Total Synthesis of Strychnine

Article abstract of DOI:10.1002/chem.201704455

The total synthesis of the flagship Strychnos indole alkaloid, strychnine, has been accomplished. The developed synthetic sequence features a novel vinylogous 1,4-addition, a challenging iodinium salt mediated silyl enol ether arylation, a palladium-catalyzed Heck reaction, and a streamlined late-stage conversion to strychnine. Furthermore, an application of asymmetric counterion-directed catalysis (ACDC) in the context of target-oriented organic synthesis has been rendered access to an optically active material. The synthetic sequence described herein represents the most concise entry to optically active strychnine to date.

Full text of DOI:10.1002/chem.201704455

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Title: Total Synthesis of Strychnine
Authors: David Yu-Kai Chen
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Total Synthesis of Strychnine
Geun Seok Lee, Gil Namkoong, Jisook Park, and David Y.-K. Chen*
Dedicated to Professor Robert Burns Woodward
Abstract: Total synthesis of the flagship Strychnos indole alkaloid,
strychnine, has been accomplished. The developed synthetic
sequence featured a novel vinylogous 1,4-addition, a challenging
iodinium salt mediated silyl enol ether arylation, a palladium-
catalyzed Heck reaction, and a streamlined late-stage conversion to
strychnine. Furthermore, an application of asymmetric counterion-
directed catalysis (ACDC) in the context of target-oriented organic
synthesis has been demonstrated to render access to optically
Scheme 1. Retrosynthetic Analysis of Strychnine (1) in This Work Leading to
Building Blocks 2 to 5. Boc = t-butoxycarbonyl; Ac = acetate; TBS = tert-
butyldimethylsilyl.
active material. The synthetic sequence described herein represents
the most concise entry to optically active strychnine to date.
details, see Supporting Information), 2 and 3 reacted smoothly
to afford TBS-enol ether 6 (and 6a) instead of the initially
anticipated aldehyde 18 (for structure, see Scheme 4). This
unexpected result, as we shall see, proved essential for the
immediate following synthetic transformation, and aided our
mechanistic understanding of this newly developed process. A
wide-spectrum of Lewis acids could be employed without
stringent exclusion of air and moisture, and for selected Lewis
acids the crude reaction mixture could be directly concentrated
and subjected to chromatographic purification. Unfortunately,
despite extensive optimization of the reaction conditions,
exclusive formation of TBS enol ether 6 could not be achieved.
Zn(OTf)2 proved to be the catalyst of choice in view of its low
cost, operational ease and a slight preference towards the
formation of TBS enol ether 6 (6:6a 1.4~1.7:1). Since variation of
reaction conditions could not rectify the regioselectivity issue, we
turned to surrogates of TBS silyl ketene acetal 3 while retaining
enal 2 as the electrophilic counterpart (Scheme 3). In this study,
crotonaldehyde-derived TBS enol ether 12[5] generated some
early excitements with the exclusive formation of TBS enol ether
13, together with its aldehyde functionality conveniently matched
the C12 oxidation state in strychnine (1). Silyl N,O-ketene acetal
14 was recently reported by Schneider and co-workers in a
highly enantioselective organocatalytic 1,4-addition reaction.[6] In
our study with enal 2, silyl N,O-ketene acetal 14 underwent
facile hydrolysis under Lewis acidic conditions, while under the
organocatalytic condition developed by Schneider aldehyde 17
was obtained as a single regioisomer in a modest 30% yield
(unoptimized). Unfortunately, although enal 13 and aldehyde 17
could be prepared regioselectively, these compounds could not
be fully capitalized due to their limited reaction scope and
practicality issue for our ensuing synthetic studies.
Since Woodward’s landmark synthesis in 1954, the celebrated
indoline alkaloid Strychnine (1) continues to stimulate the
imagination of generations of synthetic organic chemists to seek
new strategic and methodological advances.[1] To date,
approximately twenty syntheses of strychnine have been
documented, showcasing the state-of-the-art in terms of
practicality, step-economy and asymmetric catalysis. If we
further consider the number of chromatographically purified
intermediates, single-pot operations, and the amount of
strychnine synthesized, it soon became apparent that only
“collectively” these monumental achievements constituted the
most “ideal” solution to date.[2] It is with this notion in mind we
set out to seek an alternative strychnine synthesis, a journey
that undoubtedly will compel new chemical innovations.
Our synthetic strategy is outlined in Scheme 1. In short, a
sequential unification of building blocks 2, 3, 4, and 5 was
envisaged to forge the C15C16, C6C7 and C14C21 bonds
(strychnine numbering), via an vinylogous 1,4-addition
(C15C16), a silyl enol ether -arylation (C6C7), and a
palladium-catalyzed
cross-coupling
reaction
(C14C21).
Stereochemically, the nitrogen-bearing C16 center created in the
opening transformation was expected to orchestrate all of the
remaining diastereoselective processes leading to strychnine (1).
With enal 2[3] and TBS silyl ketene acetal 3[4] (ca 5:1 mixture of
geometric isomers) readily prepared through well-documented
literature procedures (Scheme 2a), the proposed vinylogous 1,4-
addition reaction was investigated in earnest. In the absence of
any promoter, enal 2 and TBS silyl ketene acetal 3 exhibited
excellent stability over a range of aprotic solvents examined.
Gratifyingly, under the influence of Lewis-acid catalysis (for
Next, our attention turned to the installation of the aryl-
bearing, all-carbon quaternary C7 stereocenter. As summarized
in Scheme 4, early attempts towards the challenging C7
arylation were primarily based on aldehyde 18, which could be
easily obtained through desilylation (KF, 99% yield) of TBS enol
ether 6. Numerous Fischer-indolization conditions[7] were
examined on aldehyde 18 but largely afforded complex mixtures,
or a speculated 1,2-migratory product 20 instead of the desired
spirocyclic imine 19. Inspired by the work of Snyder and co-
worker in their total synthesis of scholarisine A,[8] conceptually
related 1,5-radical abstraction or transition-metal based CH-
activation type processes also did not prevail. Recognizing the
[a]
Geun Seok Lee, Gil Namkoong, Jisook Park, Prof. Dr. David Y.-K.
Chen
Department of Chemistry
Seoul National University
Gwanak-1 Gwanak-ro, Gwanak-gu
Seoul 151-742, South Korea
E-mail: davidchen@snu.ac.kr
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. a. Total Synthesis of Strychnine (1); b. Reported Conversion of Enamine Methyl Esters 35 to Wieland-Gumlich Aldehyde (31) via C13 Epimerization; c.
Total Synthesis of Akuammicine (38). Reagents and Conditions: a) 2 (1.0 equiv), 3 (1.2 equiv), Zn(OTf)2 (0.1 equiv), CH2Cl2, 23 °C, 16 h, 6:59%, 6a:35%; b) 4
(1.1 equiv), THF/MeCN (1:2), 78 to 23 °C, 4 h, 63% c) TiCl3 (12% in HCl, 8.0 equiv), NH4OAc(sat. aq.)/acetone (1:1), 23 °C, 2 h, 69%; d) DBU (2.0 equiv),
toluene, 23 °C, 16 h, 91%; e) TFA, 23 °C, 1.5 h, concentrate; then 5 (1.5 equiv), iPr2NEt (3.0 equiv), MeCN, 23 °C, 1 h, 91%; f) Pd(OAc)2 (0.25 equiv), PPh3 (0.5
equiv), Et3N, 70 °C, 5 h, 68%; g) Dibal-H (6.0 equiv), CH2Cl2, 78 °C, 30 min; then AcOH, NaBH3CN (5.0 equiv), 23 °C, 1 h, 61%; h) Dibal-H (4.6 equiv), CH2Cl2,
78 °C, 45 min; i) malonic acid (26 equiv), Ac2O (8.0 equiv), NaOAc (35 equiv), AcOH, 110 °C, 2 h, 36% over two steps; j) 37 (1.5 equiv), iPr2NEt (3.0 equiv),
MeCN, 23 °C, 1 h; then Pd(OAc)2 (0.5 equiv), PPh3 (1.0 equiv), Et3N, 70 °C, 5 h, 58% overall yield. FGI = functional group interchange; AcOH = acetic acid; Ac2O
= acetic anhydride; OAc = acetate; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; Dibal-H = diisobutylaluminium hydride; TFA = trifluoroacetic acid, OTf =
trifluoromethanesulfonate.
Scheme 3. Addition of Silyl Enol Ether 12 and Silyl N,O-ketene Acetal 14 to
Enal 2. Reagents and Conditions: a) Zn(OTf)2 (0.1 equiv), 12 (1.2 equiv),
CH2Cl2, 23 °C, 6 h, 77%; b) Zn(OTf)2 (0.1 equiv), 14 (1.2 equiv), CH2Cl2, 78
to 23 °C, 6 h; or BF3•OEt2 (0.1 equiv), 14 (1.2 equiv), CH2Cl2, 78 to 23 °C, 6
h; c) 15 (0.1 equiv), PNBA (0.1 equiv), 14 (1.2 equiv), toluene/EtOH (1:1),
CH2Cl2, 23 °C, 16 h, 17:30%, 2:53%. TES = triethylsilyl; PNBA = para-
nitrobenzoic acid.
nucleophilicity of TBS enol ether 6, a palladium-catalyzed direct
arylation[9] reaction was also attempted but largely afforded
intractable reaction mixtures. Finally, the recent surge of
iodonium salt based arylation chemistry provided the most
valuable clue, and the use of iodonium fluoride pioneered by
Koser and later refined by Kozmin and Rawal offered the
ultimate solution.[10] In this context, the original condition
reported by Koser, Kozmin and Rawal was extensively
optimized (for details, see Supporting Information). The quality
of the iodonium fluoride 4 proved most crucial for the efficiency
of the reaction while minimizing desilylative protonation of TBS
Scheme 4. Selected Exploration in C7 Quaternary Center Installation
.
enol ether 6. A modified arylation condition using iodonium
iodide in the presence of AgF was attempted to circumvent the
preparation of iodonium fluoride 4, but proved largely
unsuccessful. Cu(I)/Cu(II)-catalyzed arylations independently
reported by Gaunt and MacMillan groups[11] were also examined
but failed to afford any desired product in our system. In the end,
the optimized reaction conditions consistently provided
nitroarene 7 as a single stereoisomer on multi-gram scale
(Scheme 2a), and in doing so vindicated the utility of TBS enol
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ether 6 over aldehyde 18 (vide supra). Advancing nitroarene
aldehyde 7 next called for the reduction of its nitro functionality,
and the so-generated aniline was expected to undergo
condensation with the proximal aldehyde to afford imine 8
(Scheme 2a). This easily stated objective was realized only after
extensive investigations, and revealed the TiCl3-NH4OAc
reagent system uniquely effective to deliver imine 8 in 69% yield.
Imine 8 underwent smooth ring closure via an aza-Baylis-
Hillman process[12] in which DBU proved most effective
compared to nBu3P and DABCO.
elimination. The elegant studies by MacMillan and co-workers
had previously demonstrated an N-PMB version of indoline 25
afforded
N-PMB-protected
Wieland-Gumlich
aldehyde
exclusively, and in the absence of the PMB protecting group
formation of enamine 32 was postulated.[1q] In our study,
application of the Heck reaction conditions developed by
MacMillan and co-workers afforded neither Wieland-Gumlich
aldehyde (31) nor enamine 32, but trace amount of imine 33
analogous with the recent findings reported by the Vanderwal
group in their synthesis of valparicine (34).[16]
Next, TFA-mediated Boc removal followed by N-alkylation
of the intermediate TFA salt 9 with allylic bromide 5[13] (iPr2NEt,
83% yield over two steps) furnished 24, the prerequisite
substrate for the C14C21 bond formation. As shown in Table 1,
in addition to the parent substrate 24, diol 25 was easily
obtained from 24 via reduction (Dibal-H, 84% yield), while the
preparation of diester 26 was unsuccessful primarily due to
elimination to afford ynoate 27. A variety of reaction conditions
were considered for the C14C21 bond construction while
keeping in mind of the C8/C13 oxidation state required for
strychnine (1). Application of the stannyl anion protocol
developed by Mori and Shibasaki [(CH3)3SiSnBu3, CsF][14] only
afforded the protonation product 28. Iodine-lithium exchange
conditions developed by Zhu in the total synthesis of
aspidophylline A[15] resulted in a complex mixture with alkynyl
alcohol 29 as the only identifiable constituent, while the Ni(0)-
mediated cross-coupling [Ni(COD)2, Et3N] also did not prevail.
After failing to secure pentacycle 30 with the desired C8/C13
oxidation state for strychnine via reductive Heck conditions,
standard Heck conditions [Pd(OAc)2, PPh3, Et3N] proceeded
smoothly to afford enamine 10 in respectable yield (68% yield).
Before concluding our discussion on the C14C21 bond
formation, we also pondered if diol 25 could undergo productive
Heck process to afford Wieland-Gumlich aldehyde (31) directly,
or enamine 32, depending on the directionality of the -hydride
With enamine 10 in hand, we recognized several closely
related synthetic intermediates en-route to strychnine (1) had
already been documented.[1c,h,l,n] However, on close examination
of the reported end-game transformations on these structurally
related substrates (35, Scheme 2b), functional group
transformations, sequential reductions, and especially an
epimerization was carried out to secure the desired C13
stereochemistry. We pondered if a more streamlined process
could be developed, by synchronizing the pedestrian functional
group transformations and bypassing the C13 epimerization.
The first of the two objectives was readily accomplished as
acetoxy enamine 10 underwent reductive removal of its acetate
group (Dibal-H) followed by acidic quench at low temperature
(AcOH, 78°C) and introduction of NaCNBH3 to afford, after
aqueous workup, methyl ester 11 in 61% overall yield (Scheme
2a). With methyl ester 11 in hand, instead of the widely adopted
NaOMe-mediated C13 epimerization,[1d-g] partial reduction
through the action of Dibal-H directly afforded Wieland-Gumlich
1
aldehyde (31) as suggested by H NMR analysis of the crude
reaction mixture. We speculated the initially formed aldehyde 36
may have undergone epimerization, and the hemiacetal system
in Wieland-Gumlich aldehyde (31) could have served as a
thermodynamic sink. Finally, total synthesis of strychnine (1)
was completed upon treatment of crude Wieland-Gumlich
aldehyde (31) under the reported reaction conditions.[1u]
Table 1. C14C21 Bond Formation Studies. Reagents and Conditions: a) 5 (1.5 equiv), i-Pr2NEt (3.0 equiv), MeCN, 23 °C, 1 h, concentrate; b) Dibal-H (6.0 equiv),
c
CH2Cl2, 78 to 0 °C, 2 h, 84%. aBased on 1H NMR analysis of crude reaction mixture; bIsolated yield; Based on 1H NMR and LCMS analysis of crude reaction
mixture, trace amount of compound 29 was identified; dSuggested structure based on 1H NMR and LCMS analysis of crude reaction mixture. TMS = trimethylsilyl;
COD = 1,5-cyclooctadiene; DMF = N,N'-dimethylformamide; HMPA = hexamethylphosphoramide; TBAC = tetra-n-butyl ammonium chloride; EtOAc = ethyl
acetate. For complete list, see Supporting Information.
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In this developed synthetic pathway for strychnine (1), several
aqueous workups and chromatographic purifications were
upgraded.[18] The operational ease together with low catalyst
loading further added to the synthetic appeal of this newly
bypassed over the nine-step sequence from enal 2. Furthermore, developed process, and to the best of our knowledge, this
akuammicine (38) was also conveniently prepared from
intermediate TFA salt 9 as illustrated in Scheme 2c.
constitutes one of the first example of ACDC in target-oriented
total synthesis. To further ensure the optical purity of 6 could not
be compromised via a reversible hetero-1,6-addition process
(Scheme 5d), arylation of optically enriched TBS enol ether 6
was carried out to afford optically enriched nitroarene aldehyde
7 without any erosion of optical purity (Scheme 5c).
In conclusion, a novel and expedient entry to the legendary
indoline alkaloid strychnine (1), has been achieved. Salient
features of the developed synthesis included an unprecedented
vinylogous 1,4-addition between enal 2 and silyl ketene acetal 3,
a challenging iodinium salt mediated silyl enol ether arylation to
Finally, our efforts toward an optically active TBS enol
ether 6, hence an asymmetric entry to strychnine (1), are
outlined in Scheme 5. Aided by the speculation that the
developed Lewis acid mediated reaction between 2 and 3 may
have operated through a “silyl-activation” pathway (TBS-X,
Scheme 5a), our suspicion was reinforced when several
conventional chiral Lewis acidic conditions all afforded racemic
products. While an oxidative kinetic resolution process was
shown to be feasible on racemic TBS enol ether 6 (Scheme
5b),[17] after considerable experimentations we were pleased to
find an application of the asymmetric counteranion-directed
catalysis (ACDC) recently reported by List and co-workers[4]
delivered optically active TBS enol ether 6 in 82:18 e.r. together
with a much improved regioselectivity (6:6a ~5:1). To date, the
application of chiral disulfonimides (DSI) family of catalysts are
still largely limited to the List group, compounded with
elaborated catalyst preparation and limited commercial
availability precluded the extensive optimization of reaction
conditions in this work. We believe through the application of
modified DSIs, the enantioselectivity (and regioselectivity, 6 vs
6a) of this newly developed process could be significantly
cast the all-carbon C7 quaternary stereocenter, and
a
streamlined late-stage conversion to strychnine (1). Through
mechanistic understanding of the newly developed vinylogous
1,4-addition reaction,
a
recently emerged asymmetric
counteranion-directed catalysis (ACDC) was successfully
implemented. This step-economical synthesis (of which 5 steps
obviated aqueous workup and
3
steps required no
chromatography purification) represents the most concise
asymmetric entry to strychnine (1) to date, and generated more
than 30 miligrams of synthetic strychnine in a single run. Further
application of the developed synthetic methods to related
polycyclic alkaloids are currently in progress.
Scheme 5. a. Lewis Acid Mediated Reaction between Enal 2 and TBS Silyl Ketene Acetal 3, and the Speculated “Silyl-Activation” Pathway; b. Kinetic Resolution
of Racemic TBS Enol Ether 6 via Sharpless Asymmetric Dihydroxylation; c. Preparation of Optically Active TBS Enol Ether 6 and Nitroarene 7 via Asymmetric
Counteranion-Directed Catalysis (ACDC); d. Hypothetical Racemization / Epimerization Pathway via Retro-1,6 and 1,6-Addition.
thank Jurim Jang, Sohyun Park and Jiwon Kim for preliminary
synthetic studies.
Acknowledgements
This work was supported by Seoul National University Foreign
Faculty Fund, New Faculty Resettlement Fund, National
Conflict of interest
Research Foundation of Korea (NRF) grant funded by the
Korean government (MSIP) (Nos. 2012R1A2A2A01002895,
2013R1A1A2057837, and 2014-011165, Center for New
Directions in Organic Synthesis), and Novartis. Jisook Park was
supported by the BK21Plus Program, Ministry of Education. We
The authors declare no conflict of interest.
Keywords: strychnine • total synthesis • catalysis • arylation •
natural product
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[13] For the preparation of allylic bromides 5, 23 and 37, see: a) J. A.
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10.1002/chem.201704455
Chemistry - A European Journal
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Geun Seok Lee, Gil Namkoong, Jisook
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Total Synthesis of Strychnine
An expedient total synthesis of strychnine has been accomplished via a newly
developed reaction sequence involving a catalytic asymmetric counteranion-
directed vinylogous 1,4-addition, a silyl enol ether quaternary arylation and an
intramolecular Heck reaction.
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