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Stereocontrolled Nucleophilic Additions of Lithiated Heterocycles to Nitrones. Synthesis and Structural Characterization of Novel Chiral (Hydroxyamino)methyl Heterocycles

Pedro Merino, Santiago Franco, Inmaculada Martínez, Francisco L. Merchan and Tomas Tejero

http://wzar.unizar.es/acad/fac/cie/quiorg/MTM.html Departamento de Quimica Organica, ICMA, Facultad de Ciencias, Universidad de Zaragoza,E-50009 Zaragoza, Aragon,Spain

INTRODUCTION

Nucleophilic addition of metalated heterocycles to C=X p bonds is a simple and common synthetic operation, and development of a chiral version leading to optically active compounds is obviously desiderable (Scheme 1) because of the broad range of biological activity possessed by these heterocyclic compounds[1]  and their versatility as key synthetic intermediates[2]. A variety of heterocyclic systems including oxazolines[3], benzotriazole[4], furan[5] and thiazole[6] can be used as synthetic equivalents of several functionalities such as formyl and carboxyl groups.

 
Scheme 1
    Several work has been devoted to the nucleophilic addition of metalated heterocycles to chiral aldehydes[7] and imines[8]. Despite good results with simple substrates, the stereodifferentiation is often inadequate since a total stereocontrol of the addition reaction is difficult to achieve. Over the last years we have concerned with the addition of metalated heterocycles such as thiazole[9] or furan[10] over several a-alkoxy-[11] and a-amino nitrones[12]. These studies led us to develop new methodologies which have been successfully applied to the synthesis of several compounds with biological interest[13].
    Chiral nitrones have shown to be excellent substrates for stereocontrolled nucleophilic additions by using Lewis acids as precomplexing agents[14], and the addition products, chiral hydroxylamines, can be versatile intermediates for a variety of synthetic targets[15]. Thus, we have chosen to investigate the reaction between nitrones and metalated heterocycles.
 
RESULTS AND DISCUSSION
 
    The readily available N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN)[16] 1 was chosen as a substrate, and several lithiated heterocycles, prepared as described[17], were used as nucleophiles (Scheme 2). Previous and new results of Table 1 point out quite clearly the different facial diasteroselection of the nucleophilic addition of lithiated heterocycles 2-8 to nitrone 1. Invariably, when the reaction was carried out in the absence of any additive the syn adducts were obtained as the major products. In contrast, when nitrone 1 was previously treated with 1.0 equivalent of Et2AlCl prior to the addition, the anti adducts were obtained predominantly. Both chemical yield and diastereoselectivity were high in all cases (see Table 1) and reproducibility was tested by carrying out the reaction twice or three times. Mixtures of hydroxylamines, when obtained, were easily separated by column chromatography and invidual pure isomers could be obtained.
Scheme 2
 
Table 1 Stereoselective addition of lithiated heterocycles to BIGN 1
 Het-     additive   syn : anti   yield (%)   major adduct   [a]D (c, CHCl3)    mp (°C)  
none 
Et2AlCl		 92 : 8 
3 : 97		 82 
84		 9a 
9b		 -7.8 (0.74) 
-9.0 (0.39)		 oil 
157-159
none 
Et2AlCl		 94 : 6 
5 : 95		 98 
94		 10a 
10b		 -28.9 (0.79) 
-13.2 (1.00)		 oil 
119-120
  none 
Et2AlCl		 88 : 12 
21 : 79		 81 
76		 11a 
11b		 +17.2 (1.50) 
-14.2 (0.88)		 103-105 
118-120
  none 
Et2AlCl		 >95 : 5 
22 : 78		 90 
86		 12a 
12b		 -24.9 (0.41) 
-14.6 (0.32)		 117-119 
126-128
  none 
Et2AlCl		 94 : 6 
25 : 75 		 83 
86		 13a 
13b		 -25.7 (0.36) 
-31.2 (0.40)		 153-155 
188-190
  none 
Et2AlCl		 >95 : 5 
>5 : 95		 91 
83		 14a 
14b		 -30.4 (0.26) 
-22.3 (0.41)		 129-131 
97-99
  none 
Et2AlCl		 >95 : 5 
30 : 70 		 88 
84		 15a 
15b		 -35.2 (0.30) 
-22.3 (0.60)		 102-104 
127-129
 
 MECHANISTIC CONSIDERATIONS
 
    Te results of the reactions summarized in Table 1 are not surprising from the mechanistic point of view, if one considers previous precedents of additions to BIGN 1. According to our previous results and studies, the observed syn selectivity in the absence of chelating agents can be predicted by the Houk open-chain model A. As we demonstrated by means of semiempirical calculations, other models should be disfavoured in the cases examined.
    In striking contrast to these results, the addition in the presence of 1.0 equiv of Et2AlCl leads to the anti isomers as major products with stereochemical outcome apposite to that predicted by model A. The anti selectivity, could be explained by assuming a b-chelate model B which should be favoured by the complexing ability of Et2AlCl.
 
 
 
 STRUCTURAL CHARACTERIZATION
    With two exceptions only (furan and benzothiophene), the absolute stereochemical outcome for each reaction was determined by X-ray crystallographic analyses. The stereochemical assignements for furfurylhydroxylamines 10 were ascertained previously[18] and assuming that the probability of a total reversal of the stereochemical progress of the reaction as a result of the changes made is small we tentatively assigned the syn and anti configuration to the hydroxylamines 15a and 15b, respectively. Accompanying 3D models show the crystal structures of the hetarylmethyl hydroxylamines studied by X-ray diffraction, and Table 2 compares the most relevant structural parameters of those compounds.
 
Table 2. Comparison of selected bond distances (Å) and bond angles (°) according to the following numbering scheme: 
9b
11a
12a
13a
14a
N1-O1
1.458(13)
1.445(5)
1.450(3)
1.47(2)
1.492(6)
C1-C2
1,53(2)
1.493(7)
1.510(4)
1.53(2)
1.500(9)
C2-C3
1.56(2)
1.524(7)
1.-522(4)
1.51(2)
1.510(8)
C3-C4
1.60(2)
1.507(7)
1.505(4)
1.49(2)
1.521(9)
O2-C3
1,47(2)
1.423(6)
1.431(3)
1.41(2)
1.412(7)
O3-C4
1.40(2)
1.398(6)
1.437(4)
1.43(2)
1.361(9)
O2-C5
1.45(2)
1.415(6)
1.427(3)
1.45(2)
1.430(11)
O3-C5
1.40(2)
1.413(7)
1.436(3)
1.42(2)
1.414(8)
N1-C8
1.482(14)
1.460(6)
1.471(4)
1.44(2)
1.453(8)
N1-C2
1.53(2)
1.455(6)
1.476(4)
1.49(2)
1.480(8)
C1-C2-C3
109.1(14)
112.2(4)
110.2(2)
112.1(16)
108.7(6)
C1-C2-N1
107.2(13)
108.4(4)
116.3(2)
113.9(14)
106.8(5)
O1-N1-C8
108.2(11)
106.5(4)
105.4(2)
108.3(14)
101.5(5)
N1-C2-C3
107.2(13)
108.1(4)
110.7(2)
111.1(14)
113.1(5)
 
     Trelevant data for the crystal-structure analyses are summarized in Table 3. The data were collected on a Siemens P4 diffractometer with graphite monochromated Mo-Ka radiation (l = 0.71073), using q-2q scan mode. All reflections were corrected for Lorentz and polarization effects; no correction for absorption was considered. All the structures were solved by direct methods of SHELXS-86[19] and refined by full-matrix least-squares on F2 using SHELXL-93 program[20]. The hydrogen atoms were located in calculated positions riding on the attached carbon atoms. The absolute configuration was not considered on the basis of the known (S)-configuration of the nitrone 1 at the only chiral center. All calculations were carried out on a VAX-alpha computer of the "Instituto de Ciencia de Materiales de Aragon (ICMA,Zaragoza, Spain)". In addition to the above programs, CrystalDesignerTM and Chem3DTM were used for the study of the geometrical aspects of the crystal and molecular structures.
 
 
Table 3. Experimental data for the X-ray analyses 
9b
11a
12a
13a
14a
Formula C16H20N2O3S  C17H23N3O3 C17H21NO3S C20H22N2O3S   C21H23NO4
M
320.40
317.38
319.41
370.46
 353.40
space group
P61
P212121
P32
P21
P212121
a (Å)
9.818
8.388
9.6530
8.563
5.926
b (Å)
9.818
10.527
9.6530
11.992
15.487
c (Å)
30.981
19.730
15.683
9.865
20.413
V (Å3)
2986.4
1742.2
1265.6
959.0
1873.4
Z
6
4
3
2
4
Dx (Mg m-3)
1.197
1.210
1.257
1.283
1.253
reflections for lattice paramete (No.)
40
62
39
32
40
q range (°)
9-14
6-25
10-25
10-24
10-21
F (000)
1020
680
510
392
752
m
0.195
0.084
0.203
0.190
0.087
No. of measured reflections
3191
1822
1735
2194
5633
No. of unique reflections
1243
1659
1311
1816
4974
R (int)
0.1573
0.0196
0.0168
0.1219
0.0769
No. of reflections used (N)
1243
1659
1311
1812
4974
No. of reflections with I > 2s(I)
393
1120
1275
649
1360
No. of refined parameters (P)
200
216
204
240
241
Extinction parameter (SHELXL), q
0
0.011
0
0.0252
0.007
wR2 = [Sw(DF2)2/Sw(Fo2)2]1/2
0.0540
0.1009
0.0690
0.1523
0.1915
wR2 for all data
0.0886
0.1225
0.0699
0.2625
0.2860
S2 = [Sw(DF2)2/(N-P)]1/2
1.391
1.043
1.066
1.027
0.0936
R1 = S*DF*/S*Fo* for I > 2s(I) 
0.0566
0.0465
0.0276
0.0843
0.0962
R1 for all data
0.2451
0.0853
0.0288
0.2666
0.3183
g (w=1/[s2(Fo2)+(g(Fo2+2Fc2)/3)2] 
0.0098
0.0503
0.0395
0.0677
0.1048
standard decay (%)
9.66
3.70
4.60
10.06
7.33
 
 
 CONCLUSIONS

    Oearlier studies dealing with the addition of 2-lithiothiazole and 2-lithiofuran to nitrones has been extended to other lithiated heterocycles. The absence/presence of Et2AlCl induces a dramatic change in the stereochemistry of the reaction, and chiral syn and anti heterocycle-containing hydroxylamines can be prepared in a stereocontrolled way.
    Application of this technology to the synthesis of various heterocyclic compounds now becomes of interest, and further synthetic applications of the obtained products are under investigation in our laboratory.
 

Acknowledgements

Financial support from MEC (CICYT, Madrid, Spain) is gratefully acknowledged. One of us (S.F.) also thanks MEC for a contract. We are also indebted to the University of Zaragoza for technical support concerning WWW tools.

References

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 [7]  See for instance: (a) Tsutsumi, S.; Okonogri, T.; Shibahara, S.; Ouchi, S.; Hatsushiba, E.; Patchett, A.A.; Christensen, B.G. J. Med. Chem. 1994, 37, 3492-3502. (b) Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Togo, H. J. Chem. Soc. Perkin Trans. 1, 1997, 29-33. (c) Hodges, J.C.; Patt, W.C.; Connolly, C.J. J. Org. Chem. 1991, 56, 449-452. (d) Reetz, M.T.; Holdgrun, X. Heterocycles, 1989, 28, 707-710.

 [8] (a) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev. 1995, 95, 1677-1716. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Merino, P. unpublished results.

 [9]  (a) Dondoni, A.; Junquera, F.; Merchan, F.L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1992, 33, 4221-4224. (b) Dondoni, A.; Franco, S.; Merchan, F.L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1993, 34, 5475-5478.

 [10]  (a) Dondoni, A.; Franco, S.; Merchan, F.L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1993, 34, 5479-5482. (b) Dondoni, A.; Junquera, F.; Merchan, F.L.; Merino, P.; Tejero, T. Synthesis, 1994, 1450-1456.

[11] (a) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.L.; Merino, P.; Tejero, T.; Bertolasi, V. Chem. Eur. J. 1995, 1, 505-520. (b) Dondoni, A.; Junquera, F.; Merchan, F.L.; Merino, P.; Scherrmann, M.-C.; Tejero, T. J. Org. Chem. 1997, 62, 5484-5496.

 [12]  (a) Lanaspa, A.; Merchan, F.L.; Merino, P.; Tejero, T.; Dondoni, A. Electronic Conference on Trends in Organic Chemistry (ECTOC-1). Rzepa, H.S.; Goodman, J.C. (Eds.). CD-ROM. Royal Societry of Chemistry Publications. 1995. ISBN 0-85404-899-5.(b) Merino, P.; Lanaspa, A.; Merchan, F.L.; Tejero, T. Electronic Conference on Trends in Organometallic Chemistry (ECTOC-3). Rzepa, H.S.; Leach, C. (Eds.). CD-ROM. Royal Societry of Chemistry Publications. 1997. ISBN 0-85404-889-8.

 [13]  (a) Dondoni, A.; Franco, S.; Merchan, F.L.; Tejero, T. Synlett 1993, 78-80. (b) Dondoni, A.; Junquera, F.; Merchan, F.L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1994, 35, 9439-9442. (c) Dondoni, A.; Junquera, F.; Merchan, F.L.; Merino, P.; Tejero, T. Chem. Commun. 1995, 2127-2128.

[14] (a) Merino, P.; Anoro, S.; Castillo, E.; Merchan, F.L.; Tejero, T. Tetrahedron: Asymmetry 1996, 7, 1887-1890. (b) Merino, P.; Castillo, E.; Merchan, F.L.; Tejero, T. Tetrahedron: Asymmetry 1997, 8, 1725-1729. (c) Merino, P.; Franco, S.; Merchan, F.L.; Tejero, T. Trends Org. Chem. 1998 (in press).
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