Efficient diastereo- and enantioselective synthesis of exo-nitroprolinates by 1,3-dipolar cycloadditions catalyzed by Chiral phosphoramidite·silver(I) complexes

Article abstract of DOI:10.1002/adsc.201400563

Chiral complexes formed by privileged phosphoramidites and silver triflate or silver benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides generated from α-amino acid-derived imino esters and nitroalkenes aff

Full text of DOI:10.1002/adsc.201400563

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DOI: 10.1002/adsc.201400563
Efficient Diastereo- and Enantioselective Synthesis of
exo-Nitroprolinates by 1,3-Dipolar Cycloadditions Catalyzed by
Chiral Phosphoramidite·Silver(I) Complexes
Luis M. Castellꢀ,a,d Carmen Nꢁjera,a,d,* Josꢂ M. Sansano,a,d,* Olatz LarraÇaga,b,d
Abel de Cꢀzar,b,c,d and Fernando P. Cossꢃob,c,d,
*
a
Departamento de Quꢃmica Orgꢁnica, Instituto de Sꢃntesis Orgꢁnica (ISO), and Centro de Innovaciꢀn en Quꢃmica
Avanzada (ORFEO-CINQA). Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Fax : (+34)-965-903-549; phone: (+34)-965-903-549; e-mail: cnajera@ua.es or jmsansano@ua.es
Departmento de Quꢃmica Orgꢁnica I, Facultad de Quꢃmica, Universidad del Paꢃs Vasco, P. K. 1072, E-20018 San
Sebastiꢁn, Spain
b
Fax : (+34)-943-212-236; phone: (+34)-943-212-236 (for computational part); e-mail: fp.cossio@ehu.es
IKERBASQUE, Basque Foundation for Science, E-48011 Bilbao, Spain
Centro de Innovacꢃon en Quꢃmica Avanzada (ORFEO-CINQA)
c
d
Received: June 18, 2014; Published online: && &&, 0000
Dedicated to Prof. Max Malacria on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400563.
Abstract: Chiral complexes formed by privileged tallization. The mechanism and the justification of
phosphoramidites and silver triflate or silver ben- the experimentally observed stereodiscrimination of
zoate are excellent catalysts for the general 1,3-dipo- the process are supported by DFT calculations.
lar cycloaddition between azomethine ylides generat- These enantiomerically enriched exo-nitroprolinates
ed from a-amino acid-derived imino esters and nitro- can be used as reagents for the synthesis of nitropi-
alkenes affording with high dr the exo-cycloadducts peridines, by ester reduction and ring expansion,
4,5-trans-2,5-cis-4-nitroprolinates in high ee at room which are inhibitors of farnesyltransferase.
temperature. In general, better results are obtained
using silver rather than copper(II) complexes. In
many cases the exo-cycloadducts can be obtained in Keywords: asymmetric synthesis; azomethine ylides;
enantiomerically pure form just after simple recrys- dipolar cycloaddition; phosphoramidites; silver
Introduction
kenes are the most suitable dipolarophiles. Special
mention has been paid to nitroalkenes,[1h] which intro-
Since the first catalytic enantioselective 1,3-dipolar duces the versatile nitro group at the 4-position of the
cycloaddition (1,3-DC)[1] involving azomethine ylides pyrrolidine skeleton. Particularly, exo-4-nitroproli-
and electrophilic alkenes was described in 2002 using nates with a 2,5-cis-4,5-trans-configuration 1 have
chiral bisphosphine·silver(I)[2] and zinc(II)[3] com- been used as leukocyte function associated antigen-
plexes, a wide variety of silver and copper complexes 1 antagonists during a cancer evolution,[5] with impor-
have been mainly used for the diastereoselective syn- tant activity as inhibitors of a4b1-integrin-mediated
thesis of endo- and exo-prolinates, respectively. The hepatic melanoma metastasis and even for treatments
diastereo- and enantioselective generation of up to of other diseases.[6] More simple exo-nitroprolinates 2
four stereogenic centers in only one step enhanced have shown a high efficiency as organocatalysts in
the interest of many researchers also using chiral or- asymmetric aldol reactions (Figure 1).[7]
ganocatalysts, allowing the synthesis of polysubstitut-
ed pyrrolidines (including prolines) with many inter- employed as azomethine ylide precursors in the enan-
esting biological activities.[4]
tioselective 1,3-DC with nitroalkenes employing orga-
N-Arylideneamino esters 3 (Figure 2) have been
As 1,3-dipole precursors N-arylidene-a-amino nocatalysts and chiral metal complexes. In the first ex-
esters are generally used and electron-deficient al- ample, a chiral thiourea 5[8] catalyzed the 1,3-DC of
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Luis M. Castellꢀ et al.
Figure 3. Chiral privileged ligands.
Figure 1. Useful exo-nitroprolinates.
3,[16] we were surprised not to find any efficient 1,3-
a malonate derivative (3, R1 =CO2Et).[9] The major DC with b-nitroalkenes.[17] Only Fukuzawaꢅs group re-
contributions using a-amino esters derived imines ported a highly effective asymmetric cycloaddition
were achieved under the control of chiral Lewis using glycine-derived imino esters 4 (R1 =H) and ni-
acids[10] formed by copper(I) 6–9,[11] copper(II) 10,[12a] troalkenes catalyzed by silver(I)·thioclickferrophos
and 11[12b] gold(I) 12[13] and nickel(II) 13[14] complexes. complexes 14.[18]
These metal complexes showed preferential exo-ap-
In this article, we will report the first highly effi-
cient silver(I)-catalyzed enantio- and diastereoselec-
proaches[15] at their most favorable TS.
The only exception reported in all these examples tive 1,3-DC of imino esters 3 and nitroalkenes testing
is the employment of copper(II) pyridyl bis(imidazoli- privileged ligands such as (Sa)-Binap (15), (Sa)-Mono-
dine) 10 as chiral complex,[12a] which afforded the phos (16), and phosphoramidite 17 (Figure 3).
endo-adducts. Very interesting switchable systems are
catalysts of the type 7–9 by varying the electronic
properties of the aryl groups of the P atom of the Results and Discussion
chiral P,N-ferrocene ligands.[7,11b]
With all these precedents, and taking in account Initial studies for the cycloaddition of methyl benzyli-
that silver(I) is traditionally the most suitable cation deneglycinate (3a) and nitrostyrene with Binap (15)
[19]
to stabilize a metallodipole derived from imino esters and AgClO4 or Monophos (16) and AgClO4 as cat-
Figure 2. Imino esters 3 and 4, as precursors of stabilized azomethine ylides, and catalysts used for enantioselective 1,3-DC.
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Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates
Table 1. Optimization of the 1,3-DC between imino ester 3a and b-nitrostyrene.
Entry
Ligand
MX
Conversion [%][a]
exo/endo 18[b]
ee [%][c]
1
2
3
4
5
6
7
15
16
17
17
17
17
ent-17
17
17
AgClO4
AgClO4
AgClO4
AgOAc
AgOTFA
AgOBz
AgOBz
AgOTf
5
45
nd
nd
10
94
94
89
98
À96
96
99
54/46[d]
91/9
>95
>95
>95
>95
>95
>95
95
90/10[d]
70/30[d]
91/9
91/9
8
90/10[d]
89/11
9[e]
Cu(OTf)2
[a]
Unless otherwise specified: ligand (5 mol%), MX (5 mol%), 3a (0.2 mmol), b-nitrostyrene (0.2 mmol), Et3N (5 mol%) in
toluene (2 mL), room temperature for 17 h.
From the crude product, determined by H NMR (nd=not determined).
For the major exo-stereoisomer.
Other stereoisomers were detected in low proportions.
Ref.[12b]
[b]
[c]
[d]
[e]
1
alysts gave low conversions (Table 1, entries 1 and 2). HPLC using chiral columns and comparison with the
In the second case an equimolar mixture of endo/exo data obtained for the same known product.[12b]
adducts was obtained with very low ee for the result-
In order to gain a better understanding of these ex-
ing exo-compound 18a (Table 1, entry 2).[20] To our perimental results and, in particular, the origins of the
surprise, when the chiral complex formed between unexpected exo-selectivity found for the silver-cata-
(Sa,R,R)-17 and AgClO4,[21] related to the Cu(OTf)2 lyzed 1,3-DC described in Table 1, DFT calculations
complex 11,[12b] was used product exo-18a was ob- were performed. We selected the reaction of imino
tained with a 91/9 dr and 94% ee (Table 1, entry 3). ester 3a and b-nitrostyrene in the presence of
Other different silver salts were then evaluated in the (Sa,R,R)-17·AgOTf catalytic system as a model reac-
in situ generation of the corresponding 17·silver(I) tion. In previously reported computational works we
complex (5 mol% as optimal catalyst loading, 30 min, showed the importance of the counterion on the ob-
toluene at 258C). The difference between using silver served selectivity of the reaction.[12b,22] Therefore, we
acetate and silver trifluoroacetate (TFA) was very sig- included the OTf fragment in these calculations. The
nificant in terms of both diastereo- and enantioselec- most stable N-metallated complexes computed at the
tions (Table 1, compare entries 4 and 5). The highest ONIOM level of theory are depicted in Figure 4.
enantiodiscrimination (98% ee) was achieved by the Analogous previously reported copper(II) triflate
complex formed by phosphoramidite 17 or its enan- complexes 11 are also included for comparison.[12b]
tiomer and silver benzoate (Table 1, entries 6 and 7).
These calculations show that the metallic centers
In addition, the reaction performed with silver triflate are coordinated to both the nitrogen atom and the
gave a lower dr than the analogous reaction catalyzed carboxy group of the azomethine ylide, to the phos-
with silver perchlorate, but with slightly higher ee phorous atom of chiral ligand 17 and to an oxygen
(Table 1, entry 8), this result served us to compare atom of the triflate anion. Nevertheless, in both cases
this work with that already published involving cop- the coordination pattern is slightly different. Copper
per(II) triflate.[12b] A 99% ee of exo-18a with a slightly atom presents an almost regular tetrahedral environ-
lower dr (89/11) was obtained in this last example ment in which both prochiral faces are partially
(Table 1, entry 9).[12b]
blocked by the ligand or the triflate moiety. Calcula-
Several solvents such as DCM, Et2O, THF, and tions of the complete profile for the copper complex
MeOH, as well as other different bases like DIPEA, showed that the blockage by triflate is more effective
DABCO, DBU did not improve on the results ob- due to a Coulombic repulsion generated when the in-
tained by employing toluene as solvent and triethyl- coming dipolarophile approaches to the azomethine
A
ylide complex.[12b] On the other hand, silver com-
The absolute configuration of exo-cycloadduct 17a plexes present a trigonal pyramidal geometry in
was established according to the retention times in which the azomethine ylide, the silver atom and the
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Figure 4. Structures and relative energies (in kcalmolÀ1) of complexes derived from imine 3a and (A) (Sa,R,R)-17·Cu(OTf)2
and (B) (Sa,R,R)-17·AgOTf at M06/LANL2DZ//ONIOM(B3LYP/LANL2DZ:UFF)+DZPCE level of theory. High and low-
level atoms in ONIOM partitions are shown as ball & stick or tube representations, respectively. Light grey and dark gray
surfaces represent solvent accessible surface areas of the chiral ligand and the triflate counterion, respectively. The hollow
arrows show the preferential prochiral side of silver complexes.
oxygen of the OTf moiety are almost coplanar. In this the CF3 resonance is observed at d=À78.58 ppm.
case, only one of the prochiral faces is accessible, These results indicate that in the former case the tri-
namely the 2Si,5Re-face in the most stable ylide flate anion is closer to the copper(II) centre, whereas
[(Sa,R,R)-17·Ag-OTf-II].
in the latter case the average distance between Ag(I)
These computational results are compatible with and the triflate is longer, thus leaving one prochiral
19F NMR experiments on Cu(OTf)2 and AgOTf com- face less congested.[23]
plexes of (Sa,R,R)-17 and imine 3a in the absence of
In order to assess whether the OTf moiety remains
base. In the case of Cu(OTf)2, the 19F signals appear close to the silver atom along the reaction coordinate,
at d=À78.04 ppm, whereas in the presence of AgOTf we computed the hypothetical OTf-b-nitrostyrene ex-
Scheme 1. Reaction energy of the OTf–b-nitrostyrene exchange on the silver coordination sphere computed at M06/
LANL2DZ//ONIOM(B3LYP/LANL2DZ:UFF)+DZPCE level of theory.
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Figure 5. Main geometrical features and relative energies (in kcalmolÀ1) of transition structures associated with the first step
of the 1,3-DC reaction of imine 3a and b-nitrostyrene catalyzed by (Sa,R,R)-17·AgOTf. See caption of Figure 4 for additional
details. Distances are in ꢆ.
change on the metal coordination sphere to yield silver coordination sphere. It is noticeable that in the
À
(Sa,R,R)-17·Ag-RC (Scheme 1). These results show endo-approaches, there is a lengthening of the P Ag
that this process is endergonic, and no OTf-b-nitro- distance of about 1 ꢆ compared to their exo-ana-
styrene exchange occurs during the reaction. There- logues. Moreover, the effective blockage of one pro-
fore, no stabilizing endo interaction between the chiral face by the (Sa,R,R)-17·AgOTf catalytic system
silver and the nitro group can be expected along the is pointed out by the energetic difference of 3.8 kcal
reaction path.
molÀ1 between (S,S)-TS1-exo-18a and (R,R)-TS1-exo-
We also located the transition structures corre- 18a in favor to the former one. This energetic differ-
sponding to the first step of the selected 1,3-DC reac- ence means a theoretical eeexo of about 99%, in good
tion. The main geometric features and relative ener- agreement with the experimental results.
gies of the least energetic transition structures are col-
lected in Figure 5.
The complete reaction mechanism that yields the
product exo-18a was also studied. The energetic pro-
The computed transition structures correspond to file and the main geometrical features of the second
a stepwise mechanism[24] in which the first step con- transition structure (S,S)-TS2-exo-18 are depicted in
sists of a Michael addition of the enolate moiety in Figure 6.
the N-metallated azomethine ylide to b-nitrostyrene
The computed activation barrier associated with
forming a zwiterionic intermediate (S,S)-INT1 that the second step was lower than the one associated to
undergoes an intramolecular Mannich-like reaction to the first step by ca 5 kcalmolÀ1. It is noteworthy than
yield the final cycloadduct (vide infra). Our results the formation of the major complexed cycloadduct is
show the predicted preference of the exo-approaches thermodynamically disfavored. The driving force that
over the endo-ones due to the presence of OTf on the ensures the completion of the catalytic cycle is the
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Figure 6. Main geometrical features of the second transition structure and relative energies (in kcalmolÀ1) associated with
the 1,3-DC reaction of imine 3a and b-nitrostyrene catalyzed by (Sa,R,R)-17·AgOTf. See caption of Figure 4 for additional
details. Distances are in ꢆ.
1
final equilibrium between the complexed and released product determined by H NMR), (Table 2, entries 1
(3+2) cycloadducts exo-18a, that is highly exothermic and 2). In consequence, the study of the scope of the
[Erxn (3)=11.8 kcalmolÀ1] thus ensuring the recovery reaction was done with methyl esters as precursors.
of the reactive ylide complex.
The variation of the aryl substituent of the dipolar-
The scope of the reaction was made with different ophile induced higher chemical yields, exo-diastereo-
nitroalkenes, a-amino esters and benzylideneimino selectivties and enantioselections in products 18 when
esters (Scheme 2 and Table 2). Parallel studies were the reactions occurred in the presence of (Sa,R,R)-
carried out for the reaction performed with ligand 17 17·AgOBz rather than with the triflate derivative
and AgOTf or AgOBz. Firstly, the influence of an iso- (Table 2, entries 3–7). In particular, the heteroaromat-
propyl instead of a methyl ester showed almost identi- ic moiety bonded to the nitro component (2-furyl)
cal ee for the two silver complexes with a slightly was more appropriate for the system built with the
better exo-diastereoselection for the isopropyl ester. chiral silver benzoate complex achieving 77% of
However, the lower yield of the exo/endo mixture ob- chemical yield and 98% ee of exo-18h (Table 2,
tained in the case of the reaction with isopropyl ester entry 8). In general, better results were observed with
obeyed to the appearance of a proportion of other (Sa,R,R)-17·AgOBz than with Cu(OTf)2.[12b] When the
unidentified diastereoisomers (ca. 28% from crude nitroalkene incorporated an aliphatic cyclohexyl
group a reversal diastereoselectivity was observed in
the 17·AgOTf-catalyzed 1,3-DC. The exclusive endo
isomer was isolated in 71% yield but as a racemic
mixture. However, an equimolar mixture of endo/exo
diastereoisomers in 75% overall yield in the analo-
gous reaction performed with AgOBz. Again, the
adduct endo-18i was isolated as a racemate, whilst the
exo-isomer 18i was obtained in low 32% yield but
with a 96% ee (Table 2, entry 9). On the other hand
the 1,3-DC with this nitroalkene failed with the
Cu(OTf)2 complex 11.[12b]
When alanine, leucine, and phenylalanine derived
imino esters were employed as azomethine ylide pre-
cursors, an increment of the endo-diastereoisomer
was observed. Chemical yields were moderate to
Scheme 2. Scope of the diastereo- and enantioselective 1,3-
DC between imino esters 3 and nitroalkenes catalyzed by
(Sa,R,R)-17·AgOBz or (Sa,R,R)-17·AgOTf.
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Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates
Table 2. Scope of the diastereo- and enantioselective 1,3-DC between imino esters 1 and nitroalkenes catalyzed by (Sa,R,R)-
17·AgOBz or (Sa,R,R)-17·AgOTf.[a]
(Sa,R,R)-17·AgOTf
(Sa,R,R)-17·AgOBz
Entry Ar
R1 R2 R3
18
exo/endo[b] Yield [%][c] ee [%][d] exo/endo[b] Yield [%][c] ee[d] [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
Me Ph
Pri Ph
18a 90/10[e]
18b 98/2[e]
80 (65)
69 (51)
52 (41)
74 (60)
64
96 (99)
96 (99)
89 (99)
97 (99)
94
91/9
88
70 (54)
92
88
76
99
96 (99)
98
99
90
93/7[e]
93/7
Me 4-MeC6H4 18c 70/30[e]
Me 4-FC6H4
Me 2-BrC6H4 18e 76/24[e]
Me 3-BrC6H4 18f
81/19[e]
Me 4-BrC6H4 18g 85/15[e]
Me 2-furyl
Me C6H11
18d 89/11[e]
92/8
91/9[e]
81/19[e]
82/18
84/16
50/50
27/73
35/65
50/50[e]
75/25[e]
87/13
88/12[e]
90/10
88/12
94/6[e]
80/20[e]
61
56
50
86
98
92
61
77
77
92
97
98
18h 68/32[e]
[g]
9
18i
1/99
71[f]
14[d] 63[f]
46
–
33[d] 42[e]
21[d] 69[f]
21[d] 53[f]
33[d] 33[f]
56
96[g]
92[g]
98[g]
99[g]
90
10
11
12
13
14
15
16
17
18
19
Me Me Ph
Bui Me Ph
Bn Me Ph
H
H
H
H
H
H
H
18j
21/79[e]
87[g]
97
18k 92/8[e]
18l
54/46[e]
42[d] 40[f]
33
98[g]
82
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-(MeO)C6H4
4-FC6H4
4-BrC6H4
2-naphthyl
Me Ph
Me Ph
Me Ph
Me Ph
Me Ph
Me Ph
Me Ph
18m 56/44[e]
18n 76/24[e]
18o 94/6[e]
18p 93/7[e]
18q 88/12[e]
65
79
81
72
77
70
88
92
96
99
99
85
79 (66)
60
75
83
83
81 (90)
94
92
92
98
18r
18s
91/9[e]
86/14[e]
66
75
[a]
To chiral phosphoramidite 17 (0.05 mmol) and AgOTf (0.05 mmol) in dry toluene (3 mL) under an argon atmosphere was
added a solution of imino ester (1 mmol) and nitroalkene (1 mmol) in toluene (5 mL). To the resulting suspension triethyla-
mine (0.05 mmol, 7 mL) was added and the mixture stirred at room temperature (20–308C) for 16–24 h.
From the crude product, determined by H NMR.
Isolated yield (for the exo-adduct) after purification by flash chromatography. In brackets yields of the recrystallized exo-
products.
For the exo-stereoisomer (HPLC). In brackets ee of the recrystallized samples.
Other stereoisomers were detected in noticeable proportions.
For de of endo-18 isomer.
[b]
[c]
1
[d]
[e]
[f]
[g]
The endo-18 isomer was obtained as a racemic mixture.
good, maintaining a very high enantioselection for the arenes also provided high diasteresoselections, good
exo-adducts 18j–l (up to 99% ee). Higher amounts of chemical yields and excellent enantioselections of
other different diastereoisomers were identified in the compounds 18p–r (Table 2, entries 16–18) under the
1
crude reaction H NMR spectra when these a-substi- presence of both of the chiral silver(I) complexes and
tuted imino esters were used (Table 2, entries 10–12). with better results than with Cu(OTf)2. Finally in the
However, in the case of the Cu(OTf)2 complex 11, the case of the 2-naphthyl substituent, exo-18s was ob-
alanine derivative failed and in the case of leucine tained with up to 72% de and 85% ee when AgOTf
similar results were obtained as with AgOTf. On the was used, i.e., better results than with Cu(OTf)2 and
other hand, for the phenylalanine imino ester the AgOBz (Table 2, entry 19).
Cu(OTf)2 catalyst 11 was better than the silver salts
The selective isolation of Michael-type addition
compound 20 was possible by performing the reaction
ones giving 18l in 51% yield and 98% ee.[12b]
With respect to the use of different methyl benzyli- at lower temperatures followed by an acidic-basic
deneiminoglycinates The more sterically hindered treatment. This fact also supports the existence of
ortho-tolyl imino group also favored the generation of a stepwise mechanism. The syn-diastereoselection was
the endo-isomer 18m but in less proportion in the observed when silver benzoate was employed whilst
case of AgOBz than with Cu(OTf)2. On the other the reaction in the presence of silver triflate failed. A
hand, the exo-18m was obtained in an ee up to 90% comprehensive study of the reaction conditions is re-
with AgOBz compared with 54% ee for Cu(OTf)2 ported in Table 3, obtaining the best results at À808C
(Table 2, entry 13). It seems that the lower the steric (Table 3, entry 6). At this temperature equimolar
repulsion the higher are the proportion of exo-adduct amounts of compounds 18a and syn-20a were generat-
and the enantioselection. This effect can be observed ed. Cyclic product 18a was obtained in 91:9 exo:endo
in the series of ortho-, meta-, and para-tolyl substitu- ratio and 98% ee in 40% yield and the desired Mi-
ents (Table 2, entries 13–15). Other 4-substituted
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Table 3. Temperature dependent cycloadduct 18a/Michael type adduct syn-20 ratio.
18a
20a
[b]
[b]
Entry
Temperature [8C]
18a/19
exo/endo[a]
erexo
Yield[c] [%]
syn/anti[a]
ersyn
1
2
3
4
5
6
24
10
0
À40
À60
À80
>99:1
93:7
88/12
72/28
63/37
50/50
89/11
89/11
89/11
89/11
90/10
91/9
99:1
99:1
99:1
99:1
99:1
99:1
–
–
–
–
33
40
–
–
>99/1
>99/1
>99/1
>99/1
>99/1
98:2
98:2
98:2
98:2
98:2
[a]
1
From the crude product, determined by H NMR. Other stereoisomers were detected in low proportions.
Determined by HPLC using chiral columns.
Isolated yield of the syn-isomer 20a after flash chromatography (SiO2).
[b]
[c]
chael-type adduct syn-20a was isolated in 40% yield oped by Cossyꢅs group.[26] Thus, nitroalcohol 22a
as a unique diastereoisomer and with a 98:2 er. (non-purified) was obtained as an optically pure com-
We next focused our attention on a series of nitro- pound, in almost quantitative yield, after reduction
piperidines 21, which are potent farnesyltransferase with NaBH4/Na(AcO)3BH.[27] Finally, product 23a
inhibitors with promising antitumoral activity.[25] We could be synthesized in 77% overall yield by forming
envisaged that these products 21 can be accessed the tertiary amine with benzyl bromide and mesyla-
through the enantiomerically enriched proline deriva- tion of the primary alcohol, the corresponding ring
tives 18 by a ring-expansion of their cyclic b-amino al- expansion taking place with complete retention of the
cohol derivatives following the methodology devel- configuration (Scheme 3).
Conclusions
We have demonstrated in this work the efficiency of
chiral phosphoramidite·silver(I) salts to obtain dia-
stereo- and enantioselectively exo-nitroprolinates
through an unusual exo-1,3-DC of azomethine ylides
and nitroolefins. The reactions using methyl imino
esters resulted to be much more clean and efficient
and the scope of the reaction was very high. AgOBz
and AgOTf derived chiral complexes are the best cat-
alysts. However, for the Michael-type reaction only
the AgOBz derived complex was effective at À808C.
These exo-nitroprolinates are appropriate precursors
of potential farnesyltransferase inhibitiors by stereo-
specifice ring expansion.
Calculations demonstrated the blocking effect of
the triflate anion over one prochiral face such as oc-
curred in the precedent 1,3-DC copper(II)-catalyzed
Scheme 3. Synthetic approach to the potential farnesyltrans-
ferase inhibitor 23a from enantiomerically enriched exo-ni-
troprolinate 18a.
8
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Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates
To
a solution of the amino alcohol 22a (40 mg,
reactions reported by us. Also, the interchange of the
triflate anion by the nitro group in the reaction inter-
mediate was not energetically favored at all.
0.134 mmol) in CH2Cl2 (2 mL), BnBr (20 mL, 0.162 mmol)
and Et3N (38 mL, 0.268 mmol) were successively added. The
reaction mixture was stirred under reflux for 16 h before
being cooled. Then solvent was evaporated under reduced
pressure. The crude was purified by flash chromatography
(hexane/EtOAc 95/5 to 70/30) to afford the tertiary amine
which was dissolved in CH2Cl2 (5 mL) at 08C. Et3N (77 mL,
0.5 mmol) and mesyl chloride (35 mL, 0.44 mmol) were care-
fully added in this order. After stirring at reflux for 5 h,
H2O was added to the reaction mixture. Then the aqueous
phase was extracted with CH2Cl2 and the organic layer dried
with MgSO4, filtered, and concentrated under reduced pres-
sure. After purification by flash chromatography on silica
gel (hexane/EtOAc 95/5 to 70/30) 23a was isolated as yellow
oil; yield: 42 mg (77%).
Experimental Section
For experimental details, please see the Supporting Informa-
tion.
General Procedure for the 1,3-Dipolar Cycloaddition
of Imino Esters and Dipolarophiles
To a solution of the chiral phosphoramidite 17 (0.05 mmol)
and AgX (0.05 mmol) in dry toluene (3 mL) under an argon
atmosphere was added a solution of imino ester (1 mmol)
and nitroalkene (1 mmol) in toluene (5 mL). To the result-
ing suspension triethylamine (0.05 mmol, 7 mL) was added
and the mixture stirred at room temperature (20–308C) for
16–24 h (see main text). The crude reaction mixture was fil-
tered through a small Celite pad. The residue was purified
by flash chromatography yielding pure exo-cycloadducts.
Solid products were recrystallized in mixtures of n-hexane/
ether.
Acknowledgements
This work has been supported by the Spanish Ministerio de
Ciencia e Innovaciꢀn (MICINN) (Consolider INGENIO
2010 CSD2007-00006, CTQ2010-20387), FEDER, Generali-
tat Valenciana (PROMETEO/2009/039abd PROMETEOII/
2014/017), and by the University of Alicante. L. M. C. thanks
the MICINN for an FPI fellowship. Financial support was
provided by the MICINN and FEDER (projects CTQ2010-
16959/BQU, and Consolider-Ingenio CSD2007-00006), the
University of the Basque Country (UPV/EHU, UFI11/22
QOSYC), the Basque Government (GV/EJ, grant IT-324-07).
The authors thank the SGI/IZO-SGIker UPV/EHU and the
DIPC for generous allocation of computational resources.
General Procedure for the Synthesis of Michael-Type
Addition Product syn-20a
A solution of phosphoramidite (0.05 mmol) and Cu(OTf)2
(0.05 mmol) in dry toluene (3 mL) was stirred for one hour
prior to introduction of the resulting colorless solution in
a Dewar flask at À808C. After 15 min a solution of imino
ester 3a (326 mg, 1 mmol) and nitrostyrene (149 mg,
1 mmol) in dry toluene (5 mL) was added and the reaction
mixture was stirred over a period of 10 min. Then, triethyl-
ACHTUNGTRENNUNGamine (0.05 mmol) was added and the mixture was stirred at
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Michael product was extracted with ethyl acetate. The or-
ganic layers were combined, dried over MgSO4 and concen-
trated under reduced pressure affording pure compound
syn-20a.
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10
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ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!

FULL PAPERS
Efficient Diastereo- and Enantioselective Synthesis of exo-
Nitroprolinates by 1,3-Dipolar Cycloadditions Catalyzed by
Chiral Phosphoramidite·Silver(I) Complexes
11
Adv. Synth. Catal. 2014, 356, 1 – 11
Luis M. Castellꢀ, Carmen Nꢁjera,* Josꢂ M. Sansano,*
Olatz LarraÇaga, Abel de Cꢀzar, Fernando P. Cossꢃo*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢄ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
These are not the final page numbers!