Relaying asymmetry of transient atropisomers of o-iodoanilides by radical cyclizations

Article abstract of DOI:10.1021/ja055666d

Atropisomers of N-2°-alkyl-N-acryloyl-2-iodoanlides have been resolved by chromatography and crystallization-induced asymmetric transformation. These molecules have atropisomerization barriers of 23-24 kcal/mol and return to equilibrium ratios over severa

Full text of DOI:10.1021/ja055666d

Published on Web 10/05/2005
Relaying Asymmetry of Transient Atropisomers of o-Iodoanilides by Radical
Cyclizations
Marc Petit, Andre J. B. Lapierre, and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received August 18, 2005; E-mail: curran@pitt.edu
Unlike most ionic and pericyclic reactions, the rates of radical
and diradical reactions are often faster than common conformational
changes in organic molecules. A growing number of processes
involving memory or transfer of chirality1 use the lightning speed
of radical reactions to translate a transient feature of asymmetry in
a precursor into a permanent feature in a product. For example, a
ring2 or chain3 conformational preference in a precursor can be
relayed to a stereocenter in a product. We report herein that simple
o-iodoacrylanilides can be resolved, and that the asymmetry of the
resulting transient atropisomers can be locked into a stereocenter
by a subsequent rapid radical cyclization.
In an early attempt to use chiral auxiliaries in radical cycliza-
To address this question, we prepared iodoacrylanilide 5 from
(S)-phenethylamine and studied its radical cyclizations in detail (eq
3). NMR spectroscopic studies show that 5 exists as an equilibrium
mixture of atropisomers (M,S)-5/(P,S)-5 in a ratio of 68/32 at room
tions,4 Jones and McCarthy reported that cyclizations of acrylanil-
ides bearing chiral N-substituents formed dihydroindolones with
very low levels of asymmetric induction.5 For example, cyclization
of N-2-phenylethyl acrylanilide 1 with Bu3SnH in toluene at 105
°C provided dihydroindolone 2 as a 51/49 mixture of stereoisomers
(eq 1). This apparent failure to observe stereoselectivity has been
accommodated by a standard model in which a single intermediate
aryl radical partitions between two diastereomeric cyclization
pathways of about equal energy.
temperature.7 Radical cyclization of this mixture provided the
expected 50/50 ratio of products (R,S)-6 and (S,S)-6 at 110 °C,7
but the ratio increased as the reaction mixture was cooled through
20 °C (78/22) to 0 °C (81/19) down to -20 °C (84/16). There was
no further increase on cooling to -78 °C. This unusual temperature
dependence is symptomatic of a change in mechanism. Interestingly,
however, the level of stereoselectivity observed at the low temper-
ature limit (84/16) actually exceeds the starting rotamer ratio (68/
32).
To the best of our knowledge, there are no examples of resolution
of mono-ortho-substituted anilides, except when the ortho-substitu-
ent is tert-butyl.8 Nonetheless, we were able to resolve 5 into its
atropisomeric components (M,S)-5 and (P,S)-5 by preparative HPLC
experiments. The isolated atropisomers interconvert with a barrier
∆G ≈ 23 kcal/mol (t1/2 ≈ 2.5 h at 25 °C, see Supporting Information
for measurements). Cyclization at -78 °C of a 91/9 ratio of (M,S)-
5/(P,S)-5 gave (R,S)-6 and (S,S)-6 in a 95/5 ratio, while a mixture
in a 2/98 ratio gave (R,S)-6/(S,S)-6 in 16/84 ratio. Thus, each
atropisomer of 5 cyclizes to a different major product 6. But
consistent with the results of cyclization of the equilibrium mixture
at low temperature, the cyclization of one of the atropisomers
[(M,S)-5] is more selective than that of the other [(P,S)-5].
We interpret these results within the mechanistic framework
shown in Figure 1. Tributyltin radical abstracts iodine from
Results on radical cyclizations of iodoanilides like 3 bearing
methyl groups at the other ortho position6 (eq 2) began to suggest
to us that, when viewed within the proper mechanistic framework,
the Jones/McCarthy experiment could actually be a success. Iodo-
anilides 3 can be resolved and are relatively stable at room temper-
ature. Radical cyclizations of the individual enantiomers of 3 pro-
vide dihydroindoles 4 with levels of chirality transfer of about 90%.
Accordingly, we hypothesized that molecules like 1 lacking a
second ortho substituent should also exist in solution as a pair of
equilibrating atropisomers. In turn, these atropisomers could produce
a pair of diastereomeric radicals that cyclize faster than they inter-
convert. In other words, perhaps the low selectivity observed by
Jones and McCarthy (eq 1) masks two highly selective cyclizations
of atropisomeric radicals that are generated in about equal ratio.
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10.1021/ja055666d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
of iodoanilides 11a,b (eq 5) by rapid preparative chromatography
over a Whelk-O chiral column. Cyclizations of these enantioen-
riched samples indeed occurred with good levels of chirality transfer
to produce enantioenriched samples of dihydroindolones (R)- or
(S)-12a,b.
Figure 1. Proposed mechanism for temperature-dependent cyclizations of
aryl radicals derived from 5.
atropisomers (M,S)-5 and (P,S)-5 with about equal rates to give
radicals 7â and 7R in a ratio that reflects that starting iodide ratio.9
These radicals must have a significantly lower barrier to intercon-
version than 5, but they now have the competitive option of radical
cyclization. The lack of selectivity observed at 110 °C suggests
that interconversion of 7â and 7R is more rapid than cyclization in
the high-temperature regime (kr, kr′ > kcR, kcâ). On cooling,
cyclization begins to compete with rotation. Somewhere below 0
°C, transition to the low-temperature regime is complete. Here the
two radicals 7R,â no longer interconvert, and each cyclizes with
its own selectivity in favor of opposite diastereomers 8. Radical
7â cyclizes to (R,S)-8 with high fidelity, while 7R cyclizes
predominately to (S,S)-8 but with significant (∼20%) leakage to
(R,S)-8. This leakage accounts for the observation that the product
ratios differ from the starting atropisomer ratios when (P,S)-5 is
present in significant amounts.
These results show that the atropisomeric o-iodoanilides bearing
only a hydrogen atom at the other ortho-position can be resolved
and handled rapidly under ambient laboratory conditions. The asym-
metry present in these transient atropisomers can then be locked
into a stereocenter by a subsequent radical cyclization, which occurs
with good to excellent levels of chirality transfer. Among other
implications, the results suggest that a chiral auxiliary that provides
a high equilibrium bias for one of the diastereomeric atropisomeric
iodides will provide a single product stereoselectivity without the
need to resolve the precursors. Likewise, the diastereoselective
formation of a complex between a chiral Lewis acid and a racemate
like 11 could provide a single product enantioselectively.
Acknowledgment. We thank the National Science Foundation
for funding this work. Dedicated to the memory of Prof. Dr. Hanns
Fischer, 1935-2005.
We next prepared iodoanilide 9 from L-valine (eq 4). At ambient
temperature, this exists as a 58/42 equilibrium mixture of (M,S)
and (P,S) rotamers, which were again separable by preparative
HPLC. Also, slow crystallization of the equilibrium mixture from
hexanes deposited exclusively (M,S)-9 in a crystallization-induced
asymmetric transformation.
Supporting Information Available: Full experimental details,
crystal structure data, and copies of key spectra (PDF, CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1-16. (b) Fuji,
K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373-376.
(2) (a) Dalgard, J. E.; Rychnovsky, S. D. Org Lett 2004, 6, 2713-2716. (b)
Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J. Org. Lett.
2001, 3, 807-810. (c) Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2000, 122, 9386-9390. (d) Buckmelter, A. J.; Powers,
J. P.; Rychnovsky, S. D. J. Am. Chem. Soc. 1998, 120, 5589-5590.
(3) (a) Giese, B.; Wettstein, P.; Sta¨helin, C.; Barbosa, F.; Neuburger, M.;
Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999, 38, 2586-2587.
(b) Seiler, M.; Schumacher, A.; Lindemann, U.; Barbosa, F.; Giese, B.
Synlett 1999, 1588-1590. (c) Sinicropi, A.; Barbosa, F.; Basosi, R.; Giese,
B.; Olivucci, M. Angew. Chem., Int. Ed. 2005, 44, 2390-2393.
(4) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH:
Weinheim, 1996; Chapter 2. (b) Porter, N. A. In Radicals in Organic
Synthesis, 1st ed.; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, pp 416-440.
(5) Jones, K.; McCarthy, C. Tetrahedron Lett. 1989, 30, 2657-2660.
(6) (a) Curran, D. P.; Liu, W. D.; Chen, C. H.-T. J. Am. Chem. Soc. 1999,
121, 11012-11013. (b) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001,
123, 5130-5131. (c) Curran, D. P.; Chen, C. H.-T.; Geib, S. J.; Lapierre,
A. J. B. Tetrahedron 2004, 60, 4413-4424. (d) Petit, M.; Geib, S. J.;
Curran, D. P. Tetrahedron 2004, 60, 7543-7552.
(7) Assignments of configuration are presented in the Supporting Information.
(8) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 3131-3132. (b) Curran, D. P.; Geib, S.; DeMello, N.
Tetrahedron 1999, 55, 5681-5704. (c) During the publication process of
this paper, resolutions of two o-iodoanilides were reported: Adler, T.;
Bonjoch, J.; Clayden, J.; Font-Bard´ıa, M.; Pickworth, M. Solans, X., Sole,
D. Vallverdu´, Org. Biomol. Chem. 2005, 3, 3173-3183.
(9) Control experiments at partial conversion showed that (M,S)-5 and (P,S)-5
were consumed at about equal rates, so diastereoselective iodine abstraction
seems unlikely.
The interconversion barrier between the rotamers of 9 is 24.3
kcal/mol. Cyclization of a 99/1 mixture of rotamers (M,S)-9/(P,S)-9
faithfully provided (R,S)-10 (94/6-97/3), while cyclization of a
97/3 mixture enriched in (P,S)-9 faithfully provided (S,S)-10 (91/
9).
The successful resolution and selective cyclization of dia-
stereomeric atropisomers in eqs 3 and 4 suggests that analogous
enantioselective transformations are possible. Indeed, despite the
low rotation barriers (23 kcal/mol, see Supporting Information),
we succeeded in obtaining significantly enantioenriched samples
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