Tandem vinylogous Mannich and hetero Diels-Alder reactions: Concise total synthesis of (±)-Alstoscholarisine E

Article abstract of DOI:10.1016/j.tet.2021.132150

The shortest synthesis to date of (±)-alstoscholarisine E was accomplished in 15.2% overall yield requiring only seven linear steps from commercially available reagents. The approach features a tandem vinylogous Mannich reaction and an intramolecular hetero Diels-Alder reaction to access the cis-oxahydroisoquinolone core. Following the coupling of this cis-oxahydroisoquinolone subunit with a 3-methylindole derivative via a Suzuki reaction, a novel tactic to induce the challenging diastereoselective reduction of the cyclic vinyl ether moiety was discovered. Completion of the synthesis was achieved using a new procedure we developed for iridium-catalyzed, reductive formation of aminals from tertiary lactams, thereby expanding the utility of tertiary amides and lactams as surrogates for iminium ions.

Full text of DOI:10.1016/j.tet.2021.132150

Tetrahedron 89 (2021) 132150
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem vinylogous Mannich and hetero Diels-Alder reactions:
Concise total synthesis of ( )-Alstoscholarisine E*
Michael D. Wood, Daniel W. Klosowski, Stephen F. Martin*
Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The shortest synthesis to date of ( )-alstoscholarisine E was accomplished in 15.2% overall yield
requiring only seven linear steps from commercially available reagents. The approach features a tandem
vinylogous Mannich reaction and an intramolecular hetero Diels-Alder reaction to access the cis-oxa-
hydroisoquinolone core. Following the coupling of this cis-oxahydroisoquinolone subunit with a 3-
methylindole derivative via a Suzuki reaction, a novel tactic to induce the challenging diaster-
eoselective reduction of the cyclic vinyl ether moiety was discovered. Completion of the synthesis was
achieved using a new procedure we developed for iridium-catalyzed, reductive formation of aminals
from tertiary lactams, thereby expanding the utility of tertiary amides and lactams as surrogates for
iminium ions.
Received 8 March 2021
Received in revised form
1 April 2021
Accepted 2 April 2021
Available online 22 April 2021
Keywords:
Total synthesis
Indole alkaloid
Vinylogous Mannich reaction
Intramolecular hetero Diels-Alder reaction
Suzuki reaction
© 2021 Elsevier Ltd. All rights reserved.
Reductive aminal formation
1. Introduction
medicines for the treatment of a range of ailments, stimulated adult
hippocampal NCS proliferation [6]. Ensuing phytochemical in-
One of the hallmarks of Alzheimer’s disease, Huntington’s dis-
ease, Parkinson’s disease and other neurodegenerative disorders is
the gradual loss of brain functions that are manifested in cognitive
deficits and physical impairments resulting in significant health-
care challenges [1]. Although palliative treatments have been
developed to alleviate some symptoms associated with these
debilitating diseases, there are no effective treatments that prevent
or reverse the progressive neuronal decline common to these
conditions [2]. New disease-altering approaches to address these
unmet medical needs are required, and one promising option that
has recently emerged is neural stem cell (NSC) therapy [3,4].
Because stem cell proliferation can be controlled using small mol-
ecules, there is considerable interest in the discovery of novel
compounds that regulate stem cells and might serve as leads to
treat neurodegenerative processes [5].
vestigations resulted in the identification of alstoscholarisines AeE
(1e5), which provided enhanced NSC proliferation (10 g/mL)
relative to the total alkaloid extracts (30 g/mL), and alstoscholar-
m
m
isine A (1) and E (5), respectively, are among the most potent
compounds (Fig. 1). Additional investigations determined that 1
improves NSC sphere formation and promotes NSC differentiation
and neuronal fate commitment. As part of their ongoing work to
identify novel indole alkaloids from Alstonia scholaris, Pan et al. also
isolated alstoscholarisines HeJ (6e8) and reported their syntheses,
although 6e8 exhibited no effect on NSC proliferation or PC12 cell
differentiation [7].
Among these structurally related alkaloids, 1e5 comprise a
similar pentacyclic framework containing
a cis-fused oxahy-
droisoquinolone ring system (highlighted in blue), a subunit com-
mon to a number of indole alkaloids. Notably, the tetrahydropyran
ring is bridged by the indole moiety via a cyclic aminal with the
piperidine ring to establish the caged structure bearing five
contiguous stereocenters. Alstoscholarisines AeE are differentiated
by the stereochemistry at C-19 with 1 and 2 possessing an equa-
torial methyl group, whereas this methyl group is in an axial
orientation in 3e5. The structures also differ in substitution at the
C-16 bridgehead center, which is fully substituted in 2e4 and bears
an ester or carboxylic acid group. The related alkaloids 6e8 possess
As part of their efforts to identify biologically active natural
products, Luo et al. discovered that the crude alkaloid extracts from
the leaves of Alstonia scholaris, an Asian tree used in traditional
*
Dedicated to our friend and former colleague Guangbin Dong in recognition of
his being a recipient of the Tetrahedron Young Investigator Award for 2021.
* Corresponding author.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
https://doi.org/10.1016/j.tet.2021.132150
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
Fig. 1. Structures of alstoscholarisines AeE and HeJ. The cis-fused oxahy-
droisoquinolone ring is highlighted in blue.
a similar structure with a ring-opened variant of the oxahy-
droisoquinolone ring.
The structural complexity of the alstoscholarisines 1e5 coupled
with their interesting biological activity has motivated numerous
synthetic endeavors and inspired varying strategies for forming the
challenging cis-fused oxahydroisoquinolone and bridged aminal
ring systems (Fig. 2) [8]. The synthesis of ( )ealstoscholarisine A
was first achieved in 2016 by Bihelovic and Ferjancic using an
approach that relied upon an enamine cascade initiated by
condensation of amine 9 with aldehyde 10 to create the cyclic
aminal 12. After forming the tetrahydropyran to establish the
bridged ring system, the synthesis of 1 was completed in 15 steps
[9] in the longest linear sequence (LLS) from commercially available
reagents [10]. A synthesis of (ꢀ)-alstoscholarisine A was reported in
2016 by Yang and coworkers [11]. Enantioselective construction of
the fused indoyl lactam 13, and subsequent elaboration led to the
bridged tetrahydropyran 14. Reductive amination of the aldehyde
in 14 and partial reduction of the amide, followed by cyclization to
form the bridged aminal ring completed the synthesis of (ꢀ)-1 in
14-steps [9] (LLS) from commercially available reagents. Weinreb
and coworkers developed a divergent strategy emanating from the
N-sulfonylactam 15 that was applied to the syntheses of racemic
alstoscholarisines AeE (1e5) [12,13]. In this approach, 15 was
elaborated in a sequence that involved partial reduction of an in-
termediate lactam with DIBALH leading to the hemiaminal 16.
Treating 16 with trifluoroacetic acid cleaved the Boc-protecting
group and triggered cyclization to produce the aminal ring in 17.
Subsequent formation of the bridged tetrahydropyran ring led to
1e5 by sequences requiring a total of 15e17 steps [9] (LLS) from
commercially available starting materials.
Most recently, Liao and coworkers reported the enantioselective
syntheses of 1 and 5 from a mixture of diastereomeric cis- and
trans-oxahydroisoquinolones 18 and 19a,b [14]. Elaboration of 18
by a Suzuki reaction gave 20 and stereoselective hydrogenation of
the enol ether moiety led to 22. The bridged aminal ring was
formed via partial reduction of the lactam in 23 with tributyltin
hydride in the presence of Tf2O, followed by reductive N-methyl-
ation in a two-step, one-pot sequence that completed the synthesis
of alstoscholarisine A (1) in 12 steps [9] (LLS) from commercially
available materials. Toward alstoscholarisine E (5), epimerization of
19b to give the corresponding cis-oxahydroisoquinolone and sep-
aration from 19a was first required prior to the Suzuki coupling that
would furnish 21. The ensuing hydrogenation to provide 23 was
only modestly selective, giving a mixture (2.2:1) of C-16 di-
astereomers. Then as before, the bridged aminal ring was formed
Fig. 2. Prior strategies for forming the bridging aminal ring of alstoscholarisines A-E.
via partial reduction of the lactam in 23 followed by reductive N-
methylation to complete the synthesis of 5 in 13 steps [9] (LLS) from
commercially available reagents.
We have had a longstanding program directed toward devel-
oping novel approaches for the syntheses of indole and other al-
kaloids [15,16]. Indeed, our interest in the heteroyohimboid
alkaloid tetrahydroalstonine (32) led to the development of an
intramolecular hetero Diels-Alder reaction to construct cis-fused
oxahydroisoquinolones [15,17e22] and to the discovery and
development of the vinylogous Mannich reaction [23]. In particular,
we found that the vinylogous Mannich reactions of trimethylsily-
loxydiene 27 with the readily available dihydrocarboline 24 in the
presence of acyl chlorides 25 and 26 provided the heterodienes 28
and 29 (Scheme 1) [20e22]. Upon heating, 28 and 29 underwent
intramolecular hetero Diels-Alder reactions to deliver the cisefused
oxahydroisoquinolones 30 and 31, thereby enabling remarkably
efficient access to various indole alkaloids 32e36 [18e21,24,25].
With this as background, we recognized that a tandem vinyl-
ogous Mannich reaction and an intramolecular hetero Diels-Alder
reaction to form cisefused oxahydroisoquinolones could be
applied in the design of a concise approach to the alstoscholarisine
alkaloids. At the outset of our work, the synthesis of alstoscholar-
isine E had not yet been achieved. Accordingly, we focused on the
total synthesis of ( )ealstoscholarisine E (5), which we recently
2

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
anticipated that the cis-oxahydroisoquinolone 39 (R ¼ H) would be
accessible via the intramolecular hetero Diels-Alder reaction of
heterodiene 40, which would be prepared via a vinylogous Man-
nich reaction using commercially available hexahydrotriazine 41,
crotonyl chloride (25), and trimethylsilyloxybutadiene 27. Treating
hexahydrotriazines such as 41 with an acyl chloride is known to
induce fragmentation enabling nucleophilic capture with a variety
of nucleophiles [27e30], including enol ethers in modest yield [28],
but we are not aware of any such process involving a nucleophilic
diene like 27.
In accord with this plan, the first step in the synthesis of alsto-
scholarisine E (5) required the vinylogous Mannich reaction of 25,
27, and 41 to deliver the heterodiene 40. Although a superficially
straightforward transformation, considerable experimentation was
required to optimize this process (Table 1). Acyl chloride-initiated
fragmentations of hexahydrotriazines similar to 41 and capture of
the intermediate N-a-chloroalkylamides have typically been per-
formed in dichloromethane at 0 ꢁC [27e31]. In analogy with these
findings, we discovered that treating 41 with crotonyl chloride (25)
at 0 ꢁC, followed by heating the resulting mixture under reflux prior
to adding trimethylsilyloxydiene 27 (ca 9:1 E/Z) at 0 ꢁC delivered 40
in 29% yield together with the regioisomer 43 in 5% yield (entry 1).
We queried whether a Lewis acid might be beneficial, but the
presence of TMSeOTf offered no improvement (entry 2).
Exchanging dichloromethane with acetonitrile provided lower
yields in the absence of a Lewis acid (entry 3), but in the presence of
TMSeOTf (0.1 eq), 40 and 43 were obtained in 62% and 10% yield,
respectively. Slightly lower yields were obtained when the reaction
was performed in dichloroethane, but yields were greatly dimin-
ished in THF and DMF (entries 5e7). Because including TMSeOTf in
the reaction was important, other Lewis acids were evaluated.
Although ethylaluminum dichloride (EtAlCl2) was nearly as effec-
tive as TMSeOTf (entry 8), boron trifluoride etherate was clearly
inferior (entry 9). Altering the stoichiometry of trimethylsilylox-
ydiene 27 relative to hexahydrotriazine 41 also had little effect
(entries 10,11).
Scheme 1. General strategy for alkaloid synthesis via cis-fused oxahydroisoquinolones.
disclosed [26], and we now report the details of those studies.
2. Results and discussion
The retrosynthetic analysis of our convergent approach to
( )-alstoscholarisine E (5) is presented in Scheme 2. The final stage
of the synthesis features transformation of the advanced interme-
diate 37 into 5 via stereoselective reduction of the enol ether group
in 37, followed by partial reduction of the tertiary lactam and
spontaneous cyclization of the intermediate iminium ion to form
the bridging aminal ring in 5. The synthesis of 37 requires a Negishi
or Suzuki cross-coupling reaction to join the cis-oxahy-
droisoquinolone 39 (X ¼ I) with a 3-methylindole derivative such as
38 [R ¼ ZnCl, B(OH)2]. Based upon our previous work, we
This simple operation delivered a mixture (6.2:1) of the isomeric
heterodienes 40 and 43 by a process that is considerably shorter
than our previous synthesis of a related heterodiene (Table 1, entry
4) [17]. However, based upon our varied experiences with vinyl-
ogous Mannich reactions [23], we were somewhat surprised by the
formation of significant amounts of 43, which results from reaction
at the more hindered a-carbon atom of the silyl enol ether 27. We
wondered whether reaction at this carbon atom might be sup-
pressed by increasing the steric bulk of the silyl group, thereby
improving the ratio of 40 and 43. Consistent with this hypothesis,
when tert-butyldimethylsilyloxydiene 42 (R ¼ TBS, 100% E) [32]
was used as the nucleophile, 40 was obtained in 63% yield, and the
ratio of isomers improved to 10.5:1 (Table 1, entry 12). Moreover,
further increasing the size of the silyl group by using the known
triisopropylsilyloxydiene 42 (R ¼ TIPS, 100% E) [33] furnished 40 in
68% yield together with the isomeric diene 43 in a mere 2% yield
(Table 1, entry 13). These improvements notwithstanding, we
continued the synthesis using commercially available trimethylsi-
lyloxydiene 27 and were thus able to prepare 40 in single step and
on a gram scale to set the stage for the intramolecular hetero Diels-
Alder reaction.
In accord with our previous studies [17,18,22], 40 underwent
cyclization when heated under reflux in mesitylene to afford an
easily separable mixture (5.4:1) of the cis- and trans-fused cyclo-
adducts 44 and 45 in 77% combined yield (Scheme 3) [21]. Having
formed the racemic cis-oxahydroisoquinolone 44, we queried
whether the cycloaddition might be catalyzed by a chiral Lewis acid
to provide 44 in enantioenriched form. Given that both the diene
and dieneophile in 40 are electron deficient and contain a Lewis-
Scheme 2. Retrosynthetic analysis of alstoscholarisine E.
3

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
Table 1
The vinylogous Mannich reaction of 1,3,5-trimethylhexahydrotriazine (41).
entry
[Si] (equiv)
Lewis acid (equiv)
solvent
yield 40 (%)a
yield 43 (%)a
1
2
3
4
5
6
7
8
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (4)
TMS (6)
TMS (2.2)
TBS (4)
none
TMSOTf (0.1)
none
DCM
DCM
MeCN
MeCN
DCE
29
29
7
5
6
3
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
EtAlCl2 (0.2)
BF3$OEt2 (1.0)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
62b
57
13
0
10b
12
3
THF
DMF
0
12
5
9
11
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
57
29
58
56
63
68
9
10
11
12
13
b
b
6
2
b
b
TIPS (4)
a
Yield determined by 1H NMR spectroscopy with internal standard.
Isolated yield determined after chromatographic purification.
b
To set the stage for the cross-coupling of the cycloadduct 44
with a suitable indole derivative, it was first necessary to regiose-
lectively introduce a halogen atom onto the enol ether moiety of 44.
Previous reports with structurally related glycals show that addi-
tion of N-iodosuccinimide (NIS) to enol ethers occurs readily to
generate iodo succinimide adducts, whereas in the presence of
catalytic amounts of silver nitrate (20 mol %), the vinyl iodide is
produced in high yield [41,42]. In the event, treating 44 with NIS
and silver nitrate (10e35 mol %) furnished 45 as the sole isolable
product in yields ranging from 55 to 83% (Table 2). Lower quantities
of silver nitrate generally provided improved yields, and the best
results were obtained using 10 mol % of silver nitrate (entry 4).
We first explored Negishi couplings as a simple and direct
approach to metallate and couple the indole 46 with the vinyl io-
dide 45 in a single operation. Following treatment of the known 3-
methylindole 46 [43] with tert-butyllithium and subsequent
transmetalation, the zincated intermediate 47 was subjected to
several standard conditions for performing Negishi couplings
(Table 3) [44]. Direct cross-coupling using catalytic Pd(PPh3)4,
Pd(PPh)2Cl2, or Pd(OAc)2 did not give detectable amounts of 37,
even when heated to 125 ꢁC (entries 1e3). Subjecting 37 and 45 to a
combination of Pd(dba)2 and P(o-fur)3 also failed to deliver 37
(entry 4). Use of RuPhos with either Pd(dba)2 or Pd(OAc)2 according
Scheme 3. Intramolecular hetero DielsdAlder reaction of heterodiene 40.
basic carbonyl group that might interact with the catalyst, we were
cognizant that realization of this goal was a significant challenge.
Many of the known methods for promoting hetero Diels-Alder re-
actions with chiral Lewis acids utilize substrates that are more
electronically predisposed to cyclization [34,35]. Moreover, we had
previously tried, without success, to induce Lewis acid catalyzed
[4 þ 2] cycloadditions with substrates similar to 40 [17]. Undeterred
by these precedents, we evaluated the chiral Lewis acids 46e50
[36e40], which are known to promote enantioselective Diels-Alder
and hetero Diels-Alder reactions. However, treating 40 with each of
these catalysts following the reported protocols [36e40] in a
number of experiments failed to provide detectable quantities of
cycloadducts 44 and 45, even at elevated temperatures ranging
from 25 to 140 ꢁC. We were therefore relegated to using racemic 44
to complete the synthesis of ( )-alstoscholarisine E.
Table 2
Synthesis of the vinyl iodide 45.
entry
AgNO3 (mol %)
yield (%)a
1
2
3
4
35
30
20
10
55
67
79
83
a
Isolated yields determined after chromatographic purification.
4

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
Table 3
the vinyl iodide 45 under several standard conditions (Table 3,
entries 1,2), but no 37 was isolated.
Attempts at Negishi coupling of 45 and 47.
We were aware that Buchwald and coworkers had overcome the
challenges associated with cross-couplings of 2-heterocyclic
boronic acids related to 48 using palladium precatalysts such as
SPhos Pd G2 that are rapidly activated under mild conditions and
exhibit high catalytic activity [48e50]. Indeed, contemporaneous
with our efforts, Liao and coworkers reported a similar cross-
coupling in their synthesis of (ꢀ)-alstoscholarisines A and E [14].
However, when we tried to apply the protocol reported by Liao
using three equivalents of indole 46 and SPhos Pd G2 (5 mol %), the
coupled product 37 was isolated in only 18% yield (entry 3).
Increasing the number of equivalents of indole 46 led to improved
yields (entries 4,5). Eventually we discovered that increasing the
loading of SPhos Pd G2 to 10 mol % and using four equivalents of
indole 46 delivered 37 in 79% yield on a gram scale (entry 6).
With 37 in hand, the stereoselective reduction of vinyl ether 37
was investigated. Although we had originally considered catalytic
hydrogenation as a possible option, the related work of Liao and
coworkers confirmed our concern regarding the lack of stereo-
selectivity of such a process [14]. We favored an alternative
approach that would involve the diastereoselective, axial proton-
ation of the enol ether moiety in 37 from the less hindered face,
followed by hydride reduction of the intermediate carbocation to
give 49 (Scheme 4). Toward this goal, a solution of oxahy-
droisoquinolone 37, triethylsilane, and trifluoroacetic acid (TFA) (5
equiv) in dichloromethane was stirred for 12 h, but the desired
deprotected, reduction product 49 was not observed. Rather, an
unexpected mixture (ca. 1:1) containing two major products, which
were tentatively assigned as being the two bicyclic acetals 50 and
51, was isolated in 60% combined yield (Scheme 4). Although pro-
tonation of the enol ether occurred as anticipated, it was not ster-
eoselective, and the intermediate carbocation was not captured by
hydride, but rather by rapid cyclization with the N-carbamate
group on the indole ring to give an acyloxy acetal that was stable to
ionic reduction in the presence of TFA.
entry
catalyst
ligand
solvent
T (ꢁC)
1
2
3
4
5
6
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
none
none
none
P(o-fur)3
RuPhos
RuPhos
THF
rt to 125
80
80
rt to 125
80
80
DMAc
DMAc
THF
THF
DMAc
Quantifiable formation of 37 was not observed via LCMS of the crude reaction
mixtures.
to a protocol reported by Buchwald was also unsuccessful (entries
5,6) [45]. Each of these reactions provided significant quantities of
returned 45, and the only byproducts detected were 44 and 3-
methylindole.
We then turned to the Suzuki-Miyaura reaction of 45 with the
known indole boronic acid 48 as an alternative strategy [43,46].
However, competitive protodeboronation of 2-heterocyclic boronic
acids is a well-known problem in Suzuki cross-couplings [47]. For
example, 48 was reportedly only stable if kept in a diethyl ether
solution after an aqueous work up, yet high yields were achieved in
a Suzuki coupling with a related vinyl halide [46]. Encouraged by
this report, we attempted a slightly modified protocol, wherein a
solution of 46 in THF at ꢀ78 ꢁC was treated with tert-butyllithium,
followed by rapid addition of trimethyl borate (Table 4). After
quenching the reaction mixture with a saturated solution of
aqueous ammonium chloride, analysis (1H NMR) revealed that the
crude boronic acid 48 was obtained in near quantitative yield.
Because of its instability, we tried to directly couple crude 48 with
Despite the fact that the ionic reduction had not occurred as
predicted, we were undeterred and explored this process further.
Surprised by the rapid cyclization of the tert-butyl carbamate in the
presence of acid, the concentration of TFA was increased (15 equiv)
to assess whether removal of the Boc-protecting group might be
faster. However, these conditions led to even more rapid cyclization
and delivered a mixture (ca. 3.3:1) of the acyloxy acetal di-
astereomers 50 and 51 in 96% combined crude yield (Table 5, entry
1). This experiment suggested protonation and cyclization prefer-
entially led to the undesired stereochemistry at C-16 in 50.
Furthermore, the results of the experiment depicted from Scheme 4
suggested that the acyloxy acetals might undergo equilibration
Table 4
Suzuki-Miyaura coupling of 45 and 48.
entry
1
46 (equiv)
conditions
yielda (%)
0b
1.2
Pd(PPh3)4 (10 mol %), NaHCO3
THF/H2O (2:1), 80 ꢁC
Pd(OAc)2 (10 mol %)
2
1.2
0b
SPhos (12 mol %)Cs2CO3
dioxane/H2O (5:1), 80 ꢁC
SPhos Pd G2 (5 mol %)
K3PO4 PhMe/H2O, 60 ꢁC
SPhos Pd G2 (5 mol %)
K3PO4 PhMe/H2O, 60 ꢁC
SPhos Pd G2 (5 mol %)
K3PO4 PhMe/H2O, 60 ꢁC
SPhos Pd G2 (10 mol %)
K3PO4 PhMe/H2O, 60 ꢁC
3
4
5
6
3
4
5
4
18
54
51
79
a
Isolated yields determined after chromatographic purification.
b
Quantifiable formation of 37 was not observed via LCMS of the crude reaction
mixture.
Scheme 4. Attempted ionic reduction of 37.
5

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
Table 5
Table 6
Acid mediated acyloxy acetal formation from 37.
Reduction of the bicyclic acyloxy acetal 51.
entry
conditions
yield (%)
entry
acid/solvent
time (h)
yield (%)a
1
2
3
4
5
TiCl4 (20 equiv), CH2Cl2, e78 ꢁC to rt
TMSOTf (5 equiv), MeCN, ꢀ40 ꢁC to rt
Sc(OTf)3 (1.5 equiv), CH2Cl2, 0 ꢁC to rt
BF3 $ OEt2 (10 equiv), CH2Cl2, 0 ꢁC
EtAlCl2, CH2Cl2, e40 to 0 ꢁC
RSMa
RSMa
RSMa
RSMa
97b
(50:51)b
1
2
3
4
TFA (15 equiv)/CH2Cl2
HCl (2 M)/dioxane
HCl (1 M)/dioxane
HCl (0.4 M)/dioxane
1.5
3
5
96c (3.3:1)
59 (0:1)
69 (0:1)
77 (0:1)
31
a
Quantifiable formation of 49 was not detected via LCMS of the crude reaction
a
Isolated yields determined after chromatographic purification.
mixture and only returned starting material (RSM) was observed.
b
The ratio of 50:51 was determined by 1H NMR analysis of the crude reaction
b
Isolated yield determined after chromatographic purification.
mixture.
c
The yield was determined after flash chromatography, but the products were
contaminated with small amounts of impurities (see Supporting Information).
51, it was necessary to induce the reductive opening of the bicyclic
acyloxy acetal. Triethylsilane in the presence of Lewis acids such as
TiCl4, TMSeOTf, Sc(OTf)3, and BF3$OEt2 has been routinely used to
reduce structurally related bicyclic lactone acetals, but applying
these conditions to 51 only returned starting material (Table 6,
entries 1e4) [52e54]. We eventually discovered that treating 51
with triethylsilane in the presence of excess EtAlCl2 (7 equiv)
resulted in clean reductive opening at the anomeric carbon atom
and subsequent decarboxylation to provide 49 in 97% yield.
Incomplete conversion was observed when fewer equivalents of
EtAlCl2 were used. The high diastereoselectivity achieved in this
novel sequence of acyloxy acetal formation and reduction is notable
given that a two-step process for removing the Boc-protecting
under the reaction conditions. Accordingly, we turned to other
acids in hopes of achieving a stereoselective process that favored
formation of 51. Gratifyingly, when oxahydroisoquinolone 37 was
treated with a solution of HCl (2 M) in dioxane, 51 was isolated in
59% yield as a single diastereomer (entry 2); the structure of 51 was
established by X-ray crystallography [51]. Because loss of some of
the Boc-group from 37 was observed (LCMS analysis) under these
conditions, the concentration of HCl was reduced (1 M), and 51 was
obtained in 69% yield as a single diastereomer (entry 3). Further
reducing the concentration of HCl (0.4 M) and extending the re-
action time to 31 h delivered 51 in 77% yield (entry 4).
group and hydrogenation of
a
similar indolyl oxahy-
Suspecting that stereochemical outcome of the cyclization may
have resulted from equilibration of the acyloxy acetal 50, we per-
formed an exploratory experiment to test this hypothesis. A solu-
tion of oxahydroisoquinolone 37 in dichloromethane was treated
with TFA (5 equiv), and a mixture of diastereomeric acyloxy acetals
50 and 51 (ca. 1.3:1) was observed (1H NMR analysis) (Scheme 5).
This crude mixture was dissolved in dioxane containing HCl
(0.5 M), and after stirring for 25 h, only 51 was observed. Because
we did not determine the yield in this preliminary experiment, we
cannot be certain that 50 was not lost to some unknown decom-
position pathway rather than converted by equilibration to 51.
However, we presently believe that the results from this experi-
ment and those gathered in Table 5 suggest that 51 is the ther-
modynamically favored product.
droisoquinolone in Liao’s synthesis of (ꢀ)-alstoscholarisine E pro-
ceeded with little selectivity [14].
To complete the synthesis of alstoscholarisine E (5), all that
remained was the partial reduction of the lactam moiety of 49
followed by cyclization to form the bridging aminal ring. Related
partial reduction strategies using DIBALH, Schwartz reagent [55], or
Tf2O in the presence of tributyltin hydride are known and were
applied in prior syntheses of the alstoscholarisines [12e14] and
some aspidosperma alkaloids [56,57], but applying these condi-
tions to the indolyl oxahydroisoquinolone 49 failed to deliver sig-
nificant quantities of 5 [26]. Hydrosilylation is another technique to
induce partial reduction of amides and has recently emerged as a
useful tactic for the reductive refunctionalization of amides via CeC
bond formation [58e60]. However, lactam hydrosilylation followed
by capture of the intermediate N,O-acetal with a nitrogen atom to
generate an aminal was unknown, so we decided to evaluate the
feasibility of extending reductive amide refunctionalizations to
CeN bond formation. A preliminary experiment following a pro-
cedure reported by Buchwald for effecting the partial reduction of
amides to aldehydes using Ph2SiH2 delivered only trace quantities
of alstoscholarisine E (5) (Table 7, entry 1) [61]. We then discovered
that treating 49 with 1,1,3,3-tetramethyldisiloxane (TMDS) and
Ti(Oi-Pr)4 at room temperature according to a protocol developed
by Lemaire produced 5 in 36% yield, and when this reaction was
heated at 50 ꢁC, 5 was isolated in 56% yield (entries 2,3) [62]. These
results were encouraging, but the reactions required excess
amounts of Ti(Oi-Pr)4, so we sought a superior method. We thus
turned to a procedure disclosed by Nagashima using a catalytic
amount of Vaska’s complex (2 mol %) in toluene and obtained 5 in
56% yield (entry 4) [63]. Upon switching the solvent to dichloro-
methane, alstoscholarisine E was obtained in 77% yield (entry 5).
Having secured the correct stereochemistry at the C-16 center in
Scheme 5. Equilibration of a mixture of acyloxy acetal diastereomers.
6

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
Table 7
for high-resolution mass spectral data, the UT Austin X-ray
diffraction lab for crystallographic data, and the NIH (Grant Number
1 S10 OD021508-01) for funding the Bruker AVANCE III 500 NMR
spectrometer used for characterization of synthetic intermediates.
Completion of the synthesis of ( )-alstoscholarisine E via lactam hydrosilylation and
aminal formation.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132150.
entry
conditions
yield (%)
tracea
References
1
2
3
4
5
Ph2SiH2, Ti(Oi-Pr)4, THF, 50 ꢁC
TMDS, Ti(Oi-Pr)4, PhMe, rt
TMDS, Ti(Oi-Pr)4, PhMe, 50 ꢁC
TMDS, IrCl(CO)(PPh3)2, PhMe, rt
TMDS, IrCl(CO)(PPh3)2, CH2Cl2, rt
[1] L. Gan, M.R. Cookson, L. Petrucelli, A.R. La Spade, Converging pathways in
neurodegeneration, from genetics to mechanisms, Nat. Neurosci. 21 (2018)
1300e1309.
[2] For example, see: M. Citron, Alzheimer’s disease: strategies for disease
modification Nat. Rev. Drug Discov. 9 (2010) 387e398.
b
36
56b
56c
77b
a
[3] S.A. Goldman, Stem and progenitor cell-based therapy of the central nervous
system: hopes, hype, and wishful thinking, Cell Stem Cell 18 (2016) 174e188.
[4] T. Duncan, M. Valenzuela, Alzheimer’s disease, dementia, and stem cell
therapy, Stem Cell Res. Ther. 8 (2017) 111.
[5] C.A. Lyssiotis, L.L. Lairson, A.E. Boitano, H. Wurdak, S.T. Zhu, P.G. Schultz,
Chemical control of stem cell fate and developmental potential, Angew. Chem.
Int. Ed. 50 (2011) 200e242.
Small, non-quantifiable amounts of 5 were observed in the LCMS of the crude
reaction mixture.
b
Isolated yield after chromatographic purification.
c
Yield determined by 1H NMR spectroscopy with an internal standard.
[6] X.-W. Yang, C.-P. Yang, L.-P. Jiang, X.-J. Qin, Y.-P. Liu, Q.-S. Shen, Y.-B. Chen, X.-
D. Luo, Indole alkaloids with new skeleton activating neural stem cells, Org.
Lett. 16 (2014) 5808e5811.
Although partial reduction of amides using Vaska’s complex and
TMDS followed by nucleophilic trapping of the intermediate is
known [64e69], to our knowledge the conversion of 49 to 5 rep-
resents the first example in which the intermediate is captured by a
nitrogen nucleophile to generate an aminal. Accordingly, this rep-
resents a new and mild protocol for the iridium-catalyzed reductive
aminal formation from tertiary lactams and amides that might be
useful for the late-stage formation of other aminals.
[7] Z. Pan, X.-J. Qin, Y.-P. Liu, T. Wu, X.-D. Luo, C. Xia, H.-J. Alstoscholarisines,
Indole alkaloids from Alstonia scholaris: structural evaluation and bioinspired
synthesis of alstoscholarisine, H. Org. Lett. 18 (2016) 654e657.
[8] J.D. Mason, S.M. Weinreb, The alstoscholarisine alkaloids: isolation, structure
determination, biogenesis, biological evaluation, and synthesis, in: H.-
€
J. Knolker (Ed.), The Alkaloids: Chemistry and Biology, vol. 81, Academic Press,
London, 2019, pp. 115e150.
[9] The step count of each previous synthesis is determined from the reported
sequence of chemical operations. In cases where a known compound is used
with reference to a previous literature citation, the step count for its prepa-
ration from a reasonably-priced (<$25/g) starting material are applied. We
define a step as a chemical operation that is concluded by any form of puri-
fication or separation, including aqueous work-up or solvent removal or
exchange.
[10] F. Bihelovic, Z. Ferjancic, Total synthesis of ( )-Alstoscholarisine A, Angew.
Chem. Int. Ed. 55 (2016) 2569e2572.
[11] X. Liang, S.-Z. Jiang, K. Wei, Y.-R. Yang, Enantioselective total synthesis of
(ꢀ)-Alstoscholarisine A, J. Am. Chem. Soc. 138 (2016) 2560e2562.
[12] J.D. Mason, S.M. Weinreb, Total syntheses of the monoterpenoid indole al-
3. Summary and conclusion
In summary, we have completed a concise and efficient syn-
thesis of ( )-alstoscholarisine E (5) that proceeds in 15.2% overall
yield and requires only seven chemical steps (LLS) from commer-
cially available reagents. As such, it is considerably shorter than
previous syntheses of structurally related alstoscholarisines. The
approach features a number of interesting transformations. In
particular, the synthesis commences with a unique variant of a
tandem vinylogous Mannich reaction and an intramolecular hetero
Diels-Alder reaction to deliver the cis-oxahydroisoquinolone 44 in
just two steps. The challenging coupling of cis-oxahy-
droisoquinolone and indole subunits was achieved by a Suzuki
reaction catalyzed by a precatalyst described by Buchwald. The
stereochemistry at the C-16 bridging carbon atom was set by a
novel, yet unplanned, sequence involving stereoselective, acid-
mediated cyclization of the Boc-carbamate of 37 onto the vinyl
ether moiety to furnish an acyloxy acetal that was converted to 49
by Lewis-acid promoted reduction and decarboxylation. To com-
plete the synthesis of 5, a new method for the iridium-catalyzed
reductive aminal formation from a lactam was invented that may
be more generally useful for late-stage formation of aminals from
tertiary lactams and amides.
kaloids
( )-Alstoscholarisine B and C, Angew. Chem. Int. Ed. 56 (2017)
16674e16676.
[13] J.D. Mason, S.M. Weinreb, Synthesis of alstoscholarisines AeE, monoterpene
indole alkaloids with modulating effects on neural stem cells, J. Org. Chem. 83
(2018) 5877e5896.
[14] L. Hu, Q. Li, L. Yao, B. Xu, X. Wang, X. Liao, Enantioselective and divergent
syntheses of alstoscholarisines A, E and their enantiomers, Org. Lett. 20 (2018)
6202e6205.
[15] S.F. Martin, Natural products and their mimics as targets of opportunity for
discovery, J. Org. Chem. 82 (2017) 10757e10794.
[16] S.F. Martin, Strategies for the synthesis of alkaloids and novel nitrogen het-
erocycles, Heterocycl. Chem. 110 (2013) 73e117.
[17] S.F. Martin, B. Benage, S.A. Williamson, S.P. Brown, Applications of the intra-
molecular Diels-Alder reactions of heterodienes to the syntheses of indole
alkaloids, Tetrahedron 42 (1986) 2903e2910.
[18] S.F. Martin, C.W. Clark, J.W. Corbett, Applications of vinylogous Mannich re-
actions. Asymmetric synthesis of the heteroyohimboid alkaloids (-)-Ajmali-
cine, (þ)-19-epi-Ajmalicine, and (-)-Tetrahydroalstonine, J. Org. Chem. 60
(1995) 3236e3242.
[19] S.F. Martin, K.X. Chen, C.T. Eary, An enantioselective total synthesis of
(þ)-Geissoschizine, Org. Lett. 1 (1999) 79e82.
[20] S.F. Martin, B. Benage, J.E. Hunter, A concise strategy for the syntheses of
indole alkaloids of the heteroyohimboid and corynantheioid families. Total
syntheses of ( )-tetrahydroalstonine, ( )-cathenamine and ( )-geissoschi-
zine, J. Am. Chem. Soc. 110 (1988) 5925e5927.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[21] S.F. Martin, J.E. Hunter, B. Benage, L.S. Geraci, M. Mortimore, Unified strategy
for synthesis of indole and 2-oxindole alkaloids, J. Am. Chem. Soc. 113 (1991)
6161e6171.
[22] M. Ito, C.W. Clark, M. Mortimore, J.B. Goh, S.F. Martin, Biogenetically inspired
approach to the strychnos alkaloids. Concise syntheses of ( )-Akuammicine
and ( )-Strychnine, J. Am. Chem. Soc. 123 (2001) 8003e8010.
[23] S.F. Martin, Evolution of the vinylogous Mannich reaction as a key construc-
tion for alkaloid synthesis, Acc. Chem. Res. 35 (2002) 895e904.
[24] S.F. Martin, C.W. Clark, M. Ito, M. Mortimore, A biomimetic approach to the
strychnos alkaloids. A novel, concise synthesis of ( )-Akuammicine and a
Acknowledgment
We are grateful to the Robert A. Welch Foundation (F-0652) for
funding. We also thank the UT Austin Mass Spectrometry Facility
7

M.D. Wood, D.W. Klosowski and S.F. Martin
Tetrahedron 89 (2021) 132150
route to ( )-Strychnine, J. Am. Chem. Soc. 118 (1996) 9804e9805.
[25] A. Deiters, K. Chen, C.T. Eary, S.F. Martin, Biomimetic entry to the sarpagan
family of indole alkaloids: total synthesis of (þ)-Geissoschizine and (þ)-N-
methylvellosimine, J. Am. Chem. Soc. 125 (2003) 4541e4550.
9145e9157.
[48] T. Kinzel, Y. Zhang, S.L. Buchwald, A new palladium precatalyst allows for the
fast SuzukiꢀMiyaura coupling reactions of unstable polyfluorophenyl and 2-
heteroaryl boronic acids, J. Am. Chem. Soc. 132 (2010) 14073e14075.
[49] M.A. Düfert, K.L. Billingsley, S.L. Buchwald, Suzuki-Miyaura cross-coupling of
unprotected, nitrogen-rich heterocycles: substrate scope and mechanistic
investigation, J. Am. Chem. Soc. 135 (2013) 12877e12885.
[50] N.C. Bruno, M.T. Tudge, S.L. Buchwald, Design and preparation of new palla-
dium precatalysts for CeC and CeN cross-coupling reactions, Chem. Sci. 4
(2013) 916e920.
[51] Crystallographic Data Has Been Deposited with the Cambridge Crystallo-
graphic Data Center, Deposition number 1947103.
[52] O. Gaertzen, A.M. Misske, P. Wolbers, H.M.R. Hoffmann, Synthesis of enan-
tiopure C-glycosides and pseudo C-glycosides. Lewis acid mediated cleavage
of [3.3.1] oxabicyclic lactones, Synlett (1999) 1041e1044.
[53] S.P. Cakir, K.T. Mead, L.T. Smith, Studies towards diarylheptanoid synthesis.
Part 2: synthesis and ring cleavage reactions of tetrahydro-4H-furo[2,3-b]
pyran-2-ones, Tetrahedron Lett. 44 (2003) 6355e6358.
[54] J.A. Yin, T. Linker, Stereoselective diversity-oriented syntheses of functional-
ized saccharides from bicyclic carbohydrate 1,2-lactones, Tetrahedron 67
(2011) 2447e2461.
[26] M.D. Wood, D.W. Klosowski, S.F. Martin, Stereoselective total synthesis of
(
)-Alstoscholarisine, E. Org. Lett. 22 (2020) 786e790.
[27] S. Gronowitz, Z. Lidert, A convenient synthesis of N-substituted N-chlor-
omethyl carboxamides, Synthesis 10 (1979) 810.
[28] K. Ikeda, Y. Terao, M. Sekiya, New syntheses of alpha;-N-
alkylacetamidomethylated carbonyl compounds, Chem. Pharm. Bull. 29
(1981) 1156e1159.
[29] R. Amoroso, G. Cardillo, C. Tomasini, P. Tortoreto, A new route to the synthesis
of amino acids through the mercury cyclization of chiral amidals, J. Org. Chem.
57 (1992) 1082e1087.
[30] S. Majumdar, K.B. Sloan, Synthesis, hydrolyses and dermal delivery of N-alkyl-
N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of phenol, imide
and thiol containing drugs, Bioorg. Med. Chem. Lett 16 (2006) 3590e3594.
[31] K.G. Siver, K.B. Sloan, Alkylation of 6-mercaptopurine (6-MP) with N-alkyl-N-
alkoxycarbonyl)aminomethyl chlorides: S6-(N-alkyl-N-alkoxycarbonyl)ami-
nomethyl-6-MP prodrug structure effect on the dermal delivery of 6-MP,
J. Pharmacol. Sci. 79 (1990) 66e73.
[32] B.M. Trost, L.S. Chupak, T. Lübbers, Short preparation of (S)-(E)-1-(O-meth-
ylmandeloxy)butadiene, J. Org. Chem. 62 (1997) 736.
[33] A. Devasagayaraj, L. Schwink, P. Knochel, Preparation and reactions of dio-
rganozincs from dienic silyl enol ethers, J. Org. Chem. 60 (1995) 3311e3317.
[34] K. Ishihata, A. Sakakura, Comprehensive Organic Synthesis II, second ed., 2014,
pp. 409e465.
[55] J.T. Spletstoser, J.M. White, A.R. Tunoori, G.I. Georg, Mild and selective
hydrozirconation of amides to aldehydes using Cp2Zr(H)Cl: scope and
mechanistic insight, J. Am. Chem. Soc. 129 (2007) 3408e3419.
[56] J.W. Medley, M. Movassaghi,
A concise and versatile double-cyclization
strategy for the highly stereoselective synthesis and arylative dimerization
of aspidosperma alkaloids, Angew. Chem. Int. Ed. 51 (2012) 4572e4576.
[57] M. Mizutani, F. Inagaki, T. Nakanishi, C. Yanagihara, I. Tamai, C. Mukai, Total
syntheses of (ꢀ)- and (þ)-Goniomitine, Org. Lett. 13 (2011) 1796e1799.
[58] D. Addis, S. Das, K. Junge, M. Beller, Selective reduction of carboxylic acid
derivatives by catalytic hydrosilylation, Angew. Chem. Int. Ed. 50 (2011)
6004e6011.
[35] G. Desimoni, G. Faita, P. Quadrelli, Forty years after "heterodiene syntheses
with
a,b-unsaturated carbonyl compounds": enantioselective syntheses of
3,4-dihydropyran derivatives, Chem. Rev. 118 (2018) 2080e2248.
[36] K. Gademann, D.E. Chavez, E.N. Jacobsen, Highly enantioselective inverse-
electron-demand hetero-Diels-Alder reactions of a,b-unsaturated aldehydes,
Angew. Chem. Int. Ed. 41 (2002) 3059e3061.
[59] A. Volkov, F. Tinnis, T. Slagbrand, P. Trillo, H. Adolfsson, Chemoselective
reduction of carboxamides, Chem. Soc. Rev. 45 (2016) 6685e6697.
[60] D. Matheau-Raven, P. Gabriel, J.A. Leitch, Y.A. Almehmadi, K. Yamazaki,
D.J. Dixon, Catalytic reductive functionalization of tertiary amides using
Vaska’s complex: synthesis of complex tertiary amine building blocks and
natural products, ACS Catal. 10 (2020) 8880e8897.
[61] S. Bower, K.A. Kreutzer, S.L. Buchwald, A mild general procedure for the one-
pot conversion of amides to aldehydes, Angew. Chem. Int. Ed. 35 (1996)
1515e1516.
[62] S. Laval, W. Dayoub, A. Favre-Reguillon, P. Demonchaux, G. Mignani,
M. Lemaire, A mild titanium-based system for the reduction of amides to
aldehydes, Tetrahedron Lett. 51 (2010) 2092e2094.
[63] Y. Motoyama, M. Aoki, N. Takaoka, R. Aoto, H. Nagashima, Highly efficient
synthesis of aldenamines from carboxamides by iridium-catalyzed silane-
reduction/dehydration under mild conditions, Chem. Commun. (2009)
1574e1576.
[37] B. Wang, X.M. Feng, Y.Z. Huang, H. Liu, X. Cui, Y.Z. Jiang, A highly enantiose-
lective hetero-Diels-Alder reaction of aldehydes with Danishefsky’s diene
catalyzed by chiral titanium(IV) 5,5’,6,6 ’,7,7’,8,8’-octahydro-1,1’-bi-2-
naphthol complexes, J. Org. Chem. 67 (2002) 2175e2182.
[38] A. Graven, M. Johannsen, K.A. Jorgensen, A highly chemo- and enantio-
selective hetero-Diels-Alder reaction catalysed by chiral aluminium com-
plexes, Chem. Commun. (1996) 2373e2374.
[39] D.H. Ryu, E.J. Corey, Triflimide activation of a chiral oxazaborolidine leads to a
more general catalytic system for enantioselective Diels-Alder addition, J. Am.
Chem. Soc. 125 (2003) 6388e6390.
[40] N.M. Benjamin, Enantioselective Synthesis of 2,2,5-Tri- and 2,2,5,5-
Tetrasubstituted Tetrahydrofurans and Synthesis of Diketopiperazine Con-
taining Natural Products, Ph.D. Dissertation, University of Texas at Austin,
2012.
[41] L. Laupichle, C.E. Sowa, J. Thiem, Synthesis and structural studies of
asparagine-modified 2-deoxy-
a
-N-glycopeptides associated with the renin-
[64] A.W. Gregory, A. Chambers, A. Hawkins, P. Jakubec, D. Dixon, J. Iridium-
catalyzed reductive nitro-mannich cyclization, Chem. Eur J. 21 (2015)
111e114.
[65] A.L.F. De Arriba, E. Lenci, M. Sonawane, O. Formery, D. Dixon, J. Iridium-
catalyzed reductive strecker reaction for late-stage amide and lactam cyana-
tion, Angew. Chem. Int. Ed. 56 (2017) 3655e3659.
Angiotensin system, Bioorg. Med. Chem. 2 (1994) 1281e1294.
[42] S. Dharuman, Y.D. Vankar, N-Halosuccinimide/AgNO3-Efficient reagent sys-
tems for one-step synthesis of 2-haloglycals from glycals: application in the
synthesis of 2C-branched sugars via heck coupling reactions, Org. Lett. 16
(2014) 1172e1175.
[43] R. Kuwano, M. Kashiwabara, Ruthenium-catalyzed asymmetric hydrogenation
of N-Boc-indoles, Org. Lett. 8 (2006) 2653e2655.
[66] M. Yoritate, Y. Takahashi, H. Tajima, C. Ogihara, T. Yokoyama, Y. Soda, T. Oishi,
T. Sato, N. Chida, Unified total synthesis of stemoamide-type Alkaloids by
chemoselective assembly of five-membered building blocks, J. Am. Chem. Soc.
139 (2017) 18386e18391.
[67] L.G. Xie, D.J. Dixon, Tertiary amine synthesis via reductive coupling of amides
with Grignard reagents, Chem. Sci. 8 (2017) 7492e7497.
[44] D. Haas, J.M. Hammann, R. Greiner, P. Knochel, Recent developments in
Negishi cross-coupling reactions, ACS Catal. 6 (2016) 1540e1552.
[45] J.E. Milne, S.L. Buchwald, An extremely active catalyst for the Negishi cross-
coupling reaction, J. Am. Chem. Soc. 126 (2004) 13028e13032.
[46] C.B. De Koning, J.P. Michael, R. Pathak, W.A.L. Van Otterlo, The synthesis of
[68] L.G. Xie, D.J. Dixon, Iridium-catalyzed reductive Ugi-type reactions of tertiary
amides, Nat. Commun. 9 (2018) 2841.
indolo- and pyrrolo[2,1-a]isoquinolines, Tetrahedron Lett. 45 (2004)
1117e1119.
[69] X.N. Hu, T.L. Shen, D.C. Cai, J.F. Zheng, P.Q. Huang, The iridium-catalysed
reductive coupling reaction of tertiary lactams/amides with iso-
cyanoacetates, Org. Chem. Front. 5 (2018) 2051e2056.
[47] P.A. Cox, A.G. Leach, A.D. Campbell, G.C. Lloyd-Jones, Protodeboronation of
heteroaromatic, vinyl, and cyclopropyl boronic acids: pHerate profiles,
autocatalysis, and disproportionation, J. Am. Chem. Soc. 138 (2016)
8