Diels–Alder reaction between 1,3,3-trisubstituted-2-vinylcyclohexenes and quinones under exceptionally mild conditions: a concise entry to the cassane-type furanoditerpenoid skeleton

Article abstract of DOI:10.1016/j.tetlet.2016.06.133

Extremely mild (no metal Lewis acid catalyst, ambient temperature) and experimentally simple (no high-pressure apparatus needed) conditions were established for the Diels–Alder reaction between sterically demanding 1,3,3-trisubstituted-2-vinylcyclohexenes and non-symmetrically substituted quinones. This allowed for the successful implementation of a highly convergent strategy to the cassane-type furanoditerpenoid skeleton.

Full text of DOI:10.1016/j.tetlet.2016.06.133

Accepted Manuscript
Diels–Alder reaction between 1,3,3-trisubstituted-2-vinylcyclohexenes and qui-
nones under exceptionally mild conditions: A concise entry to the cassane-type
furanoditerpenoid skeleton
Eirini Tzouma, Ioannis Mavridis, Veroniki P. Vidali, Emmanuel N. Pitsinos
PII:
S0040-4039(16)30819-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.133
TETL 47860
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 May 2016
25 June 2016
30 June 2016
Please cite this article as: Tzouma, E., Mavridis, I., Vidali, V.P., Pitsinos, E.N., Diels–Alder reaction between 1,3,3-
trisubstituted-2-vinylcyclohexenes and quinones under exceptionally mild conditions: A concise entry to the
cassane-type furanoditerpenoid skeleton, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.133
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Graphical Abstract
Diels–Alder reaction between 1,3,3-trisubstituted-
2-vinylcyclohexenes and quinones under exceptionally
Leave this area blank for abstract info.
mild conditions: A concise entry to the cassane-type furanoditerpenoid skeleton
Eirini Tzouma, Ioannis Mavridis, Veroniki P. Vidali, Emmanuel N. Pitsinos
O
O
O
O
O
O
O
O
ambient pressure
H
no metal Lewis acid
H
+
O
:
+
O
OH
F3C CF3
H
H
rt, 64%
7
1
R
R
R
vs.
Cassane-Type
Furanoditerpenes
(e.g. Taepeenin D)
ZnBr2, CH2Cl2
12 kbar
"standard conditions"

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Diels–Alder reaction between 1,3,3-trisubstituted-2-vinylcyclohexenes and
quinones under exceptionally mild conditions: A concise entry to the cassane-
type furanoditerpenoid skeleton
Eirini Tzoumaa,b , Ioannis Mavridisa , Veroniki P. Vidalia , Emmanuel N. Pitsinosa, ∗
aNCSR “Demokritos”, I.N.N., P.O. Box 60228, GR-153 10 Ag. Paraskevi, Athens, Greece.
bNational & Kapodistrian University of Athens, Department of Pharmacy, GR-157 71 Zografou, Athens, Greece.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Extremely mild (no metal Lewis acid catalyst, ambient temperature) and experimentally simple
(no high-pressure apparatus needed) conditions were established for the Diels–Alder reaction
between sterically demanding 1,3,3-trisubstituted-2-vinylcyclohexenes and non-symmetrically
substituted quinones. This allowed for the successful implementation of a highly convergent
strategy to the cassane-type furanoditerpenoid skeleton.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
cycloaddition
organocatalysis
high-pressure reaction
enyne metathesis
Taepeenin D
———
∗Corresponding author. Tel.: +30-210-650-3789; E-mail address: e.pitsinos@inn.demokritos.gr

2
Tetrahedron
Introduction
The above strategy outlines a potentially highly concise and
convergent route towards taepeenin D and related cassane-type
furanoditerpenes. In parallel, its investigation offers an
opportunity to address known challenges associated with two
powerful synthetic transformations: a) the ring-closing re-
arrangement of 6,6-disubstituted-1-en-7-ynes, and b) the
intermolecular DA reaction of hindered 1,3,3-trisubstituted-2-
vinylcyclohexenes.
Numerous cassane-type furano-diterpenes and/or related
butenolides have been identified as constituents of extracts
derived from traditional medicinal plants belonging to the
Leguminosae (or Fabaceae) family.1,2 Representative examples
include sucutiniranes A–C (Figure 1, 1–3),2a cordylanes A–B (4–
5),2b caesanine A (6)2c and caesaljaponins (7–8).2d
O
O
O
Concerning the former transformation, the outcome of metal-
catalyzed skeletal reorganization of 1,7-enynes is difficult to
predict7a,b and 6,6-disubstituted enynes such as 13 are reported to
be poor substrates for Ru-based carbene catalysts.7c-f
O
R
H
H
H
H
H
H
R1
OAc
With regards to the DA transformation, 1,3,3-trisubstituted-2-
vinylcyclohexenes are sterically demanding dienes that do not
readily participate in intermolecular DA reactions.9 In particular,
it should be stressed that, in sharp contrast to the [4+2]
H
OAc
R2
OAc
4 R1 = OAc, R2 = OH
5 R1 = OH, R2 = OAc
1 R = OH
3
2 R = H
16
O
cycloaddition
between
1,3,3-trimethyl-2-vinylcyclohexene
O
O
15
11
10
(Scheme 2; 11a, R = Me) and unsubstituted benzoquinone (12b;
20
1
4
R1 = R2 = H) that proceeds satisfactorily at low temperature in
14
AcO
H
H
R1
R2
H
N
8
or AlCl3,10e related cycloadditions with
10a,c
17
the presence of SnCl4
6
H
substituted quinones (e.g. 12c, R1 = OMe, R2 = H) require not
only the use of a Lewis acid, but also extreme pressures (~12
kbar) and prolonged reaction times (5–14 days).10a-d Thus,
although such DA reactions have been used for the synthesis of
terpenes,10f-h widespread exploitation of their potential is
hampered by the need to employ specialized and not widely
available apparatus in order to achieve the required high
pressures.10i Furthermore, reactions between dienes of type 11
and quinones of type 12 could potentially lead to a multitude of
products (Scheme 2). Apart from the anticipated endo- and exo-
adducts (16 and 17 respectively), formation of the corresponding
hydroquinones (18) and quinones (19) has also been observed.10c
In the case of non-symmetrically substituted dienes (Scheme 2;
11, R ≠ Me) and quinones (12, R1 ≠ R2), additional products can
be envisioned (e.g. 20, 21) making the profile of such a reaction
intractable in the absence of diastereo- (i.e. facial) and regio- (i.e.
orientational) selectivity.
H
MeO2C
OAc
H
19
H
18
MeO2C
CO2Me
7 R1 = OH, R2 = Me
8 R1 = Me, R2 = OH
6
9
Figure 1. Examples of cassane-type furanoditerpenes.
Our interest in this class of natural products stems from the
identification of taepeenin D (9) as a constituent of Acacia
pennata possessing Hh/Gli-mediated transcription inhibitory
activity (IC50 1.6 µM) and selective cytotoxicity against cancer
cells with increased Hh signalling levels (IC50 3.2–3.4 µM).2e
O
O
O
O
R4
R3
Cassane-type
O
+
12a
Furanoditerpene
DA
R1 R2
R1 R2
11
10
Results and discussion
R1, R2 = Me, CO2R, CH2OR
Ring-Closing
Rearrangement
R3, R4 = Me, OR or
Aware of the aforementioned challenges, the feasibility of the
demanding DA reaction, which was cornerstone to our plan, was
investigated first. To this end, the readily obtainable11 1,3,3-
trimethyl-2-vinylcyclohexene (11a) was employed in exploratory
studies. The failure to observe [4+2] cycloaddition adducts of this
diene (11a) with furanobenzoquinone (12a), in various solvents
and employing different activation methods (Table 1, entry 1; see
footnote f), corroborated its reluctance to participate in DA
reactions.9,10 Nonetheless, 1H NMR analysis of a partially
purified product, obtained in trace amount upon heating
(microwave, 200 °C, 30 min, sealed vessel) a mixture of diene
11a and quinone 12a in methanol, indicated it as a likely
cycloaddition adduct. This observation prompted the evaluation
of hexafluoroisopropanol (HFIP) as a reaction medium since this
high hydrogen bonding donor ability, yet low nucleophilicity,
alcohol is known to accelerate a variety of transformations,12
including DA reactions.12i-k
R
3 = R4 = O
TMS
Suzuki
Asymmetric
CO2tBu
15
R1 R2
14
R1 R2
Phase-Transfer
Cat. Alkylation
13
Scheme 1. A DA-based strategy towards the cassane-type
furanotirpene taepeenin D.
A concise and versatile strategy is required for the total
synthesis of taepeenin D (9), as well as, the preparation of related
derivatives bearing different C(14) substituents.3,4 In this context,
it is tempting to exploit the proven power of the Diels–Alder
(DA) reaction.5 Thus, cycloaddition of a 1,3,3-trisubstituted-2-
vinylcyclohexene (11, Scheme 1) and furanobenzoquinone (12a)6
could furnish the desired tetracyclic system 10. A ring-closing
rearrangement of 13 (either
cycloisomerization7a,b or
metal carbene-catalyzed enyne
metathesis7c–e) was envisioned as an entry to non-symmetrically
a
metal cation-catalyzed
Gratifyingly in this solvent, the reaction between 11a and 12a
proceeded in fair yield (62%) without the need for additional
activation, (i.e. either increased temperature or pressure).
Furthermore, it exhibited exclusive endo- and very high
orientational selectivity to provide an inseparable mixture of
phenanthro[3,2-b]furandione 16a and its regio-isomer
a
substituted dienes 11 (R1 ≠ R2) and
a recently reported
asymmetric phase-transfer alkylation reaction8 might be
exploited for controlling the stereochemistry of the all-carbon
quaternary center of precursor 14.
phenanthro[2,3-b]-furandione 20a along with traces of
a

3
quinonoid adduct 19a in 39:5:1 ratio (Scheme 2; Table 1, entry
11b (Scheme 2; R ≠ Me). Adaptation of the phase transfer
1).13
asymmetric alkylation methodology developed by Maruoka and
co-workers8 for the construction of the α-chiral 1,5-enyne 23
featuring an all-carbon quaternary center marked the
commencement of our efforts to this end (Scheme 3). Thus, a
mixture of alkyne 15 and allene 15'8a was treated, in mesitylene
at –20 °C, with allylbromide and powdered potassium hydroxide
in the presence of (R)-22 as phase transfer catalyst. The chiral
alkynyl ester 23 was obtained in good yield (75%) and was
tentatively assigned the (R)-stereochemistry based on literature
precedence.8c Determination of its enantiomeric purity could not
be achieved at this point and had to await its transformation to a
more rigid derivative (vide infra).
Similar results were obtained with benzoquinone (12b; entry
2), methoxybenzoquinone (12c; entry 3) or methylbenzoquinone
(12d; entry 4) as the dienophile. In all cases, fair yields of the
corresponding cycloadducts were isolated (with the exception of
methylbenzoquinone) with exquisite endo-selectivity and high
regio-selectivity (i.e. 16:17 and 16:20 ratios respectively). An
exo-cycloadduct (17c) could be detected in trace amount13 only in
the case of methoxybenzoquinone. Intriguingly, no reaction was
observed with diethylfumarate or chromone as the dienophile
under these conditions.
These results parallel those of similar reactions run under
high-pressure conditions[10c] and encouraged the pursuit of diene
R1
R1
R1
O
R2
O
R2
HO
R2
R1
12a R1–R2 = OCHCH
12b R1, R2 = H
H
H
O
R2
12c R1 = OMe, R2 = H
12d R1 = H, R2 = Me
O
O
OH
H
16
H
17
4
4
4
O
18
R1
R
R
R
R1
R2
O
R2
O
R1
O
R2
1
11a R = Me
H
H
3
11b R = CH2OTBDMS
O
O
O
H
21
H
20
R
4
4
4
19
R
R
R
Scheme 2. Possible products of the envisioned DA reaction.
Table 1. DA reactions between dienes 11 and quinones 12.a
Diene
(equiv)
Dienophile
(equiv, concentration)
Reaction
timeb
Yield
(Product ratio)
62%d,f
Entry
1
Product(s)
16a, R = Me; R1−R2 = OCH=CH
20a, R = Me; R1−R2 = OCH=CH
19a,c R = Me; R1−R2 = OCH=CH
11a
(3.0)
12a
,
4 d
(16a:20a:19a =
(1.0, 0.1 M)
39:5:1)
11a
(3.0)
,
12b
(1.0, 0.1 M)
,
16b, R = Me; R1, R2 = H
19b, R = Me; R1, R2 = H
16c, R = Me; R1 = OMe; R2 = H
17c, R = Me; R1 = OMe; R2 = H
18%e,g,h
37%e,i
2
3
4 d
4 d
11a
(3.0)
,
12c
,
59%e,f,j
(1.0, 0.2 M)
Tracef,k,l
16d, R = Me; R1 = H; R2 = Me
20d, R = Me; R1 = H; R2 = Me
19d,c R = Me; R1, R2 = H, Me
17%e
4%e
11a
(3.0)
,
12d
(1.0, 0.1 M)
,
4
14 d
Tracel
rac
(1.1)
-
11b
,
12b,
(1.0, 0.1 M)
5
6
7 d
5 d
16e, R = CH2OTBS; R1, R2 = H
28%e
64%d
16f, R = CH2OTBS; R1−R2 = OCH=CH
20f, R = CH2OTBS; R1−R2 = OCH=CH
rac
(2.4)
-
11b
,
12a
(1.0, 0.1 M)
(16f:20f = 7:1)
a Reactions were run in degassed HFIP at ambient temperature and pressure under an Ar atmosphere. b Reactions were terminated
upon complete consumption of the quinone except in the case of entry 4. c Unidentifiable regio-isomer. d Yields of products isolated as
mixtures based on the limiting reactant (dienophile). e Yields of chromatographically separated products based on the limiting reactant
(dienophile). f No cycloadduct was formed when the reactants were treated neat or in solution in toluene or acetic acid using
conventional or microwave9m,14 heating up to 300 °C; ultrasonication;15 or in the presence of SnCl4,
AlCl3, or MeAlCl2.9l
10a,c
10e
g Reported 80% yield (based on the limiting diene) using AlCl3, toluene, 0 °C, 24 h.10e h Reported 67% yield (based on the limiting
dienophile) using ZnBr2, 12 kbar, 1 h, r.t.10c i Reported 8% yield (based on the limiting dienophile) using ZnBr2, 12 kbar, 1 h, r.t.10c
j Reported 86% yield (based on the limiting diene) using 12 kbar, 14 d, r.t.10c k Reported 10% yield (based on the limiting diene) using
12 kbar, 14 d, r.t.10c l Not isolated; detected by 1H NMR in the crude reaction mixture.13

4
Tetrahedron
CO2tBu
From the above results it appears that, although the DA
AllylBr, KOH (2.5 equiv),
TMS
H
reaction between 1-vinyl-2,2,6-trisubstituted cyclohexenes and
quinones can occur in HFIP at ambient temperature and pressure
with very high endo- and regio- selectivity, the electronic nature
of the quinone substituents may greatly influence the observed
yield. The dramatic effect of HFIP in performing these reactions
without the need of additional activation is notable. As
previously mentioned, the use of HFIP to accelerate DA reactions
is known12i-k and this beneficial effect has been attributed to its
H-bonding donation ability, as well as, to high polar nature of the
solvent and solvophobic interactions.12b,k The same parameters
could be at play in the present case. However, it should be noted
that the dienes / dienophiles previously employed12i-k participate
in DA reactions without the need to resort to extreme
temperatures or pressures and do not suffer from the reluctance
that characterizes 1,3,3-trisubstituted-2-vinylcyclohexenes.9,10 To
the best of our knowledge the use of HFIP as solvent has not
been reported to date as an alternative to the extreme pressures
required for the successful DA reaction between 1,3,3-
trisubstituted-2-vinylcyclohexenes and substituted quinones.12
(R)-22 or Bu4NBr (2 mol%),
TMS
15
CO2tBu
mesitylene, –20 °C, 24 h
·
75%
CO2tBu
23
Ar
TMS
15'
Bu
N
1) 9-BBN, THF, 0 °C, 2 h
Bu
(15 : 15' = 3 : 7)
78%
2) K3PO4, Br-prop-2-ene,
PdCl2(dppf)2CH2Cl2,
DMF, 16 h
Br
Ar
(R)-22, Ar = 3,4,5-F3C6H2
LiAlH4, THF
0 °C, 75%
TBAF, THF
98%
TMS
CO2tBu
24
CO2tBu
25
OR
28, R = H
29, R = TBS
TBSCl, Et3N,
DMAP, CH2Cl2
92%
N
N
N
N
Ar
Ar
Ar
Ar
Cl2Ru
Cy3
Cl2Ru
27 (25 mol%), C2H2,
toluene, 80 °C, 24 h
48%
P
O
iPr
26, Ar = 2,4,6-Me3C6H2
27, Ar = 2-MeC6H4
11b, R = OTBS
11c, R = OH
11d, R = (S)-MTPA ester of 11c
AcOH/THF/H2O
(2 : 1 : 1), 36 h, 88%
R
O
11e, R = (S)-MTPA ester of rac-11c
O
O
O
O
H
H
Scheme 3. Synthesis of the dissymmetric diene 11b.
+
O
H
H
Chemoselective hydroboration of the 1,5-enyne 23 with 9-
BBN16 followed by Suzuki–Miyaura coupling17 of the thus
formed alkylborane with 2-bromo-propene led to the 1,7-enyne
24 in good overall yield (78%). Cleavage of the trimethylsilyl
protecting group secured the precursor for the challenging ring-
closing rearrangement (25). Attempts to bring about the cycloiso-
merization of 25 employing cationic metal catalysts (Pt(II)
chloride7a or Rh(II) trifluoroacetate7b) failed to give the desired
vinylcyclohexene derivative. Similarly, no ring-closing
metathesis product(s), either six-membered (exo-product) or
seven-membered (endo-product),7d,e could be obtained from
substrate 25 using ruthenium carbene catalysts under a variety of
conditions.18 In an effort to reduce the steric demand of the enyne
substrate, tert-butyl ester 25 was reduced to the corresponding
alcohol 28 and subsequently converted into silylether 29. Even
with this substrate, the second generation Grubbs catalyst (26)19
proved inefficient requiring the use of 40 mol% to provide only
trace amounts of the desired product 11b. In contrast, the less
sterically demanding catalyst 2720 was far more efficient in
mediating this demanding ring-closing enyne metathesis,7c–f
furnishing the desired vinylcyclohexene 11b in 48% yield.
Deprotection to afford the primary alcohol 11c and comparison
MeMgI
Et2O, 0 °C
20a
16a
16a : 20a = 39 : 5
56%
9%
O
O
O
H
O
H
OH
H
OH
H
31
30
Scheme 4. Entry to the cassane-type furanoditerpenoid skeleton.
Finally, the angular endo-configuration of the cycloadducts
obtained from the reaction of 1,3,3-trimethyl-2-vinylcyclohexene
(11a) and furanobenzoquinone (12) was exploited for the regio-
and diastereo-selective addition of MeMgI to the less hindered
carbonyl and proceeding from the more exposed, convex face of
the molecules furnishing 30 and 31 as the sole products (Scheme
4). Thus, an entry to the cassane-type furanoditerpenoid skeleton
was secured.
Conclusion
1
of the H NMR spectra of the (S)-Mosher esters of 11c and rac-
In summary, we have established that the use of HFIP as
solvent is pivotal for the Diels–Alder reaction between sterically
demanding 1,3,3-trisubstituted-2-vinylcyclohexenes and non-
symmetrically substituted quinones. These newly established
conditions are extremely mild and experimentally simple
compared to the combination of Lewis acid and high pressures
previously known to be a prerequisite for the successful
implementation of such transformations. In combination with the
successful implementation of a challenging ring-closing enyne
metathesis to provide the required dissymmetric diene, these
conditions allowed to demonstrate the validity of a highly
convergent approach to the cassane-type furanoditerpenoid
skeleton. Efforts to improve the enantioselectivity of the diene
preparation that will allow the total synthesis of taepeenin D, as
well as, several other related terpenes are underway.
11c24 indicated that the initial alkylation step had proceeded with
77% ee.
Having secured the dissymmetric diene 11b, attention was
focused on its reactivity towards DA reactions with quinones.
Although reaction of this sterically more demanding diene with
benzoquinone (12b; Table 1, entry 5) proceeded in lower yield
(28%) it solely furnished the endo-cycloadduct 16e as a single
diastereoisomer (no C(4) epimer could be detected).13 The
combination of rac-11b with furanobenzoquinone (12a; entry 6)
gave in equally high selectivities (endo- and diastereo-) and
higher yield (64%) the desired cycloadduct 16f.13 The complete
diastereoselectivity observed when the dissymmetric diene rac-
11b was employed (i.e. only 16 and none of the
diastereoisomeric 21 was detected; entries 5 and 6) can be
attributed to the differential steric requirements imposed by the
two C(2) substituents that leads to exclusive endo- approach of
the dienophile from the less hindered face of the diene.
Acknowledgments
This study was implemented in the frame of and with the
financial support of the research project "3069 - GliTerIn"

5
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13. Structures were assigned by comparison of NMR data with those
reported in the literature10c (Table 1, entries 2, 3) or based on
established telltale signals10c in the 1H NMR spectra (low field
multiplet at ~2.4 ppm, attributable to the axial C(1) hydrogen,
signifies endo-configuration; a signal at 5.7–5.8 ppm, attributable
to the C(6) hydrogen, along with the absence of signals
attributable to C(8) and C(9) hydrogens signifies a quinonoid
cycloadduct). Furthermore, diastereoisomers (i.e endo- or exo-
configuration as well as relative C(4) stereochemistry) were
distinguished based on 2D NMR (NOESY) analysis and regio-
isomers were distinguished based on 2D NMR (HSQC, HMBC)
analysis (see ESI).
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24. Prepared as shown in Scheme 3 in analogy to 11c by substituting
catalyst (R)-22 with nBu4NBr.
Supplementary data
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Highlights





Cassane-type furanoditerpenes encompass a large number of natural products.
A strategy towards this motif based on a demanding DA reaction is proposed.
Hexafluoroisopropanol allows this reaction to proceed under normal pressure.
A concise and enantioselective construction of the required diene is reported.
The feasibility of the proposed strategy has been demonstrated.