Highly Enantioselective, Organocatalytic, and Scalable Synthesis of a Rare cis,cis-Tricyclic Diterpenoid

Article abstract of DOI:10.1002/chem.202000164

A highly enantioselective, organocatalytic, and scalable synthesis of a very unusual cis-decalin-cis-hydrindane tricyclic diterpenoid system has been achieved. Despite the prevalent pharmacological space that the related trans,trans and trans,cis-systems occupy, there have been no reports of an asymmetric synthesis of the cis,cis systems in the literature until now. We demonstrate the flexibility of our approach not only through access to a diverse range of products, all of which are attained in exceptionally high selectivities, but also by showing their easy conversion to the corresponding trans,cis-system and other derivatives.

Full text of DOI:10.1002/chem.202000164

A Journal of
Accepted Article
Title: Highly Enantioselective, Organocatalytic and Scalable Synthesis
of a rare cis-cis-Tricyclic Diterpenoid
Authors: Alexander John Andre Cobb, Daniel Townsend, Kenneth
Shankland, Alex Weymouth-Wilson, Zofia Komsta, and Tim
Evans
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202000164
Link to VoR: http://dx.doi.org/10.1002/chem.202000164
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COMMUNICATION
Highly Enantioselective, Organocatalytic and Scalable Synthesis
of a rare cis-cis-Tricyclic Diterpenoid
Daniel Townsend,[a] Kenneth Shankland,[b] Alex Weymouth-Wilson,[c] Zofia Komsta,[c] Tim Evans,[c] and
Alexander J. A. Cobb*[a]
Abstract: A highly enantioselective, organocatalytic and scalable
synthesis of very unusual cis-decalin-cis-hydrindane tricyclic
Nevertheless, although in synthetic terms the trans-decalin-trans-
hydrindanes and to lesser extent the trans-decalin-cis-
a
a
diterpenoid system has been achieved. Despite the prevalent
pharmacological space that the related trans-trans and trans-cis-
systems occupy, there have been no reports of an asymmetric
synthesis of the cis-cis systems in the literature until now. We
demonstrate the flexibility of our approach not only through access to
a diverse range of products, all of which are attained in exceptionally
high selectivities, but also by showing their easy conversion to the
corresponding trans-cis-system and other derivatives.
hydrindane systems (as occur in the cardenolides) are well
established, other stereochemical variations are extremely rare.
This is astonishing given that alternative unnatural configurations
offer the potential to explore new pharmacological space.
Specifically, examples of a cis-decalin fused to a cis-hydrindane
are extremely rare; either in steroidal syntheses or otherwise.[6] In
fact, we could find just three examples of this framework in the
literature, none of which were enantioselective or capable of
achieving any significant structural diversity. Pattenden and co-
workers serendipitously accessed the steroidal target containing
this fragment via a radical cascade reaction (Figure 2a).[6a] The
second example by Deslongchamps and co-workers led to three
different isomers of these systems via a transannular Diels-Alder
reaction (Figure 2b).[6b] Finally, Kocór and co-workers
demonstrated a dynamic kinetic resolution a cardenolide-like
precursor to give the corresponding cis-decalin-cis-hydrindane
(Figure 2c).[6c] Our approach to constructing this system was to
use organocatalytic methodology - specifically using the nitro
group as a handle – a functionality we have exploited with some
success in the past.[7] In addition, we felt that not only would this
unique cis-cis tricyclic structure enable the exploration of
undiscovered chemical space, but would also be dynamic enough
as a central fragment to derivatize easily to other terpenoid
structures, owing to the orthogonal reactivity of the functional
group handles on each ring system.
Diterpenes and triterpenes such as steroids are amongst the most
important and well-studied class of biomolecule owing to their
incredibly broad biological properties, their fascinating chemistry,
and their spectrum of therapeutic potential.[1] Although tricyclic
systems whereby there exists a decalin unit fused to a hydrindane
one only occur in a handful of diterpenes discovered thus far –
e.g. verrucosane,[2] neoverrucosane[3] and the stellettins (Figure
1a),[4] this tricyclic arrangement is ubiquitous within almost every
steroidal system known. Referred to as the BCD ring system,
these three rings are the source of most of the structural diversity
within steroidal systems (Figure 1b). It is no surprise, therefore,
that the expedient synthesis of these scaffolds has been the focus
of much study over the last half century.[5]
(a)
Me
Me
Me
H
Me
H
Pattenden et al 6a
O
O
H
CO2Me
H
CO2Me
MeO2C
Bu3SnH
AIBN
MeO2C
H
Me
Me
Verrucosane
Neoverrucosane
H
H
45%
Me
Me
PhSe
Me
H
O
(b)
O
H
H
O
Me
C
Deslongchamps et al 6b
D
H
Me
OH
OH
H
Me
HO
R
A
B
O
O
H
H
H
Me
H
O
O
D
HO
H
Stellettin A
H
H
Typical Steroidal
Framework (R=H)
Me
O
+
Me
O
+
Aphidicolin
H
H
H
H
For cardenolides, R=OH
Figure 1: Example natural product frameworks where a decalin is fused to a
hydrindane
Kocór et al 6c
OAc
OH
Me
OH
Me
OH
O
O
Ac2O,
pyridine
H
H
[a]
D. Townsend, Dr. A. J. A. Cobb
H
H
Department of Chemistry, King’s College London
7 Trinity Street, London SE1 1DB (UK)
E-mail: andre.cobb@kcl.ac.uk
rt, 12h
MeO
MeO
This work (concept)
O
[b]
[c]
Prof. Dr. K. Shankland
School of Chemistry, Food and Pharmacy, University of Reading
Whiteknights, Reading, Berks RG6 6AD (UK)
Dr A. Weymouth-Wilson, Dr Z. Komsta, Dr. T. Evans
Dextra Laboratories Ltd,
Thames Valley Science Park, The Gateway
1 Collegiate Square, Reading RG2 9LH (UK)
O
NO2
R
R
O2N
Asymmetric
Aminocatalysis
( )n
H
O
H
OH
O
O
( )n
1
3
2
Figure 2 : None of the three literature examples of cis-decalin-cis-hydrindane
tricycle syntheses are enantioselective, nor open to significant substrate scope.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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In our design we sought to use asymmetric aminocatalysis to
reaction with exceptional stereocontrol. Interestingly, for all
catalysts IV to VI, the tricyclic product was produced as a single
diastereoisomer, whilst the acyclic intermediate 4, representing
the majority of the product, was obtained in a 1:1 dr, suggesting
epimierization under the reaction conditions. In the case of
catalyst VI, these diastereoisomers were produced as single
enantiomers.
The absolute stereochemistry of tricyclic system 3, showing
the cis-cis arrangement of the system (Figure 3) was established
by reference to tricyclic system 6 (Figure 6), whose absolute
stereochemistry was determined unambiguously by X-ray
crystallography.
encourage
nitrocyclopentadione 2 to cyclohexanone 1. We hoped that the
resulting enolate would undergo an intramolecular
an
enantioselective
Michael
addition
of
desymmetrising aldol reaction with the resulting dione to form the
desired tricyclic system. The latter part of this sequence is of
course known, originating from the works of Hajos-Parrish[8] and
Eder, Sauer and Wiechert.[9] More recently, the excellent work of
both Nagorny[10] and Deslongchamps[11] constructed the cis-
hydrindane, fused to a trans-decalin in a variety of cardenolides
through such a desymmetrising process, giving us hope that this
approach would be valid for our target.
To test the feasibility of our hypothesis, our investigation began
by screening the reaction of 1 and 2 with a range of catalytic
systems, each of which have been utilized to varying degrees of
success in conjugate addition chemistry, along with 3-
nitrobenzoic acid as a co-catalyst additive (Table 1). Surprisingly,
neither the Hayashi-Jørgensen[12] I, nor the MacMillan[13] II
systems catalyzed the process to any degree (Entries 1 and 2).
Bifunctional thiourea systems III were also unsuccessful (Entry
3).[14] To our delight, however, proline IV,proline tetrazole[15] V and
the primary amine cinchona alkaloid[16] VI gave us the product we
desired (Entries 4-6).
Figure 3 : One of the two unique molecules in the asymmetric unit of the crystal
structure of tricyclic adduct 3a. The other molecule differs only in terms of the
rotation of the nitro group (CCDC : 1967524)
Our attention then focused on improving the yield of the reaction,
Although the organocatalyst was unable to push the reaction all
the way to the tricycle, we theorized that if we could optimize the
formation of acyclic intermediate product 4, which was the major
product anyway, we could then force the subsequent cyclization
using alternative conditions (Table 2). It was found that the co-
catalyst used was critical to the success of the reaction, and that
changing the solvent also had a profound effect on yield. The
Whilst the proline catalysts only directed the reaction with
moderate selectivity, we were very pleased to see that the well-
established conjugate addition catalyst VI was able to control the
Table 1. Organocatalyst screen for the Michael-Aldol sequence between
cyclohexenone 1 and nitroalkane 2.[a]
Table 2. Solvent screen for the Michael addition between cyclohexenone 1
and nitroalkane 2.[a]
O
O
H
Me
Me
O
O
catalyst
(20 mol%)
O2N
H
Me
O
O2N
O2N
H
+
O
H
Me
+
O
O
3-nitrobenzoic
acid
(10 mol%)
CH2Cl2, rt, 7d
O2N
H
O
O
Me
O
H
OH
O
O2N
VI (20 mol%)
+
2
1
4a
dr 1:1
co-catalyst
(10 mol%)
various
3a
O
O
2
temp/solvent
1
4a
dr 1:1
OMe
N
O
Me
NH
NH
N
Ph
Entry
Solvent
1 : 2
Co-
catalyst
T,
oC
time,
h
Yield
4
(%)[b]
ee 4
(%)[c]
N
Ph
S
N
N
H
H
OTMS
Ph
I
III
II
F3C
CF3
1
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
PhMe
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
2 : 3
2 : 1
2-FBA
AcOH
p-TSA
3-NBA
3-NBA
3-NBA
3-NBA
3-NBA
3-NBA
3-NBA
3-NBA
23
23
23
23
23
23
23
23
40
23
23
168
168
168
96
0
-
-
-
2
0
OMe
O
N
N
N
N
H
N
3
0
H
OH
HN N
NH2
VI
N
IV
V
4
32
41
59
48
43
55
59
70
92, 96
Entry
Catalyst
Yield 3a
(%)
ee 3a
(%)
Yield 4a
(%)[b]
ee 4a
(%)[c]
5
24
95, 98
6
CHCl3
THF
72
97, 98
1
2
3
4
5
6
I
0
-
-
-
0
-
-
-
7
72
>99, >99
86, 91
II
0
0
8
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
24
III
IV
V
0
0
9
24
96, 96
8
-52
-42
>99
16
18
58
nd
nd
>99,>99
10
11
48
>99, >99
>99, >99
12
12
48
VI
[a] Reactions performed on a 1mmol scale [b] Isolated as a 1:1 mixture of
diastereoisomers as determined by 1H NMR [c] Determined by chiral HPLC
analysis.
[a] Reactions performed on a 1mmol scale [b] Isolated as a mixture of
diastereoisomers [c] Determined by chiral HPLC analysis
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most significant effect on selectivity, however, came from the
stoichiometry of the process, with two equivalents of cyclohexene
giving Michael adduct 4 in exceptional enantioselectivity.
cycloheptene in place of partner 1 gave the single addition
product 4k – again in 1:1 dr and excellent enantioselectivities for
both diastereoiomers – but unfortunately did not cyclize to the
tricyclic system under our current conditions.
With an excellent synthesis of tricyclic precursor 4 in hand, we
then went on to examine conditions to enable the cyclization.
Whilst both Brønsted acid and base conditions led to substrate
degradation, primarily through a retro-Michael pathway,[17] we
were delighted to discover that a screen of Lewis Acids resulted
in the formation of the desired adduct, observed previously (Table
3). The initial catalyst screen resulted in the observation of
elimination product 5, but a screen of solvent, temperature and
stoichiometry led to us finding the optimal conditions for the
exclusive formation of the cis-decalin-cis-hydrindane 3a in good
yield.
Table 4. Substrate scope for the synthesis of cis-cis-tricyclic systems.[a]
NO2
R
H
O
1.
VI (20 mol%)
3-nitrobenzoic acid (10 mol%)
CH2Cl2, rt, 72 h
O2N
O
( )n
R
O
O
+
H
OH
2. BF3.OEt2, MeCN, rt, various h
( )n
1
2
3
O
O
O
Me
O2N
O2N
O2N
73%
74%
70%
60%, 45 h
>19:1 dr
98% ee
H
H
H
H
73%, 16 h
>19:1 dr
98% ee
80%, 5 h
>19:1 dr
>99% ee
OH
O
H
OH
O
H
OH
O
3c
3b
Table 3. Lewis acid screen for the Aldol cyclization of 4a.[a]
3a
O
H
Me
O
O
Me
O2N
H
Me
O
O2N
O2N
O
Lewis Acid
CH2Cl2, rt
O
H
O
O2N
72%
O2N
O2N
+
O
O
H
82%
75%
57%, 16 h
>19:1 dr
98% ee
65%, 7 h
>19:1 dr
>99% ee
H
OH
O
H
H
H
61%, 16 h
>19:1 dr
>99% ee
H
OH
O
H
OH
O
4a
dr 1:1
H
OH
O
3a
5
3d
3e
3f
Entry
Lewis Acid (eqs)
SnCl4 (1.2)
Solvent
T, h
72
24
72
72
96
96
5
Yield 3, %
Yield 5, %
Cl
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
0
0
S
O
O
O
O2N
O2N
O2N
69%
71%
BF3.OEt2 (1.2)
TiCl4 (1.2)
33
0
17
0
75%
H
H
H
59%, 16 h
>19:1 dr
>99% ee
44%, 16 h
>19:1 dr
>99% ee
62%, 16 h
>19:1 dr
>99% ee
H
OH
O
H
OH
O
H
OH
O
3h
3i
3g
AlCl3 (1.2)
8
6
O
O
Me
Me
BF3.OEt2 (1.2)
BF3.OEt2 (1.2)
BF3.OEt2 (2)
BF3.OEt2 (3)
17
53
79
73
25
4
O2N
O2N
H
81%
H
65%, 60 h
>19:1 dr
>99% ee
41%
1:1 dr
99% ee (both)
MeCN
MeCN
MeCN
O
O
H
OH
O
0
3j
4k
5
0
[a] Reactions scales vary depending on substrate, see SI for details. Ee
determined by chiral HPLC analysis.
[a] Reactions performed on a 0.7 mmol scale.
With our optimized conditions in hand, we examined the
generality of this process using a range of different substrates as
shown in Table 4. We were very pleased to observe that the
selectivities were excellent for all substrates, showing only a
single diastereoisomer and >99% enantiomeric excess for most.
Remarkably, there appear to be no general methodologies to
allow for variation in the substituent at the hydrindane bridgehead
position of any terpene or steroidal target. Indeed, the only
departure from methyl at that position appear to be the
progestone oral contraceptives, which have ethyl or
hydroxymethyl variations at that position. Our methodology
addresses this paucity and thus opens the door to greater
pharmacological space. We have successfully introduced larger
substituents such as isopropyl (3b) and 1-napthyl (3h) in good
yield and excellent selectivity, as well as thiophene (3g), benzyl
(3e) and para-chlorbenzyl (3i) which are all capable of further
derivation. Pleasingly, we also used our methodology to
successfully access the D-homosteroid-like system (3j) – again in
excellent diastereo- and enantioselectivity.[21] Use of
(b)
(a)
Nu
R
d-
O
O
O
R
N
N
N
O
H
H
d+
Ar
N
H
N
H
Ar
H
R
O
O
Figure 4 : Although the stereoselective outcome of our process fits the
model of Melchiorre (Figure 4a, ref 17), our stoichiometry and co-catalyst
are slightly different. (b) Bifunctional activation of the enone and nucleophile
is also a possibility (ref 16).
Although the origin of stereochemistry in the Michael addition
fits the model proposed by Melchiorre and co-workers (Figure
4a),[17] which describes optimal conditions of 2:1 co-catalyst to
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COMMUNICATION
amine catalyst, we found that better yields were obtained in a
1:2 ratio (Table 1, Entry 11). We therefore do not discount the
possibility of a bifunctional effect of the catalyst on the
enantioselective outcome (Figure 4b), as has been described
for other related processes,[16] although further study is
required. Under the reaction conditions, the -proton of the
nitro group epimerizes, giving a 1:1 mix of diastereoisomers as
is evident in Table 2. This epimerization also occurs under the
subsequent Lewis acid conditions, which is a critical point
because we theorize that only one of these epimers is able to
cyclize under these conditions. This is demonstrated in Figure
5, where both epimers are shown in the conformations they are
required to adopt in order to cyclize. Our main assumption is
that in both, the large nitro group must adopt an equatorial-like
position in the transition state. For the preferred (R)-epimer
(Figure 5a), this sets up the stereoelectronic requirements for
favourable axial attack. As one might expect, this also sets up
the preference for the reacting group to approach from the face
on which it resides, giving the observed cis-geometry. In the
case of the (S)-epimer, the nitro group is again assumed to
prefer an equatorial-like position (Figure 5b), but this time in
order for the corresponding nitronate to react, it needs to come
in from the anti-face. This is very unfavorable owing to the
resulting steric demands where there is a steric clash between
the -hydrogen and the reacting carbonyl. Thus, as the
substrate epimerizes, and more of the favored epimer is
generated, the reaction is driven towards the cyclized product.
imidazole leads to C-6 epimer 7 where the nitro group is now in a
preferred, thermodynamically favourable equatorial position.
Finally, we have also demonstrated that the nitro-group can be
removed altogether via a radical denitration to obtain tricycle 8,
and that it is possible to discriminate between the two ketones of
the product by selective acetal protection of the cyclohexanone.
O
O
O
Me
Me
Me
O2N
O2N
HCl(g)
CH2Cl2
O2N
Imidazole
CH2Cl2, rt
H
H
H
>99%
55%
H
OH
O
H
OH
O
H
OH
O
7
3a
6
Bu3SnH, PhSiH3
AIBN, PhMe
65%
O
Me
O
Me
PPTS
CH(OMe)3
MeOH
H
H
H
OH
OMe
OMe
H
OH
O
65%
9
8
Scheme 1. Epimerization of tricycle 3a and subsequent transformations.
(a)
Nitro group
preference for equatorial
position sets up reactive conformation
favoured axial attack
Stereoelectronically
BF3
O
H
O
O
Me
O
O2N
H
O2N
H
O2N
Me
OH
H
H
Me
H
OH
O
OH
O
cis-decalin-cis-hydrindane
Figure
6 : X-Ray crystal structure of the epimerized trans-decalin-cis
hydrindane system 6, showing that the nitro group is now axial (CCDC:
1967525)
vs epimer
(b)
Less favourable
non-axial trajectory
H
O
O
H
Me
O2N
H
O2N
OH
O2N
H
O
In conclusion, we have developed the first enantioselective
synthesis of a cis-decalin-cis-hydrindane tricycle. Adducts were
OH
O
H
O
Me
H
Me
OH
O
trans-decalin-cis-hydrindane
Steric clash
between axial
proton and
carbonyl
obtained in exceptionally good selectivities and
a model
NOT observed
rationalizing this is proposed. It was also shown that we could
access a diverse range of structural configurations, such as the
C9-C10 unsaturated system 5 and the C10-epimer 6. We also
showed it was possible to epimerize the nitro group effectively, as
well as remove it altogether. Future work will focus on examining
the biological activity of these systems and their derivatives as
well as utilizing them towards the synthesis of cardenolide
analogues.
Figure 5 : The requirement for the nitro-functionality to reside in a pseudo-
equatorial position means that only one of the two epimers is set up to cyclize.
Since the starting material epimerises under the reaction conditions, this means
that the overall reaction is driven toward the formation of the preferred epimer
and thus the cyclized product. (a) The reactive epimer leads to the cis-cis-
tricycle. (b) The other epimer does not have the steric or stereoelectronic
requirements to cyclize.
In order to demonstrate that it was also possible to access the
more common trans-decalin-cis-hydrindane from these systems,
we subjected tricyclic system 3a to HCl gas in dichloromethane
and pleasingly obtained the corresponding C-10 epimer 6
(Scheme 1). Interestingly, this leads to the nitro-group going from
an equatorial position to an axial one (Figure 6), which is
demonstrated by the fact that treatment of compound 6 with
Acknowledgements
We wish to thank Dextra and King’s College London for financial
support, and the Chemical Analysis Facility (CAF) at the
University of Reading for provision of X-ray crystallographic
facilities.
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10.1002/chem.202000164
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COMMUNICATION
Nagorny, Org. Lett. 2018, 20, 154-157; c) W. Kaplan, H. R. Khatri, P.
Nagorny, J. Am. Chem. Soc. 2016, 138, 7194-7198; d) N. R. Cichowicz,
W. Kaplan, Y. Khomutnyk, B. Bhattarai, Z. Sun, P. Nagorny, J. Am. Chem.
Soc. 2015, 137, 14341-14348.
Keywords: terpenes • asymmetric synthesis • organocatalysis •
• cis-hydrindane • cis-decalin
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10.1002/chem.202000164
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Daniel Townsend, Kenneth Shankland,
Alex Weymouth-Wilson, Zofia Komsta,
Tim Evans, and Alexander J. A. Cobb*
O
O
R
R
O2N
n
Im
H
+
Page No. – Page No.
O
BF3.OEt2
O
H
OH
O
O2N
Highly Enantioselective,
Organocatalytic and Scalable
Synthesis of a rare cis-cis-Tricyclic
Diterpenoid
cis-hydrindane-cis-decalin
Text for Table of Contents
10 examples
All >19:1 dr
98 - >99% ee
R=Me, n=1
The highly enantioselective synthesis of a tricyclic terpenoid system is described with
a remarkable cis-cis-configuration of the fused decalin and hydrindane systems. This
intriguing selectivity is thought to be due to the nitro-group dictating the transition
state of the cyclization adopted.
This article is protected by copyright. All rights reserved.