Expedient and Diastereodivergent Assembly of Terpenoid Decalin Subunits having Quaternary Stereocenters through Organocatalytic Robinson Annulation of Nazarov Reagent

Article abstract of DOI:10.1002/chem.201604541

We report an expedient approach to highly functionalized cis- and trans-decalines that could function as key structural subunits toward the synthesis of various classes of terpenoids. Key to the strategy is an organocatalyzed Robinson annulation reaction

Full text of DOI:10.1002/chem.201604541

DOI: 10.1002/chem.201604541
Full Paper
&
Asymmetric Synthesis
Expedient and Diastereodivergent Assembly of Terpenoid Decalin
Subunits having Quaternary Stereocenters through
Organocatalytic Robinson Annulation of Nazarov Reagent
Barbara Berkes,[a] Kristꢀf Ozsvꢁth,[a] Laura Molnꢁr,[a] Tamꢁs Gꢁti,[b] Tamꢁs Holczbauer,[a]
Gyçrgy Kardos,[a] and Tibor Soꢀs*[a]
Dedicated to the memory of Professor Csaba Szꢀntay
Abstract: We report an expedient approach to highly func-
tionalized cis- and trans-decalines that could function as key
structural subunits toward the synthesis of various classes of
terpenoids. Key to the strategy is an organocatalyzed Robin-
son annulation reaction of the Nazarov reagent that affords
chiral enone building blocks with high enantioselectivities.
The quaternary carbon stereogenic center can direct the
subsequent reactions and allow the rapid and diastereocon-
vergent assembly of complex decalines with contiguous ste-
reocenters.
Introduction
terpenoids resulted in the frequent application of three key
building blocks, the Hagemann’s ester,[7] the Wieland–Miescher
ketone[8] and the Hajos–Parrish ketone,[9] which have clear ste-
reochemical and operational advantages in quaternary carbon
stereocenter construction. These venerable compounds have
enabled the synthesis of many target compounds of previously
perceived impractical complexity. Consequently, further expan-
sion of the repository of easily available intermediates, having
even more elaborate structure, is of the utmost importance to
underpin streamlined synthetic ventures in terpenoids’ chemis-
try and also in drug development.
Despite their evident potential, terpenoids play only a minor
role in contemporary pharmaceutical developments because
of their structural complexity, limited chemical tractability and
availability.[1] Their complex molecular architectures often dis-
courage medicinal chemists to select terpenoids or their struc-
tural units as an attractive starting point for drug discovery
programs. As a result, one of the focuses of current organic
synthesis is the development of streamlined synthetic path-
ways that can render chemical synthesis as an enabling tool
for exploring and leveraging the pharmaceutical potential of
terpenoids or their fragments.[2–4] Along these lines, we report
a highly expedient, enantio- and diastereoselective synthesis of
decalines bearing quaternary stereogenic centers, which are
key substructural motifs found in many terpenoids. This ac-
complishment also serves as a proof-of-principle for the ena-
bling use of cyclohexenones 1 for diastereodivergent synthetic
processes.
We were intrigued to develop methods using easily accessi-
ble building blocks that might confer synthetic practicality in
total synthesis of several terpenoids. Accordingly, we sought to
identify synthetically exploitable structural subunits with qua-
ternary carbon stereocenters in a broad variety of sesqui- and
diterpenoids, including drimanes, labdanes, clerodanes, and
kauranes. After deliberating over the list of biologically relevant
targets, highly oxygenated cis- or trans-decalines I and II with
contiguous stereocenters and suitable level of functionalities
were selected (Figure 1).[10] Accordingly, the goal that served to
focus and unify our synthetic efforts was to achieve a highly
expedient and stereoselective synthesis of these chiral building
blocks.
De novo synthesis of terpenoids is a well-established disci-
pline; however, apart from a few skeletal arrangements, their
synthesis remains a highly complex and challenging undertak-
ing.[5] The prominent element of these challenges is the stereo-
selective construction of quaternary carbon stereocenters,[6] of
which terpenoids are richly endowed. These very features of
The above appeal had to be translated into expedient syn-
thetic pathways; therefore, it was envisaged that decaline I
and II structures could be assembled in a concise and diver-
gent manner starting from cyclohexenones 1. Considering that
these chiral starting materials should have enhanced (e.g.,
double activated olefinic bond) and versatile reactivities and
that the quaternary carbon stereocenter might govern the out-
come of the subsequent transformations, we reasoned that its
Diels–Alder and iso-Diels–Alder[11] reactions could be used to
form I and II in a few steps. These skeleton-forming reactions
[a] B. Berkes, K. Ozsvꢀth, L. Molnꢀr, T. Holczbauer, G. Kardos, T. Soꢁs
Institute of Organic Chemistry, Hungarian Academy of Sciences
1519 Budapest, P.O. Box 286 (Hungary)
E-mail: soos.tibor@ttk.mta.hu
[b] T. Gꢀti
Servier Research Institute of Medicinal Chemistry
Zꢀhony Street 7, 1031 Budapest (Hungary)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201604541.
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Figure 2. Tautomerization of bifunctional reagents 2 and 3 and their envis-
aged cascade reaction to afford 1.
egy was confirmed because the reaction afforded the desired
product (1a) when triethylamine was applied as a catalyst
(Table 1, entry 1). We then undertook a systematic investiga-
tion of bifunctional thiourea and squaramide organocatalysts,
because of their commanding performance in asymmetric Mi-
chael addition reactions. The quinine-based thiourea catalyst
4a[17a,18] and the analogous Takemoto’s catalyst[19] 4b showed
moderate performance, furnishing product 1a with modest
yields and enantioselectivities (entries 2 and 3). However, varia-
tion of the thiourea moiety of the catalyst with more acidic
double hydrogen-bond donor squaramide[20] revealed that it
had a large influence on the enantioselectivity, with catalysts
5a–c affording significantly improved enantioselectivities (en-
tries 4–6). This gave us impetus to uncover structural features
of bifunctional squaramide organocatalysts that could signifi-
cantly affect the enantiomeric excess of the model reaction.
We were intrigued by the observation that introduction of
an additional chiral element adjacent to the squaramide
moiety in catalyst 5d led to a higher ee value (Table 1, entry 6
vs. 7); however, use of the diastereomeric catalyst 5e (entry 7
vs. 8) resulted in only a slight improvement. Accordingly, the
configuration of the benzylic position played a negligible role
in the performance of these catalysts. Therefore, we presumed
that the steric hindrance might be more important for the cat-
alyst’s efficiency enhancement. Thus, sterically more crowded
systems were probed by utilizing naphthalenyl and binaphtha-
lenyl derivatives 5 f and 5g. These structural tunings led to no-
table improvements, with the sterically most crowded catalyst
5g displaying a superior efficiency in the model reaction
(entry 10). At this stage, we also noted that running the reac-
tion at ambient temperature and the use of 1,4-dioxane as sol-
vent was essential for realization of the desired enantioinduc-
tion.[21]
Figure 1. Selected examples of terpenoids having a decaline core and envi-
sioned building blocks.
were devised to be able to simultaneously set up the function-
ality needed for a broad range of terpenoid targets, including
also the requisite array of stereochemistry.
Results and Discussion
Whereas several of these synthetic transformations involved
chemistry previously reported in connection with related un-
dertakings,[11,12] the envisioned cyclohexenone 1 has not been
forthcoming. Accordingly, as a first foray, we initiated the de-
velopment of a mild, high yielding and scalable process that
could deliver chiral cyclohexenone building blocks 1 with
a quaternary carbon stereocenter. As outlined in Figure 2, we
envisioned that our goal could be achieve in an organocatalyt-
ic Robinson-type annulation between Nazarov reagent 2 and
prochiral 2-formylester 3. Despite this apparently simple and
direct approach, several synthetic challenges lay ahead. Al-
though there have been ample precedents for the organocata-
lytic application of Nazarov reagent 2,[13] none of those reac-
tions were Robinson-type annulations.[14] In those transforma-
tions, the bifunctional Nazarov reagent 2 functioned as
a nucleophilic reagent because it sequentially acted as a Mi-
chael donor and then a Michael acceptor. An additional techni-
cal problem is that the Nazarov reagent 2 has a restricted use
in some annulations because of its instability.[15] Nevertheless,
with the insight gained from bifunctional organocatalysis,[16,17]
we questioned whether it would still be possible to reverse
the order of reactivity by employing a more CÀH acidic nucleo-
phile as a substrate.
Having established effective conditions for the model reac-
tion, the scope of this organocatalytic Robinson annulation re-
action was then explored. As revealed in Table 2, the reaction
was amenable to changes in steric features of the reacting
partners. Nazarov reagents 2a–c, bearing different alkyl sub-
stituents on the ester group, underwent clean reactions, af-
fording the desired cyclized products 1a–c. Moving from
methyl (2b) to tert-butyl (2c) esters resulted in slightly higher
yields and enhanced levels of enantioenrichment. Subsequent-
ly, the scope of the reaction with respect to the 2-methyl-3-ox-
We chose the annulation of the Nazarov reagent 2a with
2-methyl-3-oxopropanoate 3a shown in Table 1 as a model re-
action to identify an efficient organocatalyst and appropriate
reaction conditions. First, the viability of the annulation strat-
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Table 1. Robinson annulation of Nazarov reagent (2a) with prochiral 2-
formyl ester 3a promoted by bifunctional organocatalysts.[a]
Table 2. Scope of the organocatalytic Robinson annulation of Nazarov re-
agent.[a]
Entry
Catalyst
Conv. [%][b]
ee [%][c]
1[d]
2
3
4
5
6
TEA
4a
4b
5a
5b
5c
74 (71)
47
65
72
62
–
61
À66[e]
79
77
83
73
7
8
9
5d
5e
5 f
71 (68)
68
64
85
86
89
10
5g
78 (73)
91
[a] Unless otherwise specified, all reactions were conducted with the Naz-
arov reagent (2a; 0.4 mmol), ethyl 2-methyl-3-oxopropanoate (3a;
1.1 equiv, 0.44 mmol) and catalyst (0.008 mmol, 2 mol%) in 1,4-dioxane
(0.4 mL) at room temperature for 48 h. [b] Conversion was determined by
GC-MS spectroscopic analysis of the crude mixture with hexadecane as
internal standard; the data in parentheses are the yields of isolated prod-
ucts after column chromatography. [c] Determined by HPLC analysis
using a chiral stationary phase (Daicel Chiralpak IC column). [d] 20 mol%
TEA was used as a catalyst. [e] Opposite enantiomer. TEA=triethylamine.
[a] Unless otherwise noted, the reactions were performed with 2a–
e (3 mmol), 3a–h (3.3 mmol), and catalyst 5g (0.06 mmol) in 1,4-dioxane
(3 mL) at 258C for 3 days. The yields of isolated products were deter-
mined after column chromatography on silica gel. The ee and the d.r.
were determined by HPLC analysis on a chiral stationary phase. [b] Reac-
tion time was 2 days. [c] The reaction was carried out on a 6 mmol scale
for 2 days. [d] The reaction was carried out on a 60 mmol scale for 4 days.
[e] Reaction time was 4 days. [f] Reaction time was 7 days. [g] The reac-
tion was carried out on a 30 mmol scale for 4 days. [h] 0.12 mmol of cata-
lyst 5g in 1,4-dioxane (1.5 mL) and THF (1.5 mL) was stirred for 7 days.
opropanoate was investigated. This survey revealed an exactly
opposite trend across the surveyed small, medium, and large
ester variants; the sterically more bulky tert-butyl ester (3c)
substantially retarded the stereoselectivity of the process (1e
vs. 1a, 1d and 1 f). Next, variation of the a-substituents of the
prochiral 3-oxopropanoate was studied. By using linear or
branched alkyl substituents, such as isopropyl (3d), cyclohexyl
(3e) or allyl (3g, 3h), the reaction performed well. Efforts to
extend the scope of the reaction with respect to the nucleo-
philic partner toward a-aryl substituted derivatives (3 f) were
also probed; however, both the yield of 1i and the enantiose-
lectivity significantly decreased.
hexenones 1m–o were obtained with high enantio- and dia-
stereoselectivity, albeit in low yield.[22]
To showcase the scalability and practicality of this Robinson
annulation methodology, we performed reactions with select-
ed substrates on a larger scale (30–60 mmol). Pleasingly, the
desired enones 1a, 1d, and 1l, bearing the quaternary carbon
stereocenter, were obtained with high conversions without al-
tering enantioselectivities (Table 2).
Having established the methodology to construct cyclohexe-
nones with an allylic stereogenic quaternary carbon, we
wished to demonstrate their potential and versatility for the
targeted synthesis of bicyclic structures I and II. Along these
lines, we examined a range of Diels–Alder and iso-Diels–Alder
strategies to reach possible diastereomers of the envisioned
cis- and trans-fused decaline fragment.
The formation of the cyclohexenone products 1a–i has
been limited to the use of the unsubstituted Nazarov reagents
2a–c. Nevertheless, we wondered whether b-substituted Naza-
rov reagents could be suitable partners in this organocascade
reaction. Since the b-alkyl substituent should deactivate the
Nazarov reagent for both electronic and steric reasons, the
outcome of this reaction was questionable. Pleasingly, when
3a,b was reacted with methyl substituted Nazarov reagent
2d,e in the presence of 4 mol% catalyst 5g, the desired cyclo-
Initially, we explored the feasibility of using the Diels–Alder
route to transform cyclohexenone 1d into cis-decalines bear-
ing an additional quaternary stereogenic carbon center at the
ring junction (Scheme 1). Under achiral Lewis acid promotion,
isoprene (6) and silyloxy-butadiene 7 underwent ready reac-
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tions to afford cis-decalines 8a and 9a,b products with com-
plete regioselectivity and, most importantly, high p-facial dia-
streoselectivity. Accordingly, the incorporation of a quaternary
stereogenic center in the allylic position of dienophile 1d ex-
erted directing influence in a non-chelation pathway. Given
that the preferred approach of the investigated dienes was syn
to the more bulky ester group, it seems that the electronic
control could override the steric effect in this reaction.[23] It is
also revealed that there was no exo/endo selectivity when sily-
loxy-butadiene 7 reacted; however, these diastereomers could
be separated by chromatography.
Hosomi–Sakurai allylation[25] followed by alkylation of the resul-
tant 12 enol with allyl bromide. Pleasingly, the Hosomi–Sakurai
reaction proceeded with high diastereoselectivity, and the
same sense of diastereoselectivity was observed as in Diels–
Alder reactions. Attempts to directly C-alkylate enol 12 failed,
which might be a consequence of 1,3-axial interaction with the
existing stereogenic quaternary center. However, a stepwise
O-allylation reaction followed by a thermal Claisen rearrange-
ment afforded the desired 14 diallyl compound, albeit as an in-
separable 1:1 stereoisomer. The subsequent ring-closing meta-
thesis proceeded in high yields and afforded chromatographi-
cally separable 15a,b cis- and trans-decalines.
Scheme 1. Diastereodivergent construction of cis-decalines. Reagents and
conditions: a) ZnCl2 (2 equiv), Et2O, 0–258C, 71% yield; b) ZnCl2 (2 equiv),
Et2O, 0–258C; c) TFA, CH2Cl2, 258C, 88% yield over two steps; d) Cs2CO3
(1.5 equiv), EtOAc, 258C, 68% yield; e) pTsOH, toluene, 808C, 88%;
pTsOH=p-Toluenesulfonic acid.
Scheme 2. Synthetic routes toward trans-decalines. Reagents and condi-
tions: a) allyl trimethylsilane, ZnCl2 (1 equiv), CH2Cl2, 0–258C, 87% yield;
b) allyl bromide, Cs2CO3, DMF, 0–258C, 82%; c) neat, 1508C, 24 h; d) Hovey-
da–Grubbs Catalyst 2nd generation (5 mol%), CH2Cl2, 258C, 93% over two
steps; e) allyl trimethylsilane, ZnCl2 (1 equiv), CH2Cl2, 0–258C, 91% yield;
f) Hoveyda–Grubbs Catalyst 2nd generation (5 mol%), CH2Cl2, 258C, 72%
yield.
An “anionic Diels–Alder reaction”, the Deslongchamps annu-
lation[24] was then probed. As an emerging methodology for
the synthesis of cis-decalines, the method fuses the cesium
enolate of the Nazarov reagents with highly reactive cyclohex-
enone-type dienophiles. Pleasingly, the Nazarov reagent 2 f un-
derwent Cs2CO3-promoted annulation with cyclohexenone 1d
to generate cis-decalines 10a,b with reversed p-facial diaste-
reoselectivity. This type of annulation thus establishes a prefer-
ence for trans addition with the carboxylic substituents of 1d
in competition with a methyl group. The reversal of facial dia-
stereoselectivity encountered is unexpected, but hold signifi-
cant synthetic promise: the Diels–Alder and the Deslong-
champs annulation seem to be complementary approaches for
the controlled construction of contiguous stereocenters in the
targeted cis-decalines. As exemplified, three out of the four
possible stereoisomers of cis-decalines were prepared in a con-
cise manner (9a, 9b, and 11 in Scheme 1).
Having thus developed diastereodivergent methodologies
from 1d for the synthesis of cis-decalines, we then sought to
establish concise routes to trans-decalines II from the same
chiral precursor. To this end, we considered applying the iso-
Diels–Alder sequence developed by Danishefsky.[11] As outlined
in Scheme 2, this route was realized in a four-step sequence.
The requisite metathesis precursor was constructed through
Being cognizant of the diastereoselectivity of the Hosomi–
Sakurai reaction of 1d, we presumed that allyl substituted cy-
clohexanone 1l would also be amenable to the construction
of trans-decaline. Thus, chiral enone 1l was subjected to
Hosomi–Sakurai allylation by using achiral ZnCl2 catalyst.
Again, high diastereoselectivity was observed in this allylation
reaction (d.r. 14:1). The resultant diallyl compound 16 easily
underwent ring-closing olefin metathesis to deliver the desired
trans-decaline 17 in high yield.
Conclusions
An organocatalytic Robinson-type annulation of Nazarov re-
agent was realized that afforded cyclohexenones bearing
a quaternary carbon stereocenter. These chiral products have
several useful features: 1) their synthesis is enantioselective,
diastereoselective, and scalable, and 2) the stereogenic quater-
nary center of the scaffold allows exquisite diastereochemical
control in the course of subsequent synthetic elaborations
toward cis- and trans-decalines in multigram scale with contig-
uous quaternary and tertiary stereocenters. These rigid, poly-
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Acknowledgements
We gratefully acknowledge the generous support from Servier
Research Institute of Medicinal Chemistry and the financial
support from the National Research, Development and Innova-
tion Office (K-116150).
Keywords: asymmetric synthesis · diastereoselectivity · fused-
ring systems · organocatalysis · terpenoids
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Published online on && &&, 0000
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FULL PAPER
Reaching the start: An expedient ap-
proach to highly functionalized cis- and
trans-decalines has been developed (see
scheme). Key to the strategy is an orga-
nocatalyzed Robinson annulation reac-
tion of the Nazarov reagent to afford
chiral enone building blocks with high
enantioselectivities. The quaternary
carbon stereogenic center can direct
the subsequent reactions and allow the
rapid assembly of complex decalines in
a diastereodivergent manner.
&
Asymmetric Synthesis
B. Berkes, K. Ozsvꢀth, L. Molnꢀr, T. Gꢀti,
T. Holczbauer, G. Kardos, T. Soꢁs*
&& – &&
Expedient and Diastereodivergent
Assembly of Terpenoid Decalin
Subunits having Quaternary
Stereocenters through Organocatalytic
Robinson Annulation of Nazarov
Reagent
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
7
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ