Stereoselective Double Alkylation of the Acetoacetate Ester α-Carbon on a d-Glucose-Derived Template: Application to the Synthesis of Enantiopure Cycloalkenones Bearing an Asymmetric Quaternary Carbon

 

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Abstract

The previously developed d-glucose derivative, i.e., ­methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside, served as a significant stereocontrolling element for the ­diastereoselective alkylation of the α-carbon in its acetoacetate at C-4 with two types of alkyl halides. The thus obtained doubly ­alkylated acetoacetate moiety bearing both methyl and allyl groups was efficiently converted into functionalized cycloalk-2-en-1-one derivatives by means of an intramolecular aldol strategy. Furthermore, the synthetic utility of the cycloalkenones was exemplified through the 1,4-addition to the thus obtained cyclopentenone ­derivative.

References and Notes

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All new compounds were fully characterized by spectral means (¹H NMR and ¹³C NMR, IR, and HRMS). Yields refer to isolated products after purification by column chromatography on silica gel.

We examined the following bases for the second benzylation, which was carried out in THF. The yield of 7 using NaHMDS (-78 °C to r.t.), 18%; using LiHMDS
(-18 °C to r.t.), 35%; and using NaH (-78 °C to r.t.), 74%.

The yield of the first benzylation (BnBr, EtONa, THF, 0 °C to r.t.) was 97%. The conditions and yields of the second methylation for the two diastereomers, i.e., 7 and its epimer at the α-carbon, were as follows: a) MeI and KHMDS in THF at -18 °C to r.t., 46% and 10%; b) EtONa as the base at -78 °C to r.t., 64% and 16%; c) MeONa as the base at -78 °C to r.t., 63% and 14%. In all cases, the major product was 7.

We also synthesized the S-antipode of 8 from the minor α-dialkylated acetoacetate obtained by the reverse double alkylation of 5 with the same alkyl halides followed by the analogous pyrazoline formation used for the case of 7. The synthesized S-isomer possessed the following optical rotation: [α]_D ²¹ +180 (c 0.30, CHCl₃).

Compound 12: TLC: R _f = 0.50 (EtOAc-hexane, 1:3); [α]_D ²⁵ +64.1 (c 1.49, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.09, 0.10 (2 s, each 6 H), 0.84, 0.91 (2 s, each 9 H), 1.05 (d, 3 H, J = 6.3 Hz), 1.42 (s, 3 H), 2.53, 3.45 (2 ddd, each 1 H, J = 19.2, 2.2, 2.2 Hz), 3.33 (s, 3 H), 3.56-3.64 (m, 1 H), 3.66 (dd, 1 H, J = 8.7, 3.5 Hz), 3.87 (t, 1 H, J = 8.7 Hz), 4.60 (d, 1 H, J = 3.5 Hz), 4.72 (dd, 1 H, J = 9.8, 8.7 Hz), 6.17 (ddd, 1 H, J = 5.6, 2.2, 2.2 Hz), 7.74 (ddd, 1 H, J = 5.6, 2.2, 2.2 Hz). ¹³C NMR (68 MHz, CDCl₃): δ = -4.2 × 2, -3.2, -2.6, 17.5, 17.9, 18.5, 21.9, 26.0 × 3, 26.2 × 3, 42.1, 53.7, 54.8, 65.3, 72.0, 74.6, 78.2, 99.8, 131.5, 163.0, 170.3, 205.8. IR (neat): 2950, 2850, 2750, 2710, 1730, 1715, 1590, 1450, 1360 cm^-1. HRMS (EI): m/z calcd for C₂₂H₃₉O₇Si₂ [M⁺ - t-Bu]: 471.2234; found: 471.2233.

(1S,5S)-5-Hydroxymethyl-5-methyl-2-cyclopenten-1-ol (14): TLC: R _f = 0.44 (EtOAc); [α]_D ²³ +65.6 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.09 (s, 3 H), 1.98 (d, 1 H, J = 17.1 Hz), 2.48 (dd, 1 H, J = 17.1, 2.1 Hz), 3.63, 3.70 (2 d, each 1 H, J = 11.1 Hz), 4.44 (br s, 1 H), 5.74-5.76 (m, 1 H), 5.95-5.97 (m, 1 H). ¹³C NMR (68 MHz, CDCl₃): δ = 24.0, 41.9, 45.2, 68.3, 85.4, 131.6, 134.9. IR (neat): 3250, 3060, 2930, 1730, 1460 cm^-1. HRMS (EI): m/z calcd for C₇H₁₂O₂ [M⁺]: 128.0837; found: 128.0841

We explored the removal of the sugar template from 12 directly by methanolysis (MeONa in MeOH). In this case, compound 12 was quantitatively recovered. The removal of the sugar template from the protected forms of the allylic alcohol 13 as its TBS or MOM ethers was also fruitless. For these ethers, saponification or hydride attack resulted in the recovery of the starting material.

The configuration of newly introduced allylic carbinol carbon in 19 as depicted was confirmed by the NOE experiment in which a significant (7.3%) signal enhancement of the proton at the allylic carbinol carbon was observed when the adjacent methyl group was irradiated.

The DIBAL-H reduction of 18 (1.5 equiv, CH₂Cl₂, -78 °C) also provided 19 as a single product in a less effective yield of 63%.

In this case, the sugar template 1 was recovered in 19% yield. Under the harsh DIBAL-H reduction of 19, the silyl group at C-2 in 1 was unexpectedly deprotected to a large extent. Thus, the 3-O-TBS derivative was obtained in a significant yield of 75%.

We also examined the 1,4-addition using n-Bu₂CuLi under analogous conditions as those used for the Me₂CuLi addition. The 1,4-addition proceeded with complete stereoselectivity to provide a single 1,4-adduct in 75% yield. Unfortunately, we could not establish the configuration at the β-carbon of this adduct unambiguously from ¹H NMR spectral analysis.