Enantioselective Synthesis and Racemization of (?)-Sinoracutine

Article abstract of DOI:10.1002/anie.201608206

Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers

Full text of DOI:10.1002/anie.201608206

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International Edition: DOI: 10.1002/anie.201608206
German Edition: DOI: 10.1002/ange.201608206
Alkaloids
Enantioselective Synthesis and Racemization of (ꢀ)-Sinoracutine
ˇ
Giulio Volpin, Nynke A. Veprek, Andreas B. Bellan, and Dirk Trauner*
Dedicated to Professor Gilbert Stork
Abstract: Sinoracutine is a recently isolated alkaloid with
unusual stereochemical and biological properties. It features an
unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-
methylpyrrolidine ring fused to a cyclopentenone. Interest-
ingly, both enantiomers of sinoracutine have been independ-
ently isolated from the same plant, yet the molecule does not
appear to occur as a racemate. Here, we present a short
synthesis of (ꢀ)-sinoracutine that relies on a highly diastereo-
selective Pauson–Khand reaction and a Mandai–Claisen
reaction to install the quaternary stereocenter. Our work
establishes the absolute configuration of the levorotatory
isomer and suggests that the optical purity of sinoracutine
varies in nature due to its gradual racemization. Experimental
evidence supports this proposal, and a plausible mechanism for
the racemization is provided.
(S)-Reticuline and its enantiomer (R)-reticuline are key
intermediates in the biosynthesis of a variety of important
alkaloids (Scheme 1). The former can be isomerized to the
latter through a series of enzymatic steps[1,2] and both can
undergo phenolic couplings and further downstream trans-
formations to generate a vast array of molecules. Most of
these possess a quaternary stereocenter in benzylic position,
to which a two-carbon chain terminating in a nitrogen is
attached. This nitrogen can be connected to the remainder of
the skeleton at different positions to provide structures that
contain various five- or six-membered heterocycles.
In the (R)-series, phenolic coupling of initially leads to
(+)-salutaridine, from which the morphine alkaloids are
derived. The analogous reaction in the (S)-series affords (ꢀ)-
salutaridine, which was initially named sinoacutine. It was
first isolated from Sinomenium acutum, a member of the
Menispermaceae family. A migration of the C–N bond from
C9 to C14 in sinoacutine or a related intermediate contracts
the piperidine ring and affords the hasubanan alkaloids, which
feature a pyrrolidine ring. They are exemplified here by
hasubanonine. Further oxidations at C10 and additional ring
contractions can occur, which yield alkaloids such as meta-
phanine and acutumine, respectively.[3–7]
Scheme 1. Structural diversity of alkaloids derived from reticuline.
The occurrence of enantiomeric natural products in
different producing organisms is well documented but the
isolation of a racemate or a scalemic mixture from the same
producing organism is rare.[8,9] Therefore, we were intrigued
by several recent reports on a new alkaloid termed sinor-
acutine. The first one, published in 2009, described the
isolation of
a levorotatory isomer from Sinomenium
acutum.[10] Its optical rotation was measured as ½aꢁ2D5 = ꢀ7.4
(c = 0.35, CHCl3) and an X-ray structure was reported that
features a racemate and not a single enantiomer. One year
later, the “optical isomer” (+)-sinoracutine was isolated from
the same plant.[11] Unfortunately, no optical rotation was
reported in this case. The assigned structure was confirmed by
a second X-ray analysis that again featured the racemate. In
2010, (ꢀ)-sinoracutine was also found to occur in Stephania
cepharantha, another member of the Menispermaceae family.
ˇ
[*] G. Volpin, N. A. Veprek, A. B. Bellan, Prof. Dr. D. Trauner
Department of Chemistry
Ludwig-Maximilians-Universitꢀt Mꢁnchen
81377 Munich (Germany)
E-mail: dirk.trauner@lmu.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608206.
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In this case, the optical rotation was reported to be consid-
erably higher, ½aꢁ2D5 = ꢀ754.5 (c = 1.14, CHCl3).[12]
Sinoracutine has some unusual and attractive structural
features. Compared to other reticuline-derived alkaloids, it
lacks one carbon atom, which is presumably lost through
decarboxylation. This hypothesis is supported by the recent
isolation of sinoraculine, the carboxymethyl analogue of
sinoracutine, from Stephania cepharanta.[13] Furthermore,
sinoracutine possesses a cyclopentenone and an N-methyl-
pyrrolidine ring that is connected to the remaining carbon
skeleton at C5. This motif had not been observed previously
in hasubanan and morphine alkaloids. It also features an
extended p-system that presumably arises from several
oxidations and eliminations.[14] An intramolecular hydrogen
bond between the phenolic hydroxyl and the tertiary amine
renders sinoracutine more lipophilic than structurally related
compounds with a free phenol and a tertiary amine. In terms
of its bioactivity, (ꢀ)-sinoracutine was shown to increase cell
viability against hydrogen peroxide induced damage in PC12
cells. As such, it could serve as a template for new neuro-
protective agents.[10]
The unanswered questions concerning the optical purity
of sinoracutine, its attractive structure, and its bioactivity
prompted us to devise a synthetic route that could access the
natural product in racemic as well as in enantiopure form.
Our retrosynthetic analysis is shown in Scheme 2. It was based
Scheme 3. Stereoselective synthesis of tricycle 8. a) TMSCCH, Et3N,
CuI, Pd(PPh3)2Cl2, THF, 608C, then allylMgBr 08C, then KOH, MeOH,
08C to RT, 74% overall; b) Dess–Martin periodinane, NaHCO3,
CH2Cl2, 08C to RT, 66%; c) (ꢀ)-B-chlorodiisopinocampheylborane,
ꢀ608C to ꢀ408C, 72%; d) tert-butyldimethylchlorosilane, imidazole,
DMF, RT, 89%; e) Co2(CO)8, 1,2-dichloroethane, then trimethylamine
N-oxide dihydrate, 08C to RT, 70%; f) LiAlH4, Et2O, 08C, 98%;
g) NaH, THF; then phenyl vinyl sulfoxide, KH, 08C to RT; h) NaHCO3,
1,2-dichlorobenzene, 1768C; 57% over 2 steps.
emic series 5 could be made directly from 2 via allylation and
protection (see the Supporting Information).
Scheme 2. Retrosynthesis via Pauson–Khand reactions.
The Pauson–Khand reaction of 5 under oxidative con-
ditions delivered tricycle 6 in good yield and as a single
diastereoisomer whose absolute configuration was assigned
by X-ray analysis.[42] The stereochemical control of this
reaction is attributable to the bulky benzylic TBS ether of 5
which conformationally locks the aryl-alkyne.[26,27] This sub-
strate outperformed its free hydroxy and acetoxy analogues in
terms of yield and diastereoselectivity. The subsequent 1,2-
reduction proceeded stereoselectively from the top face to
deliver allylic alcohol 7 in excellent yield.
Attempts to introduce the benzylic quaternary stereocen-
ter by Eschenmoser and Johnson–Claisen reactions were not
successful; neither was the thermal rearrangement of a pre-
formed vinyl ether.[28–31] Ultimately, we resorted to a two-step
protocol developed by Mandai: Michael-type addition of 7 to
phenyl vinyl sulfoxide gave an intermediate sulfoxide that
underwent elimination of sulfenic acid and subsequent
sigmatropic rearrangement at high temperature to afford
aldehyde 8.[32,33] This stereoselective sequence installed the
crucial benzylic quaternary stereocenter and set the stage for
the formation of the next ring.
on our desire to install the five-membered ring through
a Pauson–Khand reaction. Initial attempts were geared
toward enamine-ynes of type 1.[15–18] This plan was ultimately
discarded due to our failure to develop a satisfying asym-
metric synthesis of such a precursor. We therefore turned our
attention to enynes of type 2. Although the benzylic
quaternary stereocenter could not be directly installed using
such an approach, it provided a short route to the target
molecule that could be easily rendered asymmetric.
The synthesis began with the known isovanillin derivative
3, which had been previously employed in Overmanꢀs elegant
total synthesis of morphine (Scheme 3).[19] Sonogashira cou-
pling with trimethylsilylacetylene followed by addition of
allylmagnesium bromide and in situ desilylation furnished an
allylic alcohol which was oxidized to 4 with Dess–Martin
periodinane. Enantioselective reduction was best accom-
plished (96% ee) with (ꢀ)-B-chlorodiisopinocampheylbor-
ane and delivered silyl ether 5 after treatment with tert-
butyldimethylchlorosilane (TBSCl).[20–22] Several direct asym-
metric allylation protocols investigated failed, underscoring
the recalcitrance of o-substituted benzaldehydes to undergo
stereoselective catalytic allylation reactions.[23–25] In the rac-
With aldehyde 8 in hand we proceeded to introduce the
nitrogen and complete the synthesis (Scheme 4). Reductive
amination of 8 proceeded as planned and gave secondary
amine 9. The cis-fused pyrrolidinocyclopentenone was intro-
2
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Scheme 4. Completion of the synthesis. a) MeNH2, MgSO4, then NaBH4, MeOH, 08C to RT, 97%; b) N-iodosuccinimide, CH2Cl2, then
evaporation; dimethylsulfoxide, Et3N, RT, 64%; c) camphor-10-sulfonic acid, benzene, RT, 69%; d) lithium diisopropylamide, THF, ꢀ788C, then N-
tert-butylbenzenesulfinimidoyl chloride, ꢀ788C, 87%; e) trifluoroacetic acid, pentamethylbenzene, 08C to 408C, 73%.
duced using a tandem iodoamination–Kornblum oxidation.
To this end, 9 was dissolved in CH2Cl2 and treated with
2 equiv of N-iodosuccinimide to afford an intermediate
iodoamine that proved unstable to aqueous workup. How-
ever, evaporation of the solvent, followed by dissolution of
the intermediate in dimethyl sulfoxide and addition of
triethylamine, delivered the a-amino ketone 10 in good
yield. The addition of silver salts, which are routinely
employed to facilitate analogous oxidations, was not neces-
sary, probably due to neighboring group participation of the
tertiary amine.[34,35] Elimination of TBS-OH under acidic
conditions then gave tetracycle 11, whose relative configu-
ration was confirmed by an X-ray analysis of the racemic
compound.
these data suggest that in Sinomenium acutum, sinoracutine
occurs in scalemic form and that the racemate crystallizes
preferentially.[39] The large difference in absolute value of the
optical rotations indicates that (ꢀ)-sinoracutine isolated from
Stephania cepharanta is also scalemic albeit of higher optical
purity than the material derived from Sinomenium acutum.
From a biosynthetic point of view, it seems unlikely that
the oxidative phenolic coupling and subsequent downstream
processing occurs for both enantiomers of reticuline. This left
us with the possibility that (ꢀ)-sinoracutine undergoes
racemization once it is formed. Two reasonable mechanisms
for this racemization are shown in Scheme 5. They could
(ꢀ)-Sinoracutine could be reached from 11 but we found
it more convenient to access it from intermediate 10.
Mukaiyama oxidation[36] of Kornblum product 10 gave cyclo-
pentenone 12, which was treated with trifluoroacetic acid.[37,38]
This resulted both in elimination of the silyl alcohol and in
debenzylation and afforded sinoracutine in one step. In the
racemic series, we obtained crystals of (ꢂ)-sinoracutine that
were suitable for X-ray analysis.
The spectral data of our synthetic material were in full
agreement with those of the natural isolate and HPLC
analysis on a chiral stationary phase confirmed the enantio-
meric purity of our synthetic material. The optical rotation
was determined to be ½aꢁD25 = ꢀ1067.3 (c = 0.35, CHCl3). This
unusually high value may be due to the rigidity and twist of
the extended p-system. Comparison of the crystallographic
data of purported (+)-sinoracutine[11] and that of our racemic
material revealed that both crystals have identical cell
parameters and belong to the centrosymmetric space group
Pbca whose unit cell contains both enantiomers. Further-
more, the reported X-ray structure of purported (ꢀ)-sinor-
acutine also exhibited a centrosymmetric unit cell with both
enantiomers present, namely P21/n. It was erroneously
reported as the chiral space group P21.[10] Taken together,
Scheme 5. Proposed mechanism for the racemization of sinoracutine.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749)
and Center for Integrated Protein Science Munich (CIPSM)
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Andrea Stegner, Till Reinhardt, and Felix Pultar for exper-
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[42] CCDC 1499488 (6), 1499484 (11), and 1499488 ((ꢂ)-sinoracu-
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Manuscript received: August 22, 2016
Final Article published: && &&, &&&&
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Communications
Alkaloids
Make and mix: A synthesis of the unusual
alkaloid (ꢀ)-sinoracutine relies on a dia-
stereoselective Pauson–Khand reaction
and a Mandai–Claisen rearrangement to
install the quaternary stereocenter. Stud-
ies establish the absolute configuration of
the levorotatory isomer and suggest that
optical purity of the natural product is
determined by slow racemization.
ˇ
G. Volpin, N. A. Veprek, A. B. Bellan,
D. Trauner*
&&&& — &&&&
Enantioselective Synthesis and
Racemization of (ꢀ)-Sinoracutine
6
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