Stereoselective total synthesis of Oxylipin from open chain gluco-configured building block

Article abstract of DOI:10.1016/j.carres.2017.03.002

Total synthesis of naturally occurring Oxylipin has been achieved from open chain gluco-configured building block which is readily assembled from inexpensive and commercially available D-(+)-gluconolactone. Grignard reaction and Wittig olefination reactions are key steps for the requisite C–C bond formation.

Full text of DOI:10.1016/j.carres.2017.03.002

Accepted Manuscript
Stereoselective total synthesis of Oxylipin from open chain gluco-configured building
block
Santosh Ramdas Borkar, Indrapal Singh Aidhen
PII:
S0008-6215(17)30092-7
10.1016/j.carres.2017.03.002
CAR 7331
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 4 February 2017
Revised Date: 2 March 2017
Accepted Date: 2 March 2017
Please cite this article as: S.R. Borkar, I.S. Aidhen, Stereoselective total synthesis of Oxylipin
from open chain gluco-configured building block, Carbohydrate Research (2017), doi: 10.1016/
j.carres.2017.03.002.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Stereoselective Total Synthesis of Oxylipin from Open Chain gluco-
Configured Building Block
Santosh Ramdas Borkar, Indrapal Singh Aidhen*
*Department of chemistry, Indian Institute of Technology Madras, Chennai-600036, India
Abstract
Total synthesis of naturally occurring Oxylipin has been achieved from open chain gluco-
configured building block which is readily assembled from inexpensive and commercially
available D-(+)-gluconolactone. Grignard reaction and Wittig olefination reactions are key
steps for the requisite C-C bond formation.
Keywards:
Carbohydrates, Wittig olefination, Grignard reaction, Barton-McCombie deoxygenation.
1. Introduction
Oxylipins are the naturally occurring lipids derived from fatty acids. They are functioning as
important signalling molecules in plants and fungi.1 In fungi and mammals oxylipins are
involved in synthesis of secondary metabolites. Oxylipins are also medicinally important,
because of their anti-fungal, anti-bacterial and anti-diabetic activities.2,3 Structurally oxylipins
are also known as hydroxy fatty acids (HFAs), due presence of extra hydroxy groups and
have different physical properties such as higher melting point, viscosity and reactivity as
compared to non-hydroxylated fatty acids.4 In this context, HFAs have been used as
precursors for manufacture of polymers, as additives in the manufacture of lubricants,
emulsifiers and stabilisers.5
O
OH
R2
O
OH OH
OH
OH
OH
OH
6
7
3
R1
OH
O
OH
6
OH OH
2 R1 = OH, R2 = H
1
4
3
R1 = H, R2 = OH
Figure 1. Analogues of Oxylipins
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Pizza et al. isolated four novel oxylipins (1-4) from the extract of corms of the plant D.
Loretense (Figure 1).6a They have studied immunostimulatory effect of these compounds on
Human Peripheral Blood Mononuclear Cells (PBMCs). As a result of this study they found
that compound 2 exhibits immunostimulatory effect at 10 µM, whereas compound 4 was
found to be least reactive towards cell proliferation. To date there is one report available for
the synthesis of Oxylipin 4.6b Due to biological importance of these molecules and our own
interests in exploring surfactant properties of poly-hydroxylated long chain fatty acids, we
undertook synthesis of Oxylipin 4, envisaging use of open chain D-gluco configured building
block 5.7 The multi-gram quantities of building block 5 are readily accessible in three simple
steps from inexpensive and commercially available D-(+)-gluconolactone as the starting
material. Grignard reaction onto the morpholine amide was visualised for the incorporation of
n-octyl chain, while hexenyl chain was envisaged through Wittig reaction on the latent
aldehyde at C-5 carbon of the building block 5 (Figure 2).
Figure 2. Retrosynthetic analysis of Oxylipin 4
2. Results and discussion
The addition of heptylmagnesium bromide onto morpholine amide 5 gave the ketone 6 in 85-
90 %. The absence of any over addition product during addition of Grignard reagents onto
morpholine amides has been rationalized in the literature through the participation of ring
oxygen.8 The ring oxygen of 7 has been proposed for chelation in the tetrahedral intermediate
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8. This chelation presumably prevents it collapse to the ketone 9 (until aq. work-up) and
thereby over-addition product 10 (Scheme 1). To understand whether this factor was really
responsible for the successful formation of the ketone 6, in our case with amide 5, piperidine
based amide 11, devoid of ring oxygen was synthesized from D-(+)-gluconolactone using the
same three steps. Both amides (5 and 11) were then treated with phenylmagnesium bromide
as an illustrative Grignard reagent which gave phenyl ketone 11 as exclusive product. No
over addition product 13 was isolated in either case. The successful formation of the ketone
12 from the substrates 5 and 11 clearly reveals that some factor other than chelation from the
morpholine ring oxygen is operating for stabilization of the tetrahedral intermediate.
Scheme: 1 Synthesis of Ketone 6
In case of amide 5 (Figure 3), presumable participation from morpholine ring oxygen (A) or
α-OBn group (B) or is responsible for preventing collapse of the tetrahedral intermediate in
situ, leading to possible formation of ketone, before work-up, whereas in case of amide 11 the
chelation of from the α-OBn group in the tetrahedral intermediate (C) seems to be the only
factor. The observation revealed that there is no need of morpholine amide and any other
tertiary amide would be sufficient for the obtainment of ketone 6.
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Figure: 3 Possible intermediates in Grignard reagent addition on morpholine/piperidine
amide
The ketone 6 was subjected to reduction by NaBH4 in methanol, which afforded mixture of
alcohols 14 in 80-90% yields. Deoxygenation of distereomeric alcohols 14 was effected by
two step protocol, Bartone-McCombie deoxygenation9, 10 to give protected polyol 15 in 55-
60% yields over two steps. Selective hydrolysis of terminal isopropylidene protection in
compound 15 was achieved by Zn(NO3)2·6H2O in acetonitrile 11, 12 at 50 °C to give diol 16 in
60-66% yield (Scheme 2).
Scheme: 2 Synthesis of diol 16
Since for the incorporation second alkyl chain containing terminal acid functionality, we had
visualised use of Wittig reaction, the oxidative cleavage of diol 16 was carried out by NaIO4
in CH3CN/H2O mixture to release the latent aldehyde functionality envisaged at C-5 carbon
in the building block 5. The phosphonium salt 19 was derived from readily available 6-
bromohexanoic acid 18. The acid functionality of 18 was protected with methyl ester and
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bromo compound was treated with triphenylphosphine to give Wittig salt 19 in good yields.
Wittig reaction of aldehyde 17 and Wittig salt 19 afforded cis-olefin 20 in 42-45 % yield in
two steps (Scheme 3). The cleavage of benzyl ether protection in compound 20, could be
achieved with DDQ in dry dichloromethane as solvent. The debenzylated compound 21 was
obtained in 70-80% yield over different reaction trials. The ester hydrolysis was carried out in
basic condition by using LiOH/THF/H2O to give acid compound 22 with 77% yield. Finally
isopropylidene protection of diol was removed in acidic conditions by using TFA/DCM/H2O
affording the target Oxylipin 4.
Scheme: 3 Synthesis of Oxylipin 4
3. Conclusion:
Successful synthesis of naturally occurring Oxylipin 4 from open chain gluco-configured
building block 5 has been realized. The morpholine based amide 5 derived from D-(+)-
gluconolactone in three steps is the requisite building block. Wittig reaction and Grignard
reaction were the key steps for C-C bond formation. Simple synthetic transformations and
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wide possibility in changing the nature of alkyl residues open up great avenues for other
analogues of naturally occurring Oxylipin 4 is an additional merit of the developed synthetic
route.
4. Experimental section
4.1 General
For the reaction purposes and column chromatography, distilled and dry solvents were used.
For column chromatography, 100-200 mesh size silica gels were used. All the reactions were
followed up by a TLC analysis. This was done using precoated ‘MERCK F254’ plates. The
spot detection on TLC was done by exposure of plate under UV light or dipping in to the
solution of Hanessian’s stain followed by charring on hot plate. High resolution NMR
experiments were recorded on BRUKER AV 400 FT NMR or AV 500 FT NMR instruments.
Infra-Red spectra were recorded using JASCO FT/IR spectrophotometer. High resolution
mass spectra (HRMS) were recorded on a MICRO Q-TOF mass spectrometer using ESI
technique at 10eV.
4.2 Synthesis of 1-Heptyl-2-O-benzyl-3,4:5,6-di-O-isopropylidene-D-glucose (6)
Magnesium turnings (1.00 equiv) were activated by addition of piece is I2 and heating under
vacuum for 5 min in double neck round bottom flask. Then dry THF (2 mL/ mmol) was
added to the reaction flask under inert atmosphere. After that aryl / alkyl bromide (1.00
equiv) was added and reaction mixture was allowed to stir at room temperature. In case of
alkyl bromide reaction mixture was heated at 60 °C for 15-20 min. After complete
consumption of magnesium, the Grignard reagent was used for the reaction.
To a solution of morpholine amide 9 (1.00 mmol, 1.00 equiv) in 2 mL of dry THF, a solution
of alkylmagnesium bromide (3.00 mmol, 3.00 equiv) in dry THF (4 mL), was added under
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inert atmosphere at 10-15 °C and reaction mixture was stirred for 3 h at 15 °C to room
temperature. Thin layer chromatography revealed the complete consumption of starting
material. Subsequent hydrolysis was achieved by the cautious addition of saturated NH4Cl
solution. Aqueous layer was extracted with ethyl acetate (60-80mL). Organic extract was
washed with water (20 mL × 3), dried over Na2SO4 and evaporated to get crude product. This
was purified by column chromatography to get the desired ketone 6.
Nature: Viscous oil; Yield: 80%; TLC (Rf): 0.40 (Ethyl acetate / Hexanes, 1: 9); [α]23
=
D
+47.3 (c = 1.0, CHCl3); IR (Thin film) νmax: 3020 (C-H), 1600 (C=O), 1424 (=C-H), 1215 (C-
O) cm−1; 1H-NMR [CDCl3, 500 MHz]: δ 7.29-7.36 (m, 5H, Aromatic); 4.66 (d, 1H, J = 11.5
Hz, PhCHaHbO); 4.49 (d, 1H, J = 12.0 Hz, PhCHaHbO); 4.20 (dd, 1H, J1 = 7.0 Hz, J2 = 2.5
Hz); 4.00-4.05 (m, 2H); 4.10-4.13 (m, 1H); 3.94 (d, 1H, J = 2.5 Hz); 3.86 (m, 1H); 2.67 (ddd,
1H, J = 6.3, 8.5, 18.5 Hz, COCHaHbCH2); 2.54 (ddd, 1H, J = 6.5, 8.5, 18.0 Hz,
COCHaHbCH2); 1.54-1.57 (m, 2H, CH2); 1.34 (s, 3H, CCH3CH3); 1.33 (s, 3H, CCH3CH3);
1.32 (s, 6H, CCH3CH3); 1.26-1.29 (m, 8H, CH2); 0.87 (t, 3H, J = 7.0 Hz, CH2CH3); 13C-
NMR [CDCl3, 125 MHz]: δ 212.1 (CO); 137.4 (C); 128.6 (CH); 128.5 (CH); 128.1 (CH);
127.9 (CH); 110.2 (C), 109.8 (C), 84.1 (CH); 81.2 (CH); 77.1 (CH); 77.0 (CH), 73.6 (CH2);
67.9 (CH2), 39.3 (CH2); 31.8 (CH2), 29.23 (CH2), 29.21 (CH2); 27.3 (CH3), 26.76 (CH3),
26.71 (CH3), 25.2 (CH3), 22.9 (CH2), 22.7 (CH2), 14.2 (CH3); HRMS (ESI): Calcd. for
C26H40O6Na, 471.2723, [M+Na]+ , found 471.2718.
4.3 Synthesis and 1-Piperidino-2-O-benzyl-3,4:5,6-di-O-isopropylidene-D-gluconamide
(11)
For the synthesis of piperidine amide 11 similar procedure has been used as described in Ref.
7 by using D-(+)-gluconolactone as starting material.
1-Piperidino-3,4:5,6-di-O-isopropylidene-D-gluconamide (11a)
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Nature: Viscous oil; Yield: 64%; TLC (Rf): 0.68 (Ethyl acetate / Hexanes, 3: 7); [α]32
=
D
−9.74 (c = 1.0, CHCl3); IR (Thin film) νmax: 3020 (C-H); 1639 (C=O); 1215 (C-O) cm−1; 1H-
NMR [CDCl3, 400 MHz]: δ 4.55 (d, 1H, J = 4.8 Hz, CHCHC=O); 4.14-4.17 (m, 1H); 4.02-
4.06 (m, 2H); 3.93-3.97 (m, 2H); 3.88-3.92 (m, 1H); 3.72-3.78 (m, 1H, NCHaHb); 3.44-3.50
(m, 2H, NCH2); 3.34-3.39 (m, 1H, NCHaHb); 1.62-1.69 (m, 2H, CH2); 1.54-1.60 (m, 4H, 2 ×
13
CH2); 1.41 (s, 3H, CH3); 1.40 (s, 3H, CH3); 1.35 (s, 3H, CH3); 1.32 (s, 3H, CH3); C-NMR
[CDCl3, 100 MHz]: δ 169.9 (CO); 110.8 (C); 109.7 (C); 80.8 (CH); 77.8 (CH); 77.3 (CH),
68.3 (CH2); 66.4 (CH); 45.9 (CH2); 43.9 (CH2); 27.3 (CH3); 26.7 (CH3); 26.5 (CH3); 26.3
(CH2); 25.5 (CH2); 25.3 (CH3); 24.5 (CH2); HRMS (ESI): Calcd. for C17H29NO6Na, [M+Na]+
366.1893, found 366.1906.
1-Piperidino-2-O-benzyl-3,4:5,6-di-O-isopropylidene-D-gluconamide (11)
Nature: Yellowish solid (Recrystallized in EtOAc) ; Yield: 85%; m.p. 62-64 °C; TLC (Rf):
0.52 (Ethyl acetate / Hexanes, 3:7); [α]32D = +17.9 (c = 1.0, CHCl3); IR (Thin film) νmax: 3020
1
(C-H); 1648 (C=O); 1215 (C-O) cm−1; H-NMR [CDCl3, 400 MHz]: δ 7.27-7.33 (m, 5H,
aromatic); 4.71 (d, 1H, J = 11.6 Hz, OCHaHbPh); 4.44 (d, 1H, J = 11.6 Hz, OCHaHbPh);4.39
(d, 1H, J = 3.2 Hz, CHCOPh); 4.22 (dd, 1H, J = 3.2, 6.8 Hz, CHCHOBn); 4.05-4.11 (m, 3H,
8.0 Hz); 3.82-3.90 (m, 2H); 3.70-3.73 (m, 1H); 3.58-3.63 (m, 1H); 3.36-3.39 (m, 1H); 1.49-
1.61 (m, 6H), 1.35-1.37 (2 × s, 6H, 2 × CH3); 1.30 (2 × s, 6H, 2 × CH3); 13C-NMR [CDCl3,
100 MHz]: δ 168.0 (CO); 137.4 (C); 128.5 (CH); 127.97 (CH); 127.93 (CH); 110.2 (C);
109.7 (C); 80.68 (CH); 80.62 (CH); 77.4 (CH); 77.3 (CH), 72.6 (CH2); 67.5 (CH2); 46.1
(CH2); 44.0 (CH2); 27.4 (CH3); 26.8 (CH3); 26.65 (CH3); 26.62 (CH2); 25.9 (CH2); 25.3
(CH3); 24.5 (CH2); HRMS (ESI): Calcd. for C24H35NO6K [M+K]+ 472.2101, found
472.2111.
4.4 1-Phenyl-2-O-benzyl-3,4:5,6-di-O-isopropylidene-D-glucose (12)
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Nature: Viscous oil; Yield: 70 %; TLC (Rf): 0.40 (Ethyl acetate / Hexanes, 1: 9); [α]23
=
D
+53.9 (c = 1.0, CHCl3); IR (Thin film) νmax: 3020 (C-H), 1667 (C=O), 1424 (=C-H), 1215 (C-
1
O) cm−1; H-NMR [CDCl3, 400 MHz]: δ 8.11-8.09 (m, 2H); 7.56 (t, 1H, J = 5.6 Hz); 7.45-
7.42 (m, 2H); 7.31-7.24 (m, 5H); 4.74 (d, 1H, J = 2.8 Hz, CHCOPh); 4.66 (d, 1H, J = 11.2
Hz, OCHaHbPh); 4.37 (d, 1H, J = 10.4 Hz, OCHaHbPh); 4.36 (dd, 1H, J = 2.8, 7.6 Hz,
CHCHOBn); 4.14 (t, 1H, J = 8.0 Hz, CHCHCH); 4.13(dd, 1H, J = 6.0, 8.4 Hz, CHaHbCH);
4.08-4.03(ddd, 1H, J = 5.6, 8.0, 11.2 Hz, CH2CH); 3.88(dd, 1H, J = 5.2, 8.4 Hz, CHaHbCH);
1.44 (s, 3H, CH3); 1.33 (s, 3H, CH3); 1.308 (s, 3H, CH3); 1.30 (s, 3H, CH3); 13C-NMR
[CDCl3, 100 MHz]: δ 199.5 (CO); 137.3 (C); 135.8 (C); 133.3 (CH); 129.4 (CH); 128.5
(CH); 128.4 (CH); 128.2 (CH); 128.0 (CH); 110.6 (C); 109.7 (C); 82.4 (CH); 81.1 (CH);
77.43 (CH); 77.3 (CH); 72.8 (CH2); 67.9 (CH2); 27.3 (CH3); 26.7 (CH3); 26.6 (CH3); 25.3
(CH3); HRMS (ESI): Calcd. for C25H30O6Na, 449.1940, [M+Na]+ , found 449.1940.
4.5 Synthesis of 1-Deoxy-1-Heptyl-(2-O-benzyl-3,4:5,6-di-O-isopropylidene)-D-glucitol
(15)
The ketone 6 (0.730 g, 1.627 mmol) was dissolved in methanol (4.8 mL). Then this solution
was cooled to 0 °C temperature and NaBH4 (0.093 g, 2.441 mmol) was added to it. Reaction
mixture was then allowed to stir at 0 °C to room temperature for 30 min. After consumption
of starting material, solvent was evaporated and saturated solution of NH4Cl was added
carefully to the reaction mixture till effervescences stopped. The organic compound was then
extracted in 90 mL DCM (30 mL × 3) and organic part washed with 50 mL brine (25 mL ×
2), dried over Na2SO4 and evaporated to get crude compound which was purified on column
to give mixture of alcohol 14 (0.744 g, 1.651 mmol). The Alcohol 20 was dissolved in dry
toluene (5.1 mL) and to this solution, 1,1’-thiocarbonyldiimidazole (0.588 g, 3.302 mmol)
was added in inert atmosphere. Then reaction mixture was allowed to stir at 110 °C for 8-10
h. After that solvent was evaporated and compound was filtered through small column to give
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thionocarbonate derivative as gummy compound. The thionocarbonate was dissolved in dry
toluene (24 mL). To this solution tributyltin hydride (0.55 mL, 1.883 mmol) was added in
inert atmosphere. Then AIBN (0.041 g, 0.251 mmol) was added to the reaction mixture. The
reaction mixture was then stirred at 80 °C for 7-8 h. After that solvent was evaporated to give
crude compound which was purified by column chromatography to give alkane 15.
Nature: Viscous oil, Yield: 60 %; TLC (Rf): 0.50 (Ethyl acetate/Hexanes, 1:9) [α]23D = −1.15
(c = 1.0, CHCl3); IR (Thin film) νmax: 3019 (C-H), 1423 (=C-H), 1215 (C-O) cm−1; 1H-NMR
[CDCl3, 400 MHz]: δ 7.26-7.36 (m, 5H, Aromatic); 4.63 (ABq, 2H, J = 11.6 Hz, Benzylic);
4.12-4.04 (m, 2H); 4.02-3.99 (m, 2H); 3.89 (dd, 1H, J = 4.8, 7.2 Hz); 3.51 (dt, 1H, J = 2.0,
8.0 Hz); 1.71-1.63 (m, 2H); 1.42 (s, 3H, CH3); 1.38 (s, 6H, 2 × CH3), 1.34 (s, 3H, CH3); 1.27
(br, 12H); 0.88 (t, 3H, J = 6.8 Hz, CH2CH3); 13C-NMR [CDCl3, 100 MHz]: δ 138.9 (C);
128.4 (CH);, 127.8 (CH); 127.6 (CH); 109.7 (C); 109.5 (C); 82.1 (CH); 78.4 (CH); 77.5
(CH); 77.40 (CH); 72.7 (CH2); 67.6 (CH2), 32.0 (CH2); 31.3 (CH2); 29.9 (CH2); 29.6 (CH2);
29.4 (CH2), 27.4 (CH3), 27.2 (CH3); 26.6 (CH3), 26.0 (CH2), 25.4 (CH3), 22.8 (CH2), 14.2
(CH3); HRMS (ESI): Calcd. for C26H42O5Na, 457.2930, [M+Na]+ , found 457.2951.
4.6 Synthesis of 1-Deoxy-1-Heptyl-(2-O-benzyl-3,4-O-isopropylidene)-D-glucitol (16)
To a solution of compound 15 (0.607 g, 1.396 mmol) in 7 mL CH3CN, Zn(NO3)2.6H2O was
added and reaction mixture was heated at 50 °C for 6-7 h. After complete consumption of
starting material, solvent was evaporated to give gummy residue. The residue was then which
dissolved in ethyl acetate (100 mL) and washed with brine (40 mL × 2). The organic solvent
was dried on Na2SO4 and evaporated to give crude compound which was purified by column
chromatography to offer pure compound 16.
Nature: White amorphous solid, Yield: 66% ; m.p. 55-58 °C; TLC (Rf): 0.56 (Ethyl
acetate/Hexanes, 1:4); [α]23D = −7.90 (c = 1.0, CHCl3); IR (Thin film) νmax: 3019 (C-H), 1423
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(=C-H), 1215 (C-O) cm−1; 1H-NMR [CDCl3, 400 MHz]: δ 7.38-7.30 (m, 5H, Aromatic); 4.67
(bs, 2H, Benzylic); 3.99 (dd, 1H, J = 3.2, 8.0 Hz); 3.90 (t, 1H, J = 8.0 Hz); 3.77-3.64 (m, 4H),
3.62-3.59 (m, 1H); 2.20 (br, 1H); 1.72-1.65 (m, 1H); 1.61-1.53 (m, 2H); 1.51-1.46 (m, 1H);
1.39 (s, 3H, CH3); 1.36 (s, 3H, CH3), 1.26 (br, 10H); 0.88 (t, 3H, J = 8.0 Hz); 13C-NMR
[CDCl3, 100 MHz]: δ 137.3 (C), 128.7 (CH), 128.45 (CH), 128.41 (CH), 109.0 (C), 80.6
(CH), 78.3 (CH), 76.8 (CH), 73.7 (CH2), 72.6 (CH), 64.2 (CH2), 32.0 (CH2), 30.2 (CH2), 29.8
(CH2), 29.6 (CH2), 29.3 (CH2), 27.09 (CH3), 27.05 (CH3), 26.6 (CH2), 22.8 (CH2), 14.2
(CH3); HRMS (ESI): Calcd. for C23H38O5Na, 417.2617, [M+Na]+ , found 417.2621.
4.7 Synthesis of (6-Methoxy-6-oxohexyl)-Triphenylphosphonium bromide (19)
6-bromohexanoic acid 18 (4.886 g, 25.100 mmol) was dissolved in methanol (75 mL). To
this solution, Conc. H2SO4 (0.3 mL) was added and reaction mixture refluxed for 8 h. Then
solvent evaporated and residue was dissolved in ethyl acetate (200 mL). The organic part was
then washed with saturated solution of NaHCO3 (50 mL × 3), dried and evaporated to give
pure ester compound (4.626 g, 22.200 mmol). For making Wittig salt, bromo-ester compound
was dissolved in dry CH3CN (70 mL) followed by addition triphenylphosphine (7.000 g,
26.600 mmol). The reaction mixture was then refluxed for 36 h. After that solvent evaporated
to give gummy residue which was washed with hexanes (20 mL × 3) to give compound 19.
Nature: Viscous oil, Yield: 90%; IR (Thin film) νmax: 3019 (C-H), 1730 (C=O), 1215 (C-O)
cm−1; 1H-NMR [CDCl3, 400 MHz]: δ 7.21-7.83 (m, 15H, Aromatic); 3.78 (br, 2H, CH2); 3.61
(s, 3H, OCH3); 2.78 (br, 2H, CH2); 1.69 (br, 4H, 2 × CH2); 1.25 (s, 2H, CH2); 13C-NMR
[CDCl3, 100 MHz]: δ 173.9 (C=O); 135.1 (CH); 135.0 (CH); 133.7 (CH); 133.6 (CH); 130.6
(CH); 130.4 (CH); 118.6 (C); 117.8 (C); 51.5 (OCH3); 33.4 (CH2); 29.7, 29.6 (CH2); 24.3
(CH2); 22.9 (CH2); 22.4 (CH2); HRMS (ESI): Calcd. for C25H29O2P, 392.1905, [M−Br]+,
found 392.1888 .
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4.8 Synthesis of L-xylo-10-O-Benzyl-8,9-O-isopropylidene-Methyl-(8,9,10-trihydroxy)-6-
cis-Octadecenoate (20)
Diol 16 (0.100 g, 0.253 mmol) was dissolved in 1 mL of CH3CN/H2O (1:1) and this was
cooled up to 0 °C followed by the addition of NaIO4 (0.108 g, 0.507 mmol). The reaction
mixture was allowed to stir at 0 °C to room temperature up to 1 h. Then reaction mixture was
diluted with 10% ethyl acetate/hexanes and filter through small pad of Na2SO4. After that
solvents evaporated to give crude aldehyde compound 17 (0.100 g) which was subjected to
next step without further purification.
The Wittig salt 19 (0.194 g, 0.414 mmol) was dissolved in dry THF (8 mL) and cooled up to
0 °C. To this solution n-BuLi (2 M solution in cyclohexane, 0.3 mL, 0.551 mmol) was added
and reaction mixture stirred for 20 min. After that solution of aldehyde 17 (0.100 g) in dry
THF (2 mL) was added to the reaction mixture at 0 °C and reaction mixture was stirred up to
6-7 h at 0 °C to room temperature. Then reaction was quenched by addition saturated solution
of NH4Cl (2 mL) and organic compound was extracted in 30 mL ethyl acetate (10 mL × 3).
The organic part was then washed with water (10 mL × 2), dried and evaporated to give crude
compound which was purified by column chromatography using ethyl acetate / hexanes as
eluent to give alkene 20 (0.055 g).
Nature: Viscous oil, Yield: 45% over two steps, TLC (Rf): 0.54 (Ethyl acetate/Hexanes 1:9);
[α]23 = −11.2 (c = 1.0, CHCl3); IR (Thin film) νmax: 3020 (C-H); 1735 (C=O); 1215 (C-O)
D
1
cm−1; H-NMR [CDCl3, 400 MHz]: δ 7.36-7.28 (m, 5H, Aromatic); 5.64 (dt, 1H, J = 7.6,
10.8 Hz, CH2CH=CH); 5.40 (dd, 1H, J = 9.2, 10.8 Hz, CH2CH=CH); 4.66-4.62 (m, 3H,
Benzylic CH2 , CH=CHCH); 3.81 (dd, 1H, J = 4.8, 8.0 Hz, CHCHCH); 3.65 (s, 3H, COCH3);
3.42 (ABq, 1H, J = 5.6 Hz, CHCHCH2); 2.26 (t, 2H, J = 7.6 Hz, CH2); 2.15 (quintd, 1H, J =
1.2, 8.0 Hz, CH=CHCHaHb); 2.04 (quintd, 1H, J = 1.6, 7.2 Hz, CH=CHCHaHb); 1.61-1.57
12

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(m, 2H, CH2); 1.53-1.49 (m, 2H, CH2); 1.44-1.35 (m, 8H, 2 × CH3, CH2); 1.25 (br, 12H,
6×CH2); 0.88 (t, 3H, J = 7.2 Hz, CH2CH3); 13C-NMR [CDCl3, 100 MHz]: δ 174.0 (CO);
138.9 (C); 135.6 (CH); 128.6 (CH); 127.8 (CH); 127.5 (CH); 127.3 (CH); 108.8 (C); 83.1
(CH); 78.4 (C); 73.0 (CH); 72.4 (CH2); 51.6 (CH3); 31.8 (CH2); 31.8 (CH2); 30.8 (CH2); 29.7
(CH2); 29.5 (CH2); 29.2 (CH2); 28.9 (CH2); 27.4 (CH3); 27.0 (CH3); 25.6 (CH2); 24.5 (CH2);
22.6 (CH2); 14.1 (CH3); HRMS (ESI): Calcd. for C29H46O5Na, 497.3243, [M+Na]+ , found
497.3231.
4.9 Synthesis of L-xylo-(8,9-O-Isopropylidene)-Methyl-(8,9,10-trihydroxy)-6-cis-
Octadecenoate (21)
To a solution of alkene 20 (0.070 g, 0.148 mmol) in dry DCM (4 mL), 2,3-Dichloro-5,6-
dicyano-1,4-benzoquinone [DDQ] (0.502 g, 2.212 mmol) was added at room temperature.
The reaction mixture was stirred for 6 h. After that reaction mixture diluted with DCM (30
mL). The organic part was washed with 20 mL of saturated solution of NaHCO3 (10 mL × 2),
dried and evaporated to give crude compound which was purified by column chromatography
to give alcohol 21 (0.057 g).
Nature: Viscous oil, Yield: 82%, TLC (Rf): 0.54 (Ethyl acetate/Hexanes 1:4); [α]23 = −18.7
D
(c = 1.0, CHCl3); IR (Thin film) νmax: 3020 (C-H); 1720 (C=O); 1424 (=C-H) cm−1; 1H-NMR
[CDCl3, 400MHz]: δ 5.67 (dt, 1H, J = 7.6, 10.8 Hz, CH2CH=CH); 5.38 (dd, 1H, J = 9.2, 10.8
Hz, CH2CH=CH); 4.70 (t, 1H, J = 8.8 Hz, CH=CHCH); 3.65 (s, 3H, COCH3); 3.55 (dd, 1H, J
= 3.2, 8.4 Hz, CHCHCH); 3.44-3.42 (m, 1H, CHCHCH2); 2.31 (t, 2H, J = 7.6 Hz, CH2);
2.24-2.08 (m, 2H, CH=CHCH2); 1.68-1.61 (m, 2H, CH2); 1.55-1.36 (m, 10H, 2 × CH3, 2 ×
CH2); 1.31-1.20 (m, 12H, 6 × CH2); 0.87 (t, 3H, J = 7.2 Hz, CH2CH3); 13C-NMR [CDCl3,
100 MHz]: δ 174.1 (CO); 136.1 (CH); 126.8 (CH); 109.0 (C); 83.6 (CH); 77.4, 77.1, 76.8,
73.2 (CH); 69.6 (CH); 51.6 (CH3); 35.1 (CH2); 33.9 (CH2); 32.0 (CH2); 29.7 (CH2); 29.6
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(CH2); 29.3 (CH2); 29.1 (CH2); 27.5 (CH3); 27.4 (CH3); 27.1 (CH2); 25.8 (CH2); 24.5 (CH2);
22.8 (CH2); 14.2 (CH3); HRMS (ESI): Calcd. for C22H40O5Na, 407.2773, [M+Na]+, found
407.2781.
4.10 Synthesis of L-xylo-(8,9,10-Trihydroxy)-6-cis-Octadecenoic acid (4)
Ester compound 21 (0.032 g, 0.0832 mmol) was dissolved in THF/H2O (0.9 mL, 2:1)
followed by addition of LiOH (0.006 g, 0.0249 mmol) at room temperature. The reaction
mixture was then stirred for 6 h. Then 2 mL ether/H2O (1:1) was added to the reaction
mixture and stirred for 5 min. The ether layer was then discarded and basic aqueous layer was
neutralized by 2N HCl. To this aqueous part 1 mL ether was added and stirred for 5 min. The
ether part was then evaporated to give pure acid compound 22 (0.024 g, 77 %).
The acid compound 22 was dissolved in 0.8 mL TFA/DCM/H2O (2:2:1) and reaction mixture
stirred for 15 min at room temperature. After that reaction mixture made basic by addition of
saturated solution of NaHCO3. Then 1 mL ether was added to the reaction mixture and stirred
for 5 min. After that ether layer was discarded. Basic aqueous layer was neutralized by 2N
HCl and 1 mL ether was added. Finally, ether part was evaporated to give pure compound 4
(0.020 g, 95 %).
Nature: Viscous oil, Yield: 73% (two steps); TLC (Rf): 0.12 (Ethyl acetate/Hexanes 4:1);
[α]22D = −17.8 (c = 0.2, MeOH); IR (Thin film) νmax: 3019 (C-H); 1657 (C=O); 1424 (=C-H)
1
cm−1; H-NMR [CDCl3, 400 MHz]: δ 5.60 (dt, 1H, J = 7.6, 10.8 Hz, CH2CH=CH); 5.44 (t,
1H, J = 9.2 Hz, CH2CH=CH); 4.50 (t, 1H, J = 7.6 Hz, CH=CHCH); 3.58 (t, 1H, J = 6.4 Hz,
CHCHCH2); 3.28 (d, 1H, J = 5.6 Hz, CHCHCH); 2.33 (t, 2H, J = 7.2 Hz, CH2), 2.23-2.08
(m, 2H, CH2); 1.66-1.61 (m, 2H, CH2); 1.59-1.50 (m, 2H, CH2); 1.45-1.40 (m, 4H, 2 × CH2);
1.35-1.15 (br,12H, 6 × CH2); 0.87 (t, 3H, J = 6.4 Hz); 13C-NMR [CDCl3, 100 MHz]: δ 177.8
(CO); 134.5 (CH); 128.8 (CH); 75.8 (CH); 71.6 (CH); 69.1 (CH); 34.4 (CH2); 33.6 (CH2);
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32.0 (CH2); 29.74 (CH2); 29.71 (CH2); 29.4 (CH2); 28.7 (CH2); 27.3 (CH2); 25.8 (CH2); 24.2
(CH2); 22.8 (CH2); 14.2 (CH3); HRMS (ESI): Calcd. for C18H34O5Na, 353.2304, [M+Na]+,
found 353.2299.
Acknowledgements
The authors thank DST New Delhi for funding toward the 400 MHz and 500 MHz NMR
spectrometer to the Department of Chemistry, IIT Madras under the IRPHA scheme. S.R.B.
is thankful to IIT-Madras for HTRA fellowship.
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Highlights
•
•
•
Total synthesis of naturally occurring Oxylipin has been achieved from open chain gluco-
configured building block.
Grignard reaction and Wittig olefination reactions are key steps for the requisite C-C
bond formation.
Simple synthetic transformations and wide possibility for other analogues of naturally
occurring Oxylipin is an additional merit of the developed synthetic route.