Catalytic asymmetric synthesis of descurainin via 1, 3-dipolar cycloaddition of a carbonyl ylide using Rh2(R-TCPTTL)4

Article abstract of DOI:10.1016/j.tetlet.2010.10.036

A catalytic asymmetric synthesis of descurainin has been achieved by incorporating an enantioselective 1,3-dipolar cycloaddition, a stereoselective alkene hydrogénation, an oxidation with Fremy's salt and a regioselective demethylation with NbCl₅

Full text of DOI:10.1016/j.tetlet.2010.10.036

Tetrahedron Letters 51 (2010) 6572–6575
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Catalytic asymmetric synthesis of descurainin via 1,3-dipolar cycloaddition
of a carbonyl ylide using Rh2(R-TCPTTL)4
Naoyuki Shimada, Taiki Hanari, Yasunobu Kurosaki, Masahiro Anada, Hisanori Nambu,
⇑
Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic asymmetric synthesis of descurainin has been achieved by incorporating an enantioselective
1,3-dipolar cycloaddition, a stereoselective alkene hydrogenation, an oxidation with Fremy’s salt and a
regioselective demethylation with NbCl5 as the key step. The 1,3-dipolar cycloaddition of a carbonyl ylide
derived from tert-butyl 2-diazo-5-formyl-3-oxopetanoate with 4-hydroxy-3-methoxyphenylacetylene in
the presence of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(R)-tert-leucinate], Rh2(R-TCPTTL)4, pro-
vided an 8-oxabicyclo[3.2.1]octane skeleton in 95% ee.
Received 17 September 2010
Revised 4 October 2010
Accepted 7 October 2010
Available online 14 October 2010
Keywords:
Carbonyl ylide
Ó 2010 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition
Chiral dirhodium(II) catalyst
Descurainin
In 2004, Li and co-workers isolated descurainin (1) from the
seeds of Descurainia sophia (L.) Webb ex Prantl, which are widely
used as Chinese traditional medicine to relieve coughing, prevent
asthma, reduce edema, and promote urination.1 Compound 22
and cartorimine (3),3 possessing an 8-oxabicylo[3.2.1]oct-3-en-2-
one ring system, were isolated from Ligusticum chuanxing Hort.
and Carthamus tinctorius L. by the Wen and He groups, respectively.
Snider and Grabowski reported a concise total synthesis of ( )-1–3,
in which the fully functionalized 8-oxabicyclo[3.2.1]octenone skel-
eton was efficiently constructed by a possible biomimetic [5+2]
cycloaddition of oxidopyrylium ion.4
with phenylacetylene derivatives using dirhodium(II) tetrakis[N-tet-
rachlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4 (4),13–15 as a
catalyst.16 The reaction between tert-butyl 2-diazo-5-formyl-3-oxo-
petanoate (6) and 4-hydroxy-3-methoxyphenylacetylene (7) pro-
vided 8-oxabicyclo[3.2.1]octane derivative 8 in 73% yield with 95%
ee (Eq. 1). Using this catalytic methodology, we achieved the first
asymmetric synthesis of ent-2.16 The absolute maximal molar circu-
lar dichroism of synthetic material ent-2 (
played a startling difference in magnitude to that of natural
product 2 (
+0.01 at 355 nm).2 This observation suggested that nat-
De
ꢀ3.81 at 348 nm) dis-
De
ural product 2 might be biosynthesized in near-racemic form like
polygalolides A and B.17,18 Our results provided experimental support
for the biogenetic hypothesis by Snider’s group.4b As an extension of
our study in this field, we herein report an asymmetric synthesis of
descurainin (1) using the carbonyl ylide cycloaddition methodology.
MeO
OH
MeO
OH
OH
OMe
HO2C
H
OH
MeO
OH
MeO
OMe
H
O
O
H
O
O
O
OH
OH
OH
OH
O
7
N2
H
O
CO tBu
4 (1 mol %)
2
descurainin (1)
2
cartorimine (3)
H
O
CO2tBu
O
H
O
O
OH
CF3C6H5, 23 °C
1 h
O
The dirhodium(II) complex-catalyzed tandem cyclic carbonyl
ylide formation–1,3-dipolar cycloaddition reaction sequence repre-
sents one of the most powerful methods for the rapid assembly of
complex oxapolycyclic systems.5–8 An enantioselective version of
this sequence catalyzed by chiral dirhodium(II) complexes has also
been developed.9–12 Recently, we reported an enantioselective 1,3-
dipolar cycloaddition of a six-membered cyclic formyl-carbonyl ylide
6
8
ent-2
73% (95% ee)
ð1Þ
Cl
O
Cl
O
O
N
O
N
Cl
Cl
Cl
Cl
Cl
H
O
H
O
Cl
O
O
Rh Rh
Rh2(S-TCPTTL)4 (4)
Rh Rh
Rh2(R-TCPTTL)4 (5)
⇑
Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981.
E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.036

N. Shimada et al. / Tetrahedron Letters 51 (2010) 6572–6575
6573
oselectivities (26% ee and 20% ee, respectively) compared to those
with 11a (entries 2 and 3). The use of acetyl-protected phenylacet-
ylene 11d caused a sharp drop in enantioselectivity, though cyc-
loadduct 12d was obtained in good yield (62% yield, 1% ee, entry
4). It is noteworthy that the steric and electronic nature of dipol-
arophiles markedly influenced both product yield and enantiose-
lectivity.10b,c These unsatisfactory results led us to change our
strategy. We envisioned that the enantiomer of bicyclic compound
8 possessing a 40-hydroxy-30-methoxybenzene ring would be an
intermediate for the synthesis of 1 via installation of a methoxy
group at the C50 position on the aromatic ring. Thus, the reaction
of 6 with 4-hydroxy-3-methoxyphenylacetylene (7) as a dipolaro-
phile in the presence of Rh2(R-TCPTTL)4 (5) was performed to pro-
MeO
O
OH
OH
MeO
OR
OMe
MeO
OR
OMe
OMe
H
O
H
O
CO2tBu
O
H
O
CO2tBu
O
descurainin (1)
9
10
OMe
OR
OMe
OR
Rh2(R-TCPTTL)4
(5)
OMe
11
+
OMe
O+
Rh
H
N2
vide the desired cycloadduct ent-8, ½a D22
ꢀ148.5 (c 1.09, CHCl3), in
ꢁ
CO2tBu
O
H
O
CO2tBu
77% yield with virtually the same enantioselectivity (95% ee) as
those found in our previous study (entry 5).16,20
O
enantioselective
1,3-dipolar cycloaddition
6
Catalytic hydrogenation of ent-8 provided exclusively the de-
sired endo-bicyclic compound 13 as a single diastereomer in 99%
yield (Scheme 2).21 We then investigated installation of a hydroxy
group at the C50 position on the aromatic ring via formation of o-
quinone. Treatment of phenol 13 with (KSO3)2NO (Fremy’s salt)22
in the presence of KH2PO4 gave o-quinone 14. Keeping the reaction
time short prevented significant loss of product yield. The resultant
o-quinone 14 was immediately converted into catechol 15 by
treatment with Na2S2O4 in 73% yield in two steps from 13.23 Since
attempts at regioselective methylation of 15 were unsuccessful,24
we turned our attention to the viability of a regioselective demeth-
ylation of trimethoxybenzene derivative. Treatment of 15 with MeI
(4 equiv) and K2CO3 afforded per-methylated product 16 in quan-
titative yield.
Scheme 1. Retrosynthetic analysis of descurainin (1).
Our synthetic strategy is outlined retrosynthetically in Scheme
1. We envisaged that 1 would be accessible from b-ketoester 9,
which would be derived from bicyclic compound 10 in a stereocon-
trolled manner. On the basis of our previous work,16 we envisioned
that the cycloaddition of a carbonyl ylide derived from a-diazo-b-
ketoester 6 with phenylacetylene derivative 11 using Rh2(R-
TCPTTL)4 (5)19 would provide cycloadduct 10.
Toward this end, we initially examined the reaction of a-diazo-
b-ketoester 616 with a variety of 3,5-dimethoxy-4-hydroxyphenyl-
acetylene derivatives 11a–d in the presence of 1 mol % of Rh2(R-
With an efficient installation of a methoxy group at the C50 po-
sition realized, the stage was now set for completion of the asym-
metric synthesis of 1 as illustrated in Scheme 3. Treatment of
ketone 16 with NaHMDS at ꢀ78 °C followed by addition of PhNTf2
and subsequent palladium-catalyzed reduction of the resulting
enol triflate25 furnished alkene 17 in 81% yield. Reduction of 17
with LiAlH4 provided alcohol 18 in quantitative yield. Next, regio-
selective demethylation of 18 was investigated under a variety of
conditions. This transformation turned out to be even more diffi-
cult than we anticipated, as the bicyclic component was prone to
decomposition under acidic conditions (HBr, TMSI, MeSO3H/NaI
or BF3ꢂOEt2/NaI) frequently used in this type of regioselective
demethylation.26 After considerable experimentation, the Arai–
Nishida protocol with NbCl5 proved to be the method of choice.27
Eventually, treatment of 18 with NbCl5 in 1,2-dichloroethane at
TCPTTL)4 (5) in
a,a,a-trifluorotoluene at room temperature (Ta-
ble 1, entries 1–4). The reaction of 6 with phenylacetylene 11a
bearing a free phenolic hydroxy group gave cycloadduct 12a in
55% yield (entry 1). The enantiomeric excess of 12a was deter-
mined to be 50% by HPLC using a Chiralcel OD-H column. Switch-
ing the dipolarophile to tert-butyldimethylsilyl (TBS)- or methyl-
protected phenylacetylenes 11b and 11c resulted in a noticeable
drop in both product yields (39% and 44%, respectively) and enanti-
Table 1
Enantioselective 1,3-dipolar cycloaddition of a carbonyl ylide derived from 6 with
11a–d and 7 using Rh2(R-TCPTTL)4 (5)a
OMe
MeO
R1
R1
4'
3'
5'
R2
R2
N2
11a–d, 7 (3 equiv)
H
O
CO2tBu
MeO
OH
MeO
OH
MeO
O
H
O
CO2tBu
O
Rh2(R-TCPTTL)4 (5)
(1 mol %)
CF3C6H5, 23 °C, 1 h
O
5'
O
6
12a–d, ent-8
a
b
H
O
CO2tBu
O
H
O
CO2tBu
O
H
O
CO2tBu
O
Entry
Dipolarophile
Product
R1
R2
Yieldb (%)
eec (%)
ent-8
13
14
1
2
3
11a
OH
OTBS
OMe
OAc
OH
OMe
OMe
OMe
OMe
H
12a
12b
12c
12d
ent-8
55
39
44
62
77
50
26
20
1
MeO
OH
MeO
OMe
OMe
11b
11c
11d
7
OH
4
5d
95
a
c
d
Unless otherwise noted, reactions were carried out as follows: a solution of 6
H
O
CO2tBu
O
H
O
CO2tBu
O
(45.3 mg, 0.2 mmol) and dipolarophile (3 equiv) in CF3C6H5 (1 mL) was added over
1 h to a stirred solution of Rh2(R-TCPTTL)4 (5) (3.95 mg, 1 mol %) in CF3C6H5 (1 mL)
at 23 °C.
15
16
b
Isolated yield.
c
Determined by HPLC. See the Supplementary data for details.
The reaction was performed on a 7.0 mmol scale, in which the addition time
Scheme 2. Reagents and conditions: (a) H2, 10% Pd/C, MeOH, 1 h, 99%; (b)
(KSO3)2NO, KH2PO4, acetone/H2O (3:1), 10 min; (c) Na2S2O4, KH2PO4, EtOAc/H2O
(5:1), 0.5 h, 73% (two steps); (d) MeI, K2CO3, acetone, reflux, 1 h, 99%.
d
was 3 h.

6574
N. Shimada et al. / Tetrahedron Letters 51 (2010) 6572–6575
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B. B.; Grabowski, J. F. Tetrahedron 2006, 62, 5171–5177.
MeO
OMe
OMe
MeO
O
OMe
OMe
MeO
O
OMe
OMe
5. For books and reviews on 1,3-dipolar cycloadditions of carbonyl ylides, see: (a)
Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223–269; (b) Doyle, M. P.;
McKervey, M. A.; Ye, T. In Modern Catalytic Methods for Organic Synthesis with
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Wiley-VCH: Weinheim, 2005. Chapter 19.
6. For a book and reviews on the syntheses of natural products by a carbonyl ylide
cycloaddition strategy, see: (a) McMills, M. C.; Wright, D. In Synthetic
Applications of 1, 3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley & Sons: Hoboken,
2003. Chapter 4; (b) Padwa, A. Helv. Chim. Acta 2005, 88, 1357–1374; (c) Padwa,
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2009, 38, 3072–3081.
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Int. Ed. 2006, 45, 6197–6201; (b) Hirata, Y.; Nakamura, S.; Watanabe, N.;
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a,b
c
d
H
O
H
CO2tBu
O
H
CO2tBu
OH
16
17
MeO
18
MeO
OR
OTBDPS
OMe
MeO
OH
OMe
OMe
f,g
h
H
e
O
H
O
H
O
O
OR
OTBDPS
OH
O
19: R = H
20: R = TBDPS
21
1 (95% ee)
[α]D23 +327.5 (c 0.55, MeOH)
lit.1 [α]D23 +1.7 (c 0.23, MeOH)
Scheme 3. Reagents and conditions: (a) NaHMDS, THF, ꢀ78 °C, 1 h, then PhNTf2,
ꢀ78 to ꢀ10 °C, 3 h, 96%; (b) Pd(OAc)2, PPh3, nBu3N, HCO2H, DMF, 60 °C, 40 min,
84%; (c) LiAlH4, THF, 0 °C, 1.5 h, 99%; (d) NbCl5, ClCH2CH2Cl, 70 °C, 1 h, 79%; (e)
TBDPSCl, imidazole, DMAP, DMF, 24 h, 84%; (f) SeO2, dioxane, reflux, 24 h, 81%; (g)
MnO2, CH2Cl2, 15 h, 90%; (h) TBAF, THF, 2 h, 74%.
70 °C facilitated regioselective demethylation, affording phenol 19
as a sole product in 79% yield. Protection of the two hydroxy
groups with TBDPSCl and imidazole provided bis-TBDPS ether 20
in 84% yield. Allylic oxidation of 20 with SeO2 followed by oxida-
tion of the resulting allylic alcohol with MnO2 afforded enone 21
in 73% yield. Finally, removal of the two TBDPS protecting groups
with TBAF completed the asymmetric synthesis of descurainin
(1). The optical rotation of the synthetic material 1 (95% ee),28
9. (a) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett. 1997, 38,
6471–6472; (b) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun.
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101, 5450–5454; (g) Hodgson, D. M.; Glen, R.; Redgrave, A. J. Tetrahedron:
Asymmetry 2009, 20, 754–757.
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Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417–1418; (b) Kitagaki, S.;
Yasugahira, M.; Anada, M.; Nakajima, M.; Hashimoto, S. Tetrahedron Lett. 2000,
41, 5931–5935; (c) Tsutsui, H.; Shimada, N.; Abe, T.; Anada, M.; Nakajima, M.;
Nakamura, S.; Nambu, H.; Hashimoto, S. Adv. Synth. Catal. 2007, 349, 521–526;
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S. Org. Lett. 2008, 10, 3603–3606; (e) Nambu, H.; Hikime, M.; Krishnamurthi, J.;
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(f) Kurosaki, Y.; Shimada, N.; Anada, M.; Nambu, H.; Hashimoto, S. Bull. Korean
Chem. Soc. 2010, 31, 694–696.
11. Suga and co-workers reported enantioselective 1,3-dipolar cycloadditions of
carbonyl ylides using chiral Lewis acid catalysts: (a) Suga, H.; Inoue, K.; Inoue,
S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124, 14836–14837; (b) Suga, H.; Inoue, K.;
Inoue, S.; Kakehi, A.; Shiro, M. J. Org. Chem. 2005, 70, 47–56; (c) Suga, H.;
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Baba, T. Tetrahedron 2010, 66, 3070–3089.
12. Very recently, Iwasawa and co-workers reported a catalytic asymmetric [3+2]
cycloaddition of platinum-containing carbonyl ylides with vinyl ethers. Ishida,
K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842–8843.
13. For the effective use of Rh2(S-TCPTTL)4 (4) in enantioselective aminations, see:
(a) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S.
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M.; Hashimoto, S. Tetrahedron 2009, 65, 3069–3077.
½
a 2D3
ꢁ
+327.5 (c 0.55, MeOH), was greatly different from the litera-
ture value [lit.1
½ ꢁ
a 2D3
+1.7 (c 0.23, MeOH)], albeit with the same
sign. This observation suggests that 1 could be biosynthesized in
near-racemic form like natural product 2.
In summary, we have achieved the first catalytic asymmetric
synthesis of descurainin. The key features of this synthesis include
an efficient construction of the 8-oxabicyclo[3.2.1]octane skeleton
employing Rh2(R-TCPTTL)4-catalyzed tandem formyl-derived car-
bonyl ylide formation–1,3-dipolar cycloaddition, a stereoselective
alkene hydrogenation, an oxidation with Fremy’s salt and a regio-
selective demethylation with NbCl5 developed by the group of Arai
and Nishida. Further application of the catalytic enantioselective
carbonyl ylide cycloaddition methodology to asymmetric synthesis
of biologically active natural products is currently in progress.
Acknowledgments
This research was supported, in part, by a Grant-in-Aid for Sci-
entific Research on Innovative Areas (Project No. 2105: Organic
Synthesis Based on Reaction Integration) from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan. We thank S.
Oka, M. Kiuchi and T. Hirose of the Center for Instrumental Analysis
at Hokkaido University for mass measurements and elemental
analysis.
14. Charette and co-workers recently reported highly efficient asymmetric
cyclopropanation with
a-nitro diazoacetophenones using Rh2(S-TCPTTL)4 (4),
where the X-ray crystal structure of 4 was determined: Lindsay, V. N. G.; Lin,
W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383–16385.
15. Iwabuchi and co-workers recently reported highly enantioselective
intramolecular aza-spiroannulation onto an indole nucleus catalyzed by
Rh2(S-TCPTTL)4 (4). (a) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. J. Org.
Chem. 2009, 74, 7522–7524; (b) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y.
Chem. Commun. 2009, 6264–6266.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.036.
16. Shimada, N.; Hanari, T.; Kurosaki, Y.; Takeda, K.; Anada, M.; Nambu, H.; Shiro,
M.; Hashimoto, S. J. Org. Chem. 2010, 75, 6039–6042.
17. (a) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew. Chem., Int. Ed.
2006, 45, 6532–6535; (b) Snider, B. B.; Wu, X.; Nakamura, S.; Hashimoto, S. Org.
Lett. 2007, 9, 873–874.
References and notes
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2 could be
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backing model system (10% moisture at 200 °C for 15 min). They also reported
that 2 suppressed the bacterial lipopolysaccharide-mediated expression of two
1486.
2. Wen, Y.; He, S.; Xue, K.; Cao, F. Zhong Cao Yao 1986, 17, 122. Chem. Abstr. 1986,
105, 75884m.

N. Shimada et al. / Tetrahedron Letters 51 (2010) 6572–6575
6575
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23. LaLonde and Zhang reported installation of a hydroxy group at the C50 position
19. Assuming that descurainin (1) might also possess the same absolute
configuration as that of natural product 2, we used Rh2(R-TCPTTL)4 (5)
instead of Rh2(S-TCPTTL)4 (4).
20. The absolute configuration of ent-8 was determined to be (1S,5S) by
comparison of the sign of the optical rotation with the data reported in
Ref. 16.
of a-conidendrin possessing a
40-hydroxy-30-methoxybenzene ring via
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24. The reaction of 15 with MeI (1.0 equiv) and K2CO3 (1.0 equiv) in acetone at
room temperature for 12 h gave a mixture of non-selectively methylated
products, bis-methylated product 16 and substrate 15.
21. Hodgson and co-workers reported exo-selective alkene hydrogenation of
8-oxabicyclo[3.2.1]oct-6-en-2-one derivatives. (a) Hodgson, D. M.; Avery, T.
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Avery, T. D.; Donohue, A. C.; Brückl, T. J. Org. Chem. 2004, 69, 8796–8803.
22. (KSO3)2NO, often referred to as Fremy’s salt, has been used in the preparation
of o- and p-benzoquinones, naphthoquinones, and some polycondensed
quinones and in the oxidation of indolines. For a review, see: (a) Zimmer, H.;
Lankin, D. C.; Horgan, S. W. Chem. Rev. 1971, 71, 229–246; For recent examples
of oxidation with Fremy’s salt used in the total syntheses of natural products,
see: (b) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.; Haidour,
A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-Samti, H. Chem.
Commun. 2009, 592–594; (c) Nielsen, L. B.; Slamet, R.; Wege, D. Tetrahedron
2009, 65, 4569–4577; (d) Ishii, S.; Fujii, M.; Akita, H. Chem. Pharm. Bull. 2009,
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26. (a) Kuhn, M.; Keller-Juslén, C.; von Wartburg, A. Helv. Chim. Acta 1969, 52, 944–
947; (b) Thurston, L. S.; Irie, H.; Tani, S.; Han, F.-S.; Liu, Z.-C.; Cheng, Y.-C.; Lee,
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28. The enantiomeric purity of the synthetic material 1 was determined to be 95%
ee by comparison of the HPLC retention time with a racemic sample of 1, which
was prepared according to the literature. See Ref. 4b.