Syntheses and X-ray crystal structures of cassiferaldehyde and analogs

Article abstract of DOI:10.1080/00397911.2010.523921

Cassiferaldehyde, a recently discovered naturally occurring tyrosinase inhibitor, and six of its analogs, in which the aldehyde group has been replaced by various other functionalities, have been synthesized by a short and simple sequence starting from 2,

Full text of DOI:10.1080/00397911.2010.523921

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Syntheses and X-Ray Crystal Structures
of Cassiferaldehyde and Analogs
Jessica L. Levasseur a & Dasan M. Thamattoor a
a Department of Chemistry, Colby College, Waterville, Maine, USA
Accepted author version posted online: 18 Jul 2011.Published
online: 14 Sep 2011.
To cite this article: Jessica L. Levasseur & Dasan M. Thamattoor (2012): Syntheses and X-Ray Crystal
Structures of Cassiferaldehyde and Analogs, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:2, 292-298
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Synthetic Communications1, 42: 292–298, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523921
SYNTHESES AND X-RAY CRYSTAL STRUCTURES
OF CASSIFERALDEHYDE AND ANALOGS
Jessica L. Levasseur and Dasan M. Thamattoor
Department of Chemistry, Colby College, Waterville, Maine, USA
GRAPHICAL ABSTRACT
Abstract Cassiferaldehyde, a recently discovered naturally occurring tyrosinase inhibitor,
and six of its analogs, in which the aldehyde group has been replaced by various other
functionalities, have been synthesized by a short and simple sequence starting from 2,3-
dihydroxybenzaldehyde. Single-crystal x-ray structures of cassiferaldehyde as well as its
methyl ketone, nitrile, and carboxylic acid analogs are reported.
Keywords Alkylation; bioorganic chemistry; natural products; phenols; Wittig reaction
INTRODUCTION
Cinnamomum cassia Blume (Lauraceae), which is widely distributed in East
Asia, has been a source of many natural products with a broad range of biological
activity.[1] The twigs of this species have been used in traditional Chinese medicine to
treat a variety of ailments.[2] In the course of a study to screen plants for tyrosinase
inhibition, it was recently reported that the methanolic extract of the twigs of
C. cassia afforded several new phenolics including cassiferaldehyde (3a), which
was found to be a potent inhibitor of the enzyme.[3] Tyrosinase is known to play a
key role in the synthesis of melanin and has been implicated as a participant in
the oxidative stress chemistry that leads to Parkinson’s disease.[4] Thus, tyrosinase
inhibitors appear to offer the potential for treating this debilitating ailment which,
after Alzheimer’s, is the most common neurodegenerative disorder, affecting about
1–2% of the population more than 65 years of age.[5]
Herein we report a simple syntheses of cassiferaldehyde and analogs
in which the aldehyde functionality has been substituted by ketone, ester,
Received August 17, 2010.
Address correspondence to Dasan M. Thamattoor, Department of Chemistry, Colby College,
Waterville, ME 04901, USA. E-mail: dmthamat@colby.edu
292

CASSIFERALDEHYDE AND ANALOGS
293
Scheme 1. Syntheses of cassiferaldehyde and analogs.
nitrile, and carboxylic acid groups, starting from 2,3-dihydroxybenzaldehyde (1,
Scheme 1). In the first step, the procedure of Boger and coworkers was used to selec-
tively methylate the hydroxy group that is ortho to the aldehyde to afford
3-hydroxy-2-methoxybenzaldehyde (2).[6] This selectivity is made possible by the
ortho hydroxy group having a lower pKa than the one that is meta.[7] In the sub-
sequent step, we adapted a recently published procedure8 to react 2 with a host of
stable, commercially available Wittig reagents bearing electron-withdrawing groups
to obtain 3a–3f. The carboxylic acid derivative 3g was prepared by hydrolyzing the
methyl ester analog 3d. After purification by column chromatography, the (unopti-
mized) yields for the Wittig reactions ranged from 34% for cassiferaldehyde (3a) to
89% for the ethyl ester analog 3e. The melting point of cassiferaldehyde that we pre-
pared (119–122 ꢀC) was higher than that reported in the literature (78–80 ꢀC).[3] It
should be noted, however, that our material was crystalline, whereas the naturally
occurring version was an amorphous powder.[3] In all cases, except for 3f
1
(R CN), an analysis of the H NMR spectra of the crude products revealed an over-
=
whelming preference for the E isomers. In the case of 3f, however, the Z isomer was
favored over E by a margin of 2:1.
Slow diffusion of pentane into a solution of 3a in dichloromethane provided
crystals suitable for analysis by x-ray crystallography.[9] The same approach was
used to grow crystals of 3b. Slow evaporation of the fractions from column chroma-
tography (1:9 ethyl acetate–hexanes) also provided single crystals of 3f appropriate
for structure determination. We were unable, however, to crystallize the phenyl
ketone analog 3c and the two esters, 3d and 3e, which were viscous oils. Refluxing
the methyl ester analog (3d) in aqueous sodium hydroxide followed by an acidic
workup did afford the solid carboxylic acid derivative 3g. Recrystallization of 3g
from chloroform-ethyl acetate gave crystals amenable to x-ray analysis. The crystal
structures of these four compounds are shown in Figure 1.[10] Some of the key crys-
tallographic parameters are shown in Table 1. In all four structures the E stereo-
chemistry about the double bond is evident and the methoxy group is twisted
away from the plane of the aryl ring.

294
J. L. LEVASSEUR AND D. M. THAMATTOOR
Figure 1. X-ray crystal structures of cassiferaldehyde (3a), and its methyl ketone (3b), nitrile (3f), and
carboxylic acid (3g) analogs.
Table 1. Selected crystallographic data for 3a, 3b, 3f, and 3g
Entry
3a
3b
3f
3g
Chemical formula
Formula weight
Crystal system
Space group
Unit cell
C
178.8
10H10O3
C11H12O3
192.21
Triclinic
P-1
C10H9NO2
175.18
Monoclinic
C10H10O4
194.18
Triclinic
P-1
Monoclinic
P2(1)
P2(1)=c
˚
˚
˚
˚
a ¼ 6.54 A,
a ¼ 6.73 A,
a ¼ 7.28 A,
a ¼ 4.90 A,
dimensions
a ¼ 90ꢀ
a ¼ 69.14ꢀ
a ¼ 90ꢀ
a ¼ 80.74ꢀ
˚
˚
˚
˚
b ¼ 6.68 A,
b ¼ 7.84 A,
b ¼ 8.27 A,
b ¼ 7.45 A,
b ¼ 91.06ꢀ
b ¼ 76.63ꢀ
b ¼ 91.37ꢀ
b ¼ 85.68ꢀ
˚
˚
˚
˚
c ¼ 9.87 A,
c ¼ 10.32 A,
c ¼ 14.84 A,
c ¼ 13.01 A,
c ¼ 90ꢀ
c ¼ 86.45ꢀ
c ¼ 90ꢀ
c ¼ 79.87ꢀ
[3]
˚
[3]
˚
[3]
˚
[3]
˚
Volume
Z
431.1 A
2
494.2 A
2
893.0 A
4
460.59 A
2
Final R indices
[I > 2sigma(I)]
R indices (all data)
R1 ¼ 0.0295,
wR2 ¼ 0.0779
R1 ¼ 0.0300,
wR2 ¼ 0.0782
R1 ¼ 0.0470,
wR2 ¼ 0.1226
R1 ¼ 0.0641,
wR2 ¼ 0.1364
R1 ¼ 0.0446,
wR2 ¼ 0.1263
R1 ¼ 0.0481,
wR2 ¼ 0.1318
R1 ¼ 0.0436,
wR2 ¼ 0.1190
R1 ¼ 0.0535,
wR2 ¼ 0.1295

CASSIFERALDEHYDE AND ANALOGS
295
EXPERIMENTAL
General Procedure for Syntheses of 3a–3f
3-Hydroxy-2-methoxybenzaldehyde[6] (2, 1 mmol) and the Wittig reagent (1.2
equivalents) in toluene (1 mL) were magnetically stirred and heated in an oil bath,
which was maintained at 80 to 85 ꢀC, for 1 h. After evaporation of solvent, the
reaction mixture was subjected to flash chromatography over silica gel using ethyl
acetate–hexanes (1:9) as eluent. In all cases, except 3f, fractions containing the pure
E isomers were obtained initially followed by later fractions that also included minor
amounts of Z (in addition to E, which was predominant). In the case of the cyano
analog 3f, the E and Z isomers, which were formed in comparable amounts, could
be separated and purified individually. Yields and characterization data are given.
Cassiferaldehyde (3a)
Yellow solid; yield: 34%; mp: 119–122 ꢀC (lit.[3] 78–80 ꢀC); 1H NMR (500 MHz,
CDCl3): 9.74 (d, J ¼ 7.7 Hz, 1H), 7.71 (d, J ¼ 16.1 Hz, 1H), 7.19–7.00 (m, 3H), 6.79
(dd, J ¼ 16.1, 7.7 Hz, 1H), 5.80 (s, 1H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3):
194.1, 149.5, 146.9, 146.4, 130.1, 127.5, 125.4, 119.8, 118.7, 62.4; FTIR (ATR): 3335,
2840, 1661, 1646, 1134 cmꢁ1; MS (EI, 70 eV): m=z ¼ 178, 147, 107. Anal. calcd. for
C10H10O3: C, 67.41; H, 5.66. Found: C, 67.15; H, 5.86.
Methyl Ketone Analog (3b)
Colorless solid; yield: 69%; mp: 107–109 ꢀC; 1H NMR (500 MHz, CDCl3): 7.76
(d, J ¼ 16.4 Hz, 1H), 7.15–7.08 (m, 1H), 7.06–7.01 (m, 2H), 6.78 (d, J ¼ 16.4 Hz, 1H),
6.16 (s, 1H), 3.84 (s, 3H), 2.41 (s, 3H); 13C NMR (126 MHz, CDCl3): 198.9, 149.5,
146.6, 137.8, 128.5, 127.9, 125.2, 119.3, 118.0, 62.3, 27.5; FTIR (ATR): 3088,
1670, 1621, 1264 cmꢁ1; MS (EI, 70 eV): m=z ¼ 192, 177, 161, 134. Anal. calcd. for
C11H12O3: C, 68.74; H, 6.29. Found: C, 68.84; H, 6.48.
Phenyl Ketone Analog (3c)
1
Colorless oil; yield: 68%; H NMR (500 MHz, CDCl3): 8.08–7.97 (m, 3H),
7.68–7.57 (m, 2H), 7.55–7.47 (m, 2H), 7.25–7.19 (m, 1H), 7.11–7.00 (m, 2H), 5.87
(s, 1H), 3.85 (s, 3H); 13C NMR (126 MHz, CDCl3): 190.6, 149.5, 146.7, 139.1,
138.1, 132.9, 128.7, 128.5, 128.4, 125.2, 123.7, 119.8, 117.7, 62.4; FTIR (film):
3368, 1659, 1582, 1285 cmꢁ1; MS (EI, 70 eV): m=z ¼ 254, 223, 165, 134. Anal. calcd.
for C16H14O3: C, 75.57; H, 5.55. Found: C, 75.37; H, 5.83.
Methyl Ester Analog (3d)
1
Colorless oil; yield: 68%; H NMR (500 MHz, CDCl3): 7.89 (d, J ¼ 16.1 Hz,
1H), 7.04 (m, 3H), 6.51 (d, J ¼ 16.1 Hz, 1H), 5.77 (s, 1H), 3.82 (2 overlapping
singlets, 6H); 13C NMR (126 MHz, CDCl3): 167.5, 149.3, 146.3, 139.1, 127.8,
125.2, 119.6, 119.5, 117.5, 62.4, 51.8; FTIR (film): 3396, 1698, 1634, 1286 cmꢁ1
;

296
J. L. LEVASSEUR AND D. M. THAMATTOOR
MS (EI, 70 eV): m=z ¼ 208, 177, 162, 134. Anal. calcd. for C11H12O4: C, 63.45; H,
5.81. Found: C, 63.62; H, 6.08.
Ethyl Ester Analog (3e)
1
Colorless oil; yield: 89%; H NMR (500 MHz, CDCl3): 7.88 (d, J ¼ 16.1 Hz,
1H), 7.14–6.89 (m, 3H), 6.51 (d, J ¼ 16.1 Hz, 1H), 5.77 (s, 1H), 4.28 (q, J ¼ 7.1 Hz,
2H), 3.83 (s, 3H), 1.35 (t, J ¼ 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): 167.0,
149.3, 146.3, 138.8, 127.9, 125.1, 120.1, 119.5, 117.4, 62.4, 60.6, 14.3; FTIR (film):
3392, 1712, 1633, 1286 cmꢁ1; MS (EI, 70 eV): m=z ¼ 222, 191, 177, 163. Anal. calcd.
for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.98; H, 6.77.
Nitrile Analog (3f)
Colorless solid; yield: 86%.
E Isomer. Mp: 149–151 ꢀC; 1H NMR (500 MHz, CDCl3): 7.58 (d, J ¼ 16.8 Hz,
1H), 7.13–6.92 (m, 3H), 6.01 (d, J ¼ 16.8 Hz, 1H), 5.61 (s, 1H), 3.82 (s, 3H).
13C NMR (126 MHz, CDCl3): 149.4, 145.9, 145.2, 127.0, 125.5, 119.0, 118.6,
118.2, 98.2, 62.3; FTIR (ATR): 3291, 2228, 1610, 1581, 1283 cmꢁ1; MS (EI,
70 eV): m=z ¼ 175, 160, 147, 132.
1
Z Isomer. Mp: 57–60 ꢀC; H NMR (500 MHz, CDCl3): 7.66 (d, J ¼ 7.8 Hz,
1H), 7.44 (d, J ¼ 12.2 Hz, 1H), 7.18–7.00 (m, 2H), 5.69 (s, 1H), 5.54 (d, J ¼ 12.2 Hz,
1H), 3.80 (s, 3H); 13C NMR (126 MHz, CDCl3): 149.0, 145.9, 142.9, 127.1, 125.3,
119.8, 118.5, 117.1, 96.7, 62.7; FTIR (ATR): 3352, 2925, 2226, 1613, 1568,
1210 cmꢁ1; MS (EI, 70 eV): m=z ¼ 175, 160, 147, 132.
Anal. calcd. for C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found (for E=Z mix):
C, 68.63; H, 5.52; N, 7.69.
Carboxylic Acid Analog 3g
An E=Z mixture (3:1) of the methyl ester analog (3d, 296 mg, 1.4 mmol) was
refluxed for 1 h in 2.5 M aqueous NaOH. The reaction mixture was cooled and
extracted with ether (15 mL), and the aqueous layer was acidified with 6 M aqueous
HCl. The carboxylic acid was extracted from the aqueous layer with ether (3 ꢂ 25 mL),
and this second set of ether extracts was combined, washed with water, and freed of
solvent to obtain a white solid. Recrystallization of this solid from aqueous ethanol
gave 3g as the E isomer.
Colorless solid; yield: 53%; mp: 217–220 ꢀC.
1H NMR (500 MHz, DMSO-d6): d ¼ 12.36 (s, 1H), 9.57 (s, 1H), 7.77 (d,
J ¼ 16.2 Hz, 1H), 7.15 (d, J ¼ 7.4, 1H), 7.00–6.85 (m, 2H), 6.46 (d, J ¼ 16.1 Hz, 1H),
3.74 (s, 3H); 13C NMR (126 MHz, DMSO-d6): d ¼ 168.2, 150.9, 147.1, 139.0, 128.3,
124.7, 120.2, 119.1, 118.2, 61.0; FTIR (ATR): 3412, 2602, 1684, 1622, 1201 cmꢁ1
;
MS (EI, 70 eV): m=z ¼ 194, 177, 163, 147, 134. Anal. calcd. for C10H10O4: C, 61.85;
H, 5.19. Found: C, 61.79; H, 5.16.

CASSIFERALDEHYDE AND ANALOGS
297
General Procedure for X-Ray Structure Determination
X-ray data were collected at 173 K for 3a and 3b, and ambient temperature
for 3f and 3g, on a Bruker Smart Apex charge-coupled device (CCD) diffractometer
˚
using graphite monochromated Mo Ka radiation (c ¼ 0.71073 A) and processed with
the Bruker Apex2 suite of programs.[11] The frames were integrated with the Bruker
SAINT software package using a narrow-frame algorithm. Data were corrected for
absorption effects using the multiscan method (SADABS).[12] All structures were
solved by direct methods and refined by full-matrix least-squares on F2, using the
Bruker SHELXTL software package.[11,13] All nonhydrogen atoms were refined ani-
sotropically, and the hydrogens were calculated on a riding model. The software pro-
gram enCIFer[14] was used in conjunction with the checkCIF=Platon facility of the
International Union of Crystallography to validate cif files. Crystallographic data
(excluding structure factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre and assigned the following deposition
numbers: CCDC 771896, 771897, 771898, and 771899 for 3a, 3b, 3f, and 3g respect-
ively. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
ACKNOWLEDGMENT
We thank the National Science Foundation for supporting this work through
Grant No. CHE-0719335.
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