The concise total syntheses of the bis(pyrroloindolines) (−)-lansai B and (+)- nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)-nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation

Reisman, Sarah E.

Wang, Haoxuan

Caltech Authors - Main

Enantioselective Total Synthesis of (−)-Lansai B and (+)-
Nocardioazines A and B **
Haoxuan Wang and Prof. Sarah E. Reisman*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
(USA)
Abstract
The concise total syntheses of the bis(pyrroloindolines) (−)-lansai B and (+)- nocardioazines A
and B are reported. The key pyrroloindoline building blocks are rapidly prepared by
enantioselective formal (3 + 2) cycloaddition reactions. The macrocycle of (+)-nocardioazine A is
constructed by an unusual intramolecular diketopiperazine formation.
Keywords
lansai B; nocardioazines; natural products; total synthesis; diketopiperazine synthesis
Pyrroloindoline natural products are a growing family of alkaloids that exhibit promising
biological properties, including antibacterial and anticancer activities. 1 Within this family, a
number of bis(pyrroloindolines) that are joined through a central diketopiperazine (DKP)
ring have been identified.2 These structures include (−)-lansai B (1), (+)-nocardioazine A
(2), and (+)- nocardioazine B (3). Nocardioazine A (2) is of particular interest due to its
activity as an inhibitor of P-glycoprotein, a transmembrane protein overexpressed in many
multi-drug resistant tumors.2b Although these natural products appear quite similar
structurally, close analysis reveals subtle differences in the relative stereochemistry of the
pyrroloindoline units. Whereas 1 is composed of two exo-pyrroloindolines, 2 and 3 each
possess one endo- and one exo-pyrroloindoline. Moreover, the endo- and exo-
pyrroloindolines are in the opposite enantiomeric series, which is necessary to geometrically
accommodate the macrocycle of 2. This interesting stereochemical relationship makes 2 and
3 appealing synthetic targets for asymmetric catalysis, where selection of the appropriate
enantiomer of catalyst dictates the absolute stereochemistry of the pyrroloindoline building
**We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical
equipment, as well as Materia, Inc. and Sigma-Aldrich for kind donations of chemicals. We are grateful to Dr. David VanderVelde for
assistance with NMR structure analysis, and Mr. Larry Henling for X-ray structure determination. The Bruker KAPPA APEXII X-ray
diffractometer was purchased via an NSF Chemistry Research Instrumentation award to Caltech (CHE-0639094). NMR spectra were
obtained on a spectrometer funded by the NIH (RR027690). S.E.R. is a fellow of the Alfred P. Sloan Foundation, a Camille Dreyfus
Teacher-Scholar, and an American Cancer Society Research Scholar. Financial support from the California Institute of Technology,
the NIH (NIGMS RGM097582A), and DuPont is gratefully acknowledged.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
*reisman@caltech.edu, Homepage: http://reismangroup.caltech.edu.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201xxxxxx.
NIH Public Access
Author Manuscript
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2015 June 10.
Published in final edited form as:
Angew Chem Int Ed Engl. 2014 June 10; 53(24): 6206–6210. doi:10.1002/anie.201402571.
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block. The first diastereoselective total synthesis of 3 was reported in 2012 by the Ye group
and required 10 steps starting from L- and D-tryptophan;3 no total syntheses of 1 or 2 have
been published to date.
Recently, we reported a new method to prepare enantioenriched pyrroloindolines from C3-
substituted indoles and 2-amidoacrylates using SnCl4 and catalytic (R)-3,3′-dichloro-BINOL
(Figure 1). 4 Based on the retrosynthetic analysis shown in Figure 1, we anticipated that this
formal (3 + 2) cycloaddition reaction could be used to rapidly and enantioselectively prepare
natural products 1, 2 and 3. Herein, we report the successful execution of this plan and
demonstrate the utility of this catalytic asymmetric method for the synthesis of
diketopiperazine-containing bis(pyrroloindolines).
We first targeted (−)-lansai B (1, Figure 1); retrosynthetically, it was envisioned that the
DKP core could be prepared from the union of pyrroloindolines exo-4 and exo-5 via
sequential peptide bond formation. The required pyrroloindolines could in turn be
synthesized by formal (3 + 2) cycloaddition reactions of the corresponding indoles 13 and
16 (Scheme 1).
Our efforts commenced with Suzuki-Miyaura coupling of bromoindole 114a and
prenylboronate 12 to furnish reverse-prenylated indole 13 in good yield.5 Subjection of
indole 13 and methyl 2-trifluoroacetamidoacrylate (9a) to our formal (3 + 2) cycloaddition
conditions on 0.2 mmol scale provided pyrroloindoline 14 in 84% yield and 92% ee.
However, lower yields of 14 were obtained when the reaction was conducted on
preparatively useful scales (>1.0 mmol). It was hypothesized that on small scale trace water
might help to turn over the chiral catalyst; a survey of several protic additives revealed that
addition of 0.4 equiv 2,6-dibromophenol to the reaction mixture improves the scalability of
the reaction, providing 14 in 85% yield, 14:1 dr, and 92 % ee (major diastereomer).
Presumably 2,6-dibromophenol facilitates turnover of the chiral catalyst, but is not reactive
enough to protonate the transient enolate directly in a non-selective fashion. Cleavage of the
TFA group with anhydrous HCl provided amine 15. 6 Likewise, pyrroloindoline 17 could be
prepared from 1,3-dimethyl indole 16 and acrylate 9a in 79% yield, 12:1 dr, and 93% ee
(major diastereomer). Treatment with LiOH chemoselectively hydrolyzed the methyl ester
to give carboxylic acid 18.
With orthogonally-protected pyrroloindolines 15 and 18 in hand, completion of the synthesis
required DKP formation. Unfortunately, amide 19 was not formed under a wide variety of
peptide coupling conditions (Scheme 1);7 instead, decomposition of acid 18 was observed.
We note that Danishefsky and coworkers successfully couple two orthogonally-protected
exo-pyrroloindolines in their synthesis of amauromine; however, in contrast to 18, the
carboxylic acid partner in the Danishefsky system contained electron-withdrawing t-
butylcarbamate protecting groups on both nitrogen atoms.8 Taken together, these findings
reveal that the N-substitution of the exo-pyrroloindoline significantly influences the stability
of the activated ester under peptide coupling conditions. After considerable experimentation,
it was determined that pyrroloindolines 17 and 14 could be converted to amino acids 20 and
21 by TFA deprotection and saponification (Scheme 2). Although we recognized that use of
the amino acids in the coupling reaction could give rise to a mixture of three possible
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diketopiperazines (the desired heterodimer and two homodimers), we reasoned that the
overall process could still be more efficient than proceeding through a series of protecting
group manipulations. Thus, treatment of an equimolar mixture of amino acids 20 and 21
with BOP-Cl delivered (−)-lansai B (1) in 38% yield. Each of the two homodimers was also
isolated in 20% yield. 9 Despite the modest yield on the final coupling step, the natural
product is accessible in only six steps (longest linear sequence) and 20% overall yield from
commercially available materials.
Having completed the synthesis of 1, we turned our attention to the synthesis of
nocardioazines A (2) and B (3). Retrosynthetically, it was envisioned that both 2 and 3 could
be accessed from the DKP generated by coupling pyrroloindolines endo-6 and exo-7 (Figure
1). In the forward sense, treatment of a solution of N-methyl-3-allyl indole (22) and acrylate
9a with (S)-BINOL (20 mol %) and SnCl4 (1.6 equiv) delivered exo-pyrroloindoline 23 in
52% yield and 90% ee (Scheme 3). These conditions were highly diastereoselective for
exo-23 (19:1); however, the yield is modest due to allyl migration from C3 to C2 of the
indole under the reaction conditions.9 Neither addition of 2,6-dibromophenol nor use of
other catalysts improved the yield of 23. Cleavage of the TFA group using TfOH in
anhydrous methanol provided, upon basic workup, exo-amine 24.
On the other hand, treatment of N-allylindole 25 and benzyl trifluoroacetamidoacrylate (9b)
with (R)-3,3′-dichloro-BINOL (20 mol %), SnCl4 (1.6 equiv) and 2,6-dibromophenol (0.4
equiv) furnished exo-pyrroloindoline 26 in 57% yield and 98% ee (Scheme 3). The modest
yield of exo-26 results from the moderate diastereoselectivity (5.8:1) of the transformation.
Following transesterification, epimerization using LiHMDS followed by cleavage of the
methyl ester with BBr3 delivered endo-pyrroloindoline 27.
With access to endo-acid 27 and exo-amine 24, we were poised to prepare key DKP 29
(Scheme 3). In contrast to our unsuccessful efforts to couple exo-pyrroloindolines 15 and 18,
it was determined that slow addition of acid 27 to 2.0 equiv amine 24 and BOP-Cl provides
28 in 84% yield.10 Importantly, the unreacted amine 24 was recovered by silica gel
chromatography. When compared to the challenges encountered in the coupling of exo-
pyrroloindolines 15 and 18, the ability to couple exo-24 and endo-27 reveals that, in addition
to the identity of the N-substituents, the relative stereochemistry of the pyrroloindoline
coupling partners is determinate of the ease of peptide formation. Saponification of 28 with
LiOH followed by acidification with 1M HCl delivered DKP 29. Subsequent Pd-catalyzed
deallylation of 29 gave amine 30,11 which upon cross metathesis with 2-methyl-2-butene12
provided (+)- nocardioazine B (3). Thus, the enantioselective total synthesis of (+)-3 was
completed in nine linear steps and 21% overall yield from 3-methylindole.
At this stage, our focus shifted to advancing amine 30 to (+)- nocardioazine A (2). Cross
metathesis of 30 with excess methacrolein delivered enal 31 in 76% yield as a 10:1 E/Z
mixture (Scheme 4). Luche reduction followed by Finkelstein chlorination provided allyl
chloride 33. Gratifyingly, treatment of 33 with TBAI and base in acetonitrile at 80 °C
promoted intramolecular N-alkylation, furnishing macrocycle 34. Unfortunately, exposure of
34 to a wide variety of epoxidation conditions, including dimethyldioxirane, m-
chloroperbenzoic acid, and Jacobsen epoxidation catalysts, failed to produce the natural
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product; instead, the major product was unstable N-oxide 35. Use of excess oxidant or
efforts to isolate 35 and resubject it to epoxidation conditions were also unfruitful, indicating
that the trisubstituted alkenes of 34 and 35 are remarkably inert toward epoxidation.
Inspection of the crystal structure of alkene 34 suggests that the poor reactivity does not
simply result from steric shielding of the double bond; instead, the electron-withdrawing
allylic nitrogen might inductively deactivate the alkene toward electrophiles.
Alternatively, it was possible to diastereoselectively dihydroxylate alkene 34 using
potassium osmate. 13 Selective mesylation at the secondary alcohol and exposure to
potassium carbonate in methanol delivered epi-(C2”)-nocardioazine A (37). Unfortunately,
attempts to correct the stereochemistry by double inversion strategies or oxidation/reduction
sequences were unsuccessful.
Given the challenges encountered in attempting to epoxidize 34, a revised strategy utilizing
an early-stage epoxidation and diketopiperazine-forming macrocyclization was pursued
(Scheme 5). Thus, 3a-allyl pyrroloindoline 23 was converted to allylic alcohol 39 in two
steps. Sharpless asymmetric epoxidation delivered epoxy alcohol 40 in 10:1 dr, 14 which
was converted to mesylate 41. Concomitantly, amine 43 was prepared from endo-
pyrroloindoline 42 by Pd-catalyzed deallylation. After extensive optimization of the reaction
parameters, it was found that treatment of amine 43 and mesylate 41 with catalytic TBAI
and Hünig’s base in acetonitrile at 90 °C delivers bis(pyrroloindoline) 44 in 74% yield.
Exposure of 44 to excess LiOH resulted in saponification of the methyl esters and hydrolysis
of the trifluoroacetamides to give bis(amino acid) 45. We were pleased to find that
subjection of 45 to PyBroP in DMF promoted intramolecular DKP formation to afford (+)-
nocardioazine A (2). The optical rotation of synthetic 2 was determined to be the same sign
and similar magnitude as that reported by Capon and coworkers in the original isolation
paper.2b As a result, we have revised Capon’s assignment of the absolute stereochemistry of
(+)-2 to that shown throughout this manuscript, which is consistent with Ye and coworkers’s
reassignment of (+)-3.3 The synthesis of (+)-2 requires nine linear steps and proceeds in
11% overall yield from 3-allylindole. In addition, these findings establish the viability of
macrocyclization by intramolecular DKP formation.
In summary, the enantioselective total syntheses of the DKP-containing pyrroloindoline
natural products (−)-lansai B (1), (+)- nocardioazine A (2), and (+)-nocardioazine B (3) were
accomplished. These studies demonstrate the utility of enantioselective formal (3 + 2)
cycloaddition reactions to prepare highly functionalized pyrroloindolines for applications in
total synthesis. In addition, subtle changes in the relative stereochemistry and nitrogen
substitution patterns of pyrroloindolines were shown to significantly influence the ability to
prepare bis(pyrroloindolines) by DKP formation. Further investigations of 3 as an inhibitor
of P-glycoprotein are ongoing in our laboratory.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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References
[1]. a) Shaw KTY, Utsuki T, Rogers J, Yu Q-S, Sambamurti K, Brossi A, Ge Y-W, Lahiri DK, Greig
NH. Proc. Natl. Acad. Sci. U.S.A. 2001; 98:7605–7610. [PubMed: 11404470] b) Isham CR,
Tibodeau JD, Jin W, Xu R, Timm MM, Bible KC. Blood. 2007; 109:2579–2588. [PubMed:
17090648]
[2]. a) Tuntiwachwuttikul P, Taechowisan T, Wanbanjob A, Thadaniti S, Taylor WC. Tetrahedron.
2008; 64:7583–7586.b) Raju R, Piggott AM, Huang X, Capon RJ. Org. Lett. 2011; 13:2770–
2773. [PubMed: 21513295]
[3]. Wang M, Feng X, Cai L, Xu Z, Ye T. Chem. Commun. 2012; 48:4344–4346. This communication
resulted in the reassignment of the absolute stereochemistry of nocardioazine B.
[4]. a) Repka LM, Ni J, Reisman SE. J. Am. Chem. Soc. 2010; 132:14418–14420. [PubMed:
20873714] c) Repka LM, Reisman SE. J. Org. Chem. 2013; 78:12314. [PubMed: 24295135] Ni
J, Wang H, Reisman SE. Tetrahedron. 2013; 69:5622–5633. [PubMed: 24039305] For a review
of catalytic, asymmetric methods to prepare pyrroloindolines, see:
[5]. Yang Y, Buchwald SL. J. Am. Chem. Soc. 2013; 135:10642–10645. [PubMed: 23837686] L1 =
dicyclohexyl(2-(2-methoxynaphthalen-1-yl)phenyl)phosphine, see Supporting Information for
structure.
[6]. King SB, Ganem B. J. Am. Chem. Soc. 1994; 116:562–570.
[7]. Valeur E, Bradley M. Chem. Soc. Rev. 2009; 38:606. [PubMed: 19169468]
[8]. Depew KM, Marsden SP, Zatorska D, Zatorski A, Bornmann WG, Danishefsky SJ. J. Am. Chem.
Soc. 1999; 121:11953–11963.
[9]. See Supporting Information.
[10]. See Supporting Information for optimization experiments.
[11]. Garro-Helion F, Merzouk A, Guibe F. J. Org. Chem. 1993; 58:6109–6113.
[12]. Chatterjee AK, Sanders DP, Grubbs RH. Org. Lett. 2002; 4:1939–1942. [PubMed: 12027652]
[13]. Eames J, Mitchell HJ, Nelson A, O’Brien P, Warren S, Wyatt P. J. Chem. Soc., Perkin Trans. 1.
1999:1095–1104.
[14]. Gao Y, Klunder JM, Hanson RM, Masamune H, Ko SY, Sharpless KB. J. Am. Chem. Soc. 1987;
109:5765–5780.
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Figure 1.
Retrosynthetic analysis of (−)-lansai B (1), (+)-nocardioazine A (2), and (+)-nocardioazine
B (3). TFA=trifluoroacetamido.
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Scheme 1.
Synthesis of the pyrroloindoline fragments of (−)-lansai B (1). AcCl=acetyl chloride.
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Scheme 2.
Synthesis of (−)-lansai B (1). BOP-Cl=bis(2-oxo-3-oxazolidinyl) phosphinic chloride,
DIPEA=N,N-diisopropylethylamine
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Scheme 3.
Synthesis of (+)-nocardioazine B (3). LiHMDS=lithium hexamethyl-disilazide,
TfOH=trifluoromethane-sulfonic acid, dba=dibenzylideneacetone, DCE=dichloroethane,
DMBA=1,3-dimethylbarbituric acid, dppb=1,4-bis(diphenylphosphino)butane
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Scheme 4.
Synthesis of the nocardioazine A macrocycle. MsCl=methanesulfonyl chloride,
TBAI=tetrabutylammonium iodide.
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Scheme 5.
Synthesis of (+)-nocardioazine A (2). PyBroP= bromotripyrro-lidinophosphonium
hexafluorophosphate, DMF=N,N-dimethylformamide.
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Enantioselective Total Synthesis of (-)-Lansai B and (+)-Nocardioazines A and B

Enantioselective Total Synthesis of (−)-Lansai B and (+)-
Nocardioazines A and B **
Haoxuan Wang and Prof. Sarah E. Reisman*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
(USA)
Abstract
The concise total syntheses of the bis(pyrroloindolines) (−)-lansai B and (+)- nocardioazines A
and B are reported. The key pyrroloindoline building blocks are rapidly prepared by
enantioselective formal (3 + 2) cycloaddition reactions. The macrocycle of (+)-nocardioazine A is
constructed by an unusual intramolecular diketopiperazine formation.
Keywords
lansai B; nocardioazines; natural products; total synthesis; diketopiperazine synthesis
Pyrroloindoline natural products are a growing family of alkaloids that exhibit promising
biological properties, including antibacterial and anticancer activities. 1 Within this family, a
number of bis(pyrroloindolines) that are joined through a central diketopiperazine (DKP)
ring have been identified.2 These structures include (−)-lansai B (1), (+)-nocardioazine A
(2), and (+)- nocardioazine B (3). Nocardioazine A (2) is of particular interest due to its
activity as an inhibitor of P-glycoprotein, a transmembrane protein overexpressed in many
multi-drug resistant tumors.2b Although these natural products appear quite similar
structurally, close analysis reveals subtle differences in the relative stereochemistry of the
pyrroloindoline units. Whereas 1 is composed of two exo-pyrroloindolines, 2 and 3 each
possess one endo- and one exo-pyrroloindoline. Moreover, the endo- and exo-
pyrroloindolines are in the opposite enantiomeric series, which is necessary to geometrically
accommodate the macrocycle of 2. This interesting stereochemical relationship makes 2 and
3 appealing synthetic targets for asymmetric catalysis, where selection of the appropriate
enantiomer of catalyst dictates the absolute stereochemistry of the pyrroloindoline building
**We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech Center for Catalysis and Chemical Synthesis for access to analytical
equipment, as well as Materia, Inc. and Sigma-Aldrich for kind donations of chemicals. We are grateful to Dr. David VanderVelde for
assistance with NMR structure analysis, and Mr. Larry Henling for X-ray structure determination. The Bruker KAPPA APEXII X-ray
diffractometer was purchased via an NSF Chemistry Research Instrumentation award to Caltech (CHE-0639094). NMR spectra were
obtained on a spectrometer funded by the NIH (RR027690). S.E.R. is a fellow of the Alfred P. Sloan Foundation, a Camille Dreyfus
Teacher-Scholar, and an American Cancer Society Research Scholar. Financial support from the California Institute of Technology,
the NIH (NIGMS RGM097582A), and DuPont is gratefully acknowledged.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
*reisman@caltech.edu, Homepage: http://reismangroup.caltech.edu.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201xxxxxx.
NIH Public Access
Author Manuscript
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2015 June 10.
Published in final edited form as:
Angew Chem Int Ed Engl. 2014 June 10; 53(24): 6206–6210. doi:10.1002/anie.201402571.
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block. The first diastereoselective total synthesis of 3 was reported in 2012 by the Ye group
and required 10 steps starting from L- and D-tryptophan;3 no total syntheses of 1 or 2 have
been published to date.
Recently, we reported a new method to prepare enantioenriched pyrroloindolines from C3-
substituted indoles and 2-amidoacrylates using SnCl4 and catalytic (R)-3,3′-dichloro-BINOL
(Figure 1). 4 Based on the retrosynthetic analysis shown in Figure 1, we anticipated that this
formal (3 + 2) cycloaddition reaction could be used to rapidly and enantioselectively prepare
natural products 1, 2 and 3. Herein, we report the successful execution of this plan and
demonstrate the utility of this catalytic asymmetric method for the synthesis of
diketopiperazine-containing bis(pyrroloindolines).
We first targeted (−)-lansai B (1, Figure 1); retrosynthetically, it was envisioned that the
DKP core could be prepared from the union of pyrroloindolines exo-4 and exo-5 via
sequential peptide bond formation. The required pyrroloindolines could in turn be
synthesized by formal (3 + 2) cycloaddition reactions of the corresponding indoles 13 and
16 (Scheme 1).
Our efforts commenced with Suzuki-Miyaura coupling of bromoindole 114a and
prenylboronate 12 to furnish reverse-prenylated indole 13 in good yield.5 Subjection of
indole 13 and methyl 2-trifluoroacetamidoacrylate (9a) to our formal (3 + 2) cycloaddition
conditions on 0.2 mmol scale provided pyrroloindoline 14 in 84% yield and 92% ee.
However, lower yields of 14 were obtained when the reaction was conducted on
preparatively useful scales (>1.0 mmol). It was hypothesized that on small scale trace water
might help to turn over the chiral catalyst; a survey of several protic additives revealed that
addition of 0.4 equiv 2,6-dibromophenol to the reaction mixture improves the scalability of
the reaction, providing 14 in 85% yield, 14:1 dr, and 92 % ee (major diastereomer).
Presumably 2,6-dibromophenol facilitates turnover of the chiral catalyst, but is not reactive
enough to protonate the transient enolate directly in a non-selective fashion. Cleavage of the
TFA group with anhydrous HCl provided amine 15. 6 Likewise, pyrroloindoline 17 could be
prepared from 1,3-dimethyl indole 16 and acrylate 9a in 79% yield, 12:1 dr, and 93% ee
(major diastereomer). Treatment with LiOH chemoselectively hydrolyzed the methyl ester
to give carboxylic acid 18.
With orthogonally-protected pyrroloindolines 15 and 18 in hand, completion of the synthesis
required DKP formation. Unfortunately, amide 19 was not formed under a wide variety of
peptide coupling conditions (Scheme 1);7 instead, decomposition of acid 18 was observed.
We note that Danishefsky and coworkers successfully couple two orthogonally-protected
exo-pyrroloindolines in their synthesis of amauromine; however, in contrast to 18, the
carboxylic acid partner in the Danishefsky system contained electron-withdrawing t-
butylcarbamate protecting groups on both nitrogen atoms.8 Taken together, these findings
reveal that the N-substitution of the exo-pyrroloindoline significantly influences the stability
of the activated ester under peptide coupling conditions. After considerable experimentation,
it was determined that pyrroloindolines 17 and 14 could be converted to amino acids 20 and
21 by TFA deprotection and saponification (Scheme 2). Although we recognized that use of
the amino acids in the coupling reaction could give rise to a mixture of three possible
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diketopiperazines (the desired heterodimer and two homodimers), we reasoned that the
overall process could still be more efficient than proceeding through a series of protecting
group manipulations. Thus, treatment of an equimolar mixture of amino acids 20 and 21
with BOP-Cl delivered (−)-lansai B (1) in 38% yield. Each of the two homodimers was also
isolated in 20% yield. 9 Despite the modest yield on the final coupling step, the natural
product is accessible in only six steps (longest linear sequence) and 20% overall yield from
commercially available materials.
Having completed the synthesis of 1, we turned our attention to the synthesis of
nocardioazines A (2) and B (3). Retrosynthetically, it was envisioned that both 2 and 3 could
be accessed from the DKP generated by coupling pyrroloindolines endo-6 and exo-7 (Figure
1). In the forward sense, treatment of a solution of N-methyl-3-allyl indole (22) and acrylate
9a with (S)-BINOL (20 mol %) and SnCl4 (1.6 equiv) delivered exo-pyrroloindoline 23 in
52% yield and 90% ee (Scheme 3). These conditions were highly diastereoselective for
exo-23 (19:1); however, the yield is modest due to allyl migration from C3 to C2 of the
indole under the reaction conditions.9 Neither addition of 2,6-dibromophenol nor use of
other catalysts improved the yield of 23. Cleavage of the TFA group using TfOH in
anhydrous methanol provided, upon basic workup, exo-amine 24.
On the other hand, treatment of N-allylindole 25 and benzyl trifluoroacetamidoacrylate (9b)
with (R)-3,3′-dichloro-BINOL (20 mol %), SnCl4 (1.6 equiv) and 2,6-dibromophenol (0.4
equiv) furnished exo-pyrroloindoline 26 in 57% yield and 98% ee (Scheme 3). The modest
yield of exo-26 results from the moderate diastereoselectivity (5.8:1) of the transformation.
Following transesterification, epimerization using LiHMDS followed by cleavage of the
methyl ester with BBr3 delivered endo-pyrroloindoline 27.
With access to endo-acid 27 and exo-amine 24, we were poised to prepare key DKP 29
(Scheme 3). In contrast to our unsuccessful efforts to couple exo-pyrroloindolines 15 and 18,
it was determined that slow addition of acid 27 to 2.0 equiv amine 24 and BOP-Cl provides
28 in 84% yield.10 Importantly, the unreacted amine 24 was recovered by silica gel
chromatography. When compared to the challenges encountered in the coupling of exo-
pyrroloindolines 15 and 18, the ability to couple exo-24 and endo-27 reveals that, in addition
to the identity of the N-substituents, the relative stereochemistry of the pyrroloindoline
coupling partners is determinate of the ease of peptide formation. Saponification of 28 with
LiOH followed by acidification with 1M HCl delivered DKP 29. Subsequent Pd-catalyzed
deallylation of 29 gave amine 30,11 which upon cross metathesis with 2-methyl-2-butene12
provided (+)- nocardioazine B (3). Thus, the enantioselective total synthesis of (+)-3 was
completed in nine linear steps and 21% overall yield from 3-methylindole.
At this stage, our focus shifted to advancing amine 30 to (+)- nocardioazine A (2). Cross
metathesis of 30 with excess methacrolein delivered enal 31 in 76% yield as a 10:1 E/Z
mixture (Scheme 4). Luche reduction followed by Finkelstein chlorination provided allyl
chloride 33. Gratifyingly, treatment of 33 with TBAI and base in acetonitrile at 80 °C
promoted intramolecular N-alkylation, furnishing macrocycle 34. Unfortunately, exposure of
34 to a wide variety of epoxidation conditions, including dimethyldioxirane, m-
chloroperbenzoic acid, and Jacobsen epoxidation catalysts, failed to produce the natural
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product; instead, the major product was unstable N-oxide 35. Use of excess oxidant or
efforts to isolate 35 and resubject it to epoxidation conditions were also unfruitful, indicating
that the trisubstituted alkenes of 34 and 35 are remarkably inert toward epoxidation.
Inspection of the crystal structure of alkene 34 suggests that the poor reactivity does not
simply result from steric shielding of the double bond; instead, the electron-withdrawing
allylic nitrogen might inductively deactivate the alkene toward electrophiles.
Alternatively, it was possible to diastereoselectively dihydroxylate alkene 34 using
potassium osmate. 13 Selective mesylation at the secondary alcohol and exposure to
potassium carbonate in methanol delivered epi-(C2”)-nocardioazine A (37). Unfortunately,
attempts to correct the stereochemistry by double inversion strategies or oxidation/reduction
sequences were unsuccessful.
Given the challenges encountered in attempting to epoxidize 34, a revised strategy utilizing
an early-stage epoxidation and diketopiperazine-forming macrocyclization was pursued
(Scheme 5). Thus, 3a-allyl pyrroloindoline 23 was converted to allylic alcohol 39 in two
steps. Sharpless asymmetric epoxidation delivered epoxy alcohol 40 in 10:1 dr, 14 which
was converted to mesylate 41. Concomitantly, amine 43 was prepared from endo-
pyrroloindoline 42 by Pd-catalyzed deallylation. After extensive optimization of the reaction
parameters, it was found that treatment of amine 43 and mesylate 41 with catalytic TBAI
and Hünig’s base in acetonitrile at 90 °C delivers bis(pyrroloindoline) 44 in 74% yield.
Exposure of 44 to excess LiOH resulted in saponification of the methyl esters and hydrolysis
of the trifluoroacetamides to give bis(amino acid) 45. We were pleased to find that
subjection of 45 to PyBroP in DMF promoted intramolecular DKP formation to afford (+)-
nocardioazine A (2). The optical rotation of synthetic 2 was determined to be the same sign
and similar magnitude as that reported by Capon and coworkers in the original isolation
paper.2b As a result, we have revised Capon’s assignment of the absolute stereochemistry of
(+)-2 to that shown throughout this manuscript, which is consistent with Ye and coworkers’s
reassignment of (+)-3.3 The synthesis of (+)-2 requires nine linear steps and proceeds in
11% overall yield from 3-allylindole. In addition, these findings establish the viability of
macrocyclization by intramolecular DKP formation.
In summary, the enantioselective total syntheses of the DKP-containing pyrroloindoline
natural products (−)-lansai B (1), (+)- nocardioazine A (2), and (+)-nocardioazine B (3) were
accomplished. These studies demonstrate the utility of enantioselective formal (3 + 2)
cycloaddition reactions to prepare highly functionalized pyrroloindolines for applications in
total synthesis. In addition, subtle changes in the relative stereochemistry and nitrogen
substitution patterns of pyrroloindolines were shown to significantly influence the ability to
prepare bis(pyrroloindolines) by DKP formation. Further investigations of 3 as an inhibitor
of P-glycoprotein are ongoing in our laboratory.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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References
[1]. a) Shaw KTY, Utsuki T, Rogers J, Yu Q-S, Sambamurti K, Brossi A, Ge Y-W, Lahiri DK, Greig
NH. Proc. Natl. Acad. Sci. U.S.A. 2001; 98:7605–7610. [PubMed: 11404470] b) Isham CR,
Tibodeau JD, Jin W, Xu R, Timm MM, Bible KC. Blood. 2007; 109:2579–2588. [PubMed:
17090648]
[2]. a) Tuntiwachwuttikul P, Taechowisan T, Wanbanjob A, Thadaniti S, Taylor WC. Tetrahedron.
2008; 64:7583–7586.b) Raju R, Piggott AM, Huang X, Capon RJ. Org. Lett. 2011; 13:2770–
2773. [PubMed: 21513295]
[3]. Wang M, Feng X, Cai L, Xu Z, Ye T. Chem. Commun. 2012; 48:4344–4346. This communication
resulted in the reassignment of the absolute stereochemistry of nocardioazine B.
[4]. a) Repka LM, Ni J, Reisman SE. J. Am. Chem. Soc. 2010; 132:14418–14420. [PubMed:
20873714] c) Repka LM, Reisman SE. J. Org. Chem. 2013; 78:12314. [PubMed: 24295135] Ni
J, Wang H, Reisman SE. Tetrahedron. 2013; 69:5622–5633. [PubMed: 24039305] For a review
of catalytic, asymmetric methods to prepare pyrroloindolines, see:
[5]. Yang Y, Buchwald SL. J. Am. Chem. Soc. 2013; 135:10642–10645. [PubMed: 23837686] L1 =
dicyclohexyl(2-(2-methoxynaphthalen-1-yl)phenyl)phosphine, see Supporting Information for
structure.
[6]. King SB, Ganem B. J. Am. Chem. Soc. 1994; 116:562–570.
[7]. Valeur E, Bradley M. Chem. Soc. Rev. 2009; 38:606. [PubMed: 19169468]
[8]. Depew KM, Marsden SP, Zatorska D, Zatorski A, Bornmann WG, Danishefsky SJ. J. Am. Chem.
Soc. 1999; 121:11953–11963.
[9]. See Supporting Information.
[10]. See Supporting Information for optimization experiments.
[11]. Garro-Helion F, Merzouk A, Guibe F. J. Org. Chem. 1993; 58:6109–6113.
[12]. Chatterjee AK, Sanders DP, Grubbs RH. Org. Lett. 2002; 4:1939–1942. [PubMed: 12027652]
[13]. Eames J, Mitchell HJ, Nelson A, O’Brien P, Warren S, Wyatt P. J. Chem. Soc., Perkin Trans. 1.
1999:1095–1104.
[14]. Gao Y, Klunder JM, Hanson RM, Masamune H, Ko SY, Sharpless KB. J. Am. Chem. Soc. 1987;
109:5765–5780.
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Figure 1.
Retrosynthetic analysis of (−)-lansai B (1), (+)-nocardioazine A (2), and (+)-nocardioazine
B (3). TFA=trifluoroacetamido.
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Scheme 1.
Synthesis of the pyrroloindoline fragments of (−)-lansai B (1). AcCl=acetyl chloride.
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Scheme 2.
Synthesis of (−)-lansai B (1). BOP-Cl=bis(2-oxo-3-oxazolidinyl) phosphinic chloride,
DIPEA=N,N-diisopropylethylamine
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Scheme 3.
Synthesis of (+)-nocardioazine B (3). LiHMDS=lithium hexamethyl-disilazide,
TfOH=trifluoromethane-sulfonic acid, dba=dibenzylideneacetone, DCE=dichloroethane,
DMBA=1,3-dimethylbarbituric acid, dppb=1,4-bis(diphenylphosphino)butane
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Scheme 4.
Synthesis of the nocardioazine A macrocycle. MsCl=methanesulfonyl chloride,
TBAI=tetrabutylammonium iodide.
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Scheme 5.
Synthesis of (+)-nocardioazine A (2). PyBroP= bromotripyrro-lidinophosphonium
hexafluorophosphate, DMF=N,N-dimethylformamide.
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English

https://authors.library.caltech.edu/45476/13/nihms-597340.pdf

Enantioselective Total Synthesis of (-)-Lansai B and (+)-Nocardioazines A and B

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