An efficient approach to the stereoselective synthesis of 2,6-disubstituted dihydropyrans via stannyl-Prins cyclization

Article abstract of DOI:10.1016/j.tetlet.2007.11.128

A general method has been developed for the stereoselective construction of 2,6-disubstituted dihydropyrans based on the Lewis acid-catalyzed intramolecular reactions of oxocarbenium ions with vinylstannanes. This novel methodology was applied to the enan

Full text of DOI:10.1016/j.tetlet.2007.11.128

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Tetrahedron Letters 49 (2008) 678–681
An efficient approach to the stereoselective synthesis of
2,6-disubstituted dihydropyrans via stannyl-Prins cyclization
Magdalena Dziedzic, Bartłomiej Furman *
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 28 September 2007; revised 9 November 2007; accepted 21 November 2007
Abstract
A general method has been developed for the stereoselective construction of 2,6-disubstituted dihydropyrans based on the Lewis acid-
catalyzed intramolecular reactions of oxocarbenium ions with vinylstannanes. This novel methodology was applied to the enantioselec-
tive total synthesis of (À)-centrolobine.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Vinylstannanes; Dihydropyrans; Prins cyclization; (À)-Centrolobine
Substituted tetrahydropyrans are common structural
motifs of many natural products and biologically active
compounds. A number of strategies for their synthesis
have been reported.1 The related 2,6-disubstituted dihydro-
pyran ring system is a particularly attractive target because
of its occurrence in natural products and the synthetic use-
fulness of the olefin function for further functionalization.
The latter makes this system a key intermediate in the
preparation of many substituted tetrahydropyrans.2 Some
of the most widely used methods for the preparation of
dihydropyrans are based on hetero-Diels–Alder cycloaddi-
tions,3 electrophile-initiated alkylation of glycals,4 olefin
metathesis,5 intramolecular silyl-modified Sakurai reac-
tion,6 or vinylsilane cyclization of oxocarbenium ions
(silyl-Prins cyclizations).7
of the alkene reagent. If the alkene moiety in the homo-
allylic alcohol bears a silyl substituent, the reaction can
be terminated following cyclization by elimination of the
silyl group, leading to the unsaturated product.9
Herein, we report that (Z)-vinylstannanes of type 1 par-
ticipate in highly diastereoselective Prins cyclizations with
oxocarbenium ions en route to 2,6-disubstituted dihydropy-
rans 2. Moreover, we also demonstrate, in the context of a
total synthesis of (À)-centrolobine (3) (Scheme 1), that the
necessary Prins cyclization substrates can be quickly assem-
bled from readily available optically pure epoxides.10
The preparation of vinylstannanes of type 1 required for
the Prins cyclization was easily accomplished by the regio-
and stereoselective hydrostannylation of terminal alkynes 4
bearing a hydroxyl group at the homopropargylic position
(Scheme 2).11
The vinylstannanes 1 thus prepared were reacted with
various aldehydes in the presence of TMSOTf12 at
À78 °C in Et2O to afford the corresponding 2,6-disubsti-
tuted dihydropyrans 2 (Table 1).13
The Lewis acid used above (TMSOTf) has previously
been shown to be effective at catalyzing Prins cyclizations.14
In most cases, as shown in Table 1, good chemical yields
and appreciable cis selectivities, verified by the qualitative
NOE enhancements, were obtained. The stereochemical
The Prins cyclization is one of the most effective reac-
tions for the synthesis of oxacyclic rings.8 Most Prins cycli-
zations involve coupling of homoallylic alcohols with
simple aldehydes under acid catalysis. Considerable effort
has been directed towards improving the efficiency of the
Prins cyclization, mainly by increasing the nucleophilicity
*
Corresponding author. Tel.: +48 3432128; fax: +48 6326681.
E-mail address: furbar@icho.edu.pl (B. Furman).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.128

M. Dziedzic, B. Furman / Tetrahedron Letters 49 (2008) 678–681
679
R1
O
HO
Bu3Sn
+
R2
H
O
R1
O
R2
MeO
OH
2
(-)-centrolobine (3)
1
Scheme 1.
1. Bu2Sn(OTf)H
hexane,25oC
2. n-BuLi
1a R1 =H
82%
87%
OH
OH
1b R1 =C6H5
R1
R1
1
1c
R =C6H13 85%
SnBu3
4
Scheme 2.
Table 1
Table 2
Synthesis of 2,6-disubstituted dihydropyrans
Prins cyclization of 5 with various aldehydes
OH
O
O
HO
Ph
Me3SiOTf (2 equiv.)
Et2O, -78 oC, 2-4h
R
Me3SiOTf (2 equiv.)
-78 oC, Et2O, 2-4h
+
H
+
SnBu3
5 (91% ee)
R1
R2
H
R1
O
R2
Ph
O
R
SnBu3
6
1
2
Entry
R
Yield of 6a (%)
eeb (%)
Entry
R1
R2
Yield of 2a (%)
cis/transb
1
2
3
4
a
C6H5
p-BrC6H4
p-TsOC6H4
C6H5(CH2)2
95
88
95
80
91
91
91
87
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
H
H
C6H5
C6H5(CH2)2
C6H5
p-BrC6H4
p-TsOC6H4
p-MeOC6H4
C6H5(CH2)2
c-C6H11
92
86
94
80
93
80
76
72
87
91
86
78
87
83
69
—
—
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
Cis only
Cis only
Cis only
3.5:1
Cis only
Cis only
Cis only
Cis only
Cis only
2:1
All yields are based on isolated product after purification by column
chromatography.
b
Determined by HPLC analysis employing Daicel chiral columns.
C6H13
C6H5
pure 2,6-disubstituted dihydropyrans 6 without racemi-
zation (Table 2).
p-BrC6H4
p-MeOC6H4
p-TsOC6H4
C6H5(CH2)2
c-C6H11
Finally, we applied our methodology to the total synthe-
sis of the natural product (À)-centrolobine (1), an antibi-
otic isolated from the heartwood of Centrolobium
robustum.16 The total synthesis of this natural product
has been reported previously by several research groups.17
The synthetic strategy employed by us is outlined in
Scheme 3.
Cis only
Cis only
Cis only
All yields are based on isolated product after purification by column
chromatography.
b
The ratio of products was determined by 1H NMR (500 MHz).
The starting enantiomerically enriched epoxide 8 was
prepared from the corresponding olefin 7 via Sharpless
asymmetric dihydroxylation18 followed by tosylation of
the primary hydroxyl group and NaOH treatment. The
optical purity of 8 was found to be 90% ee by chiral HPLC
and the absolute configuration of the intermediate chiral
diol was established by CD-spectroscopy.19 The ring open-
ing of epoxide 8 with lithium acetylide–ethylenediamine
complex in DMSO and subsequent hydrostannylation11
afforded alcohol 9 in a good yield (60% over two steps).
The Prins cyclization of 9 with 4-tosyloxybenzaldehyde
(10) in the presence of TMSOTf yielded dihydropyran 11
in 87% yield. The structure and stereochemistry of the
cyclized product 11 were confirmed unambiguously by
outcome of this reaction is in accord with previous observa-
tions and with the expectation that cyclization should occur
via a chair-like transition state with R1 and R2 disposed
equatorially and with initial formation of an (E)-oxocarbe-
nium ion.7,13 It should be noted that the electron density in
the aromatic ring of the aryl-substituted oxocarbenium ions
appears to have a significant influence on the diastereomeric
ratio (see entries 6 and 12). Such a result could be ascribed
to theE/Z isomerization of the respective oxocarbenium
ions.7c,15
In the case of the series of cyclization experiments pre-
sented in Table 1 we used racemic starting materials. The
use of optically pure starting material 5 produced optically

680
M. Dziedzic, B. Furman / Tetrahedron Letters 49 (2008) 678–681
SnBu3
O
a, b, c
d, e
HO
OBn
OBn
8
7
9
OBn
f
g
O
O
OHC
10
OTs
TsO
OH
TsO
OBn
11
12
h, i, j
(-)-centrolobine (3)
Scheme 3. Reagents and conditions: (a) AD-mix-a, t-BuOH–H2O, 0 °C, 80%, 90% ee; (b) TsCl, pyridine, 0 °C, 88%; (c) NaOH, Et2O–H2O, 93%; (d)
lithium acetylide–EDA, DMSO, 0 °C, 83%, 87% ee; (e) Bu2Sn(OTf)H then n-BuLi, 72%; (f) 10, TMSOTf (2.0 equiv), Et2O, À78 °C, 87%; (g) Pd/C, H2,
EtOAc, 78%; (h) TBSCl, imidazole, 95%; (i) Mg (10 equiv), MeOH, 25 °C, 50%; (j) NaH, MeI, THF then Bu4NF, THF, 0 °C, 73% (over two steps).
Fig. 1. The X-ray structure of 11.
single-crystal X-ray analysis (Fig. 1).20 Catalytic hydroge-
nation removed the olefin double bond and cleaved the benzyl
ether leading to the tetrahydropyran 12 in 78% yield. Sub-
sequent protection of the phenol group as the TBS ether
followed by detosylation,21 methylation and deprotection
of the silyl ether afforded (À)-centrolobine in a 15% overall
yield. The physical and spectroscopic data obtained for
compound 3 were in full agreement with the literature.15,22
In conclusion, we have developed a simple approach to
functionalized 2,6-dihydropyrans and demonstrated the
utility of this methodology by the enantioselective synthesis
of (À)-centrolobine. The utilization of this strategy in syn-
thesis of the other natural tetrahydropyrans is underway
and will be reported in due course.
Acknowledgement
The authors would like to express our sincere gratitude
to Dr. I. Justyniak (Institute of Physical Chemistry PAS)
for X-ray crystallographic analysis.
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12. The other Lewis acids generally did not exhibit reactivity compared to
that of TMSOTf, furnishing the same product, but in appreciably
lower yields.
13. Typical experimental procedure for the trimethylsilyl trifluoro-
methanesulfonate mediated reaction: To a solution of vinylstannane
(0.1 mmol) and aldehyde (0.15 mmol) in Et2O (5 mL) at À78 °C,
under argon, TMSOTf (0.2 mmol) was added dropwise. The reaction
was stirred at À78 °C for 2–4 h. After completion of the reaction
(TLC), the solution was allowed to warm to 0 °C, then poured into a
saturated aqueous solution of NaHCO3 (10 mL) and extracted with
Et2O (2 Â 10 mL). The combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure to give
the crude product, which was purified by flash column chromato-
graphy (typically hexane/Et2O 98:2).
20. Crystallographic data for structure 11 in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Number CCDC 662516. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 1223 336033 or
e-mail: deposit@ccdc.com.ac.uk].
21. Sridhar, M.; Kumar, B. A.; Narender, R. Tetrahedron Lett. 1998, 39,
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22. Compound 3: solid, mp 86–87 °C; [a]D À90.3 (c 0.9, CHCl3); lit.16a
;
mp 84–86 °C; [a]D À93.1 (c 0.19, CHCl3); IR (neat) cmÀ1 3391,
3012, 2935, 1614, 1515, 1445, 1367, 1247, 1176, 887 cmÀ1 1H
;
NMR (500 MHz, acetone-d6) d (ppm): 8.07 (s, 1H), 7.32–7.29 (m,
2H), 7.04–6.99 (m, 2H), 6.90–6.86 (m, 2H), 6.74–6.71 (m, 2H), 4.30
(dd, J = 11.3, 2.2 Hz, 1H), 3.78 (s, 3H), 3.44 (m, 1H), 2.72–2.57
(m, 2H), 1.94–1.60 (m, 6H), 1.43 (m, 1H), 1.29 (m, 1H); 13C NMR
(125 MHz, acetone-d6) d (ppm): 159.8, 156.1, 137.1, 133.9, 130.1,
127.7, 115.8, 114.2, 79.9, 77.7, 55.4, 39.5, 34.7, 32.5, 32.1, 31.4;
HRMS (ESI) m/z: (M+Na)+ calcd for C20H24O3Na, 335.1618;
found, 335.1603.