Stereoselective 6π-electron electrocyclic ring closures of 2-halo-amidotrienes via a remote 1,6-asymmetric induction

Article abstract of DOI:10.1021/ol102693e

A diastereoselective 6π-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote asymmetric induction is described. This new asymmetric manifold for pericyclic ring closure further underscores the significance of the allena

Full text of DOI:10.1021/ol102693e

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5768-5771
Stereoselective 6π-Electron Electrocyclic
Ring Closures of 2-Halo-Amidotrienes
via a Remote 1,6-Asymmetric Induction
Ryuji Hayashi, Mary C. Walton, Richard P. Hsung,* John H. Schwab, and
Xueliang Yu
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received November 6, 2010
ABSTRACT
A diastereoselective 6π-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote asymmetric induction is
described. This new asymmetric manifold for pericyclic ring closure further underscores the significance of the allenamide chemistry.
Identifying a highly stereoselective manifold for 6π-electron
electrocyclic ring closure of 1,3,5-hexatrienes remains a
challenge in the field of pericyclic processes.1,2 We recently
reported that a 1,3-H shift of allenamides 13,4 provides an
excellent entry to amidotrienes 2, which could undergo 6π-
electron pericyclic ring closure.5,6 The ring closure could
be rendered in tandem with the 1,3-shift,5,6 leading to the
facile construction of rare chiral cyclic amidodienes 3
[Scheme 1].7,8 While we were able to demonstrate the
possibility of attaining a stereoselective ring closure using
2, the level of selectivity was very modest. However, these
efforts unveiled an invaluable opportunity not only to develop
a new and attractive template for conducting stereoselective
6π-electrocyclic ring closures but also to achieve a highly
challenging 1,6-asymmetric induction.9 Consequently, we
examined isomerizations of 1 via electrophilic halogenations,
leading to 2-halo-amido-trienes 5 through N-acyl iminium
ions 4.
(1) For reviews for pericyclic ring closures, see: (a) Marvell, E. N.
Thermal Electrocyclic Reactions; Academic Press: New York, 1980. (b)
Okamura, W. H.; de Lera, A. R. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991;
Vol. 5, pp 699-750. For reviews on ring-closure in natural product
synthesis, see: (c) Pindur, U.; Schneider, G. H. Chem. Soc. ReV. 1994, 409.
(d) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105,
4757
.
(2) For recent examples of 6-π-electron electrocyclic ring closures of
1,3,5-hexatrienes, see: (a) Bishop, L. M.; Barbarow, J. E.; Bergmen, R. G.;
Trauner, D. Angew. Chem., Int. Ed. 2008, 47, 8100. (b) Sofiyev, V.; Navarro,
G.; Trauner, D. Org. Lett. 2008, 10, 149. (c) Kan, S. B. J.; Anderson, E. A.
Org. Lett. 2008, 10, 2323. (d) Hulot, C.; Blong, G.; Suffert, J. J. Am. Chem.
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2545. (f) Pouwer, R. H.; Schill, H.; Williams, C. M.; Bernhardt, P. V. Eur.
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63, 3682. For examples on accelerated ring closures of 1,3,5-hexatrienes,
see: (h) Su¨nnemann, H. W.; Banwell, M. G.; de Meijere, A. Eur. J. Org.
Chem. 2007, 3879. (i) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G.
J. Am. Chem. Soc. 2006, 128, 4946. (j) Huntley, R. J.; Funk, R. L. Org.
Lett. 2006, 8, 3403. (k) Yu, T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X. J. Org.
Chem. 2006, 71, 6157. (l) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y.
We recognized two distinct advantages of this electrophilic
isomerization over the thermal one:3b,5,10,11 (i) installing a
(3) For a leading review on allenamide chemistry, see: (a) Hsung, R. P.;
Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773. For general reviews
on allenes, see: (b) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004; Vols. 1 and 2.
J. Am. Chem. Soc. 2004, 126, 1624
.
10.1021/ol102693e  2010 American Chemical Society
Published on Web 11/19/2010

element in the ring closure to achieve the desired 1,6-
asymmetric induction. We envisioned that a disrotatory ring
closure through amidotrienes 7 in the upward direction could
be significantly favored with enhanced steric interaction
between the R1 group on the chiral amide and R3 [H versus
X] on the triene. We disclose here our success in developing
a stereoselective 6π-electron pericyclic ring closure of
halogen-substituted amidotrienes via a 1,6-remote asym-
metric induction.
Scheme 1. A New Torquoselective Manifold via 1,6-Induction
Our efforts commenced with electrophilic brominations
of the R-benzyl-substituted allenamide 812,13 as summarized
in Table 1. Initial attempts involved reacting 2 equiv of
Table 1. Electrophilic Bromination of Allenamides
halogen substituent at the C2-position of amidotrienes 5
allows for strategic functionalizations at C1 of 6 that is
originally the central allenic ꢀ-carbon; and (ii) more impor-
tantly, the halogen atom can serve as a key chirality relaying
entrya
equiv of 8
base
time [min]
yield [%]b
1
2
3
4
5
6
2.0
1.5
1.0
1.0
1.0
1.0
-
-
-
20
20
20
45
45
45
96
64
45
82
59
88
(4) Given the large volume of recent activities in allenamide chemistry,
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J. E.; Houk, K. N.; Hsung, R. P. Org. Lett. 2010, ASAP (DOI: 10.1021/
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Elsegood, M. R. J.; Kimber, M. C. J. Org. Chem. 2010, 75, 5406. (d)
Persson, A. K. Å.; Ba¨ckvall, J.-E. Angew. Chem., Int. Ed. 2010, 49, 4624.
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R. P. Chem. Science 2010, 1, 387. (f) Danowitz, A. M.; Taylor, C. E.;
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Et3N
K2CO3
DABCO
a 100 mg of 4 Å MS per 0.1 mmol of 8 were used for entries 1-3; 50
mg of 4 Å MS per 0.1 mmol of 8 were used for entries 4-6. b Isolated
yield. The E stereochemistry was determined using NOE. c Using NBS
afforded 29% yield of 10.
allenamide 8 with pyridinium tribromide salt 9 in the
presence of 4 Å MS in CH2Cl2, and the desired 2-bromo-
amidodiene 1014 was found in an encouraging 96% yield
with exclusive E-stereoselectivity [entry 1]. In this reaction,
4 Å MS was utilized as a neutral acid scavenger for the
corresponding byproduct HBr.15 However, yields dropped
(5) Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G. Org.
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Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421. (d) Krohn, K. Angew.
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Ann. 1996, 1023.
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Clizbe, L. A.; Freerks, R. L.; Marlowe, C. K. J. Am. Chem. Soc. 1981,
103, 2807. Also see: (b) Farmer, M. L.; Billups, W. E.; Greenlee, R. B.;
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481. (b) Wallace, D. J.; Klauber, D. J.; Chen, C. Y.; Volante, R. P. Org.
Chem. 2003, 5, 4749. (c) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B.
Chem.sEur. J. 2004, 10, 484.
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I.; Dlgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org.
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Y. In Science of Synthesis, Houben-Weyl Methods of Molecular Transfor-
mations; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: 2005; Chapter
21.4
.
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(14) See Supporting Information.
.
Org. Lett., Vol. 12, No. 24, 2010
5769

noticeably when the stoichiometry of the allenamide was
decreased [entries 2 and 3]. We attribute this loss in the yield
to hydrolysis of the starting allenamide due to the byproduct
HBr; evidently the excess amount of allenamide used in
earlier attempts was simply being sacrificed to soak up HBr.
Consequently, we screened a number of bases and found
that the addition of 2 equiv of DABCO [entry 6] to be the
most optimal in effectively promoting this bromination
reaction without sacrificing excess allenamide.
Having established the optimized conditions for bromi-
nation, a diverse array of de noVo 2-halo-3-amidodi- and
-trienes were prepared in synthetically useful overall yields
with E-stereoselectivity [Table 2]. In addition to bromination,
allenamides over alkynes [21, entry 2]. Subsequently, a range
of allenamides containing R-allylic systems could be em-
ployed in a chemoselective manner, leading to preparations
of chiral 2-halo-3-amidotrienes [entries 4-17].
In addition, 2-iodo-3-amidotrienes 25 and 29 could be
accessed using NIS in 69% yield and 96% yield from 13a
and 15a, respectively [entries 6 and 12]. Allenamides
containing protected alcohol [see 14] and protected amines
[see 15a and 15b] also underwent bromination, chlorination,
and iodination [see 26-29, entries 9-13].
Our success in accessing novel chiral 2-halo-3-amidotrienes
provided an invaluable opportunity for us to achieve diaste-
reoselective 6π-electron electrocyclizations via highly chal-
lenging 1,6-remote asymmetric induction. We proceeded to
examine thermal 6π-electron pericyclic ring closures of these
trienes to construct rare cyclic 1-halo-2-amidodienes. As shown
in Table 3, under thermal conditions in the range of 90-110
Table 2. Synthesis of 2-Halo-Amido-Di- and Trienes
Table 3. Stereoselective Electrocyclization
a All reactions were run in toluene [0.05 M] at 110 °C for 16 h in the
presence of 1 equiv of AlMe3. b Isolated yield. c Determined by 1H NMR.
d Product was aromatized.
a All reactions were run in CH2Cl2 [0.1 M] with 2 equiv of DABCO
and 4 Å MS [50 mg/0.1 mmol] for 16 h at rt. b Isolated yield. c All di- or
trienes were exclusively E-selective.
chlorinations could also be accomplished in good yields using
NCS [see 22, entries 3, 5, and 11]. It is noteworthy that
brominations using NBS were less successful than when
using NCS and that the tribromide salt 9 was the best
bromination source. More importantly, this halogenation
protocol appears to be highly chemoselective in reacting
°C in toluene, chiral 2-halo-3-amidotriene 30 decomposed in a
few hours without observing any ring-closure products. How-
(15) (a) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M.
J. Org. Chem. 2002, 67, 3412. (b) Hayashi, R.; Cook, G. R. Org. Lett.
2007, 9, 1311. (c) Kaneko, M.; Hayashi, R.; Cook, G. R. Tetrahedron Lett.
2007, 48, 7085.
5770
Org. Lett., Vol. 12, No. 24, 2010

ever, interestingly, addition of AlMe3 effectively promoted the
electrocyclization of 30, leading to the desired cyclic product
34. We are not sure at this point the role of AlMe3; we screened
several Lewis acids including BF3-Et2O, TiCl4, ZnCl2,
Cu(OTf)2, PtCl2, and AuCl but rapid decomposition of ami-
dotrienes occurred.
A proposed model for the stereoselective electrocyclization
is shown in Figure 2. Based on B3LYP/6-31G* calculations,17
While electrocyclization of chiral 2-halo-3-amidotriene 31
with substitution at the C5-position resulted in aromatization
of the initial product to give the aniline derivative 35 [entry 2],
we observed a high diastereoselectivity in the ring closure of
triene 23a [entry 3]. This high diastereoselectivity was rather
surprising because when we previously attempted electrocy-
clizations of 3-amido-6-alkyl-trienes,6 1,6-remote induction only
led to a diastereomeric ratio of 3:1 [see Scheme 1]. However,
it appears that, upon introduction of a halogen substitution, a
high level of 1,6-remote induction could be attained.
We subsequently screened trienes that are substituted chiral
oxazolidinones 23a-c [entries 3-7]; the benzyl-substituted
oxazolidinone 23a seemed to be the most appropriate chiral
auxiliary for this asymmetric transformation providing the
desired cyclic diene 36a in 95% yield with a dr of 90:10. The
stereochemistry of the newly formed center was determined
using the X-ray structure of a single crystal of 36b [Figure 1].
Figure 2. A proposed mechanistic model.
there is a 2.48 kcal mol-1 energy difference between two
possible conformers A and B for these halo-amidotrienes.
Although the Curtin-Hammett principle could be at play, if
assuming the more stable conformer A is also the operable one,
then the chiral auxiliary is blocking the lower face of the plane
of the triene. Proceeding through an aromatic transition state
for the 6π-electron electrocyclization, both bromine and the Ph-
substituent on the two terminal vinyl strands of the triene would
rotate in a disrotatory manner away from the Ph-ring on the
oxazolidinone auxiliary. This would lead to the formation of
the observed major diastereomer 36b.
We have accomplished here a synthetic access to rare
2-halo-3-amidodi- and -trienes via electrophilic halogenations
of allenamides. These novel trienes were useful to achieve
stereoselective electrocyclizations via 1,6-remote asymmetric
induction. Further mechanistic studies and applications of
this novel asymmetric manifold for pericyclic ring closure
are underway.
Figure 1. X-ray structure of 36b.
This diastereoselectivity is believed to be due to kinetic control
based on the control study of subjecting one of the minor
isomers [36c′] to the reaction conditions.16 Electrocyclization
of the chlorinated triene 24 afforded 37 in 61% yield with a
87:13 ratio, while the iodinated triene 25 gave 38 in 73% yield
with 90:10 dr. The nature of halogen does not appear to have
a significant impact on the diastereomeric ratio. Electrocycliza-
tions of other more exotic halogen-substituted trienes 26-29
were also examined [entries 8-12]. Ring-closure products
39-42 were attained in good yield and diastereoselectivity.
Unfortunately, triene 33 also led to the aromatized product
tetrahydronaphthlene 43 [entry 13].
Acknowledgment. The authors thank the NIH [GM066055]
for financial support and Dr. Victor Young [University of
Minnesota] for X-ray structural analysis.
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra, characterizations, and X-ray
structural files are available for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102693E
(17) B3LYP/6-31G* calculation for other halo-amidotrienes.
(16) Independent heating of minor isomer 36c′ led to no observable
amount of the other compound.
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