Asymmetric Synthesis of Protected 2-Keto-1,3-diol and 1,2,3-Triol Building Blocks Bearing a Quaternary Stereogenic Center

Abstract

A s y m m e t r i c S y n t h e s i s o f P r o t e c t e d 2 -K e t o -1 , 3 -dAbstract: The asymmetric synthesis of protected 2-keto-1,3-diols 5 and 1,2,3-triols 6 bearing a quaternary stereogenic center starting from 2,2-dimethyl-1,3-dioxan-5-one (1) is described. The stereogenic centers are generated by sequential a-alkylation of 1 using the SAMP/RAMP hydrazone method and stereoselective reduction of ketones 5 with L-selectride. The products are obtained in good yields and high diastereomeric and enantiomeric excesses.A common structural feature of a large variety of polyoxygenated biologically active compounds is a tertiary alcohol moiety with a methyl group as one of the substituents. For example, it is found in many nucleosides, such as trachycladine A and B 1 or in sugars such as L-mycarose, 2 part of the antibiotic erythromycin, 3 or L-vancosamine, 4 part of glycopeptide vancomycin. 5 General procedures for the enantioselective formation of this characteristic moiety 6 are the 1,2-addition to a prochiral ketone, 7 the Jacobsen epoxidation of alkenes 8 with subsequent cleavage or the Sharpless-dihydroxylation 9 of trisubstituted alkenes. A common drawback of these reactions is the need to synthesize pure E-or Z-alkenes and further, the reductive opening of an epoxide or the removal of a hydroxy group.We now describe an efficient diastereo-and enantioselective synthesis of protected 2-keto-1,3-diols and 1,2,3-triols starting from the readily available dihydroxy acetone equivalent 1,3-dioxan-5-one (1) 10 employing the SAMP/ RAMP-hydrazone method. 11,12 As shown in Scheme 1, our synthesis starts from 1,3-dioxan-5-one 1, which was synthesized according to a literature procedure. 13 In the first step, this ketone was transformed to the corresponding RAMP-hydrazone 2.Two alkylations at the a-and a'-position with methyl iodide led to the RAMP-hydrazone 3 with the two methyl substituents in a trans-relationship. The key step in our synthesis was a subsequent third metalation and alkylation of 3 to install the quaternary stereocenter. The smooth metalation of 3 was achieved with tert-butyllithium; and the alkylation with various electrophiles led to the a-quaternary hydrazones 4 in excellent yields and diastereomeric excesses ( Table 1). One of the hydrazones 4g was a colorless crystalline solid and could be analyzed by X-ray diffraction (Figure). 14 The structure showed the twist-boat conformation of the six-membered dioxane ring, and the two methyl groups in cis-position. This meant that the electrophilic attack is again from the lithium-coordinated side and therefore consistent with a metallo-retentive mechanism. 11 Further, NOE data showed this to apply also for hydrazones 4a, c-f. The alkylation of 3 with isopropyl iodide lead to a nearly 1:1 mixture of both possible epimers 4b at position 4, the metallo-retentive and the inverse one (Table 1), which could be separated by column chromatography. Apparently, a sterically hindered electrophile leads to a diminished stereo differentiation.Scheme 1 Reagents and c...

The Dihydroxyacetone Unit—A Versatile C3Building Block in Organic Synthesis

“…[42,43] However, hydrazones 48 bearing a quaternary stereogenic center could only be cleaved with ozone to the ketones. Sterically hindered electrophiles led to diminished stereodifferentiation (% 0 % de in the case of RX = iPrI).…”

“…[32c] Furthermore, we were able to show that even a third alkylation step can be carried out in the case of the symmetrically substituted hydrazone 47 (Scheme 16). [42,43] However, hydrazones 48 bearing a quaternary stereogenic center could only be cleaved with ozone to the ketones. Sterically hindered electrophiles led to diminished stereodifferentiation (% 0 % de in the case of RX = iPrI).…”

Die Dihydroxyaceton‐Einheit – ein nützlicher C3‐Baustein in der Organischen Synthese

“…[42,43] Es sollte jedoch erwähnt werden, dass die Hydrazone 48 mit einem quartären Stereozentrum nur mit Ozon zu den Ketonen gespalten werden konnten. Sterisch anspruchsvolle Elektrophile führ-ten zu einer verminderten Stereodifferenzierung (% 0 % de für RX = iPrI).…”

First Asymmetric Synthesis of (+)‐Sordidin and (–)‐7‐epi‐Sordidin, Aggregation Pheromones of the Banana Weevil Cosmopolites sordidus

“…[11,13] In the next step, the quaternary stereocenter bearing the desired tertiary alcohol function was generated using benzyloxymethyl chloride (BOMCl) as the electrophile to trap the lithiated hydrazone 7 according to our dioxanone procedure. [14] The α-quaternary hydrazone 8 was thus obtained in very good yield (92 %) and excellent diastereomeric and enantiomeric excesses (de, ee Ն 96 %, 13 C NMR, GC) with the required cis relationship of the methyl substituents at the α-and αЈ-positions as a consequence of the typical relative topicity in RAMP-hydrazone alkylations in the third step. Subsequent ozonolysis at -78°C occurred without epimerisation and provided the trisubstituted dioxanone 9 in 79 % yield.…”