Stereocontrolled Synthesis of Kalihinol C

Article abstract of DOI:10.1021/jacs.7b01124

We report a concise chemical synthesis of kalihinol C via a possible biosynthetic intermediate, “protokalihinol”, which was targeted as a scaffold en route to antiplasmodial analogs. High stereocontrol of the kalihinol framework relies on a heterodendrale

Full text of DOI:10.1021/jacs.7b01124

Communication
pubs.acs.org/JACS
Stereocontrolled Synthesis of Kalihinol C
Christopher A. Reiher and Ryan A. Shenvi*
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: We report a concise chemical synthesis of
kalihinol C via a possible biosynthetic intermediate,
“protokalihinol”, which was targeted as a scaffold en
route to antiplasmodial analogs. High stereocontrol of the
kalihinol framework relies on a heterodendralene cascade
to establish the target stereotetrad. Common problems of
regio- and chemoselectivity encountered in the kalihinol
class are explained and solved.
he kalihinols (Figure 1) possess the highest skeletal and
functional group complexity of the biologically enigmatic
T
isocyanoterpene (ICT) class.1,2 Kalihinol A3a also exhibits the
highest reported potency of the ICTs against Plasmodium
falciparum,3b killing with an EC50 of 1 nM, but the mechanism of
action has not been rigorously assigned. Proposed mechanisms
to explain phenotypic effects of the ICTs include inhibition of
heme detoxification4 or copper chelation,5 but these proposals
do not fully account for the structure−activity relationships and
life-cycle activities reported. For example, our discovery that the
amphilectenes and adocianes are cytotoxic against liver-stage
parasites militates against heme detoxification inhibition as the
exclusive antiplasmodial mechanism.6 Copper chelation is
simply not possible for congeners with distant isonitriles. As
part of a program to investigate the biological activity of ICTs,
we have begun to develop effective chemical syntheses2,6,7 and
associated methods8 to produce and modify three main
structural classes: amphilectenes, adocianes, and kalihinols.1,2
Prior syntheses9 of the kalihinol class have fought to control
stereochemistry in the functionally dense scaffolds, and each
contains at least one uncontrolled (ca. 1:1 d.r.) stereogenic
step.10 Here we report a short and fully stereocontrolled
synthesis of kalihinol C (1) enabled by a new heterodendralene
building block, a directed alkene isomerization, and a new
method for isonitrile synthesis.
Figure 1. (a) Kalihinol congeners; (b) hypothetical biosynthesis that
informs a proposed chemical synthesis.
Scheme 1. Routes to Building Blocks
highly diastereoselective Diels−Alder cascades. Given the
structural correspondence between amphilectenes and kalihi-
nols, we realized that a dendralene-based approach might
emulate the proposed biosynthetic pathway if the oxy-
nucleophile of 4 were embedded in a dendralene.
Short and efficient routes to the heterodendralene and double-
dienophile partners are shown in Scheme 1. Preliminary
reconnaissance identified two important features of each
component. First, the dimethylamine substituent15 in 5 was
necessary to offset the electron-withdrawing carboxylate, which
rendered the dendralene less reactive with electron-deficient
dienophiles. Second, the diethylphosphonate substituent in 6
The kalihinols appear to derive from a common intermediate,
a “protokalihinol,” (2a) where the tetrahydrofurans or -pyrans
derive from oxidative cyclization of a pendant prenyl unit. The
protokalihinol framework (a dihydroxy-bifloran diterpene)1
would arise from bisabolyl cation intermediate 3 via cation-
olefin cyclization and concomitant stereoselective capture of
water.11 Although such a pathway might globally simplify
formation of the kalihinol stereotetrad (in blue), we thought
intramolecular capture of oxygen in synthon 4 might be more
realistic than stereoselective carbocation hydration.12
Recently, our lab reported short syntheses of amphilectene7
and adociane6 ICTs that relied on a new class of polarized
dendrimeric polyene13 (Danishefsky dendralenes) that forged
the stereochemically dense core of these and other terpenes14 in
Received: February 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b01124
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
activated the dienophile for ambient-temperature cycloaddition
but was not so destabilizing as to complicate isolation.
Table 1. Alkoxide-Directed Alkene Isomerization
Building block 5 was synthesized by condensation of tert-butyl
acetoacetate 7 with dimethylformamide dimethyl acetal (DMF-
DMA) to yield vinylogous amide 8, which was doubly silylated
to 5 with loss of the tert-butyl group. Geranyl-phosphonate 6 was
also synthesized in two steps by addition of diethyl ethyl-
phosphonate to ethyl geranylacetate (9), followed by in situ
selenation and subsequent oxidation/elimination of the
selenoxide.16
Cycloaddition of 5 to 6 occurred at 22 °C in CH2Cl2 to yield
an inconsequential mixture of diastereomers at the dimethyla-
mino group, which was eliminated to an enone (see synthon 4)
by treatment with hydrogen fluoride. The silylester was also
cleaved to the corresponding unsaturated carboxylic acid, which
engaged in a nearly quantitative intramolecular Diels−Alder
cycloaddition17 to provide, after tautomerization, β-keto-lactone
10, possessing the targeted stereotetrad of the kalihinols. The
stereoisomers (5:1 ratio) corresponded to epimers at the C−P
bond, and were converged in the next step.18
entry
1
variations (and % conversion)
none (78)
2:14
%2a
7:1
5:1
1:1
54
55
28
0
a
2
4 equiv. KOt-Bu, no KH (82)
16 equiv. KOt-Bu, no KH (86)
1.2 equiv. n-BuLi, no KH (0)
DMPU instead of DMSO (0)
a
3
4
5
0
alternate conditions
b
6
20 mol % RhCl3, EtOH/H2O, 70 °C (56)
1:1
28
<5
a
c
7
2 mol % [Co], 4 mol % PhSiH3, PhH (42)
<1:20
Lactone 10 was converted to diol 11 by (1) Krapcho-like
dephosphonylation, (2) stereoselective methyl addition to the B-
ring ketone, and (3) lactone hydrolysis/decarboxylation; each
step deserves some comment. First, the desphonylation is a little-
precedented transformation that required the development of a
new procedure [LiCl, Py·HCl (aq.), 90→110 °C] to spare the
acid-sensitive tert-alkyl lactone and the electrophilic ketones,
which underwent retro-Dieckmann reactions under other
conditions. Addition of a methyl group prior to decarboxylation
preserved the trans-decalin geometry, whereas the correspond-
ing ketone weakly favored the cis-decalin after lactone cleavage.
Preferential formation of the disfavored trans-decalin (of 11) has
remained unsolved in prior work,2,9,10 and in this case is enabled
by the fused lactone, which locks the geometry. Through this
short process, multigram quantities of decalone 11 could be
generated in a single pass for elaboration to protokalihinol 2a
and the metabolite itself (1).
a
b
c
1H NMR. GC−MS. Co(Salt‑Bu,t‑Bu)Cl·H2O.
A Sharpless-type directed epoxidation24 was identified as the
only method capable of controlling the stereochemistry of the
targeted tetrahydrofuran. But to our chagrin, the Δ3,4 ring-alkene
reacted faster than the Δ14,15 chain-alkene and delivered a C3,4
epoxide opposite to that required for elaboration to the
isocyano-hydrin of 1 (16, see Figure 2). Fortunately, these
same conditions also mediated a slower, but stereoselective
(93:7 d.r.) epoxidation of the side-chain alkene, as well as
concomitant 5-exo-tet cyclization to the targeted tetrahydrofur-
an, whereas the A-ring epoxide was spared attack. Consequently,
a sodium iodide/zinc metal-mediated epoxide deoxygenation
selectively removed the unwanted ring epoxide, whereas the
C14,15 oxidation was retained as the incipient hydroxy-
tetrahydrofuran (see Figure 2).
However, establishment of the required Δ3,4 unsaturation was
undermined by formation of the Δ4,5 isomer, which predomi-
nated upon enolization of ketone 11. Such preference is well-
precedented for 2-decalone enolizations19 as well as alkene
isomerizations in the heavily studied amorphane sesquiter-
penes.20 Attempts to generate endocyclic alkene 2 by ionization
of the tertiary alcohol derived from ketone 11 delivered the
isomeric Δ4,5 alkene with unrelenting regularity. Because
Brønsted bases can mediate alkene isomerization at high
temperatures,21 we wondered if the tertiary alcohol proximal
to the C3 methylene of 11 could mediate a selective alkene
isomerization as its strongly basic alkoxide. Indeed, we found
that the potassium salt 12 could be heated to 140 °C in DMSO
to deliver protokalihinol 2a with 7:1 selectivity for Δ3,4
unsaturation (2) over Δ4,5 (14, Table 1). Consistent with this
mechanistic model, increased equivalents of base led to
increased amounts of 14 (entries 1−3), which would derive
from intermolecular deprotonation. Small amounts (ca. 15%) of
isomers derived from chain isomerization (Δ15,16: 2b, 14b) also
were observed, but could be removed from 2a (or carried
forward and removed from 15). Other alkali metals besides
potassium and other solvents besides DMSO performed poorly
(entries 4 and 5; see SI for a list of other variations). Methods
like coordinative isomerization22 or HAT isomerization23
(entries 6 and 7) delivered mixtures of alkenes or the Δ4,5
isomer exclusively.
Figure 2. Stereoselective oxidative cyclization to 15.
The full kalihinol skeleton and correct oxidation state were
thus established in eight steps from heterodendralene 5; we next
investigated elaboration to a known metabolite. Elimination of
the exocyclic tertiary alcohol was effected by selective
trifluoroacetylation and syn-elimination via thermolysis since
ionizing conditions resulted in hydride shift from the
tetrahydrofuran methine. In the same flask, we trifluoroacety-
lated the remaining alcohol and then installed the B-ring
equatorial tert-alkyl isonitrile with our solvolytic stereoinver-
B
DOI: 10.1021/jacs.7b01124
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Journal of the American Chemical Society
Communication
Scheme 2. Synthesis of Kalihinol C
sion.8 The logic leading to this route (Scheme 2) requires some
discussion.
ring substituents proved mutually incompatible in the tandem
solvolysis sequence reported by Vanderwal.9e
Consequently, we relied on a simple but effective aminolysis
to generate regioselectively the requisite A-ring functionality
(Scheme 2 and Table 2, entry 5). First, chemoselective oxidation
of the alkene of 25 occurred in preference to the isonitrile if
carried out with dimethyldioxirane (DMDO) in the strongly
hydrogen bond-donating solvent HFIP, which we posit
deactivates the isonitrile against oxidation (Scheme 2).
We had originally targeted a tandem epoxide opening/
trifluoroacetate stereoinversion of 20 (Figure 3) using our
solvolysis conditions to install the bis-isonitrile motif. This
approach was reported by Vanderwal to be successful, but low-
yielding in his kalihinol B synthesis.9e We similarly found that
this tandem reaction yielded only small amounts of the bis-
isonitrile 21 (5−6%). The basis of the low yield was not the
epoxide opening step, which was efficient and regioselective in
substrate 20. Instead, the subsequent B-ring stereoinversion8
was low-yielding by virtue of competitive elimination (22→
23).25 Because the epoxide opening occurred faster than
trifluoroacetate ionization, and the resulting isocyanohydrin
caused elimination in ring B, we concluded that the B-ring C−N
bond must be in place prior to epoxidation.
a
Table 2. Isocyanohydrin Installation
R1/R2
conditions [N]
R1/R2
A:B:C:D
OTFA/Me
OH/Me
Me/NC
TMSCN, Sc(OTf)3 [NC] OTFA/Me
TMSCN, Sc(OTf)3 [NC] OTMS/Me
TMSCN, Sc(OTf)3 [NC] Me/NC
83:0:17:0
100:0:0:0
61:0:39:0
54:31:0:15
100:0:0:0
Me/NHCHO TMSCN, Sc(OTf)3 [NC] Me/NHCHO
Me/NC NH3, MeOH [NH2] Me/NC
a
Figure 3. Tandem isonitrile formation is very low yielding.
Any silylethers were converted to alcohols with TBAF.
We were dismayed to find that the B-ring functional groups
influenced the course of epoxide ionization. As shown in Table 2,
the B-ring axial trifluoroacetate and alcohol led to A with high
selectivity, whereas the equatorial isonitrile or formamide
skewed the ratio to favor substantial quantities of regioisomers
B and C, as well as semipinacol product D.26 So, the A- and B-
Aminolysis in methanol cleanly opened the epoxide to deliver
a sec-alkyl amino tert-alcohol,27 which was converted to the
isocyanohydrin of 1 via difluorocarbene derived from difluor-
omethyl triflate28 and KOt-Bu. More orthodox methods for
amine to isonitrile conversion worked poorly: chloroform/
sodium hydroxide29 generated appreciable amounts of a
C
DOI: 10.1021/jacs.7b01124
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Journal of the American Chemical Society
Communication
dichlorocyclopropane and an amide; formylation of the hindered
amine occurred slowly due to buildup of acid (isonitriles are
produced by subsequent formamide dehydration).30 Our
alternative use of difluorocarbene for isonitrile synthesis
therefore offers some advantages over existing methods,
especially when multiple functional groups are present or the
amine is hindered. This three-step procedure provides an
efficient, stereo- and chemoselective strategy to install the
kalihinol A-ring isocyanohydrin motif.
In summary, we have demonstrated a concise route to access
the kalihinol (bifloran) ICTs via a putative biosynthetic
intermediate, protokalihinol (2a) that we anticipate can be
divergently advanced to the natural series of metabolites. The
synthesis compares favorably to the current best approach to the
kalihinols by Vanderwal: it is longer in total step count (17 vs
12), but higher in yield by one order of magnitude (1.3% vs
0.13%). The higher efficiency derives from solutions to
stereochemical and chemoselectivity problems raised by prior
work, but left unsolved. Some of these solutions include (1) a
method to synthesize the kalihinol stereotetrad using an iterative
cycloaddition of the new building block, “heterodendralene” 5;
(2) an alkoxide-directed isomerization method to access the
thermodynamically disfavored Δ3,4 unsaturated trans-bifloran
skeleton found throughout the diterpene class, and (3) a short,
high-yielding, regio- and stereoselective strategy for installing the
A-ring isocyanohydrin motif, including difluorocarbene-medi-
ated isonitrile synthesis. This short and divergent route from
protokalihinol 2a allowed us to generate several analogs related
to the metabolite series. We are currently using these
compounds to interrogate the antiplasmodial activity and
mechanism(s) of the kalihinol class.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b01124.
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Data for C19H26O4 (CIF)
Detailed experimental procedures, spectral data, chroma-
tograms, and X-ray crystallography (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*rshenvi@scripps.edu
ORCID
(22) Harrod, J. F.; Chalk, A. J. J. Am. Chem. Soc. 1964, 86, 1776.
Ryan A. Shenvi: 0000-0001-8353-6449
Funding
́
(23) Crossley, S. W. M.; Barabe, F.; Shenvi, R. A. J. Am. Chem. Soc.
2014, 136, 16788.
Financial support for this work was provided by the NIH
(GM105766) and the NSF (GRFP to C.A.R.). Additional
support was provided by Eli Lilly, Novartis, Bristol-Myers
Squibb, Amgen, Boehringer-Ingelheim, the Sloan Foundation
and the Baxter Foundation.
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(27) Wood accesses a related amino alcohol (ref 9b) by epoxide-
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reported to reduce isonitriles.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Dr. Milan Gembicky, Dr. Curtis Moore, and Professor
Arnold L. Rheingold for X-ray crystallographic analysis. We
thank Chris Vanderwal (UC Irvine) for open communication
about his ongoing work on the ICTs.
D
DOI: 10.1021/jacs.7b01124
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX