Enantioselective Synthesis of Caprolactam and Enone Precursors to the Heterocyclic DEFG Ring System of Zoanthenol

Article abstract of DOI:10.1002/ejoc.201600223

The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting-group strategy led to the modification of this approach beginning with (±)-glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero-Diels-Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition into the corresponding enone synthon. Addition of a model alkyne provides support for the late-stage addition of a hindered alkyne to the caprolactam building block.

Full text of DOI:10.1002/ejoc.201600223

DOI: 10.1002/ejoc.201600223
Communication
Alkaloids
Enantioselective Synthesis of Caprolactam and Enone
Precursors to the Heterocyclic DEFG Ring System of Zoanthenol
Jeffrey T. Bagdanoff,[a] Douglas C. Behenna,[a] Jennifer L. Stockdill,[a] and Brian M. Stoltz*[a]
Abstract: The enantioselective synthesis of both caprolactam cient approach was developed by employing an asymmetric
and enone synthons for the DEFG ring system of zoanthenol hetero-Diels–Alder reaction. The caprolactam building block
are described. The evolution of this approach proceeds first can be converted by an interesting selective Grignard addition
through a synthesis using the chiral pool as a starting point. into the corresponding enone synthon. Addition of a model
Challenges in protecting-group strategy led to the modification alkyne provides support for the late-stage addition of a hin-
of this approach beginning with ( )-glycidol. Ultimately, an effi- dered alkyne to the caprolactam building block.
Introduction
Zoanthenol (1) is a complex, polycyclic alkaloid belonging to
the zoanthamine family of natural products.[1] These com-
pounds exhibit a range of biological activities including anti-
osteoporotic, anti-inflammatory, cytotoxic (P-388 murine leu-
kaemia), and antibacterial activity.[2] Significant synthetic efforts
toward the zoanthamines have been disclosed by a number of
research groups, including the syntheses of norzoanthamine
and zoanthenol by Miyashita in 2004 and 2009[3] and nor-
zoanthamine by Kobayashi in 2008.[4] Our efforts toward the
zoanthamines has focused on zoanthenol (1), which features an
unusual oxidized aromatic A ring with collagen-selective anti-
platelet aggregation activity.[5] In addition to Miyashita's total
synthesis of zoanthenol (1), both Hirama and co-workers[6] and
our own group[7] have reported advanced strategies for its com-
pletion. In this communication, we disclose the enantioselective
synthesis of substituted caprolactam and enone precursors,
which enable two potential routes toward the synthesis of the
DEFG ring system of zoanthenol.[8,9]
With seven rings and nine stereocenters, zoanthenol is a
densely functionalized, topographically complex target mol-
ecule. Our initial simplifying disconnection involved unravelling
the heterocyclic bis-hemiaminal portion of zoanthenol (1 0 2)
based on the pioneering work of the Kobayashi and Williams
groups (Scheme 1).[10] We envisioned that the resulting teth-
Scheme 1. Retrosynthesis of zoanthenol.
ered side chain could be severed at either the C(8)–C(9) bond
to reveal tricyclic core 3 and enone 5 or at the C(6)–C(7) bond
to unveil carbocyclic core 4 and caprolactam 6.
It was anticipated that enone 5 could be derived directly
from caprolactam 6, thus allowing entry into either synthetic
[a] The Arnold and Mabel Beckman Laboratory for Chemical Synthesis
Division of Chemistry and Chemical Engineering, California Institute of
Technology
Pasadena, CA 91125, USA
E-mail: stoltz@caltech.edu
http://stoltz.caltech.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600223.
Scheme 2. Retrosynthetic analysis of DEFG synthons.
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Communication
approach from a single DEFG synthon (Scheme 2). Caprolactam opening with the anion of ethyl propiolate (16) to provide
6 was disconnected across the amide C–N bond to reveal Wein- known alkyne 17.[15] Unsaturated lactone 14 was quickly ac-
reb amide 7. Phthalimide 7 could in turn be derived from δ- cessed through Lindlar reduction of alkyne 17, followed by
lactone 8, accessible from α,ꢀ-unsaturated lactone 9.
cyclization upon exposure to mild acid. With suitably protected
lactone 14 in hand, a highly diastereoselective cuprate addition
with the Gilman reagent proceeded smoothly, yielding scalea-
ble quantities of saturated lactone 18 as a single observed dia-
stereomer.[13a] Installation of the primary amine was accom-
plished through hydrogenolysis of the benzyl ether, followed by
Mitsunobu reaction with phthalimide, providing the crystalline
intermediate 7.
Ultimately, we were able to access δ-lactone 9 more directly
by employing the hetero-Diels–Alder catalyst developed by Jac-
obsen and co-workers (21; Scheme 5).[16] Thus, following reac-
tion of diene 19, aldehyde 20, and catalyst 21, desired dihydro-
pyran 22 was isolated in 72 % yield and >99 % ee and could be
converted into the necessary lactone 9 using acidic pyridinium
dichromate conditions. At this point, selective 1,4-addition was
accomplished by treatment of 9 with Gilman's reagent to afford
23 as a single diastereomer.[17] Treatment with acidic resin in-
duced desilylation to provide alcohol 24, and subsequent Mit-
sunobu reaction provided phthalimide derivative 8.[18]
Results and Discussion
Our synthetic efforts began by targeting a lactone such as 9
in enantioenriched form. Initially, we investigated an approach
beginning from tri-O-acetyl- -glucal 10. Unsaturated lactone 11
D
was accessed in good yield by PCC oxidation according to
known methods (Scheme 3).[11] The extraneous acetate was re-
moved by reduction with activated Zn dust in acetic acid fol-
lowed by reconjugation upon treatment with catalytic DBU to
provide 12.[11] Following removal of the acetate group, our ini-
tial attempts at protection with a more suitable group were
unproductive, because intermediates related to 12 were very
sensitive to base. However, mild acidic conditions for benzyl
protection ultimately were developed to provide δ-lactone 14
using trichloroacetimide 13.[12]
Scheme 3. Synthesis of a chiral unsaturated δ-lactone.
Despite the initial appeal of utilizing the chiral pool as the
starting point for the synthesis of enone 14, the necessity to
shuffle protecting groups prompted the exploration of a route
starting from racemic glycidol 15 (Scheme 4). The enantio-
selective route could be secured upon completion of the race-
mic route from readily available (S)-glycidol.[13,14] According to
literature preparations, the sequence began with benzyl protec-
tion of racemic glycidol 15, followed by nucleophilic epoxide
Scheme 5. Toward a catalytic asymmetric synthesis of synthons 5 and 6.
Chiral lactone 8 was then treated under standard conditions
for Weinreb amide formation, and the intermediate alcohol was
immediately trapped by addition of TBSOTf and 2,6-lutidine to
yield Weinreb amide 7 (Scheme 6). Treatment of 7 with hydraz-
ine hydrate in refluxing ethanol revealed the free primary
amine, which spontaneously cyclized to form a caprolactam.
Carbamate formation with Boc anhydride provided caprolactam
synthon 6. The final step in accessing enone synthon 5 was to
add a single vinyl equivalent to the Boc-protected caprolactam.
Thus, treatment of 6 with vinylmagnesium bromide provided
isolable Grignard adduct 25. The chelation of Mg2+ between
the Boc carbonyl group and the amide carbonyl group encour-
ages addition of a single equivalent of the nucleophile, and
we anticipate that a similar hydrogen-bonding event slows the
collapse of hemiaminal 25. Upon standing in CHCl3, desired
enone 5 is produced.
Scheme 4. Access to Weinreb amide 7 from ( )- or (S)-glycidol.
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Communication
Conclusions
These studies constitute the synthesis of two fully functional-
ized, enantiopure DEFG synthons (5 and 6) ready for late-stage
coupling with our carbocyclic core structures (3 and 4). The
synthetic approaches described encompass strategies begin-
ning from a chiral glycal, racemic or enantiopure glycidol, and
ultimately a catalytic enantioselective approach employing a
hetero-Diels–Alder reaction followed by a diastereoselective
conjugate addition. Additionally, selective ring-opening and
ring-closing events allow for the efficient elaboration of the key
δ-lactone. The strategic choice of Boc as the amide protecting
group enables selective mono-addition of vinylmagnesium
bromide, and ultimately a neopentylalkyne, to the caprolactam.
Efforts to combine these synthons with carbocyclic core struc-
tures analogous to 3 and 4 are ongoing.
Scheme 6. Conversion of the δ-lactone to the ε-lactam and enone synthons.
Acknowledgments
In order to determine the feasibility of the addition of hin-
dered alkyne 4 to caprolactam 6, a model alkyne was synthe-
sized. In order to generate a single diastereomer of the addition
product, it was necessary to generate the model alkyne as a
single enantiomer. Fortunately, α-quaternary allyl ketone 26
was readily available using our asymmetric alkylation method-
ology[19] and could be advanced to a suitable model system
(Scheme 7). Thus, allyl ketone 26 was smoothly isomerized to
the internal olefin, which was then ketalized to provide olefin
27. Ozonolysis with mild reductive workup allowed access to
desired aldehyde 28. Treatment with the Ohira–Bestman rea-
gent (29) induced sluggish Gilbert–Seyferth homologation to
afford alkyne 30 and recovered aldehyde 28. Deprotonation of
the alkyne with KHMDS and trapping with caprolactam 6 pro-
vided alkynone 31. Hydrogenation of the alkyne readily pro-
vided the final side-chain appended model product 32. This
unoptimized approach provides a key proof-of-concept sup-
porting the challenging disconnection of tethered tricycle 2 to
carbocyclic core 4 and caprolactam 6.
The authors wish to thank the NIH-NIGMS (R01GM080269), the
Tobacco Related Disease Research Program (Fellowship to
J. T. B.), the John and Fannie Hertz Foundation (predoctoral fel-
lowship to D. C. B.), Novartis (predoctoral fellowship to J. L. S.),
the Philanthropic Education Organization (Scholar Award to
J. L. S.), and Abbott, Amgen, Boehringer-Ingelheim, Bristol-My-
ers Squibb, Merck, and Caltech for their generous financial sup-
port. The authors thank Professor Karl Scheidt (Northwestern)
for helpful early discussions.
Keywords: Zoanthamines · Zoanthenol · Enantioselectivity ·
Hetero-Diels–Alder reaction · Allylation
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Received: February 26, 2016
Published Online: April 19, 2016
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