An Enyne Cope Rearrangement Enables Polycycloalkane Synthesis from Readily Available Starting Materials

Article abstract of DOI:10.1002/anie.201703186

Cyclohexanone-derived Knoevenagel adducts (cyclohexylidenemalononitriles) and two different propargyl electrophiles serve as carbon sources for assembling diverse 6/7/5 tricycloalkanes, a common terpenoid framework. The sequence involves three unique reac

Full text of DOI:10.1002/anie.201703186

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Accepted Article
Title: An Enyne Cope Rearrangement Enables Polycycloalkane
Synthesis from Abundant Starting Materials by a Simple Strategy
Authors: Sarah K. Scott and Alexander J. Grenning
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703186
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10.1002/anie.201703186
Angewandte Chemie International Edition
COMMUNICATION
An Enyne Cope Rearrangement Enables Polycycloalkane
Synthesis from Abundant Starting Materials by a Simple Strategy
Sarah K. Scott,[a] and Alexander J. Grenning*[a]
Dedication ((optional))
Abstract:
Cyclohexanone-derived
Knoevenagel
adducts
Second, the coupling reactions (deconjugative α-alkylation) are
(cyclohexylidenemalononitriles) and two different propargyl
electrophiles serve as carbon sources for assembling diverse 6/7/5
tricycloalkanes, a common terpenoid framework. The sequence
involves three unique reactions: (i.) deconjugative propargylation,
operationally simple due to the ease of Knoevenagel adduct
anion generation (γ-C–H pKa
necessitates the exploration of
<
10).12 The strategy also
a
rare 1,5-enyne Cope
rearrangement;9 this reaction is known (three isolated
examples9a-c) and computationally examined,9d but has little to
no application in synthesis.13 However, the related propargyl
enol ether Claisen counterpart is more established and utilized.14
The final feature is the use of the allenic-Pauson-Khand reaction
(PKR). When preparing hydroazulenes by PKR, it is essential
that the “alkene” coupling partner be an allene.6f,k,10,11
R3
(ii.)
one-pot
enyne
Cope
rearrangement/deconjugative
propargylation, and (iii.) allenic-Pauson-Khand reaction.
Simplifying access to complex terpenoid scaffolds for application
in the drug discovery process is a major goal of modern organic
chemistry.1 For example, natural product analogs can be
accessed by (a) semisynthesis,2 (b) “total” or de novo
synthesis,3 and by (c) diversity-oriented synthesis.4 Efforts in our
laboratory are aimed at identifying combinations of abundant
starting materials and simple reaction sequences that can be
used to tunably and scalably assemble common terpenoid
cores.5 This way, diverse scaffolds can be prepared and
derivatized for biological evaluation.
propargyl electrophiles
Br
iii.
NC
NC
Br
2’
iv.
R3
R2
5
2
2’
R2
CN
R3
O
R1
NC
α
NC
CN
NC
NC
H
γ
R2
R2
R1
R1
6
R1
reactions utilized:
1
4
NC
NC
O
H
BzO
AcO
H
OH
OH
OH
i. deconjugative propargylation
ii. enyne Cope rearrangement
iii. deconjugative propargylation
ii.
H
O
i.
R2
H
HO
H
O
H
2
O
O
AcO
iv. allenic Pauson-Khand reaction
OH
O
H
3
R1
H
O
Scheme 1. The strategy for assembling 6/7/5 scaffolds.
OH
brevifoliol
O OH
radianspene C
ineleganolide
caribenol A
R2
NC
E
E
Br
Figure 1. Representative 6/7/5 tricycloalkane terpenes.
NC
150 ºC
NaH
rt
E
+
NC
2 – 15h
R1
4a – 4f
[not isolated]
R
Inspired by synthetically challenging6 and bioactive7 6/7/5
tricyclic terpenoid natural products (Figure 1), we devised the
following reaction sequence to tunably assemble their cores
decorated with numerous functional groups (Scheme 1):
R1
3a – 3f
2a – 2e
OAc
5
R1
E = CN or CO2Me
OAc
R
NC
NC
NC
deconjugative α-alkylation8 of Knoevenagel adduct
1 with
H
NC
NC
5aa, R = H, 35%
5ab, R = Me, 20%
propargyl bromide 2 prepares the 1,5-enyne 3. Enyne Cope
rearrangement9 results in γ-allenyl Knoevenagel adduct 4 and
repeating the deconjugative α-propargylation step affords the
1,7-allenyne 5. Finally, allenic-Pauson-Khand reaction6f,k,10,11
yields the target cores from abundant carbon sources.
MeO2C
5ac, R = Ph, 25%
5ad, CH2OAc, 21%
Me
3a + 2a-d →
5aa – 5ad
3b + 2d → 5bd
3c + 2d → 5cd
38%, >20:1 dr
25%, 1:1 dra
R
OAc
OAc
This synthetic hypothesis has several notable features. First,
NC
5dd, R = CH2OAc
24%, >20:1 dr
NC
NC
NC
NC
NC
it employs only abundant starting materials (ketones
+
H
H
H
malononitrile = Knoevenagel adducts; propargyl electrophiles).
5de, R = TMS
24%, > 20:1 dr
R
N
CO2Et
R = Boc
3e + 2d→ 5ed
48%, >20:1 dr
3f + 2d → 5fd
56%, >20:1 dr
[a]
S. K. Scott, Prof. A. J. Grenning
3d + 2d-e →
5dd – 5de
Department of Chemistry, University of Florida
PO Box 117200, Gainesville FL 32611-7200
E-mail: grenning@ufl.edu
standard protocol: 300 mg – 2 g of 1,5-enyne substrate 3a – 3f, toluene (0.1 M),
150 ºC, then swap toluene for THF (0.5 M), add NaH (1.1 equiv.) and propargyl
bromide derivative (1.5 equiv.), rt. a reaction ran at 170 ºC.
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Scope of 1,7-allenyne synthesis.
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10.1002/anie.201703186
Angewandte Chemie International Edition
COMMUNICATION
To begin our studies, 1,5-enynes 3a – 3f bearing a terminal
alkyne were prepared by deconjugative propargylation. We were
pleased to find that the 1,5-enyne Cope rearrangement went
forward at 150 °C in toluene in screw-cap pressure flasks
(Scheme 2). It was most practical and efficient to perform a
telescoped sequence where the γ-allenyl Knoevenagel adducts
generated in situ were directly treated with NaH and a 1°
propargyl bromide derivative to yield the 1,7-allenynes 5 (20% –
56% yields of 1,7-allenynes 5 from 1,5-dienes 3). Reported in
Scheme 2 are two-step yields, averaging 45% – 75% yield per
step, where inexpensive and abundant starting materials are
converted into synthetically useful 1,7-allenyes. Notably, the
procedure is scalable and reproducible; the sequence was
routinely examined on the 300 mg – 2 gram scale. Through the
sequence, cyclohexenyl substitution is altered by choice of
cycloalkanone starting material and alkyne substitution is varied
by choice of propargyl bromide starting material. Furthermore,
cyclohexenyl substitution renders the Cope rearrangement
diastereoselective (>20:1 dr). Finally, bicyclic 1,7-allenynes 5ed
and 5fd could be accessed from tropinone (3e) and the (4+3)
adduct (3f) of cyclopentadiene and trichloroacetone.
propargyl bromide 2d yielding allenynes 7 in a significantly
higher yield compared to the original protocol (Scheme 2).
Furthermore, the new method allows for increased scope:
enynes 3l and 3m decompose under thermal, Hantzsch ester-
free conditions. The addition of Hantzsch ester to the thermal
transformation results in a [3,3] rearrangement then rapid
consumption of the unstable alkylidene thus avoiding
decomposition. Generally speaking, the alkylidene reduction
step is non-diastereoselective unless the core contains an
additional stereocenter, as was the case for the acetamide-
containing substrate (7ld).
OAc
NC
NC
NC
CN
H
NaH
2d
NC
NC
200º
Tol
R
H
THF
rt
R
X
X
R
5hd – 5kd
X
3h – 3k
OAc
OAc
NC
NC
OAc
OAc
NC
NC
NC
NC
NC
NC
H
H
H
H
OAc
We next examined the Cope rearrangement of 1,5-enynes
3g – 3k bearing an internal alkyne (eq. 1 and Scheme 3).
Unfortunately, internal alkyne substrates such as 3g required
higher temperatures (200 °C) to rearrange, which resulted in
decomposition (eq. 1). However, the bridged bicyclic substrates
3h – 3k underwent an efficient Cope rearrangement and the
desired allenynes could be isolated in good yields over the
telescoped sequence. We suspect that the increased stability of
the bicyclic allenynes (Scheme 3) vs. monocyclic allenes
(Scheme 2) is a result of a locked, non-acidic conformation (eq.
2).
R
R
R
Ph
N
N
N
OAc
R = Boc
5jd 44%
>20:1 dr
R = Boc
5hd 59%
>20:1 dr
R = Boc
5id 41%
>20:1 dr
5kd 53%
>20:1 dr
(i.) standard protocol: ~300 mg of 1,5-enyne substrate 3h – 3k, toluene (0.1 M),
200 ºC, then swap toluene for THF (0.5 M), add NaH (1.1 equiv.) and propargyl
bromide derivative 2d (1.5 equiv.), rt.
Scheme 3. Cope Rearrangement of 1,5-enynes bearing an internal alkyne.
OAc
NC
NC
CN
H
Hantzsch
ester (HE)
NC
NC
NC
K2CO3
R
NC
CN
H
H
NC
NC
NC
NC
X
H
+ 2d
DMF, rt
toluene
130 ºC
Δ
H
R
H
(1)
R
7
R
[Ia]
3
OAc
[decomposition]
AcO
R
OAc
CO2Et
OAc
OAc
OAc
NC
NC
OAc
NC
NC
CO2Et 3g
5g CO2Et
NC
NC
CN
CN
CN
CN
R
H
H
H
NC
NC
H
H
H
H
H
R
(2)
H
H
X
CN
H
O
O
CN
CO2Et
NHAc
R
locked in non-acidic
conformation
3a + HE + 2d
→ 7ad
48%, 2:1 dr
3b + HE + 2d
→ 7dd
3l + HE + 2d
→ 7ld
68%, >20:1 dr
3m + HE + 2d
→ 7md
57%, 1.5:1 dr
non-acidic conformer
acidic conformer
49%, 2:1:1 dra
(i.) standard protocol: 100 mg of 1,5-enyne substrate, Hantzsch ester (2 equiv.),
toluene (0.1 M), 140 ºC, then swap toluene for DMF (0.5 M), add K2CO3 (3 equiv.)
and propargyl bromide derivative 2d (2 equiv.), rt. a major diastereomer shown
Although the enyne [3,3] rearrangement/deconjugative
alkylation sequence is reproducible and scalable (ranging from
300 mg – 2 g), we wished to find ways of improving the overall
efficiency, as yields in the 20 – 35% range would likely limit the
utility of the transformation. We suspect that observed yields are
a result of significant decomposition by isomerization enabled by
the high acidity of the γ-C–H (eq. 2).9c Thus, an enyne-[3,3]
rearrangement/alkylidene reduction/alkylation sequence was
examined to prepare similar scaffolds (Scheme 4). Fortunately,
Hantzsch ester was a selective and mild reductant of the
alkylidenemalononitrile moiety. Thus, heating a mixture of 1,5-
enyne 3 and Hantzsch ester at 130 °C results in allenyl
malononitriles [Ia], which could be directly alkylated with
Scheme
4.
Allenyne
synthesis
by
enyne-[3,3]
rearrangement/reduction/propargylation
Allenes are generally useful for intramolecular
cycloisomerization.15 As such, other functionalized electrophiles
were examined to prepare diverse allene/tethered-π substrates
(Scheme 5).
Enyne Cope rearrangement/allylation with
cinnamyl bromide resulted in separable products 8a and 8b in
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10.1002/anie.201703186
Angewandte Chemie International Edition
COMMUNICATION
60%
and
23%
yields,
respectively.
Enyne
Cope
Using the allenic-Pauson-Khand reaction,6f,k,10,11 the 1,7-
allenynes were converted into their respective 6/7/5
tricycloalkane cores 6 without incident by the standard literature
protocol developed and applied by Brummond and others
(Scheme 6).6f,k,10,11 The cores are highly complex and diverse,
considering the sequence is four steps from abundant starting
materials.
rearrangement/Pd-catalyzed allylation with cinnamyl acetate
intriguingly resulted in diastereo-, γ-, and branch-selective
allylation in good yield (product 8c16). Additionally, enyne Cope
rearrangement/Pd-catalyzed allylation with sorbyl acetate
resulted exclusively in linear-selective deconjugative α-allylation
(8d). Finally, enyne-Cope rearrangement/alkylation with a furan-
containing electrophile resulted in
deconjugative α-alkylation product 8e and γ-alkylated product 8f.
a
separable mixture of
We also examined the furan-containing allene 8e for
intramolecular Diels-Alder furan (IMDAF) reactivity (Scheme
7A).17 We were pleased to find that thermal conditions could
convert 8e to the functionally dense polycycloalkane 9 in 39%
NC
NC
Ph Ph
yield.
9 contains a 6/6/7 tricycloalkane framework, two-
NC CN
NC CN
NC
NC
heteroatomic bridges, and numerous other functional groups
and was prepared in four steps from inexpensive commercial
materials. Notably, there are terpenoid natural products that
bear a related tricycloalkane ring system (Scheme 7B).18
H
H
H
H
Δ
3e
H
R
N
Ph
R
N
R
N
H
then
NaH
R
N
8a
8b
8c
Ph
X = Br; 7a : 7b : 7c = 60% : 23% : 0% yields
X = OAca; 7a : 7b : 7c = 0% : 0% : 61%
R = Boc
X = Br, OAca
X
NC
NC
NC
NC
A
NC
H
O
Δ
NC
NC
NC
H
CO2Et
CN
R
N
150 ºC
H
R
N
OAc
O
then
CO2Et
H
R
NaH/Pda
N
H
tol (0.1 M),
9 h, 39%
3e
O
CO2Et
8d 41%
R
NC
N
CO2Et
NC CN
8e
NC
NC
Cl
NC
NC
equivalent
structures
R = Boc
H
N
Boc
O
O
CO2Et
Δ
9
H
H
H
O
B
R
N
R
N
then
NaH
OH
H
H
R
N
8e 30%
>20:1 dr
8f 20%
>20:1 dr
HO
EtO2C
3e
H
H
H
H
HO
OH
(i.) standard protocol: 300 mg 3e, toluene (0.1 M), 150 ºC, then swap toluene for
a
THF (0.5 M), add NaH (1.1 equiv) and alkyl halide derivative (1.5 equiv.).
mol% Pd(PPh3)4
5
O
HO
O
aphidicolin
aspergilloxide
barekoxide
Scheme 5. Other allene/tethered π-systems prepared.
Scheme 7. A. An intramolecular Diels-Alder furan reaction. B. Related 6/6/7
tricycloalkane natural products.
O
10 mol%
[Rh(CO)2Cl]2
NC
NC
NC
NC
OAc
OAc
OAc
OH
1 atm CO
p-xylene, 110 ºC
O
O
6aa 52% (30%a)
NC
NC
NC
NC
NC
NC
5aa
H
H
H
AcO
TMS
H
AcO
O
AcO
O
O
O
O
10a 97%
10b 50%
NC
NC
NC
NC
NC
NC
6dd
4:1 dra
1:1 drb
NC
H
H
NC
H
CO2Me
CO2Me
CO2Me
AcO
R
N
OAc
O
OAc
CO2Me
CO2Me
O
5ed→ 6ed
R = Boc, 75%a
AcO
5cd → 6cd
5dd → 6dd
44%a
5de → 6de
NC
NC
O
NC
NC
32%a
48%a
NC
NC
H
AcO
AcO
AcO
H
O
OAc
H
O
O
O
NC
NC
OAc
6kd
OAc
NC
NC
NC
NC
NC
NC
H
O
10c 84%
H
H
H
O
10d, 35%c
Ph
>20:1 dra
H
a ~ 1.5 equiv. mCPBA, DCM (0.1 M), 0 ºC – rt b 2 equiv. NaBH4, MeOH (0.5 M)
R
N
R
N
OAc
OAc
0 ºC. c 3 equiv. styrene, ethylene (1 atm), 3 mol% Grubbs II, 60 ºC
O
5hd → 6hd
R = Boc, 29%a
5jd → 6jd
R = Boc, 59%
7md → 6md
50%, 1.5:1 dr
5kd → 6kd
50%
Scheme 8. Functional group interconversion reactions.
50 – 400 mg of allenyne 5, 1 atm CO, 10 mol% [Rh(CO)2Cl]2, p-xylene (0.005
M), 110 ºC. a tol (0.01 M) in lieu of p-xylene, 5 mol% [Rh(CO)2Cl]2, 90 ºC
As final experiments, we examined preliminary functional
group interconversion reactions on the scaffolds (Scheme 8).
The most reactive olefin toward epoxidation was the γ,δ-olefin
Scheme 6. Synthesis of 6/7/5 tricycloalkane frameworks.
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10.1002/anie.201703186
Angewandte Chemie International Edition
COMMUNICATION
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O. Lahtigui; F. Emmetiere; W. Zhang; L. Jirmo; S. Toledo-Roy; J. C.
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on the conjugated dienone for substrate 6dd yielding product
10a. For the more strained scaffold 6kd, the bicyclo[3.2.1]octene
was most reactive yielding 10c. Also, the ketone could be
reduced using NaBH4 to prepare 10b. Finally, ring-opening/cross
metathesis could be performed on the bicyclo[3.2.1]octene core
yielding 10d.
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In conclusion, we have examined a new route to 6/7/5
tricycloalkane frameworks. The sequence hinged on the
development of poorly understood 3,3-dicyano-1,5-enyne Cope
rearrangement. We have developed conditions and outlined
current understanding and limitation for this transformation. Per
the inspiration of the route, we examined the synthesis of
diverse linear 6/7/5 tricycloalkanes and also prepared a highly
complex 6/6/7 tricycloalkane, all in four steps from
cycloalkanone, malononitrile, and two different propargyl-, allyl-,
and/or furan-containing electrophiles. Future directions include
target and analog synthesis, rendering the strategy asymmetric,
and further examination of the enyne Cope rearrangement to
identify many previously inaccessible allenes for processing into
polycycloalkane architectures by ring-forming reactions (e.g.
Diels-Alder and cycloisomerization).
(7)
Experimental Section
(8)
See the supporting information for detailed experimental procedures,
characterization data, and spectral reprints
Acknowledgements
(9)
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Huntsman; J. A. De Boer; M. H. Woosley J. Am. Chem. Soc. 1966, 88,
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(d) K. A. Black; S. Wilsey; K. N. Houk J. Am. Chem. Soc. 1998, 120 ,
5622.
We thank the College of Liberal Arts and Sciences and the
Department of Chemistry at the University of Florida for start-up
funds.
(10) For a review of allenic-PKR see: B. Alcaide; P. Almendros Eur. J. Org.
Chem. 2004, 3377.
Keywords: Knoevenagel Adducts • 1,5-enyne Cope
rearrangement • allenic Pauson-Khand reaction • terpenoid
natural products
(11) For select examples of allenic-PKR in synthesis see: (a) L. Jørgensen;
S. J. McKerrall; C. A. Kuttruff; F. Ungeheuer; J. Felding; P. S. Baran,
Science 2013, 341, 878. (b) B. Wen; J. K. Hexum; J. C. Widen; D. A.
Harki; K. M. Brummond Org. Lett. 2013, 15, 2644. (c) T. Hirose; N.
Miyako-shi; C. J. Mukai Org. Chem. 2008, 73, 1061.
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10.1002/anie.201703186
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Text for Table of Contents
Sarah K Scott,[a] and Alexander J.
Grenning*[a]
Page No. – Page No.
An Enyne Cope Rearrangement
Enables Polycycloalkane Synthesis
from Abundant Starting Materials by
a Simple Strategy
This article is protected by copyright. All rights reserved.