Memory of chirality in cascade rearrangements of enediynes

Article abstract of DOI:10.1021/ja106668d

The cascade rearrangement of chiral enediynes 1c-e, involving successively 1,3-proton shift, Saito-Myers cyclization, 1,5-hydrogen atom transfer, and intramolecular coupling of the resulting biradical, proceeded at 80°C to form tri- and tetracyclic heterocycles possessing a quaternary stereogenic center with a very high level of memory of chirality.

Full text of DOI:10.1021/ja106668d

Published on Web 09/29/2010
Memory of Chirality in Cascade Rearrangements of Enediynes
Malek Nechab,*,† Damien Campolo,† Julien Maury,† Patricia Perfetti,† Nicolas Vanthuyne,‡
Didier Siri,† and Miche`le P. Bertrand*,†
Laboratoire Chimie ProVence, LCP UMR 6264, and Laboratoire de Ste´re´ochimie Dynamique et Chiralite´,
ISM2, UMR 6263, Aix-Marseille UniVersite´, Faculte´ des Sciences St Je´roˆme, AVenue Escadrille Normandie-Niemen,
13397 Marseille Cedex 20, France
Received July 27, 2010; E-mail: michele.bertrand@univ-cezanne.fr; malek.nechab@univ-provence.fr
of 2b were isolated in 34 and 24% yield, respectively. Up to 23%
of the starting material was recovered.
In the cascade, the first elementary step (step a) leads to
enynallene A, which spontaneously undergoes Saito-Myers cy-
clization to give biradical B (step b). The following 1,5-hydrogen
shift gives rise to biradical C (step c), which eventually forms
product 2 through intramolecular coupling of the two reactive
Abstract: The cascade rearrangement of chiral enediynes 1c-e,
involving successively 1,3-proton shift, Saito-Myers cyclization,
1,5-hydrogen atom transfer, and intramolecular coupling of the
resulting biradical, proceeded at 80 °C to form tri- and tetracyclic
heterocycles possessing a quaternary stereogenic center with a
very high level of memory of chirality.
centers (step d). We thought that hydrogen abstraction from a
captodative position should offer several advantages, such as
Since the discovery of the mighty anticancer properties of natural
products containing enediynes moieties, mechanistic studies, syn-
theses, and evaluation of new compounds in this family have
stimulated the creativity of multidisciplinary researchers.1 The
biological activity of these compounds is related to their aptitude
to rearrange according to Bergman2 or Saito-Myers cyclizations.3
These processes lead to highly reactive (σ,σ) and (σ,π) biradicals,4
respectively, capable to abstract hydrogen atoms from DNA strands
and, as a consequence, to induce DNA cleavage and apoptosis. In
spite of the impressive number of publications that can be listed in
this field,5 there are still some trails left unexplored in the reactivity
of these compounds.
enhancing the rate of step c.13
Scheme 1
We disclose in this Communication a polar-radical crossover
cascade rearrangement that proceeds with memory of chirality at
80 °C. Memory of chirality (MOC) is intended here as defined by
Fuji and Kawabata,6,7 i.e., “an asymmetric transformation in which
the chirality of the starting material is preserved in the conforma-
tionally labile intermediate during the transformation”.
Elegant examples of biradicals rearrangements via 5-exo ring
closure or intramolecular hydrogen shift subsequent to Bergman
or Saito-Myers cyclization have already been explored, mainly
by Grissom8 and by Wang.9 The choice of substrates of type 1
should open routes to dihydrobenzoisochromenes or tetrahydroben-
zoisoquinolines.10
The efficiency of the planned rearrangement was first tested on
achiral substrates 1a and 1b. The mechanism of the reaction and
the experimental results are given in Scheme 1.
Investigation of the MOC in the reaction was by far the most
exciting purpose.6,7,14 Most examples of application of the concept
of MOC involve carbanionic species.15 A limited number of articles
are concerned with cationic16 or radical intermediates.17,18 Among
the latter, four reports refer to intramolecular coupling of biradicals
resulting from Norrish type II photochemical processes.17a,b,i,j It
must be emphasized that, in their seminal articles, Giese and
co-workers17a,b demonstrated that biradicals generated from a
photochemically excited ketone could lead to high enantiomeric
excess (ee), provided that the triplet state was quenched.
Therefore, the reactivity of both racemic 1c and optically active
substrate (S)-1c (97.5% ee) was investigated in order to measure
the ee in the cyclization products (Scheme 2).
Optimization of the reaction conditions was achieved on the gly-
cine derivative 1a. This led to select acetonitrile as the solventsfor
the sake of a faster reaction ratesand Al2O3 as the base to form
the intermediate enynallene.11 Under these conditions, the rear-
rangement of 1a was completed within 5 h at 65 °C (99%
Reasonable chances to observe MOC in the process could be
anticipated from the following statements:
1
conversion according to H NMR using pentamethylbenzene as
internal standard) and led to 2a as a unique stereoisomer that was
• Only one conformation of the side chain enables the transfer
of the hydrogen atom from the stereogenic center. Therefore,
intermediate Cc should be generated in a chiral conformation at
the captodative center (Figure 1, DFT B3LYP/6-31G(d)19).
• The captodative radical center in Cc should be planar, and what
is more, owing to the rotational barrier around bond R,20 it should
retain its initial conformation during the recombination step (d).
isolated in 82% yield.12
Under the same experimental conditions, ester 1b led to 2b as a
60:40 mixture of diastereomers after 24 h at 65 °C. The two isomers
† Laboratoire Chimie Provence.
‡ Laboratoire de Ste´re´ochimie Dynamique et Chiralite´.
9
14742 J. AM. CHEM. SOC. 2010, 132, 14742–14744
10.1021/ja106668d  2010 American Chemical Society

C O M M U N I C A T I O N S
(R)-enantiomer. It was possible to demonstrate that the reaction
proceeded with retention of configuration at the stereogenic center.
The assignment of the absolute configurations resulted from the
X-ray analyses of (11R,11aS)-2d, i.e., the major cis enantiomer
isolated from (S)-1d, and of (11R,11aR)-2d, i.e., the major trans
enantiomer isolated from (R)-1d.
Scheme 3
Figure 1. Conformation of “native” biradical Cc.
• Racemization of the captodative center can also result from
rotation around bond ꢀ. Therefore, in order to observe MOC, an
additional condition has to be fulfilled. Not only does rotation
around the sp2C-N bond (R) have to be impeded, but also rotation
around the sp3C-N bond (ꢀ), controlled by the bulk of the two
substituents at nitrogen, must be slow compared to rotation around
the sp2C-sp3C bond (γ).
All these requirements being satisfied, ideally, only two clockwise
and two counterclockwise rotation modes around σ bonds γ and δ
should be allowed. They should control the lifetime of biradical
Cc. Two diastereoisomers should result. One should expect the
tricyclic product to be formed in a stereospecific way, with retention
of configuration at the initial stereogenic carbon.
In this case, owing to the restriction of the number of degrees
of freedom in the intermediate biradical Cd, the cyclic structure
advantageously compensates the loss of the captodative character
of the intermediate radical. However, a longer time of reaction was
needed to reach completion. The preferential formation of the cis
diastereomer is likely to be the consequence of π-stacking interac-
tions between the aryl groups of two adjacent susbtituents, as shown
in the solid-state structure (Figure 2).
Scheme 2
Figure 2. ORTEP structure of (11R,11aS)-cis-2d.
As summarized in Scheme 2, introducing a methyl group at the
stereogenic center had two consequences. First, (3S,4S) and (3S,4R)
diastereomers of the cyclized product 2c were formed in 29 and
34% isolated yield,21 with 81.5 and 78.5% ee, respectively.22 Even
though the reaction was slower in benzene, the latter was used to
replace acetonitrile, which led to lower ee’s. Second, a new product
(3c), resulting from a regiospecific dismutation between the two
radical centers instead of recombination, was isolated in 20% yield.
We assumed that the reaction proceeded with retention of
configuration at the stereogenic center, which was demonstrated
in further studies performed with 1d (Vide infra). We tentatively
ascribe the limitation of the ee to the fact that the rates of rotation
around σ bonds are not independent of each other. In particular,
rotation around bond ꢀ becomes easier as the nitrogen atom moves
out of the plane of the aromatic system. This probably explains
the difference in ee’s observed for cis and trans isomers.
When the reaction was carried out with K2CO3, only trans-2d
was formed in 86% ee and 75% yield. Contrary to Al2O3 (pKa 8-9),
K2CO3 (pKa 10.2) induced a fast epimerization of the stereogenic
center in position R with respect to the tosyl group in cis-2d.23
This was confirmed by treating isolated cis-2d with K2CO3.
The rearrangement of 1e led similarly to a mixture of cis and
trans diastereomers that were isolated in 30 and 45% yield,
respectively.24 In all likelihood, the reaction also proceeded with
retention of configuration. The ee of cis-2e was 94.5%, whereas
the ee of trans-2e was 87% (Scheme 4). As compared to 1d, little
epimerization of the cis isomer occurred when K2CO3 was used as
the base. According to chiral HPLC analysis, cis and trans isomers
were formed in a 33:67 ratio, with 91 and 89.5% ee, respectively.
Scheme 4
The formation of 3c results from hydrogen abstraction at the
methyl group by the benzylic radical center. It is likely to occur at
a stage where benzylic stabilization is significantly lowered by
rotation around bond δ. This “dismutation” process is a limitation
that no longer interfered in the cyclization of substrates 1d and 1e
(Schemes 3 and 4).
As shown in Scheme 3, the rearrangement of (S)-1d led to a
mixture of cis and trans diastereomers, isolated in 50 and 29% yield,
respectively. The ee of cis-2d was 93.5%, whereas the ee of trans-
2d was only 80%. The reaction was also achieved on the
9
J. AM. CHEM. SOC. VOL. 132, NO. 42, 2010 14743

C O M M U N I C A T I O N S
(13) For the incidence of the interception of the Bergman cyclization through
intramolecular hydrogen abstraction from an activated position, see:
Baroudi, A.; Mauldin, J.; Alabugin, I. V. J. Am. Chem. Soc. 2010, 132,
967.
The observation of a higher ee for the cis diastereomers than
for the trans ones probably reflects the variation of steric crowding
all along the pathways (either conrotatory or disrotatory) leading
to these isomers.
(14) For the concept of “self-regeneration of a chiral center” and a pioneering
example of memory of chirality, see: (a) Seebach, D.; Sting, A. R.;
Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (b) Seebach,
D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971.
(15) For recent examples, see: (a) Branca, M.; Pena, S.; Guillot, R.; Gori, D.;
Alezra, V.; Kouklovsky, C. J. Am. Chem. Soc. 2009, 131, 10711. (b) Branca,
M.; Gori, D.; Guillot, R.; Alezra, V.; Kouklovsky, C. J. Am. Chem. Soc.
2008, 130, 5864. (c) Ghorai, M. K.; Ghosh, K.; Yadav, A. K. Tetrahedron
Lett. 2009, 50, 476. (d) Kawabata, T.; Moriyama, K.; Kawakami, S.;
Tsubaki, K. J. Am. Chem. Soc. 2008, 130, 4153. (e) Kawabata, T.; Matsuda,
S.; Kawakami, S.; Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006,
128, 15394. (f) Kawabata, T.; Majumdar, S.; Tsubaki, K.; Monguchi, D.
Org. Biomol. Chem. 2005, 3, 1609. (g) Carlier, P. R.; Zhao, H.; De Guzman,
J.; Lam, P.C.-H. J. Am. Chem. Soc. 2003, 125, 11482. (h) Bonache, M. A.;
Gerona-Navarro, G.; Garcia-Aparicio, C.; Alias, M.; Martin-Martinez, M.;
Garcia-Lopez, M.-T.; Lopez, P.; Cativiela, C.; Gonzalez-Muniz, R. Tet-
rahedron: Asymmetry 2003, 14, 2161. (i) Kawabata, T.; Kawakami, S.;
Majumdar, S. J. Am. Chem. Soc. 2003, 125, 13012. For previous references,
the reader is referred to refs 6 and 7.
In conclusion, the four-step cascade rearrangement of enediynes
of type 1, involving successively 1,3-proton shift, Saito-Myers
cyclization, 1,5-hydrogen atom transfer, and intramolecular coupling
of the resulting biradical, was shown to occur with memory of
chirality, which opens routes to the asymmetric synthesis of
heterocyclic R-aminoester derivatives with a quaternary stereogenic
center. It is remarkable that, in this process, the phenomenon of
MOC led to high ee’s at a temperature as high as 80 °C. Mechanistic
studies, including theoretical approach and introduction of structural
diversity, are currently under investigation. New results will be
reported in due course.
Acknowledgment. We thank Prof. C. Roussel for fruitful
discussions and the ANR (JCJC MOCER2) for financial support.
(16) Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.; Maki,
T.; Onomura, O. Org. Lett. 2000, 2, 1689.
(17) (a) Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.; Neuburger, M.;
Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999, 38, 2586. (b)
Sinicropi, A.; Barbosa, F.; Basosi, R.; Giese, B.; Olivucci, M. Angew.
Chem., Int. Ed. 2005, 44, 2390. (c) Curran, D. P.; Liu, W.; Chen, C. H.-T.
J. Am. Chem. Soc. 1999, 121, 11012. (d) Schmalz, H.-G.; Koning, C. B. D.;
Bernicke, D.; Siegel, S.; Pfletschinger, A. Angew. Chem., Int. Ed. 1999,
38, 1620. (e) Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D. J. Am.
Chem. Soc. 2000, 122, 9386. (f) Dalgard, J. E.; Rychnovsky, S. D. Org.
Lett. 2004, 6, 2713. (g) Griesbeck, A. G.; Kramer, W.; Lex, J. Angew.
Chem., Int. Ed. 2001, 40, 577. (h) Resendiz, M. J. E.; Family, F.; Fuller,
K.; Campos, L. M.; Khan, S. I.; Lebedeva, N. V.; Forbes, M. D. E.; Garcia-
Garibay, M. A. J. Am. Chem. Soc. 2009, 131, 8425. (i) Sakamoto, M.;
Kawanishi, H.; Mino, T.; Fujita, T. Chem. Commun. 2008, 2132. (j)
Sakamoto, M.; Kawanishi, H.; Mino, T.; Kasashima, Y.; Fujita, T. Chem.
Commun. 2006, 4608.
Supporting Information Available: Experimental procedures,
characterization data, HPLC analyses, NMR spectra for all new
compounds, computational details, and X-ray data for (3S*,4R*)-2c,
trans-2d, and cis-2d (PDF, CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For selected relevant references, see: (a) Smith, A. L.; Nicolaou, K. C.
J. Med. Chem. 1996, 39, 2103, and references therein. (b) Nicolaou, K. C.;
Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387, and references
therein. (c) Nicolaou, K. C.; Dai, W. M.; Tsay, S. C.; Estevez, V. A.;
Wrasidlo, W. Science 1992, 256, 1172. (d) Ahlert, J.; Shepard, E.;
Lomovskaya, N.; Zazopoulos, E.; Staffa, A.; Bachmann, B. O.; Huang,
K.; Fonstein, L.; Czisny, A.; Whitwam, R. E.; Farnet, C. M.; Thorson,
J. S. Science 2002, 297, 1173.
(18) For an example of stereochemical memory in alkene radical cation/anion
contact ion pairs, see: Crich, D.; Ranganathan, K. J. Am. Chem. Soc. 2005,
125, 9924.
(19) For a discussion of theoretical methods suitable for the calculations of singlet
biradicals, see: Gra¨fenstein, J.; Kraka, E.; Filatov, M.; Cremer, D. Int. J.
Mol. Sci. 2002, 3, 360.
(20) There are no data for the rotational barrier in such a radical; however, a 17
kcal mol-1 barrier was measured by ESR by Ru¨chardt et al. for pivaloyl
dimethylaminomethyl radical: Welle, F. M.; Beckhaus, H.-D.; Ru¨chardt,
C. J. Org. Chem. 1997, 62, 552. On the basis of this rotational barrier, a
rate constant of 438 s-1 was estimated for the racemization of the
captodative radical center, at 80 °C, through rotation around bond R. Typical
rotational barriers around sp2C -sp3C bonds are about 7.5 kcal mol-1. This
means that rotation around bond ꢀ is nearly 6 orders of magnitude faster
than racemization.
(21) The structures’ assignment was based both on the chemical shift of the
proton in position R relative to the tosyl group, which is more deshielded
when it is cis with respect to the carbethoxy group (δ ) 4.74 ppm in
(3S,4R)-2c; δ ) 4.50 ppm in (3S,4S)-2c), and on the chemical shift of the
carbon of the methyl group attached to the quaternary center that is more
shielded in (3S,4R)-2c (δ ) 23.4 ppm), than in (3S,4S)-2c (δ ) 29.5 ppm).
The crystal structure obtained for racemic (3S*,4R*)-2c confirmed this
assignment.
(22) The temperature was increased to 80 °C for the rearrangement to be
completed in an acceptable time. At 65 °C, the starting material was not
totally consumed after 24 h and the ee’s of the products were not
significantly modified.
(23) In the case of 1c, the use of potassium carbonate resulted in the formation
of a mixture of rearranged products that could not be identified.
(24) The cis and trans structures were assigned from dihedral angles determined
from Chem3D models. In the cis isomer, one dihedral angle in the CH2-
CH2 moiety of the γ-lactam ring is very close to 90°. This explains why
one vicinal coupling constant in the four-spin system is zero. This leads to
dd splitting patterns for the related protons. Conversely more complex ddd
patterns are observed in the spectrum of the trans isomer.
(2) Jones, R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
(3) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111,
8057. (b) Myers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1989, 111,
9130. (c) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron
Lett. 1989, 30, 4995.
(4) For the competitive rearrangement of Schmittel, see: Schmittel, M.;
Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975.
(5) For reviews, see: (a) Kar, M.; Basak, A. Chem. ReV. 2007, 107, 2861. (b)
Rawat, D. S.; Zaleski, J. M. Synlett 2004, 393. (c) Wang, K. K. Chem.
ReV. 1996, 96, 207. (d) Grissom, J. W.; Gunawardena, G. U.; Klingberg,
D.; Huang, D. Tetrahedron 1996, 52, 6453.
(6) Fuji, K.; Kawabata, T. Chem.sEur. J. 1998, 4, 373.
(7) For general reviews and more precise definitions, see also: (a) Zhao, H.;
Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1. (b) Kawabata, T.; Fuji, K. In
Topics in Stereochemistry; Denmark, S. E., Ed.; Wiley and Sons Inc.; New
York, 2003, Vol. 23, pp 175-205.
(8) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem.
1997, 62, 603, and references therein.
(9) (a) Li, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2003, 68, 5512. (b)
Tarli, A.; Wang, K. K. J. Org. Chem. 1997, 62, 8841. (c) Wang, K. K.;
Wang, Z.; Tarli, A.; Gannett, P. J. Am. Chem. Soc. 1996, 118, 10783. (d)
Wang, K. K.; Zhang, H.-R.; Petersen, J. L. J. Org. Chem. 1999, 64, 1650.
(10) A similar cascade leading to a tetracarbocyclic aromatic compound via a
triarylmethyl radical intermediate was reported in ref 9d.
(11) Triethylamine was also tested, but side products were observed by NMR
in the 1H spectrum of the crude mixture. It led to only 52% isolated yield
at the same temperature within 5 h.
(12) The 1.8 Hz vicinal coupling constant between the CH group protons in the
heterocyclic ring indicates an ax-eq or eq-eq relationship. The second
proposal, implying a trans relationship, seems more likely.
JA106668D
9
14744 J. AM. CHEM. SOC. VOL. 132, NO. 42, 2010