Synthesis and structural reassignment of (+)-epicalyxin F

Article abstract of DOI:10.1021/ol702200t

We have established the structure of (+)-epicalyxin F through chemical synthesis. An acid-promoted rearrangement of synthetic benzopyran 6 led to the identification of the natural product as (3S,5S,7R)-epicalyxin F (22). Comparison with NMR spectra and op

Full text of DOI:10.1021/ol702200t

ORGANIC
LETTERS
2
007
Vol. 9, No. 24
955-4958
Synthesis and Structural Reassignment
of ( )-Epicalyxin F
4
+
Xia Tian and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
srychnoV@uci.edu
Received August 2, 2007
ABSTRACT
We have established the structure of (+)-epicalyxin F through chemical synthesis. An acid-promoted rearrangement of synthetic benzopyran
6
led to the identification of the natural product as (3S,5S,7R)-epicalyxin F (22). Comparison with NMR spectra and optical rotation of the
natural product confirms our assignment, and the reassigned structure is compatible with the proposed biosynthetic pathway.
2
The plant species Alpinia blepharocalyx is widely distributed
in southwestern China, and its seeds are commonly used in
traditional medicine for the treatment of various stomach
disorders. Kadota and co-workers reported the isolation of
a family of related polyphenolic natural products from these
correlation. However, the structure of our original target,
epicalyxin F, remained a mystery.
We reasoned that calyxin F (3) and epicalyxin F had
similar structures based on their very similar proton and
carbon NMR spectra. Previously, we had synthesized 3-epi-
calyxin F (4) and the 6′′-methoxy regioisomer of the
proposed structure for epicalyxin F (1) and shown that
neither of these compounds matched the reported NMR data
1
seeds. We were drawn to the unique structure of (+)-epi-
calyxin F (1) (the most biologically active member of the
family) and its epimer (+)-calyxin F (2) (Figure 1). We
synthesized the reported structure of epicalyxin F (1) through
2
for epicalyxin F. The current project was initiated with the
2
,3
a Prins cyclization and Friedel-Crafts cascade sequence.
proposal that benzopyran 6 represented the true structure of
epicalyxin F (Figure 1). We set out to synthesize compound
6 to test this hypothesis. Eventually, we found that one of
the assumptions underlying the hypothesis was incorrect, vide
infra.
Unfortunately, data for our synthetic sample did not match
2
that of the natural product. Subsequently, we discovered
an acid-mediated isomerization of compound 1 that led to
the isolation of calyxin F. The proposed structure of calyxin
F (2) was shown to be incorrect, and we reassigned calyxin
F as structure 3 through spectroscopic studies and chemical
Our synthetic strategy (Figure 2) was designed to access
the proposed epicalyxin F structure from three simple pieces,
8
, 9, and 10, that would be coupled together utilizing practical
(
1) (a) Prasain, J. K.; Li, J. X.; Tezuka, Y.; Tanaka, K.; Basnet, P.; Dong,
coupling reactions, namely, the Mitsunobu reaction and olefin
metathesis. Each of these components would be appropriately
protected. An intramolecular Michael addition of enone 7
would close the remaining ring, and deprotection and ketone
reduction would produce the target 6.
H.; Namba, T.; Kadota, S. J. Chem. Res. (S) 1998, 22-23; J. Chem. Res
(
M) 1998, 265-279. (b) Gewali, M. B.; Tezuka, Y.; Banskota, A. H.; Ali,
M. S.; Saiki, I.; Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733-1736. (c)
Tezuka, Y.; Gewali, M. B.; Ali, M. S.; Banskota, A. H.; Kadota, S. J. Nat.
Prod. 2001, 64, 208-213.
(2) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006, 71,
3
176-3183.
3) For a related approach to 4-aryl THP rings, see: Yang, X.-F.; Wang,
M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912-1916.
The synthesis commenced with the preparation of triflate-
protected homoallylic alcohol 12 (Scheme 1). Keck allylation
(
1
0.1021/ol702200t CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/25/2007

Scheme 1. Synthesis of Alkene Fragments
of the phenols could be selectively protected as THP ethers
in the presence of the unreactive hydrogen-bonded phenol,
which was subsequently methylated under standard condi-
tions. The choice of THP as a protecting group generates
multiple diastereomeric products; however, their ease of
7
removal and low cost made them the ideal choice. Isomer-
ization of the flavanone 16 to the open chalcone was
8
accomplished under basic conditions. Deprotection followed
by acylation of the more reactive phenols provided chalcone
17 in good overall yield. This synthesis established the
correct methyl regioisomer and the requisite free phenol for
the planned Mitsunobu reaction. The acetyl groups serve the
dual role of protecting two of the phenols and enhancing
the acidity of the free phenol.
Figure 1. Proposed structures of calyxin F and epicalyxin F. The
correct structure for calyxin F is 3, and the correct structure for
epicalyxin F is given in the abstract (current work).
2
generated the homoallylic alcohol in good yield and high
4
5
ee. Enone 14 was prepared from known aldehyde 13 by
6
addition of vinylmagnesium bromide followed by oxidation.
Preparation of the requisite chalcone derivative 17 began
with commercially available narigenin 15 (Scheme 2). Two
Scheme 2. Synthesis of Chalcone Moiety
With all three components in hand, we investigated their
union to form the full carbon skeleton of the natural product
(Scheme 3). Mitsunobu reaction between alcohol 12 and
phenol 17 produced the ether 18 in excellent yield. Elimina-
(4) The enantiomeric excess was determined by HPLC on a Chiracel
OD-H column. Details may be found in the Supporting Information.
(
(
5) Bratt, K.; Sunnerheim, K. J. Chem. Ecol. 1999, 25, 2703-2714.
6) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5
507.
(7) Use of MOM was problematic due to the harsh deprotection
conditions required. TBS ethers were unstable to the methylation conditions.
Acetate esters gave C-alkylation during methylation.
(
8) (a) Arcus, V. L.; Simpson, C. D.; Main, L. J. Chem. Res. (S) 1992,
0-81. (b) Solladie, G.; Gehrold, N.; Maignan, J. Eur. J. Org. 1999, 2303-
2314. (c) Wang, Y.; Tan, W.; Li, W. Z.; Li, Y. J. Nat. Prod. 2001, 64,
96-199.
Figure 2. Retrosynthetic analysis of a proposed structure for
epicalyxin F (6).
8
1
4956
Org. Lett., Vol. 9, No. 24, 2007

Scheme 3. Synthesis of the Proposed Epicalyxin F Structure (6)
tion of the benzyl alcohol was observed with related sub-
strates, but the use of a triflate protecting group in 12 mini-
mized this side reaction. Olefin cross-metathesis between 18
gave an inseparable 4:1 mixture of diastereomeric alcohols
6 and 3-epi-6. Spectroscopic analysis of compound 6 and
3-epi-6 demonstrated that neither one corresponded to the
1
(
1 equiv) and 14 (3 equiv) provided the desired inter-
natural product epicalyxin F. The H NMR spectra were
mediate 19 as a single alkene isomer without interference
from the chalcone moiety.9,10 Several catalysts were evaluated
to promote the intramolecular conjugate addition that would
drastically different than that reported for epicalyxin F and
did not match any of the known calyxin natural products.
This outcome forced us to reevaluate the possible structure
of epicalyxin F.
form the final carbon-carbon bond in the target. AuCl
3
and
1
1
BF •OEt gave satisfactory yields of the product 20;
3
2
Upon close examination of the NMR data, we realized
that the tabulated data for epicalyxin F did not match with
however, the selectivity at the newly formed methine carbon
was low (2:1 and 1:1, respectively). The use of TMS-OTf
gave a 67% yield of the benzopyran 20 as a 5:1 mixture of
1
4
the actual (unpublished) proton spectrum. Given the very
similar spectra for calyxin F and epicalyxin F, it was
reasonable to propose that epicalyxin F was simply epimeric
at the C3 position. Reexamination of the proton and carbon
NMR data for the previously synthesized (3R,5R,7S)-3-epi-
1
2
diastereomers. The labile THP ether was cleaved by
adventitious acid under the reaction conditions. This three-
step sequence assembled the full skeleton of the target 6 with
good selectivity and efficiency.
2
calyxin F (4) demonstrated that it matched epicalyxin F.
The synthesis was completed by a deprotection and
reduction. Ketone 20 was treated with potassium methoxide
in THF at ambient temperature to give the fully deprotected
Scheme 4. Rearrangement of Enone 6 to (+)-Epicalyxin F
13
compound 21 in good yield. Sodium borohydride reduction
(9) (a) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360-11370. (b) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. (c) Grubbs,
R. H. Tetrahedron 2004, 60, 7117-7140.
(10) Unreacted 18 was recovered in 30% yield. The yield of 19 based
on recovered 18 was 60%.
11) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. AdV. Synth. Catal.
003, 345, 1247-1252.
12) The mixture of isomers was separated by preparative HPLC to give
(
2
(
pure cis isomer 20 for subsequent reactions.
Org. Lett., Vol. 9, No. 24, 2007
4957

event, heating enone 6 in neat acetic acid at 90 °C for 12 h
gave a 65% yield of benzopyran 22 (Scheme 4). The NMR
data for compound 22 matched the unpublished spectrum
Scheme 5. Proposed Biosynthesis of Several Calyxin Natural
Products
1
4
for epicalyxin F, and the optical rotation was of the same
1
5
sign. Thus the correct absolute configuration of natural
epicalyxin F is 3S,5S,7R. Natural (+)-epicalyxin F is
epimeric with natural (+)-calyxin F at the 5 and 7 positions,
but both have the S-configuration at the C3 alcohol center.
The biosynthetic pathway for the calyxin natural products
1
a
as proposed by Kadota is shown in Scheme 5. Reduction
of the enone (23) followed by ionization of the allylic alcohol
would generate an allylic cation that could be captured by
chalcone 8 in a regioselective but not stereoselective manner
to give two epimeric products (25). Subsequent protonation
of the alkene produces a benzylic cation that can be attacked
by the para-phenol or the free alcohol (the ortho-phenol is
not nucleophilic due to hydrogen bonding to the carbonyl
of the chalcone). Closure onto the phenol would yield calyxin
F and epicalyxin F, and cyclization of the alcohol would
form calyxin L. All three natural products have the same
configuration at C3, as would be expected from this
biosynthetic scheme.
A calyxin F regioisomer, enone 6, was proposed as a
possible structure of epicalyxin F. Synthesis of enone 6 was
accomplished in a highly convergent strategy from compo-
nents 12, 14, and 17. Structure 6 did not correspond to
epicalyxin F, but this work led to a reexamination of the
data and the identification of the relative configuration of
epicalyxin F. Ultimately, enone 6 was shown to rearrange
to epicalyxin F on treatment with acid. The absolute
configuration of (+)-epicalyxin F was assigned based on this
concise synthesis of the natural product.
Acknowledgment. This work was supported by the
National Cancer Institute (CA-081635) and by a generous
donation from the Schering Plough Research Institute. We
thank Professor S. Kadota (Toyama Medical and Pharma-
ceutical University) for providing NMR spectra of calyxin
F and epicalyxin F.
Supporting Information Available: Preparation and
characterization of all compounds are described. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
We were finally able to assign the relative configuration of
epicalyxin F as that shown in structure 4.
The absolute configuration of epicalyxin F was not known.
Compound 4 had been prepared on a very small scale, and
we did not have an optical rotation for comparison with the
natural product. Fortunately, we could make use of our
synthetic enone 6. Acid-catalyzed isomerization of enone 6
to the benzopyran 22 had good precedent from our previous
OL702200T
(14) The doublet at 7.27 ppm had been mistakenly tabulated as a doublet
at 7.58 ppm (ref 1b). Professor Kadota kindly provided copies of the original
spectral data.
2
studies, and benzopyran 22 is the enantiomer of 4. In the
(15) The optical rotation of 22 was of the same sign, but there is a
25
discrepancy in the magnitude: [R] D ) +13.2 (c 0.20, MeOH); lit. (ref
2
5
1
b), [R] D ) +103.1 (c 0.05, MeOH). Note that the rotation of synthetic
25
(13) Over time, the ketone 20 isomerized to the cyclic hemiacetal by
calyxin F (3) is [R] D ) +16.3 (c 0.175, MeOH), very much in accord
with the magnitude of the rotation of synthetic epicalyxin F.
closure onto the phenol. Ketone 20 was characterized as the hemiacetal.
4958
Org. Lett., Vol. 9, No. 24, 2007