Extending pummerer reaction chemistry. Application to the oxidative cyclization of tryptophan derivatives

Article abstract of DOI:10.1021/ol048974+

(Equation Presented) The diastereoselective oxidative cyclization of a β-oxygenated tryptophan derivative is reported. This process, which utilizes a new variant of the Pummerer reaction, may have application in TMC-95A synthesis.

Full text of DOI:10.1021/ol048974+

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2849-2852
Extending Pummerer Reaction
Chemistry. Application to the Oxidative
Cyclization of Tryptophan Derivatives
Ken S. Feldman* and Andrew G. Karatjas
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
ksf@chem.psu.edu
Received June 3, 2004
ABSTRACT
The diastereoselective oxidative cyclization of a â-oxygenated tryptophan derivative is reported. This process, which utilizes a new variant of
the Pummerer reaction, may have application in TMC-95A synthesis.
The stereoselective oxidative cyclization of tryptophan
derivatives to form spirocyclic butyrolactone oxindole prod-
ucts, 1 f 4, Scheme 1,1 has remained an enduring problem
in alkaloid synthesis, primarily in response to the structural
challenges posed by toxins within the tryptoquivaline family
of mycotoxin metabolites.1e,f,i,j With a singular exception,1e
diastereoselectivity is scarcely seen upon formation of
oxindoles 4. Identification of the structural/stereoelectronic
factors that might influence the stereochemical outcome of
this cyclization is complicated by lack of a clear mechanistic
understanding. For example, three distinct species, the three-
membered ring-bearing 2a,1a,d,g the orthoquinone iminium
ion 2b (this work), and the C(3) oxidized indoline 2c,1b,c,i,j
have all been postulated by different authors to occupy
central roles in the process. Arguments that link the resident
stereochemistry at the R-position to the forming C(3)
stereogenic center have not been forthcoming, perhaps
because of the discouragingly poor diastereoselectivity
typically observed. Introduction of additional stereochemical
control elements might favorably influence the diastereo-
selectivity of these cyclizations, but a lack of appropriately
functionalized target molecules (* tryptoquivalines) did little
to motivate such pursuits.
Scheme 1. Mechanistic Speculation Governing the Oxidative
Cyclization of Tryptophan Derivatives
(1) (a) Lawson, W. B.; Patchornik, A.; Witkop, B. J. Am. Chem. Soc.
1960, 82, 5918-5923. (b) Hinman, R. L.; Bauman, C. P. J. Org. Chem.
1964, 29, 1206-1214. (c) Hinman, R. L.; Bauman, C. P. J. Org. Chem.
1964, 29, 2431-2437. (d) Nagasaka, T.; Ohki, S. Chem. Pharm. Bull. 1971,
19, 545-551. (e) Bu¨chi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y.
J. Am. Chem. Soc. 1979, 101, 5084-5086. (f) Ohnuma, T.; Kimura, Y.;
Ban, Y. Tetrahedron Lett. 1981, 22, 4969-4972. (g) Palla, G.; Marchelli,
R.; Casnati, G.; Dossena, A. Gazz. Chim. Ital. 1982, 112, 535-536. (h)
Ohnuma, T.; Kasuya, H.; Kimura, Y.; Ban, Y. Heterocycles 1982, 17, 377-
380. (i) Nakagawa, M.; Taniguchi, M.; Sodeoka, M.; Ito, M.; Yamaguchi,
K.; Hino, T. J. Am. Chem. Soc. 1983, 105, 3709-3710. (j) Nakagawa, M.;
Sodeoka, M.; Yamaguchi, K.; Hino, T. Chem. Pharm. Bull. 1984, 32, 1373-
1384. (k) Labroo, R. B.; Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org.
Chem. 1991, 56, 3637-3642.
10.1021/ol048974+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004

However, the recent report describing the structure of the
20S proteosome inhibitor TMC-95A (5) (and congeners),2
with its C(3) oxidized oxindole core, simulated a reinvestiga-
tion of this dormant area of tryptophan chemistry. One
approach to the synthesis of this microbial metabolite might
pass through the spirocyclic butyrolactone oxindole construct
6 as part of the fragment coupling strategy summarized in
Scheme 2.
Scheme 3. Model for Diastereoselective Cyclization of
Tryptophan Derivatives Bearing an Ether Substituent at the
Indolic Position
Scheme 2. Retrosynthetic Analysis for TMC-95A
The initial attempt to probe this strategy for introducing
stereoselectivity into tryptophan oxidative cyclizations relied
on the normally dependable brominative cyclization pro-
cedure1a,b,g,i to convert a C(â)-oxidized tryptophan derivative
into the desired oxindole, Scheme 4. Construction of the
Scheme 4. Model Brominative Cyclizations
The synthesis sub-goal 6 bears a C(7) ether moiety (TMC-
95A numbering) that may be the missing stereochemical
determinant in tryptophan oxidative cyclizations. Two di-
astereotopic transition states can be envisioned, 7a and 7b,
for the cyclization of a C(7) functionalized tryptophan
derivative (Scheme 3). In these models, a generic C(3) sp2-
hybridized electrophile is indicated since the mechanistic
uncertainty described with Scheme 1 makes further refine-
ment impossible. In particular, a burgeoning steric interaction
(cf. 7b) between the C(7) ether substituent and the peri-
positioned hydrogen Hp might serve to steer the cyclization
of 7 down an alternate pathway favoring formation of the
diastereomer 8a. Transition state construct 7a also may enjoy
an additional energetic benefit via Felkin-Ahn-type LUMO-
LUMO mixing between σ*C-O and the p orbital of the
electrophile, an advantage that is not available in the
diastereomeric species 7b. On the basis of the results with
the simple tryptophan derivatives highlighted in Scheme 1,
the influence of the R-stereogenic (NHR) center is not
expected to overwhelm any of these putative control ele-
ments. The test of this hypothesis is described below.
C(R)-(S)/C(â)-(S) diastereomer 10 followed from known
enoate 93 by application of a protocol developed by Boger
et al.4 The Sharpless bishydroxylation5 of indole derivative
9 provided a diol product in g99% ee (HPLC, OJ-H column).
The low yield for this sequence can be attributed to a
problematical azide reduction/acylation step, but a disap-
pointing cyclization outcome provided little reason to pursue
optimization studies. Treatment of tryptophan derivative 10
under a variety of bromonium ion initiated oxidative cy-
clization procedures afforded varying amounts of a single
cyclization product. Under the most favorable conditions
(NBS, NaHCO3), yields as high as 67% could be obtained.
Spectroscopic analysis (e.g., IR 1764 cm-1; compare 1800
cm-1 for structures of the type 4)1g of this diastereomerically
pure tricycle led to the conclusion that incorporation of the
(2) Isolation: (a) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda,
M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65,
990-995. Total synthesis. (b) Lin, S.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2002, 41, 512-515. (c) Albrecht, B. K.; Williams, R. M. Org.
Lett. 2003, 5, 197-200. (d) Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama,
M. Angew. Chem., Int. Ed. 2003, 42, 2654-2657. Synthesis studies: (e)
Ma, D.; Wu, Q. Tetrahedron Lett. 2000, 41, 9089-9093. (f) Ma, D.; Wu,
Q. Tetrahedron Lett. 2001, 42, 5279-5281. (g) Kaiser, M.; Siciliano, C.;
Assfalg-Machleidt, I.; Groll, M.; Milbradt, A. G.; Moroder, L. Org. Lett.
2003, 5, 3435-3437. (h) Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J.
J. Org. Chem. 2003, 68, 9835-9838. (i) Yang, Z.-Q.; Kwok, B. H. B.;
Lin, S.; Koldobskiy, M. A.; Crews, C. M.; Danishefsky, S. J. ChemBioChem
2003, 4, 508-513. (j) Lin, S.; Yang, Z.-Q,; Kwok, B. H. B.; Koldobskiy,
M.; Crews, C. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347-
6355.
(3) Bran˜a, M. F.; Garranzo, M.; de Pascual-Teresa, B.; Pe´rez-Castells,
J.; Torres, M. R. Tetrahedron 2002, 58, 4825-4836.
(4) Boger, D. L.: Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994, 116,
8544-8556.
(5) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
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Org. Lett., Vol. 6, No. 17, 2004

C(â)-(S) ether substituent diverted the reaction down an
unexpected channel, and a C(2) rather than a C(3) cyclized
product resulted. The stereochemical relationship between
the ring fusion and the C(R)/C(â) stereogenic centers was
not determined. It is possible that an intermediate related to
2c preceded nucleophilic acid addition to C(2) of the oxidized
indole core.
Scheme 5. Pummerer-Based Oxidative Cyclization of a Simple
Tryptophan Derivative
This unexpected turn was rendered even more curious by
the cyclization results obtained upon exposing the diaster-
eomeric species 12 (OTIPS instead of OTBS) to the same
brominative reaction conditions. Oxidative cyclization sub-
strate 12 was prepared by a strategy similar to that used for
the synthesis of 10, and the Sharpless amidohydroxylation
procedure6 provided hydroxyamide product in g99% ee
(HPLC, OJ-H column) and 10:1 regiochemical selectivity.
In this instance, the only cyclized material isolated from a
relatively more complex reaction mixture was the butyro-
lactone-containing oxindole 13 (IR 1810 cm-1). Despite the
modest yield, the formation of a single stereoisomeric product
was encouraging, especially since the specific stereochemical
relationship between the C(â) OTIPS moiety and the
oxindole’s spirocyclic center corresponded to that expected
from application of the cyclization model shown in Scheme
3. Unfortunately, this diastereomeric relationship does not
match the one desired for TMC-95A (10 might have led to
that species).
The basis for the regiochemically disparate cyclization
outcomes with 10 and 12 remains uncertain, but it is apparent
that the C(R) group NHCBz must be exerting some influence
after all. Possible eclipsing steric interactions between the
OTBS and NHCBz groups in the cyclization transition state
derived from 10, which are absent (or at least minimized)
in the alternative transition state extending from 12, may
play a role in raising the energy of the former process. In
this view, alternative, normally higher energy cyclization
modes (e.g., f 11) then may have a chance to be expressed.
Whatever the reason, these divergent cyclization results bring
into focus a more general problem with oxidative cyclizations
of these C(â)-functionalized tryptophan constructs-a lack
of predictable regiochemical control.
15, readily available via completely regioselective C(2)
sulfenylation of NBOC tryptophan 14,8 was treated with the
standard Pummerer trigger trifluoroacetic anhydride (TFAA)
to furnish modest amounts of the spirocyclic butyrolactone
17 (IR 1798 cm-1) as a 1:1 mixture of diastereomers. This
transformation may pass through the reactive, electrophilic
orthoquinone imine sulfonium ion 16, a species that re-
sembles the bromonium ion generated orthoquinone iminium
ion 2b. The product thioimidate 17 could be hydrolyzed in
good yield to afford the desired oxindole 18. No better
cyclization diastereoselectivity attends this cyclization pro-
cedure than typically is observed with other oxidants in the
tryptophan series.1 Yield optimization studies, in which the
Pummerer initiator (trifluoroacetic anhydride, triflic anhy-
dride, TBSOTf) and base (i-Pr2NEt, pyridine, 2,6-lutidine,
Et3N) were varied (solvent ) CH2Cl2, -78 °C), did not lead
to improvements over the example shown in Scheme 5.
Nevertheless, formation of the desired spirocycle attested to
the feasibility of this approach to using tryptophan oxidative
cyclizations for selective spiro butyrolactone oxindole syn-
thesis and prompted attempts to apply this methodology to
the TMC-95A problem.
Assembly of the key cyclization precursor 21 began with
2-chloroindole-3-carboxaldehyde (19)9 and used a nucleo-
philic sulfur source to introduce the requisite Pummerer
functionality, Scheme 6. Sharpless dihydroxylation provided
An approach to solving the problem of regiochemical
control in indole oxidative cyclizations has been described
recently.7 This methodology uses a variant of the Pummerer
reaction to effect C(3)-selective oxidative cyclization of
pendant carbon nucleophiles to furnish spirocyclic 2-thio-
imidate and/or derived oxindole products. The extension of
this chemistry to the tryptophan series requires successful
participation of a carboxylic acid derivative as the nucleo-
phile, Scheme 5.
Scheme 6. Pummerer-Based Oxidative Cyclization of a
Functionalized TMC-95A Core Model
Initial attempts to effect cyclization with 2-thiophenyl
tryptophan derivatives featuring either a free carboxylic acid
or its derived methyl ester were not productive. However,
switching to a silyl ester 15 did provide the first evidence
that this transformation was possible. Cyclization substrate
(6) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998,
39, 2507-2510.
(7) (a) Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869-1871.
(b) Feldman, K. S.; Vidulova, D. B. Tetrahedron. Lett. 2004, 45, 5035-
5037.
Org. Lett., Vol. 6, No. 17, 2004
2851

a chiral diol intermediate (ee g 99%, HPLC, OJ-H column)
that could be processed on to the azido silyl ether 21 using
chemistry similar to that described for the preparation of 10.
Surprisingly, treatment of the sulfoxide derived from 21 (not
shown) with a variety of electrophilic Pummerer triggers did
not lead to any butyrolactone spirocyclic product, nor were
related attempts with the analogous silyl ester or methyl ester
rewarded. These disappointing results, in contrast to the
simpler system 15, point to unexpected complications
engendered by introduction of the â-silyloxy substituent.
Fortunately, use of the unconventional Pummerer initiator
PhI(CN)OTf7b,10 with sulfide 21 did lead to a productive
cyclization that furnished a single butyrolactone thioimidate
product 23 in moderate yield. With this particular substrate,
use of functional variants such as the silyl or methyl esters,
or an NHBOC group in place of the azide, did not improve
the yield shown. In fact, participation of the NHCO2t-Bu
substrate’s carbonyl in bond formation to C(3) provided a
glimpse of some of the difficulties that can hamper this
cyclization. The butyrolactone product 23 was formed with
a diastereomeric relationship between C(6) and C(7) that is
both consistent with the cyclization model described in
Scheme 3 and on track for TMC-95A synthesis. As with
the simpler system 17, ready hydrolysis of the thioimidate
unit delivered the desired oxindole 24.
These studies demonstrate that, for the first time, possibly
biomimetic oxidative cyclization of a tryptophan derivative
to form a butyrolactone product can be achieved with both
high and predictable stereochemical control. This advance
is tied to the use of a hypervalent iodine reagent in a
Pummerer-based oxidative cyclization protocol.
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences Division, for support of
this work (GM35727).
Supporting Information Available: Spectral data in-
cluding 1H NMR, 13C NMR, IR, and MS for 10-13, 15, 17,
18, 20, 21, 23, and 24. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Crich, D.; Davies, J. W. Tetrahedron Lett. 1989, 30, 4307-4308.
(9) Hollis Showalter, H. D.; Sercel, A. D.; Leja, B. M.; Wolfangel, C.
D.; Ambroso, L. A.; Elliott, W. L.; Fry, D. W.; Kraker, A. J.; Howard, C.
T.; Lu, G. H.; Moore, C. W.; Nelson, J. M.; Roberts, B. J.; Vincent, P. W.;
Denny, W. A.; Thompson, A. M. J. Med. Chem. 1997, 40, 413-426.
(10) Stang, P. J.; Williamson, B. L.; Zhdankin, V. V. J. Am. Chem. Soc.
1991, 113, 5870-5871.
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