Highly Enantioselective Synthesis of 1,2-Amino Alcohol Derivatives via Proline-Catalyzed Mannich Reaction

multicomponent reactions - organocatalysis - oxa­zolidinones - aminoalcohols

The proline-catalyzed direct asymmetric three-componen­t Mannich reaction between ketones, aldehyde­s, and p-anisidine produces β-amino ketones 1 in enantio- and diastereoselectivities of up to >99% (Scheme [1] ). [2] [3] A useful application of our reaction would be a general synthesis of α-amino acid derivatives. We pursue a route that centers on the oxidative glycol- or Baeyer-Villiger-type α-cleavage of products 1 with R² = OH. [4] Combined with an oxidative removal of the N-protecting group such a sequence could result in a short and practical catalytic asymmetric synthesis of α-amino acids. Here we present significant progress towards this goal with an efficient conversion of Mannich products 1 (R¹ = Me, R² = OH) into 1,2-amino alcohol derivatives via previously unknown 5-acyloxy-oxazolidin-2-ones.

Scheme 1 The proline-catalyzed direct asymmetric three-component Mannich reaction (PMP = p-methoxyphenyl)

Chiral 1,2-amino alcohol derivatives are useful precursors of important non-racemic compounds such as drugs, amin­o acids, and chiral auxiliaries and ligands. The developmen­t of new efficient methods for their asymmetr­ic synthesis is of high current interest. [5] In this regard, the Sharpless catalytic asymmetric amino­hydroxylatio­n is one of the most powerful procedures previous­ly described. [6] [7] In addition, several other interestin­g methods have been reported. [8]

Our strategy for a new organocatalytic synthesis of chiral 1,2-amino alcohols is based on our proline-catalyzed asymmetric Mannich reaction with hydroxyacetone as the donor component. We expected the produced α-hydroxy-β-amino ketones (1, R² = OH, Scheme [1] ) to be useful precurso­rs of 1,2-amino alcohols via straightforward redo­x processes. These could involve an oxidative PMP-removal and α-hydroxy ketone cleavage, [9] followed by a reduction. Our first generation approach was developed to determine the absolute configuration of the Mannich products and was based on a lead tertaacetate mediated glycol cleavage. [2a] The sequence, starting from the Mannic­h product to give N-BOC-protected valinol, require­d seven chemical operations. Later we developed an improved synthesis by using a Baeyer-Villiger-oxidatio­n-based approach that gave N-BOC-protected 1,2-amino alcohols in high yields and in five chemical operatio­ns. [2b] This second-generation approach worked well with aliphatic and aromatic substituents. However, we found that the use of aromatic aldehydes with electron-withdrawing groups, which gave excellent ee’s in the Mannich reaction, led to extensive racemization in the fina­l reduction step. We now report a significantly improve­d, high-yielding, and racemization-free third-generation approach that gives oxazolidin-2-ones 4 and Cbz-protected 1,2-amino alcohols 5 in only three steps from Mannich products 1. Further, we use previously undescribe­d 5-acetoxy substituted oxazolidin-2-ones 3 as new chiral α-amino aldehyde equivalents.

The required diastereomerically pure syn-α-hydroxy-β-aminoketones 1a-d were synthesized in good yields and in high diastereoselectivities and enantioselectivities via proline-catalyzed three-component Mannich reaction of hydroxyacetone with p-anisidine, and aldehydes as describe­d earlier. [2b] Reacting Mannich products 1a-d with triphosgene followed by cerium ammonium nitrate (CAN) gave oxazolidinones 2 in good yields (Scheme [2] ). Baeyer-Villiger oxidation of 5-acyl-oxazolidinones 2 with in situ generated trifluoroperacetic acid [10] then gave 5-acetoxy oxazolidin-2-ones 3 (trans-stereochemistry assigne­d from ¹H NMR). Although Baeyer-Villiger oxidation­s of such α-carbamoyl-oxyketones are unprecedente­d, the observed complete regioselectivity was expected and is based on the high migratory aptitude of oxyalkyl groups. [11]

Scheme 2 Synthesis of 5-acetoxy oxazolidin-2-ones 3

To explore the utility of 5-acetoxy substituted oxazolidin-2-ones (3) as chiral α-amino aldehyde equivalents we studied their reactivity towards nucleophiles. Remarkably, NaBH₄-reduction of acetals 3a-c did not provide the expected 1,2-amino alcohols but oxazolidin-2-ones 4a-c in high yields (Scheme [3] ). Evidently, instead of reducing the ester functionality, the hydride source directly substitute­s OAc with hydrogen. The corresponding Cbz-protected amino alcohols (5a-d) can also be obtained afte­r a work-up that consists of base-treatment followed by in situ protection. That no racemization occurred durin­g the reduction was confirmed in all cases by measuring­ the ee of the produced amino alcohols 5. [12] The preference of 5-acetoxy oxazolidin-2-ones 3 to react with nucleophiles via substitution instead of nucleophilic additio­n was further confirmed by treating ester 3a with Na₂CO₃/MeOH, which gave methoxy derivative 6 as a single stereoisomer (trans-stereochemistry assigned from ¹H NMR). Moreover, if ester 3a was treated with a 1:1 mixture of ethynylmagnesium bromide and AlMe₃, alkyne 7 was obtained in 54% yield as a single stereoisome­r (cis-stereochemistry assigned from ¹H NMR).

Scheme 3 Reactions of 5-acetoxy oxazolidin-2-ones 3

While the complete cis-stereoselectivity in this novel carbo­n-carbon bond-forming reaction is consistent with an S_N2-type mechanism, the complete trans-selectivity in the synthesis of acetal 6 may be thermodynamic in nature and is likely the result of a double S_N2 reaction at the labil­e acetal center. The intrinsic propensity of 5-acyloxy-oxazolidin-2-ones 3 to undergo nucleophilic substitutions at their acetal center is remarkable and contrasts the known behavior of N-BOC-substituted oxazolidinones, which invariably react with nucleophiles at their ring carbony­l carbon. [2] [8b] Presumably, the C-OAc-bond is weakened by an anomeric effect of the ring oxygen atom.

In conclusion, we have developed an efficient and highly enantioselective synthesis of α-amino acid derivatives 3-7. Our sequence is based on the proline-catalyzed asymmetric three-component Mannich reaction, combined with a Baeyer-Villiger oxidation to furnish previously undescrib­ed 5-acyloxy-oxazolidin-2-ones 3. All steps of the developed sequence are operationally simple, rapid, give good chemical yields, and provide the products in high optical purity. Our methodology is best suited for the synthesis of aryl glycine derivatives because the initial Mannich reaction provides the highest steroselectivities with aromatic aldehydes. As such, the presented scheme nicely complements our recently developed catalytic asymmetric aldehyde α-amination reaction, which furnishes aliphatic α-amino acid derivatives in excellent enantioselectivities. [13] Future work will focus on the intrigu­ing yet underexplored chemistry of 5-acyloxy-oxazolidin-2-ones 3 and on the application of our methodolog­y to the synthesis of biologically active compound­s.

Acknowledgment

Support by the NIH (GM-63914) is gratefully acknowledged. We thank M. G. Finn and his group for sharing chemicals.

References

1

New Address: Max-Plank-Institut für Kohlenforschung, 45470 Mülheim an der Ruhr, Germany.
E-mail: [e-mail]

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10b

MCPBA was less efficient in these reactions.

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12

Aliphatic amino alcohol 5d was obtained enantiomerically pure after recrystallization of an intermediate, see ref. [1]

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