Asymmetric synthesis of neolignans (-)-epi-Conocarpan and (+)-Conocarpan via Rh(II)-catalyzed C-H insertion process and revision of the absolute configuration of (-)-epi-Conocarpan

Article abstract of DOI:10.1021/jo900502d

(Chemical Equation Presented) Catalytic asymmetric synthesis of neolignan natural products (-)-epi-conocarpan and (+)-conocarpan has been achieved by exploiting an enantio- and diastereoselective intramolecular C-H insertion reaction to construct a cis-2-

Full text of DOI:10.1021/jo900502d

devoted to the stereocontrolled synthesis of 2-aryl-2,3-dihy-
drobenzofuran derivatives.6
Asymmetric Synthesis of Neolignans
(-)-epi-Conocarpan and (+)-Conocarpan via
Rh(II)-Catalyzed C-H Insertion Process and
Revision of the Absolute Configuration of
(-)-epi-Conocarpan
Yoshihiro Natori,† Hideyuki Tsutsui,† Naoki Sato,†
Seiichi Nakamura,† Hisanori Nambu,† Motoo Shiro,‡ and
Shunichi Hashimoto*,†
(+)-Conocarpan (1), first isolated from the wood of Cono-
carpus erectus by Hayashi and Thomson in 1975,1 exhibits a
diverse array of biological activities, including insecticidal,7
antifungal,8 and antitrypanosomal properties.9 (-)-epi-Cono-
carpan (2) was isolated from the roots of Piper regnellii by Kato
and co-workers in 1999.2 The absolute configuration of (+)-
conocarpan was assigned as (2R,3R) by comparing the CD curve
of conocarpan acetate with those of reference compounds
possessing different substitution patterns in the aromatic rings.1,10
However, a later chiroptical study of 2,3-dihydrobenzofurans
fused to the steroid nucleus11 indicated that its absolute
configuration should be reversed. Recently, Clive and Stoffman
established the absolute configuration of (+)-conocarpan as
(2S,3S) through their asymmetric synthesis of (-)-conocarpan
(vide infra).12 Since the absolute configuration of (-)-epi-
conocarpan was determined to be (2S,3R) by CD spectra,2 this
assignment should also be reversed.
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan, and Rigaku Corporation,
Akishima, Tokyo 196-8666, Japan
hsmt@pharm.hokudai.ac.jp
ReceiVed March 6, 2009
Racemic conocarpan can be easily synthesized either by an
1,13
oxidative dimerization of p-propenylphenol with FeCl3
or
by a Mn(OAc)3-based oxidative cycloaddition of 4-(3-chloro-
propyl)-2-cyclohexenone with anethole.14 Kato and co-workers
reported an enantioselective conversion of p-propenylphenol to
(+)-conocarpan by an enzyme fraction obtained from Piper
regnellii leaves.13 Clive and Stoffman have accomplished an
asymmetric synthesis of (-)-conocarpan by means of a Sharp-
less asymmetric epoxidation and a radical cyclization of optically
active benzylic ethers.12 The Zheng and Che groups achieved
the synthesis of (()-epi-conocarpan by employing a ruthe-
nium(II) porphyrin-catalyzed intramolecular C-H insertion of
aryl tosylhydrazone salt as a key step.15 However, to the best
of our knowledge, an asymmetric synthesis of (-)-epi-cono-
carpan has not been reported. In this respect, we have provided
a protocol for asymmetric synthesis of cis-2-aryl-3-methoxy-
Catalytic asymmetric synthesis of neolignan natural products
(-)-epi-conocarpan and (+)-conocarpan has been achieved
by exploiting an enantio- and diastereoselective intramo-
lecular C-H insertion reaction to construct a cis-2-aryl-2,3-
dihydrobenzofuran ring system as a key step. The C-H
insertion reaction of 5-bromoaryldiazoacetate catalyzed by
Rh2(S-PTTEA)4, a new dirhodium(II) carboxylate complex
that incorporates N-phthaloyl-(S)-triethylalaninate as chiral
bridging ligands, provided 2-aryl-5-bromo-3-methoxycarbo-
nyl-2,3-dihydrobenzofuran with exceptionally high diaste-
reoselectivity (cis/trans ) 97:3) and high enantioselectivity
for the cis isomer (84% ee).
(6) Sefkow, M. Synthesis 2003, 2595–2625.
(7) Chauret, D. C.; Bernard, C. B.; Arnason, J. T.; Durst, T. J. Nat. Prod.
1996, 59, 152–155.
(8) De Campos, M. P.; Filho, V. C.; Da Silva, R. Z.; Yunes, R. A.; Zacchino,
S.; Juarez, S.; Bella Cruz, R. C.; Bella Cruz, A. Biol. Pharm. Bull. 2005, 28,
1527–1530.
(9) Luize, P. S.; Ueda-Nakamura, T.; Filho, B. P. D.; Cortez, D. A. G.;
Nakamura, C. V. Biol. Pharm. Bull. 2006, 29, 2126–2130.
(10) Achenbach, H.; Gross, J.; Dominguez, X. A.; Cano, G.; Star, J. V.;
Brussolo, L. D. C.; Mun˜oz, G.; Salgado, F.; Lo´pez, L. Phytochemistry 1987,
26, 1159–1166.
Neolignan natural products containing a 2-aryl-2,3-dihy-
drobenzofuran ring, such as conocarpan,1 epi-conocarpan,2 3′,4-
di-O-methylcedrusin,3 and brugnanin,4 display a wide range of
biological activities.5 Consequently, much effort has been
(11) Kurta´n, T.; Baitz-Ga´cs, E.; Majer, Z.; Antus, S. J. Chem. Soc., Perkin
Trans. 1 2000, 453–461.
(12) (a) Clive, D. L. J.; Stoffman, E. J. L. Chem. Commun. 2007, 2151–
2153. (b) Clive, D. L. J.; Stoffman, E. J. L. Org. Biomol. Chem. 2008, 6, 1831–
1842.
(13) Sartorelli, P.; Benevides, P. J. C.; Ellensohn, R. M.; Rocha, M. V. A. F.;
Moreno, P. R. H.; Kato, M. J. Plant Sci. 2001, 161, 1083–1088.
(14) Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978–6984.
(15) Zheng, S.-L.; Yu, W.-Y.; Xu, M.-X.; Che, C.-M. Tetrahedron Lett. 2003,
44, 1445–1447.
† Hokkaido University.
‡ Rigaku Corporation.
(1) Hayashi, T.; Thomson, R. H. Phytochemistry 1975, 14, 1085–1087.
(2) Benevides, P. J. C.; Sartorelli, P.; Kato, M. J. Phytochemistry 1999, 52,
339–343.
(3) Pieters, L.; De Bruyne, T.; Claeys, M.; Vlietinck, A. J. Nat. Prod. 1993,
56, 899–906.
(4) Shang, S.; Long, S. Chem. Nat. Compd. 2008, 44, 186–189.
(5) Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. ReV. 2003, 2, 201–217.
4418 J. Org. Chem. 2009, 74, 4418–4421
10.1021/jo900502d CCC: $40.75 2009 American Chemical Society
Published on Web 05/01/2009

SCHEME 2. Preparation of 5-Bromoaryldiazoacetate 9a
FIGURE 1. Structure of chiral dirhodium(II) complexes.
carbonyl-2,3-dihydrobenzofurans 6 via enantio- and diastereo-
selective C-H insertions of phenyldiazoacetates 5 catalyzed by
dirhodium tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4
(3a) (Figure 1), wherein perfect cis selectivity and high
enantioselectivity (up to 94% ee) are achieved (eq 1).16,17 In
mixtures of cis and trans isomers with 32% ee for 10b.18,22
Davies and co-workers reported that Rh2(S-PTAD)4 (3c),23
derived from adamantylglycine, is an effective catalyst for the
reaction of 9b, providing stereoisomers 8b/10b in 72% yield
with a 14:1 preference for the cis isomer 8b and 79% ee for
8b.23a,24
5-Bromoaryldiazoacetate 9a was prepared as shown in
Scheme 2. O-Alkylation of methyl (5-bromo-2-hydroxyphenyl)-
acetate (11)25 with 4-(triisopropylsilyloxy)benzyl bromide (12)26
provided 5-bromoarylacetate 13 in 68% yield. Since attempted
direct diazo transfer to 13 with p-acetamidebenzenesulfonyl
azide and DBU in CH3CN gave decomposition products, we
used the Danheiser modification of Regitz’s diazo transfer
reaction.27 Deprotonation of 13 with LiHMDS in THF at -78
°C followed by treatment of the resulting enolate with trifluo-
roethyl trifluoroacetate afforded a trifluoroacetylated product,
which upon diazo transfer with methanesulfonyl azide and
triethylamine in CH3CN gave 5-bromoaryldiazoacetate 9a in
75% yield.
order to demonstrate the synthetic potential of this catalytic
methodology, we herein report asymmetric synthesis of (-)-
epi-conocarpan and (+)-conocarpan and a revision of the
absolute configuration of natural (-)-epi-conocarpan.
SCHEME 1. Retrosynthetic Analysis of 1 and 2
On the basis of our previous work,16 we initially explored
the intramolecular C-H insertion of 9a in toluene using 1 mol
(16) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto,
S. Org. Lett. 2002, 4, 3887–3890.
(17) Taber and Song reported the first stereocontrolled Rh(II)-mediated
cyclizations of diazo esters to form five-membered ring cyclic ethers. (a) Taber,
D. F.; Song, Y. Tetrahedron Lett. 1995, 36, 2587–2590. (b) Taber, D. F.; Song,
Y. J. Org. Chem. 1996, 61, 6706–6712. (c) Taber, D. F.; Song, Y. J. Org. Chem.
1997, 62, 6603–6607. For a review of natural product synthesis by Rh(II)-
mediated intramolecular C–H insertion, see: (d) Taber, D. F.; Stiriba, S.-E.
Chem.sEur. J. 1998, 4, 990–992.
(18) Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003, 1028–1030.
(19) Wada, H.; Kido, T.; Tanaka, N.; Murakami, T.; Saiki, Y.; Chen, C.-M.
Chem. Pharm. Bull. 1992, 40, 2099–2101.
Our retrosynthetic analysis of 1 and 2 is outlined in Scheme
1. It has been documented that thermodynamically less-stable
cis-2-(4-hydroxyphenyl)-2,3-dihydrobezofurans are epimerized
to trans isomers by treatment with an acid (TFA in CH2Cl2)18
or a base (Na2CO3 in MeOH).19 Thus, synthesis of 1 would be
achieved by epimerization at the C2 stereocenter of 2. We
carefully selected the TIPS ether as the protecting group for
the phenolic moiety, reasoning that a TIPS-protected p-cresol
is stable under basic conditions.20 It was anticipated that a
propenyl group at C5 would be introduced by a Suzuki-Miyaura
coupling of 5-bromo-2,3-dihydrobenzofuran 8a with propenyl-
boronic acid (7).21 As mentioned above,16 we envisioned that
Rh2(S-PTTL)4-catalyzed C-H insertion of methyl [5-bromo-
2-(4-triisopropylsilyloxybenzyloxy)phenyl]diazoacetate (9a) would
provide cis-(2R,3S)-5-bromo-2,3-dihydrobenzofuran 8a. C-H
insertion reactions of 5-bromoaryldiazoacetates catalyzed by
chiral dirhodium(II) complexes have already been reported by
two research groups (eq 2). Fukuyama and co-workers dem-
(20) Davies, J. S.; Higginbotham, C. L.; Tremeer, E. J.; Brown, C.; Treadgold,
R. C. J. Chem. Soc., Perkin Trans. 1 1992, 3043–3048.
(21) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(22) Fukuyama and co-workers reported the total synthesis of (-)-ephedradine
A, wherein an optically active trans-2,3-dihydrobenzofuran intermediate was
elaborated by Rh2(S-DOSP)4-catalyzed C–H insertion of 5-bromoaryldiazoacetate
containing the pyrrolidinyl (S)-lactamide chiral auxiliary. (a) Kurosawa, W.; Kan,
T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 1028–1030. (b) Kurosawa, W.;
Kobayashi, H.; Kan, T.; Fukuyama, T. Tetrahedron 2004, 60, 9615–9628.
(23) (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437–
3440. (b) Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9,
2625–2628. (c) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
10312–10313. (d) Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun.
2008, 1238–1240. (e) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787–
790. (f) Nadeau, E.; Li, Z.; Morton, D.; Davies, H. M. L. Synlett 2009, 151–
154. (g) Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L. Tetrahedron
2009, 65, 3052–3061.
(24) Davies and co-workers reported that enantioselective intramolecular C–
H insertion of aryldiazoacetates catalyzed by Rh2(S-DOSP)4 (4) afforded 2,2-
disubstituted 2,3-dihydrobenzofurans in up to 94% ee. Davies, H. M. L.; Grazini,
M. V. A.; Aouad, E. Org. Lett. 2001, 3, 1475–1477.
(25) Greenspan, P. D.; Fujimoto, R. A.; Marshall, P. J.; Raychaudhuri, A.;
Lipson, K. E.; Zhou, H.; Doti, R. A.; Coppa, D. E.; Zhu, L.; Pelletier, R.; Uziel-
Fusi, S.; Jackson, R. H.; Chin, M. H.; Kotyuk, B. L.; Fitt, J. J. J. Med. Chem.
1999, 42, 164–172.
(26) Ohshima, T.; Gnanadesikan, V.; Shibuguchi, T.; Fukuta, Y.; Nemoto,
T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 11206–11207.
(27) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org.
Chem. 1990, 55, 1959–1964. (b) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.
Org. Synth. 1996, 73, 134–143.
onstrated that the reaction of 5-bromoaryldiazoacetate 9b
catalyzed by Rh2(S-DOSP)4 (4) afforded the corresponding
5-bromo-2,3-dihydrobenzofurans 8b/10b in 72% yield as 3:2-5:1
J. Org. Chem. Vol. 74, No. 11, 2009 4419

TABLE 1. Enantioselective C-H Insertion of Aryldiazoacetate 9a Catalyzed by Chiral Dirhodium(II) Complexes 3a,ba
ee (%)
10ae
entry
Rh(II) catalyst
solvent
additive
temp (°C)
time (h)
yield (%)b
8a:10ac
8ad
1
2
3
4
5
6
7
8
Rh2(S-PTTL)4 (3a)
Rh2(S-PTTL)4 (3a)
Rh2(S-PTTL)4 (3a)
Rh2(S-PTTL)4 (3a)
Rh2(S-PTTL)4 (3a)
Rh2(S-PTTEA)4 (3b)
Rh2(S-PTTEA)4 (3b)
Rh2(S-PTTEA)4 (3b)
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-23
-23
-40
-60
-60
-40
-60
-60
2.5
0.5
1
12
14
3
62
72
88
68
78
87
34f
80f
98:2
53
75
76
85
82
82
89
84
89:11
84:16
71:29
74:26
98:2
32
28
22
22
4 Å MS
4 Å MS
22
24
97:3
97:3
a All reactions were carried out as follows: Rh(II) catalyst (1 mol %) was added to a solution of 9a (0.10 mmol) in the indicated solvent (1 mL) at
the indicated temperature. b Combined yield of cis and trans isomers. c Determined by 1H NMR analysis of the crude product. d Determined by HPLC
(Chiralcel OD-H). e Determined by HPLC (Chiralpak IA). f Isolated yield of cis isomer.
SCHEME 3.
Preparation of Rh2(S-PTTEA)4 (3b)
% of Rh2(S-PTTL)4 (3a) at -23 °C (Table 1, entry 1). The
reaction proceeded to completion in less than 2.5 h, giving a
98:2 cis/trans mixture of 2-aryl-5-bromo-2,3-dihydrobenzo-
furans 8a/10a in 62% combined yield. The enantiomeric excess
of the cis isomer 8a was determined to be 53% by HPLC
analysis (Chiralcel OD-H). The preferred absolute configuration
of 8a was assigned as (2R,3S) by single-crystal X-ray analysis
(see Supporting Information).28,29 Switching the solvent from
toluene to CH2Cl2 improved the reaction rate, product yield and
enantioselectivity, although a considerable drop in diastereo-
selectivity was observed (cis/trans ) 89:11, entry 2). While
lowering the reaction temperature to -40 °C had little impact
on selectivities (cis/trans ) 84:16, 76% ee, entry 3), the reaction
at -60 °C increased enantioselectivity but significantly reduced
diastereoselectivity (85% ee, cis/trans ) 71:29, entry 4). The
addition of 4 Å molecular sieves (MS) at -60 °C led to minor
improvements in product yield and diastereoselectivity with a
slight erosion in enantioselectivity (78% yield, cis/trans ) 74:
26, 82% ee, entry 5).
To further enhance the diastereoselectivity, we directed our
efforts to the development of new dirhodium(II) carboxylate
catalysts. Eventually, we found that the reaction with dirhod-
ium(II) tetrakis[N-phthaloyl-(S)-triethylalaninate], Rh2(S-PT-
TEA)4 (3b) (vide infra), characterized by an exceptionally large
triethylmethyl group, proceeded at -40 °C to afford 2,3-
dihydrobenzofurans 8a/10a in 87% yield as a 98:2 mixture of
stereoisomers with 82% ee for 8a (entry 6). Although the reason
for the decreased diastereoselectivity in the reaction using Rh2(S-
PTTL)4 (3a) at a lower temperature is unclear at present, Rh2(S-
PTTEA)4 (3b) proved to be more effective than 3a in terms of
diastereoselectivity. Aside from high cis selectivity, the highest
enantioselectivity (89% ee) was observed at -60 °C, although
the product yield was only 34% (entry 7). Gratifyingly, this
problem could be overcome with the addition of 4 Å MS as a
desiccant. The reaction in the presence of 4 Å MS afforded cis
isomer 8a in 80% yield with a similar level of enantioselectivity
(84% ee, entry 8).
The new dirhodium(II) carboxylate catalyst 3b was prepared
from the known carboxylic acid 1430 (Scheme 3). Bromination
of 14 with bromine and PCl331 followed by azidation with NaN3
provided R-azidocarboxylic acid 15. Optical resolution of 15
was accomplished through formation of diastereomeric carbox-
imides with (S)-4-benzyl-2-oxazolidinone32 as a resolving
reagent. The absolute configuration of more polar isomer 16
was established as (4S,2′S) by single-crystal X-ray analysis.28
Hydrolytic removal of the chiral auxiliary33 and azide reduction
followed by recrystallization from MeOH-H2O furnished amino
acid 18. Rh2(S-PTTEA)4 (3b) was prepared from amino acid
18 in 72% yield according to the reported procedure for the
preparation of Rh2(S-PTTL)4 (3a).34
With the efficient construction of (2R,3S)-cis-2-aryl-5-bromo-
2,3-dihydrobenzofuran 8a realized, the stage was now set for
the completion of the asymmetric synthesis of (-)-epi-cono-
(30) Rabjohn, N.; Phillips, L. V.; Stapp, P. R. J. Chem. Eng. Data 1962, 7,
543–544.
(28) CCDC 703985 (8a) and CCDC 695667 (16) contain the crystallographic
data for this paper. These can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(29) The preferred absolute configuration of trans isomer 10a was determined
to be (2S,3S) by comparison of the sign of optical rotation with that of the
compound obtained by epimerization of 8a at the C3 stereocenter. See Supporting
Information.
(31) Homeyer, A. H.; Whitmore, F. C.; Wallingford, V. H. J. Am. Chem.
Soc. 1933, 55, 4209–4214.
(32) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–82.
(33) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28,
6141–6144.
(34) Tsutsui, H.; Abe, T.; Nakamura, S.; Anada, M.; Hashimoto, S. Chem.
Pharm. Bull. 2005, 53, 1366–1368.
4420 J. Org. Chem. Vol. 74, No. 11, 2009

SCHEME 4.
Synthesis of 1 and 2
to be optimal in a wide range of enantioselective C-H insertion
reactions,16,36 newly developed Rh2(S-PTTEA)4 has been found
to exhibit even higher diastereoselectivity (cis/trans ) 97:3)
and slightly higher enantioselectivity (84% ee) compared to
those of Rh2(S-PTTL)4 in this system. Using this catalytic
methodology, we have achieved the first asymmetric synthesis
of (-)-epi-conocarpan (2) in nine steps and 20% overall yield
from methyl arylacetate 11 and an asymmetric synthesis of (+)-
conocarpan (1) via epimerization of (-)-2. We also described
a revision of the originally reported absolute configuration of
(-)-epi-conocarpan. Further application of this methodology to
asymmetric synthesis of biologically active neolignans contain-
ing a 2,3-dihydrobenzofuran skeleton is currently in progress.
Experimental Section
Representative Procedure for the C-H Insertion of 9a
(Table 1, entry 8). Rh2(S-PTTEA)4 (3b)·2EtOAc (47.7 mg, 0.03
mmol, 1 mol %) was added to a mixture of 9a (1.60 g, 3.0 mmol)
and 4 Å MS (1.60 g) in CH2Cl2 (30 mL) at -60 °C under Ar
atmosphere. After stirring at this temperature for 24 h, the 4 Å MS
was filtrated through a Celite pad, and the filtrate was concentrated
1
in vacuo. The ratio of 8a/10a was determined to be 97:3 by H
carpan (2) and (+)-conocarpan (1) as illustrated in Scheme 4.
Reduction of (2R,3S)-8a (84% ee) with DIBAL-H was followed
by tosylation of the resultant hydroxy group to afford tosylate
21 in 93% yield. Trituration of 21 [84% ee, mp 69.0-71.0 °C,
NMR of the crude product. The residue (1.7 g) was purified by
column chromatography (silica gel 90 g, 25:1 hexane/Et2O) to give
8a (1.21 g, 80%) as a white solid: Rf ) 0.50 (6:1 hexane/Et2O);
mp 62.0-63.0 °C for 84% ee; [R]21 -31.4 (c 1.15, CHCl3) for
D
[R]21 +4.9 (c 1.18, CHCl3)] in hexane-EtOAc produced
84% ee; IR (CHCl3) ν 1738 cm-1; 1H NMR (270 MHz, CDCl3) δ
1.08 (d, J ) 7.2 Hz, 18H), 1.20-1.29 (m, 3H), 3.27 (s, 3H), 4.56
(d, J ) 9.9 Hz, 1H), 5.94 (d, J ) 9.9 Hz, 1H), 6.80-6.85 (m, 3H),
7.17 (d, J ) 8.6 Hz, 2H), 7.33-7.36 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 12.6, 17.9, 51.8, 53.6, 86.1, 111.4, 112.8, 119.7, 127.0,
127.5, 128.9, 129.0, 132.3, 156.3, 159.6, 169.7; HRMS (EI) calcd
for C25H33O4SiBr (M+) 504.1331, found 504.1332. Anal. Calcd for
C25H33O4SiBr: C, 59.40; H, 6.58; Br, 15.81. Found: C, 59.11; H,
6.36; Br, 16.11. The enantiomeric excess of 8a was determined to
be 84% by HPLC with a Chiralcel OD-H column (100:1 hexane/
i-PrOH, 0.5 mL/min): tR (major) ) 20.6 min for (2R,3S)-8a; tR
(minor) ) 25.6 min for (2S,3R)-8a.
D
optically pure material [mp 54.0-55.0 °C, [R]22D +6.2 (c 1.15,
CHCl3)] from the mother liquor in 83% yield. Suzuki-Miyaura
coupling of 21 (>99% ee) with propenylboronic acid 7 in the
presence of Pd(PPh3)2Cl2 and K2CO3 provided the coupling
product 22 in 76% yield. Reduction of 22 with LiEt3BH
followed by removal of the TIPS protecting group with TBAF
in THF-AcOH furnished (-)-epi-conocarpan (2) in 83% yield
without epimerization of the C2 stereocenter. The spectroscopic
data (1H and 13C NMR, IR, and CD) of this product were
consistent with those reported for natural (-)-2.2 Although an
optical rotation of synthetic product (2R,3S)-2, [R]21 -9.7
D
(c 0.45, MeOH), was lower than that of natural (-)-2 [lit.2 [R]21
Acknowledgment. This research was supported, in part, by
a Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformations of Carbon Resources”
from the Ministry of Education, 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.
D
-33.3 (c 0.03, MeOH)], the enantiomeric purity of synthetic
(-)-2 was confirmed to be >99% by HPLC analysis (Chiralcel
OD-H). Based on the identical CD spectrum and sign of optical
rotation of synthetic (2R,3S)-2 compared to those reported for
natural (-)-epi-conocarpan,2 the absolute configuration of (-)-
epi-conocarpan should be revised to be (2R,3S). Epimerization
of (-)-2 with Na2CO3 in MeOH19,35 followed by recrystalli-
zation from hexane-EtOAc provided (+)-conocarpan (1) in
71% yield. Synthetic material 1 was spectroscopically (1H and
13C NMR, and IR) identical to natural (+)-11 and also had an
optical rotation, [R]22D +117 (c 1.18, MeOH), in good agreement
Supporting Information Available: Full experimental,
1
characterization data, and copies of H and 13C NMR spectra
for all new compounds, as well as X-ray crystallographic data
in CIF format for 8a and 16. This material is available free of
charge via the Internet at http://pubs.acs.org.
with the literature value [lit.10 [R]21 +122 (c 1.03, MeOH)].
D
In summary, the Rh2(S-PTTEA)4-catalyzed intramolecular
C-H insertion reaction of 5-bromoaryldiazoacetate showed
considerable promise for asymmetric synthesis of cis-2-aryl-5-
bromo-2,3-dihydrobenzofurans. While Rh2(S-PTTL)4 has proven
JO900502D
(36) (a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimoto, S.
Synlett 1996, 85–86. (b) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39,
79–82. (c) Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.; Nakajima, M.;
Hashimoto, S. Chem. Commun. 2001, 1604–1605. (d) Minami, K.; Saito, H.;
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(35) The epimerization afforded a 12:1 mixture of (+)-conocarpan (1)/(-)-
epi-conocarpan (2) in 98% yield. These isomers could not be separated by column
chromatography on silica gel.
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