Synthesis of camphor-derived chiral auxiliaries and their application in asymmetric Morita-Baylis-Hillman reactions

N -Substituted 2-exo -hydroxybornyl-10-sulfonamides, prepared as potential chiral auxiliaries for use in asymmetric Morita-Baylis-Hillman (MBH) reactions, have been treated with acryloyl chloride to afford the corresponding 2-exo -acrylate esters as MBH substrates. Reaction of selected 2-exo -acrylate ester substrates with pyridine-4-carbaldehyde and 6-methylpyridine-2-carbaldehyde in the presence of DABCO gave the expected MBH adducts in > 91% yield and with diastereoselectivities of 7-33% d.e.


Introduction
The conformational rigidity and steric demands of the bicyclic camphor system account for its use in the construction of a wide range of chiral auxiliaries. 1 These include Oppolzer′s classic camphorsultams 2 and the sterically hindered systems developed by Helmchen. 3In earlier studies, we have explored the application of camphor-derived chiral auxiliaries in the asymmetric αbenzylation of carboxylic esters prepared using the borneol derivative 1, 4 Simmons-Smith asymmetric cyclopropanation of α,β-unsaturated acetals prepared using the chiral diol 2, 5 and preliminary asymmetric Morita-Baylis-Hillman (MBH) reactions involving chiral acrylate esters. 6he chiral auxiliary used in these preliminary MBH reactions was the N-adamantyl-2-exohydroxybornyl-10-sulfonamide (3), and the promising level of diastereoselectivity observed in one of these reactions prompted us to investigate the preparation of a series of N-substituted analogues as potential chiral auxiliaries for asymmetric MBH reactions.

Results and Discussion
Synthetic access to the series of chiral auxiliaries 7 and 8 and the corresponding acrylate ester derivatives 9 and 10 is outlined in Scheme 1.Thus, each of primary or secondary amines 5a-j was treated with (1S)-(+)-camphor-10-sulfonyl chloride (4) in the presence of a catalytic quantity of 4-(dimethylamino)pyridine (DMAP) in acetonitrile.Work-up and purification furnished the corresponding N-substituted camphor-10-sulfonamides 6a-j in good to excellent yields (83-100%; Table 1).Reduction of the carbonyl group in each of the N-substituted camphor-10-sulfonamides 6a-j was effected using NaBH4 to afford the epimeric 2-hydroxybornyl-10-sulfonamides 7a-j and 8a-h,j in moderate to excellent yields (53-100%) and, generally, with high diastereoselectivity 100% in the case of the 2-imidazolyl derivative 7i), as shown in Table 1.The dicyclohexyl derivative 7j has been used previously as a chiral auxiliary by Oppolzer et al. in asymmetric Diels-Alder reactions 7 and in the asymmetric synthesis of aldols, 8 halohydrins and epoxides, 9 and αamino acids. 10Semi-preparative HPLC permitted isolation of analytical samples of the 2-exo-and 2-endo-hydroxy epimers, eight of which are new compounds.The C-2 configurations assigned to these epimeric products are supported by their 1 H NMR chemical shift and coupling constant data.Dominance of the 2-exo-hydroxy epimers 7 may be attributed to preferential hydride delivery to the less hindered endo face of the carbonyl group in the ketone precursors 6. Scheme 1. Reagents and conditions: i) DMAP, CH3CN, 0 o C; ii) NaBH4, EtOH-H2O, 0 o C; iii) Al2O3, CH2=CHCOCl; and iv) in situ HCl.
Formation of the acrylate esters 9 and 10 was achieved as reported previously. 6The alcohols 7 and 8 were added, generally as epimeric mixtures, to neutral Al2O3 (1.5 eq.), followed by acryloyl chloride (2 eq.).The resulting dispersions were allowed to stand at r.t. for 72 h without stirring.Flash chromatographic separation of the products, following work-up, proved impossible, necessitating the use of semi-preparative HPLC to obtain analytical samples; even then, the products, in some cases, remained slightly contaminated.The major products were, typically, the 2-exo-acryloyloxybornane-10-sulfonamides 9 and their 2-exo-[(3-chloropropanoyl)oxy]bornane-10-sulfonamide derivatives 11, the latter arising from conjugate addition to the former by the HCl released as a by-product.[We have shown previously 6 that dehydrochlorination (11 → 9) can be readily achieved using triethylamine.]Minor products, isolated in some cases, included the 2-endo-[(3-chloropropanoyl)oxy]bornane-10-sulfonamide derivatives due to the presence of low concentrations of the 2-endo alcohols in the substrate mixtures.
Table 1.Data for the preparation of the camphor-10-sulfonamides 6 and the diastereomeric bornyl alcohols 7 and 8 a Total yield for both diastereomers.
In the present study, attention was focused on using the 2-exo-acryloyloxybornane-10sulfonamides 9a,b,f as chiral MBH substrates.Pyridinecarbaldehydes tend to react rapidly under MBH conditions, 11 and pyridine-4-carbaldehyde and 6-methylpyridine-2-carbaldehyde were selected as the electrophiles and the tertiary amine, DABCO, as the nucleophilic catalyst for these reactions (Scheme 2).The reactions were allowed to run for 90 h and the desired series of MBH adducts 12 and 13 were obtained with excellent conversion levels (91-100%) as determined by 1 H NMR analysis after preliminary flash chromatography of the reaction mixtures.The diastereoselectivities were determined by comparing the relative integrals of the signals R corresponding to the vinylic methylene and hydroxymethine protons (between 5 and 6 ppm) in the 1 H NMR spectra of the mixtures of the major and minor MBH products.The results, summarised in Scheme 2, reveal that while a measure of diastereoselectivity (7-33% d.e.) was observed in all cases, there is considerable room for improvement, and careful optimisation of the methodology is required to establish reproducibility of our encouraging, preliminary results (up to 95% d.e.) obtained earlier. 6As observed previously, reactions with the more sterically hindered aldehyde, 6methylpyridine-2-carbaldehyde exhibit significantly higher diastereo-selectivities than reactions with pyridine-4-carbaldehyde, confirming the expectation that steric effects play a major role in diastereocontrol.It is expected that future efforts will focus on using inter-and/or intramolecular coordination effects to increase transition-state rigidity and thus enhance diastereoselectivity in such MBH reactions.

Conclusions
A number of borneol derivatives have been prepared with the potential to serve as chiral auxiliaries in various transformations, and the use of three of these compounds has been explored in asymmetric MBH reactions.Future challenges include the optimisation of reaction conditions and structural modifications to enhance diastereoselectivity.

Experimental Section
General.Reagents and solvents were used without further purification. 1H and 13 C NMR spectra were recorded on Bruker AMX400 or Avance II + 600 MHz spectrometers, and were calibrated using solvent signals; coupling constants are given in Hertz (Hz).Melting points were determined using a hot-stage apparatus, and are uncorrected.IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer.High-resolution mass spectra were recorded at the University of Stellenbosch Mass Spectrometry Unit.Flash chromatography was carried out using Merck silica gel 60 [230-240 mesh (particle size 0.040-0.063mm)] and preparative layer chromatography was conducted using silica gel 60 PF254.5][16][17] General procedures and analytical data for new compounds are as follows.