9622 Chem. Commun., 2012, 48, 9622–9624 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 9622–9624

Catalytic asymmetric Mannich reaction of glycine Schiff bases

with a-amido sulfones as precursors of aliphatic imineswzElier Hernando, Ramon Gomez Arrayas* and Juan C. Carretero*

Received 18th July 2012, Accepted 5th August 2012

DOI: 10.1039/c2cc35160a

A general and practical CuI–Fesulphos-catalyzed Mannich reaction

of glycinate Schiff bases with aliphatic imines generated in situ from

a-amido sulfones is described. Imines with linear and branched

alkyl chains, including substrates bearing functional groups, can

be efficiently applied. The resulting syn-configured orthogonally

protected b-alkyl-a,b-diamino acid derivatives are produced with

excellent levels of diastereo- (typically syn/anti>90 : o10) and

enantioselectivity (generally Z 90% ee).

Optically active a,b-diamino acids are attractive targets because

they are prevalent in peptide-based drugs and other bioactive

compounds, as well as versatile synthetic building blocks.1 The

direct catalytic asymmetric Mannich reaction between a prochiral

nitrogen nucleophile and an imine is one of the most convergent

routes to non-proteinogenic a,b-diamino acids.2,3 Glycinate Schiff

bases are particularly attractive pronucleophiles due to their ready

availability and facile deprotection of the resulting products.

Although very efficient catalytic asymmetric glycine Mannich

procedures have been devised ever since the pioneering work by

Jørgensen et al.,4,5 these studies are still limited in scope. Most of

the reported protocols are restricted to imines derived from

aromatic aldehydes, whereas only isolated examples involving

the more challenging aliphatic imines are described. A primary

reason for this scarcity is the instability of aliphatic imines and

their propensity to undergo tautomerization to enamines, thus

hampering an efficient nucleophilic addition. Furthermore, few

catalyst systems provide combined high diastereo- and enantio-

control with this type of substrate.6

We have reported the CuI–Fesulphos-catalyzed asymmetric

Mannich reaction of glycine derivatives with aromaticN-sulfonyl

aldimines, leading to a,b-diamino acid derivatives with either

anti- or syn-configuration in a highly diastereo- and enantio-

controlled manner.7 However, aliphatic aldimines turned out

to be unsuitable substrates. Herein we describe a practical

solution to this limitation by using a-amido sulfones as precursors

of N-Ts aliphatic aldimines, thereby providing a new pathway

for accessing optically active b-alkyl-a,b-diamino acid derivatives

with high control of the relative and absolute configuration.

Despite the widespread use of a-amido sulfones as valuable

bench-stable precursors of unstable imines,8 as far as we are

aware, only one catalytic asymmetric glycine Mannich reaction

based on this strategy has been reported. Barbas et al. devised a

highly diastereo- and enantioselective catalyst system for a-amido

sulfones derived from aromatic aldehydes.9 However, aliphatic

a-amido sulfones have not been exploited in this reaction.

Among aliphatic imines, those from small linear aldehydes

are considered to be very problematic because of the difficulty

in controlling their high reactivity. In particular, the imine of

acetaldehyde is, to the best of our knowledge, yet to be applied

in glycinate catalytic asymmetric Mannich reaction. Therefore, we

chose the model reaction of the a-amido sulfone derived from

acetaldehyde 1awith glycinemethyl ester (2a) under CuI–Fesulphos

for catalyst optimization.

A screening of the reaction parameters10 led us to find

Cs2CO3 (1.5 equiv.) and THF as the optimal base and solvent,

in the presence of a 10 mol% of a combination of a commercially

available Fesulphos ligand and Cu(CH3CN)4PF6. Under these

conditions the desired product 3 was obtained in acceptable

52% yield and good stereocontrol (syn/anti=88 : 12, 93% ee,

Table 1, entry 1).11 We then moved on to tune the electronic

and steric nature of the two reaction components for further

optimization. The sterically encumbered tert-butyl ester 2b

caused a positive impact on the yield (67%), as well as on the

diastereo- (syn/anti = 96 : 4) and enantiocontrol (97% ee,

entry 2). Instead, no further improvement was observed by

performing the reaction at�20 1C (entry 3). Regarding electronic

modification of the imine part of the glycinate,12 better reactivity

and stereocontrol was observed with the more electrophilic

4,40-dichlorobenzophenone 2c (entry 4). To our delight, the

4,40-difluorobenzophenone 2d remarkably improved the yield

of the desired product 6 (74%), as well as both diastereo- (syn/

anti = >98 : o2) and enantiocontrol (>99% ee, entry 5).

The reaction also demonstrated high sensitivity to the nature

of the N-protecting group at the a-amido sulfone (Table 2). The

N-Boc-protected substrate 1b failed to react with 2d (entry 2).

N-Arylsulfonyl a-amido sulfones such as those with p-nosyl (1c)

or (2-naphthyl)sulfonyl (1d) groups participated in the Mannich

reaction, albeit with lower efficiency than the parent substrate

1a (32% and 54% yield, respectively; entries 3 and 4). In all

cases the a-amido sulfones 1a–d were completely consumed in

Departamento de Quımica Organica, Universidad Autonoma deMadrid (UAM), Cantoblanco, 28049 Madrid, Spain.E-mail: juancarlos.carretero@uam.es, ramon.gomez@uam.es;Tel: +34 914973925w This article is dedicated to the memory of Dr Christian G. Claessens.z Electronic supplementary information (ESI) available: Experimentalprocedures and characterization data for new compounds and copiesof NMR spectra. See DOI: 10.1039/c2cc35160a

ChemComm Dynamic Article Links

www.rsc.org/chemcomm COMMUNICATION

Dow

nloa

ded

by P

urdu

e U

nive

rsity

on

14 M

arch

201

3Pu

blis

hed

on 0

7 A

ugus

t 201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3516

0AView Article Online / Journal Homepage / Table of Contents for this issue

This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 9622–9624 9623

the reaction, suggesting that the lower yield in the latter cases is

due to the competing decomposition of the in situ generated

reactive imine.

A varied range of a-amido sulfones derived from enolizable

aliphatic aldehydes provided the corresponding diamino acid

derivatives in good yields (typically Z 70%) and excellent

diastereo- and enantioselectivities (Table 3). Linear alkyl

groups, regardless of the length of the chain (products

20–22, 92–98% de, 93–99% ee), as well as sterically more

demanding side chains branched at the a- or b-position,irrespective of the acyclic (isobutyl, 2-pentyl) or cyclic (cyclo-

pentyl, Cy) nature of the substituent (23–26, syn/anti =

96 : 4–>99 : o1, 97–99% ee), were accommodated with no

impact on yield or stereocontrol. Amido sulfones containing

functional groups (aryl, alkene or benzyloxy) also behaved

very well (27–29, syn/anti = 90 : 10–96 : 4, 93–99% ee),

providing useful handles for further manipulation. To demon-

strate the practicality of the methodology, the reaction of

cyclohexyl-substituted amido sulfone 16 with glycinate 2b

was ten-fold scaled up (1.5 mmol) without significant loss of

chemical or stereochemical efficiency (product 26, 80% yield,

syn/anti = 98 : 2, 96% ee).

Our attention was drawn to formaldehyde-derived a-amido

sulfone 30 (Scheme 1) because formaldehyde does not form

stable imines and because optically active 2,3-diamino-propa-

noic acid derivatives display various biological activities.1,13

Notably, the Mannich reaction of 30 with glycinate 2d enabled

a practical and straightforward method for a-aminomethyla-

tion of glycine derivatives (product 31, 80% yield, 83% ee).

To the best of our knowledge, neither the use of formaldehyde

a-amido sulfones in catalytic asymmetric Mannich reactions

nor the asymmetric aminomethylation of glycine derivatives

has been documented.14

Scheme 2 shows the sequential double amino deprotection

of the Mannich adduct 26 and its transformation into the

optically active imidazolidinone trans-33, which also served to

confirm otherwise the syn-configuration of 26.11,15

As in our previous results from aryl aldimines,7b the high

enantio- and diastereoselectivity observed in favour of the products

with syn-(2S,3R)-configuration can be explained assuming the

participation of the Z-enolate I16 as the catalytically active

Table 1 Tuning of the electronic and steric properties of the glycinateketimine counterparta

Entry R Ar (glycinate) T (1C)Yieldb (%)(product) syn/antic eed (%)

1e Me Ph (2a) rt 52 (3) 88 : 12 932e t-Bu Ph (2b) rt 67 (4) 96 : 4 973f t-Bu Ph (2b) �20 40 (4) 96 : 4 974f t-Bu 4-ClC6H4 (2c) �20 62 (5) >98 : o2 985f t-Bu 4-FC6H4 (2d) �20 74 (6) >98 : o2 >99

a Conditions: amidosulfone 1 (0.19 mmol), glycinate 2 (0.15 mmol),

Cs2CO3 (0.22 mmol), Cu(CH3CN)4PF6 (10 mol%), Fesulphos

(10 mol%), THF (2 mL). b Isolated yield after chromatography.c Determined by 1H NMR and/or HPLC from the crude reaction

mixture. d Determined by HPLC. e Reaction time: 5 h. f Reaction

time: 17 h.

Table 2 Influence of the N-protecting group on the reactivity

Entry PG (substrate) Product Yielda (%) syn/antib eec (%)

1 Ts (1a) 6 74 >98 : o2 >992 Boc (1b) 7 — — —3 p-Ns (1c) 8 32 >98 : o2 974 2-NaphSO2 (1d) 9 54 >98 : o2 97

a Isolated yield after chromatography. b Determined by 1H NMR

and/or HPLC from the crude reaction mixture. c Determined by

HPLC.

Table 3 Catalytic enantioselective synthesis of b-alkyl-a-b-diaminoacid derivativesa

a Conditions: amidosulfone (0.19 mmol), glycinate 2 (0.15 mmol),

Cs2CO3 (0.22 mmol), Cu(CH3CN)4PF6 (10 mol%), Fesulphos

(10 mol%), THF (2 mL). b Reaction temperature: rt.

Scheme 1 Catalytic asymmetric aminomethylation of glycinate 2d

with a-amidosulfone derived from formaldehyde 30.

Scheme 2 Amino-deprotection and synthetic applications.

Dow

nloa

ded

by P

urdu

e U

nive

rsity

on

14 M

arch

201

3Pu

blis

hed

on 0

7 A

ugus

t 201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3516

0A

View Article Online

9624 Chem. Commun., 2012, 48, 9622–9624 This journal is c The Royal Society of Chemistry 2012

nucleophile (Scheme 3). In this complex the high steric congestion

imposed by the tert-butyl group at the sulfur atom in close

proximity to the copper center hinders the approach of the

N-sulfonyl imine from the Re C-a enolate face of the azomethine.4

Thus, the approach of I from the more accessible Si C-a enolate

face to the N-sulfonyl imine accounts for the high stereoselectivity

attained in the formation of the C(2S) stereocenter (TS-II).10 The

high syn-diastereocontrol can be tentatively rationalized invoking

a severe steric repulsion of the bulky N-diarylmethylene group in

the ketimine nucleophile with the N-sulfonyl group,4,7b thereby

disfavouring IIIa (leading to anti-configured products) and forcing

the imine to approach from its Si-face via the intermediate IIIb

that would account for the formation of the syn-(2S,3R)-adducts.

In conclusion, an efficient and practical asymmetric

CuI-catalyzedMannich reaction of glycine derivatives with aliphatic

imines generated in situ from a-amido sulfones has been

devised. b-Alkyl-a,b-diamino acid derivatives are produced

in good yields and excellent diastereo- and enantiocontrol

(typically syn/anti = Z90 : r10 and Z90% ee). The selective

orthogonal N-deprotection under mild conditions is demonstrated.

Acknowledgements

We thank the Ministerio de Ciencia e Innovacion (MICINN,

CTQ2009-07791) and the Consejerıa de Educacion de la

Comunidad de Madrid (programme AVANCAT, S2009/

PPQ-1634) for financial support. E.H. thanks the Gobierno

Vasco for a predoctoral fellowship.

Notes and references

1 Reviews on synthesis and biological significance of a,b-diamino acids:(a) A. Viso, R. Fernandez de la Pradilla, A. Garcıa andA. Flores,Chem.Rev., 2005, 105, 3167; (b) A. Viso, R. F. de la Pradilla, M. Tortosa,A. Garca and A. Flores, Chem. Rev., 2011, 111, PR1–PR42.

2 For recent reviews on catalytic asymmetric Mannich reaction:(a) A. Ting and S. E. Schaus, Eur. J. Org. Chem., 2007, 5797;(b) J. M. M. Verkade, L. J. C. vanHemert, P. J. L. M. Quaedfliegand F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37, 29.

3 For a recent review on the synthesis of a,b-amino acids via catalyticasymmetric direct Mannich reaction, see: R. Gomez Arrayas andJ. C. Carretero, Chem. Soc. Rev., 2009, 38, 1940.

4 L. Bernardi, A. S. Gothelf, R. G. Hazell and K. A. Jørgensen,J. Org. Chem., 2003, 68, 2583.

5 For examples on glycinate (and related species) Mannich reaction,see: (a) T. Ooi, M. Kameda, J.-i. Fujii and K. Maruoka,Org. Lett.,2004, 6, 2397; (b) A. Okada, T. Shibuguchi, T. Ohshima, H. Masu,

K. Yamaguchi and M. Shibasaki, Angew. Chem., Int. Ed., 2005,44, 4564; (c) M. M. Salter, J. Kobayashi, Y. Shimizu andS. Kobayashi, Org. Lett., 2006, 8, 3533; (d) T. Shibuguchi,H. Mihara, A. Kuramochi, T. Ohshima and M. Shibasaki,Chem.–Asian J., 2007, 2, 794; (e) G. A. Cutting, N. E. Stainforth,M. P. John, G. Kociok-Kohn and M. C. Willis, J. Am. Chem. Soc.,2007, 129, 10632; (f) D. Uraguchi, Y. Ueki and T. Ooi, J. Am. Chem.Soc., 2008, 130, 14088; (g) S. Kobayashi, R. Yazaki, K. Seki andY. Yamashita, Angew. Chem., Int. Ed., 2008, 47, 5613; (h) X.-X. Yan,Q. Peng, Q. Li, K. Zhang, J. Yao, X.-L. Hou and Y.-D. Wu, J. Am.Chem. Soc., 2008, 130, 14362; (i) D. Shang, Y. Liu, X. Zhou, X. Liuand X. Feng, Chem.–Eur. J., 2009, 15, 3678; (j) L. Li, M. Ganesh andD. Seidel, J. Am. Chem. Soc., 2009, 131, 11648; (k) G. Liang,M.-C. Tong, H. Tao and C.-J. Wang, Adv. Synth. Catal., 2010,352, 1851; (l) X. Liu, L. Deng, X. Jiang, W. Yan, C. Liu andR. Wang, Org. Lett., 2010, 12, 876; (m) X. Chen, S. Dong, Z. Qiao,Y. Zhu, M. Xie, L. Lin, X. Liu and X. Feng, Chem.–Eur. J., 2011,17, 2583; (n) G. Lu, T. Yoshino, H. Morimoto, S. Matsunaga andM. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 4382; (o) J. Jiang,H.-D. Xu, J.-B. Xi, B.-Y. Ren, F.-P. Lv, X. Guo and L.-Q. Jiang,J. Am. Chem. Soc., 2011, 133, 8428; (p) S.-H. Shi, F.-P. Huang, P. Zhu,Z.-W. Dong and X.-P. Hui, Org. Lett., 2012, 14, 2010;(q) S. Nakamura, Y. Maeno, M. Ohara, A. Yamamura,Y. Funahashi and N. Shibata, Org. Lett., 2012, 14, 2960.

6 For the highly enantioselective Mannich reaction of a-substitutedazlactones with enolizable aliphatic imines: (a) W.-Q. Zhang,L.-F. Cheng, J. Yu and L.-Z. Gong, Angew. Chem., Int. Ed., 2012,51, 4085; (b) A. D.Melhado, G.W. Amarante, Z. J.Wang,M. Lupariaand F. D. Toste, J. Am. Chem. Soc., 2011, 133, 3517. See also ref. 5h.

7 (a) J. Hernandez-Toribio, R. Gomez Arrayas and J. C. Carretero,J. Am. Chem. Soc., 2008, 130, 16150; (b) J. Hernandez-Toribio,R. Gomez Arrayas and J. C. Carretero, Chem.–Eur. J., 2010,16, 1153.

8 Review on applications of a-amido sulfones in asymmetric catalysis:B. Yin, Y. Zhang and L.-W. Xu, Synthesis, 2010, 3583.

9 (a) N. S. Chowdari, M. Ahmad, K. Albertshofer, F. Tanaka andC. F. Barbas, III, Org. Lett., 2006, 8, 2839. For the catalyticasymmetric Mannich reaction of phosphoglycine Schiff bases witha-amido sulfones, see: (b) R. D. Momo, F. Fini, L. Bernardi andA. Ricci, Adv. Synth. Catal., 2009, 351, 2283.

10 See ESIz for base, solvent and chiral ligand screening. Catalystloading of 5 mol% led to decreased reactivity.

11 The absolute and relative configuration of the Mannich productswas determined by preparation of the known compound 260

(methyl ester derivative of product 26) and comparison of theNMR data and optical rotation with those described in theliterature (see ref. 4 and ESIz).

12 Pioneering work by Kobayashi’s group has revealed that thenature of the imine pronucleophile can significantly influence itsreactivity and stereoselectivity in Mannich-type reactions:S. Kobayashi, T. Tsubogo, S. Saito and Y. Yamashita, Org. Lett.,2008, 10, 807. See also ref. 5g and 7.

13 G. Kumaraswamy and A. Pitchaiah, Helv. Chim. Acta, 2011,94, 1543.

14 For previous catalytic asymmetric Mannich reactions withformaldehyde-derived imines or iminium ions, see: (a) I. Ibrahem,J. Casas and A. Cordova, Angew. Chem., Int. Ed., 2004, 43, 6528;(b) Y. Chi and S. H. Gellman, J. Am. Chem. Soc., 2006, 128, 6804;(c) I. Ibrahem, W. Zou, J. Casas, H. Sunden and A. Cordova,Tetrahedron, 2006, 62, 357.

15 For cis- and trans-assignment on imidazolidinones derived froma,b-diamino acid derivatives, see: S. H. Lee, J. Yoon, S. H. Chungand Y. S. Lee, Tetrahedron, 2001, 57, 2139.

16 The complex I was found to be the most stable geometry in thecoordination of the metal atom with Fesulphos and the azomethinespecies: S. Cabrera, R. Gomez Arrayas, B. Martın-Matute,F. P. Cossıo and J. C. Carretero, Tetrahedron, 2007, 63, 6587.

Scheme 3 Working stereochemical model.

Dow

nloa

ded

by P

urdu

e U

nive

rsity

on

14 M

arch

201

3Pu

blis

hed

on 0

7 A

ugus

t 201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3516

0A

View Article Online