Application of Horner-Wadsworth-Emmons olefination for the synthesis of granulatamide A, its: E isomer and other amides of tryptamine

Article abstract of DOI:10.1039/c5nj03533c

Horner-Wadsworth-Emmons (HWE) Z-selective olefination was used for the first synthesis of a naturally occurring cytotoxic tryptamine derivative, granulatamide A. The E-isomer of granulatamide A was synthesized by E-selective HWE olefination. Furthermore,

Full text of DOI:10.1039/c5nj03533c

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DOI: 10.1039/C5NJ03533C
Journal Name
ARTICLE
Application of Horner–Wadsworth–Emmons olefination for the
synthesis of Granulatamide A, its E isomer and other amides of
tryptamine
Received 00th January 20xx,
Accepted 00th January 20xx
Deepali Pakharea, and Radhika Kusurkar*a
DOI: 10.1039/x0xx00000x
Horner–Wadsworth–Emmons (HWE) Z-selective olefination was used for the first synthesis of naturally occurring cytotoxic
tryptamine derivative, Granulatamide A. The E-isomer of granulatamide A was synthesized by E-selective HWE olefination.
Further, two other tryptamine derived amides were prepared by using the same strategy.
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Introduction
Indole skeleton is a key structural unit in many natural products and
pharmaceutical compounds. Moreover, tryptamine based molecules
are generally considered as esteemed structures with drug-like
qualities and expectant effects for different types of diseases. The
best selling drugs rizatriptan1 and eletriptan2 are tryptamine based
molecules. LE300 analogues3 having polycyclic scaffolds with
tryptamine skeleton have been synthesized widely and exhibit quite
potent affinities on drug targets such as dopamine receptors (DRs),
serotonin receptors (5-HTRs), and α-1-adrenergic receptor (α1-AR).
Granulatamides A, 1 and B, 2 (Figure 1) were isolated4 from the 2-
propanol extract of the soft coral Eunicella granulata collected in
Senegal. It showed moderate in vitro cytotoxicity against a panel of
human tumour cells.
Figure 1: Granulatamides A (1) and B (2)
Results and discussion
The synthesis was started with the readily available tryptamine (3)
which was converted to its bromoacetamide derivative10 4 by
modifying the reaction (Scheme 1). Further, treatment of compound
4 with diphenyl phosphite in presence of NaH in anhydrous
tetrahydrofuran at 0 °C resulted in phosphonate 5 which was purified
and characterized by NMR. The structure was supported by
observing the coupling of phosphorous with protons and carbons in
the respective spectrum.
A stabilized ylide when treated with ketone or aldehyde in Horner–
Wadsworth–Emmons (HWE) reaction5 furnished predominantly E
olefin. By adjusting the reaction conditions, kinetically favoured Z
olefin also can be synthesized as shown by Breuer6, Patois and
Savignac7 and Still and Gennari.8 Recently Ando9 reported the use of
diphenyl phosphonate for the synthesis of the Z isomer selectively.
The advantage of the HWE protocol is its versatility and
receptiveness to diverse reaction conditions.
In the present paper, the synthesis of granulatamide A and its E
isomer along with two other tryptamine based amides has been
described using HWE olefination strategy.
Scheme 1: Reagents and Conditions: a) bromoacetyl bromide, DIPEA,
THF 0 °C to rt, 2h, 95%; b) diphenyl phosphite, NaH, THF, 0 °C to rt
, 12h, 90%; c) 2-undecanone, KtOBu, THF, -78 °C, 6h, 80%
a.Department of Chemistry, Savitribai Phule Pune University (formerly University
of Pune), Pune - 411 007, Maharashtra, India. E-mail: *rsk@chem.unipune.ac.in
Electronic Supplementary Information (ESI) available: 1H and 13C NMR data in the
electronic format. See DOI: 10.1039/x0xx00000x
Further, Horner–Wadsworth–Emmons olefination reaction of
phosphonate 5 with 2-undecanone at -78 °C using KtOBu furnished
granulatamide A (1) having Z double bond and its E isomer (6) in 90%
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and 10% yield respectively. This indicated the Z selectivity of nitrogen, two from alkyl chain and absence of NOE for allylic methyl
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phosphonate 5 which is expected from the analogy with Ando’s group, confirming the E geometry of doubleDbOonI:d1.0.1039/C5NJ03533C
phosphonates.
Now, in order to investigate the synthetic utility of phosphonate 7, it
The E isomer 6, formed in minor amount in the above Z-selective was used for the synthesis of other two tryptamine based amides, 8
HWE reaction, is not reported in the literature. E-selective and 9. Amide 8 is an intermediate for the synthesis of hermitamide
phosphonates 7 required for the synthesis of compound 6 in major B11 and amide 9 can be used as an intermediate for the synthesis of
amount, was prepared as shown in Scheme 2.
prebalamide12. Furthermore, amide 9 is known13 to show SIRT2
inhibition. Thus, phosphonate 7 was treated with paraformaldehyde
at room temperature using NaH as a base to give compound 8 in
good yield (Scheme 3). Terminal olefinic carbon was identified in
DEPT experiment which supported the structure of compound 8.
Further, compound 9 was prepared in 85% yield by treating
phosphonate 7 with benzaldehyde.
Scheme 3: Reagents and Conditions: a) paraformaldehyde, NaH, THF,
0 °C to rt, 5h, 80%; b) PhCHO, KtOBu, THF, 0 °C to rt, 4h, 85%
Scheme 2: Reagents and Conditions: a) triethyl phosphite, 80 °C, 3h,
90%; b) 2-undecanone, KtOBu, THF, rt, 5h, 85%.
Conclusions
Thus, using Arbuzov reaction, compound 4 was treated with neat
triethylphosphite at 80 °C to furnish phosphonate 7 in 90% yield.
Further, it was reacted with 2-undecanone at room temperature in
presence of KtOBu in anhydrous THF to furnish E-olefin (6) in 92% and
Z-olefin (1) in 8%. These results revealed the E selectivity of the
phosphonates 7 and are in accordance with the earlier reports5 of
other E selective phosphonates. The down field position of allylic
methylene protons in granulatamide A (1) and allylic methyl protons
in its E isomer (6) can be explained by the anisotropic effect of
carbonyl group which supported the structures of Z and E isomers
respectively.
The Z and E selective new phosphonates
for the first time. The first total synthesis of biologically active
natural product granulatamides A ( ) has been successfully
achieved in 68% overall yield, using phosphonates in Z
selective Horner–Wadsworth–Emmons olefination. Also the E
isomer of granulatamides A was synthesized in 73% overall
yield using phosphonates in E selective Horner–Wadsworth–
Emmons olefination. The phosphonates was also used for the
and
5 and 7 were prepared
1
5
6
7
7
synthesis of tryptamine based amides
8
9.
Experimental section
General remarks
Chemicals and all solvents were commercially available and
used without further purification. Reactions and products were
routinely monitored by thin layer chromatography (TLC) on
silica gel (Kieselgel 60 F254, Merck). Column chromatographic
purifications were performed using 100-200 mesh silica gel and
activated neutral aluminium oxide. 1H NMR (200 and 500 MHz)
and 13C NMR (75 and 125 MHz) spectra were recorded on
Bruker AV 200, Varian Mercury 300, Bruker AV III HD 500
1
instruments using TMS as an internal standard. H NMR peaks
expressed as s, brs, brd, brt, d, t, q, dd, td and m correspond to
singlet, broad-singlet, broad-doublet, broad-triplet, doublet,
triplet, quartet, doublet of doublet, triplet of doublet and
multiplet respectively. HRMS spectra were obtained on a Bruker
Daltonik GmbH Impact II UHR-ToF Mass Spectrometer using ESI
(Electron Spray Ionization) source.
Figure 2: NOE study of compounds 1 and 6
In addition to this, both isomers were distinguished by carrying out
NOE experiments. For granulatamide A (1), olefinic proton (Figure 2)
showed NOE with one methylene and one methyl protons which
confirmed the presence of Z olefin. However, for E-isomer 6, olefinic
proton showed NOE with one methylene protons attached to amide
Experimental procedures
Synthesis of 4
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To a stirring solution of tryptamine (7.51 g, 21.36 mmol) in and water, dried over anhydrous Na2SO4 and concentrated in
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anhydrous THF (100 mL) under a nitrogen atmosphere at 0
were added diisoproylethylamine (4.1 mL, 23.53 mmol) and on silica gel (pet ether-ethyl acetate) provided compounds
bromoacetyl bromide (2.05 ml, 23.53 mmol) and stirred at rt. and in 9:1 ratio (both as pale yellow oil) in 80% yield.
After 2 hours, ethyl acetate was added and reaction mixture 1H NMR of compound
(500 MHz, CDCl3): δ 8.16 (s, 1H, D2O
°C
vacuo after filtration. The column chromDaOtoI:g1r0a.1p0h3i9c/Cse5NpJa0r3a5t3io3Cn
1
6
1
was washed with water twice, 1N hydrochloric acid and brine. exchangeable), 7.61-7.63 (d, J = 7.63 Hz, 1H), 7.36-7.39 (m, 1H),
The organic layer was dried over anhydrous sodium sulphate, 7.20-7.23 (td, J = 7.55, 1.07 Hz, 1H), 7.11-7.14 (m, 1H), 7.04-7.05
filtered and concentrated on a rotary evaporator. Further, (d, J = 2.14 Hz, 1H), 5.40-5.45 (brs, 2H, 1H is D2O exchangeable),
purification by column chromatography on silica (pet ether- 3.63-3.67 (q, J = 6.71 Hz, 2H), 3.0 (t, J = 6.71 Hz, 2H), 2.61 (t, J =
ethyl acetate as an eluent) yielded compound
solid in 95% yield. M.p 82 C.
1H NMR (200 MHz, CDCl3): δ 8.28 (brs, 1H); 7.55-7.63 (m, 1H), 13C NMR (125 MHz, CDCl3): δ 166.46, 154.64, 136.11, 127.07,
7.31-7.40 (m, 1H), 7.07-7.26 (m, 2H), 7.01-7.02 (d, J = 2 Hz, 1H), 121.89, 121.75, 119.17, 118.52, 118.27, 112.92, 110.93, 38.99,
6.58 (brs, 1H), 3.79 (s, 2H), 3.55-3.64 (q, J = 6 Hz, 2H), 2.99 (t, J 32.75, 31.64, 29.55, 29.43, 29.34, 29.07, 28.08, 25.14, 24.42,
4
as an off-white 7.5 Hz, 2H), 1.78-1.79 (d, J = 1.53 Hz, 3H), 1.38-1.48 (m, 2H),
1.25-1.30 (m, 12H), 0.88 (t, J = 7 Hz, 3H).
°
= 6 Hz, 2H).
22.41, 13.86
13C NMR (100 MHz, CDCl3): δ 165.45, 136.34, 127.03, 122.19, HRMS (ESI): m/z calcd for C23H34N2NaO (M+Na)+, 377.2567;
122.15, 119.41, 118.53, 112.22, 111.29, 40.30, 29.21, 24.90
HRMS (ESI): m/z calcd for C12H13BrN2NaO (M+Na)+, 303.0103;
found, 303.0099.
found, 377.2563.
Synthesis of 7
A slurry of bromoacetamide
4 (0.5 g, 1.78 mmol) in triethyl
Synthesis of 5
phosphite (0.32 mL, 0.3 g, 1.8 mmol) was heated under N2
C for 3 h. The residue was purified by column
mmol) in THF (10 mL) was added diphenyl phosphite (0.59 g, chromatography using pet ether and ethyl acetate as an eluent
2.13 mmol) drop wise at 0 C during a period of 20 min. After to get product as brownish oil in 90% yield.
half an hour, the gas evolution had ceased and bromoacetamide 1H NMR (500 MHz, CDCl3):
8.4-8.6 (brd, 1H, D2O
(0.5 g, 2.13 mmol) was added drop wise over a period of 20 exchangeable), 7.58-7.60 (d, J = 7.93 Hz, 1H), 7.34-7.35 (d, J =
To a suspension of NaH (60% in mineral oil, 0.085 g, 2.13 atmosphere at 80
°
°
7
δ
4
min. The cooling bath was removed and the reaction mixture 8.24 Hz, 1H), 7.17 (t, J = 7.63 Hz, 1H), 7.08-7.12 (m, 1H), 7.06
was stirred at rt for 12 h. A saturated aqueous solution of NH4Cl (brs, 1H), 6.79 (brs, 1H), 4.00-4.08 (m, 4H), 3.58-3.62 (q, J = 6.51
(20 mL) was added to the mixture. The organic layer was Hz, 2H), 2.98 (t, J = 6.87 Hz, 2H), 2.76-2.82 (d, J = 20 Hz, 2H), 1.26
separated and the aqueous layer was extracted with diethyl (t, J = 7.02 Hz, 6H).
ether (3×10 mL). The combined organic layers were dried 13C NMR (125 MHz, CDCl3): δ 163.89, 136.34, 127.15, 122.30,
(Na2SO4) and the solvents were removed under reduced 121.91, 119.20, 118.53, 112.38, 111.20, 62.69-62.64 (d, J = 6.3
pressure. The residue was purified by column chromatography Hz), 40.00, 35.54-34.50 (d, J = 131.04 Hz), 25.00, 16.22-16.17 (d,
using pet ether and ethyl acetate as an eluent to give a product J = 6.3 Hz).
5
as a pale yellow solid in 90% yield. M.p 109
°C.
HRMS (ESI): m/z calcd for C16H23N2NaO4P (M+Na)+, 361.1288;
1H NMR (500 MHz, CDCl3): δ 8.24-8.42 (m, 1H), 7.52-7.53 (d, J = found, 361.1291.
15 Hz, 1H), 7.23- 7.30 (m, 5H), 7.04-7.18 (m, 8H), 6.87 (brs, 1H),
6.77 (m, 1H), 3.52 (q, J = 5 Hz, 2H), 3.02- 3.10 (d, J = 20 Hz, 2H), Synthesis of 6
2.85 (t, J = 5 Hz, 2H).
1M potassium tert-butoxide (0.33 g, 2.95 mmol) in THF was
13C NMR (125 MHz, CDCl3): δ 162.65, 149.72, 149.72, 149.65, added to a solution of phosphonate
7 (0.5 g, 1.44 mmol) in 10
136.29, 129.83, 127.05, 125.64, 122.34, 121.87, 120.58, 120.54, mL of THF at room temperature. After stirring for 10 min, a
119.17, 118.45, 112.07, 111.27, 40.02, 35.42- 34.36 (d, J = solution of 2-undecanone (0.45 mL, 0.37 g, 0.88 mmol) in THF
133.56 Hz), 24.86.
was added and stirring was continued for 5 h. Then saturated
HRMS (ESI): m/z calcd for C48H46N4NaO8P2 (2M+Na)+, 891.2689; aqueous NH4Cl solution was added and then organic layer was
found, 891.2670.
separated and aqueous layer was extracted ethyl acetate. The
combined organic extracts were washed with water, dried over
anhydrous Na2SO4 and concentrated in vacuo after filtration.
Synthesis of granulatamides A (1)
1M potassium tert-butoxide (0.39 g, 2.3 mmol) in THF was Silica gel column chromatography (pet: ether-ethyl acetate)
added to a solution of phosphonate (0.5 g, 1.15 mmol) in 15 provided compounds and in 9.2:0.8 ratio. Yield 85%.
mL of THF at room temperature. After stirring for 1 h, reaction 1H NMR of compound
(500 MHz, CDCl3): δ 8.21 (brs, 1H, D2O
mixture was cooled to -78 C. Then, a solution of 2-undecanone exchangeable), 7.63-7.65 (d, J = 7.93 Hz, 1H), 7.39-7.41 (d, J =
5
6
1
6
°
(0.29 g, 0.35 mL, 1.7 mmol) in THF was added and stirring was 8.24 Hz, 1H), 7.21-7.25 (m, 1H), 7.13-7.17 (m, 1H), 7.07 (brs, 1H),
continued for another 15 min. The reaction mixture was 5.48-5.52 (brt, 1H, D2O exchangeable), 5.47 (brs, 1H), 3.67 (q, J
warmed to room temperature and the stirring was continued = 6.41 Hz, 2H), 3.02 (t, J = 6.71 Hz, 2H), 2.15 (d, J = 0.92 Hz, 3H),
for 24 h. Further, a saturated aqueous NH4Cl solution was added 2.06 (t, J = 6.75 Hz, 2H), 1.40-1.47 (m, 2H), 1.27-1.33 (m, 12H),
and the reaction mixture was extracted with CH2Cl2. The 0.90 (t, J = 6.87 Hz, 3H)
combined organic extracts were washed with Na2S2O3 solution
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13C NMR (125 MHz, CDCl3): δ 167.24, 154.68, 136.41, 127.40,
122.18, 122.08, 119.47, 118.84, 117.91, 113.23, 111.24, 40.80,
39.42, 31.91, 29.54, 29.50, 29.34, 29.28, 27.49, 25.46, 22.71,
18.24, 14.15
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DOI: 10.1039/C5NJ03533C
Acknowledgements
We are thankful to Mrs. Shital Bansode and Mr. Dattatraya
Ukale for NMR spectra and Mr. Rahul Yewale for HRMS. D.S.P.
is thankful to Council of Scientific and Industrial Research, New
Delhi, India for financial assistance through fellowship and
contingency.
HRMS (ESI): m/z calcd for C23H35N2O (M+H)+, 355.2749; found,
355.2747.
Synthesis of 8
A solution of phosphonate
was added to NaH (0.08 g, 2 mmol) in THF (5 mL) under an N2
atmosphere at 0 C. The reaction mixture was stirred at this
7 (0.34 g, 1.0 mmol) in 5 mL THF
Notes and references
°
temperature for 30 min. Then, paraformaldehyde (0.03 g, 1.0
mmol) was added in one portion and the reaction mixture was
stirred at rt for 5 h. Before adding water (10 mL), reaction was
1
2
Yao, G.; Hao, Ting-ting; Luo, Xiang-dan; Yu, Ting-min. Jilin
Daxue Xuebao, Yixueban 2014, 40, 981.
a) Kertesz, D. P.; Trabekin, O.; Vanetik, M. S. Journal of ECT
2015, 31, 105. b) Sun, Hui; Zhou, Weicheng; Zhang, Shunli.
Faming Zhuanli Shenqing (2014), CN 104230895 A 20141224.
Decker, M.; Lehmann, J. Pharmazie 2006, 61, 248.
Fernando R., Rocio M., Rogelio F. J. Nat. Prod. 2006, 69, 668.
a) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733. b) Boutagy, O.; Thomas, R. Chem. Rev. 1974,
cooled to 0 °C. Then solvent was removed under reduced
pressure and residue was extracted with CH2Cl2 (3×10 mL).
Combined organic layers were dried and evaporated under
reduced pressure, afforded the crude product which was
purified by column chromatography (pet ether- ethyl acetate)
3
4
5
to get product 8 as a yellow oil in 80% yield.
74, 87. c) Bisceglia J. A.; Orelli, L. R. Curr. Org. Chem. 2012, 16
2206. d) Bisceglia J. A.; Orelli, L. R. Curr. Org. Chem. 2015, 19
744.
,
,
1H NMR (500 MHz, DMSO-d6): δ 10.82 (brs, 1H), 8.23 (t, J = 5.04
Hz, 1H), 7.53-7.55 (d, J = 7.93 Hz, 1H), 7.33-7.35 (d, J = 7.93 Hz,
1H), 7.15 (s, 1H), 7.07 (t, J = 7.48 Hz, 1H), 6.96-7.00 (m, 1H), 6.1-
6.25 (dd, J = 10 Hz, 17 Hz, 1H), 6.05-6.15 (d, J = 16.5 Hz 1H), 5.57-
5.59 (d, J = 10 Hz, 1H), 3.41-3.45 (q, J = 6.92 Hz, 2H), 2.86 (t, J =
7.32 Hz, 2H)
6
7
Breuer, E.; Bannet, D. M. Tetrahedron Let. 1977, 18, 1141.
a) Patois, C.; Savignac, P. Synlett 1991, 1991, 517; Patois, C.;
b) Savignac, P. Tetrahedron Let. 1991, 32, 1317.
Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
a) Ando, K. Tetrahedron Let.. 1995, 36, 4105. b) Ando, K. J.
8
9
13C NMR (125 MHz, DMSO-d6): δ 164.50, 136.18, 131.89,
127.15, 124.83, 122.59, 120.88, 118.19, 111.72, 111.33, 39.46,
25.10.
HRMS (ESI): m/z calcd for C13H14N2NaO (M+Na)+, 237.0998;
found, 237.0998.
Org. Chem. 1997, 62, 1934. c) Ando, K. J. Org. Chem. 1998, 63
8411. d) Ando, K. J. Org. Chem. 1999, 64, 8406.
,
10 Khalil, E. M.; Cole, P. A. J. Am. Chem. Soc. 1998, 120, 6195.
11 De Oliveira, E. O.; Graf, K. M.; Patel, Manoj K.; Baheti, A.; Kong,
Hye-Sik; MacArthur, L. H.; Dakshanamurthy, S.; Wang, K.;
Brown, M. L.; Paige, M. Bioorg. Med. Chem. 2011, 19, 4322.
12 Johansen, M. B.; Leduc, A. B.; Kerr. M. A. Synlett 2007, 16
,
2593.
Synthesis of 9
13 Kiviranta, P.H.; Salo, H. S.; Leppanen, J.; Rinne, V. M.;
Kyrylenko, S.; Kuusisto, E.; Suuronen, T.; Salminend, A.; Poso,
A.; Lahtela-Kakkonen, M.; Wallen, E. A. A. Bioorg. Med.
Chem. 2008, 16, 8054
A solution of phosphonate
was added 1M potassium tert-butoxide (0.33 g, 2.95 mmol) in
THF under an N2 atmosphere at 0 C. The reaction mixture was
7 (0.5 g, 1.44 mmol) in 20 mL THF
°
stirred at this temperature for 30 min. Then benzaldehyde
(prewashed with aqueous NaHCO3 solution to remove benzoic
acid, 0.18 g, 1.72 mmol) in THF (5 mL) was added slowly and the
reaction mixture was stirred at rt for 4 h. Then, water (10 mL)
was added, the solvent was removed under reduced pressure
and the residue was extracted with CH2Cl2 (3×15 mL). Combined
organic layers were dried and evaporated under reduced
pressure, affording the crude product which was purified by
column chromatography (pet ether: ethyl acetate) to get
product 9 as brownish solid in 85% yield. M.p. 115 °C.
1H NMR (500 MHz, CDCl3): δ 8.37 (brs, 1H), 7.57-7.63 (m, 2H),
7.40-7.45 (m, 2H), 7.34-7.37 (d, J = 8 Hz, 1H) 7.29-7.33 (m, 3H),
7.19 (t, J = 7.32 Hz, 1H), 7.11 (t, J = 7 Hz, 1H), 7.00-7.01 (d, J =
1.65 Hz, 1H), 6.27-6.30 (d, J = 15 Hz, 1H), 5.88 (brt, J = 5.34 Hz,
1H), 3.69-3.73 (q, J = 6.7 Hz, 2H), 3.02 (t, J = 6.7 Hz, 2H).
13C NMR (125 MHz, CDCl3): δ 165.96, 140.81, 136.39, 134.73,
129.58, 128.73, 127.71, 127.27, 122.20, 122.10, 120.74, 119.40,
118.67, 112.74, 111.31, 39.94, 25.26.
HRMS (ESI): m/z calcd for C19H18N2NaO (M+Na)+, 313.1313;
found, 313.1311.
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DOI: 10.1039/C5NJ03533C
Graphical Abstract
Application of Horner–Wadsworth–Emmons olefination for the synthesis of Granulatamide A,
its E isomer and other amides of tryptamine
Deepali Pakharea, and Radhika Kusurkar*a