A remarkable temperature effect in the desymmetrisation of bridged meso-tricyclic succinic anhydrides with chiral oxazolidin-2-ones

Abstract

A temperature dependent reversal of diastereoselectivity was observed in the desymmetrisation of bridged meso-tricyclic succinic anhydrides with lithiated chiral oxazolidin-2-ones that appears to be kinetically driven at low temperature while the reversibility of the reaction sets in at higher temperatures and thermodynamics governs the reaction outcome.

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Desymmetrisation products of bridged meso-tricyclic succinic anhydrides are well known intermediates in various syntheses.¹ A great deal of research has been carried out to achieve high enantiomeric/diastereoisomeric purity by involving an achiral alcohol in combination with a chiral catalyst^2–4 or chiral reagents like alcohols⁵ and amines.⁶ Chiral oxa-/iso-oxazolines and oxazolidin-2-ones^7,8 have recently been introduced for the desymmetrisation of various symmetric anhydrides. The choice of the oxazolidin-2-one class of chiral reagents was made because this fragment is widely used as a powerful auxiliary for controlling diastereoselective reactions⁹ when attached to a carboxylic acid group and it is easy to remove. While the effect of solvent, concentrations and additives for the desymmetrisation¹⁰ of various prochiral anhydrides show a drastic improvement in stereoselectivity and/or even inversion of stereoselectivity, change of temperature is known to have a minimal effect. Herein, we report for the first time a remarkable temperature dependent change of diastereofacial selectivity in the desymmetrisation of bridged meso-tricyclic anhydrides with chiral oxazolidin-2-ones and also established the structural parameters of the oxazolidin-2-ones required for optimum diastereoselectivity.

Lithiated SuperQuat¹¹oxazolidin-2-one 1a (Fig. 1) has been used successfully by us⁸ for the desymmetrisation of 3-substituted glutaric anhydrides at −78 °C in THF–DMPU. When meso-tricyclic anhydride 2a (Fig. 1) was reacted with Li-1a following the reported⁸ conditions, diastereoisomeric esters 5a and 6a (5a/6a = 50/50) were isolated in 76% yield after diazomethane esterification (Scheme 1). Similar results were obtained with other tricyclic anhydrides 2b–d leading to methyl esters in good yield but with almost no diastereoselectivity (Fig. 2; 5b/6b = 44/56, 71%; 5c/6c = 52/48, 70%; 5d/6d = 50/50, 75%). Although the results are disappointing, they created a challenge to find a solution to the problem.

Fig. 1 Structures of chiral oxazolidin-2-ones and anhydrides.

Fig. 2 Methyl esters of products from the desymmetrisation of various meso-anhydrides with lithiated oxazolidin-2-ones 1a–d.

Scheme 1 Desymmetrisation of bridged meso-tricyclic anhydride 2a.

Besides other factors,¹² temperature plays a significant role in controlling the selectivities of a reaction. Under normal circumstances, the diastereoselectivity of a reaction performed under kinetic control commonly increases with lowering of reaction temperature. An exception to this is reported in certain examples where the selectivity was dramatically increased and/or inverted at higher temperatures.^13,14 There are no reports for such instances in anhydride desymmetrisations or reactions involving bridged tricyclic systems.

We therefore, set to study the effect of temperature on the opening of bridged tricyclic anhydride 2a with Li-1a in THF-DMPU (4/1; 0.17M)‡ over a temperature range of −78 °C to 35 °C. No selectivity (Fig. 3) was observed at −78 °C. As the temperature was increased to −28 °C the diastereoselectivity was increased to 36/64 in favor of 6a. Increase in temperature from here decreases the diastereoselectivity until there is nearly no selectivity in the vicinity of 0 °C. With further increase in temperature, a reversal as well as sharp improvement in the diastereoselectivity was seen until about 35 °C§ (5a/6a = 91/9). Thus a simple change in reaction temperature led to products where the lithiated oxazolidin-2-one apparently reacted selectively at every other carbonyl groups of the anhydride 2a.

Fig. 3 Effect of temperature and oxazolidin-2-one structures on desymmetrisation selectivity of anhydride 2a.

To ascertain the role of the structural feature of oxazolidin-2-ones, if any, anhydride 2a was reacted with lithiated Seebach's,¹⁵Evans'¹⁶ and Sibi's¹⁷oxazolidin-2-ones Li-1b, Li-1c and Li-1d, respectively. At −78 °C, the selectivity was good with 1b providing diastereoisomers 8a and 7a in a ratio of 90/10 and it did not change up to −35 °C (Fig. 3). Between −15 °C and 0 °C, a reversal in selectivity was observed and the diasteroisomer 7a became now major. At 28 °C, a reasonably high selectivity (dr = 20/80) in favor of the diasteroisomer 7a was finally achieved. Between −78 °C and −35 °C, the reaction of 2a with Li-1c or Li-1d (Fig. 3) was unselective and thereafter the selectivity increased slowly followed by a rapid jump above 0 °C. At 28 °C, the diastereoisomer ratio 10a/9a was found to be 96/4. With Li-1d, the reaction became completely diastereoselective providing exclusively the diastereoisomer 11a at 10 °C and above. The SuperQuartoxazolidin-2-ones 1a and 1b showed a clear cut reversal in diastereoselectivity with increasing temperature and an equiselective temperature in the vicinity of 0 °C. The oxazolidin-2-ones 1c and 1d did not show a reversal of selectivity in the temperature range studied but a steady increase in selectivity with the rise in temperature.

To see the generality of this temperature effect, Li-1a was reacted with meso-tricyclic anhydrides 2b–d in THF–DMPU (4/1; 0.17M) at −78 °C and at 28 °C (Table 1). In all cases, the desymmetrisation reactions were unselective at −78 °C but highly selective at 28 °C with excellent yield in all cases (Table 1, entries 2–4). It is interesting to note that meso-, mono- and bi-cyclic anhydrides 3a, 4a and 4b (Fig. 1) showed negligible variation in diastereofacial selectivity (Table 1, entries 5–7) providing the same set of major (13, 15a,b) and minor esters (14, 16a,b) (Fig. 2) at both the temperatures. Thus, the temperature dependent desymmetrisation selectivity does depend more on the anhydride structures than the oxazolidin-2-ones. Only tricyclic meso-anhydrides behaved in this fashion.

Table 1 Desymmetrisation of meso-anhydrides with lithiated oxazolidin-2-one 1a at −78 °C and 28 °C

Entry	Anhydride	Products	Diastereoisomer ratio^a (% yield^b)
			at −78 °C	at 28 °C
a Determined by ^1H NMR of the crude methyl esters. b Combined yield of diastereoisomers.
1	2a	5a, 6a	50/50 (76)	90/10 (88)
2	2b	5b, 6b	44/56 (71)	93/07 (82)
3	2c	5c, 6c	52/48 (70)	92/08 (84)
4	2d	5d, 6d	50/50 (75)	96/04 (79)
5	3a	13, 14	87/13 (81)	84/16 (83)
6	4a	15a, 16a	82/18 (85)	78/22 (85)
7	4b	15b, 16b	92/08 (85)	89/11 (84)

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To probe the generality of the high selectivity of Li-1d, tricyclic anhydrides 2b–f were reacted with it at 28 °C (Table 2). In all cases, the selectivity and yield were excellent. The results are also compared with the selectivity observed at −78 °C. This is also a successful attempt³ to desymmetrise anhydrides 2c and 2d with such high selectivity.

Table 2 Desymmetrisation of meso-tricyclic anhydrides by oxazolidin-2-one 1d at −78 °C and 28 °C

Entry	Anhydride	Products^a	Diastereoisomer ratio^b (% yield)
			at −78 °C	at 28 °C
a Absolute configurations were determined by chemical correlations (see, the Electronic Supplementary Information). b Determined by ^1H NMR of the crude methyl esters. c Combined yield of diastereoisomers.
1	2a	11a, 12a	60/40	>99/1 (85)
2	2b	11b, 12b	60/40	>99/1 (85)
3	2c	11c, 12c	76/24	>99/1 (80)
4	2d	11d, 12d	33/67	>99/1 (79)
5	2e	11e, 12e	80/20	95/05 (85)^c
6	2f	11f, 12f	48/52	>99/1 (84)

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To understand the origin of this temperature effect, anhydride 2a was reacted with Li-1a in THF–DMPU at −35 °C or at 0 °C but quenched after raising the reaction temperature to 28 °C. In both cases, the diastereoisomers ratio (5a/6a) found did not match with the values obtained at −35 °C or 0 °C but matched with the values at 28 °C. Furthermore, the same reaction was performed at 28 °C, the temperature was lowered slowly to −35 °C and then the reaction was quenched. In this case, the proportion of methyl esters 5a/6a matched with the values at 28 °C. We have also carried out crossover experiments by reacting anhydride 2a with Li-1a at −35 °C or 28 °C. After 0.5 h, equiv amount of anhydride 2c was added into the reaction mixture and quenched after 10 min at 28 °C. We did not see any transamidation product in both cases and a mixture of products 5a and 6a were formed only from anhydride 2a. We thus speculate that the initial stereoinduction step is the kinetic addition of the Li-1a to one of the prostereogenic carbonyls of the anhydride to give the minor lithium salt 17a and major lithium salt 18a which appeared to be stable at low temperature (Scheme 2). Quenching the reaction at low temperature provided a mixture of methyl ester 5a and 6a at par with kinetic ratio. At higher temperature, the lithium salt 18a transforms into the thermodynamically stable lithium salt 17a by an intramolecular transfer of the oxazolidin-2-one group. Quenching and esterification lead to a mixture of methyl esters 5a and 6a at par with thermodynamic ratio. Thus the kinetically favored diastereoisomer was obtained at low temperature while thermodynamically controlled diastereoisomer was obtained at high temperature quenching. The thermodynamically favored diastereoisomer once formed could not revert to the kinetically favored one even when the temperature was lowered presumably due to conversion of 17a and 18a to carboxylates 19a and 20a, respectively at higher temperature.

Scheme 2 Mechanistic studies.

In conclusion, oxazolidin-2-ones are a class of molecules which in stoichiometric amounts could be efficiently employed for the desymmetrisation of prochiral anhydrides. Bridged tricyclic anhydrides only showed temperature-dependent diastereoselectivity which is specific to their structure. Study of more such related reactions with bridged tricyclic structures are under active investigation.

References

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Footnotes

† Electronic supplementary information (ESI) available: Typical experimental procedure, full characterization data, copies of ¹H and ¹³C NMR. See DOI: 10.1039/c1ra00483b

‡ It was established that this solvent combinations and reaction concentration were essential for optimal selectivity and yield.

§ Above this temperature, the product yield dropped sharply with formation of unidentified by-products.

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