Total synthesis of (+)-bretonin B: Access to the (E,Z,E)-triene core by a late-stage Peterson elimination of a convergently assembled silyl ether

Article abstract of DOI:10.1039/c2cc36604e

The title compound was synthesised in a concise route (nine linear steps, 31% overall yield) employing an α-silyl epoxide ring opening, a Julia-Kocienski olefination and a late-stage Peterson elimination as key steps.

Full text of DOI:10.1039/c2cc36604e

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COMMUNICATION
Total synthesis of (+)-bretonin B: access to the (E,Z,E)-triene core by a
late-stage Peterson elimination of a convergently assembled silyl etherw
Thomas Neubauer,z Claire Kammerer-Pentierz and Thorsten Bach*
Received 11th September 2012, Accepted 15th October 2012
DOI: 10.1039/c2cc36604e
The title compound was synthesised in a concise route (nine linear
steps, 31% overall yield) employing an a-silyl epoxide ring opening,
a Julia–Kocienski olefination and a late-stage Peterson elimination
as key steps.
For the latter reaction a Julia–Kocienski olefination13 was
considered to be best suited and an enantioselective approach
towards sulfone 4 was therefore required. It was anticipated
that the Peterson elimination would be best induced under
acidic conditions and the relative configuration at the stereo-
genic centers had therefore to be (6R,7R) or (6S,7S) in order to
form a Z-double bond via a stereospecific anti-elimination.11
Since the absolute configuration at these stereogenic centers is
irrelevant, the epoxide precursor had not to be used in
enantiomerically pure form but could be used as racemate
(rac-3). In this communication we disclose the successful
execution of the delineated strategy, which culminated in the
first synthesis of (+)-bretonin B and the proof of its structure.
The synthesis of sulfone 4 commenced with isopropylidene
glycerol, which is commercially available in either enantio-
meric form and which provides the required stereogenic
center. Regioselective functionalisation of this compound is
straightforward14 and it was initially attempted to introduce
the O-protected para-hydroxybenzoyl group by acylation.
It turned out, however, that this reaction is more difficult than
that expected because the reactivity of the secondary alcohol was
low after the two primary positions were appropriately protected
or alkylated. Reaction with O-protected para-hydroxybenzoyl
chlorides or with the respective free acids in the presence of a
coupling reagent did not produce any of the desired products.
Bretonin B (1) is a minor component in extracts isolated
from an unidentified sponge of the Demospongiae class, which
occurs in North Brittany sea water.1 Chemically, the compound
is a glycerol derivative which is esterified at the secondary
alcohol by a para-hydroxybenzoyl group and etherified at one
primary alcohol position by a (4E,6Z,8E)-trienic C12 carbon
chain. (+)-Bretonin B has been characterised only by 1H-NMR
spectroscopy. However, the diacetate of its enantiomer has been
prepared in a non-selective fashion1 and was compared to the
diacetate of the natural product. Furthermore, the structure
assignment was based on analogy to its more abundant (E,E,E)-
isomer bretonin A.2
Our interest in bretonin B was initiated by the presence of
the relatively rarely occurring (E,Z,E)-triene moiety. A few natural
products of this compound class have been prepared,3–8 all of
which, however, show further conjugation, either to a carbonyl
group or to other double bonds. Our preliminary synthetic
studies showed the high propensity of the central double bond
towards Z - E isomerisation and let us consider a synthetic
approach, in which this sensitive group would be liberated at
the very end of the synthesis. Inspired by work of Nakai et al.9
and by Pohnert and Boland,10 who had used a Peterson
olefination11,12 for the synthesis of non-functionalised trienes
and tetraenes, we envisioned a late-stage elimination from
a suitably protected b-silyl-substituted silyl ether 2/20 as
an appropriate way to generate the central double bond
(Scheme 1). A high convergence in the construction of this
key precursor was expected to be possible if epoxide 3 could be
ring opened selectively at the silyl-substituted position and if an
olefination reaction would subsequently allow for the stereo-
selective formation of the double bond between C4 and C5.
Lehrstuhl fur Organische Chemie I, Technische Universitat Munchen,
¨
¨
¨
85747 Garching, Germany. E-mail: thorsten.bach@ch.tum.de;
Fax: +49 89 28913315; Tel: +49 89 28913330
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, and NMR spectra for all intermediates
and final products. See DOI: 10.1039/c2cc36604e
z Both authors contributed equally to the project.
Scheme 1 Retrosynthetic disconnection of (+)-bretonin B (1) leading
to epoxide rac-3 and olefination reagent 4 as key building blocks.
c
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Chem. Commun., 2012, 48, 11629–11631 11629

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Scheme 3 Synthetic sequence of (+)-bretonin B (1) and its diacetate
(17) from epoxide rac-3 including a regioselective epoxide ring opening
and a Julia–Kocienski olefination.
Scheme 2 Preparation of 1-phenyl-1H-tetrazol-5-yl-sulfone 4 from
glycerol derivative 5.
Under more forceful conditions, protecting group migration
from the primary to the secondary alcohol was observed in
some instances with the acylation occurring at the primary
alcohol site. In order to circumvent this issue we resorted to
the Mitsunobu reaction15 for the introduction of the benzoate.
Consequently, the (S)-configured isopropylidene glycerol 5
was alkylated with the para-methoxybenzyl (PMB) protected
mesylate derived from 1,4-butanediol16 (Scheme 2). Removal
of the diol protecting group from the resulting product 6 was
achieved under acidic conditions delivering diol 7. After
monosilyl protection with tert-butyldiphenylsilyl chloride
(TBDPSCl), benzoate 9 could be smoothly formed from
alcohol 8 using TBDPS-protected para-hydroxybenzoic acid
as a nucleophile in the Mitsunobu reaction. The PMB group at
the distal alcohol group was removed under oxidative condi-
tions with 2,3-dichloro-5,6-dicyanoquinone (DDQ).17 The
1-phenyl-1H-tetrazol-5-yl-sulfone was introduced via the
respective sulfide in a Mitsunobu reaction18 of alcohol 10.
Oxidation of sulfide 11 to the olefinating reagent 4 was
achieved using meta-chloroperbenzoic acid (MCPBA).19 The
enantiomeric purity (>95% ee) of this compound was proven
after TBDPS removal by chiral HPLC (see ESIw for further
information).
Attempts to open epoxide rac-12 with alkenylstannanes23 or
alkenyllithium compounds24 were not successful. Only tetra-
vinylstannane delivered stereospecifically the parent product
after transmetalation with Bu2CuCNLi2 in the presence of
BF3ꢀOEt2. Further experiments to convert this terminal alkene
into a 1,2-disubstituted alkene by cross metathesis were not
undertaken, however. Silylation with tert-butyldimethylsilyl
triflate (TBSOTf) at the secondary alcohol position of rac-13
delivered protected diol rac-14, which was chemoselectively
converted into aldehyde rac-1625 via the deprotected primary
alcohol rac-15. Aldehyde rac-16 was stable to chromato-
graphic purification and was taken as the limiting reagent in
the Julia–Kocienski olefination. Optimised reaction conditions
include the preformation of the deprotonated sulfone at
ꢁ78 1C and the subsequent addition of an aldehyde solution
in THF to an excess (2 equiv.) of the olefination reagent.
Under these conditions clean (4E)-configured products 2 and
20 were obtained. Although 1H- and 13C-NMR spectra did not
allow a distinction between 2 and 20, it is clear that the products
must be a ca. 1/1-mixture of diastereoisomers because aldehyde
rac-16 was used in racemic form.
The final elimination reaction was initially performed with
an excess of ZnBr2 (5 equiv.) in CH2Cl2 generating the doubly
TBDPS-protected product in 89% yield (three steps from
rac-15). However, after complete deprotection to 1, minor
impurities (o10%) of the (E,E,E)-product, bretonin A, were
detectable by 1H-NMR. It was subsequently found that the
elimination–deprotection can be performed more cleanly with
HF–pyridine (HFꢀpy) and pyridine in THF. Under these
conditions, no other isomer was observed and (+)-bretonin
B (1) was the only product. 1H-NMR-spectral data were
identical to the natural product with the coupling constant
between protons H6 and H7 (3J = 10.9 Hz) supporting the
The left-hand fragment of bretonin B was assembled starting
from propargyl alcohol, which was converted in two steps into
the known epoxy-alcohol rac-3.20 The respective PMB ether
rac-12 was best prepared by alkylation with PMB trichloro-
acetimidate (Scheme 3). A regioselective ring opening of epoxide
rac-12 was achieved by treatment with (E)-configured 1-pentenyl-
1-magnesium bromide and copper(I) iodide (10 mol%).21,22 The
magnesium reagent was prepared by halogen–lithium exchange
from the respective bromide and subsequent transmetalation.
Product rac-13 was obtained as a single regio- and diastereoisomer.
c
11630 Chem. Commun., 2012, 48, 11629–11631
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(Z)-configuration at the central double bond. The compound
was dextrorotatory but the specific rotation was relatively
small. The compound was therefore converted into the diacetate,
which was – if derived from the natural product – levorotatory.1
Acetylation was facile and delivered bretonin B diacetate (17)
in 69% yield. Indeed, this compound turned out to show a
significant levorotatory specific rotation and matched the
reported spectral data of the diacetate.1 The conversion of
aldehyde rac-16 to (+)-bretonin B was also feasible without
isolation of the intermediary products by immediate treatment
of the crude product mixture of the olefination reaction with
HFꢀpy and py in THF. Although the Z - E isomerisation of
bretonin B to bretonin A was observed upon standing at room
temperature, a quantitative double bond isomerisation was
possible neither under photochemical conditions nor under
thermal conditions.
In summary, the first total synthesis26 of (+)-bretonin B has
been achieved starting from propargyl alcohol (commercially
available precursor to epoxide rac-3) in a longest linear
sequence of nine steps and a total yield of 31%. The synthesis
demonstrates that the late-stage Peterson elimination is a
useful tool for the stereoselective generation of (Z)-configured
double bonds in conjugated oligo- and polyenes.
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c
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Chem. Commun., 2012, 48, 11629–11631 11631