Alkene protection against acid using a bromide substituent: Application in a total synthesis of (-)-6,7-dideoxysqualestatin H5

Article abstract of DOI:10.1039/c8cc02690d

The presence of a bromide substituent, instead of a hydrogen or methyl group, on a carbon-carbon double bond, protects the alkene from addition reactions when exposed to trifluoroacetic acid. This concept is used to circumvent concomitant loss of unsaturation in a late-stage acid-catalysed 6,8- to 2,8-dioxabicyclo[3.2.1]octane rearrangement towards (-)-6,7-dideoxysqualestatin H5. The inertness of the alkenyl bromide functionality is demonstrated through several synthetic transformations in the assembly of the rearrangement substrate. Completion of the natural product synthesis is facilitated by post-rearrangement removal of the bromide substituent through stereoselective C-C cross-coupling in the presence of ester and hydroxyl functionalities.

Full text of DOI:10.1039/c8cc02690d

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Alkene protection against acid using a bromide
substituent: application in a total synthesis of
(À)-6,7-dideoxysqualestatin H5†
Cite this:DOI: 10.1039/c8cc02690d
Received 3rd April 2018,
Accepted 3rd May 2018
Hasanain A. A. Almohseni,‡ Hamad H. Al Mamari,§ Anne Valade,¶
Herman O. Sintim 8 and David M. Hodgson
*
DOI: 10.1039/c8cc02690d
rsc.li/chemcomm
The presence of a bromide substituent, instead of a hydrogen or
methyl group, on a carbon–carbon double bond, protects the
alkene from addition reactions when exposed to trifluoroacetic acid.
This concept is used to circumvent concomitant loss of unsaturation
in a late-stage acid-catalysed 6,8- to 2,8-dioxabicyclo[3.2.1]octane
rearrangement towards (À)-6,7-dideoxysqualestatin H5. The inert-
ness of the alkenyl bromide functionality is demonstrated through
several synthetic transformations in the assembly of the rearrange-
ment substrate. Completion of the natural product synthesis is
facilitated by post-rearrangement removal of the bromide substituent
through stereoselective C–C cross-coupling in the presence of ester
and hydroxyl functionalities.
(À)-6,7-Dideoxysqualestatin H5 (DDSQ) 5 (Scheme 1) is a member
of the zaragozic acid/squalestatin family of natural products which
display a variety of interesting bioactivities.1,2 Structurally, DDSQ
possesses a synthetically challenging 2,8-dioxabicyclo[3.2.1]octane
Scheme 1 Transketalisation approaches to (À)-6,7-dideoxysqualestatin
H5 5.
core bearing a hydroxyl and three carboxylic acid groups and an bond from such unwanted reactivity. While masking the alkene
unsaturated hydrocarbon side-chain at C-1. In an earlier study, we could potentially be achieved in numerous ways,4 we were
attempted to access DDSQ through acid-catalysed transketalisation attracted to the idea of reducing its propensity to protonation
of the advanced intermediate 1.3 Rearrangement to the desired through the presence of a temporary halide substituent. Here, we
core could be induced, however concomitant loss of the unsatura- communicate the realisation of this concept, and its application
tion in the side-chain by protonation/Friedel–Crafts cyclisation to in a synthesis of DDSQ 5 by halide replacement of the alkenyl
give tetralin 2 could not be avoided. Although this problem could methyl group in rearrangement substrate 1 (italicised Me).
be solved by introducing the olefin after the rearrangement
The Z-alkenyl halide functionality envisaged in the rearran-
(3 - 4 - 5),2b we became intrigued by the issue of how to gement substrate for DDSQ synthesis discussed above would
directly protect this type of electron-rich carbon–carbon double not only have to remain inert during transketalisation. It would
also be required to pass unscathed through several synthetic
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
steps in the construction of the substrate (vide infra), and
yet would need enough reactivity to undergo stereoretentive
Mansfield Road, Oxford OX1 3TA, UK. E-mail: david.hodgson@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Experimental procedures,
(and chemoselective – in the presence of ester functionality)
cross-coupling with a methyl donor;5 we therefore focused on
bromide (rather than iodide or chloride) as the halide substitu-
ent. Before embarking on the target synthesis with this mod-
ification in place, the following observations provided initial
support for the idea of alkene protection from an acid such as
TFA, by a bromide substituent. 2-Methyl-1-octene (6a, Scheme 2)
is known to be entirely converted to the corresponding tertiary
model studies and copies of 1H NMR and 13C NMR spectra of all new compounds.
See DOI: 10.1039/c8cc02690d
‡ Permanent address: University of Kufa, Najaf Governorate, Iraq.
§ Present address: Department of Chemistry, College of Science, Sultan Qaboos
University, P.O. Box 36, Al Khoud 123, Muscat, Sultanate of Oman.
¶ Present address: New Medicines, UCB Biopharma, Avenue de l’Industrie,
1420 Braine-l’Alleud, Belgium.
8 Present address: Department of Chemistry, Purdue University, West Lafayette,
IN 47907–2112, USA.
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expected to arise through application of Seebach’s tartrate
alkylation methodology2b,13 using the enolate of tartrate 15
and iodide 16.
Access to the Z-alkenyl bromide-containing iodide 16 for
tartrate alkylation was achieved from R-aldehyde 1714 (Scheme 4).
Wittig olefination (known to proceed without erosion of enantio-
integrity with such an ester-stabilised ylide on a related a-methyl
aldehyde15) to give E-enoate 18, was followed by bromination–
dehydrobromination15 to give the Z-a-bromoenoate 19. The
dianion of ethyl acetoacetate16 was efficiently alkylated with the
derived allylic bromide 20, and the resulting b-ketoester 21 was
reduced to the 1,3-diol 22 using NaBH4 in MeOH/THF.17 Iodina-
tion of the primary alcohol and TES protection of the secondary
alcohol gave the iodide 16.
Scheme 2 Addition and cyclisation reactions of alkenes with acids.
trifluoroacetate 7 within 20 min using TFA (5 equiv.) in CH2Cl2 at
0 1C,6,7 whereas 2-bromo-1-octene (6b)8 was recovered unchanged
from exposure to the acidic conditions typically necessary to
induce the acid-catalysed 6,8- to 2,8-dioxabicyclo[3.2.1]octane
rearrangement [TFA/CH2Cl2/H2O (10 : 20 : 1), 40 1C, 48–68 h].2b,9
Also, 2-methyl-5-phenylpentene (8a) is known to undergo Friedel–
Crafts cyclisation to 1,1-dimethyltetralin (9) with acid,10 and, simi-
larly, we found 2,4-dimethyl-5-phenyl-2-pentene (10) with TFA gave
the corresponding tetralin 11 in 95% yield (Scheme 2); in contrast,
2-bromo-5-phenylpentene (8b)11 was recovered quantitatively
from exposure to the standard TFA rearrangement conditions.
For the prospective synthesis of (À)-DDSQ 5, the Z-alkenyl
bromide-bearing rearrangement substrate 12 was anticipated
to be available through a Rh(II)-catalysed tandem carbonyl ylide
formation and cycloaddition of a diazoketone 13 with methyl
glyoxylate (Scheme 3).12 In turn, diazoketone 13 was considered
as being accessible from substituted tartrate 14, with the latter
Scheme 4 Synthesis of iodide 16.
Initial availability of the 1,3-diol 22 (from rac-17) provided an
early opportunity to test the stability of the Z-alkenyl bromide
motif under the TFA rearrangement conditions. Pleasingly,
reaction of 1,3-diol 22 gave the bistrifluoroacetate 25 (quant.,
Scheme 5), in which the alkenyl bromide was unaffected.
Moreover, stereoretentive Suzuki reactions between the 1,3-diol-
derived mono- and bis-TBS ethers 23 and 24 and the borinate
complex 26 (from MeLi and 9-MeO-9-BBN)5 gave E-alkenes 27 and
28 in 75% and 76% yields, respectively.18
Scheme 3 Outline of projected route to Z-alkenyl bromide-bearing
rearrangement substrate 12.
Scheme 5 Stability of alkenyl bromide functionality to TFA, and stereo-
retentive methylation.
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The chemistry in Scheme 5 encouraged progression of iodide 16 trimethyl ester 33, which underwent global saponification
towards (À)-DDSQ 5. Thus, tartrate alkylation,2b,13 followed by using anhydrous KOH23 to give 5.2
oxidation19 of the resulting alkylated tartrate 14 gave hydroxy
The present work exemplifies prevention of electrophilic attack
acetonide 29 (Scheme 6). The acidic conditions necessary to remove (protonation/Friedel–Crafts cyclisation) of an alkene by using a
acetone from 29 resulted in concomitant desilylation, but the silyl vinylic bromine substituent. Conceptually, this differs from earlier
group was reinstalled during formation of the bis-TES ether 30 from approaches, that mask a CQC bond by transient addition of
the intermediate lactol. This bis-TES ether 30 underwent condensa- elements across it, which are then subsequently eliminated.4
tion with tosylhydrazide, followed by Et3N-induced generation of During the sequence to prepare 5, the alkenyl bromide function-
diazo functionality;20 under the basic reaction conditions partial ality is also robust enough to survive a variety of other chemistry
desilylation of the secondary TES ether occurred and this was (Schemes 4 and 6), before being selectively replaced in a C–C bond-
completed by addition of aqueous acetic acid. The lability of the forming event at the penultimate step. The strategy should find
secondary TES ether under mild conditions was crucial, as it, along application in other synthetic endeavours.
with mild Dess–Martin oxidation of the resulting intermediate
We thank the Higher Committee for Education Development in
secondary alcohol, allowed access to ketone 13 in which both the Iraq, the Sultanate of Oman and the University of Oxford for
tertiary TES ether and the diazo functionality were retained.9
studentship support (to H. A. A. A., H. H. A. M., and H. O. S.,
respectively), and the European Union for a Marie Curie Fellowship
(MEIF-CT-2004-515366 to A. V.).
Conflicts of interest
There are no conflicts to declare.
Notes and references
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3 H. O. Sintim, DPhil thesis, University of Oxford, 2002.
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Scheme 6 Completion of the synthesis of (À)-6,7-dideoxysqualestatin H5 5.
¨
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