One-step catalytic enantioselective α-quaternary 5-hydroxyproline synthesis: An asymmetric entry to highly functionalized α-quaternary proline derivatives

Article abstract of DOI:10.1002/adsc.201100911

The highly enantioselective cascade reaction between N-protected α-cyanoglycine esters and α,β-unsaturated aldehydes is disclosed. The reaction represents a one-step entry to polysubstituted 5-hydroxyproline derivatives having a quaternary α-stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two-step entry to functionalized α-quaternary proline derivatives.

Full text of DOI:10.1002/adsc.201100911

UPDATES
DOI: 10.1002/adsc.201100911
One-Step Catalytic Enantioselective a-Quaternary
5-Hydroxyproline Synthesis: An Asymmetric Entry to Highly
Functionalized a-Quaternary Proline Derivatives
Palle Breistein,a Jonas Johansson,a Ismail Ibrahem,a Shuangzheng Lin,b,d
Luca Deiana,b,d Junliang Sun,c,d and Armando Cordovaa,b,c,d,
*
a
Department of Natural Sciences, Engineering and Mathematics, SE-851 70 Sundsvall, Sweden
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Fax : (+46)-8-162-479; e-mail: acordova@organ.su.se or armando.cordova@miun.se
Department of Structural Chemistry, The Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Berzelii Center EXSELENT on Porous Materials, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden
b
c
d
Received: November 23, 2011; Published online: April 4, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100911.
Abstract: The highly enantioselective cascade reac-
tion between N-protected a-cyanoglycine esters and
a,b-unsaturated aldehydes is disclosed. The reaction
represents a one-step entry to polysubstituted 5-hy-
droxyproline derivatives having a quaternary a-ste-
reocenter generally in high yields with up to >95:5
dr and 99:1 er. It is also a direct catalytic two-step
entry to functionalized a-quaternary proline deriva-
tives.
sis of highly substituted a-quaternary proline deriva-
tives.[4] Most of these methods rely on catalytic enan-
tioselective [3+2]dipolar cycloadditions.[5,6] With re-
spect to the synthesis of 5-hydroxyproline derivatives,
there are only two reports describing the use of
highly enantioselective catalysis.[7] For example, the
organocatalytic enantioselective tandem reaction be-
tween a,b-unsaturated aldehydes and N-acyl 2-amino-
malonate esters delivers 5-hydroxy-3-aryl-substituted
proline derivatives.[7a] Moreover, the organocatalytic
addition of oxazolones to enals followed by subse-
quent deprotection of the isolated Michael adducts is
a two-step route to 5-hydroxyprolines.[7b] We recently
developed a catalytic asymmetric one-pot, three-com-
ponent reaction between a-cyanoglycine esters, alde-
hydes and a,b-unsaturated aldehydes.[8] During this
work we found that under certain reaction conditions
Keywords: asymmetric catalysis; hemiaminals;
metal-free catalysis; proline derivatives; quaternary
stereocenters; tandem reactions
Highly functional chiral pyrrolidine and proline deriv- an imine was formed as two diastereoisomers (1:1 dr)
atives are important natural products, building blocks by the catalytic reaction between the a-cyanoglycine
for total and diversity-oriented synthesis, pharmaceut- ester and the enal components [Eq. (1)].
icals and organocatalysts.[1] In this, context, 5-hydroxy-
Based on these findings and the importance of a-
prolines are versatile synthons for the synthesis of quaternary 5-hydroxyproline derivatives, we decided
other proline derivatives and conformational restrict- to investigate the synthesis of these type of com-
ed peptidomimetics.[2] Moreover, there are several
proline derivatives with a quaternary stereocenter
that
exhibit
important
biological
activities
(Figure 1).[3] For example, the 5-oxo-functionalized
proline derivatives 1a and 1b are salinosporamide nat-
ural products[3c] with anti-cancer activities and 1c is
present in lipopolysaccharides of mycobacteria.[3d]
Thus, there is a need for developing methods for
the asymmetric synthesis of 5-hydroxyproline and
proline derivatives. In this context, there are only
Figure 1. Example of natural occurring proline derivatives
a few reports on the catalytic enantioselective synthe- 1a–1c.
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Adv. Synth. Catal. 2012, 354, 1156 – 1162

One-Step Catalytic Enantioselective a-Quaternary 5-Hydroxyproline Synthesis
accelerating the iminium activation of enal 3a.[12] The
highest dr and er of 4a were obtained when chiral
amine 6b and 2-fluorobenzoic acid were used as coca-
talysts in MeOH. Decreasing the temperature to
ꢀ208C improved the diastereo- and enantioselectivity
of the catalytic tandem reaction and proline deriva-
tive 4a was formed in high conversion with 83:17 dr
and 97:3 er (entry 7). Changing the nucleophile to N-
acetyl-protected a-cyanoglycine ester 2b increased
the stereoselectivity of the catalytic tandem reaction
and the corresponding a-quaternary 5-hydroxyproline
derivative 4b was formed in high conversion with
88:12 dr and 97:3 er (entry 11).
The cocatalytic asymmetric cascade reaction be-
tween N-Boc-protected 2c and enal 3a gave the corre-
pounds by means of catalytic asymmetric cascade re- sponding proline derivative 4c in high conversion with
actions.[9,10] The retrocatalytic analysis implies that moderate dr and high er at room temperature
a chiral amine-catalyzed metal-free enantioselective (entry 15). Selecting the Cbz-protected 2d as the nu-
Michael/hemiaminal cascade reaction between N-pro- cleophile improved the diastereoselectivity of the re-
tected a-cyanoglycine esters 2 and enals 3 would give action (86:14 dr) and delivered 4d with 92:8 er
the corresponding a-quaternary 5-hydroxyproline de- (entry 16). With these results in hand, we decided to
rivatives 4 in one-step [Eq. (2)]. Thus, the initial cata- probe the scope of the catalytic enantioselective
tandem reaction between 2a or 2b and enals 3 using
6b and 2-fluorobenzoic acid as the cocatalysts in
MeOH at ꢀ208C (Table 2).
To our delight, the cocatalytic reactions delivered
the corresponding a-quaternary 5-hydroxyproline de-
rivatives 4 in high yields (68–90%), dr (80:20–>95:5)
and er (96:4–97:3) when b-aryl-substituted enals 3
were used as the starting materials. The reaction did
also give the corresponding proline derivatives 4 with
a chiral quaternary a-stereocenter with excellent er
(up to 99:1) when aliphatic enal 2l was employed as
the substrate (entry 12). Thus, the disclosed catalytic
enantioselective cascade reaction is a direct one-step
asymmetric entry to an aliphatic 3-substituted-5-hy-
droxyproline derivative. Proline derivatives containing
lytic enantioselective Michael reaction would give 5 a quaternary a-stereocenter are very useful as men-
and subsequent hemiaminal formation would push tioned in the introductory part.[3] Thus, we also devel-
the equilibrium towards formation of product 4. How- oped a procedure for the two-step synthesis of highly
ever, it would be very challenging to control the ste- functionalized a-quaternary proline derivatives
7
reoselectivity during the formation of the chiral qua- (Scheme 1). The procedure started with the catalytic
ternary stereocenter [for example, Eq. (1)]. Herein, cascade reaction between 2 and 3 that delivered 4.
we report a highly enantioselective cascade synthesis Next, mild removal of the 5-hydroxy group of 4 gave
of a-quaternary proline derivatives 4 in high yields the corresponding proline derivatives 7 in good to
and up to >95:5 dr and 99:1 er [Eq. (2)].
high yields.
In initial experiments, we screened the catalytic re-
The absolute configuration of the 5-hydroxyproline
action between N-benzoyl-a-cyanoglycine ester 2a derivatives 4 was determined by X-ray analysis of 4m
and cinnamic aldehyde 3a using chiral amines 6 as the (2S, 3S, 5R, Figure 2).[13]
catalysts in different solvents (Table 1). For example,
Based on the absolute configuration of proline de-
the 6b[11]-catalyzed reaction in MeOH at room tem- rivatives 4, we propose the following reaction mecha-
perature delivered 4a in high conversion but moder- nism to account for the observed stereochemistry
ate dr (4a:4a’=67:33) and high er (entry 1). Only the (Scheme 2). Accordingly, acid-accelerated iminium
a-anomer was formed in the hemiaminal formation formation between chiral amine 6 and enal 3 delivers
1
step as determined by H NMR analysis of the crude iminium intermedtiate I.[14] Enolization of 2 provides
reaction mixture. The employment of an organic acid the corresponding enol that can perform a nucleophil-
as the cocatalyst increased the rate of the reaction by ic attack on iminium intermediate I, of which the Re-
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UPDATES
Table 1. Screening for reaction conditions.[a]
Entry R1
Product Additive
Solvent Temperature
Time
[h]
Catalyst Conversion[b]
[%]
dr[b]
(4:4’)
er[c]
[8C]
1
2
3
Ph
Ph
Ph
4a
4a
4a
–
MeOH r.t.
7
7
7
6b
6b
6b
90
>98
>98
67:33
67:33
83:17
92.5:7.5
90:10
68.5:31.5
2-FC6H4CO2H MeOH r.t.
2-FC6H4CO2H i- r.t.
PrOH
2-FC6H4CO2H toluene r.t.
2-FC6H4CO2H THF r.t.
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4a
4a
4a
4a
4a
9
9
9
13
13
6b
6b
6b
6b
6b
96
95
90
95
88
50:50
50:50
75:25
83:17
83:17
56:44
81:19
56.5:43.5
97:3
2-FC6H4CO2H CHCl3 r.t.
2-FC6H4CO2H MeOH ꢀ20
3-
MeOH ꢀ20
MeOH ꢀ20
94:6
NO2C6H4CO2H
4-
NO2C6H4CO2H
9
Ph
4a
13
6b
95
80:20
97:3
10
11
12
13
14
15
Me
Me
Me
Me
Me
t-
4b
4b
4b
4b
4b
4c
2-FC6H4CO2H MeOH ꢀ20
2-FC6H4CO2H MeOH ꢀ20
2-FC6H4CO2H MeOH ꢀ20
2-FC6H4CO2H MeOH ꢀ20
2-FC6H4CO2H MeOH ꢀ20
2-FC6H4CO2H MeOH r.t.
13
13
13
13
13
24
6d
6b
6a
6c
6e
6b
85
98
98
98
4
75:25
88:12
80:20
88:12
n.d.
64:36
97:3
89:11
91.5:8.5
n.d.
98
67:33
91.5:8.5
BuO
16
BnO 4d
2-FC6H4CO2H MeOH r.t.
41
6b
70
86:14
92:8
[a]
Amide 2 (0.2 mmol, 1 equiv.) was added to a stirred solution of aldehyde 3a (0.4 mmol, 2 equiv.), catalyst 6 (10 mol%)
and additive (10 mol%) in solvent (0.4 mL). The reaction mixture was stirred for the given time and temperature.
Determined by H NMR analysis. The a:b-ratio of 4 was always >20:1.
Determined by chiral-phase HPLC analysis. Bn=benzyl.
[b]
[c]
1
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One-Step Catalytic Enantioselective a-Quaternary 5-Hydroxyproline Synthesis
Table 2. Catalytic asymmetric tandem Michael/hemiaminal formation between 2 and 3.[a]
Entry
R1
R
Product
4a
Yield [%][b]
dr[c]
ee [%][d]
1
2
83
88
83:17
83:17
97:3 (91.5:8.5)[h]
96:4 (88:12)[h]
4e
3
4
5
4f
4g
4h
68
78
84
86:14
80:20
80:20
96:4 (89:11)[h]
96:4 (92.5:7.5)[h]
96:4 (90.5:9.5)[h]
6
7
8
Me
Me
Me
4i
89 (92)[f]
88:12 (89:11)[f]
92:8
97:3 (96:4)[f]
96:4
4j
4k
90
85
80:20
98:2
9
Me
Me
4l
90
68
91:9
91:9
95.5:4.5 (97.5:2.5)[h]
97:3
10
11
4m
Me
Me
4n
4o
81
>95:5
96:4
12[e]
55 g] (47)[i]
67:33 g] (67:33)[i]
97.5:2.5[g] (99:1),[i] (91.5:8.5)[h,i]
[a]
Amide 2 (0.2 mmol) was added to a stirred solution of aldehyde 3 (0.4 mmol), catalyst 6b (10 mol%) and 2-FC6H4CO2H
(10 mol%) in MeOH at ꢀ208C (0.4 mL). The reaction mixture was stirred for the given time and temperature.
Isolated yield after silica-gel column chromatography.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis. The a:b-ratio of 4 was always >20:1.
Determined by chiral-phase HPLC analysis.
The reaction was run in i-PrOH.
The reaction performed at a 1.0 mmol scale of 2.
Reaction run at 48C.
The er of 4’.
The results from the reaction run at ꢀ208C.
[g]
[h]
[i]
face (R=aryl) is efficiently shielded by the bulky further investigated the importance of the bulky N-
chiral group of 6, either from its Si-face (A) or its Re- protected amino group of the a-cyanoglycine deriva-
face (B). The Si-facial attack on the iminium species I tive 2. Thus, the a-cyanoacetate ester 2e was investi-
was predominantly occurring from the enolꢁs Si-face gated as a nucleophile for the catalytic asymmetric
(A), which afforded enamine intermediate II. Subse- Michael/hemiaminal cascade reaction with enals 3.
quent protonation and hydrolysis of iminium inter- The reaction gave the corresponding hemiaminal 8a
mediate III regenerates the chiral amine catalyst 6 in high yield and very low dr and er under the acid
and provides the Michael aldehyde intermediate 5, additive condition [Eq. (3)]. The use of a base addi-
which undergoes Re-facial hemiaminal formation to tive instead gave the corresponding heminals 8 with
give the final 5-hydroxyproline derivative 4. We also high er but low dr.[15] For example, after removal of
Adv. Synth. Catal. 2012, 354, 1156 – 1162
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Palle Breistein et al.
UPDATES
Scheme 1. Two-step synthesis of 3-substituted a-quaternary
proline derivatives 7.
the anomeric hydroxy group lactams 9o and 9o’ were
formed in a 57:43 ratio and isolated in 74% combined
yield with 95:5 and 97.5:3.5 er, respectively. Further-
more, as shown above the cascade reaction with a-cy-
anoglycine ester as the substrate was not diastereose-
lective [Eq. (1)]. Thus, these results show that the
bulky N-protected amino group of 2 was crucial for
achieving high diastereoselectivity of the catalytic
asymmetric cascade reaction.
In summary, we report highly enantioselective pro-
cedures for the one-step synthesis of a-quaternary 5-
hydroxyproline derivatives, which are formed in high
yields with up to >95:5 dr and 99:1 er. Moreover, the
Scheme 2. Proposed reaction mechanism.
catalytic metal-free cascade reaction represents a ver-
satile asymmetric entry to different useful a-quaterna-
ry proline derivatives.
Experimental Section
Typical Experimental Procedure for the Cocatalytic
Asymmetric Synthesis of a-Quaternary 5-Hydroxy-
proline Derivatives 4
Experimental procedure for a reaction performed at 1 mmol
scale: The desired nucleophile 2 (1.0 mmol, 1.0 equiv.) was
added to
a stirred solution of aldehyde 3 (2.0 mmol
2.0 equiv.), catalyst 6b (0.2 mmol, 20 mol%) and 2-fluoro-
benzoic acid (14 mg, 0.1 mmol, 10 mol%) in MeOH
(2.0 mL) at 08C. The reaction mixture was then placed
under constant stirring at ꢀ208C for 14 h. Next the crude re-
action mixture was directly loaded on and purified by silica
Figure 2. ORTEP picture of the crystalline compound 4m.
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One-Step Catalytic Enantioselective a-Quaternary 5-Hydroxyproline Synthesis
gel chromatography (pentane/EtOAc or toluene/EtOAc
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Typical Experimental Procedure for the Synthesis of
a-Quaternary Proline Derivatives 7 from 4
BF3·Et2O (78.1 mg, 67 mL, 0.55 mmol) was added to a stirred
solution of the pyrrolidine
4 (0.50 mmol) and Et3SiH
(58.1 mg, 80 mL, 0.50 mmol) in CH2Cl2 (15 mL) at ꢀ788C
under an N2 atmosphere. After 30 min BF3·Et2O (78.1 mg,
67 mL, 0.55 mmol) and Et3SiH (58.1 mg, 80 mL, 0.50 mmol)
were added once again, and the reaction mixture was left at
room temperature over night. The reaction mixture was di-
luted with pentane/EtOAc and then directly loaded and pu-
rified by silica gel chromatography (3:1 pentane/EtOAc!
100% EtOAc) to afford 7 as a colourless oil.
Supporting Information
Experimental procedures, full spectroscopic data for all new
described compounds, NMR spectra, HPLC traces and HR
mass spectra are available in the Supporting Information.
Acknowledgements
We thank European Union and Carl Trygger foundation for
financial support. The Berzelii Center EXSELENT is finan-
cially supported by Swedish National Research Council (VR)
and the Swedish Governmental Agency for Innovations Sys-
tems (VINNOVA).
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UPDATES
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[15] The low er when the acid additive was used as com-
pared to the employment of base could be due to
a rapid retro-Michael reaction that leads to racemiza-
tion under the acidic conditions.
1162
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1156 – 1162