Concise synthesis of pentenyl phenyl acrylic acid

Article abstract of DOI:10.1080/00397910701473333

Pentenyl phenyl acrylic acid is a structural unit of pepticinnamin E, a natural product and a bisubstrate inhibitor of FPTase. In this article, a new synthetic strategy was developed to prepare pentenyl phenyl acrylic acid with high stereoselectivity and

Full text of DOI:10.1080/00397910701473333

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Concise Synthesis of Pentenyl Phenyl Acrylic
Acid
Dequn Sun a , Pengxiang Lai a , Weidong Xie a , Jingen Deng b & Yaozhong
Jiang b
a Marine College, Shandong University at Weihai , China
b Chengdu Institute of Organic Chemistry , CAS, China
Published online: 30 Aug 2007.
To cite this article: Dequn Sun , Pengxiang Lai , Weidong Xie , Jingen Deng & Yaozhong Jiang (2007) Concise
Synthesis of Pentenyl Phenyl Acrylic Acid, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:17, 2989-2994, DOI: 10.1080/00397910701473333
To link to this article: http://dx.doi.org/10.1080/00397910701473333
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Synthetic Communicationsw, 37: 2989–2994, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701473333
Concise Synthesis of Pentenyl Phenyl
Acrylic Acid
Dequn Sun, Pengxiang Lai, and Weidong Xie
Marine College, Shandong University at Weihai, China
Jingen Deng and Yaozhong Jiang
Chengdu Institute of Organic Chemistry, CAS, China
Abstract: Pentenyl phenyl acrylic acid is a structural unit of pepticinnamin E, a natural
product and a bisubstrate inhibitor of FPTase. In this article, a new synthetic strategy
was developed to prepare pentenyl phenyl acrylic acid with high stereoselectivity and
high overall yield of 78.6%. The method used in producing these effects involved the
application of a five-step procedure. Pentenyl phenyl acrylic acid was synthesized
starting from 2-iodo-benzyl alcohol through an E-selective Wittig–Horner reaction,
and then the Sonogashira reaction was used to produce 2-(1-pentynyl)-E-ethyl-cinna-
moylate, which was quantitatively hydrogenated, catalyzed by Lindlar catalyst.
Keywords: pentenyl phenyl acrylic acid, quantitative hydrogenation, Sonogashira
reaction, stereoselectivity, Wittig–Horner reaction
INTRODUCTION
Pepticinnamin E[1] was isolated from Sereptomyces OH-4652, which was
identified as the potent FPTase inhibitor and was first synthesized by
Waldmann and his group.[2] Their research proved the S configuration at the
central new 3,4-dihydroxy-D-L-phenylalanine (DOPA) analog and also
showed that pepticinnamin E is a bisubstrate inhibitor. Until now, pepticinna-
min E has been the only bisubstrate inhibitor produced from nature. There are
two components in the structure of pepticinnamin E: one component is the
Received in China October 5, 2006
Address correspondence to Dequn Sun, Marine College, Shandong University at
Weihai, China. E-mail: dequn.sun@sdu.edu.cn
2989

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D. Sun et al.
pentenyl phenyl acrylic acid, and the other is the new DOPA analog. Devel-
oping new methods to synthesize the two components is necessary to
complete the synthesis of pepticinnamin E. These new methods are also
important for the study of the structure–activity relationship between pepti-
cinnamin E and the inhibitivity to FPTase. Our work emphasis was focused
on the preparation of both DOPA analog and o-(Z-pentenyl)cinnamic acid 15.
RESULTS AND DISCUSSION
The synthesis of pentenyl phenyl acrylic acid reported by Waldmann started
from benzoic acid, using a trans-selective Knoevenagel condensation and a
cis- selective Wittig’s reaction, which needed to be performed at 21008C to
obtain diastereomerical purity (de ¼ 84%). By using a five-step sequence, the
target compound acrylic acid was synthesized with an overall yield of 38%.[2a]
In our study, we developed a new method for the preparation of pentenyl
phenyl acrylic acid, which apparently improved the overall yield toward the
target compound 15. First, the key Sonogashira reaction was used for
obtaining 2 quantitatively, followed by oxidation to yield aldehyde 3.
Wittig’s reaction with phosphonium and butyllithium then gave a high
E-selective product 4, which was treated with a base to provide arylacetylene
5 with 35–41% yield. Alkylation of 5 was investigated under different con-
ditions and was ultimately considered to be the steric effect of the tert-butox-
ycarbonylvinyl group as shown in Scheme 1.
The hydroxy group of 2-iodobenzyl alcohol 1 was then protected with the
tetrahydropyran (THP) group to give 7. Then 7 was coupled with 2-methyl-3-
Scheme 1. Organic synthesis of control compounds.

Pentenyl Phenyl Acrylic Acid
2991
Scheme 2. Organic synthesis of control compounds.
butyn-2-ol using the Sonogashira reaction catalyzed by palladium to give 8, and
the acetone was subsequently removed from 8 with sodium hydride to yield ary-
lacetylene 9. However, the propylation of 9 to afford the desired compound 10
was unfortunately unsuccessful under different basic conditions (Scheme 2).
Because the steric effect for propylation of 5 and 9 could not be avoided,
the Sonogashira reaction was used to form the alkyne directly. Then, the
synthetic route in Scheme 3 was developed to obtain the target compound
15. The procedure started with an E-selective Wittig–Horner reaction[3] to
obtain 12 with nearly quantitative yield and excellent stereoselectivity
(.99%). Next, the key Sonogashira reaction[4] was used to form the alkyne
13. After this, a quantitative hydrogen reduction was catalyzed by Lindlar
catalyst[5] to give 14. Finally, hydrolysis was used to afford the target
compound 15 with an overall yield of 78.6%.
Scheme 3. Organic synthesis of target compound.

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D. Sun et al.
CONCLUSION
In summary, we reported a new synthetic route for the preparation of an
important component of pepticinnamin E, the pentenyl phenyl acrylic acid,
based on the Sonogashira reaction and quantitative hydrogen reduction
catalyzed by Lindlar catalyst with an overall yield of 78.6% for five steps.
This strategy permits the preparation of analogs of pentenyl phenyl acrylic
acid from different alkynyl compounds.
EXPERIMENTAL
Melting points were determined with a Electrothermal digital melting-point
apparatus and were uncorrected. Optical rotations were recorded on a
Perkin-Elmer model 341 polarimeter, at the sodium D line. Elemental
analyses were recorded on Carlo-1106 model automatic instrument. Infrared
1
spectra (IR) were run on Nicolet MX-1 and Nicolet-560 Magna. H NMR
and spectra were run either on Bruker-200, Bruker-300, or Varian-400 instru-
ments at 258C; 13C NMR was given by Bruker-200 instrument at 258C. MS-EI
mass spectra were obtained on a V.G. 7070E instrument.
All solvents were handled in the standard ways before use.
2-Iodo-E-ethyl-cinnamoylate (12)
To a solution of 2-iodobenzyl alcohol 1 (1.40 g, 6.0 mmol) in 50 ml of dry
CH2Cl2, fresh MnO2 (4.43 g, 51 mmol) was added. The reaction mixture
was refluxed for 6 h, then filtered. The filtrate was concentrated in vacuo to
give 2-iodobenzaldehyde 11 as a slightly yellow solid (1.25 g, yield 90%,
mp 40–418C). IR (KBr): n ¼ 1693, 1650, 1583, 1445, 1395, 1010, 760 cm21
.
To a suspension of NaH (0.3 g, 7.5 mmol) in 25 ml of dry CH2Cl2, (EtO)2-
P(O)CH2COOEt (1.1 ml, 5.5 mmol) was added dropwise at 08C. After
stirring for 5 min, the solution of 11 (1.16 g, 5 mmol) in 20 ml of dry
CH2Cl2 was added dropwise, and then the reaction mixture was kept
stirring at 08C for 30 min. Then the reaction mixture was carefully diluted
with 10 ml of cold water. The aqueous layer was extracted three times with
CH2Cl2, and the combined organic phase was dried over Na2SO4 and concen-
trated in vacuo to give 12 as slightly yellow slurry (solidified under 08C),
(0.298 g, yield 98.7%). C11H11IO2 (302.1): calcd. C, 43.73; H, 3.67; found
1
C, 43.71; H, 3.64. IR (neat): n ¼ 1713, 1635, 1313, 1178 cm21. H NMR
(200 MHz, CDCl3): d ¼ 7.91 (d, J ¼ 16 Hz, 1H, CH55), 7.90 (d, J ¼ 9.4 Hz,
1H, Ar-H), 7.55 (d, J ¼ 9.4 Hz, 1H, Ar-H), 7.34 (t, J ¼ 7.6 Hz, 1H, Ar-H),
7.04 (t, 1H, J ¼ 7.6 Hz, Ar-H), 6.30 (d, J ¼ 16 Hz, 1H, 55CH), 4.30
(q, J ¼ 7.2 Hz, 2H, OCH2), 1.34 (t, J ¼ 7.2 Hz, 1H, CH3) ppm. MS-EI
(m/z): 302 (Mþ).

Pentenyl Phenyl Acrylic Acid
2993
2-(1-Pentynl)-E-ethyl-cinnamoylate (13)
To a suspension of Ph3P (5.0 mg, 0.0191 mmol), Pd(Ph3P)4 (10 mg,
0.00865 mmol), CuI (0.906 g, 3.00 mmol), and 12 in 3 ml of dry THF, 6 ml
of iPr2NH and 1-pentyne (0.50 ml, 5.0 mmol) were added at room tempera-
ture; the reaction mixture was kept stirring for 10 min, then stirred at 538C
for 10 min. The reaction mixture was filtered to remove the white solid and
washed with EtOAc. The filtrate was concentrated in vacuo, and the residue
was diluted with EtOAc, then washed sequentially with cold 0.1 N HCl to
pH , 7 (sat. NaCl to pH ¼ 7). The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo to give crude product, which was
purified by chromatography (eluted with petr./ethyl acetate, 30:1) to afford
13 as a slightly yellow slurry (0.668 g, yield 92%). C16H18O2 (242.3) calcd.
C, 79.31; H, 7.49; found C, 79.34; H, 7.44. IR (neat): n ¼ 3040, 2965,
2933, 2210, 1714, 1635, 1267, 1194, 1177 cm21 1H NMR (200 MHz,
.
CDCl3): d ¼ 8.2 (d, J ¼ 16 Hz, 1H, CH55), 7.63–7.24 (m, 4H, Ar-H), 6.51
(d, J ¼ 16 Hz, 1H, CH55), 4.27 (q, J ¼ 7.1 Hz, 2H, OCH2), 2.46
;;
(t, J ¼ 7.0 Hz, 2H,
CCH2), 1.70 (m, 2H, CH2), 1.34 (t, J ¼ 7.1 Hz, 3H,
CH3), 1.13 (t, J ¼ 7.3 Hz, 3H, CH3) ppm. MS-EI (m/z): 242 (Mþ).
2-(1-Z-Pentenyl)-E-ethyl-cinnamoylate (14)
To a solution of compound 13 (0.242 g, 1.0 mmol) in 12 ml of dry CH3OH,
Lindlar catalyst (0.242 g, 100% wt) was added. Then the equal molar of
hydrogen was bubbled up into the reaction suspension with stirring at room
temperature. The reaction process was monitored carefully by thin-layer
chromatography (TLC) (n-hexane/ethyl acetate). The catalyst was removed
by filtration, and the filtrate was concentrated in vacuo to give crude
product, which was purified by chromatography (eluted gradually with
n-hexane/ethyl acetate) to afford 14 as slightly yellow slurry (0.228 g, yield
98.3% based on recovered starting material, 12 mg of 13). C16H20O2
(244.3): calcd. C, 78.65; H, 8.25; found C, 78.69; H, 8.20. IR (neat):
n ¼ 3010, 2960, 2936, 1716, 1632, 1311, 1269, 1174 cm21
.
1H NMR
(400 MHz, CDCl3): d ¼ 7.84 (d, J ¼ 16 Hz, 1H, CH55), 7.11–7.65 (m, 4H,
Ar-H), 6.44 (d, J ¼ 12.0 Hz, 1H, CH55), 6.29 (d, J ¼ 16 Hz, 1H, CH55),
5.78 (d, J ¼ 12.0 Hz, 1H, CH55), 4.18 (q, J ¼ 7.1 Hz, 2H, OCH2), 1.97
(m, 2H, CH2), 1.39 (m, 2H, CH2), 1.26 (t, J ¼ 7.1 Hz, 3H, CH3), 0.79
(t, J ¼ 7.2 Hz, 3H, CH3) ppm. MS-EI (m/z): 244 (Mþ).
2-(1-Z-Pentenyl)-E-cinnamic Acid (15)
To a solution of compound 14 (152 mg, 0.622 mmol) in 2 ml of ethyl alcohol,
.
LiOH H2O (111 mg, 2.5 mmol) was added at 08C and then stirred for 19 h at

2994
D. Sun et al.
room temperature. The reaction mixture was acidified at 08C with 0.1 N HCl
to pH ¼ 3.5 and extracted four times with EtOAc. The combined organic layer
was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude
white product, which was recrystallized two times from n-hexane/ethyl
acetate to afford 15 as a white solid (132 mg, yield 97.8%). Mp 99–1018C.
C14H16O2 (216.3): calcd. C, 77.75; H, 7.46; found: C, 77.78; H, 7.41. IR
(KBr): n ¼ 3500, 3005, 2957, 2929, 1687, 1623, 1331, 1223 cm21
.
1H
NMR (200 MHz, CDCl3): d ¼ 8.0 (d, J ¼ 8.0 Hz, 1H, CH55), 7.65–7.22
(m, 4H, Ar-H), 6.55 (d, J ¼ 11.6 Hz, 1H, CH55), 6.41 (d, J ¼ 16.0 Hz, 1H,
CH55), 5.86 (m, 1H, CH55), 2.02 (m, 2H, CH2), 1.38 (m, 2H, CH2), 0.86
(t, J ¼ 6.8 Hz, 3H, CH3) ppm. 13C NMR (200 MHz, CDCl3): d ¼ 172.5
(C55O), 145.5 (HC55), 138.8, 135.4, 132.4, 130.4, 130.1, 130.0 (Ar-C),
127.2, 126.7, 126.6, 117.9 (HC55), 31.4 (CH2), 22.6 (CH2), 13.8 (CH3)
ppm. MS-EI (m/z): 216 (Mþ).
ACKNOWLEDGMENT
The authors thank the Chengdu Institute of Organic Chemistry, CAS, and
Shandong University at Weihai for financial support.
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