A new entry to the synthesis of primin via a B-alkyl suzuki-miyaura cross-coupling reaction

Article abstract of DOI:10.3987/COM-12-S(N)104

Primin, a biologically active benzoquinone natural product, was efficiently synthesized in 56% overall yield in six steps starting from commercially available 5-iodovanillin. The synthetic method involves crucial steps, including a B-alkyl Suzuki-Miyaura

Full text of DOI:10.3987/COM-12-S(N)104

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 985 - 989. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2012, Accepted, 17th August, 2012, Published online, 28th August, 2012
DOI: 10.3987/COM-12-S(N)104
A NEW ENTRY TO THE SYNTHESIS OF PRIMIN VIA A B-ALKYL
SUZUKI–MIYAURA CROSS-COUPLING REACTION
Kazuhiro Watanabe, Tomohiro Sugizaki, Yumi Tozawa, and Tadashi
Katoh*
Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical
Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,
Sendai 981-8558, Japan. E-mail: katoh@tohoku-pharm.ac.jp
Dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday
Abstract – Primin, a biologically active benzoquinone natural product, was
efficiently synthesized in 56% overall yield in six steps starting from
commercially available 5-iodovanillin. The synthetic method involves crucial
steps, including a B-alkyl Suzuki–Miyaura cross-coupling reaction to directly
install an alkyl side chain in an aromatic ring and elaboration of quinone
functionality by degradative oxidation using Fremy’s salt to yield the target primin.
Primin, 2-methoxy-6-pentyl-1,4-benzoquinone (1) (Figure 1), was first isolated as the allergenic principle
of the plant Primula obconia.1 Subsequently, this natural product was also isolated from the plant
Miconia sp.2 and the fungus Botryosphaeria sp.3 In 2001, Kingston et al. reported the isolation of 1 from
the plant Miconia lepidota collected from the Suriname rainforest.4 This substance was found to exhibit
antiproliferative activity against M109 murine lung cancer cells (IC50 = 10 !g/mL) and A2780 human
ovarian cancer cells (IC50 = 2.9 !g/mL).4 It has also been reported that primin displays antibacterial
activity against Staphylococcus aureus (ATTC 25923) and methicillin-resistant Staphylococcus aureus
(MRSA) with equal MIC values of 8 !g/mL.5
O
1
MeO
2
Me
6
5
3
4
O
primin (1)
Figure 1. Structure of primin (1)

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HETEROCYCLES, Vol. 86, No. 2, 2012
In the course of our continuing research on the synthesis of biologically active quinoid natural products,6
we became interested in the synthesis of primin and its analogues with the aim of searching for potential
anticancer agents. Several reports on the synthesis of primin have been published to date,4,7 which
involved strategic methods for the introduction of the alkyl side chain at the aromatic nucleus and the
formation of the 1,4-benzoquinone moiety via oxidation of hydroquinone or phenol derivatives. However,
some of these syntheses required severe and/or difficult reaction conditions, the yields were often
unsatisfactory, and several of these methods are limited by the nature of the substituent in the aromatic
rings. Therefore, we investigated an alternative, more flexible, and reliable method for the synthesis of
primin, as well as its analogues. In this paper, we describe our results on the synthesis of primin using a
B-alkyl Suzuki–Miyaura cross-coupling reaction8 and degradative phenol oxidation9 as the key steps.
Our synthetic plan for primin (1) is outlined in Scheme 1. We envisioned that the target molecule 1 could
be derived from phenolic compound 2 by its oxidative degradation to the corresponding quinone.9
Intermediate 2 with the requisite alkyl side chain and appropriate functional groups was to be prepared
via the B-alkyl Suzuki–Miyaura cross-coupling reaction8 between aryl iodide 3, which is accessible from
5-iodovanillin (5), and organoborane 4. To the best of our knowledge, the utilization of the direct
alkylation method (cf. 3 + 4 ! 2) for synthesizing 1 is unknown to date, and thus, this approach posed a
challenge from the viewpoint of synthesis.
O
OR
MeO
Me
MeO
Me
O
X
2
primin (1)
OR
MeO
I
Me
+
B
4
X
3
OH
MeO
I
R = H or protective group
O
CHO
X = CH2OH or
O
5
Scheme 1. Synthetic plan for primin (1)

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987
As shown in Scheme 2, the synthesis commenced with protection of the phenolic hydroxy group in
commercially available 5-iodovanillin (5) to give the corresponding benzyl (Bn) ether 6 in 86% yield.
Initial attempts to realize the B-alkyl Suzuki–Miyaura cross-coupling reaction of 6 and organoborane 4
[prepared in situ by hydroboration of 1-pentene with 9-borabicyclo[3.3.1]nonane (9-BBN)] resulted in an
unsatisfactory yield of the coupling product (ca. ~50%). Therefore, we decided to conduct this
cross-coupling reaction after protecting the sensitive formyl group in 6 as the ethylene acetal 7 (88%). As
a result, the critical cross-coupling reaction of 7 with 4 proceeded smoothly and cleanly under the
optimized conditions [PdCl2(dppf) (5 mol%), Cs2CO3, THF, reflux, 30 min]; the desired coupling product
810 was obtained in high yield (92%). Subsequent acidic hydrolysis of the ethylene acetal moiety in 8
followed by hydrogenation of the resulting aldehyde 9 (H2, 10% Pd/C, EtOH, rt, 3 h), provided
p-hydroxybenzyl alcohol 10 in 94% yield after the two steps. Finally, the critical quinone formation
reaction was successfully achieved by oxidative degradation of 10 using Fremy’s salt [(KSO3)2NO] in pH
6.0 phosphate buffer/CHCl3 (4:1) at room temperature, resulting in the formation of target 111 in high
yield (86%).
OBn
OBn
OR
MeO
I
MeO
Me
MeO
I
b
c
O
O
O
O
CHO
5 : R = H
6 : R = Bn
a
7
8
OR
X
O
O
MeO
Me
MeO
Me
d
f
9 : R = Bn, X = CHO
10 : R = H, X = CH2OH
1 ( primin )
e
Scheme 2. Synthesis of primin (1). (a) benzyl bromide, K2CO3, acetone, reflux, 86%; (b) ethylene glycol,
p-TsOH·H2O, benzene, reflux, 88%; (c) 1-pentene, 9-BBN, THF, rt; add. 7, PdCl2(dppf) (5 mol%),
Cs2CO3, THF, reflux, 92%; (d) 1 M HCl, THF, rt, 99%; (e) H2, 10% Pd/C, EtOH, rt, 95%; (f) Fremy’s salt,
pH 6.0 phosphate/CHCl3 (4:1), rt, 86%. 9-BBN = 9-borabicyclo[3.3.1]nonane, dppf =1,1’-bis(diphenyl-
phosphino)ferrocene, Fremy’s salt = potassium nitrosodisulfonate.
Thus, we have accomplished the synthesis of primin (1) in 56% overall yield in six steps from the
commercially available starting material 5. The key steps of the synthesis involve the B-alkyl
Suzuki–Miyaura cross-coupling reaction of aryl iodide 7 and organoborane 4 to introduce the requisite

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HETEROCYCLES, Vol. 86, No. 2, 2012
alkyl side chain in the aromatic ring (7 ! 8, Scheme 2) and elaboration of the quinone functionality by
oxidative degradation of phenolic compound 10 to complete the projected synthesis (10 ! 1, Scheme 2).
The main advantages of the present methods are the higher yield, milder reaction conditions, and greater
flexibility in producing primin analogues that with various alkyl side chains when compared to other
reported methods.4,7 On the basis of the results of this study, we are currently synthesizing additional
analogues of 1 with the aim of exploring their structure–activity relationships. In addition, further
investigations to identify the action mechanism of 1 by using synthetic samples are in progress.
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for the Strategic Research Foundation Program at
Private Universities (2010–2014) from the Ministry of Education, Culture, Sports, Science and
Technology, Japan (MEXT). K. Watanabe would like to acknowledge the contribution of a Grant-in-Aid
for Young Scientists (B) (No. 23790018) from MEXT, and T. Katoh is grateful to MEXT for the
provision of a Grant-in-Aid for Scientific Research (C) (No. 24590017).
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10. Data for 8. Colorless oil; IR (neat) 1091, 1158, 1216, 1507 cm"1; 1H NMR (400 MHz, CDCl3) ! 0.84
(3H, t, J = 6.8 Hz), 1.25–1.29 (4H, m), 1.48–1.57 (2H, m), 2.54 (2H, dt, J = 1.9, 7.8 Hz), 3.89 (3H,
s), 4.02–4.07 (2H, m), 4.14–4.17 (2H, m), 4.97 (2H, s), 5.73 (1H, s), 6.89 (1H, d, J = 1.9 Hz), 6.92
(1H, d, J = 1.9 Hz), 7.82–7.39 (3H, m), 7.45 (2H, dd, J = 1.4, 6.8 Hz); 13C NMR (100 MHz, CDCl3)
! 13.9, 22.4, 30.1, 30.2, 31.8, 55.7, 65.2 (2C), 74.6, 103.7, 107.7, 120.1, 127.7, 127.9, 128.1, 128.2,
128.3, 132.9, 136.9, 137.9, 146.6, 152.7; HRMS (EI) calcd for C22H28O4 (M+), 356.1988, found
356.1994.
11. Data for primin (1). Yellow crystals: mp 62–63 °C (from MeOH) {lit.,2b mp 64–65 °C; lit.,7a mp
1
62–63 °C; lit.,7c mp 64.5–65.5 °C; lit.,7h mp 61–62 °C}; IR (KBr) 1655, 1681 cm"1; H NMR (400
MHz, CDCl3) ! 0.88 (3H, t, J = 6.8 Hz), 1.31–1.34 (4H, m), 1.47–1.55 (2H, m), 2.41 (2H, t, J = 7.3
13
Hz), 3.82 (3H, s), 5.87 (1H, s), 6.48 (1H, s); C NMR (100 MHz, CDCl3) ! 13.9, 22.3, 27.4, 28.6,
31.3, 56.2, 107.1, 132.9, 147.6, 158.8, 182.1, 187.6; HRMS (EI) calcd for C12H16O3 (M+), 208.1099,
found 208.1099.