Palladium-Catalyzed Formation of Substituted Tetrahydropyrans: Mechanistic Insights and Structural Revision of Natural Products

Article abstract of DOI:10.1055/s-0037-1611708

A comprehensive study on the stereochemical outcome of palladium-catalyzed formation of 2,4,6-trisubstituted tetrahydropyrans through cyclization of the corresponding allylic acetates using both Pd(0) and Pd(II) catalysts is presented. We have found that

Full text of DOI:10.1055/s-0037-1611708

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–P
feature
A
en
F. Della-Felice et al.
Feature
Synthesis
Palladium-Catalyzed Formation of Substituted Tetrahydropyrans:
Mechanistic Insights and Structural Revision of Natural Products
Proposed structures.
This work
Franco Della-Felicea
Francisco F. de Assisa
Ariel M. Sarottib
OH
*
OH
O
Ph
O
R2
*
*
O
Pd(0)
Pd(II)
Ronaldo A. Pilli*a
and/or
DP4+
calculations
Ph
O
OAc
OH
OH
OR1
OH
OH
OH
O
a University of Campinas, Institute of Chemistry,
13084-971, Campinas, SP, Brazil
Ph
R2
Cryptoconcatone K
*
*
*
R2
Ph
*
*
*
R1 = OH, OAc
2 = (CH2)2OPMB
NMR data
pilli@iqm.unicamp.br
OAc
b Instituto de Química Rosario, Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional
de Rosario-CONICET, Suipacha 531, S2002 LRK,
Rosario, Argentina
R
OH
O
Asymmetric
synthesis
O
O
Ph
O
Ph
O
OH
Putative structure of
Cryptoconcatone H
Cryptoconcatone L
This work is dedicated to Professor Albert J.
Kascheres for his guidance and positive example to
one of us (R.A.P.).
Received: 17.09.2018
Accepted after revision: 26.11.2018
Published online: 29.01.2019
combined Ru-catalyzed ene-yne coupling, followed by a Pd-
catalyzed asymmetric allylation.3
Hansen and Lee studied the formation of a variety of 2-
alkenyl-4-methylene THP derivatives catalyzed by
Pd(PPh3)4, and succeeded in the transfer of stereochemical
information from the starting material to the product and
gaining access to either 2,6-cis or 2,6-trans configuration.4
For the preparation of THPs with an unsubstituted vinyl
group, Trost’s chiral amine ligand was found to promote
formation of the cis isomer in up to 10:1 ratio, although for
the trans isomer selectivity was in the range of 2:1.
Uenishi and co-workers described the use of
PdCl2(CH3CN)2 to stereospecifically catalyze the formation
of either cis or trans THP from syn- or anti-2,8-diol, respec-
tively, and they proposed that the stereogenic center in the
secondary allylic alcohol transfers stereochemical informa-
tion to the newly generated stereogenic center in the pyran
ring in a syn-SN2′ type process.5
DOI: 10.1055/s-0037-1611708; Art ID: ss-2018-z0628-fa
Abstract A comprehensive study on the stereochemical outcome of
palladium-catalyzed formation of 2,4,6-trisubstituted tetrahydropyrans
through cyclization of the corresponding allylic acetates using both
Pd(0) and Pd(II) catalysts is presented. We have found that the stereo-
chemical outcome of this cyclization is dependent not only on the
stereochemistry of the acyclic precursor but also on the nature of the
palladium catalyst. These results were applied to the total synthesis of
the putative structure of cryptoconcatone H. Experimental and compu-
tational DP4+ NMR results were used to assess the structures proposed
for cryptoconcatones K and L.
Key words tetrahydropyran, palladium catalysis, DP4+, structural re-
vision, natural product synthesis
Introduction
The widespread presence of the tetrahydropyran (THP)
moiety in Nature has raised interest in the development of
stereoselective procedures for its formation, requiring ste-
reochemical control in order to achieve efficiency and scal-
ability.
Several methodologies can be found in the literature for
the construction of THP rings.1 Lewis and Brønsted acids, as
well as transition-metal-catalyzed cyclization of allylic
alcohols (and/or their respective ester, carbonate or phos-
phate) to form THPs has taken a major role in the last de-
cade, with the palladium-mediated construction of this
motif being one of the most versatile procedures. Both
Pd(0) and Pd(II) methodologies can lead to substrate-
controlled, regioselective cyclization with retention of con-
figuration (Scheme 1).2
Later, Hanessian and co-workers explored Uenishi’s
methodology for the cyclization of allylic diols bearing a
methyl substituent at C-2 in the allylic alcohol position and
they found that a non-stereoselective process took place
providing a mixture of cis- and trans-2,6-dihydropyrans.6
While other Pd(II) species such as PdCl2 or PdCl2(PPh3)2
failed to catalyze the conversion, diastereoselection favor-
ing the 2,6-cis dihydropyran could be restored when cation-
ic Pd(CH3CN)4(BF4)2 or a Lewis acid such as BF3·OEt2,
Fe(ClO4)2·xH2O or Cu(OTf)2, or even a Brønsted acid such as
TfOH or p-TsOH, were employed. The 2,6-cis preference was
independent of the configuration at the allylic carbinolic
stereogenic center, as demonstrated for the conversion of
1,3-syn and anti diols into the same 2,6-cis dihydropyran in
almost the same yields and diastereoselectivities when
treated with BF3·OEt2.
In 2002, Trost and co-workers described the enantiose-
lective formation of a series of substituted heterocycles, in-
cluding tetrahydrofurans and tetrahydropyrans, through a
Krische and co-workers examined the formation of sev-
eral 2,6-cis and 2,6-trans 4-hydroxy-tetrahydropyrans
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

B
F. Della-Felice et al.
Feature
Synthesis
through the use of chiral palladium and iridium complex
catalysts. In accordance with the results of Hansen and Lee,
they emphasized that the 2,6-trans diastereoisomers were
intrinsically more challenging to obtain in high selectivity
because of rapid interconversion of the diastereoisomeric
-allyl intermediates.7
cal properties of this class of natural products, and knowing
the proper relative stereochemistry in THP-containing com-
pounds is of paramount importance. In this regard, despite
the enormous progress in spectrometric techniques avail-
able for the characterization of organic compounds over the
last decades, structural misassignments are still found in
the literature,8 and total synthesis comes into play as one of
the most effective approaches for structural elucidation.9
The three-dimensional disposition of the substituents
around the THP ring is crucial for the biological and chemi-
Biographical Sketches
Franco Della-Felice obtained
his BSc degree in chemistry at
the National University of
Rosario (UNR, Argentina) in
2013 under the guidance of
Professors Edmundo A. Rúveda
and María I. Colombo. In 2014,
he joined Professor Ronaldo A.
Pilli group at the University of
Campinas (Brazil) focusing on
synthesis and structural revision
of natural products.
Francisco F. de Assis ob-
tained his BSc degree in chemis-
try at the University of São
Paulo (USP) in 2011 and his PhD
in Organic Chemistry at the Fed-
eral University of São Carlos
(UFSCar) in 2016, under the su-
pervision of Professor Kleber T.
de Oliveira. In the same year he
joined Professor Pilli’s research
group as postdoctoral fellow to
work on the synthesis of mole-
cules with potential antihyper-
glycemic activity. Between
2017 and 2018 he temporarily
joined the group of Professor
Eric Meggers at the University
of Marburg (Germany) to work
on the development of asym-
metric visible-light photocataly-
sis methodologies. Currently, he
continues his postdoctoral re-
search in Professor Pilli’s group.
Ariel M. Sarotti received his
PhD from the National Universi-
ty of Rosario (UNR, Argentina)
in 2007, under supervision of
Prof Alejandra G. Suárez. After
his postdoctoral research in
computational chemistry at
IQUIR, he became researcher of
the Argentine National Council
Research (CONICET). Currently,
he is Associate Professor of
Organic Chemistry at UNR, and
Independent Researcher at
CONICET. His scientific interests
include green and sustainable
chemistry, asymmetric synthe-
sis, computational chemistry,
NMR spectroscopy and medici-
nal chemistry.
Ronaldo A. Pilli graduated
imines. After
a
post-doctoral
natural products where he is
now Professor of Chemistry. His
interests include the total syn-
thesis and biological properties
of natural compounds and ana-
logues.
from
the
University
of
stint at the University of Califor-
nia, Berkeley under the supervi-
sion of Professor Clayton H.
Heathcock, he returned to
Campinas to start his indepen-
dent career working on the
stereoselective synthesis of
Campinas, Brazil in 1977 and
got his PhD from the same uni-
versity in 1981, under the
supervision of Professor Albert
J. Kascheres working on the re-
activity of strained cyclopropen-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

C
F. Della-Felice et al.
Feature
Synthesis
TMS
Trost et al.
Hansen and Lee.
R2
R1
R2
R1
OH
OCO2Et
OBn
TMS
OH
1. CpRu(CH3CN)3PF6
OBn
OBn
R1
Pd(PPh3)4
(5 mol%)
O
O
(5 mol%)
R
R
O
O
R2
+
TMS
2. [(η3-C3H5)PdCl]2
(2 mol%), chiral amide I
(6 mol%)
OH
OCO2Et
OAr
OBn
R1
R2
R
single diastereoisomer
dr > 97:3
Uenishi et al.
Hanessian et al.
R1
OH
OH
R2
OH OH
BnO
R1
R2
R2
Pd(MeCN)4BF4
(10 mol%)
R1
3
PdCl2(MeCN)2
(10 mol%)
O
O
R2
R1
R1
BnO
O
or
OH
OH
R2
OH OH
BnO
.
BF3 OEt2
(10 mol%)
dr 3:1 to 99:1
R2
R2
R1
3
R1
single diastereoisomer
Krische et al.
OH
OH
OH OH
OAc
OAc
.
[Ir(cod)Cl]2
(3 mol%)
[Pd2(dba)3] CHCl3
R
R
O
R
R
O
O
O
O
O
(3 mol%)
R
P
N
OH
OH
N
N
Chiral
phosphoramidite
(6 mol%)
OH OH
H
H
Chiral amide I
(9 mol%)
PPh2 Ph2P
R
OMe
OMe
O
O
Chiral amide I
(or enantiomer)
Chiral phosphoramidite
dr 3:1 to 9:1
dr >20:1
Scheme 1 Representative examples of Pd-mediated construction of THPs
Recently, we presented a stereochemical revision of the
structure of natural cryptoconcatone H, a trisubstituted
tetrahydropyran styryl lactone isolated by Kong, Luo and
co-workers from Cryptocarya concinna (Figure 1).10 Al-
together, these authors reported twelve new styryl lac-
tones, named cryptoconcatones A–L, with interesting bio-
logical activities. Whereas cryptoconcatones D, H and I
showed moderate anti-inflammatory activity, as evaluated
by NO production, cryptoconcatones K and L were moder-
ately active against Huh7 tumor cell line.11
As can be noted, the THP ring in the proposed struc-
tures of cryptoconcatones K (2) and L (3) features the same
relative configuration as originally proposed for cryptocon-
catone H (4). On the other hand, the stereochemical con-
nection between the THP ring and the carbinolic center at
the dihydropyranone moiety present in 2 and 3 was as-
signed the opposite configuration to that in structure 4.
In our previous synthetic studies on cryptoconcatones,
we employed the Pd(II)-catalyzed THP ring formation to
stereoselectively secure the formation of the 2,4,6-trisub-
stituted tetrahydropyran ring of the reassigned structure of
cryptoconcatone H (1). Further investigation revealed that
the stereochemical outcome of the palladium-catalyzed
formation of styryl tetrahydropyrans via cyclization of the
allylic alcohols or acetates bearing a ,ζ-diol was dependent
not only on the stereochemistry of the acyclic precursor but
also on the nature of the palladium catalyst.
OH
O
OH
O
4'
2
O
6
O
6'
2'
Ph
O
Ph
O
Cryptoconcatone H (1)
(4)
Reassigned structure
by Pilli
Proposed structure
for cryptoconcatone H
by Kong and Luo
Herein, we would like to report a comprehensive study
on such reactions and their application to the total synthe-
sis of the putative structure originally assigned to crypto-
concatone H (4). In addition, a configurational analysis of
the structures proposed for cryptoconcatones K and L (2
and 3, respectively) through DFT calculations of NMR
chemical shifts is also presented.
OR
O
O
O
OH OH OH
O
Ph
O
Ph
OH
Cryptoconcatone D
Cryptoconcatone K (2)
R = Ac Cryptoconcatone L (3)
R = H
Proposed structures by
Kong and Luo
Figure 1 Secondary metabolites isolated from C. concinna by Kong,
Luo and co-workers
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

D
F. Della-Felice et al.
Feature
Synthesis
Results and Discussion
In our previous work,10 it was reported that 9 gave a
complex mixture of products under Tsuji–Trost conditions.
After extensive analysis, it was found that the desired 2,6-
trans THP 16 was formed along with the corresponding iso-
mer 17 and diol 18 (Scheme 4), in a 36:22:30 ratio, respec-
tively.15 Surprisingly, under the same conditions, precursor
10 gave only the expected 2,6-cis THP 17.
Preparation of the 2,6-trans THP ring present in 1 and
the 2,6-cis THP counterpart present in 2–4, were envi-
sioned through a Tsuji–Trost reaction of allylic acetates 9
and 10 (Scheme 2).
OH OPMB
OH OPMB
OH OH OPMB
a
b
c
As the mechanism of the Tsuji–Trost reaction involves a
Pd--allyl carbocation intermediate, we rationalized that
the free alcohol at C-4′ (cryptoconcatone numbering) takes
a major role in the outcome of the reaction as it can coordi-
nate to the intervening Pd species (Scheme 5). According to
this rationale, when the Pd(0) catalyst interacts with 10 and
positions itself on the same side as the C-4′ hydroxyl group,
the cationic Pd--allyl intermediate undergoes coordina-
tion with the free hydroxyl group at C-4′, leading to a
stereoelectronically favored conformation for the formation
of the 2,6-cis THP 17 (conformer A). On the other hand,
when the cationic Pd--allyl intermediate interacts with
the hydroxyl at C-4′ in 9, it leads to a conformation in which
the stereoelectronics does not favor the cyclization path
(conformer B). This would extend the half-life of the Pd--
allyl carbocation species, giving rise to either rotation along
the C5′–C6′ axis (conformer C), allowing the formation of
THP 16, or isomerization of the Pd--allyl carbocation to
structure D,16 thus leading to THP 17. Additionally, a com-
petitive -elimination pathway leading to 18 may be opera-
tional.17
Intrigued by these results, we next focused in changing
the stereochemistry at the C-4′ position to further explore
the impact of the hydroxyl configuration on the stereo-
chemistry of the THPs to be formed via Tsuji–Trost cycliza-
tion. After preparing 19 and 20 in a similar fashion as de-
picted in Scheme 2, these two new substrates were subject-
ed to the same Pd(0) conditions described earlier
(Scheme 4). In this case, whereas 19 gave the rearranged
diol 21 in moderate yield as the only isolated product, com-
pound 20 afforded the cyclic product 22 as the major prod-
uct, along with the formation of the rearranged compound
21 and a minor byproduct that was identify as the C6′-epi-
mer of 21. In a tentative attempt to rationalize these events,
and considering that complexation of the palladium species
with the free hydroxyl plays a pivotal role in the stereo-
chemical outcome of these reactions, the behavior observed
5
6
7
OAc
OAc
OH
OH
OH
OPMB
OPMB
d
Ph
OH
OH
OPMB
9
OH
8
e
Ph
10
Scheme 2 Reagents and conditions: (a) (S)-(BINAP--allyliridium-C,O-
benzoate) catalyst (5 mol%), Cs2CO3, 3-Cl-4-NO2-BzOH, AcOAllyl,
THF/H2O, 110 °C, 40 h, 95% (ee ≥ 99%); (b) OsO4 (1 mol%), NaIO4,
1,4-dioxane/H2O, r.t., 4 h, then NaBH4, 0 °C, 15 min, 90%; (c)
[Ir(cod)Cl]2 (2.5 mol%), (R)-BINAP (5 mol%), Cs2CO3, 3-Cl-4-NO2-BzOH,
AcOAllyl, THF, 110 °C, 40 h, 72% (dr> 95:5); (d) (S)-15 (150 mol%),
Hoveyda–Grubbs II catalyst (3 mol%), CH2Cl2, Δ, 2 h, 89%; (e) (R)-15
(150 mol%), Hoveyda–Grubbs II catalyst (3 mol%), CH2Cl2, Δ, 2 h, 82%.
These two epimeric structures at the benzylic position
were prepared starting from monoprotected PMB ether 5,
followed by Krische asymmetric allylation employing chiral
(S)-(BINAP- -allyliridium-C,O-benzoate) catalyst to give 6
in high yields and excellent enantioselectivity.12 Alkene 6
was next transformed into its corresponding alcohol 7 after
a one-pot Lemieux–Johnson oxidation/NaBH4 reduction,
followed by a protecting group-free Krische asymmetric
allylation13 to obtain 8 in high selectivity. Finally, cross-
metathesis reaction with either (S)- or (R)-15 gave 9 or 10,
respectively.
For the preparation of enantiomerically enriched ester
15, we explored the Sharpless asymmetric epoxidation
(SAE) of cinnamyl alcohol (11)14 to introduce the required
stereogenic center in high yield and selectivity (12, Scheme
3). After conversion into the corresponding bromide 13, ep-
oxide opening with n-BuLi, followed by esterification, pro-
vided 15 in 70% overall yield without erosion of the enan-
tiomeric ratio initially obtained from the SAE reaction.
for compound 19 can be explained through
a six-
membered-ring conformation involving the palladium spe-
cies and OH-4′ (conformer E, Scheme 6), which precludes
attack of the free OH-2′ to the Pd--allyl carbocation. As a
result, the cyclization and elimination pathways are not
productive, allowing the rearrangement pathway to occur
preferentially through the opposite face to that where pal-
ladium coordinates, thus providing the rearranged product
21 bearing S configuration at the allylic stereogenic center
OH
R
R
a,b
c,d
O
Ph
Ph
Ph
11
12 R = OH
13 R = Br
14 R = OH
15 R = OAc
Scheme 3 Reagents and conditions: (a) tBuOOH, (–)- DIPT (10 mol%),
Ti(OiPr)4 (7.5 mol%), MS 4 Å, CH2Cl2, –30 °C, 14 h, 91% (ee 90%);
(b) CBr4, PPh3, CH2Cl2, r.t., 30 min, 81%; (c) n-BuLi, THF, –78 °C, 1 h,
99%; (d) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 1 h, 96% (ee 90%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

E
F. Della-Felice et al.
Feature
Synthesis
OH
OH
O
Pd(PPh3)4
(5 mol%)
4'
OAc
OH
OPMB
+
OPMB
+
OH
OH
OH
OPMB
OPMB
6' 2'
THF, rt
8'
4'
Ph
2'
Ph
O
Ph
Ph
9
16*
(36%)
17*
(22%)
18*
(30%)
OH
OAc
OH
OH
OPMB
as above
as above
as above
OPMB
Ph
Ph
Ph
O
10
17
(92%)
OAc
OH
OAc
OAc
OH
OH
OH
OH
OPMB
OPMB
OPMB
Ph
Ph
19
21
(48%)
OH
OPMB
OAc
OH
OH
OH
OPMB
+
Ph
O
Ph
20
22*
21*
(41%)
(13%)
Scheme 4 Pd(0)-mediated reaction of compounds 9, 10, 19 and 20. * Yield estimated based on molar ratio (1H NMR spectroscopic analysis).15
H
H
H
O
H
[Pd]
4'
OH OH
H
OAc
OH
OH
H
OPMB
6'
[Pd]
2'
H
Cyclization
(17)
H
[Pd]
4'
2'
Ph
R
O
8'
4'
Ph
2'
AcO
H
R
10
AcO
A
Ph
H
H
H
H
H
H
4'
H
R
[Pd]
H
6'
OH
4'
H
H
6'
OAc
OH
OH OPMB
[Pd]
2'
O
H
H
H
H
Elimination
(18)
2'
O
OAc
Ph
H
H
4'
O
2'
Ph
8'
4'
2'
Ph
H
O
OAc
Ph
AcO
R
[Pd]
[Pd]
H
9
H
HO
R
B
D
H
H
H
H
4'
H
6'
[Pd]
H
2'
O
Cyclization
(16)
Coordination
H
Ph
OH
Bond formation
H
R
OAc
C
Scheme 5 Mechanistic reasoning for the product distribution in the Tsuji–Trost reaction of ζ-hydroxy allylic acetates 9 and 10 (R = CH2CH2OPMB)
formed.18 Compound 20, epimeric to 19 at the allylic ace-
tate, would also form a six-membered-ring conformer with
the palladium catalyst (conformer F). Here, the OH-2′ is
either able to equilibrate to conformer G, leading to the for-
mation of 22 as the stereoelectronics required for the
cyclization are favorable, or to coordinate with the palladi-
um species and give rise to conformer H, where a re-
arrangement pathway seems possible, or undergo isomeri-
zation of the Pd--allyl carbocation to structure I, giving
access to the formation of 21 as the minor product observed
(Scheme 6).
To overcome the complex mixture observed when 9 was
treated under Tsuji–Trost conditions, we explored the use
of the allylic alcohol corresponding to 9 in a stereospecific
Pd(II)-catalyzed cyclization.5 After a detailed study of this
reaction, we found that under Uenishi’s conditions the de-
sired THP 16 was formed predominantly, along with small
amounts of the all-cis THP 17 (Scheme 7). When 10, epi-
meric to 9 at the allylic acetate position, was employed, the
all-cis THP 17 was the major product, with 16 detected as
the minor stereoisomer. From 19, a C-4′ epimer of 9, tetra-
hydropyran 23, was obtained as the major product, with 22
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

F
F. Della-Felice et al.
Feature
Synthesis
R
OH
Coordination
2'
H
Bond formation
H
4'
H
6'
OAc
OH
OH
OPMB
[Pd]
H
Rearrangement
(21)
O
H
8'
4'
Ph
2'
OAc
19
[Pd]
E
Ph
H
R
OH
2'
2'
H
H
R
OH
H
4'
4'
H
H
6'
H
6'
OAc
OH
OH
OPMB
[Pd]
H
H
Cyclization
[Pd]
[Pd]
HO
HO
8'
4'
2'
Ph
(22)
20
AcO
R
AcO
Ph
Ph
F
G
H
H
2'
R
2'
AcO
H
4'
H
4'
H
6'
H
6'
O
OH
H
Ph
H
Rearrangement
Rearrangement
(21)
AcO
HO
HO
[Pd]
[Pd]
H
Ph
I
Scheme 6 Mechanistic reasoning for the formation of 21 and 22 via Tsuji–Trost reaction from 19 and 20 (R = CH2CH2OPMB)
formed in small proportion. Finally, starting from 20, epi-
meric at C-8′ when compared to 19 or at C-4′ when com-
pared to 10, only the cyclization product 22 was obtained.
The results above show that, in the Pd(II)-catalyzed cy-
clization, the configuration at C-6′ is determined by the
configuration of the allylic acetate used as the precursor of
the reacting allylic alcohol: S configuration at C-8′ will lead
to THPs bearing S configuration at C-6′ as the major product
(16 and 23 from 9 and 19, respectively) while the opposite
configuration is observed when substrates with R configu-
ration at C-8′ are employed (17 and 22 from 10 and 20, re-
spectively). Most interestingly to note is the formation of
the side products observed when using 9, 10 and 19.19 As the
overall transformation is described as an SN2′ substitution of
OH
OH
1. K2CO3,
MeOH, rt
OAc
OH
OPMB
OPMB
OH
OPMB
+
+
+
2. PdCl2(MeCN)2
(10 mol%),
THF, 0 °C
8'
4'
Ph
2'
Ph
O
Ph
O
9
16
(70%)
17*
(6%)
OH
OH
OAc
OAc
OH
OPMB
OPMB
OPMB
OPMB
OH
OH
OPMB
OPMB
as above
Ph
Ph
Ph
Ph
O
Ph
Ph
O
10
17
(59%)
16*
(6%)
OH
OH
as above
OH
O
O
19
23
22*
(46%)
(3%)
OH
as above
OAc
OH
OPMB
OH
OPMB
Ph
Ph
O
20
22
(60%)
Scheme 7 Pd(II)-mediated reaction of compounds 9, 10, 19 and 20. * Yield estimated based on molar ratio (1H NMR spectroscopic analysis).15
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

G
F. Della-Felice et al.
Feature
Synthesis
an allylic alcohol with an internal alcohol moiety, there are
two possible mechanisms to consider that may clarify the
observed results.
take place, a situation disfavored considering the inherent
electrophilicity of Pd(II). On the other hand, if the anti coor-
dination is to proceed, the system could also experience a
syn oxypalladation followed by anti-elimination of water,
giving access to 17 and 22, respectively (Scheme 9, path D).
In this alternative, the allylic alcohol and the nucleophilic
hydroxyl group are on opposite sides, interrupting the in-
ternal hydrogen bonding between them and disfavoring the
elimination step to generate the double bond. No further
analysis could be made for the results obtained with com-
pound 20a, where no formation of side products were de-
tected. As the only difference between 20 and 10 is the
stereochemistry at C-4′, possessing all three hydroxyls at
the same side, we can only speculate a further interaction
of OH-4′ with the Pd-intermediate that would favor cycliza-
tion to 22.
During their work, Uenishi et al. proposed a syn coordi-
nation of the Pd species to the double bond with respect to
the free allylic alcohol,5 followed by a syn approximation of
the nucleophilic hydroxyl group to the double bond (Si face)
to form a syn oxypalladation intermediate with concomi-
tant formation of HCl (Scheme 8, path A). Finally, syn elimi-
nation of PdCl(OH) would generate the double bond with E
configuration. Alternatively, Ess, Aponick and co-workers
reported a mechanistic analysis of such reaction supported
by DFT calculations.20 In their study, the lowest energy path
would correspond to an anti coordination of the Pd species
to the double bond with respect to the allylic alcohol, fol-
lowed by an anti oxypalladation process and final anti elim-
ination of water, promoted by an internal hydrogen bond
between the allylic alcohol and the nucleophilic hydroxyl
group (Scheme 8, path B). Both mechanisms account for the
observed stereospecificity of the major products obtained
in Scheme 8.
Secondary pathways may be involved in the formation
of the observed minor products (Scheme 7), bearing the op-
posite configuration at C-6′ compared to the major prod-
ucts.
In compounds 9a and 19a, if a syn coordination is in-
volved, the system can pass through an anti oxypalladation
process (Re face attack) generating HCl, and final syn elimi-
nation of PdCl(OH) to give access to either 17 or 22, respec-
tively (Scheme 9, path C). No coordination of the nucleo-
philic hydroxyl group with the palladium species would
Total Synthesis of the Putative Structure
of Cryptoconcatone H and Stereochemical
Analyses of Cryptoconcatones K and L
The results from the previous study on the Pd(II)- and
Pd(0)-catalyzed cyclization of ζ-hydroxy allylic alcohols
and acetates led us to contribute to the structure validation
of other representatives of the cryptoconcatone family be-
yond our previous study of stereochemical revision for
cryptoconcatone H (Figure 1).10 Guided by quantum calcu-
lations of NMR shifts, the large discrepancies found be-
tween the calculated NMR shifts of 4 (the originally pro-
posed structure of cryptoconcatone H) and the experimen-
R1
R1
OH
H
OH
R
Path A
– PdCl(OH)
– HCl
R
R2
R2
Ph
Ph
O
Pd(II) coord.
syn OH-8'
syn
syn
elimination
H2'
O
H
R1
ClPd
oxypalladation
Cl2Pd
R1
R2 OH
H
OH
R
R2
Ph
8'
4'
Ph
2'
R
O
H
R1
R1
– PdCl2
– H2O
9a R1 = OH; R2 = H
19a R1 = H; R2 = OH
H
H
O
16 R1 = OH; R2 = H
23 R1 = H; R2 = OH
Cl2Pd
Cl2Pd
R
R
Path B
R2
R2
Ph
H
Ph
H
H
O
H
O
Pd(II) coord.
anti OH-8'
anti
oxypalladation
anti
elimination
O
H
R1
OH
OH
R1
Path A
– PdCl(OH)
– HCl
R
R
O
HO
Ph
Ph
Pd(II) coord.
syn
syn
R1
R2
R2
PdCl
PdCl2
syn OH-8'
oxypalladation
elimination
R1 R2
OH
R
OH
O
Ph
R2
8'
4'
2'
Ph
R
17 R1 = H; R2 = OH
22 R1 = OH; R2 = H
H
R1
H
10a R1 = OH; R2 = H
20a R1 = H; R2 = OH
H
– PdCl2
– H2O
H
H
H
R1
H
H
O
Path B
O
O
R
R
Ph
Ph
O
Pd(II) coord.
anti OH-8'
anti
oxypalladation
anti
elimination
R2
R2
Cl2Pd
PdCl2
Scheme 8 Mechanistic reasoning for the Pd(II)-catalyzed cyclization of the observed major products from the allylic alcohols derived from 9, 10, 19
and 20 (R = CH2CH2OPMB)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

H
F. Della-Felice et al.
Feature
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H
R1
H
R1
OH
HO
R
H
– PdCl(OH)
Path C
– HCl
R2
R
R2
Ph
O
Pd(II) coord.
syn OH-8'
anti
oxypalladation
syn
elimination
HO
Ph
PdCl2
H
R1
R1 R2
PdCl
OH
OH
R
R2
8'
4'
Ph
2'
R
O
H
R1
9a R1 = OH; R2 = H
19a R1 = H; R2 = OH
Ph
H
R1
– PdCl2
– H2O
OH
HO
R
H
17 R1 = OH; R2 = H
22 R1 = H; R2 = OH
Path D
R2
R
HO
R2
Ph
Pd(II) coord.
anti OH-8'
syn
anti
elimination
HO
Ph
PdCl2
oxypalladation
PdCl2
OH
OH
H
H
OH
OH
OH
– HCl
– PdCl(OH)
Path C
R
R
R
Ph
H
Ph
Pd(II) coord.
syn OH-8'
anti
oxypalladation
O
syn
elimination
H
H
OH
2'
ClPd
OH
O
H
R
H
Cl2Pd
OH
OH
OH
Ph
H
O
8'
4'
2'
Ph
R
H
– PdCl2
– H2O
16
OH
10a
Path D
OH
Ph
R
H
H
O
H
H
Cl2Pd
Pd(II) coord.
anti OH-8'
syn
anti
elimination
Ph
2'
oxypalladation
O
H
Cl2Pd
Scheme 9 Mechanistic reasoning for the Pd(II)-catalyzed cyclization of the observed minor products from the allylic alcohols derived from 9, 10 and 19
(R = CH2CH2OPMB)
OH
OTBDPS
OH
tal values reported for the natural product, allowed us to
settle structure 1 (featuring a 2,4-cis/2,6-trans substituted
THP ring) as the correct isomer for cryptoconcatone H with-
out the requirement for synthesizing first the putative
structure 4.
OPMB
a
b,c
Ph
Ph
O
Ph
Ph
O
17
24
OH
O
OH
4'
2
O
OR
d
In 2016, two new related styryl lactones were isolated
from C. concinna, namely cryptoconcatones L and K.11b
Based on ROESY correlations, the authors settled the all-cis
relative configuration at the THP ring of both natural prod-
ucts. In addition, due to the paucity of sample of the natural
products, the absolute configuration in the THP ring was ar-
bitrarily assigned as originally described for cryptoconca-
tone H based on comparison of their NMR spectra. As the
structure of natural cryptoconcatone H was shown to be in
error, and considering similar biosynthetic pathway for
these natural products, we found necessary to validate the
relative stereochemistry proposed for THPs 2 and 3 by com-
paring their reported NMR data with those of 1 and 4. For
this, we took advantage of the stereoselective outcome of
the cyclization of ζ-hydroxy allylic alcohol 10 under Tsuji–
Trost conditions, which provided the all-cis THP 17 to con-
tinue up to the synthesis of 4, having the same proposed
relative configuration in the THP moiety as those reported
for cryptoconcatones K and L.
Starting from THP 17, TBDPS protection followed by
PMB cleavage provided alcohol 24 (Scheme 10). Subsequent
allylation using the Krische protocol provided the corre-
sponding homoallylic alcohol 25 in good yield as an 85:15
diastereoisomeric mixture. Esterification of the newly
formed secondary alcohol with acryloyl chloride, followed
by RCM of acrylate 26 with Grubbs I catalyst, and deprotec-
tion of the silyl group, finally delivered THP 4.
6' 2'
O
6
O
4
25 R = OH
26 R = C(O)CH=CH2
Scheme 10 Reagents and conditions: (a) i. TBDPSCl, imidazole, CH2Cl2,
r.t., 1 h; ii. CAN, acetone:H2O, 0 °C, 1 h, 26% (two steps); (b) [Ir(cod)Cl]2
(2.5 mol%), (R)-BINAP (5 mol%), Cs2CO3, 3-Cl-4-NO2-BzOH, AcOAllyl,
THF, 120 °C, 40 h, 62% (85% brsm; dr 85:15); (c) Acryloyl chloride, Et3N,
CH2Cl2, 0 °C, 2 h, 55%; (d) i. Grubbs I catalyst (10 mol%), CH2Cl2, 40 °C,
14 h; ii. TBAF, AcOH, EtOAc, r.t., 20 h, 61% (two steps).
To address the question of whether two different struc-
tures may have indistinguishable NMR spectra,21a,b and in
perfect agreement with our previous computational predic-
tions, comparison of the NMR data of 4 with those of natu-
ral cryptoconcatone H clearly showed a low correlation, re-
vealing large differences in the chemical shifts for most of
the hydrogens and carbons (differences of 0.78, 0.40, and
0.39 ppm were observed in the 1H NMR spectrum for H-6′,
H-2′, and H-5b′, respectively, and 6.0, 3.6, and 3.5 ppm in
the 13C NMR spectrum for C-1′, C-5′, and C-3′, among oth-
ers), as depicted in Figure 2. Additionally, the specific opti-
20
cal rotation for synthetic 4 {[]D +22 (c 0.1, MeOH)} dif-
fered greatly from that described for natural cryptoconca-
tone H {[]D25 –24 (c 0.1, MeOH)}.21c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

I
F. Della-Felice et al.
Feature
Synthesis
Figure 2 Comparison of selected 1H and 13C NMR data of THP 4 and
natural cryptoconcatone H
Figure 3 Comparison of selected 1H and 13C NMR data of natural cryp-
toconcatone K vs. THP 1 and 4
From the NMR data of the reassigned structure of cryp-
toconcatone H (1) and 4, we turned our attention to the
NMR data reported for natural cryptoconcatones K and L,
keeping in mind that their structures were proposed based
on comparison with the misassigned structure originally
proposed for cryptoconcatone H.
OH
O
OR
O
H
H
H
H
R
R
Focusing on cryptoconcatone K, comparison of its 1H
and 13C NMR data with those for 1 and 4 (Figure 3) revealed
small Δ for natural cryptoconcatone K and synthetic 4, es-
pecially for the carbinolic protons of the THP ring, which
supports the proposition that cryptoconcatone K and 4 bear
the same relative configuration in the THP ring. Further-
more, the reported ROESY correlations of cryptoconcatone
K matched well with an all-cis configuration in the THP
ring, as observed for 4 (Figure 4), thus supporting the rela-
tive stereochemistry found in the THP ring in structure 2
proposed by Kong, Luo and co-workers.
Focusing on cryptoconcatone L, although the presence
of the acetyl group in C-4′ influences its spectroscopic
properties, comparison of the 1H and 13C NMR chemical
shifts of the natural product with those observed for 1 and
4 reveals that the differences are smaller for THP 1, particu-
larly for H-2′/C-2′ and H-6′/C-6′, suggesting the same ste-
reochemical pattern in the THP moiety for crytoconcatone L
and structure 1 (Figure 5).
Ph
Ph
H
H
H
Observed NOESY for
4 and Cryptoconcatone K
Observed NOESY for
1 and Cryptoconcatone L
Figure 4 NOESY correlations observed for natural cryptoconcatone K
and L, synthetic 4 and 1
During the stereochemical description of cryptoconca-
tone L by the isolation team, ROESY correlations between
H-2′/H-4′ and H-4′/H-6′ were described to support the ste-
reochemical assignment of the THP fragment. However, af-
ter detailed analysis of the ROESY spectra provided in the
Supporting Information of the original reference, clear
cross-peaks between the vinylic protons H-7′ and H-8′ with
the signals assigned to H-2′ and H-4′ were noted, as found
in the NOESY spectra of 1 (Figure 4). Such correlations pres-
ent strong evidence suggesting that the proposed structure
for cryptoconcatone L might be in error.
Considering that the NMR data comparison was carried
out from similar, but not stereoisomeric compounds, we
undertook computational calculations on the NMR spectra
for the assigned structures of cryptoconcatone K and L to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

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F. Della-Felice et al.
Feature
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Cryptoconcatone K
OH
O
OH
O
OH
OH
O
O
27
28
29
30
DP4 = 85%
DP4 = 0.2%
DP4 = 14.3
DP4 < 0.1%
DP4+ > 99.9%
Proposed config.
by Kong and Luo
DP4+ < 0.1%
DP4+ < 0.1%
DP4+ < 0.1%
Cryptoconcatone L
OAc
O
OAc
OAc
OAc
O
O
O
31
32
33
34
DP4 < 0.1%
DP4 < 0.1%
DP4 < 0.1%
DP4 > 99.9%
DP4+ < 0.1%
Proposed config.
by Kong and Luo
DP4+ < 0.1%
DP4+ < 0.1%
DP4+ > 99.9%
Figure 6 Plausible THP cores for cryptoconcatone K and L and their
DP4 and DP4+ probabilities
By following the recommended methodology, and after
exhaustive exploration of the conformational space at the
MMFF level, the NMR shifts of the simplified systems bear-
ing the THP core of cryptoconcatones K and L were comput-
ed at the PCM/mPW1PW91/6-31+G**//B3LYP/6-31G* level
of theory using chloroform as solvent, followed by Boltzmann
averaging.24a With the theoretical NMR shifts in hand, we
next correlated them with the experimental 1H and 13C
chemical shifts values reported for the C2′–C6′ region of the
natural products. As shown in Figure 6, both DP4 and DP4+
suggested that the originally proposed THP ring 27 of crypto-
concatone K was correct, whereas the original THP ring 31
proposed for cryptoconcatone L was unlikely. Instead, the
cis/trans arrangement present in 34 was the most likely
structure, resembling the THP structure found in 1. Inter-
estingly, when correlating the NMR data calculated for 27–
30 with the chemical shifts experimentally observed for
these compounds, DP4+ correctly identified the corre-
sponding isomer in high confidence (>99.9%), providing
support for our previous assignment (see Supporting Infor-
mation).
Finally, we carried out NMR calculations followed by
DP4+ analysis on the full molecular systems of cryptocon-
catones K and L. In both cases, the configuration at C-6 was
proposed as R based on a negative Cotton effect at 250 nm,
whereas the configuration at C-5 was also set as R based on
a small coupling constant observed between H-5 and H-6
(2.4 Hz for cryptoconcatone K and 2.6 Hz for cryptocon-
catone L), clearly indicating a syn arrangement in these sys-
tems.11b,25 Hence, the corresponding set of eight possible
diastereoisomers of cryptoconcatones K and L were built by
fixing the configurations at C-5 and C-6 as R,R. After ex-
haustive conformational searches at the MMFF level, the
geometries were optimized first at the HF/3-21G level, fol-
lowed by final optimizations at the B3LYP/6-31G* level and
NMR calculations at the PCM/mPW1PW91/6-31+G** level.
Figure 5 Comparison of selected 1H and 13C NMR data of natural
cryptoconcatone L vs. THP 1 and 4
provide further support for our analysis. For this, quantum
chemical calculations of NMR shifts were considered to be a
powerful and affordable strategy to facilitate structural elu-
cidation.22 Among the different strategies available to settle
structural issues of organic molecules from a computation-
al point of view,22b we decided to use the DP4+ probability,
an updated and improved version of the DP4 method,23 that
includes the use of scaled and unscaled chemical shifts
computed at higher levels of theory.24
To establish the most likely relative configuration at the
THP rings in cryptoconcatones K and L, and to provide fur-
ther confidence to our assignment, we initially carried out a
fragment-based approach. Hence, the complete structures
of the natural products were simplified to THP fragments
displaying similar substitution pattern (compounds 27–30
and 31–34 for cryptoconcatones K and L, respectively;
Figure 6). In addition, given that the experimental NMR
data of structures 27–30 were available,7 this approach
offered a prime opportunity to test the DP4+ performance
for setting the relative configuration of 2,4,6-trisubstituted
THP systems.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

K
F. Della-Felice et al.
Feature
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When using the experimental NMR data of cryptoconca-
tone K, structures 2 and 35 are the most probable candi-
dates, in line with the calculations on the simplified model
system (Figure 7). Although the DP4+ values slightly favored
35 (with all the configurations inverted at the THP ring as
originally proposed), it is important to point out that the
theoretical NMR shifts of both candidates reflected high
similarities. In fact, the corrected mean absolute error
(CMAE) values computed for 2 (1.3 ppm and 0.12 ppm for
carbon and proton data, respectively) were identical to
those calculated for 35.
Cryptoconcatone L
OAc
O
OAc
O
(S)
(R)(S)
(R)
(S)(R)
O
O
(R)
(R)
(R)
(R)
Ph
O
Ph
O
OH
O
OH
3
42
DP4+ < 0.1%
Proposed structure
by Luo and Kong
DP4+ < 0.1%
OAc
OAc
O
(S)
(R)(R)
(R)
(S)(S)
O
O
(R)
(R)
(R)
(R)
Ph
O
Ph
O
OH
O
OH
43
44
Cryptoconcatone K
DP4+ < 0.1%
DP4+ < 0.1%
OH
O
OH
O
OAc
OAc
O
(S)
(R)(S)
(R)
(S)(R)
O
O
(R)
(R)
(R)
(R)(S)
O
(S)
(S)(R)
O
(R)
(R)
(R)
(R)
Ph
O
Ph
O
(R)
(R)
Ph
O
Ph
O
OH
OH
2
35
45
46
DP4+ = 39.2%
Proposed structure
by Kong and Luo
DP4+ = 60.8%
OH
O
OH
DP4+ < 0.1%
DP4+ < 0.1%
OAc
OAc
O
OH
O
OH
O
(S)
(S)(S)
(R)
(R)(R)
O
O
(S)
(R)(R)
(R)
(S)(S)
O
O
(R)
(R)
(R)
(R)
(R)
(R)
Ph
O
Ph
O
(R)
(R)
Ph
O
Ph
O
OH
OH
47
48
OH
OH
DP4+ = 23.0%
DP4+ = 77.0%
36
37
DP4+ < 0.1%
DP4+ < 0.1%
Isomers 3, 42–46
OH
O
OH
O
(<0.1%)
(R)
(R)(S)
(S)
(S)(R)
O
O
(R)
(R)
Isomer 47
(23.0%)
(R)
(R)
Ph
O
Ph
O
38
39
OH
OH
DP4+ < 0.1%
DP4+ < 0.1%
Isomer 48
(77.0%)
OH
O
OH
O
(S)
(S)(S)
(R)
(R)(R)
O
O
(R)
(R)
(R)
(R)
Ph
O
Ph
O
Figure 8 Plausible isomers for cryptoconcatone L and their DP4+ prob-
OH
OH
abilities
40
41
DP4+ < 0.1%
DP4+ < 0.1%
the highest DP4+ values. In this case, isomer 48 (with C-2′
and C-4′ configurations inverted as originally reported) was
pointed out as the most probable structure of cryptoconca-
tone L. Here again, minor differences were noted when
comparing the calculated NMR shifts of 47 (CMAE = 1.9
ppm and 0.20 ppm for carbon and proton data, respective-
ly) and 48 (CMAE = 1.8 ppm and 0.17 ppm for carbon and
proton data, respectively).
Isomers 36–41
(<0.1%)
Isomer 2
(39.2%)
Isomer 35
(60.8%)
Given that the absolute configuration at C-4′ was mis-
assigned by the isolation team when proposing 4 as the
structure of cryptoconcatone H, there is a high probability,
based on biosynthetic considerations, that C-4′ in cryptocon-
catone K and L displays the same stereochemistry at the THP
ring as in 1.
According to the present analysis, structures 35 and 48
can then be proposed for cryptoconcatones K and L, respec-
tively (Figure 7 and Figure 8). Nevertheless, on the basis of a
tight stereochemical relationship between the studied iso-
mers, the spectroscopic similarity exhibited between the
Figure 7 Plausible isomers for cryptoconcatone K and their DP4+
probabilities
On the other hand, when correlating the calculated
NMR data of 3, 42–48 with the experimental shifts of natu-
ral cryptoconcatone L, the originally proposed structure 3
was the least probable isomer among eight candidates (Fig-
ure 8). In its place, and in excellent agreement with our pre-
liminary results obtained with the model system, struc-
tures 47 and 48 (featuring a cis/trans THP system) showed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

L
F. Della-Felice et al.
Feature
Synthesis
first and second ranked candidates, and the known tenden-
cy of DP4 (or DP4+) to overestimate the probabilities
rates,10,23 isomers 2 and 47 should not be ruled out as possi-
ble structures of cryptoconcatone K and L, respectively.
0.1 M) under nitrogen atmosphere was heated to reflux in an oil bath
at 45 °C. After 2 h, the reaction mixture was concentrated under re-
duced pressure. Purification of the crude residue by flash column
chromatography (gradient, 5 to 100% EtOAc/Hex) gave acetate (R)-15
(25.0 mg 0.142 mmol; 40% recovered) as a colorless oil, followed by
diol 10 (90 mg, 0.21 mmol; 89% yield) as a light-brown oil.
Rf 0.17 (50% EtOAc/Hex); []D22 –10 (c 1.0, CHCl3).
Conclusion
FTIR (ATR): 3449, 2938, 1733, 1612, 1513, 1371, 1244, 1087, 1031,
700 cm–1
.
A comprehensive study on the stereochemical outcome
of palladium-catalyzed formation of styryl tetrahydropy-
rans through cyclization of the corresponding allylic ace-
tates or alcohols using both Pd(0) and Pd(II) catalysts, re-
spectively, was presented wherein coordination of the pal-
ladium species with free hydroxyl groups present in the
molecule can direct the outcome of the reaction, providing
evidence for the role of a stereoelectronic effect when em-
ploying Pd(0) or Pd(II) species for THP formation.
1H NMR (CDCl3, 250 MHz):  = 7.40–7.20 (m, 7 H), 6.88 (d, J = 8.7 Hz,
2 H), 6.28–6.18 (m, 1 H), 5.81–5.71 (m, 2 H), 4.45 (s, 2 H), 4.20–4.08
(m, 1 H), 3.98 (td, J = 5.7, 11.6 Hz, 1 H), 3.81 (s, 3 H), 3.76–3.55 (m,
3 H), 3.08–2.85 (m, 1 H), 2.31–2.21 (m, 2 H), 2.10 (s, 3 H), 1.97–1.77
(m, 2 H), 1.63–1.56 (m, 2 H).
13C NMR (CDCl3, 63 MHz):  = 170.0, 159.3, 139.4, 131.2, 130.2, 129.8,
129.3, 128.5, 128.0, 126.9, 113.8, 76.1, 73.0, 69.4, 69.0, 68.1, 55.2,
42.1, 40.4, 36.2, 21.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C25H32O6Na: 451.2097;
found: 451.2116.
We applied these results to the total synthesis of the
structure initially proposed for cryptoconcatone H by Kong,
Luo and co-workers (structure 4). Along with DP4+ compu-
tational studies, a structural elucidation analysis was per-
formed for two other natural tetrahydropyrans, cryptocon-
catones K and L, which had their stereochemistry estab-
lished only by spectroscopic techniques. Our analyses led us
to the conclusion that the relative configuration of the THP
moiety shown for structures 2 and 35 is correct for crypto-
concatone K, and to suggest the most probable stereochem-
istry of the THP ring for cryptoconcatone L is displayed by
structures 47 or 48.
(2S,3R)-2-(Bromomethyl)-3-phenyloxirane (13)
To a solution of epoxy alcohol 12 (796 mg, 5.30 mmol, 100 mol%) and
CBr4 (1.82 g, 5.43 mmol, 102 mol%) in CH2Cl2 (10.6 mL, 0.5 M) at 0 °C
under nitrogen atmosphere was added a solution of PPh3 (1.50 g, 5.43
mmol, 102 mol%) in CH2Cl2 (4.5 mL, 1.2 M). After 40 min, the reaction
mixture was concentrated under reduced pressure and the residue
was purified by flash column chromatography (SiO2; 0 to 8% EtO-
Ac/Hex). Bromide 13 (901 mg, 4.23 mmol, 80% yield) was obtained as
a colorless oil.
Rf 0.63 (30% EtOAc/Hex); []D21 +13 (c 1.0, CHCl3); antipode: []D21 –5
(c 1.0, CHCl3); {Lit.26 []D25 +11.3 (c 1, CHCl3)}.
FTIR (ATR): 3034, 1497, 1460, 1412, 1246, 1220, 1026, 904, 870, 768,
746, 695 cm–1
.
Starting materials and reagents were obtained from commercial
sources and used as received unless otherwise specified. CH2Cl2, tri-
ethylamine, and 2,6-lutidine were treated with calcium hydride and
distilled before use. THF was treated with metallic sodium and dis-
tilled before use. Anhydrous reactions were carried out with continu-
ous stirring under an atmosphere of dry nitrogen. Progress of the re-
actions was monitored by thin-layer chromatography (TLC) analysis
(silica gel 60 F254 on aluminum plates) and visualized under UV light,
p-anisaldehyde standard solution and/or KMnO4 standard solution.
Flash column chromatography was performed on silica gel (300–400
mesh) applying positive air pressure. Melting points were recorded
with a Electrothermal 9100 apparatus. Optical rotations were record-
ed with a Perkin Elmer 341 polarimeter. FTIR spectra were recorded
with a Thermo Nicolet iS5 spectrophotometer and are reported in
cm–1. 1H and 13C NMR and 2D experiments (1H 1H COSY, 1H 13C HSQC,
1H 13C HMBC, NOESY) were recorded on 250, 400 or 500 MHz equip-
ment; chemical shifts () are reported in parts per million (ppm) rela-
tive to deuterated solvent as the internal standard (CDCl3  = 7.27,
77.0 ppm) unless otherwise specified. Mass spectra were recorded
with a Q-Tof equipment operating in electrospray mode (ESI).
1H NMR (CDCl3, 250 MHz):  = 7.40–7.24 (m, 5 H), 3.81 (d, J = 1.7 Hz,
1 H), 3.51 (s, 1 H), 3.49 (s, 1 H), 3.31 (dt, J = 1.9, 6.0 Hz, 1 H).
13C NMR (CDCl3, 63 MHz):  = 136.0, 128.6, 125.6, 60.9, 60.2, 31.9.
HRMS (ESI-TOF): m/z [M]+ calcd for C9H9BrO: 212.9915; found:
212.9923.
(S)-1-Phenylprop-2-en-1-ol (14)
To a stirred solution of bromide 13 (1.81 g, 8.48 mmol, 100 mol%) in
THF (34 mL, 0.25 M) under nitrogen atmosphere at –78 °C was added
dropwise n-BuLi (6.36 mL, 8.90 mmol, 105 mol%, 1.6 M in THF). After
stirring at –78 °C for 1 h, the reaction was quenched with water (17
mL) at –78 °C and the mixture was stirred at r.t. for 30 min. The aque-
ous layer was extracted (Et2O), and the combined organic layers were
washed with brine, dried over MgSO4, and concentrated under reduce
pressure. The resultant residue was purified by flash column chroma-
tography (gradient, 5 to 30% EtOAc/Hex) to give alcohol (S)-14 (1.13 g,
8.40 mmol, 99% yield) as a colorless oil. The spectroscopic properties
of this compound were consistent with the data available in the liter-
ature.27a,b
Compounds 6–9, and 16 were synthesized and purified as described
21
Rf 0.34 (30% EtOAc/Hex); []D –3 (c 1.0, CHCl3, 90% ee) {Lit. (anti-
previously.10
pode)27c []D20 +1.3 (c 1.0, CHCl3, > 99% ee)}.
FTIR (ATR): 3358, 3028, 2980, 2867, 1494, 1453, 1409, 1195, 1114,
(1R,5R,7R,E)-5,7-Dihydroxy-9-((4-methoxybenzyl)oxy)-1-phenyl-
non-2-en-1-yl Acetate (10)
1024, 989, 927, 761, 699 cm–1
.
1H NMR (CDCl3, 250 MHz):  = 7.44–7.28 (m, 5 H), 6.07 (ddd, J = 6.0,
10.1, 17.1 Hz, 1 H), 5.37 (td, J = 1.3, 17.1 Hz, 1 H), 5.27–5.17 (m, 2 H),
1.93 (br s, 1 H).
A solution of diol 8 (66.8 mg, 0.238 mmol, 100 mol%), acetate (R)-15
(62.5 mg, 0.356 mmol, 150 mol%) and Hoveyda–Grubbs 2nd genera-
tion catalyst (4.6 mg, 7.1 mol, 3 mol%) in anhydrous CH2Cl2 (2.8 mL,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

M
F. Della-Felice et al.
Feature
Synthesis
13C NMR (CDCl3, 63 MHz):  = 142.6, 140.2, 128.4, 127.6, 126.3, 115.0,
75.2.
85:15 ACN/H2O for 1 min; flow: 15.5 mL/min; detector: 254 nm; tR =
11.10 (16), 11.51 (18), 11.83 (17)] furnished isomers 16,10 17 and 18
pure enough for characterization.
(S)-1-Phenylallyl Acetate (15)
Compound 18
Alcohol (S)-14 (410.7 mg, 3.06 mmol, 100 mol%), DMAP (3.7 mg, 0.03
mmol, 1 mol%) and TEA (1.72 mL, 12.2 mmol, 400 mol%) were dis-
solved in CH2Cl2 (15 mL, 0.2 M) at 0 °C under a nitrogen atmosphere.
Acetic anhydride (0.6 mL, 6.1 mmol, 200 mol%) was added dropwise
and the mixture was stirred at r.t. for 1 h. The reaction was then
quenched with sat. aq NaHCO3, the aqueous layer was extracted
(Et2O), and the combined organic layers dried over MgSO4 and con-
centrated under vacuo. Purification of the resultant residue by flash
column chromatography (gradient, 3 to 12% EtOAc/Hex) gave acetate
(S)-15 (510 mg, 2.89 mmol; 96% yield) as a colorless oil. The spectro-
scopic properties of this compound were consistent with the data
available in literature.28a,b
23
White solid; Rf 0.28 (50% EtOAc/Hex); m.p. 77.3–81.5 °C; []D –7 (c
0.5, CHCl3).
FTIR (ATR): 3396, 2937, 2866, 1612, 1513, 1488, 1302, 1248, 1174,
1806, 1033, 991, 820, 749, 692 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.42–7.39 (m, 2 H), 7.32 (t, J = 7.6 Hz,
2 H), 7.26–7.21 (m, 3 H), 6.89 (d, J = 8.8 Hz, 2 H), 6.79 (dd, J = 10.6,
15.6 Hz, 1 H), 6.56 (d, J = 15.6 Hz, 1 H), 6.46 (br dd, J = 10.6, 15.2 Hz,
1 H), 5.89 (dd, J = 5.9, 15.2 Hz, 1 H), 4.57 (br s, 1 H), 4.46 (s, 2 H), 4.19
(br t, J = 8.8 Hz, 1 H), 3.80 (s, 3 H), 3.74–3.70 (m, 1 H), 3.66 (dt, J = 3.9,
9.2 Hz, 1 H), 3.59 (br s, 1 H), 3.19 (br s, 1 H), 1.91 (dtd, J = 4.4, 9.0,
14.6 Hz, 1 H), 1.81 (ddd, J = 3.5, 8.7, 14.6 Hz, 1 H), 1.72 (br td, J = 3.2,
4.6 Hz, 1 H), 1.69 (br td, J = 3.1, 4.6 Hz, 1 H).
13C NMR (CDCl3, 101 MHz):  = 159.3, 137.3, 136.5, 132.3, 130.0,
129.8, 129.4, 128.6, 128.4, 127.5, 126.3, 113.9, 73.1, 70.0, 69.6, 69.0,
55.3, 42.6, 36.3.
HRMS (ESI-TOF) m/z [M – OH]+ calcd for C23H27O3: 351.1960; found:
351.1964.
Rf 0.68 (30% EtOAc/Hex); []D21 +59 (c 1.0, CHCl3), antipode: []D21 –40
(c 1.0, CHCl3); {Lit.28a []D25 +30.42 (c 0.48, CHCl3, 96% ee)}.
FTIR (ATR): 3034, 1740, 1371, 1231, 1020, 936, 700 cm–1
.
1H NMR (CDCl3, 250 MHz):  = 7.40–7.29 (m, 5 H), 6.28 (br d, J =
5.8 Hz, 1 H), 6.02 (ddd, J = 5.8, 10.4, 16.4 Hz, 1 H), 5.31 (td, J = 1.2,
14.5 Hz, 1 H), 5.25 (td, J = 1.2, 7.8 Hz, 1 H), 2.13 (s, 3 H).
13C NMR (CDCl3, 101 MHz):  = 169.9, 138.9, 136.3, 128.6, 128.1,
127.1, 116.9, 76.2, 21.2.
(3S,5R,7R,E)-5,7-Dihydroxy-9-((4-methoxybenzyl)oxy)-1-phenyl-
non-1-en-3-yl Acetate (21)
(2R,4S,6R)-2-(2-((4-Methoxybenzyl)oxy)ethyl)-6-((E)-styryl)tetra-
hydro-2H-pyran-4-ol (17)
Compound 21 (31.5 mg, 73.5 mol, 48% yield) was obtained as a col-
orless oil from alcohol 19 (65.1 mg, 0.152 mmol) in a similar proce-
dure to that described for THP 17.
Rf 0.26 (50% EtOAc/Hex); []D20 –49 (c 2.0, CHCl3).
To a stirring solution of Pd(PPh3)4 (65.5 mg, 37.5 mol, 5 mol%) in THF
(3.2 mL, 12 mM) was added dropwise a solution of diol 10 (321.0 mg,
0.749 mmol, 100 mol%) in THF (12.8 mL, 0.06 M) under a nitrogen at-
mosphere at r.t. After 90 min, the reaction mixture was concentrated
under reduced pressure and purified by flash column chromatogra-
phy (gradient, 30 to 100% EtOAc/Hex). Alcohol 17 (275 mg, 0.694
mmol; 93% yield) was obtained as a yellow oil.
FTIR (ATR): 3434, 2939, 2918, 2865, 1734, 1613, 1514, 1449, 1372,
1302, 1246, 1174, 1091, 1032, 967, 821, 751, 694 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.42–7.37 (m, 2 H), 7.36–7.31 (m, 2 H),
7.30–7.24 (m, 3 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.65 (d, J = 16.0 Hz, 1 H),
6.20 (dd, J = 7.0, 16.0 Hz, 1 H), 5.68 (dt, J = 6.3, 7.0 Hz, 1 H), 4.48–4.46
(m, 2 H), 4.12–4.04 (m, 1 H), 4.01–3.87 (m, 3 H), 3.82 (s, 3 H), 3.70 (td,
J = 5.3, 9.3 Hz, 1 H), 3.64 (ddd, J = 4.8, 7.6, 9.3 Hz, 1 H), 2.14 (s, 3 H),
1.84–1.81 (m, 2 H), 1.80–1.69 (m, J = 0.9 Hz, 2 H), 1.68–1.61 (m, 1 H),
1.60–1.53 (m, 1 H).
13C NMR (CDCl3, 101 MHz):  = 171.2, 159.2, 136.2, 132.1, 130.0,
129.3, 128.5, 127.9, 127.4, 126.5, 113.8, 72.9, 71.7, 71.5, 68.1, 68.1,
55.2, 43.1, 43.0, 37.0, 21.2.
Rf 0.26 (50% EtOAc/Hex); []D22 +47 (c 1.0, CHCl3).
FTIR (ATR): 3449, 2938, 1733, 1612, 1513, 1371, 1244, 1087, 1031,
968, 821, 700 cm–1
.
1H NMR (CDCl3, 250 MHz):  = 7.43–7.19 (m, 7 H), 6.87 (d, J = 8.7 Hz,
2 H), 6.59 (d, J = 16.0 Hz, 1 H), 6.21 (dd, J = 5.7, 16.0 Hz, 1 H), 4.46 (d,
J = 1.4 Hz, 2 H), 4.00 (br tdd, J = 1.5, 5.8, 11.1 Hz, 1 H), 3.94–3.82 (m,
1 H), 3.77 (s, 3 H), 3.69–3.54 (m, 3 H), 2.10 (br tdd, J = 2.1, 4.3, 12.2 Hz,
1 H), 2.00 (br tdd, J = 1.6, 4.2, 11.6 Hz, 1 H), 1.94–1.79 (m, 2 H), 1.37
(td, J = 11.4, 11.9 Hz, 1 H), 1.24 (td, J = 11.6, 12.2 Hz, 1 H).
HRMS (ESI-TOF) m/z: [M – C2H3O2]+ calcd for C23H29O4: 369.2066;
found: 369.2070; [M + K]+ calcd for C25H32O6K: 467.1836; found:
467.1859.
13C NMR (CDCl3, 63 MHz):  = 159.1, 136.7, 130.5, 130.1, 129.6, 129.1,
128.4, 127.5, 126.4, 113.7, 75.7, 72.6, 72.5, 68.0, 66.1, 55.1, 41.1, 41.0, 36.1.
HRMS (ESI-TOF): m/z [M – OH]+ calcd for C23H27O3: 351.1960; found:
351.1971.
Tsuji–Trost Reaction with Compound 20
To a stirring solution of Pd(PPh3)4 (13.2 mg, 11.4 mol, 6 mol%) in THF
(0.9 mL, 13 mM) was added dropwise a solution of diol 20 (168 mg,
0.392 mmol, 100 mol%) in THF (5.8 mL, 0.07 M) under nitrogen atmo-
sphere at r.t. After 70 min, the reaction mixture was concentrated un-
der reduced pressure to give a yellow oil (complex 1H NMR). Purifica-
tion by flash column chromatography (gradient, 30 to 70% EtO-
Ac/Hex) gave compound 22 (41% yield, molar ratio by 1H NMR) and 21
(13% yield, molar ratio by 1H NMR).
Tsuji–Trost Reaction with Compound 9
To a stirring solution of Pd(PPh3)4 (28.5 mg, 19.6 μmol, 6 mol%) in THF
(2 mL, 10 mM) was added dropwise a solution of diol 9 (168 mg,
0.392 mmol, 100 mol%) in THF (5.8 mL, 0.07 M) under nitrogen atmo-
sphere at r.t. After 2 h, the reaction mixture was concentrated under
reduced pressure and purified by flash column chromatography (gra-
dient, 30 to 100% EtOAc/Hex) to give 16, 17, and 18 (127.1 mg) as an
inseparable mixture in a 36:22:30 molar ratio (1H NMR), respectively.
Semipreparative HPLC separation on C18 SiO2 column [dimensions: 19
mm × 100 mm; particle size: 5 m; elution: started in 25:75
ACN/H2O, finished at 85:15 ACN/H2O in 18 min period, then steady at
Compound 22
Yellow oil; Rf 0.36 (50% EtOAc/Hex); []D20 +55 (c 2.0, CHCl3).
FTIR (ATR): 3348, 2916, 2865, 1612, 1513, 1450, 1363, 1302, 1247,
1174, 1092, 1035, 967, 820, 747, 694 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

N
F. Della-Felice et al.
Feature
Synthesis
1H NMR (CDCl3, 400 MHz):  = 7.42–7.38 (m, 2 H), 7.35–7.27 (m, 4 H),
7.27–7.21 (m, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.60 (d, J = 16.0 Hz, 1 H),
6.21 (dd, J = 5.9, 16.0 Hz, 1 H), 4.53–4.43 (m, 3 H), 4.30 (br s, 1 H),
4.11–4.03 (m, 1 H), 3.78 (s, 3 H), 3.70–3.57 (m, 2 H), 1.92–1.78 (m,
3 H), 1.74–1.65 (m, 2 H), 1.63–1.53 (m, 1 H).
1H NMR (C6D6, 500 MHz):  = 7.25 (dd, J = 8.0, 13.4 Hz, 4 H), 7.10 (t, J =
7.5 Hz, 2 H), 7.05–7.00 (m, 1 H), 6.80 (d, J = 8.6 Hz, 2 H), 6.66 (d, J =
16.0 Hz, 1 H), 6.23 (dd, J = 5.5, 16.0 Hz, 1 H), 4.56 (br dd, J = 5.5,
11.5 Hz, 1 H), 4.36 (dd, J = 11.8, 18.7 Hz, 2 H), 4.24–4.17 (m, 1 H), 3.85
(t, J = 2.7 Hz, 1 H), 3.70 (ddd, J = 6.0, 8.0, 9.0 Hz, 1 H), 3.59 (td, J = 5.9,
9.2 Hz, 1 H), 3.28 (s, 3 H), 1.93 (tdd, J = 5.7, 8.4, 14.0 Hz, 1 H), 1.80
(dddd, J = 4.2, 6.6, 7.7, 14.0 Hz, 1 H), 1.56 (br qd, J = 2.3, 13.6 Hz, 1 H),
1.47–1.40 (m, 2 H), 1.31 (ddd, J = 2.7, 11.5, 13.8 Hz, 1 H).
13C NMR (CDCl3, 101 MHz):  = 159.0, 136.9, 130.6, 130.4, 129.9,
129.2, 128.4, 127.4, 126.4, 113.7, 72.5, 72.0, 68.7, 66.4, 64.5, 55.2,
38.6, 38.5, 36.3.
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H28O4Na: 391.1885; found:
391.1884.
and the combined organic layers were treated with brine, dried over
Na2SO4 and concentrated under reduce pressure. The remaining col-
orless oil was used in the next step without further purification.
To a stirring solution of the previous crude oil in THF (1.4 mL) under
nitrogen atmosphere at 0 °C was added PdCl2(MeCN)2 (1.8 mg, 6.9
mol) in one portion. After 40 min, the reaction mixture was directly
concentrated under reduce pressure to give a yellow oil. Purification
by flash column chromatography (gradient, 30 to 60% EtOAc/Hex)
gave 23 (10 mg, 27.1 mol, 46% yield) as a light-yellow oil and 22 (3%
yield by 1H NMR molar ratio) as a light-yellow oil.15,19
Compound 23
Rf 0.2 (50% EtOAc/Hex); []D20 +18 (c 1.0, CHCl3).
FTIR (ATR): 3394, 2919, 2849, 1612, 1513, 1450, 1367, 1302, 1247,
1174, 1091, 1033, 968, 821, 748, 694 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.41–7.36 (m, 2 H), 7.31 (t, J = 7.5 Hz,
2 H), 7.26 (d, J = 8.3 Hz, 2 H), 7.25–7.21 (m, 1 H), 6.86 (d, J = 8.6 Hz,
2 H), 6.58 (d, J = 16.1 Hz, 1 H), 6.31 (dd, J = 5.9, 16.0 Hz, 1 H), 4.46 (s,
2 H), 4.36–4.29 (m, 2 H), 4.11 (tt, J = 4.3, 9.1 Hz, 1 H), 3.78 (s, 3 H),
3.61–3.54 (m, 2 H), 2.13–2.01 (m, 2 H), 1.85 (br td, J = 3.8, 13.0 Hz,
1 H), 1.77 (ddd, J = 5.0, 7.3, 14.4 Hz, 1 H), 1.70 (ddd, J = 5.3, 9.5,
13.0 Hz, 1 H), 1.52 (td, J = 9.2, 12.7 Hz, 1 H).
13C NMR (CDCl3, 101 MHz):  = 159.1, 136.8, 130.5, 130.4, 130.1,
129.3, 128.5, 127.6, 126.5, 113.8, 72.8, 69.8, 68.6, 66.8, 64.6, 55.2,
40.3, 38.2, 32.6.
Methanolysis of 9 and Reaction with PdCl2(MeCN)2
To a solution of acetate 9 (351 mg, 0.820 mmol, 100 mol%) in MeOH
(3.3 mL, 0.25 M) was added K2CO3 (567 mg, 4.10 mmol, 500 mol%) in
parts at 0 °C. After stirring at r.t. for 12 h, the mixture was diluted
with EtOAc (12 mL) and water (12 mL), then the reaction was
quenched with NaHCO3 (s). The aqueous phase was extracted (EtOAc),
and the combined organic layers were treated with brine, dried over
Na2SO4 and concentrated under reduce pressure. The remaining col-
orless oil was used in the next step without further purification.
HRMS (ESI-TOF) m/z [M–OH]+ calcd for C23H27O3: 351.1960; found:
351.1969.
To a stirring solution of the previous crude oil in THF (1.4 mL) under
nitrogen atmosphere at 0 °C was added PdCl2(MeCN)2 (21.5 mg, 82.9
mol) in one portion. After 30 min, the reaction mixture was directly
concentrated under reduce pressure to give a yellow oil. Purification
by flash column chromatography (gradient, 30 to 80% EtOAc/Hex)
gave 16 (210 mg, 0.57 mmol, 70% yield) as a light-yellow oil and 17
(6% yield by 1H NMR molar ratio) as a yellow oil.15,19
Methanolysis of 20 and Reaction with PdCl2(MeCN)2
To a solution of acetate 20 (30 mg, 0.070 mmol, 100 mol%) in MeOH
(0.27 mL, 0.25 M) was added K2CO3 (48.4 mg, 0.350 mmol, 500 mol%)
in portions at 0 °C. After stirring at r.t. for 12 h, the mixture was dilut-
ed with EtOAc (1 mL) and water (1 mL), and the reaction was
quenched with NaHCO3 (s). The aqueous phase was separated and ex-
tracted (EtOAc), and the combined organic layers were treated with
brine, dried over Na2SO4 and concentrated under reduce pressure. The
remaining colorless oil was used in the next step without further pu-
rification.
Methanolysis of 10 and Reaction with PdCl2(MeCN)2
To a solution of acetate 10 (30 mg, 0.070 mmol, 100 mol%) in MeOH
(0.27 mL, 0.25 M) was added K2CO3 (48.4 mg, 0.350 mmol, 500 mol%)
in portions at 0 °C. After stirring at r.t. for 12 h, the mixture was dilut-
ed with EtOAc (1 mL) and water (1 mL), and the reaction was
quenched with NaHCO3 (s). The aqueous phase was extracted (EtOAc),
and the combined organic layers were treated with brine, dried over
Na2SO4 and concentrated under reduce pressure. The remaining col-
orless oil was used in the next step without further purification.
To a stirring solution of the previous crude oil in THF (1.4 mL) under
nitrogen atmosphere at 0 °C was added PdCl2(MeCN)2 (1.8 mg, 6.9
mol) in one portion. After 30 min, the reaction mixture was directly
concentrated under reduce pressure to give a yellow oil. Purification
by flash column chromatography (gradient, 30 to 60% EtOAc/Hex)
gave 22 (15.5 mg, 41.0 mol, 60% yield) as a light-yellow oil.
To a stirring solution of the previous crude oil in THF (1.4 mL) under
nitrogen atmosphere at 0 °C was added PdCl2(MeCN)2 (1.8 mg, 6.9
mol) in one portion. After 30 min, the reaction mixture was directly
concentrated under reduce pressure to give a yellow oil. Purification
by flash column chromatography (gradient, 30 to 60% EtOAc/Hex)
gave 17 (15.1 mg, 41.0 mol, 59% yield) as a light-yellow oil and 16
(6% yield by 1H NMR molar ratio) as a yellow oil.15,19
2-((2R,4S,6R)-4-((tert-Butyldiphenylsilyl)oxy)-6-((E)-styryl)tetra-
hydro-2H-pyran-2-yl)ethan-1-ol (24)
To a solution of alcohol 17 (178 mg, 0.483 mmol, 100 mol%) and imid-
azole (66.4 mg, 0.966 mmol, 200 mol%) in CH2Cl2 (1 mL, 0.5 M) at 0 °C
under nitrogen atmosphere was added TBDPSCl (0.19 mL, 0.72 mmol,
150 mol%) dropwise. After stirring at r.t. for 1 h, the reaction mixture
was poured into sat. aq NaHCO3 (5 mL) and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over Na2SO4
and concentrated under reduced pressure. The resulting residue was
then dissolved in a 9:1 mixture of acetone/water (4.8 mL), and CAN
(802 mg, 1.45 mmol, 300 mol%) was added in three equal portions ev-
ery 20 min at 0 °C, with the third addition at r.t. After completion, the
mixture was diluted with EtOAc (13 mL) and water (13 mL) and treat-
ed with sat. aq NaHCO3 (13 mL). The aqueous phase was extracted
(EtOAc), and the combined organic layer was washed with brine,
Methanolysis of 19 and Reaction with PdCl2(MeCN)2
To a solution of acetate 19 (25.0 mg, 58.3 mol, 100 mol%) in MeOH
(0.27 mL, 0.22 M) was added K2CO3 (48 mg, 0.35 mmol, 600 mol%) in
portions at 0 °C. After stirring at r.t. for 12 h, the mixture was diluted
with EtOAc (1 mL) and water (1 mL), and then the reaction was
quenched with NaHCO3 (s). The aqueous phase was extracted (EtOAc),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P

O
F. Della-Felice et al.
Feature
Synthesis
dried over MgSO4 and concentrated under reduced pressure. Purifica-
tion of the resultant residue by flash column chromatography (gradi-
ent, 10 to 40% EtOAc/Hex) gave alcohol 24 (60.6 mg, 0.125 mmol; 26%
yield for two steps) as a yellow gum.
trated under reduced pressure. Purification of the resultant residue by
flash column chromatography (gradient, 0 to 9% EtOAc/Hex; 2% Et3N)
gave ester 26 (17.9 mg, 30.8 mol; 55% yield) as a light-yellow oil.
Rf 0.56 (10% EtOAc/Hex); []D23 –34 (c 2.0, CHCl3).
Rf 0.44 (30% EtOAc/Hex); []D21 –32 (c 2.0, CHCl3).
FTIR (ATR): 2931, 2857, 1723, 1428, 1405, 1270, 1195, 1112, 1072,
FTIR (ATR): 3464, 2932, 2858, 1646, 1428, 1112, 1075, 823, 743, 702
966, 822, 742, 702 cm–1
.
cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.71–7.67 (m, 4 H), 7.46–7.37 (m, 6 H),
7.36–7.32 (m, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.22 (t, J = 7.1 Hz, 1 H),
6.47 (d, J = 16.0 Hz, 1 H), 6.34 (dd, J = 1.4, 17.3 Hz, 1 H), 6.11 (dd, J =
5.8, 16.0 Hz, 1 H), 6.06 (dd, J = 10.4, 17.3 Hz, 1 H), 5.80–5.70 (m, 2 H),
5.18–5.11 (m, 1 H), 5.10–5.04 (m, 2 H), 3.84 (tt, J = 4.7, 10.7 Hz, 1 H),
3.75 (dd, J = 5.8, 11.3 Hz, 1 H), 3.34 (td, J = 6.0, 11.6 Hz, 1 H), 2.42–2.30
(m, 2 H), 1.97 (td, J = 7.6, 14.7 Hz, 1 H), 1.90–1.82 (m, 2 H), 1.69 (td, J =
4.9, 14.5 Hz, 1 H), 1.48 (q, J = 11.5 Hz, 1 H), 1.36 (q, J = 12.3 Hz, 1 H),
1.07 (s, 9 H).
1H NMR (CDCl3, 400 MHz):  = 7.71–7.67 (m, 4 H), 7.44–7.39 (m, 5 H),
7.38–7.33 (m, 3 H), 7.32–7.28 (m, 2 H), 7.24 (d, J = 7.0 Hz, 1 H), 6.48
(d, J = 16.1 Hz, 1 H), 6.13 (dd, J = 6.0, 16.0 Hz, 1 H), 3.89–3.81 (m, 2 H),
3.79–3.71 (m, 2 H), 3.48 (dddd, J = 2.0, 2.8, 8.8, 11.1 Hz, 1 H), 2.56 (br
s, 1 H), 1.91 (tdd, J = 2.3, 4.7, 12.6 Hz, 1 H), 1.86–1.78 (m, 1 H), 1.78–
1.72 (m, 1 H), 1.67 (tdd, J = 3.8, 6.0, 14.7 Hz, 1 H), 1.55–1.46 (m, 2 H),
1.07 (s, 9 H).
13C NMR (CDCl3, 101 MHz):  = 136.6, 135.7, 134.20, 134.17, 130.3,
129.7, 129.4, 128.5, 127.6, 126.4, 76.1, 75.7, 69.1, 61.2, 41.3, 41.1,
37.8, 26.9, 19.1.
13C NMR (CDCl3, 101 MHz):  = 165.6, 136.8, 135.7, 134.3, 134.2, 133.4,
130.3, 130.1, 129.69, 129.66, 129.64, 128.8, 128.4, 127.6, 127.6, 127.5,
126.4, 117.9, 75.8, 72.9, 70.9, 69.3, 41.3, 41.1, 39.8, 38.8, 26.9, 19.1.
HRMS (ESI-TOF) m/z [M –OH]+ calcd for C31H37O2Si: 469.2563; found:
469.2572.
HRMS (ESI-TOF): m/z [M + K]+ calcd for C37H44O4SiK: 619.2646; found:
619.2603.
(R)-1-((2R,4S,6R)-4-((tert-Butyldiphenylsilyl)oxy)-6-((E)-styryl)tet-
rahydro-2H-pyran-2-yl)pent-4-en-2-ol (25)
Synthesis of 4
A solution of alcohol 24 (58.7 mg, 120 mol, 100 mol%) in anhydrous
THF (0.6 mL, 0.2 M) was added to a sealed tube charged with
[Ir(cod)Cl]2 (2.1 mg, 30 mol, 2.5 mol%), (R)-BINAP (3.8 mg, 60 mol,
5 mol%), Cs2CO3 (7.9 mg, 24 mol, 20 mol%), 4-Cl-3-NO2-BzOH (2.5
mg, 12 mol, 10 mol%) and allyl acetate (131 L, 1.21 mmol, 1000
mol%) under nitrogen atmosphere. The reaction mixture stirred in an
oil bath at 120 °C for 40 h and then concentrated under reduced pres-
sure. Purification of the resultant residue by flash column chromatog-
raphy (gradient, 4 to 20% EtOAc/Hex) gave alcohol 25 (39.2 mg, 74.4
mol; 62% yield, dr 85:15 according quantitative 13C NMR) as a yellow
gum and alcohol 24 (15.6 mg, 32.1 mmol; 27% recovered) as a yellow
gum.
To a solution of ester 26 (16.0 mg, 27.5 mol, 100 mol%) in CH2Cl2 (5.5
mL, 5 mM) was added Grubbs I catalyst (2.3 mg, 2.8 mol, 10 mol%) in
two portions over 1 h, and the mixture was heated to reflux in an oil
bath at 45 °C. After 14 h of refluxing, the reaction mixture was con-
centrated under reduced pressure. The resulting residue was then dis-
solved in EtOAc (1 mL) and glacial AcOH (1.6 L, 27.5 mol, 100 mol%)
and then TBAF (82.5 L, 82.5 mmol, 1 M in THF; 300 mol%) were add-
ed at 0 °C and the mixture was stirred at r.t. After 20 h, the reaction
mixture was treated with sat. aq NaHCO3 and the aqueous phase was
extracted (EtOAc). The combined organic phases were washed with
brine, dried over Na2SO4 and concentrated under reduced pressure.
Purification of the resultant residue by flash column chromatography
(gradient, 50 to 100% EtOAc/Hex, then 3 to 9% MeOH/EtOAc) gave lac-
tone 4 (5.3 mg, 17 mol; 61% yield over two steps) as a yellow gum.
Rf 0.63 (30% EtOAc/Hex); []D23 –19 (c 1.0, CHCl3).
FTIR (ATR): 2934, 2857, 1733, 1428, 1113, 1073, 965, 912, 822, 739,
Rf 0.42 (100% EtOAc); []D23 +22 (c 0.1, MeOH).
702 cm–1
.
FTIR (ATR): 3404, 2920, 2849, 1715, 1390, 1251, 1607, 1039, 968, 810,
1H NMR (CDCl3, 500 MHz):  = 7.70 (d, J = 7.7 Hz, 4 H), 7.44–7.39 (m,
6 H), 7.36–7.31 (m, 3 H), 7.31–7.28 (m, 1 H), 7.24 (t, J = 7.1 Hz, 1 H),
6.48 (d, J = 15.9 Hz, 1 H), 6.13 (dd, J = 5.9, 16.0 Hz, 1 H), 5.84 (tdd, J =
7.1, 10.0, 17.1 Hz, 1 H), 5.13–5.06 (m, 2 H), 3.90–3.83 (m, 3 H), 3.73
(br s, 1 H), 3.50 (t, J = 10.5 Hz, 1 H), 2.26 (td, J = 6.8, 14.0 Hz, 1 H), 2.19 (td,
J = 6.5, 14.0 Hz, 1 H), 1.95–1.91 (m, 1 H), 1.79 (d, J = 10.4 Hz, 1 H), 1.73–
1.65 (m, 1 H), 1.59–1.52 (m, 2 H), 1.46 (q, J = 11.7 Hz, 1 H), 1.08 (s, 9 H).
13C NMR (CDCl3, 126 MHz):  = 136.5, 135.7, 134.9, 134.2, 134.1,
130.4, 129.7, 129.1, 128.5, 127.7, 127.6, 126.4, 117.2, 76.8, 76.1, 71.2,
68.9, 41.9, 41.8, 41.5, 41.2, 26.9, 19.1.
731, 695 cm–1
.
1H NMR (CDCl3, 500 MHz):29  = 7.38 (br d, J = 7.2 Hz, 2 H), 7.31 (t, J =
7.2 Hz, 2 H), 7.24 (tt, J = 1.9, 7.2 Hz, 1 H), 6.89 (ddd, J = 2.5, 6.0, 9.7 Hz,
1 H), 6.58 (d, J = 16.0 Hz, 1 H), 6.19 (dd, J = 5.8, 16.0 Hz, 1 H), 6.03 (br
dd, J = 2.5, 9.7 Hz, 1 H), 4.67 (dtd, J = 4.1, 6.0, 11.6 Hz, 1 H), 4.01 (tdd,
J = 1.8, 5.8, 11.3 Hz, 1 H), 3.92 (tt, J = 4.3, 11.3 Hz, 1 H), 3.73 (dddd, J =
1.8, 5.5, 8.0, 11.3 Hz, 1 H), 2.51 (tdd, J = 2.5, 11.6, 18.4 Hz, 1 H), 2.40
(dddd, J = 1.9, 4.1, 6.0, 18.4 Hz, 1 H), 2.18 (ddd, J = 6.0, 8.0, 14.5 Hz,
1 H), 2.10 (tdd, J = 1.8, 4.3, 12.3 Hz, 1 H), 2.04 (tdd, J = 1.8, 4.3, 12.3 Hz,
1 H), 1.89 (ddd, J = 5.5, 6.0, 14.5 Hz, 1 H), 1.37 (td, J = 11.3, 12.3 Hz,
1 H), 1.30 (td, J = 11.3, 12.3 Hz, 1 H).
HRMS (ESI-TOF): m/z [M + K]+ calcd for C34H42O3SiK: 565. 2540;
found: 565.2518.
13C NMR (CDCl3, 101 MHz):29  = 164.7, 145.7, 136.8, 130.7, 129.5,
128.8, 128.0, 126.7, 121.5, 76.3, 75.2, 71.6, 68.1, 41.4, 40.8, 40.6, 29.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H23O4: 315.1596; found:
315.1592.
(R)-1-((2R,4S,6R)-4-((tert-Butyldiphenylsilyl)oxy)-6-((E)-styryl)tet-
rahydro-2H-pyran-2-yl)pent-4-en-2-yl Acrylate (26)
Triethylamine (24 L, 0.17 mmol, 300 mol%) was added to a solution
of alcohol 25 (29.5 mg, 56.0 mol, 100 mol%) in CH2Cl2 (0.9 mL, 0.2 M)
at 0 °C under nitrogen atmosphere. After stirring for 10 min, acryloyl
chloride (9.5 L, 0.11 mmol, 200 mol%) in CH2Cl2 (0.5 mL, 0.2 M) was
added dropwise. After 2 h of stirring at r.t., the reaction mixture was
treated with sat. aq NaHCO3 and extracted (CH2Cl2). The combined or-
ganic layers were washed with brine, dried over MgSO4, and concen-
Funding Information
The authors are grateful to FAPESP (grants 2013/07607-8,
2014/25474-8,
and
2016/12541-4)
and
CONICET
(PIP
11220130100660CO) for financial support.
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P
F. Della-Felice et al.
Feature
Synthesis
Supporting Information
(13) (a) Hassan, A.; Lu, Y.; Krische, M. J. Org. Lett. 2009, 11, 3112.
(b) Dechert-Schmitt, A.-M. R.; Schmitt, D. C.; Krische, M. J.
Angew. Chem. Int. Ed. 2013, 52, 3195.
(14) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037–1611708.
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(15) When a mixture of products was formed, the yield of each com-
ponent was estimated from the mass and the molar ratio
observed in the 1H NMR spectrum of chromatographically puri-
fied compounds.
(16) See for example: (a) Mackenzie, P. B.; Whelan, J.; Bosnich, B. J.
Am. Chem. Soc. 1985, 107, 2046. (b) Auburn, P. R.; Mackenzie, P.
B.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2033. (c) Granberg, K.
L.; Baeckvall, J. E. J. Am. Chem. Soc. 1992, 114, 6858. (d) Trost, B.
M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996,
118, 6297.
(17) Hansen and Lee (ref. 4) and Uenishi and co-workers (ref. 5b)
also mentioned during their studies the formation of a side
product coming from beta-hydride elimination of the Pd--allyl
complex
(18) The (6′S) configuration in 21 was defined with Kishi’s method
after deacetylation, observing C-4′ at 68.1 ppm in CD3OD, corre-
sponding to a syn/anti motif. See: Kobayashi, Y.; Tan, C.-H.;
Kishi, Y. Helv. Chim. Acta 2000, 83, 2562.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–P