Assembly of Terpenoid Cores by a Simple, Tunable Strategy

Article abstract of DOI:10.1002/anie.201608863

Oxygenated, polycyclic terpenoid natural products have important biological activities. Although total synthesis of such terpenes is widely studied, synthetic strategies that allow for controlled placement of oxygen atoms and other functionality remains a challenge. Herein, we present a simple, scalable, and tunable synthetic strategy to assemble terpenoid-like polycycloalkanes from cycloalkanones, malononitrile, and allylic electrophiles, abundantly available reagent classes.

Full text of DOI:10.1002/anie.201608863

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Communications
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International Edition: DOI: 10.1002/anie.201608863
German Edition: DOI: 10.1002/ange.201608863
Terpene Synthesis
Assembly of Terpenoid Cores by a Simple, Tunable Strategy
Ouidad Lahtigui+, Fabien Emmetiere+, Wei Zhang, Liban Jirmo, Samira Toledo-Roy,
John C. Hershberger, Jocelyn M. Macho, and Alexander J. Grenning*
Dedicated to John A. Porco and Jon A. Tunge
Abstract: Oxygenated, polycyclic terpenoid natural products
have important biological activities. Although total synthesis of
such terpenes is widely studied, synthetic strategies that allow
for controlled placement of oxygen atoms and other function-
ality remains a challenge. Herein, we present a simple, scalable,
and tunable synthetic strategy to assemble terpenoid-like
polycycloalkanes from cycloalkanones, malononitrile, and
allylic electrophiles, abundantly available reagent classes.
and uses abundant reagent classes would allow for countless
terpenoid natural product analogs to be prepared for
biological evaluation.[11]
Our goal is to devise an analog-oriented11 synthetic route
to polycyclic terpenoid frameworks where sole carbon
sources are abundantly available and the reactions utilized
are operationally simple thus allowing for rapid structural
tuning. We have envisaged a sequence utilizing ketone-
derived Knoevenagel adducts 1[12] and allylic electrophiles 2/2’
(Scheme 1).[13] Specifically, deconjugative alkylation[13–15]
T
here are many oxygenated, polycyclic terpenes of medic-
inal value (Figure 1).[1–9] The terpenoid carbon framework
Figure 1. Representative oxygenated terpenoid natural products.
Scheme 1. Tunable terpenoid synthesis from abundant carbon sources.
rigidity and the differences in substitution and oxidation
patterns result in the rich array of biological activity.
Terpenoid synthesis can be achieved with varying degrees of
efficiency depending on the target and the synthetic route
utilized.[10] From a medicinal chemistry perspective, a tunable
synthetic route that relies on operationally simple reactions
between Knoevenagel adduct 1 and allylic electrophile 2
yields 1,5-dienes 3, which can undergo a conjugation-driven
[3,3] Cope rearrangement to g-allyl Knoevenagel adduct
4.[14a,c,d,f,16,17] Repeating the deconjugative alkylation with
allylic electrophile 2’ followed by ring-closing metathesis
(RCM)[17] yields common terpenoid cores 6 where substitu-
tion patterns can be modified by choice of Knoevenagel
adduct 1 and allylic electrophiles 2 and 2’. The chemical
transformations are envisioned to be operationally simple:
[*] O. Lahtigui,[+] F. Emmetiere,[+] W. Zhang, L. Jirmo, S. Toledo-Roy,
J. M. Macho, Prof. A. J. Grenning
Department of Chemistry, University of Florida
PO Box 117200, Gainesville FL 32611-7200 (USA)
E-mail: grenning@ufl.edu
À
The key C C fragment couplings proceed via easily generated
carbanions prepared from Knoevenagel adducts 1 and 4 (g-
À
C H DMSO pKa < 10), the [3,3] rearrangement will proceed
Prof. J. C. Hershberger
Department of Chemistry and Physics, Arkansas State University
Jonesboro AR, 72467 (USA)
under thermal conditions[16,17] and medium-sized ring syn-
thesis by RCM is well precedented using commercial meta-
thesis catalysts.[18]
[+] These authors contributed equally.
The proposed architectures 6 will bear a gem-dinitrile
functional group at the 2-position. The dinitrile is significant
to implementing the proposed route (Scheme 1), but its
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608863.
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incorporation will also facilitate diversification. Quaternary
dinitriles and related functional groups are known to undergo
a variety of reactions including decyanation, hydrolysis and
other nucleophilic addition reactions.[19] From a medicinal
chemistry perspective, a nitrile is sterically small (A value =
0.17), has noted metabolic stability, decreases lipophilicity,
and is isosteric to a halogen.[20]
We first examined the scope of the sequence with respect
to the different reagent classes (Scheme 2). It is well
precedented that alkyl halides can undergo deconjugative
alkylation with Knoevenagel adducts,[14] however we ulti-
mately decided to utilize allylic acetates and carbonates due
to their bench-stability. As representative conditions, 4a was
prepared by Pd-catalyzed deconjugative allylation with 2a
followed by heating at 1508C to promote [3,3] rearrangement.
The sequence could be telescoped in > 95% yield over the 2
steps. 6a was prepared by repeating the deconjugative
allylation (via 5a) followed by ring-closing metathesis. We
prepared a series of bicycloalkanes 6b–6j by varying the
starting materials. As we are interested in unique oxidation
patterns, we utilized oxygenated Knoevenagel adducts 1a–1c,
and 1e to yield 6a–6c, and 6e. Oxygenated allylic electro-
philes translate into unique oxidation patterns about the
cycloheptyl ring (6h, 6j). Other cyclic systems could also be
prepared (6d and 6 f). As a final point, when terminally
substituted allylic reagents are utilized for the initial alkyla-
tion (e.g. 4i and 4j), the allylic transposition results in two
new stereocenters diastereoselectively.
Scheme 3. Synthesis of 8-oxo bicycloalkanes.
We realized that an additional unique oxidation pattern
could be accessed by starting from cyclic, allylated 1,3-diones
7 (Scheme 3). Beginning with 7a, a Knoevenagel condensa-
tion yields g-allyl Knoevenagel adduct 4k, which can be
processed as previously described by deconjugative allylation
then ring-closing metathesis to 8-oxobicycle 6k. In addition to
the 8-keto functional group in the cyclopentenone (6k) or
hexenone (6l–6p), oxygenation and aliphatic substitution can
be varied in the cycloheptyl ring resulting in unique bicyclo-
alkanes (6n–6p). Furthermore, bicycloalkane 6q was pre-
pared on the gram-scale. 6q or related structures may be
useful in the synthesis of pseudoguaianolide natural products.
We next examined cyclic allylic electrophile 2h (Sche-
me 4A). We were pleased to find that deconjugative alkyla-
tion of 1h and the cyclic allyl bromide yielded 8a, which
underwent diastereoselective Cope rearrangement to 8b (two
steps, 70% yield). Repeating the deconjugative allylation
followed by ring-closing metathesis yielded the angularly
fused tricycloalkane (two steps, 29% yield). Excitingly, this is
a rapid entry into a challenging class of natural products
(tigliane and daphnane).
Using a variant of Tungeꢀs decarboxylative allylation[14c,21]
we were able to convert 9a to the 1,5-diene 9b bearing
a tetrasubstituted olefin (Scheme 4B). It should be pointed
out that the decarboxylative method is essential to generating
the more substituted Knoevenagel adductꢀs allyl anion as
standard deprotonation conditions results in deprotonation
from the less substituted g-position (see many of the schemes
above). Excitingly, we were able to realize a [3,3] rearrange-
ment to prepare a quaternary center. In this case, the
conjugation-driving force allows for a favorable allylic trans-
position.[17] Using the standard protocol, 9c was then con-
Scheme 2. Synthesis of uniquely functionalized and oxygenated
bicycloalkanes.
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Scheme 5. Other cyclization reactions in lieu of ring-closing metathe-
sis.
dihydroxylation followed by concomitant intramolecular
nitrile hydrolysis.[19e] The acetal 6j could be selectively
deprotected.[27] Substrate 6k underwent a variety of chemo-
selective transformation in good to excellent yield including
hydrogenation, reductive decyanation,[19a,b] dehydrocyana-
tion,[19g,h] and ketone reduction. Building block 6q also
underwent reductive decyanation[19a,b] diastereoselectively
yielding substrate 15g bearing an ester moiety. Alternatively
ester hydrolysis and decarboxylation provides access to the
mononitrile 15h.[28] 16a was prepared by the standard
procedure on the 10-gram scale (see the Supporting Informa-
tion). The nitrile could be converted to the methyl ester 15i
diastereoselectively under simple conditions. We also exam-
ined conditions for the synthesis of the allyl ester 15j, which
are precedented to undergo a variety of chemical trans-
formation including decarboxylative protonation (deprotec-
tion) and allylation.[21,29,30] Finally, using Dashꢀs simple pro-
tocol for nitrile hydrolysis,[19d] amide 15k and tricyclic imide
15l were prepared.
In conclusion, we have developed an operationally simple
strategy to prepare common terpenoid frameworks from
abundant reagent classes. The strategy is tunable over the
four-step sequence to yield unique functionalization and
oxygenation patterns about the scaffolds. Future directions
are four-fold: a) increase the diversity, scope, and complexity
of the general strategy, b) use the method in the total
synthesis and analog synthesis of specific natural product
targets, c) develop asymmetric versions of the strategy, and
d) collaboratively explore the biological profiles of the
molecules prepared.
Scheme 4. Variations on the strategy.
verted to the bicycloalkane 9d bearing an angular methyl
group.
An additional unique oxygenation pattern can be pre-
pared by utilizing exocyclic 1,3-dione 10a (Scheme 4C). 10a
is prepared from cyclohexanone by Claisen condensation with
cinnamoyl chloride, then methylation (K2CO3, MeI).[22] 10a
was then subjected to standard Knoevenagel condensation
conditions and 10b was isolated. Interestingly, the molecule
contains two ketones but condensation was only observed at
the cyclohexanone. The sequence is then completed as
previously described to yield a 6-oxygenated scaffold 10c.
Thus far, we have described sequences terminated by ring-
closing metathesis. However, other cyclization reactions can
be utilized (Scheme 5). For example, 11a, prepared by
deconjugative a-allylation/[3,3] Cope rearrangement, under-
went intramolecular deconjugative a-allylation to yield the
decalin 11b. Though not initially of interest at the outset of
our studies, decalin natural products,[23a] such as marrubiin,[23b]
may be synthetically viable targets beginning from ketones,
malonic acid derivatives, and bis-allylic reagents. g-Propargyl
Knoevenagel adducts 12a–b were prepared by alkylation then
Knoevenagel condensation from their respective commer-
cially available cyclic b-keto esters. Deconjugative alkylation
(to 13a–b) with furfuryl bromide followed by intramolecular
Diels–Alder furan (IMDAF) cycloaddition[24] yields the
tricyclic frameworks 14a–14b. Although the cycloaddition
yields are modest, this has the potential to be a simple
approach to diterpenoid natural product analogs related to
icetexane[25] and neodolastane[26] families.
For our final studies, we examined functional group
interconversions (Scheme 6). Under Upjohn conditions, the
lactone 15a was isolated as a single diastereomer via
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Scheme 6. Examples of functional group interconversion reactions.
Acknowledgements
We thank the College of Liberal Arts and Sciences and the
Department of Chemistry at the University of Florida for
start-up funds.
Keywords: [3,3] Cope rearrangement · allylic alkylation ·
deconjugative alkylation · Knoevenagel adducts ·
terpene synthesis
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Received: September 10, 2016
Revised: October 24, 2016
Published online: && &&, &&&&
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Communications
Terpene Synthesis
O. Lahtigui, F. Emmetiere, W. Zhang,
L. Jirmo, S. Toledo-Roy, J. C. Hershberger,
J. M. Macho,
A. J. Grenning*
&&&& — &&&&
Assembly of Terpenoid Cores by a Simple,
Tunable Strategy
How to Cope with a synthesis problem:
Total synthesis of oxygenated, polycyclic
terpenes is widely studied, although syn-
thetic strategies that allow for controlled
placement of oxygen atoms and other
functionality remains a challenge. Here
presented is a simple, scalable, and
tunable synthetic strategy to assemble
terpenoid-like polycycloalkanes from
cycloalkanones, malononitrile, and allylic
electrophiles.
6
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