Forskolin Editing via Radical Iodo- A nd Hydroalkylation

Article abstract of DOI:10.1055/s-0040-1706003

The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- A nd reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl?-catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

Full text of DOI:10.1055/s-0040-1706003

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
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Synthesis
E. Pruteanu et al.
Feature
Forskolin Editing via Radical Iodo- and Hydroalkylation
Elena Pruteanu◊a,b
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Nicholas D. C. Tappin◊a
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14R
O
HO
O
CO2Et
Vladilena Gîrbua,b
Olga Morarescub
0
0
0
0
-0
0
0
1
-
7
7
6
1
-
0
4
2
X
O
ICH2CO2Et
DLP, 77 °C
14R-major
0
0
0
0
-
0
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7
1
5
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8
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OAc
I
Fabrice Dénèsa
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-3
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O
H
H
O
HO
OH
Veaceslav Kulciţki*b
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-
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6
1
5
O
OH
14S
CO2Et
14S-major
Philippe Renaud*a
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OH
OH
O
OAc ICH2CO2Et
OH
OH
Et B, air, rt
3
a
OAc
Department of Chemistry, Biochemistry and Pharmaceutical Sciences,
University of Bern, Freiestrasse 3, 3012 Bern, Switzerland
philippe.renaud@dcb.unibe.ch
Institute of Chemistry MECR, 3 Academiei str., MD-2028, Chișinău,
Republic of Moldova
then KHF2
(
–)-forskolin
H
b
kulcitki@yahoo.com
◊
These authors contributed equally
Corresponding Authors
6
7
Received: 01.11.2020
Accepted after revision: 30.11.2020
Published online: 11.01.2021
trients, plant growth hormones, and the method of ex-
8
traction. Presently, plant extracts remain the main source
DOI: 10.1055/s-0040-1706003; Art ID: ss-2020-z0561-fa
of forskolin: studies to improve the efficiency of its ex-
traction from C. forskohlii and that of the plant’s growth
rate are in progress. Forskolin (1) and its water-soluble ana-
logue, colforsin daropate hydrochloride (NKH 477; 2) (Fig-
ure 1), possess a wide range of biological effects. The main
mechanism of action is based on the direct activation of the
Abstract The modification of highly oxygenated forskolin as well as
manoyl and epi-manoyl oxide, two less functionalized model substrates
sharing the same polycyclic skeleton, via intermolecular carbon-cen-
tered radical addition to the vinyl moiety has been investigated. Highly
regio- and reasonably stereoselective iodine atom transfer radical addi-
tion (ATRA) reactions were developed. Unprotected forskolin afforded
an unexpected cyclic ether derivative. Protection of the 1,3-diol as an
acetonide led the formation of the iodine ATRA product. Interestingly,
by changing the mode of initiation of the radical process, in situ protec-
tion of the forskolin 1,3-diol moiety as a cyclic boronic ester took place
during the iodine ATRA process without disruption of the radical chain
process. This very mild radical-mediated in situ protection of 1,3-diol is
expected to be of interest for a broad range of radical and non-radical
transformations. Finally, by using our recently developed tert-butyl-
catechol-mediated hydroalkylation procedure, highly efficient prepara-
tion of forskolin derivatives bearing an extra ester or sulfone group was
achieved.
9
adenylate cyclase enzyme, which generates cAMP, a trans-
mitter of intracellular signals that regulates many cellular
1
0
functions. Beneficial effects of forskolin (1) have been re-
ported in preclinical and clinical studies on the treatment
of cystic fibrosis, asthma, cardiovascular diseases, liver fi-
11
brosis, and others. Importantly, it has numerous relevant
anticancer effects, such as the inhibition of proliferation,
motility, and migration in many types of cancer cells, and
also the enhancement of the sensitivity to conventional an-
tineoplastic drugs, which makes forskolin (1) a promising
molecule for potential application in cancer therapy.12
Key words radical reaction, natural product modification, alkenes,
boronic ester, 1,3-diol protecting group, triethylborane
O
O
HO
HO
O
O
OH
OH
OH
O
Introduction
OAc
OAc
H
H
NMe2·HCl
(
–)-forskolin 1
colforsin daropate
hydrochloride
(NKH 477) 2
(
–)-Forskolin (1; 7-acetoxy-1,6,9-trihydroxy-8,13-
O
(
formerly colforsin)
epoxylabd-14-en-11-one) (Figure 1), is a polyfunctional-
ized labdane diterpene presenting the 8,13-epoxylabd-14-
en-11-one diterpenoid skeleton and isolated in 1977 from
Coleus forskohlii, an important medicinal plant which grows
in tropical and subtropical regions of Asia and Africa. C.
AcO
AcO
1
O
R
ptychantin A 3 (R = OH)
ptychantin B 4 (R = OAc)
H
H
2
OAc
forskohlii is the only species among Coleus and Plectranthus
Figure 1 (–)-Forskolin (1) and related labdane diterpenoids
genera of the Labiatae family found to contain forskolin
3
(
1). This natural product is mostly present in the roots, be-
Since its isolation, the polyoxygenated, tricyclic skeleton
4
tween 0.1% and 2.8% only. The content in the plant extracts
depends on different factors including the genotype, the
biotechnology approaches, the organic and inorganic nu-
of forskolin (1) has stimulated the development of different
4
13,14
strategies for its synthesis.
Similarly, different routes
5
have been explored for its hemisynthesis. For instance,
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1248
Synthesis
E. Pruteanu et al.
Feature
Biographical Sketches
(
from left to right) Elena Pruteanu studied
mations of natural compounds under the
guidance of Prof. Philippe Renaud (Universi-
ty of Bern). Now, she works as a scientific
researcher in the Laboratory of Chemistry
of Natural and Biologically Active Com-
pounds, Institute of Chemistry MECR,
Chișinău.
Veaceslav Kulciţki, born 1969 in Oliscani
(Republic of Moldova), studied chemistry at
the Moldovan State University (MSU), Chisi-
nau. He prepared his Ph.D. thesis under the
guidance of Prof. Pavel Vlad and Prof. Nicon
Ungur, receiving a doctoral degree in 1998
from the Academy of Sciences of Moldova
(ASM). His postdoctoral training included
several research stays with Prof. Tadeusz
Chojnacki (IBB/PAN, Warsaw), Prof. Guido
Cimino (IBC/CNR, Naples), Prof. Daniel
Baden (CMS/UNCW, Wilmington), Prof. Oli-
ver Reiser (Regensburg University). He was
appointed associate professor in the Insti-
tute of Chemistry ASM in 2006 and in 2018
defended his habilitation thesis. Now, he is
the head of Laboratory of Chemistry of Nat-
ural and Biologically Active Compounds, In-
stitute of Chemistry MECR, Chișinău. His
field of scientific activity is synthetic organ-
ic chemistry and chemistry of natural prod-
ucts.
chemistry at the University of Academy of
Sciences of Moldova (now USDC). She per-
formed her Bachelor and Master thesis un-
der the supervision of Prof. V. Kulciţki. After
receiving a Swiss Government Scholarship
(
ESKAS) she started her Ph.D. in the group
of Prof. P. Renaud. Her doctoral research is
focused on implementation and optimiza-
tion of radical-mediated modifications of
natural scaffolds, biological properties, and
structure activity relationship studies.
Fabrice Dénès was born in Paris (France).
He completed his undergraduate and post-
graduate studies at the University Pierre et
Marie Curie (Paris, France) and received his
Ph.D. in 2002 under the supervision of Prof.
J.-F. Normant and F. Chemla. He then joined
the group of Prof. P. Renaud at the Universi-
ty of Bern (Switzerland) as a Postdoctoral
Associate. In 2005, he joined the University
of Nantes (France) as an Assistant Professor
in the group of Prof. J. Lebreton (lab. CEIS-
AM). In 2020, he moved back to the Univer-
sity of Bern (Switzerland) where he joined
the group of Prof. P. Renaud as a Research
Associate. His current research interests in-
clude the development of synthetic meth-
ods based on radical and organometallic
reactions and their application to the syn-
thesis of relevant targets.
Nicholas D. C. Tappin was born and bred
1
0 km east of Manchester in the foothills of
the Peak District in the UK. He obtained his
M.Sci. in 2009 from Queens’ College, Uni-
versity of Cambridge, after studies in flow
chemistry at the Innovative Technology
Centre under the direction of Prof. Steven
V. Ley. In 2019 he received his doctorate
(
summa cum laude) on the subject of 1-bo-
ryl radicals under the tutelage of Prof.
Philippe Renaud and continued there, at
the University of Bern, Switzerland, for
short postdoctoral studies on new radical
initiation strategies and radical chain reac-
tions involving organoboron. In 2020 he
joined the Magauer Group at the University
of Innsbruck, Austria on a Swiss National
Science Foundation fellowship to work on
the total synthesis of natural products.
Philippe Renaud was born in Neuchâtel
(Switzerland). After undergraduate study at
the University of Neuchâtel, he continued
his education at the ETH Zürich through
Ph.D. studies in 1986 under the supervision
of Prof. D. Seebach. In 1987, he was a post-
doctoral associate of Prof. M. A. Fox at the
University of Texas at Austin. He started in
1988 an independent research program at
the University of Lausanne. He moved in
Olga Morarescu was born in Edineţ, Re-
public of Moldova in 1985, studied chemis-
try at the Moldova State University (MSU),
Chişinau. Her Ph.D. thesis was prepared un-
der the supervision of Professor Dr. Hab.
Nicon Ungur on the synthetic transforma-
tions of ent-kaur-16-en-19-oic and ent-tra-
chyloban-19-oic acids; her doctoral degree
was awarded in 2019 by the Institute of
Chemistry MECR. Since 2016, she has worked
as a scientific researcher in the Laboratory of
Chemistry of Natural and Biologically Active
Compounds, Institute of Chemistry MECR,
Chișinău. Her research is focused on organic
synthesis and chemistry of natural products.
Vladilena Gîrbu, born 1989 in Chisinau
(
1993 to the University of Fribourg as an as-
Republic of Moldova), studied chemistry
sociate professor. Since 2001, he is profes-
sor of organic chemistry at the University of
Bern. His research interests include the de-
velopment of synthetic methods with par-
ticular emphasis on radical reactions and
the synthesis of biologically active com-
pounds.
and chemical engineering at the Moldovan
State University (MSU), Chisinau. She pre-
pared her Ph.D. thesis under the guidance
of Prof. Dr. hab. Veaceslav Kulciţki and Prof.
Dr. hab. Nicon Ungur, receiving a doctoral
degree in 2020 from the Institute of Chem-
istry MECR. In 2017 she had a research
scholarship and worked on radical transfor-
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1249
Synthesis
E. Pruteanu et al.
Feature
labdane diterpenoids ptychantin A and B (3 and 4, Figure 1)
are relatively abundant compounds isolated from Ptychan-
bonate moiety, 5-exo-trig cyclization of the resulting tertia-
ry carbon-centered radical intermediate, and hydrogen
1
5
19
thus striatus and they have been used as starting material
atom transfer from the chain carrier reagent (Scheme 1).
1
6
for the hemisynthesis of (–)-forskolin (1). In contrast, ex-
amples of late-stage functionalization of forskolin (1), to
prepare analogues for SARs studies or biological applica-
tions, are rare. Analogues have been prepared using well-
established strategies by taking advantage of the free hy-
droxyl groups in forskolin (1) (Figure 2). 1-O-Propargyl-
forskolin was synthesized and engaged in copper-catalyzed
Huisgen cycloaddition to provide analogues containing a
triazole moiety such as 5.17 Other ester analogues have been
S
O
O
O
O
O
Bu3SnS
Bu3SnH, AIBN
O
O
O
toluene, reflux
85%
OAc
OAc
H
H
OH
OH
9
8
Scheme 1 König’s attempt to prepare deoxygenated (–)-forskolin un-
der radical conditions
1
25
obtained to prepare, among others,
I-labeled analogues
1
8
such as 7. Tetracyclic analogue 6 presenting a seven-
membered-ring carbonate moiety was prepared by König
and co-workers by treatment of thionocarbonate 8 (see
Scheme 1 for structure) with 1,3-dimethyl-2-phenyl-1,3,2-
diazaphospholidine (Corey–Winter conditions).19
With the exception of this last example, in which the
participation of the alkenyl side chain was not originally
planned, to our knowledge no effort has been made to use
the C=C bond as a partner in radical transformations.
Therefore, we decided to explore the reactivity of the pen-
dant terminal alkene in radical C–C bond-forming reac-
tions. Since this allylic ether is electron-rich, radical reac-
O
O
O
O
O
N
tions employing reagents of the general formula I-CH -EWG
EWG = electron-withdrawing group) seemed appropriate
2
Ph
N
O
O
N
(
OH
OAc
OAc
to achieve this goal. Accordingly, we have selected the atom
H
H
OH
OH
25,26
transfer radical addition (ATRA), pioneered by Kharasch,
5
6
2
7
28,29
O
H
Curran, and others
and the hydroalkylation reaction
HO
OH
30
125I
developed by some of us to explore the reactivity of the
forskolin skeleton under radical conditions. Before tackling
the polyhydroxylated skeleton of forskolin, we decided to
investigate the reactivity of less functionalized analogues.
As model substrates for our study, we first turned our at-
tention to manoyl oxide (10) and epi-manoyl oxide (epi-10),
which share with forskolin the same tricyclic skeleton, with
a terminal alkene in a sterically hindered environment.
These products are easily prepared in one step from sclare-
ol, a readily available natural product from Salvia sclarea es-
O
O
OH
OH
H
N
O
N
H
O
7
Figure 2 Examples of analogues prepared from (–)-forskolin
Despite the fact that unactivated alkenes can serve as an
entry to introduce diversity on the skeleton of natural prod-
ucts, this opportunity has received only limited attention
in the case of forskolin. Simple hydrogenation of forskolin
has been carried out to convert the vinyl side chain into the
corresponding ethyl group21 as well as for the preparation
2
0
3
1
sential oil production. Diastereomers 10 and epi-10 can be
separated by flash column chromatography using 10%
AgNO impregnated silica gel.
3
3
of the corresponding radioisotopic labeled [ H]-dihydrocol-
2
2
forsin. The side chain has been elongated by Lett and
Delpech using a sequence involving ozonolysis and subse-
quent Wittig olefination.23 Romo and co-workers showed
that alkynyl diazo ester could be employed under rhodium
Iodoalkylation (ATRA reaction) of Manoyl and
epi-Manoyl Oxide
2
4
catalysis to form cyclopropane derivatives from forskolin.
The ATRA was first investigated with ethyl iodoacetate,
using dilauroyl peroxide (DLP) as a radical initiator.28 Iodo-
alkylation of manoyl oxide (10) with ethyl iodoacetate in
the presence of sub-stoichiometric quantities of DLP (5
mol% every 2 h) resulted in low conversion and long reac-
tion times (10–18 h, in refluxing benzene). Under these
conditions, radical deiodination and ionic elimination side
reactions led to the corresponding reduced product and
alkenes. Increasing the quantity of DLP (1.0 equiv) led to
nearly full conversion of 10 after only 3 hours. Gratifyingly,
under these conditions the expected adduct 11 was ob-
tained in 74% yield as a mixture of diastereomers (dr 61:39)
The alkenyl side chain in forskolin was found to participate
in 1,3-dipolar additions as illustrated by the formation of
bis-cycloadducts as side products in the reaction of 1-O-
propargylforskolin with oximes aiming at the synthesis of
isoxazoles. In an attempt to remove the 9-hydroxy group
via the thiocarbonate 8 under classical radical conditions
21
(
Bu SnH, AIBN), König and co-workers reported that, in-
3
stead of the expected deoxygenated product, tetracyclic for-
skolin analogue 9 was obtained in a highly stereoselective
manner, following regioselective cleavage of the thionocar-
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1250
Synthesis
E. Pruteanu et al.
Feature
(
Scheme 2a). Longer reaction times and higher loading of
rated with one keto group and three hydroxyl groups, one
of them being acetylated. (–)-Forskolin (1) was first en-
gaged in an iodoalkylation reaction in refluxing ethyl ace-
tate using DLP (1 equiv) as a radical initiator (Scheme 3).
Under these reaction conditions, a clean reaction took place
that delivered the tetracyclic compound 12 in high yield as
mixture of diastereomers (dr 78:22) instead of the expected
iodoalkylated product. The structure of this new forskolin
analogue was determined by careful NMR analysis and un-
ambiguously confirmed by X-ray diffraction data analysis of
a single crystal of the major isomer of (14R)-12. Interesting-
ly, the biological properties of the forskolin analogue 15-hy-
droxy-9,14-epoxyforskolin presenting a similar tetracyclic
initiator resulted in increased amounts of side products,
thus reducing the efficiency of the reaction. Surprisingly,
the use of milder reaction conditions (Et B/air, room tem-
perature) to achieve the iodoalkylation led to an increase in
the amount of decomposition products. The presence of an
inorganic base as an additive (NaHCO ) did not significantly
improve the yields, the iodinated adduct being isolated in a
modest 37% yield (dr 64:36). With epi-manoyl oxide (epi-
1
product epi-11 (78–80% yields, Scheme 2b), presumably as
a result of a slightly higher stability of the iodinated prod-
uct towards elimination under the reaction conditions. The
S-configuration at the C-14 position of the minor isomer of
3
3
0) both reaction conditions gave good yields of the ATRA
3
3
skeleton has been previously reported.
epi-11 (EWG = CO Et) was unambiguously assigned by sin-
2
H
1
gle crystal X-ray diffraction data analysis.32 Interestingly,
the diastereoselectivity of these ATRA reactions remains
unusually high for such a transformation, especially in the
case of epi-manoyl oxide (epi-10).
4R
O
HO
O
CO2Et
O
9
12
14
OAc
O
11
9
1
5
H
HO
13
OH
ICH2CO2Et (2 equiv)
DLP (1 equiv)
O
(14R)-12 (major)
I
2
3
1
4
1
0
8
CO2Et
12
14
5
OH
6
+
EtOAc, reflux, 4 h
77% (dr 78:22)
14S
1
0
1
15
CO2Et
7
OAc
O
1
3
H
1
4
H
HO
O
9
O
O
OH
2
3
ICH2CO2Et
A or B
11
1
8
(a)
O
H
6
H
(–)-forskolin 1
9
5
7
A: 74% (dr = 61:39)
B: 37% (dr = 64:36)
H
H
OAc
1
0
H
OH
14S)-12 (minor)
I
(
14R
CO2Et
O
H
(
14R)-epi-11 (major)
H
O
ICH2CO2Et
A or B
+
(b)
(14R)-12 (major)
I
H
H
14S
CO2Et
epi-10
O
H
(14S)-epi-11 (minor)
A: 80% (dr = 73:27)
B: 78% (dr = 74:26)
H
Scheme 3 Alkoxyalkylation of (–)-forskolin (1) in refluxing EtOAc; X-ray
single crystal structure of (14R)-12 (major diastereomer) (50% probabil-
ity ellipsoids)
A: ICH2CO2Et (2 equiv), DLP (1 equiv),
A: benzene, reflux, 3 h
B: ICH2CO2Et (1.5 equiv), Et3B (1.3 equiv), air,
B: NaHCO3 (1 equiv), CH2Cl2, rt, 1 h
The formation of tetracyclic compound 12 arises from
the nucleophilic displacement of the iodine atom in the
ATRA product intermediate via an intramolecular nucleop-
hilic substitution with inversion. The cyclization of the ma-
jor isomer appeared to be faster since mainly the major di-
astereomer of 12 was observed after 2 hours together with
the minor diastereomer of the iodoalkylated product. In
situ nucleophilic displacement of the iodide atom in I-ATRA
products has been reported by using ICH CO SnBu in re-
(
14S)-epi-11 (minor)
Scheme 2 Iodoalkylation of manoyl oxide (10) and epi-manoyl oxide
epi-10); X-ray single crystal structure of (14S)-epi-11 (minor diastereo-
mer) (50% probability ellipsoids)
(
2
2
3
3
4
fluxing benzene, or with 2-iodoacetamide and 2-iodoace-
35
Iodoalkylation and Alkoxyalkylation of
tic acid upon heating in water or ethanol. In the second
case, the ATRA reaction with 2-iodoacetic acid led to a mix-
ture of -lactone and tetrahydrofuran when carried out on
pent-4-en-1-ol, indicating that displacement of the iodide
(
–)-Forskolin
3
5
Encouraged by our results in the manoyl oxide and epi-
could also be achieved by a free hydroxyl group. Similarly,
the reaction of -iodo esters and -iodonitriles with allylic
alcohols initiated by Et B/O and carried out in water,
manoyl series, we undertook the exploration of iodoalkyla-
tion to modify the potentially more problematic forskolin.
It shares the same skeleton with manoyl oxide but is deco-
3
2
ethanol, or a mixture of both, in the presence of a base,
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1251
Synthesis
E. Pruteanu et al.
Feature
delivered epoxides through the cyclization of the halohy-
drin intermediates.36 In contrast, no cyclization involving
the C–I bond was observed in less polar solvents (1,2-di-
chloroethane, ethyl acetate, or toluene) by Cordero-Vargas
and co-workers. They showed that, upon initiation with
DLP in refluxing 1,2-dichloroethane, the ATRA reaction of
iodoacetic acid with allylic alcohols exclusively led to -
iodo--lactones following preferential lactonization of the
ATRA products between the carboxylic acid moiety and the
free hydroxyl group.37 The products resulting from bromine
atom transfer are more robust but can nevertheless be con-
verted into -lactones upon heating.26
uct, but a cyclic boronic ester indicating that in situ protec-
39,40
tion of the diol is taking place.
By monitoring the
1
reaction by H NMR, the formation of the unprotected iodo-
alkylated product 16 could be observed. After 2 hours, the
starting forskolin (1) was fully consumed and only the cy-
clic boronic ester 15 could be isolated. Deprotection of the
1,3-diol was achieved in a methanolic solution of KHF to
2
afford the sensitive iodide 16 in almost quantitative yield as
4
0,41
a 70:30 mixture of diastereomers.
The S-configuration
at C-14 of the major diastereomer of 16 was only tentatively
assigned by analogy with the iodoalkylation of forskolin
acetonide 13 that proceeds with a comparable diastereose-
lectivity (see Scheme 4). In a pleasing and unplanned way,
In the conversion of (–)-forskolin into tetracyclic com-
pound 12, the efficient formation of the ether ring under
our reaction conditions is facilitated by the proximity of the
OH at C-9 and the iodide at C-14, which favors the nucleop-
hilic substitution reaction.38 To prevent the cyclization
leading to 12, we decided to protect (–)-forskolin as forsko-
lin acetonide 13. This was easily accomplished by protec-
tion of the 1,3-diol moiety in (–)-forskolin with 2,2-dime-
this approach uses Et B not only as a radical initiator but
3
also as a reagent for the protection of the reactive 1,3-diol
moiety providing, after easy hydrolysis of the boronic ester,
the desired product of iodoalkylation in excellent yield
compared to the classical acetonide protection described in
Scheme 4.
14
Et
O
I
thoxypropane. In this case, the I-ATRA reaction was car-
O
B O
HO
2 2
ICH CO Et (1.5 equiv)
O
CO2Et
ried out in the presence of a base (NaHCO ) and gave the
Et B (1.3 equiv)
3
O
3
O
NaHCO3 (1 equiv)
corresponding adduct 14 in a moderate isolated yield of 42%
OH
OH
CH2Cl2, rt, 2 h
79% (14S/14R 70:30)
OAc
(
dr 71:29) (Scheme 4). The relative configuration at C-14 of
H
OAc
H
OH
the major diastereomer of 14 was assigned by single crystal
15
(
–)-forskolin (1)
X-ray diffraction data analysis.32
I
I
O
O
OH
14S
CO2Et OH
14R
CO2Et
I
O
O
KHF2 (3 equiv)
MeOH, rt, 2 h
O
+
OH
OH
OH
O
O
14S
CO2Et
OAc
OAc
91%
O
H
H
OH
(14R)-16 (minor)
O
O
(14S)-14 (major)
(
14S)-16 (major)
ICH2CO2Et (1.5 equiv)
Et3B (1.3 equiv)
NaHCO3 (1 equiv)
O
OAc
I
H
O
OH
Scheme 5 Iodoalkylation of unprotected (–)-forskolin (1); configura-
tion at C-14 tentatively assigned by comparison with the product of
iodoalkylation of forskolin acetonide 13
+
CH2Cl2, rt, 1 h
42% (dr 71:29)
OAc
O
O
H
O
14R
CO2Et
OH
forskolin acetonide 13
O
(
14R)-14 (minor)
OAc
Guindon and co-workers observed a similar in situ pro-
H
OH
tection of 1,3-diols as boronic esters using Et B and air
3
4
2
during the generation of -ester radicals. However, the
mechanism of formation of the cyclic boronic ester was not
elucidated. Interestingly, only one equivalent of Et B was
3
necessary to protect the 1,3-diol moiety and to initiate the
ATRA process. A tentative mechanism involving a radical
(14S)-14 (major)
chain process is proposed in Scheme 6. This mechanism is
Scheme 4 Iodoalkylation of the (–)-forskolin acetonide 13; X-ray single
crystal structure of (14S)-14 (major diastereomer) (50% probability el-
lipsoids)
43,44
based on the observation that Et B–water
and Et B–
3
3
4
4–46
MeOH
complexes are efficient reducing agent for car-
bon-centered radicals. The rate constant for the hydrogen
atom transfer from the complex Et B–MeOH to a secondary
3
6
–1 –1
46
The iodoalkylation of unprotected (–)-forskolin (1) was
alkyl radical has been estimated in the 10 M
s
range.
then carried out at room temperature in CH Cl2 using 1
Remarkably, the formation of the cyclic boronic ester does
not compete with the radical initiation process since the
ethyl radical (in red) is regenerated during the formation of
the boronic ester. This radical can either initiate the iodine
ATRA process or be further involved in the boronic ester
formation.
2
equivalent of Et B and air to initiate the reaction. Under
3
these reaction conditions, the product of iodoalkylation 15
was obtained in high yield, without subsequent nucleophil-
ic displacement of the iodine atom (Scheme 5). Interesting-
ly, 15 was not the expected unprotected iodine ATRA prod-
©
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1252
Synthesis
E. Pruteanu et al.
Feature
transfer (i.e., attack) from the re face (front side) is partially
blocked (or disfavored) by the substituents on the polycyclic
framework (axial H-atom at C-7, axial OR group at C-9 and
equatorial OAc group at C-7) and the si face (back side) at-
tack becomes the major pathway (14S/14R 71:29 for 14),
Scheme 4). The same model may also explain the stereose-
lectivity outcome with unprotected forskolin (1) and its cy-
clic boronic ester derivative.
(
ATRA intemediate)
CH2CO2Et
initiation
of ATRA Et–I
air
ICH2CO2Et
Et3B
Et
Et
Et
B
Et3B
O
H
O
O
OH
Et B OH OH
3
3
Et B
Et–H
chain process
leading to
boronic ester
formation
Et Et
backside
(si face)
B
Et3B
CO2Et
O
O
O
OH
Me
Me
Me
Me
Me
Me
CO2Et
Me
Me
O
chair
O
H
H
I
Me
H
Me
H
Et–H
Et Et
front side
(re face)
Et
H
H
11r
11 (dr 64:36)
Et2B
B
H
O
OH
O
O
backside (re face)
attack favored
CO2Et
2
CO Et
I
H
H
Me
Scheme 6 Initiation of ATRA and radical chain mechanism leading to
cyclic ethylboronic ester
14R
Me
Me
Me
Me
Me
Me
Me
O
O
chair
Me
H
Me
H
H
H
epi-11r
(14R)-epi-11 (14R/14S 74:26)
Stereoselectivity of the Iodoalkylation
backside
si face)
attack favored
(
boat
Me O Me
OH
Me O Me
Me
The stereoselectivity of the iodoalkylation deserves
some comment as the levels of stereoselectivity are from
moderate to unusually high for such an iodine ATRA reac-
tion involving non-stabilized acyclic radicals.47 The ATRA
reaction with manoyl oxide (10) goes through the radical
adduct 11r with an all-chair conformation (Scheme 7). In
this conformation, the radical center is located on an equa-
torial side chain, far away from the bulky substituents on
the polycyclic framework. As a result, a very modest level of
stereoselectivity (dr 64:36) was observed (Scheme 2a). The
iodoalkylation of epi-manoyl oxide (epi-10) gave a higher
level of stereocontrol (14R/14S 74:26, Scheme 2b) that can
be rationalized by an iodine atom transfer step taking place
from the least hindered re face of the carbon-centered radi-
cal intermediate in the conformation epi-11r depicted in
Scheme 7. In this all-chair conformation, the side chain
bearing the carbon-centered radical adopts an axial posi-
tion, the hydrogen atom on the radical pointing towards the
tetrahydropyran ring to minimize steric interactions with
the angular methyl group. The latter shields the si face
Me
Me
Me
OH
O
O
OAc
H
OAc 14S
O
O
Me
O
O
H
I
Me
H
H
Me Me
Me Me
CO2Et
2
CO Et
1
4r
(
14S)-14 (14S/14R 71:29)
Scheme 7 Stereoselectivity of the iodoalkylation of 10, epi-10, and 13
Hydroalkylation of Manoyl and epi-Manoyl
Oxide
Next, we turned our attention to the hydroalkylation re-
action developed by some of us that proved to be effective
3
0,49
for terminal and non-terminal alkenes.
The reaction re-
quires the combination of Et B and a catechol derivative,
3
which plays the role of hydrogen atom donor. Unlike tin hy-
dride, catechol derivatives are very selective for nucleophil-
ic carbon-centered radicals. As a result of favorable polar ef-
fects in the transition state, the hydrogen atom transfer
(HAT) from 4-tert-butylcatechol (TBC) is about three orders
of magnitude faster to secondary alkyl radicals than to ester
(front side) of the radical epi-11r making the re face (back
6
–1 –1
side) attack more favored. Despite the same relative config-
uration at C-13 as manoyl oxide (10), (–)-forskolin (1) as
well as its acetonide 13, adopt a different conformation. It
was demonstrated by NMR analysis that (–)-forskolin (1)
adopts a flattened boat-like conformation of ring C in solu-
enolyl radicals (k = 1.3 × 10 M
s
at 80 °C for secondary
H
3
–1 –1
alkyl radical; k ≈ 2 × 10 M
s
at 80 °C for an ester enolyl
H
3
0
radical). This allows for efficient intra- and intermolecular
additions to take place with electrophilic carbon-centered
radicals and electron-rich alkenes. A simplified mechanism
of the hydroalkylation of non-activated alkenes with iodo-
acetate is depicted in Scheme 8. It involves the fast iodine
atom abstraction from ethyl iodoacetate by the ethyl radical
4
8
tion. A similar boat-like conformation was also observed
for in the X-ray single crystal structure of the acetonide 13
(
Scheme 7). In this conformation, the vinyl side chain
7
–1 –1
50
adopts a flagpole position with the hydrogen atom at the
internal carbon atom of the alkene pointing towards the
ring. This is very likely to be the case as well for the second-
ary carbon-centered radical intermediate 14r. Iodine atom
(kIAT = 2.6 ×10 M
s
in benzene at 50 °C) generated in
the initiation step from Et B by its reaction with molecular
oxygen. The resulting electrophilic enolyl radical A adds
to the terminal position of the electron-rich alkene to give a
3
5
1
©
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1253
Synthesis
E. Pruteanu et al.
Feature
secondary alkyl radical B that can either be trapped by HAT
from the catechol derivative to give the expected product or
alternatively, abstracts the iodine atom from ethyl iodoace-
tate. Based upon the relative rate constants, the second
pathway is more likely, at least in the early stage of the reac-
tion. The secondary alkyl iodide C formed in the ATRA pro-
cess can undergo iodine atom abstraction by the ethyl radi-
cal to regenerate the secondary alkyl radical B. At high con-
version, the concentration in ethyl iodoacetate become
sufficiently low for the HAT from 4-tert-butylcatechol to
progressively overcome the conversion of B into C. The oxy-
of Et B (added in two portions) and 2 equiv of TBC. With
3
these optimized reaction conditions in hand, the reaction
was extended to the use of iodomethyl phenyl sulfone, and
the corresponding sulfone adduct 17b was obtained in 38%
yield (51% yield, brsm). Similar conditions applied to epi-
manoyl oxide (epi-10) led to the corresponding ester epi-
17a and sulfone adduct epi-17b in 67% (81% brsm) and 37%
(62% brsm) yields, respectively. Trace amounts (≤5% in most
cases) of uncharacterized olefinic byproducts were ob-
served in all cases.
•
EWG
gen-centered radical ArO generated in the HAT step reacts
then with Et B to propagate the radical chain. It has also
3
ICH2EWG (1.2 equiv)
3
been demonstrated that the exceptional efficacy of the hy-
droalkylation reaction is also linked to a repair mechanism
Et B (2.6 equiv), air
TBC (2 equiv)
NaHCO3 (1 equiv)
O
O
H
3
0,52
H
involving TBC and Et B.
3
CH Cl , rt
2
2
H
H
10
17a (EWG = CO2Et): 48% (58% brsm)
ArOBEt2
ICH2CO2Et
Et–I
Et
17b (EWG = PhSO2): 38% (51% brsm)
Et3B
ArO
EWG
Et3B, air
ICH2CO2Et
CH2CO2Et
A
ICH2EWG (1.5 equiv)
Et3B (2.6 equiv), air
TBC (2 equiv)
R
H
R
R
O
ArOH
CO2Et
O
NaHCO3 (1 equiv)
H
B
H
CH2Cl2, rt
CO2Et
H
H
epi-10
epi-17a (EWG = CO2Et): 67% (81% brsm)
epi-17b (EWG = PhSO2): 37% (62% brsm)
Et–I
ICH2CO2Et
Et–I
Et
R
Scheme 9 Hydroalkylation of manoyl oxide (10) and epi-manoyl oxide
(epi-10)
I
C
CO2Et
Hydroalkylation of (–)-Forskolin
Scheme 8 Simplified mechanism for the Et B-mediated hydroalkyla-
3
tion of alkenes
The hydroalkylation of forskolin acetonide 13 was inves-
tigated next. As previously observed in the manoyl oxide
series, the formation of non-iodinated products via the hy-
droalkylation reaction could be achieved in higher yields
than the corresponding iodoalkylation, presumably due to
the in situ reduction of the sensitive iodides (Scheme 10).
Hydroalkylation of the acetonide 13 with ethyl iodoacetate
and iodomethyl phenyl sulfone under the optimized condi-
tions provided 18a and 18b in 59% and 31% yields, respec-
tively. The cleavage of the acetonide moiety in 18a and 18b
to give 20a and 20b was not attempted. Gratifyingly, hy-
droalkylation of the unprotected (–)-forskolin (1) under our
optimized reaction conditions gave the corresponding
functionalized adducts 19a in 91% yield (compared to 79%
for the iodoalkylation reaction). The hydroalkylation with
iodomethyl phenyl sulfone gave the corresponding sulfone
adducts 19b in 63% yield from (–)-forskolin (1). The subse-
quent deprotection of boronic esters 19a and 19b was
achieved in high yield upon treatment with methanolic
A rapid optimization of the previously reported reaction
conditions was performed on manoyl oxide (10). Based
upon our previous work on the iodoalkylation of manoyl
oxide, which stressed the relative instability of iodinated
products in this series, NaHCO was selected as an additive
3
to trap the hydroiodic acid and/or molecular iodine formed
under the reaction conditions and which presumably leads
to the decomposition of the product in an autocatalytic pro-
cess. The hydroalkylation reaction was tested in the manoyl
oxide and epi-manoyl oxide series (Scheme 9) with two dif-
ferent reagents (ethyl iodoacetate and iodomethyl phenyl
sulfone). Under standard reaction conditions (1.2 equiv of
ethyl iodoacetate and 1.3 equiv of Et B), with only 1 equiv
3
of tert-butylcatechol (TBC) as a reducing agent, no reduced
product was formed and the only product isolated from the
reaction mixture was the product of iodoalkylation 11. In-
creasing the quantity of TBC to 2 equiv allowed for the iso-
lation of the desired reduced product in low yield (19%).
Eventually, a satisfactory 48% yield (58% yield, brsm) of hy-
droalkylation product 17a was obtained by using 2.6 equiv
KHF at room temperature, delivering the unprotected for-
2
skolin adducts 20a and 20b.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1254
Synthesis
E. Pruteanu et al.
Feature
ing alkene residues. The mild radical chemistry reported
here offers many opportunities to prepare elaborated ana-
logues for biological studies that are not accessible by con-
ventional methods.
ICH2EWG (1.5 equiv)
Et3B (2.6 equiv), air
TBC (2 equiv)
O
O
O
O
O
EWG
O
O
O
NaHCO3 (1 equiv)
CH2Cl2, rt
OAc
OAc
H
H
OH
OH
forskolin acetonide 13
1
1
8a (EWG = CO2Et): 59%
8b (EWG = PhSO2): 31%
For details of techniques, materials, and instrumentation, see the
Supporting Information.
Et
ICH2EWG (1.5 equiv)
O
O
B
HO
Et B (2.6 equiv), air
3
EWG
O
O
9
O
TBC (2 equiv)
NaHCO3 (1 equiv)
O
Manoyl Oxide (10) and epi-Manoyl Oxide (epi-10)
OH
OAc
CH2Cl2, rt
To a solution of sclareol (3.0 g, 9.72 mmol) in deoxygenated dry MeCN
H
OAc
OH
H
(
90 mL) under an inert atmosphere was added cerium ammonium ni-
OH
(
–)-forskolin 1
trate (6.4 g, 1.2 equiv). The mixture was stirred at rt and monitored by
TLC. Upon completion (10–11 h), the solvent was removed under re-
duced pressure. The mixture was diluted with water and extracted
1
1
9a (EWG = CO2Et): 91%
9b (EWG = PhSO2): 63%
O
OH
EWG
with Et O (2 ×). The combined organic phases were washed succes-
O
2
KHF2 (3.0 equiv)
MeOH, rt
OH
OH
sively with sat. aq NaHCO soln, water, and brine, dried (Na SO ), fil-
3
2
4
2
0a (EWG = CO2Et): 90%
OAc
tered, and concentrated under reduced pressure. The crude was puri-
H
20b (EWG = PhSO2): 88%
fied by flash column chromatography (Et O/pentane 1:99) to afford
2
the mixture of manoyl oxide (10) and its 13-epimer epi-10 (2.10 g,
Scheme 10 Hydroalkylation of forskolin (1) and its acetonide 13
6
5%, dr 3:1). The diastereomers were isolated individual on a 10%
AgNO3 impregnated silica gel flash column chromatography
(
Et O/pentane from 1:99 to 3:97) to afford the 13-epi-manoyl oxide
2
(
epi-10; 0.5 g) and manoyl oxide (10; 1.4 g). Physical and spectral data
3
1b,53,54
Conclusion
are in accordance with literature data.
We have reported examples of functionalization of the
forskolin skeleton via intermolecular radical additions to
the alkenyl moiety. The studies conducted on manoyl oxide
and epi-manoyl oxide as model substrates revealed that the
iodinated products resulting from an iodine ATRA process
were formed with complete regioselectivity in moderate to
good yields and stereoselectivities. The use of the recently
Manoyl Oxide (10)
Colorless oil (white solid at 4 °C); R
= 0.6 (Et O/pentane 5:95) and R =
2 f
f
0
.31 (AgNO /silica 1:10; Et O/pentane 5:95).
3
2
1H NMR (CDCl
(
, 300 MHz):  = 5.87 (dd, J = 17.4, 10.7 Hz, 1 H), 5.14
dd, J = 17.4, 1.6 Hz, 1 H), 4.91 (dd, J = 10.7, 1.6 Hz, 1 H), 1.86–1.71 (m,
3
2 H), 1.69–1.31 (m, 11 H), 1.29 (d, J = 1.1 Hz, 3 H), 1.27 (s, 3 H), 1.26–
1.05 (m, 2 H), 0.93 (dd, J = 12.2, 2.5 Hz, 1 H), 0.85 (s, 3 H), 0.79 (s, 3 H),
0.78 (s, 3 H).
developed Et B/catechol-mediated radical hydroalkylation
3
1
3
C NMR (CDCl , 75 MHz):  = 148.1, 110.4, 75.2, 73.4, 56.6, 55.8, 43.4,
3
reaction proved to be particularly well-adapted to access
stable functionalized derivatives in these series. The highly
oxygenated skeleton of (–)-forskolin, with its free hydroxyl
group at C-9, led to the formation of an interesting cyclic
ether during initial attempts to run the iodoalkylation in re-
fluxing ethyl acetate. This tetracyclic product results for-
mally from an alkoxyalkylation of the vinyl moiety and in-
volving an iodine ATRA followed by an intramolecular nuc-
leophilic substitution process. As anticipated, the ionic
substitution in forskolin could be avoided by running the
reaction with an acetonide-protected derivative. Deploying
4
2.2, 39.1, 37.1, 35.8, 33.5, 33.4, 28.7, 25.7, 21.5, 20.1, 18.7, 15.6, 15.4.
1
3-epi-Manoyl Oxide (epi-10)
White powder; R = 0.6 (Et O/pentane 5:95) and R = 0.62 (AgNO /sili-
ca 1:10; Et O/pentane 5:95); mp 95.5–97.3 °C (Et O/pentane) (Lit.
mp 96 °C).
f
2
f
3
54
2
2
1
H NMR (CDCl , 300 MHz):  = 6.00 (dd, J = 17.9, 11.0 Hz, 1 H), 5.01–
3
4
.86 (m, 2 H), 2.27–2.13 (m, 1 H), 1.76 (dt, J = 11.2, 3.0 Hz, 1 H), 1.63
(ddt, J = 10.0, 6.3, 3.7 Hz, 3 H), 1.56–1.32 (m, 7 H), 1.32–1.07 (m, 3 H),
1.22 (s, 3 H), 1.12 (s, 3 H), 0.94 (dd, J = 12.1, 2.5 Hz, 1 H), 0.84 (s, 3 H),
0
.77 (s, 3 H), 0.71 (s, 3 H).
13C NMR (CDCl
, 75 MHz):  = 147.8, 109.6, 76.2, 73.4, 58.6, 56.6, 43.2,
2.3, 39.5, 36.9, 35.0, 33.47, 33.41, 32.8, 24.1, 21.4, 20.0, 18.8, 16.01,
5.99.
Et B as a radical initiator circumnavigated the necessity for
3
3
4
1
a protecting group installation prior to ATRA functionaliza-
tion, thanks to the in situ formation of a cyclic boronic ester
intermediate which acts as a protecting group for the free
hydroxyl groups. Thus, the iodinated compounds could be
isolated in excellent yields. This unexpected in situ protec-
tion of diols under mild radical conditions may be of gener-
al interest for radical reactions (and probably other con-
certed ionic reactions) involving 1,3-diols. Finally, the hy-
droalkylation of forskolin proceeds efficiently and
demonstrates further the potential of this method to intro-
duce functionalized side chain in natural products contain-
Forskolin 1,9-Acetonide (13)
To a solution of forskolin (1; 616 mg, 1.5 mmol) in acetone (30 mL,
0.05 M) at 0 °C under an inert atmosphere was added 2,2-dimethoxy-
propane (4.3 mL, 23 equiv) and p-TsOH (32 mg, 12 mol%). The mix-
ture was stirred at rt and monitored by TLC. Upon completion (6 h),
sat. aq NaHCO3 soln was added and the mixture was extracted with
Et
O (2 ×). The combined organic phases were washed with water and
2
brine, dried (Na SO ), filtered, and concentrated under reduced pres-
sure. The crude was purified by flash column chromatography
2
4
©
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1255
Synthesis
E. Pruteanu et al.
Feature
(
EtOAc/heptane 1:5) to afford 13 (620 mg, 92%) as a white powder;
0.61 (s, 3 H); minor (selected peaks)  = 4.08–4.00 (m, 1 H), 3.92 (q, J =
7.1 Hz, 2 H), 2.70–0.62 (m, 20 H), 1.28 (s, 3 H), 1.12 (s, 3 H), 0.937 (t,
J = 7.1 Hz, 3 H), 0.79 (s, 3 H), 0.75 (s, 3 H), 0.62 (s, 3 H).
R = 0.54 (EtOAc/heptane 3:7); mp 207.9–210.3 °C (Et O/pentane)
f
2
5
5
(Lit. mp 224–225 °C). Physical and spectral data are in accordance
1
4,55
with literature data.
1
13
C NMR (major, C D , 75 MHz,):  = 172.2, 76.0, 74.1, 60.2, 57.7, 56.5,
6
6
H NMR (CDCl , 300 MHz):  = 5.91 (dd, J = 17.1, 10.6 Hz, 1 H), 5.33 (d,
54.2, 43.1, 42.4, 39.2, 36.9, 36.6, 35.4, 33.5, 33.4, 30.6, 24.6, 22.9, 21.5,
20.1, 19.0, 15.9, 15.8, 14.3.
3
J = 3.7 Hz, 1 H), 5.25 (dd, J = 17.1, 1.6 Hz, 1 H), 4.92 (dd, J = 10.6, 1.6 Hz,
1
H), 4.43 (s, 1 H), 4.28 (dd, J = 3.9, 2.0 Hz, 1 H), 2.95 (d, J = 19.4 Hz, 1
H), 2.63 (d, J = 19.4 Hz, 1 H), 2.22 (d, J = 2.5 Hz, 1 H), 2.14 (s, 3 H),
.13–2.00 (m, 1 H), 1.78 (td, J = 13.5, 4.2 Hz, 1 H), 1.70 (br s, 1 H), 1.60
s, 3 H), 1.47 (s, 3 H), 1.42–1.07 (m, 1 H), 1.39 (s, 3 H), 1.27 (s, 3 H),
13
C NMR (minor, C D , 75 MHz,):  = 172.5, 75.8, 74.0, 60.2, 58.1, 56.4,
6
6
5
2
5.1, 43.0, 42.3, 39.2, 39.1, 36.9, 35.4, 33.4, 33.4, 30.5, 25.4, 24.7, 21.5,
0.1, 19.0, 16.0, 15.9, 14.3.
2
(
HRMS (ESI): m/z [M + H]+ calcd for C24H42IO : 505.2179; found:
3
1.26 (m, 7 H), 1.09–1.02 (m, 1 H), 1.01 (s, 3 H).
5
05.2155.
1
3
C NMR (75 MHz, CDCl ):  = 207.4, 169.8, 147.1, 110.6, 99.9, 81.0,
3
8
2
0.1, 76.7, 73.8, 70.2, 70.1, 50.1, 42.7, 37.8, 36.2, 34.4, 33.6, 33.3, 31.6,
5.1, 23.7, 22.9, 22.3, 21.3, 17.6.
Ethyl (13S,14R/S)-14-Iodo-8,13-epoxylabdan-15-ylacetate (epi-11)
According to GPA from epi-manoyl oxide (epi-10; 51 mg, 0.172
mmol), NaHCO (15 mg, 0.172 mmol), ethyl iodoacetate (75 mg, 0.344
mmol), and DLP (72 mg, 0.172 mmol) in dry benzene (1.7 mL). The
crude mixture was purified by flash column chromatography
3
Carboiodination Initiated by Dilauroyl Peroxide (DLP); General
Procedure A (GPA)
To a mixture of alkene (1.0 equiv) and NaHCO (1.0 equiv) in dry ben-
3
(Et O/pentane 2:98) to afford the mixture of diastereomers (69 mg,
2
zene or EtOAc (0.1 M to alkene) under an inert atmosphere were add-
ed sequentially the alkylating reagent (2.0 equiv) and DLP (1.0 equiv).
The mixture was warmed up to reflux (90 °C bath temperature) and
monitored by TLC. After completion (3 h), the mixture was diluted
8
0%, dr 73:27).
According to GPB from epi-manoyl oxide (epi-10; 69 mg, 0.233
mmol), NaHCO3 (20 mg, 1.0 equiv), ethyl iodoacetate (75 mg, 1.5
equiv), and Et B (0.27 mL, 1.3 equiv, 1.15 M in dry C D ) in dry CH Cl
3
6
6
2
2
with deionized water and extracted with Et O (3 ×). The combined or-
2
(
1.3 mL). The crude mixture was purified by flash column chromatog-
ganic phases were washed water and brine, dried (Na SO ), filtered,
2
4
raphy (Et O/pentane, gradient from 2:98 to 3:97) to afford a mixture
2
and concentrated under reduced pressure (with a low bath tempera-
ture).
of diastereomers (92 mg, 78%, dr 74:26).
The mixture of diastereomers was purified by flash column chroma-
tography (Et O/pentane, gradient from 0:100 to 3:97), to afford clean
fraction of major epi-11 and enriched fraction of minor epi-11 (80%).
The enriched fraction of the minor diastereomer recrystallized at 4 °C
Carboiodination Initiated by Triethylborane (Et B); General Proce-
dure B (GPB)
2
3
To a mixture of alkene (1.0 equiv) and NaHCO3 (1.0 equiv) in dry
CH Cl (0.1 M to alkene) under inert atmosphere were added, sequen-
(
Et O/pentane 1:5; fridge, sensitive to light) to give a single crystal
2
2
2
suitable for X-ray diffraction analysis.
tially the alkylating reagent (1.2–1.5 equiv) and Et B (1.3 equiv, 1.15
3
M in dry benzene). The mixture was opened to air with a CaCl guard
tube, protected from light, and stirred vigorously at rt and monitored
by TLC. After completion (1 h), the mixture was diluted with deion-
2
(
14R)-epi-11 (major)
Colorless oil; R = 0.32 (Et +25 (c 1.0, CH Cl ).
O/pentane 5:95); [] 20
2 D 2 2
f
ized water and extracted with Et O (3 ×). The combined organic
IR: 2979, 2923, 2866, 1733, 1457, 1374, 1179, 1073, 957, 593 cm–1
2
.
phases were washed with brine, dried (Na SO ), filtered, and concen-
2
4
1
H NMR (C D , 300 MHz):  = 4.24 (dd, J = 11.3, 1.7 Hz, 1 H), 3.95 (q, J =
6
6
trated under reduced pressure (with a low bath temperature). In or-
der to remove borane residues, the mixture was then filtered through
7
.1 Hz, 2 H), 2.83–2.68 (m, 2 H), 2.42–2.33 (m, 1 H), 2.28–2.10 (m, 2
H), 1.80–1.66 (m, 2 H), 1.40 (s, 3 H), 1.58–1.25 (m, 7 H), 1.22–1.02 (m,
H), 1.01 (d, J = 1.0 Hz, 3 H), 0.98–0.93 (m, 3 H), 0.79 (s, 3 H), 0.74 (dd,
J = 12.4, 2.3 Hz, 1 H), 0.74 (s, 3 H), 0.63 (dd, J = 12.5, 4.1 Hz, 1 H), 0.59
a short pad of neutral alumina (eluting with Et O) and concentrated
2
4
under reduced pressure.
(
1
s, 3 H).
Ethyl (13R,14R/S)-14-Iodo-8,13-epoxylabdan-15-ylacetate (11)
According to GPA from manoyl oxide (10; 64 mg, 0.22 mmol), NaHCO3
3
C NMR (C D , 75 MHz):  = 172.2, 75.8, 75.0, 60.3, 56.5, 55.2, 49.3,
6
6
4
1
3.6, 42.3, 39.0, 37.1, 36.4, 35.4, 33.5, 33.3, 30.8, 25.7, 25.1, 21.5, 20.2,
8.9, 15.4, 15.1, 14.3.
(
(
18 mg, 0.216 mmol), ethyl iodoacetate (94 mg, 0.43 mmol), and DLP
91 mg, 0.22 mmol) in dry benzene (2.0 mL). The crude mixture was
HRMS (ESI): m/z [M + Na]+ calcd for C24H41IO Na: 527.1998; found:
5
purified by flash column chromatography (Et O/pentane 2:98) to af-
3
2
27.1964.
ford an inseparable mixture of diastereomers 11 (81 mg, 74%, dr
6
1:39).
According to GPB from manoyl oxide (10; 73 mg, 0.25 mmol), NaHCO3
21 mg, 1.0 equiv), ethyl iodoacetate (80 mg, 1.5 equiv), and Et B (0.28
(
14S)-epi-11 (minor)
White powder; Rf = 0.29 (Et O/pentane 5:95); mp 65.4–67.9 °C
(
IR: 2977, 2923, 2865, 2844, 1731, 1456, 1375, 1260, 961 cm–1
(
2
3
Et O/pentane).
2
mL, 1.15 M in C D ) in dry CH Cl (1.3 mL). The crude mixture was
purified by flash column chromatography (Et O/pentane 2:98) to af-
6
6
2
2
2
.
ford an inseparable mixture of diastereomers 11 (46 mg, 37%, dr
1
H NMR (C D , 300 MHz, selected peaks):  = 4.40 (dd, J = 11.4, 2.1 Hz,
H), 3.93 (q, J = 7.1 Hz, 2 H), 2.61–2.50 (m, 2 H), 2.13–1.96 (m, 2 H),
6
6
64:36).
1
Colorless oil; R = 0.3 (Et O/pentane 5:95).
1.95–1.87 (m, 1 H), 1.34 (m, 6 H), 0.95 (t, J = 7.1 Hz, 3 H), 0.79 (s, 3 H),
f
2
IR: 2977, 2924, 2864, 1733, 1464, 1375, 1180, 1116, 956, 497 cm–1
.
0.74 (s, 3 H), 0.65 (s, 3 H).
1
3
1
C NMR (C D , 75 MHz):  = 172.5, 76.0, 74.6, 60.3, 56.6, 55.2, 54.9,
6 6
H NMR (mixture, C D , 300 MHz): major (selected peaks)  = 4.08–
6
6
4
1
3.9, 42.4, 39.2, 37.2, 35.4, 33.5, 33.3, 31.9, 30.7, 28.7, 24.7, 21.5, 20.2,
8.9, 15.5, 15.4, 14.3.
4.00 (m, 1 H), 3.92 (q, J = 7.1 Hz, 2 H), 2.70–0.62 (m, 20 H), 1.28 (s, 3
H), 1.07 (s, 3 H), 0.940 (t, J = 7.1 Hz, 3 H), 0.81 (s, 3 H), 0.75 (s, 3 H),
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1256
Synthesis
E. Pruteanu et al.
Feature
HRMS (ESI): m/z [M + Na]+ calcd for C24H41IO Na: 527.1998; found:
1
H NMR (CDCl , 400 MHz):  = 5.30 (d, J = 3.9 Hz, 1 H), 4.44 (t, J = 3.4
3
3
5
27.1964.
Hz, 1 H), 4.25–4.20 (m, 1 H), 4.16–4.14 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2
H), 3.40 (d, J = 16.5 Hz, 1 H), 2.63–2.49 (m, 2 H), 2.50 (d, J = 16.5 Hz, 1
H), 2.25 (d, J = 2.8 Hz, 1 H), 2.23–2.15 (m, 1 H), 2.14 (s, 3 H), 2.08 (tdd,
J = 14.3, 4.5, 2.0 Hz, 1 H), 1.92–1.82 (m, 1 H), 1.78 (td, J = 13.5, 4.3 Hz,
Ethyl (13R,14R/S)-7-Acetoxy-1,6-dihydroxy-11-oxo-8,13:9,14-
diepoxylabdan-15-ylacetate (12)
1
(
1
H), 1.65 (s, 3 H), 1.50 (s, 3 H), 1.49–1.40 (m, 1 H), 1.46 (s, 3 H), 1.44
s, 3 H), 1.43 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.26 (s, 3 H), 1.05 (ddd, J =
3.1, 4.3, 2.4 Hz, 1 H), 1.00 (s, 3 H).
13C NMR (CDCl
, 101 MHz):  = 208.2, 172.9, 169.6, 100.2, 81.9, 81.7,
According to GPA from forskolin (1; 85 mg, 0.207 mmol), ethyl iodo-
acetate (89 mg, 0.414 mmol), and DLP (83 mg, 0.207 mmol) in dry
EtOAc (2.0 mL). The crude mixture was purified by flash column chro-
matography (EtOAc/heptane 1:4) to isolate a mixture of diastereo-
mers 12 (79 mg, 77%, dr 78:22). A clean fraction of each diastereomer
was identified and concentrated for full characterization. Major iso-
3
76.3, 76.0, 70.2, 70.1, 60.7, 51.1, 47.5, 42.8, 38.2, 36.4, 34.5, 34.3, 33.5,
31.5, 30.7, 29.3, 25.2, 23.8, 23.1, 22.1, 21.5, 17.6, 14.4.
mer (14R)-12 crystallized from Et O/pentane (1:5) to give a single
crystal suitable for X-ray diffraction analysis.
HRMS (ESI): m/z [M + Na]+ calcd for C29H45IO Na: 687.2006; found:
2
9
6
87.2009.
(
14S)-12 (minor)
(
14S)-14 (major)
20
Yellowish oil; R = 0.42 (EtOAc/heptanes 6:4); []D –47 (c 0.7, CH Cl ).
IR: 3489, 3421, 2978, 2928, 2869, 2856, 1733, 1446, 1371, 989 cm–1
f
2
2
Colorless crystals; R = 0.33 (Et O/pentane 4:6); mp 147.7–151.9 °C
(Et
f
20
2
.
2
O/pentane); []
D
–48.17 (c 1.85, CH Cl ).
2 2
1
IR: 3447, 2976, 2933, 2860, 1735, 1715, 1445, 1374, 1250, 1116 cm–1
H NMR (CDCl , 400 MHz):  = 5.32 (d, J = 3.8 Hz, 1 H), 4.44 (t, J = 3.3
.
3
Hz, 1 H), 4.31 (t, J = 2.7 Hz, 1 H), 4.18–4.09 (m, 3 H), 2.65 (d, J = 19.2
Hz, 1 H), 2.57–2.38 (m, 3 H), 2.18 (s, 3 H), 2.11 (d, J = 2.8 Hz, 1 H),
1
H NMR (CDCl , 400 MHz):  = 5.26 (d, J = 3.8 Hz, 1 H), 4.48 (dd, J =
3
1
4
2
0.8, 2.1 Hz, 1 H), 4.39 (t, J = 3.3 Hz, 1 H), 4.23 (dd, J = 3.9, 2.0 Hz, 1 H),
.15 (q, J = 7.2 Hz, 2 H), 3.49 (d, J = 19.0 Hz, 1 H), 2.65–2.57 (m, 1 H),
.54 (d, J = 19.0 Hz, 1 H), 2.49–2.39 (m, 1 H), 2.39–2.29 (m, 1 H), 2.18
2.07–1.85 (m, 3 H), 1.67–1.56 (m, 1 H), 1.50 (s, 3 H), 1.49 (s, 3 H),
1.50–1.43 (m, 1 H), 1.26 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.15 (s, 3 H),
1.05 (s, 3 H), 1.07–1.01 (m, 1 H).
(
d, J = 2.6 Hz, 1 H), 2.13 (s, 3 H), 2.07 (tdd, J = 14.8, 4.6, 2.3 Hz, 1 H),
1
3
C NMR (CDCl , 101 MHz):  = 201.0, 172.5, 170.1, 85.4, 81.4, 79.4,
2.01–1.92 (m, 1 H), 1.77 (td, J = 13.5, 4.3 Hz, 1 H), 1.55 (s, 3 H), 1.50–
1.40 (m, 1 H), 1.47 (s, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.37 (s, 3 H), 1.27
(t, J = 7.1 Hz, 3 H), 1.25 (s, 3 H), 1.05 (ddd, J = 13.0, 4.3, 2.4 Hz, 1 H),
0.99 (s, 3 H).
13C NMR (CDCl
7
3
3
7
2
7.1, 73.1, 72.9, 69.9, 60.9, 46.0, 43.9, 42.9, 36.1, 34.8, 33.2, 30.7, 27.6,
5.9, 25.1, 24.9, 21.8, 21.3, 19.9, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C26H41O : 497.2751; found:
9
496.2723.
3
, 101 MHz):  = 206.8, 172.8, 169.4, 100.0, 81.9, 81.4,
6.05, 76.02, 70.3, 70.2, 60.5, 52.2, 50.9, 42.7, 38.0, 36.2, 35.6, 34.4,
3.6, 31.9, 30.2, 28.0, 25.1, 23.7, 22.7, 22.2, 21.3, 17.6, 14.4.
(
14R)-12 (major)
HRMS (ESI): m/z [M + Na]+ calcd for C29H45IO Na: 687.2006; found:
687.2009.
White powder; R = 0.36 (EtOAc/heptanes 6:4); mp 127.5–128.2 °C
9
f
2
0
(
TBME/heptanes 1:4); []D –9 (c 1.5, CH Cl ).
2 2
IR: 3481, 3434, 2977, 2929, 2869, 1731, 1446, 1372, 990 cm–1
.
Ethyl (13R,14R/S)-7-Acetoxy-1,6,9-trihydroxy-11-oxo-8,13-epox-
ylabdan-15-ylacetate (16)
1
H NMR (CDCl , 300 MHz):  = 5.44 (d, J = 3.8 Hz, 1 H), 4.40 (t, J = 3.3
3
Hz, 1 H), 4.34–4.31 (m, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.91 (dd, J = 10.8,
According to GPB from forskolin (1; 100 mg, 0.241 mmol), NaHCO3
3.4 Hz, 1 H), 2.62 (d, J = 18.9 Hz, 1 H), 2.60–2.32 (m, 3 H), 2.38 (d, J =
18.9 Hz, 1 H), 2.17 (s, 3 H), 2.04 (d, J = 2.6 Hz, 1 H), 2.00–1.82 (m, 3 H),
1.49 (s, 3 H), 1.49–1.44 (m, 1 H), 1.47 (s, 3 H), 1.25 (s, 3 H), 1.24 (t, J =
7.2 Hz, 3 H), 1.10 (s, 3 H), 1.04 (s, 3 H), 1.03–0.99 (m, 1 H).
(
21 mg, 0.241 mmol), ethyl iodoacetate (77 mg, 0.362 mmol), and
Et B (0.21 mL, 0.241 mmol, 1.15 M in dry C D ) in dry CH Cl (1.5 mL).
3
6
6
2
2
The mixture was stirred at rt for 2 h (for complete formation of boron-
ic ester derivative; more stable). The crude mixture was purified by
1
3
C NMR (CDCl , 75 MHz):  = 201.5, 173.0, 169.9, 84.7, 80.0, 79.2,
3
flash column chromatography (Et O/pentane 3:7) to afford 15 as a
2
7
2
6.9, 73.1, 70.7, 69.7, 60.8, 50.6, 43.6, 43.0, 35.9, 34.7, 33.5, 29.6, 25.8,
5.14, 25.10, 24.6, 21.5, 21.3, 19.6, 14.3.
mixture of diastereomers (118 mg, 79%, dr 70:30). Enriched fractions
of each diastereomer were collected for individual characterization.
HRMS (ESI): m/z [M + H]+ calcd for C26H41O : 497.2751; found:
9
497.2745.
(
14S)-15 (major)
Whitish oil; R = 0.36 (Et O/pentane 1:1).
IR: 3470, 2975, 2952, 2933, 2874, 1721, 1441, 1374, 1342, 1213 cm–1
f
2
Ethyl (13R,14R/S)-7-Acetoxy-6-hydroxy-1,9-(isopropylidenedi-
oxy)-14-iodo-11-oxo-8,13-epoxylabdan-15-ylacetate (14)
.
1
H NMR (C D , 400 MHz):  = 5.47 (d, J = 4.0 Hz, 1 H), 4.58 (d, J = 3.1
6
6
According to GPB from forskolin 1,9-acetonide (13; 79 mg, 0.17
mmol), NaHCO3 (15 mg, 1.0 equiv), ethyl iodoacetate (56 mg, 1.5
equiv), and Et B (0.2 mL, 1.15 M in dry C D ) in dry CH Cl (1.0 mL).
Hz, 1 H), 4.48 (dd, J = 10.8, 1.8 Hz, 1 H), 4.23 (dt, J = 4.3, 2.3 Hz, 1 H),
3
2
1
.96 (q, J = 7.1 Hz, 2 H), 3.39 (d, J = 16.4 Hz, 1 H), 2.74–2.64 (m, 2 H),
.53–2.44 (m, 1 H), 2.37 (d, J = 16.4 Hz, 1 H), 2.24–2.12 (m, 1 H), 1.92–
.84 (m, 1 H), 1.83 (s, 3 H), 1.62 (s, 3 H), 1.61–1.51 (m, 2 H), 1.50 (s, 3
3
6
6
2
2
The crude mixture was purified by flash column chromatography
Et O/pentane 1:4) to afford 14 as a mixture of diastereomers (44 mg,
(
2
H), 1.49 (d, J = 2.8 Hz, 1 H), 1.30 (s, 3 H), 1.21 (s, 3 H), 1.04 (t, J = 7.7 Hz,
42%, dr 71:29). Individual fractions of each diastereomer were isolat-
3
0
H), 0.97 (t, J = 7.1 Hz, 3 H), 0.94–0.89 (m, 1 H), 0.86–0.79 (m, 2 H),
.80 (s, 3 H).
ed for characterization.
1
3
C NMR (C D , 101 MHz):  = 201.3, 171.2, 168.9, 81.9, 81.8, 77.5,
(
14R)-14 (minor)
6
6
7
2
5.9, 73.4, 70.1, 60.3, 51.4, 50.4, 43.4, 40.1, 36.4, 35.2, 34.2, 32.9, 30.9,
7.5, 24.6, 23.8, 22.9, 20.7, 18.9, 14.3, 8.3, 7.3 (broad signal).
2
0
Colorless oil; R = 0.44 (Et O/pentane 4:6); [] –19 (c 1.05, CH Cl ).
IR: 3503, 2977, 2928, 2858, 1726, 1715, 1456, 1374, 1249, 907 cm–1
f
2
D
2
2
.
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1257
Synthesis
E. Pruteanu et al.
Feature
1
1
B NMR (C D , 96 MHz):  = 31.8.
2.40 (dt, J = 16.5, 7.7 Hz, 1 H), 2.30 (d, J = 14.9 Hz, 1 H), 2.21–2.13 (m,
1 H), 2.12 (d, J = 2.9 Hz, 1 H), 2.00–1.92 (m, 1 H), 1.92–1.86 (m, 1 H),
6
6
HRMS (ESI): m/z [M + H]+ calcd for C28H45BIO : 663.2201; found:
6
9
1
1
3
.86 (s, 3 H), 1.64 (s, 3 H), 1.58 (s, 3 H), 1.48 (td, J = 14.6, 3.6 Hz, 1 H),
.28 (br s, 2 × 3 H), 0.95 (t, J = 7.1 Hz, 3 H), 0.89–0.81 (m, 2 H), 0.86 (s,
H).
63.2196.
(
14R)-15 (minor)
1
3
C NMR (C D , 101 MHz):  = 207.0, 172.5, 169.1, 82.8, 82.7, 77.5,
6
6
Whitish oil; R = 0.45 (Et O/pentane 1:1).
IR: 3515, 2975, 2951, 2933, 2874, 1721, 1374, 1342, 1211, 1056 cm–1
f
2
7
2
7.0, 74.6, 70.3, 60.3, 51.8, 46.7, 43.3, 43.2, 36.3, 34.7, 34.4, 32.7, 30.9,
8.6, 27.0, 24.3, 24.0, 21.0, 20.2, 14.2.
.
1
H NMR (C D , 400 MHz):  = 5.52 (d, J = 3.9 Hz, 1 H), 4.58 (t, J = 2.9
HRMS (ESI): m/z [M + H]+ calcd for C26H42IO : 625.1874; found:
6
6
9
Hz, 1 H), 4.40 (dd, J = 11.4, 1.8 Hz, 1 H), 4.36 (t, J = 3.1 Hz, 1 H), 3.93 (q,
J = 7.1 Hz, 2 H), 3.28 (d, J = 15.7 Hz, 1 H), 2.50–2.44 (m, 2 H), 2.25 (d,
J = 15.7 Hz, 1 H), 2.05–1.95 (m, 1 H), 1.94–1.86 (m, 1 H), 1.85 (s, 3 H),
1
1
6
25.1848.3.
Hydroalkylation; General Procedure C (GPC)
.75 (ddt, J = 11.5, 9.1, 5.7 Hz, 1 H), 1.67 (s, 3 H), 1.62 (s, 3 H), 1.65–
.56 (m, 2 H), 1.55 (d, J = 2.9 Hz, 1 H), 1.24 (s, 3 H), 1.22 (s, 3 H), 1.09
To a solution of alkene (1.0 equiv) and NaHCO3 (1.0 equiv) in dry
CH Cl2 (0.1 M to alkene) under an inert atmosphere were added se-
(t, J = 7.7 Hz, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 0.96–0.91 (m, 1 H), 0.93–
2
quentially the alkylating reagent (1.2–1.5 equiv), 4-tert-butylcatechol
0
1
.87 (m, 2 H), 0.85 (s, 3 H).
3
(
1.0 equiv), and Et B (1.3 equiv, 1.15 M in benzene). The mixture was
3
C NMR (C D , 101 MHz):  = 202.9, 172.8, 168.9, 81.65, 81.56, 77.0,
6
6
opened to air with a CaCl guard tube, covered from light, and stirred
2
7
2
6.2, 73.4, 70.0, 60.4, 50.9, 46.8, 43.4, 41.0, 37.1, 34.3, 34.2, 32.9, 30.9,
8.3, 24.7, 23.9, 23.4, 21.0, 18.9, 14.2, 8.3, 7.3 (broad signal).
vigorously at rt. After 1 h, 4-tert-butylcatechol (1.0 equiv) and Et3B
(
1.3 equiv) were added to the mixture. After completion (3 h), the
1
1
B NMR (C D , 96 MHz):  = 31.7.
mixture was diluted with sat. aq Na S O soln and extracted with Et O
6
6
2
2
3
2
HRMS (ESI): m/z [M + H]+ calcd for C28H45BIO : 663.2201; found:
(3 ×). The combined organic phases were washed successively with
deionized water and brine, dried (Na SO ), filtered, and concentrated
under atmospheric pressure. The crude was passed through a short
9
6
63.2197.
To a solution of iodoboronic esters 15 (120 mg, 0.181 mmol) in MeOH
3.6 mL, 0.05 M) was added to KHF (43 mg, 0.544 mmol, 3.0 equiv) at
2
4
pad of neutral alumina (elution with Et O) in order to remove borane
2
(
2
residues and concentrated under reduced pressure. The crude mix-
ture was then purified by flash column chromatography. If required,
removal of the olefinic side products (elimination products) possess-
rt. The mixture was stirred for 2 h at rt, then concentrated in vacuo.
The residue was diluted with Et O, filtered, and concentrated under
2
reduced pressure. The crude mixture was purified by flash column
chromatography (EtOAc/heptane 23:77) to afford 16 (102 mg, 91%, dr
ing same R value as the hydroalkylation product was done by epoxi-
f
dation on the crude mixture (see below).
6
8:32) as an inseparable mixture of diastereomers.
Epoxidation with meta-Chloroperbenzoic Acid (m-CPBA); General
Procedure D (GPD)
(
14S)-16 (major)
According to procedure above, major isomer (14S)-16 (17 mg, 87%)
was obtained from major isomer (14S)-15 (21 mg, 0.03 mmol) and
KHF (8 mg, 0.09 mmol) in MeOH (1.0 mL) for individual characteriza-
tion; colorless oil; R = 0.49 (EtOAc/heptane 4:6).
IR: 3480, 3406, 2980, 2927, 2870, 2856, 1715, 1372, 1235, 1037 cm–1
To a solution of mixture composed of the hydroalkylation product
and olefinic side products (0.05–0.1 mmol) in CH Cl2 (0.5–1 mL, 0.1
2
2
M) were added NaHCO3 (1.0 equiv) and m-CPBA (1.0 equiv) at 0 °C.
The mixture was stirred at rt under inert atmosphere until comple-
f
.
tion (1–3 h). The mixture was diluted with sat. aq NaHCO soln and
3
1
H NMR (C D , 400 MHz):  = 5.81 (d, J = 4.1 Hz, 1 H), 4.75–4.71 (m, 1
extracted with Et
successively with water and brine, dried (Na
2
O (3 ×). The combined organic phases were washed
SO ), filtered, and con-
6
6
H), 4.45 (s, 1 H), 4.30 (d, J = 3.6 Hz, 1 H), 3.97 (q, J = 7.1 Hz, 2 H), 3.77
2
4
(
(
d, J = 16.4 Hz, 1 H), 2.78 (dddd, J = 16.5, 8.3, 6.3, 2.2 Hz, 1 H), 2.67
ddd, J = 16.2, 9.7, 4.6 Hz, 1 H), 2.52–2.41 (m, 1 H), 2.44 (d, J = 16.3 Hz,
centrated under reduced pressure. The crude mixture was purified by
flash column chromatography.
1
1
H), 2.25–2.13 (m, 1 H), 2.10 (d, J = 3.3 Hz, 1 H), 2.00–1.88 (m, 1 H),
.83 (s, 3 H), 1.57–1.47 (m, 1 H), 1.54 (s, 3 H), 1.52 (s, 3 H), 1.38 (s, 3
Ethyl (13R)-8,13-Epoxylabdan-15-ylacetate (17a)
H), 1.27 (s, 3 H), 0.99 (t, J = 7.1 Hz, 3 H), 0.93–0.85 (m, 2 H), 0.85–0.83
According to GPC from manoyl oxide (10; 52 mg, 0.177 mmol),
(m, 3 H).
NaHCO (15 mg, 0.177 mmol), ethyl iodoacetate (46 mg, 0.213 mmol),
3
1
3
C NMR (C D , 101 MHz):  = 205.2, 172.2, 168.6, 104.3, 82.9, 82.5,
tert-butylcatechol (2 portions, 2 × 30 mg, 2 × 0.177 mmol), and Et3B
(2 portions, 2 × 0.2 mL, 2 × 0.230 mmol, 1.15 M in benzene) in dry
CH Cl (1.0 mL). The crude was subjected to epoxidation (according to
6
6
7
3
7.3, 76.7, 74.8, 70.3, 60.2, 51.4, 51.3, 43.3, 43.1, 36.3, 35.3, 34.4, 32.8,
0.9, 27.0, 24.3, 23.5, 20.8, 20.3, 14.3.
2
2
HRMS (ESI): m/z [M + Na]+ calcd for C26H41IO Na: 647.1693; found:
GPD) and then purified by flash column chromatography (EtOAc/hep-
9
tane 4:96) to give 17a (32 mg, 48%, 58% brsm) as a colorless oil; R =
647.1662.
f
2
0
0
.42 (Et O/pentane 1:9); [] +3 (c 1.03, CH Cl ).
2 D 2 2
IR: 2981, 2935, 2925, 2868, 1737, 1463, 1373, 1235, 1044, 847, 634
(
14R)-16 (minor)
–
1
cm
.
According to procedure above, minor isomer (14R)-16 (18 mg, quant)
was obtained from minor isomer (14R)-15 (20 mg, 0.03 mmol) and
1H NMR (CDCl
, 300 MHz):  = 4.11 (q, J = 7.1 Hz, 2 H), 2.26 (td, J = 7.5,
3
KHF (8 mg, 0.09 mmol) in MeOH (1.0 mL) for individual characteriza-
2.6 Hz, 2 H), 1.75–1.57 (m, 4 H), 1.53 (m, 3 H), 1.48–1.28 (m, 5 H),
1.28–1.20 (m, 2 H), 1.25 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.20 (s, 3 H),
1.17–1.03 (m, 3 H), 0.92 (dd, J = 12.3, 3.0 Hz, 1 H), 0.88–0.83 (m, 1 H),
2
tion; whitish oil; R = 0.49 (EtOAc/heptanes 4:6).
f
IR: 3455, 3267, 2952, 2923, 2855, 1712, 1443, 1374, 1258, 1035 cm–1
.
0.84 (s, 3 H), 0.82–0.78 (m, 1 H), 0.78 (s, 3 H), 0.75 (s, 3 H).
1
H NMR (C D , 400 MHz):  = 5.86 (d, J = 4.3 Hz, 1 H), 4.46 (dd, J = 11.4,
6
6
2.0 Hz, 1 H), 4.39 (t, J = 3.6 Hz, 1 H), 4.36 (s, 1 H), 3.91 (qd, J = 7.1, 1.5
Hz, 2 H), 3.63 (d, J = 14.8 Hz, 1 H), 2.52 (ddd, J = 16.9, 7.9, 5.1 Hz, 1 H),
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1258
Synthesis
E. Pruteanu et al.
Feature
1
3
IR: 2923, 2864, 1736, 1446, 1373, 1235, 1044, 962, 635, 598 cm–1
C NMR (CDCl , 75 MHz):  = 174.1, 74.8, 72.7, 60.2, 58.4, 56.5, 45.1,
.
3
4
1
3.2, 42.3, 39.3, 37.0, 36.4, 34.9, 33.47, 33.42, 27.7, 25.0, 21.4, 20.0,
9.5, 18.8, 15.9, 15.5, 14.4.
1
H NMR (CDCl , 400 MHz):  = 7.93–7.89 (m, 2 H), 7.68–7.62 (m, 1 H),
.56 (ddt, J = 8.3, 6.5, 1.5 Hz, 2 H), 3.07 (t, J = 7.7 Hz, 2 H), 1.86–1.17
3
7
HRMS (ESI): m/z [M + H]+ calcd for C24H43O : 379.3212; found:
(m, 17 H), 1.14 (dd, J = 13.3, 3.7 Hz, 1 H), 1.09 (s, 3 H), 1.05 (s, 3 H),
0.91 (dd, J = 12.1, 2.5 Hz, 1 H), 0.87–0.82 (m, 1 H), 0.84 (s, 3 H), 0.77 (s,
3
379.3209.
3
H), 0.73 (s, 3 H).
1
3
(
13R)-8,13-Epoxylabdan-15-ylmethyl Phenyl Sulfone (17b)
C NMR (CDCl , 101 MHz):  = 139.3, 133.7, 129.4 (2 C), 128.2 (2 C),
3
According to GPC from manoyl oxide (10; 52 mg, 0.179 mmol),
NaHCO3 (15 mg, 0.179 mmol), iodomethyl phenyl sulfone (62 mg,
75.1, 72.6, 57.2, 57.0, 56.6, 43.6, 42.2, 39.9, 39.3, 37.1, 37.0, 33.5, 33.4,
30.1, 24.2, 21.4, 20.1, 18.7, 18.2, 15.8, 15.3.
0
.215 mmol), tert-butylcatechol (2 portions, 2 × 30 mg, 2 × 0.179
HRMS (ESI): m/z [M + H]+ calcd for C27H43O : 447.2933; found:
447.2927.
3
mmol), and Et B (2 portions, 2 × 0.2 mL, 2 × 0.230 mmol, 1.15 M in
benzene) in dry CH Cl (1.0 mL). The crude was subjected to epoxida-
3
2
2
tion (according to GPD) and then purified by flash column chroma-
Ethyl (13R)-7-Acetoxy-6-hydroxy-1,9-(isoproylidenedioxy)-11-
oxo-8,13-epoxylabdan-15-ylacetate (18a)
tography (EtOAc/heptane 7:93) to give 17b (30 mg, 38%, 51% brsm) as
2
0
a colorless sticky oil; R = 0.28 (EtOAc/heptanes 2:8); []D –5 (c 0.7,
f
According to GPC from forskolin 1,9-acetonide (13; 100 mg, 0.22
mmol), NaHCO3 (19 mg, 0.22 mmol), ethyl iodoacetate (71 mg, 0.33
mmol), tert-butylcatechol (2 portions, 2 × 37 mg, 2 × 0.22 mmol), and
CH Cl ).
2
2
IR: 2992, 2921, 2862, 1446, 1375, 1305, 1147, 959, 597, 529 cm–1
.
1
H NMR (CDCl , 300 MHz):  = 7.94–7.88 (m, 2 H), 7.68–7.61 (m, 1 H),
Et B (2 portions, 2 × 0.25 mL, 2 × 0.286 mmol, 1.15 M in benzene) in
3
3
7.56 (dd, J = 8.3, 6.6 Hz, 2 H), 3.16–3.08 (m, 2 H), 1.86–1.73 (m, 2 H),
dry CH Cl (1.4 mL). The crude was purified by flash column chroma-
2
2
1
.67–1.55 (m, 4 H), 1.54–1.23 (m, 10 H), 1.21 (s, 3 H), 1.19–1.15 (m, 1
tography (EtOAc/heptane 1:5) to give 18a (70 mg, 59%) as a white
powder; R = 0.35 (EtOAc/heptanes 3:7); mp 119.7–122.8 °C (Et O/
H), 1.14 (s, 3 H), 1.12–0.88 (m, 2 H), 0.90–0.79 (m, 1 H), 0.86 (s, 3 H),
f
2
0.78 (s, 3 H), 0.73 (s, 3 H).
pentane); []D20 –35 (c 1.48, CH Cl ).
2
2
1
3
C NMR (CDCl , 75 MHz):  = 139.5, 133.6, 129.3 (2 C), 128.2 (2 C),
IR: 3519, 2933, 1731, 1712, 1456, 1372, 1241, 1046, 961, 789, 508
cm .
3
–
1
7
3
4.9, 72.6, 58.4, 57.0, 56.5, 43.4, 43.1, 42.3, 39.2, 36.9, 36.4, 33.46,
3.41, 27.9, 24.8, 21.4, 19.9, 18.7, 17.4, 15.9, 15.4.
1
H NMR (CDCl , 300 MHz):  = 5.22 (d, J = 3.8 Hz, 1 H), 4.41 (t, J = 3.3
3
HRMS (ESI): m/z [M + H]+ calcd for C27H43O S: 447.2933; found:
4
Hz, 1 H), 4.23–4.17 (m, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.01 (d, J = 17.7
Hz, 1 H), 2.37 (d, J = 17.7 Hz, 1 H), 2.29 (td, J = 7.1, 5.1 Hz, 2 H), 2.21 (d,
J = 2.7 Hz, 1 H), 2.12 (s, 3 H), 2.04 (ddd, J = 14.2, 4.3, 2.0 Hz, 1 H), 1.84–
3
47.2926.
1
.59 (m, 5 H), 1.57 (s, 3 H), 1.55–1.49 (m, 1 H), 1.47 (s, 3 H), 1.44 (s, 3
H), 1.37 (s, 3 H), 1.25 (s, 3 H), 1.24 (t, J = 6.9 Hz, 3 H), 1.23 (s, 3 H),
.09–1.00 (m, 1 H), 0.99 (s, 3 H).
Ethyl (13S)-8,13-Epoxylabdan-15-ylacetate (epi-17a)
According to GPC from epi-manoyl oxide (epi-10; 64 mg, 0.216
1
mmol), NaHCO (18 mg, 0.216 mmol), ethyl iodoacetate (70 mg, 0.324
3
HRMS (ESI): m/z [M + Na]+ calcd for C29
H O Na: 561.3040; found:
mmol), tert-butylcatechol (2 portions, 2 × 36 mg, 2 × 0.216 mmol),
46 9
and Et B (2 portions, 2 × 0.24 mL, 2 × 0.281 mmol, 1.15 M in benzene)
561.3009.
3
in dry CH Cl (1.2 mL). The crude was purified by flash column chro-
2
2
matography (EtOAc/heptane 4:96) to give epi-17a (55 mg, 67%, 81%
(13R)-7-Acetoxy-6-hydroxy-1,9-(isopropylidenedioxy)-11-oxo-
8,13-epoxylabdan-15-ylmethyl Phenyl Sulfone (18b)
2
0
brsm) as a colorless oil; R = 0.35 (EtOAc/heptanes 1:9); []
+16 (c
f
D
1
.5, CH Cl ).
2 2
According to GPC from forskolin 1,9-acetonide (13; 97 mg, 0.213
IR: 2937, 2866, 1736, 1464, 1373, 1235, 1044, 963, 846, 607 cm–1
.
mmol), NaHCO (18 mg, 0.213 mmol), iodomethyl phenyl sulfone (92
3
1
mg, 0.320 mmol), tert-butylcatechol (2 portions, 2 × 36 mg, 2 × 0.213
H NMR (CDCl , 400 MHz):  = 4.11 (q, J = 7.1 Hz, 2 H), 2.26 (td, J = 7.3,
3
mmol), and Et B (2 portions, 2 × 0.24 mL, 2 × 0.277 mmol, 1.15 M in
1
.8 Hz, 2 H), 1.80–1.28 (m, 15 H), 1.25–1.21 (m, 1 H), 1.24 (t, J = 7.2
Hz, 3 H), 1.23 (s, 3 H), 1.21–1.17 (m, 1 H), 1.14 (dd, J = 13.2, 4.3 Hz, 1
H), 1.10 (s, 3 H), 0.93 (dd, J = 12.0, 2.5 Hz, 1 H), 0.88–0.79 (m, 1 H),
3
benzene) in dry CH Cl (1.6 mL). The crude was purified by flash col-
2
2
umn chromatography (EtOAc/heptane 1:3) to give 18b (40 mg, 31%)
as a white powder; R = 0.23 (EtOAc/heptanes 4:6); mp 171.1–175.2
0
1
.84 (s, 3 H), 0.78 (s, 3 H), 0.75 (s, 3 H).
f
2
0
°
C (Et O/pentane); [] –18 (c 1.0, CH Cl ).
2 D 2 2
3
C NMR (CDCl , 101 MHz):  = 173.8, 75.0, 73.1, 60.3, 57.7, 56.6, 43.7,
3
IR: 3514, 2930, 1712, 1447, 1373, 1304, 1148, 961, 745, 690 cm–1
.
4
2
2.3, 40.8, 39.3, 37.4, 37.1, 35.1, 33.48, 33.39, 30.2, 24.4, 21.4, 20.4,
0.1, 18.7, 15.8, 15.4, 14.4.
1
H NMR (CDCl , 400 MHz):  = 7.96–7.91 (m, 2 H), 7.68–7.62 (m, 1 H),
3
HRMS (ESI): m/z [M + Na]+ calcd for C24H42O Na: 401.3032; found:
7.60–7.54 (m, 2 H), 5.18 (d, J = 3.8 Hz, 1 H), 4.39 (t, J = 3.5 Hz, 1 H),
3
4
1
2
.20 (dd, J = 3.9, 1.9 Hz, 1 H), 3.20 (dt, J = 14.5, 7.7 Hz, 1 H), 3.09 (dt, J =
4.5, 7.1 Hz, 1 H), 2.92 (d, J = 17.8 Hz, 1 H), 2.41 (d, J = 17.7 Hz, 1 H),
.18 (d, J = 2.7 Hz, 1 H), 2.10 (s, 3 H), 2.04 (ddd, J = 14.2, 4.3, 2.0 Hz, 1
401.3026.
(
13S)-8,13-Epoxylabdan-15-ylmethyl Phenyl Sulfone (epi-17b)
H), 1.94–1.57 (m, 4 H), 1.59–1.53 (m, 1 H), 1.56 (s, 3 H), 1.47 (s, 3 H),
.45–1.40 (m, 1 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.25 (s, 3 H), 1.21 (s, 3
H), 1.04 (ddd, J = 13.1, 4.3, 2.5 Hz, 1 H), 0.99 (s, 3 H).
According to GPC from epi-manoyl oxide (epi-10; 63 mg, 0.213
1
mmol), NaHCO (18 mg, 0.213 mmol), iodomethyl phenyl sulfone (92
3
mg, 0.319 mmol), tert-butylcatechol (2 portions, 2 × 35 mg, 2 × 0.213
1
3
C NMR (CDCl , 75 MHz):  = 208.3, 169.5, 139.7, 133.6, 129.3 (2 C),
3
mmol), and Et B (2 portions, 2 × 0.24 mL, 2 × 0.276 mmol, 1.15 M in
3
1
4
1
28.2 (2 C), 99.9, 81.8, 80.6, 76.2, 74.4, 70.2, 70.1, 56.7, 50.7, 44.3,
2.7, 38.0, 36.2, 34.5, 33.5, 31.8, 31.0, 25.2, 23.7, 22.9, 22.5, 21.3, 17.6,
7.5.
benzene) in dry CH Cl (1.4 mL). The crude was purified by flash col-
2
2
umn chromatography (EtOAc/heptane 7:93) to give epi-17b (35 mg,
7%, 62% brsm) as a white sticky oil; R = 0.27 (EtOAc/heptanes 2:8);
3
f
2
0
HRMS (ESI): m/z [M + H]+ calcd for C32
07.2935.
[]D +20 (c 1.05, CH Cl ).
H O S: 607.2941; found:
47 9
2
2
6
©
2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1259
Synthesis
E. Pruteanu et al.
Feature
1
Ethyl(13R)-7-Acetoxy-1,6,9-trihydroxy-11-oxo-8,13-epoxylabdan-
5-ylacetate (20a)
H NMR (CDCl , 300 MHz):  = 7.97–7.86 (m, 2 H), 7.68–7.57 (m, 1 H),
3
1
7.61–7.47 (m, 2 H), 5.12 (d, J = 4.0 Hz, 1 H), 4.35 (dd, J = 6.5, 2.6 Hz, 2
H), 3.26–3.14 (m, 1 H), 3.11–2.99 (m, 2 H), 2.90 (d, J = 16.0 Hz, 1 H),
2
(
3
1
According to GPC from forskolin (1; 95 mg, 0.23 mmol), NaHCO (19
3
.22 (d, J = 15.9 Hz, 1 H), 2.14–2.10 (m, 1 H), 2.10 (s, 3 H), 2.09–1.96
m, 1 H), 1.95–1.68 (m, 3 H), 1.60 (s, 3 H), 1.58–1.41 (m, 1 H), 1.51 (s,
H), 1.36 (d, J = 2.7 Hz, 1 H), 1.22 (s, 3 H), 1.20 (s, 3 H), 1.07 (dt, J =
3.4, 3.5 Hz, 1 H), 0.94 (s, 3 H), 0.89–0.80 (m, 3 H), 0.64 (dt, J = 7.9, 6.9
mg, 0.23 mmol), ethyl iodoacetate (74 mg, 0.344 mmol), tert-butyl-
catechol (2 portions, 2 × 38 mg, 2 × 0.23 mmol), and Et B (2 portions,
3
2
× 0.26 mL, 2 × 0.3 mmol, 1.15 M in benzene) in dry CH Cl (1.3 mL).
2 2
The crude was purified by flash column chromatography (EtOAc/hep-
tane 28:72) to give boronic ester 19a (112 mg, 91%) as a whitish oil;
Rf = 0.63 (EtOAc/heptanes 1:1).
Hz, 2 H).
1
3
C NMR (CDCl , 75 MHz):  = 204.2, 169.7, 139.4, 133.6, 129.3 (2 C),
3
IR: 3480, 2975, 2930, 2869, 2857, 1733, 1713, 1458, 1373, 1059 cm–1
128.1 (2 C), 81.5, 80.5, 76.0, 75.7, 73.1, 69.5, 56.5, 49.7, 44.5, 44.0,
.
4
6
3.0, 39.7, 36.1, 34.2, 33.0, 29.9, 24.4, 23.8, 23.2, 21.2, 18.7, 17.4, 8.0,
.8 (broad signal).
1
H NMR (CDCl , 400 MHz):  = 5.21 (d, J = 4.0 Hz, 1 H), 4.40 (dt, J = 4.5,
3
2
.5 Hz, 1 H), 4.35 (t, J = 3.0 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.03 (d, J =
5.8 Hz, 1 H), 2.28 (dt, J = 11.4, 7.2 Hz, 2 H), 2.21 (d, J = 15.8 Hz, 1 H),
.14 (s, 3 H), 2.05 (tdd, J = 14.3, 4.1, 2.6 Hz, 1 H), 1.82–1.79 (m, 1 H),
.78–1.64 (m, 2 H), 1.62 (s, 3 H), 1.62–1.57 (m, 1 H), 1.54 (s, 3 H),
.53–1.44 (m, 2 H), 1.42 (d, J = 2.6 Hz, 1 H), 1.26–1.22 (m, 9 H), 1.09
1
1
B NMR (CDCl , 96 MHz):  = 31.5.
1
2
1
1
3
+
HRMS (ESI): m/z [M + Na] calcd for C31H45BO SNa: 627.2775; found:
9
627.2767.
To a solution of boronic ester 19b (35 mg, 0.06 mmol) in MeOH (1.0
(dt, J = 13.0, 3.4 Hz, 1 H), 0.96 (s, 3 H), 0.93 (t, J = 7.8 Hz, 3 H), 0.75 (m,
mL) was added KHF (14 mg, 0.17 mmol, 3.0 equiv) at rt. The mixture
2
2
H).
was stirred at rt for 2 h. The mixture was concentrated in vacuo, dilut-
1
3
C NMR (CDCl , 101 MHz):  = 205.0, 173.9, 169.7, 81.6, 80.4, 76.5,
ed with Et O, filtered, and concentrated under reduced pressure. The
3
2
7
2
6.1, 73.2, 69.7, 60.2, 49.5, 45.3, 43.1, 39.8, 36.3, 34.6, 34.3, 33.1, 30.2,
4.5, 23.9, 23.3, 21.2, 19.2, 18.8, 14.4, 8.0, 6.9 (broad signal).
crude mixture was purified by flash column chromatography (EtOAc/
heptane 35:65) to give 20b (31 mg, 89%) as a colorless oil; R = 0.28
f
(EtOAc/heptanes 1:1); []D20 +3 (c 0.5, CH Cl ).
1
1
B NMR (CDCl , 96 MHz):  = 31.6.
2
2
3
IR: 3463, 3278, 2976, 2947, 2930, 2869, 2856, 1737, 1714, 1144 cm–1
.
+
HRMS (ESI): m/z [M + Na] calcd for C28H45BO Na: 559.3054; found:
9
1
559.3036.
H NMR (CDCl , 400 MHz):  = 7.93–7.88 (m, 2 H), 7.69–7.62 (m, 1 H),
3
7
.56 (dd, J = 8.4, 7.0 Hz, 2 H), 6.64 (br s, 1 H, OH), 5.80 (dd, J = 4.7, 2.9
To a solution of boronic ester 19a (40 mg, 0.07 mmol) in MeOH (1.0
Hz, 1 H), 4.59 (d, J = 2.9 Hz, 1 H), 4.15 (d, J = 4.7 Hz, 1 H), 3.24–3.14 (m,
3
1
mL) was added KHF (18 mg, 0.22 mmol, 3.0 equiv) at rt. The mixture
2
H), 2.26 (d, J = 2.9 Hz, 1 H), 2.22–2.14 (m, 2 H), 2.09 (s, 3 H), 1.98–
.88 (m, 2 H), 1.81–1.54 (m, 3 H), 1.49 (s, 3 H), 1.4–1.36 (m, 1 H), 1.41
was stirred at rt for 2 h. The mixture was concentrated in vacuo, dilut-
ed with Et O, filtered, and concentrated under reduced pressure. The
2
(
(
s, 3 H), 1.26 (s, 3 H), 1.14 (dt, J = 13.5, 3.4 Hz, 1 H), 1.08 (s, 3 H), 0.98
s, 3 H).
crude mixture was purified by flash column chromatography (EtOAc/
heptane 1:4) to give 20a (33 mg, 90%) as a white powder; R = 0.46
f
20
13
(
EtOAc/heptanes 1:1); mp 46.3–50.8 °C (Et O); []D –6 (c 0.6, CH Cl ).
C NMR (CDCl , 101 MHz):  = 207.8, 171.0, 139.4, 133.8, 129.3 (2 C),
3
2
2
2
IR: 3431, 3254, 2974, 2930, 2867, 2857, 1731, 1710, 1445, 1373 cm–1
128.3 (2 C), 82.5, 82.2, 76.2, 74.7, 73.7, 71.4, 56.7, 49.0, 43.4, 43.3,
2.4, 36.5, 34.1, 33.0, 30.8, 27.1, 23.3, 22.7, 21.8, 19.8, 17.7.
HRMS (ESI): m/z [M + H]+ calcd for C29H43O S: 567.2628; found:
.
4
1
H NMR (CDCl , 400 MHz):  = 6.50 (br s, 1 H, OH), 5.44 (d, J = 4.2 Hz, 1
3
H), 4.54 (t, J = 2.9 Hz, 1 H), 4.44 (dd, J = 4.3, 2.9 Hz, 1 H), 4.11 (q, J = 7.1
Hz, 2 H), 3.25 (d, J = 15.8 Hz, 1 H), 2.51 (br s, 1 H, OH), 2.36–2.18 (m, 5
H), 2.15 (s, 3 H), 1.80–1.66 (m, 4 H), 1.62 (s, 3 H), 1.56–1.47 (m, 1 H),
9
5
67.2622.
1.45 (s, 3 H), 1.40 (dq, J = 15.0, 3.4 Hz, 1 H), 1.256 (s, 3 H), 1.248 (s, 3
H), 1.245 (t, J = 7.1 Hz, 3 H), 1.12 (dt, J = 13.3, 3.4 Hz, 1 H), 1.02 (s, 3 H).
Funding Information
1
3
C NMR (CDCl , 101 MHz):  = 208.2, 174.1, 169.8, 82.9, 81.5, 77.0,
3
This work was funded by the Swiss National Science Foundation:
project IZ73Z0_152346/1 (SCOPES program involving VK and PR) and
project 200020_172621 (PR). EP and VG were both partly supported
by the State Secretariat for Education and Innovation (SERI) via a
Swiss Government Excellence Scholarships for Foreign Scholars and
7
2
6.2, 74.7, 70.0, 60.3, 49.8, 45.3, 43.1, 36.3, 34.51, 34.47, 33.0, 30.1,
7.1, 24.3, 23.7, 21.3, 20.1, 19.2 (2 C), 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C26H43O : 499.2907; found:
9
499.2902.
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(
13R)-7-Acetoxy-1,6,9-trihydroxy-11-oxo-8,13-epoxylabdan-15-
ylmethyl Phenyl Sulfone (20b)
Acknowledgment
According to GPC from forskolin (1; 100 mg, 0.244 mmol), NaHCO3
(
21 mg, 0.244 mmol), iodomethyl phenyl sulfone (105 mg, 0.365
We thank the group of Chemical Crystallography of the University of
Bern (Prof. Dr. P. Macchi, PD Dr. Simon Grabowsky and Dr. Michal
Andrzejewski) for measuring, solving, refining, and summarizing the
X-ray structures.
mmol), tert-butylcatechol (2 portions, 2 × 41 mg, 2 × 0.244 mmol),
and Et B (2 portions, 2 × 0.28 mL, 2 × 0.32 mmol, 1.15 M in benzene)
in dry CH Cl (2.0 mL). The crude was purified by flash column chro-
3
2
2
matography (EtOAc/heptane 1:3) to give boronic ester 19b (56 mg,
3%) as a colorless oil; R = 0.53 (EtOAc/heptanes 1:1).
6
f
IR: 3517, 2974, 2949, 2933, 2870, 2856, 1718, 1446, 1304, 1145 cm–1
.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706003.
S
u
p
p
ortingInformati
o
nS
u
p
p
orting Informatio
n
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2021. Thieme. All rights reserved. Synthesis 2021, 53, 1247–1261

1260
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