Facile synthesis of naturally occurring nor-lignans (±)-Machicendiol and its analogs

Article abstract of DOI:10.1080/00397911.2017.1285936

A facile synthesis of naturally occurring (±)-machicendiol and its analogs has been accomplished in moderate to good yield from 2-aryl-5-formly-7-methoxy-benzofurans through two simple, efficient approaches involving the application of Reformatsky reaction and Claisen condensation.

Full text of DOI:10.1080/00397911.2017.1285936

A Facile Synthesis of Naturally Occurring Nor-Lignans (±)-Machicendiol and its
Analogs
Kishor R. More1, R. S. Mali1
1Garware Research Centre, Department of Chemistry, University Of Pune, Pune, India
Corresponding authors Kishor R. More E-mail: kishor.more@ipca.com
Abstract
A facile synthesis of naturally occurring (±)-Machicendiol and analogs have been
accomplished in moderate to good yield from 2-aryl-5-formly-7-methoxy-benzofurans
via two simple, efficient approaches involving the application of Reformatsky reaction
and Claisen condensation.
Graphical Abstract
KEYWORDS: (±)-Machicendiol, Reformatsky reaction, Claisen condensation, β-
hydroxy esters, β-ketoesters
INTRODUCTION
(±)-Machicendiol 1, a nor-lignan isolated from the leaves of Machilus glaucescens has
been shown to be 2-(3,4-methylenedioxyphenyl)-5-(1,3-dihydroxypropyl)-7-
methoxybenzofuran on the basis of UV, IR and NMR spectral properties.1 The bark of
1

the Machilus glaucescens has been used in the treatment of asthma, tuberculosis and
rheumatism. The leaves of this plant are used in the treatment of ulcers.2 Hirano et al
have reported that (±)-Machicendiol show cytostatic activity against human leukemic
HL-60 cells.3 In view of its broad spectrum biological applications, several research
groups have reported the partial and total synthesis of (±)-Machicendiol. Careful
examination of those reported methods indicates that there are many drawbacks
associated with its synthesis like multistep reaction sequences, cross coupling reaction;
harsh reaction conditions.4-6 Due to this overall yield of desired compound is generally
very low. Therefore, more efficient and convenient method is highly desired.
Retrosynthetic analysis (Fig. 1) of (±)-Machicendiol indicates that it can be obtained
from β-hydroxyester 3a which in turn can either be obtained from 5-formylbenzofuran 2a
(Route 1) or from β-ketoester 5 which can also be prepared from 5-formylbenzofuran 2a
(Route 2). It is well known that Reformatsky reaction involves the formation of β-hyroxy
ester from ethyl haloacetates and aldehydes/ ketones.7 Considering the application of
Reformatsky reaction we projected the synthesis of β-hydroxyester 3a by the reaction of
aldehyde 2a with ethyl bromoacetate in presence of zinc dust. Conversion of this β-
hydroxyester 3a into (±)-Machicendiol can be easily achieved by using sodium
borohydride. Synthesis of Machicendiol via route 2 was accomplished by the
condensation reaction of aldehyde 2a with ethyl diazoacetate in the presence of activated
alumina to give β-ketoester 5 which on reduction with sodium borohydride directly
furnished natural product (±)-Machicendiol.
2

In this paper, we wish to present two simple and different approaches for the synthesis of
(±)-Machicendiol and analogs.
RESULTS AND DISCUSSION
Strategy visualized for the synthesis of Machicendiol 1 from aldehyde 2a is presented in
Scheme 1. The key step in the synthesis was the conversion of aldehyde 2a into β-
hydroxyester 3a using Reformatsky reaction. Aldehyde 2a was prepared as per the
methods reported in the literature.8 Aldehyde 2a was reacted with 3 equivalents of ethyl
bromoacetate in presence of zinc dust in the solvent mixture of benzene and ether at
temperature 50 °C. The reaction was completed in 2hr. β-hydroxyester 3a was obtained
as a solid product from the reaction mass on acidic workup with yield of 70%. The next
step is the conversion of β-hydroxyester 3a into (±)-Machicendiol. In first attempt we
used lithium aluminium hydride in diethyl ether at 0 °C. Though the reaction was
completed in 1 hr but due to the number of spots observed on TLC, the required product
was untraceable. This led us to do the reduction with an alternate reagent sodium
borohydride. The compound 3a was reacted with 0.086 equivalents of sodium
borohydride in monoglyme at 0 °C. The reaction was completed in 20 hr. Crude solid
product obtained after workup was subjected to column chromatography and a white
solid of (±)-Machicendiol was obtained in moderate yield ~66%. The structure of desired
compound 1 was confirmed on the basis of melting point, elemental analysis and PMR
spectral properties. As the synthesis of 1 was successfully achieved in good yield, it was
considered worthwhile to check the generality of this methodology. For this few more
3

derivatives (4b, 4c, and 4d) of (±)-Machicendiol were synthesized using similar reaction
conditions.
Second approach involves the formation of β-ketoester 5 by the Claisen condensation of
aldehyde 2a with ethyl diazoacetate (EDA). As per reported literature, the Lewis acid
catalyzed condensation is convenient as compared to thermally activated reactions. But
due to the limitation associated with Lewis acid catalyzed reactions like low yields and
toxicity of tin compounds, 9, 10 several surface mediated solid phase reactions have been
developed for such condensation reactions.11 We explored this methodology for the
synthesis of compound 1 from aldehyde 2a using EDA through a solvent free reaction on
the surface of activated alumina (Scheme 2).
For this purpose, EDA was prepared from glycine ester hydrochloride using reported
method.12 β-ketoester 5 was obtained in 65% yield on reaction of aldehyde 2a with 1.2
equivalents of EDA in chloroform at room temperature in presence of activated alumina
for 1 hr. Next target was the reduction of β-ketoester 5 directly into required compound 1.
This was achieved on using excess moles (5 moles) of sodium borohydride and
increasing reaction time up to 20 hr. The yield of (±)-Machicendiol 1 in this reaction was
found to be 70%.
(±)-Machicendiol 1 can also be converted into another nor-lignan named Machicenonol
6. So far only one method has been reported by Talapatra et al for this conversion in
which they have used Fetizon’s reagent.13 We thought of using manganese oxide for the
4

oxidation of benzylic hydroxyl and by reacting compound 1 with 10 equivalents of MnO2
in dichloromethane for 10 hr, we achieved required compound 6 in 65% yield (Scheme
3).
EXPERIMENTAL
General Procedure For The Preparation Of Compounds (3a-3d)
A solution of aldehyde (2a-2d; 1 mmol) and ethyl bromoacetate (2.9 mmol) in benzene:
ether (8:2) was added to zinc (previously dried at 100°C, 2.8 mmol). The reaction mixture
was refluxed for 0.5 hr., cooled to 5 °C and H2SO4 (5%, 10 mL) was added to it under
stirring. The organic layer was separated and the aqueous layer was extracted with
benzene (10 mL). The combined organic layer was washed with sodium bicarbonate
solution (2%, 10 mL) followed by water and the dried over (Na2SO4). The solvent was
removed under reduced pressure to give solid product, which was chromatographed over
silica gel using hexane: ethylacetate (9.5: 0.5) as an eluent to afford the ester 3a-3d.
General Procedure For The Preparation Of Compounds (1, 4b-4d)
Sodium borohydride (2.15 mmol) was added in lots to a well cooled solution (at 0 °C) of
ester 3a, 3b-3d (1.0 mmol) in monoglyme (10 mL). The reaction mixture was stirred and
allowed to come to room temperature and stirred for a further period of 20 hr. It was
quenched with ice cold water and dried (Na2SO4). The solvent was removed under
reduced pressure to give a crude solid product, which was chromatographed over silica
gel using hexane: ethylacetate (1: 1) as an eluent to furnish alcohol 1, 4b-4d.
5

Characteristic Data Of (±)-Machicendiol 1 And Machicenonol 6
1: m.p. 146-47 °C (lit4a. 148-149 °C). [Found: C, 66.60; H, 5.30 C19H18O6 requires C,
66.66; H, 5.23%]; 1H NMR (400MHz, DMSO-d6) δ 7.40-7.44(m, 2H), 7.25(s, 1H),
7.10(s, 1H), 7.04(d, 1H, J= 8Hz), 6.88(s, 1H), 6.09(s, 2H), 5.18(d, 1H, J= 4.4Hz), 4.72(t,
1H, J= 4Hz), 4.43(t, 1H, J= 4.6Hz ), 3.96(s, 3H), 3.51(t, 2H, J= 5.2Hz), 1.83-1.72(m,
2H); 13C NMR (100MHz, DMSO-d6) δ 155.7, 148.4, 148.3, 144.7, 143.3, 142.5, 130.6,
124.5, 130.6, 124.5, 119.2, 110.2, 109.3, 105.4, 101.9, 101.8, 70.4, 58.5, 56.2, 43.2;
IR(KBR); 3313 cm-1.
Preparation Of 2-(3,4-Methylenedioxyphenyl)-5-(1,3-Dihydroxypropyl)- 7-
Methoxybenzofuran [(±)-Machicendiol, 1 From Β-Ketoester 5]
Sodium borohydride (0.04g, 1.05 mmol) was added to a well cooled solution (0 °C) of
ester 5 (0.075 g, 0.196 mmol) in monoglyme (10 mL). The reaction mixture was stirred at
room temperature for 20 hr. Decomposed with ice cold water (10 mL) and extracted with
dichloromethane (3 x 10 mL). The combined organic layer was washed with water and
dried over Na2SO4. The solvent was removed under reduced pressure to give the crude
solid product, which was chromatographed over silica gel using hexane: ethyl acetate (1:
1) as an eluent to afford 1 (0.047g, 70%), m.p. 145-46 °C.
Preparation Of 2-(3,4-Methylenedioxyphenyl)-5-(1-Keto-3- Dihydroxypropyl)-7-
Methoxybenzofuran (Machicenonol, 6)
A mixture of 1 (0.02g, 0.058 mmol), manganese dioxide (0.026 g, 0.2 mmol) in
dichloromethane (5 mL) was refluxed for 10 hr. The reaction mixture was cooled to room
6

temperature and filtered. The solvent from the filtrate was removed under reduced
pressure and the residue obtained was chromatographed over silica gel using hexane:
ethylacetate (9: 1) as an eluent to give 6 (0.013 g, 65%), m.p. 173-74 °C (lit13. 175 °C).
[Found: C, 67.12; H, 4.85 C19H16O6 requires C, 67.05; H, 4.73%].1H NMR (400MHz,
DMSO-d6): δ 7.82(bs, 1H), 7.47(bs, 1H), 7.44(dd, 1H, J=1.5Hz, 8.4Hz), 7.34(d, 1H,
J=1.5Hz), 6.93(s, 1H), 6.90(d, J=8.4Hz, 1H), 6.04(s, 2H), 4.09(m, 5H), 3.30(t, J=5.4Hz,
2H), 1.70(bs, 1H, OH); 13C NMR (100MHz, DMSO-d6) δ 178.6, 153.8, 144.8, 148.3,
143.3, 142.7, 138.6, 130.5, 125.9, 110.3, 105.4, 102.8, 102.4, 70.4, 58.6, 56.5, 43.3;
IR(KBR); 3434, 1668cm-1.
CONCLUSION
Simple, efficient and distinct approaches have been described for the synthesis of natural
product (±)-Machicendiol. The present Reformatsky approach is general one and give
access to variously substituted (±)-Machicendiol analogs from the corresponding
aldehydes into moderate to good yield.
SUPPLEMENTARY INFORMATION
Full experimental details, 1H NMR data, IR data and 1H, 13C NMR spectra of final
compounds. This material can be found via the “Supplementary Content” section of this
article’s webpage.
REFERENCES
1.
Talapatra, B.; Ray, T.; Talapatra, S.K. Indian J. Chem. 1976, 14B, 613-614.
7

2.
Hooker, J.D. The Flora of British India; L. Reeve & Co., London, 1872; Vol. 1,
489.
3.
Hirano, T.; Gotoh, M.; Oka, K. Life Sci. 1994, 55, 1061-1069.
4.
(a) Schneiders, G.E.; Stevenson, R. J. Org. Chem. 1979, 44, 4710-4711; (b)
Rathke, M.W. J. Am. Chem. Soc. 1970, 92, 3222-3223; (c) Rathke, M.W.; Sullivan, D.F.
J. Am. Chem. Soc. 1973, 95, 3050-3051.
5.
K.; Ohta, A. Heterocycles, 1995, 41, 1077-1084.
6. a) Clough, J.M.; Mann, I.S.; Widdowson, A. Tetrahedron Lett. 1987, 28, 2645-
2648. b) Mann, I.S.; Widdowson, D.A. Tetrahedron, 1991, 47, 7981-7990.
Aoyagi, Y.; Mizusaki, T.; Hatori, A.; Asakura, T.; Aihara, T.; Inaba, S.; Hayatsu,
7.
8.
Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210-1211.
Choi, D.H.; Hwang, J.W.; Lee, H.S.; Yang, D. Mo.; Jun, J.- G. Bull. Korean
Chem. Soc. 2008, 29, 1594-1596.
9.
Holquist, C.R.; Rosekamp, E.J. J. Org. Chem. 1989, 54, 3258-3260.
10.
11.
Aparicio, F.J.; Herrera, F.J.; Fernandez, M.V. An. Quim. 1978, 74, 1561-1565.
(a) Posner, G.S. Angew. Chem. Int. Ed. Engl. 1978, 17, 487-496; (b) Cornellis, A.;
Laszio, P. Synthesis 1985, 909-918.
12.
13.
Serale, N.E. Org. Syn. 1963, Coll. Vol. IV, 424-426.
Talapatra, B.; Ray, T.; Talapatra, S.K. J. Ind. Chem. Soc. 1978, 55, 1204-1208.
8

Scheme 1. Reagents and conditions: a) BrCH2CO2Et, Zn, benzene, 80 C, 70-80% yield;
b) NaBH4, 0 C-rt, monoglyme, 50-80% yield
9

Scheme 2. Reagents and conditions: a) EDA, activated alumina, rt, 65% yield; b) NaBH4,
monoglyme, rt, 70% yield
10

Scheme 3. Reagents and conditions: a) MnO2, MDC, rt, 65% yield
11

Figure 1. Retrosynthesis of (±) Machicendiol
12