A stereoselective synthesis of (+)-gonyautoxin 3

Article abstract of DOI:10.1021/ja805651g

An asymmetric synthesis of the paralytic shellfish poison (PSP), (+)-gonyautoxin 3, is described. A unique, Rh-catalyzed amination reaction provides rapid access to the heteratom-rich, tricyclic core of the toxin, which is common to more than 30 related natural products. The completed route should facilitate the preparation of other naturally occurring PSPs and designed analogues thereof. Copyright

Full text of DOI:10.1021/ja805651g

Published on Web 08/29/2008
A Stereoselective Synthesis of (+)-Gonyautoxin 3
John V. Mulcahy and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 20, 2008; E-mail: jdubois@stanford.edu
The waters of the “red tide” are awash with noxious agents, the
most infamous of which are the paralytic shellfish poisons (PSPs).1
Small molecule, bis-guanidinium structures s saxitoxin, neosax-
itoxin, and the gonyautoxins s unique in both their form and
function, represent the principle constituents of PSPs.2 These highly
polar, heteroatom-rich compounds are exquisitely designed corks
that act to stopper ion flux through voltage-gated Na+ channels
(NaV), thus inhibiting electrical conduction in cells.3 The intricate
molecular shape common to these toxins coupled with their
importance as pharmacological tools for ion channel study have
inspired efforts aimed at their de novo assembly. Three prior works
have described preparations of saxitoxin (STX) and one a decar-
bamoyloxy form.4,5 The first synthetic path to any member of the
more than 20 known sulfated poisons, gonyautoxin 3 (GTX 3), is
outlined in this report (Figure 1).6,7
Figure 1. Pyrrole oxidation highlights synthetic approach to GTX 3.
The five-membered cyclic guanidine in GTX 3 became the focal
point of our synthetic analysis following our recent disclosure of
an oxidative method for 2-aminoimidazoline formation.8 This
transformation is thought to proceed through the intermediacy of a
Rh-bound guanidine nitrene, a reactive species capable of modifying
both C-H and π-bonds. For the purpose of crafting GTX 3,
amination of a pyrrole nucleus by the guanidine nitrenoid presented
a novel application of this technology (Figure 1). Such a reaction
could occur through either a strained aziridine 3 or dipolar species
4, attack of which by a nucleophile at either C10 or C12 would
generate the desired tricyclic core.9 This regiochemical issue
notwithstanding, such a strategy simplifies the GTX problem to a
rather unassuming bicyclic intermediate 1. Pursuant to this approach,
a route to bis-guanidine 1 was formulated that would exploit an
intramolecular addition of a pyrrole to an activated imine. Although
limited in precedent, this type of Pictet-Spengler reaction could be
quickly evaluated, as the necessary precursor 2 is easily accessed
from serine.
with pyrrole modification. Acetic acid, produced as a byproduct in
this transformation, adds regio- and stereoselectively to the putative
1
aziridine, affording N,O-acetal 8 as the only product based on H
NMR analysis of the reaction mixture.12,13 In spite of the fact that
acetate attack occurs exclusively at C10 instead of C12, the isolated
tricycle 8 is suitably disposed for completion of the GTX 3
synthesis.
The stability of 8 toward handling and purification proved
somewhat capricious, thus prompting a decision to reduce the
presumably labile N,O-acetal unit. This transformation is
smoothly performed with Et3SiH and BF3 · OEt2, giving the
C11-C12 alkene in 81% yield. None of the transposed olefin
product is detected under these conditions. Installation of the
1° carbamate is then made possible using C13CC(O)NCO.14
Intermediate 9 contains all of the necessary carbon centers found
in the natural product.
The synthesis of GTX 3 commences with a three-step sequence
that transforms L-serine methyl ester to aldehyde 5 (Scheme 1).10
Condensation of this aldehyde with allylamine is followed by
treatment with BF3 ·OEt2, which effects the desired ring closure to
furnish the trans-substituted urea 6 with >20:1 diastereoselectiv-
ity.11 Assuming the C5/C6 stereochemistry (GTX numbering) in
this product is established under kinetic control, a conformation
that minimizes allylic strain between the substituents on C6 and
N7 could account for the observed sense of induction. Forwarding
6 to the requisite amination precursor 7 was efficiently achieved
through a sequence of four transformations; of note is the
development of a single step process for sequential allyl deprotec-
tion and isothiourea formation (cf., step e, 6f7, Tces )
SO3CH2CCl3).
Alternative approaches for transforming alkene 9 to the
corresponding R-ketol have been examined. Regioselective
ketohydroxylation would provide the most expeditious route to
the desired target; such conditions have not yet been identified.4f
By contrast, olefin dihydroxylation using 2 mol % OsO4 and
N-methylmorpholine-N-oxide is quite effective and affords diol
10 as a single stereoisomer. Analysis of molecular models
indicates that the ꢀ-face of the alkene in 9 is more exposed,
consistent with the observed selectivity. Protection of the
C11-OH is accomplished under highly optimized conditions
that employ benzoyl cyanide and DMAP. Other, more standard
acylating agents (e.g., PhC(O)Cl) in combination with 3° amine
or pyridine bases produce inseparable mixtures of isomeric,
benzoylated materials. While it is possible to install alternative
t
Successful application of the Rh-catalyzed amination reaction
with guanidine 7 assembles the tricyclic frame of GTX 3 in a
singular, defining event. The reaction is chemoselective, as C-H
insertion into the proximal C6 center does not appear to compete
blocking groups such as BuMe2Si- at C11, their larger steric
volume prevents subsequent oxidation of the C12 alcohol. With
11, ketone formation at C12 is enabled using Dess-Martin
periodinane.15
9
12630 J. AM. CHEM. SOC. 2008, 130, 12630–12631
10.1021/ja805651g CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1a
a Conditions: (a) pyrrole-1-carboxylic acid, DCC, Et3N, CH2Cl2, 65%; (b) tBuPh2SiCl, imidazole, DMF, 97%; (c) iBu2AlH, CH2Cl2, -90 °C; (d) allylamine,
BF3 ·OEt2, CH2Cl2, 56% (2 steps, >20:1 trans/cis); (e) Pd(PPh3)4, 1,3-dimethylbarbituric acid, CH2Cl2; then Na2CO3, TcesNd(SMe)Cl, 94%; (f) EtOSO2CF3,
i
2,4,6-tri-tert-butylpyrimidine, CH2Cl2, 47 °C, 78%; (g) NH3, NH4OAc, MeOH, 60 °C, 82%; (h) CCl3C(O)Cl, Pr2NEt, CH2Cl2, -20 °C, 87%; (i) 5 mol%
Rh2(esp)2, PhI(OAc)2, MgO, CH2Cl2, 42 °C, 61%; (j) Et3SiH, BF3 ·OEt2, CH2Cl2, 81%; (k) nBu4NF, THF; (l) Cl3CC(O)NCO, CH2Cl2, -20 °C; then MeOH,
76% (2 steps); (m) 2 mol% OsO4, NMO, THF/H2O, 81%; (n) PhC(O)CN, DMAP, CH2Cl2/MeCN, -78 °C, 67%; (o) Dess-Martin periodinane, CH2Cl2,
79%; (p) H2, Pd/C, CF3CO2H, MeOH; then NH3, MeOH, 83%; (q) DMF ·SO3, 2,6-di-tert-butyl-4-methylpyridine, NMP, 71%.
Removal of all three protecting groups in 12 through a single
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)
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Acknowledgment. J.V.M. is grateful to the National Science
Foundation for a graduate fellowship. This work has been supported
by a grant from the NIH and by generous gifts from Pfizer, Amgen,
Boehringer-Ingelheim, and GlaxoSmithKline.
Supporting Information Available: Analytical data for selected
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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