Development of a new synthetic strategy for procyanidin dimer condensation using peracetylated electrophiles

Article abstract of DOI:10.3987/COM-13-S(S)103

Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, are found in many edible plants and show interesting various biological activities. We report a simple new proanthocyanidin synthesis strategy in which an electrophile derived from a flavan-3-ol peracetate is condensed with 1.5 eq. of a benzylated nucleophile. We demonstrate here the synthesis of procyanidin B1, a (-)-epicatechin-(4β-8)-(+)-catechin dimer, to demonstrate the utility of this method. This strategy is applicable for the synthesis of various commercially available flavan-3-ol and various oligomeric flavonoids.

Full text of DOI:10.3987/COM-13-S(S)103

HETEROCYCLES, Vol. 88, No. 2, 2014
1595
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1595 - 1602. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 30th July, 2013, Accepted, 3rd October, 2013, Published online, 15th October, 2013
DOI: 10.3987/COM-13-S(S)103
DEVELOPMENT OF A NEW SYNTHETIC STRATEGY FOR
PROCYANIDIN DIMER CONDENSATION USING PERACETYLATED
ELECTROPHILES
Sayaka Ishihara,1 Syoma Doi,1 Kota Harui,1 Taisuke Okamoto,1 Shuhei
Okamoto,1 Joji Uenishi,1 Takashi Kawasaki,2 Noriyuki Nakajima,3* and
Akiko Saito1*
1Graduate School of Engineering, Osaka Electro-Communication University
(OECU), 18-8 Hatsu-cho, Neyagawa-shi, Osaka 572-8530, Japan; E-mail:
a-saito@isc.osakac.ac.jp
2Department of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1
Nojihigashi,
Kusatsu,
Shiga
525-8577,
Japan;
E-mail:
kawa0227@fc.ritsumei.ac.jp
3Biotechnology Research Center and Department of Biotechnology, Toyama
Prefectural University, 5180,ꢀKurokawa, Imizu, Toyama 939-0398, Japan; E-mail:
nori@pu-toyama.ac.jp
Abstract – Proanthocyanidins, also known as condensed tannins and/or
oligomeric flavonoids, are found in many edible plants and show interesting
various biological activities. We report a simple new proanthocyanidin synthesis
strategy in which an electrophile derived from a flavan-3-ol peracetate is
condensed with 1.5 eq. of a benzylated nucleophile. We demonstrate here the
synthesis of procyanidin B1, a (!)-epicatechin-(4!-8)-(+)-catechin dimer, to
demonstrate the utility of this method. This strategy is applicable for the synthesis
of various commercially available flavan-3-ol and various oligomeric flavonoids.
There is currently great interest in the research efforts investigating of compounds that have strong
antioxidant activity and superior radical scavenging ability. Furthermore, foods containing active
ingredients that can eliminate active oxygen species and free radicals have recently received increased

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HETEROCYCLES, Vol. 88, No. 2, 2014
attention. Polyphenols are found in various plants, which are regularly consumed by us. It is widely
believed that these polyphenols have a beneficial impact on health, and there are a variety of health foods
that contain polyphenols. Furthermore, the scientific investigation of polyphenolic compounds is now
increasingly important because of their various strong biological activities. For example,
epigallocatechin-3-O-gallate (EGCG), a major polyphenol from green tea, which is a flavan-3-ol, has
notably been the focus of intense research for its protective effect against a various types of cancers,
including lung, prostate and breast cancers.1 Surface plasmon resonance experiments have demonstrated
that the 67-kDa laminin receptor, which is widely expressed at high levels in cancer cell membranes, is an
EGCG reseptor2 and is an evidence of EGCG’s selective cytotoxicity against cancer cells.
Proanthocyanidins (condensed tannins or oligomeric flavonoids)3,4 are known to be extremely strong
antioxidants; investigating them has become increasingly important because of their various strong
biological activities. However, in many cases, proanthocyanidins are obtained as a mixture of various
analogs, making purification of each compound difficult. In an elegant contribution, Kozikowski et al.,5
reported the synthesis of oligomeric catechin and epicatechin derivatives.6 We also developed and
reported a simple, versatile, and stereoselective method for synthesizing procyanidin oligomers, including
(!)-epicatechin (1) and (+)-catechin.7–18 Our synthetic methodology is applicable to variety of procyanidin
oligomers, such as 3-O-substituted oligomers. The key step in our method of procyanidin synthesis is the
coupling reaction between a nucleophile and a monomeric electrophile using a Lewis acid activator, such
as TiCl4, SnCl4 or trimethylsilyl trifluoromethanesulfonate (TMSOTf). We created 2-ethoxyethoxy
derivatives on the C-4 position as building blocks for procyanidin synthesis. These condensation reactions
proceeded smoothly and afforded a good yield of 4!8 condensed oligomers and stereoselectivity (Scheme
1), but the nucleophile had to be used in four-fold excess to avoid higher oligomer formation. Therefore,
we were challenged to develop a new, simple, stereoselective, and regioselective synthetic strategy
applicable for the synthesis of a wide-range of procyanidin oligomers. In this report, we describe a new
oligomer synthetic strategy that uses a condensation reaction between a peracetyl electrophile and 1.5
equiv. of nucleophiles to give procyanidin dimers (Scheme 2).
OBn
OBn
OBn
OBn
BnO
O
BnO
O
TMSOTf
O
OR
O
OR
O
OBn
OBn
OBn
OBn
OBn
BnO
OBn O
BnO
OR
OR
nucleophile
(4.0 equiv.)
electrophile
OBn
OBn
Scheme 1. Our previously-developed synthesis of procyanidin oligomers

HETEROCYCLES, Vol. 88, No. 2, 2014
1597
OAc
OAc
OAc
AcO
O
AcO
O
OAc
R
SnCl4
OAc
O
OAc
R
OBn
OBn
OAc
BnO
OAc OH
OBn
OBn
BnO
O
OR
OR
electrophile
OBn
nucleophile
(1.5 equiv.)
OBn
Scheme 2. Our newly-developed synthesis of procyanidin oligomers
A benzyl group is the group most commonly used to protect the phenolic functionalities of procyanidin
synthesis. However, the large-scale synthesis of benzyl (+)-catechin and (-)-epicatechin is very limited
because of the by-products formation at benzyl-protection.19,20 It is well-known that acetylation of
flavan-3-ol and proanthocyanidins proceeds smoothly and affords their peracetates in quantitative yield.
The electron-withdrawing acetyl moieties reduce reactivity at the C-8 position of the A-ring. Electrophilic
C-4-oxyganated peracetates and C-4-halogenated peracetates have been reported and used for
proanthocyanidin synthesis.21 We re-examined the synthesis of peracetylated electrophiles and found that
C-4-hydoroxylated electrophile (3) could be obtained from C-4-brominated peracetates by heating with
NaHCO3 in DMSO (Scheme 3). One-pot bromination with NBS and hydroxylation with NaHCO3 in
DMSO proceeded rapidly at 60 °C and afforded 3 with a yield of 57% yield. This reaction is also
applicable to the synthesis of electrophiles derived from (+)-catechin and EGCG in approximately
10%–50% yields (data not shown).
Condensation of 3 with 1.5 eq. of (+)-catechin nucleophile (4a), performed in the presence of SnCl4 at
0 °C afforded dimmer product (5a) with a yield of 33%. When TMSOTf was used as a catalyst, 33%
isolation yield was obtained. This condensation method could be also adapted for various nucleophiles
(4b-4d) derived from (!)-epicatechin, (!)-epigallocatechin, and (!)- epigallocatechin gallate (EGCG)
with yields of 19%, 32%, and 26%, respectively, as shown in Scheme 4. The reaction yield are not so
good for the instability of an acetyl group, however, only dimeric procyanidin derivative can be obtained
under this reaction conditions without higher oligomer formation.
Because of peak broadening in the NMR spectra, the structure determination of 5a was difficult; therefore,
the 3”-hydroxygroup of 5a was acetylated to give acetate 6a in quantitative yield (Scheme 4). We have
previously experienced peak broadening in NMR spectra during the synthesis of protection-free
procyanidin oligomers that have (!)-epicatehin as an upper unit. Surprisingly, the peak-broadening
phenomenon observed with 5a was disappeared upon acetylation of only the 3”-hydroxyl moiety.
Furthermore, the structure was ascertained by comparing the spectral data of peracetate 6 with those of

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HETEROCYCLES, Vol. 88, No. 2, 2014
synthesized authentic samples. Deprotection of the four benzyl groups of 5a under hydrogenation
conditions and acetylation using a general procedure yielded peracetate 7 with a yield of 92% yield
(Scheme 5). All spectral data agreed with the structure portrayed in Scheme 5. Deprotection of Ac and Bn
group from compound 5a by alkaline hydrolysis with K2CO3, followed by hydrogenation using
Pd(OH)2/C under H2 atmosphere was achieved to synthesize procyanidin B1 (8) with 56% yield.
Finally, in initial experiments, to confirm the applicability of this condensation reaction for the synthesis
of related molecules, we have confirmed that dimeric procyanidin derivatives can be obtained from
condensation reactions between 3 and various nucleophiles (5b-5d) derived from (-)-epicatechin,
(!)-epigallocatechin, and (!)-EGCG with yields of 19%, 32%, and 26%, respectively.
OAc
OH
OH
OAc
OAc
1) NBS, AIBN,
CCl4-CH2Cl2 (4:1)
AcO
O
Ac2O
HO
O
AcO
O
OAc
2) DMSO, 60 °C,
then NaHCO3
Py, Et3N, DMAP
quant.
OAc
OH
OAc
OAc OH
OH
OAc
2 steps 57%
3
1
2
Scheme 3. Synthesis of peracetyl electrophile (3)
R1
R1
OBn
OAc
OAc
OAc
OAc
BnO
O
AcO
O
AcO
O
OBn
R2
OAc
O
OAc
O
R3
(1.5 eq.)
SnCl4, CH2Cl2, 0 °C
OBn
OBn
OBn
OBn
OBn
OAc
BnO
OAc
BnO
4
Ac2O, Py
3
DMAP, CH2Cl2
R2
OAc
R3
OBn
4a: R1=H, R2=OH, R3=H
4b: R1=H, R2=H, R3=OH
4c: R1=OBn, R2=H, R3=OH
OBn
5a: R1=H, R2=OH, R3=H (33%)
5b: R1=H, R2=H, R3=OH (19%)
5c: R1=OBn, R2=H, R3=OH (32%)
6a (98%)
4d: R1=OBn, R2=H, R3=OCOC6H2(OBn)3
5d: R1=OBn, R2=H, R3=OCOC6H2(OBn)3 (26%)
Scheme 4. Coupling reaction of peracetyl electrophile (3) and nucleophiles(4a-4d)
OAc
OH
OH
AcO
O
HO
1) K2CO3, MeOH-CH2Cl2
O
OAc
1) Pd(OH)2/C,
THF-MeOH-H2O
OAc
O
OH
O
OAc
OAc
OH
OH
5a
OAc
AcO
OH
HO
2) Pd(OH)2/C, H2
THF-MeOH-H2O
2) Ac2O, Py, DMAP
2 steps 92%
2 step 56%
OAc
OH
OAc
OH
7
8
Scheme 5. Synthesis of procyanidin B1 (8) and its structure determination

HETEROCYCLES, Vol. 88, No. 2, 2014
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EXPERIMENTAL
General: All commercially available chemicals for chemical synthesis were used without further
purification. All reactions were performed under an argon atmosphere and monitored by thin-layer
chromatography with 0.25-mm pre-coated silica gel plates (60F254 Art 5715; Merck, Darmstadt,
1
Germany). Optical rotation was measured with an ATAGO AP-300 spectrometer. H-NMR spectra were
recorded on a Varian Inova 500 NMR Spectrometer (500 MHz). Chemical shifts were reported in ppm (d)
relative to an internal standard (tetramethylsilane). Fast atom bombardment mass spectra at normal
(FABMS) and high resolution (FABHRMS) were obtained using a JEOL JMS-AX500 mass spectrometer.
HPLC purification was performed on a Mightysil RP-18 GP column (Kanto Chemical Co. Inc., Japan;
250 x 20 mm, 5 mm) using eluents A [0.05% HCO2H in MeCN/H2O (20/80)] and B (0.05% HCO2H in
MeCN). Elution was performed with a linear gradient of 20%–100% B in in A over 20 min (flow rate, 2.0
mL/min).
4-Hydroxy-penta-O-acetyl-(!)-epicatechin (3). A mixture of penta-O-acetyl-(!)-epicatechin (2; 1.00 g,
2.00 mmol) and NBS (0.71 g, 4.00 mmol) in the presence of AIBN (32.8 mg, 0.20 mmol) was refluxed in
CH2Cl2–CCl4 (1:4, v/v) for 12 h. NaHCO3 (0.50 g, 5.99 mmol) and DMSO (30 mL) were added to the
solution and stirred at 60 °C for 1 h. The reaction mixture was quenched with ice water and extracted with
EtOAc. The organic phase was washed with water and brine, and then dried with solid Na2SO4. Filtration,
concentration, and silica gel column chromatography (Hex:EtOAc, approximately 7:1!1:3) afforded 0.59
g of 3 as a colorless amorphous powder (1.15 mmol, 57%). ["]D24 + 40.8 (c 0.098, CHCl3); 1H NMR (500
MHz, CDCl3) d = 7.25 (1H, d, J = 8.5 Hz), 7.17 (1H, dd, J = 1.5, 8.5 Hz), 7.14 (1H, d, J = 1.5 Hz), 6.39
(1H, br s), 6.30 (1H, br s), 6.15 (1H, br s), 5.62 (1H, t, J = 4.0 Hz), 5.45 (1H, br s), 2.32 (3H, s), 2.304
(3H, s), 2.299 (3H, s), 2.290 (3H, s), 2.04 (3H, s); the hydroxyl group was not observed. FABMS (m/z)
517 ([M+H]+, 10), 516 (10), 499 (18), 415 (32), 397 (23), 372 (20), 306 (100); FABHRMS calcd for
C25H25O12 [M+H]+, 517.1346; found: 517.1371.
[4,8]-2,3-cis-3,4-trans-2”,3”-trans-3,5,7,3’4’-Penta-O-acetyl-5”,7”,3”’,4”’-tetra-O-benzyl-(!)-
epicatechin-(+)-catechin (5a). To a solution of 3 (130 mg, 0.25 mmol) and 4a (244 mg, 0.38 mmol) in
CH2Cl2 (20 mL) was added dropwise SnCl4 (0.50 mL, 0.50 mmol, 1.0 M solution in CH2Cl2) at 0 °C.
After stirring for 5 min, the pale yellow reaction mixture was quenched with saturated aqueous NaHCO3.
The mixture was extracted with CHCl3 and the organic phase was washed with water and brine, and then
dried with solid Na2SO4. Filtration, concentration, and preparative silica gel TLC purification
(hexane:EtOAc, 1:1) afforded a 95 mg of 5a (0.082 mmol, 33%) of as a colorless amorphous powder:
24
["]D + 79.2 (c 0.10, CHCl3); NMR signals from a solution of 5a were quite broad, making peak

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HETEROCYCLES, Vol. 88, No. 2, 2014
assignment impossible.
[4,8]-2,3-cis-3,4-trans-2”,3”-trans-3,5,7,3’4’3”-Hexa-O-acetyl-5”,7”,3”’,4”’-tetra-O-benzyl-(!)-
epicatechin-(+)-catechin (6a). A solution of 5a (13.1 mg, 0.011 mmol) in CH2Cl2 (5 mL) was acetylated
by a general procedure using Ac2O.7-17 After stirring for 30 min at room temperature, the reaction mixture
was quenched with water and extracted with CHCl3. The organic phase was washed with water and brine
and dried with MgSO4. Filtration, concentration, and chromatography on a short silica gel column
24
(hexane/EtOAc, 1:2) afforded 13.3 mg of 6a (0.011 mmol, 98%) as a colorless amorphous powder: ["]D
1
-49.2 (c 0.061, CHCl3); H NMR (500 MHz, CDCl3, 0.75:0.75 mixture of rotational isomers) major
isomer: 7.47!6.88 (18H, m), 6.84 (0.75H, d, J = 8.0 Hz), 6.69 (0.75H, s), 6.59 (0.75H, d, J = 8.0 Hz),
6.32 (0.75H, s), 6.26 (0.75H, s), 6.26 (0.75H, s), 5.79 (0.75H, s), 5.51 (0.75H, s), 5.38 (0.75H, s),
5.12!4.93 (6H, m), 4.62 (0.75H, s), 4.21 (0.75H, d, J = 9.5 Hz), 3.23 (0.75H, dd, J = 7.0, 17.0 Hz), 2.60
(0.75H, dd, J = 8.5, 17.0 Hz), 2.19-1.95 (13.5H, m); minor isomer: 7.47!6.88 (6.5H, m), 6.49 (0.25H, s),
6.33 (0.25H, s), 6.18 (0.25H, s), 5.36 (0.25H, s), 5.28 (0.25H, s), 5.12!4.93 (2.25H, m), 4.70 (0.25H, d, J
= 10.5 Hz), 4.51 (0.25H, s), 4.46 (0.25H, d, J = 10.5 Hz), 3.22!3.18 (0.25H, m), 2.75 (0.25H, dd, J = 8.5,
13
16.5 Hz), 2.19!1.95 (4.5H, m); C NMR (125 MHz, CDCl3)major isomer: 169.8, 169.2, 168.9, 168.4,
168.00, 167.98, 156.5, 155.42, 155.37, 154.2, 148.7, 148.62, 148.59, 148.0, 141.9, 141.6, 137.5, 137.3,
136.9, 136.78, 136.70, 128.7-127.1 (Cx6), 128.7, 128.5, 128.4, 128.3, 127.3, 127.1, 127.0, 124.3, 123.0,
121.8, 120.5, 114.7, 113.6, 113.1, 108.24, 108.18, 106.6, 104.1, 91.1, 78.9, 74.1, 71.3, 71.2, 70.74, 70.66,
70.0, 69.0, 33.2, 27.0, 21.0, 20.8, 20.7, 20.6, 20.5, 20.0; minor isomer: 169.8, 169.2, 169.0, 168.4, 168.1,
168.0, 156.8, 156.4-148.6 (Cx7), 141.8, 141.2, 137.5-136.7 (Cx4), 136.1, 130.0, 128.7-127.1 (Cx6),
128.04, 127.99, 127.8, 127.5, 127.4, 127.2, 124.3, 122.8, 121.7, 120.2, 114.6, 114.0, 113.6, 108.9, 108.2,
107.4, 102.2, 91.9, 78.6, 74.5, 71.7, 71.6, 71.3-70.7 (Cx3), 70.0, 68.7, 29.7, 25.8, 21.2, 21.0-20.5 (Cx3),
20.3, 20.2.
[4,8]-2,3-cis-3,4-trans:2”,3”-trans-Deca-O-acetyl-(!)-epicatechin-(+)-catechin (7). A solution of 5a
(7.20 mg, 0.0063 mmol) in 11 mL of THF/MeOH/H2O (20:1:1) was hydrogenated over 20% Pd(OH)2/C
(2 mg) for 12 h at room temperature. Filtration and concentration afforded a pale brown solid, which was
acetylated using a general procedure to give 5.8 mg of 7 (0.0058 mmol, 92%) as an amorphous solid. All
spectral data of 7 agreed with those of the synthetic compound previously reported.11
Procyanidin B1 (8). To a solution of 5a (18.1 mg, 0.016 mmol) in CH2Cl2!MeOH (1:1) was added
K2CO3 (13.1 mg, 0.095 mmol) at 0 °C, and the mixture was stirred for 30 min. The reaction mixture was
quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. After concentration, the

HETEROCYCLES, Vol. 88, No. 2, 2014
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mixture was dissolved with 11 mL of THF:MeOH:H2O (20:1:1) and hydrogenated over 20% Pd(OH)2/C
(2 mg) for 3 h at room temperature. Filtration and concentration afforded a pale brown solid that was
purified by HPLC purification to give 5.2 mg of pure 8 (0.090 mmol, 56%) as an amorphous solid. All
spectral data obtained for 8 agreed with those of the synthesized compound previously reported.11
ACKNOWLEDGEMENTS
This work was supported by BRAIN: Program for Promotion of Basic and Applied Research for
Innovations in Bio-oriented Industry (to A. Saito) and JSPS KAKENHI Grant Number 23780123
(Grant-in-Aid for Young Scientist (B) to A. Saito).
REFERENCES
1. C. S. Yang, P. Maliakai, and X. Meng, Annu. Rev. Pharmacol. Toxicol., 2002, 42, 25.
2. H. Tachibana, K. Koga, Y. Fujimura, and K. Yamada, Nat. Struct. Mol. Biol., 2004, 11, 380.
3. J. B. Harborne, The Flavonoids: Advances in research from 1986. Chapman and Hall: London, 1993.
4. J. B. Harborne and H. Baxter, The Handbook of Natural Flavonoids, John Wiley & Sons, NY (1999).
5. (a) W. Tuckmantel, A. P. Kozikowski, and L. J. Romanczyk, J. Am. Chem. Soc., 1999, 121, 12073;
(b) A. P. Kozikowski, W. Tuckmantel, and C. George, J. Org. Chem., 2000, 65, 5371; (c) A. P.
Kozikowski, W. Tuckmantel, G. Boettcher, and L. J. Romanczyk Jr., J. Org. Chem., 2003, 68, 1641.
6. (a) K. Ohmori, N. Ushimaru, and K. Suzuki, Proc. Natl. Acad. Sci. U.S.A., 2004, 101, 12002; (b) I.
Tarascou, K. Barathieu, Y. Andre, I. Pianet, E. Dufourc, and E. Fouquet, Eur. J. Org. Chem., 2006,
5367; (c) P. K. Sharma, A. Kolchinski, H. A. Shea, J. J. Nair, Y. Gou, L. J. Romanczyk Jr., and H. H.
Schmitz, Org. Process Res. Dev., 2007, 11, 422; (d) Y. Mohri, M. Sagehashi, T. Yamada, Y. Hattori,
K. Morimura, T. Kamo, M. Hirota, and H. Makabe, Tetrahedron Lett., 2007, 48, 5891; (e) K. Oyama,
M. Kuwano, M. Ito, K. Yoshida, and T. Kondo, Tetrahedron Lett., 2008, 49, 3176; (f) A. C. Matthew,
S. L. Bonnet, and J. H. van der Westhuizen, Org. Lett., 2008, 10, 3865; (g) Y. Mohri, M. Sagehashi,
T. Yamada, Y. Hattori, Y. Morimura, K. Hamauzu, T. Kamo, M. Hirota, and H. Makabe,
Heterocycles, 2009, 79, 549; (h) G. Watanabe, K. Ohmori, and K. Suzuki, Chem. Commun., 2013,
5210.
7. A. Saito, N. Nakajima, A. Tanaka, and M. Ubukata, Biosci. Biotechnol. Biochem., 2002, 66, 1764.
8. A. Saito, N. Nakajima, A. Tanaka, and M. Ubukata, Tetrahedron, 2002, 58, 7829.
9. A. Saito, N. Nakajima, A. Tanaka, and M. Ubukata, Tetrahedron Lett., 2003, 44, 5449.
10. A. Saito, N. Nakajima, A. Tanaka, and M. Ubukata, Heterocycles, 2003, 61, 287.
11. A. Saito, N. Nakajima, M. Matsuura, A. Tanaka, and M. Ubukata, Heterocycles, 2004, 62, 479.
12. A. Saito, A. Tanaka, M. Ubukata, and N. Nakajima, Synlett, 2004, 1069.

1602
HETEROCYCLES, Vol. 88, No. 2, 2014
13. A. Saito, A. Tanaka, M. Ubukata, and N. Nakajima, Synlett, 2004, 2040.
14. A. Saito, Y. Doi, N. Matsuura, A. Tanaka, M. Ubukata, and N. Nakajima, Bioorg. Med. Chem., 2004,
12, 4783.
15. A. Saito, M. Emoto, A. Tanaka, Y. Doi, K. Shoji, Y. Mizushina, H. Ikawa, H. Yoshida, N. Matsuura,
and N. Nakajima, Tetrahedron, 2004, 60, 12043.
16. A. Saito, Y. Mizushina, H. Ikawa, H. Yoshida, Y. Doi, A. Tanaka, and N. Nakajima, Bioorg. Med.
Chem., 2005, 13, 2759.
17. H. Sakuda, A. Saito, Y. Mizushina, H. Ikawa, H. Yoshida, A. Tanaka, and N. Nakajima, Heterocycles,
2006, 67, 175.
18. A. Saito, Y. Mizushina, A. Tanaka, and N. Nakajima, Tetrahedron, 2009, 65, 7422.
19. S. Nakayama, K. Oyama, T. Kondo, and K. Yoshida, Heterocycles, 2007, 73, 451.
20. P. K. Sharma, A. Kolchinski, H. A. Shea, J. J. Nair, Y. Gou, L. J. Jr. Romanczyk, and H. H. Schmitz,
Org. Process Res. Dev., 2007, 11, 422.
21. (a) J. Michaud, J. Masquelier, and A. M. Roudge, Annales Pharmaceutiques Françaises, 1973, 31,
385; (b) J. A. Steenkamp, J. C. S. Malan, and D. Ferreira, J. Chem. Soc., Perkin Trans. 1, 1988,
2179.