Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (-)-2(S)-Cathafoline, and (-)-Aspidophylline A

Article abstract of DOI:10.1021/jacs.5b12880

The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (-)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described.

Full text of DOI:10.1021/jacs.5b12880

Communication
pubs.acs.org/JACS
Enantioselective Total Syntheses of Akuammiline Alkaloids
(
+)-Strictamine, (−)-2(S)‑Cathafoline, and (−)-Aspidophylline A
†
†
Jesus Moreno, Elias Picazo, Lucas A. Morrill, Joel M. Smith, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
*
S Supporting Information
succumbed to total synthesis. We have targeted the total
ABSTRACT: The akuammiline alkaloids are a family of
natural products that have been widely studied for decades.
Although notable synthetic achievements have been made
recently, akuammilines that possess a methanoquinoliz-
idine core have evaded synthetic efforts. We report an
asymmetric approach to these alkaloids, which has
culminated in the first total syntheses of (−)-2(S)-
cathafoline and the long-standing target (+)-strictamine.
Moreover, the first enantioselective total synthesis of
aspidophylline A is described.
synthesis of two such alkaloids: strictamine (1) and 2(S)-
11
12
cathafoline (2), isolated in 1966 and 2014, respectively. As a
salient feature of their caged methanoquinolizidine cores, each
of these natural products also contains a densely functionalized
cyclohexane ring that is part of two conjoined [3.3.1]-
azabicycles. Strictamine (1) possesses an indolenine motif
and four stereocenters, whereas 2(S)-cathafoline (2) bears an
indoline unit and five contiguous stereocenters. The rich
13
history, structural complexity, and bioactivity of 1 have
prompted many synthetic efforts beginning with seminal
1
4a−d
studies by Dolby and Bosch and Bennasar.
More recent
14e
14f
approaches by the laboratories of Sakai, Cook, Tokuya-
he akuammiline alkaloids are a family of bioactive natural
14g
14h
14i
1
ma,
Matsuo,
and Zhu have also been put forward.
T
products that have been studied for over a century. To
date, over 30 akuammilines have been isolated, examples of
which are shown in Figure 1 (1−6). These natural products can
be divided into four structural subclasses, with completed total
syntheses recently reported in three of these categories.
Aspidophylline A (3), an example of the furoindoline-
containing subclass, has been accessed synthetically by our
Herein, we describe an enantioselective approach to several
akuammilines, including family members that contain the
elusive methanoquinolizidine core. These efforts result in the
first enantioselective total syntheses of aspidophylline A (3),
strictamine (1), and 2(S)-cathafoline (2).
Our retrosynthetic analysis for the enantioselective total
syntheses of strictamine (1) and 2(S)-cathafoline (2) is shown
in Scheme 1. It was envisioned that both natural products could
2
3
4
group and the laboratories of Zhu and Ma. In addition, our
laboratory has completed the total synthesis of picrinine (6), a
5
C5-oxidized akuammiline. With regard to the skeletally
Scheme 1
rearranged akuammilines, breakthroughs include total syntheses
6
7
8
of vincorine (4) by Qin, Ma, and MacMillan, and total
9
10
syntheses of scholarisine A (5) by Smith and Snyder.
Despite these synthetic triumphs, one structural subclass of
the akuammilines has remained inaccessible. Namely, com-
pounds that possess a methanoquinolizidine core have not yet
Received: December 9, 2015
Figure 1. Representative akuammiline alkaloids 1−6.
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b12880
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
be derived from tetracyclic chloride 8. In the forward sense,
Scheme 3
late-stage deprotection and cyclization would forge the
15
methanoquinolizidine core (see transition structure 7). In
turn, chloride 8 would arise from methanolysis and subsequent
chlorination of lactone 9. This key late-stage compound would
be accessed from phenylhydrazine (11) and ketolactone 12
using an uncommon reductive variant of the interrupted
16−18
Fischer indolization reaction.
The success of this step
would lead to the introduction of two new rings and two
stereogenic centers, including the C2 stereocenter seen in 2(S)-
cathafoline (2) (via transition structure 10) and the challenging
C7 quaternary center common to all akuammilines. Ketolac-
tone 12, which would also be a viable intermediate toward
aspidophylline A (3), would be prepared from enone 13, the
19
product of a gold-mediated cyclization of enantioenriched
silyl enol ether 14.
Our synthetic studies commenced with the asymmetric
construction of the akuammiline [3.3.1]-azabicyclic core and
the formation of enal 20 (Scheme 2). Beginning with
Scheme 2
23
an intermediate mixed acetal bearing an iodide, thus setting
24
the stage for a Ueno−Stork cyclization. Exposure of this
compound to radical cyclization conditions efficiently delivered
C7-alkylated product 23 with diastereocontrol about the two
newly formed stereocenters. From 23, the desired ketolactone
1
2 could be readily accessed via a sequence involving hydrolysis
and reduction (23 → 24), followed by lactonization and
alcohol oxidation (24 → 12).
2
Having accessed ketolactone 12 in an enantioenriched form,
we opted to pursue the asymmetric total synthesis of
aspidophylline A (3) (Scheme 3). As suggested earlier, three
prior total syntheses of 3 have been reported, all of which
2
2
−4
deliver racemic material.
Analogous to our earlier efforts,
albeit with a nosyl protecting group instead of a tosyl group,
ketolactone 12 was exposed to phenylhydrazine (11) and TFA
to provide Fischer indolization adduct 25. In the same pot,
treatment of 25 with K CO in methanol furnished furoindo-
2
0
dibenzoate 15, a Trost desymmetrization was performed. In
the event, dibenzoate 15 was treated with sulfonamide 16 in the
presence of a suitable Pd precatalyst and (R, R)-DACH-phenyl
Trost ligand. Direct saponification of the product furnished
alcohol 17 in 89% yield. Subsequent oxidation delivered enone
2
3
line 27, presumably via transition structure 26. This trans-
formation serves to introduce two new rings, four new bond
linkages, and the challenging C7 quaternary stereocenter, all
with complete diastereoselectivity. For reasons that shall soon
become apparent, it should be noted that no evidence of
epimerization at C16 is seen in this complexity-generating
transformation. To complete the synthesis of (−)-aspidophyl-
1
8, a crystalline compound that was deemed suitable for X-ray
21
analysis. By virtue of the heavy atom, it was found that the
desired C3 stereocenter had been introduced in the Trost
desymmetrization step. To attempt the key gold-mediated
cyclization, ketone 18 was advanced to silyl enol ether 14,
which in turn was subjected to a modification of Li’s cyclization
conditions. This transformation smoothly delivered a 10:1
mixture of isomeric bicyclic adducts 13 (96% ee) and 19, even
when performed on multigram scale. Although the bicycles
were inseparable, exposure of the mixture to a previously5
established two step epoxidation/Wittig olefination sequence
allowed enantioenriched enal 20 to be isolated in 49% yield
from silyl enol ether 14.
With enal 20 in hand, our next task was to install a C7 alkyl
substituent and access ketolactone 12 (Scheme 3). Toward this
endeavor, enal 20 was first oxidized by NIS in the presence of
potassium carbonate in methanol to provide enoate 21. Next,
treatment of enoate 21 with vinyl ether 22 and NIS furnished
25
line A (3), interrupted Fischer indolization adduct 27
underwent nosyl cleavage using a solid-supported thiol resin,
followed by N-formylation.
1
9
We next directed our attention to the methanoquinolizidine
1
4
alkaloids, which have evaded prior synthetic efforts. As shown
in Scheme 4, Fischer indolization product 25 was accessed as
demonstrated previously. However, this intermediate was
directly intercepted by a hydride nucleophile. Interestingly,
this process occurred in high yield and with complete control of
stereochemistry to give the depicted 2S diastereomer of
product 9. The overall conversion of 12 to 9 represents an
22
18
uncommon reductive variant of the interrupted Fischer
indolization reaction, and is also one of the most complex
B
DOI: 10.1021/jacs.5b12880
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Communication
Scheme 4
Scheme 5
features a gold-mediated cyclization to assemble the [3.3.1]-
azabicyclic core of the natural products, a reductive interrupted
Fischer indolization reaction to introduce the key C7
quaternary stereocenter and access late-stage compounds, and
a series of carefully executed late-stage transformations to
complete the total syntheses. Moreover, we have also
completed the first enantioselective total synthesis of
aspidophylline A (3). These studies constitute new achieve-
ments in the popular area of akuammiline alkaloid synthesis,
and provide many lessons that should impact future endeavors
in the synthesis of complex molecules.
2
6
examples of this venerable synthetic method. It proceeds by
introducing two stereocenters (at C2 and C7) and establishes
an intricate pentacyclic framework bearing five contiguous
stereocenters.
From product 9, we pursued the seemingly simple
conversion to hydroxyester 29 (Scheme 4). Although
intermediate 25 readily underwent smooth ring-opening (see
Scheme 3), we were disappointed to find that exposure of its
reduced counterpart (9) to methoxide or two-step hydrolysis/
methylation protocols failed to furnish 29. Instead, C16 epimer
2
8 was formed. Exhaustive efforts to overcome this roadblock
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b12880.
were undertaken. For example, epimerization under a variety of
acidic or basic conditions, attempted lactone opening via
amidation, Pd-catalyzed ring-opening, or S 2 displace-
ments, all proved fruitless. With our best efforts thwarted,
we pursued a more stepwise approach. Reduction of 9, followed
by selective silylation of the less hindered primary alcohol,
proceeded without stereochemical erosion at C16 and gave
alcohol 30. Lastly, an oxidation/esterification sequence (30 →
■
*
S
2
7
28
N
2
9
Detailed experimental procedures and compound char-
acterization data (PDF)
X-ray crystallographic data for 18 (CIF)
3
1), with in situ desilylation, provided a reliable means to
AUTHOR INFORMATION
Corresponding Author
neilgarg@chem.ucla.edu
Author Contributions
J.M. and E.P. contributed equally.
Notes
The authors declare no competing financial interest.
■
synthesize the coveted late-stage intermediate 29. Of note, the
Dess−Martin oxidation was achieved in the presence of the
indoline, a conversion that was not possible when other
oxidants were tried.
Having accessed alcohol 29, we set our sights on accessing
the elusive methanoquinolizidine alkaloids (Scheme 5). Initial
efforts to elaborate aminoalcohol 29 without using protecting
groups were deemed challenging. However, a mesylation/
chlorination sequence was found to be viable and delivered
aminochloride 8 in 77% yield. To our delight, chloride 8 could
be elaborated to strictamine (1) and 2(S)-cathafoline (2). The
former of the natural products was accessed via oxidation of the
indoline with PCC, followed by denosylation. To access 2(S)-
cathafoline (2), an N-methylation/deprotection sequence was
performed. In both cases, the denosylation step proceeded with
the desired in situ chloride displacement by the liberated amine
to establish the hexacyclic methanoquinolizidine framework.
NMR spectra of synthetic (+)-1 and (−)-2 were found to be in
accord with spectra for the natural samples.
*
†
30
ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Foundation
(CHE-0955864 and CHE-1464898), Bristol−Myers Squibb,
the Dreyfus Foundation, the UCLA Gold Shield Alumnae, and
the University of California, Los Angeles, for financial support.
We are grateful to the NIH-NIGMS (F31-GM113642 to J.M.),
the Foote Family (J.M. and L.A.M.), and the UCLA Cota-
Robles Fellowship Program (E.P.). J.M.S. acknowledges the
National Science Foundation for a GRFP (DGE-1144087) and
the UCLA Graduate Division for a Dissertation Year
Fellowship. We are grateful to Prof. T.-S. Kam (University of
Malaya) for providing authentic samples of aspidophylline A,
strictamine, and 2(S)-cathafoline. These studies were supported
by shared instrumentation grants from the NSF (CHE-
In summary, we have completed the first total syntheses of
two akuammiline natural products that possess a methano-
quinolizidine core. Our asymmetric approach to 1 and 2
C
DOI: 10.1021/jacs.5b12880
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Journal of the American Chemical Society
048804) and the National Center for Research Resources
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