Asymmetric syn-dihydroxylation of γ-substituted (2 R)- N-(β,γ-enoyl)bornane-10,2-sultams

Asymmetric syn-dihydroxylation of γ-substituted (2 R)- N-(β,γ-enoyl)bornane-10,2-sultams - pdf for free download
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TETRAHEDRON: ASYMMETRY Pergamon

Tetrahedron: Asymmetry 11 (2000) 1027–1041

Asymmetric syn-dihydroxylation of γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams Jerzy Raczko,a Michal Achmatowicz,a Piotr Kwiatkowski,b Christian Chapuis,a,† Zofia Urba´nczyk-Lipkowska a and Janusz Jurczak a,b,∗ a

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland b Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland Received 31 December 1999; accepted 12 January 2000

Abstract Various γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams have been examined in diastereoselective OsO4 syn-dihydroxylation. In contrast to the C(α)-atom, the bornane-10,2-sultam auxiliary exerts a very poor influence on the C(β)-carbon. Spontaneous stereoselective hydrolysis of the minor diastereoisomer (3S,4S)-5c opens the way to enantiomerically pure building blocks. © 2000 Elsevier Science Ltd. All rights reserved.

1. Introduction Oppolzer and Barras reported the diastereoselective OsO4 syn-dihydroxylation of simple substituted α,β-alkenoyl-(2R)-bornane-10,2-sultams of type (−)-1a,b to the corresponding unstable diols (2R,3S)-

2a,b.1 We later showed that these diols could be isolated and fully characterized and we extended this methodology to synthetically more interesting carboxylic and aromatic β-substituted derivatives.2 In continuing our studies on applications of sultam derivatives in stereocontrolled reactions3 we have decided to use substrates with the target double bond distant from the inducing auxiliary, i.e. β,γ-alkenoyl sultams 3. We also believed that any detrimental influence of the increased distance from bornanesultam to the double bond could be counterbalanced by introduction of the second chiral auxiliary into the molecule.

∗ †

Corresponding author. E-mail: [email protected] Present address: Firmenich SA, R&D Corporate Division, PO Box 239, CH-1211 Geneva 8, Switzerland.

0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. P I I: S0957-4166(00)00024-0

tetasy 3247

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2. Results Acylation of commercially available (2R)-bornane-10,2-sultam4 by 3-butenoyl chloride5 or 3-hexenoyl chloride6 using classical conditions (NaH, toluene) gave exclusively the known conjugated derivatives (−)-1a,b (Scheme 1).1,4 Although (−)-3a was earlier obtained under neutral conditions, by treatment of the free sultam with methyl 3-butenoate in the presence of AlMe3 7 we preferred to use the conditions developed by Kociensky et al.8 Thus, when the silylated auxiliary was treated with the corresponding alkenoyl chlorides, (−)-3a,b were obtained in 35 and 85% yield, respectively (Scheme 2). The unreported substrates (−)-1c and (−)-3c, possessing two prosthetic groups, were similarly obtained in 77 and 92% yield, respectively, using 1,6-hex-2E-9a and 1,6-hex-3E-endicarboxyloyl chloride.10 Finally, the new analogues (−)-1d and (−)-3d were isolated in 62 and 52% yield, respectively, after equimolar addition of the corresponding mono-9b or diacid chlorides, followed by methanolysis.

Scheme 1. Reaction conditions: (a) OsO4 /NMO, t-BuOH/DMF

Scheme 2. Reaction conditions: (a) OsO4 /NMO, t-BuOH/DMF; (b) RuCl3 /NaIO4 , MeCN/AcOEt/H2 O, 0°C; (c) 2,2-dimethoxypropane, acetone, pTsOH, rt

As in our previous report,2 the syn-dihydroxylation was carried out using either OsO4 (Nmethylmorpholine N-oxide monohydrate) or with the more reactive RuO4 (RuCl3 , NaIO4 , MeCN:AcOEt 1:1).11 The diastereoisomeric ratios were determined by 1 H NMR analyses and confirmed by HPLC and the absolute configurations were ascertained by chiroptical comparison of the corresponding γ-lactones.12 First of all, the OsO4 syn-dihydroxylation of the conjugated olefin (−)-1c afforded at 0°C a 92:8 mixture of (2R,3S)-2c/(2S,3R)-2c in 90% yield. Two recrystallizations furnished pure (2R,3S)-2c (41% yield), a potential intermediate for a direct access to the (4S,5R)-(+)-L-Factor, a proposed autoregulator for anthracycline biosynthesis in streptomyces.13 Hydrolyzed material of similar purity was obtained

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from (−)-2d, suggesting that the second prosthetic group, separated by two methylene units, is too far away to sterically influence the approach.‡ When applied to the non-conjugated substrates (−)-3a,b, both oxidative methods provided chromatographically inseparable mixtures of diastereoisomers (3R,4R)-4a,b/(3S,4S)-4a,b; the poor diastereoselectivity observed could not be improved by temperature or metal counter ion modifications (see Table 1). In order to facilitate NMR spectra interpretations, and the purification procedure, 4a was isolated in its dihydroxylic form, due to partial hydrolysis of the chiral auxiliary during the acetalization. Substrate (−)-3c allows the detailed study of the cumulative steric influence of both prosthetic groups on the C(β)carbon. Table 1 Asymmetric dihydroxylation of N-enoyl-(2R)-bornane-10,2-sultams (−)-1c, (−)-3a–d and diester (−)-6

Unexpectedly, we obtained, in this case, acetal (3R,4R)-5c as a pure diastereoisomer. Transesterification with TiCl4 /iPrOH to isopropylidene derivative of diester (3R,4R)-8,14 followed by acidic treatment, ‡

Similarly, OsO4 syn-dihydroxylation of (2R)-bornane-10,2-sultam N-hex-4E-en-1,6-dioic acid 1-yl-6-methyl ester gave at 0°C a 1:1 mixture of inseparable diastereoisomers.

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afforded the enantiomerically pure (3R,4R)-dihydroxyadipic-γ,γ0 -dilactone 9 in 42% overall yield. Because of the lower chemical yield obtained during this process, we decided to perform the acetalization directly on the reaction mixture, rather than after the aqueous work-up, and thus obtained at 0°C a 58:42 diastereoisomeric mixture in 68% yield.§ Interestingly, the minor diastereoisomer hydrolyzes selectively, probably due to a specific conformation of one of the generated hydroxyl groups. Alternatively, when the mono-(2R)-bornane-10,2-sultam analogue (−)-3d was oxidized with OsO4 at 0°C, a similar 56:44 mixture of (3R,4R)-4d/(3S,4S)-4d was obtained in 63% yield, thus indicating a very low co-operative effect of both prosthetic groups.15 Finally, when a purely steric inducer was used, as in the reported but not fully characterized di(R)-menthyl 1,6-diester (−)-6,16 oxidation afforded diol 7 in 95% yield as a 47:53 inseparable mixture (Scheme 3).

Scheme 3. (a) OsO4 /NMO, t-BuOH/DMF; (b) TiCl4 , iPrOH; (c) 2N HCl, THF/H2 O

The X-ray structure analysis of substrate (−)-3c shows several interesting features and is characterized by a crystallographic disorder around one of the sultam SO2 moieties, due to two possible conformations of the five membered ring (Fig. 1). This substrate thus manifests the correlation that we found earlier between the S–N–C_O dihedral angle and the degree of pyramidalization of the N atom.17 For one sultam moiety (S–N–C_O=161.2(6)°), the pyramidalization of the N atom is of 0.19(1) Å, while for the second unit the N is either more planar (S–N–C_O=170(1)°, ∆hN=0.13(2)) or remarkably pyramidalized (S–N–C_O=143(1)°; ∆hN=0.31(5) Å). This analysis also suggests that the conformations of the C(O) and C(β) atoms are very similar to the conjugated α,β-enoyl derivatives.4,18

Fig. 1. X-Ray structure of compound (−)-3c with arbitrary numbering

Indeed, the C(O) moiety remains anti-periplanar to the SO2 group and the C(α)–C(β) bond is synperiplanar to the C(O) function, thus projecting the C(β)_C(γ) double bond in a thermodynamically §

This is the only case where traces of free sultam were observed and attracted our attention, thus precluding hydrolytic artefacts in all other examples reported.

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favoured anti-periplanar direction with respect to the C(O)–C(α) bond. As a consequence, the C(β)-re face is slightly more accessible, hypothetically due to the steric and/or electrostatic interactions19 of both pseudo-axial S_O(1)/S_O(10 ) groups, on the convex C(β)-si face of the transition state. This is even more visible from the X-ray structure analysis of product 5c, which shows the same features (Fig. 2). However, one should admit that in relation to the low selectivities obtained, the proposed course of reaction is only speculation and can be influenced by reaction conditions (Table 2).

Fig. 2. X-Ray structure of compound 5c showing its (3R,4R) configuration and arbitrary numbering Table 2 Selected bond lengths [Å] and dihedral angles [°] for (−)-3c and (3R,4R)-5c

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3. Conclusions In contrast to the strong influence exerted on the C(α)-carbon, as evidenced for example by the diastereoselective OsO4 syn-dihydroxylation of (−)-1c, the bornane-10,2-sultam auxiliary exerts a very poor influence on the C(β)-carbon, as formerly pointed out by Curran et al.20,21 for the thermal C(β) cyclohexyl radical addition to α,β-enoyl derivatives. In the absence of electronic conjugation, this poor diastereoselectivity mainly results from the lack of steric influence from the auxiliary. However, by recrystallization of (2R,3S)-2c, and due to a fortuitous stereoselective spontaneous hydrolysis of the minor diastereoisomer (3S,4S)-5c, this methodology allows some enantiomerically pure building blocks to be obtained.

4. Experimental All reactions with acid chlorides were carried out under argon atmosphere with anhydrous solvents dried according to standard laboratory methods. 1 H and 13 C NMR spectra were measured on Bruker AM500 (500 and 125 MHz) and Varian Gemini (200 and 50 MHz) spectrometers using residual CHCl3 as internal reference. Mass spectra were carried out with an AMD-604 Intectra instrument. Optical rotations were measured on a JASCO DIP-360 polarimeter with a thermally jacketed 10 cm cell. Infrared s...

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