A tandem 1,3-H-shift-6π-electrocyclization-cyclic 2-amido-diene intramolecular Diels-Alder cycloaddition approach to BCD-ring of atropurpuran

Article abstract of DOI:10.1021/ol203030a

An approach toward the BCD-ring of atropurpuran via a sequence of allenic 1,3-H shift, 6π-electron pericyclic ring closure, and intramolecular Diels-Alder cycloaddition of cyclic 2-amidodiene is described.

Full text of DOI:10.1021/ol203030a

ORGANIC
LETTERS
2012
Vol. 14, No. 1
252–255
A Tandem 1,3-H-ShiftÀ6π-
ElectrocyclizationÀCyclic 2-Amido-diene
Intramolecular DielsÀAlder Cycloaddition
Approach to BCD-Ring of Atropurpuran
Ryuji Hayashi, Zhi-Xiong Ma, and Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry,
University of Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received November 9, 2011
ABSTRACT
An approach toward the BCD-ring of atropurpuran via a sequence of allenic 1,3-H shift, 6π-electron pericyclic ring closure, and intramolecular
DielsÀAlder cycloaddition of cyclic 2-amidodiene is described.
We recently1 reported a highly stereoselective tandem
sequence consisting of an allenic 1,3-hydrogen shift,2 a
6π-electron pericyclic ring closure,3 and an intramolec-
ular DielsÀAlder cycloaddition. This three-bond forma-
tion cascade provides a facile transformation of simple
allenamide 14,5 into the bridged tricycle 4 with four new
stereocenters through theintermediacyof1,3,5-hexatriene
2 and the rare chiral cyclic 2-amido-diene 36À9 [Scheme 1].
While both the hexatriene 2 and the cyclic diene 36 are
stable entities that could be intercepted and serve for the
ensuing purpose, the entire sequence could proceed in
tandem commencing with R-allylated allenamide 1. In
addition, depending upon the substitution pattern of the
hexatriene 2 [X = H or halogen], its pericyclic ring closure
could be rendered in a diastereoselective manner,10 thereby
constituting a rather impressive long-range 1,6-induction,11
while setting up a stereochemically regulated intramolec-
ular DielsÀAlder cycloaddition [albeit 3a and 3b would
(1) Hayashi, R.; Feltenberger, J. B.; Hsung, R. P. Org. Lett. 2010, 12,
1152.
(2) (a) Crandall, J. K.; Paulson, D. R. J. Am. Chem. Soc. 1966, 88,
4302. For examples of allenamide isomerizations, see: (b) Overman,
L. E.; Clizbe, L. A.; Freerks, R. L.; Marlowe, C. K. J. Am. Chem. Soc.
1981, 103, 2807. (c) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117.
(3) For reviews, see: (a) Marvell, E. N. Thermal Electrocyclic Reac-
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In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp 699À750.
(4) For a leading review on allenamide chemistry, see: Hsung, R. P.;
Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36, 773.
(8) 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, 2005;
Chapter 21.4.
(5) For general reviews on allenes, see: (a) Krause, N.; Hashmi,
A. S. K. Modern Allene Chemistry; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2004; Vol 1 and 2.
(6) (a) Hayashi, R.; Hsung, R. P.; Feltenberger, J. B.; Lohse, A. G.
Org. Lett. 2009, 11, 2125. (b) Hayashi, R.; Feltenberger, J. B.; Lohse,
A. G.; Walton, M. C.; Hsung, R. P. Beil. J. Org Chem. 2011, 7, 410.
(7) 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. (d) Krohn, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1582. (e) Enders, D.; Meyer, O. Liebigs Ann.
1996, 1023.
(9) For some examples cyclic amido-dienes, 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.
Chem. 2003, 5, 4749. (c) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B.
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(10) Hayashi, R.; Walton, M. C.; Hsung, R. P.; Schwab, J.; Yu, X.
Org. Lett. 2010, 12, 5768.
r
10.1021/ol203030a
Published on Web 12/13/2011
2011 American Chemical Society

has engineered, examples of diterpenes are rare. Most of
them are C18-, C19-, and C20-diterpenoid alkaloids and
possess a superb array of medicinal properties.13 Very
recently, Kobayashi14 reported an elegant approach to
the pentacyclic core of atropurpuran.
Scheme 1. A Stereoselective Three-Bond Formation Cascade
We have been drawn to the synthesis of the BCD-ring of
atropurpuran with the intent to feature our chemistry. As
shown in Scheme 2, our tandem sequence could allow
transformation of allenamide 9, a significantly simplified
retron, to the ABCD-tetracycle 6 in one operation. The
ensuing steps leading to 5 would involve enamide oxida-
tion chemistry that was developed in our group,15À18 and
the final E-ring formation could be envisioned through the
formation of C5ÀC6 bonds. While we are poised with a
plan and have elected allenamide 10 to demonstrate the
proof-of-concept, the challenge would be that, unlike in
allenamide 1, the dienophile for the DielsÀAlder cycload-
dition in allenamide 10 [or 9] is tethered in the internal
olefinic position of the R-allyl group.
More specifically, we had found that when using an
allenamide suchas 12[prepared from 1319,20] substitutedat
the internal olefinic position of the R-allyl group [Scheme 3],
the ring-closure step from the triene 14 is problematic, and
the resulting cyclic amido diene tends to isomerize and is
also prone to oxidation, leading to a mixture of dienes 15
along with arene 16. The usage of 1.0 equiv of AlMe3 pro-
ved to be useful in lowering the thermal activation barrier
of the ring closure,10,21 allowing a more clean isolation of
the desired cyclic 2-amido diene 17. Nevertheless, air oxi-
dation and aromatization of 17 remained a problem.
converge to the same cycloadduct 4]. We have since been
developing a potential application of this methodology to
demonstrate its power as this tandem cascade. We wish
to communicate here the possibility of employing this
tandem sequence as an approach toward the BCD-ring
of atropurpuran.
Scheme 2. An Approach to the BCD-Ring of Atropurpuran
Scheme 3. Potential Impediment of an Internal Tethering
Wang et al. reported the isolation of diterpene atropur-
puran [Scheme 2] from Aconitum hemsleyanum var.
atropurpureum, unveiling an unusual pentacyclic motif
containing two contiguous bicyclo[2.2.2]octanes.12 Although
atropurpuran represents the latest example of a unique
and brilliant structural topology that Aconitum genus
(14) Suzuki, T.; Aya Sasaki, A.; Egashira, N.; Kobayashi, S. Angew.
Chem., Int. Ed. 2011, 50, 9177.
(15) Xiong, H.; Hsung, R. P.; Shen, L.; Hahn, J. M. Tetrahedron Lett.
2002, 43, 4449.
(16) Also see: (a) Adam, W.; Bosio, S. G.; Wolff, B. T. Org. Lett.
2003, 5, 819. (b) Sivaguru, J.; Saito, H.; Poon, T.; Omonuwa, T.; Franz,
R.; Jockusch, S.; Hooper, C.; Inoue, Y.; Adam, W.; Turro, N. J. Org.
Lett. 2005, 7, 2089. (c) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.;
Nagasaka, T. Tetrahedron 2000, 56, 8855.
(17) For a leading review on enamide chemistry, see: Carbery, D. R.
Org. Biomol. Chem. 2008, 9, 3455.
(18) Also see: (a) Rappoport, Z. The Chemistry of Enamines in The
Chemistry of Functional Groups; John Wiley and Sons: New York, 1994.
(b) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. (c) Hickmott,
P. W. Tetrahedron 1982, 38, 1975 and 3363.
(11) For some examples of 1,6-remote asymmetric inductions, see:
(a) Paterson, I.; Dlgado, O.; Florence, G. J.; Lyothier, I.; Scott., J. P.;
Sereinig, N. Org. Lett. 2003, 5, 35. (b) Arai, Y.; Ueda, K.; Xie, J.;
Masaki, Y. Synlett 2001, 529.
(12) Tang, P.; Chen, Q.-H.; Wang, F.-P. Tetrahedron Lett. 2009, 50,
460.
(13) For recent reviews, see: (a) Wang, F.-P.; Liang, X.-T. In The
Alkaloids; Cordell, G. A., Ed.;Academic Press: San Diego, CA, 2002; Vol. 59,
pp 1À280. (b) Atta-ur-Rahman; Choudhary, M. I. Diterpenoid and
Steroidal Alkaloids. Nat. Prod. Rep. 1999, 16, 619. Nat. Prod. Rep. 1997,
14, 191. Nat. Prod. Rep. 1995, 12, 361. (c) Yunuzov, M. S. Diterpenoid
Alkaloids. Nat. Prod. Rep. 1993, 10, 471.
(19) See Supporting Information.
Org. Lett., Vol. 14, No. 1, 2012
253

Scheme 4. A Successful Sequence with an Internal N-Tethering
Figure 1. X-ray structure of 26 and proposed endo-TS.
Scheme 5. Success in an All-Carbon Internal Tethering
Intending to investigate these potential problems fur-
ther, we proceeded to prepare achiral allenamide 22 from
ester 1822 with nitrogen tethering at the internal olefinic
carbon. We found that a 1,3-H shift is actually very fast
and had occurred during the allylation stage, thereby
yielding the triene 23 directly from 21-Li [Scheme 4]. The
ring closure of 23 proved to be challenging, as we initially
failed when using high temperature conditions in toluene,
xylene, or decane, or employing 1.0 equiv of AlMe3. Only
after switching the Lewis acid to Ti(O-i-Pr)4 in 2 equiv, we
were able to effectively carry out the ring closure in tandem
with an intramolecular DielsÀAlder cycloaddition, lead-
ing to the endo cycloadduct 26 as the only isomer. The rela-
tive position of the CH2ÀNTs fragment defines the endo
and exo sense.
The relative stereochemistry of 26 was unambiguously
assigned using the X-ray structure of a single crystal
[Figure 1]. It is noteworthy that it would appear that the
proposed transition states for both exo-25 and endo-26 are
equally feasible, but only the endo product was isolated. In
addition, we were intrigued by, based on the proposed endo-
TS, whether long-range stereochemical induction could be
again observed here when using chiral amides as shown in
cyclic 2-amido diene 27a [see inside the box of Figure 1].
However, we also recognize that 27 could exist as two possi-
ble CÀN rotameric conformations a and b, which could
impede or work unfavorably for such a stereoinduction.
Consequently, we turned our attention to chiral allena-
mide 31-Bn, which was synthesized from enal 2823 [Scheme 5].
It was quickly evident that each of these internally
tethered systems behaves quite differently. Initial attempts
to directly take 31 to tricycle 34 completely failed under
thermal conditions including the use of AlMe3. We then
isomerized 31 to triene 32 using 10 mol % CSA and found
that, with the use of 1.0 equiv of AlMe3, 32 underwent
almost quantitative ring closure to give cyclic 2-amidodiene
33. However, the intramolecular DielsÀAlder cycloaddi-
tionproved tobe problematichere.24 To effectively achieve
the synthesis of tricycle 34, the ultimate conditions would
involve those adopted in Scheme 4. Tricycle 34 was
attained in 46% yield as a mixture of two diastereomers,
which would be the two possible endo-isomers. The modest
ratio implies that achieving a long-range stereochemical
(20) For R-alkylation of allenamides, see: Xiong, H.; Hsung, R. P.;
Wei, L.-L.; Berry, C. R.; Mulder, J. A.; Stockwell, B. Org. Lett. 2000, 2,
2869.
(21) For recent examples using a Lewis acid to mediate 6-π-electron
electrocyclic ring closures of 1,3,5-hexatrienes, see: (a) Magomedov,
N. A.; Ruggiero, P. L.; Tang, Y. C. Org. Lett. 2004, 6, 3373. (b) Bishop,
L. M.; Barbarow, J. E.; Bergmen, R. G.; Trauner, D. Angew. Chem., Int.
Ed. 2008, 47, 8100.
(22) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413.
(23) (a) Snider, B. B.; Zhou, J. Org. Lett. 2006, 8, 1283. (b) Dai, X.;
Davies, H. ML. Adv. Synth. Catal. 2006, 348, 2449.
(24) IMDA of cyclic 2-amidodiene 33 failed even at 200 °C and with
1.0 equiv of AlMe3. When we attempted 10 mol % Rh(PPh3)3Cl and/or
with AgSbF6 at 110 °C, these conditions were also not useful.
254
Org. Lett., Vol. 14, No. 1, 2012

induction is more challenging here based on the TS in
Figure 1, or the two competing conformational positions
of the amido group [see 27a versus 27b] preclude the possi-
bility of having a favorable facial differentiation, although
the specifics will await future suitable computational
analysis.
Scheme 6. X-ray Confirmation and Enamide Oxidation
Changing the Bn substituent on the Evans auxiliary in
31-Bn to a Ph group did not improve the diastereoselec-
tivitybutgavethe respectivetricycle35a/b in a significantly
better overall yield [Scheme 6]. To both demonstrate the
enamide oxidation chemistry and concisely assign the
relative stereochemistry, we elected to epoxidize 35a/b as
a 2:1 isomeric mixture, and subsequent hydrolysis of the
epoxy intermediate 36 unveiled hydroxy ketone 37 as a
single diastereomer in 85% yield over two steps. The fact
that 37 is a single isomer further suggests that the 2:1 ratio
represents the ratio of the two endo isomers and not that of
endo/exo. It is also noteworthy that the DMDO epoxida-
tion of 35a/b was completely stereoselective in favoring the
more accessible face of the tricyclic manifold. It is not clear
at this point whether the chiral auxiliary plays a coopera-
tive role in the selectivity of the oxidation.
The ensuing Wittig olefination of the C16-carbonyl in 37
afforded allyl alcohol 38 in 73% yield. Preparation of the
2,4-dinitrobenzoyl ester derivative 39 from 38 as well as
attaining its X-ray structure allowed us to unambiguously
assign the complete carbon skeleton of 38, which would
match that of the BCD-ring of atropurpuran. Given the
endo nature of the intramolecular DielsÀAlder cycloaddi-
tion, it appears that to complete a synthesis of atropurpuran,
a key epimerization at C9 would be required, which
represents an achievable operation based on our actual
synthetic plan.
required the assistance of a Lewis acid, the entire process is
highly stereoselective in favor of the endo-cycloadduct.
Total synthesis efforts toward atropurpuran and a mech-
anistic understanding of the overall stereoinduction in this
process are currently underway.
Acknowledgment. Authors thank the NIH [GM066055]
for financial support and Dr. Victor Young [University of
Minnesota] for X-ray structural analysis.
We have described here the feasibility of a synthetic
approach toward the BCD-ring of atropurpuran via a
sequence of allenic 1,3-H shift, 6π-electron pericyclic ring
closure, and intramolecular DielsÀAlder cycloaddition of
cyclic 2-amidodiene. While the pericyclic ring closure
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.
Org. Lett., Vol. 14, No. 1, 2012
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