Total synthesis of (-)-blepharocalyxin D and analogues

Article abstract of DOI:10.1021/ol400736w

An efficient strategy for the total synthesis of (-)-blepharocalyxin D and an analogue is described. The key step involves an acid-mediated cascade process in which reaction of methyl 3,3-dimethoxypropanoate with γ,δ- unsaturated alcohols possessing diastereotopic styrenyl groups gives trans-fused bicyclic lactones with the creation of two rings and four stereocenters in one pot.

Full text of DOI:10.1021/ol400736w

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2046–2049
Total Synthesis of (ꢀ)-Blepharocalyxin D
and Analogues
Benjamin D. Cons, Adam J. Bunt, Christopher D. Bailey, and Christine L. Willis*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
chris.willis@bristol.ac.uk
Received March 20, 2013
ABSTRACT
An efficient strategy for the total synthesis of (ꢀ)-blepharocalyxin D and an analogue is described. The key step involves an acid-mediated
cascade process in which reaction of methyl 3,3-dimethoxypropanoate with γ,δ-unsaturated alcohols possessing diastereotopic styrenyl groups
gives trans-fused bicyclic lactones with the creation of two rings and four stereocenters in one pot.
Kadota and co-workers have reported the isolation of a
family of related polyphenolic compounds from extracts of
the seeds of Alpinia blepharocalyx.1 Their structures were
determined originally using spectroscopic methods. More
recent synthetic studies by Rychnovsky and co-workers
have led to structural reassignment of some of these
compounds.2 We were drawn to one particular diaryl-
heptanoid blepharocalyxin D (1), which was isolated in
very small quantities from seeds of A. blepharocalyx.
Figure 1. (ꢀ)-Blepharocalyxin D.
Blepharocalyxin D exhibits potent antiproliferative activ-
ity against murine colon 26-L5 carcinoma and human HT-
the oxane rings.4 However, introduction of the C-5 equa-
torial side chain proved challenging. An interesting Prins-
pinacol reaction gave predominantly an unwanted axial
aldehyde atC-5 which was epimerizedprior toa Julia chain
extension to the required styrenyl group. Our goal was to
develop a new synthetic strategy to blepharocalyxin D in
which both rings of the trans-fused bicyclic framework
would be generated in one-pot with all side chains equa-
torial. The approach was to be versatile to provide ana-
logues of potential biological interest.
1080 fibrosarcoma cells.3 It has an unusual structure assem-
bled upon a trans-2,8-dioxabicyclo[4.4.0]decane adorned
by four side chains each in an equatorial position (Figure 1).
We now describe a flexible strategy for the synthesis of
trans-2,8-dioxabicyclo[4.4.0]decanones in which two
rings and four stereocenters are created in a one-pot
cascade process and culminates in the total synthesis
of blepharocalyxin D and an analogue of the natural
product.
Lee and co-workers have reported the only previous
total synthesis of blepharocalyxin D in which they em-
ployed two separate Prins cyclizations to construct each of
Our retrosynthetic analysis of 1 is shown in Scheme 1.
The C-9 side chain would be introduced via a Grignard
addition to lactone 2 followed by reduction of the resultant
lactol. An advantage of using the lactone is that various
(1) Tezuka, Y.; Gewali, M. B.; Ali, M. S.; Banskota, A. H.; Kadota,
S. J. Nat. Prod. 2001, 64, 208.
(2) (a) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006,
71, 3176. (b) Tian, X.; Rychnovsky, S. D. Org. Lett. 2007, 9, 4955.
(3) (a) Ali, M. S.; Tezuka, Y.; Banskota, A. H.; Kadota, S. J. Nat.
Prod. 2001, 64, 491. (b) Tezuka, Y.; Ali, M. S.; Banskota, A. H.; Kadota,
S. Tetrahedron Lett. 2000, 41, 5903.
(4) (a) Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah,
M. S.; Lee, E. Org. Lett. 2007, 9, 141. (b) Ko, H. M.; Lee, D. G.; Kim,
M. A.; Kim, H. J.; Park, J.; Lah, M. S.; Lee, E. Tetrahedron 2007, 63,
5797.
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10.1021/ol400736w
Published on Web 04/05/2013
2013 American Chemical Society

Grignard reagents could be used to prepare analogues of
the natural product.
Scheme 2. Synthesis of Bicyclic Lactone 7
Scheme 1. Retrosynthesis of Blepharocalyxin D
The second approach to 7 involved the direct reaction of
γ,δ-unsaturated alcohol 5 with commercially available
methyl 3,3-dimethoxypropanoate 8 giving, after optimiza-
tion, lactone 7 in 67% yield. These studies established an
approach for the direct conversion of γ,δ-unsaturated
alcohols to trans fused bicyclic lactones with equatorial
groups at both C-3 and C-7.
For the proposed synthesis of blepharocalyxin D
(Scheme 2), a γ,δ-unsaturated dienol 3 was required as
the substrate for the key cyclization to generate the bicyclic
framework with an equatorial styrenyl group at C-5.
Following the studies outlined in Scheme 2, we selected
dienol 16 with phenyl groups as the initial target.
Dienol 16 was prepared from the known9 (S)-homoallylic
alcohol 9 as shown in Scheme 3. Following protection of the
secondary alcohol as TBS ether 10, the double bond was
oxidatively cleaved with OsO4/NaIO4 to give aldehyde 11. A
HornerꢀWadsworthꢀEmmons chain extension of 11 using
phosphonate 12 and K2CO3 gave (E)-R,β-unsaturated
ketone 13 with excellent stereocontrol. The final carbonꢀ
carbon bond was formed via a rhodium-mediated 1,4-
addition of styrenyl boronic acid to enone 13 under the
conditions reported by Hiyashi10 to give ketone 14 in 94%
yield as a 1:1 mixture of diastereomers. The lack of stereo-
control was not a problem as this newly created stereocenter
would be destroyed later in the synthesis as the target, dienol
16, has two identical (E)-phenylethenyl side chains.
We envisaged that the second double bond of 15 could
be readily generated from ketone 14 via reduction to an
alcohol followed byelimination. While reduction ofketone
14 with NaBH4 proceeded smoothly to give the expected
benzylic alcohol as a mixture of isomers, the elimination
step proved problematic via either the corresponding
acetate or mesylate. However, the rarely used xanthate
formation/Chugaev elimination in this instance worked
well. Thus, conversion of the alcohol to a xanthate using
NaH/CS2/MeI followed by refluxing with NaHCO3 in
The trans-2,8-dioxabicyclo[4.4.0]decanone (2) would be
assembled from γ,δ-unsaturated alcohol 3 in which the
double bond is placed one position further away from the
hydroxyl group than in homoallylic alcohols and deriva-
tives commonly used in Prins cyclizations.5 The success of
this strategy relied upon reaction of 3 (to be prepared from
(S)-homoallylic alcohol 4) with an electrophile to generate
an intermediate oxycarbenium I with diastereotopic styr-
enyl groups. Cyclization was predicted to proceed to give
stabilized carbocation II with the first of the oxane rings
with an equatorial substituent at C-5. Intramolecular
trapping of the resultant carbocation with an ester would
generate the second heterocycle giving lactone 2 with an
equatorial substituent at C-7.6
To establish conditions for the proposed cyclization,
first the known7 γ,δ-unsaturated alcohol 5 was converted
to enol ether 6 using methyl propiolate and catalytic
quinuclidine. Treatment of 6 with TMSOTf gave bicyclic
lactone 7 in 69% yield (Scheme 2).8 The structure was
elucidated by NMR spectroscopy and confirmed by X-ray
crystallography.
(5) For reviews on Prins cyclizations, see: (a) Olier, C.; Kaafarani,
M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron 2010, 66, 413. (b) Crane,
E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316.
(6) For examples of the use of intramolecular trapping using tethered
ꢀ
oxygen nucleophiles, see: (a) Frater, G.; Muller, U.; Kraft, P. Helv.
Chim. Acta 2004, 87, 2750. (b) Elsworth, J. D.; Willis, C. L. Chem.
Commun. 2008, 13, 1587. (c) Yadav, J. S.; Chakravarthy, P. P.; Borkar,
P.; Reddy, B. V. S.; Sarma, A. V. S. Tetrahedron Lett. 2009, 50, 5998.
(d) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Reddy, P. P.; Kunwar,
(9) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1998, 75, 12.
(10) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J. Am. Chem. Soc. 1998, 120, 5579.
(11) Chugaev, L. Chem. Ber. 1899, 32, 3332. For selected examples of
the Chugaev elimination in synthesis, see: (a) Meulemans, T. M.; Stork,
G. A.; Macaev, F. Z.; Jansen, B. J. M.; deGroot, A. J. J. Org. Chem.
1999, 64, 91178. (b) Padwa, A.; Zhang, H. J. Org. Chem. 2007, 72, 2570.
(c) Nicolaou, K. C.; Ortiz, A.; Zhang, H.; Dagneau, P.; Lanver, A.;
Jennings, M. P.; Arseniyadis, S.; Faraoni, R.; Lizos, D. E. J. Am. Chem.
Soc. 2010, 132, 7149.
ꢀ
A. C.; Sridhar, B.; Gree, R. Org. Biomol. Chem. 2012, 10, 1349.
(e) Reddy, B. V. S.; Jalal, S.; Borkar, P.; Yadav, J. S.; Reddy, P. P.;
Kunwar, A. C.; Sridhar, B. Org. Biomol. Chem. 2012, 10, 6562.
(7) Bunt, A. J.; Bailey, C. D.; Cons, B. D.; Edwards, S. J.; Elsworth,
J. D.; Pheko, T.; Willis, C. L. Angew. Chem., Int. Ed. 2012, 51, 3901.
(8) Previous examples of Prins reactions using enol ethers include:
(a) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499. (b) Barry, C. S.;
Bushby, N.; Harding, J. R.; Willis, C. L. Org. Lett. 2005, 7, 2683.
(c) Yang, Y.; Jia, P.; Liu, S.; Yu, W. Chin. J. Chem. 2012, 30, 1439.
Org. Lett., Vol. 15, No. 8, 2013
2047

xylene to effect a Chugaev elimination11 gave the required
alkene 15 in 68% overall yield from ketone 14 and with
excellent E-selectivity. Silyl ether 15 was deprotected using
2% HCl in ethanol to give the required γ,δ-unsaturated
alcohol 16.
Scheme 4. Completing the Synthesis Blepharocalyxin D
Analogue 18 and Crystal Structure of 18
Scheme 3. Synthesis of Dienols 16 and 29
co-workers4 had used a p-methoxyphenyl group which was
deprotected using LiSPr/HMPA. However, the unsatu-
rated p-methoxyphenyl derivative 19 has an activated
electron-donating aromatic ring and proved unstable to
the TMSOTf-promoted cyclization conditions (Scheme 5).7
In contrast, the acid-mediated reaction of methyl 3,3-
dimethoxypropanoate 8 and unsaturated alcohol 20
with the electron-withdrawing p-phenylsulfonyl group
gave bicyclic lactone 21 in 93% yield. Hence the use of
phenylsulfonyl esters was selected for the total synthesis
of blepharocalyxin D.
Scheme 5. Reaction of Alkenols with 8
With dienol 16 in hand, the key cyclization was carried
out with acetal 8 and TMSOTf in CH2Cl2 at ꢀ30 °C giving
bicyclic lactone 17 with the creation of four new stereo-
centers (Scheme 4). The presence of the three equatorial
substituents and trans ring junction was determined from
1
the H NMR spectrum which showed the expected trans
diaxial couplings for each of the methine protons. It was
evident that there was excellent stereocontrol at C-5 with
cyclization occurring to give exclusively the equatorial
styrenyl side-chain.
For the natural product, a similar synthetic strategy was
used to dienol intermediate 29 as for the analogue 16
(Scheme 3).12 The chain extension of aldehyde 24 to 26
was achieved in 91% yield using a Wittig reaction with
With five out of the six asymmetric centers of the
blepharocalyxin D framework intact, the final carbonꢀ
carbonbond-formingreactionintroduced the side-chainat
C-9. Treatment of 17 with 2-(p-methoxyphenyl)ethyl-
magnesium bromide followed by reduction of the resultant
lactol with TMSOTf, Et3SiH gave 18 in 48% yield over the
two steps. The NMR data were consistent with the side
chains all being in equatorial positions and was confirmed
by X-ray crystallography. It is interesting to note the π
stacking between the 7-phenyl ring and the styrenyl side
chain at C-5 in the crystal structure.
(12) In this case, the synthetic route began with the novel
(S)-homoallylic alcohol 22 which was prepared in 98% yield via a
Nokami crotyl transfer reaction.
Turning to the synthesis of blepharocalyxin D, the first
challenge was to prepare a dienol with appropriate para-
substituted phenyl groups. In their total synthesis, Lee and
Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168.
2048
Org. Lett., Vol. 15, No. 8, 2013

stabilized ylide 25; this was a significant improvement on
the HWE reaction used to prepare enone 13 (65% yield).
The rhodium-mediated 1,4-addition to enone 26 using
the novel boronic acid (prepared from vinyl boronic acid
MIDA boronate and p-sulfonylstyrene13) gave ketone
27 which was converted to the required dienol 29 using
the same reduction/elimination sequence as for ana-
logue 16.
Scheme 6. Completing the Synthesis of 1
Reaction of dienol 29 with acetal 8 and TMSOTf gave
bicyclic lactone 30 as a single diastereomer with the crea-
tion of the two rings and four stereocenters in 75% yield
(Scheme 6). The C-9 side chain was introduced via a
Grignard addition/reduction protocol giving 31 with the
fully assembled carbon framework of our target. Finally
deprotection of the phenolic groups with LiSPr/HMPA
gave (ꢀ)-blepharocalyxin D (1) in 85% yield. Interestingly
Lee and co-workers4 reported that their synthetic blephar-
ocalyxin D exhibited variable specific rotation values in
methanol (ranging from ꢀ77.1 to ꢀ89.9 depending on
concentration), our synthetic sample [R]D ꢀ79.2 (c 0.23,
MeOH) was in accord with their data.15
In conclusion, a new synthetic strategy to (ꢀ)-ble-
pharocalyxin D and an analogue has been developed.
The approach proceeds via γ,δ-unsaturated dienols 16
and 29 prepared using an efficient rhodium-mediated
conjugate addition to enones 13 and 26 followed by
reduction of the resultant ketones and xanthate forma-
tion/Chugaev elimination to the required (E)-double
bond. The key step involves reaction of the dienols with
methyl 3,3-dimethoxypropanoate 8 to give bicyclic lac-
tones 17 and 30 via a one-pot cascade to generate two
rings and four stereocenters. A Grignard addition/
reduction protocol followed by deprotection gave ble-
pharocalyxin D. The bicyclic lactones are flexible inter-
mediates for use as building blocks in organic synthesis
and have potential widespread value.
(13) Initial attempts to synthesize boronic acid including the hydro-
boration of the corresponding alkyne and lithiation of the correspond-
ing β-halostyrene followed by quenching with triisopropylborane were
unsuccessful. Instead the required reagent was synthesized in 92% yield
from vinyl boronic acid MIDA boronate and p-sulfonylstyrene using
conditions reported by Burke.14
Acknowledgment. We are grateful to the EPSRC for
funding and to Dr. M. Haddow, School of Chemistry,
University of Bristol, for X-ray crystallography.
Supporting Information Available. Preparation and
characterization of the compounds described in this
paper. This material is available free of charge via the
Internet at http://pubs.acs.org
(14) Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65,
3130.
(15) The optical rotation for the natural product reported by Kadota
and co-workers3 was [R]D þ18.5 (c 0.025, MeOH), but Lee reports that
the NMR spectra of the natural product contained impurities.4
The authors declare no competing financial interest.
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