First total synthesis of tenuifolin via PIFA mediated oxidative biaryl coupling

Article abstract of DOI:10.1016/j.tetlet.2011.04.069

The first total synthesis of a sesquiterpenoid, tenuifolin, was achieved in seven linear steps. Phenyliodine(III) bis(trifluoacetate) (PIFA) mediated oxidative biaryl coupling was employed as a key step to construct the central seven-membered ring with a double bond. The double bond formation was also exploited.

Full text of DOI:10.1016/j.tetlet.2011.04.069

Tetrahedron Letters 52 (2011) 3275–3278
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Tetrahedron Letters
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First total synthesis of tenuifolin via PIFA mediated oxidative biaryl coupling
Changhua Tang a, Ziyuan Li a, Yiyun Wang a, Jinyi Xu a, Lingyi Kong b, Hequan Yao a, , Xiaoming Wu c,
⇑
⇑
a Department of Medicinal Chemistry, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, PR China
b Department of Natural Medicinal Chemistry, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, PR China
c Center for Drug Discovery, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of a sesquiterpenoid, tenuifolin, was achieved in seven linear steps. Phenylio-
dine(III) bis(trifluoacetate) (PIFA) mediated oxidative biaryl coupling was employed as a key step to con-
struct the central seven-membered ring with a double bond. The double bond formation was also
exploited.
Received 15 March 2011
Revised 6 April 2011
Accepted 11 April 2011
Available online 22 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Tenuifolin
Oxidative biaryl coupling
Wittig coupling
Antitumor
Biaryl compounds bearing 6, 7, 6-ring system were found in a
variety of natural products and synthetic pharmaceuticals, such
as alkaloids, as well as cyclolignans (Fig. 1).1 Several of these com-
pounds have been proved to be active against many cancer cell
lines. For example, allocolchicine (1), derived from Colchicine (2),
could bind to the cytoskeletal protein tubulin, disrupting the
microtubule-dependent functions in the cell and thereby suppress-
ing the cell division process.2 The tricyclic core with a central se-
ven-membered B ring has generally been known to play an
important role in bioactivity. Recently, Lin et al. isolated a new ses-
quiterpenoid, tenuifolin (4) from the stems of Cinnamomum tenu-
ifolium.3 Extensive 2D-NMR experiments elucidated the structure
of 4, showing that 4 contains an additional double bond on B-ring.
Although 4 was found to bear a similar scaffold as allocolchicine, a
preliminary bioassay indicated that 4 only displayed weak antipro-
liferative activity against tumor cell line DU145.3 The interesting
structure of 4 and the difference in biological activity between 4
and other compounds bearing 6, 7, 6-ring system promote us to
initiate the total synthesis of 4 for further pharmacological study.
Due to their remarkably unique structural features and interest-
ing bioactive properties, these natural products have attracted syn-
thetic and medicinal chemists for several decades and the total
synthesis of several related compounds have been achieved.1a
The key step of most synthetic strategies was the construction of
the central B ring at a late stage. In recent years, many approaches
have been developed toward the synthesis of the B ring, such as
palladium catalyzed direct C–H arylation for 1 and its analog,4
intramolecular thallium(III) trifluoroacetate-mediated non-pheno-
lic oxidative cyclization for (À)-N-acetylcochinol,5 siloxane cou-
pling-ring expansion route to racemic N-acetylcochinol-O-methyl
ether (racemic NSC 51046)6 and intramolecular Nicholas reaction
for enantiomerailly pure NSC 51046.7 About two decades ago, Kita
et al. reported an elegant oxidative biaryl coupling reaction using
PhI(OCOCH3)2, (PIDA), or (PIFA) as an oxidant.8 This method is
MeO
MeO
MeO
NHAc
O
A
B
A
NHAc
B
MeO
OMe
C
OMe
C
CO2Me
OMe
Colchicine (2)
Allocolchicine (1)
HO
O
MeO
HO
HO
A
B
OH
A
B
OH
C
C
O
OH
O
HO
Metasequirine B (3)
Tenuifolin (4)
⇑
Corresponding authors. Tel.: +86 25 83271042; fax: +86 25 83301606 (H.Y.);
tel.: +86 25 83271501; fax: +86 25 83301606 (X.W.).
E-mail addresses: hyao@cpu.edu.cn (H. Yao), xmwu@cpu.edu.cn (X. Wu).
Figure 1. Structures of naturally occurring biaryl molecules.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.069

3276
C. Tang et al. / Tetrahedron Letters 52 (2011) 3275–3278
at late stage using PIFA mediated oxidative biaryl coupling from es-
MeO
Reduction
MeO
PIFA
OEt
O
OEt
O
ter 6, which, in turn, would be acquired through a coupling reac-
tion between aldehyde 7 and bromoester 8. Finally, 8 could be
derived from commercially available benzodioxole 11.
4
The synthesis of two fragments, aldehyde 7 and bromoester 8,
was depicted in Scheme 2. A Darzens condensation between benz-
aldehyde (12) and ClCH2COOEt and sequential treatment with
aqueous NaOH, followed by HCl smoothly furnished fragment 7
(55% over three steps). A Friedel–Crafts acylation of benzodioxole
11 using ethyl 2-chloro-2-oxoacetate (15) (92%), followed by
reduction using NaBH4 (98%) and a bromination using PBr3 (72%)
afforded fragment 8 in good yield.10
O
O
O
O
6
5
OH
Br
O
O
O
O
O
O
O
O
O
O
O
With fragments 7 and 8 in hand, we focused our attention on
the coupling reaction between them to generate the double bond
as shown in Scheme 3 and Table 1. First, we tried intermolecular
Horner–Wadsworth–Emmons (HWE) reaction. Thus, phosphono
ester 16 was prepared from 8 and distilled P(OEt)3 via Michae-
lis–Arbuzov reaction in 98% yield. It was reported that the con-
densation of 16 and benzaldehyde could produce the olefination
product in moderated yield with high E-selectivity.10 However,
our initial attempts of HWE reaction between 16 and phenylacet-
aldehyde 7 under DBU/LiCl in THF at room temperature only gave
the desired 6 in low yield with poor E-selectivity (Table 1, entry
1). The mixture of E-6 and Z-6 was inseparable by flash chroma-
tography. We then examined the reaction conditions by changing
base and solvent and found that the total yield of 6, as well as the
E-selectivity was not yet well improved (Table 1, entries 2 and 3).
Next, we tried Wittig reaction in neutral condition. Treatment of
8 with PPh3 in anhydrous toluene and subsequently basification
with aqueous NaOH provided the Wittig reagent 17. Unfortu-
nately, Wittig coupling between 7 and 17 at low or elevated tem-
perature also afforded Z-6 (E:Z = 1:5.3–1:14) as a major product.
These results clearly indicated that higher temperature or loading
of 17 favored the formation of the Z-isomer (Table 1, entries 4–
8).11 The configuration of double bond of Z-6 was confirmed by
ROESY analysis of alcolol 19, which was reduced from Z-6 by DI-
BAL-H. Finally, we tried the Reformatsky reaction-dehydration to
generate the double bond. Treatment of 8 with activated Zn pow-
der in THF and coupling with 7 afforded b-hydroxyester 18 in 90%
yield. Elimination of the hydroxyl group of 18 with MsCl in
CH2Cl2 at room temperature for 12 h proceeded smoothly to af-
8
+
9
CHO
O
O
O
7
10
11
F-C coupling
O
CHO
O
O
12
Scheme 1. Retrosynthetic analysis of tenuifolin (4).
rather atom economic and has been successfully applied to the
synthesis of various biaryl molecules.9 Herein we wish to describe
the first total synthesis of 4 using this strategy.
Our initial retrosynthetic analysis of 4 is outlined in Scheme 1.
Compound 4 could be readily prepared via a reduction of ester 5.
We envisioned that the biaryl scaffold of 5 could be constructed
O
O
ford
6 in 89% yield with slightly improved E-selectivity
MeO
MeO
MeO
MeO
CHO
a
c
OEt
(E:Z = 1:2) (Table 1, entry 9).
After we successfully achieved the desired product 6, we next
investigated the PIFA mediated biaryl coupling reaction. Thus,
treatment of the mixture of 6 (E:Z = 1:2) with 1.0 equiv of PIFA in
the presence of BF3–Et2O at À45 °C for 4–6 h (Scheme 4) success-
fully furnished the corresponding product 5 in 56% isolated yield.12
Very interstingly, E-6 and most of Z-6 were found to be consumed
after 4 h. According to Dominguez’s report13 that the proximity of
two aromatic rings is needed for this biaryl coupling, theoretically,
our reaction should give the desired product in less than 33% yield.
Therefore, we presumed that Z-6 might undergo the isomerization
to E-6, which subsequently converted to 5, rendering the higher
yield than the theoretical one. The isomerization was indeed ob-
served when Z-6 was treated with BF3–Et2O or PIFA in CH2Cl2 at
low temperature. Encouraged by this result, we further used the
mixture of 6 (E:Z = 1:14) for the coupling reaction. Indeed, the de-
sired product 5 could be achieved in 45–58% yield (see Supplemen-
tary data S1). Finally, the ester 5 was reduced with DIABL-H in THF
at À78 °C to afford tenuifolin 4 in excellent yield (91%, Scheme 4).
The structure of 4 was confirmed by 1H NMR, 13C NMR, IR, and HR-
MS (ESI).14 NOESY analysis of 4 clearly indicated the E-configura-
tion of double bond on B ring. The spectroscopic data of synthetic
tenuifolin (4) were identical to those of an authentic sample re-
ported in the literature.
13
12
7
b
O
O
O
CHO
ONa
OEt
14
10
O
d
O
O
O
O
O
OEt
11
Cl
15 O
e
OH
Br
OEt
f
O
OEt
O
O
O
O
O
8
9
Scheme 2. Synthesis of fragments 7 and 8. Reagents and conditions: (a) ClCH2COO-
Et, EtONa, EtOH, 15–20 °C; (b) NaOH, H2O, 15–20 °C; (c) NaH2PO4, HCl, H2O, rt (55%
over three steps); (d) AlCl3, CH2Cl2, 0 °C (92%); (e) NaBH4, EtOH, À20 °C (98%); (f)
PBr3, CH2Cl2, 0 °C (72%).

C. Tang et al. / Tetrahedron Letters 52 (2011) 3275–3278
3277
OEt
EtO
P
O
a
HWE coupling
8
O
OEt
O
O
Entries 1-3
MeO
16
MeO
OEt
O
PPh3
b
Wittig coupling
+
O
8
OEt
EtOOC
Entries 4-8
O
O
O
O
17
O
O
E-6
Z-6 (favored)
OH
O
Entry 9
MeO
OEt
O
d
MeO
c
dehydration
8
Reformatsky reaction
O
18
HO
19
O
O
Scheme 3. Reagents and conditions: (a) distilled P(OEt)3, reflux, 6 h, (98%); (b) Ph3P, anhydrous toluene, 70 °C, overnight; then aq NaOH (88%); (c) Zn powder, anhydrous THF,
rt then 7, rt to reflux, 2 h (90%); (d) DIBAL-H, THF, À78 °C, 92%.
Table 1
The formation of the double bond on B-ring under various conditions
Entry
Condition
Yielda (%) (6)
Ratiob (E:Z by 1H NMR)
1
2
3
4
5
6
7
8
9
DBU, LiCl, CH3CN, then 7, rt
NaH, THF, then 7, rt
BuOK, THF, LiCl, then 7, rt
1.0 equiv of 17, toluene, rt
1.5 equiv of 17 + 1.0 equiv of 7, toluene, 50 °C, 36 h
1.0 equiv of 17 + 1.0 equiv of 7, toluene, 90 °C, 36 h
1.5 equiv of 17+1.0 equiv of 7, toluene, 90 °C, 36 h
2.0 equiv of 17 + 1.0 equiv of 7, toluene, 90 °C, 36 h
MsCl, NEt3, DBU, CH2Cl2, 0 °C to rt, 12 h
16
24
29
Trace
11
35
75
89
89
1:2.0
1:4.0
1:3.3
—
1:3.6
1:5.3
1:12.0
1:14.0
1:2.0
a
Total isolated yields (E-6 + Z-6) after flash chromatography.
b
Determined by 1H NMR.
NOE
MeO
MeO
OEt
O
a
b
OH
6
O
O
E : Z =1 : 2
O
O
or 1:14
5
tenuifolin (4)
Scheme 4. The synthesis of tenuifolin (4). Reagents and conditions: (a) PIFA (1 equiv), BF3–Et2O (1 equiv), CH2Cl2, À45 °C, 45–58%; (b) DIBAL-H, THF, À78 °C, 91%.
In conclusion, the first total synthesis of tenuifolin in seven lin-
ear steps without any protecting group was successfully achieved
using readily available starting materials. The synthetic route is
highlighted by the oxidative biaryl coupling reaction to construct
a seven-membered B ring bearing a double bond. Efforts on the
application to the synthesis of other related natural products and
the structural modification of tenuifolin for further pharmacologi-
cal study are undergoing in our laboratory and will be reported in
due course.
2009ZX09103-128 and Fundamental Research Funds for the Cen-
tral Universities (JKZ2009002 for H.Y.) are highly appreciated.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.069.
References and notes
1. (a) Graening, T.; Schmalz, H. G. Angew. Chem., Int. Ed. 2004, 43, 3230; (b) Hamel,
E. Med. Res. Rev. 1996, 16, 207; (c) Micheletti, G.; Poli, M.; Borsotti, P.;
Martinelli, M.; Imberti, B.; Taraboletti, G.; Giavazzi, R. Cancer Res. 2003, 63,
1534.
2. (a) Perez-Ramirez, B.; Gorbunoff, M. J.; Timasheff, S. N. Biochemistry 1998, 37,
1646; (b) Guan, J.; Zhu, X.; Brossi, A.; Tachibana, Y.; Bastow, K. F.; Verdier-
Pinard, P.; Hamel, E.; McPhail, A. T.; Lee, K. Collect. Czech. Chem. Commun. 1999,
Acknowledgments
Financial support the National Natural Science Foundation (No.
20902111), Program for New Century Excellent Talents in Univer-
sity (NCET 2008) by the Ministry of Education of China,

3278
C. Tang et al. / Tetrahedron Letters 52 (2011) 3275–3278
64, 217; (c) Buttner, F.; Bergemann, S.; Guenard, D.; Gust, R.; Seitz, G.; Thoret, S.
J = 7.7 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 167.1, 159.8,
147.4, 147.1 142.2, 140.4, 134.2, 129.7, 128.6, 123.3, 120.9, 114.4, 111.6, 110.3,
108.1, 101.1, 61.0, 55.2, 35.7, 14.3; ESI-MS m/z 341.2 [M+H]+; HR-MS(ESI) m/z
calcd for C20H20O5: 340.1318; found: 340.1305.
Bioorg. Med. Chem. 2005, 13, 3497; (d) Nakagawa-Goto, K.; Jung, M. K.; Hamel,
E.; Wu, C. C.; Bastow, K. F.; Brossi, A.; Ohta, S.; Lee, K. H. Heterocycles 2005, 65,
541.
3. Lin, R. J.; Cheng, M. J.; Huang, J. C.; Lo, W. L.; Yeh, Y. T.; Yen, C. M.; Lu, C. M.;
Chen, C. Y. J. Nat. Prod. 2009, 72, 1816.
4. Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849.
12. Ester 5: white solid; mp 97–99 °C; IR (KBr) 2958, 2924, 2843, 1710, 1607, 1501,
1483, 1433, 1309, 1273, 1256, 1233, 1178, 1154, 1122, 1097, 1042, 933, 868,
815, 771, 739 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.40 (d, J = 8.52 Hz, 1H), 7.27
;
5. (a) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15; (b) Broady, S. D.; Golden, M. D.;
Leonard, J.; Muir, J. C.; Maudet, M. Tetrahedron Lett. 2007, 48, 4627; (c) Sawyer,
J. S.; Macdonald, T. Tetrahedron Lett. 1988, 38, 4839.
6. Seganish, W. M.; Deshong, P. Org. Lett. 2006, 8, 3951.
7. Djurdjevic, S.; Green, J. R. Org. Lett. 2007, 9, 5505.
8. (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.; Sakurai, H.;
Oka, S. J. Am. Chem. Soc. 1994, 116, 3684; (b) Kita, Y.; Tohma, H.; Inagaki, M.;
Hatanaka, K.; Yakura, T. Tetrahedron Lett. 1991, 32, 4321; (c) Dohi, T.; Ito, M.;
Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Tetrahedron 2009, 65, 10797.
9. (a) Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org.
Biomol. Chem. 2006, 4, 2193; (b) Kita, Y.; Takada, T.; Mihara, S.; Tohma, H.
Synlett 1995, 211; (c) Kita, Y.; Takada, T.; Mihara, S.; Whelan, B. A.; Tohma, H. J.
Org. Chem. 1995, 60, 7144; (e) Arisawa, M.; Ramesh, N. G.; Nakajima, M.;
Tohma, H.; Kita, Y. J. Org. Chem. 2001, 66, 59.
(t, J = 6.5 Hz, 1H), 7.05 (s, 1H), 7.02 (s, 1H), 6.85 (q, J = 2.3 Hz, 1H), 6.77 (d,
J = 2.0 Hz, 1H), 6.01 (d, J = 4.0 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.22
(dd, J = 12.1, 8.4 Hz, 1H), 2.84 (dd, J = 12.1, 7.0 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 166.9, 159.3, 146.9, 145.7, 141.7, 140.1, 134.8,
131.3, 130.9, 130.5, 126.6, 112.2, 111.9, 109.6, 108.9, 101.2, 60.9, 55.3, 33.6,
14.2; EI-MS m/z 339.2 [M+]; HR-MS(ESI) m/z calcd for C20H18O5: 338.1157;
found: 338.1148.
13. Moreno, I.; Tellito, I.; Etayo, J.; Sanmartin, R.; Doninguez, E. Tetrahedron 2001,
57, 5403.
14. Tenuifolin (4): white solid; mp 116–119 °C; IR (KBr) 3319, 2961, 2924, 2861,
1720, 1606, 1501, 1483, 1401, 1307, 1275, 1258, 1231, 1154, 1121, 1039, 930,
748 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.38 (d, J = 8.5 Hz, 1H), 7.13 (s, 1H). 7.07
;
(s, 1H), 6.83 (q, J = 2.5 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.16 (t, J = 7.1 Hz, 1H),
6.02 (d, J = 1.9 Hz, 2H), 4.48 (d, J = 12.8 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H), 3.83 (s,
3H), 3.08 (dd, J = 12.6, 8.2 Hz, 1H), 2.77 (dd, J = 12.8, 6.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 159.2, 146.4, 143.6, 137.4, 134.6, 131.2, 130.6, 129.8, 127.6,
111.7, 111.5, 109.5, 106.0, 101.2, 66.1, 55.3, 33.1; EI-MS m/z 297.2 [M+H]+; HR-
MS(ESI) m/z calcd for C18H16O4: 296.1052; found: 296.1043.
10. Ianni, A.; Waldvogel, S. R. Synthesis 2006, 13, 2103.
11. Z-6: coloress oil; IR (KBr) 2985, 2938, 2896, 2831, 1711, 1600, 1584, 1503,
1489, 1437, 1369, 1259, 1235, 1149, 1101, 1038, 935, 865, 812, 764, 749,
697 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.26–7.11 (m, 2H), 6.82 (d, J = 7.9 Hz,
;
1H), 6.77-6.67 (m, 5H), 5.98 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.41 (d,