A Radical-Polar Crossover Annulation to Access Terpenoid Motifs

Article abstract of DOI:10.1021/jacs.9b07346

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

Full text of DOI:10.1021/jacs.9b07346

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Communication
A radical-polar crossover annulation to access terpenoid motifs
William P. Thomas, Devon J. Schatz, David George, and Sergey V. Pronin
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A radical-polar crossover annulation to access terpenoid motifs
William P. Thomas, Devon J. Schatz, David T. George†, and Sergey V. Pronin*
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Department of Chemistry, University of California, Irvine, California 92697-2025, United States
Supporting Information Placeholder
● Previous work (ref. 5b)
ABSTRACT: A new catalytic radical-polar crossover
radical-polar
N
annulation between two unsaturated carbonyl com-
pounds is described. The annulation proceeds under ex-
ceptionally mild conditions and provides direct and ex-
pedient access to complex terpenoid motifs. Application
of this chemistry allows for synthesis of forskolin, a
densely functionalized terpenoid, in 14 steps from com-
mercially available material.
crossover
polycyclization
H
H
Me
Me
Me
O
O
OH
then deprotection
Me
Me
H
O
TMSO
41%
O
H
Me
● This work
radical-polar
crossover
annulation
R5
O
R5
R1
OH
O
O
R1
R3
H
37–73%
R2
R4
R4
R3
R2
R6
O
R6
Annulations allow for rapid increase in structural com-
plexity and have found broad application in organic syn-
thesis. Of particular note are transformations involving
fusion of new rings via two new carbon-carbon bonds,
which can dramatically simplify construction of poly-
carbocyclic motifs present in terpenoid and polyketide
natural products.1 Among those, Diels-Alder cycloaddi-
tions have demonstrated exceptional flexibility with re-
spect to the accessible connectivity patterns and feature
prominently in many successful syntheses.2 A require-
ment for the acyclic 1,3-diene to adopt the s-cis confor-
mation often imposes limitations on the presence of sub-
stituents at the terminal positions, and formation of qua-
ternary carbons originating from the diene component is
challenging in bimolecular settings.3,4 Here we demon-
strate a new annulation between two unsaturated car-
bonyl components that allows for construction of satu-
rated six-membered carbocycles and is particularly well-
suited for installation of fully substituted carbons (Fig-
ure 1). Development of this transformation builds on our
previous efforts in the synthesis of paxilline in-
doloterpenoids, where a hydrogen atom transfer (HAT)-
initiated radical-polar crossover polycyclization allowed
for rapid assembly of the shared tricyclic scaffold and
selective installation of vicinal quaternary centers.5 The
new HAT-initiated radical-polar crossover annulation
proceeds under exceptionally mild conditions and pro-
vides direct and expedient access to complex terpenoid
motifs, including those related to labdane and scalarane
families of natural products.6–8 We also show that appli-
cation of this chemistry allows for a 14-step synthesis of
forskolin (1), a densely functionalized labdane
Me
Me
Me
H
Me
forskolin (1):
OH
prepared in 14 steps from
2,6-dimethylbenzoquinone
1
O
OAc
10
4OH
5
Me
OH
H
H
H
Figure 1. Radical-polar crossover annulation allows for
rapid assembly of complex terpenoid motifs.
diterpenoid, from commercially available material.
We began our studies with the annulation of γ,δ-
unsaturated aldehyde 2 and methacrolein (3, Table 1).
After considerable optimization the desired cyclohexa-
nol 4 could be obtained in a highly diastereoselective
manner and moderate levels of efficiency. This trans-
formation likely involves HAT to the electron-rich 1,1-
disubstituted alkene followed by the conjugate addition
of the resulting tert-alkyl radical to the enal, reduction to
the corresponding enolate, and subsequent aldol reaction
with the pendant aliphatic aldehyde functionality.6,9–11
Our investigations revealed that slow addition of a mix-
ture of 3 and silane to an excess of 2 was beneficial to
allow for selective engagement of the γ,δ-unsaturated
carbonyl component in the HAT event and attenuation of
the competing reductive aldol pathway.8 Notably, pres-
ence of the α-substituent in 3 was required for complete
propagation of the HAT-initiated cascade and only traces
of the expected cyclized product were observed in the
case of acrolein. Other α-substituted acroleins per-
formed similarly to methacrolein (3) and cyclohexanols
5 and 6 were obtained in a highly diastereoselective
manner.12 2-Methyl-2-cyclopentenone also participated
1
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Table 1. Radical-polar crossover annulation of α,β- and
alized tricyclic motif found in several scalarane terpe-
γ,δ-unsaturated carbonyl compoundsa,b
noids.14
1
2
3
4
5
6
7
8
We next set out to test the applicability of our annula-
tion in the synthesis of terpenoids and chose forskolin
(1, see Figure 1) as our primary target.15 This densely
functionalized diterpene exhibits allosteric stimulation
of adenylyl cyclases and a derivative is currently ap-
proved for acute heart failure treatment in Japan.16,17
Since its discovery, forskolin has been a subject of fre-
quent inquiry by organic chemists, which culminated in
several successful syntheses that expanded our under-
standing of the chemistry of highly oxidized labdane
motifs.18 We envisioned that the radical-polar crossover
annulation would allow for construction of the C4–C5
and C1–C10 bonds of the decalin fragment. Thus, sub-
jection of enone 14 and aldehyde 2 to our optimized
conditions resulted in efficient formation of the desired
polycyclic motif, albeit with low diastereoselectivity at
C1 and only slight preference for desired product 16
(Scheme 1). Nevertheless, the annulation was readily
5 mol% Fe(acac)3
3 equiv. PhSiH2(Oi-Pr)
3 equiv. (CH2OH)2, CH2Cl2
O
Me
OH
Me
Me
O
O
54%, d. r. >10:1c
Me
H
Me
● slow addition of 3 and silane
● excess of 2
2
3
4
[FeIII–H]
hydrogen atom transfer
intramolecular aldol
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10
11
12
13
14
15
16
17
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19
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21
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59
60
Me
Me
O
O
O
Me
Me
radical addition/ reduction
[FeII]
Me
O
Me
Ph
Me
Me
H
OH
Me
O
OH
OH
Me
Me
O
OH
H
Me
H
H
Me
Me
5 (62%; d. r. >10:1)c,d
6 (46%; d. r. >10:1)c,e
7 (42%; d. r. >10:1)c
Me3Si
Me
Me
Me
H
Me
OH
Me
Me
O
O
O
O
Scheme 1. Annulation en route to forskolin (1)
Me
Me
OH
H
Me
Me
Me
Me
1 3 equiv. 2
10 mol% Fe(acac)3
PhSiH2(Oi-Pr)
Me
O
O
H
HO
1
54%; d. r. 1.2:1 (8:9)f
9
10 (72%; d. r. >10:1)c,g
Me
H
8
H
Me
Me
Me
Me
Me
39% of 16
OH
Me
Me
OH
OH
O
Me
Me
O
Me
(+ 34% of 15)
OH
H
H
O
Me Me O
15
H
H
14
Me
Me
H
Me
H
H
Me
Me
11 (52%; d. r. >10:1)c,h
12 (58%; d. r. 5.8:1)c,d
13 (37%; d. r. >10:1)c
2
3
TBSOTf,
2,6-Lutidine
t-Bu
H
Me
Si
O
H
OH
Me
O
O
1
bTypical reaction conditions: 2–3 equiv. γ,δ-unsaturated
carbonyl compound, 5–50 mol% Fe(acac)3, 1.5–3 equiv.
PhSiH2(Oi-Pr), 1–3 equiv. (CH2OH)2, 0.2 M in CH2Cl2; see
H
Me
H
Me
170 ℃
84% from 16
2 steps
H
H
Me Me O
16
Me
Me
O
b
17
SI for details. Diastereomeric ratios were determined by
c
1H NMR analysis of crude product mixtures. Yields are
d
scalable and allowed for production of multigram quan-
tities of alcohol 16. Furthermore, diastereomer 15 could
be converted to alcohol 16 via consecutive oxidation and
reduction events in 87% yield over two steps.19 Facile
epimerization at C1 to the undesired configuration ne-
cessitated protection, which was followed by a retro-
Diels-Alder reaction to reveal the enedione motif. This
sequence secured access to intermediate 17 in four steps
from 2,6-dimethylbenzoquinone and was rendered
asymmetric by taking advantage of oxazaborolidine ca-
talysis in the preparation of Diels-Alder adduct 14 in
96% ee.19,20 Notably, previous investigations employed a
circuitous cycloaddition-based route that necessitated
multiple functional group manipulations to obtain race-
mic silyl ether 17 in eight steps from commercially
available material.21
reported for the depicted analytically pure isomers. Struc-
ture was confirmed by X-ray crystallographic analysis, see
e
SI for details. After reduction and recrystallization, see SI
f
for details. Isolated and characterized as a mixture of iso-
g
h
mers. After silylation, see SI for details. After reduction,
see SI for details.
in the annulation with good levels of diastereocontrol,
and hexahydroindanone derivative 7 could be isolated in
a synthetically useful yield.13 At the same time, applica-
tion of isopropenyl methyl ketone resulted in a nearly
stoichiometric mixture of diastereomeric aldol products
8 and 9, presumably due to unselective formation of E
and Z isomers of the intermediate iron enolate. Remark-
ably, γ,δ-unsaturated ketones were also found to be suit-
able annulation partners, and products 10 and 11 were
formed with high diastereoselectivity after derivatization
of the intermediate hydroxyaldehydes, which proved
necessary to prevent retro-aldol reactions during the
chromatographic purification. Other modifications of the
γ,δ-unsaturated component were tolerated and allowed
for diastereoselective formation of decalin 12 and
perhydrophenanthrene 13, which contains the function-
Regio- and stereoselective addition of lithio derivative
of alkyne 18 to racemic enedione 17 followed by epi-
merization at C5 afforded trans-octalin 19 (Scheme 2).22
Subsequent reduction of the remaining keto group and
epoxidation of the alkene allowed for a highly diastere-
oselective production of diol 20. We discovered that the
2
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Scheme 2. Synthesis of (±)-forskolin (1)
1
2
3
4
5
6
7
8
O
O
O
O
18
O
Me
Si
O
Me
Me
O
O
Me
Me
Me
Me
t-Bu
H
1
2
5
Cs2CO3, CsF,
CO2, DMF; CDI
3
4
DIBAL-H
90%
Me
O
Me
OH
Me
H
Me
O
n-BuLi; 88%
Me
O
H
H
H
H
O
Me
Me
Me
H
O
Me
Me
H
1
m-CPBA
93%
Al2O3, 111 ℃
54–88%
91%, 21:22 1:3
O
O
5
Me
t-Bu
OH
O
Me
Me
O
OH
H
O
H
OH
Si
H
Me
H
Me
O
t-Bu
O
Si
O
H
Me
Me
Me
Me
17
19
20
21
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Me
13
O
Me
Li
CuCN,
BF3•OEt2
O
O
Me
Me
Me
Me
Me
O
H
H
Me
Me
Me
9
TsOH, MeOH
66%, d. r. >10:1
8
6
7
TsOH, MeOH;
K2CO3
H
H
Me
Me
Me
H
OH
H
Me
O
OH
Me
H
H
O
Me
OH
O
O
OH
O
OAc
OH
OH
1
O
Me
H
MeC(OMe)=CH2,
TsOH
62%, 2 steps
O
O
Me
44%, d. r. 5:1
(+ 28% of 23)
O
10 Ac2O, Py; 81%
H
O
OH
Me
OH
H
H
Me
O
H
O
H
H
O
Me Me
H
Me Me
forskolin (1)
23
22
24
epoxidation pathway was competing with oxidation of
the secondary allylic alcohol to enone 19, and applica-
tion of tetrahydrofuran-based solvent mixtures was nec-
essary for attenuation of this undesired pathway.23 In-
tramolecular displacement of the epoxide with in situ
generated monoalkylcarbonate required deprotection of
the hydroxy group at C1, which proceeded under the
reaction conditions and could be accelerated in the pres-
ence of cesium fluoride.24,25 Addition of carbonyldiimid-
azole to the reaction solution led to formation of a mix-
ture of cyclic carbonates 21 and 22. Acid-catalyzed cy-
clization of a mixture of protected ynones 21 and 22
resulted in efficient formation of the desired dihydropy-
ranone motif, and treatment with base resulted in hy-
drolysis of the carbonate moieties. Selective protection
of the resulting tetraol delivered acetonide 23, and the
structure was confirmed by X-ray crystallographic stud-
ies. We found this switch of protecting groups to be nec-
essary for achieving the desired facial selectivity during
the installation of stereocenter at C13. Thus, conjugate
addition to acetonide 23 delivered desired tetrahydropy-
ranone 24 with good diastereoselectivity, while applica-
tion of the corresponding dicarbonate led exclusively to
the undesired configuration at C13. Acetonide 24 was
readily deprotected and the penultimate tetraol could be
isolated as a single diastereomer.25 Acetylation of 7-
deacetylforskolin under previously described conditions
delivered the target natural product, completing the syn-
thesis in 14 steps from commercially available starting
material.25,26
efficient asymmetric induction. We anticipate that the
radical-polar crossover annulation will be valuable in the
synthesis of other functionalized terpenoids and will
simplify production of natural and unnatural congeners
for biological studies.
ASSOCIATED CONTENT
Experimental procedures and characterization data for all
new compounds and relevant CIF files. This material is
available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
spronin@uci.edu
Present Address
†D.T.G.: Bristol-Myers Squibb, New Brunswick, NJ 08901
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Institutes of Health
(R01GM121678), the School of Physical Sciences and the
Chao Family Comprehensive Cancer Center at the Univer-
sity of California, Irvine, and the Natural Sciences and En-
gineering Research Council of Canada (PGSD3-487506-
2016 to D.J.S.) is gratefully acknowledged. We thank Pro-
fessors Larry Overman, Chris Vanderwal, and Scott Rych-
novsky for providing routine access to their instrumentation
and helpful discussions.
In summary, we disclose a new radical-polar crossover
annulation that allows for direct and diastereoselective
construction of cyclic aldol motifs. In contrast to the
venerable Diels-Alder reaction, this transformation is
well suited for bimolecular assembly of multiple quater-
nary centers, offering a complementary approach to the
synthesis of six-membered carbocycles. We also demon-
strate application of this chemistry to the synthesis of
forskolin that allows for rapid assembly of this highly
oxidized labdane diterpenoid and is readily amenable to
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(4) For elegant solutions to this problem see: (a) Zutterman, F.;
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42.
Diels-Alder-reactionen
mit
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cyclopropylidenprop-1-enyl-ethyl-ether als 1,3-dien. Helv. Chim. Acta
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(5) (a) George, D. T.; Kuenstner, E. J.; Pronin, S. V. A concise ap-
proach to paxilline indole diterpenes. J. Am. Chem. Soc. 2015, 137,
15410–15413. (b) Godfrey, N. A.; Schatz, D. J.; Pronin, S. V.
Twelve-step asymmetric synthesis of (–)-nodulisporic acid. J. Am.
Chem. Soc. 2018, 140, 12770.
(6) For an early example of relevant reactivity see: Lo, J. C.; Kim,
D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez,
S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. Fe-
catalyzed C–C bond construction from olefins and radicals. J. Am.
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cycloreductions and cycloadditions catalyzed by Co(dpm)2-silane
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Fehlhaber, H.-W. Structures and stereochemistry of new labdane
diterpenoids from Coleus forskohlii briq. Tetrahedron Lett. 1977, 18,
1669.
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signaling. Cell. Mol. Neurobiol. 2003, 23, 305.
(dpm
= 2,2,6,6-tetramethylheptane-3,5-dionate): mechanism and
partitioning of hydrometallative versus anion radical pathways. J. Am.
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(8) For relevant reductive aldol reactions see: Isayama, S.; Mukai-
yama, T. Cobalt(II) catalyzed coupling reaction of α,β-unsaturated
compounds with aldehydes by the use of phenylsilane. New method
(17) Hosoda, S.; Motomiya, T.; Katagiri, T.; Takano, T.; Sasaya-
ma, S.; Toshima, H.; Ogawa, N. Acute effect of NHK477, a novel
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(18) (a) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. A synthetic
(22) For a detailed study of closely related addition-epimerization
sequences see ref. (21)(a). For previous application in the synthesis of
forskolin see ref. (18)(e).
(23) For example of relevant reactivity see: Shih, T.-L.; Lin, Y.-L.
Epoxidation of protected (1,4,5)-cyclohex-2-ene-triols and their acid
hydrolysis to synthesize quercitols from D-(–)-quinic acid. Synth.
Commun. 2005, 35, 1809.
(24) Myers, A. G.; Widdowson, K. L. Direct transformation of 2,3-
epoxy alcohols into hydroxyl carbonates under mildly basic condi-
tions. Tetrahedron Lett. 1988, 29, 6389.
route to forskolin. J. Am. Chem. Soc. 1987, 109, 8115. (b) Hashimoto,
S.; Sakata, S.; Sonegawa, M.; Ikegami, S. A total synthesis of (±)-
forskolin. J. Am. Chem. Soc. 1988, 110, 3670. (c) Corey, E. J.; Da
Silva Jardine, P.; Rohloff, J. C. Total synthesis of (±)-forskolin. J.
Am. Chem. Soc. 1988, 110, 3672. (d) Delpech, B.; Calvo, D.; Lett, R.
Total synthesis of forskolin - part II. Tetrahedron Lett. 1996, 37,
1019. (e) Hylse, O.; Maier, L.; Kučera, R.; Perečko, T.; Svobodová,
A.; Kubala, L.; Paruch, K.; Švenda, J. A concise synthesis of for-
skolin. Angew. Chem. Int. Ed. 2017, 56, 12586.
1
2
3
4
5
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7
8
9
(19) See SI for details.
(25) For related displacement of epoxide with carbamate see ref.
(18)(d).
(26) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J. Reac-
tions of forskolin, a biologically active diterpenoid from Coleus for-
skohlii. J. Chem. Soc., Perkin Trans. 1 1982, 767.
(20) Liu, D.; Canales, E.; Corey, E. J. Chiral oxazaborolidine–
aluminum bromide complexes are unusually powerful and effective
catalysts for enantioselective Diels-Alder reactions. J. Am. Chem. Soc.
2007, 129, 1498.
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(21) (a) Kienzle, F.; Stadlweiser, J.; Rank, W.; Schönholzer, P. Die
synthese des labdanditerpenes erigerol und analoger verbindungen.
Helv. Chim. Acta 1990, 73, 1108. (b) See ref. (18)(e).
radical-polar
crossover
annulation
R5
O
R5
R1
OH
Me
O
O
R1
R3
H
37–73%
R2
R4
R4
R3
R2
R6
O
R6
Me
Me
Me
H
Me
forskolin:
prepared in 14 steps from
2,6-dimethylbenzoquinone
OH
O
OAc
OH
Me
OH
H
H
H
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