Facile and efficient addition of terminal alkynes to benzotriazole esters: Synthesis of d-erythro-sphingosine using ynones as the key intermediate

Article abstract of DOI:10.1016/j.tetlet.2013.10.082

From the perspective of synthesis, ynones are compounds of considerable interest because of their occurrence in a wide variety of biologically active molecules and as key synthetic intermediates. In this context, a facile and highly efficient synthesis of ynones was developed based on the high reactivity of benzotriazole esters formed in situ. Lithium acetylides can alkylate various carboxylic acids in yields ranging from 60% to 92%. To determine whether our methodology is useful for synthesising complex and biologically relevant molecules, we synthesise d-erythro-sphingosine in four steps and with 33% overall yield from l-serine.

Full text of DOI:10.1016/j.tetlet.2013.10.082

Tetrahedron Letters 54 (2013) 7111–7114
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile and efficient addition of terminal alkynes to benzotriazole
esters: synthesis of D-erythro-sphingosine using ynones as the key
intermediate
José Antonio Morales-Serna a, Alejandro Sauza a, Gabriela Padrón de Jesús a, Rubén Gaviño a,
Gustavo García de la Mora b, Jorge Cárdenas a,
⇑
a Instituto de Química, Universidad Nacional Autónoma de México Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México D.F., Mexico
b Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Circuito Interior, Ciudad Universitaria, Coyoacán 04510, México D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
From the perspective of synthesis, ynones are compounds of considerable interest because of their occur-
rence in a wide variety of biologically active molecules and as key synthetic intermediates. In this con-
text, a facile and highly efficient synthesis of ynones was developed based on the high reactivity of
benzotriazole esters formed in situ. Lithium acetylides can alkylate various carboxylic acids in yields
ranging from 60% to 92%. To determine whether our methodology is useful for synthesising complex
Received 24 September 2013
Revised 15 October 2013
Accepted 17 October 2013
Available online 30 October 2013
and biologically relevant molecules, we synthesise
overall yield from -serine.
D-erythro-sphingosine in four steps and with 33%
Keywords:
Ynones
Benzotriazol esters
Alkynes
L
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Lithium
Sphingosine
The synthesis of
a
,b-acetylenic carbonyl compounds, or ynones,
to acyl chlorides during the synthesis of ynones. Carbodiimides
dehydrate the carboxylic acid, facilitating the nucleophilic addition
of an alkoxy group and generating the corresponding ester14 or
lactone.15 HOBT circumvents problematic side reactions, such as
N-acylurea formation or racemisation, during peptide bond forma-
tion. Numerous HOBT derivatives16 have been synthesised for use
in either solution or solid phase. However, in every case, species I
and II were proposed as reaction intermediates (Equation in
Table 1).17 In our hands, benzotriazole esters I and II have become
important intermediates during the synthesis of macrolactones,18
ter-butyl esters19 and alcohols from carboxylic acids.20 Therefore,
in this study, we report a facile and highly efficient synthesis of
ynones based on the highly reactive benzotriazole esters I and II
formed in situ at room temperature. Lithium acetylides can alkyl-
ate various carboxylic acids in yields ranging from 40% to 92%. Fi-
nally, we used the reaction as a key step during the total synthesis
has attracted considerable interest because they appear as key
intermediates during the synthesis of natural compounds.1 The
attractive utility of ynones has led many organic chemists to focus
on developing methods for their synthesis; the goals of exploring
new synthetic strategies include the following: (a) palladium-cat-
alysed coupling reactions between acyl chlorides and terminal
alkynes,2 (b) the acylation of alkynyl organometallic reagents
based on silver,3 copper,4 zinc,5 indium,6 silicon,7 aluminium8
and tin9 using acyl chlorides, (c) the palladium-catalysed reaction
between acyl chlorides and lithium alkynyltriisopropoxyborates10
and (d) the addition of alkynyllithium reagent tomorpholine11
and Weinreb amides.12
Despite having made considerable progress, the synthesis of
ynones in high yield with good functional group tolerance remains
a notable challenge. An alternative approach involves transforming
the carboxylic acid into a stable, yet highly reactive, intermediate
that can be formed under mild reaction conditions. Consequently,
we thought to use 1-ethyl-3-(3-dimethylaminopropyl) carbodiim-
ide (EDC) and 1-hydroxybenzotriazole (HOBT), which is a classic
coupling system in peptide chemistry,13 to furnish the benzotria-
zole esters I and II (Equation in Table 1) as an attractive alternative
of
D-erythro-sphingosine.
The formation of benzotriazol esters I and II is a rapid process
that may occur at room temperature in different solvents, such
as CHCl3, CH2Cl2 or THF, without the need for rigorously dry condi-
tions. Therefore, we initially studied the formation of benzotriazole
esters of phenyl acetic acid 1a using an EDC/HOBT system in
CH2Cl2. Once those benzotriazole esters are formed, as established
by thin layer chromatography (TLC), the solvent is eliminated; to
remove the residual water, the intermediates can be co-distilled
⇑
Corresponding author. Tel.: +52 55 5622 4413; fax: +52 55 5616 2217.
E-mail address: rjcp@unam.mx (J. Cárdenas).
0040-4039/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.082

7112
J. A. Morales-Serna et al. / Tetrahedron Letters 54 (2013) 7111–7114
Table 1
Optimisation of reaction conditions for the synthesis of ynone 3a
O
N
System
N
OH
R
Pent
Activation
+
N
N
O
N
O
O
10 min.
2a-2b
N
O
O
1a
I
Ynone 3a
II
Entry
R
Activation system
Reaction conditions
Yieldc
%
1
2
3
4
5
2a Lia
2b H
2b H
2b H
2b H
EDC/HOBTb
EDC/HOBTb
EDC/HOBTb
EDC/HOBTb
EDC/HOBTb
THF, À70 °C, 15 min. and then rt 15 min.
P2-Et, THF, À70 °C 15 min. and then rt 15 min.
P2-Et, THF, rt 18 h.
Hydrotalcite, THF, reflux, 18 h.
[PdCl2(PPh3)2, CuI, TEA, THF or 1,4-dioxane, rt to reflux, 1 h to 18 h.
92
—
—
—
—
a
Reagents and conditions to prepare lithium acetylides: alkyne (3 mmol), n-BuLi (3.1 mmol), THF, À70 °C, 15 min.
b
Reagents and conditions: Carboxylic acid (1 mmol), EDC (1.1 mmol), HOBT (1.1 mmol), CH2Cl2, rt, 10 min. The organic layer was concentrated in vacuo and subsequently
co-distilled with dry toluene.
Yield of isolated product after chromatographic purification.
c
Table 2
The reaction scope for the synthesis of ynones from benzotriazole esters and lithium acetylides
Entry
1
Carboxylic acids
Terminal Alkynes
Ynone
Yielda
75
%
O
Li
Li
Pent
Pent
O
2a
OH
1b
3b
Pent
O
O
2a
OH
2
3
60
70
Pent
1c
3c
Cl
Cl
O
Li
Pent
O
2a
OH
Pent
1d
3d
O
O
O
O
Li
Li
Li
Pent
Pent
O
O
2a
2a
4
5
60
65
OH
3e
1e
1f
Pent
Pent
OH
OH
3f
O
O
6
7
78
75
77
65
68
4a
Li
4a
Li
4a
Li
4a
Li
4a
1b
3g
O
O
OH
1c
3h
Cl
Cl
O
O
OH
8
1d
3i
O
O
O
O
O
O
OH
9
1e
1f
3j
OH
10
3k
a
Yield of isolated product after chromatographic purification.
with toluene or dried under vacuum.21 Subsequently, lithium
out under Sonogashira conditions (Pd0/CuI),2 ynone 3a was not
observed, even after long reaction times; in this case a complex
reaction mixture was obtained (Table 1, entry 5).
pentylacetylide 2a was added in THF, furnishing the desired
22
ynone 3a in 92% yield (Table 1, entries 1 and 2). Unfortunately,
attempts to generate the acetylide using other bases, such as
hydrotalcite or phosphazene bases (EtP2), do not generate 3a
(Table 1, entries 2–4). Similarly, when the reaction was carried
With the optimised conditions in hand, the scope of these reac-
tions was investigated using different carboxylic acids. Aromatic
and aliphatic carboxylic acids smoothly underwent transformation

J. A. Morales-Serna et al. / Tetrahedron Letters 54 (2013) 7111–7114
7113
Benzotriazole esters
N
I
N
O
N
O
Li
C13H27
N
Boc
O
Boc
O
6
O
Boc
N
EDC/HOBT
N
C13H27
Ynone 7
O
O
OH
O
CH2Cl2
THF, 0 °C, 15 min.,
then r.t., 15 min.
60%
O
r.t., 15 min
N
5
N
Boc
N
N
O
II
NaBH4, CeCl3
MeOH, -20 °C,
3h.
65 %
dr = 80:20
Boc
a) Li, EtNH2
-78 °C, 1h.
NH2
OH
N
C13H27
9
HO
C13H27
O
b) 1N HCl, THF,
-70 °C, 18 h.
OH
85% two steps
8
D-erythro-sphingosine
Scheme 1. Synthesis of
D-erythro-sphingosine.
to generate the desired products (3b–3k), in moderate to excellent
yields (60–78%, Table 2). Moreover, the reactions worked well with
aromatic carboxylic acids (1b–1d) to give ynones 3b–3d and 3g–3i
(Table 2, entries 1–3 and 6–8). Aliphatic carboxylic acids (1e and
1f) were also compatible, furnishing moderate yields (Table 2, en-
tries 4,5,9,10). Notably, the activation time varied between the aro-
matic and aliphatic carboxylic acids. The latter required short
activation times (10–30 min), while aromatic carboxylic acids
needed one hour or more. However, the activation reaction may
be easily monitored by TLC to ensure the activation is complete.
Finally, to determine whether our methodology is useful for the
synthesis of complex and biologically relevant molecules, we
Therefore, the synthesis began with the addition of lithium acety-
lide 6 to benzotriazole esters I and II, generating ynone 7 in 60%
yield. Subsequently, the ketone was reduced with NaBH4 (65%
yield), while Benkeser’s reduction conditions were used to reduce
the alkyne and eliminate the protective groups (85% yield, two
steps) to obtain
thesis from acid
D
-erythro-sphingosine 9 (Scheme 1). The total syn-
L
-serine-derived 5 was performed with 33% overall
yield in only four steps: (i) ynone preparation, (ii) carbonyl reduc-
tion, (iii) alkyne reduction and (iv) deprotection. Synthetic -ery-
D
thro-sphingosine 9 exhibited a 72–74 °C melting point (lit.28 mp
72–75 °C), [
a]
D = À1.6 (c 0.9 in CHCl3) (lit.28
[
a]
D = À1.6) (c1 in
CHCl3)), and the 300 MHz 1H and 75 MHz 13C NMR spectroscopic
data matched those reported for the synthetic product.28
examined its applicability during the synthesis of
gosine 9 from acid -serine derived 5 (Scheme 1).
D-erythro-sphin-
L
In summary, we developed new protocol to synthesise ynones
in yields ranging from 60% to 92% from benzotriazol esters and
lithium acetylides. This approach facilitated efficient synthesis of
Sphingolipids were named by Johann Ludwig Wilhelm
Thudichum23 in 1884 after the Greek Sphinx due to their enigmatic
function, emerging in recent decades as a family of key signalling
molecules, including sphingosine 9.24 Sphingolipids, together with
glycerophospholipids and cholesterol, are essential building blocks
that play essential roles as structural cell membrane components
and participate in higher order physiological processes, including
inflammation and vasculogenesis.25 Recent studies implicate
sphingolipids in numerous common human diseases, including
microbial infections, diabetes, various cancers, Alzheimer’s disease,
and many others.26 The basic sphingolipid structure consists of a
sphingosine linked to a fatty acid through an amide bond with
the 2-amino group and a polar head group at C-1 through an ester
bond. There are four sphingosine stereoisomers with a wide range
D-erythro-sphingosine in four steps from L-serine with a 33% overall
yield. We believe that our protocol demonstrates an attractive use
of benzotriazole esters as acyl synthons, transcending their simple
use as peptide-coupling intermediates
Acknowledgment
We wish to thank Carmen Márquez and Eréndira García Ríos for
their technical assistance.
Supplementary data
of biological activities.27 The
D-erythro isomer is the most common
Supplementary data associated with this article can be found, in
the online version, athttp://dx.doi.org/10.1016/j.tetlet.2013.10.
082.
metabolite and has been meticulously studied. Because sphingo-
sine and its derivatives are available in limited amounts from nat-
ural sources, there is a continuing interest in developing efficient
methods for their synthesis. Numerous methods for synthesising
sphingosine are reported in the literature,27 and they can be classi-
fied into four categories: (i) those using carbohydrates as the
source of chirality, (ii) those that use the Sharpless asymmetric
epoxidation to generate the asymmetric centres, (iii) those using
an aldol reaction with a chiral auxiliary, and (iv) those using serine
as the source of chirality. However, most methods require multi-
step reactions and result in low total yields. Consequently, our
choice of starting material was dictated by the type of reaction nec-
essary for developing a cost-effective and efficient synthesis.
References and notes
1. Unsworth, W. P.; Cuthbertson, J. D.; Taylor, R. J. K. Org. Lett. 2013, 15, 3306–
3309.
2. For recent publications see: (a) Chinchilla, R.; Carmen Nájera, C. Chem. Rev.
2007, 107, 874–922; (b) Bakherad, M. Appl. Organomet. Chem. 2013, 27, 125–
140; (c) Navidi, M.; Movassagh, B. Monatsh. Chem. 2013, 144, 1363–1367; (d)
Yuan, H.; Jin, H.; Li, B.; Shen, Y.; Yue, R.; Shan, L.; Sun, Q.; Zhang, W. Can. J. Chem.
2013, 91, 333–337; (e) Navidi, M.; Movassagh, B.; Rayati, S. Appl. Catal. A 2013,
452, 24–28.
3. Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443–445.
4. Sun, W.; Wang, Y.; Wu, X.; Yao, X. Green Chem. 2013, 15, 2356–2360.

7114
J. A. Morales-Serna et al. / Tetrahedron Letters 54 (2013) 7111–7114
5. Keivanloo, A.; Bajherad, M.; Bahramian, B.; Baratnia, S. Tetrahedron Lett. 2011,
52, 1498–1502.
reaction. Completely anhydrous conditions were crucial for attaining good
yields.
6. Pérez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123, 4155–4160.
7. Gallagher, W. P.; Maleczka, R. E., Jr. J. Org. Chem. 2003, 68, 6775–6779.
8. Wang, B.; Bonin, M.; Micouin, L. J. Org. Chem. 2005, 70, 6126–6128.
9. Luu, T.; Morisaki, Y.; Cunningham, N.; Tykwinski, R. R. J. Org. Chem. 2007, 72,
9622–9629.
10. Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004, 45, 8545–8548.
11. Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org. Chem. 2002, 67,
5032–5035.
12. Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6793–6805.
13. El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557–6602.
14. Balcom, B. J.; Patersen, N. O. J. Org. Chem. 1989, 54, 1922–1927.
15. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
16. (a) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606–631; (b) Joullié, M. M.;
Lassen, K. M. ARKIVOC 2010, viii, 189–250.
22. General procedure for the synthesis of ynones: To a flame-dried, single-necked
50 mL round-bottomed flask equipped with a magnetic stir bar was added a
solution of acetylene (3 mmol) in anhydrous THF (10 mL). The solution was
cooled to À78 °C before n-BuLi (3.1 mmol) was added via syringe through the
septum. The reaction was stirred for 15 min at À78 °C. Subsequently, a solution
of the benzotriazole esters (1 mmol) in anhydrous THF was added slowly
through the septum using a syringe. The mixture was stirred for 15 min at
À78 °C. The cooling bath was removed and the reaction solution was allowed
to warm to room temperature before being quenched with saturated aqueous
ammonium chloride solution. The aqueous layer was separated and extracted
with ethyl acetate (3 Â 15 mL). The combined organic layers were washed
successively with 10% citric acid solution (2 Â 20 mL), 10% NaHCO3 solution
(2 Â 20 mL), 10% K2CO3 solution (2 Â 20 mL) and brine (3 Â 20 mL), dried over
magnesium sulfate, filtered and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on silica gel
using Hexane-EtOAc.
17. (a) König, W.; Geiger, R. Chem. Ber. 1970, 103, 788–798; (b) Carpino, L. A.;
Ferrer, F. J. Org. Lett. 2001, 3, 2793–2795.
18. (a) Cárdenas, J.; Morales-Serna, J. A.; Sánchez, E.; Lomas, L.; Guerra, N.; Negrón,
G. ARKIVOC 2005, vi, 428–435; (b) Morales-Serna, J. A.; Sánchez, E.; Velázquez,
R.; Bernal, J.; García-Ríos, E.; Gaviño, R.; Negrón-Silva, G.; Cárdenas, J. Org.
Biomol. Chem. 2010, 8, 4940–4948; (c) Morales-Serna, J. A.; Jaime-Vasconcelos,
M. A.; García-Ríos, E.; Cruz, A.; Angeles-Beltrán, D.; Lomas-Romero, L.;
Negrón-Silva, G. E. RSC Adv. 2013, 3, 23046–23050.
23. Thudichum, J. L. W. A Treatise on the Chemical Constitution of the Brain; Bailliere,
Tindall and Cox: London, 1884.
24. (a) Tani, M.; Ito, M.; Igarashi, Y. Cell. Signal. 2007, 19, 229–237; (b) Merrill, A. H.,
Jr. Chem. Rev. 2011, 111, 6387–6422.
25. (a) Argraves, K. M.; Wilkerson, B. A.; Argraves, W. S.; Fleming, P. A.; Obeid, L.
M.; Drake, C. J. J. Biol. Chem. 2004, 279, 50580–50590; (b) Kraut, R. J. Neurochem.
2011, 116, 764–778; (c) Hirabayashi, Y. Proc. Jpn. Acad., Ser. B 2012, 88, 129–
143.
19. Morales-Serna, J. A.; Vera, A.; Paleo, E.; García-Ríos, E.; Gaviño, R.; García de la
Mora, G.; Cárdenas, J. Synthesis 2010, 4261–4267.
20. Morales-Serna, J. A.; García-Ríos, E.; Bernal, J.; Paleo, E.; Gaviño, R.; Cárdenas, J.
Synthesis 2011, 1375–1382.
26. (a) Kolter, T.; Sandhoff, K. Biochim. Biophys. Acta 2006, 1758, 2057–2079; (b)
Kolter, T. Chem. Phys. Lipids 2011, 164, 590–606.
21. General procedure for the preparation of benzotriazole esters:
A
solution of
27. For reviews, see: (a) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075–
1091; (b) Liao, J.; Tao, J.; Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715–4733; (c)
Morales-Serna, J. A.; Llaveria, J.; Matheu, M. I.; Díaz, Y.; Castillón, S. Curr. Org.
Chem. 2010, 14, 2483–2521.
28. (a) Morales-Serna, J. A.; Llaveria, J.; Díaz, Y.; Matheu, M. I.; Castillón, S. Org.
Biomol. Chem. 2008, 6, 4502–4504; (b) Morales-Serna, J. A.; Díaz, Y.; Matheu, M.
I.; Castillón, S. Synthesis 2009, 710–712.
carboxylic acid (1 mmol), EDC (1.1 mmol) and HOBT (1.1 mmol) in CH2Cl2
(20 mL) was stirred at room temperature until the starting material
disappeared. The reaction was monitored by TLC. The solvent was eliminated
under reduced pressure, and the residue was co-distilled three times with dry
toluene to obtain benzotriazole esters
I and II. These compounds were
dissolved in anhydrous THF (5 mL) and stored under argon before the next