Studies towards diarylheptanoid synthesis. Part 2: Synthesis and ring cleavage reactions of tetrahydro-4H-furo[2,3-b]pyran-2-ones

Article abstract of DOI:10.1016/S0040-4039(03)01421-7

Lewis acid promoted anomeric substitution reactions of a series of tetrahydro-4H-furo[2,3-b]pyran-2-one derivatives were studied as a model for diarylheptanoid synthesis.

Full text of DOI:10.1016/S0040-4039(03)01421-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6355–6358
Studies towards diarylheptanoid synthesis. Part 2: Synthesis and
ring cleavage reactions of
ꢀ
tetrahydro-4H-furo[2,3-b]pyran-2-ones
Sidika Polat Cakir, Keith T. Mead* and Laura T. Smith
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Received 16 May 2003; revised 2 June 2003; accepted 3 June 2003
Abstract—Lewis acid promoted anomeric substitution reactions of a series of tetrahydro-4H-furo[2,3-b]pyran-2-one derivatives
were studied as a model for diarylheptanoid synthesis.
©
2003 Elsevier Ltd. All rights reserved.
The blepharocalyxins represent a class of biologically
active diarylheptanoid constituents recently isolated
from Alpinia blepharocalyx. Among them, blepharo-
calyxin E (Fig. 1) has shown particular promise as a
potential drug candidate for the treatment of human
tumors, displaying potent in vitro inhibitory activity
towards human fibrosarcoma HT-1080 carcinoma cells.
Blepharocalyxin E framework. Toward this goal we set
out to develop a stereoselective route to compounds of
general structure 2, which were viewed as potential
intermediates to the final target 1 (Fig. 1). For this
purpose, the use of tetrahydro-4H-furo[2,3-b]pyran-2-
ones was considered as a viable option (Scheme 1).
Compound 5b appeared to be a suitable model
target on which to test this strategy. Based on sound
1
,2
3
The lack of general utility of fused-ring bicyclic lactones
in synthesis initiated us to investigate novel applications
of these structures. With the aim of laying the ground-
work for a synthesis of blepharocalyxin D, we have
previously shown that hexahydro-2H,5H-pyrano[2,3-
b]pyran-2-ones can act as pyranosyl donors in the
stereoselective construction of thermodynamic C-aryl
literature precedent, this was expected to be formed
stereoselectively by the addition of anisole to oxocarbe-
nium ion 4 (R=CH ), generated from the thermody-
3
namically favored exo-substituted bicylic lactone
derivative 3c on exposure to Lewis acid. Herein we
report the results of our preliminary investigations into
this method.
3
pyranosides. Our goal in this study was to develop a
related strategy for C-aryl pyranoside synthe-
sis that could be applied to the construction of the
For the synthesis of bicyclic lactones 3, established
4
protocols were adopted (Scheme 2). Thus, treatment of
Figure 1. Partial retrosynthetic analysis of blepharocalyxin E (P=protective group).
Keywords: blepharocalyxin; diarylheptanoid; oxocarbenium ion; C-aryl pyranoside.
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Supplementary data associated with this article can be found at doi:10.1016/S0040-4039(03)01421-7
*
Corresponding author. Tel.: (662) 325-3584; fax: (662) 325-1618; e-mail: kmead@ra.msstate.edu
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01421-7

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S. P. Cakir et al. / Tetrahedron Letters 44 (2003) 6355–6358
a mixture of 2,3-dihydropyran 6 and potassium methyl
constant was determined to be 4.6 Hz, clearly identify-
ing a cis-stereochemistry between the C2 and C3 sub-
stituents. For compound 14 (entry 6) the value of this
coupling constant was 5.8 Hz. Stereocontrol in the
reactions of allyl (entry 4), alkynyl (entry 5) and cyano
(entry 6) nucleophiles presumably arises from a kinetic
preference for axial nucleophilic addition to the oxocar-
5
malonate with ceric ammonium nitrate gave com-
pound 8, which was decarboxylated by refluxing in wet
DMF to yield structure 3a. Application of this two-step
reaction sequence to racemic 4-phenyl-2,3-dihydropy-
ran 7 provided derivative 3b as a single isomer. The exo
stereochemistry of compound 9, also formed as a single
isomer, was verified by X-ray crystallography. Methyla-
tion of compound 3b with LHMDS gave the antici6-
pated exo diastereomer 3c as a single isomer.
Interestingly, when KHMDS was used as base, a 1:1
mixture of compound 3c and its methyl diastereomer
was formed in low yield (52%).
7
benium ion intermediate (see Scheme 1).
When anisole was the nucleophile, the b-stereoisomer
(entry 7) was strongly favored, in agreement with
8
related C-aryl pyranoside syntheses. Reaction of lac-
tone 3b with anisole gave a single diastereomer iden-
tified as compound 5a by the characteristic trans
coupling constant (J =9.95 Hz). Unexpectedly, a-
Ring cleavage substitution reactions of these bicyclic
lactones proceeded in yields which varied from moder-
ate to very good (Table 1), with titanium tetrachloride
being the Lewis acid of choice. Remarkably, no reac-
tion was observed with BF ·OEt or TMSOTf. Pre-
2,3
methylated derivative 3c gave a completely different
product under the same reaction conditions (entry 8). A
single compound was isolated which was identified as
the g-lactone 15 based on it’s IR and proton NMR
spectral data. It is unlikely that the g-lactone product
15 derives directly from compound 3c, as the acyloxy
group is by far the better leaving group. A more
reasonable explanation is that the initial titanium car-
boxylate product of arylation equilibrates to structure
16 under the reaction conditions (Scheme 3). Why this
did not happen with lactone 3b is unclear, and will be
a topic of future investigations. For our purposes, this
unforeseen reaction did not pose a problem to our
ultimate goal, as g-lactone 15, isolated following pro-
tolytic work-up of carboxylate salt 16, was cleanly
converted to C-aryl pyranoside 17, the methyl ester of
our model target 5b (see Scheme 1), on exposure to 5%
anhydrous HCl in methanol.
3
2
dictably, hydride reductions of 3a and 3b yielded acid
derivatives 10 and 11, respectively (entries 1 and 2).
More surprising was the observation that products
formed as a single isomer in almost every case with
carbon nucleophiles. The only exceptions to this were
observed in the reaction of lactones 3a and 3b with
allyltrimethylsilane (entries 3 and 4), which gave 1:1
(
inseparable) and 4:1 (separable) diastereomeric mix-
tures of products, respectively. The major allylation
product of compound 3b was identified as compound
1
2 by X-ray crystallography. For other pyranoside
products (entries 5–7), the stereochemistry could be
readily determined from the coupling constant J . For
2,3
compound 13, for example (entry 5), this coupling
Scheme 1. Model for synthesis of compounds 2.
Scheme 2. Synthesis of tetrahydro-4H-furo[2,3-b]pyran-2-one substrates. Reagents and conditions: (a) CH O CCH CO K,
3
2
2
2
Ce(NH ) (NO ) , Cu(OAc) CH CO H (40%, R=H; 52%, R=Ph); (b) DMF, H O, reflux (64%, R=H; 95%, R=Ph); (c)
4
2
3 6
2
3
2
2
LHMDS, CH I, THF, −78°C (93%).
3

S. P. Cakir et al. / Tetrahedron Letters 44 (2003) 6355–6358
Table 1. Ring-opening substitution reactions of bicyclic lactones 3
6357
Scheme 3.

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S. P. Cakir et al. / Tetrahedron Letters 44 (2003) 6355–6358
In summary, Lewis acid promoted ring cleavage substi-
tution reactions of tetrahydro-4H-furo[2,3-b]pyran-2-
ones have been demonstrated for the first time and
appear to be particularly useful for the synthesis of
b-C-aryl pyranosides. Moreover, the stereochemical
bias imposed by the tetrahydrofuropyranone ring sys-
tem is conducive to the synthesis of structures related to
blepharocalyxin E (see Fig. 1). To that end, we are
currently pursuing routes to C3-arylated bicyclic lac-
tones.
3. See the preceding article in this journal, Tetrahedron Let-
ters 2003, 44, 6351.
4. del Rosario-Chow; Ungwitayatorn, J.; Currie, B. L. Tetra-
hedron Lett. 1991, 32, 1011–1014.
5. D’Annibale, A.; Trogolo, C. Tetrahedron Lett. 1994, 35,
2083–2086.
6. For examples of stereoselective alkylations of related
fused-ring structures, see: Depres, J.-P.; Greene, A. E. J.
Org. Chem. 1980, 45, 2036–2037.
7. For an explanation for this stereoelectronic preference, see:
(
a) Deslongchamps, P. Stereoelectronic Effects in Organic
X-Ray crystallographic data: Crystallographic data
Chemistry; Pergamon: New York, 1983; pp. 209–221. For
examples of this type of preferential axial attack, see: (b)
Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976–4978; (c) Stewart, A. O.; Williams, R. M.
J. Am. Chem. Soc. 1985, 107, 4289; (d) Schmidt, R. R.;
Hoffmann, M. Tetrahedron Lett. 1982, 23, 409; (e)
Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett.
1984, 25, 2383; (f) Brown, D. S.; Bruno, M.; Davenport,
R.; Ley, S. V. Tetrahedron 1989, 45, 4293.
. For examples, see the preceding article, Tetrahedron Let-
ters 2003, 44, 6351, and: (a) Hosomi, A.; Sakata, Y.;
Sakurai, H. Tetrahedron Lett. 1984, 25, 2383; (b) Mat-
sumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett.
1989, 30, 833–836; (c) Toshima, K.; Matsuo, G.; Ishizuka,
T.; Ushiki, Y.; Nakata, M.; Matsumara, S. J. Org. Chem.
1998, 63, 2307–2313; (d) Kaelin, D. E., Jr.; Lopez, O. D.;
Martin, S. F. J. Am. Chem. Soc. 2001, 123, 6937–6938.
(
excluding structure factors) for structures 9 and 12
reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supple-
mentary publications numbers CCDC 192335 and
2
08762, respectively. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: int. code
+44(1223)336-033; E-mail: deposit@ccdc.cam.ac.uk].
8
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