A Route to the C,D,E Ring System of the Aspidosperma Alkaloids

Article abstract of DOI:10.1021/acs.orglett.6b01674

A short synthetic sequence leading to the formation of the C,D,E-ring subunit of the Aspidosperma alkaloids is reported. This route is based on a ring fragmentation/intramolecular azomethine ylide 1,3-dipolar cycloaddition reaction sequence that gives the

Full text of DOI:10.1021/acs.orglett.6b01674

Letter
pubs.acs.org/OrgLett
A Route to the C,D,E Ring System of the Aspidosperma Alkaloids
Geoffrey M. Giampa, Jian Fang, and Matthias Brewer*
Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: A short synthetic sequence leading to the formation of the
C,D,E-ring subunit of the Aspidosperma alkaloids is reported. This route is
based on a ring fragmentation/intramolecular azomethine ylide 1,3-dipolar
cycloaddition reaction sequence that gives the desired tricyclic product as a
single diastereomer. A γ-amino-β-hydroxy-α-diazo carbonyl compound is
shown to fragment in the presence of a Lewis acid to give an iminium
product that can be directly reduced to the corresponding amine.
he Aspidosperma alkaloids are a group of structurally
Scheme 1. Ring Fragmentation/Intramolecular Azomethine
T
complex indole alkaloids comprised of over 250 members
Ylide 1,3-Dipolar Cycloaddition Approach to Polycyclic 2,5-
Dihydropyrroles
that contain the pentacyclic aspidospermidine skeleton (Figure
1).1 The structural complexity and interesting biological activities
Figure 1. Structure of aspidospermidine and aspidospermine.
of this family of compounds have made them favored synthetic
targets for evaluating new synthetic methods in the context of
complex molecule synthesis. Over the years, a large number of
elegant synthetic routes have been devised to prepare
aspidospermidine.2 Many of these routes, including Stork’s
landmark 1963 total synthesis of aspidospermine,3 hinge on the
synthesis of the nonindoline tricyclic core structure (i.e., the
C,D,E ring system, Figure 1) of the Aspidosperma alkaloids as a
key intermediate.
We have developed a convenient two-step reaction sequence
to prepare polycyclic 2,5-dihydropyrroles by a Lewis acid
mediated fragmentation of a γ-silyloxy-β-hydroxy-α-diazo
carbonyl compound giving a tethered aldehyde ynoate4 (e.g., 1
→ 2, Scheme 1) that can be used in a subsequent intramolecular
azomethine ylide 1,3-dipolar cycloaddition. This sequence is
fairly general, and it provides a variety of 2,5-dihydropyrroles in
good to excellent yields.5 We have recently used this method-
ology in the synthesis of the steroidal alkaloid demissidine6 and
the ergot alkaloid cycloclavine.7 In order to further develop the
scope and utility of this methodology we identified the C,D,E
ring system of the Aspidosperma alkaloids as a target of interest,
and in this letter we report a concise synthetic route to this key
tricyclic structure. In addition, we show that a γ-amino-β-
hydroxy-α-diazo carbonyl compound can also fragment leading
to an iminium product.
Our initially conceived approach to aspidospermidine is
shown in Scheme 2. The final target would be prepared by
hydrolysis of ester 4 followed by acid catalyzed decarboxylation
in the presence of sodium cyanoborohydride. The indoline ring
in 4 would be formed by an intramolecular Heck reaction of
hydroxyl amine 5 followed by N−O bond cleavage, and the
requisite aryl hydroxyl amine fragment could be incorporated
onto the key tricycle 6 by a N-nitroso Mukaiyama aldol reaction.8
We envisioned the tricyclic target coming from the intra-
molecular cycloaddition of the azomethine ylide derived by
fluoride mediated desilylation of iminium 7.9 This iminium ion
could potentially come from the fragmentation of γ-amino-β-
hydroxy-α-diazo carbonyl compound 8. At the outset of this
work we had no experimental evidence that a γ-amino derivative
would fragment productively, but the similarity of these species
to the γ-silyloxy derivatives made this seem like a reasonable
proposition. The required diazo carbonyl could in turn be
formed by the aldol-type addition of lithiated ethyl diazoacetate
to octahydroquinolin-8-one derivative 9.
Received: June 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01674
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Organic Letters
Letter
Scheme 2. Initial Retrosynthetic Disconnection of
Aspidospermidine
Scheme 4. Unsuccessful Attempt To Fragment Bicyclic Diazo
15
With the failure of diazo 15 to fragment, we developed the
alternative approach to iminium ion 7 shown in Scheme 5. This
Scheme 5. Alternative Approach to Iminium 7
Our initial studies focused on determining if γ-amino diazo
carbonyl compounds would fragment similarly to their γ-silyloxy
counterparts leading directly to an iminium product. With this in
mind, we prepared the ethyl diazoacetate addition product of 2-
(phenylamino)cyclohexanone (11) as a simple model system
(Scheme 3). Treating this compound with SnCl4 resulted in gas
Scheme 3. Fragmentation of a γ-Amino-β-hydroxy-α-diazo
Carbonyl Compound
route involves fragmentation of γ-silyloxy-β-hydroxy-α-diazo
carbonyl 18 to give aldehyde 17 that could condense with a
pendent amine to give 7. Fragmentation precursor 18 could in
turn be prepared from enone 19 by conjugate addition of an ethyl
group followed by oxidation α to the carbonyl and aldol type
addition of lithiated ethyl diazoacetate.
Our initial route to enone 19 is shown in Scheme 6. A Doebner
modified Knoevenagel condensation11 of m-anisaldehyde and 2-
cyanoacetic acid provided acrylonitrile 22 in 75% yield.
Reduction of the acrylonitrile moiety gave m-(3-aminopropyl)-
anisol, which was alkylated with (iodomethyl)trimethylsilane to
evolution, and upon aqueous workup aldehyde tethered ynoate
(2, Scheme 1) was isolated in low and variable yield. However,
adding sodium borohydride in diglyme to the crude
fragmentation mixture gave amine 12 in 80% yield.
Scheme 6. Initial Route to Intermediate 19
In an attempt to apply this fragmentation to a model system
that was more similar to the aspidospermine core, we prepared
diazo ester 15, which lacks the angular ethyl group, by the route
shown in Scheme 4. Exhaustive reduction of 8-hydroxyquinoline
and alkylation of the resulting amine with (iodomethyl)-
trimethylsilane gave decahydroquinoline derivative 14 as a
mixture of diastereomers in 43% yield. Oxidation under Swern
conditions gave the corresponding ketone, and aldol addition of
lithiated ethyl diazoacetate gave the desired fragmentation
precursor 15 in 35% yield. Unfortunately, all attempts to
fragment this compound were unsuccessful and starting material
was returned. The inability of 15 to fragment may be a
ramification of the bicyclic structure causing poor stereo-
electronic alignment of the reacting groups,10 or the presence
of a more basic tertiary amine which could coordinate to the
Lewis acid.
B
DOI: 10.1021/acs.orglett.6b01674
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Organic Letters
Letter
give anisole 23 in 68% yield over the two steps. Birch reduction
and acid catalyzed isomerization gave enone 24 in 84% yield.
This compound was unstable as a free base but could be stored as
the amine hydrochloride salt. Boc protection of the amine gave
the desired enone (19) in 72% yield. While this route provided
access to 19, it was lengthy and we encountered difficulties when
attempting to scale up; the acrylonitrile reduction step proved to
be irreproducible, and the Birch reduction step became
inconvenient on a larger scale.
Scheme 8. Results of Initial Fragmentation Studies of Diazo
18
To circumvent these scalability issues, we developed the
significantly more concise route to 19 shown in Scheme 7. N-
This material, which would be the direct precursor of the
requisite azomethine ylide, was apparently formed by a
serendipitous sequence of reactions involving Lewis acid
mediated fragmentation, Boc cleavage, and subsequent intra-
molecular condensation.
Scheme 7. Preparation of Fragmentation Precursor 18 via
Optimized Route to 19
To optimize the formation of iminium 7 the reaction time was
extended to 24 h with little effect. Changing the work up
procedure from quenching with a saturated aqueous NaHCO3
solution to quenching with water resulted in a noticeable increase
in the yield of the iminium that was isolated. Adding molecular
sieves to the fragmentation reaction and running the reaction at
room temperature for 12 h further promoted the formation of
the desired iminium salt. Under these reaction conditions the
desired product was isolated in 90% yield after trituration with
hexanes in a form that was sufficiently pure to carry on without
further purification (Scheme 9). Treating this material with
Scheme 9. Ring Fragmentation/Intramolecular Azomethine
Ylide 1,3-Dipolar Cycloaddition To Give the Aspidosperma
Tricyclic Core
Boc-N-(trimethylsilyl)methylallylamine (25), prepared by alky-
lation of N-Boc-allylamine, was subjected to a one-pot
hydroboration/Suzuki coupling sequence,12 which gave enone
19 in 92% yield on gram scale. With convenient access to 19 now
in hand, copper catalyzed 1,4-conjugate addition of ethyl
magnesium bromide in the presence of TMSCl provided
enoxysilane 27 in 89% yield. Subjecting this material to a
biphasic Rubottom oxidation using in situ generated DMDO as
oxidant gave the α-hydroxy ketone, and subsequent TMS
protection of the alcohol provided silyl ether 28 as a mixture of
two diastereomers in 65% yield. Aldol addition of lithiated ethyl
diazoacetate to this mixture provided the desired ring
fragmentation precursor (18) in 73% yield as a mixture of
diastereomers. The lack of diastereoselectivity in these steps is
inconsequential since both stereocenters adjacent to the oxygen
atoms are cleared during the fragmentation step.
With diazo ester 18 in hand, we attempted the key
fragmentation reaction. We were disappointed to discover that
subjecting 18 to the standard fragmentation conditions (SnCl4, 0
°C) led to a complex mixture of products; no aldehyde was
present in the crude mixture, and it was clear that the Boc group
had been cleaved. In prior studies4 we had determined that
indium(III) triflate was also effective in promoting the
fragmentation of γ-silyloxy-β-hydroxy-α-diazo carbonyl com-
pounds and we were pleased to observe that treating 18 with a
suspension of indium(III) triflate in CH2Cl2 at −5 °C for 2 h
(Scheme 8) gave the expected tethered aldehyde ynoate 17 in
66% yield. Importantly, we also isolated trace quantities of a
highly polar material that we identified as being iminium salt 7.
cesium fluoride in acetonitrile generated the requisite
azomethine ylide, which underwent intramolecular 1,3-dipolar
cycloaddition with the pendent alkyne to give the target 2,5-
dihydropyrrole 6, the tricyclic core of the Aspidosperma alkaloids,
in 60% yield as a single diastereomer.
In summary, we have devised a short sequence leading to the
formation of the C,D,E-ring subunit of the Aspidosperma
alkaloids. Fragmentation of a γ-silyloxy-β-hydroxy-α-diazo
carbonyl containing a side chain bearing a Boc-protected
amine led directly to an iminium ion by in situ cleavage of the
Boc protecting group and subsequent condensation of the amine
with the newly formed aldehyde. Incorporation of a
(trimethylsilyl)methyl group onto the amine prior to fragmenta-
tion led directly to an azomethine ylide precursor, which upon
treatment with CsF provided the desired tricyclic product as a
single diastereomer. Although an octahydroquinolin-8-one
derived substrate (15) failed to fragment productively, we have
shown that a γ-amino-β-hydroxy-α-diazo carbonyl compound
(11) does fragment in the presence of a Lewis acid to give an
iminium product that can be directly reduced to the
corresponding amine.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01674.
C
DOI: 10.1021/acs.orglett.6b01674
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Matthias.brewer@uvm.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NIH (National
Institute of General Medical Sciences Award Number
R01GM092870). Its contents are solely the responsibility of
the authors and do not necessarily represent the official views of
NIGMS or NIH. Mass spectrometry data were acquired by Bruce
O’Rourke on instruments purchased through instrumentation
grants provided by the NIH (S10 OD018126). The National
Science Foundation supported this work through instrumenta-
tion grants CHE-1039436, CHE-1126265, and CHE-0821501.
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