Tandem phenolic oxidative amidation-intramolecular diels-alder reaction: An approach to the himandrine core

Article abstract of DOI:10.1021/ol1003669

An oxidative cyclization of dienic sulfonamides mediated by iodobenzene diacetate in TFA, followed by a tandem intramolecular Diels-Alder reaction, achieves desymmetrization of a "locally symmetrical" dienone with good levels of diastereoselectivity and leads to valuable synthetic intermediates for the himandrine alkaloids.

Full text of DOI:10.1021/ol1003669

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1760-1763
Tandem Phenolic Oxidative
Amidation-Intramolecular Diels-Alder
Reaction: An Approach to the
Himandrine Core
Huan Liang and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received February 11, 2010
ABSTRACT
An oxidative cyclization of dienic sulfonamides mediated by iodobenzene diacetate in TFA, followed by a tandem intramolecular Diels-Alder
reaction, achieves desymmetrization of a “locally symmetrical” dienone with good levels of diastereoselectivity and leads to valuable synthetic
intermediates for the himandrine alkaloids.
Exposure of phenolic substrates 1 to hypervalent iodine
reagents1 such as PhI(OAc)2 (“DIB”) and PhI(OCOCF3)2
Scheme 1. The Oxidative Amidation of Phenols
(“PIFA”) induces formation of dienones 2 (Scheme 1), which
are valuable educts in alkaloid synthesis. This transformation
is described as the oxidative amidation of phenols,2 and it
may be carried out in the intramolecular3 or in the bimo-
lecular4 regime. While dienones 2 are “locally symmetrical”,
various artifices enable their stereocontrolled desymmetri-
zation. This causes the N-bearing spiro C atom to become
stereogenic and to acquire a specific configuration. Desym-
metrization may be accomplished via 1,4-addition5 or 1,3-
dipolar cycloaddition reactions.6 In this paper, we demon-
strate dienone desymmetrization via a diastereoselective
intramolecular Diels-Alder reaction (IMDA),7 which leads
to densely functionalized intermediates that are generally
useful in synthetic chemistry, but that may be especially
(1) Reviews: (a) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96,
1123. (b) Stang, P. J. Chem. ReV. 2002, 102, 2523. (c) Moriarty, R. M. J.
Org. Chem. 2005, 70, 2893. (d) Kita, Y. Yakugaku Zasshi 2002, 122, 1011.
(e) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. Monograph: (f)
Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic Press:
San Diego, CA, 1997.
(2) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.;
Chai, D. Synthesis 2007, 3759.
(3) (a) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667. (b) Braun, N. A.; Bray, J.; Ciufolini,
M. A. Tetrahedron Lett. 1999, 40, 4985. (c) Braun, N. A.; Bray, J.; Ousmer,
M.; Peters, K.; Peters, E.-M.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem.
2000, 65, 4397. (d) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.;
Ciufolini, M. A. Tetrahedron Lett. 2002, 43, 5193.
(5) Canesi, S.; Bouchu, D.; Ciufolini, M. A. Angew. Chem., Int. Ed.
2004, 43, 4336; Angew. Chem. 2004, 116, 4436.
(6) (a) Mendelsohn, B.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.;
Ciufolini, M. A. Org. Lett. 2009, 11, 1539. (b) Frie, J.; Jeffrey, C. S.;
Sorensen, E. J. Org. Lett. 2009, 11, 5394.
(4) (a) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299. (b)
Canesi, S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175.
(7) Ciganek, E. Org. React. 1984, 32, 1.
10.1021/ol1003669  2010 American Chemical Society
Published on Web 03/23/2010

valuable for the assembly of the core unit of the structurally
unique alkaloid, himandrine, 3.8
The studies described here were motivated by the realiza-
tion that the spirocyclic core of 3 may be brought within
the scope of oxidative amidation chemistry as adumbrated
in Scheme 2. Indeed, a key subunit of 3 is embedded in
1310 with commercial 2-chloroethylsulfonyl chloride and with
1-(1,3-butadien)ylsulfonyl chloride,11 followed by desilylation
(Scheme 3). While the original procedure for the oxidative
Scheme 3. Substrates for Ortho-Oxidative Amidation
Scheme 2. Retrosynthetic Hypotheses for Himandrine
cyclization of similar substrates utilized costly hexafluoroiso-
propanol as the solvent,3d we found that the reaction proceeds
as efficiently, if not better, in neat trifluoroacetic acid (TFA).
Treatment of 16-17 with DIB in TFA thus furnished 18-19.
This is an example of ortho-oxidative amidation of phenols.12
Chromatographic purification of these sensitive materials caused
unacceptable losses. We found it expedient to dilute the crude
reaction mixture with toluene and heat to reflux to induce IMDA
cyclization. Products 20-21 emerged in 40% and 34% yield
after chromatography,13 and their structures were ascertained
by X-ray diffractometry.14 Somewhat surprisingly, the sulfonyl-
diene moiety of 19 had thus behaved exclusively as a dienophile,
while the dienone played the role of the diene, presumably
thanks to its constrained s-cis-type diene geometry. The finding
that 19 cyclizes to form exclusively a bicyclo[2.2.2]octenone
system, and none of the desired product of the type 5 (R ) H),
signaled the demise of pathway b.
intermediates 4-6, each one of which, in turn, could
conceivably derive from the oxidative cyclization of a
phenolic sulfonamide,3d followed by IMDA reaction. An
oxy-Cope rearrangement9 (cf. 7) would also be required to
elaborate 8 into 4. We note that the decalin segment of 3
displays the trans ring junction, whereas the sequences
leading to 4-6 would produce the cis-fused diastereomers.
An MM+ study indicated that the trans-isomers of 4-6 were
considerably more stable (∆E > 4 kcal/mol). We thus
anticipated that 5 and 6 would epimerize to the trans-isomers
under mildly basic conditions, while 4 could be epimerized
after conversion into an enone of the type 5.
The investigation of pathway a continued with compound
20, which according to the logic of Scheme 2 would now
undergo addition of a vinyl nucleophile to the CdO group.
Unexpectedly, this reaction was problematic. Thus, vinylmag-
nesium bromide in THF, with or without added HMPA or other
promoters, such as TMEDA15 or CeCl3,16 as well as vinyl-
lithium prepared from either vinyltributyl tin/BuLi17 or tetravinyl
(10) Prepared as detailed in the Supporting Information.
(11) Lee, Y. S.; Ryu, E. K.; Yun, K.-Y.; Kim, Y. H. Synlett 1996, 247.
This method furnishes a mixture of trans- and cis-isomers. Remarkably,
these were chromatographically separable with only modest losses (see the
Supporting Information).
The exploration of pathways a-b required compounds 16
and 17, which were obtained respectively by reaction of amine
(8) Isolation: (a) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.;
Hughes, G. K.; Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem.
1956, 9, 283. Bioactivity: (b) Cobbin, L. B.; Thorp, R. H. Aust. J. Exptl.
Biol. Med. Sci. 1957, 35, 15. Structural work: (c) Guise, G. B.; Mander,
L. N.; Prager, R. H.; Rasmussen, M.; Ritchie, E.; Taylor, W. C. Aust.
J. Chem. 1967, 20, 1029. (d) Willis, A. C.; O’Connor, P. D.; Taylor, W. C.;
Mander, L. N. Aust. J. Chem. 2006, 59, 629. Synthetic studies: O’Connor,
P. D.; Mander, L. N.; McLachlan, M. M. W. Org. Lett. 2004, 6, 703. Total
synthesis: Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem. Soc. 2009,
131, 9648.
(12) For the first example of ortho-oxidative amidation of phenols see:
Canesi, S. Dissertation, University Claude Bernard Lyon 1, 2004.
(13) For a similar reaction see: Drutu, I.; Njardarson, J. T.; Wood, J. L.
Org. Lett. 2002, 4, 493.
(14) The structure of 20 is published: Liang, H.; Canesi, S.; Patrick,
B. O.; Ciufolini, M. A. Z. Kristallogr.-New Cryst. Struct. 2009, 224, 83.
(15) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
(16) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(9) Key reviews: (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b)
Toure, B. B.; Hall, D. G. Chem. ReV. 2009, 109, 4439. See also ref 22.
(17) Seyferth, D.; Weiner, M. A.; Vaughan, L. G.; Raab, G.; Welch,
D. E.; Cohen, H. M.; Alleston, D. L. Bull. Soc. Chim. Fr. 1963, 7, 1364.
Org. Lett., Vol. 12, No. 8, 2010
1761

tin/BuLi18 at various temperatures, fared uniformly poorly
(10-15% yield after a difficult purification). Conversely,
addition of the bromomagnesio derivative of TMS-acetylene19
was efficient and stereoselective (Scheme 4). Deprotection
tive of 27 was reacted with acrolein in the presence of
t-BuOK and the resulting product was desilylated to deliver
28. Pleasingly, exposure of the latter to DIB in TFA, followed
by addition of toluene and heating to reflux, produced 30 in
39% yield after chromatography.25 The structure of this
compound was ascertained by X-ray diffractometry, and its
configuration is consistent with the anticipated occurrence
of the IMDA step in the endo mode. This encouraging
outcome induced us to address the problem of exerting
stereocontrol at the level of the spirocenter. The spiro carbon
in 29 is chirotopic and nonstereogenic, but it becomes
stereogenic during the IMDA step. To produce a given
configuration of the spirocenter in 30, the sulfonyldiene must
interact selectively with the pro-R or the pro-S double bond
of the dienone. Precedent5,6a suggested that such an objective
might be attained with substrate 31 (Scheme 6), wherein the
Scheme 4. Failed Oxy-Cope Rearrangement of 24
Scheme 6. Expected Course of the IMDA Reaction of 31
(TBAF) and LAH reduction of the triple bond20 converted 22
into 24.21 While solid precedent exists for the oxy-Cope rear-
rangement of systems similar to 24, e.g, the isomerization of 25 to
26,22 thermal activation of 24 gave none of the rearranged product.
The substrate was recovered virtually intact after heating to 200
°C, above which temperature it decomposed. Attempts to induce
rearrangement in the anionic mode23 also failed.
We thus turned to pathway c, which entailed the initial
creation of 28 (Scheme 5). The (E)-1-(1,3-butadienyl)sul-
Scheme 5. Tandem Oxidative Amidation-IMDA Reaction of 28
N-atom bearing carbon is now stereogenic. An endo-
Diels-Alder cyclization of 31 may proceed through either
of two diastereomeric conformers, which may be described
as syn-31 and anti-31 (Scheme 6), leading respectively to
diastereomers syn-32 and anti-32 of the cycloadduct. Pre-
sumably, the sulfonyl group will tend to avoid nonbonding
interactions with substituent R during the reaction; therefore,
product anti-32 should be dominant.
The foregoing hypothesis was probed with use of substrate
36, obtained from L-tyrosinol methanesulfonamide, 33,26 as
shown in Scheme 7. Accordingly, bis-O-silylation and
N-BOC-derivatization afforded 34. Tozer reaction of the
fonamide moiety of the substrate was installed on 27 by a
Tozer-type condensation.24 Accordingly, the N-BOC deriva-
(22) (a) Juo, W.-J.; Lee, T.-H.; Liu, W.-C.; Ko, S.; Chittimalla, S. K.;
Rao, C. P.; Liao, C.-C. J. Org. Chem. 2007, 72, 7992. (b) Lee, T.-H.; Liao,
C.-C.; Liu, W.-C. Tetrahedron Lett. 1996, 37, 5897.
(18) Dunne, K. S.; Lee, S. E.; Gouverneur, V. J. Organomet. Chem.
2006, 691, 5246.
(19) Prepared in situ by reaction of the acetylene with EtMgBr in THF.
(20) Chanley, J. D.; Sobotka, H. J. Am. Chem. Soc. 1949, 71, 4140.
(21) It should be noted that: (i) The acetylenic Grignard was superior
to the lithium variant in the addition reaction. (ii) Lindlar hydrogenation
[(a) Lindlar, H.; Dubuis, R. Org. Synth. 1973, 5 (Collect.), 880. (b) Lindlar,
H. HelV. Chim. Acta 1952, 35, 446.] of the alkyne failed, presumably on steric
grounds. Thus, attempted Lindlar hydrogenation of 23 resulted in exclusive
reduction of the olefin (iii) Schwartz hydrozirconation [Hart, D. W.; Schwartz,
J. J. Am. Chem. Soc. 1974, 96, 8115.] of the ethynyl group also failed; (iv)
the configuration of 23 was ascertained by NOESY spectroscopy.
(23) Lutz, R. Chem. ReV. 1984, 84, 205. Deprotonation of the OH group
was effected with KH, NaH, or KHMDS, with and without 18-crown-6, in
benzene, toluene, THF, and DMSO.
(24) Tozer, M. J.; Woolford, A. J. A.; Linney, I. D. Synlett 1998, 186.
(25) The conversion of 29 into 30 reflects an unprecedented mode of
reactivity. However, related Diels-Alder reactions of quinone monoketal
cognates of 29 are documented: (a) Breuning, M.; Corey, E. J. Org. Lett.
2001, 3, 1559. (b) Yu, M.; Danishefsky, S. J. J. Am. Chem. Soc. 2008,
130, 2783. (c) Hayden, A. E.; DeChancie, J.; George, A. H.; Dai, M.; Yu,
M.; Danishefsky, S. J.; Houk, K. N. J. Org. Chem. 2009, 74, 6770.
1762
Org. Lett., Vol. 12, No. 8, 2010

cumulative 32% yield. The two compounds were difficult
to separate, but a chromatographic fraction enriched in the
major product deposited crystals suitable for an X-ray
diffractometric study. Surprisingly, the material thus obtained
proved to be the trans-fused isomer 41 of the presumed
primary product 38. Thus, the tandem oxidative amidation/
IMDA cyclization had produced directly a compound with
the himandrine-like trans-fusion of the decalin system. We
suppose that this unexpected result is due to epimerization
of 38 through TFA-promoted equilibration with enol 39.
No such isomerization occurred in the sequence leading
to the unsubstituted congener 30. Attempts to rationalize such
a difference in behavior have been unfruitful. For instance,
an MM+ calculation estimated that the energy difference
between the cis and trans isomers of the cycloadducts is very
similar regardless of substitution at the nitrogen-bearing
carbon (∆E ) -5.6 kcal/mol for 30 vs -5.2 kcal/mol for
38), as are the energy differences between the cis-adducts
and the corresponding enols (∆E ) -7.5 kcal/mol for 30
vs -7.4 kcal/mol for 38), signifying that the more facile
isomerization of 38 is unattributable to a greater thermody-
namic drive to attain the trans-fused arrangement of the
decalin domain. Then, the different behavior of 30 and 38
must be due to subtle kinetic factors. It would be imprudent
to speculate on the nature of these at the present time.
In summary, we have extended the desymmetrization of
“locally symmetrical” dienones emerging from the oxidative
amidation of phenols to the IMDA mode. Reaction pathways
a-c have served as platforms to explore aspects of the
chemistry of a number of heretofore unknown systems.
Finally, intermediates of the type 41 could be useful as
building blocks for himandrine.
Scheme 7. Desymmetrization of the “Locally Symmetrical”
Dienone via Stereocontrolled IMDA Reaction of 37
latter with acrolein in the presence of t-BuOK as seen
previously gave 35, desilylation of which delivered 36.
Notice that relative to himandrine, susbtance 36 has the
opposite configuration of the nitrogen-bearing center. But
of course, whatever diastereoselectivity might be attained
during the crucial oxidative cyclization/IMDA reaction would
later be duplicated in an enantiomeric series of compounds
produced from D-33. The now familiar oxidative treatment
of 36 with DIB in TFA afforded an 8:1 mixture (1H NMR)
of the anticipated anti adduct (major component) and of its
syn diastereomer (minor, not fully characterized), in a
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, NSERC,
CIHR, and MerckFrosst Canada for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds, plus
NMR (1H and 13C) spectra of several molecules. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Available from commercial homotyrosine as detailed in ref. 5.
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