A Photorearrangement to Construct the ABDE Tetracyclic Core of Palau'amine

Article abstract of DOI:10.1021/acs.orglett.8b00819

A synthesis of the ABDE tetracyclic carbon core of palau'amine was achieved in 9 steps from commercial materials. The core's most notable feature, a highly strained trans cyclopenta[c]pyrrolidine, was obtained in high yield using a ring contraction strategy starting from a much less strained trans bicyclic lactam derivative that is accessible in only 7 steps.

Full text of DOI:10.1021/acs.orglett.8b00819

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Photorearrangement To Construct the ABDE Tetracyclic Core of
Palau’amine
Samuel Aubert-Nicol, Jean Lessard, and Claude Spino*
́ ́ ́ ́
Departement de Chimie, Universite de Sherbrooke, 2500 Boul. Universite, Sherbrooke, Quebec, Canada, J1K 2R1
S
* Supporting Information
ABSTRACT: A synthesis of the ABDE tetracyclic carbon core of palau’amine
was achieved in 9 steps from commercial materials. The core’s most notable
feature, a highly strained trans cyclopenta[c]pyrrolidine, was obtained in high yield
using a ring contraction strategy starting from a much less strained trans bicyclic
lactam derivative that is accessible in only 7 steps.
ince its isolation in 1993 from the marine sponge Stylotella
Agminata by the group of Scheuer,1 palau’amine (1, Figure
1) has garnered much attention from the chemical community.
analysis,5−7 computational methods,8,9 and chemical syn-
thesis.10
S
This revision added a new challenge in approaching the core
structure, since the revised trans-bicyclo[3.3.0]octane contains
approximately 27 kJ/mol more strain energy than its cis
counterpart.9,11,12 It also makes palau’amine stand out as one of
the very few known natural products containing such a feature,
structures 7−10 being examples (Figure 1).13−16 Furthermore,
to our knowledge, the only natural products bearing a trans-
azabicyclo[3.3.0]octane core are palau’amine and its closely
related congeners, for example, styloguanidine (4) and their
respective bromo (2, 5) and dibromo (3, 6) derivatives.
Understandably, the reassignment of the junction’s geometry
foiled many ongoing total syntheses in various research
groups.17 On the other hand, synthetic strategies directed
toward the biosynthetically related axinellamines (11−14) and
massadines (15−16, Figure 2) became adaptable to generate a
common precursor on the way to palau’amine. This allowed the
Figure 1. A few examples of strained natural products containing a 5,5-
trans ring junction.
From a medicinal standpoint, palau’amine exhibits potent
biological activity, mainly as an immunosuppressant and
cytotoxic agent.1−3 From a synthetic perspective, palau’amine’s
unique and densely functionalized core is an interesting
challenge and ground for the development of innovative
synthetic methodologies and strategies.4 Among the difficulties
included in this core, and one of its most unique features, is the
junction of the two five-membered D and E rings: originally
assigned as cis, the ring junction was later revised as trans by the
efforts of independent groups using a combination of NMR
Figure 2. Natural products biosynthetically related to palau’amine.
Received: March 13, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b00819
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Baran group to complete the first total synthesis of the
racemic,18 and subsequently nonracemic,19 alkaloid.
Scheme 2. Strategies toward the trans
Azabicyclo[3.3.0]octane Core of Palau’amine by the Groups
To address the challenge of the trans-cyclopenta[c]-
pyrrolidine, they first generated a “macro-palau’amine” 17
precursor and used a transannular cyclization to obtain the trans
ring-junction (Scheme 1a). The macrocyclic template kept both
of (a) Romo and (b, c) Feldman
Scheme 1. Strategies toward the trans
Azabicyclo[3.3.0]octane Core of Palau’amine by the Groups
of (a) Baran and (b) Namba and Tanino
Scheme 3. Unexpected trans-Azabicyclo[3.3.0]octane Core
atoms involved in the cyclization in close proximity, which was
a key factor in overcoming the increase in strain during the
ring-closing event. This strategy might be biosynthetically
inspired, as a similar ring closing event was suggested for the
biosynthesis of a related alkaloid.20
The second of the only two completed syntheses of
palau’amine reported so far was published by the groups of
Namba and Tanino, and also used a transannular cyclization
strategy to access the trans-azabicyclo[3.3.0]octane moiety. The
authors report calculations and experimental studies which
indicate that the macrocyclic template 18 was held together by
the coordination of a lithium cation by an amide anion and an
ester carbonyl group (Scheme 1b).3
Three other approaches to palau’amine were successful in
yielding the azabicyclo[3.3.0]octane core. Opening a cis-fused
lactam to the sulfonamide-alcohol 20 in 5 steps, the group of
Romo used an SN2 displacement of an activated alcohol by a
sulfonamide under Mitsunobu conditions to give a high yield of
the desired trans-cyclopenta[c]pyrrolidine structure 21
(Scheme 2a).21 The other two approaches were reported by
the Feldman group and gave low to modest yields of the trans-
cyclopenta[c]pyrrolidines 23 and 25 (Scheme 2b and c).22
We have developed a strategy employing a photochemical
rearrangement of a N-mesyloxylactam to generate the strained
trans-cyclopenta[c]pyrrolidine in high yield. The rearrangement
is related to the more familiar Lossen rearrangement, but is
unique in its mechanism and scope.23 We had previously
demonstrated our rearrangement’s potential to generate a trans-
cyclopenta[b]pyrrolidine (Scheme 3).24 The yield of 29 was
only 16%, but this product was totally unexpected, and we
knew that it could be improved. Herein, we report an efficient
synthesis of the ABDE tetracyclic carbon framework of
palau’amine using this strategy.
To obtain the requisite trans-fused bicyclic hydroxamic acid
precursor for our key rearrangement, we devised the synthesis
described in Scheme 4, starting by the conversion of
cyclohexene to adipaldehyde by ozonolysis. Reacting adipalde-
hyde with methyl cyanoacetate under secondary amine catalysis
allowed us to obtain aldehyde 33 as a mixture of two
equilibrating epimers at the acidic α-cyanoester center. The
substituents on the five-membered ring were in a trans
relationship. Due to the initially very low yields obtained for
this reaction, many different conditions were tested with
varying factors, including the amine catalysts, solvents, and
reaction temperature. The most impactful factor was the nature
of the secondary amine catalyst. Proline showed an almost 3-
fold increase in yield over any other amine tested. Although the
yield remained modest, we decided against optimizing further
B
DOI: 10.1021/acs.orglett.8b00819
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Scheme 4. Synthesis of the Precursor for the Key Photochemical Rearrangement
at this stage, since synthesis of the actual palau’amine would
certainly need a different starting material.
Scheme 5. Result of the Key Photochemical Rearrangement
The rest of the synthesis proceeded smoothly. First, the
condensation of benzylhydroxylamine afforded oxime 34 as a
mixture of four isomers. Flash chromatography of the mixture
allowed separation of the two geometric isomers about the
oxime double bond, and each fraction consisted of a mixture of
the two epimers at the α-cyanoester position. Upon standing,
both fractions converted back to a mixture of the four initial
isomers. The equilibrating fractions were combined and used
together in a one-pot reduction/cyclization sequence to afford
the protected hydroxamic acid 35 as a mixture of two
stereoisomers. Cobalt-catalyzed chemoselective reduction of
the nitrile and treatment with Boc2O afforded the protected
primary amines 36a and 36b, which were at this point separable
by flash chromatography. They were obtained in a 3:1 ratio in
favor of the desired diastereomer. The assignment of the
diastereomers was established by NMR analysis and later
confirmed by the XRD spectrum of the minor diastereomer
(see Supporting Information (SI)). Again, optimization of this
ratio was unnecessary for the model study. Finally, deprotection
and activation of the cyclic hydroxamic acid allowed us to
obtain the desired precursor 37a to test our key rearrangement
step.
To our delight, treatment of precursor 37a in the photolysis
conditions previously developed in our laboratory gave two
compounds, 38a and 39a, both containing the desired
substituted trans-azabicyclo[3.3.0]octane core. They were
obtained in high yield with no optimization required (Scheme
5). The yield of 83% is remarkable, given the introduction of
such severe strain in the structure: the difference in strain
energy between trans-bicyclo[4.3.0]nonane and trans bicyclo-
[3.3.0]octane amounts to 44 kJ/mol.11,12 The developing strain
actually does not seem to influence the yield of the product at
all, as it is comparable or even superior to other rearrangements
performed on unstrained substrates. It even compares favorably
to some substrates with fully substituted (quaternary) migrating
centers, which usually rearrange in higher yields than their
lesser substituted analogs.23,24 N-Mesyloxylactam 37b, obtained
from the minor diastereomer 36b, rearranged with equal ease
to give a similar mixture of 38b and 39b in comparable yield
(81%).
Both isolated products 38a and 39a arise from the desired
photochemical rearrangement. The first is the carbamate 38a,
which is formed by the trapping of the intermediate acylium ion
by methanol used as solvent: this is the trapping product that is
usually observed. The second product is the urea 39a, which is
generated from the intramolecular trapping of the intermediate
by the Boc protected amine. The rearrangement was run in
triplicate, and each time, the yield and the ratio of carbamate to
urea differed only slightly, ranging from 81% to 84%, and from
48:52 to 57:43, respectively. We were also able to isolate urea
39a as the sole reaction product when the reaction was run in
dichloromethane instead of methanol. In this case, however, the
overall yield of the reaction was slightly lower (76%).
Importantly, the ratio of these two products is inconsequential
to the rest of the synthesis: both rearrangement products could
be combined and used to complete the ABDE core of
palau’amine.
From the mixture of compounds 38a and 39a, the target
molecule was obtained by a one-pot sequence of four reactions,
as described in Scheme 6. First, treatment of the combined
rearrangement products with aqueous acid allowed the rapid
cleavage of the Boc protecting group. Then, hydrolysis of both
C
DOI: 10.1021/acs.orglett.8b00819
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Scheme 6. Completion of the ABDE Core of Palau’amine
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.8b00819.
Experimental procedures and copies of proton and
carbon NMRs for all compounds (PDF)
Accession Codes
CCDC 1829434−1829435 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: Claude.Spino@USherbrooke.ca.
ORCID
Claude Spino: 0000-0001-6249-5908
Notes
the carbamate and urea moieties was performed by heating the
mixture in a sealed tube, converting both substrates to the same
diammonium intermediate 41. We next cooled down the
reaction mixture to 75 °C, neutralized it with aqueous sodium
hydroxide, and added compound 40, which allowed us to
perform a Paal−Knorr synthesis of the requisite pyrrole.
Finally, basification of the reaction medium and stirring at room
temperature overnight yielded the desired ABDE core of
palau’amine 43. The whole operation proceeded in 37% yield
for the four chemical transformations in a single pot, averaging
a yield of 78% per transformation. The single crystal XRD data
from 43 confirmed its relative stereochemistry (Figure 3).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Natural Sciences and
Engineering Council of Canada, through a Discovery Grant to
C.S. and a postgraduate scholarship to S.A.N., as well as by the
Universite
́
de Sherbrooke.
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