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1. Synthesis of Optically Active b-Amino Alcohols Changyou Yuan
Department of Chemistry
Michigan State University
2. The beta amino alcohol moiety is a common structural component in a vast group of naturally occurring and
synthetic molecules. The presence of this moiety and the relative (as well as absolute) stereo-chemistry are generally important for the biological
activity of molecules containing a vicinal amino alcohol.
Three general groups of vicinal amino alcohols have been reported in the literature: (1) naturally occurring molecules containing vicinal amino alcohols; (2) synthetic pharmacologically active molecules containing vicinal amino alcohols; (3) catalysts containing vicinal amino alcohols.
dipeptide bestatin. Structurally bestatin contains a syn-a-hydroxy-b-amino acid. Bestatin is an aminopeptidase inhibitor that exhibits immunomodulatory activity, and is used clinically as an adjuvant in cancer chemotherapy.
Hapalosin is an anti-bhydroxy-g-amino acid containing depsipeptide recently isolated from bluegreen algae. People are interested in Hapalosin because
its ability to inhibit multidrug resistance (MDR) in drug resistant cancer cells.
A host of synthetic molecules used as drugs or pharmacological agents also contain the vicinal amino alcohol moiety.
Among the best known are the peptide analogues of the HIV protease inhibitor saquinavir, 1
enantiomerically pure amino alcohols as ligands or chiral auxiliaries . The best known are the `Evans auxiliaries' (e.g. 3). These amino alcohol derived oxazolidinones have been used for a host of reactions ranging from aldol condensations to Diels alder reactions.
The oxaborolidines (4) derived from proline have been extensively used for the asymmetric reductions of carbonyl compounds.
The beta amino alcohol moiety is a common structural component in a vast group of naturally occurring and
synthetic molecules. The presence of this moiety and the relative (as well as absolute) stereo-chemistry are generally important for the biological
activity of molecules containing a vicinal amino alcohol.
Three general groups of vicinal amino alcohols have been reported in the literature: (1) naturally occurring molecules containing vicinal amino alcohols; (2) synthetic pharmacologically active molecules containing vicinal amino alcohols; (3) catalysts containing vicinal amino alcohols.
dipeptide bestatin. Structurally bestatin contains a syn-a-hydroxy-b-amino acid. Bestatin is an aminopeptidase inhibitor that exhibits immunomodulatory activity, and is used clinically as an adjuvant in cancer chemotherapy.
Hapalosin is an anti-bhydroxy-g-amino acid containing depsipeptide recently isolated from bluegreen algae. People are interested in Hapalosin because
its ability to inhibit multidrug resistance (MDR) in drug resistant cancer cells.
A host of synthetic molecules used as drugs or pharmacological agents also contain the vicinal amino alcohol moiety.
Among the best known are the peptide analogues of the HIV protease inhibitor saquinavir, 1
enantiomerically pure amino alcohols as ligands or chiral auxiliaries . The best known are the `Evans auxiliaries' (e.g. 3). These amino alcohol derived oxazolidinones have been used for a host of reactions ranging from aldol condensations to Diels alder reactions.
The oxaborolidines (4) derived from proline have been extensively used for the asymmetric reductions of carbonyl compounds.
3. Strategies Available for the Synthesis of Optically Active b-Amino Alcohols
4. Outline
5. Outline
6. Lithiation of O-benzyl Carbamates–imine Addition a carbamate protecting group to favour deprotonation, in the presence of
TMEDA this group increases the kinetic acidity of the a protons and stabilizes the lithio derivatives by chelation.
Deprotonation of O-benzyl carbamates 1 with sec-BuLi in the presence of TMEDA, racemic -oxybenzyllithium compounds 2, were generated,
Alkylation of 2 with the p-anisidine-derived imine resulted in the formation of protected threo and erythro -amino alcohols 4 and 5.
alkylation conditions has a strong influence on the stereoselectivity.
Thus, when the reaction was two hours at -78°C, and allowed to warm to room temperature before quenching, the erythro -amino alcohol derivatives 5a–c were obtained as major products, though with modest diastereoselectivity
. However, when at –78°C for 72 h, complete reversal of the stereochemical outcome was observed and the threo -amino alcohol
derivative 4a was obtained as a single diastereomer, albeit in moderate yield (33%).
The stereochemical outcome of the reaction could be explained in terms of the most
favourable transition state for the addition. We can assume that the -oxybenzylcarbanion 2 is stabilised by
coordination of lithium to the carbonyl oxygen. There-fore, if the imine approaches anion 2 with coordination
of the nitrogen atom to the lithium metal, an approach from the Si face would be more favourable, minimising
the repulsion between the two phenyl groups in the transition state. Similar diastereoselectivity has been
reported in the addition of -aminobenzyllithium salts to benzylidene-p-anisidine.13
Nevertheless, This reversal of stereoselection could also be observed on carbamate 1b, obtaining the threo -amino alcohol derivative 4b as the
major product, though with almost no diastereoselectivity.
a carbamate protecting group to favour deprotonation, in the presence of
TMEDA this group increases the kinetic acidity of the a protons and stabilizes the lithio derivatives by chelation.
Deprotonation of O-benzyl carbamates 1 with sec-BuLi in the presence of TMEDA, racemic -oxybenzyllithium compounds 2, were generated,
Alkylation of 2 with the p-anisidine-derived imine resulted in the formation of protected threo and erythro -amino alcohols 4 and 5.
alkylation conditions has a strong influence on the stereoselectivity.
Thus, when the reaction was two hours at -78°C, and allowed to warm to room temperature before quenching, the erythro -amino alcohol derivatives 5a–c were obtained as major products, though with modest diastereoselectivity
. However, when at –78°C for 72 h, complete reversal of the stereochemical outcome was observed and the threo -amino alcohol
derivative 4a was obtained as a single diastereomer, albeit in moderate yield (33%).
The stereochemical outcome of the reaction could be explained in terms of the most
favourable transition state for the addition. We can assume that the -oxybenzylcarbanion 2 is stabilised by
coordination of lithium to the carbonyl oxygen. There-fore, if the imine approaches anion 2 with coordination
of the nitrogen atom to the lithium metal, an approach from the Si face would be more favourable, minimising
the repulsion between the two phenyl groups in the transition state. Similar diastereoselectivity has been
reported in the addition of -aminobenzyllithium salts to benzylidene-p-anisidine.13
Nevertheless, This reversal of stereoselection could also be observed on carbamate 1b, obtaining the threo -amino alcohol derivative 4b as the
major product, though with almost no diastereoselectivity.
7. Asymmetric Lithiation of O-benzyl Carbamates–imine Addition in the presence of the chiral diamine (-)-sparteine, enantioselective deprotonation reactions of carbamates could be carried out with organolithiums.
deprotonation with sec-BuLi/(-)-sparteine, to react with imine 3 gave the 4
in direct contrast to the results obtained with TMEDA, when the reaction mixtures were kept at –78°C for 2 h and allowed to warm to rt, in all cases, the threo isomers 4a–c were obtained as the major diastereomers (entries 1, 6, and 8), although with modest e.e.
When the temperature was kept at –78°C for 6 h, 4c were obtained as single diastereomers, with e.e.s of 56 and 76%, respectively. the enantiomeric purity of the products was significantly improved after Crystallisation.
Mechanism:
Although the stereo- chemical course of the electrophilic substitution of chi-
ral benzyllithium compounds is still unclear, it has been established that some electrophiles show strong tenden-
cies for stereoinversion (alkyl and acyl halides, CO2, carbon disulphide, silyl and stannyl chlorides) while
others for stereoretention (protonation with alcohols or acids, reaction with aldehydes or esters).4d In the latter case, it can be assumed that a pre-association of the
reagent at the cation occurs.
In a series of experiments, carbamate 1b was deprotonated with s-BuLi in the presence of (-)-sparteine, and quenched by the addition of CO2, followed by esterification with diazomethane. The methoxycarbonyl derivatives were obtained with modest e.e. in Et2O (14%), which was improved in hexane
up to 82%. Thus, in accord with the (S)-configuration of the methoxycarbonyl derivative obtained, the configuration of the favoured ion-pair was assumed to be (S).
the favoured ion pair is (S)-2, which reacts with imine 3 with retention of configuration to give the threo products RR 4.
in the presence of the chiral diamine (-)-sparteine, enantioselective deprotonation reactions of carbamates could be carried out with organolithiums.
deprotonation with sec-BuLi/(-)-sparteine, to react with imine 3 gave the 4
in direct contrast to the results obtained with TMEDA, when the reaction mixtures were kept at –78°C for 2 h and allowed to warm to rt, in all cases, the threo isomers 4a–c were obtained as the major diastereomers (entries 1, 6, and 8), although with modest e.e.
When the temperature was kept at –78°C for 6 h, 4c were obtained as single diastereomers, with e.e.s of 56 and 76%, respectively. the enantiomeric purity of the products was significantly improved after Crystallisation.
Mechanism:
Although the stereo- chemical course of the electrophilic substitution of chi-
ral benzyllithium compounds is still unclear, it has been established that some electrophiles show strong tenden-
cies for stereoinversion (alkyl and acyl halides, CO2, carbon disulphide, silyl and stannyl chlorides) while
others for stereoretention (protonation with alcohols or acids, reaction with aldehydes or esters).4d In the latter case, it can be assumed that a pre-association of the
reagent at the cation occurs.
In a series of experiments, carbamate 1b was deprotonated with s-BuLi in the presence of (-)-sparteine, and quenched by the addition of CO2, followed by esterification with diazomethane. The methoxycarbonyl derivatives were obtained with modest e.e. in Et2O (14%), which was improved in hexane
up to 82%. Thus, in accord with the (S)-configuration of the methoxycarbonyl derivative obtained, the configuration of the favoured ion-pair was assumed to be (S).
the favoured ion pair is (S)-2, which reacts with imine 3 with retention of configuration to give the threo products RR 4.
8. Asymmetric Lithiation of O-benzyl Carbamates–imine Addition
9. Addition of a-Sulfinyl Carbanions to N-p-Tolylsulfinylketimines Reactions of sulfinamide 3with both enantiomers of sulfoxides 1 at -78 °C afford mixtures of amino sulfoxides 5A and 5B,
starting from (S)-1, or 6A and 6B, starting from (R)-1, in combined yields higher than 80%.
The diastereoselectivity from (R)-1 (80% de, entry 5) is slightly higher than from (S)-1 (60% de, entry 1).. At 0 °C, yields are in general moderate, around
65% (entries 2, 4, 6, and 8), but in some cases stereoselectivities are higher (compare entries 1 and 5 with 2 and
6 respectively).
From the results in Table 1, it can thus be concluded that the reactions of ketimine 3 with both
sulfoxides at 0 °C are completely stereoselective affording compounds 5A (entry 2) and 6A (entry 6) as single
diastereomers (de > 98%, estimated by 1H NMR on the reaction crudes).
Reactions of sulfinamide 3with both enantiomers of sulfoxides 1 at -78 °C afford mixtures of amino sulfoxides 5A and 5B,
starting from (S)-1, or 6A and 6B, starting from (R)-1, in combined yields higher than 80%.
The diastereoselectivity from (R)-1 (80% de, entry 5) is slightly higher than from (S)-1 (60% de, entry 1).. At 0 °C, yields are in general moderate, around
65% (entries 2, 4, 6, and 8), but in some cases stereoselectivities are higher (compare entries 1 and 5 with 2 and
6 respectively).
From the results in Table 1, it can thus be concluded that the reactions of ketimine 3 with both
sulfoxides at 0 °C are completely stereoselective affording compounds 5A (entry 2) and 6A (entry 6) as single
diastereomers (de > 98%, estimated by 1H NMR on the reaction crudes).
10. Addition of a-Sulfinyl Carbanions to N-p-Tolylsulfinylketimines As before, the condensation of the ethyl sulfoxide with ketimines afforded the corresponding compounds, with good yields and variable diastereoselectivities
In all reactions, only two of the four possible diastereomeric 2-sulfinyl-1-propylamines are formed, which suggests that they evolve with a complete control of the stereoselectivity in one of the two newly created chiral centers.
From the results shown above it is evident that the configuration at the carbon bonded to nitrogen is completely controlled
by the sulfur configuration at the sulfinyl ketimine, regardless of the configuration of the sulfinyl group at the nucleophile.
Results indicate that the configuration at the carbon bonded to the sulfur atom is mainly controlled by that of the nucleophile. Thus, (R)-2 mainly induces the (S) configuration whereas (S)-2 gives the (R) configuration.
The small variations observed in the stereoselectivity with variable temperature and nature of the aromatic residue are difficult to explain, but the E/Z isomerization of the imine and the association of the 2-methoxynaphthyl residue to the lithium may play some role.
As before, the condensation of the ethyl sulfoxide with ketimines afforded the corresponding compounds, with good yields and variable diastereoselectivities
In all reactions, only two of the four possible diastereomeric 2-sulfinyl-1-propylamines are formed, which suggests that they evolve with a complete control of the stereoselectivity in one of the two newly created chiral centers.
From the results shown above it is evident that the configuration at the carbon bonded to nitrogen is completely controlled
by the sulfur configuration at the sulfinyl ketimine, regardless of the configuration of the sulfinyl group at the nucleophile.
Results indicate that the configuration at the carbon bonded to the sulfur atom is mainly controlled by that of the nucleophile. Thus, (R)-2 mainly induces the (S) configuration whereas (S)-2 gives the (R) configuration.
The small variations observed in the stereoselectivity with variable temperature and nature of the aromatic residue are difficult to explain, but the E/Z isomerization of the imine and the association of the 2-methoxynaphthyl residue to the lithium may play some role.
12. Addition of a-Sulfinyl Carbanions to N-p-Tolylsulfinylketimines - stereocontrol The six-membered TS involving the association of the lithium to the sulfinyl oxygen and the nucleophilic carbon. The chair like TS B, avoiding the 1,3-diaxial interaction between the aromatic residue at the N-arylsulfinyl group and the methyl group of the ketimine present in TS A, must be highly favored.
On the basis that only TS B can be involved, the structure of the attacking carbon at the TS of the nucleophilic addition could be described like a trigonal bipyramid with the apical positions occupied by the bulkier substituents (C=N and SOTol). Four possible transition states can be postulated.
TS-IIS and TS-IIR have the C-sulfinyl oxygen associated to the lithium atom
whereas such association does not exist for the corresponding TS-IS and TS-IR.
In the two latter cases, free rotation around the C-S bond is possible and the S-O bond will arrange anti with respect
to the C-Li bond in order to minimize the electrostatic interactions. Moreover, the methyl group joined to C-Li
will adopt the less hindered anti relationship with respect to the bulkier phenyl. Thus, the methyl group adopts a
pseudoaxial arrangement in TS-IR (derived from (R)-2), but a more stable pseudoequatorial position in TS-IS.
When the C-sulfinyl oxygen is associated with the lithium, the relative stability of the TS’s is related to the
steric interactions of the substituents at the four membered ring, which necessarily adopt an eclipsed
arrangement. Thus, the preferred configuration of the carbanion is the one that avoids the Tol/Me interaction.
it is easily deduced that TS-IIS is now less stable than TS-IIR, due to the relative orientation of the
methyl group in the chair like conformation.
If we assume the equilibration of the two possible transition states for
each enantiomer (TS-I and TS-II) the experimental results can be satisfactorily explained.
The equilibrium must be shifted toward TS-I, thus explaining the higher proportion of compounds B obtained in all the reactions
shown in Table 2.
Nevertheless the shifting toward TSIS must be higher than for TS-IR. An increase of the
temperature would weak even more the association of the sulfinyl group to the lithium atoms, thus provoking
the shift of the equilibrium toward TS-I, which would increase the proportion of the B isomers.The six-membered TS involving the association of the lithium to the sulfinyl oxygen and the nucleophilic carbon. The chair like TS B, avoiding the 1,3-diaxial interaction between the aromatic residue at the N-arylsulfinyl group and the methyl group of the ketimine present in TS A, must be highly favored.
On the basis that only TS B can be involved, the structure of the attacking carbon at the TS of the nucleophilic addition could be described like a trigonal bipyramid with the apical positions occupied by the bulkier substituents (C=N and SOTol). Four possible transition states can be postulated.
TS-IIS and TS-IIR have the C-sulfinyl oxygen associated to the lithium atom
whereas such association does not exist for the corresponding TS-IS and TS-IR.
In the two latter cases, free rotation around the C-S bond is possible and the S-O bond will arrange anti with respect
to the C-Li bond in order to minimize the electrostatic interactions. Moreover, the methyl group joined to C-Li
will adopt the less hindered anti relationship with respect to the bulkier phenyl. Thus, the methyl group adopts a
pseudoaxial arrangement in TS-IR (derived from (R)-2), but a more stable pseudoequatorial position in TS-IS.
When the C-sulfinyl oxygen is associated with the lithium, the relative stability of the TS’s is related to the
steric interactions of the substituents at the four membered ring, which necessarily adopt an eclipsed
arrangement. Thus, the preferred configuration of the carbanion is the one that avoids the Tol/Me interaction.
it is easily deduced that TS-IIS is now less stable than TS-IIR, due to the relative orientation of the
methyl group in the chair like conformation.
If we assume the equilibration of the two possible transition states for
each enantiomer (TS-I and TS-II) the experimental results can be satisfactorily explained.
The equilibrium must be shifted toward TS-I, thus explaining the higher proportion of compounds B obtained in all the reactions
shown in Table 2.
Nevertheless the shifting toward TSIS must be higher than for TS-IR. An increase of the
temperature would weak even more the association of the sulfinyl group to the lithium atoms, thus provoking
the shift of the equilibrium toward TS-I, which would increase the proportion of the B isomers.
14. Radical Addition of Hydroxymethyl and Vinyl Groups to C=N Bonds Nonpolar radical additions to C=N bonds could efficiently construct crowded C-C bonds, and tolerate highly functionalized precursors. The problem is can this process be stereocontrolled?
Recently, the Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral R-hydroxyhydrazones were achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a temporary silicon connection.
Nonpolar radical additions to C=N bonds could efficiently construct crowded C-C bonds, and tolerate highly functionalized precursors. The problem is can this process be stereocontrolled?
Recently, the Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral R-hydroxyhydrazones were achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a temporary silicon connection.
15. Hydroxymethyl Addition to Oxime Ethers efforts to extract 5 into an acidic aqueous phase or chromatograph it on silica gel were thwarted by decomposition. Direct Tamao oxidation of the crude cyclization product gave a complex mixture. Because hydroxylamines are prone to oxidation, it seemed prudent to acylate the basic nitrogen before exposure to oxidant.
Cyclization of oxime ether 1 under standard tin-mediated conditions led to oxasilacyclopentane 2 is unstable,
Acylation of 2 could be achieved with methyl chloroformate and pyridine; Tamao oxidation of this product then
gave a mixture of three oxazolidinones cis-3, trans-3, and 4 in an overall 52% yield from 1 (Scheme 2). Although
cis-3 and 4 were each separated from the mixture by silica gel chromatography, trans-3 was not obtained in
pure form. After this two-stage derivatization, the anti/syn ratio was 9:1. Two similar derivatization experiments
resulted in anti/syn ratios of 4.9:1 and 11.6:1, with low isolated yields. Because all three experiments began with
the same crude cyclization material, the ratio of oxazolidinones apparently does not reflect the actual diastereomer
ratio from radical cyclization. efforts to extract 5 into an acidic aqueous phase or chromatograph it on silica gel were thwarted by decomposition. Direct Tamao oxidation of the crude cyclization product gave a complex mixture. Because hydroxylamines are prone to oxidation, it seemed prudent to acylate the basic nitrogen before exposure to oxidant.
Cyclization of oxime ether 1 under standard tin-mediated conditions led to oxasilacyclopentane 2 is unstable,
Acylation of 2 could be achieved with methyl chloroformate and pyridine; Tamao oxidation of this product then
gave a mixture of three oxazolidinones cis-3, trans-3, and 4 in an overall 52% yield from 1 (Scheme 2). Although
cis-3 and 4 were each separated from the mixture by silica gel chromatography, trans-3 was not obtained in
pure form. After this two-stage derivatization, the anti/syn ratio was 9:1. Two similar derivatization experiments
resulted in anti/syn ratios of 4.9:1 and 11.6:1, with low isolated yields. Because all three experiments began with
the same crude cyclization material, the ratio of oxazolidinones apparently does not reflect the actual diastereomer
ratio from radical cyclization.
16. Hydroxymethyl Addition to Hydrazones Cyclization of hydrazone 5 using standard tin hydride conditions (1.4 equiv of Bu3SnH, 10 mol % AIBN, PhH,
0.02 M) resulted in very clean, efficient C-C bond construction to furnish heterocycles 6. These cyclic silanes were unstable to normal silica gel chromatography but could be stored indefinitely in benzene at -5 °C without significant decomposition. In the same flask, Tamao oxidation(??) for oxidative removal of the tether then smoothly delivered anti-2-hydrazino-1,3-diols 13 in good yields. It is
worth noting that the Tamao oxidation occurs cleanly in the presence of an unprotected hydrazine; this contrasts
with the behavior of hydroxylamine 5 described above.
Cyclization of hydrazone 5 using standard tin hydride conditions (1.4 equiv of Bu3SnH, 10 mol % AIBN, PhH,
0.02 M) resulted in very clean, efficient C-C bond construction to furnish heterocycles 6. These cyclic silanes were unstable to normal silica gel chromatography but could be stored indefinitely in benzene at -5 °C without significant decomposition. In the same flask, Tamao oxidation(??) for oxidative removal of the tether then smoothly delivered anti-2-hydrazino-1,3-diols 13 in good yields. It is
worth noting that the Tamao oxidation occurs cleanly in the presence of an unprotected hydrazine; this contrasts
with the behavior of hydroxylamine 5 described above.
17. Tandem Thiyl Addition-Cyclization: Vinyl Addition to Hydrazones Treatment of vinylsilane ether 8 with thiophenol and AIBN (cyclohexane, reflux) resulted in very clean, efficient C-C bond construction
to furnish cyclic silane 9. 9 was smoothly converted to allylic hydrazino alcohol 10 (racemic) by the action of excess KF .
This one-pot process achieves vinyl addition to a C=N bond under neutral conditions, without toxic and difficult-to remove stannane reagents.
For R are Me, tBu, iPr, Ph, all gave high diasteroeselectivity and OK to good yield.
A value : magnitute of equatorial preference
Treatment of vinylsilane ether 8 with thiophenol and AIBN (cyclohexane, reflux) resulted in very clean, efficient C-C bond construction
to furnish cyclic silane 9. 9 was smoothly converted to allylic hydrazino alcohol 10 (racemic) by the action of excess KF .
This one-pot process achieves vinyl addition to a C=N bond under neutral conditions, without toxic and difficult-to remove stannane reagents.
For R are Me, tBu, iPr, Ph, all gave high diasteroeselectivity and OK to good yield.
A value : magnitute of equatorial preference
18. Diastereocontrol in Radical Addition – Cyclization Beckwith-Houk Model The Beckwith-Houk model(??) predicts enhancement of diastereoselectivity upon increasing
substituent steric demand in 4-substituted 5-hexenyl radical cyclizations.
The present method was conceived in expectation that a similar transition state model would apply.
The observed diastereoselectivity in the cyclizaiton proecss can be explained by the Beckwith-Houk model.
A transition state resembling chairlike conformation A, wherein the pseudoequatorial orientation of substituent R minimizes allylic strain, is consistent with the observed anti diastereoselection. The minor syn product would be expected from disfavored chair-axial (B) and/or boat (C) conformations. Boat-axial conformations are considered to have negligible contributions to stereocontrol in 5-hexenyl radical cyclizations.
The diastereoselectivity of vinyl addition, 90:10 or higher in all cases, is also attributable to the conformational
constraints described above.
The vinyl additions occurred with consistently higher stereoselectivity in
comparison to hydroxymethyl addition. This fact may be rationalized by considering the relative reactivities of the
two radical intermediates A and D. If the more reactive silylmethyl radicals A are assumed to have
earlier transition states than the more substituted alkyl radicals D, this might elicit a decreased contribution from
the cyclohexane-like conformational constraints described above and a decreased differentiation of the diastereomeric
transition states leading to the alternative anti and syn products.
The Beckwith-Houk model(??) predicts enhancement of diastereoselectivity upon increasing
substituent steric demand in 4-substituted 5-hexenyl radical cyclizations.
The present method was conceived in expectation that a similar transition state model would apply.
The observed diastereoselectivity in the cyclizaiton proecss can be explained by the Beckwith-Houk model.
A transition state resembling chairlike conformation A, wherein the pseudoequatorial orientation of substituent R minimizes allylic strain, is consistent with the observed anti diastereoselection. The minor syn product would be expected from disfavored chair-axial (B) and/or boat (C) conformations. Boat-axial conformations are considered to have negligible contributions to stereocontrol in 5-hexenyl radical cyclizations.
The diastereoselectivity of vinyl addition, 90:10 or higher in all cases, is also attributable to the conformational
constraints described above.
The vinyl additions occurred with consistently higher stereoselectivity in
comparison to hydroxymethyl addition. This fact may be rationalized by considering the relative reactivities of the
two radical intermediates A and D. If the more reactive silylmethyl radicals A are assumed to have
earlier transition states than the more substituted alkyl radicals D, this might elicit a decreased contribution from
the cyclohexane-like conformational constraints described above and a decreased differentiation of the diastereomeric
transition states leading to the alternative anti and syn products.
19. Comparison of the Addition Reactions
20. Outline
21. Asymmetric Hydrogenations of a-N-substituted ß-keto esters - Preparation the Syn ß– Amino Alcohols DKR in association with Ru-catalyzed hydrogenation turned out to be a powerful synthetic tool to control two adjacent stereogenic centers in one single chemical operation.
Using the S-SYNPHOS Ru catalyst, the syn-a -benzamido ß -hydroxy esters 5 were synthesized in good yields (up to 92%) by hydrogena-tion
of the corresponding ß -keto esters 3, good to excel-lent syn diastereoselectivities (86 to 99% de) were ob-served. excellent levels of enantioselectivity were achieved (9799% ee).
It is noteworthy that the diastereoisomeric excesses ob-tained are directly linked to the steric hindrance created by
the side chain; the higher the steric hindrance, the better the diastereoselectivity of the reaction [for the long chain
3d (R C15H31) or branched chain 3e (R iPr) substrates.DKR in association with Ru-catalyzed hydrogenation turned out to be a powerful synthetic tool to control two adjacent stereogenic centers in one single chemical operation.
Using the S-SYNPHOS Ru catalyst, the syn-a -benzamido ß -hydroxy esters 5 were synthesized in good yields (up to 92%) by hydrogena-tion
of the corresponding ß -keto esters 3, good to excel-lent syn diastereoselectivities (86 to 99% de) were ob-served. excellent levels of enantioselectivity were achieved (9799% ee).
It is noteworthy that the diastereoisomeric excesses ob-tained are directly linked to the steric hindrance created by
the side chain; the higher the steric hindrance, the better the diastereoselectivity of the reaction [for the long chain
3d (R C15H31) or branched chain 3e (R iPr) substrates.
22. Asymmetric Hydrogenations of a-N-substituted ß-keto esters - Preparation the Anti ß– Amino Alcohols The crude hydrogenated products were treated with benzoic anhydride and triethyl-amine to afford the corresponding a -benzamido ß –hydroxy esters 5.
According to these preliminary results, we found that dichloromethane was the most appropriate solvent to slow down the reaction rate and favor better discrimination by the Ru-catalyst.
Using the same catalyst while with the free amino group, the anti alpha benzamido beta hydroxy ester were obtained.
Because of the poor solubility of the a –amino ß -keto ester hydrochlorides 4 in dichloromethane,
the hydrogenations were carried out with 9% of alcoholic solvent (MeOH or EtOH), allowing better homogeneity of
the reaction medium. After optimization of the conditions, we found that 2 mol % of catalyst were required to ensure
complete conversion and that the atropisomeric ligand SYNPHOS ?, provided high selectivitiey.
Both anti-(2S,3S) and (2R,3R) configurations of the a –benzamido ß -hydroxy esters 5 were obtained efficiently with
equal ease.
Finally, high enantioselectivities (from 91 to 97%) and diastereoselectivities, ranging from 86% for 4a (R C3H7,
Entries 1 and 2) to 99% for 4e (R iPr, Entry 9), were achieved with this catalytic system. Once again, the de fol-lowed
the same tendency as previously observed, according to the nature of the side chain and its hindrance (Scheme 5).
Although we have no clear evidence to explain the stereo-chemical
outcome of the hydrogenation of these a –amino ß -keto ester hydrochlorides (high anti selectivity), we postu-late
that the reaction proceeds through a favored chair-like transition state (a) with the ketone and the ester carbonyl
function chelated on the ruthenium and the NH2.HCl group in an equatorial position rather than a transition
state (b) with NH2.HCl in an axial position The crude hydrogenated products were treated with benzoic anhydride and triethyl-amine to afford the corresponding a -benzamido ß –hydroxy esters 5.
According to these preliminary results, we found that dichloromethane was the most appropriate solvent to slow down the reaction rate and favor better discrimination by the Ru-catalyst.
Using the same catalyst while with the free amino group, the anti alpha benzamido beta hydroxy ester were obtained.
Because of the poor solubility of the a –amino ß -keto ester hydrochlorides 4 in dichloromethane,
the hydrogenations were carried out with 9% of alcoholic solvent (MeOH or EtOH), allowing better homogeneity of
the reaction medium. After optimization of the conditions, we found that 2 mol % of catalyst were required to ensure
complete conversion and that the atropisomeric ligand SYNPHOS ?, provided high selectivitiey.
Both anti-(2S,3S) and (2R,3R) configurations of the a –benzamido ß -hydroxy esters 5 were obtained efficiently with
equal ease.
Finally, high enantioselectivities (from 91 to 97%) and diastereoselectivities, ranging from 86% for 4a (R C3H7,
Entries 1 and 2) to 99% for 4e (R iPr, Entry 9), were achieved with this catalytic system. Once again, the de fol-lowed
the same tendency as previously observed, according to the nature of the side chain and its hindrance (Scheme 5).
Although we have no clear evidence to explain the stereo-chemical
outcome of the hydrogenation of these a –amino ß -keto ester hydrochlorides (high anti selectivity), we postu-late
that the reaction proceeds through a favored chair-like transition state (a) with the ketone and the ester carbonyl
function chelated on the ruthenium and the NH2.HCl group in an equatorial position rather than a transition
state (b) with NH2.HCl in an axial position
23. Outline
24. To achieve an efficient cross-coupling between aldehydes and aldimines, it is significant for either substrate to be more easily reduced to the corresponding reactive
species which reacts with another substrate without homo-coupling.
Treatment of a mixture of ferrocenecarboxaldehyde (1) and N-alkyl ferrocenylideneamines 2a, 2b or hydrazone
derivatives 2d, 2e with samarium iodide in THF gave homo-coupling ‚-diol 4 as a diastereomeric mixture along
with recovered ferrocenylideneamine or its hydrolyzed ferrocenecarboxaldehyde depending on the structure of
ferrocenylimine (entries 1, 2, 4, and 5). With N-phenyl ferrocenylideneamine (2c), two corresponding homocoupling
products, 1,2-diol 4 and diamine 5, were obtained as a diastereomeric mixture, respectively.
However, it was fortunately found that electronwithdrawing N-sulfonyl ferrocenylideneamine was critical
for the effective cross-coupling with ferrocenecarboxaldehyde. Thus, the reductive cross-coupling of
N-arylsulfonyl ferrocenylideneamines 2f, 2g with ferrocenecarboxaldehyde (1) gave anti-‚-amino alcohol 3 as
a single diastereomer (entries 6 and 7) without any formation of the corresponding homo-coupling products
and the stereoisomer of the b‚-amino alcohol.
With N methanesulfonyl ferrocenylideneamine (2h), the corresponding anti-amino alcohol was obtained as the major diastereomer along with a small amount of syn-amino
alcohol (entry 9). Interestingly, the ‚-amino alcohol derivatives obtained in this reductive cross-coupling were
anti diastereomers, while the homo-pinacol coupling of the planar chiral ferrocenecarboxaldehydes gave exclusively
syn-‚-diols.To achieve an efficient cross-coupling between aldehydes and aldimines, it is significant for either substrate to be more easily reduced to the corresponding reactive
species which reacts with another substrate without homo-coupling.
Treatment of a mixture of ferrocenecarboxaldehyde (1) and N-alkyl ferrocenylideneamines 2a, 2b or hydrazone
derivatives 2d, 2e with samarium iodide in THF gave homo-coupling ‚-diol 4 as a diastereomeric mixture along
with recovered ferrocenylideneamine or its hydrolyzed ferrocenecarboxaldehyde depending on the structure of
ferrocenylimine (entries 1, 2, 4, and 5). With N-phenyl ferrocenylideneamine (2c), two corresponding homocoupling
products, 1,2-diol 4 and diamine 5, were obtained as a diastereomeric mixture, respectively.
However, it was fortunately found that electronwithdrawing N-sulfonyl ferrocenylideneamine was critical
for the effective cross-coupling with ferrocenecarboxaldehyde. Thus, the reductive cross-coupling of
N-arylsulfonyl ferrocenylideneamines 2f, 2g with ferrocenecarboxaldehyde (1) gave anti-‚-amino alcohol 3 as
a single diastereomer (entries 6 and 7) without any formation of the corresponding homo-coupling products
and the stereoisomer of the b‚-amino alcohol.
With N methanesulfonyl ferrocenylideneamine (2h), the corresponding anti-amino alcohol was obtained as the major diastereomer along with a small amount of syn-amino
alcohol (entry 9). Interestingly, the ‚-amino alcohol derivatives obtained in this reductive cross-coupling were
anti diastereomers, while the homo-pinacol coupling of the planar chiral ferrocenecarboxaldehydes gave exclusively
syn-‚-diols.
25. Cross-Coupling of Planar Chiral N-Tosyl Ferrocenylideneamine and Ferrocenecarboxaldehydes the samarium iodide-mediated cross-coupling of a combination between the planar chiral
N-tosyl R-substituted ferrocenylideneamines 8 and ferrocenecarboxaldehydes 7.
(7a) was coupled with (8a) to give anti-b-amino alcohol 9a in 92% yield (entry 1). Similarly, the cross-coupling of R-halogenated ferrocenyl compounds produced the corresponding anti-‚-amino alcohols without
reduction of the halogen atom in good yields. However, N-tosyl 2-trimethylsilyferrocenylideneamine (8d)
gave no cross-coupling product probably due to steric hindrance (entries 5 and 9).
the samarium iodide-mediated cross-coupling of a combination between the planar chiral
N-tosyl R-substituted ferrocenylideneamines 8 and ferrocenecarboxaldehydes 7.
(7a) was coupled with (8a) to give anti-b-amino alcohol 9a in 92% yield (entry 1). Similarly, the cross-coupling of R-halogenated ferrocenyl compounds produced the corresponding anti-‚-amino alcohols without
reduction of the halogen atom in good yields. However, N-tosyl 2-trimethylsilyferrocenylideneamine (8d)
gave no cross-coupling product probably due to steric hindrance (entries 5 and 9).
26. Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines In the cross-coupling with the planar chiral N-tosyl R-substituted ferrocenylideneamines, samarium iodide
attacks the anti-oriented C=N double bond to the substituent from the exo-side to generate dianion
intermediate 21, which is configurationally stable against epimerization (Figure 3).22 No epimerization between 21
and 22 would be attributed to an interaction of the p-orbital of alpha-carbon with the d-orbital of the iron metal,
resulting in the formation of an exo-cyclic double bond character 23.
Taking into account the following transition states 24a and 24b, the N-tosyl group is oriented anti to the carbonyl oxygen of arylaldehydes due to dipole-dipole
repulsion. The carbonyl oxygen of the planar chiral ferrocenecarboxaldehydes is also known to exist preferentially
in the anti conformation to the ortho substituent. When the planar chiral arylaldehydes 7 were coupled
with a dianion intermediate, the transition state 24a caused a severe steric interaction between the FeCp ring
of ferrocenecarboxaldehyde and ferrocenylimine because of the same planar chirality of both substrates. Therefore,
the anti-oriented carbonyl oxygen in transition state 24a would be isomerized to the alternative syn-oriented
transition state 24b, giving the anti-‚-amino alcohols 9. In the cross-coupling with the planar chiral N-tosyl R-substituted ferrocenylideneamines, samarium iodide
attacks the anti-oriented C=N double bond to the substituent from the exo-side to generate dianion
intermediate 21, which is configurationally stable against epimerization (Figure 3).22 No epimerization between 21
and 22 would be attributed to an interaction of the p-orbital of alpha-carbon with the d-orbital of the iron metal,
resulting in the formation of an exo-cyclic double bond character 23.
Taking into account the following transition states 24a and 24b, the N-tosyl group is oriented anti to the carbonyl oxygen of arylaldehydes due to dipole-dipole
repulsion. The carbonyl oxygen of the planar chiral ferrocenecarboxaldehydes is also known to exist preferentially
in the anti conformation to the ortho substituent. When the planar chiral arylaldehydes 7 were coupled
with a dianion intermediate, the transition state 24a caused a severe steric interaction between the FeCp ring
of ferrocenecarboxaldehyde and ferrocenylimine because of the same planar chirality of both substrates. Therefore,
the anti-oriented carbonyl oxygen in transition state 24a would be isomerized to the alternative syn-oriented
transition state 24b, giving the anti-‚-amino alcohols 9.
27. Reaction Mechanism of Cross-Coupling with N-Tosyl Ferrocenylideneamines On the other hand, the reactive species generated from achiral ferrocenylideneamine 2g rapidly equilibrates at
the stereogenic center due to a lack of the R-substituent on the Cp ring (Figure 4). The planar chiral R-substituted
ferrocenecarboxaldehyde could intercept either configurated species among the equilibrated carbanions depending
on the planar chirality of arylaldehydes.
Thus, the anti-oriented carbonyl of the planar chiral ferrocenecarboxaldehydes 7
is attacked via transition state 27 giving a single anti-amino alcohol 16. On the other hand, ent-7
gave the antipode anti-‚-amino alcohol, ent-16, via the transition state 28.
In the cross-coupling of the achiral ferrocenylideneamine with planar chiral arylaldehydes,
dynamic kinetic resolution takes place among the equilibrating R-ferrocenyl carbanion configuration.
On the other hand, the reactive species generated from achiral ferrocenylideneamine 2g rapidly equilibrates at
the stereogenic center due to a lack of the R-substituent on the Cp ring (Figure 4). The planar chiral R-substituted
ferrocenecarboxaldehyde could intercept either configurated species among the equilibrated carbanions depending
on the planar chirality of arylaldehydes.
Thus, the anti-oriented carbonyl of the planar chiral ferrocenecarboxaldehydes 7
is attacked via transition state 27 giving a single anti-amino alcohol 16. On the other hand, ent-7
gave the antipode anti-‚-amino alcohol, ent-16, via the transition state 28.
In the cross-coupling of the achiral ferrocenylideneamine with planar chiral arylaldehydes,
dynamic kinetic resolution takes place among the equilibrating R-ferrocenyl carbanion configuration.
28. Cross-Coupling of Benzylideneamines with Aldehydes the cross-coupling of N-methanesulfonyl benzylideneamine (29a) with benzaldehyde 11 and 14 gave the
corresponding ‚-amino alcohol derivatives 30 in good yields without formation of homo-coupling products
. However, the diastereoselectivity of anti- and syn-‚-amino alcohols was extremely low (entries 1-3).
With N-tosyl benzylideneamine (29b) was used, the diastereoselectivity of the cross-coupling products increased appreciably
(entries 7-10). The cross-coupling of benzaldehyde chromium complex (14a) with N-tosyl benzylideneamine (29b) gave
‚-amino alcohol derivative 30d with high diastereoselectivity in 73% overall yield.
The increase of diastereoselectivity by the tricarbonylchromium complexation would be attributed to a stereoelectronic effect
of the tricarbonylchromium fragment.
Interestingly, the major ‚-amino alcohol 30 obtained was the syn isomer. The
predominant formation of the syn-‚-amino alcohol in this combination is in sharp contrast to the reductive crosscoupling
of N-tosyl ferrocenylideneamine with arylaldehydes giving the anti-‚-amino alcohols as mentioned above.
The transition state giving the syn amino alcohols is proposed as the coordination structure of the samarium with both nitrogen and carbonyl oxygen
atoms 36 or 37 via dynamic kinetic resolution of the generated reactive species depending on the planar
chirality of benzaldehyde chromium complexes.
An alternative transition state might be proposed in the cross-coupling with N-tosyl benzylideneamine from the following results.
The reaction of benzylideneamine 29b with aliphatic aldehydes was different from the cross-coupling of N-tosyl
ferrocenylideneamine with aliphatic aldehydes. Thus, N-tosyl benzylideneamine (29b) gave a complex mixture
by reaction with aliphatic aldehydes, while the ferrocenylideneamine afforded the expected ‚-amino alcohols by
coupling with both aromatic and aliphatic aldehydes in good yields as shown above. These results indicate that
in the cross-coupling of 29b with arylaldehydes, both ketyl radical species generated from the imine and
arylaldehydes might be coupled via a coordination structure 38 with the samarium metal without stepwise
reaction. On the other hand, in the combination between N-tosyl ferrocenylideneamine and aldehydes, the dianion
species would be initially generated from the imine and the generated reactive species reacts with aldehydes to
give the ‚-amino alcohols. Further elucidation of the reaction mechanism is necessary for an explanation of
the stereochemically distinguished cross-coupling between N-tosyl ferrocenylideneamine and benzylideneamine.
the cross-coupling of N-methanesulfonyl benzylideneamine (29a) with benzaldehyde 11 and 14 gave the
corresponding ‚-amino alcohol derivatives 30 in good yields without formation of homo-coupling products
. However, the diastereoselectivity of anti- and syn-‚-amino alcohols was extremely low (entries 1-3).
With N-tosyl benzylideneamine (29b) was used, the diastereoselectivity of the cross-coupling products increased appreciably
(entries 7-10). The cross-coupling of benzaldehyde chromium complex (14a) with N-tosyl benzylideneamine (29b) gave
‚-amino alcohol derivative 30d with high diastereoselectivity in 73% overall yield.
The increase of diastereoselectivity by the tricarbonylchromium complexation would be attributed to a stereoelectronic effect
of the tricarbonylchromium fragment.
Interestingly, the major ‚-amino alcohol 30 obtained was the syn isomer. The
predominant formation of the syn-‚-amino alcohol in this combination is in sharp contrast to the reductive crosscoupling
of N-tosyl ferrocenylideneamine with arylaldehydes giving the anti-‚-amino alcohols as mentioned above.
The transition state giving the syn amino alcohols is proposed as the coordination structure of the samarium with both nitrogen and carbonyl oxygen
atoms 36 or 37 via dynamic kinetic resolution of the generated reactive species depending on the planar
chirality of benzaldehyde chromium complexes.
An alternative transition state might be proposed in the cross-coupling with N-tosyl benzylideneamine from the following results.
The reaction of benzylideneamine 29b with aliphatic aldehydes was different from the cross-coupling of N-tosyl
ferrocenylideneamine with aliphatic aldehydes. Thus, N-tosyl benzylideneamine (29b) gave a complex mixture
by reaction with aliphatic aldehydes, while the ferrocenylideneamine afforded the expected ‚-amino alcohols by
coupling with both aromatic and aliphatic aldehydes in good yields as shown above. These results indicate that
in the cross-coupling of 29b with arylaldehydes, both ketyl radical species generated from the imine and
arylaldehydes might be coupled via a coordination structure 38 with the samarium metal without stepwise
reaction. On the other hand, in the combination between N-tosyl ferrocenylideneamine and aldehydes, the dianion
species would be initially generated from the imine and the generated reactive species reacts with aldehydes to
give the ‚-amino alcohols. Further elucidation of the reaction mechanism is necessary for an explanation of
the stereochemically distinguished cross-coupling between N-tosyl ferrocenylideneamine and benzylideneamine.
29. Cross-Coupling of Benzylideneamines with Aldehydes by using planar chiral benzaldehyde chromium complexes, optically active ‚-amino alcohol derivatives were prepared.
Enantiomerically pure chromium complex (17b) was coupled with 29b, followed by removing chromiun with sunlight gave a
chromium-free amino alcohol derivative 34 in 99% ee.
On the other hand, an antipode chromium complex (ent-17b) produced the amino alcohol ent-34 under the same reaction sequence.
In this way, both enantiomers of syn-‚-amino alcohol
could be prepared by the coupling of N-tosyl benzylideneamine with the planar chiral benzaldehyde chromium complexes.
by using planar chiral benzaldehyde chromium complexes, optically active ‚-amino alcohol derivatives were prepared.
Enantiomerically pure chromium complex (17b) was coupled with 29b, followed by removing chromiun with sunlight gave a
chromium-free amino alcohol derivative 34 in 99% ee.
On the other hand, an antipode chromium complex (ent-17b) produced the amino alcohol ent-34 under the same reaction sequence.
In this way, both enantiomers of syn-‚-amino alcohol
could be prepared by the coupling of N-tosyl benzylideneamine with the planar chiral benzaldehyde chromium complexes.
30. Proline-Catalyzed Direct Asymmetric Mannich Reaction Among the most effective and enantioselective proline-catalyzed Mannich reactions are those that involve hydroxyacetone as the
donor. The corresponding aldol reactions provided anti-diols in excellent diastereo- and enantioselectivities. In contrast,
proline-catalyzed Mannich reactions with hydroxyacetone to typically furnish syn-1,2-amino alcohols in high
chemo-, regio-, diastero-, and enantioselectivities and in good yields. In particular, the reactions using aromatic aldehydes
provide the products in useful selectivities (Table 5).
In the reactions of hydroxyacetone with different p-substituted aromatic aldehydes we discovered a strong effect of the
electronic properties of the aromatic moiety on the stereoselectivity. The enantioselectivity correlates well with Hammett
Ûp-values, and a linear Hammett plot was obtained. The reaction constant F for the proline-catalyzed three-component Mannich reaction was determined to be 1.36 (R2 ) 0.95) (Figure 3).35,36
Our results suggest negative charge formation in the enantioselectivity- determining step, which is consistent with the
proposed nucleophilic addition of an enamine to an imine.
A main difference between proline-catalyzed aldol and Mannich reactions concerns the stereoselectivity. Typically,
aldols result from a re-enantiofacial attack on the aldehyde, whereas Mannich products are formed via si-face attack on an
imine. Moreover, if substituted ketone donors are used, in the aldol reaction, anti-diastereoselectivity is typically observed
while excellent syn-selectivity was found in the corresponding Mannich reactions. Consequently, the enamine-enantiofaciality
(si, if the substituent X is of highest priority) is the same in both reactions, but the electrophile-faciality is reversed resulting
in like topicity (lk) in the Mannich reaction and in unlike topicity (ul) in the aldol reaction.38 That both enamine and imine may
adopt both (E)- and (Z)-configurations complicates an analysis of the entire sortiment of plausible transition states.39 In our
originally proposed mechanism, we employed (Z)-imines to account for the reversed enantioselectivity. However, while
imines may undergo (E)-(Z) isomerization,40 and (Z)-imines have been implicated earlier in related transition states,7 typically
they are present in only low equilibrium concentrations. On the basis of these considerations we have developed advanced
transition-state models that explain the contrasting stereoselectivities of proline-catalyzed aldol and Mannich (Scheme 3).
Accordingly, in the Mannich transition state we assume (E)-configurations of both the proline enamine and the imine. The
si-face of the imine is selectively attacked by the enamine to allow for protonation of its lone pair and compensation of
negative charge formation. Attack of the imine re-face would result in unfavorable steric interactions between the pyrrolidine
and aromatic ring (Scheme 3, arrow a). These interactions do not exist in the aldol reaction, and steric repulsion between
aldehyde and enamine carbon substituents dominates (Scheme3, arrow b).
Among the most effective and enantioselective proline-catalyzed Mannich reactions are those that involve hydroxyacetone as the
donor. The corresponding aldol reactions provided anti-diols in excellent diastereo- and enantioselectivities. In contrast,
proline-catalyzed Mannich reactions with hydroxyacetone to typically furnish syn-1,2-amino alcohols in high
chemo-, regio-, diastero-, and enantioselectivities and in good yields. In particular, the reactions using aromatic aldehydes
provide the products in useful selectivities (Table 5).
In the reactions of hydroxyacetone with different p-substituted aromatic aldehydes we discovered a strong effect of the
electronic properties of the aromatic moiety on the stereoselectivity. The enantioselectivity correlates well with Hammett
Ûp-values, and a linear Hammett plot was obtained. The reaction constant F for the proline-catalyzed three-component Mannich reaction was determined to be 1.36 (R2 ) 0.95) (Figure 3).35,36
Our results suggest negative charge formation in the enantioselectivity- determining step, which is consistent with the
proposed nucleophilic addition of an enamine to an imine.
A main difference between proline-catalyzed aldol and Mannich reactions concerns the stereoselectivity. Typically,
aldols result from a re-enantiofacial attack on the aldehyde, whereas Mannich products are formed via si-face attack on an
imine. Moreover, if substituted ketone donors are used, in the aldol reaction, anti-diastereoselectivity is typically observed
while excellent syn-selectivity was found in the corresponding Mannich reactions. Consequently, the enamine-enantiofaciality
(si, if the substituent X is of highest priority) is the same in both reactions, but the electrophile-faciality is reversed resulting
in like topicity (lk) in the Mannich reaction and in unlike topicity (ul) in the aldol reaction.38 That both enamine and imine may
adopt both (E)- and (Z)-configurations complicates an analysis of the entire sortiment of plausible transition states.39 In our
originally proposed mechanism, we employed (Z)-imines to account for the reversed enantioselectivity. However, while
imines may undergo (E)-(Z) isomerization,40 and (Z)-imines have been implicated earlier in related transition states,7 typically
they are present in only low equilibrium concentrations. On the basis of these considerations we have developed advanced
transition-state models that explain the contrasting stereoselectivities of proline-catalyzed aldol and Mannich (Scheme 3).
Accordingly, in the Mannich transition state we assume (E)-configurations of both the proline enamine and the imine. The
si-face of the imine is selectively attacked by the enamine to allow for protonation of its lone pair and compensation of
negative charge formation. Attack of the imine re-face would result in unfavorable steric interactions between the pyrrolidine
and aromatic ring (Scheme 3, arrow a). These interactions do not exist in the aldol reaction, and steric repulsion between
aldehyde and enamine carbon substituents dominates (Scheme3, arrow b).
31. Proline-Catalyzed Assemble of Aldehydes, Ketones, and Azodicarboxylic Acid Asters The coupling of acetone, propionaldehyde, and dibenzyl azodicarboxylate in one pot
with L-proline (20 mol %). the scope of the assembly reaction using various aldehyde
donors. Aldehydes bearing olefin, aromatic and alicyclic substituents reacted smoothly in the one-pot assembly
reaction to provide various functionalized amino alcohols with excellent yields and ees. A ‚-branched aldehyde
afforded the product with high anti selectivity (Table 2, entry8).
The coupling of acetone, propionaldehyde, and dibenzyl azodicarboxylate in one pot
with L-proline (20 mol %). the scope of the assembly reaction using various aldehyde
donors. Aldehydes bearing olefin, aromatic and alicyclic substituents reacted smoothly in the one-pot assembly
reaction to provide various functionalized amino alcohols with excellent yields and ees. A ‚-branched aldehyde
afforded the product with high anti selectivity (Table 2, entry8).
33. Outline
34. Aminolytic Kinetic Resolution with Amines ring opening of 1,2-disubstituted epoxides using amines is usually anti-stereospecific, a regio- and enantioselective
aminolysis of trans-epoxides would constitute a useful method for the catalytic asymmetric preparation of anti-â-amino
alcohols with complete control of diastereoselectivity
[Cr(Salen)-Cl] was chosen as the catalyst for its high selectivities in different asymmetric ring-opening reactions;
reaction of racemic trans-stilbene oxide (2 equiv) with aniline 3a (1 equiv) providing a high yield of the desired amino alcohol adduct 4a with complete anti-selectivity and good enantiocontrol (86% ee, entry 1).
Generally, the stereoselectivity of the kinetic resolution displays a strong temperature dependence. Performing the
reaction at -10 °C affords 4a with excellent enantioselec-tivity (97% ee, entry 2).
The optimal balance between reactivity and selectivity is achieved by carrying out the reaction at 0 °C.
Another crucial requirement for a simple and synthetically useful preparation of chiral anti-â-amino alcohols is the use
of an easily removable N-protecting group. Indeed, the use of p- and o-anisidine 3b and 3c provides the corresponding
N-aryl amino alcohols 4b and 4c, respectively, which can be efficiently deprotected by oxidative dearylation without
erosion of stereochemical integrity.12
the high reactivity of o-anisidine 3c allowed the aminolysis of
trans-stilbene oxide 2 to be run at -10 °C. Under these conditions, the anti-â-amino alcohol 4c was isolated in very
high yield and enantioselectivity (entry 8).ring opening of 1,2-disubstituted epoxides using amines is usually anti-stereospecific, a regio- and enantioselective
aminolysis of trans-epoxides would constitute a useful method for the catalytic asymmetric preparation of anti-â-amino
alcohols with complete control of diastereoselectivity
[Cr(Salen)-Cl] was chosen as the catalyst for its high selectivities in different asymmetric ring-opening reactions;
reaction of racemic trans-stilbene oxide (2 equiv) with aniline 3a (1 equiv) providing a high yield of the desired amino alcohol adduct 4a with complete anti-selectivity and good enantiocontrol (86% ee, entry 1).
Generally, the stereoselectivity of the kinetic resolution displays a strong temperature dependence. Performing the
reaction at -10 °C affords 4a with excellent enantioselec-tivity (97% ee, entry 2).
The optimal balance between reactivity and selectivity is achieved by carrying out the reaction at 0 °C.
Another crucial requirement for a simple and synthetically useful preparation of chiral anti-â-amino alcohols is the use
of an easily removable N-protecting group. Indeed, the use of p- and o-anisidine 3b and 3c provides the corresponding
N-aryl amino alcohols 4b and 4c, respectively, which can be efficiently deprotected by oxidative dearylation without
erosion of stereochemical integrity.12
the high reactivity of o-anisidine 3c allowed the aminolysis of
trans-stilbene oxide 2 to be run at -10 °C. Under these conditions, the anti-â-amino alcohol 4c was isolated in very
high yield and enantioselectivity (entry 8).
35. Aminolytic Kinetic Resolution with Amines The scope of the present asymmetric aminolytic kinetic resolution (AKR) was demonstrated by the reaction of
various aromatic epoxides (5a-h) with p-anisidine 3b. Although regiocontrol is generally difficult to achieve in the ring opening of 1,2- disubstituted oxiranes, the asymmetric aminolysis of aromatic epoxides with anilines catalyzed by 1 proceeds with complete regioselectivity for the benzylic carbon.
Racemic trans-1,2- disubstituted aromatic epoxides 5a-h with different
substituents in the 2-position or with a fluorine on the aromatic ring, all undergo asymmetric aminolysis
smoothly providing anti-amino alcohols 6 with complete regio- and diastereoselectivity 14 and in good ee (up to 86%).
The presence of coordinating functional groups does not affect the catalytic activity of the system. In
particular, the tolerance of Lewis basic phosphonate group allowed the AKR of epoxide 5d to
obtain optically active anti-ç-amino-â-hydroxy phosphonate 6d in high yield and good enantioselectivity (entry 4). Such
molecules are of interest as potential phosphate mimics that are resistant to phosphatase hydrolysis.The scope of the present asymmetric aminolytic kinetic resolution (AKR) was demonstrated by the reaction of
various aromatic epoxides (5a-h) with p-anisidine 3b. Although regiocontrol is generally difficult to achieve in the ring opening of 1,2- disubstituted oxiranes, the asymmetric aminolysis of aromatic epoxides with anilines catalyzed by 1 proceeds with complete regioselectivity for the benzylic carbon.
Racemic trans-1,2- disubstituted aromatic epoxides 5a-h with different
substituents in the 2-position or with a fluorine on the aromatic ring, all undergo asymmetric aminolysis
smoothly providing anti-amino alcohols 6 with complete regio- and diastereoselectivity 14 and in good ee (up to 86%).
The presence of coordinating functional groups does not affect the catalytic activity of the system. In
particular, the tolerance of Lewis basic phosphonate group allowed the AKR of epoxide 5d to
obtain optically active anti-ç-amino-â-hydroxy phosphonate 6d in high yield and good enantioselectivity (entry 4). Such
molecules are of interest as potential phosphate mimics that are resistant to phosphatase hydrolysis.
36. Aminolytic Kinetic Resolution with carbamates extend the use of this catalyst to the carbamate-based AKR of terminal epoxides.
However, reaction of -+-glycidyl phenyl ether 4 (2.2 ) with tert-butyl carbamate
3a (1 equiv) in the presence of complex 1 (0.016 equiv, 1.5 mol % relative to racemic epoxide) in CH2Cl2 led to no Conversion
Thus, we turned our attention to the Jacobsen’s (salen)Co III -OAc complex 2a that had been
demonstrated to be a highly effective and enantioselective catalyst for the hydrolytic kinetic resolution of racemic
terminal epoxides. Use of the acetate complex 2a, afforded the N-Boc-protected amino alcohol 5a in moderate yield but in very
high optical purity (96% ee, entry 3).
In situ generation of 2a under AKR conditions by suspension of 2 in the solvent
and addition of HOAc under an aerobic atmosphere resulted in a more reactive system (entry 4).
The identity of the counterion 8 for the (salen)Co III catalyst and the reaction solvent proved to be crucial in terms of both
reactivity and selectivity: performing the reaction in tert-butyl methyl ether (TBME) in the presence of complex 2
(1.5 mol %) and p-nitrobenzoic acid (3 mol %) as the oxidizing additive resulted in 85% conversion of 3a after
20 h and formation of 5a in enantiomerically pure form .
The optimized procedure (2 mol % of 2, 4 mol %of
additive, entry 8) afforded enantiopure product 5a in 99% isolated yield based on carbamate after 24 h at room
temperature.
The AKR of 4 is also effective with different nucleophiles such as benzyl carbamate 3b, ethyl carbamate (urethane )3c and 9-fluorenyl- methyl carbamate 3d (entries 9-11). In particular, the
reaction of 3b and 3d proceeds with very high selectivity although a slight decrease in reactivity is observed.
. extend the use of this catalyst to the carbamate-based AKR of terminal epoxides.
However, reaction of -+-glycidyl phenyl ether 4 (2.2 ) with tert-butyl carbamate
3a (1 equiv) in the presence of complex 1 (0.016 equiv, 1.5 mol % relative to racemic epoxide) in CH2Cl2 led to no Conversion
Thus, we turned our attention to the Jacobsen’s (salen)Co III -OAc complex 2a that had been
demonstrated to be a highly effective and enantioselective catalyst for the hydrolytic kinetic resolution of racemic
terminal epoxides. Use of the acetate complex 2a, afforded the N-Boc-protected amino alcohol 5a in moderate yield but in very
high optical purity (96% ee, entry 3).
In situ generation of 2a under AKR conditions by suspension of 2 in the solvent
and addition of HOAc under an aerobic atmosphere resulted in a more reactive system (entry 4).
The identity of the counterion 8 for the (salen)Co III catalyst and the reaction solvent proved to be crucial in terms of both
reactivity and selectivity: performing the reaction in tert-butyl methyl ether (TBME) in the presence of complex 2
(1.5 mol %) and p-nitrobenzoic acid (3 mol %) as the oxidizing additive resulted in 85% conversion of 3a after
20 h and formation of 5a in enantiomerically pure form .
The optimized procedure (2 mol % of 2, 4 mol %of
additive, entry 8) afforded enantiopure product 5a in 99% isolated yield based on carbamate after 24 h at room
temperature.
The AKR of 4 is also effective with different nucleophiles such as benzyl carbamate 3b, ethyl carbamate (urethane )3c and 9-fluorenyl- methyl carbamate 3d (entries 9-11). In particular, the
reaction of 3b and 3d proceeds with very high selectivity although a slight decrease in reactivity is observed.
.
37. Aminolytic Kinetic Resolution with carbamates a wide range of structurally and electronically varied terminal epoxides 6 can be opened with tert-butyl carbamate 3a providing enantiopure N-Boc-protected 1,2-amino alcohols 7a-i in high yield and complete regioselectivity for the terminal position;
Both linear (entries 1-3) and relatively hindered (entry 4) aliphatic epoxides undergo AKR with extraordinary
selectivity. The presence of coordinating functional groups does not appear to affect the efficiency of the system, as
both 1-naphthyl glycidyl ether and epichlorohydrin afford the corresponding 1-amino-2-ols 7e and 7f in good yield and
in enantiomerically pure form (entries 5 and 6).
The exceptionally high levels of selectivity observed in the AKR are consistent with other highly selective
(salen)Co III -catalyzed kinetic resolutions of terminal epoxides
in which a peculiar, bimolecular, nearly perfect chiral
recognition mechanism is operating.(??)15 A thorough investiga-tion
to elucidate the mechanism of catalysis is underway and will be reported in due course.a wide range of structurally and electronically varied terminal epoxides 6 can be opened with tert-butyl carbamate 3a providing enantiopure N-Boc-protected 1,2-amino alcohols 7a-i in high yield and complete regioselectivity for the terminal position;
Both linear (entries 1-3) and relatively hindered (entry 4) aliphatic epoxides undergo AKR with extraordinary
selectivity. The presence of coordinating functional groups does not appear to affect the efficiency of the system, as
both 1-naphthyl glycidyl ether and epichlorohydrin afford the corresponding 1-amino-2-ols 7e and 7f in good yield and
in enantiomerically pure form (entries 5 and 6).
The exceptionally high levels of selectivity observed in the AKR are consistent with other highly selective
(salen)Co III -catalyzed kinetic resolutions of terminal epoxides
in which a peculiar, bimolecular, nearly perfect chiral
recognition mechanism is operating.(??)15 A thorough investiga-tion
to elucidate the mechanism of catalysis is underway and will be reported in due course.
39. Conclusion
Optically active b-amino alcohols have been prepared through:
Addition of carbanions, free radicals to C=N.
Asymmetric hydrogenations of a-N-substituted ß- keto esters
Coupling of imines and aldehyes
Kinetic resolution of racemic epoxides
Much remains to be done:
Scope of substrates
Relative and absolute stereochemisry
40. Acknowledgement Dr. Hollingsworth
Dr. Wulff
Dr. Borhan
Hollingsworth Group
Xuezheng Carol
Chang Xiaoyu
Li Kun
Zhen Trevor
Joel Felica
41. Proline-Catalyzed Direct Asymmetric Three Component Mannich Reaction Accordingly, the ketone reacts with proline to give an enamine. In a second preequilibrium between the aldehyde
and the aniline, an imine is formed. Imine and enamine then react to give after hydrolysis the enantiomerically enriched
Mannich product. This mechanism is similar to the one we proposed for the proline-catalyzed aldol reaction with the only
difference being that the aldehyde is first converted into an imine before reacting with the presumed proline enamine.
Accordingly, in the Mannich transition state we assume (E)-configurations of both the proline enamine and the imine. The
si-face of the imine is selectively attacked by the enamine to allow for protonation of its lone pair and compensation of
negative charge formation. Attack of the imine re-face would result in unfavorable steric interactions between the pyrrolidine
and aromatic ring (Scheme 3, arrow a). These interactions do not exist in the aldol reaction, and steric repulsion between
aldehyde and enamine carbon substituents dominates (Scheme3, arrow b).
Accordingly, the ketone reacts with proline to give an enamine. In a second preequilibrium between the aldehyde
and the aniline, an imine is formed. Imine and enamine then react to give after hydrolysis the enantiomerically enriched
Mannich product. This mechanism is similar to the one we proposed for the proline-catalyzed aldol reaction with the only
difference being that the aldehyde is first converted into an imine before reacting with the presumed proline enamine.
Accordingly, in the Mannich transition state we assume (E)-configurations of both the proline enamine and the imine. The
si-face of the imine is selectively attacked by the enamine to allow for protonation of its lone pair and compensation of
negative charge formation. Attack of the imine re-face would result in unfavorable steric interactions between the pyrrolidine
and aromatic ring (Scheme 3, arrow a). These interactions do not exist in the aldol reaction, and steric repulsion between
aldehyde and enamine carbon substituents dominates (Scheme3, arrow b).
42. Proline-Catalyzed assemble of aldehydes, ketones, and azodicarboxylic acid esters When we treated racemic aminated propionaldehyde (1) with acetone in the presence of L-proline, products 2 and 3 were
obtained with yield, diastereoselectivity, and enantioselectivity identical to those found in the reaction involving (R)-
amino aldehyde (1) (Table 1, entry 7, and Scheme 2). Next we performed a reaction with propionaldehyde and azodicarboxylate
for 3 days and determined that the resulting amino aldehyde was racemic. Thus, proline can act to
racemize the amino aldehyde over time. These two findings suggest that the reaction proceeds as outlined in Scheme 2.
Amination of propionaldehyde using D,L-proline or L-proline
with extended reaction times (3 days) provides racemic
amino aldehyde (1). The reaction of rac-amino aldehyde (1)
with acetone in the presence of L-proline in CH3CN affordedthe four possible enantiomers in a ratio of 99:28:229:1
(HPLC data). The amino aldehyde reacts on the exo face of 1-isopropenyl pyrrolidine-2-carboxylic acid, the typical face
selectivity observed in the proline-catalyzed aldol reactions since this approach facilitates hydrogen bonding between the
carboxylate and the aldehyde acceptor.4 Intermolecular hydrogen bonding and steric hindrance between enamine and
amino aldehydes as shown in TS 1 and TS 2 then likely control the facial reactivity of the amino aldehyde. In the
case of (R)-amino aldehyde, intermolecular hydrogen bonding between the carboxylate group and the aldehyde oxygen
is less effective due to steric hindrance between N-substituted groups or the R-methyl group and the enamine, affording
diastereomers (R,R)-2 and (S,R)-3 with a modest de of 56%. The (S)-amino aldehyde afforded diastereomers (R,S)-3 and
(S,S)-2 with a very high de of 99%. Here, potential intermolecular hydrogen bonding between the aldehyde
oxygen and carboxylate group effectively directs the facial selectivity of the attack of the enamine on the aldehyde. The
enantiofacial selectivity involving (R)-amino aldehydes is decreased as compared to other known proline-catalyzed
aldol reactions involving simple aldehydes. This is the first observation that substituent modifications on the acceptor
aldehyde can alter the stereochemistry of proline-catalyzed aldol reactions. Since racemization of the amination product
is faster than the subsequent aldol reaction, the aldol reaction occurs between the ketone donor and racemic aminated
propionaldehyde. When we treated racemic aminated propionaldehyde (1) with acetone in the presence of L-proline, products 2 and 3 were
obtained with yield, diastereoselectivity, and enantioselectivity identical to those found in the reaction involving (R)-
amino aldehyde (1) (Table 1, entry 7, and Scheme 2). Next we performed a reaction with propionaldehyde and azodicarboxylate
for 3 days and determined that the resulting amino aldehyde was racemic. Thus, proline can act to
racemize the amino aldehyde over time. These two findings suggest that the reaction proceeds as outlined in Scheme 2.
Amination of propionaldehyde using D,L-proline or L-proline
with extended reaction times (3 days) provides racemic
amino aldehyde (1). The reaction of rac-amino aldehyde (1)
with acetone in the presence of L-proline in CH3CN affordedthe four possible enantiomers in a ratio of 99:28:229:1
(HPLC data). The amino aldehyde reacts on the exo face of 1-isopropenyl pyrrolidine-2-carboxylic acid, the typical face
selectivity observed in the proline-catalyzed aldol reactions since this approach facilitates hydrogen bonding between the
carboxylate and the aldehyde acceptor.4 Intermolecular hydrogen bonding and steric hindrance between enamine and
amino aldehydes as shown in TS 1 and TS 2 then likely control the facial reactivity of the amino aldehyde. In the
case of (R)-amino aldehyde, intermolecular hydrogen bonding between the carboxylate group and the aldehyde oxygen
is less effective due to steric hindrance between N-substituted groups or the R-methyl group and the enamine, affording
diastereomers (R,R)-2 and (S,R)-3 with a modest de of 56%. The (S)-amino aldehyde afforded diastereomers (R,S)-3 and
(S,S)-2 with a very high de of 99%. Here, potential intermolecular hydrogen bonding between the aldehyde
oxygen and carboxylate group effectively directs the facial selectivity of the attack of the enamine on the aldehyde. The
enantiofacial selectivity involving (R)-amino aldehydes is decreased as compared to other known proline-catalyzed
aldol reactions involving simple aldehydes. This is the first observation that substituent modifications on the acceptor
aldehyde can alter the stereochemistry of proline-catalyzed aldol reactions. Since racemization of the amination product
is faster than the subsequent aldol reaction, the aldol reaction occurs between the ketone donor and racemic aminated
propionaldehyde.
43. Asymmetric hydrogenations of a-N-substituted ß-keto esters An elegant and efficient pathway to syn-a –amino ß -hydroxy esters through ruthenium-mediated hydroge-nation
of the corresponding a -amino ß -keto esters by dy-namic kinetic resolution (DKR) has been developed since
the end of the 1980s.
The a -acetamido ß -keto ester was efficiently hydrogenated, under optimized conditions, dis-playing high syn diastereoselectivity with (R)-BINAP- and
(S,S)-CHIRAPHOS-ruthenium catalyst (Scheme 1).
Since these pioneering works, this syn selection has been more generally obtained in the hydrogenation of acyclic a –amido ß -keto esters.
Two different models to explain the origin of this syn diastereoselectivity have been suggested. Noyori’s inter-pretation
is based on a Felkin Anh transition state, with reference to chelation of the ketone and the ester carbonyl
function on the metal. [9a,10] Another explanation has been proposed by our group, and is based on the formation of
a transition chair-like chelate ruthenium amide complex in which the amide carbonyl group and the ketone are bonded
to the metal.An elegant and efficient pathway to syn-a –amino ß -hydroxy esters through ruthenium-mediated hydroge-nation
of the corresponding a -amino ß -keto esters by dy-namic kinetic resolution (DKR) has been developed since
the end of the 1980s.
The a -acetamido ß -keto ester was efficiently hydrogenated, under optimized conditions, dis-playing high syn diastereoselectivity with (R)-BINAP- and
(S,S)-CHIRAPHOS-ruthenium catalyst (Scheme 1).
Since these pioneering works, this syn selection has been more generally obtained in the hydrogenation of acyclic a –amido ß -keto esters.
Two different models to explain the origin of this syn diastereoselectivity have been suggested. Noyori’s inter-pretation
is based on a Felkin Anh transition state, with reference to chelation of the ketone and the ester carbonyl
function on the metal. [9a,10] Another explanation has been proposed by our group, and is based on the formation of
a transition chair-like chelate ruthenium amide complex in which the amide carbonyl group and the ketone are bonded
to the metal.
44. Addition of a-Sulfinyl Carbanions to N-p-Tolylsulfinylketimines - stereocontrol The six-membered TS involving the association of the lithium to the sulfinyl oxygen and the nucleophilic carbon. The chair like TS B, avoiding the 1,3-diaxial interaction between the aromatic residue at the N-arylsulfinyl group and the methyl group of the ketimine present in TS A, must be highly favored.
On the basis that only TS B can be involved, the structure of the attacking carbon at the TS of the nucleophilic addition could be described like a trigonal bipyramid with the apical positions occupied by the bulkier substituents (C=N and SOTol). Four possible transition states can be postulated.
TS-IIS and TS-IIR have the C-sulfinyl oxygen associated to the lithium atom
whereas such association does not exist for the corresponding TS-IS and TS-IR.
In the two latter cases, free rotation around the C-S bond is possible and the S-O bond will arrange anti with respect
to the C-Li bond in order to minimize the electrostatic interactions. Moreover, the methyl group joined to C-Li
will adopt the less hindered anti relationship with respect to the bulkier phenyl. Thus, the methyl group adopts a
pseudoaxial arrangement in TS-IR (derived from (R)-2), but a more stable pseudoequatorial position in TS-IS.
When the C-sulfinyl oxygen is associated with the lithium, the relative stability of the TS’s is related to the
steric interactions of the substituents at the four membered ring, which necessarily adopt an eclipsed
arrangement. Thus, the preferred configuration of the carbanion is the one that avoids the Tol/Me interaction.
it is easily deduced that TS-IIS is now less stable than TS-IIR, due to the relative orientation of the
methyl group in the chair like conformation.
If we assume the equilibration of the two possible transition states for
each enantiomer (TS-I and TS-II) the experimental results can be satisfactorily explained.
The equilibrium must be shifted toward TS-I, thus explaining the higher proportion of compounds B obtained in all the reactions
shown in Table 2.
Nevertheless the shifting toward TSIS must be higher than for TS-IR. An increase of the
temperature would weak even more the association of the sulfinyl group to the lithium atoms, thus provoking
the shift of the equilibrium toward TS-I, which would increase the proportion of the B isomers.The six-membered TS involving the association of the lithium to the sulfinyl oxygen and the nucleophilic carbon. The chair like TS B, avoiding the 1,3-diaxial interaction between the aromatic residue at the N-arylsulfinyl group and the methyl group of the ketimine present in TS A, must be highly favored.
On the basis that only TS B can be involved, the structure of the attacking carbon at the TS of the nucleophilic addition could be described like a trigonal bipyramid with the apical positions occupied by the bulkier substituents (C=N and SOTol). Four possible transition states can be postulated.
TS-IIS and TS-IIR have the C-sulfinyl oxygen associated to the lithium atom
whereas such association does not exist for the corresponding TS-IS and TS-IR.
In the two latter cases, free rotation around the C-S bond is possible and the S-O bond will arrange anti with respect
to the C-Li bond in order to minimize the electrostatic interactions. Moreover, the methyl group joined to C-Li
will adopt the less hindered anti relationship with respect to the bulkier phenyl. Thus, the methyl group adopts a
pseudoaxial arrangement in TS-IR (derived from (R)-2), but a more stable pseudoequatorial position in TS-IS.
When the C-sulfinyl oxygen is associated with the lithium, the relative stability of the TS’s is related to the
steric interactions of the substituents at the four membered ring, which necessarily adopt an eclipsed
arrangement. Thus, the preferred configuration of the carbanion is the one that avoids the Tol/Me interaction.
it is easily deduced that TS-IIS is now less stable than TS-IIR, due to the relative orientation of the
methyl group in the chair like conformation.
If we assume the equilibration of the two possible transition states for
each enantiomer (TS-I and TS-II) the experimental results can be satisfactorily explained.
The equilibrium must be shifted toward TS-I, thus explaining the higher proportion of compounds B obtained in all the reactions
shown in Table 2.
Nevertheless the shifting toward TSIS must be higher than for TS-IR. An increase of the
temperature would weak even more the association of the sulfinyl group to the lithium atoms, thus provoking
the shift of the equilibrium toward TS-I, which would increase the proportion of the B isomers.
