Enhanced asymmetric induction in cycloadditions to bridgehead-chiral vinyl dioxazaborocines

Article abstract of DOI:10.1016/S0040-4039(00)00571-2

Vinyl dioxazaborocines 5 with asymmetric centres on the nitrogen bridgehead substituent have been prepared and assayed in nitrile oxide and nitrone cycloadditions, giving asymmetric inductions of up to 70 and 74% ee, respectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00571-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4229–4233
Enhanced asymmetric induction in cycloadditions to
bridgehead-chiral vinyl dioxazaborocines
Christopher D. Davies,a Stephen P. Marsden a,∗ and Elaine S. E. Stokes b
aDepartment of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, UK
bAstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 20 March 2000; accepted 4 April 2000
Abstract
Vinyl dioxazaborocines 5 with asymmetric centres on the nitrogen bridgehead substituent have been prepared
and assayed in nitrile oxide and nitrone cycloadditions, giving asymmetric inductions of up to 70 and 74% ee,
respectively. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; boron and compounds; cycloaddition; isoxazolines; nitrile oxides; nitrones.
The control of absolute stereochemistry in dipolar cycloadditions continues to occupy the attention of
organic chemists. In contrast to the Diels–Alder reaction, progress towards catalytic asymmetric dipolar
cycloadditions has been limited and is generally restrictive in terms of both substrate structure and the
nature of the dipole.1 In particular, there has been only one approach outlined towards catalytic asym-
metric nitrile oxide cycloadditions,2 and so the development of efficient and general chiral auxiliaries for
these transformations remains an important goal.3
We have previously shown that chiral vinyl dioxazaborocines 1 can be prepared from vinyl boronic
acids and readily available diethanolamine ligands, and that these compounds undergo diastereoselective
nitrile oxide cycloadditions (with concomitant loss of the boronyl group) to yield 5-substituted ∆2-
isoxazolines 2 in up to 33% ee.4 From the X-ray crystal structure of the β-boronyl acrylate derived
dioxazaborocine, we were able to rationalise the observed sense of asymmetric induction in terms of
attack upon the exposed face of the olefin in one of two extreme conformations derived from rotation
about the B–C bond. The sole solid state conformer (and presumed major solution phase conformer)
shown (Fig. 1) is favoured since the alternative conformation suffers eclipsing interactions between the
α-vinyl proton and the pseudo-axial proton on the dioxazaborocine ring.
Given the close proximity of the nitrogen substituent at the bridgehead to the olefin, we were interested
to investigate the effects of incorporating a further asymmetric centre at this position upon the levels of
asymmetric induction observed. Herein we disclose the results of this investigation.
∗
Corresponding author. Tel: (44) 20 7594 5790; fax: (44) 20 7594 5804; e-mail: s.marsden@ic.ac.uk (S. P. Marsden)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00571-2
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Fig. 1.
A range of diethanolamines 3a–g were prepared from the appropriate α-chiral amines and (R)-styrene
oxide5 and condensed with the β-boronyl acrylate 46 to yield the corresponding dioxazaborocines
1
5a–g. As expected, H NMR indicated that these compounds exist entirely in the closed form. These
compounds were then subjected to 1,3-dipolar cycloaddition with in situ generated benzonitrile oxide
under our optimised conditions4 to yield isoxazoline 6 (Scheme 1). The optical purity of the isoxazolines
was assayed by chiral shift 1H NMR studies in the presence of (R)-binaphthol.7 The results are shown in
Table 1.
Scheme 1. Reagents and conditions: (i) 3, 4, Et2O, rt; (ii) (Ph)CIC_N-OH, Et3N, THF, rt
Table 1
Synthesis and dipolar cycloaddition reactions of vinyl dioxazaborocines 5a–g
Several observations arise from these results. Firstly, it can be seen from entries a and c that the
introduction of an extra asymmetric centre on the nitrogen bridgehead can lead to much improved levels
of asymmetric induction compared to the simple N-benzyl substrates 1. Secondly, these two entries also
demonstrate that there is no advantage to be gained by increasing the bulk of the aryl group: this is to be
expected since the X-ray structure of 1 clearly shows that the aryl substituent is oriented to the rear of the
dioxazaborocine ring, well away from the site of reaction. Thirdly, as can be clearly seen from comparison
of entries a and b, c and d, and f and g, a matched/mismatched situation exists between the ring and
bridgehead substituents. Thus, in matched situations the bridgehead substituent is located in the same
region as the pseudo-axial hydrogen, as in structure 7, leading to an increased preference for the olefin to
be oriented as shown. In the mismatched cases, the bridgehead substituent and the pseudo-axial hydrogen
are in opposite regions, leading to competing conformers 8a and 8b, which expose diastereotopic faces
of the olefin.

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Given that the influence of the asymmetric centre on the nitrogen bridgehead appears to override that
of the dioxazaborocine ring, we were interested to investigate the effect of changing the ring substituents
in bridgehead-chiral systems. Thus, dioxazaborocines 5h–j were prepared by the usual method from
diethanolamines 3h–j8 and their behaviour in cycloaddition reactions examined (Scheme 2, Table 2).
Scheme 2. (i) 1, 2, Et2O, rt; (ii) (Ph)CIC_N-OH, Et3N, THF, rt
Table 2
Synthesis and dipolar cycloaddition reactions of vinyl dioxazaborocines 5h–j
From these results it can be seen that the presence of ring substituents is not crucial for asymmetric
induction but does lead to enhanced selectivity. We believe that a large substituent is required to control
the conformation of the dioxazaborocine rings. If R1 is large and R2 is hydrogen, conformer 9a should
dominate, with the olefin being oriented as shown. If R1 is methyl or hydrogen, contributions from
conformer 9b in which the opposite diastereotopic face of the olefin is presented might become important,
leading to a lower overall asymmetric induction. Supporting evidence for this theory is the broadened
nature of the dioxazaborocine ring proton signals in the 1H NMR spectrum of 5h and 5i compared to the
sharp signals observed for 5a, which could be indicative of conformational mobility. The tetramethyl
substituted dioxazaborocine 5j gives compound 6 of the opposite configuration to that from 5a,h,i.
This is presumed to arise because conformer 9a is destabilised relative to 9b when R1=R2=Me, and
so predominant attack on 9b as shown would lead to the observed enantiomer.
Having settled on the amine 3a as the optimal ligand for dioxazaborocine formation, we investigated
its application in two further nitrile oxide cycloadditions (Scheme 3). We examined the effect of making
changes in both the olefin and nitrile oxide substituents. Thus, styryl dioxazaborocine 10 reacted with
benzonitrile oxide to yield isoxazoline 11 of 61% ee, while carboethoxycarbonylnitrile oxide reacted

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with acryloyl dioxazaborocine 5a to give isoxazoline 12 of 59% ee. Thus, it appears that the auxiliary
will prove applicable to the asymmetric synthesis of a range of isoxazolines.
Scheme 3.
We also investigated the use of dioxazaborocine 5a in nitrone-olefin cycloadditions (Scheme 4).
Cycloaddition with formaldehyde or glyoxalate derived benzyl nitrones 13a,b gave isoxazolidines with
the boron still appended; this could be oxidatively cleaved using basic peroxide to generate hydroxylated
heterocycles 14a and 14b. The enantiomeric purities of the heterocycles were determined by Mosher’
ester derivitisation, and found to be 65 and 74%,respectively. The sense of asymmetric induction has
not been rigorously proven but is indicated as shown by analogy with the facial selectivity demonstrated
in the nitrile oxide cycloadditions. Compound 14b was isolated as a single diastereoisomer which is
tentatively assigned as shown, although the low yield means that claims regarding the influence of the
auxiliary upon endo/exo selectivity in the cycloaddition are premature.
Scheme 4.
In summary, we have developed much improved dioxazaborocine auxiliaries for asymmetric dipolar
cycloadditions to acrylates by the incorporation of bridgehead chirality. Nitrile oxide cycloadditions
yield isoxazolines from which the auxiliary has been cleaved in up to 70% ee. Nitrones also undergo
cycloaddition, and the extra degree of saturation allows for the retention of the boronyl function.
Oxidative removal of the boron yields hydroxylated isoxazolidines in up to 74% ee. Further applications
of chiral vinyl dioxazaborocines in synthesis will be reported in due course.9
Acknowledgements
We thank the EPSRC and Zeneca Pharmaceuticals for an Industrial CASE award (to C.D.D.), and the
Royal Society for additional financial support.
References
1. For example, chiral Lewis acids have been used to promote nitrone cycloadditions to oxazolidinone-substituted olefins
(Jensen, K. B.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1997, 62, 2471–2477 and references cited
therein) or enol ethers (Simonsen, K. B.; Bayón, P.; Hazell, R. G.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc.
1999, 121, 3845–3853 and references cited therein), while chiral rhodium catalysts have been used to promote asymmetric

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cycloadditions of oxonium ylides. (Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun. 1999, 2185–2186 and
references cited therein).
2. (a) Yoshida, Y.; Ukaji, Y.; Fujinami, S.; Inomata, K. Chem. Lett. 1998, 1023–1024; (b) Shimizu, M.; Ukaji, Y.; Inomata, K.
Chem. Lett. 1996, 455–456; Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1847–1850.
3. Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–909.
4. Davies, C. D.; Marsden, S. P.; Stokes, E. S. E. Tetrahedron Lett. 1998, 39, 8513–8516.
5. Owing to the availability to us of only a single enantiomer of 2-aminoindan, amine 3g was in fact prepared from (R)-
aminoindan and (S)-styrene oxide-the enantiomeric structure is shown in the paper for ease of comparison of data.
6. Martinez-Fresneda, P.; Vaultier, M. Tetrahedron Lett. 1989, 30, 2929–2932.
7. Addition of (R)-binaphthol (0.044 g) to a sample of racemic isoxazoline (6) (0.005 g) in CDCl3 resolved the signals for
H4a/H4b from an overlapping multiplet at 3.65 ppm such that the outer doublets could be distinguished for each enantiomer
in the 1H NMR spectrum recorded at 400 MHz. We thank Mr. Dick Sheppard and Mr. Paul Hammerton of this department
and Mr. Rob Horton of AstraZeneca for running these experiments.
8. Compound 3h was prepared from (S)-α-methylbenzylamine and (S)-propylene oxide; the enantiomeric structure is shown
here for clarity. Compound 3i was prepared from (R)-α-methylbenzylamine and ethylene oxide. Compound 3j was
prepared by condensation of (R)-α-methylbenzylamine with two equivalents of ethyl bromoacetate followed by exposure
to excess methylmagnesium bromide.
9. Farthing, C. N.; Marsden, S. P. Tetrahedron Lett. 2000, 41, 4235–4238.