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Communication | Special issue | Vol. 86, No. 1, 2012, pp. 147-153
Received, 11th June, 2012, Accepted, 10th July, 2012, Published online, 13th July, 2012.
DOI: 10.3987/COM-12-S(N)31
Construction of All-Carbon Quaternary Stereocenters by Zinc-Mediated Barbier-Type Allylation in Aqueous Media

Ken-ichi Takao,* Tomo Miyashita, Nozomi Akiyama, Takuya Kurisu, Kohei Tsunoda, and Kin-ichi Tadano*

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku Yokohama 223-8522, Japan

Stereoselective synthesis of all-carbon quaternary stereocenters by Barbier-type allylation in aqueous media is described. Sugar-derived aldehydes, 2,3-O-isopropylidene-D-glyceraldehyde and 2,4-O-benzylidene-D-threose, were reacted with geranyl chloride in the presence of zinc powder to provide γ-adducts bearing quaternary stereocenters with good stereoselectivity.

Quaternary stereocenters are found in a wide range of complex natural products and pharmaceuticals. For example, (+)-hyperforin (1),1 (+)-perforatumone (2),2 and (+)-vibsanin A (3)3 share a structural motif with a common all-carbon quaternary stereogenic center (Figure 1). In developing a method for the synthesis of these natural products, we were faced with the challenge of developing a practical method to synthesize the quaternary stereocenter. The construction of quaternary stereocenters remains a difficult problem in organic synthesis.4 One approach to this challenge is the use of 3,3’-disubstituted allymetal reagents. Although extensive research has been carried out developing stereoselective carbonyl allylation reactions,5 the synthesis of organic compounds containing quaternary stereocenters through the addition of allylmetals to aldehydes is still a challenge.6 The majority of nucleophilic addition reactions using organometallic reagents involve lithium and magnesium. These reactions require the strict exclusion of moisture. Some classes of the Barbier-type allylation, however, do not require rigorously anhydrous reaction conditions and can be performed effectively in aqueous media.7 Zinc is the most popular metal for this type of reaction because it is easy to handle and stable in air. Herein, we describe the construction of an all-carbon quaternary stereocenter using a diastereoselective zinc-mediated Barbier-type allylation of chiral aldehydes in aqueous media.

To achieve the desired Barbier-type allylation, the reaction was investigated using easily available sugar derivatives as chiral aldehydes.8 We observed that 2,3-O-isopropylidene-D-glyceraldehyde (4)9 stereoselectively reacted with geranyl chloride (5)10 in the presence of zinc powder in a mixture of aqueous NH4Cl–THF11 at –5 °C (Table 1). The reaction produced γ-adducts with complete regioselectivity which were separated into 3R-isomers 7-A/7-B (4R/4S = 1:4) and 3S-isomers 7-C/7-D (4R/4S = 5:1) by column chromatography in yields of 6% and 77%, respectively (entry 1).12 When using 5, (3S,4R)-isomer 7-C was the major product. By using neryl chloride (6)13 in place of 5 as the allyl halide, (3S,4S)-isomer 7-D with the opposite configuration of the quaternary stereocenter (4-position) was preferentially obtained, but a decrease in stereoselectivity was observed (entry 2).

The stereochemistry of the newly formed contiguous stereocenters in adducts 7 was determined by chemical transformation as shown in Scheme 1. The major isomers 7-C/7-D (dr = 5:1) were hydrolyzed to triols, which were subjected to oxidative cleavage followed by reduction of the resultant aldehyde to afford the enantioenriched alcohol (+)-8. By comparing the optical rotation of (+)-8 with that of the known (–)-8,14 whose absolute stereochemistry had been determined {[α]D23 +13.2 (c 1.04, CHCl3) for synthetic (+)-8; lit.14 [α]D –16.9 (c 1.23, CHCl3) for authentic (–)-8}, the configuration of the quaternary stereocenter in 7-C was assigned as (R). The oxidation of 7-C/7-D provided ketone 9 as a (4R):(4S) = 5:1 mixture, while 7-A/7-B (dr = 1:4) provided a (4R):(4S) = 1:4 mixture of 9. Therefore, all the configurations at the 4-position in adducts 7A-D were unambiguously assigned. To determine the configurations at the 3-position, 7-A/7-B and 7-C/7-D were treated with acid. The migration of the isopropylidene group occurred in only 7-A/7-B, affording trans-dioxolane 10-A/10-B. These results indicate that 7-A/7-B are 2,3-syn isomers and 7-C/7-D are 2,3-anti isomers.15

To expand the scope of this reaction, we explored the use of other sugar-derived aldehydes. The use of 2,4-O-benzylidene-D-threose (11), prepared from D-galactose in a two-step reaction,16 was found to be effective in generating the quaternary stereocenter with (S)-configuration (Table 2).17 Although the reaction temperature was increased from –5 °C to room temperature in order to complete the reaction, the Barbier reaction of 11 with 5 resulted in good stereoselectivity, similar to that observed in the reaction of 4. (4R,5S)-Isomer 12-B was preferentially obtained along with (4R,5R)-isomer 12-A (12-A/12-B = 1:5) in 68% yield (entry 1).18 When the reaction was conducted using 6, (4R,5R)-isomer 12-A was obtained as the major isomer in slightly lower yield and stereoselectivity (entry 2).

Repeating a similar transformation to that of Scheme 1, the stereochemistry of the quaternary stereocenters in adducts 12 was assigned (Scheme 2). The hydrolyzed products, 13-A/13-B, prepared from 12-A/12-B (dr = 1:5) were recrystallized to provide the almost diastereomerically pure form of 13-B, which was then converted into highly enantioenriched (–)-8.19 The stereochemistry of the 4-position in 12 was determined by NOE experiments of the isopropylidene derivatives 14-A/14-B and 14-C/14-D.

The stereochemical outcomes obtained in the reaction of 4 or 11 can be explained using the transition states depicted in Scheme 3. Through a combined experimental and theoretical mechanistic investigation, the zinc-mediated Barbier-type allylations in aqueous media were estimated to proceed through a six-membered chair-like transition state.20 In addition, organozinc reagents have a tendency to form a chelate complex involving the carbonyl and the β-alkoxy group.21 Therefore, the reaction of 4 or 11 with 5 preferentially produces 7-C or 12-B in accordance with the β-chelation/six-membered model. The lower stereoselectivity observed in the case of 6 may be caused by the steric repulsion of the homoprenyl group adopting an axial position in the six-membered transition state.

In conclusion, we have developed a stereoselective construction of an all-carbon quaternary stereocenter through a zinc-mediated Barbier-type allylation of sugar-derived aldehydes in aqueous media. This reaction can be performed without the need of rigorously anhydrous conditions, providing a practical and operationally simple method for the construction of quaternary stereocenters. Further studies and applications of this work to natural product synthesis are in progress and will be reported in due course.

This work was supported in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2012-2016.


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Barbier-type allylation of aldehyde 4 with 5: To a stirred solution of 4 (10.1 g, 77.7 mmol) in THF (60 mL) and 20wt% aqueous NH4Cl (160 mL) was added zinc powder (24.0 g, 312 mmol). The mixture was cooled to –5 °C and a solution of 5 (8.99 g, 51.9 mmol) in THF (20 mL) was added dropwise over 1.5 h. After being stirred at –5 °C for 14 h, the mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The combined filtrate and washings were washed with saturated brine (100 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:70) to provide 0.83 g (6%) of 7-A/7-B (dr = 1:4) and 10.6 g (77%) of 7-C/7-D (dr = 5:1). Compound 7-C/7-D (dr = 5:1) was obtained as a colorless oil: TLC Rf 0.61 (EtOAc/hexane, 1:3); IR 3490, 2985, 2915 cm–1; 1H NMR (300 MHz) for 7-C δ 0.99 (s, 3H), 1.34 (s, 3H), 1.41 (s, 3H), 1.42-1.52 (m, 2H), 1.59 (s, 3H), 1.68 (s, 3H), 1.85-1.97 (m, 2H), 2.02 (br d, 1H, J = 3.2 Hz, OH), 3.75 (br dd, 1H, J = 3.2, 2.8 Hz), 3.85-3.95 (m, 2H), 4.16 (dt, 1H, J = 2.8, 7.1 Hz), 5.03 (dd, 1H, J = 17.5, 1.3 Hz), 5.03-5.15 (m, 1H), 5.14 (dd, 1H, J = 10.9, 1.3 Hz), 5.78 (dd, 1H, J = 17.5, 10.9 Hz); 13C NMR (75 MHz) for 7-C δ 17.7, 18.1, 22.5, 25.3, 25.6, 26.4, 37.9, 42.9, 64.3, 76.4, 76.7, 107.4, 114.2, 124.6, 131.3, 143.0; HRMS calcd for C16H28O3 (M+) m/z 268.2038, found 268.2027.
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The reaction of 2,4-O-benzylidene-D-erythrose, prepared from D-glucose, with 5 or 6 gave poor stereoselectivity.
Barbier-type allylation of aldehyde 11 with 5: To a stirred solution of 11 (263 mg, 1.38 mmol) in 20wt% aqueous NH4Cl (6 mL) was added zinc powder (604 mg, 9.23 mmol). The mixture was cooled to 0 °C and a solution of 5 (159 mg, 0.920 mmol) in THF (3 mL) was added dropwise. After being stirred at room temperature for 72 h, the mixture was filtered through a pad of Celite and washed with CH2Cl2. The combined filtrate and washings were diluted with H2O (40 mL) and saturated brine (10 mL) and extracted with CH2Cl2 (20 mL × 4). The combined extracts were dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:10) to provide 216 mg (68%) of 12-A/12-B (dr = 1:5) and 12.1 mg (4%) of 12-C/12-D (dr = 5:1). Compound 12-A/12-B (dr = 1:5) was obtained as a colorless oil: TLC Rf 0.47 (EtOAc/hexane, 1:2); IR 3443, 2969, 2920 cm-1; 1H NMR (500 MHz) for 12-B δ 1.12 (s, 3H), 1.46-1.62 (m, 2H), 1.56 (s, 3H), 1.66 (s, 3H), 1.90-1.95 (m, 2H), 2.81 (br, 1H, OH), 3.14 (br, 1H, OH), 3.69 (d, 1H, J = 6.5 Hz), 3.82 (m, 1H), 3.92 (dd, 1H, J = 6.5, 1.2 Hz), 4.07 (dd, 1H, J = 12.1, 1.5 Hz), 4.24 (dd, 1H, J = 12.1, 1.8 Hz), 5.07 (m, 1H), 5.07 (dd, 1H, J = 17.5, 1.5 Hz), 5.15 (dd, 1H, J = 10.9, 1.5 Hz), 5.53 (s, 1H), 5.92 (dd, 1H, J = 17.5, 10.9 Hz), 7.33-7.39 (m, 3H), 7.47-7.49 (m, 2H); 13C NMR (125 MHz) for 12-B δ 17.6, 18.2, 22.5, 25.6, 37.4, 43.9, 64.8, 72.4, 76.4, 79.4, 100.6, 113.6, 124.8, 125.8 (2C), 128.1 (2C), 128.8, 131.2, 137.7, 143.4; HRMS calcd for C21H30O4 (M+) m/z 346.2144, found 346.2139.
By the similar transformation, the configuration of the quaternary stereocenter in 12-C was assigned as (R).
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