Enantioselective synthesis of Axially chiral hydroxy carboxylic acid derivatives by rhodium-catalyzed [2 〈 2 〈 2] cycloaddition

Article abstract of DOI:10.1021/jo1024255

Axially chiral hydroxy carboxylic acid derivatives were successfully synthesized with high yields and ee values by the cationic rhodium(I)/axially chiral biaryl bisphosphine complex-catalyzed enantioselective [2 〈 2 〈 2] cycloaddition. Axially chiral hydroxy and dihydroxy carboxylic acid derivatives, bearing the aryl group at the ortho-position of the alkoxycarbonyl group, were also synthesized with high regio- and enantioselectivity.

Full text of DOI:10.1021/jo1024255

NOTE
pubs.acs.org/joc
Enantioselective Synthesis of Axially Chiral Hydroxy Carboxylic Acid
Derivatives by Rhodium-Catalyzed [2 þ 2 þ 2] Cycloaddition
Shuichiro Ogaki,† Yu Shibata,† Keiichi Noguchi,‡ and Ken Tanaka*,†
†Department of Applied Chemistry, Graduate School of Engineering, and ‡Instrumentation Analysis Center, Tokyo University of
Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
S Supporting Information
b
ABSTRACT: Axially chiral hydroxy carboxylic acid derivatives
were successfully synthesized with high yields and ee values
by the cationic rhodium(I)/axially chiral biaryl bisphosphine
complex-catalyzed enantioselective [2 þ 2 þ 2] cycloaddition.
Axially chiral hydroxy and dihydroxy carboxylic acid derivatives,
bearing the aryl group at the ortho-position of the alkoxy-
carbonyl group, were also synthesized with high regio- and
enantioselectivity.
Scheme 1
unctionalized axially chiral biaryls are important compounds
as various chiral ligands, catalysts, and optical resolution agents.1
F
For example, axially chiral hydroxy carboxylic acid derivatives, such as
20-methoxy-1,10-binaphthyl-2-carboxylic acid, were used as chiral deri-
vatizing agents for determination of enantiomeric purities and absolute
configurations of optically active alcohols and amines.2 These are also
useful starting materials for the synthesis of axially chiral biarylamide-3
and biarylamine-derived ligands4 and axially chiral ammonium betaine
organocatalysts.5 Therefore, their asymmetric synthesis has been well
investigated to date, and several successful examples have been
reported.6-9 As a cross-coupling approach, the diastereoselective
nucleophilic aromatic substitution on chiral 1-alkoxy-2-naphtholates
with aryl Grignard reagents2a,b,6 and the enantioselective Suzuki-
Miyaura cross-coupling7 were reported (Scheme 1). As a conceptually
different approach, a number of enantioselective ring-opening reactions
of biaryl lactones, possessing configurationally unstable biaryl axes, were
reported (Scheme 1).8
Scheme 2
On the other hand, our research group reported the asym-
metric synthesis of functionalized biaryl compounds by the
cationic rhodium(I)/axially chiral biaryl bisphosphine complex-
catalyzed enantioselective [2 þ 2 þ 2] cycloaddition.10-13 We
report herein the enantioselective synthesis of axially chiral
hydroxy carboxylic acid derivatives,14 which consist of one
naphthol and one benzoic acid moiety, by the rhodium-catalyzed
[2 þ 2 þ 2] cycloaddition (Scheme 2). The enantioselective
benzannulation by the rhodium-catalyzed [2 þ 2 þ 2] cycload-
dition is highly attractive because of not only high catalytic
activity and enantioselectivity but also facile introduction of
various substituents at the ortho-position of the alkoxycarbonyl
group (R1, Scheme 2) upon benzannulation.
We first investigated the reaction of 2-methoxynaphthalene-
derived alkynylester 2a with ether-linked 1,6-diyne 1a (1.2 equiv)
in the presence of the cationic rhodium(I)/(S)-BINAP complex (5
mol %). Pleasingly, the reaction proceeded at room temperature for
only 1 h to give the desired [2 þ 2 þ 2] cycloaddition product 3aa
with high yield and enantioselectivity (Table 1, entry 1). It was
found that the steric bulk of the alkoxycarbonyl group exhibits a
modest impact on yield and enantioselectivity (entries 1-3). The
highest yield and enantioselectivity were obtained by using sterically
demanding i-propyl ester 2c (entry 3).
Effect of axially chiral biaryl bisphosphine ligands (Figure 1) on
yield and enantioselectivity was also examined as shown in Table 2.
Among the bis(diphenylphosphine) ligands examined (entries 1-
3), the use of (S)-BINAP furnished 3aa with the highest
Received: December 8, 2010
Published: February 16, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo1024255 J. Org. Chem. 2011, 76, 1926–1929
|

The Journal of Organic Chemistry
NOTE
Table 1. Effect of Alkoxyl Groups of Monoynes 2a-c on Rh-
Catalyzed Enantioselective [2 þ 2 þ 2] Cycloaddition with
1,6-Diyne 1a
Table 3. Rh-Catalyzed Enantioselective [2 þ 2 þ 2]
Cycloaddition of Symmetrical 1,6- and 1,7-Diynes 1a-d with
Monoynes 2c-ea
entry
2
R
3
yielda (%)
ee (%)
1
2
3
2a
2b
2c
Me
Et
(þ)-3aa
(þ)-3ab
(þ)-3ac
88
99
91
94
96
i-Pr
>99
a Isolated yield.
Figure 1. Structures of axially chiral biaryl bisphosphine ligands.
Table 2. Effect of Ligands on Rh-Catalyzed Enantioselective
[2 þ 2 þ 2] Cycloaddition of 1,6-Diyne 1a with Monoyne 2c
entry
ligand
yielda (%)
ee (%)
1
(S)-BINAP
>99
97
97
99
99
97
96 (þ)
94 (þ)
88 (þ)
96 (þ)
91 (þ)
95 (-)
2
(S)-H8-BINAP
(S)-Segphos
(S)-tol-BINAP
(S)-xyl-BINAP
(R)-BINAP
3
4
5
6
a Reactions were conducted using [Rh(cod)2]BF4 (5 mol %), (S)-
BINAP (5 mol %), 1a-d (1.2 equiv), and 2c-e (1 equiv) in CH2Cl2
at room temperature for 1 h. b Isolated yield.
a Isolated yield.
enantioselectivity (entry 1). The effect of the steric bulk of the aryl
group on the phosphorus of BINAP was then examined. The study
revealed that the use of (S)-BINAP and (S)-tol-BINAP provided
the same yields and enantioselectivities (entries 1 and 4), while that
of (S)-xyl-BINAP decreased the enantioselectivity (entry 5). The
use of (R)-BINAP instead of (S)-BINAP furnished the opposite
enantiomer with almost identical yield and ee value (entry 6).
Thus, we tested the generality of the reaction with respect to both
cycloaddition partners as shown in Table 3. With respect to the
substituents at the 2-position of the 1-alkynylnaphthalene, not only
methoxy (2c, entry 1) but also benzyloxy and methoxymethoxy
derivatives 2d and 2e (entries 2 and 3) were suitable substrates for this
process. With respect to the diynes, not only ether-linked 1,6-diyne 1a
but also tosylamide-linked 1,6-diyne 1b (entry 4) and methylene-
linked 1,6-diyne 1c (entry 5) were suitable substrates for this process.
Furthermore, 1,7-diyne 1d (entry 6) was able to react with 2c to give
the corresponding biaryl 3dc in good yield with high ee value. The
absolute configuration of the biaryl (þ)-3bc was unambiguously
determined to be R by an X-ray crystallographic analysis.15
The following two experiments clearly indicated that the 2-meth-
oxynaphthalene unit is necessary to achieve high enantioselectivity.
The reaction of 2-methoxybenzene-derived alkynylester 2f with 1a
in the presence of the cationic rhodium(I)/(S)-BINAP complex at
room temperature furnished the corresponding biaryl 3af in
excellent yield, while the ee value was extremely low (Scheme 3).
The reaction of 2-methylnaphthalene-derived alkynyl ester 2g with
1a was also examined under the same reaction conditions, which
furnished the corresponding biaryl 3ag in good yield with low ee
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The Journal of Organic Chemistry
NOTE
Scheme 3
Scheme 6
Scheme 4
In conclusion, axially chiral hydroxy carboxylic acid derivatives
were successfully synthesized at room temperature with high yields
and ee values by the cationic rhodium(I)/axially chiral biaryl bispho-
sphine complex-catalyzed enantioselective [2 þ 2 þ 2] cycloaddi-
tion. Axially chiral hydroxy and dihydroxycarboxylic acid derivatives,
bearing the aryl group at the ortho-position of the alkoxycarbonyl
group, were also synthesized with high regio- and enantioselectivity.
Future work will focus on application of new axially chiral hydroxy
and dihydroxy carboxylic acid derivatives in organic synthesis.
Scheme 5
’ EXPERIMENTAL SECTION
Typical Procedure for the Rhodium-Catalyzed Enantiose-
lective [2 þ 2 þ 2] Cycloaddition (Table 3, Entry 1). (S)-
BINAP (6.2 mg, 0.010 mmol) and [Rh(cod)2]BF4 (4.1 mg, 0.010 mmol)
were dissolved in CH2Cl2 (1.0 mL), and the mixture was stirred at room
temperature for 5 min. H2 (1atm) wasintroducedtotheresultingsolutionin
a Schlenk tube. After being stirred at room temperature for 1 h, the resulting
solution was concentrated and dissolved in CH2Cl2 (0.4 mL). To this
solution was added a CH2Cl2 (0.4 mL) solution of 2c (53.7 mg, 0.200
mmol), and then a CH2Cl2 (1.2 mL) solution of 1a (29.3 mg, 0.240 mmol)
was added dropwise over 20 min at room temperature. After being stirred at
room temperature for 1 h, the resulting solution was concentrated and
purified by preparative TLC (toluene/EtOAc = 10:1), which furnished (þ)-
3ac (77.9 mg, 0.199 mmol, >99% yield, 96% ee) as a yellow solid: mp 35.4-
value (Scheme 4). Therefore, both the naphthalene moiety and the
methoxy group are essential for high enantioselection.
As aryl substitution at the ortho-position of the alkoxycarbonyl
group is important for the synthesis of axially chiral organocatalysts,5
the reaction of unsymmetrical 1,6-diyne 1e, possessing phenyl and
methyl at each alkyne terminus, and 2b was examined (Scheme 5).
Pleasingly, the desired biaryl 3eb, bearing the phenyl group at the
ortho-position of the ethoxycarbonyl group, was obtained in high
yield with good ee value along with a small amount of minor
regioisomer 4eb by using the cationic rhodium(I)/(S)-H8-BINAP
catalyst.16
Finally, the enantio- and diastereoselective synthesis of a 1,3-
terayl compound, possessing the protected dihydroxy carboxylic
acid structure, was examined (Scheme 6). The reaction of
2-methoxynaphthalene-derived 1,6-diyne 1f and 2c proceeded
with perfect regioselectivity by using the cationic rhodium-
(I)/(S)-Segphos catalyst to give the desired 1,3-teraryl com-
pound 3fc as a major diastereomer with good yield and ee value
along with minor diastereomer 4fc. The relative and absolute
configurations of the 1,3-teraryl (-)-3fc was unambiguously
determined to be 4R,6S by an X-ray crystallographic analysis.
Interestingly, the absolute configuration (S) of the axial chirality
derived from monoyne 2c is opposite to that of (þ)-3bc (R).
Therefore, the axial chirality derived from diyne 1f would
be determined enantioselectively by the ligand and that
derived from monoyne 2c would be subsequently determined
diastereoselectively.15
36.6 °C; [R]25 þ50.8 (c 3.76, CHCl3, 96% ee); IR (KBr) 2978, 1720,
D
1594, 1466, 1264 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.87 (d, J = 9.0 Hz,
1H), 7.80-7.73 (m, 1H), 7.36-7.27 (m, 3H), 7.25-7.17 (m, 1H), 5.26-
5.16 (m, 4H), 4.59 (sept, J = 6.3 Hz, 1H), 3.86 (s, 3H), 2.25 (s, 3H), 1.78 (s,
3H), 0.69 (d, J = 6.3 Hz, 3H), 0.42 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 168.4, 154.2, 139.0, 137.7, 135.2, 133.5, 133.3, 129.4, 128.7,
128.5, 127.5, 126.3, 125.5, 125.2, 123.4, 121.3, 113,1, 74.1, 74.0, 67.6, 56.5,
21.0, 20.5, 16.3, 15.9; HRMS (ESI) calcd for C25H26O4Na [M þ Na]þ
413.1723, found 413.1731; CHIRALPAK IC, hexane/THF = 95:5, 0.5 mL/
min, retention times 22.2 min (minor isomer) and 24.9 min (major isomer).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
compound characterization data, and X-ray crystallographic files
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
tanaka-k@cc.tuat.ac.jp
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NOTE
’ ACKNOWLEDGMENT
see the following. Co:(a) Gutnov, A.; Heller, B.; Fischer, C.; Drexler,
H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew. Chem.,
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Takagi, K. J. Am. Chem. Soc. 2004, 126, 8382. Rh:(c) Tanaka, K.;
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(12) For enantioselective syntheses of axially chiral biaryls posses-
sing alkoxycarbonyl groups by the transition-metal-catalyzed [2 þ 2 þ
2] cycloaddition, see: (a) Tanaka, K.; Nishida, G.; Ogino, M.; Hirano,
M.; Noguchi, K. Org. Lett. 2005, 7, 3119. (b) Nishida, G.; Suzuki, N.;
Noguchi, K.; Tanaka, K Org. Lett. 2006, 8, 3489. (c) Shibata, T.; Arai, Y.;
Takami, K.; Tsuchikama, K.; Fujimoto, T.; Takebayashi, S.; Takagi, K.
Adv. Synth. Catal. 2006, 348, 2475. (d) Nishida, G.; Ogaki, S.; Yusa, Y.;
Yokozawa, T.; Noguchi, K.; Tanaka, K. Org. Lett. 2008, 10, 2849.
(13) For enantioselective syntheses of axially chiral biaryl phospho-
nates and phosphine oxides by the transition-metal-catalyzed [2 þ 2 þ
2] cycloaddition, see: (a) Heller, B.; Gutnov, A.; Fischer, C.; Drexler,
H.-J.; Spannenberg, A.; Redkin, D.; Sundermann, C.; Sundermann, B.
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(d) Doherty, S.; Smyth, C. H.; Harrington, R. W.; Clegg, W. Organo-
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(14) Syntheses of racemic axially chiral hydroxy carboxylic acid
derivatives by benzannulation were reported. For the nickel-catalyzed
[2 þ 2 þ 2] cycloaddition, see: (a) Sato, Y.; Ohashi, K.; Mori, M.
Tetrahedron Lett. 1999, 40, 5231. (b) For the Diels-Alder cycloaddi-
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(15) Unfortunately, precise mechanisms for the diastereo- and/or
enantioselective formation of (R)-(þ)-3bc and (4R,6S)-(-)-3fc are
difficult to demonstrat at the present stage.
This work was supported partly by Grants-in-Aid for Scientific
Research (Nos. 20675002 and 21 906) from MEXT, Japan. We
thank Takasago International Corp. for the gift of Segphos, H8-
BINAP, tol-BINAP, and xyl-BINAP and Umicore for generous
support in supplying a rhodium complex.
3
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