Substrate-controlled diastereoselectivity switch in catalytic asymmetric direct mannich reaction of glycine derivatives with imines: from anti- to syn-α,β-diamino acids

Article abstract of DOI:10.1002/chem.200902258

(Chemical equation Presented) Back and forth: A diastereoselectivity switch has been devised in the Fesulphos-Cu^I-catalyzed glycine direct Mannich reaction with N-(8-quinolyl)sulfonyl imines by tuning the steric and electronic properties of the glycine component (see scheme). αβ-Diamino acids of syn configuration are produced under high diastereo- and enantiocontrol with glycinate esters derived from electron-deficient benzophenonetype ketimines, in contrast to aldiminederived pronucleophiles that lead to anti-configured products.

Full text of DOI:10.1002/chem.200902258

COMMUNICATION
DOI: 10.1002/chem.200902258
Substrate-Controlled Diastereoselectivity Switch in Catalytic Asymmetric
Direct Mannich Reaction of Glycine Derivatives with Imines:
From anti- to syn-a,b-Diamino Acids
Jorge Hernꢀndez-Toribio, Ramꢁn Gꢁmez Arrayꢀs,* and Juan Carlos Carretero*[a]
The construction of multiple stereocenters in flexible acy-
clic molecules in a single operation with complete diastereo-
and enantiocontrol constitutes a central challenge within the
field of asymmetric catalysis. Driven by their biological sig-
nificance and synthetic value, the synthesis of optically
active a,b-diamino acids[1] via catalytic asymmetric direct
Mannich reaction[2] between a prochiral nitrogen pronucleo-
phile and an imine represents a touchstone in meeting this
challenge and has recently emerged as an active research
area.[3] Two complementary approaches are receiving great
attention: the direct Mannich reaction of glycine ester Schiff
bases (and related species) with imines[4] and the direct aza-
Henry reaction either between nitro compounds and a-
imino esters,[5] or between a-nitro acetates and imines.[6,7]
Despite the development of very efficient organometallic-
based and metal-free catalytic procedures, which show high
asymmetric induction and syn- or anti-diastereocontrol, the
development of diastereoselective switchable methods pro-
viding access to either syn- or anti-configured a,b-diamino
acids remains elusive. Just one catalyst system has been
shown to enable tuning of diastereoselectivity, leading to
either anti- or syn-configured a,b-diamino acid esters in
good yields and high diastereo- and enantioselectivities.[4i] In
such an example, a dramatic anti/syn diastereoselectivity
switch was achieved in the Mannich reaction of glycine de-
rivatives with imines by modifying the electronic properties
of the chiral phosphine ligand. As a useful complementary
method, herein we describe that the syn- or anti-diastereose-
lectivity of the Mannich products can be efficiently switched
by tuning the steric and electronic properties of the pronu-
cleophile component (i.e., the glycinate imine) while main-
taining the same catalyst system.
Recently, we reported a route to anti-a,b-diamino acid de-
rivatives based on the CuI–Fesulphos-catalyzed reaction of
glycine ester aldimine pronucleophiles with the readily
available N-(8-quinolyl)sulfonyl aldimines[8] (Scheme 1a).
We envisioned that the use of ketimine-derived glycine pro-
nucleophiles, instead of aldimine derivatives, could result in
new critical steric interactions in the transition state that
could potentially lead to a reversal in the sense of facial se-
lectivity of the imine approach to the ester enolate, thus
providing access to products with the opposite syn-configu-
ration (Scheme 1b).
Scheme 1. Envisioned diastereoselectivity switch in the Mannich route to
a,b-diamino acid derivatives.
Our working hypothesis was validated in the reaction of
the glycine methyl ester benzophenone Schiff base 2a with
differently N-protected aldimines 3a–g under the optimized
Fesulphos–CuI catalyst system,[8,9] in all cases the syn-config-
ured adduct being predominant in the reaction mixture
(Table 1). However, very low syn-diastereocontrol was ach-
ieved with most of the protecting groups examined, except
for the encouraging values provided by the Boc (substrate
3a, entry 1) and N-(8-quinolyl)sulfonyl[10] (substrate 3 f,
entry 6) groups. The nitrogen of the 8-quinolyl moiety seems
to play an important role for high diastereocontrol since the
[a] J. Hernꢀndez-Toribio, Dr. R. Gꢁmez Arrayꢀs,
Prof. Dr. J. C. Carretero
Departamento de Quꢂmica Orgꢀnica
Universidad Autꢁnoma de Madrid (UAM)
Facultad de Ciencias, Cantoblanco, Cantoblanco
28049 Madrid (Spain)
Fax : (+34)91-497-3966
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902258.
Chem. Eur. J. 2010, 16, 1153 – 1157
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1153

Table 1. Reaction of benzophenone-derived glycine derivatives 2a and 2b with aldimines 3.
has been conducted on altering
the steric or electronic proper-
ties of the imine moiety of
these pronucleophiles.[12] The
fluorenone imine 13, which was
reported to be much more reac-
tive than the corresponding
benzophenone imine in Man-
nich reactions,[12b] led to com-
plete reaction with 3 f in only
30 min at room temperature, al-
though with virtually no diaste-
reocontrol (entry 1). The diaste-
reoselectivity was not improved
to a practical level by lowering
the reaction temperature to
À788C, whereas the asymmetric
induction remained very high
(>90% ee for both anti and syn
adducts, entry 2). The electron-
rich 4,4’-dimethoxybenzophe-
Entry
R
PG (imine)
Product
syn/anti[a]
Yield [%][b]
ee [%][c]
syn
anti
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
tBu
tBu
tBu
Boc (3a)
Ts (3b)
4
5
6
7
8
9
10
11
12
12
73:27
55:45
58:42
68:32
60:40
77:23
52:48
55:45
84:16
88:12
93
85
78
78
94
79
94
86
83
80
96
95
–
97
–
97
–
93
97
97
98
94
–
[d]
[d]
(2-thienyl)SO2 (3c)
(2-pyridyl)SO2 (3d)
o-nosyl (3e)
(8-quinolyl)SO2 (3 f)
(1-naphthyl)SO2 (3g)
Boc (3a)
88
–
[d]
[d]
96
–
[d]
[d]
99
–
–
[d]
9
(8-quinolyl)SO2 (3 f)
(8-quinolyl)SO2 (3 f)
10[e]
[d]
[a] Determined by 1H NMR from the crude reaction mixture. [b] In pure product (mixtures syn+anti) after
chromatography. [c] Determined by chiral HPLC. [d] Not determined. [e] Reaction performed at À208C.
sterically similar 1-naphthylsulfonyl imine (3g) afforded a
55:45 mixture of syn/anti diastereomers under identical con-
ditions (entry 7). The more encumbered tert-butyl ester de-
rivative 2b (R=tBu) led to a drop in diastereoselectivity in
the case of the N-Boc imine 3a (entry 8), whereas it pro-
duced a positive impact in the case of the N-(8-quinolyl)sul-
fonyl imine (3 f) (syn/anti 84:16, entry 9). The diastereo-
meric ratio was further increased to syn/anti 88:12 by per-
forming the reaction at À208C, while maintaining high reac-
tivity (80% yield) and excellent enantiocontrol (97% ee for
the syn product, entry 10).
The electronic and steric nature of the glycinate compo-
nent was tuned for further optimization (Table 2). Notewor-
thy despite the widespread use of glycinate imines in the
synthesis of a-amino acid derivatives,[11] benzophenone
imines are generally the substrates of choice and little work
none derivative 2c displayed decreased reactivity (55% con-
version after 8 h at room temperature) but slightly higher
diastereocontrol (entry 3) than the parent substrate 2b. In
contrast, electron-withdrawing substituents at the para-posi-
tion of the phenyl rings of the benzophenone unit led to a
marked beneficial effect on both reactivity and diastereo-
control, without altering the outstanding level of enantiose-
lectivity. For instance, the 4,4’-dichlorobenzophenone (2d)
afforded the corresponding diamino ester derivative in ex-
cellent yield (91%), syn selectivity (syn/anti 93:7) and enan-
tiocontrol (99% ee for both the syn and anti adducts) after
2 h at room temperature (entry 4). Moreover, the diastereo-
selectivity value was increased to syn/anti 97:3 at À208C,
keeping the level of reactivity and enantioselectivity
(entry 5). Further temperature decrease did not improve the
values of diastereo- and enantiocontrol (entry 6). The more
electrophilic 4,4’-difluorobenzo-
phenone glycinate (2e) showed
Table 2. Fine tuning of the electronic and steric properties of the glycinate ketimine.
slightly lower performance
(entry 7). The somewhat better
behaviour of the sterically en-
cumbered tert-butyl ester over
the corresponding methyl ester
was confirmed in the latter two
substrates (entries 8 and 9).
Entry
R1
R2 (Substrate)
T [8C]/t [h]
Product
syn/anti[a]
Yield [%][b]
ee [%][c]
syn
anti
The scope of this syn-diaste-
reoselective synthesis of a,b-di-
amino ester derivatives was
evaluated with a wide range of
non-enolizable imines, including
aryl, heteroaryl and a,b-unsatu-
rated substrates (Table 3). Ali-
phatic imines could not be ex-
plored since we have not suc-
ceeded so far in the isolation of
this more labile type of N-(het-
[e]
[e]
1
2
3
4
5
6
7
8
9
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
Me
fluorene[d] (13)
fluorene[d] (13)
4-OMeC6H4 (2c)
4-ClC6H4 (2d)
4-ClC6H4 (2d)
4-ClC6H4 (2d)
4-FC6H4 (2e)
4-ClC6H4 (2 f)
4-FC6H4 (2g)
25/0.5
À78/4
25/8
14
14
15
16
16
16
17
18
19
55:45
70:30
88:12
93:7
97:3
97:3
94:6
95:5
90:10
76
71
55[f]
91
88
77
71
74
73
–
–
94
92
[e]
[e]
–
–
25/2
98
99
99
98
99
98
99
99
99
99
99
99
À20/3
À40/6
À20/3
À40/5
À20/2
[a] Determined by 1H NMR from the crude reaction mixture. [b] In pure product (mixtures syn+anti) after
chromatography. [c] Determined by chiral HPLC. [d] Fluorenone imine. [e] Not determined. [f] Conversion
yield.
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Chem. Eur. J. 2010, 16, 1153 – 1157

Catalytic Asymmetric Direct Mannich Reaction
COMMUNICATION
Table 3. Scope of the direct Mannich approach to syn-a,b-diamino acid derivatives.
42), whereas cleavage of the 8-
quinolylsulfonyl group was
easily achieved with excess of
Mg turnings in MeOH (product
43, 72% yield), this latter step
being
strongly
accelerated
Entry
R
Imine
T [8C]
Product
syn/anti[a]
Yield [%][b]
ee [%][c]
under sonication. Scheme 3
shows the sequential double
amino deprotection of 18 and
its transformation into the
known optically active urea
trans-45,[13] which served to con-
firm the (2S,3R) configuration
of the syn-Mannich adducts.
The optically active amino ester
syn-44 was obtained from 18
upon acid hydrolysis. The trans-
formation of 44 into the enan-
1
2
3
4
5
6
7
8
4-ClC6H4
20
21
22
23
24
25
26
27
28
29
30
À20
À40
À20
À20
À40
À40
À20
À40
À20
À20
À20
31
32
33
34
35
36
37
38
39
40
41
95:5
99:1
89:11
94:6
95:5
97:3
90:10
90:10
99:1
97:3
85
81
84
80
82
82
80
83
80
78
76
99
99
98
98
99
99
99
99
99
98
98
4-(CF3)C6H4
4-OMeC6H4
2-naphthyl
1-naphthyl
2-MeC6H4
2-furyl
2-thienyl
3-pyridyl
PhCH=CH-
(2-furyl)CH=CH-
9
10
11
95:5
1
[a] Determined by H NMR from the reaction mixture. [b] In pure product (mixtures syn+anti) after chroma-
tography. [c] Determined by chiral HPLC.
eroaryl)sulfonyl imines. The homogeneously high values of
reactivity (76–85% yield), diastereoselectivity (syn/anti
89:11–99:1) and, especially, enantiocontrol (98–99% ee) ach-
ieved in the 12 cases studied highlight the high degree of fi-
delity of the Fesulphos–CuI catalyst system. In addition to
Scheme 3. Sequential double amino deprotection of 18 and transforma-
sterically and electronically varied aromatic imines (en-
tries 1–6), heteroaryl imines are also excellent substrates for
this reaction (entries 7–9), including the 3-pyridinecarboxal-
dehyde-derived substrate 28 (80% yield, syn/anti 99:1, 99%
ee, entry 9). It is also noteworthy the comparable excellent
performance, in terms of reactivity as well as diastereo- and
enantiocontrol, displayed by a,b-unsaturated imines such as
those from cinnamaldehyde (substrate 29, entry 10) and 3-
(2-furyl)-2-propenal (substrate 30, entry 11). The resulting
g,d-unsaturated-a,b-diamino acid products (40 and 41, re-
spectively) offer interesting possibilities for further function-
alization and serve as an alternative method to the use of
aliphatic imines (upon hydrogenation). In spite of this inter-
est, few catalyst systems have been reported for the direct
Mannich reaction of glycinate derivatives with a,b-unsatu-
rated imines (only from cinnamaldehyde).[4c,f,k]
tion into a cyclic urea derivative.
tiopure urea trans-45,[13] was achieved in good yield by treat-
ment with triphosgene (CH2Cl2, 08C to RT, 2 h) and subse-
quent N-sulfonyl deprotection (Mg, MeOH, RT, 3 h).
The participation of the (Z)-enolate I as the active nucle-
ophile in the direct Mannich reaction (Scheme 4) was as-
sumed on the basis of previous experimental evidences and
Scheme 4. Working stereochemical models.
Scheme 2. Orthogonal deprotection of diamino acid derivative 16.
computational studies on the participation of the chiral Fes-
ulphos–copper(I) enolate of glycine Schiff bases in azome-
thine ylide 1,3-dipolar cycloaddition reactions.[14] The tetra-
coordinated complex I, showing a highly distorted tetrahe-
dral structure around the copper atom, was found to be the
most stable geometry in the coordination of the metal atom
with the P,S ligand Fesulphos and the azomethine species. In
Taking advantage of the orthogonal protection of the a,b-
diaminoester adducts, Scheme 2 illustrates the selective de-
protection of either of the two amino protecting groups of
product 16 in good yield under mild reaction conditions.
The imino function of 16 was removed quantitatively via
smooth acid hydrolysis (10% aq HCl, CH2Cl2, RT, product
Chem. Eur. J. 2010, 16, 1153 – 1157
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1155

R. Gꢁmez Arrayꢀs, J. C. Carretero and J. Hernꢀndez-Toribio
this complex the high steric congestion imposed by the tert-
butyl group linked to the sulfur atom in close proximity to
the copper center hinders the approach of the N-(8-quino-
lyl)sulfonyl imine from the Re C-a enolate face of the azo-
methine. Thus, the approach of I from the more accessible
Si C-a enolate face to the N-sulfonyl imine could explain
the high stereoselectivity attained in the formation of the
a,b-diamino esters with (2S) configuration in both the syn-
and anti-configured a,b-diamino acid derivatives. As a work-
ing hypothesis, the diastereoselectivity switch from anti
(when using aldimine-derived glycinate esters as pronucleo-
philes) to syn (in the case of ketimine-derived glycinates)
could be explained invoking steric interactions during the
approach of the imine to the enolate I (intermediates II).
For instance, the reaction with aldimine pronucleophiles
(R1 =H) is assumed to proceed more favourably via the in-
termediate IIa, which accounts for the observed anti-(2S,3S)
configuration in the Mannich adducts. The Re face approach
of the N-sulfonyl aldimine minimizes the steric repulsion be-
tween its bulky N-sulfonyl substituent and the glycinate
imine group (R1 =H, Scheme 3). In contrast, the presence of
a bulky N-diarylmethylene group (R1 =Ar) in the ketimine
pronucleophile would disfavor IIa because of its severe
steric repulsion with the N-(8-quinolyl)sulfonyl group, thus
forcing the imine to approach from its Si face via the inter-
mediate IIb that would account for the formation of the
syn-(2S,3R)-adducts.
In summary, a diastereoselectivity switch from anti- to
syn- has been devised in the catalytic asymmetric direct
Mannich reaction of glycine derivatives with N-(8-quinolyl)-
sulfonyl imines by tuning the steric and electronic properties
of the glycine imine. a,b-Diamino acids of syn-configuration
are produced with glycinate esters derived from electron-de-
ficient benzophenone-type ketimines, in contrast to aldi-
mine-derived pronucleophiles that lead to anti-configured
products. The Fesulphos–CuI catalyst is crucial for achieving
high asymmetric induction. The selective orthogonal N-de-
protection of the resulting a,b-diamino ester adducts can be
effected under mild conditions in good yields.
Acknowledgements
This work was supported by the Ministerio de Ciencia e Innovaciꢁn
(MICINN, project CTQ2006-01121). J.H.T. thanks the MICINN for a
predoctoral fellowship.
Keywords: copper catalysis · diastereoselectivity · glycine ·
Mannich reaction
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Experimental Section
Representative procedure for the synthesis of syn-a,b-diamino acid deriv-
atives: Reaction of tert-butylglycinate 4,4’-dicholorobenzophenone Schiff
base (2d) with N-benzylidene-N-[(8-quinolyl)sulfonyl]imine (3 f) to
afford (2S,3R)-tert-butyl 2-[(bis(4-chlorophenyl)methylene)amino]-3-
phenyl-3-[(8-quinolyl)-sulfonylamino]propanoate (16): To a solution of
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Fesulphos ligand (R)-1 (1.9 mg, 0.005 mmol) and CuACTHNUTRGNE(UNG CH3CN)4PF6
(2.3 mg, 0.005 mmol), in THF (0.5 mL) at À208C, were successively
added a solution of 2d (36.4 mg, 0.1 mmol) in THF (1.0 mL), Et3N
(1.4 mL, 0.01 mmol) and a solution of 3 f (32.6 mg, 0.11 mmol) in THF
(1.0 mL). The mixture was stirred at À208C for 3 h before it was filtered
through Celite and the filtrate concentrated to dryness. The residue was
1
analyzed by H NMR to determine the diastereomeric ratio and then pu-
rified by flash chromatography (n-hexane/EtOAc 3:1) to afford 16 as a
white solid (58.1 mg, 88%, syn/anti 97:3). M.p. 98–998C. See Supporting
Information for spectroscopic data.
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Chem. Eur. J. 2010, 16, 1153 – 1157

Catalytic Asymmetric Direct Mannich Reaction
COMMUNICATION
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[12] Pioneering work by Kobayashiꢄs group has revealed that the nature
of the imine pronucleophile can significantly influence its reactivity
and stereoselectivity in the Mannich-type reaction: a) S. Kobayashi,
T. Tsubogo, S. Saito, Y. Yamashita, Org. Lett. 2008, 10, 807; b) S. Ko-
[14] S. Cabrera, R. Gꢁmez Arrayꢀs, B. Martꢂn-Matute, F. Cossꢂo, J. C.
Carretero, Tetrahedron 2007, 63, 6587.
Received: August 14, 2009
Published online: December 18, 2009
Chem. Eur. J. 2010, 16, 1153 – 1157
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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