Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels Alder cycloadditions

Article abstract of DOI:10.1021/ja0625430

A concise synthetic approach to the hetisine C²⁰-diterpenoid alkaloids is reported. The total synthesis of (±)-nominine was accomplished in a 15-step sequence employing a dual cycloaddition strategy. Key features of the synthesis include a reve

Full text of DOI:10.1021/ja0625430

Published on Web 06/17/2006
Efficient Synthetic Access to the Hetisine C20-Diterpenoid Alkaloids. A
Concise Synthesis of Nominine via Oxidoisoquinolinium-1,3-Dipolar and
Dienamine-Diels-Alder Cycloadditions
Kevin M. Peese and David Y. Gin*,†
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received April 12, 2006; E-mail: gind@mskcc.org
Chart 1
The hetisine natural products are a family of complex C20-
diterpenoid alkaloids isolated from the Aconitum, Consolida,
Delphinium, Rumex, and Spiraea genera, plants that have been
widely used in traditional herbal medicine.1 Several of the more
than 100 members of the hetisine alkaloids, exemplified by
nominine (1, Chart 1),2 kobusine (2),3 and hetisine (3),4 exhibit a
diverse spectrum of biological activities, including potent vasodi-
lating, antiarrhythmic, immunomodulating, and analgesic activities,
in vivo.1 Although the hetisine alkaloids have been known for more
Scheme 1
than a half-century, the majority of synthetic efforts directed at these
complex targets have involved only a handful of synthetic model
preparations of aza-polycyclic substructures.5 In fact, the total
synthesis of any member of the hetisine alkaloids remained elusive
until the recent landmark work of Muratake and Natsume, in which
a 40-step synthesis of (()-nominine (1) was accomplished in 2004.6
Scheme 2 a
We now report a convergent, dual-cycloaddition approach to the
hetisine alkaloids, illustrated by an exceedingly concise synthesis
of the antiarrhythmic agent nominine (1).
Consideration of the structure of nominine (1) in a conformational
representation (Scheme 1) reveals a potentially expedient route to
the hetisine core via two cycloaddition processes (i.e., 4). These
include an aza-1,3-dipolar cycloaddition (1,3-DC) to construct the
bridged pyrrolidine ring, followed by a Diels-Alder (DA) reaction
to assemble the [2.2.2]-bicyclic substructure within 1. Because
functional group compatibility issues would likely preclude a
tandem double-cycloaddition event, synthetic efforts commenced
with the preparation of a substrate incorporating the requisite
dipole-dipolarophile complement in conjunction with a latent
diene-dienophile pair.
Synthesis of a suitable dipolarophile precursor was accomplished
a Reagentsandconditions: (a)t-BuLi,Et2O,-23°C;ClCH2C(O)N(OMe)Me,
in a short series of steps, beginning with ortho-lithiation of
p-anisaldehyde dimethyl acetal (5, Scheme 2),7 followed by its
nucleophilic addition to 2-chloro-N-methoxyl-N-methylacetamide,
to provide the aryl ketone 6 (52%). Subsequent exchange of the
R-chloro substituent in 6 to its R-azido counterpart (NaN3, 95%)
and acid-catalyzed rearrangement afforded the cyclic bis(acetal) 7
as a 3:2 mixture of diastereomers (99%). The dipolarophile
component was accessed efficiently from 3-methylcyclohexenone
(8), in which conjugate cyanation8 followed by enolate trapping
with Tf2O led to enol triflate 9 (81%). Sequential nitrile reduction
to the aldehyde (DIBAL-H, 92%) and Pd0-catalyzed cross coupling
52%; (b) NaN3, acetone, 23 °C, 95%; (c) AcCl, MeOH, 23 °C, 99% (3:2
dr); (d) AlEt2CN, benzene, 23 °C; TBAT, Tf2O, benzene, 23 °C, 81%; (e)
DIBAL-H, PhMe, 0 °C, 92%; (f) Zn(CN)2, Pd(PPh3)4, DMF, 60 °C, 85%;
(g) 7, 10, PBu3, NaBH(OAc)3, CH2Cl2, 23 °C, 79% (3:3:2:2 dr); (h) 10%
TFA in CH2Cl2, 0 °C, 93%.
TFA-catalyzed MeOH extrusion and isomerization to the 4-oxido-
isoquinolinium betaine 12 (93%), which served as a suitable aza-
1,3-dipole.
1,3-Dipolar cycloadditions involving oxidopyridinium betaines
have proven to be valuable in alkaloid synthesis;10 however, the
use of oxidoisoquinolinium betaines in this capacity is compara-
tively rare.11 When a solution of betaine 12 in THF (5 mM) was
heated in a sealed tube at 180 °C (Scheme 3), intramolecular
cycloaddition occurred with 97% conversion to provide an easily
separable mixture of pyrrolidine constitutional isomers 15 and 16,
each arising from differential facial approach of the dipole-
dipolarophile partners. While the desired cycloadduct 15 was formed
as the minor constituent (15:16, 1:3.6),12 the isomeric ratio was
verified to be the result of thermodynamic selection. Indeed, the
cycloaddition event was found to be reVersible under the reaction
9
with Zn(CN)2 provided the ene-nitrile dipolarophile 10 (85%),
ready to be condensed with the aza-dipole precursor 7. This
convergent step was accomplished with a Staudinger-aza-Wittig
reaction (7, 10, PBu3) in conjunction with imine reduction (NaBH-
(OAc)3) to afford the amine 11 (79%) as a mixture of four
diastereomers. All four diastereomers 11 were then converged via
† Address correspondence to: Department of Molecular Pharmacology
and Chemistry, The Sloan-Kettering Institute, Memorial Sloan-Kettering
Cancer Center, 1275 York Avenue, New York, NY 10021.
9
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J. AM. CHEM. SOC. 2006, 128, 8734-8735
10.1021/ja0625430 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
15-step sequence with only a single protective group manipulation.
Notable features include a reversible intramolecular 4-oxidoiso-
quinolinium betaine 1,3-dipolar cycloaddition as well as a pyrro-
lidine-induced dienamine isomerization/Diels-Alder cascade. This
rapid synthetic access into the hetisine skeleton should pave the
way for the construction of other, more highly oxidized, members
of the C20-diterpenoid alkaloids such as the antiarrhythmic guan-
fu bases.1
Acknowledgment. This research was supported by the NIH-
NIGMS (GM67659), Abbott, Eli Lilly, Johnson & Johnson, Merck,
and Pfizer. A Pharmacia (Pfizer) predoctoral fellowship to K.M.P.
is acknowledged. We thank Dr. H. Muratake for supplying spectral
data for 1.
Supporting Information Available: Experimental details (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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conditions, thereby enabling reiterative thermal re-equilibration of
the isolated undesired cycloadduct 16 to enhance the production
of 15 with minimal loss of material.
Advancement of the cycloadduct 15 continued with a ketone-
to-methylene reduction to form 17 (NaBH4; SOCl2; Bu3SnH, AIBN,
68% overall) and conversion of the nitrile to the alkene 18 (DIBAL-
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Birch reduction (Na0, Me2CHOH, THF, NH3, -78 °C)13 of the
aromatic ring in 18 and acidic workup led to the formation of the
â,γ-unsaturated cyclohexenone 19 (97%), which, upon exposure
to pyrrolidine in MeOH at 60 °C, afforded the intramolecular
Diels-Alder adduct 21 in 78% yield after silica gel chromatography.
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(12) 1H NMR analysis of the 1,3-dipolar cycloadditions revealed production
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Through the establishment of a dual cycloaddition strategy, a
short total synthesis of (()-nominine (1) was accomplished in a
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