Enantioselective Synthesis of cis-2,6-Disubstituted-4-methylene Tetrahydropyrans via Chromium Catalysis?

Article abstract of DOI:10.1002/cjoc.202000296

Enantioenriched 2,6-disubstituted 4-methylene tetrahydropyrans have been obtained via a two-step sequence consisting of a highly enantioselective chromium-catalyzed carbonyl 2-(trimethylsilyl methyl)allylation and Prins cyclization. Commercially available (2-(chloromethyl)allyl)trimethylsilane serves as the bifunctional linchpin to combine two aldehydes to assemble the 2,6-disubstituted pyrans. A variety of functional groups are compatible under the mild reaction conditions. The synthetic utility of this methodology was demonstrated by the asymmetric synthesis of 16 examples of homoallylic alcohol and 8 examples of 2,6-disubstituted 4-methylene tetrahydropyrans, including an advanced intermediate which could be transformed to natural product centrolobine via a known procedure.

Full text of DOI:10.1002/cjoc.202000296

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Enantioselective Synthesis of cis-2,6-Disubstituted-4-methylene
Tetrahydropyrans via Chromium Catalysis
Authors: Jing Bai, Bin Chen, Guozhu Zhang*
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This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000296.
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Chinese Journal
of Chemistry
Enantioselective, Chromium-catalyzed, Natural Product, Prins cyclization,
Tetrahydropyran
Report
CJC
中
国 化 学 - An International Journal
Enantioselective Synthesis of cis-2,6-Disubstituted-4-methylene Tetrahydropyrans
via Chromium Catalysis
Jing Bai, Bin Chen, Guozhu Zhang*
a State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China.
Cite this paper: Bai, J.; Chen, B.; Xu, M. Zhang, G. Chin. J. Chem. 2020, 38, XXX—XXX. DOI: 10.1002/cjoc.202000XXX
Summary of main observation and conclusion. Enantioenriched 2,6-disubstituted 4-methylene tetrahydropyrans have been obtained via a two-step
sequence consisting of a highly enantioselective chromium-catalyzed carbonyl 2-(trimethylsilyl methyl)allylation and Prins cyclization. Commercially
available (2-(chloromethyl)allyl)trimethylsilane serves as the bifunctional linchpin to combine two aldehydes to assemble the 2,6-disubstituted pyrans. A
variety of functional groups are compatible under the mild reaction conditions. The synthetic utility of this methodology was demonstrated by the
asymmetric synthesis of 16 examples of homoallylic alcohol and 8 examples of 2,6-disubstituted 4-methylene tetrahydropyrans, including an advanced
intermediate which could be transformed to natural product centrolobine via a known procedure.
tetrahydropyrans under mild reaction conditions with tolerance of
broad and sensitive functionalities are highly desired.
Background and Originality Content
As functionalized heterocycles are widely present in bioactive
natural products and medicinally relevant molecules, efficient,
practical and stereoselective synthetic methods for heterocycles
are critical to both medicinal and synthetic organic chemistry.
Especially, chiral pyrans represent a ubiquitous class of heterocyclic
compounds. Within them, 2,6-disubstituted 4-methylene
tetrahydropyrans attract historically prolonged research interests
as this moiety are observed as cores in a number of macrolactone
natural products, such as enigmazole A and zampanolide, which
exhibit potent and special anti-cancer bioactivities (Scheme 1).1
Several elegant synthetic strategies have been developed to
construct this segment, including Smith’s Petasis−Ferrier
union/rearrangement strategy2a and the intramolecular ene
reaction. 2b Very recently, Trost et al. reported an elegant synthesis
of bryostatin 3, notably, a metal-catalyzed enyne cyclization
cascade was used to construct the 4-methylene tetrahydropyran
ring.3a Song et al. completed an expedient synthesis of bryostatin 8
via a organosilane intermediate.3b Within those preparation,
carbonyl allylation - Prins cyclization4 in the presence of chiral agent
holds the promise for a convergent synthetic approach. To date, a
variety of allylic organometallic reagents utilizing boron,5 silicon,6
tin,7 zinc,8 nickel,9 indium,10 and ruthenium11 have been
successfully applied to the carbonyl addition, however mainly in
stoichiometric and racemic versions. Asymmetric catalysis have
limited success using tin reagent.7b,7c Given the wide occurrence of
this type of molecular skeleton, new catalytic systems for
asymmetric preparation of 2,6-disubstituted 4-methylene
To this end, we turned our attention to enantioselective
chromium-catalyzed addition of functionalized carbohalides to
aldehyde, well-known as the Nozaki-Hiyama-Kishi reaction when
catalytic amount of Ni salt was employed. 12a-f The discovery of this
catalytic system, as well as the chiral ligands, led to a number of
elegant synthesis of complex natural product.12g-i On the other
hand, utilization of the commercially available 2-
(chloromethyl)allyl)trimethylsilane in 2,6-disubstituted 4-
methylene tetrahydropyrans synthesis has been only briefly
investigated in chromium and indium catalysis in an symmetric
version.13 The asymmetric version, however, remains an unrealized
challenge. In line with our interests in developing efficient
asymmetric chromium catalyst,14 we expect a suitable chiral
catalytic system should impart enantioselectivity in this important
transformation. Herein, we wish to report a highly enantioselective
2-(trimethylsilyl methyl)allylation reaction highlighted by
a
chromium catalysis system. The resulting homoallylic alcohols
were treated with TMSOTf in the presence of aldehydes, providing
synthetically useful enantioenriched 2,6-disubstituted 4-
methylene tetrahydropyrans as single diastereomers. To our
delight, this reaction exhibits broad functional group compatibility
and mild reaction conditions.
Scheme 1 Representative Natural Products.
e
M
O
N
O
O
O
O
O
O
OH
O
O
OR1
O
O
N
O
H
R2
O
O
P
HO OH
O
O
O
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(
differences between this version and the Version of Record. Please cite this article as doi:
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First author et al.
Report
4
L4
34
69
35
60
18
75
81
70
80
86
85
--
5
L5
6
L6
7
CrCl2 5 mol %, L1 10 mol %
Without CoPc
NiCl2 instead of CoPc
THF instead of DME
CH3CN instead of DME
Without CrCl2
Without NaI
8
9
75
83
10
11
12
13
14
15
16
17
18
trace
--
--
--
Results and Discussion
30
--
Based on our previous research experiences and many
others’,14,15
a
general
experimental
procedure
for
Without PS
<5%
trace
36
--
organochromium allylation was designed as follows to initiate our
research (Scheme 2) : (1) chromium chiral catalyst could be formed
in-situ through complexation step in which CrCl2 was treated with
chiral ligand and bases, preferred proton sponge for easily handing;
(2) allylic radical species could be generated via treatment of allylic
chloride with radical initiator, such as CoPc, and subsequently
transformed to allylic chromium(III) utilizing chromium chiral
catalyst; (3) The resulting chiral allylic chromium (III) would be
subject to addition of the aldehyde, followed by Zr or Si
dissociation of O-Cr bond, to yield the desired enantioenriched
homoallylic alcohol. During this process, Mn was selected as a
reducing reagent.17a
CsI instead of NaI
LiI instead of NaI
--
84
85
87
Allyl iodide instead of chloride 83
1 mmol of aldehyde 87
aThe reactions were carried out at 0.2 mmol scale unless noted
c
otherwise. bIsolated yield. Determined by chiral HPLC analysis,
absolute configuration was assigned by comparison of the specific
d
rotation to literature value (see the Supporting Information).
without NaI. PS = proton sponge.
In addition to ligand screening, the impact of various deviations
from the standard reaction conditions was also evaluated. Lower
catalyst loading (CrCl2 5 mol %, L1 10 mol %) resulted in decreased
yield and ee (60% yield, 85% ee, Table 1, entry 7). The presence of
CoPc and NaI proved critical to the efficiency of the coupling
reaction, as the yield of 1c decreased under conditions with
absence of either of two components (Table 1, entry 8 and 13).
CoPc were reported to significantly increase the rate of Cr-
catalyzed process; 16 NaI have similar functions to increase the rate
of transmetallation to the chiral chromium complex and likely
facilitate the reduction of allyl halide through Cl/I exchange,
notably, the reaction of allyl iodide provided similar result. The
screening of solvents revealed that DME was optimal among those
tested (entry 10 and 11). Both TMSCl 17 and ZrCp2Cl2 18 worked well
as dissociating agent of chromium-alkoxides. In this case, ZrCp2Cl2
was selected for further studies because deprotection of TMS
might be problematic due to the coexistence of same functionality
in the product. It’s worthy to point out, no allylation took place in
the absence of CrCl2, indicating the formation of products through
allylcobalt and allylzirconium species are less likely (Table 1, entry
Scheme 2 proposed reaction mechanism
r
C
L
III
)
Cl
(
TMS
TMS
TMS
r
L
C
II Cl
( )
o
C
III
( )
o
C
II
( )
n
1/2M II
(
)
O
R
n
n
1/2M
1/2M II
0
( )
(
)
n
1/2M
0
(
H
)
r
L
C
III Cl
( )
TMS
TMS
TMS
r
OZ Cp2Cl
r
O
H
L
OC III
(
)
r
R
Z Cp2Cl2
R
R
To practice our proposal and encouraged by previous success
with carbazole-based bisoxazolines (Nakada ligands),15f a number
of representative chiral ligands (was selected in our preliminary
model study utilizing (2-(chloromethyl)allyl)trimethylsilane (1a)
and 3-phenylpropanal (1b) (Table 1).
Table 1 Evaluation of Chiral Ligands and Other Reaction Parameters
r
L1
mo
l%
O
C Cl2 10
(
)
s
OH
,
mo
mo
20 l%
(
20
(
l%
)
P
)
TMS
Cl
TMS
+
l
c
1
,
a
b
m
r
1
0 2
o
c
i
o
I
e
u v
q
i
)
.
C
2
P
5
)
l% Cp2Z Cl2
1
(
(
)
.
.
,
,
,
m
l RT
)
n
e
q
u v
a
N
e
u v
mmo
e
q
u v
i
M
1
q
i
DME 0 3
1 2
(
(
)
(
12).
Scheme 3 Proposed transition state
=
=
=
=
=
1
:
r
L1
L2
L3
L4
L5
R
R
iP
tB
N
N
H
1
1
:
u
H
O
O
O
O
:
:
:
N
N
N
N
R
R
R
PhCH2
Ph
1
1
R1
E
t
R1
L6
l
C
N
H
i
r
entrya
ligand and
P
O
deviation from the standard
None
yield (%)b
88
ee (%)c
87
N
r
C
O
N
O
R
1
2
3
TM
S
L2
L3
57
60
81
77
i
r
P
=
a ac
i tt k R
ar or a en
rou s
g
yl p
lk yl
S
(
)
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Scheme 4 Substrate Scope Studies with aldehyde a,b
r
L1
mo
C Cl2 10
l%
P
TMS
Cl
(
)
,
mo
l
%
)
s
mo
l
%
)
OH
20
(
20
(
+
R
CHO
TMS
R
,
o
c
u v
i
mo
r
e
u v
q
i
)
.
C
2
P
5
)
l% Cp2Z Cl2
1
a
Notably, the reaction scale could be increased to 1 mmol with
maintenance of the efficiency (Table 1, entry 18). All those
experimental results are consistent with our proposed mechanism
(Scheme 3). A transition state was also proposed to account for the
preferential formation of the (S)- enantiomer of product (Scheme
3).
(
)
(
c
b
,
,
,
m
l RT
n
M
e
q
a
e
u v
N
I
1
(
q
i
DME 0 3
(
)
(
)
,
,
a en ar
=
a
R
lkyl lk yl yl
O
H
O
OH
OH
TMS
TMS
N
TBDPSO
TM
S
c
2
O
c
4
c
3
=
=
Y
37
%
89%
Y
83
%
86%
=
Y
60
%
80%
=
=
ee
ee
=
ee
Utilizing our optimized conditions found in the model study, this
highly enantioselective synthesis of 1c could also be expanded to
reactions with a broad range of aldehydes to yield desired products
with high enantioselectivity (80 – 97% ee, Scheme 4). In addition,
the versatility of this reaction was also proved through the efficient
ally additions to most of the 16 highly representative aldehydes
with aliphatic (alkyl, alkenyl), aromatic and heterocyclic functional
groups. Notably, the low yield of 4c is possibly due to the steric
hindrance. The ketone in 16c interfered with the nucleophilic
addition resulting in low yield.
e
OM OH
OH
OH
TMS
TMS
TMS
S
F
c
5
=
c
7
c
6
Y
ee
73
%
85%
=
=
Y
74
%
94%
=
Y
76
%
97%
=
=
ee
ee
OH
OH
OH
H
N
TMS
TMS
F3C
TMS
c
8
c
9
c
10
=
75
%
=
=
=
74
Y
74
Y
ee
Y
ee
%
%
84%
=
93%
=
ee
9
4
%
OH
OH
OH
TMS
TMS
TM
S
With the enantioenriched homoallylic alcohols in hand, our
attention turned to the synthesis of 2,6-disubstituted 4-methylene
tetrahydropyrans through Prins cyclization. After a brief condition
screening, we found that 1.5 equivalents of TMSOTf appeared to
be the most efficient reagent to combine the homoallylic alcohol
with the aldehyde to yield the desired product as a single
diastereomer. In order to demonstrate the synthetic potential of
our methodology, 8 diversified 2,6-disubstituted 4-methylene
tetrahydropyrans (R’ = alkyl, alkenyl and aryl) was synthesized with
perfect diastereomer ratio (Scheme 5) which is in accordance with
literature reports.7b,7c Within the products, it is worthy to mention
that compound 1d comprised the whole carbon skeleton and all
stereocenters of natural product centrolobine, and could be
transformed to the natural product with a known procedure.10a
e
M
O
c
c
13
12
c
11
=
=
=
=
Y
76
%
89%
Y
83
96%
%
Y
6
7
%
=
=
ee
ee
ee
96%
OH
OH
O
OH
TMS
TMS
TMS
c
c
16
14
c
15
=
=
=
=
Y
60
94%
Y
ee
64%
Y
35%
87
%
%
=
=
ee
ee
9
4
%
aReaction conditions: CrCl2 (10 mol%), L1 (20 mol%), Ps (20 mol%), CoPc (5
mol%), Cp2ZrCl2 (1 equiv), Mn (2 equiv), NaI (1 equiv), DME (0.3 ml), RT.
bIsolate yields.
Scheme 5 2,6-Disubstituted 4-methylene tetrahydropyrans
.
'
OH
e
u v
q
i
)
R
H
O
C
2 0
(
TMS
.
R
e
u v
q
i
)
TMSOTf 1 5
'
(
R
R
O
d
c
°
-
,
Et2O 78 C
S
O
O
n
B
O
O
OTBDPS
e
e
O
M
O
M
OTBS
2d
3d
1d
80
%
=
=
=
Y
62
%
Y
Y
41
%
O
O
O
4d
68
=
5d
56
%
Y
%
6d
=
=
Y
Y
62
%
O
O
O
e
M
O
OH
7d
62
8d
62
%
=
en ro o ne
bi
=
Y
C
t
l
%
Y
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
the reaction mixture was diluted with undried ethyl acetate (2 ml).
Then resulting suspension was filtered over a pad of silica gel using
cosolvent (hexane: ethyl acetat = 5:1) as eluent. Volatiles were
evaporated in vacuo. The residue was purified by basified (Et3N)
chromatography which afforded the final product.
Conclusions
In summary, a highly enantioselective synthesis of 2,6-
disubstituted 4-methylene tetrahydropyrans has been achieved
through a two-step cascade including a novel chromium-
catalyzed asymmetric carbonyl allylation followed by a Prins
cyclization. As an overall picture of the whole cascade, the
The ee was determined by HPLC analysis with Chiralcel OD and
IE et al. columns. The absolute configuration was assigned by
comparing the optical rotation with that of reported analogs. 7
(R)-1-phenyl-5-((trimethylsilyl)methyl)hex-5-en-3-ol (1c) (8.4
mg, 0.04 mmol) was prepared from 3-phenylpropanal (6.7 mg, 0.05
mmol) as yellow oil in 80% yield.1H NMR (400 MHz, CDCl3) δ 7.33-
7.16 (m, 1H), 4.70 (d, J = 3.7 Hz, 1H), 3.77-3.69 (m, 1H), 2.87-2.78
(m, 1H), 2.74-2.63 (m, 1H), 2.17 (dd, J = 13.5, 2.8 Hz, 1H), 2.05 (dd,
J = 13.6, 9.5 Hz, 1H), 1.91 (d, J = 1.9 Hz, 1H), 1.79 (ddd, J = 11.4, 8.2,
5.2 Hz, 1H), 1.52 (dd, J = 31.2, 11.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ = 144.5, 142.1, 128.4, 128.3, 125.7, 110.5, 67.8, 46.6, 38.6,
32.1, 26.6, -1.4. IR (neat) cm-1 ṽ: 3407. 3069. 3027. 2951. 2924.
2858, 1631, 1604, 1495, 1454, 1418, 1247, 1154, 1071, 1052, 1030,
839, 769, 745, 697, 631; HRMS (EI(+), 70 eV) : C16H26OSi [M-H2O]+:
calcd. 244.1647, found. 244.1645; [α]D20 = +33.7 (c = 0.70, CH2Cl2);
HPLC (Chiralcel OD-H column, hexanes:i-PrOH = 90:10, 1.0 ml/min,
210 nm), tminor = 4.0 min, tmajor = 5.3 min, 87% ee.
General procedure for the synthesis of 1d-8d: To a solution of
β-hydroxy allylsilane (1.0 equiv) in diethyl ether (2.0 ml), aldehyde
(2.0 equiv) was added, and the mixture was cooled to -78 ℃.
TMSOTf (1.5 equiv) was added and the mixture was stirred for 1h
at -78 ℃. Aqueous NaOH solution (1 M) was added and the
mixture was brought to rt., then transferred to a separatory funnel.
The layers were separated and the aqueous layer was extracted
with ethyl acetate (3 × 5 ml). The organic layers were combined
and washed with brine (5 ml), then dried over MgSO4. The solvents
were evaporated under reduced pressure and the crude material
was purified by flash chromatography to afford 2,6-cis-
disubstituted 4-methylenetetrahydropyrans.
commercially
available
2-(chloromethyl)allyl)trimethylsilane
serves as a linchpin to connect two pieces of aldehydes together
to form highly functionalized pyran moiety.
synthetic approach provides powerful tools to access
ubiquitous 2,6-disubstituted 4-methylene tetrahydropyrans in a
highly stereocontrolled and convergent manner. Future work will
focus on expanding this catalytic system to other chromium-
mediated transformations and applying this protocol to the
synthesis of complex molecules with biological and medicinal
significance.
19
This catalytic
a
Experimental
Generally information
Unless stated otherwise, all reactions were carried out in
flame-dried glassware under a dry nitrogen atmosphere. All
solvents were purchased and without further purified and dried.
All manipulations were carried out under nitrogen using 10 ml tube
with a seal. All glassware was oven or flame dried prior to use. All
solvents were purified and dried according to standard methods prior
to use, unless stated otherwise. All reagents were obtained from
commercial sources and used without further purification. Thin-layer
chromatography (TLC) was performed using 60 mesh silica gel plates
visualized with short-wavelength UV light (254 nm). Silica gel 60 (200 -
300 mesh) was used for column chromatography. 1H NMR spectra
were obtained at 400 MHz and recorded relative to the
tetramethylsilane signal (0 ppm) or residual proton-solvent. 13C NMR
spectra were obtained at 100 MHz, and chemical shifts were recorded
tert-butyl(4-(2-((2S,6S)-6-(4-methoxyphenyl)-4-
1
relative to the solvent resonance (CDCl3, 77.0 ppm). Data for H NMR
methylenetetrahydro-2H-pyran-2-yl)ethyl)phenoxy)dimethylsilane
(1d) (87 mg, 0.2 mmol) was prepared from 11c (66.1 mg, 0.25
mmol) as colorless oil in 80% yield. 1H NMR (400 MHz, CDCl3) δ
7.37-7.33 (m, 2H), 7.08-7.04 (m, 2H), 6.94-6.90 (m, 2H), 6.79-6.74
(m, 2H), 4.79 (d, J = 1.5 Hz, 2H), 4.28 (dd, J = 11.4, 2.3 Hz, 1H), 3.82
(s, 3H), 3.47-3.37 (m, 1H), 2.84-2.63 (m, 2H), 2.47 (d, J = 13.2 Hz,
1H), 2.26 (t, J = 12.6 Hz, 2H), 2.08 (t, J = 12.3 Hz, 1H), 2.01–1.92 (m,
1H), 1.87-1.74 (m, 1H),1.00 (s, 9H), 0.20 (s, 6H);13C NMR (100 MHz,
CDCl3) δ = 158.9, 153.5, 144.8, 134.9, 134.8, 129.3, 127.1, 119.8,
113.7, 108.7, 79.5, 55.2, 42.5, 40.5, 38.0, 30.8, 25.7, 18.2, -4.4. IR
(neat) cm-1 ṽ: 3072, 2931, 2895, 2857, 1652, 1611, 1585, 1510,
1464, 1248, 1172, 1093, 1067, 1006, 912, 825, 778, 689, 624; HRMS
(EI(+), 70 eV) : C27H38O3Si [M]+: calcd. 438.2590, found. 438.2600;
[α]D20 = -27.4 (c =3.16 , CH2Cl2).
are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br =
broad singlet, coupling constant(s) in Hz, integration). IR spectra were
recorded on a Nicolet FT-IR spectrometer and only major peaks are
reported in cm-1. For EI-HR and ESI-HR spectrometer were applied.
Chemicals were purchased from commercial suppliers. Unless
stated otherwise, all the substrates and solvents were purified and
dried according to standard methods prior to use. Reactions
requiring inert conditions were carried out in glove box.
General procedure for coupling products
General procedure for the synthesis of 1c-16c: To a mixture of
anhydrous chromium(II) chloride (10 mol%), 1,8-bis((S)-4-
isopropyl-4,5-dihydrooxazol-2-yl)-9H-carbazole (L1, 20 mol%) and
proton sponge (20 mol%) was added DME (0.3 ml) under an
nitrogen atmosphere. The mixture was stirred vigorously at room
temperature for 2h before it was transferred into a vessel charged
with CoPc (0.5 mol%), NaI (1.0 equiv), Zr(Cp)2Cl2 (1.0 equiv), and
manganese powder (2.0 equiv). Then aldehyde (0.2 mmol, 1.0
equiv) and (2-(chloromethyl)allyl)trimethylsilane (1.5 equiv) were
added. The resulting suspension was left stirred at ambient
temperature for 18 hours. After the full consumption of aldehyde,
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Synthesis of 2,6-Disubstituted-4-methylene Tetrahydropyrans. Org.
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Acknowledgement
We are grateful to NSFC-21772218, 21821002, XDB20000000,
the “Thousand Plan” Youth program, State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
and the Chinese Academy of Sciences.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Entry for the Table of Contents
XXX
,
a
r
mo
an
mo
d
20 l %
(
C Cl 10
l% lig
)
(
2
)
)
TMS
Cl
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RT 2 h
)
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H
R1 CHO
.
mo
l
%
PS 20
(
+
R
R
CHO
TMS
Enantioselective Synthesis
of cis-2,6-Disubstituted-4-
methylene
Tetrahydropyrans via
Chromium Catalysis
R1
exam es
R
R
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,
, ,
ves
dditi
RT 18 h
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)
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exam es
TMSOTf 1 5
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(
)
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=
8
pl
Et2O 78 °C
a
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lkyl lk yl yl
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en ar
Enantioenriched 2,6-disubstituted 4-methylene tetrahydropyrans have been obtained
via a two-step sequence consisting of a highly enantioselective chromium-catalyzed
carbonyl 2-(trimethylsilyl methyl)allylation and Prins cyclization. Commercially
available (2-(chloromethyl)allyl)trimethylsilane serves as the bifunctional linchpin to
combine two aldehydes to assemble the 2,6-disubstituted pyrans.
Jing Bai, Bin Chen, Guozhu Zhang*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.