Regioselective lactonization of unsymmetrical 1,4-diols: An efficient access to lactone lignans

Article abstract of DOI:10.1039/c0cc04926c

A Cp*Ru-based bifunctional catalyst system (Cp* = η⁵-C₅(CH₃)₅) with a suitably-designed PN ligand (PN = chelating tertiary phosphine-protic amine ligand) has been developed for a regioselective lactonization of

Full text of DOI:10.1039/c0cc04926c

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COMMUNICATION
Regioselective lactonization of unsymmetrical 1,4-diols: an efficient
access to lactone lignansw
Masato Ito,ab Akira Shiibashib and Takao Ikariya*b
Received 12th November 2010, Accepted 7th December 2010
DOI: 10.1039/c0cc04926c
A Cp*Ru-based bifunctional catalyst system (Cp* = g5-
C5(CH3)5) with a suitably-designed PN ligand (PN = chelating
tertiary phosphine-protic amine ligand) has been developed for a
regioselective lactonization of unsymmetrically substituted
1,4-diols, which may provide an expeditious access to a variety
of lactone lignans.
convertible in acetone as an external hydrogen acceptor to the
corresponding g-lactones under mild conditions.3c Encouraged
by the marked catalyst performance, we have next examined
the lactonization of unsymmetrically substituted 1,4-diols with
two primary hydroxyl groups using a diverse array of Cp*Ru
catalyst systems with a structurally different PN ligand (2), in
order to clarify the steric effect of the ligand structure on the
regiochemical outcome. Moreover, the high regioselectivity
gained by this fine-tuning has proven beneficial in the
preparation of lactone lignans that display a substantial range
of biological activities.5 Herein, we wish to report these results.
As illustrated in Scheme 2, we initially examined the
lactonization of 2-benzyl-1,4-butanediol (3a) in acetone as a
model reaction,6 to see if the catalyst molecule can discriminate
two primary hydroxyl groups with subtle steric difference in
3a. The reaction was carried out at 30 1C for 1 h in acetone
We have recently found that a bifunctional catalyst system of
Cp*RuCl(Ph2PCH2CH2NH2) (1a) and KOt-Bu effects the
reversible hydrogen transfer between alcohols and carbonyls,
possibly through a pericyclic transition state as illustrated in
Scheme 1.1–4 This feature was clearly demonstrated by the
intramolecular hydrogen transfer of secondary alcohols. For
example, optically active secondary alcohols undergo rapid
racemization,3a and allylic secondary alcohols undergo redox
isomerization to ketones,3b in toluene containing this catalyst
system under mild conditions. Notably, primary alcohols are
much more susceptible to the similar-type intramolecular
hydrogen transfer as exemplified with a very rapid H–D
scrambling of PhCD2OH in toluene.3c On the other hand,
the same catalyst system promotes the intermolecular
hydrogen transfer when a sacrificial hydrogen acceptor including
acetone, methyl vinyl ketone or acrylates is present in the
reaction system.3a,b Furthermore, a wide range of 1,4-diols
with a primary hydroxyl group at one end are very rapidly
containing the catalyst system (3a : Ru : KOt-Bu
=
100 : 1 : 1). The binary catalyst system of 1a and KOt-Bu
promoted the lactonization of 3a efficiently to give a mixture
of b-benzyl-g-lactone (4a) and a-benzyl-g-lactone (5a) with a
molar ratio of 77 : 23 within 1 h (Table 1, entry 1). Almost
identical catalyst performance in terms of activity and regio-
selectivity was observed when the preformed complex 1a was
replaced with in situ generated catalyst from the ligand 2a and
Scheme
1 Reversible hydrogen transfer between alcohols and
carbonyls.
a Institute for Materials Chemistry and Engineering,
Kyushu University, Kasuga, Fukuoka 816-8580, Japan.
E-mail: mito@cm.kyushu-u.ac.jp; Fax: +81 92-583-7810;
Tel: +81 92-583-7808
b Department of Applied Chemistry, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
E-mail: tikariya@apc.titech.ac.jp; Fax: +81 3-5734-2637;
Tel: +81 3-5734-2636
w Electronic supplementary information (ESI) available: Experimental
procedures for the lactonization and characterization data for the
products as well as other new compounds. See DOI: 10.1039/
c0cc04926c
Scheme 2 Cp*Ru(PN)-catalyzed lactonization of 3 in acetone.
c
2134 Chem. Commun., 2011, 47, 2134–2136
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Table 1 Regioselectivity in the lactonization of 3a
Catalyst system
employedb
Ratio of
productsc
Entry
Substrate
PN ligand
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
A
A
B
A
A
A
A
A
A
B
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2n
2n
2n
77 : 23
82 : 18
83 : 17
81 : 19
80 : 20
90 : 10
76 : 24
78 : 22
81 : 19
88 : 12
96 : 4
Scheme 3 Reaction course for the lactonization.
9
found that the dehydrogenation of 6a in acetone containing
the catalyst system of 1n and KOt-Bu gave 5a and a
substantial amount of 4a (6a : 1n : KOt-Bu = 100 : 1 : 1,
[6a] = 0.5 M in acetone, 30 1C, 1 h, 4a : 5a = 40 : 60). This
result may suggest that the intermediary isomeric lactols, 6a
and 7a, are interconvertible with each other via 3a, as
illustrated in Scheme 3, and hence the regioselectivity in the
first dehydrogenation step does not necessarily determine the
overall regioselectivity in the present lactonization. In fact, the
similar reaction of 6a in the absence of acetone resulted in the
formation of 3a in addition to 4a and 5a (6a : 1n : KOt-Bu =
100 : 1 : 1, [6a] = 0.5 M in toluene, 30 1C, 1 h, 3a : 4a : 5a =
48 : 13 : 39). This result clearly indicated that 6a can serve not
only as a hydrogen donor but also as a hydrogen acceptor, to
promote disproportionation into the diol and isomeric lactones.
Furthermore, the hydrogen acceptor ability of 6a should be
much higher than that of acetone to allow the formation of 4a
via 3a and 7a even in acetone. Therefore, the differentiations of
the two primary hydroxyl groups in the unsymmetrical diols as
well as of two regioisomeric lactols are crucial for determining
the overall regioselectivity in the present lactonization.
10
11
12
13
14
15
16
17
B
B
94 : 6d
82 : 18
92 : 8
A
A
A
A
A
92 : 8
92 : 8
92 : 8
a
Reaction conditions: 3 : Ru : KOt-Bu = 100 : 1 : 1, [3] = 0.5 M in
acetone, 30 1C. All reactions completed within 1 h to give lactones
exclusively as a mixture of 4 and 5. Procedure A: the binary catalyst
b
system of Cp*RuCl(PN) and KOt-Bu (Ru : KOt-Bu = 1 : 1).
Procedure B: the ternary system of Cp*RuCl(isoprene), 2, and
c
KOt-Bu (Ru : 2 : KOt-Bu = 1 : 1 : 1). Determined by integration
of well-resolved signals of 4 and 5 in 1H NMR spectra of a crude
d
product. 48 h.
Cp*RuCl(isoprene) or [Cp*Ru(CH3CN)3]OTf. However, the
use of
a
non-methylated cyclopentadienyl congener,
[(Z5-C5H5)Ru(CH3CN)3]PF6, in place of [Cp*Ru(CH3CN)3]OTf
resulted in the moderate regioselectivity (56 : 44). In contrast
with the negative impact of a less substituted cyclopentadienyl
ligand,7a the structural modification of the PN ligand in
Cp*RuCl(PN) complexes mostly exerted a positive effect for
the preferential formation of 4a. Although the alkyl substitution
at the N-a-carbon had no dramatic impact on the regio-
selectivity (entries 4, 5, 7), N-alkyl substitution in the PN ligand
slightly improved the regioselectivity for 4a (entries 2 and 3).
By contrast, the introduction of geminal two substituents at
the P-a-carbon improved the regioselectivity reaching to
90 : 10 (entry 6). While the change of substituents on the
phosphorous in the PN ligand 2g from phenyl group to p-tolyl
(2h) or 3,5-xylyl (2i) groups resulted in little change in the
regioselectivity (entries 7–9), the similar change in the ligand
2a with o-tolyl group (2j) or cyclohexyl (2k) and tert-butyl (2l)
groups significantly improved the regioselectivity (entries 1,
10–12). Additionally, the replacement of the ethylene
linkage in the ligand 2a with the propylene (2m) or the
benzylic one (2n) gradually improved the regioselectivity
for 4a (entries 13 and 14). The catalyst system of
Cp*RuCl[(2-Ph2P)C6H4CH2NH2] (1n) and KOt-Bu also
promoted the lactonization of structurally similar unsymmetrical
1,4-diols 3b–d to give b-benzylic-g-lactones (4b–d) in a highly
regioselective manner (entries 15–17).7b Therefore, the
substituents on the aryl group in the substrates 3 may have
little effect on the regioselectivity of the lactonization.
Our present method provides
a convenient access to
biologically important lactone lignans. As illustrated in
Scheme 4, the Rh-catalyzed 1,4-addition of suitable aryl-
boronic acids to a-methylene-g-butyrolactone gave 5a–d
quantitatively. Their catalytic hydrogenation2f followed by the
present lactonization with 1n afforded 4a–d, in which the position
of their benzylic groups is switched from a to b. We found that
the minor byproducts 5a–d did not become a major obstacle in
the subsequent stereocontrolled C–C bond formation.9 For
example, the deprotonation of the crude 4c (92 : 8 mixture
of 4c and 5c) with LDA followed by the reaction with
3-(benzyloxy)-1-(bromomethyl)benzene allowed easy isolation of
(ꢀ)-O,O0-dibenzyl enterolactone by silica gel chromatography.
Valuable information on the origin of regioselectivity was
provided by control experiments using 3-benzyl-2-tetrahydro-
furanol (6a, Scheme 3), which was separately prepared as a
diastereomeric mixture from 5a by DIBAL reduction.8 We
Scheme 4 Preparation of a lactone lignan. Reagents and conditions:
(a) arylboronic acid (1.1 equiv.), triethylamine (1.1 equiv.),
[RhCl(cod)]2 (3 mol%), dioxane–H2O, 30 1C. (b) See ref. 2f. (c) see
Table 1 (entries 14–17). (d) See ESI.w
c
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Chem. Commun., 2011, 47, 2134–2136 2135

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and T. Ikariya, Organometallics, 2003, 22, 4190–4192; (c) M. Ito,
A. Sakaguchi, C. Kobayashi and T. Ikariya, J. Am. Chem. Soc.,
2007, 129, 290–291; (d) M. Ito, L.-W. Koo, A. Himizu,
C. Kobayashi, A. Sakaguchi and T. Ikariya, Angew. Chem., Int.
Ed., 2009, 48, 1324–1327; (e) M. Ito, C. Kobayashi, A. Himizu and
T. Ikariya, J. Am. Chem. Soc., 2010, 132, 11414–11415;
(f) T. Ikariya, M. Ito, A. Shiibashi and T. Ootsuka, PCT Int.
Pat. Appl. WO, 2010/004883 A1, Jan 14, 2010; (g) T. Ikariya,
M. Ito and T. Ootsuka, PCT Int. Pat. Appl. WO, 2010/073974 A1,
July, 1, 2010.
3 (a) M. Ito, A. Osaku, S. Kitahara, M. Hirakawa and T. Ikariya,
Tetrahedron Lett., 2003, 44, 7521–7523; (b) M. Ito, S. Kitahara and
T. Ikariya, J. Am. Chem. Soc., 2005, 127, 6172–6173; (c) M. Ito,
A. Osaku, A. Shiibashi and T. Ikariya, Org. Lett., 2007, 9,
1821–1824.
Scheme 5 Preparation of arylnaphthalene lactone lignans.
The present regioselective lactonization was also applicable
to the synthesis of naturally occurring arylnaphthalene lactone
lignans. For example, the catalyst system of 1n and KOt-Bu
promoted the lactonization of 2,3-bis(hydroxymethyl)-1-aryl-
naphthalenes 8 or 9 ([8] = 0.5 M in acetone, 8 : 1n : KOt-Bu =
100 : 1 : 1, 30 1C, 1 h, >99% yield; [9] = 0.1 M in acetone,
9 : 1n : KOt-Bu = 50 : 1 : 1, 30 1C, 15 h, 93% yield) to
furnish 10 or Justicidin E, respectively, and no trace of 11 or
Taiwanin C was detected10 (Scheme 5). These results along
with the aforementioned preferential formation of 4 from 3
may indicate that the sterically less demanding primary
hydroxyl group is favorably susceptible to two-step dehydro-
genation by the catalyst system of 1n and KOt-Bu.
4 M. Ito, A. Osaku, C. Kobayashi, A. Shiibashi and T. Ikariya,
Organometallics, 2009, 28, 390–393.
5 (a) D. C. Ayres and J. D. Loike, Lignans: Chemical, Biological and
Clinical properties, Cambridge University Press, Cambridge, 1990;
(b) S. S. C. Koch and A. R. Chamberlin, Stud. Nat. Prod. Chem.,
1995, 15, 687–725; (c) R. S. Ward, Stud. Nat. Prod. Chem., 2000,
24, 739–798; (d) J. D. Sellars and P. G. Steel, Eur. J. Org. Chem.,
2007, 3815–3828.
6 (a) L. Shao, S. Miyata, H. Muramatsu, H. Kawano, Y. Ishii,
M. Saburi and Y. Uchida, J. Chem. Soc., Perkin Trans. 1, 1990,
1441–1445; (b) S. Kamlage, M. Sefkow, N. Zimmermann and
M. G. Peter, Synlett, 2002, 77–80.
7 (a) The use of [(Z5-indenyl)Ru(PPh3)(Ph2PCH2CH2NH2)]Cl in
place of 1a resulted in very sluggish reaction with moderate
regioselectivity (3 mol%, 50 1C, 21 h, 4a : 5a = 56 : 44). This
result also indicated a possible catalyst poisoning by PPh3;
(b) Although the regioselectivity proved almost identical, the
catalytic activity of the ternary system of [Z5-1,2,3-
(CH3)3C5(CH2)4]RuCl(isoprene), 2n, and KOt-Bu was lower than
the binary system of 1n and KOt-Bu possibly due to excessive steric
congestion arising from the bicyclic cyclopentadienyl ligand. These
results will be reported separately.
8 (a) O. Temme, S.-A. Taj and P. G. Andersson, J. Org. Chem., 1998,
63, 6007–6015; (b) X. Verdaguer, S. C. Berk and S. L. Buchwald,
J. Am. Chem. Soc., 1995, 117, 12641–12642.
9 (a) J. W. Bode, M. P. Doyle, M. N. Protopopova and Q.-L. Zhou,
J. Org. Chem., 1996, 61, 9146–9155 and references therein;
(b) A. van Oeveren, J. F. G. A. Jansen and B. L. Feringa,
J. Org. Chem., 1994, 59, 5999–6007.
In summary, we have developed
a
Cp*Ru-based
bifunctional catalyst system for the regioselective lactonization
of unsymmetrical 1,4-diols. The fine-tuning of the skeleton of
PN ligands in the catalyst system has proven crucial for the
selective dehydrogenation at the sterically less demanding
primary hydroxyl group. Further studies to demonstrate the
synthetic utility of the present catalytic method are in progress.
This work was financially supported by the MEXT (Nos.
16750073 and 18065007 ‘‘Chemistry of Concerto Catalysis’’), by
the Asahi Glass Foundation (M. I.) and by the GCOE Program.
Notes and references
10 (a) T. L. Holmes and R. Stevenson, J. Org. Chem., 1971, 36,
3450–3453; (b) Y. Ishii, T. Ikariya, M. Saburi and S. Yoshikawa,
Tetrahedron Lett., 1986, 27, 365–368; (c) S. R. Flanagan,
D. C. Harrowven and M. Bradley, Tetrahedron, 2002, 58,
5989–6001.
1 (a) M. Ito and T. Ikariya, Chem. Commun., 2007, 5134–5142;
(b) M. Ito and T. Ikariya, J. Synth. Org. Chem. Jpn., 2008, 66,
1042–1048.
2 (a) M. Ito, M. Hirakawa, K. Murata and T. Ikariya, Organo-
metallics, 2001, 20, 379–381; (b) M. Ito, M. Hirakawa, A. Osaku
c
2136 Chem. Commun., 2011, 47, 2134–2136
This journal is The Royal Society of Chemistry 2011