 1149.
[2] For selected reviews on the enzymatic in situ regeneration of the
cofactor NAD(P)H, see: a) H. K. Chenault, E. S. Simon, G. M.
Whitesides, Biotechnol. Genet. Eng. Rev. 1988, 6, 221 – 270; b) A.
Weckbecker, H. Grçger, W. Hummel, Adv. Biochem. Eng./
Biotechnol. 2010, 120, 195 – 242.
Angew. Chem. Int. Ed. 2013, 52, 8382 –8386
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8385

.
Angewandte
Communications
through hydrogenation and biomimetic reduction, see: b) Y.
Sun, X. Wan, J. Wang, Q. Meng, H. Zhang, L. Jiang, Z. Zhang,
Org. Lett. 2005, 7, 5425 – 5427; c) J. W. Yang, B. List, Org. Lett.
2006, 8, 5653 – 5655; d) N. Erathodiyil, H. Gu, H. Shao, J. Jiang,
J. Y. Ying, Green Chem. 2011, 13, 3070 – 3074, and references
therein.
the Supporting Information for more details of our investigation
into the amount of 3b required for the reaction.
[15] For selected examples of the synthesis of a-amino acid esters
through hydrogenation and transfer hydrogenation, see: a) G.
Shang, Q. Yang, X. Zhang, Angew. Chem. 2006, 118, 6508 – 6510;
Angew. Chem. Int. Ed. 2006, 45, 6360 – 6362; b) G. Li, Y. Liang,
J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 5830 – 5831; c) C. Zhu,
T. Akiyama, Adv. Synth. Catal. 2010, 352, 1846 – 1850, and
references therein.
[16] When H2-3b (1.0 equiv) was used in the absence of [Fe3(CO)12]
and the Fe salt under Ar (1 atm) in toluene, only a trace amount
of product 2r (1.7% yield) was found by GC analysis. When
[Fe3(CO)12] (3.33 mol%) or Fe(OTf)3 (3.6 mol%) was added
under otherwise identical conditions, the yield of 2r increased to
33 and 66%, respectively.
[11] a) S. Zhou, K. Junge, D. Addis, S. Das, M. Beller, Angew. Chem.
2009, 121, 9671 – 9674; Angew. Chem. Int. Ed. 2009, 48, 9507 –
9510; b) S. Zhou, S. Fleischer, K. Junge, S. Das, M. D. Addis, M.
Beller, Angew. Chem. 2010, 122, 8298 – 8302; Angew. Chem. Int.
Ed. 2010, 49, 8121 – 8125; c) S. Zhou, S. Fleischer, K. Junge, M.
Beller, Angew. Chem. 2011, 123, 5226 – 5230; Angew. Chem. Int.
Ed. 2011, 50, 5120 – 5124; d) S. Fleischer, S. Zhou, K. Junge, M.
Beller, Chem. Asian J. 2011, 6, 2240 – 2245.
[12] See the Supporting Information for details of the optimization of
the reaction conditions.
[13] a-Hydroxyesters substituted with alkyl groups were found to be
volatile under reduced pressure, so only the yields determined by
GC are provided.
[17] In toluene, Fe(OTf)3 gave better results than Fe(OTf)2 in the
presence of ligand 4a. The ligand is believed to improve the
solubility of the Fe salt in toluene. See the Supporting
Information for details of our investigation of ligand effects.
[14] For the reaction of 1q, the loading of catalyst 3b could be
reduced to 10 mol% with the same efficiency (98% yield). See
8386
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 8382 –8386