Torquoselective ring closures of chiral amido trienes derived from allenamides. A tandem allene isomerization - pericyclic ring-closure- intramolecular diels-alder cycloaddition

Article abstract of DOI:10.1021/ol902821w

Chemical Equation Presented A new torquoselective ring-closure of chiral amide-substituted 1,3,5-hexatrienes and its application in tandem with [4+2] cyloaddition are described. the trienes were derived via either a 1,3-H or 1,3-H-1,7-H shift of α-substituted allenamides, and the entire sequence through the [4 + 2] cycloaddition could be in tandem from allenamides.

Full text of DOI:10.1021/ol902821w

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1152-1155
Torquoselective Ring Closures of Chiral
Amido Trienes Derived from
Allenamides. A Tandem Allene
Isomerization-Pericyclic
Ring-Closure-Intramolecular
Diels-Alder Cycloaddition
Ryuji Hayashi, John B. Feltenberger, and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received December 7, 2009
ABSTRACT
A new torquoselective ring-closure of chiral amide-substituted 1,3,5-hexatrienes and its application in tandem with [4 + 2] cycloaddition are
described. The trienes were derived via either a 1,3-H or 1,3-H-1,7-H shift of r-substituted allenamides, and the entire sequence through the
[4 + 2] cycloaddition could be in tandem from allenamides.
We recently reported isomerizations of R-substituted alle-
namides 1 to give amido dienes 2 via stereoselective 1,3-H
shift (Scheme 1).1 In addition, with R ) vinyl, the resulting
1,3,5-hexatrienes 2′ were found to be well suited for a 6π-
electron electrocyclic ring closure that could be in tandem
with the 1,3-H shift, leading to novel chiral cyclic amido
dienes 32,3 directly from allenamides.4,5 The rapid access of
1,3,5-hexatrienes via a simple isomerization of allenes6–8
allowed us to envision a new torquoselective ring-closure9–13
involving chiral amido trienes 4. This asymmetric transfor-
mation could potentially lead to a remote 1,6-stereochemical
induction while affording cyclic amido dienes 5, which
should be useful for cycloadditions. We communicate here
this torquoselective process and its application in tandem
with [4 + 2] cycloadditions.
(3) (a) For a review on the synthesis of enamides, see: Tracey, M. R.;
Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.; Zhang,
Y. In Science of Synthesis, Houben-Weyl Methods of Molecular Transfor-
mations; Weinreb, S. M., Ed.; Georg Thieme Verlag: Stuttgart, 2005;
Chapter 21.4. (b) For a leading review on recent chemistry of enamides,
see: Carbery, D. R. Org. Biomol. Chem. 2008, 9, 3455. (c) Rappoport, Z.
The Chemistry of Enamines in The Chemistry of Functional Groups; John
Wiley and Sons: New York, 1994.
(1) Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G. Org.
Lett. 2009, 11, 2125.
(2) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M. Synthesis 1981, 753. (c)
Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421. Also see: (d) Krohn, K.
Angew. Chem., Int. Ed. 1993, 32, 1582. (e) Enders, D.; Meyer, O. Liebigs
(4) For a leading review on allenamide chemistry, see: Hsung, R. P.;
Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773.
Ann. 1996, 1023
.
10.1021/ol902821w  2010 American Chemical Society
Published on Web 02/19/2010

Scheme 1
.
New Torquoselective Pericyclic Ring Closure
Scheme 3. Unexpected Competing 1,7-H Shift
Our intention was quickly met with two unexpected
findings. Initially, when heating allenamide 614,15 in
ClCH2CH2Cl at 135 °C, instead of isolating the desired amido
diene 8 from ring closure of the triene 7, we found 916 in
almost quantitative yield, thereby implying a 1,5-H shift had
taken place (Scheme 2). Similar results were attained when
using triene 7 generated from 6 via an acid-promoted 1,3-H
shift using 10 mol % of p-TsOH.
Figure 1. Torquoselective disrotatory ring closure.
Scheme 2. Complication with the 1,5-H Shift into Conjugation
in 1:4.5 ratio with 14a being a 10:1 diastereomeric mixture.
The latter implied the presence of amido triene 12a, which
could be rationalized through an antarafacial 1,7-H shift9,17
from the initial amido triene 11a, via the methyl group (in
red) syn to the terminal olefin (in blue). More importantly,
stereochemistry for the major isomer of 14a could be
assigned using its single-crystal X-ray structure (Figure 1).
This unambiguous assignment suggests that a favored
disrotatory course could proceed through the transition state
as shown for amido triene 12a.
(7) For some examples of thermal allene isomerizations, see: (a)
Crandall, J. K.; Paulson, D. R. J. Am. Chem. Soc. 1966, 88, 4302. (b) Bloch,
R.; Perchec, P. L.; Conia, J.-M. Angew. Chem., Int. Ed. 1970, 9, 798. (c)
Jones, M.; Hendrick, M. E.; Hardie, J. A. J. Org. Chem. 1971, 36, 3061.
(d) Patrick, T. B.; Haynie, E. C.; Probat, W. J. Tetrahedron Lett. 1971, 27,
423. (e) Lehrich, F.; Hopf, H. Tetrahedron Lett. 1987, 28, 2697. (f) Meier,
H.; Schmitt, M. Tetrahedron Lett. 1989, 5873.
We quickly made a minor substrate adjustment to prevent
such 1,5-H shift, but that led to the second unexpected finding
as shown in Scheme 3. Heating R-prenylated allenamide 10a
led to a mixture of two ring-closure products: the desired
2-amido diene 13a and the unexpected 1-amido diene 14a
(8) For examples of allenamide isomerizations, see: (a) Overman, L. E.;
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.;
Kurtz, A. N. J. Org. Chem. 1966, 31, 2885. For an allenamide isomerization
via Grubb’s catalyst, see: (c) Kinderman, S. S.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3,
2045. (d) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117.
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Org. Lett. 2010, DOI: 10.1021/ol1001494.
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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
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Org. Lett., Vol. 12, No. 6, 2010
1153

Table 1. Tandem 1,3-H-1,7-H Shift Pericyclic Ring Closure
Scheme 4. Directional Preference in the 1,7-H Shift
Probing further mechanistically, we found two phenom-
ena associated with this 1,7-H shift process. First, heating
either triene 16, derived from γ-substituted allenamideto
no observable 1,7-H shift with cyclic diene 19 as the only
identifiable product. Isolation of 19 implies the ring
closure of triene 16 had taken place to give 18 followed
by 1,5-H shift (Scheme 4). This experiment suggests that
there exists a directional preference for the 1,7-H shift in
these amido trienes and that it is not sufficient simply
having a methyl group (in red) at one terminus of the triene
syn to the other terminus (in blue).
a All 3-amido trienes 11b-e were attained from the respective
allenamides 10b-e via 1,3-H shift promoted by CSA (10 mol %).
Reactions were run in CH2Cl2 at rt for 10 min, and isolated yields are
shown in the respective brackets. b For all entries: conc ) 0.10 M; temp
) 135 °C; time ) 20 h. c Isolated yields. d Ratios determined by 1H
and/or 13C NMR.
The tandem 1,3-H-1,7-H shift appears to be general
whether commencing from amido trienes 11b-e (entries
1-4 in Table 1) or directly from R-prenylated allenamides
10b-e (entries 5-8). It is noteworthy that in the case of
allenamide 10b and 10c cyclic amido dienes 14b and 14c
were the only products resulting from a tandem 1,3-
H-1,7-H shift-pericyclic ring closure. In addition, there
was no equilibration between 13 and 14 under the reaction
conditions.18
Scheme 5. Diverging Tandem Pathway: E- vs Z-Olefin
(11) For some examples on recent 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. Soc. 2008, 130, 5046. (e) Benson, C. L.; West, F. G. Org.
Lett. 2007, 9, 2545. (f) Pouwer, R. H.; Schill, H.; Williams, C. M.;
Bernhardt, P. V. Eur. J. Org. Chem. 2007, 4699. (g) Jung, M. E.; Min,
S.-J. Tetrahedron 2007, 63, 3682.
(12) For recent work on accelerated ring closures of 1,3,5-hexatrienes,
see: (a) Barluenga, J.; Merino, I.; Palacios, F. Tetrahedron Lett. 1990, 31,
6713. (b) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc.
2004, 126, 1624. (c) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G.
J. Am. Chem. Soc. 2006, 128, 4946. (d) Huntley, R. J.; Funk, R. L. Org.
Lett. 2006, 8, 3403. (e) Yu, T.-Q.; Fu, Y.; Liu, L.; Guo, Q.-X. J. Org.
Chem. 2006, 71, 6157. (f) Su¨nnemann, H. W.; Banwell, M. G.; de Meijere,
A. Eur. J. Org. Chem. 2007, 3879.
(13) For theoretical studies on substituent effects on electrocyclic ring
closure of 1,3,5-hexatrienes, see: (a) Spangler, C. W.; Jondahl, T. P.;
Spangler, B. J. Org. Chem. 1973, 38, 2478. (b) Guner, V. A.; Houk, K. N.;
Davies, I. A. J. Org. Chem. 2004, 69, 8024. (c) Yu, T.-Q.; Fu, Y.; Liu, L.;
Guo, G. X. J. Org. Chem. 2006, 71, 6157. (d) Duncan, J. A.; Calkins,
D. E. G.; Chavarha, M. J. Am. Chem. Soc. 2008, 130, 6740.
(14) (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117. (b) Shen,
L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7,
3081.
Second, we found a distinct dependence of the 1,7-H shift
on the olefinic geometry. As shown in Scheme 5, reactions
of allenamides 20-Z and 20-E proceeded through distinctly
different tandem pathways. 15, or 15 led While 1,3-H-1,7-H
shift occurred with 20-Z en route to cyclic amido diene 22
via pericyclic ring closure of triene 21, the reaction of
(15) Xiong, H.; Hsung, R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.;
Stockwell, B. Org. Lett. 2000, 2, 2869.
(16) See the Supporting Information.
(18) Independent heating of 13b or 14b led to no observable amount of
the other compound.
(17) For recent examples in thermal antarafacial 1,7-H shift of 1,3,5-
hexatrienes, see: (a) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004,
6, 457. (b) Mousavipour, S. H.; Ferna´ndez-Ramos, A.; Meana-Pan˜eda, R.;
Mart´ınez-Nu´n˜ez, E.; Va´zquez, S. A.; R´ıos, M. A. J. Phys. Chem. A 2007,
111, 719. (c) Gu, Z.; Ma, S. Chem.sEur. J. 2008, 14, 2453. (d) Shu, X.-
Z.; Ji, K.-G.; Zhao, S.-C.; Zheng, Z.-J.; Chen, J.; Lu, L.; Liu, X.-Y.; Liang,
Y.-M. Chem.sEur. J. 2008, 14, 10556.
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Org. Lett., Vol. 12, No. 6, 2010

allenamide 20-E gave 24 with no observable 1,7-H shift.
Relative stereochemistry in 22 was assigned on the basis of
a disrotatory ring closure, while the absolute stereochemistry
was assessed on the basis of 14a. Cyclic amido diene 24
was found as a 3:1 isomeric mixture with respect to C5,
thereby implying that albeit modest and unassigned at this
time,19a rather impressive 1,6-asymmetric induction took
place during the ring closure.
In contrast, reactions of allenamides 25-E (for a direct
comparison with 25-Z) and 29-E led the respective tricycles
31a and 31b (assigned via X-ray: see Figure 2) in excellent
yields and high diastereoselectivity proceeding from amido-
trienes 30a and 30b or directly from the allenamides in a
triple tandem process. In either case, the [4 + 2] cycload-
dition presumably went through the diastereomeric pairs 32a/
a′ (X ) O) and 32b/b′ (X ) NTs) given the modest 1,6-
induction found for 20-E. It is noteworthy that despite not
having assigned these diastereomers with ratios under-
mined,20 both pairs would actually converge to give 31a and
31b, respectively. These tandem processes provide a rapid
assembly of complex tricycles from very simple allenamides,
thereby manifesting their tremendous power and synthetic
potential.
Scheme 6. In Tandem with [4 + 2] Cycloaddition
Figure 2. X-ray structure of 31b.
We have described here a new torquoselective ring closure
of chiral amide-substituted 1,3,5-hexatrienes and its applica-
tion in tandem with [4 + 2] cycloaddition. The 1,3,5-
hexatrienes were derived via either a 1,3-H or 1,3-H-1,7-H
shift of R-substituted allenamides, and the entire sequence
through the Diels-Alder could be in tandem from allena-
mides. Applications of these new tandem processes as well
as mechanistic understanding and improvement of the
observed 1,6-asymmetric induction are underway.
To both accentuate this dichotomy and render these
stereoselective ring closures synthetically useful, we em-
barked on tandem processes that would include [4 + 2]
cycloadditions. As shown in Scheme 6, reactions of allena-
mides 25-Z and 26-Z led to tricycles 28a and 28b as a single
isomer through a highly stereoselective [4 + 2] cycloaddition
of cyclic amido dienes 27a and 27b, respectively, thereby
constituting a quadruple tandem process of 1,3-H-1,7-H
shift-6π-electron pericyclic ring-closure-[4 + 2] cycload-
dition. Stereochemical outcome of the cycloaddition was
controlled through the C5-stereocenter, which was installed
during the torquoselective ring closure.
Acknowledgment. We thank the NIH (GM066055) for
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. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Attempts were made to attain an X-ray but were not successful
mainly because of difficulties in the separation of diastereomers. Further
efforts are ongoing.
(20) Unfortunately, Diels-Alder cycloadditions of 32a/a′ or 32b/b′ in
Scheme 6 did not provide conclusive insight into the stereochemical outcome
of ring closures of 30a and 30b.
OL902821W
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