Optimization of Partial Hydrogenation Parameters Envisaged Flow Synthesis of 1 PARTIAL ALKYNE REDUCTION IN FLOW: ADAPTATION OF THE LINDLAR PROTOCOL PROMPTED BY A FLOW SYNTHESIS OF COMBRETASTATIN A-4 Laurent De Backer, Eduard Dolušić , Stéphane Collin and Steve Lanners * Laboratoire de Chimie Organique de Synthèse, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), Université de Namur, rue de Bruxelles 61, B-5000 Namur, Belgium [email protected] Combretastatin A-4 (1) is a natural product isolated from the South African bushwillow tree Combretum caffrum and endowed with a powerful inhibitory activity on microtubule formation as well as a related antiangiogenic activity. 1 As such, 1 has a strong potential in anticancer therapy. A lot of effort has been done on the development of new derivatives of this compound, in order to improve the properties such as solubility and stability, and to understand the structure-activity relationships around this series. 2 Introduction The synthesis of active pharmaceutical ingredients (API) using only flow chemistry has been pioneered by S.V. Ley et. al. in 2010. 3 In order to further illustrate the feasibility of this strategy, we have devised a synthetic route for 1 which only relies on flow chemistry (Scheme 1). Scheme 1. Proposed flow synthesis of Combretastatin A-4 1. a) Lin, C. M., et al, Mol. Pharmacol. 1988, 34, 200; b) Holt, H., et al, Top. Heterocycl. Chem. 2006, 11, 465; c) Kerr, D. J., et al, Bioorg. Med. Chem. 2007, 15, 3290. 2. a) Marrelli, M., et al, Curr. Med. Chem. 2011, 18, 3035; b) Shan, Y., et al, Curr. Med. Chem. 2011, 18, 523; c) Spatafora, C., et al, Anticancer Agents Med. Chem. 2012, 12, 902; d) Mikstacka, R., et al, Cell.Mol. Biol. Lett. 2013, 18, 368. 3. Hopkin, M. D., et al, Chem. Comm. 2010, 2450. 4. a) Baxendale, I. R., et al, Angew. Chem. Int. Ed. 2009, 48, 4017; b) Zhang, Y., et al, Org. Lett. 2011, 13, 280; c) Chandrasekhar, S., et al, Tetrahedron Lett. 2011, 52, 3865. References and Acknowledgment The envisaged Bestmann-Ohira 4a and Sonogashira 4b reactions have already been accomplished in flow. However, we anticipated that the partial hydrogenation of alkyne 5 might be problematic. Lindlar-type hydrogenation of disubstituted alkynes using H-Cube® (Fig. 1.) has been described, 4c but not on bis-aryl alkynes. We used diphenylacetylene 6 as the model substrate. Various reaction parameters were investigated. The selected results are shown in Table 1. The selected conditions were used with moderate success in a preliminary assay of hydrogenation of the alkyne precursor of 1 (Scheme 2). Figure 1. ThalesNano H-Cube® Table 1. Hydrogenation of diphenylacetylene 6. Product ratios were determined by integration of relevant signals in the 1 H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl when quinoline added) CatCart [6] / mgmL -1 quinol ine solvent temp. flow rate % 6 % 7 % 8 % 9 5% Pd/BaCO 3 25 - hexane 20 °C 2 ml/min 0 0 0 100 5% Pd/CaCO 3 /Pb 25 - hexane 20 °C 2 ml/min 1 46 2 51 5% Pd/CaCO 3 /Pb 25 - hexane 20 °C 3 ml/min 5 79 1 15 5% Pd/CaCO 3 /Pb 25 - hexane 30 °C 3 ml/min 3 70 3 24 5% Pd/CaCO 3 /Pb 25 - hexane 50 °C 3 ml/min <1 53 1 46 5% Pd/CaCO 3 /Pb 25 - MeOH 20 °C 3 ml/min 3 53 3 41 5% Pd/CaCO 3 /Pb 25 - EtOAc 20 °C 3 ml/min 6 56 4 44 5% Pd/CaCO 3 /Pb 25 - EtOH 20 °C 3 ml/min 29 22 trac es 49 5% Pd/CaCO 3 /Pb 25 - toluene 20 °C 3 ml/min 0 23 0 77 5% Pd/CaCO 3 /Pb 12,5 - hexane 20 °C 3 ml/min 3 60 3 34 5% Pd/CaCO 3 /Pb 50 - hexane 20 °C 3 ml/min 3 51 trac es 44 5% Pd/CaCO 3 /Pb 25 1 eq. hexane 20 °C 3 ml/min 20 80 0 0 5% Pd/BaCO 3 25 1 eq. hexane 20 °C 3 ml/min 4 75 4 17 5% Pd/BaCO 3 25 2 eq. hexane 20 °C 3 ml/min 3 89 3 5 5% Pd/BaCO 3 25 3 eq. hexane 20 °C 3 ml/min 10 86 trac es 2 Scheme 2. Synthesis of combretastatin A-4 using Lindlar hydrogenation in flow Extending the Reaction Scope and Conclusion We decided to expand the optimized reaction conditions to a wider range of structurally various alkynes (Scheme 3 and Table 2). In some cases (substrates 16 and 17), mixtures with alcohols were used as the solvents to ensure complete solubility. The above optimized conditions gave good results for the less reactive alkynes (10 – 12); in the latter case, 10 bar of H 2 had to be applied to achieve a satisfactory outcome. On the other hand, adding as much as 5 equiv. of quinoline could not completely suppress overreduction of the more reactive substrates. In conclusion, while the generality of our method is reasonable within the substrate scope explored, fine tuning of the reaction conditions is still necessary in order to improve the selectivity towards (Z)- alkenes. Scheme 3. Lindlar hydrogenation in flow of a range of alkynes Table 2. Lindlar hydrogenations in flow. Product ratios were determined by integration of relevant signals in the 1 H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl) 7 22 80 60 6 7 7 11 [% ] with 2 eq. quin. com b. yield = 74% [% ] with 3 eq. quin. com b. yield = 84% O O Si Si - - 18 26 [% ] with 2 eq. quin. com b. yield = 26% [% ] with 3 eq. quin. com b. yield = 11% 82 74 9 45 47 35 - 55 53 65 100 - - - - - - - - [% ] with 2 eq. quin. com b. yield = 75% [% ] with 3 eq. quin. com b. yield = 46% [% ] with 2 eq. quin. 1.5 m L/m in com b. yield = 82% [% ] with 2 eq. quin. 10 barH2 com b. yield = 75% O Si - - - 24 39 76 - - - 76 61 24 [% ] with 2 eq. quin. com b. yield = 48% [% ] with 3 eq. quin. com b. yield = 30% [% ] with 5 eq. quin. com b. yield = 70% 3 4 11 26 51 52 6 4 - 65 41 37 [% ] with 2 eq. quin. com b. yield = 100% [% ] with 3 eq. quin. com b. yield = 100% [% ] with 5 eq. quin. com b. yield notdeterm . O O - 8 - 92 n -hex./M eOH/EtOH 1/1/1 [% ] with 2 eq. quin. com b. yield = 87% N H N - 3 - - - - 100 97 [% ] with 2 eq. quin. com b. yield = 32% [% ] with 3 eq. quin. com b. yield = 32% O O - - 27 49 5 3 68 48 5% M eOH in n -hexane [% ] with 2 eq. quin. com b. yield = 52% 5% M eOH in n -hexane [% ] with 3 eq. quin. com b. yield = 33% OH O 10 11 12 13 14 15 16 17 O OMe M eO M eO M eO M eO OMe OMe OMe OMe PG O /HO M eO OMe OMe M eO M eO O N 2 P O OMe OMe KO tBu in M eO H 30 m in,100°C Q P-BZA A -21 Br OH M eO 170°C ,30 m in,C opperTube N H S NH 2 Q P-TU Bu 4 NOAC H -C ube catalyst:Pd-CaCO 3 Pd-BaC O 3 PG O /HO NH 2 SO 3 H NMe 2 A -15 2 3 1 5 4 + + OMe MeO MeO OMe OH 1 H-Cube, CatCart temperature solvent concentration flow rate catalyst quinoline 6 7 8 9 H 2 (g), 1 bar H 2 (g),1 bar H-Cube Pd/BaCO 3 hexane, 20°C 3 mL/min, 12mg /7mL 2 eq.quinoleine MeO OMe OMe OMe OH MeO OMe MeO HO MeO HO OMe MeO OMe OMe OMe OH OMe OMe MeO 5 1 ~66% ~0% ~33% R 1 R 2 R 1 R 2 (Z) H 2 (H-Cube; 1 -10 bar) Lindlar catalyst quinoline (2-5 equiv.) solvent 20°C, 1,5 -3 mL/min
Optimization of Partial Hydrogenation Parameters
Feb 24, 2016
PARTIAL ALKYNE REDUCTION IN FLOW: ADAPTATION OF THE LINDLAR PROTOCOL PROMPTED BY A FLOW SYNTHESIS OF COMBRETASTATIN A-4 Laurent De Backer, Eduard Dolušić , Stéphane Collin and Steve Lanners * Laboratoire de Chimie Organique de Synthèse , Namur Medicine & Drug Innovation Center (NAMEDIC ), - PowerPoint PPT Presentation
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Optimization of Partial Hydrogenation Parameters
O
OMeMeO
MeO
MeO
MeOOMe
OMe
OMe
OMePGO/HO
MeO
OMe
OMeMeOMeO
O
N2
PO
OMeOMe
KOtBu in MeOH
30 min, 100°C
QP-BZA
A-21
Br
OHMeO
170°C, 30 min, Copper Tube
NH
S
NH2
QP-TU
Bu4NOAC
H-Cubecatalyst: Pd-CaCO3Pd-BaCO3
PGO/HO
NH2
SO3H
NMe2
A-15
2
3
1
5
4
+
+
Envisaged Flow Synthesis of 1
PARTIAL ALKYNE REDUCTION IN FLOW: ADAPTATION OF THE LINDLAR PROTOCOL PROMPTED BY A FLOW SYNTHESIS OF COMBRETASTATIN A-4
Laurent De Backer, Eduard Dolušić, Stéphane Collin and Steve Lanners*
Laboratoire de Chimie Organique de Synthèse, Namur Medicine & Drug Innovation Center (NAMEDIC),Namur Research Institute for Life Sciences (NARILIS), Université de Namur, rue de Bruxelles 61, B-5000 Namur, Belgium
Combretastatin A-4 (1) is a natural product isolated from the South African bushwillow tree Combretum caffrum and endowed with a powerful inhibitory activity on microtubule formation as well as a related antiangiogenic activity.1 As such, 1 has a strong potential in
anticancer therapy. A lot of effort has been done on the development of new derivatives of this compound, in order to improve the properties such as solubility and stability, and to understand the structure-activity relationships around this series.2
Introduction
The synthesis of active pharmaceutical ingredients (API) using only flow chemistry has been pioneered by S.V. Ley et. al. in 2010.3 In order to further illustrate the feasibility of this strategy, we have devised a synthetic route for 1 which only relies on flow chemistry (Scheme 1).
Scheme 1. Proposed flow synthesis of Combretastatin A-4
1. a) Lin, C. M., et al, Mol. Pharmacol. 1988, 34, 200; b) Holt, H., et al, Top. Heterocycl. Chem. 2006, 11, 465; c) Kerr, D. J., et al, Bioorg. Med. Chem. 2007, 15, 3290.2. a) Marrelli, M., et al, Curr. Med. Chem. 2011, 18, 3035; b) Shan, Y., et al, Curr. Med. Chem. 2011, 18, 523; c) Spatafora, C., et al, Anticancer Agents Med. Chem. 2012, 12, 902; d) Mikstacka, R., et al, Cell.Mol. Biol. Lett. 2013, 18, 368.3. Hopkin, M. D., et al, Chem. Comm. 2010, 2450.4. a) Baxendale, I. R., et al, Angew. Chem. Int. Ed. 2009, 48, 4017; b) Zhang, Y., et al, Org. Lett. 2011, 13, 280; c) Chandrasekhar, S., et al, Tetrahedron Lett. 2011, 52, 3865.
This work is supported by WBGREEN – MICROECO (Convention No. 1217714).
References and Acknowledgment
OMeMeO
MeO
OMe
OH
1
The envisaged Bestmann-Ohira4a and Sonogashira4b reactions have already been accomplished in flow. However, we anticipated that the partial hydrogenation of alkyne 5 might be problematic. Lindlar-type hydrogenation of disubstituted alkynes using H-Cube® (Fig. 1.) has been described,4c but not on bis-aryl alkynes. We used diphenylacetylene 6 as the model substrate. Various reaction parameters were investigated. The selected results are shown in Table 1.The selected conditions were used with moderate success in a preliminary assay of hydrogenation of the alkyne precursor of 1 (Scheme 2).
Figure 1. ThalesNano H-Cube®
Table 1. Hydrogenation of diphenylacetylene 6. Product ratios were determined by integration of relevant signals in the 1H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl when quinoline added)
CatCart [6] / mgmL-1 quinoline solvent temp. flow rate % 6 % 7 % 8 % 95% Pd/BaCO3 25 - hexane 20 °C 2 ml/min 0 0 0 100
5% Pd/CaCO3/Pb 25 - hexane 20 °C 2 ml/min 1 46 2 51
5% Pd/CaCO3/Pb 25 - hexane 20 °C 3 ml/min 5 79 1 15
5% Pd/CaCO3/Pb 25 - hexane 30 °C 3 ml/min 3 70 3 24
5% Pd/CaCO3/Pb 25 - hexane 50 °C 3 ml/min <1 53 1 46
5% Pd/CaCO3/Pb 25 - MeOH 20 °C 3 ml/min 3 53 3 41
5% Pd/CaCO3/Pb 25 - EtOAc 20 °C 3 ml/min 6 56 4 44
5% Pd/CaCO3/Pb 25 - EtOH 20 °C 3 ml/min 29 22 traces 495% Pd/CaCO3/Pb 25 - toluene 20 °C 3 ml/min 0 23 0 775% Pd/CaCO3/Pb 12,5 - hexane 20 °C 3 ml/min 3 60 3 345% Pd/CaCO3/Pb 50 - hexane 20 °C 3 ml/min 3 51 traces 445% Pd/CaCO3/Pb 25 1 eq. hexane 20 °C 3 ml/min 20 80 0 0
5% Pd/BaCO3 25 1 eq. hexane 20 °C 3 ml/min 4 75 4 175% Pd/BaCO3 25 2 eq. hexane 20 °C 3 ml/min 3 89 3 55% Pd/BaCO3 25 3 eq. hexane 20 °C 3 ml/min 10 86 traces 2
H-Cube, CatCart
temperaturesolventconcentrationflow ratecatalystquinoline6
7 8 9
H2 (g), 1 bar
H2 (g), 1 barH-Cube
Pd/BaCO3hexane, 20°C
3 mL/min, 12mg / 7mL2 eq.quinoleine
MeOOMe
OMe
OMeOH
MeOOMe
MeOHO
MeO HOOMe
MeOOMe
OMeOMe
OH
OMeOMeMeO
5 1
~66% ~0% ~33%
Scheme 2. Synthesis of combretastatin A-4 using Lindlar hydrogenation in flow
Extending the Reaction Scope and ConclusionWe decided to expand the optimized reaction conditions to a wider range of structurally various alkynes (Scheme 3 and Table 2). In some cases (substrates 16 and 17), mixtures with alcohols were used as the solvents to ensure complete solubility. The above optimized conditions gave good results for the less reactive alkynes (10 – 12); in the latter case, 10 bar of H2 had to be applied to achieve a satisfactory outcome. On the other hand, adding as much as 5 equiv. of quinoline could not completely suppress overreduction of the more reactive substrates. In conclusion, while the generality of our method is reasonable within the substrate scope explored, fine tuning of the reaction conditions is still necessary in order to improve the selectivity towards (Z)-alkenes.
R1
R2
R1 R2
(Z)H2 (H-Cube; 1 - 10 bar)
Lindlar catalystquinoline (2 - 5 equiv.)
solvent20°C, 1,5 - 3 mL/min
Scheme 3. Lindlar hydrogenation in flow of a range of alkynes
Table 2. Lindlar hydrogenations in flow. Product ratios were determined by integration of relevant signals in the 1H-NMR spectra of the crude reaction mixtures (extraction with 5% aq. HCl)
7 22
80 60
6 7
7 11
[%] with 2 eq. quin. comb. yield = 74%
[%] with 3 eq. quin. comb. yield = 84%
O
OSi
Si
- -
18 26
[%] with 2 eq. quin. comb. yield = 26%
[%] with 3 eq. quin. comb. yield = 11%
82 749
45 47 35 -
55 53 65 100
- - - -
- - - -
[%] with 2 eq. quin. comb. yield = 75%
[%] with 3 eq. quin. comb. yield = 46%
[%] with 2 eq. quin. 1.5 mL / min
comb. yield = 82%
[%] with 2 eq. quin. 10 bar H2
comb. yield = 75%
OSi
- - -
24 39 76
- - -
76 61 24
[%] with 2 eq. quin. comb. yield = 48%
[%] with 3 eq. quin. comb. yield = 30%
[%] with 5 eq. quin. comb. yield = 70%
3 4 11
26 51 52
6 4 -
65 41 37
[%] with 2 eq. quin. comb. yield = 100%
[%] with 3 eq. quin. comb. yield = 100%
[%] with 5 eq. quin. comb. yield not determ.
O
O-
8
-
92
n -hex./MeOH/EtOH 1/1/1 [%] with 2 eq. quin. comb. yield = 87%
NH
N
- 3
- -
- -
100 97
[%] with 2 eq. quin. comb. yield = 32%
[%] with 3 eq. quin. comb. yield = 32%
O
O- -
27 49
5 3
68 48
5% MeOH in n -hexane [%] with 2 eq. quin. comb. yield = 52%
5% MeOH in n -hexane [%] with 3 eq. quin. comb. yield = 33%
OH
O
10
11
12
13
14
15
16
17
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