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Synlett 2017; 28(08): 970-972
DOI: 10.1055/s-0036-1588412
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© Georg Thieme Verlag Stuttgart · New York

Undemanding Synthesis of Novel C19 and C17 Analogues of C18-Guggultetrol

Ganesh R. Dhage
Department of Chemistry, Prof. John Barnabas Post Graduate School for Biological Studies, Ahmednagar College, Ahmednagar Station Road, Ahmednagar-414001, Maharashtra, India   Email: srthopate@gmail.com
,
Shankar R. Thopate*
Department of Chemistry, Prof. John Barnabas Post Graduate School for Biological Studies, Ahmednagar College, Ahmednagar Station Road, Ahmednagar-414001, Maharashtra, India   Email: srthopate@gmail.com
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Further Information

Publication History

Received: 16 November 2016

Accepted after revision: 17 January 2017

Publication Date:
06 February 2017 (online)

 
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Dedicated to the memory of Dr. B. P. Hiwale (Founder of Ahmednagar College).

Abstract

A simple and undemanding synthesis of (2S,3R,4R,5R)-nonadecane-1,2,3,4,5-pentol and (2S,3R)-heptadecane-1,2,3-triol as novel C19 and C17 analogues of C18-guggultetrol was achieved by using l-ascorbic acid as a chiral pool.


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Key words

ascorbic acid - chiral pool - guggultetrol - asymmetric synthesis - nonadecanepentol - heptadecanetriol

In ayurveda, the time-honored Indian system of phytomedicine, guggul has been used since prehistory to treat rheumatoid arthritis, inflammation, obesity, and lipid disorders.[1] Guggul is produced from the gum resin of Commiphora mukul (also known as C. wightii), which is endemic to the Indian subcontinent. Kumar and Dev isolated d-xylo-C18-guggultetrol (1; Figure [1, a]) and d-xylo-C20-guggultetrol from this plant.[2]

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Figure 1

With the expectation that guggultetrols might be plausible bioisosteres[3] of biologically significant phytosphingolipids,[4] several researchers have synthesized the fatty alcohols.[5] Indeed, several meritorious methods have been reported in the literature, and have contributed to the ongoing scientific development of syntheses of C18-guggul­tetrol.[1c] [2] [5a] [c] [d] [6] However, the C18-guggultetrol analogues 2 and 3 have not previously been synthesized. Although C18-guggultetrols are biologically important molecules, few attempts have made to synthesize their analogues.

Since its discovery, l-ascorbic acid has become a cynosure in the eyes of many in the scientific community because of its vital role in many biological functions, as well as its role in synthetic chemistry as a chiral pool.[7] The catalytic reduction of l-ascorbic acid to form two additional chiral centers stereospecifically gives l-gulonolactone, a venerable and useful synthon in carbohydrate chemistry and natural-product synthesis.[8]

Here, we report the synthesis of the novel analogues of C18-guggultetrol 2 and 3. Our chiral-pool approach used a series of highly efficient, practical, undemanding, and general reaction steps, starting from the cheaply available material l-ascorbic acid. In our retrosynthetic analysis (Figure [1, b]), we surmised that analogues 2 and 3 might be obtained from the advanced-stage intermediate 8. Alcohol 8, in turn, might be synthesized by Wittig olefination of lactol 7 as a crucial step. Lactol 7 might then be obtained from l-gulonolactone (5), which in turn might be prepared from l-ascorbic acid (4).

Because of its inherent stereochemistry, metal-catalyzed hydrogenation should be the method of choice for incorporating two additional chiral centers in l-ascorbic acid (4) to give l-gulonolactone (5). Working along these lines, Andrews and co-workers reported that this transformation proceeded using hydrogen, 10% palladium on carbon, and water as the solvent to give a 99% yield in 24 hours at 50 °C under 50 psi of hydrogen pressure.[9] Following this report, Pearson and co-workers found that the same reaction could be performed in up to 75% yield with an average reaction time of seven days at 50 °C under 75 psi of hydrogen pressure.[10] Bull and co-workers recently demonstrated that l-ascorbic acid could be reduced to l-gulonolactone (5) in 83% yield by using palladium on carbon in water for 72 hours at 50 °C under 130 psi of hydrogen pressure.[11] However, we found these reactions difficult to reproduce. Nevertheless, we found that l-ascorbic acid was efficiently reduced to l-gulonolactone (5) by using the method of Soriano et al.,[12] with 5% rhodium on alumina as a catalyst for 90 minutes under 55–60 psi of hydrogen pressure at room temperature, with an improved yield of up to 95% (Scheme [1]). This method has generally been overlooked in the literature, but in our hands we found it to be effective and reproducible.

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Scheme 1 Synthesis of analogues 2 and 3 from l-ascorbic acid

Having successfully prepared l-gulonolactone (5), we protected it as its diacetonide 6 by treatment with two equivalents of acetyl chloride in acetone as a solvent (Scheme [1]). Reduction of diacetonide 6 with DIBAL-H in anhydrous CH2Cl2 at –78 °C afforded 2,3:5,6-O-diisopropylidene-l-gulofuranose (7) in 79% yield. Witting olefination of 7 with Br– Ph3P+(CH2)12Me and BuLi gave the alkene 8 as an inseparable mixture of E- and Z-isomers in 88% yield. The Wittig salt Br– Ph3P+(CH2)12Me had been previously prepared by heating 1-bromotridecane with triphenylphosphine at 140 °C under an inert atmosphere for five hours. Catalytic hydrogenation of the double bond in alkene 8 with 10% palladium on carbon as a catalyst under 50 psi of hydrogen pressure gave the saturated diacetonide 9 in 87% yield. Subsequent acid-catalyzed deprotection of acetonide 9 gave the novel hydroxymethyl C18-guggultetrol homologue 2.[13] Therefore, the use of l-ascorbic acid as a chiral pool afforded the nonobvious product, (2S,3R,4R,5R)-nonadecane-1,2,3,4,5-pentol (2), which might not otherwise have been prepared by conventional approaches, due to difficulties in synthesis and purification.

Finally, in situ deprotection and cleavage of acetonide 9 with periodic acid in THF gave an aldehyde, which, without further purification, was subjected to reduction by NaBH4 in methanol, followed by acid-catalyzed deprotection, to give the novel analogue (2S,3R)-heptadecane-1,2,3-triol (3) in 24% yield over the three steps.[14]

In summary, we have developed a straightforward chiral-pool strategy for the synthesis of (2S,3R)-heptadecane-1,2,3-triol (3) and (2S,3R,4R,5R)-nonadecane-1,2,3,4,5-pentol (2), which are analogues of C18-guggultetrol (1) that might otherwise have remain untouched by conventional synthetic approaches.


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Acknowledgment

This work was supported by the Council of Scientific and Industrial Research (CSIR), (No. 02(0001)/11/EMR-II), New Delhi-110001. G.D. thanks CSIR, New Delhi for S.R.F. We wish to thank Dr. R. J. Barnabas (Ahmednagar College, Ahmednagar) for providing helpful discussions and suggestions. We are also grateful to SAIF, Punjab University, Chandigarh and CIF, Savitribai Phule Pune University, Pune, for analytical support.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1588412.
  • Supporting Information

  • References and Notes

  • 2 Kumar V, Dev S. Tetrahedron 1987; 43: 5933
    CrossrefSearch in Google Scholar
  • 7 Tripathi RP, Singh B, Bisht SS, Pandey JJ. Curr. Org. Chem. 2009; 13: 99
    Search in Google Scholar
  • 9 Andrews GC, Crawford TC, Bacon BE. J. Org. Chem. 1981; 46: 2976
    CrossrefSearch in Google Scholar
  • 10 Hering KW, Karaveg K, Moremen KW, Pearson WH. J. Org. Chem. 2005; 70: 9892
    CrossrefPubMedSearch in Google Scholar
  • 11 Archer RM, Royer SF, Mahy W, Winn CL, Danson MJ, Bull SD. Chem. Eur. J. 2013; 19: 2895
    CrossrefPubMedSearch in Google Scholar
  • 12 Soriano DS, Meserole CA, Mulcahy FM. Synth. Commun. 1995; 25: 3263
    CrossrefSearch in Google Scholar
  • 13 (2S,3R,4R,5R)-Nonadecane-1,2,3,4,5-pentol (2) Compound 9 (1.4 g, 3.27 mmol) was added to THF (20 mL), and the mixture was cooled to 0 °C. 5% dil aq HCl was added, and the mixture was stirred for 1 h. When the reaction was complete (TLC), the desired compound precipitated out and was collected by filtration then washed with H2O and 5% EtOAc–hexane to give a white solid; yield: 0.5 g (1.44 mmol, 44%); mp 128–130 °C; [α]D 25 +20.45 (c 0.4, MeOH). IR (neat): 3433, 3254, 2915, 2848, 1468, 1064, 933, 766, 719 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 4.54 (d, J = 4.4 Hz, 1 H), 4.44 (t, J = 5.7 Hz, 1 H), 4.32 (dd, J = 5.9, 2.6 Hz, 2 H), 4.01 (d, J = 6.6 Hz, 1 H), 3.73–3.70 (m, 1 H), 3.58–3.53 (m, 1 H), 3.51–3.35 (m, 3 H), 3.27–3.21 (m, 1 H), 1.65–1.56 (m, 1 H), 1.51–1.41 (m, 1 H), 1.35–1.03 (br s, 24 H), 0.86 (t, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 74.82, 73.76, 70.33, 68.82, 62.51, 33.14, 31.30, 29.40, 29.23, 29.14, 29.12, 29.10, 29.08, 29.02, 28.71, 25.19, 22.08, 13.87. HRMS (ESI): m/z [M + H]+ calcd for C19H41O5: 349.2949; found: 349.2950.
  • 14 (2S,3R)-Heptadecane-1,2,3-triol (3) H5IO6 (1.04 g, 4.58 mmol) was added to a soln of 9 (1.4 g, 3.27 mmol) in anhydrous THF (20 mL) at 0 °C, and the mixture was stirred for 6 h at r.t. The mixture was neutralized with NaHCO3 (1.1 g), stirred for 30 min, and filtered through a Celite pad. The filtrate was evaporated to give the crude aldehyde that was used as prepared, without purification, in the next reaction. NaBH4 (248 mg, 6.54 mmol) was added portionwise to a solution of the aldehyde in MeOH (15 mL), and mixture was stirred for 1 h. When the reaction was complete (TLC), the reaction was quenched with sat. aq NH4Cl (20 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to give a crude alcohol that was used as prepared, without purification, in the next reaction. The crude alcohol was dissolved in THF (7 mL), and the solution was cooled to 0 °C. 5% dil aq HCl was added, and the mixture was stirred for 1 h. When the reaction was complete (TLC), the desired compound precipitated out and was collected by filtration then washed with H2O and 5% EtOAc–hexane to give a white solid; yield: 0.250 g (0.786 mmol, 24%); mp 110–112 °C; [α]D 25 +9.32 (c 1.0, MeOH). IR (neat): 3432, 3190, 3000, 2870, 1498, 1080, 903, 888, 719 cm–1. 1H NMR (500 MHz, MeOD): δ = 3.73 (dd, J = 11.3, 3.9 Hz, 1 H), 3.60 (dd, J = 11.3, 6.5 Hz, 1 H), 3.56–3.50 (m, 1 H), 3.54–3.46 (m, 1 H), 1.71–1.61 (m, 1 H), 1.60–1.50 (m, 1 H), 1.46–1.23 (br s, 24 H), 0.91 (t, J = 6.9 Hz, 3 H). 13C NMR (125 MHz, MeOD): δ = 74.85, 72.54, 63.40, 32.75, 31.57, 29.39, 29.29, 29.27, 29.25, 28.93, 25.35, 22.20, 12.89. HRMS (ESI): m/z [M + Na]+ calcd for C17H36NaO3: 311.2562; found: 311.2561.

  • References and Notes

  • 2 Kumar V, Dev S. Tetrahedron 1987; 43: 5933
    CrossrefSearch in Google Scholar
  • 7 Tripathi RP, Singh B, Bisht SS, Pandey JJ. Curr. Org. Chem. 2009; 13: 99
    Search in Google Scholar
  • 9 Andrews GC, Crawford TC, Bacon BE. J. Org. Chem. 1981; 46: 2976
    CrossrefSearch in Google Scholar
  • 10 Hering KW, Karaveg K, Moremen KW, Pearson WH. J. Org. Chem. 2005; 70: 9892
    CrossrefPubMedSearch in Google Scholar
  • 11 Archer RM, Royer SF, Mahy W, Winn CL, Danson MJ, Bull SD. Chem. Eur. J. 2013; 19: 2895
    CrossrefPubMedSearch in Google Scholar
  • 12 Soriano DS, Meserole CA, Mulcahy FM. Synth. Commun. 1995; 25: 3263
    CrossrefSearch in Google Scholar
  • 13 (2S,3R,4R,5R)-Nonadecane-1,2,3,4,5-pentol (2) Compound 9 (1.4 g, 3.27 mmol) was added to THF (20 mL), and the mixture was cooled to 0 °C. 5% dil aq HCl was added, and the mixture was stirred for 1 h. When the reaction was complete (TLC), the desired compound precipitated out and was collected by filtration then washed with H2O and 5% EtOAc–hexane to give a white solid; yield: 0.5 g (1.44 mmol, 44%); mp 128–130 °C; [α]D 25 +20.45 (c 0.4, MeOH). IR (neat): 3433, 3254, 2915, 2848, 1468, 1064, 933, 766, 719 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 4.54 (d, J = 4.4 Hz, 1 H), 4.44 (t, J = 5.7 Hz, 1 H), 4.32 (dd, J = 5.9, 2.6 Hz, 2 H), 4.01 (d, J = 6.6 Hz, 1 H), 3.73–3.70 (m, 1 H), 3.58–3.53 (m, 1 H), 3.51–3.35 (m, 3 H), 3.27–3.21 (m, 1 H), 1.65–1.56 (m, 1 H), 1.51–1.41 (m, 1 H), 1.35–1.03 (br s, 24 H), 0.86 (t, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 74.82, 73.76, 70.33, 68.82, 62.51, 33.14, 31.30, 29.40, 29.23, 29.14, 29.12, 29.10, 29.08, 29.02, 28.71, 25.19, 22.08, 13.87. HRMS (ESI): m/z [M + H]+ calcd for C19H41O5: 349.2949; found: 349.2950.
  • 14 (2S,3R)-Heptadecane-1,2,3-triol (3) H5IO6 (1.04 g, 4.58 mmol) was added to a soln of 9 (1.4 g, 3.27 mmol) in anhydrous THF (20 mL) at 0 °C, and the mixture was stirred for 6 h at r.t. The mixture was neutralized with NaHCO3 (1.1 g), stirred for 30 min, and filtered through a Celite pad. The filtrate was evaporated to give the crude aldehyde that was used as prepared, without purification, in the next reaction. NaBH4 (248 mg, 6.54 mmol) was added portionwise to a solution of the aldehyde in MeOH (15 mL), and mixture was stirred for 1 h. When the reaction was complete (TLC), the reaction was quenched with sat. aq NH4Cl (20 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to give a crude alcohol that was used as prepared, without purification, in the next reaction. The crude alcohol was dissolved in THF (7 mL), and the solution was cooled to 0 °C. 5% dil aq HCl was added, and the mixture was stirred for 1 h. When the reaction was complete (TLC), the desired compound precipitated out and was collected by filtration then washed with H2O and 5% EtOAc–hexane to give a white solid; yield: 0.250 g (0.786 mmol, 24%); mp 110–112 °C; [α]D 25 +9.32 (c 1.0, MeOH). IR (neat): 3432, 3190, 3000, 2870, 1498, 1080, 903, 888, 719 cm–1. 1H NMR (500 MHz, MeOD): δ = 3.73 (dd, J = 11.3, 3.9 Hz, 1 H), 3.60 (dd, J = 11.3, 6.5 Hz, 1 H), 3.56–3.50 (m, 1 H), 3.54–3.46 (m, 1 H), 1.71–1.61 (m, 1 H), 1.60–1.50 (m, 1 H), 1.46–1.23 (br s, 24 H), 0.91 (t, J = 6.9 Hz, 3 H). 13C NMR (125 MHz, MeOD): δ = 74.85, 72.54, 63.40, 32.75, 31.57, 29.39, 29.29, 29.27, 29.25, 28.93, 25.35, 22.20, 12.89. HRMS (ESI): m/z [M + Na]+ calcd for C17H36NaO3: 311.2562; found: 311.2561.

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Zoom Image
Figure 1
Zoom Image
Scheme 1 Synthesis of analogues 2 and 3 from l-ascorbic acid