Communication

Cite This: J. Am. Chem. Soc. 2019, 141, 7715−7720 pubs.acs.org/JACS

Total Synthesis of (+)-Arborisidine

Zhiyao Zhou, Alison X. Gao, and Scott A. Snyder*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
*
S Supporting Information

Scheme 1. Structures of Several Alkaloids Containing a

ABSTRACT: The first total synthesis of arborisidine, a Shared Tetracyclic Indolenine Framework and a Generalized
unique Kopsia indole alkaloid possessing a fully sub- Retrosynthetic Plan for Arborisidine (4)
stituted cyclohexanone ring system with two quaternary
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carbons, has been achieved in seven steps in racemic

format from tryptamine and in nine steps in asymmetric
format from D-tryptophan methyl ester. Key elements of
the design include a carefully orchestrated decyanation
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protocol to finalize the asymmetric formation of an aza-

quaternary center that is challenging to access in optically
active format via direct Pictet−Spengler cyclizations with
tryptamine, a metal-promoted 6-endo-dig cyclization of an
enyne to establish the second core quaternary center, and
regiospecific functionalizations of the resultant complex
diene to finalize the target structure. The distinct and
efficient nature of the developed solution is highlighted by
several unsuccessful approaches and unexpected rear-
rangements.

O ver the past several years, efforts to achieve the laboratory

synthesis of an array of caged indolenine alkaloids drawn
from several plant species have served as a powerful vehicle for
driving innovation. Indeed, targets such as scholarisine A (1,
Scheme 1),1 strictamine (2),2 and arboridinine (3),3 among
others,4 have proven to be strong tests of available chemical
tools, with their constrained frameworks typically necessitating
the development of new reactions and synthetic strategies if they
are to be fashioned effectively. Arborisidine (4)5 is a recent and
valuable addition to this collection, having been isolated and
characterized in 2016 in relatively minute quantities (0.2 mg/kg controlled by stereoelectronic effects or intramolecularly as
bark) from Malayan Kopsia arborea trees5 and shown in a patent directed by the adjacent secondary amine. Our desire to use this
disclosure to inhibit gastric cancer in vivo when used in substrate was based on lessons learned in failed attempts to
combination with pimelautide.6 While 4 shares some general effect late-stage C−C bond formation from compounds of type
structural features with other caged alkaloids, such as 1−3, its 7 (similarly described by Qin)7 as well as allylic functionalization
most striking element is its fully substituted cyclohexanone core of 6, likely due to the considerable conformational strain and
that includes two quaternary centers, one of which is an aza- steric bulk surrounding the starred methylenes. As a result, we
quaternary carbon that has not yet been observed in related envisioned that the exocyclic olefin of 5 could serve to
molecules. As highlighted by the only published study toward circumvent these issues by pushing the reactive center away
this target,7 that core system provides significant synthetic from the steric bulk of the aza-quaternary carbon. To fashion
challenges in ways that might not be obvious upon initial that diene, we projected that a 6-endo-dig cyclization2c,e using
inspection. Herein, we describe the first racemic and asymmetric enyne 8 could rise to the occasion, potentially obtained from
syntheses of this target in seven and nine steps, respectively, aminoketone 9 through nucleophilic addition and alcohol
through a plan featuring several regiospecific and chemo- dehydration. As a result, the total synthesis of (+)-4 would then
selective events to appropriately fashion its distinctive structural require an asymmetric synthesis of the lone quaternary center
elements. within 9, an event of high challenge given the paucity of effective
As shown in Scheme 1, our design for arborisidine (4) was enantioselective Pictet−Spengler reactions using ketones.8,9
predicated on forming its pyrrolidine ring system last. For that
event, we anticipated the need to regiospecifically functionalize Received: March 25, 2019
the exocyclic alkene of diene 5, either intermolecularly as Published: April 21, 2019

© 2019 American Chemical Society 7715 DOI: 10.1021/jacs.9b03248

J. Am. Chem. Soc. 2019, 141, 7715−7720
Journal of the American Chemical Society Communication

However, as we observed in our own efforts with targets such as (SI) section for details) ultimately illustrated that NaBH3CN15
strictamine (2),2e the challenges found in forging chiral centers could rise to the occasion, yet the desired product (9) was
at these positions (as in 10 → 11) and then effecting cyclization formed only in low yield, as the majority of the material
chemistries (as in 11 → 12) can also afford powerful converted instead into the aromatized natural product
opportunities for reaction discovery and development. harmalane (18, Table 1, entry 1). That aromatization could
Our initial preparation of aminoketone 9 in racemic format
proceeded without incident simply by stirring tryptamine (13) Table 1. Screening of Conditions To Effect Enhanced
and 2,3-butadione in acidic MeOH at 60 °C,10 affording 9 in Preparations of 9 and Minimize the Formation of Aromatic
moderate yield (50%) in the gram-scale quantities needed to Side Product 18
probe the remaining elements of the sequence (Scheme 2). By

Scheme 2. Racemic and Enantioselective Syntheses of

Aminoketone 9a

entrya additive reaction time (h) yield of 9 (%)b

1 none 8 <20c
2 C6H5CHO 3 50
3 C6H5CHO 8 56
4 4-MeOC6H4CHO 8 42
5 4-ClC6H4CHO 8 46
6 4-CF3C6H4CHO 8 69
7 4-CF3C6H4CHOd,e 8 71
8 BnOH 8 13c
a a
Reagents and conditions: (a) 2,3-butadione (1.1 equiv), TFA (1.0 Conditions: substrate (0.2−0.3 mmol), NaBH3CN (2.0 equiv, 1.0 M
equiv), MeOH, 60 °C, 20 h, 50%; (b) 2,3-butadione (2.5 equiv), in THF), additive (3.0 equiv), MeOH (0.1 M), 65 °C. bIsolated yield.
c
MeOH, 65 °C, 20 h, 95%, 1.9:1 dr, 62% desired diastereomer; (c) The major product is 18. dPerformed on 5 mmol scale. e2.6 equiv of
NH3 in MeOH, 23 °C, 15 h; then concentrate; then Et3N (2.0 equiv), aldehyde was used.
TFAA (1.0 equiv), THF, 23 °C, 1 h; Et3N (1.0 equiv), TFAA (0.5
equiv), 23 °C, 1.5 h, 96%; (d) 4-trifluoromethylbenzaldehyde (2.6 not be suppressed even with degassed solution and the addition
equiv), NaBH3CN (2.0 equiv), MeOH/THF, 65 °C, 8 h, 71%. of BHT as a radical scavenger. Such results led us to believe that
the expelled cyanide ion might be involved in the aromatization
contrast, the means to achieve an asymmetric synthesis of the process in a redox-neutral pathway similar to a retro-benzoin
same compound was non-obvious based on existing Pictet− condensation as shown in Scheme 3 via intermediate 20.
Spengler precedent, since no substrates of this type in a chiral
format have been prepared directly; the closest analogies are a Scheme 3. Proposed Mechanism for the Reductive
few examples that incorporated α-ketoamides8 with others Decyanation in the Presence of Aromatic Aldehydes
utilizing cyclic N-acyliminium intermediates.9 Following initial
failures to identify a de novo catalytic solution using varied Lewis
and phosphoric acid promoters, we wondered if the use of D-
tryptophan methyl ester (14) could provide an efficient
diastereoselective alternative. Strong precedent to that general
effect in Pictet−Spengler reactions between both D-/L-
tryptophan methyl esters with aldehydes was known,11 but not
with diketones.12 Pleasingly, moderate diastereoselectivity could
in fact be achieved, favoring the formation of 15 versus its
separable diastereomer in a 1.9:1 ratio, leading to an isolated
yield of 62% for 15. Its structure and absolute configuration were
confirmed by X-ray analysis of ent-15 formed from initial
experiments using L-tryptophan methyl ester.
Despite that success, the added steric bulk and electron-
withdrawing effects of the ester and ketone groups α to the
amine made subsequent chemistry quite difficult to achieve.
First, efforts to protect the amine were universally non-
successful, likely leading to the failures observed when common
decarboxylation methods13 were screened directly with 15.
Thus, we elected to transform that ester into the nitrile of 17
through a one-pot aminolysis/dehydration process,11b hoping to To test this hypothesis, we added benzaldehyde as a cyanide
effect a seemingly standard decyanation reaction,14 through scavenger and, gratifyingly, the yield of aminoketone 9 increased
reduction of the imine formed via cyanide expulsion, without to 50% (Table 1, entry 2). In support of our overall mechanistic
impacting the ketone. Again, such chemoselectivity proved hypothesis, the cyanohydrin of benzaldehyde was observed in
challenging but was necessary since if the ketone was reduced, its the 1H NMR spectrum of the crude mixture as was the
re-oxidation could not be achieved smoothly in the presence of deuterated cyanohydrin of the expelled methyl ketone when no
the free amine. Extensive screening (see Supporting Information reductant was present. As shown in the remainder of Table 1,
7716 DOI: 10.1021/jacs.9b03248
J. Am. Chem. Soc. 2019, 141, 7715−7720
Journal of the American Chemical Society Communication

further optimization of the scavenger revealed that more material was advanced as well in commensurate yields, albeit on
electron-deficient aldehydes were superior, with 4-trifluoro- smaller scales (see SI).
methyl benzaldehyde working best in 69% and 71% yield on test Differentiation of the diene system was now needed. Initial
and gram-scale runs, respectively (entries 6 and 7). Finally, efforts using polarity-inverse radical additions17 led to either
although full or partial reduction of the added aldehyde recovery of starting material or decomposition as a result of the
derivatives was observed in all of the experiments listed in generally harsh conditions used for these processes. Fortunately,
entries 2−7, those alcohols had no impact in preventing a regiospecific bromination of the diene motif at its exocyclic
aromatization as revealed by the control experiment using only terminus could be achieved under mild conditions using
added benzyl alcohol (entry 8). bis(2,4,6-trimethylpyridine)bromine(I) hexafluorophos-
With both racemic and asymmetric routes to 9 secured, we phate;18 following solvent removal and re-dissolution in 1,4-
focused next on forming cyclic dienes of type 5 (cf. Scheme 1). dioxane, that intermediate could be converted directly into
As shown in Scheme 4, that goal could be achieved in three steps methyl ester 24 in 56% yield through a Pd-catalyzed carbon-
ylation using Xantphos.19 Of note, the isolated yield of vinyl
Scheme 4. Completion of the Total Synthesis of Arborisidine bromide 23 was lower than this one-pot bromination/
(4)a carbonylation sequence. We attribute this result to the possible
formation of an allylic bromide which was unstable to column
purification, but which under the carbonylation conditions
could funnel to the desired dienoate through isomerization.
From here, we next sought to achieve a regioselective 1,4-
reduction to generate 26; such an operation was viewed as
feasible based on three-dimensional models showing that the β-
position within this framework should be more accessible than
the β-position, with the hydride source adding from the less-
hindered Si-face. However, conventional dienoate hydro-
genation20a20b20c and conjugate reduction20d methods either
provided no conversion, no selectivity, or, in the case of Raney
Nickel,20e predominately 1,6-reduction to generate 25 (struc-
ture confirmed by X-ray crystallographic analysis) with a 10:1
preference over 26. Inspired by the pioneering work of
Magnus21a21b and Shenvi21c in manganese-catalyzed hydrogen
atom transfer (HAT) processes, a reaction that was previously of
high use to us in the synthesis of another complex alkaloid,21d we
were pleased to find that such conditions could deliver the
desired 1,4-reduction product exclusively. Extensive optimiza-
a
Reagents and conditions: (a) 1-propynyllithium (4.0 equiv), THF, tion (see SI for more details) showed that the use of Mn(dpm)3
−78 °C, 2 h; (b) pyridine (3.5 equiv), TFAA (2.2 equiv), CH2Cl2, in a 50 mol% loading in combination with PhSiH3 gave the best
−78 to 23 °C, 2 h, 53% for two steps; (c) Ph3PAuCl (0.1 equiv), conversion, using trace air as the activator21b of the catalyst.
AgBF4 (0.1 equiv), MeOH, 40 °C, 17 h, 74%; (d) Br(coll)2PF6 (1.02 When conducted on larger scales (>50 mg), the portion-wise
equiv), CH2Cl2, −78 to 23 °C, 1 h; then concentrate; then Pd(OAc)2 addition of PhSiH3 in excessive amounts was necessary to
(0.02 equiv), Xantphos (0.04 equiv), dioxane/MeOH/Et3N, CO
achieve full conversion, but at the price of the extra silane
(balloon), 70 °C, 13 h, 56%; (e) Mn(dpm)3 (0.5 equiv), PhSiH3 (2.0
equiv), i-PrOH/(CH2Cl)2, 23 °C, 10 h; PhSiH3 (1.0 equiv), 23 °C, 7 causing challenges in purification. As a result, the crude mixture
h; PhSiH3 (1.0 equiv), 23 °C, 4 h; then concentrate; then NaBH4 (10 of 26 was treated directly, following initial solvent evaporation,
equiv), MeOH, 23 °C, 1 h; 100 °C, 9 h, 50%, imine/amine = 1:2; (f) with methanolic NaBH4. This operation excised the trifluor-
BH3·THF (5.0 equiv), 23 °C, 12 h; then H2O (2.0 equiv), Me3NO· oacetamide protecting group, effected lactam formation, and
2H2O (1.1 equiv), THF, 65 °C, 2 h; then concentrate; then PhIO afforded partial reduction of the indolenine system. The
(1.5 equiv), CH2Cl2, 23 °C, 2.5 h; then NaHCO3 (5.0 equiv), Dess− resultant mixture of imine and amine products (separable for
Martin periodinane (1.5 equiv), 23 °C, 1 h, 34% 4, 40% 29; (g) purposes of characterization but also readily purified as a
NaHCO3 (5.0 equiv), Dess−Martin periodinane (1.0 equiv), CH2Cl2, mixture) was then exposed to a carefully executed sequence in
23 °C, 30 min, 74%; (h) Raney Ni, THF, H2 (balloon), 23 °C, 86%, hope of affording arborisidine (4) directly. Those operations
25:26= 10:1. Br(coll)2PF6 = bis(2,4,6-trimethylpyridine)bromine(I)
hexafluorophosphate.
included initial treatment with excess BH3 in THF to effect
alkene hydroboration and full imine and lactam reduction. After
quenching any remaining BH3 with H2O, the resultant
through propyne addition, dehydration of the resultant alcohol alkylborane was oxidized into a secondary alcohol using
as promoted by trifluoroacetic anhydride (TFAA) (a step that Me3NO·2H2O,22 with PhIO23 then added to oxidize the
also protected the amine), and a 6-endo-dig cyclization2c,e dihydroindole domain, and Dess−Martin periodinane
promoted by a mixture of catalytic amounts of both Au(I) and (DMP)24 added last to oxidize the secondary alcohol. Upon
Ag(I) salts in MeOH at 40 °C. While such endo selectivity has quenching, this one-pot operation afforded arborisidine (4) in
been commonly observed in other explorations using similar 34% yield along with partially oxidized 29 in 40% yield. As such,
enynes,16 most systems studied to date underwent further a seven-step racemic synthesis (and nine-step asymmetric
rearrangements post-cyclization to afford products devoid of an synthesis) of the target was achieved, with material supplies of
sp3-hybridized quaternary center. These steps proceeded here in the natural product enhanced by the separate oxidation of 29
39% overall yield on gram scale, noting that the yield values using DMP. Pleasingly, all spectral and optical rotation data of 4
shown refer to reactions performed with racemic material; chiral matched that of the natural sample as reported by Kam and co-
7717 DOI: 10.1021/jacs.9b03248
J. Am. Chem. Soc. 2019, 141, 7715−7720
Journal of the American Chemical Society Communication

workers5 with its structure further confirmed by X-ray analysis. X-ray crystallographic data for ent-15 (CIF)
To date, close to 50 mg of 4 has been accumulated (∼40 mg X-ray crystallographic data for 25 (CIF)
racemic, ∼5 mg enantioenriched) from all runs of the sequence. X-ray crystallographic data for 37 (CIF)

■
As one example of the uniqueness of the developed solution in
terms of advancing forward from diene 22 through intermo-
lecular chemo- and regioselective transformations, significant AUTHOR INFORMATION
efforts were also made to reach the target through intramolecular Corresponding Author
cyclizations as tethered by the adjoining N-atom of the aza- *sasnyder@uchicago.edu
quaternary center. Scheme 5 documents one such attempt, ORCID
Zhiyao Zhou: 0000-0002-2792-8429
Scheme 5. Attempted Intramolecular [3+2]-Cycloaddition Scott A. Snyder: 0000-0003-3594-8769
and an Unexpected Rearrangementa
Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank Dr. Alexander Filatov and Mr. Andrew McNeece for
obtaining X-ray crystal structures of 4, ent-15, 25, and 37, and
Dr. Antoni Jurkiewicz and Dr. C. Jin Qin for assistance with
NMR and mass spectrometry, respectively. Financial support
came from the University of Chicago and the National Institutes
of Health (NIH R01-124295A).

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