Stereoselective Total Synthesis of (±)-Alstoscholarisine e

Article abstract of DOI:10.1021/acs.orglett.9b04093

The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in seven linear steps from commercially available reagents and 15.2% overall yield. The approach features a tandem vinylogous Mannich reaction and hetero-Diels-Alder reaction to access the core. A novel tactic to induce diastereoselective reduction of the cyclic vinyl ether was discovered, and a mild procedure to form the bridged aminal ring by partial reduction of the lactam ring via iridium-catalyzed hydrosilylation was developed.

Full text of DOI:10.1021/acs.orglett.9b04093

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Stereoselective Total Synthesis of (± )-Alstoscholarisine E
Michael D. Wood, Daniel W. Klosowski, and Stephen F. Martin*
Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States
*
S Supporting Information
ABSTRACT: The shortest synthesis to date of (±)-alstoscho-
larisine E was accomplished in seven linear steps from
commercially available reagents and 15.2% overall yield. The
approach features a tandem vinylogous Mannich reaction and
hetero-Diels−Alder reaction to access the core. A novel tactic to
induce diastereoselective reduction of the cyclic vinyl ether was
discovered, and a mild procedure to form the bridged aminal
ring by partial reduction of the lactam ring via iridium-catalyzed
hydrosilylation was developed.
7
rogressive neuronal decline is a salient feature of
Alzheimer’s disease and other neurodegenerative disor-
enantioselective syntheses of alstoscholarisine A, as well as the
7c,8
P
synthesis of racemic B−D, have been achieved; the racemic
and enantioselective syntheses of alstoscholarisine E were only
ders that lead to severe cognitive impairments and create
1
7c,d
significant healthcare challenges. Despite extensive efforts,
recently disclosed.
Despite these successes, the reported
there are no effective treatments that prevent or reverse the
9
syntheses of 1−5 require 12−17 chemical steps in their
longest linear sequence (LLS) and proceed with modest
overall yields that range from 1.0 to 4.6%. We now report a
concise and high-yielding synthesis of (±)-alstoscholarisine E
2
neuronal deficits associated with these debilitating diseases.
One approach that has recently attracted significant attention
as a potential disease-altering option is neural stem cell (NSC)
3
therapy. Because small molecules can be exploited to effect
(
5).
chemical control over stem cell proliferation, they have
emerged as useful tools to develop new therapies to treat
Our convergent approach to (±)-alstoscholarisine E (5) is
4
outlined in retrosynthetic format in Scheme 1. We envisaged
that the advanced intermediate 6 would be transformed into 5
via stereoselective reduction of the enol ether group in 6,
neurodegenerative processes. It is therefore notable that the
indole alkaloids alstoscholarisines A−E (1−5), which were
5
isolated in 2014, promote NSC proliferation (Figure 1).
Scheme 1. Retrosynthetic Analysis of Alstoscholarisine E
Figure 1. Structures of alstoscholarisines A−E.
Alstoscholarisine A (1) and E (5), respectively, are among the
most potent members of the family, and 1 was found to
promote neuronal fate commitment. Although they differ in
substitution at C-16 and stereochemistry at C-19, 1−5
comprise a similar pentacyclic framework containing a cis-
fused oxahydroisoquinolone ring bearing five contiguous
stereocenters. The tetrahydropyran ring is bridged by an
indole moiety that forms a cyclic aminal with the piperidine
ring to create the novel caged structure.
The structural complexity of the alstoscholarisines coupled
with their interesting biological activity quickly captured the
attention of the synthetic community. Two racemic and two
Received: November 15, 2019
6
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04093
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
followed by partial reduction of the lactam moiety and
spontaneous transannular cyclization to form the bridging
aminal moiety in 5. Access to 6 would be achieved by cross-
coupling of a suitable 3-methylindole derivative 7 with the cis-
oxahydroisoquinolone 8 (X = Br, I) using a Negishi, Suzuki, or
Stille reaction. The synthesis of cis-oxahydroisoquinolones
similar to 8 via intramolecular hetero-Diels−Alder reactions of
heterodienes related to 9 is well precedented in our
competitive protodeborylation, a well-known side reaction of
2-heterocyclic boronic acids in Suzuki reactions, resulted in
low yields. We turned to the SPhos Pd G2 precataylst,
18
19
which is reported to promote Suzuki couplings of challenging
substrates and was contemporaneously shown to induce the
7d
cross-coupling of 17 with a similar oxahydroisoquinolone.
Although initial efforts gave 18 in only 18% yield because of
persistent protodeborylation of 17, we eventually discovered
that increasing the catalyst loading from 5 to 10 mol % and
using 4 equiv of 17 afforded 18 in 79% yield on a gram scale.
Our original plan to induce the stereoselective reduction of
18 in one step to provide 21 anticipated an ionic reduction
initiated by diastereoselective, axial protonation of the enol
ether moiety in 18 from the less hindered face followed by
hydride reduction of the intermediate carbocation (Scheme 3).
1
0
laboratories, and we have implemented this cycloaddition
11
in the syntheses of several natural products. The vinylogous
1
2
Mannich reaction, a construction we pioneered and
13
showcased in the syntheses of numerous alkaloids, might
be exploited to generate 9 in a single step via reaction of
trimethylsilyloxydiene 10 with the N-acyliminium ion
generated from N-acylation of hexahydrotriazine 11 with
crotonyl chloride (12) and subsequent fragmentation.
The synthesis of alstoscholarisine E commenced with
converting the hexahydrotriazine 11 directly to 9 (Scheme
Scheme 3. Stereoselective Reduction of Enol Ether Moiety
2
). The N-acylation of triazines such as 11 is known to
Scheme 2. Synthesis of the Indolyl Oxahydroisoquinolone
Somewhat surprisingly, treatment of 18 with Et SiH in the
3
presence of CF CO H furnished a mixture (1:1, 60% yield) of
3
2
the bicyclic acetal 19 and a diastereomer that has been
tentatively identified as 20; none of the desired product 21 was
obtained. Armed with this unexpected result, we queried
whether we might optimize this cyclization to selectively
furnish 19. After some experimentation, we discovered that
treating 18 with 0.4 M HCl in dioxane delivered 19 as a single
diastereomer in 77% yield. The structure of 19 was confirmed
by X-ray crystallography.
generate transient N-acyliminium ions that can be captured by
14
a variety of nucleophiles, including enol ethers, but we are
not aware of any application of such a process to a vinylogous
Mannich reaction using π-nucleophiles such as 10. Gratify-
ingly, we discovered that stirring a solution of hexahydro-
triazine 11 and crotonyl chloride in MeCN at 80 °C, followed
by reaction with diene 10 (ca. 9:1 E/Z) at 0 °C in the presence
of TMS-OTf provided the desired ene−aldehyde 9 in 62%
yield together with 10% of the regioisomer 13. Consistent with
The bicyclic acetal moiety in 19 proved to be remarkably
resistant toward reductive opening under acidic conditions.
Hydride reduction in the presence of a variety of Lewis acids
that were known to promote reductive opening of bicyclic
1
0,11b,c
20
our earlier studies,
heating 9 in mesitylene under reflux
lactone acetals returned only starting material. Eventually, we
afforded a readily separable mixture (5.4:1) of the cis- and
trans-fused cycloadducts 14 and 15 in 77% combined
discovered that use of EtAlCl in the presence of Et SiH led to
2
3
smooth reductive opening and decarboxylation to deliver 21 in
97% yield. The diastereoselectivity achieved in this two-step
reduction sequence is notable given that catalytic hydro-
genation of an indolyl oxahydroisoquinolone similar to 18 in
Liao’s synthesis of (−)-alstoscholarisine E gave a mixture
1
1a,15
yield.
Treating 14 with N-iodosuccinimide (NIS) in the
presence of a catalytic amount of AgNO3 (10 mol %),
according to a slight modification of a protocol reported by
1
6
Vankar furnished the vinyl iodide 16 in 83% yield.
7d
The stage was then set for the cross-coupling of 16 with a
suitable derivative of 3-methylindole to give 18. After
numerous attempted Negishi couplings failed, we turned to a
(2.2:1) of diastereomers.
All that remained to complete the synthesis of (±)-al-
stoscholarisine E was partial reduction of the lactam moiety of
21 followed by cyclization to form the bridging aminal ring in
17
Suzuki reaction using the known indole boronic acid 17.
A
7c,d,8
variety of catalysts were screened to couple 16 and 17, but
accord with similar cyclizations in the prior art.
However,
B
DOI: 10.1021/acs.orglett.9b04093
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
only trace quantities of 5 were observed in early attempts using
known conditions to achieve this transformation (Table 1,
considerably shorter and more efficient than previous
syntheses of members of the alstoscholarisine family of natural
products.
Table 1. Completion of the Synthesis of
ASSOCIATED CONTENT
Supporting Information
(± )-Alstoscholarisine E via Reductive Cyclic Aminal
■
Formation
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04093.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
Accession Codes
entry
conditions
yield (%)
CCDC 1947103 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
1
2
3
4
5
6
DIBAL-H, CH Cl , −78 °C
trace
trace
trace
2
2
a
Cp ZrHCl, THF, 70 °C
Bu SnH, Tf O, MeCN, −40 °C to rt
2
a
3
2
a
Ph SiH , Ti(Oi-Pr) , THF, 50 °C
trace
2
2
4
b
TMDS, Ti(Oi-Pr)4, PhMe, 50 °C
56
56
c
TMDS, IrCl(CO)(PPh ) , PhMe, rt
3
2
b
AUTHOR INFORMATION
Corresponding Author
7
TMDS, IrCl(CO)(PPh ) , CH Cl , rt
77
■
3
2
2
2
a
Small, nonquantifiable formation of 5 was observed in LCMS of
crude reaction mixture. Isolated yield after chromatographic
purification. Yield determined by H NMR spectroscopy with an
internal standard.
b
*
E-mail: sfmartin@mail.utexas.edu.
c
1
ORCID
Stephen F. Martin: 0000-0002-4639-0695
Notes
entries 1−3). We then turned to hydrosilylation of the amide
21
as an alternative tactic. In the event, attempted reduction of
The authors declare no competing financial interest.
2
1 using Ph SiH under conditions developed by Buchwald
2 2
ACKNOWLEDGMENTS
produced a mixture containing only small quantities of 5
■
2
2
(
entry 4). Alternatively, reaction of 21 with 1,1,3,3-
We are grateful to the Robert A. Welch Foundation (F-0652)
for funding. We also thank the UT Austin Mass Spectrometry
Facility for high-resolution mass spectral data, the UT Austin
X-ray diffraction lab for crystallographic data, and the NIH
Grant No. 1 S10 OD021508-01) for funding the Bruker
AVANCE III 500 NMR spectrometer used for characterization
of synthetic intermediates.
tetramethyldisiloxane (TMDS) and Ti(Oi-Pr)4 at 50 °C
according to a modification of a protocol reported by Lemaire
23
produced 5 in 56% yield (entry 5). When 21 was treated
with TMDS in the presence of a catalytic amount of Vaska’s
complex (2 mol %) in PhMe following conditions reported by
Nagashima, 5 was isolated in similar yields, but some
overreduction to the amine was observed (entry 6). However,
simply switching the solvent for the reduction to CH Cl
(
2
4
2
2
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D
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E
DOI: 10.1021/acs.orglett.9b04093
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