Suzuki coupling reactions of 2,4,6-trialkoxyphenylboronic acids with enol triflates: Asymmetric synthesis of a lactone template for calyxin assemblage

Article abstract of DOI:10.1016/j.tetlet.2006.01.159

Suzuki coupling reactions between 2,4,6-trialkoxyphenylboronic acids and enol triflates have been found to occur in excellent yield, while the use of an enol tosylate failed to give any of the desired product. This coupling reaction has led to the synthes

Full text of DOI:10.1016/j.tetlet.2006.01.159

Tetrahedron Letters 47 (2006) 2451–2454
Suzuki coupling reactions of 2,4,6-trialkoxyphenylboronic
acids with enol triflates: asymmetric synthesis of a lactone
template for calyxin assemblage
Sidika Polat Cakir and Keith T. Mead*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Received 25 July 2005; revised 11 November 2005; accepted 13 January 2006
Available online 17 February 2006
Abstract—Suzuki coupling reactions between 2,4,6-trialkoxyphenylboronic acids and enol triflates have been found to occur in
excellent yield, while the use of an enol tosylate failed to give any of the desired product. This coupling reaction has led to the syn-
thesis of a lactone which could serve as a precursor to several calyxin analogues.
Ó 2006 Elsevier Ltd. All rights reserved.
Efforts in our lab are currently focused on developing a
general strategy for synthesizing several members of the
calyxin family of natural products, such as 6-hydroxy-
calyxin F (1),1 epicalyxin F (2),2 and blepharocalyxin
E (3).3 Isolated by Kadota and co-workers, all three
have been shown to possess significant antiproliferative
activity against HT-1080 fibrosarcoma and colon 26-
L5 carcinoma cell lines, making them potential drug
candidates for the treatment of human tumors. Most
of our work to date has centered on the most complex
of these, blepharocalyxin E, using the tetrahydro-4H-
furo[2,3-b]pyran-2-one ring system to control the stereo-
chemistry at C7.4,5 Herein, we address the stereocon-
trolled synthesis of the core tetrahydropyran unit.
Lactones 4 (Scheme 1) were viewed as useful targets for
their potential as common intermediates for the synthe-
sis of several calyxin analogs, including compounds 1–3.
We envisioned deriving these lactones from a Suzuki
coupling between enol triflate 5, prepared from the
known lactone 6,6 and the arylboronic acids 7. Yao
and Deng have reported the synthesis of 4-aryl couma-
rins using a related coupling strategy,7 while others have
found success using enol tosylates.8 However, to the best
of our knowledge an example of a successful coupling of
either substrate with a 2,4,6-trialkoxyphenylboronic
acid derivative has not been reported.9 In light of this,
a study was initiated to determine the feasibility of the
proposed coupling reaction.
HO 4'
4'' OH
HO
OH
1'
3
O
O
7
OH
1''
1
H
5
R
H
7
HO
HO
OH
H
HO
HO
O
OH
OH
HO
OMe
O
OMe
1 R = OH (6-Hydroxycalyxin F)
2 R = H (Epicalyxin F)
3 (Blepharocalyxin E)
Keywords: Calyxins; Epicalyxins; Suzuki coupling; Trialkoxyphenylboronic acids.
*
Corresponding author. Tel.: +1 662 325 3584; fax: +1 662 325 1618; e-mail: kmead@ra.msstate.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.159

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S. P. Cakir, K. T. Mead / Tetrahedron Letters 47 (2006) 2451–2454
BnO
BnO
BnO
O
O
O
O
O
O
B(OH)2
OR
RO
RO
Br
OR
OTf
5
6
4a R = MOM
4b R = Bn
OMe
7
OMe
Scheme 1. Retrosynthesis of lactone targets.
Initial work focused on the synthesis of the hindered
trialkoxyphenylboronic acids 7. Attempts to synthesize
all three derivatives 7a–c met with limited success.
The known trimethoxy derivative 7c (Scheme 2) was
prepared according to the published procedure by
direct lithiation of 1,3,5-trimethoxybenzene in the pres-
ence of TMEDA.10 For derivatives 7a and 7b, lithia-
tion was attempted by metal–halogen exchange from
their bromo precursors 9a and 9b, respectively. In the
event, the yield of formation of 7a was disappointing,
whereas none of compound 7b formed under these
conditions.
derivative 7c (entry 1) was disappointing. However,
the addition of water (entry 2) gave the desired product
in excellent yield. Variations in protective groups also
gave reproducible high yields using the same conditions
(entries 3 and 5). Interestingly, when the corresponding
enol tosylate 13 was used in place of the triflate, none of
the desired product was isolated (entry 4).
Compound 16 (Scheme 4) was treated with catalytic
hydrogenation conditions with the intention of selec-
tively reducing the lactone double bond. However, phe-
nol 17 was the only product. Continued catalytic
hydrogenation eventually gave compound 18 as a single
diastereomer, which was benzylated to provide interme-
diate 19. Finally, aromatic bromination of compound 19
with NBS proceeded without incident to give the target
lactone 4a.
Two different enol triflates were prepared for studying
Suzuki coupling reactions. The synthesis of benzyl deriv-
ative 5 is representated in Scheme 3. Lactone 6 was syn-
thesized asymmetrically according to the published
procedures6 and converted to alcohol 10 by an epoxida-
tion-reductive cleavage strategy.11 Oxidation of com-
pound 10 gave dione 11, which was converted to enol
triflate 5 using standard conditions.
In summary, a general strategy for preparing lactones 4
has been demonstrated, although limitations clearly ex-
ist concerning the choice of protective groups at posi-
tions 2 and 6 on the trialkoxyphenyl substituent. Total
syntheses of calyxin analogues 1–3 are planned using
the lactone template 4a.
Table 1 summarizes the results of Suzuki couplings. The
first attempt between enol triflate 12 and trimethoxy
Br
Br
B(OH)2
MeO
OMe
HO
OH
RO
OR
RO
OR
c
a
b
OMe
OMe
OMe
OMe
9a R = MOM
9b R = Bn
7a R = MOM
7b R = Bn
7c R = Me
8
Scheme 2. Synthesis of trialkoxyphenylboronic acids. Reagents and conditions: (a) 9a: NaH, MOMCl, DMF, 0 °C–rt, 12 h (76%); 9b: BnBr, NaH,
DMF, rt, 12 h (87%); (b) 7a: n-BuLi, B(OMe)3, À78 °C then rt, 5 h (32%); 7b: n-BuLi, B(OMe)3, À78 °C then rt, 12 h (0%); (c) 7c: n-BuLi, TMEDA,
B(OMe)3, THF, À78 °C to rt, 12 h, then NH4Cl(aq) (62%).
BnO
BnO
BnO
BnO
O
O
O
O
O
O
O
O
O
a
b
c
OTf
OH
10
11
5
6
Scheme 3. Synthesis of enol triflate 5. Reagents and conditions: (a) (i) H2O2, 6 N NaOH(aq), EtOH, 0 °C, 2 h; (ii) PPTS, PhH, reflux, 2 h (79%, two
steps); (iii) Ph2Se2, NaBH4, EtOH, 0 °C, 2 h (88%); (b) PCC, CH2Cl2, 0 °C–rt, 12 h (62%); (c) Tf2O, NEt3, CH2Cl2, À78 °C, 30 min (74%).

S. P. Cakir, K. T. Mead / Tetrahedron Letters 47 (2006) 2451–2454
Table 1. Results of Suzuki coupling reactions
2453
R1O
R1O
O
O
O
O
Ar-B(OH)2
+
R2O
OR2
12 R1 = Me, R2 = Tf
13 R1 = Me, R2 = Ts
5 R1 = Bn, R2 = Tf
14 R1 = Me, R2 = Me
15 R1 = Me, R2 = MOM
16 R1 = Bn, R2 = MOM
OR2
OMe
Entry
1
Substrate
Ar–B(OH)2
Reaction conditions
Producta
Yieldb (%)
B(OH)2
OMe
MeO
12
12
12
13
5% PdCl2(PPh3)2, THF, K2CO3, reflux, overnight
5% PdCl2(PPh3)2, THF, 2 N K2CO3, reflux, 2 h
5% PdCl2(PPh3)2, THF, 2 N K2CO3, reflux, 2 h
5% PdCl2(PPh3)2, THF, 2 N K2CO3, reflux, 6 h
14
24
92
94
0
7c
OMe
B(OH)2
OMe
MeO
2
3
4
14
15
15
7c
OMe
B(OH)2
OMOM
MOMO
7a
OMe
B(OH)2
OMOM
MOMO
7a
OMe
B(OH)2
MOMO
OMOM
5
5
5% PdCl2(PPh3)2, THF, 2 N K2CO3, reflux, 3 h
16
98
7a
OMe
a All products were fully characterized by 1H NMR, 13C NMR, and HRMS.
b Yield refers to the isolated product of Suzuki coupling.
RO
RO
BnO
O
O
O
O
O
O
b
d
MOMO
OMOM
MOMO
OMOM
MOMO
Br
OMOM
OMe
OMe
OMe
16 R = Bn
17 R = H
18 R = H
19 R = Bn
4a
a
c
Scheme 4. Synthesis of compound 4a. Reagents and conditions: (a) H2, Pd/C (10 mol %), EtOAc–EtOH (1:1), rt, 45 h (92%); (b) H2, Pd/C
(10 mol %), EtOAc–EtOH (1:1), rt, 72 h (76%); (c) BnBr, NaH, DMF, 0 °C, 1 h (87%); (d) NBS (2 equiv), CH2Cl2, rt, 3 h (94%).

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S. P. Cakir, K. T. Mead / Tetrahedron Letters 47 (2006) 2451–2454
3. Tezuka, Y.; Ali, M. S.; Banskota, A. H.; Kadota, S.
Acknowledgements
Tetrahedron Lett. 2000, 41, 5903–5907.
4. Cakir, S. P.; Mead, K. T.; Smith, L. Tetrahedron Lett.
2003, 44, 6355–6358.
5. Cakir, S. P.; Mead, K. T. J. Org. Chem. 2004, 69, 2203–
2205.
We thank the National Institutes of Health, through
NCI Grant No. R15 CA09806201A1, for financial
support of this research.
6. (a) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett.
2005, 46, 2021–2024; (b) Boulard, L.; Bouz, S.; Cossy, J.;
Supplementary data
`
Franck, X.; Figadere, B. Tetrahedron Lett. 2004, 45, 6603–
6605.
The following supplementary data are available with the
paper: a 1H NMR peak listing for compound 17, 1H and
13C NMR peak listings for compounds 4a, 5, 7a, 9a, 9b,
10, 12–16, 18, and 19, HRMS data for compounds 4a,
14–16, 18, and 19, and a general procedure for the
Suzuki coupling. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.01.159.
7. Yao, M.-L.; Deng, M.-Z. Heteroatom Chem. 2000, 11,
380–382.
8. (a) Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.; Yang, Z.
J. Org. Chem. 2003, 68, 670–673; (b) Wu, J.; Wang, L.;
Fathi, R.; Yang, Z. Tetrahedron Lett. 2002, 43, 4395–
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9. For examples of Suzuki couplings of tri- and tetra-
methoxyphenylboronic acids with aryl halides, see: (a)
Muller, D.; Fleury, J. P. Tetrahedron Lett. 1991, 32, 2229–
2232; (b) Huang, C. Q.; Grigoriadis, D. E.; Liu, Z.;
McCarthy, J. R.; Ramphal, J.; Webb, T.; Whitten, J. P.;
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A. Helv. Chim. Acta 2004, 87, 1825–1831.
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