Regioselective formation of optically active cycloheptatrienes by chiral tethered buechner reaction

Article abstract of DOI:10.1246/cl.2004.404

Optically active cycloheptatrienes were prepared by addition of the rhodium carbenoid to polysubstituted phenyl rings connected by a 2,4-pentanediol tether in sufficient regio- and stereoselectivity.

Full text of DOI:10.1246/cl.2004.404

404
Chemistry Letters Vol.33, No.4 (2004)
Regioselective Formation of Optically Active Cycloheptatrienes
¨
by Chiral Tethered Buchner Reaction
Takashi Sugimura,Ã Naoko Ohuchi, Masami Kagawa, Kazutake Hagiya, and Tadashi Okuyama
Graduate School of Material Science, Himeji Institute of Technology, University of Hyogo,
Kohto, Kamigori, Ako-gun, Hyogo 678-1297
(Received December 19, 2003; CL-031257)
Optically active cycloheptatrienes were prepared by addi-
manipulation of the rhodium catalyst. Various optically active
cycloheptatrienes are generally available from the reaction using
proper phenol derivatives as starting materials.
tion of the rhodium carbenoid to polysubstituted phenyl rings
connected by a 2,4-pentanediol tether in sufficient regio- and
stereoselectivity.
The first two substrates, 3c and 3d,9 have electron-with-
drawing m-substituents, the directing effects of which on electro-
philic additions are different. When 3c was treated with
Rh2(OAc)4 in dichloromethane (1.5 M) at room temperature
(30 min), intramolecular addition did not proceed quantitatively
as did with 1 and 3a–b, and gave 4c only in 26% yield after silica
gel chromatography. The obtained 4c was regio- and stereo-
chemically pure, and its regio- and stereoisomers were not de-
tected in the reaction mixture. The low reactivity due to the elec-
tron deficiency at the aromatic ring was overcome by using a
Rh2(OCOCF3)4 catalyst. The product yield was improved to
78%, while a mixture of 4c and 5c was produced in a ratio of
95:5 (Table 1).10
The chiral tethered reaction is a versatile reaction design for
asymmetric synthesis where strict stereocontrol can be achieved
during the reaction between reagent and substrate elements con-
nected by a chiral 2,4-pentanediol (PD) tether.1 Chiral cyclohep-
tatrienes in optically active forms became available by applying
this reaction design to the Buchner reaction.2,3 The PD-tethered
¨
carbenoid addition with 1 is highly stereocontrolled to result in a
quantitative yield of 2 with no trace formation of epi-2
(<0:2%).4 In addition to the high stereoselectivity, reactions
with substrates, 3a4 and 3b,5 having a substituent at the 3-posi-
tion (m-position) proceed regioselectively to give 4 exclusive of
5.
The treatment of 3d with Rh2(OAc)4 catalyst produced 4d in
50% yield. The yield for the intramolecular addition can be im-
proved again with Rh2(OCOCF3)4 to 90%, but in this reaction,
the loss in the regiocontrol is obvious because it gives a mixture
of 4d and 5d in a ratio of 65:35. The high product yield (80%)
and the strict regiocontrol (>98%) as well as the stereocontrol
Regioselectivity in the Buchner reaction is generally poor
¨
for the intermolecular addition to substituted benzenes,6 but in-
tramolecular reactions of some m-methoxy derivatives showed
high regioselectivity.7,8 However, the selectivity is dependent
on the substituents, and the m-methyl or 3,4-dimethoxy analogue
showed poorer selectivity even in the same intramolecular con-
ditions. In this sense, the high regioselectivity observed with
both 3a and 3b is remarkable, and the extension of this PD-teth-
ered reaction to other m-substituted substrates is worthy of ex-
amination. The high regioselectivity of the PD-tethered reaction
is now confirmed for substrates with the electron-withdrawing
m-substituents, and more challenging selectivity with unsym-
metrically 3,5-disubstituted substrates are further achieved with
11
could be achieved with 3d when Rh2(OCOCPh3)4 was em-
ployed as a catalyst. Through the reaction with the m-substituted
substrates 3a–d, the regioselectivity of the intramolecular addi-
tion is generally high, and is not much affected by the electronic
nature of m-substituent. It was also disclosed that optically active
cycloheptatrienes having electron-withdrawing groups can also
be obtained in a good yield by using Rh2(OCOCPh3)4.
The regiocontrol with 3a–d must be due to the relative ge-
ometry of the rhodium carbenoid to the internal reaction sites
of the aromatic ring by the tethering. The differentiation of the
two m-positions, substituted vs unsubstituted (X vs H in 3 to lead
to 4 vs 5) was extended to the differentiation of two different m-
substituents, X vs methyl. For the sake of simplicity in analysis
of the steric factors, two substrates 6a and 6b were employed to
compare the methyl group with ethyl and isopropyl; the former is
more challenging than the latter in their differentiation.
N2
O
O
O
O
O
O
Rh2(OAc)4
O
O
O
(quantitative)
1
2
epi-2
The 3,5-disubstituted substrates 6a and 6b were synthesized
according to the procedure for the other substrates.12,13 When
they were treated with Rh2(OAc)4 in dichloromethane at room
temperature, mixtures of regioisomers 7 and 8 were produced
in ratios of 55:45 from 6a and 74:26 from 6b. The
Rh2(OCOCF3)4 catalyst reduced the regioselectivity to give ap-
proximately equal amounts of 7 and 8. Improvement of the re-
gioselectivity with 6b was achieved by using catalysts having
bulkier ligands, and the observed regioselectivity increased with
their bulkiness; acetate < octanoate < pivalate < triphenlyace-
tate (Table 1). As a result, 7b was obtained in over 98% regio-
(> 99.8%)
(< 0.2%)
N2
O
O
Rh2(OAc)4
O
O
O
O
O
O
O
X
3a. X = Me
X
3b. X = OMe
3c. X = COOMe
3d. X = Cl
4
5 X
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.4 (2004)
405
Table 1. Regioisomeric ratios of 4 vs 5 and 7 vs 8 for the reaction of 3c–d and 6a–b, respectively, with varied rhodium catalystsa
Substrate
Rh2(OAc)4
Rh2(OCOCF3)4
Rh2(OCOC7H15)4
Rh2(OCOt-Bu)4
Rh2(OCOCPh3)4
3c
3d
>98:<2
>98:<2
55:45
95: 5
65:35
50:50
50:50
—
—
58:42
82:18
—
—
69:31
86:14
>98:<2
>98:<2
81:19
6ab
6bb
a
74:26
>98:<2
The reaction was carried out at room temperature, and the isomeric retios were determined by 1H NMR of the reaction mixture.
b
The reaction mixture contained only 7 and 8 except for the adduct with contaminated water.
References and Notes
N2
1
T. Sugimura, in ‘‘Recent Research Developments in Organic
Chemistry,’’ ed. by S. G. Pandalai, Transworld Research
Network, Trivandrum (1998), Vol. 2, pp 47–53.
O
O
O
O
Rh2(OCOR)4
X
O
O
O
O
O
2
3
T. Sugimura, S. Nagano, and A. Tai, Chem. Lett., 1998, 45.
For Buchner reaction, see: H. M. L. Davies, in ‘‘Comprehen-
¨
X
6a. X = Et
6b. X = iPr
X
7
8
sive Organic Synthesis,’’ ed. by B. M. Trost, Pergamon,
Oxford (1991), Vol. 4, pp 1031–1067; G. Mass, in ‘‘Topics
in Current Chemistry,’’ Springer-Verlag, Berlin (1987),
Vol. 137, pp 75–253; M. P. Doyle, M. A. McKervey, and
T. Ye, ‘‘Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds,’’ Wiley, New York (1998), Chap. 6.
T. Sugimura, K. Hagiya, Y. Sato, T. Tei, A. Tai, and T.
Okuyama, Org. Lett., 3, 37 (2001).
T. Sugimura, M. Kagawa, K. Hagiya, and T. Okuyama,
Chem. Lett., 2002, 260.
A. J. Anciaux, A. Demonceau, A. F. Noels, A. J. Hubert, R.
Warin, and P. Teyssie, J. Org. Chem., 46, 873 (1981).
M. P. Doyle, M. S. Shanklin, and H. Q. Pho, Tetrahedron
Lett., 29, 2639 (1988).
Scheme 2.
chemical purity from the reaction of 6b with Rh2(OCOCPh3)4.
The reaction of 6a differentiating methyl and ethyl groups was
more difficult to control. The selectivity with Rh2(OAc)4 could
be improved with bulkier catalysts though the regioselectivity
was not high enough even with very bulky Rh2(OCOCPh3)4
(up to 7a:8a = 4:1).
Generality of the regiocontrol by m-substituent was then
demonstrated with a 3,4-disubstituted substrate 9. Starting with
5-hydroxyindane, four-step conversion proceeded under strict
regiocontrol (>98%) as well as stereocontrol to give a single iso-
mer of ring-fused cycloheptatriene 10 (Scheme 3). Although 10
is not fully stable for epimerization or olefinic isomerization,14
its two-step conversion gave a stable and stereochemically pure
compound 11, a potent chiral synthon for polyquinane terpe-
noids.15
4
5
6
7
8
M. Kennedy, M. A. McKervey, A. R. Maguire, S. M.
Tuladhar, and M. F. Twohig, J. Chem. Soc., Perkin Trans.
1, 1990, 1047.
9
The substrates 3c and 3d were prepared by applying the
reported method2 as follows: a) Mitsunobu reaction of
(2R,4R)-2,4-pentanediol with 3-chlorophenol or 3-methoxy-
carbonylphenol (79.6 and 86.5% yields, respectively), b) for-
mation of acetoacetate ester with diketene and triethylamine
(89.3 and 88.3%), treatment with p-tosyl azide and triethyl-
amine, and then c) reaction with aqueous sodium hydroxide
(85.1 and 79.5%). Stereochemical purities of 3 were con-
firmed as over 99% pure by GLC analysis after necessary
conversions.
The regioselectivity of the PD-tethered Buchner reaction
¨
was found to be controlled and enhanced by the steric bulkiness
of the ligands of the catalyst. The results display an additional
advantage of the PD-tethered reaction inaccessible with conven-
tional inter- and intramolecular reactions.
OH
O
O
N2
a, b, c
O
10 This catalyst was also effective for p-methoxycarbonyl
substrate. The product yield by Rh2(OAc)4 (31.7%) was
improved to 68.7%.
9
11 S. Hashimoto, N. Watanabe, and S. Ikegami, Tetrahedron
Lett., 33, 2709 (1992); S. Hashimoto, N. Watanabe, and S.
Ikegami, J. Chem. Soc., Chem. Commun., 1992, 1508.
12 5-Ethyl-3-methylphenol was prepared from 5-methylresorci-
nol by the sequence of i-PrBr/K2CO3 (46.9%), Tf2O/Et3N
(96.5%), EtMgBr/NiCl2dppe (58.7%), and BBr3 (quant).
13 Isolated yields for the three-steps preparation procedure
shown in the Ref. 9: For 6a, a) ca. 70%, b) 84.8%, c)
76.4%. For 6b, a) 67.5%, b) 95.2%, c) 63.4%.
14 T. Sugimura, W. H. Kim, M. Kagawa, and T. Okuyama, Org.
Lett., 4, 2059 (2002).
15 L. A. Paquette and A. M. Doherty, ‘‘Polyquinane Chemis-
try,’’ Springer-Verlag, New York (1987).
O
O
OH
O
O
O
e, f
d
11
10
Scheme 3. Reagents and conditions. a: (2R,4R)-2,4-pentane-
diol/diisopropyl azodicarboxylate/PPh3 (74.3%), b: diketene/
triethylamine (91.2%), c: TsN3/triethylamine, then 1 M NaOH
aq (87.3%), d: Rh2(OAc)4 (82.8%), e: LiAlH4/À78 ꢀC (quant.),
f: TsOHÁPy/THF/rt (70.6%).
Published on the web (Advance View) March 6, 2004; DOI 10.1246/cl.2004.404