Stereoselective multimodal transformations of planar chiral 9-membered diallylic amides

Article abstract of DOI:10.1021/ol202009x

Intermolecular reactions of planar chiral 9-membered diallylic amides provide a variety of bicyclic compounds with central chiralities in a stereospecific fashion with high group selectivity. Lewis-acid-promoted intramolecular reactions of the obtained bicyclic compounds provide transannular products in a stereospecific fashion. Furthermore, a direct transannular reaction of diallylic amide involving sequential intermolecular-intramolecular reactions has been developed.

Full text of DOI:10.1021/ol202009x

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4926–4929
Stereoselective Multimodal Transformations
of Planar Chiral 9-Membered Diallylic Amides
Katsuhiko Tomooka,*,† Masaki Suzuki,‡ Maki Shimada,‡ Runyan Ni,§ and
Kazuhiro Uehara†
Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-shi,
Fukuoka 816-8580, Japan, Department of Applied Chemistry, Graduate School of
Science and Engineering, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552,
Japan, and Interdisciplinary Graduate School of Engineering Sciences,
Kyushu University, 6-1 Kasuga-koen, Kasuga 816-8580, Japan
ktomooka@cm.kyushu-u.ac.jp
Received July 26, 2011
ABSTRACT
Intermolecular reactions of planar chiral 9-membered diallylic amides provide a variety of bicyclic compounds with central chiralities in a
stereospecific fashion with high group selectivity. Lewis-acid-promoted intramolecular reactions of the obtained bicyclic compounds provide
transannular products in a stereospecific fashion. Furthermore, a direct transannular reaction of diallylic amide involving sequential
intermolecularꢀintramolecular reactions has been developed.
The stereochemical study of macrocyclic alkenes is
classical and an important issue in structural organic
chemistry and has attracted much attention in connection
with stereoselective transformations of conformationally
restricted olefins and their application for stereoselective
synthetic approaches.1 It is well-known that the olefinic
moiety in medium-sized cyloalkenes is approximately per-
pendicular to the plane of the ring. Since one face of the
olefinic π-system is severely hindered by the position of the
allylic moiety and by the transannular ring moiety, it
would be expected that an intermolecular reaction would
only occur from the outer peripheral face. To the contrary,
intramolecular transannular reactions only occur from the
† Institute for Materials Chemistry and Engineering, Kyushu University.
‡ Tokyo Institute of Technology.
§ Interdisciplinary Graduate School of Engineering Sciences, Kyushu
University.
(2) For a review of transannular reactions in medium-sized rings, see:
(a) Cope, A. C.; Martin, M. M.; McKervey, M. A. Q. Rev., Chem. Soc.
1966, 20, 119–152. For reviews of stereoselective transformation of
macrocyclic compounds, see: (b) Still, W. C.; Galynker, I. Tetrahedron
1981, 37, 3981–3996. (c) Nubbemeyer, U. Eur. J. Org. Chem. 2001, 1801–
1816.
(1) (a) Conformational Analysis of Medium-Sized Heterocycles; Glass,
R. S., Ed.; VCH Publishers, Inc.: New York, 1988. (b) Stereochemistry of
Organic Compounds; Eliel, E. L., Wilen, S. H., Mander, L. N., Eds.; Wiley:
New York, 1994.
r
10.1021/ol202009x
Published on Web 08/23/2011
2011 American Chemical Society

inner peripheral face.2 On the basis of this stereochemical
principle, the stereoselective transformation of alkenes has
been accomplished in conformationally restricted macro-
cylic systems.3 However, this kind of strategy is often pre-
vented by the number of stable conformers and their easy
interconversion by low-energy-barrier pseudorotation.
Recently, we have reported a novel cyclic amide 1 that
has only two enantiomeric conformers at ambient tem-
perature and displays stable planar chirality arising from
its topological constraint (Figure 1).4 Both of its two
olefins are approximately perpendicular to the ring and,
hence, amide 1 will be a superior substrate for the above-
mentioned stereoselective transformation. Herein, we re-
port the stereo- and group-selective transformation of 1 by
a variety of intermolecular reactions and a stereospecific
transannular reaction of the resulting products.
explained by its distortion: the C3ꢀC4 bond is twisted by
ca. 30°, while the C7ꢀC8 bond is almost flat (ca. 3°) as per
X-ray crystallographic analyses.4a,8,9 A similar reaction of
(S)-1b (R, R0 = H) (>98% ee) also provides the C3ꢀC4
epoxide (3R, 4R)-2b as the major product in 72% yield,
although it requires a much longer reaction time [m-CPBA
(1.5 equiv) at 0 °C for 22 h]. All of the obtained epoxides
2ꢀ4 are diastereomerically and enantiomerically pure, and
their stereochemistry attests to the fact that the epoxida-
tion reaction only occurs from the outer peripheral faces,
as we expected.
Scheme 1. Epoxidation of 1
Similar C3ꢀC4 olefin selectivity and stereoselectivity
were observed in cyclopropanation reactions. As shown
in Scheme 2, both the Simmons-Smith reaction and di-
chlorocyclopropanation provide 5 (X = H or Cl) as the
major product.
Scheme 2. Cyclopropanation of 1a
Figure 1. Stable confomers of 1 and their expected reaction sites.
At the outset, we examined the epoxidation reaction of 1
using m-CPBA (Scheme 1).5 A reaction of (S)-1a (R, R0 =
Me) (>98% ee) with 1.3 equiv of m-CPBA at 0 °C for 4 h
provided C3ꢀC4 epoxide (3R, 4R)-2a, C7ꢀC8 epoxide
(7R, 8S)-3a, and diepoxide (3R, 4R, 7R, 8S)-4a in 64, 10,
and 24% yields, respectively.6,7 The observed group selec-
tivity between the C3ꢀC4 olefin and C7ꢀC8 olefin can be
(3) For representative examples of natural product synthesis based
on stereoselective transformation of macrocyclic compounds, see: (a)
Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493–2495. (b) Larionov, O. V.;
Corey, E. J. J. Am. Chem. Soc. 2008, 130, 2954–2955.
(4) (a) Tomooka, K.; Suzuki, M.; Shimada, M.; Yanagitsuru, S.;
Uehara, K. Org. Lett. 2006, 8, 963. For the ether congeners, see: (b)
Tomooka, K.; Komine, N.; Fujiki, D.; Nakai, T.; Yanagitsuru, S. J. Am.
Chem. Soc. 2005, 127, 12182. For the organosulfur congeners, see: (c)
Uehara, K.; Tomooka, K. Chem. Lett. 2009, 38, 1028.
(8) The relationship between alkene strain and reactivity of epoxida-
tion has been investigated, see: Shea, K. J.; Kim, J.-S. J. Am. Chem. Soc.
1992, 114, 3044–3051.
(9) In contrast, a similar epoxidation of acyclic congener a shows low
and opposite group selectivity (b/c = 34: 66).
(5) Enantio-enriched 1 can be prepared by the enantioselective
cyclization of readily available acyclic precursors, see: Tomooka, K.;
Uehara, K.; Nishikawa, R.; Suzuki, M.; Igawa, K. J. Am. Chem. Soc.
2010, 132, 9232–9233.
(6) All new compounds were fully characterized by 1H-, 13C NMR,
IR, and HRMS analysis. The enantiomeric purity of products was
determined by a HPLC analysis using a chiral stationary column; see
Supporting Information for details.
(7) The structures of 4a, 7b, 8, 10a, 11, 12a, 12c, 13b, and 14b were
determined by X-ray crystallography; see Supporting Information.
Org. Lett., Vol. 13, No. 18, 2011
4927

A much higher group selectivity was realized in a [2 þ 2]-
cycloaddition reaction with alkoxyketene.10,11 The reac-
tion of (S)-1a (>98% ee) with methoxyketene, which was
prepared in situ from methoxyacetyl chloride and Hunig’s
Plausible mechanisms for these transannular reactions
are shown in Scheme 4. The reactions of 2a and 8a should
involve C3-cation intermediates i or ii, which are formed
by epoxide or cyclobutanone ring cleavage, respectively.
Then, a CꢀC bond formed between C3 and C8 (i.e., C3
and C7a in 9 and 10) followed by the elimination of a
proton to yield 9 and 10. In a similar manner, the reaction
of 3aforms a C7-cation intermediateiii, whichprovides the
C4-cation intermediate iv via direct C3ꢀC7 bond forma-
tion or via skeletal rearrangement of the C3-cation inter-
mediate v. Then, C4ꢀO bond formation provides 11.
base in the presence of BF3 OEt2, yields C3ꢀC4 cyclobu-
3
tanone 8 as the sole product in 81% yield with >98% dr
and >98% ee along with recovered (S)-1a (19%) (eq 1).12
Scheme 4. Plausible Mechanisms for the Transannular Reac-
tions of 2a, 3a, and 8a
The obtained compounds 2, 3, and 8 have strained small
rings, which can be activated by Lewis acids, and the C7ꢀ
C8 or C3ꢀC4 olefin is properly located at the back side of
the rings. Therefore, they would be suitable substrates for
transannular reactions. As shown in Scheme 3, BF3 OEt2-
3
promoted reactions of (3R, 4R)-2a and (3R, 4R)-8a pro-
vide octahydroisoindole derivatives 9 and 10, respectively,
as a mixture of the regioisomer of the olefin moiety in good
to excellent yields with high stereoselectivity. In contrast, a
similar reaction with (7R, 8S)-3a provides a unique oxa-
and aza-tricyclo decane 11 as the sole product, which again
occurs with high stereoselectivity.
Scheme 3. BF3 OEt2-Promoted Transannular Reactions of 2a,
3
3a, and 8a
Furthermore, we found a direct transannular reaction of
1a, as shown in Scheme 5. The reaction of 1a with NBS or
NIS provides the octahydroisoindole derivatives 12 or 13,
respectively, as a mixture of the regioisomer of the olefin
moiety in an excellent yield with high stereoselectivity.13
(12) A similar reaction without Lewis acid also provides 8, albeit in
low yield (30%) along with recovered 1a (67%).
(13) It has been reported that halogenation-induced cyclization of
1-aza-4-cyclooctene provides transannular aminohalogenation product,
see: (a) Wilson, S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44, 287–291. (b)
Royzen, M.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2008, 130,
3760–3761.
(14) For the pioneering work of phosphoramide-promoted reaction,
see: Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626–
9627.
(15) For recent work of phosphoramide-promoted reaction, see: (a)
Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem.,
Int. Ed. 2008, 47, 593–596. (b) Schneekloth, J. S., Jr.; Kim, J.; Sorensen,
E. J. Tetrahedron 2009, 65, 3096–3101.
(10) The related [2 þ 2] cycloaddition of alkoxyketene has been
reported, see: Matsui, S.; Kinbara, K.; Saigo, K. Tetrahedron Lett.
1999, 40, 899–902.
(11) The reaction was performed by a slightly modified procedure of
the one described by: Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 1999, 121, 9726–9727.
(16) A similar reaction using other acids such as (PhO)2POOH and
CF3COOH does not provide any transannular product; a substrate 1a
was recovered quantitatively.
4928
Org. Lett., Vol. 13, No. 18, 2011

involve cationic activation at the C3ꢀC4 olefin of 1a
from the outer face and transannular C4ꢀC7 bond (i.e.,
C3ꢀC7a bond in 14) formation. Thus, theobservedunique
reactivity of 1a is due to the high reactivity of the C3ꢀC4
olefinand the presenceof a properly located C7ꢀC8olefin.
In summary, we described stereoselective multimodal
transformations of a planar chiral 9-membered diallylic
amide to provide a variety of chiral molecules that are
otherwise difficult to obtain. Further work is in progress
to strengthen the synthetic utility of the planar chiral
heterocycles.
Scheme 5. Direct Transannular Reactions of 1a
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.), Management Expenses Grants for Na-
tional Universities Corporations and MEXT Project of
Integrated Research on Chemical Synthesis]. We thank
S. Yanagitsuru (Tokyo Instit. of Tech.) for his effort
of the primitive study on the epoxidation reaction of
1 and Y. Tanaka (IMCE, Kyushu Univ.) for HRMS
measurements.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
In addition, a similar reaction using (PhO)2PONHTf
provides 14 in a good yield.14ꢀ16 These reactions should
Org. Lett., Vol. 13, No. 18, 2011
4929