The diastereoselective synthesis of quaternary substituted thioindolines from sulfur ylide intermediates

Article abstract of DOI:10.1021/jo0482413

(Chemical Equation Presented) The Rh(II)-catalyzed coupling of chiral 2-thiopyranylindoles with vinyl diazoacetates results in the generation of indolines having quaternary substitution at C(3) in high diastereoselectivity.

Full text of DOI:10.1021/jo0482413

The Diastereoselective Synthesis of
Quaternary Substituted Thioindolines from
Sulfur Ylide Intermediates
Abijah M. Nyong and Jon D. Rainier*
Department of Chemistry, University of Utah,
315 South 1400 East, Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received October 6, 2004
From a desire to control the relative stereochemistry
of these reactions we recently reported that racemic
thiopyranyl indole 3 was capable of transferring its
chirality from the position adjacent to sulfur to the
3-position on the indole when vinyl diazoacetate 4 was
used in the coupling reaction (eq 2).7
The Rh(II)-catalyzed coupling of chiral 2-thiopyranylindoles
with vinyl diazoacetates results in the generation of indo-
lines having quaternary substitution at C(3) in high dias-
tereoselectivity.
The presence of highly substituted indoles and indo-
lines in a variety of bioactive molecular targets has
inspired a number of groups, including ours, to develop
new and improved routes to their synthesis.1-3 Along
these lines, we have found that ylide-derived Claisen
rearrangements of 2-thioindoles result in the generation
of indolines having quaternary substitution at C(3).4-6
Described in this paper are studies that extend the
scope of these initial experiments through the examina-
tion of a more extensive array of vinyl carbenoid precur-
sors and optically active thiopyranyl indoles. Also de-
scribed are related investigations that examine ring
expansion reactions of thiopyranyl indoles through their
coupling with malonate and â-ketoester carbenoid sys-
tems.
(1) For recent reviews of indole-containing natural products, see:
(a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278. (b) Somei,
M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216. (b) Faulkner, D. J. Nat.
Prod. Rep. 1999, 16, 155.
To establish the stereocenter that we hoped would
ultimately end up controlling the facial selectivity in the
carbenoid coupling chemistry we turned to a one-pot
DIBAl-Grignard reaction and tryptophan derivative 6.8
N-Boc protected D-tryptophan 6 was subjected to DIBAl
and MeMgBr to give 7 in 52% yield. In addition to
MeMgBr, both PhMgBr and vinyl MgBr also added to
the tryptophan/DIBAl mix to give amino alcohols 8 and
9, respectively. As expected from the work of Polt,
Yamamoto, and Angle the threo isomer was the major
or, in the case of 7, the only diastereomer that was
isolated from these reactions.
Outlined in Scheme 1 is our conversion of amino
alcohol 7 into thiopyran 11. Displacement of the tosylate
from 7 with KSAc gave thiol 10 after acetate hydrolysis.
Oxidative cyclization provided the desired thiopyran 11.9
With a reasonably efficient approach to 11 in hand,
we examined its conversion into thioimidates 13 and 14
through its Rh2(OAc)4-catalyzed coupling with vinyl
(2) For a recent review covering approaches to the synthesis of
indoles and indole alkaloids see: Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045.
(3) For representative examples of the synthesis of indolines having
quaternary substitution at C(3) see: (a) Overman, L. E.; Paone, D. V.;
Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702. (b) Overman, L. E.;
Paone, D. V. J. Am. Chem. Soc. 2001, 123, 9465. (c) Marsden, S. P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
(d) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83,
1175. (e) Nakazawa, K.; Hayashi, M.; Tanaka, M.; Aso, M.; Suemune,
H. Tetrahedron: Asymmetry 2001, 12, 897. (f) Kawahara, M.; Nishida,
A.; Nakagawa, M. Org. Lett. 2000, 2, 675. (g) Fuji, K.; Kawabata, T.;
Ohmori, T. Heterocycles 1998, 47, 951. (h) Bruncko, M.; Crich, D.;
Samy, R. J. Org. Chem. 1994, 59, 5543. (i) Booker-Milburn, K. I.;
Feduoloff, M.; Paknoham, S. J.; Strachan, J. B.; Melville, J. L.; Voyle,
M. Tetrahedron Lett. 2000, 41, 4657. (j) Sebahar, P. R.; Williams, R.
M. J. Am. Chem. Soc. 2000, 122, 5666. (k) Onishi, T.; Sebahar, P. R.;
Williams, R. M. Org. Lett. 2003, 5, 3135.
(4) (a) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org. Lett. 2001,
3, 2407. (b) Novikov, A. N.; Kennedy, A. R.; Rainier, J. D. J. Org. Chem.
2003, 68, 993.
(5) We are aware of three other examples of ylide initiated [3,3]-
sigmatropic rearrangements. See: (a) Nakano, H.; Ibata, T. Bull. Chem.
Soc. Jpn. 1995, 68, 1393. (b) Wood, J. L.; Moniz, G. A.; Pflum, D. A.;
Stoltz, B. M.; Holubec, A. A.; Dietrich, H.-J. J. Am. Chem. Soc. 1999,
121, 1748. (c) Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371. (d)
May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426.
(6) For relevant reviews covering ylide-initiated cascades see: (a)
Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223. (b) Doyle, M.
P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (c) Hodgson, D. M.; Pierard,
F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50.
(7) Novikov, A. V.; Sabahi, A.; Nyong, A. M.; Rainier, J. D.
Tetrahedron: Asymmetry 2003, 14, 911.
(8) (a) Polt, R.; Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992,
57, 5469. (b) Ibuka, T.; Habashita, H.; Otaka, A.; Fufii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1991, 56, 4370. (c) Angle,
S. R.; Breitenbucher, J. G.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5947.
(9) Ishizuka, N.; Sato, T.; Makisumi, Y. Chem. Pharm. Bull. 1990,
38, 1396.
10.1021/jo0482413 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/24/2004
746
J. Org. Chem. 2005, 70, 746-748

TABLE 1
TABLE 3
entry
R
alcohol
dr
yield, %
1
3
3
Me
7
8
9
>95:5
7:1a
52
56
48
entry
n
thiomidate
yield, %
anti:syna
Ph
1
2
1
0
17
18
72
63
>19:1
>21:1
vinyl
4:1b
a Obtained after conversion into the corresponding cyclic car-
bamate. b Obtained from the integration of the vinyl signals in the
1H NMR of the crude reaction mixtue.
a From the integration of the vinyl signals in the 1H NMR of
the crude reaction mixture.
ether lone pair that sits on the face of the thiopyran
opposite the methyl substituent.
TABLE 2
Having shown that the isoprenyl diazoacetate 4 coupled
with 11 with a high level of stereoselectivity, we set out
to determine whether related vinyl diazoacetates would
give similar results. We were pleased to find that both
cyclohexenyl and cyclopentenyl diazo acetates 15 and 16
gave the corresponding thioimidates 17 and 18, respec-
tively, with high anti:syn diastereoselectivity.
The thioimidates from the carbenoid couplings are
potentially useful precursors to other indoles and indo-
lines. For example, by stirring 14 with NaH in THF we
were able to induce an intramolecular Michael addition
to give tetracyclic adduct 19 as a single diastereomer in
81% yield (eq 3). The C(3) isoprenoid group in 14 can be
entry
R
thiomidate
yield, %
anti:syna
1
2
H
Me
13
14
64
87
3:1
>21:1
a From the integration of the vinyl signals in the 1H NMR of
the crude reaction mixture.
SCHEME 1
induced to undergo a stereoselective Cope rearrangement
when 14 is exposed to HgCl2. This results in the genera-
tion of 20 as a single diastereomer in 85% yield (eq 4).
Interestingly, the corresponding thermal rearrangement
gave a 1.6:1 mixture of diastereomers in an 80% yield.
diazoacetates 12 and 4, respectively (Table 2). Interest-
ingly, we found that the diastereoselectivity of the
reaction was dependent upon the level of substitution on
the diazo moiety; gem-dimethyl-substituted vinyl car-
benoid 4 gave indoline 14 having vicinal quaternary
substitution in 87% yield with a >21:1 diastereomeric
ratio while the parent vinyl diazo acetate 13 gave much
lower levels of diastereoselectivity.10,11 Through the use
of 2D NMR experiments, we were able to show that the
major diastereomer in both cases was the anticipated
anti-product resulting from ylide formation on the thio-
Having demonstrated the utility of thiopyranylindole
11 in the synthesis of quaternary substituted indolines,
we turned our attention to the use of 11 in other ylide-
initiated cascades. First on the list was the reaction of
11 with malonate and â-ketoester carbenoids (Table 4).
Previously, we had demonstrated that acyclic 2-thio-
indoles undergo ylide-derived Stevens’ rearrangements
when exposed to malonate and â-ketoester carbenoids;
if a similar reaction occurred with 11, this would result
in a novel one-carbon ring expansion reaction. To our
delight, we found this to be the case; both malonate and
â-ketoester rhodium carbenoids underwent successful
Stevens’ rearrangements to generate thiepines 21 and
(10) The lower levels of diastereoselectivity observed with 12 may
be due to a competitive direct C(3) alkylation of the unsubstituted vinyl
carbenoid.
(11) It is also possible that the lower levels of selectivity with 12
may be due to the formation of a configurationally unstable ylide. We
thank a reviewer for this suggestion.
J. Org. Chem, Vol. 70, No. 2, 2005 747

TABLE 4
lines and indoles in high yield and moderate to high
levels of diastereoselectivity. We are continuing to explore
these reactions including their application to the syn-
thesis of interesting targets. These efforts will be reported
in due course.
Acknowledgment. We are grateful to The
National Institutes of Health, General Medical Sciences
(GM61608) for support of this work. We would also like
to thank Dr. Charles L. Mayne and Mr. Elliot M.
Rachlin for help with NMR and mass spectrometry,
respectively.
R
R′
thiepine
ds
yield, %
Me
t-Bu
OMe
Me
21
22
64
60
6:1
22, respectively. Impressively, 22 was isolated as a 6:1
mixture of diastereomers although the reaction was run
at 80 °C.
In conclusion, we have shown that the coupling of
optically active thiopyranylindoles with diazoacetates in
the presence of Rh2(OAc)4 gives highly substituted indo-
Supporting Information Available: Characterization
data and copies of 1H NMR and 13C NMR for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0482413
748 J. Org. Chem., Vol. 70, No. 2, 2005