Enantioselective Total Synthesis of (R)-α-Lipoic Acid: An Application of Thermodynamically Controlled Deracemization of (±)-2-(2-Methoxyethyl)cyclohexanone

Abstract

According to the concept of thermodynamically controlled deracemization, racemic 2-(2-methoxyethyl)cyclohexanone was converted into the R-isomer (99% ee) in 90% yield using (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi­ro[5.4]decane as a host molecule under basic conditions. As an application, a short and enantioselective synthesis of (R)-α-lipoic acid was accomplished in 44% overall yield from (±)-2-(2-methoxyethyl)cyclohexanone.

(R)-α-Lipoic acid (1) (Figure  [¹] ), which was isolated as a growth-promoting enzyme cofactor, [¹] plays an important role as a protein-bound transacylating cofactor of several multi-enzymatic α-keto acid dehydrogenase complexes. Since its discovery, (R)-α-lipoic acid (1) has attracted great attention because of its fascinating biological activity. For example, it shows effects in diabetes mellitus [²] and hepatic diseases. [³] It has also been reported that 1 and its derivatives are highly active as anti-HIV [4] and antitumor agents. [5]

Lipoic acid is often used in its racemic form for therapy purposes because the S-enantiomer shows no significant biological side effects. However, the enantioselective synthesis of the R-enantiomer 1 has attracted a great deal of interest among organic and medicinal chemists. For example, the synthesis has been achieved by using of ‘chiral pool’ starting materials, [6] baker’s yeast reductions, [7] asymmetric allylation, [8] asymmetric dihydroxylation/hydrogenation, [9] Sharpless asymmetric epoxidation, [¹0] and so on. [¹¹]

Recently, we developed thermodynamically controlled deracemization of racemic α-monosubstituted cycloalkanones utilizing a chiral host molecule under basic suspension media. [¹²] For example, the use of (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi­ro[5.4]decane (2a) [¹³] (1.0-2.0 equiv) or (4R,5R)-α,α,α′,α′,2-pentaphenyl-1,3-dioxolane-4,5-dimethanol (2b) [¹³] as host molecules with sodium hydroxide in aqueous methanol converted racemic 2-allylcyclohexanone [(±)-3] and 2-(2-methoxyethyl)cyclohexanone [(±)-4] into their R-isomers with 74% ee and 94% ee, respectively, in quantitative yields (Scheme  [¹] ).

In the course of our detailed investigations on deracemization, we found that the proportion of water in aqueous methanol influenced the enantiomeric purity of the ketone (R)-3. [¹4] Based on this finding, we succeeded in obtaining (R)-3 with 93% ee in 70% yield, when the recovery of 3 was sacrificed to some extent by filtration. We then synthesized (-)-(R)-epilachnene, an antipode of the defensive droplets from the Mexican bean beetle Epilachna varivestis, in a few steps using (R)-3 as the starting material.

As another application of the deracemization, we have successfully accomplished an enantioselective total synthesis of (R)-α-lipoic acid (1) starting from (±)-4 in five steps (Scheme  [²] ). Here, we report the results in detail.

We reported previously that 250 mg of (±)-4 was converted into the R-isomer (94% ee) in 96% yield using 2a (2 equiv) with sodium hydroxide (4 equiv) in a mixture of water-methanol (2:1) (vide supra) after stirring for two days. [¹²c] However, a prolonged reaction time (7 d) was required for a 500-mg scale deracemization. To reproduce the 250-mg scale result, the period of reaction had to be extended up to one week. Then, optical resolution by inclusion complexation was carried out to remove the unfavorable enantiomer (S-isomer) of 4. This was accomplished by mixing the obtained (R)-4 again with 2a (2 equiv) in a fresh mixture of water-methanol (2:1) without base for one day. After filtration, a solid residue was recovered and subjected to silica gel column chromatography to afford (R)-4 with 99% ee in 90% yield from (±)-4 (Scheme  [³] ), and host molecule 2a (>99%) that was reusable after recrystallization. In contrast, (R)-4 with 5.9% ee was recovered in 9.0% yield from the filtrate.

The R-isomer (R)-4 was subjected to Baeyer-Villiger oxidation using 3-chloroperoxybenzoic acid with anhydrous sodium dihydrogen phosphate to afford lactone 5 in 93% yield (Scheme  [4] ). Treatment of 5 with diiodosilane [¹5] cleaved the methyl ether linkage with concomitant ring-opening iodination of the lactone via a S_N2-type mechanism at C6. Without further purification, the resulting primary alcohol 6 was subsequently converted into mesylate 7. The final step was achieved by treating 7 with a mixture of sodium sulfide and sulfur in N,N-dimethylformamide at 80 ˚C without protection of the carboxylic acid. Silica gel column chromatography of the resulting mixture gave 1 in 79% yield [mp 43-45 ˚C (pentane), [α]_D ^¹9 +112 (c 0.24, benzene)], whose physical properties compared well with those in the literature [¹6] [mp 46-48 ˚C, [α]_D ^²5 +104 (c 0.88, benzene)]. Thus, (R)-α-lipoic acid (1) was synthesized quite satisfactorily in five steps (44% overall yield) starting from (±)-2-(2-methoxyethyl)cyclohexanone [(±)-4].

The deracemization of (±)-2-(2-methoxyethyl)cyclohexanone [(±)-4] was accomplished utilizing (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspi­ro[5.4]decane (2a) as a host molecule to afford (R)-4, which was employed as a starting material for the total synthesis of (R)-α-lipoic acid (1).

This illustrates that thermodynamically controlled deracemization could provide a convenient and excellent method for the preparation of optically active α-mono­-substituted cyclohexanones. Further studies to disclose the principle of the molecular recognition process and the applicability of the present method are now in progress.

Melting points were determined on a Yanaco MP-3 apparatus and are uncorrected. IR spectra were recorded from either neat liquid films or solids in KBr pellets on a Jasco Model FT/IR-410 spectrophotometer. ^¹H NMR spectra were recorded on a Varian Gemini 200 (200 MHz), Varian Unity 200 (200 MHz), Varian Mercury 300 (300 MHz), or Varian 400 MR (400 MHz) spectrometer in CDCl₃ relative to internal TMS. ^¹³C NMR spectra were taken on a Varian 400 MR (100 MHz) and chemical shifts were referenced to the residual solvent signal (CDCl₃: δ = 76.9). Mass spectra including HRMS were recorded on a Jeol AX-500 spectrometer.

Optional rotations were measured on a Jasco DIP-1000 polarimeter using a 10-cm microcell. Capillary gas chromatographic analyses were performed on a Shimadzu GC-14A gas chromatograph equipped with 30 m × 0.25 mm fused-silica α-DEX120 and β-DEX325 SUPELCO columns. Helium was used as the carrier gas and peak area integrations were uncorrected for flame ionization detector response. Analytical HPLC was performed on a Jasco system consisting of a pump (PU-980) and a photodiode array detector (UV-970, set at 330 nm) and equipped with a Daicel Chiracel OJ or OD column. Peak areas were measured by electronic integration on a Shimadzu C-R7Aplus chromatopac.

In general, reagent grade solvents were used. DMF was distilled from CaH₂ under reduced pressure. CH₂Cl₂ and Et₃N were distilled from CaH₂ under an argon atmosphere. Analytical TLC was performed on precoated silica gel 60 F-254 plates (0.2-mm layers) on glass with fluorescent indicator, supplied by E. Merck. For column chromatography, Fuji silysia BW-127ZH (53-150 µm) or BW-300 (32-53 µm) was used.

Deracemization of (±)-2-(2-Methoxyethyl)cyclohexanone (4); Preparation of ( R )-4

To a soln of (±)-4 (500 mg, 3.20 mmol) [¹7] in MeOH (16.7 mL) was added host compound 2a (3.25 g, 6.41 mmol, 2 equiv), then distilled H₂O (20.5 mL) and aq 1 M NaOH (12.8 mL, 4 equiv) were added. The resulting mixture was stirred vigorously at r.t. for 7 d and then it was poured into sat. aq NH₄Cl soln (100 mL) and extracted with Et₂O (3 × 100 mL). After evaporation of the ethereal solns in vacuo, the residue was chromatographed (silica gel, 200 g, toluene-Et₂O to hexane-Et₂O) to afford ketone (R)-4 (503 mg, >99%, 92% ee) as a colorless oil and 2a (3.31 g, >99%). The obtained (R)-4 was mixed again with fresh host 2a (3.25 g, 2 equiv) in 33% aq MeOH (50 mL) without base. After vigorous stirring at r.t. for 1 d, the resulting mixture was filtered and the residue was washed with H₂O-MeOH (2:1, 3 × 5 mL). The residue was subjected to column chromatography (silica gel, 200 g, toluene-Et₂O to hexane-Et₂O) to afford (R)-4; yield: 90% [from (±)-4]; 99% ee [GLC (chiral column, SUPELCO, α-DEX120, 110 ˚C): t _R = 24.6 min]; R _f  = 0.36 (hexane-EtOAc, 3:1).

[α]_D ^²¹ +0.82 (c 1.00, CHCl₃) [Lit. [¹8] [α]_D +0.38 (c 9, CHCl₃)].

^¹H NMR (400 MHz, CDCl₃): δ = 3.43 (ddd, J = 9.4, 6.5, 5.9 Hz, 1 H, H2′a), 3.39 (ddd, J = 9.4, 6.9, 5.9 Hz, 1 H, H2′b), 3.31 (s, 3 H, CH₃), 2.53-2.45 (m, 1 H), 2.44-2.36 (m, 1 H), 2.36-2.27 (m, 1 H), 2.18-2.10 (m, 2 H), 2.10-2.02 (m, 1 H), 1.90-1.81 (m, 1 H), 1.75-1.60 (m, 2 H), 1.45-1.33 (m, 2 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 213.0, 70.3, 58.4, 47.1, 42.1, 34.2, 29.3, 28.0, 25.0.

( R )-7-(2-Methoxyethyl)oxepan-2-one (5)

To a mixture of (R)-4 (660 mg, 4.22 mmol) and NaH₂PO₄ (1.53 g, 12.7 mmol) in CH₂Cl₂ (40 mL) was added MCPBA (1.56 g, 6.33 mmol, 1.5 equiv). The mixture was stirred at r.t. for 6 h and then filtered through Celite. The filtrate was diluted with CH₂Cl₂ (50 mL) and washed with sat. aq Na₂S₂O₃ (150 mL), sat. aq NaHCO₃ (150 mL), and sat. aq NaCl (100 mL). The organic layer was dried (MgSO₄), filtered, and concentrated. Purification of the residue by column chromatography (silica gel, 27 g, hexane-Et₂O, 3:1) yielded 5 (683 mg, 93%) as a colorless oil; R _f  = 0.35 (hexane-EtOAc, 3:1).

[α]_D ^²5 -63.3 (c 1.00, CHCl₃).

IR (neat): 1729 cm^-¹ (C=O).

^¹H NMR (400 MHz, CDCl₃): δ = 4.45 (td, J = 8.8, 4.3 Hz, 1 H, H7), 3.56 (ddd, J = 9.4, 8.8, 4.5 Hz, 1 H, H9a), 3.45 (dt, J = 9.6, 5.1 Hz, 1 H, H9b), 3.34 (s, 3 H, CH₃), 2.72-2.59 (m, 2 H, H3), 1.99-1.88 (m, 4 H), 1.80 (dddd, J = 14.3, 8.8, 5.3, 3.9 Hz, 1 H), 1.70-1.56 (m, 3 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 175.7, 76.9, 68.2, 58.7, 36.4, 34.8, 34.6, 28.1, 22.9.

MS (CI): m/z = 173 ([M + H]⁺, base peak), 155, 141, 123, 81.

HRMS (CI): m/z [M + H]⁺ calcd for C₉H₁₇O₃: 173.1178; found: 173.1174.

( S )-6-Iodo-8-(methylsulfonyloxy)octanoic Acid (7)

A soln of SiH₂I₂ (300 µL, 2.99 mmol) in anhyd CH₂Cl₂ (4 mL) was added to a soln of lactone 5 (101 mg, 0.585 mmol) in anhyd CH₂Cl₂ (3 mL) under an argon atmosphere and the mixture was stirred at 50 ˚C for 1 d. The resulting mixture was quenched with sat. aq NaHCO₃ soln (20 mL) and sat. aq Na₂CO₃ (40 mL) and washed with CH₂Cl₂ (3 × 50 mL). After acidification of the aqueous layer with 6 M HCl soln (pH 1) followed by addition of NaCl, the mixture was extracted with CH₂Cl₂ (5 × 100 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated to afford unpurified (S)-8-hydroxy-6-iodooctanoic acid (6) (153 mg).

To a soln of crude 6 in anhyd CH₂Cl₂ (5 mL) was added Et₃N (405 µL, 2.91 mmol) and MsCl (200 µL, 2.58 mmol) at -30 ˚C and the mixture was stirred for 10 min. 2 M HCl (15 mL) was added followed by extraction with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated. Purification of the residue by column chromatography (silica gel, 6 g, hexane-EtOAc, 5:1 to 3:1, 2:1, and 1:1) yielded 7 (134 mg, 67%) as a colorless oil; R _f  = 0.38 (hexane-EtOAc, 1:3).

[α]_D ^²² +12.2 (c 1.00, CHCl₃).

IR (neat): 2938 (OH), 1708 cm^-¹ (C=O).

^¹H NMR (400 MHz, CDCl₃): δ = 10.9 (br s, 1 H, COOH), 4.45 (dt, J = 10.2, 5.1 Hz, 1 H, H8a), 4.40-4.32 (m, 1 H, H8b), 4.21-4.13 (m, 1 H, H6), 3.06 (s, 3 H, CH₃), 2.40 (t, J = 7.3 Hz, 2 H, H2), 2.20-2.13 (m, 2 H, H7), 1.98-1.87 (m, 1 H, H5a), 1.84-1.73 (m, 1 H, H5b), 1.73-1.56 (m, 3 H, H3, H4a), 1.56-1.43 (m, 1 H, H4b).

^¹³C NMR (100 MHz, CDCl₃): δ = 178.6, 69.6, 40.0, 39.3, 37.3, 33.4, 32.0, 28.7, 23.6.

MS (CI): m/z = 365 [M + H]⁺, 347 (base peak), 269, 237, 219, 123.

HRMS (CI): m/z [M + H]⁺ calcd for C₉H₁₈IO₅S: 364.9920; found: 364.9918.

( R )-α-Lipoic Acid (1)

Na₂S˙9 H₂O (76.8 mg, 0.320 mmol) and sulfur (10.4 mg, 0.325 mmol) were stirred in anhyd DMF (8 mL) at 80 ˚C for 1 h under an argon atmosphere in the dark and then a soln of 7 (102 mg, 0.279 mmol) in anhyd DMF (4 mL) was added to the mixture. The mixture was stirred at 80 ˚C for 2 h, distilled H₂O (20 mL) and 2 M HCl (2 mL) were added, and the resulting mixture was extracted with Et₂O (3 × 40 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated. Purification of the residue by column chromatography (silica gel, 10 g, hexane-Et₂O, 5:1 to 3:1) yielded 1 (46 mg, 79%, 93% ee) as a yellow solid. Recrystallization (pentane) gave 1; 99% ee [HPLC (chiral column, Daicel, Chiralcel OD; hexane-i-PrOH-TFA, 99:1:0.05; UV 330 nm), t _R = 29.9 min]; mp 43-45 ˚C (pentane) (Lit. [¹6] 46-48 ˚C); R _f  = 0.37 (hexane-EtOAc, 1:1).

[α]_D ^¹9 +112.2 (c 0.24, benzene) [Lit. [¹6] [α]_D ^²5 +104 (c 0.88, benzene)].

IR (KBr): 3040 (OH), 1705 cm^-¹ (C=O).

^¹H NMR (400 MHz, CDCl₃): δ = 10.6 (br s, 1 H, COOH), 3.58 (dtd, J = 8.3, 6.4, 6.3 Hz, 1 H, H6), 3.19 (dddd, J = 11.0, 7.0, 5.3, 0.3 Hz, 1 H, H8a), 3.12 (dt, J = 11.0, 6.9 Hz, 1 H, H8b), 2.47 (dtd, J = 11.9, 6.6, 5.4 Hz, 1 H, H7a), 2.38 (t, J = 7.3 Hz, 2 H, H2), 1.92 (dtd, J = 12.8, 7.0, 6.9 Hz, 1 H, H7b), 1.78-1.61 (m, 4 H, 2 CH₂), 1.59-1.41 (m, 2 H, CH₂).

^¹³C NMR (100 MHz, CDCl₃): δ = 178.3, 56.2, 40.1, 38.4, 34.5, 33.4, 28.6, 24.3.

MS (EI): m/z = 206 (M⁺, base peak), 173, 149, 105, 123, 95.

HRMS (EI): m/z [M]⁺ calcd for C₈H₁₄O₂S₂: 206.0435; found: 206.0433.

Acknowledgment

This work was supported in part by a Grant-in-Aid for Scientific Research (C, 19590028) from MEXT (the Ministry of Education, Culture, Sports, Science and Technology of Japan). We are also thankful to MEXT.HAITEKU, 2003-2007.

References

• 1 Reed LJ. DeBusk BG. Gunsalus IC. Hornberger CS. Science  1951,  114:  93 
  CrossrefSearch in Google Scholar
• 2 Jacob S. Ruus P. Hermann R. Tritschler HJ. Maerker E. Renn W. Augustin HJ. Dietze GJ. Rett K. Free Radical Biol. Med.  1999,  27:  309 
  CrossrefSearch in Google Scholar
• 3 Thoelen H. Zimmerli W. Rajacic Z. Experientia  1985,  41:  1042 
  CrossrefSearch in Google Scholar
• 4 Baur A. Harrer T. Peukert M. Jahn G. Kalden JR. Fleckenstein B. Klin. Wocheschr.  1991,  69:  722 ; Chem. Abstr. 1992, 116, 207360.
  CrossrefSearch in Google Scholar
• 5 Bingham PM, and Zachar Z. inventors; WO  0,024,734.  ; Chem. Abstr. 2000, 132, 308192.
• 6a Tolstikov AG. Khakhalina NV. Savateeva EE. Spirikhin LV. Khalilov LM. Odinokov VN. Tolstikov GA. Bioorg. Khim.  1990,  16:  1670 
  Search in Google Scholar
• 6b Yadav JS. Mysorekar SV. Pawar SM. Gurjar MK.
  J. Carbohydr. Chem.  1990,  9:  307 
  Search in Google Scholar
• 6c Brookes MH. Golding BT. J. Chem. Soc., Perkin Trans. 1  1988,  9 
• 6d Rama Rao AV. Gurjar MK. Garyali K. Ravindranathan T. Carbohydr. Res.  1986,  148:  51 
  Search in Google Scholar
• 6e Brookes MH. Golding BT. Howes DA. Hudson AT. J. Chem. Soc., Chem. Commun.  1983,  1051 
• 7a Dasaradhi L. Fadnavis NW. Bhalerao UT. J. Chem. Soc., Chem. Commun.  1990,  729 
• 7b Gopalan AS. Jacobs HK. J. Chem. Soc., Perkin Trans. 1  1990,  1897 
• 8 Zimmer R. Hain U. Berndt M. Gewald R. Reissig H.-U. Tetrahedron: Asymmetry  2000,  11:  879 
  CrossrefSearch in Google Scholar
• 9 Upadhya TT. Nikalje MD. Sudalai A. Tetrahedron Lett.  2001,  42:  4891 
  CrossrefSearch in Google Scholar
• 10a Page PCB. Rayner CM. Sutherland IO. J. Chem. Soc., Perkin Trans. 1  1990,  1615 
• 10b Page PCB. Rayner CM. Sutherland IO. J. Chem. Soc., Chem. Commun.  1986,  1408 
• 11a Bose DS. Fatina L. Rajender S. Synthesis  2006,  1863 
• 11b Chavan SP. Praveen C. Ramakrishna G. Kalkote UR. Tetrahedron Lett.  2004,  45:  6027 
  Search in Google Scholar
• 11c Zimmer R. Peritz A. Czerwonka R. Schefzig L. Reißig H.-U. Eur. J. Org. Chem.  2002,  3419 
• 11d Ganaha M. Yamauchi S. Kinoshita Y. Biosci. Biotechnol. Biochem.  1999,  63:  2025 
  Search in Google Scholar
• 11e Bringmann G. Herzberg D. Adam G. Balkenhohl F. Paust J. Z. Naturforsch., B: Chem. Sci.  1999,  54b:  655 
  Search in Google Scholar
• 11f Adger B. Bes MT. Grogan G. McCague R. Pedragosa-Moreau S. Roberts SM. Villa R. Wan PWH. Willetts AJ. Bioorg. Med. Chem.  1997,  5:  253 
  Search in Google Scholar
• 11g Bezbarua M. Saikia AK. Barua NC. Kalita D. Ghosh AC. Synthesis  1996,  1289 
• 11h Laxmi YRS. Iyengar DS. Synthesis  1996,  594 
• 11i Adger B. Bes MT. Grogan G. McCague R. Pedragosa-Moreau S. Roberts SM. Villa R. Wan PWH. Willetts AJ. J. Chem. Soc., Chem. Commun.  1995,  1563 
• 11j Menon RB. Kumar MA. Ravindranathan T. Tetrahedron Lett.  1987,  28:  5313 
  Search in Google Scholar
• 11k Rama Rao AV. Purandare AV. Reddy ER. Gurjar MK. Synth. Commun.  1987,  17:  1095 
  Search in Google Scholar
• 11l Rama Rao AV. Mysorekar SV. Gurjar MK. Yadav JS. Tetrahedron Lett.  1987,  28:  2183 
  Search in Google Scholar
• 11m Elliott JD. Steele J. Johnson WS. Tetrahedron Lett.  1985,  26:  2535 
  Search in Google Scholar
• 12a Kaku H. Takaoka S. Tsunoda T. Tetrahedron  2002,  58:  3401 
  Search in Google Scholar
• 12b Kaku H. Ozako S. Kawamura S. Takatsu S. Ishii M. Tsunoda T. Heterocycles  2001,  55:  847 
  Search in Google Scholar
• 12c Tsunoda T. Kaku H. Nagaku M. Okuyama E. Tetrahedron Lett.  1997,  38:  7759 
  Search in Google Scholar
• 13 Seebach D. Beck AK. Imwinkelried R. Roggo S. Wonnacott A. Helv. Chim. Acta  1987,  70:  954 
  CrossrefSearch in Google Scholar
• 14 Kaku H. Okamoto N. Nakamaru A. Tsunoda T. Chem. Lett.  2004,  33:  516 
  CrossrefSearch in Google Scholar
• 15 Keinan E. Sahai M. J. Org. Chem.  1990,  55:  3922 
  CrossrefSearch in Google Scholar
• 16 Merck Index   12th ed.:  Budavari S. O’Neil MJ. Smith A. Heckelman PE. Kinneary JF. Merck & Co., Inc.; Whitehouse Station NJ: 1996.  1591. p.No. 9462 
• 17 Dotani M. inventors; JP 2007,297,352  A.  ; Chem. Abstr. 2007, 147: 521898.
• 18 Meyers AI. Williams DR. Erickson GW. White S. Druelinger M. J. Am. Chem. Soc.  1981,  103:  3081 
  CrossrefSearch in Google Scholar

References

• 1 Reed LJ. DeBusk BG. Gunsalus IC. Hornberger CS. Science  1951,  114:  93 
  CrossrefSearch in Google Scholar
• 2 Jacob S. Ruus P. Hermann R. Tritschler HJ. Maerker E. Renn W. Augustin HJ. Dietze GJ. Rett K. Free Radical Biol. Med.  1999,  27:  309 
  CrossrefSearch in Google Scholar
• 3 Thoelen H. Zimmerli W. Rajacic Z. Experientia  1985,  41:  1042 
  CrossrefSearch in Google Scholar
• 4 Baur A. Harrer T. Peukert M. Jahn G. Kalden JR. Fleckenstein B. Klin. Wocheschr.  1991,  69:  722 ; Chem. Abstr. 1992, 116, 207360.
  CrossrefSearch in Google Scholar
• 5 Bingham PM, and Zachar Z. inventors; WO  0,024,734.  ; Chem. Abstr. 2000, 132, 308192.
• 6a Tolstikov AG. Khakhalina NV. Savateeva EE. Spirikhin LV. Khalilov LM. Odinokov VN. Tolstikov GA. Bioorg. Khim.  1990,  16:  1670 
  Search in Google Scholar
• 6b Yadav JS. Mysorekar SV. Pawar SM. Gurjar MK.
  J. Carbohydr. Chem.  1990,  9:  307 
  Search in Google Scholar
• 6c Brookes MH. Golding BT. J. Chem. Soc., Perkin Trans. 1  1988,  9 
• 6d Rama Rao AV. Gurjar MK. Garyali K. Ravindranathan T. Carbohydr. Res.  1986,  148:  51 
  Search in Google Scholar
• 6e Brookes MH. Golding BT. Howes DA. Hudson AT. J. Chem. Soc., Chem. Commun.  1983,  1051 
• 7a Dasaradhi L. Fadnavis NW. Bhalerao UT. J. Chem. Soc., Chem. Commun.  1990,  729 
• 7b Gopalan AS. Jacobs HK. J. Chem. Soc., Perkin Trans. 1  1990,  1897 
• 8 Zimmer R. Hain U. Berndt M. Gewald R. Reissig H.-U. Tetrahedron: Asymmetry  2000,  11:  879 
  CrossrefSearch in Google Scholar
• 9 Upadhya TT. Nikalje MD. Sudalai A. Tetrahedron Lett.  2001,  42:  4891 
  CrossrefSearch in Google Scholar
• 10a Page PCB. Rayner CM. Sutherland IO. J. Chem. Soc., Perkin Trans. 1  1990,  1615 
• 10b Page PCB. Rayner CM. Sutherland IO. J. Chem. Soc., Chem. Commun.  1986,  1408 
• 11a Bose DS. Fatina L. Rajender S. Synthesis  2006,  1863 
• 11b Chavan SP. Praveen C. Ramakrishna G. Kalkote UR. Tetrahedron Lett.  2004,  45:  6027 
  Search in Google Scholar
• 11c Zimmer R. Peritz A. Czerwonka R. Schefzig L. Reißig H.-U. Eur. J. Org. Chem.  2002,  3419 
• 11d Ganaha M. Yamauchi S. Kinoshita Y. Biosci. Biotechnol. Biochem.  1999,  63:  2025 
  Search in Google Scholar
• 11e Bringmann G. Herzberg D. Adam G. Balkenhohl F. Paust J. Z. Naturforsch., B: Chem. Sci.  1999,  54b:  655 
  Search in Google Scholar
• 11f Adger B. Bes MT. Grogan G. McCague R. Pedragosa-Moreau S. Roberts SM. Villa R. Wan PWH. Willetts AJ. Bioorg. Med. Chem.  1997,  5:  253 
  Search in Google Scholar
• 11g Bezbarua M. Saikia AK. Barua NC. Kalita D. Ghosh AC. Synthesis  1996,  1289 
• 11h Laxmi YRS. Iyengar DS. Synthesis  1996,  594 
• 11i Adger B. Bes MT. Grogan G. McCague R. Pedragosa-Moreau S. Roberts SM. Villa R. Wan PWH. Willetts AJ. J. Chem. Soc., Chem. Commun.  1995,  1563 
• 11j Menon RB. Kumar MA. Ravindranathan T. Tetrahedron Lett.  1987,  28:  5313 
  Search in Google Scholar
• 11k Rama Rao AV. Purandare AV. Reddy ER. Gurjar MK. Synth. Commun.  1987,  17:  1095 
  Search in Google Scholar
• 11l Rama Rao AV. Mysorekar SV. Gurjar MK. Yadav JS. Tetrahedron Lett.  1987,  28:  2183 
  Search in Google Scholar
• 11m Elliott JD. Steele J. Johnson WS. Tetrahedron Lett.  1985,  26:  2535 
  Search in Google Scholar
• 12a Kaku H. Takaoka S. Tsunoda T. Tetrahedron  2002,  58:  3401 
  Search in Google Scholar
• 12b Kaku H. Ozako S. Kawamura S. Takatsu S. Ishii M. Tsunoda T. Heterocycles  2001,  55:  847 
  Search in Google Scholar
• 12c Tsunoda T. Kaku H. Nagaku M. Okuyama E. Tetrahedron Lett.  1997,  38:  7759 
  Search in Google Scholar
• 13 Seebach D. Beck AK. Imwinkelried R. Roggo S. Wonnacott A. Helv. Chim. Acta  1987,  70:  954 
  CrossrefSearch in Google Scholar
• 14 Kaku H. Okamoto N. Nakamaru A. Tsunoda T. Chem. Lett.  2004,  33:  516 
  CrossrefSearch in Google Scholar
• 15 Keinan E. Sahai M. J. Org. Chem.  1990,  55:  3922 
  CrossrefSearch in Google Scholar
• 16 Merck Index   12th ed.:  Budavari S. O’Neil MJ. Smith A. Heckelman PE. Kinneary JF. Merck & Co., Inc.; Whitehouse Station NJ: 1996.  1591. p.No. 9462 
• 17 Dotani M. inventors; JP 2007,297,352  A.  ; Chem. Abstr. 2007, 147: 521898.
• 18 Meyers AI. Williams DR. Erickson GW. White S. Druelinger M. J. Am. Chem. Soc.  1981,  103:  3081 
  CrossrefSearch in Google Scholar