Diastereoselective synthesis of 3-amino-1,2-diols by reductive alkylation of 2,3-dialkoxynitriles

Article abstract of DOI:10.1016/S0040-4039(00)00202-1

The addition of Grignard reagents to acetonide protected syn 2,3- dihydroxynitriles, followed by reduction of the resulting magnesioimines, affords all syn 1,3-disubstituted 3-amino-1,2-diols in high enantiomeric purities. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00202-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2369–2372
Diastereoselective synthesis of 3-amino-1,2-diols by reductive
alkylation of 2,3-dialkoxynitriles
Pierre Hutin and Marc Larchevêque ∗
Laboratoire de Synthèse Organique associé au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 8 December 1999; accepted 26 January 2000
Abstract
The addition of Grignard reagents to acetonide protected syn 2,3-dihydroxynitriles, followed by reduction of the
resulting magnesioimines, affords all syn 1,3-disubstituted 3-amino-1,2-diols in high enantiomeric purities. © 2000
Published by Elsevier Science Ltd. All rights reserved.
Keywords: aminoalcohols; cyanohydrins; Grignard reagents; diastereoselection.
The stereocontrolled synthesis of aminoalcohols and aminodiols have attracted much interest in recent
years because these core units are implicated in the synthesis of various biologically active molecules
such as proteases inhibitors,1 glycosphingolipides2 or polyhydroxylated nitrogen heterocycles.3
These may be prepared by opening of an epoxyalcohol with a nitrogen nucleophile,4 a reaction which
regioselectivity is sometimes difficult to control, or by the stereocontrolled addition of organometallic
reagents to imines and related compounds derived from protected polyhydroxylated aldehydes.5
We wish to report here a method which allows the stereoselective synthesis of all syn 1,3-disubstituted
3-amino-1,2-diols in high enantiomeric purity by reductive alkylation of syn 2,3-dialkoxynitriles.
In contrast with simple aliphatic nitriles, which are partially deprotonated in the α position by Grignard
reagents, the α-alkoxy nitriles give the addition only, a reaction which allows the synthesis of α-alkoxy
ketones after acidic hydrolysis. Starting from α-silyloxy nitriles, the reduction of the intermediate imines
by sodium borohydride allowed the access to anti 1,2-aminoalcohols in good diastereoselectivity.6 Very
recently, the sequential addition of Grignard and organocerium reagents to dialkoxynitriles was applied
to the synthesis of α,α-disubstituted α-amino acids.7
We thought that by using the acetonide protected syn 2,3-dihydroxynitriles 1, the synthesis of which
we have recently described,8 it would be possible to stereoselectively synthesize protected aminodiols
such as 2 or 3 (Scheme 1).9
∗
Corresponding author. Fax: (33) 1 43 25 79 75; e-mail: larchm@ext.jussieu.fr (M. Larchevêque)
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00202-1
tetl 16482

2370
Scheme 1.
However, due to the presence of two oxygen atoms, it was difficult to predict a priori the stereoselec-
tivity of this reaction. Indeed it is well known that the stereoselectivity of the addition of organometallic
compounds to diprotected derivatives of glyceraldehyde,10 or to the corresponding imines,5 is highly
dependent on the protecting groups.
First attempts were achieved with the unsubstituted nitrile 1a which was prepared in nearly quantitative
yield from the corresponding ester by transformation into primary amide (NH3–EtOH, 25°C, 2 days)
followed by dehydration with cyanuric chloride.11 The condensation of n-BuMgBr in ether, followed by
NaBH4 reduction of the resulting imine, afforded the corresponding amine as a 30:70 mixture of syn
and anti diastereomers (Table 1). After transformation into the N-Boc compounds 4aA and 5aA, the
stereochemistry of the major diastereomer was determined by GC, according to the results previously
observed during the reductive amination of the corresponding ketones.12 We were unable to increase
this diastereomeric ratio regardless of the reducing agent we used (L-selectride, Red-Al®, LiAlH4,
BH3–THF). Moreover, when using zinc borohydride, we observed an inversion of stereochemistry
leading to compounds 2aA and 3aA with a 60:40 ratio.
Table 1
Reductive alkylation of nitriles 1
We then turn our attention toward the substituted nitriles 1b–f. When using Grignard reagents in ether13
and sodium borohydride as reducing agent, we obtained mainly the all syn aminodiols 2 in addition to
a small amount of their stereoisomers 3, as shown by NMR analysis (Table 1). After protection of the
amino group, the two diastereomers were easily separated to give the compounds 4 and 5 in good yields.14
Moreover, this separation was facilitated by the fact that, in all cases, the all syn isomer 4 was eluted first.
The best results were obtained using sodium borohydride as a reducing agent in presence of methanol.

2371
However, it was also possible to reduce the magnesium salt directly with zinc borohydride in ether but,
in this case, the diastereomeric excess was lowered.
The relative configuration of compounds 4dB, 4eD and 4dD was determined after deprotection of the
diol moiety and its oxidative cleavage, followed by esterification of the resulting N-Boc amino acids using
diazomethane (Scheme 2). The specific rotations of compounds 6 allowed us to determine the absolute
configuration of the carbon in position 3, according to the values found in literature for Boc-L-Val-OMe
and Boc-L-Phe-OMe.
Scheme 2.
This configuration was confirmed using chiral GC by comparison of compounds 6 with authentic
samples of L- and racemic Boc-Val-OMe and Boc-Phe-OMe.15 These amino esters were found to be
enantiomerically pure by these methods.
The configuration of the other compounds of structure 4 was determined by 1H and 13C NMR on the
basis of the differences observed between 4dB, 4eD, 4dD and their respective diastereomer 5. In all cases,
the proton attached to the nitrogen atom was found in CDCl3 at lower field for the all syn diastereomer
4 (δNH(4)–δNH(5)=0.5–0.9 ppm)). Moreover, the coupling constant between H-2 and H-3 was smaller
for compounds 4 (0.6–1.0 Hz) than for their diastereomers 5 (7.3–9.3 Hz). In 13C NMR, the carbon C-3
appeared also clearly at higher field for the all syn compounds (δC-3(4)–δC-3(5)≥−3 ppm).
The stereoselectivity observed may be explained by a competition between an α- and a β-chelation.
Indeed, after addition of the Grignard reagent, the magnesium atom of the magnesioimine may be
chelated to the oxygen in position α or β. The formation of the α-chelate is probably disfavoured by the
steric hindrance between the R1 and the R2 groups when R1 is not a hydrogen (Scheme 3). Moreover, in
the β-chelate, a C–O bond is perpendicular to the C_N plane. In such case, according to the Felkin–Ahn
model, the resulting overlap between the π*CN and the σ*CO orbitals leads to a more electrophilic imine
by lowering the LUMO energy.
Scheme 3.
However, given that methanol was added before sodium borohydride, it must be pointed out that
the true nature of the intermediate (i.e. magnesioimine or free imine) is not clearly defined. So, the
stereoselectivity may also be explained by α- or β-chelation between the free imine and one of the
oxygen atoms through an intramolecular hydrogen bond.

2372
In conclusion, the reductive alkylation of acetonide protected syn 2,3-dihydroxynitriles constitutes
a new and efficient way to prepare all syn 1,3-disubstituted 3-amino-1,2-diols in high enantiomeric
purities.
References
1. Kempf, D.; Sham, H. Curr. Pharm. Des. 1996, 2, 225–246.
2. Peterson, M. A.; Polt, R. J. Org. Chem. 1993, 58, 4309–4314 and references cited herein.
3. For some recent syntheses, see: Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721–4722; Veith, U.; Schwardt, O.;
Jäger, V. Synlett 1996, 1181–1183; Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.; Cornia, M.; Casiraghi, G.
Tetrahedron: Asymmetry 1996, 7, 1169–1180; Hümmer, W.; Dubois, E.; Gracza, T.; Jäger, V. Synthesis 1997, 634–642; Du
Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179–3180.
4. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619; Rayner, C. Synlett 1997, 11–21.
5. Bloch, R. Chem. Rev. 1998, 98, 1407–1438 and references cited herein.
6. Krepski, L. R.; Jensen, K. M.; Heilmann, M.; Rasmussen, J. K. Synthesis 1986, 301–303; Brussee, J.; Dofferhoff, F.; Kruse,
C. G.; Van der Gen, A. Tetrahedron 1990, 46, 1653–1658; Jackson, W. R.; Jacobs, H. A.; Jayatilafe, G. S.; Matthews, B.
R.; Watson, K. G. Aust. J. Chem. 1990, 43, 2045–2062; Effenberger, F.; Gutterer, B.; Ziegler, T. Liebigs Ann. Chem. 1991,
269–273; Urabe, H.; Aoyama, Y.; Sato, F. J. Org. Chem. 1992, 57, 5056–5057.
7. Charette, A. B.; Mellon, C. Tetrahedron 1998, 54, 10 525–10 535.
8. Hutin, P.; Larchevêque, M. Synthesis, in press.
9. To the best of our knowledge, the only previously reported preparation of such compounds, with R1 and R2 figuring alkyl
or aryl groups, is based on the vanadium-catalyzed cross-coupling of aldehydes with chiral α-amino aldehydes: Konradi, A.
W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem. Soc. 1994, 116, 1316–1323.
10. Mead, K.; Macdonald, T. L. J. Org. Chem. 1985, 50, 422–424; Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42,
447–488.
11. Olah, G. A.; Narang, S. C.; Fung, A. P.; Gupta, B. C. G. Synthesis 1980, 657–658; Maetz, P.; Rodriguez, M. Tetrahedron
Lett. 1997, 38, 4221–4222.
12. Hutin, P.; Petit, Y.; Larchevêque, M. Tetrahedron Lett. 1998, 39, 8277–8280.
13. It must be outlined that the Grignard reagents do not react with nitriles 1 in pure THF, a result which is perhaps due to the
formation of agregates. The reaction is however possible in a 2:1 mixture of diethyl ether and THF.
14. In a typical experiment, 4.5 mmol of Grignard reagent in ether was added to a solution of 3 mmol of dialkoxynitrile 1 in
dry ether at −15°C. The mixture was stirred at rt until completion of the reaction as indicated by TLC (4–6 h). After cooling
at −15°C, 3 ml of anhydrous methanol were added followed by 6 mmol of solid NaBH4. The mixture was vigorously
stirred overnight at rt, then carefully quenched with H2O and extracted with ether. The combined organic phases were dried
(MgSO4) and concentrated. The residue was dissolved in THF, then aqueous 1N NaOH (3.3 ml) and of Boc2O (3 mmol)
were added. After vigorous stirring for 6 h, the mixture was diluted with ether. The organic phase was washed with 1N
HCl and the combined aqueous phases were extracted with ether. The combined organic phases were dried (MgSO4) and
concentrated. The crude product was purified by flash chromatography to give the protected aminodiols 4 and 5. Selected
data for compounds 4 and 5: [α]2D0 4bB +15.5 (c 1.88, CHCl3); 5bB −20.8 (c 0.72, CHCl3); 4cC +17.9 (3.07, CHCl3); 4cB
+11.7 (c 2.29, CHCl3); 4dD −6.3 (c 2.29, CHCl3); 5dD −53.4 (c 1.46, MeOH); 4dB −7.0 (c 2.58, CHCl3); 5dB −71.0
(c 1.55, MeOH); 4eD +2.9 (c 3.36, MeOH); 5eD −16.8 (c 1.90, MeOH); 4eA +3.1 (c 2.54, MeOH); 5eA −37.1 (c 2.93,
CHCl3); 4fB +10.0 (c 1.09, MeOH). 1H NMR (400 MHz) δ ppm (CDCl3) 4dD 0.86 (d, 3H, J=6.7 Hz), 0.91 (d, 3H, J=6.8
Hz), 1.51 (s, 9H), 1.54 (s, 3H), 1.57 (s, 3H), 1.73 (m, 1H), 3.50 (ddd, 1H, J=0.6, 7.4, 10.5 Hz), 3.84 (dd, 1H, J=0.6, 8.6
Hz), 4.66 (d, 1H, J=8.7 Hz), 4.96 (d, 1H, J=10.4 Hz, NH), 7.4 (m, 5H). 5dD 0.80 (d, 3H, J=6.9 Hz), 0.91 (d, 3H, J=6.9
Hz), 1.44 (s, 9H), 1.51 (s, 3H), 1.57 (s, 3H), 2.17 (septd, 1H, J=6.9, 3.2 Hz), 3.77 (dd, 1H, J=7.6, 9.3 Hz), 3.87 (td, 1H,
J=3.2, 9.5 Hz), 4.01 (d, 1H, J=10.4 Hz, NH), 4.93 (d, 1H, J=7.6 Hz), 7.2–7.4 (m, 5H). 13C NMR (50 MHz) δ ppm (CDCl3)
4dD 19.09 (CH3), 19.73 (CH3), 27.09 (CH3), 27.26 (CH3), 28.53 (3×CH3), 32.21 (CH), 52.96 (CH–N), 79.33 (C), 80.02
(CH), 83.45 (CH), 109.08 (C), 126.62 (2×CH), 128.17 (CH), 128.65 (2×CH), 137.69 (C), 156.33 (C); 5dD 15.56 (CH3),
19.74 (CH3), 27.13 (CH3), 27.38 (CH3), 28.48 (3×CH3), 28.99 (CH), 57.71 (CH–N), 79.28 (C), 83.04 (2×CH), 109.40 (C),
127.58 (2×CH), 128.28 (CH), 128.53 (2×CH), 139.18 (C), 155.73 (C).
15. The N-Boc amino esters were analyzed on a 25 m Chirasil-D-Val column (Chrompack) on which such compounds with L
configuration are eluted in first.