Stereodivergent synthesis of pseudotabersonine alkaloids

Article abstract of DOI:10.1021/acs.orglett.7b02635

An eight-step stereodivergent synthesis of enantiomerically pure (-)-14-epi-pseudotabersonine and (+)-pseudotabersonine has been developed from a common N-tert-butanesulfinyl ketimine key intermediate.

Full text of DOI:10.1021/acs.orglett.7b02635

Letter
pubs.acs.org/OrgLett
Stereodivergent Synthesis of Pseudotabersonine Alkaloids
Mihail Kazak,† Martins Priede,† Kirill Shubin,† Hannah E. Bartrum,‡ Jean-Francois Poisson,‡
̧
and Edgars Suna*,†
†Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
‡Univ. Grenoble Alpes, CNRS, DCM UMR 5250, 38000 Grenoble, France
S
* Supporting Information
ABSTRACT: An eight-step stereodivergent synthesis of
enantiomerically pure (−)-14-epi-pseudotabersonine and
(+)-pseudotabersonine has been developed from a common
N-tert-butanesulfinyl ketimine key intermediate.
Aspidosperma alkaloids, a large family of monoterpenoid indole
natural products,1 have attracted considerable attention because
of their diverse biological activities and the synthetic challenge
associated with their complex polycyclic structure.2 Most
alkaloids of this class of natural products possess a pentacyclic
core with a cis-junction between the C and D rings, as
exemplified by the famous cancer chemotherapy medication
vincristine (Figure 1). Among the plethora of Aspidosperma
literature. Herein we report a stereodivergent synthesis of
unnatural trans ring-fused (−)-14-epi-pseudotabersonine 1 and
its cis-fused analog (+)-pseudotabersonine 2, a member of the
Aspidosperma alkaloids family. The synthesis of both (−)-1 and
(+)-2 was accomplished from the common starting material
possessing a tert-butanesulfinyl group (Ellman’s chiral auxil-
iary).8 The versatility of this diastereoselective synthetic
approach may be highly valuable for further medicinal
chemistry studies offering a structural diversity that could
lead to a wider spectrum of biological activities.9
We envisioned three key retrosynthetic disconnections for
the stereodivergent asymmetric synthesis of natural products
(−)-1 and (+)-2 (Scheme 1). Specifically, ring D in tetracycles
3 and 4 would be formed by intramolecular allylic alkylation of
the activated forms of syn- and anti-1,3-amino alcohols 5 and 6.
The C3 stereogenic centers (for numbering in 1 and 2, see
Figure 1. Representative Aspidosperma alkaloids.
Scheme 1. Retrosynthetic Analysis of (−)-14-epi-
alkaloids, only a few members bear trans-junction of the C and
D rings, such as the recently isolated vidolicine (Figure 1).3
Trans ring-fused pentacyclic analogs of natural cis-fused
Aspidosperma alkaloids belong to apparently unexplored
chemical space, which renders them highly attractive for
applications in pharmaceutical research. Surprisingly, stereo-
selective synthesis of nonracemic trans-epimers of the
Aspidosperma alkaloids is not reported in the literature as
opposed to the large number of synthetic approaches toward
enantiomerically pure natural products with cis-junction of the
C and D rings.4 Clearly, a stereoselective synthesis method to
access both the trans- and the cis-fused pentacyclic systems in
enantiomerically pure form is highly desirable.
Pseudotabersonine 1 and (+)-Pseudotabersonine 2
After isolation from Pandaca caducifolia in 1975,5 pseudota-
bersonine 2 has been targeted in a number of total syntheses.6
However, only Stephenson succeeded in obtaining 2 in
enantiomerically pure form.6e Racemic 14-epi-pseudotaberso-
nine 1 has also been prepared;7 however, stereoselective
synthesis of nonracemic 1 has never been reported in the
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02635
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Letter
Figure 1) would be established by diastereoselective, and
stereodivergent, reduction of (S)-N-tert-butanesulfinylketimine
7a.10 Furthermore, we envisioned that the Ellman’s chiral
auxiliary would also control the formation of the asymmetric
C14 center in a diastereoselective aldol-type reaction between
2-ethylacrolein and (S)-N-tert-butanesulfinylketimine 8a.
Hence, Ellman’s chiral auxiliary would direct the formation of
both stereogenic C3 and C14 centers, thus providing access to
both cis- and trans-fused pseudotabersonine alkaloids from a
common intermediate 8a (Scheme 1). Finally, the config-
uration at C7 will be controlled by the C3 stereogenic center
during the conversion of tetracycles 3 and 4 into the targets 1
and 2 as described for cis-fused systems.4j,7 (S)-N-tert-
Butanesulfinylketimine 8a was prepared in two steps from the
commercially available 1,2,3,9-tetrahydro-4H-carbazol-4-one by
an initial N-protection of the indole nitrogen, followed by
condensation with (S)-tert-butanesulfinamide at 75 °C in the
presence of Ti(OEt)4 (75% over two steps; see Supporting
Information (SI) for details).11 Imine (E,S)-8a was obtained as
a single E diastereomer; the E configuration of the imine was
assigned based on X-ray crystallographic analysis of structurally
closely related analogue (E,S)-8k.12
Figure 2. Diastereoselective aldol-type reaction.
The diastereoselective aldol-type reaction of the imine (E,S)-
8a with 2-ethylacrolein was next addressed. In a previous study,
we have shown that the aldol-type reaction between lithium
enamides of cyclic (S)-N-tert-butanesulfinylketimines (such as
(E,S)-8b) and methoxymethanol (an easy-to-handle source of
monomeric anhydrous formaldehyde) proceeds with excellent
diastereocontrol (99:1 dr; eq 1).12 We have also reported a
(S)-tert-butanesulfinyl ketimine (E,S)-8k underwent a highly
diastereoselective (99:1 dr) reaction with cinnamaldehyde
yielding (SS,R,R)-7k, whereas the related benzosuberone
ketimine (E,S)-8l reacted with poor syn/anti selectivity.15
A
range of nonenolizable aldehydes, such as aromatic ones,
furfural, cinnamaldehyde, and pivalaldehyde, can be successfully
engaged in this aldol-type reaction (Figure 2).
The relative anti configuration of the two newly created
asymmetric carbons was determined by X-ray crystallographic
analysis of aldol product (SS,R,R)-7g (see SI). We have
extrapolated the (SS,R,R) relative configuration for all other
aldol products (Figure 2). This configuration of the aldol
products implies an approach of the aldehyde to the
deprotonated (S)-tert-butanesulfinyl enamine intermediates
from the opposite face to the bulky tert-butyl group, with a
most probable cyclic transition state templated by titanium (for
stereoinduction model see SI, p S26). The asymmetric
induction for the aldol reaction of tert-butanesulfinyl ketimines
(E,S)-8a−k is in full agreement with that observed earlier for
tert-butanesulfinyl imidates.13
The stereodivergent synthesis of pseudotabersonine alkaloids
1 and 2 required a highly diastereoselective reduction of the
three stereogenic-centers-containing tert-butanesulfinyl keti-
mine (SS,R,R)-7a, either from the Re face (en route to target
1) or from the Si face (for target 2).
Importantly, Ellman has demonstrated that the reduction
diastereoselectivity of the CN bond in β-hydroxy-N-sulfinyl
ketimines is controlled by the stereochemistry of the tert-
butanesulfinyl group, with no influence of the β-alcohol.16
Likewise, we have shown that the stereogenic center in the α-
highly diastereoselective (up to 98:2 dr) aldol-type reaction of
(R)-tert-butanesulfinylimidates with a range of nonenolizable
aldehydes with excellent syn/anti selectivity (eq 2).13 In the
latter case, the use of a weak base Et3N in combination with
TiCl2(O-iPr)2 was crucial to prevent the retro-aldol process. In
both cases, a similar facial selectivity for the two aldol-type
reactions was observed: aldehydes approach the opposite face
of the bulky tert-butyl group of the Ellman’s chiral auxiliary.
We envisioned that the titanium-based aldolization should
also be amenable to the condensation of imine (E,S)-8a with 2-
ethylacrolein. Indeed, we were pleased to find that the desired
1,3-iminoalcohol (SS,R,R)-7a was readily formed in 85% yield,
with excellent diastereoselectivity (99:1 dr) and complete syn/
anti control (Figure 2). The scope of the reaction was examined
with a range of cyclic tert-butanesulfinyl ketimines and a variety
of nonenolizable aldehydes (Figure 2). Excellent levels of facial
selectivity (>99:1 dr) were observed for the formation of all
aldol products (SS,R,R)-7b−k. Excellent syn/anti selectivities
(up to 99:1 dr) were observed for the formation of aldol
products (SS,R,R)-7b−h,j from α-tetralone ketimine (E,S)-8b.14
Structurally related ketimines (E,S)-8i,j afforded the corre-
sponding aldolization products (SS,R,R)-7i,j with slightly
reduced syn/anti selectivity (94:6 dr). Indan-1-one-derived
Scheme 2. Diastereoselective Reduction of Imine (SS,R,R)-7a
B
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Scheme 3. Synthesis of (−)-14-epi-Pseudotabersonine (−)-1 and (+)-Pseudotabersonine (+)-2
position to the tert-butanesulfinyl ketimine moiety also does
not influence diastereoselectivity of the reduction.12 Hence, the
diastereoselective reduction of the CN bond would be
controlled solely by the Ellman’s chiral auxiliary. We envisioned
that the formation of (SS,S,R,R)-5 would require a chelation-
assisted delivery of hydride from the Re face, involving a
complexation between the sulfinyl oxygen and a reducing
agent.17 Indeed, the reduction of the imine (SS,R,R)-7a with
BH3−THF proceeded with excellent diastereoselectivity (99:1
dr; see Scheme 2) and afforded the desired N-sulfinyl amine
(SS,S,R,R)-5. Synthesis of the diastereomeric N-sulfinyl amine
(SS,R,R,R)-6 apparently required the delivery of hydride on the
less hindered Si face. This was achieved with excellent
diastereoselectivity (99:1 dr) by using LiBHEt3, a reducing
agent that cannot coordinate to sulfinyl oxygen (Scheme 2).
Hence, a proper choice of reducing agent selectively led to the
formation of either configuration at C3 in a predictable way.
The formation of pseudotabersonine D ring by intra-
molecular allylic alkylation of enantiomerically pure 1,3-amino
alcohols (SS,R,R,R)-5 and (SS,S,R,R)-6 was next addressed.
Disappointingly, extensive screening of cyclization conditions
such as intramolecular Pd-catalyzed (Tsuji−Trost) cyclization
of allylic alcohols18 or allylic acetates,19 as well as intramolecular
allylic amination in the presence of Brønsted or Lewis acids,20
did not result in the cyclized product, from neither (SS,R,R,R)-5
nor (SS,S,R,R)-6. Neither successful were attempts to effect the
cyclization under Mitsunobu reaction conditions.21
To overcome this problem, we thought of an alternative
strategy based on an initial allylic isomerization by an external
nucleophile, which would act as a leaving group in a subsequent
SN2-type cyclization (see Scheme 3). We reasoned that the
external nucleophile had to be (a) sufficiently reactive to effect
an SN2′-type allyl substitution; (b) bulky enough to react at the
less hindered side of the allyl moiety (SN2′ vs SN2 substitution);
and (c) serve as a good leaving group for a subsequent
cyclization. After some experimentation, iodine was chosen as
the external nucleophile. Iodide (SS,S,S)-9 was obtained as an
inseparable 85:15 mixture of E/Z isomers from (SS,S,R,R)-5
under modified Appel conditions (see Scheme 3). Disappoint-
ingly, only the minor Z-isomer underwent the SN2 cyclization
affording the tetracyclic (SS,S,S)-3 (12% yield), leaving the
major E-isomer unreacted. The latter could only partially be
recovered as a result of its decomposition under the cyclization
conditions.
found that the E/Z ratio could be reversed to 40:60 upon
irradiation with visible LED light (1400 lm for 1 h at rt).
Gratifyingly, the cyclization of the Z-enriched allyl iodide in the
presence of LiHMDS afforded the trans ring-fused tetracycle
(SS,S,S)-3 in 55% yield over two steps (Scheme 3).
Unfortunately, prolonged irradiation with visible light failed
to further increase the amount of the Z-isomer suggesting that
the 40:60 ratio corresponds to thermodynamic equilibrium. An
attempt to effect the light-mediated E/Z equilibration under the
cyclization conditions (LiHMDS, −78 °C) failed: the isomer-
ization did not proceed at −78 °C, whereas at −20 °C the Z-
isomer underwent various side reactions.22
Tetracycle (SS,S,S)-3 was next elaborated into (−)-14-epi-
pseudotabersonine 1 in a four-step sequence (Scheme 3).
Cleavage of Ellman’s chiral auxiliary was followed by alkylation
with 2-bromoethanol to afford (S,S)-11 (80% in two steps).
Subsequent one-pot sequential N-deprotection/O-sulfonyla-
tion, followed by Bosch−Rubiralta spirocyclization4j,7b,23
afforded pentacycle (S,S,R)-13 in 71% yield. Finally, C-acylation
of the lithium-enamide24 of (S,S,R)-13 using Mander’s
reagent25 afforded enantiomerically pure (−)-1 (46% yield).
(+)-Pseudotabersonine 2 was synthesized from 1,3-amino
alcohol (SS,R,R,R)-6 using a similar sequence (Scheme 3).
Notably, the synthesis of allyl iodide (SS,R,S)-10 required the
use of the less bulky Ph2PMe, instead of Ph3P, in combination
with iodine and imidazole for a more efficient transformation
(51% compared to 15% with PPh3). The less hindered Ph2PMe
facilitates the Appel-type reaction of the more sterically
hindered allylic alcohol (SS,R,R,R)-6 as compared to the less
hindered (SS,S,R,R)-5 (Scheme 3). The following steps were
effected without any modification, affording (+)-2. Analytical
data for (+)-2 (e.g., 1H and 13C NMR spectra, optical rotation)
were in complete agreement with those reported in the
literature.5,7a
In summary, a stereodivergent eight-step synthesis of
enantiomerically pure (−)-14-epi-pseudotabersonine (10.5%
overall yield) and (+)-pseudotabersonine (7.3% overall yield)
has been developed from a common N-tert-butanesulfinyl-
ketimine intermediate. The most notable steps are (1) a highly
diastereoselective (99:1 dr) aldol-type reaction between tert-
butanesulfinyl ketimine and 2-ethylacrolein, creating two
adjacent stereogenic centers, and (2) diastereodivergent
reduction of an intermediate N-tert-butanesulfinyl ketimine
from either the Re face (for (−)-14-epi-pseudotabersonine) or
from the Si face (for (+)-pseudotabersonine). This strategy
secured the desired cis- or trans-fusion between C and D rings
An E to Z isomerization of double bond of allyl iodide
(SS,S,S)-9 would solve the cyclization problem. It was ultimately
C
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02635.
Synthetic details; NMR data (PDF)
X-ray crystallographic data for (SS,R,R)-7g (CIF)
X-ray crystallographic data for (E)-16 (CIF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: edgars@osi.lv.
ORCID
Edgars Suna: 0000-0002-3078-0576
Notes
(12) Priede, M.; Kazak, M.; Kalnins, T.; Shubin, K.; Suna, E. J. Org.
Chem. 2014, 79, 3715.
The authors declare no competing financial interest.
(13) Bartrum, H. E.; Viceriat, A.; Carret, S.; Poisson, J.-F. Org. Lett.
2014, 16, 1972.
ACKNOWLEDGMENTS
■
(14) Equally high syn/anti selectivities were observed in the reaction
of benzaldehyde with tert-butanesulfinyl ketimine (E,S)-8b (99:1 dr)
and with the corresponding nonchiral tert-butanesulfonyl ketimine
(E)-15 (99:1 dr; see SI). In the latter case, the major diastereomer of
racemic amino alcohol (E)-16 was formed with anti configuration as
evidenced by single crystal X-ray data (see SI).
(15) Exact syn/anti ratio for (SS)-7l cannot be determined because of
the concomitant formation of the corresponding dehydration product.
(16) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002,
124, 6518. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276.
(17) (a) Martjuga, M.; Shabashov, D.; Belyakov, S.; Liepinsh, E.;
Suna, E. J. Org. Chem. 2010, 75, 2357. (b) Martjuga, M.; Belyakov, S.;
Liepinsh, E.; Suna, E. J. Org. Chem. 2011, 76, 2635.
(18) (a) Muzart, J. Tetrahedron 2005, 61, 4179. (b) Banerjee, D.;
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This work was in part funded by the Latvian Institute of
Organic Synthesis (LIOS; internal grant for support of PhD
research for M.K). H.E.B. acknowledges the Marie Curie
program for a postdoctoral fellowship (Project Metalk). We
also thank Dr. S. Belyakov (LIOS) for X-ray crystallographic
analyses.
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