Addition of Chiral and Achiral Allyltrichlorostannanes to Chiral α-Alkoxy Aldehydes

Allylsilanes and allylstannanes are among the most important groups of organometallic-type reagents available for the control of acyclic stereochemistry and their reaction with aldehydes in the presence of Lewis acids is an important procedure for the preparation of homoallylic alcohols. The addition of allylstannanes bearing a stereogenic center to chiral aldehydes is particularly interesting in organic synthesis. We recently communicated that in situ prepared chiral allyltrichlorostannanes react with chiral aldehydes to give 1,4-syn homoallylic alcohols with high levels of diastereoselectivity. We wish to describe here a stereocontrolled reaction between achiral and chiral allyltrichlorostannanes with chiral lactate-derived aldehydes to give fragments which can be found in a large variety of naturally-occurring products with promising biological activities. This study details our efforts to understand the double stereodifferentiating stereocontrol elements involved in chiral allyltrichlorostannane additions to chiral aldehydes.


Introduction
Allylsilanes and allylstannanes are among the most important groups of organometallic-type reagents available for the control of acyclic stereochemistry and their reaction with aldehydes in the presence of Lewis acids is an important procedure for the preparation of homoallylic alcohols. 1,2he addition of allylstannanes bearing a stereogenic center to chiral aldehydes is particularly interesting in organic synthesis.We recently communicated that in situ prepared chiral allyltrichlorostannanes react with chiral aldehydes to give 1,4-syn homoallylic alcohols with high levels of diastereoselectivity. [3][4][5][6][7][8][9][10][11] We wish to describe here a stereocontrolled reaction between achiral and chiral allyltrichlorostannanes with chiral lactate-derived aldehydes to give fragments which can be found in a large variety of naturally-occurring products with promising biological activities. 12This study details our efforts to understand the double stereodifferentiating stereocontrol elements involved in chiral allyltrichlorostannane additions to chiral aldehydes. 13

Results and Discussion
][6][7][8][9][10][11]14 According to previously established experimental procedures, the allylsilanes were mixed with SnCl 4 (1.0 equiv. in CH 2 Cl 2 ) before the addition of a solution of the aldehyde in order to promote the SiMe 3 /SnCl 3 exchange leading to the corresponding allyltrichlorostannanes 5-8 (Scheme 1). 5 To the best of our knowledge, the first spectroscopic information available on exchange reactions involving allylsilanes and SnCl 4 was reported by Denmark and co-workers in 1988. 13In 1999, we described the first direct evidence for interaction between SnCl 4 and chiral allylic silane 3 bearing an ether functionality that generated a new species by means of NMR spectroscopy. 5In a continuation of these initial studies we have done a spectroscopic study ( 1 H and 119 Sn NMR) of the reactions of allylsilanes 1-4 (0.15 molL -1 solution in CDCl 3 ) with SnCl 4 leading to the corresponding allyltrichlorostannanes 5-8, respectively (Scheme 1).
For allyltrimethylsilane 1 the SiMe 3 /SnCl 3 exchange producing allyltrichlorostannane 5 and Me 3 SiCl is complete after 2 h at room temperature (Scheme 1). 5 For allylsilane 2 the SiMe 3 /SnCl 3 exchange to give 6 and Me 3 SiCl is faster, as expected for a 1,1-disubstituted electron-rich olefin, being complete after 10 minutes at room temperature. 14pon addition of SnCl 4 to a solution of allylsilanes (R)-3 and (S)-4 in CDCl 3 , at −60 o C, slightly yellow homogeneous solutions were obtained.The resulting NMR spectrum at −60 o C showed formation of Me 3 SiCl and complete consumption of both allylsilanes within less than 1 minute to give allyltrichlorostannanes (R)-7 and (S)-8, respectively.It appears that the oxygen functionality is responsible for the rapid SiMe 3 /SnCl 3 exchange reaction observed even at low temperatures for these particular allylsilanes and SnCl 4 .The SiMe 3 /SnCl 3 exchange is probably facilitated by coordination of tin to this oxygen followed by cleavage of the carbon-silicon bond by a free chloride ion.
Analysis of the corresponding 1 H NMR spectrum showed a deshielding for hydrogens H 1 to H 4 in allylstannane Vol. 20, No. 4, 2009   Scheme 1. SiMe 3 /SnCl 3 exchange reaction of allylsilanes 1-4 5 when compared to the same signals for allylsilane 1 (Table 1). 5e same trend is observed for allylstannane 6 when compared to allylsilane 2 (Table 2). 14 the case of (R)-7, the deshielding of the hydrogens H 6 to H 9 in the 1 H NMR spectrum provides the best diagnostics (Table 3).The methylenic hydrogens H 6 and H 7 as well as the benzylic hydrogens H 8 and H 9 are too far away from the trichlorotin group to suffer from inductive effects.We believe that the deshielding observed for these hydrogens in (R)-7 is due to the internal coordination of this oxygen to tin, as proposed in Table 3. 5 A similar behavior is observed for allylstannane (S)-8 when compared to allylsilane (S)-4 (Table 4).
In addition, we have observed 119 Sn resonance signals at −28 ppm for allylstannane 5 (Figure 1). 5 The tin chemical shift for allylstannane (R)-7 appeared at −187 ppm and for allylstannane (S)-8 appeared at −169 ppm.The tin chemical shift for complexes 9 and 10 are −301 ppm and −599 ppm, respectively, while for free SnCl 4 it is −156 ppm.We believe that tin chemical shifts are highly sensitive to oxygen bonding, as observed for 9 and 10, and the tin chemical shifts observed for (R)-7 and (S)-8 are strong evidence in favor of the proposed complexed intermediates.
The corresponding chiral aldehydes 11 and 12 were prepared in excellent yields from methyl lactate (Figure 2). 15,16These substrates have been selected to be representative of the complex fragments that might be coupled in polyacetate and polypropionate-derived aldol-type reactions.For aldehydes 11, internal chelation is presumably prevented since, with few exceptions, silyl ethers are generally recognized for their poor coordinating and chelating abilities. 17n order to check the facial selectivities of aldehydes 11 and 12, we reacted them with achiral allyltrichlorostannanes 5 and 6.Achiral allyltrichlorostannane 5 reacted with chiral α-alkoxy aldehyde (S)-11 in CH 2 Cl 2 at -78 o C to give the corresponding 1,2-syn product 13 (anti-Felkin isomer) as the major isomer in 45% yield for the two-step sequence (preparation of the aldehyde from the ester and coupling reaction), with 60:40 diastereoselectivity (Scheme 2). 18,19chiral allyltrichlorostannane 6 addition to the same aldehyde gave the corresponding 1,2-syn product 15 as the major isomer in 40% yield for the two-step sequence, again with 60:40 diastereoselectivity (Scheme 2).The stereoinduction observed in these reactions indicates that the intrinsic facial bias imposed by the resident α-OTBS substituent results in preferential formation of the 1,2-syn diastereomer, with a small preference for the anti-Felkin type approach. 19One might project that the transition states of these reactions exhibit less charge separation than the aldol processes and are, accordingly, less subject to the electrostatic influence of the α-OTBS function.
The relative stereochemistry for the major product 13 was confirmed by comparison with data described in the literature. 20In addition, we have also confirmed the relative stereochemistry for both 13 and 15 by analysis of the 1 H and 13 C NMR chemical shifts for both syn and anti isomers, as described by Heathcock 21 and Hoffmann 22 for similar structures and applied to more complex substrates in this work. 1H NMR and 13 C NMR spectroscopy are very useful tools to study substituent effects on the electronic environment of a given carbon, as well as to determine the relative stereochemistry in acyclic molecules, especially by analysis of the coupling constants (J) in the corresponding 1 H NMR spectra.In the case of homoallylic alcohols 13-16, it is possible to assign the relative stereochemistry by 1 H and 13 C NMR analysis, as these compounds, by adopting an internal hydrogen-bonded conformation, exhibit magnetically distinct NMR environments.
The intramolecular hydrogen bond leads to a 5-member ring in which the substituents are trans (13 and 15) or cis (14 and 16) and the predominance of hydrogen-bonded conformations should be reflected in different 1 H and 13 C chemical shifts (Table 5).In fact, very strong experimental evidence for the existence of intramolecular hydrogen bonds in alcohols 13-16 comes from the observed chemical shifts in the 1 H NMR and 13 C NMR spectra measured in CDCl 3 (Table 5).We have shown previously that the intrinsic low basicity of silyl ethers does not affect the capacity of the oxygen attached to the silicon atom to form intramolecular hydrogen bonds. 23The 1 H NMR spectra for compounds 13-16 are first order and the coupling constants (J) and chemical shifts (δ) are directly measured from the spectra.The 1 H NMR chemical shifts of H a and H b for both 1,2-syn isomers 13 and 15 are more shielded than the corresponding signals for H a and H b in 1,2-anti homoallylic alcohols 14 and 16.For alcohol 13 (R = TBS), the 1 H chemical shifts are 3.38 (Ha) and 3.70 (Hb), showing a trans orientation between these two hydrogens.For alcohol 14, the 1 H chemical shifts are 3.56 (Ha) and 3.78 (Hb), showing a cis orientation between these two hydrogens.The same trend is observed for syn and anti homoallylic alcohols 15 and 16.
In addition, the 13 C chemical shifts for the methyl group in syn compounds 13 and 15 are more deshielded when compared to the 13 C chemical shifts in 14 and 16.
We next examined the stereochemical impact of a benzyl-protecting group at the oxygen in position α to the carbonyl aldehyde.Before starting the study described in Scheme 3, we expected that under conditions favouring internal chelation, the carbonyl facial bias of aldehyde (S)-12 should be highly predictable.In fact, that proved to be the case.The facial bias of aldehyde (S)-12 was determined after reaction with allyltrichlorostannane 5 in CH 2 Cl 2 at −78 °C to give a 97:3 mixture of diastereoisomers 17 and 18, in 45% yield over the two step sequence (Scheme 3).
This benzyl-protecting group imposes an intrinsic facial bias on the carbonyl that results in the formation of the  1,2-syn-dioxygen relationship.This leads to higher levels of diastereoselection when compared to the use of a TBS protecting group.The 1,2-syn relative stereochemistry for adduct 17 was confirmed by comparison of 1 H-and 13 C NMR data as well as its optical rotation with literature values. 24[5][6][7][8][9][10][11] At this point we initiated the double stereodifferentiating studies involving allyltrichlorostannane (R)-7 and chiral aldehydes 11 and 12. Addition of allyltrichlorostannane (R)-7 to aldehyde (S)-11 in CH 2 Cl 2 at −78 °C gave an 85:15 mixture of diastereoisomers 19 and 20, respectively, in 70% yield for the two-step sequence (Scheme 4).
The facial bias of this chiral allyltrichlorostannane is dominated by the α−methyl stereocenter and tends to give the 1,4-syn isomer with Si-face attack, but the facial bias of this particular aldehyde is to give the 1,2-syn product.We were surprised with the result with aldehyde (R)-11 as we were expecting a higher level of diastereoselection in favor of the product 21.
The relative stereochemistry for the major products was determined after conversion to the corresponding dimethylacetonides (Scheme 5).Treatment of a mixture of 19 and 20 with TBAF in THF at room temperature gave diols 23 and 24 (67% yield), which was followed by reaction with 2,2-dimethoxypropane and catalytic amounts of camphorsulphonic acid (CSA) to give acetonides 25 and 26 in 40% yield after purification by flash column chromatography (Scheme 5).
The cis-acetonide 25 comes from the 1,2-anti isomer 19 and the trans-acetonide 26 originates from the corresponding 1,2-syn isomer 20.The dimethyl groups (Me a and Me b ) in both trans and cis dimethylacetonides are in different (average) chemical environments, giving rise to characteristic signals.As observed by Lombardo and coworkers 25 the difference in chemical shifts of the methyl groups (Me a and Me b ) in the five member ring of the dimethylacetonides is larger for the cis isomer (0.12-0.14 ppm) when compared to the trans isomer (0.01-0.04 ppm). 25In Figure 3 we can observe the partial 1 H NMR for cis and trans acetonides 25 and 26 .
There is a larger difference in chemical shifts for the methyl groups (Me a and Me b ) in the cis isomer (∆δ = 0.12 ppm) when compared to the chemical shifts for the same methyl groups of the trans isomer (∆δ = 0.05 ppm).Based on this result we conclude that the 1,2-anti isomer 19 is the major product. 26he relative stereochemistry for compounds 21 and 22 was determined based on the same strategy (Scheme 6).
As before, we observed that the most intense signals come from the trans-acetonide 30, which in this case originates from the 1,2-syn adduct 21 (Figure 4).
It is interesting to point out that as the facial bias of this aldehyde is to give the 1,2-syn products, we expected a matched case and much higher levels of diastereoselectivity in the reaction of (R)-7 with (R)-12.Again, we were surprised to see that this was not the case.
The relative stereochemistries for both 31 and 33 were determined by applying the same methodology based on the 13 C NMR chemical shifts described before for 13-16 (Table 5).The 1,2-anti isomer is the major product as we can observe from the 13 C NMR chemical shifts for the more shielded Me c (Figure 5).In the case of 31 and 32, the 13 C chemical shifts for Me c in 31 appears more shielded (14.8 ppm) when compared to 32 (15.5 ppm).
In the case of 33 and 34, we were able to confirm that the 1,2-syn is the major product, based on the 13 C chemical shifts for Me c in 33 (15.5 ppm) and 34 (14.5 ppm).
We next examined the addition of the same allylstannane to the enantiomeric aldehyde (R)-11 affording a 75:25 mixture of isomers 37 and 38 in 47% yield for the twostep sequence.Again, these reactions with α-OTBS aldehydes are characterized by poor levels of diastereoselectivity.
The relative stereochemistry for the major products was again determined based on the analysis of the 13 C NMR chemical shifts of the corresponding 5-membered dimethylacetonides (Scheme 9).Treatment of 35 and 36 with TBAF at rt followed by treatment of the corresponding diols under acidic conditions with 2,2-dimethoxypropane gave acetonides 41 and 42, respectively.
The 1 H NMR methyl resonances observed at 1.34 and 1.46 for 41 are characteristic of a cis-acetonide and 1 H NMR methyl resonances at 1.38 and 1.40 for 42 are consistent with a trans-acetonide (Figure 6). 25 The same strategy was applied to 37 and 38, providing acetonides 45 and 46 (Scheme 10).
As can be seen from Figure 7, the trans-acetonide, which comes from the 1,2-syn adduct is the major isomer observed in this reaction.
The selectivity in the latter case was somewhat disappointing, given the result observed in the reaction of aldehyde 12 with allyltrichlorostannane 5 (Scheme 3).
The relative stereochemistries for both 47 and 49 were determined by applying the same methodology described before for 13-16 (Table 5).The 1,2-anti isomer is the major product as can be observed from the 13 C NMR chemical shifts for the more shielded Me c (Figure 8).In the case of 49 and 50, the 13 C chemical shifts for Me c in 50 appears more shielded (14.7 ppm) when compared to 49 (15.6 ppm).

Conclusions
The examples presented in this work show that the levels of π−facial selection are dependent on the absolute stereochemistries of the aldehydes as well as of the allyltrichlorostannanes.The results from these experiments suggest that the stereochemical relationships between the allyltrichlorostannane and aldehyde substituents may confer either a reinforcing (matched) or opposing (mismatched) facial bias on the carbonyl moiety.One possible reason for this result could be attributed to the involvement of energetically similar chair and twist-boat transition states that lead to diastereomeric product formation.Another possibility to consider in these reactions is that nonbonded interactions between the allyltrichlorostannane and α substituents on the aldehyde may not be significant in pericyclic transition states leading to either Felkin or anti-Felkin addition products. 13We believe that this chemistry is significant in the context of acyclic diastereoselection and will prove to be useful in the synthesis of more complex molecules, like polyacetate and polypropionate-derived natural products. 27,28