Magnesiate Addition/Ring-Expansion Strategy to Access the 6-7-6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b02260

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C₂₀-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to

Full text of DOI:10.1021/acs.orglett.7b02260

Letter
pubs.acs.org/OrgLett
Magnesiate Addition/Ring-Expansion Strategy To Access the 6−7−6
Tricyclic Core of Hetisine-Type C -Diterpenoid Alkaloids
20
Jason J. Pflueger, Louis C. Morrill,† Justine N. deGruyter, Melecio A. Perea, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
*
S Supporting Information
ABSTRACT: A synthetic strategy to access the fused 6−7−6 tricyclic core of hetisine-type C -diterpenoid alkaloids is reported.
20
This strategy employs a Diels−Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a
vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium−halogen exchange with
a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6−7−6
tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C−N bond formation and subsequent
elaboration.
iterpenoid alkaloid natural products have emerged as
attractive synthetic targets by virtue of their complex
Scheme 1. Synthetic Strategy toward the Hetisine Core
D
caged skeletons and intriguing biological interactions, partic-
ularly with voltage-gated ion channels. Among the many
1
structural classifications that have been established, the hetisine-
type C -diterpenoid alkaloids have emerged as compounds of
20
particular interest. They possess one of the most complex
frameworks of any of the diterpenoid alkaloids, with a tertiary
amine embedded in a caged heptacyclic core (see nominine
(1), Figure 1), and are one of the most prominent diterpenoid
5
6
2
004 and again by Gin in 2006. Despite these initial
Figure 1. Hetisine- and hetidine-type diterpenoid alkaloids.
successes, the synthesis of more highly oxygenated hetisine-
type alkaloids remains elusive, and new strategies to access
these secondary metabolites with suitable functional group
handles are required. The synthesis of the related hetidine-type
core, which lacks the N−C6 bond (Figure 1), has seen more
2
alkaloid types, with over 120 known members. Furthermore,
the hetisine-type alkaloid guan-fu base A (3, Scheme 1) is
currently in clinical use in China for the treatment of
7
3
recent success, with routes from our group as well as the
arrhythmia, highlighting the therapeutic potential of these
8
9
laboratories of Baran and Qin. While early work by Okamoto
natural products. The observed biological effects of guan-fu
base A and many other diterpenoid alkaloid natural products
are believed to arise from their interactions with voltage-gated
ion channels, which are emerging as important therapeutic
suggested a final N−C6 bond could be formed at a late stage
10
through HLF-type chemistry, this transformation has not
been successfully realized by other investigators, suggesting the
need for novel strategies that incorporate the formation of this
N−C6 bond into the synthetic plan.
4
targets.
To date, only a single hetisine-type diterpenoid alkaloid
natural product has succumbed to total synthesis: the
monohydroxylated alkaloid nominine (1, Figure 1). This
molecule was first synthesized by Natsume and Muratake in
Received: July 23, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02260
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Our research group has identified a central fused 6−7−6
tricycle (Scheme 1, highlighted in red) as a key structural motif
in the core scaffold of these complex alkaloids. This design
choice arises from a network analysis approach to retrosyn-
Scheme 3. Retrosynthesis
1
1
thesis in which the [2.2.2]bicycle is forged late-stage through
a [4 + 2] cycloaddition reaction on a derivative of vinyl arene 5.
Further disconnection of the C−N bonds leads both the
hetidine and hetisine cores back to an all-fused 6−7−6 tricycle
(6), the key target for our collective synthetic strategies.
Initial efforts in our group utilized a gallium(III)-catalyzed
cycloisomerization reaction to convert alkyne 7 into 6−7−6
7
tricycle 8. While this reaction proceeds in a high 89% yield,
alkyne 7 takes 13 steps to synthesize (longest linear sequence),
and the resulting tricycle is relatively unfunctionalized (Scheme
2). Several steps are then required to introduce key functional
Scheme 4. Dienophile Synthesis and Diels−Alder
Cycloaddition
Scheme 2. Efforts toward the Central 6−7−6 Tricycle
After exploring a wide range of nucleophiles, we discovered
benzylic ester 17 (readily synthesized through esterification of
3
-methoxyphenylacetic acid) adds with complete chemo-
selectivity into the desired carbonyl group (Scheme 5).
groups for both the C−N bond forming reactions and the [4 +
Scheme 5. Elaboration to Vinyl Lactone−Acetal
2
] cycloaddition. Despite these challenges, the overall strategy
was validated with the successful synthesis of the hetidine-type
core, which was further elaborated to dihydronavirine (2,
Figure 1), the formal hydrogenation product of the natural
product navirine.
On the basis of this precedent, we embarked on a
streamlined and higher yielding synthesis of a tricycle that
would be more ideally functionalized to access the hetisine-type
core. We envisioned diketoaldehyde 10 as an ideal precursor,
with carbonyl groups at all three carbon atoms that form C−N
bonds in the hetisine-type alkaloids (Scheme 3). Intramolecular
addition of the aromatic ring moiety in 9 was predicted to
enable the synthesis of this desired tricycle. We envisioned a
rapid synthesis of this compound from bicyclic anhydride 11,
which could be readily accessed through a Diels−Alder
cycloaddition from diene 12 and dienophile 13.
The synthesis begins with the construction of maleic
anhydride dienophile 13 (Scheme 4) following a sequence
used to synthesize a related compound by Wood and co-
Treatment of the resulting adduct with HCl then cleaves the
silyl ether, and the resulting primary hydroxyl group
spontaneously cyclizes to form lactone acetal 18. A Krapcho-
type decarboxylation with lithium chloride facilitates removal
of the methyl ester, after which a one-pot alkene hydro-
genation/benzyl ether hydrogenolysis provides primary alcohol
19. A Grieco elimination completes the installation of the vinyl
group needed for eventual formation of the [2.2.2]bicycle,
affording 9. This sequence proceeds in only five steps and 52%
1
2
workers. In this route, benzyl protection of commercially
available 3-butyn-1-ol (14) is followed by a palladium-catalyzed
dicarboxylation reaction to access diester 16 in 65% yield over
two steps after optimization. Saponification of the diester
enabled a dehydrative cyclization reaction in the presence of
acetic anhydride to give dienophile 13 in four steps. Diels−
14
13
Alder cycloaddition with known diene 12 then affords Diels−
Alder adduct 11 in 72% yield as a single diastereomer.
B
DOI: 10.1021/acs.orglett.7b02260
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overall yield from Diels−Alder adduct 11, allowing rapid access
to the cyclization precursor.
we have now designed an efficient route to a highly
functionalized 6−7−6 tricycle. This route features a highly
diastereoselective Diels−Alder cycloaddition, chemoselective
addition of a benzyl enolate nucleophile, and a finely tuned
magnesiate addition/ring-expansion/oxidation sequence to
access the desired tricycle. This tricycle possesses key functional
groups at strategic locations, with carbonyl groups at all three
carbon atoms bearing C−N bonds in the hetisine-type
alkaloids, as well as the aromatic ring and vinyl group required
for the eventual [4 + 2] cycloaddition reaction. Further studies
will focus on the selective derivatization and elaboration of this
tricycle into the hetisine-type core, selected natural products,
and structural derivatives for biological evaluation.
We initially explored using a direct Friedel−Crafts cyclization
to forge the desired C−C bond. Despite screening a variety of
Lewis acids, cyclization was not observed, with most attempts
simply leading to recovery of starting material. We then turned
to the formation of a discrete aromatic nucleophile via metal−
halogen exchange of an aryl iodide. An investigation of
electrophilic iodination conditions, including iodine mono-
chloride and NIS, with and without Bronsted or Lewis acid
additives, identified an indium(III) triflate-catalyzed protocol
15
developed by Romo and co-workers as the most effective,
producing the desired aryl iodide (21), along with its ortho-
positioned isomer (20), in a roughly 1:1 mixture (Scheme 6).
ASSOCIATED CONTENT
Supporting Information
■
Scheme 6. Completion of the Desired 6−7−6 Tricycle
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02260.
Experimental details and spectroscopic data (PDF)
Compound 10 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: rsarpong@berkeley.edu.
ORCID
Louis C. Morrill: 0000-0002-6453-7531
Richmond Sarpong: 0000-0002-0028-6323
Present Address
†School of Chemistry, Cardiff University, Main Building, Park
Place, Cardiff, CF10 3AT, U.K.
These isomers were readily separated, and the undesired isomer
could be recycled through metal−halogen exchange to
regenerate vinyl lactone−acetal 9 (see the Supporting
Information for details). Ultimately, a 65% yield of desired
aryl iodide 21 (based on recovered starting material) could be
obtained.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
With aryl iodide 21 in hand, conditions for metal−halogen
We are grateful to the NIH (NIGMS R01 GM084906) for
financial support. We thank the NSF and Eli Lilly for graduate
fellowships to J.J.P. and the Amgen Scholars Program for
summer fellowships to J.N.D. and M.A.P. We also thank A.
DiPasquale (UC Berkeley) for solving the crystal structure of
10 (displayed with CYLView), supported by the NIH Shared
Instrumentation Grant (S10-RR027172).
16
exchange were then investigated. Lithium-halogen exchange
proved to be too reactive, leading only to nonspecific
decomposition products. Direct Grignard formation with
magnesium turnings was likewise unsuccessful, returning only
17
starting material. Classic magnesium-halogen exchange with
iso-propyl magnesium chloride or with the Turbo Grignard
1
8
reagent likewise proved to be too unreactive to lead to
product formation. Lithium trialkylmagnesiates, developed by
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■
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the crude reaction mixture was directly oxidized with Dess−
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DOI: 10.1021/acs.orglett.7b02260
Org. Lett. XXXX, XXX, XXX−XXX