A Nitrone Dipolar Cycloaddition Strategy toward an Enantioselective Synthesis of Massadine

Article abstract of DOI:10.1021/acs.orglett.8b01464

An enantioselective route to the C,D-bicycle of massadine is reported. Enantiopure intermediates were generated by a single stereoselective reduction using the Corey-Bakshi-Shibata reagent. This initial stereoinduction was translated into the five contigu

Full text of DOI:10.1021/acs.orglett.8b01464

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A Nitrone Dipolar Cycloaddition Strategy toward an Enantioselective
Synthesis of Massadine
,†
Jeffrey S. Cannon*
Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, California 92697-2025, United States
S Supporting Information
*
ABSTRACT: An enantioselective route to the C,D-bicycle of
massadine is reported. Enantiopure intermediates were generated
by a single stereoselective reduction using the Corey−Bakshi−
Shibata reagent. This initial stereoinduction was translated into the
five contiguous stereocenters of the massadine D-ring by a synthetic
route that features a diastereoselective and stereospecific Ireland−
Claisen rearrangement of a trianionic enolate followed by a
diastereoselective nitrone dipolar cycloaddition of a highly electron-
poor oxime.
he pyrrole-imidazole alkaloids are a large, structurally
advantage of massadine’s functional density could enable an
enantioselective synthesis where a single initial stereocenter
could be relayed to the remaining seven centers.
The retrosynthetic analysis of massadine (1) aimed to use
the high heteroatom count as an asset toward both stereo-
selectivity and chemoselectivity (Scheme 1). The inherent
T
diverse, and bioactive family of marine-isolated natural
1
−5
products constructed of oroidin units.
Of this family, the
molecules derived from the oxidative dimerization of oroidin
are the most structurally complex and synthetically challeng-
6
,7
8
ing. Massadine (1) and related natural products axinell-
9
10,11
amine and palau’amine
have been the subject of much
although only the Baran, Chen, and
Namba groups have published completed syntheses of any of
1
2−25
synthetic work,
Scheme 1. Retrosynthetic Analysis
2
6−32
these molecules.
Central to the synthetic challenge posed
by these molecules is the high heteroatom content (approx-
imately 2:1 C/N), especially the proximal arrangement of two
positively charged guanidinium functional groups. Massadine,
in particular, contains a highly congested and stereochemically
rich tetracyclic core. The central tetrahydropyran B-ring is
flanked by two cationic aminoimidazoline units in addition to
the fully substituted cyclopentanol D-ring. Its eight contiguous
stereocenters contain a fully substituted amine center (C13) as
well as trans-oriented vicinal aminomethyl groups that require
special synthetic attention. The high heteroatom count presents
a further challenge for the chemoselectivity of the current
synthetic methods.
These natural products are proposed to have a shared
biosynthesis that stems from a “pre-axinellamine” structure that
contains the shared central cyclopentane flanked by two
1
oxidized aminoimidazole units. This biosynthetic proposal
indicates that a synthesis of these molecules that focuses on the
early assembly of the core cyclopentane has the potential to be
broadly applicable to the family at large. A strategy that utilizes
pericyclic reactions might take advantage of the inherent
stereoselectivity of their highly organized transition states. This
approach was inspired by work from the Overman laboratory,
where an azomethine ylide was used to construct advanced
33−36
intermediates toward palau’amine.
It was thought, there-
Received: May 9, 2018
fore, that the sequential use of pericyclic reactions that take
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01464
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
functionality of the natural product could therefore be utilized
as a set of handles to direct the desired transformations. The
retrosynthetic analysis followed some of the precedent from the
Baran and Chen groups as well as our own model studies,
which suggested that the central tetrahydropyran B-ring could
be formed from a structure such as 2 by reduction of a
glycocyamidine followed by oxidative cyclization onto the
Emmons olefination of the aldehyde derived from ethanol-
amine (7). Reduction of ketone 8 to alcohol 9 was followed by
acylation with acryloyl chloride and conjugate addition onto the
resultant acrylate with dibenzylamine to provide ester 10. Two
Boc-protected allylic esters were also synthesized: one with an
unsubstituted side chain (13a) and another with additional
oxidation at the terminal carbon (13b). These substrates would
present fully anionic nitrogen atoms under the Ireland−Claisen
conditions. Both were obtained from Wittig olefination of Boc-
glycinal with the requisite ketophosphorane (11). Reduction
of ketone 12a followed by nucleophilic ring-opening reaction of
N-Boc-β-lactam provided racemic ester 13a. Ketone 12b was
reduced enantioselectively with the (S)-CBS-oxazaborolidine
reagent and was acylated by carbodiimide coupling with N-Boc-
β-alanine to provide allylic ester 13b. A stoichiometric amount
of oxazaborolidine was required to ensure both high yield and
enantioselectivity were achieved. The enantiopurity and
absolute configuration of 13b were confirmed by Mosher
ester analysis of the intermediate alcohol.
2
8,30,31
aminoimidazole.
The guanidine functionality would then
be installed onto a cyclopentanol precursor such as 3.
Construction of the cyclopentanol was envisioned to arise
from intramolecular nitrone dipolar cycloaddition of ene−
nitrone 4 followed by cleavage of the isoxazolidine N−O
41
3
7−40
bond.
Preferential pseudoequatorial orientation of the
substituents in the chairlike cycloaddition transition structure
would establish the C2 and C13 stereocenters. This reaction
would also directly install heteroatom functionality where it
would be needed for late-stage guanidine installation. Cyclo-
addition substrate 4 could be synthesized from carboxylic acid
5, which in turn would be produced by a stereospecific
Ireland−Claisen rearrangement of an allylic ester. It was
thought that the nature of the nitrogen protecting groups at this
stage would be critical in controlling the diastereoselectivity of
this rearrangement. The Ireland−Claisen rearrangement
substrate could be derived from alcohol 6 by acylation with a
β-alanine derivative. One salient feature of this strategy was that
the forward synthesis could be easily rendered enantioselective
with the single stereoisomer of allylic alcohol 6 directing the
establishment of all eight stereocenters in massadine (1).
Three allylic esters were prepared to study the Ireland−
Claisen rearrangement (Scheme 2). An allylic ester with basic
amine functionality was prepared by Horner−Wadsworth−
The Ireland−Claisen strategy hinged around transmitting
easily established carbon−oxygen stereochemistry to the C1−
C15 bond in massadine. The C1 stereocenter would be set by
the absolute stereochemistry of the allylic ester, but the C15
center would necessitate selectively synthesizing the Z-enolate
42
of the appropriate ester (i.e., 14, Table 1). We anticipated
a
Table 1. Ireland−Claisen Rearrangement
Scheme 2. Allylic Ester Synthesis
anti/
b
entry
1
R, N
base (equiv) yield (15) (%)
syn
H, NBn (10)
LDA (2)
75 (15a)
66 (15a)
30:70
62:38
>20:1
>20:1
>20:1
>20:1
2
c
2
H, NBn (10)
LDA (2)
2
d
3
4
H, NHBoc (13a)
H, NHBoc (13a)
H, NHBoc (13a)
OTBS, NHBoc (13b)
LDA (4)
33 (15b)
d
LHMDS (4)
LHMDS (4)
LHMDS (4)
58 (15b)
e
d
5
42 (15b)
d
6
48 (15c)
a
b
[
10/13] = 0.1 M, 4 equiv TMSCl, −78 to +40 °C. Determined by
1
H NMR analysis of the unpurified reaction mixture. The
configuration of syn-15a was confirmed by X-ray crystallographic
c
analysis (see the SI for details). Solvent: 23% HMPA in THF.
d
e
Quantitative recovery of starting material. With 6 equiv of LiCl.
that the nearby nitrogen atoms would allow the use of natural
functionality to direct the stereochemistry of deprotonation.
Specifically, chelation of the β-nitrogen atom would force
4
3,44
deprotonation to provide a Z-enolate such as 14.
Rearrangement of enolate 14 would then stereoselectively
provide a γ,δ-unsaturated carboxylic acid (15).
Benzyl-protected diaminoester 10 was initially used to study
the Ireland−Claisen rearrangement (Table 1). For all
rearrangements, it was found that productive reactions only
occurred when base was added to freshly distilled TMSCl
premixed with the ester. Addition of TMSCl after deprotona-
tion resulted in decomposition to the alcohol, presumably
through ketene elimination. Under standard rearrangement
conditions, lithium diisopropylamide (LDA) and TMSCl,
rearrangement of 10 occurred in good yield to provide a
3
0:70 mixture of diastereomers, favoring the undesired syn
isomer of 15a (entry 1). The preferential formation of syn-15a
B
DOI: 10.1021/acs.orglett.8b01464
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indicated that the E-enolate was generated predominantly, and
this product is the expected major diastereomer for these
45
kinetic deprotonation conditions. Therefore, the hypothesis
that the Lewis basic nitrogen atoms would enforce Z-selectivity
in enolate synthesis does not hold for this substrate. Conditions
that typically favor Z-enolate formation, such as addition of
HMPA (entry 2), did reverse the selectivity to the desired
diastereomer (anti-15a) but failed to produce synthetically
useful yields or diastereoselectivities. Other additives, such as
epimeric alcohol at C14 (18). This configuration was
confirmed by NOESY studies and by chemical correlation. It
appeared that the hydride reduction of ketone 17a selectively
provided the undesired configuration, which is the predicted
product of both Felkin- and chelation-controlled hydride
addition models.
ZnCl , or lithium salts also failed to improve the diaster-
2
4
3,44,46
eoselectivity.
It was then hypothesized that an anionic nitrogen might
more strongly enforce Z-enolate intermediate 14 in the
Ireland−Claisen rearrangement. Under standard rearrangement
conditions, allylic ester 13a reacted in modest yield to provide
γ,δ-unsaturated acid 15b as a single diastereomer (entry 3). A
survey of bases identified LHMDS as the optimal base for this
transformation, providing 15b in 58% yield (entry 4). Attempts
to improve conversion by either increasing the reaction
temperature or by influencing potential lithium aggregates
with additives failed to increase the yield of 15b (e.g., entry 5);
however, nearly quantitative recovery of unreacted starting
material was possible under the optimized conditions. These
conditions were also ideal for the rearrangement of silyloxy-
substituted ester 13b (entry 6). It is important to note that
under all conditions tested, only a single diastereomer of acid
In order to circumvent this issue with stereoselectivity, the
order of cycloaddition and reduction was reversed. Nitrone
dipolar cycloadditions of double electron-withdrawing oximes
47,48
are not well precedented,
and indeed, nitrone 17 proved to
be a more challenging substrate for dipolar cycloaddition than
its corresponding C14 alcohol (Table 2). Thermal cyclo-
a
Table 2. Nitrone Dipolar Cycloaddition
1
5b/c was produced, with no evidence of the syn diastereomer
1
visible by H NMR analysis. These results indicate high
selectivity for the Z-enolate stereoisomer, directed by intra-
molecular chelation of the nearby carbamate. The fully anionic
nature of the carbamate group appears to be required to
enforce the stereoselectivity of this deprotonation as compared
to the neutral tertiary amine substituents that were initially
investigated.
b
c
entry
R
Lewis acid
temp (°C)
yield (%)
dr
d
1
2
3
4
H
H
H
150
0−60
0
3:1
e
Zn(OTf)2
23
50
MgBr ·OEt2
MgBr ·OEt2
55
10:1
3:1
2
d
OTBS
OTBS
60
d
40
2
e
5
ZnCl2
50
46
3:1
γ,δ-Unsaturated acids 15b and 15c were then elaborated to
the oxime substrate for intramolecular nitrone-dipolar cyclo-
addition (Scheme 3). Acids 15 could be activated as the acyl
a
b
[
17] = 0.05 M, 0.1 equiv of Lewis acid. Isolated yield of
c
1
diastereomerically pure 19. Determined by H NMR analysis of the
unpurified reaction mixture. Conducted in a microwave reactor. 0.5
d
e
equiv of Lewis acid.
Scheme 3. Synthesis of Oxime Substrates
addition provided variable yields of cyclopentanone 19 in only
modest diastereoselectivities (entry 1). Furthermore, these
conditions were not amenable to scale, as 19 decomposed
under the reaction conditions. Lewis acids were then
investigated as they have been shown to accelerate cyclo-
49
addition reactions of electron-poor dipoles. A survey of Lewis
acids found that magnesium bromide was uniquely useful for
the desired cycloaddition (entries 2 and 3). The reduced
temperatures allowed by MgBr catalysis enabled reproducible
2
production of isoxazolidine 19a in good yield and high
diastereoselectivity. Interestingly, nitrone 17b, with additional
oxidation at the allylic position was more effectively cyclized
with ZnCl (entries 4 and 5). Diastereoselectivities for this
2
substrate were also noticeably lower, but the two diastereomers
were readily separated by chromatographic methods.
imidazole derivatives by reaction with 1,1′-carbonyldiimidazole
The resulting cyclopentanones were reduced stereoselec-
tively and protected to give alcohols 20 (Scheme 4).
Diastereoselective reduction of ketone 19 was likely directed
by the adjacent amine in conjunction with the bulky tert-butyl
ester to give hydride addition to the concave face of the
bicyclooctane. This is supported by the observation that
diastereoselectivity was reduced if the amine was protected
before ketone reduction. Cleavage of the N−O bond with
samarium diiodide to 21 followed by chemoselective oxidation
(
CDI). Reaction of these acyl imidazoles with the lithium
enolate of tert-butylacetate afforded β-ketoesters 16 in good
yield. β-Ketoesters 16 could then be nitrosated with sodium
nitrite under acidic conditions to provide key cycloaddition
substrates 17.
Reduction of the ketone of 17a followed by thermal nitrone
dipolar cycloaddition successfully provided a fully substituted
cyclopentane (eq 1). However, this reduction provided the
C
DOI: 10.1021/acs.orglett.8b01464
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Conversion to Functionalized Cyclopentane
Hydrogenation of the N−O bond required the addition of
base and provided C,D-bicycle 25 in good yield. Under these
basic conditions, however, the TBS protecting group migrated
between the two vicinal alcohols. This equilibrium favored the
primary silyl ether 25 and occurred in the absence of the
palladium catalyst. Minor isomer 26 was crystalline, allowing
for the unambiguous determination of the relative stereo-
chemical configuration of the fully substituted cyclopentane.
This sequence provided the spirocyclic C,D ring system with
the proper functionalization and stereochemical arrangement
for the eventual elaboration to the natural product (1).
A concise and stereoselective route to the fully substituted
cyclopentane ring of the dimeric pyrrole-imidazole alkaloids
massadine, axinellamines A−B, and palau’amine has been
developed. The present route takes advantage of two key
stereospecific transformations to synthesize complex enantio-
pure intermediates. Challenging Ireland−Claisen rearrange-
ments of trianionic intermediates (13) were shown to proceed
with high diastereoselectivity. The templating effect of the
nearby nitrogen functionality was found to rely on this anionic
character. Additionally, an unprecedented 1,3-dipolar cyclo-
addition of an α-nitroso-β-ketoester (17) generated the fully
substituted cyclopentane. Lewis acid catalysis of this cyclo-
addition improved the yield, diastereoselectivity, and reprodu-
cibility of this reaction. This strategy utilized the intrinsic
functionality of massadine to affect the selective synthesis of
functionally dense and stereochemically rich polycycles.
of the resulting alcohol provided fully substituted cyclo-
pentanols 22, representing the complete massadine D-ring.
Initial studies to elaborate carbocycles 22 focused on
conversion to a bromoketone (e.g., 3) in order to intercept
model studies that identified such a compound as a promising
intermediate. Unfortunately, neither methyl ketone 22a or
silyloxyketone 22b was a suitable substrate for this conversion.
Both α-oxidation strategies and attempts to convert the silyl
ether to a bromide were challenged by the steric congestion
and functional group density of ketones 22.
It was thought that installation of the glycocyamidine C ring
might alleviate some of the steric congestion that plagued these
attempts (Scheme 5). Reduction of ketone 19b was followed by
silver-mediated guanylation of the isoxazolidine to provide
differentially substituted guanidine 23. Hydrogenolysis of the
Cbz protecting group initiated cyclization to tricycle 24.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01464.
Experimental details, 1H and 13C NMR spectra of new
compounds, and crystallographic data for syn-15a and 26
Scheme 5. Synthesis of C-Ring
(PDF)
Accession Codes
CCDC 1839960−1839961 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: jcannon@oxy.edu.
ORCID
Jeffrey S. Cannon: 0000-0002-3407-2235
Present Address
†(
J.S.C.) Department of Chemistry, Occidental College, 1600
Campus Rd M-5, Los Angeles, CA 90041.
Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS
■
The author gratefully acknowledges Prof. Larry Overman (UC
Irvine) for mentorship and Dr. Nicole White (UC Irvine) for
helpful suggestions. This work was financially supported in part
D
DOI: 10.1021/acs.orglett.8b01464
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
by the National Heart, Lung, and Blood Institute (HL-25854)
and a fellowship from Bristol-Myers Squibb. NMR and mass
spectra were obtained with the assistance of NSF and NIH
shared instrumentation grants. Dr. Joe Ziller (UC Irvine) is
acknowledged for assistance with X-ray diffraction studies on
compounds syn-15a and 26. Other unrestricted support from
Amgen, Merck, and Pfizer is gratefully acknowledged. 3D
renderings were generated using the program CYLview (www.
cylview.org).
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DOI: 10.1021/acs.orglett.8b01464
Org. Lett. XXXX, XXX, XXX−XXX