Gold(I)-catalyzed dearomative rautenstrauch rearrangement: Enantioselective access to cyclopenta[ b ]indoles

Article abstract of DOI:10.1021/jacs.5b00613

A highly enantioselective dearomative Rautenstrauch rearrangement catalyzed by cationic (S)-DTBM-Segphosgold(I) is reported. This reaction provides a straightforward method to prepare enantioenriched cyclopenta[b]indoles. These studies show vast differenc

Full text of DOI:10.1021/jacs.5b00613

Communication
pubs.acs.org/JACS
Gold(I)-Catalyzed Dearomative Rautenstrauch Rearrangement:
Enantioselective Access to Cyclopenta[b]indoles
Weiwei Zi,† Hongmiao Wu,†,‡ and F. Dean Toste*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210046, P. R. China
S
* Supporting Information
ABSTRACT: A highly enantioselective dearomative
Rautenstrauch rearrangement catalyzed by cationic (S)-
DTBM-Segphosgold(I) is reported. This reaction provides
a straightforward method to prepare enantioenriched
cyclopenta[b]indoles. These studies show vast difference
in enantioselectivity in the reactions of propargyl acetates
and propargyl acetals in the chiral ligand-controlled
Rautenstrauch reaction.
ince its first report in 1984, the Rautenstrauch rearrange-
S
ment1a and related reactions have received attention as
efficient approaches for the assembly of substituted carbocyclic
compounds. Although earlier studies utilized palladium-based
catalysts, other transition metals (Pt, Ru, Au) were
subsequently found to catalyze this transformation through
analogous mechanisms involving the 2,3-acyloxy migration of
propargyl esters.1,2 Generally, vinylogous metal carbenoid
species have been proposed as intermediates in the reaction
(Figure 1a).3a,b However, our group reported excellent chirality
transfer in a gold-catalyzed Rautenstrauch rearrangement,
which is inconsistent with an achiral carbenoid intermediate.1g
Experimental and computational studies have supported a
mechanism in which chirality transfer occurs through a
transition state with helical chirality (Figure 1b).3c Although
this asymmetric transformation provided a route to enantioen-
riched cyclopentenones from readily obtained chiral secondary
propargyl alcohols, the lack of straightforward methods for the
preparation of tertiary propargyl alcohols limited the scope of
this process. Meanwhile, an enantioselective Rautenstrauch
rearrangement of racemic propargyl esters is still an unresolved
challenge for transition-metal catalysis.4
Figure 1. Mechanistic background for proposed studies.
this 1-aminopentadienyl intermediate would be subject to an
imino-Nazarov rearrangement8,9 providing a chiral dearomat-
ized indole product, which could subsequently isomerize to the
indole product.10 Moreover, we posited that, in contrast to our
previously report of chirality transfer,1g,3c the achiral gold
carbenoid intermediate incorporated in the transformation
might allow for a ligand controlled enantioselective Rauten-
strauch rearrangement.
Initial studies revealed that, in the presence of cationic gold
catalyst, indole-derived propargyl acetate 1a indeed rearranged
to deliver the proposed dearomative Rautenstrauch reaction
product 2a (Scheme 1). This result prompted us to examine
chiral phosphine ligands to potentially render this trans-
formation enantioselective.11 However, low enantioselectivity
was obtained even when sterically demanding ligands were
employed. Efforts to improve the enantioselectivity by tuning
the reaction conditions were uniformly unsuccessful. We
hypothesized that reaction might be proceeding through a
cyclic intermediate (A, Scheme 2) rather than a 1-amino-
pentadienyl carbenoid species, hence a chirality transfer process
Indolines with a fused five-membered ring at the C2 and C3
positions (cyclopenta[b]indoles) represent a key structural
motif of a number of natural products which exhibit a wide
range of biological activities.5 A number of methods have been
developed to prepare this skeleton, but enantioselective variants
are limited.6 In 2005, Sarpong et al. reported a platinum-
catalyzed Rautenstrauch-like rearrangement of indole-derived
substrates,1c showing reactivity that was consistent with that of
vinylogous carbenoid intermediate (Figure 1c, path a). In
contrast, we rationalized that the presence of a cation-stabilizing
amino group suggested that the intermediate might be best
represented by taking into account the delocalized cationic
resonance form.7 As an alternative mechanism, we envisioned
Received: January 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b00613
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Journal of the American Chemical Society
Communication
were evaluated and among them, DTB-MeO-Biphep (entry 2)
and DTBM-Segphos (entry 5) gave the highest ee but the yield
was moderate. Replacing the ketal moiety with a less hindered
acetal (substrate 1c) improved the yield to 74% without loss of
enantioselectivity (entry 6 vs entry 2). Finally, both yield and
enantioselectivity improved when the reaction was performed
at higher concentration (75 yield, 95% ee, entry 7).
Scheme 1. Preliminary Results
With these optimized conditions in hand, the substrate scope
of this transformation was explored (Table 2). The substituents
on the indole ring were first investigated. Substrates with an
electron-withdrawing group (Br, F) or an electron-donating
group (MeO, Me) at the C5 position were well-tolerated
(entries 2−5). Substitution on the C6 and C7 position
provided satisfactory results as well (entries 7−9). However,
a substrate with substitution at the C4 position (entry 6) gave
diminished enantioselectivity (66% yield, 81% ee), possibly as a
consequence of restricted rotation of the indole ring resulting
from the steric interaction between the C4 substituent and R2.
Similarly, diminished enantioselectivities were observed for
substrates bearing bulkier R2 substituents (compare entries 5,
10 and 11). Changing the ester group from a methyl ester to an
ethyl ester had no obvious effect to the enantioselectivity and
yield. An allylic ester was also investigated, giving the desired β-
keto allylic ester in 78% yield with 94% ee (entry 13).
Interestingly, no alkene cyclopropanation product was observed
in this case. Reactions for substrates with other electron-
withdrawing R3 groups were also examined. The reaction for
the benzoyl substrate proceeded to give the product with
acceptable enantioselectivity; however, moderate ee was
obtained when the less bulky acetyl was employed (entries
14 and 15). Finally, a pyrrole-based substrate was tested under
the standard reaction conditions. The reaction was complete in
1 min and the corresponding bicyclic product isolated in a
moderate yield but still excellent ee (entry 16). Finally, to
explore the scalability of the process, substrate 1a was subjected
to standard reaction conditions on a 1 mmol scale, employing 1
mol % catalyst. Under these conditions, the desired product 1a
was isolated in 67% yield, without affecting the enantiose-
lectivity (entry 17).14
Scheme 2. Mechanistic Hypothesis
dominated instead of the desired ligand-controlled cyclization.
In analogy to our previous carboalkoxylation,12 we reasoned
that the use of a ketal13 in place of the acetoxy group in 1a
might lead to fully planar and achiral intermediate (B) that
could undergo cyclization in a ligand-controlled manner.
To this end, we prepared propargyl ketal 1b and subjected it
to our previously developed conditions. In the presence of (S)-
DTBM-MeO-Biphep(AuCl)2/AgSbF6 in dichloromethane, 1b
furnished the corresponding dearomatized indole in signifi-
cantly improved ee, compared to substrate 1a (Table 1,
entry1). Different ligands based on the bisphosphine backbone
Table 1. Optimization of the Reaction Conditions
Given the propensity of the dearomatized adducts to
racemize and isomerize to the indole product (see Supporting
Information), we sought methods for their derivatization to
stereochemically stable compounds.16 As shown in Scheme 3,
reduction of the Rautenstrauch reaction product furnished
products with high yield and diastereoselectivity. Reduction of
the ketone under Luche conditions gave the corresponding
alcohol 4 in 53% combined yield from 1c with 97% ee. Further
catalytic hydrogenation of the alkene in 4 led to multi-
substituted cyclopenta[b]indoles 5 in nearly quantitative yield
with excellent diastereoselectivity. X-ray structure of 5 revealed
that both the Luche reduction and the palladium-catalyzed
hydrogenation occurred with approach from the convex face.
A proposed mechanism is shown in Scheme 4 using 1c as a
representative example. Upon initial coordination of the alkyne
moiety in 6, anti attack of the ethoxy ether of the acetal leads to
the formation of oxonium species 7. Rapid cleavage of the C−
O bond in 7 generates acyclic oxocarbenium 8, which extrudes
acetaldehyde to give gold-substituted 1-aminopentadienyl
intermediate 9 (which could also be represented by carbenoid
resonance structure 9′). Enantiodetermining C−C bond
formation occurs through a chiral phosphinegold-controlled
imino-Nazarov cyclization of 9 to afford 10. Decomplexation of
a
b
c
entry
substrate
ligand
yield (%)
ee (%)
1
2
3
4
5
6
1b
1b
1b
1b
1b
1c
1c
L1
L2
L3
L4
L5
L2
L5
72
69
62
54
63
74
75
87
92
40
83
91
92
95
d
7
a
Reaction conditions: (1) 5 mol % gold catalyst, 10 mol % AgSbF6,
0.05 mmol substrate, 10 mg 4 Å molecular sieves, 1 mL CH2Cl2. (2) 5
b
mg PTSA·H2O, 1 mL acetone, 0.1 mL H2O. Isolated yields after two
c
steps. ee was determined by chiral HPLC analysis of the crude
product.16 0.1 mmol scale, c = 0.1 M, 20 min.
d
B
DOI: 10.1021/jacs.5b00613
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Journal of the American Chemical Society
Communication
a
a
Table 2. Substrate Scope
Scheme 3. Synthetic Transformations
a
(a) Reaction conditions: (1) 2.5 mol % (S)-DTBM-Segphos(AuCl)2,
5 mol % AgSbF6, 0.5 mmol 1c, 50 mg 4 Å molecular sieve, 2.5 mL
CH2Cl2, 20 min. (2) 10 mg PTSA·H2O, 2 mL acetone, 0.2 mL H2O, 3
min. (3) CeCl3·7H2O, NaBH4, DCM/EtOH, −78 to 0 °C. (4) 20 atm
1
H2, EtOH/EtOAc. (b) Isolated yields. d.r. were determined by H
NMR analysis of the crude product. ee was determined by chiral
HPLC.
Scheme 4. Proposed Catalytic Cycle
of electrophilic platinum and gold catalysis. In this case, these
differences in product selectivity can, in part, be attributed to
the milder reaction conditions of the gold-catalyzed reaction
allowing isolation on the initially formed dearomatization
adduct. While carbenoid intermediates generated by 1,2-
propargyl shifts are often treated as identical, profoundly
different selectivity was observed through vinylgold-carbenoid
intermediates generated from propargyl acetals and esters.15
Utilizing acetal-based substrates, the Rautenstrauch reaction
proceeds through a planar and achiral intermediate and thus
allows the cyclization proceed in a ligand-controlled manner.
a
(a) Reaction conditions: (1) 5 mol % (S)-DTBM-Segphos(AuCl)2,
10 mol % AgSbF6, 0.1 mmol substrate, 20 mg 4 Å molecular sieve, 1
mL CH2Cl2, 20 min. (2) 10 mg PTSA·H2O, 1 mL acetone, 0.1 mL
H2O, 3 min. See Supporting Information for details. (b) Isolated yields
after two steps; ee was determined by chiral HPLC analysis of the
crude product.16. (c) Absolute stereochemistry assigned by analogy to
b
2f. 2.5 mol % (S)-DTBM-Segphos(AuCl)2, 5 mol % AgSbF6 was
c
d
used. Reaction was performed at 0 °C for 1 min. 1.0 mmol scale, 1
mol % (S)-DTBM-Segphos(AuCl)2, 2 mol % AgSbF6, 40 mg 4 Å
molecular sieve, 3 mL CH2Cl2, 1 h.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
cationic gold(I) furnishes the product 3b which is subsequently
hydrolyzed to 2a.
In conclusion, we have developed the first gold-catalyzed
dearomative Rautenstrauch rearrangement. The (S)-DTBM-
Segphos(AuCl)2/AgSbF6-catalyzed reactions provides access to
cyclopenta[b]indoles with excellent enantioselectivities. The
work highlights the divergent transformations achievable with
AUTHOR INFORMATION
Corresponding Author
*fdtoste@berkeley.edu
■
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/jacs.5b00613
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Journal of the American Chemical Society
Communication
2008, 47, 7354. (d) Lin, C.-C.; Teng, T.-M.; Tsai, C.-C.; Liao, H.-Y.;
Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16417. (e) Bhunia, S.; Liu, R.-S.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NIHGMS (RO1 GM073932) for
financial support and the College of Chemistry CheXray (NIH
Shared Instrumentation Grant S10-RR027172) and Antonio
DiPasquale for X-ray crystallographic data. We thank Yi-Ming
Wang (MIT) for helpful discussion during the preparation of
this manuscript.
J. Am. Chem. Soc. 2008, 130, 16488. (f) Suar
́
ez-Pantiga, S.; Rubio, E.;
Alvarez-Rua, C.; Gonzalez, J. M. Org. Lett. 2009, 11, 13.
́
́
(10) For recent example of catalytic enantioselective dearomatization
reactions of indole and pyrrole see: (a) Zhang, X.; Yang, Z.-P.; Liu, C.;
You, S.-L. Chem. Sci. 2013, 4, 3239. (b) Zhang, X.; Han, L.; You, S.-L.
Chem. Sci. 2014, 5, 1059. (c) Mei, G.; Yuan, H.; Gu, Y.; Chen, W.;
Ching, L. M.; Li, C.-C. Angew. Chem., Int. Ed. 2014, 126, 11231.
(d) Zheng, C.; Zhuo, C.-X.; You, S.-L. J. Am. Chem. Soc. 2014, 136,
16251. For a review of asymmetric dearomatization: Zhuo, C.-X.;
Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. For
reviews of dearomatization of heterocylces see: Ding, Q.; Zhou, X.;
Fan, R. Org. Biomol. Chem. 2014, 12, 4807. Roche, S. P.; Tendoung, J.-
REFERENCES
■
(1) Transition-metal-catalyzed Rauntenstrauch reaction. For palla-
dium see: (a) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
(b) Caruana, P. A.; Frontier, A. J. Tetrahedron 2007, 63, 10646. For
platinum see: (c) Prasad, B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am.
Chem. Soc. 2005, 127, 12468. (d) Zhao, J.; Clark, D. A. Org. Lett. 2012,
14, 1668. (e) Nakanishi, Y.; Miki, K.; Ohe, K. Tetrahedron 2007, 63,
12138. For ruthenium see: (f) Miki, K.; Ohe, K.; Uemura, S. J. Org.
Chem. 2003, 68, 8505. For gold see: (g) Shi, X. D.; Gorin, D. J.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 10646.
(2) Selected examples for Rauntenstrauch related reactions initiated
by 2,3-acyloxy migration: (a) Harrak, Y.; Blaszykowski, C.; Bernard,
M.; Cariou, K.; Mainetti, E.; Mouries
Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004, 126, 8656.
(b) Mamane, V.; Gress, T.; Krause, H.; Furstner, A. J. Am. Chem. Soc.
́
J. Y.; Treguier, B. Tetrahedron doi:10.1016/j.tet.2014.06.054.
(11) For reviews of asymmetric gold catalysis: (a) Pradal, A.; Toullec,
P. Y.; Michelet, V. Synthesis 2011, 10, 1501. (b) Sengupta, S.; Shi, X.
ChemCatChem 2010, 2, 609. (c) Wang, Y.-M.; Lackner, A. D.; Toste,
F. D. Acc. Chem. Res. 2014, 47, 889.
(12) Zi, W.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 12600.
(13) (a) Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 12598.
(b) Iqbal, N.; Sperger, C. A.; Fiksdahl, A. Eur. J. Org. Chem. 2013, 5,
907. (c) Siah, H.-S. M.; Kaur, M.; Iqbal, N.; Fiksdahl, A. Eur. J. Org.
Chem. 2014, 8, 1727.
̀
, V.; Dhimane, A.-L.;
̈
(14) Changing the indole N-protecting group of 2h from Ts to Boc
resulted in lower enantioselectitity (35% ee).
́ ̀
2004, 126, 8654. (c) Marion, N.; de Fremont, P.; Lemiere, G.;
Stevens, E. D.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Chem.
Commun. 2006, 2048. (d) Gorin, D. J.; Watson, I. D. G.; Toste, F. D. J.
Am. Chem. Soc. 2008, 130, 3736. (e) Shu, X.-Z.; Huang, S.; Shu, D.;
Guzei, I. A.; Tang, W. Angew. Chem., Int. Ed. 2011, 50, 8153.
(15) For previous works on the reactivity of vinylgold carbenoids:
(a) Shapiro, N. D.; Shi, Y.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
11654. (b) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130,
9244. (c) Briones, J. F.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
13314. For a review on alternative methods for gold-carbenoid
generation see: (d) Aian, D.; Zhang, J. Chem. Soc. Rev. 2015, 44, 677.
(e) Shu, X.-Z.; Shu, D.; Schienebeck, C. M.; Tang, W. Chem. Soc. Rev.
2012, 42, 7698.
(3) (a) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692. (b) Marion,
N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (c) Faza, O. N.;
́
́
Lopez, C. S.; Alvarez, R.; de Lera, A. R. J. Am. Chem. Soc. 2006, 128,
2434.
(4) For enantioselective transformation of Rautenstrauch carbenoid
intermediate: (a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F.
D. J. Am. Chem. Soc. 2005, 127, 18002. (b) Uemura, M.; Watson, I. D.
G.; Katsukawa, M.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 3464.
(c) Liu, F.; Wang, Y.; Ye, W.; Zhang, J. Org. Chem. Front. 2015, 2, 221.
(d) Zhu, X.-Z.; Schienebeck, C. M.; Song, W.; Guzei, I. A.; Tang, W.
Angew. Chem., Int. Ed. 2013, 52, 13601.
(16) The ees in Tables 1 and 2 were obtained before purification
since the products were optically unstable during chromatography. See
Supporting Information for details.
(5) (a) Hillier, M. C.; Marcoux, J.-F.; Zhao, D.; Grabowski, E. J. J.;
McKeown, A. E.; Tillyer, R. D. J. Org. Chem. 2005, 70, 8385.
(b) Cheng, K.-F.; Cheung, M.-K.; Kong, Y. C. Aust. J. Chem. 1997, 50,
349.
́
(6) (a) Barluenga, J.; Tudela, E.; Ballesteros, A.; Tomas, M. J. Am.
Chem. Soc. 2009, 131, 2096. (b) Lian, Y.; Davies, H. M. L. J. Am. Chem.
Soc. 2010, 132, 440. (c) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc.
2014, 136, 6288. (d) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng,
Y.-G.; Guo, Q.-X. Angew. Chem., Int. Ed. 2012, 51, 1059.
(7) (a) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.;
Goddard, W. A.; Toste, F. D. Nat. Chem. 2009, 1, 482. (b) Ing, G. S.;
Mynott, R.; Furstner, A. Angew. Chem., Int. Ed. 2009, 14, 2510.
̈
(8) (a) Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tuis, M. A.
Org. Lett. 2010, 12, 440. (b) Ma, Z.-X.; He, S.; Song, W.; Hsung, R. P.
Org. Lett. 2012, 14, 5736. (c) Bonderoff, S. A.; Grant, T. N.; West, F.
G.; Tremblay, M. Org. Lett. 2013, 15, 2888. (d) William, R.; Wang, S.;
Ding, F.; Arviana, E. L.; Liu, X.-W. Angew. Chem., Int. Ed. 2014, 53,
10742. (e) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. (f) Tius,
M. A.; Chie, C. C.; Mieves-Colberg, R. Tetrahedron Lett. 2001, 42,
2419. (g) For a review on the generation of pentadienyl cation
intermediates see: Spencer, W. T., III; Vaidya, T.; Frontier, A. J. Eur. J.
Org. Chem. 2013, 3621.
(9) For examples of gold-catalyzed reactions involving Nazarov
cyclizations see: (a) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128,
1442. (b) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912.
(c) Lemiere, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.-
L.; Fensterbank, L.; Malacria, M. Org. Lett,. 2007, 9, 2207. (d) Sethofer,
S. G.; Staben, S. T.; Hung, O. Y.; Toste, F. D. Org. Lett. 2008, 10,
4315. (f) Sanz, R.; Miguel, D.; Rodrigues, F. Angew. Chem., Int. Ed.
D
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