Enantioselective synthesis of planar chiral organonitrogen cycles

Article abstract of DOI:10.1021/ja1024657

Enantioselective synthesis of a planar chiral organonitrogen cycle has been newly developed based on the unprecedented prochiral face-selective cyclization of achiral linear precursors by an appropriate chiral promoter.

Full text of DOI:10.1021/ja1024657

Published on Web 06/21/2010
Enantioselective Synthesis of Planar Chiral Organonitrogen Cycles
Katsuhiko Tomooka,*,† Kazuhiro Uehara,†,‡ Rie Nishikawa,‡ Masaki Suzuki,‡ and Kazunobu Igawa†
Institute for Materials Chemistry and Engineering, Kyushu UniVersity, Kasuga, Fukuoka 816-8580, Japan, and
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152-8552, Japan
Received March 24, 2010; E-mail: ktomooka@cm.kyushu-u.ac.jp
whether 1a is obtainable in an enantioenriched form or not. The
Abstract: Enantioselective synthesis of a planar chiral organo-
reaction was carried out in biphasic 40-50 wt % aq K2CO3-CH2Cl2
nitrogen cycle has been newly developed based on the unprec-
edented prochiral face-selective cyclization of achiral linear
precursors by an appropriate chiral promoter.
containing a chiral PTC (100 mol %) at 0 °C for 24 h,6 and selected
results are summarized in Table 1.
Scheme 2. A Strategy for Enantioselective Synthesis of 1
A series of nine-membered diallylic organonitrogen cycles 1
display appreciable planar chirality arising from their topological
constraint.1 Notably, the planar chirality in 1 is completely
transmittable to central chirality in their chemical transformation
into multiply functionalized nitrogen-containing compounds such
as 2-4 (Scheme 1). Moreover, this class of compounds serve as
useful chiral building blocks to provide a number of alkaloids in a
highly stereospecific manner.2 Unfortunately, however, such great
synthetic potential of 1 has not been fully developed because the
preparative method relied on the optical resolution of (()-1.3
Chiral PTCs including the salts of (-)-sparteine/MeI or (S,S)-
Therefore, the development of a practical enantioselective synthesis
ꢀ-Nap-NAS-Br7 promoted the cyclization efficiently (81 and 71%,
respectively), but (()-1a was obtained in both cases. However,
cinchona alkaloid derived 8a-c did furnish enantioenriched (S)-
1a and their ee values were ranging from 28-37% (entries 1-3).8
It should be noted that the decrease of the amount of 8a-c from
100 to 10 mol % did not cause any deterioration of the stereose-
lectivity (entries 4-6). Not surprisingly, (R)-1a with 23% ee was
obtained with 9, which should be one of the readily available
surrogates for the antipode of 8 (entry 7).8c Unfortunately, however,
we were not successful in finding a superior chiral PTC any further
in terms of enantioselectivity.9 Accordingly, we then turned our
attention toward structural modification of the anionic part instead
of the cationic part in CP.
of 1 was desirable for further studies.4
Scheme 1. Planar Chiral 1 and Their Synthetic Elaboration
As illustrated in Scheme 2, we originally prepared (()-1 by
intramolecular Mitsunobu reaction of achiral amino alcohol 5 (X
) OH).1a On the other hand, we also found that the similar amino
halides 6 (X ) Cl) or 7 (X ) Br) furnish (()-1 upon treatment
with an aqueous alkaline base containing TBAI as a phase transfer
catalyst (PTC) (see Supporting Information). In either case, prochiral
face selection at the designated olefin in 5, 6, or 7 should be
involved to develop planar chirality in 1. Accordingly, we began
to explore a suitable chiral promoter (CP) in the hope of inducing
enantioselectivity in these processes. As a result, we found that
not only chiral PTC5 but also sugar-derived chiral alkoxides
effectively promote unprecedented asymmetric cyclization to give
1 in a highly enantioselective manner. Herein, we disclose this novel
asymmetric cyclization, whose enantioselectivity is determined as
dextral or sinistral by lithium ion-mediated steric interaction
between linear substrates and chiral alkoxides.
Table 1. Asymmetric Cyclization of 7a Using Chiral PTCs
a Isolated yield.b Determined by chiral HPLC analysis.
In fact, the stoichiometric use of lithium alkoxides 10 and 11,10
which are structurally similar to 8b and 9, provided enantioenriched
1a with moderate stereoselectivities [45% ee (S), 40% ee (R),
respectively], although the reaction rates were lowered (15% yield
after 80 h and 30% yield after 60 h, respectively, in CH2Cl2 at 0
We first examined the impact of several chiral PTCs in the
cyclization of 7a (R1 ) Me, R2 ) Me) as a model reaction to see
† Kyushu University.
‡ Tokyo Institute of Technology.
9
9232 J. AM. CHEM. SOC. 2010, 132, 9232–9233
10.1021/ja1024657  2010 American Chemical Society

C O M M U N I C A T I O N S
°C). Surprisingly, the lithium salt of diacetone D-glucose 12 having
no amino group11 was also equally effective to give (R)-1a under
otherwise identical conditions with 51% ee in 52% yield after 48 h,
and the use of double amounts of 12 greatly improved enantiose-
lectivity as well as chemical yield to give (R)-1a with 63% ee in
59% yield after 48 h. It was conceivable that the extra amount of
12 possibly serves merely as a base to generate the conjugate base
of 7a (Vide infra) since the pretreatment of 7a with n-BuLi followed
by the cyclization with an equimolar amount of 12 gave almost
identical results (66% ee, 55% yield). Notably, lithium was the
alkaline metal of choice, because the replacement of lithium with
sodium or potassium in 12 gave only disappointing enantioselectivity.
Figure 1. Possible transition states for asymmetric cyclization.
previous studies should increase the synthetic value of planar chiral
heterocycles as new chiral building blocks in asymmetric synthesis.
Acknowledgment. This research was supported by MEXT,
Japan [Grant-in-Aid for Scientific Research on Priority Areas (A)
No. 16073209, Basic Area (B) No. 22350019 and Global COE
Program (Kyushu Univ.)] and by The Asahi Glass Foundation.
These results encouraged us to explore a variety of sugar-derived
lithium alkoxides, among which 13 and 14 have proved to be the
most appropriate CPs for the cyclization of 7a and 7b (R1 ) H, R2
) Me) (Scheme 3). For example, the reaction of 7a with an excess
amount of D-glucose derived 13 provided (R)-1a with 93% ee in
89% yield.12 Moreover, the similar reaction of 7b provided (R)-1b
in 66% ee under otherwise identical conditions. In sharp contrast,
D-galactose-derived 14 completely reversed the mode of cyclization
from dextral to sinistral to give (S)-1a with 80% ee and (S)-1b with
62% ee, respectively. It should be noted that 13 and 14 can be prepared
from readily available sugar derivatives,13 recovered easily from the
reaction mixture, and used repeatedly to provide both enantiomers of
1. The usefulness of our present method was demonstrated by the
preparation of (R)-1a with >98% ee in moderate scale after fractional
recrystallization as well as by the total synthesis of both enantiomers
of kainic acid using (S)- or (R)-1b as a starting material.2b
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Tomooka, K.; Suzuki, M.; Shimada, M.; Yanagitsuru, S.; Uehara, K.
Org. Lett. 2006, 8, 963. For the ether derivatives, see: (b) Tomooka, K.;
Komine, N.; Fujiki, D.; Nakai, T.; Yanagitsuru, S. J. Am. Chem. Soc. 2005,
127, 12182. For the organosulfur derivatives, see: (c) Uehara, K.; Tomooka,
K. Chem. Lett. 2009, 38, 1028.
(2) (a) Tomooka, K.; Suzuki, M.; Uehara, K.; Shimada, M.; Akiyama, T. Synlett
2008, 2518. (b) Tomooka, K.; Akiyama, T.; Man, P.; Suzuki, M.
Tetrahedron Lett. 2008, 49, 6327.
(3) Separation of (()-1 is effected by (i) HPLC with a semipreparative chiral
stationary phase column, by (ii) kinetic resolution with asymmetric
transformations and by (iii) fractional crystallization of ammonium salt
prepared from 1 (Y ) H) and chiral acids. For details, see ref 1a.
(4) Elegant asymmetric syntheses of planar chiral cycloalkenes have been
reported. Stereospecific transformation using central chirality in the
precursor: (a) Cope, A. C.; Mehta, A. S. J. Am. Chem. Soc. 1964, 86, 5626.
(b) Cope, A. C.; Funke, W. R.; Jones, F. N. J. Am. Chem. Soc. 1966, 88,
4693. (c) Cope, A. C.; Banholzer, K.; Jones, F. N.; Keller, H. J. Am. Chem.
Soc. 1966, 88, 4700. (d) Corey, E. J.; Shulman, J. I. Tetrahedron Lett.
1968, 9, 3655. (e) Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008,
130, 2954 Asymmetric photoisomerization of stereogenic olefin moiety: (f)
Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem. 1992, 57,
1332. (g) Sugimura, T.; Shimizu, H.; Umemoto, S.; Tsuneishi, H.; Hakushi,
T.; Inoue, Y.; Tai, A. Chem. Lett. 1998, 27, 323.
Scheme 3. Enantioselective Synthesis of 1 with Chiral Lithium
Alkoxides Derived from Sugar Derivativesa
(5) For recent reviews on the application of chiral PTC, see: (a) Lygo, B.;
Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. (b) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506. (c) Hashimoto, T.; Maruoka, K. Chem. ReV.
2007, 107, 5656.
(6) Substrate 7a was prepared from nerol in four steps; see Supporting
Information.
a >98% ee: after fractional recrystallization.
(7) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139.
(8) Chiral PTC 8a and 8b were prepared according to reported procedures: (a)
Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106,
446. (b) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353. 8c was newly synthesized from cinchonidine. 9 was newly
synthesized from cinchonine which is well konwn as a surrogate for the
antipode of cinchonidine; see: (c) Kacprzak, K.; Gawro´nski, J. Synlett 2001,
961.
(9) The replacement of R in 8b from a Bn group to a Me, CH2C6H4pCF3,
CH2C6H4pOMe, or 9-anthracenylmethyl group and that of X from Cl to
Br or I caused no remarkable improvement in terms of enantioselectivity.
(10) Alkoxides 10 and 11 were prepared from cinchonidine or cinchonine with
n-BuLi.
(11) We have separately reported that 12 acts as an efficient CP for enantio-
selective Stevens rearrangement: Tomooka, K.; Sakamaki, J.; Harada, M.;
Wada, R. Synlett 2008, 683.
(12) More than 2 equiv of 13 or 14 only improved the chemical yields, while
the enantioselectivity remained roughly constant.
(13) (a) Soler, T.; Bachki, A.; Falvello, L. R.; Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2000, 11, 493. (b) Sato, K.; Akai, S.; Sakuma, M.; Kojima,
M.; Suzuki, K. Tetrahedron Lett. 2003, 44, 4903.
(14) Performed with Gaussian 03 on a TSUBAME system at Tokyo Institute
of Technology.
To gain further insight into the stereochemistry of this novel
asymmetric cyclization, we next performed calculations of possible
transition states for the reaction of lithium salt of 7a and 12 at the
HF/3-21G level.14 As shown in Figure 1, the 1:1 complex of the
lithium salt of 7a and 12 through N--Li--O and O--Li--OdSdO
interaction provided the lowest energy geometries i and ii, which
were most suitable for dextral and sinistral cyclizations, respectively
(Vide supra). Although these results might oversimplify the effect
of protonated 12 and solvent in the reaction mixture, the calculated
energy of i was lower than that of ii by ∆E ) 1.22 kcal/mol, which
was consistent with the preferential dextral cyclization mode.
In summary, we have developed the unprecedented asymmetric
cyclization of achiral linear amino halides to provide planar chiral
organonitrogen cycles, in which chiral lithium alkoxides derived from
readily available sugar derivatives play a key role for determining the
cyclization mode as dextral or sinistral. These results along with our
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