Total Synthesis of Gypsetin, Deoxybrevianamide E, Brevianamide E, and Tryprostatin B:  Novel Constructions of 2,3-Disubstituted Indoles

Schkeryantz, Jeffrey M.; Woo, Jonathan C. G.; Siliphaivanh, Phieng; Depew, and Kristopher M.; Danishefsky, Samuel J.

doi:10.1021/ja9925249

Cited by 174 publications

(118 citation statements)

References 49 publications

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“…Preechinulin (5) [17][18][19][20][21] was synthesized starting from isoprenyl L-tryptophan derivative 15a (Chart 4). Deprotection of N-phthaloyl group in 15a [22][23][24] with hydrazine and coupling of the resulting amine with N-Boc-L-Ala gave 16a. Deprotection of N-Boc group in 16a and thermal cyclization afforded preechinulin (5).…”

Section: Resultsmentioning

confidence: 99%

“…The organic layer was evaporated to give a crude residue, which was purified by a preparative TLC (hexanes : EtOAcϭ2 : 1) to afford 3 (46 mg, 52%) as a yellow amorphous solid. (1,1-dimethyl-2-propenyl)-1H-indol-3yl]propionate 16a To a solution of 15a 22,23) (350 mg, 0.84 mmol) in EtOH (8.5 ml) was added hydrazine monohydrate (0.14 ml, 2.94 mmol), and the mixture was stirred at rt for 3 d. The mixture was filtrated and washed with MeOH, and the resultant filtrate was evaporated to give a crude amine.…”

Section: Ethyl 2-(tert-butyloxycarbonylamino)-3-[(z)-2-(11-dimethyl-mentioning

confidence: 99%

“…To a solution of 15b 22,23) (27 mg, 65 mmol) in EtOH (1.0 ml) was added hydrazine monohydrate (12 ml, 250 mmol), and the mixture was stirred at rt for 3 d. The mixture was filtrated and washed with MeOH, and the resultant filtrate was evaporated to give a crude amine.…”

Section: Methyl (2r)-2-[(2s)-2-tert-butyloxycarbonylaminopropylamino]mentioning

confidence: 99%

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Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Kuramochi

Ohnishi

Fujieda

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Peroxynitrite (ONOO), is a potent oxidant that can cause severe cell damage.1) Specifically, peroxynitrite promotes the oxidation of biomolecules such as lipids, proteins and nucleic acids, [2][3][4] as well as the nitration of tyrosine residues in proteins. 5,6) Furthermore, it has been suggested that peroxynitrite formation plays a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. [7][8][9] Neoechinulin A (1), an isoprenyl indole alkaloid, can protect neuronal PC12 cells from ONOO Ϫ -induced death. [10][11][12] We have previously shown that the biological effects, rather than scavenging activity against ONOO Ϫ , are likely to play a role in the cytoprotective action of neoechinulin A.12) However, the precise molecular mechanism remains elusive. To investigate the potential mechanism of action, we have designed and prepared a series of neoechinulin A analogues (2-6). We then examined the structure-activity relationships of these analogues in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against ONOO Ϫ derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells (Fig. 1). The results showed that: 1) the presence of the C-8/C-9 double bond is indispensable for anti-nitration and anti-oxidant activities as well as cytoprotective activity of neoechinulin A against ONOO Ϫ toxicity; 2) in conjunction with the C-8/C-9 double bond, the presence of an intact diketopiperazine moiety is essential for the anti-nitration activity but not for antioxidant or cytoprotective activity. Results and DiscussionCompound 2 was synthesized from 2-tert-butyl-1H-indole (7) 13) (Chart 1). Methoxy methyl (MOM) protection of 7, followed by the Vilsmeier reaction, gave aldehyde 9. A coupling reaction of the aldehyde 9 with diketopiperazine 10 using tBuOK in DMF afforded 11.14) Subsequent deprotection of protective groups provided the desired product 2. 15)Compound 3 was prepared by coupling of aldehyde 12 with N-Boc-Gly-OEt, followed by treatment of the resulting We synthesized a series of neoechinulin A derivatives and examined the structure-activity relationships in terms of their anti-nitration and anti-oxidant activities as well as their cytoprotective activity against peroxynitrite from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride) using PC12 cells. Our results showed that the C-8/C-9 double bond, which constitutes a conjugate system with indole and diketopiperazine moieties of neoechinulin A is essential for anti-nitration and anti-oxidant activities as well as protection against SIN-1 cytotoxicity. The presence of an intact diketopiperazine moiety is an additional requirement for anti-nitration activity but not for the cytoprotective action. Our results suggest that the antioxidant activity or electrophilic nature of the C-8 carbon, both of which are afforded by the C-8/C-9 double bond, may play a role in the cytoprotective properties of this alkaloid.

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Section: Resultsmentioning

confidence: 99%

Section: Ethyl 2-(tert-butyloxycarbonylamino)-3-[(z)-2-(11-dimethyl-mentioning

confidence: 99%

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Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Kuramochi

Ohnishi

Fujieda

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Signals for the four protons at positions 4, 5, 6 and 7 of the indole ring were clearly observed (Table S1), and revealed that the prenyl moiety is connected to N-1 or C-2 of the indole ring. The signals of the methyl groups in the reverse prenyl moieties attached to C-2 of the indole rings of some diketopiperazine derivatives, for example, in echnulin-and isoechinulin-type alkaloids, [2][3][4] in deoxybrevianamide E [5] or okaramines, [6,7] were usually found in the range of 1.40 to 1.55 ppm. In comparison, the signals of the methyl groups in the prenyl moieties of the enzymatic products of CdpNPT are significantly up-field shifted to 0.9 to 1.1 ppm.…”

mentioning

confidence: 99%

Reinvestigation of a Cyclic Dipeptide N‐Prenyltransferase Reveals Rearrangement of N‐1 Prenylated Indole Derivatives

Ruan

Yin

et al. 2008

ChemBioChem

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“…Link and Overman (43) have also reported a bis-enolate alkylation approach to bispyrroloindoline containing natural products. The Danishefsky group has used enantiopure tryptophan-based starting materials for their asymmetric synthesis of amauromine and the ardeemins (44,45). Their strategy relies on stereochemical induction from a resident stereocenter derived from tryptophan in a cascade selenationring-closing protocol.…”

mentioning

confidence: 99%

Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

Austin

Kim

Sinz

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

442

117

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Pyrroloindoline and bispyrroloindoline are a subclass of alkaloid structural motifs that commonly exhibit biological activity. An enantioselective organocatalytic approach to the synthesis of pyrroloindoline architecture is described. The addition-cyclization of tryptamines with ␣,␤-unsaturated aldehydes in the presence of imidazolidinone catalysts 1 and 8 provides pyrroloindoline adducts in high yield and excellent enantioselectivities. This transformation is successful for a wide range of tryptamine and ␣,␤-unsaturated aldehyde substrates. This amine-catalyzed sequence has been extended to the enantioselective construction of furanoindoline frameworks. Application of this pyrroloindoline-forming reaction to natural product synthesis has been accomplished in the context of the enantioselective synthesis of (؊)-flustramine B.

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Total Synthesis of Gypsetin, Deoxybrevianamide E, Brevianamide E, and Tryprostatin B: Novel Constructions of 2,3-Disubstituted Indoles

Cited by 174 publications

References 49 publications

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Synthesis and Biological Activities of Neoechinulin A Derivatives: New Aspects of Structure-Activity Relationships for Neoechinulin A

Reinvestigation of a Cyclic Dipeptide N‐Prenyltransferase Reveals Rearrangement of N‐1 Prenylated Indole Derivatives

Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

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