Synthesis of highly substituted 2,6-anti-configured tetrahydropyrans. First steps towards an efficient access to amphidinol 3 ring system

Article abstract of DOI:10.1016/j.tetlet.2005.04.041

Highly functionalised and polysubstituted tetrahydropyrans, akin to the middle core of the amphidinols, can be efficiently synthesised, with full stereocontrol and in good yields, using as key steps an anti-allylation reaction coupled with an intramolecul

Full text of DOI:10.1016/j.tetlet.2005.04.041

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4005–4009
Synthesis of highly substituted 2,6-anti-configured
tetrahydropyrans. First steps towards an efficient
access to amphidinol 3 ring system
a
Christophe Dubost, Istvan E. Marko and Justin Bryans
a,
b
*
´
a
´ ´
Universite catholique de Louvain, Departement de Chimie, Unite de chimie organique et medicinale,
Batiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la Neuve, Belgium
´
´
ˆ
bPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, England, UK
Received 21 February 2005; revised 1 April 2005; accepted 8 April 2005
Abstract—Highly functionalised and polysubstituted tetrahydropyrans, akin to the middle core of the amphidinols, can be efficiently
synthesised, with full stereocontrol and in good yields, using as key steps an anti-allylation reaction coupled with an intramolecular
Sakurai cyclisation. Three approaches were devised in order to reach a broad range of substitution patterns.
Ó 2005 Elsevier Ltd. All rights reserved.
Marine dinoflagellates are a rich source of natural prod-
ucts endowed with diverse structures and highly specific
bioactivity.1 Among these cyclic polyketides, amphidi-
nols are unique metabolites, exhibiting high haemolytic
and antifungal properties. The first member of this fam-
ily was isolated by Yasumoto in 19912 and new deriva-
tives are continuously being identified.3 The relative
and absolute stereochemistry of amphidinol 3 1 has re-
cently been elucidated through an elegant combination
of spectroscopic analysis and degradation studies4
(Fig. 1).
AB ring system, and the highly oxygenated northern
side chain. Recently, Cossy and Bouzbouz reported5
the preparation of the C1–C14 part of amphidinol 3 1.
However, to the best of our knowledge, no total syn-
thesis of amphidinol 3 has yet been described. In this
communication, we wish to present the successful
implementation of a concise and flexible methodology
for the rapid assembly of the fully functionalised tetra-
hydropyran fragments of 1.
We have previously shown6 that enantiomerically pure
syn–anti and syn–syn configured triol units such as 4
and 5 could be synthesised efficiently by the SnCl4-med-
iated allylation of chiral a-benzyloxyaldehydes 3 with
the uniquely functionalised allylstannane 2. Remarkably,
The challenging complexity of this structure lies in two
main parts: the presence of two similarly substituted
and anti-configured tetrahydropyrans, constituting the
OH OH
H
OH OH
OH
31
1
14
HO
OH
A
2
O
OH
OH
OH
OH
OH
OH
2 OH
OH
H
1
OH
OH
HO
53
67
B
O
H
H
3
OH
OH
Figure 1. Amphidinol 3.
Keywords: Tetrahydropyrans; Amphidinols; Sakurai reaction; Allylation; Tin.
*
Corresponding author. Tel.: +32 10 47 8773; fax: +32 10 47 2788; e-mail: marko@chim.ucl.ac.be
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.041

4006
C. Dubost et al. / Tetrahedron Letters 46 (2005) 4005–4009
O
OBn O
N(iPr)2
81-96%
d.e. >90%
e.e. >95%
R
R
TMS
1 eq. SnCl4
2 eq. SnCl4
SnBu3
TMS
4
OH
OBn
O
O
H
(Pri)2N
O
+
R
OBn O
N(iPr)2
TMS
3
2
O
70-83%
d.e. >90%
e.e. >95%
R= H, CH3, C6H7
OH
5
Figure 2.
the stereochemistry of these adducts was governed solely
by the amount of Lewis acid employed (Fig. 2).
Various Lewis acids were then screened in order to
shorten the reaction time and improve this process.
Strong Lewis acids such as SnCl4, TiCl4 or TiCp2(OTf)2
led mainly to desilylation of the starting material and
pure ZnCl2 proved to be totally ineffective. A major
breakthrough was observed when the unprotected com-
pound 4 was submitted to this condensation reaction. In
the presence of an orthoester and zinc dichloride ether-
ate, allylsilane 4 unexpectedly generated the diastereo-
isomeric cyclic acetals 8 and 9 (syn:anti = 3:1) in
excellent overall yield8 (Fig. 4).
The resulting structures possess a stereodefined polyoxy-
genated triad as present in rings A and B of the amph-
idinols. Our efforts therefore focused on the subsequent
transformation of adducts 4 and 5 into these important
subunits. Acylation of alcohol 4 provided the corre-
sponding, enantiomerically pure, acetate 6 in 85% yield
(Fig. 3).
Unfortunately, numerous attempts at functionalising
the allylsilane residue of 6 met with little success. Either
no reaction was observed or desilylation took place.
Interestingly, treatment of 6 with trimethylorthofor-
mate7 gave the b,c-unsaturated acetal 7a in 50% yield.
Employing the more strained 2-methoxy 1,3-dioxolane
afforded, in the presence of zinc dichloride etherate,
adduct 7b in up to 96% yield.
It is noteworthy that only the cyclic acetal, bearing a
methoxy group, is obtained even when 2-methoxy-1,3-
dioxolane is employed. It is assumed that this sequence
proceeds via an initial transetherification reaction, lead-
ing to 10, followed by the generation of the oxonium
cation 11 and its subsequent intramolecular capture by
the pendant allylsilane residue.
O
O
O
OBn O
OAc
N(iPr)2
TMS
OBn O
OAc
N(iPr)2
OBn O
OH
N(iPr)2
(ii)
(i)
7a R = Me
7b R = CH2CH2
TMS
O
R
O
R
4
6
Figure 3. Reagents and conditions: (i) Ac2O, pyridine, DMAPcat (85%); (ii) (CH3O)3CH, ZnCl2ÆEt2O, SnCl4, DCM, rt (50%) or 2-methoxy-1,3
dioxolane, ZnCl2ÆEt2O, DCM, reflux (96%).
(Pri)2N
O
O
(Pri)2N
O
OBn O
OH
N(iPr)2
O
O
(i)
+
TMS
O
O
O
O
H
H
4
H
H
8
OBn
9
OBn
ZnCl2.Et2O
(MeO)3CH
O
O
OBn O
N(iPr)2
TMS
10
OBn O
N(iPr)2
TMS
11
MeO
O
O
OMe
OMe
Figure 4. Reagents and conditions: (i) 2-methoxy-1,3-dioxolane, ZnCl2ÆEt2O, DCM, reflux (93%) or (MeO)3CH, ZnCl2ÆEt2O, DCM, reflux (96%).

C. Dubost et al. / Tetrahedron Letters 46 (2005) 4005–4009
4007
Table 1. Preparation of cyclic acetals
Entry
Allylsilane
Productsa
Yieldb (%)
(Pri)2N
O
H
(Pri)2N
O
H
O
OBn O
OH
N(iPr)2
TMS
1
96c
O
O
O
O
O
O
4
H
H
H
OBn
OBn
8
9
(Pri)2N
O
O
O
O
OBn O
OH
N(iPr)2
TMS
2
83c
O
O
O
H
5
OBn
12
(Pri)2N
O
H
(Pri)2N
O
O
O
OBn O
OH
N(iPr)2
TMS
3
95d
O
O
O
H
H
H
OBn
OBn
4
13
14
a Enantiomerically pure.
b Isolated yields.
c Conditions: (MeO)3CH, ZnCl2ÆEt2O, DCM.
dConditions: (EtO)3CH, ZnCl2ÆEt2O, DCM.
The syn–syn isomer 5 was also submitted to these condi-
tions and afforded exclusively the syn-diastereoisomer 12
in 83% yield. Finally, the use of triethylorthoformate led
smoothly to the ethoxy-containing cyclic acetals 13 and
14 (Table 1).
stereoselectively, an oxygen-containing substituent in
the final pyran ring system and hence access regio-
complementary structures, we took advantage of the
Et2AlCl-promoted ene reaction of allylsilane 20.10 Thus,
condensation of aldehyde 21 with 20 gave the expected
ene adduct 22, as a single double bond geometric isomer,
in 73% yield. Addition of ZnCl2ÆEt2O and (MeO)3CH to
homoallylic alcohol 22 led smoothly to the desired pyran
derivative 23 in 66% yield (Fig. 6).
In order to broaden the scope of this methodology, sev-
eral other cyclic acetals were prepared, according to effi-
cient and connective procedures previously developed in
this laboratory.9 Thus, treatment of allylselenide 15 with
1 equiv of n-BuLi, followed by the addition of an alde-
hyde, afforded the substituted allylsilanes 16 and 17
bearing an unprotected homoallylic alcohol function
(Fig. 5).
The last operation in this three-step synthesis of highly
substituted pyrans involved the transformation of these
acetals into the alkylated, 2,6-anti-configured, hetero-
cycles. It is well known in the literature11 that carbohy-
drate derivatives easily undergo alkylation, with a high
preference for the axial isomer, in the presence of a
Lewis acid and a soft nucleophilic agent. The most com-
mon procedure employs TMSOTf or BF3ÆEt2O, as the
Lewis acid, and allyltrimethylsilane as the alkylating
agent. Accordingly, several acetals were submitted to
these conditions.12 In all cases, a single diastereoisomer
possessing the 2,6-anti relationship was obtained, even
when an epimeric mixture of substrates was initially
engaged in the reaction. The results are displayed in
Table 2.
Applying our optimised conditions to these compounds
produced the desired cyclic acetals 18 and 19 in good to
excellent yields (79–99%). With the aim of introducing
OH
(ii)
(i)
TMS
R
R
O
OMe
SeMeTMS
H
H
15
18 R = CH3(CH2)2 (79%)
19 R = C6H5 (99%)
16 R = CH3(CH2)2 (78%)
17 R = C6H5 (67%)
Based solely upon spectroscopic data, the relative ste-
reochemistry of these adducts proved to be difficult to
Figure 5. Reagents and conditions: (i) n-BuLi, RCHO, THF, ꢀ78 °C;
(ii) (MeO)3CH, ZnCl2ÆEt2O, DCM, reflux.
H
OBn
TBSO
TMS
OTBS
21
OH
O
(ii)
TMS OTBS
20
(i)
OBn
BnO
O
OMe
22
H
H
23
Figure 6. Reagents and conditions: (i) Et2AlCl, Et2O, ꢀ78 °C (73%); (ii) (MeO)3CH, ZnCl2ÆEt2O, DCM, reflux (66%).

4008
C. Dubost et al. / Tetrahedron Letters 46 (2005) 4005–4009
Table 2. Allylation of cyclic acetals
O
(Pri)2N
O
Entry Allylsilane
Products
Yielda
(%)
OBn O
OH
N(iPr)2
TMS
O
4
(i)
3
2
5
6
(Pri)2N
O
(Pri)2N
O
H
1
O
H
H
1
82b
O
OBn
O
4 Syn-Anti
5 Syn-Syn
29 2,3-Anti/ 2,6-Syn (80%)
30 2,3-Syn/ 2,6-Syn (73%)
O
O
O
O
H
H
H
H
OBn
OBn
8 + 9
24
(Pri)2N
O
O
(Pri)2N
O
O
(Pri)2N
O
(Pri)2N
O
O
2
80b
O
4
(ii)
3
2
5
6
O
H
12
O
1
O
O
H
H
H
H
OBn
OBn
25
H
H
OBn
OBn
24 2,3-Anti/ 2,6-Anti
25 2,3-Syn/ 2,6-Anti
31 2,3-Anti/ 2,6-Anti (67%)
32 2,3-Syn/ 2,6-Anti (72%)
3
4
69c
O
H
O
H
O
H
Figure 7. Reagents and conditions: (i) Bi(OTf)3, butyraldehyde, THF,
0 °C; (ii) TsNHNH2, AcOK, H2O, reflux.
H
H
18
26
The terminal alkene of the 2,6-anti-configured pyrans
24 and 25 was chemoselectively reduced, using in situ
generated diimide. Gratifyingly, both the NMR chemical
shifts and the coupling constants of these compounds
differed in the two series, confirming the proposed 2,6-
anti-configuration for pyrans 31 and 32. For example,
the H5–H6 coupling constants were 4.6 and 5.5 Hz, in
the case of the 2,6-anti isomer 31, while the 2,6-syn iso-
mer 29 exhibited coupling constants of 2.4 and 11.4 Hz.
78c
O
H
27
O
H
19
O
H
OTBS
OTBS
5
81c
BnO
O
BnO
O
O
H
H
H
H
23
28
a Isolated yields.
At this stage, a single stereogenic centre was missing to
mimic the Amphidinol 3 rings. The exocyclic double
bond of acetals 8 and 9 was cleaved by ozonolysis
(Fig. 8). In contrast to the ketone derived from the
2,6-anti acetal 9, which was smoothly transformed into
the desired axial product 35 by a variety of bulky
reducing agents, the 2,6-syn acetal 8 always gave the
equatorial alcohol, regardless of the reducing agent em-
ployed. Only DIBALH afforded a significant amount of
33. After extensive optimisation of the reaction condi-
tions, axial alcohol 33 could be obtained in 86% yield.
The hydroxy function of 33 and 35 was next converted
into an acetate group and the resulting acetals 34
and 36 were submitted to the allylation protocol.
b Enantiomerically pure.
c Racemic mixture.
establish reliably. To determine unambiguously their
relative configuration, it was decided to synthesise the
corresponding 2,6-syn-configured pyrans 29 and 30
and to compare them with 31 and 32. The Intramolecu-
lar Silyl-Modified Sakurai (ISMS) reaction, a process
well known to afford exclusively 2,6-syn-oxocenes,13
was selected for that purpose. Accordingly, allylsilanes
4 and 5 were condensed with butyraldehyde, in the pres-
ence of Bi(OTf)3, to give the desired 2,6-syn-pyrans 29
and 30 in good yields (Fig. 7).
(Pri)2N
O
(Pri)2N
O
(Pri)2N
O
OH
OAc
O
O
O
(i)
(ii)
(Pri)2N
O
H
O
O
O
O
O
H
34
O
H
H
H
H
OAc
H
OBn
OBn
OBn
O
33
8
O
(iii)
(Pri)2N
O
(Pri)2N
O
(Pri)2N
O
O
H
37
OH
OAc
OBn
O
O
(iv)
(ii)
O
O
O
O
O
O
H
H
H
H
H
H
OBn
OBn
OBn
35
36
9
Figure 8. Reagents and conditions: (i) O3, Me2S, DCM, ꢀ78 °C then toluene, DIBALH, ꢀ40 °C (86%); (ii) Ac2O, pyridine, DMAPcat, rt (86%);
(iii) TMSOTf, allylsilane, MeCN, ꢀ40 to 0 °C (92%); (iv) O3, Me2S, DCM, ꢀ78 °C then L-Selectride, THF, ꢀ78 °C (84%).

C. Dubost et al. / Tetrahedron Letters 46 (2005) 4005–4009
4009
by column chromatography on silica gel (PE 10/EA 1) to
afford the desired product in pure form (445 mg, 96%);
anti-isomer 9: H NMR (300 MHz, CDCl3) d: 7.32–7.14
Gratifyingly, treatment of a mixture of 34 and 36 with
allyltrimethylsilane, in the presence of TMSOTf, gave
exclusively 37 in an exquisite 92% yield. This final prod-
uct possesses all the functions and the correct stereo-
chemical relationship present in rings A and B of the
Amphidinols.
1
(5H, m), 5.50 (1H, d, J = 9.9 Hz), 4.83 (1 H, s), 4.80 (2H,
s), 4.51 (1H, d, J = 11.7 Hz), 4.45 (1H, d, J = 11.7 Hz),
3.89 (2H, br m), 3.73 (1H, q, J = 6.3 Hz), 3.57 (1H, d,
J = 9.6 Hz), 3.29 (3H, s), 2.61 (1H, d, J = 13.5 Hz), 2.42
(1H, d, J = 13.5 Hz), 1.26–1.06 (15H, m); 13C NMR
(75 MHz, CDCl3) d: 153.64, 140.52, 138.08, 128.42,
128.18, 127.50, 108.25, 98.55, 74.55, 72.21, 71.87, 70.26,
54.90, 46.20–45.92, 38.99, 21.66–20.63, 16.04; MS (APCI)
In summary, an efficient methodology for the rapid
assembly of 2,6-anti-configured pyrans has been devel-
oped. This sequence tolerates a wide range of substitu-
ents and leads to a high diversity in the final adducts.
The preparation of adduct 37, embodying the correct
functionalities and stereochemical relationships of
amphidinol 3, has been accomplished with complete dia-
stereo- and enantioselectivity. Current efforts are now
dedicated towards linking these two rings and append-
ing the two side chains of 3. These results will be re-
ported in due course.
D
m/z: 374.1 (MꢀMeO); ½aꢁ20 +106.9 (c 1.0, CH2Cl2); syn-
1
isomer 8: H NMR (300 MHz, CDCl3) d: 7.32–7.14 (5H,
m), 5.42 (1H, d, J = 9.6 Hz), 4.84 (1H, s), 4.73 (1H, s), 4.52
(1H, d, J = 10.2 Hz), 4.45 (1H, d, J = 10.2 Hz), 4.27 (1H,
dd, J = 1.8; 13.5 Hz), 3.88 (2H, br m), 3.73 (1H, qd,
J = 1.8; 9.6 Hz), 3.42 (3H, s), 3.26 (1H, dd, J = 1.8;
9.6 Hz), 2.54 (1H, dd, J = 2.4; 13.5 Hz), 2.38 (1H, t,
J = 13.5 Hz), 1.26–1.06 (15H, m); 13C NMR (75 MHz,
CDCl3) d: 153.41, 141.66, 138.25, 128.16, 128.10, 127.38,
108.59, 103.23, 79.59, 72.33, 71.89, 70.47, 56.30, 46.24–
45.84, 40.59, 21.60, 20.76–20.58, 15.92; MS (APCI) m/z:
D
Acknowledgements
374.1 (MꢀMeO); ½aꢁ20 +14.5 (c 1.0, CH2Cl2).
9. Krief, A.; Dumont, W.; Marko, I. E.; Murphy, F.;
Vanherck, J.-C.; Duval, R.; Ollevier, T. Synlett 1998,
1219–1222.
´
Financial support for this work by the Universite
catholique de Louvain and Pfizer Ltd (studentship
to C.D.) is gratefully acknowledged.
10. Marko, I. E.; Dumeunier, R.; Leclercq, C.; Leroy, B.;
Plancher, J.-M.; Mekhalfia, A.; Bayston, D. J. Synthesis
2002, 7, 958–972.
References and notes
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Paterson, I.; Cumming, J. G. Tetrahedron Lett. 1992, 33,
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K. A. J. Am. Chem. Soc. 2000, 122, 168–169; (e) Greer, P.
B.; Donaldson, W. A. Tetrahedron 2002, 58, 6009–6018.
12. In a flame dried flask, a mixture of cyclic acetals 8 and 9
(100 mg, 0.24 mmol, 1 equiv) was dissolved in 4 ml of dry
MeCN and cooled to ꢀ40 °C under argon. Allyltrimeth-
ylsilane (156 mg, 1.22 mmol, 5 equiv) was added and
1 equiv of freshly distilled TMSOTf (54.8 mg, 44 ll,
0.246 mmol) was added dropwise. The reaction mixture
was allowed to reach 0 °C and the conversion was
monitored by TLC. When completion was reached, the
mixture was quenched with a saturated solution of
NaHCO3 and the aqueous layer was extracted twice with
DCM (20 ml). The organic layers were combined, dried
over MgSO4 and the solvents removed under vacuum. The
crude was purified by column chromatography on silica
gel (PE 10/EA 1) to afford the desired product 24 in pure
1. (a) Tachibana, K.; Scheuer, J.; Kikichi, H.; Engen, D. V.;
Clardy, J.; Schmitz, F. J. Am. Chem. Soc. 1981, 103, 2469–
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James, J. C. J. Am. Chem. Soc. 1981, 103, 6773–6775;
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8. In a flame dried flask were mixed, at room temperature,
trimethylorthoformate (250 ll, 242 mg, 2.29 mmol,
2 equiv) and 4.59 ml of a 1 M solution of ZnCl2 in Et2O
(4.59 mmol, 4 equiv). The mixture was stirred for 15 min
at 20 °C and then 1.14 ml of a 1 M solution of allylsilane 4
in dry DCM (1.14 mmol, 1 equiv) was added. After
completion of the addition, the solution was heated to
reflux and the reaction followed by TLC. When the
reaction was complete, the mixture was cooled to 0 °C and
a saturated aqueous solution of NaHCO3 was added
dropwise. An intense gas evolution was observed. The
organic layer was separated and the aqueous layer
extracted twice with DCM (20 ml). The organic layers
were combined, dried over MgSO4 and the solvents
removed under vacuum. The crude product was purified
1
form (84 mg, 82%); H NMR (500 MHz, CDCl3) d: 7.29–
7.17 (5H, m), 5.73 (1H, m), 5.22 (1H, d, J = 6.0 Hz), 5.02
(1H, d, J = 17.5 Hz), 4.98 (1H, d, J = 17.5 Hz), 4.88 (1H,
s), 4.82 (1H, s), 4.53 (1H, d, J = 11.5 Hz), 4.39 (1H, d,
J = 11.5 Hz), 3.99 (1H, br s), 3.86 (1H, m), 3.73 (1H, br s),
3.66 (1H, m), 3.59 (1H, t, J = 6.0 Hz), 2.36 (1H, dd,
J = 4.3; 13.5 Hz), 2.32 (1H, m), 2.20 (1H, dd, J = 6.0 Hz;
13.5 Hz), 2.15 (1H, m), 1.18–1.12 (15H, m); 13C NMR
(75 MHz, CDCl3) d: 154.54, 141.35, 138.70, 134.83,
128.42, 128.37, 127.68, 117.16, 111.19, 78.53, 72.37,
72.14, 71.87, 71.48, 46.69–45.63, 37.64, 37.13, 21.85–
20.74, 16.35; MS (APCI) m/z: 416.0 (M+H+).
13. Leroy, B.; Marko, I. E. Tetrahedron Lett. 2001, 42, 8685–
8688.