Stereoselective total synthesis of (?)-galantinic acid and 1-deoxy-5-hydroxysphingolipids via prins cyclization

Article abstract of DOI:10.1016/j.tetlet.2020.152149

The stereoselective total synthesis of (?)-galantinic acid 1 and 1-deoxy-5-hydroxysphingolipids 4 is described via Prins cyclization protocol followed by reductive ring opening sequence of substituted pyrenol derivative 6. The target molecules were synthesized using a common synthetic intermediate epoxide 5. Besides, we also proposed synthetic pathways to achieve other structural analogues using common intermediates.

Full text of DOI:10.1016/j.tetlet.2020.152149

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis of (À)-galantinic acid
and 1-deoxy-5-hydroxysphingolipids via prins cyclization
Md. Ataur Rahman a,b, , Ashanul Haque , Jhillu Singh Yadav
⇑
c
a,
⇑
a
Centre for Semiochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
Experimental Research Building, New York University, Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates
Department of Chemistry, College of Science, University of Hail, Hail 81451, Saudi Arabia
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of (À)-galantinic acid 1 and 1-deoxy-5-hydroxysphingolipids 4 is
described via Prins cyclization protocol followed by reductive ring opening sequence of substituted pyr-
enol derivative 6. The target molecules were synthesized using a common synthetic intermediate epoxide
Received 18 April 2020
Revised 9 June 2020
Accepted 11 June 2020
Available online xxxx
5. Besides, we also proposed synthetic pathways to achieve other structural analogues using common
intermediates.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Prins cyclization
Reductive ring opening sequence
Sharpless epoxidation
Mitsunobu reaction
Introduction
isomers and related analogues. Following this, Bethuel and
Gademann [5] reported six steps synthetic protocol for the synthe-
sis of (À)-galantinic acid (1) via a sequence of Heathcock–Claisen
condensation, Evans reduction and deprotection with overall yield
of 10%. Besides, other methods were also reported with pros and
cons over preceding protocols. In order to obtain an efficient and
diverse protocol, synthetic chemists are continuously working in
this direction.
Similarly, sphingolipids are diverse class of lipids that serve as
the constituent of cell membranes and play important biochemical
roles. For example, 1-deoxy-5-hydroxysphingolipid 4 and its ana-
logues have demonstrated promising anti-prostate cancer poten-
tial [6].
In order to realize 1,3 diols and chiral substituted tetrahydropy-
ran moiety, Prins cyclization emerged as a powerful tool. Prins
cyclization reaction offers opportunity to synthesize stereoselec-
tive multi-substituted tetrahydropyrans moiety in single operation
using chiral homoallylic alcohol. Several groups, including us
reported total synthesis of various NPs utilizing Prins cyclization
reaction [7]. In our continuous interest towards the synthesis of
biologically relevant NPs, herein we report total synthesis of 1,3-
diol compounds (À)-galantinic acid (À)-1 and 1-deoxy-5-hydrox-
ysphingolipid 4 via Prins cyclization strategy. Besides, the scope
of the protocol for obtaining other 1,3 syn & anti amino diols have
also been discussed.
The 1,3-diol systems are important class of molecular scaffold
and are ubiquitously found in nature [1]. A number of natural
products (NPs) bearing syn-1,3- and anti-1,3-diols have been dis-
covered with potential biological applications [1]. One such exam-
ple is the galantinic acid (a seven carbon-containing non-
proteinogenic natural amino acid 1, Fig. 1) which serve as the back-
bone of antibiotic galantin (2, Fig. 1) [2]. However incorrect, the
chemical structure of this scaffold was suggested as cyclic tetrahy-
dropyranoide 3. After one and half decades, Sakai and Ohfune [3]
reported the first total synthesis and revised acyclic chemical
structure of 1. Following this report and attracted by its intriguing
biological profile, a plethora of research appeared delineating total
synthesis of (+)-galantinic acid (1) and derivatives thereof [4].
Kumar and co-workers [4b] reported
enantioselective synthesis of (À)-galantinic acid (1) employing
the Sharpless asymmetric epoxidation and dihydroxylation
procedures as the source of chirality. As per the authors, the
reported method could be further extended to obtain other
a
twelve steps
⇑
Corresponding author.
E-mail addresses: marahmanpub@gmail.com (M.A. Rahman), a.haque@uoh.edu.
sa (A. Haque).
https://doi.org/10.1016/j.tetlet.2020.152149
0
040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: M. A. Rahman, A. Haque and J. S. Yadav, Stereoselective total synthesis of (À)-galantinic acid and 1-deoxy-5-hydroxysphin-
golipids via prins cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152149

2
M.A. Rahman et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Chemical structures of proposed and revised structure of (À)-galantinic acid
1), galantin (2), and 1-deoxy-5-hydroxysphingolipid (4).
(
Scheme 2. Synthesis of allylic alcohol 15. Reagent & Conditions:- a) (S, S)-Jacobsen
catalyst, AcOH, H O, THF, 0 °C to 25 °C, 36 h, 46%; b) Vinyl Grignard, CuCN, THF,
, THF, À78 °C, 1 h, 75%; d) i) TFA, acrolein
OH, 25 °C, 3 h, 65% over 2 steps; e) TsCl,
, 0 °C to 25 °C, 5 h, 87%; f) Ag O, BnBr, CH Cl , 0 °C to 25 °C, 5 h,
2
À78 °C to À40 °C, 4 h, 92%; c) Na, LiqÁNH
3
Result and discussion
8
, CH
2
Cl
2
, 0 °C to 25 °C, 5 h; ii) K
SnO, CH Cl
2 3 3
CO , CH
Et N, Bu
3
2
2
2
2
2
2
Retrosynthetic analysis
95%; g) NaI, acetone, reflux, 12 h, 89%; h) Zn, ethanol, reflux, 6 h, 86%.
In our retrosynthetic analysis (Scheme 1), we envisaged that the
target molecules (À)-galantinic acid 1 and 1-deoxy-5-hydroxysph-
ingo lipid 4 could be obtained from a common intermediate 5,
which can be achieved by the reductive ring opening followed by
Sharpless epoxidation of chiral 2,4,6-trisubstituted tetrahydropy-
ran 6. The 2,4,6-trisubstituted tetrahydropyran core 6 could be
obtained by Prins cyclization reaction between homoallylic alcohol
tetrahydropyranol 6 in 65% yield over two steps with high
diastereoselectivity (Scheme 2) [7]. Chemoselective tosylation of
primary alcohol of Prins product 6 with 1.1 equivalent of tosyl
chloride in the presence of triethylamine (Et N) with catalytic
3
amount of dibutyltin oxide (Bu SnO) in dichloromethane (CH Cl )
2
2
2
resulted the corresponding mono-tosylated compound 12 in 87%
yield [11,7d]. Secondary alcohol 12 was protected as benzyl ether
under mild basic condition using benzyl bromide in the presence
of silver oxide (Ag O) in CH Cl affording the benzyl ether 13 in
7
and acrolein 8 (Scheme 1).
Our strategy for the synthesis of homoallylic alcohol 7 is
depicted in (Scheme 2). The homoallylic alcohol 7 was synthesized
from (R)-glycidyl benzyl ether 10 which was achieved from the
hydrokinetic resolution of (±) glycidyl benzyl ether 9 using (S,S)-
Jacobsen catalyst [8]. The regioselective opening of (R)-glycidyl
benzyl ether 10 with vinyl magnesium bromide (molar solution)
afforded compound 11 [9], which upon debenzylation under Birch
reduction condition (Na/LiqÁNH3) yielded homoallylic alcohol 7 in
2
2
2
95% yield [12]. Treatment of tosylated compound 13 with NaI in
refluxing acetone afforded iodopyranyl 14 in 89% yield. The
reductive opening of iodopyranyl adduct under Boord reduction
7
7
5% yield [10]. Treatment of acrolein 8 with a homoallylic alcohol
under Prins cyclization condition yielded 2,4,6-cis-trisubstituted
Scheme 3. Synthesis of (À)-galantinic acid 1. Reagent & Conditions:- a) (À)-DET,
i
Ti(O Pr)
8
4
, CH
2
Cl
2
, 4 Ǻ MS, À30 °C, 36 h, 90%; b) Ag
2
O, BnBr, CH
2
Cl
2
, 0 °C to 25 °C, 5 h,
N,
, CCl
9%; c) benzyl alcohol, BF
3
.OEt
, 0 °C to 25 °C, 6 h; ii) NaN
CN:H O (1:1:1.5), 25 °C, 2 h, 70%; f) Pd/C, H
2
, CH
, DMF, 80 °C, 7 h, 88%; e) RuCl
, CH OH, 25 °C, 89%.
2
Cl
2
, 0 °C to 25 °C, 6 h, 93%; d) i) MsCl, Et
3
Scheme 1. Retrosynthetic analysis of (À)-galantinic acid 1 and 1-deoxy-5-hydrox-
ysphingolipid 4.
CH
CH
2
Cl
2
3
3
Á6H O, NaIO
2
4
4
:
3
2
2
3
Please cite this article as: M. A. Rahman, A. Haque and J. S. Yadav, Stereoselective total synthesis of (À)-galantinic acid and 1-deoxy-5-hydroxysphin-
golipids via prins cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152149

M.A. Rahman et al. / Tetrahedron Letters xxx (xxxx) xxx
3
condition using activated zinc in refluxing ethanol produced 1,3-
of compound 4 were identical to the data reported in the literature
anti diol 15 in 86% yield [7d].
[19].
The resulting allyl alcohol 15 was subjected to Sharpless asym-
i
metric epoxidation with (À)-DET, Ti(O Pr)
4 2 2
and TBHP in dry CH Cl
Scope of the protocol
to obtain epoxide 16 in 90% yield (Scheme 3). It is worthwhile to
mention here that under the given reaction condition, we did not
observed any diastereomeric product [13]. The secondary alcohol
As demonstrated, (À)-galantinic acid 1 and 1-deoxy-5-hydrox-
ysphingolipid 4 can be obtained in respectable yield using the
reported protocol. In addition, this protocol also offers an opportu-
nity to obtain other leads/principles with intriguing bioactivity [6].
Example includes, but not limited to, enigmol 24, SSR-enigmol 25,
1
6 was protected as benzyl ether using benzyl bromide and Ag
in CH Cl furnished compound 5 in 89% yield [12]. Compound 5
was then used as common precursor to obtain (À)-galantinic acid
and 1-deoxy-5-hydroxysphingolipids 4.
2
O
2
2
1
1
SRR-enigmol 26 N-methyl enigmol 27 and fumonisin B 28 (Fig. 2)
could be achieved via the minor modification of the intermediate
compounds.
Herein, we briefly describe the steps to obtain new pharma-
cophores. It should be noted that the schemes are tentative and
may require modification in more or more steps. We propose that
Synthesis of (À)-galantinic acid (1)
To synthesize (À)-galantinic acid 1, regioselective epoxide
opening of compound 5 was performed using benzyl alcohol with
1
,3-syn diol 30 can be realized by the inversion of secondary
hydroxyl functionality of 2,4,6-trisubstituted tetrahydropyran core
via Mitsunobu protocol [20] followed by reductive ring opening
Scheme 5a). The diol 30 could be further structurally modified
to obtain enigmol 24, an orally active anti-prostate cancer agent
catalytic amount of BF
3 2 2 2
.OEt in CH Cl leading to compound 17 in
9
3% yield (Scheme 3) [14]. Conversion of secondary hydroxyl group
6
(
of compound 17 to its corresponding azide under Mitsunobu reac-
tion condition furnished compound 18 in 88% yield [15]. The ter-
minal olefinic compound 18 was converted to its corresponding
[
6] and its derivative 28.
carboxylic acid 19 in 70% yield using sodium periodate (NaIO
4
)
Similarly, one can obtain leads 36 and 37 following the similar
with RuCl O catalyst [16]. Hydrogenation of compound 19
3
Á6H
2
approaches, which can be then utilized to realize compounds such
as SSR-enigmol 24 and SRR-enigmol 25 (Scheme 5b). The hydroki-
netic resolution of (±) glycidyl benzyl ether 9 using (S, S)-Jacobsen
catalyst would produce (S)-(À)-glycidyl benzyl ether 31, a precur-
sor for the isomeric amino diols. Regioselective opening of 31 ? 32
with 10% palladium on carbon (Pd/C) in MeOH yielded (À)-galan-
tinic acid [17a,4b,17b] 1 in 89% yield. The analytical data of (À)-
galantinic acid 1 were found to be similar to the data reported in
the literature [17a,b].
(
using vinyl magnesium bromide) followed by debenzylation
under Birch reduction condition would give homoallyl alcohol
3. Finally, sequential steps involving tetrahydropyran core forma-
Synthesis of 1-deoxy-5-hydroxysphingolipid (4)
3
tion (via Prins cyclization) [7], stereo-inversion (via Mitsunobu
protocol) and reductive ring opening can be used to obtain 36
and 37.
Following the successful synthesis of (À)-galantinic acid 1, our
next target was to realize 1-deoxy-5-hydroxysphingolipid 4 using
the common intermediate 5. To this end, the reductive ring open-
2 2
ing of epoxide 5 was performed using DIBAL-H in CH Cl leading to
compound 20 in 85% yield (Scheme 4). Compound 20 was sub-
jected to cross metathesis reaction with 1-dodecene using second
2 2
generation Grubbs catalyst in CH Cl under reflux condition to
afford compound 21 in 72% yield [18]. Conversion of secondary
hydroxyl functionality of compound 21 to its corresponding azide
under Mitsunobu reaction condition furnished 22 in 85% yield
(Scheme 4). Finally, compound 22 was reduced using 10% palla-
dium on carbon (Pd/C) and H in MeOH to afford 1-deoxy-5-
2
1
13
hydroxysphingolipid 4 in 91% yield. The spectral data ( H & C)
Scheme 4. Synthesis of 1-deoxy-5-hydroxysphingolipid (4). Reagent & Condi-
tions:- a) DIBAL-H, CH
CH Cl , 60 °C, 5 h, 72%; c) i) MsCl, Et
0 °C, 7 h, 85% over two steps; d) Pd/C, H
2 2
Cl , 0 °C , 6 h, 85%; b) 1-dodecene, Grubb’s 2nd (5 mol%),
2
2
3
N, CH
2
Cl
2
, 0 °C to 25 °C, 6 h; ii) NaN
OH, 18 h, 25 °C, 91%.
3
, DMF,
Fig. 2. Representative amino diols and 1-deoxy-5-hydreoxy Sphingolipids ana-
logues that can be achieved via reported protocol.
8
2
, CH
3
Please cite this article as: M. A. Rahman, A. Haque and J. S. Yadav, Stereoselective total synthesis of (À)-galantinic acid and 1-deoxy-5-hydroxysphin-
golipids via prins cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152149

4
M.A. Rahman et al. / Tetrahedron Letters xxx (xxxx) xxx
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152149.
References
[
[
1] P. Gupta, N. Mahajan, S.C. Taneja, Catal. Sci. 3 (2013) 2462.
2] J.I. Shoji, R. Sakazaki, Y. Wakisaka, K. Koizumi, M. Mayama, S. Matsuura, J.
Antibiot. 28 (1975) 122.
Scheme 5a. Synthesis of enigmol and its derivative.
[
3] (a) N. Sakai, Y. Ohfune, Tetrahedron Lett. 31 (1990) 4151;
(
b) N. Sakai, Y. Ohfune, J. Am. Chem. Soc. 114 (1992) 998.
[
4] (a) A.H. Merrill Jr, K. Sandhoff, New Compr. Biochem, Elsevier, 2002, p. 373;
(
(
(
(
(
(
b) S.K. Pandey, S.V. Kandula, P. Kumar, Tetrahedron Lett. 45 (2004) 5877;
c) W. Chaładaj, J. Jurczak, Euro. J. Org. Chem. 2011 (2011) 1223;
d) A. Dubey, S.V. Kauloorkar, P. Kumar, Tetrahedron 66 (2010) 3159;
e) B. Dhotare, A. Chattopadhyay, Tetrahedron: Asymmetry 2009 (2007) 20;
f) X. Moreau, J.-M. Campagne, Tetrahedron Lett. 42 (2001) 4467;
g) S.-I. Kiyooka, K. Goh, Y. Nakamura, H. Takesue, M.A. Hena, Tetrahedron
Lett. 41 (2000) 6599.
[
[
5] Y. Bethuel, K. Gademann, Synlett 2006 (2006) 1580.
6] E.C. Garnier-Amblard, S.G. Mays, R.F. Arrendale, M.T. Baillie, A.S. Bushnev, D.G.
Culver, T.J. Evers, J.J. Holt, R.B. Howard, L.S. Liebeskind, ACS Med. Chem. Lett. 2
(
2011) 438.
7] (a) G. Sabitha, M.N. Prasad, K. Shankaraiah, N.M. Reddy, J.S. Yadav, Synthesis
010 (2010) 3891;
b) J.S. Yadav, D. Chandrakanth, Y.G. Rao, K. Ravindar, B.V.S. Reddy, Helv. Chim.
Acta 93 (2010) 1432;
c) J.S. Yadav, N. Thrimurtulu, M.A. Rahman, J.S. Reddy, A. Prasad, B.S. Reddy,
Synthesis 2010 (2010) 3657;
d) J.S. Yadav, N. Mallikarjuna Reddy, N. Venkateswar Rao, M.A. Rahman, A.R.
Prasad, Helv. Chim. Acta 95 (2012) 227;
[
2
(
(
(
(
(
e) J.S. Yadav, N.M. Reddy, M.A. Rahman, A.R. Prasad, Euro. J. Org. Chem. 2014
2014) 5574.
[
8] (a) S.E. Schaus, B.D. Brandes, J.F. Larrow, M. Tokunaga, K.B. Hansen, A.E. Gould,
M.E. Furrow, E.N. Jacobsen, J. Am. Chem. Soc. 124 (2002) 1307;
(
b) B.S. Dyer, J.D. Jones, G.D. Ainge, M. Denis, D.S. Larsen, G.F. Painter, J. Org.
Chem. 72 (2007) 3282;
c) O.C. Finch, D.P. Furkert, M.A. Brimble, Tetrahedron 70 (2014) 590.
9] (a) P.P. Reddy, K.-F. Yen, B.-J. Uang, J. Org. Chem. 67 (2002) 1034;
(
[
Scheme 5b. Synthesis of enigmol and its derivative.
(
(
b) D.S. Reddy, D.K. Mohapatra, Euro. J. Org. Chem. 2013 (2013) 1051;
c) J. Yadav, M.A. Rahman, N.M. Reddy, A. Prasad, Tetrahedron Lett. 56 (2015)
365.
[
10] (a) D.K. Mohapatra, P.R. Naidu, D.S. Reddy, S. Nayak, S. Mohapatra, Euro. J. Org.
Chem. 2010 (2010) 6263;
Conclusion
(
b) J. Yadav, N. Thrimurtulu, K.U. Gayathri, B.S. Reddy, A. Prasad, Tetrahedron
In summary, a new method of synthesizing (À)-galantinic acid 1
and 1-deoxy-5-hydroxysphingolipids 4 using a common intermedi-
ate 5 is reported. This approach successfully utilizes Prins cycliza-
tion, reductive opening, Sharpless asymmetric epoxidation, Grubb’s
cross metathesis and palladium catalyzed hydrogenation reaction
to achieve both the natural products, (À)-galantinic acid 1 with
Lett. 49 (2008) 6617.
11] (a) A. Shanzer, Tetrahedron Lett. 21 (1980) 221;
[
[
(
b) S. David, S. Hanessian, Tetrahedron 41 (1985) 643.
12] C. Taillier, V. Bellosta, J. Cossy, Organic Lett. 6 (2004) 2149.
[13] R.S. Coleman, J.-S. Kong, J. Am. Chem. Soc. 120 (1998) 3538.
[
14] (a) H.-S. Byun, R. Bittman, Tetrahedron Lett. 30 (1989) 2751;
b) W.F. Berkowitz, D. Pan, R. Bittman, Tetrahedron Lett. 34 (1993) 4297.
(
[
15] (a) D.L. Hughes, R.A. Reamer, J. Org. Chem. 61 (1996) 2967;
(b) O. Mitsunobu, Synthesis 1981 (1981) 1;
1
6.79% overall yield from homoallylic alcohol 7 with 11 linear syn-
(
(
c) B. Srinivas, D.S. Reddy, N.A. Mallampudi, D.K. Mohapatra, Organic Lett. 20
2018) 6910.
thetic steps and 1-deoxy-5-hydroxysphingolipid 4 with 15.59% over-
all yield from homoallylic alcohol 7 with 11 linear synthetic steps.
Besides, we also proposed pathways (Scheme 5a & 5b) to achieve
other structural analogues using common intermediates.
[
16] (a) Y. Rew, D. Sun, ACS Publications (2014);
(b) D. Amans, V. Bellosta, J. Cossy, Chem. Euro. J. 15 (2009) 3457.
17] (a) S. Raghavan, S.R. Reddy, J. Org. Chem. 68 (2003) 5754;
[
(
(
b) K. Nagaiah, D. Sreenu, K.V. Purnima, R.S. Rao, J.S. Yadav, Synthesis 2009
2009) 1386.
Declaration of Competing Interest
[18] (a) A.K. Chatterjee, D.P. Sanders, R.H. Grubbs, Organic Lett. 2002 (1939) 4;
(
(
(
(
b) A.K. Chatterjee, T.-L. Choi, D.P. Sanders, R.H. Grubbs, J. Am. Chem. Soc. 125
2003) 11360;
c) D.S. Reddy, B. Padhi, D.K. Mohapatra, J. Org. Chem. 80 (2015) 1365;
d) S. Kumar Dey, M. Ataur Rahman, A. Alkhazim Alghamdi, B.V.S. Reddy, J.S.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Yadav, Euro. J. Org. Chem. 2016 (2016) 1684.
[
[
19] (a) J.M. Wiseman, F.E. McDonald, D.C. Liotta, Organic Lett. 7 (2005) 3155;
(
b) P.P. Saikia, A. Goswami, G. Baishya, N.C. Barua, Tetrahedron Lett. 50 (2009)
328.
20] J.S. Yadav, M.A. Rahman, N.M. Reddy, A.R. Prasad, A.A.K. Al Ghamdi, Synlett 25
2014) 661.
Acknowledgements
1
(
M.A. Rahman and JSY thanks CSIR, New Delhi, India for the
award of a fellowship.
Please cite this article as: M. A. Rahman, A. Haque and J. S. Yadav, Stereoselective total synthesis of (À)-galantinic acid and 1-deoxy-5-hydroxysphin-
golipids via prins cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152149