Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies

Article abstract of DOI:10.1021/jacs.8b03404

The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2(S)-cathafoline, (+)-akuammiline, and (-)-ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof.

Full text of DOI:10.1021/jacs.8b03404

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Enantioselective Total Syntheses of Methanoquinolizidine-
Containing Akuammiline Alkaloids and Related Studies
Elias Picazo, Lucas A. Morrill, Robert Susick, Jesus Moreno, Joel Smith, and Neil K. Garg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03404 • Publication Date (Web): 25 Apr 2018
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Enantioselective Total Syntheses of Methanoquinolizidine-
Containing Akuammiline Alkaloids and Related Studies
Elias Picazo,† Lucas A. Morrill,† Robert B. Susick, Jesus Moreno, Joel M. Smith, and Neil K. Garg*
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Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095
ABSTRACT: The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in
various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine
core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)ꢀstrictamine, (–)ꢀ2(S)ꢀ
cathafoline, (+)ꢀakuammiline, and (–)ꢀΨꢀakuammigine. Our strategy relies on the development of the reductive interrupted Fischer
indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to lateꢀstage
formation of the methanoquinolizidine framework using a deprotection–cyclization cascade. The total syntheses of (–)ꢀΨꢀ
akuammigine and (+)ꢀakuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine
core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)ꢀstrictamine and (+)ꢀ
akuammiline to ultimately provide (–)ꢀ10ꢀdemethoxyvincorine and a new analogue thereof.
Introduction
The akuammiline alkaloids are an important class of natuꢀ
The complexity of 1–4, coupled with attractive biological
activities (vide infra), have prompted numerous synthetic efꢀ
forts. Following seminal studies by Dolby,10 Bosch and Benꢀ
nasar,11 and Sakai12 beginning more than four decades ago, the
laboratories of Cook,13 Tokuyama,14 and Matsuo15 have more
recently described promising synthetic approaches. However,
a total synthesis of any methanoquinolizidineꢀcontaining akuꢀ
ammiline alkaloid had proven elusive.16 Moreover, to date, no
total syntheses of methanoquinolizidineꢀcontaining akuammilꢀ
ines that also bear vicinal quaternary centers (e.g., 3 and 4)
have been reported.
ral products isolated from plants found in India, Africa, and
Southeast Asia. These alkaloids, thought to be the active inꢀ
gredients in traditional medicines used to treat a multitude of
ailments in humans and livestock,1 have been the subject of
intense investigations spanning structural elucidation, biosynꢀ
thesis, biological evaluation, and chemical synthesis.2 More
than 75 akuammilines have now been unambiguously characꢀ
terized,3 many of which display exciting biological profiles,
and all of which possess provocative chemical structures. Deꢀ
spite their enticing characteristics and biosynthetic relation to
the popular Strychnos alkaloids,4 the akuammiline family has
been comparatively less studied by synthetic chemists relative
to the Strychnos alkaloids. It was not until recently that the
synthetic community launched efforts toward the akuammiline
alkaloids, which have now culminated in total syntheses of
several subclasses.5 This is particularly noteworthy, as even
the simplest akuammilines contain at least five interconnected
rings, a multitude of stereocenters, and one or more basic niꢀ
trogen atoms.
Herein, we describe a full account of our enantioselective
approach
to
several
methanoquinolizidineꢀcontaining
akuammilines and subsequent biomimetic manipulations. Key
to the success of these studies is the development of the
reductive interrupted Fischer indolization reaction17,18,19 to
construct a complex pentacyclic intermediate, as well as the
lateꢀstage formation of the methanoquinolizidine framework
using a deprotection–cyclization cascade. These studies result
in the
N
N
H
H
H
N
Me
Me
Me
N
N
We became interested in a subset of the akuammiline alꢀ
kaloids that possess a methanoquinolizidine core. This cageꢀ
like scaffold, along with several methanoquinolizidineꢀ
containing akuammilines, are shown in Figure 1 (i.e., 1–4).6
(+)ꢀStrictamine (1)7 features an indolenine and four stereocenꢀ
ters, whereas (–)ꢀ2(S)ꢀcathafoline (2)8 has an indoline core
resulting in five contiguous stereocenters. (+)ꢀAkuammiline
(3) and (–)ꢀΨꢀakuammigine (4)9 display an additional layer of
complexity with vicinal quaternary centers at C7 and C16.
Moreover, (–)ꢀΨꢀakuammigine (4) also bears a furoindoline
motif, leading to six interconnected rings and five contiguous
stereocenters, thereby rendering it the most complex member
of this akuammiline subclass.
H
H
CO2Me
CO2Me
(+)-Strictamine (1)
(–)-2(S)-Cathafoline (2)
N
N
H
H
Me
Me
Me
N
N
16
O
16
7
H
H
7
CO2Me
CO2Me
OAc
methanoquinolizidine
(–)-Ψ-Akuammigine (4)
(+)-Akuammiline (3)
Figure 1. Representative methanoquinolizidineꢀcontaining
akuammiline alkaloids.
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first total syntheses of (+)ꢀstrictamine (1) and (–)ꢀ2(S)ꢀ
reductive interrupted Fischer indolization reaction.17 If
cathafoline (2), which we communicated in 2016.5l We then
exploit a previously undesired epimerization event to access
(+)ꢀakuammiline (3) and (–)ꢀΨꢀakuammigine (4), each of
which bear vicinal quaternary stereocenters embedded in their
methanoquinolizidine cores. Lastly, we describe lateꢀstage
reductive rearrangements of (+)ꢀstrictamine (1) and (+)ꢀ
akuammiline (3), inspired by the proposed biosynthesis of
akuammiline alkaloids20 to give pyrrolidinoindoline scaffolds.
successful, this transformation would introduce two new rings.
Moreover, two stereogenic centers would be generated,
including the C2 stereocenter seen in 2(S)ꢀcathafoline (2) (via
7) and the challenging C7 quaternary center common to all
akuammilines. Ketolactone 9 would ultimately be obtained
from enone 10, which, in turn, would arise from a goldꢀ
catalyzed cyclization of silyl enol ether 11.22 Finally, 11 would
be accessed in enantioenriched fashion from sulfonamide 12
and dibenzoate 13 via a Pdꢀcatalyzed desymmetrization and
subsequent manipulations. 23
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Results and Discussion
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(+)-Strictamine and (–)-2(S)-Cathafoline: Isolation,
Biological Activity, and Retrosynthetic Analysis
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Enantioselective Synthesis of the Fischer Indolization
Substrate
(+)ꢀStrictamine (1) and (–)ꢀ2(S)ꢀcathafoline (2) were seꢀ
lected as our initial synthetic targets. (+)ꢀStrictamine (1) was
isolated in 19667 from the plant Rhazya stricta, whereas (–)ꢀ
2(S)ꢀcathafoline (2) was extracted from Alstonia macrophylla
in 2014.8 (+)ꢀStrictamine (1) inhibits the transcription factor
NFꢀκB,21 and may therefore serve as a lead compound for the
discovery of new drugs for the treatment of cancer or inflamꢀ
matory diseases. (–)ꢀ2(S)ꢀCathafoline (2) shows moderate
activity in overturning drug resistance in vincristineꢀresistant
KB cells.8 Despite the aforementioned synthetic pursuits, neiꢀ
ther 1 or 2 had succumbed to total synthesis. In the case of (+)ꢀ
strictamine (1), this is especially noteworthy given that the
compound had been known for more than 50 years.
To initiate our forward synthetic studies, we sought to
prepare enone 16 in enantioenriched form, as this could serve
as a precursor for later construction of the necessary [3.3.1]ꢀ
azabicycle (Scheme 2). Although we initially examined severꢀ
al possible routes, including enzymatic desymmetrization24
and the use of Koga bases,25 we found a Pdꢀcatalyzed Trost
desymmetrization23 was ultimately most successful. Upon
treatment of dibenzoate 13 and sulfonamide 12 with a suitable
Pd precatalyst and (R,R)ꢀDACHꢀphenyl Trost ligand 14, the
desired desymmetrization took place. Direct saponification of
the product furnished alcohol 15 in 89% yield. Subsequent
PCCꢀmediated oxidation of the resultant secondary alcohol
delivered enone 16 in excellent yield. Enone 16 could be crysꢀ
tallized at the interface of EtOAc and heptane; Xꢀray diffracꢀ
tion studies confirmed the desired absolute stereochemistry
had been obtained in the desymmetrization reaction.26
Our retrosynthetic analysis of (+)ꢀstrictamine (1) and (–)ꢀ
2(S)ꢀcathafoline (2) is shown in Scheme 1. We envisioned
forming the methanoquinolizidine scaffold by lateꢀstage
construction of the C5–N4 bond. Thus, 1 and 2 would be
accessed from primary alkyl chloride 5 through a tandem
deprotection–cyclization reaction, followed by manipulation
of the indoline ring system. Chloride 5 would derive from
indoline lactone 6 through methanolysis and halide formation.
In a key retrosynthetic disconnection, we envisaged indoline
lactone 6 arising from ketolactone 9 and phenylhydrazine (8)
via a
Scheme 2. Trost desymmetrization and synthesis of enone 16.
Ns
OBz
i. [PdCl(C3H5)]2 (1.5 mol%)
ligand 14 (4.5 mol%)
N
Me
Cs2CO3, CH2Cl2, 23 °C
NsHN
+
Me
12
ii. LiOH•H2O, MeOH, 23 °C
OBz
(89% yield)
OH
13
15
Pd-Catalyzed
Desymmetrization
Scheme 1. Retrosynthetic analysis of (+)ꢀstrictamine (1) and (–)ꢀ
2(S)ꢀcathafoline (2).
PPh2
Ns
N
O
NH
O
O
Me
PCC
NH
CH2Cl2, 23 °C
PPh2
X-ray
(93% yield)
16
14
Having synthesized enone 16, we sought to introduce the
[3.3.1]ꢀazabicycle of the natural product and perform further
elaborations (Scheme 3). Upon treatment with TBDPSOTf and
2,6ꢀlutidine, enone 16 was converted to silyl enol ether 11 in
high yield. This set the stage for a pivotal goldꢀmediated
cyclization, inspired by precedent from Li and coworkers.22
Using our optimized protocol, silyl enol ether 11 was treated
with (PMe3)AuCl and AgOTf, followed by quenching with
tosic acid hydrate in the same pot, to ultimately afford bicycle
10 as the major product. This sequence is thought to proceed
by initial formation of oxocarbenium ion intermediate 17,
which undergoes nucleophilic attack by tꢀBuOH to give silyl
enol ether 18. In the presence of acid and water, 18 is
hydrolyzed to give the desired enone 10. Chiral SFC analysis
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at this stage revealed that 10 had been prepared in 96% ee. It
should also be noted that the key goldꢀmediated cyclization
1
gave an undesired by product, 19, in minor quantities.
Although 10 and 19 were inseparable, the mixture could be
taken forward through an epoxidation and Wittig
homologation.5h,k Aqueous workup of the Wittig product led to
enol ether hydrolysis with epoxide fragmentation to cleanly
deliver enal 20 as a single constitutional isomer in 49% yield
from silyl enol ether 11.
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Scheme 3. Goldꢀcatalyzed cyclization to construct the [3.3.1]ꢀ
azabicycle and elaboration to enal 20.
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intermediate. Subsequent reaction with tributyltin hydride and
AIBN led to cyclization at C7 to deliver acetal 23 as an
inconsequential mixture of diastereomers.27 Acidꢀmediated
hydrolysis of the acetal and reduction of the resultant lactol
provided diol 24. Finally, lactonization, followed by alcohol
oxidation, afforded the desired ketolactone 9.
Reductive Interrupted Fischer Indolization Reaction
With ketolactone 9 in hand, we developed the key
reductive interrupted Fischer indolization reaction. Our
laboratory had extensive experience in developing Fischer
indolizations in the context of methodology18 and complex
molecule synthesis.5b,h,k Thus we began by surveying a range
of acid sources that were utilized in the Fischer indolization
reaction literature and those we had previously deemed most
promising. As shown in Table 1, the reactions of
phenylhydrazine (8, 3 equiv) and ketolactone 9 using 5.0
equiv of acid were performed at 60 °C for 6 h to provide
meaningful comparison data. Most attempts, including those
with Lewis acids and very strong protic acids, were met with
disappointment (entries 1–5). Whereas the use of AcOH gave
modest yield using water as the solvent (entry 6), an
improvement was seen in switching the solvent to acetic acid
(entry 7). Lastly, the use of TFA gave the most promising
result, delivering Fischer indolization product 26 in 38% yield
(entry 8). It should be noted that this transformation proceeds
with complete diastereoselectivity and sets the C7 quaternary
stereocenter. The diastereoselectivity is thought to be
governed by approach of the phenyl ring on the less hindered
faced of the [3.3.1]ꢀazabicycle during the chargeꢀaccelerated
[3,3]ꢀsigmatropic rearrangement (see transition structure 25).
Using the sequence shown in Scheme 4, enal 20 was
elaborated to ketolactone 9, the substrate for our key reductive
interrupted Fischer indolization reaction. One of the synthetic
challenges we encountered was the introduction of a
hydroxyethyl group on C7. Initial approaches using metalꢀ
mediated conjugate addition strategies were met without
success, so instead we targeted Ueno–Stork cyclization
methodology.27 En route to testing this approach, aldehyde 20
was converted to the corresponding methyl ester, 21, using an
NISꢀbased oxidative esterification protocol.28 Next, 21 was
treated with ethyl vinyl ether (22) and NIS to give a mixed
iodoacetal
Table 1. Survey of acids to promote the Fischer indolization
reaction of ketolactone 9 and 8.
Scheme 4. Synthesis of ketolactone 9, the substrate for the
reductive Fischer indolization reaction.
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Undesired C16 Epimerization and Synthesis of Unnatural
C16 Epimers of Strictamine and 2(S)-Cathafoline
1
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3
4
5
6
7
8
9
Having executed the key reductive interrupted Fischer
indolization reaction, we sought to prepare chloroester 30 en
route to the desired natural products through a seemingly
straightforward sequence (Scheme 6). Boc protection of
indoline 6 proceeded smoothly to furnish 27. Subsequently, a
two step hydrolysis/methylation protocol was used to arrive at
hydroxyester 28. Although we found 28 to be somewhat
unstable, we found it could be used directly in the subsequent
step. Treatment under Appelꢀlike conditions cleanly provided
29, which unfortunately possessed the undesired
stereochemistry at C16. Despite a survey of alternative
methanoloysis conditions prior to performing the chlorination,
the undesired C16 epimer, 29, was routinely formed as the
major product. We surmise that C16 epimerization of 27
occurs more favorably than methanolysis or hydrolysis of the
lactone. Several workarounds were pursued, such as attempted
lactone opening via amidation,31 Pdꢀcatalyzed ringꢀopening,32
or SN2 displacements,33 none of which were successful.
Additionally, efforts to epimerize C16 of 29 and related
compounds to provide the desired C16 epimer also proved
fruitless.
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a
Yields were determined by 1H NMR analysis using 1,3,5ꢀ
trimethoxybenzene as an external standard.
Our next objective was to further optimize the Fischer
indolization reaction and develop the desired reductive
variant.17 We were delighted to find that slight changes in our
reaction conditions (i.e., 40 °C and 12 h), greatly improved
conversion to indolenine lactone 26 (Scheme 5). Moreover, it
was found that by simply adding triethylsilane and additional
TFA to the Fischer indolization reaction with stirring at 23 °C,
we obtained the reductive Fischer indolization product 6 in
83% yield. Overall, the conversion of ketolactone 9 to indoline
6 proceeds with installation of two new rings, three new
bonds, and two new stereocenters, all with complete diastereꢀ
oselectivity. This transformation represents one of the most
complex Fischer indolization reactions reported in the literaꢀ
ture.29 Interestingly, hydride approach from the more congestꢀ
ed face of the [3.3.1]ꢀazabicycle appears to be favorable (see
transition structure 7). Although counterintuitive in some reꢀ
spects, the stereochemical outcome may be rationalized by the
kinetic preference for the formation of a cis ring juncture beꢀ
tween the pyrrolidine and cyclohexyl units. The stereochemiꢀ
cal outcome is consistent with reports from the Styrchnos alkaꢀ
loid literature30 as well as a similar C2 reduction in akuamꢀ
miline synthesis.5v
Scheme 6. Undesired C16 epimerization.
Faced with the undesired epimerization leading to
chloroester 29, we saw an opportunity to develop lateꢀstage
transformations and synthesize unnatural epimeric analogs of
strictamine and 2(S)ꢀcathafoline. As shown in Scheme 7, the
C16 epimer of strictamine 34 could be accessed in three steps
from chloroester 29. Deprotection of 29 furnished indoline 31
in quantitative yield. Treatment of 31 with PCC led to indoline
oxidation, thus providing the corresponding indolenine motif.
Lastly, we pursued the key deprotection–cyclization step,
analogous to that outlined in our retrosynthetic analysis (see
Figure 1). Exposure of the indolenine intermediate to a solidꢀ
supported thiol resin 3234 and Cs2CO3 in acetonitrile at 65 °C
delivered 16ꢀepiꢀstrictamine (34), presumably by way of
transition structure 33. Analogous to our earlier study toward
the total synthesis of picrinine,5h,k the use of 32 proved
instrumental in facilitating purification of the basic tertiary
amine product. More importantly, this sequence demonstrated
Scheme 5. Reductive interrupted Fischer indolization reaction
delivers 6.
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that our overall approach involving a lateꢀstage deprotection–
cyclization could be used to access the challenging
methanoquinzolidine framework.
1
2
3
Enantioselective Total Syntheses of (+)-Strictamine and
(–)-2(S)-Cathafoline
Despite the C16 epimerization setback, we returned to the
primary task of completing the total syntheses of (+)ꢀ
strictamine and (–)ꢀ2(S)ꢀcathafoline (Scheme 8). We first
sought a means to open the lactone ring of 6 under nonꢀbasic
reaction conditions, to hopefully avoid the undesired
epimerization. To this end, indoline lactone 6 was treated with
lithium borohydride to give the corresponding diol with the
C16 stereochemistry unperturbed. Subsequent protection of
the more accessible primary alcohol furnished silyl ether 37.
Next, a straightforward threeꢀstep sequence was performed to
elaborate the C16 hydroxymethyl group of 37 to the
corresponding methyl ester, 38. From hydroxyester 38, a twoꢀ
step chlorination protocol gave alkyl chloride 5,35 which
proceeded in the presence of the free N–H of the indoline unit
and set the stage for the final steps of the total syntheses. (+)ꢀ
Strictamine (1) was accessed in quantitative yield from 5 by
indoline oxidation, followed by deprotection–cyclization.
Similarly, the total synthesis of (–)ꢀ2(S)ꢀcathafoline (2) was
achieved by Nꢀmethylation of 5, followed by deprotection–
4
5
6
7
8
9
Scheme 7. Synthesis of 16ꢀepiꢀstrictamine (34).
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We also explored two complementary routes to the C16
epimer of 2(S)ꢀcathafoline 35, which are depicted in Figure 2.
Beginning from intermediate alkyl chloride 31, reductive amiꢀ
nation using formaldehyde led to Nꢀmethylation.5c Subsequent
deprotection–cyclization provided 35, albeit in only 10%
yield. Given the modest synthetic efficiency of this sequence,
cyclization.
In
both
cases,
the
pentacyclic
methanoquinolizidine framework was established in the final
step of the total synthesis. NMR spectra of synthetic (+)ꢀ1 and
(–)ꢀ2 correlated with spectra of the natural samples. This
synthetic effort marked the first total syntheses of 1 and 2,
which was initially communicated concurrently with Zhu’s
synthesis of 1.16 Other synthetic routes to 1 have subsequently
been reported by the labs of Fujii and Ohno,5o Gaich,5p,t
Snyder,5r Qin,5u and Zu.5v
we
pursued
an
alternative
path
that
involved
methanoquinolizidine formation prior to Nꢀmethylation.
Deprotection–cyclization of sulfonamide 29, followed by
acidic deprotection of the indoline, furnished the
methanoquinolizidineꢀcontaining product 36 in 76% yield over
two steps. Finally, a reductive amination involving the
indoline nitrogen afforded 16ꢀepiꢀ2(S)ꢀcathafoline (35). The
synthetic routes to 34 and 35 not only permitted access to unꢀ
natural analogs of strictamine and 2(S)ꢀcathafoline, but also
gave us critical experience in performing lateꢀstage operations,
particularly for introduction of the methanoquinolizidine unit
and purification of polar natural productꢀlike compounds.
Scheme 8. Total syntheses of (+)ꢀstrictamine (1) and (–)ꢀ2(S)ꢀ
cathafoline (2).
Figure 2. Synthetic routes to 16ꢀepiꢀ2(S)ꢀcathafoline (35).
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(–)-Ψ-Akuammigine: Isolation, Biological Activity, and
Retrosynthetic Analysis
1
Attempted Introduction of the Furoindoline Motif
2
3
4
5
6
7
8
9
Having validated our strategy toward the total syntheses
of natural products containing the methanoquinolizidine core,
we directed our attention toward (–)ꢀΨꢀakuammigine (4), the
most structurally complex of the methanoquinolizidineꢀ
containing akuammiline alkaloids. (–)ꢀΨꢀAkuammigine (4)
was isolated from Picralima klaineana in 1932.9 Biological
studies later revealed promising activity as an antiꢀ
inflammatory agent.36 Moreover, (–)ꢀΨꢀakuammigine (4)
To initiate our studies toward (–)ꢀΨꢀakuammigine (4), we
focused on the scalable preparation of aldehyde 42 following
the route shown in Scheme 10. Knowing the commonly
encountered difficulties associated with lateꢀstage endeavors
in akuammiline total synthesis, we expected our expedition
would require us to perform the key, reductive interrupted
Fischer indolization17 step on a large scale. Thus, we first
prepared more than 10 grams of ketolactone 9. In the key
reductive Fischer indolization step, we were heartened to find
that gramꢀscale reaction of ketolactone 9 and phenylhydrazine
(8) under acidic conditions proceeded smoothly to deliver
intermediate indolenine 26. Reduction in the same pot using
triethylsilane then furnished the pentacyclic indoline lactone 6
belongs to
a subset of akuammilines bearing vicinal
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quaternary centers, a structural motif which continues to be a
notable synthetic challenge. In fact, only recently have there
been reported total syntheses of akuammiline alkaloids
bearing this motif.5w–y Despite these triumphant efforts,
akuammilines containing both the methanoquinolizidine and
vicinal quaternary centers have yet to succumb to total
synthesis.37
Scheme 10. Scalable preparation of aldehyde 42.
Our initial retrosynthetic analysis of (–)ꢀΨꢀakuammigine
(4) is shown in Scheme 9. The natural product (4) was
proposed to arise from lateꢀstage intermediate 39, possessing a
furoindoline motif and an alkyl chloride. In the forward sense,
removal of the nosyl group was expected to enable C5–N4
bond formation and forge the methanoquinolizidine core,
analogous to the strategy used to synthesize (+)ꢀstrictamine (1)
and (–)ꢀ2(S)ꢀcathafoline (2). Chloride 39 would be synthesized
from furoindoline 40 through oxidative esterification and
elaboration of the silyl ether. In a key maneuver, furoindoline
40 would ultimately be derived from aldehyde 42 through a
sequence involving C16 hydroxymethylation, followed by Nꢀ
methylation and cyclization (see transition structure 41).
Although not depicted, it was envisioned that the namesake of
the natural product family, (+)ꢀakuammiline (4), could also be
accessed from 42 or derivatives thereof. Finally, aldehyde 42
was anticipated to be available from indoline lactone 6, which
should be readily accessible by the reductive interrupted
Fischer indolization reaction17 described above (see Scheme
5).
in 93% yield. Elaboration of indoline lactone 6 through a 3ꢀ
step sequence involving lactone reduction, selective alcohol
protection, and simultaneous oxidation of the indoline and
remaining alcohol afforded indolenine aldehyde 42.
With aldehyde 42 in hand, we sought to tackle three
structural challenges presented by Ψꢀakuammigine (4): the
vicinal quaternary centers, the furoindoline moiety, and the
methanoquinolizidine core. As shown in Scheme 11, treatment
of aldehyde 42 with paraformaldehyde under basic
conditions5x,y provided diol 43 in 58% yield. Of note, this
transformation establishes the second of the vicinal quaternary
centers and proceeds with Tischenkoꢀtype reduction of the
aldehyde.38 Next, we pursued introduction of the furoindoline
moiety by exposing diol 43 to excess methyl iodide and
K2CO3.39 This allowed for differentiation of the C16
hydroxymethyl groups and furnished furoindoline alcohol 44
in 66% yield. Lastly, we sought to forge the
methanoquinolizidine core of the natural product. A threeꢀstep
oxidation/esterification sequence delivered ester 45, which
was poised to undergo C5–N4 bond formation upon C5
activation and removal of the nosyl group. Unfortunately,
removal of the silyl ether group present in 45 failed to deliver
the desired alcohol 47. Instead, we exclusively obtained an
undesired isomer, furoindoline 46, in 67% yield using
Ph3PBr2,40 and in high efficiencies under other conditions
(e.g., acetic acid, TBAF). It is hypothesized that the presumed
in situ structural rearrangement of furoindoline 47 to isomer
46 is thermodynamically driven, with 46 being significantly
more stable.41
Scheme 9. Retrosynthetic analysis of (–)ꢀΨꢀakuammigine (4).
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stable and could not be isolated. We ultimately found that the
alcohol intermediate could be activated by conversion to diꢀ
phenyl phosphate ester 49.43 This set the stage for methanoꢀ
quinolizidine formation. Treatment of 49 with solidꢀsupported
thiol resin 32 under basic conditions provided ester 36.5h,k,l
Reduction of ester 36 with LiBH4 afforded the corresponding
alcohol with concomitant borylation of the tertiary amine to
give indoline alcohol 50 in 69% yield.44 Although unintentionꢀ
al, the introduction of the amineꢀborane functional group
proved beneficial, as it masked the basic tertiary amine and
dramatically facilitated purification of lateꢀstage intermediates.
Scheme 11. Attempted introduction of the furoindoline motif and
2
undesired isomerization to afford 46.
3
4
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Scheme 13. Introduction of the methanoquinolizidine framework
and fortuitous amineꢀborane complexation.
Enantioselective Total Synthesis of (–)-Ψ-Akuammigine
The discovery of the undesired furoindoline isomerization
prompted us to reassess our synthetic approach toward (–)ꢀΨꢀ
akuammigine (4) (Scheme 12). Rather than installing the fuꢀ
roindoline prior to the methanoquinolizidine, we sought to
reverse the order in which these key structural features were
formed. Thus, we targeted epimeric esters 36 or 48 and derivaꢀ
tives thereof that contain the methanoquinolizidine core, but
lack the vicinal quaternary centers and furoindoline, as potenꢀ
tial precursors to (–)ꢀΨꢀakuammigine (4).42 It should be noted
that the C16 stereochemistry was considered inconsequential,
as this stereocenter would be controlled during a subsequent
alkylation step. However, the strategy would likely require the
handling and purification of polar compounds due to the earliꢀ
er installation of the tertiary amine. Given limited options, we
pursued this revised strategy.
The final steps to complete the total synthesis of (–)ꢀΨꢀ
akuammigine (4) focused on installation of the C16 quaternary
stereocenter and the furoindoline motif (Scheme 14). Double
oxidation of indoline alcohol 50 with PCC yielded the correꢀ
sponding indolenine aldehyde, which was a suitable substrate
for C16 alkylation. Exposure of the indolenine aldehyde to
paraformaldehyde (9 equivalents) and Cs2CO3 provided diol
51 in 43% yield over two steps. In a key ploy, we pursued
furoindoline formation by exposing 51 to methyl iodide under
basic conditions.39 This gave rise to the desired product, fuꢀ
roindoline alcohol 53, in 45% yield, with 33% recovered 51.
We presume the reaction proceeds through activated indolenꢀ
inium 52 to deliver an intricate scaffold bearing both the
methanoquinolizidine and the furoindoline motifs. Notably, if
the reaction was allowed to proceed with higher conversion,
borane removal and N4ꢀmethylation occured to give an
undesired ammonium salt byproduct. Nonetheless, oxidation
to the aldehyde, followed by oxidative esterification28 with
borane removal,45 furnished (–)ꢀΨꢀakuammigine (4) in 86%
yield over two steps. All spectral data for (–)ꢀΨꢀakuammigine
(4) were consistent with reported data and authentic samples.46
Scheme 12. Reassessment of synthetic approach.
Scheme 14. Total synthesis of (–)ꢀΨꢀakuammigine (4).
With the aim of installing the methanoquinolizidine and
setting the stage for furoindoline formation, we developed the
sequence described in Scheme 13. Beginning with the product
of our reductive interrupted Fischer indolization reaction, inꢀ
doline lactone 6, we performed a oneꢀpot saponificaꢀ
tion/methylation reaction. This net methanolysis of the lactone
proceeded smoothly, with the expected epimerization of the
C16 stereocenter. Several attempts were made to activate the
resultant primary alcohol (e.g., tosylate, mesylate, halides,
etc.), but the desired products of such efforts were highly unꢀ
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Structural Rearrangement of Methanoquinolizidines to
Pyrrolidinoindolines
One interesting the
1
2
3
notion
regarding
methanoquinolizidineꢀcontaining akuammiline alkaloids is
that, biosynthetically, they serve as precursors to the
pyrrolidinoindolineꢀcontaining akuammilines.20 As such, we
wondered if such structural rearrangements could efficiently
be performed in the laboratory under mild reaction conditions.
Exciting precedent for such conversions exists from the
Zn/AcOHꢀmediated rearrangement of strictamine reported by
Banerji and Chakrabarti in 1966, albeit without a reported
yield.50 We were particularly enticed to attempt the
rearrangement of the methanoquinolizidineꢀcontaining natural
products (+)ꢀstrictamine (1) and (+)ꢀakuammiline (3) using the
mild reducing agent samarium diodide51 (Figure 3). Samarium
diiodide has been utilized to reductively cleave C–N bonds of
αꢀamino carbonyls, even in the context of akuammiline
chemistry.5v However, there have been no previous examples
of the corresponding reductive cleavage of C–N bonds with
SmI2 using αꢀamino imine substrates. Given that previous
reductive rearrangements of the methanoquinolizidine core
have been low yielding,50 we viewed this as an opportunity to
improve their efficiencies.
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Enantioselective Total Synthesis of (+)-Akuammiline
Lastly with regard to the synthesis
of
methanoquinolizidineꢀcontaining akuammilines, we sought to
prepare (+)ꢀakuammiline (3, Scheme 15), the namesake of the
natural product family. Akuammiline (3) was isolated
alongside (–)ꢀΨꢀakuammigine (4) in 1932 and has not been
synthesized previously.9 (+)ꢀAkuammiline (3) is structurally
similar to (–)ꢀΨꢀakuammigine (4), but possesses a C16
acetoxymethyl group, rather than a furoindoline unit.
The results of our rearrangement studies are shown in
Figure 3. Upon treatment of (+)ꢀstrictamine (1) with SmI2 in
THF and methanol at 23 °C, the desired reductive
rearrangement took place to furnish pyrrolidinoindoline
compound 56. Subsequent methylation afforded (–)ꢀ10ꢀ
demethoxyvincorine (57), a bioactive natural product isolated
in 20148 from Alstonia macrophylla, that had yet to be
synthesized. Next, we applied the same reductive
rearrangement conditions to (+)ꢀakuammiline (3). To our
delight, the rearrangement proceeded in quantitative yield to
provide the unnatural akuammiline derivative 58. Of note, 58
bears a pyrrolidinoindoline core with vicinal quaternary
stereocenters at C7 and C16, and is therefore reminiscent of
complex akuammilines bearing those structural features.52
We were delighted to find that lateꢀstage intermediate alꢀ
cohol 50 served as a suitable precursor to (+)ꢀakuammiline (3)
(Scheme 15). Double oxidation of indoline alcohol 50 providꢀ
ed boraneꢀprotected indolenine aldehyde 54. C16 alkylation of
54 proceeded smoothly to establish the vicinal quaternary cenꢀ
ters and provide aldehyde 55.47 It was optimal to use only 1.2
equivalents of paraformaldehyde to preserve the aldehyde
moiety and avoid reduction to the corresponding diol as we
had observed earlier (see 51, Scheme 14). To complete the
total synthesis of (+)ꢀakuammiline (3), aldehyde 55 was elaboꢀ
rated through a multistep protocol involving acetylation, conꢀ
version to the methyl ester, and borane removal.48 Synthetic
(+)ꢀakuammiline (3) was spectroscopically comparable to an
authentic sample of the natural product.49
Scheme 15. Total synthesis of (+)ꢀakuammiline (3).
Figure 3. Structural rearrangement to access pyrrolidinoindolines
(–)ꢀ10ꢀdemethoxyvincorine (57) and 58.
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Family (J.M., E.P., and L.A.M.), the MajetiꢀAlapati family (E.P.),
and the UCLA CotaꢀRobles Fellowship Program (E.P.). J. M. S.
acknowledges the National Science Foundation GRFP (DGEꢀ
1144087) and the UCLA Graduate Division for a Dissertation
Year Fellowship. We are grateful to Professor T.ꢀS. Kam (Univerꢀ
sity of Malaya) for providing authentic samples of aspidophylline
A, strictamine, and 2(S)ꢀcathafoline and Professors L. Evanno and
E. Poupon (Université ParisꢀSaclay) for providing authentic samꢀ
ples of (+)ꢀakuammiline and (–)ꢀΨꢀakuammigine. These studies
were supported by shared instrumentation grants from the NSF
(CHEꢀ1048804) and the National Center for Research Resources
(S10RR025631).
Conclusion
2
We have completed the first enantioselective total syntheꢀ
ses of five akuammiline alkaloids, in addition to several unꢀ
natural compounds. Our synthetic approach to the methanoꢀ
quinolizidineꢀcontaining natural products 1–4 features a numꢀ
ber of key steps, including: a) a Trost desymmetrization to
govern absolute stereochemistry, b) a goldꢀmediated cyclizaꢀ
tion to construct the [3.3.1]ꢀazabicycle, c) a reductive interꢀ
rupted Fischer indolization to arrive at pentacycle 6, and d)
lateꢀstage formation of the methanoquinolizidine using a
deprotection–cyclization cascade. In the case of (+)ꢀ
akuammiline (3) and what is arguably the most complex
3
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methanoquinolizidineꢀcontaining
alkaloid,
(–)ꢀΨꢀ
REFERENCES
akuammigine (4), lateꢀstage introduction of the vicinal quaterꢀ
nary stereocenters was achieved by employing challenging
C16 alkylations. Additionally, in the case of (–)ꢀΨꢀ
akuammigine (4), a means to install the furoindoline was
crafted, while avoiding an undesired furoindoline isomerizaꢀ
tion that plagued our early approaches. Lastly, bioinspired
reductive rearrangements of (+)ꢀstrictamine (1) and (+)ꢀ
akuammiline (3) provided (–)ꢀ10ꢀdemethoxyvincorine (57)
and a C16 analogue thereof 58, by rearrangement of the methꢀ
anoquinolizidine core to pyrrolidinoindoline scaffolds.
1
Baliga, M. S. Chin. J. Integr. Med. 2012, DOI: 10.1007/s11655ꢀ 011ꢀ
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For reviews on akuammiline alkaloids, see: (a) Ramírez, A.; García–
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These efforts mark the first total syntheses of some of the
most complex akuammilines known, including those that posꢀ
sess both a methanoquinolizidine core and vicinal quaternary
stereocenters. It is expected that our studies will enable biologꢀ
ical investigations of akuammilines and unnatural analogs.
Moreover, the lessons learned from our synthetic endeavors,
including the delicate lateꢀstage manipulations and various
undesired setbacks, will inform synthetic forays toward akuꢀ
ammilines and other challenging natural products.
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ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures and compound characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
neilgarg@chem.ucla.edu
Author Contributions
†E.P. and L.A.M. contributed equally.
ACKNOWLEDGMENT
The authors are grateful to the National Science Foundation
(CHEꢀ0955864 and CHEꢀ1464898), 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 NIHꢀNIGMS (F31ꢀGM113642 to J. M., F31ꢀ
GM117945 to E.P., and F31ꢀGM121016 to L.A.M.), the Foote
6
Equilibrium geometry calculations for the methanoquinolizidine scaffold
were performed using Spartan ‘16 (B3LYP/6ꢀ31(G)). The 3D representaꢀ
tion was prepared from the calculated equilibrium geometry using CYLꢀ
view. For CYLview, see: Legault, C. Y. CYLview, 1.0b; Université de
́
Sherbrooke: Quebec, 2009; http://www.cylview.org.
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For the initial isolation of (+)ꢀstrictamine (1), see: (a) Schnoes, H. K.;
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8 For the initial isolation of (–)ꢀ2(S)ꢀcathafoline (2), see: Lim, S.ꢀH.; Low,
Y.ꢀY.; Sinniah, S. K.; Yong, K.ꢀT.; Sim, K.ꢀS.; Kam, T.ꢀS. Phytochemis-
try 2014, 98, 204–215.
30
For an example of an indolenine reduction to an indoline in Strychnos
alkaloid synthesis, see: Kim, J.ꢀY.; Suhl, C.ꢀH.; Lee, J.ꢀH.; Cho, C.ꢀG.
9 For the initial isolation of (+)ꢀ akuammiline (3) and (–)ꢀΨꢀakuammigine
(4), see: Henry, T. A. J. Chem. Soc. 1932, 2759–2768.
9
Org. Lett. 2017, 19, 6168–6171; see also references therein.
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34
For the removal of nosyl groups using a solidꢀsupported thiol reagent,
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Komatsu, Y.; Yoshida, K.; Ueda, H.; Tokuyama, H. Tetrahedron Lett.
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16 For our laboratory’s communication detailing the first total syntheses of
(+)ꢀstrictamine and (–)ꢀ2(S)ꢀcathafoline, see ref 5l. Simultaneously Zhu’s
group reported the total synthesis of (±)ꢀstrictamine, see ref 5m.
37
For a reported effort toward (–)ꢀΨꢀakuammigine (4), see: Andreansky,
E. S.; Blakey, S. B. Org. Lett. 2016, 18, 6492–6495.
38
17
(a) Sung, M. J.; Lee, H. I.; Lee, H. B.; Cha, J. K. J. Org. Chem. 2003,
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Reider, P. J.; Houghton, P. Tetrahedron 1997, 53, 10983−10992.
18 For methodology studies of the interrupted Fischer indolization, see: (a)
Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458–
3461. (b) Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.; Garg, N.
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García, A.; Castedo, L.; Domínguez, D. Tetrahedron 1996, 52, 5929–
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40 Le, D. D.; Cortesi, A. T.; Myers, S. A.; Burlingame, A. L.; Fujimori, D.
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41
Equilibrium geometry calculations were performed using Spartan ‘16
19
(B3LYP/6ꢀ31(G)). The results indicated that furoindoline 46 is nearly 8
kcal/mol lower in energy than desired furoindoline 47.
For a pertinent review of our laboratory’s Fischer indolization studies,
see: Susick, R. B.; Morrill, L. A.; Picazo, E.; Garg, N. K. Synlett 2017, 28,
1–11.
42
Additional strategies were investigated. For example, we attempted to
20 Scott, A. I. Acc. Chem. Res. 1970, 3, 151–157.
introduce the C16 quaternary stereocenter prior to Fischer indolization on
a model system. However, Fischer indolization efforts using i were unsucꢀ
cessful, presumably due to the difficulty of performing the [3,3]ꢀ
sigmatropic rearrangement when trying to access vicinal quaternary stereꢀ
ocenters. With regard to lateꢀstage efforts, intermediates such as diol ii
could not be elaborated to substrates suitable for methanoquinolizidine
formation.
21
Hou, Y.; Cao, X.; Wang, L.; Cheng, B.; Dong, L.; Luo, X.; Bai, G.;
Giao, W. J. Chromatogr. B 2012, 908, 98–104.
22
(a) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nat. Chem. 2013, 5, 679–683. (b)
Xiong, X.; Li, Y.; Lu, Z.; Wan, M.; Deng, J.; Wu, S.; Shao, H.; Li, A.
Chem. Commun. 2014, 50, 5294–5297.
23
For a review on catalytic asymmetric allylic alkylation employing hetꢀ
eroatom nucleophiles, see: Trost, B. M.; Zhang, T.; Sieber, J. D. Chem.
Sci. 2010, 1, 427–440.
24 Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1–55.
25 Aoki, K.; Koga, K. Chem. Pharm. Bull. 2000, 48, 571–574.
26 For the crystallographic data of 16, refer to CCDC number 1440684.
43 Wilk, A.; Grajkowski, A.; Phillips, L. R.; Beaucage, S. L. J. Org. Chem.
1999, 64, 7515–7522.
44
27 SalomꢀRoig, X. J.; Dénès, F.; Renaud, P. Synthesis 2004, 1903–1928.
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liams, R. F.; Minter, D. E. Heterocycles 1987, 25, 251–258. (b) Lu, X.;
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ing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501–3504.
28
McDonald, C.; Holcomb, H.; Kennedy, K.; Kirkpatrick, E.; Leathers,
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3
4
5
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7
8
Schwartz, M. A.; Rose, B. F.; Vishnuvajjala, B. J. Am. Chem. Soc.
1973, 95, 612–613.
For the Zn / strong acidꢀpromoted rearrangement of the methanoquinoꢀ
lizidine in low yield (or no reported yield), see ref 7a and: (a) Savaskan,
S.; Kompis, I.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1972, 55, 2861–
2867. (b) Banerji, J.; Chakrabarti, R. Indian J. Chem. Sect. B 1984, 23B,
453–454.
46
For (–)ꢀΨꢀakuammigine (4) characterization data, see: Hu, W.ꢀL.; Zhu,
J.ꢀP.; Hesse, M. Planta Med. 1989, 55, 463–466.
47 Attempts to install the furoindoline from aldehyde 55 en route to (–)ꢀΨꢀ
akuammigine (4) were unsuccessful.
51 Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065–1066.
52
An exemplary akuammiline natural product of this variety is echiꢀ
48 Picot, A.; Lusinchi, X. Bull. Soc. Chim. Fr. 1977, 1227–1234.
tamine, first isolated in 1875. For the seminal isolation report, see: Groupꢀ
9
Besanez, v. Justus Liebigs Ann. Chem. 1875, 176, 88−89.
49
For (+)ꢀakuammiline (3) characterization data, see: Benayad, S.;
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Ahamada, K.; Lewin, G.; Evanno, L.; Poupon, E. Eur. J. Org. Chem.
2016, 1494–1499.
TOC
N
methanoquinolizidine-
containing
akuammiline alkaloids
N
N
N
H
*
H
H
*
Me
Me
Me
Me
N
N
N
O
H
H
H
*
*
CO2Me
CO2Me
CO2Me
OAc
(+)-Strictamine
Ψ
(–)- -Akuammigine
(+)-Akuammiline
11
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