Dynamic chirality of (E)-5-cyclononen-1-one and its enolate

Article abstract of DOI:10.1021/ja1092375

It has been found that (E)-5-cyclononen-1-one (2a) exhibits marginal planar chirality owing to an insufficient topological constraint, whereas the enolates 3 derived from 2a show robust planar chirality. Enantioenriched enolates are easily prepared by enzymatic hydrolysis, and they show an ability to serve as chiral nucleophiles.

Full text of DOI:10.1021/ja1092375

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Dynamic Chirality of (E)-5-Cyclononen-1-one and its Enolate
Katsuhiko Tomooka,*,† Takayuki Ezawa,‡ Hiroko Inoue,§ Kazuhiro Uehara,† and Kazunobu Igawa†
†Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Fukuoka 816-8580, Japan
‡Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
§Department of Molecular and Material Sciences, Kyushu University, Kasuga, Fukuoka 816-8580, Japan
S Supporting Information
b
(E)-cyclononene skeleton, shows more stable chirality than
that of 1.5,6 On the basis of this structure and stereochemical
ABSTRACT: It has been found that (E)-5-cyclononen-1-
one (2a) exhibits marginal planar chirality owing to an
insufficient topological constraint, whereas the enolates 3
derived from 2a show robust planar chirality. Enantioen-
riched enolates are easily prepared by enzymatic hydro-
lysis, and they show an ability to serve as chiral
nucleophiles.
stability relationship, we expected ketone 2a having the (E)-
cyclononene skeleton with one additional trigonal carbon to
be a chiral molecule and assumed its stereochemical stability
to lie in between those of 1 and 4.7 More importantly,
conversion of ketone 2a to enolate 3 should increase the
stereochemical stability to a level similar to that of 4, owing to
the introduction of an additional trigonal carbon. Thus, these
molecular designs will allow unique control and modification
of stereochemical stability by a simple keto-enol trans-
formation.8-10 Herein, we describe a detailed stereochemical
analysis of thus designed ketone and its enolate in addition to
their asymmetric synthesis and transformations.
etone is one of the most fundamental and important motifs
K
in organic chemistry.1 While the trigonal planar structure
function of ketonic functionalities allows their widespread use as
prochiral structural motifs in asymmetric synthesis, little
attention has been paid to their use as stereogenic elements.
In this situation, introduction of inherent chirality to ketones
is a challenging issue, and it would open a new field of
molecular chirality. To this end, we anticipated that a ketone
incorporated in a reasonably strained trans-cycloalkene skele-
ton may show a unique dynamic chirality without the presence
of any stereogenic carbon (Scheme 1). It is well-known that
certain medium-sized trans-cycloalkenes have planar chirality
and their stereochemical stabilities are highly dependent on
the ring size.2 For example, (E)-cyclooctene has a remarkably
stable planar chirality, whereas its one-carbon homologue (E)-
cyclononene (1) has only marginal chirality.3,4 On the other
hand, the presence of additional trigonal carbon in the ring
also may affect the stereochemical stability owing to the
decrease of the conformational flexibility. For example, it
was estimated by calculation that (1E,5Z)-cyclonona-1,5-
diene (4), having two additional trigonal carbons on the
Ketone 2a along with its substituted analogues 2b-d were
readily synthesized by a ring-enlarging anionic oxy-Cope rear-
rangement of 5 in good yields (eq 1).11
The existence of isolable enantiomers of 2a was revealed by a
HPLC analysis using a chilled chiral stationary column equipped
with a CD spectropolarimeter. As shown in Scheme 2, both
enantiomers of 2a were successfully separated on an analytical as
well as a semipreparative scale.12
The half-lives of the optical activity for 2a in hexane at -5, 0, 5,
and 10 °C are 22.1, 10.7, 5.1, and 2.4 h, respectively. The
activation parameters for the racemization of 2a are calculated
from an Eyring plot by the analysis of the rate constants of
racemization as ΔHq= 21.7 kcal mol-1 and ΔSq = -1.96
Scheme 1. Design of Dynamic Chiral Ketone 2a and its
Enolate 3
cal mol-1 K-1 13
This result clearly demonstrates that ketone
.
2a has dynamic chirality at ambient temperature and its stereo-
chemical stability is higher than that of 1 (ΔHq = 19.4 kcal
mol-1),4 as we expected. The absolute stereochemistry of
enantiomers of 2a was determined by formation of a Pt-complex
derivative as shown in Scheme 2.14,15 Reaction of rac-2a with
PtCl2(2,4,6-trimethylpyridine)(CH2dCH2) provided rac-6 in
92% yield, and its separation by chiral HPLC afforded both
Received: October 14, 2010
Published: January 25, 2011
r
2011 American Chemical Society
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Scheme 2. Stereochemical Behavior and Determination of
Absolute Stereochemistry of Ketone 2aa
Scheme 3. Stereochemical Behavior and Determination of
Absolute Stereochemistry of Enolate 3a
a Reagents and conditions: (a) PtCl2(2,4,6-trimethylpyridine)(CH2d
CH2), CH2Cl2, rt, 92%; (b) PPh3, CH2Cl2, -30 °C. bORTEP drawing
of 6 (60% probability ellipsoids).
a Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C, 53%; (b) n-
BuLi, THF, -78 °C. bORTEP drawing of 7a (60% probability
ellipsoids).
enantiomers of 6 in enantiopure crystalline form.12 X-ray diffrac-
tion revealed the stereochemistry of the (-)-isomer of 6 to be
(S) and that of the (þ)-isomer of 6 to be (R).16 Treatment of
(S)-6 with PPh3 at -30 °C provided 2a as an enantioenriched
form, and its CD spectrum was identical to that of (þ)-2a;
therefore, we unequivocally determined that (þ)-2a has an (S)-
configuration. Furthermore, we found that substituted analogues
2b-d also possess planar chirality at ambient temperature, as
revealed by chiral HPLC analysis.12 Monosubstituted 2b and 2c
are stereochemically less stable than 2a (t1/2 = 4.1 and 1.6 h,
respectively, at 0 °C in hexane).13 In contrast, introduction of
dimethyl substituents in the olefin moiety dramatically increased
the stereochemical stability; enantiopurity of 2d remained un-
changed at 40 °C for at least 200 h.17 These results demonstrate
that it is possible to produce chiral ketones having a variable
stereochemical stability by introducing the appropriate substitu-
ent on the olefin.
It is noteworthy that the ester moiety of 3 permits hydrolysis
which provides an opportunity for kinetic resolution of enantiomers
of 3 by enzyme-mediated asymmetric hydrolysis.21 For instance, a
reaction of rac-3a with porcine pancreatic lipase (PPL) type II
provides (S)-3a with 70% ee and >98% ee in 49% and 32% yields,
respectively (eq 2).22 Thus, a large-scale preparation of enantioen-
riched 3 via this simple technique can be accomplished.
The molecular modeling shows that the enolate plane of 3 is
approximately perpendicular to the plane of the ring; thus, the
intermolecular reaction is expected to occur only from the outer
peripheral face. Therefore, the planar chirality of enolate 3 can be
transformed to central chirality in a stereospecific manner.
Indeed, a reaction of lithium-enolate 3e derived from (S)-3a
(>98% ee) with methyl iodine and subsequent hydrogenation
provided chiral ketone (R)-9 (>98% ee) which is known as a key
intermediate in an asymmetric synthesis of (R)-(-)-phoracantholide
I, a component of the defensive secretion of the eucalypt longicorn
beetle (Scheme 4).23-26
With the dynamic chiral ketone in hand, we next turned our
attention to changing stereochemical behavior via a keto-enol
transformation. Enol acetate 3a was prepared from ketone 2a, as
a sole (E)-isomer in 67% yield by a reaction with KH in DME and
subsequent acetylation. The configuration of 3a was determined
by X-ray analysis of its epoxide 7a (Scheme 3).16
Using similar chiral HPLC separation and a measurement of
the half-lives of the optical activity mentioned above, we found
that 3a has robust chirality (t1/2 = 134 h, at 25 °C in hexane)
(ΔHq = 24.5 kcal mol-1, ΔSq = -4.20 cal mol-1 K-1).12,18 The
difference in the half-lives of the optical activity between 3a and
2a, which was estimated by a calculation, indicates that a simple
keto-enol transformation increases the stereochemical stability
by more than 520 times at 0 °C. A transformation from 3a to 2a
with retention of optical activity was achieved by a low-tempera-
ture treatment with an alkyl lithium reagent such as MeLi or
n-BuLi followed by protonation. By applying this procedure, the
absolute stereochemistry of (þ)-3a was determined as (S) by
comparison of the specific rotation and CD spectrum after
conversion to ketone 2a. We also prepared 3b-d bearing
different ester groups. Stereochemical analysis shows that the
difference in ester moiety (Y) does not significantly influence the
stereochemical stability (t1/2 = 114 h for 3b, 130 h for 3c, 122 h
for 3d at 25 °C in hexane).12,19,20
Scheme 4. Transformation of Planar Chirality of 3 to Central
Chiralitya
a Reagents and conditions: (a) MeLi, THF, -78 °C; (b) MeI, THF,
-78 f 0 °C, 88% (2 steps); (c) H2, 10% Pd-C, AcOEt, rt, 97%;
(d) m-CPBA; see ref.25,26
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COMMUNICATION
In summary, we have shown that newly designed cyclic ketone
exhibits marginal planar chirality owing to an insufficient topo-
logical constraint. This chiral ketone can be converted to the
corresponding enolate derivatives that possess robust planar
chirality. In other words, the stereochemical behavior of a
medium-sized cycloalkene can be drastically changed by intro-
duction of a ketone moiety as well as by a keto-enol transforma-
tion. This phenomenon should be applied to a wide range of
molecules to develop novel dynamic chiral chemistry.
(8) Owing to the symmetric structure of 2a, only one regioisomer of
3 is present.
(9) It is known that the length of the CdC bond of enol ether is
nearly identical to that of simple alkene; see Samdal, S.; Seip, H. M.
J. Mol. Struct. 1975, 28, 193–203. Therefore, it can be anticipated that
the rigidity of the ring conformation, and hence the stereochemical
stability of 3, would be at a level similar to that of 4
(10) The generation and synthetic application of dynamic chiral
enolate from R-chiral ketone has been reported by Fuji and Kawabata’s
group; see (a) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991,
113, 9694–9696. (b) Fuji, K.; Kawabata, T. Chem.;Eur. J. 1998, 4, 373–
376 and references cited therein.
’ ASSOCIATED CONTENT
(11) Kato and coworkers originally synthesized 2a in 60% yield by a
thermal oxy-Cope rearrangement of 5a; see ref 7b. A similar transforma-
tion by anionic oxy-Cope rearrangement provides a rather high yield of
2a (86%). For a review of a ring-enlarging oxy-Cope rearrangement, see
Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609–626.
(12) Analytical HPLC and GC: CHIRALPAK AS-H (4.6 mm ꢀ 250
mm) for 2a, 2b, 2d; CHIRALPAK AD-H (4.6 mm ꢀ 250 mm) for
3a-d; CHIRALCEL OD-H (4.6 mm ꢀ 250 mm) for 2c, 6; SUPELCO
γ-DEX 225 (0.25 mm ꢀ 30 m) for 9; see Supporting Information for
details.
S
Supporting Information. Experimental procedures and
b
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
ktomooka@cm.kyushu-u.ac.jp
(13) We estimated the racemization energy by DFT calculation
[B3LYP/6-311G(d,p)] as ΔEq = 22.2, 20.7, and 26.7 kcal mol-1 for 2a,
2b, and 3a, respectively; see Supporting Information for details.
(14) Determination of the absolute stereochemistry of 2a itself was
difficult, owing to its stereochemical instability at ambient temperature
and noncrystallinity.
(15) Recently, we have synthesized a PtCl2(2,4,6-trimethylpyridine)
complex of planar chiral nitrogencycles. Tomooka, K.; Shimada, M.;
Uehara, K.; Ito, M. Organometallics 2010, 29, 6632–6635.
(16) The structures of 6 and 7a were determined by X-ray crystal-
lography; see Supporting Information.
’ ACKNOWLEDGMENT
This research was supported by MEXT, Japan [Grant-in-Aid
for Scientific Research on Basic Area (B) No. 22350019, Global
COE Program (Kyushu Univ.), and MEXT Project of Integrated
Research on Chemical Synthesis]. We thank Prof. Kazutsugu
Matsumoto (Meisei Univ.) for valuable and helpful discussion on
asymmetric hydrolysis.
(17) Stereochemical stabilizing effect of dimethyl substituent in (E)-
cyclodecene system has been reported; see Marshall, J. A.; Konicek,
T. R.; Flynn, K. E. J. Am. Chem. Soc. 1980, 102, 3287–3288.
(18) By comparison of activation parameters for the racemization, a
stereochemical stability of 3a lies between those of compounds 1 and 4
(ref 5).
(19) (E,E)-Stereochemistry of 3d was determined by X-ray diffrac-
tion of PtCl2(2,4,6-trimethylpyridine) complex derivative; see Support-
ing Information for details.
(20) Silyl enol ether congener of 3 has been synthesized; see Kende,
A. S.; Nelson, C. E. M.; Fuchs, S. Tetrahedron Lett. 2005, 46, 8149–8152.
However, its stereochemical behavior has not been reported.
(21) Enzyme-mediated asymmetric hydrolysis of prochiral or R-
chiral enolates has been reported; see (a) Matsumoto, K.; Ohta, H.
Chem. Lett. 1989, 1109–1112. (b) Matsumoto, K.; Tsutsumi, S.; Ihori,
T.; Ohta, H. J. Am. Chem. Soc. 1990, 112, 9614–9619.
(22) We measured the conversion yields by HPLC analysis. The
enantiopurity of ketone 2a was not determined due to its rapid
racemization. We also performed a 100-mg-scale reaction and isolated
an enantioenriched 3a in 32% yield with >96% ee; see Supporting
Information for details.
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