A highly stereoselective Diels-Alder cycloaddition of enones with chiral cyclic 2-amidodienes derived from allenamides

Article abstract of DOI:10.1021/ol402254p

Lewis acid promoted Diels-Alder cycloadditions of a series of de novo chiral cyclic 2-amidodienes are described. These cyclic 2-amidodienes are derived from chiral α-allyl allenamides via a sequence of E-selective 1,3-H shift and 6π-electron pericyclic ring closure. With enones serving as effective dienophiles, these cycloadditions can be highly diastereoselective depending upon the chiral amide substituent, thereby representing a facile entry to optically enriched [2.2.2]bicyclic manifolds.

Full text of DOI:10.1021/ol402254p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Highly Stereoselective DielsꢀAlder
Cycloaddition of Enones with Chiral Cyclic
2‑Amidodienes Derived from Allenamides
Li-Chao Fang, Richard P. Hsung,* Zhi-Xiong Ma, and William R. Presser
Division of Pharmaceutical Sciences and Department of Chemistry,
University of Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received August 7, 2013
ABSTRACT
Lewis acid promoted DielsꢀAlder cycloadditions of a series of de novo chiral cyclic 2-amidodienes are described. These cyclic 2-amidodienes are
derived from chiral R-allyl allenamides via a sequence of E-selective 1,3-H shift and 6π-electron pericyclic ring closure. With enones serving as
effective dienophiles, these cycloadditions can be highly diastereoselective depending upon the chiral amide substituent, thereby representing a
facile entry to optically enriched [2.2.2]bicyclic manifolds.
We recently reported1 a highly stereoselective 1,3-hydro-
gen shift involving allenamides2ꢀ4 that proves to be a facile
entry to valuable dienamides or trienamides [1f2 in
Scheme 1].5ꢀ7 With the E-selectivity in this acid or ther-
mally promoted 1,3-H shift, the resulting 2-amidotrienes 2
Scheme 1. Cyclic 2-Amidodienes in [4 þ 2] Cycloadditions
(1) (a) Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G.
Org. Lett. 2009, 11, 2125. (b) Hayashi, R.; Feltenberger, J. B.; Hsung,
R. P. Org. Lett. 2010, 12, 1152. (c) Hayashi, R.; Walton, M. C.; Hsung,
R. P.; Schwab, J.; Yu, X. Org. Lett. 2010, 12, 5768. (d) Hayashi, R.;
Feltenberger, J. B.; Lohse, A. G.; Walton, M. C.; Hsung, R. P. Beil. J.
Org Chem 2011, 7, 410.
(2) For leading reviews on allenamide chemistry, see: (a) Lu, T.; Lu,
Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 130, 4862. (b)
Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773.
(3) Also see: (a) Standen, P. E.; Kimber, M. C. Curr. Opin. Drug
Discovery Dev. 2010, 13, 645. (b) Deagostino, A.; Prandi, C.; Tabasso,
S.; Venturello, P. Molecules 2010, 15, 2667.
(4) For general reviews on allenes, see: (b) Krause, N.; Hashmi,
A. S. K. Modern Allene Chemistry; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2004; Vol. 1 and 2.
(5) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M. Synthesis 1981, 753. (c)
are perfectly set up to undergo a 6π-electron pericyclic ring
Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421. (d) Krohn, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1582. (e) Enders, D.; Meyer, O. Liebigs
Ann. 1996, 1023.
closure8 to give chiral cyclic 2-amidodienes 3.1 While
2-amino- or 2-amidodienes can find sufficient precedents,9ꢀ11
cyclic 2-amidodienes 3 represent rare cyclic dienes.12
While DielsꢀAlder cycloadditions of amino- and amido-
dienes are known,6ꢀ13 cycloadditions of respective
cyclic dienes are much less known.12 To the best of our
(6) For a recent review on chemistry of enamides, see: (a) Carbery,
D. R. Org. Biomol. Chem. 2008, 9, 3455. Also see: (b) Rappoport, Z. The
Chemistry of Enamines in The Chemistry of Functional Groups; John
Wiley and Sons: New York, 1994. (c) Whitesell, J. K.; Whitesell, M. A.
Synthesis 1983, 517. (d) Hickmott, P. W. Tetrahedron 1982, 38, 1975–
3363.
r
10.1021/ol402254p
XXXX American Chemical Society

knowledge cycloaddition of dienes such as 3 has not been
explored in a systematic manner.14 Cyclic dienes 3 are
unique, as they contain a chiral amino auxiliary at the
C2-position. However, the rotation along the CꢀN bond
potentially poses two possible coplanar conformations
that could present a significant challenge in controll-
ing the facial preference for the approaching dienophile
[4 versus 40]. We wish to report here our efforts in develop-
ing stereoselective DielsꢀAlder cycloadditions of these
chiral cyclic 2-amidodienes.
Given our prior experience with a 1,5-H shift that had
led to the formation of thermodynamically more favorable
cyclic 1-amidodienes [see 6],1b our first challenge was to
ensure that cycloadditions of these cyclic 2-amidodienes
can take place competitively without the interference of a
1,5-H shift. Toward that goal, we screened a variety of
Lewis acids inanattempt tolower the activationbarrierfor
the cycloaddition. As shown in Table 1, the reaction of
diene 4 with methyl vinyl ketone [MVK] was carried out
with a series of Lewis acids, and we found that SnCl4 is the
most effective in promoting the cycloaddition, leading to
cycloadduct 7a and 7b as an isomeric mixture in 86% yield
when also using 4 A MS [entry 6].15 On the other hand,
TiCl4, AlCl3, TMSOTf, Yb(OTf)3, and InCl3 [entries 1, 2,
9, 11, and 12, respectively] are met with marginal success,
while EtAlCl2, Et2AlCl, Sc(OTf)3, MgBr2, and LiClO4 did
not work with no observable reactions taking place in the
last two cases [entries, 3, 4, 10, 13, and 14, respectively].
When using less than 1.0 equiv of SnCl4, the reaction
gave lower yields [entries 7 and 8]. It is noteworthy that
while the diastereomeric ratio was moderate, under these
conditions, the reaction was quite facile even at ꢀ78 °C,
thereby suppressing the thermally driven 1,5-H shift.
Although stereochemical assignment was confirmed later
with another cyclic diene [vide infra], both isomers are
showntobe endocycloadductswiththe major isomerbeing
7a and the minor being 7b.
We quickly found that enones such as ethyl and aryl
vinyl ketone could also serve as useful dienophiles when
reacting with diene 4 [Table 2]. Yields in these reactions are
moderate, but the diastereoselectivity was improved when
using ethyl vinyl ketone [see 8] under the conditions of 1.0
equiv of SnCl4 and 4 A MS, albeit with only a 55% yield.
Unfortunately, for reasons that are currently not clear to
us, other enones including 2-cyclohexenone and ynone as
well as unsaturated esters were not suitable as dieno-
philes under these conditions. Instead, we observed a
significant substrate decomposition of the starting diene
4. Intriguingly, when using p-benzoquinone, we observed
Table 1. Identification of a Suitable Lewis Acid
temp temp yield
dr
entry
LA
TiCl4
additive solvent
[°C]
[h]
[%]a ratiob
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
CH2Cl2 ꢀ78
1
50
75:25
66:37
ꢀ
AlCl3
CH2Cl2 ꢀ78
1.5 19
EtAlCl2
Et2AlCl
SnCl4
CH2Cl2 ꢀ78 to 0 2.5 0c
CH2Cl2 ꢀ78 to 0 2.5 0c
ꢀ
CH2Cl2 ꢀ78
1
1
1
1
1
75
86
46
30
30
88:12
83:17
83:17
83:17
N.D.f
ꢀ
˚
SnCl4
4 A MS CH2Cl2 ꢀ78
d
˚
SnCl4
4 A MS CH2Cl2 ꢀ78
e
˚
SnCl4
4 A MS CH2Cl2 ꢀ78
TMSOTf
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
CH2Cl2 ꢀ78
10 Sc(OTf)3
11 Yb(OTf)3
12 lnCl3
CH2Cl2
0
1.5 0c
CH2Cl2 rt
CH2Cl2 rt
2
6
25
30
N.D.
N.D.
ꢀ
13 MgBr2
14 LiClO4
THF
Et2O
rt
rt
12 no rxng
12 no rxn
ꢀ
a Isolated yields; in all cases 1.0 equiv of Lewis acid was used with
(11) For leading examples of 2-amidodienes, see: (a) Ha, J. D.; Kang,
C. H.; Belmore, K. A.; Cha, J. K. J. Org. Chem. 1998, 63, 3810. (b)
exceptions of entries 7 and 8. b Ratios determined using 1H and/or 13
C
NMR. c A complex mixture likely resulting from decomposition of 6 was
obtained with no observable desired cycloadduct. d 0.50 equiv of SnCl4
was used. e 0.25 equiv of SnCl4 was used. f N.D. = Not Determined.
g Complete recovery of starting diene 6.
ꢀ
ꢀ
Gonzalez-Romero, C.; Bernal, P.; Jimenez, F.; Cruz, M. C.; Fuentes-
Benites, A.; Benavides, A.; Bautista, R.; Tamariz, J. Pure Appl. Chem.
2007, 79, 181and references cited therein. (c) Movassaghi, M.; Hunt,
D. K.; Tjandra, M. J. Am. Chem. Soc. 2006, 128, 8126.
(12) For some rare examples cyclic amidodienes, see: (a) Martınez,
´
ꢀ
ꢀ
R.; Jimenez-Vazquez, H. A.; Delgado, F.; Tamariz, J. Tetrahedron 2003,
59, 481. (b) Wallace, D. J.; Klauber, D. J.; Chen, C. Y.; Volante, R. P.
Org. Lett. 2003, 5, 4749. (c) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B.
Chem.;Eur. J. 2004, 10, 484.
(13) (a) Terada, A.; Murata, K. Bull. Chem. Soc. Jpn. 1967, 40, 1644.
(b) Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc. 1976, 98, 2352. (c)
Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979, 4537. (d)
Smith, A. B., III; Wexler, B. A.; Tu, C.-Y.; Konopelski, J. P. J. Am.
Chem. Soc. 1985, 107, 1308. (e) Schlessinger, R. H.; Pettus, T. R. R.;
Springer, J. P.; Hoogsteen, K. J. Org. Chem. 1994, 59, 3246. (f) Kozmin,
S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165. (h) Huang, Y.;
Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 5950. (g) Robiette,
R.; Cheboub-Benchaba, K.; Peeters, D.; Marchand-Brynaert, J. J. Org.
Chem. 2003, 68, 9809.
(7) 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
Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: Chapter
21.4, 2005.
(8) For reviews, see: (a) Marvell, E. N. Thermal Electrocyclic Reac-
tions; 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 699ꢀ750.
(9) For reviews on chemistry of 2-amino- or 2-amidodienes: (a)
Krohn, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1582. (b) Enders,
D.; Meyer, O. Liebigs Ann. 1996, 1023.
(14) We have examined cycloadditions of related dienes in a tandem
and intramolecular mode. See: (a) Feltenberger, J. B.; Hsung, R. P. Org.
Lett. 2011, 13, 3114. (b) Hayashi, R.; Ma, Z.-X.; Hsung, R. P. Org. Lett.
2012, 14, 252.
(10) For leading examples of 2-amino-dienes, see: (a) Enders, D.;
Meyer, O.; Raabe, G. Synthesis 1992, 1242. (b) Barluenga, J.; Canteli,
R.-M.; Flrez, J.; Garca-Granda, S.; Gutirrez-Rodrguez, A.; Martın, E.
´
J. Am. Chem. Soc. 1998, 120, 2514and references cited therein.
(15) See Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

an entirely different pathway that led to a benzofuran
product.16
substituted with the Sibi18 and Seebach auxiliary,19 respec-
tively, afforded 22 and 23 in 82% and 80% yield essentially
as a single isomer, thereby establishing a facile entry to
optically enriched [2.2.2]bicyclic manifolds. The single
crystal X-ray structure of 22a provided unambiguous
confirmation of the endo-I selectivity [left Figure 1].20,21
Table 2. Some Limitations on Dienophilesa,b
Figure 1. X-ray structures of 22a, 27b, and 29a.
a For each reaction, conditions would follow those described for
entry 6 in Table 1. All are isolated yields. b Ratios denote endo-I to endo-
II and are determined using 1H and/or 13C NMR. c For 3-butyne-2-one:
ZnCl2 in CH2Cl2 at 0 °C to rt was also examined. d For 2-cyclohexenone:
AlCl3 in toluene as well as TfOH in CH2Cl2 at 0 °C to rt was also
examined.
Table 3. A Highly Stereoselective [4 þ 2] Cycloadditiona,b
Scheme 2. Effect of the Chiral Auxiliary on Selectivity
On the other hand, we found that when using cyclic
2-amidodienes with other chiral amide auxiliaries, both
stereoselectivity and efficiency could be drastically im-
proved. As shown in Scheme 2, although using the Ph-
substituted Evans auxiliary, cycloaddition with MVK led
tocycloadduct 20withdiminished selectivity, diene 17with
the i-Pr-substituted Evans auxiliary gave 21 in 72% yield
with a 93:7 ratio. Cyclic 2-amidodienes 18 and 19
a Reactions conditions followed those described for entry 6 in
Table 1. All are isolated yields. b Ratios denote endo-I to endo-II and
are determined using 1H and/or 13C NMR. c The two minor isomers
appear to be exo-I and exo-II (see ref 20).
(16) When using p-benzoquinone, tetrahydro-dibenzofuran i was
found in 47% yield, thereby constituting a [3 þ 2] annulation process.
The stereochemistry of i is tentatively assigned based on an endo
approach of p-benzoquinone similar to the DielsꢀAlder transition state.
(17) For some examples of related annulations, see: (a) Brannock,
K. C.; Brupitt, R. D.; Davis, H. E.; Pridgen, H. S.; Thweatt, J. G. J. Org.
Chem. 1964, 29, 2579. (b) Duthaler, R. O.; Lyle, P. A.; Heuberger, C.
Helv. Chim. Acta 1984, 67, 1406. (c) Hilgeroth, A.; Brachwitz, K.;
Baumeister, U. Heterocycles 2001, 55, 661.
Success in finding chiral amides that can provide a high
level of diastereoselectivity allowedus tobroadenthescope
(18) (a) Sibi, M. P.; Ji, J. G. Angew. Chem., Int. Ed. 1996, 35, 190. (b)
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. (c) Sibi, M. P.;
Soeta, T.; Jasperse, C. P. Org. Lett. 2009, 11, 5366.
(19) (a) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81,
2093. (b) Gaul, C.; Seebach, D. Org. Lett. 2000, 2, 1501. (c) Gaul, C.;
Schweizer, B. W.; Seiler, P.; Seebach, D. Helv. Chim. Acta 2002, 85, 1546.
Org. Lett., Vol. XX, No. XX, XXXX
C

of this cycloaddition significantly as shown in Table 3.
Several key features are as follows: (a) substitutions at the
R-position of the enone are feasible; (b) while aryl vinyl
ketones in general are less selective than alkyl vinyl ke-
tones, diene 18 with the Sibi auxiliary proves to be useful
for aryl vinyl ketones in both yields and diastereoselec-
tivity; (c) X-ray structures of cycloadducts 27b and 29a
providefurther confirmation thatthe majorisomerisendo-
I and the minor is endo-II [center and right, respectively, in
Figure 1]; and (d) when using diene 19 with the Seebach
auxiliary and arylvinyl ketones, wefound three isomers for
the first time [see 39ꢀ41]. The two minor isomers of 39ꢀ41
are inseparable and have been assigned as a mixture of exo-
I and exo-II isomers based on the following experiments.
Hydrolysis of the minor cycloadducts of 39 with p-TSA
gave ketone 42 as a single isomer [Scheme 3]. This result
suggests that, after removal of the chiral amide, the exo-I
and exo-II isomeric pair would lead to 42 and ent-42,
respectively, which are indistinguishable spectroscopically.
When using DBU in refluxing toluene to equilibrate the
minor isomers, two new cycloadducts were found with one
matching the major endo-I isomer, thereby further con-
firming that the minor isomers are exo-I and exo-II.22
Figure 2. Different facial preference of chiral amides.
products were found with again complete recovery of both
13b and 27b. These results suggest that no retro-cycloaddi-
tion and equilibration took place under these reactions
conditions and that the observed diastereoselectivity is
likely a kinetic one.23
With that, a proposed explanation on various degrees in
the ability of different chiral amides in inducing diaster-
eoselectivity is shown in Figure 2. Given the assumption
that the oxazolidinone ring is coplanar with the diene motif
to allow for maximum delocalization of the nitrogen lone
pair, the assignment of endo-I being the major cycloadduct
would suggests that dienophiles approach from the bottom
face because of shielding of the top face by the substituent
on the chiral oxazolidinone auxiliary [ꢀPh, ꢀBn, ꢀCHPh2].
With this assumption in hand, it may be rationalized
that diene 16 with the Ph-substituted Evans auxiliary
would contribute the least amount of facial bias. On the
other hand, diene 18 [or, 17 as well as 19] could provide the
most facial differentiation because unlike in diene 4 where
the Bn group can still rotate away, leading to insufficient
shielding, the diphenyl methyl motif can enhance the
shielding through one of the two Ph rings. These are only
preliminary analyses, and thus, efforts to improve our
mechanistic understanding of this cycloaddition through
more thorough calculations are ongoing.
Scheme 3. Assignment of Possible exo-Cycloadducts
We have described here a Lewis acid promoted Dielsꢀ
Alder cycloaddition using de novo chiral cyclic 2-amido-
dienes. Under these conditions, enones prove to be the
most suitable dienophiles, leading to optically enriched
[2.2.2]bicyclic manifolds in a highly regio- and diastereo-
selective manner. Its applications in natural product synth-
esis are currently underway.
To probe whether this cycloaddition is reversible, the
minor cycloadduct 15b was resubjected to the same reac-
tion conditions, and we observed no corresponding major
isomer 15a with complete recovery of 15b. Furthermore,
when a 1:1 mixture of minor cycloadducts 13b and 27b
were resubjected to the same conditions, no crossover
Acknowledgment. The authors thank the NIH [GM0-
66055] for financial support and Dr. Victor Young at
University of Minnesota for X-ray structural analysis.
(20) Preliminary X-ray structure of cycloadduct 23a was also ob-
tained to avoid surprises that we had when using Seebach’s chiral
auxiliary in diastereoselective (4 þ 3) cycloadditions where CHꢀπ
interactions reversed the stereochemical outcome [see ref 21]. However,
the resolution of this structure, while sufficient for unambiguous stereo-
chemical assignment, is not suitable for publication at the present state.
Thus, the structural representation is shown in the Supporting Informa-
tion, but the CIF file is not submitted.
(21) (a) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.;
Hsung, R. P. Chem. Sci 2010, 1, 387. (b) Antoline, J. E.; Krenske, E. H.;
Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2011, 133,
14443.
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.
(23) We thank one of the referees for suggesting these control studies.
The authors declare no competing financial interest.
(22) We obtained similar results when using a 2:1 mixture of the
minor isomers from 41.
D
Org. Lett., Vol. XX, No. XX, XXXX