Letter pubs.acs.org/OrgLett
Enantiospecific Synthesis of β‑Substituted Tryptamines Heather N. Rubin, Kinney Van Hecke, Jonathan J. Mills, Jennifer Cockrell, and Jeremy B. Morgan* Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Dobo Hall, Wilmington, North Carolina 28403, United States S Supporting Information *
ABSTRACT: Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis where isomer formation can be controlled. 3,5Dinitrobenzoyl (DNB)-protected aziridines undergo regioselective, enantiospecific ring opening to produce β-substituted tryptamines for a series of indoles. Attack at the more substituted aziridine carbon occurs in an SN2-like fashion to generate DNBtryptamine products as synthetic precursors.
T
from disubstituted aziridines when a substituent directs the aziridine ring opening,7b,9 or enantioselective desymmetrization of meso-aziridines is accomplished.10 Terminal aziridines offer an opportunity for site-selective attack based on the carbon backbone substitution. Recently, catalytic methods for the synthesis of enantioenriched β-substituted tryptamines (5) by aziridine ring opening have been reported (Scheme 1).11 Regioselectivity was generally controlled by functionalized R1 groups in aziridine 4 that favor ring opening at the more hindered aziridine carbon. Less reactive substrates with R1 = alkyl groups were generally omitted, and the N-sulfonyl activating group is necessary.12 A short study of terminal 2alkyl N-nosylaziridine (6) ring opening with 2-phenylindole was conducted in pursuit of a GnRH antagonist.13 Our group has developed methods for the synthesis of 3,5-dinitrobenzoyl (DNB) protected aziridines (8), which undergo regioselective ring-opening under Lewis acid conditions.14 Indole addition to 2-alkyl DNB-aziridines proceeds with complete stereochemical transfer to generate novel β-tryptamines (9) that can be deprotected under mild conditions. Under Lewis acid conditions, aziridine 10 participates in stereospecific ring opening with an indole (11) to produce a tryptamine derivative (12, Table 1). The initial conditions employed 10 mol % of Zn(OTf)2 (entry 1); however, only a moderate yield of 12 was observed despite complete consumption of the starting aziridine. Heine rearrangement14a,15 to oxazoline 13 was observed as a major side product. A Lewis acid screen was initiated to improve reaction yield. Standard triflate Lewis acid complexes generally showed little improvement relative to Zn(OTf)2 (entries 2−8). In all cases, significant material loss occurred leading to unidentified byproducts. Altering the zinc counterion showed only a slightly improved yield (entry 9). Though we had hoped to develop a
ryptamines are important indole alkaloids in neurobiology and complex molecule biosynthesis.1 Derived from tryptophan, most natural tryptamines lack substitution on the ethyl backbone or contain only α-substitution. However, βsubstituted tryptamine derivatives have been investigated for use as a nonaddictive sleep aid (1)1d,2 and anticancer therapy (2, Figure 1).3 Naturally occurring hapalindole alkaloids (3)
Figure 1. Biologically active β-substituted tryptamine derivatives.
possess broad antimicrobial activity.4 β-Substituted tryptamines can be synthesized directly from indoles via Friedel−Crafts alkylation with nitrogen-containing electrophiles. The enantioselective conjugate addition of indoles to nitro alkenes produces β-substituted tryptamine precursors and has been extensively studied.5 An alternative direct approach involves the addition of an indole to an aziridine where stereo- and regiocontrol are required for the efficient synthesis of βtryptamines as a single stereoisomer. Herein, we report the selective ring opening of DNB-aziridines with indoles to access enantioenriched β-tryptamines. Early efforts in tryptamine synthesis from aziridine derivatives focused on aziridinium ions as electrophiles.6 Incorporation of Lewis acid catalysts and nitrogen protecting groups enabled the production of enantioenriched tryptophan derivatives.7 The ring opening of N-acyloxy and N-acylaziridines produces primarily α-substituted tryptamine derivatives.7a,8 Selective β-substituted tryptamine synthesis is possible © 2017 American Chemical Society
Received: August 9, 2017 Published: September 7, 2017 4976
DOI: 10.1021/acs.orglett.7b02474 Org. Lett. 2017, 19, 4976−4979
Letter
Organic Letters
10). Other common protecting groups for indole gave complex product mixtures (entries 13 and 14). The BF3-promoted ring-opening conditions were examined in detail by varying the structure of the aziridine (8) and indole (Table 2). The tryptamine products (9) were isolated, and the
Scheme 1. Tryptamine Synthesis by Aziridine Ring Opening
Table 2. Exploration of Substrate Scope for Tryptamine Derivative Synthesisa
catalyst
R
methodb
convc (%)
yieldc (%) of 12/13
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Zn(OTf)2 Cu(OTf)2 Sc(OTf)3 Y(OTf)3 La(OTf)3 Yb(OTf)3 Dy(OTf)3 AgOTf Zn(NTf2)2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2
H H H H H H H H H H methyl allyl TBDPS Boc
A A A A A A A A A B B B B B
100 100 100 100 73 98 89 100 100 94 100 100 100 95
46/11 37/24 38/22 46/14 28/2 51/13 44/9 46/30 52/17 60/3 86/0 71/0 complex mix complex mix
R1
R2
R3
yieldb (%)
eec (%)
1 2 3 4d 5 6 7 8 9 10 11
methyl methyl methyl ethyl isobutyl methyl methyl methyl methyl methyl methyl
H methyl TBS methyl methyl H H H H H H
H H H H H 5-methyl 5-OCH3 5-F 5-Br 6-F 6-Cl
67 82 73 83 72 61 56 62 78 72 72
>99 >99 >99 >99 >99 98.6 >99 >99 >99 >99 >99
a
Table 1. Lewis Acid Screen for Aziridine Ring Opening with Indolesa
entry
entry
Reactions were performed with 0.2 mmol of aziridine, 0.6 mmol of indole, and 0.2 mmol of BF3·OEt2 in CH2Cl2 (0.2 M). bIsolated yield for an average of two or more runs. cDetermined by HPLC following Boc protection. dThe R enantiomer of aziridine was used.
ee was determined by HPLC. Unprotected indole generated good product yield with complete stereochemical transfer (entry 1). As observed during the catalyst screen, the introduction of electron-rich indole protecting groups was beneficial to product yield (entries 2 and 3). N-TBS-indole (entry 3) provided a much cleaner reaction than the TBDPS protecting group (see entry 13, Table 1). The effect of aziridine structure on the reaction outcome was also investigated (entries 4 and 5). Aziridines substituted with simple alkyl groups underwent ring opening in very good to excellent yields as single isolated regioisomers.16 Functionalized indoles were also employed as nucleophiles, where substitution at the 5 and 6 positions were well-tolerated (entries 6−11). Electron-donating groups gave moderate yields with high stereospecificity (entries 6 and 7). Halogenated indoles performed well without the need for an indole nitrogen protecting group (entries 8−11). Attempts to incorporate stronger electron-withdrawing groups resulted in very low yields and slow conversion (data not shown). A gram-scale tryptamine synthesis was performed under standard conditions with enantiopure aziridine 10. A slight erosion in yield occurred (compared to Table 2, entry 4), but tryptamine 14 was isolated as a single enantiomer (Scheme 2). The β-substituted tryptamine products are valuable synthons once protecting groups are removed. The DNB protecting group required for aziridine activation can be replaced via mild basic hydrolysis following Boc protection.17 Tryptamine 14 is converted to the Boc derivative (15) in high yield through nitrogen protection followed by aqueous 2 M NaOH for selective DNB cleavage. The Boc group is readily removed from tryptamines under acidic conditions.18
a
Reactions were performed with 0.1 mmol of 10 and 0.3 mmol of 11 in CH2Cl2 (0.2 M). bMethod A: 10 mol % of Lewis acid, rt, 24 h. Method B: 100 mol % of BF3·OEt2, −78 °C, 1 h. cDetermined by 1H NMR after the addition of 1,3,5-trimethoxybenzene as internal standard.
method catalytic in Lewis acid, use of stoichiometric BF3 facilitated ring opening at much lower temperature. As a result, little or no Heine rearrangement occurs under optimized conditions (entries 10−12). We also noted that N-alkylindoles gave higher yields than indole itself (entries 11 and 12 versus 4977
DOI: 10.1021/acs.orglett.7b02474 Org. Lett. 2017, 19, 4976−4979
Letter
Organic Letters Scheme 2. Reaction Scale-Up and Protecting Group Manipulation
Scheme 4. Proposed Mechanism for Tryptamine Synthesis
The high enantiospecificity observed during aziridine ring opening suggests an SN2-type reaction mechanism with inversion of stereochemistry where aziridine binding by the Lewis acid selectively activates the more substituted carbon− nitrogen bond. However, the Lewis acid catalyzed rearrangement of aziridines to oxazolines is known to occur with retention of stereochemistry.15b,19 In order to shed light on the reaction mechanism, the R enantiomer of 120 was converted to the bis-Boc derivative 16 in 68% yield over two steps (Scheme 3). Dechlorination was accomplished by standard hydro-
An enantiospecific synthesis of β-substituted tryptamines is reported from DNB-protected terminal aziridines. The reaction is highly regioselective for addition to the internal carbon and occurs with inversion of stereochemistry. Efforts are currently underway to expand the aziridine substrate scope and incorporate other electron-rich aromatic nucleophiles. Applications of β-substituted tryptamines in complex small molecule synthesis will also be investigated.
Scheme 3. Proof of Tryptamine Absolute Configuration
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02474. Detailed experimental procedures including analytical data (PDF) NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jeremy B. Morgan: 0000-0002-6174-7330
genation conditions; however, over-reduction of the indole was observed by 1H NMR. Treatment of the crude reduction product with DDQ reoxidized the indole to produce tryptamine 17. Relation of our tryptamine products was accomplished by converting a ring-opening product (entry 7, Table 2) directly to ent-17 by Boc protection and DNB cleavage. HPLC comparison of enantiomers independently establishes the absolute configuration of ent-17 as S; hence, inversion of stereochemistry took place during the aziridine ring-opening event. A proposed mechanism begins with Lewis acid complex formation between BF3 and aziridine 8 (Scheme 4). The nitrogen of N-acylaziridines is pyramidalized and basic, but we suggest the O-bound complex 18 with the oxophilic Lewis acid.15b At −78 °C, intermediate 18 is stable to rearrangement or racemization, but activation of the internal carbon−nitrogen bond is favored. Indole attack occurs in an SN2-like fashion with inversion of stereochemistry. Proton transfer from intermediate 19 may occur prior to the quench; however, the reaction cannot be performed with catalytic BF3 under the reported conditions.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the Donors of the American Chemical Society Petroleum Research Fund for financial support. HRMS data were collected from a Bruker MicrOTOF-Q II instrument purchased with funds from the National Science Foundation (CHE-1039784) and University of North Carolina Wilmington. The 600 MHz NMR data was obtained using a Bruker instrument purchased with funds from the National Science Foundation (CHE-0821552).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02474 Org. Lett. 2017, 19, 4976−4979
