Asymmetric Total Synthesis of (-)- trans -Blechnic Acid via Rhodium(II)-Catalyzed C-H Insertion and Palladium(II)-Catalyzed C-H Olefination Reactions

Article abstract of DOI:10.1055/s-0033-1340291

An asymmetric total synthesis of (-)-trans-blechnic acid, a dihydrobenzofuran neolignan, has been achieved. The key steps involve an elaboration of the cis-2,3-dihydrobenzofuran core structure by enantio- and diastereoselective intramolecular C-H insertion using dirhodium(II) tetrakis[N-phthaloyl-(R)-tert-leucinate] [Rh₂(R-PTTL)₄] and a direct coupling of an acrylate unit with the core structure employing Yu's palladium(II)-catalyzed intermolecular C-H olefination. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340291

288▌
LETTER
lAettserymmetric Total Synthesis of (–)-trans-Blechnic Acid via Rhodium(II)-Cata-
lyzed C–H Insertion and Palladium(II)-Catalyzed C–H Olefination Reactions
Asymmetric Total Synthesis of (–)-trans-Blechnic Acid
Motoki Ito, Ryosuke Namie, Janagiraman Krishnamurthi, Hitomi Miyamae, Koji Takeda, Hisanori Nambu,
Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan
Fax +81(11)7064981; E-mail: hsmt@pharm.hokudai.ac.jp
Received: 19.09.2013; Accepted after revision: 22.10.2013
enantioselectivity (up to 94% ee) and perfect cis selectiv-
Abstract: An asymmetric total synthesis of (–)-trans-blechnic acid,
ity are achieved (Scheme 1).9,12,13 Using this catalytic
a dihydrobenzofuran neolignan, has been achieved. The key steps
methodology, we recently achieved asymmetric syntheses
of (–)-epi-conocarpan (8) and (+)-conocarpan (9) that was
involve an elaboration of the cis-2,3-dihydrobenzofuran core struc-
ture by enantio- and diastereoselective intramolecular C–H inser-
tion using dirhodium(II) tetrakis[N-phthaloyl-(R)-tert-leucinate] formed via ready epimerization at the C2 stereocenter of
8 (Figure 3),17,18 wherein a trans-propenyl unit was intro-
duced by a Suzuki–Miyaura coupling.
[Rh2(R-PTTL)4] and a direct coupling of an acrylate unit with the
core structure employing Yu’s palladium(II)-catalyzed intermolec-
ular C–H olefination.
Key words: chiral dirhodium(II) catalyst, C–H insertion, C–H ole-
CO2H
CO2H
fination, dihydrobenzofuran neolignan, blechnic acids
CO2H
CO2H
OH
OH
Neolignan natural products containing a 2-aryl-2,3-dihy-
drobenzofuran ring, such as blechnic acids,1 lithospermic
acid,2 conocarpan,3 and epi-conocarpan,4 exhibit a diverse
array of biological activities including anticancer, anti-
HIV, and anti-inflammatory properties.5 Not surprisingly,
these molecules have presented themselves as attractive
and important targets for synthetic investigations. Follow-
ing a number of nonasymmetric stereoselective synthe-
ses,6a a great deal of effort has been devoted to an
asymmetric synthesis of optically active dihydrobenzo-
furan neolignans.6b,7,8
O
O
OH
(–)-trans-blechnic acid (1)
CO2H
OH
OH
OH
(–)-7-epi-blechnic acid (2)
HO2C
CO2H
CO2H
O
OH
OH
O
OH
(+)-8-epi-blechnic acid (3)
OH
OH
OH
(–)-cis-blechnic acid (4)
(–)-trans-Blechnic acid (1) with a 2,3-cis stereochemistry
that is not common in naturally occurring dihydrobenzo-
furan neolignans was isolated from the fronds of Blechna-
ceous ferns by Tanaka and coworkers in 1992 along with
trans isomers (–)-7-epi-blechnic acid (2) and (+)-8-epi-
blechnic acid (3) (Figure 1).1a In 2001, Lewis and cowork-
ers isolated (–)-cis-blechnic acid (4) from the fronds of
Blechnum spicant.1b To the best of our knowledge, no to-
tal synthesis of these natural products has been reported to
date.
Figure 1 Structures of blechnic acids
O
R
O
R
R
R
N
N
R
R
H
H
O
O
O
O
O
O
Rh
Rh
Rh
Rh
R = Me: Rh2(S-PTTL)4 (5a)
R = Et: Rh2(S-PTTEA)4 (5b)
R = Me: Rh2(R-PTTL)4 (5c)
R = Et: Rh2(R-PTTEA)4 (5d)
The rhodium(II)-catalyzed asymmetric intramolecular
C–H insertion reaction of aryldiazoacetates bearing an ar-
ylmethyloxy group at the ortho position represents one of
the most powerful methods for constructing optically ac-
tive 2,3-dihydobenzofurans.9–16 In this area, we have pro-
vided a protocol for the asymmetric synthesis of 2-aryl-
3-methoxycarbonyl-2,3-dihydrobenzofurans 7 via intra-
molecular C–H insertion of phenyldiazoacetates 6 cata-
lyzed by dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-
leucinate] [Rh2(S-PTTL)4 (5a), Figure 2], wherein high
Figure 2 Structures of chiral dirhodium(II) complexes
CO2Me
CO2Me
3S
Rh2(S-PTTL)4
(1 mol%)
N2
R1
O
2R
toluene
–78 °C
O
R2
R1
78–89%
7
R2
>99:1 cis-selectivity
6
up to 94% ee
R1 = H, Cl, OMe, OTBS
2 = H, OTBS
R
SYNLETT 2014, 25, 0288–0292
Advanced online publication: 03.12.2013
DOI: 10.1055/s-0033-1340291; Art ID: ST-2013-U0890-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 Intramolecular C–H insertion reaction catalyzed by
Rh2(S-PTTL)4

LETTER
Asymmetric Total Synthesis of (–)-trans-Blechnic Acid
289
sis of 8,17 we decided to protect the phenolic moiety at C2
as the TIPS ethers throughout the synthesis.
HO
HO
CO2H
O
O
After careful consideration, the MOM ether was selected
for protection of the phenolic OH group at C7, and the two
carboxyl groups were protected as allyl and trichloroethyl
esters. We envisaged that 1 would be accessible from an
appropriately protected intermediate 11a, which would be
derived from cis-2,3-dihydrobenzofuran 12 via Yu’s C–H
olefination process. On the basis of our previous work,9,17
we expected that the intramolecular C–H insertion of
aryldiazoacetate 13 using Rh2(R-PTTL)4 (5c) or
Rh2(R-PTTEA)4 (5d) would provide cis-2,3-dihydrobenzo-
furan 12 with 2S,3R configuration.
R1
R2
CO2H
O
R1 = 4-HOC6H4, R2 = H:
(–)-epi-conocarpan (8)
R1 = H, R2 = 4-HOC6H4:
(+)-conocarpan (9)
OH
O
OH
OH
(+)-lithospermic acid (10)
Figure 3 Structures of conocarpans and (+)-lithospermic acid
In 2011, Wang and Yu reported a highly convergent total
synthesis of (+)-lithospermic acid (10)19 using palladi-
um(II)-catalyzed intermolecular C–H olefination
reaction20 developed by the Yu group as the key step,
which enabled a late-stage coupling of the fully function-
alized acrylate unit with the trans-2,3-dihydrobenzofu-
ran-3-carboxylic acid that was constructed by employing
an asymmetric intramolecular C–H insertion using Davies
catalyst Rh2(S-DOSP)410 and a chiral auxiliary developed
by Fukuyama and Kan.11 While this work is a notable re-
cent landmark,21 the carboxyl-directed arene C–H olefina-
tion has not yet been applied to the sterically congested
cis-2,3-dihydrobenzofuran system. Thus, our interest fo-
cused on an asymmetric synthesis of cis-2,3-dihydroben-
zofuran-containing neolignans by the combination of our
rhodium(II)-catalyzed C–H insertion protocol and Yu’s
palladium(II)-catalyzed C–H olefination method. Herein,
we report an asymmetric total synthesis of (–)-trans-
blechnic acid involving two completely different C–H
functionalization steps.22
The requisite aryldiazoacetate 13 was prepared from the
known 2-allyloxyphenol 1423 as shown in Scheme 3. Pro-
tection of the phenolic hydroxy group as the MOM ether
followed by a Claisen rearrangement gave phenol 15 in
77% yield. O-Alkylation of 15 with 3,4-bis(triisopropyls-
ilyloxy)benzyl alcohol24 under Mitsunobu conditions pro-
vided benzyl ether 16 in 90% yield. Oxidative cleavage of
the C–C double bond of 16 followed by Lindgren–Kraus
oxidation25 furnished carboxylic acid 17 in 86% yield.
Treatment of 17 with allyl bromide and Cs2CO3 afforded
allyl ester 18 in 85% yield. Disappointingly, diazo transfer
to 18 under our usually employed conditions9,10a,17 did not
proceed well. After considerable experimentation, the
Taber protocol26 proved to be the method of choice for
this purpose. Thus, deprotonation of 18 with LHMDS at
–78 °C followed by treatment with benzoyl chloride afford-
ed an α-benzoylated ester, which, upon diazo transfer with
p-nitrobenzenesulfonyl azide and DBU, gave aryldiazo-
acetate 13 in 86% yield for the two steps.
Our retrosynthetic analysis of 1 is outlined in Scheme 2.
Since cis-2,3-dihydrobenzofurans are prone to epimerize
to the thermodynamically more stable trans isomers under
acidic11a,18 or basic conditions,1a,7a,17 the achievement of
this goal relies on the judicious selection of protecting
groups that can be removed under exceptionally mild con-
ditions. Following an instructive precedent in the synthe-
As mentioned above, we initially explored the intramolec-
ular C–H insertion of 13 using 1 mol% of Rh2(R-PTTL)4
(5c). The reaction in toluene at 0 °C in the presence of
4 Å molecular sieves proceeded to completion in less than
12 minutes to give cis-2-aryl-2,3-dihydrobenzofuran 12 in
87% yield with no signs of the formation of a trans isomer
(Table 1, entry 1). The enantioselectivity of this
reaction was determined to be 73% ee by HPLC analysis
(Chiralpak IF). A survey of solvents revealed that toluene
was the optimal solvent for this transformation (Table 1,
entry 1 vs. entries 2 and 3). Lowering the reaction temper-
ature improved the enantioselectivity to 80% ee, wherein
–20 °C was found to be the temperature limit in terms of
product yield (Table 1, entry 4 vs. entry 5).27 We then
evaluated the performance of Rh2(R-PTTEA)4 (5d),
which was exceptionally effective in the synthesis of
(–)-epi-conocarpan.17 Although catalysis with 5d provid-
ed the highest level of enantioselectivity (83% ee), a
marked decrease in product yield was observed (63%
yield, Table 1, entry 6).
CO2H
CO2CH2CCl3
CO2H
CO2H
4
4
3
3
OH
OTIPS
OTIPS
2
2
O
O
7
7
OH
OH
OMOM
11a
(–)-trans-blechnic acid (1)
C–H
olefination
Pd(II)
H
CO2Allyl
H
CO2Allyl
C–H
insertion
3R
N2
OTIPS
OTIPS
Rh(II)
2S
O
OMOM
O
With cis-2-aryl-2,3-dihydrobenzofuran 12 in hand, the
stage was now set for the coupling with an acrylate unit
using Yu’s C–H olefination reaction20 (Scheme 4). Re-
ductive deprotection of the allyl ester provided carboxylic
acid 19a in 85% yield. C–H olefination of 19a with 1.2
OMOM
12
OTIPS
OTIPS
13
Scheme 2 Retrosynthetic analysis of 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 288–292

290
M. Ito et al.
LETTER
OTIPS
OTIPS
HO
1. MOMCl
i-Pr2NEt
MeCN
50 °C, 94%
DEAD, Ph3P
2. 180 °C
82%
toluene–Et2O–THF
90%
O
OH
OMOM
15
OH
14
1. OsO4, NMO
Et2O–t-BuOH–H2O, 0 °C
2. NaIO4
Et2O–H2O
CO2H
3. NaClO2, NaH2PO4
2-methylbut-2-ene
t-BuOH–H2O–Et2O
O
OMOM
O
86%, 3 steps
OMOM
OTIPS
OTIPS
OTIPS
OTIPS
16
17
1. LiHMDS
CO2Allyl
O
then PhCOCl
THF, –78 °C
95%
allyl bromide
Cs2CO3
13
2. p-NBSA, DBU
CH2Cl2, 90%
DMF
85%
OMOM
OTIPS
OTIPS
18
Scheme 3 Preparation of aryldiazoester 13
equivalents of trichloroethyl acrylate (20)28 in the pres- stantial product decomposition. In the next step, removal
ence of 20 mol% of Pd(OAc)2 and 40 mol% of N-acetyl- of the MOM protecting group, we encountered serious
isoleucine under O2 (1 atm) was carried out in tert-amyl difficulties probably due to the electron-withdrawing ef-
alcohol at 50 °C for eight hours to furnish the desired cou- fect of the acrylate introduced.29 Thus, we decided to re-
pling product 11a in 51% yield, while attempts to increase move the MOM ether in advance of the coupling. As
the reaction temperature to improve the yield led to sub- expected, treatment of 19a with TMSOTf (5 equiv) and
2,2′-bipyridyl (7.5 equiv) under Fujioka conditions30 fol-
Table 1 Enantio- and Diastereoselective C–H Insertion of Aryldi-
lowed by exposure to Et2O–H2O afforded phenol 19b as
the sole product in 72% yield. Gratifyingly, we found that
azoacetate 13 Catalyzed by Chiral Dirhodium(II) Complexesa
CO2Allyl
CO2Allyl
19b bearing a phenolic OH group could be coupled with
acrylate 20 under the foregoing conditions to give dihy-
drobenzofuranylacrylate 11b in 50% yield.31 Finally, se-
quential deprotection of the trichloroethyl ester and two
TIPS ethers provided (–)-trans-blechnic acid (1) in 76%
yield without epimerization at the C2 stereocenter. The
Rh(II) catalyst
(1 mol%)
3R
N2
OTIPS
4 Å MS
toluene
2S
O
O
OMOM
OTIPS
OMOM
OTIPS
12
>99:1 cis-selectivity
OTIPS
1
spectroscopic data (IR, H NMR, 13C NMR, HRMS) of
13
the synthetic material 1 were consistent with those report-
ed for natural (–)-trans-blechnic acid (1). Trituration of
the synthetic material 1 {80% ee, [α]D –22.6 (c 0.83,
Entry Rh(II) catalyst
Temp
(°C)
Time
(min)
Yield ee
(%)b
(%)c
26
MeOH)} in H2O produced an enantiomerically enriched
material from the mother liquor in 78% yield, and its op-
tical rotation {[α]D26 –27.2 (c 0.78, MeOH)} was in good
1
Rh2(R-PTTL)4 (5c)
Rh2(R-PTTL)4 (5c)
Rh2(R-PTTL)4 (5c)
Rh2(R-PTTL)4 (5c)
Rh2(R-PTTL)4 (5c)
Rh2(R-PTTEA)4 (5d)
0
0
12
12
87
80
74
81
68
63
73
38
65
80
80
83
2d
3e
4
23
agreement with the literature value {lit.1a [α]D –28.0 (c
0
12
1.00, MeOH)}.32 It was reported that 1 could be converted
into (–)-7-epi-blechnic acid (2)1a and (–)-cis-blechnic acid
(4)1c via epimerization or UV irradiation, respectively.
Thus, our synthesis of (–)-1 also comprises the formal
total syntheses of 2 and 4.
–20
–30
–20
60
5
150
60
6
a All reactions were carried out on a 0.2 mmol scale.
b Isolated yield.
In summary, we have achieved the first asymmetric total
synthesis of (–)-trans-blechnic acid in 15 steps and 9%
overall yield from the known 2-allyloxyphenol.23 This
synthesis also constitutes the asymmetric formal total syn-
c Determined by HPLC analysis (Chiralpak IF).
d CH2Cl2 was used as solvent.
e Et2O was used as solvent.
Synlett 2014, 25, 288–292
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Total Synthesis of (–)-trans-Blechnic Acid
291
(5) (a) For a review, see: Apers, S.; Vlietinck, A.; Pieters, L.
Phytochem. Rev. 2003, 2, 201. (b) Abd-Elazem, I. S.; Chen,
H. S.; Bates, R. B.; Huang, R. C. C. Antiviral Res. 2002, 55,
91. (c) Coy, E. D.; Cuca, L. E.; Sefkow, M. Bioorg. Med.
Chem. 2009, 19, 6922.
H
H
CO2Allyl
Ar
CO2H
Pd(PPh3)4
NaBH4
OTIPS
OTIPS
THF–MeOH
85%
O
O
OMOM
OR
(6) For reviews on stereoselective synthesis of neolignans, see:
(a) Sefkow, M. Synthesis 2003, 2595. (b) Bertolini, F.;
Pineschi, M. Org. Prep. Proced. Int. 2009, 41, 385.
(7) For recent examples of asymmetric total synthesis of natural
products containing 2-aryl-2,3-dihydrobenzofuran, see:
(a) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496.
(b) Jiménez-González, L.; García-Muñoz, S.; Álvarez-
Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem.
Eur. J. 2006, 12, 8762. (c) Clive, D. L. J.; Stoffman, E. J. L.
Org. Biomol. Chem. 2008, 6, 1831. (d) Adams, H.; Gilmore,
N. J.; Jones, S.; Muldowney, M. P.; von Reuss, S. H.;
Vemula, R. Org. Lett. 2008, 10, 1457. (e) Calter, M. A.; Li,
N. Org. Lett. 2011, 13, 3686. (f) Ghosh, A. K.; Cheng, X.;
Zhou, B. Org. Lett. 2012, 14, 5046. (g) Ortega, N.; Beiring,
B.; Urban, S.; Glorius, F. Tetrahedron 2012, 68, 5185.
(h) Chen, C.-Y.; Weisel, M. Synlett 2013, 24, 189.
(8) (a) Fischer, J.; Savage, G. P.; Coster, M. J. Org. Lett. 2011,
13, 3376. (b) Varadaraju, T. G.; Hwu, J. R. Org. Biomol.
Chem. 2012, 10, 5456.
TMSOTf
19a, R = MOM
19b, R = H
2,2'-bipyridyl
CH2Cl2, 0 °C
then Et2O–H2O
72%
12 (80% ee)
Ar = 3,4-(TIPSO)2C6H3
CO2CH2CCl3
CO2CH2CCl3
20
1. Zn, KH2PO4
Et2O–H2O
89%
CO2H
Pd(OAc)2
Ac-Ile-OH
OTIPS
OTIPS
O2, KHCO3
t-amyl-OH
50 °C
2. TBAF
THF, 0 °C
85%
O
OR
11a, R = MOM (51%)
11b, R = H (50%)
CO2H
mp 199.0–200.5 °C,
[α]D26 –22.6 (c 0.83, MeOH)
mp 196.0–197.0 °C
trituration
78%
CO2H
[α]D26 –27.2 (c 0.78, MeOH)
OH
lit.1a mp 198.0–198.5 °C
O
[α]D23 –28.0 (c 1.00, MeOH)
OH
(–)-trans-blechnic acid (1)
OH
(9) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887.
(10) (a) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett.
2001, 3, 1475. (b) Davies, H. M. L.; Morton, D. Chem. Soc.
Rev. 2011, 40, 1857.
Scheme 4 Synthesis of 1
(11) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003,
1028. (b) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am.
Chem. Soc. 2003, 125, 8112. (c) Koizumi, Y.; Kobayashi,
H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am.
Chem. Soc. 2008, 130, 16854. (d) Matsumoto, S.; Asakawa,
T.; Hamashima, Y.; Kan, T. Synlett 2012, 23, 1082.
(12) For the effective use of an immobilized catalyst based on
Rh2(S-PTTL)4 in this system, see: Takeda, K.; Oohara, T.;
Anada, M.; Nambu, H.; Hashimoto, S. Angew. Chem. Int.
Ed. 2010, 49, 6979.
(13) Davies and co-workers reported that Rh2(S-PTAD)4 is a
highly effective catalyst for the construction of cis-2-aryl-
2,3-dihydrobenzofurans. See: Reddy, R. P.; Lee, G. H.;
Davies, H. M. L. Org. Lett. 2006, 8, 3437.
(14) (a) García-Muñoz, S.; Álvarez-Corral, M.; Jiménez-
González, L.; López-Sánchez, C.; Rosales, A.; Muñoz-
Dorado, M.; Rodríguez-García, I. Tetrahedron 2006, 62,
12182. (b) López-Sánchez, C.; Álvarez-Corral, M.;
Jiménez-González, L.; Muñoz-Dorado, M.; Rodríguez-
García, I. Tetrahedron 2013, 69, 5511.
theses of (–)-7-epi-blechnic acid and (–)-cis-blechnic acid.
The key features of the synthesis include an enantio- and
diastereoselective construction of the cis-2,3-dihydroben-
zofuran core structure utilizing a Rh2(R-PTTL)4-catalyzed
intramolecular C–H insertion and a direct coupling of the
acrylate unit with the sterically congested cis-2,3-dihy-
drobenzofuran-3-carboxylic acid employing Yu’s palladi-
um(II)-catalyzed intermolecular C–H olefination. Yet
another feature is that all of the protecting groups used
could be cleanly removed with no signs of epimerization.
Acknowledgment
This research was supported, in part, by a Grant-in-Aid for Scienti-
fic Research from the Japan Society for the Promotion of Science.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(15) Very recently, the Yu and Davies groups reported a
conceptually new asymmetric approach to highly
functionalized trans-2,3-dihydrobenzofurans by a sequence
involving a Rh2(R-PTTL)4-catalyzed enantioselective
intermolecular C–H insertion followed by a Pd-catalyzed
intramolecular C–H activation–C–O cyclization. See:
Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L.
J. Am. Chem. Soc. 2013, 135, 6774.
References and Notes
(1) (a) Wada, H.; Kido, T.; Tanaka, N.; Murakami, T.; Saiki, Y.;
Chen, C.-M. Chem. Pharm. Bull. 1992, 40, 2099. (b) Wang,
C.-Z.; Davin, L. B.; Lewis, N. G. Chem. Commun. 2001,
113. (c) Davin, L. B.; Wang, C.-Z.; Helms, G. L.; Lewis, N.
G. Phytochemistry 2003, 62, 501.
(2) Kelley, C. J.; Mahajan, J. R.; Brooks, L. C.; Neubert, L. A.;
Breneman, W. R.; Carmack, M. J. Org. Chem. 1975, 40,
1804.
(3) Hayashi, T.; Thomson, R. H. Phytochemistry 1975, 14,
1085.
(4) Benevides, P. J. C.; Sartorelli, P.; Kato, M. J.
Phytochemistry 1999, 52, 339.
(16) Zheng, S.-L.; Yu, W.-Y.; Xu, M.-X.; Che, C.-M.
Tetrahedron Lett. 2003, 44, 1445.
(17) Natori, Y.; Tsutsui, H.; Sato, N.; Nakamura, S.; Nambu, H.;
Shiro, M.; Hashimoto, S. J. Org. Chem. 2009, 74, 4418.
(18) Kan and co-workers recently accomplished an asymmetric
total synthesis of (–)-aperidine containing a cis-2,3-
dihydrobenzofuran ring via a Rh2(S-PTTL)4-catalyzed C–H
insertion process. See: Wakimoto, T.; Miyata, K.; Ohuchi,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 288–292

292
M. Ito et al.
LETTER
H.; Asakawa, T.; Nukaya, H.; Suwa, Y.; Kan, T. Org. Lett.
2011, 13, 2789.
min for the major enantiomer, tR = 49.2 min for the minor
enantiomer.
(19) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767.
(20) (a) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science
2010, 327, 315. (b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2010, 132, 14137. (c) Engle, K. M.; Mei,
T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
(21) For further illustrations of the power of a late-stage
intermolecular C–H olefination strategy, see references 7f
and 15.
(22) For a recent review on C–H functionalization in natural
products synthesis, see: Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K. Angew. Chem. Int. Ed. 2012, 51, 8960.
(23) Hurd, C. D.; Greengard, H.; Pilgrim, F. D. J. Am. Chem. Soc.
1930, 52, 1700.
(28) Boutevin, B.; Rigal, G.; Rousseau, A.; Bosc, D. J. Fluorine
Chem. 1988, 38, 47.
(29) Under Fujioka conditions (see ref. 30), deprotection of the
MOM group did not proceed at all; instead, epimerization of
11a was observed (2,3-cis/2,3-trans = 57:43).
(30) (a) Fujioka, H.; Kubo, O.; Senami, K.; Minamitsuji, Y.;
Maegawa, T. Chem. Commun. 2009, 4429. (b) Fujioka, H.;
Minamitsuji, Y.; Kubo, O.; Senami, K.; Maegawa, T.
Tetrahedron 2011, 67, 2949.
(31) Procedure for the Pd(II)-Catalyzed C–H Olefination of
Compound 19b
To a solution of 19b (340 mg, 0.566 mmol), Pd(OAc)2 (25
mg, 0.113 mmol, 20 mol%), KHCO3 (199 mg, 1.98 mmol),
and Ac-Ile-OH (39 mg, 0.226 mmol, 40 mol%) in tert-amyl-
OH (5 mL) was added a solution of trichloroethyl acrylate
(129 mg, 0.633 mmol) in tert-amyl alcohol (1 mL) under O2
(1 atm, balloon). The reaction mixture was stirred for 8 h at
50 °C. The mixture was partitioned between EtOAc and 10%
aq citric acid, and the aqueous layer was separated. The
organic layer was washed with brine and dried over Na2SO4.
Filtration and evaporation in vacuo furnished the crude
product (510 mg), which was purified by column
(24) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Gelin, C. F.
Tetrahedron 2008, 64, 4736.
(25) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980,
45, 1175. (c) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091. (d) Hayashida, J.; Rawal, V. H.
Angew. Chem. Int. Ed. 2008, 47, 4373.
(26) Taber, D. F.; You, K.; Song, Y. J. Org. Chem. 1995, 60,
1093.
(27) Procedure for the Rh2(R-PTTL)4-Catalyzed
Intramolecular C–H Insertion of Compound 13
Rh2(R-PTTL)4 (63.9 mg, 0.045 mmol, 1 mol%) was added to
a stirred solution of 4 Å MS (3.20 g) and 13 (3.20 g, 4.49
mmol) in toluene (45 mL) at –20 °C. After stirring for 1 h,
the reaction mixture was filtered through a Celite pad. The
filtrate was concentrated in vacuo, and the residue was
purified by column chromatography (silica gel; toluene–
EtOAc, 200:1) to give 12 as a white solid (2.50 g, 81%); Rf
chromatography (silica gel; toluene–MeCN, 25:1) to give
11b (226 mg, 50%) as a pale yellow amorphous; Rf = 0.41
(hexane–EtOAc, 3:1); [α]D20 –17.3 (c 0.98, CHCl3). IR
(neat): ν = 2945, 2867, 1716, 1610 cm–1. 1H NMR (400
MHz, CDCl3): δ = 1.04–1.11 (m, 36 H), 1.23–1.31 (m, 6 H),
4.65 (d, J = 9.2 Hz, 1 H), 4.82 (s, 2 H), 5.94 (d, J = 9.2 Hz,
1 H), 6.36 (d, J = 16.0 Hz, 1 H), 6.82–6.86 (m, 2 H), 6.90–
6.94 (m, 2 H), 7.21 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 16.0 Hz,
1 H). 13C NMR (100 MHz, CDCl3): δ = 13.0, 13.1, 18.1,
53.3, 74.2, 87.5, 95.2, 115.7, 117.3, 118.3, 119.0, 120.0,
121.9, 123.9, 126.7, 127.7, 142.9, 143.2, 147.1, 147.6,
147.7, 165.3, 171.2. ESI-HRMS: m/z calcd for
20
= 0.56 (toluene–EtOAc, 100:1); mp 67.0–68.5 °C; [α]D
–10.5 (c 0.33, CHCl3). IR (neat): ν = 2945, 2867, 1744 cm–
1. 1H NMR (400 MHz, CDCl3): δ = 1.03–1.09 (m, 36 H),
1.15–1.29 (m, 6 H), 3.51 (s, 3 H), 4.10 (ddt, J = 1.6, 6.0, 13.6
Hz, 1 H), 4.23 (ddt, J = 1.6, 6.0, 13.6 Hz, 1 H), 4.65 (d, J =
10.0 Hz, 1 H), 5.07 (d, J = 1.6 Hz, 1 H), 5.11 (dt, J = 1.6, 6.0
Hz, 1 H), 5.24 (s, 2 H), 5.52–5.62 (m, 1 H), 5.90 (d, J = 10.0
Hz, 1 H), 6.73 (s, 1 H), 6.74 (s, 1 H), 6.77 (s, 1 H), 6.88 (t, J
= 7.6 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz,
1 H). 13C NMR (100 MHz, CDCl3): δ = 13.1, 13.3, 18.0,
18.1, 54.0, 56.4, 65.6, 86.2, 95.6, 117.2, 118.1, 118.4, 119.4,
119.5, 119.8, 121.8, 126.3, 129.6, 131.9, 141.7, 146.7,
147.3, 149.8, 169.3. ESI-HRMS: m/z calcd for
C38H55Cl3O8NaSi2 [M + Na]+: 823.2420; found: 823.2413.
(32) Data for Synthetic (–)-trans-Blechnic Acid (1)
A colorless needle; Rf = 0.27 (hexane–EtOAc–AcOH,
1:2:0.3); mp 196.0–197.0 °C (H2O); [α]D26 –27.2 (c 0.78,
MeOH). 1H NMR (500 MHz, CD3OD): δ = 4.59 (d, J = 9.0
Hz, 1 H), 5.93 (d, J = 9.0 Hz, 1 H), 6.26 (d, J = 16.0 Hz, 1
H), 6.75 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 6.84
(dd, J = 2.0, 8.5 Hz, 1 H), 6.96 (d, J = 2.0 Hz, 1 H), 7.14 (d,
J = 8.5 Hz, 1 H), 7.56 (d, J = 16.0 Hz, 1 H). 13C NMR (125
MHz, acetone-d6): δ = 54.4, 87.7, 114.9, 115.5, 117.6, 117.9,
119.4, 122.1, 124.2, 129.0, 129.1, 142.4, 144.5, 145.4,
145.9, 149.0, 167.9, 170.9. ESI-HRMS: m/z calcd for
C18H14O8Na [M + Na]+: 381.0634; found: 381.0621.
C38H60O7NaSi2 [M + Na]+: 707.3770; found: 707.3768. The
ee of 12 was determined to be 80% by HPLC with a
Chiralcel IF (hexane–iPrOH, 300:1, 0.5 mL/min): tR = 35.9
Synlett 2014, 25, 288–292
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