A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-14,15-Dehydrostrempeliopine

Article abstract of DOI:10.1002/anie.201910593

The total synthesis of representative members of the schizozygine alkaloids, (+)-vallesamidine and (+)-14,15-dehydrostrempeliopine, were completed from a late-stage divergent intermediate. The synthesis took advantage of efficient nitro-group reactions wi

Full text of DOI:10.1002/anie.201910593

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Accepted Article
Title: A Divergent Synthetic Route to the Vallesamidine, Strempeliopine
and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine
and (+)-14,15-Dehydrostrempeliopine
Authors: James Clive Anderson and Xiangyu Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910593
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
A Divergent Synthetic Route to the Vallesamidine, Strempeliopine
and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine
and (+)-14,15-Dehydrostrempeliopine
Xiangyu Zhang and James. C. Anderson*
Dedication ((optional))
Abstract: The total synthesis of representative members of the
Schizozygine alkaloids (+)-vallesamidine and (+)-14,15-
workers reported a study on 14,15-dehydrostrempeliopine (6), a
model towards schizozygine (3), through 15-hydroxyl
precursor, but the final dehydration failed. We report here a
distinctive synthetic strategy towards the schizozygine alkaloids
based on a synthetically valuable late stage C-14,15 alkene
divergent intermediate 7 (Scheme 1). Notable aspects of our
a
[
8]
dehydrostrempeliopine were completed from a late stage divergent
intermediate. The synthesis took advantage of efficient nitro group
reactions with the A/B/C ring skeleton constructed concisely in gram
scale through
an asymmetric Michael addition, nitro-
Mannich/lactamisation, Tsuji-Trost allylation and intramolecular C-N
coupling reaction. Other key features of the synthesis are a novel
synthesis include
cyclisation, the exploitation of the nitro functional group for the
synthesis of of the rings, the demonstration of a
a
novel [1,4]-hydride transfer/Mannich
[
1,4]-hydride transfer/Mannich type cyclisation to build ring E and a
diastereoselective ring closing metathesis reaction to construct ring D.
This gave access to late stage C-14,15 alkene divergent
intermediate that could be simply transformed into (+)-vallesamidine,
+)-14,15-dehydrostrempeliopine and potentially other schizozygine
3
5
diastereoselective ring closing metathesis and the gram-scale
synthesis of late stage intermediates in high stereoselectivity and
yield. We show the divergence of this route by the total synthesis
of (+)-vallesamidine (1) and (+)-14,15-dehydro-strempeliopine (6)
in 2-3 simple transformations. Compound 6 is skelatally identical
to schizozygine (3).[9] The strategy could deliver other
schizozygine alkaloids 3-5 and we demonstrate the synthesis of
analogous unnatural structures.
a
(
alkaloids and unnatural derivatives.
Introduction
Vallesamidine (1) and strempeliopine (2) are monoterpene indole
alkaloids isolated from Vallesia dichotoma Ruiz et Pav[1] and
Strempeliopsis strempelioides K Schum[2] respectively, and are
structurally related to similar, but more complex, schizozygine
alkaloids 3-5[3] that contain an additional C-14,15 alkene and
oxygenated aromatic cores (Figure 1). Their potential
bioactivities[ and highly fused, polycyclic ring skeletons have
attracted many efforts towards their total synthesis. Currently, the
total syntheses of schizozygine alkaloids 3-5 have not been
reported,[5] but the total synthesis of vallesamidine (1) and
strempeliopine (2)[7] have been completed. Heathcock’s
ingenious landmark racemic synthesis of vallesamidine (1) was
completed in 8 steps in 19% overall yield.[6a,b] Asymmetric variants
4]
[6]
Figure 1. vallesamine and schizozygine alkaloids
Retrosynthetically access to both targets 1 and 6 would be
have relied upon formal syntheses[6c,d] from this, or new
by forming ring
D by a diastereoselective ring closing
approaches[
6e,f,h]
and all vary in length from 15-23 steps.
metathesis[10a-c,g] of 8 to a common intermeduate 7 (Scheme 1).
The bis-C-20 vinyl substituents would be derived from malonate
Strempeliopine (2) has been prepared using biomimetic[7a]
,
racemic[7c] and asymmetric multi-step syntheses[7d] in similar step
count. In all of these elegant approaches the opportunity to enable
a divergent synthesis to the structurally related schizozygine
alkaloids is denied because the C-14,15 single bond was present
from the beginning and it would be synthetically challenging to
introduce the required C-14,15 double bond. Hájíček and co-
9. For the formation of ring E we proposed a novel [1,4]-hydride
transfer (HT)/Mannich cyclisation on the piperidine ring C of 10.
The synthesis of the precursor to this (11) relies upon the diverse
chemistry of the nitro functional group and was guided by our
studies on the stereoselective nitro-Mannich reaction[ and the
formation of indolines from the chemoselective cyclisation of 1,2-
diamines.[12] The precursor to ring B (12) bearing a quaternary
carbon (C-2) would be prepared through a Tsuji-Trost allylation of
nitro lactam 13, a known skeleton that could be assembled
through nitro-Mannich/ lactamisation cascade from nitro malonate
11]
[*]
X. Zhang and Prof. Dr. J. C. Anderson
Department of Chemistry
University College London
20 Gordon Street, London, WC1H 0AJ, UK
1
4.[13] Asymmetry would be introduced by an enantioselective
E-mail: j.c.anderson@ucl.ac.uk
Michael addition on nitro alkene 15 and the diastereoselectivity of
the subsequent nitro-Mannich reaction dictated by the chiral
centre formed.[14]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
impressive results indicated the stereochemical requirements and
possibilities for applying the [1,4]-HT/cyclisation on piperidines.
Results and Discussion
The total synthesis of (+)-vallesamidine (1) and (+)-14,15-
dehydrostrempeliopine (6) commenced with the asymmetric
Michael addition of diethyl malonate to 2-bromonitrostyrene 15
using chiral nickel (II) complex 16, developed by Evans et al, as
the catalyst.[
20]
The ease of catalyst preparation and mild
conditions made the reaction scalable and the enantioselectivity
of adduct 14 could be maintained at 95:5 er at 20 grams scale.
The nitro-Mannich/lactamisation cascade was followed by
Krapcho decarboxylation of the crude reaction mixture to give the
nitro lactam 13 in 84% overall yield in ~5:1 dr at C-2. The
diastereoselectivity was immaterial as subjection of the mixture to
a palladium catalysed Tsuji-Trost allylation to introduce the C-2
quaternary centre stereoselectively (13-a) and the allylated
product 12 was obtained in 86% yield with 95:5 dr. Reduction of
the nitro group with Zn/HCl provided the free amine quantitatively
and the crude product was directly used in the intramolecular C-
N coupling reaction. The palladium catalysed C-N coupling
Scheme 1. Retrosynthesis of (+)-vallesamidine (1)
3 4
reaction (Pd(PPh )
/t-BuONa/PhMe)[12] was attempted first and
the desired indoline 17 was obtained in 65% yield. Ligand free
Ullmann type coupling using cheaper CuI catalyst only gave 56%
conversion and 40% yield and increasing the catalyst loading from
5
mol% to 10 mol% improved the yield to only 55%. The moderate
yield of this clean reaction led us to consider adding ligands to
accelerate the progress.[21] We first tested Ma’s conditions[22]
using commercial proline as ligand and it significantly shortened
the reaction time to 1 h and improved the yield of crude indoline
to 94% without further purification (see SI for spectral comparison).
Protection of the free indoline in neat methyl chloroformate gave
1 in 86% yield over three steps from 12.[
23]
1
Scheme 2. [1,n]-HT/cyclisation strategy of piperidines
The [1,n]-hydride transfer (HT)/cyclisation, also regarded as
an internal redox neutral C-H functionalisation, is an unusual
method for ring formation that has been recently developed for
more complex systems[15] since the first examples that were
classified under the term the ‘tert-amino effect’[16] (Scheme 2). In
this transformation, the conformational requirement for hydride
donor and acceptor in a spatially closed relationship is crucial and
thus substrate scopes are still limited. Based on our
retrosynthesis a [1,4]-HT/cyclisation on a 3-substituted piperidine
was proposed to construct the C/E bicyclic skeleton and install the
C-20 quaternary centre. Currently there have been very few
Scheme 3. Synthesis of ABC ring intermediate 11. Conditions: a)
n
diethylmalonate, cat. 16 (1.0 mol%), PhMe, rt, 72 h, 80%; b) PMBNH , (HCHO) ,
2
o
o
3 4
EtOH, 80 C, 2 h; c) NaCl, DMSO, 160 C, 16 h, 84% from 14; d) Pd(PPh ) (1.0
o
mol%), allyl acetate, DBU, CH
2
Cl
2
, 0 C, 30 min, 86%; e) Zn dust, 6 M HCl aq.,
reports of [1,4]-HT/cyclisation reactions and all of these involved
benzylic C-H bonds.[17] The work by Sames[18] and Saá[19]
disclosed the [1,6] and [1,5]-HT/cyclisation on 3-substituted
piperidines with alkynes as hydride acceptors and these
EtOH/EtOAc, 0 oC, 1 h, quant.; f) CuI (10 mol%), L-proline (20 mol%),
2.0 eq.), DMSO, 80 oC, 1 h; g) ClCO Me (neat), 65 oC, 16 h, 86% from 12.
3 4
K PO
(
2
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RESEARCH ARTICLE
PMBNH
2
= p-methoxybenzylamine; DMSO = dimethylsulfoxide; DBU = 1,8-
trifluoroacetic acid acted as in situ protection, which upon
ozonolysis, smoothly gave the aldehyde in 90% yield.[24] In
preparation for the late stage ring closing metathesis to form ring
D, the PMB group had to be removed and changed to the allyl
group. Therefore, treatment of the aldehyde with allyl
chloroformate yielded the allyl carbamate 19 in an acceptable
yield of 56% (77% brsm). Increasing the reaction time slightly
improved the yield but the starting material could not be fully
converted. Based on the conformation of the aldehyde, we
suggest that hyperconjugation between the nitrogen lone pair
diazabicyclo [5.4.0]undec-7-ene.
Ring E was formed using a [1,4]-HT/Mannich cyclisation
(
Scheme 4). The expected challenges for the desired hydride
transfer/cyclisation were the accessibility of the necessary
reactive conformation for hydride transfer and good affinity
between the Lewis acid and malonate motif over the basic
piperidine nitrogen atom. Normally
a basic amine would
sequester the Lewis acid and prohibit the hydride
transfer/cyclisation to occur, presumably why most hydride
transfer/cyclisation substrates are aniline type structures. From
an inspection of the likely conformation of our desired precursor
*
[25]
orbital and  orbital of the aldehyde inhibits the nucleophilicity
of the piperidine amine and accounts for the slow, incomplete
functional group interconversion. To explore this hypothesis and
increase the efficiency of the PMB/allyl group exchange,
dioxolane compound 21 was prepared through oxidative cleavage
of alkene 11,[ followed by aldehyde protection and catalytic
amide reduction.[27] The reaction of 21 with allylchloroformate was
10 we speculated that the correct stereoelectronic geometry could
be easily obtained and that the steric complexity around the
piperidine nitrogen could inhibit coordination of a Lewis acid. To
this end piperidine 18 was obtained in high yield by
chemoselective reduction via an in situ thionium ion formed by
sequential treatment of lactam 11 with Lawesson’s reagent, MeI
26]
significantly improved with complete conversion,
a shorter
reaction time (1 h) and reduced reagent usage (10.0 eq. to 5.0 eq.
of allylchloroformate). The crude product, after removal of any
volatile species, was subjected to acidic hydrolysis directly and
aldehyde 19 was obtained in 72% yield from 21.
and NaBH
4
. The oxidative cleavage of the allyl group in 18 was
/NaIO
initially problematic either with ozonolysis or OsO
conditions, probably due to the oxidation sensitive piperidine
nitrogen. Protonation of the basic piperidine nitrogen with
4
4
Scheme 4. Synthesis of ABCE ring intermediate 9 through [1,4]-hydride transfer/Mannich cyclisation. Conditions: a) Lawesson’s reagent, PhMe, 80 oC, 1 h, 93%;
o
o
o
o
b) MeI, reflux, 2 h, then NaBH
4
, MeOH, 0 C, 1 h, quant.; c) TFA, 0 C, CH
(2.5 mol%), CH Cl , rt, 1 h, 92%; f) dimethyl malonate, L-proline, DMSO, rt, 24 h, 96%; g) Yb(OTf)
(2 mol%), NMO, 2,6-lutidine, acetone-H
(10 mol%), PhSiH
, THF, 65 oC, 8 h, 76% over 2 steps; k) allylchloroformate, NaHCO
2
Cl
2
, 10 min, then O
3
, CH
2
Cl
2
, -78 C, then Me
2
S, -78 C to rt, 90%; d) allyl chloroformate,
o
DCE, 75 C, 48 h, 56%; e) Pd(PPh
)
3 4
2
2
3
(10 mol%), PhMe, reflux,
80%; h) OsO
4
2
O, 24 h, then PhI(OAc)
2
0.5 h, 78%; i) (CH
2
OTMS)
2
, TMSOTf (10 mol%), CH
2
Cl
2
, -78 oC to rt, quant; j)
o
o
Mo(CO)
6
3
3
, DCE, 80 C, 1 h, then AcOH, THF-H
2
O, 90 C, 24 h, 72% from 21.
Lawesson’s regent = 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane; TFA = trifluoroacetic acid; DCE = 1,2-dichloroethane.
Subsequent treatment of allyl carbamate 19 with catalytic
Pd(PPh triggered the decarboxylative allylation to give 20 and
Knoevenagel condensation with dimethyl malonate afforded the
-unsaturated malonate 10, the precursor for the [1,4]-
HT/Mannich cyclisation again in high yields. To our satisfaction,
treatment of 10 with catalytic Yb(OTf) in reflux toluene promoted
the desired [1,4]-hydride transfer/Mannich cyclisation cleanly to
give the ABCE ring intermediate 9 in 80% yield for the efficient
formation of the second quaternary centre. The relative
stereochemistry was confirmed by a NOESY experiment. This
construction in alkaloids synthesis and may find potential
application in the synthesis of other complex molecules.
Manipulations to form the metathesis precursor 8 for the
formation of the ring D began with the chemoselective reduction
of malonate 9 to the corresponding diol under optimised
3 4
)

3
conditions (LiAlH
4
, room temperature, 15 min) (Scheme 5). A
concise route to 8, based on Feldman’s work,[
10a,c]
was to oxidise
the diol to dialdehyde, followed by Wittig reaction to give dialkene
8. However, degradation was observed during the oxidation and
no appropriate conditions could be found. Therefore a sequential
olefination sequence was necessary and began with the selective
unique transformation provided
a good example of ring
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
mono-protection of the diol on the sterically less hindered hydroxyl
group in 51% yield from 9. Oxidation of the remaining alcohol
using IBX in EtOAc[28] gave the aldehyde 22 quantitatively but with
epimerisation at C-20 (~1:1), either from silyl exchange before
oxidation or Mannich type retro ring opening/re-cyclisation.
Fortunately, simple treatment of the epimers with silica gel in
tetrahydrofuran; Im
=
imidazole; IBX
=
2-Iodoxybenzoic acid; Cp =
cycopentadienyl;
Hoveyda-Grubbs
2nd
catalyst
=
(1,3-Bis-(2,4,6-
trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxy-phenyl-
methylene) ruthenium; TBAF = tetra-n-butylammonium fluoride.
As an example of the opportunities this divergent route
dichloromethane led to the nearly diastereomerically pure desired, opens for the synthesis of unnatural analogues of the
thermodynamically more stable isomer 22 (93:7). The Petasis
olefination was applied on hindered aldehyde 22 and the crude
alkene was treated with TBAF to give 23 in 65% yield. Ultimately,
the trialkene intermediate 8 was obtained in good yield after a
schizozygine alkaloid family, we isolated two new structures
during our studies towards the synthesis of 14,15-dehydro-
strempeliopine (6) (Scheme 6). Treatment of 23 with
methanesulfonyl chloride gave the mesylate 26 in quantitative
yield. After ring closing metathesis to 27, attempted displacement
Swern oxidation and Wittig olefination sequence.
A
o
diastereoselective ring closing metathesis was then performed
and the ring D cyclised product 7 was isolated as a single
diastereomer in 76% yield.
The ABCDE ring intermediate 7 represents a divergent
intermediate from which vallesamidine, strepeliopine and
schizozygine type alkaloids can be prepared. For example 7 was
of the mesyl group with KCN in DMSO at 100 C gave two new
products 28 (32%)and 29 (31%).These represent key molecules
for SAR studies around the importance of the lactam function of
the schizozygine alkaloids for biological activity.
4
subjected to LiAlH reduction to give dehydrovallseamidine 24
and catalytic hydrogenation proceeded uneventfully to give (+)-
vallesamidine (1), the spectral data of which were consistent with
literature data.[6] For the preparation of 14,15-dehydro-
strempeliopine (6), that possesses the same skeletal features as
schizozygine (3), regioselective hydroboration/oxidation[30] of 7
was performed first to provide primary alcohol 25. Hydrolysis of
the carbamate followed by oxidative cyclisation gave 6 and the
spectral data of the core skeleton was in agreement with that of
schizozygine (1).[31]
Scheme 6. Manipulation of alcohol 23 and preparation of unnatural analogues
, 0 oC to rt, 1.5 h, quant.; b)
2
8 and 29. Conditions: a) MsCl, Et N, CH Cl
3 2 2
Hoveyda-Grubbs cat. (10 mol%), PhMe, 80 oC, 4 h, 80%; c) KCN, DMSO, 100
oC, 16 h, 28 32% and 29 31%. Ms = methanesulfonyl.
Conclusion
In conclusion, an efficient, high yielding and selective
asymmetric synthetic route to a late stage C-14,15 alkene
divergent intermediate 7 that could be simply transformed into (+)-
vallesamidine (1) and (+)-14,15-dehydrostrempeliopine (6) has
been realised. Although the step count of this synthetic approach
(
23 steps to vallesamidine) is slightly higher than other
asymmetric routes to inidividual alkaloids of this family, such as
vallesamidine, our route only required 14 chromatographic
purifications and we have shown its valuable and unique synthetic
diversity to other natural and unnatural structurally related
strempeliopine and schizozygine alkaloid skeletons. The route is
flexible in terms of absolute stereochemistry, the opportunity for
more functionalised aromatic cores in the Michael reaction of the
starting nitro alkene 15 and other late stage synthetic
manipulations. The synthesis makes good use of simple
nitroalkane/alkene chemistry, including Michael addition, nitro-
Mannich/ lactamisation, Tsuji-Trost allylation and nitro-
reduction/C-N coupling reaction, to quickly generate complexity in
the A/B/C ring skeleton in high yield and gram scale. A novel and
high yielding Lewis acid catalysed [1,4]-hydride transfer/Mannich
type cascade cyclisation was used to construct ring E in gram
scale. This C-H functionalisation reaction should be highly useful
for the synthesis of other complex molecules. The successful
installation of the key C-14,15 double bond in ring D was achieved
Scheme 5. Synthesis of divergent intermediate 7 and total synthesis of (+)-
vallesamidine (1) and (+)-14,15-dehydrostrempeliopine (6). Conditions: a)
LiAlH
; c) IBX, EtOAc, reflux, 2 h, then silica gel, CH
oC, simple work-up, then TBAF, THF, 70 oC, 3 h, 65% from IBX oxidation; e)
COCl) , DMSO, Et N, CH Cl PCH Br,
, -78 to 0 oC, simple work-up, then Ph
NaHMDS, THF, -78 C to rt, 76%; f) Hoveyda-Grubbs 2nd catalyst (10 mol%),[29]
4
, THF, 0 to 22 oC, 15 min; b) TBDPSCl, Et
3
N, DMAP, CH
2
Cl
2
, 51% from
9
2
Cl
2
, 2 h; d) Cp TiMe
2
2
, PhMe, 80
(
2
3
2
2
3
3
o
o
o
PhMe, 80 C, 1.5 h, 76%; g) LiAlH
MeOH, rt, 3 h, 77%; i) c-Hex
BH, then NaBO .
00 oC, 16 h; k) TPAP (10 mol%), NMO, CH
4
, THF, 0 to 65 C , 30 min, 80%; h) Pd/C, H
O, THF; j) 6M KOH aq., MeOH,
Cl , 30 min, 34% from 7. THF =
2
,
2
3 2
H
1
2
2
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
through a diastereoselective ring closing metathesis. We are
using this divergent route for the synthesis of similar alkaloid
targets for the investigation of their biological activity.
[8]
T. Pilarcik, J. Havlicek, J. Hajicek, Tetrahedron Lett. 2005, 46, 7909–
7911.
[
[
9]
We could not exemplify the synthesis of schizozygine (3) directly as the
corresponding starting material, the aldehyde piperonal, is a restricted
substance as it is a precursor to illicit drug manufacture.
Experimental Section
Experimental details, compounds characterisation data and spectra are
attached in supporting information.
10] For examples of late-stage ring closing metathesis in indole alkaloids
synthesis in the presence of tertiary amine, see: a) K. S. Feldman, J. F.
Antoline, Tetrahedron 2013, 69, 1434–1445; b) Y. Hayashi, F. Inagaki,
C. Mukai, Org. Lett. 2011, 13, 1778–1780; c) K. S. Feldman, J. F.
Antoline, Org. Lett. 2012, 14, 934–937; d) S. A. Kozmin, T. Iwama, Y.
Huang, V. H. Rawal, J. Am. Chem. Soc. 2002, 124, 4628–4641; e) P.
Selig, T. Bach, Angew. Chem. Int. Ed. 2008, 47, 5082–5084; Angew.
Chem. 2008, 120, 5160–5162; f) P. Selig, E. Herdtweck, T. Bach, Chem.
Eur. J. 2009, 15, 3509–3525; g) H. Zhang, D. P. Curran, J. Am. Chem.
Soc. 2011, 133, 10376–10378; h) H. Zhang, K. O. Jeon, E. Ben Hay, S.
J. Geib, D. P. Curran, M. G. Laporte, Org. Lett. 2014, 16, 94–97; i) A.
Umehara, H. Ueda, H. Tokuyama, Org. Lett. 2014, 16, 2526–2529.; j) A.
F. G. Goldberg, R. A. Craig, N. R. O’Connor, B. M. Stoltz, Tetrahedron
Lett. 2015, 56, 2983–2990; k) N. Goli, S. Kallepu, P. S. Mainkar, J. K.
Lakshmi, R. Chegondi, S. Chandrasekhar, J. Org. Chem. 2018, 83,
Acknowledgements
We thank the China Scholarship Council and University College
London for funding, and Dr M.K. Corpinot for the single crystal X-
ray structure determination of 11.
Keywords: Total synthesis, Asymmetric synthesis, Alkaloids,
Nitro-Mannich, Hydride transfer/cyclisation
[
[
1]
2]
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RESEARCH ARTICLE
X. Zhang and J. C. Anderson*
Page No. – Page No.
A Divergent Synthetic Route to the
Vallesamidine, Strempeliopine and
Schizozygine Alkaloids: Total
Necessity is the mother of invention and never more so than in target synthesis. The
total synthesis of (+)-vallesamidine and (+)-14,15-dehydrostrempeliopine were
achieved from a common intermediate that is related to other alkaloids and
necessitated the development of a novel [1,4]-hydride transfer/Mannich cyclisation to
build ring E.
Synthesis of (+)-Vallesamidine and
(
+)-14,15-Dehydrostrempeliopine
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