A brief synthesis of the Aplasmomycin tetrahydrofuran

Article abstract of DOI:10.1016/S0040-4039(00)00614-6

A highly stereoselective iodocyclisation of the 3-alkene-1,2-diol 9, derived from asymmetric dihydroxylation of the dienyl benzoate 8, gives the β-iodotetrahydrofuran 10 and thence the Aplasmomycin precursor 13, following deiodination and Mitsunobu inversion. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00614-6

Tetrahedron Letters 41 (2000) 4453±4456
A brief synthesis of the Aplasmomycin tetrahydrofuran
Sean P. Bew, David W. Knight* and Robert J. Middleton
Department of Chemistry, Cardi€ University, PO Box 912, Cardi€, CF10 3TB, UK
Received 29 February 2000; accepted 10 April 2000
Abstract
A highly stereoselective iodocyclisation of the 3-alkene-1,2-diol 9, derived from asymmetric dihydroxylation
of the dienyl benzoate 8, gives the b-iodotetrahydrofuran 10 and thence the Aplasmomycin precursor 13,
following deiodination and Mitsunobu inversion. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Aplasmomycin; 5-endo; iodocyclisation; asymmetric; tetrahydrofuran.
In the foregoing paper,1 we report that 5-endo-iodocyclisations of 3-alkene-1,2-diols are often
very ecient and highly stereoselective. It occurred to us that such methodology could be useful
in an expedient synthesis of the b-hydroxytetrahydrofuran 2, a key component of the symmetrical,
boron-containing bis-macrolide Aplasmomycin 1.2 We were especially keen to test our new
methodology in this way, as previous approaches to this seemingly simple intermediate and related
structures had necessitated at least 11 steps and in one route, many more.3 5
Our results provided us with a number of options. However, before examining these, we considered
employing 5-endo-cyclisations of 4-alkene-1,2-diol derivatives 4 which we anticipated might lead
to the b-iodotetrahydrofurans 3, potential precursors to the target 2. Such substrates are known
to undergo exclusively 5-exo-cyclisations6 involving the distal 1-hydroxyl group. However, we felt
that it might be possible to block this group as shown [i.e. 4, R=SiR3, R1CO, etc.] and hence
facilitate the desired 5-endo process. In the event, all such attempts failed; in each case, only 5-exo
products6 were obtained, even when highly electron-de®cient protecting groups such as tri¯uoro-
acetyl [4, R=COCF3] were used. This was not a serious drawback, as it obviated the need for a
potentially awkward and inecient double inversion at the b-iodo centre, necessary in order to intro-
duce the correct hydroxyl group stereochemistry, but did once again con®rm the propensity of
5-exo-cyclisations to occur in preference to 5-endo processes when these are in direct competition.7
We therefore analysed the problem in terms of our new methodology,1 leading to the conclusion
that such cyclisations, speci®cally of (E)-3-alkene-1,2-diols (5 or 7), should give b-hydroxy-
tetrahydrofurans having the correct 2,5-trans stereochemistry necessary to access the target 2, given
that such cyclisations were viable with substrates having a second, distal allylic oxygen function
and that a suitable protecting group (`R' in 5 and 7) could be found. Initially, iodocyclisations of
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00614-6

4454
the anti-alkene-1,2-diols 5 seemed the best option, as access to tetrahydrofuran 2 would require
deiodination and protecting group manipulation. However, such precursors are not especially
amenable to stereoselective assembly: routes via non-chelation controlled additions of acetylides
to lactaldehydes give anti:syn ratios of around 85:15 at best8 while asymmetric dihydroxylation
(AD) approaches would require the use of (Z)-alkene precursors 6 which often give poor levels of
asymmetric induction.9 However, we were keen to utilise the excellent AD method which has
resulted in the abbreviation of so many reaction sequences since its discovery. We reasoned that
use of an (E)-alkene precursor would be preferable, as this would be expected to give very high
levels of enantiomeric enrichment in the AD reaction; iodocyclisation of the resulting syn-alkene-
1,2-diols 7 should also give the required 2,5-trans stereochemistry in the resulting tetra-
hydrofuran1 but necessitate an additional b-hydroxyl inversion step. Despite this latter feature,
we pursued this approach, especially because the Sharpless group have reported that the dienyl
benzoate 8 undergoes highly regio- and enantioselective AD reactions.10

4455
In the event, asymmetric dihydroxylation of dienyl benzoate 8 was highly regioselective when
carried out at 0ꢀC using 0.01 equiv. of (DHQD)2-PHAL and 0.004 equiv. of K2OsO4 together
with 3 equiv. each of potassium carbonate and potassium ferricyanide and 1 equiv. of
MeSO2NH2 in 1:1 aqueous t-butanol.9,10
The desired (R,R)-alkene-diol 9 was isolated after chromatography in 50±55% yields, with
some losses resulting from benzoate hydrolysis during work-up. The material showed [ꢀ]D +2.1
(c 2.10, CHCl3) [lit.10 [ꢀ]D +2.2 (c 2.00, CHCl3)]; we thus assumed 98% ee, as reported by
Sharpless et al.9
According to our model work,1 iodocyclisation was expected to deliver the desired iodotetra-
hydrofuran with stereoselectivities in the range 4±6:1. Under the usual conditions (3 equiv. each
of iodine and NaHCO3 in dry acetonitrile, protected from light), cyclisation onto the relatively
electron-poor alkene was slow, but after 72 h at ambient temperature, a good yield of an iodo-
1
tetrahydrofuran was obtained as largely a single isomer according to H NMR data. Further
optimisation established better conditions in which 2 equiv. of iodine monobromide were used in
place of elemental iodine, which resulted in complete cyclisation at ^10ꢀC during 16 h. The
resulting product was obtained with an enhanced 14:1 ratio in favour of the desired isomer 10
which was secured in a pure state in 78% yield by fractional crystallisation, m.p. 78±80ꢀC.
Nuclear Overhauser experiments were inconclusive but the expected stereochemistry was
con®rmed by single crystal X-ray analysis.11 Subsequent deiodination (Bu3SnH, AIBN, C6H6,
80ꢀC), which provided 70±75% isolated yields of the hydroxytetrahydrofuran 11, was followed by
Mitsunobu inversion12 using diisopropyl azodicarboxylate, triphenylphosphine and p-nitro-
benzoic acid.13 Problems in completely separating the resulting ester 1214 from by-products were
obviated by treating the crude mixture with catalytic methanolic sodium methoxide which,
following chromatography, delivered the desired diol 13 in 78% isolated yield from these two
steps.15 This showed [ꢀ]D +45.1 (c 1.01, CHCl3) [lit.3 [ꢀ]D +45.7 (c 0.84, CHCl3)], suggesting
>95% optical purity, and previously has been converted into the corresponding aldehyde 14,
prior to homologation using a Julia condensation to establish the (E)-alkene function during
introduction of much of the remainder of the target 1.
The excellent level of stereocontrol observed in the key 5-endo-cyclisation may be due to
intramolecular hydrogen bonding between the two hydroxy groups. On the reasonable assump-
tion that the pendant methyl group adopts a pseudoequatorial position, allowing hydrogen
bonding between the reacting hydroxyl group and the now pseudoaxial b-hydroxyl, as depicted in
structure 15, cyclisation would result in the major product 10, at least initially in conformation
16.
This example demonstrates the potential of such cyclisations and highlights the use of iodine
monobromide as a useful alternative to molecular iodine. Work aimed at further developing this
theme is underway.

4456
Acknowledgements
We thank the EPSRC Mass Spectrometry Service, Swansea University for the provision of
high resolution mass spectral data and the EPSRC and Cardi€ University for ®nancial support.
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