A Concise, Enantioselective Approach for the Synthesis of Yohimbine Alkaloids

Article abstract of DOI:10.1021/jacs.9b12319

We report a concise, enantioselective synthesis of the yohimbine alkaloids (-)-rauwolscine and (-)-alloyohimbane. The key transformation involves a highly enantio- and diastereoselective NHC-catalyzed dimerization and an amidation/N-acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations. This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future biomedical investigations.

Full text of DOI:10.1021/jacs.9b12319

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A Concise, Enantioselective Approach for the Synthesis of
Yohimbine Alkaloids
Eric R. Miller, M. Todd Hovey, and Karl A. Scheidt*
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ABSTRACT: We report a concise, enantioselective synthesis of the yohimbine alkaloids (−)-rauwolscine and (−)-alloyohimbane.
The key transformation involves a highly enantio- and diastereoselective NHC-catalyzed dimerization and an amidation/N-
acyliminium ion cyclization sequence to furnish four of the five requisite rings and three of the five stereocenters in two operations.
This route also provides efficient access to all four diastereomeric arrangements of the core stereotriad of the yohimbine alkaloids
from a common intermediate. This platform approach in combination with the ability to access both enantiomers from the carbene-
catalyzed reaction is a powerful strategy that can produce a wide range of complex alkaloids and related structures for future
biomedical investigations.
lkaloids are secondary metabolites containing a basic
nitrogen atom that are ubiquitous in nature and
functionalized E-ring precursor followed by tethering of the
tryptamine subunit and ring closure.16,17 This general strategy
has been utilized in a myriad of total and formal syntheses, and
continues to be the predominant approach to these natural
products today.18−21 While this conventional approach has
been successful in accessing specific natural products, the key
β-carboline pharmacophore is not introduced until the latter
stages of the synthesis.22 Consequently, efficient access to
related analogues with biomedical potential is thereby limited
and would require reworking of the early stages of the
synthesis in order to introduce structural variation in the
terpene portion of the molecule. Syntheses that introduce the
E-ring last are comparatively less explored,18,23−25 but have
increased potential for access to a large array of related
alkaloids.26,27 In the context of this broad synthetic landscape,
we sought to develop a general approach for the synthesis of
yohimbine alkaloids that would (a) be fewer than 10 steps for
maximum efficiency to drive future biomedical exploration,
and (b) be derived from a key intermediate that could be easily
converted into the different subtype structures (see Scheme 1).
Our retrosynthetic plan is depicted in Scheme 1. We
envisioned accessing (−)-rauwolscine (2) from the known β-
ketoester 526 via diastereoselective reduction. β-Ketoester 5
would be obtained by reduction and homologation of diester 6
followed by ring closure. This key intermediate would arise
from an amidation/N-acyliminium ion cyclization sequence
with enol lactone 7,28−31 which could be accessed via NHC-
catalyzed dimerization of commercially available aldehyde 8.32
Additionally, we envisioned allo-configured tetracycle 6 as a
potential precursor to access the diastereomeric normal, pseudo,
A
medicine.1 The prevalence of these molecules in pharmaceut-
icals and the increased desire to investigate sp3-carbon-rich
molecules in drug discovery campaigns necessitates the
efficient construction of complex nitrogen-containing hetero-
cycles with high levels of enantiocontrol.2,3 Moreover, the
design of adaptable syntheses that enable rapid access to a
diverse array of structurally related molecules is of comparable
importance. Over the past 15 years, the field of N-heterocyclic
carbene (NHC) catalysis has distinctively enabled the
construction of enantioenriched heterocycles,4−6 and the
power of cascade and one-pot processes has led to an ever-
increasing level of synthetic efficiency in the assembly of
complex architectures.7−9 Herein we report the union of these
strategies for the synthesis of yohimbine alkaloids.
The yohimbine natural products are a family of pentacyclic
indole alkaloids derived from the amino acid tryptophan and
the secoiridoid monoterpene secologanin (Scheme 1).10
Following the isolation of yohimbine (1) by Spiegel in 1900
and its structural determination by Witkop in 1943,11 a wide
variety of yohimbine stereoisomers have been identified. These
alkaloids can be divided into four different subfamilies, normal,
allo, pseudo, or epiallo, which differ in their stereochemical
arrangement around the D-ring; yohimbine (1), rauwolscine
(2), pseudoyohimbine (3), and reserpine (4) are representa-
tive members, respectively (Scheme 1). These alkaloids show a
wide range of activity within the central nervous system
(CNS), and although the structural variations between
diastereomeric subfamilies are modest, they lead to an
impressive degree of divergence in their pharmacology.12−15
It is therefore of great interest to be able to access these
alkaloids in a concise, modular, and stereoselective fashion to
enable thorough investigation of structural analogues.
Received: November 25, 2019
The traditional approach to the yohimbines follows
precedent set by Woodward and co-workers in their landmark
synthesis of 4 in 1958, which involves construction of a fully
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delivered 6 as a separable 80:20 mixture of diastereomers in
74% yield on decagram scale.30 Selective reduction of the
lactam with BH3·DMS then provided tertiary amine 11 in 94%
yield, whose structure was confirmed by X-ray crystallography
of its TFA salt.
Scheme 1. Representative Yohimbine Alkaloids and
Retrosynthetic Approach
With the ABCD ring system assembled, we turned our
attention to construction of the E-ring, which required the
homologation of both ester side chains by one carbon,
followed then by ring closure. Unfortunately, attempts to
directly homologate 11 using Arndt-Eistert33 or Kowalksi34
conditions returned starting material or decomposition
products, respectively, and LAH reduction to the diol followed
by various logical conditions for SN2 with cyanide anion
resulted only in quaternization of the tertiary amine.35 We then
turned our attention to Wittig−Horner-type homologation
conditions. Since an ester oxidation state was desired for the
ring closure step, known phosphonate 12 reported by
Mikołajczykand co-workers was selected because the resulting
ketene dithioacetal can be easily converted to an ester.36 We
also elected to employ conditions disclosed by Takacs in our
experimental design, wherein the partial reduction is
performed in the presence of the metalated phosphonate to
mitigate overreduction and ensure high efficiency in this
transformation.37 A temperature and reducing reagent screen
revealed that using lithium diisobutyl-tert-butoxyaluminum
hydride (LDBBA)38 at 0 °C in the presence of excess 12
afforded 13 in 70% yield on multigram scale. Although 13
could be converted to the bis(methyl ester) under forcing
acidic conditions [p-TsOH (10 equiv), MeOH, 80 °C], its
cyclization under the Dieckmann conditions reported
previously led to a mixture of 14a, 14b.26 Even more
confounding was that these compounds and their enol isomers
proved inseparable under multiple conditions and derivatiza-
tions. These roadblocks necessitated an alternative tactic for
cyclization. We soon discovered that using a milder set of
conditions [p-TsOH (2 equiv), DCM/MeOH, 0−45 °C]
delivered an easily separable 60:40 mixture of α-oxo ketene
dithioacetal 15 (major) and its regioisomer (not shown) in
80% combined yield. This transformation not only provided
the ring closed product, but also showed the desired
regioselectivity along with much needed separability. The
unmasking of the resultant α-oxo-ketene dithioacetal of 15
with HgCl2 and BF3·OEt2 in methanol then provided the
desired methyl ester 5 in 62% yield on >100 mg scale.
Temperature proved to be critical to the success of this
transformation; reactions conducted below 40 °C were
exceedingly sluggish, while those in excess of 50 °C produced
significant amounts the ring-opened bis(methyl ester).
and epiallo yohimbine cores by selective stereochemical
inversions at the C/D and D/E ring junctions.
Our synthesis commenced with the construction of
enantioenriched enol lactone 7 from aldehyde 8 (Scheme 2).
After evaluating various conditions (see the Supporting
Information for details), it was found that the use of 1 mol
% of NHC precatalyst 9 delivered 7 in 83% yield with excellent
control of the enantio- and diastereoselectivity; notably, this
transformation could be conducted on 30-g scale without loss
of efficiency. With ample quantities of 7, we began to explore
the key amidation/N-acyliminium ion cyclization sequence
with tryptamine to access 6. Initial experiments revealed that
the acylation of tryptamine by 7 was rapid, but intramolecular
N-acyliminium ion formation was inhibited by intermolecular
imine formation with an additional equivalent of tryptamine.
This side reaction proved to be minimally reversible even in
the presence of water, as only 55% conversion of 7 was seen
after 3 days when using equimolar quantities of 7 and
tryptamine (see Figure S1). However, we were pleased to find
that acidification of the reaction mixture triggered facile imine
hydrolysis, and N-acyliminium ion formation and cyclization
occurred readily upon addition of TFA. Additional optimiza-
tion revealed that treatment of 7 with 2 equiv of 10 in a
biphasic solvent system of CH2Cl2 and aqueous Na2CO3
followed by acidification and TFA-promoted cyclization
At this stage, we were poised to investigate the final
disconnection from our retrosynthetic analysis, the diaster-
eoselective reduction of β-ketoester 5. Using NaBH4, 17-epi-
rauwolscine 16 was furnished in good yield, with no detectable
amount of 2 produced.26 To circumvent this, we sought out
reagents that would provide some semblance of the presumed
thermodynamic control. A survey of the literature suggested
that SmI2 would be well suited for this application.39 Initial
i
experiments using alcoholic additives such as MeOH, PrOH,
or tBuOH returned the starting material unchanged. However,
when H2O was used as the protic additive, SmI2 rapidly
delivered (−)-rauwolscine 2 as a single diastereomer in 65%
yield. Additionally, β-ketoester 5 could be decarboxylated
using LiOH followed by a modified Wolff−Kishner deoxyge-
nation to provide the unsubstituted E-ring product (−)-al-
B
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Scheme 2. Synthesis of (−)-Rauwolscine (2) and (−)-Alloyohimbane (17)
loyohimbane 17 in 36% yield over 3 steps. Notably, the step
economy of our syntheses of 2, 16, and 17 compare favorably
to previously reported asymmetric syntheses.40−43
d.r. and 78% yield). However, performing the reaction at 40 °C
rather than −78 °C lead to reversal of diastereoselectivity,
providing 19, a potential precursor for epiallo yohimbines, in
69% yield and 73:27 d.r. (entry 7).
With an efficient and general route to allo configured
yohimbines secured, we began investigating methods to access
other diastereomeric yohimbine frameworks. We began by
exploring conditions to control the diastereoselectivity of the
key N-acyliminium ion cyclization step. To fully examine
activating agents for this transformation, we elected to conduct
the N-acyliminium ion cyclization under anhydrous conditions.
Hence, the intermediate hydroxylactam 18 (∼85:15 d.r.) was
isolated by extraction following the imine hydrolysis step in the
initially optimized conditions (Table 1). In this new two-step
process, employing acetyl chloride at cryogenic temperatures
further improved selectivity for 6 over the previous one-pot
conditions (entry 1). At higher temperatures (entry 2) or with
the use of alternative acetate activating agents (entry 3), the
reaction efficiency and selectivity decreased markedly. Lewis
and Brønsted acids could also be employed successfully
(entries 4−6), with high levels of selectivity and efficiency for 6
being observed with TMSCl at cryogenic temperatures (95:5
To gain further understanding of the diastereoselectivity,
pure 6 was subjected to the reaction conditions employed in
entry 7, and the same diastereomeric ratio (6:19 = 27:73) was
obtained after 4 days at 40 °C (entry 8); extended reaction
times or the use of chiral additives (thioureas or phosphoric
acids)31,44 did not alter this ratio. Additionally, treatment of 18
with anhydrous HCl instead of TMSCl at 40 °C did not
provide the same product distribution (entry 9), indicating
that acid catalysis is not responsible for equilibration. Our
current working model based on this data is that the high
diastereoselectivity observed at cryogenic temperatures is the
result of a kinetically controlled ring closure,27 whereas at
elevated temperatures, an equilibrating mechanism is oper-
ative,45 delivering the more thermodynamically stable tetra-
cycle 19 as the major diastereomer.
Using the new conditions outlined in Table 1, the allo
configured product 6 could be readily secured with high levels
C
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Table 1. Effect of Additives and Temperature on Cyclization
Scheme 3. Access to All Yohimbine Stereoisomeric Cores
Diastereoselectivity
a
b
c
Isolated yield over 2 steps starting from 7. No reaction. Reaction
d
e
time of 2 days. Starting material was pure 6. Reaction time of 4
days. n.d. = not determined.
of diastereoselectivity (Scheme 3). The subjection of 6 to
NaOEt in THF-EtOH (1:1) at −20 °C led to selective
epimerization of the C-15 (yohimbine numbering) stereo-
center, producing the pseudo configured product 20 in 52%
yield. Alternatively, the oxidation of 20 to the enamide using
copper(II) acetate in an atmosphere of molecular oxygen
followed by reduction with NaBH4 in AcOH provided the
normal configured tetracycle 21 in 72% yield (2 steps) as a
single diastereomer.46 Finally, as shown in Table 1 above,
simple modulation of the conditions for cyclization delivered
the epiallo configured product 19 in 69% yield with modest
control of the diastereoselectivity (73:27 d.r.). Combined,
these connected approaches provide concise entry into
multiple yohimbine stereoisomer subfamilies.
In conclusion, we have developed a concise synthesis of
(−)-rauwolscine 2 and (−)-alloyohimbane 17 from commer-
cially available ethyl 4-oxobutenoate 8. The key NHC
catalyzed annulation product 7 is readily accessible in
enantiopure form and can be converted to the complex
tetracyclic lactam 6 in a single operation on multigram scale,
which allows facile access to allo-configured yohimbines.
Selective manipulation of this intermediate also facilitates
entry into the normal, pseudo, and epiallo classes of this
important natural product family. Additionally, by employing
either enantiomeric NHC catalyst (+ or −), it is feasible that
all eight possible stereoisomeric cores of these alkaloids are
accessible, enabling production of a wide range of molecules to
drive the discovery of new biologically active molecules.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b12319.
■
sı
Experimental procedures and spectroscopic data for
compounds (PDF)
X-ray data (11) (CIF)
X-ray data (2) (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Karl A. Scheidt − Northwestern University, Evanston,
Illinois; orcid.org/0000-0003-4856-3569;
Email: scheidt@northwestern.edu
Other Authors
Eric R. Miller − Northwestern University, Evanston,
Illinois
M. Todd Hovey − Northwestern University, Evanston,
Illinois
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b12319
Notes
The authors declare no competing financial interest.
D
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2013, 5, 126−31.
ACKNOWLEDGMENTS
■
Financial support from the National Institutes of Health and
Northwestern University is acknowledged (NIGMS R01
GM073072 and GM131431). The authors thank Keegan
Fitzpatrick (Northwestern) for X-ray crystallographic analysis
of 11 and 2 and Allison Devitt (Northwestern) for assistance
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