Iridium-Catalyzed Aza-Spirocyclization of Indole-Tethered Amides: An Interrupted Pictet-Spengler Reaction

Article abstract of DOI:10.1021/acs.orglett.9b02194

A mild, reductive spirocyclization of indole-linked amides and lactams for the efficient and selective synthesis of aza-spirocyclic indoline products is described. The catalytic reductive activation of tertiary amides or lactams by Vaska's complex with tetramethyldisiloxane as the terminal reductant allowed iminium ion formation, before a diastereoselective 5-endo-trig spirocyclization of the tethered indole moiety was triggered. Terminal reduction affords the aza-spiroindoline products in an overall highly chemoselective and diastereoselective one-pot process.

Full text of DOI:10.1021/acs.orglett.9b02194

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Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Aza-Spirocyclization of Indole-Tethered Amides:
An Interrupted Pictet−Spengler Reaction
Pablo Gabriel, Alex W. Gregory, and Darren J. Dixon*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A mild, reductive spirocyclization of indole-linked amides and lactams for the efficient and selective synthesis of
aza-spirocyclic indoline products is described. The catalytic reductive activation of tertiary amides or lactams by Vaska’s
complex with tetramethyldisiloxane as the terminal reductant allowed iminium ion formation, before a diastereoselective 5-
endo-trig spirocyclization of the tethered indole moiety was triggered. Terminal reduction affords the aza-spiroindoline products
in an overall highly chemoselective and diastereoselective one-pot process.
he aza-spiroindoline ring system is common to numerous
Previous mechanistic studies on the Pictet−Spengler reaction
Tbioactive compounds and natural products that are have established the existence of a dynamic interplay among
three isomeric cationic species [8a−8c (Scheme 2)],8 prior to
irreversible proton loss from 6-endo-trig cyclization intermediate
8b to afford rearomatized tetrahydro-β-carboline 9. We
reasoned that the use of Vaska’s catalyst 11 in conjunction
with tetramethyldisiloxane reductant 12 on suitable indole-
linked amide/lactam substrates not only would provide access to
these cationic intermediates9 but also could facilitate irreversible
hydridic interception of the resulting spiroindolenium inter-
mediate 8c. If this pathway outcompeted the alternative 6-endo-
trig pathway, reduced aza-spiroindoline 10, the interrupted
Pictet−Spengler product, would result.
structurally and biologically relevant.1 These range from the
infamous poison strychnine 12 to the potent anticancer
compound vinblastine 2.3 Oxidized structural relatives include
the spirooxindoles4 of which horsefiline 3 is arguably the
simplest, but well-known, member (Scheme 1a). The prevalence
of this intricate ring system within important families of
compounds continues to attract the development of new
strategies and new methods for their efficient synthesis. Whereas
tetrahydro-β-carbolines can be readily accessed by the classical
Pictet−Spengler reaction, and its many variants, between
tryptamine derivatives and aldehydes,5 building the aza-
spiroindoline core has proven to be more challenging due to
the propensity for rearomatization.6 Previous approaches have
typically employed reactive electrophilic intermediates (imidoyl
triflate 4a,6a−d π-allyl cation 4b,6e,f and N-acyl iminium 4c6g) for
accessing spirocyclic indolenines 5a−5c (Scheme 1b). A
subsequent reduction step after spirocyclization is, however,
required to generate aza-spiroindoline 6.
To probe this concept, tryptamine-derived lactam 7a was
selected as a relevant model system and its reactivity toward
Vaska’s complex and various silanes was studied.
In accordance with the recent reductive functionalization
reaction of amides,10 a toluene solution of model substrate 7a at
room temperature was treated with Vaska’s catalyst 11 and 2
equiv of TMDS 12 (Scheme 1). Very pleasingly, aza-
spiroindoline 10a was indeed obtained in 55% NMR yield
after 60 min (Table 1, entry 1). The reaction was selective for the
syn diastereoisomer (80:20 dr), and importantly, no sign of the
Pictet−Spengler product was detectable. With this excellent
proof of concept in hand, we turned to optimize the reaction for
both yield and diastereoselectivity. In contrast to previous
As part of our ongoing work toward structurally complex, sp3-
rich nitrogen-containing architectures based on an iridium-
catalyzed reductive activation of amides and lactams,7 we were
drawn to the idea of developing a new approach to the aza-
spiroindoline core. Our aim was to develop a direct and general
strategy from readily available starting materials that, through
the incorporation of multiple points of diversity in the products,
could be applied to both drug discovery and library generation.
Herein, we describe our findings.
Received: June 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02194
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Letter
Scheme 1. (a) Examples of Aza-Spiroindoline Ring Systems
in Nature and (b) Known Aza-Spirocyclization
Scheme 2. Proposed Iridium-Catalyzed Interrupted Pictet−
Spengler Reaction
Methodologies via Reactive Cationic Intermediates
tolerated at positions 4−7 [10b−10g (Scheme 3)]. Exploiting
the possibility of generating and trapping a nucleophilic lithium
enolate of the lactam,14 we could readily synthesize α-
substituted starting materials and subject them to the reaction
conditions. This extra stereocenter provided control over the
relative configuration of the newly formed pyrrolidine ring (10i
and 10j). Attack of the cyclic iminium ion on the least hindered
face gave predominantly anti-10i, as proven by single-crystal X-
ray analysis. Substrates containing α-quaternary centers could
also be cyclized (10k and 10l), although the high steric
hindrance demanded longer reaction times as well as increased
catalyst loading. To showcase the chemoselectivity of the
catalytic system, ketone 7l was cyclized to give indoline 10l in
good yield, with the ketone carbonyl group remaining
unaffected. Remarkably, no epimer at the α-quaternary center
could be observed for this substrate or for primary alcohol 10k.
Medium-sized ring substrates derived from capro-, enantho-,
and caprylolactam could be cyclized (7m−7o to 10m−10o),
albeit in slightly reduced yield and diastereoselectivity.15
Acyclic amides also underwent spirocyclization, and various
aryl/heteroaryl (10p−10s) and sterically demanding amides
(10h and 10t−10y) were smoothly transformed into the desired
indolines in good to excellent yields, showing the general
applicability of this new methodology. Notably, pyridine 10s
was formed as a single anti diastereoisomer; its relative
configuration was determined by single-crystal X-ray diffraction
analysis. Interestingly, if substantial steric hindrance was
introduced at the amide α-position, diastereoselectivity was
improved to ≥95:5 dr (t-Bu 10u, adamantyl 10v, or α-diethyl
10h) but at the expense of increased reaction time (24 h) and
catalyst loading (5 mol %). Furthermore, branching at the
relatively distant β-position of the alkyl chain on the nitrogen
atom resulted in reduced reactivity and diastereocontrol (10x,
51:49 dr).16
Table 1. Proof of Concept and Optimization Studies of
Model System 7a
a
b
entry
solvent
silane (equiv)
temp
rt
rt
rt
rt
rt
rt
rt
rt
yield (%)
dr
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
THF
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
TMDS (2)
TMDS (3)
PhSiH3 (3)
Ph2SiH2 (3)
Et3SiH (3)
TMDS (3)
TMDS (3)
TMDS (3)
TMDS (3)
TMDS (3)
55
77
0
0
0
32
74
93
90
91
80:20
80:20
−
−
−
86:14
66:34
90:10
91:9
96:4
0 °C
−15 °C
10
a
1H NMR yield determined against m-nitro dimethylaniline as an
internal standard. Determined by H NMR analysis of the crude
product.
b
1
studies, 3 equiv of TMDS was required to reach full conversion
(entry 2).11 Recourse to other silanes proved to be ineffective
(entries 3−5)12 but a solvent screen identified dichloromethane
as the best solvent, both for yield and for diastereocontrol.13
Furthermore, excellent diastereoselectivity (96:4 dr) was
achieved when the reaction temperature was decreased to −15
°C (entry 10).
With optimized conditions established, the scope of the
reaction with respect to the indole and the lactam moiety was
explored. Variations to the indole aromatic ring revealed that
both electron-withdrawing and electron-donating groups were
In line with the observations of Taylor,6g we believe the origin
of diastereoselectivity is likely facial recognition between the
indole and the iminium ion in the key addition step (Scheme 5).
Two possible diastereoisomers can arise from the spirocycliza-
tion step. In the endo-transition structure, steric repulsion would
occur between any aliphatic cyclic or acyclic side chain and the
indole ring, resulting in a higher-energy transition structure then
in the exo case (Scheme 4, case 1). The observed diastereomeric
ratios of the products are in agreement with these observations,
particularly for bromo-substituted lactam 10f where the
proximity of the bromine atom appears to further enhance the
B
DOI: 10.1021/acs.orglett.9b02194
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e
Scheme 3. Scope of the Iridium-Catalyzed Reductive Spirocyclization Reaction
a
b
c
d
e
With 5 mol % catalyst, rt, 24 h. With 1 mol % catalyst, rt, 6 h. With 1 mol % catalyst, rt, 1 h. With 4 equiv of TMDS. Standard conditions: 3
equiv of TMDS, 1 mol % catalyst, −15 °C, 1 h.
Scheme 4. Postulated Origins of Diastereocontrol
Scheme 5. Double-Digit Parts per Million Catalyst Loading
on a Multigram Scale Reaction
diastereocontrol.17 The seven-, eight-, and nine-membered
lactams seem to lack the rigidity needed for the steric clash to
hamper the addition. However, when the amide moiety was
relatively flat [i.e., derived from (hetero)aromatic carboxylic
acids, such as in 10p−10s], the steric clash in the endo-transition
structure would be minimized, thus reducing the differential in
energy and resulting in almost no observed diastereocontrol
(Scheme 4, case 2). In the case of pyridyl indoline 10s, π-
interactions between the electron-rich indole and the electron-
poor pyridine ring are likely to lower the energy of the endo-
transition structure even further when these rings are in the
proximity of each other, giving rise to the exclusive formation of
the anti diastereoisomer.
Moreover, when the lactam possesses an α-stereocenter,
diastereofacial control can be observed. This control is only
partial in the formation of α-alkyl 10i and 10j, as the addition of
the indole is naturally, but imperfectly, directed to the face
opposite the alkyl group. Substantial control at this position is
however observed when a carbonyl or a primary alcohol is
present (10k and 10l). We believe this is due to a stabilization of
C
DOI: 10.1021/acs.orglett.9b02194
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Letter
the vacant π-orbital of the iminium ion by the oxygen atom
(neighboring group participation) completely directing the
indole addition to the opposite face.
In addition to a broad scope, we also wanted to demonstrate
practical scalability, with a particular emphasis on the catalyst
loading. Following a series of investigations, we were pleased to
find that subjecting 3 g of the simple tryptamine derived lactam
7a to the same reaction conditions but with a catalyst loading of
25 ppm (240 μg) resulted in complete conversion to spirocyclic
indoline 10a.
In conclusion, an iridium(I)-catalyzed interrupted reductive
Pictet−Spengler reaction giving access to complex azaspirocy-
clic indoline structures from readily available indole-linked
lactams and amides has been developed. The reaction was
shown to be highly chemoselective and diastereoselective at the
newly formed contiguous stereocenters, and the very mild
reductive conditions allowed for good functional group
tolerance. Furthermore, the turnover number for the catalyst
was in the range of at least 40000 when the reaction was
performed on a gram scale.
REFERENCES
■
(1) (a) Zhu, X.; Zeng, X.; Sun, C.; Chen, S. Biosynthetic pathway of
terpenoid indole alkaloids in Catharanthus roseus. Front. Med. 2014, 8,
285−293. (b) O’Connor, S. E. Comprehensive Natural Products II;
Mander, L., Liu, H.-W., Eds.; Elsevier: Amsterdam, 2010; Vol. 1, p 977.
(c) Powell, N. A.; Kohrt, J. T.; Filipski, K. J.; Kaufman, M.; Sheehan, D.;
Edmunds, J. E.; Delaney, A.; Wang, Y.; Bourbonais, F.; Lee, D.-Y.;
Schwende, D.; Sun, F.; McConnell, P.; Catana, C.; Chen, H.; Ohren, J.;
Perrin, L. A. Novel and selective spiroindoline-based inhibitors of sky
kinase. Bioorg. Med. Chem. Lett. 2012, 22, 190−193. (d) Zhu, X.-X.;
Fan, Y.-Y.; Xu, L.; Liu, Q.-F.; Wu, J.-P.; Li, J.-Y.; Li, J.; Gao, K.; Yue, J.-
M. Four Rearranged Indole Alkaloids from Alstonia scholaris. Org. Lett.
2019, 21, 1471−1474. (e) Yap, W.-S.; Gan, C.-Y.; Sim, K.-S.; Lim, S.-
H.; Low, Y.-Y.; Kam, T.-S. Aspidofractinine and Eburnane Alkaloids
from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused,
and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora. J.
Nat. Prod. 2016, 79, 230−239. (f) Nge, C.-E.; Chong, K.-W.; Thomas,
N. F.; Lim, S.-H.; Low, Y.-Y.; Kam, T.-S. Ibogan, Aspidosperman,
Vincamine, and Bisindole Alkaloids from a Malayan Tabernaemontana
corymbosa: Iboga Alkaloids with C-20α Substitution. J. Nat. Prod.
̈
2016, 79, 1388−1399. (g) Zlotos, D. P.; Trankle, C.; Holzgrabe, U.;
Gundisch, D.; Jensen, A. A. Semisynthetic Analogues of Toxiferine I
̈
and Their Pharmacological Properties at α7 nAChRs, Muscle-Type
nAChRs, and the Allosteric Binding Site of Muscarinic M2 Receptors. J.
Nat. Prod. 2014, 77, 2006−2013.
(2) Lawrence, D.; McLinskey, N.; Huff, J. S.; Holstege, C. P. In Clinical
Neurotoxicology, Syndromes, Substances, Environment; Dobbs, M. R., Ed.;
Elsevier: Amsterdam, 2009; pp 30−46.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02194.
■
S
(3) (a) Neuss, N.; Neuss, M. N. In The Alkaloids; Brossi, A., Suffness,
M., Eds.; Academic: San Diego, 1990; Vol. 37, pp 229−240. (b) Pearce,
H. L. In The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San
Diego, 1990; Vol. 37, pp 145−204. (c) Kuehne, M. E.; Marko, I. In The
Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San Diego, 1990;
Vol. 37, pp 77−132.
Synthetic procedures and full characterization data of all
compounds (PDF)
Accession Codes
CCDC 1906300−1906303 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
(4) For a review of the use of spirooxindoles as scaffolds in anticancer
agents, see: Yu, B.; Yu, D.-Q.; Liu, H.-M. Spirooxindoles: Promising
scaffolds for anticancer agents. Eur. J. Med. Chem. 2015, 97, 673−698.
(5) (a) Kovvuri, J.; Nagaraju, B.; Lakshma Nayak, V.; Akunuri, R.;
Rao, M. P. N.; Ajitha, A.; Nagesh, N.; Kamal, A. Design, synthesis and
biological evaluation of new β-carboline-bisindole compounds as DNA
binding, photocleavage agents and topoisomerase I inhibitors. Eur. J.
Med. Chem. 2018, 143, 1563−1577. (b) Yu, Q.; Guo, P.; Jian, J.; Chen,
Y.; Xu, J. Nine-step total synthesis of (−)-strychnofoline. Chem.
Commun. 2018, 54, 1125−1128. (c) Kayhan, J.; Wanner, M. J.;
Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Consecutive Pictet−
Spengler Condensations toward Bioactive 8-Benzylprotoberberines:
Highly Selective Total Syntheses of (+)-Javaberine A, (+)-Javaberine B,
and (−)-Latifolian A. Eur. J. Org. Chem. 2016, 2016, 3705−3708.
(d) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J.
Enantiopure Tetrahydro-β -carbolines via Pictet−Spengler Reactions
with N-Sulfinyl Tryptamines. Org. Lett. 2000, 2, 1955−1958.
(e) Seayad, J.; Seayad, A. M.; List, B. Catalytic Asymmetric Pictet-
Spengler Reaction. J. Am. Chem. Soc. 2006, 128, 1086−1087. (f) Wang,
S.-G.; Xia, Z.-L.; Xu, R.-Q.; Liu, X.-J.; Zheng, C.; You, S.-L.
Construction of Chiral Tetrahydro-β-Carbolines: Asymmetric Pic-
tet−Spengler Reaction of Indolyl Dihydropyridines. Angew. Chem., Int.
Ed. 2017, 56, 7440−7443.
(6) For other aza-spiroindoline syntheses, see: (a) Medley, J. W.;
Movassaghi, M. Synthesis of Spirocyclic Indolines by Interruption of
the Bischler Napieralski Reaction. Org. Lett. 2013, 15 (14), 3614−3617.
(b) White, K. L.; Mewald, M.; Movassaghi, M. Direct Observation of
Intermediates Involved in the Interruption oft he Bischler-Napieralski
Reaction. J. Org. Chem. 2015, 80, 7403−7411. (c) Antropow, A. H.;
Garcia, N. R.; White, K. L.; Movassaghi, M. Enantioselective Synthesis
of (−)-Vallesine: Late-Stage C17-Oxidation via Complex Indole
Boronation. Org. Lett. 2018, 20, 3647−3650. (d) Medley, J. W.;
Movassaghi, M. A Concise and Versatile Double-Cyclization Strategy
for the Highly Stereoselective Synthesis and Arylative Dimerization of
Aspidosperma Alkaloids. Angew. Chem., Int. Ed. 2012, 51, 4572−4576.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: darren.dixon@chem.ox.ac.uk.
ORCID
Pablo Gabriel: 0000-0002-3462-5151
Darren J. Dixon: 0000-0003-2456-5236
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the EPSRC (Leadership
Fellowship to D.J.D., Studentship to A.W.G.) and AstraZeneca
for funding. P.G. is grateful to the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine (EP/L015838/
1) for a studentship, generously supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer,
Syngenta, Takeda, UCB, and Vertex. The authors thank Prof.
Robert Paton (Colorado State University, Fort Collins, CO) for
helpful input into the mechanistic pathway. The authors thank
Heyao Shi (University of Oxford) for X-ray structure
determination and Dr. Amber L. Thompson and Dr. Kirsten
E. Christensen (Oxford Chemical Crystallography Service) for
X-ray mentoring and help.
D
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(e) Zhuo, C.-X.; Zhou, Y.; Cheng, Q.; Huang, L.; You, S.-L.
Enantioselective Construction of Spiroindolines with Three Con-
tiguous Stereogenic Centers and Chiral Tryptamine Derivatives via
Reactive Spiroindolenine Intermediates. Angew. Chem., Int. Ed. 2015,
54, 14146−14149. For a method to rearomatize aza-spiroindolines into
Pictet−Spengler-like products, see: (f) Wu, Q.-F.; Zheng, C.; Zhuo, C.-
X.; You, S.-L. Highly efficient synthesis and stereoselective migration
reactions of chiral five-membered azaspiroindolenines: scope and
mechanistic understanding. Chem. Sci. 2016, 7, 4453−4459. For
methods using more reactive acyl iminium ions, nitrilium ions, N-
sulfonyl iminium ions, or triflyl imidates, see: (g) Chambers, S. J.;
Coulthard, G.; Unsworth, W. P.; O’Brien, P.; Taylor, R. J. K. From
Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective
Synthesis and 3D Shape Analysis. Chem. - Eur. J. 2016, 22, 6496−6500.
(h) Li, Y.; Zhang, Q.; Du, Q.; Zhai, H. Rh-Catalyzed [3 + 2]
Cycloaddition of 1-Sulfonyl-1,2,3-triazoles: Access to the Framework of
Aspidosperma and Kopsia Indole Alkaloids. Org. Lett. 2016, 18, 4076−
4079. (i) Saya, J. M.; Roose, T. R.; Peek, J. J.; Weijers, B.; de Waal, T. J.
S.; Vande Velde, C. M. L.; Orru, R. V. A.; Ruijter, E. Iodospirocycliza-
tion of Tryptamine-Derived Isocyanides: Formal Total Synthesis of
Aspidofractinine. Angew. Chem., Int. Ed. 2018, 57, 15232−15236.
(j) Saya, J. M.; Oppelaar, B.; Cioc, R. C.; van der Heijden, G.; Vande
Velde, C. M. L.; Orru, R. V. A.; Ruijter, E. Synthesis of polycyclic
spiroindolines by highly diastereoselective interrupted Ugi cascade
reactions of 3-(2-isocyanoethyl)indoles. Chem. Commun. 2016, 52,
12482−12485. (k) Delgado, R.; Blakey, S. B. Cascade Annulation
Reactions To Access the Structural Cores of Stereochemically Unusual
Strychnos Alkaloids. Eur. J. Org. Chem. 2009, 2009, 1506−1510.
(7) (a) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.;
Dixon, D. J. Iridium-Catalyzed Reductive Nitro-Mannich Cyclization.
Chem. - Eur. J. 2015, 21, 111−114. (b) Tan, P. W.; Seayad, J.; Dixon, D.
J. Expeditious and Divergent Total Syntheses of Aspidosperma
Alkaloids Exploiting Iridium(I)-Catalysed Generation of Reactive
Enamine Intermediates. Angew. Chem., Int. Ed. 2016, 55, 13436−
13440. (c) Fuentes de Arriba, A. L.; Lenci, E.; Sonawane, M.; Formery,
O.; Dixon, D. J. Iridium-Catalyzed Reductive Strecker Reaction for
Late-Stage Amide and Lactam Cyanation. Angew. Chem., Int. Ed. 2017,
56, 3655−3659. (d) Xie, L.-G.; Dixon, D. J. Tertiary amine synthesis via
reductive coupling of amides with Grignard reagents. Chem. Sci. 2017,
8, 7492−7497. (e) Xie, L.-G.; Dixon, D. J. Iridium-catalyzed reductive
Ugi-type reactions of tertiary amides. Nat. Commun. 2018, 9, 2841.
(8) (a) Maresh, J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.;
Asymmetric Total Synthesis of Fasicularin by Chiral N-Alkoxyamide
Strategy. Org. Lett. 2019, 21, 1868−1871. (f) Gammack Yamagata, A.
D.; Dixon, D. J. Enantioselective Construction of the ABCDE
Pentacyclic Core of the Strychnos Alkaloids. Org. Lett. 2017, 19,
1894−1897. (g) Huang, P.-Q.; Ou, W.; Han, F. Chemoselective
reductive alkynylation of tertiary amides by Ir and Cu(I) bis-metal
sequential catalysis. Chem. Commun. 2016, 52, 11967−11970.
(h) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.;
Chida, N. An Iridium-Catalyzed Reductive Approach to Nitrones from
N-Hydroxyamides. J. Am. Chem. Soc. 2016, 138 (16), 5246−5249.
(i) Yang, Z.-P.; Lu, G.-S.; Ye, J.-L.; Huang, P.-Q. Ir-catalyzed
chemoselective reduction of β-amido esters: A versatile approach to
β-enamino esters. Tetrahedron 2019, 75 (12), 1624−1631. (j) Une, Y.;
Tahara, A.; Miyamoto, Y.; Sunada, Y.; Nagashima, H. Iridium-PPh3
Catalysts for Conversion of Amides to Enamines. Organometallics 2019,
38, 852−862. (k) Hu, X.-N.; Shen, T.-L.; Cai, D.-C.; Zheng, J.-F.;
Huang, P.-Q. Iridium-Catalysed Reductive Coupling Reaction of
Tertiary Lactams/Amides with Isocyanoacetates. Org. Chem. Front.
2018, 5, 2051−2056. For the reductive functionalization of secondary
amides, see: (l) Ou, W.; Han, F.; Hu, X.-N.; Chen, H.; Huang, P.-Q.
Iridium-catalyzed Reductive Alkylations of Secondary Amides. Angew.
Chem., Int. Ed. 2018, 57, 11354−11358. (m) Takahashi, Y.; Yoshii, R.;
Sato, T.; Chida, N. Iridium-Catalyzed Reductive Nucleophilic Addition
to Secondary Amides. Org. Lett. 2018, 20, 5705−5708.
(11) Transient silylation of the indoline nitrogen was observed,
1
consuming a further equivalent of the silane. H−31Si HMBC proved
the existence of this N−Si bond when the reaction was carried out in an
NMR tube (see the Supporting Information). However, a control
experiment on 3-methyl indole (skatole) showed that the silylation is
not occurring on the indole N−H under the reaction conditions, thus
indicating that it must be taking place on either indolenium 8c or
indoline product 10.
(12) Previous studies have found a “dual-silane” effect making TMDS
a more effective silane reducing agent. See: (a) Hanada, S.; Motoyama,
Y.; Nagashima, H. Dual Si−H effects in platinum-catalyzed silane
reduction of carboxamides leading to a practical synthetic process of
tertiary-amines involving self-encapsulation of the catalyst species into
the insoluble silicone resin formed. Tetrahedron Lett. 2006, 47, 6173−
6177. (b) Pesti, J.; Larson, G. L. Tetramethyldisiloxane: A Practical
Organosilane Reducing Agent. Org. Process Res. Dev. 2016, 20, 1164−
1181.
(13) The concentration had little effect on the yield or
diastereoselectivity.
̈
Panjikar, S.; Trout, B. L.; Stockigt, J.; Peters, B.; O’Connor, S.
(14) Double deprotonation of model substrate 7a with LDA followed
by alkylation with alkyl iodides afforded α-alkylated products 7h−7j.
Strictosidine Synthase: Mechanism of a Pictet-Spengler Catalyzing
Enzyme. J. Am. Chem. Soc. 2008, 130, 710−723. (b) Klausen, R. S.;
Kennedy, C. R.; Hyde, A. M.; Jacobsen, E. N. Chiral Thioureas Promote
Enantioselective Pictet−Spengler Cyclization by Stabilizing Every
Intermediate and Transition State in the Carboxylic Acid-Catalyzed
Reaction. J. Am. Chem. Soc. 2017, 139, 12299−12309. (c) Zheng, C.;
Xia, Z.-L.; You, S.-L. Unified Mechanistic Understandings of Pictet-
Spengler Reactions. Chem. 2018, 4, 1952−1966.
́
For similar strategies, see: (a) Amat, M.; Ramos, C.; Perez, M.; Molins,
E.; Florindo, P.; Santos, M. M. M.; Bosch, J. Enantioselective formal
synthesis of ent-rhynchophylline and ent-isorhynchophylline. Chem.
Commun. 2013, 49, 1954−1956. (b) Herrmann, J. L.; Kieczykowski, G.
R.; Normandin, S. E.; Schlessinger, R. H. High yield stereospecific total
syntheses of Eburnamonine and Eburnamine. Tetrahedron Lett. 1976,
801−804.
(9) Previous work by our group has established that both iminium and
enamine species can be accessed via reductive activation. Their fate
depends on the nature of the reaction partner and conditions (see ref 7,
in particular refs 7a−c).
(15) For these substrates, the major reaction byproduct was the
saturated cyclic amine. The reason for the loss of diastereoselectivity is
unclear, but could be attributed to the greater flexibilty of the seven-,
eight-, and nine-membered rings lowering the steric clash in the endo-
TS.
(16) We postulate that with groups bulkier than a N-Me, the increased
steric clash with the alkyl chain of the iminium ion increases the energy
of the exo-TS relative to that of the endo-TS, hence reducing the
diastereoselectivity.
(10) (a) Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.; Nagashima,
H. Highly efficient synthesis of aldenamines from carboxamides by
iridium-catalyzed silane-reduction/dehydration under mild conditions.
Chem. Commun. 2009, 12, 1574−1576. (b) Nakajima, M.; Sato, T.;
Chida, N. Iridium-Catalyzed Chemoselective Reductive Nucleophilic
Addition to N-Methoxyamides. Org. Lett. 2015, 17, 1696−1699.
(c) Nakayama, Y.; Maeda, Y.; Kotatsu, M.; Sekiya, R.; Ichiki, M.; Sato,
T.; Chida, N. Enantioselective Total Synthesis of (+)-Neostenine.
Chem. - Eur. J. 2016, 22, 3300−3303. (d) Yoritate, M.; Takahashi, Y.;
Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.;
Chida, N. Unified Total Synthesis of Stemoamide-Type Alkaloids by
Chemoselective Assembly of Five-Membered Building Blocks. J. Am.
Chem. Soc. 2017, 139, 18386−18391. (e) Yamamoto, S.; Komiya, Y.;
Kobayashi, A.; Minamikawa, R.; Oishi, T.; Sato, T.; Chida, N.
(17) This method is complementary to those developed by Taylor (ref
6g) and Movassaghi (ref 6a) as the opposite diastereoselectivity is
observed.
E
DOI: 10.1021/acs.orglett.9b02194
Org. Lett. XXXX, XXX, XXX−XXX