Prins Cyclization Using Magnesium Halides: Mild Access to 4-Halogenated Polysubstituted Tetrahydropyrans with a Special Feature

Article abstract of DOI:10.1055/s-0033-1340739

Different 4-halo-substituted polyfunctionalized tetra?hydropyrans were easily synthesized by segment-coupling Prins cyclization utilizing magnesium halides. The moderate Lewis acidity allows transformation of substrates bearing acid-labile functional groups. A solvent dependency of the stereochemistry at the C4 carbon was observed. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340739

LETTER
▌817
letter
Prins Cyclization Using Magnesium Halides: Mild Access to 4-Halogenated
Polysubstituted Tetrahydropyrans with a Special Feature
Prins Cyclization Using Magnesium Halides
Mario Walter, Dieter Schinzer*
Chemisches Institut, Otto-von-Guericke-Universität, Universitätsplatz 2, 39104 Magdeburg, Germany
Fax +49(391)6712223; E-mail: dieter.schinzer@ovgu.de
Received: 20.12.2013; Accepted after revision: 13.01.2014
Abstract: Different 4-halo-substituted polyfunctionalized tetra-
hydropyrans were easily synthesized by segment-coupling Prins cy-
clization utilizing magnesium halides. The moderate Lewis acidity
allows transformation of substrates bearing acid-labile functional
groups. A solvent dependency of the stereochemistry at the C4 car-
bon was observed.
O O
O
O
O
O
OH
O
H
H
Key words: Prins cyclization, magnesium halides, halogenated tet-
rahydropyrans, solvent-dependent stereochemistry, polysubstituted
tetrahydropyrans
OH
OH
HO
(+)-sorangicin A
Figure 1
In connection with our studies to synthesize the complex
natural product (+)-sorangicin A1 (Figure 1) we envi-
sioned a new methodology for a general approach to poly-
substituted tetrahydropyrans. Sorangicins, secondary
metabolites of myxo bacteria,2 are a new class of powerful
antibiotics with several structural challenges, including a
31-membered macrolide, 15 stereogenic centers, and an
unusual dioxobicyclo[3.2.1]octane system in conjunction
with a rare Z,Z,E-trienate linkage.
Here we wish to report our investigations3 along these
lines using the Prins cyclization as one of the most effec-
tive and frequently used methods to synthesize polysub-
stituted tetrahydropyrans – a common structural motif
featured in a large number of natural products and biolog-
ical active compounds.4–6 Originally, the Prins cyclization
is an intermolecular condensation of homoallylic alcohols
and carbonyl compounds utilizing Brønstedt or Lewis
acids. In many cases the reactions are saddled with vari-
ous side reactions often leading to decreased yields and
limitations of substrate scope.7 New mechanistic insights
owing to extensive investigations and improved proce-
dures led to a constantly growing scope of application and
a range of products.8 Therefore, this acid-mediated cou-
pling reaction became a commonly used synthetic tool
and is utilized for macrocyclizations as well.5,6
Halogenated THP are of broad interest due to the oppor-
tunity of subsequent functionalization. Numerous Lewis
acids have been utilized to introduce halogen substitu-
ents.9 Due to the necessity of a relatively high acidity, the
Prins cyclization only shows limited tolerance to acid-
labile functional groups in particular. One of the key steps
of our synthesis of the 2,3,4,6-tetrasubstituted tetrahydro-
O
O
O
f
c, d
OH
OH
OH
a, b
2
D-Ribose
O
O
O
O
O
e
g
1
4
Ph Ph
O
O
O
O
MeO
MeO
3
B
Ph Ph
5
Scheme
1 Reagents and conditions: (a) H2SO4 (cat.), acetone; (b) Ph3PMeBr, t-BuOK, 68% (2 steps); (c) Et3N, Bu2SnO, TsCl; (d) NaH,
97% (2 steps); (e) NaIO4, silica gel, quant.; (f) Mg, Li2CuCl4 (cat.), cis-1-bromoprop-1-ene, 89%; (g) 5, 4 Å MS, 80%.
SYNLETT 2014, 25, 0817–0820
Advanced online publication: 13.02.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340739; Art ID: ST-2013-B1156-L
© Georg Thieme Verlag Stuttgart · New York

818
M. Walter, D. Schinzer
LETTER
pyran fragment of (+)-sorangicin A was to prepare 4-ha- Improvement could be achieved by intramolecularization
logenated tetrahydropyrans 7. Z-Homoallylic alcohol 4 as of the reaction through transformation of 4 into the mixed
one of the key intermediates can be synthesized in just a acetal 88c,11 and utilization of magnesium halides as Lewis
few steps starting from D-ribose (Scheme 1). The natural acids (Scheme 2). The only moderate acidity effects a no-
sugar was converted into diol 110 which can then be trans- ticeable decrease in hydrolysis and side reactions.
formed into 4 through two different routes. Preparation of
Magnesium bromide in dichloromethane gives two iso-
mers 7a and 7b (Table 1). Similar observations were made
epoxide 211 and subsequent Grignard reaction12 gave 4 in
58% yield over five steps. Stereoselective allylation of al-
with other substrates.8,15 Nucleophilic attack on the inter-
dehyde 3, obtained by glycol cleavage of 2,13 using boron
mediate oxocarbenium ion in the chairlike transition state
can occur through an axial and equatorial trajectory alike.
reagent 514 led to 4 in 54% yield over four steps.
The intermolecular coupling of homoallylic alcohol 4 In the course of optimization we surprisingly observed a
with aldehyde 6 only led to numerous side reactions. Due solvent dependency of the stereochemical outcome. Addi-
to the high acidity and a low reaction rate of the intermo- tion of coordinating oxygen-containing solvents decreas-
lecular cyclization in comparison to, for example, cleav- es the Lewis acidity of the metal salt. Using a mixture of
age of the acetonide, transketalization, and racemization, dichloromethane and ether results in an enhanced yield
in none of the cases a clean product could be observed.
and eliminates the axial isomer. Unfortunately, the equa-
torial 4-ethoxy-substituted tetrahydropyran 7c emerges as
a new side product as a result of solvent attack. Best
performance can be achieved by the use of magnesium
bromide diethyl etherate in dichloromethane (Table 1).
Analogous effects can be observed with magnesium io-
dide – a Lewis acid so far also unemployed in Prins cycli-
zations. In this case each of the isomers 7d and 7e can be
promoted to the main product and be produced in good
yields by simple variation of the solvent mixture (Table
2).
O
BnO
O
OH
OBn
O
6
O
X
O
O
*
X
a, b
4
7
OAc OBn
O
The stereochemistry of the reaction is a result of the chair-
like transition state and the two possible pathways for
nucleophilic attack.8 Addition of Lewis acid induces for-
mation of α-halo ether 9 and solvolysis provides the inti-
mate ion pair 10. Cyclization produces carbenium
intermediate 11, still as an intimate ion pair. At this stage
O
O
8
Scheme
2
Reagents and conditions: (a) DCC, DMAP,
HOOCCH2CH2OBn; (b) i. DIBAL-H, ii. Ac2O, pyridine, DMAP,
89% (2 steps).
Table 1 Prins Cyclization of Acetal 4 with Magnesium Bromide
OAc OBn
O
O
O
8
conditions
0 °C
BnO
BnO
BnO
O
O
O
O
O
O
O
O
O
+
+
OEt
Br
Br
7a
7b
7c
Lewis acid
Solvent
CH2Cl2
Yield of 7a (%)
Yield of 7b (%)
Yield of 7c (%)
MgBr2
MgBr2
38
52
82
15
–
–
CH2Cl2–Et2O (3:1)
CH2Cl2
31
–
MgBr2·OEt2
–
Synlett 2014, 25, 817–820
© Georg Thieme Verlag Stuttgart · New York

LETTER
Prins Cyclization Using Magnesium Halides
819
Table 2 Prins Cyclization of Acetal 8 with Magnesium Iodide
OAc OBn
O
O
O
8
MgI2
conditions
BnO
+
O
BnO
BnO
+
O
O
O
O
O
O
O
O
OEt
I
I
7c
7d
7e
Solvent
Temp
Yield 7d (%)
Yield 7e (%)
Yield 7c (%)
CH2Cl2
THF
0 °C
r.t.
–
49
–
–
–
–
CH2Cl2–THF (1:2)
CH2Cl2–THF (9:1)
Et2O
r.t.
<20
15
–
<10
60
–
–
0 °C
r.t.
–
–
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (1:1)
CH2Cl2–Et2O (3:1)
0 °C
r.t.
40
55
62
–
59
19
10
8
r.t.
8
there are two possible pathways – proximal attack of ha- functional groups. The unprecedented solvent depen-
logenide leading to axial isomers 7b or 7e or dissociation dency of the stereochemical outcome in the case of mag-
to a solvent-separated ion pair 12 which will then be at-
tacked through an equatorial trajectory to give isomers 7a
or 7d (Scheme 3).
R2
R2
MgX2
R1
O+
R2
Decisive for the outcome of the reaction is whether the at-
tack from the intimate ion pair is faster than solvation or
not. It seems that ether accelerates solvation, perhaps
O
R1
OAc
O
R1
X–
10
X
9
–
through promotion of MgX3 formation thus decreasing
8
nucleophilicity and enabling solvent attack. Whereas THF
apparently in the first instance moderates the reactivity of
the Lewis acid.
R1
R1
To the best of our knowledge, there are no reports on such
a solvent-dependency of stereochemistry in Prins cycliza-
tion. Admittedly, in some cases it has been accomplished
to synthesize selectively one epimer or the other, but only
by usage of different kinds of Lewis acids and utilization
of additives.8b,15a,c
O
R2
O
X–
+
+
R2
H
H
X–
12
11
R1
O
R2
R2
R1
O
In summary, we discovered a mild method for the Prins
cyclization by the use of magnesium halides, which en-
ables to convert mixed acetal 8 into different halogen-sub-
stituted, highly functionalized tetrahydropyrans.16 The
moderate acidity of these metal salts may expand the
scope of the reaction to compounds bearing acid-labile
X
7a, d
X
7b, e
Scheme 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 817–820

820
M. Walter, D. Schinzer
LETTER
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mL/mmol of 8) at given temperatures. Reaction mixture was
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Benzyloxyethyl)-4-bromo-6-[(4R,5S)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl]-3-methyltetrahydropyran (7a)
Yield 82%; colorless oil; [a]D +43 (c 2.00, CHCl3). 1H NMR
(600 MHz, CDCl3): δ = 7.27–7.37 (5 H, m, C6H5), 5.83 (1 H,
ddd, J = 16.8, 10.0, 6.5 Hz, CH=CH2), 5.34 (1 H, dd, J =
17.1, 1.5 Hz, CH=CH2), 5.14 (1 H, d, J = 10.5 Hz, CH=CH2),
4.64 (1 H, dd, J = 6.3, 6.3 Hz, CHCH=CH2), 4.44–4.51 (2 H,
m, CH2Ph), 4.42 (1 H, dt, J = 12.8, 4.3 Hz, H-4), 3.97 (1 H,
dd, J = 8.4, 6.3 Hz, 6-CH), 3.39–3.52 (1 H, m, H-2), 3.48–
3.52 (2 H, m, CH2CH2OBn), 3.36 (1 H, td, J = 9.8, 2.4 Hz,
H-6), 2.20 (1 H, dt, J = 10.2, 2.8 Hz, H-5), 1.92–1.99 (2 H,
m, H-5 and H-3), 1.78–1.85 (1 H, m, CH2CH2OBn), 1.60–
1.66 (1 H, m, CH2CH2OBn), 1.45 [3 H, s, C(CH3)2], 1.36 [3
H, s, C(CH3)2], 1.07 (3 H, d, J = 6.9 Hz, 3-CH3). 13C NMR
(100 MHz, CDCl3): δ = 138.2 (Car,q), 133.6 (CH=CH2),
128.4 (Car), 127.6 (Car), 117.4 (CH=CH2), 108.7 [C(CH3)2],
79.2 (6-CH), 78.6 (CHCH=CH2), 76.6 (C-2), 76.3 (C6), 73.0
(CH2Ph), 66.9 (CH2CH2OBn), 54.0 (C-4), 39.7 (C-3), 34.6
(C-5), 33.9 (CH2CH2OBn), 27.7 [C(CH3)2], 25.3 [C(CH3)2],
7.6 (3-CH3). MS: m/z (%) = 424 (70), 422 (70), 301 (50), 231
(75), 141 (55), 137 (70), 127 (100). HRMS: m/z calcd for
C22H31BrO4: 438.1403 [M]+; found: 438.1404.
Synlett 2014, 25, 817–820
© Georg Thieme Verlag Stuttgart · New York