An Ireland-claisen rearrangement/lactonisation cascade as a key step in studies towards the synthesis of (-)-euonyminol

Article abstract of DOI:10.1055/s-0031-1289543

Progress towards the asymmetric total synthesis of (-)-euonyminol is described with the focus on the installation of the -oxygenation pattern on the lower rim of the molecule. An Ireland-Claisen rearrangement/lactonisation cascade has been developed and studies towards further elaboration have uncovered an intriguing tunable diastereoselective -bromination of the resulting γ-lactone. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289543

LETTER
2693
An Ireland–Claisen Rearrangement/Lactonisation Cascade as a Key Step in
Studies Towards the Synthesis of (–)-Euonyminol:
An
Ireland–Claisen
A
p
a
proach to
E
t
uonym
t
inol hew J. Webber,a Matthew Weston,b Damian M. Grainger,a,b Stacy Lloyd,a Sarah A. Warren,a Lyn Powell,c
Alexander Alanine,d Jeffrey P. Stonehouse,e Christopher S. Frampton,f Andrew J. P. White,a Alan C. Spivey*a,b
a
Department of Chemistry, South Kensington Campus, Imperial College, London SW7 2AZ, UK
Fax +44(20)75945841; E-mail: a.c.spivey@imperial.ac.uk
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
AstraZeneca Process Research and Development, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
b
c
d
F. Hoffmann-La Roche Ltd, Pharma Research & Early Development, pRED, Medicinal Chemistry, Grenzacherstraße, CH-4070 Basel,
Switzerland
e
AstraZeneca R and D, Charnwood, Department of Medicinal Chemistry, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK
Pharmorphix® Solid State Services, Sigma-Aldrich Group, 250 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK
f
Received 30 August 2011
containing the upper rim hydroxyl functionality of eu-
Abstract: Progress towards the asymmetric total synthesis of (–)-
onyminol (1).3 The focus of the later stages of the synthe-
euonyminol is described with the focus on the installation of the
sis is functionalisation of the lower rim of this molecule.
oxygenation pattern on the lower rim of the molecule. An Ireland–
Claisen rearrangement/lactonisation cascade has been developed
To this end, initial steps towards the introduction of this
and studies towards further elaboration have uncovered an intrigu- functionality have been developed on a model system 48
ing tunable diastereoselective a-bromination of the resulting g-lac-
tone.
(Scheme 1).
It was envisaged that following esterification of tertiary
alcohol 4, an Ireland–Claisen [3,3]-sigmatropic
rearrangement9 of the resulting allylic ester 5 would allow
for the installation of the C-7/C-11 C–C bond required in
the target. The anticipated product of the rearrangement
was silyl ester 6 having the desired axial stereochemistry
at C-7 (Scheme 2).
Key words: Ireland–Claisen, Celastraceae, bromination, euonymi-
nol, sesquiterpene
The natural products of the Celastraceae family of medic-
inal plants have provided inspiration for a wealth of re-
search in both the biological sciences and synthetic
organic chemistry.1 In particular, the b-dihydroagaro-
furan-based sesquiterpene derivatives have been the sub-
ject of a number of synthetic studies in recent years.2 The
vast number of structures of this type isolated to date
(>200) renders the selection of a single target molecule
challenging. We have noted previously however, that
compounds of this class having a symmetrical oxygen-
ation pattern across the upper rim invariably display nota-
ble biological activity.3 One structure in particular with
such a pattern, (–)-euonyminol (1)4 forms the basic scaf-
fold of some of the most biologically relevant natural
products isolated from the family thus far, including
triptonine B5 and hypoglaunine B,6 both of which show
promise as anti-HIV agents.7 Consequently, the heavily
oxygenated euonyminol core can be considered the arche-
typal high value synthesis target in this field and racemic
euonyminol (1) has been the subject of just one previous
synthesis by White and colleagues8 (Figure 1).
However, following optimisation of reaction conditions,
the silyl ester epoxide 6 was not isolated. Instead, lactone
7 was formed exclusively in 76% yield, presumably as the
result of in situ 5-exo-trig lactonisation, C-5/C-6 double
OH
OH OH
HO
OH
OH
O
β-dihydroagarofuran
O
OH
OH
OH
CO2Me
(–)-euonyminol (1)
O
O
O
OAc
AcO OAc
AcO OAc
O
O
AcO
O
O
OAc
O
O
O
O
OH
O
OAc
OH
This communication reports progress towards the enantio-
selective synthesis of (–)-euonyminol (1) and related de-
rivatives of the Celastraceae. We have reported
previously the enantioselective desymmetrisation of a
meso-diallylic alcohol to give an advanced intermediate 2
OAc
O
O
O
O
HO
HO
O
O
N
N
triptonine B
hypoglaunine B
SYNLETT 2011, No. 18, pp 2693–2696
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289543; Art ID: D27811ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 b-Dihydroagarofuran, (–)-euonyminol (1) and derived
bioactive natural products of the Celastraceae

2694
M. J. Webber et al.
LETTER
quaternary stereocenter via protection of the allylic alco-
hol as the benzoyl ester 8 then lactone a-bromination to
give bromolactone 9a (Scheme 3).
OH
OH OH
N
O
O
OH
HO
OH
OH
OH
O
O
HO
OH
OH
HO
O
=
7
3
5
6
4
N
N
OH
O
OH
O
OH
11
OH
OH
LDA, TMSCl, NBS
THF, –78 °C to r.t.
(S)
OH
OH
(S)
(R)
S)
(R)
(S)
OBz
2
1
>95% ee (ref. 3)
(–)-euonyminol
76%
(R)
O
(
O
11
OR
Br
N
N
N
O
O
Bz2O, Et3N, DMAP
CH2Cl2, –78 °C to r.t.
100%
7a R = H
R = Bz
9a (dr >95:5)
=
8
OH
OH
OH
OH
O
O
OH
OH
O
Scheme 3 a-Bromination of benzoate ester g-lactone 7a
OH
OH
OH
4
3
Enantiomerically pure bromolactone 9a provided crystals
suitable for single crystal X-ray structure determination
(Figure 2 and Supporting Information). Furthermore,
analysis of the anomalous dispersion Flack parameters12
for this diffraction experiment allowed unambiguous
assignment of the absolute stereochemistry for this prod-
uct, for which L-(+)-DIPT had been used as the chiral
ligand in the asymmetric epoxidation leading to epoxide 4.3
The absolute stereochemistry was confirmed to be
(2R,3S,6R,7R,8S,10S,11S)-9a (i.e. as drawn in Scheme 3)
and as required for natural (–)-euonyminol (1).
model system
model 'target' with fully
functionalized bottom rim
>95% ee (ref. 3)
Scheme 1 Chiral intermediates 2 and 4 for the synthesis of (–)-
euonyminol (1) and the model system 3, respectively
N
N
TMSCl, LHMDS
THF, –78 °C to 70 °C
5
3
7
6
4
OR
O
O
O
O
n-BuLi, (EtCO)2O
THF, r.t., 88%
4 R = H
5 R = COEt
6
TMS
76%
N
N
t-BuOK
t-BuOH, 90 °C
O
O
11
OH
OH
91%
O
O
7a (dr >95:5)
7 (dr 3:1)
Scheme 2 Ireland–Claisen [3,3]-sigmatropic rearrangement/lacto-
nisation cascade of propionate ester 5
Figure 2 Molecular structure of bromolactone 9a showing two
distinct conformational isomers in the unit cell
bond migration and epoxide ring opening. This expedi-
tious cascade sets up not only the anticipated contra-
thermodynamic axial C-7/C-11 C–C bond but also the
requisite equatorial C-6 C–O bond and axial C-3 C–O
bond stereochemistries. Two related cascade sequences
have been reported previously, albeit with the lactonisa-
tion step being initiated as a separate step.10,11 Taking
these results and our own into account, one can envisage
this desymmetrising epoxidation/rearrangement cascade
as being a powerful general method for the enantioselec-
tive preparation of such heavily substituted 5-vinyl-g-lac-
tones.
The striking aspect of the molecular structure of a-bromo-
lactone 9a is the unexpected stereochemistry at C-11.
Bromine has been introduced from what appears to be the
more hindered concave face of the molecule.13 Intrigued
by this observation and speculating as to a possible non-
steric role for the C-3 benzoate ester in influencing this se-
lectivity, three similar substrates (10–12) were synthe-
sised with ether protecting groups on the C-3 alcohol.
These alkyl and silyl ethers were brominated under the
optimised conditions with NBS (Table 1).
The choice of C-3 alcohol protecting group clearly has a
dramatic influence on the stereoselectivity of the a-bromi-
nation.14 For benzyl ether 10 (entry 1), the reaction was
seen to be unselective; both C-11 epimers formed equally.
However, the use of the more bulky TES and TBS ethers
strongly favoured a-bromination on the convex face of the
molecule; i.e. on the opposite face to that obtained when
using the benzoate ester 8 (entries 2 and 3 in Table 1,
Although the g-lactone 7 was formed as a 3:1 mixture of
C-11 epimers, treatment with t-BuOK in t-BuOH gave the
thermodynamically favoured epimer 7a exclusively (X-
ray structure, see Supporting Information).
Further synthetic work towards installing the bottom rim
functionality was performed on the single epimer model
lactone 7a. The initial objective was to establish the C-11
Synlett 2011, No. 18, 2693–2696 © Thieme Stuttgart · New York

LETTER
An Ireland–Claisen Approach to Euonyminol
2695
MoOPD,15 a variant of the MoOPH reagent initially intro-
duced by Vedejs.16 However, reaction with the lithium
enolate of g-lactone 12 did furnish the a-hydroxylactone
17 as a single C-11 epimer with the electrophile having
being introduced on the expected convex face.14 With the
hope of inducing a stereochemical switch in the outcome
of the oxidation, the benzoate ester lactone 8 was em-
ployed next as a substrate. Interestingly, no switch in fa-
cial selectivity was observed and a-hydroxylactone 17,
also resulting from electrophile introduction from the con-
vex face, was isolated as a single epimer. It is possible that
the large size of the MoOPD reagent dominates any inher-
ent preference of the system for concave face attack of an
electrophile. However, MoOPD has been previously sug-
gested to behave like a ‘small’ electrophile17 and it is plau-
sible that the more polarisable bromonium ion is
susceptible to a directing influence resulting from coordi-
nation to the Lewis basic benzoate ester carbonyl group or
even a transient bromonium ion type interaction with the
C-3/C-4 alkene.
Table 1 a-Bromination of g-Lactones 10–12 Bearing the C-3 Alco-
hol Protected as Three Different Ethers
N
N
N
TMSCl, LDA
NBS, THF
–78 °C to r.t.
+
3
O
O
O
OR
OR
OR
Br
Br
O
O
O
10 R = Bn
11 R = TES
12 R = TBS
13a R = Bn
14a R = TES
15a R = TBS
13b R = Bn
14b R = TES
15b R = TBS
Entry
R
Starting material Yield (%)
Ratio a/ba
ca. 50:50b
18:82
1
2
3
Bn
10
11
12
ca. 66a
90
TES
TBS
68
<5:95
a Determined by 1H NMR spectroscopy (see ref. 16).
b Products not isolated.
cf. Scheme 3). The TBS-protected bromolactone 15b was
formed as a single diastereoisomer and its stereochemistry
was confirmed by an X-ray structure determination (see
Supporting Information).
Access to an alcohol derivative with presumed inverted
stereochemistry at C-11 was eventually found to be possi-
ble by subjecting benzoate ester lactone 8 to a Mitsunobu-
type reaction using p-methoxyphenol (PMP-OH).18 This
gave a product that was tentatively assigned as the ring-
opened, inverted product 18, based on mechanistic analy-
sis, in an unoptimised 35% yield.19
The dramatic dependence of the stereoselectivity of lac-
tone a-bromination on the nature of the remote C-3 alco-
hol protecting group clearly offers valuable flexibility in
synthetic route planning towards the target. However, we
were keen to see if oxygen-based electrophiles would be-
have similarly, as control of this C-11 stereocentre bear-
ing an oxygen-based substituent would be particularly
powerful (Scheme 4).
In conclusion, we have described an Ireland–Claisen/
lactonisation cascade and subsequent diastereoselective
C-11 functionalisation protocols that constitute expedi-
tious approaches to much of the functionality present on
the bottom rim of the natural product core (–)-euonyminol
(1). The ability to tune the stereochemistry at C-11 as a
function of the nature of the remote protecting group on
the C-3 alcohol is likely to prove instructive to the design
of approaches to many Celastraceae sesquiterpenoids and
related highly oxygenated trans-decalin-based natural
products. Investigations are ongoing into the utility of the
densely functionalised g-lactones described herein for the
synthesis of (–)-euonyminol (1) and related natural prod-
ucts. Results relating to this will be reported in due course.
N
N
LDA, MoOPD
–78 °C to r.t.
3
O
O
OR
OR
HO
O
O
8 R = Bz
12 R = TBS
16 R = Bz, 59%
17 R = TBS, 63%
Ph3P, DIAD, PMP-OH
toluene–THF, 100 °C, 35%
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures, characterisation and NMR spectra for all
compounds.
N
OH
OPMP
11
OBz
Acknowledgment
CO2PMP
This work was supported by the EPSRC, Pfizer, AstraZeneca and
F. Hoffmann-La Roche.
18
Scheme 4 Diastereoselective a-hydroxylation of g-lactones 8 and
12 using MoOPD
References and Notes
The silylketene acetal of TBS ether lactone 12 was found
to be unreactive to the peroxomolybdenum species
(1) For reviews, see (a) Spivey, A. C.; Weston, M.; Woodhead,
S. Chem. Soc. Rev. 2002, 31, 43. (b) Brinker, A. M.; Ma, J.;
Lipsky, P. E.; Raskin, I. Phytochemistry 2007, 68, 732.
Synlett 2011, No. 18, 2693–2696 © Thieme Stuttgart · New York

2696
M. J. Webber et al.
LETTER
(2) For selected recent examples, see: (a) Zhou, G.; Gao, X.; Li,
W. Z.; Li, Y. Tetrahedron Lett. 2001, 42, 3101. (b) Li, W.
Z.; Zhou, G.; Gao, X.; Li, Y. Tetrahedron Lett. 2001, 42,
4649. (c) Mehta, G.; Kumaran, R. S. Tetrahedron Lett. 2003,
44, 7055. (d) Lee, C. A.; Floreancig, P. E. Tetrahedron Lett.
2004, 45, 7193. (e) Siwicka, A.; Cuperly, D.; Tedeschi, L.;
Le Vézouet, R.; White, A. J. P.; Barrett, A. G. M.
Tetrahedron 2007, 63, 5903.
E.; Muller, J.-C.; Ourisson, G. J. Org. Chem. 1974, 39, 186.
(d) Alberto Marco, J.; Carda, M. Tetrahedron 1987, 43,
2523. (e) Shimoma, F.; Kusaka, H.; Azami, H.; Wada, K.;
Suzuki, T.; Hagiwara, H.; Ando, M. J. Org. Chem. 1998, 63,
3758. (f) Huguchi, Y.; Shimoma, F.; Ando, M. J. Nat. Prod.
2003, 66, 810. (g) Crow, J. R.; Thomson, R. J.; Mander, L.
N. Org. Biomol. Chem. 2006, 4, 2532. (h) Ando, M.; Wada,
T.; Isogai, K. J. Org. Chem. 1991, 56, 6235. (i) The
example most similar to ours involves the a-bromination of
an a-(–)-santonin derivative (compound 19, see Supporting
Information) for which the stereochemistry of the product
was assigned by NOE (see ref. 13h). We repeated this
reaction under both their conditions (LiCPh3, BrCH2CH2Br,
37% yield) and ours (TMSCl, LDA, NBS, 80% yield),
obtained the same product 20 they report for both reactions,
and confirmed the reported stereochemistry by a single
crystal X-ray structure determination (see Supporting
Information). Oxidation of lactone 19 also proceeded on the
convex face to give a-hydroxylactone 21 (LDA, MoOPD,
62% yield; cf. Scheme 4; see Supporting Information).
(14) Stereochemical assignments were made based upon NMR
spectroscopic comparisons with bromolactones 9a and
15b for which X-ray structural data were obtained (see
Supporting Information).
(3) Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I.
Angew. Chem. Int. Ed. 2001, 40, 769.
(4) Beroza, M. J. Am. Chem. Soc. 1953, 75, 44.
(5) Duan, H.; Takaishi, Y.; Imakura, Y.; Jia, Y.; Li, D.;
Cosentino, L. M.; Lee, K.-H. J. Nat. Prod. 2000, 63, 357.
(6) Duan, H.; Takaishi, Y.; Bando, M.; Kido, M.; Imakura, Y.;
Lee, K. H. Tetrahedron Lett. 1999, 40, 2969.
(7) Horiuch, M.; Murakami, C.; Fukamiya, N.; Yu, D.; Chen,
T.-H.; Bastow, K. F.; Zhang, D.-C.; Takaishi, Y.; Imakura,
Y.; Lee, K. H. J. Nat. Prod. 2006, 69, 1271.
(8) White, J. D.; Shin, H.; Kim, T.-S.; Cutshall, N. S. J. Am.
Chem. Soc. 1997, 119, 2404.
(9) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94,
5897.
(10) Hutchison, J. M.; Hong, S.-P.; McIntosh, M. C. J. Org.
Chem. 2004, 69, 4185.
(11) Oh, K.; Parsons, P. J.; Cheshire, D. Synlett 2004, 2771.
(12) Thompson, A. L.; Watkin, D. J. Tetrahedron: Asymmetry
2009, 20, 712.
(13) This selectivity is in contrast to other examples of cis-
fused g-lactone a-brominations that we are aware of in the
literature, all of which are reported to give products resulting
from approach of the electrophile from the least hindered
convex face, see: (a) Greene, A. E.; Edgar, M. T. J. Org.
Chem. 1989, 54, 1468. (b) Greene, A. E.; Muller, J.-C.;
Ourisson, G. Tetrahedron Lett. 1972, 2489. (c) Greene, A.
(15) Anderson, J. C.; Smith, S. C. Synlett 1990, 107.
(16) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944.
(17) Osamu, H.; Takizawa, J.-I.; Yamatake, T.; Makino, K.;
Hamada, Y. Tetrahedron Lett. 1999, 40, 7787.
(18) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Tetrahedron
Lett. 2003, 44, 3609.
(19) Product 18 was not fully characterised due to lack of
material and this line of investigation has not been pursued
further to allow verification of the stereochemistry at C-11.
Synlett 2011, No. 18, 2693–2696 © Thieme Stuttgart · New York

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