Total synthesis of (-)-blepharocalyxin D

Full text of DOI:10.1021/ol0627956

ORGANIC
LETTERS
2007
Vol. 9, No. 1
141-144
Total Synthesis of (−)-Blepharocalyxin D
Haye Min Ko,† Dong Gil Lee,† Min Ah Kim,† Hak Joong Kim,† Jaejoon Park,‡
Myoung Soo Lah,‡ and Eun Lee*,†
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity,
Seoul 151-747, Korea, and Department of Chemistry and Applied Chemistry,
Hanyang UniVersity, 1271 Sa-1-dong, Ansan, Kyunggi-do 426-791, Korea
eunlee@snu.ac.kr
Received November 17, 2006
ABSTRACT
The Prins cyclization strategy was successfully applied in the total synthesis of (−)-blepharocalyxin D, a cytotoxic dimeric diarylheptanoid
isolated from Alpinia blepharocalyx.
Blepharocalyxin D (1)1 is a unique member of dimeric
diarylheptanoid natural products isolated from the seeds of
Alpinia blepharocalyx.2,3 It is an antiproliferative agent (ED50
3.61 µM) against murine colon 26-L5 carcinoma cells. The
most characteristic feature of blepharocalyxin D (1) is a rare
2,8-dioxabicyclo[4.4.0]decane core, to which four p-hydroxy-
phenyl groups are appended.4 No general strategy has
evolved for the generation of this dioxabicyclodecane system,
and there have been no advances made toward synthesis of
this interesting natural product.5 In this communication, we
describe a concise total synthesis of 1 employing two
distinctive Prins cyclization reactions.
In our retrosynthetic analysis, the oxane derivative A was
considered as a pivotal intermediate in the synthesis of
blepharocalyxin D (1). A number of different synthetic routes
may be considered for the efficient conversion from A to 1.
Intermediate A may be prepared from homoallylic alcohol
B and aldehyde C. This type of Prins cyclization has already
been reported by Willis and co-workers6 (Scheme 1).
† Seoul National University.
‡ Hanyang University.
(1) (a) Tezuka, Y.; Ali, M. S.; Banskota, A. H.; Kadota, S. Tetrahedron
Lett. 2000, 41, 5903-5907. (b) Ali, M. S.; Tezuka, Y.; Banskota, A. H.;
Kadota, S. J. Nat. Prod. 2001, 64, 491-496.
(2) A large number of bioactive diarylheptanoid natural products were
isolated recently by Kadota and co-workers from the seeds of Alpinia
blepharocalyx K. Schum, a member of the Zingiberaceae family: (a) Kadota,
S.; Prasain, J. K.; Li, J. X.; Basnet, P.; Dong, H.; Tani, T.; Namba, T.
Tetrahedron Lett. 1996, 37, 7283-7286. (b) Prasain, J. K.; Tezuka, Y.; Li,
J. X.; Tanaka, K.; Basnet, P.; Dong, H.; Namba, T.; Kadota, S. Tetrahedron
1997, 53, 7833-7842. (c) Prasain, J. K.; Li, J.-X.; Tezuka, Y.; Tanaka, K.;
Basnet, P.; Dong, H.; Namba, T.; Kadota, S. J. Nat. Prod. 1998, 61, 212-
216. (d) Gewali, M. B.; Tezuka, Y.; Banskota, A. H.; Ali, M. S.; Saiki, I.;
Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733-1736. (e) Tezuka, Y.;
Gewali, M. B.; Ali, M. S.; Banskota, A. H.; Kadota, S. J. Nat. Prod. 2001,
64, 208-213. (f) Ali, M. S.; Tezuka, Y.; Awale, S.; Banskota, A. H.; Kadota,
S. J. Nat. Prod. 2001, 64, 289-293.
Sulfur trioxide-DMSO oxidation of 3-(p-methoxyphenyl)-
propan-1-ol (2) yielded the corresponding aldehyde, which
was converted into homoallylic alcohol 4 (92% ee) via
reaction with allyltributylstannane in the presence of the
(4) As far as we know, blepharocalyxin D (1) is the only natural product
known to possess a 2,8-dioxabicyclo[4.4.0]decane core.
(5) There is one reference claiming to be a model study for synthesis of
blepharocalyxin D (1): Li, W.; Mead, K. T.; Smith, L. T. Tetrahedron
Lett. 2003, 44, 6351-6353.
(6) (a) Barry, C. S. J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.;
King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429-2432.
(b) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. L.
Org. Lett. 2002, 4, 577-580.
(3) More recently, synthetic investigations by Rychnovsky and co-
workers led to revised structures of some of the diarylheptanoids, calyxins
L, F, M, and G: Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem.
2006, 71, 3176-3183.
10.1021/ol0627956 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/07/2006

and oxidative deprotection produced diol 9, from which
diacetate 10 was obtained via acetylation. Cross metathesis
reaction of 4 with 2 equiv of olefin 10 in the presence of
the second-generation Hoveyda-Grubbs catalyst (11)10
proceeded smoothly producing a new homoallylic alcohol
12 in 67% yield (Scheme 3). Use of the second-generation
Scheme 1. Retrosynthetic Analysis
Scheme 3. Preparation of the B Fragment
catalyst 3 following the Maruoka protocol.7 The (S)-
configuration of homoallylic alcohol 4 was confirmed by
NMR analysis of the ester derivative which was produced
via reaction with (O)-acetyl-(S)-mandeloyl chloride.8 The
NMR spectra of the major product 5 exhibited vinylic proton
signals at δ 5.42, 4.81, and 4.78, compared to the signals of
the minor isomer 6 at δ 5.72, 5.07, and 5.06 (Scheme 2).
Scheme 2. Asymmetric Allylation
Grubbs catalyst under identical reaction conditions provided
the product 12 in 48% yield. Use of alternative olefin
partners, for example, diol 9 or its bis(TBS) ether, led to
more sluggish reactions producing the corresponding prod-
ucts in 10∼20% yield in the presence of the second-
generation Grubbs catalyst.
For the crucial Prins cyclization of homoallylic alcohol
12 with p-anisaldehyde, reaction conditions of Willis and
co-workers6 were modified for maximum efficiency: in our
hands, use of 4 equiv of triethylsilyl triflate and 1 equiv of
trimethylsilyl acetate in 40 equiv of acetic acid worked best
producing the oxane product 13 stereoselectively in 60%
yield. No sign of racemization was noticed originating from
the oxonia-Cope rearrangement.11 Use of 2 equiv of boron
trifluoride etherate, 4 equiv of trimethylsilyl acetate, and 4
equiv of acetic acid in cyclohexane produced 13 in 18∼26%
yield.
Ways for preparation of the dioxabicyclodecane system
were examined, and a prominent possibility appeared to be
a second Prins cyclization. Exhaustive deacetylation of 13
led to the corresponding triol, which was converted into
thionocarbonate 14 in 67% yield. Cyclic acetal formation
of 14 with 3-(p-methoxyphenyl)propanal was accomplished
using ionic liquid [SOClMIm]Cl,12 and thermal elimination
Sulfur trioxide-DMSO oxidation of the cyclic acetal
prepared from triol 7 yielded aldehyde 8.9 Wittig olefination
(10) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(7) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K.
Chem. Eur. J. 2003, 9, 4405-4413.
(11) For a recent discussion on oxonia-Cope rearrangement, see: Jasti,
R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127,
9939-9945.
(8) For extensive use of (O)-acetylmandelate NMR correlation, see: Lee,
E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim, M. S.; Yun, J. S. J. Org. Chem.
1994, 59, 1444-1456.
(12) Li, D.; Shi, F.; Peng, J.; Guo, S.; Deng, Y. J. Org. Chem. 2004, 69,
3582-3585.
(9) Kim, E. J.; Ko, S. Y. Bioorg. Med. Chem. 2005, 13, 4103-4112.
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Org. Lett., Vol. 9, No. 1, 2007

was carried out in hot diphenyl ether to provide the seven-
membered cyclic acetal 16. The second Prins reaction
proceeded smoothly in the presence of boron trifluoride
etherate producing a mixture of the axial aldehyde 17 (83%)
and the equatorial aldehyde 18 (2%). As far as we know,
this type of Prins cyclization using methylidene-substituted
seven-membered cyclic acetals is unprecedented. The high
stereoselectivity is surprising, as the Prins-pinacol sequence
on related diol substrates is known to yield mainly equatorial
aldehydes.13,14 The kinetic preference in our case may be
explained by conformational constraints originating from the
steric crowding.
atoms in the dioxabicyclodecane system presented more basic
sites. Eventually, blepharocalyxin D (1) was obtained in
acceptable yield using lithium propanethiolate in hot HMPA16
(Scheme 4).
Scheme 4. Synthesis of Blepharocalyxin D (1)
Under basic conditions, aldehyde 17 was converted into
a mixture favoring the equatorial aldehyde 18 (18, 52%; 17,
25%). Epimerization at C5′ (from 17 to 18) was accompanied
by the diagnostic upfield shift of the aldehyde proton signals
in the 1H NMR spectra: the aldehyde proton of 17 exhibits
a singlet at δ 9.68 compared to a doublet at δ 8.38 (J ) 4.7
Hz) for the same proton of 18. The axial aldehyde 17
recovered could be recycled to produce additional samples
of 18. Julia-Julia reaction15 of the lithiated sulfone 19 with
aldehyde 18 proceeded smoothly, and a 77% yield of the
(E)-olefin 20 was obtained stereoselectively (50:1). Crystals
of 20 were obtained from carbon tetrachloride-pentane
solution, and the crystallographic data confirmed the assigned
structure (Figure 1).
The synthetic sample of blepharocalyxin D (1) exhibited
variable specific rotation values, particularly in methanol.
Some values are [R]22D -88.1 (c 0.43, MeOH), [R]22D -77.1
(c 0.11, MeOH), [R]22 -89.9 (c 0.027, MeOH), [R]23
D
D
-72.9 (c 0.32, acetone), and [R]24D -85.0 (c 0.31, MeOH-
DCM (1:1)). These values are at odds with the value reported
by Kadota and co-workers:1 [R]25D +18.5 (c 0.025, MeOH).
The synthetic sample has (3S)-configuration, but at this point,
determination of the absolute stereochemistry of the natural
product is not possible. Examples of unreliable optical
rotation values of related polyphenols have already been
reported by Rychnovsky and co-workers.3
Figure 1. Crystal structure of 20. (One of the phenyl groups was
statistically disordered: the minor part of the disordered phenyl
group is shown in broken lines.)
A synthetic sample of blepharocalyxin D (1) was converted
back into the tetramethyl ether derivative 20 using io-
domethane and potassium carbonate in hot acetone. The
Global demethylation of 20 was not possible under various
reaction conditions using Lewis acids: presumably, oxygen
specific rotation of this sample ([R]23 -87.8 (c 0.065,
D
(13) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
1092-1093.
CHCl3)) was almost identical with the value of the original
(14) For more discussions on Prins-pinacol reactions, see: Overman,
L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143-7157.
(15) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175-1178.
(16) For a recent example of the use of lithium alkanethiolate in hot
HMPA for aromatic ether demethylation, see: Nakatani, M.; Nakamura,
M.; Suzuki, A.; Inoue, M.; Katoh, T. Org. Lett. 2002, 4, 4483-4486.
Org. Lett., Vol. 9, No. 1, 2007
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sample ([R]14D -90.4 (c 0.32, CHCl3)) of 20, which confirms
the structure of the synthetic sample of 1 beyond any doubt.
In this synthesis, two oxane rings in blepharocalyxin D
(1) were constructed via two different types of Prins
cyclization reactions. The synthetic scheme adopts a highly
modular approach, and the strategy may easily be adapted
to library synthesis.
Korea 21 graduate fellowship grants to H. M. Ko, D. G.
Lee, M. A. Kim, and H. J. Kim are gratefully acknowledged.
The authors thank Prof. Kadota of Toyama Medical and
Pharmaceutical University for providing spectroscopic data
of the natural sample of blepharocalyxin D (1).
Supporting Information Available: Experimental pro-
cedures and 1H NMR and 13C NMR spectra of the intermedi-
ates and products (42 pages). This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by a grant
from the Korea Research Foundation (MOEHRD) (KRF-
2005-070-C00073) and a grant from the Center for Bioactive
Molecular Hybrids (Yonsei University and KOSEF). Brain
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