Synthesis of pyrroloindolines through formal [3 + 2]-cycloaddition of indoles with chiral N-2-acetamidoacrylyl oxazolidinones

Article abstract of DOI:10.1016/j.tetlet.2020.151947

Chiral N-2-acetamidoacrylyl oxazolidinones were produced and reacted with indoles under Lewis acid conditions to generate hexahydropyrrolo[2,3-b]indole products in a formal [3 + 2] cycloaddition process. Optimal conditions included the use of tin(IV) chloride in methylene chloride at 0 °C. Pyrroloindoline products were obtained from various indoles with shorter reaction times (12 hr) up to 91% yield with high, >20:1 exo selectivity. A mechanism involving reversible conjugate addition followed by an enamine lone-pair-iminium capture, tautomerization, and tin-enolate protonation accounts for the selectivity. The method enables selective applications to pyrroloindoline targets and further refinement with chiral catalysts.

Full text of DOI:10.1016/j.tetlet.2020.151947

Journal Pre-proofs
Synthesis of pyrroloindolines through formal [3+2]-cycloaddition of indoles
with chiral N-2-acetamidoacrylyl oxazolidinones
Isaac T. Smith, Jared B. Neeley, Tanner D. Brinley, Peter R. Fullmer, Merritt
B. Andrus
PII:
S0040-4039(20)30390-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151947
TETL 151947
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Tetrahedron Letters
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10 February 2020
7 April 2020
13 April 2020
Please cite this article as: Smith, I.T., Neeley, J.B., Brinley, T.D., Fullmer, P.R., Andrus, M.B., Synthesis of
pyrroloindolines through formal [3+2]-cycloaddition of indoles with chiral N-2-acetamidoacrylyl oxazolidinones,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151947
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Synthesis of Pyrroloindolines through
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Formal [3+2]-Cycloaddition of Indoles with
Chiral N-2-Acetamidoacrylyl Oxazolidinones
Isaac T. Smith, Jared B. Neeley, Tanner D. Brinley, Peter R. Fullmer, Merritt B. Andrus*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of pyrroloindolines through formal [3+2]-cycloaddition of indoles with
chiral N-2-acetamidoacrylyl oxazolidinones
Isaac T. Smith, Jared B. Neeley, Tanner D. Brinley, Peter R. Fullmer, Merritt B. Andrus*
Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, Utah 84602, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Chiral N-2-acetamidoacrylyl oxazolidinones were produced and reacted with indoles under
Lewis acid conditions to generate hexahydropyrrolo[2,3-b]indole products in a formal [3+2]
cycloaddition process. Optimal conditions included the use of tin(IV) chloride in methylene
chloride at 0 °C. Pyrroloindoline products were obtained from various indoles with shorter
reaction times (12 hr) up to 91% yield with high, >20:1 exo selectivity. A mechanism involving
reversible conjugate addition followed by an enamine lone-pair-iminium capture,
tautomerization, and tin-enolate protonation accounts for the selectivity. The method enables
selective applications to pyrroloindoline targets and further refinement with chiral catalysts.
Available online
Keywords:
pyrroloindoline
oxazolidinone
[3,2]-cycloaddition
Tin(IV) chloride
2020 Elsevier Ltd. All rights reserved.
Introduction
Pyrroloindoline (hexahydropyrrolo[2,3-b]indole) containing natural products constitute an important class of alkaloids that possess
challenging structural features and diverse biological activities.1 Derived bio-synthetically through tryptophan cyclization, these agents
hold medicinal value and potential as seen with physostigmine, isolated from the calabar bean, used to treat glaucoma and gastric
disorders (Scheme 1).2 Common pyrroloindoline polycyclic variations include diketopiperidines, typified by norcadioazine A, which
possesses an unusual epoxide containing tether, and the more complex dimeric calycanthine/chimonanthine type compounds joined
contiguous indole C3-quaternary stereocenters.3 Variations include prenylation, hydroxylation, and N-indole substitutions at the C3-
pyrroloindoline position and numerous disulfide diketopiperidine variations.1 A highly selective synthesis of the pyrroloindoline core
common to these agents is now reported using a formal [3+2]-cycloaddition of indoles reacted with chiral acetamidoacrylate substituted
oxazolidinones.
Synthetic approaches to pyrroloindolines commonly involve cyclization of tryptophan derivatives initiated by C3-protonation1a and
other electrophilic halogen,4 sulfur, and selenium-based reagents.5 Cyclization has also been developed for oxygen and nitrogen based
reagents giving C3-hydroxy and amino products.6 Allyl and aryl couplings with indoles at C3 also lead to pyrroloindolines in similar
fashion using transition-metal catalysis.7 More recent routes to pyrroloindolines from indoles include the use of aziridines,8
phenyltriazoles,9 conjugated enones under organo-catalysis,10 intramolecular photo-catalysis with aryloxyamides,11 and reductive
coupling of tethered malonic diamides.12 Multistep alkylation routes using amino oxindoles also generate pyrroloindolines upon
reductive cyclization.13 Other routes include the use of anilines reacted with isocyanoacetate,14 ketonitrones with activated alkynes,15
and intramolecular reactions with aryl isocyanate amides.16

2
Tetrahedron Letters
Piersanti and co-workers reported a new, formal [3+2]-cycloaddition approach to pyrroloindolines using zirconium(IV) chloride
Lewis acid (2 equiv.) with indoles 1 added to methyl N-acetamidoacrylate 2 (Scheme 2). Exo-products 3 were obtained as the major
diastereomer with up to 9:1 selectivity in modest yield.17 Reisman and co-workers concurrently developed an enantioselective [3+2]
approach using (R)-BINOL (20 mol%) and tin(IV) chloride (1.2 equiv.) at room temperature employing the more selective substrate,
N-trifluoroacetamidoacrylate adding to indoles.18 The exo-product was favored with modest 3:1 to 6:1 selectivity over the minor endo-
isomer. Yields were good to excellent with enantiomeric excesses ranging from 84 to 94% for various indole substrates. Epimerization
using DBU was shown to provide access to the thermodynamic endo-isomer (10:1). Follow up publications included an analysis of the
step-wise mechanism and a multistep synthetic application.19
Results and Discussion
In an effort to access pyrroloindolines with enhanced exo-
selectivity and to explore a wider range of acetamidoacrylate
reactivity, new chiral auxiliary based substrates were envisioned.
Enhanced reactivity was anticipated through bidentate two-point
Lewis acid binding using acyl oxazolidinones,20 in contrast to the
single point binding of previous acetamidoacrylate esters 2.
Oxazolidinone auxiliaries remain the standard for many asymmetric
transformations, including alkylation, aldol, and cycloadditions, and
they also often serve as the starting point for catalytic asymmetric
development with achiral oxazolidinone substrates.21
To initiate the effort, new acetamidoacrylate substituted
oxazolidinones were designed and produced (Figure 1). Known (S)-
4-benzyl-N-methacryloxazolidin-2-one 422 was treated with ozone
to access the pyruvyl derivative 5.23 Direct acylation efforts to form
5 using either pyruvic acid or pyruvyl chloride were unsuccessful.
Oxime 6 was generated allowing for production of either the
acetamidoacrylate or the trifluoro acetamidoacrylate 7 using
trifluoroacetic acid (TFA) and the anhydride (TFAA) reacted with
iron powder in DMF (52 °C).24
Conditions for the formal [3+2] reaction of the
acetamidoacrylates 7 with 1,3-dimethylindole 1 were explored
using various Lewis acids to generate the desired pyrroloindoline
product 8 (Table 1). Reactions with acetamidoacrylate (R=Me) 7 and 1 performed at –78 °C with various Lewis acids and equivalents
gave no product formation (entry 1). Reaction of 1 and 7 (1:1 equiv.) with SnCl4 (1.2 equiv.) added last at 0 °C or at room temperature
in methylene chloride for 24 hours, gave product 8 in 69% isolated yield (entries 2,3). Diastereoselectivity was poor at 1:3.2 and 1:1
exo/endo ratio in these cases. Only two of the four possible diastereomeric products were obtained in these reactions. Use of TiCl4
added last gave product in lower yield, 40% with improved selectivity to 5:1 exo/endo (entry 4). Adding TiCl4 first to 7 followed by
addition of 1 led to increased yield to 77% and selectivity, 6:1 (entry 5). Trifluoroacetamidoacrylate 7 (R=CF3) was found to react at
faster rates and higher selectivity.

3
Use of Lewis acid added first to 7 (R=CF3), followed by 1 at room temperature for 3 hours, gave product exo-8 as a single isomer
(>20:1, entries 6). Extended reaction times at room temperature did not improve the yield. Use of SnCl4 at 0 °C for 3 hours surprisingly
eroded the selectivity to 4:1 exo/endo (entry 7). The same conditions for 6 hours improved both the yield (84%) and selectivity (6:1,
entry 8). Extended time (72hr) at 0 °C was found to give optimal yield (85%) with complete selectivity, >20:1. Equilibrium favoring the
1
exo-Lewis acid complex may account for these findings. Diagnostic H NMR signals at 6.54 ppm for exo-8 and 6.47 ppm for endo-8
were used to assign the selectivity, in accord with previous results with the methyl acetamido acrylate substrate 2.18 Both exo-8 and
endo-8 isomers are observed as ~3:1 mixtures of N-amide rotamers by NMR.
The major product 8 exo was confirmed by conversion and comparison to the known exo methyl ester product as discussed below.
An X-ray structure was also obtained from a product with an indole variant used to explore the scope of the process below. The two
other diastereomeric products, iso 8 exo and iso 8 endo, were not seen under the conditions explored, being formed in only trace
amounts (Scheme 3).
The optimal SnCl4 conditions developed using dimethylindole 1 were applied to various indole substrates to explore the scope of the
process (Table 2). High selectivity was seen with 1 reacted for 72 hours, 85% yield. Electron deficient 5-Fluoro 9 required 27 hours
reacting with 7 giving the pyrroloindoline product 10 with complete exo-selectivity in 83% isolated yield. More hindered N-Methyl
tetrahydrocarbazole 11 reacted to access product 12 in reduced yield. Single crystal X-ray analysis of product 12 confirmed the absolute
exo-stereochemistry as indicated (supplementary material). 5-Methoxy-1,3-dimethylindole 13 reacted (12 hr) with acetamidoacrylate 7
with high exo-selectivity and yield, 89% to access product 14. 3-Allyl-1-methylindole 15 reacted to give 16 in 91% yield with excellent
exo-selectivity (12 hr). 1-Allyl-3-methylindole 17 required 24 hr to generate product 18 with the selectivity lowered to 6:1 exo/endo
ratio obtained.
Acylated oxazolidinones are readily converted to the corresponding carboxylic acids using base mediated hydrolysis.21c The versatile
Weinreb N-methoxy-N- methylamide can also be formed in one step. Alternatively, reductive conditions can be used to access alcohols.
In the case of exo-product 8, the known methyl ester exo- 19 was directly obtained from exo-8 using ytterbium(III) triflate-methanol
conditions reported recently by Stevens and Frantz (Figure 2).25 The deacylated oxazolidinone was also recovered in this step. Spectral
data for ester exo-19 matched that reported previously.18,19 Treatment with DBU was reported previously with exo-19 to access the more
stable thermodynamic endo-20 isomer with 10:1 selectivity (85%).1,18,19

4
Tetrahedron Letters
The origin of the diastereoselectivity for the process appears to result from the Lewis acid-acetamidoacrylate 7 s-cis complex
(Scheme 4). Nucleophilic conjugate attack by the indole 1 below the plane of alkene, as indicated away from the S-oxazolidinone
benzyl moiety, sets the indole 3-position stereocenter. Planar chelation activation has been established for acrylate oxazolidinones for
asymmetric Diels-Alder and other related electrophilic transformations.21 This initial addition step is assumed to be reversible in accord
with the mechanistic findings of Reisman under similar tin(IV) chloride conditions at room temperature.19a Reversibility of this iminium
Lewis acid complex may account for the improved selectivity observed with extended reactions times (Table 1). The pyrrole
intermediate is then formed upon enamine lone pair addition to the indole iminium ion. The trifluoroacetamide rotates away from the
oxazolidinone benzyl group placing the attached proton trans-disposed relative to the adjacent ring fusion proton. This and subsequent
steps are presumed to be faster for the diastereomeric intermediate shown. Tautomerization to an imidic acid then provides a suitable
proton source to set the final stereocenter. This differs from the BINOL-tin(IV) chloride conditions where the phenol complex functions
as the proton source. The imidic proton transfers to the tin enolate from the same face to generate the kinetic pyrroloindoline exo-
product 8. This step places the oxazolidinone benzyl group anti-disposed to the trifluoromethyl amide moiety. High 20:1 exo-selectivity
in this case may be attributed to the enhanced size of the oxazolidinone substrate and the reactivity of the chelated enolate. Previous
selectivities with methyl acetamidoacrylates were more modest with 6:1 exo/endo diastereoselectivity.17–19
Conclusions
A new approach to asymmetric pyrroloindoline formation has been developed using chiral acetamidoacrylyl oxazolidinones reacted
under Lewis acid conditions. The kinetic exo-products were obtained with high selectivity with a broad range of indole substrates. A
model for the origin of the stereoselectivity involves reversible conjugate addition, equilibration of the Lewis acid complex, lone-pair
attack, and tin-enolate protonation steps. C3 and C5-indole variations along with N-1 substituents react with high yield and near
complete exo-selectivity. The exo products can be readily epimerized to the endo-isomers allowing for flexibility with target directed,
multi-step applications. The product is converted to the known methyl ester in one step; however, the auxiliary synthesis and removal
detract from the overall efficiency compared to the catalytic BINOL method.18,19 Success with this new bi-dentate acetamidoacrylyl
oxazolidinone provides a means to achieve high diastereoselectivity and a basis for further development with chiral catalysts. Other
asymmetric transformations can also be envisioned using this versatile acetamidoacrylate substrate based on these promising findings.
Declaration of Competing Interest
The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
Financial support was provided by the Simmons Cancer Center at Brigham Young University to I.T.S. Undergraduate research
awards were provided to J.N., T.D.B., P.F. by the Department of Chemistry and Biochemistry.

5
Supplementary Material
Supplementary material to this article can be found online at https://doi.org.
Experimental procedures, characterization, 1H, 13C NMR spectra, X-ray crystallography (PDF)
References
[1] (a) D. Crich, A. Banerjee, Acc. Chem. Res. 40 (2007) 151. (b) P. Ruiz-Sanchis, S.A. Savina, F. Alberico, M. Álvarez, Chem. Eur. J. 17 (2011) 1388.
[2] R. Raju, A.M. Piggott, X.-C. Huang, R.J. Capon, Org. Lett. 13, (2011) 2770.
[3] (a) A. Steven, L.E. Overman, Angew. Chem. Int. Ed. 46 (2007) 5488. (b) P. Lindovska, M. Movassaghi, J. Am. Chem. Soc. 139 (2017) 17590.
[4] (a) P. Ruiz-Sanchis, S.A. Savina, G.A. Acosta, F. Alberico, M. Álvarez, Eur. J. Org. Chem. (2012) 67. (b) W. Xie, G. Jiang, H. Liu, J. Hu, X. Pan,
H. Zhang, X. Wan, Y. Lai, D. Ma, Angew. Chem. Int Ed. 52 (2013) 12924. (c) N. Shibata, T. Tarui, Y. Doi, K.L. Kirk, Angew. Chem. Int. Ed. 40
(2001) 4461.
[5] (a) M. Tayu, Y. Hui, S. Takeda, K. Higuchi, N. Saito, T. Kawasaki, Org. Lett. 19 (2017) 6582. (b) S.P. Marsden, K.M. Depew, S.J. Danishefsky, J.
Am. Chem. Soc. 116 (1994) 11143.
[6] (a) L. Zhao, J.P. May, J. Huang, D.M. Perrin, Org. Lett. 14 (2012) 90. (b) T.M. Kamenecka, S.J. Daniskefsky, Angew. Chem. Int. Ed. 37 (1999)
2995. (c) Y. Li, L. Li, X. Lu, Y. Bai, Y. Wang, Y. Wu, F. Zhong, Chem. Commun. 55 (2019) 63. (d) E.C. Gentry, L.J. Rono, M.E. Hale, R.
Matsuura, R.R. Knowles, J. Am. Chem. Soc. 140 (2018) 3394. (e) Q. Li, T. Xia, L. Yao, H. Deng, X. Liao, Chem. Sci. 6 (2015) 3599. (f) Z. Shen,
Z. Xia, H. Zhao, J. Hu, X. Wan, Y. Lai, C. Zhu, W. Xie, Org. Biol. Chem. 13 (2015) 5381.
[7] (a) B.M. Trost, J. Quancard, J. Am. Chem. Soc. 128 (2006) 6314. (b) J.M. Müller, C.B.W. Stark, Angew. Chem. Int. Ed. 55 (2016) 4798. (c) H.
Hakamata, S. Sato, H. Ueda, H. Tokuyama, Org. Lett. 19 (2017) 5308. (d) S. Zhu, D.W.C. MacMillan, J. Am. Chem. Soc. 134 (2012) 10815. (e)
M.E. Kieffer, K.V. Chuang, S.E. Reisman, Chem. Sci. 3 (2012) 3170. (f) X. Chen, J. Fan, G. Zeng, J. Ma, C. Wang, Y. Wang, Y. Zhou, X. Deng,
J. Org. Chem. 83 (2018) 8322.
[8] (a) J.-Q. Zhang, F. Tong, B.-B. Sun, W.-T. Fan, J.-B. Chen, D. Hu, X.-W. Wang, J. Org. Chem. 83 (2018) 2882. (b) D.J. Rivinoja, Y.S. Gee, M.G.
Gardiner, J.H. Ryan, C.J.T. Hyland, J. Org. Chem. 82 (2017) 13517. (c) Z. Chai, Y.-M. Zhu, P.-J. Yang, S. Wang, S. Wang, Z. Liu, G. Yang, J.
Am. Chem. Soc. 137 (2015) 10088. (d) L. Wang, D. Yang, F. Han, D. Li, D. Zhao, R. Wang, Org. Lett. 17 (2015) 176.
[9] J.E. Spangler, H.M.L. Davies, J. Am. Chem. Soc. 135 (2013) 6802.
[10] (a) Q. Cai, C. Liu, X.-W. Liang, S.-L. You, Org. Lett. 14 (2012) 4588. (b) J.F. Austin, S.-G. Kim, C.J. Sinz, W.-J. Xiao, D.W.C. MacMillan, Proc.
Nat. Acad. Sci. 101 (2004) 5482.
[11] (a) K. Wu, Y. Du, T. Wang, Org. Lett. 19 (2017) 5669.
[12] F. Fan, W. Xie, D. Ma, Chem. Commun. 48 (2012) 7571.
[13] (a) X. Shen, J. Zhao, Y. Xi, W. Chen, Y. Zhao, X. Yang, H. Zhang, J. Org. Chem. 83 (2018) 14507. (b) A. Singh, G.P. Roth, Tetrahedron Lett. 53
(2012) 4889. (c) T. Bui, S. Syed, C.F. Barbas III, J. Am. Chem. Soc. 131 (2009) 8758.
[14] H. Cheng, R. Zhang, S. Yang, M. Wang, X. Zeng, L. Xie, C. Xie, J. Wu, G. Zhong, Adv. Synth. Catal. 358 (2016) 970.
[15] C.B. Huehls, J. Huang, J. Yang, Tetrahedron 71 (2015) 3593.
[16] P.C. Knipe, M. Gredičak, A. Cernijenko, R.S. Paton, M.D. Smith, Chem. Eur. J. 20 (2014) 3005.
[17] S. Lucarini, F. Bartoccini, F. Battistoni, G. Diamantini, G. Piersanti, M. Righi, G. Spadoni, Org. Lett. 12 (2010) 3844.
[18] L.M. Repka, J. Ni, S.E. Reisman, J. Am. Chem. Soc. 132 (2010) 14418.
[19] (a) J. Ni, H. Wang, S.E. Reisman, Tetrahedron 69 (2013) 5622. (b) H. Wang, S.E. Reisman, Angew. Chem. Int. Ed. 53 (2014) 6206.
[20] (a) M.M. Heravi, V. Zadsirjan, B. Farajpour, RSC Adv. 2016, 6, 30498–30551. (b) Heravi, M. M.; Zadsirjan, V. Tetrahedron Asymm. 2013, 24,
1149–1188.
[21] (a) Li, M.; Carreras, V.; Jalba, A.; Ollevier, T. Org. Lett. 20 (2018) 995. (b) A. Sakakura, R. Kondo, Y. Matsumura, M. Akakura, K. Ishihara, J.
Am. Chem. Soc. 131 (2009) 17762. (c) D.A. Evans, D.M. Barnes, J.S. Johnson, T. Lectka, P. von Matt, S.J. Miller, J.A. Murry, R.D. Norcross,
E.A. Shaughnessy, K.R. Campos, J. Am. Chem. Soc. 121 (1999) 7582.
[22] T. Hosokawa, T. Yamanaka, M. Itotani, S. Murahashi, S. J. Org. Chem. 60 (1995) 6159.
[23] J.F. Bower, A.J. Williams, H.L. Woodward, P. Szeto, R.M. Lawrence, T. Gallagher, Org. Biomol. Chem. 5 (2007) 2636.
[24] (a) F. Heaney, J. Fenlon, P. McArdle, D. Cunningham, Org. Biomol. Chem. 1 (2003) 1122. (b) M.J. Burk, G. Casy, N.B. Johnson, J. Org. Chem.
63 (1998) 6084.
[25] J.M. Stevens, A.C. Parra-Rivera, D.D. Dixon, G.L. Beutner, A.J. Del Monte, D.E. Frantz, J.M. Janey, J. Paulson, M.R. Talley, J. Org. Chem. 83
(2018) 14245.
Highlights
• Chiral acetamide oxazolidinones produced
• Reactions with indoles gave pyrroloindoline products
• This structure is found in many natural products
• Numerous indoles gave up to 91% yield with high selectivity

6
Tetrahedron
Table 1. [3+2]-Cycloaddition to pyrroloindolines 8 exo and 8 endo.
entry R=
LA
LA
order
time,
hr
temp
°C
yield
%
8 exo/
a
endob
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
SnCl4 last
SnCl4 last
SnCl4 last
24
–78
-
24
24
24
24
3
0
rt
0
69
69
40
77
59
43
84
85
1:3.2
1:1
TiCl4
TiCl4
last
5:1
first
0
6:1
SnCl4 first
SnCl4 first
SnCl4 first
SnCl4 first
rt
0
>20:1
4:1
3
6
0
6:1
72
0
>20:1
aIsolated yield following silica gel chromatography.
bSelectivity determined by 1H NMR.