Chiral azo compounds: Enantioselective synthesis and transformations into β-amino alcohols and α-amino acids with a quaternary stereocenter

Article abstract of DOI:10.1016/j.tetlet.2010.11.137

Taking advantage of radical carboaminations producing azo compounds, a new chemo-enzymatic approach to enantiomerically enriched azo alcohols, β-amino alcohols and non-natural (aromatic) amino acids with a quaternary stereocenter is reported.

Full text of DOI:10.1016/j.tetlet.2010.11.137

Tetrahedron Letters 52 (2011) 655–657
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral azo compounds: enantioselective synthesis and transformations into
b-amino alcohols and a-amino acids with a quaternary stereocenter
Friedrich R. Dietz a, , Agnes Prechter b, , Harald Gröger a, , Markus R. Heinrich b,
⇑
⇑
a Organische Chemie, Department Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestraße 42, 91054 Erlangen, Germany
b Pharmazeutische Chemie, Department Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Taking advantage of radical carboaminations producing azo compounds, a new chemo-enzymatic
approach to enantiomerically enriched azo alcohols, b-amino alcohols and non-natural (aromatic) amino
acids with a quaternary stereocenter is reported.
Received 4 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Azo compounds belong to the ‘classic’ organic molecules with a
long and impressive history in organic chemistry of by far more
than a century.1 Applications are of wide industrial importance,
for example, in the field of dyes. However, this is true in particular
for aromatic azo compounds, whereas the synthesis of non-
aromatic azo compounds is less known and still challenging. Most
surprisingly, in spite of the long history of azo compounds there is
a lack of enantiomerically pure or even enantiomerically enriched
chiral azo compounds of general type 1 (Fig. 1).2 Recently it has
been shown that chemical transformations involving free radicals
can offer uniquely fast and efficient ways to access such racemic
azo molecules of type rac-1.3 Nonetheless, the control of the ste-
reochemistry of these reactions, especially in terms of enantiose-
lectivity, so far remains an unsolved task. Inspired by the power
of biocatalysis4,5 we envisioned that a concept unifying the devel-
oped radical carboamination chemistry with the field of enzyme
catalysis according to Scheme 1 might prove a useful strategy to
overcome this limitation. Our particular interest was on the enan-
tioselective synthesis of chiral azo compounds of type 2, bearing a
quaternary stereogenic center, due to their potential to be easily
transformed into the pharmaceutically important classes of b-ami-
noalcohols of type 3 and non-natural (aromatic) amino acids of
type 4 with a quaternary carbon center (Fig. 1). Thus, such a che-
moenzymatic approach would not only lead to the first example
of an enantiomerically enriched azo compound of type 1/2 but also
provide a novel alternative synthesis to the challenging compound
classes 3 and 4 in an enantioselective fashion.
R1
N
Ar
N
NH2
NH2
N
N
Ar
OH
Ar
*
*
*
Ar
OH
COOH
R2
R4
*
R3
2
3
4
1
Ar = aryl
Figure 1. Chiral azo compounds 1 and derivatives thereof.
or rac-7,3 which are readily accessible from arenediazonium tetra-
fluoroborates 5 and 2-methallyl alcohol (6) or 2-methallyl acetate
(8) with practically no restrictions on the aromatic substitution
pattern (Scheme 1).
The search for a suitable biocatalytic resolution for the synthesis
of enantiomerically enriched azo compounds of type 2, however,
turned out to be very challenging. The difficulty in resolving race-
mates bearing a quaternary stereogenic center with enzymes is
widely known in general, and for the kinetic resolution of acetates
bearing quaternary stereocenters in b-position only very few bio-
catalytic resolutions have been developed up to date.6 Underlining
this difficulty, our attempts to achieve an enzymatic (enantioselec-
tive) acetylation of rac-2a (Scheme 1, upper pathway, R1 = p-OMe)
failed, leading to extremely low selectivities (data not shown).
As an alternative we then focused on the enzymatic hydrolysis of
the acetate rac-7a (R1 = p-OMe). When screening a set of commer-
cially available hydrolases (comprising lipases, proteases, and ester-
ases), most of these enzymes again gave unsatisfactory results (see
Supplementary data). In the presence of lipase B from Candida ant-
arctica, however, we were pleased to find that resolution proceeds
enantioselectively with 87% ee for the desired product 2a (for initial
experiments and results from optimization studies, see Supplemen-
tary data). No by-products were detected by 1H NMR or HPLC. Nota-
bly, a dramatic loss of enantioselectivity was found when carrying
out the reaction in pure buffer and buffer/isooctane with E-values
of only 2 and 6, respectively, and a negligible conversion of <2%
A key advantage of this envisioned chemoenzymatic approach
to enantiomerically enriched azo compounds of type 2 is the ele-
gant and straightforward access to the required racemates rac-2
⇑
Corresponding authors. Tel.: +49 9131 85 22554; fax: +49 9131 85 21165
(H.G.); tel.: +49 9131 85 24115; fax: +49 9131 85 22585 (M.R.H.).
E-mail addresses: Harald.Groeger@chemie.uni-erlangen.de (H. Gröger), Markus.
Heinrich@medchem.uni-erlangen.de (M.R. Heinrich).
Both authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.137

656
F. R. Dietz et al. / Tetrahedron Letters 52 (2011) 655–657
R1
R1
enantio-
selective
acetylation
R1
R1
N
N
N
N
OH
OH
OAc
*
6
FeSO4
2
7
rac-
(R)- or (S)-
R1
Biocatalytic
resolution
Radical
carboamination
N2 BF4
R1
R1
5
enantio-
selective
hydrolysis
OAc
R1
R1
N
N
N
8
N
FeSO4
OAc
OH
*
rac-7
(R)- or (S)-2
Scheme 1. Chemoenzymatic concepts for synthesis of (R)- or (S)-2 and 7.
was obtained when using a buffer/toluene biphasic reaction media.
Thus, further process development with the aim of increased con-
versions was done based on the use of a buffer/MTBE biphasic sol-
vent system as the preferred reaction medium, and led to an
increase of the formation of 2a with a conversion to 42% and enan-
tiomeric excess of 86% ee after a prolonged reaction time (Table 1,
entries 1 and 2).7 A preliminary study of the substrate spectrum
using the optimized conditions (entries 1 and 2) revealed that the
corresponding meta- and ortho-substituted derivatives are tolerated
as well (entries 3–5). Starting from the meta-substituted substrate
rac-7b, enzymatic resolution gave the desired alcohol 2b with 10%
conversion and an enantioselectivity of 83% ee after 3 days (entry
3) and with 18% conversion (85% ee) after 7 days (entry 4). The
synthesis of the ortho-substituted alcohol 2c proceeded analo-
gously, leading to a conversion of 7% and an enantioselectivity of
86% ee (entry 5). Notably, azo compounds of type rac-7 bearing more
than one substituent also serve as suitable substrates. When using
the meta, para-dimethoxy-substituted azo compound rac-7d as a
substrate, enzymatic resolution gave the desired alcohol 2d with
17% conversion and 92% ee (entry 6). Again, the conversion can be
increased by means of a prolonged reaction time, leading to 2d with
38% conversion and 90% ee (entry 7). Other types of substituents are
tolerated as well (entries 8–10). Since fluoro-substituted aromatic
compounds are of specific interest in medicinal chemistry we also
used the para-fluorinated azo compound rac-7e as a model sub-
strate. The enzymatic resolution of this substrate also proceeds in
an enantioselective mode, leading to the desired product 2e with
8% conversion and 82% ee (entry 8). Within this pioneering study,
most of the reactions shown in Table 1 were carried for 3 days lead-
ing to so far moderate conversions of 7–24% but generally good to
high ee values. As evidenced by comparative experiments (entries
2, 4 and 7), the conversions can be significantly increased by a pro-
longed reaction time without the formation of by-products or the
loss of enantioselectivity.
This first enantioselective approach toward chiral azo com-
pounds of type 1, exemplified for azo compounds of type 2 bearing
a quaternary stereocenter, also enabled us to focus on their trans-
formation into the corresponding enantiomerically enriched non-
natural b-amino alcohols of type 3 and
a-methylated a-amino
acids of type 4. Both product classes are of high pharmaceutical
interest,8,9 and at the same time, efficient synthetic approaches
with a low number of synthetic steps are rare.10,11 To start with
the synthesis of b-amino alcohols 3 bearing a quaternary carbon
center, these compounds were easily synthesized starting from
enantiomerically enriched 2 by means of a practical one-step
reduction with Zn/HCl (Scheme 2). When using the azo compound
2a (87% ee) as a model substrate, the resulting b-amino alcohol 3a
bearing a quaternary carbon center was formed in high yield of
89% and with a nearly unchanged enantiomeric excess of 86% ee.
The same method was employed for the preparation of the enanti-
omerically enriched amino alcohol 3g from 2g. By comparison with
an authentic sample of 3g obtained by LiAlH4-mediated reduc-
Table 1
Kinetic enzymatic resolution of azo compounds rac-77
R1
R2
R1
R2
R2
R2
R1
CAL-B
buffer pH = 7
R1
N
N
N
N
(MTBE-H2O)
OAc
OH
*
tion12 from commercially available (S)-
a-methyl-phenylalanine,
the absolute stereochemistry of 3g (obtained from the enzymatic
resolution) was determined to be (R).
rac-7a-g
Entry Product R1
2a-g
R2
H
t (days) Conversion (%)a ee of 2 [%]b
1
2
3
2a
2b
p-OMe
3
7
3
7
3
3
7
3
3
3
20
42
10
18
7
17
38
8
90
86
83
85
86
92
90
82
60
86
Furthermore, non-natural
a-methylated amino acids of type 4
can be obtained in enantiomerically enriched form by oxidation
of the corresponding b-amino alcohols of type 3. By means of this
synthetic concept we oxidized 3a (86% ee) successfully under for-
m-OMe
H
4
5
2c
o-OMe
H
6
2d
p-OMe m-OMe
mation of the desired
yield and with unchanged high enantiomeric excess of 86% ee
(Scheme 2).13,14 The (R)-amino acid 4a represents the
-methylated
derivative of the non-natural -amino acid -O-methyltyrosine.
-amino acids
a,O-dimethylated tyrosine 4a in quantitative
7
8
9
10
2e
2f
2g
p-F
p-CN
H
H
H
H
a
24
15
D
D
Especially as intermediates in the synthesis of drugs,
are of generally high interest.8
D
a
Determined by 1H-NMR.
Determined by chiral HPLC; accuracy 1%.
b

F. R. Dietz et al. / Tetrahedron Letters 52 (2011) 655–657
657
2. diastereoselective synthesis of related azo compounds based on
A
R
N
macrocyclization has been reported in: Heinrich, M. R.; Blank, O.; Wetzel, A.
Synlett 2006, 3352–3355.
3. (a) Blank, O.; Raschke, N.; Heinrich, M. R. Tetrahedron Lett. 2010, 51, 1758–
1760; (b) Blank, O.; Wetzel, A.; Ullrich, D.; Heinrich, M. R. Eur. J. Org. Chem.
2008, 3179–3189; (c) Heinrich, M. R.; Blank, O.; Wetzel, A. J. Org. Chem. 2007,
72, 476–484; (d) Blank, O.; Heinrich, M. R. Eur. J. Org. Chem. 2006, 4331–4334;
(e) Heinrich, M. R.; Blank, O.; Wölfel, S. Org. Lett. 2006, 8, 3323–3325.
4. For recent examples combining biocatalysis and radical reactions for
enantioselective synthesis, see: (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc.
2007, 129, 4124–4125; (b) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton,
K.; MacMillan, D. W. C. Science 2007, 316, 582–585; (c) Gastaldi, S.; Escoubet,
S.; Vanthuyne, N.; Gil, G.; Bertrand, M. P. Org. Lett. 2007, 9, 837–8395.
5. Enzyme Catalysis in Organic Synthesis; Drauz, K., Waldmann, H., Eds., 2nd ed.;
Wiley-VCH: Weinheim, 2002; (b) Gröger, H. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed., 3rd ed.; John Wiley & Sons: Hoboken, New Jersey, 2010. Chapter
6.
R
R
Zn, HCl
(MeOH)
NH2
N
OH
OH
2a (87% ee)
2g (86%ee)
a
3a
(89%, 86% ee)
3g (84% ee)
: R = OMe
g: R = H
for Na2Cr2O7, NaIO4
R = OMe
(H2SO4-H2O)
MeO
NH2
6. (a) Tauchi, T.; Sakuma, H.; Ohno, T.; Mase, N.; Yoda, H.; Takabe, K. Tetrahedron:
Asymmetry 2006, 17, 2195–2198; (b) Solares, L. F.; Brieva, R.; Quirós, M.;
Llorente, I.; Bayod, M.; Gotor, V. Tetrahedron: Asymmetry 2004, 15, 341–345; (c)
Acherar, S.; Audran, G.; Vanthuyne, N.; Monti, H. Tetrahedron: Asymmetry 2003,
14, 2413–2418.
COOH
4a (quant., 86% ee)
7. General procedure for the enzymatic resolution of racemic acetates 7: A solution of
rac-7 (0.10 mmol) in methyl tert-butyl ether (MTBE, 4 mL) was added to a
stirred mixture of lipase Candida antarctica B (CAL-B, formulation Novozym
435, 80.0 mg) in phosphate buffer (pH 7, 50 mM, 4 mL). The reaction vessel was
sealed, warmed to 40° C, and stirring was continued for 3 or 7 days. The organic
phase was then separated and combined with the solutions obtained from two
further extractions of the aqueous phase with MTBE (2 Â 4 mL) After drying
over Na2SO4 and concentration under reduced pressure, the crude product was
analyzed by 1H NMR to determine the conversion of the reactant 7. For the
enantiomeric excess, the remaining acetate 7 and the alcohol 2 were first
separated by column chromatography on silica gel (hexane/ethyl acetate) and
then analyzed by chiral HPLC.
8. For recently reported BACE-1 inhibitors with amino alcohols 3 as substructure,
see: Rajapakse, H. A.; Nantermet, P. G.; Selnick, H. G.; Barrow, J. C.; McGaughey,
G. B.; Munshi, S.; Lindsley, S. R.; Young, M. B.; Ngo, P. L.; Holloway, M. K.; Lai,
M.-T.; Espeseth, A. S.; Shi, X.-P.; Colussi, D.; Pietrak, B.; Crouthamel, M.-C.;
Tugusheva, K.; Huang, Q.; Xu, M.; Simon, A. J.; Kuo, L.; Hazuda, D. J.; Graham, S.;
Vacca, J. P. Bioorg. Med. Chem. Lett. 2010, 20, 1885–1889.
Scheme 2. Further transformation of the enantiomerically enriched alcohols 2a and
2g.
In summary, we have presented a conceptually new synthesis
for enantiomerically enriched azo compounds, b-amino alcohols
and non-natural (aromatic) amino acids bearing a quaternary car-
bon center. Taking into account the simple and scalable access to
the substrates rac-7 starting from easily available chemicals (as de-
scribed above), we believe that this short sequence represents one
of the most straightforward synthetic approaches to these chal-
lenging compound classes developed so far. To further increase
the attractiveness of the new radical-chemoenzymatic route to
b-amino alcohols of type 3 and non-natural a-amino acids of type
4, our current investigations focus on the increase of enzyme activ-
ity (to achieve shorter reaction times) as well as on more sustain-
able protocols for the reduction and oxidation steps.
9. Kleemann, A.; Engels, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances:
Syntheses, Patents, Applications, 4th ed.; Thieme: Stuttgart, 2001.
10. Even enzymatic approaches as the state of the art in industrial amino acid
production are very rare for the synthesis of
a-methylated amino acids. An
exception is the efficient amidase-catalyzed resolution of racemic amino acid
amides, see: Schulze, B.; de Vroom, E. In Drauz, K., Waldmann, H., Eds., 2nd ed.;
Enzyme Catalysis in Organic Synthesis; Wiley-VCH: Weinheim, 2002; Vol. 2.,
chapter 12.2.3.
Acknowledgments
We thank the FAU Erlangen-Nürnberg and the Evonik Degussa
GmbH for generous support. F.R.D. thanks the Evonik Stiftung for
a scholarship award.
11. An attractive organocatalytic approach toward enantiomerically enriched
a-
methylated amino acids is the phase-transfer-catalyzed double alkylation of
glycinates or monoalkylation of alaninates, which, however, requires the use of
totally protected amino acids as starting materials and the cleavage of these
protecting groups at a later stage. For this approach, see: Hashimoto, T.;
Maruoka, K. Chem. Rev. 2007, 107, 5656–5682.
Supplementary data
12. The LiAlH4-mediated reduction was carried out according to the following
literature procedure: Grote, C. W.; Kim, D. J.; Rapoport, H. J. Org. Chem. 1995,
60, 6987–6997.
13. The oxidation was carried out according to the following literature procedure:
Alsters, P.; Bouttemy, S.; Schmieder-van de Vondervoort, E.; Padron Carillo,
J. M. PCT WO 01/53240A1, 2001.
Supplementary data associated with (experimental procedures,
analytical data and NMR spectra are available for all new com-
pounds) this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.137.
14. The enantiomeric excess of 4a was determined after its conversion to the ethyl
ester derivative 9a (see Supplementary data).
References and notes
1. The Chemistry of the Hydrazo, Azo and Azoxy Groups; Patai, S., Ed., 1st ed.; John
Wiley and Sons: Chichester, 1997.