Diastereo- and enantioselective synthesis of 1,3,5,7-tetraol structural units using a Prins cyclisation-reductive cleavage sequence

Article abstract of DOI:10.1039/c4cc02702g

Stereocontrolled and efficient access to all the diastereomers of 1,3,5,7-tetraol structural units was developed using a Prins cyclisation-reductive cleavage sequence applied to tetrahydropyran aldehydes. Furthermore, these tetraols can be selectively functionalized. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02702g

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Diastereo- and enantioselective synthesis of
1,3,5,7-tetraol structural units using a Prins
cyclisation–reductive cleavage sequence†‡
Cite this: Chem. Commun., 2014,
50, 6718
Received 11th April 2014,
Accepted 1st May 2014
Elodie Brun, Veronique Bellosta and Janine Cossy*
´
DOI: 10.1039/c4cc02702g
www.rsc.org/chemcomm
Stereocontrolled and efficient access to all the diastereomers compounds 3 and 30 were separated by column chromato-
of 1,3,5,7-tetraol structural units was developed using a Prins graphy on silica gel. A good control of the stereogenic centers
cyclisation–reductive cleavage sequence applied to tetrahydro- at C8 and C12 was observed and the ratio of the diastereomers 3
pyran aldehydes. Furthermore, these tetraols can be selectively and 30 is the result of the moderate control of the stereogenic
functionalized.
center at C10.9 In all cases, the substituents at C8, C10 and C12
are all cis in the major isomer.10 The results are reported in
Polyols are present in a great diversity of natural products, with Table 1.
different bioactive profiles.1a Therefore, a number of synthetic
To transform 3a–3d and 30a–30d into the corresponding
methods and strategies have been developed in the past few tetraols A, the bis-tetrahydropyrans 3a–3d and 30a–30d were
decades to access these scaffolds.1 The most straightforward treated with NaI (acetone, m-wave irradiation, 120 1C) and the
strategy involves an iterative sequence, including a step using obtained iodinated compounds were then treated with zinc
chiral reagents, to access 1,3,5-triols which relies on one- (NH4Cl, EtOH, 90 1C) using the conditions reported by Yadav
directional chain elongation.2 Desymmetrisation of meso- and co-workers.8c The corresponding tetraols 4a–4d and 40a–40d
polyols and/or derivatives has also been reported.3 For our part, were isolated in yields around 60% over the two steps, as single
we have reported the synthesis of optically active syn- and anti- diastereomers (Table 2, entries 1–8). The hydroxyl at C10, in
1,3-polyols by using highly diastereo- and enantioselective the bis-tetrahydropyrans 3, can be protected with different
allyltitanations4 and we have demonstrated the utility of this groups such as a TBDPS group (compound 3e) (Table 2, entry
method to synthesize a diversity of natural products and/or 9) and the resulting ethers were engaged in the iodination/
bioactive compounds.5
ring-opening sequence (conditions A) to give the corresponding
Herein, we would like to report the synthesis of 1,3,5,7- tetraols. It is worth noting that it is necessary to use a different
tetraol structural units A with excellent diastereoselectivities sequence of reactions to introduce other protecting groups
from bis-tetrahydropyrans B obtained by using a homoallylic such as MOM and Boc groups, due to their instability under
alcohol controlled Prins cyclisation applied to tetrahydropyran the iodination conditions. However, iodination of compounds
aldehydes C (Scheme 1).
3, followed by protection and reductive cleavage of the tetra-
Enantiopure tetrahydropyrans 1a and 1b6 were involved in a hydropyran units (conditions B), gave the doubly protected
Prins cyclisation7 with enantiopure homoallylic alcohols (+)-2
or (ꢀ)-2 in the presence of TFA (26 equiv., CH2Cl2, rt, 3 h).8 After
treatment under aqueous basic conditions (aqueous NaHCO3,
Et3N), the bis-tetrahydropyrans were obtained as a mixture of
diastereomers 3 and 30, in a ratio of around 70 : 30, with a yield
in between 50% and 80% (Table 1). We have to point out that
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
UMR 8231, ESPCI ParisTech/CNRS/PSL* Research University, 10 rue Vauquelin,
75231 Paris Cedex 05, France. E-mail: janine.cossy@espci.fr
† This communication is dedicated to Prof. Taylor on the occasion of his 65th
birthday.
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Retrosynthetic analysis.
c4cc02702g
6718 | Chem. Commun., 2014, 50, 6718--6721
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Table 1 Diastereoselective Prins cyclisation
Entry
1
1
2
Major 3
Minor 30
Ratio 3/30
Yielda (%)
3a/30a = 70 : 30
3b/30b = 75 : 25
66
51
2
3
3c/30c = 65 : 35
3d/30d = 75 : 25
80
55
4
a
Isolated yield for the mixture of diastereomers 3 + 30.
tetraols 4f–4i in good yields and diastereoselectivities (Table 2,
entries 10–12).
Table 2 Access to 1,3,5,7-tetraols
To prove the relative stereochemistry of the hydroxyl groups
at C5 and C7 in the tetraols, and to confirm that the control is
due to the homoallylic alcohol used, compounds 4f and 4g were
treated with 2,2-dimethoxypropane (PPTS, acetone, rt) to form
the corresponding acetonides 5f and 5g. The relationship
between the substituents at C5 and C7 of the acetonides 5
was established by NMR analysis and was confirmed to be trans
in compound 5f and cis in compound 5g (Scheme 2).11
The differentiation of the two terminal olefins can be
achieved with compound 4h by applying the Bartlett–Smith
iodocarbonate cyclization.12 After protection of 4h as an
acetonide, followed by treatment with NIS (CH3CN, ꢀ40 1C to
rt, 4.5 h), the cyclic iodocarbonate 6 was isolated in 72% yield as
a mixture of two diastereomers in a ratio of 90 : 10 in favour of
the cis isomer. After basic treatment (K2CO3, MeOH, rt to 40 1C,
3
4 (yield %)a
Entry
1b
8 h), iodocarbonate 6 was transformed to the hydroxy epoxide 2b
7 in 76% yield in a ratio of 87 : 13 in favour of the syn isomer
(Scheme 3).13 As all the functionalities are orthogonally
protected, this compound can be used to realize the synthesis
3b
of complex molecules.
In summary, we have developed a general and diastereo-
selective method to prepare functionalized 1,3,5,7-tetraol struc-
tural units, which should provide access to all the possible
diastereomers, using an iterative Prins cyclisation–reductive
cleavage sequence. The stereochemistry of the hydroxy groups
is controlled during the Prins cyclisation and is dependent on
4b
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Table 2 (continued)
3
4 (yield %)a
Entry
5b
Scheme 2
6b
7b
Scheme 3
8b
Notes and references
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synthesis of polyketide natural products is ongoing in our
laboratory and will be reported in due time.
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