Bicyclic oxygen heterocycles from γ,δ-unsaturated alcohols: Synthetic targets inspired by blepharocalyxin D

Article abstract of DOI:10.1002/anie.201108315

trans-2,8-Dioxabicyclodecanes were prepared in high yield with the creation of up to three stereocenters in a single pot by the acid-mediated reaction of γ,δ-unsaturated alcohols with aldehydes (see scheme, Bn=benzyl). This versatile reaction enables the stereoselective introduction of substituents at the C3, C4, C7, and C9 positions of the bicyclic framework. Copyright

Full text of DOI:10.1002/anie.201108315

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Chemie
DOI: 10.1002/anie.201108315
Synthetic Methods
Bicyclic Oxygen Heterocycles from g,d-Unsaturated Alcohols:
Synthetic Targets Inspired by Blepharocalyxin D**
Adam J. Bunt, Christopher D. Bailey, Benjamin D. Cons, Sophie J. Edwards, Jon D. Elsworth,
Tshepo Pheko, and Christine L. Willis*
The development of strategies for the synthesis of fused
heterocycles is an important goal as many such compounds
display valuable properties. In this study we focus on the
development of an efficient approach for the assembly of 2,8-
dioxabicyclo[4.4.0]decanes. These scaffolds are present, for
example, in the antiproliferative diarylheptanoid blepharo-
calyxin D (Scheme 1),[1] a rearrangement product of the
Scheme 2. Proposed cyclization of g,d-unsaturated alcohol 1.
P=protecting group
into a single molecule, a cascade process would lead to the
required bicyclic products 4 with concomitant generation of
three new stereocenters.[5] This is an attractive strategy as
competing oxonia-Cope rearrangements, which may occur in
Prins cyclizations with homoallylic alcohols, are not an issue.[6]
Scheme 1. Structure of blepharocalyxin D.
To be successful, it was anticipated that stabilization of the
proposed carbocation 3 would be required. Mohr[7] as well as
antibiotic pseudomonic acid A,[2] and
a
series of
Kjellgren and Szabo[8] have shown that allylsilanes provide
carbocation stabilization in the synthesis of 3-vinyltetra-
hydropyrans.[9]
pyranobenzopyrans[3] of interest as the core structures of
liquid crystals.
The acid-promoted Prins cyclization of an oxocarbenium
ion that is generated in situ, for example, from the reaction of
a homoallylic alcohol with an aldehyde or from a homoallylic
acetal or a-acetoxy ether, is a powerful synthetic method for
the stereoselective synthesis of functionalized tetrahydropyr-
ans.[4] Indeed, in their total synthesis of blepharocalyxin D,
Lee and co-workers used two Prins cyclizations to generate
the bicyclic skeleton.[1b,c] We proposed that this framework
could be efficiently assembled in a single step from g,d-
unsaturated alcohol 1, in which the alkene is placed one
position further away from the hydroxyl group than in
substrates that are commonly used in Prins cyclizations
(Scheme 2). By tethering the electrophile and nucleophile
We used a phenyl group to provide the necessary
stabilization. The required substrate 8 was readily prepared
in 76% overall yield from commercially available a-vinyl-
benzyl alcohol (5) by using a Johnson–Claisen rearrangement
to establish the E configuration of the alkene. Reduction of
methyl ester 6 with diisobutylaluminium hydride (DIBALH)
and addition of MeMgBr to the resultant aldehyde 7 gave 8
(Scheme 3).
The initial electrophile for the key cyclization was
protected 3-hydroxypropanal (Scheme 4). Various acid-medi-
ated conditions for the coupling of alcohol 8 with 3-
benzyloxypropanal (9) were investigated and trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in CH2Cl2 was selected
as the most promising for further study. At À108C trans-2,8-
dioxabicyclo[4.4.0]decane (10) was the major product (77%
yield) and was readily separated from the minor cis-isomer 11
(8% yield) by chromatography. At À508C, 10 was isolated in
[*] A. J. Bunt, Dr. C. D. Bailey, B. D. Cons, S. J. Edwards,
Dr. J. D. Elsworth, T. Pheko, Prof. C. L. Willis
School of Chemistry, University of Bristol
Bristol, BS8 1TS (UK)
E-mail: chris.willis@bris.ac.uk
[**] We are grateful to the following for provision of PhD studentships:
EPSRC, IUST, the Government of Botswana and the Bristol
Chemical Synthesis Doctoral Training Centre funded by the EPSRC
(EP/G 36764/1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108315.
Scheme 3. Preparation of unsaturated alcohol 8. THF=tetrahydofuran.
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Scheme 6. Conversion of bromide 16 to alcohol 22.
stituent, was subjected to the standard cyclization reaction,
decomposition occurred (Scheme 4). The styrene portion of
17 is highly activated by the electron-rich aromatic ring and
such styrenes are known to be susceptible to polymeri-
zation.[13] Indeed, treatment of 17 alone with TMSOTf in
CH2Cl2 led to rapid decomposition. In contrast, when the key
cyclization was conducted on the g,d-unsaturated alcohol 18,
which contains the electron-deficient aromatic ring with a p-
phenylsulfonyl group, dioxabicycle 19 was isolated in 83%
yield as a single diastereomer. Hydrolysis of the sulfonyl ester
with potassium carbonate in methanol at reflux gave alcohol
22 in 79% yield. Many biologically important compounds
contain fluorine, and pleasingly the electron-deficient aro-
matic system 20 with the p-trifluoromethyl group also cyclized
cleanly to give the trans-2,8-dioxabicycle 21 in a 73% yield of
isolated product.
Scheme 4. Reaction of alkenols with 3-benzyloxypropanal. Bn=benzyl
a similar yield with only a trace of 11. The ratio of products
was readily determined from the chemical shift of the H7 in
1
the H NMR spectrum of the crude mixture (the trans-fused
product 10, d = 3.95 ppm (d, J = 10 Hz); the cis-fused deriv-
ative 11 d = 4.71 ppm (d, J = 11 Hz)).[10]
The conformational flexibility of the alkyl side-chain
allows the alkene of 8 to achieve the required orbital overlap
with the oxocarbenium ion in two orientations (Scheme 5).
However the preference for the trans-product 10 can be
rationalized by the Zimmerman–Traxler transition-state
models.[11]
With an efficient strategy for the assembly of 2,8-dioxa-
bicycles in hand, the requirement for stabilization of the
C7 carbocation was confirmed by using hydroxydiene 23,
which was prepared by allylation of ester 6 and subsequent
reduction to the primary alcohol with LiAlH4. Reaction of 23
with aldehyde 9 under the standard conditions gave no trace
of product 26 from cyclization through the terminal double
bond (Scheme 7). The sole product that was isolated from this
reaction was the 4-propenyl derivative 25, in accordance with
the reaction proceeding via the stabilized carbocation 24. This
Scheme 5. Formation of the two diastereomers 10 and 11.
Having established that this cascade process was success-
ful in generating both rings in 10 with the concomitant
creation of three new stereogenic centers, we aimed to extend
the synthetic utility of the reaction by using various function-
alized aromatic groups. The acid-mediated reaction of (E)-6-
(4-chlorophenyl)hex-5-en-2-ol (12) with 3-benzyloxypropanal
gave the trans-fused product 13 in 75% isolated yield, and the
reaction with the analogous bromide 15 gave 16 (Scheme 4).
These halogenated products open the way for the synthesis
a wide variety of derivatives. As many natural products,
including blepharocalyxin D, contain para-hydroxylated
phenyl groups, we focused on the conversion of bromide 16
to the analogous alcohol. Treatment of 16 with tBuLi and
B(OiPr)3 then subsequently with H2O2 under conditions
modified from those reported by Lemieux, Snieckus, et al.,[12]
gave phenol 22 in 76% yield (Scheme 6).
An alternative approach to 2,8-dioxabicycles with
p-oxygenated phenyl groups at the C7 position is to start
with the corresponding g,d-unsaturated alcohol. However,
when alcohol 17, which contains a p-methoxyphenyl sub-
Scheme 7. Cyclization of dienol 23.
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enabled the stereoselective introduction
of an allyl group at the C4 position with
the potential for further manipulation
to a diverse range of functional groups.
Blepharocalyxin D is assembled on
a
trans-2,8-dioxabicyclo[4.4.0]decane
scaffold that has equatorial side-chains
at the C3, C5, C7, and C9 positions
(Scheme 1).[1] Having established that
this bicyclic framework with equatorial
groups at the C3 and C7 positions may
be assembled efficiently from g,d-unsa-
turated alcohols, we turned our atten-
tion to the incorporation of a further
substituent at the C9 position to give Scheme 9. Preparation of trisubstituted 2,8-dioxabicyclodecanes.
analogues of blepharocalyxin D. The
acid-mediated reaction of racemic unsa-
turated alcohol 8 with (R)-3-benzyloxybutanal (27) gave two
bicyclic products 28 and 29 from the reaction of the
enantiopure aldehyde with each enantiomer of alcohol 8
(Scheme 8). The reactions are likely to proceed via tetrahy-
dropyrans I and II, which each have three equatorial sub-
stituents that are generated from the cyclization of the
initially formed oxocarbenium ions. In the case of (3R)-
diastereomer I, the second ring closure leads to an equatorial
group at the C9 position to give 28, whereas the (3S)-isomer II
gave the bicyclic product 29, which has an axial methyl group
(H9 in 28, d = 3.75 (dqd, J = 11, 6, and 2 Hz); H9 in 29 d = 4.5
(apparent quin, J = 7 Hz)). The two products were readily
separated by chromatography and the structures were con-
firmed by extensive NMR spectroscopic studies.
All of the studies described above involve racemic (E)-2-
hydroxy-6-arylhex-5-en-2-ols as substrates, which lead to 2,8-
Scheme 10. Enantioselective synthesis of 40. DMSO=dimethylsulfox-
ide; TBS=tert-butyldimethylsilyl.
dioxabicycles with an equatorial methyl group at the C3 posi-
tion. In contrast, blepharocalyxin D has a 2-arylethyl group at
the C3 position. Hence, for the synthesis of further analogues
of blepharocalyxin D, racemic alcohol 30, which has a p-
methoxyarylethyl group (Scheme 9), was prepared by the
addition of the requisite Grignard reagent to aldehyde 7. The
reaction of 30 with (S)-3-benzyloxyaldehyde 31 under the
standard conditions gave (À)-2,8-dioxabicycle 32 in 35%
yield (from cyclization with the R enantiomer of 30) and
diastereomer 33 in 35% yield (from cyclization with the
S enantiomer of 30).
34 was prepared by a Keck allylation of dihydrocinnamalde-
hyde,[15] and was then protected as silyl ether 35. After
hydroboration of the alkene with 9-borabicyclo[3.3.1]nonane
(9-BBN)/H2O2, the resultant primary alcohol 36 was oxidized
under Swern conditions to give aldehyde 37 in 68% yield over
the 2 steps. Treatment of 37 with diethyl benzylphosphonate
in the presence of nBuLi gave 38 with the required
E geometry at the double bond. Subsequent deprotection of
the silyl ether of 38 gave alcohol 39.[16] Treatment of 39 with 3-
benzyoxylpropanal in the presence of TMSOTf gave (À)-2,8-
dioxa[4.4.0]bicyclodecane (40) in 86% yield.
To extend the utility of this method, a route for the
enantioselective synthesis of (+)-g,d-unsaturated alcohol 39
was developed (Scheme 10). The known[14] (S)-allylic alcohol
In conclusion, an efficient approach
for the rapid stereocontrolled assembly of
2,8-dioxa[4.4.0]bicyclodecanes from g,d-
unsaturated alcohols has been reported.
The substrates for the key cyclizations are
readily prepared in high yield by using
either a Johnson–Claisen rearrangement
or Horner–Wadsworth–Emmons reaction
to establish the E configuration at the
double bond. The cascade process gener-
ates the two heterocyclic rings and creates
Scheme 8. Preparation of trisubstituted 2,8-dioxabicyclodecanes.
up to three new stereogenic centers in
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ents to be introduced at the C3, C4, C7, and C9 positions of
the bicyclic framework with excellent stereocontrol.
Received: November 25, 2011
Published online: March 5, 2012
Keywords: carbocations · cyclization · heterocycles ·
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