Modular synthesis of optically active lactones by Ru-catalyzed asymmetric allylic carboxylation and ring-closing metathesis reaction

Article abstract of DOI:10.1039/c2cc18137a

A new synthetic route to optically active unsaturated γ- and δ-lactones has been demonstrated via asymmetric allylic carboxylation with a planar-chiral Cp′Ru catalyst and ring-closing metathesis reaction with a Grubbs II catalyst, and successfully applied to the enantioselective synthesis of (R)-(-)-massoialactone. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc18137a

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COMMUNICATION
Modular synthesis of optically active lactones by Ru-catalyzed
asymmetric allylic carboxylation and ring-closing metathesis reactionw
Koichiro Takii, Naoya Kanbayashi and Kiyotaka Onitsuka*
Received 29th December 2011, Accepted 27th February 2012
DOI: 10.1039/c2cc18137a
Table 1 Screening of reaction conditionsa
A new synthetic route to optically active unsaturated c- and
d-lactones has been demonstrated via asymmetric allylic carboxylation
with a planar-chiral Cp0Ru catalyst and ring-closing metathesis
reaction with a Grubbs II catalyst, and successfully applied to
the enantioselective synthesis of (R)-(ꢀ)-massoialactone.
Optically active lactones constitute a structural motif shared by
many natural products and biologically relevant molecules.1
The efficient synthesis of such molecules remains an exciting
challenge in organic chemistry even though a number of
ingenious reactions have been developed by utilizing metal
catalysts2 and organocatalysts3 in the last decade. The ring-
closing metathesis reaction (RCM) is a powerful tool for the
synthesis of cyclic compounds4 and has been successfully used for
the synthesis of unsaturated lactones.5 Thus, the combination of
RCM and enantioselective reaction giving chiral diolefinic esters
offers a new approach to chiral unsaturated lactones.
Carboxylic
acid
Yieldb
2a/3 (%)
eed
(%)
Entry Catalyst
4/5c
1
2
3
4
5
6
rac-1a (Ar = Ph)
3a (R = H) 2.0 61
3a 5.0 95
3b (R = Me) 2.0 98
1/1
1/1
—
—
rac-1a
rac-1a
(R)-1a
>20/1 —
>20/1 88
1/1 54
>20/1 97
3b
2.0 99
2.0 82
2.0 97
(R)-1b (Ar = o-tolyl) 3b
(R)-1c (Ar = 3,5-xylyl) 3b
We have been involved in the asymmetric catalysis of planar-
chiral cyclopentadienyl-ruthenium (Cp0Ru) complexes (1).6,7
Recently, we reported the highly regio- and enantioselective
allylic substitution of mono-substituted allylic chlorides with
oxygen nucleophiles to give allylic ethers, esters, and alcohols in
good yields.8 As the resulting compounds are useful chiral building
blocks because they have reactive terminal olefins, we focused our
attention on the further transformation of allylic esters by RCM.
We describe herein a new synthetic route to optically active
lactones via asymmetric allylic carboxylation followed by RCM.
Very recently, Feringa and coworkers reported a similar approach
to optically active g-lactones, which was based on Cu-catalyzed
asymmetric allylic alkylation and RCM.9 However, the reaction
has some limitations because a Grignard reagent is used as an
alkyl source in the asymmetric allylic substitution, and the
formation of styrene as a byproduct of metathesis is unfavorable
from the viewpoint of atom economy.
a
Reaction conditions:
3 (0.5 mmol), cat. (1 mol%), Na2CO3
b
(1.5 mmol), THF (2 mL). Isolated yield. Determined by 1H NMR.
c
d
Determined by HPLC analysis using a chiral stationary phase.
The representative results are summarized in Table 1. Treatment
of 2a with acrylic acid (3a) in a 2 : 1 ratio using 1 mol% of
racemic Cp0Ru catalyst 1a under basic conditions gave a 1 : 1
mixture of branched and linear allylic esters (4aa and 5aa) in
61% yield (entry 1). As we have evidence that the use of an
excess amount of 2a suppresses the formation of linear ester,8b
we performed the reactions using 5 equiv. of 2a. Unfortunately,
no significant change was observed in the selectivity of 4aa and
5aa although the yield increased to 95% (entry 2). However,
high selectivity for the branched ester was achieved in the
reaction that used trans-2-butenoic acid (3b) instead of 3a.
Treatment of 2a with 3b selectively produced 4ab in 98% yield
(entry 3). When (R)-1a was used as catalyst, 4ab was obtained
in 99% yield with 88% ee (entry 4). Meanwhile, (R)-1b that has
o-tolyl groups on the phosphine ligand led to decreases in yield
as well as regio- and enantioselectivities (entry 5), whereas (R)-1c
having 3,5-xylyl groups showed high enantioselectivity (97% ee)
with good yield and regioselectivity (entry 6).8c
First, we investigated the asymmetric allylic carboxylation
of cinnamyl chloride (2a) with a,b-unsaturated carboxylate.
Department of Macromolecular Science, Graduate School of Science,
Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043,
Japan. E-mail: onitsuka@chem.sci.osaka-u.ac.jp;
Fax: +81-6-6850-5474; Tel: +81-6-6850-5449
The reactions of a variety of allylic chlorides with unsaturated
carboxylates were conducted under optimized conditions
(Table 2). Not only aryl-substituted allylic chlorides but also
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data of new compounds. See DOI: 10.1039/
c2cc18137a
c
3872 Chem. Commun., 2012, 48, 3872–3874
This journal is The Royal Society of Chemistry 2012

Table 2 Regio- and enantioselective allylic carboxylation with planar-chiral Cp0Ru catalysta
Entry
Allylic chloride
Carboxylic acid
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
2a (R1 = Ph)
2b (R1 = p-C6H4Br)
2c (R1 = p-C6H4CF3)
2d (R1 = 1-naphthyl)
2e (R1 = p-C6H4CO2Me)
2f (R1 = CH2OBn)
2a
3b (R2 = H, R3 = Me, n = 0)
3b
3b
3b
4ab
4bb
4cb
4db
4eb
4fb
4ac
4ad
4ae
97
99
99
99
99
97
99
99
91
97
96
98
96
95
90
94
97
95
3b
3b
7d
8e
9e
3c (R2 = Me, R3 = H, n = 0)
3d (R2 = H, R3 = Me, n = 1)
3e (R2 = R3 = H, n = 2)
2a
2a
a
b
c
Reaction conditions: 2 (1.0 mmol), 3 (0.5 mmol), (R)-1c (5 mmol), Na2CO3 (1.5 mmol), THF (2 mL). Isolated yield. Determined by HPLC
d
e
analysis using a chiral stationary phase. (R)-1c (15 mmol). 2a (2.5 mmol), (R)-1c (15 mmol).
an alkyl-substituted one was applicable to the present system
to give corresponding allylic trans-2-butenoates 4bb–4fb in
quantitative yields with excellent regio- and enantioselectivities
(entries 2–6). The reaction with methacrylic acid (3c) produced
allylic methacrylate 4ac in 99% yield with 94% ee. Allylic
esters 4ad and 4ae were obtained from the reactions with
b,g- and g,d-unsaturated carboxylates in good yields with high
enantioselectivities, although 5 equiv. of 2a was required for
the high regioselectivity.
Table 3 RCM of allylic a,b-unsaturated carboxylates giving g-lactonesa
Then, the resulting allylic esters were subjected to RCM. As
shown in Table 3, treatment of allylic esters with 2 mol% of
the Grubbs II catalyst in CH2Cl2 resulted in the formation of
corresponding a,b-unsaturated g-lactones 6 in good yields
(entries 1–4). High enantiomeric purities were achieved except
for the reaction of 1-(p-carbomethoxyphenyl)allyl ester 4eb.
Simultaneous isomerization took place in the reaction of 4eb
to give achiral b,g-unsaturated g-lactones 7eb in 75% yield
(entry 5).
Entry Ester
Product Yieldb (%) eec (%)
1
4ab (R1 = Ph, R2 = H,
6ab
6bb
6cb
6db
7eb
6fb
6ac
89
99
78
62
75
82
82
97
98
95
99
—
95
97
R3 = Me, 97% ee)
2
4bb (R1 = p-C6H4Br,
R2 = H, R3 = Me, 96% ee)
4cb (R1 = p-C6H4CF3,
R2 = H, R3 = Me, 98% ee)
4db (R1 = 1-naphthyl,
R2 = H, R3 = Me, 96% ee)
4eb (R1 = p-C6H4CO2Me,
R2 = H, R3 = Me, rac)
4fb (R1 = CH2OBn,
3
4d
5d
6d
7d
The reaction of b,g-unsaturated ester 4ad was tricky because
parts of resulting b,g-unsaturated d-lactone 8 isomerized to
a,b-unsaturated lactone 9,10 which could not be separated.
After careful examination of the reaction conditions, we found
that the reaction in CH2Cl2 at 30 1C for 12 h selectively
produced 8 in 77% yield (Scheme 1). On the other hand, the
addition of 2-propanol promoted the sequential isomerization
to give 9 as the sole product in 56% yield.11 Furthermore, the
sequential treatment with hydrogen gave saturated d-lactone
10 in 60% yield.12 No loss of enantiopurity was observed in
these tandem transformations.
R2 = H, R3 = Me, 90% ee)
4ac (R1 = Ph, R2 = Me,
R3 = H, 94% ee)
a
Reaction conditions: 4 (0.3 mmol), Grubbs II (6 mmol), CH2Cl2 (6 mL),
b
c
25 1C, 16 h. Isolated yield. Determined by HPLC analysis using a
chiral stationary phase. Reflux.
d
to the Na+ adducts of trimer and tetramer 12b and 12c
(n = 3 and 4) as well as linear dimer 13 were observed in
the spectrum, 4ae was suitable not for RCM but for the cross
metathesis reaction.13
When g,d-unsaturated ester 4ae was treated under similar
conditions, a complex mixture was obtained (Scheme 2).
The formation of e-lactone 11 could not be confirmed from
the 1H NMR spectrum. However, the ESI-MS spectrum
exhibited a major peak due to the Na+ adduct of dimer 12a
(n = 2) and a small peak due to the H+ adduct of desired
e-lactone 11 was detected as well. As small peaks assignable
The efficient synthesis of optically active a,b-unsaturated
g-lactone 6 was achieved by one-pot sequential reactions, as
shown in Scheme 3. The enantioselectivities of 6ab and 6bb
were the same as those furnished by the two-step reactions,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3872–3874 3873

enantioselectivity was not determined at this stage. Unfortunately,
the tandem RCM–isomerization by a Grubbs II catalyst was
unsuccessful. However, the one-pot stepwise reactions of RCM
and isomerization with DBU produced (R)-(–)-massoialactone 14
in 73% yield with 90% ee.15 This protocol provides an easier
route to 14 compared to the known ones.16
In conclusion, we have developed an efficient method for the
synthesis of optically active unsaturated g- and d-lactones,
which proceeds via asymmetric allylic carboxylation with
planar-chiral Cp0Ru catalyst and RCM with Grubbs II
catalyst. This protocol was successfully applied to the enantio-
selective synthesis of (R)-(ꢀ)-massoialactone. The broad scope
of allylic chloride in the present reaction underscores its high
potential for the synthesis of bioactive organic compounds
with unsaturated g- and d-lactone skeletons.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology (Japan) as well as the Sumitomo Foundation.
Scheme 1 RCM of allylic b,g-unsaturated carboxylates giving g-lactones.
Notes and references
1 (a) I. Collins, J. Chem. Soc., Perkin Trans. 1, 1999, 1377; (b) V. Boucard,
G. Broustal and J. M. Campagne, Eur. J. Org. Chem., 2007, 225.
2 (a) E. L. Carswell, M. L. Snapper and A. H. Hoveyda, Angew.
Chem., Int. Ed., 2006, 45, 7230; (b) B. M. Trost and J. Hitce, J. Am.
Chem. Soc., 2009, 131, 4572.
3 (a) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2003, 125, 1192; (b) H. Ube, N. Shimada and
M. Terada, Angew. Chem., Int. Ed., 2010, 49, 1858.
4 S. Monfette and D. E. Fogg, Chem. Rev., 2009, 109, 3783.
5 A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199.
6 (a) N. Dodo, Y. Matsushima, M. Uno, K. Onitsuka and S. Takahashi,
J. Chem. Soc., Dalton Trans., 2000, 35; (b) Y. Matsushima,
N. Komatsuzaki, Y. Ajioka, M. Yamamoto, H. Kikuchi,
Y. Takata, N. Dodo, K. Onitsuka, M. Uno and S. Takahashi,
Bull. Chem. Soc. Jpn., 2001, 74, 527.
Scheme 2 Metathesis reaction of allylic g,d-unsaturated carboxylates.
7 (a) Y. Matsushima, K. Onitsuka, T. Kondo, T. Mitsudo and
S. Takahashi, J. Am. Chem. Soc., 2001, 123, 10405; (b) K. Onitsuka,
Y. Matsushima and S. Takahashi, Organometallics, 2005, 24, 6472.
8 (a) K. Onitsuka, H. Okuda and H. Sasai, Angew. Chem., Int. Ed.,
2008, 47, 1454; (b) N. Kanbayashi and K. Onitsuka, J. Am. Chem.
Soc., 2010, 132, 1206; (c) N. Kanbayashi and K. Onitsuka, Angew.
Chem., Int. Ed., 2011, 50, 5197.
Scheme 3 One-pot synthesis of g-lactones.
9 B. Mao, K. Geurts, M. Fananas-Mastral, A. W. van Zijl, S. P. Fletcher,
A. J. Minnaard and B. L. Feringa, Org. Lett., 2011, 13, 948.
10 A. E. Sutton, B. A. Seigal, D. F. Finnegan and M. L. Snapper,
J. Am. Chem. Soc., 2002, 124, 13390.
although the yields were slightly lower (Tables 2 and 3,
entries 1 and 2).
11 B. Schmidt, Chem. Commun., 2004, 742.
12 J. Louie, C. W. Bielawski and R. H. Grubbs, J. Am. Chem. Soc.,
2001, 123, 11312.
13 E. B. Pentzer, T. Gadzikwa and S. T. Nguyen, Org. Lett., 2008,
10, 5613.
Finally, we examined the applicability of our method to the
synthesis of a biologically active lactone (Scheme 4).14 Treatment
of 2-octenyl chloride (2g) with 3d gave 4gd in 77% yield though
14 C. Bressy, F. Bargiggia, M. Guyonnet, S. Arseniyadis and J. Cossy,
Synlett, 2009, 565.
15 G. W. K. Cavill, D. V. Clark and F. B. Whitfield, Aust. J. Chem.,
1968, 21, 2819.
16 (a) W. H. Pirkle and P. E. Adams, J. Org. Chem., 1980, 45, 4117;
(b) M. M. Midland, A. Tramontano, A. Kazubski, R. S. Graham,
D. J. S. Tsai and D. B. Cardin, Tetrahedron, 1984, 40, 1371;
(c) F. Bennett, D. W. Knight and G. Fenton, J. Chem. Soc., Perkin
Trans. 1, 1991, 1543; (d) S. Takano, M. Setoh and K. Ogasawara,
Tetrahedron: Asymmetry, 1992, 3, 533; (e) P. V. Ramachandran,
M. V. R. Reddy and H. C. Brown, Tetrahedron Lett., 2000, 41, 583;
(f) F. Marion, F. R. Le, C. Courillon and M. Malacria, Synlett, 2001,
138; (g) L. Fournier, P. Kocienski and J.-M. Pons, Tetrahedron, 2004,
60, 1659; (h) R. Touati, V. Ratovelomanana-Vidal, H. B. Ben and
J.-P. Genet, Tetrahedron: Asymmetry, 2007, 17, 3400; (i) L. Carosi
and D. G. Hall, Can. J. Chem., 2009, 87, 650; (j) J. M. Oliveira,
J. C. R. Freitas, J. V. Comasseto and P. H. Menezes, Tetrahedron,
2011, 67, 3003; (k) A. Harbindu and P. Kumar, Synthesis, 2011, 1954.
Scheme 4 Enantioselective synthesis of (R)-massoialactone.
3874 Chem. Commun., 2012, 48, 3872–3874
c
This journal is The Royal Society of Chemistry 2012