Concise enantioselective synthesis of δ,δ-disubstituted δ-valerolactones

Article abstract of DOI:10.1016/j.tetlet.2014.04.006

Efficient access to enantioenriched δ,δ-disubstituted δ-valerolactones is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst allowed for direct catalytic asymmetric γ-addition of allyl cyanide to ketones, producing tertiary homoallylic alcohols with a Z-configured α,β-unsaturated nitrile. Electrophilic activation of the nitrile functionality triggered 6-exo-dig cyclization, and subsequent N-acylation gave rise to the δ-valerolactone skeleton via CN bond cleavage.

Full text of DOI:10.1016/j.tetlet.2014.04.006

Tetrahedron Letters 55 (2014) 3167–3171
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise enantioselective synthesis of d,d-disubstituted
d-valerolactones
a,b,
Akira Saito a, Naoya Kumagai a, , Masakatsu Shibasaki
⇑
⇑
a Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
b JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient access to enantioenriched d,d-disubstituted d-valerolactones is described. A soft Lewis acid/hard
Received 1 March 2014
Revised 31 March 2014
Accepted 2 April 2014
Available online 12 April 2014
Brønsted base cooperative catalyst allowed for direct catalytic asymmetric
c-addition of allyl cyanide to
ketones, producing tertiary homoallylic alcohols with a Z-configured ,b-unsaturated nitrile. Electrophilic
a
activation of the nitrile functionality triggered 6-exo-dig cyclization, and subsequent N-acylation gave rise
to the d-valerolactone skeleton via CAN bond cleavage.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Valerolactone
Cyclization
Nitrile
Silver
Introduction
addition of allyl cyanide 2 to ketones 1 to afford the requisite cycli-
zation precursors 3 with perfect atom economy. Herein we report a
The d-valerolactone skeleton is a ubiquitous substructure in
biologically active natural products.1 The optically active d-mono-
substituted d-valerolactone core is readily accessed by the
corresponding enantioenriched secondary alcohols through lacton-
ization of d-hydroxy carboxylic acids or ring-closing metathesis via
acryloylated homoallylic alcohols.1 In contrast, d,d-disubstituted d-
valerolactones are less accessible.2 Only a limited collection of
compounds with a chiral tertiary alcohol unit are present in the
chiral pool,3 and enantioselective synthesis of chiral tertiary alco-
hols is much less explored than that of secondary alcohols.4 More-
over, lactonization of carboxylic acid bearing a tertiary alcohol at
the d-position generally requires forcing conditions due to steric
hindrance. This steric issue also retards the formation of acryloyl
ester for ring-closing metathesis. We recently disclosed a catalytic
protocol that allows for enantioselective access to chiral tertiary
one-pot protocol to convert chiral d-hydroxy
nitriles to d,d-disubstituted unsaturated d-valerolactones
(Scheme 1).
a,b-unsaturated
3
Results and discussion
Enantioselective construction of tetrasubstituted stereogenic
centers has been a sustained topic in modern synthetic organic
chemistry.6 In particular, a catalytic asymmetric transformation
that fulfills CAC bond formation with perfect atom economy offers
the most productive synthetic protocol.7,8 Our research in this field
recently revealed that a soft Lewis acid/hard Brønsted base cooper-
ative
catalyst
comprising
[Cu(CH3CN)4]ClO4/(R,R)-Ph-BPE/
Li(OC6H4-p-OMe) with hard Lewis acidic bisphosphine oxide addi-
tive 5 efficiently promotes the direct addition of allyl cyanide 2 to
ketones 1 (Scheme 2).5,9 The reaction proceeds through a simple
alcohols bearing a pendant Z-configured
a,b-unsaturated nitrile
3.5 We reasoned that this specific transformation is particularly
suitable for producing d,d-disubstituted d-valerolactones because;
(1) the Z-configuration of olefin is beneficial to cyclization; (2)
nitrile is in the carboxylic acid oxidation state and thus the
oxidation/reduction process can be avoided; and (3) 1–2 mol % of
a designed cooperative catalyst is sufficient to promote the direct
proton transfer between substrates, and c-addition via a six-mem-
bered transition state selectively produces enantioenriched ter-
tiary alcohol 3 bearing a Z-configured olefin. We attempted the
intramolecular cyclization of a model compound 3a to provide d-
valerolactone.10 The use of mild protic acids resulted in no conver-
sion whereas strong acids induced dehydration of the hydroxyl
group, suggesting that chemoselective activation of a nitrile would
be a viable strategy. Various soft Lewis acids that could be coordi-
nated by nitrile functionality in an end-on fashion were therefore
investigated. In combination with DBU, the addition of AgOTf or
⇑
Corresponding authors. Tel.: +81 3 3441 7779; fax: +81 3 3441 7589.
E-mail addresses: nkumagai@bikaken.or.jp (N. Kumagai), mshibasa@bikaken.or.
jp (M. Shibasaki).
http://dx.doi.org/10.1016/j.tetlet.2014.04.006
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3168
A. Saito et al. / Tetrahedron Letters 55 (2014) 3167–3171
Scheme 1. Synthetic strategies for d-substituted d-valerolactones.
Scheme 2. Direct catalytic asymmetric addition of allyl cyanide.
CuOTfꢀtoluene0.5 salts at room temperature rendered the rapid dis-
appearance of 3a within 10 min to give transient cyclic imidate 6
as detected by 1H NMR analysis (Table 1, entries 1, 2).11 All
attempts to directly convert imidate 6 to d-valerolactone failed,
presumably due to an unwanted ring-opening reaction. To elimi-
nate the nitrogen functionality under hydrolytic conditions,
appendage of an electron-withdrawing group on the imide nitro-
gen was examined. In situ acetylation of imidate 6 produced the
desired d-valerolactone 4a in 16% yield after subsequent acidic
hydrolysis with 1 M HCl aq (entry 3). The use of TFAA to generate
more electron-withdrawing trifluoroacetylated imidate outper-
formed Ac2O to furnish 4a in 32% yield with retention of the
enantiopurity (entry 4). The use of sulfonylating reagents was
not effective to direct the desired reaction pathway, resulting in
complicated reaction mixtures (entries 5, 6). Hydrolysis under
milder acidic conditions (1 M AcOH aq) allowed for the isolation
of N-mesylated imide 7, suggesting that sulfonylated imide had
enhanced stability to prevent the subsequent liberation of sulfon-
amide (entry 7). The hydrolytic pathway was dependent on the
acidic medium and 1 M AcOH proved to be the best in terms of
yield of d-valerolactone 4a (76%) and reaction time (10 min)
(entries 8–10).12 The cyclization/trifluoroacetylation/hydrolysis
sequence was performed in one-pot without quenching or purifi-
cation. In contrast to the smooth formation of imidate 6 with cat-
ionic Cu or Ag salts,13 the Ag salts of more intimate ion pairs were
not sufficient to induce the initial cyclization. The use of AgNO3
allowed for the partial formation of imidate 6 over an extended
period of time and d-valerolactone 4a was obtained in moderate
yield after subsequent trifluoroacetylation/hydrolysis (entry 11).
Increasing the reaction temperature was not beneficial to accel-
erate the cyclization and 4a was obtained in even lower yield
(entry 12). No indication of the formation of 6 was observed with
AgOAc or Ag2CO3 and the following reactions afforded trifluoro-
acetylated substrate 8 and the recovery of 3a (entries 13, 14). Other
cationic transition metal salts were much less effective for induc-
ing the initial cyclization, even at an elevated temperature, and
several unidentified byproducts were associated (entries 15, 16).
The scope of the present one-pot protocol for d,d-disubstituted
d-valerolactones 4 is summarized in Table 2 with the synthesis of
cyclization precursor 3, produced by a previously reported proce-
dure.5b Ketone 1d bearing a trifluoromethyl group at the para posi-
tion is a previously unexplored substrate and the corresponding
product 3d was obtained in 80% yield and 98% ee with 1 mol % of
catalyst loading (entry 4). Higher catalyst loading (2 mol %) was

A. Saito et al. / Tetrahedron Letters 55 (2014) 3167–3171
3169
Table 1
Transformation of 3a to d,d-disubstituted d-valerolactone 4a
Entry
1. Formation of 6
2. Activation
3. Hydrolisis
Yield of 4ab (%)
Remarks
Soft Lewis acid
Time (min)
N-Acylation (sulfonylation)
Hydrolytic conditionsa
1
2
3
4
5
6
7
8
9
10
11
12d
13
14
15f
16f
CuOTfc
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgNO3
AgNO3
AgOAc
Ag2CO3
10
10
10
10
10
10
10
10
10
10
60
60
180
180
180
180
—
—
HCl
HCl
HCl
HCl
HCl
HCl
AcOH
H2SO4
H3PO4
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
0
0
16
32
0
6 was detected
Ac2O
TFAA
Tf2O
MsCl
MsCl
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
TFAA
0
0
7 (40%)
53
63
76
46
40
0
0
0
18
3a (73%), 8 (16%)
3a (44%), 8 (39%)
3a (13%), 8 (31%)
3a (11%), 8 (0%)
e
Ni(OTf)2
Fe(OTf)3
a
b
c
d
e
f
1 M Aqueous acid solution (equal volume to the reaction mixture) was added.
Isolated yield.
CuOTfꢀtoluene0.5 was used.
Reaction temperature was 50 °C.
0.55 equiv of Ag2CO3 (1.1 equiv based on Ag content) was used.
Reaction temperature was 60 °C.
Table 2
Direct catalytic asymmetric addition of allyl cyanide 2 to ketones 1 to afford cyclization precursors 3 and the subsequent one-pot formation of d,d-disubstituted d-valerolactones 4
Entry Ketone
Product
x
Time
Yielda
(%)
eeb
(%)
Entry d-Valerolactone
Yielda
(%)
Enantiopurityb
(%)
(mol %) (h)
1
1
1
2
40
40
40
83
78
67
99
98
99
10
76
80
72
98
98
99
2
3
20
30
4
1
40
80
98
40
78
98
(continued on next page)

3170
A. Saito et al. / Tetrahedron Letters 55 (2014) 3167–3171
Table 2 (continued)
Entry Ketone
Product
x
Time
Yielda
(%)
eeb
(%)
Entry d-Valerolactone
Yielda
(%)
Enantiopurityb
(%)
(mol %) (h)
5
1
1
40
72
84
68
99
94
50
69
76
98
95
6c
60
7c
1
2
72
72
68
68
96
99
70
80
72
74
96
98
8c
a
Isolated yield.
b
Determined by chiral stationary phase HPLC analysis.
c
LiOtBu was used instead of Li(OC6H4-p-OMe).
Scheme 3. Formation of racemic d-valerolactone from allylic alcohol 3i and retention of enantiopurity by selective hydrogenation.
applied to the reaction using tetralone 1h to increase the yield,
resulting in comparable enantioselectivity (previous report:
1 mol %, 72 h, 53%, 98% ee).5b The obtained Z-configured homoal-
subjected to the optimized conditions for lactone formation
(Table 1, entry 10). Irrespective of the substituents on the aromatic
ring, the one-pot protocol produced the corresponding d,d-disub-
stituted d-valerolactones 4 (entries 10–50). Tertiary alcohols 3f
lylic tertiary alcohols
3 bearing a nitrile functionality were

A. Saito et al. / Tetrahedron Letters 55 (2014) 3167–3171
3171
and 3g derived from ethyl ketone and n-propyl ketone, respec-
References and notes
tively, served as suitable substrates to afford lactones 4f and 4g
(entries 60, 70). An intriguing spirolactone 4h was obtained in 74%
yield from 3h (entry 80). All of the d-valerolactones 4 were obtained
in high enantiopurity without loss of enantiopurity.14
1. Boucard, V.; Broustal, G.; Campagne, J. M. Eur. J. Org. Chem. 2007, 225.
2. For selected examples for the enantioselective synthesis of d,d-disubstituted
unsaturated d-valerolactones: (a) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000,
122, 10470; (b) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.; Jamieson, J. Y.; Schrock,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 3139; (c) Moreau, X.; Bazán-
Tejeda, B.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 7288; (d) Liu, Z.;
Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352; (e) Zhao, D.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440; (f) Shen,
L.-T.; Shao, P.-L.; Ye, S. Adv. Synth. Catal. 1943, 2011, 353; (g) Mo, J.; Chen, X.;
Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810.
In marked contrast to the reliable formation of enantioenriched
d-valerolactones 4 using benzylic tertiary alcohols 3 as presented
in Table 2, homoallylic alcohol 3i (88% ee) derived from ketone
1i afforded d-valerolactone 4i in a racemic form under identical
conditions (Scheme 3a). This undesired racemization was presum-
ably due to the enhanced stability of allylic cation intermediate 9.
Addition of H2O and re-cyclization of the resulting acyclic imide 10
led to the formation of racemic d-valerolactone 4i (pathway a). Our
assumption was further supported by the isolation of primary
amide 11 that would be formed via imide 10 by hydrolysis of the
trifluoroacetimide moiety (pathway b). Consistently, performing
the one-pot protocol with the use of partially hydrogenated 3i-
H2, prepared by selective hydrogenation of a styryl group of 3i over
Pd/C in acetonitrile, afforded d-valerolactone 4i-H2 while maintain-
ing the enantiopurity and avoiding undesired ring-opened byprod-
uct 11-H2 (Scheme 3b). Intriguingly, fully reduced 3i-H4, obtained
by hydrogenation in AcOEt at room temperature, gave d-valerolac-
tone in much lower yield,15 confirming the beneficial and essential
effect of Z-configured olefin to facilitate the initial cyclization.
3. For reviews, see: (a) Hanessian, S.; Ugolini, A.; Hodges, P. J.; Beaulieu, P.; Dubé,
D.; André, C. Pure Appl. Chem. 1987, 59, 299; (b) Blaser, H. U. Chem. Rev. 1992,
92, 935; (c) Koskinen, A. M. P. Pure Appl. Chem. 2011, 83, 435.
4. For recent reviews of catalytic asymmetric synthesis of tertiary alcohols, see:
(a) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873; (b) Shibasaki, M.;
Kanai, M. Chem. Rev. 2008, 108, 2853; (c) Hatano, M.; Ishihara, K. Synthesis
2008, 1647; (d) Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963; (e)
Adachi, S.; Harada, T. Eur. J. Org. Chem. 2009, 3661; For a general and efficient
protocol for the synthesis of optically active tertiary alcohols from
enantioenriched secondary alcohol, see: (f) Stymiest, J. L.; Bagutski, V.;
French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
5. (a) Yazaki, R.; Nitabaru, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 3195; (b) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
5522.
6. For reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388; (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591; (c)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363; (d)
Christoffer, J.; Baro, A. Quaternary Stereocenters; Wiley: Weinheim, 2005; (e)
Trost, B. M.; Jiang, C. Synthesis 2006, 369; (f) Marek, I.; Sklute, G. Chem.
Commun. 2007, 1683; (g) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org.
Chem. 2007, 5969.
Conclusions
7. Trost, B. M. Science 1991, 254, 1471.
8. Recent reviews on asymmetric catalysis with particular emphasis on CAC
bond-forming reactions with perfect atom economy, see: (a) Kumagai, N.;
Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4760; (b) Matsunaga, S.;
Shibasaki, M. Chem. Commun. 2014, 1044.
9. For recent reviews of cooperative catalysis, see: Lewis acid/Brønsted base: (a)
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187; Lewis acid/Lewis
base: (b) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491; (c)
Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc.
Chem. Res. 2008, 41, 655; Lewis acid/Brønsted acid and Lewis acid/Lewis acid:
(d) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 1924, 2005, 44;
(e)Yamamoto, H., Futatsugi, K., Ishihara, K., Eds.Acid Catalysis in Modern
Organic Synthesis; Wiley-VCH: Weinheim, 2008.
In summary, a one-pot procedure affording enantioenriched
d,d-disubstituted unsaturated d-valerolactones was developed.
The specific products, Z-configured homoallylic tertiary alcohols
bearing nitrile functionality derived from the direct addition of
allyl cyanide to ketones, were directly converted to the title com-
pounds via a one-pot three-step sequence. Application of the
thus-obtained d,d-disubstituted d-valerolactones as deoxygenated
sugar units to the development of novel glycosides and their bio-
logical evaluation is underway.
10. The intramolecular cyclization of the corresponding secondary alcohol was
reported under less efficient reduction/oxidation sequence: Otsuka, Y.; Takada,
H.; Yasuda, S.; Kumagai, N.; Shibasaki, M. Chem. Asian J. 2013, 8, 354.
11. See Supplementary Material.
Acknowledgments
12. DBU afforded the best result among amine bases studied under otherwise
identical conditions (Et3N: 67%, pyridine: 59%, DMAP: 65%).
This work was financially supported by JST, ACT-C, and JSPS
KAKENHI Grant Number 25713002. We thank Dr. Yasunari Otsuka
at the Institute of Microbial Chemistry for initial experiments at
the early stage of this study.
13. AgOTf ($136/25 g, Sigma-Aldrich) was used throughout the study because of
its lower cost compared with CuOTfꢀtoluene0.5 ($275.5/5 g, Sigma-Aldrich). The
use of Cu(OTf)2 ($206.5/25 g, Sigma-Aldrich) provided a comparable reaction
outcome under otherwise identical conditions. Cu(OTf)2 can be prepared in
large quantities starting from inexpensive Cu salt.
14. Slight difference of enantiomeric excess of 3 and 4 for some cases was ascribed
to rounding off to the closest whole number.
Supplementary data
15. Starting material almost disappeared and several unidentified by-products
were observed.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2014.04.006.