CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0025-0029
DOI: 10.1055/s-0037-1609082
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Cycloaddition of Benzyne with Alkoxy-Substituted Pyrroline-N-oxides­: Unexpected Rearrangement to an N-Phenylpyrrole

a  Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
b  Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
,
Bhushan B. Khairnar
a  Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
,
Anna Ranzenigo
a  Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
b  Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
,
a  Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
b  Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
› Author Affiliations
The authors thank the Italian Ministry of Education, University and Research (MIUR-Rome), for financial support (PRIN20109Z2XRJ). C.I.N.M.P.I.S. is acknowledged for partial financial support of a Fellowship for A. R. Mrs. Nesrin Yumitkan, an Erasmus Placement student from Uludağ University (Turkey), is acknowledged for her contribution to this work.
Further Information

Publication History

Received: 04 December 2017

Accepted after revision: 04 January 2018

Publication Date:
31 January 2018 (online)

 

Abstract

Reaction of enantiopure 3,4-dialkoxy-pyrroline N-oxides with benzyne affords the expected tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazoles along with an unexpected 2,3-disubstitued-N-phenyl-pyrrole derived from an unprecedented rearrangement of the adduct of nitrone with two molecules of benzyne. A mechanism for the unusual rearrangement is proposed. The benzo[d]isoxazolidine derivatives are conveniently converted into 2-(2-hydroxyphenyl)-3,4-dialkoxypyrrolidines by reductive opening of the N–O bond.


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Highly reactive arynes are recognized as an important synthetic tool in organic synthesis. The development of milder methods for the generation of arynes has increased the interest in employing them in the synthesis of complex polycyclic systems and in the total synthesis of natural products.[1] The use of ortho-silyl aryl triflates as aryne precursors by Kobayashi has enabled the generation of the reactive intermediate under almost neutral conditions.[2] Cycloaddition reactions of arynes have the advantage of functionalizing instantly an aromatic ring by forming multiple carbon–carbon or carbon–heteroatom bonds in a single step. Among these processes, 1,3-dipolar cycloaddition of hydroxylated pyrroline N-oxide nitrones with arynes can be a useful entry to analogues of bioactive natural products such as the codonopsinine and radicamine alkaloids[3] (Figure [1]), according to the strategy outlined in Scheme [1].[4]

Hydroxylated pyrroline N-oxides are a class of compounds readily achievable from natural sources through straightforward high yielding procedures.[5] In our group, 3,4-dialkoxy pyrroline N-oxides have been widely used in the synthesis of bioactive pyrrolidine, pyrrolizidine, and indolizidine heterocycles.[6]

Zoom Image
Figure 1 Structures of natural pyrrolidines codonopsinine and radicamine B
Zoom Image
Scheme 1 Retrosynthetic analysis of 2-aryl-polyhydroxy-pyrrolidines

Although several dipoles have been systematically studied for their reactivity with arynes, leading to interesting heterocycles, only a few nitrones, mostly acyclic and achiral ones, have been investigated as dipole partners for arynes.[7] [8] Following the seminal work of Kaliappan’s goup,[4] we studied the cycloaddition of dialkoxypyrroline N-oxides with benzyne as another entry to radicamine or codono­psinine analogues. In particular, the lack of substitution on C-5 of the nitrone could allow the introduction of various substituents by following the well-known alkylation of the nitrone following the oxidative opening of the hexahydropyrrolo[1,2-b]isoxazolidine ring.[5] [9]

The 1,3-dipolar cycloaddition of 3,4-bis-tert-butoxypyrroline-N-oxide (1a)[6d] with 2.4 equivalents of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2) in the presence of CsF as fluoride source in anhydrous tetrahydrofuran (THF) afforded two new diastereomeric cycloadducts 3 and 4 with low diastereoselectivity (58–64% ds) along with an unexpected third product, which was found to be the pyrrole derivate 5a (see below) (Scheme [2] and Table [1]).

In particular, the reaction of 1a with 2.4 equivalents of 2 in the presence of an excess of CsF in THF was not complete at room temperature after 5 days and afforded 3 and 4 in 57% overall yield along with traces of 5a (Table [1], entry 1). By heating at 65 °C, adducts 3 and 4 were obtained with a similar overall yield (56%), whereas 5a was isolated in 18% yield (entry 2). In this case, the conversion was incomplete and unreacted nitrone was recovered after chromatography.

In the presence of 3 equivalents of 2, nitrone 1a was completely consumed (TLC analysis) after 20 h at room temperature, affording 3 and 4 in 71% overall yield along with 23% 5a (Table [1], entry 3). Lower yields of the products were obtained when the same reaction was performed at 60 °C (entry 4). When MeCN was used as solvent, nitrone 1a was totally consumed after only 2 h at room temperature, but unfortunately analysis of the reaction mixture showed that pyrrole 5a was the main product (29%) whereas adducts 3 and 4 were only present in trace amounts (entry 5).

Zoom Image
Scheme 2 Cycloaddition reactions of nitrones 1a and 1b with benzyne

Table 1 Optimization of Cycloaddition Reaction of Nitrone 1a with Benzyne

Entry

2 (equiv)

Fluoride source (equiv)

Reaction conditions

Yield (%)a

3

4

5

1

2.4b

CsF (6)

THF, r.t., 5 d

37 (41)

20 (22)

trace

2

2.4b

CsF (6)

THF, 65 °C, 39 h

33 (39)

23 (27)

18 (22)

3

3

CsF (6)

THF, r.t., 20 h

41

30

23

4

3

CsF (6)

THF, 60 °C, 23 h

35

20

15

5

3

CsF (6)

MeCN, r.t., 2 h

trace

trace

29

6

1.5

Bu4NF (1.2)

DMF, r.t., 2.5 h

39

29

13

a Isolated yield after chromatography; yields based on conversion given in parentheses.

b Nitrone conversion: 91% (entry 1), 83% (entry 2).

Finally, the best result was observed by using Bu4NF as fluoride source and anhydrous DMF as solvent. In this case, a lower excess of 2 was necessary (1.5 equiv) to consume 1a at room temperature.[10] The reaction was faster than in THF and after only 2.5 h, 3 and 4 were obtained in an acceptable 68% overall yield (1.3:1 ratio) along with 5a (13% yield) (Table [1], entry 6).

Major and minor adducts 3a [11] and 4a [12] form as the result of anti-3-OtBu and syn-3-OtBu approach, respectively, of benzyne to nitrone 1a. The relative configuration was assigned on the basis of a less intense NOE difference effect between hydrogens 1-H and 9b-H in 3a than in 3b (1% vs. 2%) in accord with the proposed structures.

Comparing our results with those obtained by Kaliappan,[4] the cycloaddition yields are similar. In contrast, however, the diastereoselectivity observed is poor in our case. This is likely due to the third benzyloxy substituent on the nitrones such as C (R′ = Bn; R = CH2OBn, Scheme [1]) used by Kaliappan, which can induce a much higher diastereofacial control in cycloadditions.[5] [9b] [9c] [13]

As noted above, side product 5a was always found in the reaction mixture with a yield up to 29%, according to the different reaction conditions. Compound 5a contains a phenol substituted pyrrole ring, a substructure that recalls the occurrence of a cycloaddition process, but the pyrrolidine ring, besides aromatization, has lost a t-BuO substituent, and, moreover, has undergone N-phenyl substitution. Structure 5a was readily assigned by NMR spectroscopic analysis.[14] In particular, 1H NMR deuterium exchange experiments showed that the singlet at 8.18 ppm disappears on addition of D2O, consistent with the presence of a phenol moiety. Moreover, the NMR resonances corresponding to 4-H and 5-H [6.14 and 6.84 ppm (d, J = 3.2 Hz)] and C-4 and C-5 [105.1 ppm (dd, J = 173.3, 7.2 Hz) and 122.4 (dd, J = 187.6, 7.0 Hz)] are very similar to the corresponding signals previously measured on analogously substituted pyrroles.[15]

Switching to a differently protected nitrone, bis-benzoyloxy nitrone 1b [6c] was reacted with benzyne under the same conditions (Bu4NF/DMF/r.t.).[10] The reaction afforded an inseparable mixture of cycloadducts 3b and 4b, and, again, the corresponding pyrrole derivative 5b in roughly 1.1:1:0.4 ratio, respectively. In this case, as expected, the cycloaddition diastereoselectivity was lower compared with the corresponding cycloaddition of 1a, because of the minor steric demand of the benzoyloxy group. Adducts 3b and 4b are characterized by 1-H/9b-H coupling constant values similar to the corresponding tert-butoxy derivatives 3a and 4a [J 1/9b(Hz): 3a and 3b ca. 0; 4a and 4b 6.8 and 6.3]. The 1H NMR spectrum of pyrrole 5b shows the same AX system of 5a due to the resonance of protons 4-H and 5-H [7.02 and 6.43 ppm (d, J = 3.2 Hz)].

It has therefore been demonstrated that formation of the side-product 5 occurs in the presence of both the tert-butyl and benzoyl protecting groups. Moreover, control experiments of mixing 4a with 2 under the usual reaction conditions established that 5 originates from reaction of a molecule of cycloadduct with a second molecule of benzyne.

The mechanism shown in Scheme [3] is consistent with the experimental data. The rather nucleophilic cycloadduct adds to the electrophilic benzyne, which, in turn, can extract the benzylic 9b-H proton. Intermediate I then undergoes N–O bond cleavage to II. Intramolecular deprotonation and aromatization by elimination of a molecule of ROH provides pyrrole 5.

To our knowledge this is the first example of such a rearrangement of nitrone-aryne cycloadducts. In Kaliappan’s work[4] there is no mention of such a rearrangement product. However, the absence of the side product in those reactions can be explained by the lower nucleophilicity of the isoxazolidine nitrogen in B (R′ = Bn; R = CH2OBn, Scheme [1]), which is shielded by a bulky adjacent benzyloxymethylene group.

Zoom Image
Scheme 3 Proposed mechanism for conversion of adducts 3 and 4 into pyrrole 5

Cycloadduct 3a was smoothly reduced with Zn in acetic acid/water (1:1) at 70 °C for 2 h to obtain o-hydroxyaryl pyrrolidine 6a [16] in 75% yield (Scheme [4]).

Zoom Image
Scheme 4 Reduction of 3a

The inseparable cycloaddition mixture of 3b, 4b, and 5b was more conveniently reduced by hydrogenation on Pd/C to obtain pyrrolidines 6b [17] and 7b [18] and pyrrole 5b [19] in 29, 27, and 8% two-step yield, respectively, after chromatographic separation (Scheme [5]).

Zoom Image
Scheme 5 Cycloaddition of 1b with aryne and reduction of the resulting reaction mixture

In summary, 1,3-dipolar cycloaddition of enantiopure cyclic nitrones 1 with benzyne affords benzisoxazole derivatives that can be employed to produce analogues of radicamine and codonopsinine alkaloids; this is work that is in progress in our laboratory. The adducts of both 3,4-di-tert-butoxy- and 3,4-bis(benzoyloxy)-pyrroline N-oxides 1 with benzyne undergo an unprecedented rearrangement involving a second molecule of benzyne under the reaction conditions. This novel rearrangement influences the overall yield of the cycloaddition process and should be taken into consideration by the scientific community involved in studies of alkoxypyrroline nitrone reactions with arynes.


#

Supporting Information

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  • 10 General Procedure for the Cycloaddition Reaction: A mixture of nitrone 1 (300 mg), 2 (1.5 equiv), and Bu4NF (1 M in THF, 1.2 equiv) in anhydrous DMF (final nitrone concentration of 0.09–0.1 M) was stirred at room temperature for 2.5 h. The DMF was evaporated under a flow of nitrogen and the crude residue was purified by chromatography on silica gel
  • 11 Compound 3a: Rf  = 0.33 (EtOAc/petroleum ether, 1:16); [α]D 24 = –90.6 (c = 0.25, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.25 (dm, J = 7.4 Hz, 1 H, 9-H), 7.17–7.12 (m, 1 H, 7-H), 6.90 (pseudo dt, J = 0.9, 7.4 Hz, 1 H, 8-H), 6.73 (br d, J = 8.0 Hz, 1 H, 6-H), 4.77 (br s, 1 H, 9b-H), 4.13–4.10 (m, 1 H, 1-H), 3.96 (ddd, J = 6.0, 4.9, 3.6 Hz, 1 H, 2-H), 3.58 (dd, J = 11.6, 4.9 Hz, 1 H, 3-Ha), 3.16 (ddm, J = 11.6, 6.0 Hz, 1 H, 3-Hb), 1.29 (s, 9 H, 3 × CH3), 1.06 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 156.3 (s, C-5a), 128.5 (d, C-7), 127.1 (s, C-9a), 123.4 (d, C-9), 120.9 (d, C-8), 107.1 (d, C-6), 82.0 (d, C-1), 76.6 (d, C-2), 75.6 (d, C-9b), 74.5 (s, CMe3), 73.6 (s, CMe3), 62.1 (t, C-3), 28.7 (q, 3C, 3 × CH3), 28.3 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2871, 1597, 1480, 1456, 1390, 1365, 1253, 1190, 1099, 1079 cm–1. MS (+ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.56; H, 8.69; N, 4.98
  • 12 Compound 4a: Rf  = 0.23 (EtOAc/petroleum ether, 1:16). [α]D 21 = –12.7 (c = 0.22, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.32 (br d, J = 7.5 Hz, 1 H, 9-H), 7.17 (pseudo tm, J = 8.0 Hz, 1 H, 7-H), 6.91 (pseudo dt, J = 0.8, 7.4 Hz, 1 H, 8-H), 6.76 (br d, J = 8.1 Hz, 1 H, 6-H), 4.87 (d, J = 6.8 Hz, 1 H, 9b-H), 4.24 (pseudo t, J = 7.2 Hz, 1 H, 1-H), 3.82 (pseudo q, J = 7.9 Hz, 1 H, 2-H), 3.49 (dd, J = 14.0, 7.6 Hz, 1 H, 3-Ha), 3.23 (dd, J = 14.0, 8.6 Hz, 1 H, 3-Hb), 1.28 (s, 9 H, 3 × CH3), 1.11 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 157.2 (s, C-5a), 128.4 (d, C-7), 125.9 (d, C-9), 125.2 (s, C-9a), 120.8 (d, C-8), 107.2 (d, C-6), 77.6 (d, C-1), 74.3 (s, CMe3), 73.7 (s, CMe3), 73.0 (d, C-2), 68.4 (d, C-9b), 62.5 (t, C-3), 28.5 (q, 6C, 6 × CH3). IR (CDCl3): 2977, 2935, 1593, 1474, 1458, 1390, 1365, 1236, 1192, 1119 cm–1. MS (ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.51; H, 9.12; N, 4.56
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  • 14 Compound 5a: Rf  = 0.35 (EtOAc/petroleum ether, 1:32), one orange spot with p-anisaldehyde stain. Mp = 110–112 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H, OH, disappears on addition of D2O), 7.30–7.25 (m, 2 H, HAr), 7.24–7.18 (m, 1 H, HAr), 7.11–7.01 (m, 4 H, HAr), 6.84 (d, J = 3.2 Hz, 1 H, 5-H), 6.60–6.51 (m, 2 H, HAr), 6.14 (d, J = 3.2 Hz, 1 H, 4-H), 1.23 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 153.7 (s, CAr), 140.7 (s, CAr), 139.5 (s, CAr), 130.8 (d, CHAr), 128.9 (d, 2C, CHAr), 128.0 (d, CHAr), 126.3 (d, CHAr), 125.3 (d, 2C, CHAr), 122.4 (d, C-5), 120.9 (s, CAr), 119.6 (d, CHAr), 119.0 (s, CAr), 118.3 (d, CHAr), 105.1 (d, C-4), 81.6 (s, CMe3), 28.0 (q, 3C, 3 × CH3). C/H coupled 13C NMR (CDCl3, 100 MHz): δ = (selection of signals) = 122.4 (dd, J = 187.6, 7.0 Hz, C-5), 105.1 (dd, J = 173.3, 7.2 Hz, C-4). IR (CDCl3): 3255 (broad), 3075, 2981, 2934, 1599, 1556, 1502, 1352, 1235, 1164 cm–1. MS (+ESI): m/z = 330 [M+Na]+. MS (ESI): m/z = 307 [M]. HRMS (+ESI): m/z [MH]+ calcd for C20H22NO2 +: 308.16451; found: 308.16444
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    • 15b Zhang M. Fang X. Neumann H. Beller M. J. Am. Chem. Soc. 2013; 135: 11384
  • 16 Compound 6a: Rf  = 0.31. Mp = 124–125 °C. [α]D 21 = –43.4 (c = 0.43, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.13 (pseudo dt, J = 1.7, 7.7 Hz, 1 H, HAr), 7.00 (dd, J = 7.5, 1.7 Hz, 1 H, HAr), 6.80 (dd, J = 8.1, 1.1 Hz, 1 H, HAr), 6.74 (pseudo dt, J = 1.1, 7.4 Hz, 1 H, HAr), 4.08 (dd, J = 7.9, 5.3 Hz, 1 H, 3-H), 3.99 (dd, J = 7.4, 5.3 Hz, 1 H, 4-H), 3.94 (d, J = 7.9 Hz, 1 H, 2-H), 3.30 (dd, J = 10.6, 7.4 Hz, 1 H, 5-Ha), 3.01 (dd, J = 10.6, 4.4 Hz, 1 H, 5-Hb), 1.19 (s, 9 H, 3 × CH3), 0.93 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 158.0 (s, CAr), 129.6 (d, CHAr), 128.7 (d, CHAr), 123.3 (s, CAr), 118.4 (d, CHAr), 116.7 (d, CHAr), 80.7 (d, C-3), 76.3 (d, C-4), 74.6 (s, CMe3), 73.8 (s, CMe3), 66.6 (d, C-2), 50.9 (t, C-5), 28.7 (q, 3C, 3 × CH3), 28.6 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2935, 1589, 1489, 1392, 1367, 1257, 1190, 1106, 1068 cm–1. MS (+ESI): m/z = 308 [M+H]+. MS (ESI): m/z = 306 [M–H]. C18H29NO3 (307.43): calcd. C, 70.32; H, 9.51; N, 4.56; found: C, 70.53; H, 9.66; N, 4.17
  • 17 Compound 6b: Rf  = 0.15 (EtOAc/petroleum ether, 1:4). Mp = 162–164 °C. [α]D 27 = –57.4 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.08–8.03 (m, 2 H, HBz), 8.96–7.91 (m, 2 H, HBz), 7.63–7.58 (m, 1 H, HBz), 7.57–7.52 (m, 1 H, HBz), 7.50–7.44 (m, 2 H, HBz), 7.43–7.37 (m, 2 H, HBz), 7.23 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 7.18 (pseudo dt, J = 1.6, 7.7 Hz, 1 H, HAr), 6.88 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.80 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.71 (dd, J = 4.3, 1.6 Hz, 1 H, 3-H), 5.62 (pseudo dt, J = 5.5, 1.6 Hz, 1 H, 4-H), 4.68 (d, J = 4.3 Hz, 1 H, 2-H), 3.70 (dd, J = 12.1, 5.5 Hz, 1 H, 5-Ha), 3.44 (dm, J = 12.1 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.7 (s, CO), 165.3 (s, CO), 157.8 (s, CAr), 133.5 (d, CHBz), 133.3 (d, CHBz), 129.9 (d, 2C, CHBz), 129.7 (d, 2C, CHBz), 129.3 (s, CBz), 129.2 (s, CBz), 129.1 (d, CHAr), 128.5 (d, 2C, CHBz), 128.4 (d, CHAr), 128.3 (d, 2C, CHBz), 121.1 (s, CAr), 119.2 (d, CHAr), 117.4 (d, CHAr), 83.0 (d, C-3), 77.3 (d, C-4), 67.0 (d, C-2), 51.2 (t, C-5). IR (CDCl3): 3348, 3065, 2959, 2858, 1719, 1602, 1585, 1491, 1451, 1278, 1258, 1110 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.08; H, 5.07; N, 3.44
  • 18 Compound 7b: Rf  = 0.34 (EtOAc/petroleum ether, 1:4). Mp = 60–62 °C. [α]D 26 = –45.3 (c = 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.11–8.07 (m, 2 H, HBz), 7.97–7.93 (m, 2 H, HBz), 7.66–7.60 (m, 1 H, HBz), 7.54–7.47 (m, 3 H, HBz), 7.40–7.35 (m, 2 H, HBz), 7.08–7.00 (m, 2 H, HAr), 6.76 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.72 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.77 (dd, J = 4.7, 1.1 Hz, 1 H, 3-H), 5.55 (dm, J = 5.1 Hz, 1 H, 4-H), 4.97 (d, J = 4.7 Hz, 1 H, 2-H), 3.85 (dd, J = 12.6, 5.1 Hz, 1 H, 5-Ha), 3.35 (dd, J = 12.6, 2.3 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.3 (s, CO), 165.2 (s, CO), 159.2 (s, CAr), 133.6 (d, CHBz), 133.2 (d, CHBz), 129.9 (d, 2C, CHBz), 129.8 (d, 2C, CHBz), 129.3 (s, CBz), 129.1 (s, CBz +d, CHAr), 128.6 (d, 2C, CHBz), 128.5 (d, CHAr), 128.3 (d, 2C, CHBz), 118.8 (d, CHAr), 118.4 (s, CAr), 117.1 (d, CHAr), 78.8 (d, C-3), 77.1 (d, C-4), 65.0 (d, C-2), 50.3 (t, C-5). IR (CDCl3): 3366, 3065, 2958, 2871, 1721, 1601, 1586, 1492, 1452, 1316, 1260, 1109 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.44; H, 5.13; N, 3.37
  • 19 Compound 5b: Rf  = 0.52 (EtOAc/petroleum ether, 1:4), one red spot with p-anisaldehyde stain. Mp = 135–137 °C (dec). 1H NMR (CDCl3, 400 MHz): δ = 8.15–8.09 (m, 2 H, HBz), 7.62–7.56 (m, 1 H, HBz), 7.49–7.42 (m, 2 H, HBz), 7.31–7.11 (m, 6 H, HAr), 7.03 (d, J = 3.2 Hz, 1 H, 5-H), 6.93 (dm, J = 8.2 Hz, 1 H, HAr), 6.88 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 6.76–6.69 (m, 1 H, HAr), 6.44 (d, J = 3.2 Hz, 1 H, 4-H), 6.06 (br s, 1 H, OH). 13C NMR (CDCl3, 100 MHz): δ = 165.8 (s, CO), 154.8 (s, CAr), 139.6 (s, CAr), 136.8 (s, CAr), 133.6 (d, CHBz), 132.1 (d, CHAr), 130.3 (d, 2C, CHBz), 130.1 (d, CHAr), 129.0 (d, 2C, CHAr), 128.9 (s, CHBz), 128.5 (d, 2C, CHBz), 126.8 (d, CHAr), 124.9 (d, 2C, CHAr), 121.6 (d, C-5), 120.1 (d, CHAr), 117.3 (s, CAr), 116.4 (s, CAr), 116.1 (d, CHAr), 103.3 (d, C-4). IR (CDCl3): 3072, 2927, 1726, 1600, 1502, 1356, 1267, 1228, 1068, 1025 cm–1. MS (+ESI): m/z = 356 [M+1]+. MS (ESI): m/z = 354 [M–1]. HRMS (+ESI): m/z [MH]+ calcd for C23H18NO3 +: 356.12812; found: 356.12788

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  • 10 General Procedure for the Cycloaddition Reaction: A mixture of nitrone 1 (300 mg), 2 (1.5 equiv), and Bu4NF (1 M in THF, 1.2 equiv) in anhydrous DMF (final nitrone concentration of 0.09–0.1 M) was stirred at room temperature for 2.5 h. The DMF was evaporated under a flow of nitrogen and the crude residue was purified by chromatography on silica gel
  • 11 Compound 3a: Rf  = 0.33 (EtOAc/petroleum ether, 1:16); [α]D 24 = –90.6 (c = 0.25, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.25 (dm, J = 7.4 Hz, 1 H, 9-H), 7.17–7.12 (m, 1 H, 7-H), 6.90 (pseudo dt, J = 0.9, 7.4 Hz, 1 H, 8-H), 6.73 (br d, J = 8.0 Hz, 1 H, 6-H), 4.77 (br s, 1 H, 9b-H), 4.13–4.10 (m, 1 H, 1-H), 3.96 (ddd, J = 6.0, 4.9, 3.6 Hz, 1 H, 2-H), 3.58 (dd, J = 11.6, 4.9 Hz, 1 H, 3-Ha), 3.16 (ddm, J = 11.6, 6.0 Hz, 1 H, 3-Hb), 1.29 (s, 9 H, 3 × CH3), 1.06 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 156.3 (s, C-5a), 128.5 (d, C-7), 127.1 (s, C-9a), 123.4 (d, C-9), 120.9 (d, C-8), 107.1 (d, C-6), 82.0 (d, C-1), 76.6 (d, C-2), 75.6 (d, C-9b), 74.5 (s, CMe3), 73.6 (s, CMe3), 62.1 (t, C-3), 28.7 (q, 3C, 3 × CH3), 28.3 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2871, 1597, 1480, 1456, 1390, 1365, 1253, 1190, 1099, 1079 cm–1. MS (+ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.56; H, 8.69; N, 4.98
  • 12 Compound 4a: Rf  = 0.23 (EtOAc/petroleum ether, 1:16). [α]D 21 = –12.7 (c = 0.22, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.32 (br d, J = 7.5 Hz, 1 H, 9-H), 7.17 (pseudo tm, J = 8.0 Hz, 1 H, 7-H), 6.91 (pseudo dt, J = 0.8, 7.4 Hz, 1 H, 8-H), 6.76 (br d, J = 8.1 Hz, 1 H, 6-H), 4.87 (d, J = 6.8 Hz, 1 H, 9b-H), 4.24 (pseudo t, J = 7.2 Hz, 1 H, 1-H), 3.82 (pseudo q, J = 7.9 Hz, 1 H, 2-H), 3.49 (dd, J = 14.0, 7.6 Hz, 1 H, 3-Ha), 3.23 (dd, J = 14.0, 8.6 Hz, 1 H, 3-Hb), 1.28 (s, 9 H, 3 × CH3), 1.11 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 157.2 (s, C-5a), 128.4 (d, C-7), 125.9 (d, C-9), 125.2 (s, C-9a), 120.8 (d, C-8), 107.2 (d, C-6), 77.6 (d, C-1), 74.3 (s, CMe3), 73.7 (s, CMe3), 73.0 (d, C-2), 68.4 (d, C-9b), 62.5 (t, C-3), 28.5 (q, 6C, 6 × CH3). IR (CDCl3): 2977, 2935, 1593, 1474, 1458, 1390, 1365, 1236, 1192, 1119 cm–1. MS (ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.51; H, 9.12; N, 4.56
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  • 14 Compound 5a: Rf  = 0.35 (EtOAc/petroleum ether, 1:32), one orange spot with p-anisaldehyde stain. Mp = 110–112 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H, OH, disappears on addition of D2O), 7.30–7.25 (m, 2 H, HAr), 7.24–7.18 (m, 1 H, HAr), 7.11–7.01 (m, 4 H, HAr), 6.84 (d, J = 3.2 Hz, 1 H, 5-H), 6.60–6.51 (m, 2 H, HAr), 6.14 (d, J = 3.2 Hz, 1 H, 4-H), 1.23 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 153.7 (s, CAr), 140.7 (s, CAr), 139.5 (s, CAr), 130.8 (d, CHAr), 128.9 (d, 2C, CHAr), 128.0 (d, CHAr), 126.3 (d, CHAr), 125.3 (d, 2C, CHAr), 122.4 (d, C-5), 120.9 (s, CAr), 119.6 (d, CHAr), 119.0 (s, CAr), 118.3 (d, CHAr), 105.1 (d, C-4), 81.6 (s, CMe3), 28.0 (q, 3C, 3 × CH3). C/H coupled 13C NMR (CDCl3, 100 MHz): δ = (selection of signals) = 122.4 (dd, J = 187.6, 7.0 Hz, C-5), 105.1 (dd, J = 173.3, 7.2 Hz, C-4). IR (CDCl3): 3255 (broad), 3075, 2981, 2934, 1599, 1556, 1502, 1352, 1235, 1164 cm–1. MS (+ESI): m/z = 330 [M+Na]+. MS (ESI): m/z = 307 [M]. HRMS (+ESI): m/z [MH]+ calcd for C20H22NO2 +: 308.16451; found: 308.16444
    • 15a McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2 1991; 1999
    • 15b Zhang M. Fang X. Neumann H. Beller M. J. Am. Chem. Soc. 2013; 135: 11384
  • 16 Compound 6a: Rf  = 0.31. Mp = 124–125 °C. [α]D 21 = –43.4 (c = 0.43, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.13 (pseudo dt, J = 1.7, 7.7 Hz, 1 H, HAr), 7.00 (dd, J = 7.5, 1.7 Hz, 1 H, HAr), 6.80 (dd, J = 8.1, 1.1 Hz, 1 H, HAr), 6.74 (pseudo dt, J = 1.1, 7.4 Hz, 1 H, HAr), 4.08 (dd, J = 7.9, 5.3 Hz, 1 H, 3-H), 3.99 (dd, J = 7.4, 5.3 Hz, 1 H, 4-H), 3.94 (d, J = 7.9 Hz, 1 H, 2-H), 3.30 (dd, J = 10.6, 7.4 Hz, 1 H, 5-Ha), 3.01 (dd, J = 10.6, 4.4 Hz, 1 H, 5-Hb), 1.19 (s, 9 H, 3 × CH3), 0.93 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 158.0 (s, CAr), 129.6 (d, CHAr), 128.7 (d, CHAr), 123.3 (s, CAr), 118.4 (d, CHAr), 116.7 (d, CHAr), 80.7 (d, C-3), 76.3 (d, C-4), 74.6 (s, CMe3), 73.8 (s, CMe3), 66.6 (d, C-2), 50.9 (t, C-5), 28.7 (q, 3C, 3 × CH3), 28.6 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2935, 1589, 1489, 1392, 1367, 1257, 1190, 1106, 1068 cm–1. MS (+ESI): m/z = 308 [M+H]+. MS (ESI): m/z = 306 [M–H]. C18H29NO3 (307.43): calcd. C, 70.32; H, 9.51; N, 4.56; found: C, 70.53; H, 9.66; N, 4.17
  • 17 Compound 6b: Rf  = 0.15 (EtOAc/petroleum ether, 1:4). Mp = 162–164 °C. [α]D 27 = –57.4 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.08–8.03 (m, 2 H, HBz), 8.96–7.91 (m, 2 H, HBz), 7.63–7.58 (m, 1 H, HBz), 7.57–7.52 (m, 1 H, HBz), 7.50–7.44 (m, 2 H, HBz), 7.43–7.37 (m, 2 H, HBz), 7.23 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 7.18 (pseudo dt, J = 1.6, 7.7 Hz, 1 H, HAr), 6.88 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.80 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.71 (dd, J = 4.3, 1.6 Hz, 1 H, 3-H), 5.62 (pseudo dt, J = 5.5, 1.6 Hz, 1 H, 4-H), 4.68 (d, J = 4.3 Hz, 1 H, 2-H), 3.70 (dd, J = 12.1, 5.5 Hz, 1 H, 5-Ha), 3.44 (dm, J = 12.1 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.7 (s, CO), 165.3 (s, CO), 157.8 (s, CAr), 133.5 (d, CHBz), 133.3 (d, CHBz), 129.9 (d, 2C, CHBz), 129.7 (d, 2C, CHBz), 129.3 (s, CBz), 129.2 (s, CBz), 129.1 (d, CHAr), 128.5 (d, 2C, CHBz), 128.4 (d, CHAr), 128.3 (d, 2C, CHBz), 121.1 (s, CAr), 119.2 (d, CHAr), 117.4 (d, CHAr), 83.0 (d, C-3), 77.3 (d, C-4), 67.0 (d, C-2), 51.2 (t, C-5). IR (CDCl3): 3348, 3065, 2959, 2858, 1719, 1602, 1585, 1491, 1451, 1278, 1258, 1110 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.08; H, 5.07; N, 3.44
  • 18 Compound 7b: Rf  = 0.34 (EtOAc/petroleum ether, 1:4). Mp = 60–62 °C. [α]D 26 = –45.3 (c = 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.11–8.07 (m, 2 H, HBz), 7.97–7.93 (m, 2 H, HBz), 7.66–7.60 (m, 1 H, HBz), 7.54–7.47 (m, 3 H, HBz), 7.40–7.35 (m, 2 H, HBz), 7.08–7.00 (m, 2 H, HAr), 6.76 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.72 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.77 (dd, J = 4.7, 1.1 Hz, 1 H, 3-H), 5.55 (dm, J = 5.1 Hz, 1 H, 4-H), 4.97 (d, J = 4.7 Hz, 1 H, 2-H), 3.85 (dd, J = 12.6, 5.1 Hz, 1 H, 5-Ha), 3.35 (dd, J = 12.6, 2.3 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.3 (s, CO), 165.2 (s, CO), 159.2 (s, CAr), 133.6 (d, CHBz), 133.2 (d, CHBz), 129.9 (d, 2C, CHBz), 129.8 (d, 2C, CHBz), 129.3 (s, CBz), 129.1 (s, CBz +d, CHAr), 128.6 (d, 2C, CHBz), 128.5 (d, CHAr), 128.3 (d, 2C, CHBz), 118.8 (d, CHAr), 118.4 (s, CAr), 117.1 (d, CHAr), 78.8 (d, C-3), 77.1 (d, C-4), 65.0 (d, C-2), 50.3 (t, C-5). IR (CDCl3): 3366, 3065, 2958, 2871, 1721, 1601, 1586, 1492, 1452, 1316, 1260, 1109 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.44; H, 5.13; N, 3.37
  • 19 Compound 5b: Rf  = 0.52 (EtOAc/petroleum ether, 1:4), one red spot with p-anisaldehyde stain. Mp = 135–137 °C (dec). 1H NMR (CDCl3, 400 MHz): δ = 8.15–8.09 (m, 2 H, HBz), 7.62–7.56 (m, 1 H, HBz), 7.49–7.42 (m, 2 H, HBz), 7.31–7.11 (m, 6 H, HAr), 7.03 (d, J = 3.2 Hz, 1 H, 5-H), 6.93 (dm, J = 8.2 Hz, 1 H, HAr), 6.88 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 6.76–6.69 (m, 1 H, HAr), 6.44 (d, J = 3.2 Hz, 1 H, 4-H), 6.06 (br s, 1 H, OH). 13C NMR (CDCl3, 100 MHz): δ = 165.8 (s, CO), 154.8 (s, CAr), 139.6 (s, CAr), 136.8 (s, CAr), 133.6 (d, CHBz), 132.1 (d, CHAr), 130.3 (d, 2C, CHBz), 130.1 (d, CHAr), 129.0 (d, 2C, CHAr), 128.9 (s, CHBz), 128.5 (d, 2C, CHBz), 126.8 (d, CHAr), 124.9 (d, 2C, CHAr), 121.6 (d, C-5), 120.1 (d, CHAr), 117.3 (s, CAr), 116.4 (s, CAr), 116.1 (d, CHAr), 103.3 (d, C-4). IR (CDCl3): 3072, 2927, 1726, 1600, 1502, 1356, 1267, 1228, 1068, 1025 cm–1. MS (+ESI): m/z = 356 [M+1]+. MS (ESI): m/z = 354 [M–1]. HRMS (+ESI): m/z [MH]+ calcd for C23H18NO3 +: 356.12812; found: 356.12788

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Figure 1 Structures of natural pyrrolidines codonopsinine and radicamine B
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Scheme 1 Retrosynthetic analysis of 2-aryl-polyhydroxy-pyrrolidines
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Scheme 2 Cycloaddition reactions of nitrones 1a and 1b with benzyne
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Scheme 3 Proposed mechanism for conversion of adducts 3 and 4 into pyrrole 5
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Scheme 4 Reduction of 3a
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Scheme 5 Cycloaddition of 1b with aryne and reduction of the resulting reaction mixture