Double Diastereoselect ion in Anti Aldol Reactions Mediated by Dicyclohexylchloroborane between An L-Erythrulose Derivative and Chiral Aldehydes

Anti aldol reactions of an l-erythrulose derivative with several α-chiral aldehydes mediated by dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results are best explained when the reactions are assumed to occur via boat-like transition states with minimization of 1,3-allylic strain and avoidance of syn pentane interactions.


Introduction
The aldol reaction is a powerful and general method for the stereocontrolled construction of carbon-carbon bonds. 1 It may be performed through the use of various types of metal enolates or also in an organocatalytic, metal-free manner. 2,3rom the many enolate types investigated thus far, boron enolates have proven to be particularly versatile because of their good reactivity and high stereoselectivity. 4In the last decade, we have been investigating the outcome of aldol reactions of boron enolates of protected L-erythrulose derivatives such as 1, generated with Chx 2 BCl (dicyclohexylboron chloride). 5With these ketones, the latter reagent gives rise to the highly stereoselective formation of syn aldols 2 via the Z enolate 6 1 B in reactions with achiral aldehydes RCHO (Scheme 1). 7 Scheme 1 Aldol additions of a Z boron enolate of chiral ketone 1 to achiral aldehydes via a chair-like transition state (TS) (Chx = cyclohexyl; TBS = tert-butyldimethylsilyl).
Subsequently to these initial investigations, we wondered whether or not the facial bias of chiral enolate 1 B would be strong enough to overcome the inherent facial preferences of the carbonyl group in aldehydes having a stereocentre in the α-carbon atom (double diastereoselection). 1a-e Therefore, we investigated the aldol reactions of 1 B with a range of α-chiral aldehydes in both antipodal forms.In the initial study, the aldehydes had only carbon substituents (α-methyl aldehydes 3) or else one oxygen (α-alkoxy aldehydes 4) bound to the α-carbon atom (in all these aldehydes, P is a protecting group, and R is a variable fragment). 8The study was subsequently extended to the case of α-amino and α-fluoro aldehydes. 9The 40 results of all these aldol reactions are summarized in Scheme 2. The compounds depicted in the Scheme are the only diastereomers detected in the aldol reaction mixture by means of NMR (d.r.> 95:5).For the meaning of R and P, see ref s. 8,9 Scheme 2 Aldol additions of enolate 1 B to aldehydes (R)/(S)-3, (R)/(S)-4, (R)/(S)-8 and (R)/(S)-9 (Bn = benzyl).
In all successful cases, a practically exclusive attack of the enolate Re face on the aldehyde carbonyl Re face was observed. 10We explained the stereochemical course of these aldol reactions by assuming the generally accepted model of cyclic, six-membered transition states of the Zimmerman-Traxler type (Scheme 1). 11,12In the case of α-chiral aldehydes, where issues of double diastereoselection are at work, 1a-c we completed the mechanistic paradigm with the inclusion of the Felkin-Anh model and its subsequent refinements. 13,14As matters evolved, however, we found that strict adherence to this model did not allow for a satisfactory account of all observed results, most particularly with aldehydes having highly electronegative atoms (F,O) bound to the α-carbon.In such cases, it was found that additional inclusion of features of the Cornforth model 15 provided a much better explanation. 8,9This conclusion was further supported by means of density funcional calculations. 9hort after the beginning of our research on boron aldol reactions with ketone 1, and relying on findings of Paterson and coworkers, 6a we wondered whether the replacement of one or more of the electron-donating O-protecting groups of 1 by electron-withdrawing counterparts would change from syn to anti the stereochemical course of the aldol reaction.Indeed, and in line with Paterson´s idea, chiral ketone 13, which bears two benzoyl protecting groups, was found to stereoselectively give anti aldols 14 with achiral aldehydes (Scheme 3), 16 most likely through the corresponding E boron enolate. 17Later quantum-mechanical studies of our group provided theoretical basis for this mechanistic assumption.5d In a more recent development, the dibenzoylated ketone 13 has been replaced by its monobenzoylated counterpart 15, which is easier to prepare and yields anti aldols 16 with similar degrees of stereoselectivity.Scheme 3 Anti aldol additions of boron enolates of ketones 13 and 15 to achiral aldehydes (Bz = benzoyl).
The purpose of the present investigation is the study of the double diastereoselection in anti aldol reactions of ketone 15 with α-chiral aldehydes.

Results and discussion
The α-chiral aldehydes (R)/(S)-3, (R)/(S)-4 and (R)/(S)-9, used in the present study (Fig. 1), are also those of our previous publications 8,9 and have been prepared by means of the same 45 procedures (α-fluoro aldehydes 8 have not been included in the present study).For a mechanistic explanation of the stereochemical course of these reactions, we cannot directly adapt the chair-like Zimmerman-Traxler model used in our previous publications that discussed the formation of syn aldols via Z enolates. 8,9deed, theoretical calculations of our group have led to the 10 proposal that anti aldol reactions of ketone 13 with achiral aldehydes mediated by Chx 2 BCl take place through a transition structure (TS) of the "boat B" type (Scheme 5).5d,12g One salient feature of this TS is the arrangement of the groups around the stereocentre in the enolate moiety, which is in such 15 a way as to minimize the 1,3-allylic strain 19 within the enolate E olefinic bond.As a consequence, the benzoate points inside the cyclic TS but, due to the boat shape of the latter, this does not lead here to a steric crowding with the cyclohexyl ligands at the boron atom (compare with the chair-like TS in Scheme 20 1).
[15] Scheme 5 Proposed TS for the aldol addition step of the E boron enolate of ketone 13 and achiral aldehydes RCHO.If the stereochemical model of Scheme 5 is applied to the reactions of 15 B with aldehydes (R)-and (S)-3a,b, we obtain the four boat-like transition structures (TS-1 to TS-4) depicted in Scheme 6.The formation of aldols 17a,b in the case of (S)-3a,b can be reasonably explained with transition structure TS-1.It can be seen that the spatial arrangement of the three groups at the α-carbon of the aldehyde (H, Me, CH 2 OP) closely adheres to the Felkin-Anh model (anti orientation of the bulky CH 2 OP group and the attacking nucleophile).Since no unfavourable steric features are present in TS-1, it is not surprising that these reactions take place with good results, both in terms of yield and stereoselectivity, to yield yield anti aldols 17a,b.Rotation of the aldehyde C α −CO bond in TS-1 yields the alternative transition structure TS-2, which would yield in principle the same final product.However, this is markedly higher in energy contents, as it shows two very unfavourable features: a) a non-Anh arrangement 20 of the three groups at the α-carbon of the aldehyde.b) a syn pentane interaction 21,22 between the Me and OTBS groups.Particularly the latter effect has been shown to be quantitatively very important in aldol and allylation reactions, often overriding the stereoelectronic preference associated to a Felkin-Anh geometry. 8,9,21In consequence, we may assume than the aldol reactions of 15 B with aldehydes (S)-3a,b take place only through TS-1.
The situation is different in the case of aldehydes (R)-3a,b, which react with 15 B to give complex mixtures of aldols together with decomposition products (Scheme 4).In Scheme 6, a plausible explanation for this result is proposed.The reaction may take place through either TS-3 or TS-4: TS-3 is of the Felkin-Anh type but also shows an unfavourable syn pentane interaction, whereas TS-4 is of the non-Anh type.Both reactions therefore must traverse unfavourable transition 35 structures and become accordingly slower, with the expected loss of stereoselectivity and increased probability of decomposition pathways.
A similar situation is found in the case of α-oxygenated aldehydes (R)-and (S)-4a,b, even though the R enantiomers 40 are those reacting efficiently here, with the S enantiomers giving complex aldol mixtures and decomposition products (Scheme 4).As above, four boat-like transition structures (TS-5 to TS-8), depicted in Scheme 7, may be proposed for these reactions.In the same line of reasoning disclosed above, 45 the successful reactions of aldehydes (R)-4a,b are proposed to occur through transition structures like TS-6, which is of the Felkin-Anh type and does not display unfavourable steric features.In contrast, TS-5 shows an unfavourable syn pentane effect.The same effects are also seen in transition structures 50 TS-7 and TS-8, which should be relevant for the reactions of aldehydes (S)-4a,b.It is thus not surprising that these reactions yield complex aldol mixtures and decomposition products.It is also worth mentioning that TS-8 also belongs to the Felkin-Anh type 13 (see above) whereas TS-5 and TS-7 55 belong to the Cornforth type (anti orientation of the electronegative OP group and the aldehyde C=O bond). 15onetheless, the energetically important contribution of the syn pentane interaction is able to override the aforementioned effects.As regards the aldol reactions of aldehydes (S)-9a,b,c, TS-11 (Cornforth) and TS-12 (Felkin-Anh) would seem in principle suitable TSs.However, both show a syn pentane interaction.Accordingly, and as observed for aldehydes (S)-4a,b, only complex aldol mixtures and decomposition products should be expected.Instead, aldols 20a,b,c are diastereoselectively formed with good yields.A plausible explanation for this result is the assumption of the alternative TS-13, which is devoid of energetically unfavourable syn pentane effects, even if it shows neither the stereoelectronic benefit of the Felkin-Anh geometry nor the favourable Cornforth-like anti arrangement of the polar C=O and C−N bonds.As commented above, syn pentane effects have been shown to be quantitatively very important in aldol and allylation reactions, often overriding the stereoelectronic preference associated to a Felkin-Anh geometry. 8,9,21oreover, the lower electronegativity of nitrogen as compared with oxygen may make the energetic advantage of the Cornforth geometry in the former case less important than in the latter.Indeed, as previously observed in the aldol additions of the Z enolate 1 B , Cornforth-like TSs are relevant mainly for aldehydes bearing highly electronegative atoms 35 (O,F) in the α carbon but even in this case, the minimization of the dipolar repulsion was not found able to override a syn pentane effect. 9Experimental General 40 NMR spectra were recorded at 500 MHz ( 1 H NMR) and 125 MHz ( 13 C NMR) in CDCl 3 solution at 25 °C, if not otherwise indicated, with the solvent signals as internal reference. 13C NMR signal multiplicities were determined with the DEPT pulse sequence.Mass spectra were run in the EI (70 eV), the FAB (m-45 nitrobenzyl alcohol matrix) or the electrospray (ESMS) mode.IR data, which were measured as films on NaCl plates (oils) or as KBr pellets (solids), are given only when relevant functions (C=O, OH) are present.Optical rotations were measured at 25 °C.Reactions which required an inert atmosphere (all except those 50 involving water in the reaction medium) were carried out under dry N 2 with flame-dried glassware.Commercial reagents were used as received.THF and Et 2 O were freshly distilled from sodium-benzophenone ketyl.Dichloromethane was freshly distilled from CaH 2 .Toluene was freshly distilled from sodium wire.Tertiary amines were freshly distilled from KOH.Unless detailed otherwise, "work-up" means pouring the reaction mixture into brine, followed by extraction with the solvent indicated in parenthesis.If the reaction medium was acidic, an additional washing of the organic layer with 5% aq NaHCO 3 was performed.If the reaction medium was basic, an additional washing with aq NH 4 Cl was performed.Where solutions were filtered through a Celite pad, the pad was additionally washed with the same solvent used, and the washings incorporated to the main organic layer.The latter was dried over anhydrous Na 2 SO 4 and the solvent was eliminated under reduced pressure.Column chromatography of the residue on a silica gel column (60-200 μm) was performed with elution with the indicated solvent 15 mixture.
General experimental procedure for aldol additions of ketone 15 mediated by dicyclohexylboron chloride.Chx 2 BCl (neat, 395 μL, ca.1.8 mmol) was added under Ar via syringe to an icecooled solution of Et 3 N (280 μL, 2 mmol) in anhydrous Et 2 O (5 20 mL).Erythrulose derivative 15 (453 mg, 1 mmol) was dissolved in anhydrous Et 2 O (5 mL) and added dropwise via syringe to the reagent solution.The reaction mixture was then stirred for 30 min.and then cooled to −78ºC.After dropwise addition of a solution of the appropriate aldehyde 8,9 (4 mmol) in anhydrous ether (6 mL), the reaction mixture was stirred at −78ºC for 5 h.Then phosphate buffer solution (pH 7, 6 mL) and MeOH (6 mL) were added, followed by 30% aq H 2 O 2 solution (3 mL).After stirring for 1 h at room temperature, the mixture was worked up (extraction with Et 2 O).Removal of volatiles under reduced pressure and column chromatography of the residue on silica gel (hexanes-EtOAc mixtures) afforded the aldol addition product.Yields and diastereoisomeric ratios are indicated in Scheme 4.