Diastereoselective synthesis of quaternary substituted thioindolines from sulfur ylide intermediates

Article abstract of DOI:10.1016/S0957-4166(03)00077-6

We have examined the coupling reactions of 2-thioindoles with vinyl diazoacetates in the presence of Rh(II) catalysts. While attempted enantio- and/or diastereoselective couplings using chiral catalysts and/or chiral auxiliaries on the vinyl diazoacetate have been largely unsuccessful, substrates having resident chirality on fused thiopyrans gave thioindolines with moderate to high diastereoselectivities.

Full text of DOI:10.1016/S0957-4166(03)00077-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 911–915
Diastereoselective synthesis of quaternary substituted
thioindolines from sulfur ylide intermediates
Alexei V. Novikov, Amir Sabahi, Abijah M. Nyong and Jon D. Rainier*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
Received 18 December 2002; accepted 9 January 2003
Abstract—We have examined the coupling reactions of 2-thioindoles with vinyl diazoacetates in the presence of Rh(II) catalysts.
While attempted enantio- and/or diastereoselective couplings using chiral catalysts and/or chiral auxiliaries on the vinyl
diazoacetate have been largely unsuccessful, substrates having resident chirality on fused thiopyrans gave thioindolines with
moderate to high diastereoselectivities. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Presumably, 5 results from a [3,3]-sigmatropic rear-
rangement of sulfur ylide 4.5,6
The presence of C(3) quaternary substitution in a vari-
ety of indolines containing natural and non-natural
products has inspired a number of groups, including
ours, to develop new and improved routes for their
synthesis.1–3 Our interest in this area is the result of our
ability to generate quaternary substituted thioindolines
from the coupling of vinyl diazoacetates with 2-thio-3-
alkylindoles in the presence of Rh(II) (Scheme 1).4
While pleased with our results thus far, we realized that
the application of the 1“5 transformation to the syn-
thesis of interesting indoline containing targets was
dependent upon our ability to extend its scope to
include the synthesis of diastereomerically and/or enan-
tiomerically enriched substrates. Herein, we report the
results of our preliminary efforts to address this issue
through the use of chiral substrates and chiral catalysts.
In spite of the fact that only modest levels of enantiose-
lectivity have been observed when chiral catalysts have
been used in related oxygen and sulfur ylide-induced
[2,3]-sigmatropic rearrangements,7 we decided to
explore the effect of chiral catalysts on our coupling
reaction. As outlined in Table 1, chiral Rh(II) and
Cu(I) catalysts gave disappointing results; we isolated
indoline 8 in moderate to low yields and with low levels
of enantioselectivity when
6
was exposed to
78 and Rh2(DOSP)4 9,9 Rh2(S-TBSP)4 10,9 or
Cu(I)bisoxazoline (from Cu(CH3CN)PF6 and bisoxazo-
line 11).10
In addition to chiral catalysts, we have also examined
the effect of chiral substrates on the coupling reaction.
As depicted in Table 2, when tryptamide 6 was exposed
to pantolactone vinyl diazoester 1211 and either
Rh2(OAc)4 or Rh2(TBSP)4, we isolated indoline 13 as a
less than satisfactory 2:1 mixture of diastereomers,
which could not be improved upon regardless of the
reaction conditions.
Scheme 1.
* Corresponding author. E-mail: rainier@chem.utah.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00077-6

912
A. V. No6iko6 et al. / Tetrahedron: Asymmetry 14 (2003) 911–915
Table 1.
Catalyst
Conditions
Solvent Temp.
Yield (%)
e.r.a
Catalyst
Conditions
Solvent Temp.
Yield (%)
e.r.a
Rh2(OAc)4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhH
Rt
Rt
0°C
−30°C
Rt
Rt
Rt
Rt
Rt
83
68
36
0
21
59
50
65
45
0
–
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Rh2(S-TBSP)4
Cu(CH3CN)PF6, 11
Cu(CH3CN)PF6, 11
Cu(CH3CN)PF6, 11
CH2Cl2
PhCH3
PhCl
CHCl3
CH3CN
THF
Et2O
PhH
CH2Cl2
CH3CN
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
28
0
60
41
5
0
62
9
62:38
–
62:38
58:42
62:38
–
59:41
53:47
53:47
53:47
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
62:38
61:39
–
–
PhCl
62:38
59:41
63:37
60:40
–
CHCl3
CH3CN
Et2O
10
24
THF
Rt
a Measured using a Chiralcell OD HPLC column.
Table 2.
Catalyst
Conditions
Yield (%)
d.r.a
Solvent
Temp.
Rh2(OAc)4
Rh2(OAc)4
Rh2(S-TBSP)4
Rh2(R-TBSP)4
CH2Cl2
ClCH2CH2Cl
CH2Cl2
Rt
83°C
Rt
16
89
29
21
2:1
2:1
2:1
5:3
CH3CN
Rt
a Ratio was determined from integration of the vinyl signals in the crude 1H NMR spectra.

A. V. No6iko6 et al. / Tetrahedron: Asymmetry 14 (2003) 911–915
913
2.3:1 mixture of indolines 20 and 21 in 82% overall
yield.19 Surprisingly, the vinyl group was positioned syn
to the thiopyran substituent in the major diastereomer
(Scheme 3).20
Having had little success with chiral catalysts or chiral
vinyl diazoacetates,12 we opted to investigate chiral
indoles where the chirality would reside on a thiopyran
ring fused to the indole (e.g. 14). These studies were
made all the more compelling by the ready availability
of thiopyran ring systems having substitution a-, b-,
and g- to sulfur and by the notion that the thiopyran
might prove useful in its own right subsequent to the
coupling reaction (Fig. 1).13
Having examined b- and g-substituted thiopyrans, we
next investigated the influence of substitution at the
position a- to sulfur. Clearly, if the selectivity was
dependent upon the diastereoselective formation of a
sulfur ylide intermediate, a-substitution should have an
impact. In order to test this notion, the previously
unknown a-methyl thiopyran 25 was synthesized in
racemic form via the route outlined in Scheme 4. Alkyl-
ation of ethyl acetoacetate with gramine21 was followed
by decarboxylation and reduction to give 24.22 Dis-
placement of the mesylate from 24 with KSAc gave 25
following hydrolysis23 and oxidative cyclization of the
resulting acyclic thiol using I2 in DMF.
Our initial experiments examined the coupling of a
b-substituted thiopyran, tryptophan derivative 15.14
The coupling of 15 with vinyl diazoacetate 7 in the
presence of Rh2(OAc)4 resulted in the generation of
indolines 16 and 17 as a 2:1 mixture of diastereomers in
90% overall yield (Scheme 2).15–17
From the notion that the position of the stereogenic
center might be important, we also examined g-substi-
tuted thiopyran 18.18 The coupling of 18 with 19 gave a
Thioindole 25 was subjected to vinyl diazoacetate 7 and
Rh2(OAc)4 at rt (Eq. (1)). We were extremely pleased to
isolate thioindoline 26 as
a
>95:5 mixture of
diastereomers in 81% yield (Eq. (5)).24,25 The success of
this experiment is exciting to us for two reasons: firstly,
it demonstrates that thioindole-vinyl diazoacetate cou-
pling reactions can be used to generate indolines with
high stereoselectivity and secondly, from this result it
appears likely that the mechanism presented in Scheme
1 is accurate. This finding will undoubtedly play a
significant role in our use of this transformation in
chemical synthesis.
Figure 1.
Scheme 2.
Scheme 3.
Scheme 4.

914
A. V. No6iko6 et al. / Tetrahedron: Asymmetry 14 (2003) 911–915
(1)
2. Conclusions
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.; Hol-
ubec, 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.
In conclusion, the coupling of thioindoles with vinyl
diazoacetates in the presence of Rh(II) gives the corre-
sponding indolines in high yield and high diastereose-
lectivity depending upon the substrate. While we have
been unable to find a chiral catalyst or a chiral dia-
zoester capable of influencing the enantio- or
diastereoselectivity of the reaction, we have found a
successful method by utilizing a chiral thiopyran. We
are continuing to explore these reactions and will report
our efforts in due course.
7. For examples of sulfur ylide-initiated [2,3]-sigmatropic
rearrangements see Ref. 6 and: (a) Nishibayashi, Y.; Ohe,
K.; Uemura, S. J. Chem. Soc., Chem. Commun. 1995,
1245; (b) Fukuda, T.; Irie, R.; Katsuki, T. Tetrahedron
1999, 55, 649; (c) McMillen, D. W.; Varga, N.; Reed, B.
A.; King, C. J. Org. Chem. 2000, 65, 2532; (d) Zhang, X.;
Qu, Z.; Ma, Z.; Shi, W.; Jin, X.; Wang, J. J. Org. Chem.
2002, 67, 5621.
Acknowledgements
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 Dr. Elliot M. Rachlin for help with NMR
and mass spectrometry, respectively.
8. Davies, H. M. L.; Houghland, P. W.; Cantrell, W. R., Jr.
Synth. Commun. 1992, 22, 971.
9. Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
10. (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul,
M. M. J. Am. Chem. Soc. 1991, 113, 726; (b) Lowenthal,
R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett. 1990,
31, 6005.
References
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16, 155.
2. For recent reviews covering approaches to the synthesis
of indoles and indole alkaloids, see: (a) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045; (b) Hibino, S.;
Choshi, T. Nat. Prod. Rep. 2002, 19, 148.
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.
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Chim. Acta 2000, 83, 1175; (e) Nakazawa, K.; Hayashi,
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Nakagawa, M. Org. Lett. 2000, 2, 675; (g) Fuji, K.;
Kawabata, T.; Ohmori, T. Heterocycles 1998, 47, 951; (h)
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11. (a) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.;
Olive, J. L. J. Am. Chem. Soc. 1993, 115, 9468; (b) Doyle,
M. P.; Yan, M. Tetrahedron Lett. 2002, 43, 5929.
12. In light of the similar size of each of the thioether
substituents in 6, it is probably not surprising that we
have observed low levels of stereoselectivity with chiral
catalysts and chiral diazoacetates. Assuming that the
selectivity is determined during the ylide forming step and
because of the similar environment about both sides of
sulfur, the chiral carbenoid is unable to distinguish
between the two diastereotopic sulfur lone pairs. We are
currently testing this notion by examining thioethers hav-
ing more and less sterically demanding substituents
attached to sulfur.
13. The thiol from hydrolysis of the thioindoline should be
amenable to a number of transformations including cou-
pling and oxidation reactions.
14. 15 is available in five steps from
L-tryptophan. See:
Ishizuka, N.; Sato, T.; Yasuo, M. Chem. Pharm. Bull.
1990, 38, 1396.
15. Ratio determined from the relative integration of the
1
vinyl signals in the crude H NMR spectrum.
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., in press.
16. The 2:1 ratio represents a slight improvement over our
experiments with 2-thiotryptophan where we had isolated
a 1:1 mixture of diastereomers. See Ref. 4b.

A. V. No6iko6 et al. / Tetrahedron: Asymmetry 14 (2003) 911–915
915
17. The relative stereochemistry shown for 16 was assumed
based upon the notion that the major ylide intermediate
would have the allyl group on the face opposite the
amino group.
21. Somei, M.; Karasawa, Y.; Kaneko, C. Heterocycles
1981, 16, 941.
22. Presumably, optically active 24 would form from asym-
metric reduction of the ketone that arises from decar-
boxylation of 23.
18. 18 is available in eight steps from
L-malic acid. See:
23. We believe that the relatively low yield from the
thioester hydrolysis is due to the formation of a by-
product in 30% yield. Although we have little structural
proof at this point, we have tentatively assigned the
by-product to be a disulfide dimer. Reduction of the
by-product with LiAlH4 followed by oxidative cycliza-
tion also gave 25.
Ishizuka, N.; Shiro, M.; Mukisumi, Y. J. Chem. Soc.
Perkin 1 1990, 4, 827.
19. The diastereomeric ratio of 20:21 was determined spec-
1
troscopically by integration of the vinyl signals in the H
NMR spectrum of the crude reaction mixture. The rela-
tive stereochemistry of 20 and 21 was also determined
spectroscopically using the following rationale: (a)
NOEs were observed between the vinyl ester and the
siloxy CH2 in the major diastereomer 20; (b) an NOE
was observed between the TBSOCH2CH proton and the
vinyl ester in the minor diastereomer 21.
24. The 95:5 ratio represents a lower limit; we observed
1
none of the other diastereomer by 300 MHz H NMR.
25. The relative stereochemistry about 26 was elucidated
spectroscopically; NOEs were observed between the
hydrogen adjacent to sulfur and: (a) the olefin hydro-
gens; (b) one of the methyl groups at the allylic posi-
tion.
20. We are currently exploring this phenomenon; we do not
currently have a reasonable explanation for the predom-
inance of the syn isomer from this experiment.