Synthesis of ent-[3]-Ladderanol: Development and Application of Intramolecular Chirality Transfer [2+2] Cycloadditions of Allenic Ketones and Alkenes

Article abstract of DOI:10.1021/jacs.7b09844

An enantioselective synthesis of ent-[3]-ladderanol is presented. The ladderanes are an interesting class of molecules for their unique structure of fused cyclobutane rings as well as their perceived biological function of organism protection. The route h

Full text of DOI:10.1021/jacs.7b09844

Communication
pubs.acs.org/JACS
Synthesis of ent-[3]-Ladderanol: Development and Application of
Intramolecular Chirality Transfer [2+2] Cycloadditions of Allenic
Ketones and Alkenes
Nathan J. Line,# Brittany P. Witherspoon,# Erin N. Hancock, and M. Kevin Brown*
Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
Scheme 1. Prior Work and Synthetic Strategy
ABSTRACT: An enantioselective synthesis of ent-[3]-
ladderanol is presented. The ladderanes are an interesting
class of molecules for their unique structure of fused
cyclobutane rings as well as their perceived biological
function of organism protection. The route hinges on the
development and application of a chirality transfer [2+2]
cycloaddition of an allenic ketone and alkene. Further
stereocontrolled transformations allowed for completion
of the synthesis. The scope of the chirality transfer [2+2]
cycloaddition is also presented.
he ladderane family of natural products (Scheme 1A),
Tisolated in 2002 from the annamox bacteria, is an
intriguing class of molecules due to their highly unusual
structure of fused cyclobutane rings and their perceived
biological function of organism protection.1 It has been
postulated that the ladderane incorporates into the lipid
bilayer to render a denser cell membrane, which contributes
to a tighter barrier against diffusion of toxic intermediates.2,3
This process is crucial to the survival of the organism as it
compartmentalizes toxic N2H4, which is an intermediate in the
+
−
conversion of NH4 and NO2 to N2 and 2H2O for energy
production. Due to the paucity of these molecules from
biological sources, unconfirmed function, and interesting
structure, which could inspire new strategies/methods, we
sought to develop a synthesis of these molecules.4 At the
outset of our studies, only one enantioselective synthesis of
[5]-ladderanoic acid (2) was known and was reported by
Corey in 2006.5 Therefore, we initially targeted the synthesis
of [3]-ladderanol (1). However, during our efforts, Burns and
co-workers developed a synthesis of [3]-ladderanol (1), [5]-
ladderanoic acid (2), as well as the fully assembled
phospholipid (3).6
Our synthetic design is illustrated in Scheme 1B. We
envisioned that the three fused cyclobutanes could be
assembled by a late-stage [2+2] cycloaddition between
cyclobutene 4 and cyclobutene itself (or a surrogate). Further
disconnection of 4 by stereocontrolled transformations
revealed [4.2.0]-bicycle 5. Inspired by our group’s previous
efforts toward development of allenoate alkene [2+2]
cycloadditions,7,8 a strategy was devised in which 5 could be
prepared by intramolecular cycloaddition of allenic ketone
6.9,10 This cycloaddition is notable in that it would represent
an unusual chirality transfer [2+2] cycloaddition.11
To implement the strategy outlined in Scheme 1B, a
straightforward and enantioselective synthesis of allenic ketone
6 was required. Although enantioselective synthesis of allenic
ketones is unprecedented, we were encouraged by known
methods for the enantioselective synthesis of allenoates by
enantioselective isomerization of β,γ-alkynyl esters.12,11f
Application of this methodology required the synthesis of
β,γ-alkynyl ketone 9, which was accomplished by a two step
protocol involving addition of the acetylide derived from 7 to
epoxide 8 and subsequent oxidation with Dess-Martin
periodinane (Scheme 2). With access to β,γ-alkynyl ketone
9, it was determined that the enantioselective isomerization
could be promoted by thiourea catalyst 10 to provide the
allene 11.13−15 Direct addition of MeNO2 and Bi(OTf)3 to
the reaction mixture allowed for chirality transfer [2+2]
cycloaddition to generate 13 in 57% yield and 94:6 er.9,16 It
should be noted that while the allene was not isolated in the
Received: September 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b09844
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Chirality Transfer [2+2] Cycloaddition
Scheme 3. Chirality Transfer [2+2] Cycloaddition: Scope
synthesis of 13, it could be isolated in 72% yield and 94:6 er.
A model for the chirality transfer [2+2] cycloaddition is
illustrated in Scheme 2 (12). The alkene tether likely
approaches the allene distal to the larger −CH2OSiR3
group. In addition, the alkene is aligned perpendicular to
the allene in accordance with models proposed for related
ketene-alkene [2+2] cycloadditions.17
We have found this sequence to be a generally effective
method for the enantioselective synthesis of [4.2.0]-fused
bicycles (Scheme 3). The γ-substituent of the allene could be
varied from n-alkyl (products 14 and 15) to sterically
demanding cyclopropyl or t-butyl groups (products 16 and
17, respectively). Vinyl and aryl groups were also tolerated
(products 18, 19, 21, respectively); however, one notable
exception is that reaction with an electron-rich aryl group led
to formation of 20 in low yield and enantioselectivity. In this
example, the rate of cycloaddition was reduced, which likely
allowed for competitive racemization of the allene prior to
cycloaddition.
With regard to the alkene tether, this method permits
access to the formation of product 22, which contains a
quaternary center, in good yield and enantioselectivity
(Scheme 3). Reaction with a cis-1,2-disubstiuted alkene
resulted in formation of product 23 as a single diastereomer.
The preservation of the alkene geometry in product 23
suggests a cycloaddition that is stereospecific in nature.
Therefore, it is proposed that the cycloaddition proceeds
through a concerted mechanism, or at least involves a short-
lived intermediate.17,18 Reaction with a related substrate led
initially to the formation of 24; however, upon purification
cycloadduct 25 was isolated. This is likely due to two factors:
(1) destabilization of 24 from the eclipsing Ph groups, and
(2) stabilization of 25 by formation of a conjugated
alkenylarene.
a
See the Supporting Information for details. Yield of isolated product
after purification. Average of two experiments (0.5 mmol).
Enantiomeric ratio (er) determined by HPLC analysis with a chiral
column.
G319,20 and stereoselective hydrogenation from the convex
face with Crabtree’s catalyst21 furnished 27, after deprotection
with TBAF, as a single diastereomer in 69% yield over four
steps. Oxidation to the carboxylic acid followed by
decarboxylation in the presence of BrCCl3 allowed for
formation of the corresponding cyclobutyl bromide in 7:3
dr.22 Treatment of this mixture with KOSiMe3 provided 28 as
well as unreacted minor diastereomer of bromide, which was
separable by chromatography.23
Several strategies were envisioned for the completion of the
synthesis (Scheme 4). Initially, a direct [2+2] cycloaddition of
cyclobutene and 28 was attempted on the basis of seminal
reports from Hill and Koichi.24 Under various conditions,
however, <2% of the cycloadduct was observed, which is likely
due to the difficulties associated with photoexcitation (with or
without a sensitizer) of cyclobutene without photoinduced
decomposition of the starting material. Efforts were directed
toward the exploration of a photocycloaddition with cyclo-
butene ester/acid (29) based off reports from Wender.25 In
this case, while trace quantities of the cycloadduct were
observed, optimization did not lead to notable improvements.
Since the [2+2] cycloaddition with cyclobutene or 29
proved to be challenging, we directed our efforts toward
cyclopentenone as this is well-known to undergo reaction with
a variety of alkenes.26 This strategy would require a ring
contraction, which we reasoned could be accomplished by
Having established an efficient method for the synthesis of
13, advancement to 27 was readily accomplished through a
four-step sequence (Scheme 4). Stereoselective 1,4-reduction
of 13 with L-selectride and enol triflate formation allowed for
the corresponding trisubstituted alkene. Negishi cross-
coupling with zinc reagent 26 promoted by Pd-CPhos-
B
DOI: 10.1021/jacs.7b09844
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Journal of the American Chemical Society
Communication
application of the Favorskii27 or Wolff rearrangements.5b,28 In
the event, stereoselective cycloaddition of cyclobutene 28 with
cyclopentenone led to formation of 30 as a mixture of
regioisomers (only one shown as it is inconsequential to the
synthesis) (Scheme 4). While attempted application of the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b09844.
■
S
Experimental procedures (PDF)
1
Analytical data (IR, H and 13C NMR and HRMS) for
Scheme 4. Synthesis of ent-[3]-Ladderanol (1)
all new compounds (PDF)
X-ray crystallographic data for 21 (CIF)
AUTHOR INFORMATION
Corresponding Author
*brownmkb@indiana.edu
■
ORCID
M. Kevin Brown: 0000-0002-4993-0917
Author Contributions
#These authors contributed equally to the completion of this
work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Indiana University and the NIH (5R01GM114443)
for generous financial support.
■
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