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

Article abstract of DOI:10.1055/s-0036-1588412

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.

Full text of DOI:10.1055/s-0036-1588412

SYNLETT
0
9
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5
2
1
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1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–C
letter
A
G. R. Dhage, S. R. Thopate
Letter
Synlett
Undemanding Synthesis of Novel C19 and C17 Analogues of C18-
Guggultetrol
Ganesh R. Dhage
OH OH
HO
Shankar R. Thopate*
OH OH
HO
Department of Chemistry, Prof. John Barnabas Post
Graduate School for Biological Studies, Ahmednagar
College, Ahmednagar Station Road, Ahmednagar-
414001, Maharashtra, India
O
(2S,3R,4R,5R)-nonadecane-1,2,3,4,5-pentol
O
HO
OH
HO
L-Ascorbic acid
OH
srthopate@gmail.com
HO
Dedicated to the memory of Dr. B. P. Hiwale (Founder
of Ahmednagar College).
OH
(2S,3R)-heptadecane-1,2,3-triol
Received: 16.11.2016
Accepted after revision: 17.01.2017
Published online: 06.02.2017
phora 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
DOI: 10.1055/s-0036-1588412; Art ID: st-2016-b0770-l
Abstract A simple and undemanding synthesis of (2S,3R,4R,5R)-nona-
decane-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.
With the expectation that guggultetrols might be plau-
sible bioisosteres3 of biologically significant phytosphingo-
lipids,4 several researchers have synthesized the fatty alco-
hols.5 Indeed, several meritorious methods have been re-
ported in the literature, and have contributed to the
ongoing scientific development of syntheses of C18-guggul-
tetrol.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 at-
tempts have made to synthesize their analogues.
Key words ascorbic acid, chiral pool, guggultetrol, asymmetric syn-
thesis, nonadecanepentol, heptadecanetriol
In ayurveda, the time-honored Indian system of phyto-
medicine, guggul has been used since prehistory to treat
rheumatoid arthritis, inflammation, obesity, and lipid dis-
orders.1 Guggul is produced from the gum resin of Commi-
a) Structure of D-xylo-C18-guggultetrol and its analogues
OH
OH OH
HO
HO
OH OH
OH OH
D-xylo-C18-guggultetrol (1)
(2S,3R,4R,5R)-nonadecane-1,2,3,4,5-pentol (2)
OH
HO
OH
(2S,3R)-heptadecane-1,2,3-triol (3)
b) Retrosynthetic analysis
OH
HO
C13H27
O
OH
HO
HO
O
H
O
O
O
O
OH
OH
O
O
O
HO
HO
3
OH OH
11
O
O
HO
HO
OH
OH
O
O
HO
C13H27
7
5
4
OH OH
8
2
Figure 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

B
G. R. Dhage, S. R. Thopate
Letter
Synlett
Since its discovery, L-ascorbic acid has become a cyno-
sure in the eyes of many in the scientific community be-
cause of its vital role in many biological functions, as well
as its role in synthetic chemistry as a chiral pool.7 The cata-
lytic 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 gen-
eral reaction steps, starting from the cheaply available ma-
terial L-ascorbic acid. In our retrosynthetic analysis (Figure
1, b), we surmised that analogues 2 and 3 might be ob-
tained 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-cata-
lyzed hydrogenation should be the method of choice for in-
corporating 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 pres-
sure.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 How-
ever, we found these reactions difficult to reproduce. Nev-
ertheless, we found that L-ascorbic acid was efficiently re-
duced 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 litera-
ture, but in our hands we found it to be effective and repro-
ducible.
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 an-
hydrous CH2Cl2 at –78 °C afforded 2,3:5,6-O-diisopro-
pylidene-L-gulofuranose (7) in 79% yield. Witting olefina-
tion 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 previ-
ously prepared by heating 1-bromotridecane with triphen-
ylphosphine 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 ace-
tonide 9 gave the novel hydroxymethyl C18-guggultetrol ho-
mologue 2.13 Therefore, the use of L-ascorbic acid as a chiral
pool afforded the nonobvious product, (2S,3R,4R,5R)-nona-
decane-1,2,3,4,5-pentol (2), which might not otherwise
have been prepared by conventional approaches, due to dif-
ficulties 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
n-BuLi
Br–Ph3P+(CH2)12Me
O
O
HO
HO
H
H
H
H
O
O
acetone
H2 (50 psi)
DIBAL-H
O
O
O
O
O
OH
O
O
HO
HO
Rh/alumina
r.t., 1.5 h
H2O
CH2Cl2, –78 °C
1 h
AcCl, r.t.
24 h
–78 °C to r.t.
O
O
O
O
HO
HO
OH
OH
4
5
6
7
O
O
OH OH
H
H
OH
OH
H2 (50 psi)
THF
O
O
HO
C13H27
Pd/C, MeOH
1.5 h, r.t.
dil. HCl, 0 °C to r.t.
1–2 h
11
11
OH OH
O
O
O
O
2
8
9
E/Z mixture
1. H5IO6, THF
r.t., 6 h
OH
dil. HCl
HO
THF, 0 °C to r.t.
1–2 h
2. NaBH4, MeOH
r.t., 1 h
OH
3
Scheme 1 Synthesis of analogues 2 and 3 from L-ascorbic acid
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

C
G. R. Dhage, S. R. Thopate
Letter
Synlett
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 chi-
ral-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-pen-
tol (2), which are analogues of C18-guggultetrol (1) that
might otherwise have remain untouched by conventional
synthetic approaches.
Ziólkowski, M. Tetrahedron: Asymmetry 1996, 7, 2711.
(f) Herdeis, C.; Telser, J. Eur. J. Org. Chem. 1999, 1407.
(g) Gerfaud, T.; Chiang, Y.-L.; Kreituss, I.; Russak, J. A.; Bode, J. W.
Org. Process Res. Dev. 2012, 16, 687.
(9) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J. Org. Chem. 1981,
46, 2976.
(10) Hering, K. W.; Karaveg, K.; Moremen, K. W.; Pearson, W. H.
J. Org. Chem. 2005, 70, 9892.
(11) Archer, R. M.; Royer, S. F.; Mahy, W.; Winn, C. L.; Danson, M. J.;
Bull, S. D. Chem. Eur. J. 2013, 19, 2895.
(12) Soriano, D. S.; Meserole, C. A.; Mulcahy, F. M. Synth. Commun.
1995, 25, 3263.
(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 com-
plete (TLC), the desired compound precipitated out and was col-
lected 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]D25 +20.45 (c 0.4, MeOH). IR (neat): 3433, 3254,
2915, 2848, 1468, 1064, 933, 766, 719 cm–1. 1H NMR (400 MHz,
DMSO-d6): 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-d6): 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.
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 ana-
lytical support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588412.
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References and Notes
(14) (2S,3R)-Heptadecane-1,2,3-triol (3)
(1) (a) Anurekha, J.; Gupta, V. B. Indian J. Tradit. Knowl. 2006, 5, 478.
(b) Ulbricht, C.; Basch, E.; Szapary, P.; Hammerness, P.;
Axentsev, S.; Boon, H.; Kroll, D.; Garraway, L.; Vora, M.; Woods,
J. Complement. Ther. Med. 2005, 13, 279. (c) Sridhar, P. R.;
Suresh, M.; Kumar, P. V.; Seshadri, K.; Rao, C. V. Carbohydr. Res.
2012, 360, 40.
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 solu-
tion 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 concen-
trated to give a crude alcohol that was used as prepared,
without purification, in the next reaction.
(2) Kumar, V.; Dev, S. Tetrahedron 1987, 43, 5933.
(3) (a) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72, 6312.
(b) Venkatesan, K.; Srinivasan, K. V. Tetrahedron: Asymmetry
2008, 19, 209.
(4) (a) Ogretmen, B. FEBS Lett. 2006, 580, 5467. (b) Nixon, G. F. Br. J.
Pharmacol. 2009, 158, 982. (c) Ekiz, H. A.; Baran, Y. Int. J. Cancer
2010, 127, 1497. (d) Duan, R.-D. J. Dig. Dis. 2011, 12, 60.
(5) (a) Prasad, K. R.; Chandrakumar, A. Tetrahedron 2007, 63, 1798.
(b) George, S.; Suryavanshi, G.; Sudalai, A. Tetrahedron: Asym-
metry 2010, 21, 558. (c) Borkar, S. R.; Manjunath, B. N.;
Balasubramaniam, S.; Aidhen, I. S. Carbohydr. Res. 2012, 358, 23.
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(6) (a) Kjer, A.; Kjer, D.; Skrydstrlip, T. Tetrahedron 1986, 42, 1439.
(b) George, S.; Suryavanshi, G.; Sudalai, A. Tetrahedron: Asym-
metry 2010, 21, 561.
(7) Tripathi, R. P.; Singh, B.; Bisht, S. S.; Pandey, J. J. Curr. Org. Chem.
2009, 13, 99.
(8) (a) Hubschwerlen, C. Synthesis 1986, 962. (b) Vekemans, J. A. J.
M.; de Bruyn, R. G. M.; Caris, R. C. H. M.; Kokx, A. J. P. M.;
Konings, J. J. H. G.; Godefroi, E. F. J. Org. Chem. 1987, 52, 1093.
(c) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
45, 319. (d) Fleet, G. W. J.; Ramsden, N. G.; Nash, R. J.; Fellows, L.
E.; Jacob, G. S.; Molyneux, R. J.; di Bello, I. C.; Winchester, B. Car-
bohydr. Res. 1990, 205, 269. (e) Czarnocki, Z.; Mieczkowski, J. B.;
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 filtra-
tion 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;
25
[α]D +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.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C